Ebook Irwin and rippe’s intensive care medicine (8/E): Part 1

(BQ) Part 1 book Irwin and rippe’s intensive care medicine'' has contents: Procedures, techniques and ultrasonography, minimally invasive monitoring, palliative care and ethical issues in the critical care unit, shock and trauma and sepsis management,... and other contents.

Irwin and Rippe’s Intensive Care Medicine EIGHTH EDITION Irwin and Rippe’s Intensive Care Medicine EIGHTH EDITION Editors Richard S Irwin, MD, Master FCCP Professor of Medicine and Nursing University of Massachusetts Medical School Chair, Critical Care Operations UMass Memorial Medical Center Worcester, Massachusetts Craig M Lilly, MD, FCCP Professor of Medicine, Anesthesiology, and Surgery University of Massachusetts Medical School Vice Chair, Critical Care Operations Director, Tele-ICU Program UMass Memorial Medical Center Worcester, Massachusetts Paul H Mayo, MD, FCCP Academic Director Critical Care Division of Pulmonary, Critical Care, and Sleep Medicine Department of Medicine Northwell Health LIJ/NSUH Medical Center Professor of Clinical Medicine Zucker School of Medicine at Hofstra/Northwell Hempstead, New York James M Rippe, MD Founder and Director Rippe Lifestyle Institute Shrewsbury, Massachusetts Acquisitions Editor: Brian Brown Product Development Editor: Lauren Pecarich Marketing Manager: Dan Dressler Production Project Manager: David Saltzberg Design Coordinator: Holly Reid McLaughlin Manufacturing Coordinator: Beth Welsh Prepress Vendor: S4Carlisle Publishing Services Eighth edition Copyright © 2018 by Richard S Irwin, M.D., James M Rippe, M.D., and Craig M Lilly, M.D 7th Edition © 2012 by Richard S Irwin, M.D and James M Rippe, M.D., 6th Edition © 2008 by Richard S Irwin, M.D and James M Rippe, M.D., 5th Edition © 2003 by Richard S Irwin, M.D and James M Rippe, M.D., 4th Edition © 1999 by Richard S Irwin, M.D., Frank B Cerra, M.D., and James M Rippe, M.D., 3rd Edition © 1996 by James M Rippe, M.D., Richard S Irwin, M.D., Mitchell P Fink, M.D., and Frank B Cerra, M.D., 2nd Edition © 1991 by James M Rippe, M.D., Richard S Irwin, M.D., Joseph S Alpert, M.D., and Mitchell P Fink, M.D., 1st Edition © 1985 by James M Rippe, M.D., Richard S Irwin, M.D., Joseph S Alpert, M.D., and James E Dalen, M.D All rights reserved This book is protected by copyright No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews Materials appearing in this book prepared by individuals as part of their official duties as U.S government employees are not covered by the above-mentioned copyright To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at permissions@lww.com, or via our website at lww.com (products and services) Printed in China Library of Congress Cataloging-in-Publication Data ISBN-13: 978-1-4963-0608-1 e-ISBN: 978-1-9751-0223-4 (eBook) ISBN-10: 1-4963-0608-2 Cataloging-in-Publication data available on request from the Publisher This work is provided “as is,” and the publisher disclaims any and 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Transplant Center University of Texas Health Science Center, San Antonio San Antonio, Texas Konstantin Abramov, MD, MHL Assistant Professor of Medicine Division of Renal Medicine UMass Memorial Medical Center Worcester, Massachusetts Christopher D Adams, PharmD Clinical Assistant Professor Department of Pharmacy Robert Wood Johnson University at Somerset Somerville, New Jersey Sumera R Ahmad, MD Division of Pulmonary, Allergy and Critical Care Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts Alfred Aleguas, Jr, BS Pharm, PharmD, DABAT, FAACT Managing Director Florida Poison Information Center-Trauma Tampa General Hospital Tampa, Florida Gilman B Allen, MD Associate Professor Department of Medicine Division of Pulmonary Medicine and Critical Care University of Vermont Medical Center Burlington, Vermont Jennifer E Allen, MD Palliative Medicine Consultant Department of Oacis Services Lehigh Valley Health Network Allentown, Pennsylvania Diana C Anderson, MD, MArch Founder, Dochitect Physician, American Board of Internal Medicine (ABIM) Architect, American College of Healthcare Architects (ACHA) Montreal, Quebec, Canada Gustavo Guillermo Angaramo, MD Associate Professor of Anesthesiology and Critical Care Director of Perianesthesia Unit Department of Anesthesiology and Perioperative Medicine University of Massachusetts Medical School Worcester, Massachusetts Luis F Angel, MD Professor, Department of Medicine Professor, Department of Cardiothoracic Surgery Medical Director, Lung Transplantation NYU Langone Health New York Kevin E Anger, PharmD Pharmacy Supervisor Department of Pharmacy Brigham and Women’s Hospital Boston, Massachusetts Derek C Angus, MD Distinguished Professor and Mitchell P Fink Endowed Chair Department of Critical Care Medicine University of Pittsburg School of Medicine Pittsburgh, Pennsylvania Robert Arntfield, MD Associate Professor of Critical Care Western University Department of Critical Care London Health Sciences Centre London, Ontario Neil Aronin, MD Chief, Division of Endocrinology Professor, University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Seth M Arum, MD Clinical Associate Professor of Medicine Department of Medicine/Endocrinology UMass Memorial Medical Center Worcester, Massachusetts Samuel J Asirvatham, MD Consultant Department of Cardiovascular Medicine Division of Pediatric Cardiology Department of Physiology and Biomedical Engineering Professor of Medicine and Pediatrics Medical Director, Electrophysiology Laboratory Director of Strategic Collaborations Center for Innovation, Program Director Electrophysiology Fellowship Program Mayo Clinic Rochester, Minnesota Philip J Ayvazian, MD Department of Urology UMass Memorial Medical Center Worcester, Massachusetts Riad Azar, MD Associate Professor of Medicine Washington University School of Medicine Gastroenterology Division Department of Internal Medicine Barnes-Jewish Hospital- North Campus St Louis, Missouri Ednan K Bajwa, MD, MPH Assistant Professor of Medicine Division of Pulmonary and Critical Care Medicine Harvard Medical School Massachusetts General Hospital Boston, Massachusetts Jerry P Balikian, MD Professor Thoracic Imaging UMass Memorial Medical Center Worcester, Massachusetts Ian M Ball, MD, MSc(Epi), FACEP, FCCP, FRCPC Assistant Professor Department of Epidemiology and Biostatistics Division of Critical Care Medicine Western University Critical Care Trauma Center London Health Sciences Center London, Ontario, Canada Julia Baltz, MD Chief Resident Dermatology Residency Program Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts Stephen L Barnes, MD, FACS Professor and Chief, Acute Care Surgery Department of Surgery University of Missouri Hospital and Clinics Columbia, Missouri Ribal Bassil, MD Chief Resident Department of Neurology University of Massachusetts Medical School Worcester, Massachusetts David M Bebinger, MD Assistant Professor of Medicine Department of Infectious Disease and Immunology UMass Memorial Medical Center Worcester, Massachusetts Robert W Belknap, MD Director, Denver Metro TB Program Department of Public Health and Infectious Diseases Denver Health and Hospital Authority Denver, Colorado Isabelita R Bella, MD Associate Professor of Clinical Neurology Department of Neurology UMass Memorial Medical Center Worcester, Massachusetts Emanuelle A Bellaguarda, MD Assistant Professor Department of Medicine Gastroenterology, Hepatology Northwestern University Feinberg School of Medicine Chicago, Illinois Michael C Bennett, MD Instructor of Medicine Department of Internal Medicine Division of Gastroenterology Washington University Barnes-Jewish Hospital St Louis, Missouri Hannah Bensimhon, MD Chief Resident Physician Department of Medicine University of North Carolina Chapel Hill, North Carolina Andrew C Bernard, MD Professor, Chief of Trauma and Acute Care Surgery Department of Surgery University of Kentucky Healthcare Lexington, Kentucky Kristen Berrebi, MD Division of Dermatology University of Massachusetts Medical School Worcester, Massachusetts Mary T Bessesen, MD Associate Professor of Medicine University of Colorado Denver Chief, Infectious Diseases Department of Internal Medicine VA-Eastern Colorado Healthcare System Denver, Colorado Michael C Beuhler, MD Medical Director, Carolinas Poison Center Department of Emergency Medicine Carolinas Medical Center Charlotte, North Carolina Bonnie J Bidinger, MD Rheumatologist Division of Rheumatology Milford Regional Medical Center Mendon, Massachusetts Christine L Bielick, MD Assistant Professor Department of Medicine Division of Pulmonary, Allergy and Critical Care University of Massachusetts Medical School Worcester, Massachusetts Steven B Bird, MD Professor Department of Emergency Medicine University of Massachusetts Medical School Worcester, Massachusetts Luke Bisoski, MD Emergency Medicine Specialist Sinai-Grace Hospital Detroit, Michigan Bruce R Bistrian, MD Professor of Medicine, Harvard Medical School Chief, Clinical Nutrition Department of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts Robert M Black, MD Clinical Professor of Medicine University of Massachusetts Medical School Director, Division of Renal Medicine Department of Renal Medicine St Vincent Hospital Worcester, Massachusetts Marc P Bonaca, MD, MPH Medical Director Aortic Center Assistant Professor Department of Medicine Division of Vascular Medicine and Cardiology Brigham and Women’s Hospital Boston, Massachusetts Naomi F Botkin, MD Associate Professor of Medicine Department of Medicine Division of Cardiology University of Massachusetts Medical School UMass Memorial Medical Center 55 Lake Avenue North Worcester, Massachusetts Adel Bozorgzadeh, MD, FACS Professor of Surgery Chief, Division of Organ Transplantation Department of Surgery UMass Memorial Medical Center Worcester, Massachusetts Suzanne F Bradley, MD Professor, Department of Internal Medicine Medical Services, Division of Infectious Diseases Veterans Affairs Ann Arbor Healthcare System University of Michigan Medical School Ann Arbor, Michigan Brian Buchanan, BSc (Hon), MD, FRCPC Clinical Lecturer Department of Critical Care Medicine University of Alberta Edmonton, Alberta Jennie A Buchanan, MD Denver Health & Hospital Authority Staff Physician Rocky Mountain Poison & Drug Center Staff Physician Associate Professor University of Colorado Department of Emergency Medicine Denver, Colorado Keith K Burkhart, MD Division of Applied Regulatory Science Office of Clinical Pharmacology Office of Translational Science Center for Drug Evaluation and Research United States Food and Drug Administration Silver Spring, Maryland Mitchell Cahan, MD, MBA, FACS Associate Professor of Surgery Director of Acute Care Surgery University of Massachusetts Medical School Worcester, Massachusetts Brian T Callahan, MD Medical Director Surgical Services Emerson Hospital Concord, Massachusetts Alexis P Calloway, MD Physician, Digestive Healthcare of Georgia, PC Department of Gastroenterology Piedmont Atlanta Hospital Atlanta, Georgia Christine Campbell-Reardon, MD Associate Professor of Medicine Department of Pulmonary and Critical Care Medicine Boston University School of Medicine Boston Medical Center Boston, Massachusetts Jason P Caplan, MD Professor and Chair of Psychiatry Department of Psychiatry Creighton University School of Medicine, Phoenix Phoenix, Arizona Raphael A Carandang, MD Assistant Professor Departments of Neurology, Anesthesiology and Surgery University of Massachusetts Medical School Vascular and Critical Care Neurology UMass Memorial Medical Center Worcester, Massachusetts Paul A Carpenter, MD Professor of Pediatrics Clinical Research Division Fred Hutchinson Cancer Research Center Seattle, Washington James E Carroll, Jr, MD, FACS Assistant Professor of Surgery Department of Surgery Division of General and Laparoscopic Surgery UMass Memorial Medical Center University of Massachusetts Medical School Worcester, Massachusetts Karen C Carroll, MD Professor of Pathology Department of Pathology Division of Medical Microbiology The Johns Hopkins University School of Medicine John Hopkins Hospital Baltimore, Maryland Benjamin E Cassell, MD Fellow Division of Gastroenterology Washington University School of Medicine St Louis, Missouri Richard Castriotta, MD Professor and Director Department of Internal Medicine Division of Pulmonary and Sleep McGovern Medical School University of Texas Health Science Center at Houston Houston, Texas David R Cave, MD, PhD Professor of Medicine Department of Internal Medicine UMass Memorial Medical Center Worcester, Massachusetts Kelly L Cervellione, MA, Mphil Director, Department of Clinical Research Jamaica Hospital Medical Center Jamaica, New York David A Chad, MD Associate Professor of Neurology Department of Neurology Massachusetts General Hospital Neuromuscular Diagnostic Center Boston, Massachusetts Steven Y Chang, MD, PhD Associate Professor of Medicine Department of Medicine Division of Pulmonary and Critical Care David Geffen School of Medicine at UCLA Los Angeles, California Sarah H Cheeseman, MD Professor of Medicine, Pediatrics and Microbiology, and Physiological Systems Division of Infectious Diseases and Immunology UMass Memorial Medical Center Worcester, Massachusetts Annabel A Chen-Tournoux, MD Assistant Professor Department of Cardiology Jewish General Hospital Montreal, Quebec, Canada Sonia Nagy Chimienti, MD Vice Provost for Student Life and Campus Enrollment Clinical Associate Professor, Medicine Department of Medicine/Infectious Diseases UMass Memorial Medical Center Worcester, Massachusetts William K.Chiang, MD Associate Professor of Emergency Medicine NYU School of Medicine Bellevue Hospital Center New York, New York Eunpi Cho, MD Hematology/Oncology Fellow Department of Medicine University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington Eric S Christenson, MD Medical Oncology Clinical Fellow Department of Medical Oncology Johns Hopkins Hospital Baltimore, Maryland Felicia C Chu, MD Assistant Professor Department of Neurology University of Massachusetts Medical School Worcester, Massachusetts Mary Dawn T Co, MD Assistant Professor of Medicine Department of Medicine, Infectious Disease University of Massachusetts Medical School Worcester, Massachusetts Christopher M Coleman, MD Post Doctoral Fellow Microbiology and Immunology University of Maryland School of Medicine Baltimore, Maryland Nancy A Collop, MD Emory Sleep Disorders Center Wesley Woods Health Center Emory University Atlanta, Georgia Brandon Colvin, MD General Surgery Resident University of Massachusetts Medical School Worcester, Massachusetts Laura S Connelly-Smith, MBBCh, DM Assistant Clinical Professor Division of Hematology School of Medicine University of Washington Assistant Medical Director of Apheresis and Cellular Therapy Seattle Cancer Care Alliance Seattle, Washington Sara E Cosgrove, MD Professor of Medicine Division of Infectious Disease The Johns Hopkins University School of Medicine Baltimore, Maryland Filippo Cremonini, MD, PhD, MSc Professor of Gastroenterology, Italian Ministry of University (MIUR) Las Vegas Gastroenterology Las Vegas, Nevada Gerard Criner, MD, FACP, FACCP Chairman, Department of Thoracic Medicine and Surgery Temple University Department of Thoracic Medicine and Surgery Philadelphia, Pennsylvania Ruy J Cruz, Jr, MD, PhD Associate Professor of Surgery Surgical Director, Intestinal Rehabilitation and Transplant Center Thomas E Starzl Transplantation Institute University of Pittsburgh Pittsburgh, Pennsylvania Hongyi Cui, MD, PhD, FACS Clinical Associate Professor of Surgery Department of Surgery University of Massachusetts Medical School Worcester, Massachusetts Armagan Dagal, MD, FRCA Associate Professor Service Chief of Spine and Orthopaedic Anesthesia Services Enhanced PeriOperative Care (EPOC)Program Co-Medical Director Department of Anesthesiology and Pain Medicine Department of Orthopedics and Sport Medicine Department of Neurological Surgery (Adj.) Harborview Medical Center University of Washington Seattle, Washington Seth T Dahlberg, MD Associate Professor of Medicine and Radiology University of Massachusetts Medical School Department of Cardiology UMass Memorial Medical Center Worcester, Massachusetts Jennifer S Daly, MD Professor of Medicine, Microbiology and Physiological Systems Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts Lloyd E Damon, MD Professor of Clinical Medicine Department of Medicine Division of Hematology–Oncology University of California San Francisco, California Raul E Davaro, MD Associate Professor of Clinical Medicine Department of Internal Medicine UMass Memorial Medical Center Worcester, Massachusetts Konrad L Davis, MD, FCCP, FCCM Associate Professor of Medicine Department of Pulmonary and Critical Care Medicine Uniformed Services University of Health Sciences Naval Medical Center San Diego San Diego, California James A de Lemos, MD Professor Department of Medicine UT Southwestern Medical Center Dallas, Texas Gregory J Della Rocca, MD, PhD, FACS Associate Professor Department of Orthopaedic Surgery University of Missouri Missouri Orthopaedic Institute Columbia, Missouri Mario De Pinto, MD Associate Professor Department of Anesthesiology University of California San Francisco, California G William Dec, MD Roman W DeSanctis Professor of Medicine Division of Cardiology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Jeremy R Degrado, PharmD Clinical Pharmacist Department of Pharmacy Brigham and Women’s Hospital Boston, Massachusetts Elizabeth R DeGrush, DO Resident Physician Department of Neurology and Psychiatry University of Massachusetts Medical School Worcester, Massachusetts Paul F Dellaripa, MD Associate Professor of Medicine Harvard Medical School Staff Physician Department of Rheumatology Brigham and Women’s Hospital Boston, Massachusetts Thomas G Deloughery, MD, MACP, FAWN Professor of Medicine, Pathology, and Pediatrics Department of Hematology Oregon Health & Sciences University Portland, Oregon Deborah M DeMarco, MD, FACP Professor of Medicine Department of Medicine Senior Associate Dean of Clinical Affairs University of Massachusetts Medical School Worcester, Massachusetts Mark Dershwitz, MD, PhD Professor of Anesthesiology and Biochemistry & Molecular Pharmacology Department of Anesthesiology University of Massachusetts Medical School Worcester, Massachusetts Asha V Devereaux, MD, MPH Associate Professor of Clinical Medicine UCSD-Pulmonary Division San Diego, California Clinical Pulmonologist Department of Pulmonary/Critical Care Medicine Disaster Medicine Consultant Sharp Coronado Hospital Coronado, California Christopher R DeWitt, MD Associate Professor of Emergency Medicine and Consulting Medical Toxicologist Department of Emergency Medicine and British Columbia Drug and Poison Centre University of British Columbia Saint Paul’s Hospital Vancouver, British Columbia, Canada Abduljabbar Dheyab, MD Fellow Division of Pulmonary, Allergy, and Critical Care Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts Kate H Dinh, MD, MS Resident Department of Surgery University of Massachusetts Medical School Worcester, Massachusetts Christian P DiPaola, MD Assistant Professor Spine Surgery Division Department of Orthopaedics and Rehabilitation Department of Radiation Oncology UMass Memorial Medical Center Worcester, Massachusetts Peter Doelken, MD Pulmonary Critical Care Medicine Pulmonary Medicine Albany Medical Center Albany, New York Jon D Dorfman, MD, FACS Assistant Professor of Surgery Department of Surgery Division of Trauma and Surgical Critical Care UMass Memorial Medical Center—University Campus Worcester, Massachusetts Robert P Dowsett, BMBS, GDipClinEd, FACEM Senior Lecturer (Assessment) Department of Medical Education Melbourne Medical School Melbourne, Australia David A Drachman, MD (deceased) Professor of Neurology Chairman Emeritus Department of Neurology University of Massachusetts Medical School Worcester, Massachusetts David F Driscoll, PhD Associate Professor of Medicine Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts Dino Druda, MB, BCh, FACEM Consultant Emergency Physician and Clinical Toxicologist Monash Toxicology, Emergency Medicine Program, Monash Health Dandenong Hospital Dandenong, Victoria, Australia David L Dunn, MD Vice President for Health Sciences Professor of Surgery Department of Microbiology and Immunology University at Buffalo Executive Vice President for Health Affairs University of Louisville Louisville, Kentucky Angelina Edwards, MD Nephrologist Department of Nephrology Memorial Hermann Houston, Texas Heather Elias, MD Assistant Professor Division of Endocrinology Metabolism and Diabetes University of Massachusetts Medical School Worcester, Massachusetts Richard T Ellison, III, MD Hospital Epidemiologist Professor of Medicine, Microbiology and Physiological Systems University of Massachusetts Medical School Department of Medicine Division of Infectious Diseases UMass Memorial Medical Center Worcester, Massachusetts Ashkan Emadi, MD, PhD Associate Professor of Medicine, Pharmacology and Experimental Therapeutics Director, Hematology & Medical Oncology Fellowship Department of Medicine, Hematology/Medical Oncology University of Maryland School of Medicine Marlene & Stewart Greenebaum Comprehensive Cancer Center Baltimore, Maryland Charles H Emerson, MD Professor Emeritus of Medicine Division of Endocrinology and Metabolism University of Massachusetts Medical School Worcester, Massachusetts Timothy A Emhoff, MD, FACS Chief Trauma and Surgical Critical Care Department of Surgery UMass Memorial Medical Center Worcester, Massachusetts Jennifer L Englund, MD Emergency Medicine Physician Maplewood, Minnesota Robert M Esterl, Jr, MD Professor of Surgery Department of Surgery The University of Texas Health Science Center at San Antonio San Antonio, Texas Julien Fahed, MD Resident Department of Internal Medicine UMass Memorial Medical Center Worcester, Massachusetts Pang-Yen Fan, MD Professor of Medicine Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts James C Fang, MD Adjunct Professor Department of Medicine Case Western Reserve University School of Medicine Cleveland, Ohio John Fanikos, BS, MBA Director of Pharmacy Department of Pharmacy Brigham and Women’s Hospital Boston, Massachusetts Harrison W Farber, MD Professor of Medicine Director, Pulmonary Hypertension Center Boston University Boston Medical Center Boston, Massachusetts Khaldoun Faris, MD Clinical Associate Professor Director, Anesthesiology CCM Department of Anesthesiology University of Massachusetts Medical School Worcester, Massachusetts Alan P Farwell, MD Chief, Section of Endocrinology, Diabetes and Nutrition Department of Medicine Boston Medical Center/Boston University Boston, Massachusetts Alan M Fein, MD Clinical Professor of Medicine Department of Pulmonary and Critical Care Hofstra Northwell School of Medicine Lake Success, New York Stacey Feinstein, DO, MBA Emergency Physician Department of Emergency Memorial Hospital Pembroke Pembroke Pines, Florida Sean Figy, MD Resident Physician Division of Plastics and Reconstructive Surgery Department of Surgery University of Massachusetts Medical School Worcester, Massachusetts Robert W Finberg, MD Richard M Haidack Professor Medicine Professor, Microbiology & Physiological Systems Chair, Department of Medicine University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Kimberly A Fisher, MD Assistant Professor Department of Medicine Division of Pulmonary and Critical Care University of Massachusetts Medical Center Worcester, Massachusetts Christina Fitch, DO, MPH Assistant Professor Department of Palliative Care University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Avegail G Flores, MD Assistant Professor, Hepatology Program Division of Gastroenterology Department of Medicine Washington University St Louis, Missouri Dee W Ford, MD, MSCR Associate Professor of Medicine Department of Pulmonary and Critical Care Medicine Medical University of South Carolina Charleston, South Carolina Marsha D Ford, MD Emergency Medicine Carolinas Medical Center Charlotte, North Carolina Kyle Fraielli, PharmD Clinical Pharmacist Department of Pharmacy UMass Memorial Medical Center Worcester, Massachusetts Joseph J Frassica, MD Head, Phillips Research the Americas Chief Medical Officer, Phillips North America Professor, The Practice Institute for Medical Engineering and Science Massachusetts Institute of Technology Senior Consultant, Pediatric Critical Care Massachusetts General Hospital for Children Boston, Massachusetts Ann-Kristin U Friedrich, MD Surgical Resident Department of Surgery University of Massachusetts Medical School Worcester, Massachusetts Saint Mary’s Hospital Waterbury, Connecticut Matthew B Frieman, MD Associate Professor Department of Microbiology and Immunology University of Maryland, School of Maryland Baltimore, Maryland R Brent Furbee, MD, FACMT Professor Emeritus, Clinical Emergency Medicine Department of Emergency Medicine Division of Medical Toxicology Indiana University School of Medicine Indianapolis, Indiana Brian S Furukawa, MD Assistant Professor Department of Medicine Division of Pulmonary and Critical Care Medicine Loma Linda University Loma Linda, California Christos Galatas, MD Cardiology Fellow Department of Cardiology McGill University Montreal, Quebec, Canada Sumanth Gandra, MD, MPH Resident Scholar The Center For Disease Dynamics, Economics & Policy New Dehli, India Javier Barreda Garcia, MD Assistant Professor Department of Internal Medicine Division of Pulmonary and Critical Care Medicine The University of Texas Health Science Center at Houston Houston, Texas Anne Garrison, MD Director Obstetrics-Gynecology Clerkship Assistant Professor University of Massachusetts Medical School UMass Memorial Medical Center - Memorial Campus Worcester, Massachusetts James Geiling, MD, MPH Professor of Medicine, Geisel School of Medicine at Dartmouth Veterans Affairs Medical Center White River Junction, Vermont Edith S Geringer, MD Boston, Massachusetts Terry Gernsheimer, MD Professor of Medicine Division of Hematology Medical Director of Transfusion Seattle Cancer Care Alliance University of Washington Seattle, Washington Hayley B Gershengorn, MD Assistant Professor Department of Medicine Albert Einstein College of Medicine Montefiore Medical Center Bronx, New York Michael M Givertz, MD Medical Director, Heart Transplant and Mechanical Circulation Support Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts Richard H Glew, MD Professor of Medicine and Microbiology and Physiological Systems Department of Medicine/Infectious Diseases UMass Memorial Medical Center Worcester, Massachusetts Richard P Goddeau, Jr, DO, FAHA Associate Professor of Neurology Department of Neurology University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Dori Goldberg, MD Assistant Professor Division of Dermatology University of Massachusetts Medical School Worcester, Massachusetts Andrew J Goodwin, MD, MSCR Assistant Professor Division of Pulmonary, Critical Care, Allergy and Sleep Medicine Medical University of South Carolina Charleston, South Carolina Susan E Gorman, MD Associate Director for Science Division of Strategic National Stockpile Centers for Disease Control and Prevention Bethesda, Maryland Andis Graudins, MBBS (Hons), PhD, FACEM, FCMT Professor of Emergency Medicine and Toxicology Research School of Clinical Sciences at Monash Health, Monash University Director, Clinical Toxicology Services Monash Toxicology, Emergency Medicine Program, Monash Health Dandenong Hospital Dandenong, Victoria, Australia Gay Graves, MS, RD/LDN Nutrition Support Dietitian Department of Center for Human Nutrition Vanderbilt University Hospital Center for Human Nutrition Nashville, Tennessee Damian J Green, MD Assistant Member and Assistant Professor of Medicine Clinical Research Division Fred Hutchinson Cancer Research Center University of Washington Seattle, Washington Bruce Greenberg, MD Assistant Professor Department of Medicine Assistant Director UMass Memorial Medical Center Division of Pulmonary, Allergy and Critical Care University of Massachusetts Medical School Worcester, Massachusetts Thomas C Greenough, MD Associate Professor Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts Bonnie C Greenwood, PharmD, BCPS Clinical Program Director Department of Clinical Pharmacy Services University of Massachusetts Medical School Shrewsbury, Massachusetts Peeyush Grover, MD Cardiology Fellow Department of Cardiology UMass Memorial Medical Center Worcester, Massachusetts Rainer W G Gruessner, MD, FACS, FICS Professor of Surgery Chief of Transplantation Department of Surgery and Transplant Services SUNY Upstate Medical University Syracuse, New York C Prakash Gyawali, MD Professor of Medicine Division of Gastroenterology Barnes Jewish Hospital Washington University in St Louis St Louis, Missouri Michelle K Haas, MD Assistant Professor of Medicine Division of Infectious Diseases University of Colorado Health Science Center Denver Public Health and Hospital Authority Denver, Colorado Shirin Haddady, MD, MPH Clinical Assistant Professor Department of Internal Medicine Division of Endocrinology Boston Medical Center Boston University School of Medicine Boston, Massachusetts Wiley R Hall, MD Director of Neurocritical Care UMass Memorial Medical Center Worcester, Massachusetts Hurst M Hall, MD Assistant Professor Department of Medicine Division of Cardiology UT Southwestern Medical Center Dallas, Texas Neil A Halpern, MD, MCCM, FACP, FCCP Professor of Clinical Medicine Professor of Medicine and Clinical Anesthesiology Weill Cornell Medical College Director, Critical Care Center Chief, Critical Care Medicine Service Department of Anesthesiology and Critical Care Medicine Memorial Sloan Kettering Cancer Center New York, New York Tarek Abou Hamdan, MD Gastroenterology and Interventional Endoscopy Consultant Division of Gastroenterology Clemenceau Medical Center Affiliated with Johns Hopkins International Beirut, Lebanon Samuel Y Han, MD Fellow Department of Gastroenterology University of Colorado Aurora, Colorado Stephen B Hanauer, MD Professor Department of Medicine (Gastroenterology, Hepatology) Northwestern University Feinberg School of Medicine Chicago, Illinois Sundaram Hariharan, MD Professor of Medicine and Surgery Robert J Corry Chair of Surgery Department of Medicine and Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania David M Harlan, MD William and Doris Krupp Professor of Medicine Co-Director, Diabetes Center of Excellence Department of Medicine Division of Diabetes UMass Memorial Medical Center Worcester, Massachusetts Laura Harrell Raffals, MD, MS Associate Professor of Medicine Section of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota Steven Hatch, MD, MS Associate Professor of Medicine Division of Infectious Diseases University of Massachusetts Medical School Worcester, Massachusetts Ashley Haynes, MD Assistant Professor Department of Emergency Medicine Division of Medical Toxicology University of Texas Southwestern Parkland Health and Hospital System Dallas, Texas Lawrence J Hayward, MD Professor of Neurology Department of Neurology UMass Memorial Medical Center University of Massachusetts Medical School Worcester, Massachusetts Stephen O Heard, MD Professor of Anesthesiology and Surgery Department of Anesthesiology and Perioperative Medicine UMass Memorial Medical Center University of Massachusetts Medical School Worcester, Massachusetts Kennon Heard, MD Professor of Emergency Medicine Department of Emergency Medicine University of Colorado School of Medicine Aurora, Colorado Benedikt H Heidinger, MD Research Fellow Department of Radiology Harvard Medical School Beth Israel Deaconess Medical Center 330 Brookline Avenue Boston, Massachusetts Vitaly Herasevich, MD, PhD, FCCM Associate Professor of Anesthesiology and Medicine Department of Anesthesiology Mayo Clinic Rochester, Minnesota Daniel Hetherman, MD Resident Department of Surgery University of Massachusetts Medical School Worcester, Massachusetts Thomas L Higgins, MD, MBA, FACP, MCCM Chief Medical Officer and Interim President and CEO Baystate Franklin Medical Center Greenfield, Massachusetts Professor of Medicine and Surgery and Anesthesiology Tufts University School of Medicine Boston, Massachusetts Nicholas S Hill, MD Chief Department of Pulmonary, Critical Care and Sleep Division Tufts Medical Center Boston, Massachusetts John B Holcomb, MD, FACS Professor and Vice Chair Department of Surgery Memorial Hermann Hospital Houston, Texas Judd E Hollander, MD Associate Dean for Strategic Health Initiatives Vice Chair for Finance and Healthcare Enterprises Department of Emergency Medicine Thomas Jefferson University Hospital Philadelphia, Pennsylvania Helen M Hollingsworth, MD Associate Professor of Medicine Boston University School of Medicine Boston Medical Center Department of Pulmonary Allergy and Critical Care Medicine UpToDate—Wolters Kluwer Health Waltham, Massachusetts Shelley A Holmer, MD Psychiatrist Duke Health Durham, North Carolina Jonathan E Holtz, MD Clinical Instructor Advanced Heart Failure Cardiologist Department of Medicine University of Pittsburgh Medical Center Altoona, Pennsylvania Donough Howard, MD Consultant Rheumatologist Hermitage Medical Clinic Dublin, Ireland Michael D Howell, MD, MPH Chief Quality Officer Director, Center for Healthcare Delivery Science and Innovation University of Chicago Medicine Chicago, Illinois Misha Huang, MD Attending Physician Denver Veterans Affairs Medical Center Instructor Department of Infectious Diseases University of Colorado Aurora, Colorado Rolf D Hubmayr, MD Professor of Medicine and Physiology Department of Pulmonary and Critical Care Mayo Clinic St Louis Park, Minnesota John Terrill Huggins, MD Associate Professor Department of Medicine Division of Pulmonary and Critical Care Medical University of South Carolina Charleston, South Carolina Abhinav Humar, MD Thomas E Starzl Professor in Transplantation Surgery Clinical Director, Thomas E Starzl Transplantation Institute Chief, Division of Transplant Surgery Department of Surgery University of Pittsburgh Pittsburgh, Pennsylvania Benjamin Hyatt, MD Assistant Professor of Medicine Division of Gastroenterology UMass Memorial Medical Center Worcester, Massachusetts Richard S Irwin, MD, Master FCCP Professor of Medicine and Nursing University of Massachusetts Medical School Chair, Critical Care Operations UMass Memorial Medical Center Worcester, Massachusetts Margaret Isaac, MD Adult Medicine Clinic and Palliative Care Service Harborview Medical Center Assistant Professor University of Washington School of Medicine Seattle, Washington Janetta L Iwanicki, MD Assistant Professor, Emergency Medicine and Medical Toxicology Department of Emergency Medicine Denver Health and Hospital Authority University of Colorado School of Medicine Denver, Colorado Colleen L Jay, MD, MS Assistant Professor of Surgery University Transplant Center University of Texas Health Science Center, San Antonio San Antonio, Texas Donald H Jenkins, MD, FACS Professor/Clinical Division of Trauma and Emergency Surgery Vice Chair for Quality Department of Surgery Betty and Bob Kelso Distinguished Chair in Burn and Trauma Surgery Associate Deputy Director Military Health Institute University of Texas Health Science Center, San Antonio San Antonio, Texas Thanjira Jiranantakan, MD, MPH Lecturer, Medical Toxicologist Department of Preventive and Social Medicine Division of Toxicology, Occupational & Environmental Medicine Faculty of Medicine Siriraj Hospital Mahidol University Medical Toxicology Attending Physician Siriraj Poison Control Center Bangkok Noi, Bangkok Scott B Johnson, MD Chief of General Thoracic Surgery Department of Cardiothoracic Surgery University of Texas Health Science Center at San Antonio San Antonio, Texas Dejah R Judelson, MD Resident Division of Vascular Surgery UMass Memorial Medical Center Worcester, Massachusetts Bryan S Judge, MD Associate Professor Department of Emergency Medicine Spectrum Health Grand Rapids Medical Education Partners/Michigan State University College of Human Medicine Program in Emergency Medicine Grand Rapids, Michigan Firas Kaddouh, MD Neurology Resident Department of Neurology UMass Memorial Medical Center Worcester, Massachusetts Marc J Kahn, MD, MBA, FACP Peterman-Prosser Professor Senior Associate Dean Departments of Medicine and Pharmacology Division of Hematology/Medical Oncology Tulane University School of Medicine Office of Admissions and Student Affairs New Orleans, Louisiana Biren B Kamdar, MD, MBA, MHS Assistant Professor Division of Pulmonary and Critical Care Medicine David Geffen School of Medicine at University of California Los Angeles, California Padmanaidu Karnam, MD Rheumatology Fellow Department of Rheumatology UMass Memorial Medical Center Worcester, Massachusetts Sheetal Karne, MD Hematology Oncology Fellow Marlene and Stewart Greenebaum Cancer Center University of Maryland School of Medicine Baltimore, Maryland Jason N Katz, MD, MHS Associate Professor of Medicine Department of Medicine Division of Cardiology and Pulmonary & Critical Care Medicine Medical Director, UNV Mechanical Heart Program Medical Director, Cardiac Intensive Care Unit Medical Director, Cardiothoracic Surgical Intensive Care Unit & Critical Care Service Director, Cardiovascular Clinical Trials University of North Carolina School of Medicine Chapel Hill, North Carolina Carol A Kauffman, MD Professor, Department of Internal Medicine Chief, Division of Infectious Diseases Veterans Affairs Ann Arbor Healthcare System University of Michigan Medical School Ann Arbor, Michigan Andrew M King, MD Assistant Professor Department of Emergency Medicine Wayne State University School of Medicine Detroit Medical Center Detroit, Michigan Mary A King, MD, MPH Pediatric Critical Care Medicine Medical Director, PICU Harborview Medical Center Associate Professor University of Washington Seattle, Washington Mark A Kirk, MD Associate Professor Department, Emergency Medicine UVA Health System Charlottesville, Virginia Karen M Knops, MD Medical Director, Palliative Care Program Department of Palliative Care Overlake Medical Center Bellevue, Washington Meghan S Kolodziej, MD Instructor in Psychiatry Department of Psychiatry Brigham and Women’s Hospital Boston, Massachusetts Scott E Kopec, MD Associate Professor Department of Medicine Division of Pulmonary, Allergy and Critical Care University of Massachusetts Medicine School Worcester, Massachusetts Pierre Kory, MD Chief Critical Care Service Medical Director, Trauma and Life Support Center Department of Medicine University of Wisconsin Hospital and Clinics Madison, Wisconsin Stephen J Krinzman, MD Clinical Associate Professor Medicine University of Massachusetts Medical School Division of Pulmonary and Critical Care Department of Medicine UMass Memorial Medical Center Worcester, Massachusetts Jason M Kurland, MD Assistant Professor of Medicine Division of Renal Medicine University of Massachusetts Medical School Worcester, Massachusetts Jennifer LaFemina, MD, FACS Assistant Professor of Surgery Department of Surgery Division of Surgical Oncology University of Massachusetts Medical School Worcester, Massachusetts Laura A Lambert, MD Associate Professor Department of Surgery Divisions of Surgical Oncology and Palliative Medicine UMass Memorial Medical Center Worcester, Massachusetts Anthony J Lembo, MD Associate Professor of Medicine Department of Medicine Harvard Medical School Beth Israel Deaconess Medical Center Boston, Massachusetts Adam B Lerner, MD Director, West Campus Clinical Operations Department of Anesthesiology and Critical Care Beth Isreael Deaconess Medical Center Boston, Massachusetts Stephanie M Levine, MD Professor of Medicine Department of Medicine Division of Pulmonary Diseases and Critical Care University of Texas Health Center, San Antonio San Antonio, Texas William J Lewander, MD Vice Chair Pediatric Emergency Medicine Department of Emergency Hasbro Children’s Hospital Providence, Rhode Island Daniel H Libraty, MD Professor of Medicine Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts Craig M Lilly, MD, FCCP Professor of Medicine, Anesthesiology, and Surgery University of Massachusetts Medical School Vice Chair, Critical Care Operations Director, Tele-ICU Program UMass Memorial Medical Center Worcester, Massachusetts Christopher H Linden, MD Professor Division of Medical Toxicology Department of Emergency Medicine UMass Medical School Department of Emergency Services Milford Regional Medical Center Milford, Massachusetts Mark S Link, MD Professor of Medicine Department of Cardiology UT Southwestern Medical Center Dallas, Texas Carol F Lippa, MD Professor and Interim Chair Department of Neurology Drexel University College of Medicine Philadelphia, Pennsylvania Mauricio Lisker-Melman, MD Professor of Medicine Director of Hepatology Department of Gastroenterology & Hepatology Washington University School of Medicine Barnes Jewish Hospital St Louis, Missouri Diana E Litmanovich, MD Staff Radiologist, Cardiothoracic Imaging, BIDMC Director, Cardiac Imaging Director, Cardiothoracic Imaging Fellowship Program Associate Professor of Radiology Harvard Medical School Boston, Massachusetts Norman Scott Litofsky, MD Professor and Chief, Director of Radiosurgery and Neuro-Oncology Division of Neurological Surgery University of Missouri School of Medicine Columbia, Missouri Afroza Liton, MD Attending Physician Department of Internal Medicine St Peters Hospital Albany, New York Frederic F Little, MD Assistant Professor of Medicine Program Director, Allergy/Immunology Fellowship Medical Director, Pulmonary, Allergy and Sleep Clinics Department of Medicine Boston University School of Medicine Boston Medical Center Boston, Massachusetts Nancy Y N Liu, MD Clinical Associate Professor Department of Rheumatology University of Massachusetts Medical School UMass Memorial Medical Center-Memorial Campus Worcester, Massachusetts Melanie R Loberman, MD Instructor in Anaesthesia Harvard Medical School Department of Anesthesia, Critical Care & Pain Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts Dana Lustbader, MD Professor of Medicine Chair, Department of Palliative Care Hofstra Northwell School of Medicine ProHEALTH Care, an Optum Company Lake Success, New York Alice D Ma, MD Professor of Medicine Department of Hematology/Oncology University of North Carolina Chapel Hill, North Carolina J Mark Madison, MD Professor of Medicine and Microbiology and Physiological Systems Chief, Division of Pulmonary, Allergy and Critical Care Medicine Department of Medicine UMass Memorial Medical Center University of Massachusetts Medical School Worcester, Massachusetts Garbo Mak, MD Assistant Professor Division of Critical Care, Pulmonary and Sleep Medicine University of Texas Health Science Center at Houston, Houston, Texas Suzana K E Makowski, MD, MMM Co-Chief, Division of Palliative Care Department of Medicine University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Atul Malhotra, MD Professor Department of Medicine University of California San Diego La Jolla, California Samir Malkani, MD, MRCP (UK) Clinical Professor of Medicine University of Massachusetts Medical School Diabetes Center of Excellence Worcester, Massachusetts Mary E Maloney, MD Chair, Division of Dermatology University of Massachusetts Medical School Worcester, Massachusetts Max Mandelbaum, MD, PhD Resident Department of Neurology UMass Memorial Medical Center Worcester, Massachusetts Paul E Marik, MD, FCCM Chief, Pulmonary and Critical Care Medicine Department of Medicine Eastern Virginia Medical School Sentara Norfolk General Hospital Norfolk, Virginia William L Marshall, MD Associate Professor Department of Medicine Division of Infectious Diseases University of Massachusetts Medical School Worcester, Massachusetts Carlos Martinez-Balzano, MD Assistant Professor of Medicine Division of Pulmonary, Critical Care and Sleep SUNY Upstate Medical University Syracuse, New York Paulo Martins, MD, PhD Assistant Professor University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Christina Massey, MA Predoctoral Intern Department of Psychiatry Massachusetts General Hospital Boston, Massachusetts Ryan C Maves, MD, FACP, FIDSA Attending Physician Associate Professor of Medicine Department of Infectious Disease and Critical Care Medicine Uniformed Services University San Diego, California Paul H Mayo, MD, FCCP Academic Director Critical Care Division of Pulmonary, Critical Care, and Sleep Medicine Department of Medicine Northwell Health LIJ/NSUH Medical Center Professor of Clinical Medicine Zucker School of Medicine at Hofstra/Northwell Hempstead, New York Guy Maytal, MD Medical Director, Ambulatory Psychiatry Department of Psychiatry Massachusetts General Hospital Boston, Massachusetts Melanie Maytin, MD Instructor in Medicine Division of Cardiovascular Medicine Brigham and Women’s Hospital Boston, Massachusetts Joyce K McIntyre, MD Assistant Professor of Surgery, Pediatrics and Neurosurgery Departments of Surgery, Pediatrics and Neurosurgery Division of Plastics and Reconstructive Surgery University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Brandy McKelvy, MD Associate Professor Department of Internal Medicine Division of Pulmonary, Critical Care and Sleep Medicine Memorial Herman Hospital Texas Medical Center Lyndon B Johnson General Hospital University of Texas Health Science Center at Houston Houston, Texas Lloyd C Meeks, MD Intensivist, Regional Medical Director Advanced ICU Care St Louis, Missouri Brendan Merchant, MD Fellow, Cardiovascular Medicine Division of Cardiology University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Marco Mielcarek, MD Associate Professor of Medicine/Associate Member Department of Medical Oncology Clinical Research Division, FHCRC University of Washington Seattle, Washington Abdul Mikati, MD Neurology resident, Dept of Neurology University of Massachusetts Medical School 55 Lake Ave North Worcester, Massachusetts Ann L Mitchell, MD Clinical Associate Professor University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Lawrence C Mohr, Jr, MD, ScD, FACP, FCCP Professor of Medicine, Biometry and Epidemiology Director, Environmental Biosciences Program Medical University of South Carolina Charleston, South Carolina Jahan Montague, MD Clinical Associate Professor of Medicine Director, Nephrology Fellowship Department of Medicine Division of Renal Medicine UMass Memorial Medical Center Worcester, Massachusetts Bruce Montgomery, MD Professor Department of Medicine University of Washington and Seattle Cancer Alliance Seattle, Washington Majaz Moonis, MD, MRCP, DM, FRCP (I), FAAN, FAHA, FAASM Professor of Neurology Director of the Stroke Services UMass Memorial Medical Center Worcester, Massachusetts Andrew H Moraco, MD, MS Fellow Division of Pulmonary, Allergy and Critical Care Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts John P Mordes, MD Professor of Medicine/Endocrinology Department of Medicine UMass Memorial Medical Center Worcester, Massachusetts David A Morrow, MD, MPH Professor of Medicine Harvard Medical School Directory, Levine Cardiac Intensive Care Unit Division of Cardiovascular Brigham and Women’s Hospital Boston, Massachusetts Babak Movahedi, MD, PhD Assistant Professor of Surgery Department of Surgery Division of Organ Transplantation UMass Memorial Medical Center Worcester, Massachusetts James B Mowry, PharmD, DABAT, FAACT Director, Indiana Poison Center Emergency Medicine and Trauma Center Indiana University Health Methodist Hospital Indianapolis, Illinois Karol Mudy, MD Cardiothoracic Clinics Hennepin County Medical Center Minneapolis, Minnesota Susanne Muehlschlegel, MD, MPH, FNCS, FCCM Associate Professor of Neurocritical Care Department of Neurology, Anesthesia, Critical Care and Surgery University of Massachusetts Medical School Worcester, Massachusetts Diana Wells Mulherin, PharmD, BCPS, BCNSP Clinical Pharmacy Specialist, Nutrition Support Department of Pharmacy Clinical Programs and Center for Human Nutrition Vanderbilt University Medical Center Nashville, Tennessee Saori A Murakami, MD Attending Psychiatrist Assistant Medical Director, McLean Franciscan Child and Adolescent Inpatient Program Child and Adolescent Psychiatry McLean Hospital Brighton, Massachusetts John G Myers, MD Professor and Chief Division of Trauma and Emergency Surgery University of Texas San Antonio San Antonio, Texas Nandita R Nadig, MD, MSCR Assistant Professor of Pulmonary and Critical Care Department of Medicine Medical University of South Carolina Charleston, South Carolina Ramana K Naidu, MD Assistant Professor Department of Anesthesia and Perioperative Care Division of Pain Medicine University of California, San Francisco San Francisco, California Girish B Nair, MD, FACP, FCCP Associate Professor of Clinical Medicine Division of Pulmonary and Critical Care Medicine Oakland University William Beaumont School of Medicine William Beaumont Hospital Royal Oak, Michigan Niyada Naksuk, MD Division of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota Lena M Napolitano, MD, FACS, FCCM, MCCM Professor of Surgery Division Chief, Acute Care Surgery Department of Surgery University of Michigan Ann Arbor, Michigan Reenu Nathan, PharmD, BCPS Clinical Pharmacist Department of Pharmacy UMass Memorial Medical Center Worcester, Massachusetts Theresa A Nester, MD Medical Director of Integrated TSL Bloodworks Northwest Medical Center Associate Professor Department of Laboratory Medicine University of Washington Seattle, Washington Michael S Niederman, MD, MACP, FCCP, FCCM, FERS Clinical Director, Pulmonary and Critical Care Medicine New York Presbyterian/Weill Cornell Medical Center Professor of Clinical Medicine Weill Cornell Medical College New York, New York Matthew A Niemi, MD Assistant Professor of Medicine Division of Renal Medicine Department of Medicine UMass Memorial Medical Center Worcester, Massachusetts Anna Nolan, MD, MS Assistant Professor of Medicine and Environmental Medicine Department of Medicine and Environmental Medicine Division of Pulmonary and Critical Care New York University School of Medicine New York, New York Dominic J Nompleggi, MD Chief, Gastroenterology Associate Professor University of Massachusetts Medical School Worcester, Massachusetts Sean E Nork, MD Associate Professor of Orthopaedics and Sports Medicine UW Medicine Harborview Medical Center Seattle, Washington Gary O Noroian, MD Staff Nephrologist Division of Nephrology St Vincent Hospital Worcester, Massachusetts Robert Lee Norris, MD Professor of Surgery Division of Emergency Medicine Stanford University School of Medicine Stanford, California Patrick T O’Gara, MD Watkins Family Distinguished Chair in Cardiology Division of Cardiovascular Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts Paulo J Oliveira, MD, FCCP Associate Professor of Medicine Director of Interventional Pulmonary Medical Director of Respiratory Care Division of Pulmonary, Allergy and Critical Care Medicine Department of Medicine UMass Memorial Medical Center Worcester, Massachusetts Kent R Olson, MD Co-Medical Director San Francisco Division California Poison Control System Clinical Professor of Medicine & Pharmacy University of California San Francisco, California Steven M Opal, MD Professor of Medicine Department of Infectious Diseases Alpert Medical School of Brown University Rhode Island Hospital Ocean State Clinical Coordinating Center Providence, Rhode Island Achikam Oren-Grinberg, MD Director, Critical Care Echocardiography Department of Anesthesia, Critical Care and Pain Management Beth Israel Deaconess Medical Center Boston, Massachusetts David E Ost, MD, MPH Professor of Medicine Department of Pulmonary Medicine The University of Texas AD Anderson Cancer Center Houston, Texas John Scott Parrish, MD Associate Program Director Department of Pulmonary and Critical Care Medicine Naval Medical Center San Diego San Diego, California Polly E Parsons, MD Professor of Medicine Chair, Department of Medicine University of Vermont Medical Center Burlington, Vermont Payal K Patel, MD Clinical Lecturer and Staff Infectious Diseases Physician Division of Infectious Diseases Department of Internal Medicine Veterans Affairs Ann Arbor Healthcare System University of Michigan Medical School Ann Arbor, Michigan Krunal Patel, MD Fellow (Physician) Division of Gastroenterology University of Massachusetts Medical School Worcester, Massachusetts Marie T Pavini, MD, FCCP Intensivist Department of Intensive Care Unit Rutland Regional Medical Center Rutland, Vermont William D Payne, MD Professor Department of Surgery University of Minnesota Minneapolis, Minnesota Randall Pellish, MD Assistant Professor of Medicine Fellowship Program Director Department of Medicine Division of Gastroenterology University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Catherine A Phillips, MD Associate Professor of Neurology Department of Neurology University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts David J Prezant, MD Chief Medical Officer Special Advisor to the Fire Commissioner for Health Policy Co-Director WTC Medical Monitoring and Treatment Programs New York City Fire Department Professor of Medicine Division of Pulmonary Albert Einstein College of Medicine Montefiore Medical Center Bronx, New York Timothy A Pritts, MD, PhD, FACS Professor of Surgery Chief, Section of General Surgery Department of Surgery University of Cincinnati Medical Center Cincinnati, Ohio Juan Carlos Puyana, MD Associate Professor of Surgery Department of Critical Care Medicine and Clinical Translational Science The University of Pittsburgh Pittsburgh, Pennsylviania John Querques, MD Chief, Inpatient Services Department of Pyschology Tufts Medical Center Boston, Massachusetts Jacob A Quick, MD Assistant Professor of Surgery Department of Surgery University of Missouri Columbia, Missouri Sunil Rajan, MD, FCCP Pulmonary and Critical Care Physician Department of Medicine Centra Southside Community Hospital Farmville, Virginia Navitha Ramesh, MD Associate Geisinger Health Wilkes Barre, Pennsylvania Rajeev Ramgopal, MD Chief Resident Department of Internal Medicine Barnes Jewish Hospital/Washington University Saint Louis, Missouri Britney M Ramgopal, MD Resident Physician Department of Internal Medicine Barnes Jewish Hospital/Washington University Saint Louis, Missouri Abbas A Rana, MD Assistant Professor of Surgery Department of Surgery, Abdominal Transplantation Baylor College of Medicine Houston, Texas Paula D Ravin, MD Department of Neurology UCLA Health Los Angeles, California Daniel E Ray, MD, MS, FAAHPM Chief, Section of Palliative Medicine and Hospice Department of Medicine Lehigh Valley Health Network Allentown, Pennsylvania Mary Jane Reed, MD, FACS, FCCM, FCCP Medical Director Geisinger System Bio Containment Unit Associate Departments of Critical Care Medicine and Trauma Surgery Geisinger Medical Center Danville, Pennsylvania Harvey S Reich, MD, FACP, FCCP, FFSMB Director, Critical Care Medicine Department of Critical Care Rutland Regional Medical Center Rutland, Vermont Jennifer E Reidy, MD, MS, FAAHPM Co-Chief, Division of Palliative Care Department of Medicine and Family Medicine UMass Memorial Medical Center Assistant Professor University of Massachusetts Medical School Worcester, Massachusetts Carole A Ridge, MD Consultant Radiologist Mater Misericordiae University Hospital Dublin James M Rippe, MD Founder and Director Rippe Lifestyle Institute Shrewsbury, Massachusetts Ray H Ritz, BA, RRT, FAARC Manager of Respiratory Care Department of Respiratory Care Beth Israel Deaconess Medical Center Boston, Massachusetts William P Robinson, III, MD Associate Professor of Surgery Program Director Department of Vascular Surgery University of Virginia School of Medicine Charlottesville, Virginia Kimberly A Robinson, MD, MPH Medical Director ICU Department of Pulmonary and Critical Care Medicine UMass Memorial Medical Center—Marlborough Campus Marlborough, Massachusetts Mark J Rosen, MD Division of Pulmonary, Critical Care and Sleep Medicine North Shore University and Long Island Jewish Health System Professor of Medicine Hofstra North Shore-Long Island Jewish School of Medicine New Hyde Park, New York Marc S Sabatine, MD Professor of Medicine Harvard Medical School Physician Chairman TIMI Study Group Cardiology Division Brigham and Women’s Hospital Boston, Massachusetts Marjorie S Safran, MD, FACE Clinical Professor Medicine Division of Endocrinology University of Massachusetts Medical School Worcester, Massachusetts Johnny S Salameh Associate Professor, Department of Neurology Program Director, Neurology Residency Chair, Quality Advisory Council Director, ALS Clinic American University of Beirut Medical Center Beirut, Lebanon Benkole Samuel, MD General Surgery Resident Department of Surgery UMass Memorial Medical Center Worcester, Massachusetts Rolando Sanchez Sanchez, MD Clinical Assistant Professor Division of Pulmonary Diseases, Critical Care University of Iowa Iowa City, Iowa Todd W Sarge, MD Director, Critical Care Department of Anesthesia, Critical Care and Pain Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts Yaw Sarpong, MD, eMBA Chief Resident Division of Neurological Surgery University of Missouri Columbia, Missouri Gregory A Schmidt, MD Professor Division of Pulmonary Diseases, Critical Care, and Occupational Medicine Associate Chief Medical Officer—Critical Care University of Iowa Hospitals and Clinics Iowa City, Iowa Benjamin M Scirica, MD, MPH Senior Investigator TIMI Study Group Associate Professor of Medicine Harvard Medical Group Department of Medicine Division of Cardiovascular Brigham and Women’s Hospital Boston, Massachusetts Joshua R Scurlock, MD Department of Surgery UMass Memorial Medical Center 55 Lake Avenue Worcester, Massachusetts Douglas L Seidner, MD, AGAF, FACG, FASPEN, CNSC Associate Professor of Medicine Director, Vanderbilt Center for Human Nutrition Division of Gastroenterology Vanderbilt University Medical Center Nashville, Tennessee Myron Michael Shabot, MD, FACS, FCCM, FACMI Executive Vice President/System Chief Clinical Officer Department of Executive Offices Memorial Hermann Health System Houston, Texas Shahzad Shaefi, MD Assistant Professor in Anesthesia Harvard Medical School Department of Anesthesia, Critical Care and Pain Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts Andrew W Shaffer, MD Fellow Department of Cardiothoracic Surgery University of Minnesota Medical Center Minneapolis, Minnesota Robert Sheiman, MD, BS, Ch Eng Professor of Abdominal and Interventional Radiology University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Richard D Shih, MD Professor Clinical Biomedical Science Department of Integrated Medical Science Florida Atlanta University College of Medicine Boynton Beach, Florida Ryan G Shipe, MD Assistant Professor Department of Medicine Division of Pulmonary, Allergy and Critical Care Medicine University of Massachusetts Medical School Worcester, Massachusetts Andrew F Shorr, MD, MPH Associate Director of Pulmonary and Critical Care Medicine Chief Pulmonary Clinic MedStar Washington Hospital Center Washington, DC Bing Shue, MD Resident Physician Department of Vascular Surgery University of Massachusetts Medical School Worcester, Massachusetts Sara J Shumway, MD Professor of Surgery Vice Chief, Division of Cardiothoracic Surgery University of Minnesota Minneapolis, Minnesota Michael G Silverman, MD Fellow Department of Cardiovascular Medicine Brigham and Women’s Hospital Boston, Massachusetts Bruce J Simon, MD Associate Director, Trauma and Surgical Critical Care Associate Professor, University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Marco L A Sivilotti, MD, MSc, FRCPC, FACEP, FACMT Professor, Departments of Emergency Medicine and of Biomedical & Molecular Sciences Queen’s University at Kingston Ontario, Canada Craig S Smith, MD Assistant Professor Medical Director, Coronary Care Unit Department of Medicine and Cardiology University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Heidi L Smith, MD, PhD Assistant Professor Department of Medicine University of Massachusetts Medical School Mas Biologics of the University of Massachusetts Medical School, Clinical Affairs Boston, Massachusetts Brian S Smith, PharmD Vice President Clinical Services and Quality Department of Pharmacy UMass Memorial Specialty Pharmacy UMass Memorial Medical Center Worcester, Massachusetts Nicholas A Smyrnios, MD, FACP, FCCP Professor of Medicine Associate Chief of Pulmonary, Allergy and Critical Care Medicine University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Haley Snadecki, MD Dermatology Resident Division of Dermatology University of Massachusetts Medical School Worcester, Massachusetts Rahul N Sood, MD Division of Pulmonary and Critical Care Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts Andres F Sosa, MD Pulmonary and Critical Care Associate Physician Department of Medicine Baptist Hospital of Miami South Florida Pulmonary and Critical Care Miami, Florida Judith A Stebulis, MD Assistant Professor of Medicine Department of Medicine and Rheumatology University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Mary Kathryn Steiner, MD Instructor, Harvard Medical School Pulmonary and Critical Care Attending Division of Pulmonary, Critical Care Department of Medicine Deaconess Medical New England Baptist Hospital Boston, Massachusetts Jay S Steingrub, MD, FACP, FCCP Director, Medical Intensive Care Unit Vice-chair of Research, Department of Medicine Baystate Medical Center Springfield, Massachusetts Professor of Medicine Tufts University School of Medicine Boston, Massachusetts Theodore A Stern, MD Chief, Avery D Weisman Psychiatry Consultation Service, Massachusetts General Hospital Director, Office for Clinical Careers, Massachusetts General Hospital Ned H Cassem Professor of Psychiatry in the Field of Psychosomatic Medicine/Consultation Department of Psychiatry Harvard Medical School Massachusetts General Hospital Boston, Massachusetts Garrick C Stewart, MD Associate Physician Department of Cardiovascular Medicine Brigham and Women’s Hospital Boston, Massachusetts Glenn Stokken, MD Cardiology Fellow Department of Cardiology University of Massachusetts Medical School Worcester, Massachusetts Michael B Streiff, MD, FACP Associate Professor of Medicine and Pathology Division of Hematology Department of Medicine Johns Hopkins University School of Medicine Baltimore, Maryland Shusen Sun, PharmD Clinical Assistant Professor Department of Pharmacy Practice Western New England University College of Pharmacy Springfield, Massachusetts Banu Sundar, MD Assistant Professor Department of Neurology UMass Memorial Medical Center Worcester, Massachusetts Arvind K Sundaram, MD Associate Department of Critical Care Medicine and Pulmonary Geisinger Commonwealth School of Medicine Danville, Pennsylvania Colin T Swales, MD Medical Director Transplant Hepatology Hartford Hospital Hartford, Connecticut Joan M Swearer, PhD, ABPP Professor of Clinical Neurology and Psychology Department of Neurology University of Massachusetts Medical School Worcester, Massachusetts Milton Tenenbein, MD, FRCPC, FAAP, FACCT, FACMT Professor of Pediatrics and Child Health and Community Health Sciences University of Manitoba Children’s Hospital Winnipeg, Manitoba, Canada Jeffrey J Teuteberg, MD Medical Director Advanced Heart Failure Department of Heart and Vascular Institute University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Jerry D Thomas, MD Assistant Professor Emergency Medicine Medical Toxicologist Emory University Hospital Midtown Atlanta, Georgia John A Thompson, MD Fred Hutchinson Cancer Research Center Seattle, Washington Michael J Thompson, MD Clinical Research Chief, Adult Diabetes Physician Unit Chief Clinical Professor University of Massachusetts Medical School Worcester, Massachusetts Robert M Tighe, MD Assistant Professor of Medicine Department of Medicine Division of Pulmonary, Allergy and Critical Care Duke University Medical Center Durham, North Carolina Colleen Timlin, PharmD, BCOP Clinical Pharmacy Specialist, Hematology/Oncology Department of Pharmacy—Ground Rhoads Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Mira Sofia Torres, MD Associate Professor and Fellowship Program Director Department of Medicine Division of Endocrinology University of Massachusetts Medical School Worcester, Massachusetts Ulises Torres, MD Assistant Professor of Surgery Chief Quality Officer Department of Surgery Associate Program Director, General Surgery Residency Program Director, Trauma Education and Outreach UMass Memorial Medical Center Worcester, Massachusetts Matthew J Trainor, MD Assistant Professor of Medicine Medical Director, University Dialysis Services University of Massachusetts Medical School Division of Renal Medicine UMass Memorial Medical Center Worcester, Massachusetts Christoph Troppmann, MD Professor of Surgery Department of Surgery University of California, Davis School of Medicine Sacramento, California Craigan T Usher, MD Associate Professor Department of Psychiatry Oregon Health & Science University Portland, Oregon Vaibhav R Vaidya, MD Instructor in Medicine Department of Cardiovascular Diseases Mayo Clinic Rochester, Minnesota John-Paul B Velasco, MD Vascular and Interventional Radiology Department of Radiology University of Massachusetts Medical School Worcester, Massachusetts Vivek Venugopal, MD Orthopedic Surgery Resident Baylor College of Medicine Houston, Texas Charles G Volk, MD Fellow Department of Pulmonary Naval Medical Center San Diego, California Javier C Waksman, MD Associate Clinical Professor Medicine-Clinical Pharmacology/Toxicology Director Medical Toxicology Practice University of Colorado Aurora, Colorado J Matthias Walz, MD, FCCP Academic Vice Chair Department of Anesthesiology and Perioperative Medicine UMass Memorial Medical Center Worcester, Massachusetts Richard Y Wang, DO Senior Medical Officer National Center for Environmental Health Centers for Disease Control and Prevention Atlanta, Georgia Wahid Y Wassef, MD Director of Endoscopy Professor of Medicine Department of Medicine UMass Memorial Medical Center Worcester, Massachusetts Paul M Wax, MD, FACMT Clinical Professor of Emergency Medicine (Medical Toxicology) UT Southwestern Medical School Executive Director, American College of Medical Toxicology Dallas, Texas Randy Wax, MD, MEd, FRCPC Section Chief/Assistant Professor Lakeridge Health/Queen’s University Department of Critical Care Medicine Hospital Court Oshawa, Ontario, Canada John P Weaver, MD Associate Professor of Neurosurgery Department of Neurosurgery University of Massachusetts Medical School Worcester, Massachusetts Michael D Weiden, MS, MD Associate Professor of Medicine and Environmental Medicine New York University School of Medicine New York, New York Mark Weir, MB, ChB, MRCP Assistant Professor Department of Thoracic Medicine and Surgery Lewis Katz School of Medicine Philadelphia, Pennsylvania Vaughn E Whittaker, MD, FACS Assistant Professor of Surgery Department of Surgery Upstate Medical University Syracuse, New York Matthew J Wieduwilt, MD, PhD Assistant Clinical Professor of Medicine Department of Medicine Division of Blood and Marrow Transplantation UC San Diego, Moores Cancer Center La Jolla, California Martin N Wijkstrom, MD Assistant Professor of Surgery Department of Surgery/Transplant Division University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Mark M Wilson, MD Associate Professor of Medicine Associate Director Medical Intensive Care Units Department of Medicine University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts John J Wixted, MD Assistant Professor of Clinical Orthopedics Department of Orthopedic Surgery Beth Israel Deaconess Medical Center Boston, Massachusetts Krysta S Wolfe, MD Fellow Department of Pulmonary and Critical Care Medicine University of Chicago Medicine Chicago, Illinois Ann E Woolfrey, MD Member, Fred Hutchinson Cancer Research Center Seattle, Washington Peggy Wu, MD Assistant Professor Department of Rheumatology UMass Memorial Medical Center Worcester, Massachusetts Omar Z Yasin, MD, MS Internal Medicine Resident Division of Cardiovascular Medicine Department of Internal Medicine Mayo Clinic Rochester, Minnesota Shan Yin, MD, MPH Assistant Professor of Pediatrics Cincinnati Children’s Hospital Drug and Poison Information Center Cincinnati, Ohio Luke Yip, MD Department of Medicine Section of Medical Toxicology Denver Health Rocky Mountain Poison and Drug Center Denver, Colorado Hanbing Zhou, MD Department of Orthopaedics and Rehabilitation UMass Memorial Medical Center Worcester, Massachusetts Marya D Zilberberg, MD, MPH, FCCP Founder, President and CEO of EviMed Research Group, LLC Adjunct Associate Professor The School of Public Health and Health Sciences at the University of Massachusetts—Amherst Senior Fellow Jefferson School of Population Health Thomas Jefferson University Philadelphia University of Massachusetts Amherst Amherst, Massachusetts Iva Zivna, MD Assistant Professor Division of Infectious Diseases UMass Memorial Medical Center Worcester, Massachusetts Marc S Zumberg, MD Professor of Medicine Section Chief, Benign Hematology Department of Medicine University of Florida Gainesville, Florida Section Editors Neil Aronin, MD Chief, Division of Endocrinology Professor, University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Steven B Bird, MD Professor Department of Emergency Medicine University of Massachusetts Medical School Worcester, Massachusetts Mitchell Cahan, MD, MBA, FACS Associate Professor of Surgery Director of Acute Care Surgery University of Massachusetts Medical School Worcester, Massachusetts Akshay S Desai, MD, MPH Associate Physician, Advanced Heart Disease Section Cardiovascular Division, Brigham and Women’s Hospital Instructor in Medicine, Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts David A Drachman, MD (deceased) Professor of Neurology Chairman Emeritus Department of Neurology University of Massachusetts Medical School Worcester, Massachusetts Timothy A Emhoff, MD, FACS Chief Trauma and Surgical Critical Care Department of Surgery UMass Memorial Medical Center Worcester, Massachusetts Pang-Yen Fan, MD Professor of Medicine Department of Medicine University of Massachusetts Medical School Worcester, Massachusetts Robert W Finberg, MD Richard M Haidack Professor Medicine Professor, Microbiology & Physiological Systems Chair, Department of Medicine University of Massachusetts Medical School UMass Memorial Medical Center Worcester, Massachusetts Patrick F Fogarty, MD Rare Disease, Global Product Development/ Medical Affairs Pfizer, Inc Collegeville, Pennsylvania Joseph J Frassica, MD Head, Phillips Research the Americas Chief Medical Officer, Phillips North America Professor, The Practice Institute for Medical Engineering and Science Massachusetts Institute of Technology Senior Consultant, Pediatric Critical Care Massachusetts General Hospital for Children Boston, Massachusetts Neil A Halpern, MD, MCCM, FACP, FCCP Professor of Clinical Medicine Professor of Medicine in Clinical Anesthesiology Weill Cornell Medical College Director, Critical Care Center Chief, Critical Care Medicine Service Department of Anesthesiology and Critical Care Medicine Memorial Sloan Kettering Cancer Center New York, New York David M Harlan, MD William and Doris Krupp Professor of Medicine Co-Director, Diabetes Center of Excellence Department of Internal Medicine Division of Diabetes UMass Memorial Medical Center Worcester, Massachusetts Kennon Heard, MD Professor of Emergency Medicine Department of Emergency Medicine University of Colorado School of Medicine Aurora, Colorado Stephen O Heard, MD Professor of Anesthesiology and Surgery Department of Anesthesiology and Perioperative Medicine UMass Memorial Medical Center University of Massachusetts Medical School Worcester, Massachusetts Richard S Irwin, MD, Master FCCP Professor of Medicine and Nursing University of Massachusetts Medical School Chair, Critical Care Operations UMass Memorial Medical Center Worcester, Massachusetts Stephanie M Levine, MD Professor of Medicine Department of Medicine Division of Pulmonary Diseases and Critical Care University of Texas Health Center, San Antonio San Antonio, Texas Nancy Y N Liu, MD Clinical Associate Professor University of Massachusetts Medical School UMass Memorial Medical Center-Memorial Campus Worcester, Massachusetts J Mark Madison, MD Professor of Medicine and Microbiology and Physiological Systems Chief, Division of Pulmonary, Allergy and Critical Care Medicine Department of Medicine UMass Memorial Medical Center University of Massachusetts Medical School Worcester, Massachusetts Lawrence C Mohr, Jr, MD, ScD, FACP, FCCP Professor of Medicine, Biometry and Epidemiology Director, Environmental Biosciences Program Medical University of South Carolina Charleston, South Carolina David A Morrow, MD, MPH Professor of Medicine Harvard Medical School Directory, Levine Cardiac Intensive Care Unit Division of Cardiovascular Brigham and Women’s Hospital Boston, Massachusetts Dominic J Nompleggi, MD Chief, Gastroenterology Associate Professor University of Massachusetts Medical School Worcester, Massachusetts Patrick T O’Gara, MD Watkins Family Distinguished Chair in Cardiology Division of Cardiovascular Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts David Paydarfar, MD Professor, Chair of Neurology Interim Co-Director Mulva Clinic for the Neurosciences General Neurology Dell Medical School at The University of Texas Austin, Texas John Querques, MD Chief, Inpatient Services Department of Pyschology Tufts Medical Center Boston, Massachusetts Jennifer E Reidy, MD, MS, FAAHPM Co-Chief, Division of Palliative Care Department of Medicine and Family Medicine UMass Memorial Medical Center Assistant Professor University of Massachusetts Medical School Worcester, Massachusetts James M Rippe, MD Founder and Director Rippe Lifestyle Institute Shrewsbury, Massachusetts Todd W Sarge, MD Director, Critical Care Department of Anesthesia, Critical Care and Pain Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts Luke Yip, MD Denver HealthRocky Mountain Poison and Drug Center Department of Medicine, Section of Medical Toxicology Denver, Colorado Preface It is with great pleasure that we present the eighth edition of Irwin and Rippe’s Intensive Care Medicine As with previous editions, the editorial challenge that we faced with this edition was to continue to ensure that the book remained at the cutting edge, evolving as the field has evolved It also needed to continue to meet the varied and rigorous demands placed on it by the diverse group of specialty physicians and nonphysicians practicing in the adult intensive care environment without losing strengths that have made previous editions very useful and popular We believe that the eighth edition of Irwin and Rippe’s Intensive Care Medicine has met these challenges Over the past 32 years since the publication of the first edition of our book in 1985, dramatic changes have occurred in virtually every area of critical care, and these are reflected in the evolution of our book Although our book initially focused primarily on medical intensive care medicine, it now provides an interprofessional emphasis on anesthesia, surgery, trauma, neuro and cardiovascular, as well as medical intensive care, with strong collaboration across all these disciplines This reflects the reality that intensive care medicine has inevitably become more interprofessional and collaborative The eighth edition is approximately the same length as the previous edition To update the text without expanding it, every section editor and author rose to the challenge and carefully balanced each chapter, emphasizing new evidence-based as well as state-of-the-art information and discarding outdated material We take great pride in the quality of the section editors and chapter authors who have contributed to our eighth edition All chapters in every section have been updated with recent references and other materials that reflect current information, techniques, and principles New chapters have been added to reflect emerging areas of interest An entirely new section has been added on “Palliative Care and Ethical Issues in the Critical Care Unit” that was ably edited by Jennifer E Reidy Since publication of our last edition, point-of-care ultrasonography has become an important and arguably indispensable part of the bedside intensivist’s tool kit As such, its use is prominently featured in this edition To reflect the rising importance of this diagnostic and therapeutic tool to the practice of modern intensive care medicine, a total of five hours video materials have been embedded into 23 chapters to aid and educate intensivists on the use of this tool Each video has been personally selected, edited, and narrated by one of our senior editors, Paul H Mayo, who is internationally known for his knowledge and expertise in ultrasonography Evidence-based medicine continues to play an ever-more prominent role in all branches of medicine including critical care With this in mind, we have asked every chapter author, as in previous editions, to make recommendations that specifically reflect recent trials with a particular emphasis on prospective, randomized controlled trials Authors have summarized such evidence when the data have allowed, with helpful tables In intensive care medicine, important changes and advances have occurred since the publication of the seventh edition These include managing our ICUs according to the following guiding principles: (1) making our ICUs safer for our patients; (2) decreasing variability by following clinical practice guidelines based on the best available evidence to ensure better outcomes for our patients; and (3) doing more with less by choosing wisely to decrease the cost of caring for our patients Although these principles have always been espoused, it has become clear that we must more consistently follow them The appropriate uses of not only the electronic medical records, computer physician order entry, and clinical decision support tools, but also tele-ICU can help us operationalize these principles All of these issues are covered in the section entitled “ICU Design, Organization, Operation, and Outcome Measures” edited by Neil A Halpern With respect to managing cardiovascular problems and providing coronary care, it has been interesting to see how cardiovascular intensive care has dramatically changed since the publication of our first few editions as the advances in cardiology and cardiac surgery have become implemented With respect to these problems, co-section editors Akshay S Desai, David A Morrow, and Patrick T O’Gara have completely revamped their section to reflect the current state of their discipline Equally important advances have occurred in surgical critical care, shock, and trauma, including new therapies and techniques in a variety of conditions treated in this environment These sections remain strengths of this book We welcome new section editors, Mitchell Cahan for “Surgical Problems in the Intensive Care Unit” and Timothy A Emhoff for “Shock, Trauma, and Sepsis Management.” Both have done masterful jobs updating these sections Although our book has been updated and broadened to include new understandings, information, and techniques, our goal has been to maintain the practical, clinically oriented approach that readers have come to expect from previous editions Our editorial focus remains on clinically relevant studies and information that readers have found very useful in the previous seven editions As in the past, our book opens with a detailed section on commonly performed procedures, techniques, and ultrasound in the intensive care unit, followed by a section covering minimally invasive monitoring All chapters in these sections have been updated with new figures and descriptions of techniques that have been added to reflect changes since the seventh edition of the book We are indebted to section editors Stephen O Heard and Todd W Sarge, who have done a superb job on these sections The Pharmacology, Overdoses, and Poisoning section, consisting of 30 chapters, remains a great strength of this book and essentially represents a textbook on the topics embedded into our larger book For their tireless efforts on this outstanding and comprehensive section, we thank Luke Yip, Kennon Heard, and Steven B Bird Our team of section editors continues to do a wonderful job coordinating large bodies of information that comprise the core of modern intensive care Many of our section editors have been with us for one or more editions Robert W Finberg (Infectious Disease), Neil Aronin and David M Harlan (Endocrinology), Stephanie M Levine (Transplantation), Dominic J Nompleggi (Gastroenterology and Metabolism/Nutrition), J Mark Madison (Pulmonary), John Querques (Psychiatry), Nancy Y N Liu (Rheumatology), Pang-Yen Fan (Renal), Patrick F Fogarty (Hematology and Oncology), Lawrence C Mohr Jr (Critical Care Consequences of Weapons [or Agents] of Mass Destruction), David A Drachman and David Paydarfar (Neurology), and Joseph J Frassica (Appendix, Calculations Commonly used in Critical Care) all fall into this category and have again made outstanding contributions As with previous editions, our emphasis remains on clinical management Discussions of basic pathophysiology are also included and guided and supplemented by extensive references to help clinicians and researchers who wish to pursue more in-depth knowledge of these important areas When therapies reflect institutional or individual bias or are considered controversial, we have attempted to indicate this We hope and believe that the outstanding efforts of many people over the past 5 years have continued to result in an evidence-based and stateof-the-art and comprehensive book that will elucidate the important principles in intensive care and will continue to guide and support the best efforts of practitioners in this challenging environment in their ongoing efforts to diagnose and treat complicated diseases and relieve human suffering RICHARD S IRWIN, MD, MASTER FCCP CRAIG M LILLY, MD, FCCP PAUL H MAYO, MD, FCCP JAMES M RIPPE, MD Acknowledgments Numerous outstanding individuals have made significant contributions to all phases of writing and production of this book and deserve special recognition and thanks First and foremost is our managing editor, Elizabeth Grady Beth literally lives and breathes this book as it works its way through the production cycle every 4 to 5 years She is the guiding and organizing force behind this book It would simply not be possible without Beth’s incredible organizational skills, good humor, and enormous energy She has guided this book through eight editions—this book is as much hers as it is ours The major innovation of this edition is the focus on point-of-care ultrasonography Assisting Paul H Mayo with the task of developing the high-quality ultrasound videos was Yonathan Greenstein, while assisting in preparation of the utility of ultrasonography sections were Gisela Banauch, Ariel Shiloh, and Lewis Eisen For their outstanding work, we owe them a large debt of gratitude Our administrative assistants, office assistants, and clinical coordinators, Sherry Jakubiak and Cynthia French, Linda Doherty, Debra Adamonis, and Carol Moreau have helped us continue to coordinate and manage our complex professional and personal lives and create room for the substantial amount of time required to write and edit Our section editors have devoted enormous skill, time, and resources to every editions of this book We have very much appreciated their deep commitment to this book and to advancing the field of intensive care medicine Our editors at Lippincott Williams & Wilkins including Brian Brown, Executive Editor, have been a source of great help and encouragement As with the last edition, Nicole Dernoski continues to be extremely helpful and accommodating in supervising and coordinating all phases of production in an outstanding way Lauren Pecarich handled the day-today details necessary with a book of this size Last, we are grateful to Samson Premkumar and his staff for the outstanding job they have done copyediting the manuscript for this edition It is with great sadness that we report that David A Drachman passed away before the publication of the edition of this book David was a good friend and wonderful colleague who had been the neurology section editor or co-editor on every one of the eight editions of Intensive Care Medicine He will be greatly missed Our families support our efforts with unfailing encouragement and love To them, and the many others who have helped in ways too numerous to count, we are deeply grateful RICHARD S IRWIN, MD, MASTER FCCP CRAIG M LILLY, MD, FCCP PAUL H MAYO, MD, FCCP JAMES M RIPPE, MD Contents Contributors List Section Editors Preface Acknowledgments Section 1 PROCEDURES, TECHNIQUES AND ULTRASONOGRAPHY Chapter 1  Point-of-Care Critical Care Ultrasonography Paul H Mayo Chapter 2  Anesthesia for Bedside Procedures Mark Dershwitz Chapter 3  Management of Pain in the Critically Ill Mario De Pinto, Armagan Dagal, and Ramana K Naidu Chapter 4  Therapeutic Paralysis Khaldoun Faris Chapter 5  Cerebrospinal Fluid Aspiration Firas Kaddouh, Susanne Muehlschlegel, and John P Weaver Chapter 6  Central Venous Catheters Andrew H Moraco and Scott E Kopec Chapter 7  Arterial Line Placement and Care Carlos Martinez-Balzano and Scott E Kopec Chapter 8  Airway Management and Endotracheal Intubation J Matthias Walz and Stephen O Heard Chapter 9  Tracheostomy Christine L Bielick, Scott E Kopec, and Timothy A Emhoff Chapter 10 Bronchoscopy Paulo J Oliveira, Rahul N Sood, and Richard S Irwin Chapter 11 Lung Ultrasonography Pierre Kory, Navitha Ramesh, and Paul H Mayo Chapter 12 Thoracentesis Mark M Wilson and Richard S Irwin Chapter 13 Chest Tube Insertion and Care Ulises Torres and Joshua R Scurlock Chapter 14 Cardiopulmonary Resuscitation Bruce Greenberg and Abduljabbar Dheyab Chapter 15 Cardioversion and Defibrillation Glenn Stokken, Mark S Link, and Naomi F Botkin Chapter 16 Critical Care Echocardiography Brian Buchanan, Robert Arntfield, and Paul H Mayo Chapter 17 Pericardiocentesis Peeyush Grover and Craig S Smith Chapter 18 Temporary Cardiac Pacing Brendan Merchant and Seth T Dahlberg Chapter 19 Pulmonary Artery Catheters Harvey S Reich Chapter 20 Gastrointestinal Endoscopy Samuel Y Han, Randall Pellish, David R Cave, and Wahid Y Wassef Chapter 21 Endoscopic Placement of Feeding Tubes Lena M Napolitano Chapter 22 Gastroesophageal Balloon Tamponade for Acute Variceal Hemorrhage Marie T Pavini and Juan Carlos Puyana Chapter 23 Paracentesis and Diagnostic Peritoneal Lavage Lena M Napolitano Chapter 24 Interventional Radiology: Percutaneous Drainage Techniques John-Paul B Velasco, Brian T Callahan, and Robert Sheiman Chapter 25 Percutaneous Suprapubic Cystostomy Philip J Ayvazian Chapter 26 Aspiration of the Knee and Synovial Fluid Analysis Padmanaidu Karnam, Bonnie J Bidinger, and Deborah M DeMarco Section 2 MINIMALLY INVASIVE MONITORING Chapter 27 Routine Monitoring of Critically Ill Patients Krysta S Wolfe and Michael D Howell Chapter 28 Minimally Invasive Hemodynamic Monitoring Brian S Furukawa, Ednan K Bajwa, Atul Malhotra, and Andrew J Goodwin Chapter 29 Echocardiography as a Monitor in the ICU Achikam Oren-Grinberg, Todd W Sarge, and Adam B Lerner Chapter 30 Respiratory Monitoring during Mechanical Ventilation Melanie R Loberman, Ray H Ritz, and Todd W Sarge Chapter 31 Neurologic Multimodal Monitoring Raphael A Carandang and Wiley R Hall Chapter 32 Telemedicine and Critical Care Delivery Lloyd C Meeks, Shahzad Shaefi, and Craig M Lilly Section 3 PALLIATIVE CARE AND ETHICAL ISSUES IN THE CRITICAL CARE UNIT Chapter 33 Integrating Palliative Care in the Intensive Care Unit Nandita R Nadig, Dana Lustbader, and Dee W Ford Chapter 34 Effective Communication and Ethical Decision-Making in the ICU Daniel E Ray, Jennifer E Allen, and Karen M Knops Chapter 35 Managing Symptoms in Critically Ill Patients Richard Castriotta, Jennifer E Reidy, Javier Barreda Garcia, Garbo Mak, and Brandy McKelvy Chapter 36 Being with Suffering: Addressing Existential and Spiritual Distress Margaret Isaac, Suzana K E Makowski, and Christina Fitch Section 4 SHOCK AND TRAUMA AND SEPSIS MANAGEMENT Chapter 37 Resuscitation from Shock Following Hemorrhage Jacob A Quick, Donald H Jenkins, John B Holcomb, and Stephen L Barnes Chapter 38 Trauma Systems Daniel Hetherman and Timothy A Emhoff Chapter 39 The Management of Sepsis Paul E Marik Chapter 40 Multiple Organ Dysfunction Syndrome Timothy A Pritts and Andrew C Bernard Chapter 41 Traumatic Brain Injury Wiley R Hall and Raphael A Carandang Chapter 42 Spinal Cord Trauma Hanbing Zhou and Christian P DiPaola Chapter 43 Thoracic and Cardiac Trauma Bruce J Simon, Scott B Johnson, and John G Myers Chapter 44 Critical Care of the Patient with Abdominal Trauma Jon D Dorfman Chapter 45 Orthopedic Injury Gregory J Della Rocca, Sean E Nork, Vivek Venugopal, and John J Wixted Chapter 46 Burn Management Sean Figy and Joyce K McIntyre Section 5 SURGICAL PROBLEMS IN THE INTENSIVE CARE UNIT Chapter 47 Surgeon and Intensivist Collaboration in the Care of the ICU Patient Gustavo Guillermo Angaramo and Craig M Lilly Chapter 48 Surgical Infections in the Intensive Care Unit Ann-Kristin U Friedrich and Mitchell Cahan Chapter 49 Care of the Patient with Necrotizing Fasciitis Brandon Colvin, Benkole Samuel, and Hongyi Cui Chapter 50 The ICU Management of Patients Undergoing Major Surgery for Gastrointestinal Cancers Kate H Dinh and Jennifer LaFemina Chapter 51 The ICU Approach to the Acute Abdomen James E Carroll, Jr Chapter 52 Abdominal Compartment Syndrome Jon D Dorfman Chapter 53 Management of the Obstetrical Patient in the Intensive Care Setting Anne Garrison Chapter 54 Acute Limb Ischemia in the ICU Population Dejah R Judelson, Bing Shue, and William P Robinson, III Chapter 55 Palliative Surgery in the Intensive Care Unit Laura A Lambert Section 6 TRANSPLANTATION Chapter 56 Management of the Organ Donor Christoph Troppmann Chapter 57 Critical Care Problems in Kidney Recipients Abbas A Rana and Rainer W G Gruessner Chapter 58 Critical Care of Liver Transplant Recipients and Live Liver Donors Babak Movahedi, Paulo Martins, Sonia Nagy Chimienti, and Adel Bozorgzadeh Chapter 59 Critical Care of the Lung Transplant Recipient Luis F Angel and Stephanie M Levine Chapter 60 Specific Critical Care Problems in Heart and Heart–Lung Transplant Recipients Andrew W Shaffer, Karol Mudy, and Sara J Shumway Chapter 61 Care of the Pancreas Transplant Recipient Colleen L Jay, Gregory A Abrahamian, and Angelina Edwards Chapter 62 Critical Care of Intestinal Transplant Recipients Robert M Esterl, Jr, William D Payne, Abhinav Humar, and Ruy J Cruz, Jr Chapter 63 Immunosuppression in Solid-Organ Transplantation Martin N Wijkstrom, Sundaram Hariharan, and Abhinav Humar Chapter 64 Hematopoietic Cell Transplantation Ann E Woolfrey, Marco Mielcarek, and Paul A Carpenter Chapter 65 Management of Graft-versus-Host Disease, Infection, Malignancy, and Rejection in Transplant Recipients Vaughn E Whittaker, Abbas A Rana, David L Dunn, and Rainer W G Gruessner Section 7 RHEUMATOLOGIC, IMMUNOLOGIC, AND DERMATOLOGIC DISEASES IN THE INTENSIVE CARE UNIT Chapter 66 Rheumatologic Diseases in the Intensive Care Unit Nancy Y N Liu and Judith A Stebulis Chapter 67 Vasculitis in the Intensive Care Unit Paul F Dellaripa and Donough Howard Chapter 68 Therapeutics for Immune-Mediated Rheumatic Diseases Peggy Wu Chapter 69 Anaphylaxis Frederic F Little and Helen M Hollingsworth Chapter 70 Dermatology in the Intensive Care Unit Julia Baltz, Kristen Berrebi, Dori Goldberg, Mary E Maloney, and Haley Snadecki Section 8 INFECTIOUS DISEASE PROBLEMS IN THE INTENSIVE CARE UNIT Chapter 71 Approach to Fever in the ICU Patient Raul E Davaro and Richard H Glew Chapter 72 Prevention and Control of HealthcareAcquired Infections in the Intensive Care Unit Sumanth Gandra and Richard T Ellison, III Chapter 73 Use of Antimicrobials in the Treatment of Infection in the Critically Ill Patient Iva Zivna, Richard H Glew, and Jennifer S Daly Chapter 74 Life-Threatening Community-Acquired Infections: Toxic Shock Syndrome, Meningococcemia, Overwhelming Postsplenectomy Infection, Malaria, Rocky Mountain Spotted Fever, and Others Misha Huang and Mary T Bessesen Chapter 75 Acute Infection in the Immunocompromised Host Jennifer S Daly and Robert W Finberg Chapter 76 Intensive Care of Patients with HIV Infection Thomas C Greenough, Sarah H Cheeseman, and Mark J Rosen Chapter 77 Infectious Complications of Drug Abuse Afroza Liton and William L Marshall Chapter 78 Infective Endocarditis and Infections of Intracardiac Prosthetic Devices Sarah H Cheeseman, Karen C Carroll, and Sara E Cosgrove Chapter 79 Infections Associated with Vascular Catheters Payal K Patel, Suzanne F Bradley, and Carol A Kauffman Chapter 80 Urinary Tract Infections Steven M Opal Chapter 81 Central Nervous System Infections Heidi L Smith Chapter 82 Tuberculosis Michelle K Haas and Robert W Belknap Chapter 83 Serious Epidemic Viral Pneumonias Daniel H Libraty Chapter 84 Middle East Respiratory Syndrome (MERS) Coronavirus Christopher M Coleman and Matthew B Frieman Chapter 85 Critical Care of Patients Infected with Ebola Virus Steven Hatch Chapter 86 Botulism David M Bebinger and Richard T Ellison, III Chapter 87 Tetanus Mary Dawn T Co and Richard T Ellison, III Section 9 HEMATOLOGIC AND ONCOLOGIC PROBLEMS IN THE INTENSIVE CARE UNIT Chapter 88 Disorders of Hemostasis in Critically Ill Patients Alice D Ma Chapter 89 Transfusion Therapy: Blood Components and Transfusion Complications Terry Gernsheimer Chapter 90 Anemia in the Critical Care Setting Marc S Zumberg, Marc J Kahn, and Alice D Ma Chapter 91 Thrombocytopenia Thomas G Deloughery Chapter 92 Venous Thromboembolism and Associated Prothrombotic Disorders in the Intensive Care Unit Eric S Christenson, Sheetal Karne, Ashkan Emadi, and Michael B Streiff Chapter 93 Antithrombotic Pharmacotherapy Kevin E Anger, Christopher D Adams, Bonnie C Greenwood, Jeremy R Degrado, and John Fanikos Chapter 94 Critical Care of Patients with Hematologic Malignancies Matthew J Wieduwilt and Lloyd E Damon Chapter 95 Oncologic Emergencies Eunpi Cho, Bruce Montgomery, Colleen Timlin, John A Thompson, and Damian J Green Chapter 96 Therapeutic Apheresis: Technical Considerations and Indications in Critical Care Laura S Connelly-Smith and Theresa A Nester Section 10 PHARMACOLOGY, OVERDOSES, AND POISONINGS Chapter 97 General Considerations in the Evaluation and Treatment of Poisoning Ian M Ball Chapter 98 Acetaminophen Poisoning Steven B Bird Chapter 99 Alcohols and Glycol Poisoning Jennifer L Englund, Marco L A Sivilotti, and Marsha D Ford Chapter 100 Amphetamines Michael C Beuhler Chapter 101 Antiarrhythmic Agents Steven B Bird Chapter 102 Anticholinergic Poisoning Keith K Burkhart Chapter 103 Anticonvulsant Poisoning Steven B Bird Chapter 104 Antidepressant Poisoning Andrew M King, Luke Bisoski, and Cynthia K Aaron Chapter 105 Antipsychotic Poisoning Steven B Bird Chapter 106 Beta-Blocker Poisoning Shan Yin and Javier C Waksman Chapter 107 Calcium Channel Antagonist Poisoning Christopher R Dewitt Chapter 108 Cardiac Glycoside Poisoning Bryan S Judge and Mark A Kirk Chapter 109 Cholinergic Poisoning Cynthia K Aaron and Andrew M King Chapter 110 Cocaine Poisoning Richard D Shih, Stacey Feinstein, and Judd E Hollander Chapter 111 Corrosives Poisoning Robert P Dowsett and Kennon Heard Chapter 112 Heavy Metal Poisoning Luke Yip Chapter 113 Hydrocarbon Poisoning William J Lewander and Alfred Aleguas, Jr Chapter 114 Hydrofluoric Acid Poisoning Kennon Heard Chapter 115 Iron Poisoning Milton Tenenbein Chapter 116 Isoniazid Poisoning James B Mowry and R Brent Furbee Chapter 117 Lithium Poisoning Thanjira Jiranantakan and Kent R Olson Chapter 118 Methylxanthine Poisoning Janetta L Iwanicki Chapter 119 Opioid Poisoning Luke Yip and Robert P Dowsett Chapter 120 Pesticide—Herbicide Poisoning William K Chiang and Richard Y Wang Chapter 121 Phencyclidine and Hallucinogen Poisoning Jennie A Buchanan and Luke Yip Chapter 122 Salicylate and Other Nonsteroidal Antiinflammatory Drug Poisoning Marco L A Sivilotti and Christopher H Linden Chapter 123 Sedative-Hypnotic Agent Poisoning Andis Graudins and Dino Druda Chapter 124 Terrestrial Envenomations Robert Lee Norris Chapter 125 Therapeutic Agents for Overdoses and Poisonings Luke Yip, Susan E Gorman, Jerry D Thomas, and Ian M Ball Chapter 126 Withdrawal Syndromes Paul M Wax and Ashley Haynes Section 11 CRITICAL CARE CONSEQUNECES OF WEAPONS (OR AGENTS) OF MASS DESTRUCTION Chapter 127 Planning and Organization for Emergency Mass Critical Care Ryan C Maves, Mary A King, Lawrence C Mohr, Jr, and James Geiling Chapter 128 Chemical Agents of Mass Destruction James Geiling, Randy Wax, and Lawrence C Mohr, Jr Chapter 129 The Management of Acute Radiation Casualties Arvind K Sundaram, Mary Jane Reed, John Scott Parrish, James Geiling, and Lawrence C Mohr, Jr Chapter 130 Critical Care Consequences of Weapons (or Agents) of Mass Destruction— Biological Agents of Mass Destruction Ryan C Maves, Konrad L Davis, Charles G Volk, and Asha V Devereaux Section 12 ICU DESIGN, ORGANIZATION, OPERATION, AND OUTCOME MEASURES Chapter 131 Intensive Care Unit Design: Current Standards and Future Trends Diana C Anderson and Neil A Halpern Chapter 132 Intensive Care Unit Organization and Management Thomas L Higgins and Jay S Steingrub Chapter 133 Critical Care Information Systems: Structure, Function, and Future Joseph J Frassica, Vitaly Herasevich, and Myron Michael Shabot Chapter 134 Defining and Measuring Patient Safety in the Critical Care Unit Hayley B Gershengorn, Steven Y Chang, David E Ost, Kelly L Cervellione, and Alan M Fein Chapter 135 Assessing the Value and Impact of Critical Care in an Era of Limited Resources: Outcomes Research in the ICU Andrew F Shorr, Marya D Zilberberg, and Derek C Angus Section 13 ENDOCRINE PROBLEMS IN THE INTENSIVE CARE UNIT Chapter 136 Management of Hyperglycemia in Critically Ill Patients Michael J Thompson, David M Harlan, Samir Malkani, and John P Mordes Chapter 137 Diabetic Comas: Ketoacidosis and Hyperosmolar Hyperglycemic State Samir Malkani, David M Harlan, Michael J Thompson, and John P Mordes Chapter 138 Hypoglycemia John P Mordes, Michael J Thompson, David M Harlan, and Samir Malkani Chapter 139 Hypoadrenal Crisis and the Stress Management of the Patient on Chronic Steroid Therapy Heather Elias and Neil Aronin Chapter 140 Disorders of Mineral Metabolism Seth M Arum Chapter 141 Severe Hyperthyroidism Marjorie S Safran Chapter 142 Myxedema Coma Mira Sofia Torres and Charles H Emerson Chapter 143 Nonthyroidal Illness Syndrome (Sick Euthyroid Syndrome) in the Intensive Care Unit Shirin Haddady and Alan P Farwell Section 14 NEUROLOGIC PROBLEMS IN THE INTENSIVE CARE UNIT Chapter 144 An Approach to Neurologic Problems in the Intensive Care Unit David A Drachman Chapter 145 Evaluating the Patient with Altered Consciousness in the Intensive Care Unit Raphael A Carandang, Lawrence J Hayward, and David A Drachman Chapter 146 Metabolic Encephalopathy Paula D Ravin, Abdul Mikati, and Susanne Muehlschlegel Chapter 147 Mental Status Dysfunction in the Intensive Care Unit: Postoperative Cognitive Impairment Joan M Swearer and Elizabeth R DeGrush Chapter 148 Generalized Anoxia/Ischemia of the Nervous System Banu Sundar, Carol F Lippa, and Majaz Moonis Chapter 149 Cerebrovascular Diseases Richard P Goddeau, Jr, John P Weaver, and Majaz Moonis Chapter 150 Subarachnoid Hemorrhage Ribal Bassil and Susanne Muehlschlegel Chapter 151 Status Epilepticus Felicia C Chu and Catherine A Phillips Chapter 152 Guillain–Barré Syndrome Isabelita R Bella and David A Chad Chapter 153 Myasthenia Gravis in the Intensive Care Unit Isabelita R Bella and Johnny S Salameh Chapter 154 Newly Acquired Weakness in the Intensive Care Unit: Critical Illness Myopathy and Neuropathy David A Chad Chapter 155 Neuro-oncologic Problems in the Intensive Care Unit Norman Scott Litofsky and Yaw Sarpong Chapter 156 Miscellaneous Neurologic Problems in the Intensive Care Unit Max Mandelbaum and Ann L Mitchell Section 15 PSYCHIATRIC ISSUES IN INTENSIVE CARE Chapter 157 Diagnosis and Treatment of Agitation and Delirium in the Intensive Care Unit Patient Jason P Caplan Chapter 158 Diagnosis and Treatment of Anxiety in the Intensive Care Unit Patient Shelley A Holmer and Robert M Tighe Chapter 159 Diagnosis and Treatment of Depression in the Intensive Care Unit Patient Edith S Geringer, John Querques, Meghan S Kolodziej, and Theodore A Stern Chapter 160 Managing the Suicidal Patient in the Intensive Care Unit Saori A Murakami and Christina Massey Chapter 161 Problematic Behaviors of Patients, Family, and Staff in the Intensive Care Unit Craigan T Usher Chapter 162 Recognition and Management of Staff Stress in the Intensive Care Unit Guy Maytal Section 16 PULMONARY PROBLEMS IN THE INTENSIVE CARE UNIT Chapter 163 Acute Respiratory Failure due to Acute Respiratory Distress Syndrome and Pulmonary Edema Gilman B Allen and Polly E Parsons Chapter 164 Acute Respiratory Failure in Pregnancy Christine Campbell-Reardon and Helen M Hollingsworth Chapter 165 Extrapulmonary Causes of Respiratory Failure Helen M Hollingsworth and Richard S Irwin Chapter 166 Invasive Mechanical Ventilation and Extracorporeal Life Support for Respiratory Failure Rolando Sanchez Sanchez and Gregory A Schmidt Chapter 167 Mechanical Ventilation—Part II: NonInvasive Mechanical Ventilation for the Adult Hospitalized Patient Nicholas S Hill Chapter 168 Discontinuation of Mechanical Ventilation Nicholas A Smyrnios, Richard S Irwin, and Rolf D Hubmayr Chapter 169 Respiratory Adjunct Therapy Scott E Kopec, Ryan G Shipe, and Richard S Irwin Chapter 170 Aspiration Kimberly A Robinson and Richard S Irwin Chapter 171 Drowning Nicholas A Smyrnios and Richard S Irwin Chapter 172 Acute Exacerbation of Asthma J Mark Madison and Richard S Irwin Chapter 173 Critical Care of Acute Exacerbations of COPD Mark Weir and Gerard Criner Chapter 174 Pulmonary Hypertension in the Intensive Care Unit Kimberly A Fisher and Harrison W Farber Chapter 175 Managing Hemoptysis Paulo J Oliveira, Kimberly A Robinson, and Richard S Irwin Chapter 176 Pleural Diseases of the Critically Ill Patient Peter Doelken and John Terrill Huggins Chapter 177 Gas Embolism Syndromes Mark M Wilson Chapter 178 Acute Inhalation Injury Anna Nolan, Michael D Weiden, Lawrence C Mohr, Jr, and David J Prezant Chapter 179 Chest Radiographic Examination Carole A Ridge, Benedikt H Heidinger, Jerry P Balikian, and Diana E Litmanovich Chapter 180 Severe Upper Airway Infections Sumera R Ahmad, Stephen J Krinzman, Sunil Rajan, and Richard S Irwin Chapter 181 Acute Infectious Pneumonia Girish B Nair and Michael S Niederman Chapter 182 Interventional Pulmonary in the Intensive Care Unit Andres F Sosa and Paulo J Oliveira Chapter 183 Sleep Issues in the Intensive Care Unit Setting Biren B Kamdar and Nancy A Collop Chapter 184 Disorders of Temperature Control, Part I: Hypothermia Mary Kathryn Steiner and Richard S Irwin Chapter 185 Disorders of Temperature Control, Part II: Hyperthermia Mary Kathryn Steiner and Richard S Irwin Section 17 CARDIOVASCULAR PROBLEMS AND CORONARY CARE Chapter 186 The Evolution of the Modern Cardiovascular Intensive Care Unit Hannah Bensimhon and Jason N Katz Chapter 187 ST-Segment Elevation Myocardial Infarction Hurst M Hall, David A Morrow, and James A de Lemos Chapter 188 Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction, the Non– ST-Elevation Acute Coronary Syndromes Michael G Silverman and Marc S Sabatine Chapter 189 Management of Common Arrhythmias in Intensive Care Unit Niyada Naksuk, Vaibhav R Vaidya, Omar Z Yasin, and Samuel J Asirvatham Chapter 190 Pharmacologic Management of Cardiogenic Shock and Hypotension Michael M Givertz and James C Fang Chapter 191 Mechanical Complications of Myocardial Infarction Christos Galatas and Annabel A ChenTournoux Chapter 192 Valvular Heart Disease Garrick C Stewart and Patrick T O’Gara Chapter 193 Acute Aortic Syndromes Marc P Bonaca Chapter 194 Management of Acute Decompensated Heart Failure G William Dec Chapter 195 Management of the Cardiac Arrest Survivor Michael G Silverman and Benjamin M Scirica Chapter 196 Management of Cardiac Devices in the ICU Melanie Maytin Chapter 197 Long-Term Mechanical Support for Advanced Heart Failure Jonathan E Holtz and Jeffrey J Teuteberg Section 18 RENAL PROBLEMS IN THE INTENSIVE CARE UNIT Chapter 198 Metabolic Acidosis and Metabolic Alkalosis Robert M Black and Jason M Kurland Chapter 199 Disorders of Plasma Sodium and Plasma Potassium Robert M Black and Gary O Noroian Chapter 200 Acute Kidney Injury in the Intensive Care Unit Konstantin Abramov and Jahan Montague Chapter 201 Renal Replacement Therapy in the Intensive Care Unit Matthew J Trainor, Matthew A Niemi, and Pang-Yen Fan Chapter 202 Drug Dosing in Renal and Hepatic Failure: A Pharmacokinetic Approach to the Critically Ill Patient Brian S Smith, Shusen Sun, Kyle Fraielli, and Reenu Nathan Section 19 GASTROINTESTINAL DISEASE PROBLEMS IN THE INTENSIVE CARE UNIT Chapter 203 Upper and Lower Gastrointestinal Bleeding Michael C Bennett and C Prakash Gyawali Chapter 204 Stress Ulcer Disease Benjamin E Cassell and C Prakash Gyawali Chapter 205 Gastrointestinal Motility for the Critically Ill Patient Filippo Cremonini and Anthony J Lembo Chapter 206 Hepatic Dysfunction Avegail G Flores, Rajeev Ramgopal, and Mauricio Lisker-Melman Chapter 207 Evaluation and Management of Liver Failure Avegail G Flores, Britney M Ramgopal, and Mauricio Lisker-Melman Chapter 208 Severe and Complicated Biliary Tract Disease Tarek Abou Hamdan and Riad Azar Chapter 209 Acute Pancreatitis Krunal Patel and Wahid Y Wassef Chapter 210 Diarrhea Julien Fahed, Benjamin Hyatt, Colin T Swales, and Laura Harrell Raffals Chapter 211 Fulminant Colitis and Toxic Megacolon Emanuelle A Bellaguarda and Stephen B Hanauer Section 20 METABOLISM/NUTRITION Chapter 212 Nutritional Therapy in the Critically Ill Patient Dominic J Nompleggi Chapter 213 Parenteral and Enteral Nutrition in the Intensive Care Unit David F Driscoll and Bruce R Bistrian Chapter 214 Disease-Specific Nutrition Diana Wells Mulherin, Alexis P Calloway, Gay Graves, and Douglas L Seidner Appendix Index Section 1 PROCEDURES, TECHNIQUES AND ULTRASONOGRAPHY STEPHEN O HEARD Chapter 1 Point-of-Care Critical Care Ultrasonography PAUL H MAYO Critical care ultrasonography encompasses any application of ultrasonography that can be productively employed by the intensivist at the bedside for the diagnosis and management of the patient In recognition of the importance of ultrasonography to intensive care medicine, the editors of this edition decided to incorporate the subject into the textbook insofar as possible Where it is relevant, the reader will find within each chapter a section titled “Utility of Ultrasonography” that is written in cooperation with the chapter authors by a separate writing group, all of whom have been course leaders or senior faculty at American College of Chest Physicians national critical care ultrasonography courses and all of whom use ultrasonography in their daily critical care practice Each ultrasonography section will connect to a video library coordinated with the subject matter of chapter that can be called out for review while reading the text By design, the ultrasonography sections of the textbook do not emphasize technical aspects of machine design or ultrasound physics These are well summarized in standard ultrasonography textbooks Rather, the emphasis is on procedure- or disease-specific clinical applications of ultrasonography that are immediately relevant to the frontline intensivist, and that are well within their capability The goal is to review those aspects of ultrasonography that a “typical” bedside intensivist would use on a routine basis Complex aspects of ultrasonography are not part of the discussion, because they require expert level radiology and cardiology level capability COMPETENCE By definition, the intensivist in charge of the case personally performs all aspects of the ultrasonography examination: image acquisition, image interpretation, and application of the results at point of care This is very different from ultrasonography performed by the consultative service of radiology and cardiology, where the examination is delayed in its performance, and where the consultant is disassociated from the clinical reality of case In using ultrasonography at point of care, the intensivist uses an imaging modality that is uniquely suited to the demands of intensive care medicine: immediately available, relatively inexpensive, flexible, and with multipurpose applications Competence in key parts of critical care ultrasonography are summarized in the ACCP/SRLF Statement on Competence in Critical Care Ultrasonography [1].This document lists the basic elements of the field that need to be mastered by the intensivist, and may be regarded as a minimum standard This textbook reviews many other applications that are not listed in this Statement Competence in critical care ultrasonography requires mastery of image acquisition, image interpretation, and the cognitive elements of the field Training in image acquisition may be accomplished initially on normal human subjects, but also requires scanning of patients under the direct supervision of a competent instructor Training in image acquisition requires access to an image set that includes a large number of abnormal findings The cognitive base is mastered by study of relevant material in a blended form comprising written material, lectures, or Internet-based information Requirements for training relevant to the elements of the Competence Statement are summarized in the Statement on Training in Critical Care Ultrasonography that represents a multinational consensus on this subject [2] At present, there is no national level certification process for critical care ultrasonography either in North America or any country in Europe Competence is defined by local standards, so the intensivist has an important responsibility to seek out adequate training that focuses on achieving the standards defined in the Competence Statement Some applications reviewed in this textbook are not mentioned in the Competence Statement, but have clinical utility Competence in these is only assured by specific institutional standards Critical care ultrasonography, once adopted by the active clinician, lends itself to an element of invention, local training effort, and adoption of techniques that are not initially widely used One purpose of this textbook is to disseminate information on critical care ultrasonography that is not defined in the Competence Statement Machine Requirements High-quality portable ultrasonography machines are widely available Their cost is not prohibitive when compared to alternatives, such as computerized tomography (CT), and their operating costs are low In addition, a team that uses ultrasonography as its primary imaging tool reduces utilization of other standard imaging methods [3]; this accrues cost savings, because more expensive imaging modalities are not used as often Most recent generation machines have good image quality (with a few exceptions), so purchase decision should be predicated on other factors Some key questions to consider include the following: Is the machine durable? Can the machine be dropped, can the transducers be dropped, and is it impervious to fluid spills? What is the service record of the company? Is the cost of the service contract included in the price of the machine, or is the machine a “loss leader” that requires an expensive service contract in addition? What is the turnaround time for service? Is the machine easy to operate? What is the turn-on time? Is the control surface simple and easy to operate? Is there well-designed memory capability that uses a widely accepted video image format? Is the machine truly portable? Can it be easily removed from the stand for situations that require a hand-carried device? What is the footprint of the stand? Can the machine and probes be easily and safely cleaned with disinfecting fluids? The intesive care unit (ICU) machine requires two probes The linear vascular probe is high frequency, so that it has excellent resolution, but poor penetration This makes it ideal for vascular access, examination of pleural morphology, and to characterize structures near the skin surface such as lymph nodes The phased array cardiac transducer has less resolution, but better penetration, because it is designed for examination of deeper structures Most machines allow the phased-array cardiac transducer to be configured for abdominal scanning This results in cost savings, because the machine does not then need to be equipped with a curvilinear abdominal transducer which adds significantly to acquisition cost p p Machine Controls and Scanning Technique Even with a simple-to-operate portable machine, a common failure point for the inexperienced scanner is poor gain, depth, frequency, and orientation control This is remedied by effective hands-on training Scanning technique is an important element of image acquisition Excepting certain types of vascular access, the machine and the scanner are always placed on the same side as the patient This permits the examiner to operate the machine controls with one hand while holding the probe with the other This requires that the clinician be ambidextrous in terms of holding the probe, given that the patient may be surrounded by a variety of life support devices Probe hold requires that some part of the hand rests on the patient while holding the probe in order to provide a stable image Scope of Practice In considering the scope of practice of critical care ultrasonography, it is important to emphasize that not every intensivist needs to be competent in all aspects of the field The consultative attending intensivist may not need any training, because their practice needs are not such that it is required Other clinicians may wish to focus on procedural guidance with ultrasonography For the active frontline intensivist, the Competence Statement is a good guide for the scope of practice, with additional skills added according to interest and practice requirements This will require a higher level of training Competence should be defined by the scope of practice, but in some situations, there is an added layer of complexity The hospital credentialing committee must grant the privilege to perform critical care ultrasonography If the clinician has achieved competence during fellowship training as defined by their program director, hospital credentialing committees routinely grant privileges This may not be the case for attending level intensivists, where other physician specialists perceive economic or political threat to granting the privilege to a physician who is not a radiologist or cardiologist In this case, the intensivist may be competent, and yet be blocked from performing within their scope of practice One solution to this problem is to provide strong evidence of training, such that the credentialing committee cannot but grant privileges This evidence would include a comprehensive log of all scanning activity, cognitive training, image review, and course attendance The American College of Chest Physicians has designed a training program to provide competence and to fulfil requirements to obtain hospital privileges Limitations of Critical Care Ultrasonography Competence in critical care ultrasonography requires an understanding of its limitations These include the following: Related to patient factors: Obesity, heavy musculature, and edema may degrade the ultrasonography image to a major extent The presence of subcutaneous air may block transmission of ultrasound, so that deeper structures cannot be visualized Skin dressing and devices may block transmission of ultrasound The critically ill patient often cannot be positioned for optimal image acquisition For example, most critically ill patients are supine, so that posterior structures may be difficult to image Related to environmental factors: High ambient light levels degrade image quality The patient may be surrounded by equipment that blocks access for scanning Related to the physics of ultrasonography: The physics of ultrasound limit the resolution and penetration of ultrasound in body tissues, and artifacts are common that may mimic abnormalities Ultrasound is blocked by air owing to intense reflection such that the presence of air precludes any visualization of underlying structures Bones markedly attenuate transmission of ultrasound, so that underlying structures are shadowed Structures in the lung that are completely surrounded by air are invisible, ribs block visualization of the heart or brain, whereas gas-filled intestine blocks visualization of abdominal structures Related to the operator: The intensivist who performs critical care ultrasonography is responsible for all the aspects of image acquisition, interpretation, and application of the results to the clinical problem at hand There is no expert radiologist or cardiologist to perform these critical functions A limitation of critical care ultrasonography relates to the need for the intensivist to be fully trained and therefore competent in those aspects that are relevant to their practice needs Related to paradigm shift: The standard paradigm for imaging in the ICU is that the radiology or cardiology service is responsible for all aspects of image acquisition and interpretation The intensivist is a passive participant in this process The full integration of critical care ultrasonography into the daily function of the ICU requires a paradigm shift where the intensivists rely on their own skill at image acquisition and interpretation, and believe that ultrasonography often replaces standard imaging methods such as chest radiography and CT scan As summarized by Oks et al.: “This approach to critical care ultrasonography requires several dedicated machines, a number of frontline intensivists who are skilled at critical care ultrasonography, the deployment of ultrasonography as a primary tool on work rounds, a team decision to rely on ultrasonography as a primary imaging tool as much as possible, and the decision that confirmatory imaging is not required for ultrasonography examinations performed by the MICU team.” [3] CONCLUSIONS Critical care ultrasonography is an important aspect of intensive care medicine Rather than having several stand-alone chapters summarizing various aspects of ultrasonography, the editors have embedded ultrasonography in a disease- or procedure-specific manner that is clinically relevant to the frontline intensivist The accompanying video library serves to provide guidance for a wide variety of critical care ultrasonography applications REFERENCES Mayo PH, Beaulieu Y, Doelken P, et al: American College of Chest Physicians/La Sociộtộ de Rộanimation de Langue Franỗaise statement on competence in critical care ultrasonography Chest 135:10501060, 2009 Cholley, B: International expert statement on training standards for critical care ultrasonography Expert Round Table on Ultrasound in ICU Intensive Care Med 37:1077–1083, 2011 Oks M, Cleven KL, Cardenas-Garcia J, et al: The effect of point-of-care ultrasonography on imaging studies in the medical ICU: a comparative study Chest 146:1574–1577, 2014 Chapter 2 Anesthesia for Bedside Procedures MARK DERSHWITZ When a patient in an intensive care unit (ICU) requires a bedside procedure, it is usually the attending intensivist, as opposed to a consultant anesthesiologist, who directs the administration of the necessary hypnotic, analgesic, and/or paralytic drugs Furthermore, unlike in the operating room, the ICU usually has no equipment for the administration of gaseous (e.g., nitrous oxide) or volatile (e.g., isoflurane) anesthetics Anesthesia for bedside procedures in the ICU is thus accomplished via a technique involving total intravenous anesthesia (TIVA) COMMON PAIN MANAGEMENT PROBLEMS IN ICU PATIENTS Dosing of Agent Selecting the proper dose of an analgesic to administer is problematic for several reasons, including difficulty in assessing the effectiveness of pain relief, pharmacokinetic (PK) differences between the critically ill and other patients, and normal physiologic changes associated with aging Assessing the Effectiveness of Pain Relief Critically ill patients often are incapable of communicating their feelings because of delirium, obtundation, or endotracheal intubation This makes psychological evaluation quite difficult, because surrogate markers of pain intensity (e.g., tachycardia, hypertension, and diaphoresis) are inherent in the host response to critical illness Pharmacokinetic Considerations Most of the pressors and vasodilators administered in the ICU by continuous intravenous (IV) infusion have relatively straightforward PK behavior: They are water-soluble molecules that are minimally bound to plasma proteins In contrast, the hypnotics and opioids used in TIVA have high lipid solubility, and most are extensively bound to plasma proteins, causing their PK behavior to be far more complex After a single or a few bolus injections, these medications are typically short acting because of rapid redistribution out of the brain However, following infusions of long duration (i.e., hours or days), the processes of metabolism and elimination become more important and drug effects can have a longer duration The PK behavior of the lipid-soluble hypnotics and analgesics given by infusion may be described by their context-sensitive half-times (CSHTs) This concept may be defined as follows: When a drug is given as an IV bolus followed by an IV infusion designed to maintain a constant plasma drug concentration, the time required for the plasma concentration to fall by 50% after termination of the infusion is the CSHT [1] Figure 2.1 depicts the CSHT curves for the medications most likely to be used for TIVA in ICU patients PK behavior in critically ill patients is unlike that in normal subjects for several reasons Because ICU patients frequently have renal and/or hepatic dysfunction, drug metabolism or excretion is often significantly impaired Hypoalbuminemia, common in critical illness, decreases protein binding and increases free-drug concentration Because free drug is the only moiety available to tissue receptors, decreased protein binding increases the pharmacologic effect for a given plasma concentration It is therefore more important in the ICU patient that the doses of medications used for TIVA are individualized for a particular patient FIGURE 2.1 The context-sensitive half-times for propofol [26], midazolam [27], sufentanil [28], remifentanil [29], and dexmedetomidine [30] as a function of infusion duration Physiologic Changes Associated with Aging People 65 years of age and older comprise the fastest growing segment of the population and constitute the majority of patients in many ICUs Aging leads to (1) a decrease in total body water and lean body mass; (2) an increase in body fat and, hence, an increase in the volume of distribution of lipid-soluble drugs; and (3) a decrease in drug clearance rates, because of reductions in liver mass, hepatic enzyme activity, liver blood flow, and renal excretory function There is a progressive, agedependent increase in pain relief and electroencephalographic suppression among elderly patients receiving the same dose of opioid as younger patients There is also an increase in central nervous system (CNS) depression in elderly patients following administration of identical doses of benzodiazepines Selection of Agent Procedures performed in ICUs today (Table 2.1) span a spectrum that extends from those associated with mild discomfort (e.g., esophagogastroscopy) to those that are quite painful (e.g., orthopedic manipulations, wound debridement, tracheostomy) Depending on their technical difficulty, these procedures can last from minutes to hours To provide a proper anesthetic, medications should be selected according to the nature of the procedure and titrated according to the patient’s response to surgical stimuli In addition, specific disease states should be considered in order to maximize safety and effectiveness TABLE 2.1 Bedside Procedures and Associated Levels of Discomfort Mild to moderately uncomfortable    Transesophageal echocardiographya    Transtracheal aspiration    Thoracentesisa    Paracentesisa Moderately to severely uncomfortable    Endotracheal intubationa    Flexible bronchoscopya    Thoracostomya    Bone marrow biopsy    Colonoscopy    Intraaortic balloon insertiona    Peritoneal dialysis catheter insertiona    Peritoneal lavagea    Percutaneous gastrostomya    Percutaneous intraaortic balloon insertiona Extremely painful    Rigid bronchoscopy    Debridement of open wounds    Dressing changes    Orthopedic manipulations    Tracheostomya    Pericardiocentesis/pericardial windowa    Open lung biopsy    Ventriculostomya aProcedures in which the level of discomfort may be significantly mitigated by the use of local anesthesia Head Trauma Head-injured patients require a technique that provides effective yet brief anesthesia, so that the capacity to assess neurologic status is not lost for extended periods of time In addition, the technique must not adversely affect cerebral perfusion pressure If the effects of the anesthetics dissipate too rapidly, episodes of agitation and increased intracranial pressure (ICP) may occur that jeopardize cerebral perfusion In contrast, if the medications last too long, there may be difficulty in making an adequate neurologic assessment following the procedure p p Coronary Artery Disease Postoperative myocardial ischemia following cardiac and noncardiac surgery strongly predicts adverse outcome [2] Accordingly, sufficient analgesia should be provided during and after invasive procedures to reduce plasma catecholamine and stress hormone levels Renal and/or Hepatic Failure The association between sepsis and acute renal failure has been recognized for many years The risk of an adverse drug reaction is at least three times higher in azotemic patients than in those with normal renal function This risk is magnified by excessive unbound drug or drug metabolite(s) in the circulation and changes in the target tissue(s) induced by the uremic state Liver failure alters the volumes of distribution of many drugs by impairing synthesis of the two major plasma-binding proteins, albumin and α1-acid glycoprotein In addition, reductions in hepatic blood flow and hepatic enzymatic activity decrease the clearance rates of many drugs CHARACTERISTICS OF SPECIFIC AGENTS USED FOR BEDSIDE PROCEDURES Hypnotics The characteristics of the hypnotics are listed in Table 2.2, and their recommended doses are listed in Table 2.3 When rapid awakening is desired, propofol or etomidate is the hypnotic agent of choice Ketamine may be useful when a longer duration of anesthesia is needed Midazolam is rarely used alone as a hypnotic; however, its profound anxiolytic and amnestic effects render it useful in combination with other agents Dexmedetomidine does not reliably produce unconsciousness; however, its sedation is not accompanied by ventilatory depression and it potentiates opioid analgesia, thereby permitting lower opioid doses TABLE 2.2 Characteristics of Intravenous Hypnotic Agents Propofol Etomidate Ketamine Midazolam Dexmedetomidine Onset Fast Fast Fast Intermediate Intermediate Duration Short Short Intermediate Intermediate Intermediate Cardiovascular ↓ effects None ↑ Minimal ↓ Ventilatory effects ↓ ↓ Minimal ↓ None Analgesia None None Profound None Moderate Amnesia Mild Mild Profound Profound None The listed doses should be reduced by 50% in elderly patients Entries in bold type indicate noteworthy differences among the drugs TABLE 2.3 Usual Doses of Intravenous Anesthetic Agents Given by Continuous Infusion Propofol Etomidate Ketamine Midazolam Sufentanil Remifentanil Bolus dose (mg/kg) Infusion rate (μg/kg/min) 1–2 0.2–0.3 1–2 0.05–0.15 0.5–1.5 100–200 NRa 25–100 0.25–1.5 0.01–0.03 The “usual doses” are for patients without preexisting tolerance and significant cardiovascular disease The required doses will be higher in patients with tolerance, and should be reduced in elderly patients and in patients with decreased cardiovascular function In all cases, the medications should be titrated to specific end points as described in the text aNot recommended because of the possibility of prolonged adrenal suppression Propofol Description Propofol is a hypnotic agent associated with pleasant emergence and hangover characteristics It is extremely popular because it is readily titratable and has more rapid onset and offset kinetics than midazolam Thus, patients emerge from anesthesia more rapidly after propofol than after midazolam, a factor that may make propofol the preferred agent for sedation and hypnosis in general, and in particular for patients with altered level of consciousness The CSHT for propofol is about 10 minutes following a 1-hour infusion, and the CSHT increases about 5 minutes for each additional hour of infusion for the first several hours, as shown in Figure 2.1 Thus, the CSHT is about 20 minutes after a 3-hour infusion The CSHT rises much more slowly for infusions longer than a day; a patient who is sedated (but not rendered unconscious) with propofol for 2 weeks will recover in approximately 3 hours [3] This rapid recovery of neurologic status often makes propofol a desirable sedative in ICU patients, especially in those with head trauma, who may not tolerate mechanical ventilation without pharmacologic sedation Even though recovery following termination of a continuous infusion is faster with propofol than with midazolam, a comparative trial showed that the two drugs were roughly equivalent in effectiveness for overnight sedation of ICU patients [4] For long-term sedation (e.g., more than 1 day), however, recovery is significantly faster in patients given propofol p p In spontaneously breathing patients sedated with propofol, respiratory rate appears to be a more predictable sign of adequate sedation than hemodynamic changes The ventilatory response to rebreathing carbon dioxide during a maintenance propofol infusion is similar to that induced by other sedative drugs (i.e., propofol significantly decreases the slope of the carbon dioxide response curve) Nevertheless, spontaneously breathing patients anesthetized with propofol are able to maintain normal end-tidal carbon dioxide values during most minor surgical procedures Bolus doses of propofol in the range of 1 to 2 mg per kg induce loss of consciousness within 30 seconds Maintenance infusion rates of 100 to 200 μg/kg/min are adequate in younger subjects to maintain general anesthesia, whereas doses should be reduced by 20% to 50% in elderly individuals Adverse Effects Cardiovascular Propofol depresses ventricular systolic function and lowers afterload, but has no effect on diastolic function Vasodilation results from calcium channel blockade In patients undergoing coronary artery bypass surgery, propofol (2 mg per kg IV bolus) produced a 23% fall in mean arterial blood pressure, a 20% increase in heart rate, and a 26% decrease in stroke volume In pigs, propofol caused a dose-related depression of sinus node and His-Purkinje system functions, but had no effect on atrioventricular node function or on the conduction properties of atrial and ventricular tissues In patients with coronary artery disease, propofol administration may be associated with a reduction in coronary perfusion pressure and increased myocardial lactate production Neurologic Propofol may improve neurologic outcome and reduce neuronal damage by depressing cerebral metabolism Propofol decreases cerebral oxygen consumption, cerebral blood flow, and cerebral glucose utilization in humans and animals to the same degree as reported for thiopental and etomidate Propofol frequently causes pain when injected into a peripheral vein Injection pain is less likely if the injection site is located proximally on the arm or if the injection is made via a central venous catheter Metabolic The emulsion used as the vehicle for propofol contains soybean oil and lecithin and supports bacterial growth; iatrogenic contamination leading to septic shock is possible Currently available propofol preparations contain ethylenediamine tetraacetic acid (EDTA), metabisulfite, or benzyl alcohol as a bacteriostatic agent Because EDTA chelates trace metals, particularly zinc, serum zinc levels should be measured daily during continuous propofol infusions Hyperlipidemia may occur, particularly in infants and small children Accordingly, triglyceride levels should be monitored daily in this population whenever propofol is administered continuously for more than 24 hours Etomidate Description Etomidate has onset and offset PK characteristics similar to propofol and an unrivaled cardiovascular profile, even in the setting of cardiomyopathy [5] Not only does etomidate lack significant effects on myocardial contractility, but baseline sympathetic output and baroreflex regulation of sympathetic activity are well preserved Etomidate depresses cerebral oxygen metabolism and blood flow in a dose-related manner without changing the intracranial volume–pressure relationship Etomidate is particularly useful (rather than thiopental or propofol) in certain patient subsets: Hypovolemic patients, multiple trauma victims with closed head injury, and those with low ejection fraction, severe aortic stenosis, left main coronary artery disease, or severe cerebral vascular disease Etomidate may be relatively contraindicated in patients with established or evolving septic shock because of its inhibition of cortisol synthesis (see below) Adverse Effects Metabolic Etomidate, when given by prolonged infusion, may increase mortality associated with low plasma cortisol levels [6] Even single doses of etomidate can produce adrenal cortical suppression lasting 24 hours or more in normal patients undergoing elective surgery [7] These effects are more pronounced as the dose is increased or if continuous infusions are used for sedation Etomidate-induced adrenocortical suppression occurs because the drug blocks the 11β-hydroxylase that catalyzes the final step in the synthesis of cortisol It is also noteworthy that etomidate causes the highest incidence of postoperative nausea and vomiting of any of the IV anesthetic agents In 2005, Jackson warned against the use of etomidate in patients with septic shock [8] Since then, there have been several studies that have attempted to confirm or refute the safety of etomidate in critically ill patients, including those with sepsis Unfortunately, some of these studies purportedly confirmed the danger of etomidate, whereas others support its continued use in patients with sepsis Two recent metaanalyses of the available studies came to divergent conclusions [9,10] Giving hydrocortisone to patients with septic shock may decrease overall mortality in patients who received etomidate for intubation as compared to other hypnotic agents [11] Ketamine Description Ketamine induces a state of sedation, amnesia, and marked analgesia in which the patient experiences a strong feeling of dissociation from the environment It is unique among the hypnotics in that it reliably induces unconsciousness by the intramuscular route Ketamine is rapidly metabolized by the liver to norketamine that is pharmacologically active Ketamine is both slower in onset and offset as compared with propofol or etomidate following IV administration p p Many clinicians consider ketamine to be the analgesic of choice in patients with a history of bronchospasm In the usual dosage, it decreases airway resistance, probably by blocking norepinephrine uptake that in turn stimulates beta-adrenergic receptors in the lungs In contrast to many beta-agonist bronchodilators, ketamine is not arrhythmogenic when given to asthmatic patients receiving aminophylline Ketamine may be safer than other hypnotics or opioids in unintubated patients because it depresses airway reflexes and ventilatory drive to a lesser degree It may be particularly useful for procedures near the airway, where physical access and ability to secure an airway is limited (e.g., gunshot wounds to the face) Because ketamine increases salivary and tracheobronchial secretions, an anticholinergic (e.g., 0.2 mg glycopyrrolate) should be given prior to its administration In patients with borderline hypoxemia despite maximal therapy, ketamine may be the drug of choice, because ketamine does not inhibit hypoxic pulmonary vasoconstriction Another major feature that distinguishes ketamine from most other IV anesthetics is that it stimulates the cardiovascular system (i.e., raises heart rate and blood pressure) This action appears to result both from direct stimulation of the CNS with increased sympathetic nervous system outflow and from blockade of norepinephrine reuptake in adrenergic nerves Because pulmonary hypertension is a characteristic feature of acute respiratory distress syndrome, drugs that increase right ventricular afterload should be avoided In infants with either normal or elevated pulmonary vascular resistance, ketamine does not affect pulmonary vascular resistance as long as constant ventilation is maintained, a finding also confirmed in adults Cerebral blood flow does not change when ketamine is injected into cerebral vessels In mechanically ventilated pigs with artificially produced intracranial hypertension in which ICP is on the shoulder of the compliance curve, 0.5 to 2.0 mg per kg IV ketamine does not raise ICP; likewise, in mechanically ventilated preterm infants, 2 mg per kg IV ketamine does not increase anterior fontanelle pressure, an indirect monitor of ICP Unlike propofol and etomidate however, ketamine does not lower cerebral metabolic rate It is relatively contraindicated in patients with an intracranial mass, with increased ICP, or who have suffered recent head trauma Adverse Effects Psychological Emergence phenomena following ketamine anesthesia have been described as floating sensations, vivid dreams (pleasant or unpleasant), hallucinations, and delirium These effects are more common in patients older than 16 years, in females, after short operative procedures, after large doses (>2 mg per kg IV), and after rapid administration (>40 mg per minute) Pre- or concurrent treatment with benzodiazepines or propofol usually minimizes or prevents these phenomena [12] Cardiovascular Because ketamine increases myocardial oxygen consumption, there is risk of precipitating myocardial ischemia in patients with coronary artery disease if ketamine is used alone On the other hand, combinations of ketamine plus diazepam, ketamine plus midazolam, or ketamine plus sufentanil are well tolerated for induction in patients undergoing coronary artery bypass surgery Repeated bolus doses are often associated with tachycardia This can be reduced by administering ketamine as a constant infusion Ketamine produces myocardial depression in the isolated animal heart Hypotension has been reported following ketamine administration in hemodynamically compromised patients with chronic catecholamine depletion Neurologic Ketamine does not lower the minimal electroshock seizure threshold in mice When administered with aminophylline, however, a clinically apparent reduction in seizure threshold is observed Midazolam Description Although capable of inducing unconsciousness in high doses, midazolam is more commonly used as a sedative Along with its sedating effects, midazolam produces anxiolysis, amnesia, and relaxation of skeletal muscle Anterograde amnesia following midazolam (5 mg IV) peaks 2 to 5 minutes after IV injection and lasts 20 to 40 minutes Because midazolam is highly (95%) protein bound (to albumin), the drug effect is likely to be exaggerated in ICU patients Recovery from midazolam is prolonged in obese and elderly patients and following continuous infusion because it accumulates to a significant degree In patients with renal failure, active conjugated metabolites of midazolam may accumulate and delay recovery Although flumazenil may be used to reverse excessive sedation or ventilatory depression from midazolam, its duration of action is only 15 to 20 minutes In addition, flumazenil may precipitate acute anxiety reactions or seizures, particularly in patients receiving chronic benzodiazepine therapy Midazolam causes dose-dependent reductions in cerebral metabolic rate and cerebral blood flow, suggesting that it may be beneficial in patients with cerebral ischemia Because of its combined sedative, anxiolytic, and amnestic properties, midazolam is ideally suited both for brief, relatively painless procedures (e.g., endoscopy) and for prolonged sedation (e.g., during mechanical ventilation) Adverse Effects Respiratory Midazolam (0.15 mg per kg IV) depresses the slope of the carbon dioxide response curve and increases the dead space–tidal volume ratio and arterial PCO2 Ventilatory depression is even more marked and prolonged in patients with chronic obstructive pulmonary disease Midazolam also blunts the ventilatory response to hypoxia Cardiovascular Small ( 10, and complicated translaryngeal intubation or a nonpalpable cricoid cartilage or a cricoid cartilage Day 7) Tracheoinnominate artery fistula Tracheomalacia Tracheal stenosis Necrosis and loss of anterior tracheal cartilage Tracheoesophageal fistula Major aspiration Chronic speech and swallowing deficits Tracheocutaneous fistula Multiple studies have suggested an increased complication rate of surgical tracheostomy in patients with a BMI > 30 [8,83] There is conflicting evidence regarding the complication rate of percutaneous tracheostomy in these patients Byhahn et al found a complication rate of percutaneous tracheostomy of 43.8% in 32 patients with a BMI > 27, compared to 18.2% in 73 patients with a BMI < 27 (p < 0.001) Additionally, the rate of severe complication in the obese group was nearly five times that of those in the nonobese group [84] However, a subsequent study by Romero et al of 25 obese patients and 80 nonobese patients undergoing fiber-optic bronchoscopy-guided percutaneous tracheostomy with ultrasound support did not show any significant difference in complication rates (8% vs 7.5%, p = 1) [85] In the largest study to date, McCague et al retrospectively reviewed 131 obese patients and 295 nonobese patients undergoing bronchoscopy-guided percutaneous tracheostomy and did not find a significant difference in complication rate [86] Overall, these studies are limited by the small numbers; retrospective or observational nature; and lack of long-term follow-up Obstruction Obstruction of the tracheostomy tube is a potentially life-threatening complication The tube may become plugged with clotted blood or inspissated secretions In this case, the inner cannula should be removed immediately and the patient suctioned Should that fail, it may be necessary to remove the outer cannula also, a decision that must take into consideration the reason the tube was placed and the length of time it has been in place Obstruction may also be caused by angulation of the distal end of the tube against the anterior or posterior tracheal wall An undivided thyroid isthmus pressing against the angled tracheostomy tube can force the tip against the anterior tracheal wall, whereas a low superior transverse skin edge can force the tip of the tracheostomy tube against the posterior tracheal wall An indication of this type of obstruction is an expiratory wheeze Division of the thyroid isthmus, and proper placement of transverse skin incisions prevent anterior or posterior tube angulation and obstruction Tube Displacement/Dislodgment Dislodgment of a tracheostomy tube that has been in place for 2 weeks or longer is managed by replacing the tube If it cannot be immediately replaced or if it is replaced and the patient cannot be ventilated (indicating that the tube is not in the trachea), orotracheal intubation should be performed Immediate postoperative displacement can be fatal, if the tube cannot be promptly replaced and the patient cannot be reintubated Dislodgment in the early postoperative period is usually caused by one of several technical problems Failure to divide the thyroid isthmus may permit the intact isthmus to ride up against the tracheostomy tube and thus displace it Excessively low placement of the stoma (i.e., below the second and third rings) can occur when the thoracic trachea is brought into the neck by overextending the neck or by excessive traction on the trachea When the normal anatomic relationships are restored, the trachea recedes below the suprasternal notch, causing the tube to be dislodged from the trachea The risk of dislodgment of the tracheostomy tube, a potentially lethal complication, can be minimized by (a) transection of the thyroid isthmus at surgery, if indicated; (b) proper placement of the stoma; (c) avoidance of excessive neck hyperextension and/or tracheal traction; (d) application of sufficiently tight tracheostomy tube retention tapes; (e) suture of the tracheostomy tube flange to the skin in patients with short necks; and (f) insertion of a tracheostomy tube of an appropriate length for the patient’s anatomy Some surgeons apply retaining sutures to the trachea for use in the early postoperative period in case the tube becomes dislodged, allowing the trachea to be pulled into the wound for reintubation Making a Bjork flap involves suturing the inferior edge of the trachea stoma to the skin, thus allowing a sure pathway for tube placement Bjork flaps, however, tend to interfere with swallowing and promote aspiration Reintubation of a tracheostomy can be accomplished by using a smaller, beveled endotracheal tube and then applying a tracheostomy tube over the smaller tube, using the Seldinger technique [87] p 84 p 85 If a tracheostomy becomes dislodged within 7 to 10 days of surgery, we recommend translaryngeal endotracheal intubation to establish a safe airway The tracheostomy tube can then be replaced under less urgent conditions, with fiber-optic guidance if needed Subcutaneous Emphysema Approximately 5% of patients develop subcutaneous emphysema after tracheostomy [87] It is most likely to occur when dissection is extensive and/or the wound is closed tightly Partial closure of the skin wound is appropriate, but the underlying tissues should be allowed to approximate naturally Subcutaneous emphysema generally resolves over the 48 hours after tracheostomy, but when the wound is closed tightly and the patient is coughing or on positive-pressure ventilation, pneumomediastinum, pneumopericardium, and/or tension pneumothorax may occur [3] Pneumothorax and Pneumomediastinum The cupola of the pleura extends well into the neck, especially in patients with emphysema; thus, the pleura can be damaged during tracheostomy This complication is more common in the pediatric age group because the pleural dome extends more cephalad in children The incidence of pneumothorax after tracheostomy ranges from 0% to 5% [79,87] Many surgeons routinely obtain a postoperative chest radiograph Hemorrhage Minor postoperative fresh tracheostomy bleeding occurs in approximately 12.5% of cases and is the most common complication of this procedure [88] Postoperative coughing and straining can cause venous bleeding by dislodging a clot or ligature Elevating the head of the bed, packing the wound, and/or using homeostatic materials usually controls minor bleeding Major bleeding can occur in up to 5% of tracheotomies and is caused by hemorrhage from the isthmus of the thyroid gland; loss of a ligature from one of the anterior jugular veins; or injury to the transverse jugular vein that crosses the midline just above the jugular notch Persistent bleeding may require a return to the operating room for management Techniques to decrease the likelihood of early posttracheostomy hemorrhage include (a) use of a vertical incision; (b) careful dissection in the midline, with care to pick up each layer of tissue with instruments rather than simply spread tissues apart; (c) liberal use of ligatures rather than electrocautery; and (d) careful division and suture ligation of the thyroid isthmus Late hemorrhage after tracheostomy is usually because of bleeding granulation tissue or another relatively minor cause However, in these late cases, a tracheoinnominate artery fistula needs to be ruled out Tracheoinnominate Artery Fistula At one point, it had been reported that 50% of all tracheostomy bleeding occurring more than 48 hours after the procedure was because of an often fatal complication of rupture of the innominate artery caused by erosion of the tracheostomy tube at its tip or cuff into the vessel [87] However, because of the advent of the low-pressure cuff, the incidence of this complication has decreased considerably and occurs less than 1% of the time [89] Eighty-five percent of tracheoinnominate fistulas occur within the first month after tracheostomy [90], although they have been reported as late as 7 months after operation Other sites of delayed exsanguinating posttracheostomy hemorrhage include the common carotid artery; superior and inferior thyroid arteries; aortic arch; and innominate vein [90] Rupture and fistula formation are caused by erosion through the trachea into the artery because of excessive cuff pressure or by angulation of the tube tip against the anterior trachea Infection and other factors that weaken local tissues, such as malnourishment and steroids, also seem to play a role [91] The innominate artery rises to about the level of the sixth ring anterior to the trachea, and low placement of the stoma can also create close proximity of the tube tip or cuff to the innominate artery Rarely, an anomaly of the innominate, occurring with an incidence of 1% to 2% [90], is responsible for this disastrous complication Pulsation of the tracheostomy tube is an indication of potentially fatal positioning [90] Initially, hemorrhage from a tracheoinnominate fistula is usually not exsanguinating Herald bleeds must be investigated promptly using fiber-optic tracheoscopy If a tracheoinnominate fistula seems probable (minimal tracheitis and anterior pulsating erosions), the patient should be taken to the operating room for evaluation Historically, definitive management involves resection of the artery However, there are several reported cases of successful treatment with endovascular stenting of the innominate artery [92,93] The mortality rate approaches 100%, even with emergent surgical intervention [3] Sudden exsanguinating hemorrhage may be managed by hyperinflation of the tracheostomy cuff tube or reintubation with an endotracheal tube through the stoma, attempting to place the cuff at the level of the fistula A lower neck incision with blind digital compression on the artery may be part of a critical resuscitative effort If a tracheoinnominate artery fistula is suspected, the patient should be evaluated in the operating room and preparations should be made for a possible sternotomy Misplacement of Tube Misplacement of the tube can occur at the time of surgery or when the tube is changed or replaced through a fresh stoma If not recognized, associated mediastinal emphysema and tension pneumothorax can occur, along with alveolar hypoventilation Injury to neurovascular structures, including the recurrent laryngeal nerve, is possible [3] The patient must be orally intubated or the tracheostoma recannulated Some advise placing retaining sutures in the trachea at the time of surgery The availability of a tracheostomy set at the bedside after tracheostomy facilitates emergency reintubation Tracheal Cartilage Fracture Tracheal ring fracture is a common, though likely unrecognized, complication, with a rate of 9.6% in one series of 219 percutaneous tracheostomy procedures [94].These fractures likely are associated with the development of stenosis over time Many preventative techniques have been suggested, including assuring bronchoscopic confirmation of placement; avoiding rotational torque at insertion site; perpendicular insertion; application of counterforce to the anterior tracheal wall with the endotracheal tube/bronchoscope; complete adequate skin incision and blunt soft tissue dissection to prevent excessive force on insertion; ensuring proper fit between tracheostomy and obturator; the use of tapered tracheostomies; and the smallest tracheostomy required by the patient p 85 p 86 Stomal Infections A less than 2% incidence of local infection rate has been reported with tracheostomy [8] The risk of serious infection is less than 0.5% [79] Attention to the details of good stoma care and early use of antibiotics are advised However, prophylactic antibiotics are not recommended [95] Tracheoesophageal Fistula Tracheoesophageal fistula caused by injury to the posterior tracheal wall and cervical esophagus occurs in less than 1% of patients, more commonly in the pediatric age group Early postoperative fistula is a result of iatrogenic injury during the procedure [87] The chances of creating a fistula can be minimized by entering the trachea initially with a horizontal incision between two tracheal rings (the second and third), thereby eliminating the initial cut into a hard cartilaginous ring [3] A late tracheoesophageal fistula may be because of tracheal necrosis caused by tube movement or angulation, as in neck hyperflexion, or excessive cuff pressure [87] A tracheoesophageal fistula should be suspected in patients with cuff leaks, abdominal distention, recurrent aspiration pneumonia, and reflux of gastric fluids through the tracheostomy site It may be demonstrated on endoscopy and contrast studies Tracheoesophageal fistulas require surgical repair For patients who could not tolerate a major surgical procedure, placement of an esophageal and a tracheal stent may be used [96] Tracheal Stenosis Some degree of tracheal stenosis is seen in 40% to 60% of patients following tracheostomy [80,97] However, only 3% to 12% of these stenoses are clinically significant enough to require intervention [98] Stenosis most commonly occurs at the level of the stoma or just above the stoma, but distal to the vocal cords [3] The stenosis typically results from bacterial infection or chondritis of the anterior and lateral tracheal walls Granulation tissue usually develops first Ultimately, the granulation tissue matures, becoming fibrous and covered with a layer of epithelium The granulation tissue itself can also result in other complications, such as obstructing the airway at the level of the stoma, making changing the tracheostomy tube difficult, and occluding tube fenestrations Identified risk factors for developing tracheal stenosis include sepsis; stomal infections; hypotension; advanced age; male gender; corticosteroid use; excess motion of the tracheostomy tube; oversized tube; prolonged placement; elevated cuff pressures; excessive excision of the anterior tracheal cartilage; and fracturing a tracheal ring during PDT [99] Using properly sized tracheostomy tubes, inflating cuffs only when indicated, and maintaining intracuff pressures to less than 15 to 20 mm Hg may decrease the incidence of tracheal stenosis [100] Tracheal stenosis, as well as other long-term complications, appears to be less frequent with the percutaneous procedure [101,102] Treatment options for granulation tissue include topical strategies (such as topical antibiotic or steroids, silver nitrate, and polyurethane form dressings) or surgical strategies (laser excision, electrocautery, and surgical removal) [3] Treatment options for symptomatic tracheal stenosis include dilatation with a rigid bronchoscopy with coring, intralumen laser excision, or surgical resection with end-to-end tracheal anastomosis Tracheomalacia Tracheomalacia is a weakening of the tracheal wall resulting from ischemic injury to the trachea, followed by chondritis, then destruction, and necrosis of the tracheal cartilage Consequently, there is collapse of the affected portion of the trachea with expiration, resulting in airflow limitation, air trapping, and retention of airway secretions Tracheomalacia may ultimately result in the patient failing to wean from mechanical ventilation A short-term therapeutic approach to tracheomalacia is to place a longer tracheostomy tube to bypass the area of malacia Long-term treatment options include stenting, tracheal resection, or tracheoplasty Dysphagia and Aspiration The major swallowing disorder associated with tracheostomy is aspiration (see the section Oral Feeding and Swallowing Dysfunction Associated with Tracheostomies) Because of the high risk for aspiration, we do not recommend oral feeding in ICU patients with tracheostomies Tracheocutaneous Fistula Although the tracheostoma generally closes rapidly after decannulation, a persistent fistula may occasionally remain, particularly when the tracheostomy tube is present for a prolonged period If this complication occurs, the fistula tract can be excised and the wound closed primarily under local anesthesia More complicated or persistent fistulas required a more formal procedure under general anesthesia involving the use of a local muscle flap between the tracheal opening and the subcutaneous tissues CONCLUSIONS Tracheostomy is one of the most common surgical procedures preformed in the ICU and appears to be the airway of choice for patients requiring mechanical ventilation for more than 10 to 14 days In the majority of patients, there is unlikely a benefit to tracheostomy prior to 7 to 10 days of mechanical ventilation The physician performing the tracheostomy procedure needs to assess each patient to determine the best technique (whether it be performed bedside percutaneously or open in the operating room) for that specific patient The patient’s medical condition; the physician’s experience with the various techniques; and the hospital’s resources all need to be considered in determining the type of procedure performed REFERENCES Clec’h C, Alberti C, Vincent F, et al: Tracheostomy does not improve the outcome of patients requiring mechanical ventilation: a propensity analysis Crit Care Med 35:132, 2007 Combes A, Luyt CE, Nieszkowska A, et al: Is tracheostomy associated with better outcomes for patients requiring long-term mechanical ventilation? Crit Care Med 25:802, 2007 Kopec SE, Emhoff TA: Tracheostomy, in Irwin RS, Rippe JM (eds): Intensive Care Medicine 7th ed Lippincott, Williams, and Wilkins, Philadelphia, 2012, p 105 Heffner JE: Tracheostomy application and timing Clin Chest Med 24:389, 2003 Durbin CG: Indications for and timing of tracheostomy Respir Care 50:483, 2005 Conlan AA, Kopec SE: Tracheostomy in the ICU J Intensive Care Med 15:1, 2000 p 86 p 87 Auzinger G, O’Callaghan GP, Bernal W, et al: Percutaneous tracheostomy in patients with severe liver disease and a high incidence of refractory coagulopathy: a prospective trial Crit Care 11:R110, 2007 El Solh AA, Jaafar W: A comparative study of the complications of surgical tracheostomy in morbidly obese critically ill patients Crit Care 11:R3, 2007 Aldawood AS, Arabi YM, Haddad S: Safety of percutaneous tracheostomy in obese critically ill patients: a prospective cohort study Anaesth Intensive Care 36:69, 2008 10 Milanchi S, Magner D, Wilson MT, et al: Percutaneous tracheostomy in neurosurgical patients with intracranial pressure monitoring is safe J Trauma Injury Infect Crit Care 65:73, 2008 11 Griffiths J, Barber VS, Morgan L, et al: Systematic review and metaanalysis of studies of the timing of tracheostomy in adult patients undergoing artificial ventilation BMJ 330:1243, 2005 12 Rodriguez JL, Steinberg SM, Luchetti FA, et al: Early tracheostomy for primary airway management in the surgical critical care setting Surgery 108:655, 1990 13 Sugerman HJ, Wolfe L, Pasquele MD, et al: Multicenter, randomized, prospective trial on early tracheostomy J Trauma 43:741, 1997 14 Brook AD, Sherman G, Malen J, et al: Early versus late tracheostomy in patients who require prolonged mechanical ventilation Am J Crit Care 9:352, 2000 15 Rumbak MJ, Newton M, Truncale T, et al: A prospective, randomized study comparing early percutaneous dilatational tracheostomy to prolonged translaryngeal intubation in critically ill medical patients Crit Care Med 32:1689, 2004 16 Scales DC, Thiruchelvam D, Kiss A, et al: The effect of tracheostomy timing during critical illness on long-term survival Crit Care Med 36:2547, 2008 17 Blot F, Similowski T, Trouillet JL, et al: Early tracheostomy versus prolonged endotracheal intubation in unselected severely ill ICU patients Intensive Care Med 34:1779, 2008 18 Durbin CG, Perkins MP, Moores LK: Should tracheostomy be performed as early as 72 hours in patients requiring prolonged mechanical ventilation? Respir Care 55:76, 2010 19 Terragni PP, Antonelli M, Fumagalli R, et al: Early vs late tracheostomy for prevention of pneumonia in mechanically ventilated adult ICU patients JAMA 303:1483, 2010 20 Wang F, Wu Y, Bo L, et al: The timing of tracheotomy in critically ill patients undergoing mechanical ventilation: a systematic review and meta-analysis of rnadomized controlled trials Chest 140(6):1456– 1465, 2011 21 Young D, Harrison DA, Cuthbertson BH, et al: Effect of early vs late tracheostomy placement on survival in patients receiving mechanical ventilation; the TracMan randomized trial JAMA 309:20, 2013 22 Lesnik I, Rappaport W, Fulginiti J, et al: The role of early tracheostomy in blunt, multiple organ trauma Am Surg 58:346, 1992 23 Armstrong PA, McCarthy MC, Peoples JB: Reduced use of resources by early tracheostomy in ventilator-dependent patients with blunt trauma Surgery 124:763, 1998 24 Teoh WH, Goh KY, Chan C: The role of early tracheostomy in critically ill neurosurgical patients Ann Acad Med Singapore 30:234, 2001 25 Romero J, Vari A, Gambarrutta C, et al: Tracheostomy timing in traumatic spinal cord injury Eur Spine J 18:1452, 2009 26 Sellers BJ, Davis BL, Larkin PW, et al: Early predictors of prolonged ventilator dependence in thermally injured patients J Trauma 43:899, 1997 27 Stock CM, Woodward CG, Shapiro BA, et al: Perioperative complications of elective tracheostomy in critically ill patients Crit Care Med 14:861, 1986 28 Skaggs JA, Cogbill CL: Tracheostomy: management, mortality, complications Am Surg 35:393, 1969 29 American College of Surgeons Committee on Trauma: Advanced Trauma Life Support Course for Physicians, Instructor Manual Chicago, American College of Surgeons, 1985, p 159 30 Kline SN: Maxillofacial trauma, in Kreis DJ, Gomez GA (eds): Trauma Management Boston, Little, Brown, 1989 31 Cole RR, Aguilar EA: Cricothyroidotomy versus tracheotomy: an otolaryngologist’s perspective Laryngoscope 98:131, 1988 32 Sise MJ, Shacksord SR, Cruickshank JC, et al: Cricothyroidotomy for long term tracheal access Ann Surg 200:13, 1984 33 O’Connor JV, Reddy K, Ergin MA, et al: Cricothyroidotomy for prolonged ventilatory support after cardiac operations Ann Thorac Surg 39:353, 1985 34 Kuriloff DB, Setzen M, Portnoy W, et al: Laryngotracheal injury following cricothyroidotomy Laryngoscope 99:125, 1989 35 Hawkins ML, Shapiro MB, Cue JI, et al: Emergency cricothyrotomy: a reassessment Am Surg 61:52, 1995 36 Mace SE: Cricothyrotomy J Emerg Med 6:309, 1988 37 Robinson RJS, Mulder DS: Airway control, in Mattox KL, Feliciano DV, Moore EE (eds): Trauma New York, McGraw-Hill, 2000, p 171 38 Brantigan CO, Grow JB: Subglottic stenosis after cricothyroidotomy Surgery 91:217, 1982 39 Epstein SK: Anatomy and physiology of tracheostomy Respir Care 50:476, 2005 40 Walts PA, Murthy SC, DeCamp MM: Techniques of surgical tracheostomy Clin Chest Med 24:413, 2003 41 Ciaglia P, Firsching R, Syniec C: Elective percutaneous dilatational tracheostomy: a new simple beside procedure Preliminary report Chest 87:715, 1985 42 Freeman BD, Isabella K, Lin N, et al: A meta-analysis of prospective trials comparing percutaneous and surgical tracheostomy in critically ill patients Chest 118:412, 2000 43 Delancy A, Bagshaw SM, Nalos M: Percutaneous dilatational tracheostomy versus surgical tracheostomy in critically ill patients: a systemic review and meta-analysis Crit Care 10:R55, 2006 44 Higgins KM, Punthakee X: Meta-analysis comparison of open versus percutaneous tracheostomy Laryngoscope 117:447, 2007 45 Oliver ER, Gist A, Gillespie MB: Percutaneous versus surgical tracheostomy: an updated meta-analysis Laryngoscope 117:1570, 2007 46 Dulguerov P, Gysin C, Perneger TV, et al: Percutaneous or surgical tracheostomy: a meta-analysis Crit Care Med 27:1617, 1999 47 Anderson JD, Rabinovici R, Frankel HL: Percutaneous dilational tracheostomy vs open tracheostomy Chest 120:1423, 2001 48 Heffner JE: Percutaneous dilational vs standard tracheostomy: a metaanalysis but not the final analysis Chest 118:1236, 2000 49 Susanto I: Comparing percutaneous tracheostomy with open surgical tracheostomy BMJ 324:3, 2002 50 Angel LF, Simpson CB: Comparison of surgical and percutaneous dilational tracheostomy Clin Chest Med 24:423, 2003 51 Massick DD, Yao S, Powell DM, et al: Bedside tracheostomy in the intensive care unit: a perspective randomized trial comparing surgical tracheostomy with endoscopically guided percutaneous dilational tracheotomy Laryngoscope 111:494, 2001 52 Garland A: Improving the ICU: part 1 Chest 127:2151, 2005 53 Combes A, Luyt CE, Trouillet JL, et al: Adverse effects on a referral intensive care unit’s performance of accepting patients transferred from another intensive care unit Crit Care Med 33:705, 2005 54 Stocchetti N, Parma A, Lamperti M, et al: Neurophysiologic consequences of three tracheostomy techniques: a randomized study in neurosurgical patients J Neurosurg Anesthesiol 12:307, 2000 55 Shlugman D, Satya-Krishna R, Loh L: Acute fatal haemorrhage during percutaneous dilatational tracheostomy Br J Anaesth 90:517, 2003 56 Ayoub OM, Griffiths MV: Aortic arch laceration: a lethal complication after percutaneous tracheostomy Laryngoscope 117:176, 2007 57 Otchwemah R, Defosse J, Wappler F, et al: Percutaneous dilatation tracheostomy in the critically ill: use of ultrasound to detect an aberrant course of the brachiocephalic trunk J Cardiothorac Vasc Anesth 26:e72, 2012 58 Khan SM, Alzahrani T: Common carotid artery surprise during percutaneous dilatational tracheostomy—a near miss, confirmed with ultrasound Saudi J Anaesth 5:353, 2011 59 Gilbey P: Fatal complications of percutaneous dilatational tracheostomy Am J Otolaryngol 33:770, 2012 60 Yavuz A, Yılmaz M, Göya C, et al: Advantages of US in percutaneous dilatational tracheostomy: randomized controlled trial and review of the literature Radiology 273:927, 2014 61 Rudas M, Seppelt I, Herkes R, et al: Traditional landmark versus ultrasound guided tracheal puncture during percutaneous dilatational tracheostomy in adult intensive care patients: a randomised controlled trial Crit Care 18:514, 2014 62 Grillo HZ, Cooper JD, Geffin B, et al: A low pressured cuff for tracheostomy tubes to minimize tracheal inner injury J Thorac Cardiovasc Surg 62:898, 1971 63 Seegobin RD, van Hasselt GL: Endotracheal cuff pressure and tracheal mucosal blood flow, endoscopic study of effects of four large volume cuffs BMJ 288:965, 1984 64 Hess DR: Tracheostomy tubes and related appliances Respir Care 50:497, 2005 65 Wright SE, van Dahn K: Long-term care of the tracheostomy patient Clin Chest Med 24:473, 2003 66 Lewis RM: Airway clearance techniques for patients with artificial airways Respir Care 47:808, 2002 67 Tabaee A, Lando T, Rickert S, et al: Practice patterns, safety, and rationale for tracheostomy tube changes: a survey of otolaryngology training programs Laryngoscope 117:573, 2007 68 Shaker R, Dodds WJ, Dantas EO: Coordination of deglutitive glottic closure with oropharyngeal swallowing Gastroenterol 98:1478, 1990 69 Buckwater JA, Sasaki CT: Effect of tracheostomy on laryngeal function Otolaryngol Clin North Am 21:701, 1988 70 Devita MA, Spierer-Rundback MS: Swallowing disorders in patients with prolonged intubation or tracheostomy tubes Crit Care Med 18:1328, 1990 71 Romero CM, Marambio A, Larrondo J, et al: Swallowing dysfunction in nonneurologic critically ill patients who require percutaneous dilatational tracheostomy Chest 137(6):1278–1282, 2010 72 Tolep K, Getch CL, Criner GJ: Swallowing dysfunction in patients receiving prolonged mechanical ventilation Chest 109:167, 1996 73 Metheny NA, Clouse RE: Bedside methods for detecting aspiration in tube-fed patients Chest 111:724, 1997 74 Muz J, Hamlet S, Mathog R, et al: Scintigraphic assessment of aspiration in head and neck cancer patients with tracheostomy Head Neck 16:17, 1994 75 Leder SB, Tarro JM, Burell MI: Effect of occlusion of a tracheostomy tube on aspiration Dysphagia 11:254, 1996 76 Fernandez R, Bacelar N, Hernandez G, et al: Ward mortality in patients discharged from the ICU with tracheostomy may depend on patient’s vulnerability Intensive Care Med 34:1878, 2008 77 Martinez GH, Fernandez R, Casado MS, et al: Tracheostomy tube in place at intensive care unit discharge is associated with increased ward mortality Respir Care 54:1644, 2009 78 Cetto R, Arora A, Hettige R, et al: Improving tracheostomy care: a prospective study of the multidisciplinary approach Clin Otolaryngol 36:482–488, 2011 79 Goldenberg D, Ari EG, Golz A, et al: Tracheostomy complications: a retrospective study of 1130 cases Otolaryngol Head Neck Surg 123:495, 2000 80 Walz MK, Peitgen K, Thurauf N, et al: Percutaneous dilatational tracheostomy—early results and long-term outcome of 326 critically ill patients Intensive Care Med 24:685, 1998 p 87 p 88 81 Petros S, Engelmann L: Percutaneous dilatational tracheostomy in a medical ICU Intensive Care Med 23:630, 1997 82 Shinkwin CA, Gibbin KP: Tracheostomy in children J R Soc Med 89:188, 1996 83 Cordes SR, Best AR, Hiatt KK: The impact of obesity on adult tracheostomy complication rate Laryngoscope 125:105–110, 2015 84 Byhahn C, Lischke V, Meininger D, et al: Perio-operative complications during percutaneous tracheostomy in obese patients Anaesthesia 60:12–15, 2005 85 Romero CM, Cornejo RA, Ruiz MH, et al: Fiberoptic bronchoscopyassisted percutaneous tracheostomy is safe in obese critically ill patients: a prospective and comparative study J Crit Care 24:494– 500, 2009 86 McCague A, Aljanabi H, Wong D: Safety analysis of percutaneous dilational tracheostomies with bronchscopy in the obese patient Laryngoscope 122:1031–1034, 2012 87 Heffner JE, Miller KS, Sahn SA: Tracheostomy in the intensive care unit, 2: complications Chest 90:430, 1986 88 Glossop AJ, Meekings TC, Hutchinson SP, et al: Complications following tracheostomy insertion in critically ill patients-experience from a large teaching hospital JICS 12:4:301–306, 2011 89 Schaefer OP, Irwin RS: Tracheoarterial fistula: an unusual complication of tracheostomy J Intensive Care Med 10:64, 1995 90 Mamikunian C: Prevention of delayed hemorrhage after tracheotomy Ear Nose Throat J 67:881, 1988 91 Oshinsky AE, Rubin JS, Gwozdz CS: The anatomical basis for posttracheotomy innominate artery rupture Laryngoscope 98:1061, 1988 92 Deguchi J, Furuya T, Tanaku N, et al: Successful management of trachea-innominate artery fistula with endobronchial stent graph repair J Vasc Surg 33:1280, 2001 93 Palchik E, Bakkan AM, Saad N, et al: Endobronchial treatment of tracheoinnominate artery fistula: a case report Vasc Endovasc Surg 41:258, 2007 94 Ferraro F, Marfella R, Esposito M, et al: Tracheal ring fracture secondary to percutaneous tracheostomy: is tracheal flaccidity a risk factor? J Cardiothorac Vasc Anesth 29(3):560–564, 2015 95 Myers EN, Carrau RL: Early complications of tracheostomy Incidence and management Clin Chest Med 12:589, 1991 96 Dartevelle P, Macchiarini P: Management of acquired tracheoesophageal fistula Chest Surg Clin North Am 6:819, 1996 97 Dollner R, Verch M, Schweiger P, et al: Laryngotracheoscopic findings in long-term follow-up after Griggs tracheostomy Chest 122:206, 2002 98 Streitz JM, Shapshay SM: Airway injury after tracheostomy and endotracheal intubation Surg Clin North Am 71:1211, 1991 99 Stauffer JL, Olsen DE, Petty TL: Complications and consequences of endotracheal intubation and tracheostomy: a prospective study of 150 critically ill adult patients Am J Med 70:65, 1981 100 Arola MK, Puhakka H, Makela P: Healing of lesions caused by cuffed tracheotomy tubes and their late sequelae: a follow-up study Acta Anaesthesiol Scand 24:169, 1980 101 Friedman Y, Franklin C: The technique of percutaneous tracheostomy: using serial dilation to secure an airway with minimal risk J Crit Illn 8:289, 1993 102 Crofts SL, Alzeer A, McGuire GP, et al: A comparison of percutaneous and operative tracheostomies in intensive care patients Can J Anaesth 42:775, 1995 Chapter 10 Bronchoscopy PAULO J OLIVEIRA • RAHUL N SOOD • RICHARD S IRWIN Flexible bronchoscopy (FB) was first introduced in 1968 by Dr Shigeto Ikeda, the Japanese physician, who is regarded as the “father” of FB Since then, further technological advances have facilitated its widespread utilization and it has evolved into an invaluable tool for diagnosis and therapy of a wide variety of respiratory diseases in the intensive care unit (ICU) [1] Because of its safety and low complication rate [2], FB has largely replaced rigid bronchoscopy as the procedure of choice for most endoscopic evaluations of the airway and lung parenchyma However, rigid bronchoscopy still plays a potential and pivotal role in the evaluation and management of (a) brisk, massive hemoptysis, defined broadly as 200 to 600 mL per 24 hours; (b) extraction of foreign bodies; (c) endobronchial resection of granulation tissue that can occur after traumatic and/or prolonged intubation; (d) biopsy of potentially vascular tumors (e.g., bronchial carcinoid), in which brisk and excessive bleeding can be controlled by packing and enhanced suction capabilities; (e) endoscopic-mechanical and laser-based debridement/destruction of airway tumors; and (f) dilation of tracheobronchial strictures and management of extrinsic airway constriction via placement of airway stents In the last three decades, there has been renewed interest in the use of rigid bronchoscopy by pulmonologists, driven by the advent of dedicated endobronchial prostheses (airway stents) in the early 1990s for the management of both malignant and benign central airway obstruction [3,4] These advances have fueled the growth of the established field of interventional pulmonology (IP); comprehensive guidelines have been published in the last decade by the American College of Chest Physicians and European Respiratory Society [3,5] In this chapter, we discuss primarily the role of FB in the ICU but the reader is referred to Chapter 182 for the role of IP in the ICU GENERAL CONSIDERATIONS Because FB can be performed easily even in intubated patients, the same general indications apply to critically ill patients on ventilators and noncritically ill patients; however, only the diagnostic and therapeutic indications most commonly encountered in the ICU are discussed here Where relevant, the potential application of advanced bronchoscopic diagnostic and therapeutic interventions in the ICU setting are also discussed COMMON DIAGNOSTIC INDICATIONS Hemoptysis Hemoptysis is one of the most common clinical problems for which bronchoscopy is indicated [6] Whether the patient complains of blood streaking or massive hemoptysis, bronchoscopy should be considered to localize/lateralize the site of bleeding and possibly diagnose the cause Localization of the site of bleeding is crucial if temporizing or definitive therapy, such as surgery, becomes necessary, and it is also useful to guide angiographic procedures (bronchial or pulmonary artery embolization) Whenever patients have an endotracheal or tracheostomy tube in place, hemoptysis should always be evaluated, because it may indicate potentially life-threatening tracheal injury Unless the bleeding is massive, a flexible bronchoscope, rather than a rigid bronchoscope, is the initial instrument of choice for evaluating hemoptysis In the setting of massive hemoptysis, however, the patient is at risk of imminent decompensation and death due to asphyxiation Stabilization of the patient, focusing on establishing a secure airway, and timely communication with pulmonology/IP, thoracic surgery, anesthesiology, and interventional radiology is of utmost importance This coordinated, interprofessional effort should focus on rapid transfer to the operation room suite for rigid bronchoscopy The rigid bronchoscope is ideal in this situation because it provides a secure route for ventilation, serves as a larger conduit for adequate suctioning, and can quickly isolate the lung in the case of a lateralized bleeding source In most situations, once an adequate airway has been established and initial suctioning of excessive blood has been performed, the flexible bronchoscope can be used as a complementary modality inserted through the rigid bronchoscope to more accurately assess, localize, and temporize the source of bleeding within and beyond the main bronchi [7] p 88 p 89 Diffuse Parenchymal Disease The clinical setting influences the choice of procedure When diffuse pulmonary infiltrates suggest sarcoidosis, lymphangitic carcinomatosis, or eosinophilic pneumonia, for example, transbronchial lung biopsy (TBLB) should be considered initially because it has an extremely high yield in these situations However, TBLB has a low yield for the definitive diagnosis of most idiopathic interstitial pneumonias, inorganic pneumoconiosis, and pulmonary vasculitides [8]; when these disorders are suspected, surgical lung biopsy is the gold standard and procedure of choice Although TBLB is usually not adequate for histologic diagnosis of pulmonary fibrosis and acute interstitial pneumonia, it may provide sufficient information to guide therapy in a critically ill patient by excluding infection Ventilator-Associated Pneumonia The ability to determine the probability of ventilator-associated pneumonia (VAP) is very limited, with a sensitivity of only 50% and a specificity of 58% [9] Quantitative cultures obtained via bronchoscopy may thus play an important role in the diagnostic strategy Quantitative cultures of bronchoalveolar lavage (BAL) fluid and protected specimen brush (PSB), with thresholds of 104 colony-forming units (CFU) per mL and 103 CFU per mL, respectively, are most commonly employed prior to initiation of antimicrobial therapy when a semi-invasive approach is taken Cultures of bronchial washings do not add to the diagnostic yield of quantitative BAL culture alone [10] For a brief description of how to perform BAL and obtain PSB cultures, see the “Procedure” section, given later in the chapter For BAL, an evidence-based analysis of 23 prior investigations yielded a sensitivity of 73% and a specificity of 82%, indicating that BAL cultures fail to diagnose VAP in almost one-fourth of all cases [11] A similar analysis of PSB cultures indicates a very wide range of results, with a sensitivity of 33% to greater than 95% and a median of 67%, and a specificity of 50% to 100% with a median of 95% [12] PSB is thus more specific than it is sensitive, and negative results may not be sufficient to exclude the presence of VAP Blind protected telescoping catheter specimens yield similar results to bronchoscopically directed PSB and BAL cultures [13] Despite the greater accuracy of quantitative bronchoscopic cultures, prospective randomized trials of early invasive diagnostic strategies employing bronchoscopy and quantitative lower respiratory tract cultures for VAP have not demonstrated significant advantages in mortality or other major clinical end points over simpler methods [14] A Cochrane database review combining five such randomized controlled trials showed no improvement in mortality, duration of mechanical ventilation, or length of ICU stay [15] On the basis of these findings, routine use of bronchoscopy over semiquantitative endotracheal suctioning cultures in immunocompetent adults with suspected VAP cannot be recommended Pulmonary Infiltrates in Immunocompromised Patients When an infectious process is suspected, the diagnostic yield depends on the organism and the immune status of the patient Numerous recent investigations have examined the utility of bronchoscopy in immunocompromised patients Most of these investigations have found that the diagnostic yield of BAL in such patients is approximately 50% and that the results of BAL lead to a change in treatment in 17% to 38% of patients In one prospective multicenter trial [16], BAL was the only conclusive diagnostic study in 33% of patients Although it is difficult to distinguish respiratory decompensation caused by bronchoscopy from the natural history of the patients’ underlying disease, the same study found that 48% of patients developed deterioration in respiratory status after bronchoscopy and 27% of patients were intubated Because of these concerns, novel approaches to FB have been used in such patients including the utilization of noninvasive positive pressure ventilation or high flow nasal cannula during the procedure [17] Transbronchial biopsy may add only a little to the diagnostic yield of BAL in immunocompromised patients, with an incremental yield of 7% to 12% [18] In some series, the major complication rate of transbronchial biopsy was greater than the diagnostic utility, including a 14% incidence of major bleeding requiring intubation [18] However, in AIDS patients, the sensitivity of lavage and/or TBLB for identifying all opportunistic organisms can be as high as 87% [19] Transbronchial biopsy adds significantly to the diagnostic yield in AIDS patients and may be the sole means of making a diagnosis in up to 24% of patients, including diagnoses of Pneumocystis jirovecii, Cryptococcus neoformans, Mycobacterium tuberculosis, and occasionally nonspecific interstitial pneumonitis [20] Lavage alone may have a sensitivity of up to 97% for the diagnosis of P jirovecii pneumonia [21] However, because induced sputum samples can also be positive for P jirovecii in up to 79% of cases [21], induced expectorated sputum, when available, should be evaluated first for this organism before resorting to bronchoscopy More recently, the use of serum-based markers such as β-2 glucan and galactomannan have also been used in certain settings to guide diagnosis and therapy [22] when P jirovecii and aspergillus infections are considered Acute Inhalation Injury In patients suffering from smoke inhalation, flexible nasopharyngoscopy, laryngoscopy, and bronchoscopy are indicated to identify the anatomic level and severity of injury Prophylactic intubation should be considered if considerable upper airway mucosal injury is noted early; acute respiratory failure is more likely in patients with mucosal changes seen at segmental or lower levels Upper airway obstruction is a life-threatening problem that usually develops during the initial 24 hours after inhalation injury It correlates significantly with increased size of cutaneous burns, burns of the face and neck, and rapid intravenous fluid administration, and also portends a greater mortality [23] Blunt Chest Trauma Patients may present with atelectasis, pulmonary contusion, hemothorax, pneumothorax, pneumomediastinum, or hemoptysis Prompt bronchoscopic evaluation of such patients has a diagnostic yield of 53%; findings may include tracheal or bronchial laceration or transection (14%), aspirated material (6%), supraglottic tear with glottic obstruction (2%), mucus plugging (15%), and distal hemorrhage (13%) [24,25] Many of these diagnoses may not be clinically evident and require surgical intervention p 89 p 90 Postresectional Surgery and Lung Transplantation FB can identify a disrupted suture line causing bleeding and pneumothorax following surgery and an exposed endobronchial suture causing refractory cough In these postpneumonectomy situations, the location of dehiscence and the subsequent bronchopleural fistula (BPF) can be identified visually via FB at the stump site However, when the BPF occurs in the setting of acute respiratory distress syndrome (ARDS) or necrotizing pneumonia, localization at the segmental and subsegmental level (defects less than 2 to 5 mm in diameter) can be more challenging FB also appears to be safe and effective in guiding clinical management in critically ill lung transplant recipients when considering infection or rejection [26] Assessment of Intubation-Related Injury When a nasotracheal or orotracheal tube of the proper size is in place, the balloon can be routinely deflated and the tube withdrawn over the bronchoscope to look for upper airway injury The technique involves withdrawing the tube up through the vocal cords and over the flexible bronchoscope to assess glottic and supraglottic damage This technique may be useful after reintubation for stridor, or when deflation of the endotracheal tube cuff does not produce a significant air leak, suggesting the potential for life-threatening upper airway obstruction when extubation takes place The flexible bronchoscope may readily identify mechanical problems such as increased airway granulation tissue leading to airway obstruction, tracheal tears, tracheal stenosis at pressure points along the artificial airway–tracheal interface, and tracheobronchomalacia THERAPEUTIC INDICATIONS Atelectasis Bronchoscopy has a success rate of up to 89% in cases of lobar atelectasis, but only produced clinical improvement in 44% of patients when performed for retained secretions [27] Two randomized trials found no advantage of bronchoscopy over a very aggressive regimen of frequent chest physiotherapy, recruitment maneuvers, saline nebulization, and postural drainage [28,29] These studies also found that the presence of air bronchograms on the initial chest X-ray predicted relative failure of either intervention to resolve the atelectasis Occasionally, the direct instillation of N-acetylcysteine through the bronchoscope may be necessary to liquefy the thick, tenacious inspissated mucus [30] Because N-acetylcysteine may induce bronchospasm in patients with asthma, these patients should be pretreated with a bronchodilator In cases of complete lobar collapse, a bronchoscope with the largest suction/working channel diameter available (3 to 3.2 mm working channel) should be used Foreign Bodies Although the rigid bronchoscope is considered by many to be the instrument of choice for removing foreign bodies, especially in the pediatric population, devices with which to grasp objects have been created and are available for use with the flexible bronchoscope A recent systematic review of the adult literature showed that FB has a high success rate (92%) in removal of inhaled foreign bodies [31] The success of FB for foreign body removal can be enhanced by rigorous preprocedure preparation, assuring the availability of appropriate ancillary grasping equipment, practicing a “dry run,” and ensuring that a bronchoscopist with experience in foreign body removal is involved It is also important to have an appreciation for situations for which rigid bronchoscopy with added ancillary interventions, such as laser therapy or cryotherapy, might be useful (e.g., an embedded foreign body with significant granulation tissue reaction at risk of bleeding) [32] Endotracheal Intubation Intubation under endoscopic visualization may be planned in cases of a suspected difficult airway that cannot be easily intubated or properly ventilated using the flexible bronchoscope as an obturator for tube passage [33] This is also useful for the intubation of patients with central airway stents, as blind intubation carries the risk of stent migration and malpositioning of the endotracheal tube [34] The bronchoscope of choice should be one with an outer diameter of 5.7 mm or more because thinner more flexible scopes lack the stiffness and enhanced maneuverability needed for successful intubation Hemoptysis On rare occasions where brisk bleeding threatens asphyxiation, endobronchial tamponade may stabilize the patient before definitive therapy is performed With the use of the flexible bronchoscope, usually passed through a rigid bronchoscope or endotracheal tube, a Fogarty catheter with balloon is passed into the bleeding lobar orifice When the balloon is inflated and wedged tightly, the patient may be transferred to surgery or angiography for bronchial arteriography and bronchial artery embolization [35] Other bronchial blocking and lung separation techniques have been described and reviewed in the literature [36] The Arndt blocker is a dedicated bronchial blocker that has a wire loop at its distal end, which when looped around the distal end of the flexible bronchoscope, can be guided to the bleeding airway and inflated Its position can be adjusted under direct visualization and it can be fixed to the outer proximal portion of the endotracheal tube More simple techniques that take advantage of the flexible bronchoscope’s ability to act as a stylet for a single-lumen endotracheal tube can be used to isolate one lung One can use the bronchoscope to preferentially intubate the right main or left main bronchus in an emergent situation Hemostasis may also be achieved by using FB to apply oxidized regenerated cellulose mesh to the bleeding site, instill thrombin/thrombin–fibrinogen preparations, tranexamic acid and more traditionally, perform iced saline lavage or apply topical epinephrine (1:20,000) to decrease the bleeding [37] In the case of a visibly bleeding endobronchial tumor, hemostasis can be attained with laser photocoagulation (Nd-YAG laser), electrocautery, or argon plasma coagulation Central Obstructing Airway Lesions Some patients with cancer and others with benign lesions that obstruct the larynx, trachea, and major bronchi can be treated by electrocautery, laser photoresection, argon plasma coagulation, cryotherapy, or photodynamic therapy applied through the bronchoscope (rigid or flexible) [38,39] FB can also be used to place catheters that facilitate endobronchial delivery of radiation (brachytherapy) Metallic or silicone endobronchial stents can be placed bronchoscopically to relieve stenosis of large central airways Adequate insertion of stents and relief of stenosis (especially due to extrinsic compression) is typically accompanied by dilation of the airway via rigid bronchoscopy or with balloon dilation applied with the aid of FB Several issues regarding airway stents should be noted: silicone stents can only be placed via rigid bronchoscopy and metallic stents should generally not be used in the setting of a nonmalignant central airway obstruction because they are associated with excessive growth of granulation tissue with subsequent worsening of airway obstruction and can be very challenging to remove once this complication occurs [40] The primary goal of the interventions described earlier for the management of malignant central airway obstruction is palliative In many instances, these procedures also facilitate liberation from mechanical ventilation and liberation from the ICU [41] It appears that for intubated ICU patients, FB performed at the bedside with stent deployment and resective interventions, when necessary, is just as effective as rigid bronchoscopic interventions in the appropriately selected patient [42] p 90 p 91 Closure of Bronchopleural Fistula After placement of a chest tube, drainage of the pleural space, and stabilization of the patient (e.g., infection and cardiovascular and respiratory systems), bronchoscopy can be used to visualize a proximal BPF or localize a distal BPF; it can also be used in attempts to close the BPF [43] Please see Chapter 176 that comprehensively covers this topic Percutaneous Dilatational Tracheostomy Flexible bronchoscopic guidance is extremely helpful during bedside percutaneous tracheostomy [44,45] Please see Chapter 9 that comprehensively covers this topic COMPLICATIONS When performed by a trained specialist, routine FB is extremely safe [2] The rare deaths have been due to excessive premedication or topical anesthesia, respiratory arrest from hemorrhage, laryngospasm or bronchospasm, and cardiac arrest from acute myocardial infarction [46] Nonfatal complications occurring within 24 hours of the procedure include fever that is usually cytokine mediated (1.2% to 24%), pneumonia (0.6% to 6%), vasovagal reactions (2.4%), laryngospasm or bronchospasm (0.1% to 0.4%), cardiac arrhythmias (0.9% to 4%), pneumothorax, anesthesia-related problems (0.1%), and aphonia (0.1%) [47] Most investigations have found that the incidence of bacteremia after transoral FB is very low (0.7%) [48] Current guidelines by the American Heart Association for respiratory tract procedures recommend prophylactic antibiotics only when incision or biopsy of the respiratory tract mucosa is anticipated Prophylaxis is further restricted to patients with high-risk cardiac conditions (prosthetic valves, prior history of infective endocarditis, congenital heart disease, and cardiac transplantation with valvulopathy) only and no distinction is made between rigid bronchoscopy and FB [49] Although routine bronchoscopy is extremely safe, critically ill patients appear to be at higher risk for complications Patients with asthma are prone to develop laryngospasm and bronchospasm Bone marrow and stem cell transplant recipients are more likely to develop major bleeding during bronchoscopy (0% to 14%) [50], particularly if PSB or TBLB is performed (7% to 14% vs 1.5% for BAL alone) One investigation found that aspirin use did not increase bleeding risk after transbronchial biopsy [51] However, a prospective cohort study showed that clopidogrel use greatly increases the risk of bleeding after TBLB and therefore should be discontinued 7 days before bronchoscopy with biopsies [52] In critically ill, mechanically ventilated patents, bronchoscopy causes a transient decrease in PaO2 (partial arterial oxygen pressure) of approximately 25% [53], and TBLB is more likely to result in pneumothorax (7% to 23%), particularly in patients with ARDS (up to 36%) [54] CONTRAINDICATIONS Bronchoscopy should not be performed (a) unless an experienced bronchoscopist is available; (b) when the patient will not or cannot cooperate; (c) when adequate oxygenation cannot be maintained during the procedure; (d) in unstable cardiac patients [55]; and (e) in untreated symptomatic patients with asthma [56] British Thoracic Society (BTS) guidelines recommend a platelet count of at least 20,000 per μL for FB with BAL, but to liaison with the hematology team if TBLB is considered [1] Other considerations include patients with uremia and lung transplantation, who are also at a higher risk of bleeding with TBLB [1] In patients with recent cardiac ischemia, the major complication rate is low (3% to 5%) and is similar to that of other critically ill populations [57] The major contraindications to rigid bronchoscopy include inability to tolerate general anesthesia, an unstable cervical spine, limited range of motion of the spine, any condition that inhibits opening of the jaw, and an inexperienced operator and staff [3] Consideration of bronchoscopy in neurologic and neurosurgical patients requires attention to the effects of bronchoscopy on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) In patients with head trauma, bronchoscopy causes the ICP to increase by at least 50% in 88% of patients and by at least 100% in 69% of patients despite the use of deep sedation and paralysis [58] Because mean arterial pressure tends to rise in parallel with ICP, there is often no change in CPP A recent retrospective cohort study showed no increase in neurologic or sedationspecific complications in patients with malignant space occupying brain lesions undergoing flexible or rigid bronchoscopy [59] In such patients, the procedure should be accompanied by deep sedation, paralysis, and medications for cerebral protection for which thiopental and lidocaine should be considered Cerebral hemodynamics should be continuously monitored to ensure that ICP and CPP are within acceptable levels in high-risk patients whenever possible Caution is warranted in patients with markedly elevated baseline ICP or with borderline CPP PROCEDURE For nonintubated patients, FB can be performed by the transnasal or transoral route with a bite block There has also been a recent interest in performing noninvasive ventilation-assisted FB via face mask, first described in eight immunocompromised patients with infiltrates and severe hypoxemia (PaO2/FiO2 < 100) [60] The procedure was well tolerated with either maintenance of or an improvement in oxygenation noted throughout, and none of the patients required intubation Since then, multiple small randomized controlled trials using similar applications of noninvasive ventilation during bronchoscopy in expanded patient populations with severe hypoxemia (PaO2/FiO2 < 200) have been described with similar outcomes [61] Thus, it appears that this technique, augmented by BAL, appears to be a safe, effective, and viable option for obtaining an early and accurate diagnosis of pneumonia in nonintubated, otherwise marginally stable, patients with severe hypoxemia In intubated and mechanically ventilated patients, the flexible bronchoscope can be passed into the tube through a swivel adapter with a rubber diaphragm that will prevent loss of the delivered respiratory gases To prevent dramatic increases in airway resistance and an unacceptable loss of tidal volume, the lumen of the endotracheal tube should be at least 2 mm larger than the outer diameter of the bronchoscope [62] Thus, FB with an average adult-sized instrument (outside diameter of scope 4.8 to 5.9 mm) can be performed in a ventilated patient if there is an endotracheal tube in place that is 8 mm or larger in internal diameter If the endotracheal tube is smaller, a pediatric bronchoscope (outside diameter 3.5 mm) or intubation endoscope (outside diameter 3.8 mm) must be used to prevent damage to the bronchoscope Both diagnostic and therapeutic interventions via FB have also been performed more frequently in the last decade through laryngeal mask airways used to secure the airway in spontaneously breathing under general anesthesia [63] p 91 p 92 Premedication Topical anesthesia may be achieved using nebulized lidocaine with lidocaine jelly as a lubricant and by instilling approximately 3 mL of 1% or 2% lidocaine at the main carina and, if needed, into the lower airways Lidocaine is absorbed through the mucus membranes, producing peak serum concentrations that are nearly as high as that when the equivalent dose is administered intravenously, although toxicity is rare if the total dose does not exceed 6 to 7 mg per kg In 2000, a study performed in otherwise healthy patients with asthma demonstrated the safety of topical lidocaine doses up to 8.2 mg per kg in this population [64] and subsequently led to this upper limit being recommended by the BTS in their guidelines for diagnostic FB [65] A recent randomized control trial showed 1% lidocaine solution to be as effective as the 2% solution in achieving adequate topical anesthesia, at significantly lower cumulative doses [66] In patients with hepatic or cardiac insufficiency, lidocaine clearance is reduced, and the dose should be decreased to a maximum of 4 to 5 mg per kg [67] Administering nebulized lidocaine prior to the procedure substantially increases the total lidocaine dose without improving cough or patient comfort [68] Moderate sedation with incremental doses of midazolam, titrated to produce light sleep, produces amnesia in more than 95% of patients, but adequate sedation may require a total of greater than 20 mg in some subjects [69] Cough suppression is more effective when narcotics are added to benzodiazepine premedication regimens [70] Premedication with intravenous anticholinergics has not been found to reduce secretions, decrease coughing, or prevent bradycardia, and has been associated with greater hemodynamic fluctuations when compared to placebo [71] Propofol and fospropofol [72] have also been used with success during moderate sedation for bronchoscopy, and may have the advantage of more rapid onset and shorter recovery time More recently, a double blinded prospective study showed that a sedative regimen of dexmedetomidine and propofol was associated with fewer episodes of desaturation when compared to remifentanil and propofol in patients undergoing FB, though it was associated with longer recovery times and slightly worse bronchoscopist satisfaction scores [73] Mechanical Ventilation Maintaining adequate oxygenation and ventilation while preventing breath stacking and positive end expiratory pressure (auto-PEEP) may be challenging when insertion of the bronchoscope reduces the effective lumen of the endotracheal tube by more than 50% PEEP caused by standard scopes and tubes will approach 20 cm H2O with the potential for volutrauma The inspired oxygen concentration must be temporarily increased to 100% prior to starting the procedure Expired volumes should be constantly monitored to ensure that they are adequate [62] Meeting these ventilatory goals may require increasing the high-pressure limit in volume-cycled ventilation to near its maximal value, allowing the ventilator to overcome the added resistance caused by the bronchoscope Although this increases the measured peak airway pressure, the alveolar pressure is not likely to change significantly because the lung is protected by the resistance of the bronchoscope [62] Alternatively, decreasing the inspiratory flow rate in an attempt to decrease measured peak pressures may paradoxically increase alveolar pressures by decreasing expiratory time and thus increasing auto-PEEP Suctioning should be kept to a minimum and for short periods of time because it will decrease the tidal volumes being delivered and may lead to derecruitment and associated hypoxemia [74] Quantitative Cultures BAL is performed by advancing the bronchoscope until the tip wedges tightly in a distal bronchus in the area of greatest clinical interest If the disease process is diffuse, perform the procedure in the right middle lobe because this is the area from which the largest returns are most consistently obtained Three aliquots of saline, typically 35 to 50 mL, are then instilled and withdrawn; in some protocols, the first aliquot is discarded to prevent contamination with more proximal secretions A total instilled volume of 100 mL with at least 5% to 10% retrieved constitutes an adequate specimen [75] PSB may be performed through a bronchoscope by advancing the plugged catheter assembly until it projects from the bronchoscope When the area of interest is reached (e.g., purulent secretions can be seen), the distal plug is ejected and the brush is then fully advanced beyond the protective sheath After the specimen is obtained, the brush is pulled back into the sheath and only then is the catheter assembly removed from the bronchoscope ACKNOWLEDGMENTS Dr Stephen Krinzman contributed to previous editions of this chapter REFERENCES Du Rand IA, Blaikley J, Booton R: BTS guideline for diagnostic flexible bronchoscopy in adults Thorax 68:i1–i44, 2013 Facciolongo N, Patelli M, Gasparini S: Incidence of complications in bronchoscopy: multi-centre prospective study of 20,986 bronchoscopies Monaldi Arch Chest Dis 71:8–14, 2009 Bolliger CT, Mathur PN, Beamis JF, et al: ERS/ATS statement on interventional pulmonology Eur Respir J 19(2):356–373, 2002 Wahidi MM, Ernst A: Role of the interventional pulmonologist in the intensive care unit J Intensive Care Med 20(3):141–146, 2005 Ernst A, Silvestri GA, Johnstone D: Interventional pulmonary procedures, guidelines from the American College of Chest Physicians Chest 123:1693–1717, 2003 Sakr L, Dutau H Massive hemoptysis: an update on the role of bronchoscopy in diagnosis and management Respiration 80(1):38– 58, 2010 Susanto I: Managing a patient with hemoptysis J Bronchol 9:40–45, 2002 Bradley B, Branley HM, Egan JJ, et al: Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society Thorax 63[Suppl 5]:v1–v58, 2008 Fartoukh M, Maitre B, Honore S, et al: Diagnosing pneumonia during mechanical ventilation: the clinical infection score revisited Am J Respir Crit Care Med 168:173, 2003 10 Pinckard JK, Kollef M, Dunne WM: Culturing bronchial washings obtained during bronchoscopy fails to add diagnostic utility to culturing the bronchoalveolar lavage fluid alone Diagn Microbiol Infect Dis 43:99, 2002 11 Torres A, El-Ebiary M: Bronchoscopic BAL in the diagnosis of ventilator-associated pneumonia Chest 117:198, 2000 12 Baughman RP: Protected-specimen brush technique in the diagnosis of ventilator associated pneumonia Chest 117:203S–206S, 2000 13 Fujitani S, Yu VL: Diagnosis of ventilator-associated pneumonia: focus on nonbronchoscopic techniques (nonbronchoscopic bronchoalveolar lavage, including mini-BAL, blinded protected specimen brush, and blinded bronchial sampling) and endotracheal aspirates J Intensive Care Med 21:17–21, 2006 p 92 p 93 14 Canadian Critical Care Trials Group: A randomized trial of diagnostic techniques for ventilator-associated pneumonia N Engl J Med 355:2619, 2006 15 Berton DC, Kalil AC, Teixeira PJZ: Quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia Cochrane Database Syst Rev 10:CD006482, 2014 16 Azoulay, E, Mokart, D, Rabbat A, et al: Diagnostic bronchoscopy in hematology and oncology patients with acute respiratory failure: prospective multicenter data Crit Care Med 36:100, 2008 17 Simon M, Braune S, Frings D, et al: High-flow nasal cannula oxygen versus non-invasive ventilation in patients with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy—a prospective randomised trial Crit Care 18(6):712, 2014 18 Patel N, Lee P, Kim J, et al: The influence of diagnostic bronchoscopy on clinical outcomes comparing adult autologous and allogeneic bone marrow transplant recipients Chest 127:1388, 2005 19 Broaddus C, Dake MD, Stulbarg MS, et al: Bronchoalveolar lavage and transbronchial biopsy for the diagnosis of pulmonary infections in the acquired immunodeficiency syndrome Ann Intern Med 102:747, 1985 20 Raoof S, Rosen MJ, Khan FA: Role of bronchoscopy in AIDS Clin Chest Med 20:63, 1999 21 Hopewell PC: Pneumocystis carinii pneumonia: diagnosis J Infect Dis 157:1115, 1988 22 Desmet S, Van Wijngaerden E, Maertens J, et al: Serum (1–3)-beta-Dglucan as a tool for diagnosis of Pneumocystis jirovecii pneumonia in patients with human immunodeficiency virus infection or hematological malignancy J Clin Microbiol 47:3871–3874, 2009 23 Dries DJ, Endorf FW: Inhalation injury: epidemiology, pathology, treatment strategies Scand J Trauma Resusc Emerg Med;21:31, 2013 24 Barmada H, Gibbons JR: Tracheobronchial injury in blunt and penetrating chest trauma Chest 9:74–78, 1994 25 Hara KS, Prakash UBS: Fiberoptic bronchoscopy in the evaluation of acute chest and upper airway trauma Chest 96:627, 1989 26 Mohanka MR, Mehta AC, Budev MM, et al: Impact of bedside bronchoscopy in critically ill lung transplant recipients J Bronchology Interv Pulmonol 21(3):199–207, 2014 27 Kreider ME, Lipson DA: Bronchoscopy for atelectasis in the ICU: a case report and review of the literature Chest 124:344, 2003 28 Jaworski A, Goldberg SK, Walkenstein MD, et al: Utility of immediate postlobectomy fiberoptic bronchoscopy in preventing atelectasis Chest 94(1):38–43, 1988 29 Marini JJ, Pierson DJ, Hudson LD: Acute lobar atelectasis: a prospective comparison of fiberoptic bronchoscopy and respiratory therapy Am Rev Respir Dis 119:971, 1979 30 Lieberman J: The appropriate use of mucolytic agents Am J Med 49:1, 1970 31 Sehgal IS, Dhooria S, Ram B, et al: Foreign body inhalation