Lung Biology in Health and Disease Volume 179 Acute Respiratory Distress Syndrome

ACUTE RESPIRATORY DISTRESS SYNDROME

LUNG BIOLOGY IN HEALTH AND DISEASE Executive Editor Claude Lenfant Director, National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland 1. Immunologic and Infectious Reactions in the Lung, edited by C.H. Kirkpatrick and H.Y.Reynolds 2. The Biochemical Basis of Pulmonary Function, edited by R.G.Crystal 3. Bioengineering Aspects of the Lung, edited by J.B.West 4. Metabolic Functions of the Lung, edited by Y.S.Bakhle and J.R.Vane 5. Respiratory Defense Mechanisms (in two parts), edited by J.D.Brain, D.F.Proctor, and L.M.Reid 6. Development of the Lung, edited by W.A.Hodson 7. Lung Water and Solute Exchange, edited by N.C.Staub 8. Extrapulmonary Manifestations of Respiratory Disease, edited by E.D. Robin 9. Chronic Obstructive Pulmonary Disease, edited by T.L.Petty 10. Pathogenesis and Therapy of Lung Cancer, edited by C.C.Harris 11. Genetic Determinants of Pulmonary Disease, edited by S.D.Litwin 12. The Lung in the Transition Between Health and Disease, edited by P.T. Macklem and S.Permutt 13. Evolution of Respiratory Processes: A Comparative Approach, edited by S.C.Wood and C.Lenfant 14. Pulmonary Vascular Diseases, edited by K.M.Moser 15. Physiology and Pharmacology of the Airways, edited by J.A.Nadel

16. Diagnostic Techniques in Pulmonary Disease (in two parts), edited by M.A.Sackner 17. Regulation of Breathing (in two parts), edited by T.F.Hornbein 18. Occupational Lung Diseases: Research Approaches and Methods, edited by H.Weill and M.Turner-Warwick 19. Immunopharmacology of the Lung, edited by H.H.Newball 20. Sarcoidosis and Other Granulomatous Diseases of the Lung, edited by B.L.Fanburg 21. Sleep and Breathing, edited by N.A.Saunders and C.E.Sullivan 22. Pneumocystis carinii Pneumonia: Pathogenesis, Diagnosis, and Treatment, edited by L.S.Young 23. Pulmonary Nuclear Medicine: Techniques in Diagnosis of Lung Disease, edited by H.L.Atkins 24. Acute Respiratory Failure, edited by W.M.Zapol and K.J.Falke 25. Gas Mixing and Distribution in the Lung, edited by L.A.Engel and M. Paiva 26. High-Frequency Ventilation in Intensive Care and During Surgery, edited by G.Carlon and W.S.Howland 27. Pulmonary Development: Transition from Intrauterine to Extrauterine Life, edited by G.H.Nelson 28. Chronic Obstructive Pulmonary Disease: Second Edition, edited by T.L Petty 29. The Thorax (in two parts), edited by C.Roussos and P.T.Macklem 30. The Pleura in Health and Disease, edited by J.Chrétien, J.Bignon, and A.Hirsch 31. Drug Therapy for Asthma: Research and Clinical Practice, edited by J. W.Jenne and S.Murphy 32. Pulmonary Endothelium in Health and Disease, edited by U.S.Ryan 33. The Airways: Neural Control in Health and Disease, edited by M.A. Kaliner and P.J.Barnes 34. Pathophysiology and Treatment of Inhalation Injuries, edited by J.Loke

35. Respiratory Function of the Upper Airway, edited by O.P.Mathew and G.Sant’Ambrogio 36. Chronic Obstructive Pulmonary Disease: A Behavioral Perspective, edited by A.J.McSweeny and I.Grant 37. Biology of Lung Cancer: Diagnosis and Treatment, edited by S.T. Rosen, J.L.Mulshine, F.Cuttitta, and P.G.Abrams 38. Pulmonary Vascular Physiology and Pathophysiology, edited by E.K. Weir and J.T.Reeves 39. Comparative Pulmonary Physiology: Current Concepts, edited by S.C. Wood 40. Respiratory Physiology: An Analytical Approach, edited by H.K.Chang and M.Paiva 41. Lung Cell Biology, edited by D.Massaro 42. Heart-Lung Interactions in Health and Disease, edited by S.M.Scharf and S.S.Cassidy 43. Clinical Epidemiology of Chronic Obstructive Pulmonary Disease, edited by M.J.Hensley and N.A.Saunders 44. Surgical Pathology of Lung Neoplasms, edited by A.M.Marchevsky 45. The Lung in Rheumatic Diseases, edited by G.W.Cannon and G.A. Zimmerman 46. Diagnostic Imaging of the Lung, edited by C.E.Putman 47. Models of Lung Disease: Microscopy and Structural Methods, edited by J.Gil 48. Electron Microscopy of the Lung, edited by D.E.Schraufnagel 49. Asthma: Its Pathology and Treatment, edited by M.A.Kaliner, P.J. Barnes, and C.G.A.Persson 50. Acute Respiratory Failure: Second Edition, edited by W.M.Zapol and F.Lemaire 51. Lung Disease in the Tropics, edited by O.P.Sharma 52. Exercise: Pulmonary Physiology and Pathophysiology, edited by B.J. Whipp and K.Wasserman 53. Developmental Neurobiology of Breathing, edited by G.G.Haddad and J.P.Farber 54. Mediators of Pulmonary Inflammation, edited by M.A.Bray and W.H. Anderson

55. The Airway Epithelium, edited by S.G.Farmer and D.Hay 56. Physiological Adaptations in Vertebrates: Respiration, Circulation, and Metabolism, edited by S.C.Wood, R.E.Weber, A.R.Hargens, and R. W.Millard 57. The Bronchial Circulation, edited by J.Butler 58. Lung Cancer Differentiation: Implications for Diagnosis and Treatment, edited by S.D.Bernal and P.J.Hesketh 59. Pulmonary Complications of Systemic Disease, edited by J.F.Murray 60. Lung Vascular Injury: Molecular and Cellular Response, edited by A. Johnson and T.J.Ferro 61. Cytokines of the Lung, edited by J.Kelley 62. The Mast Cell in Health and Disease, edited by M.A.Kaliner and D.D. Metcalfe 63. Pulmonary Disease in the Elderly Patient, edited by D.A.Mahler 64. Cystic Fibrosis, edited by P.B.Davis 65. Signal Transduction in Lung Cells, edited by J.S.Brody, D.M.Center, and V.A.Tkachuk 66. Tuberculosis: A Comprehensive International Approach, edited by L.B. Reichman and E.S.Hershfield 67. Pharmacology of the Respiratory Tract: Experimental and Clinical Research, edited by K.F.Chung and P.J.Barnes 68. Prevention of Respiratory Diseases, edited by A.Hirsch, M.Goldberg, J.-P.Martin, and R.Masse 69. Pneumocystis carinii Pneumonia: Second Edition, edited by P.D. Walzer 70. Fluid and Solute Transport in the Airspaces of the Lungs, edited by R. M.Effros and H.K.Chang 71. Sleep and Breathing: Second Edition, edited by N.A.Saunders and C. E.Sullivan 72. Airway Secretion: Physiological Bases for the Control of Mucous Hypersecretion, edited by T.Takishima and S.Shimura 73. Sarcoidosis and Other Granulomatous Disorders, edited by D.G. James

74. Epidemiology of Lung Cancer, edited by J.M.Samet 75. Pulmonary Embolism, edited by M.Morpurgo 76. Sports and Exercise Medicine, edited by S.C.Wood and R.C.Roach 77. Endotoxin and the Lungs, edited by K.L.Brigham 78. The Mesothelial Cell and Mesothelioma, edited by M.-C.Jaurand and J. Bignon 79. Regulation of Breathing: Second Edition, edited by J.A.Dempsey and A.L.Pack 80. Pulmonary Fibrosis, edited by S.Hin. Phan and R.S.Thrall 81. Long-Term Oxygen Therapy: Scientific Basis and Clinical Application, edited by W.J.O’Donohue, Jr. 82. Ventral Brainstem Mechanisms and Control of Respiration and Blood Pressure, edited by C.O.Trouth, R.M.Millis, H.F.Kiwull-Schöne, and M.E.Schläfke 83. A History of Breathing Physiology, edited by D.F.Proctor 84. Surfactant Therapy for Lung Disease, edited by B.Robertson and H.W. Taeusch 85. The Thorax: Second Edition, Revised and Expanded (in three parts), edited by C.Roussos 86. Severe Asthma: Pathogenesis and Clinical Management, edited by S.J. Szefler and D.Y.M.Leung 87. Mycobacterium avium-Complex Infection: Progress in Research and Treatment, edited by J.A.Korvick and C.A.Benson 88. Alpha 1-Antitrypsin Deficiency: Biology • Pathogenesis • Clinical Manifestations • Therapy, edited by R.G.Crystal 89. Adhesion Molecules and the Lung, edited by P.A.Ward and J.C. Fantone 90. Respiratory Sensation, edited by L.Adams and A.Guz 91. Pulmonary Rehabilitation, edited by A.P.Fishman 92. Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease, edited by J.P.Derenne, W.A.Whitelaw, and T.Similowski

93. Environmental Impact on the Airways: From Injury to Repair, edited by J.Chrétien and D.Dusser 94. Inhalation Aerosols: Physical and Biological Basis for Therapy, edited by A.J.Hickey 95. Tissue Oxygen Deprivation: From Molecular to Integrated Function, edited by G.G.Haddad and G.Lister 96. The Genetics of Asthma, edited by S.B.Liggett and D.A.Meyers 97. Inhaled Glucocorticoids in Asthma: Mechanisms and Clinical Actions, edited by R.P.Schleimer, W.W.Busse, and P.M.O’Byrne 98. Nitric Oxide and the Lung, edited by W.M.Zapol and K.D.Bloch 99. Primary Pulmonary Hypertension, edited by L.J.Rubin and S.Rich 100. Lung Growth and Development, edited by J.A.McDonald 101. Parasitic Lung Diseases, edited by A.A.F.Mahmoud 102. Lung Macrophages and Dendritic Cells in Health and Disease, edited by M.F.Lipscomb and S.W.Russell 103. Pulmonary and Cardiac Imaging, edited by C.Chiles and C.E.Putman 104. Gene Therapy for Diseases of the Lung, edited by K.L.Brigham 105. Oxygen, Gene Expression, and Cellular Function, edited by L.Biadasz Clerch and D.J.Massaro 106. Beta2-Agonists in Asthma Treatment, edited by R.Pauwels and P.M. O’Byrne 107. Inhalation Delivery of Therapeutic Peptides and Proteins, edited by A.L. Adjei and P.K.Gupta 108. Asthma in the Elderly, edited by R.A.Barbee and J.W.Bloom 109. Treatment of the Hospitalized Cystic Fibrosis Patient, edited by D.M. Orenstein and R.C.Stern 110. Asthma and Immunological Diseases in Pregnancy and Early Infancy, edited by M.Schatz, R.S.Zeiger, and H.N.Claman 111. Dyspnea, edited by D.A.Mahler

112. Proinflammatory and Antiinflammatory Peptides, edited by S.I.Said 113. Self-Management of Asthma, edited by H.Kotses and A.Harver 114. Eicosanoids, Aspirin, and Asthma, edited by A.Szczeklik, R.J. Gryglewski, and J.R.Vane 115. Fatal Asthma, edited by A.L.Sheffer 116. Pulmonary Edema, edited by M.A.Matthay and D.H.Ingbar 117. Inflammatory Mechanisms in Asthma, edited by S.T.Holgate and W. W.Busse 118. Physiological Basis of Ventilatory Support, edited by J.J.Marini and A. S.Slutsky 119. Human Immunodeficiency Virus and the Lung, edited by M.J.Rosen and J.M.Beck 120. Five-Lipoxygenase Products in Asthma, edited by J.M.Drazen, S.-E. Dahlén, and T.H.Lee 121. Complexity in Structure and Function of the Lung, edited by M.P. Hlastala and H.T.Robertson 122. Biology of Lung Cancer, edited by M.A.Kane and P.A.Bunn, Jr. 123. Rhinitis: Mechanisms and Management, edited by R.M.Naclerio, S.R. Durham, and N.Mygind 124. Lung Tumors: Fundamental Biology and Clinical Management, edited by C.Brambilla and E.Brambilla 125. Interleukin-5: From Molecule to Drug Target for Asthma, edited by C.J. Sanderson 126. Pediatric Asthma, edited by S.Murphy and H.W.Kelly 127. Viral Infections of the Respiratory Tract, edited by R.Dolin and P.F. Wright 128. Air Pollutants and the Respiratory Tract, edited by D.L.Swift and W.M. Foster 129. Gastroesophageal Reflux Disease and Airway Disease, edited by M.R. Stein 130. Exercise-Induced Asthma, edited by E.R.McFadden, Jr. 131. LAM and Other Diseases Characterized by Smooth Muscle Proliferation, edited by J.Moss

132. The Lung at Depth, edited by C.E.G.Lundgren and J.N.Miller 133. Regulation of Sleep and Circadian Rhythms, edited by F.W.Turek and P.C.Zee 134. Anticholinergic Agents in the Upper and Lower Airways, edited by S.L Spector 135. Control of Breathing in Health and Disease, edited by M.D.Altose and Y.Kawakami 136. Immunotherapy in Asthma, edited by J.Bousquet and H.Yssel 137. Chronic Lung Disease in Early Infancy, edited by R.D.Bland and J.J. Coalson 138. Asthma’s Impact on Society: The Social and Economic Burden, edited by K.B.Weiss, A.S.Buist, and S.D.Sullivan 139. New and Exploratory Therapeutic Agents for Asthma, edited by M. Yeadon and Z.Diamant 140. Multimodality Treatment of Lung Cancer, edited by A.T.Skarin 141. Cytokines in Pulmonary Disease: Infection and Inflammation, edited by S.Nelson and T.R.Martin 142. Diagnostic Pulmonary Pathology, edited by P.T.Cagle 143. Particle-Lung Interactions, edited by P.Gehr and J.Heyder 144. Tuberculosis: A Comprehensive International Approach, Second Edition, Revised and Expanded, edited by L.B.Reichman and E.S. Hershfield 145. Combination Therapy for Asthma and Chronic Obstructive Pulmonary Disease, edited by R.J.Martin and M.Kraft 146. Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Disease, edited by T.D.Bradley and J.S.Floras 147. Sleep and Breathing in Children: A Developmental Approach, edited by G.M.Loughlin, J.L.Carroll, and C.L.Marcus 148. Pulmonary and Peripheral Gas Exchange in Health and Disease, edited by J.Roca, R.Rodriguez-Roisen, and P.D.Wagner 149. Lung Surfactants: Basic Science and Clinical Applications, R.H.Notter 150. Nosocomial Pneumonia, edited by W.R.Jarvis

151. Fetal Origins of Cardiovascular and Lung Disease, edited by David J.P. Barker 152. Long-Term Mechanical Ventilation, edited by N.S.Hill 153. Environmental Asthma, edited by R.K.Bush 154. Asthma and Respiratory Infections, edited by D.P.Skoner 155. Airway Remodeling, edited by P.H.Howarth, J.W.Wilson, J.Bousquet, S.Rak, and R.A.Pauwels 156. Genetic Models in Cardiorespiratory Biology, edited by G.G.Haddad and T.Xu 157. Respiratory-Circulatory Interactions in Health and Disease, edited by S. M.Scharf, M.R.Pinsky, and S.Magder 158. Ventilator Management Strategies for Critical Care, edited by N.S.Hill and M.M.Levy 159. Severe Asthma: Pathogenesis and Clinical Management, Second Edition, Revised and Expanded, edited by S.J.Szefler and D.Y.M. Leung 160. Gravity and the Lung: Lessons from Microgravity, edited by G.K.Prisk, M.Paiva, and J.B.West 161. High Altitude: An Exploration of Human Adaptation, edited by T.F. Hornbein and R.B.Schoene 162. Drug Delivery to the Lung, edited by H.Bisgaard, C.O’Callaghan, and G.C.Smaldone 163. Inhaled Steroids in Asthma: Optimizing Effects in the Airways, edited by R.P.Schleimer, P.M.O’Byrne, S.J.Szefler, and R.Brattsand 164. IgE and Anti-IgE Therapy in Asthma and Allergic Disease, edited by R. B.Pick, Jr., and P.M.Jardieu 165. Clinical Management of Chronic Obstructive Pulmonary Disease, edited by T.Similowski, W.A.Whitelaw, and J.-P.Derenne 166. Sleep Apnea: Pathogenesis, Diagnosis, and Treatment, edited by A.I. Pack 167. Biotherapeutic Approaches to Asthma, edited by J.Agosti and A.L. Sheffer 168. Proteoglycans in Lung Disease, edited by H.G.Garg, P.J.Roughley, and C.A.Hales

169. Gene Therapy in Lung Disease, edited by S.M.Albelda 170. Disease Markers in Exhaled Breath, edited by N.Marczin, S.A.Kharitonov, M.H.Yacoub, and P.J.Barnes 171. Sleep-Related Breathing Disorders: Experimental Models and Therapeutic Potential, edited by D.W.Carley and M.Radulovacki 172. Chemokines in the Lung, edited by R.M.Strieter, S.L.Kunkel, and T. J.Standiford 173. Respiratory Control and Disorders in the Newborn, edited by O.P. Mathew 174. The Immunological Basis of Asthma, edited by B.N.Lambrecht, H.C. Hoogsteden, and Z.Diamant 175. Oxygen Sensing: Responses and Adaptation to Hypoxia, edited by S. Lahiri, G.L.Semenza, and N.R.Prabhakar 176. Non-Neoplastic Advanced Lung Disease, edited by J.R.Maurer 177. Therapeutic Targets in Airway Inflammation, edited by N.T.Eissa and D.P.Huston 178. Respiratory Infections in Allergy and Asthma, edited by S.L.Johnston and N.G.Papadopoulos 179. Acute Respiratory Distress Syndrome, edited by M.A.Matthay 180. Venous Thromboembolism, edited by J.E.Dalen 181. Upper and Lower Respiratory Disease, edited by J.Corren, A.Togias, and J.Bousquet ADDITIONAL VOLUMES IN PREPARATION Acute Exacerbations of Chronic Obstructive Pulmonary Disease, edited by N.M.Siafakas, N.R.Anthonisen, and D.Georgopolous Lung Volume Reduction Surgery for Emphysema, edited by H.E. Fessler, J.J.Reilly, Jr., and D.J.Sugarbaker Idiopathic Pulmonary Fibrosis, edited by J.Lynch III Therapy for Mucus-Clearance Disorders, edited by B.K.Rubin andC. P.van der Schans Pleural Disease, edited by D.Bouros

Pharmacotherapy in Chronic Obstructive Pulmonary Disease, edited by B.R.Celli The opinions expressed in these volumes do not necessarily represent the views of the National Institutes of Health.

