(BQ) Part 1 book Evidence based practice of critical care has contents: Critical care versus criticalillness, what is the role of noninvasive ventilation in the intensive care unit, have critical care outcomes improved, have critical care outcomes improved,... and other contents.
EVIDENCE-BASED PRACTICE of CRITICAL CARE second edition Clifford S Deutschman, MS, MD, FCCM Vice Chair, Research, Department of Pediatrics Professor of Pediatrics and Molecular Medicine Hofstra North Shore-LIJ School of Medicine New Hyde Park, New York Investigator, Feinstein Institute for Medical Research Manhasset, New York Patrick J Neligan, MA, MB, FRCAFRCSI Department of Anaesthesia and Intensive Care University College Galway Galway, Ireland iii 1600 John F Kennedy Blvd Ste 1800 Philadelphia, PA 19103-2899 EVIDENCE-BASED PRACTICE OF CRITICAL CARE, SECOND EDITION ISBN: 978-0-323-29995-4 Copyright © 2016 by Elsevier, Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein Previous edition copyrighted 2010 Library of Congress Cataloging-in-Publication Data Deutschman, Clifford S., editor | Neligan, Patrick J., editor Evidence-based practice of critical care / [edited by] Clifford S Deutschman, Patrick J Neligan Second edition | Philadelphia, PA : Elsevier, [2016] | Includes bibliographical references and index LCCN 2015041109 | ISBN 9780323299954 (pbk : alk paper) | MESH: Critical Care | Evidence-Based Medicine | Intensive Care Units LCC RC86.7 | NLM WX 218 | DDC 616.02/8—dc23 LC record available at http://lccn.loc.gov/2015041109 Senior Content Strategist: Suzanne Toppy Senior Content Development Specialist: Jennifer Ehlers Publishing Services Manager: Patricia Tannian Senior Project Manager: Claire Kramer Design Direction: Julia Dummitt Printed in the United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1 To my family: Chris, who makes everything possible—and worthwhile Cate, Nicki, and Beth, who are now adults, and still make us proud every day, and Linus, who makes it entertaining To my former colleagues in the Surgical Intensive Care Unit at the Hospital of the University of Pennsylvania (including my coauthor): For tolerating 20 years of “Teaching by Confrontation” without ever taking it personally To my new colleagues at the Cohen Children’s Medical Center and the Feinstein Institute for Medical Research: We will figure it out Clifford S Deutschman, MS, MD New York To Diane, David, Conor, and Kate and to my parents Maurice and Dympna Neligan for their continued support and wisdom Patrick J Neligan, MA, MB, FRCAFRCSI Contributors Gareth L Ackland, PhD, FRCA, FFICM William Harvey Research Institute Queen Mary University of London London, United Kingdom Chapter 48 What Is the Role of Autonomic Dysfunction in Critical Illness? Dijillali Annane, MD General Intensive Care Unit Raymond Poincaré Hospital (AP-HP) University of Versailles SQY Laboratory of Inflammation and Infection U1173 INSERM Garches, France Chapter 71 Is There a Place for Anabolic Hormones in Critical Care? Pierre Asfar, MD, PhD Département de Réanimation Médicale et de Médecine Hyperbare Centre Hospitalier Universitaire Angers Angers, France Chapter 40 What MAP Objectives Should Be Targeted in Septic Shock? John G Augoustides, MD, FASE, FAHA Professor Anesthesiology and Critical Care Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania Chapter 52 When Is Hypertension a True Crisis, and How Should It Be Managed in the Intensive Care Unit? Chapter 82 Which Anticoagulants Should Be Used in the Critically Ill Patient? How Do I Choose? Hollman D Aya, MD Clinical and Research Fellow Intensive Care Department St George’s University Hospitals NHS Foundation Trust London, United Kingdom Chapter 84 Does ICU Admission Improve Outcome? Lorenzo Ball, MD IRCCS AOU San Martino-IST Department of Surgical Sciences and Integrated Diagnostics University of Genoa Genoa, Italy Chapter How Does One Evaluate and Monitor Respiratory Function in the Intensive Care Unit? Arna Banerjee, MD Associate Professor of Anesthesiology, Surgery, and Medical Education Department of Anesthesiology and Critical Care Vanderbilt University Medical Center Nashville, Tennessee Chapter 73 How Does One Diagnose, Treat, and Reduce Delirium in the Intensive Care Unit? John Bates, MD Anaesthesia and Intensive Care Medicine University Hospital Galway Galway, Ireland Chapter 24 How Do I Transport the Critically Ill Patient? S V Baudouin, MD, FRCP, FICM Department of Anaesthesia Royal Victoria Infirmary Newcastle upon Tyne, United Kingdom Chapter 36 Are Anti-inflammatory Therapies in ARDS Effective? Michael Bauer, MD Center for Sepsis Control and Care Department of Anesthesiology and Critical Care Medicine Jena University Hospital Jena, Germany Chapter 68 How Does Critical Illness Alter the Liver? Jeremy R Beitler, MD, MPH Division of Pulmonary and Critical Care Medicine University of California, San Diego San Diego, California Chapter 28 What Is the Clinical Definition of ARDS? Rinaldo Bellomo, MD, FCICM Australia and New Zealand Intensive Care Research Centre Department of Epidemiology and Preventive Medicine Monash University Melbourne, Australia Chapter Do Early Warning Scores and Rapid Response Teams Improve Outcomes? Franỗois Beloncle, MD Dộpartement de Rộanimation Mộdicale et de Médecine Hyperbare Centre Hospitalier Universitaire Angers Angers, France Chapter 40 What MAP Objectives Should Be Targeted in Septic Shock? vii viii Contributors Kimberly S Bennett, MD, MPH Associate Professor Pediatric Critical Care University