in the adult population: experience of 25,998 bronchoscopies and systematic review of the literature Respir Care 60(10):1438–1448, 2015 32 Mehta AC, Rafanan AL: Extraction of airway foreign body in adults J Bronchol 8:123–131, 2001 33 Apfelbaum JL, Hagberg CA, Caplan RA, et al: American Society of Anesthesiologists Task Force on Management of the Difficult Airway Practice guidelines for management of the difficult airway: an updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway Anesthesiology 118(2):251–270, 2013 34 Bonnet M, Monteiro MB: Fiberoptic bronchoscopy in intensive care— particular aspects Rev Port Med Int 12:17–19, 2003 35 Schramm R, Abugameh A, Tscholl D, et al: Managing pulmonary artery catheter-induced pulmonary hemorrhage by bronchial occlusion Ann Thorac Surg 88:284–287, 2009 36 Campos JH: An update on bronchial blockers during lung separation techniques in adults Anesth Analg 97:1266–1274, 2003 37 Valipour A, Kreuzer A, Koller H, et al: Bronchoscopy-guided topical hemostatic tamponade therapy for the management of life threatening hemoptysis Chest 127:2113, 2005 38 Beamis J: Interventional pulmonology techniques for treating malignant large airway obstruction: an update Curr Opin Pulm Med 11:292, 2005 39 Ernst A, Feller-Kopman D, Becker HD, et al: Central airway obstruction Am J Respir Crit Care Med 169:1278–1297, 2004 40 Swanson KL, Edell ES, Prakash UB, et al: Complications of metal stent therapy in benign airway obstruction J Bronchol 14:90–94, 2007 41 Colt HG, Harrell JH: Therapeutic rigid bronchoscopy allows level of care changes in patients with acute respiratory failure from central airways obstruction Chest 112:202–206, 1997 42 Saad CP, Murthy S, Krizmanich G, et al: Self-expandable metallic airway stents and flexible bronchoscopy Chest 124:1993–1999, 2003 43 Lois M, Noppen M: Bronchopleural fistulas, an overview of the problem with special focus on endoscopic management Chest 128:3955–3965, 2005 44 Madi JM, Trottier SJ: Percutaneous dilatational tracheostomy technique J Bronchol 10:146–149, 2003 45 Madsen KR, Guldager H, Rewers M, et al: Danish Guidelines 2015 for percutaneous dilatational tracheostomy in the intensive care unit Dan Med J 61(3), 2015 46 Suratt PM, Smiddy JF, Gruber B: Deaths and complications associated with fiberoptic bronchoscopy Chest 69:747, 1976 47 Stubbs SE, Brutinel WM: Complications of bronchoscopy, in Prakash USB (ed): Bronchoscopy New York, Lippincott Williams & Wilkins, 1994, p 357 48 Yigla M, Oren I, Solomonov A, et al: Incidence of bacteraemia following fiberoptic bronchoscopy Eur Respir J 14:789, 1999 49 Wilson M, Taubert KA, Gewitz M, et al: Prevention of endocarditis, guidelines from the American Heart Association Circulation 116:1736– 1754, 2007 50 Dunagan DP, Baker AM, Hurd DD: Bronchoscopic evaluation of pulmonary infiltrates following bone marrow transplantation Chest 111:135, 1997 51 Herth FJ, Becker HD, Ernst A: Aspirin does not increase bleeding complications after transbronchial biopsy Chest 122:1461, 2002 52 Ernst A, Eberhardt R, Wahidi M, et al: Effect of routine clopidogrel use on bleeding complications after transbronchial biopsy in humans Chest 129(3):734–737, 2006 53 Antonelli M, Conti G, Rocco M, et al: Noninvasive positive-pressure ventilation vs conventional oxygen supplementation in hypoxemic patients undergoing diagnostic bronchoscopy Chest 121(4):1149–1154, 2002 54 Bulpa PA, Dive AM, Mertens L, et al: Combined bronchoalveolar lavage and transbronchial lung biopsy: safety and yield in ventilated patients Eur Respir J 21:489, 2003 55 Luck JC, Messeder OH, Rubenstein MJ, et al: Arrhythmias from fiberoptic bronchoscopy Chest 74:139, 1978 56 Sahn SA, Scoggin C: Fiberoptic bronchoscopy in bronchial asthma: a word of caution Chest 69:39, 1976 57 Dweik RA, Mehta AC, Meeker DP, et al: Analysis of the safety of bronchoscopy after recent acute myocardial infarction Chest 110:825, 1996 58 Kerwin AJ, Croce MA, Timmons SD, et al: Effects of fiberoptic bronchoscopy on intracranial pressure in patients with brain injury; a prospective clinical study J Trauma 48:878, 2000 59 Grosu HB, Morice RC, Sarkiss M, et al: Safety of flexible bronchoscopy, rigid bronchoscopy, and endobronchial ultrasound-guided transbronchial needle aspiration in patients with malignant spaceoccupying brain lesions Chest 147(6):1621–1628, 2015 60 Antonelli M, Conti G, Riccioni L, et al: Noninvasive positive-pressure ventilation via face mask during bronchoscopy with BAL in high-risk hypoxemic patients Chest 110:724–728, 1996 61 Simon M, Braune S, Frings D, et al: High-flow nasal cannula oxygen versus non-invasive ventilation in patients with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy—a prospective randomized trial Crit Care 18(6):712, 2014 62 Lawson RW, Peters JI, Shelledy DC: Effects of fiberoptic bronchoscopy during mechanical ventilation in a lung model Chest 118:824, 2000 63 Sung A, Kalstein A, Radhakrishnan P, et al: Laryngeal mask airway: use and clinical applications J Bronchol 14:181–188, 2007 64 Langmack EL, Martin RJ, Pak J, et al: Serum lidocaine concentration in asthmatics undergoing research bronchoscopy Chest 117:1055– 1060, 2000 65 Honeybourne D, Jabb J, Bowie P, et al: British Thoracic Society guidelines on diagnostic flexible bronchoscopy Thorax 56[Suppl I]:i1– i21, 2001 66 Kaur H, Dhooria S, Aggarwal AN, et al: A randomized trial of 1% vs 2% lignocaine by the spray-as-you-go technique for topical anesthesia during flexible bronchoscopy Chest 148(3):739–745, 2015 67 Bose AA, Colt HG: Lidocaine in bronchoscopy: practical use and allergic reactions J Bronchology 15:163–166, 2008 68 Stolz D, Chhajed PN, Leuppi J, et al: Nebulized lidocaine for flexible bronchoscopy: a randomized, double-blind, placebo-controlled trial Chest 128:1756, 2005 69 Williams TJ, Bowie PE: Midazolam sedation to produce complete amnesia for bronchoscopy: 2 years’ experience at a district hospital Respir Med 93:361, 1999 70 Cowl CT, Prakash UBS, Kruger BR: The role of anticholinergics in bronchoscopy: a randomized clinical trial Chest 118:188, 2000 71 Malik JA, Gupta D, Agarwal AN, et al: Anticholinergic premedication for flexible bronchoscopy—a randomized, double-blind, placebocontrolled study of atropine and glycopyrrolate Chest 136(2):347–354, 2009 72 Silvestri GA, Vincent BD, Wahidi MM, et al: A phase-3, randomized, double blind study to assess the efficacy and safety of fospropofol disodium injection for moderate sedation in patients undergoing flexible bronchoscopy Chest 135:41–47, 2009 73 Ryu JH, Lee SW, Lee JH, et al: Randomized double-blind study of remifentanil and dexmedetomidine for flexible bronchoscopy Br J Anaesth 108(3):503–511, 2012 74 Lindholm CE, Ollman B, Snyder JV, et al: Cardiorespiratory effects of flexible fiberoptic bronchoscopy in critically ill patients Chest 74(4):362–368, 1978 75 Meyer KC: The role of bronchoalveolar lavage in interstitial lung disease Clin Chest Med 25:637, 2004 Chapter 11 Lung Ultrasonography PIERRE KORY • NAVITHA RAMESH • PAUL H MAYO INTRODUCTION Dr Daniel Lichtenstein defined the key elements of lung ultrasonography (LUS) with the publication of a series of landmark articles that described the important features and the standard semiology of the field Based on his original work, there have been numerous subsequent studies from other groups which have served to further validate and define the clinical applications of LUS LUS is easy to learn, simple to perform, and has strong utility for the critical care that are well supported by the literature, in particular for the evaluation of respiratory failure BASIC PRINCIPLES OF LUS Air-filled lung at the pleural surface prevents visualization of normal lung parenchyma owing to intense reflection of ultrasound that occurs at the interface of the aerated lung and overlying chest wall The clinical utility of LUS in the critically ill is based on two factors: (1) in cases of respiratory distress or failure, over 90% of attributable lung pathology will contact the pleura at some point in the thorax, revealing identifiable pathologic patterns to the provider at the pleural surface and (2) these patterns can be correlated with discrete causes of respiratory dysfunction [1,2] MACHINE REQUIREMENTS LUS may be performed with a wide variety of ultrasound machines with two-dimensional (2D) scanning capability A 3.5 to 5.0 MHz transducer similar to one used for cardiac applications is used for the entire spectrum of applications Higher frequency (7.5 to 10 MHz) linear probes work well for identification of lung sliding and detailed characterization of pleural morphology PERFORMANCE OF LUS By convention, the transducer is held in a longitudinal scanning plane The transducer should be held like a pen, perpendicular to the chest wall with the transducer orientation marker pointing cephalad The screen marker should be set to the left upper side of the screen This being the case, cephalad structures will be projected to the left on the screen, whereas those that are caudad will be projected to the right on the screen The scanning axis is perpendicular to the pleural surface In areas of the thorax where the pleural surface is curvilinear, the probe is adjusted to obtain a perpendicular to the pleural surface, requiring the operator to tilt the transducer to ensure proper orientation of the ultrasonography beam Proper probe orientation results in a horizontally orientated pleural line on the screen Unlike a chest radiograph, where an entire view of both hemithoraces is obtained in one image; thoracic ultrasonography relies on examining the pleural surfaces at multiple sites over each hemithorax, thus creating an image map of the lungs that is the summation of multiple tomographic cuts produced by movement of the ultrasonography scanning plane over the thorax Many different scanning protocols have been proposed for LUS Most divide the thorax into the anterior area, bordered by the sternum and the anterior axillary line; the lateral area, bordered by the anterior axillary and posterior axillary lines; and the posterior area, bordered by the posterior axillary line and the spine Investigators designate specific points within these areas for examination and assign point values to the focal findings at each point This is useful for research purposes, but impractical for clinical practice The simplest protocol is that proposed by Lichtenstein that examines three defined points on each hemothorax in the anterior, lateral, and posterolateral area with characterization of LUS findings at each site [2] An alternative approach is to perform a series of adjacent scan lines over the chest in order to define areas of abnormality that require more focused scanning (Chapter 11 Video 11.1) The importance of examining the posterolateral chest is emphasized for the critically ill patient, given that the majority of pleural effusions and consolidations are found in the dependent hemithoraces To adequately image this area, the transducer base is pressed into the mattress with the probe face angled anteriorly Alternatively, the patient may be rolled to a lateral decubitus position to fully expose the posterior thorax IMAGING PATTERNS IN LUS Pleural line artifacts and associated appearances of lung and pleural pathology described in the following sections are differentially produced according to the ratio of fluid and air produced by the various disease processes These artifacts and patterns include analysis of the pleural line; the horizontal appearing reverberation artifacts seen in “dry” lung (A lines); the vertical appearing artifacts seen with interstitial fluid (B lines); the airless or fluid-filled lung seen in alveolar consolidation; and the accumulation of fluid seen with pleural effusions MAIN LUS PATTERNS Novice lung ultrasonographers are often challenged by the lack of visually familiar anatomical correlates that are seen when scanning other organs such as the heart or kidney whose boundaries can be well delineated Many lung images are not intuitively obvious to the novice, given that the condition of the lung is often abstracted from artifactual linear echogenic patterns deep to the pleural line These patterns are few, discrete, and easy to master The key findings of LUS for critical care applications are as follows: NORMAL ANATOMY On ultrasonography examination, the chest wall consists of skin overlying a layer of soft tissue and muscle covering the rib cage Below the inner surface of the ribs lies the parietal pleura, against which the outer surface of lung, the visceral pleura, moves in respirophasic and cardiophasic synchrony The rib edges form a distinctive hyperechoic curvilinear line The pleural line is the first horizontal hyperechoic line just below the ribs and represents the interface between parietal and visceral pleura (Chapter 11 Video 11.2) The interface of visceral and parietal pleura is readily visible with ultrasonography Deep to the visceral pleura are the air-filled alveoli within lobules that are subtended by the interlobular septa These septa insert into the visceral pleura, but cannot be seen under normal conditions, because their width is below the resolution of standard diagnostic ultrasonography transducers With normally aerated lung, ultrasonography is intensely reflected from the pleural surface, so that the air-filled lung is not visible as an identifiable structure It is only when the interlobular septae or the alveolar compartment underlying the visceral pleura are diseased that they become visible to the examiner These resulting patterns allow ultrasonography to discriminate normal from abnormal lung FINDINGS OF LUS Lung Sliding With the transducer in a longitudinal orientation, perpendicular to the skin surface, and centered between two adjacent ribs; the pleural line is first located as detailed above, followed by identification of the dynamic movement of the pleural surfaces during the respiratory cycle This movement, seen as a shimmering mobile pleural line that moves in synchrony with the respiratory cycle, is called lung sliding (Chapter 11 Video 11.3) A related finding is lung pulse, whereby the pleural line moves with cardiophasic movement caused by transmitted cardiac pulsations (Chapter 11 Video 11.4) The identification of lung sliding or lung pulse excludes the presence of a pneumothorax at the site of transducer application with certainty [3] Lung sliding and pulse can only be seen when the ultrasound waves propagate to the visceral pleura When pleural air is interposed between the pleural surfaces, as that occurs with pneumothorax, the air acts as a barrier to ultrasound, so the movement of the underlying visceral pleura cannot be seen In this case, lung sliding and lung pulse will be absent (Chapter 11 Video 11.5) As air within the pleural space usually distributes to the anterior thorax in the supine patient, the critically ill patient is ideally positioned to examine for pneumothorax Multiple rib interspaces sites may be rapidly examined for sliding lung over both hemithoraces, so that the intensivist can promptly and confidently rule out a clinically significant pneumothorax with superior accuracy to chest radiography [3–5] Although the presence of lung sliding rules out the presence of pneumothorax at the site being examined, the absence of lung sliding is not diagnostic of pneumothorax Loss of lung sliding may occur in other processes that reduce the movement of the visceral pleura such as pleural symphysis from inflammatory, neoplastic, or therapeutic pleurodesis Mainstem bronchial intubation or occlusion (e.g., mucus plug, blood clot, foreign body, and tumor) will also ablate lung sliding on the side of the blockage In summary, the presence of lung sliding is a very useful sign, because it rules out the possibility of a pneumothorax being present The absence of lung sliding is less useful, and always requires the clinician to consider whether there might be an alternative explanation for the lack of lung sliding Lung Point When faced with the loss of lung sliding, identifying a lung point can confirm the presence of pneumothorax The lung point represents the border of the pneumothorax, where the partially collapsed lung interfaces with the air-filled pneumothorax space Some pneumothoraces are total, but most are partial with some remaining apposition of the visceral and parietal pleura at some point in the thorax, usually lateral or posterior depending on the size of the pneumothorax A lung point is described as the intermittent respirophasic appearance of lung sliding from the edge of the screen (Chapter 11 Video 11.6) Although 100% specific for pneumothorax, lung point has only a 66% sensitivity for detection of pneumothorax [3] A Lines The normally aerated lung yields characteristic air artifacts called “A lines.” An A line is a horizontally orientated line that is deep to the pleural line and separated by the same distance as the probe is to the pleural line (Chapter 11 Video 11.7) The A line is a reverberation of the pleural line, caused by echoes which reflect off of the visceral pleura owing to the inability of ultrasound to penetrate aerated lung tissue The reflected pulse returns to the probe face and is reflected off of its surface to be in turn reflected back from the pleural line When this pulse returns to transducer, it is interpreted by the ultrasound machine as arising from an identical, but more distant tissue plane This is known as a reverberation artifact and occurs when there is an air–tissue interface deep to the probe A lines can appear singly or multiply and are separated from each other by the same distance When A lines appear with lung sliding, this represents a normal aeration pattern When present without sliding lung, A lines represent either air between the visceral and parietal pleura (i.e., a pneumothorax) or aerated lung in association with lack of lung sliding as might occur with pleurodesis from inflammation or intervention B Lines Using standard scanning technique with depth set to examine deeper structures, LUS may yield a characteristic pattern of artifact termed B lines B lines have several distinct characteristics, as follows (Chapter 11 Video 11.8) B lines are vertical in orientation and may occur as one or more per field They originate at the pleural interface They extend ray-like to the bottom/far periphery of the screen They move in synchrony with lung sliding (although mobility is not required, as in the case of B lines in the absence of lung sliding) They are hyperechoic They efface A lines at their point of intersection B lines reflect the presence of a process that infiltrates or widens the interlobular septae of the lung, such as inflammation, neoplasm, or scarring; or that fills the alveolar space [6,7] The presence of B lines is strongly correlated with alveolar or interstitial pattern abnormalities on computed tomography (CT) scan (ground-glass or reticular pattern abnormality) [8] Depending on the disease process that is causing the B lines, they may be focal, scattered, or diffuse in distribution Like any radiographic abnormality on standard chest radiograph or chest CT, clinical correlation is required to determine the cause of the B lines More than two B lines in a single field are considered significant, with the exception that in normal individuals, several B lines may be present in the basilar-dependent rib interspaces Pneumonia may manifest with focal B lines detected in the segment or lobe that is involved Cardiogenic pulmonary edema (CPE) is associated with profuse, bilateral, and often anterior B lines, whereas idiopathic pulmonary fibrosis results in scattered, irregularly appearing B lines in association with pleural line irregularity (Chapter 11 Video 11.9) The artifacts that are sometimes confused with B-lines include Z lines and E lines Z-lines are artifacts arising from the pleural line, but attenuate before the periphery and are not as discrete B lines Z lines have no pathologic significance E Lines are vertical appearing artifacts that arise proximal to the pleural line from subcutaneous emphysema p 95 p 96 As B lines originate from the visceral pleural surface, their presence indicates that the lung is fully inflated at the site of the transducer application to the chest wall The presence of B lines therefore rules out a pneumothorax [9] Loss of lung sliding may occur in ARDS, because the lung is so diseased and the tidal volume so low that it could cause loss of pleural movement Multiple B lines are characteristic of ARDS, so their presence assures the clinician that no pneumothorax is present, if this is a concern Consolidation Consolidated lung yields a characteristic tissue density pattern on ultrasound examination (Chapter 11 Video 11.10) [10] Consolidated lung has an echogenicity that is similar to liver (sonographic hepatization of the lung) If the bronchial structures that supply the affected consolidated lung are patent, the consolidated lung may have sonographic air bronchograms within it, appearing as small hyperechoic foci within the parenchyma.These represent small amounts of air in the bronchi They may be mobile, reflecting movement of air within the bronchus owing to respiratory activity (Chapter 11 Video 11.11) Dynamic air bronchograms are highly suggestive of pneumonia as the cause of the consolidation [11] The examiner may localize consolidation to a specific lobe or segment of the lung The finding of consolidation with LUS is strongly correlated with results of chest CT [8] The finding of consolidation on LUS is purely descriptive, and similar to the finding of consolidation on chest radiography or chest CT Any process that renders the alveolar compartment airless will demonstrate consolidation on LUS or with other radiographic techniques All causes of airless lung, such as atelectasis (compressive, resorptive, or cicatricial), infiltrative processes (tumor, purulent material as in pneumonia), or severe pulmonary edema with complete filling of the alveolar compartment will yield the ultrasonographic finding of lung consolidation LUS identifies the consolidation; the clinician determines its cause PATTERN ANALYSIS OF LUS Differentiating Causes of Acute Respiratory Failure and Dyspnea Knowledge of LUS patterns allows the intensivist to improve the accuracy of diagnosis of acute respiratory failure when compared to use of standard clinical testing and assessment [12,13] Given the utility of LUS to identify the cause of respiratory failure, the thoracic ultrasound examination may replace standard chest radiography as a more effective and efficient imaging modality [14–16] When evaluating the patient with dyspnea and/or respiratory failure, the critical care clinician associates various profiles described below with the corresponding cause of respiratory failure compromise This allows for early categorization of the disease process Generalized A Lines with Lung Sliding This normal aeration pattern is seen among healthy patients; but when it is associated with dyspnea, the diagnostic possibilities include (1) the airway compartment (Chronic Obstructive Pulmonary Disease [COPD] or asthma), (2) the vascular compartment (pulmonary embolism), or (3) non-pulmonary causes such as neurologic, neuromuscular, metabolic, and toxic This pattern rules out diseases that compromise the alveolar and/or interstitial compartment (pulmonary edema, pneumonia, fibrosis, etc.) or the pleural compartment Identification of a normal aeration pattern of the dyspneic patient where pulmonary embolism is a concern requires the intensivist to perform a study for venous thromboembolism (see Chapter 92 on Venous Thromboembolism) A Lines, Absence of Lung Sliding, Presence of Lung Point When lung sliding is absent with A lines, pneumothorax is a possibility For this situation, identification of a lung point confirms that there is a pneumothorax If no lung point is identified, other methods are required to confirm if there is a pneumothorax, given the low sensitivity of lung point The presence of lung pulse, B lines, or consolidation also rules out pneumothorax at the interspace being examined Multiple interspaces are examined in a short period of time Alveolar/Interstitial Disease: B Line Patterns Detection of profuse B lines at multiple symmetric points over the anterior chest indicates a high probability of an alveolar and/or interstitial process CPE with profuse B line pattern is associated with a smooth pleural line morphology.This requires examination of the pleural line with the high frequency linear vascular probe A rare cause of unilateral profuse B line pattern with smooth pleural morphology is unilateral CPE related to asymmetric mitral valve regurgitation Detection of multiple focal B lines with asymmetric distribution suggests primary lung injury pattern such as pneumonia, acute respiratory distress syndrome (ARDS), or other alveolar/interstitial process For instance, when B lines are detected from subsegmental, segmental, lobar, or unilateral distribution, or involving one hemithorax with A line pattern for the rest of the lung, pneumonia is a prime consideration Primary lung injury results in irregular pleural morphology This requires examination of the pleural line with the highfrequency linear vascular probe Thus, depending on the pattern of B profiles over the hemithorax (unilateral vs bilateral; irregular pleural line; sliding or non-sliding lung; sparing or uniform areas), the provider can differentiate CPE versus primary lung injury as the cause of respiratory failure Alveolar Consolidation Pattern Alveolar consolidation is readily identified with LUS It may appear as small multifocal areas of consolidation immediately below the pleural interface or in subsegmental, segmental, lobar, whole lung pattern with unifocal or multifocal distribution As with chest radiography and chest CT, the finding of alveolar consolidation pattern with LUS is descriptive and not diagnostic, given that there are many causes for alveolar consolidation For pneumonia, the consolidation appears as tissue density without volume loss (Chapter 11 Video 11.10) The interface between the pleural surface and the consolidation is linear, whereas the interface between the consolidation and the adjacent aerated lung is irregular and often is associated with comet tail artifacts This irregular interface is called the “shred sign” (Chapter 11 Video Clip 11.12) Pneumonias often contain dynamic air bronchograms, which appear as mobile, branching, and hyperechoic within the parenchyma (Chapter 11 Video 11.11) Although suggestive of pneumonia, mobile air bronchograms may be found in association with non-pneumonia consolidation; a hypoechoic area with well-defined borders within an area of alveolar consolidation is consistent with necrosis or abscess (Chapter 11 Video 11.13) p 96 p 97 Atelectasis of lung results in an alveolar consolidation pattern that can be readily identified with LUS The mechanism of the atelectasis may differ (compressive, resorptive, or cicatricial), but there is a characteristic loss of lung volume in association with the alveolar consolidation Mobile air bronchograms are uncommon, although static air bronchograms are often present, unless the cause for the atelectasis is complete endobronchial occlusion [11] A common cause of alveolar consolidation is that which occurs with pleural effusion Compressive atelectasis from a pleural effusion causes the atelectatic lung to float within the effusion often in association with respirophasic or cardiophasic movement of the lung (Chapter 11 Video 11.14) Areas of posterior basilar alveolar consolidation commonly occur in patients on ventilatory support The dual mechanism of compressive and resorptive atelectasis results in the airless lung that reinflates when the patient is successfully extubated Differentiation from pneumonia may be challenging and requires clinical correlation Endobronchial occlusion by mucus; tumor; foreign body aspiration; or block of the left mainstem bronchus with the endotracheal tube balloon (because of unintentional right mainstem bronchial intubation) results in resorptive atelectasis that is detected as alveolar consolidation with LUS Bronchial occlusion results in absence of mobile air bronchograms If the blockage is at the mainstem bronchial level, the affected lung undergoes major volume loss with associated marked ipsilateral shift of mediastinal and cardiac structures This can occur rapidly if the patient is on a high FiO2 as is the case immediately following endotracheal intubation CLINICAL APPLICATIONS OF LUS Clarification of the Ambiguous Chest Radiograph The technique of the intensive care unit (ICU) chest radiograph is often suboptimal The anteroposterior projection combines with rotation, penetration, and density summation artifact to make interpretation difficult Chest radiography results in a 2D representation of a complex structure, whereas thoracic ultrasonography yields a three-dimensional representation of the thoracic compartment by virtue of the multiple tomographic planes used in the examination LUS may replace chest radiography for evaluation of the dyspneic patient; for identification of consolidation related to pneumonia; and for the evaluation of pleuritic chest pain [14–16] The routine use of LUS was associated with reduced use of chest radiography and chest CT in a medical ICU [17] An ambiguous chest radiograph requires clarification with LUS As performance of LUS is superior to the standard ICU chest radiograph for detection of normal aeration pattern, alveolar/interstial pattern, consolidation, pneumothorax, and pleural effusion [8]; the argument may be made that LUS could largely replace chest radiography in the ICU [18] Although chest radiography does remain useful for determining the location of a variety of intrathoracic devices (see Chapter 179 Chest Radiographic Examination), the location of central venous catheters may, in many cases, be determined with ultrasonography (See Chapter 6 Central Venous Catheters) Differentiation of ARDS from Cardiogenic Pulmonary Edema Copetti et al demonstrated the ability of LUS to discriminate between acute respiratory distress syndrome (ARDS) and CPE [19] The most specific sign for ARDS was the finding of both an area of normal aeration within a single interspace co-existing with a focus on B lines/interstitial syndrome Such a pattern was found in 100% of ARDS patients and 0% of CPE patients Pleural line abnormalities such as thickening >2 mm, coarse irregular appearance, or subpleural consolidations were found in 100% of ARDS patients and 25% of CPE patients Profuse B line pattern with a smooth pleural surface was highly suggestive of CPE The finding of new onset B lines bilaterally during cardiac stress testing is indicative of inducible cardiac ischemia with increase in left-sided filling pressures [20] An increase in extravascular lung water—as assessed independently by chest CT, chest X-ray, and thermodilution techniques—is associated with B lines [21] Prediction of Extubation Failure The amount of extravascular lung water and non-aerated lung can be accurately estimated using the LUS scoring system proposed by Rouby et al [22] In their scoring system, a value of 0 is assigned to any interspace examined which revealed A lines with sliding lung, a value of 1 to interspaces with regularly spaced B lines consistent with interlobular septal thickening, a value of 2 to interspaces with confluent B lines filling the visualized interspace, and a value of 3 was assigned to interspaces with consolidation Assigning a score to 6 interspaces over each hemithorax led to a maximum LUS score of 36 When performing LUS scores before and after a 30-minute spontaneous breathing trial (SBT), an increase in the LUS score of more than 4 points predicted extubation failure Additionally, any end-SBT LUS score >17 strongly predicted extubation failure Measurement of Lung Recruitment with PEEP The above LUS score can also be used to predict the effects of positive end-expiratory pressure (PEEP) in ARDS patients [23] When varying PEEP levels from 0 to 15, a decrease of 8 points in the LUS score described above using the higher PEEP, resulted in an average increase of lung volume >600 mL If the LUS score increased by 4 or less, the volume increased by an average of 75 to 450 mL The authors of this report caution that they could not distinguish whether the augmentation of lung volume resulted from lung recruitment or from overdistention of lung Diagnosis of Pneumonia LUS is useful in establishing the diagnosis of pneumonia and following its evolution [24,25] Of interest to the intensivist, the resolution of ventilator associated pneumonia (VAP) with antibiotic therapy can tracked with LUS [26], and the combination of LUS with sputum analysis is useful for the diagnosis of VAP [27] Algorithmic Diagnosis of Respiratory Failure Dr Lichtenstein has developed a useful algorithm for the use of LUS in determining the cause of respiratory failure (the bedside lung ultrasound in emergency [BLUE] protocol) [2] Using a simple three-point examination technique and simple LUS signs, the algorithm identified the etiology of respiratory failure in a high proportion of cases Estimates of Left Atrial Pressure Patients with symptomatic CPE have a bilateral B line pattern Conversely, if the patient has A line pattern with lung sliding, there is a high probability that the pulmonary occlusion pressure is below 18 mm Hg and probably less that 12 mm Hg [28] Beyond its clinical utility in diagnosis of respiratory failure, this information has application during cardiac stress testing EKG monitoring and serial segmental wall analysis with echocardiography are standard means of detecting ischemia during the stress test The sudden appearance of B lines coincident with the onset of dyspnea while under exercise load is consistent with elevation of left atrial pressures with resultant CPE precipitated by cardiac ischemia [20] p 97 p 98 Combination of LUS with Echocardiography In evaluating patients with acute respiratory failure, Bataille et al reported that the addition of echocardiography to LUS was superior to performing LUS alone [29] Sekiguchi et al confirmed that LUS is productively combined with echocardiography for the evaluation of respiratory failure [30] Diagnosis of Pulmonary Embolism Koenig et al and Nazerian et al both found that LUS combined with echocardiography and DVT study is a means of reducing unnecessary chest CT angiograms when pulmonary embolism is a diagnostic consideration A definite alternative diagnosis of pulmonary embolism using ultrasonography excluded pulmonary embolism with a high level of certainty [31,32] Mathis et al reported that pulmonary emboli commonly result in small areas of consolidation immediately deep to the pleural interface with preferential distribution to the lower lobes of the lung [33] This is a difficult area to image in the critically ill patient who is generally in supine position, so their results have uncertain application for the intensivist Timing of Chest Tube Removal Maury et al used LUS to document lung expansion following chest tube insertion for pneumothorax [34] Once the lung is fully inflated by LUS criteria, the chest tube is clamped and LUS performed to observe for recurrence of the PTX If there is no recurrence by LUS, the chest tube may be safely removed The investigators found that this method was superior to standard chest radiography From a practical point of view, this method offers a convenient, efficient, and cost-effective means of timing the removal of chest tube LUS for Guidance of Procedures LUS may be used to guide transthoracic needles to biopsy peripheral lung lesions that abut the chest wall and thus are visible, given that no aerated lung is interposed [35] Similarly, intraparenchymal lung abscess can be drained if clinically indicated [36] Utility of LUS for Thoracic Trauma The utility of LUS for thoracic trauma is reviewed in Chapter 43 on Thoracic and Cardiac Trauma Utility of LUS for Airway Management The utility of LUS for airway management is reviewed in Chapter 8 on Airway Management REFERENCES Lichtenstein D: Whole body ultrasonography in the critically ill Heidelberg: Springer, 2010 Lichtenstein DA, Mezière GA: Relevance of lung ultrasound in the diagnosis of acute respiratory failure: the BLUE protocol Chest 134:117–125, 2008 Lichtenstein DA, Menu Y: A bedside ultrasound sign ruling out pneumothorax in the critically ill: lung sliding Chest 108:1345–1348, 1995 Soldati G, Testa A, Sher S, et al: Occult traumatic pneumothorax: diagnostic accuracy of lung ultrasonography in the emergency department Chest 133:204–211, 2008 Blaivas M, Lyon M, Duggal SA: Prospective comparison of supine chest radiography and bedside ultrasound for the diagnosis of traumatic pneumothorax Acad Emerg Med 12:844–849, 2005 Lichtenstein D, Meziére G: A lung ultrasound sign allowing bedside distinction between pulmonary edema and COPD: the comet-tail artifact Intensive Care Med 2:1331–1334, 1998 Agricola E, Bove T, Oppizzi M, et al: “Ultrasound comet-tail images”: a marker of pulmonary edema Chest 127:1690–1695, 2005 Lichtenstein D, Goldstein I, Mourgeon E, et al: Comparative diagnostic performances of auscultation, chest radiography, and lung ultrasonography in acute respiratory distress syndrome Anesthesiology 100:9–15, 2004 Lichtenstein D, Mezière G, Biderman P, et al: The comet-tail artifact: an ultrasound sign ruling out pneumothorax Intensive Care Med 25:383–388, 1999 10 Lichtenstein DA, Lascols N, Mezière G, et al: Ultra-sound diagnosis of alveolar consolidation in the critically ill Intensive Care Med 30:276– 281, 2004 11 Lichtenstein D, Meziere G, Seitz J: The dynamic air bronchogram A Lung ultrasound sigh of alveolar consolidation ruling out atelectasis Chest 135(6):1421–1425, 2009 12 Laursen CB, Sloth E, Lambrechtsen J, et al: Focused sonography of the heart, lungs, and deep veins identifies missed life-threatening conditions in admitted patients with acute respiratory symptoms Chest 144(6):1868–1875, 2013 13 Silva S, Biendel C, Ruiz J, et al: Usefulness of cardiothoracic chest ultrasound in the management of acute respiratory failure in critical care practice Chest 144(3):859–865, 2013 14 Zanobetti M, Poggioni C, Pini R: Can chest ultrasonography replace standard chest radiography for evaluation of acute dyspnea in the ED? Chest 139(5):1140–1147, 2011 15 Cortellaro F, Colombo S, Coen D, et al: Lung ultrasound is an accurate diagnostic tool for the diagnosis of pneumonia in the emergency department Emerg Med J 29:19–23, 2012 16 Volpicelli G, Caramello V, Cardinale L, et al: Diagnosis of radio-occult pulmonary conditions by real-time chest ultrasonography in patients with pleuritic pain Ultrasound Med Biol 34(11):1717–1723, 2008 17 Oks M, Cleven KL, Cardenas-Garcia J, et al: The effect of point-of-care ultrasonography on imaging studies in the medical ICU: a comparative study Chest 146:1574–1577, 2014 18 Xirouchaki N, Magkanas E, Vaporidi K, et al: Lung ultrasound in critically ill patients: comparison with bedside chest radiography Intensive Care Med 37:1488–1493, 2011 19 Copetti R, Soldati G, Copetti P: Chest sonography: a useful tool to differentiate acute cardiogenic pulmonary edema from acute respiratory distress syndrome Cardiovasc Ultrasound 6:16, 2008 20 Agricola E, Picano E, Oppizzi M, et al: Assessment of stress-induced pulmonary interstitial edema by chest ultrasound during exercise echocardiography and its correlation with left ventricular function J Am Soc Echocardiogr 19:457–463, 2006 21 Picano E, Frassi F, Agricola E, et al: Ultrasound lung comets: a clinically useful sign of extravascular lung water J Am Soc Echocardiogr 19:356–363, 2006 22 Soummer A, Perbet S, Brisson H, et al; the Lung Ultrasound Study Group: Ultrasound assessment of lung aeration loss during a successful spontaneous breathing trial predicts postextubation distress Crit Care Med 40:2064–2072, 2012 23 Bouhemad B, Bresson H, Le-Guen M, et al: Bedside ultrasound assessment of positive end-expiratory pressure-induced lung recruitment Am J Resp Crit Care Med 183:341–347, 2011 24 Ye X, Xiao H, Chen B, et al: Accuracy of lung ultrasonography versus chest radiography for the diagnosis of adult community-acquired pneumonia: review of the literature and meta-analysis PLoS One 10(6):e0130066, 2015 25 Reissig A, Copetti R, Mathis G, et al: Lung ultrasound in the diagnosis and follow-up of community-acquired pneumonia: a prospective, multicenter, diagnostic accuracy study Chest 142:965–972, 2012 26 Bouhemad B, Liu ZH, Arbelot C, et al: Ultrasound assessment of antibiotic-induced pulmonary reaeration in ventilator-associated pneumonia Crit Care Med 38:84–92, 2010 27 Mongodi S, Via G, Girard M, et al: Lung ultrasound for early diagnosis of ventilator-associated pneumonia Chest 149:969–980, 2016 28 Lichtenstein DA, Mezière GA, Lagoueyte JF, et al: A-lines and B-lines: lung ultrasound as a bedside tool for predicting pulmonary artery occlusion pressure in the critically ill Chest 136:1014–1020, 2009 29 Bataille B, Riu B, Ferre F, et al: Integrated use of bedside lung ultrasound and echocardiography in acute respiratory failure: a prospective observational study in ICU Chest 146:1586–1593, 2014 30 Sekiguchi H, Schenck LA, Horie R, et al: Critical care ultrasonography differentiates ARDS, pulmonary edema, and other causes in the early course of acute hypoxemic respiratory failure Chest 148:912–918, 2015 p 98 p 99 31 Koenig S, Chandra S, Alaverdian A, et al: Ultrasound assessment of pulmonary embolism in patients receiving CT pulmonary angiography Chest 145:818–823, 2014 32 Nazerian P, Vanni S, Volpicelli G, et al: Accuracy of point-of-care multiorgan ultrasonography for the diagnosis of pulmonary embolism Chest 145:950–957, 2014 33 Mathis G, Blank W, Reissig A, et al: Thoracic ultrasound for diagnosing pulmonary embolism: a prospective multicenter study of 352 patients Chest 128:1531–1538, 2005 34 Galbois A, Ait-Oufella H, Baudel JL, et al: Pleural ultrasound compared with chest radiographic detection of pneumothorax resolution after drainage Chest 138:648–655, 2010 35 Yang PC: Ultrasound-guided transthoracic biopsy of peripheral lung, pleural, and chest-wall lesions J Thorac Imaging 12:272–284, 1997 36 Yang PC, Luh KT, Lee YC, et al: Lung abscesses: US examination and US-guided transthoracic aspiration Radiology 180:171–175, 1991 Chapter 12 Thoracentesis MARK M WILSON • RICHARD S IRWIN Thoracentesis is an invasive procedure that involves the introduction of a needle, cannula, or trocar into the pleural space to remove accumulated fluid or air Although a few studies have critically evaluated the clinical value and complications associated with it [1–6], most studies concerning thoracentesis have dealt with the interpretation of the pleural fluid analyses [7–11] INDICATIONS Although history (cough, dyspnea, or pleuritic chest pain) and physical findings (dullness to percussion, decreased breath sounds, and decreased vocal fremitus) suggest that an effusion is present, chest radiography or ultrasonic examination is essential to confirm the clinical suspicion Thoracentesis can be performed for diagnostic or therapeutic reasons When done for diagnostic reasons, the procedure should be performed whenever possible before any treatment has been given to avoid confusion in interpretation Analysis of pleural fluid has been shown to yield clinically useful information in more than 90% of cases The four most common diagnoses for symptomatic and asymptomatic pleural effusions are malignancy, congestive heart failure (CHF), parapneumonia, and postoperative sympathetic effusions A diagnostic algorithm for evaluation of a pleural effusion of unknown etiology is presented in Figure 12.1 In patients whose exudative pleural effusion remains undiagnosed after thoracentesis, closed pleural biopsy or thoracoscopy should be considered Thoracoscopy provides for visualization of the pleura and directed biopsy, and yields a diagnosis in more than 80% of patients with recurrent pleural effusions that are not diagnosed by repeated thoracentesis, closed pleural biopsy, or bronchoscopy FIGURE 12.1 Diagnostic algorithm for evaluation of pleural effusion CHF, congestive heart failure; Dx, diagnosis; USGT, ultrasound-guided thoracentesis; VATS, video-assisted thoracoscopic surgery; Bx, biopsy; TB, tuberculosis; Ca, cancer (Adapted from Smyrnios NA, Jederlinic PJ, Irwin RS: Pleural effusion in an asymptomatic patient Spectrum and frequency of causes and management considerations Chest 97:192, 1990) Therapeutic thoracentesis is indicated to remove fluid or air that is causing cardiopulmonary embarrassment, or for relief of severe symptoms Definitive drainage of the pleural space with a thoracostomy tube must be done for a tension pneumothorax (PTX) and should be considered for: a PTX that is slowly enlarging; any size PTX in the mechanically ventilated patient; hemothorax; or the instillation of a sclerosing agent after drainage of a recurrent malignant pleural effusion CONTRAINDICATIONS Absolute contraindications to performing a thoracentesis are an uncooperative patient; a lack of expertise in performing the procedure; and the presence of a coagulation abnormality that cannot be corrected Relative contraindications to a thoracentesis include entry into an area where known bullous lung disease exists; a patient on positive endexpiratory pressure (PEEP); and a patient who has only one “functioning” lung (the other having been surgically removed or that has severe disease limiting its gas exchange function) COMPLICATIONS A number of prospective studies have documented that complications associated with the procedure are not infrequent [1–6,12] The overall complication rate has been reported to be as high as 50% to 78% and can be further categorized as major (15% to 19%) or minor (31% to 63%) [12] Complication rates appear to be inversely related to experience level of the operator; the more experienced the operator, the fewer the complications Although death due to the procedure is infrequently reported, complications may be life threatening Major complications include PTX; bleeding (e.g., hemopneumothorax, hemoperitoneum, and hematoma); hypotension; soft tissue infection; empyema; spleen or liver puncture; and reexpansion pulmonary edema The reported incidence of PTX is up to 30% (with most studies reporting rates of nearly 12%) and up to one-third to one-half of those with demonstrated PTX requiring subsequent intervention [2,12] Tube thoracostomy should be considered for any PTX that is large or progressive and in any patient that is mechanically ventilated or symptomatic after the procedure Several nonrandomized studies involving spontaneously breathing patients undergoing ultrasoundguided thoracentesis (USGT) performed by trained operators have demonstrated a reduction in the rate of PTX to less than 2% [5,6,13] The risk of PTX for patients receiving positive-pressure mechanical ventilation is approximately 1% to 7% with the use of USGT [1,3] The use of PEEP does not appear to increase the risk of PTX for USGT [11] Various investigators have reported associations (“risk factors”) between PTX and underlying lung disease (chronic obstructive pulmonary disease, prior thoracic radiation, prior thoracic surgery, and lung cancer); needle size and technique; number of passes required to obtain a sample; aspiration of air during the procedure; operator experience; use of a vacuum bottle; smaller size of the effusion; and mechanical ventilation versus spontaneously breathing patients [2,12] Small sample sizes and observational study design limit the generalization of reported findings to allow for the delineation of a clear risk profile for the development of a PTX due to thoracentesis The presence of baseline lung disease; low level of operator experience with the procedure; lack of use of ultrasound guidance; and the use of positivepressure mechanical ventilation appear for now to be the best-established risk factors in the literature Recognition and optimization of modifiable risk factors has been shown to improve the safety of thoracentesis [5,6,13] Given the evidence of the value of ultrasound guidance in the performance of thoracentesis [1,3,5,6,13–16], the Accreditation Council for Graduate Medical Education (ACGME) has stated that effective July 2012 pulmonary/critical care fellows “must demonstrate competence in procedural and technical skills, including: use of ultrasound techniques to perform thoracentesis and place intravascular and intracavitary tubes and catheters.” Thoracic ultrasound techniques for the sampling/removal of pleural fluid are described in more detail below p 99 p 100 Although PTX is most commonly caused by laceration of lung parenchyma, room air may enter the pleural space around or through a thoracentesis needle or catheter that is open to room air when a spontaneously breathing patient takes a deep breath (intrapleural pressure is subatmospheric) The PTX may be small and asymptomatic, resolving spontaneously, or large and associated with respiratory compromise, requiring chest tube drainage Hemorrhage can occur from laceration of an intercostal artery or unintentional puncture of the liver or spleen, even if coagulation studies are normal The risk of intercostal artery laceration is greatest in the elderly because of increased tortuosity of their vessels This last complication is potentially lethal, and risk is minimized at sites 9 to 10 cm lateral to the spine (essentially the posterior axillary line, and this is the preferred puncture site, assuming accessibility of the fluid collection) [17,18] Hypotension may occur during the procedure (as part of a vasovagal reaction or tension PTX) or hours after the procedure (uncommon, but most likely because of reaccumulation of fluid into the pleural space or the pulmonary parenchyma from the intravascular space) Hypotension in the latter settings responds to volume expansion; it can usually be prevented by limiting pleural fluid drainage to 1.5 L or less or alternatively by using serial measurements of pleural pressure (manometry) during large volume thoracentesis to determine a “safe” volume of fluid to be removed (described elsewhere) [19] Other major complications are rare and may include implantation of tumor along the needle tract of a previously performed thoracentesis; venous and cerebral air embolism (the so-called pleural shock); and accidental shearing of the catheter in the pleural space [12] p 100 p 101 Minor complications include dry tap or insufficient fluid; pain; subcutaneous hematoma or seroma; anxiety; dyspnea; and cough Reported rates for these minor complications range from 16% to 63% [12] Dry tap and insufficient fluid are technical problems and expose the patient to increased risk of morbidity because of the need to perform multiple needle passes or repeated thoracentesis attempts at an alternate site Pain may originate from parietal pleural nerve endings from inadequate local anesthesia; unintentional scraping of rib periosteum; or piercing an intercostal nerve during a misdirected needle thrust PROCEDURES General Considerations The most common techniques for performing thoracentesis are catheterover-needle; needle only; and needle under direct sonographic guidance (multiple commercially available kits available) The catheter-throughneedle technique has been used much less frequently over the past few decades Performing thoracentesis without ultrasound guidance (using auscultation and percussion exam techniques to establish a fluid level) is suggested only in the presence of a large, free-flowing effusion and limited availability of ultrasound Otherwise, USGT is the method of choice Technique for Diagnostic Sampling of a Large, Freely Flowing Pleural Effusion (Clinical Exam Guided) Obtain a lateral decubitus chest radiograph to confirm a large, freeflowing pleural effusion This is only required if ultrasonography is not available Describe the procedure to the patient and obtain written informed consent Operators should be thoroughly familiar with the procedure that they will perform, and should receive appropriate supervision from an experienced operator before performing thoracentesis on their own With the patient sitting, arms at sides, mark the inferior tip of the scapula on the side to be tapped This approximates the eighth intercostal space and should be the lowest interspace punctured, unless it has been previously determined by sonography that a lower interspace can be safely entered, or chest radiographs and sonography show the diaphragm to be higher than the eighth intercostal space Position the patient sitting at the edge of the bed, comfortably leaning forward over a pillow-draped, height-adjusted, bedside table (Fig 12.2) The patient’s arms should be crossed in front to elevate and spread the scapulae An assistant should stand in front of the patient to prevent any unexpected movements Percuss the patient’s posterior chest to determine the highest point of the effusion The interspace below this point should be entered in the posterior axillary line, unless it is below the eighth intercostal space Gently mark the superior aspect of the rib in the chosen interspace with your fingernail (The inferior portion of each rib contains an intercostal artery and should be avoided.) Cleanse a wide area with 0.05% chlorhexidine or 10% povidone–iodine solution and allow it to dry Using sterile technique, drape the area surrounding the puncture site Perform a time out and anesthetize the superficial skin with 2% lidocaine using a 25-gauge needle Change to an 18- to 22-gauge needle, 2 inches long, and generously anesthetize the deeper soft tissues, aiming for the top of the rib Always aspirate through the syringe as the needle is advanced and before instilling lidocaine to ensure that the needle is not in a vessel or the pleural space Carefully aspirate through the syringe as the pleura is approached (the rib is 1 to 2 cm thick) Pleural fluid enters the syringe on reaching the pleural space The patient may experience discomfort as the needle penetrates the well-innervated parietal pleura Be careful not to instill anesthetic into the pleural space; it is bactericidal for most organisms, including Mycobacterium tuberculosis Place a gloved finger at the point on the needle where it exits the skin (to estimate the required depth of insertion) and remove the needle Attach a three-way stopcock to a 20-gauge, 1.5-inch needle and to a 50-mL syringe The valve on the stopcock should be open to the needle to allow aspiration of pleural fluid during needle insertion Insert the 20-gauge needle (or the catheter-over-needle apparatus) into the anesthetized tract with the bevel of the needle down and always aspirate through the syringe as the needle/catheter-over-needle is slowly advanced When pleural fluid is obtained using the needleonly technique, stabilize the needle by attaching a clamp to the needle where it exits the skin to prevent further advancement of the needle into the pleural space Once pleural fluid is obtained with the catheterover-needle technique, direct the needle-catheter apparatus downward to ensure that the catheter descends to the most dependent area of the pleural space Advance the catheter forward in a single smooth motion as the inner needle is simultaneously pulled back out of the chest 10 Once you have reached a point when pleural fluid can easily be obtained, fill a heparinized blood gas syringe from the side port of the three-way stopcock for measurement of fluid pH Express all air bubbles from the sample, cap it, and place it in a bag containing iced slush for immediate transport to the laboratory 11 Fill the 50-mL syringe and transfer its contents into the appropriate collection tubes and containers Always maintain a closed system during the procedure to prevent room air from entering the pleural space For most diagnostic studies, 50 to 100 mL should be an ample volume [20,21] Always ensure that the three-way stopcock has the valve closed toward the patient when changing syringes 12 When the thoracentesis is completed, remove the needle (or catheter) from the patient’s chest as they hum or perform a Valsalva maneuver Apply pressure to the wound for several minutes, and then apply a sterile bandage 13 A routine chest radiograph after thoracentesis is not generally indicated for most asymptomatic, nonventilated patients Obtain a post-procedure upright end-expiratory chest radiograph if air was aspirated during the procedure; if PTX is suspected by developing signs or symptoms; or if multiple needle passes were required [1,12,22] Whether a post-thoracentesis chest radiograph is necessary for patients who are mechanically ventilated is controversial [3,22]; however, it should be remembered that any PTX in a ventilated patient creates the risk that a tension PTX may occur rapidly FIGURE 12.2 Catheter-over-needle technique for thoracentesis of freely flowing pleural field A: The patient is comfortably positioned, sitting up and leaning forward over a pillow-draped, height-adjusted, bedside table The arms are crossed in front of the patient to elevate and spread the scapulae The preferred entry site is along the posterior axillary line B: The catheter apparatus is gently advanced through the skin and across the upper surface of the rib The needle is advanced several millimeters at a time while continuously aspirating through the syringe C: As soon as the parietal pleura has been punctured, pleural fluid will appear in the syringe D: Before the catheter is advanced any farther, the apparatus is directed downward E,F: In rapid sequence, the catheter is advanced fully to the chest wall and the needle withdrawn from the apparatus The one-way valve in the apparatus maintains a closed system until the operator manually changes the position of the stopcock to allow drainage of the pleural fluid Technique for Therapeutic Removal of Freely Flowing Fluid To perform the technique for therapeutic removal of freely flowing fluid, steps 1 to 7 should be followed as described previously Removal of more than 100 mL pleural fluid generally involves placement of a catheter into the pleural space to minimize the risk of PTX from a needle during this longer procedure Commercially available kits generally use a catheterover-needle system, although catheter-through-needle systems are still available in some locations Each kit should have a specific set of instructions for performing this procedure, and all will generally mirror the procedure described above Operators should be thoroughly familiar with the recommended procedure for the catheter system that they will use and should receive appropriate supervision from an experienced operator before performing thoracentesis on their own p 101 p 102 Technique for Removal of Freely Moving Pneumothorax The technique for removal of freely moving PTX is as follows: Follow the same catheter-over-needle protocol described for removing freely moving fluid, but position the patient supine with the head of the bed elevated 30 to 45 degrees Prepare the second or third intercostal space in the anterior midclavicular line (this avoids hitting the more medial internal mammary artery) for the needle and catheter insertion 3 Have the bevel of the needle facing up, and direct the needle upward so that the catheter can be guided toward the superior aspect of the hemithorax Air can be actively withdrawn by syringe or pushed out when intrapleural pressure is supraatmospheric (e.g., during a cough) as long as the catheter is intermittently open to the atmosphere In the latter setting, air can leave but not reenter if the catheter is attached to a one-way check-valve apparatus (Heimlich valve) or if it is put to underwater seal When local anesthesia and skin cleansing are not possible because a tension PTX is life threatening, perform the procedure without them If a tension PTX is known or suspected to be present and a chest tube is not readily available, quickly insert a 14-gauge needle and 16-gauge catheter according to the above technique to avoid puncturing the lung If a tension PTX is present, air escapes under pressure When the situation has stabilized and the tension PTX has been diagnosed, leave the catheter in place until a sterile chest tube can be inserted p 102 p 103 Utility of Ultrasonography for Guidance of Thoracentesis Whether to guide simple needle insertion for diagnostic thoracentesis or to perform more complex pleural procedures, the use of ultrasonography should be considered as a key feature of any pleural intervention Ultrasonography guidance of thoracentesis reduces the rate of PTX [2,23]; facilitates the identification and targeting of the pleural effusion; and is more accurate in determining a safe site for needle insertion than physical examination [24] It allows for performance of thoracentesis on patients who are on mechanical ventilator support [14] and for targeted insertion of drainage catheters into loculated pleural effusion Ultrasonography is effective for the identification of pleural fluid, because the fluid is either anechoic or hypoechoic compared to soft tissue; it also allows for characterization of the location, volume, and internal complexity of the effusion (Chapter 12 Video 12.1, Video 12.2, Video 12.3, Video 12.4, Video 12.5, Video 12.6, Video 12.7, Video 12.8, Video 12.9, Video 12.10, Video 12.11, Video 12.12, Video 12.13, Video 12.14, Video 12.15, Video 12.16, Video 12.17, Video 12.18, Video 12.19, Video 12.20, Video 12.21, Video 12.22, Video 12.23, Video 12.24, Video 12.25, Video 12.26, Video 12.27, Video 12.28, Video 12.29, Video 12.30, Video 12.31, Video 12.32 and Video 12.33) Although this information may provide details regarding the etiology of the effusion, sampling the fluid is often an important part of management, as is the need for pleural interventions that require catheter insertion There are several considerations when using ultrasonography to guide thoracentesis Equipment The ultrasonography examination is performed using a phased-array cardiac probe (3.5 to 5.0 MHz) whose small footprint allows for examination between rib interspaces A curvilinear adominal probe may also be used The linear high frequency probe lacks sufficient penetration to visualize deeper thoracic structures such as atelectatic lung underlying the pleural effusion Scanning Technique A series of scan lines are performed over the chest in order to identify and characterize the pleural effusion, and to establish a safe site for needle insertion that avoids injury to adjacent organs Patient Position The critically ill patient is generally in the supine position, which makes it difficult to identify a safe site for needle insertion unless the pleural effusion is large, because pleural fluid, unless loculated, assumes a dependent position in the thorax In the case of a smaller effusion in a supine patient, the effusion will be posterior in location and readily identified by pressing the probe into the mattress with anterior angulation However, this probe position cannot be duplicated by the needle–syringe assembly, which is a key requirement for safe needle insertion trajectory In the case of a large effusion, the effusion will be visible with ultrasonography in a more anterior position, with a probe angulation that may be duplicated with the needle–syringe assembly In the case of a small effusion, if no safe site can be identified with the patient in supine position, the head of the bed may be raised to semirecumbent position and the ipsilateral arm adducted in order to expose the posterolateral chest The probe is used to scan the lower posterolateral chest to establish a safe site for needle insertion The limitation of this method is that a team member must hold the patient in position for the entire duration of the procedure An alternative is to place the patient in a lateral decubitus position with the hemithorax contralateral to the effusion in the dependent position The pleural effusion is identified by scanning over the posterior nondependent hemithorax Both of these methods require significant movement of the patient who may be intubated with various life support devices in place Care is taken to avoid accidental extubation or dislodgement of other life support equipment This requires that several team members be involved with the procedure For the patient who is able to sit up while leaning forward on an examination table, which is the standard position for thoracentesis performed by the intensivist, the effusion is identified by scanning over the posterior thorax Identification of Fluid The examiner seeks three characteristic findings that are typical for a pleural effusion a An anechoic or relatively hypoechoic space that is surrounded by typical anatomic boundaries This space represents the pleural effusion b Typical anatomic boundaries: This requires unequivocal identification of the chest wall, the surface of the lung, and the diaphragm The heart may form an anatomic boundary on the left side Identification of the diaphragm is a critical element of safe site selection as subdiaphragmatic device insertion may result in splenic or hepatic injury Identification of the diaphragm requires definitive identification of the subdiaphragmatic organs (spleen or liver; and kidneys) The inexperienced scanner may misidentify the hepatorenal or splenorenal space as the diaphragm and consider the overlying liver or spleen to be an echo-dense effusion, because the spaces may appear as a curvilinear structure that may be mistaken for the diaphragm This dangerous error is avoided by emphasizing the identification of the kidney as a discrete structure that is well below the diaphragm c Dynamic changes: This requires identification of dynamic changes that are typical of a pleural effusion such as diaphragmatic movement; lung movement; and movement of internal echogenic elements within the pleural effusion Site Selection Once the pleural effusion is identified, the transducer is moved over the target area in order to identify a safe site for needle insertion that maximizes the distance between the chest wall and the underlying lung while avoiding adjacent anatomic structures such as the diaphragm or heart (on the left side) As much as possible, the examiner holds the probe perpendicular to the chest wall, because this angle is easiest to duplicate with the needle–syringe assembly Once a suitable site is identified, it is marked; the depth of needle penetration to access the fluid is measured; and the angle of the probe is determined This angle will be duplicated by the operator during needle insertion A rare complication of thoracentesis is laceration of an intercostal wall vessel with subsequent hemothorax This risk may be reduced by using the high-frequency vascular probe to scan the proposed needle trajectory Using color Doppler, identification of a vessel may allow the operator to select an alternative site [25] Performance of Needle Insertion Once the site is selected, there can be no further patient movement, because this may shift the position of the pleural effusion within the chest cavity relative to the insertion site The time between the ultrasonography examination and needle insertion is minimized Immediately before the sterile preparation, the operator rechecks the site, angle, and depth for needle insertion The thoracentesis is performed with free hand technique by inserting the needle–syringe assembly at the site mark, duplicating the angle at which the probe was held to determine a safe trajectory Real-time guidance of needle insertion is not required for safe thoracentesis If a wire is inserted through the needle for Seldinger technique device insertion, some operators identify the wire position before using the dilator Likewise, final device position may be determined with ultrasonography p 103 p 104 As a routine, the patient should be checked for PTX before the procedure by examining for lung sliding, lung pulse, and/or B lines Their presence reliably rules out PTX (see Chapter 11 on Lung Ultrasonography) Following the procedure, the examination is repeated The continued presence of these three signs rules out PTX so reliably that chest radiography is not necessary, and may be misleading [26] Their absence is strong evidence of a procedure-related PTX Pitfalls of Imaging a Skin compression: In the edematous or obese patient, skin compression artifact may cause an underestimation of the depth for successful needle insertion In this case, the operator pushes the probe into the skin surface in order to improve image quality This causes indentation of the skin surface at the target site that rebounds when the probe is removed This is problematic at the time of needle insertion, because the operator must insert the needle to a depth greater than that measured with indentation of the skin b Site mark movement: If lateral force is applied to the skin at the time of marking the insertion site, the skin mark may be moved to a substantial extent This is of particular concern when accessing a smaller effusion At the time of needle insertion, the operator takes care to not move the mark site when applying pressure to the skin surface c Difficult scanning conditions: It may be difficult to achieve adequate image quality in the massively obese or edematous patient The pleural effusion may be so echogenic that it could cause uncertainty as to its size or location INTERPRETATION OF PLEURAL FLUID ANALYSIS To determine the etiology of a pleural effusion, a number of tests on pleural fluid are helpful The initial determination should be to classify the effusion as a transudate or an exudate using the criteria discussed below Additional studies can then be ordered to help establish a final diagnosis for the etiology of the pleural effusion, especially in the setting of an exudate Transudates Versus Exudates A transudate is biochemically defined by meeting all of the following classic (Light’s) criteria [7]: pleural fluid–serum total protein ratio of less than 0.5; pleural fluid–serum lactate dehydrogenase (LDH) ratio of less than 0.6; and pleural fluid LDH of less than two-thirds the normal serum level Transudates are generally caused by hydrostatic or oncotic pressure imbalances, or from the migration of pleural fluid from peritoneal or retroperitoneal spaces to the pleural space An exudate is present when any of the foregoing criteria for transudates are not met Exudates arise through a variety of mechanisms that result primarily from inflammation of the lung or pleura, impaired lymphatic drainage, or migration of fluid from the peritoneal space A wide variety of alternative diagnostic criteria have been studied since Light’s original work was published Abbreviated criteria with similar diagnostic accuracy, but without the need for concurrent serum measurements, have been proposed [8–10] A meta-analysis of 8 studies (1,448 patients) indicates that a classic transudate can be identified with equal accuracy by the combination of both pleural fluid cholesterol of less than 45 mg per dL and a pleural fluid LDH less than 0.45 times the upper limit of normal for serum LDH [8] Clinical judgment will be required when analyzing any borderline test results If a transudate is present, generally no further tests on pleural fluid are indicated (Table 12.1) If an exudate is identified, further laboratory evaluation is generally warranted (Fig 12.1) If subsequent testing does not narrow the differential diagnosis and tuberculous pleuritis is a diagnostic consideration, a percutaneous pleural biopsy should be considered given the improved sensitivity over thoracentesis alone If mesothelioma is considered a distinct possibility, consideration should be given to proceeding directly to thoracoscopic or open pleural biopsy to provide a large enough tissue sample to optimize diagnostic success Thoracoscopy-guided pleural biopsy should be considered in patients with pleural effusion of unknown etiology while following the abovelisted evaluation TABLE 12.1 Causes of Pleural Effusions Etiologies of Effusions That Are Virtually Always Transudates Congestive heart failure Nephrotic syndrome Hypoalbuminemia Urinothorax Trapped lung Cirrhosis Atelectasis Peritoneal dialysis Constrictive pericarditis Superior vena caval obstruction Malignanciesb Carcinoma Lymphoma Mesothelioma Leukemia Chylothoraxc Etiologies of Effusions That Are Typically Exudates Infections Parapneumonic Tuberculous pleurisy Parasites (amebiasis, paragonimiasis, and echinococcosis) Fungal disease Atypical pneumonias (virus, Mycoplasma, Q fever, and Legionella) Nocardia, Actinomyces Subphrenic abscess Hepatic abscess Splenic abscess Hepatitis Spontaneous esophageal rupture Iatrogenic Drug-induced (nitrofurantoin and methotrexate) Esophageal perforation Esophageal sclerotherapy Central venous catheter misplacement or migration Enteral feeding tube in space Noninfectious Inflammations Pancreatitis Benign asbestos pleural effusion Pulmonary embolisma Radiation therapy Uremic pleurisy Sarcoidosisc Postcardiac injury syndrome Hemothorax Endocrine Disorders Hypothyroidismc Ovarian hyperstimulation syndrome Chronically Increased Negative Intrapleural Pressure Atelectasis Trapped lungc Cholesterol effusion Connective Tissue Disease Lupus pleuritis Rheumatoid pleurisy Mixed connective tissue disease Churg–Strauss syndrome Wegener’s granulomatosis Familial Mediterranean fever Lymphatic Disorders Malignancy Yellow nail syndrome Lymphangioleiomyomatosis Acute respiratory distress syndrome Movement of Fluid from Abdomen to Pleural Space Pancreatitis Pancreatic pseudocyst Meigs’ syndrome Malignant ascites Chylous ascites a 10% to 20% may be transudates b 3% to 10% are transudates c Occasional transudates Adapted from Sahn SA: The pleura Am Rev Respir Dis 138:184, 1988 Selected Tests that are Potentially Helpful to Establish Etiology for a Pleural Effusion pH Pleural fluid pH determinations may have diagnostic and therapeutic implications [12] For instance, the differential diagnosis associated with a pleural fluid pH of less than 7.2 is consistent with systemic acidemia; bacterially infected effusion (empyema); malignant effusion; rheumatoid pleuritis; tuberculous effusion; ruptured esophagus, noninfected parapneumonic effusion that needs drainage; paragonimiasis; and urinothorax Pleural effusions with a pH of less than 7.2 are potentially sclerosis provoking and require consideration for chest tube drainage to aid resolution [12] Glucose All transudates and most exudates will have pleural glucose levels similar to blood glucose concentrations Some exudates will have low pleural fluid glucose values (defined as less than 60 mg per dL) and in this situation, the differential diagnosis overlaps with those causes listed above for low pH effusions Potentially important to note is that whereas pleural glucose levels are not significantly impacted by the duration of time the sample awaits analysis or the presence of air or lidocaine in the same sampling syringe, there can be clinically significant increases (time delay, air) or decreases (lidocaine) noted in the pleural fluid pH by these factors [27] Therefore, glucose levels may serve as a surrogate for pleural fluid pH if there is any concern that the measured pH may be inaccurate Protein, LDH, and Protein Gradient The main purpose for measuring pleural fluid protein and LDH levels is the separation of transudative from exudative effusions An additional key point is that the pleural fluid LDH can serve as an indirect reflection of the degree of pleural inflammation, and any effusion classified as an exudate based on LDH criterion alone (and not by protein level as well) suggests the presence of pleural space infection or a malignant effusion Also, importantly, the serum protein minus pleural fluid protein gradient may be of value in distinguishing a truly transudative effusion due to CHF in a patient who has undergone diuresis, from a truly exudative effusion If in the setting of a patient who has undergone diuresis for CHF, the protein gradient is greater than 3.1 g per dL (or if greater than 1.2 g per dL when an albumin gradient is measured instead), that effusion is most likely transudative in nature and caused by CHF Amylase A pleural fluid amylase level that is greater than the normal serum level may be seen in patients with acute and chronic pancreatitis; pancreatic pseudocyst that has dissected or ruptured into the pleural space; malignancy; and esophageal rupture Salivary isoenzymes predominate with malignancy and esophageal rupture, whereas intrinsic pancreatic disease is characterized by the presence of pancreatic isoenzymes p 104 p 105 Triglyceride and Cholesterol Chylous pleural effusions are biochemically defined by a triglyceride level greater than 110 mg per dL and the presence of chylomicrons on a pleural fluid lipoprotein electrophoresis [12] The usual appearance of a chylous effusion is milky, but an effusion with elevated triglycerides may also appear serous The measurement of a triglyceride level is therefore important Chylous effusions occur when the thoracic duct has been disrupted somewhere along its course The most common causes are trauma and malignancy (e.g., Non–Hodgkin lymphoma) as well as in 25% of patients with lymphangioleiomyomatosis A pseudochylous effusion appears grossly milky because of an elevated cholesterol level (>220 mg per dL), but the triglyceride level is usually normal and no chylomicrons are present Chronic effusions, especially those associated with rheumatoid and tuberculous pleuritis are characteristically pseudochylous Adenosine Deaminase Adenosine deaminase (ADA) is abundant in lymphocytes and therefore is potentially a good marker for tuberculous pleural effusion, especially given its simpler testing methodology and lower cost as compared with measurement of pleural fluid interferon gamma level or nucleic acid polymerase chain amplification assessment [28] Meta-analysis of ADA for the diagnosis of pleural TB has shown a sensitivity and specificity of 92% and 90%, respectively [29] Whereas a pleural fluid ADA level 40 IU per L support the diagnosis and ADA levels >70 IU per L highly suggest pleural TB [24] Because the predictive value of any test is dependent on the prevalence of disease in the specific population being tested, the use of a highly sensitive test such as the ADA in the majority of the USA (generally a low prevalence area for pleural TB) implies that the major strength of the ADA is in its negative predictive value Multiple possible causes of falsepositive ADA testing exist and include: infection, malignancy (especially lymphoma), and connective tissue diseases [29] p 105 p 106 Cell Counts and Differential Although pleural fluid white blood cell count and differential are never diagnostic of any disease, it would be distinctly unusual for an effusion other than one associated with bacterial pneumonia to have a white blood cell count exceeding 50,000 per μL In an exudative pleural effusion of acute origin, polymorphonuclear leukocytes predominate early, whereas mononuclear cells predominate in chronic exudative effusions Although pleural fluid lymphocytosis is nonspecific, severe lymphocytosis (greater than 80% of cells) is suggestive of tuberculosis or malignancy Finally, pleural fluid eosinophilia (≥10%) is nonspecific and is most commonly associated with either blood or air in the pleural space A red blood cell count of 5,000 to 10,000 cells per μL must be present for a fluid to appear pinkish Grossly bloody effusions containing more than 100,000 red blood cells per μL are most consistent with trauma, malignancy, or pulmonary infarction To distinguish a traumatic thoracentesis from a preexisting hemothorax, several observations are helpful First, because a preexisting hemothorax has been defibrinated, it does not form a clot on standing Second, a hemothorax is suggested when a pleural fluid hematocrit value is 50% or more of the serum hematocrit value Cultures and Stains To maximize the yield from pleural fluid cultures, anaerobic and aerobic cultures should be obtained Because acid-fast stains may be positive in up to 20% of tuberculous effusions, they should always be performed in addition to smears using Gram’s stain By submitting closed pleural biopsy pieces to pathology and microbiology laboratories, it is possible to diagnose up to 95% of tuberculous effusions with the combination of thoracentesis and percutaneous biopsy [7] Cytology Malignancies can produce pleural effusions by implantation of malignant cells on the pleura or impairment of lymphatic drainage secondary to tumor obstruction The tumors that most commonly cause pleural effusions are lung, breast, and lymphoma Pleural fluid cytology should be performed for an exudative effusion of unknown etiology, using at least 60 mL fluid [20,30] If initial cytology results are negative and strong clinical suspicion exists, additional samples of fluid can increase the chance of a positive result to approximately 60% to 70% The addition of a directed pleural biopsy (i.e., thoracoscopy) increases the yield to over 90% In addition to malignancy, cytologic examination can definitively diagnose rheumatoid pleuritis, whose pathognomonic picture consists of slender, elongated macrophages and giant, round, multinucleated giant cells (“tadpole cells”), accompanied by an amorphous granular background material REFERENCES Ault MJ, Rosen BT, Scher J, et al: Thoracentesis outcomes: a 12 year experience Thorax 70:127–132, 2015 Gordon CE, Feller-Kopman D, Balk EM, et al: Pneumothorax following thoracentesis: a systematic review and meta-analysis Arch Intern Med 170:332–339, 2010 Goligher EC, Leis JA, Fowler RA, et al: Utility and safety of draining pleural effusions in mechanically ventilated patients: a systematic review and meta-analysis Crit Care 15:R46, 2011 Hibbert RM, Atwell TD, Lekah A, et al: Safety of ultrasound-guided thoracentesis in patients with abnormal preprocedural coagulation parameters Chest 144:456–463, 2013 Mercaldi CJ, Lanes SF: Ultrasound guidance decreases complications and improves the cost of care among patients undergoing thoracentesis and paracentesis Chest 143:532–538, 2013 Perazzo A, Gatto P, Barlascini C, et al: Can ultrasound guidance reduce the risk of pneumothorax following thoracentesis? J Bras Pneumol 40:6–12, 2014 Light RW, MacGregor MI, Luchsinger PC, et al: Pleural effusions: the diagnostic separation of transudates and exudates Ann Intern Med 77:507–513, 1972 Heffner JE, Brown LK, Barbieri CA: Diagnostic value of tests that discriminate between exudative and transudative pleural effusions Chest 111:970–980, 1997 Gonlugur U, Gonlugur TE: The distinction between transudates and exudates J Biomed Sci 12:985–990, 2005 10 Kummerfeldt CE, Chiuzan CC, Huggins JT, et al: Improving the predictive accuracy of identifying exudative effusions Chest 145:586– 592, 2014 11 Wilcox ME, Chong CA, Stanbrook MB, et al: Does this patient have an exudative pleural effusion? The Rational Clinical Examination systematic review JAMA 311:2422–2431, 2014 12 Wilson MM, Irwin RS: Thoracentesis, in Irwin RS, Rippe JM (eds): Intensive Care Medicine 7th ed Philadelphia, PA, Wolters Kluwer/Lippincott Williams & Wilkins, 2012, pp 95–101 13 Daniels CE, Ryu JH: Improving the safety of thoracentesis Curr Opin Pulm Med 17:232–236, 2011 14 Mayo PH, Goltz HR, Tafreshi M, et al: Safety of ultrasound-guided thoracentesis in patients receiving mechanical ventilation Chest 125:1059–1062, 2004 15 Barnes TW, Morgenthaler TI, Olson EJ, et al: Sonographically guided thoracentesis and rate of pneumothorax J Clin Ultrasound 33:442– 446, 2005 16 Duncan DR, Morganthaler TI, Ryu JH, et al: Reducing iatrogenic risk in thoracentesis: establishing best practice via experimental training in a zero-risk environment Chest 135:1315–1320, 2009 17 Salmonsen M, Ellis S, Paul E, et al: Thoracic ultrasound demonstrates variable location of the intercostal artery Respiration 83:323–329, 2012 18 Helm EJ, Rahman NM, Talakoub O, et al: Course and variation of the intercostal artery by CT scan Chest 143:634–639, 2013 19 Feller-Kopman D, Walkey A, Berkowitz D, et al: The relationship of pleural pressure to symptom development during therapeutic thoracentesis Chest 129:1556–1560, 2006 20 Abouzgheib W, Bartter T, Dagher H, et al: A prospective study of the volume of pleural fluid required for accurate diagnosis of malignant pleural effusion Chest 135:999–1001, 2009 21 Swiderek J, Morcos S, Donthireddy V, et al: Prospective study to determine the volume of pleural fluid required to diagnose malignancy Chest 137:68–73, 2010 22 Temes RT: Thoracentesis N Engl J Med 356:641, 2007 23 Cavanna L, Mordenti P, Bertè R, et al: Ultrasound guidance reduces pneumothorax rate and improves safety of thoracentesis in malignant pleural effusion: report on 445 consecutive patients with advanced cancer World J Surg Oncol 12:139, 2014 24 Diacon AH, Brutsche MH, Solèr M: Accuracy of pleural puncture sites: a prospective comparison of clinical examination with ultrasound Chest 123:436–441, 2003 25 Kanai M, Sekiguchi H: Avoiding vessel laceration in thoracentesis: a role of vascular ultrasound with color Doppler Chest 147:e5–e7, 2015 26 Reissig A, Kroegel C: Accuracy of transthoracic sonography in excluding post-interventional pneumothorax and hydropneumothorax Comparison to chest radiography Eur J Radiol 53:463–470, 2005 27 Rahman NM, Mishra EK, Davies H, et al: Clinically important factors influencing the diagnostic measurement of pleural fluid pH and glucose Am J Respir Crit Care Med 178:483–490, 2008 28 Gopi A, Madhavan S, Sharma SK, et al: Diagnosis and treatment of tuberculous pleural effusion 2008 Chest 131:880–889, 2007 29 Light RW: Update on tuberculous pleural effusion Respirology 15:451–458, 2010 30 Heffner JE, Klein JS: Recent advances in the diagnosis and management of malignant pleural effusions Mayo Clin Proc 83:235– 250, 2008 Chapter 13 Chest Tube Insertion and Care ULISES TORRES • JOSHUA R SCURLOCK Chest tube insertion involves placement of a sterile tube into the pleural space to evacuate air or fluid into a closed collection system to restore negative intrathoracic pressure; promote lung expansion; and prevent potentially lethal levels of pressure from developing in the thorax Most life-threatening thoracic injuries can be treated with airway control or an appropriately placed chest tube or needle [1] PLEURAL ANATOMY AND PHYSIOLOGY The pleural space is a potential space that separates the visceral and parietal pleura with a thin layer of lubricating fluid Although up to 500 mL per day of fluid may enter the pleural space, 0.1 to 0.2 mL per kg surrounds each lung in the pleural space at any given time These two layers are lined by an extensive lymphatic network that ultimately drains into the thoracic duct via the mediastinal and intercostal lymph nodes These lymphatics prevent the accumulation of this pleural fluid It is estimated that this mechanism allows clearance of up to 20 mL of pleural fluid per hour per hemithorax in a 70-kg human The elastic coil of the chest wall and lung creates a subatmospheric pressure in the space, between −5 and −10 cm H2O, which binds the lung to the chest wall [2,3] Drainage of the pleural space is necessary when the normal physiologic processes are disrupted by increased fluid into the space owing to alterations in hydrostatic pressures (e.g., congestive heart failure) or oncotic pressures or by changes of the parietal pleura itself (e.g., inflammatory diseases that reduce the area available for fluid resorption) A derangement in lymphatic drainage—as with lymphatic obstruction; disruption of pleural anatomy; and/or lung parenchymal anatomy due to malignancy—may also result in excess fluid accumulation CHEST TUBE PLACEMENT Indications The indications for closed intercostal drainage include a variety of disease processes in the hospital setting (Table 13.1) The procedure may be performed to palliate a chronic disease process or to relieve an acute, lifethreatening process Chest tubes also may provide a vehicle for pharmacologic interventions, as when used with antibiotic therapy; tissue plasminogen activator/fibrinolytic agents; or instillation of sclerosing agents to prevent recurrence of malignant effusions TABLE 13.1 Indications for Chest Tube Insertion Pneumothorax  Primary or spontaneous  Secondary    Chronic obstructive pulmonary disease    Pneumonia    Abscess/empyema    Malignancy  Traumatic  Iatrogenic    Central line placement    Positive-pressure ventilation    Thoracentesis    Lung biopsy Hemothorax  Traumatic    Blunt    Penetrating (trauma or biopsy)  Iatrogenic  Malignancy  Pulmonary arteriovenous malformation  Blood dyscrasias  Ruptured thoracic aortic aneurysm Empyema  Parapneumonic  Posttraumatic  Postoperative  Septic emboli  Intra-abdominal infection Chylothorax  Traumatic  Surgical  Congenital  Malignancy Pleural effusion  Transudate  Exudate (malignancy, inflammatory) Pneumothorax Accumulation of air in the pleural space is the most common indication for chest tube placement Symptoms include tachypnea, dyspnea, and pleuritic pain, although some patients (in particular, those with a small spontaneous pneumothorax) may be asymptomatic Physical findings include increased work of breathing, diminished breath sounds, and hyperresonance to percussion on the affected side Diagnosis is often confirmed by chest radiography or ultrasound (US) (details of performing this examination can be found below) The size of a pneumothorax may be estimated, but this is at best a rough approximation of a three-dimensional space using a two-dimensional view Although the gold standard for the identification of a pneumothorax (independent of location within the thorax) has been a computed tomography (CT) scan of the chest, US identification has been shown to have the same sensitivity as that of a CT scan Furthermore, US estimates of the extension of the pneumothorax correlate well with CT scan [4] The sensitivity of detecting a pneumothorax with US ranges from 86% to 89%, compared to a range of 28% to 75% with a supine chest X-ray [4–6] Immediate tube decompression is indicated for patients who are symptomatic; those who have a large or expanding pneumothorax; or those who are being mechanically ventilated The mechanically ventilated patient is of particular concern because of acute deteriorating oxygenation that occurs with a pneumothorax in the setting of increased pleural pressure However, a small, stable, asymptomatic pneumothorax can be followed with serial chest radiographs Reexpansion occurs at the rate of approximately 2.2% of lung volume per day [7] p 107 p 108 Persistent leaking of air into the pleural space with no route of escape will ultimately collapse the affected lung, flatten the diaphragm, and eventually produce contralateral shift of the mediastinum This is referred to as a tension pneumothorax The combination of a collapsed lung on the affected side and the increasing pressure on the contralateral lung results in hypoxemia The accompanying hypotension is a result of pressure on the inferior vena cava which compromises venous return Emergency needle decompression with a 14- or 16-gauge catheter in the midclavicular line of the second intercostal space may be lifesaving while preparations for chest tube insertion are being made Hemothorax Accumulation of blood in the pleural space can be classified as spontaneous, iatrogenic, or traumatic Attempted thoracentesis or tube placement may result in injury to the intercostal arteries, internal mammary arteries or to the pulmonary parenchyma Up to a third of patients with traumatic rib fractures may have an accompanying pneumothorax or hemothorax [8] Pulmonary parenchymal bleeding from chest trauma is often self-limited owing to the low pressure of the pulmonary vascular system However, systemic sources (intercostal, internal mammary, or subclavian arteries, aorta, or heart) may persist and become life threatening Indications for open thoracotomy in the setting of traumatic hemothorax include initial blood loss greater than 1,500 mL or continued blood loss exceeding 200 mL per hour for 2 to 4 hours This decision is not based solely on the rate of continuing blood loss, but also on the patient’s physiologic status If a hemothorax is suspected, placement of large-bore (36 to 40 French [Fr]) drainage tubes encourages evacuation of blood and helps determine the need for immediate thoracotomy [1] Empyema The management principles for pleural infection have come a long way from employing antibiotic therapy and thoracentesis to the current availability of semi-invasive and invasive procedures like video assisted thoracostomy and fibrinolytics Use of advanced imaging like US and CT scans widens the scope of diagnosing and for treating effusions seen on a routine posteroanterior chest radiograph Observation is usually adequate for a small (50,000/μL)—should be checked and, when possible, quickly normalized prior to the procedure If clinically feasible, the procedure should be postponed until the international normalized ratio (INR) is less than 1.4, and an anti-Xa level is recommended for patients receiving low– molecular weight heparin For emergent pericardiocentesis performed on anticoagulant therapy, prolonged and continuous drainage is recommended Second, many critical care specialists advocate performance of all pericardiocentesis procedures in the catheterization laboratory with concomitant right heart pressure monitoring to document efficacy of the procedure and to exclude a constrictive element of pericardial disease, although excessive delays must be avoided Finally, efforts to ensure a cooperative and stationary patient during the procedure greatly facilitate the performance, safety, and success of pericardiocentesis ANATOMY The clinical presentation of pericardial effusion is greatly influenced by pericardial anatomy and physiology The pericardium is a membranous structure with two layers: the visceral and parietal pericardium The visceral pericardium is a monolayer of mesothelial cells adherent to the epicardial surface by a loose collection of small blood vessels, lymphatics, and connective tissue The parietal pericardium is a relatively inelastic 2 mm-dense outer network of collagen and elastin with an inner surface of mesothelial cells It is invested around the great vessels and defines the shape of the pericardium, with attachments to the sternum, diaphragm, and anterior mediastinum while anchoring the heart in the thorax [10] Posteriorly, the visceral epicardium is absent, with the parietal epicardium attached directly to the heart at the level of the vena cavae [11] The potential space between the visceral and parietal mesothelial cell layers normally contains 15 to 50 mL of serous fluid in the AV and interventricular grooves, which is chemically similar to plasma ultrafiltrate [12] The pericardium is relatively avascular, but is well innervated and may produce significant pain with vagal responses during procedural manipulation or inflammation [13] p 138 p 139 Owing to the inelastic physical properties of the parietal pericardium, the major determinant of when and how pericardial effusions come to clinical attention is directly related to the speed of accumulation Effusions that collect rapidly (over minutes to hours) may cause hemodynamic compromise with volumes of 250 mL or less These effusions are usually located posteriorly and are often difficult to detect without echocardiography or other imaging modalities such as multislice computed tomography (CT) or cardiac magnetic resonance imaging (MRI) In contrast, effusions developing slowly (over days to weeks) allow for dilation of the fibrous parietal membrane Volumes of 2,000 mL or greater may accumulate without significant hemodynamic compromise As a result, chronic effusions may present with symptoms owing to compression of adjacent thoracic structures such as cough, dyspnea, dysphagia, or early satiety Conversely, intravascular hypovolemia; impaired ventricular systolic function; and ventricular hypertrophy with decreased elasticity of the myocardium (diastolic dysfunction) may exacerbate hemodynamic compromise without significant effusions present evident by imaging methods Effusive-constrictive pericarditis (up to 7% of patients with tamponade) results from the accumulation of fluid between the visceral and parietal pericardium and may be transient (chemotherapy) or persistent This diagnosis is important to make owing to its likelihood to evolve into a persistent constriction [14] It is defined as failure of the right atrial pressure to decrease by more than 50% or to 10 mm are considered large (500 mL), and guidelines recommend pericardiocentesis for effusions >20 mm, regardless of the presence of hemodynamic compromise [7] Typically, at least 250 mL of fluid is required for safe pericardiocentesis The routine use of echocardiography has resulted in two major trends in clinical practice: First, 2D echocardiography is commonly used to guide pericardiocentesis, with success rates comparable to traditionally fluoroscopic guided procedures [19,23–25] Second, approaches other than the traditional subxiphoid method have been investigated owing to the ability to clearly define the anatomy (location and volume) of each patient’s effusion [22] In one series of postsurgical patients, the subxiphoid approach was the most direct route in only 12% of effusions [26] With the use of echocardiographic guidance, apical and parasternal pericardiocentesis are increasingly performed with comparable success rates to the subxiphoid approach In the apical approach, the needle is directed parallel to the long axis of the heart toward the aortic valve Parasternal pericardiocentesis is performed with needle insertion 1 cm lateral to the sternal edge, to avoid internal mammary laceration All approaches employ a Seldinger technique of over-the-wire catheter insertion Because the subxiphoid approach remains the standard of practice and is the preferred approach for unguided emergent pericardiocentesis, it is described below Regardless of the approach used, confirmation of appropriate positioning is mandatory and preferably performed before a dilation catheter is advanced over the wire Direct visualization of the needle with either echocardiography or fluoroscopy and injection of agitated saline (echo-guided) contrast (fluoroscopy-guided) should be performed to confirm the correct position [21] In addition to two large-bore peripheral intravenous lines for aggressive resuscitative efforts, standard electrocardiographic monitoring is mandatory Historically, an electrocardiogram (ECG) lead directly attached to the puncture needle has been used to detect contact with the myocardium via the appearance of a large “injury current” (ST elevation) Owing to the fact that a suboptimally grounded needle could fibrillate the heart (and the widespread availability of echocardiography), it is considered an inadequate safeguard [7] The materials required for bedside pericardiocentesis are listed in Table 17.1 Table 17.2 lists the materials required for simultaneous placement of an intrapericardial drainage catheter The materials are available in prepackaged kits or individually (Figures 17.1 and 17.2) TABLE 17.1 Materials for Percutaneous Pericardiocentesis Site preparation  Antiseptic  Gauze  Sterile drapes and towels  Sterile gloves, masks, gowns, caps  5-mL or 10-mL syringe with 25-gauge needle  1% lidocaine (without epinephrine)  Code cart  Atropine (1-mg dose vial) Procedure  No 11 blade  20-mL syringe with 10 mL of 1% lidocaine (without epinephrine)  18-gauge, 8-cm, thin-walled needle with blunt tip  Multiple 20- and 40-mL syringes  Hemostat  Electrocardiogram machine  Three red-top tubes  Two purple-top (heparinized) tubes  Culture bottles Postprocedure  Suture material  Scissors  Sterile gauze and bandage TABLE 17.2 Materials for Intrapericardial Catheter Catheter placement  Teflon-coated flexible J-curved guidewire  6 Fr dilator  8 Fr dilator  8 Fr, 35-cm flexible pigtail catheter with multiple fenestrations (end and side holes) Drainage systema  Three-way stopcock  Sterile IV tubing  500-mL sterile collecting bag (or bottle)  Sterile gauze and adhesive bag (or bottle)  Suture material FIGURE 17.1 Materials required for pericardiocentesis (clockwise from upper left): 1% lidocaine solution; suture material; 10-mL syringe with 25-gauge needle; 10-mL syringe with 22-gauge needle; no 11 blade; 18-gauge 8-cm thin-walled needle; 20-mL syringe; 30-mL syringe; alligator clip; hemostat; three red-top tubes; two purple-top tubes; culture bottles; and scissors FIGURE 17.2 Materials required for intrapericardial catheter placement and drainage (clockwise from lower left): Teflon-coated flexible 0.035-inch J-curved guidewire, 8 Fr dilator, 6.3 Fr dilator, 8 Fr catheter with end and side holes (35-cm flexible pigtail catheter not shown), three-way stopcock, 500-mL sterile collecting bag and tubing, suture material p 139 p 140 The subxiphoid approach for pericardiocentesis is as follows: Patient preparation: Assist the patient in assuming a comfortable supine position with the head of the bed elevated to approximately 45 degrees from the horizontal plane Extremely dyspneic patients may need to be positioned fully upright, with a wedge if necessary Elevation of the thorax allows free-flowing effusions to collect inferiorly and anteriorly, the sites that are safest and easiest to access using the subxiphoid approach 2 Needle entry site selection: Locate the patient’s xiphoid process and the border of the left costal margin using inspection and careful palpation The needle entry site should be 0.5 cm to the (patient’s) left of the xiphoid process and 0.5 to 1.0 cm inferior to the costal margin (Fig 17.3) It is helpful to estimate (by palpation) the distance between the skin surface and the posterior margin of the bony thorax: This helps guide subsequent needle insertion The usual distance is 1.0 to 2.5 cm, increasing with obesity or protuberance of the abdomen Site preparation: Strict sterile techniques must be maintained at all times in preparation of the needle entry site Prepare a wide area in the subxiphoid region and lower thorax with a povidone–iodine or alcohol chlorhexidine solution and drape the field with sterile towels, leaving the subxiphoid region exposed After a time-out, raise a 1- to 2-cm subcutaneous wheal by infiltrating the needle entry site with 1% lidocaine solution (without epinephrine) To facilitate needle entry, incise the skin with a No 11 blade at the selected site after achieving adequate local anesthesia Insertion of the needle apparatus: The angle of entry with respect to the skin should be approximately 45 degrees in the subxiphoid area Direct the needle tip superiorly, aiming for the patient’s left shoulder Continue to advance the needle posteriorly while alternating between aspiration and injection of lidocaine (with a half-filled 20 mL syringe of 1% lidocaine), until the tip has passed just beyond the posterior border of the bony thorax (Fig 17.4) The posterior border usually lies within 2.5 cm of the skin surface If the needle tip contacts the bony thorax, inject lidocaine after aspirating to clear the needle tip and anesthetize the periosteum Then, walk the needle behind the posterior (costal) margin Needle direction: Once under the costal margin, reduce the angle of contact between the needle and skin to 15 degrees: This will be the angle of approach to the pericardium; the needle tip, however, should still be directed toward the patient’s left shoulder A 15-degree angle is used regardless of the height of the patient’s thorax (whether at 45 degrees or sitting upright) (Fig.17.5) Needle advancement: Advance the needle slowly while alternating between aspiration of the syringe and injection of 1% lidocaine solution Obtain a baseline lead V tracing and monitor a continuous ECG tracing for the presence of ST-segment elevation or premature ventricular contractions (evidence of epicardial contact) as the needle is advanced Advance the needle along this extrapleural path until either: a A “give” is felt, and fluid is aspirated from the pericardial space (usually 6.0 to 7.5 cm from the skin) (Fig 17.6) Some patients may experience a vasovagal response at this point and require atropine intravenously to increase their blood pressure and heart rate b ST-segment elevation or premature ventricular contractions are observed on the electrocardiographic lead V tracing when the needle tip contacts the epicardium If ST-segment elevation or premature ventricular complexes occur, immediately (and carefully) withdraw the needle toward the skin surface while aspirating Avoid any lateral motion, which could damage the epicardial vessels Completely withdraw the needle if no fluid is obtained during the initial repositioning   If a sanguineous fluid is aspirated, the differentiation between blood and effusion must be made immediately In addition to confirming catheter position by saline, contrast, or pressure transduction, several milliliters of fluid can be kept and observed for clotting Intrinsic fibrinolytic activity in the pericardium prevents subacute/chronic effusions from clotting, where frank hemorrhage or intraventricular blood will overwhelm fibrinolysis   The patient’s hemodynamic status should improve promptly with removal of sufficient fluid Successful relief of tamponade is supported by (a) a fall of intrapericardial pressure to levels between −3 and +3 mm Hg, (b) a fall in right atrial pressure and a separation between right and left ventricular diastolic pressures, (c) augmentation of cardiac output, (d) increased systemic blood pressure, and (e) reduced pulsus paradoxus to physiologic levels (10 mm Hg or less) An improvement may be observed after removal of the first 50 to 100 mL of fluid If the right atrial pressure remains elevated after fluid removal, an effusive-constrictive process should be considered The diagnostic studies performed on pericardial fluid are outlined in Table 17.3 Several options exist for continued drainage of the pericardial space The simplest approach is to use large-volume syringes and aspirate the fluid by hand This approach is not always practical (i.e., in large-volume effusions), and manipulation of the needle apparatus may cause myocardial trauma Alternatively, most pericardiocentesis kits include materials and instructions for a catheter-over-needle technique for inserting an indwelling pericardial drain via the Seldinger technique Pericardial Drain Placement: Create a tract for the catheter by passing a 6 French (Fr) dilator over a firmly held guidewire After removing the dilator, use the same technique to pass an 8 Fr dilator Then advance an 8 Fr flexible pigtail (or side hole) catheter over the guidewire into the pericardial space Remove the guidewire Passage of the dilators is facilitated by use of a torquing (clockwise/counterclockwise) motion Proper positioning of the catheter using radiography, fluoroscopy, or bedside echocardiography can be used to facilitate fluid drainage Drainage system [27,28]: Attach a three-way stopcock to the intrapericardial catheter and close the system by attaching the stopcock to the sterile collecting bag with the connecting tubing The catheter may also be connected to a transducer, allowing intrapericardial pressure monitoring The system may be secured as follows: a Suture the pigtail catheter to the skin, making sure that the lumen is not compressed Cover the entry site with a sterile gauze and dressing b Secure the drainage bag (or bottle) using tape at a level approximately 35 to 50 cm below the level of the heart Echocardiography or fluoroscopic guidance may be used to reposition the pigtail catheter, facilitating complete drainage of existing pericardial fluid   It is recommended to drain fluid in sequential steps of PAOP PAD < PAOP PEEP trial Δ PAOP ½ ΔPEEP Respiratory variation of PAOP < ½ PALV ≥ ½ Δ PALV Catheter-tip location LA level or below Above LA level With a few exceptions [59], estimates of capillary hydrostatic filtration pressure from PAOP are acceptable It should be noted that measurement of PAOP does not take into account capillary permeability, serum colloid osmotic pressure, interstitial pressure, or actual pulmonary capillary resistance These factors all play roles in the formation of pulmonary edema, and the PAOP should be interpreted in the context of the specific clinical situation Mean PAOP correlates well with left ventricular end-diastolic pressure (LVEDP), provided the patient has a normal mitral valve and normal left ventricular function In myocardial infarction, conditions with decreased left ventricular compliance (e.g., ischemia and left ventricular hypertrophy), and conditions with markedly increased left ventricular filling pressure (e.g., dilated cardiomyopathy), the contribution of atrial contraction to left ventricular filling is increased Thus, the LVEDP may be significantly higher than the mean left atrial pressure or PAOP [55] The position of the catheter can be misinterpreted in patients with the presence of giant v waves The most common cause of these v waves is mitral regurgitation During this condition, left ventricular blood floods a normal-sized, noncompliant left atrium during ventricular systole, causing giant v waves in the occlusion pressure tracing (Fig 19.11) The giant v wave of mitral regurgitation may be transmitted to the PA tracing, yielding a bifid PA waveform composed of the PA systolic wave and the v wave Because the catheter is occluded, the PA systolic wave is lost, but the v wave remains It is important to note that the PA systolic wave occurs earlier in relation to the QRS complex of a simultaneously recorded ECG (between the QRS and T waves) than does the v wave (after the T wave) FIGURE 19.11 Pulmonary artery and pulmonary artery occlusion tracings with giant v waves distorting with pulmonary artery recording ECG, electrocardiogram Although a large v wave is not diagnostic of mitral regurgitation and is not always present in this circumstance, acute mitral regurgitation remains the most common cause of giant v waves in the PAOP tracing Prominent v waves may occur whenever the left atrium is distended and noncompliant owing to left ventricular failure from any cause (e.g., ischemic heart disease and dilated cardiomyopathy) [60], or secondary to the increased pulmonary blood flow in acute ventricular septal defect Acute mitral regurgitation is the rare instance when the PA end-diastolic pressure may be lower than the computer-measured mean occlusion pressure p 161 p 162 End expiration provides a readily identifiable reference point for PAOP interpretation because pleural pressure returns to baseline at the end of passive deflation (approximately equal to atmospheric pressure) Pleural pressure can exceed the normal resting value with active expiratory muscle contraction or use of PEEP How much PEEP is transmitted to the pleural space cannot be estimated easily, because it varies depending on lung compliance and other factors When normal lungs deflate passively, end-expiratory pleural pressure increases by approximately one half of the applied PEEP In patients with reduced lung compliance (e.g., patients with acute respiratory distress syndrome; ARDS), the transmitted fraction may be one-fourth or less of the PEEP value In the past, PEEP levels greater than 10 mm Hg were thought to interrupt the column of blood between the left atrium and PAC tip, causing the PAOP to reflect alveolar pressure more accurately than left atrial pressure However, two studies suggest that this may not hold true in all cases Teboul et al [61] could find no significant discrepancy between PAOP and simultaneously measured LVEDP at PEEP levels of 0, 10, and 16 to 20 cm H2O in patients with ARDS He hypothesized that (a) a large intrapulmonary right-to-left shunt may provide a number of microvessels shielded from alveolar pressure, allowing free communication from PA to pulmonary veins, or (b) in ARDS, both vascular and lung compliance may decrease, reducing transmission of alveolar pressure to the pulmonary microvasculature and maintaining an uninterrupted blood column from the catheter tip to the left atrium Although it is difficult to estimate precisely the true transmural vascular pressure in a patient on PEEP, temporarily disconnecting PEEP to measure PAOP is not recommended Because the hemodynamics have been destabilized, these measurements will be of questionable value Venous return increases acutely after discontinuation of PEEP [61], and abrupt removal of PEEP will cause hypoxia, which may not reverse quickly on reinstitution of PEEP [62] Cardiac Output Thermodilution Technique A catheter equipped with a thermistor 4 cm from its tip allows calculation of CO by using the thermodilution principle [45,63] The thermodilution principle holds that if a known quantity of cold solution is introduced into the circulation and adequately mixed (passage through two valves and a ventricle is adequate), the resultant cooling curve recorded at a downstream site allows for calculation of net blood flow CO is inversely proportional to the integral of the time-versus-temperature curve In practice, a known amount of cold or room temperature solution (typically 10 mL of 0.9% saline in adults, and 5 mL of 0.9% saline in children) is injected into the right atrium via the catheter’s proximal port The thermistor allows recording of the baseline PA blood temperature and subsequent temperature change The resulting curve is usually analyzed by computer, although it can be analyzed manually by simple planimetric methods Correction factors are added by catheter manufacturers to account for the mixture of cold indicator with warm residual fluid in the catheter injection lumen and the heat transfer from the catheter walls to the cold indicator Reported coefficients of variation using triplicate determinations, using 10 mL of cold injectate and a bedside computer, are approximately 4% or less Variations in the rate of injection can also introduce error into CO determinations, and it is thus important that the solution be injected as rapidly as possible Careful attention must be paid to the details of this procedure; even then, changes of less than 10% to 15% above or below an initial value may not truly establish directional validity Thermodilution CO is inaccurate in low-output states, tricuspid regurgitation, and in cases of atrial or ventricular septal defects [64] Normal values for arterial–venous oxygen content difference, mixed venous oxygen saturation, and CO can be found in Table 19.6 TABLE 19.6 Selected Hemodynamic Variables Derived from Right Heart Catheterization Hemodynamic variable Normal range Arterial–venous content difference 3.5–5.5 mL/100 mL Cardiac index 2.5–4.5 L/min/m2 Cardiac output 3.0–7.0 L/min Left ventricular stroke work index 45–60 g/beat/m2 Mixed venous oxygen content 18.0 mL/100 mL Mixed venous saturation 75% (approximately) Oxygen consumption 200–250 mL/min Pulmonary vascular resistance 120–250 dynes/sec/cm–5 Stroke volume 70–130 mL/contraction Stroke volume index 40–50 mL/contraction/m2 Systemic vascular resistance 1,100–1,500 dynes/sec/cm2 Adapted from JM Gore, JS Alpert, JR Benotti, et al: Handbook of Hemodynamic Monitoring Boston, MA, Little, Brown, 1984 Analysis of Mixed Venous Blood CO can be approximated merely by examining mixed venous (PA) oxygen saturation Theoretically, if CO rises, then the mixed venous oxygen partial pressure will rise, because peripheral tissues need to exact less oxygen per unit of blood Conversely, if CO falls, peripheral extraction from each unit will increase to meet the needs of metabolizing tissues Serial determinations of mixed venous oxygen saturation may display trends in CO Normal mixed venous oxygen saturation is 70% to 75%; values of less than 60% are associated with heart failure and values of less than 40% with shock [65] Potential sources of error in this determination include extreme low-flow states where poor mixing may occur, contamination of desaturated mixed venous blood by saturated pulmonary capillary blood when the sample is aspirated too quickly through the nonwedged catheter or in certain disease states (e.g., sepsis) where microcirculatory shunting may occur Fiber-optic reflectance oximetry PACs can continuously measure and record mixed venous oxygen saturations in appropriate clinical situations [48] p 162 p 163 Derived Parameters Useful hemodynamic parameters that can be derived using data with PACs include the following: Cardiac index = CO (L per minute)/BSA (m2) Stroke volume = CO (L per minute)/heart rate (beats per minute) Stroke index = CO (L per minute)/(heart rate [beats per minute] × BSA [m2]) Mean arterial pressure (mm Hg) = ([2 × diastolic] + systolic)/3 Systemic vascular resistance (dyne/s/cm–5) = ([mean arterial pressure − mean right atrial pressure {mm Hg}] × 80)/CO (L per minute) Pulmonary arteriolar resistance (dyne/s/cm–5) = ([mean PA pressure − PAOP {mm Hg}] × 80)/CO (L per minute) Total pulmonary resistance (dyne/s/cm–5) = ([mean PA pressure {mm Hg}] × 80)/CO (L per minute) Left ventricular stroke work index = 1.36 (mean arterial pressure − PAOP) × stroke index/100 Oxygen delivery (DO2)(mL/min/m2) = cardiac index × arterial O2 content × 10 Normal values are listed in Table 19.6 CLINICAL APPLICATIONS OF THE PULMONARY ARTERY CATHETER Normal Resting Hemodynamic Profile The finding of normal CO associated with normal left and right heart filling pressures is useful in establishing a noncardiovascular basis to explain abnormal symptoms or signs and as a baseline to gauge a patient’s disease progression or response to therapy Right atrial pressures of 0 to 6 mm Hg, PA systolic pressures of 15 to 30 mm Hg, PADPs of 5 to 12 mm Hg, PA mean pressures of 9 to 18 mm Hg, PAOP of 5 to 12 mm Hg, and a cardiac index exceeding 2.5 L/min/m2 characterize a normal cardiovascular state at rest Table 19.7 summarizes specific hemodynamic patterns for a variety of disease entities in which PACs have been indicated and provide clinical information that can impact patient care TABLE 19.7 Hemodynamic Parameters in Commonly Encountered Clinical Situations (Idealized) RA RV PA PAOP AO CI SVR PVR Normal 0–6 25/0–6 25/6–12 6–12 130/80 ≥2.5 1,500 Hypovolemic shock 0–2 15– 20/0–2 15– 20/2–6 2–6 ≤90/60 1,500 ≤250 Cardiogenic shock 50/35 35 ≤90/60 1,500 ≤250 0–6 ≤90/60 ≥2.5 450 25/12– 18 12–18 ≤90/60 1,500 ≤250 50/12 Cardiac tamponade 12– 25/12– 18 18 AMI without LVF 0–6 25/0–6 25/12– 18 ≤18 140/90 ≤2.5 >1,500 ≤250 AMI with LVF 0–6 30– 40/0–6 30– 40/18– 25 >18 140/90 >2.0 >1,500 >250 50– 60/25 18–25 120/80 ~2.0 >1,500 >250 Biventricular failure >6 secondary to LVF 50– 60/>6 RVF secondary to RVI 12– 30/12– 20 20 30/12 250 Cor pulmonale >6 80/35 1,500 >400 Idiopathic pulmonary hypertension 0–6 80– 100/ 0– 80– 100/40 500 Acute ventricular septal ruptureb 60/35 30 ≤90/60 1,500 >250 80/>6 60/6–8 COMPLICATIONS Minor and major complications associated with bedside balloon flotation PA catheterization have been reported (Table 19.8) During the 1970s, in the first 10 years of clinical catheter use, a number of studies reported a relatively high incidence of certain complications Consequent revision of guidelines for PAC use and improved insertion and maintenance techniques resulted in a decreased incidence of these complications in the 1980s [66] The majority of complications are avoidable by scrupulous attention to detail in catheter placement and maintenance TABLE 19.8 Complications of Pulmonary Artery Catheterization Associated with central venous access Balloon rupture Knotting Pulmonary infarction Pulmonary artery perforation Thrombosis, embolism Arrhythmias Intracardiac damage Infections Miscellaneous complications Complications Associated with Central Venous Access The insertion techniques and complications of central venous cannulation are discussed in Chapter 6 Reported local vascular complications include local arterial or venous hematomas, unintentional entry of the catheter into the carotid system, atrioventricular fistulas, and pseudoaneurysm formation [67] Adjacent structures, such as the thoracic duct, can be damaged, with resultant chylothorax formation Pneumothorax can be a serious complication of insertion, although the incidence is relatively low (1% to 2%) [67] The incidence of pneumothorax is higher with the subclavian approach than with the internal jugular approach in some reports [68], but other studies demonstrate no difference between the two sites [69] The incidence of complications associated with catheter insertion is generally considered to be inversely proportional to the operator’s experience Balloon Rupture Balloon rupture occurred more frequently in the early 1970s than it does now and was generally related to exceeding recommended inflation volumes The main problems posed by balloon rupture are air emboli gaining access to the arterial circulation and balloon fragments embolizing to the distal pulmonary circulation If rupture occurs during catheter insertion, the loss of the balloon’s protective cushioning function can predispose to endocardial damage and attendant thrombotic and arrhythmic complications p 163 p 164 Knotting Knotting of a catheter around itself is most likely to occur when loops form in the cardiac chambers and the catheter is repeatedly withdrawn and readvanced [70] Knotting is avoided if care is taken not to advance the catheter significantly beyond the distances at which entrance to the ventricle or PA would ordinarily be anticipated Knotted catheters usually can be extricated transvenously; guidewire placement, venotomy, or more extensive surgical procedures are occasionally necessary Knotting of PACs around intracardiac structures [71] or other intravascular catheters has been reported Rarely, entrapment of a PAC in cardiac sutures after open-heart surgery has been reported, requiring varying approaches for removal [72] Pulmonary Infarction Peripheral migration of the catheter tip (caused by catheter softening and loop tightening over time) with persistent, undetected wedging in small branches of the PA is the most common mechanism underlying pulmonary ischemic lesions attributable to PACs [73] These lesions are usually small and asymptomatic, often diagnosed solely on the basis of changes in the chest radiograph that demonstrate an occlusion-shaped pleural-based density with a convex proximal contour Severe infarctions are usually produced if the balloon is left inflated in the occlusion position for an extended period, thus obstructing more central branches of the PA, or if solutions are injected at relatively high pressure through the catheter lumen in an attempt to restore an apparently damped pressure trace Pulmonary embolic phenomena resulting from thrombus formation around the catheter or over areas of endothelial damage can also result in pulmonary infarction The reported incidence of pulmonary infarction secondary to PACs in 1974 was 7.2% [73], but subsequent studies reported much lower rates of pulmonary infarction Boyd et al [74] found a 1.3% incidence of pulmonary infarction in a prospective study of 528 PA catheterizations Sise et al [75] reported no pulmonary infarctions in a prospective study of 319 PAC insertions Use of continuous saline flush solutions and careful monitoring of PA waveforms are important reasons for the decreased incidence of this complication Pulmonary Artery Perforation A serious and feared complication of PA catheterization is rupture of the PA leading to hemorrhage, which can be massive and sometimes fatal [76,77] Rupture may occur during insertion or may be delayed a number of days [77] PA rupture or perforation has been reported in approximately 0.1% to 0.2% of patients [68,78] Pathologic data suggest the true incidence of PA perforation is somewhat higher [79] Proposed mechanisms by which PA rupture can occur include (a) an increased pressure gradient between PAOP and PA pressure brought about by balloon inflation and favoring distal catheter migration, where perforation is more likely to occur; (b) an occluded catheter tip position favoring eccentric or distended balloon inflation with a spearing of the tip laterally and through the vessel; (c) cardiac pulsation causing shearing forces and damage as the catheter tip repeatedly contacts the vessel wall; (d) presence of the catheter tip near a distal arterial bifurcation where the integrity of the vessel wall against which the balloon is inflated may be compromised; and (e) simple lateral pressure on vessel walls caused by balloon inflation (this tends to be greater if the catheter tip was occluded before inflation began) Patient risk factors for PA perforation include pulmonary hypertension, mitral valve disease, advanced age, hypothermia, and anticoagulant therapy In patients with these risk factors and in whom PADP reflects PAOP reasonably well, avoidance of subsequent balloon inflation altogether constitutes prudent prophylaxis Another infrequent but life-threatening complication is false aneurysm formation associated with rupture or dissection of the PA [80] Technique factors related to PA hemorrhage are distal placement or migration of the catheter; failure to remove large catheter loops placed in the cardiac chambers during insertion; excessive catheter manipulation; use of stiffer catheter designs; and multiple or prolonged balloon inflations Adherence to strict technique may decrease the incidence of this complication In a prospective study reported in 1986, no cases of PA rupture occurred in 1,400 patients undergoing PA catheterization for cardiac surgery [69] PA perforation typically presents with massive hemoptysis Emergency management includes immediate occlusion arteriogram and bronchoscopy; intubation of the unaffected lung; and consideration of emergency lobectomy or pneumonectomy Application of PEEP to intubated patients may also tamponade hemorrhage caused by a PAC [81] Thromboembolic Complications Because PACs constitute foreign bodies in the cardiovascular system and can potentially damage the endocardium, they are associated with an increased incidence of thrombosis Thrombi encasing the catheter tip and aseptic thrombotic vegetations forming at endocardial sites in contact with the catheter have been reported [74] Extensive clotting around the catheter tip can occlude the pulmonary vasculature distal to the catheter, and thrombi anywhere in the venous system or right heart can serve as a source of pulmonary emboli Subclavian venous thrombosis, presenting with unilateral neck vein distention and upper extremity edema, may occur in up to 2% of subclavian placements [82] Venous thrombosis complicating percutaneous internal jugular vein catheterization is fairly commonly reported, although its clinical importance remains uncertain Consistently damped pressure tracings without evidence of peripheral catheter migration or pulmonary vascular occlusion should arouse suspicion of thrombi at the catheter tip A changing relationship of PADP to PAOP over time should raise concern about possible pulmonary emboli If an underlying hypercoagulable state is known to exist, if catheter insertion was particularly traumatic, or if prolonged monitoring becomes necessary, one should consider cautiously anticoagulating the patient Heparin-bonded catheters reduce thrombogenicity [44] and are commonly used However, an important complication of heparin-bonded catheters is HIT [83] Routine platelet counts are recommended for patients with heparin-bonded catheters in place Because of the risk of HIT, some hospitals have abandoned the use of heparin-bonded catheters p 164 p 165 Rhythm Disturbances Atrial and ventricular arrhythmias occur commonly during insertion of PACs [84] Premature ventricular contractions occurred during 11% of the catheter insertions originally reported by Swan et al [1] Studies have reported advanced ventricular arrhythmias (three or more consecutive ventricular premature beats) in approximately 30% to 60% of patients undergoing right heart catheterization [68,85,86] Most arrhythmias are self-limited and do not require treatment, but sustained ventricular arrhythmias requiring treatment occur in 0% to 3% of patients [74,85,86] Risk factors associated with increased incidence of advanced ventricular arrhythmias are acute myocardial ischemia or infarction, hypoxia, acidosis, hypocalcemia, and hypokalemia [85] A right lateral tilt position (5-degree angle) during PAC insertion is associated with a lower incidence of malignant ventricular arrhythmias than is the Trendelenburg position Although the majority of arrhythmias occur during catheter insertion, arrhythmias may develop at any time after the catheter has been correctly positioned These arrhythmias are caused by mechanical irritation of the conducting system and may be persistent Ventricular ectopy may also occur if the catheter tip falls back into the RV outflow tract Evaluation of catheter-induced ectopy should include a portable chest radiograph to evaluate catheter position and assessment of the distal lumen pressure tracing to ensure that the catheter has not slipped into the RV Lidocaine may be used but is unlikely to ablate the ectopy because the irritant is not removed If the arrhythmia persists after lidocaine therapy or is associated with hemodynamic compromise, the catheter should be removed Catheter removal should be performed by physicians under continuous ECG monitoring, because the ectopy occurs almost as frequently during catheter removal as during insertion [87] Right bundle branch block (usually transient) can also complicate catheter insertion [88] Patients undergoing anesthesia induction, those in the early stages of acute anteroseptal myocardial infarction, and those with acute pericarditis appear particularly susceptible to this complication Patients with preexisting left bundle branch block are at risk for developing complete heart block during catheter insertion, and some have advocated the insertion of a temporary transvenous pacing wire, a PAC with a pacing lumen, or pacing PAC with the pacing leads on the external surface of the catheter However, use of an external transthoracic pacing device should be sufficient to treat this complication Intracardiac Damage Damage to the right heart chambers, tricuspid valve, pulmonic valve, and their supporting structures as a consequence of PA catheterization has been reported [89–91] The reported incidence of catheter-induced endocardial disruption detected by pathologic examination varies from 3.4% to 75% [92], but most studies suggest a range of 20% to 30% [90,91] These lesions consist of hemorrhage, sterile thrombus, intimal fibrin deposition, and nonbacterial thrombotic endocarditis Their clinical significance is not clear, but there is concern that they may serve as a nidus for infectious endocarditis Direct damage to the cardiac valves and supporting chordae occurs primarily by withdrawal of the catheters while the balloon is inflated [1] However, chordal rupture has been reported despite balloon deflation The incidence of intracardiac and valvular damage discovered on postmortem examination is considerably higher than that of clinically significant valvular dysfunction Infections Catheter-related septicemia (the same pathogen growing from blood and the catheter tip) was reported in up to 2% of patients undergoing bedside catheterization in the 1970s [93] However, the incidence of septicemia related to the catheter appears to have declined in recent years, with a number of studies suggesting a septicemia rate of 0% to 1% [68,94] In situ time of more than 72 to 96 hours significantly increases the risk of catheter-related sepsis Right-sided septic endocarditis has been reported [95], but the true incidence of this complication is unknown Becker et al [89] noted two cases of left ventricular abscess formation in patients with PACs and Staphylococcus aureus septicemia Incidence of catheter colonization or contamination varies from 5% to 20%, depending on the duration of catheter placement and the criteria used to define colonization [95,96] In situ catheter-related bloodstream infection may be diagnosed by quantitative blood cultures Pressure transducers have also been identified as an occasional source of infection [97] The chance of introducing infection into a previously sterile system is increased during injections for CO determinations and during blood withdrawal Approaches to reduce the risk of catheterrelated infection include use of a sterile protective sleeve and antibiotic bonding to the catheter [69,98] Scheduled changes of catheters do not reduce the rate of infection [99] Other Complications Rare miscellaneous complications that have been reported include (a) hemodynamically significant decreases in pulmonary blood flow caused by balloon inflation in the central PA in postpneumonectomy patients with pulmonary hypertension in the remaining lung, (b) disruption of the catheter’s intraluminal septum as a result of injecting contrast medium under pressure [100], (c) artifactual production of a midsystolic click caused by a slapping motion of the catheter against the interventricular septum in a patient with RV strain and paradoxic septal motion [101], (d) thrombocytopenia secondary to heparin-bonded catheters [83], and (e) dislodgment of pacing electrodes [102] Multiple unusual placements of PACs have also been reported, including in the left pericardiophrenic vein, via the left superior intercostal vein into the abdominal vasculature, and from the superior vena cava through the left atrium and left ventricle into the aorta after open-heart surgery [103] GUIDELINES FOR SAFE USE OF PULMONARY ARTERY CATHETERS Multiple revisions and changes in emphasis to the original recommended techniques and guidelines have been published [66,104] These precautions are summarized as follows: Avoiding complications associated with catheter insertion a Inexperienced personnel performing insertions must be supervised Many hospitals require that PACs be inserted by a fully trained intensivist, cardiologist, or anesthesiologist Use of ultrasound guidance is recommended b Keep the patient as still as possible Restraints or sedation may be required but the patient should be fully monitored with ECG and pulse oximetry c Strict sterile technique is mandatory A chlorhexidine skin prep solution and maximum barrier precautions are recommended d Examine the postprocedure chest radiograph (or ultrasonography) for pneumothorax (especially after subclavian or internal jugular venipuncture) and for catheter tip position Avoiding balloon rupture a Always inflate the balloon gradually Stop inflation if no resistance is felt b Do not exceed recommended inflation volume At the recommended volume, excess air will automatically be expelled from a syringe with holes bored in it that is constantly attached to the balloon port Maintaining recommended volume also helps prevent the accidental injection of liquids c Keep the number of inflation–deflation cycles to a minimum d Do not reuse catheters designed for single usage, and do not leave catheters in place for prolonged periods e Use carbon dioxide as the inflation medium if communication between the right and left sides of the circulation is suspected Avoiding knotting Discontinue advancement of the catheter if entrance to right atrium, RV, or PA has not been achieved at distances anatomically anticipated from a given insertion site If these distances have already been significantly exceeded, or if the catheter does not withdraw easily, use fluoroscopy before attempting catheter withdrawal Never pull forcefully on a catheter that does not withdraw easily Avoiding damage to pulmonary vasculature and parenchyma a Keep recording time of PAOP to a minimum, particularly in patients with pulmonary hypertension and other risk factors for PA rupture Be sure the balloon is deflated after each PAOP recording There is never an indication for continuous PAOP monitoring b Constant pressure monitoring is required each time the balloon is inflated It should be inflated slowly, in small increments, and must be stopped as soon as the pressure tracing changes to PAOP or damped c If an occlusion is recorded with balloon volumes significantly less than the inflation volume recommended on the catheter shaft, withdraw the catheter to a position where full (or nearly full) inflation volume produces the desired trace d Anticipate catheter tip migration Softening of the catheter material with time, repeated manipulations, and cardiac motion make distal catheter migration almost inevitable i Continuous PA pressure monitoring is mandatory, and the trace must be closely watched for changes from characteristic PA pressures to those indicating a PAOP or damped tip position ii Decreases over time in the balloon inflation volumes necessary to attain occlusion tracings should raise suspicion regarding catheter migration iii Confirm satisfactory tip position with chest radiographs immediately after insertion and at least daily e Do not use liquids to inflate the balloon They may prevent deflation, and their relative incompressibility may increase lateral forces and stress on the walls of pulmonary vessels f Hemoptysis is an ominous sign and should prompt an urgent diagnostic evaluation and rapid institution of appropriate therapy g Avoid injecting solutions at high pressure through the catheter lumen on the assumption that clotting is the cause of the damped pressure trace First, aspirate from the catheter Then consider problems related to catheter position, stopcock position, transducer dome, transducers, pressure bag, flush system, or trapped air bubbles Never flush the catheter in the occlusion position 5 Avoiding thromboembolic complications a Minimize trauma induced during insertion b Consider the judicious use of anticoagulants in patients with hypercoagulable states or other risk factors c Avoid flushing the catheter under high pressure d Watch for a changing PADP–PAOP relationship, as well as for other clinical indicators of pulmonary embolism Avoiding arrhythmias a Constant ECG monitoring during insertion and maintenance, as well as ready accessibility of all supplies for performing cardiopulmonary resuscitation, defibrillation, and temporary pacing, are mandatory b Use caution when catheterizing patients with an acutely ischemic myocardium or preexisting left bundle branch block c When the balloon is deflated, do not advance the catheter beyond the right atrium d Avoid over manipulation of the catheter e Secure the introducer in place at the insertion site f Watch for intermittent RV pressure tracings when the catheter is thought to be in the PA position An unexplained ventricular arrhythmia in a patient with a PAC in place indicates the possibility of catheter-provoked ectopy Avoiding valvular damage a Avoid prolonged catheterization and excessive manipulation b Do not withdraw the catheter when the balloon is inflated Avoiding infections a Use meticulously sterile technique on insertion b Avoid excessive number of CO determinations and blood withdrawals c Avoid prolonged catheterization d Remove the catheter if signs of phlebitis develop Culture the tip and use antibiotics as indicated SUMMARY Hemodynamic monitoring enhances the understanding of cardiopulmonary pathophysiology in critically ill patients Nonetheless, the risk-to-benefit profile of PA catheterization in various clinical circumstances remains uncertain [105] Large trials have concluded that there may be no outcome benefit to patients with PACs used as part of clinical decision-making [106] There is concern that data obtained during PA catheterization may not be optimally used, or perhaps in specific groups may increase morbidity and mortality A meta-analysis of 13 randomized clinical trials concluded that the use of the PAC neither increased overall mortality or hospital days, nor conferred any benefit The authors concluded that despite nearly 20 years of randomized clinical trials involving the PA catheter, there has not been a clear strategy in its use which has led to improved survival [107] Until the results of future studies are available, clinicians using hemodynamic monitoring should carefully assess the risk-to-benefit ratio on an individual patient basis The operator should understand the indications, insertion techniques, equipment, and data that can be generated before undertaking PAC insertion PA catheterization must not delay or replace bedside clinical evaluation and treatment REFERENCES Swan HJC, Ganz W, Forrester J, et al: Catheterization of the heart in man with use of a flow-directed balloon-tipped catheter N Engl J Med 283:447, 1970 Gorlin R: Current concepts in cardiology: practical cardiac hemodynamics N Engl J Med 296:203, 1977 Rao TK, Jacobs KH, El-Etr AA: Reinfarction following anesthesia in patients with myocardial infarction Anesthesiology 59:499, 1983 p 166 p 167 Hesdorffer CS, Milne JF, Meyers AM, et al: The value of Swan-Ganz catheterization and volume loading in preventing renal failure in patients undergoing abdominal aneurysmectomy Clin Nephrol 28:272, 1987 Shoemaker WC, Appel PL, Kram HB, et al: Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients Chest 94:1176, 1988 Berlauk JF, Abrams JH, Gilmour IL, et al: Preoperative optimization of cardiovascular hemodynamics improves outcome in peripheral vascular surgery: a prospective, randomized clinical trial Ann Surg 214:289, 1991 Fleming A, Bishop M, Shoemaker W, et al: Prospective trial of supernormal values as goals of resuscitation in severe trauma Arch Surg 127:1175, 1992 Tuchschmidt J, Fried J, Astiz M, et al: Elevation of cardiac output and oxygen delivery improves outcome in septic shock Chest 102:216, 1992 Boyd O, Grounds RM, Bennett ED: A randomized clinical trial or the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients JAMA 270:2699, 1993 10 Bishop MH, Shoemaker WC, Appel PL, et al: Prospective randomized trial of survivor values of cardiac index, oxygen delivery, and oxygen consumption as resuscitation endpoints in severe trauma J Trauma 38:780, 1995 11 Schiller WR, Bay RC, Garren RL, et al: Hyperdynamic resuscitation improves in patients with life-threatening burns J Burn Care Rehabil 18:10, 1997 12 Wilson J, Woods I, Fawcett J, et al: Reducing the risk of major elective surgery: randomized controlled trial of preoperative optimization of oxygen delivery BMJ 318:1099, 1999 13 Chang MC, Meredith JW, Kincaid EH, et al: Maintaining survivors’ of left ventricular power output during shock resuscitation: a prospective pilot study J Trauma 49:26, 2000 14 Polonen P, Ruokonen E, Hippelainen M, et al: A prospective, randomized study of goal-oriented hemodynamic therapy in cardiac surgical patients Anesth Analg 90:1052, 2000 15 Friese RS, Shafi S, Gentilello LM: Pulmonary artery catheter use is associated with reduced mortality in severely injured patients: a National Trauma Data Bank analysis of 53,312 patients Crit Care Med 34:1597, 2006 16 Pearson KS, Gomez MN, Moyers, JR, et al: A cost/benefit analysis of randomized invasive monitoring for patients undergoing cardiac surgery Anesth Analg 69:336, 1989 17 Isaacson IJ, Lowdon JD, Berry AJ, et al: The value of pulmonary artery and central venous monitoring in patients undergoing abdominal aortic reconstructive surgery: a comparative study of two selected, randomized groups J Vasc Surg 12:754, 1990 18 Joyce WP, Provan JL, Ameli FM, et al: The role of central hemodynamic monitoring in abdominal aortic surgery: a prospective randomized study Eur J Vasc Surg 4:633, 1990 19 Yu M, Levy M, Smith P: Effect of maximizing oxygen delivery on morbidity and mortality rates in critically ill patients Crit Care Med 21:830, 1993 20 Gattinoni L, Brazzi L, Pelosi P, et al: A trial of goal-oriented hemodynamic therapy in critically ill patients N Engl J Med 333:1025, 1995 21 Yu M, Takanishi D, Myers SA, et al: Frequency of mortality and myocardial infarction during maximizing oxygen delivery: a prospective, randomized trial Crit Care Med 23:1025, 1995 22 Durham RM, Neunaber K, Mazuski JE, et al: The use of oxygen consumption and delivery as endpoints for resuscitation in critically ill patients J Trauma 41:32, 1996 23 Afessa B, Spenser S, Khan W, et al: Association of pulmonary artery catheter use with in-hospital mortality Crit Care Med 29:1145, 2001 24 Rhodes A, Cusack RJ, Newman PJ, et al: A randomized, controlled trial of the pulmonary artery catheter in critically ill patients Intensive Care Med 28:256, 2002 25 Richard C: Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial JAMA 290:2713, 2003 26 Yu DT, Platt R, Lanken PN, et al: Relationship of pulmonary artery catheter use to mortality and resource utilization in patients with severe sepsis Crit Care Med 31:2734, 2003 27 Sandham JD, Hull RD, Brant RF, et al: A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients N Engl J Med 348:5, 2003 28 Sakr Y, Vincent JL, Reinhart K, et al: Use of the pulmonary artery catheter is not associated with worse outcome in the ICU Chest 128:2722, 2005 29 Harvey S, Harrison DA, Singer M, et al: Assessment of the clinical effectiveness of pulmonary-artery catheters in management of patients in intensive care (PAC-Man): a randomized controlled trial Lancet 366:472, 2005 30 Binanay C, Califf RM, Hasselblad V, et al: Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial JAMA 294:1625, 2005 31 The National Heart, Lung and Blood Institute ARDS Clinical Trials Network: Pulmonary artery versus central venous catheter to guide treatment of acute lung injury N Engl J Med 354:2213, 2006 32 Tuman KJ, McCarthy RJ, Spiess BD, et al: Effect of pulmonary artery catheterization on outcome in patients undergoing coronary artery surgery Anesthesiology 70:199, 1989 33 Guyatt G: A randomized control trial of right heart catheterization in critically ill patients Ontario Intensive Care Study Group J Intensive Care Med 6:91, 1991 34 Hayes MA, Timmins AC, Yau H, et al: Elevation of systemic oxygen delivery in the treatment of critically ill patients N Eng J Med 330:1717, 1994 35 Connors AF, Speroff T, Dawson NV, et al: The effectiveness of right heart catheterization in the initial care of critically ill patients JAMA 276:889, 1996 36 Valentine RJ, Duke ML, Inman MH, et al: Effectiveness of pulmonary artery catheters in aortic surgery: a randomized trial J Vasc Surg 27:203, 1998 37 Stewart RD, Psyhojos T, Lahey SJ, et al: Central venous catheter use in low risk coronary artery bypass grafting Ann Thorac Surg 66:1306, 1998 38 Ramsey SD, Saint S, Sullivan SD, et al: Clinical and economic effects of pulmonary artery catheterization in nonemergent coronary artery bypass graft surgery J Cardiothorac Vasc Anesth 14:113, 2000 39 Polanczyk CA, Rohde LE, Goldman L, et al: Right heart catheterization and cardiac complications in patients undergoing noncardiac surgery: an observational study JAMA 286:348, 2001 40 Chittock DR, Dhingra VK, Ronco JJ, et al: Severity of illness and risk of death associated with pulmonary artery catheter use Crit Care Med 32:911, 2004 41 Peters SG, Afessa B, Decker PA, et al: Increased risk associated with pulmonary artery catheterization in the medical intensive care unit J Crit Care 18:166, 2003 42 Cohen MG, Kelley RV, Kong DF, et al: Pulmonary artery catheterization in acute coronary syndromes: insights from the GUSTO IIb and GUSTO III trials Am J Med 118:482, 2005 43 Kumar A, Anel R, Bunnell E: Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects Crit Care Med 32:691, 2004 44 Hoar PF, Wilson RM, Mangano DT, et al: Heparin bonding reduces thrombogenicity of pulmonary-artery catheters N Engl J Med 305:993, 1981 45 Forrester JS, Ganz W, Diamond G, et al: Thermodilution cardiac output determination with a single flow-directed catheter Am Heart J 83:306, 1972 46 Chatterjee K, Swan JHC, Ganz W, et al: Use of a balloon-tipped flotation electrode catheter for cardiac monitoring Am J Cardiol 36:56, 1975 47 Simoons ML, Demey HE, Bossaert LL, et al: The Paceport catheter: a new pacemaker system introduced through a Swan–Ganz catheter Cathet Cardiovasc Diagn 15:66, 1988 48 Baele PL, McMechan JC, Marsh HM, et al: Continuous monitoring of mixed venous oxygen saturation in critically ill patients Anesth Analg 61:513, 1982 49 Vincent JL, Thirion M, Bumioulle S, et al: Thermodilution measurement of right ventricular ejection fraction with a modified pulmonary artery catheter Intensive Care Med 12:33, 1986 50 Nelson LD: The new pulmonary arterial catheters: right ventricular ejection fraction and continuous cardiac output Crit Care Clin 12:795, 1996 51 Haller M, Zollner C, Briegel J, et al: Evaluation of a new continuous thermodilution cardiac output monitor in critically ill patients: a prospective criterion standard study Crit Care Med 23:860, 1995 52 Tuggle DW, Pryor R, Ward K, et al: Real-time echocardiography: a new technique to facilitate Swan-Ganz catheter insertion J Pediatr Surg 22:1169, 1987 53 Alraies MC, Alraiyes AH, Salerno D: Pulmonary artery catheter placement guided by echocardiography.QJM 106:1149, 2013 54 Rimensberger PC, Beghetti M: Pulmonary artery catheter placement under transoesophageal echocardiography guidance Paediatr Anaesth 9:167, 1999 55 Marini JJ: Hemodynamic monitoring with the pulmonary artery catheter Crit Care Clin 2:551, 1986 56 Huford WE, Zapol WM: The right ventricle and critical illness: a review of anatomy, physiology, and clinical evaluation of its function Intensive Care Med 14:448, 1988 57 Alpert JS: The lessons of history as reflected in the pulmonary capillary occlusion pressure J Am Coll Cardiol 13:830, 1989 58 Forrester JS, Diamond G, McHugh TJ, et al: Filling pressures in the right and left sides of the heart in acute myocardial infarction N Engl J Med 285:190, 1971 59 Timmis AD, Fowler MB, Burwood RJ, et al: Pulmonary edema without critical increase in left atrial pressure in acute myocardial infarction BMJ 283:636, 1981 60 Pichard AD, Kay R, Smith H, et al: Large V waves in the pulmonary occlusion pressure tracing in the absence of mitral regurgitation Am J Cardiol 50:1044, 1982 61 Teboul JL, Zapol WM, Brun-Buisson C, et al: A comparison of pulmonary artery occlusion pressure and left ventricular end diastolic pressure during mechanical ventilation with PEEP in patients with severe ARDS Anesthesiology 70:261, 1989 62 DeCampo T, Civetta JM: The effect of short-term discontinuation of high-level PEEP in patients with acute respiratory failure Crit Care Med 7:47, 1979 63 Ganz W, Swan HJC: Measurement of blood flow by thermodilution Am J Cardiol 29:241, 1972 64 Grossman W: Blood flow measurement: the cardiac output, in Grossman W (ed): Cardiac Catheterization and Angiography Philadelphia, PA, Lea & Febiger, 1985, p 116 65 Goldman RH, Klughaupt M, Metcalf T, et al: Measurement of central venous oxygen saturation in patients with myocardial infarction Circulation 38:941, 1968 66 Matthay MA, Chatterjee K: Bedside catheterization of the pulmonary artery: risks compared with benefits Ann Intern Med 109:826, 1988 67 McNabb TG, Green CH, Parket FL: A potentially serious complication with Swan-Ganz catheter placement by the percutaneous internal jugular route Br J Anaesth 47:895, 1975 68 Damen J, Bolton D: A prospective analysis of 1,400 pulmonary artery catheterizations in patients undergoing cardiac surgery Acta Anaesthesiol Scand 14:1957, 1986 69 Senagere A, Waller JD, Bonnell BW, et al: Pulmonary artery catheterization: a prospective study of internal jugular and subclavian approaches Crit Care Med 15:35, 1987 70 Lipp H, O’Donoghue K, Resnekov L: Intracardiac knotting of a flowdirected balloon catheter N Engl J Med 284:220, 1971 p 167 p 168 71 Meister SG, Furr CM, Engel TR, et al: Knotting of a flow-directed catheter about a cardiac structure Cathet Cardiovasc Diagn 3:171, 1977 72 Loggam C, Sanborn TA, Christian F: Ventricular entrapment of a Swan-Ganz catheter: a technique for nonsurgical removal J Am Coll Cardiol 13:1422, 1989 73 Foote GA, Schabel SI, Hodges M: Pulmonary complications of the flowdirected balloon-tipped catheter N Engl J Med 290:927, 1974 74 Boyd KD, Thomas SJ, Gold J, et al: A prospective study of complications of pulmonary artery catheterizations in 500 consecutive patients Chest 84:245, 1983 75 Sise MJ, Hollingsworth P, Bumm JE, et al: Complications of the flow directed pulmonary artery catheter: a prospective analysis of 219 patients Crit Care Med 9:315, 1981 76 Barash PG, Nardi D, Hammond G, et al: Catheter-induced pulmonary artery perforation: mechanisms, management and modifications J Thorac Cardiovasc Surg 82:5, 1981 77 Lapin ES, Murray JA: Hemoptysis with flow-directed cardiac catheterization JAMA 220:1246, 1972 78 Shah KB, Rao TL, Laughlin S, et al: A review of pulmonary artery catheterization in 6245 patients Anesthesiology 61:271, 1984 79 Fraser RS: Catheter-induced pulmonary artery perforation: pathologic and pathogenic features Hum Pathol 18:1246, 1987 80 Declen JD, Friloux LA, Renner JW: Pulmonary artery false-aneurysms secondary to Swan-Ganz pulmonary artery catheters AJR Am J Roentgenol 149:901, 1987 81 Scuderi PE, Prough DS, Price JD, et al: Cessation of pulmonary artery catheter-induced endobronchial hemorrhage associated with the use of PEEP Anesth Analg 62:236, 1983 82 Dye LE, Segall PH, Russell RO, et al: Deep venous thrombosis of the upper extremity associated with use of the Swan-Ganz catheter Chest 73:673, 1978 83 Laster JL, Nichols WK, Silver D: Thrombocytopenia associated with heparin-coated catheters in patients with heparin-associated antiplatelet antibodies Arch Intern Med 149:2285, 1989 84 Geha DG, Davis NJ, Lappas DG: Persistent atrial arrhythmias associated with placement of a Swan-Ganz catheter Anesthesiology 39:651, 1973 85 Sprung CL, Pozen PG, Rozanski JJ, et al: Advanced ventricular arrhythmias during bedside pulmonary artery catheterization Am J Med 72:203, 1982 86 Iberti TJ, Benjamin E, Grupzi L, et al: Ventricular arrhythmias during pulmonary artery catheterization in the intensive care unit Am J Med 78:451, 1985 87 Damen J: Ventricular arrhythmia during insertion and removal of pulmonary artery catheters Chest 88:190, 1985 88 Morris D, Mulvihill D, Lew WY: Risk of developing complete heart block during bedside pulmonary artery catheterization in patients with left bundle branch block Arch Intern Med 147:2005, 1987 89 Becker RC, Martin RG, Underwood DA: Right-sided endocardial lesions and flow-directed pulmonary artery catheters Cleve Clin J Med 54:384, 1987 90 Lange HW, Galliani CA, Edwards JE: Local complications associated with indwelling Swan-Ganz catheters Am J Cardiol 52:1108, 1983 91 Sage MD, Koelmeyer TD, Smeeton WMI: Evolution of Swan-Ganz catheter related pulmonary valve nonbacterial endocarditis Am J Forensic Med Pathol 9:112, 1988 92 Ford SE, Manley PN: Indwelling cardiac catheters: an autopsy study of associated endocardial lesions Arch Pathol Lab Med 106:314, 1982 93 Prochan H, Dittel M, Jobst C, et al: Bacterial contamination of pulmonary artery catheters Intensive Care Med 4:79, 1978 94 Pinella JC, Ross DF, Martin T, et al: Study of the incidence of intravascular catheter infection and associated septicemia in critically ill patients Crit Care Med 11:21, 1983 95 Greene JF, Fitzwater JE, Clemmer TP: Septic endocarditis and indwelling pulmonary artery catheters JAMA 233:891, 1975 96 Myers ML, Austin TW, Sibbald WJ: Pulmonary artery catheter infections: a prospective study Ann Surg 201:237, 1985 97 Weinstein RA, Stamm WE, Kramer L: Pressure monitoring devices: overlooked source of nosocomial infection JAMA 236:936, 1976 98 Heard SO, Davis RF, Sherertz RJ, et al: Influence of sterile protective sleeves on the sterility of pulmonary artery catheters Crit Care Med 15:499, 1987 99 Cobb DK, High KP, Sawyer RG, et al: A controlled trial of scheduled replacement of central venous and pulmonary artery catheters N Engl J Med 327:1062, 1992 100 Schluger J, Green J, Giustra FX, et al: Complication with use of flowdirected catheter Am J Cardiol 32:125, 1973 101 Isner JM, Horton J, Ronan JAS: Systolic click from a Swan-Ganz catheter: phonoechocardiographic depiction of the underlying mechanism Am J Cardiol 42:1046, 1979 102 Lawson D, Kushkins LG: A complication of multipurpose pacing pulmonary artery catheterization via the external jugular vein approach (letter) Anesthesiology 62:377, 1985 103 Lazzam C, Sanborn TA, Christian F: Ventricular entrapment of a Swan-Ganz catheter: a technique for nonsurgical removal J Am Coll Cardiol 13:1422, 1989 104 Ginosar Y, Sprung CL: The Swan–Ganz catheter: twenty-five years of monitoring Crit Care Clin 12:771, 1996 105 Fleisher LA, Fleischmann KE, Aurbach AD, et al: 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: executive summary: a report of the American College of cardiology/American Heart Association Task Force on Practice Guidelines Circulation 130(24):2215, 2014 106 Rajram SS, Desani NK, Kaira A, et al: Pulmonary artery catheters for adult patients in critical care Cochrane Database Syst Rev 2:CD003408, 2013 107 Shah MR, Hasselblad V, Stevenson LW, et al: Impact of the pulmonary artery catheter in critically ill patients JAMA 294:1664, 2005 Chapter 20 Gastrointestinal Endoscopy SAMUEL Y HAN • RANDALL PELLISH • DAVID R CAVE • WAHID Y WASSEF Gastrointestinal (GI) endoscopy has evolved into an essential diagnostic and therapeutic tool for the treatment of patients in the intensive care unit (ICU) This chapter reviews general aspects of current indications and contraindications, provides an update of emerging technologies in the field, and concludes by discussing potential future directions PATIENT SELECTION The indications for GI endoscopy in the ICU are summarized in Table 20.1 They are divided into those for (a) evaluation of the upper GI tract (esophagus, stomach, and duodenum); (b) evaluation of the pancreaticobiliary tract; (c) evaluation of the mid-GI tract (jejunum and ileum); and (d) evaluation of the lower GI tract (colon and rectum) In general, endoscopic interventions are contraindicated when the patient is hemodynamically unstable, when there is suspected perforation, or when adequate patient cooperation or consent cannot be obtained [1] Other contraindications are listed in Table 20.2 TABLE 20.1 Indications for GI Endoscopy Upper GI endoscopy  Upper GI bleeding (variceal or nonvariceal)  Caustic or foreign body ingestion  Placement of feeding or drainage tubes Endoscopic retrograde cholangiopancreatography  Severe gallstone pancreatitis  Severe cholangitis  Bile leak Lower GI endoscopy  Lower GI bleeding  Decompression of nontoxic megacolon or sigmoid volvulus  Unexplained diarrhea in the immunocompromised (graft vs host disease and cytomegalovirus infection) GI, gastrointestinal TABLE 20.2 Contraindications to Endoscopy Absolute contraindications  Suspected or impending perforated viscus  Risks to the patient outweigh benefits of the procedure Relative contraindications  Adequate patient cooperation or consent cannot be obtained  Hemodynamic instability or myocardial infarction  Inadequate airway protection or hypoxemia  Severe coagulopathy or thrombocytopenia  Inflammatory changes with increased risk of perforation (e.g., diverticulitis or severe inflammatory bowel disease) Evaluation of the Upper Gastrointestinal Tract Common indications for evaluation of the upper GI tract in the ICU include, but are not limited to, upper GI bleeding (UGIB), caustic or foreign body ingestion (FBI), placement of gastroduodenal stents for gastric outlet obstruction (GOO), and placement of feeding tubes for nutrition Upper Gastrointestinal Bleeding With an estimated 400,000 admissions annually, acute UGIB presents as a common medical emergency with mortality rates as high as 16% in the ICU [2] This condition is suspected in patients who present with melena, hematemesis, or blood in the nasogastric (NG) aspirate, as studies have shown improved outcomes with urgent endoscopic management in critically ill patients with hemodynamic instability or continuing transfusion requirements [3,4] Urgent evaluation allows differentiation between nonvariceal (peptic ulcer, esophagitis, Mallory–Weiss tear, and angiodysplasia) and variceal lesions (esophageal or gastric varices), thereby promoting targeted therapy [5] Furthermore, urgent evaluation allows the identification and stratification of stigmata of bleeding, promoting appropriate triage and risk stratification Finally, urgent evaluation allows the early identification of patients who may require surgical or invasive radiological intervention [3] Foreign Body Ingestions FBI can be divided into two groups: (i) food impaction and (ii) caustic ingestions Food impactions constitute the majority of FBI Although most will pass spontaneously, endoscopic removal will be needed for 10% to 20% of cases, and 1% of patients will ultimately require surgery [6] Evaluation is crucial to determine the underlying cause of the obstruction (strictures, rings, and carcinoma) Although caustic ingestions constitute only a small number of FBI, they are frequently life threatening, especially when they occur intentionally in adults, and warrant endoscopic evaluation to prognosticate and triage this group of patients [7] p 168 p 169 Endoscopic Stenting for Gastric Outlet Obstruction Although GOO is typically managed conservatively with receiving nothing by mouth, intravenous (IV) fluids, and decompression with a NG tube, GOO secondary to a malignancy can be treated with an endoscopically placed stent Often used as a palliative measure, duodenal selfexpandable metal stents (SEMS) have been found effective in providing relief from obstructive symptoms, allowing patients to resume eating, and improving quality of life [8] Feeding Tubes Enteral nutrition is associated with improved outcomes for critically ill patients and is preferred over parenteral nutrition in patients with a functional GI tract [9] Although nasoenteric and oroenteric feeding tubes may be used for short-term enteral nutrition, these tubes are felt to carry a higher risk of aspiration, displacement, and sinus infections than endoscopically placed percutaneous tubes Percutaneous endoscopic gastrostomy (PEG) [10] is appropriate for most patients in the ICU when there is a reversible disease process likely to require more than 4 weeks of enteral nutrition (e.g., neurologic injury, tracheostomy, and neoplasms of the upper aerodigestive tract) [21] PEG with a jejunostomy tube and direct percutaneous endoscopic jejunostomy tubes are appropriate for selected patients in the ICU with high risk of aspiration This includes patients with severe gastroesophageal reflux disease and those with gastroparesis Enteral feeding beyond the ligament of Treitz with a nasojejunal tube or a jejunostomy tube has been demonstrated to be beneficial in patients with necrotizing pancreatitis, although a study demonstrated that there was no difference in mortality or infection rate between early, nasoenteric feeding and oral feeding 72 hours after admission in patients with acute pancreatitis [12] Occasionally, endoscopic gastrostomies or jejunostomies may be indicated for decompression in patients with GI obstruction [13] Although these procedures are technically simple and can be performed at the bedside under moderate sedation, the risks and benefits should always be weighed carefully in this critically ill group of patients Evaluation of the Pancreaticobiliary Tract The indications for evaluation of the pancreaticobiliary tract by endoscopic retrograde cholangiopancreatography (ERCP) in critically ill patients are described in detail in Chapter 208 and only briefly discussed here They include biliary tract obstruction by gallstones [14–16], pancreatic duct leaks, and bile duct leaks (generally a postoperative or traumatic complication) [17,18] ERCP with sphincterotomy and/or stenting is the treatment of choice When conventional ERCP is unsuccessful, the recent introduction of miniature endoscopes (cholangioscopes or pancreatic scopes) with direct endoscopic visualization into these ductal systems has proved to be beneficial through the use of advanced techniques such as electrohydraulic lithotripsy, laser lithotripsy, and topical glue [19] Additionally, endoscopic necrosectomy for walled-off pancreatic necrosis via endoscopic ultrasound (EUS) has been validated as a viable alternative to surgical necrosectomy for this complication of pancreatitis [20] Evaluation of the Mid-Gastrointestinal Tract (Jejunum and Ileum) Persistent, GI bleeding without an identified site is the most common indication for mid-GI tract evaluation Although this area of the GI tract had been difficult to evaluate in the past, this is no longer the case The progression of video capsule endoscope (VCE), double-balloon enteroscopy (DBE), and spiral enteroscopy has made this area of the GI tract readily accessible VCE is usually the first test performed to look for possible sites of bleeding in the jejunum and ileum (Fig 20.1A and B) If bleeding or lesions are identified, DBE (Fig 20.2) or the spiral endoscope (Fig 20.3) can be used to implement therapy FIGURE 20.1 A: Normal jejunal image as seen by video capsule endoscope (VCE) B: Bleeding seen in jejunum on VCE (Courtesy of David Cave, MD: Professor of Medicine, University of Massachusetts Medical School.) FIGURE 20.2 Bleeding in distal duodenum seen during double-balloon enteroscopy (DBE) (Courtesy of David Cave, MD: Professor of Medicine, University of Massachusetts Medical School.) FIGURE 20.3 Bleeding seen in jejunum during spiral endoscopy (Courtesy of David Cave, MD: Professor of Medicine, University of Massachusetts Medical School.) Evaluation of the Lower Gastrointestinal Tract Lower GI tract evaluation is urgently needed in ICU patients in cases of severe lower GI bleeding (LGIB), acute colonic distention, and at times of refractory diarrhea for the evaluation of infection, such as Clostridium difficile [21] Lower Gastrointestinal Bleeding Severe LGIB is predominantly a disease of the elderly It is defined as bleeding from a source distal to the ligament of Treitz for less than 3 days [22] Common causes include, but are not limited to, diverticular bleeding, ischemic colitis, and vascular abnormalities (arteriovenous malformations, AVMs) The site of bleeding is not always identified easily; as many as 11% of patients initially suspected of having a LGIB are ultimately found to have an UGIB [23] Therefore, UGIB sources should always be considered first in patients with LGIB, particularly in patients with unstable hemodynamics Once an upper GI source has been excluded, colonoscopy should be performed to evaluate the lower GI tract and administer appropriate therapy Although urgent colonoscopy within 24 to 48 hours has shown to decrease the length of hospital stay [24] and endoscopic intervention is often successful, 80% to 85% of LGIBs stop spontaneously [25] If the bleeding is severe or a source cannot be identified at colonoscopy, a technetium (TC)-99m red blood cell scan with or without angiography should be considered [26] p 169 p 170 Acute Colonic Distention This condition can be caused by acute colonic obstruction or acute colonic pseudoobstruction Acute colonic obstruction can be caused by neoplasms, diverticular disease, and volvulus [27] Volvulus is a “closedloop obstruction” and is considered an emergency because unlike the other causes of colonic obstruction, it can rapidly deteriorate from obstruction to ischemia, to perforation, and even result in death However, if identified and treated early, it can be reversed Acute colonic pseudoobstruction is a syndrome of massive dilation of the colon without mechanical obstruction that develops in hospitalized patients with serious underlying medical and surgical conditions due to impaired colonic motility Increasing age, cecal diameter, delay in decompression, and status of the bowel significantly influence mortality, which is approximately 40% when ischemia or perforation is present Evaluation of the markedly distended colon in the ICU setting involves excluding mechanical obstruction and other causes of toxic megacolon, such as C difficile infection, and assessing for signs of ischemia and perforation The risk of colonic perforation in acute colonic pseudoobstruction increases when cecal diameter exceeds 12 cm and when the distention has been present for greater than 6 days [28] PREPROCEDURAL CARE When endoscopic interventions are contemplated, for any of the previously discussed indications, a number of issues need to be addressed: appropriate resuscitation, reversal of coagulopathies, adequate sedation, and antibiotics, especially in patients with ascites or endocarditis who present with GI bleeding [29,30] In selected cases, proper sedation may simply involve light sedation [31] In other cases, such as in uncooperative, confused, or hypoxemic patients, proper sedation may require deep sedation or endotracheal intubation with general anesthesia Although this type of sedation does not significantly alter the risk of acquired pneumonia or cardiovascular events [32], it does generate controlled conditions during the procedure and may help prevent massive aspiration (especially in patients with variceal bleeding) In all patients with UGIB, an empty stomach is crucial for thorough evaluation and identification of the bleeding lesion Through proper identification and treatment, studies have shown a reduction in the risk of rebleeding and in the need for surgical intervention [33] Gastric lavage with an NG tube or through use of the endoscope can clear the stomach of blood and clot At times, the use of prokinetic agents such as erythromycin (250 mg in 50 mL of normal saline IV, 20 minutes prior to the procedure) may also be helpful Studies have in fact shown that this approach may improve the endoscopic visualization, improve the outcome, and decrease the need for “second-look” endoscopy [34] If a variceal hemorrhage is suspected, on the basis of a clinical history or physical examination that suggests portal hypertension, adjunctive therapy should be initiated immediately in the absence of contraindications Both somatostatin analogues (octreotide) or vasopressin and its analogues have been used IV to reduce portal pressures and prevent recurrent bleeding [35] Octreotide is usually given as a onetime bolus of 50 to 100 μg IV, followed by 25 to 50 μg IV per hour for 3 to 5 days In addition, prophylactic antibiotics should be given to patients with active esophageal variceal bleeding for the prevention of bacterial infections [36] In contrast to nonvariceal hemorrhage, volume resuscitation should be performed judiciously in variceal bleeding as volume repletion can theoretically increase portal pressures Unlike the other types of endoscopies discussed previously, this is the only one requiring a preprocedure bowel preparation In urgent situations, this can be done through a technique known as a rapid purge This technique is usually achieved by drinking 4 L or more polyethylene glycol–based solutions over a 2- to 3-hour period Approximately one-third of hospitalized patients require an NG tube for this type of preparation [37] Metoclopramide (10 mg IV × 1), administered prior to starting the preparation, may help to control nausea and promote gastric emptying [34] INTRAPROCEDURAL CARE Upper Gastrointestinal Endoscopy Upper Gastrointestinal Bleeding If the bleeding source is found to be a peptic ulcer, the intervention will depend on the specific endoscopic findings [38] If the ulcer has a clean base with no signs of active bleeding, endoscopic intervention is not indicated If an actively bleeding or a nonbleeding visible vessel is identified in the crater of the ulcer, endoscopic hemostatic techniques are recommended A number of endoscopic methods have been developed for hemostasis, including injection therapy, thermal cautery therapy, and mechanical hemostasis with clips (Table 20.3) The combination of injection therapy with thermal coaptive therapy is superior to either alone [36,39] Although no single solution for endoscopic injection therapy appears superior to another, an epinephrine–saline solution is usually injected in four quadrants surrounding the lesion Heater probe and multipolar electrocoagulation instruments are subsequently applied with firm pressure to achieve optimal coaptation Mechanical hemostasis with hemoclips have the advantage of minimal tissue damage, leading to potentially faster ulcer healing and it has been found effective for ulcer bleeding alone or in conjunction with other therapies (Fig 20.4) [40] Argon plasma coagulation is a noncoaptive technique that provides cautery to tissues by means of ionized argon gas This method appears to be most effective for shallow and broadly defined bleeding lesions such as vascular ectasias, but has been found to be as effective in ulcer management as other common modalities [38] The yttrium-aluminumgarnet laser has fallen out of favor in the acute management of high-risk patients because of its poor portability and associated high cost Hemospray is a hemostatic powder (Cook Medical, Winston-Salem, NC) recently introduced for the management of GI bleeding that is both a cohesive and adhesive substance that creates a mechanical barrier Applied in short bursts with carbon dioxide propulsion directly to the bleeding site, Hemospray is given until hemostasis is seen It has been studied as both primary therapy and salvage therapy and has been shown to be effective in UGIB and LGIB [41,42] Similarly, cryotherapy has gained wider recognition as it allows for tissue destruction via freezing by delivering a 25 to 30 mL per minute outflow of nitric monoxide at a temperature of −89.5°C and creating a 2 to 10 mm ice layer on the surface of the mucosa It has found particular success in the management of angiodysplasia (AVM) [43] TABLE 20.3 Endoscopic Methods for Hemostasis Thermal methods of hemostasis  Heater probe  Multipolar electrocoagulation (bicap)  Neodymium yttrium-aluminum-garnet laser  Argon plasma coagulation Injection therapy for hemostasis  Distilled water or saline  Epinephrine (adrenaline)  Sclerosants (cyanoacrylate, polidocanol, ethanol, ethanolamine oleate, sodium tetradecyl sulfate, sodium morrhuate)  Thrombin fibrin glue Mechanical methods  Clips  Band ligation  Detachable loops FIGURE 20.4 Hemostatic clip placed on a arteriovenous malformation in the proximal jejunum during a spiral enteroscopy (Courtesy of David Cave, MD: Professor of Medicine, University of Massachusetts Medical School.) p 171 p 172 In the last several years, several other modalities have emerged as effective treatment methods in UGIB The over-the-scope-clip (OTSC) system, first developed in Germany, is a device that can be used to achieve hemostasis and close perforations, fistulas, or anastamotic leaks Similar to the esophageal banding device, the OTSC cap can be loaded onto the tip of the scope, which can then be placed over the lesion, sucking the lesions in and allowing for the clip to be deployed This device has now been studied in many different indications, and has enjoyed success in cases refractory to traditional hemostatic methods [44,45] EUS has now been incorporated into the management of refractory GI bleeding Under EUS visualization of a bleeding vessel with Doppler, the vessel is punctured with a 19-gauge needle and injected with a sclerosing agent such as cyanoacrylate (glue) or coils Doppler monitoring then allows for viewing of the disappearance of the Doppler signal, signaling the cessation of bleeding This method of EUS-guided angiotherapy has found success in a variety of bleeding etiologies, including gastric varices, ulcers, and malignancy [46] In esophageal variceal bleeding, endoscopic variceal ligation (EVL) has become the procedure of choice [47,48] With this technique, the varix is suctioned into a banding device attached to the tip of the endoscope and a rubber band is then deployed at its base to obliterate the varix In contrast, endoscopic sclerotherapy (EST) causes obliteration by injection of a sclerosing agent (e.g., sodium morrhuate) in or around the bleeding varix A meta-analysis by Laine and Cook [48] suggested that EVL was superior to EST in all major outcomes (recurrent bleeding, local complications such as ulcers or strictures, time to variceal obliteration, and survival) However, EST is effective in controlling active bleeding in more than 90% of cases and can be injected even with poor visualization during an active bleed Endoscopic methods (EST, EVL, and injection of fibrin glue) have also been used for the treatment of bleeding gastric varices These methods, however, carry a considerable risk of rebleeding and mortality Patients with bleeding gastric varices generally require urgent placement of a transjugular intrahepatic portosystemic shunt [49] Balloon-occluded retrograde transvenous obliteration, a procedure first developed in Asia, has slowly been introduced in the United States, and consists of retrograde injection of sclerosing agents into gastric varices after balloon occlusion of the gastrorenal shunt, taking advantage of the tendency of gastric fundal varices to drain into the left renal vein via a gastrorenal shunt Given its high success rate, this procedure represents another viable method to treat gastric varices [50] Enteral Stents The use of uncovered SEMS has been widely studied for use in GOO secondary to a malignancy As long as a guidewire is able to be passed through the obstruction, the stent can be placed onto the guidewire and advanced under fluoroscopic guidance A large systematic review demonstrated that there were no significant differences between the stent placement and surgical gastrojejunostomy in technical success, complications, or persistent of symptoms [51] Stent placement, however, did have a higher rate of recurrent obstructive symptoms (18% vs 1%) and decreased mean survival (105 vs 164 days) Despite this, enteral stent placement does have a 90% initial clinical success rate, and should be pursued for palliative purposes in patients with a less than 6-month life expectancy Enteric Feeding Tubes Please see Chapter 21 for more details on the placement of enteric feeding tubes Pancreaticobiliary Endoscopy Refer to Chapter 208 Small Bowel Endoscopy The techniques are essentially the same as those for upper GI endoscopy (above) Lower Gastrointestinal Endoscopy Lower Gastrointestinal Bleeding The endoscopic treatment options for LGIB are similar to those for UGIB (see earlier in the chapter) and should be based on the stigmata of bleeding that are identified Hemostasis is usually approached through a combination approach of injection therapy with clipping or coagulation therapy Decompressive Endoscopy A water-soluble contrast enema or computed tomography should be the initial procedure to perform in patients with acute colonic distention This will establish the presence or absence of mechanical obstruction Subsequently, the patient should undergo resuscitation with IV fluids, frequent repositioning, NG and rectal tube placements, correction of metabolic imbalances, and discontinuation of medications known to slow intestinal transit [52] If conservative measures are unsuccessful, decompressive endoscopy with minimal inflation of air resolves acute obstruction of the colon in the majority of cases (81%) [53] Despite a high recurrence rate (23% to 57%), colonoscopy is often considered the initial procedure of choice in the absence of intestinal ischemia [54] This may be reduced with the placement of a decompression tube beyond the splenic flexure [55] In patients with mechanical obstruction, SEMS can be placed with good outcome [56] In patients with nonmechanical obstruction, medical therapy with the parasympathomimetic agent neostigmine should be considered On the basis of a double-blind, placebo-controlled, randomized trial, the parasympathomimetic agent neostigmine has been shown to reduce colonic distention significantly, reduce recurrence, with minimal risk [57] This agent should only be given in the absence of contraindications and under close cardiorespiratory monitoring with atropine at the bedside Percutaneous, endoscopic, or surgical cecostomy presents another alternative if the aforementioned interventions are unsuccessful Fecal Microbiota Transplantation The increase in prevalence of Clostridium difficile infection (CDI) and particularly recurrent CDI has brought fecal microbiota transplantation (FMT) to the forefront Numerous studies have demonstrated its high success rate, but it remains poorly studied in cases of severe CDI, which will often require ICU care [58] Nevertheless, the ability to perform FMT via upper endoscopy, colonoscopy, and rectal enema presents an alternative treatment option in patients with CDI who have failed conventional antibiotic therapy Perforations, Fistulas, and Anastamotic Leaks Recently, the OverStitch (Apollo Endosurgery Inc., Austin, TX) has emerged as an endoscopic suturing device that can also be used to closing perforations and fistulas (Fig 20.5) This system is attached to a standard endoscope and allows for a detachable needle to be used to suture lesions with a suture-cinching tool used to secure the deployed suture [59,60] This may represent a method to close small perforations and fistulas without the need for surgical intervention POST-PROCEDURAL CARE Although major complications of endoscopic procedures are infrequent, critically ill patients may be particularly sensitive to adverse outcomes due to multiple comorbidities It is crucial to monitor patients for complications post procedures These can be divided into two groups: (i) general complications and (ii) specific complications (Table 20.4) TABLE 20.4 Complications of Endoscopy General complications  Complications of conscious sedation (cardiopulmonary, allergic, paradoxical reactions)  Bleeding (e.g., treatment of lesions, sphincterotomy)  Perforation (caused by endoscope, accessories, or air insufflation)  Aspiration  Myocardial ischemia Specific complications (examples)  Endoscopic retrograde cholangiopancreatography: pancreatitis, cholangitis, perforation  Sclerotherapy: ulceration, mediastinitis  Stenting procedures: stent migration In patients with UGIB, post procedure pharmacotherapy is also indicated In patients with nonvariceal UGIB, for example, antisecretory therapy with a proton pump inhibitor (PPI) following endoscopic hemostasis is encouraged [40] IV administration of a PPI is a faster way to achieve gastric acid suppression than is oral administration of the same agent Peak suppression after IV administration occurs within hours, compared with several days later after oral administration This is crucial because it can reduce the risk of rebleeding and the need for surgery [40] The PPIs currently approved for IV use in the United States include pantoprazole, lansoprazole, and esomeprazole In contrast, patients with variceal UGIB should receive daily nonselective β-blockers for secondary prevention in addition to repeat EVL every 3 to 4 weeks until obliteration of the varices is achieved [61] FUTURE DIRECTIONS The constantly evolving landscape of endoscopic technologies and methods will continue to expand the reach of endoscopic intervention One area in particular is the developing role of endoscopic suturing in the GI tract, especially in the care and management of mucosal perforation, in the treatment of GI bleeding, and the closure of fistulas Although case reports are in the literature, larger studies are needed before this technique can be recommended on a regular basis Other areas of development are the evaluation and management of small bowel bleeding With the advent of viewers linked in to video capsule and the development of the power spiral endoscopy, this may allow earlier recognition and treatment of small bowel disease than thought previously; however, studies are needed to determine the efficacy and benefits of these techniques REFERENCES American Society for Gastrointestinal Endoscopy: Appropriate use of gastrointestinal endoscopy Gastrointest Endosc 52:831–837, 2000 Koch A, Buendgens L, Dückers H, et al: Bleeding origin, patient-related risk factors, and prognostic indicators in patients with acute gastrointestinal hemorrhages requiring intensive care treatment A retrospective analysis from 1999 to 2010 Med Klin Intensivmed Notfmed 108(3):214–222, 2013 Khamaysi I, Gralnek IM: Nonvariceal upper gastrointestinal bleeding: timing of endoscopy and ways to improve endoscopic visualization Gastrointest Endosc Clin N Am 25(3):443–448, 2015 Chak A, Cooper GS, Lloyd LE, et al: Effectiveness of endoscopy in patients admitted to the intensive care unit with upper GI hemorrhage Gastrointest Endosc 53:6–13, 2001 Beejay U, Wolfe MM: Acute gastrointestinal bleeding in the intensive care unit The gastroenterologist’s perspective Gastroenterol Clin North Am 29:309–336, 2000 Eisen GM, Baron TH, Dominitz JA, et al: Guideline for the management of ingested foreign bodies Gastrointest Endosc 55:802– 806, 2002 Poley JW, Steyerberg EW, Kuipers EJ, et al: Ingestion of acid and alkaline agents: outcome and prognostic value of early upper endoscopy Gastrointest Endosc 60:372–377, 2004 van Hooft JE, Dijkgraaf MG, Timmer R, et al: Independent predictors of survival in patients with incurable malignant gastric outlet obstruction: a multicenter prospective observational study Scand J Gastroenterol 45:1217–1222, 2010 Eisen GM, Baron TH, Dominitz JA, et al: Role of endoscopy in enteral feeding Gastrointest Endosc 55:699–701, 2002 10 Fan AC, Baron TH, Rumalla A: Comparison of direct percutaneous endoscopic jejunostomy and PEG with jejunal extension Gastrointest Endosc 56:890–894, 2002 11 DeLegge MH, McClave SA, DiSario JA, et al: Ethical and medicolegal aspects of PEG-tube placement and provision of artificial nutritional therapy Gastrointest Endosc 62:952–959, 2005 12 Bakker OJ, van Brunschot S, van Santvoort HC: Early versus ondemand nasoenteric tube feeding in acute pancreatitis N Engl J Med 371(21):1983–1993, 2014 13 Herman LL, Hoskins WJ, Shike M: Percutaneous endoscopic gastrostomy for decompression of the stomach and small bowel Gastrointest Endosc 38:314–318, 1992 14 Sharma VK, Howden CW: Metaanalysis of randomized controlled trials of endoscopic retrograde cholangiography and endoscopic sphincterotomy for the treatment of acute biliary pancreatitis Am J Gastroenterol 94:3211–3214, 1999 15 Adler DG, Baron TH, Davila RE, et al: ASGE guideline: the role of ERCP in diseases of the biliary tract and the pancreas Gastrointest Endosc 62:1–8, 2005 16 Lai EC, Mok FP, Tan ES, et al: Endoscopic biliary drainage for severe acute cholangitis N Engl J Med 326:1582–1586, 1992 17 Kaffes AJ, Hourigan L, De Luca N, et al: Impact of endoscopic intervention in 100 patients with suspected postcholecystectomy bile leak Gastrointest Endosc 61:269–275, 2005 18 Sandha GS, Bourke MJ, Haber GB, et al: Endoscopic therapy of bile leak based on a new classification: results in 207 patients Gastrointest Endosc 60:567–574, 2004 19 Tringali A, Lemmers A, Meves V: Intraductal biliopancreatic imaging: European Society of Gastrointestinal Endoscopy (ESGE) technology review Endoscopy 47(8):739–753, 2015 20 Gardner TB, Coelho-Prabhu N, Gordon SR, et al: Direct endoscopic necrosectomy for the treatment of walled-off pancreatic necrosis: results from a multicenter U.S series Gastrointest Endosc 73(4):718– 726, 2011 21 Church J, Kao J: Bedside colonoscopy in intensive care units: indications, techniques, and outcomes Surg Endosc 28(9):2679–2682, 2014 22 Davila RE, Rajan E, Adler DG, et al: ASGE guideline: the role of endoscopy in the patient with lower GI-bleeding Gastrointest Endosc 62:656–660, 2005 23 Jensen DM, Machicado GA: Diagnosis and treatment of severe hematochezia The role of urgent colonoscopy after purge Gastroenterology 95:1569–1574, 1998 24 Strate LL, Syngal S: Timing of colonoscopy: impact on length of hospital stay in patients with acute lower GI bleeding Am J Gastroenterol 98:317–322, 2003 25 Farrell JJ, Friedman LS: Review article: the management of lower gastrointestinal bleeding Aliment Pharmacol Ther 21:1281–1298, 2005 26 Strate LL, Syngal S: Predictors of utilization of early colonoscopy vs radiography for severe lower intestinal bleeding Gastrointest Endosc 61:46–52, 2005 27 Frizelle FA, Wolff BG: Colonic volvulus Adv Surg 29:131–139, 1996 28 Saunders MD, Kimmey MB: Colonic pseudo-obstruction: the dilated colon in the ICU Semin Gastrointest Dis 14(1):20–27, 2003 29 Rajala MW, Ginsberg GG: Tips and tricks on how to optimally manage patients with upper gastrointestinal bleeding Gastrointest Endosc Clin N Am 25(3):607–617, 2015 30 Tang X, Gong W, Jiang B: Antibiotic prophylaxis for GI endoscopy Gastrointest Endosc 81(6):1503–1504, 2015 31 Lichenstein DR, Jagannath S, Baron TH, et al: ASGE Standards of Practice Committee: Sedation and anesthesia in GI endoscopy Gastrointest Endosc 68(5):815–826, 2008 32 Wassef W, Rullan R: Interventional endoscopy Curr Opin Gastroenterol 21:644–652, 2005 33 Meltzer AC, Klein JC: Upper gastrointestinal bleeding: patient presentation, risk stratification, and early management Gastroenterol Clin North Am 43(4):665–675, 2014 p 173 p 174 34 Frossard JL, Spahr L, Queneau PE, et al: Erythromycin intravenous bolus infusion in acute upper gastrointestinal bleeding: a randomized, controlled, double-blind trial Gastroenterology 123:17–23, 2002 35 Wells M, Chande N, Adams P, et al: Meta-analysis: vasoactive medications for the management of acute variceal bleeds Aliment Pharmacol Ther 35(11):1267–1278, 2012 36 Barkun AN, Bardou M, Kuipers EJ, et al: International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding Ann Intern Med 152(2):101–113, 2010 37 Elta GH: Technological review Urgent colonoscopy for acute lower-GI bleeding Gastrointest Endosc 59:402–408, 2004 38 Lu Y, Chen YI, Barkun A: Endoscopic management of acute peptic ulcer bleeding Gastroenterol Clin North Am 43(4):677–705, 2014 39 Calvet X, Vergara M, Brullet E, et al: Addition of a second endoscopic treatment following epinephrine injection improves outcome in highrisk bleeding ulcers Gastroenterology 126(2):441–450, 2004 40 Laine L, McQuaid KR: Endoscopic therapy for bleeding ulcers: an evidence-based approach based on meta-analyses of randomized controlled trials Clin Gastroenterol Hepatol 7(1):33–47, 2009 41 Sulz MC, Frei R, Meyenberger C, et al: Routine use of Hemospray for gastrointestinal bleeding: prospective two-center experience in Switzerland Endoscopy 46(7):619–624, 2014 42 Changela K, Papafragkakis H, Ofori E: Hemostatic powder spray: a new method for managing gastrointestinal bleeding Therap Adv Gastroenterol 8(3):125–135, 2015 43 Fujii-Lau LL, Wong Kee Song LM, Levy MJ: New technologies and approaches to endoscopic control of gastrointestinal bleeding Gastrointest Endosc Clin N Am 25(3):553–567, 2015 44 Sulz MC, Bertolini R, Frei R, et al: Multipurpose use of the over-thescope-clip system (“Bear claw”) in the gastrointestinal tract: Swiss experience in a tertiary center World J Gastroenterol 20(43):16287– 16292, 2014 45 Mönkemüller K, Peter S, Toshniwal J, et al: Multipurpose use of the ‘bear claw’ (over-the-scope-clip system) to treat endoluminal gastrointestinal disorders Dig Endosc 26(3):350–357, 2014 46 Gavini H, Lee JH: Endoscopic ultrasound-guided endotherapy J Clin Gastroenterol 49(3):185–193, 2015 47 Baron TH, Wong Kee Song LM: Endoscopic variceal band ligation Am J Gastroenterol 104:1083–1085, 2009 48 Laine L, Cook D: Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding: a metaanalysis Ann Intern Med 123:280–287, 1995 49 Sharara AI, Rockey DC: Gastroesophageal variceal bleed N Engl J Med 345:669–681, 2001 50 Park J, Saab S, Kee S, et al: Balloon-occluded retrograde transvenous obliteration (BRTO) for treatment of gastric varices: review and metaanalysis Dig Dis Sci 60(6):1543–1553, 2015 51 Jeurnink SM, van Eijck CH, Steyerberg EW, et al: Stent versus gastrojejunostomy for the palliation of gastric outlet obstruction: a systematic review BMC Gastroenterol 7:18, 2007 52 Eisen GM, Baron TH, Dominitz JA, et al: Acute colonic pseudoobstruction Gastrointest Endosc 56:789–792, 2002 53 Grossmann EM, Longo WE, Stratton MD, et al: Sigmoid volvulus in Department of Veterans Affairs Medical Centers Dis Colon Rectum 43:414–418, 2000 54 Saunders MD, Kimmey MB: Systematic review: acute colonic pseudoobstruction Aliment Pharmacol Ther 22:917–925, 2005 55 Geller A, Petersen BT, Gostout CJ: Endoscopic decompression for acute colonic pseudo-obstruction Gastrointest Endosc 44:144–150, 1996 56 Dronamraju SS, Ramamurthy S, Kelly SB, et al: Role of self-expanding metallic stents in the management of malignant obstruction of the proximal colon Dis Colon Rectum 52(9):1657–1661, 2009 57 Ponec RJ, Saunders MD, Kimmey MB: Neostigmine for the treatment of acute colonic pseudo-obstruction N Engl J Med 341:137–141, 1999 58 Han S, Shannahan S, Pellish R: Fecal microbiota transplant: treatment options for Clostridium difficile infection in the intensive care unit J Intensive Care Med 31(9):577–586, 2016 59 Sharaiha RZ, Kumta NA, DeFilippis EM, et al: A large multicenter experience with endoscopic suturing for management of gastrointestinal defects and stent anchorage in 122 patients: a retrospective review J Clin Gastroenterol 50(5):388–392, 2016 60 Rieder E, Dunst CM, Martinec DV, et al: Endoscopic suture fixation of gastrointestinal stents: proof of biomechanical principles and early clinical experience Endoscopy 44(12):1121–1126, 2012 61 Garcia-Tsao G, Sanyal AJ, Grace ND, et al: Practice Guidelines Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology: Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis Hepatology 46(3):922– 938, 2007 Chapter 21 Endoscopic Placement of Feeding Tubes LENA M NAPOLITANO INDICATIONS FOR ENTERAL FEEDING Nutritional support is an essential component of intensive care medicine (see Chapters 212–214) National and international guidelines [1–4] and comprehensive reviews [5] all strongly recommend that enteral nutrition be used in preference to parenteral nutrition when possible Provision of nutrition through the enteral route aids in prevention of gastrointestinal mucosal atrophy, thereby maintaining the integrity of the gastrointestinal mucosal barrier Other advantages of enteral nutrition are preservation of immunologic gut functions and normal gut flora, improved use of nutrients, and reduced costs Some studies suggest that clinical outcomes are improved and infectious complications are less frequent in patients who receive enteral nutrition compared with parenteral nutrition Although there are absolute or relative contraindications to enteral feeding in selected cases, most critically ill patients can receive some or all of their nutritional requirements via the gastrointestinal tract Enteral feeding is even recommended in severe acute pancreatitis, and nasogastric or nasojejunal feedings are both well tolerated [6] Even when some component of nutritional support must be provided by parenteral nutrition, feeding via the gut is desirable Several developments—including new techniques for placement of feeding tubes, availability of smaller caliber, minimally reactive tubes, and an increasing range of enteral formulas—have expanded the ability to provide enteral nutritional support to critically ill patients Relative or absolute contraindications to enteral feeding include fistulas, intestinal obstruction, upper gastrointestinal hemorrhage, and severe inflammatory bowel disease or intestinal ischemia Enteral feeding is not recommended in patients with severe malabsorption or early in the course of severe short-gut syndrome ACCESS TO THE GASTROINTESTINAL TRACT After deciding to provide enteral nutrition, the clinician must decide whether to deliver the formula into the stomach, duodenum, or jejunum, and determine the optimal method for accessing the site, which is based on the function of the patient’s gastrointestinal tract, duration of enteral nutritional support required, and risk of pulmonary aspiration Gastric feeding provides the most normal route for enteral nutrition, but may not be tolerated in the critically ill patient because of gastric dysmotility with delayed emptying [7] Enteral nutrition infusion into the duodenum or jejunum may decrease the incidence of aspiration because of the protection afforded by a competent pyloric sphincter; however, the risk of aspiration is not completely eliminated by feeding distal to the pylorus [8–10] An advantage of this site of administration is that enteral feeding can be initiated early in the postoperative period, because postoperative ileus primarily affects the colon and stomach and only rarely involves the small intestine TECHNIQUES Enteral feeding tubes can be placed via the transnasal, transoral, or percutaneous transgastric or transjejunal routes If these procedures are contraindicated or unsuccessful, the tube may be placed by endoscopy, using endoscopic and laparoscopic technique, or surgically via a laparotomy [11] Nasoenteric Route Nasoenteric tubes are the most commonly used means of providing enteral nutritional support in critically ill patients This route is preferred for short- to intermediate-term enteral support when eventual resumption of oral feeding is anticipated It is possible to infuse enteral formulas into the stomach using a conventional 16- or 18-French (Fr) polyvinyl chloride nasogastric tube, but patients are usually much more comfortable if a small-diameter silicone or polyurethane feeding tube is used Nasoenteric tubes vary in luminal diameter (6 to 14 Fr) and length, depending on the desired location of the distal orifice: stomach, 30 to 36 inches; duodenum, 43 inches; jejunum, at least 48 inches Some tubes have tungsten-weighted tips designed to facilitate passage into the duodenum via normal peristalsis, whereas others have a stylet Most are radiopaque Some tubes permit gastric decompression while delivering formula into the jejunum Nasoenteric feeding tubes should be placed with the patient in a semiFowler’s or sitting position The tip of the tube should be lubricated, placed in the patient’s nose, and advanced to the posterior pharynx If the patient is alert and can follow instructions, the patient should be permitted to sip water as the tube is slowly advanced into the stomach To avoid unintentional airway placement and serious complications, position of the tube should be ascertained after it has been inserted to 30 cm Acceptable means of documenting intraesophageal location of the tube include a chest radiograph or lack of CO2 detection through the lumen of the tube by capnography or colorimetry If the tube is in the airway, CO2 will be detected and the tube must be removed Alternatively, commercial systems are now available to track tube progression from the esophagus through the stomach to the duodenum by electromagnetic means Proper final placement of the tube in the stomach must be confirmed by chest or upper abdominal radiograph before tube feeding is begun The following methods to assess final tube placement are unreliable and do not assess tube misdirection into the lower respiratory tract: auscultation over the left upper quadrant with air insufflation through the tube, assessment of pH with gastric content aspiration, and easy passage of the tube to its full length with the absence of gagging and coughing [12] The tube should be securely taped to the nose, forehead, or cheek without tension Nasal bridles are more effective at securing nasoenteric tubes than use of tape [13] Delayed gastric emptying has been confirmed in critically ill patients and may contribute to gastric feeding intolerance Spontaneous transpyloric passage of enteral feeding tubes in critically ill patients is commonly unsuccessful, secondary to the preponderance of gastric atony The addition of a tungsten weight to the end of enteral feeding tubes and the development of wire or metal stylets in enteral feeding tubes are aimed at improving the success rate for spontaneous transpyloric passage Once the tube is documented to be in the stomach, various bedside techniques, including air insufflation, pH-assisted, magnetguided and spontaneous passage with or without motility agents, may help facilitate transpyloric feeding tube passage Intravenous (IV) metoclopramide and erythromycin have been recommended as prokinetic agents But a Cochrane Database Systematic Review concluded that doses of 10 or 20 mg of IV metoclopramide were equally ineffective in facilitating transpyloric feeding tube placement [14] No matter which techniques are used to facilitate transpyloric passage of enteral feeding tubes, these tubes must be inserted by skilled practitioners using defined techniques If the tube does not pass into the duodenum on the first attempt, placement can be attempted under endoscopic assistance or fluoroscopic or electromagnetic guidance The latter method requires specialized equipment Endoscopic placement of nasoenteral feeding tubes is easily accomplished in the critically ill patient and can be performed at the bedside using portable equipment [15] Transnasal or transoral endoscopy can be used for placement of nasoenteral feeding tubes in critically ill patients The patient is sedated appropriately (see Chapter 20), and topical anesthetic is applied to the posterior pharynx with lidocaine or benzocaine spray A 43- to 48-inches-long nasoenteric feeding tube with an inner wire stylet is passed transnasally into the stomach The endoscope is inserted and advanced through the esophagus into the gastric lumen An endoscopy forceps is passed through the biopsy channel of the endoscope and used to grasp the tip of the enteral feeding tube The endoscope, along with the enteral feeding tube, is advanced distally into the duodenum as far as possible (Fig 21.1) FIGURE 21.1 Endoscopic placement of nasoenteral feeding tube Endoscopy forceps and gastroscope advance the feeding tube in the duodenum The endoscopy forceps and feeding tube remain in position in the distal duodenum as the endoscope is withdrawn back into the gastric lumen The endoscopy forceps are opened, the feeding tube released, and the endoscopy forceps withdrawn carefully back into the stomach On first pass, the feeding tube is usually lodged in the second portion of the duodenum The portion of the feeding tube that is redundant in the stomach is advanced slowly into the duodenum using the endoscopy forceps to achieve a final position distal to the ligament of Treitz (Fig 21.2) An abdominal radiograph is obtained at the completion of the procedure to document the final position of the nasoenteral feeding tube Endoscopic placement of postpyloric enteral feeding tubes is highly successful, eliminates the risk of transporting the patient to the radiology department for fluoroscopic placement, and allows prompt achievement of nutritional goals, because enteral feeding can be initiated immediately after the procedure FIGURE 21.2 Abdominal radiograph documenting the optimal position of an endoscopically placed nasoenteral feeding tube, past the ligament of Treitz The recent development of ultrathin endoscopes (outer diameter 5.1 to 5.9 mm vs 9.8 mm in standard gastroscope) has enabled nasoenteric feeding tube placement via transnasal endoscopy using an over-the-wire technique A 90% success rate was documented with endoscopic procedure duration of approximately 13 minutes, shorter than fluoroscopic procedure duration, and without the need for additional sedation [16] Transnasal ultrathin endoscopy without the need for sedation can also be used for feeding tube or percutaneous endoscopic gastrostomy (PEG) placement in patients who are unable to undergo transoral endoscopy, that is, those who have partial or complete occlusion of the mouth [17] p 175 p 176 Electromagnetic guidance employs a feeding tube with a guidewire that emits electromagnetic waves A box with three receivers that is placed on the patient’s xiphoid process triangulates the position of the tube The clinician is able to “view” the tip on a monitor as it passes down the esophagus through the stomach and into the duodenum An X-ray is still required to confirm and document tube placement Percutaneous Route PEG tube placement, introduced by Ponsky et al [18] in 1990, has become the procedure of choice for patients requiring prolonged enteral nutritional support PEG tubes range in size from 20 to 28 Fr PEG rapidly replaced open gastrostomy as the method of choice for enteral nutrition Unlike surgical gastrostomy, PEG does not require general anesthesia and laparotomy and eliminates the discomfort associated with chronic nasoenteric tubes This procedure can be considered for patients who have normal gastric emptying and low risk for pulmonary aspiration, and can be performed in the operating room, in an endoscopy unit, or at the bedside in the intensive care unit with portable endoscopy equipment PEG should not be performed in patients with near or total obstruction of the pharynx or esophagus, in the presence of coagulopathy, or when transillumination is inadequate Relative contraindications are ascites, gastric cancer, and gastric ulcer Previous abdominal surgery is not a contraindication The original method for PEG was the pull technique; more recent modifications are the push and introducer techniques Pull Technique The pull technique is performed with the patient in the supine position After a time-out, the abdomen is prepared and draped The posterior pharynx is anesthetized with a topical spray or solution (e.g., benzocaine spray or viscous lidocaine), and IV sedation (e.g., 1 to 2 mg of midazolam; see Chapter 20) is administered A prophylactic antibiotic, usually a firstgeneration cephalosporin, is administered before the procedure The fiberoptic gastroscope is inserted into the stomach, which is then insufflated with air The lights are dimmed, and the assistant applies digital pressure to the anterior abdominal wall in the left subcostal area approximately 2 cm below the costal margin, looking for the brightest transillumination (light reflex) The endoscopist should be able to clearly identify the indentation in the stomach created by the assistant’s digital pressure on the anterior abdominal wall (digital reflex); otherwise, another site should be chosen When the correct spot has been identified, the assistant anesthetizes the anterior abdominal wall The endoscopist then introduces a polypectomy snare through the endoscope A small incision is made in the skin, and the assistant introduces a large-bore catheter–needle stylet assembly into the stomach and through the snare The snare is then tightened securely around the catheter The inner stylet is removed, and a looped insertion wire is introduced through the catheter and into the stomach The cannula is slowly withdrawn so that the snare grasps the wire The gastroscope is then pulled out of the patient’s mouth with the wire firmly grasped by the snare The end of the transgastric wire exiting the patient’s mouth is then tied to a prepared gastrostomy tube The assistant pulls on the end of the wire exiting from the abdominal wall, whereas the endoscopist guides the lubricated gastrostomy tube into the posterior pharynx and the esophagus With continued traction, the gastrostomy tube is pulled into the stomach so that it exits on the anterior abdominal wall The gastroscope is reinserted into the stomach to confirm adequate placement of the gastrostomy tube against the gastric mucosa and to document that no bleeding has occurred The intraluminal portion of the tube should contact the mucosa, but excessive tension on the tube should be avoided because this can lead to ischemic necrosis of the gastric wall The tube is secured to the abdominal wall using sutures Feedings may be initiated immediately after the procedure or 24 hours later Push Technique The push technique is similar to the pull technique The gastroscope is inserted