ACUTE RESPIRATORY DISTRESS SYNDROME Edited by

Michael A.Matthay University of California at San Francisco San Francisco, California, U.S.A.

MARCEL DEKKER, INC. NEW YORK • BASEL

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INTRODUCTION Acute respiratory distress syndrome (ARDS) first achieved recognition about 35 years ago via a landmark observation of Dr. Thomas Petty. Since that time, there have been many reports about the severity and frequency of this disease, an incidence of 150,000 to 200,000 cases a year is mentioned in many publications, but it can be argued that the actual number is greater or smaller. One of the distinctive features of ARDS is that it may result from many primordial conditions and, if the patient recovers, it may entail significant sequelae. Even the most optimistic among us recognize that ARDS is a complicated and troubling disease. Recent experience has shown that new etiologies may appear in the most unpredictable circumstances. We need only read the penultimate chapter about the SARS story to be convinced that what we know and see today will tomorrow be issues about ARDS. Since Petty’s seminal observations, clinicians and investigators have been fascinated by this disease, but the journey into discovery has been difficult and frustrating. The Lung Biology in Health and Disease series published its first volume about five years after ARDS was initially described, and the first volume devoted to acute respiratory failure appeared just a few years later. Since that time, other volumes have updated the readership on the many advances that have occurred. There is no question that our knowledge base has expanded considerably; however, we must accept the fact that the ARDS problem remains complex and elusive. The solution, of course, is in the research—and, make no mistake about it, this is clinical and risky research! That so many outstanding investigators are devoting their time and talent to researching how to improve the treatment of and recovery from this disease is a tribute to their dedication and a blessing for public health and for the patients. Dr. Matthay and all contributors to this volume are recognized experts in this area: they provide us with an outstanding report of the latest and most challenging finding on ARDS. As the Executive Editor of this series of monographs, I thank them all for the opportunity to introduce and present this new volume to the readership. Claude Lenfant, M.D. Bethesda, Maryland

PREFACE The acute respiratory distress syndrome, also known as acute lung injury, is a major cause of acute respiratory failure in critically ill patients. The syndrome was originally described by Dr. Thomas Petty in 1967 (see Dr. Petty’s overview in Chapter 1). Over the last three decades, clinical and experimental studies have evaluated the pathophysiology, pathogenesis, and treatment for clinical lung injury. During this time, remarkable progress has been made in understanding the molecular, cellular, and physiological basis for the development and resolution of acute lung injury. Furthermore, there is recent evidence that mortality in patients with acute lung injury can be reduced with a lungprotective ventilatory strategy. However, more progress is needed to fill in major gaps in our understanding of how acute lung injury develops, as well as how it resolves. This volume in the Lung Biology in Health and Disease series is designed to integrate both basic science and clinical research in order to provide a comprehensive perspective on the status of research and treatment of the acute respiratory distress syndrome and clinical acute lung injury. In Chapter 1 Dr. Petty provides an overview regarding historical aspects of the acute respiratory distress syndrome. In Chapter 2 there is a comprehensive discussion of clinical characteristics, clinical definitions, as well as the important clinical risk factors for developing acute lung injury. Chapter 3 provides an update on the epidemiology of acute lung injury. Recent data indicate that the incidence of acute lung injury is substantial, similar to the original estimate from the National Heart, Lung, and Blood Institute in 1977, approximately 150,000–200,000 patients per year in the United States alone. Chapter 4 provides an overview of radiographic characteristics, including findings from computerized axial tomography. Chapter 5 is a review of the pathological findings in clinical lung injury, including both ultrastructural and routine histological findings. The pathogenesis of acute lung injury is discussed in Chapter 6 (experimental studies) and Chapter 7 (clinical studies). Chapter 8 considers the role of apoptosis in the pathogenesis and resolution of lung injury. Important advances in understanding ventilator-induced lung injury based on both clinical and experimental studies is discussed in Chapter 9. The role of sepsis in the development of lung injury is reviewed in Chapter 10. New data are available on the potential role of heat-shock proteins in the pathophysiology of acute lung injury, a topic covered in Chapter 11. In some patients fibrosing alveolitis develops during the course of acute lung injury, a topic that is discussed in Chapter 12. A new area in research in clinical acute lung injury and the acute respiratory distress syndrome is the influence of genetic factors in determining which patients are most susceptible to the development of acute lung injury. Chapters 13 and 14 are devoted to this new topic. Chapter 15 focuses on experimental and clinical studies of the resolution of lung injury with a particular emphasis on the resolution of alveolar edema. The remaining chapters in this volume focus on issues that pertain directly to treatment. Chapter 16 considers treatment of sepsis, the most lethal cause of clinical acute

lung injury. Chapter 17 considers how pulmonary hypertension in clinical acute lung injury can be treated. Chapter 18 reviews the clinical studies of glucocorticoid therapy for the acute respiratory distress syndrome. Chapter 19 discusses clinical trials of surfactant replacement in patients with lung injury, and Chapter 20 provides an update on the potential role of prone position for the treatment of patients with clinical lung injury. Chapter 21 provides a combined American and European perspective on lung-protective strategies for patients with clinical lung injury. Chapter 22 provides a brief overview of an important new cause of viral pneumonia, severe acute respiratory syndrome (SARS), an illness that can lead to clinical acute lung injury. The final chapter provides a brief overview of selected areas in which important progress has been made as well as a perspective on potential opportunities for future research and treatment of acute lung injury. I appreciate the hard work of each of the contributors to this edition as well as the excellent editorial supervision provided by Rebecca Cleff, Moraima Suarez, Sandra Beberman, and Dr. Claude Lenfant. Michael A.Matthay

CONTRIBUTORS Kurt H.Albertine, Ph.D. Professor, Departments of Pediatrics, Medicine, and Neurobiology/Anatomy, University of Utah, Salt Lake City, Utah, U.S.A. Antonio Anzueto, M.D. Associate Professor, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, U.S.A. Gordon R.Bernard, M.D. Melinda Owen Bass Professor of Medicine and Chief, Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, U.S.A. Laurent J.Brochard, M.D. Professor, Department of Intensive Care Medicine, Université Paris 12, INSERM U 492, and Henri Mondor Hospital, Créteil, France Roy G.Brower, M.D. Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, U.S.A. Thilo Busch, Ph.D. Research Scientist, Department of Anesthesiology and Intensive Care Medicine, Charité, Campus Virchow-Klinikum, Humboldt University, Berlin, Germany David C.Christiani, M.D., M.P.H. Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Harvard Medical School, and Massachusetts General Hospital, Boston, Massachusetts, U.S.A. Christine Clerici, M.D., Ph.D. Department of Physiology, Faculté de Medicine de Bobigny, Université Paris 13, Colombes, France Maria Deja, M.D. Department of Anesthesiology and Intensive Care Medicine, Charité, Campus Virchow-Klinikum, Humboldt University, Berlin, Germany Timothy W.Evans, M.D., Ph.D. Professor, Department of Critical Care Medicine, Imperial College School of Medicine, and Royal Brompton Hospital, London, England Konrad J.Falke, M.D., Ph.D. Professor and Chairman, Department of Anesthesiology and Intensive Care Medicine, Charité, Campus Virchow-Klinikum, Humboldt University, Berlin, Germany Xiaohui Fang, M.D. Postdoctoral Research Fellow, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California, U.S.A. James A.Frank, M.D. Assistant Adjunct Professor, Division of Pulmonary and Critical Care Medicine, and the Cardiovascular Research Institute, Department of Medicine, University of California, San Francisco, San Francisco, California, U.S.A. Luciano Gattinoni, M.D., F.R.C.P. Professor, Department of Anesthesia and Intensive Care Medicine, University of Milan, and Hospital of Milan I.R.C.C.S., Milan, Italy Herwig Gerlach, M.D., Ph.D. Professor and Chairman, Departments of Anesthesiology and Critical Care Medicine, Vivantes-Klinikum Neukoelln, Berlin, Germany Michaela C.Godzich, B.A. Staff Research Associate, Department of Anesthesia, University of California, San Francisco, San Francisco, California, U.S.A.

Michelle Ng Gong, M.D. Instructor, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Harvard Medical School, and Massachusetts General Hospital, Boston, Massachusetts, U.S.A. Philip C.Goodman, M.D. Department of Radiology, Duke University Medical Center, Durham, North Carolina, U.S.A. Richard B.Goodman, M.D. Associate Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, U.S.A. Leonard D.Hudson, M.D. Professor and Endowed Chair in Pulmonary Disease Research, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, U.S.A. Yumiko Imai, M.D. Postdoctoral Research Fellow, Arthur S.Slutsky Research Laboratory, University of Toronto, and Toronto General Hospital, Toronto, Ontario, Canada Udo Kaisers, M.D. Professor and Assistant Medical Director, Department of Anesthesiology and Intensive Care Medicine, Charité, Campus Virchow-Klinikum, Humboldt University, Berlin, Germany Hyon Lee, B.A. Senior Research Associate, Department of Anesthesia, University of California, San Francisco, San Francisco, California, U.S.A. James F.Lewis, M.D., F.R.C.P.(C) Professor, Departments of Medicine and Physiology, Lawson Health Research Institute, University of Western Ontario, and St. Joseph’s Health Center, London, Ontario, Canada Nicholas David Manzo, B.S. Research Technologist, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts, U.S.A. Richard P.Marshall, M.D., M.R.C.P.(UK), Ph.D. Centre for Respiratory Research, University College London, London, England Thomas R. Martin, M.D. Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, and VA/Puget Sound Medical Center, Seattle, Washington, U.S.A. Sadis Matalon, Ph.D. Professor, Department of Physiology and Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A. Michael A.Matthay, M.D. Professor, Departments of Medicine and Anesthesia, and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California, U.S.A. Gustavo Matute-Bello, M.D. Acting Assistant Professor, Department of Medicine, University of Washington School of Medicine, and VA/Puget Sound Medical Center, Seattle, Washington, U.S.A. Thomas M.McIntyre, Ph.D. Professor of Internal Medicine and Experimental Pathology, Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah, U.S.A. Marc Moss, M.D. Associate Professor, Department of Medicine, Emory University School of Medicine, and Grady Memorial Hospital, Atlanta, Georgia, U.S.A. Margaret J.Neff, M.D., M.Sc. Assistant Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Harborview Medical Center, University of Washington, Seattle, Washington, U.S.A.

Mitchell A.Olman, M.D. Associate Professor, Division of Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A. Thomas L.Petty, M.D. Professor, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, and Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois, U.S.A. Jean-François Pittet, M.D. Associate Professor in Residence, Departments of Anesthesia and Perioperative Care and Surgery, University of California, San Francisco, San Francisco, California, U.S.A. Desirée M.Quiñones Maymí, M.D. Fellow in Thoracic Radiology, Department of Radiology, Duke University Medical Center, Durham, North Carolina, U.S.A. Gordon D.Rubenfeld, M.D., M.Sc. Associate Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Harborview Medical Center, University of Washington, Seattle, Washington, U.S.A. Tsutomu Sakuma, M.D., Ph.D. Associate Professor, Department of Thoracic Surgery, Kanazawa Medical University, Uchinada, Ishikawa, Japan Arthur S.Slutsky, M.A.Sc., M.D. Professor, Department of Medicine; Director, Interdepartmental Division of Critical Care Medicine, University of Toronto; and Vice President (Research), St. Michael’s Hospital, Toronto, Ontario, Canada Roger G.Spragg, M.D. Professor, Department of Medicine, University of California, San Diego, and San Diego VA Medical Center, San Diego, California, U.S.A. B.Taylor Thompson, M.D. Associate Professor, Department of Medicine, Harvard Medical School, and Director, Medical Intensive Care Unit, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts, U.S.A. Joseph F.Tomashefski, Jr., M.D. Professor, Department of Pathology, Case Western Reserve University School of Medicine, and Chairman, MetroHealth Medical Center, Cleveland, Ohio, U.S.A. Lorraine B.Ware, M.D. Assistant Professor, Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, U.S.A. Aaron B.Waxman, M.D., Ph.D. Assistant Professor, Department of Pulmonary and Critical Care Medicine, Harvard Medical School, and Massachusetts General Hospital, Boston, Massachusetts, U.S.A. Arthur P.Wheeler, M.D. Associate Professor, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, U.S.A. Guy A.Zimmerman, M.D. Professor, Department of Internal Medicine, and Director, Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah, U.S.A.

CONTENTS Introduction Claude Lenfant Preface Contributors

1. Overview Thomas L.Petty 2. Definitions and Clinical Risk Factors Marc Moss and B.Taylor Thompson 3. Epidemiology of Acute Lung Injury: A Public Health Perspective Gordon D.Rubenfeld and Margaret J.Neff 4. Radiographic Findings of the Acute Respiratory Distress Syndrome Desirée M.Quiñones Maymí and Philip C.Goodman 5. Pulmonary Pathology of the Acute Respiratory Distress Syndrome: Diffuse Alveolar Damage Joseph F.Tomashefski, Jr. 6. Pathogenesis of Acute Lung Injury: Experimental Studies Nicholas David Manzo and Aaron B.Waxman 7. Pathogenesis of Acute Lung Injury: Clinical Studies Lorraine B.Ware and Timothy W.Evans 8. Is Apoptosis Important in the Pathogenesis and Resolution of the Acute Respiratory Distress Syndrome? Gustavo Matute-Bello and Thomas R.Martin 9. Pathogenesis of Ventilator-Induced Lung Injury James A.Frank, Yumiko Imai, and Arthur S.Slutsky 10. Pathogenesis of Sepsis and Septic-Induced Lung Injury Guy A.Zimmerman, Kurt H.Albertine, and Thomas M.McIntyre 11. Heat Shock Response, Heat Shock Proteins, and Acute Lung Injury Hyon Lee, Michaela C.Godzich, and Jean-François Pittet 12. Mechanisms of Fibroproliferation in Acute Lung Injury Mitchell A.Olman 13. Genetic Factors in Acute Lung Injury Richard P.Marshall

xv xvi xviii

1 6 30 44 62

103 129 158

178

217

254

275 311

14. Approach to the Genetic Epidemiology of Acute Lung Injury Michelle Ng Gong and David C.Christiani 15. Resolution of Alveolar Edema: Mechanisms and Relationship to Clinical Acute Lung Injury Michael A.Matthay, Xiaohui Fang, Christine Clerici, Tsutomu Sakuma, and Sadis Matalon 16. Sepsis in the Acute Respiratory Distress Syndrome: Treatment Implications Arthur P.Wheeler and Gordon R.Bernard 17. Modulation of Pulmonary Vascular Tone in the Acute Respiratory Distress Syndrome Udo Kaisers, Thilo Busch, Maria Deja, Herwig Gerlach, and Konrad J.Falke 18. Glucocorticoid Therapy for the Acute Respiratory Distress Syndrome Richard B.Goodman and Leonard D.Hudson 19. Surfactant Therapy in the Acute Respiratory Distress Syndrome Roger G.Spragg and James F.Lewis 20. Prone Position in the Acute Respiratory Distress Syndrome Antonio Anzueto and Luciano Gattinoni 21. Mechanical Ventilation in the Acute Respiratory Distress Syndrome Roy G.Brower and Laurent J.Brochard 22. Severe Acute Respiratory Syndrome Lorraine B.Ware 23. Acute Lung Injury: Recent Progress and Promising Directions for Future Research Michael A.Matthay Index

335 357

381

402

440 459 484 507 544 555

563

ACUTE RESPIRATORY DISTRESS SYNDROME

1 Overview THOMAS L.PETTY University of Colorado Health Sciences Center Denver, Colorado and Rush-Presbyterian-St. Luke’s Medical Center Chicago, Illinois, U.S.A.