of Colorado School of Medicine Denver, Colorado Chapter 11 Is Extracorporeal Life Support an EvidenceBased Intervention for Critically Ill Adults with ARDS? Paulomi K Bhalla, MD Fellow, Division of Neurocritical Care Neurology Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Chapter 63 How Should Aneurysmal Subarachnoid Hemorrhage Be Managed? Maneesh Bhargava, MD Assistant Professor of Pulmonary, Allergy, Critical Care, and Sleep Medicine University of Minnesota Medical School Minneapolis, Minnesota Chapter 32 Do Patient Positioning in General and Prone Positioning in Particular Make a Difference in ARDS? Alain F Broccard, MD St Vincent Seton Specialty Hospital Indianapolis, Indiana Chapter 32 Do Patient Positioning in General and Prone Positioning in Particular Make a Difference in ARDS? Josée Bouchard, MD Division of Nephrology Department of Medicine University of Montreal Montreal, Canada Chapter 56 How Does One Optimize Care in Patients at Risk for or Presenting with Acute Kidney Injury? Naomi E Cahill, RD, PhD Department of Public Health Sciences Queen’s University Kingston, Ontario, Canada Chapter 67 Is It Appropriate to “Underfeed” the Critically Ill Patient? Andrea Carsetti, MD Anaesthesia and Intensive Care Unit Department of Biomedical Sciences and Public Health Università Politecnica delle Marche Ancona, Italy Department of Intensive Care Medicine St George’s University Hospitals NHS Foundation Trust London, United Kingdom Chapter 84 Does ICU Admission Improve Outcome? Maurizio Cecconi, MD Department of Intensive Care St George’s Hospital London, United Kingdom Chapter 84 Does ICU Admission Improve Outcome? Celina D Cepeda, MD Division of Pediatric Nephrology Pediatric Department Rady Children’s Hospital Division of Nephrology and Hypertension Department of Medicine University of California, San Diego San Diego, California Chapter 56 How Does One Optimize Care in Patients at Risk for or Presenting with Acute Kidney Injury? Maurizio Cereda, MD Assistant Professor of Anesthesia and Critical Care Department of Anesthesia and Critical Care Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania Chapter 10 How Does Mechanical Ventilation Damage Lungs? What Can Be Done to Prevent It? John Chandler, MD, BDS, FDSRCS, FCARCSI Consultant in Anaesthesia and Intensive Care Cork University Hospital Cork, Ireland Chapter 24 How Do I Transport the Critically Ill Patient? Randall M Chesnut, MD, FCCM, FACS Integra Endowed Professor of Neurotrauma Department of Neurological Surgery Department of Orthopaedic Surgery Adjunct Professor School of Global Health Harborview Medical Center University of Washington Seattle, Washington Chapter 61 Is It Really Necessary to Measure Intracranial Pressure in Brain-Injured Patients? Meredith Collard, MD Department of Anesthesiology and Critical Care Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania Chapter What Are the Indications for Intubation in the Critically Ill Patient? Maya Contreras, MD, PhD, FCARCSI Department of Anesthesia St Michael’s Hospital Toronto, Ontario, Canada Chapter 31 Is Permissive Hypercapnia Useful in ARDS? David J Cooper, MD, BM, BS Australian and New Zealand Intensive Care–Research Centre School of Public Health and Preventive Medicine Monash University Alfred Hospital Campus The Alfred Hospital Melbourne, Australia Chapter What Is the Optimal Approach to Weaning and Liberation from Mechanical Ventilation? Contributors ix Craig M Coopersmith, MD Professor of Surgery Department of Surgery Associate Director Emory Critical Care Center Vice Chair of Research Department of Surgery Director Surgical/Transplant Intensive Care Unit Emory University Hospital Atlanta, Georgia Chapter 46 Is Selective Decontamination of the Digestive Tract Useful? David Cosgrave, MB, BCh, BAO Anaesthesia SPR University Hospital Galway Galway, Ireland Chapter 24 How Do I Transport the Critically Ill Patient? Cheston B Cunha, MD Assistant Professor of Medicine Division of Infectious Disease Medical Director, Antimicrobial Stewardship Program Rhode Island Hospital and the Miriam Hospital Brown University Alpert School of Medicine Providence, Rhode Island Chapter 17 What Strategies Can Be Used to Optimize Antibiotic Use in the Critically Ill? Gerard F Curley, PhD, MB, MSc, FCAI, FJFICM Departments of Anesthesia and Critical Care Keenan Research Centre for Biomedical Science of St Michael’s Hospital St Michael’s Hospital Department of Anesthesia and Interdepartmental Division of Critical Care University of Toronto Toronto, Ontario, Canada Chapter 39 What Is the Role of Empirical Antibiotic Therapy in Sepsis? Randall J Curtis, MD Professor Division of Pulmonary and Critical Care Medicine A Bruce Montgomery–American Lung Association Endowed Chair in Pulmonary and Critical Care Medicine Section Head Harborview Medical Center Director Cambia Palliative Care Center of Excellence Harborview Medical Center Seattle, Washington Chapter 87 What Factors Influence a Family to Support a Decision Withdrawing Life Support? Allison Dalton, MD Assistant Professor of Anesthesia and Critical Care Department of Anesthesia and Critical Care University of Chicago Chicago, Illinois Chapter 15 How Do I Manage Hemodynamic Decompensation in a Critically Ill Patient? Kathryn A Davis, MD, MTR Medical Director Epilepsy Monitoring Unit Assistant Professor of Neurology Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Chapter 65 How Should Status Epilepticus Be Managed? Daniel De Backer, MD, PhD Department of Intensive