and a point on the anterior abdominal wall localized, as for the pull technique Rather than introducing a looped insertion wire, however, a straight guidewire is snared and brought out through the patient’s mouth by withdrawing the endoscope and snare together A commercially developed gastrostomy tube (Sachs–Vine) with a tapered end is then passed in an aboral direction over the wire, which is held taut The tube is grasped and pulled out the rest of the way The gastroscope is reinserted to check the position and tension on the tube Introducer Technique The introducer technique uses a peel-away introducer technique originally developed for the placement of cardiac pacemakers and central venous catheters The gastroscope is inserted into the stomach, and an appropriate position for placement of the tube is identified After infiltration of the skin with local anesthetic, a 16- or 18-gauge needle is introduced into the stomach A J-tipped guidewire is inserted through the needle into the stomach, and the needle is withdrawn Using a twisting motion, a 16-Fr introducer with a peel-away sheath is passed over the guidewire into the gastric lumen [19,20] The guidewire and introducer are removed, leaving in place the sheath that allows placement of a 14-Fr Foley catheter The sheath is peeled away after the balloon is inflated with 10 mL of normal saline Some advocate this as the optimal method for PEG in patients with head and neck cancer, related to an overall lower rate of complications in this patient population [21] p 176 p 177 Percutaneous Endoscopic Gastrostomy/Jejunostomy If postpyloric feeding is desired, a PEG/jejunostomy may be performed The tube allows simultaneous gastric decompression and duodenal/jejunal enteral feeding [22] A second, smaller feeding tube can be attached and passed through the gastrostomy tube and advanced endoscopically into the duodenum or jejunum When the PEG is in position, a guidewire is passed through it and grasped using endoscopy forceps The guidewire and endoscope are passed into the duodenum as distally as possible The jejunal tube is then passed over the guidewire through the PEG into the distal duodenum, advanced into the jejunum, and the endoscope is withdrawn An alternative method is to grasp a suture at the tip of the feeding tube or the distal tip of the tube itself and pass the tube into the duodenum, using forceps advanced through the biopsy channel of the endoscope This obviates the need to pass the gastroscope into the duodenum, which may result in dislodgment of the tube when the endoscope is withdrawn Direct Percutaneous Endoscopic Jejunostomy Jejunostomy tubes can be placed endoscopically by means of a PEG with jejunal extension (PEG-J) or by direct percutaneous jejunostomy (PEJ) [23] Because the size of the jejunal extension of the PEG-J tube is significantly smaller than that of the direct PEJ, some have suggested that the PEJ provides more stable jejunal access for those who require long-term jejunal feeding Unfortunately, a low success rate (68%) and a high adverse event rate (22.5%) have been documented in the largest series to date [24] New methods using balloon-assisted enteroscopy with fluoroscopy have improved technical success rates to 96% [25] Fluoroscopic Technique Percutaneous gastrostomy and gastrojejunostomy can also be performed using fluoroscopy [26,27] The stomach is insufflated with air using a nasogastric tube or a skinny needle if the patient is obstructed proximally Once the stomach is distended and position is checked again with fluoroscopy, the stomach is punctured with an 18-gauge needle Tfastener gastropexy may be used, deployed via the 18-gauge needle A heavy-duty wire is passed, and the tract is dilated to accommodate a gastrostomy or gastrojejunostomy tube Complications The most common complication after percutaneous placement of enteral feeding tubes is infection, usually involving the cutaneous exit site and surrounding tissue [28] Gastrointestinal hemorrhage has been reported, but it is usually caused by excessive tension on the tube, leading to necrosis of the stomach wall Gastrocolic fistulas, which develop if the colon is interposed between the anterior abdominal wall and the stomach when the needle is introduced, have been reported Adequate transillumination aids in avoiding this complication Separation of the stomach from the anterior abdominal wall can occur, resulting in peritonitis when enteral feeding is initiated In most instances, this complication is caused by excessive tension on the gastrostomy tube Another potential complication is pneumoperitoneum, secondary to air escaping after puncture of the stomach during the procedure, and is usually clinically insignificant If the patient develops fever and abdominal tenderness, a Gastrografin study should be obtained to exclude the presence of a leak All percutaneous gastrostomy and jejunostomy procedures described here have been established as safe and effective The method is selected on the basis of the endoscopist’s experience and training and the patient’s nutritional needs SURGICAL PROCEDURES Since the advent of PEG, surgical placement of enteral feeding tubes is usually performed as a concomitant procedure as the last phase of a laparotomy performed for another indication Occasionally, an operation solely for tube placement is performed in patients requiring permanent tube feedings when a percutaneous approach is contraindicated or unsuccessful In these cases, the laparoscopic approach to enteral access should be considered Laparoscopic gastrostomy was introduced in 2000, 10 years after the advent of PEG Patients who are not candidates for PEG, as a result of head and neck cancer, esophageal obstruction, large hiatal hernia, gastric volvulus, or overlying intestine or liver, should be considered for laparoscopic gastrostomy or jejunostomy Gastrostomy Gastrostomy is a simple procedure when performed as part of another intra-abdominal operation It should be considered when prolonged enteral nutritional support is anticipated after surgery Complications are quite common after surgical gastrostomy This may reflect the poor nutritional status and associated medical problems in many patients who undergo this procedure Potential complications include wound infection, dehiscence, gastrostomy disruption, internal or external leakage, gastric hemorrhage, and tube migration Needle–Catheter Jejunostomy The needle–catheter jejunostomy procedure consists of the insertion of a small (5-Fr) polyethylene catheter into the small intestine at the time of laparotomy for another indication Kits containing the necessary equipment for the procedure are available from commercial suppliers A needle is used to create a submucosal tunnel from the serosa to the mucosa on the antimesenteric border of the jejunum A catheter is inserted through the needle and then the needle is removed The catheter is brought out through the anterior abdominal wall, and the limb of the jejunum is secured to the anterior abdominal wall with sutures The tube can be used for feeding immediately after the operation The potential complications are similar to those associated with gastrostomy, but patients may have a higher incidence of diarrhea Occlusion of the needle–catheter jejunostomy is common because of its small luminal diameter, and elemental nutritional formulas are preferentially used Transgastric Jejunostomy Critically ill patients who undergo laparotomy commonly require gastric decompression and a surgically placed tube for enteral nutritional support Routine placement of separate gastrostomy and jejunostomy tubes is common in this patient population and achieves the objective of chronic gastric decompression and early initiation of enteral nutritional support through the jejunostomy Technical advances in surgically placed enteral feeding tubes led to the development of transgastric jejunostomy [29] and duodenostomy tubes, which allow simultaneous decompression of the stomach and distal feeding into the duodenum or the jejunum The advantage of these tubes is that only one enterotomy into the stomach is needed, eliminating the possible complications associated with open jejunostomy tube placement In addition, only one tube is necessary for gastric decompression and jejunal feeding, eliminating the potential complications of two separate tubes for this purpose p 177 p 178 The transgastric jejunostomy tube is placed surgically in the same manner as a gastrostomy tube, and the distal portion of the tube is advanced manually through the pylorus into the duodenum, with its final tip resting as far distally as possible in the duodenum or the jejunum (Fig 21.3) The transgastric jejunostomy tube is preferred to transgastric duodenostomy tube because it is associated with less reflux of feedings into the stomach and a decreased risk of aspiration pneumonia Surgical placement of transgastric jejunostomy tubes at the time of laparotomy is recommended for patients who likely require prolonged gastric decompression and enteral feeding FIGURE 21.3 Transgastric duodenal feeding tube, which allows simultaneous gastric decompression and duodenal feeding, can be placed percutaneously (with endoscopic or fluoroscopic assistance) or surgically DELIVERING THE TUBE-FEEDING FORMULA The enteral formula can be delivered by intermittent bolus feeding, gravity infusion, or continuous pump infusion In the intermittent bolus method, the patient receives 300 to 400 mL of formula every 4 to 6 hours The bolus is usually delivered with the aid of a catheter-tipped, large-volume (60-mL) syringe The main advantage of bolus feeding is simplicity This approach is often used for patients requiring prolonged supplemental enteral nutritional support after discharge from the hospital Bolus feeding can be associated with serious side effects, including gastric distention, nausea, cramping, and aspiration The intermittent bolus method should not be used when feeding into the duodenum or the jejunum because boluses of formula can cause distention, cramping, and diarrhea Gravity-infusion systems allow the formula to drip continuously during 16 to 24 hours or intermittently during 20 to 30 minutes, four to six times per day This method requires constant monitoring because the flow rate can be extremely irregular The main advantages of this approach are simplicity, low cost, and close simulation of a normal feeding pattern Continuous pump infusion is the preferred method for the delivery of enteral nutrition in the critically ill patient A peristaltic pump can be used to provide a continuous infusion of formula at a precisely controlled flow rate, which decreases problems with distention and diarrhea Gastric residuals tend to be smaller with continuous pump-fed infusions, and the risk of aspiration may be decreased MEDICATIONS When medications are administered via an enteric feeding tube, it is important to be certain that the drugs are compatible with each other and with the enteral formula In general, medications should be delivered separately rather than as a combined bolus For medications that are better absorbed in an empty stomach, tube feedings should be suspended for 30 to 60 minutes before administration Medications should be administered in an elixir formulation via enteral feeding tubes, whenever possible, to prevent occlusion of the tube Enteral tubes should always be flushed with 20 mL of saline after medications are administered To use an enteral feeding tube to administer medications dispensed in tablet form, often the pills must be crushed and delivered as slurry mixed with water This is inappropriate for some medications, however, such as those absorbed sublingually or formulated as a sustained-released tablet or capsule COMPLICATIONS Enteral tube placement is associated with few complications if practitioners adhere to appropriate protocols and pay close attention to the details of the procedures [30] Nasopulmonary Intubation Passage of an enteral feeding tube into the tracheobronchial tree most commonly occurs in patients with diminished cough or gag reflexes as a result of obtundation, altered mental status, or other causes such as the presence of endotracheal intubation The presence of a tracheostomy or an endotracheal tube does not guarantee proper placement A chest (or upper abdominal) radiograph should always be obtained before initiating tube feedings with a new tube to ensure that the tube is properly positioned Endotracheal or transpulmonary placement of a feeding tube can be associated with pneumothorax, hydrothorax, pneumonia, pulmonary hemorrhage, abscess formation, or death [31] A chest radiograph or a means of detecting CO2 through the tube after it has been inserted 30 cm should be obtained to prevent unintentional placement of small-bore feeding tubes into the lungs Alternatively, electromagnetic guidance can reduce the risk in intrapulmonary placement Aspiration Pulmonary aspiration is a serious and potentially fatal complication of enteral nutritional support The incidence of this complication varies and depends on the patient population studied Traditional clinical monitors of aspiration with glucose oxidase strips and blue food coloring should no longer be used [32] Nonrecumbent positioning is an evidence-based method for aspiration prevention that needs to be initiated in all patients receiving enteral nutrition Major risk factors for aspiration include obtundation or altered mental status, absence of cough or gag reflexes, delayed gastric emptying, gastroesophageal reflux, persistently high gastric residual volumes, and feeding in the supine position The risk of pulmonary aspiration is minimized when the enteral feeding tube is positioned in the jejunum past the ligament of Treitz p 178 p 179 Gastrointestinal Intolerance Delayed gastric emptying is sometimes improved by administering prokinetic agents Combination therapy (metoclopramide 10 mg IV every 6 hours and erythromycin 200 mg IV every 12 hours) was highly effective compared to either agent alone for feeding intolerance in critical illness [33] Dumping syndrome (i.e., diarrhea, distention, and abdominal cramping) can limit the use of enteral feeding Dumping may be caused by delivering a hyperosmotic load into the small intestine Diarrhea in critically ill patients should not be attributed to intolerance of enteral feeding until other causes are excluded Other possible etiologies for diarrhea include medications (e.g., magnesium-containing antacids and sorbitol-containing medications), alterations in gut microflora owing to prolonged antibiotic therapy, antibiotic-associated colitis, ischemic colitis, viral or bacterial enteric infection, electrolyte abnormalities, and excessive delivery of bile salts into the colon Diarrhea can also be a manifestation of intestinal malabsorption because of enzyme deficiencies or villous atrophy [34] Even if diarrhea is caused by enteral feeding, it can be controlled in nearly 50% of cases by instituting a continuous infusion of formula (if bolus feedings are used), slowing the rate of infusion, changing the formula (lower calorie, more elemental), adding fiber to the enteral formula, or adding antidiarrheal agents (e.g., loperamide, diphenoxylate/atropine, or tincture of opium) Metabolic Complications Prerenal azotemia and hypernatremia can develop in patients fed with hyperosmolar solutions The administration of free water, either added to the formula or as separate boluses to replace obligatory losses, can avert this situation Deficiencies of essential fatty acids and fat-soluble vitamins can develop after prolonged support with enteral solutions that contain minimal amounts of fat Periodic enteral supplementation with linoleic acid or IV supplementation with emulsified fat can prevent this The amount of linoleic acid necessary to prevent chemical and clinical fatty acid deficiency has been estimated to be 2.5 to 20.0 g per day Bacterial Contamination Bacterial contamination of enteral solutions occurs when commercial packages are opened and mixed with other substances, and more commonly, it occurs with hospital-formulated and powdered feeds that require preparation compared to commercially prepared, ready-to-feed enteral formulas supplied in cans The risk of contamination also depends on the duration of feeding Contaminated formula may also play a significant role in the etiology of diarrhea in patients receiving enteral nutrition Occluded Feeding Tubes Precipitation of certain proteins when exposed to an acid pH may be an important factor leading to the solidifying of formulas Most premixed intact protein formulas solidify when acidified to a pH less than 5 To prevent occlusion of feeding tubes, the tube should be flushed with water before and after checking residuals Small-caliber nasoenteric feeding tubes should be flushed with 20 mL of water every 4 to 6 hours to prevent tube occlusion, even when enteral feedings are administered by continuous infusion Medications are a frequent cause of clogging [35] When administering medications enterally, liquid elixirs should be used, if available, because even tiny particles of crushed tablets can occlude the distal orifice of small-caliber feeding tubes If tablets are used, it is important to crush them to a fine powder and solubilize them in liquid before administration In addition, tubes should be flushed with water before and after the administration of any medications Several maneuvers are useful for clearing a clogged feeding tube The tube can be irrigated with warm saline, a carbonated liquid, cranberry juice, or a pancreatic enzyme solution (e.g., Viokase) Commonly, a mixture of lipase, amylase, and protease (Pancrease) dissolved in sodium bicarbonate solution (for enzyme activation) is instilled into the tube with a syringe and the tube clamped for approximately 30 minutes to allow enzymatic degradation of precipitated enteral feedings The tube is then vigorously flushed with saline The pancreatic enzyme solution was successful in restoring tube patency in 96% of cases where formula clotting was the likely cause of occlusion and use of cola or water had failed [36,37] Prevention of tube clogging with flushes and pancreatic enzyme are, therefore, the methods of choice in maintenance of chronic enteral feeding tubes Utility of Ultrasonography for Feeding Tube Insertion Ultrasonography has useful application related to insertion of a feeding tube The insertion of a gastric tube may be facilitated with ultrasonography by identifying the nasogastric tube in the upper esophagus and confirming its placement in the stomach by direct visualization (Video 21.1) [38,39] The tube may also be guided into a postpyloric position using real-time ultrasonography guidance (Video 21.1) [40,41] For this application when compared to blind insertion technique, ultrasonography guidance has a higher success rate, takes less time, and reduces the need for postprocedure radiograph Being a straightforward bedside technique, it has advantage over fluoroscopic, endoscopic, or electromagnetic guidance of postpyloric tube placement, given the simplicity of ultrasonography The main disadvantage to ultrasonography guidance is that abdominal wounds and dressings can prevent its use, and patient specific factors such as obesity or intestinal gas may block visualization of the tube as it passes into the duodenum or the jejunem REFERENCES Taylor BE, McClave SA, Martindale RG, et al: Society of Critical Care Medicine; American Society of Parenteral and Enteral Nutrition Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Crit Care Med 44(2):390–438, 2016 Dhaliwal R, Cahill N, Lemieux M, et al: The Canadian critical care nutrition guidelines in 2013: an update on current recommendations and implementation strategies Nutr Clin Pract 29(1):29–43, 2014 http://www.criticalcare nutrition.com/docs/CPGs%202015/Summary%20CPGs%202015%20vs%202013.p Kreymann KG, Berger MM, Duetz NEP, et al: ESPEN guidelines on enteral nutrition: intensive care Clin Nutr 25(2):210, 2006 Jacobs DG, Jacobs DO, Kudsk KA, et al: Practice management guidelines for nutritional support of the trauma patient J Trauma 57:660, 2004 Casaer MP, Van den Berghe G: Nutrition in the acute phase of critical illness N Engl J Med 370(13):1227–1236, 2014 Chang YS, Fu HQ, Xiao YM, et al: Nasogastric or nasojejunal feeding in predicted severe acute pancreatitis: a meta-analysis Crit Care 17(3):R118, 2013 Ritz MA, Fraser R, Edwards N, et al: Delayed gastric emptying in ventilated critically ill patients: measurement by 13 C-octanoic acid breath test Crit Care Med 29:1744, 2001 Alkhawaja S, Martin C, Butler RJ, et al: Post-pyloric versus gastric tube feeding for preventing pneumonia and improving nutritional outcomes in critically ill adults Cochrane Database Syst Rev 8:CD008875, 2015 Alhazzani W, Almasoud A, Jaeschke R, et al: Small bowel feeding and risk of pneumonia in adult critically ill patients: a systematic review and meta-analysis of randomized trials Crit Care 17(4):R127, 2013 10 Deane AM, Dhaliwal R, Day AG, et al: Comparisons between intragastric and small intestinal delivery of enteral nutrition in the critically ill: a systematic review and meta-analysis Crit Care 17(3):R125, 2013 p 179 p 180 11 Haslam D, Fang J: Enteral access for nutrition in the intensive care unit Curr Opin Clin Nutr Metab Care 9(2):155, 2006 12 Burns SM, Carpenter R, Blevins C, et al: Detection of inadvertent airway intubation during gastric tube insertion: capnography versus a colorimetric carbon dioxide detector Am J Crit Care 15:1, 2006 13 Bechtold ML, Nguyen DL, Palmer LB, et al: Nasal bridles for securing nasoenteric tubes: a meta-analysis Nutr Clin Pract 29(5):667–671, 2014 14 Silva CC, Bennett C, Saconato H, et al: Metoclopramide for post-pyloric placement of naso-enteral feeding tubes Cochrane Database Syst Rev 1:CD003353, 2015 15 Foote JA, Kemmeter PR, Prichard PA, et al: A randomized trial of endoscopic and fluoroscopic placement of postpyloric feeding tubes in critically ill patients JPEN J Parenter Enteral Nutr 28(3):154, 2004 16 Fang JC, Hilden K, Holubkov R, et al: Transnasal endoscopy vs fluoroscopy for the placement of nasoenteric feeding tubes in critically ill patients Gastrointest Endosc 62(5):661, 2005 17 Vitale MA, Villotti G, D’Alba L, et al: Unsedated transnasal percutaneous endoscopic gastrostomy placement in selected patients Endoscopy 37(1):48, 2005 18 Ponsky JL, Gauderer MWL, Stellato TA, et al: Percutaneous approaches to enteral alimentation Am J Surg 149:102, 1985 19 Dormann AJ, Glosemeyer R, Leistner U, et al: Modified percutaneous endoscopic gastrostomy (PEG) with gastropexy—early experience with a new introducer technique Z Gastroenterol 38:933, 2000 20 Maetani I, Tada T, Ukita T, et al: PEG with introducer or pull method: A prospective randomized comparison Gastrointest Endosc 57(7):837, 2003 21 Foster J, Filocarno P, Nava H, et al: The introducer technique is the optimal method for placing percutaneous endoscopic gastrostomy tubes in head and neck cancer patients Surg Endosc 21(6):897–901, 2007 22 Melvin W, Fernandez JD: Percutaneous endoscopic transgastric jejunostomy: a new approach Am Surg 71(3):216, 2005 23 Fan AC, Baron TH, Rumalla A, et al: Comparison of direct percutaneous endoscopic jejunostomy and PEG with jejunal extension Gastrointest Endosc 56(6):890, 2002 24 Maple JT, Petersen BT, Baron TH, et al: Direct percutaneous endoscopic jejunostomy: outcomes in 307 consecutive attempts Am J Gastroenterol 100(12):2681, 2005 25 Velázquez-Aviđa J, Beyer R, Díaz-Tobar CP, et al: New method of direct percutaneous endoscopic jejunostomy tube placement using balloon-assisted enteroscopy with fluoroscopy Dig Endosc 27(3):317– 322, 2015 26 Perona F, Castellazzi G, De Iuliis A, et al: Percutaneous radiologic gastrostomy: a 12-year series Gut Liver 4 Suppl 1:S44–S49, 2010 27 Covarrubias DA, O’Connor OJ, McDermott S, et al: Radiologic percutaneous gastrostomy: review of potential complications and approach to managing the unexpected outcome AJR Am J Roentgenol 200(4):921–931, 2013 28 Singh A, Gelrud A: Adverse events associated with percutaneous enteral access Gastrointest Endosc Clin N Am 25(1):71–82, 2015 29 Shapiro T, Minard G, Kudsk KA: Transgastric jejunal feeding tubes in critically ill patients Nutr Clin Pract 12:164, 1997 30 Baskin WN: Acute complications associated with bedside placement of feeding tubes Nutr Clin Pract 21(1):40–55, 2006 31 Sparks DA, Chase DM, Coughlin LM, et al: Pulmonary complications of 9931 narrow-bore nasoenteric tubes during blind placement: a critical review JPEN J Parenter Enteral Nutr 35(5):625–629, 2011 32 McClave SA, DeMeo MT, DeLegge MH, et al: North American Summit on Aspiration in the Critically Ill Patient: consensus statement JPEN J Parenter Enteral Nutr 26[6 Suppl]:S80–S85, 2002 33 Nguyen NQ, Chapman MJ, Fraser RJ, et al: Erythromycin is more effective than metoclopramide in the treatment of feed intolerance in critical illness Crit Care Med 35(2):483–489, 2007 34 Trabal J, Leyes P, Hervas S, et al: Factors associated with nosocomial diarrhea in patients with enteral tube feeding Nutr Hosp 23(5):500– 504, 2008 35 Phillips NM, Nay R: A systematic review of nursing administration of medication via enteral tubes in adults J Clin Nurs 17(17):2257–2265, 2008 36 Williams TA, Leslie GD: A review of the nursing care of enteral feeding tubes in critically ill adults Intensive Crit Care Nurs 21(1):5, 2005 37 Bourgalt AM, Heyland DK, Drover JW, et al: Prophylactic pancreatic enzymes to reduce feeding tube occlusions Nutr Clin Pract 18(5):398– 401, 2003 38 Chenaitia H, Brun PM, Querellou E, et al; WINFOCUS (World Interactive Network Focused On Critical Ultrasound) Group France: Ultrasound to confirm gastric tube placement in prehospital management Resuscitation 83(4):447–451, 2012 39 Brun PM, Chenaitia H, Lablanche C, et al: 2-Point ultrasonography to confirm correct position of the gastric tube in prehospital setting Mil Med 179(9):959–963, 2014 doi: 10.7205/MILMED-D-14-00044 40 Gok F, Kilicaslan A, Yosunkaya A: Ultrasound-guided nasogastric feeding tube placement in critical care patients Nutr Clin Pract 30:257–260, 2015 doi: 10.1177/0884533614567714 41 Hernández-Socorro CR, Marin J, Ruiz-Santana S, et al: Bedside sonographic-guided versus blind nasoenteric feeding tube placement in critically ill patients Crit Care Med 24(10):1690–1694, 1996 Chapter 22 Gastroesophageal Balloon Tamponade for Acute Variceal Hemorrhage MARIE T PAVINI • JUAN CARLOS PUYANA Gastroesophageal variceal hemorrhage is an acute and catastrophic condition that occurs in one-third to one-half of patients with portal pressures greater than 12 mm Hg or a portal–IVC pressure gradient of ≥5 [1] Because proximal gastric varices and varices in the distal 5 cm of the esophagus lie in the superficial lamina propria, they are more likely to bleed and respond to endoscopic treatment [2] Variceal rupture may be predicted by Child–Pugh class, red wale markings indicating epithelial thickness, and variceal size [1] Although urgent endoscopy, sclerotherapy, and band ligations are considered first-line treatments, balloon tamponade remains a valuable intervention for the treatment of bleeding esophageal varices Balloon tamponade is accomplished using a multilumen tube, approximately 1 m in length, with esophageal and gastric cuffs that can be inflated to compress esophageal varices and gastric submucosal veins, thereby providing hemostasis through tamponade, while incorporating aspiration ports for diagnostic and therapeutic usage HISTORICAL DEVELOPMENT In 1930, Westphal described the use of an esophageal sound as a means of controlling variceal hemorrhage In 1947, successful control of hemorrhage by balloon tamponade was achieved by attaching an inflatable latex bag to the end of a Miller–Abbot tube In 1949, a twoballoon tube was described by Patton and Johnson A triple-lumen tube with gastric and esophageal balloons, as well as a port for gastric aspiration, was described by Sengstaken and Blakemore in 1950 In 1955, Linton and Nachlas engineered a tube with a larger gastric balloon capable of compressing the submucosal veins in the cardia, thereby minimizing flow to the esophageal veins, with suction ports above and below the balloon The Minnesota tube was described in 1968 as a modification of the Sengstaken–Blakemore tube, incorporating the esophageal suction port, which is described later Several studies have published combined experience with tubes such as the Linton–Nachlas tube; however, the techniques described here are limited to the use of the Minnesota and Sengstaken–Blakemore tubes ROLE OF BALLOON TAMPONADE FOR THE MANAGEMENT OF BLEEDING ESOPHAGEAL VARICES Treatment of portal hypertension to prevent variceal rupture includes primary and secondary prophylaxis Primary prophylaxis consists of βblockers, band ligation, and endoscopic surveillance, whereas secondary prophylaxis includes nitrates, transjugular intrahepatic portosystemic shunt (TIPS), and surgical shunts [3] Management of acute variceal bleeding involves multiple simultaneous and sequential modalities Balloon tamponade is considered a temporary bridge within these modalities Self-expanding metal stents as an alternative to balloon tamponade are promising and currently under investigation [4,5] p 180 p 181 Splanchnic vasoconstrictors such as somatostatin; octreotide; terlipressin (the only agent shown to decrease mortality); or vasopressin (with nitrates to reduce cardiac side effects) decrease portal blood flow and pressure, and should be administered as soon as possible [6–8] In fact, Pourriat et al [9] advocate administration of octreotide by emergency medical personnel before patient transfer to the hospital Emergent therapeutic endoscopy in conjunction with pharmacotherapy is more effective than pharmacotherapy alone and is also performed as soon as possible Band ligation has a lower rate of rebleeding and complications when compared with sclerotherapy, and should be performed preferentially, provided that visualization is adequate to ligate or sclerose varices successfully [3,10] Tissue adhesives such as polidocanol and cyanoacrylate delivered through an endoscope are being used and studied outside the United States though glue embolization remains a concern [5] Balloon tamponade is performed to control massive variceal hemorrhage, with the hope that band ligation or sclerotherapy and secondary prophylaxis will then be possible (Fig 22.1) If bleeding continues beyond these measures, TIPS [11] is considered Shunt surgery [12] may be considered when TIPS is contraindicated Other alternatives include percutaneous transhepatic embolization; emergent esophageal transection with stapling [13]; esophagogastric devascularization with esophageal transection and splenectomy; and hepatic transplantation When gastric varices are noted, therapeutic options include endoscopic administration of the tissue adhesive cyanoacrylate; TIPS; balloonoccluded retrograde transvenous obliteration [14]; balloon-occluded endoscopic injection therapy [15]; and devascularization with splenectomy, shunt surgery, or liver transplantation FIGURE 22.1 Management of esophageal variceal hemorrhage Dx, diagnosis; Rx, therapy; TIPS, transjugular intrahepatic portosystemic shunt INDICATIONS AND CONTRAINDICATIONS A Minnesota or Sengstaken–Blakemore tube is indicated for patients with a diagnosis of esophageal variceal hemorrhage, in which neither band ligation nor sclerotherapy is technically possible, readily available, or has failed [16] If at all possible, making an adequate anatomic diagnosis is critical before any of these balloon tubes are inserted Severe upper gastrointestinal bleeding attributed to esophageal varices in patients with clinical evidence of chronic liver disease results from other causes in up to 40% of cases The observation of a white nipple sign (platelet plug) during endoscopy is indicative of a recent variceal bleed A balloon tube is contraindicated for patients with recent esophageal surgery or esophageal stricture [17] Some authors do not recommend balloon tamponade when a hiatal hernia is present, but there are reports of successful hemorrhage control in some of these patients [18] When there are no other options, it may be practical to titrate to the lowest effective balloon pressures especially when repeated endoscopic sclerotherapy has been performed, because there is increased risk of esophageal perforation [19] TECHNICAL AND PRACTICAL CONSIDERATIONS Airway Control Endotracheal intubation (see Chapter 8) is imperative in patients with upper gastrointestinal bleeding and hemodynamic compromise; encephalopathy; or both The incidence of aspiration pneumonia is directly related to the presence of impaired mental status [20] Suctioning of pulmonary secretions and blood that accumulates in the hypopharynx is facilitated in patients who have been intubated Sedatives and analgesics are more readily administered to intubated patients, and may be required when balloon tamponade is poorly tolerated, because retching or vomiting may lead to esophageal rupture [21] The incidence of pulmonary complications is significantly lower when endotracheal intubation is routinely used [22] Hypovolemia, Shock, and Coagulopathy Adequate intravenous access should be obtained with large-bore venous catheters for blood product administration and fluid resuscitation with crystalloids and colloids Packed red blood cells should be administered keeping four to six units available in case of severe recurrent bleeding, which commonly occurs among these patients Coagulopathies, thrombocytopenia, or qualitative platelet disorders should be treated emergently Octreotide and other vasoconstrictive therapies should be initiated as indicated Clots and Gastric Decompression If time permits, placement of an Ewald tube and aggressive lavage and suctioning of the stomach and duodenum facilitates endoscopy, diminishes the risk of aspiration, and may help control hemorrhage from causes other than esophageal varices It should be removed prior to balloon tamponade Infection, Ulceration, and Encephalopathy Mortality is increased when infection is present in bleeding cirrhotic patients The rate of early rebleeding is also increased in the presence of infection [23] Prophylactic antibiotic use reduces the incidence of early rebleeding and increases survival [24] Intravenous proton pump inhibitors are more efficacious than histamine-2-receptor antagonists for maintaining gastric pH at a goal of 7 or greater Ulcers can form from sclerotherapy, banding, or direct cuff pressure during balloon tamponade Shaheen et al [25] found that the postbanding ulcers for patients receiving a proton pump inhibitor were two times smaller than those of patients who had not received a proton pump inhibitor Rifaximin, lactulose, or lacitol may be useful, because blood and ammonia-forming bacteria in the gastrointestinal tract may contribute to encephalopathy Balloons, Ports, and Preparation All lumens should be flushed to assure patency and the balloons inflated underwater to check for leaks Two clean 100-mL (or larger) Foley-tip syringes and two to four rubber-shod hemostats should be readied for inflation of the balloons To ensure that the gastric balloon will not be positioned in the esophagus, preinsertion compliance should be tested by placing 100-mL aliquots of air up to the listed maximum recommended volumes into the gastric inflation port while recording the corresponding pressures using a manometer attached to the gastric pressure port In this way, postinsertion pressures can be compared A portable handheld manometer allows for simpler continuous monitoring as well as patient transport and repositioning When possible, a second manometer should be attached to the esophageal pressure port to facilitate inflation and continuous monitoring Place a plug or hemostat on the other arm of the esophageal inflation port instead of a 100-mL syringe, because the manometer may also be used for inflation, rendering the syringe superfluous [26,27] Both balloons are then completely deflated using suction and clamped with rubber hemostats or plugged before lubrication The Minnesota tube (Fig 22.2) includes a fourth lumen that allows for suctioning above the esophageal balloon [18], whereas the Sengstaken–Blakemore tube (Fig 22.3) must have a 14 to 18 French nasogastric tube secured a few centimeters proximal to the esophageal balloon to be used for esophageal decompression The nasogastric tube should be used even when the esophageal balloon is not inflated because inflation of the gastric balloon precludes proper drainage of esophageal secretions [28] When the patient is to be placed in an aircraft (i.e., for evacuation), water should be instilled into balloon(s) instead of air [29] p 182 p 183 FIGURE 22.2 Minnesota tube FIGURE 22.3 Sengstaken–Blakemore tube Insertion and Placement of the Tube The head of the bed should be elevated to reduce the risk of aspiration Oral suction should be readied and the correct length of the tube to reach the patient’s stomach should be selected (usually 45 to 60 cm orally) If the patient is not intubated, head down with left lateral positioning should be attained to minimize the risk of aspiration [17] When using a Minnesota tube, the esophageal aspiration port should be set to continuous suction and the tube generously lubricated with lidocaine jelly prior to inserting it through the nose or mouth into the stomach However, the nasal route is not recommended for patients with coagulopathy or thrombocytopenia When insertion is difficult, the tube may be placed endoscopically [30] or with a guidewire [31] Duarte described a technique of placing the tube in a longitudinally split Ewald tube [32] Auscultation in the epigastrium while air is injected through the gastric lumen verifies the position of the tube, but the position of the gastric balloon must be confirmed at this time radiologically or by ultrasound if it is more expedient [33], because high placement can lead to esophageal rupture and low placement to duodenal rupture [34] The manometer is then connected to the gastric pressure port and the gastric balloon is inflated with no more than 80 mL of air A pressure of greater than 15 mm Hg at this stage suggests esophageal placement [27,35] A (portable) radiograph or ultrasound must be obtained that includes the upper abdomen and lower chest (Figs 22.4 and 22.5) When it is documented that the gastric balloon is below the diaphragm, it should be further inflated with air in 100 mL aliquots to a volume of 250 to 300 mL The gastric balloon of the Minnesota tube can be inflated to 450 to 500 mL If the change of manometric pressure for an aliquot is more than 15 mm Hg of the preinsertion pressure or if the gastric balloon is underinflated causing upward migration, erroneous esophageal placement should be considered Record tube insertion depth (i.e., at the teeth) Tube balloon inlets should be clamped with rubber-shod hemostats after insufflation Hemorrhage is frequently controlled with insufflation of the gastric balloon alone without applying traction, but for patients with torrential hemorrhage, it is necessary to apply traction (vide infra) If the bleeding continues, the manometer attached to the esophageal pressure port is used to inflate the esophageal balloon to a pressure of approximately 45 mm Hg Some authors inflate the esophageal balloon for all patients immediately after insertion When there is still bleeding, deflate the esophageal balloon, apply more traction, and reinflate in the event that it is a gastric variceal bleed Pressures should be monitored and maintained p 183 p 184 FIGURE 22.4 Proper positioning of the Minnesota tube FIGURE 22.5 Radiograph showing correct position of the tube; the gastric balloon is seen below the diaphragm Note the Salem sump above the gastric balloon and adjacent to the tube (Courtesy: Ashley Davidoff, MD.) Ultrasonography for Tube Insertion Although a confirmatory radiograph is still warranted to document the final position of the inflated gastric balloon, an advantage to ultrasonography is that it can be used real time during insertion at the bedside of the patient [33,36] The examiner uses the phased array probe in abdominal preset to locate the stomach This may require several different tomographic views over the anterior and lateral upper quadrant Frequently, the stomach is easy to locate because it is often filled with blood The tube is visualized as a linear echogenic structure within the stomach If the tube is not easily visible, injection of 50 mL of air into the gastric lumen of the tube will yield a characteristic pattern of air bubbles within the stomach Once the tube is confirmed to be within the stomach, the operator slowly injects air into the gastric balloon The inflated gastric balloon is visualized as a distinct structure within the stomach that has an echogenic curvilinear surface and that generates a strong acoustic shadow (Chapter 22 Video 22.1) The balloon enlarges in size within the stomach as inflation continues The properly positioned gastric balloon is subdiaphragmatic in position Fixation and Traction Techniques Fixation of the tube, and traction on the tube depend on the route of insertion When the nasal route is used, attachment of a sponge rubber cuff around the tube at the nostril prevents skin and cartilage necrosis When traction is required, the tube should be attached to a cord that is passed over a catcher’s mask for maximum transportability [37] or a pulley in a bed with an overhead orthopedic frame and aligned directly as it comes out of the nose to avoid contact with the nostril This type of system allows maintenance of traction with a known weight of 500 to 1,500 g either temporarily with IV fluid bags [17] or more permanently with block weights When the tube is inserted through the mouth, traction is better applied by placing a football or hockey helmet on the patient and attaching the tube to the face mask of the helmet after a similar weight is applied for tension Pressure sores can occur on the head and forehead if the helmet does not fit properly or if it is used for a prolonged period Several authors recommend overhead traction for either oral or nasal insertion [38] p 184 p 185 Maintenance, Monitoring, and Care Periodically flush ports to ensure patency To reduce encephalopathy, the gastric aspiration port should be used to thoroughly lavage the stomach before being set to low intermittent suction It may be used later for medication administration The esophageal port may be set to intermittent or continuous suction, depending on the extent of bleeding and drainage [35] Tautness and inflation should be checked often and at least 1 hour after insertion, allowing for only transient fluctuations of as much as 30 mm Hg with respirations and esophageal spasm Sedation or a pressure decrease may be necessary if large pressure fluctuations persist If repositioning of the tube is required, assure that the esophageal balloon is deflated Upper limb restraints should also be in use and the head of the bed elevated The tube is left in place a minimum of 24 hours with gastric balloon tamponade maintained continuously for up to 48 hours The esophageal balloon should be deflated for 5 minutes every 6 hours to help prevent mucosal ischemia and esophageal necrosis Radiographic assurance of correct placement should be obtained every 24 hours and when dislodgement is suspected (Fig 22.5) Watch for localized cervical edema, which may signal obstruction or malpositioning [39] A pair of scissors should be kept with the apparatus in case rapid decompression becomes necessary, because balloon migration can acutely obstruct the airway or rupture the esophagus It is advisable to take care not to utilize bare hemostats and to clamp at the thicker portion of the ports, because it is possible for the lumen to become obliterated and the tube thus impacted [40] Removal of the Tube Once hemorrhage is controlled, the esophageal balloon is deflated first This may be done incrementally over time if desired The gastric balloon is left inflated for an additional 24 to 48 hours and may be deflated when there is no evidence of bleeding The tube is left in place 24 hours longer If bleeding recurs, the balloon is reinflated The tube is removed if no further bleeding occurs Primary therapy and secondary prophylaxis, as described previously, should be considered because balloon tamponade is a bridge intervention and rebleeding occurs in up to two-thirds of patients within 3 months without therapy [3] COMPLICATIONS Rebleeding when the cuff(s) is deflated should be anticipated The highest risk of rebleeding is in the first few days after balloon deflation By 6 weeks, the risk of rebleeding returns to the premorbid risk level Independent predictors of mortality of patients undergoing balloon tamponade, described by Lee et al [41], include blood transfusion greater than 10 units; coagulopathy; presence of shock; abnormal Glasgow Coma Score; and high total volume of sclerosing agent (ethanolamine) Aspiration pneumonia is the most common complication of balloon tamponade with incidence ranging from 0% to 12% Acute laryngeal obstruction and tracheal rupture are the most severe of all complications, and the worst examples of tube migration or malpositioning Migration of the tube occurs when the gastric balloon is not inflated properly after adequate positioning in the stomach or when excessive traction (>1.5 kg) is used, causing migration cephalad to the esophagus or hypopharynx Mucosal ulceration of the gastroesophageal junction is common and is directly related to prolonged traction times (>36 hours) Perforation of the esophagus has been reported as a result of misplacing the gastric balloon above the diaphragm (Fig 22.6) The incidence of complications that are a direct cause of death ranges from 0% to 20% FIGURE 22.6 Chest radiograph showing distal segment of the tube coiled in the chest and the gastric balloon inflated above the diaphragm in the esophagus (Courtesy: Ashley Davidoff, MD.) REFERENCES Rikkers LF: Surgical complications of cirrhosis and portal hypertension, in Townsend CM, Beauchamp RD, Evers BM, et al (eds): Sabiston’s Textbook of Surgery 17th ed Philadelphia, PA, WB Saunders, 2004, p 1175 Tsokos M, Turk EE: Esophageal variceal hemorrhage presenting as sudden death in outpatients Arch Pathol Lab Med 126:1197, 2002 Zaman A, Chalasani N: Bleeding caused by portal hypertension Gastroenterol Clin North Am 34:623, 2005 Zehetner J, Shamiyeh A, Wayand W, et al: Results of a new method to stop acute bleeding from esophageal varices; implantation of a selfexpanding stent Surg Endosc 22:2149–2152, 2008 El Sayed G, Tarf S, O’Beirne J, et al: Endoscopy management algorithms: role of cyanoacrylate glue injection and self-expanding metal stents in acute variceal haemorrhage Frontline Gastroenterol 6(3):208–216, 2015 Sandford NL, Kerlin P: Current management of oesophageal varices Aust N Z J Med 25:528, 1995 Stein C, Korula J: Variceal bleeding: what are the options? Postgrad Med 98:143, 1995 Erstad B: Octreotide for acute variceal bleeding Ann Pharmacother 35:618, 2001 Pourriat JL, Leyacher S, Letoumelin P, et al: Early administration of terlipressin plus glyceryl trinitrate to control active upper gastrointestinal bleeding in cirrhotic patients Lancet 346:865, 1995 10 Avgerinos A, Armonis A, Manolakpoulos S, et al: Endoscopic sclerotherapy versus variceal ligation in the long-term management of patients with cirrhosis after variceal bleeding: a prospective randomized study J Hepatol 26:1034, 1997 11 Banares R, Casado M, Rodriquez-Laiz JM, et al: Urgent transjugular intrahepatic portosystemic shunt for control of acute variceal bleeding Am J Gastroenterol 93:75, 1998 12 Lewis JJ, Basson MD, Modlin IM: Surgical therapy of acute esophageal variceal hemorrhage Dig Dis Sci 10[Suppl 1]:46, 1992 13 Mathur SK, Shah SR, Soonawala ZF, et al: Transabdominal extensive oesophagogastric devascularization with gastro-oesophageal stapling in the management of acute variceal bleeding Br J Surg 84:413, 1997 14 Kitamoto M, Imamura M, Kamada K, et al: Balloon-occluded retrograde transvenous obliteration of gastric fundal varices with hemorrhage AJR Am J Roentgenol 178:1167, 2002 15 Shiba M, Higuchi K, Nakamura K, et al: Efficacy and safety of balloonoccluded endoscopic injection sclerotherapy as a prophylactic treatment for high-risk gastric fundal varices: a prospective, randomized, comparative clinical trial Gastrointest Endosc 56:522, 2002 16 Burnett DA, Rikkers LF: Nonoperative emergency treatment of variceal hemorrhage Surg Clin North Am 70:291, 1990 17 McCormick PA, Burroughs AK, McIntyre N: How to insert a Sengstaken-Blakemore tube Br J Hosp Med 43:274, 1990 18 Minocha A, Richards RJ: Sengstaken-Blakemore tube for control of massive bleeding from gastric varices in hiatal hernia J Clin Gastroenterol 14:36, 1992 p 185 p 186 19 Chong CF: Esophageal rupture due to Sengstaken-Blakemore tube misplacement World J Gastroenterol 11(41):6563–6565, 2005 20 Pasquale MD, Cerra FB: Sengstaken-Blakemore tube placement Crit Care Clin 8:743, 1992 21 Zeid SS, Young PC, Reeves JT: Rupture of the esophagus after introduction of the Sengstaken-Blakemore tube Gastroenterology 36:128–131, 1959 22 Cello JP, Crass RA, Grendell JH, et al: Management of the patient with hemorrhaging esophageal varices JAMA 256:1480, 1986 23 Papatheodoridis GV, Patch D, Webster JM, et al: Infection and hemostasis in decompensated cirrhosis: a prospective study using thromboelastography Hepatology 29:1085, 1999 24 Pohl J, Pollmann K, Sauer P, et al: Antibiotic prophylaxis after variceal hemorrhage reduces incidence of early rebleeding Hepatogastroenterology 51(56):541, 2004 25 Shaheen NJ, Stuart E, Schmitz S, et al: Pantoprazole reduces the size of postbanding ulcers after variceal band ligation: a randomized control trial Hepatology 41:588, 2005 26 Greenwald B: Two devices that facilitate the use of the Minnesota tube Gastroenterol Nurs 27:268–270, 2004 27 Bard, Inc: Bard Minnesota four lumen esophagogastric tamponade tube for the control of bleeding from esophageal varices [package insert], 1997 28 Boyce HW: Modification of the Sengstaken-Blackmore balloon tube Nord Hyg Tidskr 267:195, 1962 29 Pinto-Marques P, Romaozinho J, Ferreira M, et al: Esophageal perforation-associated risk with balloon tamponade after endoscopic therapy Myth or reality? Hepatogastroenterology 53:536–539, 2006 30 Lin TC, Bilir BM, Powis ME: Endoscopic placement of SengstakenBlakemore tube J Clin Gastroenterol 31(1):29–32, 2000 31 Wilcox G, Marlow J: A special maneuver for passage of the SengstakenBlakemore tube Gastrointest Endosc 30(6):377, 1984 32 Duarte B: Technique for the placement of the Sengstaken-Blakemore tube Surg Gynecol Obstet 168(5):449–450, 1989 33 Lock G, Reng M, Messman H, et al: Inflation and positioning of the gastric balloon of a Sengstaken-Blakemore tube under ultrasonographic control Gastrointest Endosc 45(6):538, 1997 34 Kandel G, Gray R, Mackenzie RL, et al: Duodenal perforation by a Linton-Nachlas balloon tube Am J Gastroenterol 83(4):442–444, 1988 35 Isaacs K, Levinson S: Insertion of the Minnesota tube, in Drossman D (ed): Manual of Gastroenterologic Procedures 3rd ed New York, NY, Raven Press, 1993, pp 27–35 36 Lin A C-M, Hsu Y-H, Wang T-L, et al: Placement confirmation of Sengstaken-Blakemore tube by ultrasound Emerg Med J 23:487, 2006 37 Kashiwagi H, Shikano S, Yamamoto O, et al: Technique for positioning the Sengstaken-Blakemore tube as comfortably as possible Surg Gynecol Obstet 172(1):63, 1991 38 Hunt PS, Korman MG, Hansky J, et al: An 8-year prospective experience with balloon tamponade in emergency control of bleeding esophageal varices Dig Dis Sci 27:413, 1982 39 Juffe A, Tellez G, Eguaras M, et al: Unusual complication of the Sengstaken-Blakemore tube Gastroenterology 72(4, Pt 1):724–725, 1977 40 Bhasin DK, Zargar SA, Mandal M, et al: Endoscopic removal of impacted Sengstaken-Blakemore tube Surg Endosc 3(1):54–55, 1989 41 Lee H, Hawker FH, Selby W, et al: Intensive care treatment of patients with bleeding esophageal varices: results, predictors of mortality, and predictors of the adult respiratory distress syndrome Crit Care Med 20:1555, 1992 Chapter 23 Paracentesis and Diagnostic Peritoneal Lavage LENA M NAPOLITANO ABDOMINAL PARACENTESIS Indications Abdominal paracentesis is a simple procedure that can be easily performed at the bedside in the intensive care unit and may provide important diagnostic information or therapy for critically ill patients with ascites As a diagnostic intervention, abdominal paracentesis with removal of 20 mL of peritoneal fluid is performed to determine the etiology of the ascites or to ascertain whether infection is present, as in spontaneous bacterial peritonitis [1] It can also be used in any clinical situation in which the analysis of a sample of peritoneal fluid might be useful in ascertaining a diagnosis or guiding therapy The evaluation of ascites should therefore include ascitic fluid analysis As a therapeutic intervention, abdominal paracentesis is usually performed to drain large volumes of abdominal ascites, termed largevolume paracentesis (LVP), sometimes with removal of more than 5 L of ascitic fluid [2] Ascites is the most common presentation of decompensated cirrhosis, and its development heralds a poor prognosis, with a 50% 2-year survival rate Effective first-line therapy for ascites includes sodium restriction (2 g per day), use of diuretics, and LVP When tense or refractory ascites is present, LVP is safe and effective, and has the advantage of producing immediate relief from ascites and its associated symptoms [3] LVP can be palliative by diminishing abdominal pain from distention or relieving respiratory symptoms by allowing better diaphragmatic excursion in patients who have ascites refractory to aggressive medical management Refractory ascites occurs in 10% of patients with cirrhosis and is associated with substantial morbidity and a 1-year survival of less than 50% [4,5] For patients with refractory ascites, transjugular intrahepatic portosystemic shunt (TIPS) is superior to LVP for long-term control of ascites, but it is associated with greater encephalopathy risk and does not affect mortality [6,7] Techniques Before abdominal paracentesis is initiated, a catheter may be inserted to drain the urinary bladder, and correction of any underlying coagulopathy or thrombocytopenia should be considered A consensus statement from the International Ascites Club states that “there are no data to support the correction of mild coagulopathy with blood products prior to therapeutic paracentesis, but caution is needed when severe thrombocytopenia is present” [3] The practice guideline from the American Association for the Study of Liver Diseases (AASLD) states that routine correction of prolonged prothrombin time or thrombocytopenia is not required when experienced personnel perform paracentesis [2] This has been confirmed in a study of 1,100 LVPs in 628 patients [8] But in critically ill patients, there is still uncertainty as to the optimal platelet count and prothrombin time for the safe conduct of paracentesis The patient must next be positioned correctly In critically ill patients, the procedure is performed in the supine position with the head of the bed elevated at 30 to 45 degrees If the patient is clinically stable and therapeutic LVP is being performed, the patient can be placed in the sitting position, leaning slightly forward, to increase the total volume of ascites removed The site for paracentesis on the anterior abdominal wall is then chosen (Fig 23.1) The preferred site is in the lower abdomen, lateral to the rectus abdominis muscle and inferior to the umbilicus It is important to stay lateral to the rectus abdominis muscle to avoid injury to the inferior epigastric artery and vein In patients with chronic cirrhosis and caput medusae (engorged anterior abdominal wall veins), these visible vascular structures must be avoided Injury to these veins can cause significant bleeding because of the underlying portal hypertension and may result in hemoperitoneum The left lower quadrant of the abdominal wall is preferred over the right lower quadrant for abdominal paracentesis because critically ill patients often have cecal distention The ideal site is therefore in the left lower quadrant of the abdomen, lateral to the rectus abdominis muscle in the midclavicular line and inferior to the umbilicus It has also been determined that the left lower quadrant is significantly thinner and the depth of ascites greater compared with the infraumbilical midline position, confirming the left lower quadrant as the preferred location for paracentesis [9] FIGURE 23.1 Recommended sites and appropriate technique for paracentesis p 186 p 187 If the patient had previous abdominal surgery limited to the lower abdomen, it may be difficult to perform a paracentesis in the lower abdomen and ultrasonic guidance is recommended for site selection The point of entry, however, remains lateral to the rectus abdominis muscle in the midclavicular line If there is concern that the ascites is loculated because of a previous abdominal surgery or peritonitis, abdominal paracentesis should be performed under ultrasound guidance to prevent iatrogenic complications Abdominal paracentesis can be performed by the needle technique, by the catheter technique, or with ultrasound guidance Diagnostic paracentesis usually requires 20 to 50 mL peritoneal fluid and is commonly performed using the needle technique However, if large volumes of peritoneal fluid are required, the catheter technique is used, because it is associated with a lower incidence of complications LVP should always be performed with the catheter technique Ultrasound guidance is recommended because it can be helpful both in diagnostic paracentesis using the needle technique and in LVP using the catheter technique Utility of Ultrasonography for Guidance of Paracentesis Compared to standard landmark technique, guidance of paracentesis with ultrasonography is associated with a higher success rate and lower complication rate [10,11] Identification of Ascites Intra-abdominal fluid is readily identified with ultrasonography In small amounts, it is identified in the hepatorenal recess, the splenorenal recess, and the pelvic area (Chapter 23 Video 23.1) In larger amounts, it accumulates in the prehepatic space, the presplenic space, the subphrenic area, in the pelvis; and the flanks bilaterally (Chapter 23 Video 23.2) Air-filled bowel will float on the ascitic fluid; so characteristically, ultrasonography examination of the anterior abdomen detects air artifact with the fluid distributing in dependent position Characterization of Ascites Intra-abdominal fluid may have a variety of appearances Uncomplicated ascites, as occurs with heart failure or portal hypertension, is typically anechoic (Chapter 23 Video 23.3) Purulent ascites is more echoic and may be septated (Chapter 23 Video 23.4) Malignant ascites in the peritoneal compartment may have a variety of complex patterns (Chapter 23 Video 23.5) Air bubbles appear as small hyperechoic mobile elements within the ascites (Chapter 23 Video 23.6) Hemoperitoneum, if very recent, has a homogenous echoic pattern (Chapter 23 Video 23.7) In the absence of patient movement, the red blood cells sediment by gravitational effect to result in a distinct interface between the hypoechoic-dependent cellular collection and the anechoicnondependent plasma The interface may be distinct and linear in appearance Purulent ascites may also result in this pattern The finding of an interface has implications regarding the cell count of in the fluid when it is sampled with paracentesis If the sample is drawn from the anechoic fluid area, the cell count will be low when compared to a sample drawn from the dependent area Patient movement will result in mixing of the two compartments, with a more representative cell count of the paracentesis sample The finding of a sedimentation interface with clinical risk of hemoperitoneum immediately alerts the intensivist to the possibility of major blood loss into the peritoneal compartment p 187 p 188 Guidance of Paracentesis Equipment The ultrasonography examination is performed using a phased-array cardiac probe with abdominal preset or a standard curved array abdominal probe, if available The linear high frequency probe lacks sufficient penetration to visualize deeper abdominal structures such as bowel, but is useful for examining the planned needle trajectory for vascular structures that would contraindicate device insertion Scanning technique The lower lateral abdominal quadrant areas are the preferred site for paracentesis with the suprapubic approach as an alternative A series of scan lines are performed over the flank areas in order to identify and characterize the ascites; and to establish a safe site for needle insertion that avoids injury to adjacent organs The critically ill patient is generally in supine position, unlike thoracentesis; this in usually not a problem for paracentesis Occasionally, the patient will need to be rolled into an ipsilateral decubitus position in order to distribute the fluid into a better target position Identification of fluid The examiner seeks three characteristic findings that are typical for ascites a An anechoic or relatively hypoechoic space that is surrounded by typical anatomic boundaries This space represents the ascites b Typical anatomic boundaries: This requires unequivocal identification of bowel structures, the liver, or the spleen c Dynamic changes: This requires identification of dynamic changes that are typical of ascites such as movement of bowel within the fluid and shape change of the ascitic fluid with forward force application of the probe against the abdominal wall (Chapter 23 Video 23.8) This characteristic of shape change of the ascites does not occur with pleural fluid, because forward force application of the probe against the rigid chest wall does not alter the shape of the pleural effusion Site selection The transducer is moved over the target area, in order to identify a safe site for needle insertion that maximizes the distance between the abdominal wall and underlying bowel and anatomic structures such as the liver or spleen As much as possible, the examiner holds the probe perpendicular to the abdominal wall, because this angle is easiest to duplicate with the needle–syringe assembly Once a suitable site is identified, it is marked; the depth of needle penetration to access the fluid is measured; and the angle of the probe is determined This angle will be duplicated by the operator during needle insertion It is best avoid a needle trajectory that is adjacent to the liver or spleen A rare complication of paracentesis is laceration of an abdominal blood wall vessel with subsequent hemoperitoneum This risk may be reduced by using the high frequency vascular probe to scan the proposed needle trajectory Using color Doppler, identification of a vessel may allow the operator to select an alternative site Performance of needle insertion Once the site is selected, there can be no further patient movement, because this may shift the position of the ascites relative to the insertion site The time between the ultrasonography examination and needle insertion is minimized Immediately before the sterile preparation, the operator rechecks the site, angle, and depth for needle insertion The paracentesis is performed with free-hand technique by inserting the needle–syringe assembly at the site mark, duplicating the angle at which the probe was held to determine a safe trajectory Real-time guidance of needle insertion is not required for safe paracentesis Pitfalls of imaging a Skin compression: In the edematous or obese patient, skin compression artifact may cause an under estimation of the depth for successful needle insertion In this case, the operator pushes the probe into the skin surface in order to improve image quality causing indentation of the skin at the target site that rebounds when the probe is removed This results in a underestimation of the depth required for the needle to access the fluid This is problematic at the time of needle insertion, because the operator must insert the needle to a depth greater than measured with indentation of the skin b Site mark movement: If lateral force is applied to the skin at the time of marking the insertion site, the skin mark may be moved to a substantial extent This is of special concern when accessing a smaller amount of ascites At the time of needle insertion, the operator takes care to not move the mark site when applying pressure to the skin surface c Difficult scanning conditions: It may be difficult to achieve adequate image quality in the obese or edematous patient d Aberrant position of vascular structure: The epigastric artery is ordinarily positioned at the lateral border of the rectus muscle, so it is well away from the usual site of paracentesis which is lower in the flank area However, the vessel may have an aberrant position, and dilated veins associated with portal hypertension may be positioned in the path of needle insertion [12] Injury of an aberrant vessel may result in severe bleeding into the peritoneal cavity or formation of a pseudoaneurysm [13–15] Hiroshi et al have proposed examination of the needle trajectory before needle insertion using the high frequency vascular probe [16] If a vessel is identified, the operator seeks an alternative site Needle Technique With the patient in the appropriate position and the access site for paracentesis determined, the patient’s abdomen is prepared with 2% chlorhexidine gluconate and 70% isopropyl alcohol and sterile aseptic technique is used If necessary, intravenous sedation is administered to prevent the patient from moving excessively during the procedure (see Chapter 2) After a time out, local anesthesia, using 1% or 2% lidocaine with 1:200,000 epinephrine, is infiltrated into the site A skin wheal is created with the local anesthetic, using a short 25- or 27-gauge needle Then, using a 22-gauge, 1.5-inch needle, the local anesthetic is infiltrated into the subcutaneous tissues and anterior abdominal wall, with the needle perpendicular to the skin Before the anterior abdominal wall and peritoneum are infiltrated, the skin is pulled taut inferiorly, allowing the peritoneal cavity to be entered at a different location than the skin entrance site, thereby decreasing the chance of ascitic leak (Z-track technique) While tension is maintained inferiorly on the abdominal skin the needle is advanced through the abdominal wall fascia and peritoneum, and local anesthetic is injected Intermittent aspiration identifies when the peritoneal cavity is entered, with return of ascitic fluid into the syringe The needle is held securely in this position with the left hand, and the right hand is used to withdraw approximately 20 to 50 mL ascitic fluid into the syringe for a diagnostic paracentesis p 188 p 189 Once adequate fluid is withdrawn, the needle and syringe are withdrawn from the anterior abdominal wall and the paracentesis site is covered with a sterile dressing The needle is removed from the syringe, because it may be contaminated with skin organisms A small amount of peritoneal fluid is sent in a sterile container for Gram stain and 10 mL or quantity sufficient to achieve the fill line is inoculated into blood culture bottles immediately at bedside for culture and sensitivity The remainder of the fluid is sent for appropriate studies, which may include cytology; cell count and differential; protein; specific gravity; amylase; pH; lactate dehydrogenase; bilirubin; triglycerides; and albumin A serum to ascites albumin gradient (SAAG) greater than 1.1 g per dL is indicative of portal hypertension and cirrhosis (Table 23.1) [17] Peritoneal fluid can be sent for smear and culture for acid-fast bacilli if tuberculous peritonitis is in the differential diagnosis TABLE 23.1 Etiologies of Ascites Based on Normal or Diseased Peritoneum and SAAG Normal peritoneum Portal hypertension (SAAG >1.1 g/dL) Hepatic congestion Congestive heart failure Constrictive pericarditis Tricuspid insufficiency Budd–Chiari syndrome Liver disease Cirrhosis Alcoholic hepatitis Fulminant hepatic failure Massive hepatic metastases Hypoalbuminemia (SAAG < 1.1 g/dL) Nephrotic syndrome Protein-losing enteropathy Severe malnutrition with anasarca Miscellaneous conditions (SAAG < 1.1 g/dL) Chylous ascites Pancreatic ascites Bile ascites Nephrogenic ascites Urine ascites Ovarian disease Diseased peritoneum infections (SAAG < 1.1 g/dL) Bacterial peritonitis Tuberculous peritonitis Fungal peritonitis HIV-associated peritonitis Malignant conditions Peritoneal carcinomatosis Primary mesothelioma Pseudomyxoma peritonei Hepatocellular carcinoma Other rare conditions Familial Mediterranean fever Vasculitis Granulomatous peritonitis Eosinophilic peritonitis SAAG, serum to ascites albumin gradient; HIV, human immunodeficiency virus Catheter Technique Positioning; use of aseptic technique; and local anesthetic infiltration are the same as for the needle technique A 22-gauge, 1.5-inch needle attached to a 10-mL syringe is used to document the free return of peritoneal fluid into the syringe at the chosen site This needle is removed from the peritoneal cavity and a catheter-over-needle assembly is used to gain access to the peritoneal cavity If the anterior abdominal wall is thin, an 18- or 20-gauge Angiocath can be used as the catheter-over-needle assembly If the anterior abdominal wall is quite thick, as in obese patients, it may be necessary to use a long (5.25-inch, 18- or 20-gauge) catheter-over-needle assembly or a percutaneous single- or multiplelumen central venous catheter (18- or 20-gauge) and gain access to the peritoneal cavity using the Seldinger technique The peritoneal cavity is entered as for the needle technique The catheter-over-needle assembly is inserted perpendicular to the anterior abdominal wall using the Z-track technique; once peritoneal fluid returns into the syringe barrel, the catheter is advanced over the needle, the needle is removed, and a 20- or 50-mL syringe is connected to the catheter The tip of the catheter is now in the peritoneal cavity and can be left in place until the appropriate amount of peritoneal fluid is removed This technique, rather than the needle technique, should be used when LVP is performed, because complications (e.g., intestinal perforation) may occur if a needle is left in the peritoneal space for an extended period When the Seldinger technique is used in patients with a large anterior abdominal wall, access to the peritoneal cavity is initially gained with a needle or catheter-over-needle assembly A guidewire is then inserted through the needle and an 18- or 20-gauge single- or multiple-lumen central venous catheter is threaded over the guidewire It is very important to use the Z-track method for the catheter technique to prevent development of an ascitic leak, which may be difficult to control and may predispose the patient to peritoneal infection If continued drainage of a peritoneal fluid collection is desired, a radiologist or qualified proceduralist can place a chronic indwelling peritoneal catheter using a percutaneous guidewire technique A video for the correct procedural technique for paracentesis is available for review [18] Complications The most common complications related to abdominal paracentesis are bleeding and persistent ascitic leak Because most patients in whom ascites has developed also have some component of chronic liver disease with associated coagulopathy and thrombocytopenia, it is very important to consider correction of any underlying coagulopathy before proceeding with abdominal paracentesis In addition, it is very important to select an avascular access site on the anterior abdominal wall The Z-track technique is very helpful in minimizing persistent ascitic leak and should always be used Another complication associated with abdominal paracentesis is intestinal or urinary bladder perforation, with associated peritonitis and infection Intestinal injury is more common when the needle technique is used than when the catheter technique is used Because the needle is free in the peritoneal cavity, iatrogenic intestinal perforation may occur if the patient moves or if intra-abdominal pressure increases with Valsalva maneuver or coughing Urinary bladder injury is less common and underscores the importance of draining the urinary bladder with a catheter before the procedure This injury is more common when the abdominal access site is in the suprapubic location; therefore, this access site is not recommended when direct visualization is not available Careful adherence to proper technique of paracentesis minimizes associated complications p 189 p 190 In patients who have large-volume chronic abdominal ascites, such as that secondary to hepatic cirrhosis or ovarian carcinoma; transient hypotension; and paracentesis-induced circulatory dysfunction (PICD) may develop during LVP PICD is characterized by worsening hypotension and arterial vasodilation; hyponatremia; azotemia; and an increase in plasma renin activity Evidence is accumulating that PICD is secondary to an accentuation of established arteriolar vasodilation with multiple etiologies, including the dynamics of paracentesis (the rate of ascitic fluid extraction); release of nitric oxide from the vascular endothelium; and mechanical modifications of flow dynamics due to abdominal decompression [19] PICD is associated with increased mortality and may be prevented with the administration of plasma expanders It is very important to obtain reliable peripheral or central venous access in these patients so that fluid resuscitation can be performed if PICD develops during the procedure Systematic reviews and meta-analyses have found that albumin was associated with fewer complications of LVP (PICD, hyponatremia, and overall morbidity and mortality) compared to other treatments [20,21] AASLD guidelines suggest that albumin (6 to 8 g per liter ascites removed) can be considered for LVP in which >5 L of ascites is removed Because PICD pathogenesis may be caused by accentuated splanchnic vasodilation, trials comparing terlipressin (a vasoconstrictor), midodrine, or octreotide with albumin have reported conflicting results for improving systemic and renal hemodynamics and renal function, including the prevention of PICD Additional studies are warranted to establish their efficacy [22] LVP is only transiently therapeutic; the underlying chronic disease induces reaccumulation of the ascites Percutaneous placement of a tunneled catheter is a viable and safe technique to consider in patients who have symptomatic malignant ascites that require frequent therapeutic paracentesis for relief of symptoms [23] An automated pump system for treatment of refractory ascites is undergoing investigation [24] DIAGNOSTIC PERITONEAL LAVAGE Before the introduction of diagnostic peritoneal lavage (DPL) by Root et al [25] in 1965, nonoperative evaluation of the injured abdomen was limited to standard four-quadrant abdominal paracentesis Abdominal paracentesis for the evaluation of hemoperitoneum was associated with a high false-negative rate This clinical suspicion was confirmed by Giacobine and Siler [26] in an experimental animal model of hemoperitoneum documenting that a 500-mL blood volume in the peritoneal cavity yielded a positive paracentesis rate of only 78% The initial study by Root et al [25] reported 100% accuracy in the identification of hemoperitoneum using 1-L peritoneal lavage fluid Many subsequent clinical studies confirmed these findings, with the largest series reported by Fischer et al [27] in 1978 They reviewed 2,586 cases of DPL and reported a false-positive rate of 0.2%; false-negative rate of 1.2%; and overall accuracy of 98.5% Following its introduction in 1965, DPL was a cornerstone in the evaluation of hemoperitoneum due to blunt and penetrating abdominal injuries However, it is nonspecific for determination of the type or extent of organ injury Recent advances have led to the use of ultrasound (focused assessment with sonography in trauma [FAST]; Fig 23.2) and rapid helical computed tomography (CT) in the emergent evaluation of abdominal trauma [28] FAST has replaced DPL as the initial screening modality of choice for severe abdominal trauma, and FAST is now part of the Advanced Trauma Life Support course [29] Practice management guidelines from the Eastern Association for the Surgery of Trauma recommend FAST as the initial diagnostic modality to exclude hemoperitoneum [30] DPL remains a valuable adjunct to modern imaging techniques in early trauma assessment, particularly in hemodynamically unstable patients with initial FAST examination that is negative or equivocal and in the assessment of potential hollow visceral injury in blunt abdominal trauma [31] Diagnostic peritoneal aspiration, without a full lavage, has also been utilized successfully in these circumstances [32] FIGURE 23.2 The FAST examination FAST; focused assessment with sonography in trauma Indications The primary indication for DPL is evaluation of blunt abdominal trauma in patients with associated hypotension If the initial FAST examination is positive for hemoperitoneum, surgical intervention (laparotomy) is required If the FAST examination is negative or equivocal, DPL can be considered If the patient is hemodynamically stable and can be transported safely, CT scan of the abdomen and pelvis is the diagnostic method of choice If the patient is hemodynamically unstable or requires emergent surgical intervention for a craniotomy, thoracotomy, or vascular procedure, it is imperative to determine whether there is a coexisting intraperitoneal source of hemorrhage to prioritize treatment of life-threatening injuries FAST or DPL can be used to diagnose hemoperitoneum in patients with multisystem injury, who require general anesthesia for the treatment of associated traumatic injuries Patients with associated thoracic or pelvic injuries should also have definitive evaluation for abdominal trauma, and DPL can be used in these individuals DPL can also be used to evaluate for traumatic hollow viscus injury, and a cell count ratio (defined as the ratio between white blood cell (WBC) and red blood cell (RBC) count in the lavage fluid divided by the ratio of the same parameters in the peripheral blood) less than or equal to 1 has a specificity of 97% and sensitivity of 100% [33] DPL can also be used to evaluate penetrating abdominal trauma; however, its role differs from that in blunt abdominal trauma [34] A hemodynamically unstable patient with abdominal penetrating injuries requires no further investigation and immediate laparotomy should be undertaken Instead, the role of DPL in the hemodynamically stable patient with penetrating abdominal injury is to identify hemoperitoneum; and hollow viscus or diaphragmatic injury DPL has also been recommended as the initial diagnostic study in stable patients with penetrating trauma to the back and flank, defining an RBC count greater than 1,000 per μL as a positive test [35] Implementation of this protocol decreased the total celiotomy rate from 100% to 24%, and the therapeutic celiotomy rate increased from 15% to 80% DPL can also serve a therapeutic role It is very effective in rewarming patients with significant hypothermia DPL should not be performed for patients with clear signs of significant abdominal trauma and hemoperitoneum associated with hemodynamic instability or peritonitis These patients should undergo emergent celiotomy Pregnancy is a relative contraindication to DPL; it may be technically difficult to perform because of the gravid uterus and is associated with a higher risk of complications Bedside ultrasound evaluation of the abdomen in the pregnant trauma patient is associated with least risk to the woman and to the fetus An additional relative contraindication to DPL is multiple previous abdominal surgeries due to abdominal adhesions, and difficulty in gaining access to the free peritoneal cavity If DPL is indicated and ultrasound examination does not identify a safe pathway, it must be performed by the open technique to prevent iatrogenic complications such as intestinal injury p 190 p 191 Techniques Three techniques can be used to perform DPL: (a) the closed percutaneous technique, (b) the semiclosed technique, and (c) the open technique The closed percutaneous technique, introduced by Lazarus and Nelson [36] in 1979, is easy to perform, can be done rapidly, is associated with a low complication rate, and is as accurate as the open technique It should not be used in patients who have had previous abdominal surgery or a history of abdominal adhesions The open technique entails the placement of the peritoneal lavage catheter into the peritoneal cavity under direct visualization It is more time-consuming than the closed percutaneous technique The semiclosed technique requires a smaller incision than does the open technique and uses a peritoneal lavage catheter with a metal stylet to gain entrance into the peritoneal cavity It has become less popular, because clinicians have become more familiar and skilled with the closed technique The patient is placed in the supine position for all three techniques A catheter is placed into the urinary bladder and a nasogastric tube is inserted into the stomach to prevent iatrogenic bladder or gastric injury The nasogastric tube is placed on continuous suction for gastric decompression The skin of the anterior abdominal wall is prepared with 2% chlorhexidine solution and sterilely draped, leaving the periumbilical area exposed Standard aseptic technique is used throughout the procedure Local anesthesia with 1% or 2% lidocaine with 1:200,000 epinephrine is used as necessary throughout the procedure The infraumbilical site is used unless there is clinical concern of possible pelvic fracture and retroperitoneal or pelvic hematoma, in which case the supraumbilical site is optimal Closed Percutaneous Technique With the closed percutaneous technique, local anesthesia is infiltrated inferior to the umbilicus and a 5-mm skin incision is made just at the inferior umbilical edge An 18-gauge needle is inserted through this incision and into the peritoneal cavity, angled toward the pelvis at approximately a 45-degree angle with the skin The penetration through the linea alba and then through the peritoneum is felt as two separate “pops.” A J-tipped guidewire is passed through the needle and into the peritoneal cavity, again directing the wire toward the pelvis by maintaining the needle at a 45-degree angle to the skin The 18-gauge needle is then removed and the DPL catheter inserted over the guidewire into the peritoneal cavity, using a twisting motion and guided inferiorly toward the pelvis The guidewire is then removed, and a 10-mL syringe is attached to the catheter for aspiration If free blood returns from the DPL catheter before the syringe is attached or if gross blood returns in the syringe barrel, hemoperitoneum has been documented, the catheter is removed, and the patient is quickly transported to the operating room for emergent celiotomy If no gross blood returns on aspiration through the catheter, peritoneal lavage is performed using 1 L Ringer’s lactate solution or normal saline that has been previously warmed to prevent hypothermia The fluid is instilled into the peritoneal cavity through the DPL catheter; afterward, the peritoneal fluid is allowed to drain out of the peritoneal cavity by gravity until the fluid return slows A minimum of 250 mL lavage fluid is considered a representative sample of the peritoneal fluid [37] A sample is sent to the laboratory for determination of RBC count; WBC count; amylase concentration; and presence of bile, bacteria, or particulate matter When the lavage is completed, the catheter is removed and a sterile dressing applied over the site Suture approximation of the skin edges is not necessary when the closed technique is used for DPL p 191 p 192 Semiclosed Technique Local anesthetic is infiltrated in the area of the planned incision and a 2to 3-cm vertical incision made in the infraumbilical or supraumbilical area The incision is continued sharply down through the subcutaneous tissue and linea alba, and the peritoneum is then visualized Forceps, hemostats, or Allis clamps are used to grasp the edges of the linea alba and elevate the fascial edges to prevent injury to the underlying abdominal structures The DPL lavage catheter with a metal inner stylet is inserted through the closed peritoneum into the peritoneal cavity at a 45-degree angle to the anterior abdominal wall, directed toward the pelvis When the catheter–metal stylet assembly is in the peritoneal cavity, the DPL catheter is advanced into the pelvis and the metal stylet removed A 10-mL syringe is attached to the catheter, and aspiration is conducted as previously described When the lavage is completed, the fascia must be reapproximated with sutures, the skin closed, and a sterile dressing applied Open Technique After the administration of appropriate local anesthetic, a vertical midline incision approximately 3 to 5 cm long is made This incision is commonly made in the infraumbilical location, but in patients with presumed pelvic fractures or retroperitoneal hematomas or in pregnant patients, a supraumbilical location is preferred The vertical midline incision is carried down through the skin, subcutaneous tissue, and linea alba under direct vision The linea alba is grasped on either side using forceps, hemostats, or Allis clamps; and the fascia is elevated to prevent injury to the underlying abdominal structures The peritoneum is identified, and a small vertical peritoneal incision is made to gain entrance into the peritoneal cavity The DPL catheter is then inserted into the peritoneal cavity under direct visualization and advanced inferiorly toward the pelvis It is inserted without the stylet or metal trocar When in position, a 10-mL syringe is attached for aspiration If aspiration of the peritoneal cavity is negative (i.e., no gross blood returns), peritoneal lavage is performed, as described earlier in the chapter As in the semiclosed technique, the fascia and skin must be reapproximated to prevent dehiscence or evisceration, or both A prospective randomized study documented that closed percutaneous DPL can be performed faster than the open procedure (1 to 3 minutes vs 5 to 24 minutes) [38] The closed percutaneous technique was as accurate as the open procedure and was associated with a lower incidence of wound infections and complications The closed percutaneous technique, using the Seldinger technique, should therefore be used initially in all patients except those who have had previous abdominal surgery or in pregnant patients This has been confirmed in a study of 2,501 DPLs performed over a 75-month period for blunt or penetrating abdominal trauma [39] The majority (2,409, or 96%) were performed using the closed percutaneous technique, and 92 (4%) were done open because of pelvic fractures, previous scars, or pregnancy Open DPL was less sensitive than closed DPL in patients who sustained blunt trauma (90% vs 95%), but slightly more sensitive in determining penetration (100% vs 96%) Overall, there were few (21, [0.8%]) complications, and the overall sensitivity, specificity, and accuracy were 95%, 99%, and 98%, respectively, using an RBC count of 100,000 per μL in blunt trauma and 10,000 per μL in penetrating trauma as the positive threshold A metaanalysis concluded that the closed DPL technique is comparable to the standard open DPL technique in terms of accuracy and major complications, with the advantage of reduced performance time with closed DPL, which is offset by increased technical difficulties and failures [40] A DPL modification [41] that resulted in more rapid infusion and drainage of lavage fluid used cystoscopy irrigation tubing for instillation and drainage of the lavage fluid, saving an average of 19 minutes per patient for the DPL completion This modification can be applied to the closed percutaneous or open DPL technique to decrease the procedure time in critically ill patients Interpretation of Results The current guidelines for interpretation of positive and negative results of DPL are provided in Table 23.2 A positive result can be estimated by the inability to read newsprint or typewritten print through the lavage fluid as it returns through clear plastic tubing This test is not reliable, however, and a quantitative RBC count in a sample of the peritoneal lavage fluid must be performed [42] For patients with nonpenetrating abdominal trauma, an RBC count greater than 100,000 per μL of lavage fluid is considered positive and requires emergent celiotomy Fewer than 50,000 RBCs per μL is considered negative and RBC counts of 50,000 to 100,000 per μL are considered indeterminate The guidelines for patients with penetrating abdominal trauma are much less clear with clinical studies using an RBC count of greater than 1,000 or 10,000 per μL to greater than 100,000 per μL as the criterion for a positive DPL in patients with penetrating thoracic or abdominal trauma The lower the threshold, the more sensitive the test, but the higher the nontherapeutic laparotomy rate TABLE 23.2 Interpretation of Diagnostic Peritoneal Lavage Results POSITIVE Nonpenetrating abdominal trauma Immediate gross blood return via catheter Immediate return of intestinal contents or food particles Aspiration of 10 mL blood via catheter Return of lavage fluid via chest tube or urinary catheter RBC count >100,000/mL WBC count >500/μL Cell count ratio (defined as the ratio between WBC and RBC count in the lavage fluid divided by the ratio of the same parameters in the peripheral blood) ≥1 Amylase >175 U/100 mL Penetrating abdominal trauma Immediate gross blood return via catheter Immediate return of intestinal contents or food particles Aspiration of 10 mL blood via catheter Return of lavage fluid via chest tube or Foley catheter RBC count used is variable, from >1,000/μL to >100,000/ μL WBC count >500/μL Amylase >175 U/100 mL NEGATIVE Nonpenetrating abdominal trauma RBC count 3 organ systems in a patient over 60 years of age Transcranial gunshot wound Any disease with median survival < 4 months Family request GCS 1 week Carcinamatosis and unresectable malignancy ICU, intensive care unit; SICU, surgical intensive care unit; GCS, Glasgow Coma Scale Others have used prognostic triggers such as patients with a terminal condition as determined by the physician or a high risk of hospital death despite the continuation or escalation of medical therapies [30] Patients with advanced cancer experience a complex web of these problems and evidence has demonstrated that specialist palliative care significantly improves patient outcomes in the domains of pain, symptom control, anxiety, and also reduces hospital admissions In addition, patients with a palliative care consultation have higher rates of DNR orders before death suggesting they are protected more often from nonbeneficial cardiopulmonary resuscitation [31] Evidence shows that families of patients who have a palliative care consultation during the last month of life are more satisfied with goals-of-care discussions and staff communication prior to their loved one’s death [32] p 298 p 299 The use of proactive clinical triggers for palliative care has demonstrated favorable outcomes in many settings In the outpatient setting, patients are significantly more likely to have discussions about goals of care, improved quality of life (QOL) and lower depressive symptoms with trigger-initiated palliative care consultation Specific to critical care, several studies showed that proactive approaches to palliative care consultation improve the concordance between the care provided and the care the patient actually wanted; increased use of advance directives; increased hospice referrals, and less use of nonbeneficial life-prolonging treatments for patients who are dying A proactive palliative care approach has demonstrated a decreased ICU LOS; decreased hospital LOS; and less aggressive ICU interventions for patients that die in the ICU Proactive palliative care has also shown to improve family satisfaction with the quality of care; understanding treatment options; and bereavement outcomes Several outpatient studies have demonstrated that patients with serious illness who receive palliative care live longer, and proactive palliative care consultation has shown no increased mortality or discharge disposition [27] One study looked at objective physiologic and medical parameters to predict palliative care need without consideration of communication or psychosocial factors This study showed that about one in seven ICU patients could benefit from palliative care There was no significant variation between the type of hospital (community vs academic) or type of ICU (surgical, medical, neurologic, and mixed), and the prevalence of patients meeting certain palliative care triggers Thus, the authors concluded that approximately one in seven ICU admissions met triggers for palliative care consultation using a single set of triggers, with an upper estimate of one in five patients using multiple sets of triggers Notably, the triggers investigated by the authors were all objective, and clinical criteria and did not include issues such as ethical dilemmas, communication challenges, or symptom management; therefore, this is probably an underestimation of the number of ICU patients who would benefit from palliative care consultation [33] Because palliative care needs are not unique to medical ICUs, various professional societies have their own specific guidelines The American College of Surgeons convened a consensus panel of surgical palliative care specialists and surgical intensivists and developed “ten trigger” criteria for palliative care consultation, including multiorgan failure; expectation of death in the SICU; length of SICU stay >1 month; and more than three admissions to the SICU during the index hospitalization [34] Several of these clinical criteria directly addressed terminal conditions, whereas others associated with a poor prognosis for neurologic recovery were also included (such as a Glasgow Coma Scale score 120, and (6) positive FAST scan The more of these factors that are present, the more likely the patient should undergo massive transfusion, with early plasma administration in a fixed-ratio paradigm Damage control resuscitation strives to reach a balance between achieving optimal physiologic function, while limiting the unwanted effects of the resuscitation itself, and is most useful from the time of presentation through the period of definitive surgical, endoscopic, or interventional hemorrhage control It must expeditiously be initiated upon arrival in the emergency department, often with limited information Prolonged resuscitation should not delay definitive hemorrhage control in order to achieve distant hemodynamic or physiologic goals Time spent in the emergency department equates to lost time in the operating room, endoscopy, or interventional suites where damage control resuscitation may be continued and decisive hemorrhage control obtained The initial phase continues through the operative intervention, and damage control principles are upheld by targeting the above physiologic goals To this end, damage control surgery is often performed, which consists of surgical hemorrhage control, limitation of contamination and temporary closure, deferring definitive repair of non–life-threatening injuries until physiologic correction is achieved in the intensive care unit (ICU) in the second resuscitative phase ONGOING RESUSCITATION While initial resuscitation of hemorrhagic shock is to serve as a bridge to operative, interventional, or endoscopic hemorrhage control, ongoing resuscitation following hemorrhage aims to restore normal physiologic parameters to ensure adequate oxygen delivery to resume normal bodily functions once hemorrhage has ceased Despite effective damage control resuscitative measures, patients often exhibit varying degrees of physiologic instability in the ICU Similar principles exist in the ongoing resuscitative phase, which is typically undertaken in the ICU Patients arriving from the operating theater may remain hypovolemic, coagulopathic, hypothermic, and acidotic, necessitating further intensive management to achieve a successful resuscitation Endpoints of resuscitation should be aggressively targeted in this phase to ensure rapid resolution of metabolic derangements that may have occurred during the preceding interventions Endpoints of Resuscitation Traditional endpoints of resuscitation, such as heart rate, blood pressure, and urine output, are grossly inadequate as sole markers of physiologic normalization Although these common methods provide insights into the overall clinical picture, they fail to accurately demonstrate resuscitation success Confounding variables abound when considering these easily attainable, yet simplistic determinations For example, heart rate is altered by a variety of mechanisms that may be unrelated to the adequacy of resuscitation Pain and anxiety commonly cause tachycardia, whereas the widespread use of β-blockers and other cardiac medications may prevent it—rendering heart rate less useful Urine output has long been utilized as an endpoint signifying the adequate restoration of perfusion to an end organ However, oliguria may be present despite completion of resuscitation CT evaluation is ubiquitous, and often utilizes IV contrast which commonly results in acute tubular necrosis despite aggressive resuscitation Medications, specifically antibiotics, are known to cause acute interstitial nephritis Additionally, the initial hypoperfusion event may have caused direct tubular injury resulting in oliguria, despite adequate resuscitation Managing oliguria with large volumes of resuscitation fluid will inevitably result in the undesirable consequences of overresuscitation Conversely, entities such as diabetes insipidus and cerebral salt wasting cause polyuria and may falsely reassure the clinician Hemorrhagic shock occurs as the result of hypoperfusion, and thus markers of hypoperfusion should be sought as valid endpoints An arterial blood gas is commonly touted as the most beneficial laboratory test in the resuscitation of a patient in hemorrhagic shock because of the rapid, comprehensive information gained, including BD The BD assumes a normal pCO2, which is a crucial point to consider, because it allows for the true metabolic derangement to be elucidated Clinicians typically examine the pH, and may miss significant acidosis, especially if the patient is compensating with tachypnea For this reason, the BD is a test that requires virtually no analysis, and provides a simple number that, in hemorrhagic shock, is an accurate marker of perfusion Through the mechanisms described earlier in this chapter, acidosis results as a function of hypoperfusion and anaerobic metabolism at the cellular level As this acidosis worsens, BD becomes more negative An initial BD less than −6 is associated with the need for massive transfusion and damage control resuscitation practice implementation Similarly, a persistent BD following hemorrhage control suggests the need for further resuscitation Multiple studies have shown benefits of using the BD as an endpoint of resuscitation [53,54] The goal should be a rapid normalization of the BD Decreased mortality is associated with normalization of the BD within the first 24 hours of hospitalization Some issues with BD warrant mention however If sodium bicarbonate is employed in the initial resuscitation phase, the BD becomes useless, secondary to the addition of exogenous base to the equation Only in the most severe acidosis cases should bicarbonate even be considered Another relative indication for bicarbonate administration is to increase the effectiveness of resuscitation adjuncts, such as prothrombin complex concentrate or recombinant factor VIIa, which have decreased efficacy below a pH of 7.2 The BD may be confounded by other acidotic states, such as hyperchloremia, which is typically iatrogenic in nature Additionally, BD often lags behind the resuscitation, and its continued pursuit may lead to overresuscitation When the BD persists, the presence of a missed injury or ongoing causes for hypoperfusion should be reviewed p 342 p 343 To counter the issues associated with BD, serum lactate is employed In the setting of acute hemorrhagic shock, increases in lactate are the result of tissue and cellular mitochondrial dysfunction, and thus lactate provides insights into tissue perfusion Parallel physiologic hypoperfusion mechanisms will cause the level of lactate to increase, secondary to anaerobic metabolism Similar to BD, lactate clearance within 24 hours has been shown in many studies to be associated with lower mortality rates [55,56] Several societies have incorporated lactate into their resuscitation guidelines, including the Society of Critical Care Medicine and the Eastern Association for the Surgery of Trauma; and an internal consensus conference on hemodynamic monitoring has recommended utilization of lactate clearance as an endpoint of resuscitation Lactate clearance is affected by hepatic function, and, for those patients with either underlying or acute hepatic insufficiency, elevated lactate concentrations may persist secondary to decreased clearance by the liver and may be misleading in these circumstances Some have further criticized the ability of lactate levels to determine perfusion adequacy by citing the multiple aerobic processes, including glucose utilization in the setting of hyperglycemia, as potential nonperfusion-related causes for hyperlactatemia However, many consider lactate one of the most useful endpoints in the resuscitation of hemorrhagic shock Adequate tissue perfusion depends upon both oxygen delivery and tissue oxygen demand This supply–demand relationship can be determined by examining central venous oxygen saturation (ScvO2) measurement from a central venous catheter Normal physiologic conditions incur approximately 25% oxygen extraction at the tissue level, resulting in a ScvO2 of 75%, given an arterial saturation of 100% When tissue demand increases, or oxygen delivery decreases, as in hemorrhagic shock, more oxygen is extracted, decreasing ScvO2 ScvO2 has been shown to be a marker of both fluid responsiveness and reinstatement of normal perfusion [57] By restoring normal cardiac output with volume administration, preload and afterload optimization, and inotropic support; the delivery component of ScvO2 is corrected Complexity arises, however, in addressing the demand component of ScvO2 Peripheral vasoconstriction, as described earlier, is a compensatory mechanism in the face of hypovolemia This vasoconstriction ultimately leads to decreased tissue oxygen extraction and a rising ScvO2 Conversely, in hemorrhagic shock tissue, oxygen demand and concomitant extraction are typically increased secondary to tissue-level hypoxia, resulting from acute hypovolemia and hypoperfusion Increased oxygen extraction in response to hemorrhage leads to a delivery-dependent state and declining ScvO2 These two competing forces have resulted in an argument against the efficacy of ScvO2 as a resuscitation marker and work to confuse the interpretation of ScvO2 Despite these intricacies, ScvO2 remains an endpoint of interest, and abnormal elevations or decreases in ScvO2 should prompt the clinician to adjust resuscitation based on results In hemorrhagic shock, restoration of normal oxygen delivery (DO2) is the ultimate goal, making this calculated value extremely useful for determining sufficiency of resuscitation The equation is defined as the product of arterial oxygen content and blood flow, and involves three main components: cardiac output, hemoglobin, and oxygen saturation (SaO2) The contribution of partial pressure of oxygen is negligible and is often omitted in bedside calculations of DO2 With the equation, we simplify the concept of perfusion, by separating it into two main determinants—flow and content To address arterial oxygen content, first the SaO2 is optimized through oxygen administration, increased FiO2, or through ventilator methods to increase oxygenation Hemoglobin is then optimized, keeping in mind the clear benefit of restrictive transfusion strategies shown in virtually all patient populations Next, flow is maximized via optimization of cardiac output, which typically equates to targeting stroke volume through ongoing resuscitation or application of inotropic agents Through these methods, normalizing oxygen delivery represents a valid and complete endpoint of resuscitation for hemorrhagic shock Like the endpoints described earlier, DO2 is not without limitation In states of decreased tissue oxygen extraction, DO2 may not coincide with cellular perfusion Additionally, advanced monitoring is required to obtain stroke volume measurement, and depending upon the device used, significant error may be introduced into the equation Coagulation Endpoints Many damage control resuscitation measures are directed at controlling the early coagulopathy of hemorrhage The ongoing phase of resuscitation continues this focus Conventional coagulation tests are helpful, and provide insight into ongoing coagulopathy Considering the above endpoints, the clinician should consider normalizing coagulation function with plasma, platelets, cryoprecipitate, or pharmacologic means Understanding each of the blood components and when to utilize them is crucial in the resuscitation of hemorrhagic shock TEG and rotational thromboelastometry (ROTEM) have gained wide acceptance over the last decade owing to the ability to help guide resuscitation, and serve as a set of endpoints specifically relating to the coagulopathy associated with hemorrhage Developed in 1948 to detect congenital factor deficiencies, this technology has broadened its use to hemorrhage of all types TEG is a dynamic test that measures both the formation and lysis of the clot Results are presented graphically and numerically and allow for a global assessment of clotting function, by illuminating abnormalities at specific sites in the clotting cascade and offering detailed information regarding coagulation function TEG and ROTEM share many similarities; however, the nomenclature differs between the two Abnormalities in clot initiation are measured by R (TEG) or CT (ROTEM) Clot initiation is dependent upon clotting factors Therefore, a prolonged R or CT value corresponds to a deficiency in clotting factors Prolongations are commonly seen with anticoagulant use and in the presence of factor inhibitors Therapies include plasma transfusion, prothrombin complex concentrates, and recombinant factor VII As the clot develops, the tracing diverges and becomes parabolic in shape The initial angle of this divergence is known as alpha (α) The α corresponds to the rapidity of clot development, and is mainly dependent upon fibrinogen, with a minor role played by platelets A steep angle indicates overly rapid clot development, whereas a gradual angle indicates a slowly developing clot Hypofibrinogenemia and hyperfibrinolysis often result in a low α value Therapies include plasma, which has the greatest amount of fibrinogen, and cryoprecipitate, which has the highest concentration of fibrinogen As the clot strengthens, the parabolic curve peaks, resulting in the maximal amplitude (MA) (TEG) or maximum clot firmness (MCF) (ROTEM) of the clot This is largely dependent upon platelets, with fibrinogen and platelet–fibrinogen interactions contributing to a lesser extent Low MA/MCF values are seen with thrombocytopenia and in the presence of antiplatelet agents, such as aspirin or clopidogrel Treating low MA/MCF values is limited to platelet transfusion only The down-sloping TEG tracing represents the time for clot lysis Normal lysis at 30 minutes, LY30 (TEG) or CL30 (ROTEM), is 0% Minor increases in lysis (3% to 8%) are associated with increased mortality and should be rapidly addressed Therapy includes antifibrinolytic medications, such as tranexamic acid and ε-aminocaproic acid Plasma and cryoprecipitate may also be employed to replace lost fibrinogen, but the mainstay of treatment is to cease hyperfibrinolysis with pharmacologic means [58] p 343 p 344 Employing targeted pharmacologic and transfusion strategies based on TEG measurements allows for normalization of coagulopathy, while limiting untoward effects of overresuscitation or underresuscitation Additionally, it may result in fewer transfusions, which in turn will decrease complications related to transfusion Monitoring Today’s ICUs utilize advanced technologies to determine volume status and resuscitation parameters The Swan–Ganz pulmonary artery catheter (PAC), since its introduction in 1970, has provided a wealth of information regarding hemodynamics to a large variety of patient populations However, multiple, large randomized trials have failed to show a mortality benefit when PAC parameters were used to guide resuscitation [59,60] And, in some trials, higher mortality, increased morbidity, and larger volume fluid resuscitation were seen with PAC use Additionally, with less-invasive monitors becoming more and more available, the PAC has fallen out of favor The benefits of the PAC, however, should not be understated in certain instances Patients with significant arrhythmias or those with pulmonary hypertension may benefit from PAC catheterization, because noninvasive methods frequently fail to demonstrate accurate hemodynamic results Furthermore, perioperative use of PACs to guide resuscitation has shown in multiple studies to show a mortality and morbidity benefit [61] For hemorrhagic shock, the PAC may provide information not available from noninvasive methods and, therefore, should be considered in select patient populations In addition to PACs, a variety of minimally invasive and noninvasive techniques are available to rapidly determine endpoints of resuscitation Arterial waveform analysis methodologies have seen widespread use in recent years Continuous pulse contour cardiac output monitors (PiCCO; Phillips) utilize proprietary thermodilution arterial catheters, typically inserted in the femoral artery, to determine cardiac output through pulse contour analysis Frequent calibration is necessary, and a learning curve exists both from a physician and nursing point of view [62] Lithium dilution cardiac output (LiDCO; LiDCO Limited) is measured through the injection of lithium via a central venous access line The concentration changes of lithium are then measured with a lithium-sensitive sensor attached to an existing arterial line Again, multiple daily calibrations are necessary; however, a variety of derived variables, including cardiac output, are readily calculated and have been shown to be equivalent to thermodilutional techniques [63] Arterial waveform monitors (Vigileo; Edwards Lifesciences) provide cardiac output measurement through existing arterial lines, and do not require injection-based calibration By measuring the pulse pressure variations, stroke volume is calculated and cardiac output is derived Although typically less precise than the above dilutional methods, arterial waveform monitors provide information using existing catheters with minimal training [64] Noninvasive methods of cardiac output determination continue to be developed Ultrasonic cardiac output monitoring (USCOM; Uscom Ltd.) utilizes an ultrasound probe placed at the sternal notch to measure beatto-beat variability, cardiac output, and systemic vascular resistance It requires minimal training and has been validated against thermodilution Obesity may be a barrier to utilizing this method, and may increase error rates in measurements [65] Another noninvasive device (NICOM; Cheetah Medical) uses bioreactance to measure phase shifts and amplitude after passing a current between electrodes placed on the chest The phase change correlates well with changes in stroke volume and aortic blood volume This noninvasive monitor has shown good correlation and reliability both with Doppler ultrasound and thermodilutional methods [66] It is important to note that reliable monitoring is crucial to determining adequacy of resuscitation Blind resuscitation invariably misses the mark, resulting in either overresuscitation or underresuscitation and worsened outcomes Fluids and Component Therapy Historically, crystalloid solutions were almost exclusively utilized in resuscitation following hemorrhage Traditional regimens called for infusing crystalloids while awaiting blood products from the blood bank, with repeated bolus doses as necessary Following at least 2 L of crystalloid infusion, PRBC were considered Unfortunately, this approach led to worsened coagulopathy, worsened organ failure, and overall outcomes Recent evidence has shown improved mortality and morbidity with earlier use of blood products, including plasma transfusion As stated previously, a key component to both early damage control resuscitation and ongoing resuscitation in the ICU is that crystalloids offer little benefit for hemorrhagic shock Unlike patients in septic shock, hypotension and hemodynamic collapse are secondary to blood loss This simple idea of replacing what was lost is at the cornerstone of hemorrhagic shock management Crystalloid preparations inevitably are used to some extent, either as medication carriers or transfusion flushes However, their use should be limited as much as possible—especially in the early phases of resuscitation, before hemorrhage control is gained Once in the ICU, targeted and thoughtful use of crystalloid may be employed, but again holding true to damage control tenants Fluid shifts occurring as the result of hemorrhage are often profound and worsened by large-volume IV fluid administration Control of coagulopathy and acidosis also falls victim to isotonic and hypotonic crystalloid volume use HTS is one crystalloid formula that has proven beneficial Solutions of 3%, 5%, and 7.5% are commercially available High concentrations of sodium chloride delivered to the vascular system favor the flux of water from the interstitial space and from the cells to augment the blood volume This results in a rapid restoration of intravascular volume Infusions of small amounts of these solutions lead to hemodynamic responses equivalent to much larger volumes of crystalloid solutions This is advantageous because of both the rapidity of the response and the limited volume necessary to achieve the same goals Recent work suggests these fluids decrease the activation of neutrophils, modulate cytokine and adhesion molecule expression, and suppress the production of reactive oxygen species These immunomodulatory effects have been shown to decrease the risk of multiple organ dysfunction syndrome [67] Proponents believe that the smaller volumes lead to less tissue edema and associated potential complications Once fluid is drawn into the vascular space, sodium chloride is diluted and equilibrates across the fluid spaces of the body As this happens, the effect of the HTS is gradually lost Increases in mean arterial pressure are short-lived, with hemodynamic effects lasting only 15 to 75 minutes [68] The largest potential danger with hypertonic solutions is hypernatremia This may be accentuated in the previously dehydrated patient without additional extravascular fluid to donate to the vascular system Although some rapid and transient hypernatremia seems to be tolerated, caution in administration and careful monitoring of sodium levels are important in the safe use of these solutions Whole blood contains all of the factors lost by the bleeding patient, including plasma proteins, clotting factors, platelets, and white blood cells, as well as erythrocytes Although fresh whole blood is a superb resuscitation fluid, it has a short storage life and, therefore, has limited use in the typical civilian setting Additionally, infectious disease testing and blood banking inventory management issues have made whole blood largely unavailable However, whole blood is used in many centers, and clinical studies on whole blood are underway for civilian trauma patients Prospective data collected in these studies may present an impetus for change in blood banking and provide access to this useful and efficacious resuscitative fluid p 344 p 345 RBC transfusion is common for the resuscitation from hemorrhage, and should be utilized early in the process Initial resuscitation practices often employ uncrossed blood products with O-negative; however, packed red blood cells (PRBCs) should be typed and cross-matched as early as feasible to avoid transfusion reactions PRBCs can be stored for 42 days according to current Food and Drug Administration standards However, detrimental effects of stored PRBCs can be related to their age Hyperkalemia is a well-known problem with red cell storage, because potassium is lost into the PRBC supernatant over time Increased risk of cardiac events, infection, multisystem organ failure, and mortality are also associated with older RBCs [69,70] Despite safeguards, clerical errors lead to mismatched blood administrations, with a rate of fatal major ABO blood group reactions of between 1 in 500,000 and 1 in 2 million Currently, the risk of infection from a transfused unit is 1 in 30,000 to 1 in 150,000 for hepatitis C, and 1 in 200,000 to 1 in 2,000,000 for human immunodeficiency virus [71] The benefits of early plasma administration continue to be realized through multiple randomized trials Plasma should be considered an initial resuscitation fluid in hemorrhagic shock, along with PRBCs Thawed plasma is plasma that is stored for up to 5 days at 1°C to 6°C This storage timeline is based on similar RBC storage guidelines and preservation of factors V and VIII; however, clinical data is lacking [72,73] Because more centers are using earlier and increased amounts of plasma, thawed plasma is now routinely available at many trauma centers, and increasingly stored in emergency departments Type AB plasma, the universal donor for plasma, is chosen initially before crossmatched product is available Group A plasma has been shown to be a safe alternative to Type AB, and empiric utilization of Group A plasma may expand the use of massive transfusion protocols, and help encourage the use of early plasma transfusion where AB availability is limited [74] Having thawed plasma available in the emergency department allows for the initiation of a protocol driven high ratio of FFP to PRBCs Plasma transfusion risks of TRALI, infection, and multisystem organ failure increase at the rate of approximately 2% with each unit transfused [75] However, these observations have been made in the context of higher survival among patients who received high ratios of FFP, suggesting that those patients survived despite the potential cost of sepsis and multisystem organ failure development Platelets are transfused in two different formulations Pooled whole blood–derived platelets are generally transfused in six-unit increments from five to six different blood donors Apheresis platelet units are derived from a single donor and are transfused in volumes approximately equal to 5 to 6 units of pooled whole blood–derived platelets Because evidence continues to emerge, it is becoming clear that platelets, once an afterthought during traditional resuscitation practices, should be transfused at higher ratios Many massive transfusion protocols include platelets in the first or second tier of the transfusion guideline Improved outcomes have been seen when fixed-ratio transfusion strategies include platelets early in the schema Platelet counts of less than 20,000 per μL should always be corrected in any bleeding patient, whether or not a lifethreatening injury has been identified If the patient has a known history of antiplatelet use within the preceding 7 days, it may be necessary to transfuse platelets despite a platelet count greater than 50,000 per μL, particularly in those patients with head injury or those being managed nonoperatively for significant solid organ injury Platelet counts of less than 100,000 per μL are a relative indication for platelet transfusion in the head-injured patient with evidence of intracranial hemorrhage, whether as a single-system injury or as part of multisystem injuries It is possible that we have been overly restrictive in the use of platelet transfusions, because recent data suggests that increased and early use improves survival [52] Both pooled and apheresis platelets are stored at room temperature for up to 5 days Bacterial contamination remains the greatest risk of platelet transfusion; however, apheresis platelet units have been shown to have lower risk of infection because they are derived from a single donor Cryoprecipitate is a product of FFP that contains factor VIII, von Willebrand factor, fibrinogen, fibronectin, factor XIII, and platelet microparticles The benefits of including cryoprecipitate in massive transfusion protocols have yet to be confirmed [76] As a product of plasma, cryoprecipitate contains many of the constituents of plasma, only in concentrated, less voluminous form For this reason, unless a specific coagulation defect is targeted, cryoprecipitate likely offers little benefit over FFP in the early resuscitation of hemorrhagic shock Cryoprecipitate is made after centrifuging thawed plasma and removing the supernatant It has a shelf life of 1 year when frozen at −20°C Cryoprecipitate is customarily transfused in 10 unit bags, although this is highly variable As a result of this practice, patients generally receive 2.5 g of cryoprecipitate per transfusion Vasopressor and Inotropic Support Despite adequate volume resuscitation, some patients require additional pharmacologic means to attain hemodynamic goals In these patients, selective use of vasopressor agents may be necessary A keen understanding of each agent’s receptor targets and their resultant effects is required to effectively make use of vasopressors in the resuscitation of hemorrhagic shock Norepinephrine is widely used, and is at the forefront of many algorithms aimed to treat critically ill patients Acting weakly on β1 receptors, norepinephrine mildly increases contractility, while it acts to strongly activate α1 receptors, affording potent vasoconstriction Bradycardia is commonly seen and is, therefore, not recommended for those with bradyarrhythmias Dopamine acts on multiple receptors and is strongly associated with tachycardia and the development of tachyarrhythmia At lower doses, it acts as a dopamine (D1) receptor agonist, and may produce vasodilation through action on β2 receptors The so-called “renal dose” dopamine, at low doses, has not been shown to improve renal perfusion or treat renal insufficiency, and although theoretical advantages exist, clinically it has no benefit At somewhat higher doses, dopamine triggers β1 receptors and increases contractility and heart rate With increasing doses, α1 receptors are activated and vasoconstriction results Dopamine is typically a second-line agent for most situations relevant to hemorrhagic shock, because of the risk of tachyarrhythmia is increased in patients who are already tachycardic Epinephrine is a powerful agent acting strongly on both α and β receptors In the case of cardiac arrest, 1 mg bolus doses remain a mainstay of treatment When higher doses are used, tissue ischemia becomes more likely High-dose epinephrine infusions worsen acidosis and ultimately may result in cardiac ischemia, and therefore are not recommended Lower doses, however, may be beneficial as either intermittent boluses or infusions Particular benefits may be seen prior to anesthetic induction for procedural hemorrhage control Phenylephrine is a pure α-agent, effecting potent vasoconstriction Care should be taken when beginning a phenylephrine infusion in patients with hemorrhagic shock These patients are typically maximally vasoconstricted via endogenous catecholamine release, and cardiac output is being sustained by the patient’s tachycardia Further vasoconstriction, without stimulation of β receptors, will worsen cardiac output by causing a reflex bradycardia, and reduced cardiac output Additionally, phenylephrine infusions in elderly patients may increase afterload beyond that which the aging heart can function, causing acute heart failure and precipitous drop in cardiac output p 345 p 346 Vasopressin has been increasingly utilized in the resuscitation of patients following hemorrhage Evidence suggests endogenous vasopressin stores are rapidly depleted in response to hemorrhage, and replacement with a low-dose infusion is warranted when hemodynamic profiles are not optimized The greatest benefit appears to be when vasopressin is used in conjunction with other vasoactive medications, such as norepinephrine When norepinephrine doses are greater than 12 μg per minute, concomitant vasopressin infusion has been shown to allow norepinephrine to be titrated down, while maintaining desirable hemodynamics High-dose infusions (>0.04 units per minute) are strongly associated with coronary ischemia and are not recommended Dobutamine and milrinone are two inotropic agents that typically have limited use in hemorrhagic shock Dobutamine, a pure β-agonist, has a strong effect on contractility and heart rate It is also associated with vasodilation, and may result in up to a 10% drop in systemic vascular resistance Milrinone, a phosphodiesterase inhibitor, increases contractility by increasing cyclic adenosine monophosphate It too, acts as a vasodilator, and preferentially vasodilates the pulmonary vascular bed Owing to their vasodilating properties, both of these pharmaceuticals offer limited benefit in the resuscitation following hemorrhage In selected circumstances, principally preexisting heart failure, they may be utilized, but invasive monitoring is necessary to fully appreciate these benefits Additional Therapies Coagulopathy may persist despite aggressive initial treatment It is important to reevaluate coagulopathy within the first 48 hours of the ICU stay Preexisting conditions, such as cirrhosis, may prevent adequate coagulopathic control without repeated dosing of medications, such as vitamin K, prothrombin complex concentrates, or plasma (if volume is necessary) Similarly, hyperfibrinolysis may still be present, and require dosing of tranexamic acid If renal failure is present, the presence of uremic platelet dysfunction should be considered and treated with highdose DDAVP Steroids have been studied in many shock states; however, they have shown little benefit in hemorrhagic shock One area of interest where steroids may have benefit is in the realm of acute acquired adrenal insufficiency In patients with persistent hypotension, despite adequate volume resuscitation, a random cortisol level and empiric dosing of either hydrocortisone or dexamethasone should be considered Many clinicians use clinical judgment to guide administration of steroids in the face of a “relatively” low serum random cortisol The cortisol stimulation test is controversial, but when used, the patient’s cortisol level should increase a minimum of 9 μg per dL above baseline upon administration of cosyntropin Glycemic control should be initiated upon arrival to the ICU Hyperglycemia encourages a proinflammatory state, and results in worsened outcomes Targets should be reasonable, because iatrogenic hypoglycemia is associated with worsened outcomes as well Nutritional support should be initiated as early as prudent, depending upon the patient’s physiologic state Intra-abdominal hemorrhage and subsequent operations often preclude early enteral feeding, as do the necessity of vasopressor agents Most vasoactive medications decrease splanchnic circulation, which increases the risk of tube feed necrosis and other nutritionally related enteric disasters Evidence continues to emerge regarding the use of thromboembolic prophylaxis in the setting of hemorrhage As directed treatment of coagulopathy is associated with improved outcomes, so is thromboembolic prevention Hemorrhaging patients often are in a prothrombotic and paradoxically coagulopathic state Overactivation of the clotting cascade combined with stasis from hypotension and vascular damage from the inciting event complete Virchow’s triad, and therefore put patients at increased risk for thrombotic events Once hemorrhage control has been demonstrated, thromboembolic prophylaxis should be initiated In most cases, waiting more than 24 hours is unnecessary, and leads to higher rates of thromboembolic events Home medications should be reviewed and begun as necessary Preinjury statin use is associated with increased rates of myocardial ischemia when these medications are not restarted upon admission Withholding β-blocker medications may result in rebound tachycardia and tachyarrhythmias, and increase risk of cardiac ischemia Diuretics are typically detrimental until the patient is beyond the resuscitative phases, and are generally withheld until stability is demonstrated In those patients who take diuretics regularly, however, special attention is warranted in regard to volume overloaded states, and the development of pulmonary edema Anticoagulants should be restarted with caution Certain conditions, such as patients with mechanical heart valves or recent percutaneous coronary stents, may require anticoagulant or antiplatelet agents to be restarted as soon as possible An accurate and thorough history is essential to obtain, especially in the aging population SUMMARY Shock following hemorrhage represents a significant, multifaceted process impacting a significant number of patients Early recognition is crucial to improve outcomes Once recognized, hemorrhage control must rapidly be obtained to prevent further physiologic derangements, for without it, any resuscitation strategy is futile Hemostatic adjuncts, both topical and IV, may be utilized to reach this goal Damage control principles, with targeted treatment of coagulopathy, early use of plasma, and limited crystalloid volume, should be employed in patients at risk for exsanguination Before, during, and after hemorrhage has ceased, resuscitation efforts must proceed with goals to normalize hemodynamic, coagulation, and perfusion parameters Resuscitation endpoints should be targeted, with the combined use of advanced monitoring techniques, laboratory results, and clinical judgment REFERENCES Committee on Trauma: Advanced Trauma Life Support Program Chicago, American College of Surgeons, 2012 Sauaia A, Moore FA, Moore EE, et al: Epidemiology of trauma deaths: a reassessment J Trauma 38:185, 1995 Kauvar DS, Lefering R, Wade CE: Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations J Trauma 60:S3–S11, 2006 Gunning AC, Lansink KW, van Wessem KJ, et al: Demographic patterns and outcomes of patients in Level I Trauma Centers in three international trauma systems World J Surg 39:2677–2684, 2015 Holcomb JB, Jenkins D, Rhee P, et al: Damage control resuscitation: directly addressing the early coagulopathy of trauma J Trauma 62:307–310, 2007 Cotton BA, Harvin JA, Kostousouv V, et al: Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration J Trauma Acute Care Surg 73:365–370, 2012 Rizoli SB, Scarpelini S, Callum J, et al: Clotting factor deficiency in early trauma-associated coagulopathy J Trauma 71:S427–S434, 2011 Hess JR, Brohi K, Dutton RP, et al: The coagulopathy of trauma: a review of mechanisms J Trauma 65:748–754, 2008 Cohen MJ, Call M, Nelson M, et al: Critical role of activated Protein C in early coagulopathy and later organ failure, infection and death in trauma patients Ann Surg 255:379–385, 2012 10 Floccard B, Rugeria L, Faure A, et al: Early coagulopathy in trauma patients: an on-scene and hospital admission study Injury 43:26–32, 2012 11 Cardenas JC, Matijevic N, Baer LA, et al: Elevated tissue plasminogen activator and reduced plasminogen activator inhibitor promote hyperfibrinolysis in trauma patients Shock 41:514–521, 2014 p 346 p 347 12 Rahbar E, Cardenas JC, Baimukanova G, et al: Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients J Transl Med 13:117, 2015 13 Kozar RA, Peng Z, Zhang R, et al: Plasma restoration of endothelial glycocalyx in rodent model of hemorrhagic shock Anesth Analg 112:1289–1295, 2011 14 Kutcher ME, Redick BJ, McCreery RC, et al: Characterization of platelet dysfunction after trauma J Trauma Acute Care Surg 73:13– 19, 2012 15 Wiener G, Moore HB, Moore EE, et al: Shock releases bile acid inducing platelet inhibition and fibrinolysis J Surg Res 195:390–395, 2015 16 Cardenas JC, Wade CE, Holcomb JB: Mechanisms of trauma-induced coagulopathy Curr Opin Hematol 21:404–409, 2014 17 Toung T, Reilly PM, Fu KC, et al: Mesenteric vasoconstriction in response to hemorrhagic shock Shock 13:267–273, 2000 18 Parillo JE, Dellinger RP (eds): Critical Care Medicine 3rd ed Philadelphia PA, Mosby, 2008 19 Uhlich RM, Konie JA, Davis JW, et al: Novel microRNA correlations in the severely injured Surgery 156:834–841, 2014 20 Alam HB, Sun L, Ruff P, et al: E-and P-selectin expression depends on the resuscitation fluids used in hemorrhaged rats J Surg Res 94:145, 2000 21 Schreiber MA, Perkins JP, Kiraly L, et al: Early predictors of massive transfusion in combat casualties J Trauma 205(4):541–545, 2006 22 MacLeod J, Lynn M, McKenney MG, et al: Predictors of mortality in trauma patients Am Surg 70:805, 2004 23 Khasawneh MA, Zielinski MD, Jenkins DH, et al: Low tissue oxygen saturation is associated with requirements for transfusion in the rural trauma population World J Surg 38:1892–1897, 2014 24 Yucel N, Lefering R, Maegele M, et al: Trauma associated severe hemorrhage (TASH)-Score: probability of mass transfusion as surrogate for life threatening hemorrhage after multiple trauma J Trauma 60:1228–1237, 2006 25 McLaughlin DF, Niles SE, Salinas J, et al: A predictive model for massive transfusion in combat casualty patients J Trauma 64:S57– S63, 2008 26 Nunez TC, Voskresensky IV, Dossett LA, et al: Early prediction of massive transfusion in trauma: simple as ABC (Assessment of Blood Consumption)? J Trauma 66:346–352, 2009 27 MacIntyre, AD, Quick JA, Barnes SL: Hemostatic dressings reduce tourniquet time while maintaining hemorrhage control Am Surg 77:162–165, 2011 28 Gates KS, Baer L, Holcomb JB: Prehospital emergency care: evaluation of the junctional emergency tourniquet tool with a perfused cadaver model J Spec Oper Med 14:40–44, 2014 29 Kisat M, Morrison JJ, Hasmi ZG, et al: Epidemiology and outcomes of non-compressible torso hemorrhage J Surg Res 184:414–421, 2013 30 Qasim Z, Brenner M, Menaker J, et al: Resuscitative endovascular balloon occlusion of the aorta Resuscitation 96:275–279, 2015 31 Chang JC, Holloway BC, Amisch M, et al: ResQFoam for the treatment of non-compressible hemorrhage on the front line Mil Med 180:932– 933, 2015 32 Quick JA, Barnes SL: Correct coagulopathy quickly, effectively Lancet 385:2024–2026, 2015 33 Duchesne JC, McSwain NE, Cotton BA, et al: Damage control resuscitation: the new face of damage control J Trauma 69:976–990, 2010 34 Pollack CV, Reilly PA, Eikelboom J, et al: Idarucizumab for dabigatran reversal N Engl J Med 373:511–520, 2015 35 Shakur H, Roberts I, Bautista R, et al: Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomized, placebo-controlled trial Lancet 376:23–32, 2010 36 Harvin JA, Peirce CA, Mims MM, et al: The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis J Trauma Acute Care Surg 78:905–911, 2015 37 Morrison JJ, Dubose JJ, Rasmussen TE, et al: Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study Arch Surg 147:113–119, 2012 38 ACS TQIP Massive Transfusion in Trauma Guidelines Chicago, IL, American College of Surgeons Committee on Trauma, 2015 39 Kirkpatrick AW: Clinician-performed focused sonography for the resuscitation of trauma Crit Care Med 35[5 Suppl]:S162–S172, 2007 40 Jang T, Kryder G, Sineff S, et al: The technical errors of physicians learning to perform focused assessment with sonography in trauma Acad Emerg Med 19:98–101, 2012 41 Gaarder C, Kroepelien CF, Loekke R, et al: Ultrasound performed by radiologists—confirming the truth about FAST in trauma J Trauma 67:323–327, 2009 42 Shires GT, Carrico CJ, Baxter CR, et al: Principles in treatment of severely injured patients Adv Surg 4:255–324, 1970 43 Shires GT, Coln D, Carrico J, et al: Fluid therapy in hemorrhagic shock Arch Surg 88:688–693, 1964 44 Dillon J, Lunch LJ, Meyers R, et al: A bioassay of treatment of hemorrhagic shock Arch Surg 93:537–555, 1966 45 Ashbaugh DG, Bigelow DB, Petty TL, et al: Acute respiratory distress in adults Lancet 12:319–323, 1967 46 Rotondo MF, Schwab CW, McGonigal MD, et al ‘Damage control’: an approach for improved survival in exsanguinating penetrating abdominal injury J Trauma 35:375–383, 1993 47 Longnecker DE, French G: Fluid Resuscitation: State of the Science for Treating Combat Casualties and Civilian Injuries Washington DC, Institute of Medicine, 1999 48 Fluid Resuscitation in pre-hospital trauma care: a consensus view J R Army Med Corps 147:147–152, 2001 49 Bickel WH, Wall MJ, Pepe PE, et al: Immediate versus delayed fluid resuscitation for hypotensive patient with penetrating torso injuries N Engl J Med 331:1105–1109, 1994 50 Holcomb JB, Tilley BC, Baraniuk S, et al: Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma (PROPPR) JAMA 313:471–482, 2015 51 Smith JB, Pittet JF, Pierce A: Hypotensive resuscitation Curr Anesthesiol Rep 4:209–215, 2014 52 Holcomb JB, del Junco DJ, Fox EE, et al: The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: comparative effectiveness of a time-varying treatment with competing risks JAMA Surg 148:127–136, 2013 53 Mutschler M, Nienaber U, Brockamp T, et al: Renaissance of base deficit for the initial assessment of trauma patients: a base deficitbased classification for hypovolemic shock developed on data from 16,305 patients derived from the TraumaRegister DGU Crit Care 17:R42, 2013 54 Hodgman EI, Morse BC, Dente CJ, et al: Base deficit as a marker of survival after traumatic injury: consistent across changing patient populations and resuscitation paradigms J Trauma 72:844–851, 2012 55 Jones AE, Shapiro NI, Trzeciak S, et al: Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy JAMA 303:739–746, 2010 56 Regnier MA, Rauz M, Le Manach Y, et al: Prognostic significance of blood lactate and lactate clearance in trauma patients Anesthesiology 117:1276–1288, 2012 57 Giraud R, Siegenthaler N, Gayet-Ageron A, et al: ScvO2 as a marker to define fluid responsiveness J Trauma 70:802–807, 2011 58 Sankarankutty A, Nascimento B, Teodoro da Luz L, et al: TEG and ROTEM in trauma: similar test but different results World J Emerg Surg 7:S1, 2012 59 Sandham JD, Hull RD, Brant RF, et al: A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients N Engl J Med 348:5–14, 2003 60 Stevenson LW, Binanay C, Califf RM, et al: Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness JAMA 294:1625–1633, 2005 61 Hamilton MA, Cecconi M, Rhodes A: A systematic review and metaanalysis on the use of preemptive hemodynamic intervention to improve postoperative outcomes in moderate and high-risk surgical patients Anesth Analg 112:1392–1402, 2011 62 Litton E, Morgan M: The PiCCO monitor: a review Anaesth Intensive Care 40:393–409, 2012 63 Mora B, Ince I, Birkenberg B, et al: Validation of cardiac output measurement with the LiDCO™ pulse contour system in patients with impaired left ventricular function after cardiac surgery Anaesthesia 66:675–681, 2011 64 Biancofore G, Critchley LAH, Lee A, et al: Evaluation of a new software version of the FloTrac/Vigileo (Version 3.02) and a comparison with previous data in cirrhotic patients undergoing liver transplant surgery Anesth Analg 113:515–522, 2011 65 Beltramo F, Menteer J, Razavi A, et al: Validation of an ultrasound cardiac output monitor as a bedside tool for pediatric patients Pediatr Cardiol 37:177–183, 2016 66 Cheung H, Dong Q, Dong R, et al: Correlation of cardiac output measured by non-invasive continuous cardiac output monitoring (NICOM) and thermodilution in patients undergoing off-pump coronary artery bypass surgery J Anesth 29:416–420, 2015 67 Motaharinia J, Etezadi F, Moghaddas A, et al: Immunomodulatory effect of hypertonic saline in hemorrhagic shock Daru 23:47, 2015 68 Tyagi R, Donaldson K, Loftus CM, et al: Hypertonic saline: a clinical review Neurosurg Rev 30:277–290, 2007 69 Sadjadi J, Cureton EL, Twomey P, et al: Transfusion, not just injury severity, leads to posttrauma infection: a matched cohort study Am Surg 75:307–312, 2009 70 Murrell Z, Haukoos JS, Putnam B, et al: The effect of older blood on mortality, need for ICU care, and length of ICU stay after major trauma Am Surg 71:781–785, 2005 71 Goodnough LT, Brecher ME, Kanter MH, et al: Transfusion medicine: first of two parts—blood transfusion N Engl J Med 340:438, 1999 72 Spinella PC, Holcomb JB: Resuscitation and transfusion principles for traumatic hemorrhagic shock Blood Rev 23:231–240, 2009 73 Lamboo M, Poland DC, Eikenboom JC, et al: Coagulation parameters of thawed fresh-frozen plasma during storage at different temperatures Transfus Med 17:182–186, 2007 74 Zielinski MD, Johnson PM, Jenkins D, et al: Emergency use of prethawed Group A plasma in trauma patients J Trauma Acute Care Surg 74:69–75, 2013 75 Watson GA, Sperry JL, Rosengart MR, et al: Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and acute respiratory distress syndrome J Trauma 67:221–227, 2009 76 Holcomb JB, Fox EE, Zhang X, et al: Cryoprecipitate use in the Prospective Observational Multicenter Major Trauma Transfusion study (PROMMTT) J Trauma Acute Care Surg 75:S31–S39, 2013 Chapter 38 Trauma Systems DANIEL HETHERMAN • TIMOTHY A EMHOFF INTRODUCTION The number of preventable deaths from traumatic injuries worldwide is unfortunate, numbering in the millions annually In the United States, trauma constitutes a public health crisis and is responsible for over 130,000 lives lost annually Trauma is now the fourth leading cause of death in the United States based on 2013 statistics published by the Centers for Disease Control and Prevention (CDC) It also remains the leading cause of death among those aged 1 to 44 years Trauma represents the second highest potential years of life lost, behind only malignant neoplasms The impact of trauma goes beyond the number of deaths For every death from trauma, there are 20 individuals who are admitted to the hospital and over 200 Emergency Department visits The cost of injuries in terms of lost wages, and direct and indirect medical expenses, is estimated to exceed $400 billion annually [1–3] BACKGROUND Trauma is a time-sensitive disease Classically trauma-related deaths were described in a trimodal fashion Based on this early model, nearly half of all deaths occur immediately at the time of trauma before any medical intervention The second group of patients reflects those who have ongoing bleeding and injuries that require critical care and may need operative intervention This group best demonstrates the timesensitive nature of trauma and is best described by the “Golden Hour” concept Badly injured trauma patients have a “golden hour” during which time they should be transported to a trauma center and their injuries addressed The last group of patients reflects those with late mortality related to complications from this initial traumatic insult and resulting medical care Today, trauma systems are focused on the rapid transport of injured patients to the most appropriate level of care This means transportation to a verified trauma center rather than simply the closest hospital with an emergency department The goal of trauma systems is to get the right patient to the right facility at the right time for the best outcomes DEFINITIONS Typically, trauma patients are individuals suffering from penetrating, blunt, or thermal trauma Combinations of mechanisms may occur, as well as special circumstances such as blast, near drowning, or electrical injuries Trauma patients need to be triaged to the most appropriate facility for care Triage is based both on severity of injuries identified and on the risk of severe injury The potential severity of injuries is important because the total sum of injuries is not known until the patient has been fully evaluated at the appropriate trauma center Hemodynamic normalcy at a given point in time does not assure that the patient will remain that way Trauma centers are hospitals that have been designated by the state or other designating authority as qualified to care for injured patients The American College of Surgeons (ACS) maintains a Verification Review Committee that recommends designation for hospitals at certain levels of care using criteria in their document “Optimal Care of the Injured Patient,” the sixth edition of which was published in 2015 There are usually a small number of trauma centers in a certain geographic area assuring that each receives an adequate volume of patients required to maintain clinical expertise Most frequently, trauma centers are designated as Level I through Level IV (some states have also designated Level V trauma centers) Level I trauma centers provide the highest level of care, plus have research, teaching, and serve as a regional resource Level II trauma centers are intended to also provide for the full spectrum of trauma care, but do not have the research and teaching requirements Level III facilities do not provide the full spectrum of trauma care; they usually do not provide neurosurgical services Level IV trauma centers provide trauma care commensurate with their existing resources and usually function as “points of entry” into the system HISTORY The ACS in the 1920s established a committee to attempt to improve inhospital management of traumatic injuries This committee attempted to set standards for emergency room treatments and practices There was some initial push for more involvement of prehospital first responders, but it was not until 1966, when the National Academy of Sciences and the National Research Council published “Accidental Death and Disability: The Neglected Disease of Modern Society,” that progress was made with prehospital care This paper highlighted trauma as a major public health problem and made specific recommendations to reduce accidental death and disability Subsequent national and state legislation included the Highway Safety Act and the National Traffic and Motor Vehicle Safety Act, which was the first effort to regulate traffic safety and reduce automobile-related death and injuries Then in 1973, the EMS Systems Act identified trauma systems as one of 15 essential components of an EMS system and appropriated federal funds [4] VERIFICATION AND DESIGNATION The trauma system encompasses the complete care of the injured patient from the point of injury prehospital to the completion of the rehabilitative process Important activities of that system include injury prevention, education, research, and financial viability For this, there needs to be a lead agency established by each state that has the authority to create and execute policy for the injured patients, as well as designate the trauma centers to manage the injured patients In order to receive a designation, a hospital or medical center has to demonstrate the standards of care established by the designating authority to achieve their level of trauma center, I, II, III, or IV The trauma center is then evaluated and verified by either an internal team or an external reviewer, such as the ACS, as meeting the necessary criteria to be a trauma center in the system This verification is then recommended to the lead agency of the state for designation of a trauma center The lead agency regulates the quality of trauma systems components and establishes trauma triage guidelines The ACS Committee on Trauma (COT) wrote the “Optimal Hospital Resources for Care of the Seriously Injured” in 1976 and is presently on its sixth edition, now called the “Resources for Optimal Care of the Injured Patient.” Since the ACS established this document, it has served as the standard by which trauma systems function and the quality of care is provided The ACS verification process consists of hospital site reviews to determine a given center’s quality of care and ability to manage seriously injured patients This verification process is then often used by the state as the designating authority to either designate or maintain designation as a trauma center Verification is currently for 3 years: the rationale being that hospital systems are usually in a constant state of flux and must be verified on an ongoing review process The ACS–COT also reviews statewide trauma systems to make recommendations to the system as a whole for regional improvements [5,6] QUALITY OF CARE Early studies of trauma systems in California introduced the concept of preventable mortality These studies were able to clearly identify a group of trauma patients, in nonregionalized trauma system areas, that died from inadequate care—preventable mortalities This concept provided a tool that could be used to examine quality of trauma care in any region or system It became increasingly clear that analyses of data were important for determining quality of care, trends, and preventable mortality Trauma registries emerged as a required part of all ACS-verified trauma centers Aggregations of these hospital-based trauma registries then developed as a result of state-sponsored trauma registries and researchoriented databases With the ability to examine populations of trauma patients came the development of mathematical formulas calculating the probability of survival of an individual trauma patient and comparing quality of care at trauma centers based on patient survival [7] Trauma registries continue to support the advancement of trauma care on a national scale The National Trauma Data Bank (NTDB) is the largest aggregation of trauma patient data It produces yearly reports and establishes benchmarks for patient care The development of the ACS TQIP (Trauma Quality Improvement Program) has allowed individual centers to assess their own outcomes compared to national standards These individualized reports allow institutions to understand areas in which they excel at or need improvement in This focused feedback, compared to national standards, gives trauma centers specific information necessary to make targeted quality improvements National aggregation of trauma patient data has allowed for several organizations to emerge and set guidelines for trauma care AAST (American Association for the Surgery of Trauma), WEST (Western Trauma Association), and EAST (Eastern Association for the Surgery of Trauma) each publish practice guidelines for trauma centers They use the wide breadth of available data to provide trauma centers with best practice guidelines based on available published evidence The ability to implement best practices at trauma centers requires education of both prehospital and hospital providers The ACS–COT develops the prototype Advanced Trauma Life Support Course (ATLS) in 1978 [8] The course has been adopted and managed by the American College as one of the most successful educational programs for doctors worldwide ATLS lays out the framework for the management of trauma patients Every trauma evaluation begins with a primary survey The primary survey consists of an ABCDE assessment In the primary survey, A is for airway, B is for breathing, C is for circulation, D is for disability, and E is for exposure A secondary survey follows, during which a headto-toe physical exam is performed and pertinent history obtained The concept of the primary survey is to identify the most life-threatening problems first and begin treatment immediately The remainder of the ATLS teaches diagnostic and life-saving interventions, as well as emphasizing the need to transfer a seriously injured patient to a trauma center ATLS has been introduced in over 50 countries worldwide and is available in numerous different languages As one examines the challenges and successes of trauma systems, it remains clear that all phases of care are equally important for the successful outcome desired These phases are: A Identification/recognition of incident: The first step in any system is to identify that an injury has occurred or the patient may succumb before medical care can be started This happens not infrequently in rural and remote parts of our country Even if the patient is found and transported to an appropriate trauma center, the delay in care may result in sepsis from open fractures not cared for in a timely manner or organ failure from delays or inadequate resuscitation Some locations in our nation are so remote that even when the injured patient is recognized immediately, it can take more than 24 hours for him or her to arrive in a definitive care facility The risk for poor outcomes is the same in either case B Prehospital care and transport: Prehospital care systems are extremely variable across the United States These systems range from volunteer to government-employed professionals or contracted professionals As the first responders to any accident, these individuals often are the first to provide lifesaving treatment Quality EMS providers provide intensive care in the prehospital setting Pre-Hospital Trauma Life Support (PHTLS) has been developed as a teaching tool for EMS and other prehospital providers to provide education and teaching about care of trauma patients Inadequate or delayed care can have profound effects on outcomes Many trauma systems set up regionalized trauma triage criteria that allow the more critically injured patients to bypass closer facilities in favor of higher-level trauma centers capable of providing more definitive care This regionalization allows more critically injured patients to reach definitive care more quickly This triage process is enabled by the national trauma field triage guidelines These guidelines set up protocols for first responders to assist in the decision-making of when to bypass a closer hospital for a designated trauma center The 2006 national field triage guidelines were reviewed again in 2011 against published data and published as Guidelines for Field Triage of Injured Patients: Recommendations of the National Expert Panel on Field Triage, 2011 [9] C Emergency department (ED) care: The Emergency Department represents the advanced practioners first chance to evaluate trauma patients Even in the ED, inadequate or delayed resuscitation may contribute to a worse outcome This may happen many ways: too slow a resuscitation may result in prolonged hypotension with potential for organ damage—the brain being particularly susceptible Conversely, over aggressive resuscitation in the face of some injuries such as brain injury or pulmonary contusion may also cause problems In these cases, too much resuscitation fluid may result in unnecessary tissue edema This will cause increased intracranial pressure and poor perfusion in the closed space of the skull With the lungs, the leaky capillaries associated with pulmonary contusion will cause the contusion to worsen, with difficulty in ventilating and weaning the patient Too aggressive crystalloid resuscitation in the severely burned puts the patient at increased risk of abdominal compartment syndrome Inappropriate use of strictly crystalloid resuscitation, when blood/blood products are indicated, can lead to increased mortality Systems at individual centers are critical for the timely and effective assessment of the trauma patient At higher-level trauma centers, these systems are often resource-heavy with large teams of staff prepared to quickly evaluate and treat trauma patients However, at smaller or more rural centers, there may be only a small team or an individual practitioner who is charged with this patient’s care At these smaller facilities, prompt stabilization and transfer of critically injured patients to a higher-level center is essential D Operating room (OR) care: Prior to intensive care unit (ICU) admission, many trauma patients will have required operative intervention In the operating room, the trauma surgeon remains the principal manager of resuscitation Although the surgeon is operating, other staff and resources are essential for effective patient care Operating rooms must be capable and prepared with equipment and staff to explore any part of the body necessary Inappropriate or inadequate resuscitation during operative intervention may worsen outcomes As a result, anesthesia plays a critical role in the management of trauma patients in the operating room Many centers have moved to a massive transfusion protocol both in the emergency department and in the operating room to help guide patient fluid management These protocols focus on giving blood and blood products in predetermined ratios to optimize outcomes and trauma patient resuscitation E ICU care: ICU critical care is essential for the management of the sickest trauma patients Any and all organ systems can be adversely affected by trauma, and the ICU is critical in supporting and managing these diverse set of injuries Patients who arrive from the operating room may still be cold, acidotic, or coagulopathic; and it is incumbent on the trauma system to have effective ICU care to manage the significant burden of disease The ICU provides an opportunity to review and compile the data that has been collected to date and continue to evaluate the trauma patient for additional injuries: a socalled “tertiary survey.” Central lines placed urgently in less than sterile conditions are removed and replaced with new sterile lines; blood work and physiologic monitoring are used to provide focused care and to direct care guided by end points of resuscitation Other chapters in this section give details for the care of shock, resuscitation, management of sepsis, multiple organ dysfunction syndrome, traumatic brain injury, spinal cord injury, thoracic and cardiac trauma, abdominal trauma, burn management, and orthopedic injuries F Ward care after leaving the ICU: Critical care trauma patients will need close follow-up on the trauma center wards Sepsis may occur on the floor with MOD syndrome as well The physicians following these patients must be capable of early recognition of these problems and institute immediate therapy when such problems are recognized Highfunctioning trauma systems are not devoid of complications, but they do have systems and processes in place to “rescue” patients when they occur G Rehabilitation: Though many think the rehabilitative process begins after leaving the hospital, it should begin on the first full hospital day Patients need to be mobilized early, and physical and occupational therapy consults should be on the admission orders All patients with even minor head injuries need cognitive testing and evaluation by speech and occupational therapists Even patients on ventilators in the ICU should be part of an early mobilization program Data suggest that these early mobilization programs significantly improve long-term outcomes for trauma patients [10] Any patient with head or spinal cord injuries or with a cluster of serious injuries needs a physical medicine and rehabilitation physician involved with their care early in their hospitalization The discharge plan needs to be formulated early and the resources of the patient and families need to be understood so the maximum benefit of rehabilitation and recovery can be realized Many trauma patients are injured while using drugs or alcohol or owing to suicidal or depressive motives These patients benefit significantly from directed psychiatric or social work interventions regarding their substance abuse issues All seriously injured patients may suffer from posttraumatic stress It is the obligation of the trauma service to address these issues and have social services, counselors, and psychiatric services as part of the team so that the patient has the opportunity for the best possible outcome H Performance improvement: Providing evidence-based care and striving to provide the best care possible is the mission of every trauma service Research, education, and injury prevention are all components of that mission Opportunities for improvement in patient care from specific events or trends in complications must be recognized, dissected, and acted upon to promote quality medical care Trauma registries serve as a central database for data collection and allow for the evaluation of trends and recognition of areas of improvement As part of a verified trauma center, this information is shared with the National Trauma Data Bank at the ACS The information obtained from the trauma center registry feeds an effective PI program Using the information in the NTDB can identify areas of research and areas where injury prevention can be targeted to reduce traumatic injuries The knowledge of which injuries are prevalent in that region will direct the focus of the injury prevention program; from helmet or seat belt use to preventing childhood or elderly falls The wide research activity is encouraged at all trauma centers but is a requirement for Level I centers Finally, ongoing educational programs of all care givers involved with trauma care, including prehospital and rehabilitative services, is ensured as an essential duty of a trauma center and the trauma system DISASTER MANAGEMENT Most disasters are major incidents such as plane crashes, explosions in chemical factories, natural disasters such as hurricanes, or results of war, and terrorist activities such as the events of September 11, 2001 or at the Boston Marathon An effective trauma system should be primed to manage these disasters To successfully manage a disaster with many victims, there needs to be preplanning and organization of resources There needs to be training done within the trauma system, stockpiling of supplies, an effective communication and triage system, and a clear understanding of the resources of each hospital and trauma center in the area Without a trauma system, the wrong facilities would end up with the wrong patients (i.e., a seriously injured patient to a small hospital) or one hospital being overwhelmed while others close by go underused The trauma system needs to predefine the triage of patients of a disaster according to severity of injury and volume of patients The most important principle is triage of the most seriously injured to the higher level of care in the fastest amount of time, and to avoid overtriage of minor injuries to the major trauma center Events such as the Boston Marathon Bombing highlight how an effective regional system allowed for effective care of over 250 injured patients with no in-hospital mortality for the 127 severely injured patients who were cared for at the area’s trauma centers These unfortunate events highlight the need for disaster planning within trauma systems to be prepared both prehospital and within the hospital in order to deal with the large volume of patients and prevent in-hospital mortality [11,12] RURAL TRAUMA The establishment of a trauma system in a rural environment is a unique challenge but important nonetheless to improve outcomes of the injured patients Most of the problems with rural trauma relate to the time to definitive care at a trauma center Studies have shown that rural trauma has a higher rate or mortality than urban trauma, but that those who reach definitive care often have similar outcomes However, because of the rural environment, there is increased discovery time, time for the prehospital personnel to get to the patient, transportation over great distances, and hard terrain Transfer to the highest level of medical center may take hours or even days depending on how remote an area may be To decrease the mortality and morbidity of these patients, the trauma system needs to be firmly established; as also, there is a need to designate and train lower-level trauma centers in areas of sparse population, provide consistent training of the volunteer prehospital personnel, and establish effective communication and transport systems between the prehospital care givers and major trauma centers The American College of Surgeons sponsors specific courses for training in both rural trauma and disaster management—the Rural Trauma Team Development Course (RTTDC) and the Disaster Management and Emergency Preparedness course (DMEP) p 350 p 351 In summary, trauma systems provide for early recognition, prehospital care, resuscitation, and operative care critical care management, longterm care, and rehabilitation Performance improvement remains an essential trauma system function REFERENCES Ten Leading Causes of Death by Age Group, United States 2013 (Chart): Center for Disease Control and Prevention Johnson NB, Hayes, LD, Brown K, et al: CDC National Health Report: leading causes of morbidity and mortality and associated behavior risk and protective factors—United States, 2005-2013 MMWR Surveill Summ 63[Suppl 4]:3–27, 2014 Injury Prevention & Control: Data & Statistics (WISQARS™): Cost of Injuries Report 2010 Center for Disease Control and Prevention Simpson AT: Transporting Lazarus: physicians, the State and the creation of the Modern Paramedic and Ambulance, 1955-73 J His Med Allied Sci 68(2):163–197, 2013 Committee on Trauma, American College of Surgeons: Resources for Optimal Care of the Injured Patient 2014 Chicago: American College of Surgeons, 2014 Celso B, Tepas J, Langland-Orban B, et al: A systematic review and meta-analysis comparing outcome of severely injured patients treated in trauma centers following the establishment of trauma systems J Trauma 60(2):371–378, 2006 Cales RH, Trunkey DD: Preventable trauma deaths JAMA 254(8):1049–1053, 1985 American College of Surgeons Advanced Trauma Life Support for Doctors 9th ed Chicago: American College of Surgeons, 2012 Centers for Disease Control and Prevention: Guidelines for field triage of injured patients: recommendations of the national expert panel on field triage, 2011 MMWR Morb Mortal Wkly Rep 61(1):1–21, 2012 10 Adler J, Malone D: Early mobilization in the intensive care unit: a systematic review Cardiopulm Physi Ther J 23(1):5–13, 2012 11 Lennquist S: Management of major accidents and disasters: an important responsibility for the trauma surgeons J Trauma 62(6):1321–1329, 2007 12 Gates JD, Arabian S, Biddinger P, et al: The initial response to the Boston Marathon Bombings: lessons learned to prepare for the next disaster Ann Surg 260(6):960–966, 2014 13 Fatovich DM, Phillips M, Langford SA, et al: A comparison of metropolitan vs rural major trauma in Western Australia Resuscitation 82(7):886–890, 2011 Chapter 39 The Management of Sepsis PAUL E MARIK Sepsis is among the most common reasons for admission to ICUs throughout the world An epidemiologic study in European ICUs demonstrated a prevalence of 37% for sepsis and 30% for severe sepsis [1] The incidence of severe sepsis in the United States is estimated to be about 300 cases per 100,000 population [2–4] Sepsis is reported to be more common in men and among non-White persons [3] Surgical patients account for nearly one-third of sepsis cases in the United States; this is important as the management of “surgical” and “medical sepsis” differs somewhat Patients who have had a septic episode are at an increased risk of death for up to 5 years following the acute event [5] Data from 2004 to 2009 demonstrate a 13% average annual increase in the incidence of severe sepsis with a decrease in in-hospital mortality from 35% to 26% [2] This study estimated that there were 229,044 deaths from severe sepsis in 2009, which would place severe sepsis as the third most common cause of death in the United States, after heart disease and malignant neoplasms [2] However, several factors including international classification of disease (ICD) coding rules, the use of administrative data sets, and increased awareness and surveillance confound the interpretation of these epidemiologic data [6,7] In 1987, the Australian and New Zealand Intensive Care Society (ANZICS) developed a high-quality database that prospectively collects data from all patients admitted to 171 ICUs in Australia and New Zealand [8] An analysis of this database demonstrates a linear decrease in absolute mortality for severe sepsis and septic shock from 35% in 2000 to 16.7% in 2012, with an annual rate of absolute decrease of 1.3% [9] It should be noted that the Surviving Sepsis Campaign was not endorsed by ANZICS and was poorly adopted in these two countries [10] While it has been claimed that the Surviving Sepsis Campaign has contributed to the decline in mortality from sepsis around the world [11,12], this is clearly not the case for Australia and New Zealand Furthermore, the decline in mortally from severe sepsis and septic shock in the United States was evident long before the “adoption” of the Surviving Sepsis Campaign [3] It is likely that the earlier recognition and treatment of sepsis as well as advances in ICU care (lung-protective ventilation, conservative blood strategy, etc) are largely responsible for the improved outcomes of patients with sepsis This chapter will provide an overview of sepsis with particular emphasis on the diagnosis and management of severe sepsis and septic shock DEFINITIONS The word “sepsis” is derived from the ancient Greek word for rotten flesh and putrefaction Since then, a wide variety of definitions have been applied to sepsis, including sepsis syndrome, severe sepsis, bacteremia, septicemia, and septic shock In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) developed a new set of terms and definitions to define sepsis in a more “precise manner” [13] These definitions took into account the findings that sepsis may result from a multitude of infectious agents and microbial mediators and may not be associated with detectable bloodstream infection The term “systemic inflammatory response syndrome” (SIRS) was coined to describe the common systemic response to a wide variety of insults Four SIRS criteria were defined, namely tachycardia (heart rate >90 beats per minute), tachypnea (respiratory rate >20 breaths per minute), fever or hypothermia (temperature >38°C or less than 36°C), and leukocytosis, leukopenia, or bandemia (WBC >1,200 per μL, 38.3°C or hypothermia (120 per minute (sinus tachycardia) Systolic BP 0.5 ng per mL Bandemia >5% Lymphocytopenia 10:1) MANAGEMENT OF SEPSIS The optimal management of patients with severe sepsis and septic shock is highly controversial It is important to emphasize that there is no Level 1 evidence (data from two or more adequately powered randomized controlled trials (RCTs) or a meta-analysis of RCTs) that demonstrates that any intervention reduces the mortality of patients with severe sepsis or septic shock Multiple large RCTs have attempted to modulate the immune response or coagulation cascade in patients with severe sepsis and septic shock; these studies have universally met with failure Although the timely administration of appropriate antibiotics and adequate source control are considered the cornerstones of the management of patients with severe sepsis and septic shock, no RCTs have been performed (or are likely to be performed) that demonstrate the benefit of these interventions Furthermore, the narrow time window for the administration of antibiotics as advocated by the Surviving Sepsis Campaign Guidelines (administration within 3 hours of Emergency Department triage and within 1 hour of severe sepsis/septic shock recognition) is not supported by a meta-analysis of cohort studies that investigated this issue [81] This section will focus on appropriate antibiotic therapy, hemodynamic management, source control, and adjunctive therapies that may be of potential benefit in patients with severe sepsis and septic shock Antimicrobial Therapy Empiric intravenous antibiotic therapy should be started as soon as possible after appropriate cultures have been obtained Although the tight window as suggested by the Surviving Sepsis Campaign is not supported by scientific evidence, common sense would dictate that delaying the administration of antibiotics serves no useful purpose The choice of antibiotics is largely determined by the source or focus of infection, the patient’s immunologic status, whether the patient has risk factors for a drug-resistant pathogen (DRP) as well as knowledge of the local microbiology and sensitivity patterns Initial empiric anti-infective therapy should include one or more drugs that have activity against the likely pathogens and that penetrate into the presumed source of sepsis site Because the identity of the infecting pathogen(s) and its sensitivity pattern(s) are unknown at the time of initiation of antibiotics, for patients with severe sepsis and septic shock the initial regimen should include two or more antibiotics or an extended spectrum β-lactam antibiotic A number of studies have demonstrated that appropriate initial antimicrobial therapy, defined as the use of at least one antibiotic active in vitro against the causative bacteria, is associated with a lower mortality when compared with patients receiving initial inappropriate therapy [82,83] Once a pathogen is isolated, monotherapy is adequate for most infections; this strategy of initiating broad-spectrum cover with two or more antibiotics and then narrowing the spectrum to a single agent when a pathogen is identified is known as “antimicrobial de-escalation” [84] Antimicrobial de-escalation has been demonstrated to be associated with lower rates of hospital mortality [85] The indications for continuation of double-antimicrobial therapy include enterococcal infections and severe intra-abdominal infections In order to rapidly achieve adequate blood and tissue concentrations, antibiotics should be given intravenously, at least initially p 354 p 355 Inappropriate initial antibiotic therapy is usually associated with infection with a DRP The following factors have been shown to increase the risk of infection with a DRP, with this risk increasing with the number of risk factors: hospitalization >2 days in the previous 90 days, antibiotics during the previous 90 days, nonambulatory status, patients receiving tube feeds, immunocompromised status, acid suppressive therapy, chronic hemodialysis in the preceding 30 days, infection or colonization with methicillin-resistant Staphylococcus Aureus (MRSA) in the previous 90 days, and current hospitalization >2 days [86] With the widespread use of antibiotics, a group of pathogens have emerged that are resistant to multiple antibiotics These pathogens, referred to as the “ESKAPE bugs,” have emerged in hospitals in both the developing and the developed world and are the most important DRPs encountered in clinical practice [87,88] The ESKAPE pathogens include Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species Antimicrobial classes for which resistance has become a major problem for the ESKAPE pathogens include β-lactams, the glycopeptides (vancomycin), and fluoroquinolones [89] The appropriate length of antibiotic treatment for patients with sepsis has not been well established, with marked variation between and within different countries and healthcare settings, independent of factors such as disease severity [90] Christ-Crain and colleagues randomized 302 patients with community-acquired pneumonia to usual care or antibiotic therapy guided by PCT [91] In the PCT group, antibiotics were discontinued when the PCT fell to less than 0.25 μg per mL or if the PCT fell by more than 10% in patients with high PCT values on admission (PCT > 10 μg per mL) The median duration of antibiotics use was 5 days in the PCT group as compared with 12 days in the usual care group (p < 0.001) There were no differences of outcomes between the two groups A meta-analysis by the Cochrane group compared a short 7- to 8-day course of antibiotics with a prolonged 10- to 15-day course in patients with ventilator-associated pneumonia (VAP) [92] This meta-analysis, which included eight studies, demonstrated a reduced recurrence of VAP caused by multi-resistant organisms for the short-course group (OR 0.44; 95% CI 0.21 to 0.95) without adversely affecting other outcomes Sawyer et al [93] randomized 518 patients with complicated intra-abdominal infection and adequate source control to receive antibiotics until 2 days after resolution of fever, leukocytosis, and ileus with a maximum of 10 days or to receive a fixed course of antibiotics for 4 ± 1 days In this study, there were no differences for any of the outcomes studied between the two dosing strategies These data suggest that a 5- to 8-day course of antibiotics is adequate for most patients with sepsis who received initial appropriate therapy and have had a good clinical response, with no evidence of infection with a DRP Patients infected with a DRP generally require 10 to 14 days of treatment The trend in the PCT level may further aid in determining when it is safe to discontinue antibiotics Hemodynamic Support On November 8, 2001, Emanuel Rivers and collaborators published a study entitled “Early Goal Directed Therapy in the treatment of severe sepsis and septic shock,” in which they compared two protocols for the early resuscitation of patients with severe sepsis and septic shock (for 6 hours in the Emergency Department) [49] Both protocols used the CVP to guide fluid therapy (target CVP > 8 mm Hg) The “treatment arm” (EGDT) required placement of an oximetric central venous catheter with protocolized interventions to maintain the saturation of the central venous oxygen (ScvO2) >70% The study, which enrolled 288 patients (25 were excluded after the fact), reported a 28-day mortality of 49.2% in the control group and 33.3% in the EGDT group (p = 0.01, with an absolute reduction of the risk of death of 16%) Within a short time, this small (severely underpowered), unblinded, single-center study came to be considered the standard of care around the world and formed the basis of the 6-hour resuscitation bundle of the 2004, 2008, and 2012 Surviving Sepsis Campaign Bundles [50,94,95] However, soon after publication of the EGDT study, concerns were raised regarding the validity of the protocol as well as the conduct and reporting of the study [96–101] The basic premise of EGDT was to optimize tissue oxygen transport to reverse tissue hypoxia with the use of continuous monitoring to prespecified physiologic targets This premise is flawed as bioenergetic failure and cellular hypoxia are likely only preterminal events in patients with septic shock [102,103] Most importantly, none of the elements of the protocol were supported by strong scientific evidence [96–101]; notably, the CVP is a poor reflection of volume status and fluid responsiveness, patients with sepsis usually have a high rather than a low ScvO2, with a high rather than a low ScvO2 being predictive of a poor outcome, that transfusing patients with a hemoglobin >7 g per dL is likely to be harmful and that driving up oxygen delivery (DO2) without regard to cardiac function is potentially harmful In 2014, 13 years after the publication of the EGDT study, the ProCESS and ARISE studies were published [104,105], with PROMISE the final of the Trilogy of large multicenter RCTs being published in 2015 [106] ProCESS, ARISE, and PROMISE demonstrated that EGDT did not improve outcomes for patients with severe sepsis and septic shock Patients in the EGDT arm of PROMISE had worse organ-failure scores, a longer stay in the ICU with increased use of resources, and increased costs [106] A meta-analysis of EGDT, which included the ProCESS, ARISE, and PROMISE studies, concluded that “EGDT is not superior to usual care for Emergency Department patients with septic shock but is associated with increased utilization of ICU resources” [107] ProCESS, ARISE, and PROMISE together with this meta-analysis have now clearly established that we should move beyond EGDT This does not mean that the approach to the management of sepsis does not matter! Patients with sepsis should be managed by a thoughtful individualized approach based on an understanding of human physiology, the pathophysiologic changes that occur with sepsis, the patients’ comorbidities, and the best clinical evidence p 355 p 356 Fluid Therapy Beyond the early administration of antibiotics, aggressive “supportive measures” may be harmful, and the “less is more” paradigm appears applicable for the management of patients with severe sepsis In these highly vulnerable patients, more intensive treatment may promote the chances of unwanted adverse effects and hence iatrogenic injury [108] Current teaching suggests that aggressive fluid resuscitation is the best initial approach for the cardiovascular instability of sepsis Consequently, large volumes of fluid (10 to 15 L) are often infused in the early stages of sepsis There is, however, no human data that large fluid boluses (>30 mL per kg) reliably improves blood pressure, urine output, or end-organ perfusion [109,110] This approach is likely to lead to “iatrogenic salt water drowning” with severe ARDS, AKI, and death [111] The only reason to give a patient a fluid bolus is to increase stroke volume (SV) If the fluid bolus does not increase SV, the fluid bolus serves the patient no useful purpose and may be harmful This concept is referred to as “fluid responsiveness” [112,113] By definition, a patient is considered to be fluid responsive if his or her SV increases by ≥10% following a fluid challenge (usually 500 mL crystalloid) The chest radiograph, CVP, central venous oxygen saturation (ScvO2), and ultrasonography, including the vena-caval collapsibility index, have limited value in guiding fluid management and should not be used for this purpose [114–119] The passive leg raising maneuver (PLR) or a fluid challenge coupled with real-time SV monitoring are accurate methods for determining fluid responsiveness [112,120,121] Multiple studies of diverse populations of patients have demonstrated that only about 50% of hemodynamically unstable patients are fluid responsive [112,113] This implies that for about 50% of hemodynamically unstable patients, fluid boluses may be harmful [111] This challenges the “well established” notion in critical care medicine, anesthesiology, and emergency medicine that fluid boluses are the “cornerstone of resuscitation.” Owing to increased diastolic compliance and an increase in the unstressed blood volume of septic patients, it is likely that less than 50% of patients with severe sepsis and septic shock are fluid responsive [122] Large fluid boluses further decrease diastolic compliance of the ventricles, causing the CVP to increase more than the mean circulating filling pressure (MCFP), paradoxically decreasing the gradient for venous return [122,123] Furthermore, the increased CVP is transmitted backward, increasing venous pressure, which can impair organ function and microcirculatory flow, particularly for encapsulated organs such as the kidney and liver [111] To make matters worse, the hemodynamic response to fluids in patients with circulatory shock is small and short lived (less than an hour) because most (about 90% to 95%) of the fluid leaks into the tissues [124–127] Glassford and colleagues performed a systematic review that examined the hemodynamic response of fluid boluses in patients with sepsis [128] These authors reported that while the mean arterial pressure (MAP) increased by 7.8 ± 3.8 mm Hg immediately following the fluid bolus, the MAP had returned close to baseline at 1 hour with no increase in urine output Although having a minimal effect on blood pressure, fluid boluses may cause a fall in effective arterial elastance and systemic vascular resistance, potentiating arterial vasodilatation and the hyperdynamic state characteristic of septic shock [129,130] These data suggest that the majority of patients with severe sepsis and septic shock are not fluid responders The hemodynamic changes of the fluid responders are small, short lived, and likely to be clinically insignificant Furthermore, overaggressive fluid resuscitation will likely have adverse hemodynamic consequences including an increase in cardiac filling pressures, damage to the endothelial glycocalyx, arterial vasodilation, and tissue edema Consequently, the concept that aggressive fluid resuscitation is the “cornerstone of resuscitation” of patients with severe sepsis and septic shock should be reconsidered [50,94,95,131] The harmful effects of overaggressive fluid resuscitation on the outcome of sepsis are supported by experimental studies as well as data accumulated from clinical trials [132,133] Multiple clinical studies have demonstrated an independent association between an increasingly positive fluid balance and increased mortality in patients with sepsis [1,45,134–141] In a secondary analysis of the Vasopressin in Septic Shock Trial (VASST), Boyd and colleagues demonstrated that a greater positive fluid balance at both 12 hours and 4 days were independent predictors of death [141] Kelm and colleagues [142] evaluated the fluid status and outcome of 405 patients with severe sepsis and septic shock who were admitted to the Mayo clinic and treated with EGDT In this study, 67% of patients had clinical evidence of fluid overload at 24 hours with 48% having evidence of fluid overload at 72 hours Fluid overload was an independent predictor of mortality (odds ratio of 1.92; 95% confidence interval of 1.16 to 3.22) The most compelling data that fluid loading for sepsis is harmful comes from the landmark “Fluid Expansion as Supportive Therapy (FEAST)” study performed in 3,141 sub-Saharan children with severe sepsis [143] In this randomized study, aggressive fluid loading was associated with a significantly increased risk of death Nevertheless, despite data suggesting that “aggressive fluid resuscitation” is associated with adverse outcomes and no randomized trials to indicate that this approach improves patient outcomes, the updated Surviving Sepsis Campaign Guidelines, published in April of 2015, mandates the administration of “30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L” within 3 hours of presentation to hospital [114] In summary, these data support a “conservative” hemodynamically guided fluid resuscitation strategy in patients with severe sepsis and septic shock From an evolutionary point of view, humans have evolved to deal with hypovolemia and not hypervolemia Large fluid boluses may counter the live preserving homeostatic mechanisms of unstable critically ill patients, increasing the risk of death [144] For some patients, hypotension and tachycardia do resolve with limited fluid resuscitation It is likely that many of these patients have super-added dehydration owing to poor oral intake and a delay in seeking medical attention However, fluids alone will not reverse the hemodynamic instability of patients with more severe sepsis; for these patients, fluids alone are likely to exacerbate the vasodilatory shock and increase the capillary leak and tissue edema On the basis of these data, the initial resuscitation of patients with septic shock should logically include 500 mL boluses of crystalloid (Ringers Lactate) to a maximum of about 20 mL per kg [145] Ideally, fluid resuscitation should be guided by the determination of fluid responsiveness [112,146] Norepinephrine should be initiated in those patients who remain hypotensive (MAP < 65 mm Hg) despite this initial limited fluid strategy (see below) [145,147] The septic patient with an intra-abdominal catastrophe who requires urgent surgical intervention represents one subgroup of patients that may require more aggressive fluid resuscitation However, overly aggressive fluid resuscitation can result in intra-abdominal hypertension, which is associated with a high risk of complications and death [148,149] For these patients, continuous SV monitoring is helpful, and ongoing fluid requirements should be guided by the trend in the SV as well as the hemodynamic response to small volume fluid boluses In addition, perioperative intra-abdominal pressure monitoring is required in these patients [148] p 356 p 357 The choice of fluid in patients with severe sepsis and septic shock is controversial Normal saline (0.9% NaCl) is the most widely used crystalloid around the world However, normal saline is an unphysiologic solution that is associated with a number of adverse effects Normal saline causes a hyperchloremic metabolic acidosis [150–153]; it decreases renal blood flow [154] and increases the risk of renal failure [155] In patients with sepsis, the use of normal saline as compared with physiologic salt solutions has been associated with an increased risk of death [156] The SPLIT trial was a randomized double-blind, cluster randomized, double-crossover trial conducted in four ICUs in New Zealand that compared 0.9% Saline with Plasma-Lyte 148 for ICU fluid therapy [157] The risk of AKI (primary outcome) as well as of all secondary outcomes did not differ between the two fluid groups This study, however, has a number of significant limitations that preclude widespread generalizability of the results; most notably, 71% of patients were postoperative patients, only 4% were diagnosed with sepsis, and the volume of fluid administered was small (about 2.7 L in the first 4 days) Nevertheless, despite the findings of the SPLIT study, 0.9% Saline has no advantages over balanced salt solutions (except in patients with acute necrologic insults) and is best avoided Synthetic starch solutions increase the risk of renal failure and death in patients with sepsis and should be avoided [158,159] The role of albumin for patients with sepsis is widely debated [160] Nevertheless, the use of 4% albumin in patients with sepsis was associated with a survival benefit in the SAFE study [161] In the ALBIOS study, hyperoncotic albumin (20%) was associated with a survival benefit in patients with septic shock [162] It should be noted that exogenous albumin is one of the few therapies that can restore the endothelial glycocalyx in experimental systems [163] We recommend the use of hyperoncotic albumin (20% or 25%) in patients with “resuscitated” septic shock who have a serum albumin of less than 3 g per L Hyperoncotic albumin should not be given as a bolus because this form of administration will paradoxically dehydrate the glycocalyx If a 20/25% albumin is used to stabilize the glycocalyx, it may be preferable to give this as a continuous infusion at a rate of 10 to 20 mL per hour Vasopressors and Inotropic Agents A low MAP is a reliable predictor for the development of organ dysfunction When the MAP falls below an organ’s autoregulatory threshold, organ blood flow decreases in an almost linear fashion [164] Because the autoregulatory ranges of the heart, brain, and kidney are above 60 mm Hg [164], an MAP below this level will likely result in organ ischemia and death [165] Varpula and colleagues studied the hemodynamic variables associated with mortality of patients with septic shock [166] These authors calculated the area under the curve (AUC) for various MAP thresholds over a 48-hour time period The highest AUC values were found for an MAP < 65 mm Hg (AUC 0.83, 95% CI 0.772 to 0.934) Owing to the shift of the autoregulatory range (to the right) in patients with chronic hypertension, a higher MAP may be required in these patients In the SEPSISPAM study (The Assessment of Two Levels of Arterial Pressure on Survival in Patients with Septic Shock), patients with septic shock were randomized to achieve a target MAP of 65 to 70 or 80 to 85 mm Hg The primary outcome was 28-day mortality Secondary outcomes included 90-day mortality and organ failure A priori a secondary analysis was planned in patients with and without a history of hypertension Overall, there was no difference in either primary or secondary end-point between the two treatment groups However, the incidence of organ failure (particularly renal dysfunction) was higher in the subgroup of patients with chronic hypertension in the lower MAP group Furthermore, much like the Varpula study, the time below the 65 mm Hg (but not 80 mm Hg) threshold was an independent predictor of death On the basis of these data, we suggest targeting an initial MAP of 65 to 70 mm Hg for patients with septic shock Among those patients with a history of chronic hypertension, it may be preferable to target a slightly higher MAP (80 to 85 mm Hg) [167] Norepinephrine is the vasopressor of choice for patients with septic shock [145,168] Dopamine increases the risk of arrhythmias and death and should be avoided [168–170] Similarly, phenylephrine is not recommended as the first-line vasopressor because in experimental models it decreases cardiac output as well as renal and splanchnic blood flow [171] Furthermore, phenylephrine has not been as well studied in patients with sepsis In patients with septic shock, norepinephrine restores the stressed blood volume, increasing the MCFP, venous return, and cardiac output Norepinephrine increases arterial vascular tone, further increasing blood pressure and organ blood flow [145] Venous capacitance vessels are much more sensitive to sympathetic stimulation than are arterial resistance vessels, and consequently, low-dose α1 agonists cause greater veno- than vasoconstriction [172] The increase in the stressed blood volume following the use of norepinephrine is caused by the mobilization of blood rather than a short-lived volume expander (crystalloid) [173] Therefore, unlike fluids, the effect of α1 agonists on venous return is enduring and not associated with tissue edema The early use of norepinephrine in patients with septic shock can increase preload, rendering the fluid-responsive patient fluid unresponsive [172] This may allow the target blood pressure to be achieved and a significant reduction in the amount of fluid administered Hamzaoui et al [174] have demonstrated that the early administration of norepinephrine increased preload, cardiac output, and MAP, largely reversing the hemodynamic abnormalities of severe vasodilatory shock Abid and colleagues demonstrated that the early use of norepinephrine in patients with septic shock was a strong predictor of survival [175] It is noteworthy that norepinephrine may be safely given through a well-functioning peripheral venous catheter [176], precluding the requirement for emergent central venous catheterization, which is generally regarded as an obstacle to the early use of norepinephrine For patients with “refractory septic shock” who remain hypotensive despite an adequate dose of norepinephrine (approximately 0.1 to 0.2 μg/kg/min), we recommend further hemodynamic assessment to exclude severe systolic ventricular dysfunction, which between 10% and 20% of patients experience Ventricular function is best assessed by bedside echocardiography and confirmed by minimally invasive cardiac output monitoring Dobutamine at a starting dose of 2.5 μg/kg/min is recommended for patients with significant systolic ventricular dysfunction (milrinone is an alternative agent) [177] The dose of dobutamine should be titrated to hemodynamic response as determined by minimally invasive cardiac output monitoring [177,178] For patients with persistent hypotension and hyperdynamic ventricular function (who have severe failure of vasomotor tone), fixed-dose vasopressin (0.03 units per minute) should be initiated Vasopressin reverses the “relative vasopressin deficiency” seen among patients with septic shock and increases adrenergic sensitivity [32,179] Terlipressin is an alternative (although not FDA approved in the United States) [180,181] The VASST trial randomized patients with septic shock to norepinephrine alone or norepinephrine plus vasopressin at 0.03 units per minute [182] By intention-to-treat analysis, there was no difference in outcome between the groups However, an a priori defined subgroup analysis demonstrated that survival among patients receiving 0.2 μg/kg/min We therefore suggest the addition of vasopressin at a dose of norepinephrine between 0.1 and 0.2 μg/kg/min Thereafter, the dose of norepinephrine should be titrated to achieve an MAP of at least 65 mm Hg p 357 p 358 β-Blockers and Phenylephrine for Septic Shock As part of the stress response of patients with sepsis and septic shock, there is massive sympathetic activation with very high levels of circulating catecholamines [183] Septic patients often have an elevated heart rate, even after excluding common causes of tachycardia such as hypovolemia, fever, pain, and agitation The volume-depleted patient’s tachycardia constitutes the main mechanism that compensates for the decrease in SV However, persistence of tachycardia after fluid resuscitation (patients who are no longer fluid responsive) may indicate an inappropriate degree of sympathetic activation Persistent tachycardia has been demonstrated to be a poor prognostic sign in patients with sepsis [184] In 1987, Parker and colleagues reported that an initial heart rate of 95 beats per minute to an infusion of esmolol (short-acting β1-selective β blocker) or placebo The esmolol was titrated to achieve a heart rate between 80 and 94 beats per minute Twenty-eight-day mortality was 49.4% in the esmolol group versus 80.5% in the control group (HR 0.39; CI 0.26 to 0.59; p < 0.001) For the patients receiving esmolol, there was a significant increase in the Left Ventricular Stroke Work Index (LVSWI) and Stroke Volume Index (SVI) It is important to emphasize that a highly select group of patients were enrolled into this study; these patients may represent only a small fraction of patients presenting with sepsis The mortality in the control group was higher than that of any study published in the last two decades Echocardiography was not performed, and it is therefore unclear how many patients had severe isolated diastolic dysfunction In addition to attenuating the stress response, β-blockers modulate cytokine production, decrease energy expenditure, and modulate protein, fat, and carbohydrate metabolism β-blockers should be avoided during the initial resuscitation of patients with severe sepsis/septic shock, patients who are fluid responsive, and patients with predominant systolic LV dysfunction β-blockers may have a role in the tachycardic septic patient with significant LV diastolic dysfunction It would appear to be counterintuitive to simultaneously use an infusion of norepinephrine (β1, β2, α1 agonist) and esmolol In this situation, it would appear more rational to use phenylephrine (α1 agonist) to achieve arterial and venoconstriction together with esmolol (for improvement of diastolic dysfunction) Only a short-acting β-blocker should be used (esmolol), its dose closely titrated and the effects of this combination on cardiac output, blood pressure, and SV closely monitored β-blockers should be used only for patients who are fluid nonresponsive, for patients undergoing continuous SV monitoring, and after echocardiography has excluded systolic dysfunction Resuscitation End Points A large number of hemodynamic, perfusion, oxygenation, and echocardiographic targets have been proposed as resuscitation goals in patients with severe sepsis and septic shock [50,189,190] Most of these targets, however, are controversial and not supported by outcomes data The 2012 and updated 2015 Surviving Sepsis Campaign Guidelines recommend a CVP of 8 to 12 mm Hg (12 to 15 mm Hg if mechanically ventilated), a central venous oxygen saturation (ScvO2) > 70%, and a urine output > 0.5 mL/kg/h as targets for resuscitation [50,114] As already discussed, targeting a CVP >8 mm Hg may be harmful and, as demonstrated by the ProCESS, ARISE, and PROMISE trials, targeting a ScvO2 >70% does not improve patient outcomes [104–106] Although urine output may be a valuable marker of renal perfusion in hypovolemic states, this clinical sign becomes problematic for sepsis-associated AKI, where experimental models suggest that oliguria occurs in the presence of marked global renal hyperemia [191–193] Titration of fluids to urine output may therefore result in fluid overload Furthermore, the Surviving Sepsis Campaign guideline recommends “targeting resuscitation to normalize lactate in patients with elevated lactate levels as a marker of tissue hypoperfusion” [50] This recommendation is based on the notion that an elevated lactate is a consequence of tissue hypoxia and inadequate oxygen delivery [194] and is “supported” by two studies that used “lactate clearance” as the target of resuscitation [195,196] However, the concept that sepsis is associated with tissue hypoxia is unproven and possibly incorrect [103,197,198] Increasing oxygen delivery for patients with sepsis is often not associated with increased oxygen consumption [197,199,200] Previous studies have demonstrated that targeting supramaximal oxygen delivery does not improve outcome and may be harmful [201,202] Furthermore, in the study by Morelli et al [188], oxygen delivery was reduced in the esmolol arm as compared with control patients, yet the lactate concentration decreased among esmolol arm subjects, whereas it increased for control arm patients Although the lactate concentration is an important marker of severity of illness and the trend in lactate may be useful in prognostication, attempts to titrate treatment modalities to a lactate concentration may not be grounded on sound physiologic concepts [197,198] The updated Surviving Sepsis Campaign Guidelines [114], which are now mandated by law in the United States (National Quality Forum Measure #0500 [203], Center for Medicare and Medicaid Services SEP-1 Quality measure), require reassessment of volume status and tissue perfusion (after a 30 mL per kg fluid bolus) with either: “repeat focused exam by a licensed independent practitioner including vital signs, cardiopulmonary refill, pulse and skin findings” (all these clinical findings) or two of the following: CVP, ScvO2, bedside cardiovascular ultrasound, or dynamic assessment of fluid responsiveness with passive leg raise or fluid challenge However, it has been well established that the chest radiograph, CVP, ScvO2, and ultrasonography, including the venacaval collapsibility index, have very limited value for guiding fluid management and should not be used for this purpose [115–119,204] Furthermore, it has been well established that physical examination cannot be used to predict fluid responsiveness and that physical examination is unreliable for estimating intravascular volume status [205] These data suggest that achieving an MAP of at least 65 mm Hg should be the primary target for the resuscitation of patients with septic shock Furthermore, while attempts to achieve a supranormal cardiac index may be potentially harmful, we would suggest targeting a normal cardiac index (> 2.5 L/min/m2) [201] Although a falling arterial lactate concentration is a sign that the patient is responding to therapy (attenuation of the stress response), titrating therapy to a lactate concentration may not be grounded on sound physiologic principles [197,200] Additional end points of resuscitation remain unproven at this time p 358 p 359 Source Control It has been known for centuries that unless the source of the infection is controlled, the patient is often not cured of his/her infective process and that death will eventually ensue It is important that specific diagnoses of infection that require emergent source control be made in a timely manner (e.g., necrotizing soft-tissue infection, peritonitis, cholangitis, intestinal infarction) and surgical consultation be immediately obtained [50,206] When source control is required for a severely septic patient, the effective intervention associated with the least physiologic insult should be used (e.g., percutaneous rather than surgical drainage of an abscess) [50,207] In patients with “urosepsis,” an emergent renal ultrasound or abdominal CT scan should be obtained to exclude urinary tract obstruction, because urgent decompression of the urinary system is required for patients with evidence of obstruction If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established [83] Adjunctive Therapies A myriad of adjunctive novel pharmacologic agents and interventions have been investigated in patients with severe sepsis and septic shock To date, none of these therapies have consistently been demonstrated to improve patient outcomes Ongoing issues that remain controversial include the use of corticosteroids, glycemic control, and nutritional interventions Corticosteroids The use of low-dose corticosteroids in patients with severe sepsis remains controversial [208] It has been proposed that inadequate cellular glucocorticoid activity (Critical Illness Related Corticosteroid Insufficiency) caused by either adrenal suppression or glucocorticoid tissue resistance results in an exaggerated and protracted proinflammatory response [209] In addition to downregulating the proinflammatory response and modulating the anti-inflammatory response, corticosteroids may have additional beneficial effects including increasing adrenergic responsiveness [210] and preserving the endothelial glycocalyx [211] Although there are divergent recommendations and large geographic variations in the prescription of glucocorticoids, up to 50% of patients with severe sepsis and septic shock receive such therapy [212] A recent comprehensive meta-analysis that included a trial sequential analysis found no “evidence to support or negate the use of steroids in any dose in sepsis patients” [213] Consequently, the use of glucocorticoids for patients with sepsis remains unclear Currently, the Australian and New Zealand Intensive Care Society Clinical Trials Group are performing the ADRENAL study, in which 3,800 patients with septic shock will be randomized to receive hydrocortisone (200 mg per day as a continuous infusion) versus placebo [214] The outcome of this study will, hopefully, resolve this ongoing therapeutic dilemma Nutritional Support Current Clinical Practice Guidelines (CPG) emphasize early (within 24 to 48 hours of ICU admission) normocaloric enteral nutrition (daily caloric intake estimated to match 80% to 100% of energy expenditure) [215–218] However, a number of recent RCTs have failed to demonstrate an improvement in the outcomes for critically ill patients receiving a normocaloric feeding protocol as opposed to a strategy of intentional hypocaloric feeding Indeed, a meta-analysis that compared trophic and permissive underfeeding with normocaloric nutrition (included six RCTs) reported no difference in the risk of secondary infections, ventilator-free days, hospital mortality, or ICU length of stay [219] Early feeding may be particularly harmful for patients with sepsis Anorexia is an evolutionary preserved acute host response to infection and is likely beneficial to the host Complex and redundant pathways have evolved to ensure that the host develops anorexia during acute septic insults Folklore that dates back to the 16th century suggests that “fasting is a great remedy for fever” [220] The mechanisms whereby decreased nutrient intake is protective and promotes survival during acute illness are not entirely clear The acute phase response is associated with a dramatic fall in serum iron concentrations [221] Iron is an essential element required for the survival of many pathogens, and iron deprivation retards bacterial growth [222] Food restriction results in a dramatic reduction of iron in the liver and serum of a variety of organisms [223] It has been postulated that fever and iron deprivation act synergistically to inhibit bacterial growth [224] Starvation promotes autophagy, and this may play a key role in promoting host defenses [225,226] Autophagy is a component of innate immunity and is involved in host defense elimination of pathogens [226] Autophagy contributes to immune response against intracellular bacteria, parasites, and viruses [227] Autophagy plays a role in the degradation of both extracellular bacterial pathogens that invade the cell (e.g., group A Streptococcus) and true intracellular bacterial pathogens (e.g., Mycobacterium tuberculosis and Shigella flexneri) [228] These data suggest that it may be beneficial to withhold enteral nutrition for the first 24 to 48 hours in patients with severe sepsis Randomized controlled trials proving that starvation is detrimental to critically ill and injured patients have until recently not been performed This is likely because of the lack of equipoise by researchers and the notion that such an experiment would be unethical However, recently, the Dutch Pancreatitis Study Group reported the results of the “Early versus On-Demand Nasoenteric Tube Feeding in Acute Pancreatitis study (PYTHON trial)” [229]; this study comes close to an RCT comparing initial starvation followed by an ad libitum diet with early enteral nutrition administered via a feeding tube In this study, patients with acute severe pancreatitis were randomly assigned to nasoenteric tube feeding within 24 hours after randomization or to an oral diet initiated 72 hours after presentation with tube feeding provided the oral diet was not tolerated There was no difference in any of the outcome variables between the two groups Furthermore, there was no difference between the levels of CRP or the SIRS score between the groups over the 1st week, suggesting that early enteral nutrition did not attenuate the inflammatory response It should be recognized that in all the RCTs that failed to demonstrate a benefit from early aggressive enteral nutrition, patients received continuous rather than intermittent enteral nutrition [230] No species eats continuously (day and night), and such an evolutionary design would seem absurd The alimentary tract and metabolic pathways of humans appear designed for intermittent ingestion of nutrients a few times a day Humans have evolved as intermittent meal eaters and are not adapted to a continuous inflow of nutrients; normal physiology appears to be altered when this approach is adopted Continuous as opposed to intermittent enteral feeding likely limits protein synthesis, and this may be an important factor in promoting critical illness–acquired muscle weakness [230] In addition to adversely affecting protein synthesis, continuous enteral feeding can have other adverse consequences including uncontrolled hyperglycemia, hepatic steatosis, functional changes of the small intestine, and diminished gall bladder contraction [230] These data suggest that anorexia with limited nutrient intake is an evolutionary preserved response that may be beneficial during the first 24 to 48 hours of acute illness In those patients who are unable to resume an oral diet after this time period, enteral nutrition via orogastric tube is recommended Continuous tube feeding targeting normocaloric goals has not been proven to improve outcome; such a mode of feeding may be unphysiologic CONCLUSIONS Sepsis is a complex and dynamic disease that is difficult to manage by simple treatment algorithms and checklists [231] Each patient is unique, with a unique set of genes and comorbidities, and responds to illness and its treatment in a unique and often unpredictable manner This dictates that patients with sepsis be treated with an appropriate physiologic approach that promotes healing and limits the potential for intragenic harm REFERENCES Vincent JL, Sakr Y, Sprung CL, et al: Sepsis in European intensive care units: results of the SOAP study Crit Care Med 34:344–353, 2006 Gaieski DF, Edwards JM, Kallan MJ, et al: Benchmarking the incidence and mortality of severe sepsis in the United States Crit Care Med 41:1167–1174, 2013 Martin GS, Mannino DM, Eaton S, et al: The epidemiology of sepsis in the United States from 1979 through 2000 N Engl J Med 348:1546– 1554, 2003 Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome and associated costs of care Crit Care Med 29:1303–1310, 2001 Wang HE, Szychowski JM, Griffin R, et al: Long term mortality after sepsis Chest 21(12):E762–E769, 2013 Jolley RJ, Sawka KJ, Yergens DW, et al: Validity of administrative data in recording sepsis: a systematic review Crit Care 19:139, 2015 Whittaker SA, Mikkelsen ME, Gaieski DF, et al: Severe sepsis cohorts derived from claims-based strategies appear to be biased toward a more severely ill patient population Crit Care Med 41:945–953, 2013 Stow PJ: Development and implementation of a high-quality clinical database: the Australian and New Zealand Intensive Care Society Adult Patient Database J Crit Care 21:133–141, 2006 Kaukonen KM, Bailey M, Suzuki S, et al: Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012 JAMA 311:1308–1316, 2014 10 Hicks P, Cooper DJ, Webb S, et al: The surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008 An assessment by the Australian and New Zealand Intensive Care Society Anaesth Intensive Care 36:149–151, 2008 11 Levy MM, Dellinger RP, Townsend SR, et al: The surviving sepsis campaign: results of an international guideline-based performance improvement program targeting severe sepsis Crit Care Med 38:367– 374, 2010 12 Levy MM, Artigas A, Phillips GS, et al: Outcomes of the surviving sepsis campaign in intensive care units in the USA and Europe: a prospective cohort study Lancet Infect Dis 2012;12:919–924 13 Bone RC, Balk RA, Cerra FB, et al: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis The ACCP/SCCM Consensus Conference Committee American College of Chest Physicians/Society of Critical Care Medicine Chest 101:1644– 1655, 1992 14 Vincent JL, Opal SM, Marshall JC, et al: Sepsis definitions: time for change Lancet 381:774–775, 2013 15 Kaukonen KM, Baily M, Pilcher D, et al: Systemic inflammatory response syndrome criteria criteria in defining severe sepsis N Engl J Med 372:1629–1638, 2015 16 Whippy A, Skeath M, Crawford B, et al: Kaiser Permanente’s performance improvement system, part 3: multisite improvements in care for patients with sepsis Jt Comm J Qual Patient Saf 37:483–493, 2011 17 Singer M, Deutschman CS, Seymour CW, et al: The third international consensus definitions for sepsis and septic shock (Sepsis-3) JAMA 315:801–810, 2016 18 Shankar-Hari M, Phillips GS, Levy ML, et al: Developing a new definition and assessing new cliical criteria for septic shock For the third international consensus definitions for sepsis and septic shock (Sepsis-3) JAMA 315:775–787, 2016 19 Seymour CW, Liu VX, Iwashyna TJ, et al: Assessment of the clinical criteria for sepsis For the third international consensus definitions for sepsis and septic shock (Sepsis-3) JAMA; 315:762–774, 2016 20 Jain S, Self WH, Wunderink RG, et al: Community-acquired pneumonia requiring hospitalization among U.S adults N Engl J Med 373:415–427, 2015 21 Rittirsch D, Flierl MA, Ward PA: Harmful molecular mechanisms in sepsis Nat Rev Immunol 8:776–787, 2008 22 Parrish WR, Gallowitsch-Puerta M, Czura CJ, et al: Experimental therapeutic strategies for severe sepsis: mediators and mechanisms Ann N Y Acad Sci 1144:210–236, 2008 23 Skrupky LP, Kerby PW, Hotchkiss RS: Advances in the management of sepsis and the understanding of key immunologic defects Anesthesiol 115:1349–1362, 2011 24 Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, et al: The pathogenesis of sepsis Ann Rev Pathol 6:19–48, 2011 25 Leentjens J, Kox M, van der Hoeven JG, et al: Immunotherapy for the adjunctive treatment of sepsis: from immunosupression to immunostimulation Time for a paradigm change? Am J Respir Crit Care Med 187:1287–1293, 2013 26 Semeraro N, Ammollo CT, Semeraro F, et al: Coagulopathy of acute sepsis Semin Thromb Hemost 41:650–658, 2015 27 Nau GJ, Richmond JF, Schlesinger A, et al: Human macrophage activation programs induced by bacterial pathogens Proc Natl Acad Sci U S A 99:1503–1508, 2002 28 Osler W: The Evolution of Modern Medicine New Haven, CT: Yale University Press, 1921 29 Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis N Engl J Med 348:138–150, 2003 30 Boomer JS, To K, Chang KC, et al: Immunosuppression in patients who die of sepsis and multiple organ failure JAMA 306:2594–2605, 2011 31 Marik PE, Flemmer MC: The immune response to surgery and trauma: implications for treatment J Trauma 73:801–808, 2012 32 Landry DW, Oliver JA: Pathogenesis of vasodilatory shock N Engl J Med 345:588–595, 2001 33 Lee WL, Slutsky AS: Sepsis and endothelial permeability N Engl J Med 363:689–691, 2010 34 Ait-Oufella H, Maury E, Lehoux S et al: The endothelium: physiological functions and role in microcirculatory failure during severe sepsis Intensive Care Med 36:1286–1298, 2010 35 Goldenberg NM, Steinberg BE, Slutsky AS, et al: Broken barriers: a new take on sepsis pathogenesis Sci Translation Med 3:88ps25, 2011 36 Hernandez G, Bruhn A, Ince C: Microcirculation in sepsis: new perspectives Curr Vasc Pharm 11:161–169, 2013 37 De Backer D, Creteur J, Preiser JC, et al: Microvascular blood flow is altered in patients with sepsis Am J Respir Crit Care Med 166:98–104, 2002 38 Trzeciak S, Rivers E: Clinical manifestations of disordered microcirculatory perfusion in severe sepsis Crit Care 9 [Suppl 4]:S20–S26, 2005 39 Parker MM, Shelhamer JH, Bacharach SL, et al: Profound but reversible myocardial depression in patients with septic shock Ann Intern Med 100:483–490, 1984 40 Sanfilippo F, Corredor C, Fletcher N, et al: Diastolic dysfunction and mortality in septic patients: a systematic review and meta-analysis Intensive Care Med 41:1004–1013, 2015 41 Landesberg G, Gilon D, Meroz Y, et al: Diastolic dysfunction and mortality in severe sepsis and septic shock Eur Heart J 33:895–903, 2012 42 Brown SM, Pittman JE, Hirshberg EL, et al: Diastolic dysfunction and mortality in early severe sepsis and septic shock: a prospective, observational echocardiography study Crit Ultrasound J 4:8, 2012 43 Ognibene FP, Parker MM, Natanson C, et al: Depressed left ventricular performance: response to volume infusion in patients with sepsis and septic shock Chest 93:903–910, 1988 44 Uchino S, Kellum JA, Bellomo R, et al: Acute renal failure in critically ill patients: a multinational, multicenter study JAMA 294:813–818, 2005 45 Payen D, de Pont AC, Sakr Y, et al: A positive fluid balance is associated with a worse outcome in patients with acute renal failure Crit Care 12:R74, 2008 46 Gomez H, Ince C, De Backer D, et al: A unified theory of sepsisinduced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaption to injury Shock 41:3–11, 2014 47 Prowle JR, Kirwan CJ, Bellomo R: Fluid management for the prevention and attenuation of acute kidney injury Nat Rev Nephrol 10:37–47, 2014 48 Legrand M, Dupuis C, Simon C, et al: Association between systemic hemodynamics and septic kidney injury in critically ill patietns: a retrospective observational study Crit Care 17:R278, 2013 49 Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock N Engl J Med 345:1368– 1377, 2001 50 Dellinger RP, Levy MM, Rhodes A, et al: Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012 Crit Care Med 41:580–637, 2013 51 Mullens W, Abrahams Z, Francis GS, et al: Importance of venous congestion for worsening of renal function in advanced decompensated heart failure J Am Coll Cardiol; 53:589–596, 2009 52 Levi M, Schultz M, van der Poll T: Sepsis and thrombosis Semin Thromb Hemost 39:559–566, 2013 53 Cavallazzi R, Bennin CL, Hirani A, et al: Is the band count useful in the diagnosis of infection? An accuracy study in critically ill patients J Intensive Care Med 25:353–357, 2010 54 Ranieri VM, Thompson BT, Barie PS, et al: Drotrecogin Alfa (activated) in adults with septic shcok N Engl J Med 366:2055–2064, 2012 55 Dark P, Blackwood B, Gates S, et al: Accuracy of LightCycler SeptiFast for the detection and identification of pathogens in the blood of patients with suspected sepsis: a systematic review and meta-analysis Intensive Care Med 41:21–33, 2015 56 Chang SS, Hsieh WH, Liu TS, et al: Multiplex PCR system for rapid detection of pathogens in patients with presumed sepsis - a systemic review and meta-analysis PloS One 8:e62323, 2013 p 360 p 361 57 Bacconi A, Richmond GS, Baroldi MA, et al: Improved sensitivity for molecular detection of bacterial and Candida infections in blood J Clin Microbiol 52:3164–3174, 2014 58 Vincent JL, Brealey D, Abidi NE, et al: Rapid diagnosis of infection in the critically ill, a multicenter study of molecular detection in bloodstream infections, pneumonia, and sterile site infections Crit Care Med 43:2283–2291, 2015 59 Kirn TJ, Weinstein MP: Update on blood cultures: how to obtain, process, report, and interpret Clin Microbiol Infect 19:513–520, 2013 60 Clinical and Laboratory Standars Institute: Principles and Procedures for Blood Cultures: Approved Guideleine Wayne, PA: Clinical and Laboratlry Standards Institute, 2007 61 Li J, Plorde JJ, Carlson LG: Effects of volume and periodicity on blood cultures J Clin Microbiol 32:2829–2831, 1994 62 Lamy B, Roy P, Carret G, et al: What is the relevance of obtaining multiple blood samples for culture? A comprehensive model to optimize the strategy for diagnosing bacteremia Clin Infect Dis 35:842–850, 2002 63 Wacker C, Prkno A, Brunkhorst FM, et al: Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis Lancet Infect Dis 13:426–435, 2013 64 Schuetz P, Chiappa V, Briel M, et al: Procalcitonin algorithms for antibiotic therapy desisions A systematic review of randomized controlled trials and recommendations for clinical algorithms Arch Intern Med 171:1322–1331, 2011 65 Tromp M, Lansdorp B, Bleeker-Rovers CP, et al: Serial and panel analyses of biomarkers do not improve the prediction of bacteremia compared to one procalcitonin measurement J Infect 65:292–301, 2012 66 Brodska H, Malickova K, Adamkova V, et al: Significantly higher procalcitonin levles could differentiate Gram-negative sepsis from Gram-positive and fungal sepsis Clin Exp Med 13:165–170, 2014 67 Feezor RJ, Oberholzer C, Baker HV, et al: Molecular characterization of the acute inflammatory response to infections with gram-negative versus gram-positive bacteria Infect Immun 71:5803–5813, 2003 68 Charles PE, Ladoire S, Aho S, et al: Serum procalcitonin elevation in critically ill patients at the onset of bacteremia caused by either Gram negative or Gram positive bacteria BMC Infect Dis 8:38, 2008 69 Koivula I, Hamalainen S, Jantunen E, et al: Elevated procalcitonin predicts Gram-negative sepsis in haematological patients with febrile neutropenia Scand J Infect Dis 43:471–478, 2011 70 Matthaiou DK, Ntani G, Kontogiorgi M, et al: An ESICM systematic review and meta-analysis of procalcitonin-guided antibiotic therapy algorithm in adult critically ill patients Intensive Care Med 38:940– 949, 2012 71 Kopterides P, Siempos IL, Tsangaris I, et al: Procalcitonin-guided algorithms of antibiotic therapy in the intensive care unit: a systematic review and meta-analysis of randomized controlled trials Crit Care Med 38:2229–2241, 2010 72 Schuetz P, Maurer P, Punjabi V, et al: Procalcitonin decrease over 72 hours in US critical care units predicts fatal outcome in sepsis patients Crit Care 17:R115, 2013 73 Faix JD: Presepsin - the new kid on the sepsis block Clin Biochem 47:503–504, 2014 74 Rabensteiner J: Diagnostic and prognostic potential of presepsin in Emergency Department patients presenting with systemic inflammatory response syndrome [Letter] J Infect 69:627–630, 2014 75 Shirakawa K, Naitou K, Hirose J, et al: Presepsin (sCD14-ST): development and evaluation of one-step ELISA with a new standard that is similar to the form of presepsin in septic patients Clin Chem Lab Med 49:937–939, 2011 76 Masson S: Circulating presepsin (soluble CD14 subtype) as a marker of host response in patients with severe sepsis or septic shock: data from the multicenter, randomized ALBIOS trial Intensive Care Med 41:12– 20, 2015 77 Wu Y, Wang F, Fan X, et al: Accuracy of plasma sTREM-1 for sepsis diagnosis in systemic inflammatory patients: a systematic review and meta-analysis [Review] Crit Care 16:R229, 2012 78 Hanna WJ, Berrens Z, Langer T, et al: Interleukin-27: a novel biomarker in predicting bacterial infection among the critically ill Crit Care 19:378, 2015 79 Wong HR, Lindsell CJ, Lahni P, et al: Interleukin 27 as a sepsis diagnostic biomarker in critically ill adults Shock 40:382–386, 2013 80 Marik PE: Don’t miss the diagnosis of sepsis! Crit Care 18:529, 2014 81 Sterling SA, Miller WR, Pryor J, et al: The impact of timing of antibiotics on outcomes in Severe Sepsis and Septic Shock: a systematic review and meta-analysis Crit Care Med 43:1907–1915, 2015 82 Kollef MH, Napolitano LM, Solomkin JS, et al: Health care-associated infection (HAI): a critical appraisal of the emerging threat-proceedings of the HAI Summit Clin Infect Dis 47[Suppl 2]:S55–S99, 2008 83 Mermel LA, Farr BM, Sherertz RJ, et al: Guidelines for the management of intravascular catheter-related infections Clin Infect Dis 32:1249–1272, 2001 84 Joung MK, Lee JA, Moon SY, et al: Impact of de-escalation therapy on clinical outcomes for intensive care unit-acquired pneumonia Crit Care 15:R79, 2011 85 Garnacho-Montero J, Gutierrez-Pizarraya A, Escoresca-Ortega A, et al: De-escalation of emperical therapy is associated with lower mortality in patients with severe sepsis and septic shock Intensive Care Med 40:32–40, 2014 86 Shindo Y, Ito R, Kobayashi D, et al: Risk factors for drug-resistant pathogens in community-acquired and healthcare-associated pneumonia Am J Respir Crit Care Med 188:985–995, 2013 87 Boucher HW, Talbot GH, Bradley JS, et al: Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America Clin Infect Dis 48:1–12, 2009 88 Rice LB: Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE J Infect Dis 197:1079–1081, 2008 89 Rice LB: Mechanisms of resistance and clinical relevance of resistance to beta-lactams, glycopeptides, and fluoroquinolones Mayo Clin Proc 87:198–208, 2012 90 Aliberti S, Blasi F, Zanaboni AM, et al: Duration of antibiotic therapy in hospitalised patients with community-acquired pneumonia Eur Respir J 36:128–134, 2010 91 Christ-Crain M, Stolz D, Bingisser R, et al: Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial Am J Respir Crit Care Med 174:84–93, 2006 92 Pugh R, Grant C, Cooke RP, et al: Short-course versus prolongedcourse antibiotic therapy for hospital-acquired pneumonia in critically ill adults Cochrane Database Syst Rev CD007577, 2011 doi:10.1002/14651858.CD007577.pub3 93 Sawyer RG, Claridge JA, Nathens AB, et al: Trial of short-course antimicrobial therapy for intraabdominal infection N Engl J Med 372:1996–2005, 2015 94 Dellinger RP, Carlet JM, Masur H, et al: Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock Crit Care Med 32:858–873, 2004 95 Dellinger RP, Levy MM, Carlet JM, et al: Surviving sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 Crit Care Med 36:296–327, 2008 96 Burton TM: New therapy for sepsis infection raises hope but many questions (lead article) Wall Street J 4:1, 2008 97 Marik PE, Varon J: Goal-directed therapy in sepsis N Engl J Med 346:1025, 2002 98 Bellomo R, Warrillow SJ, Reade MC: Why we should be wary of singlecenter trials Crit Care Med 37:3114–3119, 2009 99 Marik PE, Varon J: Early Goal Directed Therapy (EGDT): On terminal lIfe support? Am J Emerg Med 28:243–245, 2010 100 Marik PE: Surviving sepsis guidelines and scientific evidence? J Intensive Care Med 26:201–202, 2011 101 Marik PE: Surviving sepsis: going beyond the guidelines Ann Intensive Care 1:17, 2011 102 Marik PE: The demise of early goal-directed therapy for severe sepsis and septic shock Acta Anaesthesiol Scand 59:561–567, 2015 103 Hotchkiss RS, Karl IE: Reevaluation of the role of cellular hypoxia and bioenergetics failure in sepsis JAMA 267:1503–1510, 1992 104 ProCESS Investigators, Yealy DM, Kellum JA, et al: A randomized trial of protocol-based care for early septic shock N Engl J Med 370:1683– 1693, 2014 105 ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, et al: Goal-directed resuscitation for patients with Early Septic Shock N Engl J Med 371:1496–506, 2014 106 Mouncey PR, Osborn TM, Power S, et al: Trial of early, goal-directed resuscitation for septic shock N Engl J Med 372:1301–1311, 2015 107 Angus DC, Barnato AE, Bell D, et al: A systematic review and metaanalysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe investigators Intensive Care Med 41:1549– 1560, 2015 108 Knox M, Pickkers P: “Less is More” in Critically ill patients Not too intensive JAMA Intern Med 173:1369–1372, 2013 109 Hilton AK, Bellomo R: A critique of fluid bolus resuscitation in severe sepsis Crit Care 16:302, 2012 110 Hilton AK, Bellomo R: Totem and taboo: fluids in sepsis Crit Care 15:164, 2011 111 Marik PE: Iatrogenic salt water drowning and the hazards of a high central venous pressure Ann Intensive Care 4:21, 2014 112 Marik PE, Monnet X, Teboul JL: Hemodynamic parameters to guide fluid therapy Ann Crit Care 1:1, 2011 113 Marik PE: Fluid responsiveness and the six guiding principles of fluid resuscitation Crit Care Med 44:1920–1922, 2016 114 Surviving Sepsis Campaign six hour bundle revised Available at: http://www.survivingsepsis.org/News/Pages/SSC-Six-Hour-BundleRevised.aspx Acessed January 28, 2017 115 Marik PE, Cavallazzi R: Does the Central Venous Pressure (CVP) predict fluid responsiveness: An update meta-analysis and a plea for some common sense Crit Care Med 41:1774–1781, 2013 116 Wetterslev M, Haase N, Johansen RR, et al: Predicting fluid responsiveness with transthoracic echocardiography is not yet evidence based Acta Anaesthesiol Scand 57:692–697, 2013 117 Muller L, Bobbia X, Toumi M, et al: Respiratory variations of inferior vena cava diameter predict fluid responsiveness in spontaneously breathing patients with acute circulatory failure: need for a cautious use Crit Care 16:R188, 2012 118 Juhl-Olsen P, Vistisen ST, Christiansen LK, et al: Ultrasound of the inferior vena cava does not predict hemodynamic response to early hemorrhage J Emerg Med 45:592–597, 2013 119 Corl K, Napoli AM, Gardiner F: Bedside sonographic measurement of the inferior vena cava caval index is a poor predictor of fluid responsiveness in emergency department patients Emerg Med Australas 24:534–539, 2012 120 Monnet X, Teboul JL: Passive leg raising: five rules, not a drop of fluid! Crit Care 19:18, 2015 121 Monnet X, Marik P, Teboul JL: Passive leg raising for predicting fluid responsiveness: a systematic review and meta-analysis Intensive Care Med 42:1935–1922, 2016 p 361 p 362 122 Marik P, Bellomo R: A rational apprach to fluid therapy in sepsis Br J Anaesth 116(3):339–349, 2016 123 Marik PE: The physiology of volume resuscitation Curr Anesthesiol Rep 4:353–359, 2014 124 Nunes T, Ladeira R, Bafi A, et al: Duration of hemodynamic effects of crystalloids in patients with circulatory shock after initial resuscitation Ann Intensive Care 4:25, 2014 125 Lammi MR, Aiello B, Burg GT, et al: Response to fluid boluses in the fluid and catheter treatment trial Chest 148:919–926, 2015 126 Sanchez M, Jimenez-Lendinez M, Cidoncha M, et al: Comparison of fluid compartments and fluid responsiveness in septic and non-septic patients Anaesth Intensive Care 39:1022–1029, 2011 127 Bark BP, Oberg CM, Grande PO: Plasma volume expansion by 0.9% NaCl during sepsis/systemic inflammatory response syndrome, after hemorrhage, and during a normal state Shock 40:59–64, 2013 128 Glassford NJ, Eastwood GM, Bellomo R: Physiological changes after fluid bolus therapy in sepsis: a systematic review of contemporary data Crit Care 18:2557, 2014 129 Monge-Garcia MI, Gonzalez PG, Romero MG, et al: Effects of fluid administration on arterial load in septic shock patients Intensive Care Med 41:1247–1255, 2015 130 Pierrakos C, Velissaris D, Scolletta S, et al: Can changes in arterial pressure be used to detect changes in cardiac index during fluid challenge in patients with septic shock? Intensive Care Med 38:422– 428, 2012 131 Hollenberg SM, Ahrens TS, Annane D, et al: Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update Crit Care Med 32:1928–1948, 2004 132 Brandt S, Regueira T, Bracht H, et al: Effect of fluid resuscitation on mortality and organ function in experimental sepsis models Crit Care 13:R186, 2009 133 Rehberg S, Yamamoto Y, Sousse L, et al: Selective V(1a) agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis Am J Physiol Heart Circ Physiol 303:H1245–H1254, 2012 134 Rosenberg AL, Dechert RE, Park PK, et al: Review of a large clinical series: association of cumulative fluid balance on outcome in acute lung injury: a retrospective review of the ARDSnet tidal volume study cohort J Intensive Care Med 24:35–46, 2009 135 Alsous F, Khamiees M, DeGirolamo A, et al: Negative fluid balance predicts survival in patients with septic shock: a retrospective pilot study Chest 117:1749–1754, 2000 136 Murphy CV, Schramm GE, Doherty JA, et al: The importance of fluid management in acute lung injury secondary to septic shock Chest 136:102–109, 2009 137 Chung FT, Lin SM, Lin SY, et al: Impact of extravascular lung water index on outcomes of severe sepsis patients in a medical intensive care unit Respir Med 102:956–961, 2008 138 Bouchard J, Soroko SB, Chertow GM, et al: Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury Kidney Int 76:422–427, 2009 139 Micek SC, McEnvoy C, McKenzie M, et al: Fluid balance and cardiac function in septic shock as predictors of hospital mortality Crit Care 17:R246, 2013 140 Zhang Z, Zhang Z, Xue Y, et al: Prognostic value of B-type natriuretic peptide (BNP) and its potential role in guiding fluid therapy in critically ill septic patients Scand J Trauma Resus Emerg Med 20:86, 2012 141 Boyd JH, Forbes J, Nakada T, et al: Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure increase mortality Crit Care Med 39:259–265, 2011 142 Kelm DJ, Perrin JT, Cartin-Cebra R, et al: Fluid overload in patients with severe sepsis and septic shock treated with Early-Goal Directed Therapy is associated with increaed acute need for fluid-related medical interventions and hospital death Shock 43:68–73, 2015 143 Maitland K, Kiguli S, Opoka RO, et al: Mortality after fluid bolus in african children with severe infection N Engl J Med 364:2483–2495, 2011 144 Maitland K, George EC, Evans JA, et al: Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial BMC Med 11:68, 2013 145 Marik PE: Early management of severe sepsis: current concepts and controversies Chest 145:1407–1418, 2014 146 Marik PE, Lemson J: Fluid responsiveness: an evolution of our understanding Br J Anaesth 112:620–622, 2014 147 Asfar P, Meziani F, Hamel JF, et al: High versus low blood-pressure target in patients with septic shock N Engl J Med 370:1583–1593, 2014 148 Kirkpatrick AW, Roberts DJ, De WJ, et al: Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome Intensive Care Med 39:1190–1206, 2013 149 Malbrain ML, Marik PE, Witters I, et al: De-resuscitation in the critically ill: what, why, when and how? Results of a meta-analysis and systematic review on the impact of fluid overload on morbidity and mortality Anesthesiol Intensive Ther 46:361–380, 2014 150 Scheingraber S, Rehm M, Sehmisch C, et al: Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery Anesthesiology 90:1265–1270, 1999 151 Kellum JA, Bellomo R, Kramer DJ, et al: Etiology of metabolic acidosis during saline resuscitation in endotoxemia Shock 9:364–368, 1998 152 Waters JH, Gottlieb A, Schoenwald P, et al: Normal saline versus lactated Ringer’s solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study Anesth Analg 93:817–822, 2001 153 Reid F, Lobo DN, Williams RN, et al: (Ab)normal saline and physiological Hartmann’s solution: a randomized double-blind crossover study Clin Sci 104:17–24, 2003 154 Chowdhury AH, Cox EF, Francis S, et al: A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers Ann Surg 256:18–24, 2012 155 Mohd Yunos N, Bellomo R, Hegarty C, et al: Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults JAMA 308:1566– 1572, 2012 156 Raghunathan K, Shaw A, Nathanson B, et al: Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis Crit Care Med 42:1585–1591, 2014 157 Young P, Bailey M, Beasley R, et al: Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit The SPLIT randomized clinical trial JAMA 314:1701–1710, 2015 158 Perner A, Haase N, Guttormsen AB, et al: Hydroxyethyl starch 130/0.4 versus Ringers Acetate in severe sepsis N Engl J Med 367:124–134, 2012 159 Haase N, Perner A, Hennings LI, et al: Hydroxyethyl starch 130/0.380.