Yearbook of Intensive Care and Emergency Medicine Edited by J.-L. Vincent 2009 Yearbook of Intensive Care and Emergency Medicine 2009 Edited by J.-L. Vincent With 172 Figures and 96 Tables Prof. Jean-Louis Vincent Head, Department of Intensive Care Erasme Hospital, Université libre de Bruxelles Route de Lennik 808, B-1070 Brussels, Belgium ISBN 978-3-540-92275-9 Springer-Verlag Berlin Heidelberg New York ISSN 0942-5381 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. 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Typesetting: FotoSatz Pfeifer GmbH, D-82166 Gräfelfing Printing: Stürtz GmbH, D-97080 Würzburg 21/3150 – 5 4 3 2 1 0 – Printed on acid-free paper V Table of Contents I Genomics and Proteomics Rethinking Sepsis: New Insights from Gene Expression Profiling Studies B.M. Tang, S.J. Huang, and A.S. McLean . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Mitochondrial Genetics and Sepsis A. Pyle, P. Chinnery, and S. Baudouin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Lung Proteomics in Intensive Care E. Kipnis and K. Hansen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 II Inflammatory Response The Host Response to Sepsis T.J. Hommes, W.J. Wiersinga, and T. van der Poll . . . . . . . . . . . . . . . . . . . . 39 Endotoxin Tolerance: Mechanisms and Clinical Applicability A. Draisma, J.G. van der Hoeven, and P. Pickkers . . . . . . . . . . . . . . . . . . . . 51 Oxidative Stress and Endothelial Dysfunction during Sepsis O. Huet, A. Harrois, and J. Duranteau . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Measurement of Carbon Monoxide: From Bench to Bedside F. Corrêa, F.E. Nacul, and Y. Sakr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Monitoring Immune Dysfunction in Septic Patients: Toward Tailored Immunotherapy F. Venet, A. Lepape, and G. Monneret . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 III Current and Future Management of Sepsis Source Control in the ICU J.J. De Waele, M.M.L.G. Malbrain, and I.E. De laet . . . . . . . . . . . . . . . . . . . 93 IgM-enriched Immunoglobulins in Sepsis F. Esen and S. Tugrul . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 Clarithromycin: A Promising Immunomodulator in Sepsis E.J. Giamarellos-Bourboulis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 High-flow Hemofiltration as an Adjunctive Therapy in Sepsis P.M. Honoré, O. Joannes-Boyau, and W. Boer . . . . . . . . . . . . . . . . . . . . . . . . . 119 Economic and Social Burden of Severe Sepsis E. Silva and D.V. Araujo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 VI Table of Contents IV Proposed Targets for New Therapies Lymphocyte Apoptosis in Sepsis and Potential Anti-apoptotic Strategies S. Weber, B. Baessler, and S. Schroeder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 The Pivotal Role of Beta-adrenoreceptors in Critical Illness Pathophysiology G.L. Ackland and A.J. Patterson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Non-septic Acute Lung Injury and Inflammation: Role of TLR4 E. Lorne, H. Dupont, and E. Abraham . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Hydrogen Sulfide: A Metabolic Modulator and a Protective Agent in Animal Models of Reperfusion Injury C. Szabó, P. Asfar, and P. Radermacher . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 V Septic Shock ‘Myocardial Depression’ or ‘Septic Cardiomyopathy’ K. Werdan, A. Oelke, and U. Müller-Werdan . . . . . . . . . . . . . . . . . . . . . . . . 183 Determinants of Tissue PCO2 in Shock and Sepsis: Relationship to the Microcirculation A. Dubin, V.S.K. Edul, and C. Ince . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Refining the Tools for Early Goal-directed Therapy in Septic Shock E. Kipnis, E. Robin and B. Vallet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 VI Intravenous Fluids Hyperchloremic Metabolic Acidosis: More than Just a Simple Dilutional Effect S.S. Abdel-Razeq and L.J. Kaplan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 Old versus New Starches: What do We Know about their Differences? C. Hartog, F.M. Brunkhorst, and K. Reinhart . . . . . . . . . . . . . . . . . . . . . . . 233 Impact of Hydroxethyl Starch on Renal Function G. Marx, L. Hüter, and T. Schuerholz . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 Rational Approach to Fluid Therapy in Acute Diabetic Ketoacidosis J. Ochola and B. Venkatesh . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 VII Hemodynamic Support Cardiac Filling Volumes and Pressures in Assessing Preload Responsiveness during Fluid Challenges R.-M.B.G.E. Breukers, R.J. Trof, and A.B.J. Groeneveld . . . . . . . . . . . . . . . 265 Update on Preload Indexes: More Volume than Pressure G. Della Rocca, M.G. Costa, and L. Spagnesi . . . . . . . . . . . . . . . . . . . . . . . . 275 Monitoring Arterial Blood Pressure and Cardiac Output using Central or Peripheral Arterial Pressure Waveforms J. Smith, L. Camporota, and R. Beale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 Intrathoracic Pressure Regulation for the Treatment of Hypotension I. Cinel, A. Metzger, and R.P. Dellinger . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Functional Hemodynamic Monitoring: A Personal Perspective M.R. Pinsky . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 Table of Contents VIII Airway Management Endotracheal Intubation in the ICU S. Jaber, B. Jung, and G. Chanques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Pediatric Advanced Airway Management Training for Non-anesthesia Residents A. Nishisaki, V.M. Nadkarni, and R.A. Berg . . . . . . . . . . . . . . . . . . . . . . . . . . 322 Automatic Tube Compensation in the Weaning Process J. Cohen, M. Shapiro, and P. Singer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 IX Mechanical Ventilation Extracorporeal Membrane Oxygenation for Cardiac and Pulmonary Indications: Improving Patient Safety R. Kopp, S. Leonhardt, and S. Kowalewski . . . . . . . . . . . . . . . . . . . . . . . . . . . 