The acute respiratory distress syndrome (ARDS) remains a challenge to clinicians and basic scientists alike. Although progress has been made in management, resulting in improved survival (1), the development of effective pharmacological agents to block the basic mechanisms involved in the inflammatory process, which underlies the clinical syndrome, resulting in acute respiratory failure and often multiorgan system failure, remains to be accomplished. This is due in large part to the multiplicity of mechanisms, often redundant, that promote the inflammatory cascade (2). ARDS can be traced back to World War I during which dramatically progressive clinical catastrophes resulting in sudden collapse and respiratory deaths were observed in battlefield casualties (3). Later lung injury, with associated pulmonary edema following trauma of all types, was described as “traumatic wet lung” (4). The pathological state accompanying sudden dramatic development of acute respiratory failure was termed “congestive atelectasis” based on autopsy studies (5). The contribution of the Denver Group appeared in Lancet in 1967 (6). Ashbaugh et al. described 12 patients with a rapidly developing clinical syndrome of acute respiratory failure, characterized by tachypnea-labored breathing, refractory hypoxemia, diffuse bilateral pulmonary infiltrates, and reduced overall compliance of lungs and thorax. Five patients survived with the use of a mechanical ventilator, usually volume-cycled, and the application of positive-end expiratory pressure (7), although the Denver Group had not yet coined the term PEEP (8). The patients who died had congested lungs with collapsed alveoli, cellular debris, and hyaline membranes, which bore a remarkable resemblance to the infantile respiratory distress syndrome. A surfactant abnormality was identified in two autopsy specimens in which these studies were done. Following this report, in 1968 a national conference was held in Washington, D.C., with the Committee on Trauma of the Division of Medical Sciences, National Academy of Sciences, and National Research Council (9). All attendees at this conference presented similar descriptions of the dramatic pulmonary effects of shock and resuscitation in battlefield casualties during the Vietnam war. It was apparent to all in attendance that the observations made by military surgeons were identical to that reported by the Denver Group. Considerable discussions on the role of PEEP permeated this conference (10). Very little was known about the mechanisms involved in lung injury at this juncture. A refinement of the clinical features and factors associated with prognosis

Acute respiratory distress syndrome

2

and more details on principles of management were reported in 1971 (11). Unfortunately, the author used the word “adult” in this and several other reports. This was a mistake. The youngest patient in the series was 11 (age range 11–48 years; mean age 27.3 years). Thus, patients in this series were much younger than those in a more recent series, and certainly there was less comorbidity. In 1973, the 16th Aspen Lung Conference was devoted to ARDS (12). It dealt with a growing body of basic science that was emerging in concert with numerous clinical studies. So far, three Aspen Lung Conferences have dealt with emerging concepts of lung injury and repair in ARDS. The most recent was the 41st Conference in 1998, summarized by Matthay (13). Since that time, a remarkable number of studies have elucidated the mechanisms involved in acute lung injury. Certainly the neutrophil and its products play a role, but the macrophage, an orchestra of proinflammatory cytokines, and the effects of therapy itself on the lung (oxygen high-inflation pressures, etc.) have been added to the complex story of pathogenesis, lung injury, and repair (see Chaps. 6–10). One underlying hypothesis is that ARDS is a result of oxidative stress that is operative in a variety of inflammatory disorders, but this is probably an oversimplication (14). The role of host defenses in the progression of outcome of ARDS has also been considered (15). The involvement of other organ systems, including the kidneys, liver, the hematopoietic system, and the digestive tract, has dominated both clinical and animal model studies during the past 25 years (16). A recent state-of-the-art publication by Matthay et al. made a major contribution in bringing together the diverse concepts of mechanisms of acute lung injury and related organ system dysfunction (2). The epidemiology and risk factors associated with ARDS have been described using different definitions of risk (17, 18) (see Chap. 2). Expanded definitions of ARDS have continued to evolve (19, 20). Costs of caring for ARDS have been described and estimated to be $73,100 per survivor (21). Thus, the economic burden of costs of caring for both survivors and those who die is immense, even if the estimated 150,000 cases in the United States alone is an overestimate (20). A large, multicenter, controlled clinical trial, which showed that low tidal volume ventilation was superior to high tidal volume ventilation, not only in terms of outcome, but in a reduction of multiple organ system damage, was the first major contribution leading to improved survival (22) (see Chap. 21). The ARDS Network has provided the mechanism by which any new therapeutic maneuver, used alone or in combination, can be evaluated to gain evidence concerning the best method of management of ARDS. New approaches to supportive care using nitric oxide or the prone position for mechanical ventilation are aimed at improving oxygen transport across the lung (see Chaps. 17, 20). Preliminary studies have shown increases in oxygenation in some, but not all patients (23, 24). These treatments may be useful when all else fails. It is likely that the surfactant deficiency concept in ARDS has not been adequately addressed. There seems little doubt about surfactant abnormalities in ARDS, which of course cannot be the primary pathogenetic mechanisms but may represent a therapeutic target nonetheless. Figure 1 portrays a simplistic concept, suggesting that damage to surfactant causes alveolar instability and gradual collapse of alveolar units, thus promoting increased flooding of inflammatory pulmonary edema as a result of injury to the air/ blood interface and increased capillary and epithelial permeability (25). Since the

Overview

3

role of surfactant, briefly stated, is to keep alveolar units open, dry, and free of infection, it seems attractive to consider an attack upon the surfactant system to be the “final straw” that unleashes the cascade of events ending in diffuse, yet focal massive alveolar damage (26). Effectively replacing surfactant and restoring its function using products that include surfactant-associated proteins might well be the final defense in the battle between the forces of lung damage and the factors that can thwart a massive attack on the air/blood interface. Preliminary studies suggest that

Figure 1 Hypothesis to explain how mechanisms of capillary/endothelial injury damages or inactivates a surfactant. Alveolar stability and collapse from increased elastic recoil creates hydrostatic forces, favoring further pulmonary edema formation. (From Ref. 25.) surfactant replacement may be beneficial in the early treatment of ARDS (27, 28) (see Chap. 19). The recovery process in ARDS has not been adequately studied. The Denver group reported an encouraging outcome in a small series of survivors (29), as did others (30). More recent series have shown reduction in quality of life and exercise tolerance similar to that experienced by patients with chronic disease (30). In the author’s experience, a

Acute respiratory distress syndrome

4

return to completely normal functioning is not unusual, particularly in younger individuals without comorbidities. The role of corticosteroids in promoting alveolar repair during the fibroproliferative stages of disease is still under study. Preliminary observations comparing corticosteroids with placebo have been encouraging (31). A randomized, prospective, controlled clinical trial is currently underway seeking the definitive answer (15) (see Chap. 18). The chapters in this volume consider all of the concepts presented in this introduction. This should become the new benchmark for our understanding of the pathogenesis and treatment of this common pulmonary catastrophe, which, alas, we may face with increasing frequency as a result of man’s disregard for each other (trauma) and careless life styles.

References 1. Milberg JA, Davis DR, Steinberg KP, Hudson LD. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993. JAMA 1995; 273:306–309. 2. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342:1334– 1349. 3. Simeone FA. Pulmonary complications of nonthoracic wounds: A historical perspective. J Trauma 1968; 8:625–648. 4. Burford TH, Burbank B. Traumatic wet lung. J Thorac Surg 1945; 14:415–424. 5. Jenkins MT, Jones RF, Wilson B, Moyer CA. Congestive atelectasis—a complication of the intravenous infusion of fluids. Ann Surg 1950; 132:327–347. 6. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; 2:319–323. 7. Ashbaugh DG, Petty TL, Bigelow DB, Harris TM. Continuous positive-pressure breathing (CPPB) in adult respiratory distress syndrome. J Thorac Cardiovasc Surg 1969; 57:31–41. 8. Petty TL. PEEP. Chest 1972; 61:309–310. 9. Eiseman B. Pulmonary effects of nonthoracic trauma. Introduction to conference. J Trauma 1968; 8:649–650. 10. Grillo HC, Petty TL, Drinker PA. Discussion (Pontoppidan): treatment of respiratory failure in nonthoracic trauma. J Trauma 1968; 8:946–951. 11. Petty TL, Ashbaugh DG. The adult respiratory distress syndrome. Clinical features, factors influencing prognosis and principles of management. Chest 1971; 60:233–239. 12. Petty TL, Hudson LD, Ashbaugh DG, eds. 16th Aspen Lung Conference. Acute pulmonary injury and repair: the adult respiratory distress syndrome. Chest 1974; 65:1S-67S; 66:1S-46S. 13. Matthay MA. 41st Aspen Lung Conference. Acute Lung Injury. Chest 1999; 116:1S-127S. 14. Rahman I, Macnee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 2000; 16:534–554. 15. Meduri GU. The role of the host defense response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment. Eur Respir J 1996; 9:2650–2670. 16. Bell RC, Coalson JJ, Smith JD, Johanson WG. Multiple organ system failure and infection in adult respiratory distress syndrome. Ann Intern Med 1983; 99:293–298. 17. Fowler AA, Hamman RF, Good JT, Benson KN, Baird M, Eberle DJ, Petty TL, Hyers TM. Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med 1983; 98:593–597. 18. Pepe PE, Potkin RT, Reus DH, Hudson LD, Carrico CJ. Clinical predictors of the adult respiratory distress syndrome. Am J Surg 1982; 144:124–130.

Overview

5

19. Murray JF, Matthay MA, Luce JM, Pick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988 138:720–723. 20. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R, and the Consensus Committee for the American-European Conference on ARDS. Definition, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818–824. 21. Valta P, Uusaro A, Nunes S, Ruokonen E, Takala J. Acute respiratory distress syndrome: frequency, clinical course, and costs of care. Crit Care Med 1999; 27:2367–2374. 22. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342:1301–1308. 23. Staudinger T, Kofler J, Mullner M, Locker GJ, Laczika K, Knapp S, Losert H, Frass M. Comparison of prone positioning and continuous rotation of patients with adult respiratory distress syndrome: results of a pilot study. Crit Care Med 2001; 29:51–56. 24. Dellinger RP. Inhaled nitric oxide versus prone positioning in acute respiratory distress syndrome. Crit Care Med 2000; 28:572–574. 25. Petty TL. The adult respiratory distress syndrome: Historical perspective and definition. Sem Respir Med 1981; 2:99–103. 26. Gattinoni L, Bombino M, Pelosi P, Lissoni A, Pesenti A, Fumagalli R, Tagliabue M. Lung structure and function in different stages of severe adult respiratory distress syndrome. JAMA 1994; 271:1772–1779. 27. Gregory TJ, Steinberg KP, Spragg R, Gadek JE, Hyers TM, Longmore WJ, Moxley MA, Cai GZ, Hite RD, Smith RM, Hudson LD, Crim C, Newton P, Mitchell BR, Gold AJ. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 1997; 155:1309–1315. 28. Wiswell TE, Smith RM, Katz LB, Mastroianni L, Wong DY, Willms D, Heard S, Wilson M, Hite RD, Anzueto A, Revak SD, Cochrane CG. Bronchopulmonary segmental lavage with Surfaxin (KL4-surfactant) for acute respiratory distress syndrome. Am J Respir Crit Care Med 1999; 160:1188–1195. 29. Simpson DL, Goodman M, Spector SL, Petty TL. Long-term follow-up and bronchial reactivity testing in survivors of the adult respiratory distress syndrome. Am Rev Respir Dis 1978; 117:449–454. 30. Cooper AB, Ferguson ND, Hanly PJ, Meade MO, Kachura JR, Granton JT, Slutsky AS, Stewart TE. Long-term follow-up of survivors of acute lung injury: lack of effect of a ventilation strategy to prevent barotrauma. Crit Care Med 1999; 27:2616–2621. 31. Meduri GU, Headley AS, Golden E, Carson ST, Umberger RA, Kelso T, Tolley EA. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA 1998; 280:159–165.

2 Definitions and Clinical Risk Factors MARC MOSS Emory University School of Medicine and Grady Memorial Hospital Atlanta, Georgia, U.S.A. B.TAYLOR THOMPSON Harvard Medical School and Massachusetts General Hospital Boston, Massachusetts, U.S.A.

I. Introduction The acute respiratory distress syndrome (ARDS) is characterized by increased permeability of the alveolar capillary membrane, diffuse alveolar damage, and the accumulation of proteinaceous alveolor edema. These pathological changes are accompanied by several physiological alterations including severe hypoxemia and a decrease in pulmonary compliance. ARDS is a relatively uncommon etiology of acute respiratory failure in the intensive care unit. In a 2-week survey of 36 intensive care units in France, ARDS accounted for only 6.9% of all admissions (1). Similarly, ARDS represented 18% of all the patients who required intubation and mechanical ventilation for more than 24 hours in an 8-week survey of 132 intensive care units in Sweden, Denmark, and Iceland (2). However, ARDS patients account for a disproportionately high amount of hospital resources due to the prolonged intensive care unit and length of hospital stays. In one observational study, ARDS patients who required mechanical ventilation for at least 7 days represented only 6% of intensive care unit (ICU) admissions yet comprised 33% of all intensive care unit patient-days and 24% of all hospital charges among intensive care unit patients (3). Because ARDS is a syndrome and not a disease, patients are defined as having ARDS when they meet predetermined diagnostic criteria. The goal of these diagnostic criteria is to identify a homogeneous cohort of patients that represents a unique clinical entity. The specific diagnostic criteria for ARDS have changed and probably improved over time, though the lack of a gold standard or biochemical marker for lung injury remains a limiting factor in determining the sensitivity and specificity of any definition. In this chapter, we will discuss the evolution of the definition of ARDS and the need for additional modifications of the present diagnostic criteria. Over the past two decades sophisticated epidemiological studies have identified a variety of heterogeneous clinical conditions that are associated with a higher likelihood of developing ARDS. These studies have significantly contributed to our improved understanding of the epidemiology

Definitions and clinical risk factors

7

of ARDS. We will also review the clinical and demographic conditions that alter the probability of developing ARDS and impact the likelihood of dying from ARDS.