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis BMJ 346:f839, 2013 160 Patel A, Laffan MA, Waheed U, et al: Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality BMJ 349:g4561, 2014 161 SAFE Study Investigators, Finfer S, McEvoy S, et al: Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis Intensive Care Med 37:86–96, 2011 162 Caironi P, Tognoni G, Masson S, et al: Albumin replacement in patients with severe sepsis or septic shock N Engl J Med 370:1412– 1421, 2014 163 Kremer H, Baron-Menguy C, Tesse A, et al: Human serum albumin improves endothelial dysfunction and survival during experimental endotoxemia: concentration-dependent properties Crit Care Med 39:1414–1422, 2011 164 Bellomo R, Di Giantomasso D: Noradrenaline and the kidney: friends or foes? Crit Care 5:294–298, 2001 165 Lehman LW, Saeed M, Talmor D, et al: Methods of blood pressure measurement in the ICU Crit Care Med 41:34–40, 2013 166 Varpula M, Tallgren M, Saukkonen K, et al: Hemodynamic variables related to outcome in septic shock Intensive Care Med 31:1066–1071, 2005 167 Panwar R, Lanyon N, Davies AR, et al: Mean perfusion pressure deficit during the initial management of shock-an observational cohort study J Crit Care 28:816–824, 2013 168 Avni T, Lador A, Lev S, et al: Vasopressors for the treatment of septic shock: systematic review and meta-analysis PloS One 10(8):e0129305, 2015 169 Fawzy A, Evans SR, Walkey AJ: Practice patterns and outcomes associated with choice of initial vasopressor therapy for septic shock Crit Care Med 43:2141–2146, 2015 170 De Baker D, Aldecoa C, Njimi H, et al: Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis Crit Care Med 40:725–730, 2011 171 Malay MB, Ashton JL, Dahl K, et al: Heterogeneity of the vasoconstrictor effect of vasopressin in septic shock Crit Care Med 32:1327–1331, 2004 172 Monnet X, Jabot J, Maizel J, et al: Norepinephrine increases cardiac preload and reduces preload dependency assessed by passive leg raising in septic shock patients Crit Care Med 39:689–694, 2011 173 Persichini R, Silva S, Teboul JL, et al: Effects of norepinephrine on mean systemic pressure and venous return in human septic shock Crit Care Med 40:3146–3153, 2012 174 Hamzaoui O, Georger JF, Monnet X, et al: Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension Crit Care 14:R142, 2010 175 Abid O, Akca S, Haji-Michael P, et al: Strong vasopressor support may be futile in the intensive care unit patient with multiple organ failure Crit Care Med 28:947–949, 2000 176 Cardenas-Garcia J, Schaub KF, Belchikov YG, et al: Safety of peripheral intravenous administration of vasoactive medication J Hosp Med, 2015 doi:10.1002/jhm.2394 177 Vieillard-Baron A, Caille V, Charron C, et al: Actual incidence of global left ventricular hypokinesia in adult septic shock Crit Care Med 36:1701–1706, 2008 178 Jellema WT, Groeneveld AB, Wesseling KH, et al: Heterogeneity and prediction of hemodynamic responses to dobutamine in patients with septic shock Crit Care Med 34:2392–2398, 2006 179 Landry DW, Levin HR, Gallant EM, et al: Vasopressin deficiency contributes to the vasodilation of septic shock Circulation 95:1122– 1125, 1997 180 Morelli A, Ertmer C, Lange M, et al: Effects of short-term simultaneous infusion of dobutamine and terlipressin in patients with septic shock: the DOBUPRESS study Br J Anaesth 100:494–503, 2008 181 Morelli A, Ertmer C, Rehberg S, et al: Continuous terlipressin versus vasopressin infusion in septic shock (TERLIVAP): a randomized, controlled pilot study Crit Care 13:R130, 2009 182 Russell JA, Walley KR, Singer J, et al: Vasopressin versus norepinephrine infusion in patients with septic shock N Engl J Med 358:877–887, 2008 183 Chernow B, Alexander HR, Smallridge RC, et al: Hormonal responses to graded surgical stress Arch Intern Med 147:1273–1278, 1987 p 362 p 363 184 Jardin F, Fourme T, Page B, et al: Persistent preload defect in severe sepsis despite fluid loading: a longitudinal echocardiographic study in patients with septic shock Chest 116:1354–1359, 1999 185 Parker MM, Shelhamer JH, Natanson C, et al: Serial cardiovascular variables in survivors and nonsurvivors of septic shock: heart rate as an early predictor of prognosis Crit Care Med 15:923–929, 1987 186 Ackland GL, Yao ST, Rudiger A, et al: Cardioprotection, attenuated systemic inflammation, and survival benefit of beta1-adrenoceptor blockade in severe sepsis in rats Crit Care Med 38:388–394, 2010 187 Rudiger A: Beta-block the septic heart Crit Care Med 38:S608–S612, 2010 188 Morelli A, Ertmer C, Westphal M, et al: Effect of heat rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock A randomized clinical trial JAMA 310:1683–1691, 2013 189 da Silva Ramos FJ, Azevedo LC: Hemodynamic and perfusion end points for volemic resuscitation in sepsis Shock 34[Suppl 1]:34–39, 2010 190 Bouferrache K, Amiel JB, Chimot L, et al: Initial resuscitation guided by the Surviving Sepsis Campaign recommendations and early echocardiographic assessment of hemodynamics in intensive care unit septic patients: a pilot study Crit Care Med 40:2821–2827, 2012 191 Langenberg C, Wan L, Egi M, et al: Renal blood flow and function during recovery from experimental septic acute kidney injury Intensive Care Med 33:1614–1618, 2007 192 Langenberg C, Wan L, Egi M, et al: Renal blood flow in experimental septic acute renal failure Kidney Int 69:1996–2002, 2006 193 Wan L, Bagshaw SM, Langenberg C, et al: Pathophysiology of septic acute kidney injury: what do we really know? Crit Care Med 36:S198– S203, 2008 194 Angus DC, van der Poll T: Severe sepsis and septic shock N Engl J Med 369:840–851, 2013 195 Jansen TC, van BJ, Schoonderbeek FJ, et al: Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial Am J Respir Crit Care Med 182:752–761, 2010 196 Jones AE, Shapiro NI, Trzeciak S, et al: Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial JAMA 303:739–746, 2010 197 Marik PE, Bellomo R: Lactate clearance as a target of therapy in sepsis: a flawed paradigm OA Crit Care 1:3, 2013 198 Garcia-Alvarez M, Marik P, Bellomo R: Sepsis-associated hyperlactatemia Crit Care 18:503, 2014 199 Marik PE, Sibbald WJ: Effect of stored-blood transfusion on oxygen delivery in patients with sepsis JAMA 269:3024–3029, 1993 200 Garcia-Alvarez M, Marik PE, Bellomo R: Stress Hyperlactemia Lancet Endo Diab 2:339–347, 2014 201 Hayes MA, Timmins AC, Yau E, et al: Elevation of systemic oxygen delivery in the treatment of critically ill patients N Engl J Med 330:1717–1722, 1994 202 Gattinoni L, Brazzi L, Pelosi P, et al: A trial of goal-oriented hemodynamic therapy in critically ill patients N Engl J Med 333:1025–1032, 1995 203 National Quality Forum: Severe sepsis and septic shock: managment bundle, update 2015 Available at: www.quality forum.org Accessed January 28, 2017 204 Ibarra-Estrada MA, Lopez-Pulgarin JA, Mijangos-Mendez JC, et al: Variation in carotid peak systolic velocity predicts volume responsiveness in mechanically ventilated patients with septic shock: a prospective cohort study Crit Ultrasound J 7:12, 2015 205 Saugel B, Ringmaier S, Holzapfel K, et al: Physical examination, central venous pressure, and chest radiography for the prediction of transpulmonary thermodilution-derived hemodynamic parameters in critically ill patients: a prospective trial J Crit Care 26:402–410, 2011 206 Boyer A, Vargas F, Coste F, et al: Influence of surgical treatment timing on mortality from necrotizing soft tissue infections requiring intensive care management Intensive Care Med 35:847–853, 2009 207 Bufalari A, Giustozzi G, Moggi L: Postoperative intraabdominal abscesses: percutaneous versus surgical treatment Acta Chir Belg 96:197–200, 1996 208 Marik PE: Glucocorticoids in sepsis: disectiong facts from fiction Crit Care 15:158, 2011 209 Marik PE, Pastores SM, Annane D, et al: Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine Crit Care Med 36:1937–1949, 2008 210 Annane D, Bellissant E, Sebille V, et al: Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve Br J Clin Pharmacol 46:589–597, 1998 211 Chappell D, Jacob M, Hofmann-Kiefer K, et al: Hydrocortisone preserves the vascular barrier by protecting the endothelial glycocalyx Anesthesiology 107:776–784, 2007 212 Beale R, Janes JM, Brunkhorst FM, et al: Global utilization of low-dose corticosteroids in severe sepsis and septic shock: a report from the PROGRESS registry Crit Care 14:R102, 2010 213 Volbeda M, Wetterslev J, Gluud C, et al: Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis Intensive Care Med 41:1220–1234, 2015 214 Venkatesh B, Myburgh J, Finfer S, et al: The ADRENAL study protocol: adjunctive corticosteroid treatment in critically ill patients with septic shock Crit Care Resus 15:83–88, 2013 215 Heyland DK, Dhaliwal R, Drover JW, et al: Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients JPEN 27:355–373, 2003 216 McClave SA, Martindale RG, Vanek VW, et al: Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) JPEN 33:277–316, 2009 217 Heyland DK, Dhaliwal R, Lemieux M, et al: 2015 Canadian Clinical Practice Guidelinee Available at: http://www.critical carenutrition.com/ Retrieved September 9, 2015 Accessed January 28, 2017 218 Kreymann KG, Berger MM, Deutz NE, et al: ESPEN Guidelines on Enteral Nutrition: Intensive care Clin Nutr 25:210–223, 2006 219 Marik PE, Hooper MH: Normocaloric versus hypocaloric feeding on the outcomes of ICU patients: a systematic review and meta-analysis Intensive Care Med 42:316–323, 2016 220 Feed a cold, starve a fever Available at: https://en.wiktionary.org/wiki/feed_a_cold,_starve_a_fever Accessed January 28, 2017 221 Wessling-Resnick M: Iron homeostasis and the inflammatory response Annu Rev Nutr 30:105–122, 2010 222 Sherman AR: Influence of iron on immunity and disease resistance Ann N Y Acad Sci 587:140–146, 1990 223 Conn CA, Kozak WE, Tooten PC, et al: Effect of voluntary exercise and food restriction in response to lipopolysaccharide in hamsters J Appl Physiol 78:466–477, 1995 224 Kluger MJ, Rothenburg BA: Fever and reduced iron: their interaction as a host defense response to bacterial infection Science 203:374–376, 1979 225 Choi AM, Ryter SW, Levine B: Autophagy in human health and disease N Engl J Med 368:651–662, 2013 226 Levine B, Mizushima N, Virgin HN: Autophagy in immunity and inflammation Nature 469:323–335, 2011 227 Rich KA, Burkett C, Webster P: Cytoplasmic bacteria can be targets for autophagy Cell Microbiol 5:455–468, 2003 228 Xu Y, Eissa NT: Autophagy in innate and adaptive immunity Proc Am Thorac Soc 7:22–28, 2010 229 Bakker OJ, van Goor H, Bosscha K, et al: Early versus on-demand nasoenteric tube feeding in acute pancreatitis N Engl J Med 371:1983–1993, 2014 230 Marik PE: Feeding critically ill patients the right “whey”:thinking outside the box A personal view Ann Intensive Care 5:11, 2015 231 Girbes AR, Robert R, Marik PE: More protocols: beware of regression to the mean and mediocrity Intensive Care Med 41:2218–2220, 2015 Chapter 40 Multiple Organ Dysfunction Syndrome TIMOTHY A PRITTS • ANDREW C BERNARD Care of the critically ill has advanced substantially in the past 50 years to the point that patients who previously succumbed to illness or injury may now survive their initial insult Unfortunately, this places them at risk for multiple organ dysfunction syndrome (MODS), with subsequent failure of organ systems and late mortality [1] A thorough understanding of the pathophysiology and treatment of MODS is necessary to attempt to mitigate associated secondary morbidity and mortality MODS can be defined as “the inability of one or more organs to support its activities spontaneously without intervention” [2] Initial recognition of MODS came during World War II as advances in resuscitation strategies allowed casualties to survive the initial hemorrhagic shock insult, but rendered them vulnerable to subsequent acute renal failure [3] Improved intensive care and resuscitation strategies subsequently led to the recognition of pulmonary failure in the form of acute respiratory distress syndrome (ARDS) during the Vietnam conflict [4] Although advances in support for failing organs, including continuous dialysis and advanced ventilator care, have potentially increased survival, MODS remains a common cause of death in the intensive care unit (ICU) DIAGNOSTIC CRITERIA AND SCORING SYSTEMS The severity of MODS determines mortality [5] Organ failure severity scoring was initially described by Knaus in 1985 [6] Modern scoring systems consider grade and severity and are intended to serve as predictors of outcome Among the most commonly used scoring systems are the multiple organ dysfunction syndrome (MODS), sequential organ failure assessment (SOFA), and logistic organ dysfunction score (LODS) [7–9] All include clinical and laboratory data for six organs: respiratory, cardiovascular, hematologic, hepatic, renal, and central nervous system (Table 40.1) [10] The Denver Multiple Organ Failure (MOF) score is a straightforward 4-point scale that has similar or superior specificity to the SOFA score [11] The Simplified Acute Physiology Score (SAPS) is easy to calculate with available clinical and laboratory data and may in fact be superior to acute physiology and chronic health evaluation (APACHE) in geriatric ICU patients [12] A “cellular injury score” based on measures of cellular dysfunction has also been described [13] Specialized scoring systems have been developed for unique populations For example, the cardiac surgery score (CASUS) outperformed APACHE and SAPS in that special population [14] No single scoring system has been proven superior, but all predict mortality more accurately than they predict health care resource utilization [11,15] TABLE 40.1 Criteria Used in Common Organ Dysfunction Scoring Systems Organ Variable Denver MOF [11] Respiratory PaO2/FIO2 Yes MV Hematology Platelets SOFA [8] LODS [9] MODS [7] Yes Yes Yes Yes Yes Yes WBC Hepatic Bilirubin Yes Yes Yes Prothrombin time Cardiovascular MAP Yes Yes Yes Yes Yes SBP Yes Heart rate Yes PAR [(HR × CVP)/MAP] Yes Dopamine Yes Dobutamine Yes Epinephrine Yes Norepinephrine Yes Any inotrope CNS GCS Renal Creatinine Yes Yes Yes Yes Yes Yes Yes Yes BUN Urine output Yes Yes Yes Denver MOF, Denver multiple organ failure score; SOFA, sequential organ failure assessment; LODS, logistic organ dysfunction score; MODS, multiple organ dysfunction syndrome; PaO2, blood partial pressure of oxygen; FIO2, fraction of inspired gas which is oxygen; MV, mechanical ventilation requirement; WBC, elevated white blood count; PAR, pressure-adjusted heart rate; HR, heart rate; CVP, central venous pressure; MAP, mean arterial pressure; SBP, systolic blood pressure; CNS, central nervous system; GCS, Glasgow Coma Scale score; BUN, blood urea nitrogen Modified from Mizock BA: The multiple organ dysfunction syndrome Dis Mon 55(8):476–526, 2009 All scoring systems are intended to improve upon clinical judgment The Denver Emergency Department Trauma Organ Failure Score uses six simple criteria available in the trauma room to predict MODS at 7 days more effectively than unaided emergency department attending judgment [16] Such predictive models permit resource allocation and can be used to guide patient transfers The APACHE, originally described by Knaus in 1985 [17], is a scoring system that considers patient factors unrelated to the acute illness as well as acute illness severity APACHE considers many variables and is therefore not as easily calculable at the bedside as MODS, SOFA, LODS, or Denver, but it reliably predicts both outcome and resource utilization, has been refined to its current version, APACHE IVa, and may be useful for benchmarking ICU performance [18] EPIDEMIOLOGY Incidence of MODS varies on the basis of primary diagnosis and the scoring system used to determine organ dysfunction Seventy-one percent of ICU patients have some organ dysfunction [19] and about half have MODS [20], depending on the criteria used For example, in one adult trauma ICU 47% had MODS, defined by SOFA ≤3 in two or more systems [21] Septic patients are more likely to have organ dysfunction and more organ failures than nonseptic patients, and mortality is higher in MODS when sepsis is present (31% vs 21%) [19] ETIOLOGY MODS is most often the result of shock, sepsis, and trauma, but there are many causes (Table 40.2) [22] Forty-one percent of those patients with organ dysfunction have sepsis [19] Sepsis most commonly originates in the lung (68%) and abdomen (22%), but there are many causes of sepsisinduced MODS [19] TABLE 40.2 Risk Factors for MODS Infection  Peritonitis and intra-abdominal infection  Pneumonia  Necrotizing soft tissue infections  Tropical infections (e.g., falciparum malaria, typhoid fever, dengue fever) Inflammation  Pancreatitis Ischemia  Ruptured aortic aneurysm  Hemorrhagic shock  Mesenteric ischemia Immune reactions  Autoimmune disease  Reactive hemophagocytic syndrome  Antiphospholipid antibody syndrome  Transplant rejection  Graft-versus-host disease Iatrogenic causes  Delayed or missed injury  Blood transfusion  Injurious mechanical ventilation  Treatment associated increased intraabdominal pressure Intoxication  Drug reactions (anticonvulsants, carboplatin, antiretrovirals, colchicines, propofol, amiodarone, monoclonal antibodies)  Arsenic  Drug intoxication (ecstasy, cocaine, salicylates, acetaminophen) Endocrine  Adrenal crisis  Pheochromocytoma  Thyroid storm  Myxedema coma Reproduced from Mizock BA: The multiple organ dysfunction syndrome Dis Mon 55(8):476–526, 2009 MECHANISMS OF MULTIORGAN DYSFUNCTION SYNDROME The systemic inflammatory response syndrome (SIRS) is frequently viewed as a predecessor and lies on a continuum of dysfunction with MODS Components of the SIRS response are seen in virtually all patients following an operation, febrile illness, or injury SIRS frequently resolves without progression to MODS MODS may be viewed as a result of an ongoing, dysregulated, or treatment refractory SIRS response with progressive organ system derangement Despite extensive efforts, the pathophysiology of MODS is not fully understood and remains an area of intensive investigation [23] Several mechanisms for the onset and propagation of MODS have been proposed, including an initial insult in which ischemia, oxidative stress, mitochondrial dysfunction, and activation of apoptotic pathways lead immediately to organ failure, and a “two hit” model, where an initial stimulus primes the immune system to respond to a subsequent insult or stimulus with an exuberant reaction, and the concept that dysregulated immune responses lead to MODS [23] A common theme in the onset and propagation of MODS is the presence of a disordered immune response It is likely that ongoing tissue hypoxia leads to activation of the acute inflammatory response, oxidative imbalance, structural rearrangement of cellular proteins, dysregulation of the immune system, activation of apoptotic pathways, cell death, and organ dysfunction [24] Although the inflammatory response is an important component of normal recovery from injury and illness, organ failure appears to result from a loss of the balance between the pro- and anti-inflammatory cascades [25] The proinflammatory response to a stimulus predominates initially, with increased release of proinflammatory mediators, increased capillary permeability, macrophage and neutrophil activation with tissue invasion and damage, disordered apoptosis, and microvascular thrombosis [26] This initial response is normally tempered by the anti-inflammatory response, but immune regulation may become dysfunctional Widespread activation of proinflammatory pathways and impaired balanced resolution by antiinflammatory pathways can lead to early onset of MODS If the organism survives the initial insult and onset of MODS, a period of immunosuppression can follow During this period, the patient becomes susceptible to nosocomial pathogens, with a normally survivable event such as pneumonia representing a life-threatening “second hit” [27] As research into the pathophysiology of MODS has advanced, another phase of the process has been recognized Termed PICS (persistent inflammation, immunosuppression, and catabolism syndrome), this syndrome consists of loss of lean body mass, recurrent sepsis, and increased debility [28] PICS is associated with functionally irreversible immune system paralysis and may be a significant cause of late death after recovery from the acute phase of MODS [29] CURRENT MANAGEMENT STRATEGIES Course of MODS Outcome for MODS partly depends upon host factors including genetics Some patients are genetically predisposed to enhanced immune reactivity [30] For most patients, MODS progression follows a typical sequence first described by Don Fry in 1980 [31], beginning with lung failure, followed by the liver, gastric mucosa, and kidney Lung dysfunction has since been reaffirmed as the initial manifestation of MODS in the majority of patients [32] MODS follows a bimodal onset with early and late MODS characterized by different patient characteristics and mechanisms of death [33] An important distinction must also be made with early organ dysfunction during resuscitation, which is often reversible, and not necessarily the same as early MODS [34] Respiratory organ dysfunction is the most common early manifestation of MODS but is often not associated with death [35] Renal, central nervous, and hematologic system impairments characterize MODS progression and are more strongly associated with mortality Treatment of MODS, therefore, is focused on early recognition of those at risk, removing the proinflammatory pathway trigger, and preventing MODS progression [36] Clinicians should move briskly to optimize cardiorespiratory function, remove catabolic stressors, and provide nutrition while using antimicrobials selectively and avoiding blood product transfusion Key advances in the treatment of patients with severe critical illness and MODS that is based on randomized controlled trials are summarized in Table 40.3 TABLE 40.3 Advances in Management of Multiple Organ Dysfunction Syndrome Based on Randomized Controlled Clinical Trials Advance Digestive tract or oropharynx decontamination with antimicrobials reduces 28-day mortality in ICU patients Lung protective ventilation strategies are associated with reduced mortality and increased Reference Remarks [42] [45] Not widely practiced in the United States, as it conflicts with principles of antimicrobial stewardship Lung protective strategies are commonly utilized in ICU settings ventilator-free days Aggressive enteral nutrition is associated with improved immune function and less mortality in burned children [50] Landmark study suggested that protein repletion is essential for critically ill patients Resuscitation The Surviving Sepsis Guidelines summarize current best practice regarding resuscitation as of 2013 [37] One major strategy to reduce MODS is to ensure optimal initial resuscitation Resuscitation should target adequate oxygen delivery and normalization of physiology Oxygen saturation in mixed venous blood has historically been an important, if not vital, resuscitation target (SvO2-saturation in mixed venous blood obtained from a pulmonary artery catheter or ScvO2-saturation in central venous blood obtained from a central venous catheter in superior vena cava) Rivers et al [38] showed that by using oxygen delivery as a target for resuscitation with fluid, blood, and inotropes, lactic acidemia was less severe and outcomes were improved Subsequent studies of such “goaldirected therapy” have failed to show similar benefit but those investigations have been conducted in an era when the norm in resuscitation is much more advanced monitoring [39] There is no question that inadequate initial resuscitation contributes to MODS risk [40] For a comprehensive discussion of this topic, see Chapter 39 Preventing MODS Progression Source control is critical to terminate the trigger of the proinflammatory response [36] Antimicrobials should be used early and be targeted at a broad spectrum of likely organism, then tailored and de-escalated [15] On the basis of the possible role of the gut and enteric bacteria as a “motor” for MODS, several groups have proposed cleansing the bowel of bacteria to disrupt this relationship, but studies have yielded conflicting results and this practice remains controversial [41] Although some European studies support parenteral and topical oropharyngeal antibiotics in reducing mortality, this is not widely accepted in the United States [42] Transfusion is a risk factor for MODS, suggesting that a conservative approach to blood transfusion is appropriate [43] Mechanical ventilation may contribute to distant organ dysfunction in acute lung injury (ALI) and ARDS [44] In the ARDSNet trial, the “lung protective strategy” of plateau ≤30 cm H2O and tidal volumes ≤6 mL per kg body weight was associated with a reduction in all-cause mortality of 9% compared with conventional ventilation with plateau pressures ≤50 cm H2O and tidal volumes ≤12 mL per kg body weight [45] A European study affirmed that use of a ventilation strategy with volumes greater than ARDSNet (>7.4 mL tidal volume per kg body weight) increased mortality [46] For a comprehensive discussion of this topic, see Chapters 163 and 166 Although Van den Berghe et al [47] initially reported reduced mortality with intensive insulin therapy and the mortality reduction was in septic MODS, unacceptably high rates of hypoglycemia have since been reported [48] without a mortality benefit Steroid therapy in patients with sepsis and MODS may be used for select indications For a comprehensive discussion of this topic, see Chapter 39 Nutrition Early initiation of enteral nutrition is associated with improved outcome for patients with severe trauma, surgery, sepsis, and MODS MODS may be attenuated among patients receiving enteral nutrition within 24 hours as opposed to initiation later [49,50] Recent retrospective data support early enteral feeding to reduce ICU and hospital mortality [51] Both the American and European Societies of Parenteral and Enteral Nutrition (ASPEN and ESPEN) recommend enteral nutrition for ventilated patients when hemodynamics are adequate and gastrointestinal function is sufficient [52,53] Feeding patients at their full nutritional requirements does not, appear to be necessary early in their ICU course, however [54] Arginine has been shown to be beneficial for surgical and trauma patients, but cannot be recommended for septic medical patients because of immunoinflammatory characteristics [53] However, omega fatty acids do appear beneficial for shortening length of stay, ventilator days, and mortality among septic patients in some studies Serum selenium is depleted in trauma and surgical patients, and some evidence suggests that depletion may contribute to MODS Selenium repletion reduced MODS in a multi-institutional prospective randomized trial in 2007, but subsequent prospective trials questions its efficacy [55,56] For a comprehensive discussion of this topic, see Chapters 39, 212, 213, and 214 p 366 p 367 Continuous renal replacement therapy has been associated with reduction of MODS severity, theoretically due to alteration of the balance of pro- and anti-inflammatory circulating cytokines [57], but no large studies currently support its use for this purpose Renal replacement appears to reduce outcome and length of hospital stay when initiated early but only based upon meta-analyses of smaller heterogeneous studies [58] Intense interest in renal replacement is reflected in the numerous studies published on the topic to date but well-designed, appropriately powered studies defining the optimal method, risks, and benefits have yet to be performed Other novel therapies include pharmacologic manipulation of the microcirculation or augmentation of mitochondrial oxidative metabolism to enhance oxygen delivery or utilization [15] PROGNOSIS AND ICU LENGTH OF STAY Up to 20% of patients admitted to an ICU develop aspects of MODS, with significantly increased morbidity and mortality [59] MODS severity is decreasing but ICU mortality remains stable, perhaps because overall acuity is increasing [60] In an epidemiologic study of sepsis in 2001, Angus et al [22] determined that dysfunction of one, two, or three organ systems conveys 1%, 4.7%, and 20.7% mortality, respectively Four-organ dysfunction was associated with 65% to 74% mortality [19,22] A more recent study examining the outcomes of critically ill patients reported ICU mortality of 10% for failure of three systems or less, increasing to 25% and 50% for four- and five-organ system failure, respectively Mortality of seven-system failure was 100% [61] In addition to mortality, MODS can also affect long-term functional outcomes [21] MODS is the most common reason for prolonged stays in the ICU, exceeding single organ system failure and simply the need for ventilatory support [59] Determining prognosis for individual patients with MODS remains challenging Severity of organ dysfunction at the time of ICU admission or during the ICU stay correlates well with mortality, with the highest scores suggestive of a nonsurvivable injury or illness, but does not allow clinically actionable bedside prediction of an individual patient’s outcome [7] The strongest independent risk factors for death appear to be central nervous system failure (RR = 16.06) and cardiovascular failure (RR = 11.83) [61] CONCLUSIONS MODS is largely a result of medical progress and modern ICU care A common denominator for the pathogenesis of MODS appears to be cellular hypoperfusion, leading to an imbalanced immune response, with resultant organ damage and failure Treatment of patients at risk for MODS is supportive, ensuring adequate resuscitation, nutritional support, infection or tissue injury source control, and support of individual organ system functions Despite modern critical care, MODS remains a common cause of death among critically ill patients REFERENCES Levine JH, Durham RM, Moran J, et al: Multiple organ failure: is it disappearing? World J Surg 20(4):471–473, 1996 Baue AE: Multiple organ failure—the discrepancy between our scientific knowledge and understanding and the management of our patients Langenbecks Arch Surg 385(7):441–453, 2000 Churchill ED: Surgeon to Soldiers: Diary and Records of the Surgical Consultant, Allied Force Headquarters, World War 2 Philadelphia, PA, Lippincott, 1972 Ashbaugh DG, Bigelow DB, Petty TL, et al: Acute respiratory distress in adults Lancet 2(7511):319–323, 1967 Barie PS, Hydo LJ: Influence of multiple organ dysfunction syndrome on duration of critical illness and hospitalization Arch Surg 131(12):1318–1323, 1996; discussion 1324 Knaus WA, Draper EA, Wagner DP, et al: Prognosis in acute organsystem failure Ann Surg 202(6):685–693, 1985 Marshall JC, Cook DJ, Christou NV, et al: Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome Crit Care Med 23(10):1638–1652, 1995 Vincent JL, Moreno R, Takala J, et al: The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine Intensive Care Med 22(7):707–710, 1996 Le Gall JR, Klar J, Lemeshow S, et al: The logistic organ dysfunction system A new way to assess organ dysfunction in the intensive care unit ICU Scoring Group JAMA 276(10):802–810, 1996 10 Afessa B, Gajic O, Keegan MT: Severity of illness and organ failure assessment in adult intensive care units Crit Care Clin 23(3):639–658, 2007 11 Sauaia A, Moore EE, Johnson JL, et al: Validation of postinjury multiple organ failure scores Shock 31(5):438–447, 2009 12 Haq A, Patil S, Parcells AL, et al: The simplified acute physiology score III is superior to the simplified acute physiology score II and acute physiology and chronic health evaluation II in predicting surgical and ICU mortality in the “Oldest Old” Curr Gerontol Geriatr Res 2014:934852, 2014 13 Oda S, Hirasawa H, Sugai T, et al: Cellular injury score for multiple organ failure severity scoring system J Trauma 45(2):304–310, 1998; discussion 310–311 14 Exarchopoulos T, Charitidou E, Dedeilias P, et al: Scoring systems for outcome prediction in a cardiac surgical intensive care unit: a comparative study Am J Crit Care 24(4):327–334, 2015 15 Mizock BA: The multiple organ dysfunction syndrome Dis Mon 55(8):476–526, 2009 16 Vogel JA, Newgard CD, Holmes JF, et al: Validation of the Denver Emergency Department Trauma Organ Failure Score to predict postinjury multiple organ failure J Am Coll Surg 222(1):73–82, 2016 17 Knaus WA, Draper EA, Wagner DP, et al: APACHE II: a severity of disease classification system Crit Care Med 13(10):818–829, 1985 18 Zimmerman JE, Kramer AA, McNair DS, et al: Acute Physiology and Chronic Health Evaluation (APACHE) IV: hospital mortality assessment for today’s critically ill patients Crit Care Med 34(5):1297– 1310, 2006 19 Vincent JL, Sakr Y, Sprung CL, et al: Sepsis in European intensive care units: results of the SOAP study Crit Care Med 34(2):344–353, 2006 20 Barie PS, Hydo LJ: Epidemiology of multiple organ dysfunction syndrome in critical surgical illness Surg Infect (Larchmt) 1(3):173– 185, 2000; discussion 185–186 21 Ulvik A, Kvale R, Wentzel-Larsen T, et al: Multiple organ failure after trauma affects even long-term survival and functional status Crit Care 11(5):R95, 2007 22 Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care Crit Care Med 29(7):1303–1310, 2001 23 Barie PS, Hydo LJ, Pieracci FM, et al: Multiple organ dysfunction syndrome in critical surgical illness Surg Infect (Larchmt) 10(5):369– 377, 2009 24 Rittirsch D, Flierl MA, Ward PA: Harmful molecular mechanisms in sepsis Nat Rev Immunol 8(10):776–787, 2008 25 Ward NS, Casserly B, Ayala A: The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients Clin Chest Med 29(4):617–625, viii, 2008 26 Lenz A, Franklin GA, Cheadle WG: Systemic inflammation after trauma Injury 38(12):1336–1345, 2007 27 Tschoeke SK, Hellmuth M, Hostmann A, et al: The early second hit in trauma management augments the proinflammatory immune response to multiple injuries J Trauma 62(6):1396–1403, 2007; discussion 1403–1404 28 Rosenthal MD, Moore FA: Persistent inflammation, immunosuppression, and catabolism: evolution of multiple organ dysfunction Surg Infect (Larchmt) 17(2):167–172, 2016 29 Gentile LF, Cuenca AG, Efron PA: Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care J Trauma Acute Care Surg 72(6):1491–1501, 2012 30 Villar J, Maca-Meyer N, Perez-Mendez L, et al: Bench-to-bedside review: understanding genetic predisposition to sepsis Crit Care 8(3):180–189, 2004 31 Fry DE, Pearlstein L, Fulton RL, et al: Multiple system organ failure The role of uncontrolled infection Arch Surg 115(2):136–140, 1980 32 Ciesla DJ, Moore EE, Johnson JL, et al: The role of the lung in postinjury multiple organ failure Surgery 138(4):749–757, 2005; discussion 757–758 33 Moore FA, Sauaia A, Moore EE, et al: Postinjury multiple organ failure: a bimodal phenomenon J Trauma 40(4):501–510, 1996; discussion 510–512 34 Ciesla DJ, Moore EE, Johnson JL, et al: Multiple organ dysfunction during resuscitation is not postinjury multiple organ failure Arch Surg 139(6):590–594, 2004; discussion 594–595 35 Russell JA, Singer J, Bernard GR, et al: Changing pattern of organ dysfunction in early human sepsis is related to mortality Crit Care Med 28(10):3405–3411, 2000 p 367 p 368 36 Barie PS, Hydo LJ, Shou J, et al: Decreasing magnitude of multiple organ dysfunction syndrome despite increasingly severe critical surgical illness: a 17-year longitudinal study J Trauma 65(6):1227– 1235, 2008 37 Dellinger RP, Levy MM, Rhodes A, et al: Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012 Crit Care Med 41(2):580–637, 2013 38 Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock N Engl J Med 345(19):1368–1377, 2001 39 Pope JV, Jones AE, Gaieski DF, et al: Emergency Medicine Shock Research Network (EMShockNet) Investigators Multicenter study of central venous oxygen saturation (ScvO2) as a predictor of mortality in patients with sepsis Ann Emerg Med 55(1):40–46, 2010 40 Levy B, Sadoune LO, Gelot AM, et al: Evolution of lactate/pyruvate and arterial ketone body ratios in the early course of catecholaminetreated septic shock Crit Care Med 28(1):114–119, 2000 41 Marshall JC, Christou NV, Meakins JL: The gastrointestinal tract The “undrained abscess” of multiple organ failure Ann Surg 218(2):111– 119, 1993 42 Silvestri L, van Saene HK, Zandstra DF et al: Impact of selective decontamination of the digestive tract on multiple organ dysfunction syndrome: systematic review of randomized controlled trials Crit Care Med 38(5):1370–1376, 2010 43 Napolitano LM, Kurek S, Luchette FA, et al: Clinical practice guideline: red blood cell transfusion in adult trauma and critical care Crit Care Med 37(12):3124–3157, 2009 44 Slutsky AS, Tremblay LN: Multiple system organ failure Is mechanical ventilation a contributing factor? Am J Respir Crit Care Med 157(6 Pt 1):1721–1725, 1998 45 Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome The acute respiratory distress syndrome network N Engl J Med 342(18):1301–1308, 2000 46 Sakr Y, Vincent JL, Reinhart K, et al: High tidal volume and positive fluid balance are associated with worse outcome in acute lung injury Chest 128(5):3098–3108, 2005 47 van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in the critically ill patients N Engl J Med 345(19):1359–1367, 2001 48 Mesotten D, Van den Berghe G: Glycemic targets and approaches to management of the patient with critical illness Curr Diab Rep 12(1):101–107, 2012 49 Moore FA, Moore EE: The evolving rationale for early enteral nutrition based on paradigms of multiple organ failure: a personal journey Nutr Clin Pract 24(3):297–304, 2009 50 Alexander JW, MacMillan BG, Stinnett JD, et al: Beneficial effects of aggressive protein feeding in severely burned children Ann Surg 192(4):505–517, 1980 51 Artinian V, Krayem H, DiGiovine B: Effects of early enteral feeding on the outcome of critically ill mechanically ventilated medical patients Chest 129(4):960–967, 2006 52 Kreymann KG, Berger MM, Deutz NE, et al: ESPEN Guidelines on enteral nutrition: Intensive care Clin Nutr 25(2):210–223, 2006 53 Taylor BE, McClave SA, Martindale RG, et al: Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Crit Care Med 44(2): 390–438, 2016 54 Arabi YM, Aldawood AS, Haddad SH, et al: Permissive underfeeding or standard enteral feeding in critically ill adults N Engl J Med 372(25):2398–2408, 2015 55 Angstwurm MW, Engelmann L, Zimmermann T, et al: Selenium in Intensive Care (SIC): results of a prospective randomized, placebocontrolled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock Crit Care Med 35(1):118–126, 2007 56 Chelkeba L, Ahmadi A, Abdollahi M, et al: The effect of parenteral selenium on outcomes of mechanically ventilated patients following sepsis: a prospective randomized clinical trial Ann Intensive Care 5(1):29, 2015 57 Ratanarat R, Brendolan A, Piccinni P, et al: Pulse high-volume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival Crit Care 9(4):R294–R302, 2005 58 Liu Y, Davari-Farid S, Arora P, et al: Early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury after cardiac surgery: a systematic review and meta-analysis J Cardiothorac Vasc Anesth 28(3):557–563, 2014 59 Martin CM, Hill AD, Burns K, et al: Characteristics and outcomes for critically ill patients with prolonged intensive care unit stays Crit Care Med 33(9):1922–1927, 2005 60 Ciesla DJ, Moore EE, Johnson JL, et al: A 12-year prospective study of postinjury multiple organ failure: has anything changed? Arch Surg 140(5):432–438, 2005; discussion 438–440 61 Mayr VD, Dunser MW, Greil V, et al: Causes of death and determinants of outcome in critically ill patients Crit Care 10(6):R154, 2006 Chapter 41 Traumatic Brain Injury WILEY R HALL • RAPHAEL A CARANDANG The CDC estimates that traumatic brain injury (TBI) results in over 2.5 million ER visits, nearly 300,000 hospitalizations, and over 50,000 deaths annually in the US Up to 3 million people are living in the US with disabilities related to TBI [1] Falls are the most common of the causes overall, often seen among the pediatric and elderly populations Motor vehicle accidents follow and are the most common cause among those aged 14 to 35 The estimated annual financial burden is 3 billion dollars for initial hospitalization costs to 60 billion dollars overall [2–4] TRAUMA BAY AND INITIAL CRITICAL CARE Care of the TBI patient involves early stabilization and longitudinal care to halt deterioration and maximize recovery Injury from TBI is commonly divided into two subtypes Primary injury is dealt directly to the brain by the initial insult and can be modified only by prevention Much of prehospital, emergency department, and ICU care has long been targeted at reducing secondary injury, which affects up to 91% of TBI patients [5] Hypotension, hypoxia, hemorrhage, intracranial hypertension, cerebral edema, seizures, and metabolic derangements all contribute to secondary injury [6] Studies of permissive hypotension, a strategy for hemorrhagic trauma, have excluded patients with TBI owing to the concerns over cerebral perfusion pressure [7] Systolic blood pressure is maintained over 90 mmHg, and management to maintain adequate cerebral perfusion pressure (CPP) improves outcomes [8,9] Corticosteroids are contraindicated for the management of brain edema related to TBI because they are associated with worse outcomes [10] The mainstay of urgent neuroimaging remains computed tomography (CT) Although MRI is more sensitive for axonal injury, small hemorrhage, and ischemia, CT is rapid, readily available, and more sensitive for acute SAH [11] Isotonic fluids remain the primary vehicle for volume resuscitation Studies of hypertonic saline as resuscitation fluid have been equivocal; 7.5% saline solution and 500m Osm per L sodium lactate showed improved outcome, while a study using 7% saline solution revealed no benefit [11–13] Hyponatremic or hypoosmotic fluids induce and exacerbate cerebral edema and are avoided during resuscitation and throughout the critical care phase of TBI, even in the presence of hypernatremia 5% dextrose as a resuscitation fluid for non-brain injured children has been associated with the evolution of cerebral edema [14] A rat model of TBI comparing ringers lactate and 5% dextrose infusions reported significantly increased mortality for animals treated with 5% dextrose [15] Mannitol1gm per kg IV is the first choice for measured or when elevated ICP is presumed Preoperative high-dose mannitol, 1.4gm per kg IV, benefits patients requiring emergent surgery for subdural and temporal lobe hematomas [16,17] Mannitol is infused through a 5micron filter and must not be infused through a cooled catheter such as those used for targeted temperature management, owing to the risk of precipitation of mannitol out of solution Hypertonic saline solutions including 23.4% saline may be used in place of mannitol during trauma resuscitation and may improve outcomes [18] An advantage favoring hypertonic saline is that it acts as a volume expander, whereas mannitol acts as an osmotic diuretic, possibly reducing the effectiveness of volume resuscitation However, 23.4% saline solution must be infused through a central venous catheter, and issues surrounding the storage of concentrated electrolytes in Emergency Departments raised by the Joint Commission have prevented 23.4% saline from competing effectively with mannitol for this role in many centers [19] p 368 p 369 Seizures may increase intracranial pressure and may lead to secondary injury Prophylaxis during the first 7 days after severe injury is standard of care, though this has not been shown to alter long-term mortality, or even the incidence of long-term epilepsy Phenytoin is a common choice as it is available in enteral and IV formulations, and levetiracetam is popular because of its low incidence of interactions Neither has been shown to be superior to the other [20] Reversal of Anticoagulation Reversal of anticoagulation must be performed promptly for TBI patients with ICH [21] Among patients receiving vitamin K antagonists with International Normalized ratio (INR) over 1.4, vitamin K 10 mg IV should be given, conventionally followed on days 2 and 3 by 5 to 10 mg enterally [22] Reversal of anticoagulation with four-factor prothrombin complex concentrate (PCC), dosed by weight, and INR is faster than and superior to plasma transfusion [23–25] KCentra is a PCC FDA approved for warfarin reversal among patients with major bleeding or requiring urgent surgery For patients with a history of heparin-induced thrombocytopenia in the past 90 days, plasma transfusion or factor VIIa dosing may be considered because KCentra contains a small amount of heparin The anticoagulant effects of the direct thrombin inhibitor dabigatran (Pradaxa) can be reversed by the FDA approved reversal agent idarucizumab, which binds and inactivates dabigatran If idarucizumab is not available, KCentra, hemodialysis, and hemofiltration have been attempted [26] Factor Xa inhibitors currently lack a reversal agent, though andexanet alfa is moving through the approval process and is expected to be available KCentra has been reported as a possible reversal agent [26] For patients receiving aspirin, platelet transfusions may be considered for patients requiring urgent neurosurgery [27] Transfusion is not as useful for patients receiving GPIIB/IIIa inhibitors as the transfused platelets are inactivated [26], though salvage transfusion is often considered Surgical Therapies for TBI Surgical hematoma evacuation is commonly performed acutely for subdural hematomas over 1 cm in width and epidural hematomas with significant mass effect or progression Routine evacuation of parenchymal hemorrhages is not indicated, as violation of otherwise healthy or recoverable tissue may be required to access the hematoma However, intracranial hypertension refractory to medical management may be an indication for resection of parenchymal hematomas [28,29] Decompressive craniectomy has historically been viewed as a last resort for management of TBI with intracranial hypertension [29,30] One complication of decompressive craniectomy is injury to the brain tissue and blood vessels, especially veins, at the edges of the craniotomy defect Authors recommend removal of at least a 12-cm-diameter bone flap, and extension of the craniectomy to the temporal bone is also sometimes recommended [31,32] A retrospective review of TBI patients treated with decompressive craniectomy found no outcome benefits compared to historical controls For many patients, surgery was performed late in the ICU course, and the subgroup of patients who had earlier surgery did have better outcomes at 6 months compared to controls [28] Analysis of a non-randomized series of patients with GCS ≤9 and a midline shift greater than the width of an extra axial hematoma who were considered for decompressive surgery revealed that the treated patients had worse GCS on admission, but more survived to discharge and more were discharged to home or skilled nursing than those of the non-surgical group [29] The often cited DECRA study randomized patients prospectively to decompressive surgery or medical therapy This study demonstrated harm in the treatment group, however was plagued by problems with randomization in that the treatment group had significantly more patients with unreactive pupils than the medical group, and the study had intended to exclude patients with unreactive pupils altogether [33] Neurological Critical Care Multimodality Monitoring Neurological monitoring relevant to TBI is covered in depth in Chapter 31 Although the physical examination remains the gold standard for neurological monitoring, many patients with severe TBI require sedation and other therapies, which make surrogate monitoring mandatory Although important for the reduction of the duration of mechanical ventilation and the prevention of VAP [34], interruption of sedation is contraindicated for patients with elevated ICP [35] Elevated ICP, particularly when not responsive to therapy, is associated with worse outcomes [36] The recent BEST-TRIP trial demonstrated no improvement of outcomes with a protocol driven by ICP over one guided by clinical observations [37,38] However, ICP monitoring remains the standard of care where available and is supported by consensus statements including one to which BEST-TRIPs lead investigator was a contributor Although brain edema may preclude the selection of an external ventricular drain (EVD) over a parenchymal ICP monitor, EVDs have the advantage of offering the ability to decrease ICP by draining CSF and are thus favored when feasible, especially when hydrocephalus is present [35] EEG is indicated when the mental status is worse than anticipated given the known injuries, and continuous EEG is favored [35] Poor brain tissue oxygen tension is a predictor of poor outcome, and treatment guided by brain tissue oximetry has been shown to improve outcomes [39,40], and even with the use of brain oximetry or metabolic monitoring, ICP monitoring is still required [35] See Chapter 31 for more detail Treatment of Elevated Intracranial Pressure For all patients with elevated intracranial pressure, maintenance of intravascular volume is important because it improves cerebral perfusion pressure For patients with significant acidosis or those requiring high volumes of crystalloid, the substitution of isonatremic sodium acetate for sodium chloride may limit the development of hyperchloremic metabolic acidosis [41] Adequate analgesia and anxiolysis can help maintain adequate ICP Head elevation to 30 degrees above horizontal decreases intracranial pressure without sacrificing cerebral perfusion or oxygenation [42] Mannitol Mannitol has long been known to lower intracranial pressure [43,44] Doses of 0.25 to 1.4 g per kg IV are commonly used every 3 to 8 hours [16,45–47] Our center favors 1gm per kg, rounded to the nearest 25gms, every 6 hours, to allow approximately 5 half-lives between doses and to avoid the development of idiogenic osmoles, which may lead to tolerance of osmotherapy [48,49] Acutely with rapid infusion, mannitol increases circulating volume, blood pressure, and cardiac output and decreases blood viscosity [50,51] This may lead to decreased ICP via an increase in CBF and autoregulatory decrease of cerebral blood volume (CBV) [45] Mannitol also acts as an osmotic diuretic, recruiting water from the interstitial space through the blood brain barrier, which is nearly impervious to mannitol Mannitol has been shown to preferentially shrink brain tissue where the blood–brain barrier is intact, though it has been shown that midline shift does not increase with mannitol’s use [52,53] p 369 p 370 Mannitol may leak into damaged brain tissue, but has been shown to leave that tissue once it clears the bloodstream Additionally, it does not accumulate in concentrations higher than those of plasma; thus, no reverse gradient exists to exacerbate cerebral edema [49,54,55] Mannitol clearance from the bloodstream can be monitored my measuring the osmotic gap [56,57] Hypertonic Saline Hypertonic saline (HS) may be used to decrease intracranial pressure, and like mannitol, HS has hemodynamic effects in addition to its osmotic effects on cerebral edema [48,58–60] The use of HS at concentrations varying from 3% infusions to 29.2% boluses has been shown to improve ICP both as a primary measure and when mannitol fails [41,58,61–63] At our center, we use 15 to 30 mL boluses of 23.4% sodium chloride every 4 to 6 hours when mannitol fails to control ICP or when renal failure precludes the use of mannitol Randomized trials comparing serial doses of mannitol to hypertonic saline are not conclusive Loss of efficacy of ICP control when HS is used over several days time may be due to the formation of osmolytes, as persistent hypernatremia frequently develops The relationship between hypernatremia, renal function, and outcomes is a complex one Only one study has directly examined the relationship between varying levels of hypernatremia and outcomes [64] Though patients with more severe injuries were more likely to be hypernatremic, likely owing to more aggressive osmotherapy, there was an independent association between a finding of serum sodium over 160 mEq per L and mortality Although it is well known that hypernatremia in the setting of hypovolemia is associated with renal failure [65], the safety of euvolemic hypernatremia is not known It is also known that a rapid decrease of serum sodium may lead to cerebral edema among healthy patients, and the dangers of hypotonic fluid administration for patients and experimental models with cerebral edema have been described above When significant hypernatremia develops among patients with cerebral edema, it may be safer to limit treatments which raise sodium while resisting treatments which directly lower it Diabetes insipidis is an ominous sign among those with TBI [66] Treatment with vasopressin or DDVAP to limit free water diuresis may be a safer way to combat hypernatremia in this setting than parenteral-free water administration Cerebral Perfusion Pressure and the Lund Concept In contrast to purely ICP based management, the “Lund Concept” describes a strategy for lowering ICP based partially on decreasing CPP [67,68] In this strategy, it is postulated that increases of MAP may exacerbate cerebral edema, especially when large amounts of crystalloid solutions are administered MAP is lowered to decrease hydrostatic capillary pressure and ameliorate cerebral edema Mannitol and vasopressors are generally avoided CPP is tolerated as low as 50 mmHg Multimodality monitoring, often including bedside microdialysis, is required to monitor the metabolic reaction of vulnerable tissue to decreased CPP Temperature Management Hyperthermia increases the body’s metabolic demand, worsens cognitive impairment, and has been associated with worse outcomes among multiple models of neurological insults [69] Induced hypothermia has been shown to improve neurological outcomes after witnessed cardiac arrest [70,71] Recent studies suggest a target temperature of 36°C is as effective as a target of 33degrees; however, this has not been studied for TBI [72] Induced hypothermia has been shown to improve outcomes using animal models [71,73,74] The first hour after injury was found to be critical A series of large, multicenter trials, however, failed to show a benefit of prophylactic-induced hypothermia after TBI [75–77] Still, Class I evidence shows that induced hypothermia lowers ICP [78] Side effects include hyperglycemia, immunosuppression, hypovolemia, and electrolyte imbalances largely due to “cold diuresis” [71] Rapid rewarming or overshoot may lead to rebound intracranial hypertension and impaired cerebral vasoreactivity [79] Patients presenting with mild hypothermia after TBI should not be aggressively rewarmed [71] Fever, defined as core body temperature over 38°C, affects up to 68% of TBI patients within 72 hours of admission and is associated with worse outcome [69] Although much effort is spent in ICUs to reduce fever, and induction of hypothermia remains a hot topic in critical care literature, neither effort has been conclusively shown to improve outcomes after TBI Induced Coma Pharmacologically induced coma may be an appropriate step taken when ICP and CPP cannot be managed by the above means [80,81] Prophylactic administration of barbiturates does not improve outcomes [8] Pentobarbital is the most common agent reported for this purpose and is postulated to lower ICP by reducing the cerebral metabolic rate of oxygen (CMRO2) Pentobarbital has numerous side effects, including hypotension, cardiac depression, immune system suppression, and hypothermia Close attention must be paid to the maintenance of adequate hemodynamics [81,82] Coma is induced with a slow bolus 5 to 10 mg per kg of pentobarbital, followed by an infusion of 1 to 3 mg/kg/h Although many centers check pentobarbital levels, continuous EEG monitoring provides a more useful measure of dose effect, with the goal being a reduction of ICP to acceptable levels and the induction of burst suppression on EEG [80] Serum drug levels are of value when evaluating for CNS function, for example, when brain death is contemplated and the clearance of drug from the bloodstream must be confirmed Propofol has also been described as an agent for ICP control When used to achieve burst suppression, a 2mg per kg loading dose followed by an infusion of up to 200g/kg/h is required Severe hypotension and propofol infusion syndrome are concerns when using high-dose propofol Systemic Critical Care Mechanical Ventilator Management Hypoxia and hypercarbia may exacerbate secondary injury and complicate ICP and CPP management [83] The Brain Trauma Foundation recommends maintaining SpO2 over 90% and PO2 over 60 for TBI patients [8] Advanced modes of mechanical ventilation and inotropic and/or vasopressor are frequently required to maintain CPP and adequate gas exchange For some patients, hypoxia may be resistant to conventional ventilator settings, and increases in PEEP and FIO2 may be required Concern has been raised over the effect of PEEP on ICP Published data, however, reveal varying effects of PEEP on ICP One theory posits that PEEP raises intrathoracic pressure, thus decreasing venous return to the chest and thus increasing the volume of venous blood inside the cranial vault, leading to a rise in ICP [84] In reality, it is unclear to what extent changes of PEEP are transmitted into the thoracic cavity, much less into the vascular system where venous return could be affected, especially among patients with ARDS where the stiffness of the diseased lung may not transmit PEEP efficiently [85] A series of TBI patients with ALI/ARDS reported that ICP was more tightly associated with PCO2 than levels of PEEP [86] For refractory hypoxia, prone positioning has been reported in several series Although in some neurocritical care series raised ICP has been reported, in a dedicated series on TBI patients with ARDS prone positioning was associated with improved oxygenation without detrimental effects on ICP or CPP [87,88] p 370 p 371 Ventilation of the TBI patient demands attention to systemic acid base balance and to secondary effects on cerebral blood flow Therapeutic hyperventilation (HV) is the fastest way to lower ICP, causing rapid vasoconstriction of the cerebral arterial supply Animal experiments and human observations reveal that HV causes a decrease in the partial pressure of oxygen in brain tissue (PbtO2) [89,90], is now contraindicated during the acute phase of TBI, and is discouraged by most authorities [8,89] Even for normal brain tissue, decreases of PCO2 below 30mmHg resulted in decreased CBF and evidence of anaerobic metabolism [89] Although evidence of harm with less aggressive HV is lacking, evidence for its benefit is absent This intervention cannot be recommended with enthusiasm If used when other measures fail, HV should be monitored with one of the markers for tissue stress, such as brain tissue oximetry or microdialysis [91] Glucose Management A 2001 multicenter trial revealed that tight glycemic control improves outcome in critical care populations [92] This finding leads to a revolution of ICU glucose management, with many hospitals implementing ICU-based protocols targeting maximum serum glucoses levels from 110 to 140 mg per dL More recent trials have questioned this result, prominently the NICE SUGAR trial, which revealed increased mortality of patients treated with a tight control protocol targeting serum glucose under108 mg per dL compared to a protocol targeting glucose under 180 mg per dL [93] For the TBI and neurocritical care population, concerns have been raised over glucose delivery to regions of vulnerable brain tissue, which may already be at risk of poor perfusion owing to cerebral edema A study using microdialysis to examine glucose delivery revealed significantly low brain glucose levels associated with signs of metabolic stress among patients treated with a tight glycemic control strategy [94] A meta-analysis concluded while blood sugars over 200 mg per dL were likely harmful, overly tight glycemic control was also harmful and a blood sugar target of under 180mg per dL was suggested [95] Nutrition and Metabolism A thorough review of the literature regarding energy expenditure of TBI patients found that historically held beliefs regarding brain injured patients’ elevated metabolic rates and nutritional needs are valid [96] Moderate to severely injured TBI patients exhibited metabolic rates 96% to 132% of predicted baseline when sedated and 105% to 160% over base when awake Another review documented some findings where hypermetabolism reached 200% of predicted baseline [97] TBI patients are also catabolic, exhibiting a –3 to –16gm per day nitrogen balance The resultant decrease of muscle mass and related immune function deficits may worsen outcomes [96] Although the common practice is to prescribe nutrition targeted to exceed baseline predicted needs by 40%, these authors favored the use of indirect calorimetry to better target each patient’s individual needs Although upper GI intolerance is common early among those with TBI, placing patients at risk for aspiration pneumonia, some studies do show a trend to improved outcomes with the institution of early feeding [96] No conclusive data exist to suggest favoring post-pyloric feeding to gastric feeding Prevention of Venous Thromboembolism Pulmonary embolism is the 3rd leasing cause of death among patients surviving past day one of TBI [98] Trials comparing early to late chemoprophylaxis are lacking Low molecular weight heparin (LMWH) is superior to unfractionated heparin (UFH) for preventing venous thromboembolism among patients with polytrauma and spinal cord injury, but data regarding TBI patients are limited Consensus guidelines support therapy with intermittent pneumatic compression systems within 24 hours of admission and chemoprophylaxis with LMWH or UFH starting 24 to 48 hours after admission or completion of surgery as long as there is no evidence of continued bleeding [99] Specialty Injury Subtypes Penetrating Brain Injury High-energy missile trauma produces brain injury through multiple mechanisms Brain tissue along the tract of the missile is injured directly With high-energy projectiles, a wave of energy precedes the missile, and significant damage is delivered by a wave of cavitation, which follows in the wake of the projectile This cavitation may reverberate through the cranium, reflecting off the inside surface of the dura and skull [100,101] Contusions, intracranial hemorrhage, and subdural and epidural hemorrhage may result Vascular injury is common when the path of injury crosses near vascular structures, and arterio-venous fistulas and pseudoaneurysms may develop [101] Vasospasm may develop early or late in the ICU course Critical care focuses on control of intracranial pressure using methods similar to those used for closed head injury Surgical debridement is indicated for missile and bone fragments in noneloquent areas of the brain only [102] Historically, from 15% to 50% of wounds become infected and antibiotic prophylaxis is standard practice There is no consensus on which antimicrobials are more appropriate; most surgeons favor cephalosporins, whereas some centers use combinations including cephalosporins, metronidazole, and vancomycin Invasion of an open-air sinus by the injury raises the risk of infection and may warrant broader coverage [101] Blast Related Trauma Experience in Iraq, Afghanistan, and to an extent Lebanon has revealed a previously poorly recognized variant of TBI: that delivered by blast injury [103–105] With current protective armor, many warfighters survive previously fatal battlefield injuries [104,106] Combatants and civilians exposed to high-energy blast trauma suffer brain injuries, which may have features seen in both closed and penetrating TBI [104] Pseudoaneurysms and vasospasm were commonly detected among a cohort of [103] patients imaged either because of injury known to be near or involving cerebral vasculature or because of unexplained deterioration of neurological function The prevalence of vasospasm and pseudoaneurysm in the general blast TBI population was not investigated Vasospasm was been recognized as early as 48 hours after blast TBI and may occur as late as 10 to 14 days after injury Warfighters returning to rehabilitation hospitals with severe injuries did demonstrate recoverability even in the worst cases; up to 50% of patients presenting to stateside rehabilitation with GCS score 3 to 5 eventually recovered to a Glasgow Outcome Scale (GOS) score ≥3 at 1- to 2-year follow-up [107] Associated Vascular Injuries Both blunt and penetrating trauma to the head and neck may induce the formation of aneurysms Intervention is indicated when aneurysms are accessible to surgical or endovascular repair [108,109] Dissections of the carotid and vertebral arteries may occur among TBI patients, especially when trauma also includes the cervical spine Dissections may lead to ischemic strokes by either leading to occlusion of the involved vessel or by serving as an embolic source [108,110] Treatment for dissections includes avoidance of hypertension and mitigation of embolic risk Both antiplatelet drugs and heparin have significant hemorrhagic risks for patients with concomitant brain injury [111] In extreme cases, surgical or endovascular occlusion of the affected vessel may be the safest choice to limit embolic risk [108,112] p 371 p 372 Long-Term Outcomes Prediction of outcomes after TBI is difficult due to the heterogeneity of the different injury subtypes, varying levels of concomitant nonneurological injuries, and medical complications of critical care Bedside physician estimates of prognosis are often either overly pessimistic or unrealistically optimistic When studied, physicians have reported that they feel their predictions are often inaccurate [113] The need for better prognostication tools, as well as aids for shared decision making, has been noted by the CDC as recently as 2015 and is the subject of ongoing research [114,115] Treatment by a specialized neurocritical care team is associated with decreased hospital costs, decreased length of stay, and improved outcomes at 6 months [116,117] Findings of bilaterally fixed pupils confer a 70% to 90% likelihood of death or persistent vegetative state as the final outcome [11] Absent bilateral Somatosensory Evoked Potentials (SEP) early in the ICU course predict death, whereas initially normal bilateral readings predict good outcome SEPs may fluctuate over the course of each day; thus, single recordings are less informative than serial examinations, and improvement within the first 10 days predicts recovery [118,119] Serial physical examinations combined with aggressive resuscitation for 72 hours are recommended by consensus guidelines [120,121] REFERENCES Centers for Disease Control and Prevention Report to Congress on Traumatic Brain Injury in the United States: Epidemiology and Rehabilitation National Center for Injury Prevention and Control; Division of Unintentional Injury Prevention Atlanta, GA, 2015 McGarry LJ, Thompson D, Millham FH, et al: Outcomes and costs of acute treatment of traumatic brain injury J Trauma 53(6):1152–1159, 2002 Maas AI, Stocchetti N, Bullock R: Moderate and severe traumatic brain injury in adults Lancet Neurol 7(8):728–741, 2008 Maas AI, Marmarou A, Murray GD, et al: Prognosis and clinical trial design in traumatic brain injury: the IMPACT study J Neurotrauma 24(2):232–238, 2007 Jones PA, Andrews PJ, Midgley S, et al: Measuring the burden of secondary insults in head-injured patients during intensive care J Neurosurg Anesthesiol 6(1):4–14, 1994 Tisdall MM, Smith M: Multimodal monitoring in traumatic brain injury: current status and future directions Br J Anaesth 99(1):61–67, 2007 Alsawadi A: The clinical effectiveness of permissive hypotension in blunt abdominal trauma with hemorrhagic shock but without head or spine injuries or burns: a systematic review Open Access Emerg Med 4:21–29, 2012 Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons Guidelines for the management of severe traumatic brain injury J Neurotrauma 24(Suppl 1):S1–106, 2007 Hammell CL, Henning JD: Prehospital management of severe traumatic brain injury BMJ 338:b1683, 2009 Available from: http://dx.doi.org/10.1136/bmj.b1683 10 Roberts I, Yates D, Sandercock P, et al: Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebocontrolled trial Lancet 364(9442):1321–1328, 2004 11 Moppett IK: Traumatic brain injury: assessment, resuscitation and early management Br J Anaesth 99(1):18–31, 2007 12 Vassar MJ, Fischer RP, O’Brien PE, et al: A multicenter trial for resuscitation of injured patients with 7.5% sodium chloride The effect of added dextran 70 The multicenter group for the study of hypertonic saline in trauma patients Arch Surg 128(9):1003–1011; discussion 1011–1013, 1993 13 Shackford SR, Zhuang J, Schmoker J: Intravenous fluid tonicity: effect on intracranial pressure, cerebral blood flow, and cerebral oxygen delivery in focal brain injury J Neurosurg 76(1):91–98, 1992 14 Jackson J, Bolte RG: Risks of intravenous administration of hypotonic fluids for pediatric patients in ED and prehospital settings: let’s remove the handle from the pump Am J Emerg Med 18(3):269–270, 2000 15 Feldman Z, Zachari S, Reichenthal E, et al: Brain edema and neurological status with rapid infusion of lactated ringer’s or 5% dextrose solution following head trauma J Neurosurg 83(6):1060– 1066, 1995 16 Cruz J, Minoja G, Okuchi K: Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupillary widening: a randomized trial Neurosurgery 51(3):628–637; discussion 637–638, 2002 17 Cruz J: Current international trends in severe acute brain trauma Arq Neuropsiquiatr 58(3A):642–647, 2000 18 Pascual JL, Maloney-Wilensky E, Reilly PM, et al: Resuscitation of hypotensive head-injured patients: is hypertonic saline the answer? Am Surg 74(3):253–259, 2008 19 Wanzer LJ: Implementing national patient safety goal 3 AORN J 82(3):471, 473–474, 2005 20 Jones KE, Puccio AM, Harshman KJ, et al: Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury Neurosurg Focus 25(4):E3, 2008 21 Veshchev I, Elran H, Salame K: Recombinant coagulation factor VIIa for rapid preoperative correction of warfarin-related coagulopathy in patients with acute subdural hematoma Med Sci Monit 8(12):CS98– CS100, 2002 22 Hung A, Singh S, Tait RC: A prospective randomized study to determine the optimal dose of intravenous vitamin K in reversal of over-warfarinization Br J Haematol 109:537–539, 2000 23 Frontera JA, Gordon E, Zach V, et al: Reversal of coagulopathy using prothrombin complex concentrates is associated with improved outcome compared to fresh frozen plasma in warfarin-associated intracranial hemorrhage Neurocrit Care 21:397–406, 2014 24 Woo CH, Patel N, Conell C, et al: Rapid warfarin reversal in the setting of intracranial hemorrhage: a comparison of plasma, recombinant activated factor VII, and prothrombin complex concentrate World Neurosurg 81:110–115, 2014 25 Sarode R, Milling TJ Jr, Refaai MA, et al: Efficacy and safety of a 4factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma controlled, phase IIIb study Circulation 128:1234–1243, 2013 26 Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al: Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine Neurocrit Care 24(1):6–46, 2016 27 Li X, Sun Z, Zhao W, et al: Effect of acetylsalicylic acid usage and platelet transfusion on postoperative hemorrhage and activities of daily living in patients with acute intracerebral hemorrhage J Neurosurg 118:94–103, 2013 28 Munch E, Horn P, Schurer L, et al: Management of severe traumatic brain injury by decompressive craniectomy Neurosurgery 47(2):315– 322; discussion 322–323, 2000 29 Coplin WM, Cullen NK, Policherla PN, et al: Safety and feasibility of craniectomy with duraplasty as the initial surgical intervention for severe traumatic brain injury J Trauma 50(6):1050–1059, 2001 30 Gunnarsson T, Fehlings MG: Acute neurosurgical management of traumatic brain injury and spinal cord injury Curr Opin Neurol 16(6):717–723, 2003 31 Cooper DJ, Rosenfeld JV, Murray L, et al: Early decompressive craniectomy for patients with severe traumatic brain injury and refractory intracranial hypertension – a pilot randomized trial J Crit Care 23(3):387–393, 2008 32 Wagner S, Schnippering H, Aschoff A, et al: Suboptimum hemicraniectomy as a cause of additional cerebral lesions in patients with malignant infarction of the middle cerebral artery J Neurosurg 94(5):693–696, 2001 33 Cooper DJ, Rosenfeld JV, Murray L, et al: Decompressive craniectomy in diffuse traumatic brain injury N Engl J Med 364:1493–1502, 2011 34 Girard TD, Kress JP, Fuchs BD, et al: Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and breathing controlled trial): a randomised controlled trial Lancet 371:126–134, 2008 35 Le Roux P, Menon DK, Citerio G, et al: Consensus Summary Statement of the international Multidisciplinary Consensus conference on Multimodality Monitoring in Neurocritical Care A statement of healthcare professionals from the Neurocritical Care Society and the European Society of Intensive Care Medicine Neurocrit Care 21(Suppl 2):S297–S361, 2014 36 Badri S, Chen J, Barber J, et al: Mortality and long-term functional outcome associated with intracranial pressure after traumatic brain injury Intensive Care Med 38(11):1800–1809, 2012 37 Chesnut RM, Temkin N, Carney N, et al: A trial of intracranialpressure monitoring in traumatic brain injury N Engl J Med 367(26):2471–2481, 2012 38 Chesnut RM: Intracranial pressure monitoring: headstone or a new head start The BEST TRIP trial in perspective Intensive Care Med 39(4):771–774, 2013 39 Oddo M, Levine J, Mackenzie L, et al: brain hypoxia is associated with short-tem outcome after severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion pressure Neurosurgery 69(5):1037–1045, 2011 40 Brain Tissue Oxygen Monitoring in Traumatic Brain Injury, BOSST 2 NCT 00974259 www.clinicaltrials.gov 41 Qureshi AI, Suarez JI, Bhardwaj A, et al: Use of hypertonic (3%) saline/acetate infusion in the treatment of cerebral edema: effect on intracranial pressure and lateral displacement of the brain Crit Care Med 26(3):440–446, 1998 42 Ng I, Lim J, Wong HB: Effects of head posture on cerebral hemodynamics: its influences on intracranial pressure, cerebral perfusion pressure, and cerebral oxygenation Neurosurgery 54(3):593–597; discussion 598, 2004 p 372 p 373 43 Allen CH, Ward JD: An evidence-based approach to management of increased intracranial pressure Crit Care Clin 14(3):485–495, 1998 44 McGraw CP, Howard G: Effect of mannitol on increased intracranial pressure Neurosurgery 13(3):269–271, 1983 45 Diringer MN, Zazulia AR: Osmotic therapy: fact and fiction Neurocrit Care 1(2):219–233, 2004 46 Wakai A, Roberts I, Schierhout G: Mannitol for acute traumatic brain injury [see comment][update of cochrane database syst rev 2005; (4):CD001049; PMID: 16235278] Cochrane Database Syst Rev (1):001049, 2007 47 Wakai A, Roberts I, Schierhout G: Mannitol for acute traumatic brain injury [update in cochrane database syst rev 2007;(1):CD001049; PMID: 17253453][update of cochrane database syst rev 2003; (2):CD001049; PMID: 12804397] Cochrane Database Syst Rev (4):001049, 2005 48 Doyle JA, Davis DP, Hoyt DB: The use of hypertonic saline in the treatment of traumatic brain injury J Trauma 50(2):367–383, 2001 49 Rudehill A, Gordon E, Ohman G, et al: Pharmacokinetics and effects of mannitol on hemodynamics, blood and cerebrospinal fluid electrolytes, and osmolality during intracranial surgery J Neurosurg Anesthesiol 5(1):4–12, 1993 50 Wallasch TM: The value of transcranial doppler sonography in neurosurgery Neurochirurgia (Stuttg) 33(Suppl 1):58–60, 1990 51 Burke AM, Quest DO, Chien S, et al: The effects of mannitol on blood viscosity J Neurosurg 55(4):550–553, 1981 52 Manno EM, Adams RE, Derdeyn CP, et al: The effects of mannitol on cerebral edema after large hemispheric cerebral infarct Neurology 52(3):583–587, 1999 53 Videen TO, Zazulia AR, Manno EM, et al: Mannitol bolus preferentially shrinks non-infarcted brain in patients with ischemic stroke Neurology 57(11):2120–2122, 2001 54 Maioriello AV, Chaljub G, Nauta HJ, et al: Chemical shift imaging of mannitol in acute cerebral ischemia Case report J Neurosurg 97(3):687–691, 2002 55 Wise BL, Perkins RK, Stevenson E, et al: Penetration of C14-Labeled mannitol from serum into cerebrospinal fluid and brain Exp Neurol 10:264–270, 1964 56 Garcia-Morales EJ, Cariappa R, Parvin CA, et al: Osmole gap in neurologic-neurosurgical intensive care unit: its normal value, calculation, and relationship with mannitol serum concentrations Crit Care Med 32(4):986–991, 2004 57 Worthley LI, Guerin M, Pain RW: For calculating osmolality, the simplest formula is the best Anaesth Intensive Care 15(2):199–202, 1987 58 Hartl R, Ghajar J, Hochleuthner H, et al: Hypertonic/hyperoncotic saline reliably reduces ICP in severely head-injured patients with intracranial hypertension Acta Neurochir Suppl 70:126–129, 1997 59 Hijiya N, Horiuchi K, Asakura T: Morphology of sickle cells produced in solutions of varying osmolarities J Lab Clin Med 117(1):60–66, 1991 60 Shackford SR, Schmoker JD, Zhuang J: The effect of hypertonic resuscitation on pial arteriolar tone after brain injury and shock J Trauma 37(6):899–908, 1994 61 Horn P, Munch E, Vajkoczy P, et al: Hypertonic saline solution for control of elevated intracranial pressure in patients with exhausted response to mannitol and barbiturates Neurol Res 21(8):758–764, 1999 62 Worthley LI, Cooper DJ, Jones N: Treatment of resistant intracranial hypertension with hypertonic saline Report of two cases J Neurosurg 68(3):478–481, 1988 63 Oddo M, Levine J, Frangos S, et al: Effect of Mannitol and hypertonic saline on cerebral oxygenation in patients with severe traumatic brain injury and refractory intracranial hypertension J Neurol Neurosurg Psychiatry 80(8):916–920, 2009 64 Aiyagari V, Deibert E, Diringer MN: Hypernatremia in the neurologic intensive care unit: How high is too high? J Crit Care 21(2):163–172, 2006 65 Lima EQ, Aguiar FC, Barbosa DM, et al: Severe hypernatraemia (221 mEq/l), rhabdomyolysis and acute renal failure after cerebral aneurysm surgery Nephrol Dial Transplant 19(8):2126–2129 66 Bahloul M, Chelly H, Ben Hmida M, et al: Prognosis of traumatic head injury in south tunisia: a multivariate analysis of 437 cases J Trauma 57(2):255–261, 2004 67 Grande PO: The “lund concept” for the treatment of severe head trauma – physiological principles and clinical application Intensive Care Med 32(10):1475–1484, 2006 68 Nordstrom CH: Assessment of critical thresholds for cerebral perfusion pressure by performing bedside monitoring of cerebral energy metabolism Neurosurg Focus 15(6):E5, 2003 69 Aiyagari V, Diringer MN: Fever control and its impact on outcomes: what is the evidence? J Neurol Sci 261(1–2):39–46, 2007 70 Hypothermia after Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest N Engl J Med 346(8):549–556 71 Polderman KH: Induced hypothermia and fever control for prevention and treatment of neurological injuries.[see comment] Lancet 371(9628):1955–1969, 2008 72 Nielsen N, Wetterslev J, Cronberg T, et al: Targeted temperature management at 33°C versus 36°C after cardiac arrest N Engl J Med 369:2192–2206, 2013 73 Mcilvoy LH: The effect of hypothermia and hyperthermia on acute brain injury AACN Clin Issues 16(4):488–500, 2005 74 Povlishock JT: Pathophysiology of neural injury: therapeutic opportunities and challenges Clin Neurosurg 46:113–126, 2000 75 Clifton GL, Miller ER, Choi SC, et al: Lack of effect of induction of hypothermia after acute brain injury N Engl J Med 344(8):556–563, 2001 76 Clifton GL, Choi SC, Miller ER, et al: Intercenter variance in clinical trials of head trauma – experience of the national acute brain injury study: hypothermia J Neurosurg 95(5):751–755, 2001 77 Clifton GL, Drever P, Valadka A, et al: Multicenter trial of early hypothermia in severe brain injury J Neurotrauma 26(3):393–397, 2009 78 Marion D, Bullock MR: Current and future role of therapeutic hypothermia J Neurotrauma 26(3):455–467, 2009 79 Povlishock JT, Wei EP: Posthypothermic rewarming considerations following traumatic brain injury J Neurotrauma 26(3):333–340, 2009 80 Ling GS, Marshall SA: Management of traumatic brain injury in the intensive care unit Neurol Clin 26(2):409–426, 2008 81 Tang ME, Lobel DA: Severe traumatic brain injury: maximizing outcomes Mt Sinai J Med 76(2):119–128, 2009 82 Pickard JD, Czosnyka M: Management of raised intracranial pressure J Neurol Neurosurg Psychiatry 56(8):845–858, 1993 83 Oddo M, Nduom E, Frangos S, et al: Acute lung injury is an independent risk factor for brain hypoxia after severe traumatic brain injury Neurosurgery 67(2):338–344, 2010 84 Stevens RD, Lazaridis C, Chalela JA: The role of mechanical ventilation in acute brain injury Neurol Clin 26(2):543–563, 2008 85 Luecke T, Pelosi P: Clinical review: positive end-expiratory pressure and cardiac output Crit Care 9(6):607–621, 2005 86 Mascia L, Grasso S, Fiore T, et al: Cerebro-pulmonary interactions during the application of low levels of positive end-expiratory pressure Intensive Care Med 31(3):373–379, 2005 87 Thelandersson A, Cider A, Nellgard B: Prone position in mechanically ventilated patients with reduced intracranial compliance Acta Anaesthesiol Scand 50(8):937–941, 2006 88 Reinprecht A, Greher M, Wolfsberger S, et al: Prone position in subarachnoid hemorrhage patients with acute respiratory distress syndrome: effects on cerebral tissue oxygenation and intracranial pressure Crit Care Med 31(6):1831–1838, 2003 89 Clausen T, Scharf A, Menzel M, et al: Influence of moderate and profound hyperventilation on cerebral blood flow, oxygenation and metabolism Brain Res 1019(1–2):113–123, 2004 90 Manley GT, Pitts LH, Morabito D, et al: Brain tissue oxygenation during hemorrhagic shock, resuscitation, and alterations in ventilation J Trauma 46(2):261–267, 1999 91 Stocchetti N, Maas AI, Chieregato A, et al: Hyperventilation in head injury: a review Chest 127(5):1812–1827, 2005 92 van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in the critically ill patients N Engl J Med 345(19):1359–1367, 2001 93 NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, et al: Intensive versus conventional glucose control in critically ill patients N Engl J Med 360(13):1283–1297, 2009 94 Vespa P, Boonyaputthikul R, McArthur DL, et al: Intensive insulin therapy reduces microdialysis glucose values without altering glucose utilization or improving the lactate/pyruvate ratio after traumatic brain injury Crit Care Med 34(3):850–856, 2006 95 Kramer AH, Roberts DJ, Zygun DA: Optimal glycemic control in neurocritical care patients: a systematic review and meta-analysis Crit Care 16(5):R203, 2012 96 Krakau K, Omne-Ponten M, Karlsson T, et al: Metabolism and nutrition in patients with moderate and severe traumatic brain injury: a systematic review Brain Inj 20(4):345–367, 2006 97 Foley N, Marshall S, Pikul J, et al: Hypermetabolism following moderate to severe traumatic acute brain injury: a systematic review J Neurotrauma 25(12):1415–1431, 2008 98 Geerts WH, Bergqvist D, Pineo GF, et al: Prevention of venous thromboembolism: American College of Chest Physicians evidencebased clinical practice guidelines (8th Edition) Chest 133(6 Suppl):381S–453S, 2008 99 Nyquist P, Bautista C, Jichici D, et al: Prophylaxis of venous thrombosis in neurocritical care patients: an evidence-based guideline: a statement for healthcare professionals from the neurocritical care society Neurocrit Care 24(1):47–60, 2016 100 Oehmichen M, Meissner C, Konig HG, et al: Gunshot injuries to the head and brain caused by low-velocity handguns and rifles a review Forensic Sci Int 146(2–3):111–120, 2004 101 Esposito DP, Walker JB: Contemporary management of penetrating brain injury Neurosurg Q 19(4):249–254, 2009 102 Aarabi B, Alden TD, Chesnut RM: Guidelines for the management of penetrating brain injury J Trauma 51:s1–s86, 2001 103 Armonda RA, Bell RS, Vo AH, et al: Wartime traumatic cerebral vasospasm: recent review of combat casualties Neurosurgery 59(6):1215–1225; discussion 1225, 2006 104 Ling G, Bandak F, Armonda R, et al: Explosive blast neurotrauma J Neurotrauma 26(6):815–825, 2009 105 Levi L, Borovich B, Guilburd JN, et al: Wartime neurosurgical experience in lebanon, 1982-85 II: closed craniocerebral injuries Isr J Med Sci 26(10):555–558, 1990 106 Champion HR, Holcomb JB, Young LA: Injuries from explosions: physics, biophysics, pathology, and required research focus J Trauma 66(5):1468–1477; discussion 1477, 2009 107 Bell RS, Vo AH, Neal CJ, et al: Military traumatic brain and spinal column injury: a 5-year study of the impact blast and other military grade weaponry on the central nervous system J Trauma 66(4):S104– S111, 2009 108 Guyot LL, Kazmierczak CD, Diaz FG: Vascular injury in neurotrauma Neurol Res 23(2–3):291–296, 2001 109 Halbach VV, Higashida RT, Dowd CF, et al: Endovascular treatment of vertebral artery dissections and pseudoaneurysms J Neurosurg 79(2):183–191, 1993 p 373 p 374 110 Detante O, Colle F, Vu P, et al: Pontine infarct after fracture of the skull base Rev Neurol (Paris) 159(3):326–328, 2003 111 Marion DW: Complications of head injury and their therapy Neurosurg Clin N Am 2(2):411–424, 1991 112 Matsuura D, Inatomi Y, Saeda H, et al: Traumatic extracranial vertebral artery dissection treated with coil embolization – a case report Rinsho Shinkeigaku 45(4):298–303, 2005 113 Perel P, Edwards P, Wentz R, et al: Systematic review of prognostic models in traumatic brain injury BMC Med Inform Decis Mak 6:38, 2006 114 Cai X, Robinson J, Muehlschlegel S, et al: Patient preferences and surrogate decision making in neuroscience intensive care units Neurocrit Care 23(1):131–141, 2015 115 Muehlschlegel S, Shutter L, Col N, et al: Decision aids and shared decision-making in neurocritical care: an unmet need in our NeuroICUs Neurocrit Care 23(1):127–130, 2015 116 Patel HC, Menon DK, Tebbs S, et al: Specialist neurocritical care and outcome from head injury Intensive Care Med 28(5):547–553, 2002 117 Suarez JI, Zaidat OO, Suri MF, et al: Length of stay and mortality in neurocritically ill patients: impact of a specialized neurocritical care team Crit Care Med 32(11):2311–2317, 2004 118 Amantini A, Amadori A, Fossi S: Evoked potentials in the ICU Eur J Anaesthesiol Suppl 42:196–202, 2008 119 Claassen J, Hansen HC: Early recovery after closed traumatic head injury: somatosensory evoked potentials and clinical findings Crit Care Med 29(3):494–502, 2001 120 Izzy S, Compton R, Carandang R, et al: Self-fulfilling prophecies through withdrawal of care: do they exist in traumatic brain injury, too? Neurocrit Care 19(3):347–363, 2013 121 Souter MJ, Blissitt PA, Blosser S, et al: Recommendations for the critical care management of devastating brain injury: prognostication, psychological, and ethical management Neurocrit Care 23(1):4–13, 2015 Chapter 42 Spinal Cord Trauma HANBING ZHOU • CHRISTIAN P DIPAOLA INTRODUCTION The incidence of traumatic spinal cord injury (SCI) is approximately 40 SCIs per million persons per year in the United States [1] Most traumatic spinal cord trauma (80.6%) occurs in males and most cases are among Whites (66%), followed by African Americans (26.2%) and Hispanics (8.3%) There has been an increase in the average age of injury since the 1970s from 28.7 years to 41 years This is owing to an increase in people older than 65 years in the general population and a decrease in childhood trauma [1] Traumatic SCI in the United States is reported to occur by motor vehicle accidents (47%), falls (23%), personal violence (14%), sports injuries (9%), and other sources of trauma (7%) [1] Cervical injuries (C1–C7) account for approximately 55% of all traumatic SCIs In the thoracolumbar spine, the most common location of fractures is between T12 and L2, with SCI in 10% to 25% of these fractures [2] Thoracic fracture patients with less severe neurologic deficits have more favorable prognosis in the recovery of overall general health status compared to those with more significant neurologic deficits [3] The trauma surgeon works as a part of a multidisciplinary team A high degree of suspicion for spinal column injury with neurologic impairment must be maintained upon evaluation of most trauma patients As the trauma team leader, he or she must be able to appropriately identify the pertinent history, examine the patient, provisionally stabilize the patient and the spine, and order appropriate imaging to identify or rule out injuries that may require orthopedic or neurosurgical consultation In order to execute these key fundamentals, a surgeon must understand the relevant anatomy, injury mechanisms, injury patterns, pathophysiology, and associated physical findings Familiarity with “first responder” and in-hospital provisional spinal stabilization methods, patient resuscitation measures, and monitoring is the key to proper treatment ANATOMY Spinal Column The normal spinal column consists of 33 vertebrae, including 7 cervical, 12 thoracic, 5 lumbar, 5 fused sacral, and 4 fused coccygeal vertebrae When anatomy is normal, the cervical and lumbar spines are lordotic, and the thoracic and sacral spines are kyphotic These curvatures help to balance the spine and evenly distribute forces C1, which is also called the atlas, has neither a vertebral body nor a spinous process (Fig 42.1) It is a ring-like structure with anterior and posterior arches separated by lateral masses on each side It has two superior concave facets that articulate with the occipital condyles, accounting for approximately 50% of the neck flexion and extension [4] FIGURE 42.1 Anatomy of C1 (Atlas) and C2 (Axis) [40] C2, which is also called the axis, has an odontoid process (dens) and vertebral body (Fig 42.1) It articulates with C1 (atlanto-axial) and accounts for 50% of cervical rotation There is a vascular watershed area between the apex and base of the C2, and this limited blood supply is thought to affect healing in Type II odontoid fractures The dens articulates with the posterior aspect of the anterior ring of C1 and is stabilized by the transverse ligament There is no intervertebral disc at either the atlanto-occipital or the C1–C2 joints C1–C7 vertebrae typically have a transverse foramen, and the vertebral artery travels through the transverse foramen of C1–C6 in the majority of individuals C7 has a prominent spinous process and is a useful landmark during physical examination In the thoracic spine, the articulations with the ribs lead to increased rigidity Therefore, more force is required to produce a fracture in the thoracic region than the cervical or lumbar region The cervicothoracic junction represents a region that transitions from the fairly mobile cervical spine to the fairly rigid thoracic spine Furthermore, it represents a transition from the lordotic cervical spine to the kyphotic thoracic spine Biomechanically, this construct creates significant stress on the cervicothoracic junction Disruptions of this anatomical region by trauma or tumor can lead to significant instability Similarly, at the thoracolumbar junction, the vertebral column transitions from a relatively stiff construct in the thoracic spine to a more flexible construct This transition point, especially T11–L2, acts as a zone of stress concentration and is more susceptible to injury than other adjacent portions of the spine Spinal Cord The spinal cord is a tubular nervous tissue that extends from the brainstem and typically terminates as the conus medullaris at the inferior border of L1 Extending from the distal tip of the conus medullaris, the cauda equina consists of the lumbar and sacral nerve roots and filum terminale surrounded by dura The spinal cord acts as a shuttle that relays neuronal signals from the brain to the rest of the body and vice versa Specific neural fibers with similar function form “tracts.” Ascending tracts relay sensory information from the body to the brain and the descending tracts relay motor function to the body p 375 p 376 Ascending tracts include the dorsal columns, lateral spinothalamic tract, and ventral spinothalamic tract The dorsal columns convey deep touch, proprioception, and vibratory sensation The lateral spinothalamic tract conveys pain and temperature and the ventral spinothalamic tract conveys light touch Descending tracts are comprised of lateral and ventral corticospinal tracts, which carry voluntary motor signals to the body The blood supply to the spinal cord originates from the segmental vessels, which are branches of the great vessels at the neck, thorax, and abdomen These segmental vessels divide into anterior and posterior radicular arteries, which transverse the neuroforamen along with the segmental nerve root The anterior and posterior radicular arteries finally terminate as the anterior and posterior spinal artery The anterior spinal artery is the primary blood supply of the anterior two-thirds of the spinal cord, which includes the lateral and ventral corticospinal tracts The posterior spinal artery is the primary blood supply to the dorsal sensory columns [5] CLASSIFICATION OF INJURY AND ASSESSMENT OF SPINAL STABILITY The vertebral column serves to transmit loads, permit motion, and protect the spinal cord Spinal stability is one of the most important considerations in the management of spinal trauma White and Panjabi defined spinal stability as the “ability of the spine under physiologic loads to limit patterns of displacement so as not to damage or irritate the spinal cord or nerve roots and, in addition, to prevent incapacitating deformity or pain due to structural changes [6].” An ideal spinal column injury classification should be both descriptive and prognostic The system should have consistent radiographic measures and guide clinical decision-making There are a number of historical spinal trauma classification schemes utilized to assess the stability of the spine The majority of them are not validated and based on retrospective views and experiences of individual surgeons These systems are typically based on either mechanistic or anatomic description of spinal column injuries Although there are numerous proposed injury classifications, many of them are not prognostic and do not guide clinical decision-making [7] The Denis classification is an example of a three-column theory based on anatomic description of thoracolumbar fractures This system divides the spine into anterior, middle, and posterior columns The anterior column consists of the anterior half of the vertebral body, the anterior half of the intervertebral disk, and the anterior longitudinal ligament The middle column consists of the posterior half of the vertebral body, the posterior half of the intervertebral disk, and the posterior longitudinal ligament The posterior column consists of the posterior arch, the facet joint complex, the interspinous ligament, the supraspinous ligament, and the ligamentum flavum The spine is considered unstable if two or more columns are disrupted The Denis classification system does provide for an anatomic description of the zones of injury for thoracolumbar trauma but unfortunately does not account for neurologic status and guide clinical treatment decision Holdsworth described the first mechanistic classification of spinal injuries based on experiences of over 1,000 patients by categorizing fractures as simple wedge, dislocation, rotational fracture–dislocation, extension, burst, and shear [7] This was the first classification to highlight the importance of posterior ligamentous complex (PLC) Allen and Ferguson [8], later in 1982, proposed a classification of subaxial spine fractures based on radiographic appearance and the inferred mechanism of disruptions This classification has six groups including (1) flexion compression, (2) vertical compression, (3) flexion distraction, (4) extension compression, (5) extension distraction, and (6) lateral flexion Mechanistic classifications have limited clinical application because they are mainly based on inferred mechanisms of injury rather than objective injury morphology Furthermore, similar to anatomic descriptive classifications, neurologic status of the patient is not included, which is essential in treatment decision-making [7] Because of the lack of clinical relevance of the previously established classification systems and an overall “gold standard” system, Vaccaro et al [9] proposed the Subaxial Cervical Spine Injury Classification System (SLIC) and Thoracolumbar Injury Classification and Severity Score (TLICS) [10] system that is based on injury morphology, integrity of the disco-ligamentous complex (SLIC) (Fig 42.2) or posterior ligamentous complex (TLICS) (Fig 42.3) and neurologic status These two systems were designed to incorporate key anatomic and clinical predictors of stability and severity of injury The goal of these systems is to simplify communication, help guide treatment, and provide a common language upon which further study can be performed FIGURE 42.2 Subaxial Cervical Spine Injury Classification System (SLIC) [9] FIGURE 42.3 Thoracolumbar Injury Classification and Severity Score (TLICS) [10] The three components of the SLIC system include: morphology, discoligamentous complex, and neurologic status Each component is assigned a weighted score The overall injury score is the sum of the weighted score of each component Nonoperative treatment may be considered for a score 4 If the score = 4, then either nonoperative or operative treatment may be considered The three components of the TLICS system include: morphology, posterior ligamentous complex, and neurologic involvement Similar to SLIC system, each component has a weighted score and the overall injury score is the sum of the three components Nonoperative treatment may be considered for score 4 If score = 4 then, either nonoperative or operative treatment may be considered p 376 p 377 SLIC and TLICS systems are built on three components that are independent determinants of prognosis and optimal treatment They are the first comprehensive spinal trauma classification systems that account for the neurologic status of the patient Most importantly, SLIC and TLICS systems overcame the shortcomings of the previous classification systems by demonstrating good interobserver reliability and validity [10] Furthermore, Patel et al demonstrated that these systems can be easily incorporated into large clinical practice with physicians of different levels of experience from attending surgeons to fellows and residents [11] Neurologic Injury Assessing neurologic injury is the key in determining the level of injury and the severity of injury to the spinal cord The extent of the injury can determine the treatment options and overall prognosis Motor examination includes strength measurement (Grade 0–5) of five key upper- and lower-extremity myotomes The upper extremity myotomes include C5, elbow flexion; C6, wrist extension; C7, elbow extension; C8, long finger flexion; T1, finger abductions The lower-extremity myotomes include L2, hip flexion; L3, knee extension; L4, ankle dorsiflexion; L5, great toe extension; S1, ankle plantar flexion Sensory examination is comprised of light touch and pinprick sensation along the dermatomes [12] The ASIA (American Spinal Injury Association) scoring system [13,14] was proposed to allow for easy classification of neurologic impairment The scoring system is based on motor, sensory, reflex, and rectal function (Fig 42.4) For a complete neurologic examination, it is important to consider if the patient is in spinal shock by checking the bulbocavernosus reflex This reflex is characterized by anal sphincter contraction in response to squeezing the glans penis Tugging on an indwelling Foley catheter can also elicit the reflex p 377 p 378 FIGURE 42.4 American Spinal Injury Association (ASIA) scoring system [13] documents the motor and sensory function to determine the severity of the neurologic injury The motor score is comprised of 10 key muscles groups as seen on the left column of the figure The sensory score for light touch and pinprick is comprised of sensation within 28 dermatomes Perianal sensation and anal contraction assessment is critical to determine the functional preservation in the lowest sacral segments, S4–S5 An AIS (ASIA impairment score) grade is determined based on these neurologic findings It is also important to determine the neurologic level of injury This is defined as the lowest segment with intact sensation and antigravity (grade 3 or more) motor function In the regions where there is no myotome to test, motor level is presumed to be the same as sensory level Another key component of the neurologic assessment is to determine whether the injury is complete or incomplete Complete injury is defined as no anal contraction, 0/5 distal motor score, 0/2 distal sensory score, and present bulbocavernosus reflex Incomplete is defined as voluntary anal contraction or present perianal sensation, or palpable/visible muscle contraction below the neurologic level The ASIA scoring system yields an ASIA Impairment Score (AIS), which groups each injury into five categories (A–E) based on severity (Fig 42.5) Grade A is a complete neurologic injury with no motor or sensory preserved in the sacral segments (S4–S5) Grade B, C, D are incomplete neurologic injures Grade B is defined as preserved sensory function but not motor function below the neurologic level and includes the sacral segments (S4–S5) Grade C has preserved motor function below the neurologic level and more than half of key muscles below the neurologic level have a muscle grade less than 3 Grade D has preserved motor function below the neurologic level with at least half of the key muscles below the neurologic level have a muscle grade of 3 or more Grade E has normal neurologic function FIGURE 42.5 ASIA Impairment Score (AIS) neurologic severity grading scale, A through E [13] The AIS has prognostic value for determination Fisher et al found that patients with ASIA A (complete) spinal cord injury had no distal lower extremity functional recovery 2 years after the injury Approximately half of AISA B patients will achieve ambulatory status, compared to ¾ of ASIA C patients and almost all patients with ASIA D injuries Younger patients tend to have a better prognosis as well Burns et al found 91% of patients younger than 50 years with ASIA C were ambulatory at discharge compared to 42% in patients older than 50 years [12,15] Patients with no motor or sensory function preserved in the lowest sacral segments (S4–S5) are AIS A Those with sensory sparing in the lowest sacral segments but no motor functions are AIS B Those with preserved motor function below the neurologic level but the majority of myotomes having a muscle grade of 2 or less are AIS C Those with preserved motor function below the neurologic level with majority of myotomes having a muscle grade of 3 or more are AIS D Patients with normal motor and sensory function are AIS E There are several incomplete neurologic injuries based on specific locations of the spinal cord that have predictable patterns of neurologic findings Anterior cord syndrome is characterized by loss of motor and loss of pain and temperature sensation below the level of the injury Vibratory sense and proprioception are preserved This is usually a result of flexion/compression injury that lead to either direct compression of the anterior spinal cord or disruption of anterior spinal artery (supplies anterior two-thirds spinal cord) This injury carries the worst prognosis of incomplete SCI Central cord syndrome is the most common incomplete cord injury It often occurs in the elderly with extension type injury mechanisms It is believed to be caused by spinal cord compression and central cord edema with injury/destruction of lateral corticospinal tract white matter The classical finding on physical examination is more pronounced motor deficits in the upper extremities compared to the lower extremities Hands typically have more pronounced motor deficits than arms This is owing to the fact that hands are more “centrally” located in the corticospinal tract Patients with central cord syndrome have good prognosis but full functional recovery is rare Lowerextremities function typically recovers first and hand function is last to recover [16] Posterior cord syndrome is very rare and examination findings include loss of proprioception with preserved motor, pain and light touch It is a result of direct injury to the dorsal columns Stabbing injuries to the back commonly cause this injury pattern Brown–Sequard syndrome is a complete cord hemitransection as a result of penetrating trauma or direct lateral injuries to the spinal cord Patients on examination have ipsilateral deficit in motor, vibratory sense and proprioception below the level of the injury and contralateral loss of pain and temperature sensation These patients have excellent overall prognosis with the majority of patients able to ambulate at final followup Conus medullaris syndrome presents with symmetric lowerextremity motor deficits and bowel and bladder dysfunction Patients typically have symmetric perineal or “saddle” loss of sensation This is a result of injuries to the conus medullaris at the thoracolumbar junction Because of the significant amount of nerve roots emerging from this area of the spinal cord, patients are less likely to recover neurologically compared to nerve root injury p 378 p 379 Cauda equina syndrome is defined by symptoms that result from nerve root compression in the lumbosacral region This is most commonly caused by disc herniation but in trauma patients this nerve root compression can result from retropulsion of fracture fragments or fracture dislocation of the vertebrae Key features of cauda equina syndrome include bilateral leg pain, blower and bladder dysfunction, saddle anesthesia, and lower-extremity motor and sensory deficits Certain lesions may affect the transition level between the conus medullaris and cauda equina, and symptoms may overlap Cauda equina is predominantly lower motor neuron dysfunction, and deep tendon reflexes will be intact in the levels cranial to the level of injury Patients with conus medullaris syndrome have predominantly upper motor neuron dysfunction, and patients will have absent deep tendon reflexes in the lower extremities Pathophysiology Blunt Trauma Damage to the spinal cord from blunt trauma injury occurs in two stages The primary injury phase includes a combination of mechanical factors that cause direct injury to the spinal cord This leads to direct neurologic dysfunction at and below the level of the injury This direct mechanical disruption and persistent pressure on the spinal cord leads to secondary events that worsen the initial damage [17] Within seconds to minutes after the injury (immediate phase), there is disruption of microvasculature that leads to possible hemorrhage in the gray matter, and edema in the white matter of the spinal cord [17,18] This increases the extracellular fluid and pressure, which leads to decreased perfusion in the spinal cord This decrease in perfusion ultimately results in ischemia owing to thrombosis and vasospasm [19] After the immediate phase is the early acute phase, which occurs from 2 hours to 2 days after the initial injury There is further damage from ionic dysregulation and excitotoxicity Intracellular sodium concentration increases as a result of trauma-induced activation of voltage-sensitive sodium channels [19] This increase in sodium is accompanied by influx of calcium through the sodium–calcium exchanger, which leads to intracellular acidosis and cytotoxic edema Furthermore, this influx of sodium and calcium triggers release of excitatory neurotransmitter glutamate in the presynaptic neurons This excessive accumulation of glutamate leads to amplification and propagation of depolarization, which eventually leads to postsynaptic neuron edema and death Furthermore, there is increased infiltration of neutrophils, free radicals, and inflammatory mediators in this phase that contribute to neuronal damage [20] In the subacute phase, which is from 2 days to 2 weeks postinjury, there is increased phagocytosis and apoptosis of the neuronal cells, and demyelination is followed by cyst formation [20] Penetrating Trauma Penetrating SCI comprises a distinct mechanism of spinal injury that deserves special consideration Gunshot wounds and stabbings account for the greatest proportion of penetrating SCI followed by injuries from falls onto sharp objects and industrial type accidents [21] Gunshot missiles impart damage in three ways: (1) Direct tissue destruction; (2) Pressure or shockwave effect; and (3) Temporary cavitation The extent of tissue damage from a gunshot missile is related to the energy imparted by the projectile Kinetic energy (KE) is calculated based on the equation KE = 1/2 mv2 (m = mass and v = velocity) Based on this principle, increases in velocity impart an exponential increase in kinetic energy, which transfers into a greater degree of tissue destruction In general, guns with muzzle velocity below 2,000 feet/sec are considered “low velocity” (civilian pistols) and those over 2,000 feet/sec are considered “high velocity” (military rifles or assault weapons) Shotguns impart a low velocity but high energy owing to the large mass of the pellets or slug that is delivered It is important to identify the type of weapons used as it will dictate the extent of soft-tissue damage and help guide treatment Furthermore, the path which the bullet passes through or comes to a complete stop within the patient can also affect the extent of the damage Bullets that are jacketed tend to pass through targets, whereas bullets that yaw (wobble) often enter the target at an angle thus resulting in a great cross-sectional area or tissue cavity SCI from stabbings involve cervical and thoracic locations in 80% of the cases, and are split equally in prevalence [22] “Cord hemisection” injury is more commonly seen in stabbing injuries owing to the spinal column bony anatomy The penetrating object typically finds the path of least resistance in the gutter between the transverse process and spinal process Because of the orientation of the spinous process (caudal and sagittal), the knife typically is blocked from crossing the midline This results in Brown–Sequard syndrome with loss of ipsilateral motor and proprioception and contralateral pain and temperature Acute Management Early management of a patient with potential spinal cord/spinal column injury should begin immediately at the scene of the accident Pathologic motion of the injured vertebrae can lead to worsening neurologic injury It is estimated that 3% to 25% of spinal cord injuries deteriorate neurologically after the initial trauma owing to transit or early management of the patient [12,23] There has been dramatic improvement in the neurologic status of trauma patients since the establishment of spinal immobilization protocols that stabilize patients from the scene of the accident to the hospital Current recommendations for spinal immobilization consist of a rigid cervical collar, lateral supports, and tape and body straps to secure the patient to a backboard to immobilize the entire spine Unwanted motion can still occur during transport or logrolling the patient, resulting in neurologic deterioration [12,23] It also should be emphasized that a rigid cervical orthosis does not eliminate all cervical motion [24] p 379 p 380 Physicians should review the details of the accident, the energy and mechanism of injury, and the general condition of the patient at the scene Patients with closed head injuries and facial trauma should raise suspicion for a cervical spine injury owing to transmission of force Patients with a “seat belt sign” may have a thoracolumbar spine injury consistent with flexion distraction of the spine about the fulcrum of the seatbelt Patients who have fallen from height may have lumbar burst fractures with other distracting injuries such as open calcaneus or tibial plafond fractures Physicians must be aware of certain patient populations such as pediatric patients or adults with preexisting kyphotic deformities that require special attention during prehospital management In pediatric patients, the head size is disproportionally larger than the body Anterior translation/flexion injury may occur if the patient is positioned on a flat surface An occipital recess or a mattress placed under the torso is needed to maintain neutral spinal alignment In patients with suspected neurologic injury without radiographic (plain radiograph or CT scan) abnormality (SCIWORA), MRI imaging is recommended In adult patients suspected to have ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis (DISH), physicians must be aware of a preexisting kyphotic deformity as well as the very rigid mechanical nature of their spines [12] Placing a cervical collar and taping the head to a flat backboard can worsen an extension–distraction injury, resulting in further neurologic damage Patients with AS and advanced kyphosis may require their heads to be propped up to maintain the preexisting deformities rather than cause an iatrogenic deformity that may lead to neurologic impairment [12] Initial evaluation of a patient should follow the Advanced Trauma Life Support protocols (ATLS), including Airway (A), Breathing (B), Circulation (C), Disability (D), and Exposure (E) Airway management is essential in the trauma patient In case of emergent intubation, in-line immobilization and neutral cervical position should be maintained at all times Patients with neurologic injury at or above C3 often experience acute respiratory arrest and require mechanical ventilation [12] Lowerlevel cervical or thoracic injuries may also lead to difficulty with breathing owing to impaired intercostal muscle function Maintaining oxygenation and perfusion should be a priority in trauma patients Hypotension should be treated aggressively and the etiology of suspected hemorrhage should be investigated thoroughly Patients with seatbelt injures often have intra-abdominal pathologies along with thoracolumbar flexion–distraction injury [12] Furthermore, one should suspect neurogenic shock in the setting of a hypotensive and bradycardic patient Neurogenic shock occurs in approximately 20% of cervical spinal cord injuries and is a result of loss of sympathetic tone on the peripheral vasculature [25,26] Neurogenic shock often occurs with injuries above the T4 level, and hypotension should be aggressively treated to prevent further ischemic cord damage Pharmacologic interventions should be used in case of hypotension not responsive to fluid resuscitation Alphaagonists such as dopamine and norepinephrine can increase peripheral vascular resistance [12] Radiographic Assessment The goal of cervical spine clearance is to safely and efficiently rule out an injury that might, if missed, lead to neurologic injury or late instability [12] Patients with neck pain, tenderness, and neurologic deficits and obtunded patients require radiologic evaluation Patients who are temporarily cognitively impaired should be protected with spinal precautious until a definitive clinical examination is completed Diagnostic imaging modalities utilized to assess spinal column/spinal cord pathologies include plain radiographic films, computed tomography (CT) scans, and magnetic resonance imaging (MRI) scans Two decision guidelines have previously been established to minimize use of unnecessary imaging in trauma patients NEXUS Low Rick Criteria [27] (National Emergency X-radiography Use Study) was designed to identify patients who do not need diagnostic imaging to exclude a clinically significant cervical spine injury Cervical spine radiographs are indicated unless the patients fit all of the following criteria: alert and not intoxicated, no posterior midline tenderness, no neurologic indications of injury, and have no distracting injuries CCR [28] (Canadian C-Spine Rule) guidance states, “the patients who meet the following criteria do not require radiographic study: fully alert and oriented, involved in lowenergy trauma, no neurologic symptoms, no midline tenderness, can actively rotate head 45 degrees in both directions, and have no distracting injuries” (Fig 42.6) FIGURE 42.6 The Canadian C-Spine Rule [28] Plain radiographs provide information on bony integrity and overall alignment Upright plain radiographs including flexion/extension films are often used to assess spinal column alignment under physiologic load CT scans provide a more sensitive and specific modality for evaluation of bony pathology It has enhanced resolution compared to plain radiographs and it allows visualization of the occipitocervical and cervicothoracic junctions Patients with a known diagnosis of ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis (DISH) should be treated with extra caution [12] Owing to fusion of multiple spinal segments (especially in patients with ankylosing spondylitis), nondisplaced fractures behave like diaphyseal long-bone fractures and are potentially highly unstable Previously mentioned scoring systems to assess stability do not apply to these patients and missed diagnosis can have catastrophic results Patients with AS who have been in even a minor trauma that have back/neck pain should have CT/MRI to rule out fracture Negative plain radiographs are not sufficient to make a definite diagnosis [12] A prior study demonstrated a high rate of neurologic deterioration if fractures are missed in this patient population [29] Magnetic resonance imaging (MRI) has become the gold standard for imaging neurologic tissues including the spinal cord When a patient’s neurologic examination does not match the fracture pattern seen on CT scan, MRI should be the utilized in the evaluation process MRI allows better visualization of the spinal cord, ligaments, discs, vessels, and other soft tissues Patients with cervical spine injuries have high rate of disc herniation (36%) on MRI, along with posterior ligamentous injuries (64%) [30] Furthermore, MRI allows the surgeon to plan surgically and prognosticate in the setting of spinal cord injuries Four MRI imaging patterns of spinal cord injuries have been described, and include normal cord, single-level edema, multi-level edema, and mixed hemorrhage and edema Patients with single-level edema had overall improvement of two grades in ASIA score compared to an improvement of one for patients with diffuse edema Single-level edema patients had higher chance of returning to ASIA E grade compared to those with diffuse edema Patients with edema and hemorrhage have the worst prognosis, with 95% classified as ASIA A at the time of initial presentation These patients improved one ASIA grade only 5% of the time [30] TREATMENT Nonoperative Patients with SCI often benefit from multidisciplinary nonoperative ICU care Previous studies have shown improved management and lower morbidity and mortality following acute SCI with ICU monitoring and aggressive medical management [31,32] Nonoperative SCI care can be categorized into two categories [41]: neuroprotective measures and indirect reduction with immobilization p 380 p 381 Neuroprotective measures Maintenance of adequate oxygenation and perfusion to the spinal cord may be neuroprotective against secondary SCI Hypotension in animal models of SCI results in worse neurologic outcome [31] No prospective controlled assessment of hypotension on human SCI patients has been performed, but previous observational or retrospective studies set a goal for MAP at a minimum of 85 to 90 mmHg based on evidence in the traumatic brain injury (TBI) patient population Studies of TBI suggest that MAP less than 90 mmHg has been associated with increased morbidity and mortality Current standard of care management includes support of arterial oxygenation and spinal cord perfusion pressure, and maintenance of MAP above 85 to 90 mmHg for the first 7 days following spinal cord injury is recommended [31] Pharmacologic intervention for spinal cord injury aims to minimize the secondary zone of injury [33] The most publicized intervention was the use of high-dose methylprednisolone for spinal cord injury NASCIS [34–36] (National Acute Spinal Cord Injury Studies) II and III studies found extremely modest yet inconsistent neurologic improvement with high-dose methylprednisolone However, the complication rates were significant and include wound infection, hyperglycemia, GI hemorrhage, sepsis, steroid induced myopathy, and death High-dose methylprednisolone can also significantly alter immune response with decreased T-cell count, and patients who received treatment are associated with higher rate of pneumonia and longer hospital stays [37] The authors do not recommend the use of corticosteroid in the setting of traumatic SCI GM-1 Ganglioside (Sygen) is another drug with promising results in early studies This compound is found indigenously in cell membranes of mammalian central nervous system tissue and thought to have antiexcitotoxic activity, potentiate the effects of nerve growth factor, and prevent apoptosis A multicenter study randomized 797 patients within 72 hours of injury to receive either GM-1 ganglioside or placebo Although patients with ASIA grade C and D SCI treated with GM-1 ganglioside demonstrated significant neurologic improvement compared to placebo-treated patients at 4 and 8 weeks after injury, the advantage was lost at subsequent follow-up visits No difference was noted in any of the outcome measures at 1 year [37] A number of promising pharmacologic therapies are currently under investigation for neuroprotective effect in animal models These include the sodium (Na+) channel blocker riluzole, the tetracycline derivative minocycline, the fusogen copolymer polyethylene glycol (PEG), and the tissue-protective hormone erythropoietin (EPO) [17,38] p 381 p 382 Indirect reduction and spinal immobilization The goals of SCI treatment are to prevent neurologic deterioration, reestablish spinal column stability, and regain neurologic function Neurologic deterioration is a real risk once the patient has come under the care of medical personal Understanding the functions and limitations of spine orthoses is critical to limit those occurrences SCI patients should first be immobilized with bed rest and “spine precautious.” All cervical fracture patients should be protected by cervical orthosis Previous cadaver studies have shown that specimens with cervical collar had similar cervical spine motion compared to those who did not during bed-to-bed transfer For this reason, extra caution must be used during patient transfer despite the presence of cervical orthosis In patients with high cervical injuries including occipitocervical dissociation, rigid cervical collars may not adequately immobilize those spinal segments The halo vest remains the orthosis of choice for these patients A halo vest is the most rigid cervical external immobilizer It restricts up to 75% of flexion/extension at C1–C2 level and has superior control of lateral bending and rotation compared to other cervical orthoses Halo vest should not be used in patients with advanced age, chest trauma, cranial fractures, infection, or soft-tissue damage around the proposed pin sites [39] Certain fracture/dislocations of the cervical spine may require inline cervical traction with Gardner–Wells tongs to achieve fracture reduction The patient should be awake/alert and positioned in reverse Trendelenburg position with shoulder straps attached to the end of the bed Gardner–Wells tongs are typically applied 1 cm superior to the pinna of the ears Traction weight should be applied and increased gradually and incrementally At every step, a neurologic examination and lateral cervical X-ray must be performed If reduction is successful, a postreduction CT or MRI scan should be done [39] KTT (kinetic therapy treatment) is a laterally rotating bed created to substitute frequent patient positioning in order to minimize the complications of long-term bed rest Previous cadaver studies have shown that KTT generated significantly less cervical and thoracolumbar spine motion in comparison to logroll [40] The author recommends that KTT should be used for initial immobilization for patients with cervical, thoracic, or lumbar instability Medical Management of Spinal Cord–Injured Patients Spinal cord injury may cause dysfunctions in multiple organ systems, leading to increased mortality and decreased quality of life [41] SCI above T6 vertebra disrupts the descending pathways to the sympathetic neurons in the intermediolateral column of the spinal cord from T1–L2 Loss of sympathetic control results in increased sympathetic activity below the injury and loss of inhibition of parasympathetic nervous system above the level of injury [41] Sympathetic neurons in the upper thoracic spinal cord (T1–T5) innervate the vessels of the upper body and heart [41] Neurogenic shock, which is characterized by hypotension and bradycardia, is a result of intact parasympathetic influence via vagal nerve with a loss of sympathetic tone Treatments of neurogenic shock include fluid resuscitation for hypotension, atropine in the setting of bradycardia, and vasopressors such as dopamine or norepinephrine in the setting of severe hemodynamic instability [31] Owing to decreased transmission of cardiac pain (T4), patients with SCI above that level may have impaired perception of chest pain in case of ischemic cardiac events [41] During the acute phase of SCI, vagal nerve disturbance can last 2 to 3 weeks; in certain cases, pacemakers are required to maintain a functional cardiac rhythm [41] Autonomic dysreflexia is a sudden uncontrolled sympathetic response resulting in uncontrolled arterial blood pressure This typically occurs in patients with SCI above T6 This is a life-threatening event, with blood pressures above 250 mmHg reported [42] The incidence of AD was found to be 10% to 11% during the first 3 years postinjury [42] The most common offending trigger is bladder distention owing to urinary retention or catheter blockage Other triggers include constipation, urinary tract infection, and traumatic/painful stimuli The mainstay of treatment for AD is prevention and avoidance of common triggers Pharmacologic interventions should include drugs that are rapid-onset with short duration; that is, nifedipine, hydralazine, or sodium nitroprusside [43] Respiratory insufficiency and pulmonary dysfunction are common after spinal cord injury, especially in the high cervical level owing to phrenic nerve innervation (C3–C5) [31] Early initiation of vigorous pulmonary therapy after acute SCI is associated with increased survival, reduced incidence of pulmonary complications, and decreased need for ventilator support [31] Aggressive secretion clearance, pulmonary toilet, and chest physiotherapy are highly recommended to lower the rate of pulmonary complications In the thoracic spinal cord injury population, the location of injury is a predictor of the incidence of pulmonary complications Maung et al found a higher rate of pneumonia in high thoracic injury patients (T1–T6) compared to low thoracic injury patients (T7–T12), 43.3% versus 25.4%, respectively [44,45] Spinal cord injury often leads to bladder dysfunction This dysfunction can be classified as either an upper motor neuron or lower motor neuron syndrome [41] Upper motor neuron syndrome leads to detrusor hyperactivity, where the bladder wall contracts in response to minor stretch without any voluntary external urethral sphincter control This results in frequent, involuntary voiding Lower motor neuron syndrome leads to decreased or absent detrusor contractility (flaccidity) with a distended bladder Bladder management in SCI patients include sterile intermittent catheterization (SIC) in the hospital and clean intermittent self-catheterization outside the hospital [41] Anticholinergic medications may be helpful with spastic bladder The incidence of thromboembolic events in the untreated patients with spinal cord injury is high, ranging from 7% to 100% [46,47] There is a high rate of morbidity and mortality associated with occurrence of DVT and PEs in this population Thromboembolic events are responsible for 9.7% of all deaths in the first year following SCI Furthermore, SCI patients have 500-fold increased risk of PE-related death in the first month following the injury [47] Previous systematic review has suggested that low-molecular-weight heparin (LMWH) is more effective than unfractionated heparin in preventing DVT in the SCI population [47] IVC filters are not recommended as a routine prophylactic measure, but are recommended in patients who failed or are not candidates for anticoagulation therapy p 382 p 383 Operative Operative treatment in patients with spine fractures has typically been for unstable fractures, progressive neurologic deficits, and patients unable to tolerate bracing (i.e., obesity, skin lesions, visceral injury, multi-extremity injuries) The goal of surgical intervention in patients with spinal cord injury is to achieve spinal stability, deformity correction, neurologic recovery, and pain control, and allow for rehabilitation [48] Surgical decompression and stabilization of the spine can be performed via an anterior, posterior, or combined approach The anterior approach is indicated when neurologic deficits are caused by anterior compression such as bony retropulsion or disc herniation This procedure may include corpectomy (removal of a portion of the vertebra and the adjacent intervertebral discs) and strut grafting using allograft, autograft, metal cages, or a combination of these Corpectomy is usually supplemented with additional posterior instrumentation for increased spinal column stability The posterior approach can achieve spinal cord decompression by either directly removing retropulsed vertebra through a transpedicular approach or via ligamentotaxis by restoring the vertebral height and alignment with posterior instrumentation Optimal timing of surgical intervention to achieve maximum neurologic recovery remains a controversial topic Most of the studies performed on the timing of surgical decompression is usually classified as early (72 hours) This time delineation is likely based on preclinical studies that showed that early decompression of acute spinal cord injury could lead to improved neurologic function [49] Previous data suggest that white matter is more resilient and damage is reversible up to 72 hours after injury, compared to irreversible damage to the gray matter [48] Unfortunately, in clinical trials, there is no clear evidence to support early surgical decompression in improving neurologic outcomes Dimar et al showed no benefit with early surgery compared with late surgery in a randomized controlled trial of cervical spine injury [49] Cengiz et al [50] performed a prospective randomized clinical trial on thoracic fractures, which demonstrated a nonsignificant trend toward improved neurologic recovery in the early surgery group If the goal of surgery is for spine stabilization only, retrospective studies have shown early surgical stabilization (3 to be significant variables were associated with patients who had no vital signs on admission [2] Overall, motor vehicle collisions account for 70% to 80% of all thoracic injuries The incidence of penetrating injuries varies widely but is usually more prevalent in urban centers The majority of thoracic injuries can be treated with careful observation or tube thoracostomy It is historically reported that 12% to 15% of patients with thoracic injury will require a thoracotomy In a Western Trauma Association multicenter review, only 1% of all trauma patients required nonresuscitative thoracotomy [3] With the improvements in prehospital care and transport, more severely injured patients, who would have previously died at the scene, are arriving at the hospital alive Success of the management for these injuries rests in having a high index of suspicion for the life-threatening thoracic trauma and prompt recognition and treatment of associated injuries INDICATIONS FOR URGENT SURGICAL INTERVENTION Bleeding Hemothorax is second only to rib fractures as the most common associated finding of thoracic trauma, being present in approximately 25% of patients with thoracic trauma Bleeding can arise from the chest wall, lung parenchyma, major thoracic vessels, heart, or diaphragm A small or moderate-size hemothorax that stops bleeding immediately after placement of a tube thoracostomy and full lung inflation can usually be managed conservatively However, if the patient continues to bleed at a rate of more than 200 cc per hour, exploration is indicated In addition, the accumulation of more than 1,500 cc of blood within a pleural space is considered a massive hemothorax that is likely due to larger thoracic vessel injury and is an indication for exploration If the patient becomes hemodynamically unstable at anytime and an intrathoracic source is suspected, emergent thoracotomy should be performed irrespective of chest tube drainage A chest radiograph should always be obtained after placing a tube thoracostomy to ensure proper positioning of the tube and complete drainage of the pleural space Video-assisted thoracoscopic surgery (VATS) can be considered in the stable patient with retained hemothorax or in a stable patient who continues to bleed at a slow but steady rate; however, the surgeon should not hesitate to convert to open thoracotomy if visualization is inadequate or drainage and evacuation of the pleural space is incomplete Cardiovascular Collapse The indications for resuscitative emergency department thoracotomy (EDT) continue to be debated Penetrating thoracic injuries, specifically stab wounds, have the highest rate of survival Data for blunt trauma are much less encouraging but should not be used as a deterrent, as there are several functional survivors in most reported series A retrospective study of 959 patients undergoing resuscitative thoracotomy concluded that EDT in blunt trauma with more than 5 minutes or penetrating trauma with more than 15 minutes of prehospital CPR is futile [4] A wide range of institutional protocols have been developed However, evidence indicates that almost all survivors are among the group of patients with penetrating thoracic trauma who have signs of life on arrival [5,6] These patients generally have not exsanguinated but have a penetrating cardiac injury with tamponade, which can often be treated effectively by drainage of the pericardium and repair of the injury In general, EDT is not indicated in any patients who have no signs of life or in blunt trauma patients who have only cardiac rhythm without pulses, as these patients have likely exsanguinated When performed, resuscitative thoracotomy should be done early Discovered tamponade should be released; massive pulmonary bleeding should be quickly controlled with staplers, clamping, or manual compression, and hemorrhage from cardiac wounds should be controlled With no intrathoracic source, the aorta should be clamped and internal cardiac massage continued p 384 p 385 Massive Air Leak Findings on initial presentation of significant subcutaneous emphysema, persistent pneumothorax after chest tube placement, a subsequent large or persistent air leak, or pneumomediastinum should alert the clinician to the presence of major tracheobronchial injury This injury is potentially lethal but relatively rare, which was found in only 2% to 5% of patients with thoracic trauma Significant tracheobronchial injuries may result in a massive air leak, leading to hypoventilation In this situation, maneuvers to stabilize the patient should include decreasing airway pressures to minimize leak Contralateral mainstem intubation can also be attempted Major tracheobronchial injuries generally should be repaired as early as the patient’s condition allows For patients who are too unstable for surgery, temporizing measures for ventilator support include high frequency oscillator ventilation and independent lung ventilation [7] Tamponade Cardiac tamponade results when fluid or air collects within an intact pericardial sac, resulting in compression of the right heart with subsequent obstruction of venous return and cardiovascular collapse Potential findings upon presentation include tachycardia and hypotension, cervical cyanosis, jugular venous distension, muffled heart sounds, and pulsus paradoxus The diagnosis is confirmed with beside ultrasound, pericardial window, or at the time of emergent thoracotomy Treatment requires prompt resuscitation and decompression of the pericardium, followed by repair of the bleeding source DIAGNOSTICS Diagnostic imaging plays a key role in the management of patients after chest trauma and has a considerable impact on therapeutic decisionmaking The chest radiograph (CXR) has traditionally been and remains the initial imaging study of choice to be obtained in patients with suspected chest injury In many trauma centers, the thoracic component of the bedside ultrasound (extended FAST exam) is preceding the conventional X-ray as an immediate method of identifying pneumothorax and massive hemothorax [8,9] Computed Tomography (CT) of the chest, however, is commonly used to more accurately identify the nature and severity of chest trauma CT can be useful in assessing suspected traumatic aortic, pulmonary, airway, skeletal, and diaphragmatic injuries [10,11] Magnetic resonance imaging (MRI) on the other hand has a limited role in the initial evaluation of any patient with suspected chest trauma To undergo an MRI, the patient must be stable, and many trauma patients cannot be scanned because of bulky, mechanical supportive equipment However, in selected patients who are hemodynamically stable, MRI may be particularly useful for the evaluation of vertebral ligamentous injury and spinal cord injury Other imaging modalities available to the clinician include echocardiography, angiography, and VATS, which can be both diagnostic and therapeutic when appropriately indicated Plain Chest Radiograph The frontal chest radiograph has traditionally been the initial radiographic study to obtain for the evaluation of patients with suspected chest injury This study is particularly useful for helping to rule out major injury Ideally, the radiograph should be obtained with the patient in the upright position because of mediastinal widening that is typically seen in the supine position Chest radiography has a 98% negative predictive value and is therefore quite useful when normal However, abnormal findings may be subtle and quite nonspecific Radiographic findings that may indicate mediastinal injury, such as major aortic disruption, include abnormal contour or indistinctness of the aortic knob, apical pleural cap, rightward deviation of the nasogastric tube, thickening of the right paratracheal stripe, downward displacement of the left mainstem bronchus, rightward deviation of the trachea, and, not uncommonly, nonspecific mediastinal widening Most life-threatening injuries can be screened by the plain chest radiograph and a careful physical exam Blunt thoracic injuries detected by CT alone infrequently require immediate therapy Rather, if immediate therapy is needed, findings will usually be visible on plain radiographs or obvious on clinical exam Although a plain upright chest radiograph remains one of the basic imaging studies routinely performed on initial screening, it may be over-utilized A recent study suggests that in the presence of a normal physical exam in the hemodynamically stable patient, obtaining a routine chest radiograph is actually unnecessary, since it rarely, if ever, changes clinical care [12] Chest Computed Tomography CT is highly sensitive in detecting thoracic injuries after blunt chest trauma and is superior to routine CXR for visualizing lung contusions, pneumothorax, and hemothorax, and it can often alter initial therapeutic management for a significant number of patients with suspected chest trauma It has also been shown to detect unexpected injuries and abnormalities, resulting in altered management in a substantial number of patients when applied appropriately [13] It can be particularly useful in screening for major intrathoracic aortic injury In one study, contrastenhanced CT scanning (“CT angiogram”) was 100% sensitive in detecting major thoracic aortic injury based on clinical follow-up and was 99.7% specific, with 89% positive and 100% negative predictive values for an overall diagnostic accuracy of 99.7% [14] An unequivocally normal mediastinum at CT, with no hematoma and a regular aorta surrounded by a normal fat pad, has essentially a 100% negative predictive value for aortic injury [14–17] It has also been shown that CT scanning detects 11% of thoracic aortic injuries that are not detected by routine, plain chest radiography alone [18] CT scanning can also be useful for detecting hemopericardium and/or hemothorax from any cause, injury to the brachiocephalic vessels, pneumothorax, rib fractures, pulmonary parenchymal contusion, and sternal fractures It can also be useful for detecting pneumomediastinum caused by interstitial lung injury, bronchial or tracheal rupture (commonly associated with pneumothorax), esophageal rupture, iatrogenic barotrauma from mechanical ventilation, or traumatic intubation In addition, CT scanning can detect injuries otherwise missed by routine plain radiograph In one study comparing CT scanning with plain radiography, CT scanning detected serious injuries among 65% of those patients not found to have injury by plain film These injuries included (in decreasing order of frequency) lung contusions, pneumothoraces, hemothoraces, diaphragmatic ruptures, and myocardial rupture [19] Even for patients without suspected chest trauma, CT scanning of the abdomen, which commonly includes the lower portion of the thorax, often yields important information when intrathoracic injury is present In one study, hematoma surrounding the intrathoracic aorta near the level of the diaphragmatic crura seen on intra-abdominal CT scanning was found to be a relatively insensitive but highly specific sign for thoracic aortic injury after blunt trauma Therefore, the presence of this sign seen on abdominal CT imaging should prompt more specific imaging of the thoracic aorta to evaluate potential thoracic aortic injury [20] CT scanning has also been shown to be useful to help define the extent of pulmonary contusion and identify patients at high risk for acute respiratory failure among patients with PaO2/FiO2 lower than 300 Digitally processed 3-D reconstruction views from CT scans have also been shown to be useful for diagnosing and determining the severity of sternal fractures [21] With the advent of high resolution CT scanners that can reconstruct axial, coronal, and sagittal images, even penetrating diaphragmatic injuries, which are difficult to image preoperatively, can be diagnosed with a relatively high sensitivity and specificity [22] Despite its usefulness, thoracic CT scanning is not routinely indicated for all patients with chest wall trauma In addition, although there has been a dramatic increase in the utilization of CT scanning in the last decade, its usefulness for detecting clinically relevant injury has recently come into question, especially for patients with a normal screening plain chest radiograph [23] p 385 p 386 Ultrasonography (Extended FAST Exam and TEE) Over the last 10 years, the traditional Focused Abdominal Sonogram for Trauma or “FAST” exam has evolved to include bedside assessment for thoracic injuries and is now referred to as the extended FAST exam or “eFAST.” This modality can provide immediate real-time assessment for pneumothorax by looking for secondary signs of lung inflation such as “sliding” of pleural surfaces and “comet tails” artifacts at the visceral pleura [8,9] In some situations, the eFAST lung exam obviates the need for a screening chest X-ray, particularly when the patient is to have a chest CT scan eFAST can also identify large hemothoraces and can assess the pericardium, identifying hemopericardium and tamponade The results from eFAST are operator dependent with a significant learning curve However, the results are reproduceable among those trained to use the modality and this has become part of the trauma armamentarium at most centers Transesophageal echocardiography (TEE) is rapidly gaining acceptance as an important diagnostic tool available to the trauma surgeon and is showing particular promise in diagnosing traumatic intrathoracic aortic injuries Although somewhat invasive, its portability makes it a diagnostic procedure of choice in looking at the heart and great vessels in multiply injured trauma patients particularly in the operating room setting In one study of 58 patients with thoracic trauma, TEE demonstrated its usefulness in diagnosing thoracic aortic injury and permitted the identification of small lesions not detectable by CT scanning or angiography [24] TEE has shown to be an important diagnostic tool for examining the thoracic aorta and is valuable for identifying aortic injury among high-risk trauma patients who are too unstable to undergo transport to the aortography suite When an aortic injury is present, typical findings on the TEE can include aortic wall hematomas, intimal flaps, or disruptions Several groups have shown TEE to be accurate for identifying aortic pathology after trauma, with its diagnostic efficacy mainly limited by the experience of the person performing the exam [25–27] In addition, it has been shown to be useful for diagnosing blunt cardiac rupture, when other diagnostic modalities have failed, as well as in diagnosing severe valvular regurgitation intraoperatively following foreign body removal [28,29] Angiography Thoracic aortography historically has been the gold standard for diagnosing thoracic aortic injury and for defining the extent of the injury and involvement of branch disease, when it is present Aortography has largely been supplanted by dynamic thin-cut contrast CT scaning or CT angiography [11] This modality involves a rapid high-resolution CT scan with timed contrast injection and subsequent computerized processing of the study The accuracy of this study and its specificity in defining the anatomy of the aortic injury has made it more than adequate for planning surgical or endovascular interventions Aortography is occasionally required for the rare situation when CT scan is equivocal Diagnosis of aortic injury angiographically is usually made by finding one or more of the following: an irregular or discontinued contour of the aortic lumen, an intimal flap, an aortic dissection, and/or a luminal outpouching (i.e., pseudoaneurysm) Thoracic aortography can detect blunt traumatic aortic injuries with 96% sensitivity and 98% specificity Angiography is invasive and can have associated complications The complications associated with arteriography include allergic reactions, renal failure, local puncture site problems, stroke, and even death Radiographic contrast media cause severe anaphylactic reactions in less than 2% of cases Video-Assisted Thoracoscopic Surgery (VATS) The role of thoracoscopy in trauma has been explored by a number of investigators Prior to the modern video era, Jones et al described management of 36 patients with thoracoscopy under local anesthesia as a diagnostic tool to define intrathoracic injuries and to visualize ongoing hemorrhage [30] Four patients in their series were spared abdominal exploration when the diaphragm was found devoid of injury More recently, Ochsner et al [31] and Mealy et al have demonstrated the usefulness of VATS as a diagnostic tool for the assessment of diaphragmatic integrity among cases of penetrating and blunt thoracic injuries, respectively [32] VATS has become an acceptable surgical modality in the diagnostic evaluation of suspected diaphragmatic injury and has been shown to have therapeutic benefit when evacuation of clotted hemothoraces is able to be performed in stable patients with penetrating chest injures [33] Main indications for VATS include diagnosis of and treatment for diaphragmatic injuries, diagnosis of persistent hemorrhage, management of retained thoracic collections, assessment of cardiac and mediastinal structures, diagnosis of bronchopleural fistulas, and diagnosis of and treatment for persistent posttraumatic pneumothorax In these situations, VATS has been shown to be a useful alternative to an open thoracotomy for selected patients In select situations, VATS has been used as the primarily modality of treatment for acute traumatic thoracic hemorrhage meeting the criteria for thoracotomy among hemodynamically stable patients [34] Because lung deflation with single-lung ventilation is a critical component of the technique, VATS is relatively contraindicated in patients unable to tolerate this Caution should be used in patients with suspected obliteration to their pleural cavity secondary to previous infection (“pleurisy”) or surgery VATS should have no role in the management of unstable patients and is relatively contraindicated in those patients unable to tolerate formal thoracotomy for any reason Whether VATS should be considered as the initial approach in the evaluation of all stable chest trauma patients when an intrathoracic injury is suspected is still debated, and appropriate patient selection remains important SPECIFIC INJURIES Chest Wall Rib Fractures Rib fractures are the most common injury to the thorax occurring from blunt trauma and are often associated with other injuries Rib fractures themselves may cause only minor problems in the young and otherwise healthy; however, they may be a marker of more severe injury, and it may be the underlying pulmonary contusion that often accompanies the rib fracture that may be more clinically relevant A study by Flagel et al showed that 13% of those patients in the National Trauma Data Bank who had one or more rib fractures (n = 64,750) developed complications including pneumonia, acute respiratory distress syndrome, pulmonary embolus, pneumothorax, aspiration pneumonia, empyema, and the need for mechanical ventilation They also showed that increasing number of rib fractures correlated directly with increasing pulmonary morbidity and mortality The overall mortality rate for patients with rib fractures was 10% The mortality rates were higher (p < 0.02) with each additional rib fracture, independent of patient age This ranged from 5.8% for a single rib fracture to 10% in the case of five fractured ribs The mortality rates were dramatically higher for the groups with 6, 7, and 8 or more fractured ribs to 11.4%, 15.0%, and 34.4%, respectively [35] It has been shown that rib fractures occurring in the very young should alert the clinician to possible nonaccidental trauma (NAT) In one study by Barsness et al., rib fractures in children under 3 years of age had a positive predictive value of NAT of 95%, and rib fracture was the only skeletal manifestation of NAT in 29% of the children [36] With regards to the elderly, it has been shown that there is a linear relationship between age and complications, including mortality It has been shown that elderly patients with rib fractures have up to twice the mortality of younger patients with similar injuries [37] In addition, this increase in mortality may begin to be seen in patients as early as 45 years of age when more than four ribs are involved [38] The location of the rib fracture(s) is also important, as it has been shown that left-sided rib fractures are associated with splenic injuries and right-sided rib fractures are associated with liver injuries While isolated rib fractures have an associated incidence of vascular injury of only 3%, first rib fractures in association with multiple rib fractures have a 24% incidence of associated vascular injury A first rib fracture along with findings of a widened mediastinum, upper extremity pulse deficit, brachial plexus injury, and/or expanding hematoma should prompt work-up for a possible subclavian arterial injury Pain control and effective respiratory secretion clearance remain the mainstays of therapy for rib fractures Adequacy of pain control can be monitored by the ability to perform incentive spirometry Regional analgesia by epidural or paraspinal catheter is appropriate when narcotics are inadequate to allow adequate lung volumes or are accompanied by unacceptable levels of sedation, particularly among the elderly [39–41] In Flagel’s study noted above, epidural analgesia was associated with a reduction in mortality for all patients sustaining rib fractures, particularly those with more than four fractures [35] Since this was not a prospective randomized study, it is difficult to tell if there was a correlation between patients that received epidural catheters having an overall lower injury severity score However, in one prospective randomized trial by Bulger et al., trauma patients with rib fractures were randomized to either receive epidural anesthesia or intravenous opioids for pain relief, and it was shown that those patients with epidural anesthesia had a lower incidence of nosocomial pneumonia and shorter duration of mechanical ventilation [42] The number of patients that could receive epidural anesthesia was limited, however, due to strict inclusion criteria The age of the patient sustaining rib fractures should be taken into account, as well as the location of the fractures In many protocols, patients with multiple rib fractures and a certain age threshold, anywhere from 55 to 65 years, receive an epidural analgesia proactively as their preferred modality of pain control [39–41] Flail Chest Flail chest occurs when multiple adjacent ribs are broken in two locations, thereby allowing that portion of the chest wall to move independently of respiration The anatomic definition of flail chest is the fracture of at least three consecutive ribs in two or more places; however, the clinical or functional definition requires a disjointed, “free-floating” segment of chest wall, which does not contribute to normal ventilatory excursion This gives rise to the classical “paradoxical respiration” whereby the flail segment is “sucked inward” by the negative pressure of inspiration as the rest of the rib cage moves upward and outward This is a mechanical problem in which negative pressure generated during inspiration within the thorax is dissipated by movement of the flail segment inward This movement equalizes the intrathoracic pressure, which would normally be accomplished by the movement of air into the lungs Despite this mechanical impairment, the major mortality and morbidity of flail chest can be attributed to the usual underlying pulmonary contusion, which leads to a ventilation perfusion mismatch, contributing to the hypoxia; the pain associated with multiple rib fractures can lead to splinting and contribute to lack of deep breathing, atelectasis, compromised secretion clearance, and further hypoxemia Fortunately, large segment flail chest occurs relatively infrequently Flagel et al showed an overall incidence of flail chest of 3.95% in patients with six rib fractures, 4.84% in those with seven rib fractures, and 6.42% in those with eight or more rib fractures [35] As for simple rib fracture, pain control remains the main therapy for flail chest so as to allow optimal ventilatory excursion and self-clearance of respiratory secretions” by deep breathing and coughing Obligatory ventilatory support “internal pneumatic stabilization” of the fractures, first described in 1956, has given a way to selective ventilatory support as needed, with subsequent improved outcomes [42–45] Surgical stabilization of the chest wall has been shown to be of some benefit with regard to shorter length of ventilator dependency, lower rates of pneumonia, and shorter intensive care unit stays, although this form of therapy is not yet widely practiced [46,47] A number of proprietary systems for rib fracture fixation have been developed after biomechanical studies of the stresses on ribs en vivo (i.e., Rib-Loc, Acute Innovations, Hillsboro, OR, USA; Biomet System, Jacksonville FLa., USA) The benefits and appropriate indications for rib fracture repair remain to be fully defined Pain control continues to be an important adjunct in any treatment regimen p 387 p 388 Sternal Fracture Sternal fractures have been shown to decrease the stability of the thorax in cadavers [48] They usually occur as a deceleration force during traffic accidents together with blunt force trauma from foreign objects, such as steering wheels, although they have been reported as a complication of CPR, which interestingly was found in 14% of medical autopsy cases that had received chest compressions prior to death [49] Traffic accidents are the cause of sternal fractures in almost 90% of cases, with approximately 25% of fractures graded as moderately to severely displaced Approximately 30% of patients will have associated injuries, with craniocerebral trauma and rib fractures being the most commonly associated injuries [50] Displaced fractures are more likely to have associated thoracic and cardiac injuries and are more likely to require surgical fixation However, the majority of patients can be safely observed and even discharged home as long as the following criteria are met: (1) the injury is not one of the high-velocity impacts, (2) the fracture is not severely displaced, (3) there are no clinically significant associated injuries, and (4) complex analgesia is not required Most serious complications and deaths that occur among patients with sternal fractures are not due to the fracture itself but rather are related to the associated injuries, such as flail chest, head injury, or pulmonary or cardiac contusion Although approximately 22% of patients will exhibit electrocardiographic changes, elevated cardiac injury enzymes, or echocardiographic abnormalities, only approximately 6% of patients will exhibit a clinically significant myocardial contusion In addition to myocardial contusion, other complications of sternal fracture such as mediastinal abscess, mediastinitis, and acute tamponade have all been reported Indications for operative sternal fixation are certainly not absolute and should be judged individually Generally accepted criteria include severe pain, sternal instability causing respiratory compromise, and severe displacement Only a small percentage of patients (2% in one series) actually require sternal fixation [51] A lack of consensus among surgeons on how to treat these injuries, in addition to a lack of randomized trials concerning their optimal approach, have led to this variability of practice Scapular Fracture Scapular fractures are relatively rare and were once presumed to be an indicator of severe underlying trauma and subsequent higher mortality They occur in only approximately 1% to 4% of blunt trauma patients who present to a level I trauma center and are associated with a higher incidence of thoracic injury compared to those patients who sustain blunt trauma without a scapular fracture However, more recent studies have indicated that although patients with scapular fractures tend to have more severe chest injuries and a higher overall injury severity score, their length of intensive care unit stay, length of hospital stay, and overall mortality are not necessarily increased [52,53] Treatment is usually conservative and, most of the time, aimed at the associated injuries that are commonly present Scapulothoracic Dissociation Scapulothoracic dissociation is an infrequent injury with a potentially devastating outcome Scapulothoracic dissociation results from massive traction injury to the anterolateral shoulder girdle with disruption of the scapulothoracic articulation Identification of this injury requires a degree of clinical suspicion, based upon the injury mechanism and physical findings Assessment of the degree of trauma to the musculoskeletal, neurologic, and vascular structures should be made Based upon clinical findings, a rational diagnostic approach can be navigated and appropriate surgical intervention planned Scapulothoracic dissociation is frequently associated with acromioclavicular separation, a displaced clavicular fracture, subclavian or axillary vascular disruption, and a sternoclavicular disruption Clinically, patients usually present with a laterally displaced scapula, a flail extremity, an absent brachial pulse, and massive swelling of the shoulder Vascular injury occurs in 88% of patients and severe neurologic injuries occur in 94% of patients Many of these patients have poor outcomes and present with a flail, flaccid extremity that usually results in early amputation and have an overall mortality of 10% One of the most devastating aspects of scapulothoracic dissociation is the brachial plexus injuries that occur, which are typically proximal, involving the roots and cords—brachial plexus avulsions are not unusual Attempts at repair of complete brachial plexus injuries with grafts or nerve transfers have generally been unsuccessful [54] Treatment includes arterial and venous ligation to stop exsanguination if present, orthopedic stabilization and consideration for elective above elbow amputation to allow for a more useful extremity if brachial plexus avulsion is present Overall prognosis for limb recovery is poor Pleural Space Pneumothorax This section will only focus on pneumothoraces associated with trauma For further general discussion of pneumothorax in the critically ill, readers are referred to Chapter 176 For in depth discussion of imaging studies on the topic of pneumothorax, readers are referred to Chapters 11 and 179 A traumatic pneumothorax occurs from either blunt or penetrating trauma, with resultant direct injury to the pleura Rib fractures may or may not be present Mechanical ventilation can also be considered a traumatic cause of pneumothorax and has an overall associated incidence of 5% This incidence increases dramatically in patients with underlying lung diseases, such as COPD or acute respiratory distress syndrome (ARDS) Iatrogenic causes of pneumothorax also occur in the hospital setting Central-line insertions are associated with a 3% to 6% incidence of pneumothorax All types of pneumothorax may progress to tension pneumothorax, which occurs in 1% to 3% of spontaneous pneumothoraces and can occur at any stage of treatment As tension pneumothorax is a rapidly progressive condition, early identification is essential and immediate decompression should be performed when the clinical suspicion is high Tension pneumothorax is a clinical diagnosis, and treatment should never be delayed to obtain a confirmatory X-ray Open pneumothorax is caused when a penetrating chest injury opens the pleural space to the atmosphere Negative pressure cannot be generated to inflate the lung on inspiration, leading to a collapsed lung and a “sucking” chest wound Open pneumothorax is an injury commonly seen on the battlefield In civilian life, impalement by an object is a common cause For injuries in which the chest wall wound diameter approaches two-thirds of the diameter of the trachea, air will preferentially enter the pleural space through the wound during inspiration, thereby inhibiting normal ventilation through the upper airway, leading to profound hypoventilation and subsequent hypoxia Changes in venous return can occur similar to that seen in a tension pneumothorax because the injured side is now at atmospheric pressure, while the normal side has negative pressure, creating a mediastinal shift This in turn can lead to hemodynamic instability The presence of a “sucking” chest wound makes the diagnosis obvious External wound size may not correlate with the degree of compromise, as it is the size of the atmospheric-pleural connection that correlates best Treatment includes appropriate resuscitative maneuvers, starting with the placement of a sterile occlusive dressing over the wound to allow effective negative pressure ventilation to resume If this does not suffice, intubation and positive pressure mechanical ventilation may be necessary to correct the ventilatory and hemodynamic dysfunction A standard method of coverage involves placing a nonporous dressing over the wound and taping it on three sides, allowing it to act as a one-way valve, allowing air to escape during expiration but occlusive during negative pressure inspiration A chest tube is routinely inserted at a separate site away from the injury to treat any ongoing air leak that might arise from concurrent lung injury The wound should be treated with local measures and associated injuries should be sought and treated appropriately p 388 p 389 Hemothorax After rib fractures, hemothorax is the second most common complication of chest trauma It can be caused by bleeding from anywhere in the chest cavity, including the chest wall, lung parenchyma, major thoracic vessels, heart, or diaphragm It presents in approximately 25% of patients with chest trauma Patients with hemothorax typically have decreased breath sounds and dullness to percussion over the affected side with associated dyspnea and tachypnea Depending on the amount of blood loss, they may have hemodynamic changes The major cause of significant hemothorax is usually due to a laceration to the lung or bleeding from an injured intercostal vessel or internal mammary artery Radiographic films may not reveal a fluid collection of less than 300 mL Small hemothoraces usually resolve within few days Accumulation of more than 1,500 mL of blood within a pleural space is considered massive, is more commonly seen on the left side, and is usually due to aortic rupture (blunt trauma) or pulmonary hilar or major vessel injury (penetrating trauma) Severe blunt trauma where highly displaced rib fracture fragments puncture deep into the lung parenchyma may also lead to a massive hemothorax Massive hemothorax can lead to hemodynamic instability including hypotension and circulatory collapse Neck veins may be flat or distended, depending on whether or not blood loss or increased intrathoracic pressure predominates A mediastinal shift with tracheal deviation is typically opposite from the side of blood accumulation Treatment for acute hemothorax includes supplemental oxygen therapy and, in most cases, the insertion of a large bore (i.e., 32 to 36 French) tube thoracostomy anterior to the midaxillary line at the fifth or sixth intercostal space A moderate-size hemothorax (500 to 1,500 mL) that stops bleeding immediately after a tube thoracostomy can usually be managed conservatively with a closed drainage system Bleeding from pulmonary parenchymal injuries that do not involve the hilum usually will stop spontaneously because of the low pulmonary pressures and high concentrations of tissue thromboplastin within the lung [55] If, however, the patient continues to bleed at a rate of 100 to 200 mL per hour, then exploration is indicated Likewise, if the patient bleeds out more than 1,500 mL initially through the chest tube, exploration is indicated VATS exploration has been successfully utilized to control acute thoracic bleeding in patients who are stable [34] If the patient is hemodynamically unstable at any time, and intrathoracic bleeding is suspected as the cause, emergent thoracotomy should be done regardless of chest tube output A chest radiograph should always be obtained after placing a tube thoracostomy to check position of the tube and to make sure that the pleural space is adequately drained Once the patient is stable and acute bleeding has ceased, retained hemothorax may still be a problem when a large amount of retained blood and clot remains within the pleural space for 24 to 48 hours after tube thoracostomy, semielective exploration with open evacuation should be considered VATS is an option for the stable patient with retained hemothorax However, the surgeon should not hesitate to convert to an open thoracotomy if visualization is inadequate or drainage and evacuation of the pleural space is incomplete If the retained hemothorax is not massive, nonoperative therapy can be considered as these may lyse with time Alternatively, it has been shown that a retained hemothorax can be successfully treated with instillation of thrombolytics into the pleural space This has been deemed safe even for patients who have sustained multiple trauma [56] However, the use of thrombolytics for trauma patients remains debated with some reports of reactivation of thoracic bleeding after instillation of thrombolytics into the pleural space Lung Pulmonary Contusion Pulmonary contusion is a common injury found among patients sustaining blunt chest trauma, with an approximate incidence of 30% to 75% Mortality is between 10% and 25% Hemorrhage and interstitial edema result from injury to the lung This can lead to alveolar collapse and the typical parenchymal consolidation seen on the radiograph Injury to the parenchyma from blunt force trauma is thought to be caused by a combination of events that includes alveolar stretching, parenchymal tearing, and concussive forces Lung injury in the absence of identifiable rib fractures typically exhibits diffuse injury, whereas rib fractures and flail chest are associated with more localized injuries The extravasation of blood into the alveolar space causes subsequent consolidation, which can then lead to an intrapulmonary shunt A flail chest may be associated with pulmonary contusion(s) approximately three-fourths of the time, which more than doubles the morbidity and mortality Hypoxemia, although nonspecific, is the most common clinical finding associated with pulmonary contusions Typical chest radiographic findings in the appropriate clinical setting remain the mainstay of diagnosis Typical findings usually demonstrate a focal or diffuse consolidative process that does not typically follow anatomical segments or lobes Rib fractures are the most common bony injuries seen and should raise suspicion for the diagnosis of pulmonary contusion, even if other clinical signs are absent at the time While the respiratory effects of pulmonary contusion may occur soon after injury, they may not become radiographically apparent for up to 48 hours postinjury, with an average delay of 6 hours On the other hand, CT scanning of the chest has been shown to be able to demonstrate the presence of pulmonary contusion almost immediately postinjury [57–60] In addition, it can help estimate the total volume of injured lung present This can be helpful for predicting the need for eventual ventilatory support It has been shown that when pulmonary contusion involves 28% or more of the total lung volume, essentially all patients eventually require mechanical ventilation, whereas when 18% or less of the lung volume is involved, the need for mechanical ventilatory support is unlikely [61] Treatment for pulmonary contusion is generally supportive Close respiratory monitoring and frequent clinical examination is important, as approximately half of all respiratory failures secondary to pulmonary contusion occur within the first few hours postinjury Once coexistent injuries are treated, and the need for emergent surgery is ruled out or performed as required, the patient with pulmonary contusion should be transferred to a monitored bed Optimal respiratory secretion clearance should be employed and may be achieved through several mechanisms, including airway suctioning, chest physiotherapy, and postural drainage This helps to minimize atelectasis and clear respiratory secretions If patients are still unable to clear their secretions adequately, bronchoscopy can be helpful Adequate analgesia for associated chest wall injuries is also important for maintaining adequate secretion clearance as the effects of the contusions and chest wall injuries are additive Pain control can be achieved through systemic opioids or regional analgesia Preferred methods of regional analgesia include nerve blocks, and epidural or paravertebral catheters Inadequate analgesia as determined by low vital capacity ( 7%), and ECG abnormality; regional wall motion abnormality in the baseline echocardiogram and in the control echocardiogram at follow-up; or confirmation of myocardial contusion at autopsy or intraoperatively Even though the prevalence of the injury was significant in their population, the overall prognosis was excellent, and the authors recommend that specific diagnostic and therapeutic measures should be limited to cases where cardiac complications develop The combination of a normal ECG and normal serum troponin levels, drawn at the time of presentation and 8 hours later, essentially rules out significant myocardial contusion and is sufficient, in the absence of other reasons for hospitalization, to discharge such patients safely home [75] However, patients with an abnormal ECG and elevated troponin should be monitored for at least 24 hours Cardiac contusion may lead to cardiogenic shock resistant to inotropic support The use of intra-aortic balloon counterpulsation as a mechanical means of augmenting cardiac function following cardiac contusion is rarely indicated but has been reported with success even in elderly patients [76] p 390 p 391 At the other end of the severity spectrum, high energy injuries to the heart can result in cardiac rupture Atrial and/or ventricular rupture can occur, leading to profound hemodynamic compromise Rapid recognition of such injuries is necessary for successful treatment Associated injuries are common and include closed head injury, pulmonary contusion and/or laceration, multiple rib fractures, liver and spleen injury, and traumatic aortic injury; these account for approximately 25% of fatalities seen in patients after blunt cardiac injury The usual clinical presentation of cardiac rupture is cardiac tamponade secondary to hemopericardium, although less than 15% of these patients actually manifest physiological evidence of tamponade Associated pericardial tears may allow for decompression of intrapericardial hemorrhage through the pleural space, preventing the development of cardiac tamponade but leading to exsanguinating hemothorax Pericardial rupture is rare, but can occur in isolation or with associated injuries such as blunt cardiac or diaphragmatic rupture, which has a high mortality Hypotension is usually present, and the diagnosis of cardiac rupture should be considered in any patient who has hypotension in the absence of overt blood loss The chest radiograph may not show evidence of cardiac injury, even in the face of tamponade and hemodynamic compromise, since a rapid accumulation of blood into the pericardial space can occur without significantly altering the cardiac silhouette The Extended FAST ultrasound exam can be useful in diagnosing pericardial tamponade Diagnosis of blunt cardiac rupture should be strongly suspected when hemopericardium is seen by ultrasound in the setting of blunt trauma The diagnostic dependability of pericardiocentesis is limited in the assessment of traumatic hemopericardium and potential cardiac rupture because of significant false-negative and false-positive results Performing a pericardial window in the operating room, however, can be both diagnostic and therapeutic, and it can confirm hemopericardium and allow for rapid decompression and median sternotomy Nevertheless, the diagnosis of blunt cardiac rupture requires a fair degree of clinical suspicion, particularly in the setting of hypotension that does not respond to adequate volume resuscitation Perchinsky et al reviewed a consecutive series of 27 patients seen between 1984 and 1993 with blunt cardiac rupture Overall survival rate was 41% Of note was that three out of nine (33%) patients presenting to the emergency department with no identifiable blood pressure or viable electrical heart rhythm survived resuscitation, surgery, and initial hospital care No patient survived rupture of two or more cardiac chambers in their series, however [77] Although cardiac exploration should be performed with cardiopulmonary bypass support nearby, repair of cardiac rupture does not necessarily require its use Cardiac Valvular Injuries Blunt cardiac injury may rarely result in valvular insufficiency The right ventricle is immediately behind the sternum, which makes it particularly vulnerable to injury Acute severe elevation of right intraventricular pressures has been shown to result in injury of the tricuspid valvular apparatus [71,78] The most common injury is chordal rupture, followed by rupture of the anterior papillary muscle and leaflet tears Posttraumatic aortic valve regurgitation has also been reported and affects all ages and is often found in association with sternal or multiple rib fractures [79] Traumatic mitral valve insufficiency has been shown to present with either complete papillary muscle avulsion from its ventricular attachment or with chordal tears and/or leaflet damage Those with papillary muscle avulsion typically present with severe regurgitation Those patients with less severe injuries to the mitral valve, such as chordal tears and/or leaflet damage, usually present with less severe symptoms and may even be asymptomatic Not only can blunt cardiac injury cause acute valvular incompetence, but it can also predispose patients to delayed valvular dysfunction In a study performed by Ismailov et al looking at hospital patient discharges, patients who sustained blunt cardiac injury had an associated 12-fold increased risk for developing tricuspid valve insufficiency and a 3.4-fold increased risk of developing aortic valvular insufficiency later in life, which appeared to be independent of age, race, sex, and injury severity score [80] There was no correlation found with increased risk for mitral valve insufficiency, however Traumatic valve insufficiency, depending on severity and valve involved, may necessitate surgical treatment Penetrating Cardiac Injury The clinical presentation of penetrating cardiac injury ranges from one of hemodynamic stability to complete cardiopulmonary arrest Beck’s Triad represents the classical presentation of the patient arriving in the emergency department in pericardial tamponade and includes venous hypertension with distended neck veins, arterial hypotension, and muffled heart sounds Kussmaul’s sign: jugular venous distention seen with expiration is another classic sign attributed to pericardial tamponade, though it may not necessarily be appreciated in the acute trauma setting The physiology of pericardial tamponade is related to the relative inelastic and noncompliant pericardium Sudden acute loss of intracardiac blood volume into the pericardial sac leads to an acute pressure rise and compression of the thin-walled right ventricle and atria This decreases the heart’s ability to fill, resulting in decreased left ventricular filling and ejection fraction, thus decreasing cardiac output Subxiphoid pericardial window remains the gold standard for the diagnosis of cardiac injury, though today more cases are being diagnosed almost immediately upon patient arrival by the