Care Erasme University Hospital Brussels, Belgium Chapter 13 What Is the Role of Invasive Hemodynamic Monitoring in Critical Care? Clifford S Deutschman, MS, MD, FCCM Vice Chair, Research, Department of Pediatrics Professor of Pediatrics and Molecular Medicine Hofstra North Shore–LIJ School of Medicine New Hyde Park, New York Investigator, Feinstein Institute for Medical Research Manhasset, New York Chapter Critical Care Versus Critical Illness Chapter 37 What Is Sepsis? What Is Septic Shock? What Are MODS and Persistent Critical Illness? Chapter 49 Is Sepsis-Induced Organ Dysfunction an Adaptive Response? Chapter 52 When Is Hypertension a True Crisis, and How Should It Be Managed in the Intensive Care Unit? Margaret Doherty, BMedSci, MB BCh BAO, FFARCSI, EDIC Interdepartmental Division of Critical Care Medicine University Health Network University of Toronto Toronto, Ontario, Canada Chapter 30 What Is the Best Mechanical Ventilation Strategy in ARDS? Tom Doris, MD FRCA Department of Anaesthesia Royal Victoria Infirmary Newcastle upon Tyne, United Kingdom Chapter 36 Are Anti-inflammatory Therapies in ARDS Effective? x Contributors Todd Dorman, MD, FCCM Senior Associate Dean for Education Coordination Associate Dean Continuing Medical Education Professor and Vice Chair for Critical Care Department of Anesthesiology and Critical Care Medicine Joint Appointments in Medicine, Surgery, and the School of Nursing Johns Hopkins University School of Medicine Baltimore, Maryland Chapter 85 How Should Care Within an Intensive Care Unit or an Institution Be Organized? Tomas Drabek, MD, PhD Associate Professor of Anesthesiology Scientist Safar Center for Resuscitation Research University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Chapter 22 Is Hypothermia Useful in Managing Critically Ill Patients? Which Ones? Under What Conditions? Stephen Duff, MB BCh St Vincent’s University Hospital Dublin, Ireland Chapter What Is the Optimal Approach to Weaning and Liberation from Mechanical Ventilation? Eimhin Dunne, MRCS, PG Dip (Clin pharm) Critical Care Clinical Fellow King’s College Hospital London, United Kingdom Chapter 18 Is Prophylaxis for Stress Ulceration Useful? Ali A El Solh, MD, MPH Division of Pulmonary, Critical Care, and Sleep Medicine Department of Medicine and Department of Social and Preventive Medicine State University of New York at Buffalo School of Medicine and Biomedical Sciences and School of Public Health and Health Professions VA Western New York Healthcare System Buffalo, New York Chapter 23 What Are the Special Considerations in the Management of Morbidly Obese Patients in the Intensive Care Unit? E Wesley Ely, MD, MPH Professor of Medicine Associate Director of Research GRECC Center for Health Services Research Department of Allergy, Pulmonary, and Critical Care Medicine Vanderbilt University Medical Center Nashville, Tennessee Chapter 73 How Does One Diagnose, Treat, and Reduce Delirium in the Intensive Care Unit? Andrés Esteban, MD, PhD Departamento de Cuidados Intensivos CIBER de Enfermedades Respiratorias Hospital Universitario de Getafe Madrid, Spain Chapter 28 What Is the Clinical Definition of ARDS? Laura Evans, MD Associate Professor Department of Medicine New York University School of Medicine New York, New York Chapter 43 Do the Surviving Sepsis Campaign Guidelines Work? Niall D Ferguson, MD, FRCPC, MSc Interdepartmental Division of Critical Care Medicine University Health Network University of Toronto Toronto, Ontario, Canada Chapter 30 What Is the Best Mechanical Ventilation Strategy in ARDS? Jonathan Frogel, MD Assistant Professor Anesthesiology and Critical Care Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Chapter 53 How Does One Prevent or Treat Atrial Fibrillation in Postoperative Critically Ill Patients? Jakub Furmaga, MD Assistant Professor of Emergency Medicine Faculty in Medical Toxicology University of Texas Southwestern Medical Center Dallas, Texas Chapter 79 How Do I Diagnose and Manage Patients Admitted to the ICU After Common Poisonings? Ognjen Gajic, MD Professor of Medicine Pulmonary and Critical Care Medicine Mayo Clinic Rochester, Minnesota Chapter 12 What Factors Predispose Patients to Acute Respiratory Distress Syndrome? Alice Gallo De Moraes, MD Department of Medicine–Division of Pulmonary and Critical Care Mayo Clinic Rochester, Minnesota Chapter 12 What Factors Predispose Patients to Acute Respiratory Distress Syndrome? Erik Garpestad, MD Associate Chief, Pulmonary, Critical Care, and Sleep Division Director, Medical ICU Associate Professor Tufts University School of Medicine Boston, Massachusetts Chapter What Is the Role of Noninvasive Ventilation in the Intensive Care Unit? Hayley B Gershengorn, MD Departments of Medicine and Neurology Albert Einstein College of Medicine Montefiore Medical Center Bronx, New York Chapter Have Critical Care Outcomes Improved? Contributors xi Emily K Gordon, MD Assistant Professor Anesthesiology and Critical Care Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania Chapter 52 When Is Hypertension a True Crisis, and How Should It Be Managed in the Intensive Care Unit? Chapter 82 Which Anticoagulants Should Be Used in the Critically Ill Patient? How Do I Choose? W Robert Grabenkort, PA MMSc, FCCM Director Nurse Practitioner/Physician Assistant Residency Program Emory Critical Care Center Emory Healthcare Atlanta, Georgia Chapter 86 What Is the Role of Advanced Practice Nurses and Physician Assistants in the ICU? Guillem Gruartmoner, MD