II. The Definition of ARDS The first official description of ARDS was reported in 1967 by a group of pulmonary and critical care physicians at the University of Colorado (4). This case series of 12 patients described a clinical scenario characterized by the acute onset of dyspnea, tachypnea, severe hypoxemia, chest radiographic abnormalities, and decreased static respiratory system compliance. With the increased availability of pulmonary artery catheterization in intensive care units, ARDS was reported to be a noncardiogenic form of pulmonary edema, characterized by the accumulation of both protein and cells in the alveoli in the presence of normal left ventricular filling pressures. Subsequently, several ARDS definitions were used in the early 1980s that required at least four basic clinical features, three of which are based upon physiological and radiographic criteria that were used in this original case series: hypoxemia (varying severity), decreased respiratory system compliance, and chest radiographs (often of an ill-defined type and degree). The fourth diagnostic criterion is usually the documentation of normal pulmonary artery occlusion pressures using a pulmonary artery catheter (5–10). When the mortality from ARDS did not improve during the 1980s, some investigators raised the possibility that these four strict diagnostic criteria biased the understanding of ARDS and contributed to the negative therapeutic trials for ARDS (11). One concern was that the diagnostic criteria did not have sufficient sensitivity and therefore only identified those patients with severe ARDS and a very poor prognosis. The potential lack of sensitivity was attributed to the necessity for placing a pulmonary artery catheter in order to document a normal pulmonary artery occlusion pressure (10). In a 3-month survey, Rinaldo (11) reported that only 7 of 27 patients with clinical ARDS met all of the strict diagnostic criteria for ARDS. The mortality for these 7 patients was 71% and for the remaining 20 patients only 30%. The requirement for pulmonary artery catheterization to diagnose ARDS may also delay the initiation of therapeutic agents designed to prevent the development of ARDS in at-risk individuals (12). Because approximately 50% of patients develop ARDS within the first 24 hours of meeting an at-risk diagnosis, delaying the administration of a therapy in order to insert a pulmonary artery catheter may diminish the chance of successful therapeutic intervention (13). Finally, the use of a pulmonary artery catheter has been circumstantially linked to adverse clinical outcomes, perhaps from well-intended but potentially harmful pulmonary artery catheter-guided management strategies (14). These initially proposed strict diagnostic criteria of ARDS may also lack specificity. Other pulmonary diseases that represent different inflammatory processes can fulfill all of the diagnostic criteria of ARDS. For example, patients with vasculitis and alveolar hemorrhage meet the diagnostic criteria for ARDS, yet the pathogenesis of this disorder is different from ARDS. Therefore, it is unclear whether patients with alveolar hemorrhage patients should reported as having ARDS (10). In addition, patients with an elevated pulmonary artery wedge pressure are excluded, although these patients may have lung injury in addition to either hypervolemia or congestive heart failure. Patients

Acute respiratory distress syndrome

8

with bilateral pneumonia secondary to Pneumocystis carinii meet criteria for ARDS and are sometimes included in both clinical and epidemiological studies (15, 16). Other reports have excluded patients with AIDS, and therefore individuals with Pneumocystis carinii pneumonia would not be enrolled (12, 17). These discrepancies in the inclusion of patients with bilateral pneumonia in studies of ARDS illustrate the persistent concern of variability in the diagnostic criteria used at different centers. Several investigators postulated that the differences in reported epidemiological data, such as mortality rates, could be attributed to inconsistent cutoff values for the hypoxemia criteria and variations in the interpretation of other diagnostic considerations (8). Finally, these four diagnostic criteria defined ARDS as an all-or-none phenomenon. The presentation of ARDS includes a continuum of radiographic and arterial blood gas abnormalities, and any single cutoff value for the definition of ARDS would be arbitrary. Therefore, the identification of several gradations or categories of acute lung injury that have prognostic implications would be beneficial. A. The Murray Lung Injury Score Based on these concerns, a second phase of ARDS definitions emerged that attempted to improve both the sensitivity and specificity of the diagnostic criteria by including early and limited cases of ARDS, or what some called clinical acute lung injury, while still excluding patients who did not truly have acute lung injury (10, 18). In 1988 Murray and colleagues proposed an expanded definition of ARDS that represented the first attempt to provide a quantitative scoring system to characterize mild, moderate, and more severe forms of lung injury (Table 1) (5). The lung injury score is based upon four components (chest radiograph, hypoxemia, positive end-expiratory pressure, and respiratory system compliance), two of which (chest radiograph and hypoxemia) must be available for all patients. Each component is assigned a score of 1 to 4. The final value is obtained by dividing the aggregate sum by the number of available components, and three categories of lung injury are defined. A final score of zero equals no lung injury, 0.1–2.5 constitutes mild to moderate lung injury, and >2.5 is defined as ARDS. The authors also recommended that this scoring system be used only in patients with specific diagnosis, such as sepsis and trauma. However, some studies that have subsequently used the lung injury score have not always adhered to this recommendation (19, 20). In addition, the placement of a pulmonary artery catheter and measurement of a pulmonary capillary occlusion pressure were not required. This scoring system was immediately praised and used to stratify patients with and at risk for ARDS (21). One study has evaluated the ability of the lung injury score to predict a complicated clinical course in 50 ARDS patients (22). The lung injury score was determined 4 days after the development of ARDS. Using a cutoff value of ≥2.75, the sensitivity and specificity of the lung injury score for a complicated course, defined as death before 14 days or the requirement for mechanical ventilation for longer than 14 days, were 83% and 57%, respectively. B. A Simpler Definition of ARDS In an attempt to diagnose patients earlier in the course of ARDS, Sloane and colleagues proposed a new definition of ARDS based on only two diagnostic criteria: a

Definitions and clinical risk factors

9

ratio of ≤250 in an appropriate clinical setting and bilateral infiltrates on chest radiograph within 7 days of meeting the at risk diagnosis (12). Patients with physical findings or hemodynamic measurements consistent with congestive heart failure, stage III or IV lung

Table 1 The Lung Injury Score Chest Roentgenogram Score No alveolar consolidation

0

Alveolar consolidation in one quadrant

1

Alveolar consolidation in two quadrants

2

Alveolar consolidation in three quadrants

3

Alveolar consolidation in four quadrants

4

Hypoxemia Score 0 1 2 3 4 Respiratory System Compliance Score (when ventilated) (mL/cmH2O) ≥80

0

60–79

1

40–59

2

20–39

3

19

4

Positive End-Expiratory Pressure Score (when ventilated) (cmH2O) ≤5

0

6–8

1

9–11

2

12–14

3

≥15 Final Value

4 a

No lung injury

0

Acute lung injury

0.1–2.5

Severe injury (ARDS)

>2.5

Acute respiratory distress syndrome

a

10

Obtained by dividing aggregate sum by number of components used.

cancer, Pneumocystis carinii pneumonia, organ transplantation, or younger than 15 years of age were excluded for the study. In this 2-year evaluation, 153 patients were diagnosed with ARDS. When compared to a strict definition of ARDS, this liberal definition allowed 13% of the patients to be diagnosed with ARDS 3 days earlier (23). In this study an additional 2% of patients were diagnosed with ARDS who would have not been identified using the strict criteria. Furthermore, the mortality of ARDS patients in this study was still 54%, unchanged from previously reported mortality rates (24). C. The First American-European Consensus Conference In 1994 the recommendations of the American-European Consensus Conference (AECC) on ARDS were published (25). One of the major goals of this conference was to bring “clarity and uniformity to the definition of ARDS.” ARDS was defined as a severe form of “acute lung injury,” defined as “a syndrome of inflammation and increasing permeability that is associated with a constellation of clinical, radiographic, and physiologic abnormalities that cannot be explained by, but may coexist with, left atrial or pulmonary capillary hypertension” (25). The diagnostic criteria for ARDS proposed by this committee were bilateral infiltrates on chest radiograph, and pulmonary artery occlusion pressure ≤18 mmHg when measured or no clinical evidence of left atrial hypertension. The spectrum of disease severity was also expanded to include patients with milder hypoxemia. This definition, which includes patients with ARDS, was called acute lung injury (ALI), and the diagnostic criteria were similar except the ratio was ≤300 (Table 2). The term “non-ARDS ALI” subsequently evolved of 201–300. This definition was to refer to the subgroup of patients with a immediately endorsed by the American Thoracic Society and the European Society of Intensive Care Medicine with the goal of universal acceptance and utilization (25). These three definitions—the Murray lung injury score, the simple criteria defined by Sloane and colleagues, and the AECC definition—were compared to the strict definition of ARDS requiring all of the strict diagnostic criteria in attemp to determine the accuracy of these new definitions (18). All three definitions maintained a high degree of accuracy (>90%) for those ICU patients with a clearly defined at-risk diagnosis for the development of ARDS. Therefore, it is likely that the lung injury score and the AECC definition actually identify a patient population similar to the older strict definitions of ARDS for those patients with clearly defined at-risk diagnoses. D. Update from the Second American-European Consensus Conference Over the next few years the AECC committee met several times with the primary objective of examining the pathophysiological mechanisms of lung damage as they related to mechanical ventilatory strategies and promising agents for the treatment or prevention of acute lung injury and ARDS (26). Though the primary goals of the meeting

Definitions and clinical risk factors

11

were not to examine the diagnostic criteria of ARDS, one subcommittee did recommend that ARDS be identified as the pulmonary manifestation of systemic inflammation. The

Table 2 Recommended Criteria for Acute Lung Injury and Acute Respiratory Distress Syndrome Timing

Oxygenation

Chest radiograph Pulmonary artery wedge pressure

ALI criteria

Acute onset

Bilateral infiltrates ≤18 mmHg when mmHg seen on frontal chest measured or no clinical (regardless of PEEP level) radiograph evidence of left atrial hypertension

ARDS criteria

Acute onset

Bilateral infiltrates ≤18 mmHg when mmHg seen on frontal chest measured or no clinical (regardless of PEEP level) radiograph evidence of left atrial hypertension

Table 3 Stratification System of Acute Lung Injury Letter G

Meaning Gas exchange

Scale

Definition

0 1 2 3

Gas exchange (to be combined with the numeric descriptor)

O

C

A

Organ failure

Cause

Associated diseases

A

Spontaneous breathing, no PEEP

B

Assisted breathing, PEEP 0–5 cmH2O

C

Assisted breathing, PEEP 6–10 cmH2O

D

Assisted breathing, PEEP ≥10 cmH2O

0

Lung only

1

Lung+1 organ

2

Lung+2 organs

3

Lung+≥3 organs

0

Unknown

1

Direct lung injury

2

Indirect lung injury

0

No coexisting diseases that will cause death within 5 years

1

Coexisting disease that will cause death within 5

Acute respiratory distress syndrome

12

years but not within 6 months 2

Coexisting disease that will cause death within 6 months

development of sequential dysfunction of nonpulmonary organ systems such as the kidney and liver or multiple organ dysfunction syndrome (MODS) is one of the common causes of death for ARDS patients (27). Based on this concept, the subcommittee recommended a new stratification system of acute lung injury and ARDS, the GOCA score, based on alterations in gas exchange, organ failure, the cause of acute lung injury, and associated diseases (Table 3). The scoring system was not designed to actually predict outcome, but to succinctly present important clinical information (26). Unlike the diagnostic criteria developed during the first conference, the GOCA score has not been widely accepted or reported in the medical literature.

III. Persistent Problems and Controversies Involving the Definition of ARDS In spite of several alterations in the definition of ARDS or clinical lung injury, fundamental problems still remain with the present diagnostic criteria recommended by the AECC. Variability in the identification of all three components of the AECC definition of ARDS (radiographic, oxygenation, and the exclution of a cardiogenic form of pulmonary edema) still can occur and will continue to impact the validity and reproducibility of epidemiological studies and clinical trials. Some of these issues have recently been reviewed (28). The chest radiographic criteria used to define ARDS remain problematic. In one study, 21 established investigators reviewed 28 randomly selected chest radiographs from intubated patients with a of 18 mmHg. The interrater reliability and accuracy of pulmonary artery occlusion pressures suffer from similar problems previously discussed with chest radiographic interpretations. This potential variability in the pulmonary artery occlusion pressure measurements may also account for the some of the geographic variability in epidemiological data concerning ARDS. Finally, patients with ARDS are often on high levels of PEEP. The increased intrathoracic pressures from the PEEP can often be registered by the pulmonary artery catheter and lead to a false elevation of the actual intravascular occlusion pressure. Therefore, it is possible that a patient who truly has ARDS may be excluded from clinical trials or epidemiological studies because they are severely hypoxemic and require significant levels of PEEP that cause the pulmonary artery occlusion pressure to be >18 mmHg. In regard to the diagnostic criteria related to clinical evidence of left atrial hypertension, the accuracy and reliability of the clinical assessment of this measurement is poor (28, 35–37). In addition, there are no specific recommendations by the AECC committee about what clinical signs are acceptable for estimating left atrial pressure. One group has reported that between 5 and 30% of patients meeting chest radiograph and hypoxemia criteria would be excluded from a formal diagnosis of ARDS depending on the specific diagnostic criteria used to define clinical left atrial hypertension (38). Some investigators have attempted to use simple criteria obtained from the chest radiograph to differentiate cardiogenic/hydrostatic pulmonary edema from ARDS (39, 40). Aberle and colleagues reviewed portable chest radiographs from 45 mechanically ventilated patients with pulmonary edema. The ratio of pulmonary edema fluid protein to plasma protein concentration was utilized to differentiate hydrostatic from increased permeability edema. Based on cardiac size, distribution of edema, presence of either pleural effusions, interstitial changes, or air bronchograms, and the distribution of blood flow and pulmonary blood volume, chest radiographs were classified as having hydrostatic, increased permeability, or a mixed form of pulmonary edema. Overall, 87% of patients with hydrostatic edema but only 60% of patients with increased permeability edema were correctly identified by chest radiographs. The presence of a patchy peripheral distribution

Definitions and clinical risk factors

15

of edema fluid was the most discriminating criterion for increased permeability edema. More recently, conventional portable supine chest radiographs from 33 mechanically ventilated ICU patients were evaluated by three experienced chest radiologists without any information about the clinical course of the patients, their mechanical ventilatory parameters, hemodynamic measurements, or prior chest radiographs (40). All patients had a pulmonary artery catheter in place. The investigators measured the vascular pedicle width (VPW) by dropping a perpendicular line from the point at which the left subclavian artery exits the aortic arch and measuring across to the point at which the superior vena cava crosses the right mainstem bronchus. In addition, the cardiothoracic (CT) ratio was calculated by dividing the widest transverse diameter of the cardiac silhouette by the widest transverse diameter of the thorax above the diaphragm. Patients were classified as having either cardiogenic/hydrostatic pulmonary edema or permeability pulmonary edema based on pulmonary artery occlusion pressure, cardiac index, and clinical diagnosis. The mean accuracy of the radiologists in distinguishing the two types of pulmonary edema was only 41%. However, by including additional information derived from VPW (cutoff value of >63 mm) and CT ratio (cutoff value of >0.52), the accuracy of determining the type of pulmonary edema increased to 73%. Further investigation is necessary to examine whether these simple radiographic measurements should be used to assist with identifying patients with ARDS (see Chap. 4). When ARDS was first described in 1967, the “A” stood for “adult” to differentiate it from the infantile respiratory distress syndrome, which had many similar clinical characteristics. However, with the recognition that ARDS occurs in all age groups, the “A” now stands for “acute.” There are no standard criteria to define over what length of time the syndrome of ARDS can occur. The original AECC investigators did not set a time limit for the word “acute,” but clearly ARDS needs to be differentiated from interstitial lung diseases that develop over weeks to months (25). An epidemiological study from Seattle involving 695 critically ill patients provides insight into this issue (13). ARDS developed during the first 24 hours in 54% and 29% of the patients with sepsis and trauma, respectively. Over 90% of all patients developed ARDS within 5 days of meeting the at risk diagnosis, and all patients developed ARDS by 7 days. Therefore, the length of time for the development of ARDS should be less than 7 days from the time of onset of their critical illness. C. Update from the Third American-European Consensus Conference The America-European Consensus Conference convened for a third time to discuss some of the criticisms and controversies that persist with the present diagnostic criteria for ARDS (41). The committee addressed several important concerns and suggested specific recommendations to improve the consistent usage of the diagnostic criteria. In addition, they acknowledged that the theoretical differentiation of ARDS from ALI based on severity of hypoxemia has not established two separate entities with different clinical associations and prognoses. In regard to the chest radiographic criteria, the committee stated that the “bilateral infiltrates” should be consistent with pulmonary edema, even if mild or patchy in nature.