Extended FAST ultrasound examination Jimenez et al showed that echocaradiography had 90% accuracy, 97% specificity, and 90% sensitivity in detecting penetrating cardiac injuries [81] The usefulness of the FAST cardiac echo may be in its ability to identify obvious hemopericardium, thereby allowing the trauma surgeon to proceed directly to median sternotomy and thus eliminating the need for a subxiphoid pericardial window in many cases Pericardial window can also be therapeutic and can be done under local anesthesia in the operating room to allow release of tamponade prior to the induction of general anesthesia If blood is found, then the surgeon can proceed immediately to median sternotomy and cardiorrhaphy For relatively stable patients who do not require emergency room thoracotomy, median sternotomy is the incision of choice to repair penetrating cardiac wounds [82,83] TTE has clearly emerged as the technique of choice for the diagnosis of penetrating cardiac injuries Suspected or proven pericardial tamponade with loss of vital signs due to penetrating thoracic trauma is the major indications to perform EDT [6] An anterolateral thoracotomy is typically performed in between chest compressions and should be extended through all of the subcutaneous tissues, as well as the anterior chest wall muscles, until the intercostal space is identified Typically, the patient’s vital signs quickly return to acceptable levels Internal defibrillation may be necessary, as the heart is often found to be in ventricular fibrillation Epinephrine and similar drugs should specifically be avoided, as release of the tamponade is usually more than sufficient to allow the patient’s vital signs to return Epinephrine can increase chronotropy, inotropy, and intraventricular pressures, which can potentially extend ventricular injuries and make repair difficult and unnecessarily challenging If sinus rhythm cannot be restored despite all attempts, the prognosis is grave and the outcome is invariably poor Once vital signs are reestablished, attention can then be given to repairing the cardiac injury Definitive cardiac repair does not necessarily have to be done immediately, however, and in some cases may be ill-advised when performing an emergency room thoracotomy, since it is the tamponade and not the blood loss per se that causes hemodynamic collapse Once the tamponade is released, digital pressure can be directly applied to the cardiac wound which is often all that is needed once vital signs are restored to maintain relative hemostasis until definitive repair can be done in an operating room In the authors’ opinion, the use of adjunct measures, such as balloon tamponade with a Foley catheter, can be fraught with creating more injuries or extending existing myocardial lacerations and should be avoided if possible Vascular clamps can be placed on bleeding right atrial wounds but usually are not necessary and may cause more harm than not, extending small injuries into larger ones In addition, cross-clamping of the thoracic aorta is generally not necessary and ill-advised with isolated penetrating cardiac wounds If necessary, it can be temporarily occluded digitally against the bodies of the thoracic vertebrae until adequate resuscitation has taken place An attempt should be made to trace the trajectory of the wounding agent, as missiles often enter into one thorax and then enter the contralateral hemithorax Once the tamponade has been released, the patient has regained a rhythm and a blood pressure, and the bleeding sites are identified and digitally controlled, the experienced surgeon can then attempt closure of the cardiac wound in an appropriate equipped operating room Total inflow occlusion of the heart can be done if the blood loss is substantial through the wound and proper placement of sutures difficult in the face of ongoing blood loss without the aid of cardiopulmonary bypass This maneuver is performed by placing caval tapes around both the superior and inferior vena cavae within the pericardium, which, when tethered, results in immediate emptying of the heart The tolerance of the injured heart to this maneuver is limited, however, and should be used only for short periods if found to be necessary This procedure can result in cardiopulmonary arrest and ventricular fibrillation, and appropriate plans should be made prior to caval occlusion should this happen Atrial injuries can be repaired with running 2-0 Prolene Ventricular wounds may be repaired while digitally occluding the laceration while placing a horizontal mattress stitch with a pledget surrounding the wound, usually with 2-0 Prolene Repairing cardiac injuries resulting from gunshot wounds can be more challenging when compared with stab wounds, since they tend to have associated blast effects, which can make repair difficult The repair of ventricular wounds adjacent to or involving coronary arteries can be challenging If the coronary artery is injured itself but is quite distal (e.g., distal 1/3 of the left anterior descending artery), simple ligation can be done without serious consequences However, if the injury is more proximal than this, ligation of the injury with distal bypass using a segment of saphenous vein or mammary artery is recommended This can be done on or off cardiopulmonary bypass but usually requires the expertise of an experienced cardiac surgeon to perform If the injury does not involve the coronary artery but is in close proximity, suturing of the injury may require placement of a horizontal U-stitch underneath the bed of the coronary artery, thereby closing the injury without compromising coronary blood flow Patients who have sustained injury to their coronary artery who has already sustained irreversible myocardial damage may require intra-aortic balloon counterpulsation as part of their resuscitation p 391 p 392 Recently, some cases of hemopericardium due to penetrating trauma have been managed by urgent, rather than emergent surgery for stable patients [84] Esophagus Iatrogenic injuries to the esophagus are the most common, particularly those of iatrogenic esophageal perforation Traumatic injury and Boerhaave’s syndrome account for most of the rest Patients who present with esophageal perforation usually complain of pain Findings may include fever and subcutaneous or mediastinal air Crepitus in the neck is relatively common following perforations of the cervical esophagus and can be detected on physical exam in approximately 60% of patients Pleural effusions are present in more than 50% of patients with perforations of their thoracic esophagus Radiologic studies are important for diagnosing patients with esophageal perforation A plain chest radiograph may show subcutaneous emphysema, pneumomediastinum, pleural effusion, pneumothorax, or mediastinal air–fluid levels (hydropneumothorax) Radiographic abnormalities can be found in as many as 90% of patients on plain film Contrast studies are performed to confirm the diagnosis of perforation and to define the exact site The appropriate type of contrast agent to use for this study remains controversial Water-soluble contrast agents such as Gastrografin have been the preferred agents of choice since if leakage through the perforation occurs, they will not seed the mediatinum with particulate matter that serves as a nidus for infection However, Gastrografin can cause severe pneumonitis if aspirated into the lungs, and its use may not demonstrate small leaks Because of this, some prefer to use thin barium, as it is more inert in the lungs and is better at detecting smaller leaks CT scanning can be particularly helpful for showing mediastinal findings such as air, inflammation, and fluid collections when the perforation has already sealed The optimal management of esophageal perforation is patient specific and should take into account the clinical setting [85] This includes consideration of the patient’s underlying disease process, the degree of sepsis, if any, the location of the perforation, and whether or not the perforation is contained A nonoperative approach may be considered for patients with minimal symptoms and physical findings who do not appear septic and have a small, contained leak Nonoperative management should include the use of broad-spectrum intravenous antibiotics and nothing to eat or drink by mouth (NPO) A nasogastric tube should be specifically avoided There is no clear consensus as to generally how long a patient with a contained leak should be left NPO or how long intravenous antibiotics should be continued However, clear liquids can usually be safely started within a few days and the diet advanced cautiously, especially when no further extravasation is seen on repeat contrast study Surgery should be performed if the patient appears septic, the leak freely communicates with either the peritoneal or thoracic cavities, or there is an associated mediastinal abscess Primary repair can be done regardless of the timing of the injury, as long as the tissues appear healthy at the time of surgery Drainage alone can be done for cervical perforations, especially if the perforation cannot be found at the time of operation, which is not infrequent Primary repair with drainage is the preferred method when possible; however, if the esophageal tissues do not appear viable to hold sutures, drainage alone, with or without proximal diversion may be necessary It is important when primarily repairing the esophagus that the mucosal edges are defined, as the injury seen in the muscle layer is often only the “tip of the iceberg,” and closure of the entire mucosal defect is necessary if adequate healing is to occur Esophagectomy is rarely necessary or safe in the acute trauma setting If resection must be done, diversion should be done and esophageal reconstruction deferred until sepsis and the acute catabolic state have resolved In these cases, it is better to create an end cervical esophagostomy and oversew the gastric stump with the placement of and enteral feeding catheter Esophageal injuries due to penetrating trauma are rare, with most series averaging only a handful [86–88] They result most commonly from transmediastinal gunshot wounds Asensio et al reported their experience consisting of 43 penetrating esophageal injuries managed over a period of 6 years Overall, 28 of their 32 survivors (88%) were managed by primary repair alone [89] The overall mortality for their series was 26% The authors also reported that these mortality figures were consistent with others reported in the literature, which have remained high and relatively stable for the last 20 years, thus attesting to the critical nature of these injuries Only Symbas et al (48 cases) and Defore et al (77 cases) have reported larger experiences but over much longer spans of time, 15 and 22 years, respectively [86,87] Penetrating esophageal injuries are not easily detected and require a high index of suspicion Delay in diagnosis is associated with higher mortality However, mortality can exceed 20% even for patients who are promptly diagnosed Esophagoduodenoscopy (EGD) is a sensitive and safe diagnostic test for the detection of esophageal injury A study by Flowers et al showed that EGD had a sensitivity of 100%, a specificity of 96%, and an accuracy of 97% in detecting penetrating esophageal injuries [90] There was no morbidity related to the examination, and, most importantly, no esophageal injuries were missed The authors commented that the most significant potential weakness of flexible EGD for esophageal trauma is that it actually may be too sensitive EGD is most helpful in excluding esophageal injury in patients who require a surgical procedure for another injury When found, prompt primary repair is the treatment of choice p 392 p 393 Caustic Injuries of the Esophagus Caustic injuries of the esophagus can be very challenging to manage They are most frequently due to suicide attempts in adults and accidental ingestion in children The degree of injury to the esophagus is directly proportional to the amount of caustic substance ingested Lye causes transmural liquefaction necrosis of the esophagus and therefore is most injurious Diagnosis is usually from history, although patients attempting suicide may present with no history at all or, even worse, an inaccurate one Examination of the buccal mucosa, mouth, tongue, and gums can often show chemical burns suggestive of the diagnosis Endoscopy should be performed to document the proximal extent of the injury only; there is no need to pass the endoscope further, since it may actually be harmful and potentially lead to perforation Passage of an NGT is controversial, although it may actually help to “stent” the esophagus open and be associated with lower rates of stricture formation Arterial blood gases should be obtained with particular attention paid to the base deficit, as this can be a marker for severity of injury Signs and symptoms of perforation and sepsis should be carefully monitored The patient should be made NPO, and broad spectrum intravenous antibiotics should be given Steroids are controversial but have been associated with lower rates of stricture formation in some series [91,92] Intravenous fluids should be given and consideration given to performing esophagectomy, if signs of perforation and mediastinal sepsis are present Intra-abdominal perforations can also occur, as well as injury to surrounding structures (e.g., spleen, colon) If esophageal resection becomes clinically indicated due to sepsis, immediate reconstruction is ill-advised Esophagectomy can be performed either transhiatally or transthoracically, with creation of an end cervical esophagostomy Intra-abdominal feeding tubes should be placed for enteral access Delayed reconstruction can then be performed electively once the sepsis clears and the patient heals, usually several months later Late stricture formation is common and can be difficult to manage In addition, the pharyngeal phase of swallowing can be affected, leading to debilitating problems with speech and swallowing It is not uncommon to require serial dilations or even late esophagectomy if stricture formation develops It typically involves long segments of the esophagus and is panmural in depth, often making dilation impossible or at best marginally effective Overall prognosis is variable depending on the degree of injury Thoracic Aortic Injury Traumatic disruption of the thoracic aorta immediately leads to death in majority of the patients and is a common finding of autopsy series from high-speed motor vehicle accidents These horizontal acceleration/deceleration injuries usually result from a disruption of the integrity of the aortic wall just distal to the ligamentum arteriosum Patients fortunate enough to survive initial injury usually do so because the aortic adventitial tissues are able to tamponade the tear, thereby creating an expanding pseudoaneurysm and thus preventing or delaying fatal intrathoracic exsanguination The risk of rupture is dependent on multiple factors, including the ability of the adventitial tissues to contain the leak, the patient’s systemic blood pressure, and the size of the contained pseudoaneurysm While emergent operative repair of thoracic aortic tears has long been the standard of care, after 1997 there has been emerging evidence that not all thoracic aortic tears should be treated equally In addition, associated injuries such as pulmonary contusions, intracranial hemorrhage, and/or intra-abdominal hemorrhage (which are common in these patients) may take precedence and may render major aortic surgery particularly hazardous For these cases, the aortic injury can be acutely managed medically and definitive treatment delayed, so long as certain criteria are met With careful medical management (strict blood pressure control, minimization of dP/dT), it has been shown that many thoracic aortic injuries can undergo delayed repair, perhaps resulting in superior outcomes when compared with those patients undergoing emergent repair [93,94] A recent prospective, observational study sponsored by the American Association for the Surgery of Trauma (AAST) looked at the subgroup of patients that underwent immediate repair versus those that underwent delayed repair [95] Those patients that underwent delayed repair of stable thoracic aortic injury actually had improved survival regardless of the presence of major associated injuries, although their length of ICU stay was longer It should be noted that patients with no major associated injuries who underwent delayed repair had a significantly higher complication rates when compared to those patients undergoing immediate repair Although there has not been a randomized, controlled trial of early versus delayed repair, these results probably are affected by selection bias However, selection bias, which reflects the “art” of clinical treatment planning, should not be underscored when making decisions regarding these often multiply injured patients In addition, successful nonoperative therapy of descending thoracic aortic injury has been reported [96] Justification for nonoperative therapy includes favorable anatomy of the injury (contained, small injury, hemodynamic stability) as well as the presence of coexisting injuries, which would render the operative risk prohibitively high These include patients with spinal cord injury that might make lateral decubitus positioning dangerous, patients with pulmonary contusions that may make single lung ventilation difficult, and patients with closed head injury, solid abdominal organ injury, or major fractures in which systemic heparinization would be ill-advised One accepted method of operative repair is the “clamp-and-sew” technique, in which the proximal and distal aorta are simply clamped, thereby isolating the injury so that either primary repair or interposition grafting can be performed Operative mortality is generally reported to be 10% to 20% in most series, with major morbidity including renal failure and paraplegia, which appears to increase with prolonged (i.e., >30 minutes) clamp times [97] Another accepted method of operative repair utilizes bypass of the injured segment during repair, either with partial left heart bypass or with proximal to distal aortic shunt placement (i.e., Gott shunt) Partial left heart bypass (with cannulae in the left atrium and distal aorta) allows controlled off-loading of the left heart in addition to maintaining distal aortic perfusion, especially to the kidneys, that may decrease (but not negate) the incidence of paraplegia, especially when prolonged clamp times are anticipated Since there has not been a randomized controlled trial comparing the two techniques, and there is no conclusive evidence that one technique is superior over the other in terms of outcome, both methods are acceptable, and their performance is usually based on surgeon preference p 393 p 394 The need for operative repair, however, which was once considered the gold standard, is now coming into question There have been many reports showing that “TEVAR” (Thoracic Endovasclar Aneurysmal Repair) endovascular stent grafting of selected patients may actually be superior to that of “mandatory” operative repair [98–100] A prospective, multicenter study sponsored by the AAST was recently published that clearly shows the early efficacy and safety of endovascular stent grafting in selected patients with traumatic thoracic aortic injuries [100] The patients who underwent stent grafting had a significantly lower mortality (adjusted odds ratio: 8.42; 95% CI: [2.76 to 25.69]; adjusted p value 85 degrees bAny of the following: (1) displacement of the linear image parallel to the aortic walls, (2) over position of blood flow on the linear image, and (3) similar blood flow velocities on both sides of the linear image Adapted from Vignon P, Martaillộ JF, Franỗois B, et al: Transesophageal echocardiography and therapeutic management of patients sustaining blunt aortic injuries J Trauma 58:11501158, 2005.) SUMMARY In summary, most thoracic trauma can be managed without surgery or, at most, with minimally invasive interventions Multiply injured patients with thoracic injuries need to be comprehensively evaluated and their injuries prioritized and as a result, their successful care often requires a multidisciplinary approach The treatment for thoracic injuries is evolving and requires a working knowledge of a number of both diagnostic and therapeutic modalities As with almost all other traumatic injuries, the key to optimal treatment and outcomes is dependent upon having a high index of suspicion for the injury and to identify it early The ability to competently manage all aspects of a critically injured patient is also important in effecting a successful overall outcome REFERENCES Kulshrestha P, Munshi I, Wait R: Profile of chest trauma in a level I trauma center J Trauma 57(3):576–581, 2004 Demetriades D, Murray J, Charalambides K, et al: Trauma fatalities time and location of hospital deaths J Am Coll Surg 198(1):20–26, 2004 Karmy-Jones R, Jurkovich GJ, Shatz DV, et al: Management of traumatic lung injury: a Western Trauma Association multicenter review J Trauma 51(6):1049–1053, 2001 Martin SK, Shatney CH, Sherck JP, et al: Blunt trauma patients with prehospital pulseless electrical activity (PEA): poor ending assured J Trauma 53(5):876–881, 2002 Hunt PA, Greaves I, Owens WA: Emergency thoracotomy in thoracic trauma—a review Injury 37:1–19, 2006 Johannnesdottir BK, Mogensen B, Gudbjartsson T: Emergency thoracotomy as a rescue treatment for trauma patients in Iceland Injuiry 44:1186–1190, 2013 Soni KD, Aggarwal R, Gupta A, et al: Is the use of high frequency oscillatory ventilator beneficial in managing severe chest injury with massive air leak? BMJ Case Rep, 2014 Soult MC, Weireter LJ, Britt RC, et al: Can routine trauma bay chest xray be bypassed with an extended focused assessment with sonography for trauma examination Am Surg 81(4):336–340, 2015 Abdulrahman Y, Musthafa S, Haim S, et al: Utility of extended FAST in blunt chest trauma: is it the time to be used in the ATLS algorithm? World J Surg 39:172–178, 2015 10 Blasinska-Przerwa K, Pacho R, Bestry I: The applicationof MDCT in the diagnosis of chest trauma Pneumonol Alergol Pol 81(6):518–526, 2013 11 de Mestral C, Dueck A, Sharma SS, et al: Evolution of the incidence, management and mortality of blunt thoracic aortic injury: A population-based analysis J Am Coll Surg 216:1110–1115, 2013 12 Wisbach GG, Sise MJ, Sack DI, et al: What is the role of chest x-ray in the initial assessment of stable trauma patients? J Trauma 62(1):74– 79, 2007 13 Deunk J, Dekker HM, Brink M, et al: The value of indicated computed tomography scan of the chest and abdomen in addition to the conventional radiologic work-up for blunt trauma patients J Trauma 63(4):757–763, 2007 14 Mirvis SE, Shanmuganathan K, Buell J, et al: Use of spiral computed tomography for the assessment of blunt trauma patients with potential aortic injury J Trauma 45(5):922–930, 1998 15 Wicky S, Wintermark M, Schnyder P, et al: Imaging of blunt chest trauma Eur Radiol 10:1524–1538, 2000 16 Patel NH, Stephens KE Jr, Mirvis SE, et al: Imaging of acute thoracic aortic injury due to blunt trauma: a review Radiology 209:335–348, 1998 17 Gavant ML: Helical CT grading of traumatic aortic injuries: impact on clinical guidelines for medical and surgical management Radiol Clin North Am 37:553–574, 1999 p 396 p 397 18 Ekeh AP, Peterson W, Woods RJ, et al: Is chest X-ray an adequate screening tool for the diagnosis of blunt thoracic aortic injury? J Trauma 65(5):1088–1092, 2008 19 Chen MY, Miller PR, McLaughlin CA, et al: The trend of using computed tomography in the detection of acute thoracic aortic and branch vessel injury after blunt thoracic trauma: single-center experience over 13 years J Trauma 56(4):783–785, 2004 20 Wong H, Gotway MB, Sasson AD, et al: Periaortic hematoma at diaphragmatic crura at helical CT: sign of blunt aortic injury in patients with mediastinal hematoma Radiology 231(13):185–189, 2004 21 Kehdy F, Richardson JD: The utility of 3-D CT scan in the diagnosis and evaluation of sternal fractures J Trauma 60(3):635–636, 2006 22 Stein DM, Gregory B, York GB, et al: Accuracy of computed tomography (CT) scan in the detection of penetrating diaphragm injury J Trauma 63(3):538–543, 2007 23 Plurad D, Green D, Demetriades D, et al: The increasing use of chest computed tomography for trauma: is it being overutilized? J Trauma 62(3):631–635, 2007 24 Goarin JP, Catoire P, Jacquens Y, et al: Use of transesophageal echocardiography for diagnosis of traumatic aortic injury Chest 112:71–80, 1997 25 Brooks SW, Young JC, Cmolik B, et al: The use of transesophageal echocardiography in the evaluation of chest trauma J Trauma 32:761, 1992 26 Goarin JP, Le Bret F, Riou B, et al: Early diagnosis of traumatic thoracic aortic rupture by transesophageal echocardiography Chest 103:618, 1993 27 Wolfenden H, Newman DC: Transesophageal echocardiography: an increasing role in the diagnosis of traumatic aortic rupture J Thorac Cardiovasc Surg 106:757, 1993 28 Yoon D, Hoftman N, Ren W, et al: Intraoperative transesophageal echocardiography in chest trauma J Trauma 65(4):924–926, 2008 29 Wong SSF: Penetrating thoracic injuries: the use of transesophageal echocardiography to monitor for complications after intracardiac nail removal J Trauma 64(5):E69–E70, 2008 30 Jones JW, Kitahama A, Webb WR, et al: Emergency thoracoscopy: a logical approach to chest trauma management J Trauma 21:280–284, 1981 31 Ochsner MG, Rozycki CS, Lucente F, et al: Prospective evaluation of thoracoscopy for diagnosing diaphragmatic injury in thoracoabdominal trauma: a preliminary report J Trauma 34:704–709, 1993 32 Mealy K, Murphy M, Broe P: Diagnosis of traumatic rupture of the right hemidiaphragm by thoracoscopy Br J Surg 80:210–211, 1993 33 Abolhoda A, Livingston DH, Donahoo JS, et al: Diagnostic and therapeutic video assisted thoracic surgery (VATS) following chest trauma Eur J Card Thor Surg 12:356–360, 1997 34 Wu N, Wu L, Qiu C, et al: A comparison of video-assisted thoracoscopic surgery with open thoractomy for the management of chest trauma: a systematic review and meta-analysis World J Surg 29(4):940–952, 2015 35 Flagel BT, Luchette FA, Reed RL, et al: Half-a-dozen ribs: the breakpoint for mortality Surgery 138:717–725, 2005 36 Katherine BA, Cha ES, Bensard DD, et al: The positive predictive value of rib fractures as an indicator of nonaccidental trauma in children J Trauma 54:1107–1110, 2003 37 Bulger EM, Arneson MA, Mock CN, et al: Rib fractures in the elderly J Trauma 48:1040–1047, 2000 38 Holcomb JB, McMullin NR, Kozar RA: Morbidity from rib fractures increases after age 45 J Am Coll Surg 196:549–555, 2003 39 Gage A, Rivera F, Wang J, et al: The effect of epidural placement in patients after blunt thoracic trauma J Trauma Acute Care Surg 76(1):39–46, 2014 40 Yeh DD, Kutcher ME, Knudson MM, et al: Epidural analgesia for blunt thoracic injury—which patients benefit most? Injury 43:1667–1671, 2012 41 Carrier FM, Turgeon Af, Nicole PC, et al: Effect of epidural analgesia i patients with traumatic rib fractures: a systematic review and metaanalysis of randomized controlled trials Can J Anaesth 56(3):230– 242, 2009 42 Bulger EM, Edwards T, Klotz P, et al: Epidural analgesia improves outcome after multiple rib fractures Surgery 136:426–430, 2004 43 Simon B, Ebert J, Bokhari F, et al: Management of pulmonary contusion and flail chest: an Eastern Association for the Surgery of Trauma practice management guideline J Trauma Acute Care Surg 73(5 Suppl 4):S351–S361, 2012 44 Kilic D, Findikcioglu A, Akin S, et al: Factors affecting morbidity and mortality in flail chest: comparison of anterior and lateral location Thorac Cardioasc Surg 59(1):45–48, 2011 45 Athanassiadi K, Theakos N, Kalantzi, N, et al: Prognostic factors in flail chest patients Eur J Cardiothorac Surg 38(4):466–471, 2012 46 Zhang Y, Tang X, Xie H, et al: Comparison of surgical fixation and nonsurgical management of flail chest and pulmonary contusion Am J Emerg Med 33(7):937–940, 2015 47 Tanaka H, Yukioka T, Yamaguti Y, et al: Surgical stabilization of internal pneumatic stabilization? A prospective randomized study of management of severe flail chest patients J Trauma 52:727–732, 2002 48 Watkins R IV, Watkins R III, Williams L, et al: Stability provided by the sternum and rib cage in the thoracic spine Spine 30(11):1283– 1286, 2005 49 Black CJ, Busuttil A, Robertson C: Chest wall injuries following cardiopulmonary resuscitation Resuscitation 63:339–343, 2004 50 Garrel TV, Ince A, Junge A, et al: The sternal fracture: radiographic analysis of 200 fractures with special reference to concomitant injuries J Trauma 57:837–844, 2004 51 Athanassiadi K, Gerazounis M, Moustardas M, et al: Sternal fractures: retrospective analysis of 100 cases World J Surg 26:1243–1246, 2002 52 Weening B, Walton C, Cole PA, et al: Lower mortality in patients with scapular fractures J Trauma 59:1477–1481, 2005 53 Veysi VT, Mittal R, Agarwal S, et al: Multiple trauma and scapula fractures: so what? J Trauma 55:1145–1147, 2003 54 Sedel L: The results of surgical repair of brachial plexus lesions J Bone Joint Surg Br 64:54–66, 1982 55 Sherwood SF, Hartsock RL: Thoracic injuries, in McQuillian KA, Von Rueden KT, Hartstock RL, et al (eds): Trauma Nursing From Resuscitation Through Rehabilitation 3rd ed Philadelphia, PA, Saunders, 2002 pp 543–590 56 Kimbrell BJ, Yamzon J, Petrone P, et al: Intrapleural thrombolysis for the management of undrained traumatic hemothorax: a prospective observational study J Trauma 62(5):1175–1179, 2007 57 Toombs BD, Sandlet SV, Lester RG: Computed tomography of chest trauma Radiology 140:733–738, 1981 58 Shin B, McAlslan TC, Hankins JR: Management of lung contusion Am Surg 45:168–179, 1979 59 Schild HH, Strunk H, Weber W: Pulmonary contusion: CT vs plain radiograms J Comput Assist Tomogr 13:417–420, 1989 60 Hankins JR, Attar S, Turney SZ: Differential diagnosis of pulmonary parenchymal changes in thoracic trauma Am Surg 39:309–318, 1973 61 Wagner RB, Jamieson PM: Pulmonary contusion: evaluation and classification by computed tomography Surg Clin N Am 69:211–224, 1989 62 Kishikawa M, Yoshioka T, Shimazu T: Pulmonary contusion causes long-term respiratory dysfunction with decreased functional residual capacity J Trauma 31:1203–1210, 1991 63 Roxburgh JC: Rupture of the tracheobronchial tree Thorax 42:681– 688, 1987 64 Lynn RB, Iyengar K: Traumatic rupture of the bronchus Chest 61:81– 83, 1972 65 Kiser AC, O’Brien SM, Detterbeck FC: Blunt tracheobronchial injuries: treatment and outcomes Ann Thorac Surg 71:2059–2065, 2001 66 Juvekar N, Deshpande S, Nadkarni A, et al: Perioperative management of tracheobronchial injury following blunt trauma Ann Cardiac Anaesth 16(2):140, 2013 67 Flynn AE, Thomas AN, Schecter WP: Acute tracheobronchial injury J Trauma 29:1326–1330, 1989 68 Baumgartner F, Sheppard B, de Virgilio C, et al: Tracheal and main bronchial disruptions after blunt chest trauma: presentation and management Ann Thorac Surg 50:569–574, 1990 69 Shaw RR, Paulson DL, Kee KL Jr: Traumatic tracheal rupture J Thorac Cardiovasc Surg 42:281–297, 1961 70 Marcolini EG, Keegan J: Blunt cardiac injury Emerg Med Clin North Am 33(3):19-27, 2015-11-24 71 Mehotra, D, Dalley P, Mahon B: Tricuspid valve avulsion after blunt chest trauma Texas Heart Inst J 39(5):668–670, 2012 72 Ismailov RM, Ness RB, Redmond CK, et al: Trauma associated with cardiac dysrhythmias: results from a large matched case-control study J Trauma 62(5):1186–1191, 2007 73 Lin YC, Chang YS, Chen MS, et al: Effective myocardial salvage with percutaneous coronary intervention in late diagnosed acute posttraumatic ST-elevation myocardial infarction J Emerg Med 42(1):28– 35, 2012 74 Lindstaedt M, Germing A, Lawo T, et al: Acute and long-term clinical significance of myocardial contusion following blunt thoracic trauma: results of a prospective study J Trauma 52(3):479–485, 2002 75 Clancy K, Velopulos C, Bilaniuk JW, et al: Screeing for blunt cardiac injury: an Eastern Association for the Surgery of Trauma practice management guideline J Trauma Acute Care Surg 73(5 S 4):S301– S306, 2012 76 Penney DJ, Bannon PG, Parr MJ: Intra-aortic balloon counterpulsation for cardiogenic shock due to cardiac contusion in an elderly trauma patient Resuscitation 55:337–340, 2002 77 Perchinsky MJ, Long WB, Hill JG: Blunt cardiac rupture The Emanuel Trauma Center experience Arch Surg 130(8):852–856; discussion 856–857, 1995 78 Perlroth MG, Hazan E, Lecompte Y, et al: Chronic tricuspid regurgitation and bifascicular block due to blunt chest trauma Am J Med Sci 291(2):119–125, 1986 79 Lundevall J: Traumatic rupture of the aorta, with special reference to road accidents Acta Pathol Microbiol Scand 62:29–33, 1964 80 Ismailov RM, Weiss HB, Ness RB, et al: Blunt cardiac injury associated with cardiac valve insufficiency: trauma links to chronic disease Injury 36(9):1022–1028, 2005 81 Nicol AJ, Navsaria PH, Beningfield S, et al: Screening for occult penetrating cardiac injuries Ann Surg 261:573–578, 2015 82 Asensio JA, Stewart BM, Murray J, et al: Penetrating cardiac injuries Surg Clin North Am 76:685–725, 1996 83 Duval P: Le incision median thoraco-laparotomy: Bull Et Mem Soc De Chir De Paris, xxxiii: 15 As quoted by Ballana C (1920) Bradshaw lecture The surgery of the heart Lancet CXCVIII:73–79, 1907 84 Kremer H, Wilson J: Penetrating cardiac injury with urgent not emergent thoracotomy Missouri Med 107(5):328–330, 2010 85 Makhani M, Midani D, Goldberg A, et al: Pathogenesis and outcomes of traumatic injuries of the esophagus Dis Esophagus 27(7):630–636, 2014 86 Symbas PN, Hatcher CR, Vlasis SE: Esophageal gunshot injuries Ann Surg 191:703, 1980 87 Defore WW, Mattox KL, Hansen HA, et al: Surgical management of penetrating injuries of the esophagus Am J Surg 134:734, 1977 88 Cheadle W, Richardson JD: Options in management of trauma to the esophagus Surg Gynecol Obstet 155:380, 1982 p 397 p 398 89 Asensio JA, Berne J, Demetriades D, et al: Penetrating esophageal injuries: time interval of safety for preoperative evaluation-how long is safe? J Trauma 43(2):319–324, 1997 90 Flowers JL, Graham SM, Ugarte MA, et al: Flexible endoscopy for the diagnosis of esophageal trauma J Trauma 40(2):261–265; discussion 265–266, 1996 91 Mamede RC, De Mello Filho FV: Treatment of caustic ingestion: an analysis of 239 cases Dis Esophagus 15(3):210–213, 2002 92 Bautista A, Varela R, Villanueva A, et al: Effects of prednisolone and dexamethasone in children with alkali burns of the esophagus Eur J Pediatr Surg 6:198–203, 1996 93 Pacini D, Angeli E, Fattor R, et al: Traumatic rupture of the thoracic aorta: ten years of delayed management J Thorac Cardiovasc Surg 129:880–884, 2005 94 Kwon CC, Gill IS, Fallon WF, et al: Delayed operative intervention in the management of traumatic descending thoracic aortic rupture Ann Thorac Surg 74:S1888–S1891, 2002 95 Demetriades D, Velmahos GC, Scalea TM, et al: Blunt traumatic thoracic aortic injuries: early or delayed repair—results of an American association for the surgery of trauma prospective study J Trauma 66(4):967–973, 2009 96 Hirose H, Gill IS, Malangoni MA: Nonoperative management of traumatic aortic injury J Trauma 60(3):597–601, 2006 97 Von Oppell UO, Dunne TT, De Groot MK, et al: Traumatic aortic rupture: twenty-year meta-analysis of mortality and risk for paraplegia Ann Thorac Surg 58:585–593, 1994 98 Spiliotopoulos K, Kokotsakis J, Argiriou M, et al: Endovascular repair for blunt thoracic aortic injury: 11-year outcomes and postoperative surveillance experience J Thorac Cardiovasc Surg 148(6):2956–2961, 2014 99 Piffaretti G, Benedetto F, Menegolo M: Outcomes of endovascular repair for blunt thoracic aortic injury J Vasc Surg 58(6):1483–1489, 2013 100 Demetriades D, Velmahos GC, Scalea TM, et al: Operative repair or endovascular stent graft in blunt traumatic thoracic aortic injuries: results of an American Association for the Surgery of Trauma Multicenter Study J Trauma 64(3):561–571, 2008 101 Kriel RL, Gormley ME, Krach LE, et al: Automatic garage door openers: hazards for children Pediatrics 98:770–773, 1996 102 Zanobetti M, Coppa A, Nazerian P, et al: Chest Abdominal-Focused Assessment Sonography for Trauma during the primary survey in the Emergency Department: the CA-FAST protocol Eur J Trauma Emerg Surg, 2015 103 Lichtenstein D, Mezière G, Biderman P, et al: The “lung point”: an ultrasound sign specific to pneumothorax Intensive Care Med 26:1434–1440, 2000 104 Wilkerson RG, Stone MB: Sensitivity of bedside ultrasound and supine anteroposterior chest radiographs for the identification of pneumothorax after blunt trauma Acad Emerg Med 17:11–17, 2010 105 Kirkpatrick AW, Sirois M, Laupland KB, et al: Hand-held thoracic sonography for detecting post-traumatic pneumothoraces: the Extended Focused Assessment with Sonography for Trauma (EFAST) J Trauma 57:288–295, 2004 106 Ojaghi Haghighi SH, Adimi I, Shams Vahdati S, et al: Ultrasonographic diagnosis of suspected hemopneumothorax in trauma patients Trauma Mon 19:e17498, 2014 doi: 10.5812/traumamon.17498 107 Hyacinthe AC, Broux C, Francony G, et al: Diagnostic accuracy of ultrasonography in the acute assessment of common thoracic lesions after trauma Chest 141:1177–1183, 2012 108 Leblanc D, Bouvet C, Degiovanni F, et al: Early lung ultrasonography predicts the occurrence of acute respiratory distress syndrome in blunt trauma patients Intensive Care Med 40:1468–1474, 2014 109 Vignon P, Lang RM: Use of transesophageal echocardiography for the assessment of traumatic aortic injuries Echocardiography 16:207 219, 1999 110 Vignon P, Spencer KT, Rambaud G, et al: Differential transesophageal echocardiographic diagnosis between linear artifacts and intraluminal flap of aortic dissection or disruption Chest 119:17781190, 2001 111 Vignon P, Martaillộ JF, Franỗois B, et al: Transesophageal echocardiography and therapeutic management of patients sustaining blunt aortic injuries J Trauma 58:1150–1158, 2005 112 Vignon P, Guéret P, Vedrinne JM, et al: Role of transesophageal echocardiography in the diagnosis and management of traumatic aortic disruption Circulation 92:2959–2968, 1995 Chapter 44 Critical Care of the Patient with Abdominal Trauma JON D DORFMAN The success of nonoperative treatments and the ubiquitous availability of high-resolution CT scans have changed the management and possible complications from traumatic injuries This chapter will focus on complications of abdominal trauma that an intensivist should recognize One possible origin of the word abdomen is the Latin abdere, meaning to conceal Few areas of the human body are as difficult to assess following injury or to monitor subsequently as is the abdomen, particularly in the obtunded or intubated patient Much of the morbidity and mortality due to abdominal injury results from delay in recognizing conditions that can be corrected once identified Once the patient is admitted to the intensive care unit (ICU), the ability to follow changes occurring within the abdomen deteriorates ICU ADMISSION In previous years, trauma patients arriving in the ICU were assumed to have had their injuries identified and definitively treated, frequently in the operating room Today, the ICU plays a different role in the care of blunt trauma patients, commonly continuing the initial resuscitation to specified endpoints to allow the patient to return to the operating room for definitive care In the majority of blunt trauma patients, who frequently are managed nonoperatively, the ICU must carefully follow the patients for signs of bleeding or failure of nonoperative management and monitor for the potential complications of “missed” injuries In patients, who do have operations, they may undergo “damage control” surgery; these patients have staged operations with resuscitation in the ICU between operations Furthermore, the resuscitation for traumatic abdominal injuries is now known to have systemic physiologic effects Trauma surgeons have traditionally separated injured patients into those injured by blunt mechanisms such as car crashes and falls and those injured by penetrating mechanisms, which are subdivided into gunshot wounds or stabbings Blunt trauma patients are more frequently managed nonoperatively, whereas penetrating trauma, particularly gunshots wounds, more often require operative exploration Operative trauma patients will have had a laparotomy, and their injuries should have been defined However, there still exists a rate of missed injuries of up to 10% [1] There will be a tendency for the intensivist to consider these patients identical to the elective general surgical patient who has undergone a comparable operation Although there are certainly areas of commonality, there are critical differences that must be considered The general surgical patient will usually have only a single acute problem unlike the trauma patient who may have sustained injuries to multiple body regions and possibly more than one organ in the abdomen These differences often lead to management problems and complications that would not be expected of the general surgical patient p 398 p 399 Many blunt injury patients and selective penetrating injury patients are now managed with the intention of not operating on them This approach has grown out of the recognition that many trauma laparotomies are nontherapeutic as opposed to negative For example, a laparotomy for hemoperitoneum that identifies a small liver laceration and a minor tear in the mesentery is certainly not a “negative” laparotomy, but if both injuries have stopped bleeding spontaneously, it is difficult to argue that the surgery was therapeutic Nontherapeutic laparotomies are not without consequences Operations are painful; they expose the patient to complications rates in older series of up to 41% [2] and in more recent studies of 14% [3] Complications include wound infections, pneumonia, urinary tract infections, deep venous thrombosis as well as ileus, bowel obstruction, and incisional hernias Thus, the risks and benefits of operating must be balanced by trauma surgeons NONOPERATIVE MANAGEMENT Nonoperative management of intra-abdominal injury is so widely practiced that trauma surgeons often feel they have to attempt nonoperative management or justify why they want to operate on a splenic or liver laceration Nonoperative management of abdominal solid organ injury is appropriate only for hemodynamically stable patients whose injuries are identified by imaging Hemodynamic stability is not as easy to define as it would appear Advance Trauma Life Support for Doctors defines hypotension as a systolic blood pressure of 90 mm Hg However, there are exceptions to this rule The elderly, in particular, have an increase in mortality with blood pressures lower that 110 to 120 mm Hg [4] Certainly, patients who require ongoing resuscitation with blood and blood products or pressors to maintain normotension are not considered stable Other factors to consider include tachycardia or metabolic acidosis, and if present, would also preclude a state of physiologic stability Additional factors should be considered before a decision to attempt nonoperative management is made Are there medical conditions such as portal hypertension or the use of anticoagulants? Patients with severe head injuries or ischemic heart disease are often considered to be at high operative risk, but a failure of nonoperative management also poses a high risk of mortality [5,6] As imaging has improved, trauma surgeons have been given a more precise determination of the anatomic location and severity of the injury prior to deciding whether or not an operation is indicated This information has allowed the construction of a number of models intended to predict the success of nonoperative management [7] CT-based injury grading systems have been shown to correlate with clinical outcomes, but, as with most scoring systems, work better for analyzing populations than for predicting the outcome of an individual patient [8,9] One of the most useful CT findings is the presence of extravasated vascular contrast This contrast blush usually represents either active bleeding or a pseudoaneurysm of a parenchymal artery Such patients have a higher probability of failing nonoperative management Angiographic embolization of the injured vessel may help to restore them to the nonoperative pathway [10] BLUNT TRAUMA Spleen The current practice of managing splenic injury nonoperatively comes from recognition of the immunologic importance of the spleen and the risk of overwhelming postsplenectomy sepsis Furthermore, realization grew that many splenic injuries required no intervention The practice of nonoperative management began in pediatrics and has gradually extended into the adult population, for whom nonoperative management is not as successful Nonoperative failure rates range from 2% to 13% [11] Predictors of failure of nonoperative management include grade of injury [12], active contrast extravasation, and in some studies, age over 55 years old [13] Isolated lower grade injuries are unlikely to be admitted to the ICU as the risk of failure of nonoperative management and the risk of mortality are low If low grade injury patients are admitted to the ICU, it is most likely due to concomitant injuries or significant patient comorbidities The intensivist should remember that even low grade injuries have a small chance of bleeding that would require intervention For injuries grade III and higher, the rate of failure of nonoperative management increases and is particularly significant in grade IV (60%) and grade V (75%) injuries [14] Nonoperative management fails in up to 15% of all patients with splenic injury In prior studies, 75% of these failures occur within 2 days, and almost 95% of the failures occurred within one week [13] The nonoperative management of a ruptured spleen must be a joint effort between the surgical and the ICU teams Parameters that change the management strategy should be agreed upon in advance In general, any sign of ongoing hemorrhage should lead to immediate surgery and splenectomy If the patient experiences a steadily falling hemoglobin level but never manifests any change in vital signs, there should be prior agreement regarding the number of units of packed red blood cells (PRBCs) to be transfused before intervening The absolute number will vary with the estimated operative risk, and other factors predicting success or failure Splenic embolization may be an option in some facilities for those patients whose CT demonstrates a contrast blush within the spleen Patients admitted to the ICU for nonoperative management of a higher grade (III to IV) isolated splenic injury should receive their planned immunizations, including pneumococcal, meningococcal, and Hemophilus influenza vaccine, since there is evidence that these vaccines are more effective with the spleen in situ [15] Other elements of the patient’s care are determined in conjunction with the trauma surgeon, or institution Many centers have protocols that determine the frequency of hemoglobin blood draws, the advancement of activity, when to change the diet, and when to start venothromboembolism (VTE) chemoprophylaxis Although many studies have been performed, the data have not been conclusive enough to guide the institution of these measures [16] Most centers start VTE prophylaxis within 48 hours of injury, assuming hemodynamic stability and significant bleeding has ceased Another major complication is an infection involving the injured splenic parenchyma or the perisplenic hematoma resulting in either splenic or subphrenic abscess [17] Unexplained fever, leukocytosis, or pleural effusion should lead to consideration for an abdominal CT scan looking for evidence of infection Most infections can be effectively treated with antibiotics and percutaneous drainage, but failure to respond promptly should result in exploration, evacuation of the infected hematoma, and splenectomy Liver The other commonly injured abdominal organ from blunt trauma is the liver As in splenic injuries, nonoperative management of liver injuries has a high success rate (>80%) Although the surgical options differ from the spleen, the decision to operate should be based on similar considerations The first criterion for successful nonoperative management is hemodynamic stability A patient who does not meet this condition should be taken to the operating room and explored; surgically, the options include cauterization and placement of sutures Formal liver resection has a high mortality rate Treatment can be also be staged with placement of perihepatic packing with or without interventional radiology angiography and embolization with later reexploration after resuscitation, or transfer to a center with additional capabilities p 399 p 400 Patients who remain normotensive or who are successfully resuscitated in the trauma bay will likely have had a CT scan with intravenous contrast In prior studies, contrast extravasation into the peritoneum on CT scan is likely to require an intervention (operative or angiographic), because these patients are likely to become hemodynamically unstable [18] Contrast blush or high grade injury may be considered an indication for angiogembolization Angioembolization is not without risks Risks include hepatic necrosis requiring surgical debridment and, more commonly, gallbladder ischemia requiring cholecystectomy [19,20] Liver injuries in the setting of cirrhosis, portal hypertension, or coagulopathy are much more likely to fail nonoperative management than comparable injured patients lacking these comorbidities Complications of nonoperative management include intraperitoneal hemorrhage, hemobilia, bile leak or biloma, biliary ascites, hepatic necrosis, and abdominal compartment syndrome [21] Higher grades of liver injury are associated with higher rates of complications Delayed bleeding from a liver laceration is uncommon, and if it were to happen, usually occurs within 24 hours postinjury Biliary complications occur later than delayed bleeding Rising liver function tests, fevers, tachycardia, and worsening abdominal pain are an indication for repeat CT scan, or hepatobiliary iminodiacetic acid (HIDA) scan to evaluate for a bile leak Management of biliary complications include percutaneous drainage of symptomatic bilomas, endoscopic retrograde cholangiopancreatography with biliary stenting, and laparoscopy or laparotomy Frequently, multimodality treatment is necessary Hemobilia is an uncommon complication Most cases are associated with penetrating rather than blunt hepatic trauma The classic triad of gastrointestinal hemorrhage, jaundice, and right upper quadrant pain may suggest the diagnosis, although all three signs and symptoms are infrequently present It may occur within days of the injury to years later Diagnosis is often difficult and delayed The bleeding may be intermittent so that diagnostic endoscopy may demonstrate no source for the bleeding Hepatic angiogram and embolization is considered the first-line therapy, although rarely operative intervention is required [22] Kidney Renal injury is most often the result of blunt trauma and and rarely occurs in isolation Right renal injury most frequently occurs in conjunction with hepatic injury, and left renal injury in conjunction with splenic injury Renal injury management is usually determined by hemodynamic status Hemodynamic instability due to a renal injury, typically a high grade renovascular injury (Grade V on the American College of Surgeons Scale of I to V), usually results in nephrectomy The literature on attempting surgical repair shows that this is usually unsuccessful but should be considered if the trauma patient had only a single functional kidney to begin with [23] However, in hemodynamically stable high grade IV and V injuries, nonoperative management is still possible and highly successful [24] The complications of renal injury include hemorrhage and urine leak Hemorrhage can present as hematuria, but the severity of the hematuria and the degree of the renal injury are often discordant Gross hematuria may appear dramatic, but most renal bleeding diminishes spontaneously In some persistent cases, angioembolization may be necessary Microscopic hematuria is common after blunt abdominal trauma and is of little consequence Hemorrhage requiring an operation can occur up to 4 days postinjury in some series [24] Urine leak from an injured kidney can also occur but may resolve spontaneously Extravasated contrast that is confined within Gerota’s fascia does not mandate intervention Leakage of urine as demonstrated by delayed contrast extravasation outside of Gerota’s fascia may still resolve but is more likely to require intervention Persistent urine leakage or urinoma may need treatment, which can include a combination of ureteral stents, a nephrostomy tube, or percutaneous drainage Pancreas Blunt pancreatic injury is typically the result of high-energy impact to the epigastrium from such mechanisms as handle bar injury in bicyclists or steering wheel injury in a motor vehicle crash Physical findings are usually minimal Pancreatic injury rarely occurs by itself and is usually associated with injury to adjacent organs or structures such as the liver, kidneys, or spleen Injury to these organs should heighten your vigilance The challenge in detection is that laboratory and imaging studies are often nondiagnostic Mortality rates of up to 40% are reported from high grade injuries Injury to the pancreas is one of the classic “missed injuries” that may not become apparent until days later Serum amylase and lipase may be monitored after blunt abdominal trauma Amylasemia is not specific to pancreatic injuries, and therefore the sensitivity and specificity is low For example, traumatic brain injury and salivary gland injury can lead to a rise in amylase levels Lipase is also not predictive of injury Futhermore, serum amylase drawn within 3 hours of the injury is inaccurate Finally, the extent of amylasemia elevation does not correlate with extent of injury [25] Imaging of the pancreas also has limitations Abdominal CT scans with intravenous contrast are commonly performed and are normal in up to 40% of patients with a pancreatic injury The findings may be nonspecific and may not appear for 12 hours or more after injury These findings include signs of inflammation or “stranding” around the pancreas Other signs may include lacerations, contusions, or hematoma The critical factor that determines the management strategy of pancreatic injuries is whether or not the main pancreatic duct is injured AAST low grade injuries (I and II) do not involve the duct, whereas high grade injuries (III to V) have main ductal injury If pancreatic ductal disruption is present, distal resection or internal drainage produces much less morbidity than simple drainage or noninvasive management [26] If no definitive reason for surgical exploration exists but there is reason to suspect or diagnose a pancreatic injury, it is imperative to evaluate the ductal integrity If there is any suggestion of instability or peritoneal signs, this should be performed at the time of abdominal exploration Otherwise, the patient may be a candidate for magnetic resonance cholangiopancreatography (MRCP) or ERCP Delay in diagnosing and providing definitive therapy for a ductal injury may have devastating consequences Pelvic Fracture Pelvic fractures may be the result of low-energy falls in the osteoporotic elderly or high-energy trauma in a young motorcyclist In each case, pelvic fractures can lead to life-threatening hemorrhage and complications There are multiple classification systems for pelvic fractures One of the more commonly used systems is Young and Burgess, which classifies the fracture on the basis of four impact patterns— anterior posterior compression (APC), lateral compression (LC), vertical shear, and complex—for pelvic fractures that do not fit simply into one of the previous categories APC and LC have 3 subtypes The Young and Burgess system aids in understanding the stability of the fracture and the potential complications p 400 p 401 Hemorrhage can be significant; the source of the hemorrhage and hypotension may not initially be certain given the association of pelvic fractures with intra-abdominal solid organ injuries and long bone fractures Other sources of bleeding must be considered, identified, and dealt with accordingly Pelvic fracture–associated bleeding can be from injured pelvic arteries, disrupted veins, particularly of the sacral plexus, and even the fractured pelvic bones themselves The fracture pattern has some association with potential blood loss; APC2 and APC3 fractures as well as LC3 and vertical shear are higher blood loss fracture patterns; APC3 fractures can require 10 units or more of PRBCs for resuscitation [27] Management options include closing the pelvic ring in APC2 and APC3 fracture patients who are hemodynamically unstable Wrapping the pelvis at the greater trochanters can achieve temporary closure of the pelvic ring and effectively reduce the pelvic volume External fixation by orthopedic surgery can be performed in the operating room Embolization of arterial extravasation is also an option; however, not all patients who have active extravasation on CT scan necessarily require embolization Hemodynamic instability and ongoing blood transfusion requirements due to a pelvic fracture are indications for angiography [28] Performing embolization, however, is not without potential complications Gluteal muscle and skin necrosis have been reported along with soft tissue infection requiring debridement [29] For uncontrolled venous hemorrhage, prepelvic packing is advocated at some trauma centers [30] Even with this armamentarium, the mortality rate from pelvic injury can be quite high With large retroperitoneal hematomas, abdominal distension can lead to abdominal compartment syndrome Ventilation, in particular, can be impaired as the abdominal contents reduce the thoracic volume Respiratory failure leading to intubation can occur Associated injuries with pelvic fracture include long bone fractures and intra-abdominal injury Intra-abdominal solid and hollow viscous organ injury will be addressed separately Here it is important to discuss genitourinary and rectal injury, which are more commonly associated with “open book” fractures, APC2 and APC3 Urethral injuries are relatively uncommon (2%) Men are more likely to sustain a urethral injury than women Suspicion for this injury should be elevated if blood is noted at the urethral meatus or there is a high-riding prostate on rectal examination A retrograde urethrogram can confirm the injury; if found, this injury is treated with placement of a urinary catheter or temporized with a suprapubic tube Bladder injury can occur as well and should be considered if gross hematuria is noted CT cystogram can confirm the diagnosis and determine whether the injury to the bladder leads to intraperitoneal or extraperitoneal urine leakage Intraperitoneal leakage requires operative repair via a laparotomy and with prolonged bladder decompression with a urinary catheter Extraperitoneal leakage may be managed with only a urinary catheter for 2 weeks [31] Rectal injury should also be considered for all pelvic fractures but is most commonly associated with APC2 and APC3 Blood on rectal examination should prompt rigid sigmoidoscopy and consideration for diverting colostomy Untreated rectal injuries may lead to abscess formation and pelvic sepsis Other Nonoperative management of abdominal injuries is the treatment strategy for the solid organs, including the liver and spleen, as previously discussed Hollow viscous injuries are usually managed with an intervention except in two particular circumstances These two exceptions are intramural hematoma of the duodenum and extraperitoneal rupture of the bladder Blunt duodenal injuries are primarily the result of a blunt force to the epigastrium such as from the steering wheel or seat belt in a motor vehicle crash and handle bars in a bicycle crash In the AAST grading system, duodenal hematomas are either Grade I or II injuries, depending on the length of the duodenum involved [32] Symptoms, when present, will usually be those of gastric outlet obstruction Diagnosis is made from a CT scan with oral contrast or an upper gastrointestinal study The patient should be carefully evaluated for any evidence of a concomitant pancreatic injury If there are no associated injuries, nonoperative management is recommended Gastric decompression with a nasogastric tube and nutritional support with total parenteral nutririon should be prescribed Periodic radiographic reevaluation should occur to determine whether the obstruction has resolved If it has not resolved within several weeks, evaluation for possible stricture should be considered Approximately 80% of bladder injuries occur in the setting of pelvic fracture, although only about 5% of pelvic fractures are associated with bladder injuries [33] Bladder injuries are often extraperitoneal and result from perforation of the bladder by bone fragments from fractures of the parasymphyseal pelvis This may occur even though the final position of the bone fragments as demonstrated on radiographs does not appear near the bladder Bladder injury is also suggested by the inability to void, incomplete return of catheter irrigation into the bladder, and gross hematuria Any pelvic fracture associated with gross hematuria requires a cystogram Diagnosis requires retrograde contrast injection into the bladder with images taken in both the anteroposterior (AP) and lateral views and postvoiding CT scan with contrast can also give a highquality image of the bladder by clamping the Foley catheter to distend the bladder Extraperitoneal injuries typically will heal with bladder decompression by a urinary catheter for 7 to 14 days Prior to removal of the catheter, a repeat cystogram should be obtained to confirm resolution of the injury Persistent extravasation may require surgical repair of the bladder PENETRATING INJURY In some institutions, patients with penetrating trauma may be selected for nonoperative management and admitted to the ICU for close monitoring As with blunt trauma, the fundamental requirement for nonoperative management is hemodynamic stability and the absence of peritonitis Any hemodynamic instability or the development of peritoneal signs mandates exploration Stab wounds are much more likely to be monitored nonoperatively than gunshot wounds This type of penetrating abdominal injury has a lower incidence of penetrating the posterior abdominal fascia, and even if penetration occurs, only a fraction of stabbings cause an injury that requires repair The ICU team will monitor for hemodynamic changes, a change in abdominal examination, and signs of abdominal sepsis [34] Gunshot wounds are infrequently managed nonoperatively if the bullet enters the peritoneal cavity because of the higher probability of visceral, particularly hollow viscus, injury However, CT imaging is now allowing the nonoperative management of highly selected abdominal gunshot wounds These cases are primarily patients who are hemodynamically stable, have no peritoneal signs on examination, or for whom the entire tract of the missile appears to lie within a solid organ (liver, spleen, kidney, retroperitoneum) Such patients should be monitored in a manner similar to blunt trauma patients with the exception that hollow viscus injury is still a concern [35] MISSED INJURIES Missed injuries may be a misnomer because the injury may not have been apparent or detectable at the time of arrival at the hospital Furthermore, no matter how careful the initial evaluation of the trauma patient, almost all series report an approximately 10% incidence of missed injuries that are discovered in a delayed fashion [36] Most of these are minor extremity fractures discovered as the patient begins to increase activity and reports pain The delay in diagnosis is generally inconsequential However, a delay of the diagnosis of a hollow viscus injury may have serious consequences Avoiding delays in diagnosis requires the cooperation of the entire team providing care to the patient The initial assessment should be thorough and take into account the mechanism of injury, external signs of trauma, patient complaints, and laboratory and radiographic findings In spite of such a detailed and comprehensive evaluation, additional information will often become available over the first 24 to 48 hours Bruises, abrasions, seat belt marks, will often be more apparent the next day Laboratory and even imaging studies are less sensitive when the patient arrives at the trauma center within a few hours of injury These facts have led many trauma centers to institute a formal tertiary survey within 24 hours of admission [37] During the tertiary survey, the patient should be carefully reexamined from head to toe for new evidence of traumatic injury Radiographs should be reexamined and compared with the now dictated radiology interpretation Tertiary surveys are even more important when the patient is initially unstable, and examiners may be distracted by the urgency of the situation Furthermore, patients who had altered mental status from traumatic brain injury or intoxication may now relay new symptoms Patients who were intubated and unable to communicate may provide important subjective complaints once extubated Repeat focused assessment sonography in trauma (FAST) or computed tomography (CT) scan should be considered if there is any change in status Injuries such as pancreatic, or small bowel injuries may be more apparent on a CT scan performed at 24 hours postinjury than on the initial scan Bowel One of the major concerns is the possibility of a missed bowel injury Direct bowel rupture from blunt trauma is uncommon Typically, injury occurrs to the mesentery, and therefore the blood supply to a segment of small intestine is compromised The segment of intestine supplied by injured mesentery becomes ischemic over time and may then become necrotic A patient who has a bowel injury will likely not have peritoneal signs initially Peritoneal signs develop over time but may not be apparent in a patient who has a traumatuc brain injury, intoxication, intubated on sedation, or has a distracting injury On examination, a “seat belt” sign or abdominal wall injury from the seat belt has been associated with blunt bowel injury and should increase the index of suspicion Injuries can also be missed at the time of surgical exploration Although the mesenteric injury to the small intestine may be apparent, the retroperitoneal colon injury from a seat belt would not be obvious in the operating room The intensive care team must be cognizant of the possibility of missed injury and have a heightened vigilance for the signs and symptoms in patients who are not progressing or improving as would be expected Patients arriving with “negative” abdominal CT scans and the patient admitted following abdominal exploration must be reevaluated for bowel injury if they show signs of unexplained sepsis, prolonged ileus, rising white blood cell (WBC) count, or failure to clear their acidosis Patients admitted to the ICU for planned nonoperative management are at particular risk The sensitivity and specificity of CT scanning is low for hollow viscus injury [38] Trauma CT scan protocols use intravenous contrast without oral contrast Even with oral contrast, the free leak of oral contrast into the peritoneal cavity is a relatively infrequent finding Free air may be demonstrated, but its absence certainly cannot exclude bowel injury An area of localized thickening of the bowel wall is suggestive of injury, whereas a diffuse thickening is more compatible with either excess fluid administration or poor perfusion CT findings that cause concern are intraperitoneal hemorrhage without evidence of a solid organ injury to account for the bleeding and signs of mesenteric injury There is a debate about how much free fluid (hemorrhage) is enough to create concern for bowel injury Some consider this sufficient evidence for exploration, whereas others disagree [39] Recent studies attempted to devise scoring systems based on CT imaging, physical examination, and laboratory findings; however, nearly 16% of patients still required a delayed laparotomy [40] Any mesenteric injury that is not explored surgically must be monitored carefully in the postinjury period to allow the recognition of ischemic bowel prior to perforation Even with penetrating trauma, there is a missed injury rate Urgency of hemorrhage control may lead to oversight An apparently straight missile tract may not have been so straight Bowel may have been in a different configuration at the time of penetration Tangential injuries to the intestine on the mesenteric border that appeared not to have injured the intestine are a classic location of missed injury Areas of bowel injury that did not appear transmural may have been deeper than was realized Areas that did not appear injured such as the retroperitoneum may not have been explored It is incumbent on the operating surgeon to explore the abdomen thoroughly, but in spite of this, injuries will at times be missed Neither the operating surgeon nor the intensivist caring for the patient in the ICU should dismiss the possibility if the patient is not recovering as anticipated Pancreas Signs and symptoms of pancreatic injury may not manifest immediately As previously explained, serum amylase and serum lipase will not be elevated if checked within 3 hours of the injury CT scan findings may be minimal or completely lacking within 12 to 24 hours of the injury Fluid collections (pseudocysts), pancreatic ascites, pancreatitis, and sepsis may develop days after the injury Renal Collecting System Injuries to the renal collecting system, including the renal pelvis, ureters, and bladder, may present as a rising blood urea nitrogen (BUN) without obvious explanation, as new onset nonhemorraghic ascites without evidence of cirrhosis, as drainage of serosanguineous fluid from the incision, or as a mass in the flank or pelvis The diagnosis is usually not difficult as long as a urine leak is considered CT with intravenous contrast with appropriately timed delayed images will usually establish the diagnosis Any unexplained fluid collection in the abdomen that is aspirated should be analyzed for creatinine and compared to the serum level Most injuries that are diagnosed late can be managed with decompression or stenting, although complete transection of a ureter will require operative repair Solid Organs The probability of missing a solid organ injury if the patient has received a CT scan with intravenous contrast is low CT scans with intravenous contrast identify approximately 98% of solid organ injuries The probability of missing a significant solid organ injury is even lower However, solid organ injuries can be missed if the patient does not receive a CT scan on the basis of what is perceived to be a normal physical examination with a false negative FAST examination As previously discussed, many reasons exist for an erroneous physical examination Blood in the peritoneal cavity may not cause peritoneal irritation immediately Intoxication, traumatic brain injury, or distracting injuries can alter the abdominal examination FAST examinations are intended to assess the presence or absence of free fluid in the abdomen, not injury to solid organs Some liver, spleen, or kidney lacerations produce little or no free fluid on initial examination Patients admitted to the ICU without abdominal CT scanning or with a noncontrast CT should be monitored closely Any unexplained deterioration in vital signs or change in hemoglobin should prompt an immediate FAST examination or a CT scan if the patient is sufficiently stable to be transported to radiology ABDOMINAL COMPARTMENT SYNDROME Abdominal compartment syndrome (ACS) is a recognized complication of traumatic injury and resuscitation, but the diagnosis may be delayed or missed all together Recogntion of ACS began in the 1800s with reports of the deleterious results of intra-abdominal hypertension, but the clinical diagnosis was imprecise, unreliable, and infrequently made With the publication by Kron et al [41] of the indirect measurement of intraabdominal pressure (IAP) by bladder pressure, diagnosis of ACS became feasible and quantifiable ACS assumed even greater importance with the widespread use of damage control surgical resuscitation as patients at high risk for ACS should be considered for staged closure A complete review of ACS is presented in its own chapter 52, including current definitions, pathophysiology, systemic consequences, measuring techniques, and management We discuss it briefly here as it relates specifically to abdominal trauma Pathophysiology The fundamental physiology of ACS does not differ from any other compartment syndrome It may occur as a result of bleeding, edema, or packing within the abdomen, referred to as primary compartment syndrome, or as a result of ischemia-reperfusion and capillary leak associated with other disease processes such as major burns or systemic sepsis This is referred to as secondary compartment syndrome Pressure within the abdominal compartment increases until the perfusion pressure is inadequate to meet the oxygen and nutrient needs of the tissues within the abdomen or extra-abdominal organ failure results As IAP increases, the abdomen distends until it can expand no further The increased intra-abominal pressure is transmitted to the surrounding structures Although the most direct technique involves the insertion of catheter directly into the peritoneal cavity, this is not practical or necessary for injured patients The accepted clinical technique is an indirect assessment by the bladder pressure measurement When IAP rises to a critical level, not only does it compromise blood flow to intra-abdominal organs, it also negatively impacts the respiratory, cardiovascular, and central nervous systems ACS is defined as an abdominal pressure of more than 20 mm Hg with one or more organs showing signs of dysfunction [42] Clinical Manifestations Increases in IAP impact virtually every organ system Often, the first measurable finding involves the respiratory system, where increased IAP is often the cause of hypercarbia due to decreased minute ventilation In a pressure control mode, the tidal volumes will decrease In a volume control setting, peak inspiratory pressures will rise These changes may be subtle initially, but then dramatic changes will occur rapidly [43,44] Other possible causes are frequently considered first, such as pulmonary edema and acute lung injury; however, ACS should not be forgotten on the differential diagnosis, or it will be missed and the consequences will be dire Increased IAP increases renal vein pressure with elevations in plasma renin and aldosterone as well as decreased renal blood flow, glomerular filtration, and urine output [45] The result is oliguria and then anuria In the midst of a trauma resuscitation, oliguria could easily be misinterpreted as hypovolemia and the need for additional resuscitation, which could exacerbate the problem The increase in IAP results in an elevated central venous pressure and pulmonary capillary wedge pressure In spite of this, actual venous return declines, leading to decreased cardiac output and increased systemic and pulmonary vascular resistance This compromise in venous return is transmitted to the central nervous system, resulting in increased intracranial pressure and decreased cerebral perfusion pressure Management of Intra-Abdominal Hypertension In patients judged to be at high risk for the development of ACS, the risk may be reduced by leaving the abdomen open at the time of surgery Similarly, a patient whose abdominal wall is difficult to close because of edematous bowel or a large retroperitoneal hematoma may be better managed as an open abdomen from the beginning Anytime there is a suspicion of ACS, the initial diagnostic step should be the measurement of IAP If IAP is elevated, the therapeutic choices are to either reduce the volume of the abdominal contents by removing space occupying lesions or to enlarge the abdominal compartment Bedside ultrasound allows the determination of whether there is a significant quantity of free fluid in the abdomen If so, either a paracentesis or the insertion of a drain may remove enough simple fluid to reduce the abdominal pressure Large quantities of fluid or gas within distended bowel loops may be removed with a nasogastric tube IAP may also be reduced in some patients with the use of improved analgesia and even neuromuscular blockade Although these few special cases should not be overlooked, many cases of ACS will require surgical decompression with some form of temporary abdominal closure Open Abdomen Patients whose abdomen is opened to prevent or treat ACS will require some alternative method of closure to prevent evisceration, to manage fluid loss, and to prevent loss of domain of the abdominal viscera One of the simplest forms of temporary abdominal wall closure that allows expansion of the abdominal cavity is the towel clip closure This technique is based on the rapid closure of the skin only with multiple surgical towel clips [46] Although it is inexpensive and fast, towel clip closure has largely been abandoned in recent years because it has been recognized that a significant number of patients developed a recurrent compartment syndrome Other methods of temporary closure that allow expansion of the abdominal cavity include placing absorbable mesh or gauze packing [47] Additional techniques have been based on the silo idea similar to that used for newborns with gastroschisis [46] Several materials have been utilized for the silo, from 3 L bags of fluid to adhesive drapes to sterile silastic sheets Currently, the most popular management of the open abdomen is negative pressure wound therapy [48] The fundamental principle is the application of a nonadherent barrier over the bowel, followed by negative pressure connection, and then a closed, sealed covering over the abdomen The benefits of such a negative pressure dressing include reduced wound care, removal of fluid from the peritoneal cavity, and the collapse of any free space in the abdomen The negative pressure may also minimize the retraction of the abdominal wall muscles A number of homemade devices have been described, and several commercial systems are now also available p 403 p 404 Once the patient has been resuscitated and abdominal injuries addressed, the next priority is abdominal closure The longer the abdomen remains open, the greater will be the difficulty in achieving closure as well as the greater the risk of enteroatmospheric fistula formation To achieve closure of the adbominal wall will require coordination between the surgical and ICU teams, the patient should have a negative fluid balance, and diuretics should be administered as needed Reapproximation of the midline fascia may require the use of pharmacologic muscle relaxants, multiple trips to the operating room to partially close the abdominal wall each time, or more complex surgical techniques such as component separation [49] In some cases, fascial closure cannot be obtained, and coverage by closing skin only or placement of a split thickness will be required This method is not ideal because it will lead to a ventral hernia that will require repair months to years later once the patient has recovered Prolonged exposure of the bowel by any of these techniques results in a substantial risk of enteroatmospheric fistula formation Fistula formation greatly complicates the wound management as well as fluid and nutritional management The primary goal of this phase of open abdominal management is to achieve some form of wound closure before enteroatmospheric fistula formation occurs DAMAGE CONTROL RESUSCITATION Damage Control Surgery Historically, trauma surgeons attempted a single definitive operation In patients with large injury burdens or serious physiologic derangements, recognition of the benefits of staging the operation has occurred In these carefully selected patients, hemorrhage control and then control of enteric spillage is prioritized The reconstruction to obtain gastrointestinal continuity and closure of the abdominal wall is left to later procedures once the patient’s physiologic condition improves This damage control philosophy attempts to abort the cycle of the “triad of death” [50] in which hypothermia, acidosis, and coagulopathy worsen until the patient expires This technique has become widely used and applied for traumatic and nontraumatic abdominal catastrophes Damage control has been advocated in the following circumstances: if more than 10 units of blood has been transfused, base excess of –18 mmol per L or less if patient is less than 55 years old; base excess of –8 mmol per L or less if patient is greater than 55 years old; lactic acidosis greater than 5 mmol per L; hypothermia of less than 35°C [51] Damage control surgery, as generally practiced, consists of three phases: I Limited operative intervention aimed at controlling hemorrhage, usually by ligation, shunting, or packing, and at controlling contamination, usually by ligation or stapling Little or no repair or reconstruction is performed at this stage Abdominal closure is rapid and temporary II Resuscitation in the ICU to correct hypovolemia with blood products, hypothermia by active warming, and coagulopathy by replacement of coagulation factors III Planned return to the operating room to look for additional injuries, perform definite surgical procedure, remove packs, and to close the abdominal wall This phase should take place only when the physiologic derrangements described above have been corrected Inability to resuscitate the patient and correct the physiologic deficits of acidosis, hypovolemia, hypothermia, and coagulopathy may reflect continued bleeding or an injury that needs to be addressed It is not difficult to overlook a surgical bleeding site when it is obscured by diffuse nonsurgical bleeding Furthermore, vessels may spasm and once hypotension is corrected in the ICU, may hemorrhage again Making the decision to return to the OR before correction of the deficits is a difficult one Various criteria have been described for emergent return to the OR [52], but in practice, the decision is often based on progress or the lack thereof If the temperature, the pH, the coagulation studies, and the vital signs are getting better, it is usually worth continuing with resuscitation in the ICU If there are signs of ongoing bleeding and physiologic parameters are worsening, it may be worth the risk of transporting the patient back to the OR for another look or considering angioembolization if the surgical team feels that an operative intervention will not be of benefit, for example, a liver injury that has been packed already Acidosis Hypovolemic shock of the severely injured patient produces a metabolic derangement that will not have disappeared with the restoration of normal vital signs One manifestation of this metabolic failure is a lactic acidosis A variety of endpoints for resuscitation have been proposed, but none have been shown to be more reliable than resolution of the lactic acidosis The role of crystalloid as a resuscitative fluid has changed over the past decades Intravenous fluid is acidotic, and only a fraction remains intravascular Crystalloid causes cellular swelling, organ edema, and dysfunction and is proinflammatory [53] The resuscitative volume expander of choice in patients with hemorrhagic shock has become blood and blood products with limited crystalloid administration Recent data suggest that more of the resuscitation should be based on blood and blood products with lower ratios with a proven benefit to patient outcomes [54,55] Severe acidosis increases the risk of cardiac arrhythmias, reduces the effectiveness of endogenous and exogenous catecholamines, and worsens coagulopathy The enzymes of the coagulation cascade do not function as well in pH ranges outside of homeostasis; furthermore, platelet dysfunction occurs Thus, it may be appropriate to use alkalinizing agents such as sodium bicarbonate or THAM (trishydroxymethylaminomethane) to raise the pH above 7.2 [56] There is no clinical proof of mortality benefit, however, from this practice of correcting the acidosis with alkalinizing agents Hypothermia Hypothermia and traumatic injury are a lethal combination Hypothermia in trauma begins at 36°C as opposed to isolated hypothermia from environmental exposure, which begins at 35°C Mortality rates are as high as 40% in trauma patients with temperatures of 34°C and approach 100% when the patient’s temperature is less than 32°C [51] Hypothermia of the abdominal trauma patient is usually multifactorial Patients may arrive hypothermic from exposure and shock Further exposure to cold environments in the emergency department (ED) or the operating room (OR) worsens this problem; other factors include the infusion of cold fluids and blood products, and an open peritoneal cavity in the operating room Inadequate oxygen delivery leads to a failure of heat production Vasodilation from either intoxicants or anesthetic agents and loss of shivering ability from muscle relaxants also aggravate the situation It is critical to prevent the development of hypothermia because it is difficult to correct once present However, despite efforts in the ED and the OR, many damage control patients will be delivered to the ICU already hypothermic In this circumstance, aggressive efforts must be employed, including raising the room temperature, ensuring the patient is covered with blankets, warming blankets, and warming all intravenous fluids and blood products administered Lavage of the stomach via the nasogastric tube or lavage of the pleural cavity via the chest tube with warm saline solution may be considered In severe cases of hypothermia, it may be appropriate to utilize continuous arteriovenous rewarming as described by Gentilello et al [57] The inability to correct hypothermia if these measures have been employed usually indicates a failure of adequate resuscitation p 404 p 405 Coagulopathy The cause of coagulopathy of trauma, as with many other conditions, is multifactoral The attributed etiologies include consumption of coagulation factors from hemorrhage as well as dilution from infusion of crystalloids Hypothermia and acidosis play an important part in the coagulation cascade because enzymatic processes function poorly outside of the homeostatic normal, as was discussed in previous sections Hypothermia and acidosis should be corrected to reduce the coagulopathy However, blunt trauma, and, in particular, crush injury, is associated with coagulopathy from tissue injury These patients may arrive at the hospital already coagulopathic In fact, up to 25% of patients arrive coagulopathic; this coagulopathy is associated with higher injury severity scores and predicts worse outcomes [58] On arrival in the ICU from the initial phase of damage control surgery, blood should immediately be sent to the laboratory for prothrombin time, activated partial thromboplastin time, platelet count, and fibrinogen level Thromboelastography has become more widely used and is advocated by some centers as a better and more rapid assessment of coagulopathy and a way to determine which components of the coagulation cascade to replace SUMMARY This chapter focuses on the unique aspects of critically ill abdominal trauma patients With the increased use of nonoperative management and damage control resuscitation, the role of the intensivist has changed The ICU must monitor closely for hemorrhage, signaling the failure of nonoperative management of solid organ injuries All injuries may not have been identified prior to admission to the ICU, and a high index of suspicion must be maintained for missed injuries that are not readily apparent at presentation and are not easily found on the initial CT scan For damage control resuscitation, the correction of hypovolemia, hypothermia, acidosis, and coagulopathy occurs as the patient transitions between the ED, the OR, and the ICU REFERENCES Lawson CM, Daley BJ, Ormsby CB, et al: Missed injuries in the era of the trauma scan J Trauma 70:452–458, 2011 Renz BM, Feliciano DV: Unnecessary laparotomies for trauma: a prospective study of morbidity J Trauma 38(3):350–356, 1995 Schnuriger B, Lam L, Inaba K, et al: Negative laparotomy in trauma: are we getting better? Am Surg 78(11):1219–1223, 2012 Oyetunji TA, Chang DC, Crompton JG, et al: Redefining hypotension in the elderly: normotension is not reassuring Arch Surg 146(7):865– 869, 2011 Peitzman AB, Heil B, Rivera L, et al: Blunt splenic rupture in adults: multi-institutional study of the eastern association for the surgery of trauma J Trauma 49:177–87, 2000 Godley CD, Warren RL, Sheridan RL, et al: Non-operative management of blunt splenic injury in adults: age over 55 years as a powerful indicator for failure J Am Coll Surg 183:133–139, 1996 Malhotra AK, Fabian TC, Croce MA, et al: Blunt hepatic injury: a paradigm shift from operative to non-operative management in the 1990s Ann Surg 231:804–813, 2000 Cohn SM, Arango JI, Myers JG, et al: Computed tomography grading systems poorly predict the need for intervention after spleen and liver injury Am Surg 75:133–139, 2009 MacLean AA, Durso A, Cohn SM, et al: A clinically relevant liver injury grading system by CT, preliminary report Emerg Radiol 12:34–37, 2005 10 Davis KA, Fabian TC, Croce MA, et al: Improved success in nonoperative management of blunt splenic injuries: embolization of splenic artery pseudoaneurysms J Trauma 44:1008–1013, 1998 11 Moore FA, Davis JW, Moore EE, et al: Western Trauma Association (WTA) critical decisions in trauma: management of adult blunt splenic trauma J Trauma 65:1007–1011, 2008 12 Tinkoff G, Esposito TJ, Reed J, et al: American association for the surgery of trauma organ injury scale I: spleen, liver, and kidney validation based on the national trauma data bank J Am Coll Surg 207:646–655, 2008 13 McIntyre LK, Schiff M, Jurkovich GJ: Failure of nonoperative management of splenic injuries Arch Surg 40:563–569, 2005 14 Vlahos GC, Zacharias N, Emhoff TA, et al: Management of the most severely injured spleen Arch Surg 145(5):456–460, 2010 15 Howdieshell TR, Heffernan D, Dipiro JT, et al: Surgical infection society guidelines for vaccination after traumatic injury Surg Infect (Larchmt) 7:275–303, 2006 16 Stassen NA, Bhullar I, Cheng JD, et al: Selective nonoperative management of blunt splenic injury: an eastern association for the surgery of trauma practice management guideline J Trauma Acute Care Surg 73:S294–S300, 2012 17 Sekikawa T, Shatney CH: Septic sequelae after splenectomy for trauma in adults Am J Surg 145:667–673, 1983 18 Fang JF, Wong YC, Lin BC, et al: The CT risk factors for the need of operative treatment in initially hemodynamically stable patients after blunt hepatic trauma J Trauma 61:547–554, 2006 19 Dabbs DN, Stein DM, Scalea TM: Major hepatic necrosis: a common complication after angioembolization for treatment of high-grade liver injuries J Trauma 66:621–629, 2009 20 Misselbeck TS, Teicher EJ, Cipolle MD, et al: Hepatic angioembolization in trauma patients: indications and complications J Trauma 67:769–773, 2009 21 Kozar RA, Moore FA, Cothren CC, et al: Risk factors for hepatic morbidity following nonoperative management Arch Surg 141:451– 459, 2006 22 Forleea MV, Krigea JE, Welman CJ, et al: Haemobilia after penetrating and blunt liver injury: treatment with selective hepatic artery embolisation Injury 35:23–28, 2004 23 Santucci RA, Fisher MB: The literature increasingly supports expectant (Conservative) management of renal trauma—a systematic review J Trauma 59:491–501, 2005 24 van der Wilden GM, Velmahos GC, Joseph DK, et al: Successful nonoperative management of the most severe blunt renal injuries a multicenter study of the research consortium of New England centers for trauma JAMA Surg 148(10):924–931, 2013 25 Subramanian A, Dente CJ, Feliciano DV: The management of pancreatic trauma in the modern era Surg Clin N Am 87:1515–1532, 2007 26 Olah A, Issekutz A, Haulik L, et al: Pancreatic transaction from blunt abdominal trauma: early versus delayed diagnosis and surgical management Dig Surg 20:408–414, 2003 27 Dyer GS, Vrahas MS: Review of the pathophysiology and acute management of haemorrhage in pelvic fracture Injury 37(7):602–613, 2006 28 Cullinane DC, Schiller HJ, Zielinskiv MD, et al: Eastern association for the surgery of trauma practice management guidelines for hemorrhage in pelvic fracture—update and systematic review J Trauma 71:1850– 1868, 2011 29 Yasumura K, Ikegami K, Kamohara T, et al: High incidence of ischemic necrosis of the gluteal muscle after transcatheter angiographic embolization for severe pelvic fracture J Trauma 58:985–990, 2005 30 Cothren CC, Osborn PM, Moore EE, et al: Preperitoneal pelvic packing for hemodynamically unstable pelvic fractures: a paradigm shift J Trauma 62:834–842, 2007 31 Flint L, Cryer HG: Pelvic fracture: the last 50 years J Trauma 69:483– 488, 2010 32 Moore EE, Cogbill T, Malangoni M, et al: Organ injury scaling II: pancreas, duodenum, small bowel, colon and rectum J Trauma 30:1427–1429, 1990 33 Cass AS: The multiple injured patient with bladder trauma: J Trauma 24:731–734, 1984 34 Biffl WL, Kaups KL, Cothren CC, et al: Management of patients with anterior abdominal stab wounds: a western trauma association multicenter trial J Trauma 66:1294–1301, 2009 35 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 59:1155–1161, 2005 36 Chena CW, Chub CM, Yuc WY, et al: Incidence rate and risk factors of missed injuries in major trauma patients Accid Anal Prev 43:823– 828, 2011 37 Biffl WL, Harrington DT, Cioffi WG: Implementation of a tertiary trauma survey decreases missed injuries J Trauma 54:38–43, 2003 38 Malhotra AK, Fabian TC, Katsis SB, et al: Blunt bowel and mesenteric injuries: the role of screening computed tomography J Trauma 48:991–998, 2000 39 Livingston DH, Lavery RF, Passannante MR, et al: Free fluid on abdominal computed tomography without solid organ injury after blunt abdominal does not mandate celiotomy Am J Surg 182:6–9, 2001 40 McNutt MK, Chinapuvvula NR, Beckmann NM, et al: Early surgical intervention for blunt bowel injury J Trauma Acute Care Surg 78:105–111, 2015 41 Kron IL, Harman PK, Nolan SP: The measurement of intra-abdominal pressure as a criterion for re-exploration Ann Surg 199:28–30, 1984 p 405 p 406 42 Kirkpatrick AW, Roberts DJ, De Waele J, et al: Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the world society of the abdominal compartment syndrome Intensive Care Med 39:1190–1206, 2013 43 Meldrum DR, Moore FA, Moore EE, et al: Prospective characterization and selective management of the abdominal compartment syndrome Am J Surg 174:667–672, 1997 44 Cullen DJ, Coyle JP, Teplich R, et al: Cardiovascular, pulmonary, and renal effects of massively increased intra-abdominal pressure in critically ill patients Crit Care Med 17:118–121, 1989 45 Harman PK, Kron IL, McLachlan HD, et al: Elevated intra-abdominal pressure and renal function Ann Surg 196:594–597, 1982 46 Feliciano DV, Burch JM: Towel clips, silos, and heroic forms of wound closure, in Maull KI, Cleveland HC, Feliciano DV, et al (eds): Advances in Trauma and Critical Care Vol 6 Chicago, IL, Year Book, 1991, p 231–250 47 Saxe JM, Ledgerwood AM, Lucas CE: Management of the difficult abdominal closure Surg Clin North Am 73:243–251, 1993 48 Barker DE, Kaufman HJ, Smith LA, et al: Vacuum pack technique of temporary abdominal closure: a 7 year experience with 112 patients J Trauma 48:201–206, 2000 49 Ramirez OM, Ruas E, Dellon AL: “Components separation” method for closure of abdominal wall defects: an anatomic and clinical study Plast Reconst Surg 86:519–526, 1990 50 Rotondo MF, Schwab CW, McGonigal MD, et al: “Damage control”: an approach for improved survival in exsanguinating penetrating abdominal injury J Trauma 35:375–382, 1993 51 Sagraves SG, Toschlog EA, Rotondo MF, et al: Damage control surgery —the intensivist’s role J Intensive Care Med 21(1):5–16, 2006 52 Morris JA Jr, Eddy VA, Rutherford EF: The trauma celiotomy: the evolving concepts of damage control Curr Prob Surg 33:611–700, 1996 53 Santry HP, Alam HB: Fluid resuscitation: past, present, and the future Shock 33(3):229–241, 2010 54 Borgman BA, Spinella PC, Perkins JG, et al: The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital J Trauma 63:805–813, 207 55 Holcomb JB, Tilley BC, Baraniuk S, et al: Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma the PROPPR randomized clinical trial JAMA 313(5):471–482, 2015 56 Pohlman TH, Walsh M, Aversa J, et al: Damage control resuscitation Blood Rev 29(4):251–261, 2015 57 Gentilello LM, Cobean RA, Offner PJ, et al: Continuous arteriovenous rewarming: rapid reversal of hypothermia in critically ill patients J Trauma 32:316–325, 1992 58 Brohi K, Singh J, Heron M, et al: Acute traumatic coagulopathy J Trauma 54:1127–1130, 2003 Chapter 45 Orthopedic Injury GREGORY J DELLA ROCCA • SEAN E NORK • VIVEK VENUGOPAL • JOHN J WIXTED EPIDEMIOLOGY With an annual attributable mortality of more than 100,000 people in the United States, blunt and penetrating trauma is a leading cause of death for Americans younger than 45 years of age and results in staggering losses of health among surviving trauma patients [1] Trauma evacuation systems have improved dramatically over the past few decades, and patients are much more likely to survive injuries that would have previously resulted in early mortality Many polytraumatized patients sustain significant orthopedic injuries These need to be recognized and addressed appropriately to minimize consequent morbidity and mortality A dedicated orthopedic trauma service, specifically constructed to manage patients with complex fractures and dislocations in the setting of other systemic injuries, may be associated with improved outcomes for trauma patients [2] The orthopedic traumatologist is not only trained in the surgical management of the individual orthopedic injuries, but is also comfortable functioning as a member of a multidisciplinary team that may include emergency physicians, anesthesiologists, general surgeons, neurosurgeons, urologists, and plastic surgeons Musculoskeletal injuries of trauma patients come in many varieties Long-bone fractures can have direct impact upon a patient’s early mortality and late morbidity Pelvic fractures are associated with early mortality, and their recognition and acute management is vital as part of the life-saving efforts of the trauma team Open fractures are associated with the development of sepsis if not properly managed Articular (joint) fractures represent complex injuries requiring prolonged reconstruction; although they routinely occur among polytraumatized patients, their management is beyond the scope of this discussion Compartment syndrome, a sequela of severe extremity trauma, is a soft tissue condition that can result in early morbidity, associated with the impact of myonecrosis on renal function, as well as late disability, associated with fibrosis of one or more muscles important for activities of daily living Venous thromboembolism (VTE) is a danger for all trauma patients, and the risk of VTE has been shown to be increased significantly among patients with pelvic and hip fractures Finally, lesser fractures can have dramatic implications on future function for trauma patients; it has been shown that failure to identify and/or address complex injuries of the foot, for example, is associated with poor long-term outcomes among patients who survive major trauma [3] In this chapter, we will introduce challenges and share knowledge associated with multiple problems that affect trauma patients: Open fractures, pelvic fractures, long-bone fractures, knee dislocations, compartment syndrome, deep venous thrombosis (DVT), and neurological injury It is our goal to discuss orthopedic treatment considerations for all of these trauma sequelae such that they can be integrated into the management of the patient who is the victim of polytrauma OPEN FRACTURES Open fractures, or fractures with associated skin wounds allowing communication of the external environment with the fractured bone surfaces, are present in a high percentage of polytraumatized patients These wounds are at high risk for infection without adequate and early treatment of the open wound The basic treatment protocol for open fractures includes antibiotic administration, wound debridement, wound irrigation, fracture stabilization, and wound closure Initially published in 1976 [4], the Gustilo–Anderson classification scheme is an imperfect but widely utilized classification for open fractures Type I open fractures are fractures with a clean wound measuring less than 1 cm in length Type II open fractures are fractures with a laceration measuring more than 1 cm in length and without extensive soft tissue damage Type III open fractures are fractures with extensive soft tissue damage or an open segmental fracture (a two-level fracture of the same long bone) Type III fractures, therefore, represented a highly heterogeneous group of severe open fractures; a modification of the classification scheme for type III open fractures was therefore developed and published in 1981 [5] Type IIIA open fractures have extensive soft tissue damage but adequate soft tissue coverage, or are the result of high-energy trauma irrespective of laceration size Type IIIB open fractures entail extensive soft tissue loss, periosteal stripping, bone exposure, and massive contamination No mention of requirement for muscle flap fracture coverage is made by the authors (despite the fact that many of these wounds indeed do require flap coverage); this is a modification of the classification that has been propagated over the years [6], although it was suggested by Gustilo himself in a subsequent letter to the editors of the Journal of Bone and Joint Surgery [7] Type IIIC open fractures are those associated with a vascular injury that requires repair An important point must be made about this classification scheme: It is best utilized during operative debridement of the open fracture The presence of a small open wound in the skin may belie the extensive soft tissue injury underneath, leading to a misclassification of the open fracture The reliability of this classification scheme has hence been questioned [8–10] Regardless, this system continues to be used at many institutions p 406 p 407 As infection is a feared complication of open fractures, antibiotic administration is crucial for decreasing rates of infection after open fractures [11] Short courses of first-generation cephalosporins (typically, cefazolin), initiated as soon as possible after injury, are beneficial for limiting infections after open fracture [12] Aminoglycosides and penicillins are often utilized in the treatment of type III open fractures and highly contaminated open fractures [13], respectively Older studies have demonstrated that administration of broad-spectrum antibiotics lead to decreased infection rates [14] However, the scientific evidence for this practice is limited [12] Administration of aminoglycosides for the treatment of open fractures must be accomplished judiciously to minimize risk of oto- and nephrotoxicity Quinolone antibiotics, effective against gram-negative bacteria, have been shown to be effective for reducing infection rates for type I and type II open fractures [15], but they may have an adverse effect on fracture healing, an effect suggested by animal studies [16,17] Duration of antibiotic administration is a matter of debate Older recommendations included 72 hours of antibiotic treatment for type I and type II open fractures and 120 hours for type III open fractures [18]; however, newer studies have demonstrated potentially equivalent outcomes in patients who have 24 hours of antibiotic therapy [19] Surgical debridement of open fracture wounds in a complete and expeditious manner is an important additional factor for successful management Sharp debridement should be meticulous, and all foreign material removed Bone ends should be delivered into the wound, and complete exploration of the injury zone is necessary Long longitudinal extensions of the traumatic wound are often necessary for adequate exploration All tissue which is completely devitalized, including bone fragments devoid of soft tissue attachments, should be removed [20,21] Judgments related to the removal of large articular (i.e., joint surface) fragments may be required to balance the risk of severe disability from the loss of said fragments versus the risk of infection with their retention Devitalized extra-articular fragments can be cleaned and used as a reduction aid intraoperatively when fixation is proceeding immediately, or they may be stored and utilized later when fixation is delayed [22] In general, therefore, it is better not to discard bone fragments from open fractures until the patient has arrived in the operating room for definitive management An ongoing source of debate for the management of open fractures relates to the timing of debridement The previous benchmark that had been followed internationally is for open fractures to undergo urgent irrigation and debridement procedures within 6 hours However, this has recently been questioned, as it appears to have little scientific evidence supporting it In a seminal article on treatment of open fractures, Patzakis and Wilkins [14] demonstrated no relationship between the time from injury to surgical debridement of open fractures and subsequent development of infection Another more recent prospective observational study of open fracture patients across eight trauma centers in the United States also failed to show a correlation between time to surgical debridement and the risk of infection of open fracture wounds [23] Although urgency of treatment for open fractures associated with massive contamination, vascular injury, and/or limb crush is self-evident, routine emergent management does not appear to be required for open fractures, and after-hours surgery done in a hurried fashion by underexperienced practitioners and teams may result in increased rates of minor complications [24] However, it is generally accepted among the international community that treatment of an open fracture is not an elective procedure [25] Wound irrigation follows sharp debridement Irrigation solutions generally are based upon normal saline (0.9% NaCl) Additives historically have included bacitracin, cefazolin, neomycin, soaps, bleach, Betadine, and other antiseptics (such as benzalkonium chloride) Some of these, such as antiseptics, have been shown to be detrimental to wound viability [26] Antibiotics appear to offer no benefit over normal saline alone [27] High- versus low-pressure lavage for open fracture wounds has also been a source of debate However, much of the debate on additives to irrigant solutions and the role of high-pressure saline have been put to rest, as a recent randomized control trial that failed to demonstrate any benefit to soap additives, and showed similar outcomes with high- or low-pressure washing No consensus exists on the volume of irrigant Protocols vary between institutions and even within institutions, based on surgeon preference Up to 9 L of irrigant are utilized in some centers, but there is no scientific evidence upon which a recommendation can be based Ultimately, it is the opinion of most surgeons that wound debridement is the most critical aspect of treating open fracture wounds, and that the irrigation component of this treatment is of relatively less importance Methods of fixation for open fractures are variable Historically, acute open reduction and internal fixation of open fractures was contraindicated, without good scientific evidence However, the Harborview group in Seattle demonstrated that acute open reduction and internal fixation of open ankle fractures is a safe and effective method of treatment [28] External fixation is relatively rapid and fixation points can be kept out of the zone of injury Mobilization of fracture ends can be accomplished at the time of future debridement, if necessary, and staged open reduction and internal fixation with external fixator removal is safe and effective [29–31] Plate or nail fixation at the time of irrigation and debridement is also safe and effective [28,32], but limits the surgeon’s ability to redisplace bone ends for wound exploration if repeat debridement is indicated Early wound closure or coverage is preferred, as this appears to limit rates of infection of open fracture wounds [33] Acute primary closure of open fracture wounds after debridement and fixation, if possible, has been shown to be a safe method of treatment [34] Early coverage of open fracture wounds that are unable to be closed primarily has also been shown to be safe and effective [35] Adjuncts to wound closure, especially in the setting of skin tension, include “pie-crusting” of skin about the wound(s) [36] or performing open wound management with a vessel loop closure technique to reapproximate wound edges [37] and/or use of negative-pressure wound dressings [38,39] Also, if doubts about the safety of closure at the time of initial debridement and fixation persist, then open wound management and repeat debridement are appropriate until closure or coverage is considered safe Negative-pressure wound dressings can be utilized successfully for open fracture wounds as a bridge to delayed closure with successful reduction of infection rates in some series [40], or as a bridge to delayed free tissue transfer with reduction of infection rates as compared to traditional dressings [41], perhaps allowing for a possible reduction of the need for free tissue transfer [42] However, this may be a limited process, and earlier wound closure or flap coverage may reduce infection rates over late wound closure or coverage, despite utilization of the negative-pressure dressing [43] p 407 p 408 Occasionally, the polytraumatized patient who sustains high-energy open fractures may not be a candidate for fixation, instead requiring amputation Properly indicated, a well-executed amputation can be a lifesaving procedure that can shorten rehabilitation times associated with prolonged reconstruction of a mangled extremity The debate often centers on whether a limb might be amenable to salvage versus amputation at the time of the patient’s arrival to the hospital Errors in judgment regarding this can have devastating effects to the patient’s outcome, both physiologically and psychologically Multiple assessment tools have been developed to assist surgeons with making decisions regarding limb salvage versus amputation, including the Mangled Extremity Severity Score (MESS) [44,45] (Table 45.1) However, many of these tools are mediocre at best with regard to their predictive value One example is the Lower Extremity Assessment Project (LEAP) [46,47] A historically held indication for acute amputation in the setting of a mangled extremity, the lack of plantar foot sensation, has been refuted by the LEAP study team; many patients presenting with absent plantar foot sensation recovered it completely over time, indicating that the most tibial nerve injuries are neurapraxias (as opposed to complete disruptions) [48] Ultimately, each injured patient must be carefully scrutinized, and no particular physical examination finding or trauma scale has been shown to be absolutely predictive of the success or failure of attempts at limb salvage Therefore, thoughtful interpretation of trauma scores combined with assessment of the patient’s functional goals is imperative prior to making the choice between salvage and amputation TABLE 45.1 Mangled Extremity Severity Score Type Characteristics Injuries Points Skeletal/soft tissue group Low energy Stab wound, simple closed fracture, smallcaliber GSW Medium energy Open or multilevel fractures, dislocations, moderate crush injury High energy Shotgun blast, high-velocity GSW Massive crush Logging, railroad, oil rig accidents Shock group Normotensive BP stable in field and OR Transiently hypotensive BP unstable in field, responsive to IV fluids Prolonged hypotension Systolic BP 6 h BP, blood pressure; CR, capillary refill; GSW, gunshot wound; IV, intravenous; MESS, mangled extremity severity score; OR, operating room Adapted from Helfet DL, Howey T, Sanders R, et al: Limb salvage versus amputation: preliminary results of the Mangled Extremity Severity Score Clin Orthop 256:80–86, 1990 PELVIC FRACTURES Evaluation The pelvis contains the acetabulae, which represent the articulations with the lower extremities, and the lumbosacral junction, representing the articulation with the spine Comprised of three bones (two hipbones and the sacrum) with three articulations (two sacroiliac joints and the pubic symphysis), the pelvic ring is designed to distribute the weight of the upper body onto the legs for bipedal ambulation The sacroiliac joints and pubic symphysis are thought to have minimal motion, and are connected by stout ligaments Incompetence of these joints can lead to laxity and chronic pain This may occur after trauma, complicated vaginal birth in females, or idiopathically [49,50] Further ligamentous connection between the posterior and anterior pelvis is provided by the sacrospinous and sacrotuberous ligaments The transverse processes of the fifth lumbar vertebra are attached to the posterior iliac crests by the iliolumbar ligaments Disruption of the pelvic ring of young patients requires a high-energy mechanism, such as a motor vehicle crash or fall from a significant height As the pelvis is functionally a single rigid ring, the discovery of a single break is a harbinger for others For example, pubic ramus fractures, in the anterior aspect of the pelvic ring, may be obvious on plain radiographs, but associated sacral fractures may not be readily apparent on plain radiographs due to the overlying bowel gas, radioopaque contrast agents in the bowel or bladder, or bony anatomy A high index of suspicion must be maintained, and further injury may be visible on computed tomography (CT) scanning It should also be emphasized that transverse acetabular fractures often represent a component of a pelvic ring disruption, and suspicion that such disruption has occurred should be maintained with these fracture patterns p 408 p 409 Multiple classification schemes exist that describe various aspects of pelvic ring injuries The Young and Burgess [51] classification (Table 45.2) is the most commonly utilized descriptive scheme for pelvic ring injuries, in which they are classified as anteroposterior compression (APC) injuries, lateral compression (LC) injuries, vertical shear (VS) injuries, and “complex patterns” This classification can be helpful for identification of other problems that can be associated with the pelvic ring injury, such as increased incidence of head trauma with LC injuries and of abdominal and chest trauma with APC injuries [52], and it can be somewhat predictive of transfusion requirements in trauma patients [53] Other commonly utilized classification schemes include the Tile classification [54] and the American Orthopedic (AO)/Orthopedic Trauma Association classification [55] No pelvic fracture classification scheme, however, possesses all seven of the following requisites for universally applicable schemes: Ease of use, prognostic value (outcomes), descriptive value (describe the injury), therapeutic value (direct treatment), research value (allows direct comparison between groups), intraobserver reliability, and interobserver reliability TABLE 45.2 Young and Burgess Classification System Type APC I APC I – Symphysis widening < 2.5 cm II APC II – Symphysis widening > 2.5 cm anterior SI joint diastasis Disruption of sacrotuberous and sacrospinous ligament APC III – SI dislocation with associated vascular injury III LC VS LC I – Pubic ramus fracture and ipsilateral anterior sacral ala compression fracture LC II – Rami fracture and ipsilateral posterior ilium fracture–dislocation VS – Posterior and superior directed force LC III – Ipsilateral lateral compression and contralateral APC APC, anterior posterior compression; LC, lateral compression; SI, sacroiliac; VS, vertical shear Orthopedic examination of the pelvic fracture patient is similar to the orthopedic examination of all polytraumatized patients, covering the entire musculoskeletal system in a methodical manner Focused examination of the pelvis includes observation of limb deformity; abnormal limb rotation or shortening in the setting of pelvis injury may be secondary either to pelvic deformity or to hip dislocation (with or without associated acetabular fracture), or to extrapelvic lower extremity fracture Skin about the pelvis, including about the perineum, must be carefully examined for lacerations that can be associated with open pelvic fractures Open wounds may be present within folds of skin, and a thorough examination is necessary Lacerations may lurk within the fold of skin inferior to the scrotum in males, and examination of this area cannot be neglected Extensive ecchymosis should be noted; these may be indicative of degloving injuries Blood emanating from the anus or vagina can be an indicator of open pelvic fracture Digital rectal examination is therefore required to detect occult open fractures into the rectum, and vaginal examination should be performed in a safe manner to detect open fractures violating the vaginal vault Speculum examination is not generally performed in the trauma bay Urethral disruptions can also occur with pelvic fracture, and blood at the urethral meatus can be indicative of such an injury Manual palpation of the pelvis and gentle compression of the iliac crests may detect abnormal motion or crepitus associated with an unstable disruption of the pelvic ring, although this manipulation lacks sensitivity and specificity [56] Pelvic manipulations must be undertaken judiciously; unstable pelvic ring disruptions can cause life-threatening hemorrhage, which can be exacerbated by repeated examinations Repeated examinations also can induce severe patient discomfort A neurovascular examination of both legs, as well as examination of anal sphincter tone and of the bulbocavernosus reflex, is routine Standard radiography of the pelvis begins with the anteroposterior view The inlet radiograph, with the beam tilted approximately 40° caudal, can detect anteroposterior translation of the hemipelvis and rotational hemipelvic deformities The outlet radiographs, with the beam tilted approximately 40° cephalad, can detect “vertical” translation (more often, a flexion deformity) of the hemipelvis and is useful for visualizing sacral fractures Judet radiographs, with the patient or X-ray beam tilted approximately 45° to either side, are reserved for patients with acetabular fractures detected on anteroposterior radiographs CT has become routine for polytraumatized patients, and provides extensive information regarding the bony anatomy of a pelvic fracture and/or dislocation In the setting of pelvic and acetabular fractures, CT scanning is also invaluable for planning of the surgical reconstruction The CT scan is of limited utility, however, for acetabular fractures if the hip remains dislocated during the scan Therefore, it is desirable to reduce fracture–dislocations of the hip (acetabulum) prior to CT scanning of the pelvis for adequate delineation of fracture anatomy and for preoperative planning Acute Management Pelvic fracture patients often have multiple associated injuries, all of which may contribute to the overall physiological condition of the patient Early mortality of patients with pelvic fractures may be related to patient age and occurs as a result of catastrophic hemorrhage, head injury, or multiple organ system failure [57,58] As the pelvic fracture may contribute directly to morbidity and mortality, early stabilization is preferred This stabilization may be performed at the scene of the injury by emergency medical personnel, by the application of a circumferential sheet, pelvic binder, or other compressive garment Sheets are readily available, inexpensive, and easy to apply [59] The personnel applying the sheet should do their best to avoid wrinkling of the sheet, which may cause skin compromise [60] Overcompression of the pelvic ring must be avoided, as the exact nature of the pelvic injury is unknown; overcompression of certain types of unstable fracture patterns may lead to laceration of the bladder, rectum, vagina, or other intrapelvic structures Although circumferential pelvic wraps may assist with patient transport and comfort and can successfully reduce some types of pelvic ring disruptions [61], some studies fail to demonstrate decreases of mortality, transfusion requirements, or the need for pelvic angiography by their use [62] p 409 p 410 Upon arrival at the trauma center, all circumferential clothing (including pelvic wraps/binders) is removed to allow for examination of the lower abdomen and pelvis Binders can be reapplied after examination, and an effort should be made to keep patients warm to avoid coagulopathy Although pelvic fractures may be associated with catastrophic hemorrhage, ongoing hemodynamic instability can arise from a number of causes unrelated to the specific pelvic injury Grossly unstable pelvic injuries can be treated provisionally with the application of skeletal traction, on the same side(s) of the pelvic injury(ies), through either the distal femur or the proximal tibia as the side of pelvic instability Skeletal traction is also used routinely for the provisional stabilization of acetabular fractures prior to definitive treatment in the operating room; traction can minimize contact of the femoral head with rough acetabular fracture edges Patients with pelvic ring disruptions may demonstrate hemodynamic instability that is refractory to volume resuscitation An ongoing search for sources of blood loss is vital One publication demonstrated that, at a single trauma center, 21% of patients with pelvic fractures and hemodynamic instability (systolic blood pressure < 90 mm Hg) refractory to a 2 L bolus of saline ultimately expired, and 75% of those patients expired as a result of exsanguination [63] Unstable pelvic fractures are more highly associated with pelvic hemorrhage than are stable pelvic fractures Therefore, investigation of other potential sources of hemorrhage is vital, especially for the hemodynamically unstable trauma patient with a stable pelvic fracture pattern [64] Patients with unstable APC injuries have been demonstrated to require massive transfusions, followed by those patients with VS or complex mechanism pelvic ring disruptions, and lastly by those with LC injuries [53,65] However, fracture pattern may not always be indicative of transfusion requirements or the need for angiographic arterial embolization [66] Pelvic fracture-associated bleeding comes from three sources: Fracture surfaces, lacerated or ruptured veins, or lacerated or ruptured arteries Fracture surfaces may not be a source of ongoing massive blood loss, and therefore may contribute negligibly to hemodynamic instability [67] Distinguishing between major sources of pelvic hemorrhage—arterial or venous—represents a challenging but important task, and prior studies have examined multiple factors that may be associated with successful angiographic embolization, used for arterial hemorrhage, including patient age, trauma scores, shock on arrival to the trauma center, and fracture pattern [68] Venous hemorrhage after pelvic fracture can be adequately treated with pelvic stabilization, either by circumferential pelvic wrap or by external fixation, while arterial hemorrhage can be addressed with angiographic embolization [69] Transient response to initial resuscitation, lack of response to provisional pelvic stabilization, and presence of a contrast blush on pelvic CT scanning are all thought to be indicative of arterial hemorrhage that may be amenable to angiographic embolization [70,71] Pelvic packing has been used for control of severe hemorrhage in hemodynamically unstable patients It has been proposed that packing may be a more reliable method of treating severe pelvic fractureassociated hemorrhage than angiographic embolization with regard to controlling continued hemorrhage and limiting patient death due to exsanguination [72] Angiography may also be delayed, and emergency stabilization of the fracture along with or without pelvic packing may be more reliable at controlling severe fracture-associated hemorrhage [73] Another series documented a 30-day survival rate for pelvic fracture patients treated with extraperitoneal pelvic packing of 72%, and subsequent angiography was successful in detecting arterial hemorrhage in 80% of the patients after packing Immediate increases in systolic blood pressure after packing were also noted [74] Importantly, both angiography and pelvic packing must be used in a judicious fashion; this will help minimize complications related to both (such as gluteal necrosis) Genitourinary injuries occur in a small subset of patients with pelvic fracture This frequency has been shown to approximate 4.6% in a study of the U.S.A National Trauma Data Bank [75] Another recent study estimated a genitourinary injury rate of 6.8% in pelvic fractures; importantly, 23% of these injuries were missed at the time of initial evaluation [76] Urological injuries most commonly take the form of urethral disruption, extraperitoneal bladder rupture, or intraperitoneal bladder rupture Diagnosis is often by retrograde cystourethrogram, with careful attention to postdrainage images to detect bladder ruptures not detectable when the bladder is filled with contrast [77] Urethral disruption appears to occur distal to the urogenital diaphragm, contrary to classical teaching [78] Primary realignment, when possible, is accomplished endoscopically followed by threading of the urinary catheter by the Seldinger technique [79] This repair may be accomplished at the time of pelvic fracture repair, using a team approach [80] Routine use of suprapubic catheters for the management of urethral disruptions is discouraged, as it may increase the rate of infection, especially in the setting of open reduction and internal fixation of anterior pelvic ring injuries [81] Bladder injuries are more commonly extraperitoneal Nearly all present with gross hematuria Intraperitoneal bladder ruptures are generally treated with surgical exploration, to delineate the extent of injury fully, and with Foley (preferred if open reduction and internal fixation of the pelvic ring fractures will be accomplished) or suprapubic catheters Extraperitoneal ruptures may be managed with Foley catheters; the bulk of these require no formal repair [82] However, if open reduction and internal fixation of the pelvic fracture is planned, then primary repair of the extraperitoneal rupture is also accomplished at the same time, with low rates of infection [80] Open pelvic fractures represent a subset of severe injuries with a historically high mortality rates A recent systematic review calculated the total mortality rate in open pelvic fracture patients across multiple published series prior to 1991 as 30%, and since 1991 as 18%, with the decrease likely owing to aggressive management of the pelvic fracture, selective diversion of the fecal stream, and advances in critical care medicine [83] These open fractures may be occult, localized within the rectum or vagina Visual as well as digital exploration is mandatory in these patients Examination of bowel contents for gross or occult blood is also necessary While selective fecal diversion does appear beneficial for open pelvic fracture patients with perineal wounds or for patients with extensive or posterior wounds, routine use of fecal diversion does not appear to reduce infection rates among patients with open pelvic fractures [84,85] LONG-BONE FRACTURES Femoral Shaft Fractures Femoral shaft fractures often occur in conjunction with other injuries after high-velocity blunt or penetrating trauma Fracture of the femur is associated with significant morbidity of the polytraumatized patient; significant hemorrhage can occur, even in the absence of open wounds Bilateral femoral shaft fractures are associated with higher mortality rates than are seen in patients with unilateral femoral shaft fractures [86] Open femoral shaft fractures are unusual and require significant energy to create the situation where the fracture fragments travel through the robust soft tissue envelope of the thigh Initial management of femoral shaft fractures often entails placement of traction devices in the field These devices are meant to be portable, and they rest against the ischial tuberosity, against which they provide traction through the ankle or the foot Splinting of femoral shaft fractures is marginally effective at best, as it requires a splint to include the trunk for effective immobilization Portable traction devices should be removed as quickly as possible to prevent sciatic nerve pressure injury or skin ulceration Skin or, more commonly, skeletal traction is routinely applied in the emergency department, as a temporizing measure prior to transport to the operating room and to allow for continued evaluation of the patient for other injuries This traction provides patient comfort, provides immobilization for the fracture, and limits fracture shortening It can also function as a temporary treatment modality in the setting of operating room unavailability Evaluation of the patient prior to transport to the operating room should include an investigation of the ipsilateral femoral neck with thorough radiographic imaging A high percentage of femoral neck fractures are missed in the setting of ipsilateral femoral shaft fractures, and CT scans do not appear to be 100% sensitive for their diagnosis [88] p 410 p 411 Operative management is the mainstay of therapy for fractures of the femoral shaft In the United States, definitive treatment of the femoral shaft fracture patient in skeletal traction is of historical interest only A distinct advantage of femur fracture stabilization includes the ability to mobilize the patient, thereby avoiding complications associated with prolonged bed rest in critically injured patients, such as pneumonia, pressure ulcers, and deep vein thrombosis The gold standard for treatment of closed fractures of the femoral shaft is reamed, statically locked, antegrade (from the hip region) medullary nailing This method of treatment has been demonstrated to be highly effective in numerous studies [88–90], and it can allow for early unprotected weight-bearing [91] Reaming prior to nailing appears to improve healing rates of femoral shaft fractures [92,93], although this may come at the expense of increased pulmonary injury in the setting of chest-injured patients [94] Other methods of fixation for femoral shaft fractures include open reduction and internal fixation with a plate-and-screw construct and external fixation Plate fixation is often reserved for extremely proximal or extremely distal femoral shaft fractures and for fractures in which intramedullary fixation is contraindicated (e.g., the presence of device, such as a total hip arthroplasty stem, within the femoral canal) Plate fixation has been employed successfully for polytraumatized patients with femoral shaft fractures [95] Early femoral shaft stabilization is associated with improved outcomes among polytraumatized patients [96] The method of stabilization is unimportant for these early outcomes; medullary nailing, plate-andscrew fixation, or external fixation provides benefit Controversy remains regarding the optimal method of early femur fracture stabilization for the polytraumatized patient, including chest- and head-injured patients The Hannover group has published extensively regarding the second-hit phenomenon of femoral nailing in polytraumatized patients, and has made recommendations that pulmonary- and head-injured patients perhaps undergo acute “damage-control orthopedic surgery” with external fixation of a femoral shaft fracture, followed by staged conversion from external fixation to medullary nailing when the patient’s condition has improved and resuscitation has been completed [97–99] However, some recent studies have demonstrated that reduced rates of acute respiratory distress syndrome (ARDS) can be achieved with acute nailing of femoral shaft fractures, instead of with damage-control orthopedics, for polytraumatized patients [100–102] The utilization of reaming has been shown not to create increased rates of ARDS among polytraumatized patients undergoing medullary nailing of femur fractures, as compared to patients undergoing nailing without reaming [100] Adequate resuscitation has been shown to be important prior to nailing [100] Tibial Shaft Fractures Fractures of the tibial shaft are common among polytraumatized individuals Tibial fractures have a higher likelihood of being open [103,104], perhaps secondary to the thin soft tissue envelope surrounding the human tibia This soft tissue envelope may also play a role for the increased likelihood of infection and nonunion for tibial fractures; infected nonunion is more common after tibial fracture than after any other fracture of a long bone [105] Compartment syndrome is also common after high-energy fractures of the tibia, even when the fractures are open [10] Principles of treatment for tibial shaft fractures are similar to those of femoral shaft fractures: Provide comfort, restore length, alignment, and rotation, and allow for early mobilization Tibial fractures are commonly treated with medullary nailing techniques, unless there is intra-articular involvement Nailing of tibial fractures can provide sufficient stability to allow for full weight-bearing after surgery [106] Plating of tibial fractures is often done for those fractures that involve the articular surfaces of the tibia External fixation is most often utilized in a temporary fashion, especially with large open wounds requiring repeat debridement, of complex fractures involving the tibial plateau or tibial plafond, or for patients with significant physiological instability Conversion of external fixation to nailing is safe, when the patient’s condition permits [30,31] Tibial fractures in patients sustaining multisystem trauma can be stabilized in a delayed fashion, after the physiological condition of the patient has improved Unlike femoral shaft fractures, tibial fractures can be effectively treated temporarily with long-leg splints However, splinted tibial fractures must be carefully monitored for skin breakdown from the splinting material, compartment syndrome, and impending skin compromise from unstable fracture ends Humeral Shaft Fractures Fractures of the humeral shaft are a source of morbidity among polytraumatized patients They have implications for early rehabilitation as well as for future function Humeral shaft fractures can be complicated by brachial artery and nerve injuries; the radial nerve is particularly susceptible to concomitant injury with humeral shaft fracture Management of humeral shaft fractures and their sequelae are based upon the overall condition of the patient and on nature of the injury Isolated humeral shaft fractures are particularly amenable to closed management Splinting, casting, and fracture bracing have all been noted to be highly successful in achieving union of humerus fractures [107,108], and long-term outcomes (at a minimum of 1 year) are thought to be as good as those after surgical repair [109] Considerations for the management of humerus fractures of polytraumatized patients, however, likely are different Polytraumatized patients often require the use of both arms for effective mobilization and rehabilitation They are subjected to prolonged bed rest, and may be incapable of the frequent fracture brace adjustment that is advocated by Sarmiento and colleagues [107] As fracture braces are not generally utilized during the acute phase after fracture (delay of 1 to 3 weeks prior to application is common), early splints can be cumbersome and unwieldy for patients and caregivers and are not generally removable for the purposes of skin monitoring and vascular access Obtunded patients also cannot complain about pressure points beneath a nonremovable splint, and they do not routinely change position in an effort to alleviate pressure points Skin necrosis can be a danger in this setting For all of these reasons, management of humeral shaft fractures for polytraumatized patients is typically operative Humerus fractures can be treated either with open reduction and internal fixation, utilizing a plate-and-screw construct, or with medullary nailing Advocates of plate-and-screw fixation cite the ability of humeral shaft fracture patients to utilize their arms for assistance with ambulation (i.e., weight-bearing on crutches or a walker) after fixation [110] Advocates of medullary nailing for humeral shaft fractures have demonstrated good outcomes [111], although no literature exists that provides evidence regarding immediate weight-bearing after nailing of humerus fractures Some literature exists that appears to favor plating versus nailing for humeral shaft fractures, as shoulder impingement and reoperation risk appear to be lower with plating [112–114], although there is no definitive answer regarding optimal surgical treatment of humeral shaft fractures In the setting of radial nerve palsy, present between 8% and 11% of the time [115,116], nerve exploration can also occur at the time of surgery However, radial nerve palsy is not an indication for operative exploration of the nerve [117]; the bulk of radial nerve palsies appear to be neurapraxias, and one study reported that 89% recover normal distal neurological function after closed humeral shaft fracture management [118] p 411 p 412 Forearm Fractures Forearm fractures, while not often a contributing factor to mortality of the polytraumatized patient, are a source of long-term morbidity if not properly addressed The forearm functions as a mobile unit that is dependent upon the anatomy of the radius and the ulna The radius and ulna are “parallel” but curved bones, and this anatomy is vital for the maintenance of proper forearm pronation and supination The maximal radial bow has been shown, in anatomical studies, to be approximately 16 mm and located near the junction between the middle and distal one- thirds of the forearm length [119] Encroachment of either bone or of foreign material into this region may have adverse consequences on forearm rotation, and may create limitations of pronation, supination, or both Fracture of one bone of the adult forearm often leads to injury associated with the other bone, whether it is fracture or dislocation of the other bone Dislocation, when it occurs, is either at the elbow (radius) or wrist (ulna) The anatomical connections between the radius and ulna include the proximal and distal radioulnar joints and the interosseous ligaments; deformation of one bone, due to fracture, that is not “compensated” by fracture of the other bone will cause the other bone to be drawn in the direction of the deformation, causing dislocation Typical patterns include displaced proximal ulnar shaft fractures associated with dislocations of the radial head from the capitellum (the “Monteggia” fracture–dislocation) and displaced distal radial shaft fractures associated with dislocations of the ulnar head from the distal radioulnar joint (the “Galeazzi” fracture–dislocation) Careful scrutiny of the elbow, forearm, and wrist is vital for the detection of these injuries, which may be overlooked in the setting of multiple traumas Failure to recognize these injuries acutely can result in increased difficulty with surgical reconstruction (if accomplished late) or significant disability (if reconstruction is never accomplished) Forearm fractures tend to shorten, due to the powerful investing musculature of the forearm, and surgical repair is often more straightforward when it can be undertaken within a few days of injury The repaired forearm is often protected and weight-bearing is restricted for a number of weeks However, “platform” walkers or crutches may be utilized for assistance with ambulation for many cases; the weight of assisted ambulation is borne through the elbow (as opposed to the wrist and forearm) with these devices COMPARTMENT SYNDROMES Muscle groups are divided into compartments by layers of noncompliant fascia Injury to a particular muscular compartment can induce edema and/or hemorrhage within the compartment, leading to increased intracompartmental pressures Increased intracompartmental pressure can lead to venous congestion and resultant muscle ischemia within the involved compartment(s) This scenario is termed “compartment syndrome.” The number of muscle compartments is variable based on location in the body The brachium has two muscular compartments (anterior and posterior), the forearm has three muscular compartments (dorsal, volar, and mobile wad), the thigh has three muscular compartments (anterior, posterior, and adductor), and the leg has four muscular compartments (anterior, lateral, superficial posterior, and deep posterior) (Table 45.3) The exact number of muscular compartments in the hand and the foot are a matter of debate Hand compartments include the interosseous compartments as well as the thenar and hypothenar compartments, and foot compartments include the interosseous compartments as well as the abductor and adductor compartments TABLE 45.3 Muscle Compartments Region Compartment Muscles Lower leg Anterior Lower leg: Lateral Posterior deep Posterior superficial Extensor digitorum longus, extensor hallucis longus, tibialis anterior Peroneus longus, Peroneus brevis Popliteus, tibialis posterior, flexor hallicus longus, flexor digitorum longus Gastrocnemius, soleus, plantaris Nerves Vasculature Deep peroneal nerve Anterior tibial artery Superficial peroneal Peroneal nerve, prox artery portion of deep peroneal nerve Tibial nerve Posterior tibial artery, peroneal artery Branches tibial Posterior nerve branches tibial artery, popliteal Upper leg Anterior Medial Posterior Arm Anterior Posterior Forearm Volar Dorsal Sartorius, rectus Femoral nerve femoris, vastus lateralis, vastus intermedius, vastus medialis, articularis genus Pectineus, external Obturator nerve obturator, gracilis adductor longus, adductor brevis, adductor magnus Biceps femoris, Sciatic/tibial nerve semitendinosus, Short head of semimembranosus biceps femoris innervated by common peroneal nerve Biceps brachii, Musculocutaneous brachialis, nerve coracobrachialis Triceps brachii, Radial nerve anconeus Flexor carpi radialis, Median nerve, ulnar pronator teres, nerve policis longus, flexor digitorum superficialis, flexor carpi ulnaris, flexor digitorum profundus Extensor carpi Radial nerve ulnaris, extensor digiti minimi, extensor digitorum, artery, peroneal artery, sural arteries Femoral artery Deep femoral artery, obturator artery Deep femoral artery Brachial artery Deep brachial artery Ulnar artery Radial artery Mobile wad Supinator Brachioradialis, extensor carpi radialis longus, extensor carpi radialis brevis Branches of radial nerve Radial artery The absolute intracompartmental pressure at which a compartment syndrome exists continues to be a matter of debate Some authors have previously advocated threshold intracompartmental pressures, such as absolute values of 30 mm Hg or 40 mm Hg, as diagnostic of compartment syndrome However, a differential between intracompartmental pressure and diastolic blood pressure is thought to be a more reliable indicator of evolving compartment syndrome The pressure differential thought to be diagnostic of compartment syndrome is commonly accepted to be 30 mm Hg [120] The improved reliability of ΔP measurements, as opposed to absolute measurements of intracompartmental pressures alone, was recently illustrated in a series of 101 tibial fracture patients In this series, 41 patients had continuous leg intramuscular compartment pressures more than 30 mm Hg for over 6 hours in the setting of a satisfactory ΔP No difference in outcome regarding return to function and muscle strength was noted, as compared to a control group of 60 patients without elevated intramuscular pressures [121] Compartment syndrome is a problem that can arise among patients who have sustained high-energy injuries Typical injuries associated with development of compartment syndrome include fractures, dislocations, crush injuries, and prolonged episodes of limb ischemia The syndrome can also develop after reperfusion of a dysvascular limb that occurs after a revascularization procedure or after a manipulative reduction of a fracture that reduces kinking and occlusion of vessels Penetrating injuries, such as gunshot and stab wounds, can lacerate arteries within a single compartment or multiple compartments, leading to hemorrhage under pressure into a confined environment and creating a compartment syndrome The presence of a penetrating injury or open fracture (which results in fascial disruption) should not create a false sense that compartment syndrome will not develop; compartment syndromes have been documented to occur in the setting of penetrating injury or open fracture [122] Compartment syndrome can also develop after stabilization of a fracture, such as after nailing a tibial fracture, once the compartment has been returned to its preinjury length and its available volume is thereby diminished This “finger-trap” phenomenon was initially described in the literature by Matsen and Clawson [123] Tibial traction or fracture reduction in the setting of tibial shaft fractures raises compartment pressures [124] A fracture situation in which excessive shortening is corrected, or vigorous traction is required to maintain reduction, should perhaps prompt increased vigilance for the development of compartment syndrome This risk must be balanced, however, during staged management of severe fractures, as the consequence of initial inadequate limb-length restoration may be increased difficulty of the definitive reconstructive procedure at the time of formal open reduction and internal fixation Also, a recent report revealed that among tibial plateau fractures, application of an external fixator device that spans the knee and fracture may lead to transient elevations of intracompartmental pressure, but does not appear to cause a compartment syndrome [125] p 412 p 413 Missed compartment syndromes can lead to significant morbidity Frank muscle necrosis is a normal sequela of compartment syndrome, and associated joint contractures have been extensively described in the literature Elevated levels of serum creatine phosphokinase (CPK) or the appearance of myoglobinuria (which can be misinterpreted as hematuria) are associated with muscle necrosis, and have been utilized in the past as diagnostic tools for evolving compartment syndromes [126,127] Delayed treatment of compartment syndrome is fraught with complications [128] Infection rates are dramatically increased when fasciotomy for compartment syndrome is delayed [129] Fasciotomy revision, performed in a delayed fashion for inadequate index fasciotomy (and failure to relieve compartment syndrome), has been associated with increased rates of mortality and major amputation [130] Often, it is not possible to determine the exact time of onset for a compartment syndrome Therefore, the recommendation is that fasciotomy be undertaken as expeditiously as possible after diagnosis of compartment syndrome, and that a high index of suspicion for the development of compartment syndrome should be maintained in patients with high-energy trauma or trauma patients who are obtunded Compartment syndromes should be diagnosed during the evolution phase A high clinical suspicion should be maintained for any patient who has sustained a high-energy injury Pain out of proportion to the injury should alert the examiner to the possibility of impending compartment syndrome Orthopedic injuries are very painful by their nature, and patients often have differing pain tolerances (sometimes affected by chronic narcotic use/abuse), so the examiner should be sensitive to changes in pain level as reported by the injured patient Traditionally, the “five P’s” have been utilized in the awake, responsive patient for examination of the leg and ruling out compartment syndrome: Pain with palpation of the compartment, pallor, paresthesia, pain with passive stretch, and pulselessness are commonly quoted as signs of compartment syndrome Pulselessness, however, is an extreme late finding as it requires excessive pressures, in excess of systolic pressure, to occlude arteries and likely associated with complete myonecrosis within compartments involved Excessive pain with passive stretch of muscles within each compartment should alert the examiner to evolving compartment syndrome Awareness of the patient’s injuries and their direct contribution to pain with the motion of a joint (e.g., intra-articular fracture) should be considered All compartments of a traumatized extremity should be examined Muscle compartments tend to be very firm in the setting of evolving compartment syndrome p 413 p 414 Direct monitoring of intracompartmental pressure is possible utilizing the wick catheter technique, an arterial pressure line setup, or a variety of commercially available devices These methods provide direct measurements of intracompartmental pressures in mm Hg It should be emphasized, however, that compartment syndrome is primarily a clinical diagnosis Physical examination findings consistent with evolving compartment syndrome should prompt surgical intervention, even in the setting of compartment pressure measurements that indicate normal ΔP, as the consequences of missed compartment syndrome include myonecrosis and irreversible neurological injury Complete reliance upon direct intracompartmental measurements may result in undertreatment or overtreatment of compartment syndrome Intracompartmental pressure measurements have been shown to be highest within 5 cm of the fracture, and measurements taken outside of this zone may be spuriously low and lead to undertreatment [131] Also, there is a documented decrease in diastolic blood pressure after induction of general anesthesia; intracompartmental pressure measurements obtained in a patient under anesthetic must be interpreted cautiously as the ΔP value may be spuriously low and lead to overtreatment [132] Diagnosis of compartment syndrome is variably difficult, even at large trauma centers [133], and high indices of suspicion need to be maintained in order to correctly identify and treat patients For obtunded patients, serial exams should be vigilantly completed The examiner should note compartment firmness and proceed appropriately Significant degrees of subcutaneous edema can mask tense compartments Compartment pressure monitoring with commercially available devices or with an arterial pressure line setup may be utilized for diagnosis in the obtunded patient, especially if the patient exhibits no response to painful stimuli and if physical examination of compartment tightness is impeded by extensive surrounding edema (e.g., with anasarca) Techniques of fasciotomy have been described extensively Adequate decompression of all compartments in the affected portion of the extremity is the goal During fasciotomy, nonviable muscle is debrided Following fasciotomy, closure of the fascia is not indicated and skin closure should be undertaken cautiously It is imperative to verify that all compartments of the affected extremity have been released, regardless of the surgical approach utilized Anatomy may be distorted due to fracture deformity, excessive hematoma, or soft tissue avulsion, and it occasionally can be difficult to discern fascial planes Negative-pressure wound therapy devices may also be beneficial for promoting growth of granulation tissue within a fasciotomy bed, in anticipation of skin grafting, or in maintaining smaller wound dimensions, in anticipation of delayed primary closure [134,135] Fasciotomy can be associated with both acute and long-term morbidity Multiple neurovascular structures can be injured during fasciotomy Risk can be minimized by careful and meticulous dissection technique, maintaining nerves and vessels within a cutaneous flap (if possible), and assuring that neither is directly exposed to the environment (dressing) at the conclusion of the case At least one case of profound hemorrhage after erosion of an artery beneath a negative-pressure wound therapy device has been reported [136] Analysis of long-term outcomes related to fasciotomy is difficult in the trauma setting due to the concomitant injuries that have invariably occurred and which can have an effect upon function Nevertheless, a retrospective analysis of 40 patients undergoing leg fasciotomy for a variety of reasons has been published [137] Complications of leg fasciotomy were common, and included neurological injury, hemorrhage, and infection Only 45% of legs healed with a good functional result, and 27.5% had a severely disabled leg at the time of final healing Another report indicated frequent patient complaints related to fasciotomy wounds, including decreased sensation, tethering of tendons, and recurrent ulceration [138] Other known side effects of compartment release include pruritus, reflex sympathetic dystrophy, temperature sensitivity, venous stasis, and chronic edema Despite these concerns, the morbidity and potential mortality of an untreated compartment syndrome is likely to be much higher Also, a number of published reports, reviewed by Bong et al [139], indicate that outcomes of fasciotomy for chronic exertional compartment syndrome (in the absence of trauma) are reliably good These reports, however, require cautious interpretation for their application to trauma, as they did not include patients who required fasciotomy for trauma-related compartment syndrome OTHER SEQUELAE OF ORTHOPEDIC TRAUMA Deep Venous Thrombosis Polytraumatized patients with lower extremity or pelvic fractures often are subjected to prolonged periods of immobilization or reduced mobility They are at risk for development of DVT and subsequent pulmonary thromboembolism (PE) Management of the orthopedic trauma patient must take into account the increased propensity for these patients to develop VTE disease There has been much debate in the literature about appropriate methods of DVT prophylaxis for orthopedic trauma patients The Eastern Association for the Surgery of Trauma (EAST) states that the greatest risk factors in trauma patients for development of VTE are spinal fractures and spinal cord injury EAST also states that insufficient evidence exists regarding risk of VTE in trauma patients as it relates directly to longbone fracture or pelvic fracture [139] Trauma patients with pelvic and acetabular fractures are thought to have an increased risk of VTE [140] However, there is limited high-quality evidence in the literature, regarding the best method of DVT prophylaxis [141] Prophylaxis of trauma patients, especially those with pelvic and acetabular fractures, is important to reduce the risk of DVT Trauma patients have been shown to have lower rates of DVT when both chemical and mechanical means of prophylaxis are utilized [142] Mechanical DVT prophylaxis can consist of foot pumps or pneumatic compression devices Chemical DVT prophylaxis often consists of low-molecular-weight heparin (LMWH) for hospital inpatients; for patients thought to be at higher risk of VTE and who are awaiting surgical intervention for fracture repair, chemical prophylaxis does not need to be halted in anticipation of surgery [143] Despite adequate prophylaxis, however, patients are still at risk for development of DVT [144] As there are not any high-quality studies that dictate practice guidelines, the Orthopedic Trauma Association put together the recommendations based on expert opinion [145] These recommendations include the following: Initiation of LMWH in patients with musculoskeletal injury, who do not have contraindications within 24 hours LMWH should be held for 12 hours prior and subsequent to surgery 3 Patients should be started on both pharmacological and pneumatic compression devices if able If pharmacological prophylaxis is contraindicated, pneumatic compression devices should be used For patients at high risk for VTE, the panel recommended four weeks of prophylaxis Routine screening for DVT is not recommended for asymptomatic patients with musculoskeletal injuries Low-risk patients do not require routine inferior vena cava (IVC) filter placement Though patients with closed head injuries with stable neurological exams and stable head CT can be anticoagulated in 24 to 48 hours, a neurosurgical consultation is recommended While these are current expert recommendations, the panel recommended that further highquality studies are required [145] p 414 p 415 Peripheral Nerve Injury The bulk of peripheral nerve injuries that occur as a consequence of trauma are neurapraxias, which often will recover with time Typical neurological injuries include radial nerve palsies in association with humeral shaft fractures, sciatic nerve palsies (peroneal branch, in particular) in association with pelvic and acetabular fractures, and brachial plexopathies in association with scapulothoracic dissociation Radial nerve palsies occur after approximately 12% of humeral shaft fractures [118] An early description of radial nerve palsy in association with humeral shaft fracture was published by Holstein and Lewis, and describes the association with a spiral fracture of the humeral shaft located at the junction between the middle and distal one-thirds of the diaphysis [147] The radial nerve supplies motor innervation to the extensors of the hand and wrist; patients with radial nerve motor palsies will lack the ability to extend the wrist or hyperextend the interphalangeal joint of the thumb, which is mediated by the extensor pollicis longus The extensor digitorum communis (EDC), also supplied by the radial nerve, extends the metacarpophalangeal joints of the hand, but patients may recruit other muscles or perform other functions (such as wrist flexion) that will serve to extend the digits, even though the EDC is not functional The interphalangeal joints of the fingers (index, long, ring, and small) are extended by the intrinsic muscles of the hand, which are innervated by the median and ulnar nerves, and therefore are not affected by radial nerve palsy Radial nerve–mediated sensation includes the dorsal surfaces of the forearm and hand; the most specific location for radial nerve sensation is the dorsum of the first web space on the hand Most radial nerve palsies are thought to be traction injuries (neurapraxias), as opposed to complete disruptions (neurotmesis) or impalings on bone edges [146] Rarely, the radial nerve may become entrapped within the humeral fracture site, creating neurological deficits [118] In the setting of high-velocity penetrating injury (gunshot wounds), a radial nerve palsy may be secondary to blast effect of the projectile (as opposed to nerve transaction) Radial nerve palsy at presentation of a patient with a humeral shaft fracture is not considered an indication for surgery, either for nerve exploration or humeral shaft fracture fixation In the past, humeral shaft fracture patients presenting with intact radial nerve function which then is lost after manipulation of the fracture (e.g., for reduction) was considered an indication for operative nerve exploration; it has been shown, however, that the bulk of these “iatrogenic” radial nerve palsies resolve on their own, with no residual deficit, and that fracture fixation or nerve exploration is not indicated in these patients either [118] Humeral shaft fracture fixation should be undertaken for patients who would benefit (or who specifically request fixation), after thorough risk and benefit discussions with the patients and/or their families, and should not be prompted by the presence of a radial nerve deficit Electromyography and nerve conduction studies are not helpful in the acute setting, and have low sensitivity and specificity regarding the etiology of radial nerve palsy immediately after injury Ultrasonic examination, however, can be beneficial to detect nerve laceration or entrapment, when utilized by experienced practitioners [148] Although radial nerve palsies are most often transient, their recovery can take many weeks to months During this time, flexion contractures of the wrist and digits can occur Splinting and occupational therapy, with daily manual stretching exercises, are beneficial to minimize this problem Electromyography and nerve conduction studies may be performed between 6 and 12 weeks following the onset of the radial nerve palsy if there has been absolutely no recovery of function after the injury [146] Functional recovery is slow; rapid recovery should not be expected A good rule of thumb is that nerve recovery progresses at approximately 1 mm per day [149] Therefore, an injury to the radial nerve at the midshaft of the humerus should be expected to result in dorsal hand sensory deficits for many weeks Sciatic nerve palsies can occur in conjunction with pelvic or acetabular fractures Acetabular fractures with posterior dislocation of the hip have an association with the development of sciatic nerve palsy [150] Pelvic or acetabular fractures, with extensions of fracture lines into the sciatic buttress at the greater sciatic notch, can result in direct laceration of the sciatic nerve; this pattern of fracture can also result in catastrophic hemorrhage due to laceration of the superior and/or inferior gluteal arteries Pelvic ring disruptions, with wide displacement of the hemipelvis, can also cause sciatic nerve palsies or lumbosacral plexopathies [151], perhaps due either to avulsion of nerve roots or to neurapraxia [152,153] Nerve roots may be lacerated in association with sacral fractures [154] The peroneal division of the sciatic nerve is more commonly affected than the tibial division [155]; it has been postulated that this has to do with more points at which the peroneal nerves are tethered down the lower extremity than the tibial nerves The bulk of sciatic nerve palsies are also neurapraxias [152] Prognosis of these, however, is poorer than that for radial nerve palsy, perhaps secondary to the long distance across which recovery must occur (the nerve bud must travel from the pelvis to at least the superior leg, where innervation of the peroneal muscles and ankle and toe dorsiflexors occurs) [155] Electromyography and nerve conduction studies are useful for characterizing the injury, and many patients with mild injuries regain good function [156] Scapulothoracic dissociation, likened to a closed forequarter amputation [157], occurs when the shoulder girdle and upper extremity are pulled away from the midline [158] Prompt recognition of this injury complex is vital Significant degrees of scapulothoracic dissociation can result in the rupture of subclavian or axillary vessels [157,159] The injury complex can have devastating effects upon the neurological function of the upper extremity, due to the stretch of nerves or brachial plexus, or due to the avulsion of nerve roots from the cervical spine [157] Degree of neurological injury and prognosis for recovery correlates with the location of vascular injury; more proximal vascular injury correlates with more severe neurological compromise and poorer prognosis [160] Evidence of expanding hematoma within the axilla of a patient with such an injury should prompt emergent vascular surgical consultation Careful attention to the vascular status of the distal upper extremity must be paid to any patient with a distracted clavicular fracture, a significantly displaced scapular fracture, or a clear increase in distance on anteroposterior chest radiograph between the thoracic spine and the medial border of the scapula, known as the scapular index [161] CT is of questionable benefit for initial diagnosis, as the axis of the beam may not be perfectly perpendicular to the axial skeleton, and therefore determination of scapular index may be unreliable Recovery of brachial plexus function after scapulothoracic dissociation is unreliable at best, especially after nerve root avulsion [159,160,162] REFERENCES Anderson RN, Smith BL: Deaths: leading causes for 2001 Natl Vital Stat Rep 52:1–85, 2003 Wixted JJ, Reed M, Eskander MS, et al: The effect of an orthopedic trauma room on after-hours surgery at a level one trauma center J Orthop Trauma 22(4):234–236, 2008 Stiegelmar R, McKee MD, Waddell JP, et al: Outcome of foot injuries in multiply injured patients Orthop Clin North Am 32:193–204, 2001 Gustilo RB, Anderson JT: Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones J Bone Joint Surg [Am] 58:453–458, 1976 p 415 p 416 Gustilo RB, Mendoza RM, Williams DN: Problems in the management of type III (severe) open fractures: a new classification of type III open fractures J Trauma 24:742–746, 1981 Anglen J: Letter to the editor J Orthop Trauma 21:422, 2007 Gustilo RB: Letter to the editor J Bone Joint Surg [Am] 77:1291–1292, 1995 Horn BD, Rettig ME: Interobserver reliability in the Gustilo and Anderson classification of open fractures J Orthop Trauma 7:357– 360, 1993 Brumback RJ, Jones AL: Interobserver agreement in the classification of open fractures of the tibia: the results of a survey of two hundred and forty-five orthopedic surgeons J Bone Joint Surg [Am] 76:1162–1166, 1994 10 Giannoudis PV, Papakostidis C, Roberts C: A review of the management of open fractures of the tibia and femur J Bone Joint Surg [Br] 88:281–289, 2006 11 Gosselin RA, Roberts I, Gillespie WJ: Antibiotics for preventing infection in open limb fractures Cochrane Database Syst Rev (1):CD003764, 2004 12 Hauser CJ, Adams CA Jr, Eachempati SR, et al: Surgical Infection Society guideline: prophylactic antibiotic use in open fractures: an evidence-based guideline Surg Infect (Larchmt) 7:379–405, 2006 13 Zalavras CG, Patzakis MJ: Open fractures: evaluation and management J Am Acad Orthop Surg 11:212–219, 2003 14 Patzakis MJ, Wilkins J: Factors influencing infection rate in open fracture wounds Clin Orthop 243:36–40, 1989 15 Patzakis M, Bains RS, Lee J, et al: Prospective, randomized, doubleblind study comparing single-agent antibiotic therapy, ciprofloxacin, to combination antibiotic therapy in open fracture wounds J Orthop Trauma 14:529–533, 2000 16 Huddleston PM, Steckelberg JM, Hanssen AD, et al: Ciprofloxacin inhibition of experimental fracture healing J Bone Joint Surg [Am] 82:161–173, 2000 17 Perry AC, Prpa B, Rouse MS, et al: Levofloxacin and trovafloxacin inhibition of experimental fracture-healing Clin Orthop 414:95–100, 2003 18 Wilkins J, Patzakis M: Choice and duration of antibiotics in open fractures Orthop Clin North Am 22:433–437, 1991 19 Hoff WS, Bonadies JA, Cachecho R, et al: East Practice Management Guidelines Work Group: update to practice management guidelines for prophylactic antibiotic use in open fractures J Trauma 70(3):751–754, 2011 20 Templeman DC, Gulli B, Tsukayama DT, et al: Update on the management of open fractures of the tibial shaft Clin Orthop 350:18– 25, 1998 21 Ficke JR, Pollak AN: Extremity war injuries: development of clinical treatment principles J Am Acad Orthop Surg 15:590–595, 2007 22 Barei DP, Taitsman LA, Beingessner D, et al: Open diaphyseal long bone fractures: a reduction method using devitalized or extruded osseous fragments J Orthop Trauma 21:574–578, 2007 23 Pollak AN, Jones AL, Castillo RC, et al: The relationship between time to surgical debridement and incidence of infection after open highenergy lower extremity trauma J Bone Joint Surg [Am] 92:7–15, 2010 24 Ricci WM, Gallagher B, Brandt A, et al: Is after-hours orthopedic surgery associated with adverse outcomes? A prospective comparative study J Bone Joint Surg [Am] 91:2067–2072, 2009 25 Schmidt AH: Commentary & perspective on “The relationship between time to surgical débridement and incidence of infection after open high-energy lower extremity trauma” by Andrew N Pollak, MD, et al: J Bone Joint Surg [Am] 92, 2010 26 Conroy BP, Anglen JO, Simpson WA, et al: Comparison of castile soap, benzalkonium chloride, and bacitracin as irrigation solutions for complex contaminated orthopedic wounds J Orthop Trauma 13:332– 337, 1999 27 Anglen JO: Wound irrigation in musculoskeletal injury J Am Acad Orthop Surg 9:219–226, 2001 28 Franklin JL, Johnson KD, Hansen ST Jr: Immediate internal fixation of open ankle fractures: report of thirty-eight cases treated with a standard protocol J Bone Joint Surg [Am] 66:1349–1356, 1984 29 Nowotarski PJ, Turen CH, Brumback RJ, et al: Conversion of external fixation to intramedullary nailing for fractures of the shaft of the femur in multiply injured patients J Bone Joint Surg [Am] 82:781–788, 2000 30 Bhandari M, Zlowodzki M, Tornetta P III, et al: Intramedullary nailing following external fixation in femoral and tibial shaft fractures J Orthop Trauma 19:140–144, 2005 31 Della Rocca GJ, Crist BD: External fixation versus conversion to intramedullary nailing for definitive management of closed fractures of the femoral and tibial shaft J Am Acad Orthop Surg 14:S131–S135, 2006 32 Henley MB, Chapman JR, Agel J, et al: Treatment of type II, IIIA, and IIIB open fractures of the tibial shaft: a prospective comparison of unreamed interlocking intramedullary nails and half-pin external fixators J Orthop Trauma 12:1–7, 1998 33 Okike K, Bhattacharyya T: Trends in the management of open fractures: a critical analysis J Bone Joint Surg [Am] 88:2739–2748, 2006 34 DeLong WG Jr, Born CT, Wei SY, et al: Aggressive treatment of 119 open fracture wounds J Trauma 46:1049–1054, 1999 35 Gopal S, Majumder S, Batchelor AG, et al: Fix and flap: the radical orthopedic and plastic treatment of severe open fractures of the tibia J Bone Joint Surg [Br] 82:959–966, 2000 36 Dunbar RP, Taitsman LA, Sangeorzan BJ, et al: Technique tip: use of “pie crusting” of the dorsal skin in severe foot injury Foot Ankle Int 28:851–853, 2007 37 Schnirring-Judge MA, Anderson EC: Vessel loop closure technique in open fractures and other complex wounds in the foot and ankle J Foot Ankle Surg 48:692–699, 2009 38 DeFranzo AJ, Argenta LC, Marks MW, et al: The use of vacuumassisted closure therapy for the treatment of lower-extremity wounds with exposed bone Plast Reconstr Surg 108:1184–1191, 2001 39 Herscovici D Jr, Sanders RW, Scaduto JM, et al: Vacuum assisted wound closure (VAC therapy) for the management of patients with high energy soft tissue injuries J Orthop Trauma 17:683–688, 2003 40 Stannard JP, Volgas DA, Stewart R, et al: Negative pressure wound therapy after severe open fractures: a prospective randomized study J Orthop Trauma 23:552–557, 2009 41 Rinker B, Amspacher JC, Wilson PC, et al: Subatmospheric pressure dressing as a bridge to free tissue transfer in the treatment of open tibia fractures Plast Reconstr Surg 121:1664–1673, 2008 42 Dedmond BT, Kortesis B, Punger K, et al: The use of negative-pressure wound therapy (NPWT) in the temporary treatment of soft-tissue injuries associated with high-energy open tibial shaft fractures J Orthop Trauma 21:11–17, 2007 43 Bhattacharyya T, Mehta P, Smith M, et al: Routine use of wound vacuum-assisted closure does not allow coverage delay for open tibia fractures Plast Reconstr Surg 121:1263–1266, 2008 44 Johansen K, Daines M, Howey T, et al: Objective criteria accurately predict amputation following lower extremity trauma J Trauma 30:568–572, 1990 45 Helfet DL, Howey T, Sanders R, et al: Limb salvage versus amputation: preliminary results of the Mangled Extremity Severity Score Clin Orthop 256:80–86, 1990 46 Bosse MJ, MacKenzie EJ, Kellam JF, et al: A prospective evaluation of the clinical utility of the lower-extremity injury-severity scores J Bone Joint Surg [Am] 83:3–14, 2001 47 Ly TV, Travison TG, Castillo RC, et al: Ability of lower-extremity injury severity scores to predict functional outcome after limb salvage J Bone Joint Surg [Am] 90:1738–1743, 2008 48 Bosse MJ, McCarthy ML, Jones AL, et al: The insensate foot following severe lower extremity trauma: an indication for amputation? J Bone Joint Surg [Am] 87:2601–2608, 2005 49 Garras DN, Carothers JT, Olson SA: Single-leg-stance (flamingo) radiographs to assess pelvic instability: how much motion is normal? J Bone Joint Surg [Am] 90:2114–2118, 2008 50 Siegel J, Templeman DC, Tornetta P 3rd: Single-leg-stance radiographs in the diagnosis of pelvic instability J Bone Joint Surg [Am] 90:2119–2125, 2008 51 Young JW, Burgess AR, Brumback RJ, et al: Pelvic fractures: value of plain radiography in early assessment and management Radiology 160:445–451, 1986 52 Dalal SA, Burgess AR, Siegel JH, et al: Pelvic fracture in multiple trauma: classification by mechanism is key to pattern of organ injury, resuscitative requirements, and outcome J Trauma 29:981–1000, 1989 53 Magnussen RA, Tressler MA, Obremskey WT, et al: Predicting blood loss in isolated pelvic and acetabular high-energy trauma J Orthop Trauma 21:603–607, 2007 54 Tile M: Pelvic fractures: operative versus nonoperative treatment Orthop Clin North Am 11:423–464, 1980 55 Marsh JL, Slongo TF, Agel J, et al: Fracture and dislocation classification compendium–2007: Orthopedic Trauma Association classification, database and outcomes committee J Orthop Trauma 21:S1–S133, 2007 56 Hak DJ, Smith WR, Suzuki T: Management of hemorrhage in lifethreatening pelvic fracture J Am Acad Orthop Surg 17:447–457, 2009 57 Kregor PJ, Routt MLC Jr: Unstable pelvic ring disruptions in unstable patients Injury 30:SB19–SB28, 1999 58 Sathy AK, Starr AJ, Smith WR, et al: The effect of pelvic fracture on mortality after trauma: an analysis of 63,000 trauma patients J Bone Joint Surg [Am] 91:2803–2810, 2009 59 Routt ML Jr, Falicov A, Woodhouse E, et al: Circumferential pelvic antishock sheeting: a temporary resuscitation aid J Orthop Trauma 16:45–48, 2002 60 Schaller TM, Sims S, Maxian T: Skin breakdown following circumferential pelvic antishock sheeting: a case report J Orthop Trauma 19:661–665, 2005 61 Krieg JC, Mohr M, Ellis TJ, et al: Emergent stabilization of pelvic ring injuries by controlled circumferential compression: a clinical trial J Trauma 59:659–664, 2005 62 Ghaemmaghami V, Sperry J, Gunst M, et al: Effects of early use of external pelvic compression on transfusion requirements and mortality in pelvic fractures Am J Surg 194:720–723, 2007 63 Smith W, Williams A, Agudelo J, et al: Early predictors of mortality in hemodynamically unstable pelvis fractures J Orthop Trauma 21:31– 37, 2007 64 Eastridge BJ, Starr A, Minei JP, et al: The importance of fracture pattern in guiding therapeutic decision-making in patients with hemorrhagic shock and pelvic ring disruptions J Trauma 53:446–450, 2002 65 Burgess AR, Eastridge BJ, Young JW, et al: Pelvic ring disruptions: effective classification system and treatment protocols J Trauma 30:848–856, 1990 66 Sarin EL, Moore JB, Moore EE, et al: Pelvic fracture pattern does not always predict the need for urgent embolization J Trauma 58:973– 977, 2005 67 Elzik ME, Dirschl DR, Dahners LE: Hemorrhage in pelvic fractures does not correlate with fracture length J Trauma 65:436–441, 2008 68 Starr AJ, Griffin DR, Reinert CM, et al: Pelvic ring disruptions: prediction of associated injuries, transfusion requirement, pelvic arteriography, complications, and mortality J Orthop Trauma 16:553– 561, 2002 69 Miller PR, Moore PS, Mansell E, et al: External fixation or arteriogram in bleeding pelvic fracture: initial therapy guided by markers of arterial hemorrhage J Trauma 54:437–443, 2003 70 Stein DM, O’Toole RV, Scalea TM: Multidisciplinary approach for patients with pelvic fractures and hemodynamic instability Scand J Surg 96:272–280, 2007 71 Stephen DJ, Kreder HJ, Day AC, et al: Early detection of arterial bleeding in acute pelvic trauma J Trauma 47:638–642, 1999 p 416 p 417 72 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 40:54–60, 2009 73 Gansslen A, Giannoudis P, Pape HC: Hemorrhage in pelvic fracture: who needs angiography? Curr Opin Crit Care 9:515–523, 2003 74 Totterman A, Madsen JE, Skaga NO, et al: Extraperitoneal pelvic packing: a salvage procedure to control massive traumatic pelvic hemorrhage J Trauma 62:843–852, 2007 75 Bjurlin MA, Fantus RJ, Mellett MM, et al: Genitourinary injuries in pelvic fracture morbidity and mortality using the National Trauma Data Bank J Trauma 67:1033–1039, 2009 76 Ziran BH, Chamberlin E, Shuler FH, et al: Delays and difficulties in the diagnosis of lower urologic injuries in the context of pelvic fractures J Trauma 58:533–537, 2005 77 Porter SE, Schroeder AC, Dzugan SS, et al: Acetabular fracture patterns and their associated injuries J Orthop Trauma 22:165–170, 2008 78 Carroll PR, McAninch JW: Major bladder trauma: the accuracy of cystography J Urol 130:887–888, 1983 79 Mouraviev BV, Santucci RA: Cadaveric anatomy of pelvic fracture urethral distraction injury: most injuries are distal to the external urinary sphincter J Urol 173:869–872, 2005 80 Londergan TA, Gundersen LH, van Every MJ: Early fluoroscopic realignment for traumatic urethral injuries Urology 49:101–103, 1997 81 Routt ML, Simonian PT, Defalco AJ, et al: Internal fixation in pelvic fractures and primary repairs of associated genitourinary disruptions: a team approach J Trauma 40:784–790, 1996 82 Brandes S, Borrelli J Jr: Pelvic fracture and associated urologic injuries World J Surg 25:1578–1587, 2001 83 Kotkin L, Koch MO: Morbidity associated with nonoperative management of extraperitoneal bladder injuries J Trauma 38:895– 898, 1995 84 Grotz MR, Allami MK, Harwood P, et al: Open pelvic fractures: epidemiology, current concepts of management and outcome Injury 36:1–13, 2005 85 Woods RK, O’Keefe G, Rhee P, et al: Open pelvic fracture and fecal diversion Arch Surg 133:281–286, 1998 86 Pell M, Flynn WJ, Seibel RW: Is colostomy always necessary in the treatment of open pelvic fractures? J Trauma 45:371–373, 1998 87 Nork SE, Agel J, Russell GV, et al: Mortality after reamed intramedullary nailing of bilateral femur fractures Clin Orthop 415:272–278, 2003 88 Cannada LK, Viehe T, Cates CA, et al: A retrospective review of highenergy femoral neck-shaft fractures J Orthop Trauma 23:254–260, 2009 89 Winquist RA, Hansen SV, Clawson DK: Closed intramedullary nailing of femoral fractures: a report of 520 cases J Bone Joint Surg [Am] 66:529–539, 1984 90 Wolinsky PR, McCarty E, Shyr Y, et al: Reamed intramedullary nailing of the femur: 551 cases J Trauma 46:392–399, 1999 91 Brumback RJ, Uwagie-Ero S, Lakatos RP, et al: Intramedullary nailing of femoral shaft fractures Part II: fracture-healing with static interlocking fixation J Bone Joint Surg [Am] 70:1453–1462, 1988 92 Brumback RJ, Reilly JP, Poka A, et al: Intramedullary nailing of femoral shaft fractures Part I: decision-making errors with interlocking fixation J Bone Joint Surg [Am] 70:1441–1452, 1988 93 Tornetta P III, Tiburzi D: Reamed versus nonreamed anterograde femoral nailing J Orthop Trauma 14:15–19, 2000 94 Bhandari M, Guyatt GH, Tong D, et al: Reamed versus nonreamed intramedullary nailing of lower extremity long bone fractures: a systematic overview and meta-analysis J Orthop Trauma 14:2–9, 2000 95 Pape HC, Regel G, Dwenger A, et al: Influences of different methods of intramedullary femoral nailing on lung function in patients with multiple trauma J Trauma 35:709–716, 1983 96 Bosse MJ, MacKenzie EJ, Riemer BL, et al: Adult respiratory distress syndrome, pneumonia, and mortality following thoracic injury and a femoral fracture treated either with intramedullary nailing with reaming or with a plate: a comparative study J Bone Joint Surg [Am] 79:799–809, 1997 97 Bone LB, Johnson KD, Weigelt J, et al: Early versus delayed stabilization of femoral fractures: a prospective randomized study J Bone Joint Surg [Am] 71:336–340, 1989 98 Pape HC, Hildebrand F, Pertschy S, et al: Changes in the management of femoral shaft fractures in polytrauma patients: from early total care to damage control orthopedic surgery J Trauma 53:452–461, 2002 99 Harwood PJ, Giannoudis PV, van Griensven M, et al: Alterations in the systemic inflammatory response after early total care and damage control procedures for femoral shaft fracture in severely injured patients J Trauma 58:446–452, 2005 100 Pape HC, Rixen D, Morley J, et al: Impact of the method of initial stabilization for femoral shaft fractures in patients with multiple injuries at risk for complications (borderline patients) Ann Surg 246:491–499, 2007 101 Anwar IA, Battistella FD, Neiman R, et al: Femur fractures and lung complications: a prospective randomized study of reaming Clin Orthop 422:71–76, 2004 102 Canadian Orthopaedic Trauma Society: Reamed versus unreamed intramedullary nailing of the femur: comparison of the rate of ARDS in multiple injured patients J Orthop Trauma 20:384–387, 2006 103 O’Toole RV, O’Brien M, Scalea TM, et al: Resuscitation before stabilization of femoral fractures limits acute respiratory distress syndrome in patients with multiple traumatic injuries despite low use of damage control orthopedics J Trauma 67:1013–1021, 2009 104 Howard M, Court-Brown CM: Epidemiology and management of open fractures of the lower limb Br J Hosp Med 57:582–587, 1997 105 Khatod M, Botte MJ, Hoyt DB, et al: Outcomes in open tibia fractures: relationship between delay in treatment and infection J Trauma 55:949–954, 2003 106 Patzakis MJ, Zalavras CG: Chronic posttraumatic osteomyelitis and infected nonunion of the tibia: current management concepts J Am Acad Orthop Surg 13:417–427, 2005 107 Finkemeier CG, Schmidt AH, Kyle RF, et al: A prospective, randomized study of intramedullary nails inserted with and without reaming for the treatment of open and closed fractures of the tibial shaft J Orthop Trauma 14:187–193, 2000 108 Sarmiento A, Zagorski JB, Zych GA, et al: Functional bracing for the treatment of fractures of the humeral diaphysis J Bone Joint Surg [Am] 82:478–486, 2000 109 Koch PP, Gross DF, Gerber C: The results of functional (Sarmiento) bracing of humeral shaft fractures J Shoulder Elbow Surg 11:143–150, 2002 110 Ekholm R, Tidermark J, Tornkvist H, et al: Outcome after closed functional treatment of humeral shaft fractures J Orthop Trauma 20:591–596, 2006 111 Tingstad EM, Wolinsky PR, Shyr Y, et al: Effect of immediate weightbearing on plated fractures of the humeral shaft J Trauma 49:278–280, 2000 112 Rommens PM, Kuechle R, Bord T, et al: Humeral nailing revisited Injury 39:1319–1328, 2008 113 McCormack RG, Brien D, Buckley RE, et al: Fixation of fractures of the shaft of the humerus by dynamic compression plate or intramedullary nail J Bone Joint Surg [Br] 82:336–339, 2000 114 Chapman JR, Henley MB, Agel J, et al: Randomized prospective study of humeral shaft fracture fixation: intramedullary nails versus plates J Orthop Trauma 14:162–166, 2000 115 Bhandari M, Devereaux PJ, McKee MD, et al: Compression plating versus intramedullary nailing of humeral shaft fractures–a metaanalysis Acta Orthop 77:279–284, 2006 116 Ekholm R, Adami J, Tidermark J, et al: Fractures of the shaft of the humerus: an epidemiological study of 401 fractures J Bone Joint Surg [Br] 88:1469–1473, 2006 117 Shao YC, Harwood P, Grotz MR, et al: Radial nerve palsy associated with fractures of the shaft of the humerus: a systematic review J Bone Joint Surg [Br] 87:1647–1652, 2005 118 Hak DJ: Radial nerve palsy associated with humeral shaft fractures Orthopedics 32:111, 2009 119 Schemitsch EH, Richards RR: The effect of malunion on functional outcome after plate fixation of fractures of both bones of the forearm in adults J Bone Joint Surg [Am] 74:1068–1078, 1992 120 McQueen MM, Gaston P, Court-Brown CM: Acute compartment syndrome: who is at risk? J Bone Joint Surg [Br] 82:200–203, 2000 121 Park S, Ahn J, Gee AO, et al: Compartment syndrome in tibial fractures J Orthop Trauma 23:514–518, 2009 122 Blick SS, Brumback RJ, Poka A, et al: Compartment syndrome in open tibial fractures J Bone Joint Surg [Am] 68:1348–1353, 1986 123 Matsen FA III, Clawson DK: The deep posterior compartmental syndrome of the leg J Bone Joint Surg [Am] 57:34–39, 1975 124 Egol KA, Bazzi J, McLaurin TM, et al: The effect of knee-spanning external fixation on compartment pressures in the leg J Orthop Trauma 22:680–685, 2008 125 Velmahos GC, Toutouzas KG: Vascular trauma and compartment syndromes Surg Clin North Am 82:125–141, 2002 126 Olson SA, Glasgow RR: Acute compartment syndrome in lower extremity musculoskeletal trauma J Am Acad Orthop Surg 13:436– 444, 2005 127 Sheridan GW, Matsen FA III: Fasciotomy in the treatment of the acute compartment syndrome J Bone Joint Surg [Am] 58:112–115, 1976 128 Williams AB, Luchette FA, Papaconstantinou HT, et al: The effect of early versus late fasciotomy in the management of extremity trauma Surgery 122:861–866, 1997 129 Ritenour AE, Dorlac WC, Fang R, et al: Complications after fasciotomy revision and delayed compartment release in combat patients J Trauma 64[Suppl 2]:S153–S162, 2008 130 Heckman MM, Whitesides TE Jr, Grewe SR, 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 76:1285–1292, 1994 131 Kakar S, Firoozabadi R, McKean J, et al: Diastolic blood pressure in patients with tibia fractures under anaesthesia: implications for the diagnosis of compartment syndrome J Orthop Trauma 21:99–103, 2007 132 O’Toole RV, Whitney A, Merchant N, et al: Variation in diagnosis of compartment syndrome by surgeons treating tibial shaft fractures J Trauma 67:735–741, 2009 133 Asgari MM, Spinelli HM: The vessel loop shoelace technique for closure of fasciotomy wounds Ann Plast Surg 44:225–229, 2000 134 Yang CC, Chang DS, Webb LX: Vacuum-assisted closure for fasciotomy wounds following compartment syndrome of the leg J Surg Orthop Adv 15:19–23, 2006 135 White RA, Miki RA, Kazmier P, et al: Vacuum-assisted closure complicated by erosion and hemorrhage of the anterior tibial artery J Orthop Trauma 19:56–59, 2005 p 417 p 418 136 Heemskerk J, Kitslaar P: Acute compartment syndrome of the lower leg: retrospective study on prevalence, technique, and outcome of fasciotomies World J Surg 67:744–747, 2003 137 Fitzgerald AM, Gaston P, Wilson Y, et al: Long-term sequelae of fasciotomy wounds Br J Plast Surg 53:690–693, 2000 138 Bong MR, Polatsch DB, Jazrawi LM, et al: Chronic exertional compartment syndrome: diagnosis and management Bull Hosp Jt Dis 62:77–84, 2005 139 Buerger PM, Peoples JB, Lemmon GW, et al: Risk of pulmonary emboli in patients with pelvic fractures Am Surg 59:505–508, 1993 140 Slobogean GP, Lefaivre KA, Nicolaou S, et al: A systematic review of thromboprophylaxis for pelvic and acetabular fractures J Orthop Trauma 23:379–384, 2009 141 Stannard JP, Lopez-Ben RR, Volgas DA, et al: Prophylaxis against deep-vein thrombosis following trauma: a prospective, randomized comparison of mechanical and pharmacological prophylaxis J Bone Joint Surg [Am] 88:261–266, 2006 142 Fuchs S, Heyse T, Rudofsky G, et al: Continuous passive motion in the prevention of deep-vein thrombosis: a randomized comparison in trauma patients J Bone Joint Surg [Br] 87:1117–1122, 2005 143 Stannard JP, Singhania AK, Lopez-Ben RR, et al: Deep-vein thrombosis in high-energy skeletal trauma despite prophylaxis J Bone Joint Surg [Br] 87:965–968, 2005 144 Sagi HC, Ahn J, Ciesla D, et al: Venous thromboembolism prophylaxis in orthopaedic trauma patients: a survey of OTA member practice patterns and OTA expert panel recommendations J Orthop Trauma 29(10):e355–e362, 2015 145 Patil S, Gandhi J, Curzon I, et al: Incidence of deep-vein thrombosis in patients with fractures of the ankle treated in a plaster cast J Bone Joint Surg [Br] 89:1340–1343, 2007 146 Bodner G, Buchberger W, Schocke M, et al: Radial nerve palsy associated with humeral shaft fracture: evaluation with US–initial experience Radiology 219:811–816, 2001 147 Lowe JB III, Sen SK, MacKinnon SE: Current approach to radial nerve paralysis Plast Reconstr Surg 110:1099–1113, 2002 148 Seddon HG: Nerve grafting J Bone Joint Surg [Br] 45:447–461, 1963 149 Cornwall R, Radomisli TE: Nerve injury in traumatic dislocation of the hip Clin Orthop 377:84–91, 2000 150 Helfet DL, Koval KJ, Hissa EA, et al: Intraoperative somatosensory evoked potential monitoring during acute pelvic fracture surgery J Orthop Trauma 9:28–34, 1995 151 Huittinen VM, Slatis P: Nerve injury in double vertical pelvic fractures Acta Chir Scand 138:571–575, 1971 152 Harris WR, Rathbun JB, Wortzman G, et al: Avulsion of lumbar roots complicating fracture of the pelvis J Bone Joint Surg [Am] 55:1436– 1442, 1973 153 Denis F, Davis S, Comfort T: Sacral fractures: an important problem Clin Orthop 227:67–81, 1988 154 Schmeling GJ, Perlewitz TJ, Helfet DL: Chapter 39: Early complications of acetabular fractures, in Tile M, Helfet DL, Kellam JF (eds): Fractures of the Pelvis and Acetabulum 3rd ed Philadelphia, PA, Lippincott Williams & Wilkins, 2003, p 734 155 Fassler PR, Swiontkowski MF, Kilroy AW, et al: Injury of the sciatic nerve associated with acetabular fracture J Bone Joint Surg [Am] 75:1157–1166, 1993 156 Brucker PU, Gruen GS, Kaufmann RA: Scapulothoracic dissociation: evaluation and management Injury 36:1147–1155, 2005 157 Ebraheim NA, An HS, Jackson WT, et al: Scapulothoracic dissociation J Bone Joint Surg [Am] 70:428–432, 1988 158 Althausen PL, Lee MA, Finkemeier CG: Scapulothoracic dissociation: diagnosis and treatment Clin Orthop 416:237–244, 2003 159 Sen RK, Prasad G, Aggarwal S: Scapulothoracic dissociation: level of vascular insult, an indirect prognostic indicator for the final outcome? Acta Orthop Belg 75:14–18, 2009 160 Oreck SL, Burgess A, Levine AM: Traumatic lateral displacement of the scapula: a radiographic sign of neurovascular disruption J Bone Joint Surg [Am] 66:758–763, 1984 161 Zelle BA, Pape HC, Gerich TG, et al: Functional outcome following scapulothoracic dissociation J Bone Joint Surg [Am] 86:2–8, 2004 162 Mauser N, Gissel H, Henderson C, et al: Acute lower-leg compartment syndrome Orthopedics 36(8):619–624, 2013 SUGGESTED READINGS Anglen JO: Comparison of soap and antibiotic solutions for irrigation of lower-limb open fracture wounds: a prospective, randomized study J Bone Joint Surg [Am] 87:1415–1422, 2005 Borer DS, Starr AJ, Reinert CM, et al: The effect of screening for deep vein thrombosis on the prevalence of pulmonary embolism in patients with fractures of the pelvis and acetabulum: a review of 973 patients J Orthop Trauma 19:92–95, 2005 Bosse MJ, MacKenzie EJ, Kellam JF, et al: An analysis of outcomes of reconstruction or amputation after leg-threatening injuries N Engl J Med 347:1927–1931, 2002 Cothren CC, Smith WR, Moore EE, et al: Utility of once-daily dose of lowmolecular-weight heparin to prevent venous thromboembolism in multisystem trauma patients World J Surg 31:98–104, 2007 Draeger RW, Dirschl DR, Dahners LE: Debridement of cancellous bone: a comparison of irrigation methods J Orthop Trauma 20:692–698, 2006 Ekholm R, Ponzer S, Tornkvist H, et al: Primary radial nerve palsy in patients with acute humeral shaft fractures J Orthop Trauma 22:408– 414, 2008 Goel DP, Buckley R, de Vries G, et al: Prophylaxis of deep-vein thrombosis in fractures below the knee: a prospective randomized controlled trial J Bone Joint Surg [Br] 91:388–394, 2009 Heini PF, Witt J, Ganz R: The pelvic C-clamp for the emergency treatment of unstable pelvic ring injuries: a report on clinical experience of 30 cases Injury 27:SA38–SA45, 1996 Henson JT, Roberts CS, Giannoudis PV: Gluteal compartment syndrome Acta Orthop Belg 75:147–152, 2009 Holstein A, Lewis GB: Fractures of the humerus with radial-nerve paralysis J Bone Joint Surg [Am] 45:1382–1388, 1963 Hope MJ, McQueen MM: Acute compartment syndrome in the absence of fracture J Orthop Trauma 18:220–224, 2004 Kenny C: Compartment pressures, limb length changes and the ideal spherical shape: a case report and in vitro study J Trauma 61:909– 912, 2006 Kutty S, Laing AJ, Prasad CV, et al: The effect of traction on compartment pressures during intramedullary nailing of tibial-shaft fractures A prospective randomised trial Int Orthop 29:186–190, 2005 Lindahl J, Hirvensalo E, Bostman O, et al: Failure of reduction with an external fixator in the management of injuries of the pelvic ring: longterm evaluation of 110 patients J Bone Joint Surg [Br] 81:955–962, 1999 MacKenzie EJ, Bosse MJ, Pollak AN, et al: Long-term persistence of disability following severe lower-limb trauma: results of a seven-year follow-up J Bone Joint Surg [Am] 87:1801–1809, 2005 McQueen MM, Court-Brown CM: Compartment monitoring in tibial fractures: the pressure threshold for decompression J Bone Joint Surg [Br] 78:99–104, 1996 Palmer S, Fairbank AC, Bircher M: Surgical complications and implications of external fixation of pelvic fractures Injury 28:649– 653, 1997 Petrisor B, Jeray K, Schemitsch E, et al: Fluid lavage in patients with open fracture wounds (FLOW): an international survey of 984 surgeons BMC Musculoskelet Disord 9:7, 2008 Pohlemann T, Braune C, Gansslen A, et al: Pelvic emergency clamps: anatomic landmarks for a safe primary application J Orthop Trauma 18:102–105, 2004 Ricci WM, Schwappach J, Tucker M, et al: Trochanteric versus piriformis entry portal for the treatment of femoral shaft fractures J Orthop Trauma 20:663–667, 2006 Richard MJ, Tornetta P III: Emergent management of APC-2 pelvic ring injuries with an anteriorly placed C-clamp J Orthop Trauma 23:322– 326, 2009 Rogers FB, Cipolle MD, Velmahos G, et al: Practice management guidelines for the prevention of venous thromboembolism in trauma patients: the EAST practice management guidelines work group J Trauma 53:142–164, 2002 Stover MD, Morgan SJ, Bosse MJ, et al: Prospective comparison of contrast-enhanced computed tomography versus magnetic resonance imaging veno-graphy in the detection of occult deep pelvic vein thrombosis in patients with pelvic and acetabular fractures J Orthop Trauma 16:613–621, 2002 White TO, Howell GE, Will EM, et al: Elevated intramuscular compartment pressures do not influence outcome after tibial fracture J Trauma 55:1133–1138, 2003 Zannis J, Angobaldo J, Marks M, et al: Comparison of fasciotomy wound closures using traditional dressing changes and the vacuum-assisted closure device Ann Plast Surg 62:407–409, 2009 Chapter 46 Burn Management SEAN FIGY • JOYCE K MCINTYRE DEFINITION AND GENERAL CONSIDERATIONS Patients with inappropriate or excessive exposure to thermal, chemical, electrical, or radioactive agents are burned The degree of injury and depth of burn are proportional to the amount of energy delivered to the tissue and duration of exposure to the offending agent In 2015, approximately 450,000 burn-related injuries were reported in the United States, necessitating approximately 40,000 hospitalizations The 2013 National Burn Repository Report from the American Burn Association found 3.3% of burn-related injuries were greater than 40% total body surface area (TBSA) [1] All human tissue is susceptible to burn injury, although skin and aerodigestive tissues are commonly involved The embryologically distinct epidermal and dermal layers of skin behave differently when burned Ectodermally derived epidermis is vital for fluid management, pigmentation, and protective immunologic functions, but the epidermis has little structural integrity at seven cells thick What the epidermis lacks in thickness it makes up for with its regenerative properties; the layer’s abundant stem cells heal isolated injury of this layer without scar The dermis, in contrast, is derived from mesenchymal cells and forms abundant scar while healing The dermis gives skin its strong mechanical integrity and as such is the focus of much of acute burn care [2] Burn thickness may range from superficial epidermal involvement to char of the deepest bone Accurate burn depth assessment is critical in the patient’s clinical management but remains a qualitative appraisal Significant “bench to bedside” work has been performed using both laser Doppler and hyperspectral imaging to quantify tissue injury; however, clinical judgment remains the gold standard [3] Burn depth occurs on a spectrum: superficial burns involve the thin epidermis only; partial-thickness or second-degree burns disrupt the epidermis’ basement membrane and encroach into the dermis, resulting in blisters; the dermis is burned in full-thickness or third-degree burns, which often look pale, ashen, and leathery Fourth-degree burns involve the underlying fat, fascia, or bone Third- and fourth-degree burns typically outstrip the body’s regenerative capacity and require operative excision of damaged tissues and restoration of skin integrity Because of the body’s inflammatory response to the initial traumatic insult, burn depth may change over time, colloquially described as “deepening.” Pink burned tissue with wheepy blisters on the day of presentation may progress to appear white and dry—a full-thickness injury—and much of acute burn care is directed toward preventing this conversion A burned patient is a trauma patient and should initially be evaluated in accordance with the systematic techniques of Advanced Trauma Life Support (ATLS) principles Airway should be evaluated and secured when appropriate to facilitate breathing and ongoing oxygenation, followed by an evaluation of the patient’s circulation Primary traumatic survey should encompass evidence of head injury, long bone trauma, and acute hemorrhage Evaluation of the burned tissue is part of a prompt secondary survey Accurate information around the mechanism of burn and location (closed or open space) inform the clinician’s suspicion about concomitant injuries such as inhalational injury, deep muscle injury from electrocution or fractures from a high fall, and the like The initial depth of the burn and TBSA affected should be documented in the medical record Please see the section Inhalational Injury for further management of the burned airway TBSA can be calculated with the “rule of nines” and the Lund–Browder scales (useful for contiguous injury), whereas the palmar surface of the patient’s hand, representing 1% TBSA, is used as a guide in noncontiguous injuries [4] TBSA should include only partial and fullthickness burns; superficial burns confined to the epidermis are not included in this calculation [5] Overall morbidity and mortality are influenced by TBSA, patient’s age, medical comorbidities, and presence of inhalational injury Burn patients with greater than 20% TBSA and those with inhalational injury are at risk for development of burn shock (see Burn Shock section) Age of the burned patient is of vital importance when predicting a patient’s mortality; with increasing age, risk of death is greater with lower total body burn surface area The Baux Score is a combination of TBSA and age and is predictive of burn mortality for burns greater than 15% [6] The patient’s predicted mortality rate rises to over 90% when the patient is older than 60 years, TBSA burned is more than 40%, and the patient has an inhalational injury; when two factors are present, calculated mortality is roughly 33% Death is usually caused in such cases by multisystem organ failure as a result of sepsis Burn care before the 1980s focused on topical antibiotics and delayed excision and grafting The clinical paradigm has shifted in the past 35 years to early surgery (within 5 days), and survival rates of major burns—in conjunction with advances in critical care—have dramatically improved [7] Because of the interdisciplinary care required to take care of the burned patient, prompt transfer to certified burn centers in accordance with American Burn Association guidelines has been shown to have the best outcomes, especially in cases of inhalational burns [8] BURN SHOCK Burn shock is a form of vasodilatory shock, akin to the general term “systemic inflammatory response,” and creates a significant initial fluid volume resuscitation requirement for the burned patient Large volume repletion is usually necessary only for patients with burns exceeding 20% TBSA and is essentially universal in larger surface area burns [9] This fluid need comes from the body’s systemic response to burned tissue Kinins, serotonin, histamine, prostaglandins, and oxygen radicals are the vasoactive mediators released in response to the burn injury and stimulate systemic vascular permeability These mediators increases vascular permeability, with resultant decreased capillary oncotic pressure and subsequent severe total body edema, even in nonburned tissues Albumin is functionally lost into the interstitium, thereby increasing extravascular oncotic pressure, compounding the edema [10] The burned patient’s fluid “requirement” should be thought of as that volume needed to optimize organ function and tissue perfusion Classically, this has been calculated with the Parkland formula using the patient’s TBSA burn and weight, times the coefficient of 4, with half the isotonic fluid given in the first 8 hours from injury and the second half given in the subsequent 16 hours However, goal-directed therapy is the gold standard of care, aiming for a urine output of 0.5 to 1 mL/kg/h, and the calculated fluid requirements should serve only as a general guide for meeting this goal If the patient’s urine output is greater than 1 mL/kg/h, the infusion rate should be decreased and titrated appropriately If urine output remains high, urine electrolytes and glucose should be evaluated with specific attention to glycosuria secondary to the burn hypermetabolism p 419 p 420 Albumin is an increasingly popular component of the resuscitation of a burned elderly patient or in those whose fluid requirements in practice are significantly higher than their calculated needs [11] Central venous access may be necessary to deliver the appropriate resuscitation in a timely manner and is ideally, but not essentially, placed through nonburned tissue [12] The use of pressors requires clinical judgment and should be employed only in settings of persistent hypotension despite adequate fluid resuscitation with both crystalloid and colloid rescue therapy For patients with persistent oliguria, preexisting renal failure, or congestive heart failure, a pulmonary artery catheter or the equivalent measuring tool to quantify hemodynamics is advised [13] Adrenal insufficiency should be suspected when hypotension persists despite solid volume repletion and adequate vasopressor therapy and is further suggested by concurrent hyponatremia and hyperkalemia Although somewhat unusual, a high mortality exists when disturbances of the hypothalamic–pituitary–adrenal axis are found early in a patient’s burn shock course A single blood cortisol of less than 15 µg per dL in a stressed patient is suggestive of adrenal insufficiency, although results of a corticotrophin stimulation test should not delay implementation of glucocorticoid replacement therapy in the face of circulatory collapse In questionable cases, a corticotrophin stimulation test is confirmatory and not skewed by dexamethasone, which enhances vascular tone but does not have the mineral corticoid activity seen with hydrocortisone administration [14] Glucocorticoids are known to unfavorably affect skin engraftment, although vitamin A supplementation seems to limit the wound-healing delay [15] The pathophysiologic similarities between septic shock, systemic inflammatory response, and burn shock may have a common pathway that could be interrupted to improve outcomes β-blockade, antihistamines, FFP, generous narcosis, nonsteroidal anti-inflammatory agents, and glucocorticosteroids are among the many approaches investigated to mitigate this cellular “hysteria.” None of these approaches have proven superiority in multicenter prospective trials to date [16] In the acutely burned patient, central shunting of blood compensates for anhydremia, yet deprives peripherally injured tissue of vital perfusion This low blood flow to skin keeps essential nutrients and gas exchange from partly burned tissue, resulting in conversion of partialthickness injury to full-thickness tissue loss Excessive fluid resuscitation, however, has the same result by compounding extravascular tissue edema [10] The biologic basis of burn wound conversion, also called secondary burn progression, has not been fully elucidated Direct cellular damage, inflammation, and ischemia are significant contributing factors Investigations into erythropoietin derivatives and resolvins have shown preservation of microvascular network in animal models This may allow prevention of secondary burn progression [17] The gastrointestinal tract is an underutilized resuscitative venue Enteral nutrition and resuscitation may begin on the day of injury with the caveat that patients in shock or requiring vasopressors can develop bowel ischemia and enteral feeds may increase the metabolic needs of the gut, contributing to bowel ischemia and necrosis This risk can be minimized by initiating enteral rehydration and nutrition within 24 hours of the initial burn [18] Patient’s not tolerating enteral feeds or those with abdominal hypertension (see Chapter 52) should be given total parenteral nutrition Typically, by the third postburn day, the patient’s systemic inflammatory response has dampened and vascular integrity is returning, with decreased fluid requirements After this point, it is reasonable to limit fluid replacement to maintenance levels and allow the patient to autodiurese or judiciously use diuretics in the elderly or cardiaccompromised patient [9] CARDIOVASCULAR RESPONSE Unresuscitated burn victims die of hypovolemic shock An untreated victim would show progressively decreasing preload and cardiac output Unfortunately, during the initial 4-to-24-hour postinjury period, even “adequate” volume repletion will not maintain baseline cardiac output, and decreased cardiac contractility and diastolic dysfunction prevail This decrease in contractility is more pronounced among those with an inhalational injury and is related to both increased pulmonary vascular resistance and increased systemic nitric oxide production This temporary and seemingly maladaptive cardiac dysfunction improves as time elapses from the initial injury and is followed by tachycardia, which is often maintained for weeks after burn [19,20] Given this hyperdynamic response, the elderly and patients with preinjury cardiac compromise are more susceptible to heart failure in this period Laboratory workup may reveal elevations in cardiac enzymes, including both creatine phosphokinase (CPK) and troponin-I, and although myocardium may be at risk, the evaluation of elevated cardiac labs in burn shock patients goes beyond a single lab value Elevated troponins should not be used as an indication for emergent cardiac catheterization without other signs or symptoms of acute cardiac ischemia, such as electrocardiogram changes [19] INHALATIONAL INJURY An inhalational injury occurs when toxic combustants have been inhaled, causing a systemic inflammatory response and local injury in the bronchial pulmonary tree History of fire or explosion in a closed space and findings of singed facial structures, carbonaceous sputum, and respiratory distress often corroborate the diagnosis Approximately 3.5% of adult burn admissions have inhalational injury, which increases mortality rate for like burn size; however, larger burns have an incidence of inhalational injury closer to 15% [1] Concurrent inhalational injury intensifies burn shock and