341 Patient-ventilator Interaction during Non-invasive Ventilation P. Jolliet, D. Tassaux, and L. Vignaux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350 Variable Mechanical Ventilation: Breaking the Monotony M. Gama de Abreu, P.M. Spieth, and P. Pelosi . . . . . . . . . . . . . . . . . . . . . . . . 359 Life-threatening Asthma: Focus on Lung Protection H. Quiroz Martı́nez and N.D. Ferguson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372 X Respiratory Monitoring Bedside Monitoring of Diaphragm Electrical Activity during Mechanical Ventilation C. Sinderby, L. Brander, and J. Beck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385 Electrical Impedance Tomography E.L.V. Costa, R. Gonzalez Lima, and M.B.P. Amato . . . . . . . . . . . . . . . . . . . . 394 Regional Ventilation Delay Index: Detection of Tidal Recruitment using Electrical Impedance Tomography T. Muders, H. Leupschen, and C. Putensen . . . . . . . . . . . . . . . . . . . . . . . . . . 405 Different Approaches to the Analysis of Volumetric Capnography F. Suarez Sipmann, S.H. Böhm, and G. Tusman . . . . . . . . . . . . . . . . . . . . . . . . 413 Variation in Extravascular Lung Water in ALI/ARDS Patients using Open Lung Strategy F.J. Belda, G. Aguilar, and C. Ferrando . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424 Clinical Utility of Extravascular Lung Water Measurements X. Monnet and J.-L. Teboul . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 XI Perioperative Management Rationalizing the Use of Surgical Critical Care: The Role of Cardiopulmonary Exercise Testing S.J. Davies and R.J.T. Wilson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445 Advanced Minimally Invasive Hemodynamic Monitoring of the High-risk Major Surgery Patient D.W. Green . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 VII VIII Table of Contents Post-pneumonectomy Pulmonary Edema D. Cook, E. Powell, and F. Gao-Smith . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473 The Role of Phenylephrine in Perioperative Medicine C. Ertmer, A. Morelli, and M. Westphal . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483 Role of the Calcium Sensitizer, Levosimendan, in Perioperative Intensive Care Medicine S. Rehberg, P. Enkhbaatar, and D.L. Traber . . . . . . . . . . . . . . . . . . . . . . . . . 498 Inhaled Nitric Oxide Therapy in Adult Cardiac Surgery B.C. Creagh-Brown and T.W. Evans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511 XII Cardiac Function Use of Natriuretic Peptides in the Emergency Department and the ICU T. Reichlin, M. Noveanu, and C. Mueller . . . . . . . . . . . . . . . . . . . . . . . . . . . 523 Abnormalities of the ST Segment D. Gallo, J.M. Pines, and W. Brady . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531 Functional Mitral Regurgitation in the Critically Ill J. Poelaert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543 XIII Cardiopulmonary Resuscitation Feedback to Improve the Quality of CPR J. Yeung, J. Soar, and G.D. Perkins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555 The Post-cardiac Arrest Syndrome J.P. Nolan and R.W. Neumar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565 Use of a Standardized Treatment Protocol for Post-cardiac Resuscitation Care M.A. Kuiper, P.E. Spronk, and M.J. Schultz . . . . . . . . . . . . . . . . . . . . . . . . . . . 575 Therapeutic Hypothermia after Cardiac Arrest G. Ristagno and W. Tang . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589 XIV Renal Function Biomarkers of Acute Kidney Injury in Critical Illness F. Adams and B. Venkatesh . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603 The Role of Biomarkers in Cardiac Surgery-associated Acute Kidney Injury A. Shaw, M. Stafford-Smith, and M. Swaminathan . . . . . . . . . . . . . . . . . . . 612 Neutrophil Gelatinase-associated Lipocalin: An Emerging Biomarker for Angina Renalis P. Devarajan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620 XV Hepatosplanchnic Function How does Intra-abdominal Pressure Affect the Daily Management of My Patients? I.E. De laet, J.J. De Waele, and M.L.N.G. Malbrain . . . . . . . . . . . . . . . . . . . 629 ICG Clearance Monitoring in ICU Patients E. Levesque and F. Saliba . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646 Table of Contents Acute-on-chronic Liver Failure in Cirrhosis: Defining and Managing Organ Dysfunction D. Shawcross and J. Wendon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 658 XVI Nutrition The Curse of Overfeeding and the Blight of Underfeeding N.-H.W. Loh and R.D. Griffiths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675 Enteral Feeding during Circulatory Failure: Myths and Reality M.M. Berger and R.L. Chiolero . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683 Enteral Nutrition with Anti-inflammatory Lipids in ALI/ARDS A. Pontes-Arruda and S.J. DeMichele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695 Glutamine Supplementation in ICU Patients A. Berg, O. Rooyackers, and J. Wernerman . . . . . . . . . . . . . . . . . . . . . . . . . . 705 XVII Glucose Control Burn Causes Prolonged Insulin Resistance and Hyperglycemia G.G. Gauglitz and M.G. Jeschke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719 Glucose Variability in Critically Ill Patients N.A. Ali, J.S. Krinsley, and J.-C. Preiser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728 XVIII Adrenal Function Corticosteroid Biology in Critical Illness: Modulatory Mechanisms and Clinical Implications M. Williams and D.K. Menon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741 Corticosteroid Treatment of Patients in Septic Shock C.L. Sprung, S. Goodman, and Y.G. Weiss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753 XIX Coagulation New Anticoagulants: Anti-IIa or Anti-Xa Agents? C.M. Samama . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 763 Emergency Reversal of Anticoagulants M. Levi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769 XX Neurological Aspects The Role of Imaging in Acute Brain Injury R.D. Stevens, A. Pustavoitau, and P. van Zijl . . . . . . . . . . . . . . . . . . . . . . . . 783 Monitoring and Managing Raised Intracranial Pressure after Traumatic Brain Injury M. Smith . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801 Sepsis-associated Encephalopathy S. Siami, A. Polito, and T. Sharshar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809 IX X Table of Contents XXI Malignancies Acute Tumor Lysis Syndrome: Diagnosis and Management M. Darmon, M. Roumier, and E. Azoulay . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819 Life-threatening Neurological Complications in Patients with Malignancies S. Legriel and E. Azoulay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 828 Should We Admit Critically Ill Cancer Patients to the ICU? D.D. Benoit, P.O. Depuydt, and J.M. Decruyenaere . . . . . . . . . . . . . . . . . . . . 845 XXII Drug Dosing Optimizing Drug Dosing in the ICU X. Liu, P. Kruger, and M.S. Roberts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859 Relevant CYP450-mediated Drug Interactions in the ICU I. Spriet and W. Meersseman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870 XXIII Sedation and Analgesia Sedation and Pain Management in the ICU M.A. Mirski and J.J. Lewin III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881 The Role of Dexmedetomidine in Intensive Care R. Rahman West, A. Rhodes, and R.M. Grounds . . . . . . . . . . . . . . . . . . . . . . 906 Monitoring Delirium in the ICU M. Seeling, A. Heymann, and C. Spies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915 XXIV ICU Management Intensive Care for the Elderly: Current and Future Concerns H. Wunsch, A.T. Jones, and D.C. Scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935 ICU Performance: Managing with Balanced Scorecards K. Shukri and F.S.M. Ali . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 944 XXV End-of-Life Issues Towards a Neuro-scientific Explanation of Near-death Experiences? A. Vanhaudenhuyse, M. Thonnard, and S. Laureys . . . . . . . . . . . . . . . . . . . 961 Managing Conflict at the End-of-Life K. Hillman and J. Chen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969 Strengths and Weaknesses of Substitute Decision Making in the ICU A. Lautrette, E. Azoulay, and B. Souweine . . . . . . . . . . . . . . . . . . . . . . . . . . 979 Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989 XI List of Contributors Abdel-Razeq SS Section of Trauma, Surgical Critical Care, and Surgical Emergencies Yale University School of Medicine 330 Cedar Street, BB-310 New Haven, CT 06520 USA Abraham E Department of Medicine University of Alabama at Birmingham BDB 420, 1530 3rd Avenue S Birmingham, AL 35294–0012 USA Ackland GL Department of Anesthesia Stanford University Medical Center 300 Pasteur Drive Stanford, CA 94305 USA Adams F Department of Intensive Care Princess Alexandra Hospital Ipswich Road Brisbane, QLD 4102 Australia Aguilar G Department of Anesthesiology and Critical Care Hospital Clinico Universitario de Valencia Avenida Blasco Ibanez 17 46010 Valencia Spain Ali FSM Department of Emergency Medicine King Fahad Specialist Hospital PO Box 15215 Dammam 31444 Saudi Arabia Ali NA Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine Department of Internal Medicine 201G DHLRI Columbus, OH 43210 USA Amato MBP Respiratory Intensive Care Unit University of Sao Paulo School of Medicine Av Dr Arnaldo 455 01246–903 Sao Paulo, SP Brazil Araujo DV Department of Internal Medicine Medical Sciences School Universidade do Estado do Rio de Janeiro Rio de Janeiro Brazil Asfar P Department of Intensive Care and Hyperbaric Medicine Centre Hospitalo-Universitaire Rue Dominique Larrrey 49933 Angers France XII List of Contributors Azoulay E Department of Intensive Care Hôpital Saint-Louis 1 Avenue Claude Vellefaux 75010 Paris France Baessler B Department of Anesthesiology and Intensive Care University of Bonn Sigmund-Freud-Str. 25 53105 Bonn Germany Baudouin S Department of Anesthesia Royal Victoria Infirmary Queen Victoria Road Newcastle upon Tyne, NE2 4HH United Kingdom Beale R Department of Adult Critical Care Guy’s and St Thomas’ NHS Foundation Trust St Thomas’ Hospital, 1st Floor East Wing Westminster Bridge Road London, SE1 7EH United Kingdom Berg A Department of Anesthesia and Intensive Care Karolinska Institute Huddinge University 14186 Stockholm Sweden Berg RA Department of Anesthesiology and Critical Care The Children’s Hospital of Philadelphia 34th Street and Civic Center Boulevard Philadelphia, PA 19104 USA Berger MM Department of Adult Intensive Care and Burns Centre Hospitalier Universitaire Vaudois Rue du Bugnon 47 1011 Lausanne Switzerland Boer W Department of Nephrology Atrium Medical Center 6410 CX Heerlen Netherlands Beck J Department of Pediatrics St Michael’s Hospital 30 Bond Street Toronto, ON M5B 1W8 Canada Böhm SH CSEM Nanomedicine Division Research Centre for Nanomedicine Schulstrasse 1 7302 Landquart Switzerland Belda FJ Department of Anesthesiology and Critical Care Hospital Clinico Universitario de Valencia Avenida Blasco Ibanez 17 46010 Valencia Spain Brady W Department of Emergency Medicine University of Virginia Health System 1215 Lee Street Charlottesville, VA 22908–0699 USA Benoit DD Department of Intensive Care Ghent University Hospital De Pintelaan 185 9000 Ghent Belgium Brander L Department of Intensive Care University Hospital Inselspital 30110 Bern Switzerland List of Contributors Breukers RMBGE Department of Intensive Care VU University Medical Center De Boelelaan 1117 1081 HV Amsterdam Netherlands Brunkhorst FM Department of Anesthesiology and Intensive Care Friedrich-Schiller University Erlanger Allee 101 07743 Jena Germany Camporota L Department of Adult Critical Care Guy’s and St Thomas’ NHS Foundation Trust St Thomas’ Hospital, 1st Floor East Wing Westminster Bridge Road London, SE1 7EH United Kingdom Chiolero RL Department of Adult Intensive Care and Burns Centre Hospitalier Universitaire Vaudois Rue du Bugnon 47 1011 Lausanne Switzerland Cinel I Department of Critical Care Cooper University Hospital One Cooper Plaza Dorrance Building, Suite 393 Camden, NJ 08103 USA Cohen J General Intensive Care Unit Rabin Medical Center Campus Beilinson Petah