Acute respiratory distress syndrome

16

Opacities that are not considered appropriate for the radiographic criteria for ALI/ARDS include pleural effusions, pleural thickening, or masses, pulmonary masses or nodules, chronic scarring, volume loss, lobar collapse, platelike atelectasis if the surrounding borders are sharp, extrathoracic opacities, and subcutaneous air. It is unclear if these more explicit descriptions of qualifying radiographic opacities will improve interreader variability. In regard to the timing of the onset of ALI/ARDS, the committee recognized the findings from Seattle and suggested that the diagnostic criteria of lung injury should appear over an interval not exceeding 7 days. The AECC committee also commented on the difficulty in excluding hydrostatic or cardiogenic causes as the sole cause for pulmonary edema. They acknowledged the lack of a perfect cutoff value of the pulmonary artery occlusion pressure that would differentiate the hydrostatic pulmonary edema from permeability pulmonary edema (ARDS). Additionally, the capillary filling pressures clearly fluctuate with volume resuscitation and diuresis, and the pulmonary artery occlusion pressure may occasionally rise above or below the specific cutoff value. However, no alterations in this controversial diagnostic criterion were recommended. Finally, the AECC committee identified a group of patients who spend a considerable length of time being mechanically ventilated. This new category of respiratory failure has been termed “acute lung failure” and includes all patients who require mechanical ratio of ≤300, and show any infiltrate on chest radiograph ventilation, have a (Table 4). Therefore, patients with ALI/ARDS would be a subset of “acute lung

Table 4 Diagnostic Criteria for Various Forms of Acute Pulmonary Dysfunction Chest radiographc Acute lung injurya

0–300 mmHg

Bilateral infiltrates

a

0–200 mmHg

Bilateral infiltrates

Acute lung failure

0–300 mmHg

Any infiltrate

Acute lung injury

a

Acute indicates development of the syndrome within a time period of less than 7 days. Further, both oxygenation and chest radiograph criteria must be simultaneously present within a time window of no greater than 24 hours in order to make the diagnosis. b These levels of abnormality in gas exchange should be reasonably sustained as opposed to transient. c Bilateral opacities seen on chest radiograph or computerized tomography consistent with pulmonary edema. These opacities can be mild, patchy, or asymmetrical.

failure.” Patients with pure ventilatory impairment due to neuromuscular disease, chronic obstructive pulmonary disease (COPD), and acute exacebations of asthma were excluded from this new classification. The demographics, epidemiology, and economic impact of patients with acute lung failure are presently unknown and will require future investigation.

Definitions and clinical risk factors

17

D. Future Directions Even after three consensus conferences and multiple studies, several issues still remain concerning the present diagnostic criteria for ARDS, including the heterogeneity of the patient population, the absence of a diagnostically accurate biochemical marker, and the lack of a reliable noninvasive measure of alveolar-capillary injury or permeability. Presently, ARDS can occur in a heterogeneous group of patients who develop common physiological and radiographic abnormalities. Therefore is ARDS really one unique or several different syndromes? The present definition proposed by the AECC includes a multiplicity of clinical entities ranging from autoimmune disorders, such as lupus pneumonitis, to direct lung injury attributable to causes as diverse as pneumonia or smoke inhalation, to indirect pulmonary injury from bacteremia, trauma, or pancreatitis (42). This issue was first addressed over 20 years ago, when John Murray and Thomas Petty engaged in a published debate concerning ARDS (43, 44). Murray stated that “lumping these disorders together serves no useful purpose and has the disadvantage of detracting from important and distinctive differences in pathogenesis, therapy, and prognosis.” Petty rebutted by observing that ARDS is indeed a specific clinical syndrome manifest by similar clinical, pathophysiological, and morphological features. He blamed some of the difficulties with and misunderstanding of the definition of ARDS on its misuse by clinicians who were unfamiliar with the syndrome. Finally, he concluded that ARDS is a heterogeneous disease not unlike asthma, which is still defined by the pathophysiological response caused by a variety of potential stimuli (44). In support of Murray’s opinion as a “splitter,” the level of certain mediators that are postulated to be involved in the pathogenesis of ARDS vary according to the specific atrisk diagnosis. For example, tumor necrosis factor levels are increased in the blood of patients with sepsis, and in one study the levels were positively associated with the development of ARDS (45). However, several studies have reported the absence of tumor necrosis factor (TNF) levels in trauma patients without clinically significant hypovolemia (23). Similarly, interleukin-1 β (IL-1) has been detected in some patients with sepsis, but circulating IL-1 a levels are undetectable within the first few hours of a traumatic injury (46, 47). Furthermore, there is evidence that total IL-1 production actually is decreased for the first 5 days after traumatic injury (48). Finally, in a cohort of patients with sepsis and trauma, 26% of whom developed ARDS, levels of the soluble adhesion molecules (E-selectin and intercellular adhesion molecule-1) were significantly higher in the septic patients when compared to the trauma patients (49). In addition, the circulating levels of both adhesion molecules in the trauma patients were not elevated above normal controls. These studies suggest that the pathogenesis of ARDS may be different in patients with different at-risk diagnoses or that these specific mediators are not intricately involved or necessary for the development of ARDS. The most recent AECC committee commented of this issue on heterogeneity. The committee acknowledged that the various forms of lung injury may eventually necessitate different therapeutic modalities, and that narrower definitions may be useful in the future. They did not believe that there was sufficient evidence or need to subdivide the ARDS/ALI patients according to the specific underlying process.

Acute respiratory distress syndrome

18

The identification of an accurate diagnostic, predictive, or prognostic marker for ARDS would significantly improve the ability to diagnose patients with ARDS and improve our understanding of this syndrome. The discovery of such a mediator or marker of lung injury would be analogous to the identification of CPK-MB or troponin levels in the diagnostic evaluation of acute myocardial infarctions. As described in several other chapters in this volume, ARDS is associated with the initiation and propagation of an intense inflammatory cascade involving myriad inflammatory cells and mediators that result in injury to the alveolar epithelium. Many of the mediators involved in this cascade have been identified over the last few years, and their specific actions have been carefully explored. However, these mediators require certain characteristics to be a clinically useful marker. The actual collection of the specimen from the patient must be rapid and not expose the patient to any excessive risk (50). In addition, the laboratory assay and its interpretation must be uniform among the various clinical laboratories able to perform the test. Therefore, the most likely source of a biochemical marker for ARDS would be obtained either from the peripheral blood or possibly from endotracheal tube aspirate of edema fluid or urine. Numerous studies have attempted to identify a clinically useful biochemical marker for ARDS. This extensive body of research has been reviewed (51). Although much has been learned about the pathogenesis of ARDS from these studies, there is presently no clearly identified biochemical marker for ARDS. The most fundamental physiological characteristics of ARDS is an increase in permeability to protein across the endothelial and epithelial barrier of the lung (52, 53). Measurements of pulmonary vascular permeability (PVP) are commonly used in experimental models of ARDS as a marker of acute injury. Noninvasive nuclear medicine techniques have been developed that measure this feature in patients. More specifically, positron emission tomography (PET) can measure protein flux between intravascular and extravascular components of the lung. Using this technique, ARDS patients have been reported to have increased PVP when compared to normal controls (53). The ability of PVP measurements to diagnose ARDS has also been examined. In this study, these noninvasive techniques were utilized in an attempt to differentiate patients with ARDS from those with commonly confused diagnoses such as congestive heart failure and pneumonia (54). Though PVP was significantly higher in ARDS patients when compared to those with congestive heart failure, they were not different from measurement of PVP in patients with pneumonia, both in the regions with infilitrate and in radiographically normal areas. However, some investigators consider patients with bilateral pneumonia as meeting the diagnostic criteria for ARDS. Further investigation is needed before these noninvasive measures of PVP can be incorporated into the definition of ARDS.

IV. Clinical Risk Factors for the Development of ARDS Since its initial description, ARDS has been noted to occur in patients with a variety of heterogeneous diagnoses. This heterogeneity was better defined in the 1980s, when several investigators prospectively followed critically ill patients and identified those that eventually developed ARDS (6, 7). Over a 12-month period, Fowler and colleagues at the University of Colorado (6) identified and monitored all patients who required mechanical ventilation with one of eight conditions, including cardiopulmonary bypass, burns,

Definitions and clinical risk factors

19

bacteremia, hypertransfusion, multiple long bone or pelvic fractures, disseminated intravascular coagulation, severe pneumonia, and aspiration of gastric contents (6). Patients were considered to have developed ARDS based on strict criteria including the requirement of a pulmonary artery occlusion pressure of ≤12 mmHg. In total, 88 patients developed ARDS, with an incidence rate ranging from 1.7 per 100 patients with cardiopulmonary bypass to 35.6 per 100 patients with pulmonary aspiration (Table 5). Pepe and colleagues at the University of Washington performed a similar study and followed patients with a variety of diagnoses, including sepsis syndrome, aspiration of gastric contents, pulmonary contusion, hypertransfusion, and multiple fractures (7). A total of 34% of the 136 consecutive patients identified developed ARDS. The incidence of ARDS among the various at-risk diagnoses ranged from 8% for major fractures to 38% with sepsis syndrome (Table 5). Both of these studies also reported that patients with multiple at risk diagnoses were at a markedly increased risk for developing ARDS. Several years later, Hudson and colleagues reported similar incidence rates for the development of ARDS in critically ill patients (13). In general, the majority of these heterogeneous patients who are at increased risk for the development of ARDS can be classified into four common categories: sepsis (pulmonary or nonpulmonary), pneumonia,

Table 5 Incidence of ARDS Among Patients with Specific At-Risk Diagnoses At-risk diagnosis

Incidence rates, 1980– Incidence rates, 1981 (Fowler Series) 1982 (Pepe series)

Sepsis Aspiration of gastric contents

36%

Pulmonary contusion

Incidence rates, 1983–85 (Hudson series)

38%

41%

30%

22%

17%

22%

Hypertransfusion

5%

24%

36%

Multiple fractures

5%

8%

11%

66%

33%

Near-drowning Cardiopulmonary bypass

2%

Burns

2%

major trauma, and aspiration of gastric contents. In some series, these four general categories may account for over 85% of the patients who will develop ARDS (55). Sepsis is usually the most common at-risk diagnosis and may account for approximately 50% of all ARDS cases. Whether these four categories of ARDS represent clinically different syndromes with different epidemiology and pathogenesis is presently unclear. Other investigators have recommended different methods of categorizing the various at-risk diagnoses according to whether the injury to the lung occurs through direct (primary) or

Acute respiratory distress syndrome

20

indirect (secondary) mechanisms (56, 57). There are diverse causes of direct injury, including pneumonia, aspiration of gastric contents, and smoke inhalation. The etiologies of indirect lung injury are even more heterogeneous and include such diagnoses as nonpulmonary sepsis and multiple long bone or pelvic fractures. This differentiation (between direct and indirect injury) is supported by different respiratory mechanics, responsiveness to PEEP, and radiographic manifestations on CT scanning. CT scans from ARDS patients due to direct lung injury have a prevalence of consolidation as opposed to more prevalent edema and alveolar collapse in ARDS patients from an indirect source (57). But clinical response to low tidal volume ventilation does not suggest that there is an actual difference (58). In an analysis of patients enrolled into the ARDSnet trial, the efficacy of ventilatory strategy was similar among patients with different clinical risk factors (58). More recently, one study reported that patients following pulmonary resection surgery are at increased risk for the development of ARDS. In a study of 1139 patients who underwent pulmonary resection surgery, 3.9% of the patients developed ALI or ARDS on average 4 days postoperatively (59). Over half of the operations were performed on patients with lung cancer. Because lung surgery is a fairly common procedure, this relatively low percentage still represented nearly one new ARDS patient every 2 months from pulmonary resection at a single institution. The highest frequency of ARDS (12.9%) was observed in patients who required extensive resections. A. Comorbidity, Demographics, and Incidence of ARDS Not all of the patients with a clearly defined at-risk diagnosis will eventually develop ARDS. In the classic epidemiological studies from the University of Colorado and the University of Washington in Seattle, the overall incidence of ARDS in patients with specific at-risk diagnoses was reported to be only 7% and 34%, respectively (6, 7). No individual diagnoses were associated with an incidence of ARDS of >40%. Therefore, other factors in addition to the specific at-risk diagnosis must play a role in determining which at-risk patients eventually develop ARDS. Some of these secondary demographic or comorbid conditions that alter the probability of developing ARDS have been identified. Alcohol is one of the most commonly used drugs in the world. Over 50% of the U.S. population regularly consumes alcohol (60). However, it was not until recently that an epidemiological association between alcohol abuse and ARDS was identified. Chronic alcohol abuse was reported to increase the risk of complications in trauma patients (61). The risk of respiratory failure, defined as respiratory distress requiring mechanical ventilation, was higher among the trauma patients with evidence of chronic alcohol abuse. In another study, 71% of critically patients with a history of an alcohol-related illness and a low arterial pH developed ARDS compared to only 39% of those patients with no history of alcohol abuse and a normal pH (13). More recently, 351 critically ill patients with one of seven diagnoses associated with the development of ARDS were identified and followed for the development of ARDS (17). Thirty-four percent (121/315) of the patients had a prior history of alcohol abuse. Using a strict definition of ARDS, 43% (52/121) of the alcoholics developed ARDS, as opposed to 22% (50/230) of the nonalcoholics. This effect of chronic alcohol abuse on the development of ARDS

Definitions and clinical risk factors

21

remained significant in a logistic regression model, adjusting for differences in the admission APACHE II scores, at-risk diagnosis, and gender. Recently, two studies have examined the effect of a prior history of cigarette use on the development of ARDS. Using a retrospective cohort study design, 56 ARDS patients were identified from an HMO data base of 121,012 health plan subscribers (62). The risk of ARDS was increased in those patients who were current or former smokers compared to those individuals who had never smoked. A similar association between smoking and the development of ARDS were observed in a large cohort of patients undergoing coronary artery bypass surgery (63). ARDS appears to be more common with increasing age in patients with similar underlying diagnoses (55). In the subset of trauma patients enrolled in a recent study, those individuals older than 70 were twice as likely to develop ARDS when compared to the 18- to 29-year-old patients (13). Increasing age has also been reported to have positive association with the development of ARDS in burn patients (64). Only a few studies have reported a positive association between gender and the development of ARDS. Hudson and colleagues have reported that female trauma patients were more likely to develop ARDS than male trauma patients given a similar severity of illness (13). In Kutlu’s series of patients undergoing pulmonary resection, men had a higher frequency of developing ARDS when compared to women (59). Clearly larger epidemio-logical studies are necessary to determine whether there are gender differences in the pathogenesis of ARDS. Diabetes mellitus is a secondary diagnosis that theoretically alters the incidence of ARDS due to its association with abnormalities in several aspects of the pathogenetic cascade of ARDS. A multitude of data support the theory that proinflammatory signals, and more specifically the activation and recruitment of circulating neutrophils into the lung parenchyma, are involved in the pathogenesis of ARDS. Some investigators hypothesized that the same alterations in the inflammatory cascade that predispose diabetic patients to develop serious infections may be protective for the development of ARDS. One study identified 113 patients with septic shock, of whom 28% had a history of diabetes (65). In this study, nondiabetics were more likely to develop septic shock from a pulmonary source (48%, 39/81) when compared to diabetics who were more likely to develop ARDS from an indirect source of infection such as a wound or urinary tract (25%, 8/32). Overall, 41% (46/113) of the patients with septic shock developed ADRS. The incidence of ARDS was significantly higher in the nondiabetic patients when compared to those with a history of diabetes. In a multivariate logistic regression analysis adjusting for several variables including source of infection, the effect of diabetes on the incidence of ARDS remained significant.