may require up to 50% more fluid for adequate resuscitation This component of the inhalational injury cascade appears to be driven by the sensory neuronal pathway, because the response can be truncated by sympathetic blockade in experimental animal models [21] Clinically, in the acutely burned patient with an inhalational injury, airway management is paramount The clinician should look for signs of upper airway obstruction secondary to edema, which often develops hours after initial injury Stridorous patients should be intubated urgently; preferably with an 8-Fr endotracheal tube to allow for bronchoscopy and removal of respiratory tract secretions Currently, no scale of severity for inhalational injury is used clinically Bronchoscopy is most useful to characterize the presence or absence of tracheobronchial inflammation and provide therapeutic pulmonary lavage [22] Immediate threats include carbon monoxide (CO) poisoning and cyanide (CN−) toxicity Generally, the lethal level is >60% COHgb Breathing 100% oxygen by mask or endotracheal tubes should bring the half-life of COHgb to about 60 minutes [23] CN− poisoning causes cytochrome oxidase inhibition and loss of hypoxic pulmonary vasoconstriction, increasing lung dead space CN− is lethal in levels over 1 µg per mL, while 0.02 µg per mL occurs in healthy nonsmokers For practical purposes, a normal COHgb rules out CN− toxicity [23] p 420 p 421 Inhalational injury has multiple sequelae, including endobronchial and interstitial edema, alveolar damage, mucociliary dysfunction, endobronchial slough with cast formation, functional pulmonary shunting, and decreased lung compliance Increased bronchial blood flow causes increased interstitial edema Bronchial epithelium sloughs and combines with exudates and fibrin to form “plugs” that nurture bacterial growth and create mechanical airway obstructions Aerosolized heparin in conjunction with N-acetyl-cysteine may prevent cast formation and has been shown to decrease lung injury scores and ventilator days and has been especially helpful for pediatric patients where narrow airways easily obstruct [24,25] Although burn patients are at increased risk for pneumonia because of their immunocompromised state, immobility, and inability to clear secretions, prophylactic antibiotics are not recommended Pneumonia and tracheobronchitis should be treated by culture-directed therapy, using Gram stain, culture of sputum, or bronchoscopy specimens and incorporate a hospital’s known bacterial sensitivities [26] Aspiration risks should be minimized, and lung protective ventilator settings should be used Patients’ overall condition and pulmonary performance by way of usual weaning parameters dictate extubation time [27] The risk of upper airway obstruction before extubation should be assessed by deflating the balloon and audible appreciation of air leak If no air leak is present, extubation should not be performed METABOLIC AND NUTRITIONAL CONSIDERATIONS The insensible fluid and protein losses from burn wounds are extraordinary Protein catabolism, compounded by losses through the wound bed and the interstitium, results in severe hypoproteinemia, and the hypermetabolic response that occurs after a thermal injury is more than that observed after most other forms of trauma or sepsis The loss of regulated vasomotor tone, possibly in an effort to provide maximal nutrient delivery and gas exchange to the wounded tissues, results in significant evaporative heat loss Hypothermia from weeping wounds and dwindling energy supplies from the catabolic, muscle-wasting condition of burn shock is easily avoided with external warming The ambient temperature in the patient’s room should be kept warm, 90°F to 100°F, in an effort to shunt calories away from being used in thermostasis Muscle wasting, a difficult complication of the hypermetabolism associated with burn wounds, can be ameliorated through anabolic enhancement The two most common approaches are recombinant human growth hormone (HGH) and oxandrolone HGH is associated with hyperglycemia requiring insulin support and has largely been supplanted by oxandrolone, which must be given enterally at 0.2 mg/kg/d (max dose 20 mg) divided twice daily, thereby limiting its use in patients with ileus [28,29] The patient with a major thermal injury has a metabolism characterized by increased muscle proteolysis, lipolysis, and gluconeogenesis Burn wounds use glucose in greatly increased quantities Hyperglycemia is common with burn catabolism, may exacerbate muscle wasting, and should be tightly controlled with insulin Nitrogen loss should also be supplemented to combat muscle wasting and to enhance the immune system [30] Burn patients need two to three times their basal energy expenditure in calories [30] Significant burn injuries require 2 g per kg protein, glucose should contribute 50% to 60% of the calories, and the calorie-to-nitrogen ratio should approach 150:1 All attempts should be made to feed the patient enterally, and, ideally, enteral nutrition should be initiated within 24 hours of admission Prompt enteral feeding has been shown to decrease patient’s length of hospital stay as well as burn wound infection and is thought to maintain the integrity of the gastrointestinal track [14] In addition to early enteral nutrition, supplementation with trace elements such as copper, zinc, and selenium is also important for helping decrease infectious complications [31] BURN WOUND SEPSIS Burn victims develop multiple defects in their immune system both mechanical and immunologic that predispose them to an increased risk of infection Topical antimicrobials (e.g., silver sulfadiazine or mafenide acetate) in the context of good overall wound care help decrease the incidence of frank burn wound infections However, primary treatment of infected burns remains surgical excision and tissue coverage with autograph or skin substitute (see “Early Excision and Grafting”) The signs of burn wound sepsis typically present as a greenish gray discoloration of the burn, purulent fluid from the wound, and eschar separation along with cellulitis in the surrounding unburned skin If not treated at the earliest possible time, systemic sepsis will ensue Diagnosis can be confirmed by biopsy of the wound with quantitative culture but should not preclude total and urgent excision [32] Systemic antibiotics are started if florid infection is suspected and tailored or stopped once burn biopsies for quantitative bacterial counts and blood culture results are obtained The overall hypermetabolic state associated with severe burns can have significant effects on the pharmacokinetics and pharmacodynamics of many medications including anti-infectives As one example, Mafenide acetate penetrates eschar and is most effective against Gram-negative organisms; however, Mafenide acetate is known to cause metabolic acidosis as a carbonic anhydrase inhibitor and may select for fungal overgrowth [26] Immunity and Infection Significant burn injury that induces a systemic inflammatory response may also induce a compensatory anti-inflammatory response syndrome This combination can lead to persistent inflammationimmunosuppression catabolism syndrome As such, large surface area burn patients are at high risk for infection, which is often the precipitating cause of late deaths [33] The pulmonary tree and the burn wound beds themselves are the most common sites and foci for fatal infection Early wound infections, within 10 days of injury, are typically Gram-positive organisms Later, pseudomonas is a common and potentially lethal organism, although fungal infections may occur in the subacute period and are often ominous Central lines and urinary catheters should also be evaluated as possible infectious nidi A growing and considerable body of evidence links bacterial translocation from the gut as a source of unexplained bacteremia [26] Presence of gut bacteria and endotoxin in the lymphatic system supports this theory [20] This risk may be decreased by enteral feedings and supplementation with glutamine Immunoenhancing regimens are an area of intense study [34] SURGICAL CONSIDERATIONS Early Excision and Grafting By the 1980s, the operative paradigm had shifted toward early (within 5 days) excision of full-thickness burns to limit the inflammatory forces driving “burn shock.” In the operating room, excision of full-thickness burns is performed to the level of healthy bleeding tissue Blood loss of 0.5 mL of blood per kilogram of patient weight for every percentage of TBSA excised is routine Once an area has been grafted with autologous tissue, shear forces must be minimized because the grafted skin initially lives by diffusion of nutrients from the underlying wound bed and imbibition until inosculation and neovascularization can take place The use of negative pressure wound therapy devices (NPWT) as protective dressings from graft-killing shear has become the standard of care [35] p 421 p 422 In areas of mixed partial- and full-thickness burns, excision of partialthickness burns in addition to full-thickness burns may be necessary in order to facilitate practical skin grafting Using a combination of autografts on completely excised burns and xenografts on partialthickness burns is also a means to facilitate timely healing Xenografts will function as a biologic dressing, decrease insensible fluid loss, and do not need frequent dressing changes, allowing the newly applied autografts to inosculate and neovascularize unmolested Escharotomies Burned tissue has significantly less compliance than normal unburned tissue and may acutely restrict breathing as well as blood flow to the extremities In the initial evaluation period, it is important to evaluate respiratory status as well as peripheral perfusion Poor oxygenation can be a sign of frankly restrictive respiratory physiology secondary to a burned torso, and acute limb ischemia can also develop from a badly burned limb The treatment for both of these conditions is immediate escharotomy at the affected site Torso escharatomies will improve excursion of the chest wall, and limb escharatomies alleviate the functional venous tourniquet of a significant burn, equivalent to a fasciotomy for acute compartment syndrome On the torso, escharotomy incisions are made along the anterior axillary line and connect at the level of the second rib and the xyphoid In the extremities, incisions are made along the medial and lateral aspects of the appendage In rare situations, orbital pressures can be elevated secondary to retro-orbital edema, necessitating lateral canthotomies Abdominal Compartment Syndrome The inflammatory cascade and changing oncotic pressures in a patient with an acute burn undergoing resuscitation can lead to abdominal compartment syndrome Abdominal hypertension is typically first identified by decreased urine output and restrictive airway dynamics Transurethral bladder pressures in a chemically paralyzed patient greater than 20 cm H2O are considered diagnostic for abdominal hypertension Failure to identify and treat abdominal compartment syndrome can have devastating consequences including renal and respiratory failure as well as abdominal organ ischemia secondary to abdominal vasculature compression Definitive treatment is decompressive laparotomy [36] Please see Chapter 52 for a detailed discussion of abdominal compartment syndrome SPECIFIC INJURIES Electrical Injury The magnitude of electrical injuries varies depending on the voltage of current delivered to human tissue Low-voltage (less than 1,000 V) injuries create thermal burns, injuring tissue from the outside in, whereas high voltage (greater than 1,000 V) can initially be deceiving in their devastation because a significant portion of the injury is not cutaneous but rather to the underlying muscle and bone Very high-voltage injuries will have both extensive deep tissue injury and obvious cutaneous injury [37] Immediate life-threatening conditions related to electrical injuries include cardiac dysrhythmias and spinal cord injury, either from direct injury, fall, or because of tetany resulting in spinal column fracture and cord injury Exit and entry wounds should be identified when possible, because this will help identify potentially affected tissue Compartment syndrome from myonecrosis is common, especially in the upper extremity, and patients should be monitored closely for this complication in the first 24 hours Limbs injured by electricity with resultant compartment syndrome require fasciotomies rather than simple escharotomies [38] Aggressive fluid resuscitation should be initiated quickly to limit the renal effects of myonecrosis and myoglobinuria Maintaining high urine output can help prevent kidney injury associated with myoglobin crystallization in the renal tubules Daily monitoring of CPK may be beneficial in identifying potential or ongoing muscle necrosis Persistently high levels may indicate muscle necrosis and need for surgical debridement [39] Chemical Injury Acids and alkali bases injure tissues by different mechanisms Alkali bases burn tissue by liquefactive necrosis of subcutaneous fat, thrombosing perfusing vessels Acids in turn burn by coagulation necrosis and as such are typically more superficial in their penetration of tissue [40] Hydrofluoric acid (HF) burns are unique, however, because HF is a strong calcium and magnesium chelator This can lead to devastating cardiac dysrhythmias and cardiac arrest owing to severe hypocalcemia Topical calcium gluconate slurries are a mainstay of treatment for HF burns Systemically, intravenous calcium gluconate is frequently necessary, and intra-arterial infusions have been effective for pain relief and preservation of tissue in extremity burns caused by HF [41] PSYCHIATRIC AND ANALGESIC CONSIDERATIONS Beyond the physiologic stress induced by burns, the burned patient undergoes significant psychological stress Posttraumatic stress disorder (PTSD) has been reported in up to 45% of burn patients [42], and previous psychiatric history has been shown to be a risk factor for PTSD in the broadly studied burn population Self-immolation accounts for only 4% of burn admission; however, these patients present complex patient care problems, because there is typically significant psychopathology that may hinder recovery [43] Adequate pain control during their hospitalizations and during dressing changes has been shown to limit the long-term psychiatric effects of burn trauma [44] Opiates, benzodiazepines, and the full range of dissociative medications are indicated Unlike other critically ill patients, “sedation holidays” are not commonly used because these breaks in regular analgesia can create undue physiologic and psychological stress for the patient, increase catabolism, cardiovascular stress, and risk for development of PTSD [45] Once the burn has been treated, wounds closed, and shock resolved, tapering of sedatives and narcotics can be initiated such that the patient may be weaned from the ventilator and avoid withdrawal symptoms Among patients with extremity burns, long-acting regional anesthetics may be beneficial for pain control and permit better burn care and therapy REFERENCES American Burn Association: 2015 National Burn Repository, 2015 Hussain SH, Limthongkul B, Humphreys TR: The biomechanical properties of the skin Dermatol Surg 39(2):193–203, 2013 p 422 p 423 Khatib M, Jabir S, Fitzgerald O’Connor E, et al: A systematic review of the evolution of laser Doppler techniques in burn depth assessment Plast Surg Int 2014:621792, 2014 doi:10.1155/2014/621792 Lund C, Browder N: The estimation of areas of burns Surg Gynecol Obstet 79:352–358, 1944 Veeravagu A, Yoon BC, Jiang B, et al: National trends in burn and inhalation injury in burn patients: results of analysis of the nationwide inpatient sample database J Burn Care Res 36(2):258–265, 2015 Heng JS, Clancy O, Atkins J, et al: Revised baux score and updated Charlson comorbidity index are independently associated with mortality in burns intensive care patients Burns 41(7):1420–1427, 2015 Jackson PC, Hardwicke J, Bamford A, et al: Revised estimates of mortality from the Birmingham Burn Center, 2001-2010: a continuing analysis over 65 years Ann Surg 259(5):979–984, 2014 Cassidy TJ, Edgar DW, Phillips M, et al: Transfer time to a specialist burn service and influence on burn mortality in Australia and New Zealand: A multi-center, hospital based retrospective cohort study Burns 41(4):735–741, 2015 Peeters Y, Vandervelden S, Wise R, et al: An overview on fluid resuscitation and resuscitations endpoints in burns: past, present and future Part 1-Historical background, resuscitation fluid and adjunctive treatment Anaesthesiol Intensive Ther 47(5):s6–14, 2015 doi:10.5603/AIT.a2015.0063 10 Edgar DW, Fish JS, Gomez M, et al: Local and systemic treatments for acute edema after burn injury: a systematic review of the literature J Burn Care Res 32(2):334–347, 2011 11 Lawrence A, Faraklas I, Watkins H, et al: Colloid administration normalizes resuscitation ratio and ameliorates “fluid creep.” J Burn Care Res 31(1):40–47, 2010 12 Tao L, Zhou J, Gong Y, et al: Risk factors for central line-associated bloodstream infection in patients with major burns and efficacy of the topical application of mupirocin at the Central Venous Catheter Exit Site Burns 31(8):1831–1838, 2015 13 Peeters Y, Lebeer M, Wise R, et al: An overview on fluid resuscitation and resuscitation endpoints in burns; past, present and future Part 2avoiding complications by using the right endpoints with a new personalized protocolized approach Anaesthesiol Intensive Ther 47(5):s15–26, 2015 doi:10.5603/AIT.a2015.0064 14 Mosier MJ, Lasinski AM, Gamelli RL: Suspected adrenal insufficiency in critically ill burned patients: etomidate-induced or critical illnessrelated corticosteroid insufficiency? A review of the literature J Burn Care Res 36(2):272–278, 2015 15 Wicke C, Halliday B, Allen D: Effects of steroids and retinoids on wound healing Arch Surg 135(11):1265–1270, 2000 16 Jeschke MG: Postburn hypermetabolism: past, present, and future J Burn Care Res 37(2):86–96, 2015 doi:10.1097/BCR.0000000000000265 17 Schmauss D, Rezaeian F, Finck T, et al: Treatment of secondary burn wound progression in contact burns-a systematic review of experimental approaches J Burn Care Res 36(3):e176–e189, 2015 18 Hu S, Liu W-W, Zhao Y, et al: Pyruvate-enriched oral rehydration solution improved intestinal absorption of water and sodium during enteral resuscitation in burns Burns 40(4):693–701, 2014 19 Abu-Sittah GS, Sarhane KA, Dibo SA, et al: Cardiovascular dysfunction in burns: review of the literature Ann Burns Fire Disasters 25(1):26– 32, 2012 20 Sambol J, Deitch EA, Takimoto K, et al: Cellular basis of burn-induced cardiac dysfunction and prevention by mesenteric lymph duct ligation J Surg Res 183(2):678–685, 2013 21 Nunez-Villaveiran T, Sanchez M, Millan P, et al: Systematic review of the effect of propanolol on hypermetabolism in burn injuries Med Intensiva 39(2):101–113, 2015 22 You K, Yang HT, Kym D, et al: Inhalation injury in burn patients: establishing the link between diagnosis and prognosis Burns 40(8):1470–1475, 2014 23 Huzar TF, George T, Cross JM: Carbon monoxide and cyanide toxicity: etiology, pathophysiology and treatment in inhalation injury Expert Rev Respir Med 7(2):159–170, 2013 24 Desai MH, Mlcak RP, Richardson J, et al: Reduction in mortality in pediatric patients with inhalational injury with aerosolized heparin/acetylcystine therapy J Burn Care Rehabil 19(3):210–212, 1998 25 Elsharnouby NM, Eid HE, Abou Elezz NF, et al: Heparin/Nacetylcysteine: an adjuvant in the management of burn inhalation injury: a study of different doses J Crit Care 29(1):182.e181–182.e 184, 2014 26 Ravat F, Le-Floch R, Vinsonneau C, et al: Antibiotics and the burn patient Burns 37(1):16–26, 2011 27 Smailes ST, McVicar AJ, Martin R: Cough strength, secretions and extubation outcome in burn patients who have passed a spontaneous breathing trial Burns 39(2):236–242, 2013 28 Breederveld R, Tuinebreijer W: Recombinant human growth hormone for treating burns and donor sites (Review) Cochrane Database Syst Rev (9):CD008990, 2014 doi:10.1002/14651858.CD008990.pub3 29 Li H, Guo Y, Yang Z, et al: The efficacy and safety of oxandrolone treatment for patients with severe burns: a systematic review and meta-analysis Burns 42(4):717–727, 2015 doi:10.1016/j.burns.2015.08.023 30 Rousseau AF, Losser MR, Ichai C, et al: ESPEN endorsed recommendations: nutritional therapy in major burns Clin Nutr 32(4):497–502, 2013 31 Kurmis R, Greenwood J, Aromataris E: Trace element supplementation following severe burn injury: a systematic review and meta-analysis J Burn Care Res 37(3):143–159, 2016 doi:10.1097/BCR.0000000000000259 32 Rafla K, Tredget EE: Infection control in the burn unit Burns 37(1), 5– 15, 2011 33 Linden K, Scaravilli V, Kreyer SF, et al: Evaluation of the cytosorb hemoadsorptive column in a PIG model of severe smoke and burn injury Shock 44(5):487–495, 2015 34 Williams FN, Branski LK, Jeschke MG, et al: What, how, and how much should patients with burns be fed? Surg Clin North Am 91(3):609–629, 2011 35 Kamolz LP, Lumenta DB, Parvizi D, et al: Skin graft fixation in severe burns: use of topical negative pressure Ann Burns Fire Disasters 27(3):141–145, 2014 36 Wise R, Jacobs J, Pilate S, et al: Incidence and prognosis of intraabdominal hypertension and abdominal compartment syndrome in severely burned patients: pilot study and review of the literature Anaesthesiol Intensive Ther 48(2):95–109, 2014 37 Salehi SH, Fatemi MJ, Asadi K, et al: Electrical injury in construction workers: a special focus on injury with electrical power Burns 40(2):300–304, 2014 38 Aghakhani K, Heidari M, Tabatabaee SM, et al: Effect of current pathway on mortality and morbidity in electrical burn patients Burns 41(1):172–176, 2015 39 Saracoglu A, Kuzucuoglu T, Yakupoglu S, et al: Prognostic factors in electrical burns: a review of 101 patients Burns 40(4):702–707, 2014 40 Tan T, Wong DS: Chemical burns revisited: what is the most appropriate method of decontamination? Burns 41(4):761–763, 2015 41 Wang X, Zhang Y, Ni L, et al: A review of treatment strategies for hydrofluoric acid burns: current status and future prospects Burns 40(8):1447–1457, 2014 42 Sveen J, Ekselius L, Gerdin B, et al: A prospective longitudinal study of posttraumatic stress disorder symptom trajectories after burn injury J Trauma 71(6):1808–1815, 2011 43 Caine PL, Tan A, Barnes D, et al: Self-inflicted burns: 10 year review and comparison to national guidelines Burns 42(1):215–221, 2016 44 Sheridan RL, Stoddard FJ, Kazis LE, et al: Long-term posttraumatic stress symptoms vary inversely with early opiate dosing in children recovering from serious burns: effects durable at 4 years J Trauma Acute Care Surg 76(3):828–832, 2014 45 Giannoni-Pastor A, Eiroa-Orosa FJ, Fidel Kinori SG, et al: Prevalence and predictors of posttraumatic stress symptomatology among burn survivors: a systematic review and meta-analysis J Burn Care Res 37(1):e79–e89, 2016 Section 5 SURGICAL PROBLEMS IN THE INTENSIVE CARE UNIT MITCHELL CAHAN Chapter 47 Surgeon and Intensivist Collaboration in the Care of the ICU Patient GUSTAVO GUILLERMO ANGARAMO • CRAIG M LILLY The modern intensive care unit (ICU) is teeming with technology; however, it is probably the most stressful place in the hospital [1] Advanced technology has brought sophisticated instrumentation and databases to the bedside [2] Entirely new therapies are possible for grave diseases, such as low tidal volume strategies for acute lung injury or early antimicrobial therapy for sepsis [3–5] Increasing sophistication of care leads invariably to increased complexity This complexity poses opportunities and potential hazards [2] Patient turnover is rapid and survival rates continue to improve Many caregivers are involved, and all of them expect some input into the process of care Meanwhile, a designated credentialed provider always must be responsible for the overall care plan and occasionally adjudicate differences of opinion regarding difficult decisions, or reconcile conflicting recommendations from key team members The conflicts arise not only from uncertainties about outcomes but also about what is understood as success In the clinical world, success is defined as survival to leave the ICU; however, in the moral world of families and friends, success often means a patient returning to an independent life with resumption of normal activities Effective care of patients requires that all parties involved understand each other’s point of view DEFINITION OF ICU MODELS AND LEVELS OF CARE The open ICU model is an ICU in which patients are admitted under the care of an internist, family physician, surgeon, or other primary attending of record, with intensivists often available providing expertise via elective consultation [6] Intensivist co-management is an open ICU model in which all patients receive mandatory consultation from an intensivist The internist, family physician, or surgeon is the co-attending of record with intensivists collaborating in the management of all ICU patients In a closed ICU model, patients admitted to the unit are transferred to the care of an intensivist assigned to the ICU on a full-time basis Patients are accepted to the ICU only after approval by the intensivist For periods ranging from 1 week to 1 month at a time, the intensivist’s clinical duties consist of caring for patients in the ICU, with no other clinical responsibilities A mixed ICU model may consist of directorship and daily ICU rounds by the intensivist (closed unit and/or co-management), or simply the presence of a full-time intensivist in the ICU (including examples of all three models) The American College of Critical Care Medicine has described three levels of hospital-based critical care centers to optimally match services and personnel with community needs [7]: Level I critical care centers have ICUs that provide comprehensive care for a wide range of disorders requiring intensive care They require the continuous availability of sophisticated equipment, specialized nurses, and physicians with critical care training Level II critical care centers have the capability to provide comprehensive critical care, but may not have resources to care for specific populations (e.g., cardiothoracic surgery, neurosurgery, trauma) Level III critical care centers may provide initial stabilization of critically ill patients but are limited in their ability to provide comprehensive critical care COMMUNICATION AMONG ICU TEAM MEMBERS Interprofessional tensions can threaten the delivery of quality health care in the hospital setting Such tensions have been documented at several clinical locations including the ICU [8] The ICU in particular is a nexus for interspeciality tensions because of its unique role in the care of the hospital’s most critically ill patients and associated management of critical care resources [9] Conflict in the ICU is frequent; more than 70% of ICU clinicians report experiencing conflict weekly [10,11] The combination of caring for acutely ill patients, end-of-life decisionmaking, and coordination of large interprofessional teams can lead to frustration, communication breakdown, and discord among members of the health care team The epidemiology of this conflict has been very well described in the Conflicus study [10] Conflict has been associated with lower quality patient care [12,13], higher rates of serious medical errors [14], staff burn out [15,16], and greater direct and indirect costs of care [17] ICU conflict can occur between the health care team and patients’ families, among members of the ICU team, and among different groups of clinicians caring for the same patient, most notably between surgeons and intensivists Lingard et al [9] studied the forces governing the interactions among professions (nurses and physicians) and specialties (ICU team and consultants) This group found out that the level of collaboration or conflict within the ICU team and between ICU and other specialties fluctuated on the basis of six important catalysts: authority, education, patient needs, knowledge, resources, and time Two dominant mechanisms were also described and categorized in their analysis as “the perception of ownership” and the “process of trade.” Ownership was perceived as both collective (ICU team) and individual [9] It promoted collaboration between members of the ICU team and was often established by contrast with those outside of the core team such as surgeons, internists, or nurses from the wards Individual ownership is also a dominant issue and includes instances where members recognized their own or other’s skill; this recognition is part of the smooth collaborative functioning of the team p 424 p 425 Within the process of trade, team members traded valued commodities including equipment, resources, respect, goodwill, and knowledge as they negotiated their collaborative work [9] The forces of ownership and trade have a central role in the daily negotiations that constitute teamwork in the ICU setting When ownership is not attended to, or one commodity is not offered in trade for another, tensions accumulate and collaboration is compromised [9] The Surgeon’s Perspective The qualities that define a surgical personality have been described by anthropologist Joan Cassell [18] as decisiveness, control, confidence, and certitude The surgeon often views his or her relationship with the patient as a covenant to cure Actions that threaten this covenant as relinquishing responsibility for the care of a patient to another practitioner, losing control over key decisions, and proposals toward comfort with the expectation of death can be strongly rejected by the admitting surgeon [44] This ownership searching for an ideal outcome is valuable in that the patient has a strong advocate to facilitate recovery; however, surgical obstinacy with respect to sharing responsibility for care and resulting reluctance to direct efforts toward comfort can deny the dying patient both dignity and control [19] Surgeons are affected by the increasing demands of clinical practice, spending more time in the office and in the operating room, at the cost of less available time to see and manage patients in the ICU Olson et al reported in a study on conflict of postoperative goals of care that 40% of surgeons who routinely perform high-risk operations reported conflict with critical care physicians and nurses regarding the goals of care for their patients with poor postoperative outcomes [20] Surgeons who reported higher rates of conflict had fewer years in practice and worked in an academic setting Surgeons with more experience may be more accepting and may have developed coping strategies for unwanted outcomes Additionally, surgeons who practice in a closed ICU reported higher rates of conflict about goals of care The Intensivist’s Perspective In contrast to the surgeon’s perspective, the intensivist’s point of view is often more focused on symptom relief and comfort This different perspective does not mean that intensivists are any less goal oriented than surgeons; intensivists actually embrace goal-directed care [19] From the surgeon’s perspective, persistence in the face of overwhelming odds is seen as a noble obligation From the intensivist’s perspective, persistence in the face of overwhelming odds can be costly, painful, and disrespectful if the patient has expressed any wish to avoid heroic measures The effectiveness of a dedicated intensivist caring for ICU patients has been shown in multiple reviews [21] The presence and participation of an intensivist-directed team can identify and treat problems before catastrophic complications occur Understanding of sepsis, mechanical ventilatory support for acute respiratory distress syndrome (ARDS), and description and treatment of endocrine dysfunction among the critically ill have led to protocol-driven care and improved survival [22,23] Young and Birkmeyer [24] have provided estimates of the relative reduction of annual ICU mortality resulting from conversion of all urban ICUs to an intensivist model of management Assuming an ICU mortality of 12% and estimating that 85% of urban ICUs are not currently intensivist managed, they calculated that there are approximately 360,000 preventable deaths annually in U.S urban ICUs that lack intensivists A conservative projection of a 15% relative reduction in mortality resulting from intensivist-managed ICUs yields a predicted annual saving of nearly 54,000 lives The ICU Nurse’s Perspective The ICU nurse has a fundamental role for supporting and comforting ICU patients and their families Nurses spend the most time with ICU patients and family members and thus are a valuable resource for identifying the patient and family understanding and evaluating the effectiveness of communication Moreover, nurses act as the medical intermediary for families, as well as the link between health care providers, particularly when surgeons and ICU physicians disagree [18,25,26] METHODS FOR ACHIEVING AND MAINTAINING ICU TEAM CONSENSUS Consensus is a process-based concept that is a core element of highperforming teams It allows essential communication that enables teams to effectively perform high-fidelity tasks Consensus is founded on assent of the team members and sometimes requires vetting, discussion, and even negotiation Establishing a process by which consensus is consistently achieved is an important skill for ICU team leaders Consensus is a state of acquiescence to team-based decisions that does not require that all team members are in full agreement with all of the details of a decision, rather that all key members assent to the critical concepts of the decision [27] In the context of patient care, it is better to maintain a state of consensus than to attempt to build it after disagreement has festered [28] A summary of helpful communication strategies is presented in Table 47.1 TABLE 47.1 Strategies for Achieving and Maintaining Team Consensus Include the surgeon in all decision-making sessions with the patient and family Include the surgeon on interprofessional rounds Before all decision-making sessions: Value the surgical opinion and identify points of agreement Before all decision-making sessions: Leverage consultants and diagnostic studies to resolve differences of opinion with regard to the medical facts Have the patient or his or her medical decision maker participate in interprofessional rounds Share medical images with the patient or medical decision maker in the presence of the surgeon When the surgeon believes that continued aggressive care will lead to healing, agree on a time-limited trial of continued aggressive care Discuss the functional outcome in the context of the patient’s goals and values Discuss whether continued aggressive care or a comfort- oriented plan is more consistent with the patient’s values Carefully assess how much unfavorable information the patient and the surgeon are ready to accept Allow adequate time for processing difficult information p 425 p 426 One effective approach to build and maintain consensus is including key team members in an interprofessional rounding process [29] In this context, “including” means listening and valuing input from all stakeholders and on occasion soliciting the opinions of those who may not be in consensus with the plan of care Including key personnel like the surgeon [30] on interdisciplinary rounds is one of the best methods for managing the consensus-building process [31,32] An increasing number of ICU teams have found that including the patient and family members on bedside rounds [33–35] is helpful for preventing and resolving differences of opinion regarding the patient’s goals for minimal functional outcomes [36,37] This approach has the advantage of removing the nurse or intensivist from the messenger role and allowing a more balanced discussion of the merits of alternative goals for the care plan Establishing clear patient-centered goals is often helpful for achieving consensus on specific care plan elements and increasing the comfort of reluctant team members to assent to a comfort-oriented care plan [38] The process of avoiding confrontational and emotion-laden open or hidden disagreements involves active listening skills and the thoughtful inclusion of consultants, review of medical advanced testing and imaging, and inclusion of the patient or their medical decision maker in team discussions The most important consensus-building skill for an ICU team leader is to value the dissenting opinions of team members, particularly those of the operating surgeon and nursing staff Adaptation of the patient-focused V.A.L.U.E system that was developed at the University of Washington for difficult communication can also be helpful in the context of team communication [39] In this context, “V” is for valuing comments made by dissenting team members, “A” is for acknowledging the emotions associated with their point of view, “L” is for actively listening, “U” is for understanding the dissenters as individuals, and “E” is for eliciting their comments by creating safe space for their expression This approach can be highly effective when routinely employed, and team members learn to present their opinions efficiently One key concept is a proactive ICU team approach that prepares for managing potential compromised critical care functional outcomes before they have occurred Proactive management starts by identifying gaps between the patient or surgeon’s goals for functional outcomes and those that are likely to be achieved The identification of the gap in expectations can be managed in several ways and all start with achieving agreement on the medical facts [38,39] When the medical facts are not clear, consultants, pathologic evaluation of tissue specimens, advanced laboratory studies, and radiologic testing can be helpful for achieving consensus regarding the diagnosis and for defining practically achievable alternative therapeutic approaches Establishing the medical facts and options allows the team to discuss alternative care plans and the metrics by which their success or failure can be judged Team consensus, including that of the operating surgeon, on a specific approach allows implementation of a time-limited plan of aggressive care Including “clinical milestones” or objective metrics by which the success or failure of the plan will be judged allows presentation of the plan to the patient and medical decision-makers with a date for a “difficult discussion” should the care plan not achieve the clinical milestones [38] This approach has been shown to improve outcomes and support patient-defined values because it encourages team members that favor a comfort-only approach to contribute fully to an aggressive care trial and those who favor aggressive care to transition to a comfortoriented approach [40] Time-limited trials of aggressive care that use clinical milestones that medical decision-makers can easily identify have the advantage that ICU team members spend less time explaining unpleasant information and are better able to advocate for comfort and dignity at the end of life This approach also supports physiologically improving patients because prescheduled communication events can be used to discuss preparation for the process of physical and emotional rehabilitation after severe critical illness when continued aggressive care leads to improvement The adoption of collaborative interprofessional teams that are led by critical care professionals who adopt a proactive approach that is supported by V.A.L.U.E.-based communication will only rarely require the services of an ethics consultant [41] or a palliative care specialist [42] to heal broken-down communication or to work on resolving refractory value-based differences among interprofessional team members or between the ICU team and the patient or medical decision maker SUMMARY The structure of the ICU can pose a barrier to the continuity of the surgeon–patient relationship and contributes to conflict when the surgeon is replaced as the primary decision maker for his or her patients by an intensivist [12,19,20,43] Clearly, some of the ICU models described earlier can promote conflict with juxtaposition of clinicians with unmanaged competing interests This is where valuing the input of the surgeon can have the greatest impact by ensuring that his or her patients receive an adequate trial of aggressive care The surgeon who communicates his or her wishes and participates in patient-focused discussions of alternative approaches is a valued ICU team member and patient advocate [19] Conflict is a significant public health problem that diminishes quality of care for critically ill patients Consequences of conflict underscores the importance of surgeon–patient preoperative discussion of goals and values to guide postoperative decisions in the event of an undesired outcome [20,44–46] In the absence of cooperation, conflict can affect patients and families, leading to decreased satisfaction with care and increased stress [10,13,47] It is time to move from the rhetoric of team collaboration, toward a more clear understanding of the skills required to function in the competitive setting of the interprofessional health care team These findings have educational implications for both trainees and practicing intensivists As a result, medical schools have adapted by requiring competence in domains such as communication and collaboration within the medical team [48] Communication is the most important factor for the intensivist who ensures that adverse events are reported in a timely fashion, that important decisions are discussed, and that the surgeon is included in the process The surgeon should be willing to discuss rather than dictate and consider different approaches [19] Clinicians from all backgrounds should focus on streamlining communication to allow energies to be spent more productively on better care for our critically ill postoperative patients [20] Further research, particularly into ideal communication among surgeons, intensivists, and ICU nurses, is needed REFERENCES Barie PS: Advances in critical care monitoring Arch Surg 132:734–739, 1997 Barie PS, Bacchetta MD, Eachempati SR: The contemporary surgical intensive care unit Surg Clin North Am 80(3):791–804, 2000 Fanelli V, Vlachou A, Ghannadian S, et al: Acute respiratory distress syndrome: new definition, current and future therapeutic options J Thorac Dis 5(3):326–334, 2013 Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock N Engl J Med 345(19):1368–1377, 2001 Monnet X, Teboul JL: Assessment of volume responsiveness during mechanical ventilation: recent advances Crit Care 17(2):217, 2013 Rothschild JM: “Closed” intensive care units and other models of care for critically ill patients A critical analysis of patient safety practices Agency for Healthcare Research and Quality Chapter 36: 413–414, Available at: http://archive.ahrq.gov/clinic/ptsafety/ Accessed January 31, 2017 Haupt MT, Bekes CE, Carl LC, et al: Guidelines on critical care services and personnel: recommendations based on a system of categorization of three levels of care Crit Care Med 31(11):2677–2683, 2003 Hawryluck LA, Espin S, Lingard L: Pulling together and pushing apart: tides of tension in the ICU team Acad Med 77:S73–S76, 2002 Lingard L, Espin S, Evans C, et al: The rules of the game: interprofessional collaboration on the intensive care unit team Crit Care 8:R403–R408, 2004 10 Azoulay E, Timsit JF, Sprung CL, et al: Prevalence and factors of intensive care unit conflicts: the Conflicus study Am J Respir Crit Care Med 180(9):853–860, 2009 p 426 p 427 11 Fassier T, Azoulay E: Conflicts and communication gaps in the intensive care unit Curr Opin Crit Care 16(6):654–665, 2010 12 Danjoux Meth N, Lawless B, Hawryluck L: Conflicts in the ICU: perspectives of administrators and clinicians Intensive Care Med 35(12):2068–2077, 2009 13 Studdert DM, Mello MM, Burns JP, et al: Conflict in the care of patients with prolonged stay in the ICU: types, sources, and predictors Intensive Care Med 29(9):1489–1497, 2003 14 Baldwin DC Jr, Daugherty SR: Interprofessional conflict and medical errors: results of a national multi-specialty survey of hospital residents in the US J Interprof Care 22(6):573–586, 2008 15 Embriaco N, Azoulay E, Barrau K, et al: High level of burnout in intensivists: prevalence and associated factors Am J Respir Crit Care Med 175(7):686–692, 2007 16 Poncet MC, Toullic P, Papazian L, et al: Burnout syndrome in critical care nursing staff Am J Respir Crit Care Med 175(7):698–704, 2007 17 Brinkert R: A literature review of conflict communication causes, costs, benefits and interventions in nursing J Nurs Manag 18(2):145–156, 2010 18 Cassell J: Life and Death in the Intensive Care Unit Philadelphia: Temple University Press, 2005 19 Penkoske P, Buchman T: The relationship between the surgeon and the intensivist in the surgical intensive care unit Surg Clin North Am 86:1351–1357, 2006 20 Olson TJ, Brasel KJ, Redmann AJ, et al: Surgeon reported conflict with intensivists about postoperative goals of care JAMA Surg 148(1): 29–35, 2013 21 Gasperino J: The Leapfrog initiative for intensive care unit physician staffing and its impact on intensive care unit performance: a narrative review Health Policy 102:223–228, 2011 22 Van Den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in critically ill patients N Engl J Med 345(19):1359–1367, 2001 23 The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome N Engl J Med 342:1301–1308, 2000 24 Young MP, Birkmeyer JD: Potential reduction in mortality rates using an intensivist model to manage intensive care units Eff Clin Pract 3:284–289, 2000 25 Aslakson RA, Wyskiel R, Shaeffer D, et al: Surgical intensive care unit clinician estimates of the adequacy of communication regarding patient prognosis Crit Care 14:R218, 2010 26 Asch DA, Shea JA, Jedrziewski MK, et al: The limits of suffering: critical care nurses’ views of hospital care at the end of life Soc Sci Med 45:1661–1668, 1997 27 Collins SA, Bakken S, Vawdrey DK, et al: Agreement between common goals discussed and documented in the ICU J Am Med Inform Assoc 18(1):45–50, 2011 28 Davidson JE, Powers K, Hedayat KM, et al: Clinical practice guidelines for support of the family in the patient-centered intensive care unit: American College of Critical Care Medicine Task Force 2004-2005 Crit Care Med 35(2):605–622, 2007 29 Mosenthal AC, Murphy PA, Barker LK, et al: Changing the culture around end-of-life care in the trauma intensive care unit J Trauma 64(6):1587–1593, 2008 30 Pronovost PJ, Jenckes MW, Dorman T, et al: Organizational characteristics of intensive care units related to outcomes of abdominal aortic surgery JAMA 281(14):1310–1317, 1999 31 Puntillo KA, McAdam JL: Communication between physicians and nurses as a target for improving end-of-life care in the intensive care unit: challenges and opportunities for moving forward Crit Care Med 34[11, Suppl]:S332–S340, 2006 32 DeKeyser Ganz F, Engelberg R, Torres N, et al: Development of a model of interprofessional shared clinical decision making in the ICU: a mixed-methods study Crit Care Med 44(4):680–689, 2016 33 Cypress BS: Family presence on rounds: a systematic review of literature Dimens Crit Care Nurs 31(1):53–64, 2012 34 McPherson G, Jefferson R, Kissoon N, et al: Toward the inclusion of parents on pediatric critical care unit rounds Pediatr Crit Care Med 12(6):e255–e261, 2011 35 Mangram AJ, McCauley T, Villarreal D, et al: Families’ perception of the value of timed daily “family rounds” in a trauma ICU Am Surg 71(10):886–891, 2005 36 Harris GM: Family-centered rounds in the neonatal intensive care unit Nurs Women’s Health 18(1):18–27, 2014 37 Stickney CA, Ziniel SI, Brett MS, et al: Family participation during intensive care unit rounds: goals and expectations of parents and health care providers in a tertiary pediatric intensive care unit J Pediatr 165(6):1245–1251 e1, 2014 38 Lilly CM, De Meo DL, Sonna LA, et al: An intensive communication intervention for the critically ill Am J Med 109(6):469–475, 2000 39 Lautrette A, Darmon M, Megarbane B, et al: A communication strategy and brochure for relatives of patients dying in the ICU N Engl J Med 356(5):469–478, 2007 40 Lilly CM, Sonna LA, Haley KJ, et al: Intensive communication: fouryear follow-up from a clinical practice study Crit Care Med 31[5, Suppl]:S394–S399, 2003 41 Luce JM: A history of resolving conflicts over end-of-life care in intensive care units in the United States Crit Care Med 38(8):1623– 1629, 2010 42 Villarreal D, Restrepo MI, Healy J, et al: A model for increasing palliative care in the intensive care unit: enhancing interprofessional consultation rates and communication J Pain Symptom Manage 42(5):676–679, 2011 43 Buchman TG, Cassell J, Ray SE, et al: Who should manage the dying patient?: Rescue, shame, and the surgical ICU dilemma J Am Coll Surg 194(5):665–673, 2002 44 Schwarze ML, Bradley CT, Brasel KJ: Surgical “buy-in”: the contractual relationship between surgeons and patients that influences decisions regarding life-supporting therapy Crit Care Med 38(3):843– 848, 2010 45 Redmann AJ, Brasel KJ, Alexander GC, et al: Use of advance directives for high-risk operations: a national survey of surgeons Ann Surg 255(3):418–423, 2012 46 Sudore RL, Fried TR: Redefining the “planning” in advance care planning: preparing for end-of-life decision making Ann Intern Med 153(4):256–261, 2010 47 Breen CM, Abernathy AP, Abbott KH, et al: Conflict associated with decisions to limit life sustaining treatment in intensive care units J Gen Intern Med 16(5):283–289, 2001 48 CanMEDS Roles (Canadian Medical Education Directions for Specialists), Royal College of Physicians and Surgeons of Canada: Accreditation and postgraduate training guidelines Available at: http:/ /www.royalcollege.ca/rcsite/canmeds-e Chapter 48 Surgical Infections in the Intensive Care Unit ANN-KRISTIN U FRIEDRICH • MITCHELL CAHAN INTRODUCTION Surgical infections present challenges of diagnosis and management in the intensive care setting Manifestations may vary from simple superficial surgical site infection to complex generalized infections of the abdominal cavity Abdominal infections are the third most common cause of sepsis in the intensive care unit (ICU) [1] and have been associated with high morbidity and mortality rates [2] Rarely do surgical infections present as the sole reason for admission to ICUs Patients who develop surgical site infections may have multiple comorbidities, be hemodynamically unstable, or even septic with concurrent failure of one or more organ systems, and are at high risk of treatment failure [3] Early recognition and appropriate treatment is crucial in order to mitigate and control a potentially lethal infection PATHOGENESIS Etiology of Surgical Infections Surgical infections in the ICU population represent a complex clinical entity with a number of etiologic and contributory factors This can be seen as a result of an inability of the host to adequately respond to a high number of pathogens of varying virulence Patient-associated factors therefore play a significant role, including: malnutrition, as manifested by a low serum albumin concentration; older age; obesity; smoking; diabetes mellitus; localized malperfusion caused by vascular disease or a history of radiation to the site; and generalized malperfusion caused by peri- or intraoperative shock [4,5] In addition, inadequate surgical technique, prolonged procedure time, or breaks in sterile technique may cause or contribute to the development of a surgical infection Foreign body presence in the surgical field may help organisms to fester, as the number of bacteria required to cause a clinically significant infection may be lower in the presence of such a nidus [4] In addition to skin flora as the source of causative organisms, surgical infections can be caused by spillage of enteric content or anastomotic leaks Blunt abdominal trauma can also lead to perforation of the intestine or simple translocation of bacteria into the peritoneal cavity in the setting of intestinal wall hematoma or ischemia [6] In an immunocompromised patient, this abdominal seeding may lead to peritonitis and infection, similar to a deep-organ space surgical site infection p 427 p 428 Abscess Formation Abscess formation may occur when the patient’s immune systems attempts to locally control a certain disease process, such as free entry of pathogenic organisms into the abdominal cavity via perforation, surgical intervention, or trauma Intraabdominal abscesses are confined to a part of the abdomen without free access to the peritoneal cavity Especially in sizable abscesses, free diffusion of antibiotics and host immune cells into its center is usually not possible This makes it almost impossible to control a sizable lesion with antiinfective therapy alone Drainage via either the radiologic or open surgical technique is usually required to prevent hematogenous spreading of pathogens or rupture of the abscess into the peritoneal cavity Abscess formation may occur at any location of the body, including sites of venipunctures, chronic wounds or ulcers, and around indwelling catheters, and is a frequently observed intraabdominal process in postoperative critical care patients Peritonitis Peritonitis is a generalized inflammatory reaction that may involve the partial or entire peritoneal cavity It can be classified as primary, secondary, or tertiary peritonitis The extent of peritoneal reaction may be dependent on the exact intestinal origin of the causative organism [7] Primary Peritonitis Infection of the peritoneum without obvious source or localized infection within the abdominal cavity is classified as primary peritonitis [8] Obvious disruption of the gastrointestinal (GI) tract’s anatomic barrier is absent Primary peritonitis tends to be a community-acquired disease of patients with previously existing ascites due to cirrhotic liver disease A single causative organism can usually be isolated GI flora such as enterococci and gram-negative bacilli tend to be responsible [9] Other causes of primary peritonitis include infection of an indwelling peritoneal dialysis catheter, as well as rare cases of primary peritonitis in otherwise healthy patients, primarily caused by group A streptococcus [10,11] The latter presentation can be associated with toxic shock syndrome [12] In postoperative patients in an intensive care setting, primary peritonitis is a very rare occurrence Secondary Peritonitis Peritonitis in the setting of perforation of a hollow viscus is called secondary peritonitis Gross spillage of GI flora into the peritoneal cavity follows this disruption of the anatomic barrier Causes include inflammation, malignancy, anastomotic leak, necrosis, fistula, and blunt and/or penetrating trauma Secondary peritonitis is a frequently encountered problem in surgical intensive care patients Reported mortality rates associated with secondary peritonitis range from 15% to 23%; however, this may increase in the setting of simultaneous sepsis or shock, as well as comorbid disease processes [13–15] When isolation of microbial pathogens is successful, cultures are usually polymicrobial [16] Outcomes from secondary peritonitis are dependent on adequate and timely treatment, source control, and the patient’s immune system [17] Tertiary Peritonitis Persistent peritonitis in the setting of exhaustive medical and interventional management is conventionally referred to as tertiary peritonitis [18] The range of patients who progress from secondary to tertiary peritonitis can be as high as 20% [19] It is however important to differentiate tertiary peritonitis from ongoing secondary peritonitis in the setting of inadequate source control, in the sense of failure to drain or evacuate existing abscesses or nidi of infection Tertiary peritonitis has been associated with a high incidence of nosocomial, multidrug-resistant organisms as well as immunologic dysfunction and altered endocrine stress response [20] Different disease processes seem to be more or less prone to progress to tertiary peritonitis; for example, necrotizing pancreatitis has been associated with a high progression rate [19] Tertiary peritonitis is linked to higher mortality, longer ICU stay, and more severe stage of end-organ impairment [21,22] In a retrospective observational study with 92 cases of tertiary peritonitis, Evans et al [23] could not correlate tertiary peritonitis as a sole prognostic factor of death after adjusting for other variables Rather than being the cause of a patient’s death, tertiary peritonitis may in fact be a symptom of a highly dysfunctional host response to inflammatory stress PATHOGENS The spectrum of causative pathogens in surgical infections is broad and depends on the underlying site of the primary disease as well as the clinical course of the patient Community-acquired diseases that lead to surgical postoperative infections often start with an obstructive disease pattern and eventually become superinfected by GI flora; classic examples include acute calculous cholecystitis or appendicitis The causative pathogens vary depending on the area of perforation De Ruiter et al [7] analyzed peritoneal fluid of 221 patients with abdominal sepsis due to perforated viscus at the time of the primary operation They most commonly observed aerobic and gram-negative bacteria in appendiceal and colonic perforations; gram-positive bacteria were encountered with colorectal disease Gastroduodenal perforations were associated with Candida species, most commonly Candida albicans Nosocomial infections are different for a variety of reasons Pathogens tend to be less susceptible to antibiotic regimens and may be multiresistant [24] In addition to this, the patient’s host response may be impaired or their GI flora may have been altered in the setting of prior antibiotic treatments, including potential overpopulation of virulent, ICU-acquired organisms An increased risk of infection and subsequent multiorgan failure is observed among patients who are colonized with pathogens such as Candida species, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Enterococcus faecalis [24,25] Enterococcus is frequently isolated from patients with nonappendiceal peritonitis and is associated with the pathogenesis of many surgical abdominal infections [26,27] Its involvement has been directly correlated with the severity of disease in the setting of anastomotic leakage [28] However, antibiotic coverage of Enterococcus is not always indicated Increasingly drug-resistant strains of Enterococci have emerged over the recent past and presented an increasingly difficult challenge In particular, a growing population of vancomycin-resistant enterococci is feared, as this may lead to subsequent evolvement of vancomycin-resistant Staphylococcus aureus through genetic exchange among species p 428 p 429 Another challenge of surgical site infections is that caused by fungal pathogens Fungal organisms benefit from decreased selection pressure from bacteria, especially after multiple courses of broad-spectrum antibiotics, and have been associated with the development of tertiary peritonitis [29,30] High mortality has been associated with intraabdominal candidiasis infection, especially in an ICU setting [31] Unfortunately, even adequate treatment of Candida species has not always been associated with improved outcomes [32] It is not clear whether Candida spp isolated from abdominal sources are true causative pathogens or rather a symptom of poor host immune response and severity of underlying disease DIAGNOSIS Clinical Examination Suspicion for a surgical site infection can be raised by clinical examination Erythema, drainage, or dehiscence are the first signs of a superficial infection, and may necessitate opening the incision at least partially in order to ensure adequate drainage Gentle probing of the underlying fascia can help for assessment of the depth of infection and differentiating fascial dehiscence due to an infectious process from a possible enterocutaneous fistula Deep-organ space infections can also become clinically apparent Rebound and guarding on exam, as well as inappropriate tenderness to palpation, can be signs of peritonitis or intraabdominal abscesses It is important to realize that clinical examination findings can however be obscured by coexisting diseases, altered level of consciousness, the patient’s overall clinical deterioration, and the presence of sedating or paralyzing agents Significant infections can also cause a change in vital signs, such as repeated febrile episodes as well as tachycardia, hypotension and tachypnea, and if not recognized and treated can lead to septic shock In an ICU patient, these vital sign derangements may be the only reliable indication of an infection Laboratory Analysis Persistent or increasing leukocytosis, often associated with an increased count of segmented neutrophils, should also raise suspicion of an infection of surgical and postoperative ICU patients Other valuable parameters especially for monitoring the clinical course of the infectious disease process include acute phase proteins such as C-reactive protein and procalcitonin, a precursor of the hormone calcitonin [33] Organspecific parameters may prove helpful in potentially locating an abscess, such as altered liver function parameters in the setting of an intrahepatic abscess Cultures are an important tool for tailoring antibiotic regimens and assessing the course of disease Blood cultures should be drawn in the setting of presumed sepsis and unexplained febrile episodes Fluid draining from seromas and hematomas can be cultured, as well as aspirate from superficial and deep abscesses The use of aspiration and analysis of peritoneal fluid in the setting of peritonitis remains controversial, especially as these cultures are often sterile in the setting of persistent secondary or tertiary peritonitis [16] However, when possible, the isolation of a target organism and subsequent susceptibility testing are invaluable tools for the diagnosis and treatment of surgical infections Radiology Different imaging modalities play a vital role in the setting of a surgical site infection Radiographs can reveal free air, pneumatosis of the bowel wall, which indicates ischemia or necrosis, or gas in the soft tissue as potential signs of a localized infection Ultrasound can be a helpful mobile bedside tool for evaluating the presence of an abscess It is dependent upon the ability of the ultrasonographer and the patient’s body habitus, and can be seriously limited in deep-organ spaces, when air-filled bowel loops may obstruct the view of a potential collection Computed tomography (CT) can be a very useful tool for evaluating deep surgical site infections, especially as image quality can be optimized by the application of intravenous, oral, or rectal contrast This can be limited by the fact that many hemodynamically unstable patients may not be suitable for transport to the CT suite, and use of intravenous contrast can also contribute to impaired renal function Magnetic resonance imaging may be a helpful modality for evaluating compartments for patients whose radiation exposure should be minimized, such as pregnant or pediatric patients Its use to assess surgical infections in intensive care patients is nonetheless limited due to the relatively long duration of the examination, and due to limited image quality of the thoracic and abdominal cavity due to motion artifacts from peristalsis of the bowel wall, as well as respiration and movement of the diaphragm THERAPY Antiinfective Treatment The general principles of antibiotic therapy apply in the setting of surgical site infections as well Antibiotic treatment should commence as early as possible Initially, a broad-spectrum empiric agent should be chosen, tailored to the likely site(s) of infection, local bacterial epidemiology, and known resistance patterns Coverage is dependent on location, type, and severity of the surgical infection [34] Usually, initial coverage includes gram negatives, gram positives, and anaerobes One may also consider covering Candida in a high-risk setting As a second step, antibiotic coverage is tailored to culture and susceptibility results in order to prevent the emergence of multiresistant bacterial strains [35] Antibiotic coverage should not be prolonged unless necessary, such as in the setting of failed source control or superinfection Source Control Despite adequate antiinfectious coverage, patient’s mortality rates in the setting of surgical infection may be high without proper source control [31] Source control is defined as “all physical measures undertaken to eliminate a source of infection, control ongoing contamination, and restore premorbid anatomy and function” [36] In order to optimize outcomes, controlling the source of bacterial contamination and the removal of infectious foci should be performed in a timely fashion [37] Ideally, the patient should be medically optimized before source control measures; necessary medical treatment may include fluid resuscitation, establishment of adequate intravenous access, transfusion of blood products, and optimization of coagulation However, adequate source control should not be postponed for lengthy diagnostic or radiologic studies Depending on the underlying extent of infection, source control measures may include drainage via either the open surgical or percutaneous technique, debridement of infected and necrotic tissue, decompression, diversion, or restoration of anatomy and organ function Clinical judgment and experience of the intensivist and surgeon are warranted for timely intervention to ensure control of the ongoing cause of infection without causing further harm to the patient p 429 p 430 The ideal treatment approach to surgical infections is thus multimodal Early adequate antibiotic coverage and source control ensure optimal control over pathogens, while the patient needs to be appropriately resuscitated and nutritionally supported PROGNOSIS Prognosis of surgical infection is dependent on the extent of infection, resulting organ dysfunction, adequacy of source control and antibiotic treatment, and on basic patient factors such as age and immunologic competence Origin of surgical infection may also influence outcomes; for example, appendiceal perforation as origin of infection has been found to be associated with better outcome when compared with other perforations within the abdomen [15] Increased knowledge about appropriate resuscitation and improved antibiotic use have also contributed to improving overall mortality rates [38] Surgical infections in an intensive care setting remain a challenge, but timely diagnosis and appropriate management will minimize complications and enhance rates of survival REFERENCES Moss M: Epidemiology of sepsis: race, sex, and chronic alcohol abuse Clin Infect Dis 41[Suppl 7]:S490–S497, 2005 Dohmen PM: Influence of skin flora and preventive measures on surgical site infection during cardiac surgery Surg Infect (Larchmt) 7[Suppl 1]:13–17, 2006 Friedrich AK, Cahan M: Intraabdominal infections in the intensive care unit J Intensive Care Med 5:S247–S254, 2014 Mangram AJ, Horan TC, Pearson ML, et al: Guideline for prevention of surgical site infection, 1999 Hospital Infection Control Practice Advisory Committee Infect Control Hosp Epidemiol 20:247–278, 1999 Cheadle WG: Risk factors for surgical site infection Surg Infect (Larchmt) 7[Suppl 1]:S7–S11, 2006 Barras JP, Gilg M, Regli B, et al: Secondary peritonitis after negative computerized tomography in blunt abdominal trauma Helv Chir Acta 60(4):S513–S516, 1994 de Ruiter J, Weel J, Manusama E, et al: The epidemiology of intraabdominal flora in critically ill patients with secondary and tertiary abdominal sepsis Infection 37(6):522–527, 2009 Sheer TA, Runyon BA: Spontaneous bacterial peritonitis Dig Dis 23(1):39–46, 2005 Wiest R, Krag A, Gerbes A: Spontaneous bacterial peritonitis: recent guidelines and beyond Gut 61(2):297–310, 2012 10 Elkassem S, Dixon E, Conly J, et al: Primary peritonitis in a young healthy woman: an unusual case Can J Surg 51(2):E40–E41, 2008 11 Park JY, Moon SY, Son JS, et al: Unusual primary peritonitis due to Streptococcus pyogenes in a young healthy woman J Korean Med Sci 27(5):553–555, 2012 12 Saha P, Morewood T, Naftalin J, et al: Acute abdomen in a healthy woman: primary peritonitis due to group A streptococcus J Obstet Gynaecol 26(7):700–701, 2006 13 Hynninen M, Wennervirta J, Leppäniemi A, et al: Organ dysfunction and long term outcome in secondary peritonitis Langenbecks Arch Surg 393(1):81–86, 2008 14 Riché FC, Dray X, Laisné MJ, et al: Factors associated with septic shock and mortality in generalized peritonitis: comparison between community-acquired and postoperative peritonitis Crit Care 13(3):R99, 2009 15 Gauzit R, Péan Y, Barth X, et al: Epidemiology, management, and prognosis of secondary non-postoperative peritonitis: a French prospective observational multicenter study Surg Infect (Larchmt) 10(2):119–127, 2009 16 Berger D, Buttenschoen K: Management of abdominal sepsis Langenbecks Arch Surg 383(1):35–43, 1998 17 van Till JW, van Veen SQ, van Ruler O, et al: The innate immune response to secondary peritonitis Shock 28(5):504–517, 2007 18 Malangoni MA: Evaluation and management of tertiary peritonitis Am Surg 66(2):157–161, 2000 19 Weiss G, Meyer F, Lippert H: Infectiological diagnostic problems in tertiary peritonitis Langenbecks Arch Surg 391(5):473–482, 2006 20 Buijk SE, Bruining HA: Future directions in the management of tertiary peritonitis Intensive Care Med 28(8):1024–1029, 2002 21 Chromik AM, Meiser A, Hölling J, et al: Identification of patients at risk for development of tertiary peritonitis on a surgical intensive care unit J Gastrointest Surg 13(7):1358–1367, 2009 22 Nathens AB, Rotstein OD, Marshall JC: Tertiary peritonitis: clinical features of a complex nosocomial infection World J Surg 22(2):158– 163, 1998 23 Evans HL, Raymond DP, Pelletier SJ, et al: Tertiary peritonitis (recurrent diffuse or localized disease) is not an independent predictor of mortality in surgical patients with intraabdominal infection Surg Infect (Larchmt) 2(4):255–263; discussion 264–265, 2001 24 De Waele JJ, Hoste EA, Blot SI: Blood stream infections of abdominal origin in the intensive care unit: characteristics and determinants of death Surg Infect (Larchmt) 9(2):171–177, 2008 25 Montravers P, Gauzit R, Muller C, et al: Emergence of antibioticresistant bacteria in cases of peritonitis after intraabdominal surgery affects the efficacy of empirical antimicrobial therapy Clin Infect Dis 23(3):486–494, 1996 26 Sitges-Serra A, Lopez MJ, Girvent M, et al: Postoperative enterococcal infection after treatment of complicated intra-abdominal sepsis Br J Surg 89(3):361–367, 2002 27 Swenson BR, Metzger R, Hedrick TL, et al: Choosing antibiotics for intra-abdominal infections: what do we mean by high-risk? Surg Infect (Larchmt) 10(1):29–39, 2009 28 Kaffarnik MF, Urban M, Hopt UT, et al: Impact of enterococcus on immunocompetent and immunosuppressed patients with perforation of the small or large bowel Technol Health Care 20(1):37–48, 2012 29 Panhofer P, Izay B, Riedl M, et al: Age, microbiology and prognostic scores help to differentiate between secondary and tertiary peritonitis Langenbecks Arch Surg 394(2):265–271, 2009 30 Hughes MG, Chong TW, Smith RL, et al: Comparison of fungal and nonfungal infections in a broadbased surgical patient population Surg Infect (Larchmt) 6(1):55–64, 2005 31 Bassetti M, Right E, Ansaldi T, et al: A multicenter multinational study of abdominal candidiasis: epidemiology, outcomes and predictors of mortality Intensive Care Med 41(9):1601–1610, 2015 32 Sandven P, Qvist H, Skovlund E, et al: Significance of Candida recovered from intraoperative specimens in patients with intraabdominal perforations Crit Care Med 30(3):541–547, 2002 33 Rau BM, Frigerio I, Büchler MW, et al: Evaluation of procalcitonin for predicting septic multiorgan failure and overall prognosis in secondary peritonitis: a prospective, international multicenter study Arch Surg 142(2):134–142, 2007 34 Herzog T, Chromik AM, Uhl W: Treatment of complicated intraabdominal infections in the era of multi-drug resistant bacteria Eur J Med Res 15(12):525–532, 2010 35 Augustin P, Kermarrec N, Muller-Serieys C, et al: Risk factors for multidrug resistant bacteria and optimization of empirical antibiotic therapy in postoperative peritonitis Crit Care 14(1):R20, 2010 36 Schein M, Marshall J: Source control for surgical infections World J Surg 28(7):638–645, 2004 37 De Waele JJ: Early source control in sepsis Langenbecks Arch Surg 395(5):489–494, 2010 38 Schneider CP, Seyboth C, Vilsmaier M, et al: Prognostic factors in critically ill patients suffering from secondary peritonitis: a retrospective, observational, survival time analysis World J Surg 33(1):34–43, 2009 Chapter 49 Care of the Patient with Necrotizing Fasciitis BRANDON COLVIN • BENKOLE SAMUEL • HONGYI CUI INTRODUCTION Necrotizing fasciitis (NF) originates from the Greek word nekroun, to make dead and from the Latin word fascis meaning bundle NF is an aggressive disease commonly known as a condition involving flesh-eating bacteria NF is on the broader spectrum of necrotizing soft tissue infections (NSTI) which all share common signs, symptoms, etiologies, pathophysiology, and treatments All NSTI occur in the soft tissue compartment from the dermis down to and including the muscular layer NF specifically spreads along the fascial planes at an aggressive rate In addition, administration of antibiotics alone does not cure this disease making it a true surgical emergency Mortality increases significantly if wide surgical debridement is delayed, thereby placing high importance on accurate and rapid diagnosis of this devastating disease NF has been identified for over two millennia; the first account is ascribed to Hippocrates Hippocrates referred to a case of complicated erysipelas disease ca 500 BCE, and the specific disease manifestations he described were similar to current descriptions of NF In the 1700s, the chief surgeon at a hospital in France, Claude Colles, described a condition that he had seen that was consistent with NF It was not until the American Civil War when Joseph Jones, a confederate physician whose notes are one of the mainstays of medical documentation of this war, identified an organism, specifically a bacillus, as the cause of multiple cases of gangrene After the war, Jones published documentation of over 2,600 cases of gangrene Weaponry and physical site (e.g., farmland) of battle were thought to have contributed to numerous accounts of gas gangrene, which led to one of the largest contemporaneous retrospective studies on gas gangrene In his paper, he gave the first description of what we currently call NF, with a mortality rate nearing 50% A variant of NF is Fournier gangrene and is attributed to Jean Alfred Fournier, a French dermatologist Fournier gangrene is NF of the perianal, perineal, or genital area, which will be discussed later He documented five cases of tissue necrosis of the perineum in the 1880s NF became known as Meleney gangrene after Dr Frank L Meleney discovered an association with the disease and β-hemolytic Streptococcus in the 1920s In the 1950s, Dr Ben Wilson coined the term NF as a more appropriate term [6] Throughout history, despite our advances in medicine, mortality rates remain high in NSTI: reports range in the literature from 25% to 60% One of the contributing factors to this high mortality rate is the nonspecificity of symptoms This non-specificity can make early diagnosis difficult and delay lifesaving surgical intervention, emphasizing the importance of accurate and early diagnosis Many approaches have been developed to predict the risk of an infection truly being NF The most commonly utilized is the LRINF (Laboratory Risk Indicator for Necrotizing Fasciitis) score described by Wong [1–6] EPIDEMIOLOGY AND RISK FACTORS The number of cases of adult NSTI in the United States ranges from 500 to 1,500 annually with an incidence rate 0.04/1,000 person-years [1,7,8] Comorbidities are a major risk factor for the development of NF; one study showed that greater than 80% of patients had preexisting medical conditions The most common risk factors include diabetes mellitus, age greater than 50, obesity, malnutrition, chronic renal disease, chronic liver disease, human immunodeficiency virus, immunosuppression, hypertension, peripheral vascular disease, cancer, pulmonary disease, and intravenous drug abuse (IVDA) Some studies even suggest use of nonsteroidal antiinflammatory drugs as a risk factor [9] The literature has repeatedly demonstrated that delayed surgical intervention, generally considered greater than 24 hours after diagnosis, is the main risk factor for mortality Other significant mortality factors recognized are Clostridium spp infection, development of sepsis, chronic renal disease, cardiac or pulmonary disease, IVDA, and malignancy [1,9–11] ETIOLOGIES Most cases of NF are associated with a particular trauma or inciting event, allowing the pathogen to be inoculated through a break in the epidermal or mucosal surfaces into the subcutaneous tissue NF is most commonly reported in the lower extremities, perineum, and the genitalia but can occur anywhere on the body Documented sources of NF include skin infections (abscess), trauma, infected foot ulcers, surgical wound, perforated viscus, animal and insect bites, needle sticks (IVDA or subcutaneous insulin injection), percutaneous procedures, infected grafts, pressure ulcers (sacral decubitus ulcers), burns, or incarcerated hernias While most cases of NF are trauma related, anywhere from 15% to 52% are idiopathic [1,2,4,6,9,10,12,13] PATHOPHYSIOLOGY Layers of skin from superficial to deep are epidermis, dermis, subcutaneous layer (hypodermis or superficial fascia), and deep fascia The superficial fascial layer is termed dartos fascia in the genitalia, which is a continuance of the Colles fascia in the perineum, and the Scarpa fascia of the abdominal wall The disease course is similar regardless of the etiology or location Once the pathogen has been inoculated into the subcutaneous tissue, it begins to replicate The severity of infection is also determined by other factors including the size of the inoculum, virulence of the pathogen, blood flow to the tissue, presence of foreign bodies, as well as host response Pathogens that are more virulent, if polymicrobial, work synergistically allowing for rapid reproduction in an anaerobic environment Enzymes begin to necrose the hypodermis and cause vascular thrombosis of the nutrient vessels located in the hypodermis, leading to ischemia and edema (Fig 49.1) Ischemia of the nerves causes hypoesthesia, anesthesia, and hyperesthesia (pain out of proportion to physical examination) Crepitus on physical examination and subcutaneous air seen on imaging is caused by the gas-forming anaerobic pathogens The hypodermis is more likely to develop necrosis leading to the expected later finding of overlying epidermal and dermal changes, once the cutaneous circulation has thrombosed This leads to erythema, edema, both serous and hemorrhagic bullae, and frank necrosis [1,2,7–9] p 431 p 432 FIGURE 49.1 A: Patient with left lower extremity tissue necrosis, erythema, and edema consistent with necrotizing fasciitis B: The same patient after wide surgical debridement CLASSIFICATIONS Originally two types of NF were proposed However, due to increased research and documentation, that classification has been expanded to a third and fourth type of NF as described by Misiakos et al [8] These classifications are based on the bacteria as well as the number of bacteria causing NF These classifications are also important for directing treatment which will be discussed in a later section Type I: Polymicrobial This is by far the most common type of NF, accounting for upward of 70% of NF Type I is generally seen in the elderly population and those with multiple comorbidities Most of these infections are located in the trunk or perineum At least two pathogens are detected in the surgical specimen culture, with an average of over four species identified In historical terms, Clostridium spp played a large role in type I NF In more recent years, the incidence of Clostridium has declined significantly and is rare This is thought to be due to improved sanitation, hygiene, and sterilization techniques Clostridium is commonly found in soil in endemic areas of the United States and the world with rates around 10% For further discussion of Clostridium, please refer to our discussion below of type 3 NF [1–3,7–9,13] Fournier gangrene (Fig 49.2) is considered a subtype of type I NF because it is a polymicrobial infection Fournier was first described as a necrotizing infection of the penis and scrotum Today’s definition is a little broader, and now includes the genitalia of both male and females, perineal, and perianal areas Particular considerations with this type of NF are that Scarpa fascia is continuous with Colles fascia and dartos fascia This allows for the disease to spread easily from the groin superiorly to the anterior abdominal wall, making control of this disease more difficult [1–3,7–9,13–15] FIGURE 49.2 A: Neutrophils infiltrating the subcuatenous tissues B: Coagulation necrosis that can be seen in necrotizing fasciitis (NF) p 432 p 433 Type II: Monomicrobial Gram Positive (β-Hemolytic Streptococcus A alone or with MSSA or MRSA) Group-A β-hemolytic streptococcus (gram-positive catalase-negative cocci in pairs or chains), also referred to as GAS, is the hallmark of type II NF It can either occur by itself or in conjunction with Staphylococcus aureus (gram-positive cocci catalase-positive in clusters), and both methicillin sensitive (MSSA) and methicillin resistant (MRSA) GAS (Streptococcus pyogenes) has evolved to include several mechanisms to increase its toxicity; most importantly for the discussion of pathophysiology is the M protein The M protein allows GAS to bind and activate T-cell receptors in a much larger number than would normally be activated This causes an extremely large inflammatory response, by releasing inflammatory cytokines including interleukin-1, interleukin-6, and tumor necrosis factor-α The M protein also leads to decreased phagocytosis by neutrophils In addition, GAS has exotoxins that lead to neutrophil damage, decreased phagocytosis, and breakdown of connective tissue Panton–Valentine leukocidin gene is a virulent factor seen with some S aureus that is currently being studied and is thought to contribute to the severity of disease as well as resistance to certain antibiotic therapies [4] With Staphylococcus spp., infection can lead to toxic shock syndrome, both by tissue necrosis and leukocyte destruction This type of NF is more common in the extremities in young healthy patients and is commonly caused by trauma such as surgery and IVDA Mortality rates of types I and II are comparable [2,8,9] Type III: Monomicrobial Infection Caused by Clostridium or Gram-Negative Bacteria Overall, type III NF is comparatively rare The most common pathogen of type III is Clostridium spp (gram-positive anaerobic spore-forming bacilli), with the most commonly isolated organism being Clostridium perfringens This pathogen is associated with obstetrical and intestinal surgery, significant trauma, and IVDA Other strains of Clostridium that have been implicated include C septicum in patients with certain types of cancer without a traumatic injury and C sordellii in subcutaneous injections of a particular type of heroin Clostridium species are thought to produce two main toxins responsible for their virulence: α and θ toxins α toxin causes damage locally by impairing neutrophil function, platelet function, and diapedesis θ toxin damage is systemically active and is thought to cause hemolysis, decreased systemic vascular resistance through decreasing peripheral tone, and impaired phagocytosis Gramnegative bacteria include both Vibrio spp and Aeromonas spp Vibrio vulnificus (gram-negative motile bacilli) are the most common Vibrio spp seen in NF and are normally found with upper extremity trauma in patients with hepatic, renal, or adrenal failure These bacteria are observed in warmer marine water, hence an increase in incidence during the summer months Aeromonas hydrophila and A veronii bv sobria (gram-negative rod or bacilli) are also aquatic, usually fresh or brackish water, but can also be normal flora in human Usually infection with Aeromonas spp leads to gastroenteritis but it can also cause NF [1,8,9,15,16] Type IV: Fungal This type is very unusual, but is often seen in immunocompromised patients with a traumatic inoculation Type IV NF has a very rapid course that is often attributed to the comorbidities of this patient population Fungi seen are usually Candida species, more specifically C parapsilosis [17], C albicans [18], and C tropicalis [14], as well as Zygomycetes [8] SIGNS AND SYMPTOMS Physical examination is of utmost importance for patients with NF Attention to detail, especially with change or worsening conditions within a short time period, is extremely important Pertinent signs and symptoms are listed below These are not specific to NF but can be suggestive of this disease Symptoms Pain out of proportion to exam Nausea and vomiting Diarrhea Chills Signs Skin erythema, which is common in many skin conditions and is more sensitive than specific (Fig 49.3) Skin discoloration, necrosis Bullae or blistering p 433 p 434 Warm to palpation Crepitus (more common with Clostridium or other gas-forming bacteria) Wound discharge, classically dishwater in character but can vary Induration, edema Laboratory anomalies (which will be discussed later) Fever Tachycardia Mental status changes FIGURE 49.3 A: A case of scrotal necrotizing fasciitis (Fournier gangrene), requiring extensive wide debridement of affected tissue (B) Cultures demonstrated a polymicrobial infection As the disease progresses, patients develop systemic inflammatory response syndrome (SIRS) SIRS criteria include heart rate greater than 90, white blood cell count ≤4,000, ≥12,000, or bands ≥10%, temperature greater than 38 or less than 36°C, respiratory rate greater than 20 breaths per minute or PaCO2 less than 32 Despite adequate treatment, a number of patients develop septic shock with multiorgan dysfunction syndrome DIAGNOSTICS Once again, physical examination is most important for the diagnosis of NF The aforementioned symptoms can be detected on examination but there are other tools to assist in making the diagnosis Microbiology Drainage from the wound can be sent for gram stain and culture The culture takes 24 to 72 hours to identify the pathogen, but if gram stain is positive for gram-positive cocci or bacilli, this will aid in making the diagnosis, especially in conjunction with other signs and symptoms exhibited by the patient Surgical Biopsy This can be done at the bedside or in the operating room if clinical suspicion is high The main objective is to evaluate the fascia Discoloration and peeling of unhealthy fascia is pathognomonic for NF Surgery is the only definitive method of diagnosis for NF This is the only way to truly evaluate fascial involvement X-Rays This may show air within subcutaneous tissue and musculature with edema (Fig 49.4) Radiography tends to be more useful with Clostridium or gas-forming bacterium due to the subcutaneous emphysema FIGURE 49.4 A: The patient is an 80-year-old diabetic immunosuppressed male with right ankle/foot erythema, ecchymosis, bullae, discharge, and edema B: X-ray of the ankle shows soft tissue swelling and gas Serous discharge was sent for gram stain, and culture demonstrated a polymicrobial infection He was diagnosed with necrotizing fasciitis (NF) [15] p 434 p 435 Commuted Tomography (CT) Scan CT scans can be helpful in making a diagnosis, especially with patient history and an examination Stranding on CT is suggestive of inflammation Air within fascial planes can also be better visualized on CT scans than X-rays Magnetic Resonance Imaging This can also be useful in making the diagnosis, and is the most sensitive imaging However, CT scan is often more efficient If the diagnosis is still uncertain, including both laboratory values and physical examination, a CT scan can be obtained, saving both cost and time compared to magnetic resonance imaging (MRI) Ultrasound There is some evidence showing efficacy with the use of ultrasound in NF A retrospective study evaluating the role of ultrasound in proven cases of NF revealed changes in muscle, fascia, and fat that would support evidence of an infection, but are nonspecific and are user dependent [19] Despite the availability of these diagnostic modalities, it is still difficult to definitely differentiate NF from other soft tissue infections In 2004, there was a retrospective study published in the Journal of Critical Care Medicine on the subject of NF The goal was to establish criteria to help differentiate NF from other soft tissue infections with a certain degree of reliability A scoring system was developed that was very suggestive of NF if the patient scored above 6 However, about 10% of patients with scores below 6 were also found to have NF Components of the laboratory risk factors are listed in Table 49.1 Laboratory values such as basic metabolic panel and complete blood count are routinely obtained in patients presenting to the emergency department The C-reactive protein level is the only additional value that is required for the calculation [6] TABLE 49.1 The Currently Accepted Scoring System, the LRINF [6] Variable, Units β Score 25 2.1 0 11–13.5 0.6 10 1.2 C-reactive protein, mg/L Total white cell count, per mm3 13.5 Sodium, mmol/L Creatinine, μmol/L Glucose, mmol/L Final model constructed using factors found to be independently predictive of necrotizing fasciitis (NF) on multivariate analysis β values are the regression coefficients of our model after adjusting for a shrinkage factor of 89 The maximum score is 13: a score of ≥6 should raise the suspicion of NF and a score of ≥8 is strongly predictive of this disease To convert the values of glucose to mg per dL, multiply by 18.015 To convert the values of creatinine to mg per dL, multiply by 0.01131 LABORATORIES Delay in diagnosis and time to the operating room increase mortality in patients with NF, as well as the lack of a fast and accurate imaging modality Scoring scales based upon signs to help clinicians diagnose NF earlier have also been developed The currently accepted scoring system is the LRINF TREATMENT Surgery The main goal when treating NF is removal of the involved tissues Wide surgical excision is the mainstay of therapy Patients usually require multiple returns to the operating room to evaluate the wound and to ensure all involved tissue is excised Wounds may be left open and allowed to heal by secondary intention Often multiple wet to dry dressing changes are required to adequately debride the tissue Iodine, Dakin solution, as well as other chemicals can be added to the early wet to dry dressings to help decrease the bacterial load in the wound Patients may ultimately require skin grafts if the area of debridement is extensive (Fig 49.5) FIGURE 49.5 A: The patient who was previously discussed with Fournier gangrene after surgical debridement of the scrotum B: The application of a split thickness skin graft to cover part of a large defect p 435 p 436 Antibiotics Once diagnosis is made, antibiotics are started to help control the spread of the infection Since the bacteria commonly found in this disease are gram-positive cocci, rods or anaerobes, broad-spectrum antibiotic coverage should be started initially Once surgical cultures have resulted, the type of NF can be identified and antibiotic therapy can be targeted The recommended regimen consists of a β-lactam inhibitor +/− βlactamase inhibitor (penicillin, pipercillin/tazobactam), anaerobic coverage with clindamycin/metronidazole, and MRSA coverage with vancomycin Other studies recommend use of meropenem plus clindamycin or ciprofloxacin, or clindamycin and metronidazole combination for broad-spectrum coverage Clindamycin is also used frequently because it has been shown to decrease the release of Clostridium α-toxin as well as the Streptococcal M protein [9,13,20] Intravenous Immune Globulin (IVIG) The use of IVIG for NF is supported by some case reports and mainly as an adjunct in cases of GAS infections It is not a widely accepted option for treatment and requires more research to evaluate its efficacy [9,21] Hyperbaric Oxygen Therapy The role of hyperbaric oxygen in NF appears to be as an adjunct Some retrospective studies have shown an additional benefit in patients treated primarily with surgical debridement and antibiotics At the current time, there is no randomized prospective trial evaluating the benefit of hyperbaric oxygen in these patients Use of hyperbaric oxygen still remains controversial [9] Negative Pressure Wound Therapy Negative pressure wound therapy (NPWT) has become more popular for the treatment of large wounds In cases of NF, NPWT is placed after surgical debridement has taken place It has been shown that NPWT decreases cost of therapy in the long term and decreases time to complete wound healing [22] More recently, there are case reports of adding a pure hypochlorous acid solution 0.01% (NeutroPhase, NovaBay Pharmaceuticals Inc, Emeryville, CA) for the treatment of NF Hypochlorous acid inactivates S aureus and S pyogenes toxins [14] Silver is another adjunct to NPWT described by Pour et al in a case report that decreased hospital length of stay Silver is thought to be antimicrobial by disabling growth enzymes [23] CONCLUSIONS NF is a true surgical emergency The earlier diagnosis and intervention occur, the better the potential outcome for the patient Surgery, which involves excision of all involved tissue, is the only known cure for all types of NF that have been discussed (types I-IV and Fournier) Antibiotics, IVIG, and other adjuncts can aid in the treatment The difficulty is in early recognition and diagnosis Retrospective studies have shown mortality to be between 25% and 60% [6,13] Many factors are involved in predicting mortality, including time of diagnosis, time to surgery, patient’s comorbidities and operative risk, and level of illness (SIRS, severe sepsis, septic shock, etc.) NF can easily be confused with other soft tissue infections but a good physical examination, attention to details, and potential use of imaging studies is the preferred approach for making the diagnosis REFERENCES Gamelli RL, Posluszny JA: Necrotizing soft tissue infections, in Irwin R, Rippe J (eds): Irwin and Rippe’s Intensive Care Medicine 7th ed Philadelphia: Lippincott Williams & Wilkins, 2011, pp 1619–1626 Lancerotto L, Tocco I, Salmaso R, et al: Necrotizing fasciitis: classification, diagnosis, and management J Trauma Acute Care Surg 72(3):560–566, 2012 McHenry CR, Piotrowski JJ, Petrinic D, et al: Determinants of mortality for necrotizing soft-tissue infections Ann Surg 221(5):558– 563; discussion 563–565, 1995 Su YC, Chen HW, Hong YC, et al: Laboratory risk indicator for necrotizing fasciitis score and the outcomes ANZ J Surg 78(11):968– 972, 2008 Taviloglu K, Yanar H: Necrotizing fasciitis: strategies for diagnosis and management World J Emerg Surg 2:19, 2007 Wong, CH, Khin LW, Heng KS, et al: The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections Crit Care Med 32(7):1535–1541, 2004 Hussein QA, Anaya DA: Necrotizing soft tissue infections Crit Care Clin 29(4):795–806, 2013 Misiakos EP, Bagias G, Patapis P, et al: Current concepts in the management of necrotizing fasciitis Front Surg 1:36, 2014 Hakkarainen TW, Kopari NM, Pham TN, et al: Necrotizing soft tissue infections: review and current concepts in treatment, systems of care, and outcomes Curr Probl Surg 51(8):344–362, 2014 10 Goh T, Goh LG, Ang CH, et al: Early diagnosis of necrotizing fasciitis Br J Surg 101(1):e119–e125, 2014 11 Thapaliya D, O’Brien AM, Wardyn SE, et al: Epidemiology of necrotizing infection caused by Staphylococcus aureus and Streptococcus pyogenes at an Iowa hospital J Infection Public Health 8(6):634–641, 2015 12 Khamnuan P, Chongruksut W, Jearwattanakanok K, et al: Necrotizing fasciitis: risk factors of mortality Risk Manag Healthc Policy 8:1–7, 2015 13 Machado NO: Necrotizing fasciitis: the importance of early diagnosis, prompt surgical debridement and adjuvant therapy North Am J Med Sci 3:107–118, 2011 14 Crew JR, Varilla R, Allandale Rocas Iii T, et al: Treatment of acute necrotizing fasciitis using negative pressure wound therapy and adjunctive neutrophase irrigation under the foam Wounds 25(10):272–277, 2013 15 Cui H, Hao S, Arous E: A distinct cause of necrotizing fasciitis: aeromonas veronii biovar sobria Surg Infect 8(5):523–528, 2007 16 Kuo YL, Shieh SJ, Chiu HY, et al: Necrotizing fasciitis caused by vibrio vulnificus: epidemiology, clinical findings, treatment and prevention Eur J Clin Microbiol Infect Dis 26(11):785–792, 2007 17 Zhang M, Chelnis J, Mawn LA: Periorbital necrotizing fasciitis secondary to candida parapsilosis and streptococcus pyogenes Ophthal Plast Reconstr Surg, 2015 doi:10.1097/IOP.0000000000000476 18 Chandawarkar RY, Jessie TA, Pennington GA, et al: Necrotizing fasciitis: diagnosis and management of an occult infective focus Can J Plast Surg 12(3):149–153, 2004 19 Parenti GC, Marri C, Calandra G, et al: Necrotizing fasciitis of soft tissues: role of diagnostic imaging and review of the literature Radiol Med 99(5):334–339, 2000 20 Buchanan, PJ, Mast BA, Lottenberg L, et al: Candida albicans necrotizing soft tissue infection: a case report and literature review of fungal necrotizing soft tissue infections Ann Plast Surg 70(6):739– 741, 2013 21 Yong, JM: Rationale for the use of intravenous immunoglobulin in streptococcal necrotizing fasciitis Clin Immunother 4(1):61–71, 1995 22 Ye J, Xie T, Wu M, et al: Negative pressure wound therapy applied before and after split-thickness skin graft helps healing of Fournier Gangrene: a case report (CARE-Compliant) Medicine 94(5):e426, 2015 23 Pour SM: Use of negative pressure wound therapy with silver base dressing for necrotizing fasciitis J Wound Ostomy Continence Nurs 38(4):449–452, 2011 24 Antimicrobial guidelines: Necrotizing fasciitis including Fournier’s East Kent Hospital University, NHS.Web Available at: http://www.ekh uft.nhs.uk/staff/clinical/antimicrobial-guidelines/skin-and-soft-tissue -guidelines/necrotising-fasciitis/ Updated January 29, 2015 25 Majeski J, Majeski E: Necrotizing fasciitis: improved survival with early recognition by tissue biopsy and aggressive surgical treatment South Med J 90(11):1065–1068, 1997 26 Morgan, MS: Diagnosis and management of necrotising fasciitis: a multiparametric approach J Hosp Infect 75(4):249–157, 2010 Chapter 50 The ICU Management of Patients Undergoing Major Surgery for Gastrointestinal Cancers KATE H DINH • JENNIFER LAFEMINA Major surgical procedures are now routine However, high-risk, noncardiac populations, including those who are at high risk due to the presence of cancer, are a subgroup that requires special consideration This chapter highlights operations for common gastrointestinal (GI) cancer requiring perioperative intensive care As morbidity and mortality after major oncologic surgery for cancer can be substantial, herein we focus on the complications specific to these operations, which can have significant implications on perioperative management and outcomes PANCREATIC RESECTION Pancreatic cancer is currently the fourth leading cause of cancer death in the United States; incidence and mortality rates are currently increasing While survival remains dismal with little improvement in recent decades, surgical resection currently offers the best option for long-term survival and cure The type of resection is largely dependent upon tumor characteristics such as size, location, and vascular involvement Common standard segmental resections for pancreatic cancer include pancreaticoduodenectomy (PD; also known as the Whipple procedure) and distal pancreatectomy (DP) Total pancreatectomy for neoplastic purposes may be considered for selected cases, particularly in the setting of main duct intraductal papillary mucinous neoplasm Perioperative management remains largely surgeon- and institution- dependent Early ambulation, pulmonary secretion clearance, and pain control (particularly with epidural analgesia) are paramount during the early postoperative period Following PD, nasogastric decompression may be helpful Once gastric decompression is discontinued, there is slow advancement of the diet Attention should be paid to clinical signs of perioperative complications that warrant additional workup and management Patients are at risk of postoperative diabetes and thromboembolic events and, therefore, generally receive close glucose monitoring and insulin supplementation and venous thromboembolism prevention Feeding jejunostomies and parenteral nutrition are generally unnecessary unless a complication that would result in nutritional deficiency warrants their use Contemporary series of complications following PD report an overall complication rate of 31% to 38% and mortality rate ranging from 1% to 4% [1–7] The most commonly reported complications include pancreatic fistula, hemorrhage related to pseudoaneurysm, delayed gastric emptying (DGE), and exocrine and endocrine insufficiency Additional complications include, but are not limited to, wound infections, need for reoperation, other anastomotic leakage (biliary, gastric, or duodenal), cholangitis, pancreatitis, and complications of other organ systems reported with other operations (including deep venous thrombosis, pulmonary embolus, cardiopulmonary complications, cerebral complications including stroke, and urinary tract infection) This discussion will focus on the common complications specific to pancreatic resection, including pancreatic fistula, hemorrhage related to pseudoaneurysm, DGE, and endocrine and exocrine insufficiency Postoperative Pancreatic Fistula Postoperative pancreatic fistula (POPF; also known as pancreatic leak) remains a difficult management dilemma, which contributes significantly to postoperative morbidity and mortality Numerous reports have been published exploring the incidence of this complications as well as means by which to prevent and treat this issue The reported incidence of POPF is highly variable, ranging from 2% to 12% [1–6] Many groups have proposed definitions based on surgical drain output quantity and quality, but the most commonly adopted terminology arises from the International Study Group on Pancreatic Fistula (ISGPF) This group defines POPF as “failure of healing/sealing of the pancreatic-enteric anastomosis or a parenchymal leak not directly related to the anastomosis” [7] More specifically, the ISGPF consensus defines POPF as drain fluid output on postoperative day 3 with a fluid amylase level more than three times greater than a concurrent serum amylase value Within this system, POPFs are graded A through C based on the degree of severity and impact on the patient’s clinical condition and management (Table 50.1) Grade A POPFs are generally short-lived and of little clinical significance As the patients are clinically well with without signs of infection, these do not result in changes in management Grade B fistulas are characterized by patients who are generally well, but may have a change in management: alteration in diet (i.e., nothing by mouth), use of parenteral nutrition, use of antibiotics if an infection is present, and/or use of octreotide A postoperative collection, which preferably is drained via a percutaneous or endoscopic approach, may be identified on imaging and addressed Grade C POPFs are considered the most severe and are defined by a clinically unwell patient who may be septic These POPFs require major changes in management, including reoperation and delay in discharge, and may be associated with severe complications including death TABLE 50.1 Summary of Postoperative Pancreatic Fistula Grades Postoperative Pancreatic Fistula Grade A B C Clinical condition Well Often well Unwell Management alterationa No Possible Yes Imaging findings No Possible Yes Prolonged drainage No Possible Yes Reoperation No No Yes Mortality No No Possible Readmission No Possible Possible Infection/Sepsis No/No Yes/No Yes/Yes aIncludes change in diet, use of parenteral nutrition, antibiotics, somatostatin analogs, minimal invasive drainage Amended from [7] p 437 p 438 Conservative management of POPF is the mainstay of treatment As noted previously, clinically insignificant Grade A POPFs do not require alterations in diet or additional medications However, for more severe Grade B-C POPFs, bowel/pancreatic rest (i.e., nothing by mouth) and the use of parenteral nutrition (i.e., total parenteral nutrition [TPN]) may be necessary Routine use of postoperative TPN is generally not necessary and has been associated with a higher risk of major complications [8] When collections are present, drains (whether placed surgically or postoperatively via a percutaneous approach) allow for control of contamination Antibiotics should be introduced for signs of infection or sepsis Reoperation is uncommon, but should be considered in the setting of an unstable patient or in one who fails conservative management Extensive reports have discussed, and continue to lead to a debate about, the role of octreotide in the prevention and treatment of POPF [9–14] Octreotide is a somatostatin analog and inhibits pancreatic secretion Initial work reported a decrease in the postoperative complication rate, including POPF, with routine octreotide administration However, two studies performed in the United States evaluated the role of octreotide following PD and failed to demonstrate a significant impact on postoperative complications, including POPF [11,14] Pasireotide, a somatostatin analog with a longer half-life than octreotide and a broader binding profile, was recently reported to decrease the rate of clinically significant POPF following both PD and DP [15] Similar to the role of octreotide, there is an extensive body of literature on proposed technical means to decrease the incidence of POPF It is generally accepted that careful handling of the pancreas and preservation of the blood supply are critical to minimize morbidity Variations in the technical construction of the pancreatic anastomosis have been explored Multiple studies, including a recent multicenter randomized controlled trial, have failed to demonstrate that there are differences in the rate of fistula, irrespective of whether a pancreaticojejunostomy or pancreaticogastrostomy is performed [16–19] Variations in reconstruction, with “binding” techniques, “invagination” techniques, and duct obliteration have been met with different levels of success [20–24] To date, a single method of pancreatic reconstruction has not been accepted as superior to others At least with DP, there appears to be no difference in POPF or mortality whether the pancreatic stump is hand sewn or stapled [25] The role of surgically placed drains for the prevention of POPF remains controversial In a single-institution, prospective, randomized trial, intraoperative drain placement was associated with no overall increase in complications, but placement was associated with a significantly greater incidence of intraabdominal abscesses/collections [26] The authors evaluated their more recent experience and again demonstrated that operatively placed drains were associated with a longer hospital stay, increased morbidity (including fistula rates), and increased readmission rates [27] A multicenter, prospective randomized trial recently demonstrated that subjects who did not have routine intraoperative drainage had a higher incidence of gastroparesis, intraabdominal fluid collection and abscess, severe diarrhea, need for additional drainage, and prolonged length of stay [28] Therefore, whether surgical placed drains should be routinely placed, particularly after PD, remains unclear Hemorrhage Related to Pseudoaneurysm Pseudoaneurysm, particularly pseudoaneurysm of the gastroduodenal artery (GDA) following a PD, is a life-threatening surgical emergency Patients with GDA pseudoaneurysms most commonly present with abdominal pain, massive GI hemorrhage (presenting as hematemesis, melena, or hematochezia) and hemoperitoneum Computed tomography (CT) angiogram may confirm the diagnosis, and embolization by interventional radiology can control the hemorrhage However, if embolization fails or the patient remains unstable, exploration and control of hemorrhage is warranted It is critically important to have a high level of suspicion for this complication: if recognized and treated expeditiously, mortality is up to 15% If untreated, mortality approaches 90% [29] Delayed Gastric Emptying The definition of DGE is variable The International Study Group of Pancreatic Surgery (ISGPS) defines DGE as “the inability to return to a standard diet by the end of the first postoperative week” and includes prolonged nasogastric tube (NGT) use [30] The pathologic mechanisms are poorly understood, though it has been proposed that duodenal resection, remnant duodenal length, disrupted innervation (i.e., the duodenal intestinal pacemaker), changes in motilin levels, and mechanical narrowing at the anastomosis may contribute to DGE If DGE occurs, it is important to rule out additional etiologies, such as a POPF or collection, which might be contributing The reported incidence of this common complication, particularly after PD, ranges from 7% to 16% [1–6] It was thought that the risk of DGE would be decreased with pyloruspreserving pancreaticoduodenectomy (PPPD), compared to a standard PD in which the pylorus is resected en bloc However, multiple trials have failed to demonstrate a difference in this complication based on the preservation or resection of the pylorus [31–33] Several studies have, in fact, suggested a higher incidence of DGE after PPPD [30] Gastric decompression with a NGT is an important component of management, particularly for a vomiting patient who is at risk of aspiration Motility agents such as metoclopramide and erythromycin are first-line agents The latter has been shown to significantly reduce the incidence of DGE from 30% to 19% following resection [34] If DGE is prolonged, enteral nutrition via a nasojejunostomy or gastrostomy tube, or parenteral nutrition should be considered to optimize nutritional status If a mechanical obstruction is identified, endoscopic dilation should be considered Endocrine and Exocrine Pancreatic Insufficiency The incidence of postpancreatectomy endocrine and exocrine insufficiency has been most commonly reported among studies focusing on the chronic pancreatitis population The risk for this population is perhaps greater than for the non-pancreatitis (i.e., neoplastic) population as pancreatic resection entails removal of at least some of the little remaining functional parenchyma The estimated incidence of new onset diabetes following PD ranges from 11% to 54% The risk of exocrine insufficiency followed PD has been reported as 24% to 78% [35–41] The reported incidence from a similar population may be as high as 50% for endocrine and exocrine insufficiency, respectively, following DP [42,43] Postoperative endocrine insufficiency is management with oral hypoglycemic or insulin Postoperative exocrine insufficiency may be detected by continued postoperative weight loss or steatorrhea, and may be treated with enzyme supplementation ESOPHAGEAL RESECTION Esophageal and gastroesophageal junction (GEJ) cancers remain therapeutic challenges with 5-year survivals of approximately 18% [44] Due to substantial morbidity and mortality of esophagectomy as well as the large number of patients with advanced disease in whom surgery in unlikely to be curative, there has been an increasing interest in nonsurgical options, including endomucosal resection, endoscopic ablation with techniques such as photodynamic therapy, and definitive chemoradiotherapy [45] However, esophagectomy currently remains the best option for long-term survival and cure in early stage disease and to achieve local control (e.g., reduction in the risk of tracheal or bronchial obstruction) of locally advanced disease Common operative approaches include the Ivor Lewis esophagectomy, McKeown esophagectomy, Sweet procedure (left-sided thoracotomy), left thoracoabdominal approach, and the transhiatal esophagectomy A number of factors determine the operative approach, including tumor location and stage, extent of lymphadenectomy, conduit options (e.g., stomach, colon, and small intestine), patient characteristics, and surgeon preference There is ongoing debate about a number of issues, including the role of minimally invasive surgery, the extent of lymphadenectomy, and the location of the anastomosis (cervical versus thoracic) A more thorough analysis of these ongoing debates is beyond the scope of this chapter Chest physiotherapy, optimization of pain control (for instance with epidural analgesia), early ambulation incentive spirometry, careful fluid management, and early extubation, when possible, are paramount to try to minimize perioperative morbidity Chest tubes and nasogastric decompression to prevent dilation are commonly employed, the latter to reduce distension which can lead to regurgitation and aspiration The role of feeding jejunostomy or nasoduodenal tube placement for perioperative enteral feeding is variable among surgeons Some advocate placement to allow for nutritional optimization, particularly if inadequate or delayed diet advancement is anticipated While some surgeons will proceed with diet advancement based on the patient’s clinical picture, a swallow study with Gastrografin contrast is the gold standard for diagnosis of complications, such as esophageal leak, and may be pursued prior to diet advancement Commonly reported complications include those named elsewhere in this chapter (such as cardiopulmonary complications including arrhythmias, pneumonia, and thromboembolic events), but specific to esophagectomy, morbidity can arise from esophageal anastomotic leak, DGE, dumping syndrome, anastomotic stricture, regurgitation and reflux, chylothorax, and hemi-vocal cord dysfunction from damage to the recurrent laryngeal nerve injury Esophageal Anastomotic Leak Series from large volume centers have reported leak rates of approximately 10% [46–49], though an incidence of greater than 30% has been reported for low volume centers [50] However, differences in operative techniques, such as stapled or hand-sewn anastomosis, have not necessarily shown to reduce this complication rate [51] Within the first 48 hours of surgery, if a patient develops shock, one must consider hemorrhage or a fulminant leak due to anastomotic necrosis or gangrene A chest X-ray (CXR) or CT, when patient stability allows, may help differentiate between etiologies and with the latter, localize blood, when present Exploration is generally indicated for unstable patients Should the anastomosis be the culprit, anastomotic resection with preservation of maximal esophageal length, cervical esophagostomy, and wide drainage is performed More commonly, esophageal leaks may be incidentally detected on radiologic studies (such as the planned Gastrografin swallow) or may be clinically apparent about a week after surgery One should suspect an esophageal leak in a patient with fevers, tachycardia, tachypnea, shortness of breath, and shoulder pain In the setting of a cervical anastomosis, neck pain or cellulitis may be present The diagnosis may be confirmed on Gastrografin swallow or CT of the chest and/or neck with oral contrast, which may show a pleural effusion or pooling of oral contrast If a chest tube is in place, drainage may be foul-smelling or turbid If the patient is hemodynamically stable, the patient may be managed conservatively with drainage, nutrition optimization, and antibiotics based on culture data Proton pump inhibitors that reduce gastric acid secretion may be helpful However, if these maneuvers fail or if the patient is unstable, re-exploration with drainage should be considered Primary repair may not be possible in this setting For cervical anastomotic leaks in a stable patient, the leak may be drained by opening the wound When a leak is believed to be healed, a repeat Gastrografin swallow study can confirm healing prior to diet initiation Upon diet advancement, instillation of methylene blue dye in clear liquids will also allow for determination of an active leak Delayed Gastric Emptying DGE following esophagectomy is a common complication and can occur due a number of proposed mechanisms, including the presence of vagotomy, reduced volume, inadequate emptying after gastric conduit creation, spiraling of the gastric tube, narrowing at the diaphragmatic hiatus, and inadequate pyloromyotomy or pyloroplasty The Pittsburgh group demonstrated that the risk of DGE is about 2%, and it is believed that using a pyloroplasty, rather than pyloromyotomy, may contribute to a lower rate [47] Similar to DGE associated with pancreatic resection, medications such as metoclopramide and erythromycin may be used to alleviate symptoms Endoscopic pyloric balloon dilation may be useful for cases in which an intact pylorus is contributing to the symptoms Chylothorax Chylothorax will occur in approximately 3% of cases [47] and arises from leakage of chyle from the thoracic duct or its branches with subsequent accumulation in the pleural space While uncommon, it can lead to significant morbidity and mortality, related to sepsis, acute respiratory distress syndrome, pneumonia, and need for reintubation Signs of this complication include drainage of an excessive amount of straw or cream-colored fluid, a contralateral pleural effusion, or milky fluid when enteral nutrition is given The fluid has a characteristic lymphocytic predominance and high triglyceride levels (>110 mg per dL) If the triglyceride level is 11.5% [27] p 447 p 448 Contractility of both the right and left ventricles can be impaired by IAH as well With increased thoracic pressure and decreased thoracic volume, pulmonary arterial pressures can increase The rise in pulmonary pressures can be large enough to cause significant increases in right ventricular afterload The combination of reduced venous return and increased pulmonary vascular resistance can cause right ventricular failure Due to ventricular interdependence, compromised right ventricle function can impair left ventricular function [28] In humans, decreased left ventricular function has been noted on transesophageal echocardiography when IAH is caused by intraabdominal insufflation during laparoscopic surgery [29] Not only can preload and contractility decrease, but an increase in afterload can occur, further impairing blood flow Afterload increases result from two mechanisms First, vascular resistance increases directly from increased thoracic pressure on the aorta and pulmonary vessels as well as direct pressure on the intraabdominal organs from IAH Second, due to decreased cardiac output, there is the resultant increase in systemic vascular resistance Neurologic The systemic effects of IAH are not just limited to the abdomen and chest, but also affect the central nervous system As discussed previously, the intracranial compartment is a fixed space in adults Inside this enclosed space are the brain parenchyma, cerebral spinal fluid, as well as the venous and arterial blood supply Any increase in one of these components increases intracranial pressure IAH appears to cause increased intrathoracic venous pressure that leads to elevated jugular venous pressure The higher jugular venous pressure leads to decreased venous outflow and a rise in intracranial pressure Animal model data support this hypothesis In a swine model, Bloomfield et al measured intraabdominal, intrapleural, external jugular venous, and intracranial pressures as an abdominal balloon was inflated with saline As IAH occurred, pleural pressure increased along with external jugular venous and intracranial pressure Intracranial pressure was decreased with either desufflation of the intraabdominal balloon or via median sternotomy [30] This relationship is also borne out in humans An observational trial in trauma patients with intracranial monitors measured intraabdominal, central venous, and internal jugular venous pressures Placement of a 15L fluid-filled bag externally on the abdominal wall simulated increased IAH and resulted in statistically increased intracranial pressures Temporally, pressures increased with the placement of a 15-L bag on the abdominal wall; however, the increase did not have a linear correlation between intrathoracic and intracranial pressures [31] These findings have been confirmed in nontraumatic neurologically impaired patient populations [32] as well as in case reports of decompressive laparotomy for relieving ACS with concomitant reduction in measured intracranial pressure [33] TREATMENT OPTIONS Medical Management Management strategies for ACS depend on the etiology and vary with the clinical scenario While many recommendations exist, the clinical context is important and should be individualized to the patient To reduce intraabdominal pressure, the patient should have a functional nasogastric tube to decompress the stomach A nasogastric tube is particularly important when small bowel ileus is the primary cause of IAH If the patient has Ogilvie syndrome, or a paralytic ileus of the colon, a rectal tube, colonoscopic decompression, or neostigmine should be considered A urinary indwelling catheter should also be in place, not only for monitoring of intraabdominal pressures and urine output, but also to decompress the bladder and to reduce the abdominal volume Negative fluid balance has been proposed as a useful method to reduce intraabdominal pressures Diuresis has become an important part of the armamentarium This treatment has not been specifically assessed in any clinical trial Continuous venovenous hemodialysis and slow extended daily dialysis has been studied in a small series In a study of nine patients with heterogeneous cause of critical illness, intraarterial pressure (IAP) decreased by a statistically significant difference but only from 12 to 10 mm Hg with volume removal [34] With such limited data, no recommendation regarding hemodialysis was made by the World Society of Abdominal Compartment Syndrome [1] Drainage of intraabdominal fluid collections is also an important adjunct in selected patients Ascites can develop from liver failure, severe pancreatitis, or massive volume resuscitation Hemorrhage and resultant clot formation is difficult to percutaneously drain A study of nine patients with greater than 40% total body surface area burns who developed IAH/ACS from large volume resuscitation examined the efficacy of percutaneous drainage Five required percutaneous drainage only and four failed percutaneous drainage and underwent decompressive laparotomy In the percutaneous drainage-only group, 38 ± 28 mL per kg of fluid were drained by the catheter and 45 ± 20 mL per kg were removed initially in the percutaneous/decompressive laparotomy group The author’s conclusions were that drainage is a viable technique as no patient experienced any complications directly related to the percutaneous drainage [35] In an observational matched case–control trial, 31 surgical ICU patients who had percutaneous treatment of IAH were compared with patients who had decompressive laparotomy Bedside ultrasound was used to identify IAH/ACS patients with free fluid and to place a 14 French catheter under visualization The IAH/ACS etiology was heterogeneous and included trauma (23%), burns (29%), postoperative (36%), and sepsis (12%) patients Percutaneous drainage was successful for 81% of the patients with the remaining 19% of the patients requiring a decompressive laparotomy Important predictors of failure of percutaneous drainage were drainage of less than 1,000 mL via the catheter and failure to reduce measured intraabdominal pressure by 9 mm Hg It is important to note that during the study time period, decompressive laparotomy was performed for ACS in 265 patients Therefore, percutaneous drainage was appropriate for a minority of patients [36] Given that the abdominal cavity is not completely rigid, another medical management technique may include increasing the abdominal volume by relaxing the abdominal musculature with heavy sedation and neuromuscular blockade De laet et al performed a prospective cohort study, assessing the effect of neuromuscular blockade on nine patients with IAH A single dose of cisatracurium reduced IAH from 18 to 14 mm Hg at 15 and 30 minutes, respectively [37] p 448 p 449 Surgical Management Decompressive laparotomy remains the standard of care when medical therapies fail However, the mortality remains as high as 50% despite surgical decompression [38] The mortality remains elevated as ACS is usually not the primary cause of the patient’s critical illness Furthermore, abdominal pressure remains elevated when measured after decompression [38] Pulmonary and cardiac parameters improve but do not normalize Additionally, ACS has been described in spite of the abdomen remaining open [39] Vigilance is therefore still required after surgical decompression and it would seem prudent to continue to monitor abdominal pressures Decompressive laparotomy is not without risks Enterocutaneous fistula, intraabdominal abscesses, and organ failure are associated with an open abdomen [40] The inability to close the abdominal wall may lead to a large ventral hernia After laparotomy, a variety of techniques have been employed for coverage of the abdominal viscera to prevent the development of enteroatmospheric fistulae, control fluid losses, and allow re-exploration One of the easiest methods is to close the skin while leaving the fascia open beneath Towel clips have been previously used as well as suturing the skin close These techniques are quick and inexpensive but do not expand the abdomen volume well enough Recurrent ACS is frequent Other techniques include repurposing sterile equipment as a temporary cover of the abdominal viscera Sterile 3-L infusion bags or the Bogata bag are used by some centers The use of sterile plastics covers for radiology cassettes has been described [41] The drawback to these techniques is that peritoneal fluid loss is not well controlled Negative pressure wound therapy is now commonly employed While there are commercially available products and suction devices, standard operating room equipment can be fashioned into a system The benefit of this technique is that it (1) prevents the intraabdominal viscera from becoming adherent to the abdominal wall; (2) the negative pressure controls and removes fluid; (3) the negative pressure may prevent fascial retraction allowing for easier delayed abdominal wall closure; (4) dressing changes can be performed every 3 to 4 days simplifying wound management However, cost remains a major drawback Reported delayed closure rates vary widely in the literature Abdominal closure can be facilitated by placing tension on the fascia to prevent fascial retraction [42] Protocols that specify scheduled reexploration and partial closure with each trip to operating room has been advocated and their use has been associated with abdominal wall closure rates up to 100% [43] Sequential closure, however, typically requires a week or more and multiple operations Other techniques to obtain closure include acute component separation, or planned hernia with delayed component separation Component separation closure is considered an important technique to electively repair hernias This technique has not been studied for acutely ill patients who are not medically optimized and likely malnourished The failure of component separation in the acute setting makes this method unavailable in the future for that patient when it would likely be successful Current recommendations are to reserve component separation for elective repairs for medically optimized patients [44] If the decision is to allow the patient to have a large abdominal wall hernia, coverage of the abdominal viscera with a split thickness skin graft or skin-only closure will usually be required PREVENTION Prevention of ACS is an important strategy Damage control resuscitation has been advocated for trauma patients Among these patients, low normal blood pressure is permitted and over-resuscitation avoided This concept emphasizes early control of hemorrhage, transfusion of blood and blood products, and reduced administration of crystalloids [45] The type of fluid as well as the volume infused may prove consequential in secondary compartment syndrome The use of albumin has been examined for burn patients While a single-center study showed no change in the occurrence of ACS by including albumin along with crystalloids in burn resuscitation [46], another prospective study showed decreased intraabdominal pressures [47] A meta-analysis suggested albumin use decreased the occurrence of all compartment syndromes but this study did not differentiate between the types of compartment syndromes [48] The use of fluid types other than crystalloids as well as other patient populations and fluid effects on the development of ACS is unclear Damage control surgery and deciding not to close the abdomen at the index operation is also an important part of prevention Data here is sparse For trauma patients, major liver injury or any other injury requiring packing for hemostasis is one consideration The occurrence of ACS was reduced from 80% to less than 24% in a retrospective cohort trial of severely injured trauma patients [49] A small series examined the outcomes of 27 patients with a ruptured abdominal aortic aneurysm who were repaired by the open technique In a retrospective analysis of patients who remained intubated postoperatively and had shock, colonic ischemia and ACS occurred only those patients with IAP of 21 mm Hg or higher [50] The limitation of course is that the IAP was monitored postoperatively Current societal recommendations for trauma and emergency surgery patients suggest the following intraoperative markers to consider leaving the abdomen open: large volume resuscitation defined as transfusion of greater than 10 units of packed red blood cells or the administration of greater than 15 L of crystalloid Other factors to consider include hypothermia (temperature less than 35°C) and acidosis with a pH RBC volume increase Leukocytosis Increased liver-produced clotting factors Increased fibrinogen Hypercoagulable state BUN, blood urea nitrogen; RBC, red blood cell DIAGNOSTIC RADIATION EXPOSURE When caring for any critically ill patient, diagnostic imaging is critically important When the patient is pregnant, care must be taken to weigh the risk of the imaging study with the potential change in management given the outcome of that study It is important to remember that there are no studies of humans to evaluate the risk of radiation Most evidence is case reports and data from survivors of nuclear bombings/accidents [22,23] There are four areas of potential harm when assessing radiation exposure: pregnancy loss, fetal malformations, disturbances of growth/development, and carcinogenic effects The effect radiation will have on a fetus depends on the gestational age at the time of exposure and the dose of radiation that the fetus is exposed to The majority of diagnostic procedures expose the fetus to less than 0.05 Gy of radiation There is no evidence that this level of exposure increases the risk of fetal anomalies, disability, growth restriction, or pregnancy loss at these levels; however, these low levels may increase the risk of childhood leukemia [24,25] The threshold at which a fetus sustains risk is not completely known, though evidence suggests that the risk of malformations increases at doses greater than 0.1 Gy The timing of exposure is also important The fetus is most sensitive to radiation exposure early in pregnancy In early pregnancy, the “all or none” phenomenon applies, which means that the fetus either survives intact or is resorbed This is true for the first 14 days after conception [26] After the first 14 days, an embryo can be damaged In the first trimester, the most common abnormalities seen are growth restriction or central nervous system abnormalities [27] Radiation levels needed for these mutations are 0.1 to 0.2 Gy prior to 16 weeks and 0.5 to 0.7 Gy after 16 weeks of gestation [28] Growth restriction usually is not seen until >1 Gy After 20 weeks, the fetus is resistant to the teratogenic effects of radiation [29] There are no known fetal effects from exposure to ultrasound or magnetic resonance imaging (MRI) MRI examinations are used as an adjunct to ultrasound in the second and third trimesters to aid in the diagnosis of certain fetal anomalies Contrast agents should be avoided during the first trimester [30,31] If a significant alteration in management is to be undertaken as a result of the information obtained from the procedure, the potential fetal risk should be considered If excessive radiation doses to the pelvis are administered inadvertently, it is important to calculate the fetal isodose radiation exposure An excess of 10 cGy delivered to the fetus may lead to significant fetal effects Table 53.2 outlines both the amount of radiation of common imaging studies and the potential fetal effects of radiation exposure TABLE 53.2 Radiation Dose and Fetal Effects Radiation dose to fetus (cGy) Theoretical or actual fetal effect 0–5 No reported malformation; potential for oncogenesis, and increased cancer risk 5–10 Potential for oncogenesis; potential for IUGR 10–20 Microcephaly, IUGR, 2.4% mental retardation 20–50 Microcephaly, IUGR, fetal death, mental retardation 50–100 Microcephaly, IUGR, 18% mental retardation, fetal death IUGR, intrauterine growth retardation From Gianopoulos JG: Breast disease in pregnancy, in Isaccs JH (ed): Textbook of Breast Disease Philadelphia, PA, Mosby-Year Book, 1992, p 131, with permission MEDICATIONS AND PREGNANCY Analgesic Agents Opiate narcotic agents administered for short periods of time have been shown to be safe during pregnancy They have shown no adverse fetal effects Chronic opiate use during pregnancy has been associated with intrauterine growth restriction and neonatal abstinence syndrome [32] Nonsteroidal antiinflammatory agents may decrease fetal renal blood flow, leading to oligohydramnios They also will lead to the in utero closure of the ductus arteriosus, producing fetal pulmonary hypertension after 32 weeks of gestation Short courses of indomethacin may be used with caution prior to 32 weeks of gestation Antibiotics Penicillins, cephalosporins, erythromycin, clindamycin, and vancomycin are considered safe during pregnancy There is some concern regarding renal toxicity with vancomycin Aminoglycosides have been implicated in fetal ototoxicity [33] However, only streptomycin and kanamycin have been implicated Gentamicin has not been reported to have significant ototoxicity and is used commonly during pregnancy Sulfonamides compete with bilirubin-binding sites and may lead to neonatal kernicterus if administered during the third trimester Tetracycline is teratogenic, leading to brown teeth and abnormal long bone development [33–35] (Table 53.3) TABLE 53.3 Antibiotics during Pregnancy Safe in pregnancy Penicillins/cephalosporins Fosfomycin Nitrofurantoin Vancomycin Clindamycin Azithromycin, erythromycin Risks in pregnancy Aminoglycosides: renal and ototoxic, OK in life- threatening conditions Tetracycline: bone demineralization and teeth staining Sulfa drugs: OK in second trimester, risk of birth defects in first trimester, and kernicterus in third trimester Fluoroquinolones: toxic to cartilage development p 452 p 453 Anticoagulants Unfractionated heparin, because of its molecular size and ionic negative charge, has been shown not to cross the placental membrane [36] Therefore, it is the anticoagulant of choice in all trimesters of pregnancy and may be used with relative fetal safety Fractionated heparins also have been shown not to cross the placental membrane They may be used throughout pregnancy as well If fractionated heparins are used during pregnancy, it is advised to change to unfractionated heparin late in the third trimester because when surgical intervention is needed, unfractionated heparin may be reversed with protamine sulfate and because regional anesthesia can be used after reversal [37] Warfarin and its derivatives are contraindicated during the first trimester as these agents are teratogenic, producing midline defects such as clefts, cardiac septal defect, and limb bud abnormalities In all trimesters, warfarin crosses the placenta and may lead to spontaneous fetal bleeding [38–40] In some selected cardiac patients (particularly those with mechanical valves), warfarin may be used during the second and early third trimesters Fetal intracranial bleeding has been observed with warfarin use during the late third trimester Antihypertensives Pregnant patients will require acute antihypertensive intervention when the systolic BP exceeds 160 mm Hg or the diastolic BP exceeds 110 mm Hg Preservation of the fetal circulation must be kept in mind when treating these conditions For the acute management of hypertensive crisis in pregnancy, labetolol or hydralazine are recommended [41,42] Hydralazine is dosed as 10 mg IV push Labetolol is given as a 10-mg dose IV, followed by a 20-mg dose at 10 minutes if no response is observed If still no response in BP is observed, the dose may be increased to 40 mg in 10 minutes and followed by 80 mg in 10 minutes The 80 mg dose may be repeated one time The total dose should not exceed 220 mg [43,44] Angiotensin-converting enzyme inhibitors and angiotensin receptor blocker agents are contraindicated during pregnancy They have been associated with fetal anomalies and intrauterine fetal death secondary to fetal cardiovascular collapse SPECIFIC PREGNANCY DISORDERS Hypertensive Disorders of Pregnancy Preeclampsia is most commonly defined as hypertension (>140/90) in combination with proteinuria (>300 mg per day) beginning after the 20th week of pregnancy in a previously normotensive person Eclampsia is defined as meeting the criteria for preeclampsia with the addition of seizures Preeclampsia and eclampsia are multisystem diseases that develop only during pregnancy or, more rarely, during the postpartum period Previously, preeclampsia was defined as mild or severe In 2013, the American Congress of Obstetrics and Gynecology changed the categories; preeclampsia is now defined as being “with” or “without” severe features Severe features are defined as BP >160/110 mmHg, or evidence of end organ disease They also removed proteinuria as an essential criterion for diagnosis of preeclampsia with severe features and removed massive proteinuria (5 g per 24 hours) and fetal growth restriction as possible features of severe disease [45] The underlying cause of preeclampsia is not fully understood, but likely involves maternal, fetal, and placental factors Abnormalities of blood vessel development can result in placental underperfusion, hypoxia, and ischemia [46] The severity of disease is influenced not only by maternal and placental factors but also likely by paternal and environmental factors [47] It is the complications of preeclampsia that usually indicate ICU admission Sequelae include refractory hypertension, neurologic manifestations (seizure, intercranial hemorrhage, and elevated intracranial pressure), renal failure, liver failure or rupture, pulmonary edema, HELLP syndrome, or disseminated intravascular coagulation (DIC) [6] Management Though all of the complications of preeclampsia can be treated, the ultimate treatment for preeclampsia is delivery If a patient who develops preeclampsia is near term, prompt delivery is the recommendation Patients who are preterm without evidence of severe features can be managed expectantly with close monitoring until term gestation is reached (37 weeks) or severe features develop For selected patients remote from term with severe features, expectant management can be undertaken at a tertiary care center [45] Patients remote from term should be given steroids to enhance fetal pulmonary maturity Patients with severe features should be treated with IV magnesium It has been shown to be superior to other antiepileptics for the prevention of seizure activity [48,49] Magnesium is given as a 4-g bolus IV over the first hour, then at 2 g per hour until 24 hours post delivery with monitoring of reflexes and magnesium levels ICU care involves managing the complications of preeclampsia: Severe hypertension: BP greater than 160/110 mmHg is generally treated with IV antihypertensives Labetolol and hydralazine are the drugs of choice [50] Exact dosing is the same as the algorithm above Seizures: Eclamptic seizures are treated with IV magnesium In cases unresponsive to magnesium, benzodiazepines may be used When the seizure activity persists, the next agent of choice is phenytoin In severe refractory cases, muscle paralysis with general anesthesia and ventilatory support may be needed [48] DIC: Treatment of DIC involves identifying the underlying cause Placental abruption is a common cause among those with preeclampsia Aggressive resuscitation with blood products to reverse coagulopathy is sometimes needed Pulmonary edema: Pulmonary edema may present with dyspnea or acute respiratory failure Supportive management includes supplemental oxygen and fluid restriction Diuresis is indicated when there is fluid overload, although this is rare because most patients are volume depleted Obstetrical Hemorrhage Vaginal bleeding during pregnancy is a common event The source of the bleeding is almost always maternal The evaluation, differential diagnosis, and management of bleeding differ by trimester and volume Vaginal bleeding during the third trimester can be a medical emergency When significant hemorrhage occurs, prompt medical or surgical intervention is needed Antepartum Hemorrhage The most common cause of bleeding during the first trimester is miscarriage Miscarriage is common (up to 25% of pregnancies), and significant bleeding requiring transfusion, while rare, does occur [51] Another less prevalent (∼2% of pregnancies) cause of hemorrhage during the first trimester is ectopic pregnancy Rupture of an ectopic pregnancy can be a life-threatening emergency and aggressive monitoring of hemodynamic status, fluid resuscitation, and administration of blood products may be required Vaginal bleeding in the second and third trimester is less common but may be a medical emergency dependent on etiology; the possibilities are described below p 453 p 454 Placenta Previa Placenta previa is defined as the placental tissue extending to or covering the cervical os This diagnosis is uncommon, occurring in ∼4/1,000 births [52], but the sequelae of this condition has the potential for severe bleeding Classically, the patient with placenta previa will resent with painless vaginal bleeding; however, some women will present with pain or contractions in association with bleeding [53,54] Any woman without an ultrasound documenting placental location who presents with bleeding should undergo ultrasound evaluation for placental location Ultrasound should be performed prior to digital examination of the cervix to avoid palpation of the placenta and severe hemorrhage Women with placenta previa are at increased risk of hemorrhage during the antepartum, intrapartum, and postpartum periods [55] They are therefore more likely to undergo blood transfusion, peripartum hysterectomy, uterine artery embolization to have a placenta accreta [56] Maternal mortality secondary to previa is low in resource-rich countries; however, in the third world, this remains a high risk of maternal mortality [56] Because the risk of severe bleeding and emergent, unscheduled delivery outweigh the risks of late preterm birth, delivery of patients with known previa is recommended by cesarean section between 36 and 37 weeks of gestation [57,58] Though an actively bleeding placenta previa is a potential emergency, most cases of acute bleeding are self-limited Patients should be admitted, a complete blood count and Type and Screen should be sent Fetal monitoring should be employed If the bleeding is active, both the mother and fetus should be closely monitored and supportive care provided Indications for emergent cesarean delivery include refractory, life-threatening hemorrhage, non-reassuring fetal status or a significant bleed after 34 weeks of gestation If the bleeding episode is self-limited, the patient can be monitored in the hospital A course of antenatal corticosteroids should be given for fetal benefit given the potential for preterm delivery If the patient is Rh negative, Rhogam should be given When delivery is undertaken, close coordination and planning with anesthesia should be undertaken as the presence of previa increases the risk of hemorrhage and placenta accreta and percreta Abruption Placenta Placental abruption is the premature separation of the placenta from the uterus (prior to the delivery of the infant) Abruption occurs in up to 1% of pregnancies and may be small and not clinically significant or may lead to severe life-threatening bleeding and DIC The clinical presentation of abruption is vaginal bleeding with associated uterine pain or contractions There may or may not be associated fetal distress In severe cases, DIC and coagulopathy occur The bleeding may be vaginal or confined to the uterus, so the amount of vaginal bleeding is not a reliable indicator of severity Ultrasound is not a reliable indicator of abruption (only 2% of abruption can be visualized on ultrasound) If coagulopathy occurs, resuscitation with bloodreplacement products such as fresh-frozen plasma or cryoprecipitate should occur [59] The definitive management is delivery and resuscitation If the patient is preterm and the abruption is limited and fetal status is not affected, potential inpatient surveillance can be undertaken Antenatal corticosteroids are given for fetal lung maturity Postpartum Hemorrhage Significant hemorrhage postpartum occurs among 2% to 5% of deliveries The most common cause is uterine atony Other causes include retained products of conception, lacerations of the cervix and vagina, and unrecognized coagulopathies [60] Blood loss of more than 500 mL at vaginal delivery or 1,000 mL at cesarean section is classified as postpartum hemorrhage Delayed hemorrhage, 3 to 7 days postpartum, most often is due to retained placental fragments or unrecognized congenital coagulopathies [60] The initial assessment should include a determination of the cause of hemorrhage Careful examination of the cervix and vagina to assess for unrecognized lacerations is warranted Manual exploration of the uterus is performed both to assess tone and to apply uterine massage if atony is noted If uterine atony is encountered, uterotonics are given Pitocin (oxytocin) is usually first line and is given IV with 20 to 40 units mixed in IV fluids [60–62] If uterine atony persists, several other uterotonics may be given Methergine, misoprostol and Hemabate may all be used and the order in which they are used does not appear to be important Methergine is an ergot derivative It is given as 0.2 mg IM and is contraindicated for patients with hypertension, as significant elevations in BP may occur Hemabate and misoprostol are prostaglandins Hemabate is given as 250 µg IM [63] Misoprostol is given rectally at 400 to 800 µg Hemabate may cause significant bronchospasm and is contraindicated for patients with asthma If medical management of postpartum hemorrhage is unsuccessful, surgical intervention is needed An intrauterine examination under anesthesia for retained products and dilatation and uterine curettage may be performed If still unresponsive, uterine artery embolization may be attempted In cases of unresponsive atony, laparotomy and uterineconstricting b-lynch suture may be performed If all measures have failed to resolve the bleeding, hysterectomy may be employed as a last resort [64–66] Amniotic Fluid Embolism Amniotic fluid embolism is an extremely rare event Incidence is 1 to 12 cases per 100,000 deliveries [67] Clinically, patients present with sudden onset of cardiovascular and respiratory collapse at or around the time of delivery [68] When amniotic fluid enters the intervascular space, vasoactive and fibrinolytic components precipitate cardiovascular collapse and respiratory failure Immediate identification and aggressive treatment is required Despite this, mortality rates are still as high as 50% [69] Intubation and mechanical ventilation with positive end-expiratory pressure is employed Inotropic and vasoconstrictor agents are needed for cardiac and vascular support Invasive right-sided cardiac monitoring is also indicated These patients will often experience a rapid and fulminant DIC, requiring resuscitation with fresh-frozen plasma and cryoprecipitate These patients require intensive monitoring and support Extra corporeal membrane oxygenation has been used to rescue patients with refractory cardiorespiratory collapse If the patient survives the initial insult, most will survive [70,71] Trauma Complicating Pregnancy Trauma is the most common cause of death during pregnancy not related to obstetric factors Motor vehicle accidents and domestic violence make up the majority of cases; however, there are many other potential causes of trauma Though trauma is a common occurrence during pregnancy, less than 1% will require hospitalization [72] The physiologic alterations of pregnancy are discussed in detail above Because of these, particularly the increased blood volume, the pregnant trauma patient is less likely to immediately manifest signs of shock The abdominal position of the uterus in the third trimester makes this organ more susceptible to both blunt and penetrating trauma As the uterus grows, the bladder is pulled superior and rendered more susceptible to traumatic injury in pregnancy p 454 p 455 Motor vehicle accidents account for 60% of injuries in pregnancy The pregnancy outcome is directly related to the severity of maternal injuries The most common cause of fetal death is maternal death [73,74] Following blunt injury secondary to a motor vehicle accident, placental abruption is the most common complication associated with the pregnancy Placental abruption occurs among 2% to 4% of patients with these injuries Ultrasound to detect placental abruption is not sensitive, as stated above [74–76] Contraction monitoring with a tocometer has a high negative predictive value for abruption and most abruptions will occur during the first 4 to 8 hours postinjury No consensus exists as to the length of the post-trauma monitoring interval, but at least 4 hours is recommended [77,78] Rarely, a delayed abruption up to 48 hours postinjury may occur There is no sensitive test to predict delayed abruption However, if fetal–maternal hemorrhage is observed, the incidence is higher Patients can be screened with a Kleihauer–Betke assay to assess for fetal–maternal bleeding [79] If positive, a longer period of observation may be indicated As small amounts of fetal blood may enter the maternal circulation, all patients require blood type and screen, and Rh-negative patients should receive Rhogam Continuous fetal monitoring should occur The usual markers of severity of maternal illness—BP, heart rate, hematocrit, and arterial partial pressure of carbon dioxide—are not predictive of fetal outcomes Imaging studies with ultrasound are the first line for assessment In the second and third trimesters, computed tomography scans of the abdomen and pelvis may be undertaken when indicated In severe cases, cesarean section may improve maternal outcomes, by removing the placental arteriovenous shunt [80] Potential maternal lifesaving cesarean delivery can be performed at ∼4 to 5 minutes into maternal code to attempt to remove placental blood flow Penetrating Trauma Penetrating injuries of pregnant patients most commonly are gunshot wounds or knife wounds Pregnant patients have a better prognosis after penetrating abdominal trauma as the large muscular uterus protects maternal vital organs Maternal visceral injuries complicate 19% of penetrating abdominal trauma with a 3.9% maternal mortality rate [81] The anterior and central location of the uterus subjects the fetus to significant risk from penetrating wounds The fetus is injured in 66% of these cases, with a high 40% to 70% fetal mortality rate [82] The management of these injuries remains controversial Many experts advocate surgical exploration Conservative management with imagining and observation may also be considered A coordinated effort between the trauma surgeon and obstetrician is important for achieving the best outcomes for both mother and fetus [81–83] REFERENCES Alkema L, Chou D, Hogan D, et al: Global, regional, and national levels and trends in maternal mortality between 1990 and 2015, with scenario-based projections to 2030: a systematic analysis by the UN Maternal Mortality Estimation Inter-Agency Group Lancet 387:462– 474, 2016 Hogan MC, Foreman KJ, Naghavi M, et al: Maternal mortality for 181 countries, 1980–2008: a systematic analysis of progress towards Millennium Development Goal 5 Lancet 375:1609–1623, 2010 Kassebaum NJ, Bertozzi-Villa A, Coggeshall MS, et al: Global, regional, and national levels and causes of maternal mortality during 1990– 2013: a systematic analysis for the Global Burden of Disease Study 2013 Lancet 384:980–1004, 2014 Berg CJ, Chang J, Callaghan WM, et al: Pregnancy-related mortality in the United States, 1991–1997 Obstet Gynecol 101:289, 2003 Clark SL, Belfort MA, Dildy GA, et al: Maternal death in the 21st century: causes, prevention, and relationship to cesarean delivery Am J Obstet Gynecol 199:36.e1–36.e5, 2008 Pollock W, Rose L, Dennis CL: Pregnant and postpartum admissions to the intensive care unit: a systematic review Intensive Care Med 36:1465–1474, 2010 Chapman AB, Abraham WT, Zamudio S, et al: Temporal relationships between hormonal and hemodynamic changes in early human pregnancy Kidney Int 54:2056–2063, 1998 Robson SC, Hunter S, Boys RJ, et al: Serial study of factors influencing changes in cardiac output during human pregnancy Am J Physiol 256:H1060–H1065, 1989 Metcalfe J, Ueland K: Maternal cardiovascular adjustments to pregnancy Prog Cardiovasc Dis 16:363–374, 1974 10 Grindheim G, Estensen ME, Langesaeter E, et al: Changes in blood pressure during healthy pregnancy: a longitudinal cohort study J Hypertens 30:342–350, 2012 11 Liberatore SM, Pistelli R, Patalano F, et al: Respiratory function during pregnancy Respiration 46:145–150, 1984 12 Milne JA: The respiratory response to pregnancy Postgrad Med J 55:318–324, 1979 13 Bonica JJ: Maternal respiratory changes during pregnancy and parturition Clin Anesth 10:1–19, 1974 14 Lim VS, Katz AI, Lindheimer MD: Acid-base regulation in pregnancy Am J Physiol 231:1764–1769, 1976 15 Hernandez E, Angell CS, Johnson JW: Asthma in pregnancy: current concepts Obstet Gynecol 55:739–743, 1980 16 Lund CS, Donovan JC: Blood volume during pregnancy Am J Obstet Gynecol 98:393–403, 1967 17 Pritchard JA, Rowland RC: Blood volume changes in pregnancy and the puerperium Am J Obstet Gynecol 88:391–395, 1964 18 Talbert LM, Langdell RD: Normal values of certain factors in the blood clotting mechanism in pregnancy Am J Obstet Gynecol 90:44–50, 1964 19 Walker MC, Garner PR, Keely EJ, et al: Changes in activated protein C resistance during normal pregnancy Am J Obstet Gynecol 177:162– 169, 1997 20 McColl MD, Ramsay JE, Tait RC, et al: Risk factors for pregnancy associated venous thromboembolism Thromb Haemost 78:1183–1188, 1997 21 Rasmussen PE, Nielsen FR: Hydronephrosis during pregnancy: a literature survey Eur J Obstet Gynecol Reprod Biol 27:249–259, 1988 22 Castronovo FP Jr: Teratogen update: radiation and Chernobyl Teratology 60:100–106, 1999 23 United Nations Scientific Committee on the Effects of Atomic Radiation: Sources and Effects of Ionizing Radiation, UN Publication E.94.IX.2 UN Publications, United Nations, New York, 1993 24 Brent RL: The effect of embryonic and fetal exposure to x-ray, microwaves, and ultrasound: counseling the pregnant and nonpregnant patient about these risks Semin Oncol 16:347–368, 1989 25 Stewart A, Kneale GW: Radiation dose effects in relation to obstetric xrays and childhood cancers Lancet 1:1185–1188, 1970 26 De Santis M, Cesari E, Nobili E, et al: Radiation effects on development Birth Defects Res C Embryo Today 81:177–182, 2007 27 Bentur, Y: Ionizing and nonionizing radiation in pregnancy, in Koren G (ed): Maternal-fetal Toxicology 2nd ed New York, NY, Marcel Dekker, 1994 28 www.bt.cdc.gov/radiation/prenatalphysician.asp Accessed March, 2016 29 De Santis M, Di Gianantonio E, Straface G, et al: Ionizing radiations in pregnancy and teratogenesis: a review of literature Reprod Toxicol 20:323–329, 2005 30 Shellock FG, Kanal E: Bioeffects and safety of MRI procedures, in Edelman RR, Hesselink JR, Zlatkin MB (eds): Clinical Magnetic Resonance Imaging 4th ed Philadelphia, PA, WB Saunders, 2000, p 935 31 Wienreb JC, Lowe TW, Santos-Ramos R, et al: Magnetic resonance imaging in obstetric diagnosis Radiology 154:157–161, 1985 32 Kandall SR, Albin S, Gartner LM, et al: The narcotic-dependent mother: fetal and neonatal consequences Early Hum Dev 1:159–169, 1977 33 Briggs GG, Bodendoter TW, Freeman RK, et al: Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk Baltimore, Williams & Wilkins, 1994 34 Shepard TF: Human teratogenicity Adv Pediatr 33:225–268, 1986 35 Chow AW, Jewesson RJ: Pharmacokinetics and safety of antimicrobial agents in pregnancy Rev Infect Dis 7:287–313, 1985 36 Flessa HC, Klapstrom AB, Glueck MJ, et al: Placental transport of heparin Am J Obstet Gynecol 93:570–573, 1965 37 Sanson BJ, Lensing AW, Prins ML, et al: Safety of low molecular weight heparin in pregnancy: a systematic review Thromb Haemost 81:668–672, 1999 38 Forestier F, Daffos F, Capella-Pavlousky M: Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy: study by direct fetal blood sampling under ultrasound Thromb Res 34:557–560, 1984 39 Ginsberg B, Hirsch J, Turner C, et al: Risks to the fetus of anticoagulant therapy during pregnancy Thromb Haemost 61:197– 203, 1989 40 Hall JG, Pavi RM, Wilson KM: Maternal and fetal sequelae of anticoagulants during pregnancy Am J Med 68:122–140, 1978 41 Magee LA, Cham C, Waterman ES, et al: Hydralazine for the treatment of severe hypertension in pregnancy: meta-analysis BMJ 327:955– 960, 2003 42 Magee LA, Ornstein MP, Von Dadelszen P: Fortnightly review: management of hypertension in pregnancy BMJ 318:1332–1336, 1999 43 National High Blood Pressure Education Program: Working Group Report on High Blood Pressure in Pregnancy Washington, DC, National Institutes of Health, 2000 44 Duley L, Henderson-Smart DJ: Drugs for treatment of very high blood pressure during pregnancy Cochrane Database Syst Rev 4:CD001449, 2002 p 455 p 456 45 American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy: Hypertension in pregnancy Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy Obstet Gynecol 122:1122–1131, 2013 46 Meekins JW, Pijnenborg R, Hanssens M, et al: A study of placental bed spiral arteries and trophoblast invasion in normal and severe preeclamptic pregnancies Br J Obstet Gynaecol 101:669–674, 1994 47 Trogstad L, Magnus P, Stoltenberg C: Pre-eclampsia: risk factors and causal models Best Pract Res Clin Obstet Gynaecol 25:329–342, 2011 48 Witlin AG, Sibai B: Magnesium sulfate therapy in preeclampsia and eclampsia Obstet Gynecol 92:883–889, 1998 49 Altman D, Carroli G, Duley L, et al; The Magpie Trial Collaborative Group: Do women with pre-eclampsia, and their babies, benefit from magnesium sulfate? The Magpie Trial: a randomized placebo controlled trial Lancet 359:1877–1890, 2002 50 Committee on Obstetric Practice: Committee opinion no 623: emergent therapy for acute-onset, severe hypertension during pregnancy and the postpartum period Obstet Gynecol 125:521–525, 2015 51 Nanda K, Lopez LM, Grimes DA, et al: Expectant care versus surgical treatment for miscarriage Cochrane Database Syst Rev 3:CD003518, 2012 52 Faiz AS, Ananth CV: Etiology and risk factors for placenta previa: an overview and meta-analysis of observational studies J Matern Fetal Neonatal Med 13:175–190, 2003 53 Cotton DB, Read JA, Paul RH, et al: The conservative aggressive management of placenta previa Am J Obstet Gynecol 137:687–695, 1980 54 Silver R, Depp R, Sabbagha RE, et al: Placenta previa: aggressive expectant management Am J Obstet Gynecol 150:15–22, 1984 55 Crane JM, Van den Hof MC, Dodds L, et al: Maternal complications with placenta previa Am J Perinatol 17:101–105, 2000 56 Olive EC, Roberts CL, Algert CS, et al: Placenta praevia: maternal morbidity and place of birth Aust N Z J Obstet Gynaecol 45:499–504, 2005 57 Spong CY, Mercer BM, D’alton M, et al: Timing of indicated latepreterm and early-term birth Obstet Gynecol 118:323–333, 2011 58 American College of Obstetricians and Gynecologists: ACOG committee opinion no 560: medically indicated late-preterm and early-term deliveries Obstet Gynecol 121:908–910, 2013 59 Hurd WW, Meodornik M, Hertzberg V, et al: Selective management of abruptio placentae: a prospective study Obstet Gynecol 61:467–473, 1983 60 Luea WE: Post partum hemorrhage Clin Obstet Gynecol 23:637, 1980 61 Cassidy GN, Moore DL, Bridenbaugh D: Postpartum hypertension after use of vasoconstrictor and oxytocin drugs: etiology incidences, complications and treatment JAMA 172:1011–1015, 1960 62 Hayashi RH, Castello MS, Noah ML: Management of severe postpartum hemorrhage due to uterine atony using an analogue of prostaglandin F2 Obstet Gynecol 58:426–429, 1981 63 Leary AM: Severe bronchospasm and hypotension after 15 methyl prostaglandin F2 & in atonic postpartum hemorrhage J Obstet Anesth 3:42–44, 1994 64 Schwartz PE: The surgical approach to severe postpartum hemorrhage, in Bereowitz RL (ed): Critical Care of the Obstetric Patient New York, NY, Churchill Livingstone, 1983, p 285 65 Pais SO, Glickman M, Schwartz P, et al: Embolization of pelvic arteries for control of postpartum hemorrhage Obstet Gynecol 53:754–758, 1980 66 Ferguson JE II, Bourgesis FJ, Underwood P: B-Lynch suture for postpartum hemorrhage Obstet Gynecol 95:1020–1022, 2000 67 Abenhaim HA, Azoulay L, Kramer MS, et al: Incidence and risk factors of amniotic fluid embolisms: a population-based study on 3 million births in the United States Am J Obstet Gynecol 199:49.e1–49.e8, 2008 68 Gist RS, Stafford IP, Leibowitz AB, et al: Amniotic fluid embolism Anesth Analg 108:1599–1602, 2009 69 Gilbert W, Danielsen B: Amniotic fluid embolism: decreased mortality in a population based study Obstet Gynecol 93:973–977, 1999 70 Davies S: Amniotic fluid embolism and isolated disseminated intravascular coagulation Can J Anaesth 46:456–459, 1999 71 Gilmore DA, Wakins J, Secrest J, et al: Anaphylactoid syndrome of pregnancy: a review of the literature with latest management and outcome data AANA J 71:120–126, 2003 72 Lavery J, Staton-McCormick M: Management of moderate to severe trauma in pregnancy Obstet Gynecol Clin North Am 22:69–90, 1995 73 Peckham AF, King RA: A study of intercurrent conditions observed during pregnancy Am J Obstet Gynecol 87:609–624, 1963 74 Drost RF, Rosemary AS, Sherman HF, et al: Major trauma in pregnant women: maternal/fetal outcome J Trauma 30:574–578, 1990 75 Rothenberger D, Quattlebaum F, Perry J, et al: Blunt maternal trauma, a review of 103 cases J Trauma 18:173–179, 1978 76 Goodwin T, Breen M: Pregnancy outcome and fetal maternal hemorrhage after non-catastrophic trauma Am J Obstet Gynecol 162:665–671, 1990 77 Dahmus M, Sebai B: Blunt abdominal trauma, are there any predictive factors for abruptio placentae or maternal fetal distress? Am J Obstet Gynecol 169:1054–1059, 1993 78 Connolly A, Katz V, Bash K, et al: Trauma and pregnancy Am J Perinatol 14:331–336, 1997 79 Pearlman M, Tintinalli J, Lorenz R: A prospective controlled study of outcome after trauma during pregnancy Am J Obstet Gynecol 162:1502–1507, 1990 80 Pearlman M, Tintinalli J, Lorenz R: Blunt trauma during pregnancy N Engl J Med 323:1609–1613, 1990 81 Committee on Trauma, American College of Surgeons: Advanced Trauma Life Support Program for Physicians Chicago, American College of Surgeons, 1997 82 Buchsbaum H (ed): Penetrating Injury of the Abdomen Trauma in Pregnancy Philadelphia, PA, Saunders, 1979, p 82 83 Awwad J, Azar G, Seoud M, et al: High velocity penetrating wounds of the gravid uterus: review of 16 years of civil war Obstet Gynecol 83:259–264, 1994 Chapter 54 Acute Limb Ischemia in the ICU Population DEJAH R JUDELSON1 • BING SHUE1 • WILLIAM P ROBINSON, III INTRODUCTION Acute limb ischemia (ALI) occurs as a result of sudden inadequate arterial perfusion to an extremity This state of hypoperfusion can result in a number of both local and systemic manifestations These include loss of sensory and motor function of the affected extremity, gangrene leading to sepsis, as well as systemic acid–base disturbances and increased cardiopulmonary stress Unfortunately, ALI also commonly develops in the setting of systemic illness and multiple other medical comorbidities This is especially true in the intensive care unit (ICU) setting in which concomitant conditions such as myocardial infarction, hypercoagulable states, or hypotension requiring pharmacologic support play a role in both the etiology and disease progression [1] Furthermore, revascularization can lead to ischemia–reperfusion injury impacting multiple organ systems and rhabdomyolysis as toxic by-products are reintroduced into the system circulation ALI is a devastating condition with 30-day mortality rates of 15%, and 5-year mortality rates of up to 50% In addition, amputation rates range from 10% to 30% [2] Due to its high rate of complications, ALI is a vascular surgery emergency necessitating expedient evaluation and treatment when indicated This chapter reviews the etiology, evaluation, and management of both upper and lower extremity ALI of the critically ill patient 1 These authors contributed equally to the content in this chapter ETIOLOGY The most common causes of ALI are embolism and thrombosis These two etiologies account for more than 90% of ALI cases [3,4] Less common etiologies include aortic dissection and low flow states secondary to poor cardiac output Embolic events typically originate from a cardiac source The most common condition associated with cardiac emboli is atrial fibrillation but other cardiac sources include myocardial infarction leading to mural thrombus, valvular heart disease, and endocarditis [5,6] Myocardial infarction and endocarditis are especially dreadful causes of ALI as these patients are extremely high-risk surgical candidates due to the coexisting medical comorbidities p 456 p 457 Less common causes of peripheral emboli include paradoxical emboli, aortic mural thrombus, and arterial atheroemboli The presence of a patent foramen ovale allows the thrombus to traverse from the deep venous to arterial circulation leading to an ALI event Paradoxical emboli should be suspected among patients with concomitant deep vein thrombosis and ALI without other cardioembolic risk factors [7] Aortic mural thrombus typically presents as an asymptomatic finding and is commonly seen in the setting of hypercoagulable states such as malignancy or underlying aortic pathology Atheroembolic events occur as a result of disruption of cholesterol plaque This can be related to vessel manipulation from recent interventions such as cardiac or cerebral catheterizations, or peripheral vascular interventions It can also be spontaneous in the setting of significant aortic atherosclerotic disease Atheroemboli typically migrate to the distal vasculature, resulting in distal vessel thrombosis or blue toe syndrome [8] This is in contrast to cardiac sources of emboli which typically lodge at arterial bifurcations due to the change in vessel caliber at these locations Over half of cardioemboli occur in the iliofemoral arteries; the popliteal and brachial arteries are less common areas of embolization [9] Thrombosis of native arteries or previously placed stents or grafts is an increasingly common cause of ALI In situ thrombosis of native arteries occurs among patients with significant preexisting atherosclerotic disease burden Most patients will have risk factors for peripheral arterial disease (PAD) and a portion will have a discernible history of claudication, rest pain, or nonhealing ulcers prior to their acute thrombotic event Common sites of thrombosis correlate with the location of preexisting lesions; these typically include the iliac or superficial femoral arteries [10] Low flow states, hypercoagulability, and endothelial injury lead to disruption of atherosclerotic plaques and thrombus formation This pathophysiology is exacerbated for the critically ill patient who suffers from cardiac compromise, sepsis, and vasopressor dependence Critically ill patients exhibit elevated levels of inflammatory markers such as TNFα which has been shown to affect atherosclerotic plaque stability and increase the risk of thrombosis [11] Critically ill patients also exhibit increased levels of procoagulant activity, especially in the setting of sepsis, heparin-induced thrombocytopenia, and disseminated intravascular coagulation [12] These risk factors also have a significant impact on the patency of previously placed arterial stents or bypasses Therefore, a detailed history of both endovascular and surgical revascularizations should be taken, as the presence of prior interventions will influence both the diagnosis and subsequent management Less common causes of ALI include arterial dissection, non-thrombotic limb ischemia secondary to low flow state, and traumatic arterial injury Arterial dissection can occur spontaneously or as a result of iatrogenic injury secondary to arterial catheterization Non-thrombotic limb ischemia often occurs in the setting of low cardiac output or vasopressor dependence In these instances, the vessels remain patent; however, perfusion is limited by severe vasoconstriction at the arteriole and capillary level [13] Blunt limb distraction injuries such as fractures and dislocations, or penetrating trauma from stabs or gunshot wounds, can lead to arterial injury These can have a delayed presentation, so high-risk patients should be monitored with serial vascular examinations [14] The etiology of an ALI event is critical for determining the subsequent evaluation and management Patients who suffer embolic events typically do not have robust collateral peripheral circulation and can quickly develop permanent deficits if left untreated On the other hand, thrombosis of native vessels is better tolerated due to the preexisting presence of collateral circulation in the setting of PAD However, these patients often require more extensive revascularizations due to a heavier burden of underlying disease Finally patients with non-thrombotic ALI secondary to low cardiac output or vasopressor dependence often improve with treatment of the underlying condition EVALUATION AND DIAGNOSIS OF ACUTE LIMB ISCHEMIA IN THE ICU POPULATION A careful, detailed history and physical examination to elicit the etiology of ALI can have a tremendous impact on the overall management and prognosis for a patient Assessment of the etiology, determining the extent of ischemia and neuromuscular damage, and establishing an appropriate treatment plan must be performed rapidly to minimize the time of ischemia Patients in the ICU are often unable to provide necessary history and participate in a thorough examination; therefore, a thorough examination of their documented history and interviewing the family and critical care staff is often necessary to ascertain a complete picture Medical records should be reviewed for key comorbidities including history of atrial arrhythmias, coagulation disorders, recent percutaneous interventions (i.e., cardiac catheterizations), history of claudication or rest pain, and previously lower extremity interventions should be investigated Examining previous imaging including echocardiograms, computed tomography (CT) scans demonstrating aneurysmal disease or mural thrombus, and prior angiograms should be performed to understand possible etiologies or baseline disease A comprehensive physical examination is compulsory in order to determine the duration and extent of lower extremity ischemia; this will assist in deciding the appropriate management To determine the diagnosis and duration of ALI, the six “Ps” of acute ischemia need to be evaluated—pain, paresthesias, pulselessness, pallor, poikilothermia, and paralysis Bilateral lower extremities should be evaluated to determine if there are signs of underlying chronic PAD such as dependent rubor with elevation pallor, sparse hair growth, dystrophic nail growth, ulceration or nonhealing lesions, and lack of palpable pulses The extent of pallor, coolness, sensory and/or motor deficits, and mottling often indicates the level of arterial obstruction Ischemic symptoms tend to occur one vascular bed distal to the level of obstruction—for example, mottling in the foot and calf implies an obstruction in the superficial femoral artery A careful pulse examination is a reliable method to determine the level of arterial obstruction Bilateral pulse examination should be performed including the femoral, popliteal, dorsalis pedis, and posterior tibial arteries When pulses are nonpalpable, continuous wave Doppler examination should be performed at the bedside Assessing the quality of the pulse and the phasicity of the signal is important in assessing the severity of the occlusion; comparing the affected to the unaffected side is also important Bedside ankle-brachial indices should be performed and compared to the contralateral limb and to any baselines values on the affected limb Additional signs can indicate the pathophysiology A “water hammer” pulse will indicate pulsation against an obstruction such as a recent embolus or thrombus Evaluating for pulsatility, a palpable thrill, or an audible bruit can indicate an iatrogenic pseudoaneurysm or arteriovenous fistula in the setting of recent percutaneous intervention such as central line, arterial stick, cardiac catheterization, or angiogram Whether or not additional imaging is obtained will depend on the severity and acuity of the ischemia Often a physical examination alone is enough to determine location of disease If the patient is stable and the limb is not immediately threatened, additional imaging such as a CT angiogram can precisely identify the location of disease and define the arterial lesions in the affected limb Duplex ultrasound can also be utilized, including at the bedside, to define suspected lesions Such imaging should be readily available within a short timeframe and can be extremely helpful for operative planning In cases where emergent revascularization is indicated and the burden of disease is not clear from clinical evaluation, a formal on-table angiogram in the operating room is a rapid way to define the pathophysiology and plan revascularization TREATMENT OF ACUTE LIMB ISCHEMIA IN THE ICU POPULATION Treatment of ALI in the critical care population requires understanding of the etiology of the ischemia, the viability of the affected limb, and evaluation of the patient’s overall medical status The main treatment modalities of ALI can be divided into medical and operative management Medical management includes systemic anticoagulation and supportive care A heparin infusion, with a goal partial thromboplastin time (PTT) of 60 to 80, is the usual form of systemic anticoagulation that should be initiated immediately to prevent thrombus propagation However, in the cases of heparin-induced thrombocytopenia or heparin allergy, a direct thrombin inhibitor, such as argatroban, can be used In many instances of ALI in a critical care setting, these patients require multiple pressors for blood pressure support Weaning pressors as tolerated, supporting intravascular volume, and placing the patient in a reverse Trendelenburg position to allow for the benefits of gravity, and utilizing a Bair hugger are all supportive measures that can be an effective adjuncts to systemic anticoagulation Treatment of ALI can be guided by the revised Rutherford Criteria proposed by The Society for Vascular Surgery and International Society for Cardiovascular Surgery (SVS/ISCVS) which stratifies levels of severity of ALI (Table 54.1) Category I, or viable, limbs have no sensory or motor deficits These patients are appropriate for observation or systemic anticoagulation, possible angiogram and thrombolysis if appropriate Category II limbs are the most difficult to differentiate, and are separated into two categories, IIa and IIb Category IIa limbs are marginally threatened; they have minimal sensory loss and revascularization can be directed by expeditious angiography after systemic anticoagulation Diagnostic imaging should be performed to guide treatment Duplex ultrasonography, CT angiogram, or magnetic resonance angiogram are all excellent modalities to precisely identify the location and extent of the lesion and help plan intervention Category IIb limbs are immediately threatened with both motor and sensory loss; if these patients do not undergo immediate operative revascularization, they are at a high risk of limb loss The additional time needed to get additional imaging can put them at higher risk of limb loss and often they are taken directly to the operating room without additional studies Category III limbs have sustained irreversible damage; these patients are often insensate with profound paralysis of the limb; primary amputation for pain control and avoidance of sepsis is the mainstay of therapy Attempts at revascularization will not only fail to result in limb salvage, but can be hazardous and precipitate multiorgan system dysfunction due to severe ischemia–reperfusion injury TABLE 54.1 Clinical Categories of Acute Limb Ischemia Category  I Viable Sensory Description/prognosis loss Doppler Doppler Muscle signal signal weakness (arterial) (venous) Not immediately threatened None None Audible Audible Salvageable if promptly treated Minimal (toes) or None None Inaudible Audible II Threatened  a Marginally  b Salvageable with Immediately immediate revascularization More than Mild, toes, moderate associated with rest pain Inaudible Audible III Irreversible Profound, Profound anesthetic paralysis (rigor) Inaudible Inaudible Major tissue loss or permanent nerve damage inevitable Modified from reporting criteria recommended by the Society for Vascular Surgery and the International Society for Cardiovascular Surgery [11], Vascular Surgery, and the North American Chapter p 458 p 459 For critically ill patients, their overall medical status is a guiding factor to determine if they are appropriate for revascularization If the patient is hemodynamically unstable or experiencing profound cardiopulmonary or multisystem organ dysfunction, surgical revascularization or even aggressive endovascular revascularization might precipitate the patient’s demise In these instances, revascularization should be delayed or deferred altogether to save “life over limb.” Systemic anticoagulation, ongoing observation, and conservative measures become the mainstays of treatment In rare instances of category III limb ischemia, primary amputation of a densely ischemic or secondarily infected limb is necessary to prevent failure of other organs OPEN SURGICAL REVASCULARIZATION Open surgical revascularization offers the advantage of immediate reperfusion to the affected extremity Surgical options are dictated by the level of arterial obstruction but generally include a combination of open surgical exploration with Fogarty balloon thromboembolectomy, thromboendarterectomy with patch angioplasty, and bypass The standard open operation for ALI secondary to embolism is surgical exploration with Fogarty balloon thromboembolectomy [15] Successful embolectomy occurs when the arterial intima is not damaged and the distal arterial tree was patent prior to embolization Typically a femoral exploration is performed for suspected aortic, iliac, or femoral thromboemboli while a below the knee popliteal exploration is performed for suspected popliteal or tibial thromboemboli If there is significant preexisting atherosclerotic occlusive disease, an endarterectomy with patch angioplasty may be a necessary adjunct to an embolectomy This is seen commonly with in situ thrombosis of a diseased common femoral artery When thrombosis of significant arterial segment occurs such that flow cannot be adequately restored by a focal thromboendarterectomy, a surgical bypass is generally necessary In these instances, definition of a distal target for bypass with preoperative or on-table angiography is exceedingly helpful The type of bypass is dictated by the clinical scenario For example, when there is bilateral ALI, an aortic occlusion or saddle emboli is suspected If bilateral femoral thromboembolectomy does not adequately restore perfusion, an axillobifemoral bypass may be undertaken ENDOVASCULAR ANGIOGRAPHY AND THROMBOLYSIS Catheter-directed thrombolysis (CDT) for ALI was first introduced in the 1990s [16] The goal of thrombolytic therapy is to restore flow through the occluded arterial segment and, in doing so, to “uncover” the underlying culprit lesion which can then be definitively addressed via standard open surgical or endovascular methods The major advantages of using CDT to restore blood flow in the critical care population is the avoidance of a major open surgical operation and the gradual reestablishment of blood flow to the affected extremity avoiding ischemia–reperfusion injury The most appropriate candidates for thrombolysis are patients with category I or IIa disease, or those with in situ thrombosis Patients with imminently threatened limbs that may lose neurologic function without immediate revascularization are not appropriate candidates as thrombolysis may take 2 to 3 days to restore blood flow The general procedure is as follows: Endovascular access is gained utilizing the Seldinger technique under ultrasound guidance Angiogram is accomplished to elucidate the location and extent of disease The occluded arterial segment is traversed with a guidewire A lysis catheter is placed across the occluded segment A thrombolytic agent is administered as a bolus and a continuous infusion is started Serial laboratory testing as well as neurovascular examinations are done Reimaging is done in 24 hours to ascertain the success of the thrombolysis and angioplasty/stenting can be performed at the conclusion of thrombolytic therapy Monitoring of patients undergoing thrombolysis is critical After the initiation of thrombolysis, patients are returned to the ICU Serial laboratory studies are performed to reduce the risk of a systemic thrombolytic state which would increase the risk of intracerebral hemorrhage (ICH) or other spontaneous bleeding During fibrinolysis, thrombus dissolves and the body recruits coagulation factors to reform the thrombus; therefore coagulation factors and fibrinogen are consumed Laboratory values monitored include fibrinogen, complete blood count, prothrombin time (PT)/international normalized ratio (INR), PTT A decrease in fibrinogen by more than 50% or below 100 mg per dL implies an excessive consumption of coagulation factors leading to an increased risk of ICH Serial PT/INR and PTTs should be assessed to reduce the risk of systemic anticoagulation In the United States, the most commonly used drugs are urokinase and recombinant tissue plasminogen activator usually marketed as alteplase There are two multicenter randomized clinical trials that established the efficacy of CDT [17,18] It should be noted that thrombolytic therapy is most effective for freshly formed thrombus and that the trials demonstrated poor efficacy for patients who had limb ischemia of the duration greater than 14 days Several professional societies have published consensus guidelines on the surgical management of ALI The CHEST guidelines published in 2012 recommend open surgery as compared to CDT (Level 1B evidence), yet CDT is a recommended modality for appropriate patients [19] In 2005, the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on Peripheral Artery Disease (PAD) were published in collaboration with cardiologists, vascular surgeons, vascular medicine, and interventional radiology; their conclusion was CDT is effective and indicated for patients with ALI of fewer than 14 days’ duration [20] There are several adjunctive measures to improve the success of thrombolysis, notably mechanical thrombectomy and aspiration thrombectomy There are two FDA-approved mechanical thrombectomy devices, the AngioJet and the Trellis Thrombectomy system, which can supplement thrombosis by reducing clot burden and more rapidly restoring perfusion While CDT is an attractive option for a select patient group, it is contraindicated for patients at high risk of hemorrhagic complications There are several contraindications to treatment with thrombolytic therapy (Table 54.2) When patients are selected appropriately, approximately 1% of patients will have a life-threatening hemorrhage, most ominously an ICH TABLE 54.2 Absolute and Relative Contraindications to Treatment with Thrombolytic Therapy Contraindications to thrombolytic therapy Absolute Established cerebrovascular event (including TIAs within last 2 mo) Active bleeding diathesis Recent gastrointestinal bleeding (180 mm Hg systolic or >110 mm Hg diastolic Puncture of noncompressible vessel Intracranial tumor Recent eye surgery Relative minor Hepatic failure, particularly those with coagulopathy Bacterial endocarditis Pregnancy Diabetic hemorrhagic retinopathy TIA, transient ischemic attack Modified from Working Party on Thrombolysis in the Management of Limb Ischemia: Thrombolysis in the management of lower limb peripheral arterial occlusion—consensus document J Vasc Interv Radiol 7:S337–S349, 2003 POSTOPERATIVE CARE Postoperative management of the revascularized acute limb ICU patient focuses on resuscitation and anticoagulation These patients must be aggressively resuscitated to prevent systemic complications of ischemia– reperfusion injury Additionally, systemic anticoagulation must be continued as rethrombosis or recurrent embolism occurs among 6% to 46% of patients [21,22] MANAGEMENT OF ISCHEMIA– REPERFUSION INJURY AND RHABDOMYOLSIS Ischemia–reperfusion injury may result in limb and multisystem organ dysfunction As ischemic muscle is reperfused, cellular edema and interstitial fluid shifts may occur Symptoms include pain, hypoesthesia, and weakness of the involved limb Rhabdomyolysis may occur; as the muscle groups are reperfused, the ischemic muscle is broken down and by-products are released into the bloodstream—notably myoglobin and potassium The elevated potassium can lead to cardiac arrhythmias and the myoglobin can cause acute kidney injury Treatment is mainly supportive, aggressive fluid resuscitation with an isotonic fluid; occasionally, a bicarbonate drip is indicated to alkalinize the urine In cases of severe hyperkalemia, calcium carbonate may help to stabilize the cardiac myocyte membrane while IV insulin and an ampule of D50W can help to redistribute potassium into cells Patients can become profoundly acidotic and in rare cases require hemodialysis [23] COMPARTMENT SYNDROME Compartment syndrome occurs when the reperfused muscle swells inside fixed factual compartments When compartment pressures exceed 25 to 30 mm Hg, the extravascular pressure then exceeds capillary pressure and blood flow is restricted leading to tissue infarction The first signs are pain, numbness, and paresthesias Of the four compartments to the distal lower extremity, the anterior compartment is the most susceptible to compartment syndrome Symptoms are focused around deep peroneal nerve injury and include numbness to the first web space and decreased foot dorsiflexion Management is operative; immediate fourcompartment fasciotomies are necessary to prevent any further nerve or muscle damage UPPER EXTREMITY ACUTE LIMB ISCHEMIA Upper extremity ALI is far less commonly encountered than lower extremity ALI and typically results from cardioembolic events In situ thrombosis is uncommon since atherosclerotic disease is rare in the upper extremities Emboli typically lodge at the brachial or axillary artery The clinical presentation can be similar to lower extremity ALI; however, more commonly, patients report decreased sensation and strength without pain Upper extremity ALI can be diagnosed with history and physical examination alone, although duplex imaging can confirm the diagnosis CT angiogram of the chest and upper extremities is a useful adjunct for determining the anatomic location of the occlusion and to assist with operative planning [24,25] First-line treatment for upper extremity ALI is anticoagulation Most patients report a significant improvement in symptoms with anticoagulation alone The upper extremities have robust collateral circulation compared to the lower extremities, so the risk for tissue loss is lower However, patients who develop upper extremity ALI are at risk of developing chronic arm claudication or even severe neuromuscular dysfunction with incidence rates of 50% Therefore, patients who are medically able to tolerate surgery or at risk of loss of upper extremity function should undergo revascularization [26] Surgical treatment of upper extremity ALI is generally performed through a brachial artery exploration and Fogarty balloon thromboembolectomy The procedure can be performed under local or regional anesthesia with sedation if the patient is unable to tolerate general anesthesia Postoperatively, the patient should remain anticoagulated and undergo serial neurovascular examinations Upper extremity compartment syndrome is less common, so prophylactic fasciotomies are rarely performed However, careful neurologic monitoring is indicated to identify a developing compartment syndrome In addition, a full workup including cardiac echocardiogram and CT angiography of the chest should be performed to determine the etiology of the ALI event Patency rates for upper extremity revascularizations are high and amputation rates are negligible However, studies have shown overall mortality rates of patients with upper extremity ALI to be as high as 50% over 5 years due to the incidence of multiple medical comorbidities in the population RECOMMENDATIONS In general, recommendations are as follows: Systemic anticoagulation is a mainstay in the management of ALI in all patients to minimize propagation of thrombosis and prevent recurrent events after revascularization Immediate surgical revascularization is indicated for patients with an immediate threatened limb, Rutherford classification IIb, to avoid an unacceptable delay in reperfusion In patients with a marginally threatened limb, CDT is an appropriate treatment modality Primary amputation is indicated for patients with an irreversibly ischemic limb In hemodynamically unstable patients or those with severe multisystem dysfunction, the mortality risk of revascularization may be prohibitive In these patients, conservative medical management with a “life over limb” approach may be appropriate REFERENCES Dormandy J, Heeck L, Vig S: Acute limb ischemia Semin Vasc Surg 12:148–153, 1999 Genovese EA, Baril DT, Taha AG, et al: Risk factors for long-term mortality and amputation after open and endovascular treatment of acute limb ischemia Ann Vasc Surg 30:82–92, 2016 Abbott WM, Maloney RD, McCabe CC, et al: Arterial embolism: a 44 year perspective Am J Surg 143:460–464, 1982 Elliot JP Jr, Hageman J, Szilagyi D, et al: Arterial embolization: problems of source, multiplicity, recurrence, and delayed treatment Surgery 88:833–845, 1980 Menke J, Luthje L, Kastrup A, et al: Thromboembolism in atrial fibrillation Am J Cardiol 105:502–510, 2010 Asinger RW, Mikell FL, Elsperger J, et al: Incidence of left-ventricular thrombosis after acute transmural myocardial infarction Serial evaluation by two-dimensional echocardiography N Engl J Med 305(6):297–302, 1991 Ward R, Jones D, Haponik E: Paradoxical embolism: an underrecognized problem Chest 108:549–558, 1995 Rhodes JM: Cholesterol crystal embolism: an important “new” diagnosis for the general physician Lancet 347:1641, 1996 Cambria RP, Abbott WM: Acute arterial thrombosis of the lower extremity Its natural history contrasted with arterial embolism Arch Surg 119:784–787, 1984 10 Bentzon JF, Otsuka F, Virmani R, et al: Mechanisms of plaque formation and rupture Circ Res 114:1852–1866, 2014 11 Gopalakrishnan M, Silva-Palacios F, Taytawat P, et al: Role of inflammatory mediators in the pathogenesis of plaque rupture J Invasive Cardiol 9;26(9):484–492, 2014 12 Boldt J, Papsordf M, Rothe A, et al: Changes of the hemostatic network in critically ill patients—is there a difference between sepsis, trauma, and neurosurgery patients? Crit Care Med 28(2):445–450, 2000 13 Ljungman C, Adami HO, Bergqvist D, et al: Time trends in incidence rates of acute, non-traumatic extremity ischaemia: a population-based study during a 19-year period Br J Surg 78:857–860, 1991 14 Engelmann DT, Gabram SGA, Allen L, et al: Hypercoagulability following multiple trauma World J Surg 20:5–10, 1996 15 Fogarty TJ, Cranley JJ, Krause RJ, et al: A method for extraction of arterial emboli and thrombi Surg Gynecol Obstet 116:241–244, 1963 16 Ouriel K, Shortell CK, DeWeese JA, et al: A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acuteperipheral arterial ischemia J Vasc Surg 19(6):1021–1030, 1994 p 461 p 461 17 STILE investigators: Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity The STILE trial Ann Surg 220(3):251–266, 1994; discussion 266-8 18 Ouriel K, Veith FJ, Sasahara AA: A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators N Engl J Med 16;338(16):1105–1111, 1998 19 Alonso-Coello P, Bellmunt S, McGorrian C, et al; American College of Chest Physicians: Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest 141[2, Suppl]:e669S–e690S, 2012 20 Hirsch AT, Haskal ZJ, Hertzer NR, et al: ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation Circulation 21;113(11):e463–e654, 2006 21 Henke PK: Contemporary management of acute limb ischemia: factors associated with amputation and in-hospital mortality Semin Vasc Surg 22:34–40, 2009 22 Fukuda I, Chiyoya M, Taniquchi S, et al: Acute limb ischemia: contemporary approach Gen Thorac Cardiovasc Surg 63:540–548, 2015 23 Creager M, Kaufman JA, Conte MS: Clinical practice Acute limb ischemia N Engl J Med 366:2198–2206, 2012 24 Eyers P, Earnshaw JJ: Acute non-traumatic arm ischaemia Br J Surg 85:1340–1346, 1998 25 Joshi V, Harding GE, Bottoni DA, et al: Determination of functional outcome following upper extremity arterial trauma Vasc Endovasc Surg 41:111–114, 2007 26 Hernandez-Richter T, Angele MK, Helmberger T, et al: Acute ischemia of the upper extremity: long-term results following thrombembolectomy with the Fogarty catheter Langenbecks Arch Surg 386:261–266, 2001 Chapter 55 Palliative Surgery in the Intensive Care Unit LAURA A LAMBERT Surgeons play an essential role in providing optimal palliative care for patients and families Palliative surgery is best defined as the deliberate use of a procedure in the setting of incurable disease for the intention of relieving symptoms, minimizing patient distress and improving quality of life [1] Because the goal of the surgery is not curative but rather the alleviation of suffering, the decision to proceed requires not only technical judgment, but also a sincere understanding of the patient’s symptoms, the clinical, emotional, psychological, and social situation and the goals of care of both the patient and family Typically, surgical outcomes are measured in terms of morbidity and mortality However, given the stated goals of palliative surgery, morbidity and mortality are not necessarily the most effective measures of success Rather outcomes such as the presence and duration of patient-acknowledged symptom relief may be much more salient [2,3] Treatment plans which effectively achieve these goals must balance the potential benefit of durable symptom relief with the risk of treatment toxicity, while considering the patient’s medical condition, performance status, prognosis and life expectancy, other medical treatment options and cost-effectiveness The complex decisions required to manage these patients can challenge even the most experienced surgeons For patients with an incurable disease who are in the intensive care unit (ICU), the role of surgery in the management of their care may be even less clear than for patients whose clinical condition does not require intensive care This lack of clarity is often multifactorial and includes a potentially more limited survival time, the patient’s ability to undergo anesthesia safely, the magnitude of the surgery required to address the problem, whether or not the surgical problem is the cause or effect of the patient’s critical condition, the likelihood of success of the surgery, the risk of complications, the availability of other treatment options, and the overall goals and wishes of the patient and family Furthermore, the fact that most surgical procedures tend to inflict some pain initially adds an additional element of complexity to this equation This chapter reviews the current status of, and evolving approach to, palliative surgery, as well as the management of some of the more common indications for palliative surgery consults in the ICU It will also address ways to improve communication and decrease moral distress among surgeons related to interactions with patients and families in the end of life setting CURRENT STATUS OF PALLIATIVE SURGERY The greatest experience with palliative surgery revolves largely around its use in patients with advanced malignancies Palliative surgical consultations have been reported to represent up to 40% of all inpatient surgical consultations at major cancer cancers [4] In fact, studies from two stand-alone cancer centers, the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, and the City of Hope Cancer Center in Duarte, California, showed that 6% and 12.5% of all surgical procedures were performed for palliation, respectively [5,6] In the largest study ever looking at outcomes for palliative surgery from the MSKCC, Miner et al [6] reported on the results of 1,022 palliative surgeries performed over the course of 1 year from July 2002 to June 2003 During that time, palliative interventions exceeded the combined number of esophagogastrectomies, gastrectomies, pancreatectomies, and hepatectomies performed The most common indications for palliative surgery consults included gastrointestinal obstruction (34%), neurological symptoms (23%), pain (12%), dyspnea (9%), and jaundice (7%) Symptom improvement or resolution was achieved in 80% of patients by 30 days with a median duration of symptom control of 135 days The primary symptom recurred in 25% of patients and treatment of additional symptoms was required in 29% The 30-day morbidity and mortality associated with the palliative procedures was 29% and 11%, respectively Not unexpectedly, postoperative complications had a negative impact and reduced the likelihood of symptom improvement to 17% Median survival from the time of the palliative procedure was 194 days The authors concluded that there is an opportunity for a significant number of patients to achieve durable improvement in quality of life given the median symptom-free survival of 135 days and a median survival of 194 days Others have shown similar findings including an improved overall survival associated with symptom improvement in one study [1,6–8] (Table 55.1) p 461 p 462 TABLE 55.1 Outcomes in Palliative Surgery Surgical Surgical Surgical Symptom procedure morbidity mortality improvement Author/Year Consultations (%) % % % Krouse et al [5] 240 170 (71) 70 (29) 25.9 10 12.2 NR Miner et al [6] 1,022 713 (70) 309 (30) 29 11 80 Podnos et al [8] 106 35 (33) 17 NR Miner et al [12] 227 106 (46.7) 16.7a 3.9 90.7 Badgwell et al [7] 202 86(43) 35 (17) 43 67 aGrade 3/4 major surgical morbidity only NR, not reported; QOL, quality of life Because the primary goal of palliative surgery is to improve quality of life or relieve symptoms, it has been argued that traditional surgical outcome measures such as morbidity, mortality, disease recurrence, and survival are not sufficient to determine the success or failure of a palliative intervention While understanding the risks (morbidity and mortality) of a procedure is important, it is equally important to assess the potential benefits Because the impact of different specific palliative interventions can vary significantly—i.e., the impact of an indwelling catheter for a refractory pleural effusion may be significantly greater than that of a venting gastrostomy—it is difficult to quantify and compare the benefit of different procedures One approach to addressing this issue is the use of patient-reported outcomes [2] Patient-reported outcomes are surveys used to assess a patient’s well-being from the patient’s perspective These surveys often include health-related quality of life or symptom assessment and are appropriate for assessing a surgical intervention intended to improve quality of life or relieve symptoms However, currently, there are no validated quality of life instruments solely focused on palliative surgical outcomes, making it difficult to identify patients who benefit from these interventions, and the use of patient-reported outcomes in palliative surgery is limited [1,9] One prospective pilot study using standardized, validated instruments demonstrated the challenges of interpreting outcomes after palliative interventions due to the continued loss of global health status during the end of life [1] In a second study, the authors found that the death rate of 40% prior to study completion at 90 days post-procedure had a significant impact on the questionnaire response, clearly demonstrating the challenge of measuring the success of interventions in actively dying patients [10] However, validating these interventions is essential given the high proportion of interventions that are palliative and the relatively high mortality rate which can significantly impact the overall operative mortality of an institution In this age of quality-based reimbursement, this impact cannot be ignored and a means of incorporating palliative intent as a specific data element for comparing surgical outcomes needs to be devised As with any treatment—surgical or medical—another opportunity for improving the outcomes of palliative surgery is through optimal patient selection The end of life setting presents a unique set of circumstances requiring difficult decisions with limited data Using an open-ended questionnaire, Collins et al [11] investigated the patient reasoning behind treatment choices after palliative surgical consultation Of 98 patient enrolled in this prospective study, 54 were treated nonoperatively and 44 were treated with surgery Symptom relief and/or quality of life was the reason for the treatment choice in only 46% of patients, and 40% said that they made their choice based on the doctor’s recommendation Twenty percent opted for care in hopes of prolonging their lives This study demonstrates the powerful influence of the physician in the decision-making of patients at this stage of life, and the need for clear communication about goals and expectations between all parties Another critical party in these decisions is the patient’s family To help surgeons navigate this intriguing and often challenging dynamic, Miner et al [1] have previously proposed and studied the use of the “palliative triangle” as an approach to improving patient selection and patientacknowledged outcomes for palliative surgery (Fig 55.1) Through the dynamics of the triangle, the patient’s complaints, values, and emotional support are taken into account while weighing the medical and surgical alternatives In addition, the triangle offers an opportunity to learn about and address a patient’s and/or family’s expectations regarding the intent of the proposed procedure helping to moderate any incongruent expectations between surgeon, patient, and family members Miner et al [12] prospectively investigated the use of the palliative triangle technique during palliative surgery consultation in 227 patients with symptomatic, advanced, incurable cancer This is one of the few studies that included both patients who did and did not undergo a palliative procedure More than half (53.3%) of the patients did not undergo a procedure Reasons cited included low symptom severity, decision for nonoperative palliation, patient preference, and concerns about complications Of the patients who did undergo a palliative procedure, 90.7% reported symptom resolution or improvement The morbidity and mortality associated with these procedures was 20.1% and 3.9%, respectively The median survival was 212 days The authors concluded that use of the palliative triangle can help improve patient selection which is associated with significantly better symptom resolution and few postoperative complications compared with previously published results The authors have also postulated that building this strong relationship may explain the observation of high patient satisfaction toward surgeons after palliative operation—even if there is no demonstrable benefit [1] p 462 p 463 FIGURE 55.1 The palliative triangle The palliative triangle facilitates interactions between patients, families, and surgeons, and helps guide patients to the best decisions regarding palliative surgery (From Thomay AA, Jaques DP, Miner, TJ: Surgical palliation: getting back to our roots Surg Clin North Am 89:33, 2009; permission requested.) MANAGEMENT OF COMMON PALLIATIVE SURGERY CONSULTATIONS This section reviews management options for some common palliative surgery consults in ICU patients While this list is not comprehensive, it does offer a framework for approaching any palliative surgery situation Management of other specific surgical problems encountered in the ICU is discussed elsewhere in the text When surgery is not an option, it is important to know how to palliate common symptoms in patients with advanced illness (see Chapter 35) Bowel Obstructions One of the most common palliative surgical consults is for bowel obstruction Bowel obstructions can occur at any level of the gastrointestinal tract from the stomach to the rectum Depending upon the etiology (adhesions, cancer, stricture), the management can vary from nonoperative nasogastric decompression and bowel rest to bowel resection and/or intestinal diversion In the setting of advanced illness such as cancer, and for patients who are in the ICU, management can be complicated and multimodal Regardless of the etiology, initial management of a patient with a bowel obstruction should include appropriate intravenous fluid resuscitation based upon the degree of dehydration and the site of the obstruction and correction of any metabolic abnormalities The bowel should be decompressed with a nasogastric tube if the patient is vomiting, and the patient should not be allowed to eat or drink to decrease gastrointestinal