Department of Critical Care Corporació Sanitària Universitària Parc Taulí Hospital de Sabadell Universitat Autònoma de Barcelona Barcelona, Spain Department of Intensive Care Erasmus Medical Center Rotterdam, The Netherlands Chapter 42 How Can We Monitor the Microcirculation in Sepsis? Does It Improve Outcome? Jacob T Gutsche, MD Assistant Professor Cardiothoracic and Vascular Section Anesthesiology and Critical Care Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania Chapter 26 How Do I Diagnose and Treat Pulmonary Embolism? Chapter 52 When Is Hypertension a True Crisis, and How Should It Be Managed in the Intensive Care Unit? Scott Halpern, MD, PhD Associate Professor of Medicine, Epidemiology, and Medical Ethics and Health Policy Director Fostering Improvement in End-of-Life Decision Science Program Deputy Director Center for Health Incentives & Behavioral Economics Department of Medical Ethics and Health Policy Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania Chapter 83 How Can Critical Care Resource Utilization in the United States Be Optimized? Ivan Hayes, MD Consultant Intensivist Cork University Hospital Cork, Ireland Chapter 18 Is Prophylaxis for Stress Ulceration Useful? Nicholas Heming, MD General Intensive Care Unit Raymond Poincaré Hospital (AP-HP) University of Versailles SQY Garches, France Chapter 71 Is There a Place for Anabolic Hormones in Critical Care? Daren K Heyland, MD Department of Critical Care Medicine Queen’s University Clinical Evaluation Research Unit Kingston General Hospital Kingston, Ontario, Canada Chapter 67 Is It Appropriate to “Underfeed” the Critically Ill Patient? Nicholas S Hill, MD Investigator Pulmonary Hypertension Clinic at Rhode Island Hospital Providence, Rhode Island Chief of the Pulmonary, Critical Care, and Sleep Division at Tufts-New England Medical Center Professor of Medicine Tufts University School of Medicine Boston, Massachusetts Chapter What Is the Role of Noninvasive Ventilation in the Intensive Care Unit? Eliotte Hirshberg, MD, MS Critical Care Attending Physician Intermountain Medical Center Associate Professor Internal Medicine Division of Pulmonary and Critical Care Medicine Assistant Professor (Adjunct) Pediatrics Division of Critical Care University of Utah Salt Lake City, Utah Chapter 11 Is Extracorporeal Life Support an EvidenceBased Intervention for Critically Ill Adults with ARDS? R Duncan Hite, MD Professor and Chairman Department of Critical Care Medicine Respiratory Institute Cleveland Clinic Cleveland, Ohio Chapter 11 Is Extracorporeal Life Support an EvidenceBased Intervention for Critically Ill Adults with ARDS? xii Contributors Steven M Hollenberg, MD Gabriella Jäderling, MD, PhD Richard S Hotchkiss, MD Marc G Jeschke, MD, PhD, FACS, FCCM, FRCS(C) Professor of Medicine Cooper Medical School of Rowan University Director, Coronary Care Unit Cooper University Hospital Camden, New Jersey Chapter 54 Is Right Ventricular Failure Common in the Intensive Care Unit? How Should It Be Managed? Professor of Anesthesiology, Medicine, Surgery, Molecular Biology and Pharmacology Washington University School of Medicine St Louis, Missouri Chapter 38 Is There Immune Suppression in the Critically Ill Patient? Can Ince, PhD Department of Intensive Care Erasmus Medical Center Rotterdam, The Netherlands Chapter 42 How Can We Monitor the Microcirculation in Sepsis? Does It Improve Outcome? Margaret Isaac, MD Assistant Professor of Medicine Attending Physician General Internal Medicine and Palliative Care University of Washington/Harborview Medical Center Seattle, Washington Chapter 87 What Factors Influence a Family to Support a Decision Withdrawing Life Support? Shiro Ishihara, MD Biomarkers and Heart Diseases UMR-942 Institut National de la Santé et de la Recherche Médicale (INSERM) Paris, France Nippon Medical School Musashi-Kosugi Hospitals Kanagawa, Japan Chapter 50 How Do I Manage Acute Heart Failure? Theodore J Iwashyna, MD, PhD Associate Professor, Department of Internal Medicine Faculty Associate, Survey Research Center, Institute for Social Research Research Scientist, Center for Clinical Management Research Ann Arbor VA Health Services Research and Development Co-Director, Robert Wood Johnson Foundation Clinical Scholars Program Ann Arbor, Michigan Chapter What Problems Are Prevalent Among Survivors of Critical Illness and Which of Those Are Consequences of Critical Illness? Department of Anesthesiology Surgical Services and Intensive Care Karolinska University Hospital Stockholm, Sweden Chapter Do Early Warning Scores and Rapid Response Teams Improve Outcomes? Professor at the University of Toronto Department of Surgery Division of Plastic Surgery Department of Immunology Director, Ross Tilley Burn Centre Sunnybrook Health Sciences Centre Chair in Burn Research Senior Scientist Sunnybrook Research Institute Toronto, Ontario, Canada Chapter 76 How Should Patients with Burns Be Managed in the Intensive Care Unit? Lewis J Kaplan, MD Section Chief Surgical Critical Care Philadelphia VA Medical Center Associate Professor of Surgery Division of Trauma, Surgical Critical Care, and Emergency Surgery Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania Chapter 75 What Is Abdominal Compartment Syndrome and How Should It Be Managed? Scott E Kasner, MD Professor of Neurology University of Pennsylvania Director Comprehensive Stroke Center University of Pennsylvania Health System Philadelphia, Pennsylvania Chapter 64 How Should Acute Ischemic Stroke Be Managed in the Intensive Care Unit? Colm Keane, MD Department of Anaesthesia and Intensive Care National University of Ireland Galway, Ireland Chapter 41 What Vasopressor Agent Should Be Used in the Septic Patient? Mark T Keegan, MB, MRCPI, MSc Professor Division of Critical Care Department of Anesthesiology Mayo Clinic and Mayo Clinic College of Medicine Rochester, Minnesota Chapter 69 How Is Acute Liver Failure Managed? Chapter 39 What Is the Role of Empirical Antibiotic Therapy in Sepsis? 