Tikva 49100 Israel Chanques G Intensive Care Unit, Department of Anesthesiology (DAR B) CHU, Hôpital Saint Eloi 80 avenue Augustin Fiche 34295 Montpellier Cedex 5 France Cook D Department of Anesthesia, Critical Care and Pain Birmingham Heartlands Hospital Bordesley Green East Birmingham, B9 5SS United Kingdom Chen J The Simpson Center for Health Systems Research Liverpool Hospital Locked Bag 7103 Liverpool BC, NSW 1871 Australia Corrêa F Department of Anesthesiology and Intensive Care Friedrich-Schiller University Erlanger Allee 103 07743 Jena Germany Chinnery P Mitochondrial Research Group Institute of Ageing and Health Newcastle University Newcastle upon Tyne, NE2 4HH United Kingdom Costa ELV Respiratory Intensive Care Unit University of Sao Paulo School of Medicine Av Dr Arnaldo 455 01246–903 Sao Paulo, SP Brazil XIII XIV List of Contributors Costa MG Department of Anesthesia and Intensive Care Azienda Ospedaliero-Universitaria S.M. della Misericordia P.le S. M. Misericordia 15 33100 Udine Italy Creagh-Brown BC Department of Critical Care Royal Brompton Hospital Sydney Street London, SW3 6NP United Kingdom Darmon M Department of Intensive Care Hôpital Saint-Louis 1 Avenue Claude Vellefaux 75010 Paris France Davies SJ Department of Anesthetics York Hospital Wigginton Road York, YO31 8HE United Kingdom Decruyenaere JM Department of Intensive Care Ghent University Hospital De Pintelaan 185 9000 Ghent Belgium De laet IE Department of Intensive Care ZNA Stuivenberg Lange Beeldekensstraat 267 2060 Antwerp Belgium Della Rocca G Department of Anesthesia and Intensive Care Azienda Ospedaliero-Universitaria S.M. della Misericordia P.le S. M. Misericordia 15 33100 Udine Italy Dellinger RP Department of Critical Care Medicine Cooper University Hospital One Cooper Plaza Dorrance Building, Suite 393 Camden, NJ 08103 USA DeMichele SJ Strategic and International R & D Abbott Nutrition 3300 Stelzer Road Columbus, OH 43219 USA Depuydt PO Department of Intensive Care Ghent University Hospital De Pintelaan 185 9000 Ghent Belgium Devarajan P Department of Nephrology and Hypertension Cincinnati Children’s Hospital Medical Center University of Cincinnati 3333 Burnet Avenue Cincinnati, OH 45229–3039 USA De Waele JJ Surgical Intensive Care Unit Ghent University Hospital De Pintelaan 185 9000 Ghent Belgium Draisma A Department of Intensive Care Radboud University Nijmegen Medical Center PO Box 9101 6500 HB Nijmegen Netherlands Dubin A Unit of Applied Pharmacology Faculty of Medical Science La Plata National University 1900 La Plata, Buenos Aires Argentina List of Contributors Dupont H Department of Anesthesiology and Intensive Care Centre Hospitalier Universitaire d’Amiens Place Victor Pauchet 80054 Amiens Cedex France Duranteau J Department of Anesthesiology and Surgical Intensive Care CHU de Bicêtre 78 rue du Général Leclerc 94275 Le Kremlin Bicêtre Cedex France Edul VSK Unit of Applied Pharmacology Faculty of Medical Science La Plata National University 1900 La Plata, Buenos Aires Argentina Enkhbaatar P Investigational Intensive Care Unit Department of Anesthesiology The University of Texas Medical Branch 301 University Blvd Galveston, TX 77555–0833 USA Ertmer C Department of Anesthesiology and Intensive Care University Hosptial of Münster Albert-Schweitzer-Str. 33 48149 Münster Germany Esen F Department of Anesthesiology and Intensive Care Medical Faculty of Istanbul University of Istanbul Capa Klinikleri 34093 Istanbul Turkey Evans TW Department of Critical Care Royal Brompton Hospital Sydney Street London, SW3 6NP United Kingdom Ferguson ND Toronto Western Hospital 399 Bathurst Street, 2MCL-411M Toronto, ON M5T 2S8 Canada Ferrando C Department of Anesthesiology and Critical Care Hospital Clinico Universitario de Valencia Avenida Blasco Ibanez 17 46010 Valencia Spain Gabriella C Department of Anesthesia and Intensive Care Azienda Ospedaliero-Universitaria S.M. della Misericordia P.le S. M. Misericordia 15 33100 Udine Italy Gallo D Department of Emergency Medicine University of Virginia Health System 1215 Lee Street Charlottesville, VA 22908–0699 USA Gama de Abreu M Department of Anesthesiology and Intensive Care University Hospital Carl Gustav Carus Fetscherstr. 74 01307 Dresden Germany Gao-Smith F Department of Anesthesia, Critical Care and Pain Birmingham Heartlands Hospital Bordesley Green East Birmingham, B9 5SS United Kingdom XV XVI List of Contributors Gauglitz GG Department of Dermatology and Allergology Ludwig Maximilians University Frauenlobstrasse 9–11 80337 Munich Germany Grounds RM Department of Anesthesiology and Intensive Care Friedrich-Schiller-University Erlanger Allee 101 07743 Jena Germany Giamarellos-Bourboulis EJ 4th Department of Internal Medicine Attikon University Hospital 1 Rimini Street Athens, 124 62 Greece Hansen K Cancer Center Proteomics Core University of Colorado Denver UCD Anschutz Medical Campus, RC-1 South, L18–1303 PO Box 6511, Campus Box 8119 Aurora, CO 80045 USA Gonzalez Lima R Department of Mechanical Engineering Escola Politecnica University of Sao Paulo Av Prof Melo Moraes 2231 05508–030 Sao Paulo, SP Brazil Goodman S General Intensive Care Unit Department of Anesthesiology and Critical Care Hadassah Hebrew University Medical Center PO Box 12000 Jerusalem, 91120 Israel Green DW Department of Anesthesiology King’s College Hospital Denmark Hill London, SE5 9RS United Kingdom Griffiths RD Pathophysiology Unit School of Clinical Sciences University of Liverpool Liverpool, L69 3GA United Kingdom Groeneveld ABJ Department of Intensive Care VU University Medical Center De Boelelaan 1117 1081 HV Amsterdam Netherlands Harrois A Department of Anesthesia and Surgical Intensive Care CHU de Bicêtre 78 rue du Général Leclerc 94275 Le Kremlin Bicêtre Cedex France Hartog C Department of Anesthesiology and Intensive Care Friedrich-Schiller University Erlanger Allee 101 07743 Jena Germany Heymann A Department of Anesthesiology and Intensive Care Campus Charité Mitte und Campus Virchow-Klinikum Charité-Universitätsmedizin Berlin Augustenburger Platz 1 13353 Berlin