V. Mortality from ARDS Historically, the mortality rate for patients with ARDS has usually exceeded 50%. However, mortality appears to have declined over the past few years. One single institution study reported a steady decline in mortality beginning in 1989 and reaching a low of 36% in 1993 (66). This improvement in mortality occurred in all age groups. In a subsequent study from England, the mortality rate for patients with ARDS was also

Acute respiratory distress syndrome

22

shown to have decreased from 60 to 30% from the early to mid-1990s (67). Most recently, the ARDSnet trial examining ventilatory strategies for ARDS patients reported a mortality rate of 30% in patients who received low tidal volume ventilation (16). However, this large multicenter trial excluded patients with comorbidities associated with a high mortality (such as ARDS with liver disease) and therefore may not reflect the true mortality rate for all ARDS patients. Finally, Rocco and colleagues conducted a 9-year study of 111 trauma and surgical patients with ARDS (68). From 1990 to 1994, the overall annual death rate from ARDS ranged from 67 to 80%. However, from 1995 to 1998 the annual mortality rates were all less than 50%. This improvement in mortality was most significant in those with a primary diagnosis of trauma as opposed to general surgical patients. The exact etiology for this decline in ARDS mortality is presently unclear but is likely related to improvement in general ICU care and possibly changes in ventilatory management (55) (see Chap. 21). It is important to note that the ARDS Network trial demonstrated an approximately 10% absolute mortality reduction (from 40%) and an increase in days free from multiorgan failure with low tidal volume in comparison to conventional tidal volumes (16). This important study suggests that a significant portion of the mortality from ARDS (perhaps 25%) derives from injurious ventilatory strategies per se. A recent evaluation of clinicians’ approaches to mechanical ventilation in the 1990s showed an evolution in tidal volume size from 14 mL/kg of body weight early in the decade to 10 mL/kg of body weight in the late 1990s for patients with ARDS (69). The cause of death for patients with ARDS has been traditionally divided into early causes (within 72 hours) and late causes (after 3 days) (70). Most early deaths are attributed to the original presenting illness or injury. Sepsis, persistent respiratory failure, and the development of multiple organ system dysfunction are the most common causes of death in ARDS patients who survive at least 3 days. Several secondary factors are associated with mortality in patients who develop ARDS. Patients with a primary at-risk diagnosis of sepsis have consistently been reported to have a higher mortality rate when compared to trauma patients. In one study of 423 ICU patients, those developing ARDS after trauma had significantly lower hospital mortality (14%) than did patients with a medical diagnosis (40%), the majority of whom had sepsis (71). Similarly, risk of death from ARDS was only 11 % in those trauma patients enrolled into the ARDSnet study (58). Long-term survival after ARDS also appears to be dependent on the primary at-risk diagnosis. Trauma patients with ARDS who survive to hospital discharge have an excellent prognosis over the following 2 years. However, survivors of sepsis-induced ARDS continue to be at an increased risk of dying after hospital discharge (72). This difference in long-term survival may be due to the presence of more significant and chronic comorbidities in those patients with sepsis-induced ARDS. In addition, patients with a direct cause of lung injury have been reported to have a higher mortality rate when compared to indirect at-risk diagnoses (73). Age is also associated with mortality from ARDS as older patients are more likely to die from ARDS when compared to younger patients. Zilberberg and Epstein demonstrated that age greater than 65 years was an independent predictor of hospital mortality in a cohort of 107 medical patients with ARDS (74). A study of 221 ARDS patients in Scandinavia demonstrated similar effects of age on ARDS and reported a risk ratio for mortality of nearly 2.0 when patients were stratified by age >65 (2). An analysis of the 902 patients enrolled in ARDS Network

Definitions and clinical risk factors

23

studies showed that patients over 70 years old were twice as likely to die even after adjustments for covariates. Older survivors recovered from respiratory failure at similar rates but had greater difficulty weaning from the ventilator (75). Preexisting medical conditions appear to have a dramatic impact on the mortality from ARDS. Although patients with cirrhosis of the liver are predisposed to several of the atrisk diagnoses for ARDS, such as sepsis (76), only a few reports have examined a possible association between cirrhosis and the mortality from ARDS. Matuschak and colleagues retrospectively examined 29 patients with severe liver disease awaiting transplantation and reported that their incidence of ARDS was higher than a random control group of ICU patients (77). Recently, Doyle et al. reported that the mortality from acute lung injury was increased in 26 medical patients with chronic liver disease when compared to acute lung injury patients without liver disease (78). Finally, cirrhosis was identified as the single most important predictive variable of mortality in a cohort of 259 patients with ARDS (73). Similarly, patients with a history of HIV disease, active malignancy, and organ transplantation appear to be at increased of dying form ARDS (74). Larger multi-center epidemiological studies are necessary to determine whether these multiple conditions are truly independent predictors of mortality in ARDS. Since most ARDS patients do not die of persistent respiratory failure, it might not be surprising that initial indexes of oxygenation and ventilation, including the ratio and the lung injury score, do not predict outcome (79). The ARDSnet trial reported that the patients with improved survival due to low tidal volume ventilation actually had a worse

ratio when compared to high tidal volume group. In addition, several

studies have reported that the mortality rate among patients with ALI (

ratio ≤

ratio ≤200) (13, 74, 78). These 300) is similar to those patients with ARDS ( similarities in mortality rates again raise concerns about the usefulness of differentiating between ALI and ARDS patients. In addition, these studies demonstrate that mortality is likely more closely related to the development of multiple organ dysfunction, sepsis, and the preexisting health of the patient. More recently, mean dead-space fraction, measured with a bedside metabolic monitor, was markedly elevated early in the course of ARDS and elevated values were associated with an increased risk of death (79a). Finally, there may be racial and gender differences in ARDS mortality in the United States (80). Using multiple-cause mortality data compiled by the National Center for Health Statistics, more than 333,000 patients who died with ARDS were identified over an 18-year period (1979–1996). Though controversial, ARDS was identified using International Classification of Diseases (ICD) codes for the underlying cause of death and the 20 additional conditions listed on the death certificate. Using these classifications, annual ARDS mortality rates have been continuously higher for males when compared to females and for African Americans when compared to white decedents and decedents of other racial backgrounds. When decedents were stratified by race and gender, African American males had the highest ARDS mortality rates in comparison to all other subgroups (mean annual mortality rate of 12.8 deaths per 100,000 African American males). In addition, a higher percentage of the African American ARDS decedents were reported in the youngest age categories. In those decedents who were less than 35 years of age, 27% were African American, yet only 13% of the U.S. population is African

Acute respiratory distress syndrome

24

American. The exact etiology of these differences is presently unknown. One possibility may be that men and African Americans are simply more likely to develop an at-risk diagnosis associated with the development of ARDS, such as sepsis or trauma. More recently, similar racial and gender differences have been reported in the incidence and mortality of patients with sepsis (80a).

VI. Conclusions Since 1967 the diagnostic criteria used to define ARDS have evolved. However, it remains difficult to answer the question, “What is ARDS?” (81). The ARDS definition is still based on classic physiological and radiographic alterations. These criteria are subject to variable interpretations that likely account for some of the discrepancy in the epidemiology of ARDS from different centers (82). Other questions still remain, such as, “Is ARDS a homogeneous syndrome or the combination of several different disorders loosely bound together by common physiological and radiographic abnormalities?” Eisner and colleagues have reported that low tidal volume ventilation is equally efficacious for patients with a variety of clinical risk factors (58). These findings support the original theory of Petty that ARDS is a specific disorder that responds in a uniform manner to alterations in mechanical ventilatory strategy. However, with the approval of activated protein C for the treatment of severe sepsis, the stratification of patients with ARDS by clinical risk factor (sepsis vs. nonsepsis) may also have therapeutic implications (83). The pulmonary and critical care community should attempt to focus on widespread use and understanding of current diagnostic criteria to ensure reliability and compatibility of epidemiological data from different centers. However, it is unlikely that ARDS will be defined by variations of the present diagnostic criteria in the future. Schuster (84) suggested the following general definition of ARDS: “It is a specific form of lung injury in which structural changes (characterized pathologically as diffuse alveolar damage) and functional abnormalities (principally a breakdown in the alveolar-capillary barrier function) leading first to proteinaceous alveolar edema, and then (as a consequence) to altered respiratory system mechanics and hypoxemia.” We would add that ARDS is an inflammatory disease and that inflammation begets lung injury and subsequent structural change. Presently, there is no clinically useful biochemical marker of inflammation that can be used as part of the diagnostic criteria of ARDS (51). As the pathogenesis of ARDS is more completely understood, certain biochemical tests may become available that remove the inherent subjectivity in the AECC definition of this syndrome. The identification of such an inflammatory mediator that functions as an extremely sensitive and specific marker in diagnosing ARDS would constitute a major advance in this field. Future definitions, based on biochemical or even genetic predisposition to inflammation rather than on physiological and radiographic parameters, are likely to provide more homogeneous groups of patients within the overall population of what is now called ALI (85). This should allow investigators to target subgroups of patients based on their specific pattern of an inflammatory response, opening the door to individualized therapy for ARDS (85).

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References 1. Roupie E, Lepage E, Wysocki M, Fagon JY, Chastre J, Dreyfuss D, Mentec H, Carlet J, BrunBuisson C, Lemaire F, Brochard L. Prevalence, etiologies, and outcome of the acute respiratory distress among hypoxemic ventilated patients. Int Care Med 1999; 25:920–929. 2. Luhr OR, Antonsen K, Karlsson M, Aardal S, Thorsteinsson A, Frostell CG, Bonde J. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. Am J Respir Crit Care Med 1999; 159:1849–1861. 3. Rubenfeld GD, Caldwell ES, Steinberg KP, Hudson LD. Persistent lung injury and ICU resource utilization. Am J Respir Crit Care Med 1998; 157:A498. 4. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; 2:319–323. 5. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988; 138:720–723. 6. Fowler AA, Hamman RF, Good JT, Benson KN, Baird M, Eberle DJ, Petty TL, Hyers TM. Adult respiratory distress syndrome: risk with common predispositions. Ann Int Med 1983; 98:593–597. 7. Pepe PE, Potkin RT, Reus DH, Hudson LD, Carrico CJ. Clinical predictors of the adult respiratory distress syndrome. Am J Surg 1982; 144:124–130. 8. Kraus PA, Lipman J, Lee CCJ, Wilson WE, Scribante J, Barr J, Mathivha LR, Brown JM. Acute lung injury at Baragwanath ICU: an eight-month audit and call for consensus for other organ failure in the adult respiratory distress syndrome. Chest 1993; 103:1832–1836. 9. Parsons PE, Giclas PC. The terminal complement complex (sc5b-9) is not specifically associated with the development of the adult respiratory distress syndrome. Am Rev Dis 1990; 141:98– 103. 10. Moss M, Parsons PE. What is acute respiratory distress syndrome? J Intensive Care Med 1998; 13:59–67. 11. Rinaldo JE. The prognosis of the adult respiratory distress syndrome: inappropriate pessimism? Chest 1986; 90:470–471. 12. Sloane PJ, Gee MH, Gottlieb JE, Albertine KH, Peters SP, Rurns JR, Machiedo G, Fish JE. A multicenter registry of patients with acute respiratory distress syndrome: physiology and outcome. Am Rev Respir Dis 1992; 146: 419–426. 13. Hudson LD, Mildberg JA, Anardi D, Maunder RJ. Clinical risk for development of acute respiratory distress syndrome. Am J Respir Crit Care Med 1995; 151:293–301. 14. Connors AF, Speroff T, Dawson NV, Thomas C, Harrell FE, Wagner D, Desbiens N, Goldman L, Wu AW, Califf RM, Fulkerson WJ, Vidaillet H, Broste S, Bellamy P, Lynn J, Knaus WA. The effectiveness of right heart catheterization in the initial care of critically ill patients. JAMA 1996; 276:889–897. 15. Amato MBP, Barbas CSV, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, Takagaki TY, Carvalho CR. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338:347–354. 16. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342:1301–1308. 17. Moss M, Bucher B, Moore FA, Moore EE, Parsons PE. The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults. JAMA 1996; 275:50–54. 18. Moss M, Goodman PL, Heinig M, Barkin S, Ackerson L, Parsons PE. Establishing the relative accuracy of three new definitions of the adult respiratory distress syndrome. Crit Care Med 1995; 23:1629–1637.

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19. Lewandowski K, Metz J, Deutschmann C, Preib H, Kuhlen R, Artigas A, Falke KJ. Incidence, severity, and mortality of acute respiratory distress in Berlin, Germany. Am J Respir Crit Care Med 1995; 151:1121–1125. 20. Clark JG, Milberg JA, Steinberg KP, Hudson LD. Type III procollagen peptide in the adult respiratory distress syndrome: association of increased petide levels in bronchoalveolar lavage fluid with increased risk for death. Ann Intern Med 1995; 122:17–23. 21. Petty TL. ARDS: refinement of concept and redefinition. Am Rev Respir Dis 1988; 138:724. 22. Heffner JE, Brown LK, Barbieri CA, Harpel KS, DeLeo J. Prospective validation of an acute respiratory distress syndrome predictive score. Am J Respir Crit Care Med 1995; 152:1518– 1526. 23. Bone RC. Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome: what we do and do not know about cytokine regulation. Crit Care Med 1996; 24:163–172. 24. Suchyta MR, Clemmer TP, Elliot CG, Orme JF, Weaver LK. The adult respiratory distress syndrome: a report of survival and modifying factors. Chest 1992; 101:1074–1079. 25. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall R, Morris A, Spragg R. The American-European consensus conference on ARDS: definitions, mechanisms relevant outcomes, and clinical trial co-ordination. Am J Respir Crit Care Med 1994; 149:818–824. 26. Artigas A, Bernard GR, Carlet J, Dreyfuss D, Gattinoni L, Hudson L, Lamy M, Marini JJ, Matthay MA, Pinsky MR, Spragg R, Suter PM. The American-European consensus conference on ARDS Part 2: ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling. Am J Respir Crit Care Med 1998; 157:1332–1347. 27. Deitch EA. Multiple organ failure: pathophysiology and potential future therapy. Ann Surg 1992; 216:117–134. 28. Neff MJ, Rubenfeld GD. Clinical epidemiology of acute lung injury. Sem Respir Crit Care Med 2001; 22:237–246. 29. Rubenfeld GD, Caldwell E, Granton J, Hudson LD, Matthay MA. Interobserver variability in applying a radiographic definition for ARDS. Chest 1999; 116:1347–1353. 30. Beards SC, Jackson A, Hunt L, Wood A, Frerk CM, Brear G, Edwards JD, Nightingale P. Interobserver variation in the chest radiograph component of the lung injury score. Anaesthesia 1995; 50:928–932. 31. Meade MO, Cook RJ, Guyatt GH, Groll R, Kachura JR, Bedard M, Cook DJ, Slutsky AS, Stewart TE. Interobserver variation in interpreting chest radiographs for the diagnosis of acute respiratory distress syndrome. Am J Respir Crit Care Med 2000; 161:85–90. 32. Medoff BD, Harris RS, Kesselman H, Venegas J, Amato MBP, Hess D. Use of recruitment maneuvers and high positive end-expiratory pressure in a patient with acute respiratory distress syndrome. Crit Care Med 2000; 28: 1210–1216. 33. Neff MJ, Rubenfeld GD, Caldwell ES, Hudson LD, Steinberg KP. Exclusion of patients with elevated pulmonary capillary wedge pressure from acute respiratory distress syndrome. Am J Respir Crit Care Med 1999; 159:A716. 34. Ferguson ND, Meade MO, Tomlinson G, Stewart TE. Values of the pulmonary artery occlusion pressure (PAOP) in ARDS and acute lung injury (ALI). Am J Respir Crit Care Med 1999; 159:A716. 35. Connors AF, McCaffree DR, Gray BA. Evaluation of right-heart catheterization in the critically ill patient without acute myocardial infarction. N Engl J Med 1983; 308:263–267. 36. Eisenberg PR, Jaffe AS, Schuster DP. Clinical evaluation compared to pulmonary artery catheterization in the hemodynamic assessment of critically ill patients. Crit Care Med 1984; 12:549–553. 37. Cook DJ, Simel DL. The rational clinical examination: does this patient have abnormal central venous pressure? JAMA 1996; 275:630–634.

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38. Neff MJ, Caldwell ES, Hudson LD, Rubenfeld GD. The effect of definition of left atrial hypertension (LAH) on identification of patients with acute lung injury (ALI). Am J Respir Crit Care Med 2001; 144:124–130. 39. Aberle DR, Wiener-Kronish JP, Webb WR, Matthay MA. Hydrostatic versus increased permeability pulmonary edema: diagnosis based on radiographic criteria in critically ill patients. Radiology 1988; 168:73–79. 40. Thamason JWW, Ely EW, Chiles C, Ferretti G, Freimans RI, Haponik EF. Appraising pulmonary edema using supine chest roentgenograms in ventilated patients. Am J Respir Crit Care Med 1998; 157:1600–1608. 41. Bernard G. Personal communication. 42. Abraham E, Matthay MA, Dinarello CA, Vincent JL, Cohen J, Opal SM, Glauser M, Parsons P, Fisher CJ, Repine JE. Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: time for a reevaluation. Crit Care Med 2000; 28:232–235. 43. Murray JF. The adult respiratory distress syndrome (may it rest in peace). Am Rev Respir Dis 1975; 111:716–718. 44. Petty TL. The adult respiratory distress syndrome (confessions of a lumper). Am Rev Respir Dis. 1975; 111:713–715. 45. Marks JD, Marks CB, Luce JM, Montgomery AB, Turner J, Metz CA, Murray JF. Plasma tumor necrosis factor in patients with septic shock: mortality rate, incidence of adult respiratory distress syndrome and effects of methylprednisolone administration. Am Rev Respir Dis 1990; 141:94–97. 46. Casey LC, Balk RA, Bone RC. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 1993; 119: 771–778. 47. Hoch RC, Rodriguez R, Manning T, Bishop M, Mead P, Shoemaker WC, Abraham E. Effects of accidental trauma on cytokine and endotoxin production. Crit Care Med 1993; 21:839–845. 48. Rodrick ML, Wood JJ, O’Mahoney JB, Davis CF, Grbic JT, Demling RH, Moss NH, Saporoschetz I, Jordan A, D’Eon P. Mechanisms of immunosuppression associated with severe nonthermal traumatic injuries in man: production of interleukin 1 and 2. J Clin Immunol 1986; 6:310–318. 49. Moss M, Gillespie MK, Ackerson L, Moore FA, Moore EE, Parsons PE. Endothelial cell activity varies in patients at risk for the adult respiratory distress syndrome. Crit Care Med 1996; 24:1782–1786. 50. Parsons PE, Moss M. Circulating markers of sepsis and acute lung injury. In: Fein AM, Abraham EM, Balk RA, Bernard GR, Bone RC, Dantzker DR, Fink MP, eds. Sepsis and Multiorgan Failure. Baltimore: Williams & Wilkins, 1997:277–285. 51. Pittet JF, Mackersie RC, Martin TR, Matthay MA. Biological markers of acute lung injury: prognostic and pathogenetic significance. Am J Respir Crit Care Med 1997; 155:1187–1205. 52. Staub NC. Pulmonary edema. Physiol Rev 1974; 54:678–811. 53. Calandrino FS, Anderson DJ, Mintun MA, Schuster DP. Pulmonary vascular permeability during the adult respiratory distress syndrome: a positive emission tomographic study. Am Rev Respir Dis 1988; 138:421–428. 54. Kaplan JD, Calandrino FS, Schuster DP. A positive emission tomographic comparison of pulmonary vascular permeability during the adult respiratory distress syndrome and pneumonia. Am Rev Respir Dis 1991; 143: 150–154. 55. Steinberg KP, Hudson LD. Acute lung injury and acute respiratory distress syndrome: the clinical syndrome. Clin Chest Med 2000; 21:401–417. 56. Gattinoni L, Pelosi P, Suter PM, Pedoto A, Vercesi P, Lissoni A. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease: different syndromes? Am J Respir Crit Care Med 1998; 158:3–11. 57. Pelosi P, Gattinoni L. Acute respiratory distress syndrome of pulmonary and extra-pulmonary origin: fancy or reality? Intensive Care Med 2001; 27:457–460.