263 or coma Imaging studies generally show no focal lesions, and findings on electroencephalography are usually consistent with nonfocal encephalopathy.17 Critical illness polyneuropathy and myopathy are also common, especially in patients with a prolonged ICU stay.18 Acute kidney injury is manifested as decreasing urine output and an increasing serum creatinine level and frequently requires treatment with renal replacement therapy.19 Paralytic ileus, elevated bilirubin/aminotransferase levels, altered glycemic control, thrombocytopenia and disseminated intravascular coagulation, adrenal dysfunction, and the nonthyroid illness syndrome are all relatively common in patients with severe sepsis.20 Gram Stain and Culture as an Aid to Empirical Therapy Microbiologists have access to a wide range of invasive and noninvasive diagnostic techniques, and these should be used when appropriate The institution of antimicrobial therapy should not be delayed for the sake of performing exhaustive diagnostic tests Gram stain of appropriate specimens from potential sites of infection should be used to help determine appropriate empirical or antimicrobial therapy Although the yield of useful information from Gram stains is usually not high in critically ill patients, performing this test is nevertheless of value for those patients in whom causative pathogens are identified.21-23 Gram stains from specimens obtained from certain sites such as the respiratory tract and wounds should be interpreted with caution because of high rates of colonization with nonpathogenic organisms, particularly in patients who have already been hospitalized for several days Studies have clearly demonstrated the high frequency and rapid time course of microbial colonization of ICU patients.24-26 Classic studies demonstrated that rates of colonization of the oropharynx and bronchi of critically ill patients with gram-negative organisms reached 45% and 65% within days after ICU admission, respectively, and more than 90% at both sites by day 10.27 These patients also become highly colonized with gram-positive cocci and particularly yeast soon after ICU admission Great care must be taken to differentiate colonizing organisms from true pathogens when evaluating Gram stain and culture results from nonsterile areas of the body or areas that may become colonized after the placement of foreign devices such as catheters (e.g., the urinary tract and respiratory tract) Colonization is often distinguished on the basis of Gram stain results showing multiple morphologic types of bacteria or the absence of clinically relevant signs and symptoms of infection despite the presence of microbial growth However, in critically ill patients, colonization is often extremely difficult to distinguish from true infection, and antimicrobials are initiated based on a presumptive diagnosis Blood Cultures The role of blood cultures is crucial for the correct fine- tuning of antibiotic therapy in sepsis.3 Blood cultures are the current “gold standard” of bloodstream infection diagnosis and are based on the detection of viable microorganisms present in blood Blood cultures have the advantage of allowing for the evaluation of their antimicrobial susceptibility; this characteristic has still not been paralleled by any other technique available to date This aspect is important because several studies have shown that inadequate antimicrobial therapy is an independent risk factor for mortality or microbiological failure for severely ill patients with life-threatening infections (see later) However, several factors may still reduce the overall sensitivity of blood cultures An intrinsic limitation of blood cultures is their low sensitivity to slow-growing and fastidious organisms such as Bartonella spp., Francisella tularensis, Mycoplasma spp., several molds, and Nocardia spp.28 Other uniformly uncultivable pathogens (by the usual bacterial culture systems) such as Rickettsia spp., Coxiella burnetii, Chlamydophila pneumoniae, and Tropheryma whipplei are better diagnosed by immunodiagnostic or molecular techniques.28 The presence of multiple interfering factors such as previous antimicrobial therapy, suboptimal sample collection, or incorrect preanalytic processing may deliver false-negative results even in septic patients with easy-toculture pathogens such as Staphylococci and Streptococci.29 An important factor influencing blood culture diagnostic yield is blood volume.30,31 Several studies of adults32,33 and pediatric patients34,35 confirmed that the rate of isolation from blood cultures increases with the quantity of blood submitted Another important variable is the time taken from blood withdrawal to the loading of blood culture bottles into the instrument.36 Ideally, blood cultures should be loaded immediately into the continuous-monitoring instrument to minimize the time to detection and to reduce the number of false-negative samples caused by delays in loading A decrease in recovery has been observed when bottles are held at room