Germany Hillman K The Simpson Center for Health Systems Research Liverpool Hospital Locked Bag 7103 Liverpool BC, NSW 1871 Australia List of Contributors Hommes TJ Academic Medical Center University of Amsterdam Meibergdreef 9, G2–129 1105 AZ Amsterdam Netherlands Jeschke MG Galveston Burns Unit Shriners Hospitals for Children 815 Market Street Galveston, TX 77550 USA Honoré PM Department of Intensive Care St-Pierre Para-Universitary Hospital Avenue Reine Fabiola 9 1340 Louvain-la-Neuve Belgium Joannes-Boyau O Department of Anesthesia and Intensive Care II University of Bordeaux II 33600 Pessac France Huang SJ Department of Intensive Care Nepean Clinical School University of Sydney Sydney, NSW 2750 Australia Jolliet P Department of Intensive Care University Hospital 1211 Geneva 14 Switzerland Huet O Department of Anesthesia and Surgical Intensive Care CHU de Bicêtre 78 rue du Général Leclerc 94275 Le Kremlin Bicêtre Cedex France Hüter L Department of Anesthesiology and Intensive Care Friedrich Schiller University Erlanger Allee 101 07740 Jena Germany Ince C Department of Translational Physiology Academic Medical Center University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam Netherlands Jaber S Intensive Care Unit, Department of Anesthesiology CHU, Hôpital Saint Eloi 80 avenue Augustin Fiche 34295 Montpellier Cedex 5 France Jones AT Department of Intensive Care Medicine St Thomas Hospital Westminster Bridge Road London, SE17 EH United Kingdom Jung B Intensive Care Unit, Department of Anesthesiology CHU, Hôpital Saint Eloi 80 avenue Augustin Fiche 34295 Montpellier Cedex 5 France Kaplan LJ Section of Trauma, Surgical Critical Care, and Surgical Emergencies Yale University School of Medicine 330 Cedar Street, BB-310 New Haven, CT 06520 USA Kipnis E Department of Surgical Intensive Care Hôpital Huriez Centre Hospitalier Régional Universitaire de Lille 1 rue Michel Polonovski 59037 Lille France XVII XVIII List of Contributors Kopp R Department of Surgical Intensive Care RWTH Aachen University 52074 Aachen Germany Kowalewski S Chair of Computer Science 11 RWTH Aachen University 52074 Aachen Germany Krinsley JS Department of Critical Care Stamford Hospital Columbia University College of Physicians and Surgeons 190 W Broad St. Stamford, CT 06902 USA Legriel S Department of Intensive Care Hôpital André Mignot 177 rue de Versaille 78150 Le Chesnay France Leonhardt S Philips Chair of Medical Information Technology RWTH Aachen University 52074 Aachen Germany Lepape A Intensive Care Unit Centre Hospitalier Lyon-Sud Chemin du Grand Revoyet 69495 Pierre-Benite France Kruger P Intensive Care Unit Princess Alexandra Hospital Ipswich Road Woolloongabba, Brisbane Australia Levesque E Department of Intensive Care Hôpital Paul Brousse 12, Av Paul Vaillant Couturier 94800 Villejuif France Kuiper MA Department of Intensive Care Medical Center Leeuwarden PO Box 888 8901 BR Leeuwarden Netherlands Levi M Department of Medicine (F-4) Academic Medical Center University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam Netherlands Laureys S Coma Science Group Cyclotron Research Centre University of Liège Sart-Tilman-B30 4000 Liège Belgium Lautrette A Department of Nephrology and Intensive Care CHU Gabriel Montpied 58 rue Montalembert 63000 Clermont-Ferrand France Lewin III JJ The Johns Hopkins Medical Institutions 600 N. Wolfe Street Carnegie 180 Baltimore, MD 21287–6180 USA Liu X Therapeutics Research Unit Princess Alexandra Hospital Ipswich Road Woolloongabba, Brisbane, QLD 4102 Australia List of Contributors Loh NHW Pathophysiology Unit School of Clinical Sciences University of Liverpool Liverpool, L69 3GA United Kingdom Menon DK Division of Anesthesia University of Cambridge Addenbrooke’s Hospital Cambridge, CB2 2QQ United Kingdom Lorne E INSERM ERI-12 Université Jules Verne de Picardie Centre Hospitalier Universitaire d4amiens Place Victor Pauchet 80054 Amiens Cedex France Metzger A Department of Critical Care Cooper University Hospital One Cooper Plaza Dorrance Building, Suite 393 Camden, NJ 08103 USA Luepschen H Department of Anesthesiology and Intensive Care University of Bonn Sigmund Freud Strasse 25 53105 Bonn Germany Malbrain MMLG Department of Intensive Care ZNA Stuivenberg Lange Beeldekensstraat 267 2060 Antwerp Belgium Marx G Department of Intensive Care University Hospital RWTH Aachen Pauwelsstr. 30 52074 Aachen Germany McLean AS Department of Intensive Care Nepean Clinical School University of Sydney Sydney NSW 2750 Australia Meersseman W Medical Intensive Care Unit University Hospital Herestraat 49 3000 Leuven Belgium Mirski MA Department of Anesthesiology and Critical Care Division of Neuroanesthesia/ Neurosciences Critical Care The Johns Hopkins Hospital 600 N. Wolfe Street, Meyer 8–140 Baltimore, MD 21287 USA Monneret G Flow Cytometry Unit Immunology Laboratory Hôpital E. Herriot 5 Place d’Arsonval 69437 Lyon cedex 03 France Monnet X Department of Medical Intensive Care Hôpital de Bicêtre 78 rue du Général Leclerc 94270 Le Kremlin-Bicêtre France Morelli A Department of Anesthesiology and Intensive Care University of Rome „La Sapienza” Viale del Policlinico 155 00161 Rome Italy XIX XX List of Contributors Muders T Department of Anesthesiology and Intensive Care University of Bonn Sigmund Freud Strasse 25 53105 Bonn Germany Nishisaki A Department of Anesthesiology and Critical Care The Children’s Hospital of Philadelphia 34th Street and Civic Center boulevard Philadelphia, PA 19104 USA Mueller C Department of Medicine University Hospital Petersgraben 4 4031 Basel Switzerland Nolan JP Department of Anesthesiology and Intensive Care Royal United Hospital Combe Park Bath, BA1 3NG United Kingdom Müller-Werdan U Department of Medicine III Universitätsklinikum Halle Martin-Luther-University Halle-Wittenberg Ernst-Grube-Str. 40 06097 Halle/Saale Germany Nacul FE Department of Anesthesiology and Intensive Care Friedrich-Schiller University Erlanger Allee 103 07743 Jena Germany Nadkarni VM Department of Anesthesiology and Critical Care The Children’s Hospital of Philadelphia 