stimulation and secretions Serial abdominal examinations for signs or symptoms of peritonitis are essential Imaging studies, such as an abdominal series and/or a computed tomography scan of the abdomen and pelvis, are helpful to determine the level and nature of the obstruction They can also demonstrate the presence of extraluminal air suggesting a perforation, and the presence or absence of ascites Patients who are hemodynamically stable, who do not have peritonitis and have a normal or only mildly elevated white blood count (especially in the setting of dehydration), can initially be monitored closely (with the measures mentioned above) and given a chance for the obstruction to resolve without surgery Signs and symptoms of peritonitis or an imaging study suggesting a “closed loop” obstruction (a loop of intestine twisted around its mesentery) are indications for a more urgent surgical intervention Often the exact nature of that intervention cannot be determined until the time of surgery—adding an additional element of cognitive and emotional uncertainty that must be borne by the patient, family, and surgeon Surgery may include resecting the section of obstructed intestine if it appears to be an isolated site, performing an intestinal bypass if the site cannot be resected, performing a diverting ostomy (either small or large bowel depending on the location of the obstruction), or placing a decompression gastrostomy tube for venting the stomach if the obstruction cannot otherwise be relieved In the setting of a malignancy, these operations can be challenging, both technically as well as with regard to the decision-making, and they pose a high risk for perioperative morbidity and mortality [13] If the obstruction is located in the rectum or rectosigmoid colon or duodenum, it is reasonable to consider an endoscopic stent placement rather than surgery as the initial intervention While the presence of carcinomatosis has been shown to increase the risk of failure of endoscopic stent placement for colonic obstruction, there is a 77% to 85% success rate [14–17] For patients with a limited prognosis, an opportunity to avoid an operation that could involve either an intestinal diversion and ostomy or venting gastrostomy tube is an important consideration For patients in whom it is felt that surgical or endoscopic relief of the bowel obstruction is not feasible, it is reasonable to evaluate them for a percutaneous endoscopic gastrostomy tube placement for gastric drainage Surgical decision-making becomes more challenging for end of life patients who are not stable and require a decision regarding an emergent operation It may be argued that this is not a purely palliative surgery consult as the surgical intervention has the potential to rescue the patient from a life-threatening complication of their life-limiting illness On the other hand, it may also be considered palliative as it will not cure the patient of the underlying disease process Needless to say, this is often an emotionally charged time, even for patients with long-standing illness such as advanced cancer, because they are now faced with the imminent risk of dying A recent study by Cauley et al [18] reported the results of a retrospective cohort study of 875 disseminated cancer patients undergoing emergency surgery for obstruction (n = 376) or perforation (n = 499) Of the 376 patients who underwent emergency surgery for obstruction, the 30-day mortality rate was 18% with a 41% morbidity rate and 60% were discharged to an institution Dependent functional status and ascites were independent preoperative predictors of death at 30 days Postoperative predictors of mortality included respiratory and cardiac complications Only 4% of patients had “do not resuscitate” orders in place prior to surgery Further underscoring the dismal prognosis in this particular situation, a study by Pameijer et al [19] showed that patients with metastatic cancer who presented with obstructive symptoms had a median survival of 3 months regardless of operative or no-operative management While most patients will survive the initial operation, a substantial number will die soon after the surgery and many experience postoperative complications, reoperations, stays in nursing homes, or hospital readmissions Such events clearly impact the patient’s quality of life While these data are helpful for surgeons and caregivers to advise patients of the risks of surgery, set expectations for the postoperative experience, discharge location and overall survival, both at the time when the decisions is made for surgery and if complications occur, important data regarding whether the goals of the patients and families were met and whether or not they would make the same choice again are still severely lacking at this time p 463 p 464 Gastric Outlet and Duodenal Obstruction Obstruction of the gastric outlet and/or duodenum is another common indication for palliative surgical consultation Most patients present with nausea and vomiting of undigested food Physical examination usually demonstrates upper abdominal distension and tympani Imaging studies often reveal a distended stomach with retained enteric contents As with a lower intestinal obstruction, acute symptoms should be initially managed with nasogastric decompression, bowel rest, and intravenous resuscitation, including aggressive electrolyte repletion (For patients with chronic gastric outlet obstruction, special attention should be paid to chloride replacement which is lost in large quantities with emesis of gastric secretions.) If significant weight loss is present or if there may be a delay in definitive treatment, it may be reasonable to consider parenteral nutrition while planning additional palliative measures Options for managing upper gastrointestinal obstructions include intraluminal stenting, surgical bypass, and decompression gastrostomy with possible feeding jejunostomy Similar to colonic stenting, the potential benefits of duodenal stenting include immediate palliation of nausea and vomiting with a less invasive procedure than surgical bypass and earlier return to oral nutrition [20,21] (Restoring a person’s ability to eat and drink is one of the most rewarding palliative interventions.) Stents may be particularly useful for patients with advanced malignancy, who are at increased risk of surgical complication or who are technically inoperable Flexible self-expanding metal stents can be placed using endoscopic or fluoroscopic techniques Stenting has been shown to provide a comparable survival outcome and equivalent morbidity and mortality to surgical bypass [22] In a systematic review of the literature from 1990 to 2008 comparing endoscopic stenting with open surgical bypass, Ly et al [22] found that endoscopic stenting was more likely to result in tolerance of oral intake (OR 2.6; p = 0.002) in a shorter period of time (mean difference of 6.9 days, p < 0.001) with a shorter hospital stay (mean difference 11.8 days, p < 0.001) as compared with open surgical bypass Similar findings were reported by Zheng et al [23] Based upon these findings, it is also likely that stenting is less expensive than surgical bypass The major limiting factor for the endoscopic approach is being unable to pass the scope through the obstruction The major complications reported are gastric ulceration, bowel perforation, biliary obstruction, stent dysfunction, and stent migration Stent placement would be contraindicated in patients with multiple levels of intestinal obstruction and should be considered carefully for patients with peritoneal carcinomatosis who are at risk of more distal obstructions For patients in whom stenting is not an option, surgical bypass can relieve both the symptoms of the obstruction and allow the patient to resume enteral nutrition Surgical bypass, most commonly in the form of a gastrojejunostomy, can either be performed laparoscopically or through a relatively small upper midline incision The estimated risk of morbidity and mortality from these procedures is 25% to 60% and 0% to 25%, respectively [22,23] While surgical bypass is usually technically successful, patient selection with regard to preoperative nutritional status and life expectancy is imperative to the palliative success of this approach For example, in addition to general surgical risks such as bleeding or infection, a patient with chronic gastric outlet or duodenal obstruction who is malnourished is at increased risk of a leak from the intestinal anastomosis Other potential complications specific to gastric bypass include dumping syndrome, alkaline reflux gastritis, and delayed gastric emptying Placement of a gastrostomy tube for decompression is another option for palliation of gastric outlet, duodenal and nonoperable small bowel obstruction or profound gastrointestinal dysmotility from carcinomatosis Gastrostomy tubes can be placed either endoscopically, fluoroscopically, or surgically (either laparoscopic or open) Decompression gastrostomy tubes provide patients the ability to drain the stomach as for nausea and to avoid vomiting It also allows them to drink liquids and eat some soft foods for pleasure and comfort It does not allow for the enteric maintenance of nutrition Many endoscopists, surgeons, and interventional radiologists are leery of placing gastrostomy tubes in the setting of malignant ascites They are concerned about the risk of infecting the ascites, intraperitoneal leakage from the stomach due to poor apposition to the anterior abdominal wall, as well as leakage of ascites from around the tube There is a growing body of literature demonstrating the safety of placing gastrostomy tubes in patients with malignant ascites from a variety of tumors [24–26] Paracentesis prior to or concurrent with gastrostomy placement is advisable Also, consideration of placing a peritoneal drainage catheter at the time of gastrostomy may also help lower any risk associated with the ascites As gastrostomy may be the only viable palliative option for these patients, all efforts to manage the ascites and increase the safety of gastrostomy placement are warranted Ascites and Pleural Effusions Two other common palliative surgical consultations for the ICU patient are for management of peritoneal ascites and pleural effusions Unfortunately, while the symptom relief from a paracentesis or thoracentesis is immediately helpful, it is usually temporary For patients requiring frequent drainage of either the peritoneal or pleural cavity, a tunneled intraperitoneal catheter that can be intermittently connected to a self-contained vacuum drainage system is a helpful option [27] These catheters can be placed under local anesthesia either by interventional radiology or surgery Another option for the treatment of malignant ascites is hyperthermic intraperitoneal chemotherapy (HIPEC) A number of studies have demonstrated the efficacy of HIPEC in the treatment of malignant ascites [28,29] As there is often no cytoreductive surgery involved, this can be done laparoscopically, which, although less invasive, still does require general anesthesia This option may be less appropriate for patients who are in the ICU and should typically be reserved for patients with a longer life expectancy and higher performance status Similarly, an alternative treatment option for patients with recurrent malignant pleural effusion is pleurodesis Pleurodesis can be performed using a number of different agents including talc, chemotherapy, or abrasion The intent is to create an inflammatory reaction within the pleural cavity resulting in fusion of the visceral and parietal pleura, thereby obliterating the peritoneal space and the opportunity for fluid reaccumulation Talc has been shown to be the most effective pleurodesis agent in randomized clinical trials with reported success rates of 60% to 90% [30] However, although these procedures can be done at the bedside, they do require the placement of a larger bore chest tube and can be rather painful [31] Intestinal Perforation Intestinal perforation due to a complication of a life-limiting illness can be one of the most challenging consults at the end of life in the ICU setting Unlike patients with a bowel obstruction, patients with a perforated viscus are more likely to have pain from peritonitis, adding another element of consideration to both the decision-making process and the emotional charge of the situation Currently, there is a small, but growing body of literature supporting the use of nonsurgical management for bowel perforation in select (hemodynamically stable, non-peritonitic) patients Some studies have reported a greater than 90% success rate in nonsurgical management of patients with perforated diverticulitis [32] Unfortunately, for patients with advanced cancer, who are not stable or who have peritonitis, and who undergo emergent surgery, the outcomes are even worse than for those with a bowel obstruction In the study by Cauley et al [18], among the 499 patients who underwent surgery for perforation, the 30-day mortality was 34% with a morbidity rate of 67%, and 52% of patients were discharged to an institution Independent preoperative predictors of death at 30 days included renal failure, septic shock, ascites, dyspnea at rest, and dependent functional status Postoperative respiratory complications and advanced age (greater than 75 years) were also predictors of mortality Similar to the patients who presented with a bowel obstruction, only 4% had a “do not resuscitate” order in place prior to surgery despite the advanced nature of their cancer Again, while data from studies like this may help surgeons answer questions about the risks associated with surgical interventions and guide some patients in their decisions, in a society in which people are not prepared for dying, these data can often make things harder for the surgeon who is asked to operate in the face of such overwhelming odds p 464 p 465 Avoiding Moral Distress Caught between patients who are suddenly facing their own mortality and families who are not ready to let go, the smallest amount of hope that surgery offers makes even the most daunting risks seem worth taking This is a setting in which surgeons, and other affiliated providers, experience moral distress Professionalism demands that the surgeon make a sincere effort to understand and be understanding of the perspective of the patient and family—without realistic expectation of the same in return This can be particularly challenging when the surgeon is busy or when these events occur in the middle of the night In the name of “full disclosure and informed consent,” some surgeons paint as bleak a picture as possible for the patient and family, in an effort to dissuade the patient from choosing surgery When, despite these efforts, the patient and family ask for surgery, some surgeons expect a tacit agreement that the patient will endure to the end, including any additional procedures or maneuvers that may be required—surgery, feeding tubes, tracheotomy, dialysis, rehabilitation, etc There is often a sense of frustration and betrayal on the part of the surgeon when within a few days after the index surgery, the family decides to stop any further life-prolonging care It is for this reason that understanding the perspective of the patient and family is critical to both outcome of the encounter and the surgeon’s wellbeing (see Chapter 36) It is for challenging situations like this that the palliative triangle can be most helpful As described above, use of the palliative triangle can help create a space in which all three parties are given a chance to express their concerns and be heard It is also significant in that it helps the surgeon separate the patient’s goals and understanding from that of the family’s and vice versa It also gives the surgeon’s goals and understanding equal weight in the decision-making However, success of the palliative triangle approach is predicated on the surgeon’s mind-set If the surgeon truly hopes to influence the behavior of the patient and the family in an efficient and professional manner, an outward mind-set, in which the patient’s and family’s objectives matter like the surgeon’s objectives matter, is essential The Arbinger Influence Pyramid is a proven leadership approach to influencing behavior which is readily applicable to patient–family–physician interactions [33] (Fig 55.2) Starting at the base of the pyramid, the surgeon must adjust his or her mind-set to an outward mind-set in which the goals and objectives of the patient and family matter equally with his or hers The outward mind-set will then facilitate building a relationship with the patient and those who have influence on the patient—namely the family Building this relationship can happen simply through introductions and a sincere expression of empathy for the challenging situation which the patient and family are facing Next, the surgeon needs to listen and learn what the patient and family know about the situation and what their hopes, goals, and objectives are Afterward, the surgeon can teach the patient and family what they need to know, correct any misconceptions, answer questions, review the risks, benefits, and indications for surgery and the alternative options, and make an engaged recommendation based upon the goals of all three parties From there, the surgeon, patient, and family can usually come to a mutually agreed upon goal and care plan (see “structured family meetings” in Chapter 34) There are a few key points about using the Influence Pyramid First, time and effort spent at the lower levels of the pyramid is what ensures effectiveness at the higher levels Second, the solution to a problem at one level of the pyramid will be found in spending more time at a lower level of the pyramid Third, the effectiveness at each level of the pyramid depends on the effectiveness of the level below and ultimately on the deepest level of the pyramid—the mind-set FIGURE 55.2 The Arbinger Influence Pyramid The Influence Pyramid is a proven framework designed to help influence behavior and improve results beginning with a shift in mind-set (Adapted from The Arbinger Institute: The Anatomy of Peace—Resolving the Heart of Conflict Oakland, CA: Berrett-Koehler Publishers, Inc, 2015, with permission.) BENEFITS OF EARLY PALLIATIVE CARE CONSULTS Initiation of a palliative surgery consultation is an appropriate time for initiating a palliative care consultation as well, if one has not already been obtained While some physicians and patients view a palliative care consult as “giving up,” this could not be further from the truth Unlike hospice (which is a medical insurance benefit that requires a life expectancy of less than 6 months if the life-threatening disease is untreated and the patient forgoes disease-directed treatment), all patients with symptoms from an illness or its treatment benefit from palliative care While most patients’ symptoms can be adequately palliated by their primary physician (either their primary care provider or primary specialist), advanced, life-threatening illnesses, such as cancer, can pose additional challenges in terms of physical, emotional, psychological, spiritual, and social symptomatology It is preferable to initiate a palliative care consultation before these symptoms become unmanageable, as this will make it seem less like “giving up” when there is an acute need for the expertise of a palliative care provider p 465 p 466 One way to overcome the inertia of referring patients to palliative care early is to normalize it Many institutions have made it part of their cancer center’s protocols to refer all patients with advanced cancer to palliative care from the initial cancer center visit This allows the palliative care team to tell patients and their families that all patients with advanced cancer are seen by palliative care and that it is simply part of the multidisciplinary team effort to care for the patient and family Similar efforts can also be made in the ICU for selected patients (see Chapter 33) Palliative care consultation can help take some of the burden off the primary specialist for conducting the harder conversations around goals of care and advanced directives and allowing them to focus on the plan of treatment Having these difficult conversations early is essential for the comprehensive management of life-threatening illness and should not be avoided due to provider unease Earlier palliative care involvement can also help with the transition to hospice when appropriate Recognition of that time may come first to the primary specialist when further illness-directed treatment is likely to do more harm than good to the patient and family when they decide that the burden of treatment is not worth the limited potential for more time Unfortunately, it is not infrequent that both parties do not arrive at this recognition at the same time The treating physician may find it easier to continue to treat the patient who insists on continuing to “fight” even knowing that “fighting” may take time away from the patient Similarly, the patient may find it easier to keep doing treatment rather than “disappoint” the treating physician by stopping With an early palliative care intervention, conversations about hospice as a potential option can be started early leaving plenty of time to correct any misconceptions Patients and families can learn that the mission of hospice is neither to prolong life nor hasten death but to provide comfort and dignity and optimize the quality of life that is left It can help dispel other concerns such as losing contact with the primary care provider, not being allowed to go to the hospital if necessary, not being allowed to come off hospice if a new treatment becomes available, etc They will also learn that hospice provides support to both the patient and the family through an interdisciplinary team of providers including physicians, nurses, social workers, chaplains, and volunteers Hospice also helps families prepare for their loss and provides bereavement programs after the death It has also been shown that patients who understand their poorer prognosis near the end of life are unlikely to choose invasive treatments that can prolong suffering and time away from home [34–36] A palliative care consultant who is an expert in communication can be a huge help with this aspect of the patient’s care (see Chapter 34) CONCLUSIONS Surgery and surgeons are an essential component of comprehensive palliative care Surgical decision-making for palliation in the end of life setting is complex and challenging These situations often demand the highest level of surgical judgment In addition to consideration of the risks in terms of the traditional surgical outcomes measures such as morbidity and mortality, decisions must also include end points such as the probability and duration of symptom resolution, the impact on overall quality of life, pain control, and cost-effectiveness Regardless of the indication for a palliative surgery consultation, deliberations over surgical palliation must consider the clinical condition and performance status of the patient, the prognosis of the disease process, the availability and success of nonoperative management, and the individual patient’s quality of life, life expectancy, and goals of care Clinicians must remain flexible to meet the ever-changing needs of the patient and family Use of a tool such as the palliative care triangle and the Influence Pyramid can facilitate the difficult conversations that often accompany these consults and help guide the patient, family, and surgeon to make the optimal choice for the patient Early palliative care consultation has also been shown to improve outcomes in terms of quality of life, overall survival and cost-effectiveness, as well as mitigating some of the moral distress that can arise in these emotionally charged situations REFERENCES Miner TJ, Jaques DP, Shriver CD: A prospective evaluation of patients undergoing surgery for the palliation of an advanced malignancy Ann Surg Oncol 9(7):696–703, 2002 Badgwell B, Bruera E, Klimberg SV: Can patient reported outcomes help identify the optimal outcome in palliative surgery? J Surg Oncol 109(2):145–150, 2014 Blakely AM, Heffernan DS, McPhillips J, et al: Elevated C-reactive protein as a predictor of patient outcomes following palliative surgery J Surg Oncol 110(6):651–655, 2014 Badgwell BD, Smith K, Liu P, et al: Indicators of surgery and survival in oncology inpatients requiring surgical evaluation for palliation Support Care Cancer 17(6):727–734, 2009 Krouse RS, Nelson RA, Farrell BR, et al: Surgical palliation at a cancer center: incidence and outcomes Arch Surg 136(7):773–778, 2001 Miner TJ, Brennan MF, Jaques DP: A prospective, symptom related, outcomes analysis of 1022 palliative procedures for advanced cancer Ann Surg 240(4):719–726; discussion 726–717, 2004 Badgwell BD, Aloia TA, Garrett J, et al: Indicators of symptom improvement and survival in inpatients with advanced cancer undergoing palliative surgical consultation J Surg Oncol 107(4):367– 371, 2013 Podnos YD, Juarez G, Pameijer C, et al: Impact of surgical palliation on quality of life in patients with advanced malignancy: results of the decisions and outcomes in palliative surgery (DOPS) trial Ann Surg Oncol 14(2):922–928, 2007 Podnos YD, Juarez G, Pameijer C, et al: Surgical palliation of advanced gastrointestinal tumors J Palliat Med 10(4):871–876, 2007 10 Badgwell B, Krouse R, Cormier J, et al: Frequent and early death limits quality of life assessment in patients with advanced malignancies evaluated for palliative surgical intervention Ann Surg Oncol 19(12):3651–3658, 2012 11 Collins LK, Goodwin JA, Spencer HJ, et al: Patient reasoning in palliative surgical oncology J Surg Oncol 107(4):372–375, 2013 12 Miner TJ, Cohen J, Charpentier K, et al: The palliative triangle: improved patient selection and outcomes associated with palliative operations Arch Surg 146(5):517–522, 2011 13 Paul Olson TJ, Pinkerton C, Brasel KJ, et al: Palliative surgery for malignant bowel obstruction from carcinomatosis: a systematic review JAMA Surg 149(4):383–392, 2014 14 Yoon JY, Jung YS, Hong SP, et al: Clinical outcomes and risk factors for technical and clinical failures of self-expandable metal stent insertion for malignant colorectal obstruction Gastrointest Endosc 74(4):858–868, 2011 15 Sagar J: Colorectal stents for the management of malignant colonic obstructions Cochrane Database Syst Rev (11):CD007378, 2011 doi:10.1002/14651858.CD007378.pub2 16 Kim JH, Ku YS, Jeon TJ, et al: The efficacy of self-expanding metal stents for malignant colorectal obstruction by noncolonic malignancy with peritoneal carcinomatosis Dis Colon Rectum 56(11):1228–1232, 2013 17 Caceres A, Zhou Q, Iasonos A, et al: Colorectal stents for palliation of large-bowel obstructions in recurrent gynecologic cancer: an updated series Gynecol Oncol 108(3):482–485, 2008 18 Cauley CE, Panizales MT, Reznor G, et al: Outcomes after emergency abdominal surgery in patients with advanced cancer: Opportunities to reduce complications and improve palliative care J Trauma Acute Care Surg 79(3):399–406, 2015 19 Pameijer CR, Mahvi DM, Stewart JA, et al: Bowel obstruction in patients with metastatic cancer: does intervention influence outcome? Int J Gastrointest Cancer 35(2):127–133, 2005 20 Mosler P, Mergener KD, Brandabur JJ, et al: Palliation of gastric outlet obstruction and proximal small bowel obstruction with self-expandable metal stents: a single center series J Clin Gastroenterol 39(2):124– 128, 2005 21 Holt AP, Patel M, Ahmed MM: Palliation of patients with malignant gastroduodenal obstruction with self-expanding metallic stents: the treatment of choice? Gastrointest Endosc 60(6):1010–1017, 2004 22 Ly J, O’Grady G, Mittal A, et al: A systematic review of methods to palliate malignant gastric outlet obstruction Surg Endosc 24(2):290– 297, 2010 23 Zheng B, Wang X, Ma B, et al: Endoscopic stenting versus gastrojejunostomy for palliation of malignant gastric outlet obstruction Dig Endosc 24(2):71–78, 2012 p 466 p 467 24 Pothuri B, Montemarano M, Gerardi M, et al: Percutaneous endoscopic gastrostomy tube placement in patients with malignant bowel obstruction due to ovarian carcinoma Gynecol Oncol 96(2):330–334, 2005 25 Ryan JM, Hahn PF, Mueller PR: Performing radiologic gastrostomy or gastrojejunostomy in patients with malignant ascites AJR Am J Roentgenol 171(4):1003–1006, 1998 26 Shaw C, Bassett RL, Fox PS, et al: Palliative venting gastrostomy in patients with malignant bowel obstruction and ascites Ann Surg Oncol 20(2):497–505, 2013 27 Fleming ND, Alvarez-Secord A, Von Gruenigen V, et al: Indwelling catheters for the management of refractory malignant ascites: a systematic literature overview and retrospective chart review J Pain Symptom Manage 38(3):341–349, 2009 28 Facchiano E, Risio D, Kianmanesh R, et al: Laparoscopic hyperthermic intraperitoneal chemotherapy: indications, aims, and results: a systematic review of the literature Ann Surg Oncol 19(9):2946–2950, 2012 29 Randle RW, Swett KR, Swords DS, et al: Efficacy of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in the management of malignant ascites Ann Surg Oncol 21(5):1474–1479, 2014 30 Shaw P, Agarwal R: Pleurodesis for malignant pleural effusions Cochrane Database Syst Rev (1):CD002916, 2004 doi: 10.1002/14651858.CD002916.pub2 31 Rahman NM, Pepperell J, Rehal S, et al: Effect of opioids vs NSAIDs and larger vs smaller chest tube size on pain control and pleurodesis efficacy among patients with malignant pleural effusion: the TIME1 randomized clinicalt JAMA 314(24):2641–2653, 2015 32 Dharmarajan S, Hunt SR, Birnbaum EH, et al: The efficacy of nonoperative management of acute complicated diverticulitis Dis Colon Rectum 54(6):663–671, 2011 33 The Arbinger Institute: The Anatomy of Peace—Resolving the Heart of Conflict Oakland, CA: Berrett-Koehler Publishers, 2015 34 Mack JW, Weeks JC, Wright AA, et al: End-of-life discussions, goal attainment, and distress at the end of life: predictors and outcomes of receipt of care consistent with preferences J Clin Oncol 28(7):1203– 1208, 2010 35 Weeks JC, Cook EF, O’Day SJ, et al: Relationship between cancer patients’ predictions of prognosis and their treatment preferences JAMA 279(21):1709–1714, 1998 36 Zhang B, Nilsson ME, Prigerson HG: Factors important to patients’ quality of life at the end of life Arch Intern Med 172(15):1133–1142, 2012 Section 6 TRANSPLANTATION STEPHANIE M LEVINE Chapter 56 Management of the Organ Donor CHRISTOPH TROPPMANN In 2016, over 13,000 patients on the national organ transplant waiting list in the United States died or were delisted because they had become too ill before a suitable donor organ became available [1] Almost assuredly, this number underestimates the actual magnitude of the problem Many patients with end-stage organ failure are currently not even considered for transplantation (and consequently are not listed) because of the strict recipient selection criteria that are being applied—in part as a result of the severe, ongoing organ shortage The widening gap between available deceased donor organs and the number of patients waiting is a result of the explosive, increased use of organ transplantation therapy over the past 40 years (Tables 56.1 and 56.2), with which the deceased donor pool has not kept pace (Fig 56.1) [1,2] TABLE 56.1 Number of Solid Organ Transplants from Deceased Donors per Year in the United States: 1982 versus 2014 Organ 1982 2016 Kidney 3,681 13,431 Liver   62  7,496 Pancreas   38  1,031 Heart   103  3,190 Heart–lung   8    18   —a  2,327 Lung Intestine   —a    147 aNo lung or intestinal transplants were performed in 1982 Data from references [1–4] TABLE 56.2 One-Year Graft Survival Rates (Deceased Donors): 1982 versus 2013 Organ 1982 (%)a 2015 (%) Kidney 80 94 Liver 35 89 Pancreas 23 86 Heart 65 90 Lung  —b 85 Intestine  —b 75 aResults without cyclosporin A–based immunosuppression bNo lung or intestinal transplants were performed in 1982 Data from references [4–8] (1982) and [1,2] (2015) FIGURE 56.1 Evolution of the number of overall deceased organ donors, of donors after circulatory death, and of living kidney donors between 1982 and 2016 in the United States (Data from references [1–4,9]) The single most important factor that has been identified in this equation is the failure to maximize the conversion of potential deceased donors to actual donors, primarily because of the inability to obtain consent for organ recovery The rates of consent granted by families of potential deceased donors range only from 0% to 75% and appear to vary widely among geographic regions and ethnic groups [10–12] Lack of dissemination and poor presentation of information to the public, misperceptions in the general population regarding the beneficial nature of organ transplantation, and the necessity of organ recovery from deceased donors, as well as inappropriate coordination of the approach to families of potential donors contribute to the stagnation of the organ supply [11–13] The role of physicians who care for critically ill patients in altering this current situation is crucial [14] It is their responsibility to minimize deceleration of the critical care provided to patients that have suffered a catastrophic brain injury, to identify potential donors, to seek their early referral to an organ procurement organization (OPO), and to ensure that families are adequately approached This will maximize families’ opportunities to donate a family member’s organs and allow the families to experience the beneficial effects of donation for the bereavement process (Table 56.3) [15] TABLE 56.3 Identification of Potential Organ Donors: Guidelines for Referral to the Local Organ Procurement Organization Clinical triggers All patients with a severe nonrecoverable neurologic injury on a ventilator with any of the following conditions: Head trauma Cerebral hemorrhage Primary brain tumor Hypoxic insult (including prolonged cardiopulmonary resuscitation, neardrowning, drug overdose, poisoning, cerebral Referral guidelines edema, seizures, and asphyxiation injuries) Refer patients within 1 hour of meeting one or more clinical triggers Refer all patients who meet clinical triggers regardless of age and underlying/associated diagnosis Refer all patients who meet clinical triggers prior to approaching the family regarding end-of-life decisions Refer patients prior to brain death evaluation Refer patients if the family raises the subject of donation Coroner case status does not constitute an exclusion criterion It is estimated that in the United States alone, approximately 250,000 additional life years could be saved annually if consent rates for potential deceased donors could be increased to 100% [16] Intensive care and emergency medicine physicians are obligated ethically and morally to provide the best possible outcome for a very ill patient However, after a potential donor has been identified, they are also obligated to seek the best possible outcome for patients with end-stage failure of a vital organ waiting for a transplant by attempting to ensure that organ donation occurs It is becoming increasingly evident that implementation of critical pathways and standardized donor management protocols play an important role in this context [17–25] DONOR CLASSIFICATION BASED ON THE CRITERIA USED FOR DETERMINATION OF DEATH Brain-Dead Deceased Donors Death is determined based on neurologic criteria Donation after brain death is the most common type of organ donation (currently over 80% of all donors belong in this category) [2] In most Western developed countries, brain death is legally equated with death The diagnosis of brain death rests on the irreversibility of the neurologic insult and the absence of clinical evidence of cerebral and brain stem function The details of the clinical examination that is required to unequivocally establish brain death are described in this chapter Organ procurement proceeds only after brain death has been diagnosed and death has been declared Donation After Circulatory Death Donors (Formerly Known as Donation After Cardiac Death or Non–HeartBeating Donors) Death is determined based on circulatory and respiratory criteria Further increases of the number of donors in this category are to be expected (Fig 56.1) [1,2,24,26,27] Most commonly, families of unconscious patients with severe irreversible traumatic or cerebrovascular brain injury, who do not fulfill the formal criteria of brain death, decide to forgo any further care and wish to donate the organs of their family member Under this scenario, time and place of death are controlled Circulatory and respiratory support technologies are discontinued in the critical care unit or the operating room and organ recovery is initiated once death has been pronounced by a physician not belonging to the organ recovery and transplant team [26] An alternative, by far less common donation after circulatory death (DCD) scenario—uncontrolled death—involves a patient who expires, for example, in the emergency room following massive trauma or a sudden cardiovascular event In the interest of minimizing warm ischemia time, flushing cannulas may be inserted and possibly even perfusion of internal organs with cold preservation solution might already be started while consent to proceed with organ donation is obtained from the patient’s family The discussion that surrounds this category of DCD donors includes concerns centered on when to stop the resuscitation effort and whether it is appropriate to perform a procedure (i.e., insertion of flushing cannulas) that presumes consent before actually obtaining it from the family In light of the severe organ donor shortage, there is renewed public debate about more systematically considering uncontrolled DCD at a larger scale [28] Other considerations that pertain to both controlled and uncontrolled DCD donors include: uncertainty regarding the exact definition of death after discontinuing circulatory and respiratory support (there is no standardized definition of, e.g., the minimal duration of asystole after the patient expires following withdrawal of support before death can be pronounced; this is currently subject to considerable interinstitutional variation), and the possibility of the patient at least temporarily surviving the withdrawal of support technologies (backup plans must be clearly defined by each individual institutional DCD donor protocol) Nevertheless, these considerations must be balanced with the right of self-determination based on an individual’s previously documented preferences and the final wishes of a competent patient family Further debate by the medical community and general public is crucial to address these complex ethical issues and to maximize acceptance of organ donation [28,29] Without such thorough consideration, the deceased donor concept and the donation system that is currently in place might be harmed or discredited CURRENT STATUS OF SOLID ORGAN TRANSPLANTATION The increased number of solid organ transplant procedures performed during the last 40 years has been paralleled by significant improvements in outcomes including rates of patient and graft survival (Table 56.2) This phenomenon has been attributed to a variety of factors that include (a) the introduction in the early 1980s of the powerful immunosuppressive agent cyclosporin A, followed a decade later by tacrolimus, mycophenolate mofetil, and other new immunosuppressants; (b) the availability of antilymphocyte antibody preparations to prevent and treat rejection episodes (e.g., antilymphocyte and antithymocyte globulin); (c) improvements in organ preservation (e.g., use of University of Wisconsin solution, ex vivo machine perfusion of donor organs); (d) thorough preoperative transplant candidate screening for the presence of comorbid disease processes; and (e) increasing sophistication in the postoperative intensive care of regular and high-risk recipients In addition, the availability of potent, yet nontoxic, antibacterial, antifungal, and antiviral agents has allowed opportunistic infections in immunocompromised transplant patients to be treated more effectively In combination with refinement of surgical techniques, these factors have led to increasing success of solid organ replacement therapy Thus, transplantation has become the treatment of choice for many patients with end-stage failure of the kidneys, liver, endocrine pancreas, heart, lungs, and small bowel Successful hand, arm, larynx, and face transplants from deceased donors have also been reported [30–33] Currently, the only patients who are excluded from undergoing transplantation are those with malignancies (metastatic or at high risk for recurrence) and uncontrolled infections, those who are unable to withstand transplant surgery, or those who have a significantly shortened life expectancy due to disease processes unrelated to their target organ dysfunction or failure Kidney Currently, patients undergoing kidney transplants from deceased donors exhibit excellent graft survival rates (Table 56.2) Renal transplantation dramatically improves life expectancy and quality of life, decreases cardiovascular morbidity and mortality, and rehabilitates the recipients from a social perspective Kidney transplants are also less expensive from a socioeconomic standpoint than is chronic hemodialysis For pediatric patients with chronic renal failure, a functioning renal allograft is the only way to preserve normal growth and ensure adequate central nervous, mental, and motor development Liver Patients with end-stage liver failure die unless they receive a transplant Liver transplants are an effective treatment for many patients, pediatric and adult, regardless of the cause of liver failure: congenital (i.e., structural or metabolic defects), acquired (i.e., due to infection, trauma, or toxins), or idiopathic (e.g., cryptogenic cirrhosis, autoimmune hepatitis) A dramatic improvement in graft survival occurred after the introduction of cyclosporin A (Table 56.2) Currently, there are no reliable means to substitute, even temporarily, for a failing liver other than with a transplantation Extracorporeal perfusion, using either animal livers or bioartificial liver devices (e.g., hepatocytes suspended in bioreactors), may someday bridge the gap between complete liver failure and liver transplantation, but these therapeutic modalities are still investigational and are far from becoming standard clinical tools Hepatocyte and stem cell transplants to treat fulminant liver failure and to correct congenital enzyme deficiencies are being studied but are presently not a clinical reality Intestine Small bowel transplants are performed in patients with congenital or acquired short gut, especially if liver dysfunction occurs because of longterm administration of total parenteral nutrition and when difficulty in establishing or maintaining central venous access is limiting If liver disease is advanced, a combined liver–small bowel or, in highly selected cases, a multivisceral transplant (liver, stomach, small bowel, with or without pancreas) can be performed [34] Pancreas and Islet Primary prevention of type 1 insulin-dependent diabetes mellitus is not possible, but transplantation of the entire pancreas or isolated pancreatic islets can correct the endocrine insufficiency once it occurs Glucose sensor systems that continuously monitor blood sugar levels coupled with real-time command of an insulin delivery system (implantable pump) and bioartificial and hybrid biomechanical insulin-secreting devices are not yet universally available for routine clinical use The only effective current option to consistently restore continuous nearphysiologic normoglycemia, however, is a pancreas transplant [35–37] Good metabolic glycemic control decreases the incidence and severity of secondary diabetic complications (neuropathy, retinopathy, gastropathy and enteropathy, and nephropathy) Most pancreas transplants are performed simultaneously with a kidney transplant in preuremic patients with significant renal dysfunction or in uremic patients with end-stage diabetic nephropathy Selected nonuremic patients with brittle type 1 diabetes mellitus (with progression of the autonomic neuropathy or recurrent severe hypoglycemic episodes, and with repetitive episodes of diabetic ketoacidosis) can benefit from a solitary pancreas transplant (without a concomitant kidney transplant) to improve their quality of life and to prevent the manifestation and progression of secondary diabetic complications Evidence suggests that a successful pancreas transplant can achieve these goals in uremic and in nonuremic recipients and decrease mortality [35] Islet transplants are undergoing intensive clinical investigation Results of transplanting alloislets from deceased donors are encouraging in the short term [36]; however, long-term results are less favorable [37] Heart Heart transplantation is the treatment of choice for patients with endstage congenital and acquired parenchymal and vascular diseases and is recommended generally after all conventional medical or surgical options have been exhausted After a widely publicized start in 1967, poor results were observed over the ensuing decade In the 1980s, however, the field of cardiac transplantation experienced dramatic growth (Table 56.1) because of significant improvements in outcome, probably most directly related to immunosuppressive therapy and to refinements in diagnosis and treatment of rejection episodes [38] Mechanical pumps, such as implantable ventricular assist devices or the bioartificial heart, have contributed to this success because they can also serve as a bridge during the time between end-stage cardiac failure and a transplantation Heart–Lung and Lung Heart–lung and lung transplants are an effective treatment for patients with advanced pulmonary parenchymal or vascular disease, with or without primary or secondary cardiac involvement This field has evolved rapidly since the first single-lung transplant with long-term success was performed in 1983 (Table 56.1) The significant increase in lung transplantations is mainly due to technical improvements resulting in fewer surgical complications, as well as to the extremely limited availability of heart–lung donors Previously, many patients with endstage pulmonary failure would have waited for an appropriate heart–lung donor Now, they undergo a single or a bilateral single-lung transplant instead [39] Bilateral single-lung transplants are specifically indicated in patients with septic lung diseases (e.g., cystic fibrosis, α1-antitrypsin deficiency) in which the remaining native contralateral lung could crosscontaminate a single transplanted lung Double en bloc lung transplants have been abandoned because of technical difficulties related to the bronchial anastomotic blood supply Mechanical ventilation or extracorporeal membrane oxygenation (ECMO) can be used as a temporary bridge to this type of transplant, but none of these modalities obviates the need for organ replacement therapy CURRENT STATUS OF ORGAN DONATION Current organ supply does not meet demand.This is due to an insufficient augmentation of the donor pool (Tables 56.1 and 56.2; Fig 56.1) The 55mile-per-hour speed limit, stricter seat belt and helmet laws, advances in critical care, as well as the trend toward a deceleration of care in patients that have suffered a catastrophic brain injury have all had significant impacts on the number of brain-dead organ donors [1] In 2016, the three leading causes of death among deceased donors in the United States were cerebral anoxia (e.g., due to a cardiac arrest), a cerebrovascular accident (e.g., due to a stroke or an intracranial aneurysmal bleed), and traumatic brain injury [1,2] A positive trend is the increasing number of DCD donors (Fig 56.1) [2,24] These donors constitute currently nearly 20% of the overall deceased donor pool [2] In DCD donors, refined surgical techniques allow for fast insertion of cannulas and perfusion of vital organs while these are rapidly excised Innovative approaches, such as withdrawal of support technologies in the ICU (rather than in the operating room), in the presence of the donor’s family, may further increase acceptance of DCD donation among potential donors’ families and health care professionals [26,29] Moreover, ongoing refinements of organ perfusion and preservation techniques, including maintenance of the DCD donor on ECMO until organ recovery can occur, and placement of the recovered organs on hypothermic or normothermic perfusion using a pump during the transport and preservation phase, all result in less ischemic organ injury and also allow for better organ preservation and increased utilization of DCD donor organs [24,40–43] Currently, kidneys and livers are the organs most commonly recovered and transplanted from DCD donors [2] According to estimates, there are at least 10,500 to 13,800 potential brain-dead donors in the United States per year [12] In 2016, however, there were only 9,971 actual deceased organ donors in the United States [1] According to a study, the overall consent rate (the number of families agreeing to donate divided by the number of families asked to donate) was 54% in the United States, and the overall conversion rate (the number of actual donors divided by the number of potential donors) was 42% [12] The single most important reason for lack of organ recovery from 45% to 60% of the potential donor pool is the inability to obtain consent [12,24] Several studies have shown that family refusal to provide consent and the inability to identify, locate, or contact family members to obtain consent within an appropriate time frame are the leading causes for the nonuse of many organs from potential donors [10–13,24] A public opinion survey showed that 69% of respondents would be very or somewhat willing to donate their organs, and 93% would honor the expressed wishes of a family member [44] However, only 52% of these individuals had communicated their wishes to their family Moreover, 37% of respondents did not comprehend that a brain-dead person should be considered dead and unable to recover, and 59% either believed or were unsure whether or not organs can be bought and sold on the “black market.” Also, 42% did not realize that organ donation does not cause any financial cost to the family of the deceased in the United States [44] Finally, racial differences which are likely based on historical distrust in the health care system may adversely impact donation rates as well For instance, African American families have been consistently found to be less willing to consent to organ donation than White families [45] Correcting these misperceptions and attempting to increase awareness of the importance of organ transplantation must remain the focus of public educational campaigns [24,29] The family’s knowledge of the patient’s previous wishes is central to decision-making [10,11,13] Such efforts can be successful, especially among minorities, in whom mistrust and the perception of inequitable access to medical care and organ transplant therapy have led to disappointingly low organ donation and recovery rates [24,45] It is very important that adequate communication, empathy, and an informative, humane approach to the family of the deceased occur to ensure reasonable consideration of donation Families are more likely to donate if they are approached by an OPO coordinator, view the requestor as sensitive to their needs, and experience an optimal request pattern [11,13,22] Educational efforts to enhance organ donation must therefore also be directed at health care professionals and medical students, whose views and knowledge of these issues are often inconsistent and limited [29,46] Physicians, too, need to be better trained to recognize and refer potential organ donors and to not discuss organ donation until a member of the local OPO has approached their families [11,13,22] As a result, since 1998, Conditions of Participation of the Centers for Medicare and Medicaid Services (CMS) require hospitals to use “designated requestors” to obtain family authorization Finally, the potential for financial compensation or other rewards for deceased donor families (e.g., compensation for funeral expenses) has been considered as a means to increase donation rates [46] But the potential effects of such an intervention on donation rates remain unclear OTHER OPTIONS TO INCREASE ORGAN AVAILABILITY Additional mechanisms that might help to increase the number of available organs for transplantation include (a) optimization and maximal use of the current actual donor pool; (b) increasing the number of living donor transplants, including the provision of incentives for live donation; (c) enacting presumed consent laws; (d) allowing the use of organs from executed prisoners; and (e) xenotransplants (e.g., use of animal organs as a potentially unlimited supply for transplantation into humans, particularly after genetic engineering) Only the first two options are, however, of practical interest at this time Optimal use of the Current Donor Pool As a result of the ongoing organ shortage, transplant surgeons have attempted to refine procurement techniques so that maximal use of the available donor pool occurs (Fig 56.2) [47] On average, more than three organs are recovered and transplanted from each deceased donor (Fig 56.2) [1,2] p 471 p 472 FIGURE 56.2 Transplant rates (by organ) from 8,085 deceased donors (100%; 2007) in the United States The last bar represents the mean number of organs transplanted per deceased donor for the year 2013 Tx’d, transplanted; Dec., deceased (Based on data from references [1,2]) Marginal donors—elderly patients, patients with a history of hypertension, poisoning victims, patients with significant organ injury (e.g., liver laceration due to blunt injury) or complications of brain death (e.g., hypotension, acute kidney injury with oliguria or anuria, disseminated intravascular coagulation)—are routinely used for recovery of kidneys and extrarenal organs [1,2,24] Organ recovery techniques also have been adapted to facilitate use of older donors with significant aortic atherosclerosis [48] The increased use of hypothermic machine perfusion of kidney grafts allows to assess the quality of grafts from marginal donors and facilitates—by improving preservation quality— organ allocation to geographically more distant transplant centers [42] Organs with anatomic abnormalities (e.g., multiple renal arteries or ureters, horseshoe kidney, annular pancreas) also are being used routinely Improvements in operative technique permit the en bloc transplantation of two kidneys from very young (e.g., infant) donors that would have been too small to be used separately in one recipient [49–51] Similarly, transplantation of both kidneys from an adult donor into one recipient is, on occasion, done to avoid discarding suboptimal kidneys with an insufficient individual nephron mass To maximize the use of livers, adult donor livers can be split and the two size-reduced grafts transplanted into two recipients (e.g., a pediatric and an adult recipient) A similar principle has also been proposed for the pancreas and has been reported on at least one occasion [52] Explanted livers from patients undergoing liver transplantation for hepatic metabolic disorders that cause systemic disease without affecting other liver functions (e.g., familial amyloidotic polyneuropathy, hereditary oxalosis) can be used for transplanting other patients (“domino transplant”) who are not candidates for deceased livers because of graft shortage (e.g., cirrhotic patients with hepatocellular carcinoma confined to the liver who are not in the group with good expected survival) [53] The combination of split-liver and domino transplantation can even result in transplantation of three adult patients with one deceased donor graft [54] The advent of single-lung transplants has made it possible to distribute the heart and lungs of one donor to three recipients Formerly, transplanting a heart–lung bloc into one recipient was the treatment of choice for end-stage pulmonary disease If the native heart of a heart– lung recipient is healthy, a domino transplant can be performed: The heart–lung recipient donates his or her heart to another patient in need of a heart transplant In an attempt to optimize use of scarce donor resources, the reuse of previously transplanted hearts, kidneys, and livers has also been reported However, all these methods allow only for better use of organs from the existing donor pool The cornerstone for an effective increase in the number of organ donors remains heightened awareness and education of the public, physicians, and other health care professionals to improve consent and conversion rates [11–13,24,29] Living Donors The use of organs from living donors, traditionally limited to kidney transplants, has been expanded to the liver, small bowel, pancreas, and lung [1,2] In the more distant past, most living donors were genetically related to the recipient—siblings, parents, and adult children As a result of the organ shortage, the use of living unrelated kidney donors, who are emotionally, but not genetically, related to the recipient (e.g., spouses, close friends), or are emotionally and genetically unrelated to the recipient (i.e., nondirected, “Good Samaritan” donors), has considerably increased over the past 25 years (Fig 56.1) [1,2,55] In order to increase the number of live donor transplants even further, paired-kidneyexchange programs and living donor chain transplants have been implemented [56,57] In that setting, the supply of organs is increased for instance by exchanging kidneys from living donors who are ABO or crossmatch incompatible with their intended recipients, but ABO or crossmatch compatible with another donor–recipient pair (donor A would provide a kidney to [ABO or crossmatch compatible] recipient B, and donor B would provide a kidney to [ABO or crossmatch compatible] recipient A) [56,57] In cases when paired-kidney-exchange or donor chain transplants are not available or feasible, it is alternatively possible to precondition (desensitize) the intended recipient of an ABO or crossmatch incompatible kidney (by use of plasmapheresis and/or intravenous immunoglobulin and pharmacologic intervention) to still facilitate a successful living donor kidney transplant Currently, there is considerable public debate on providing incentives for living kidney donation [58–61] The debate centers on concerns that reimbursement might lead to the commercialization of organ donation, with the inherent risk of turning potential donors and transplantable organs into a commodity [59,60] In the United States, those in support of compensating live donors stress that an Organ Procurement and Transplantation Network–run transparent system of paid living donation would ensure that donors are compensated fairly, eliminate transplant tourism to other countries, greatly diminish the currently existing black market for organs in those countries, and emphasize any potentially interested donor’s autonomy—while at the same time increasing the organ supply [58,61] In any case, paid living donation, while a reality in certain regions of the world, remains currently unlawful in the United States and most Western countries Even when assuming that (i) public attitudes toward living donation will continue to evolve favorably (Fig 56.1), (ii) innovative approaches as described above will be increasingly used, and (iii) other alternative means for finding living donors, such as donor solicitation via social media, would ultimately prove to be successful, only modest increases of the absolute number of living kidney donors could be expected [58–63] Finally, compared with renal transplantation, the proportion of living donor transplants for extrarenal organs is much smaller (less than 5% for liver and less than 0.5% for pancreas, lung, and small bowel) [1] Thus, living donor transplants will continue to help alleviate the organ shortage for certain organs (kidney, liver) to some extent, but will never be able to completely compensate— even under the best circumstances—for the severe lack of deceased donors p 472 p 473 Presumed Consent Laws Presumed consent laws have been implemented in many areas of the world, most notably in several countries in Europe These laws permit organ procurement unless the potential donor has objected explicitly A permanently and easily accessible registry of objectors is a prerequisite for such a system In the United States, proposals for presumed consent legislation have not had broad support Moreover, presumed consent would not alleviate the problem of insufficient donor identification and referral [12] The beneficial impact that such laws can have became evident in Spain In that country, presumed consent laws coupled with the creation of a decentralized network of mostly hospital-based, specifically trained transplant coordinators (most of them physicians in intensive care units) in the early 1990s led not only to more efficient identification of eligible deceased donors but also to higher consent rates Accordingly, the annual donation rate in Spain rose from 14.3 donors per million population (pmp) in 1989 to 34.2 pmp in 2008 (United States, 2008: 26.3 pmp) [64–66] Interestingly, a similar approach (without the presumed consent component) using in-house coordinators at some hospitals in the United States did yield greater consent and conversion rates, too, and underscored the advantages that such a system could have, if implemented at a larger scale [67] Organs from Executed Prisoners Certain countries (e.g., China) routinely use organs from executed prisoners This practice has been strongly rejected by the national and international transplant community [68] Moreover, proposals to use organs from executed prisoners would engender a very passionate, emotional debate that would have a negative impact on public opinion and thereby decrease overall organ availability Xenotransplantation Xenotransplantation of organs and tissues from animals into humans offers a potentially unlimited supply of donors [68,69] Past attempts have received significant public attention [69], but numerous practical problems remain before this procedure could become a clinical reality Ethical concerns regarding the use of animal organs for transplantation have also been raised Immunologic concerns include hyperacute rejection (mediated by circulating, preformed natural antibodies), which occurs in vascularized solid organ transplantation between virtually all discordant species Also, the biocompatibility of protein synthesized by an animal liver and the human organism is not fully established, and infectious diseases (e.g., caused by porcine endogenous retroviruses) could be transmitted when using nonhuman primates or pigs as donors Genetic engineering of animals before their use as donors to overcome the immunologic barriers is an area of intensive investigation Significant experimental progress in this area could fundamentally change the field of organ transplantation REGULATION AND ORGANIZATION OF ORGAN PROCUREMENT AND ALLOCATION In the early 1980s, the introduction of new immunosuppressive agents engendered a rise in organ transplant activity Tissue matching (e.g., by use of living related donor–recipient combinations) became less important, and the use of brain-dead donors increased (Fig 56.1) In the wake of these developments, consolidation and national regulation of the organ sharing and allocation organizations, which had previously functioned mainly at a local and regional level, became necessary In the United States, the National Organ Transplant Act of 1984 called for a national system to ensure equitable access to transplant therapy for all patients, a major component of which was fair organ allocation The federal government commissioned a task force on organ transplantation to define such an allocation system This task force, whose members were appointed by the U.S Department of Health and Human Services, resolved that human organs are a “national resource to be used for public good” and recommended the creation of a national Organ Procurement and Transplantation Network (OPTN) [3] In 1986, the U.S Department of Health and Human Services awarded the OPTN contract to the United Network for Organ Sharing (UNOS) Pursuant to the contract, UNOS was asked to design a network to achieve balance in the goals of equity in organ access and distribution and in optimal medical outcome [70] In 1986, the Omnibus Budget Reconciliation Act mandated that only hospital members of the OPTN could perform Medicare- and Medicaidreimbursed transplant procedures In 1988, the Organ Transplant Amendments reaffirmed the federal interest in equitable organ allocation by locating authority in UNOS as opposed to local transplant organizations The national OPTN is currently operated under contract by UNOS, which is accountable to the U.S Department of Health and Human Services All patients on waiting lists of a transplant program are registered with UNOS, which maintains a centralized computer system linking all OPOs and transplant centers The United States has been divided into 11 regions for organ procurement, allocation, and sharing purposes (Fig 56.3) Organs are registered, shared, and allocated through use of the central UNOS computer, which generates a list of recipients for each available organ Patients awaiting deceased donor transplantation are ranked according to UNOS policies, based on medical and scientific criteria that—depending on the organ—may include blood type, tissue type, length of time waiting on the list, age (pediatric vs adult), level of presensitization (percentage of panel reactive antibody), and medical status For kidneys, national sharing of virtual crossmatch compatible, very highly sensitized recipients is mandated For the vast majority of all of the other organs, though, allocation first takes place locally and then regionally If no suitable recipients are available, organs are then allocated nationally FIGURE 56.3 United Network for Organ Sharing (UNOS) regions in the United States (24-hour access number: 1-800-292-9537) The United States has been divided into 11 regions for organ procurement, allocation, and sharing purposes LEGAL ASPECTS OF ORGAN DONATION AND BRAIN DEATH Uniform Anatomical Gift Act The Uniform Anatomical Gift Act, adopted in 1968 and in force throughout the United States, allows any adult individual (over age 18 years) to donate all or part of their body for transplantation, research, or education This act also provides the legal basis for recovery of organs from both DCD and brain-dead (vide infra) donors Explicit consent is required The act also specifies who may give consent (e.g., legal next of kin) for donation [71] The 2006 Revised Uniform Anatomical Give Act honors the choice of an individual to be or not to be a donor and strengthens the language barring others from overriding a donor’s first-person authorization to make an anatomical gift The revised act also empowers minors that apply for a driver’s license to become donors and encourages and establishes standards for donor registries [72] Uniform Determination of Death Act Over the past five decades, brain death has legally become equated with death in most Western developed countries Brain death means that all brain and brain stem function has irreversibly ceased The recognition of brain death became possible only after substantial advances in intensive care medicine (e.g., provision of cardiovascular support, prolonged mechanical ventilation) The first classic description of brain death was published in 1959 in France and termed coma dépassé (beyond coma) An ad hoc commission of the Harvard Medical School defined brain death criteria in the United States in 1968 [73] These criteria were judged by some as being too extensive and too exclusive In 1981, the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research formulated the Uniform Determination of Death Act, which established a common ground for statutory and judicial law related to the diagnosis of brain death The commission stated that “an individual who has sustained irreversible cessation of all functions of the entire brain, including the brainstem, is dead,” and left the criteria for diagnosis to be determined by “accepted medical standards.” Those standards were defined in a related report to the President’s Commission on the diagnosis of death by 56 medical consultants in 1981 [74] The guidelines in that report have now been accepted as the standard for determining brain death in the United States They are as follows: “Cessation is recognized when: (1) all cerebral functions and (2) all brainstem functions are absent The irreversibility is recognized when: (1) the cause of the coma is established and is sufficient to account for the loss of brain functions, (2) the possibility of the recovery of any brain functions is excluded, and (3) the cessation of cerebral and brainstem function persists for an appropriate period of observation and/or trial of therapy” [74] Confusion regarding this well-founded and accepted medicolegal concept of the equivalence of brain death and death of a human persists to this date among physicians, other health care professionals, and the general public [11],13] Specifically, in the field of transplantation, it should be unequivocally clear to the potential donor’s family and anyone involved in the patient’s care that the time of death is the time at which the diagnosis of brain death is established and not the time of cardiac arrest during the organ recovery Providing education targeted specifically at these groups and society at large is of paramount importance to optimize consent rates [11,13] Required Request Required request laws have now been enacted in all states in the United States They obligate hospitals to notify an OPO of potential donors and to offer the option of donation to the families of potential donors (braindead and DCD donors) In order to optimize this process, the CMS’ Conditions of Participation have been requiring hospitals since 1998 to use “designated requestors” to obtain authorization from legal next of kin for donation [75] Clinical Diagnosis of Brain Death The clinical diagnosis of brain death rests on three criteria: (a) irreversibility of the neurologic insult, (b) absence of clinical evidence of cerebral function, and, most important, (c) absence of clinical evidence of brain stem function (Table 56.4) [76–79] Irreversibility is established if structural disease (e.g., trauma, intracranial hemorrhage) or an irreversible metabolic cause is known to have occurred Hypothermia, medication side effects, drug overdose, and alcohol ingestion and intoxication must be ruled out when testing for brain death Plasma concentrations of sedative or analgesic drugs sometimes correlate poorly with cerebral effects Therefore, residual effects of those drugs can be excluded only by passage of time, if any doubts exist As no evidencebased recommendations for a minimal waiting time prior to the first brain death examination can be made, good—individualized—clinical judgment is paramount The observation period between two sequential brain death examinations should be at least 6 hours for structural causes and preferably 12 to 24 hours for metabolic causes, drug overdose, or intoxication [76–79] Even with potentially reversible metabolic alterations (e.g., hepatic or uremic encephalopathy), recovery has not been described after duration of the brain death state for more than 12 hours and as long as all criteria in Table 56.4 (which are based on the 1995 American Academy of Neurology medical standards for death determination using neurologic criteria and on its 2010 update) are met [77,78] Clinical testing of cerebral and brain stem function is detailed in Table 56.4 [76–81] Although pediatric donors are not the focus of this chapter, it should be noted that brain death criteria are more stringent for very young pediatric patients, particularly newborns, in whom criteria for brain death also include demonstration of the absence of blood flow on cerebral flow studies p 474 p 475 TABLE 56.4 Brain Death Criteria and Clinical Diagnosis of Brain Death Irreversible, well-defined etiology of coma Structural disease or metabolic cause (requires documentation by neuroimaging) Exclusion of: significant hypothermia (defined as core temperature 100 mm Hg); severe electrolyte, endocrine, or acid–base disturbance; and drug, alcohol or substance intoxication (may require toxicology screen; barbiturates, if present, serum level must be 60 mm Hg or 20 mm Hg higher than the normal baseline value): The patient is preoxygenated with an FiO2 of 1.0 for 10–15 minutes to reach a PaO2 >100 mm Hg (preferably with an arterial line in place for rapid blood gas measurements) while adjusting ventilatory rate and volume such that the PaCO2 reaches ~40–45 mm Hg After a baseline arterial blood gas value is obtained and the patient is disconnected from the ventilator, O2 at 6–8 L/min is delivered through a cannula advanced 20–30 cm into the endotracheal tube (cannula tip at the level of the carina) Continuous pulse oximetry is used for early detection of desaturation, which does not usually occur when using this protocol In most cases, a PaCO2 >60 mm Hg is achieved within 3– 5 minutes after withdrawal of ventilatory support; at this point, the patient should be reconnected to the ventilator (or earlier, should hemodynamic instability, desaturation, or spontaneous breathing movements occur) Obtaining an arterial blood gas sample immediately before reinstitution of mechanical ventilation is mandatory If there is no evidence of spontaneous respirations before reinstitution of mechanical ventilation in the presence of a PaCO2 >60 mm Hg or an increase of >20 mm Hg from the normal baseline value, the criteria for a positive apnea test are met Other points Spinal reflexes, such as deep tendon reflexes and triple flexion responses, can be preserved and do not exclude the diagnosis of brain death Shivering, piloerection, arm movements, reaching of the hands toward the neck, forced exhalation, and thoracic respiratory-like movements are possible after brain death and are likely to release phenomena of the spinal cord, including the upper cervical cord All these findings are compatible with the diagnosis of brain death Confirmatory tests should be used in cases in which the observation period needs to be shortened (e.g., unstable donors), if the apnea test had to be aborted in equivocal situations in children younger than 1 year old, or if one of the potential pitfalls (Table 56.6) cannot be ruled out (demonstration of absence of intracranial circulation by conventional cerebral angiogram, Tc-99m hexamethylpropyleneamine oxime single photon-emission computed tomography, transcranial Doppler ultrasonography, or electrocerebral silence documented by an electroencephalogram) PaCO2, partial arterial carbon dioxide pressure; FiO2, fraction of inspired oxygen References [76–80] After brain death, the pupils become fixed in midposition because sympathetic and parasympathetic input is lost Decerebrate (abnormal extension) and decorticate (abnormal flexion) responses to painful stimuli imply the presence of some brain stem function and are incompatible with the diagnosis of brain death In contrast, spinal cord– mediated tendon reflexes, automatic stepping, and other complex motor activities (which can also occur during apnea testing) are compatible with brain death [78,79,82] The occurrence of these movements can be quite distressing if observed by the next of kin; therefore, it is advisable that they not be present during the apnea test Very rarely, ascending acute reversible inflammatory polyneuropathy (Guillain–Barré syndrome) can simulate brain death and inhibit all motor functions, including pupillary reactions and brain stem reflexes The typical clinical history, coupled with evidence of progressive weakness, should yield the correct diagnosis and preclude a diagnosis of brain death from being established [76–79] The American Academy of Neurology has stated that special confirmatory tests are not necessary to diagnose brain death in the vast majority of cases Only in equivocal or questionable circumstances does a study demonstrating the absence of intracranial blood flow need to be performed [76–78] The most sensitive and specific test for assessing intracranial blood flow is four-vessel catheter cerebral arteriography Alternatively, Tc-99m hexamethylpropyleneamine oxime single photonemission computed tomography may be used [78,80] Other ancillary tests are either less sensitive (e.g., digital subtraction angiography, transcranial Doppler ultrasonography), less specific (e.g., brain stem acoustic evoked potentials), or measure only hemispheric flow Four-vessel cerebral catheter arteriography is indicated in all conditions that can temporarily cause an isoelectric electroencephalogram (e.g., extreme intoxication) If the indication for cerebral arteriography is unclear, the benefits must be weighed against the potential risks of transporting an unstable patient Confirmatory tests may serve to shorten the waiting period between the two brain death examinations, should donor hemodynamic instability occur Certain potential pitfalls exist in clinical brain death testing, and the diagnosis should not be considered to have been established until these all have been excluded (Table 56.5) [79] If these cannot be excluded, confirmatory testing is mandatory [79,80] p 475 p 476 TABLE 56.5 Pitfalls in Clinical Brain Death Testing and Potential Remedial Measuresa Pitfalls Remedial Measure(s) Hypotension, shock Institute fluid resuscitation, use pressor agents Use warmed fluids, ventilatory warmer Increase time under normothermic conditions until performance of first brain death exam (several days may be necessary to clear all previously administered muscle relaxants and mood or consciousness-altering drugs) Check drug and alcohol levels and toxicology screens or increase waiting time between brain death examinations Discontinue muscle relaxants and moodor consciousness-altering medications, increase waiting time between brain death examinations Discontinue anticholinergic medications and muscle relaxants, increase waiting time between brain death examinations, obtain careful patient history Remove contact lenses before brain death examination Obtain careful medication history and patient history Current hypothermia Recent treatment with therapeutic hypothermia Intoxication, alcohol ingestion or drug overdose Presence of neuromuscular-inhibiting agents and sedative drugs, which can interfere with elicitation of motor responses Pupillary fixation, which may be caused by anticholinergic drugs (e.g., atropine given during a cardiac arrest), neuromuscular blocking agents, or preexisting disease Corneal reflexes absent due to overlooked contact lenses Oculovestibular reflexes diminished or abolished after prior use of ototoxic drugs (e.g., aminoglycosides, loop diuretics, vancomycin) or agents with suppressive side effects on the vestibular system (e.g., tricyclic antidepressants, anticonvulsants, and barbiturates) or due to preexisting disease aIf one of the listed conditions cannot be ruled out, confirmatory testing (cerebral flow studies or electroencephalography) is necessary before brain death is declared In summary, the diagnosis of brain death can be established by performance of routine neurologic examinations, including cold caloric and apnea testing on two separate occasions, coupled with prior establishment of the underlying diagnosis and prognosis in most cases [76–80] More sophisticated tests are required in cases in which the diagnosis cannot be unequivocally established [78,80] However, brain death must be diagnosed in accordance with local regulations and state laws Details on the locally prevailing regulations are available through the state medical board and the local OPO ORGAN DONATION PROCESS The three key elements leading to successful organ donation are (a) early referral of potential donors, (b) a well-coordinated approach in informing and dealing with the potential donor’s family to request and obtain consent, and (c) appropriate critical care therapy of the donor [11,13] The optimal course of events for both brain-dead and DCD donors is summarized in Table 56.6 p 476 p 477 TABLE 56.6 Organ Donation Algorithm Early identification of the potential donor by the critical care physician or health care professional (Table 56.3) Early contact with the local or regional OPO for medical, legal, and logistic assistance If the local OPO’s address or phone number is unknown, a 24-h access number to UNOS is available: 1-800-292-9537 Completion of the preliminary screening by the OPO if necessary in consultation with the transplant surgeon for decisions regarding marginal donors 4a For potential DCD donors: await family decision regarding withdrawal of care Proceed only if family decides to do so 4b For potential brain-dead donors: brain death diagnosis and confirmation (Tables 56.4 and 56.5), certification of death Family notification and explanation of brain death with its legal and medical implications Sufficient time for acceptance must be allowed Request for organ donation Must be made after, and in clear temporal separation, from step 4a or 4b After consent for organ donation is obtained, the focus switches from treatment of elevated intracranial pressure and cerebral protection to preservation of organ function and optimization of peripheral oxygen delivery (Table 56.8) All remaining laboratory and serologic studies as well as any further studies and tests required in equivocal situations are performed at this point Final organ allocation by the OPO and UNOS, coordination of the organ recovery operation, notification of the abdominal and thoracic surgical teams Modification of the final steps may become necessary under special circumstances, for example, in hemodynamically unstable donors 9 For controlled DCD donors: Support is withdrawn and death is certified (in the ICU or in the operating room) 10 Organ recovery operation (brain-dead and DCD donors) OPO, organ procurement organization; UNOS, United Network for Organ Sharing; DCD, donation after circulatory death Steps 4, 5, and 9 should not involve physicians who are part of the transplantation team Early Donor Referral Early referral of any potential donor to the local OPO minimizes the loss of transplantable organs due to unexpected cardiac arrest and death, hemodynamic instability, serious nosocomial infection, or complications related to intensive care [83,84] For example, an inverse correlation exists between the duration of mechanical ventilation and the suitability of the donor for lung donation The evidence is substantial that brain death eventually leads to cardiac arrest, even when cardiorespiratory support is maintained [83,84] Cardiac arrest occurs in 4% to 28% of potential donors in the maintenance phase, and as many as 50% of all potential donors die within 24 hours without appropriate support [83,84] The previously outlined clinical triggers for early referral to the local OPO should therefore be applied to any neurologically severely injured patient after admission to the hospital or intensive care unit (Table 56.3) Early contact with the OPO is essential as the latter will provide assistance with further screening and the evaluation of any patient who might potentially become a donor Donor Evaluation General Guidelines During the initial contact with the OPO, the physician should provide the potential donor’s name, age, sex, height, weight, and blood type Also needed are the date of admission and diagnosis, the nature and extent of any trauma, a concise medical and social history, and the time of brain death (if applicable) Whether local investigative agencies (e.g., medical examiner, coroner) need to be notified also should be specified The current medical status, including vital signs, urine output, cardiorespiratory status, medications, and culture results, must be communicated Basic laboratory results should be obtained: arterial blood gas determinations; blood urea nitrogen, creatinine, and electrolyte values; hemoglobin, hematocrit, white blood cell and platelet counts, and tests for serum amylase, total bilirubin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase; coagulation profile (including prothrombin time or International Normalized Ratio); and urinalysis and urine culture, along with electrocardiogram and chest radiograph results In the case of potential lung donors, chest circumference and radiographic thoracic measurements, as well as the results of an oxygenation challenge (partial arterial oxygen pressure [PaO2] measurement after ventilation for 10 minutes with a fraction of inspired oxygen [FiO2] of 1.0), are helpful The OPO provides further procedural, administrative, legal, and logistic help Most importantly, the OPO coordinates how the family is approached All further testing (including human leukocyte antigen tissue typing; serologic screening for cytomegalovirus [CMV], for hepatitis A, B, and C viruses [HAV, HBV, HCV], for human immunodeficiency virus [HIV], and syphilis; and blood, sputum, and urine cultures) is then coordinated through the OPO if the donor passes the preliminary screening tests The organ allocation process begins only after the family has decided to withdraw support technologies (DCD donors) or brain death has been declared and consent has been obtained If prospective tissue typing is to be done, it may occasionally be necessary to perform a bedside surgical inguinal lymph node biopsy at the donor hospital—after consent for organ donation has been obtained, but before proceeding with the actual organ recovery several hours later The medical status and the life expectancy of the potential recipient without the organ transplant are taken into account when considering the risks associated with a specific donor’s medical characteristics and the final decision about transplantation of a specific donor organ is made The ultimate decision regarding the use of a donor organ is made by the transplant surgeon At this stage, the transplant center may need to obtain further tests to assess the functional status of one or more organ systems For example, if the heart is to be recovered, an echocardiogram is usually obtained In selected donors, coronary angiography is performed Pulmonary status can be further assessed by bronchoscopy after considering the results of the chest radiograph, oxygenation challenge, and sputum cultures For potential liver donors who might have fatty liver disease, a percutaneous bedside liver biopsy can be performed If concern over the suitability of organs arises, direct inspection by the transplant surgeon is necessary at the time of the organ procurement operation In some cases, an open biopsy (e.g., for kidney or liver) and frozen section pathologic analysis obtained at the time of organ recovery also help in the final decision-making Direct inspection also is important in organ donors who suffered a blunt injury to the head and trunk (e.g., motor vehicle accident) Under these circumstances, intraabdominal organs have been used successfully despite the presence of parenchymal tears or subcapsular hematomas in either the liver or the kidney Significant injuries to the pancreas preclude its use In summary, each patient with a severe nonrecoverable neurologic injury should be referred to the local OPO as a potential donor, regardless of the type of brain injury (e.g., trauma, stroke), history, age, or medical condition (Table 56.3) With few exceptions (vide infra), organ donation should never be excluded a priori because of the clinical situation, the results of imaging studies, or the magnitude of an injury, without first having contacted the local OPO (24-hour access number: 1-800-2929537) Organ-Specific Considerations The use of kidneys from older donors, donors dying of cardiovascular disease, or donors requiring large doses of inotropic drugs for cardiovascular support entails a higher rate of delayed graft function and is associated with decreased graft survival [85,86] Nevertheless, organs from these marginal donors are routinely used given the current prolonged periods (which can be longer than 8 to 10 years in some areas) that some recipients may wait for available organs, during which their medical condition may deteriorate Marginal donor kidneys benefit from preservation on a pulsatile perfusion pump, which was shown to improve preservation quality, quality of early graft function, and long-term outcomes [42] In equivocal cases (e.g., donors with elevated baseline serum creatinine levels or a history of hypertension), renal biopsies at the time of organ recovery may quantify the amount of preexisting donor arteriosclerosis or glomerulosclerosis The critical shortage of organs has led to increasing relaxation of exclusion criteria, with satisfactory long-term results in many recipients p 477 p 478 Livers from donors with an abnormal liver enzyme or coagulation profile can frequently still be transplanted Elevated hepatic enzyme levels may reflect transient hepatic ischemia at the time of resuscitation The trends observed in the results of serial hepatic enzyme levels can be more informative than absolute values Abnormal coagulation test results may be due to disseminated intravascular coagulation (commonly a result of brain injury, not primary hepatic dysfunction) Significant donor hypernatremia (e.g., >155 mg per dL), as commonly observed in underresuscitated brain-dead donors with significant diabetes insipidus, may be a risk factor for primary liver graft nonfunction posttransplant Aggressive intervention prior to procurement is warranted and will ultimately allow for safe transplantation of liver grafts from these hypernatremic donors The decision to use a liver from a marginal donor has to be made on the basis of relatively limited information Often, only direct inspection, with or without a biopsy of the liver, at the time of organ recovery provides a final answer and may be the only way to assess a donor with a history of significant ethanol intake Severe macrovesicular hepatic steatosis is one of the most significant factors predictive of early posttransplant hepatic dysfunction or failure In general, donors older than 60 years of age are not considered for pancreas donation However, donors with hyperglycemia [caused by peripheral insulin resistance, particularly after brain death (see the section “Endocrine Therapy”) or with hyperamylasemia (which can be a consequence of severe head injury without actual pancreatitis)] are not to be excluded a priori from pancreas donation, because these factors do not necessarily influence posttransplant outcome [87,88] A pancreas transplant registry analysis suggested a slightly higher incidence of graft thrombosis for pancreata that had been procured from donors treated with desmopressin (vs those that did not) [89] Clearly, further study is necessary to confirm or refute these findings and determine their clinical significance Currently, the only absolute contraindications to pancreas donation are a history of impaired glucose tolerance or insulin-dependent diabetes mellitus, direct blunt or penetrating trauma to the pancreas, or the finding of acute or chronic pancreatitis at the time of the donor operation Regarding heart donation, an important criterion is good donor heart ventricular function immediately before retrieval, as judged by the cardiac surgeon at visual inspection during organ recovery Ideally, no potential heart donor should be excluded solely on the basis of echocardiographic wall motion abnormalities, a borderline or abnormal ejection fraction, inotropic medication requirements, or heart murmurs, arrhythmias, or other electrocardiographic changes (which often occur in brain-dead individuals in whom no cardiac disease is present) Risk factors associated with poorer outcomes after lung transplantation include a history of smoking, aspiration, purulent secretions observed during bronchoscopy, an abnormal chest radiograph, or an unsatisfactory oxygenation challenge (PaO2 less than 300 mm Hg after 10 minutes of ventilation with FiO2 of 1.0 and low positive end-expiratory pressure [PEEP] of 5 cm H2O) alone or in combination in lung donors However, even lungs with these characteristics have been successfully transplanted [90] Bronchoscopy often is performed as a final preoperative confirmatory test in the operating room by the lung recovery surgeon Direct intraoperative inspection of the lungs determines whether significant contusions are present, which could preclude use of the organs In conclusion, the traditional donor criteria have been considerably expanded over recent years, for both thoracic and abdominal organs, due to the ongoing, severe donor shortage Transmission of Infectious Diseases Transmission of bacterial or fungal infection through organ transplantation can potentially be due to an infection of the donor or contamination of the organ itself during organ procurement or storage Published evidence suggests that organs transplanted from bacteremic donors and from donors with bacterial meningitis do not transmit bacterial infection or result in poorer recipient outcomes provided that donor and recipient(s) are adequately treated with antibiotics [91] Similarly, positive urine cultures do not preclude renal donation and transplantation Organs from donors with serologic evidence of syphilis can be used as long as the recipients are given adequate antibiotic prophylaxis Seropositivity for HIV no longer constitutes an absolute contraindication to organ donation, as the federal ban on transplantation of organs from HIV-positive individuals has been lifted [92] As of late 2015, transplant hospitals that meet specific criteria set forth by the OPTN can consider HIV-positive organs for HIV-positive kidney and liver candidates Organs from donors that fulfill the Public Health Service’s behavioral criteria for being at increased risk for having acquired HBV, HCV, or HIV infection are frequently transplanted following careful case-by-case consideration and after obtaining specific recipient consent [93] Decision-making by the OPOs and transplant centers regarding the use of organs from these high-risk donors has been greatly facilitated by the now widespread use of nucleic acid testing for those viral pathogens [94] Potential donors that test positive for the HBV surface antigen, the HBe antigen, or for HBV-DNA are usually precluded from donating Serologic positivity for the hepatitis B core antigen antibody, however, does not constitute an absolute contraindication to proceed with donation [95] Acceptable organs from donors with serologic evidence of HBV are usually only transplanted into recipients that have demonstrated immunity against HBV (i.e., HBsAb positivity) [95] Selected recipients may also receive HBV immunoglobulin or an antiviral agent (e.g., entecavir) or both, beginning at the time of transplant [95] Ideally, however, all potential organ transplant recipients should have received HBV immunization prior to their pretransplant evaluation The use of HCV seropositive donors for selected recipients has become routine [96] For adequate identification of HCV-positive donors, OPOs routinely perform besides HCV antibody testing and nucleic acid testing for HCV-RNA HCV-infected livers and kidneys transplanted into HCVinfected recipients do not convey a worse outcome than HCV-negative grafts [96] The final decision regarding the use of an HCV serology– positive donor must be made on an individual basis by each transplant surgeon Factors that are taken into account in such circumstances include the likelihood of disease transmission, the recipient’s current medical and serologic status, and the availability of modern drugs for the treatment and eradication of HCV [96] CMV can also be transmitted by donor tissue, particularly to CMVseronegative patients Effective prophylaxis against, and treatment of, CMV disease has become routine because of the availability of highly effective antiviral agents such as ganciclovir and valganciclovir Positive CMV serologies do therefore not preclude organ donation but have been used to identify high-risk donor–recipient combinations (i.e., CMVseropositive donor to CMV-seronegative recipient) where enhanced prophylaxis should be used and careful surveillance for CMV disease is important However, organ donation is contraindicated if potential donors exhibit or develop active bacterial or fungal sepsis that is unresponsive to adequate source control and antibiotic therapy Similarly, active tuberculosis is a contraindication to organ donation Absolute contraindications to donation also include evidence of significant acute viral infections (e.g., viral encephalitis, systemic herpes simplex virus infections, acute viral HAV, HBV, or HCV) For similar reasons, donation should not proceed in patients in whom a definitive etiology for their febrile illness, encephalitis, meningitis, or flaccid paralysis is not ascertainable p 478 p 479 Transmission of Malignancy The risk for transmission of a donor malignancy to a solid organ recipient is low overall [97] In that regard, appropriate selection of donors with a current or past history of cancer is paramount If a potential donor has had successful cancer treatment in the past, the transplant surgeon must weigh the small potential risk of transmitting micrometastases against discarding a potentially life-saving organ In general, patients with a history of malignancy with little propensity to recur after therapy (e.g., small, noninvasive lesions treated by complete surgical excision) are considered as organ donors, particularly if they have remained without evidence of recurrence for more than 5 years Patients who have experienced invasive cancer in which a substantial risk of late recurrence exists (e.g., breast cancer, malignant melanoma, lung cancer), particularly if a large lesion was initially present and chemotherapy or radiation therapy was used, should not be considered for donation Similarly, patients with a history of leukemia or lymphoma should not be considered as donors Individuals with low-grade skin malignancies such as basal cell carcinoma and most squamous cell carcinomas, and with an in situ carcinoma of the uterine cervix are routinely used as donors Patients with tumors of the central nervous system (CNS) can be considered for donation on a case-by-case basis [97,98] It is important to ensure that a CNS tumor does not represent a focus of metastatic disease from an extracerebral primary site Metastases from choriocarcinomas, bronchial or renal malignancies, and malignant melanomas may present as what appears to be a primary brain tumor or may bleed and be mistaken for an intracranial hemorrhage Previous treatment of a neoplasm, menstrual irregularities after a pregnancy or a spontaneous abortion in women of childbearing age (suggestive of a choriocarcinoma), or evidence of suspicious lesions at other sites in the patient with a purported primary CNS malignancy should preclude organ donation Donors with primary CNS tumors should not be used if they have undergone radiotherapy, chemotherapy, ventriculoperitoneal or ventriculoatrial shunting, or craniotomies, because these treatments either are associated with high-grade malignancies or create potential pathways for the systemic dissemination of tumor cells [97,98] Patients with low-grade CNS tumors (grades I to II) should be considered as acceptable donors as long as they were not subjected to any of the aforementioned interventions [18,97,98] Those with a high-grade (grades III to IV) CNS malignancy and/or one of the aforementioned interventions are at a higher risk for malignancy transmission In those cases, the transplant surgeon must therefore carefully assess the risk of malignancy transmission versus the risk to the potential recipient of not receiving the organ [18,96,97] Required Request for Organ Donation and Consent After the OPO determines the suitability of a potential donor, the next important steps are the brain death examination (when applicable) and the legally required request for organ donation (Table 56.6) Those steps should not involve any of the physicians associated with the transplant team, as this would represent a potential conflict of interest In 1987, federal required request legislation became effective and has since been adopted by every state in the United States This requirement has been further strengthened by the CMS’s 1998 Conditions of Participation (vide supra) [75] Required request laws mandate that the family of a potential organ donor be offered the option of organ donation The hospital must notify the local OPO of the presence of a potential organ donor Several studies have shown that consent rates are highest when an OPO coordinator—rather than a member of the patient’s ICU team such as a physician or a nurse—approaches the family about organ donation [11–13,71] Brain-Dead Donors For brain-dead donors, it is of utmost importance to ensure that (a) the family understands and accepts the concept of brain death, including its legal and medical equivalence with death; (b) the request for organ donation not be made at the same time that brain death is explained (unless the family voiced the wish to consider donation earlier during the hospitalization); and (c) the approach and request be made by an OPO representative (rather than a member of the potential donor’s care team) Sufficient time must be given to the next of kin to begin coping with this information and to accept the loss of the family member Only then, in clear temporal separation from the explanation of death, should the subject of organ donation be broached and an appropriate request be made [11,13] Also, the family must be informed that, after declaration of brain death and consenting to organ donation, all hospital costs relating to donation will be paid by the OPO DCD Donors Families of patients with severe, irreversible brain injuries who do not fulfill the formal criteria of brain death might decide to forgo any further life-sustaining treatment Only then can the subject of organ donation be broached with the family As discussed earlier, it is paramount that the approach to the family and the request for organ donation be made by an OPO representative [18,26,27,99,100] Consent For those individuals that have not expressed in a legally binding form their desire to become an organ donor (“first-person authorization”), the Uniform Anatomical Gift Act of 1968 specifies the legal next-of-kin priority for donors over age 18 years in the following order: (a) spouse, (b) adult son or daughter, (c) either parent, (d) adult brother or sister, and (d) legal guardian [78] Similarly, the order of priority for donors under age 18 years is as follows: (a) both parents, (b) one parent (if both parents are not available and no wishes to the contrary of the absent parent are known), (c) the custodial parent (if the parents are divorced or legally separated), and (d) the legal guardian (if there are no parents) [71] The Revised Anatomical Gift Act of 2006 provides stipulations that bar others from overriding a donor’s first-person authorization and empowers minors that apply for a driver’s license to become donors (vide supra) [72,101] First-person authorization may be provided by signing up with a donor registry (which is now possible online in all 50 States), notation on the driver’s license, a donor card, or documentation of preferences (i) with a primary care provider, (ii) in a durable power of attorney, or (iii) in an advance directive [18] In part as a result of these now available options, an increasing proportion of patients will have previously expressed preference for organ donation (i.e., will have provided first-person authorization) In 2015, for instance, 46% of all organ recovery operations were authorized through the donor’s consent that he/she had previously registered with a state donor registry (firstperson authorization) [101] Critical care specialists must be aware that occasionally conflicts may arise from discrepancies between a donor’s wishes expressed in a first-person authorization and the views of their family members or other surrogates These sensitive situations require resolution through collaboration involving OPO representatives, ICU physicians, hospital representatives, and the patient’s surrogates [18] PERIOPERATIVE CRITICAL CARE OF THE BRAIN-DEAD ORGAN DONOR There is an overall lack of randomized, controlled studies that could lead to a more evidence-based approach to the care of these patients The levels of evidence provided by these studies are generally low It is therefore important to acknowledge that some of the following recommendations may undergo substantial revision as additional, new evidence emerges (Table 56.7) p 479 p 480 TABLE 56.7 Management of the Deceased Organ Donor: Selected Evidence Published 1993–2015 Study design Study Outcome No of cases Reference Effect of medical (primarily nonpharmacologic) interventions and of donor management protocols Case–control study Case–control study Prospective case series with historical Effect of critical donor pathway (including hormonal resuscitation protocol component) Impact of hospital-based OPO coordinators on conversion rates Impact of aggressive lung management strategies (incl Significant 270 increase of organs procured, organ quality unchanged Rosendale et al [19] Higher donor conversion rate in hospitals with hospital-based OPO coordinators Significant increase of lungs recovered without adverse NA Shafer et al [67] 711 Angel et al [102] controls RCT RCT recruitment maneuvers, fluid restriction, diuresis, aspiration precautions) on lung recovery rates and transplant outcomes Effect of multipronged lung-protective strategy (incl low tidal volume, higher PEEP) vs conventional strategy on lung recovery rate Impact of mild hypothermia (target: 34°C– 35°C) in braindead donors on early function of kidney grafts effect on transplant outcomes Lung-protective 118 strategy nearly doubled the lung recovery rate Mascia et al [103] Significant reduction of delayed graft function in recipients of kidney from the hypothermia donor group Niemann et al [104] 370 Effect of donor pretreatment—Single pharmacologic agents Retrospective cohort study Effect of catecholamine administration to brain-dead donors on graft survival Retrospective cohort study Effect of dopamine administration on quality of early graft Catecholamine 3,890 use associated in dose-dependent manner with significantly better kidney graft survival Lower recipient 254 delayed graft function rates and faster creatinine Schnuelle et al [105] Schnuelle et al [106] RCT Case–control study RCT RCT Retrospective cohort study function in the decrease in the recipients dopamine group Effect of Decreased continuous lowposttransplant dose dopamine need for >1 infusion in stable dialysis session; donors with no effect on normal renal rejection and function on early short-term graft recipient graft survival outcomes High-dose No graft survival steroids and differences for aggressive lungs from management for marginal vs marginal lung standard donors donors Effect of highImproved dose continuous posttransplant steroid infusion clinical in liver donors reperfusion on parameters (liver posttransplant enzymes, outcomes bilirubin) and less early liver rejection for grafts from the steroid group Effect of intensive No effect of singlelung donor agent management pharmacologic protocol + prerecovery (steroids or T3 or interventions on [steroids + T3] or lung yield; placebo) on significantly less prerecovery lung extravascular quality and lung lung water yield accumulation in steroid groups Effect of donor Higher thrombosis desmopressin rates in pancreas 265 Schnuelle et al [107] 194 Straznicka et al [108] 100 Kotsch et al [109] 60 Venkateswaran et al [23] 2,804 Marques et al [89] Retrospective cohort study RCT RCT RCT use on pancreas grafts from graft thrombosis donors that had rates (UNOS received recipient desmopressin database) Effect of use of Favorable impact individual drugs of steroids or on organ yield desmopressin, (UNOS donor but not T4, on database) organ yield Effect of low-dose Increase in blood vasopressin vs pressure and saline on donor decrease in hemodynamics inotrope use in and inotrope use vasopressin group Effect of T3 No differences for infusion (limited posttransplant to the duration liver graft of the organ function procurement operation) vs no T3 Effect of T3 No differences in infusion (within hemodynamics 60 mm Hg and the absence of metabolic acidosis (with or without infusion of a small amount of dopamine) with concurrent adequate urine output (at least 1 to 2 mL/kg/h) are usually better indirect indicators of donor stability and sufficient oxygen delivery to organs and tissues (Table 56.8) It is important to remember, however, that the use of vasoconstrictor or inotropic agents is not a substitute for adequate fluid resuscitation Thus, proper fluid management remains the cornerstone of successful donor management p 482 p 483 TABLE 56.8 Maintenance Therapy Endpoints for Brain-Dead Organ Donors Variable Therapeutic endpoint Systolic blood 100–120 mm Hg or mean pressure Central venous pressure Urine output Core temperature Partial arterial oxygen pressure Systemic arterial oxygen saturation pH Hemoglobin arterial pressure ≥60 mm Hg 6–8 mm Hg >1 mL/kg/h >35°C 80–100 mm Hg 95% 7.37–7.45 8–10 g/dL The use of vasopressors should be minimized if at all possible because of their splanchnic vasoconstrictive effects Efforts to elevate blood pressure beyond the normal range can adversely affect outcome and should be avoided: high doses of vasopressors can cause arrhythmias and increase myocardial oxygen consumption, and pulmonary edema after excessive fluid administration can render lungs unsuitable for transplantation After the lung, the pancreas is the organ most prone to tissue edema Normal central venous pressure and PEEP help maintain an adequate perfusion gradient across the hepatic microcirculatory bed (i.e., that between the portal vein and hepatic artery on one side and the inferior vena cava and right atrium on the other) Selective use of pulmonary artery catheterization must be considered in donors who do not respond to routine management and continue to exhibit hypotension or persistent lactic acidosis after adequate volume loading, particularly in those in whom this occurs despite use of moderate doses of dopamine Determining pulmonary artery and pulmonary artery occlusion pressures, cardiac output and index, pulmonary and systemic vascular resistive indices, oxygen availability and consumption, and other parameters helps to differentiate the cause of instability In selected patients, echocardiographic assessment of the left ventricular ejection fraction may prove useful Appropriate therapy can then be administered (e.g., fluid balance correction or PEEP adjustments, additional inotropic support, preload or afterload reduction) Once the hemodynamic instability has resolved, pulmonary artery catheters should be removed to eliminate the inherent risks of infection, induction of arrhythmias, and mechanical endomyocardial damage Cardiovascular Support Hypotension is the most common hemodynamic abnormality seen in brain-dead organ donors The usual cause is hypovolemia, because of a combination of vasomotor collapse after brain death and the effects of treatment protocols to decrease intracranial pressure, which require minimization of hydration and use of osmotic diuretics (Tables 56.9 and 56.10) After brain death is declared, adequate volume resuscitation of the donor can require several liters of fluid Until a euvolemic state is achieved, dopamine (greater than 3 µg per kg per minute) can be used temporarily; the dose should be titrated to maintain an adequate systolic blood pressure [18] Infusion rates greater than 10 µg/kg/min have been associated with increased rates of acute tubular necrosis and decreased renal allograft survival High infusion rates also lead to decreased perfusion of other organs because of splanchnic vasoconstriction TABLE 56.9 Differential Diagnosis of Hypotension in the Brain-Dead Organ Donor Diagnosis Hypovolemia Hypothermia Cardiac dysfunction Common Underlying Cause(s) see Table 56.10 Loss of central temperature control, administration of room-temperature intravenous fluids and blood products, heat loss during laparotomies and thoracotomies Arrhythmia (ischemia, catecholamines, hypokalemia, hypomagnesemia) Acidosis Hypooxygenation Excessive positive endexpiratory ventilatory pressure Congestive heart failure due to excessive fluid administration Hypophosphatemia Causes related to the injury leading to brain death (cardiac tamponade, myocardial contusion) Myocardial sequelae of autonomic storm Preexisting cardiac disease Drug side Long-acting β-blocker, effect or calcium channel overdose antagonist, antihypertensive agent Hypocalcemia Transfusions, hypomagnesemia (e.g., secondary to osmotic diuresis), acute renal failure TABLE 56.10 Differential Diagnosis of Hypovolemia in the Brain-Dead Organ Donor Arterial and venous vasomotor collapse due to loss of central neurohumoral control Dehydration (fluid restriction to treat head injury) Insufficient resuscitation after the injury leading to brain death (e.g., ongoing hemorrhagic shock with coagulopathy after trauma) Polyuria Osmotic diuresis (mannitol, hyperglycemia) Diabetes insipidus Hypothermia Administration of other diuretics Massive third spacing in response to the original injury Decreased intravascular oncotic pressure after excessive resuscitation with crystalloid fluids p 483 p 484 Dopamine is also the drug of choice if hemodynamic instability persists after fluid resuscitation and adequate volume loading Use of isoproterenol and dobutamine should be avoided in this context because of their vasodilatory effects Drugs with α-adrenergic agonist effects such as phenylephrine (IV infusion 0.15 to 0.75 µg/kg/min) and norepinephrine (IV infusion up to 0.05 µg/kg/min) should be added only if hypotension persists in the face of euvolemia and titration of the dopamine infusion up to 15 µg/kg/min α-Adrenergic agonists can cause severe peripheral vasoconstriction, reduce renal and hepatic perfusion, and may predispose to increased pulmonary capillary permeability For these reasons, they must be used judiciously Once these drugs are used, the need for their continued use must be frequently reassessed [18,25] For the majority (>80%) of donors, adequate hemodynamic goals can be achieved with volume resuscitation and low to moderate doses of a single vasopressor agent (dopamine) Several studies have suggested that administration of catecholamines, and in particular of dopamine, to brain-dead patients may exert a beneficial impact on early kidney graft function and graft survival [105–107,123] Several potential mechanisms have been invoked to explain these observations, including favorable modulatory effects on ischemia–reperfusion and on upregulation of adhesion molecules that results from the inflammatory state induced by brain death [105–107] Low-dose arginine vasopressin can serve as an alternative first-line or as an additional vasopressor It enhances vascular sensitivity to catecholamines and causes vasoconstriction through multiple effector pathways; it may thus allow minimizing catecholamine dose and side effects [111,124,125] Effective arginine vasopressin doses for improving hemodynamic stability range from 0.01 to 0.1 International Units per minute (starting dose: 0.01 to 0.04 International Units per minute) given as continuous intravenous infusion [18,111,124] The use of arginine vasopressin in brain-dead organ donors has been associated with improvement of cardiac performance and increased rates of organ recovery [125] When attempting to determine the etiology of hypotension in an organ donor, underlying cardiac disease (e.g., coronary artery disease, valve defects) and factors related to the cause of brain death (e.g., myocardial infarction, cardiac tamponade, or myocardial contusion) must be included in the differential diagnosis Electrolyte abnormalities such as hypophosphatemia, hypocalcemia, hypokalemia, and hypomagnesemia are common in brain-dead organ donors The presence of these entities must also be considered when hemodynamic instability is encountered, and frequent testing and correction of these significant electrolyte imbalances are important Hypophosphatemia and hypocalcemia can decrease myocardial contractility and provoke hypotension [126]; hypokalemia and hypomagnesemia can also impair hemodynamics by causing arrhythmias For the treatment of arrhythmias or hypertension, medications that possess rapid reversibility and a short half-life are preferred Hemodynamic instability can be pronounced after brain death, with wide swings between the extremes of hypotension and hypertension, rendering the brain-dead donor more susceptible to cardiovascular drug effects Hypertension can be treated with short-acting vasodilatory agents (e.g., nitroprusside) or a rapidly reversible β-adrenergic antagonist (e.g., esmolol hydrochloride), because hypertension is usually associated with increased circulating catecholamines Other drugs, such as calcium channel blockers (e.g., verapamil) or longer-acting β-blockers (e.g., labetalol, propranolol), should be avoided because of their negative inotropic effects and the inability to titrate them precisely Bradyarrhythmias during the early phase of brain herniation are part of Cushing’s reflex and do not usually require any treatment, unless they are associated with hypotension and asystole Because of the lack of chronotropic effects by atropine after brain death, use of either isoproterenol or epinephrine is required to treat hemodynamically significant bradyarrhythmias Tachyarrhythmias are associated with the increased catecholamine release that occurs during and immediately after brain herniation Administration of short-acting β-blockers (e.g., esmolol hydrochloride) serves not only to treat arrhythmias but also to mitigate hypertension during the autonomic storm Use of additional short-acting IV antiarrhythmics (e.g., lidocaine) may become necessary if tachyarrhythmias do not resolve after β-blocker therapy Calcium channel blockers (e.g., verapamil) must be avoided under these circumstances because of their negative inotropic effects Cardiac glycosides (e.g., digoxin) also should not be used because they can induce and potentiate bradyarrhythmias and tachyarrhythmias, and they also have splanchnic vasoconstrictive side effects Cardiac arrest can occur in up to 25% of all donors during the maintenance phase after brain death and should be treated by routine measures, with the exception that isoproterenol or epinephrine must be substituted for atropine [83,84] If these measures fail to result in the return of a cardiac rhythm, external (transcutaneous) pacing may be considered However, the efficacy of external pacing for asystole associated with brain death is unknown No intracardiac injections should be given during cardiopulmonary resuscitation because they can render the heart unsuitable for transplantation Respiratory and Acid–Base Maintenance Use of endotracheal suctioning is usually minimized during the treatment of cerebral edema to avoid any unnecessary stimulation that would increase intracranial pressure In contrast, after brain death is declared, vigorous tracheobronchial toilet is important, with frequent suctioning using sterile precautions Percussion and turning for postural drainage are instituted as well Even if the lungs are unsuitable for donation, it is important to minimize the risk of atelectasis and infection Preventing atelectasis facilitates oxygenation and may obviate the need for detrimental high levels of PEEP Steroids administered to some patients as part of the treatment for increased intracranial pressure predispose to pulmonary infectious complications The presence of pneumonia can preclude donation of the lungs as well as other organs, depending on its severity and association with systemic sepsis Routine respiratory care of all donors also includes the use of 5 cm H2O PEEP to increase alveolar recruitment and prevent microatelectasis [18,19,25] The etiology of pulmonary edema in organ donors can be cardiogenic, neurogenic, aspiration induced, a result of trauma or fluid overload, or a combination of these factors Neurogenic pulmonary edema can preclude lung or combined heart–lung donation, but not donation of other organs (e.g., heart, kidney, liver, pancreas) The treatment for pulmonary edema is supportive and should be directed at maintaining adequate arterial oxygenation without using very high levels of PEEP Fluids must be administered carefully to maintain organ perfusion while avoiding exacerbation of the edema In potential lung donors, the endotracheal tube should not be advanced more than several centimeters into the trachea, to prevent damage to areas that may become part of an anastomosis A sample of sputum should be obtained for Gram’s stain and cultures to exclude the presence of infection The samples can be obtained using bronchoscopy, a procedure that is often routinely performed before lung donation Traditionally, tidal volumes of 10 to 12 mL per kg and relatively low PEEP target ranges (3 to 5 cm H2O) have been recommended However, there is now evidence that lung-protective ventilatory strategies that have become standard of care for regular ICU patients—i.e., tidal volumes of 6 to 8 mL per kg and PEEP of 8 to 10 cm H2O—are also beneficial for the management of the often injured lungs of brain-dead donors [18,25,127,128] In a randomized trial, the number of transplanted lungs doubled when a lung-protective strategy was pursued [102] Aggressive living donor management protocols aimed at improving alveolar recruitment and oxygenation have proven successful with high rates of conversion from unacceptable to acceptable PaO2/FiO2 ratios [102] For potential lung donors, the lowest FiO2 that is capable of maintaining a PaO2 of greater than 100 mm Hg should be selected If oxygenation is insufficient, PEEP should be increased rather than increasing the FiO2 Very high levels of PEEP may negatively affect cardiac output, which should be carefully monitored in this setting If hypotension occurs, PEEP should be reduced Under these circumstances, use of pulmonary artery catheterization should be considered to balance PEEP requirements against those of organ perfusion In contrast, to correct insufficient arterial oxygenation in nonlung donors, an increase in FiO2 is preferred over high levels of PEEP [25] p 484 p 485 There is no direct evidence stemming from controlled trials that would support a specific fluid management strategy in prospective lung donors Indirect evidence from studies that involved ICU patients with acute respiratory distress syndrome, as well as prospective lung donors, supports a conservative fluid management approach with prospective donors [102,129] To date, there is no evidence that such a conservative fluid management approach in donors adversely impacts the function of kidney grafts obtained from the same donor [130] Excessive use of crystalloid fluids during the initial resuscitation after brain death is declared can render the lungs unsuitable for transplantation If relatively large amounts of fluid are required for resuscitation and hemodynamic stabilization, colloids (i.e., albumin solutions) or blood transfusions (if the hemoglobin is less than 8 g per dL) should be considered in addition to the infusion of crystalloid solutions [18] Respiratory alkalosis can develop in brain-dead organ donors secondary to mechanical hyperventilation as part of the treatment protocol for elevated intracranial pressure After brain death, the arterial pH should be adjusted to normal values because alkalosis has many undesirable side effects, such as increased cardiac output, systemic vasoconstriction, bronchospasm, and a shift to the left of the oxyhemoglobin dissociation curve The latter decreases oxygen unloading in the tissues and impairs oxygen delivery, thereby diminishing tissue oxygenation and metabolism Lactic metabolic acidosis is frequent in brain-dead donors; it should be treated by compensation with a slight respiratory alkalosis until the underlying abnormality has been corrected (e.g., dehydration, tissue ischemia) Administration of sodium bicarbonate should be contemplated only if the increased minute ventilation necessary to induce respiratory alkalosis leads to a decrease in cardiac output In either situation, the most important aspect of managing metabolic acidosis is to treat the underlying cause In selected patients this may require pulmonary artery catheterization to assess the adequacy of hydration, cardiac output, and tissue oxygen delivery Renal Function and Fluid and Electrolyte Management Maintaining adequate systemic perfusion pressure while minimizing the use of vasopressors contributes to good renal allograft function and reduces the rate of acute tubular necrosis after transplantation If the urine production is insufficient (e.g., less than 0.5 mL/kg/h) after adequate volume loading, loop diuretics (furosemide, ethacrynic acid, bumetanide) or osmotic diuretics (mannitol) can be considered to initiate diuresis Nephrotoxic drugs (e.g., aminoglycosides) and agents that may exert adverse effects on renal perfusion (e.g., nonsteroidal antiinflammatory drugs) are contraindicated Cephalosporins, monobactams, carbapenems, and quinolones are examples of less nephrotoxic but effective antibiotics that can be used if infection occurs Polyuria in brain-dead donors is a frequent finding It can be due to diabetes insipidus, osmotic diuresis (induced by mannitol administered to decrease elevated intracranial pressures or hyperglycemia), physiologic diuresis due to previous massive fluid administration during resuscitation after the original injury with return of third-space fluid into the intravascular space, or hypothermia Diabetes insipidus often heralds brain death in head-injured patients It is the most frequent cause of polyuria during the organ donor maintenance phase Found in up to 80% of all brain-dead bodies [81], it is related to insufficient blood levels of antidiuretic hormone (vasopressin), resulting in the production of large quantities of dilute urine Diabetes insipidus should be suspected when urine volumes exceed 300 mL per hour (or 7 mL/kg/h) in conjunction with hypernatremia (serum sodium greater than 150 mEq per dL), elevated serum osmolality (greater than 310 mOsm per L) and a low urinary sodium concentration In addition to hypernatremia, other electrolyte abnormalities frequently observed during diabetes insipidus include hypokalemia, hypocalcemia, and hypomagnesemia The appropriate replacement of these electrolyte losses can be guided by urinary electrolyte determinations, which easily allow calculation of the amount of the electrolyte to be replaced Because diabetes insipidus is so common, mannitol administration should be discontinued after brain death is declared Other supportive care of patients with diabetes insipidus includes replacing urine output milliliter for milliliter with free water (e.g., 5% solution of dextrose in water IV) Once urine output due to diabetes insipidus exceeds 300 mL per hour, desmopressin (desamino-8-D-arginine vasopressin), a synthetic analog of vasopressin (or arginine vasopressin), should be administered Desmopressin has a long duration of action (6 to 20 hours) and a high antidiuretic-to-pressor ratio, without any undesirable splanchnic vasoconstrictive effects that can occur with administration of normaland high-dose arginine vasopressin [18,25,131] For example, doses of 1 to 2 μg desmopressin are administered intravenously every 8 to 12 hours to achieve a urine output less than 300 mL per hour [18,25,131] Desmopressin can also be effectively administered subcutaneously, intramuscularly, and intranasally Alternatively, in donors with diabetes insipidus that are also hypotensive due to a low systemic vascular resistance (SVR), an arginine vasopressin IV infusion can be started at 0.5 International Units per hour and titrated up to 6 International Units per hour, targeting a urine output of 0.5 to 3 mL/kg/h and a serum sodium of 135 to 145 mEq per L [18,25] Compared to desmopressin, arginine vasopressin is easily titrated and adds beneficial hemodynamic effects The choice of the resuscitation fluid depends on the clinical circumstances and the donor’s electrolyte, osmolar, and acid–base state Generally, for intravascular volume replacement, an isotonic crystalloid is preferred (i.e., 0.9% saline solution [in hypoosmolar patients] or lactated Ringer’s solution [in the setting of hyperchloremic metabolic acidosis]) For correction of hypernatremia in euvolemic or near-euvolemic patients, hypotonic fluids (e.g., D5W or 0.45% saline solution) can be administered (e.g., during the initial resuscitation phase after brain death is declared) [18] For intravascular volume expansion to address acute hypotension, albumin 5% is the preferred colloid Use of low- or high-molecular-weight hydroxyethyl starch (HES) is contraindicated as it is associated with acute kidney injury and coagulopathy because it is trapped within the hepatic reticuloendothelial system Consistent with these concerns, HES use in donors was shown to result in higher delayed kidney graft function and failure rates [132] Subsequently, maintenance fluid should consist of 5% dextrose in 0.45% sodium chloride with 20 mEq potassium added to each liter, administered at a rate of 2 mL/kg/h during the maintenance phase if urine output is adequate (greater than 1 to 2 mL/kg/h) If the urine output is greater than 2 mL/kg/h, IV fluids should be administered at a rate equal to the urine output during the previous hour (IV intake = urine output) If the serum sodium concentration exceeds 150 mEq per dL, the maintenance fluid should consist of 5% dextrose solution with 20 mEq potassium added to each liter Should the hourly fluid administration rate exceed 500 mL per hour, the dextrose concentration of the maintenance fluid should be decreased to 1% to avoid excessive hyperglycemia IV maintenance fluids administered to brain-dead organ donors should contain glucose, which is important to maintain intrahepatic glycogen stores that appear to be associated with normal liver allograft function in the early posttransplant period In hypernatremic patients, the sodium content of certain IV fluids and plasma expanders (e.g., albumin solutions) must also be taken into consideration p 485 p 486 Endocrine Therapy According to prior studies, pituitary hormone blood levels do not uniformly decrease after brain death Diabetes insipidus develops in approximately 80% of brain-dead donors as a result of low or absent blood levels of vasopressin [80] These findings are a direct consequence of brain death, which abolishes vasopressin production in the hypothalamic nuclei (supraoptic and paraventricular nuclei) and vasopressin storage and release in the posterior pituitary In contrast, near-normal levels of anterior pituitary hormones, such as thyroidstimulating hormone, adrenocorticotropic hormone, and growth hormone, have been documented after brain death in some studies [133–136] Their persistence is probably due to the preservation of small subcapsular areas in the anterior pituitary, the blood supply of which is derived from small branches of the inferior hypophyseal artery The latter arises from the extradural internal carotid artery, which is relatively protected from increases in intracranial pressure [137] Clinical evidence, however, suggests deficient adrenal cortisol secretion after dynamic stimulation in brain-dead donors, irrespective of the level of pituitary dysfunction [138] The principle of pharmacologic replacement therapy for deficient posterior pituitary vasopressin after brain death is well established [18,19,25,111] A retrospective UNOS database analysis demonstrated a significant association between desmopressin use in donors and organ yield (Table 56.7) [110] Low-dose vasopressin has been shown to exert beneficial hemodynamic effect in brain-dead donors (Table 56.7) [111,125] In contrast, controversy still exists regarding the benefits of supplementation with triiodothyronine [T3] and thyroxine [T4], which are synthesized under anterior pituitary control (Table 56.7) [18,19,25,110,112,114,139–148] Initially, the presence of low T3 blood levels was demonstrated after brain death in animal experiments [149] Administration of exogenous T3 to donor animals improved a variety of metabolic parameters before and after organ preservation [150–152], as well as organ function after transplantation [153] These findings suggested possibly positive effects of T3 also in human donors A limited number of uncontrolled clinical trials suggested favorable influences of donor pretreatment with thyroid hormone on hemodynamic and metabolic parameters during the donor maintenance phase [84,154,155] and on outcome after heart transplantation [156–158] But a number of other investigators failed to observe a significant benefit of thyroid hormone administration on biochemical and hemodynamic donor parameters and on posttransplant outcomes (Table 56.7) [112,113,159,160] The latter outcomes could be explained at least in part by the findings of some studies which have suggested that the low T3 levels in human donors do not correlate with the presence of hemodynamic stability [161,162] or outcome after transplantation [163–166] to begin with The typical thyroidal hormonal pattern after brain death consists of decreased T3, normal or decreased thyroxine, and normal thyroid-stimulating hormone This pattern is not consistent with acute insufficiency of the hypothalamic–pituitary–thyroid axis or clinically overt hypothyroidism, but is similar to changes (sick euthyroid syndrome) observed in other groups of critically ill individuals Thyroid hormone administration to such patients may not only be ineffective but may theoretically even be detrimental in some cases [145,146] In summary, there is no conclusive evidence to date that supplementation of organ donors with thyroid hormone alone yields a significant clinical benefit As per a consensus recommendation by leading North American critical care medicine societies and the U.S Association of OPOs, thyroid hormone replacement therapy—either alone or as part of a combination protocol—should at present be considered for hemodynamically unstable donors with abnormal (10 μg/kg/min) or have an ejection fraction of less than 45% [18,20,21,25] Although brain death is not associated with primary pancreatic endocrine dysfunction, hyperglycemia is frequent in brain-dead donors Hyperglycemia can be caused by increased catecholamine release, altered carbohydrate metabolism, steroid administration for treatment of cerebral edema, infusion of large amounts of dextrose-containing IV fluids, or peripheral insulin resistance Treating hyperglycemia in braindead donors appears to be important with regard to pancreatic islet cell function Experimental evidence suggests that high glucose levels may produce transient or irreversible damage to beta cells in the pancreatic islets, in vitro and in vivo [170,171] This glucose toxicity was attenuated during in vivo experiments by correcting hyperglycemia [172] Clinical studies in pancreas transplant recipients have demonstrated that donor hyperglycemia is a risk factor for decreased graft survival [88] It was not established in these studies, however, whether donor hyperglycemia was indicative of marginal or insufficient beta-cell mass or whether impaired pancreatic graft function was related to islet cell dysfunction as a result of hyperglycemia p 486 p 487 Hyperglycemia in and of itself is known to cause insulin resistance [173] Studies in brain-dead donors have suggested that a state of hyperinsulinemia coupled with peripheral insulin resistance exists, as evidenced by elevated C-peptide–glucose molar ratios [174] For all the above reasons, it is prudent to maintain blood glucose levels in donors between 120 and 180 mg per dL [175] Insulin should be administered as needed according to the blood glucose values to mitigate any potential adverse effects of hyperglycemia on pancreatic islets, which could impair glucose homeostasis after transplantation [175] If hyperglycemia persists despite initial bolus insulin therapy, continuous IV insulin infusion should be instituted to facilitate titration of glucose levels As in many other critical care patients, good glycemic control is also good standard practice for brain-dead donors, because it acts to prevent ketoacidosis and osmotic diuresis, both of which can be significant problems in the management of brain-dead donors, and because it may contribute to improved overall organ recovery and transplantation rates [176] Hypothermia After brain death, the body becomes poikilothermic because of the loss of thalamic and hypothalamic central temperature control mechanisms, and hypothermia usually ensues [177] Systemic vasodilation causes additional heat loss Hypothermia can be aggravated by administering room-temperature IV fluids and cold blood products Adverse effects of significant hypothermia include decreased myocardial contractility, hypotension, cardiac arrhythmias, cardiac arrest, hepatic and renal dysfunction, and acidosis and coagulopathy [178–180] Therefore, donor core temperature should be maintained at or above 35°C It is usually sufficient to use humidified, heated ventilator gases; warmed IV fluids and blood products; and warming blankets to achieve rewarming and to maintain an adequate body temperature Rewarming with peritoneal dialysis or bladder irrigations generally should not be performed in organ donors In a randomized trial, a mildly hypothermic target temperature range of 34°C to 35°C in brain-dead patients was associated with significantly decreased delayed graft function rates in the recipients of kidneys from these donors [104] The effect of mild hypothermia on extrarenal donor organs, however, remains unknown for now It is therefore premature to recommend a mildly hypothermic core temperature target range for all brain-dead donors Coagulation System Coagulopathy and disseminated intravascular coagulation are common findings in brain-dead donors, particularly after head injuries Pathologic activation of the coagulation cascade occurs when brain tissue, which is very rich in tissue thromboplastin, comes in contact with blood after trauma Massive blood transfusions can produce dilutional thrombocytopenia, and subsequent ongoing hemorrhage, hypothermia, and acidosis are all able to trigger or further aggravate coagulopathy Clinical findings can include pathologic bleeding, abnormal prothrombin time, thrombocytopenia, hypofibrinogenemia, and increased levels of fibrin/fibrinogen degradation products Treatment of coagulopathy entails use of blood components such as platelets, fresh-frozen plasma, or cryoprecipitate and correction of the underlying pathophysiology (e.g., hypothermia, acidosis, surgical hemorrhage) ε-Aminocaproic acid and tranexamic acid should not be used because of their potential for inducing microvascular thrombosis, thereby rendering organs potentially unsuitable for transplantation [181] Other Aspects Brain death may also adversely affect the donor’s nutritional status Experimental studies have suggested a hypercatabolic state and decreased hepatic intracellular ATP levels [182] Moreover, a suboptimal organ energy and redox status along with the inflammatory changes that result from the chemokine and cytokine release associated with brain death may exert a deleterious influence on the magnitude of, and recovery from, ischemia–reperfusion injury and on posttransplant organ function in the recipient Appropriate nutritional support of the donor may be able to prevent depletion of micro- and macronutrients and may attenuate oxidative stress and ischemia–reperfusion injury However, currently, there are no clinical data available that would directly support routine nutritional supplementation of brain-dead donors For potential small bowel donors, it may be justified to continue any already instituted tube feedings given the beneficial effects of the latter for the maintenance of the intestinal mucosa’s integrity [18,34] Various pharmacologic donor pretreatment protocols to optimize donor and transplant outcomes have been reported The potential clinical effects of administration of catecholamines, vasopressin (or its analog desmopressin), and of steroids on both donor and posttransplant outcomes have already been discussed in detail (Table 56.7) In other studies, verapamil mitigated the adverse impact of elevated cytosolic calcium levels on renal allograft function [183] after donor hemodynamic instability Finally, donor pretreatment with immunosuppressants (other than steroids) may have a favorable impact by preventing upregulation of proinflammatory pathways and increased expression of major histocompatibility complex molecules that have been demonstrated to occur after brain death [120–122] The latter pretreatment modalities, however, must be investigated more extensively before they can be routinely applied Multiple-Organ Donor Operation After consent is obtained, the OPO schedules and organizes the organ recovery operation Often, several surgical teams from different locations participate; their transportation and the preparation of the recipients in the various hospitals must be meticulously coordinated After certification of death according to the state laws occurs, the brain-dead donor is brought to the operating room Full cardiovascular and ventilatory support is maintained throughout the operation, until the organs are flushed and cooled The principles of brain-dead donor management should be reviewed with the anesthesiologist, unless he or she is familiar with the specific clinical aspects of cardiovascular and ventilatory support for brain-dead organ donors Hemodynamic stability must be maintained during the surgical organ retrieval, which is the equivalent of a combined major abdominal and thoracic operation and can last up to several hours Transient tachycardia and hypertension may occur while the surgical incision is being made; they most likely reflect spinal reflexes causing vasoconstrictive responses and adrenal stimulation Subsequently, consideration must be given to the increased heat loss caused by the wide abdominal and thoracic incisions and the duration of the surgery Neuromuscular blocking agents (e.g., vecuronium, cisatracurium, or rocuronium) should be used to inhibit reflex muscular contractions [82] Tubocurarine (which is not available anymore in many countries) should also not be used in brain-dead donors because of its association with hypotension as a consequence of histamine release and ganglionic blockade Maintenance fluid administration throughout the operation must take into account the significant intraoperative fluid losses resulting from extensive dissection with evaporation and blood loss, transection of lymphatic channels, and massive third-space fluid loss p 487 p 488 All organs to be recovered are completely mobilized, and their vascular pedicles are dissected free At the end of the operation, systemic heparinization occurs and cannulas are inserted (depending on the organs to be procured) into the abdominal aorta, inferior vena cava, portal vein, aortic arch, and pulmonary artery Only then is circulatory and respiratory support terminated The organs are flushed in situ with preservation solution to remove blood and to cool the organs to a temperature of 4°C to 7°C Simultaneously, topical external cooling is provided by the application of sterile ice slush The organs are then individually removed, by dividing the remaining attachments and vascular pedicles, and then packaged [47] Storage in preservation solution at 4°C to 7°C in a cooler surrounded by crushed ice allows maximal preservation times of 4 to 6 hours for heart and lungs, approximately 30 hours for livers and pancreata, and about 40 hours for kidneys These preservation constraints are taken into consideration as organs are allocated Critical care of the donor ends when controlled cardiac arrest occurs at the completion of the surgical organ recovery This finality is ephemeral, however, because it results in the start of new lives for the recipients after a successful organ transplant PERIOPERATIVE CRITICAL CARE OF THE DCD ORGAN DONOR Preoperative Care of the Potential DCD Donor (Prior to Obtaining Consent for Organ Donation) Therapy in those patients must remain primarily aimed at treating the underlying pathology (e.g., head trauma, cerebrovascular accident) Any premature (i.e., prior to the family having made the decision to withdraw care and prior to obtaining consent) change of therapeutic objectives would be unethical and may ultimately lead to overall lower consent rates, thereby further exacerbating the current donor organ shortage [26,27,97] Preoperative Care of the Actual DCD Donor (After Having Obtained Consent for Organ Donation) Once consent to proceed with organ donation has been obtained, the focus switches from cerebral protection to preservation of organ function and optimization of peripheral oxygen delivery [26,27,97] Maintenance therapy endpoints in DCD donors are identical to those that apply for brain-dead organ donors (Table 56.8) Because DCD donors do not exhibit the same pathophysiologic characteristics as brain-dead donors, general management principles for DCD donors are more akin to those that apply to non–brain-dead patients in the ICU that are described elsewhere in this book Organ-specific considerations (e.g., use of catecholamines) are the same as those described earlier for brain-dead donors Preterminal and Intraoperative Care of DCD Donors Maintenance therapy as outlined earlier is continued until technologic support is withdrawn and the patient is extubated (either in the ICU or in the operating room) Any additional premortem interventions (e.g., surgical: insertion of femoral cannulas in preparation of organ recovery; pharmacologic: administration of intravenous heparin, opioids, and phentolamine) must occur in strict accordance with local OPO/hospital DCD protocols and policies [26,27,97,184,185] Death is then pronounced by a physician (usually the patient’s intensive care physician) not belonging to the organ recovery and transplant team, according to criteria that are specified by the local OPO/hospital DCD protocol Next, after an additional 2- to 5-minute waiting time, surgical organ recovery begins [26,184,185] For DCD donors, the use of a rapid procurement technique is mandatory in order to minimize warm ischemia time, particularly when highly ischemia-sensitive organs such as the liver, pancreas, or lungs are to be recovered as well [48] Disposition of the patient, if death does not occur within the specified waiting time (which typically ranges between 30 and 90 minutes) after withdrawal of support, is determined by the local protocol (e.g., return of patient to a non–intensive care hospital floor for comfort care only) This aspect is particularly important because as a result of the global efforts to maximize DCD, an increase in the numbers of “unsuccessful” withdrawals of support is to be expected (and must be acceptable to the providers that care for these patients during their terminal hospital admission) REFERENCES https://optn.transplant.hrsa.gov/data/ Accessed July 14, 2017 Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR): OPTN/SRTR 2015 Annual Data Report Rockville, MD, Department of Health and Human Services, Health Resources and Services Administration, 2016 https://www.srtr.org/reports-tools/srtroptn-annual-data-report/ Accessed July 14, 2017 Report of the Task Force on Organ Transplantation: Organ Transplantation: Issues and Recommendation Washington, DC, US Department of Health and Human Services, 1986, p 36 Heffron TG: Organ procurement and management of the multiorgan donor, in Hall JB, Schmidt GA, Wood LDH (eds): Principles of Critical Care New York, NY, McGraw-Hill, 1992, p 891 Najarian JS, Strand M, Fryd DS, et al: Comparison of cyclosporine versus azathioprine-antilymphocyte globulin in renal transplantation Transplant Proc 15[Suppl 1]:2463, 1983 Starzl TE, Iwatsuki S, Van Thiel DH, et al: Report of ColoradoPittsburgh liver transplantation studies Transplant Proc 15[Suppl 1]:2582–2585, 1983 Sutherland DER: Pancreas transplantation: overview and current status of cases reported to the registry through 1982 Transplant Proc 15[Suppl 1]:2597, 1983 Oyer PE, Stinson EB, Jamieson SW, et al: Cyclosporine in cardiac transplantation: a 2½-year follow-up Transplant Proc 15[Suppl 1]:2546, 1983 Evans RW, Orians CE, Ascher NL: The potential supply of organ donors: an assessment of the efficiency of organ procurement efforts in the United States JAMA 267:239–246, 1992 10 Siminoff LA, Arnold RM, Caplan AL, et al: Public policy governing organ and tissue procurement in the United States Ann Intern Med 123:10–17, 1995 11 Siminoff LA, Gordon N, Hewlett J, et al: Factors influencing families’ consent for donation of solid organs for transplantation JAMA 286:71–77, 2001 12 Sheehy E, Conrad SL, Brigham LE, et al: Estimating the number of potential organ donors in the United States N Engl J Med 349:667– 674, 2003 13 Rodrigue JR, Cornell DL, Howard RJ: Organ donation decision: comparison of donor and nondonor families Am J Transplant 6:190– 198, 2006 14 Singbartl K, Murugan R, Kaynar AM, et al: Intensivist-led management of brain-dead donors is associated with an increase in organ recovery for transplantation Am J Transplant 11:1517–1521, 2011 15 Merchant SJ, Yoshida EM, Lee TK, et al: Exploring the psychological effects of deceased organ donation on the families of the organ donors Clin Transplant 22:341–347, 2008 16 Schnitzler MA, Whiting JF, Brennan DC, et al: The life-years saved by a deceased organ donor Am J Transplant 5:2289–2296, 2005 17 Patel M, Zatarain J, De La Cruz S, et al: The impact of meeting donor management goals on the number of organs transplanted per expanded criteria donor: a prospective study from the UNOS Region 5 Donor Management Goals workgroup JAMA Surg 149:969–975, 2014 18 Kotloff RM, Blosser S, Fulda GJ, et al: Management of the potential organ donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations consensus statement Crit Care Med 43:1291–1325, 2015 19 Rosendale JD, Chabalewski FL, McBride MA, et al: Increased transplanted organs from the use of a standardized donor management protocol Am J Transplant 2:761–768, 2002 20 Rosengard BR, Feng S, Alfrey EJ, et al: Report of the Crystal City meeting to maximize the use of organs recovered from the cadaver donor Am J Transplant 2:701–711, 2002 21 Zaroff JG, Rosengard BR, Armstrong WF, et al: Consensus conference report: maximizing use of organs recovered from the cadaver donor: cardiac recommendations Circulation 106:836–841, 2002 22 Salim A, Martin M, Brown C, et al: The effect of a protocol of aggressive donor management: implications for the national organ donor shortage J Trauma 61:429–433, 2006 p 488 p 489 23 Venkateswaran RV, Patchell VB, Wilson IC, et al: Early donor management increases the retrieval rate of lungs for transplantation Ann Thorac Surg 85:278–286, 2008 24 Sung RS, Galloway J, Tuttle-Newhall JE, et al: Organ donation and utilization in the United States, 1997–2006 Am J Transplant 8:922– 934, 2008 25 Wood KE, Becker BN, McCartney JG, et al: Care of the potential organ donor N Engl J Med 351:2730–2739, 2004 26 Reich DJ, Mulligan DC, Abt PL, et al: ASTS recommended practice guidelines for controlled donation after cardiac death organ procurement and transplantation Am J Transplant 9:2004–2011, 2009 27 Gries CJ, White DB, Truog, R, et al; on behalf of the American Thoracic Society Health Policy Committee: An official American Thoracic Society/International Society for Heart and Lung Transplantation/Society of Critical Care Medicine/Association of Organ and Procurement Organizations/United Network of Organ Sharing statement: ethical and policy considerations in organ donation after circulatory determination of death Am J Respir Crit Care Med 188:103–109, 2013 28 Wall S, Plunkett C, Caplan A: A potential solution to the shortage of solid organs for transplantation JAMA, 2015 doi:10.1001/jama.2015.5328 29 D’Alessandro AM, Peltier JW, Phelps JE: Understanding the antecedents of the acceptance of donation after cardiac death by healthcare professionals Crit Care Med 36:1075–1081, 2008 30 Jones JW, Gruber SA, Barker JH, et al: Successful hand transplantation One year follow-up N Engl J Med 343:468–473, 2000 31 Landin L, Cavadas PC, Nthumba P, et al: Preliminary results of bilateral arm transplantation Transplantation 88:749–751, 2009 32 Strome M, Stein J, Esclamado R, et al: Laryngeal transplantation and 40-month follow-up N Engl J Med 344:1676–1679, 2001 33 Smith CR: Dire wounds, a new face, a glimpse in a mirror N Y Times Web:1A, 2005 34 Sudan D: The current state of intestine transplantation: indications, techniques, outcomes and challenges Am J Transplant 14:1976–1984, 2014 35 Gruessner RWG, Sutherland DER, Gruessner AC: Mortality assessment for pancreas transplants Am J Transplant 4:2018–2026, 2004 36 Shapiro J, Lakey J, Edmond R, et al: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen N Engl J Med 343:230–238, 2000 37 Ryan EA, Paty BW, Senior PA, et al: Five-year follow-up after clinical islet transplantation Diabetes 54:2060–2069, 2005 38 Kay MP: The Registry of the International Society for Heart and Lung Transplantation: tenth official report—1993 J Heart Lung Transplant 12:541–548, 1993 39 Bolman RM III, Shumway SJ, Estrin JA, et al: Lung and heart-lung transplantation: evolution and new applications Ann Surg 214:456– 468, 1991 40 Gravel MT, Arenas JD, Chenault R 2nd, et al: Kidney transplantation from organ donors following cardiopulmonary death using extracorporeal membrane oxygenation support Ann Transplant 9:57– 58, 2004 41 Wang C-C, Wang S-H, Lin C-C, et al: Liver transplantation from an uncontrolled non-heart-beating donor maintained on extracorporeal membrane oxygenation Transplant Proc 37:4331–4333, 2005 42 Moers C, Smits JM, Maathuis M, et al: Machine perfusion or cold storage in deceased-donor kidney transplantation N Engl J Med 360:7, 2009 43 Gallup poll surveys views on organ donation Nephrol News Issues 5:16, 1993 44 Callender CO, Hall LE, Yeager CL, et al: Organ donation and blacks: a critical frontier N Engl J Med 325:442–444, 1991 45 Siminoff L, Arnold, R: Increasing organ donation in the africanamerican community: altruism in the face of an untrustworthy system Ann Intern Med 130:607–609, 1999 46 Rodrigue JR, Crist K, Roberts JP, et al: Stimulus for organ donation: a survey of the American Society of Transplant Surgeons membership Am J Transplant 9:2172–2176, 2009 47 Brockmann JG, Vaidya A, Reddy S, et al: Retrieval of abdominal organs for transplantation Br J Surg 93:133–146, 2006 48 Fukuzawa K, Schwartz ME, Katz E, et al: An alternative technique for in situ arterial flushing in elderly liver donors with atherosclerotic occlusive disease Transplantation 55:445–447, 1993 49 Troppmann C, Daily MF, McVicar JP, et al: Hypothermic pulsatile perfusion of small pediatric en bloc kidneys: technical aspects and outcomes Transplantation 88:289–290, 2009 50 Troppmann C: Procurement of pediatric en bloc kidneys, in: Englesbe MJ, Mulholland MW (eds): Operative Techniques in Transplantation Surgery New York, NY, Wolters Kluwer Health, 2015, pp 9–14 51 Troppmann C, Perez RV: Transplantation of pediatric en bloc kidneys, in: Englesbe MJ, Mulholland MW (eds): Operative Techniques in Transplantation Surgery New York, NY: Wolters Kluwer Health, 2015, pp 65–80 52 Sutherland DER, Morel P, Gruessner RWG: Transplantation of two diabetic patients with one divided cadaver donor pancreas Transplant Proc 22:585, 1990 53 Azoulay D, Didier S, Castaing D, et al: Domino liver transplants for metabolic disorders: experience with familial amyloidotic polyneuropathy J Am Coll Surg 189:584–593, 1999 54 Azoulay D, Castaing D, Adam R, et al: Transplantation of three adult patients with one cadaveric graft: wait or innovate Liver Transpl 6:239–240, 2000 55 Jacobs CL, Roman D, Garvey C, et al: Twenty-two nondirected kidney donors: an update on a single center’s experience Am J Transplant 4:1110–1116, 2004 56 Ross LF, Rubin DT, Seigler M, et al: Ethics of a paired-kidneyexchange program N Engl J Med 336:1752–1755, 1997 57 Rees MA, Kopke JE, Pelletier RP, et al: A nonsimultaneous, extended, altruistic-donor chain N Engl J Med 360:1096–1101, 2009 58 Matas AJ, Hippen B, Satel S: In defense of a regulated system of compensation for living donation Curr Opin Organ Transplant 13:379–385, 2008 59 Radcliffe-Richards J, Daar AS, Guttmann RD, et al: The case for allowing kidney sales Lancet 351:1950–1952, 1998 60 Scheper-Hughes N: The global traffic in human organs Curr Anthropol 41:191–224, 2000 61 Starzl T, Teperman L, Sutherland D, et al: Transplant tourism and unregulated black-market trafficking of organs Am J Transplant 9:1484, 2009 62 Wright L, Campbell M: Soliciting kidneys on Web sites: Is it fair? Semin Dial 19:5–7, 2006 63 Steinbrook R: Public solicitation of organ donors N Engl J Med 353:441–444, 2005 64 Matesanz R, Miranda B, Felipe C, et al: Continuous improvement in organ donation Transplantation 61:1119–1121, 1996 65 Matesanz R, Marazuela R, Domínguez-Gil B, et al: The 40 donors per million population plan: an action plan for improvement of organ donation and transplantation in Spain Transplant Proc 41:3453– 3456, 2009 66 Council of Europe: International figures on donation and transplantation— 2008 Newsletter Transplant 2009; Vol 14, No 1 htt p://www.edqm.eu/medias/fichiers/Newsletter_Transplant_Vol_14_N o_1_Sept_2009.pdf Accessed February 3, 2017 67 Shafer TJ, David KD, Holtzman SM, et al: Location of in-house organ procurement organization staff in level I trauma centers increases conversion of potential donors to actual donors Transplantation 75:1330–1335, 2003 68 Sharif A, Singh MF, Trey T, et al: Organ procurement from executed prisoners in China Am J Transplant 14:2246–2252, 2014 69 Starzl TE, Fung J, Tzakis A, et al: Baboon-to-human liver transplantation Lancet 341:65–71, 1993 70 Dennis JM: A review of centralized rule-making in American transplantation Transplant Rev 6:130–137, 1992 71 Sadler AM Jr, Sadler BL, Stason EB: The uniform anatomical gift act: a model for reform JAMA 206:2505–2506, 1968 72 National Conference of Commissioners on Uniform State Laws http://www.uniformlaws.org/shared/docs/ anatomical_gift/uaga_final_aug09.pdf Accessed September 15, 2015 73 Beecher HK, Adams RD, Barger AC, et al: A definition of irreversible coma: report of the ad hoc committee of the Harvard Medical School to examine the definition of brain death JAMA 205:337–340, 1968 74 Guidelines for the determination of death: Report of the medical consultants on the diagnosis of death to the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research JAMA 246:2184–2186, 1981 75 Department of Health and Human Services, Office of the Inspector General: Medicare Conditions of Participation for organ donation: An early assessment of the new donation rule August 2000 http://oig.hh s.gov/oei/reports/oei-01-99-00020.pdf Accessed September 15, 2015 76 Wijdicks EFM: The diagnosis of brain death N Engl J Med 344:1215– 1221, 2001 77 The Quality Standards Subcommittee of the American Academy of Neurology: Practice parameters for determining brain death in adults Neurology 45:1012–1014, 1995 78 Wijdicks EF, Varelas PN, Gronseth GS, et al; American Academy of Neurology: Evidence-based guideline update: determining brain death in adults Report of the Quality of Standards Subcommittee of the American Academy of Neurology Neurology 74:1911–1918, 2010 79 Wijdicks E: Pitfalls and slip-ups in brain death determination Neurol Res 35:169–173, 2013 80 Heran MK, Heran NS, Shemie SD: A review of ancillary tests in evaluating brain death Can J Neurol Sci 35:409–419, 2008 81 Darby JM, Stein K, Grenvik A, et al: Approach to management of the heartbeating “brain dead” organ donor JAMA 261:2222–2228, 1989 82 Saposnik G, Bueri JA, Maurino J, et al: Spontaneous and reflex movements in brain death Neurology 54:221–223, 2000 83 Lytle FT, Afessa B, Keegan MT: Progression of organ failure in patients approaching brain stem death Am J Transplant 9:1446–1450, 2009 84 Taniguchi S, Kitamura S, Kawachi K, et al: Effects of hormonal supplements on the maintenance of cardiac function in potential donor patients after cerebral death Eur J Cardiothorac Surg 6:96–101, 1992 85 Troppmann C, Gillingham KJ, Benedetti E, et al: Delayed graft function, acute rejection, and outcome after cadaver renal transplantation Transplantation 59:962–968, 1995 86 Whelchel JD, Diethelm AG, Phillips MG, et al: The effect of high-dose dopamine in cadaver donor management on delayed graft function and graft survival following renal transplantation Transplant Proc 18:523– 527, 1986 87 Bouwman DL, Altshuler J, Weaver DW: Hyperamylasemia: a result of intracranial bleeding Surgery 94:318–323, 1983 88 Gores PF, Gillingham KJ, Dunn DL, et al: Donor hyperglycemia as a minor risk factor and immunologic variables as major risk factors for pancreas allograft loss in a multivariate analysis of a single institution’s experience Ann Surg 215:217–230, 1992 89 Marques RG, Rogers J, Chavin KD, et al: Does treatment of cadaveric organ donors with desmopressin increase the likelihood of pancreas graft thrombosis? Results of a preliminary study Transplant Proc 36:1048–1049, 2004 90 Bohrade SM, Vignaswaran W, McCabe MA, et al: Liberalization of donor criteria may expand the donor pool without adverse consequence in lung transplantation J Heart Lung Transplant 19:1199–1204, 2000 p 489 p 490 91 Freeman RB, Giatras I, Falagas ME, et al: Outcome of transplantation of organs procured from bacteremic donors Transplantation 68:1107– 1111, 1999 92 The White House: HIV Organ Policy Equity (HOPE) Act is now law htt ps://www.whitehouse.gov/blog/2013/11/21/hiv-organ-policy-equity-h ope-act-now-law Accessed September 15, 2015 93 Seem DL, Lee I, Umscheid CA, et al: PHS guideline for reducing human immunodeficiency virus, Hepatitis B Virus, and Hepatitis C Virus transmission through organ transplantation Public Health Rep 128:247–343, 2013 94 Theodoropoulos N, Jaramillo A, Ladner DP, et al: Deceased organ donor screening for HIV, Hepatitis B, and Hepatitis C viruses: a survey of organ procurement organization practices Am J Transplant 13:2186–2190, 2013 95 Dodson SF, Bonham CA, Geller DA, et al: Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-HBc positive donors Transplantation 68:1058–1061, 1999 96 Reese P, Abt P, Blumberg E, et al: Transplanting Hepatitis C-positive kidneys N Engl J Med 373:303–305, 2015 97 Kauffman HM, Cherikh WS, McBride MA, et al: Deceased donors with a past history of malignancy: an organ procurement and transplantation network/United Network for Organ Sharing update Transplantation 84:272–274, 2007 98 Colquhoun SD, Robert ME, Shaked A, et al: Transmission of CNS malignancy by organ transplantation Transplantation 57:970–974, 1994 99 Bernat JL, D’Alessandro AM, Port FK, et al: Report of a national conference on donation after cardiac death Am J Transplant 6:281– 291, 2006 100 Steinbrook R: Organ donation after cardiac death N Engl J Med 357: 209–213, 2007 101 Donate Life America: 2016 Annual Update https://www.donatelife.net/wpcontent/uploads/2016/06/DLA_Annual Report_2016-low-res.pdf Accessed July 14, 2017 102 Angel LF, Levine DJ, Restrepo MI, et al: Impact of a lung transplantation donor-management protocol on lung donation and recipient outcomes Am J Respir Crit Care Med 174:710–716, 2006 103 Mascia L, Pasero D, Slutsky AS, et al: Effect of a lung protective strategy for organ donors on eligibility and availability of lungs for transplantation: a randomized controlled trial JAMA 304:2620–2627, 2010 104 Niemann, C, Feiner J, Swain S, et al: Therapeutic hypothermia in deceased organ donors and kidney-graft function N Engl J Med 373:405, 2015 105 Schnuelle P, Berger S, De Boer J, et al: Effects of catecholamine application to brain-dead donors on graft survival in solid organ transplantation Transplantation 72:455–463, 2001 106 Schnuelle P, Yard BA, Braun C, et al: Impact of donor dopamine on immediate graft function after kidney transplantation Am J Transplant 4:419–426, 2004 107 Schnuelle P, Gottmann U, Hoeger S, et al: Effects of donor pretreatment with dopamine on graft function after kidney transplantation JAMA 302:1067–1075, 2009 108 Straznicka M, Follette DM, Eisner MD, et al: Aggressive management of lung donors classified as unacceptable: Excellent recipient survival one year after transplantation J Thorac Cardiovasc Surg 124:250– 258, 2002 109 Kotsch K, Ulrich F, Reutzel-Selke A, et al: Methylprednisolone therapy in deceased donors reduces inflammation in the donor liver and improves outcome after liver transplantation Ann Surg 248:1042– 1050, 2008 110 Selck FW, Deb P, Grossman EB: Deceased organ donor characteristics and clinical interventions associated with organ yield Am J Transplant 8:965–974, 2008 111 Pennefather SH, Bullock RE, Mantle D, et al: Use of low dose arginine vasopressin to support brain-dead organ donors Transplantation 59:58–62, 1995 112 Randell TT, Höckerstedt KAV: Triiodothyronine treatment in braindead multiorgan donors: a controlled study Transplantation 54:736– 738, 1992 113 Perez-Blanco A, Caturla-Such J, Canovas-Robles J, et al: Efficiency of triiodothyronine treatment on organ donor hemodynamic management and adenine nucleotide concentration Intensive Care Med 31:943–948, 2005 114 Roels L, Pirenne J, Delooz H, et al: Effect of triiodothyronine replacement therapy on maintenance characteristics and organ availability in hemodynamically unstable donors Transplant Proc 32:1564–1566, 2000 115 Venkateswaran RV, Steeds RP, Quinn DW, et al: The haemodynamic effects of adjunctive hormone therapy in potential heart donors: A prospective randomized double-blind factorially designed controlled trial Eur Heart J 30:1771–1780, 2009 116 Cooper DKC, Novitzky D, Witcomb WN: The pathophysiological effects of brain death on potential donor organs, with particular reference to the heart Ann R Coll Surg Engl 71:261–266, 1989 117 Smith M: Physiologic changes during brain stem death—lessons for management of the organ donor J Heart Lung Transplant 23:S217– S222, 2004 118 Bos EM, Leuvenink HG, van Goor H, et al: Kidney grafts from brain dead donors: inferior quality or opportunity for improvement? Kidney Int 72:797–805, 2007 119 Takada M, Nadeau KC, Hancock WW, et al: Effects of explosive brain death on cytokine activation of peripheral organs in the rat Transplantation 65:1533–1542, 1998 120 Bouma HR, Ploeg RJ, Schuurs TA: Signal transduction pathways involved in brain death-induced renal injury Am J Transplant 9:989– 997, 2009 121 Venkateswaran RV, Dronavalli V, Lambert PA, et al: The proinflammatory environment in potential heart and lung donors: prevalence and impact of donor management and hormonal therapy Transplantation 88:582–588, 2009 122 Powner DJ: Effects of gene induction and cytokine production in donor care Prog Transplant 13:9–14, 2003 123 Schnuelle P, Schmitt WH, Weiss C, et al: Effects of dopamine donor pretreatment on graft survival after kidney transplantation: a randomized trial Clin J Am Soc Nephrol 12:493-501, 2017 124 Russell JA, Walley KR, Singer J, et al: Vasopressin versus norepinephrine infusion in patients with septic shock N Engl J Med 358:877–887, 2008 125 Plurad DS, Bricker S, Neville A, et al: Arginine vasopressin significantly increases the rate of successful organ procurement in potential donors Am J Surg 204:856–860, 2012 126 Davis SV, Olichwier KK, Chakko SC: Reversible depression of myocardial performance to hypophosphatemia Am J Med Sci 295:183–187, 1988 127 Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome The Acute Respiratory Distress Syndrome Network N Engl J Med 342:1301–1308, 2000 128 Avlonitis VS, Fisher AJ, Kirby JA, et al: Pulmonary transplantation: the role of brain death in donor lung injury Transplantation 75:1928– 1933, 2003 129 National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann H, Wheeler A, et al: Comparison of two fluid-management strategies in acute lung injury N Engl J Med 354:2564–2575, 2006 130 Miñambres E, Rodrigo E, Ballesteros MA, et al: Impact of restrictive fluid balance focused to increase lung procurement on renal function after kidney transplantation Nephrol Dial Transplant 25:2352–2356, 2010 131 Richardson DW, Robinson AG: Desmopressin Ann Intern Med 103:228–239, 1985 132 Cittanova ML, Leblanc I, Legendre C, et al: Effect of Hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant recipients Lancet 348:1620–1622, 1996 133 Hall GM, Mashiter K, Lumley J, et al: Hypothalamic-pituitary function in the “brain-dead” patient Lancet 2:1259, 1980 134 Gramm H-J, Meinhold H, Bickel U, et al: Acute endocrine failure after brain death Transplantation 54:851–857, 1992 135 Howlett TA, Keogh AM, Perry L, et al: Anterior and posterior pituitary function in brain-stem-dead donors: a possible role for hormonal replacement therapy Transplantation 47:828–834, 1989 136 Powner DJ, Hendrich A, Lagler RG, et al: Hormonal changes in brain dead patients Crit Care Med 18:702–708, 1990 137 Seeger W (ed): Atlas of Topographical Anatomy of the Brain and Surrounding Structures New York, NY, Springer-Verlag, 1978 138 Dimopoulou I, Tsagarakis S, Anthi A, et al: High prevalence of decreased cortisol reserve in brain-dead potential organ donors Crit Care Med 31:1113–1117, 2003 139 Rosendale JD, Kauffman HM, McBride MA: Hormonal resuscitation yields more transplanted hearts with improved early function Transplantation 75:1336–1341, 2003 140 Rosendale JD, Kauffman HM, McBride MA, et al: Aggressive pharmacologic donor management results in more transplanted organs Transplantation 75:482–487, 2003 141 Novitzky D, Cooper DKC, Muchmore JS, et al: Pituitary function in brain-dead patients Transplantation 48:1078–1079, 1989 142 Macdonald PS, Aneman A, Bhonagiri D, et al: A systematic review and meta-analysis of of clinical trials of thyroid hormone administration to brain dead potential organ donors Crit Care Med 40:1635-1644, 2012 143 Salim A, Vassiliu P, Velmahos GC, et al: The role of thyroid hormone administration in potential organ donors Arch Surg 136:1377–1380, 2001 144 Reutzel-Selke A, Tullius SG, Zschockelt T, et al: Donor pretreatment of grafts from marginal donors improves long-term graft outcome Transplant Proc 33:970–971, 2001 145 Hershman JM: Free thyroxine in nonthyroidal illness Ann Intern Med 98:947, 1983 146 Hess ML: Letters to the Editor J Heart Transplant 5:486, 1986 147 Pennefather SH, Bullock RE: Triiodothyronine treatment in braindead multiorgan donors: a controlled study Transplantation 55:1443, 1993 148 Novitzky D, Cooper DKC, Rosendale JD, et al: Hormonal therapy of the brain-dead organ donor: experimental and clinical studies Transplantation 82: 1396–1401, 2006 149 Novitzky D, Wicomb WN, Cooper DKC, et al: Electrocardiographic, hemodynamic and endocrine changes occurring during experimental brain death in the chacma baboon J Heart Transplant 4:63, 1984 150 Novitzky D, Cooper DKC, Morrell D, et al: Change from aerobic to anaerobic metabolism after brain death, and reversal following triiodothyronine therapy Transplantation 45:32–36, 1988 151 Novitzky D, Wicomb WN, Cooper DKC, et al: Improved cardiac function following hormonal therapy in brain dead pigs: relevance to organ donation Cryobiology 24:1–10, 1987 152 Wicomb WN, Cooper DKC, Novitzky D: Impairment of renal slice function following brain death, with reversibility of injury by hormonal therapy Transplantation 41:29–33, 1986 153 Pienaar H, Schwartz I, Roncone A, et al: Function of kidney grafts from brain-dead donor pigs: the influence of dopamine and triiodothyronine Transplantation 50:580–582, 1990 154 Washida M, Okamoto R, Manaka D, et al: Beneficial effect of combined 3,5,3-triiodothyronine and vasopressin administration on hepatic energy status and systemic hemodynamics after brain death Transplantation 54:44–49, 1992 155 García-Fages LC, Antolín M, Cabrer C, et al: Effects of substitutive triiodothyronine therapy on intracellular nucleotide levels in donor organs Transplant Proc 23:2495–2496, 1991 156 Orlowski JP, Spees EK: Improved cardiac transplant survival with thyroxine treatment of hemodynamically unstable donors: 95.2% graft survival at 6 and 30 months Transplant Proc 25:1535, 1993 p 490 p 491 157 Novitzky D, Cooper DKC, Reichart B: Hemodynamic and metabolic responses to hormonal therapy in brain-dead potential organ donors Transplantation 43:852–854, 1987 158 Novitzky D, Cooper DKC, Chaffin JS, et al: Improved cardiac allograft function following triiodothyronine therapy to both donor and recipient Transplantation 49:311–316, 1990 159 Goarin J-P, Cohen S, Riou P, et al: The effects of triiodothyronine on hemodynamic status and cardiac function in potential heart donors Anesth Analg 83:41–47, 1996 160 Schwartz I, Bird S, Lotz Z, et al: The influence of thyroid hormone replacement in a porcine brain death model Transplantation 55:474– 476, 1993 161 Robertson KM, Hramiak IM, Gelb AW: Endocrine changes and haemodynamic stability after brain death Transplant Proc 21:1197– 1198, 1989 162 Koller J, Wieser C, Gottardis M, et al: Thyroid hormones and their impact on the hemodynamic and metabolic stability of organ donors and on kidney graft function after transplantation Transplant Proc 22:355–357, 1990 163 Wahlers T, Fieguth HG, Jurmann M, et al: Does hormone depletion of organ donors impair myocardial function after cardiac transplantation? Transplant Proc 20:792, 1988 164 Macoviak JA, McDougall IR, Bayer MG, et al: Significance of thyroid dysfunction in human cardiac allograft procurement Transplantation 43:824–826, 1987 165 Gifford RRM, Weaver AS, Burg JE, et al: Thyroid hormone levels in heart and kidney cadaver donors J Heart Transplant 5:249–253, 1986 166 Mariot J, Sadoune L-O, Jacob F, et al: Hormone levels, hemodynamics, and metabolism in brain dead organ donors Transplant Proc 27:793–794, 1995 167 Follette D, Rudich S, Bonacci R, et al: Importance of an aggressive multidisciplinary management approach to optimize lung donor procurement Transplant Proc 31:169–170, 1999 168 Milano CA, Buchan K, Perreas K, et al: Thoracic organ transplantation at Papworth Hospital, in Terasaki PI, Cecka JM (eds): Clinical Transplants 1999 Los Angeles, UCLA Tissue Typing Laboratory, 1999 169 Gabbay E, Williams TJ, Griffiths AP, et al: Maximizing the utilization of donor organs offered for lung transplantation Am J Respir Crit Care Med 160:265–271, 1999 170 Dohan FC, Lukens FDW: Lesions of the pancreatic islets produced in cats by administration of glucose Science 105:183, 1947 171 Collier SA, Mandel TE, Carter WM: Detrimental effect of high medium glucose concentration on subsequent endocrine function of transplanted organ-cultured fetal mouse pancreas Aust J Exp Biol Med Sci 60:437–445, 1982 172 Clark A, Bown E, King T, et al: Islet changes induced by hyperglycemia in rats: effects of insulin or chlorpropamide therapy Diabetes 31:319– 325, 1982 173 Unger RH, Grundy S: Hyperglycemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes Diabetologia 28:119– 121, 1985 174 Massen F, Thicoipe M, Gin H, et al: The endocrine pancreas in braindead donors A prospective study in 25 patients Transplantation 56:363–367, 1993 175 Powner DJ: Donor care before pancreatic tissue transplantation Prog Transplant 15:129–136, 2005 176 Van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in critically ill patients N Engl J Med 345:1359–1367, 2001 177 Powner DJ, Jastremski M, Lagler RG: Continuing care of multiorgan donor patients J Intensive Care Med 4:75, 1989 178 Swain JA: Hypothermia and blood pH Arch Intern Med 148:1643– 1646, 1988 179 Koncke GM, Nichols RRD, Mendenhall JT, et al: Ectothermic philosophy of acid-base balance to prevent fibrillation during hypothermia Arch Surg 121:303–304, 1986 180 Reuler JB: Hypothermia: pathophysiology, clinical settings, and management Ann Intern Med 89:519–527, 1978 181 Revollo J, Cuffy M, Witte D, et al: Case report: hemolytic anemia following deceased donor renal transplantation associated with tranexamic acid administration for disseminated intravascular coagulation Transplant Proc 47:2239–2242, 2015 182 Singer P, Shapiro H, Cohen J: Brain death and organ damage: the modulating effects of nutrition Transplantation 80:1363–1368, 2005 183 Korb S, Albornoz G, Brems W, et al: Verapamil pretreatment of hemodynamically unstable donors prevents delayed graft function post-transplant Transplant Proc 21:1236–1238, 1989 184 Institute of Medicine (IOM): Report: Non-heart-beating organ transplantation: practice and protocols Washington, DC, National Academy Press, 2000 185 Institute of Medicine (IOM): Report: Non-heart-beating organ transplantation: medical and ethical issues in procurement Washington, DC, National Academy Press, 1997 Chapter 57 Critical Care Problems in Kidney Recipients ABBAS A RANA • RAINER W G GRUESSNER INTRODUCTION Kidney transplantation is more than a life-enhancing endeavor; it is lifesaving A recent study estimated that more than 1.3 million life-years have been saved from over 300,000 kidney transplantations in the United States over the past 25 years [1] Other studies have calculated a projected 10-year survival benefit for an average cadaveric kidney transplantation [2] More than just survival benefit, a successful transplantation can free a patient from the demands of dialysis and provide a higher quality of life at a fraction of the overall cost compared to those not transplanted [3] In the United States, the cumulative 1-year graft survival rate was 91.3% for deceased donor recipients and 96.4% for living donor recipients; and 5-year graft survival rate of 68.9% for deceased donor recipients and 81.5% for living donor recipients The halflife graft survival is projected for deceased donor recipients to be 10 years; for living-related donor recipients, almost 18 years [4,5] Enthusiasm for kidney transplantation is undoubtedly fueled by these promising outcomes; however, a donor shortage crisis remains Over 100,000 patients are waitlisted for kidney transplantation on an evergrowing list This waitlist is in the context of just 17,000 annual kidney transplants in the United States In 2008, the median waiting time was 4.2 years, increased from 2.7 years in 1998 [6] These protracted waiting times subject our patients to a great deal of harm from the ill effects of uremia and dialysis Critical care providers, therefore, are facing a cohort of patients awaiting kidney transplantation who are sick and getting sicker This chapter discusses the salient points of critical care to optimize outcomes after kidney transplantation PRETRANSPLANT EVALUATION In addition to the aforementioned ill effects of prolonged dialysis, kidney transplant candidates are commonly plagued with significant comorbidities, often the etiology of their renal failure; including hypertension, diabetes, and cardiovascular disease It is therefore imperative that the pretransplant evaluation should be exhaustive (covering cardiovascular, gastrointestinal, pulmonary, neurologic, genitourinary, and infection disease concerns) The goal is not only that the patient should survive the operation and hospitalization, but also survive in the long term so that there is a realization of the potential graft life of the donor allograft The cardiovascular examination is the most important because cardiac events constitute the most common cause of death in the perioperative and postoperative periods [7] Ironically, our preoperative screening with noninvasive cardiac stress testing is notoriously unreliable In a metaanalysis, the sensitivity of the pretransplant cardiac perfusion study for myocardial infarction was only 0.7; and for cardiac death, only 0.8 [8,9] The onus remains on the transplant clinician to be highly suspicious of potential cardiac morbidity, even in younger patients with prolonged renal failure Abnormalities detected by stress testing require coronary angiography to investigate the need for coronary stenting or even coronary artery bypass It may also be reasonable to perform coronary angiography on high-risk patients with significant comorbidities or a pronounced history of cardiac problems with unremarkable stress testing p 491 p 492 Carotid duplex ultrasound should be used to screen candidates with a history of stroke or transient ischemic attacks (TIAs) for critical carotid stenosis Pulmonary function testing should be used to screen patients with any history of pulmonary disease including COPD and asthma Since hepatitis C exposure is so common in the hemodialysis (HD) population, screening with liver function test and hepatitis C (HCV) testing should be conducted [10] Abnormal results should prompt consultation with a hepatologist and further testing Since gastrointestinal diseases are more common in patients with end-stage renal disease, any upper GI symptoms should elicit an EGD Screening with colonoscopy is mandatory for candidates older than 50 years Recurrent urinary tract infections or bladder dysfunction requires urodynamic testing and urology consultation Candidates with any history of hypercoagulability should undergo a complete thrombophilia evaluation Abnormal results require hematology consultation and a plan for therapeutic measures in the perioperative period PERIOPERATIVE CARE Pretransplant Preparation Careful preparation in the days and hours before transplantation is essential to achieve ideal outcomes For HD-dependent patients, a routine HD session on the day prior to transplant would be acceptable If this is not the case, HD should be performed in the hours prior to surgery An electrolyte panel should be checked within hours of anesthetic induction Dialysis catheter sites should be inspected for infection for patients on HD Peritoneal fluid should be obtained for culture and Gram stain for patients on peritoneal dialysis (PD) In addition to electrolyte screening, a complete history and physical examination, electrocardiogram, chest X-ray, and laboratory examination should be performed just prior to the operation to uncover any possible health derangements since the last physician visit The history should include a comprehensive review of the medication list Anticoagulants should be held including warfarin and Plavix β-blockade should be continued through the perioperative period Intraoperative Care The degree of invasive monitoring during the operation should reflect the extent of the recipient’s comorbidities Central venous catheters are commonly introduced to guide intraoperative and postoperative fluid management This access is also essential to administer the most commonly used induction agent, thymoglobulin Continuous arterial blood pressure monitoring is also quite common and facilitates blood pressure management during the case It can also be instrumental to optimize the recipient’s blood pressure just prior to reperfusion Pulmonary artery pressure monitoring is used much more selectively It is justified when recipients have significant cardiac dysfunction, valvular abnormalities, or significant pulmonary artery hypertension A 20-F three-way Foley catheter is useful to inflate the bladder with saline that greatly facilitates the ureteroneocystostomy After completion of this anastomosis, urine output is checked frequently to guide fluid resuscitation Compression stockings and sequential compression devices provide deep venous thrombosis prophylaxis Optimizing the immediate perfusion of the allograft is vital to maximize graft function This is achieved by maintaining adequate intravascular volume with a central venous pressure (CVP) between 10 and 15 mm Hg The goal is a systolic blood pressure of greater than 120 mm Hg at the time of reperfusion If this is not achieved with appropriate volume loading, then low-dose dopamine can be used Other vasopressors should be avoided since they can effectively reduce perfusion of the allograft Another strategy, shown to decrease the incidence of acute tubular necrosis (ATN), is to give Mannitol (1 g per kg) with furosemide prior to reperfusion to increase urine flow [11] Optimizing the chance of immediate graft function requires careful communication and coordination between anesthesia and surgical teams Immediate graft function is important because both ATN and delayed graft function (DGF) have been found to increase patient mortality [12] Immediate Postoperative Care Recipients with significant comorbidities may require admission to the intensive care unit (ICU) for optimal monitoring and fluid resuscitation Most patients, however, can receive appropriate care on a solid-organ transplant ward provided there is mechanism for proper fluid resuscitation This can be challenging, with the voluminous urine output often encountered with immediate graft function The basis of the resuscitation is the equivalent replacement of urine output milliliter for milliliter, which is measured hourly A 5% dextrose and 0.45 normal saline solution should be administered; potassium replacement may also be necessary, but should not exceed 0.3 mEq/kg/h For recipients with cardiac dysfunction, replacement should be lower at 0.5 mL of replacements for 1 mL of urine After 24 hours, the fluid replacements are converted to a continuous rate between 100 and 150 mL per hour based on the recipient weight and kidney function Serial blood counts, coagulation profiles, and chemistries should be obtained in the postoperative period Electrolyte abnormalities, especially hyperkalemia, hypokalemia, hypomagnesaemia, and hypocalcaemia are common and should be corrected Serial troponins should be obtained to exclude myocardial ischemia with select recipients with significant cardiac comorbidity Chest X-ray and electrocardiograms are obtained in the immediate postoperative period ICU monitoring can become necessary at any time if complications should develop Kidney transplant recipients are prone to complications owing to their significant comorbidities, intense immunosuppression, and variable graft function It is estimated that between 15% and 30% of high-risk transplant candidates will require specific critical care CRITICAL EVALUATION OF DYSFUNCTIONAL GRAFTS Immediate graft function is reliably indicated with the combination of brisk diuresis (>100 to 200 mL per hour) and a consistent downward trend in serum creatinine Diuresis on its own may be a result of the urine produced by the recipient’s native kidneys or the residual effect of diuretics infused during the operation DGF is affected by a multitude of factors including prolonged cold ischemia time, advanced donor age, and donor diabetes among a host of others [13] While rare with living donor transplants, the incidence of DGF in cadaveric donors is about 25% [14] Most allografts with DGF start to recover by 10 days Doppler ultrasound plays a vital role in the surveillance of the allograft in DGF or for allografts with immediate function that abruptly changes Intensivists must be aware that ultrasound can rule out surgical complications that require immediate therapeutic maneuvers to salvage the graft including clearing of arterial or venous thromboses p 492 p 493 Medical Complications Leading to Early Graft Dysfunction Acute Tubular Necrosis There are a variety of medical and surgical causes of impaired kidney function after transplantation The most common culprit is ATN, which fortunately has the best prognosis It is estimated that up to 35% of deceased donor recipients have ATN, but is rare in living donor recipients About 95% of recipients with ATN will eventually recover kidney function, in some cases requiring HD for several weeks The causes of ATN are many and often multifactorial, with the most common cause being prolonged ischemia times Other indicators of poor donor quality such as advanced donor age and donor diabetes mellitus (DM) are also common culprits Donor and recipient instability requiring the use of vasopressors also contribute There is a host of immunologic risk factors that are factors causing ATN, as well, including poor human leukocyte antigen (HLA) matching and donor-specific antibodies Although most recipients with ATN recover, ATN has a detrimental effect on graft function and graft survival ATN leads to a higher incidence of rejection and chronic allograft nephropathy [15] ATN is a diagnosis of exclusion Most importantly, surgical complications need to be ruled out, most notably, thrombosis with a Doppler ultrasound Next, the clinician is obligated to rule out urologic complications and rejection Acute Rejection Acute rejection in kidney transplantation is of great significance, but a comprehensive review is beyond the scope of this chapter There are two types of acute rejection, cellular rejection and antibody-mediated rejection; both can diminish graft function and survival [16] At present, this diagnosis is secured with a kidney biopsy, although there are efforts underway for noninvasive diagnostics After vascular thrombosis and urologic complications are ruled out, the next step is often a biopsy to rule out rejection Acute cellular rejection, which is a lymphocytic attack against donor tissue, is most often treated with a course of steroids or thymoglobulin Antibody-mediated rejection that may occur in conjunction with acute cellular rejection or occur on its own is most often treated with a course of plasmapheresis and IVIG and in some cases Rituximab In antibody-mediated rejection, preformed or de novo alloantibodies target capillary endothelium and by activating the complement system can result in rapid destruction of the allograft Recurrence of Kidney Disease Most types of kidney diseases rarely recur in the acute setting; the exception, however, are focal segmental glomerulosclerosis (FSGS) and hemolytic uremic syndrome (HUS) that can cause early and profound graft dysfunction Nephrotic range proteinuria (i.e., >3.5 g per day) in a transplant recipient with known FSGS should prompt an immediate biopsy Diffuse foot process effacement on biopsy is diagnostic Early graft dysfunction with laboratory evidence of microvascular trauma including low haptoglobin levels, elevated lactate dehydrogenase levels, and the presence of schistocytes on blood smear should elicit suspicion of HUS and prompt a biopsy as well It may be recurrent or de novo, with the patient’s calcineurin inhibitor being a well-known causative agent [17] Surgical Complications Leading to Early Graft Dysfunction Hemorrhage after surgery is always a possibility but is rare in kidney transplantation because the surgical field is confined to the retroperitoneal space, so bleeding usually tamponades Reexploration is uncommon Bleeding is suspected if the patient is tachycardic, hypotensive, oliguric, and requiring blood transfusions Subscapular bleeding in the allograft is an entirely different matter, as it can lead to compression and quick deterioration of allograft function If this is recognized on Doppler ultrasound with evidence of compression, immediate reexploration is imperative to release the hematoma Arterial thrombosis is a devastating complication in kidney transplantation, as the renal arteries are end arteries without collateralization Therefore, arterial thrombosis almost invariably results in graft loss; however, fortunately it is rare (0.7% to 5%) [18] As mentioned earlier in the chapter, impaired graft function or a sudden change in urine output should elicit a Doppler ultrasound, which is usually diagnostic when thrombosis is present If discovered early, within hours, graft salvage is possible although most cases result in irreparable damage necessitating transplant nephrectomy Unidentified intimal flaps, allograft damage in the procurement, donor–recipient size discrepancy, hypotension, and technical difficulty with multiple arteries in the donor or diseased iliac vessels in the recipient are all identified causative factors [18] Renal vein thrombosis is equally devastating and uncommon and occurs in 0.3% to 4.2% of recipients It is most often diagnosed within a few days after the transplant and is characterized by sudden onset of pain and graft swelling, hematuria, and, in the case of iliofemoral thrombosis, an edematous leg In addition to the vein thrombosis, the Doppler ultrasound often shows reversal of the diastolic flow in the arterial system and an enlarged kidney possibly surrounded by hematoma Urgent allograft nephrectomy is necessary in complete thrombosis to prevent kidney rupture and devastating hemorrhage Partial thrombosis is an indication for urgent surgical thrombectomy or thrombolytic therapy It is most often caused by kinking of the anastomosis, intimal injury during organ procurement, pressure on the vein secondary to a fluid collection (i.e., lymphocele, urinoma, or hematoma), compartment syndrome, and extension of an iliofemoral thrombosis [19] Other vascular complications include aneurysms and renal artery stenosis Aneurysms can be anastomotic (pseudoaneurysm) or infected (mycotic) and require surgical repair Recipients with renal artery stenosis require percutaneous balloon dilation, or if unsuccessful, surgical repair Urologic complications are much more common than vascular complications, but if addressed systematically, rarely threaten the viability of the allograft Urologic complications, including hematuria, urine leaks, and ureteral stenosis, range from 5% to 14% [20] Hematuria is not uncommon from operating on the distal ureter and bladder and often resolves within 24 hours; however, clot formation leading to obstructive uropathy can occur, especially with poor initial urine flow Close monitoring of the urine output is necessary and any changes can indicate obstruction Large clots can cause suprapubic pain and bladder spasms Catheter irrigation can often remedy the situation If unsuccessful, manual evacuation using a 20-F Six-eye Foley catheter can be used Occasionally, hematuria can be caused by posttransplant biopsies with blot clots forming in the renal pelvis In these situations, a percutaneously placed nephrostomy tube may be necessary p 493 p 494 Urine leaks are caused by technical error with the ureteroneocystostomy, presenting in the first few postoperative days, or from ureteral ischemia and necrosis, presenting in the first few weeks The presentation can be quite varied, including wound drainage, persistent tenderness, fevers, or general swelling They are also commonly diagnosed on surveillance Doppler ultrasound where a large perinephric fluid collection is aspirated and found to have a high creatinine content Nephroscintigraphy or retrograde cystography can confirm the diagnosis Minor leaks can spontaneously resolve with bladder decompression over several weeks More significant leaks are approached with immediate exploration and reimplantation of the ureter or with percutaneous maneuvers to maximize drainage for 4 to 8 weeks Both strategies have their advocates Proponents of the percutaneous approach report success rates of 90%, avoiding significant morbidity from a reoperation [21] Ureteral stenosis usually becomes evident months after transplantation when an elevated creatinine leads to a Doppler ultrasound that reveals hydronephrosis Percutaneous nephrostomy elucidates the location and degree of stenosis as well the opportunity for therapeutic maneuvers including balloon dilatation with a temporary tent tube If this approach fails, reoperation with operative repair is necessary Extensive adhesions and lack of graft mobility make this operation quite difficult On some occasions, reimplanting the distal ureter is possible, but in most cases a ureteroureterostomy (to native ureter) or a ureteropyelostomy (native ureter to the graft’s renal pelvis) is necessary [21] Perinephric fluid collections after transplantation are common and often innocuous However, on occasion, they can cause compression of the iliac veins leading to leg edema or compression of the ureter leading to hydronephrosis In these cases, percutaneous decompression is imperative Most collections are residual hematomas or seromas and are self-limited Lymphoceles, caused from disruption of lymphatic vessels along the external iliac artery, are the exception and can be quite persistent In these cases, a surgically created peritoneal window must be created to drain the leakage and can often be approached laparoscopically NONRENAL POSTTRANSPLANTATION COMPLICATIONS Cardiovascular Complications Cardiac complications are the most common cause of death posttransplantation [22] For this reason, clinicians are often very particular with the cardiac clearance prior to transplant, but despite careful preoperative evaluation, cardiac complications are not uncommon following transplantation The immediate function of the transplanted kidney has a very influential effect on the incidence of cardiac complications Immediate function corrects uremia which in turn improves cardiac index, stroke volume, and ejection fraction On the other hand, DGF can exacerbate fluid shifts and fluid overload, as well as electrolyte derangements which can tip the patients into congestive heart failure (CHF) [23] In these cases, expedient HD is essential Patients who are at high risk for cardiac complications need careful ICU monitoring in the perioperative setting, especially for cases of DGF This includes patients with long standing diabetes, hypertension, coronary artery disease, and impaired ventricular function Further monitoring with a pulmonary artery catheter for optimal fluid management may be prudent for the highest-risk patients with diabetes and significant history of cardiac morbidity Although somewhat uncommon in the perioperative period, myocardial infarction is one of the major causes of death in the long term Perioperative myocardial infarctions are more common among patients with diabetes and a history of coronary artery disease Clinicians should maintain a high index of suspicion with this subgroup, monitoring continuous hemodynamic parameters and serial troponins in an ICU setting Studies suggest that maintaining the hematocrit above 30% in diabetic patients reduces cardiac morbidity by 24% in the initial 6 months postoperatively [24] High-risk patients with DGF should have HD initiated expeditiously Pericarditis following kidney transplantation occurs in 1% to 3% of patients [25] The most common culprit is uremia but there are other possible etiologies including: infections (e.g., cytomegalovirus), fluid overload, and medications (minoxidil) Less frequently, bacterial pericarditis develops in recipients with advanced septic complications In addition to antibiotics, bacterial pericarditis causing cardiac failure, hypotension, or tamponade requires urgent surgical or percutaneous decompression Any symptoms of pericarditis require ICU monitoring Exacerbation of underlying hypertension can be an issue in the postoperative period Fluid overload and calcineurin (CNI)-induced hypertension can lead to considerable hypertension Systolic blood pressures above 180 mm Hg or diastolic pressures above 100 mm Hg require intensive monitoring which often includes ICU monitoring with IV antihypertensive infusions (sodium nitroprusside) The patient’s home regimen should be restarted, and abrupt cessation of antihypertensives should be avoided with the exception of angiotensin-converting enzyme inhibitors Calcium-channel blockers appear to be the best at obviating the renal vasoconstriction induced by CNIs [26] The mechanism of CNIinduced hypertension is multifactorial, including vascular constriction by reducing prostacyclin and nitric oxide production while increasing serum levels of endothelin-1 Vasoconstriction of the kidney enhances sodium retention and exacerbates hypertension [27] Hypotension can be catastrophic to the newly transplanted allograft and can lead to graft loss or severe dysfunction More than just ATN, significant hypotension can perpetuate vascular thrombosis In the operating room (OR), hypotension can be related to volume depletion or anesthetic agents and should be avoided with appropriate fluid loading using central venous pressure (CVP) monitoring Induction immunosuppression with thymoglobulin can also lead to hypotension, which should be reversed by slowing the infusion rate In the postoperative period, brisk diuresis with immediate graft function can lead to inadequate fluid replacement Cardiac dysfunction and bleeding can also be contributing causes of hypotension Uremic patients have a greater incidence of deep venous thrombosis (DVT) compared to the general population, ranging from 1% to 4% This risk is linked to high-dose corticosteroid therapy in the perioperative period and a hypercoagulable state secondary to decreased fibrinolytic activity and increase in plasminogen activation inhibitors [28] Other factors for the development of DVT are postoperative immobilization, increased blood viscosity from posttransplant erythrocytosis, cyclosporine, and perinephric fluid collections that can diminish the venous return from the leg Two-thirds of the time, DVT occurs on the side of the graft Since the kidney allograft is a high-flow organ, DVT usually terminates at the level of or just distal to the renal vein anastomosis Elevated hemoglobin levels in conjunction with other risk factors such as old recipient age or diabetes are thought to predispose to DVT and aggressive therapeutic phlebotomy should be used to maintain the hematocrit level at less than 55% Once the diagnosis of DVT is established, just as with any other patient, systemic heparin is administered followed by 3 to 6 months of anticoagulation with warfarin If there is a contraindication to anticoagulation, an inferior vena cava filter can be inserted In the very rare instance that phelgmasia cerulea dolens develops, venous thrombectomy and fasciotomy must be performed Pulmonary embolism is rare ( 50: 58% Diabetic: 28% Hypertensive: 22% Waiting list mortality Organ scarcity Sensitized recipients KTx, kidney transplantation Mortality on the waiting list continues to stimulate the adoption of innovative desensitization protocols to allow high-risk recipients a transplantation opportunity This, in turn, must be met with equally innovative therapies when antibody-mediated rejection occurs in the early postoperative period Attempts at modulating the complement system are underway to mitigate early posttransplant injury in the allograft [62] REFERENCES Rana A, Gruessner A, Agopian VG, et al: Survival benefit of solid-organ transplant in the United States JAMA Surg 150(3):252–259, 2015 Wolfe RA, Ashby VB, Milford EL, et al: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant N Engl J Med 341(23):1725– 1730, 1999 Laupacis A, Keown P, Pus N, et al: A study of the quality of life and cost-utility of renal transplantation Kidney Int 50(1):235–242, 1996 Hariharan S, Johnson CP, Bresnahan BA, et al: Improved graft survival after renal transplantation in the United States, 1988 to 1996 N Engl J Med 342(9):605–612, 2000 Ishikawa N, Tanabe K, Tokumoto T, et al: Long-term results of living unrelated renal transplantation Transplant Proc 31(7):2856–2857, 1999 Matas AJ, Smith JM, Skeans MA, et al: OPTN/SRTR 2012 Annual Data Report: kidney Am J Transplant 14[Suppl 1]:11–44, 2014 Briggs JD: Causes of death after renal transplantation Nephrol Dial Transplant 16(8):1545–1549, 2001 Humar A, Kerr SR, Ramcharan T, et al: Peri-operative cardiac morbidity in kidney transplant recipients: incidence and risk factors Clin Transplant 15(3):154–158, 2001 Rabbat CG, Treleaven DJ, Russell JD, et al: Prognostic value of myocardial perfusion studies in patients with end-stage renal disease assessed for kidney or kidney-pancreas transplantation: a metaanalysis J Am Soc Nephrol 14(2):431–439, 2003 10 Fissell RB, Bragg-Gresham JL, Woods JD, et al: Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: the DOPPS Kidney Int 65(6):2335–2342, 2004 11 van Valenberg PL, Hoitsma AJ, Tiggeler RG, et al: Mannitol as an indispensable constituent of an intraoperative hydration protocol for the prevention of acute renal failure after renal cadaveric transplantation Transplantation 44(6):784–788, 1987 12 Dawidson IJ, Sandor ZF, Coorpender L, et al: Intraoperative albumin administration affects the outcome of cadaver renal transplantation Transplantation 53(4):774–782, 1992 13 Perico N, Cattaneo D, Sayegh MH, et al: Delayed graft function in kidney transplantation Lancet 364(9447):1814–1827, 2004 14 Ojo AO, Wolfe RA, Held PJ, et al: Delayed graft function: risk factors and implications for renal allograft survival Transplantation 63(7):968–974, 1997 15 Humar A, Ramcharan T, Kandaswamy R, et al: Risk factors for slow graft function after kidney transplants: a multivariate analysis Clin Transplant 16(6):425–429, 2002 16 Matas AJ, Gillingham KJ, Payne WD, et al: The impact of an acute rejection episode on long-term renal allograft survival (t1/2) Transplantation 57(6):857–859, 1994 17 Ducloux D, Rebibou JM, Semhoun-Ducloux S, et al: Recurrence of hemolytic-uremic syndrome in renal transplant recipients: a metaanalysis Transplantation 65(10):1405–1407, 1998 18 Benedetti E, Troppmann C, Gillingham K, et al: Short- and long-term outcomes of kidney transplants with multiple renal arteries Ann Surg 221(4):406–414, 1995 19 Englesbe MJ, Punch JD, Armstrong DR, et al: Single-center study of technical graft loss in 714 consecutive renal transplants Transplantation 78(4):623–626, 2004 20 Streeter EH, Little DM, Cranston DW, et al: The urological complications of renal transplantation: a series of 1535 patients BJU Int 90(7):627–634, 2002 21 Bassiri A, Simforoosh N, Gholamrezaie HR: Ureteral complications in 1100 consecutive renal transplants Transplant Proc 32(3):578–579, 2000 22 Matas AJ, Humar A, Gillingham KJ, et al: Five preventable causes of kidney graft loss in the 1990s: a single-center analysis Kidney Int 62(2):704–714, 2002 23 Debska-Slizien A, Dudziak M, Kubasik A, et al: Echocardiographic changes in left ventricular morphology and function after successful renal transplantation Transplant Proc 32(6):1365–1366, 2000 24 Djamali A, Becker YT, Simmons WD, et al: Increasing hematocrit reduces early posttransplant cardiovascular risk in diabetic transplant recipients Transplantation 76(5):816–820, 2003 25 Sever MS, Steinmuller DR, Hayes JM, et al: Pericarditis following renal transplantation Transplantation 51(6):1229–1232, 1991 26 Barbari A: Posttransplant hypertension: multipathogenic disease process Exp Clin Transplant 11(2):99–108, 2013 27 Cauduro RL, Costa C, Lhulier F, et al: Cyclosporine increases endothelin-1 plasma levels in renal transplant recipients Transplant Proc 36(4):880–881, 2004 28 Ozsoylu S, Strauss HS, Diamond LK: Effects of corticosteroids on coagulation of the blood Nature 195:1214–1215, 1962 29 Issa N, Krowka MJ, Griffin MD, et al: Pulmonary hypertension is associated with reduced patient survival after kidney transplantation Transplantation 86(10):1384–1388, 2008 30 Shorr AF, Abbott KC, Agadoa LY: Acute respiratory distress syndrome after kidney transplantation: epidemiology, risk factors, and outcomes Crit Care Med 31(5):1325–1330, 2003 31 Fishman