temperature for more than 12 hours and even more so when they are preincubated at 37° C before being loaded into the automatic instrument.36 Role of Rapid Microbiological Diagnostics to Guide Empirical Therapy The role of the clinical microbiology laboratory in the acute phase of sepsis has traditionally been marginal because at least 24 to 72 hours are necessary for the confirmation of an infectious etiology, identification of the pathogen, and evaluation of its antimicrobial susceptibility However, with the advent of rapid speciation methods, clinicians are encountering increasing windows of time when they are aware of an infecting organism’s species without yet knowing its susceptibilities.37,38 The most promising techniques are proteomic technologies, including matrix-assisted laser desorption-ionization time-of-flight mass spectrometry.39 This technique is able to identify bacteria or fungi by determining their proteomic profiles.40 It has also been used to identify bacterial virulence factors41 or antibiotic resistance markers.42 This method has the main advantage of allowing a definitive identification, or typing, of isolated microorganisms in only a few minutes In addition, several pathogen-specific, broad-range, and multiplex polymerase chain reaction–based amplification strategies have been used to identify positive blood cultures, to aid in rapid speciation, or to diagnose sepsis directly from blood samples.43 Other molecular methods are being used, including 264 Section VII SEPSIS fluorescence in situ hybridization with oligonucleotide probes targeting bacterial or fungal genes (typically ribosomal RNA genes).44 With the advent of rapid speciation techniques, there is an opportunity to improve antimicrobial coverage with the added possibility of decreasing unnecessary antimicrobial usage This will suddenly make institutional species-specific antibiograms much more clinically useful Moreover, clinicians may be able to more quickly discontinue therapy after identification of obvious culture contaminants (e.g., Corynebacterium species) or more rapidly de-escalate therapy after identification of organisms with predictable susceptibilities (e.g., Listeria monocytogenes) In some instances, species identification will result in pathogen-guided escalation before susceptibility-guided de-escalation of empirical therapy (e.g., Enterococcus species or Pseudomonas species).37 Despite the remarkable technical advances of nucleic acid testing–based approaches, their widespread use for the microbiological diagnosis of sepsis is still limited by several shortcomings For example, the detection of circulating microbial DNA (DNAemia) does not necessarily indicate the presence of a viable microorganism responsible for a given infection The high sensitivity needed for the diagnosis of sepsis may increase the risk of falsepositive results due to carryover contamination or due to the detection of environmental DNA contaminating the blood sample Moreover, DNAemia may be the footprint for transient bacteremia not related to any infection,45,46 or it may be related to the persistence of circulating DNA still detectable several days after successful anti-infectious therapy has been completed.47 Another major drawback of the available molecular assays for the diagnosis of sepsis is that they not provide information on the antimicrobial susceptibility of the detected pathogen The rapid detection of a pathogen may allow for better fine-tuning of empirical therapy with possible economic savings, but the lack of a specific susceptibility spectrum, especially with multidrug-resistant pathogens on the rise, may limit the clinical usefulness of these assays In cases in which the presence of a single gene is always associated with phenotypic resistance (i.e., the mecA gene for oxacillin resistance and van genes for vancomycin resistance), it is relatively simple to design molecular strategies that allow their detection More troublesome are cases in which the phenotypic resistance is influenced by several concurrent factors, such as the regulatory role of distinct genes that modulate the levels of expression of the gene(s) determining resistance Other Assays to Guide Empirical Antibiotic Therapy Fungi continue to be a major cause of infection-related mortality principally for ICU patients and patients with hematologic malignancies However, early diagnosis remains a challenge, mainly because of the low specificity of clinical symptoms and the low sensitivity of fungal cultures The development of an enzyme-linked immunosorbent assay for the detection of galactomannan (GM), an Aspergillus sp cell wall component, has been an important advance for the diagnosis of invasive aspergillosis.48,49 A positive test confirmed with two sequential samples is considered to be a valid index for invasive aspergillosis diagnosis with European Organisation for Research and Treatment (EORTC) diagnostic criteria.50 Although the detection of GM in serum is easy to perform, a major disadvantage of the serodiagnosis of invasive aspergillosis is the occurrence of false-positive results β-Glucan (BG) is another component of the fungal cell wall present in a wider variety of fungal species, including Candida spp.51 For most patients with confirmed invasive fungal infections, BG levels were elevated several days before clinical diagnosis.52 The limitations of blood cultures have also fostered interest in the development of sensitive and rapid laboratory tests aimed at detecting