34th Street and Civic Center Boulevard Philadelphia, PA 19104 USA Neumar RW Department of Emergency Medicine University of Pennsylvania School of Medicine Hospital of the University of Pennsylvania 3400 Spruce Street Philadelphia, PA 19104–4283 USA Noveanu M Department of Medicine University Hospital Petersgraben 4 4031 Basel Switzerland Ochola J Department of Intensive Care Princess Alexandra Hospital 199 Ipswich Road Brisbane, QLD 4102 Australia Oelke A Department of Medicine III Universitätsklinikum Halle Martin-Luther-University Halle-Wittenberg Ernst-Grube-Str. 40 06097 Halle/Saale Germany Patterson AJ Department of Anesthesia Stanford University Medical Center 300 Pasteur Drive Stanford, CA 94305 USA List of Contributors Pelosi P Department of Ambient Health and Safety Service of Anesthesia B Ospedale di Circolo University of Insubria Viale Borri 57 21100 Varese Italy Perkins GD Warwick Medical School Clinical Trials Unit University of Warwick Warwick, CV4 7AL United Kingdom Pickkers P Department of Intensive Care Radboud University Nijmegen Medical Center PO Box 9101 6500 HB Nijmegen Netherlands Pines JM Department of Emergency Medicine University of Philadelphia Pennsylvania School of Medicine Philadelphia, PA 19104–4283 USA Pinsky MR Department of Critical Care Medicine 606 Scaife Hall 3550 Terrace Street Pittsburgh, PA 15261 USA Poelaert J Department of Anesthesiology and Perioperative Medicine UZ Brussel Laarbeeklaan 101 1090 Brussels Belgium Polito A General Intensive Care Unit Raymond Poincaré Teaching Hospital (AP-HP) 104 boulevard Raymond Poincaré 92380 Garches France Pontes-Arruda A Intensive Care Nutrition Department Fernandes Tavora Hospital Rua Ildefonso Albano 777/403 Fortaleza, Ceara 60115–000 Brazil Powell E Department of Anesthesia, Critical Care and Pain Birmingham Heartlands Hospital Bordesley Green East Birmingham, B9 5SS United Kingdom Preiser JC Department of Intensive Care Centre Hospitalier Universitaire de Liège Domaine Universitaire Sart Tilman B35 4000 Liège 1 Belgium Pustavoitau A Departments of Anesthesiology and Critical Care Johns Hopkins Hospital Meyer 8–140, 600 N. Wolfe St Baltimore, MD 21287 USA Putensen C Department of Anesthesiology and Intensive Care University of Bonn Sigmund Freud Strasse 25 53105 Bonn Germany Pyle A Mitochondrial Research Group Institute of Ageing and Health Newcastle University Newcastle upon Tyne, NE2 4HH United Kingdom Quiroz Martinez H Interdepartmental Division of Critical Care Toronto Western Hospital 399 Bathurst Street, 2MCL-411M Toronto, ON M5T 2S8 Canada XXI XXII List of Contributors Radermacher P Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung Universitätsklinikum Parkstrasse 11 89073 Ulm Germany Roberts MS Intensive Care Unit Princess Alexandra Hospital Ipswich Road Woolloongabba, Brisbane, QLD 4102 Australia Rahman West R Department of Intensive Care St George’s Hospital Blackshaw Road London, SW17 0QT United Kingdom Robin E Department of Surgical intensive Care Hôpital Huriez Centre Hospitalier Régional Universitaire de Lille 1 rue Michel Polonovski 59037 Lille France Rehberg S Investigational Intensive Care Unit Department of Anesthesiology The University of Texas Medical Branch 301 University Blvd Galveston, TX 77555–0833 USA Rooyackers O Department of Anesthesia and Intensive Care Karolinska Institute Huddinge University 14186 Stockholm Sweden Reichlin T Department of Medicine University Hospital Petersgraben 4 4031 Basel Switzerland Roumier M Department of Medical Intensive Care Hôpital Saint-Louis 1 Avenue Claude Vellefaux 75010 Paris France Reinhart K Department of Anesthesiology and Intensive Care Friedrich-Schiller University Erlanger Allee 101 07743 Jena Germany Sakr Y Department of Anesthesiology and Intensive Care Friedrich-Schiller University Erlanger Allee 103 07743 Jena Germany Rhodes A Department of Intensive Care St George’s Hospital Blackshaw Road London, SW17 0QT UK Saliba F Hepatobiliary Center Hôpital Paul Brousse 12, Av Paul Vaillant Couturier 94800 Villejuif France Ristagno G Weil Institute of Critical Care Medicine 35100 Bob Hope Drive Rancho Mirage, CA 92270 USA Samama CM Department of Anesthesiology and Intensive Care Hotel-Dieu University Hospital 1 Place du Parvis de Notre-Dame 75181 Paris Cedex 04 France List of Contributors Scales DC Department of Critical Care Sunnybrook Health Sciences Centre 2075 Bayview Avenue, Room D108 Toronto, ON M4N 3M5 Canada Schroeder S Department of Anesthesiology and Intensive Care Westküstenklinikum Heide Esmarchstrasse 50 25746 Heide Germany Schuerholz T Department of Intensive Care University Hospital RWTH Aachen Pauwelsstr. 30 52074 Aachen Germany Schultz MJ Department of Intensive Care and Laboratory of Experimental Intensive Care and Anesthesiology Academic Medical Center at the University of Amsterdam Meibergdreef 9 1105 AZ Amsterdam Netherlands Seeling M Department of Anesthesiology and Intensive Care Campus Charité Mitte und Campus Virchow-Klinikum Charité-Universitätsmedizin Berlin Augustenburger Platz 1 13353 Berlin Germany Shapiro M General Intensive Care Unit Rabin Medical Center Campus Beilinson Petah Tikva 49100 Israel Sharshar T General Intensive Care Unit Raymond Poincaré Teaching Hospital (AP-HP) 104 boulevard Raymond Poincaré 92380 Garches France Shaw A Department of Anesthesiology Duke University Medical Center Durham, NC 27710 USA Shawcross D Department of Hepatology King’s College Hospital Denmark Hill London, SE5 9RS United Kingdom Shukri K Department of Critical Care King Fahad Specialist Hospital PO Box 15215 Dammam 31444 Saudi Arabia Siami S General Intensive Care Unit Raymond Poincaré Teaching Hospital (AP-HP) 104 Boulevard Raymond Poincaré 92380 Garches France Silva E Intensive Care Unit Hospital Albert Einstein Sao Paulo, SP 05651–901 Brazil Sinderby C Department of Critical Care St Michael’s Hospital 30 Bond Street Room 4–072, Queen Wing Toronto, ON M5B 1W8 Canada XXIII XXIV List of Contributors Singer P General Intensive Care Unit Rabin Medical Center Campus Beilinson Petah Tikva 49100 Israel