JA: Infection in solid-organ transplant recipients N Engl J Med 357(25):2601–2614, 2007 32 Tolkoff-Rubin NE, Rubin RH: Urinary tract infection in the immunocompromised host Lessons from kidney transplantation and the AIDS epidemic Infect Dis Clin North Am 11(3):707–717, 1997 33 Patel R, Paya CV: Infections in solid-organ transplant recipients Clin Microbiol Rev 10(1):86–124, 1997 p 498 p 499 34 Chang GC, Wu CL, Pan SH, et al: The diagnosis of pneumonia in renal transplant recipients using invasive and noninvasive procedures Chest 125(2):541–547, 2004 35 Linden PK: Approach to the immunocompromised host with infection in the intensive care unit Infect Dis Clin North Am 23(3):535–556, 2009 36 Slomka MJ, Emery L, Munday PE, et al: A comparison of PCR with virus isolation and direct antigen detection for diagnosis and typing of genital herpes J Med Virol 55(2):177–183, 1998 37 Sagedal S, Nordal KP, Hartmann A, et al: A prospective study of the natural course of cytomegalovirus infection and disease in renal allograft recipients Transplantation 70(8):1166–1174, 2000 38 Mengelle C, Pasquier C, Rostaing L, et al: Quantitation of human cytomegalovirus in recipients of solid organ transplants by real-time quantitative PCR and pp65 antigenemia J Med Virol 69(2):225–231, 2003 39 Hibberd PL, Rubin RH: Clinical aspects of fungal infection in organ transplant recipients Clin Infect Dis 19[Suppl 1]:S33–S40, 1994 40 Mora-Duarte J, Betts R, Rotstein C, et al: Comparison of caspofungin and amphotericin B for invasive candidiasis N Engl J Med 347(25):2020–2029, 2002 41 Sarosdy MF, Saylor R, Dittman W, et al: Upper gastrointestinal bleeding following renal transplantation Urology 26(4):347–350, 1985 42 Gautam A: Gastrointestinal complications following transplantation Surg Clin North Am 86(5):1195–1206, vii, 2006 43 Coccolini F, Catena F, Di Saverio S, et al: Colonic perforation after renal transplantation: risk factor analysis Transplant Proc 41(4):1189–1190, 2009 44 Flanigan RC, Reckard CR, Lucas BA: Colonic complications of renal transplantation J Urol 139(3):503–506, 1988 45 Lao A, Bach D: Colonic complications in renal transplant recipients Dis Colon Rectum 31(2):130–133, 1988 46 Scheff RT, Zuckerman G, Harter H, et al: Diverticular disease in patients with chronic renal failure due to polycystic kidney disease Ann Intern Med 92(2, pt 1):202–204, 1980 47 Pirenne J, Lledo-Garcia E, Benedetti E, et al: Colon perforation after renal transplantation: a single-institution review Clin Transplant 11(2):88–93, 1997 48 Indudhara R, Kochhar R, Mehta SK, et al: Acute colitis in renal transplant recipients Am J Gastroenterol 85(8):964–968, 1990 49 Hellstrom PM, Rubio C, Odar-Cederlof I, et al: Ischemic colitis of the cecum after renal transplantation masquerading as malignant disease Dig Dis Sci 36(11):1644–1648, 1991 50 Frankel AH, Barker F, Williams G, et al: Neutropenic enterocolitis in a renal transplant patient Transplantation 52(5):913–914, 1991 51 Love R, Starling JR, Sollinger HW, et al: Colonoscopic decompression for acute colonic pseudo-obstruction (Ogilvie’s syndrome) in transplant recipients Gastrointest Endosc 34(5):426–429, 1988 52 Stylianos S, Forde KA, Benvenisty AI, et al: Lower gastrointestinal hemorrhage in renal transplant recipients Arch Surg 123(6):739–744, 1988 53 Frick TW, Fryd DS, Sutherland DE, et al: Hypercalcemia associated with pancreatitis and hyperamylasemia in renal transplant recipients Data from the Minnesota randomized trial of cyclosporine versus antilymphoblast azathioprine Am J Surg 154(5):487–489, 1987 54 Kamalkumar BS, Agarwal SK, Garg P, et al: Acute pancreatitis with CMV papillitis and cholangiopathy in a renal transplant recipient Clin Exp Nephrol 13(4):389–391, 2009 55 Fernandez-Cruz L, Targarona EM, Cugat E, et al: Acute pancreatitis after renal transplantation Br J Surg 76(11):1132–1135, 1989 56 Johnson WC, Nabseth DC: Pancreatitis in renal transplantation Ann Surg 171(2):309–314, 1970 57 Adams HP Jr, Dawson G, Coffman TJ, et al: Stroke in renal transplant recipients Arch Neurol 43(2):113–115, 1986 58 Bruno A, Adams HP Jr: Neurologic problems in renal transplant recipients Neurol Clin 6(2):305–325, 1988 59 Lee JM, Raps EC: Neurologic complications of transplantation Neurol Clin 16(1):21–33, 1998 60 Simmons RL, Matas AJ, Rattazzi LC, et al: Clinical characteristics of the lethal cytomegalovirus infection following renal transplantation Surgery 82(5):537–546, 1977 61 Bartynski WS, Tan HP, Boardman JF, et al: Posterior reversible encephalopathy syndrome after solid organ transplantation Am J Neuroradiol 29(5):924–930, 2008 62 Colvin RB, Smith RN: Antibody-mediated organ-allograft rejection Nat Rev Immunol 5(10):807–817, 2005 Chapter 58 Critical Care of Liver Transplant Recipients and Live Liver Donors BABAK MOVAHEDI • PAULO MARTINS • SONIA NAGY CHIMIENTI • ADEL BOZORGZADEH INTRODUCTION From early experimental animal model implantations conducted in the 1950s, to the first successful liver transplant performed by Dr Starzl in 1963, liver transplantation has evolved to become a safe and widely accepted treatment for patients with end-stage liver disease (ESLD) [1] The current 1-year survival rate in recipients of deceased donor organs is approximately 91%, owing in part to improvements in surgical procurement and transplantation techniques, more effective immunosuppressive regimens, individualized approaches to immunosuppression, improved perioperative and postoperative critical care, and improvements in the management of rejection and infection (Source: OPTN data as of November 27, 2015 http://optn.transplant.hrsa.gov Accessed December 1, 2015) Despite these substantial improvements, liver transplantation is a major abdominal surgical procedure that confers significant risk for a variety of postsurgical and medical complications The content of this chapter addresses the critical care of these complex, often critically ill patients, from the intraoperative through the immediate postoperative period, reviewing the management of selected posttransplant complications Care of the live donor is also described Detailed discussions regarding care of the patient with ESLD, approaches to immunosuppression management, and the diagnosis and management of rejection, infection, and malignancy for transplant recipients are found in other sections of this textbook ORGAN ALLOCATION AND DISPARITY Expanding the Donor Pool As liver transplant outcomes have improved, the indications for liver transplantation have expanded, and the number of individuals waitlisted for liver transplant has increased dramatically According to Organ Procurement and Transplantation Network (OPTN) data, 15,064 patients were listed for liver transplant as of November 27, 2015 In the United States, 6,729 liver transplants were performed in 2014 Approximately 4% of liver transplants performed each year are from live donors (Source: OPTN data as of November 27, 2015; http://optn.transplant.hrsa.gov Accessed December 1, 2015) Given the growing problem of disparity between the number of liver transplant candidates and available donor organs, expansion of the donor pool has attracted increased interest Donors with livers that are considered marginal are now allocated to carefully selected recipients, whereas they may not have been deemed acceptable for transplantation in the past Although these so-called extended criteria donors have created opportunities for candidates who may not otherwise have received an organ, they are associated with an increased rate of primary nonfunction (PNF) In 2006, a retrospective study of more than 20,000 donors identified a number of factors associated with an increased risk of graft loss This work contributed to the development of a “donor risk index,” which is used to predict the rate of graft survival Characteristics associated with a relative risk of at least 1.5 for liver graft loss include donor age over 60 years, donation after cardiac death, and use of partial/split grafts Other donor factors, such as age between 40 and 60 years, African American race, and cerebrovascular accident, are also associated with an increased risk for graft loss, though to a lesser extent Use of the donor risk index may help to optimize donor–recipient matching Innovative surgical procedures have also been used to increase the donor pool, including living donor liver transplantation and split-liver transplantation These procedures are each associated with unique problems, as will be discussed below p 499 p 500 DCD Organs In recent years, the use of organs from donors after cardiac death (DCD) has emerged as an important source of grafts [2] DCD donors have severe neurologic injury without meeting criteria for brain death [3–5] In the United States in 2009, 4.6% of liver transplants performed were from DCD donors, up from 3% in 2004 [2–5] Kidneys from DCD donors, despite their higher rate of delayed graft function, provide similar graft survival as do kidneys from brain death donors [6] Results for liver transplantation with grafts from DCD donors have been mixed, and individual centers have reported outcomes ranging from excellent to very poor An SRTR review of over 1500 DCD liver transplants between 2001 and 2009 revealed a 3-year patient survival of 64.9% Furthermore, 13.6% required retransplantation [7] The principal problem with the use of DCD livers is the risk of biliary complications and the development of ischemic cholangiopathy, which has been reported to occur in 16% to 29% of cases, often requiring retransplantation [8] Reduced-Size and Split-Liver Transplantation In reduced-size liver transplantation (RSLT), a whole deceased donor graft is tailored to fit the recipient A portion of the liver, such as the right lobe, is resected and discarded, and the remaining left lateral segment is used for the transplantation In split-liver transplantation (SLT), an adult deceased donor liver is divided into two grafts: the left lateral segment and the remaining right trisegment (right lobe plus segment 4) Both segments can then be utilized for transplantation For most adult recipients with ESLD, the small graft size with this approach would not be sufficient Thus, while this approach may be beneficial for pediatric transplantation, it does not serve to significantly increase the adult donor pool [9] With appropriate donor and recipient selection criteria, however, SLT may be considered for two adult recipients Living Donor Liver Transplantation Living donor liver transplant (LDLT) involves removing a segment of the liver from an adult donor and transplanting the segment into a carefully selected recipient This approach typically provides sufficient liver tissue for a recipient With LDLT, the transplant is optimally performed before the recipient’s health deteriorates significantly, thereby shortening the wait time In LDLTs for pediatric recipients, the left lateral segment is used; for adult recipients, however, depending on the donor and recipient size and the liver volume, either right or left lobe could be considered In 2001, 524 LDLTs were performed in the United States, of the 5,195 liver transplants performed that year (10.1%) (OPTN data as of November 27, 2015, source http://optn.transplant.hrsa.gov) Since that all-time high, approximately 250 liver transplants each year have been LDLTs; in 2014, 280 of the 6,729 (4.2%) liver transplants performed were from live donors (OPTN data as of November 27, 2015, source http://optn.transplant.hrsa.gov) The main disadvantage of LDLT is the peri- and postoperative risk to an otherwise healthy donor All potential live liver donors are carefully evaluated through a detailed screening process, including assessment by a hepatologist, donor surgeon, independent donor advocate, social worker, psychiatrist, and other providers as indicated during the evaluation Standardized radiologic and laboratory evaluation is performed in order to detect the presence of any underlying medical issues This detailed screening process is conducted in order to ensure that the donor is medically healthy and able from both a physical and a psychosocial perspective to undergo liver donation The decision to proceed with live liver donation occurs following this extensive evaluation, after careful consideration and discussion of the risks and potential complications of liver donation Hepatitis B–Positive Donors Careful allocation of organs from donors with hepatitis B virus (HBV) infection may safely expand the donor pool The risk of transmission of HBV varies depending on the serologic status of both donor and recipient, with the highest risk observed in transplantation of grafts from donors with active HBV (HBsAg+ or HBV DNA+ donors) to naïve recipients Liver graft recipients are at highest risk for acquisition of de novo HBV, as compared with recipients of other grafts Prevention of transmission includes use of universal prophylaxis with newer generation antivirals such as entecavir, and occasionally the targeted use of hepatitis B immune globulin (HBIg) intra- and postoperatively, for a specified duration These strategies significantly lower the risk of transmission of HBV, and make this a reasonable approach, particularly for patients who may not otherwise receive a standard graft in a timely manner With the use of antiviral prophylaxis, with or without HBIg, excellent outcomes have been demonstrated with transplantation of HBV core antibodypositive donor grafts to immune (vaccinated or natural immunity) recipients The risks of transmission of HBV must be discussed with the transplant candidate in advance of transplantation, and the candidate must provide informed consent for the transplantation of organs from donors with past or active HBV infection A comprehensive consensus guideline was recently published that provides guidance with regard to the management of recipients of grafts from donors with active or prior HBV infection [10] Hepatitis C–Positive Donors Historically, transplantation of grafts from donors with a past history of hepatitis C virus (HCV) infection was reserved for recipients with active genotype 1 HCV infection Outcomes in this setting were demonstrated to be equivalent to those in HCV-positive recipients of HCV-negative grafts [11] For optimal outcomes, grafts from HCV-positive donors should be from younger donors with no significant liver fibrosis or inflammation Grafts from older donors may be associated with more rapidly progressive fibrosis related to HCV posttransplant In the new era of effective treatment of HCV-infected recipients with direct acting antivirals, the approach to the use of HCV-positive grafts for HCVpositive recipients will likely change Data and guidelines in this area are rapidly evolving PHS Increased Risk Donors Some donors engage in behaviors that may put them at increased risk for infections that can be transmitted by blood or body fluids These infections include human immunodeficiency virus (HIV), HBV, and HCV Donors with these risk behaviors are referred to as Public Health Service (PHS) Increased Risk Donors (Table 58.1) Revised guidelines for the assessment of PHS Increased Risk Donors, and for the monitoring of recipients of grafts from these donors, were published in 2013 [12] Prior to organ procurement, potential donors are tested for all of these viruses using both serologic tests and nucleic acid tests (NAT) Even in the setting of negative serologic and NAT testing, PHS Increased Risk Donors, who constitute up to 9% of the donor pool, may harbor low levels of these viruses, and may pose a risk for transmission of viral infection from donor to recipient This typically occurs during a “window period” of infection, when a donor has recently been exposed to one or more of these viruses and has not yet developed a measurable antibody response to the virus(es) The advent of NAT testing has decreased this window period dramatically, but a small risk of transmission still exists With the active antiviral treatments that are now available for HIV, HBV, and HCV, utilization of organs from PHS Increased Risk Donors is a very reasonable option for carefully selected recipients who may not otherwise receive an organ in a reasonable time frame, and for whom the risk of death from end-stage organ disease is more significant than the risk of transmission of infection from a PHS Increased Risk Donor The risks of transmission must be discussed with the transplant candidate in advance of transplantation, and the candidate must provide informed consent for the transplantation of PHS Increased Risk organs p 500 p 501 TABLE 58.1 Behaviors Associated with Increased Risk of Transmission of HIV, HBV, and HCV Infection [12] Method of exposure Risk behavior Sexual (vaginal, anal, oral) (prior 12 mo) Individuals who have had sex with a person known/suspected to have HIV, HBV, or HCV infection Men who have had sex with men (MSM) Women who have had sex with a man with a history of MSM Individuals who have exchanged sex for money or drugs Individuals who have had sex with a person who had sex in exchange for money or drugs Individuals who have had sex with a person who injected drugs (intravenous, intramuscular, or subcutaneous) for nonmedical reasons Maternal/child A child who is ≤18 mo of age and born to a mother known to be infected with, or at increased risk for, HIV, HBV, or HCV infection A child who has been breastfed within the preceding 12 mo and whose mother is known to be infected with, or at increased risk for, HIV infection Injection drugs (prior 12 mo) Individuals who have injected drugs (intravenous, intramuscular, subcutaneous) for nonmedical reasons Individuals who have been in jail/prison/correctional facility for >72 consecutive hours History of sexually New diagnosis of or treatment for syphilis, gonorrhea, transmitted Chlamydia, or genital ulcers infections (prior 12 mo) CAUSES OF LIVER FAILURE AND LIVER TRANSPLANT CANDIDATE SELECTION Indications for Liver Transplant Within the array of available options for the management of patients with chronic liver disease, liver transplantation is the most definitive one However, not every patient may benefit from a transplant, and risks and benefits of either option should be carefully evaluated for each individual patient Typically, well-compensated cirrhotics have a low mortality risk secondary to their underlying liver diseases and may be managed medically However, patients with signs of hepatic decompensation have a poor prognosis without a transplant and should be considered for transplantation Furthermore, well-selected patients with certain malignancies confined to the liver may benefit from liver transplantation In particular, patients with hepatocellular carcinoma may have excellent long-term disease-free outcome after liver transplantation As hepatic fibrosis progresses and liver function deteriorates, signs and symptoms of decompensated liver disease appear Decompensated cirrhosis is defined as the presence of any one of the following, which leads to an acute care hospitalization: (1) portosystemic encephalopathy, (2) variceal hemorrhage, (3) spontaneous bacterial peritonitis, (4) hepatorenal syndrome or acute kidney injury in the setting of cirrhosis, or (5) hepatic hydrothorax Critical care of patients with decompensated cirrhosis and fulminant hepatic failure is addressed in Chapters 206 and 207 Portal hypertension can lead to the development of esophageal varices and portal hypertensive gastropathy and eventually hemorrhage Ascites may require large volume paracentesis and can be further complicated by spontaneous bacterial peritonitis (SBP) [13] As portal blood is shunted away from the liver and ammonia is insufficiently cleared from the circulation, hepatic encephalopathy develops Other complications of ESLD include hepatorenal syndrome (HRS), hepatopulmonary syndrome, portopulmonary syndrome, protein malnutrition and muscle wasting, and severe weakness and fatigue Identifying and managing patients with decompensated cirrhosis or fulminant hepatic failure who may be candidates for orthotopic liver transplant (OLT) is a complex process, with interprofessional collaboration between medical and surgical services For patients who are hospitalized with decompensated cirrhosis and who undergo a transplantation evaluation while in the hospital, coordinated care involving the transplant and critical care teams is crucial to facilitate candidate evaluation and selection, and to optimize care in the pretransplantation period p 501 p 502 Causes of Chronic Liver Disease A variety of chronic liver diseases account for the majority of indications for liver transplantation, as compared with transplants for acute liver disease The most common causes of chronic liver disease in North America include alcohol use, hepatitis C virus (HCV) infection, and nonalcoholic steatohepatitis (NASH) Autoimmune hepatitis may also lead to cirrhosis, primarily in women, and may develop either acutely or over a period of years [14] Cholestatic disorders are also an important cause of chronic liver disease In adults, the most common cholestatic causes of chronic liver disease are primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) In children, biliary atresia is the most common cause of cholestatic liver disease Metabolic diseases that can cause chronic liver injury and cirrhosis include hereditary hemochromatosis, α1-antitrypsin deficiency, and Wilson disease [15] Hepatocellular carcinoma (HCC) may develop as a complication of cirrhosis from any cause, but is most commonly seen in patients with hepatitis B virus (HBV) infection, HCV infection, hemochromatosis, and tyrosinemia The best transplantation candidates are those with a single lesion less than 5 cm in size or with no more than three lesions, the largest no greater than 3 cm in size (known as the Milan criteria) Transplantation of patients with HCC lesions outside of these criteria is usually associated with higher recurrence rates, although some centers have shown acceptable 5-year survival in patients that have tumors that slightly exceed the Milan criteria [16,17] Other diseases that may lead to chronic liver failure that are potentially amenable to treatment with a transplant include Budd–Chiari and polycystic liver disease In order to determine the cause of ESLD, if not already known, and to begin the liver transplant evaluation process, a comprehensive laboratory evaluation is performed, to identify the etiology of cirrhosis, to determine the presence of comorbid conditions, to rule out active infectious processes requiring treatment before transplantation, and to guide vaccination strategies Causes of Fulminant Hepatic Failure Fulminant hepatic failure (FHF) is defined as the development of hepatic encephalopathy and profound coagulopathy rapidly after the onset of initial symptoms, such as jaundice, in patients without preexisting liver disease UNOS criteria for FHF (OPTN Policy 9.1.A) include all of the following: age at least 18 years old at the time of registration for transplant, and life expectancy without a liver transplant of less than 7 days and at least one of the following conditions: a acute decompensated Wilson Disease or b fulminant liver failure, without preexisting liver disease and currently in the ICU, defined as the onset of hepatic encephalopathy within 8 weeks of the first symptoms of liver disease, and has at least one of the following criteria: i ventilator dependency ii requiring dialysis, continuous venovenous hemofiltration (CVVH), or continuous venovenous hemodialysis (CVVHD) iii has an international normalized ratio (INR) greater than 2.0 Alternative criteria for FHF include the King’s College Criteria, which are listed in Table 58.2 TABLE 58.2 King’s College Criteria for ALF [20] Acetaminophen-induced ALF Strongly consider OLT listing if arterial lactate >3.5 mmol/L after early fluid resuscitation List for OLT if pH 3 mmol/L after adequate fluid resuscitation List for OLT if, within a 24-h period, all of the following are present: presence of grade 3 or 4 hepatic encephalopathy and INR >6.5 and creatinine >3.4 mg/dL Non–acetaminophen-induced ALF List for OLT if INR >6.5 (with encephalopathy present, irrespective of grade) List for OLT if any three of the following (with encephalopathy present, irrespective of grade): Age 40 y Jaundice for >7 d before development of encephalopathy INR > 3.5 Serum bilirubin > 17.6 mg/dL Unfavorable etiology (Wilson Disease, idiosyncratic drug reaction, seronegative hepatitis) ALF, acute liver failure; OLT, orthotopic liver transplant; INR, international normalized ratio The most common causes of FHF in the Western world include acetaminophen overdose, acute viral hepatitis, various drugs and hepatotoxins, and Wilson disease; often, however, no cause is identified [18] Treatment consists of appropriate critical care support and providing patients with time for spontaneous recovery The prognosis for spontaneous recovery depends on the patients’ age (those younger than 10 and older than 40 years have a poor prognosis), the underlying cause, and the severity of liver injury (as indicated by degree of hepatic encephalopathy, coagulopathy, and kidney dysfunction) [19,20] A subset of patients may have delayed onset of hepatic decompensation that occurs 8 weeks to 6 months after the onset of symptoms This condition is often referred to as subacute hepatic failure; these patients rarely recover without a transplant MELD and PELD The severity of illness and prognosis of patients with chronic liver disease can be estimated by a variety of scoring models, including the Childs– Pugh–Turcotte score and the MELD score The latter is now widely used in the United States for the allocation of organs It is based on a predicted 3-month mortality for patients awaiting a liver transplant and uses three laboratory values to generate a score that determines priority for liver transplantation The three laboratory values used are serum bilirubin, serum creatinine, and INR For pediatric patients, the scoring system is somewhat different The PELD (pediatric ESLD) score is calculated on the basis of the following factors: serum bilirubin, albumin, and INR, the age of the patient (additional points if the patient is 25 mm Hg in the setting of portal hypertension) is seen in a small proportion of patients with established cirrhosis Its exact cause is unknown [22] Diagnosing pulmonary hypertension pretransplant is critical, because major surgical procedures in the presence of irreversible pulmonary hypertension are associated with a very high risk of mortality The initial screening is usually performed with transthoracic Doppler echocardiography (TTE), which can estimate pulmonary arterial systolic pressure when tricuspid regurgitation is present TTE presents a sensitivity of 97% and a specificity of 77% in diagnosing pulmonary hypertension in the setting of liver failure In patients with elevated pulmonary arterial systolic pressure (>50 mm Hg), a more invasive assessment (right heart catheterization) is recommended It has been shown that perioperative mortality is directly proportional to the mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance For these reasons, most transplant centers consider a mPAP greater than 35 mm Hg to be an absolute contraindication for transplant If the mPAP can be lowered below that value using medications (epoprostenol, sildenafil), the patient can still be considered for transplant [22] Another absolute contraindication for liver transplantation, in case of acute liver failure, is the presence of unresponsive cerebral edema with sustained elevation of intracranial pressure (>50 mm Hg) and a persistent decrease in cerebral perfusion pressure (3 days), macrosteatosis (>30%), prolonged cold ischemia time (CIT) (>12 hours), DCD donor status, the duration in the operating room, and retransplantation [72] PNF should be considered in recipients who have signs of continued poor hepatic function after admission to the ICU, including persistent hemodynamic instability, worsening acidosis, persistent coagulopathy, poor bile production, worsening renal function, persistent hypoglycemia, or persistent altered mental status There is no effective medical treatment for PNF other than supportive care; ultimately, retransplantation may be required for survival Outcomes are typically better if retransplantation is performed as early as possible, before the development of significant multiorgan dysfunction [73] Rejection Graft rejection affects up to 30% of liver transplant recipients at some point posttransplantation A detailed discussion of the diagnosis and management of graft rejection is addressed in Chapter 65 Rejection typically manifests as elevation of serum bilirubin and/or transaminase levels, occasionally with mild fever and malaise The differential diagnosis of rejection includes vascular thrombosis, bile leaks, and underlying infection Biopsy is required to confirm a diagnosis of rejection Mild episodes may be managed by increasing the baseline level of immunosuppression, whereas moderate or severe rejection episodes usually require treatment with a pulse of high-dose intravenous corticosteroids Neurologic Complications Neurologic complications are relatively common posttransplant, affecting 15% to 30% of liver transplant recipients Neurologic issues may develop at any time in the posttransplant period, and include alterations in level of consciousness, seizures, cerebrovascular accidents, central nervous system (CNS) infections, and central pontine myelinolysis (CPM) Pretransplant conditions, such as hepatic encephalopathy, sepsis, multiorgan failure, and substance abuse, may also have an impact on posttransplant recovery [74] Alterations of the level of consciousness may result from medications administered for pain control or sedation, with reduced clearance due to impaired liver and/or renal function Immunosuppressants may also contribute, particularly the calcineurin inhibitors (CNIs), such as tacrolimus and cyclosporine The CNIs, and rarely the mTor inhibitors (sirolimus, everolimus), may cause posterior reversible encephalopathy syndrome (PRES), which develops in 50%) risk of death from lung disease within 2 years if LT is not performed, high (>80%) likelihood of surviving at least 90 days after transplantation, and a high (80%) likelihood of 5-year posttransplant survival from a general medical perspective provided that there is adequate graft function Age The 2014 ISHLT consensus document for the selection of transplant candidates [3] suggest an age >65 years in association with low physiologic reserve as a relative contraindication regardless of procedure type, and 75 years as an absolute contraindication to LT Relative Contraindications Transplantation is relatively contraindicated in patients with systemic diseases that have extrapulmonary involvement such as scleroderma, systemic lupus erythematous, polymyositis, and rheumatoid arthritis Advanced atherosclerotic disease is also considered a relative contraindication unless this can be corrected before, or in very selected cases concurrently, with transplantation Osteoporosis is a significant problem after LT, and preexisting symptomatic osteoporosis is also a relative contraindication Patients with active sites of infection are not considered to be good transplantation candidates Treated tuberculosis and fungal disease pose a particular problem but are not contraindications for LT Many centers will not consider performing a transplant in a patient who is chronically colonized with a resistant organism (e.g., Burkholderia cenocepacia, atypical mycobacterium such as abscesses), and it is recommended to try to eradicate these organisms in the pretransplant period and to consider each patient on an individual basis However, if considered, these patients are candidates only for BLT procedures since the remaining colonized lung could pose a serious threat to the new graft in the case of an SLT This issue is of particular concern in cystic fibrosis patients who are often infected with drug-resistant organisms Both Burkholderia cenocepacia (specific strains) and Burkholderia gladioli are of concern due to poor posttransplantation outcomes [4] As patients are now allocated lungs for transplantation according to the severity of their disease, requirements for invasive mechanical ventilation and extracorporeal life support are now more frequently seen During this critical period, patients usually have multiple acute changes that pose a relative or absolute contraindication to transplantation, and the candidacy for this procedure should be assessed on a continuous basis [5–7] In one small series of mechanically ventilated patients, there was a longer time on postoperative mechanical ventilation and a longer intensive care unit (ICU) stay following LT Rates of PGD, survival, and total hospital stay were similar to those in patients undergoing LT not on mechanical ventilation [6] Recently venovenous and/or venoarterial extracorporeal membrane oxygenation (ECMO) has been used as a bridge to transplantation for end-stage lung disease patients with good shortterm function and survival rates [5,7] In a large review of the United Network of Organ Sharing (UNOS) database of patients undergoing LT on mechanical respiratory support (586 on mechanical ventilation and 51 on ECMO as a bridge to LT), the authors found that patients on mechanical ventilation or ECMO have lower survival rates following LT compared with those not requiring support [8] A small study of 25 patients receiving ECMO as a bridge to transplant showed that the duration of ECMO was related to mortality (which increased steadily with time on ECMO) and morbidity (ICU length of stay, days on mechanical ventilation, and hospital stay) following LT [9] Noninvasive ventilatory support is not considered a relative contraindication to transplantation To be considered for transplantation, patients should have an ideal body weight of >70% or ≤130% predicted (BMI, 18 to 30 kg per m2) Those patients with poor nutritional status may be too weak to withstand the surgical procedure; those patients who are obese (BMI, 30–35 kg per m2) make more difficult surgical candidates and may have higher mortality rates than nonobese patients Prior thoracotomy or pleurodesis was once considered to be a relative contraindication to transplantation due to increased difficulty with the transplant pneumonectomy as well as with an increased risk of bleeding Extensive prior chest surgery with lung resection remains a relative contraindication to LT Despite this, transplantation can be successfully performed for these patients and for many of them SLT may be the best option Other relative contraindications include well-controlled human immunodeficiency (HIV) disease, and hepatitis B or C without active cirrhosis Absolute Contraindications The 2014 international guidelines identified several absolute contraindications to LT including untreatable major organ dysfunction, uncorrectable atherosclerotic disease, acute medical instability, and uncorrectable bleeding diatheses [3] Active malignancy within the prior 2 years is also a contraindication to transplantation For patients with a history of breast cancer greater than stage 2, colon cancer greater than Duke A stage, renal carcinoma, or melanoma greater than or equal to level 2, the waiting period should be at least 5 years Restaging is suggested before transplant listing Severe non-osteoporotic skeletal disease, such as kyphoscoliosis, is often an absolute contraindication to transplantation, primarily because of the technical difficulties encountered during surgery, and residual restrictive lung disease after transplantation Drug abuse and alcoholism are considered to be contraindications to transplantation because patients with these conditions are associated with a high risk for noncompliance Patients who continue to smoke despite having end-stage pulmonary disease are not candidates for LT Transplant centers require patients to abstain from cigarette smoking, alcohol use, or narcotics use for 6 months to 2 years before being considered for lung transplant evaluation The patient must be well motivated and emotionally stable to withstand the extreme stress of the pretransplantation and perioperative periods A history of nonadherence, significant psychiatric illness, or lack of an adequate support system are absolute contraindications In addition, lack of potential for rehabilitation or extreme obesity ≥35.0 kg per m2, are also absolute contraindications to LT Chronic infection with pan-resistant organisms or active Mycobacterium tuberculosis infection also preclude LT DONOR ALLOCATION AND SELECTION Until the spring of 2005, as established by the United Network of Organ Sharing, lungs were allocated primarily by time on the waiting list and not by necessity In the spring of 2005, the system for donor allocation for lungs was revised and priority was assigned for lung offers on the basis of a benefit or need-based Lung Allocation Score (LAS) [10,11] The LAS is calculated using the following measures: (1) waitlist urgency measure (i.e., the expected number of days lived without a transplant during an additional year on the waitlist); (2) posttransplant survival measure (i.e., the expected number of days lived during the 1st year after transplant); and (3) the transplant benefit measure (i.e., the posttransplant survival measure minus waitlist urgency measure) [12] Now 10 years later, many of the goals of the system (decreased waiting list deaths and times, and prioritizing patients by urgency rather than time on the list) are being accomplished, with comparable survival rates except for those with the very high LAS scores (>46 in one study and >60 in another) [13–15] In a large single-center study, patients with high LAS scores of ≥50 had lower survival rates at 30 days, 90 days, 1 year, and 3 years (92.6%, 87.8%, 71.5%, 52% vs 96.9%, 93.5%, 83.2%, and 73.9%, respectively) and increased morbidity compared with those with LAS < 50 including prolonged need for ventilator support, need for tracheotomy, and longer ICU stays [16] There also appears to be a stepwise decline in posttransplantation survival as the LAS score increases In another study, patients with high LAS scores had higher morbidity including requirements for dialysis, infections, and longer lengths of stay [17] Since the implementation of the LAS, the distribution of patient diagnoses on the list, and those transplanted, has also shifted from a majority of COPD patients to an increasing number of patients with pulmonary fibrosis In addition, sicker patients are being transplanted In the United States, donor lungs are first distributed locally, then regionally, and finally nationally Currently, the median time to transplant for waitlist patients is approximately 4.3 months (range 0.2 to 52 months) [18] and therefore close management of the listed transplant patient is required Despite this close attention, a small percentage of patients die while awaiting transplantation A shortage of donor organs remains the primary factor limiting the number of LTs performed Contributing to this shortage is the estimate that lungs for transplantation are procured from only 21% of multiorgan donors [19] The vast majority of transplanted lungs are from brain-dead donors A small number of LT procedures involving living related donors and an increasing number of lung donors from donation after circulatory death (DCD), previously referred as non–heart-beating donors, have been performed at institutions specializing in these procedures [20,21] In a recent meta-analysis of DCD donation in LT involving 271 DCD and 2,369 donation after brain death (DBD) donors, no differences were found in 1-year survival, incidence of PGD, or acute rejection [20] In the DCD Registry of the ISHLT, 306 DBD transplantations were compared to 3,992 DCD transplantations The study found that 30-day, 1-year, and 3year survival rates were comparable between the two groups The DCD recipients had a slightly longer hospital stay following transplantation 18 days versus 16 days (p = 0.016) [21] Ethical issues regarding DCD donation were recently reviewed in a multisociety policy statement [22] The usual donor selection criteria are age younger than 60 to 65 years, no history of clinically significant lung disease, normal results from a sputum Gram stain, and a limited history of smoking (less than 20 packyears) In addition, the lung fields should be clear as demonstrated by chest radiograph, and gas exchange should be adequate as demonstrated by a partial pressure of arterial oxygen (PaO2) > 300 mm Hg, while receiving fractional inspired oxygen (FIO2) equal to 1, or a PaO2/FIO2 ratio of more than 300, with a positive end-expiratory pressure (PEEP) of 5 cm H2O Bronchoscopy is also part of the evaluation of the donor The main goal of the endobronchial evaluation is to rule out gross aspiration or purulent secretions in the distal airways Lungs from extended donors (i.e., those who do not meet all of the criteria listed earlier) are now more frequently being transplanted in an attempt to expand the donor pool Commonly extended criteria include the use of lungs from older donors and those from smokers [23,24] In the Euro transplant community, lungs from extended donors are used for rescue offers with comparable outcomes [25] Some centers are actively engaged in developing protocols for optimizing marginal donor lungs, thereby rendering them transplantable [26–29] By instituting a protocol including educational and donor management interventions, and changing donor classification and selection criteria, a single-organ procurement organization was able to increase the percentage of lungs procured from 11.5% to 22.5% with an increase in the number of procedures performed, without adverse recipient outcomes [29] A similar study using a protocol of protective ventilation including ventilator recruitment maneuvers, high levels of PEEP, fluid restriction, and hormonal resuscitation therapy also showed increased procurement rates from 20% to 50% without compromised survival or incidence of PGD [26] The use of lung protective ventilation strategies such as low tidal volume ventilation to limit lung injury is now recommended when managing the potential lung donor, resulting in adequate functioning lungs [26–28,30] A multicenter randomized controlled trial of potential organ donors managed with conventional versus protective ventilator strategies revealed that the latter resulted in a significant increase in the number of eligible (54% vs 95%) and harvested (27% vs 54%) lungs for LT There were no differences in 6month survival among recipients receiving lungs from donors ventilated by either strategy [28] A new development in lung donation has been the use of ex vivo lung perfusion(EVLP), which in essence “reconditions” lungs that have previously not been acceptable for transplantation In a prospective nonrandomized clinical trial from Toronto examining high-risk donor lungs transplanted after 4 hours of EVLP, the investigators found results similar to those obtained with conventionally selected lungs, including incidence of PGD, 30-day mortality and 1-year mortality, bronchial complications, duration of mechanical ventilation, and hospital and ICU length of stay [31,32] Other studies using EVLP found similar results in addition to similar incidences of acute rejection and infection [33,34] Donors are excluded from potential lung donation if there is evidence of active infection, human immunodeficiency virus, hepatitis, or malignancy Donor and recipient compatibility is assessed by matching A, B, and O blood types and chest wall size Human leukocyte antigen (HLA) matching is not routinely performed in LT except in patients with history of preformed donor-specific antibodies SURGICAL TECHNIQUES Initially, double-lung transplantation was the procedure of choice with the anastomosis placed at the level of the trachea However, the rate of ischemic airway complications was prohibitive Now, SLT or BLT (essentially sequential SLT) with anastomoses at the level of the main stem bronchi is the preferred surgical technique At the time of donor harvest, the donor lung is usually removed through a median sternotomy The pulmonary veins are detached from the heart with a residual 5-mm cuff of left atrium Each pulmonary artery and the main stem bronchus are transected between two staple lines During transportation to the recipient site, the partially inflated donor lung graft is placed into preservation solution, usually a low-potassium dextran solution with extracellular electrolyte composition or a modified Euro-Collins solution with an intracellular electrolyte composition at 4°C p 517 p 518 For SLT, the recipient surgery is performed more commonly through a posterolateral thoracotomy or on occasion through a midsternotomy, or vertical axillary muscle-sparing minithoracotomy Most centers start with the bronchial anastomosis, without a vascular anastomosis of the bronchial circulation of the recipient and donor lungs Initially, most transplant procedures involved an end-to-end anastomosis, which was wrapped with a piece of omentum or pericardial fat with an intact vascular pedicle for assistance in bronchial revascularization Subsequently, a telescoping technique was recommended, with the recipient and donor bronchi overlapping by approximately one cartilaginous ring This procedure allowed the recipient’s intact bronchial circulation to supply the donor bronchus More recently, most anastomoses are performed with an end-to-end single suture in the membranous portion and a single or continuous suture in the cartilaginous portion, without omental wrap, and telescoping is performed when the donor and recipient bronchi differ in size and there is a natural, unforced telescoping of both bronchi [35] After the bronchial anastomosis has been performed, the donor pulmonary veins are anastomosed end-to-end to the recipient’s left atrium, and the pulmonary arteries are attached with an end-to-end anastomosis BLT is usually performed through a transverse thoracosternotomy (clamshell incision) or less frequently with median sternotomy followed by sequential single-lung procedures Cardiopulmonary bypass may be required for patients with pulmonary hypertension or those who cannot tolerate single-lung ventilation or perfusion and who experience marked hypoxemia or hemodynamic instability Although center specific, an increasing number of cases (nearly 50% of LT procedures at some institutions) are performed with the use of cardiopulmonary bypass GENERAL POSTOPERATIVE MANAGEMENT After LT, patients remain intubated, require mechanical ventilation, and are transferred to the ICU Most patients are ventilated in a volumecontrol mode, although in recent years some transplant centers have changed to pressure-control ventilation, or airway pressure release ventilation In general, low tidal volume ventilation strategies are used Airway pressures are kept as low as possible so that barotrauma and anastomotic dehiscence can be avoided Many institutions use routine pharmacologic sedation Patients are generally maintained with tidal volumes of 6 to 8 mL per kg postoperatively At most institutions, a low level of PEEP (5.0 to 7.5 cm H2O) is applied immediately after lung expansion in the operating room and is continued after transplantation Early extubation is one of the main goals after LT, and lung transplant recipients who do not experience complications are extubated within the first 12 to 24 hours postoperatively if they meet the commonly accepted weaning criteria Both postural drainage and chest physiotherapy can be routinely employed without concern for mechanical complications at the anastomosis, and patients should perform incentive spirometry soon after extubation A recent international survey, with 58% response rate, on mechanical ventilation practices after LT revealed that pressure assist control was used by 37% of respondents and volume assist control by 35% Tidal volumes were based on recipient, not donor, characteristics, and most respondents selected 6 mL per kg of recipient ideal body weight as a target Twenty-one percent selected 10 mL per kg, and none selected 15 mL per kg Most respondents favored limiting FIO2 over PEEP 69% versus 31% (p = 0.006), and the median minimum PEEP used was 5 cm H2O and median maximum was 11.5 cm H2O In the setting of PGD, the plateau pressure limit for adjusting tidal volume was 30 cm H2O [36] Certain patient populations require special ventilator management Most patients with idiopathic pulmonary hypertension undergo BLT; however, at a few centers some patients undergo SLT for pulmonary hypertension with an increased risk of reperfusion pulmonary edema because nearly all of the perfusion is going to the newly implanted lung Patients with obstructive lung disease can encounter problems if the delivered tidal volume or the required levels of PEEP are high Occasionally, clinically significant acute native lung hyperinflation can occur and can compromise the newly transplanted lung and lead to hypotension and hemodynamic instability To reduce this problem, some transplant centers avoid PEEP for patients undergoing SLT for obstructive disease However, the problem is magnified when patients experience reperfusion injury or pneumonia after transplantation; in such cases, the compliance of the transplanted lung is decreased and higher PEEP is required for maintaining oxygenation As a consequence, the more compliant emphysematous lung becomes overexpanded and can herniate toward the contralateral hemithorax [37] Attempts to prevent this possible complication by using selective independent ventilation with a double-lumen endotracheal tube have been tried Lung hyperinflation is associated with a significantly longer stay in the ICU, a longer duration of mechanical ventilation, and a trend toward higher mortality [38] Pain control is usually provided by opiates, usually fentanyl, administered intravenously, or morphine sulfate via an epidural catheter with a patient-regulated pain-control system Because many patients are nutritionally depleted before transplantation as a result of their underlying disease, postoperative nutrition is important Ideally, enteral nutrition should be provided as soon as tolerated Antibiotics are routinely administered for the first 48 to 72 hours after transplantation Antibiotic regimens include broad-spectrum antibiotic coverage for both gram-negative and gram-positive bacteria Most centers advocate empiric anaerobic coverage Gram stains and cultures of sputum from the donor and the recipient may be used when available to guide the choice of appropriate antibiotics Many centers routinely use antifungal agents such as inhaled amphotericin B, voriconazole, or itraconazole postoperatively Most transplantation programs administer valganciclovir for CMV prophylaxis if either the patient or the donor IgG serology is CMV-positive before surgery Immunosuppression is begun preoperatively with tacrolimus or cyclosporine and corticosteroids Corticosteroids are administered in the operating room as intravenous methylprednisolone 0.5 to 1 g (usually administered at the time of reperfusion) and then at doses of 1 to 3 mg per kg daily for the next 3 days, followed by 0.8 mg per kg daily and then conversion to an equivalent oral dose Many centers currently use interleukin (IL)-2 receptor blockers (e.g., basiliximab) for induction immunosuppression A retrospective registry analysis of the impact of induction therapy on survival following LT showed a survival advantage with the use of interleukin-2-receptor antagonists in both SLT and BLT recipients and in BLT recipients treated with anti-thymocyte globulin (ATG) [39] After the transplantation procedure, most patients begin a triple immunosuppression protocol with a combination of prednisone, a calcineurin agent, tacrolimus or cyclosporine, and a cell-cycle–inhibiting agent, mycophenolate mofetil or azathioprine [40] POSTOPERATIVE PROBLEMS Primary Graft Dysfunction Perhaps the most serious problem in the postoperative period after LT is PGD [41] A 2005 consensus conference attempted to standardize the grading of PGD on the basis of gas exchange and the presence of radiographic infiltrates (Table 59.2) [42] When the acute lung injury definition of acute respiratory distress syndrome (ARDS)—a PaO2/FiO2 ratio of less than 200—is used to define the most severe form of PGD (grade 3), it is estimated that as many as 5% to 25% of transplant recipients can develop PGD (grade 3) [42, 43] PGD is a diagnosis of exclusion; the condition usually occurs hours to 3 days after LT, whereas rejection and infection are more common after the first 24 hours A stenosis at the venous anastomosis presents with similar signs and symptoms, but this diagnosis can be excluded by transesophageal echocardiography However, because the timing of these disorders may vary, differentiation may be difficult p 518 p 519 TABLE 59.2 Grading of the Severity of Primary Graft Dysfunction Grade PaO2/FiO2 Radiographic infiltrates consistent with pulmonary edema >300 >300 200–300 30 days following LT, reasons for admission included respiratory failure in 50.5% and acute rejection in 16% One quarter of patients required hemodialysis, and 53.5% required mechanical ventilation In the study cohort, hospital survival was 88/101, but 6-month survival was 56.4% Predictors of hospital survival were APACHE score on admission and SLT Functional status at discharge was an independent predictor of 6month survival [62] In another study, again examining ICU admissions at >30 days post-LT in patients with diagnoses of idiopathic pulmonary fibrosis and COPD, 93% of patients required mechanical ventilation Septic shock was the reason for admission in 55% of patients ICU mortality was 62.5% Mortality was associated with more frequent hospital admissions, a high severity score (SOFA), a diagnosis of sepsis, and requirement for mechanical ventilation There was a higher incidence of BOS in nonsurvivors [63] The long-term survival of patients who recover from the ICU stay is also compromised; however, a high percentage of patients (50%) can still enjoy long-term survival after an ICU admission A recent study supports the use of high-flow nasal cannula (HFNC) as supportive therapy for patients readmitted to the ICU for acute respiratory failure and was associated with a decreased risk of mechanical ventilation (absolute risk reduction of 29.8%) The number needed to treat to prevent one intubation was three [64] In addition, those supported with HFNC had increased survival rates and did not experience adverse events Airway Complications Because of the lack of revascularization of the bronchial circulation, anastomotic complications, such as bronchial dehiscence, bronchial stenosis, and bronchial infection, are the main airway complications reported in the first few weeks to months after LT [65,66] The incidence of anastomotic complications has decreased as surgical techniques have improved and surgeons have gained experience with the procedure The reported incidence of this complication ranges widely: some studies report it to be as high as 33%; others, as low as 1.6% However, in reality, most recent series suggest a range of 7% to 18% [67], with a related mortality rate of 2% to 4% Risk factors for airway complications include ischemia of the donor bronchus during the posttransplantation period, due to loss of bronchial blood flow (only the pulmonary vessels are revascularized during LT surgery), surgical techniques for the anastomosis, length of the donor bronchi, acute rejection, and bronchial infections Airway complications can be classified as early or late Early airway complications usually occur during the first 4 to 12 weeks after transplantation and manifest themselves as a partial or complete anastomotic dehiscence or a fungal (usually Aspergillus or Candida species) or bacterial (usually Staphylococcus or Pseudomonas species) anastomotic infection These conditions can subsequently result in anastomotic strictures or bronchomalacia Clinically, bronchial dehiscence may cause prolonged air leaks in the early posttransplantation period In some cases, the dehiscence may also lead to infection or the formation of peribronchial abscesses or fistulas The results of chest radiographs and computed tomography (CT) scans are usually nonspecific; however, the appearance of extraluminal air on chest CT scans is very sensitive and specific for the diagnosis of anastomotic dehiscence Bronchoscopy is the preferred diagnostic method for evaluating the bronchial anastomosis The initial bronchoscopies are done usually before extubation and again before discharge In addition, the anastomosis is also evaluated carefully during surveillance or clinically indicated bronchoscopy particularly during the 1st year The integrity of the mucosa should be assessed, and specimens from a bronchial wash or brush should be sent for cultures and cytologic examination If there is any evidence of infection, antibiotics and antifungals (usually inhaled amphotericin with or without itraconazole or voriconazole) should be administered on the basis of culture results Late bronchial anastomotic complications, including stenosis (most common), bronchomalacia, and development of exophytic granulation tissue are often the result of ischemia, infection, or dehiscence during the early weeks after transplantation These complications manifest themselves as cough, shortness of breath, wheezing, dyspnea on exertion, and worsening obstruction as documented by pulmonary function testing The characteristic flow volume loop demonstrates a concave appearance in both the inspiratory loop and the expiratory loop Bronchial strictures or stenosis may also be seen on chest radiographs or CT scans, or by bronchoscopy Therapeutic options for anastomotic complications include balloon dilation of a stricture, stent placement, cryotherapy, argon beam coagulation, laser procedures, and, rarely, surgery Rejection Graft rejection is categorized clinically according to the time of onset after transplantation and the histopathologic pattern The three types of rejection are antibody-mediated rejection (AMR) which can rarely appear as a form of hyperacute rejection, acute cellular rejection, and chronic rejection Hyperacute rejection is an acute form of AMR caused by preexisting alloantibodies that bind to the donor vascular epithelium and lead to vessel thrombosis because of complement activation This was thought to be a rare complication after LT However, AMR or humoral rejection is currently an area of active research in the field of LT [68,69] AMR is characterized by local complement activation or the presence of antibody to donor HLAs and may be a risk factor for BOS [70] Treatment of AMR includes plasmapheresis, intravenous immunoglobulin and/or rituximab, a monoclonal antibody against the CD-20 antigen p 520 p 521 Acute Rejection As many as 50% to 55% of patients experience acute rejection during the first postoperative month, and as many as 90% will experience at least one episode of acute rejection within the 1st year [69] Acute rejection usually occurs between 10 and 90 days after LT It is not uncommon (20% of lung transplant recipients) for a single patient to experience either recurrent (more than two episodes) and/or persistent (failure to resolve with standard therapy) rejection Acute rejection usually does not occur as frequently after the first postoperative year Risk factors for acute rejection are poorly defined, but HLA mismatches may be correlated with its occurrence [71,72] Clinically, acute rejection manifests itself as cough, shortness of breath, malaise, and fever Occasionally, the presentation is asymptomatic The majority of transplantation centers advocate surveillance bronchoscopy for the detection of this condition, although outcome data are not available [40] Physical examination may detect rales or wheezing The usefulness of chest radiography depends on the time since transplantation Typically, during the 1st month the results of chest radiography can be abnormal in as many as 75% of rejection episodes; however, the results of radiography are abnormal in only 25% of rejection episodes that occur more than 1 month after transplantation The most common radiographic patterns associated with acute rejection are a perihilar flare, and alveolar or interstitial localized or diffuse infiltrates with or without associated pleural effusion In addition, CT may show ground-glass opacities, septal thickening, and volume loss New pleural fluid or increases in the amount of pleural fluid produced during the 2nd to 6th week after LT is common among patients with acute lung rejection The characteristics of the fluid are consistent with those of an exudate: the total lymphocyte count is often more than 80% of the total number of white blood cells Physiologic findings during periods of acute rejection include hypoxemia and deterioration in pulmonary function Pulmonary function abnormalities are characterized by at least a 10% to 15% decline in FEV1 from baseline and/or at least a 20% decline in forced expiratory flow (FEF) over 25% to 75% of expired vital capacity Once again, these changes are nonspecific and can also be seen with infectious processes and graft complications Because clinical criteria alone cannot differentiate acute rejection from infection and less common graft complications, transbronchial biopsy (TBBx) with bronchoalveolar lavage (BAL) has become the primary diagnostic procedure The sensitivity of diagnosing acute rejection by TBBx ranges from 61% to 94%, and the specificity ranges from 90% to 100% A histologic grading system for acute pulmonary rejection was proposed in 1990 and revised in 1996 and 2007 [73] Pathologically, acute rejection is characterized by perivascular, mononuclear lymphocytic infiltrates with or without airway inflammation; histologically, it is graded from A0 to A4 on the basis of the degree of perivascular inflammation In addition, the airway can be involved by lymphocytic bronchitis or bronchiolitis, which is graded from B0 to Bx As rejection progresses, the perivascular lymphocytic infiltrates surrounding the venules and arterioles become dense and extend into the perivascular and peribronchiolar alveolar septa Severe rejection may involve the alveolar space; parenchymal necrosis, hyaline membranes, and necrotizing vasculitis have been described; and respiratory failure requiring mechanical ventilation can occur Once acute rejection has been diagnosed, treatment consists of augmenting the level of immunosuppression Intravenous methylprednisolone (10 to 15 mg per kg daily for 3 days) followed by an increase in the maintenance regimen of prednisone regimen to 0.5 to 1 mg per kg daily, with tapering over the next several weeks, is a standard treatment regimen Maintenance immunosuppression should also be augmented Typically, symptoms resolve in days, and histologic follow-up 3 to 4 weeks later should demonstrate resolution Recurrent or persistent acute rejection may require alteration of the baseline immunosuppressive regimen Lympholytic therapy, methotrexate, photophoresis, total lymphoid irradiation, and aerosolized cyclosporine have been used with varied success [74] Chronic Lung Allograft Dysfunction Chronic lung allograft dysfunction (CLAD) encompasses varied presentations of progressive allograft dysfunction with obstructive and restrictive physiology [75] The most common form of CLAD has been equated with the histologic finding of obliterative bronchiolitis (OB); this form of chronic rejection is a primary cause of morbidity and mortality after LT and the leading single cause of death more than 1 year after transplantation [1] The incidence of OB ranges from 35% to 50% OB has been defined clinically by an obstructive functional defect and histologically by obliteration of terminal bronchioles OB generally occurs at a mean of 16 to 20 months after LT, but it has been reported as early as 3 months after transplantation More than 50% of recipients will experience some degree of OB by 5 years after transplantation [1] A less common form of CLAD, the restrictive allograft syndrome (RAS), contributes to approximately 25% to 35% of the reported cases and carries a worse prognosis than BOS It is characterized by various stages of diffuse alveolar damage and extensive fibrosis in the alveolar interstitium, visceral pleura, and interlobular septae RAS presents radiologically as upper lobe–dominant fibrosis and/or interstitial opacities sometimes often with associated pleural thickening and with a restrictive pattern in the lung function tests (Total lung capacity [TLC] below 90% of the best baseline posttransplant) [75,76] The causes of and risk factors for OB remain unclear Several possible risk factors have been proposed, including uncontrolled acute rejection, lymphocytic bronchiolitis, CMV pneumonitis, CMV infection without pneumonitis, community-acquired respiratory viruses, gastroesophageal reflux disease, PGD, AMR, HLA-A mismatches, total HLA mismatches, absence of donor antigen-specific hyporeactivity, non-CMV infection, older donor age, and bronchiolitis obliterans with organizing pneumonia [50,51,77–79] The most consistently identified risk factor is acute rejection, particularly in those patients who experience recurrent, highgrade episodes of acute rejection Clinically, OB can manifest itself as an upper respiratory tract infection and can be mistakenly treated as such Other patients exhibit no clinical symptoms, but pulmonary function testing demonstrates gradual obstructive dysfunction FEV1 has been the standard spirometric parameter used for diagnosis, but midexpiratory flow rates may be a more sensitive parameter for early detection Typically, chest radiographs are not helpful in the diagnosis of OB because their results are unchanged from the results of baseline posttransplantation radiographs High-resolution CT scans may show peripheral bronchiectasis, patchy consolidation, decreased peripheral vascular markings, air trapping, mosaicism, tree-in-bud changes, and bronchial dilation; these findings may aid in the diagnosis of OB [80] Air trapping on end-expiratory high-resolution CT scans has been shown to be a sensitive (91%) and accurate (86%) radiologic indicator of OB, but it may not be able to provide an early diagnosis of this disorder As with acute rejection, TBBx is used to diagnose OB, but primarily to exclude other diagnoses The classic pathologic finding is constrictive bronchiolitis Unfortunately, the sensitivity of TBBx for diagnosing OB is low (range: 15% to 87%), and the diagnosis of OB is often made by exclusion OB is graded physiologically on the basis of the degree of change in pulmonary function (FEV1) from baseline [78] Because of the variability in obtaining bronchioles by TBBx, the ISHLT has established a staging system for BOS This staging is based on a reduction in FEV1 of more than 20% from baseline after transplantation and is associated with a decrease in the FEF 25% to 75%, with or without the pathologic documentation of OB [78] p 521 p 522 Once OB has been diagnosed histologically or clinically by excluding alternative diagnoses, treatment involves administering high-dose methylprednisolone followed by a tapering course of oral corticosteroids Therapy may stabilize pulmonary function, but it only rarely results in substantial improvement Alternative immunosuppressants such as sirolimus have also been associated with stabilization of pulmonary function when used as rescue treatment for BOS Lympholytic depleting agents such as ATG are the most commonly used rescue medications if there is no clinical response to corticosteroids Several studies have shown prevention, stabilization, and/or improvement in BOS when azithromycin is added to the regimen or used prophylactically, likely due to the immunomodulating effects and is now a widespread practice [81,82] Other alternatives with limited clinical success include alemtuzumab, basiliximab, methotrexate, total lymphoid radiation, and photophoresis Infection, including bronchiectasis, frequently complicates intensive immunosuppression for OB and may result in death Pseudomonas is a common offender, and aerosolized aminoglycoside antibiotics or suppressive quinolone treatment may be considered Because most cases of OB can only be stabilized, strategies directed at prevention, early diagnosis, and treatments are necessary for the preservation of lung function Retransplantation has been performed with varied results Survival rates are somewhat lower than those after the initial transplantation and are superior when performed for the indication of BOS, performed more than 1 year following the initial transplant and when a bilateral transplant is performed (1 year, 71%; 3 years, 46%; and 5 years, 34%) [1,83] Infectious Complications Infections are an important cause of early and late morbidity and mortality after transplantation and are the leading single specific cause of death during the 1st year following the transplantation procedure [1,84] The incidence of infection is significantly higher among recipients of lung transplants than among recipients of most other solid-organ transplants; this higher incidence may be related to the continuous exposure of the allograft to the environment Other predisposing factors include a diminished cough reflex because of denervation, poor lymphatic drainage, decreased mucociliary clearance, recipient-harbored infection, and, occasionally, transfer of infection from the donor organ Nosocomial infections, such as urinary tract infections, ventilator-assisted pneumonia, and infections at the site of the surgical wound or the vascular access, also occur during the early postoperative period However, in most circumstances the allograft(s) is/are the primary site of infection Bacterial Infections Bacterial pneumonia is the most common life-threatening infection that develops during the early postoperative period Its incidence during the first two postoperative weeks is reported to be as high as 35% [84–87], and in a single-center retrospective cohort study, 68% of patients developed at least one episode of pneumonia [88] In another singlecenter study, 12% of patients suffered a ventilator-associated pneumonia, resulting in increases in hospital length of stay, increase in duration of mechanical ventilation, and an increase in hospital mortality Pseudomonas and Enterobacteracie were the most common pathogens Gastroperesis was associated with the development of pneumonia in this study [89] Common organisms include Pseudomonas aeruginosa and Staphylococcus species The incidence of perioperative bacterial pneumonia has been reduced to as low as 10% by prophylaxis with broadspectrum antibiotics, usually an antipseudomonal cephalosporin and clindamycin, and by routine culture of the trachea of both the donor and the recipient at the time of transplantation Prophylactic antibiotics are usually discontinued after 3 days if the results of cultures are negative; the antibiotics are tailored to the cultured organisms if the results are positive For transplant recipients with bronchiectasis, postoperative bacterial prophylaxis is usually continued for 14 days The incidence of bacterial pneumonia is high during the first 6 months after transplantation but decreases thereafter, although a second late peak of incidence often occurs when immunosuppression is augmented for the treatment of chronic rejection During the early posttransplantation period, bacterial infection due to Staphylococcus or, less commonly, Pseudomonas can develop at or distal to the site of the anastomosis It is often difficult to distinguish pneumonia from other early graft complications, such as reperfusion injury, pulmonary edema, rejection, and other causes of infection In addition, differentiating between colonization and invasion may be difficult and often requires invasive procedures such as bronchoscopy with BAL, quantitative sterile brush sampling, or TBBx Other Infections Atypical pneumonias, including those due to Legionella, Mycobacteria, and Nocardia, are uncommon during the first month after transplantation but occur among 2% to 9% of recipients of lung or heart– lung transplants At transplantation centers that routinely administer prophylaxis with trimethoprim–sulfamethoxazole during the 1st year after transplantation and continue or reinitiate it when immunosuppression is augmented, the incidence of pneumocystis pneumonia is less than 1% Most opportunistic infections occur within 6 months after transplantation Sustained immunosuppression leading to a decrease in cell-mediated immunity predisposes the patient to infection with opportunistic organisms such as Aspergillus, Mycobacterium, Nocardia, and geographically endemic fungi Viral Infections Viral infections are a primary cause of morbidity and mortality among lung transplant recipients During the first 6 months after transplantation, CMV accounts for most of the viral infections among these patients [84,87,90] The typical time period for the development of CMV infection is 30 to 150 days postoperatively; the incidence of illness (i.e., infection and disease) is approximately 50% Risk factors for CMV disease depend on the serology of the donor and the recipient and on the use of high-intensity immunosuppressive therapy, including cytolytic therapy Approximately 15% to 35% of CMV-positive patients who receive grafts from either CMV-positive or CMV-negative donors experience CMV disease, whereas approximately 55% of CMV-negative patients who receive a graft from a CMV-positive donor may experience CMV disease Most studies indicate that CMV pneumonitis contributes to the development of chronic rejection [78] CMV can cause a wide spectrum of disease, ranging from asymptomatic infection, such as shedding of the virus in the urine or BAL, to widespread dissemination The most common presentation of CMV among lung transplant recipients is pneumonitis, but the infection may also present as gastroenteritis, hepatitis, or colitis CMV pneumonitis can often be confused with acute rejection Clinical findings of CMV pneumonitis include fever, cough, flu-like illness, hypoxemia, an interstitial or alveolar infiltrate, and leukopenia A definitive diagnosis of invasive disease requires cytologic or histologic changes in a cell preparation or in tissue Therefore, diagnosis often requires flexible bronchoscopy with TBBx and BAL; this combination can detect 60% to 90% of CMV pneumonias Currently, plasma-based polymerase chain reaction (PCR) assays are used to screen patients and to detect CMV infection [91] The risk of CMV pneumonitis after LT is usually related to the serum concentration of CMV DNA, and this measure is used in many programs for the preemptive management of CMV p 522 p 523 The pathologic hallmark of CMV infection is a cytomegalic 250-nm cell containing a large central basophilic intranuclear inclusion This inclusion is referred to as an “owl’s eye” because it is separated from the nuclear membrane by a halo Identifying CMV cytologically is very specific (98%) but lacks sensitivity (21%) for detecting the presence of infection Other pathologic findings in the lung parenchyma of patients with CMV pneumonia include a lymphocytic and mononuclear-cell interstitial pneumonitis Ganciclovir intravenous and oral valganciclovir are currently the mainstays of therapy for invasive CMV disease [90] Bone marrow toxicity is one of the primary limiting side effects of ganciclovir therapy and may necessitate conversion to an alternative agent such as foscarnet Most centers also use CMV-specific hyperimmunoglobulin to treat CMV disease Prophylaxis against CMV infections has become an important strategy at most transplantation centers Initially, some centers attempted to match CMV-negative recipients with CMV-negative donors; however, the limited donor supply did not allow the continuation of this practice The use of CMV-negative blood products is advocated Prophylaxis with ganciclovir or valganciclovir seems to be effective in delaying the onset of CMV infection Most centers give prophylaxis to all patients except CMVnegative recipients who receive grafts from CMV-negative donors Prophylaxis is usually recommended for at least 90 days, but the majority of centers, particularly for CMV-negative recipients of grafts from CMVpositive donors, will continue prophylaxis for at least 1 year A randomized, controlled, multicenter study examined the efficacy of extending valganciclovir prophylaxis from the standard 3 months to 12 months in at-risk (either donor or recipient CMV-positive) patients The investigators found a significant reduction in CMV infection, disease, and disease severity without increased ganciclovir resistance or toxicity among those patients receiving the longer course of therapy [92] For patients at highest risk of infection, CMV hyperimmunoglobulin may be added to the regimen Preemptive strategies, such as initiating treatment when a high level of CMV DNA is detected by PCR, may also delay and decrease the severity of CMV infection and has become the standard of care at many centers Other viruses that affect lung transplant recipients include herpes simplex virus (early after transplantation), community-acquired respiratory viruses, such as respiratory syncytial virus, other paramyxoviruses (such as parainfluenza), influenza virus, metapneumovirus, and adenovirus [93] Some transplantation programs initiate prophylaxis with acyclovir for herpes infection after the discontinuation of ganciclovir Ribavirin has been used to treat respiratory syncytial virus infection in both nebulized and oral form, although the former is associated with bronchospasm and potential teratogenicity to health care workers Fungal Infections Fungal infections are more common among recipients of LTs than among recipients of some other solid-organ transplantations [94,95] The overall incidence of invasive fungal infection after LT ranges from 15% to 35% Such infections usually develop during the first few months after transplantation Fungal infections carry the highest morbidity and mortality rates of all infections after transplantation; mortality rates can range from 40% to 70% Aspergillus species such as A fumigatus, A flavus, A terreus, and A niger can be colonizing organisms; can cause an infection that suggests an indolent, progressive pneumonia; or can cause an acute fulminant infection that disseminates rapidly Aspergillus can invade blood vessels and may appear as an infarct on chest imaging or present with hemoptysis The radiographic findings of pulmonary aspergillosis include focal lower-lobe infiltrates, patchy bronchopneumonic infiltrates, single or multiple nodules with or without cavitation, thin-wall cavities, and opacification of the entire lung graft High-resolution CT scans may reveal a halo sign that is believed to be pathognomonic for angioinvasive fungal infections such as aspergillosis Other manifestations of Aspergillus infection include pseudomembranous tracheobronchitis, often at and distal to the site of the anastomosis Diagnosing invasive aspergillosis requires identifying organisms within tissues These organisms can appear as septate hyphae that branch at acute angles and can be detected on hematoxylin-eosin and methenamine silver stains Survival rates for patients with Aspergillus infection have been improved by the early initiation of broad-spectrum azoles (such as voriconazole or itraconazole, and more recently posaconazole), sometimes with the addition of an echinocandin, and a reduction in immunosuppressive therapy [96] In patients with airway involvement with Aspergillus and for short-term prophylaxis following transplantation, inhaled amphotericin may be used It is now rare to require systemic amphotericin or the less nephrotoxic liposomal formulation of amphotericin B Prophylaxis with the azoles (voriconazole or itraconazole) for 3 to 6 months, and/or with aerosolized amphotericin, has shown promise for decreasing the incidence of Aspergillus infection after transplantation Candidal infections may occur during the early postoperative period but usually do not cause invasive disease Candida species can cause a variety of syndromes among LT recipients; these syndromes include mucocutaneous disease, line sepsis, wound infection, and, rarely, pulmonary involvement Fluconazole and caspofungin have emerged as effective alternatives for treating infections caused by Candida albicans Fluconazole appears to be less active against other Candida species such as C glabrata and C krusei Less common causes of fungal infections among lung transplant recipients include Cryptococcus neoformans and the dimorphic fungi (Coccidioides, Histoplasma, and Blastomyces) The broad-spectrum azole agents are the initial therapeutic choices for treating serious infections with the invasive mycoses Amphotericin B can be used for disseminated disease The dose, duration of therapy, and alternative therapies differ depending on the organism Immunosuppression After LT, a typical regimen for the maintenance of immunosuppression consists of tacrolimus at a dose of approximately 0.1 mg per kg orally every day in two divided doses (adjusted to maintain a serum concentration of 8 to 15 ng per mL), or cyclosporine 5 mg per kg orally every day in two divided doses (with dose adjusted to maintain serum concentrations of 250 to 350 ng per mL), and mycophenolate mofetil at a dose of 1 to 3 g daily, or azathioprine 1 to 2 mg per kg daily (adjusted to maintain a leukocyte count higher than 4,000 to 4,500 per mL), and prednisone approximately 0.5 mg per kg daily for the 1st month and then tapered by 5 mg per week over the next few months to a final maintenance dose of 5 mg per day A minority of transplantation programs completely discontinue the administration of prednisone approximately 1 year after transplantation The role of sirolimus after LT remains to be established It is recommended that sirolimus not be used in the early perioperative period (4.0 34 mg/kg PO preoperatively; 3 mg/kg IV/PO qd postoperatively 1–3 mg/kg PO qd Data from Refs [21–25] IV, intravenously; PO, orally The antimetabolites include MMF and azathioprine These inhibit purine synthesis and thus block the proliferation of both T and B cells They are complementary to the calcineurin inhibitors Kobashigawa et al [29] demonstrated considerable benefits to MMF over azathioprine when coupled with cyclosporine in transplants performed in 1998 MMF is currently the most widely used antimetabolite in heart transplantation [26] Corticosteroids remain a cornerstone of therapy There are multiple regimens for early corticosteroid reduction to avoid the serious associated side effects including systemic hypertension, obesity, osteoporosis, and glucose intolerance In spite of the negative side effects, in 2004, approximately 75% of patients were still taking corticosteroids 1 year following their transplants [30] Monotherapy consisting of tacrolimus is currently being studied in heart transplant recipients In one study, 75% of recipients were successfully converted to monotherapy [31] Results from the group at Stanford confirm that therapy with tacrolimus and limited corticosteroid are linked to improved recipient and graft survival [28] The use of IL-2 receptor blockade has become more prevalent during the last 4 to 5 years These proliferation signal inhibitors, sirolimus and everolimus, block the activation of the T cell by binding the IL-2 receptor They have shown promise in significantly reducing the severity of cardiac allograft vasculopathy, the main threat of long-term graft survival But they remain only an adjunct to the calcineurin inhibitors that are still more effective in preventing acute rejection Outcomes The Registry of the International Society for Heart and Lung Transplantation (ISHLT) has reported on survival after cardiac transplantation in adult patients Survival rates have increased from 89% in 2008 to 94% in 2014 at 1 year [32] The UNOS/OPTN (Organ Procurement and Transplantation Network) database also reported survival rates for the years 2005 to 2007 of 88% at 1 year, 81% at 3 years, and 75% at 5 years UNOS notes that survival rates are lowest among the patients 18 to 34 years of age [2] p 531 p 532 Over the years, the average survival rate for cardiac transplant patients improves The median survival in patients who were transplanted between 1982 and 1988 was 8.1 years, and that has increased to 9.8 years for individuals transplanted between 1994 and 1998 A significant improvement that has occurred during the current era is the 1-year survival for cardiac retransplantation, which is markedly better than that reported in past eras The 1-year survival for these patients is 82.4% [2] General Complications of Heart Transplantation Right Heart Failure and Pulmonary Hypertension Frequently acute right heart failure in the postoperative heart transplant patient is secondary to pulmonary hypertension As mentioned, patient selection is crucial in identifying those recipients with fixed pulmonary hypertension Those with a pulmonary vascular resistance ≥4 WU, a systolic pulmonary artery pressure ≥60 mm Hg or a transpulmonary gradient ≥15 mm Hg that does not reverse with vasodilator therapy such as inhaled nitric oxide or a prostacyclin analogue such as epoprostenol should not receive a heart transplant Despite this, there are still recipients who will have some degree of pulmonary hypertension that will cause right heart strain posttransplantation Though right heart failure is frequently accompanied by pulmonary hypertension, other causes include donor selection, poor preservation, or prolonged ischemia time The main principles of management in all cases of right heart failure are to preserve coronary perfusion, optimize RV preload, and reduce afterload by using high inspired oxygen concentrations, inhaled nitric oxide, and/or prostacyclin [33] Intravenous milrinone or dobutamine followed later by oral sildenafil are also mainstays of therapy Finally, in severe cases of right heart failure in the acute postoperative setting, a temporary right VAD is used to bridge the heart to recovery The need for mechanical assistance typically lasts only a few days to a week and a low threshold should be kept for implanting a device Rejection Surveillance for rejection of the transplanted heart by evaluating endomyocardial biopsies of the right ventricle obtained via the right internal jugular vein is performed frequently during the first year and eventually lessens to two to three times per year There are four types of rejection: hyperacute, acute cellular, acute humoral, and chronic The grading scale for rejection was recently revised to simplify it and also because there appeared to be little clinical difference between grade 1A and 1B rejection in the old classification There was evidence of a benign clinical course for grade 2 rejection in the old classification as well [34] The new grading system is shown in Table 60.3 TABLE 60.3 ISHLT Cardiac Biopsy Grading for Acute Cellular Rejection Grade 0R 1R, mild No rejection Interstitial and/or perivascular infiltrate with up to one focus of myocyte damage 2R, Two or more foci of infiltrate with associated moderate myocyte damage 3R Diffuse infiltrate with multifocal myocyte damage ± edema, ± hemorrhage, ± vasculitis ISHLT, International Society for Heart and Lung Transplantation Data from Stewart S, Winters GL, Fishbein MC, et al: Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection J Heart Lung Transplant 24:1710, 2005 The mainstay of treatment is pulse corticosteroids administered intravenously for 3 days, with or without a subsequent taper In the case of hemodynamically significant rejection or suspected acute humoral rejection, ultrafiltration, and intravenous immunoglobulin are administered to lower circulating antibodies The addition of methotrexate or cyclophosphamide also should be considered Photopheresis has been used to treat patients who have preexistent high levels of PRAs [35] Late chronic rejection manifests as cardiac allograft vasculopathy It is thought to be owing to a combination of humoral and cellular rejection, and is the greatest threat to long-term survival When a patient has no other options to treat chronic, unrelenting rejection, the last resort is retransplantation Infection and Pneumonia Patients who have undergone thoracic organ transplantation are susceptible to bacterial, fungal, and viral infections The most morbid viral infection that occurs in thoracic organ transplant recipients is caused by cytomegalovirus (CMV) [36] Transmission of CMV by a donor organ is very common and hence prophylaxis with ganciclovir is used in CMV-mismatched thoracic transplant recipients Patients who are seronegative at the time of transplantation and receive a graft from a seropositive donor sustain the highest rate of infection and exhibit the most severe form of CMV disease Ganciclovir is the treatment of choice Pulmonary complications occur in approximately a third of heart transplant recipients [36,37] and is the most common infectious complication in heart transplant recipients In the first 6 months, hospital-acquired bacterial pneumonia is the most common pulmonary complication followed by Aspergillus pneumonia The overall mortality associated with pneumonia is 35% to 55% and accounts for 40% of allcause mortality A heightened vigilance for pulmonary infection is critical and the presence of yeast or mold-positive sputum should be aggressively treated Risk factors for pulmonary complications are older recipient age, moderate-to-severe rejection, and development of CMV antigenemia in a previously CMV-seronegative recipient [36] Coronary Allograft Vasculopathy The development of coronary allograft vasculopathy can lead to myocardial infarction and sudden death in the cardiac transplant recipient Routine annual coronary angiography with intravascular ultrasound is performed to permit an accurate assessment of the time of onset and rate of progression of coronary artery disease Graft atherosclerosis occurs in 30% to 40% of transplant recipients after 3 years and in 40% to 60% of patients by 5 years after transplantation [38] It remains the major obstacle to long-term survival in cardiac transplant recipients A correlation between CMV infection and accelerated allograft atherosclerosis has also been identified [39] Immunologically-mediated endothelial damage has been proposed as a stimulus for the development of graft atherosclerosis Treatment can be temporizing in the form of angioplasty for focal lesions; however, when the disease involves tapering of the distal vessels, only cardiac retransplantation can treat the problem Renal Failure Renal failure in the perioperative period is often transient, and it may be the direct result of nephrotoxic immunosuppressive drugs Mild impairment of renal function preoperatively is acceptable as long as the risk of severe renal impairment during the postoperative period is recognized as a possible complication The lowest acceptable level for creatinine clearance in a potential thoracic organ transplant recipient is 50 mL per minute For suitable patients, combined heart-and-kidney transplant can be considered It is also possible for a patient to be listed for a kidney transplant following thoracic organ transplantation p 532 p 533 Posttransplant Lymphoproliferative Disease Posttransplant lymphoproliferative disease is a common cause of late death following solid-organ transplantation It is more commonly seen in the pediatric population and is associated with exposure to the Epstein– Barr virus (EBV) Those at greatest risk for posttransplant lymphoproliferative disease are individuals who are EBV-seronegative before transplant who convert after their transplant Those individuals who are EBV-seropositive before transplant are at a lower risk, but are not risk free Management includes vigilant monitoring of the patient’s EBV status, EBV polymerase chain reaction testing, and regular examinations of lymph node beds for enlargement Therapy once this problem occurs has not been standardized and includes the use of antiviral agents, reduction of immunosuppression, anti-CD20 antibodies (such as rituximab), chemotherapy, and radiation therapy Many of these have been used in combination Gastrointestinal Problems Approximately 40% of patients experience gastrointestinal complications posttransplantation The majority are related to drug side effects, most notably MMF that can cause nausea, vomiting, and diarrhea [40] These are most often managed with dose adjustments Serious complications of the alimentary tract following heart and heart–lung transplantation have been well documented and remain a major source of morbidity and mortality [41] For that reason, patients with active peptic ulcer disease or diverticular disease are not considered for thoracic organ transplantation, at least until these problems have resolved Mild liver dysfunction as evidenced by elevation of serum transaminase values and hyperbilirubinemia may occur in patients receiving high doses of cyclosporine This is a chemical hepatitis that usually responds to a decrease in the dosage Other immunosuppressants such as azathioprine have been implicated in a similar process Hepatitis may also be secondary to hepatitis B, CMV, herpes simplex virus, hepatitis A, or hepatitis C Biliary tract disease is common in the thoracic organ transplant population In a series of heart transplant recipients, the incidence of cholelithiasis ranged from 30% to 39%, which is more than twice that expected for age- and gender-matched controls [42] The primary cause of this problem is thought to be gallbladder stasis and the side effects of specific immunosuppressants [43] Cardiac Retransplantation Cardiac retransplantation represents a small fraction of the transplants that are performed annually (the UNOS/OPTN database: 3% to 5% annual retransplant rate) [2] According to the ISHLT database, approximately 2% of all adult heart transplantations internationally are retransplants In the pediatric heart transplant population, this rate is approximately 6% of all transplantations Current 1-year survival for heart retransplant is 82%, closely approaching the 1-year survival of the original transplantation [44] The primary indications for retransplantation appear to be early graft failure, and in later time periods, chronic rejection or graft atherosclerosis HEART–LUNG TRANSPLANTATION Heart–lung transplants are performed almost exclusively in patients with surgically uncorrectable congenital heart disease and Eisenmenger physiology Patients with unrelated severe cardiomyopathy and pulmonary disease may also be candidates for heart–lung transplantation With the difficulty of obtaining a heart–lung block and the outcomes of these procedures, many surgeons repair the congenital heart defect and transplant only the lungs [45,46] Increasing numbers of patients with primary pulmonary hypertension are being treated with bilateral single-lung transplant rather than with heart–lung transplantation There has been a constant decline in the number of heart–lung transplants performed since the mid-1990s, both nationally and internationally, with fewer than 90 heart–lung transplants being performed annually in the current era [2] Donor Criteria and Organ Procurement The donor criteria are similar to the criteria used for heart (as listed previously) and lung transplantation (see Chapter 59) The procurement of the heart–lung block entails simultaneous use of techniques that are otherwise used to procure these same organs separately Operative Technique From the outset, the recipient is placed on cardiopulmonary bypass The recipient heart is excised first, and then each lung is removed The phrenic neurovascular bundles are protected bilaterally The left recurrent laryngeal nerve is also at risk for damage in the region of the ligamentum arteriosum For that reason, some surgeons leave a portion of the main and left pulmonary artery in situ The tracheal anastomosis is performed first Although it can be wrapped with omentum, it does not need to be, because the coronary–bronchial collateral circulation is generally excellent Performance of the right atrial anastomosis or bicaval anastomoses is followed by the aortic anastomosis Large aortopulmonary collaterals and bronchial vessels can develop in patients with chronic cyanosis and Eisenmenger physiology Extreme care must be taken during the operative procedure in these patients to avoid postoperative bleeding Postoperative Care Postoperative care of patients who have had heart–lung transplantation can be quite complex Potential complications from the heart or the lungs can arise The standard postoperative care most closely resembles that of a lung transplantation patient, and is discussed in Chapter 59 Postoperative bleeding can be quite profound in this subset of patients, even with careful operative control of collateral vessels Outcomes As of 2009, the current registry reports from ISHLT demonstrate a 1-year survival rate of only 75% for individuals undergoing a heart–lung transplantation The average survival for this group of patients who were transplanted between 1982 and 2003 was 3.2 years Because of the significant mortality rate that occurred within the first year after the transplantation, the conditional half-life was higher at 9 years [30] Early mortalities were owing to technical complications, graft failure, and nonCMV infections accounting for 73% of the deaths Mortality that occurred beyond the first year was attributed to chronic lung rejection with bronchiolitis obliterans, whereas cardiac rejection or coronary vasculopathy played a minimal role In the field of heart–lung transplantation, it was initially thought that endomyocardial biopsy would be the appropriate diagnostic test to detect rejection [47,48] However, with two organ systems involved, the lungs often reject despite normal findings on endomyocardial biopsy [45] Transbronchial biopsy reveals what is occurring in the lungs during the perioperative period and, later, complications in the lung grafts may be suggested when there are changes on chest radiograph or in pulmonary function studies, and should be evaluated with transbronchial biopsy [49] Treatment of recurrent lung rejection consists of pulse corticosteroids with or without a taper Alternate therapies including lympholytic agents, photopheresis, methotrexate, or cyclophosphamide may be used for refractory cases of rejection [50] CONCLUSION The discipline of heart transplantation has recently passed its 40th anniversary, and many major advances have been made In spite of the changes that have occurred in recipient criteria, the greater number of potential recipients coming to transplant who are more than 60 years of age, on inotropic support, or using mechanical assist, the outcomes of heart transplantation have improved with each passing year The field has also enjoyed seeing a decrease in candidate waiting times on the list and the evolution of cardiac assist devices to improve candidates for heart transplant Clearly, knowledge of cardiac transplantation is directly related to the duration of experimental and clinical experience It is expected that, as understanding continues to expand, long-term survival of transplant recipients will increase REFERENCES Toronto Lung Transplant Group: Unilateral lung transplantation for pulmonary fibrosis N Engl J Med 314(18):1140–1145, 1986 United Network for Organ Sharing Statistics Available at: http://optn transplant.hrsa.gov/latestData/step2.asp Accessed August 15, 2015 Mancini DM, Eisen H, Kussmaul W, et al: Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure Circulation 83(3):778–786, 1991 Kao W, Jessup M: Exercise testing and exercise training in patients with congestive heart failure J Heart Lung Transplant 13(4):S117– S121, 1994 Jimenez J, Edwards L, Jara J, et al: Impact of body mass index on survival following heart transplantation J Heart Lung Transplant 23:S119, 2004 Grady KL, White-Williams C, Naftel D, et al: Are preoperative obesity and cachexia risk factors for post heart transplant morbidity and mortality: a multi-institutional study of preoperative weight-height indices Cardiac Transplant Research Database (CTRD) Group J Heart Lung Transplant 18(8):750–763, 1999 Jawitz OK, Jawitz NG, Yuh DD, et al: Impact of ABO compatibility on outcomes after heart transplantation in a national cohort during the past decade J Thoracic Cardiovasc Surg 146(5):1239–1246, 2013 Kasper E, Achuff SC: Clinical evaluation of potential heart transplant recipients, in Baumgartner WA, Reitz BA, Kasper EK, et al (eds): Heart and Lung Transplantation 2nd ed Philadelphia: WB Saunders Company, 2002, pp 57–63 Boyle A, Colvin-Adams M: Recipient selection and management Semin Thoracic Cardiovasc Surg 16:358, 2004 10 Miller LW: Listing criteria for cardiac transplantation: results of an American Society of Transplant Physicians-National Institutes of Health conference Transplantation 66(7):947–951, 1998 11 Mancini D, Colombo PC: Left ventricular assist devices: a rapidly evolving alternative to transplant J Am Coll Cardiol 65(23):2542– 2555, 2015 12 Rose EA, Gelijns AC, Moskowitz AJ, et al: Long-term use of a left ventricular assist device for end-stage heart failure N Eng J Med 345(20):1435–1443, 2001 13 Miller LW, Pagani FD, Russell SD, et al: Use of a continuous-flow device in patients awaiting heart transplantation N Eng J Med 357(9):885–896, 2007 14 John R, Lietz K, Schuster M, et al: Immunologic sensitization in recipients of left ventricular assist devices J Thoracic Cardiovasc Surg 125(3):578–591, 2003 15 Jaski BE, Kim JC, Naftel DC, et al: Cardiac transplant outcome of patients supported on left ventricular assist device vs intravenous inotropic therapy J Heart Lung Transplant 20(4):449–456, 2001 16 Radovancevic B, Golino A, Vrtovec B, et al: Is bridging to transplantation with a left ventricular assist device a risk factor for transplant coronary artery disease? J Heart Lung Transplant 24(6):703–707, 2005 17 Gordon RJ, Quagliarello B, Lowy FD: Ventricular assist device-related infections Lancet Infect Dis 6(7):426–437, 2006 18 John R: Donor management and selection for heart transplantation Semin Thorac Cardiovasc Surg 16(4):364–369, 2005 19 Potapov EV, Ivanitskaia EA, Loebe M, et al: Value of cardiac troponin I and T for selection of heart donors and as predictors of early graft failure Transplantation 71(10):1394–1400, 2001 20 Potapov EV, Wagner FD, Loebe M, et al: Elevated donor cardiac troponin T and procalcitonin indicate two independent mechanisms of early graft failure after heart transplantation Int J Cardiol 92(2):163– 167, 2003 21 Ardehali A, Esmailian F, Deng M, et al: Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective, open-label, multicentre, randomised non-inferiority trial Lancet 385(9987):2577–2584, 2015 22 Smith CR: Techniques in cardiac transplantation Prog Cardiovasc Dis 32(6):383–404, 1990 23 Oyer P, Stinson E, Jamieson S, et al: Cyclosporine in cardiac transplantation: a 2 1/2 year follow-up Transplant Proc 15[Suppl 1]:2546, 1983 24 Taylor DO, Barr ML, Radovancevic B, et al: A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus J Heart Lung Transplant 18(4):336– 345, 1999 25 Reichart B, Meiser B, Vigano M, et al: European multicenter tacrolimus heart pilot study: three year follow-up J Heart Lung Transplant 20(2):249–250, 2001 26 Kobashigawa JA, Patel J, Furukawa H, et al: Five-year results of a randomized, single-center study of tacrolimus vs microemulsion cyclosporine in heart transplant patients J Heart Lung Transplant 25(4):434–439, 2006 27 Kobashigawa JA, Miller LW, Russell SD, et al: Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs cyclosporine with MMF in cardiac transplant patients: 1-year report Am J Transplant 6(6):1377–1386, 2006 28 Deuse T, Sista R, Weill D, et al: Review of heart–lung transplantation at Stanford Ann Thorac Surg 90(1):329–337, 2010 29 Kobashigawa J, Miller L, Renlund D, et al: A randomized activecontrolled trial of mycophenolate mofetil in heart transplant recipients Mycophenolate mofetil investigators Transplantation 66(4):507–515, 1998 30 Taylor DO, Edwards LB, Boucek MM, et al: Registry of the International Society for Heart and Lung Transplantation: twentysecond official adult heart transplant report—2005 J Heart Lung Transplant 24(8):945–955, 2005 31 Baran DA, Zucker MJ, Arroyo LH, et al: Randomized trial of tacrolimus monotherapy: tacrolimus in combination, tacrolimus alone compared (the TICTAC trial) J Heart Lung Transplant 26(10):992–997, 2007 32 ISHLT Database for North America Available at: http://www.ishlt.org /registries/quarterlyDataReportResults.asp?organ=HR&rptType=reci p_p_surv&continent=4 Accessed September 22, 2015 33 Stobierska-Dzierzek B, Awad H, Michler RE: The evolving management of acute right-sided heart failure in cardiac transplant recipients J Am Coll Cardiol 38(4):923–931, 2001 34 Stewart S, Fishbein MC, Snell GI, et al: Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection J Heart Lung Transplant 26(12):1229–1242, 2007 35 Sulemanjee NZ, Merla R, Lick SD, et al: The first year post-heart transplantation: use of immunosuppressive drugs and warly complications J Cardiovascular Pharmacol Ther 13(1):13–31, 2008 36 Atasever A, Bacakoglu F, Uysal F, et al: Pulmonary complications in heart transplant recipients Transplantation Proc 38:1530, 2006 37 Lenner R, Padilla ML, Teirstein AS, et al: Pulmonary complications in cardiac transplant recipients Chest 120(2):508–513, 2001 38 Hunt SA, Haddad F: The changing face of heart transplantation J Am Coll Cardiol 52(8):587–598, 2008 39 Wang SS: Treatment and prophylaxis of cardiac allograft vasculopathy Transplant Proc 40(8):2609, 2008 40 Diaz B, Vilchez FG, Almenar L, et al: Gastrointestinal complications in heart transplant patients: MITOS study Transplant Proc 39(7):2397, 2007 41 Kirklin J, Holm A, Aldrete J, et al: Gastrointestinal complications after cardiac transplantation Potential benefit of early diagnoses and prompt surgical intervention Ann Surg 211(5):538, 1990 42 Steck TB, Costanzo-Nordin MR, Keshavarzian A: Prevalence and management of cholelithiasis in heart transplant patients J Heart Lung Transplant 10(6):1029–1032, 1990 43 Stief J, Stempfle H, Götzberger M, et al: Biliary diseases in heart transplanted patients: a comparison between cyclosporine a versus tacrolimus-based immunosuppression Eur J Med Res 14(5):206, 2009 44 Everly MJ: Cardiac transplantation in the United States: an analysis of the UNOS registry Clin Transpl 35–43, 2008 45 Starnes V, Theodore J, Oyer P, et al: Evaluation of heart–lung transplant recipients with prospective, serial transbronchial biopsies and pulmonary function studies J Thorac Cardiovasc Surg 98(5, pt 1):683–690, 1989 46 Starnes VA: Heart–lung transplantation: an overview Cardiol Clin 8(1):159–168, 1990 47 Glanville AR, Imoto E, Baldwin JC, et al: The role of right ventricular endomyocardial biopsy in the long-term management of heart–lung transplant recipients J Heart Transplant 6(6):357–361, 1986 48 Griffith BP, Hardesty RL, Trento A, et al: Heart–lung transplantation: lessons learned and future hopes Ann Thoracic Surg 43(1):6–16, 1987 49 Barr ML, Meiser BM, Eisen HJ, et al: Photopheresis for the prevention of rejection in cardiac transplantation N Eng J Med 339(24):1744– 1751, 1998 50 Glanville AR, Baldwin JC, Burke CM, et al: Obliterative bronchiolitis after heart–lung transplantation: apparent arrest by augmented immunosuppression Ann Intern Med 107(3):300–304, 1987 Chapter 61 Care of the Pancreas Transplant Recipient COLLEEN L JAY • GREGORY A ABRAHAMIAN • ANGELINA EDWARDS Type 1 diabetes mellitus has two primary treatment options: (a) exogenous insulin administration or (b) β cell replacement by pancreas or islet transplantation Despite the introduction of many new and improved modalities for insulin administration, exogenous administration requires complex and frequent monitoring and responsiveness from the patient, making it burdensome Often, patients face a choice between imperfect glycemic control, predisposing them to secondary complications including retinopathy, neuropathy, and nephropathy, or too tight control possibly precipitating hypoglycemic unawareness, which can dramatically impact quality of life Pancreas and islet transplantation when successful produces a more physiologic euglycemic state and effectively treats hypoglycemia episodes However, pancreas transplantation requires major surgery in which perioperative risks are often compounded by the comorbidities frequently seen in patients with long-standing diabetes Additionally, the long-term effectiveness of islet transplantation continues to be a challenging goal Moreover, both require long-term immunosuppression to prevent rejection, resulting in increased risks of infection and cancer In 1993, The Diabetes Control and Complications Trial [1] showed that intensive insulin therapy (multiple injections per day with doses adjusted by frequent blood sugar determinations) resulted in a 60% reduction in the risk of secondary complications despite typically failing to achieve normalization of glucose [2] Current American Diabetes Association (ADA) guidelines recommend multiple-dose insulin injections (three to four injections daily of basal and prandial insulin) or continuous subcutaneous insulin pump with the goal of achieving an HbA1C 45 years old) are associated with pancreas graft failure and increased complications [90–92] Small donors ( 35 kg per m2 are virtually never used for solid-organ pancreas transplantation [61] According to International Pancreas Transplant Registry data, the following variables are associated with an increased risk of pancreas allograft thrombosis: (1) donor age > 40 years; (2) nontraumatic cause of brain death; and (3) pancreas preservation time >24 hours [53,94] Other reports have suggested that donor BMI > 30 and fatty infiltration of the pancreas gland on visual inspection increase risks of graft thrombosis [95,96] Older and obese donors (>50 years old and >30 kg per m2) are probably more suitable for islet cell than for solid-organ pancreas transplantation [61] Elevated donor sodium levels (Na > 160 mg per dL) is considered a relative contraindication by some centers due to concerns for pancreatic edema and risks of graft pancreatitis and thrombosis It is one of the factors along with donor age, BMI, duration of cardiac arrest and ICU stay, vasopressor use, and elevated serum amylase and lipase levels that make up the preprocurement pancreas allocation suitability score (PPASS), which had been associated with differences in pancreatic graft survival rates [97] Elevated amylase and lipase levels are considered contraindications by many centers, but care must be taken in interpreting amylase levels as these are frequently elevated in donors with head injury More recently, a pancreas donor risk index (PDRI) score developed by Axelrod et al [98] on the basis of multivariate regression predicts pancreas graft survival after transplantation on the basis of donor age, gender, race, BMI, height, cause of death, donation after cardiac death status, and elevated serum creatinine p 539 p 540 Still, donors after cardiac death are being used increasingly and successfully to expand the donor pool One survey showed equivalent patient and graft survival at 1, 3, and 5 years in SPK transplant recipients from donors after cardiac death compared with ideal donors after brain death [64] In general, a pancreas from a so-called marginal donor is associated with good outcome if the pancreas is found to be normal on gross inspection [64,99] In nearly 3,200 consecutive pancreas donors procured between 2000 and 2005, Vinkers et al [100] determined the influence of a “preprocurement pancreas suitability” score on the acceptance or refusal of deceased pancreatic organs The investigators assigned a weight for several preprocurement factors including age, BMI, length of ICU stay, cardiac arrest as cause of death, serum sodium, amylase and lipase levels, and need for vasopressor support to develop a donor score When the donor score was ≥17, pancreata from these deceased donors were three times more likely to be refused by transplant centers Donor scoring systems such as this one may provide more objective information about the quality of a deceased pancreatic organ to promote wider pancreas donor acceptance Pancreas Preservation University of Wisconsin solution was first used for pancreas preservation in a preclinical model in 1987 [101] As with most solid organs, in vivo flush followed by simple storage in cold University of Wisconsin solution is still the gold standard for pancreas preservation In the original canine model, pancreata were preserved for up to 96 hours [102], but in clinical transplantation, pancreas cold preservation exceeding 24 hours has been associated with increased graft dysfunction Even for less than 24 hours, it is evident that the longer the cold ischemia time, the greater the technical complication rate Therefore, every effort should be made to minimize the cold ischemia time to optimize graft function and to minimize complication rates A general trend toward shorter preservation time has been noted over time with over 50% of pancreas transplants having a preservation time under 12 hours since 2005 [6] The two-layer method (TLM) using University of Wisconsin solution and perfluorochemical has been used in clinical whole pancreas transplantation but more commonly for islet preservation [103] This method improves pancreas oxygenation, allowing for longer preservation time while providing a mechanism for repair of ischemic damage due to cold storage [104–106] Some studies show that TLM improves islet yields, islet viability, islet morphology, rates of successful islet isolations and transplants, and islet yields from marginal donors [105,107–113] Other studies report that TLM has no effect or is even detrimental for pancreas preservation and show no difference in islet yields, islet viability, or islet transplant outcomes when pancreatic organs were preserved with the TLM versus University of Wisconsin solution [54,105,108,114] More prospective, randomized, controlled trials are needed before the TLM becomes routine procedure Three main preservation solutions for pancreas transplantation are available today, including University of Wisconsin solution, Celsior, and histidine–tryptophan–ketoglutarate solution (HTK) [105,108] HTK has been increasingly used in pancreas transplantation, and its advantages include lower viscosity, less potassium, lower cost, and no need for “onshelf” cold storage, but it requires more solution to flush organs in the multiorgan donor (8 to 12 L of HTK solution vs 4 to 6 L of Celsior vs 4 to 6 L of University of Wisconsin solution) [105] In pancreas transplantation, there have been only one retrospective study [107] and two prospective randomized studies [115,116], which compare University of Wisconsin solution with Celsior, and both solutions give similar results Several reports have compared HTK with University of Wisconsin solution and most reports have described equal suitability for perfusion and organ preservation in clinical pancreas transplantation [117–121] In an analysis of the UNOS pancreas transplant database from 2004 to 2008, Stewart et al [122] noted that HTK preservation was associated with a 1.5-fold higher odds of early (10 minutes [145] Increasing donor age and BMI were associated with greater need for postoperative interventions Graft preservation with HTK solution was associated with significantly higher postoperative complications, as was preexisting cardiac disease in the recipient The choice of immunosuppression had a significant effect on pancreas-related complications, which were greater after induction therapy with rATG versus daclizumab, and maintenance immunosuppression with tacrolimus/rapamycin or cyclosporine/mycophenolate mofetil versus tacrolimus/mycophenolate mofetil The duration of the pancreas transplant operation and the presence of elevated C reactive protein were associated with significantly more postoperative complications that required interventions In another study, donor obesity (BMI > 30 kg per m2) was associated with greater risk of graft thrombosis and deep wound infections [146] Another trial [94] noted that technical failure of the pancreas graft occurred more commonly when (1) the donor BMI was >30 kg per m2, (2) the cause of donor death was other than trauma, (3) the preservation time was >24 hours, (4) the duct management was ED versus BD, and (5) recipient BMI was >30 kg per m2 In another study, multivariate analysis showed that technical failure of a pancreas transplant appeared to be the most significant risk factor for kidney graft loss [147] This evidence underscores that careful donor and recipient selection in addition to improved preservation and surgical techniques play important roles to minimize complications after pancreas transplantation [148] Surgical Complications Prevention of surgical complications has critical implications not only on pancreas graft and patient survival, but also on financial impact associated with postoperative care Early diagnosis and management of surgical complications can limit morbidity; delayed diagnosis and treatment of pancreas complications can lead not only to pancreas graft loss but also to kidney graft loss [148,149] Common surgical complications of pancreas transplantation will now be addressed: Hemorrhage: Postoperative hemorrhage is a frequent reason for early re-laparotomy in pancreas transplant recipients Hemorrhage can occur from the pancreatic parenchyma, from poorly ligated mesenteric or splenic vascular stumps or from the anastomosis in an entericdrained or bladder-drained pancreas transplant The incidence of hemorrhage ranges from 6% to 7% [91], and this risk increases with the use of anticoagulation in the immediate postoperative period Frequent physical examination and monitoring of hemoglobin help to detect early hemorrhage Heparin may be temporarily suspended to stabilize the patient Packed cells should be administered if the recipient has symptomatic anemia If hemorrhage continues, early operative intervention is indicated If hemorrhage slows down or ceases, heparin should be resumed at a lower rate and judiciously increased as tolerated p 542 p 543 Thrombosis: Thrombosis after transplant ranges from 5% to 6% [91], and remains the most common cause of early pancreas graft failure The risk increases after segmental pancreas transplantation because of the small caliber of vessels [51] Most pancreas transplant thromboses are due to technical causes Diagnosis is suspected by sudden hyperglycemia and confirmed by sonogram, computed tomography (CT) angiogram, formal angiogram, or MRI, which reveals an absence of arterial or venous flow to the graft Aggressive anticoagulation will not prevent pancreas transplant thrombosis due to technical reasons A short portal vein requiring an extension graft or atherosclerotic arteries in the pancreas graft increases the risk for thrombosis A recipient narrow pelvic inlet with a deeply placed, poorly mobilized iliac vein, atherosclerotic disease of the iliac artery, a technically difficult vascular anastomosis, kinking of the vein by the pancreas graft, significant hematoma formation around the vascular anastomosis, hypovolemia, and a hypercoagulable state are some of the factors that increase the risk for thrombosis The most common form of hypercoagulable state in the Western population is factor V Leiden mutation Its incidence ranges from 2% to 5% but may be as high as 50% to 60% in patients with a history (self or family) of vascular thrombosis [150] Other causes of hypercoagulable state include antithrombin III deficiency, protein C or S deficiency, activated protein C resistance, and anticardiolipin antibodies [151] The transplant surgeon must have a high incidence of suspicion of these hypercoagulable states and treat them aggressively to prevent pancreas graft thrombosis If thrombosis is suspected in the early postoperative period, operative exploration of the graft is warranted and findings of a thrombosed graft usually necessitates removal of the pancreas Duodenal stump leaks: The incidence of duodenal stump leaks ranges from 6% to 7% [91] A leak from the anastomosis of the duodenum stump to the bowel almost always leads to re-laparotomy Gross peritoneal contamination due to an enteric leak usually necessitates a graft pancreatectomy The diagnosis is made by elevated pancreatic enzymes in a patient who has clinical signs of acute abdomen A plain abdominal radiograph may show free air, and an abdominal CT scan may show free air and extravasation of contrast into the free peritoneal cavity The differential diagnosis is pancreatitis, abdominal infection, or acute severe rejection A Roux-en-Y anastomosis to the duodenal stump may be a preferred technique if the risk of leak is thought to be increased during the initial pancreas operation Other novel techniques such as a venting Roux-en-Y pancreatic duodenojejunostomy have been used in selected recipients [152] Small duodenal stump leaks in bladder-drained recipients are usually managed nonoperatively with prolonged catheter decompression of the urinary bladder The diagnosis of duodenal stump leak is made using plain or CT cystography Large leaks may require operative intervention, including primary repair, enteric conversion, or even transplant pancreatectomy if there is significant compromise of the duodenal stump Major intra-abdominal infections: The incidence of significant intraabdominal infections requiring reoperation ranges from 3% to 4% [91] Performance of the enteric anastomosis with associated contamination predisposes to this higher rate of intra-abdominal infection, where fungal and gram-negative organisms predominate With the advent of percutaneous procedures to drain intra-abdominal abscesses, the incidence of reoperations is fast decreasing If the infection is uncontrolled or widespread, then graft pancreatectomy followed by frequent washouts may be necessary Renal pedicle torsion: Torsion of the kidney has been reported after SPK transplantation [153,154] The intraperitoneal location of the kidney (allowing for more mobility) predisposes to this complication Additional risk factors are a long renal pedicle and a marked discrepancy between the length of artery and vein Prophylactic nephropexy to the anterior or lateral abdominal wall is recommended with intraperitoneal transplantations to avoid this problem The colon can be mobilized and reapproximated over a kidney transplant in order to prevent torsion Others: Other surgical complications that may require re-laparotomy include wound dehiscence, incisional hernia, severe pancreatitis (sometimes hemorrhagic or necrotic), pseudocysts, pseudoaneurysms, arteriovenous (AV) fistula in the graft, severe painful rejection, and bowel obstruction [155] The overall incidence of re-laparotomy for these complications decreased from 32% in the 1980s to 19% in the 1990s, and the mortality rate in recipients requiring re-laparotomy decreased from 9% to 1% over that same period Improved antibiotic prophylaxis, surgical techniques, immunosuppression, and advances in interventional radiology have all contributed to this decrease [91] Nonsurgical Complications Pancreatitis: The incidence of posttransplant pancreatitis varies based on the type of exocrine drainage Bladder-drained recipients with abnormal bladder function are at increased risk of pancreatitis secondary to incomplete bladder emptying and urinary retention causing resistance to flow of pancreatic exocrine secretions Other causes of pancreatitis include drugs (corticosteroids, azathioprine, cyclosporine), hypercalcemia, viral infections (CMV or hepatitis C), and reperfusion injury after prolonged ischemia Pancreatitis is usually manifested by an increase in serum amylase and lipase with or without local signs of inflammation An abdominal ultrasound or CT scan may identify an enlarged, edematous, hypoechoic graft The treatment usually consists of catheter decompression of the bladder for a period of 2 to 6 weeks, depending on the severity of pancreatitis In addition, octreotide therapy may be used to decrease pancreatic secretions The underlying urologic problem, if any, should be treated The patient should be placed on NPO status and total parenteral nutrition should be administered if the pancreatitis is severe If repeated episodes of pancreatitis occur, enteric conversion of a bladder-drained pancreas transplant may be indicated Rejection: The incidence of acute rejection ranges from 15% to 30% and immunologic graft loss from 2% to 15% for all types of pancreas transplants at 1 year [156] The diagnosis is usually based on increased serum amylase and lipase levels in all pancreas transplant patients, and decreased urinary amylase levels in bladder-drained recipients A sustained drop in urinary amylase levels from baseline should prompt a pancreas biopsy to rule out rejection For enteric-drained recipients, one has to rely on serum amylase and lipase levels only A rise in serum lipase levels has shown to correlate well with acute rejection in the pancreas transplant Other signs and symptoms include tenderness over the graft, unexplained fever, and hyperglycemia (which is usually a late finding) Diagnosis of rejection can be suspected by a hypoechoic, enlarged graft by ultrasound or an enlarged, edematous graft by abdominal CT scan Diagnosis of rejection can be confirmed by a percutaneous pancreas biopsy [157] In cases for which percutaneous biopsy is not possible due to technical reasons, empiric therapy for rejection may be started Rarely, open biopsy is indicated, and transcystoscopic biopsy of a bladder-drained pancreas graft, which was used in the past, has been largely abandoned Finally, in SPK recipients, isolated pancreas transplant rejection portends a worse renal allograft survival than in patients who experience no rejection [158] p 543 p 544 Others: Other findings include infectious complications such as CMV, extra-abdominal bacterial or fungal infections, posttransplant malignancy such as posttransplant lymphoproliferative disorder, and other rare complications such as graft-versus-host disease Many catheter infections are due to gram-positive organisms, with methicillin-resistant coagulase-negative isolates being quite common [159] The diagnosis and management of these complications is similar to those of other solid-organ transplantations Radiologic Studies Ultrasonography: This is the most frequent study used in pancreas recipients Noninvasive, portable, and relatively inexpensive, it provides prompt information regarding blood flow to the pancreas, the presence of arterial or venous stenosis or occlusion, thrombosis, pseudoaneurysms, AV fistulae, resistance to blood flow within the pancreas (suggestive of either rejection or pancreatitis), and peripancreatic fluid collections CT scan: A CT scan provides more detail of pancreatic and surrounding anatomy Use of oral, IV, and bladder contrast (in bladder-drained recipients) is recommended Thus, a CT cystogram can be combined with an abdominal CT scan A CT scan is frequently used as a guide in pancreatic biopsies or in placement of percutaneous drains for intra-abdominal infection Fluoroscopy: A contrast cystogram can be performed under fluoroscopy and can be used instead of, or in addition to, a CT cystogram to look for a bladder leak The combination of the tests increases the sensitivity for detecting bladder leaks Magnetic resonance angiogram (MRA): An MRA is done if vascular abnormalities are suspected on the ultrasound MRA provides accurate information about pancreatic vascular patency, but it is inferior to standard angiography in providing fine vascular detail Angiography: This is the gold standard test for evaluating arterial anatomy in and around the pancreas However, it is rarely employed, except in cases in which angiographic intervention (such as angioplasty, stenting of a stenotic segment, or coiling of an AV fistula or pseudoaneurysm) is planned Contrast nephropathy is feared in a solitary pancreas recipient with renal dysfunction, and reasonable alternatives (such as ultrasound) are available FUTURE DIRECTIONS For type 1 diabetic patients with kidney dysfunction, an SPK or PAK transplant is the standard of care A PTA, however, is less common because the long-term risks of diabetes are weighed against the long-term risks of immunosuppression A successful pancreas transplantation can improve existing neuropathy and nephropathy in diabetic recipients, and the survival after a solitary pancreas transplant is better than remaining on the waiting list [160] As the risks of immunosuppression decrease with novel methods of tolerance and immunomodulation, the balance will tilt in favor of an early transplantation The limiting factor will then be the organ shortage, which could be alleviated if xenotransplantation is able to overcome its current barrier of hyperacute rejection The application of islet transplantation is rapidly growing Recent successes suggest that islet transplants can provide all the benefits of pancreas transplants without the risks of major operation Improvements in islet isolation, islet viability, islet functionality, islet implantation, and immunotherapy will improve islet outcomes so that only one donor will be necessary to achieve insulin independence [161] Xenotransplantation of islets may be more readily achievable using encapsulation than with other organs Prolonged diabetes reversal after intraportal xenotransplant in primates has been documented [162] and may pave the way for human xenotransplant trials Also, stem cells from numerous sources (e.g., bone marrow, adipose, or cord blood) may be manipulated to differentiate into islets in order to provide a rich supply for transplantation, and islet transplants can be combined with immunomodulation and tolerogenic strategies to minimize or eliminate immunosuppression [161] This combination would provide for minimally invasive islet cell transplantations for all type 1 diabetic patients without the need for long-term immunosuppression The only scenario that would be better would be the thwarting of autoimmunity before the onset of isletitis, thereby preventing type 1 diabetes mellitus in the first place REFERENCES The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus The Diabetes Control and Complications Trial Research Group N Engl J Med 329(14):977–986, 1993 Lifetime benefits and costs of intensive therapy as practiced in the diabetes control and complications trial The Diabetes Control and Complications Trial Research Group JAMA 276(17):1409–1415, 1996 American Diabetes Association: Standards of medical care in diabetes2015 abridged for primary care providers Clin Diabetes 33(2):97–111, 2015 Ali MK, Bullard KM, Gregg EW: Achievement of goals in U.S Diabetes Care, 1999–2010 N Engl J Med 369(3):287–288, 2013 Boggi U, Vistoli F, Amorese G, et al: Results of pancreas transplantation alone with special attention to native kidney function and proteinuria in type 1 diabetes patients Rev Diabet Stud 8(2):259– 267, 2011 Gruessner AC: 2011 update on pancreas transplantation: comprehensive trend analysis of 25,000 cases followed up over the course of twenty-four years at the International Pancreas Transplant Registry (IPTR) Rev Diabet Stud 8(1):6–16, 2011 Kandaswamy R, Skeans MA, Gustafson SK, et al: OPTN/SRTR 2013 Annual Data Report: pancreas Am J Transplant 15[Suppl 2]:1–20, 2015 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 343(4):230–238, 2000 Hering BJ, Kandaswamy R, Harmon JV, et al: Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-CD3 antibody Am J Transplant 4(3):390–401, 2004 10 Hering BJ, Kandaswamy R, Ansite JD, et al: Single-donor, marginaldose islet transplantation in patients with type 1 diabetes JAMA 293(7):830–835, 2005 11 Ryan EA, Paty BW, Senior PA, et al: Five-year follow-up after clinical islet transplantation Diabetes 54(7):2060–2069, 2005 12 Krolewski AS, Warram JH, Freire MB: Epidemiology of late diabetic complications A basis for the development and evaluation of preventive programs Endocrinol Metab Clin North Am 25(2):217– 242, 1996 13 Gruessner A, Gruessner R, Moudry-Munns K, et al: Influence of multiple factors (age, transplant number, recipient category, donor source) on outcome of pancreas transplantation at one institution Transplant Proc 25(1, Pt 2):1303–1305, 1993 14 Light JA, Sasaki TM, Currier CB, et al: Successful long-term kidneypancreas transplants regardless of C-peptide status or race Transplantation 71(1):152–154, 2001 15 Weems P, Cooper M: Pancreas transplantation in type II diabetes mellitus World J Transplant 4(4):216–221, 2014 16 Sener A, Cooper M, Bartlett ST: Is there a role for pancreas transplantation in type 2 diabetes mellitus? Transplantation 90(2):121–123, 2010 17 UNOS/OPTN Organ Procurement and Transplantation Network Available from: http://optn.transplant.hrsa.gov/ governance/policies/ 2015 Accessed February 7, 2017 18 Weir GC, Cavelti-Weder C, Bonner-Weir S: Stem cell approaches for diabetes: towards beta cell replacement Genome Med 3(9):61, 2011 19 Li M, Ikehara S: Stem cell treatment for type 1 diabetes Front Cell Dev Biol 2:9, 2014 20 Muir KR, Lima MJ, Dochetry HM, et al: Cell therapy for type 1 diabetes QJM 107(4):253–259, 2014 21 Pagliuca FW, Millman JR, Gürtler M, et al: Generation of functional human pancreatic beta cells in vitro Cell 159(2):428–439, 2014 22 Sutherland DE, Gruessner RW, Dunn DL, et al: Lessons learned from more than 1,000 pancreas transplants at a single institution Ann Surg 233(4):463–501, 2001 23 Sutherland DE, Radosevich D, Gruessner R, et al: Pushing the envelope: living donor pancreas transplantation Curr Opin Organ Transplant 17(1):106–115, 2012 p 544 p 545 24 Matsumoto S, Okitsu T, Iwanaga Y, et al: Insulin independence of unstable diabetic patient after single living donor islet transplantation Transplant Proc 37(8):3427–3429, 2005 25 Farney AC, Cho E, Schweitzer EJ, et al: Simultaneous cadaver pancreas living-donor kidney transplantation: a new approach for the type 1 diabetic uremic patient Ann Surg 232(5):696–703, 2000 26 Fridell JA, Powelson JA: Pancreas after kidney transplantation: why is the most logical option the least popular? Curr Opin Organ Transplant 20(1):108–114, 2015 27 Gruessner AC, Sutherland DE, Dunn DL, et al: Pancreas after kidney transplants in posturemic patients with type I diabetes mellitus J Am Soc Nephrol 12(11):2490–2499, 2001 28 Humar A, Ramcharan T, Kandaswamy R, et al: Pancreas after kidney transplants Am J Surg 182(2):155–161, 2001 29 Sutherland DE, Gruessner RG, Humar A, et al: Pretransplant immunosuppression for pancreas transplants alone in nonuremic diabetic recipients Transplant Proc 33(1/2):1656–1658, 2001 30 Kelly WD, Lillehei RC, Merkel FK, et al: Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy Surgery 61(6):827–837, 1967 31 Squifflet JP, Gruessner RW, Sutherland DE: The history of pancreas transplantation: past, present and future Acta Chir Belg 108(3):367– 378, 2008 32 Lillehei RC, Ruix JO, Aquino C, et al: Transplantation of the pancreas Acta Endocrinol Suppl (Copenh) 205:303–320, 1976 33 Gliedman ML, Gold M, Whittaker J, et al: Clinical segmental pancreatic transplantation with ureter-pancreatic duct anastomosis for exocrine drainage Surgery 74(2):171–180, 1973 34 Gold M, Whittaker JR, Veith FJ, et al: Evaluation of ureteral drainage for pancreatic exocrine secretion Surg Forum 23:375–377, 1972 35 Sutherland DE, Goetz FC, Najarian JS: Intraperitoneal transplantation of immediately vascularized segmental pancreatic grafts without duct ligation A clinical trial Transplantation 28(6):485–491, 1979 36 Dubernard JM, Traeger J, Neyra P, et al: A new method of preparation of segmental pancreatic grafts for transplantation: trials in dogs and in man Surgery 84(5):633–639, 1978 37 Cook K, Sollinger HW, Warner T, et al: Pancreaticocystostomy: an alternative method for exocrine drainage of segmental pancreatic allografts Transplantation 35(6):634–636, 1983 38 Nghiem DD, Corry RJ: Technique of simultaneous renal pancreatoduodenal transplantation with urinary drainage of pancreatic secretion Am J Surg 153(4):405–406, 1987 39 Starzl TE, Iwatsuki S, Shaw BW Jr, et al: Pancreaticoduodenal transplantation in humans Surg Gynecol Obstet 159(3):265–272, 1984 40 Tom WW, Munda R, First MR, et al: Autodigestion of the glans penis and urethra by activated transplant pancreatic exocrine enzymes Surgery 102(1):99–101, 1987 41 Gil-Vernet JM, Fernández-Cruz L, Caralps A, et al: Whole organ and pancreaticoureterostomy in clinical pancreas transplantation Transplant Proc 17(4):2019–2022, 1985 42 Calne RY: Paratopic segmental pancreas grafting: a technique with portal venous drainage Lancet 1(8377):595–597, 1984 43 Sutherland DE, Goetz FC, Moudry KC, et al: Use of recipient mesenteric vessels for revascularization of segmental pancreas grafts: technical and metabolic considerations Transplant Proc 19(1, pt 3):2300–2304, 1987 44 Tyden G, Tibell A, Sandberg J, et al: Improved results with a simplified technique for pancreaticoduodenal transplantation with enteric exocrine drainage Clin Transplant 10(3):306–309, 1996 45 Muhlbacher F, Gnant MF, Auinger M, et al: Pancreatic venous drainage to the portal vein: a new method in human pancreas transplantation Transplant Proc 22(2):636–637, 1990 46 Rosenlof LK, Earnhardt RC, Pruett TL, et al: Pancreas transplantation An initial experience with systemic and portal drainage of pancreatic allografts Ann Surg 215(6):586–595, 1992; discussion 596–597 47 Shokouh-Amiri MH, Gaber AO, Gaber LW, et al: Pancreas transplantation with portal venous drainage and enteric exocrine diversion: a new technique Transplant Proc 24(3):776–777, 1992 48 Sutherland DE, Goetz FC, Najarian JS: Living-related donor segmental pancreatectomy for transplantation Transplant Proc 12[4, Suppl 2]:19–25, 1980 49 Sutherland DE, Gores PF, Farney AC, et al: Evolution of kidney, pancreas, and islet transplantation for patients with diabetes at the University of Minnesota Am J Surg 166(5):456–491, 1993 50 Sutherland DE, Najarian JS, Gruessner R: Living versus cadaver donor pancreas transplants Transplant Proc 30(5):2264–2266, 1998 51 Gruessner RW, Sutherland DE: Simultaneous kidney and segmental pancreas transplants from living related donors—the first two successful cases Transplantation 61(8):1265–1268, 1996 52 Gruessner RW, Sutherland DE, Drangstveit MB, et al: Pancreas transplants from living donors: short- and long-term outcome Transplant Proc 33(1/2):819–820, 2001 53 Gruessner AC, Sutherland DE: Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004 Clin Transplant 19(4):433–455, 2005 54 The CITR Coordinating Center and Investigators: The Collaborative Islet Transplant Registry 2010 Annual Report NIDDK, 2010 www.citregistry.org 55 Sutherland DE: International human pancreas and islet transplant registry Transplant Proc 12[4, Suppl 2]:229–236, 1980 56 Gremizzi C, Vergani A, Paloschi V, et al: Impact of pancreas transplantation on type 1 diabetes-related complications Curr Opin Organ Transplant 15(1):119–123, 2010 57 Dean PG, Kudva YC, Stegall MD: Long-term benefits of pancreas transplantation Curr Opin Organ Transplant 13(1):85–90, 2008 58 Allen RD, Al-Harbi IS, Morris JG, et al: Diabetic neuropathy after pancreas transplantation: determinants of recovery Transplantation 63(6):830–838, 1997 59 Kennedy WR, et al: Effects of pancreatic transplantation on diabetic neuropathy N Engl J Med 322(15):1031–1037, 1990 60 Navarro X, Sutherland DE, Kennedy WR: Long-term effects of pancreatic transplantation on diabetic neuropathy Ann Neurol 42(5):727–736, 1997 61 White SA, Shaw JA, Sutherland DE: Pancreas transplantation Lancet 373(9677):1808–1817, 2009 62 Navarro X, Kennedy WR, Loewenson RB, et al: Influence of pancreas transplantation on cardiorespiratory reflexes, nerve conduction, and mortality in diabetes mellitus Diabetes 39(7):802–806, 1990 63 Solders G, Tydén G, Persson A, et al: Improvement of nerve conduction in diabetic neuropathy A follow-up study 4 yr after combined pancreatic and renal transplantation Diabetes 41(8):946– 951, 1992 64 Salvalaggio PR, Davies DB, Fernandez LA, et al: Outcomes of pancreas transplantation in the United States using cardiac-death donors Am J Transplant 6(5, pt 1):1059–1065, 2006 65 Martinenghi S, Comi G, Galardi G, et al: Amelioration of nerve conduction velocity following simultaneous kidney/pancreas transplantation is due to the glycaemic control provided by the pancreas Diabetologia 40(9):1110–1112, 1997 66 Hathaway DK, Abell T, Cardoso S, et al: Improvement in autonomic and gastric function following pancreas-kidney versus kidney-alone transplantation and the correlation with quality of life Transplantation 57(6):816–822, 1994 67 Fioretto P, Steffes MW, Sutherland DE, et al: Reversal of lesions of diabetic nephropathy after pancreas transplantation N Engl J Med 339(2):69–75, 1998 68 Fioretto P, Sutherland DE, Najafian B, et al: Remodeling of renal interstitial and tubular lesions in pancreas transplant recipients Kidney Int 69(5):907–912, 2006 69 Coppelli A, Giannarelli R, Boggi U, et al: Disappearance of nephrotic syndrome in type 1 diabetic patients following pancreas transplant alone Transplantation 81(7):1067–1068, 2006 70 Coppelli A, Giannarelli R, Vistoli F, et al: The beneficial effects of pancreas transplant alone on diabetic nephropathy Diabetes Care 28(6):1366–1370, 2005 71 Ramsay RC, Goetz FC, Sutherland DE, et al: Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus N Engl J Med 318(4):208–214, 1988 72 Wang Q, Klein R, Moss SE, et al: The influence of combined kidneypancreas transplantation on the progression of diabetic retinopathy A case series Ophthalmology 101(6):1071–1076, 1994 73 Giannarelli R, Coppelli A, Sartini M, et al: Effects of pancreas-kidney transplantation on diabetic retinopathy Transpl Int 18(5):619–622, 2005 74 Cheung AT, Perez RV, Chen PC: Improvements in diabetic microangiopathy after successful simultaneous pancreas-kidney transplantation: a computer-assisted intravital microscopy study on the conjunctival microcirculation Transplantation 68(7):927–932, 1999 75 Larsen JL, Colling CW, Ratanasuwan T, et al: Pancreas transplantation improves vascular disease in patients with type 1 diabetes Diabetes Care 27(7):1706–1711, 2004 76 Larsen JL, Ratanasuwan T, Burkman T, et al: Carotid intima media thickness decreases after pancreas transplantation Transplantation 73(6):936–940, 2002 77 Fiorina P, La Rocca E, Venturini M, et al: Effects of kidney-pancreas transplantation on atherosclerotic risk factors and endothelial function in patients with uremia and type 1 diabetes Diabetes 50(3):496–501, 2001 78 Coppelli A, Giannarelli R, Mariotti R, et al: Pancreas transplant alone determines early improvement of cardiovascular risk factors and cardiac function in type 1 diabetic patients Transplantation 76(6):974–976, 2003 79 La Rocca E, Fiorina P, di Carlo V, et al: Cardiovascular outcomes after kidney-pancreas and kidney-alone transplantation Kidney Int 60(5):1964–1971, 2001 80 Luan FL, Miles CD, Cibrik DM, et al: Impact of simultaneous pancreas and kidney transplantation on cardiovascular risk factors in patients with type 1 diabetes mellitus Transplantation 84(4):541–544, 2007 81 Davenport C, Hamid N, O’Sullivan EP, et al: The impact of pancreas and kidney transplant on cardiovascular risk factors (analyzed by mode of immunosuppression and exocrine drainage) Clin Transplant 23(5):616–620, 2009 82 Jukema JW, Smets YF, van der Pijl JW, et al: Impact of simultaneous pancreas and kidney transplantation on progression of coronary atherosclerosis in patients with end-stage renal failure due to type 1 diabetes Diabetes Care 25(5):906–911, 2002 83 Fiorina P, La Rocca E, Astorri E, et al: Reversal of left ventricular diastolic dysfunction after kidney-pancreas transplantation in type 1 diabetic uremic patients Diabetes Care 23(12):1804–1810, 2000 84 La Rocca E, Fiorina P, Astorri E, et al: Patient survival and cardiovascular events after kidney-pancreas transplantation: comparison with kidney transplantation alone in uremic IDDM patients Cell Transplant 9(6):929–932, 2000 85 Biesenbach G, Königsrainer A, Gross C, et al: Progression of macrovascular diseases is reduced in type 1 diabetic patients after more than 5 years successful combined pancreas-kidney transplantation in comparison to kidney transplantation alone Transpl Int 18(9):1054– 1060, 2005 p 545 p 546 86 Gaber AO, Wicks MN, Hathaway DK, et al: Sustained improvements in cardiac geometry and function following kidney-pancreas transplantation Cell Transplant 9(6):913–918, 2000 87 Cashion AK, Hathaway DK, Milstead EJ, et al: Changes in patterns of 24-hr heart rate variability after kidney and kidney-pancreas transplant Transplantation 68(12):1846–1850, 1999 88 Ziaja J, Bozek-Pajak D, Kowalik A, et al: Impact of pancreas transplantation on the quality of life of diabetic renal transplant recipients Transplant Proc 41(8):3156–3158, 2009 89 Douzdjian V, Gugliuzza KG, Fish JC: Multivariate analysis of donor risk factors for pancreas allograft failure after simultaneous pancreaskidney transplantation Surgery 118(1):73–81, 1995 90 Humar A, Harmon J, Gruessner A, et al: Surgical complications requiring early relaparotomy after pancreas transplantation: comparison of the cyclosporine and FK 506 eras Transplant Proc 31(1/2):606–607, 1999 91 Humar A, Kandaswamy R, Granger D, et al: Decreased surgical risks of pancreas transplantation in the modern era Ann Surg 231(2):269– 275, 2000 92 Kapur S, Bonham CA, Dodson SF, et al: Strategies to expand the donor pool for pancreas transplantation Transplantation 67(2):284–290, 1999 93 Illanes HG, Quarin CM, Maurette R, et al: Use of small donors (1,500, >30 +2 Score additional 2 points for presence of abdominal pain or cramping Score additional 2 points for presence of bloody stools +2 Acute GVHD overall grade Skin stage Liver stage GI stage I 1–2 0 II 3 or 1 or 2–3 2–3 4 or III IV 4 or aChildren 2 × ULN AST/ALT >2 × ULN Lung Bronchiolitis obliterans based on lung biopsy Muscles, fascia, Fasciitis joints Bronchiolitis obliterans based on PFTs + radiologyd COP Myositis or polymyositis Joint stiffness or contractures secondary to sclerosis Features acknowledged as part of chronic GVHD symptomatology if the diagnosis is already confirmed Eyes Sweat impairment, ichthyosis, keratosis pilaris, hypopigmentation, hyperpigmentation Thinning scalp hair, typically patchy, coarse, dull not explained by endocrine or other causes, premature gray hair Photophobia, periorbital hyperpigmentation, blepharitis GI tract Exocrine pancreatic insufficiency Muscles/joints Edema, muscle cramps, arthralgia, or arthritis Hematology Thrombocytopenia, eosinophilia, lymphopenia Immune Lymphopenia, hypo- or hypergammaglobulinemia, autoantibodies (AIHA, ITP) Pericardial/pleural effusions, ascites, peripheral neuropathy, nephrotic syndrome, myasthenia gravis, cardiac conduction abnormality, or cardiomyopathy Skin Hair Other aSeen in chronic GVHD, but are insufficient alone to establish the diagnosis bSeen in both acute and chronic GVHD alone to establish a diagnosis of chronic GVHD cIn all cases must exclude infection, drug effects, malignancy, or other causes dDiagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer test for eyes) AIHA, autoimmune hemolytic anemia; ALT, alanine aminotransferase; AST, aspartate aminotransferase; COP, cryptogenic organizing pneumonia; GI, gastrointestinal; ITP, idiopathic (immune) thrombocytopenic purpura; PFTs, pulmonary function tests; ULN, upper limit of normal range for age Modified from Filipovich AH, Weisdorf D, Pavletic S, et al: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I Diagnosis and Staging Working Group report Biol Blood Marrow Transplant 11(12):945–956, 2005, with permission Confirming the Diagnosis of GVHD Unlike CGVHD, the clinical signs of acute GVHD are not considered sufficiently pathognomonic to establish the diagnosis, especially when there is isolated organ involvement However, the combination of rash, nausea, and voluminous diarrhea, occurring at the time of, or early after, neutrophil engraftment makes the diagnosis very likely The differential diagnosis involves ruling out other causes of rash, diarrhea, or liver toxicity as listed in Table 64.5 Tissue biopsies of the skin, liver, or stomach are recommended to confirm a histologic diagnosis of GVHD and, most importantly, to exclude opportunistic infection; however, the interpretation of biopsies performed within 3 weeks of myeloablative therapy may be problematic because it is difficult to separate cellular injury induced by chemoradiotherapy from GVHD The gastric antral mucosa provides the most sensitive site for evaluation of intestinal GVHD and is preferred to duodenal biopsy because there is less risk for bleeding complications The histologic hallmark of GVHD-induced cellular injury is apoptosis, observed in epidermal basal keratinocytes, bile duct, or intestinal crypt epithelial cells, and is often associated with infiltration by lymphocytes [146,147] Biopsy is unnecessary to confirm the presence of chronic GVHD if at least one diagnostic feature is present, but histologic confirmation or other pertinent testing is necessary when CGVHD features are only distinctive or suggestive (see Table 64.4) p 572 p 573 TABLE 64.5 Differential Diagnosis of AGVHD AGVHD manifestation Rash Differential diagnosis Drug reaction Allergic reaction Infection Diarrhea Abdominal Pain Elevated liver enzymes Regimen-related toxicity Infection (viral, fungal) Narcotic bowel syndrome (opiate withdrawal) Acute pancreatitis Acute cholesystitis (biliary sludge, stones, infection) Narcotic bowel syndrome (opiate withdrawal) Sinusoidal obstruction syndrome Medication toxicities (e.g., cyclosporine) Cholangitis lenta (sepsis) Biliary sludge syndrome Viral infections (CMV, EBV, hepatitis B) Hemolysis AGVHD, acute graft-versus-host disease; CMV, cytomegalovirus; EBV, Epstein–Barr virus Prevention of GVHD GVHD prevention strategies are almost always incorporated into the overall treatment plan, and these include optimizing the choice of allogeneic donor and stem cell product based on known risk factors for GVHD, T-cell depletion of the donor HSC graft as discussed earlier, or, most commonly, posttransplant immunosuppression Ursodeoxycholic acid should be given to all patients irrespective of the approach to GVHD prophylaxis because it improves liver function and reduces the incidence of hepatic GVHD [148] Postgrafting Immunosuppression In the absence of T-cell depletion, posttransplant immune suppression must be administered to control donor alloreactive T cells Most GVHD prophylaxis regimens include a CNI (cyclosporine or tacrolimus) in combination with one or two additional agents, such as methotrexate, mycophenolate mofetil (MMF), or sirolimus [149–152] In some settings, cyclophosphamide is given on days 3 and 4 after HCT, followed by prophylaxis with a CNI and MMF [15] Steady-state serum CNI and sirolimus levels require monitoring Dose reductions should be made when toxicities emerge or when serum trough levels exceed the upper limit of the therapeutic range Treatment of GVHD Despite GVHD prophylaxis regimens, 30% to 80% of allogeneic HCT recipients develop acute GVHD and require additional therapy with glucocorticoids Acute GVHD Glucocorticoids have been the mainstay of primary therapy for acute GVHD Initial starting doses have been recently calibrated to the severity and extent of organ involvement as demonstrated by one large retrospective study [153] For the one-third of patients who develop GVHD without liver involvement, and whose GI symptoms are defined as stage 1 (anorexia, nausea, or vomiting with peak stool volume less than 1,000 mL per day), with or without rash involving less than 50% of the body surface, treatment may reasonably begin at 1 mg/kg/d methylprednisolone (or oral equivalent) combined with topical and minimally absorbed glucocorticoids (beclomethasone and/or budesonide) When there is liver involvement, or when intestinal and skin GVHD is greater than defined above, methylprednisolone is typically begun at a dose of 2 mg/kg/d for up to 14 days [154] Once the symptoms (rash, diarrhea, abdominal pain, and liver dysfunction) are controlled, a glucocorticoid taper should be instituted For treatment of symptoms that do not respond to the initial treatment, there is no benefit for administration of doses greater than 2 mg/kg/d of methylprednisolone, and alternative approaches to steroid-refractory GVHD must be considered, as discussed below [155] Chronic GVHD In practice, systemic therapy is considered when chronic GVHD is present in more than two organs or when there are moderate to severe abnormalities of a single organ with functional impairment (Table 64.6) In contrast, systemic therapy is generally not warranted for patients with mild abnormalities of one or two organs that do not cause functional impairment However, mild chronic GVHD does warrant systemic therapy when either thrombocytopenia or steroid treatment is present at diagnosis p 573 p 574 TABLE 64.6 Indication for Systemic Immunosuppression at Day 80 Global severity of chronic GVHD High-risk featuresa Systemic therapy None Yes Noneb Mild (6 cm, number of nodules >5, and vascular invasion per the final pathology report [68] Clearly, tumor biology dictates the risk of disease recurrence [69] REJECTION The human immune system is an evolutionarily more advanced, adaptive, efficient, “specific,” and versatile host defense mechanism against the invasion of pathogens as compared with the nonspecific innate immune system of invertebrates However, a side effect of the ability of the host immune system to recognize and attack “nonself” tissues is rejection of grafted tissues posttransplantation That side effect was observed clinically for centuries before Medawar demonstrated that it was an intrinsic property of the host immune system in response to foreign tissue [70] The exogenous modulation of the host immune system to allow sustained graft function has proceeded along with—and often preceded—our understanding of the physiologic mechanism of rejection and tolerance Understanding the immune system is integral to our understanding of rejection The immunologic disparity among members of the same species of mammals that leads to lack of recognition of “self” tissue and to rejection of nonself tissue is based on the differences in cell surface molecules that are expressed In humans, these major histocompatibility antigens were first identified on leukocytes, and hence are termed human leukocyte antigens (HLAs) HLAs are subdivided into two classes: class I (HLA-A, -B, and -C), expressed on the surface of all nucleated cells, and class II (HLA-DR, -DQ, and -DP), expressed on the surface of antigenpresenting cells (APCs) The recognition of nonself tissue occurs via two distinct immunologic pathways: direct and indirect allorecognition Direct allorecognition consists of recipient T-helper cells recognizing donor HLA disparity expressed on the donor cell surface Indirect allorecognition consists of recipient APCs (e.g., activated macrophages, dendritic cells, B lymphocytes) phagocytosing donor cellular debris, including HLAs, which are then processed and re-presented on the APC surface to be recognized by recipient T-helper cells (CD4+ lymphocytes) (Fig 65.1) p 586 p 587 FIGURE 65.1 Direct, indirect pathways of allorecognition Signal 1 is delivered through the T-cell receptor after engagement by a peptide–HLA complex Signal 2, also known as costimulatory sign, is delivered by an array of cell surface molecules on the T-helper cell and the antigen-presenting cell (APC) D-APC, donor APC; R-APC, recipient APC; TH, T-helper lymphocyte; Tc, cytotoxic T lymphocytes In either pathway, costimulation signals between CD4+ T-helper lymphocytes and CD8+ cytotoxic T lymphocytes trigger a cascade of immunologic events Interleukin (IL)-2, an important and early signal in immune activation, is secreted by activated CD4+ T-helper lymphocytes, stimulating increased T-cell responsiveness, clonal expansion of alloreactive T lymphocytes, and acquisition of the cytolytic phenotype by host T lymphocytes Direct allorecognition leads to a more immediate and vigorous immune response against foreign tissue, but, in both pathways, additional helper T lymphocytes are recruited and secrete a wide array of cytokines (e.g., IL-1, interferon-γ, tumor necrosis factor-α), facilitating the further recruitment of cytotoxic T lymphocytes, natural killer cells, and B lymphocytes Then, B lymphocytes begin to secrete antibody directed against the allogeneic tissue in ever-increasing quantities Rejection mechanistically occurs by infiltration of the graft by effector cells, the binding of antibody, and the activation of complement Unchecked, the phenomenon inexorably leads in graft loss (Table 65.1) Donor–recipient mismatches between HLAs may produce an immune response by either the direct or indirect pathways; however, minor nonHLA mismatches typically produce an immune response by the indirect pathway only Rejection is classified according to the temporal relation between the implantation of the graft and its dysfunction supported by the histologic features seen in allograft The three main types of rejection are hyperacute (HAR), acute (AR), and chronic (CR) Each type is mediated by a different host immune mechanism Consequently, each type poses different problems for the patient, clinicians, and pathologists Hyperacute Rejection HAR occurs within a few minutes to a few hours after the reperfusion of the graft Preformed antibodies directed against antigens presented by the graft mediate activation of complement [71], activation of endothelial cells, and formation of microvascular thrombi, leading to graft thrombosis and loss [71] The process is irreversible; currently, no treatment is available Because HAR is mediated by circulating preformed antibodies normally directed against ABO system (comprising the four main blood types, i.e., A, B, AB, and O) antigens or against major HLA antigens, thorough screening of potential transplant recipients and strict adherence to ABO verification policies should prevent nearly all HAR The panel-reactive antibody (PRA) assay is a screening test that examines the ability of serum from potential transplant recipients to lyse lymphocytes from a panel of HLA-typed donors A numerical value, expressed as a percentage, indicates the likelihood of a positive crossmatch to the donor population Therefore, patients lacking preformed antibodies to random donor lymphocytes are defined as having a PRA of 0% and have a very low probability of eliciting a positive lymphocyte cross-match to any donor The finding of a higher PRA identifies patients at higher immunologic risk for a positive cross-match and thus for HAR and for subsequent graft loss Most often, such patients were previously sensitized by childbirth, blood transfusions, or prior transplantation Pretransplantation, cross-match testing is performed to identify preformed antibodies against class I HLAs (T-lymphocyte cross-match testing) and class II HLAs (B-lymphocyte cross-match testing) In renal and pancreas transplantation, a strong positive class I-HLA cross-match immediately pretransplant is ordinarily an absolute contraindication At most centers, heart and liver transplantations are performed without a cross-match, unless the recipient is highly sensitized or has previously received a graft possessing major antigens in common with the current donor (i.e., donor-specific antibody [DSA]) A positive B-lymphocyte cross-match indicates preformed antibodies directed against class II HLAs and is a relative, but not absolute, contraindication to a transplant Recent studies confirmed the efficacy of plasmapheresis followed by administration of immune globulin to reduce PRA levels and to convert strongly positive cross-match results to weakly positive or negative results, thereby allowing organs to be transplanted across what were previously considered as strong immunologic barriers [72] Cross-match testing helps clinicians to identify the presence of antibodies against potential donor antigens and to assess the risks of posttransplant rejection and subsequent graft loss However, these crossmatching assays are not standardized Since the mid-1960s, cross-match testing was based on the complement-dependent cytotoxicity (CDC) assay The CDC assay was further refined by adding a wash step and an antihuman globulin step, to increase its sensitivity and specificity Then, with the introduction of technology based on flow cytometry (FC), the presence of recipient antibody on the surface of donor lymphocytes could be detected independent of complement binding One of the latest developments in anti-HLA antibody screening was the introduction of Luminex technology, using HLA-coated fluorescent microbeads and FC This method in theory pinpoints the DSAs in sera of recipients with high PRA levels Because all transplant donors are currently HLA typed, a negative cross-match for recipients with high PRA levels can be ensured by avoiding the selection of donors carrying unacceptable HLA antigens (virtual cross-match) [73] The main concerns with these new developments in antibody typing and cross-match testing are between-center test variability and the thresholds of defining false-negative results (results that could deny recipients with high PRA levels a chance for a potential lifesaving transplant) Currently, it is up to an individual transplantation center to implement its own HLA typing and cross-matching policies, depending on the center’s experience, clinical outcomes, and risk tolerance Although screening has all but eliminated HAR as a clinical problem, active investigation is nonetheless directed at dissecting the underlying pathophysiologic mechanisms of HAR Another research focus is on the similar rapid rejection of xenoreactive antigens that serve as a barrier to the development of xenotransplantation Acute Rejection AR is the most common form of graft rejection in modern clinical transplantation It may develop at any time, but is most frequent during the first several months posttransplant Rarely, it occurs within the first several days posttransplant, a process termed accelerated acute rejection, most likely a combination of amnestic immune response driven by sensitized memory B lymphocytes and activation of the direct allorecognition pathway Under such circumstances, the donor antigen exposure often occurred in the distant past, and so the level of circulating DSAs would have been too low to be detected by conventional crossmatching techniques Once challenged by the same donor antigens introduced by the organ transplant, dormant memory lymphocytes reactivate, replicate, and differentiate Within several days, large numbers of antibodies are directed against the donor allograft resulting in graft rejection p 587 p 588 AR may be cell mediated, antibody mediated (AMR), or very occasionally mixed However, they are not mutually exclusive Histologically, AR generates an infiltration of activated T lymphocytes into the graft, resulting in gradually progressive endothelial damage, microvascular thrombosis, and parenchymal necrosis Pathologic grading schemes have been developed regarding the extent to which AR involves vascular damage, cellular infiltration, or a combination of both Vascular AR is thought to be mediated by the presence of DSAs, albeit not in sufficient numbers to cause HAR C4d, a complement split product detected immunohistochemically in the capillaries of biopsied graft specimens, is highly correlated with AMR [74] Without intervention, AR inevitably progresses to graft loss The clinical presentation of AR varies markedly, depending on the specific organ, on the level of immunosuppression, and on the attendant level of inflammation in the affected tissues Unless the host immune system is adequately suppressed pharmacologically, transplantation inevitably leads to AR A combination of immunosuppressive agents is typically used chronically to prevent AR, including a lymphocyte antagonist (usually a calcineurin inhibitor [CNI] such as cyclosporine or tacrolimus) and an antiproliferative agent (such as azathioprine or mycophenolate mofetil), with or without corticosteroids Antilymphocyte antibody therapy is often added during induction of immunosuppression or for treatment of “steroid-resistant” AR In the last decade, immunosuppression for transplant recipients has been undergoing a paradigm shift Since the mid-1990s, the use of antibody induction in solid-organ transplant recipients has increased from 25% to more than 90% [75] Monoclonal antibodies such as basiliximab and daclizumab (both anti-CD25 [IL-2 receptor]) use has declined in the face of increasing use of T-cell depleting agents Daclizumab is no longer on the market Furthermore, strategies such as corticosteroid avoidance and CNI-reduced or CNI-free maintenance immunosuppression were shown to be equivalent to traditional tripledrug maintenance [76] Nonetheless, all immunosuppressive agents carry some risk of toxicity and adverse reactions that may complicate therapy (Table 65.3) TABLE 65.3 Immunosuppressive Medications, Mechanisms of Action, and Common Side Effects Medications Mechanisms of action Side effects Corticosteroids Upregulate IκB Azathioprine Decrease IL-1, TNF-α, IFNγ Exert anti-inflammatory effects Acts as an antimetabolite Mycophenolate mofetil Cyclosporine Tacrolimus (FK506) Sirolimus (rapamycin) Antilymphocyte globulins IL-2 receptor blocker (or basiliximab) Acts as an antimetabolite and specifically affects lymphocytes Acts as a calcineurin inhibitor Downregulates IL-2 Acts as a Calcineurin inhibitor Downregulates IL-2, IFN-γ Blocks IL-2R, IL-4, IL-6, platelet-derived growth factor signaling Cushing syndrome, Cataracts Bone demineralization Marrow suppression GI, liver toxicity Marrow suppression GI intolerance Nephrotoxicity Neurologic symptoms Nephrotoxicity Neurotoxicity Diabetogenic Impaired wound healing Hypertriglyceridemia Act as a cytolytic antibody Leukopenia Block and deplete T cells Thrombocytopenia “Serum sickness” Blocks IL-2R Minimal impact Inhibit T-cell activation GI, gastrointestinal; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor p 588 p 589 Chronic Rejection CR is a largely frustrating and poorly understood clinical phenomenon, with slightly different manifestations in each type of graft Over time, the accumulation of microvascular injury in a graft degrades graft function, with eventual graft loss This process appears to be mediated by multiple mechanisms, likely including both immune and nonimmune factors Evidence for the contribution to CR of immune factors includes the observation that AR episodes significantly increase the likelihood of CR as well as the correlation, observed in renal transplant recipients, between a poor response to AR treatment and the subsequent development of CR [77] A similar association between a poor response to AR treatment and the subsequent development of CR has been observed in liver transplant recipients, although reversible AR has little impact Nonimmune factors also likely contribute to the development and progression of CR, including the toxic effects of immunosuppressive medication and cumulative injury from infection such as that caused by cytomegalovirus (CMV) [78] CR nearly always eventuates in graft loss, although the rapidity of the process varies considerably Renal Grafts AR occurs in 10% to 25% of renal transplant recipients Because most episodes are clinically silent, the diagnosis of AR must be considered in recipients whose serum creatinine, blood urea nitrogen, and urinary output values have normalized and whose graft function has been stable in the outpatient setting, but whose serum creatinine and blood urea nitrogen values subsequently rise while their urinary output decreases The presence of hypovolemia, drug nephrotoxicity (e.g., high calcineurin levels), ureteral obstruction or leak, lymphocele, or vascular anastomotic complications should be excluded, and the diagnosis of AR should be established via histologic examination of a percutaneous graft biopsy specimen Rarely, tenderness and swelling in the area of the graft occur, and occasionally fever or other signs of systemic inflammation, although such findings used to be common A high degree of clinical suspicion should be maintained for recipients who experience delayed graft function, as up to 30% exhibit evidence of AR on biopsy; 20% of recipients who require dialysis posttransplant have AR [79] Intriguingly, up to 30% of recipients with well-functioning grafts also have AR, per early posttransplant protocol biopsies, but whether such findings are clinically important and whether mild episodes should invariably be treated remain controversial [80] Recent studies have provided data that may allow prediction of individual risk of AR, with the potential for individualizing immunomodulatory therapy For example, a donor IL-6 genetic polymorphism is strongly associated with an increased incidence of AR posttransplantation [81] The diagnostic workup for AR includes studies that may identify alternative causes of recipient graft dysfunction (Table 65.4) It is vital to consider alternative diagnoses, particularly in the early postoperative period, including vascular problems with the arterial or venous anastomoses, ureteral obstruction, or urinary leak Other common causes of apparent graft dysfunction include the acute tubular necrosis associated with delayed graft function, hypovolemia and attendant prerenal azotemia, and the nephrotoxic effects of cyclosporine and tacrolimus To rule out the vascular and ureteral problems discussed previously, a duplex ultrasound study of the renal graft is commonly obtained Several ultrasound findings may suggest the diagnosis of AR: increased size of the graft, increased cortical thickness, enlargement of the renal pyramids, and decreased graft renal artery blood flow [82] The resistive index has not been shown to be significant in helping with the diagnosis [83] The diagnosis of AR is clearly established by percutaneous allograft biopsy and histologic examination Biopsy is generally safe when performed by an experienced practitioner; however, complications include bleeding, hematoma and arteriovenous fistula formation, and ureteral or major vascular injury TABLE 65.4 Basic Workup of Recipients with Graft Dysfunction or Acute Rejection History and physical examination Doppler ultrasound Serum chemistry Drug levels Establish and order differential diagnosis Rule out vascular surgical complication Rule out leak (e.g., biliary, ureteral) Evaluate relative blood urea nitrogen and creatinine, amylase, bilirubin, etc Detect and treat electrolyte abnormalities Evaluate for potential drug toxicity Detect inadequate Blood cell count, cultures Graft biopsy drug levels Evaluate for potential infection Firmly establish and grade graft rejection Rejection is graded according to the modified Banff Criteria, which may be used to guide therapy that has been expanded to include C4d negative antibody–mediated rejection [84] Fine-needle aspiration biopsy has been used by some centers to establish the diagnosis of AR; however, some consider the loss of microstructural data, as compared with traditional core biopsy, to be a weakness of the technique In particular, the diagnoses of acute vascular rejection and CR are difficult to make using fine-needle aspiration biopsy The treatment of AR in renal transplant recipients is not standardized and varies between centers High-dose methylprednisolone (500 to 1,000 mg per day or every other day [2 to 3 doses] is common) is often the initial approach Corticosteroid-resistant AR, or AR that is histologically graded as severe or vascular, is often treated with potent depleting antilymphocyte antibodies such as polyclonal antithymocyte globulin (antithymocyte gamma globulin, thymoglobulin) Since some AR episodes occurred while the recipients were on stable immunosuppression, their maintenance therapy was switched from cyclosporine to tacrolimus or from azathioprine to mycophenolate mofetil Most AR episodes are reversible with current therapies; however, as noted previously, the long-term outlook for preservation of graft function is lessened with each episode, especially when the posttreatment serum creatinine level does not return to the pre-AR baseline CR in renal transplant recipients is a frustrating clinical problem and appears to be multifactorial, with immunologic and nonimmunologic factors driving the gradual loss of graft function As described earlier, minimizing the frequency and severity of AR episodes is important in decreasing the likelihood of eventual CR Nonimmunologic factors thought to contribute to CR include (a) episodes of infection, particularly due to CMV and BK virus (vide infra); (b) the nephrotoxicity of CNI therapy; (c) ischemia-reperfusion injury and delayed graft function in the peritransplant period; and (d) innate cell senescence within the graft from donor-derived factors [85] Attention is being directed toward identifying inflammatory activity within the graft, in response to both immune and nonimmune insults that may contribute to the development of CR One of the leading causes of kidney retransplants is CR It remains a formidable problem that is still poorly understood Chapter 57 is devoted to kidney transplantation Hepatic Grafts The transplanted liver is considered to be immunologically “privileged” in that evidence of some degree of immune tolerance occurs in a substantial number of liver transplant recipients over time Despite that observation, all forms of rejection can occur posttransplant At one time, it was thought that HAR did not occur in the hepatic graft; this idea is now known to be incorrect, as anti-HLA antibody–mediated HAR has been described in liver transplant recipients [86] Unlike the renal graft, the hepatic graft undergoes HAR over a number of days, not minutes to hours, probably secondary to its ability to absorb a large amount of antibody and its functional reserve before the onset of the significant microthrombosis and vascular damage seen in HAR A more delayed form of antibody-mediated rejection is seen in up to 33% of patients who undergo liver transplants across ABO-incompatible blood groups, but even this barrier appears surmountable with the use of plasmapheresis along with aggressive immunosuppression AR remains an important clinical problem in liver transplantation; even with the use of standard multiagent immunosuppression, the incidence of AR ranges from 30% to 80% In two large, multicenter trials, double therapy with a CNI and steroids resulted in a 60% to 80% incidence of AR [87] The most common liver transplantation regimen consists of two doses of a monoclonal anti-IL2 receptor (basiliximab) as induction therapy and dual maintenance therapy with the CNI tacrolimus and the antimetabolite mycophenolate mofetil, which lessens the incidence and severity of rejection without increasing infection rates [88] p 589 p 590 The diagnosis of AR in liver transplant recipients is normally suggested by elevated levels of transaminases, bilirubin, or alkaline phosphatase Among patients with T-tube drainage (which is increasingly uncommon), the biliary drainage may be seen to thicken, darken, and decrease in amount The suspicion of AR mandates graft biopsy and studies to eliminate other possible causes of early hepatic graft failure Duplex ultrasonography and, in some cases, cholangiography are increasingly being replaced by magnetic resonance imaging Biopsy findings are classified, according to a standardized set of criteria, as mild, moderate, and severe, with clear implications for prognosis [89] AR is normally treated with high-dose corticosteroids, but 5% to 10% of cases are steroid resistant; such recipients are then treated with an antilymphocyte antibody or tacrolimus at higher levels CR in liver transplant recipients is characterized by vascular obliteration and bile duct loss (“the vanishing duct syndrome”) This is seen in 5% to 10% of recipients, it is more common in those with vasculitic findings during AR episodes; if larger vessels are not seen on biopsy, the diagnosis of CR may be misread as AR Tacrolimus has been used to salvage grafts in recipients with CR on cyclosporine-based immunosuppression, with a 73% success rate [90] Chapter 58 is devoted to liver transplantation Pancreas Grafts Diabetic patients undergo pancreas-alone (PTA), pancreas-after-kidney (PAK), or simultaneous pancreas–kidney (SPK) transplants and receive more potent immunosuppression than do renal transplant recipients, supported by initial studies demonstrating a higher rate of AR after pancreas transplantation Overall success rates continue to improve: the risk of AR has been reduced by standardized induction therapy with antilymphocyte antibody preparations, and it may be further reduced with mammalian target of rapamycin (mTOR) inhibitors and/or with IL2 receptor monoclonal antibodies [91] Establishing the diagnosis of AR in pancreas transplant recipients can be difficult Hyperglycemia is a late finding that only occurs with substantial loss of functional islet-cell mass By the time hyperglycemia is seen, it may be too late to salvage a functional graft Clinical findings may include fever and graft tenderness; however, pancreas graft rejection is often clinically silent For pancreas grafts transplanted along with a renal graft, a rising creatinine level is often used as a surrogate marker of rejection, with antirejection therapy aimed at both the pancreas and the renal allograft However, isolated pancreas graft rejection is observed in up to 20% of simultaneous pancreas–kidney transplant recipients who have AR [92,93] Advantages of a bladder-drained pancreas is the use of a decreasing urinary amylase level as a marker of graft rejection [94] Other possible markers of rejection (serum anodal trypsinogen, serum amylase, soluble HLA, and analysis of glucose-disappearance kinetics during a brief glucose tolerance test) have been examined but have failed to gain widespread acceptance [93] The diagnosis of pancreas graft rejection is confirmed by biopsy, which may be performed percutaneously or, in bladder-drained recipients, through a cystoscopic, transduodenal approach Complications (bleeding, arteriovenous fistula formation, graft pancreatitis) have been described, but most biopsies do not lead to complications Pancreas transplant recipients with early evidence of graft dysfunction should undergo Doppler ultrasonography to rule out graft thrombosis, which occurs in up to 10% to 20% of grafts [95] Treatment of AR for pancreas transplantation recipients is similar to that for renal or liver transplantation recipients High-dose corticosteroids are given initially, with a low threshold maintained for possibly switching to antibody-based therapy, given the relatively common steroid resistance Most AR episodes are reversed with treatment Chapter 61 is devoted to pancreas transplantation Intestinal Grafts There is no serum test for intestinal transplantation rejection As a result, biopsy of the intestinal allograft is the gold standard for diagnosis (via ostomy initially) It has the highest rates of AR and GvHD among all solid-organ transplants The results have markedly improved over the past two decades: at 1 year, patient survival rates of intestinal transplants alone are >80% and of multivisceral transplants are >70%; the respective graft survival rates are >60% and >50% Although treatment protocols for AR have significantly improved, chronic rejection remains a major issue because of its poorly understood nature in intestinal transplantation Chapter 62 is devoted to intestinal transplantation Cardiac Grafts Rejection in heart transplant recipients is a significant cause of morbidity and mortality among these patients and accounts for up to a third of the deaths All forms of rejection are seen in heart transplant recipients Albeit rare, HAR due to preformed antigraft antibodies occurs within minutes to days; it manifests with rapid deterioration of cardiac function, with prolonged need for inotropic support In recipients whose grafts fail to recover rapidly, an attempt to reverse HAR by plasmapheresis may be made, but success is uncommon, and an immediate retransplant is usually required AR in heart transplant recipients is common and usually occurs in the first 3 to 4 months posttransplantation At one time, the diagnosis was made on the basis of the development of congestive heart failure or the elaboration of electrocardiographic abnormalities However, the presentday routine of protocol endomyocardial biopsies has eliminated such late findings of AR, except in noncompliant recipients Most centers use frequent percutaneous transjugular right ventricular endomyocardial biopsies as part of a standardized surveillance protocol Biopsies are evaluated histologically, according to an international grading system [96], and therapy is directed accordingly Several investigators have developed noninvasive approaches to establishing the diagnosis of AR, including electrocardiographic frequency analysis, nuclear scintigraphic techniques, and echocardiography; however, no approach has attained sufficient sensitivity to eliminate the need for protocol biopsies The need for continued endomyocardial biopsies later than 1 year posttransplantation is controversial and center specific, with most choosing to discontinue its performance of biopsies at 1 year unless indicated on clinical grounds The treatment of AR is based on histologic findings High-dose steroid bolus therapy is used in lower-grade rejection without hemodynamic compromise; oral prednisone therapy for mild AR also has been used with success [97] Salvage therapy with an antilymphocyte antibody agent is most common in recipients with histologic findings of more severe rejection, in recipients with steroid-resistant rejection, and in recipients with signs of hemodynamic compromise Other approaches include switching from cyclosporine-based to tacrolimus-based immunosuppression in recipients with refractory AR in an effort to rescue to the graft, a strategy that was proved to be safe and efficacious [97] Photopheresis has been used in the treatment of recipients with T-cell lymphoma and autoimmune disease Studies of photopheresis and triple-drug immunosuppression have provided evidence of a decrease in the total number of AR episodes, as compared with triple-drug immunosuppression alone [97] p 590 p 591 CR manifests in heart transplantation recipients as cardiac allograft vasculopathy (CAV), an entity that is the major cause of late-term morbidity and mortality The pathologic findings of CAV include progressive intimal thickening in a concentric manner, which begins distally within the cardiac vasculature It is associated with the loss of response to endogenous (and pharmacologic) vasodilators [97] CAV is thought to be immunologically mediated because HLA donor-related matching is clearly associated with reduced rates of CAV but it could be ameliorated with the use of sirolimus [98] In addition, nonimmunologic mechanisms are thought to be involved; identifiable risk factors for CAV include hyperlipidemia, donor age older than 25 years, recipient weight gain, CMV disease, preexisting donor or recipient coronary artery disease, and increasing time posttransplantation [97] Another nonimmunologic risk factor for CAV is ischemic time during the peritransplant period Chapter 60 is devoted to heart transplantation Lung Grafts The lung graft is highly immunologic organ and as a result prone to rejection—nearly all lung transplant recipients experience at least one AR episode The clinical difficulty posed by rejection is in distinguishing it from other causes of decreased graft function, most commonly infection HAR of the lung graft [99] is mediated by recipient-preformed antibodies to the donor graft, in a fashion similar to other organs The clinical manifestation is similar to the more common ischemiareperfusion injury, which, unlike HAR, usually resolves HAR of the lung graft is rare and only described in case reports HAR is uniformly fatal in lung transplant recipients It must be prevented via initial cross-match testing and exclusion of immunologically unsuitable donor organs and strict adherence to ABO verification policies Most AR episodes occur during the first 3 to 6 months posttransplantation Some recipients experience symptoms, including fever, cough, and dyspnea Early diagnosis of AR in lung transplant recipients is essential: untreated AR can lead to respiratory insufficiency or failure, and repeated AR episodes are associated with an increased risk of bronchiolitis obliterans and eventual graft failure [99] Transbronchial biopsy is the gold standard for establishing the diagnosis of AR, although less invasive techniques continue to be assessed [99] Bronchoalveolar lavage (BAL) is also performed to rule out infection before increasing immunosuppression; infection and rejection may occur simultaneously in up to 25% of lung transplant recipients with AR [99] Early diagnosis of AR may be aided by spirometry; decreases in timed forced expiratory volume, in pulmonary capillary blood volume, and in the diffusing capacity of the lungs for carbon monoxide are associated with AR and should prompt investigation Radiography is not very sensitive The histologic findings of AR include lymphocytic infiltrates into the perivascular and interstitial spaces; AR is graded according to histologic findings [100] The initial treatment of AR in lung transplant recipients is similar to other organs with the use of high-dose corticosteroids; if they are not successful, anti–T-cell antibody therapy are the second line for steroidresistant cases Many recipients initially respond to the steroid pulse therapy, yet it may not completely clear their AR, and secondary episodes are common, and so additional therapy may be required For that reason, surveillance bronchoscopy with transbronchial biopsies and BAL are common after initial treatment [99] CR in lung transplant recipients is extremely common, affecting up to 40% of recipients at 2 years posttransplant and up to 70% of recipients after 5 years [101] The mean time to diagnosis of graft dysfunction posttransplant is 16 to 20 months A definitive histologic diagnosis of early bronchiolitis obliterans may be difficult to obtain, and so a high degree of clinical suspicion must be maintained Radiography, again, is not specific Typical presenting symptoms are cough, progressive dyspnea, and loss of exercise tolerance There are myriad of therapeutic modalities that have been attempted for recipients with bronchiolitis obliterans, but with little success Increases in immunosuppression, antilymphocyte antibody therapy, and inhaled cyclosporine have all been tried Ultimately, the progress of bronchiolitis obliterans is inexorable, with continued loss of graft function and subsequent death A lung retransplantation is the only viable option [99] Chapter 59 is devoted to lung transplantation SUMMARY For more than half a century, substantial advances in the field of solidorgan transplantation have propelled the clinical practice from an experimental to a standardized and routine stage Dramatic improvements in surgical techniques, immunosuppressive therapy, and medical/critical care have made it possible to increase the pool of potential recipients and now include those who would have been considered too sick or with too many comorbidities even a few years ago However, despite this progress, until medical science is able to develop immunosuppressive drugs and regimens without side effects, or achieve routine tolerance induction, the predominant challenges in transplantation will remain the prevention, diagnosis, and treatment of GvHD, infection, malignancy, and rejection These clinical problems have, however, improved in the nearly six decades since the first successful kidney transplant was performed; but they may become more complex throughout the 21st century as we now transplant many more complicated patients REFERENCES Starzl T, Marchioro, TL, Waddell, WR: The Reversal of rejection in human renal homografts with subsequent development of homograft tolerance Surg Gynecol Obstet 117:385–395, 1963 Hill RB, Rowlands DT, Rifkind D: Infectious pulmonary disease in patients receiving immunosuppressive therapy for organ transplantation N Engl J Med 271(20):1021–1027, 1964 Starzl TE, Penn I, Putnam CW, et al: Iatrogenic alterations of immunologic surveillance in man and their influence on malignancy Immunol Rev 7(1):112–145, 1971 Akbulut S, Yilmaz M, Yilmaz S: Graft-versus-host disease after liver transplantation: a comprehensive literature review World J Gastroenterol 18(37):5240–5248, 2012 DePaoli AM, Bitran J: Graft-versus-host disease and liver transplantation Ann Intern Med 117(2):170–171, 1992 Sun B, Zhao C, Xia Y, et al: Late onset of severe graft-versus-host disease following liver transplantation Transpl Immunol 16(3/4):250– 253, 2006 Weitz M, Strahm B, Meerpohl JJ, et al: Extracorporeal photopheresis versus alternative treatment for chronic graft-versus-host disease after haematopoietic stem cell transplantation in paediatric patients Cochrane Database Syst Rev (2):CD009898, 2014 Vidal E, Cervera C, Cordero E, et al: Executive summary Management of urinary tract infection in solid organ transplant recipients: consensus statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Network for Research in Infectious Diseases (REIPI) Enferm Infecc Microbiol Clin 33:680–687, 2015 Engels EA, Pfeiffer RM, Fraumeni JF Jr, et al: Spectrum of cancer risk among US solid organ transplant recipients JAMA 306(17):1891–1901, 2011 10 Florescu DF, Qiu F, Schmidt CM, et al: A direct and indirect comparison meta-analysis on the efficacy of cytomegalovirus preventive strategies in solid organ transplant Clin Infect Dis 58(6):785–803, 2014 11 Park UJ, Hyun SK, Kim HT, et al: Successful treatment of disseminated adenovirus infection with ribavirin and intravenous immunoglobulin in an adult renal transplant recipient: a case report Transplant Proc 47(3):791–793, 2015 12 Khedmat H, Karbasi-Afshar R, Agah S, et al: A meta-analysis of potential relationship between Epstein-Barr-Encoded-RNA (EBER) and onset time of post-transplant lymphoproliferative disorders Saudi J Kidney Dis Transpl 26(2):232–237, 2015 p 591 p 592 13 Kauffman CA, Miceli MH: Histoplasmosis and blastomycosis in solid organ transplant recipients J Fungi 1(2):94–106, 2015 14 Parapiboon W, Ingsathit A, Jirasiritham S, et al: High incidence of bacteriuria in early post-kidney transplantation; results from a randomized controlled study Transplant Proc 44(3):734–736, 2012 15 Gurusamy KS, Nagendran M, Davidson BR: Methods of preventing bacterial sepsis and wound complications after liver transplantation Cochrane Database Syst Rev (3):CD006660, 2014 16 Orlando G, Manzia TM, Sorge R, et al: One-shot versus multidose perioperative antibiotic prophylaxis after kidney transplantation: a randomized, controlled clinical trial Surgery 157(1):104–110, 2015 17 de la Torre M, Fernández R, Fieira E, et al: Postoperative surgical complications after lung transplantation Rev Port Pneumol 21(1):36– 40, 2015 18 Tevar A, Humar A, Zureikat A, et al: Pancreas transplantation, in Humar A, Sturdevant ML (eds): Atlas of Organ Transplantation: London, Springer, 2015, pp 155–222 19 Santos C, Brennan DC, Yusen RD, et al: Incidence, risk factors and outcomes of delayed-onset cytomegalovirus disease in a large retrospective cohort of lung transplant recipients Transplantation 99:1658–1666, 2015 20 Ulubay G, Kupeli E, Duvenci BO, et al: A 10-year experience of tuberculosis in solid-organ transplant recipients Exp Clin Transplant 13:214–218, 2015 21 Gallagher C, Smith JA: CNS infections in solid organ transplant recipients Neurology 9[Pt 3]:1, 2016 22 Saliba F, Pascher A, Cointault O, et al: Randomized trial of micafungin for the prevention of invasive fungal infection in high-risk liver transplant recipients Clin Infect Dis 60(7):997–1006, 2015 23 Lamoth F, Alexander BD: Antifungal Activity of SCY-078 (MK-3118) and Standard Antifungal Agents against Clinical non-Aspergillus Mold Isolates Antimicrob Agents Chemother 59:4308–4311, 2015 doi:10.1128/AAC 00234-15 24 Raad II, El Zakhem A, El Helou G, et al: Clinical experience of the use of voriconazole, caspofungin or the combination in primary and salvage therapy of invasive aspergillosis in haematological malignancies Int J Antimicrob Agents 45(3):283–288, 2015 25 Heylen L, Maertens J, Naesens M, et al: Invasive aspergillosis after kidney transplant: case-control study Clin Infect Dis 60:1505–1511, 2015 26 Cornely OA, Meems L, Herbrecht R, et al: Randomised, multicentre trial of micafungin vs an institutional standard regimen for salvage treatment of invasive aspergillosis Mycoses 58(1):58–64, 2015 27 Chen Y-C, Chang T-Y, Liu J-W, et al: Increasing trend of fluconazolenon-susceptible Cryptococcus neoformans in patients with invasive cryptococcosis: a 12-year longitudinal study BMC Infect Dis 15(1):277, 2015 28 Johnson RH, Heidari A: Coccidioidomycosis Diagnosis and Treatment of Fungal Infections Switzerland, Springer, 2015, pp 205– 216 29 Miceli MH, Kauffman CA: Treatment options for mucormycosis Cur Treat Options Infect Dis 7(3):142–154, 2015 30 Tan BH: Cytomegalovirus Treatment Cur Treat Options Infect Dis 6(3):256–270, 2014 31 Mumtaz K, Faisal N, Husain S, et al: Universal prophylaxis or preemptive strategy for cytomegalovirus disease after liver transplantation: a systematic review and meta-analysis Am J Transplant 15(2):472–481, 2015 32 Ghassemieh B, Ahya VN, Baz MA, et al: Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation J Heart Lung Transplant 32(7):701–706, 2013 33 Potena L, Bianchi G, Chiereghin A, et al: Reconstitution of CMVspecific immunity after heart transplantation may guide customization of immunosuppressive and antiviral strategies: a prospective randomized study J Heart Lung Transplant 33(4):S154–S155, 2014 34 Ahlenstiel-Grunow T, Koch A, Grosshennig A, et al: A multicenter, randomized, open-labeled study to steer immunosuppressive and antiviral therapy by measurement of virus (CMV, ADV, HSV)-specific T cells in addition to determination of trough levels of immunosuppressants in pediatric kidney allograft recipients (IVIST01trial): study protocol for a randomized controlled trial Trials 15:324, 2014 35 Masson P, Henderson L, Chapman JR, et al: Belatacept for kidney transplant recipients Cochrane Database Syst Rev (24):CD010699, 2014 36 Tan H-H, Goh C-L: Viral infections affecting the skin in organ transplant recipients: epidemiology and current management strategies Am J Clin Dermatol 7(1):13–29, 2006 37 Yamada N, Sanada Y, Okada N, et al: Successful rescue of disseminated varicella infection with multiple organ failure in a pediatric living donor liver transplant recipient: a case report and literature review Virol J 12(1):91, 2015 38 Delbue S, Bella R, Ferraresso M: Reactivation of the human herpes virus 6 in kidney transplant recipients: an unsolved question J Transplant Technol Res 5:e134, 2015 39 Chevaliez S, Pawlotsky J-M: Virology of hepatitis C virus infection Best Pract Res Clin Gastroenterol 26(4):381–389, 2012 40 Mahboobi N, Tabatabaei SV, Blum HE, et al: Renal grafts from antihepatitis B core-positive donors: a quantitative review of the literature Transpl Infect Dis 14(5):445–451, 2012 41 Buti M, Tabernero D, Mas A, et al: Hepatitis B virus quasispecies evolution after liver transplantation in patients under long-term lamivudine prophylaxis with or without hepatitis B immune globulin Transpl Infect Dis 17(2):208–220, 2015 42 Duvoux C, Villamil F, Renner EL, et al: Sustained virological response to antiviral therapy in a randomized trial of cyclosporine versus tacrolimus in liver transplant patients with recurrent hepatitis C infection Ann Transplant 20:25–35, 2014 43 Biggins S, Gralla J, Dodge J, et al: Survival benefit of repeat liver transplantation in the United States: a serial MELD analysis by hepatitis C status and donor risk index Am J Transplant 14(11):2588– 2594, 2014 44 Naggie S, Cooper C, Saag M, et al: Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1 N Engl J Med 373:705–713, 2015 45 Simonds RJ: HIV transmission by organ and tissue transplantation AIDS 7:S35–S38, 1993 46 Miro J, Agüero F, Duclos-Vallée JC, et al: Infections in solid organ transplant HIV-infected patients Clin Microbiol Infect 20[Suppl 7]:119–130, 2014 47 Sawinski D, Goldberg D, Blumberg E, et al: Beyond the NIH multicenter HIV transplant trial experience: outcomes of HIV+ liver transplant recipients compared to HCV+ or HIV+/HCV+ co-infected recipients in the United States Clin Infect Dis 61:1054–1062, 2015 48 Gavaldà J, Aguado J, Manuel O, et al: A special issue on infections in solid organ transplant recipients Clin Microbiol Infect 20[Suppl 7]:1– 3, 2014 49 Lee BT, Gabardi S, Grafals M, et al: Efficacy of levofloxacin in the treatment of BK viremia: a multicenter, double-blinded, randomized, placebo-controlled trial Clin J Am Soc Nephrol 9(3):583–589, 2014 50 Baliu C, Sanclemente G, Cardona M, et al: Toxoplasmic encephalitis associated with meningitis in a heart transplant recipient Transpl Infect Dis 16(4):631–633, 2014 51 Avila JD, Živković S: The neurology of solid organ transplantation Curr Neurol Neurosci Rep 15(7):1–10, 2015 52 Penn I Cancers in renal transplant recipients Adv Ren Replace Ther 7(2):147–156, 2000 53 Sherston SN, Carroll RP, Harden PN, et al: Predictors of cancer risk in the long-term solid-organ transplant recipient Transplantation 97(6):605–611, 2014 54 Gifford G, Fay K, Jabbour A, et al: Primary central nervous system posttransplantation lymphoproliferative disorder after heart and lung transplantation Intern Med J 45(5):583–586, 2015 55 Paya CV, Fung JJ, Nalesnik MA, et al: Epstein–Barr virus-induced posttransplant lymphoproliferative disorders Transplantation 68(10):1517–1525, 1999 56 Lauro A, Arpinati M, Pinna AD: Managing the challenge of PTLD in liver and bowel transplant recipients Br J Haematol 169(2):157–172, 2015 57 Harris NL, Ferry JA, Swerdlow SH: Posttransplant lymphoproliferative disorders: summary of society for hematopathology workshop Semin Diagn Pathol 14(1):8–14, 1997 58 Sheil AG, Disney AP, Mathew TH, et al: De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation Transplant Proc 25(1, Pt 2):1383–1384, 1993 59 Bavinck JNB, Vermeer BJ, van der Woude FJ, et al: Relation between skin cancer and HLA antigens in renal-transplant recipients N Engl J Med 325(12):843–848, 1991 60 Dahlke E, Murray CA, Kitchen J, et al: Systematic review of melanoma incidence and prognosis in solid organ transplant recipients Transplant Res 3:10, 2014 61 McKnight J, Cen H, Riddler S, et al: EBV gene expression, EBNA antibody responses and EBV+ peripheral blood lymphocytes in posttransplant lymphoproliferative disease Leuk Lymphoma 15(1):9–16, 1994 62 Robinson JK, Guevara Y, Gaber R, et al: Efficacy of a sun protection workbook for kidney transplant recipients: a randomized controlled trial of a culturally sensitive educational intervention Am J Transplant 14(12):2821–2829, 2014 63 D’Amico F, Fuxman C, Nachman F, et al: Visceral Kaposi’s sarcoma remission after intestinal transplant First case report and systematic literature review Transplantation 90(5):547–554, 2010 64 Gutierrez JCL Classification of Vascular Tumors Hemangiomas and Vascular Malformations Berlin, Springer, 2015, pp 59–65 65 Alberu J, Pascoe MD, Campistol JM, et al: Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-months results from the CONVERT trial Transplantation 92(3):303–310, 2011 66 Penn I: Evaluation of transplant candidates with pre-existing malignancies Ann Transplant 2(4):14–17, 1997 67 Xiao D, Craig JC, Chapman JR, et al: Donor cancer transmission in kidney transplantation: a systematic review Am J Transplant 13(10):2645–2652, 2013 68 Onaca N, Klintmalm GB: Liver transplantation for hepatocellular carcinoma: the baylor experience J Hepatobiliary Pancreat Surg 17:559–566, 2010 69 Halazun KJ, Patzer RE, Rana AA, et al: Standing the test of time: outcomes of a decade of prioritizing patients with hepatocellular carcinoma, results of the UNOS natural geographic experiment Hepatology 60(6):1957–1962, 2014 70 Medawar PB: Experimental work Plast Reconstr Surg 2(4):387, 1947 71 Squifflet JP, De Meyer M, Malaise J, et al: Lessons learned from ABOincompatible living donor kidney transplantation: 20 years later Exp Clin Transplant 2(1):208–213, 2004 72 Magee CC: Transplantation across previously incompatible immunological barriers Transpl Int 19(2):87–97, 2006 73 Taylor CJ, Kosmoliaptsis V, Summers DM, et al: Back to the future: application of contemporary technology to long-standing questions about the clinical relevance of human leukocyte antigen-specific alloantibodies in renal transplantation Hum Immunol 70(8):563–568, 2009 74 Haas M, Rahman MH, Racusen LC, et al: C4d and C3d staining in biopsies of ABO- and HLA-incompatible renal allografts: correlation with histologic findings Am J Transplant 6(8):1829–1840, 2006 p 592 p 593 75 Saran R, Robinson B, Ayanian J: United States renal data system, 2014 annual data report: epidemiology of kidney disease in the United States Am J Kidney Dis 66:Svii, S1–S305, 2015 76 Vincenti F, Schena FP, Paraskevas S, et al: A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients Am J Transplant 8(2):307– 316, 2008 77 Matas AJ: Impact of acute rejection on development of chronic rejection in pediatric renal transplant recipients Pediatr Transplant 4(2):92–99, 2000 78 Sayegh MH: Chronic renal allograft dysfunction (CAD): new frontiers Kidney Int 78:S1, 2010 79 Jain S, Curwood V, White SA, et al: Weekly protocol renal transplant biopsies allow detection of sub-clinical acute rejection episodes in patients with delayed graft function Transplant Proc 32(1):191, 2000 80 Dalpiaz T, Nogare ADL, Carpio V, et al: Noninvasive molecular biomarkers of acute antibody mediated rejection in renal transplant patients Transplant J 94:263, 2012 81 Marshall SE, McLaren AJ, McKinney EF, et al: Donor cytokine genotype influences the development of acute rejection after renal transplantation Transplantation 71(3):469–476, 2001 82 Kirkpantur A, Yilmaz R, Baydar DE, et al: Utility of the doppler ultrasound parameter, resistive index, in renal transplant histopathology Transplant Proc 40(1):104–106, 2008 83 Naesens M, Heylen L, Lerut E, et al: Intrarenal resistive index after renal transplantation N Engl J Med 369(19):1797–1806, 2013 84 Mubarak M: Evolution of the Banff working classification of renal allograft pathology: updates and future directions J Transplant Technol Res 03(02), 2013 85 Waaga AM, Gasser M, Laskowski I, et al: Mechanisms of chronic rejection Curr Opin Immunol 12(5):517–521, 2000 86 Demetris AJ, Zeevi A, O’Leary JG: ABO-compatible liver allograft antibody-mediated rejection Curr Opin Organ Transplant 20(3):314– 324, 2015 87 A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation N Engl J Med 331(17):1110–1115, 1994 88 Neuhaus P: Improved treatment response with basiliximab immunoprophylaxis after liver transplantation: results from a double- blind randomized placebo-controlled trial Liver Transpl 8(2):132– 142, 2002 89 Banff Working Group on Liver Allograft Pathology: Importance of liver biopsy findings in immunosuppression management: biopsy monitoring and working criteria for patients with operational tolerance Liver Transpl 18(10):1154–1170, 2012 90 Wong P, Devlin J, Gane E, et al: FK 506 rescue therapy for intractable liver allograft rejection Transpl Int 7[Suppl 1]:0934–0874, 1994 91 Gruessner RW, Gruessner AC: The current state of pancreas transplantation Nat Rev Endocrinol 9(9):555–562, 2013 92 Norman SP, Kommareddi M, Samaniego M, et al: Early pancreas graft loss is associated with increased mortality in simultaneous pancreas and kidney transplant recipients Transpl J 90, 2010 93 Gruessner RWG, Sutherland DER: Clinical diagnosis in pancreas allograft rejection, in Solez K, Racusen LC, Billingham ME (eds): Solid Organ Transplant Rejection: Mechanisms, Pathology and Diagnosis New York, NY, Marcel Dekker Inc, 1996, pp 455–499 94 Nghiem DD, Gonwa TA, Corry RJ: Metabolic effects of urinary diversion of exocrine secretions in pancreatic transplantation Transplantation 43(1):70–72, 1987 95 Gruessner AC: 2011 update on pancreas transplantation: comprehensive trend analysis of 25,000 cases followed up over the course of twenty-four years at the International Pancreas Transplant Registry (IPTR) Rev Diabet Stud 8(1):6–16, 2011 96 Everitt MD, Hammond MEH, Snow GL, et al: Biopsy-diagnosed antibody-mediated rejection based on the proposed International Society for Heart and Lung Transplantation working formulation is associated with adverse cardiovascular outcomes after pediatric heart transplant J Heart Lung Transplant 31(7):686–693, 2012 97 Hunt SA, Haddad F: The changing face of heart transplantation J Am Coll Cardiol 52(8):587–598, 2008 98 Matsuo Y, Cassar A, Yoshino S, et al: Attenuation of cardiac allograft vasculopathy by sirolimus: relationship to time interval after heart transplantation J Heart Lung Transplant 32(8):784–791, 2013 99 Martinu T, Howell DN, Palmer SM: Acute cellular rejection and humoral sensitization in lung transplant recipients Semin Respir Crit Care Med 31(2):179–188, 2010 100 Berry GJ, Burke MM, Andersen C, et al: The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation J Heart Lung Transplant 32(12):1147–1162, 2013 101 Colvin-Adams M, Valapour M, Hertz M, et al: Lung and heart allocation in the United States Am J Transplant 12(12):3213–3234, 2012 102 Gugenheim J, Samuel D, Bismuth H, et al: Liver transplantation across ABO blood group barriers Lancet 336(8714):519–523, 1990 103 Mor E, Skerrett D, Manzarbeitia C, et al: Successful use of an enhanced immunosuppressive protocol with plasmapheresis for ABOincompatible mismatched grafts in liver transplant recipients Transplantation 59(7):986–990, 1995 104 Pinsky B, Ercole P, Burroughs T, et al: Predicting long-term graft survival in adult kidney transplant recipients Saudi J Kidney Dis Transpl 23(4):693–700, 2012 105 Ekberg H, Bernasconi C, Tedesco-Silva H, et al: Calcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation Am J Transplant 9(8):1876–1885, 2009 106 Guery BP, Arendrup MC, Auzinger G, et al: Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part II Treatment Intensive Care Med 35(2):206–214, 2008 107 Fernandez-Ruiz M, Arias M, Campistol JM, et al: Cytomegalovirus prevention strategies in seropositive kidney transplant recipients: an insight into current clinical practice Transpl Int 28:1042–1054, 2015 108 Akerzoul N, Chbicheb S, El Wady W: Kaposi Sarcoma and HHV8 Oral Surg Oral Med Oral Pathol Oral Radiol 3(119):e218, 2015  ... Irwin and Rippe’s Intensive Care Medicine EIGHTH EDITION Irwin and Rippe’s Intensive Care Medicine EIGHTH EDITION Editors Richard S Irwin, MD, Master FCCP Professor of Medicine and Nursing... Copyright © 2 018 by Richard S Irwin, M.D., James M Rippe, M.D., and Craig M Lilly, M.D 7th Edition © 2 012 by Richard S Irwin, M.D and James M Rippe, M.D., 6th Edition © 2008 by Richard S Irwin, M.D and James M... Assistant Professor Department of Medicine Division of Vascular Medicine and Cardiology Brigham and Women’s Hospital Boston, Massachusetts Naomi F Botkin, MD Associate Professor of Medicine Department of Medicine