nonspecific biomarkers of sepsis Assays for C-reactive protein, procalcitonin (PCT), interleukin (IL)–6, and IL-8 have been evaluated for their clinical usefulness PCT is a propeptide of calcitonin that is ubiquitously expressed as part of the host’s inflammatory response to various insults.53 A growing body of evidence suggests that PCT is a marker of severe bacterial infection54 and can distinguish patients who have sepsis from patients who have SIRS.55 In particular, PCT levels in plasma have been correlated with sepsis-related organ failure scores and may be useful in risk assessment.56 High and persistent elevations in PCT levels have been associated with poor outcomes for ICU patients.57 Although several studies suggested that PCT is among the most promising biomarkers for sepsis, considerable controversy surrounding its clinical usefulness still remains A recent meta-analysis58 indicated that PCT cannot reliably differentiate sepsis from other noninfectious causes of SIRS in critically ill adult patients EARLY TREATMENT: THE EVIDENCE In a well-known study, Rivers et al.59 demonstrated an impressive absolute reduction of 16% in the in-hospital mortality rate of septic shock and severe sepsis in their single-center, prospective, randomized trial of early goaldirected therapy (EGDT) This was the first study to demonstrate that there was a golden hour (or to hours) for patients with severe sepsis The results of the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial60 and the Protocol-Based Care for Early Septic Shock (ProCESS) study,61 both of which evaluated the use of resuscitation bundles in sepsis, seem to refute the findings of Rivers et al These trials failed to show benefit from EGCDT versus controls One of the criticisms of EGDT as described by Rivers and of other sepsis bundles concerns the uncertain effect that individual parts of the bundle have on survival.62 EGDT as a whole seems to save lives, but individual parts of the therapy may not be efficacious (central mixed venous oxygen monitoring) or may even be harmful to patients with sepsis (i.e., blood transfusion).62 The only consistently important factor in several multivariate analyses of the utility of individual elements of the sepsis bundle has been rapid antimicrobial initiation.62 Indeed, in the ARISE and ProCESS studies, septic shock was recognized early in most patients Seventy-six percent of the patients in ProCESS received antimicrobial agents by the time they underwent randomization,61 Chapter 39 What Is the Role of Empirical Antibiotic Therapy in Sepsis? 265 which occurred a mean of hours after patients’ arrival in the emergency department (ED) The rate of antimicrobial administration hours after randomization was approximately 97%, which undoubtedly contributed to the higher rates of survival than projected in this study The potential influence of delayed antibiotic therapy was first evaluated in patients with community-acquired pneumonia (CAP) In a study involving 297 U.S acute care hospitals, Kahn et al.63 observed a 4% point reduction in 30-day mortality among Medicare patients who received antibiotics within hours of admission and appropriate oxygen therapy In the early 1990s, McGarvey and Harper64 demonstrated that care processes that included antibiotic delivery within hours were associated with lower pneumonia mortality at two community hospitals Meehan and colleagues65 undertook a multicenter retrospective study of 14,069 patients with CAP treated in 3555 U.S acute care hospitals and demonstrated that administration of antibiotics within hours of hospital arrival and collecting blood cultures within 24 hours were associated with improved 30-day survival More recently, Houck et al.66 described that among 13,771 patients who had not received outpatient antibiotic agents, antibiotic administration within hours of arrival at the hospital was associated with reduced in-hospital mortality (6.8% vs 7.4%; adjusted odds ratio [AOR], 0.85; 95% confidence interval [CI], 0.74 to 0.98) and mortality within 30 days of admission (11.6% vs 12.7%; AOR, 0.85; 95% CI, 0.76 to 0.95) In a study of 261 patients in the ED, Gaieski et al.67 confirmed the association with timing of antibiotic therapy and mortality in patients with severe sepsis or septic shock In addition, Kumar and colleaguers,68 in a retrospective cohort study of 2154 patients who received empirical antibiotic therapy, observed that the survival was 80% in patients given antibiotics within the first hour of persistent or recurrent hypotension However, for each hour of delay during the subsequent hours, the chances of survival decreased by 7.6% In multivariate analysis, the strongest predictor of outcome was time to effective antibiotic administration Only half the patients received effective antibiotics within hours of hypotension onset, and 30% had delays of more than 12 hours It is important to point out that this was a retrospective study over 15 years, and recruitment rates were relatively low, with 2154 patients included from 10 sites (14 ICUs) Only 12% of patients had received antibiotics within the first hour In addition, Kumar et al.68 focused on septic shock patients with appropriate antibiotic treatment In a prospective observational study in 77 ICUs62 based on propensity scores and adjusting for other treatments, Ferrer et al reported that among 2796 severe sepsis/septic shock patients, empirical antibiotic treatment reduced mortality (treatment within hour vs no treatment within first