Smith J Department of Adult Critical Care Guy’s and St Thomas’ NHS Foundation Trust St Thomas’ Hospital, 1st Floor East Wing Westminster Bridge Road London, SE1 7EH United Kingdom Smith M Department of Neuroanesthesia and Neuroscience Critical Care The National Hospital for Neurology and Neurosurgery University College London Hospitals Queen Square London, WC1N 3BG United Kingdom Soar J Department of Anesthetics and Intensive Care Southmead Hospital North Bristol NHS Trust Bristol, BS10 5NB United Kingdom Souweine B Department of Nephrology and Medical Intensive Care CHU Gabriel Montpied 58 rue Montalembert 63000 Clermont-Ferrand France Spagnesi L Department of Anesthesia and Intensive Care Azienda Ospedaliero-Universitaria S.M. della Misericordia P.le S. M. Misericordia 15 33100 Udine Italy Spies C Department of Anesthesiology and Intensive Care Campus Charité Mitte und Campus Virchow-Klinikum Charité-Universitätsmedizin Berlin Augustenburger Platz 1 13353 Berlin Germany Spieth PM Department of Anesthesiology and Intensive Care University Hospital Carl Gustav Carus Fetscherstrasse 74 01307 Dresden Germany Spriet I Pharmacy Department University Hospital Herestraat 49 3000 Leuven Belgium Spronk PE Department of Intensive Care Gelre Hospitals (Lukas site), PO Box 9014 7300 DS Apeldoorn Netherlands Sprung CL General Intensive Care Unit Department of Anesthesiology and Critical Care Hadassah Hebrew University Medical Center PO Box 12000 Jerusalem, 91120 Israel Stafford-Smith M Department of Anesthesiology Duke University Medical Center Erwin Road Durham, NC 27710 USA List of Contributors Stevens RD Division of Neurosciences Critical Care Departments of Anesthesiology, Critical Care Medicine, Neurology and Neurosurgery Johns Hopkins Hospital Meyer 8–140, 600 N. Wolfe St Baltimore, MD 21287 USA Suarez Sipmann F Department of Critical Care Fundacion Jimenez Diaz-UTE Avda de los Reyes Catolicos 2 28010 Madrid Spain Swaminathan M Department of Anesthesiology Duke University Medical Center Erwin Road Durham, NC 27710 USA Szabó C Department of Anesthesiology The University of Texas Medical Branch 610 Texas Avenue Galveston, TX 775553 USA Tang BM Department of Intensive Care Nepean Clinical School University of Sydney Sydney NSW 2750 Australia Tang W Weil Institute of Critical Care 35100 Bob Hope Drive Rancho Mirage, CA 92270 USA Tassaux D Department of Intensive Care University Hospital 1211 Geneva 14 Switzerland Teboul JL Department of Intensive Care Hôpital de Bicêtre 78 rue du Général Leclerc 94270 Le Kremlin-Bicêtre France Thonnard M Coma Science Group Cyclotron Research Centre University of Liège Sart-Tilman-B30 4000 Liège Belgium Traber DL Investigational Intensive Care Unit Department of Anesthesiology The University of Texas Medical Branch 301 University Blvd Galveston, TX 77555–0833 USA Trof RJ Department of Intensive Care VU University Medical Center De Boelelaan 1117 1081 HV Amsterdam Netherlands Tugrul S Department of Anesthesiology and Intensive Care Medical Faculty of Istanbul University of Istanbul Capa Klinikleri 34093 Istanbul Turkey Tusman G Department of Anesthesiology Hospital Privado de Comunidad Cordoba 4545 7600 Mar del Plata Argentina Vallet B Department of Surgical Intensive Care Hôpital Huriez Centre Hospitalier Régional Universitaire de Lille 1 rue Michel Polonovski 59037 Lille France XXV XXVI List of Contributors van der Hoeven JG Department of Intensive Care Medicine Radboud University Nijmegen Medical Center PO Box 9101 6500 HB Nijmegen Netherlands Weber S Department of Anesthesiology and Intensive Care University of Bonn Sigmund-Freud-Strasse 25 53105 Bonn Germany Van der Poll T Academic Medical Center University of Amsterdam Meibergdreef 9, G2–129 1105 AZ Amsterdam Netherlands Weiss YG General Intensive Care Unit Department of Anesthesiology and Critical Care Hadassah Hebrew University Medical Center PO Box 12000 Jerusalem, 91120 Israel Vanhaudenhuyse A Coma Science Group Cyclotron Research Centre University of Liège Sart-Tilman-B30 4000 Liège Belgium van Zijl P Department of Radiology John Hopkins Hospital Baltimore, MD 21205 USA Venet F Immunology Laboratory Hôpital E. Herriot 5 Place d’Arsonval 69437 Lyon cedex 03 France Venkatesh B Department of Intensive Care Princess Alexandra & Wesley Hospitals Brisbane, QLD 4102 Australia Vignaux L Department of Intensive Care University Hospital 1211 Geneva 14 Switzerland Wendon J Liver Intensive Care Unit and Institute of Liver Studies King’s College Hospital Denmark Hill London, SE5 9RS United Kingdom Werdan K Department of Medicine III Universitätsklinikum Halle Martin-Luther-University Halle-Wittenberg Ernst-Grube-Str. 40 06097 Halle/Saale Germany Wernerman J Department of Anesthesia and Intensive Care K32 Karolinska Institute Huddinge University 14186 Stockholm Sweden Westphal M Department of Anesthesiology and Intensive Care University Hosptial of Münster Albert-Schweitzer-Str. 33 48149 Münster Germany List of Contributors XXVII Wiersinga WJ Academic Medical Center University of Amsterdam Meibergdreef 9, G2–129 1105 AZ Amsterdam Netherlands Wunsch H Department of Anesthesiology Columbia Presbyterian Medical Center 622 W 168th St, PH5–505 New York, NY 10032 USA Williams M Division of Anesthesia University of Cambridge Addenbrooke’s Hospital Cambridge, CB2 2QQ United Kingdom Yeung J Academic Department of Anesthesia, Critical Care and Pain Heart of England NHS Foundation Trust Bordesley Green East Birmingham, B9 5SS United Kingdom Wilson RJT Department of Anesthetics York Hospital Wigginton Road York, YO31 8HE United Kingdom XXVIII Common Abbreviations AKI ALI APACHE ARDS CABG COPD CPB CPP CPR CRP CT CVP DIC EEG EKG EVLW FiO2 FRC HES HSP ICG ICP ICU IL LPS MAP MAPK MRI NF-κB NO NOS PAC PAOP PEEP ROS ScvO2 SIRS SOFA SvO2 TLR TNF Acute kidney injury Acute lung injury Acute physiology and chronic health evaluation Acute respiratory distress syndrome Coronary artery bypass graft Chronic obstructive pulmonary disease Cardiopulmonary bypass Cerebral perfusion pressure Cardiopulmonary resuscitation