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58. Eisner MD, Thompson T, Hudson LD, Luce JM, Hayden D, Schoenfeld D, Matthay MA. Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2001; 164:231–236. 59. Kutlu CA, Williams EA, Evans TW, Pastorino U, Goldstraw P. Acute lung injury and acute respiratory distress syndrome after pulmonary resection. Ann Thorac Surg 2000; 69:376–380. 60. Lieber CS. Medical disorders of alcoholism. N Engl J Med 1995; 333:1058–1065. 61. Jurkovich GJ, Rivara FP, Gurney JG, Fligner C, Ries R, Mueller BA, Copass M. The effect of acute alcohol intoxication and chronic alcohol abuse on outcome from trauma. JAMA 1993; 270:51–56. 62. Iribarren C, Jacobs DR, Sidney S, Gross MD, Eisner MD. Cigarette smoking, alcohol consumption, and risk of ARDS: a 15-year cohort study in a managed care setting. Chest 2000; 117:163–168. 63. Kaul TK, Fields BL, Riggins LS, Wyatt DA, Jones CR, Nagle D. Adult respiratory distress sydrome following cardiopulmonary bypass: incidence, prophylaxis, and management. J Cardiovasc Surg 1998; 39:777–781. 64. Dancey DR, Hayes J, Gomez M, Schouten D, Fish J, Peters W, Slutsky AS, Stewart TE. ARDS in patients with thermal injury. Intensive Care Med 1999; 25:1231–1236. 65. Moss M, Guidot DM, Steinberg KP, Duhon GF, Treece P, Wolken R, Hudson LD, Parsons PE. Diabetic patients with septic shock have a decreased incidence of the acute respiratory distress syndrome (ARDS) Crit Care Med 2000; 28:2187–2192. 66. Milberg JA, Davis DR, Steinberg KP, Hudson LD. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993. JAMA 1995; 273:306–309. 67. Abel SJC, Finney SJ, Brett SJ, Keogh BF, Morgan CJ, Evans TW. Reduced mortality in association with the acute respiratory distress syndrome (ARDS). Thorax 1998; 53:292–292. 68. Rocco TR, Reinert SE, Cioffi W, Harrington D, Buczko D, Simms HH. A 9-year, single institution, retrospective review of death rate and prognostic factors in adult respiratory distress syndrome. Ann Surg 2001; 233:414–422. 69. Thompson BT, Hayden D, Matthay MA, Brower R, Parsons PE. Clinicians’ approaches to mechanical ventilation in acute lung injury and ARDS. Chest 2001; 120:1622–1627. 70. Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1985; 132:485–489. 71. Knaus WA, Sun X, Hakim RB, Wagner DP. Evaluation of definitions for adult respiratory distress syndrome. Am J Respir Crit Care Med 1994; 150:311–317. 72. Davidson TA, Caldwell ES, Hudson LD, Steinberg KP. Long-term mortality following acute respiratory distress syndrome. Am J Respir Crit Care Med 1998; 157:A498. 73. Monchi M, Bellenfant F, Cariou A, Joly LM, Thebert D, Laurent I, Dhainaut JF, Brunet F. Early predictive factors of survival in the acute respiratory distress syndrome: a multivariate analysis. Am J Respir Crit Care Med 1998; 158:1076–1081. 74. Zilberberg MD, Epstein SK. Acute lung injury in the medical ICU: comorbid condition, age, etiology, and hospital outcome. Am J Respir Crit Care Med 1998; 157:1159–1164. 75. Ely EW, Wheeler AP, Thompson BT, Ancukiewicz M, Steinberg KP, Bernard GR. Recovery rate and prognosis in older persons who develop acute lung injury and the acute respiratory distress syndrome. Ann Int Med 2002; 136:25–36. 76. Wyke RJ. Problems of bacterial infection in patients with liver disease. Gut 1987; 28:623–641. 77. Matuschak GM, Rinaldo JE, Pinsky MR, Gavaler JS, Van Thiel DH. Effect of end-stage liver disease on the incidence and resolution of the adult respiratory distress syndrome. J Crit Care 1987; 2:162–173. 78. Doyle RL, Szaflarski N, Modin GW, Wiener-Kronish JP, Matthay MA. Identification of patients with acute lung injury: predictors of mortality. Am J Respir Crit Care Med 1995; 152:1818–1824.

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79. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342:1334–1349. 79a. Nuckton TJ, Alonso JA, Kallet RH, Daniel BM, Pittet JF, Eisner MD, Matthay MA. Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 2002; 346:1281–1286. 80. Moss M, Mannino DM. Racial and gender differences in acute respiratory distress syndrome (ARDS) deaths in the United States: Analysis of multiple-cause mortality data (1979–1996). Crit Care Med 2002; 30:1679–1685. 80a. Martin GS, Mannino DM, Eaton S, Moss M. Epidemiology of sepsis in the United States: incidence, demographics, and outcome from 1979–2000. N Engl J Med. In press. 81. Schuster DP. What is acute lung injury? What is ARDS? Chest 1995; 107: 1721–1726. 82. Garber BG, Herbert PC, Yelle JD, Hodder RV, McGowen J. Adult respiratory distress syndrome: a systematic overview of incidence and risk factors. Crit Care Med 1996; 24:687– 695. 83. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriquez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699–709. 84. Schuster D. ARDS and pornography: I know it when I see it. J Intensive Care Med 1998; 13:55–56. 85. Abraham E. Toward new definitions of acute respiratory distress syndrome. Crit Care Med 1999; 27:237–238.

3 Epidemiology of Acute Lung Injury A Public Health Perspective GORDON D.RUBENFELD and MARGARET J.NEFF Harborview Medical Center University of Washington Seattle, Washington, U.S.A.

I. Introduction Critical care clinicians are drawn to practice in the intensive care unit by the physiological nature of critical illness and the application of physiological principles to the care of critically ill patients. We frequently consider the physiological derangements of acute lung injury (ALI): the gas exchange abnormalities, the abnormal thoracic compliance, and the response to positive end expiratory pressure (PEEP). We have come to appreciate the immunological and tissue repair abnormalities seen in patients with acute lung injury. More recently, we have been able to link pathophysiology with cellular mechanisms in the concept of ventilator-induced lung injury and ventilator-induced organ failure. The clinical epidemiology of acute lung injury in terms of its diagnostic criteria, risk factors, and prognostic factors has also evolved (1). However, it is unusual for critical care clinicians and investigators to consider the public health impact of critical illness syndromes in general and, more specifically, acute lung injury. Public health professionals are less interested in the exact pathophysiological mechanism of disease and focus on the disease’s impact on the health of the public and mechanisms for reducing this impact. This is a particularly important perspective on disease, if an unusual one for critical care. Understanding the public health implications of acute lung injury places it in relation to other common diseases and helps to prioritize research and clinical funding. Understanding changes in the burden and outcome of illness tells us whether we are doing a better job at what ultimately matters: improving the health of the public. To address these questions about acute lung injury and critical illness syndromes, answers to some basic epidemiological questions are needed. What is the incidence of acute lung injury? What is the attributable mortality and morbidity of acute lung injury? Are effective treatments or preventive interventions being implemented in the community? Is the incidence, outcome, or use of effective therapies changing over time? These data are available for a variety of diseases. There are a number of populationbased studies on the incidence and outcome of cardiovascular, pulmonary, infectious, and neoplastic diseases. In the United States, the National Center for Health Statistics maintains data on the incidence and mortality of hundreds of diseases (2). Similarly, the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer

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Institute maintains high-quality data on cancer incidence and survival from selected areas across the United States (3). Similar data are not readily available for sepsis, acute lung injury, or multiple organ failure. Studying the epidemiology of ALI is not easy and may explain the lack of data. It is a syndrome that is operationally defined by laboratory, radiological, and physiological criteria that themselves have not been well defined in terms of reliability and validity (4– 7) (see Chap. 2). Even the terminology can be confusing. We will adopt the North American-European Consensus Conference (AECC) nomenclature and use ALI as a comprehensive term for the syndrome and acute respiratory distress syndrome (ARDS) to refer to a specific subset with more severe hypoxemia. There is no diagnostic test for ALI similar to troponin in myocardial infarction or serology in infectious diseases. Discharge diagnostic codes which are used to study the epidemiology of many diseases are extremely inaccurate in ALI. Compared to chronic diseases like cancer or asthma, ALI has a short duration and high mortality rate, which makes the number of prevalent cases available for study at any given time small. Despite these challenges, a growing body of literature exists to allow us to estimate the public health implications of ALI.

II. Incidence The incidence of a disease is defined as the number of new cases divided by the population at risk of developing the disease multiplied by the period of time they were at risk. Prevalence is the number of existing cases at any given time divided by the population at risk for developing the disease. Because ALI is a disease of relatively short duration, incidence and prevalence will approximate each other. It is important to distinguish which population constitutes the denominator in the incidence calculation. For population-based estimates of incidence, this will be the entire community from which patients are admitted to the hospital where ALI might be diagnosed. In epidemiological studies of ALI a more convenient denominator is often used, e.g., the “incidence” of ALI in the intensive care unit (ICU) population, in the population with acute respiratory failure, or in the population of patients with a known risk factor for ALI. These numbers are not useful for estimating the population burden of ALI. Incidence figures for ALI are important because they establish the importance of the disease to justify research and health care funding, allow tracking to explore trends in the disease, and provide data to study the potential explanations of differences in the incidence of the disease. For example, “Respiratory Distress Syndrome, Adult” is listed as a rare disease by the National Organization of Rare Disorders (8). The earliest incidence figure for ARDS is an often quoted 1972 National Heart, Lung, and Blood Institute (NHLBI) report estimate of 150,000 cases per year in the United States or about 75 per 105 person-years (9). Relatively few empirical estimates of the incidence of ALI or ARDS exist (10–13). Available empirical studies place the incidence of ARDS at much lower rates than expected by the NHLBI report: approximately 2–12 per 105 person-years (Table 1). Only one of these studies used the AECC definition for ALI. The others used more restrictive criteria, including more severe hypoxemia, a risk factor for ALI, and reduced thoracic compliance. These studies were also limited by a variety of factors: relatively short observation periods, potential for missed cases due to

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32

lack of standardized definition, lack of a generalizable study population, and estimate of population incidence made from a small number of hospitals. Several lines of reasoning suggest these incidence estimates are, at least for the United States, as much as an order of magnitude too low. Analysis of the incidence of known associated risk conditions yields incidence rates for ALI that are higher than these published estimates. For example, in all epidemiological series and clinical trials, sepsis and pneumonia are the most common risk factors for ALI. Recent data suggest that the incidence of severe sepsis in patients in ICUs is 150 per 105 person-years (Table 2) (14). Epidemiological studies and clinical trials suggest that 30–43% of patients with severe sepsis develop ARDS (15, 16). Combining these data yields incidence estimates for sepsis associated ARDS of 45–64 cases per 105 person-years. A similar calculation for severe trauma (injury severity score

Table 1 Selected ALI and ARDS Incidence Studies Study location (sample time of study) Grand Canaria (1983–1985)

Utah (12 months, 1989–1990)

Definition

Incidence

1. Risk

1.5 per 105 person-years for

2. or with PEEP 5 and no improvement in 24 h and

3.5 per 105 person-years for

also 3. Bilateral infiltrates 4. No clinical left atrial hypertension

10.6 per 105 person-years for acute respiratory failure

Ref.

51

4.8–8.3 per 105 person-years 52 1. for ARDS 2. Bilateral infiltrates 3. No clinical evidence of left atrial hypertension 4. Static thoracic compliance 2.5

3.0 per 105 person-years for 19 severe lung injury 88.6 per 105 person-years for acute respiratory failure

Maryland (1995)

ICD-9 codes

10.5–14.2 per 105 personyears

Sweden, Denmark, Iceland (8 weeks in 1997)

AECC criteria

17.9 per 105 person-years for 18 ALI 13.5 per 105 person-years for ARDS 77.6 per 105 person-years for acute respiratory failure

19a

Epidemiology of acute lung injury

33

Table 2 ARDS Incidence Estimated from Associated Conditions Associated condition

Incidence of associated condition

Patients without risk who develop ARDS

Calculated incidence of ARDS

Severe sepsis

150 per 105 personyearsa

30–43%b

45–64 per 105 personyears

Severe trauma (ISS>15)

44 per 105 person-yearsc

25–40%d

11–18 per 105 personyears

Acute respiratory failure

137 per 105 personyearse

18%f

25 per 105 personyears

a

From Ref. 14. From Refs. 15, 16. c From Ref. 53. d From Refs. 15, 54. e From Ref. 55. f From Ref. 23. b

>15) yields incidence rates for ARDS of 11–18 per 105 person-years associated with trauma alone. These estimates are conservative for the incidence of ALI because they do not include an estimate of the number of patients who meet the less strict hypoxemia criterion for ALI and do not include patients who develop lung injury from causes other than sepsis or trauma, e.g., inhalation injuries, aspiration, and burns. Several recent sources corroborate these higher incidence rates. Moss and colleagues analyzed national death data and, relying on ICD-9 coding, arrived at a figure of 19,460 deaths associated with ARDS in 1993 in the United States (1). Assuming a mortality rate for ARDS of approximately 40%, this yields a case incidence rate of 26 per 105 personyears. Goss and colleagues combined screening log data from the ARDS Network multicenter clinical trial with data on U.S. hospitals to arrive at ALI incidence rates of 45–65 per 105 person-years even assuming that ALI cases only occurred in hospitals with more than 20 ICU beds (17). Finally, two recent studies have examined the incidence of ALI in Scandinavia and Berlin. Lewandoski and colleagues studied acute respiratory failure during a 2-month period in Berlin in 1991 (18–19). They defined acute respiratory failure as intubation and mechanical ventilation of >24 hours. The incidence of acute respiratory failure was 88 per 105 person-years. The authors used a scoring system to categorize the severity of patients’ lung injury, making direct comparison to the AECC criteria difficult. Patients with ALI by AECC criteria could have a score as low as 0.75 (1 point for and 2 points for two quadrants of radiographic opacity without receiving points for PEEP or compliance, which are not in the AECC definition). Using this cutoff and excluding 108 patients in the study with cardiogenic shock or cardiogenic edema leaves an incidence of 48 cases of ALI per 105 person-years. Luhr and colleagues (19) used similar methods to study the incidence of ALI and ARDS in 132 ICUs in Scandinavia over an 8-week period and found incidences of acute respiratory failure, ALI and ARDS of 77.6, 17.9, and 13.5 per 105 person-years, respectively.