hours of diagnosis; odds ratio [OR] 0.67; 95% CI, 0.50 to 0.90; P = .008) In a more recent retrospective analysis of a large dataset of 28,150 patients with severe sepsis and septic shock prospectively collected for the SSC in Europe, the United States, and South America, Ferrer and colleagues69 showed that delay in first antibiotic administration was associated with increased in-hospital mortality There was a linear increase in mortality risk for each hour of delay in antibiotic administration Reducing the time to first antibiotic from more than hours to less than hour may result in a mortality reduction of 9.5% (33.1 to 24.6%) These data demonstrate that the association between timing of antibiotic administration and mortality is true not only for patients with septic shock but also for patients with severe sepsis Importantly, the beneficial effects of early antibiotic administration reported in this study are based on time from sepsis diagnosis and are not related to onset of hypotension On the basis of this evidence, the SSC guidelines recommend that after the recognition of severe sepsis or septic shock, IV broad-spectrum antibiotics should be administered as early as possible and always within hour (for patients identified on the general medical wards) or hours (for patients identified in the ED).3 The relationship of prompt antibiotics and better outcomes might represent a surrogate marker for the quality of care in a broader sense Other important sepsis treatments have shown time dependency, such as quantitative resuscitation59 or source control.70 In fact, in a systematic review and meta-analysis, Barochia et al.71 showed that the implementation of SSC bundles was followed by an improvement in most of the sepsis process-of-care variables, including time-to-antibiotic treatment, followed by a mortality reduction APPROPRIATE DRUG SELECTION Initial selection of adequate or appropriate drug therapy also appears to be of importance in optimizing outcomes of antimicrobial use in critically ill patients Few would argue with the initial use of broad-spectrum agents Initial empirical anti-infective therapy should include one or more drugs that have activity against the likely pathogens (bacterial or fungal) and that penetrate into the presumed source of the sepsis The choice of drugs should be guided by the susceptibility patterns of microorganisms in the community and in the hospital Selection of inadequate therapy has been demonstrated in numerous clinical studies to be associated with increased patient mortality,4,12,21,72-78 and the risk of inadequate therapy is often directly related to rates of antimicrobial resistance in certain pathogens.4,12,73,76,77 Simply put, adequate therapy is more than a reflection of “sensitive” or “resistant.” It needs to be governed by breakpoints that are relevant to the mode of action of an antibiotic and the probability that at any given dose, a drug will exceed either the concentration required for killing most strains of a given bacterial species (concentration-dependent killing) or that the concentration will remain above the minimum inhibitory concentration (MIC) of the strains for certain time periods (time-dependent killing).79 Retrospective studies conducted in the 1960s and 1970s have shown that appropriate antimicrobial therapy, defined as the use of at least one antibiotic active in vitro against the causative bacteria, reduced the mortality of gram-negative bacteremia when compared with patients receiving inappropriate therapy.80-83 In a landmark study of 173 patients with gram-negative bacteremia, who were classified in three categories according to the severity of the underlying disease categories (i.e., rapidly fatal, ultimately fatal, and nonfatal), McCabe et al.83 observed that appropriate 266 Section VII SEPSIS antibiotic therapy reduced mortality from 48% to 22% Four subsequent studies that included larger numbers of patients yielded similar results.80-82,84 In a more recent prospective study of 2124 patients with gram- negative bacteremia, mortality was 34% in 670 patients who received inappropriate antibiotics and 18% in 1454 patients who received appropriate antibiotics.85 Smaller recent studies showed that the appropriateness of the antibiotic regimen favorably influenced the outcome of patients infected with specific gram-negative bacteria, such as Enterobacter species,86 Pseudomonas aeruginosa,87 and ceftazidime-resistant Klebsiella pneumoniae or Escherichia coli.88 Fewer data have been published on the impact of appropriate antibiotic therapy in patients with gram-positive sepsis.89 Several studies evaluated the impact of appropriate antimicrobials in patients with severe infections due to gram-negative and gram-positive bacteria.4,12,77,85,90-97 In all but one study,97 appropriate antibiotic therapy was associated with a better outcome Such studies are likely to involve special groups of organisms that are known to be less virulent: thus their role as pathogens is difficult to substantiate This would include organisms such as coagulase-negative staphylococci and enterococci, in which there is controversy concerning either the diagnosis or attributable mortality and which are intrinsically less virulent organisms than gram-negative rods or Staphylococcus aureus The study by Ibrahim et al.77 of patients with bacteraemia in critical care units showed those treated inadequately with antimicrobials fared far worse than those treated adequately (mortality 61.9% vs 28.4%, P