C-reactive protein Computed tomography Central venous pressure Disseminated intravascular coagulopathy Electroencephalogram Electrocardiogram Extravascular lung water Inspired fraction of oxygen Functional residual capacity Hydroxyethyl starch Heat shock protein Indocyanine green Intracranial pressure Intensive care unit Interleukin Lipopolysaccharide Mean arterial pressure Mitogen-activated protein kinase Magnetic resonance imaging Nuclear factor-kappa B Nitric oxide Nitric oxide synthase Pulmonary artery catheter Pulmonary artery occlusion pressure Positive end-expiratory pressure Reactive oxygen species Central venous oxygen saturation Systemic inflammatory response syndrome Sequential organ failure assessment Mixed venous oxygen saturation Toll-like receptor Tumor necrosis factor Section I I Genomics and Proteomics 1 I 3 Rethinking Sepsis: New Insights from Gene Expression Profiling Studies B.M. Tang, S.J. Huang, and A.S. McLean Introduction Critically ill patients encompass an enormously heterogeneous population and, as such, therapeutic interventions, including drug therapy, can produce multiple outcomes in different patient subgroups. For example, researchers not only look for an ‘average effect’ of a drug on a typical patient, but also seek to understand individual variability. The presence of variability impacts significantly on the success of clinical trials and failure to identify this variability can result in the clinical trial being under-powdered to detect a treatment effect. For clinicians, failure to recognize variability can result in unintended toxicity or excessive harm in certain patients. Hence, understanding variability is critically important in both research and clinical practice. Nowhere is the relevance of patient variability more evident than in sepsis. Over the last two decades, numerous clinical trials have been conducted, all producing mixed results. It has been commonly observed that various patient populations responded differently to the same drug, ranging from marginal beneficial effect in some subgroups, to nil effect or increased toxicity in others. Investigators have attempted to address the heterogeneity issue by stratifying patients into groups who have different baseline mortality risk. Theoretically, identifying those patients who are most likely to respond to treatment will ensure maximal benefits and minimal harms. In the case of recombinant activated protein C (drotecogin alfa (activated)), such subgroups have been identified [1, 2]. For many other drugs, no particular subgroups were found, although investigators have long suspected patient heterogeneity was the reason for failure in these trials [3]. There is now an increased recognition that our failure to give the right treatment to the right patient reflects our current limitations in identifying and measuring heterogeneity in critically ill patients [4, 5]. In this chapter, we will redefine heterogeneity in sepsis patients using a simple conceptual model. We then review findings from recent studies that provide new insights into the sources of heterogeneity in these patients. How to Identify and Measure Heterogeneity Current methods to define patient heterogeneity in sepsis are grossly inadequate. Traditional criteria such as age, clinical settings or disease severity are commonly used to enlist patients into clinical trials. However, these are crude measures of the inherent heterogeneity of a very complex syndrome in a diverse patient population. I 4 I B.M. Tang, S.J. Huang, and A.S. McLean Although simple physiological parameters (e.g., systemic inflammatory response syndrome [SIRS] criteria), organ level indices (e.g., circulatory failure), or a combination of both (e.g., APACHE score) have been proved to be helpful in epidemiological studies, they are too non-specific as criteria to stratify patients in clinical trials. With the exception of recombinant activated protein C and anti-tumor necrosis factor (TNF) therapy, attempts to select patients based on disease severity or baseline mortality risk have consistently failed, as evidenced from analyses of clinical trials on anti-coagulant therapy, anti-inflammatory drugs, or low-dose corticosteroids [11, 12]. Investigators can also measure a vast array of physiological parameters and serum cytokines in sepsis patients. However, we do not know how these measurements relate to the observed heterogeneity, nor do we know how they can be used to predict a patient’s possible response to a new drug. Consequently, there is currently no agreed upon method to identify and measure heterogeneity in sepsis patients. Sources of Heterogeneity in Sepsis Patients The sources of heterogeneity are multiple and manifest at different levels. Study and patient level variables (e.g., trial design, disease severity) are easy to discern, as this information is readily available from published reports of clinical trials. Our current understanding of heterogeneity derives mainly from these variables [8]. While the data from these variables is useful, they represent only the tip of an iceberg (Fig. 1). The iceberg model provides a qualitative overview of the sources of heterogeneity. The complexity of the data increases progressively downwards in this model (Fig. 1). Data on organ and cellular level variables demonstrate a diverse range of complex behavior exhibited by different organs (e.g., liver vs. kidney) [9] and different cells 1. Study level Trial design, clinical settings, treatment duration 2. Patient level Age, gender, disease severity 3. Organ level Heart, lung, kidney 4. Cellular level Neutrophils, lymphocytes, endothelium 5. Molecular level Receptors, cytokines, microbial products 6. Genomic level Polymorphisms, gene-expression, proteomics Fig. 1. The iceberg model to conceptualize the sources of heterogeneity in sepsis trials. Variables on the upper levels of the model are easier to discern and study. Complexity of the data increases towards the lower levels, with most variables yet to be discovered or understood at the genomic level.