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34

Despite the difficulties in comparing the incidence of ALI across these studies, two striking and consistent findings emerge. The incidence of ALI appears to be significantly higher than the 2–12 per 105 person-years rates previously estimated for ARDS. These studies indicate that all forms of acute respiratory failure have a high mortality rate. The overall mortality rate for acute respiratory failure was 43% in the Berlin study and 41 % in the Scandinavian study. In both studies patients with acute respiratory failure, regardless of etiology, had similar mortality to patients with ALI. There is little support in the available data for a single incidence value for ALI. Variability in incidence rates between studies can reflect chance, true variability, or result simply from methodological differences. None of the existing studies on the population incidence of ALI use comparable methods or definitions: therefore, direct comparison of incidence rates is difficult. The studies used various observation periods, used different definitions for ALI and ARDS, and relied on varying degrees of quality control for case identification and data integrity. Given the evidence of interobserver variability in clinician radiographic interpretation and diagnosis of ALI (5, 6), rigorous protocolized case identification is necessary in epidemiological studies of ALI. True variability in incidence is a potential explanation of the existing studies. No single number reflects the incidence rate for myocardial infarction, colon cancer, or motor vehicle collisions, and we should not expect a single incidence figure for ALI. Potential explanations for this variability include differences in the incidence of risk factors, susceptibility (including genetic variation), and health care utilization. For example, differences in smoking, use of motor vehicles, population density, incidence of respiratory infections, and genetic factors might all influence geographic variability in the incidence of ALI. An interesting and unexplored source of variation is the effect of health care resource use on ALI incidence. Even within the United States there is wide variability in the ratio of hospital beds, ICU beds, emergency medical response time, and other medical resources. These may influence the observed incidence of ALI in two ways. To be diagnosed with ALI, patients must survive long enough to be admitted to an ICU, there must be an ICU bed to be admitted to, and they must have an arterial blood gas and a chest radiograph. Limited access to ICU care, implicit or explicit restriction of intensive care, or differences in emergency medical response time may reduce the number of observed cases of ALI. Similarly, the extent to which a region provides aggressive medical and surgical treatments may also affect the number of cases of ALI. For example, organ and bone marrow transplantation, coronary bypass grafting, and intensive chemotherapy all are associated with ALI, and countries that provide greater access to these treatments may have more cases of lung injury (20–22).

III. Attributable Mortality Attributable mortality is relatively easy to define mathematically: it is the difference in mortality rates between patients with a disease or exposure and those without. Practically, it is much more difficult to attribute a given death to a specific disease. A 68-year-old man who is an alcoholic is severely injured in a motor vehicle crash and develops ALI. After 14 days of progressive organ failure, life-sustaining treatment is withdrawn at the request of the patient’s family. Is the patient’s death attributable to alcoholism? To motor

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vehicle trauma? To ARDS? To multiple organ failure? To the decision to withdraw medical therapy? To address these complexities, it is helpful to think of attributable mortality in two categories: as deaths associated with the disease and as deaths caused by the disease that could be prevented by some therapy or intervention. The former is much easier to calculate, although the latter is more important for public health purposes. A. Attributable Short-Term Mortality Mortality rates attributed to various diseases and reported in cause-of-death tables are calculated based on death records and generally reflect deaths associated with the disease. Attributable mortality associated with ALI can be calculated by multiplying the incidence rate times the mortality rate from the disease. The U.S. adult population (over age 15) in 2000 was 215 million. While the above discussion indicates that the incidence of ALI in the United States has not been described, it is reasonable, based on the studies cited above, to estimate it at between 20 and 50 cases per 105 person-years, or 43,000–107,000 cases per year. Assuming the mortality rate of approximately 40% observed in the recent studies of acute respiratory failure, 17,000–43,000 deaths per year are associated with ALI. Although the figures are arrived at by different methods, it is important to place these numbers into context with other diseases with important public health impact (Table 3).

Table 3 Attributable Mortality for Acute Lung Injury, Acute Respiratory Failure, and Comparison Diseases Disease ALI

Attributable mortality

a

17,000–43,000

Acute respiratory failure

b

60,000–120,000 c

Acute myocardial infarction

199,454

Breast cancerc

41,528

HIV disease Asthma

c

c

14,802 4,657

a

Assumes incidence range 20–50 per 105 person-years, mortality of 40%, and U.S. 2000 census population of 215 million>age 15. b Assumes incidence range 70–140 per 105 person-years and mortality of 40%, and U.S. 2000 census population of 215 million>age 15. c Based on U.S. 1999 death certificate data (56).

One of the surprising observations from recent epidemiological studies in ALI is the similar mortality, approximately 40%, that exists among the following different categories of respiratory failure: (1) patients with ARDS, (2) patients with ALI who meet other criteria for ARDS but with less severe hypoxemia and (3) patients with acute respiratory failure (intubation and mechanical ventilation >24

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hours regardless of etiology, radiograph, or degree of hypoxemia) (23, 24). This observation provides little insight into disease mechanisms in this heterogenous population, but it has significant implications for public health. The incidence of acute respiratory failure is estimated at between 70 and 140 per 105 person-years. If 40% of these patients die, then up to 120,000 adult deaths per year are associated with mechanical ventilation. Even small reductions in the mortality or morbidity associated with mechanical ventilation would have significant implications for the public health. Identifying the independent or causal contribution of ALI to mortality is much more difficult. Two options exist for identifying this figure. By examining observational epidemiological data, one can try to control for other factors associated with mortality and estimate the independent effect of ALI on mortality. This is an important analysis because it is possible that ALI is merely a marker of severity of illness and contributes little on its own to mortality. These are difficult studies to do because they require identifying a cohort of critically ill patients, only a minority of whom will develop lung injury, and following them to compare mortality. The study by Hudson and colleagues attempted to control for this by the epidemiological technique of restriction (15). By comparing patients with ARDS to those at similar risk who did not develop ARDS, they showed that ARDS increased mortality rate in all risk conditions by an average of 3.3fold. This ranged from a relative risk for death attributed to ARDS of 1.4 in sepsis to 4.3 in trauma to 8.6 in drug overdose. The authors further controlled for APACHE in the septic patients and injury severity in the trauma patients without a significant effect on the attributable mortality. More compelling evidence of the attributable and preventable deaths in ALI would be reduction in mortality from an effective intervention to prevent ALI or to prevent death after ALI. No interventions have been shown to prevent ALI; however, recent data from two studies suggest that a ventilator strategy can reduce mortality in ALI by a risk difference of 8.8–33% (25, 26). These data can be analyzed in light of the findings in Table 3 to estimate that 3,800–35,000 deaths annually could be prevented in the United States by implementing lung-protective ventilation in ALI, depending on its incidence and the benefits of lung-protective ventilation beyond the clinical trial population (27, 28). B. Attributable Long-Term Mortality There is growing interest in the effects of critical illness syndromes on long-term outcomes. The methodological challenges are similar to those encountered in establishing attributable short-term mortality rates. Trying to separate the independent and causal effect of ALI on long-term mortality from the effects of the risk factors that cause or are associated with ALI is a challenge. Two studies have documented an effect of sepsis on long-term survival. A study by Quartin et al. showed that, even after controlling for age and comorbidity using ICD-9 diagnostic codes, patients with sepsis have a higher mortality rate than control patients (29). Among patients who survive for a year, those who had an episode of sepsis have an approximately 1.5 times greater rate of death than similar patients without an episode of sepsis. Patients who survive for 30 days after sepsis still have a median survival that is reduced from 6.24 to 2.35 years. Concerns about this study relate to the quality of the ICD-9 coding of comorbidites and the possibility that

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patients who have been admitted to the hospital for a severe illness like sepsis have more comorbidities coded than controls. A number of studies have followed ALI and ARDS patients beyond hospital discharge to explore the long-term survival in patients with lung injury. For example, a study of relatively young (mean age 48) and previously healthy ARDS patients enrolled in a clinical trial of inhaled nitric oxide showed that survivors of ARDS continued to accrue mortality from day 28 after ARDS until about day 180, where the mortality rate stabilized (29a). However, these data cannot be used to assess attributable mortality of ARDS since it only includes patients with disease. Only one study has compared long-term survival in patients who survived to hospital discharge and compared it to controls matched on severity of sepsis or trauma (30). Patients with sepsis had reduced long-term survival compared to patients with trauma, regardless of the presence of ARDS; however, there was no independent effect of ARDS on long-term mortality when the analysis was restricted to patients who survived to hospital discharge. This study was limited by two factors. It was a relatively small study, so important effects of ARDS on long-term mortality may have been missed, and authors could not completely exclude the possibility that the controls had some mild component of ALI. Nevertheless, the best current evidence suggests that ALI does not independently worsen long-term survival in patients who survive to hospital discharge. Importantly, this study found that 80% of all deaths occurred in the hospital, 77% of all deaths occurred by day 30 after the onset of ARDS, and 89% of all deaths occurred by day 100 after the onset of ARDS.

IV. Attributable Morbidity If, as recent clinical evidence suggest, mortality after ALI is declining and, in some subgroups, may be as low as 20%, then the morbidity incurred by survivors of ALI becomes an increasingly significant clinical issue. We can estimate this burden by calculating the number of ALI 5-year survivors in the U.S. health care system. Assuming that there are 107,500 cases of ALI per year (215 million adults×50 cases/100,000 person-year) (Table 3), that 70% of patients with ALI survive their acute illness, and that all patients with trauma associated ALI and 50% of sepsis associated ALI survive for 5 years, then more than 280,000 ALI survivors are alive in the United States. This conservative estimate excludes all survivors whose ALI occurred more than 5 years ago. As we improve our acute care to critically ill patients, we must address the health care sequelae of the large group of ALI survivors we are creating. While information about the late outcomes of critical illness is growing, this is an evolving field with relatively few data particularly regarding mechanisms and treatments. The same methodological limitations apply to identifying the attributable effect of ALI on morbidity as was noted for its effect on mortality. A. Attributable Effect of ALI on Functional Status For the purposes of this discussion, functional status refers to objective and physiological measures of performances after an episode of acute lung injury. This includes pulmonary function, gas exchange, exercise tolerance, and cognitive performance. A number of

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investigators have studied pulmonary function in survivors of ALI. Pulmonary function appears to be severely abnormal within 1 month of ALI onset. The abnormalities are primarily restrictive, although obstructive abnormalities have been reported (31). This is followed by a period of rapid improvement in pulmonary function of over 3–6 months. After approximately 6 months most of the improvement that will occur has occurred. The majority of patients are left with little measurable pulmonary dysfunction except for a reduced DLCO. A small minority have a persistent severe restrictive defect. These physiological data are corroborated by similar changes in radiographic studies (32, 33). Although it seems reasonable to assume that pulmonary function abnormalities are attributable to the parenchyma and vascular pathology of ALI, there are no studies comparing pulmonary function in ALI patients to a similar control group that tests this hypothesis. It is possible that diffusion abnormalities and restrictive disease in ALI survivors is due to the combination of a slowly resolving endothelial injury and critical illness polyneuropathy that are sequelae of systemic inflammation and have nothing to do with lung injury. There is a growing body of literature demonstrating acute cognitive impairment in critically ill patients (34, 35). However, the mechanism, persistence, and relationship to ALI, hypoxemia, or duration of mechanical ventilation is unclear. At one year, the majority of ALI survivors have impaired memory, attention, concentration, and/or decreased mental processing speed (36). The extent to which these cognitive abnormalities are attributable to ALI or to risk conditions is unknown, but they reflect significant morbidity in these patients. B. Attributable Effect of ALI on Psychiatric Outcomes and Quality of Life To an ALI survivor, quality of life is as important as any specific physical or functional parameter. Potential problems were initially appreciated only anecdotally as clinicians saw ALI survivors in follow-up and heard their patients describe depression or difficulty at work or with relationships. Subsequently these outcomes have been more formally studied by means of standardized questionnaires and tools (31, 37). Hopkins and colleagues confirmed results seen by other investigators who interviewed ALI survivors using the Medical Outcomes Study 36-item, short form health survey (SF-36) (36). ALI survivors showed continued poor scores when tested at one year in the categories of role emotional, mental health, bodily pain, and general health. Davidson et al. evaluated quality-of-life measures in ALI survivors as compared to matched critically ill controls who had not developed ALI and found worse results in the domains of physical functioning, general health, and vitality when measured on average 2 years after hospitalization (38). While the degree of impairment was not as profound as for patients with other severe lung diseases, many of these patients still found it difficult to function fully and to return to work. In most studies and clinical reports, patients described feelings of fatigue, memory loss, depression, and fear of relapse. In fact, Weinert and colleagues found that over 75% of survivors had scores on a depression scale that qualified for a diagnosis of depression during the first 15 months after ALI (39). In addition, another study revealed that over 50% of a cohort of critically ill patients transferred to a long-term acute care facility were

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prescribed an antidepressant (40). While historically studied in people who have suffered from trauma or war experiences, posttraumatic stress disorder (PTSD) is a similarly important mental health assessment in critically ill patients. Many clinicians have questioned whether patients suffered from memories of their intensive care unit experience, but except for anecdotes few data have been available. However, Schelling and colleagues have studied this issue using tools such as the SF-36 and the Post Traumatic Stress Syndrome-10 (41). Of the 80 patients studied there was evidence of PTSD in one third of the patient population approximately 4 years post-hospitalization. These remain important outcomes to be incorporated into the future clinical trials of ALI and to be studied among current survivors of ALI. Whether other aspects of the patient’s hospitalization, e.g., hypoxemia or level of sedation, may be associated with the development of depression or PTSD is unknown but is important to explore as we try to optimize the physical and mental well-being of ALI survivors.

V. Effect of Aging Population Age is a complex “exposure” variable. Like gender or race, it is a surrogate marker for a variety of other social and biological exposures. Identifying an association between age and other variables sheds little light on the causal factors associated with age that may actually be driving the relationship. Because age is strongly associated with the decision to admit patients to the ICU and to withdraw life-sustaining treatments in the ICU, the relationships between age and other variables are confounded by these physician decisions. Similarly, associations between age and other variables may not reflect an effect of age, per se, but of other variables that are frequently associated with age. For example, while age is crudely associated with mortality in many studies of critical illness, the effect disappears or is mitigated when comorbidities are accounted for (42). Therefore, the effect of age alone is less than the effect of diabetes, heart failure, and malnutrition which occur more frequently in the elderly than in other populations. These mechanistic issues are of less concern to the public health epidemiologist. Regardless of the mechanism, if older people are at greater risk of developing ALI or at greater risk of mortality and morbidity from ALI, then age is an important factor in the clinical epidemiology of the disease. It is particularly important given the realities of the aging population in the United States. By the year 2050, the population over the age of 65 will increase from 16% of the population to 25% of the population, with approximately 82 million people in this age group (43). There are relatively few data to model the effect of an aging population on incidence and mortality from ALI. We know that the incidence of risk factors for ALI including sepsis and pneumonia increases with age (44). There is a gradual increase in the incidence of sepsis during the adult years (1 mm in diameter), which correspond to the vascular filling defects demonstrated by bedside balloon occlusion pulmonary angiography in 48% of patients with ARDS, are more prevalent in patients who die in the early phase (52, 54). Thromboemboli detected only by light microscopy (microthrombi) are as prevalent as macrothrombi but tend to be distributed throughout all phases of ARDS (52). Microthrombi are of two types: hyaline platelet-fibrin thrombi in capillaries and arterioles and laminated fibrin clots in preacinar and large intra-acinar arteries (52, 55). Platelet fibrin thrombi confined to small arterioles and capillaries are most numerous in the acute phase of ARDS and are thought to represent localized

Figure 21 Enlarged, fibrous-walled airspaces are arranged in a honeycomb pattern (Movat pentachrome stain; original magnification×160). (From Ref. 84.) or disseminated intravascular coagulation (DIC). Microthrombi contribute to the reduction in peripheral arterial filling on postmortem arteriograms (Fig. 22) Larger clots may be embolic or formed in situ; morphologically it is impossible to tell the difference. In ARDS, it is likely that both mechanisms of clot deposition occur. Critically ill patients with indwelling vascular catheters are predisposed to pulmonary embolism (56). In a study of injured and burned patients, Eeles and Sevitt concluded that

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pulmonary microthrombi and macrothrombi arose as emboli from systemic venous thrombi (55). Thromboembolism also has been considered to be a major initiating cause of ARDS, especially in patients with traumatic shock (57, 58). On the other hand, pulmonary endothelial injury can cause localized intrapulmonary or disseminated intravascular coagualtion (59, 60). Platelet sequestration has been shown to occur in ARDS, and an injurious role for platelets has been suggested (61, 62). Whether or not they are the primary triggering mechanisms, thromboemboli can contribute to lung injury at any stage, further reducing the pulmonary vascular bed and so causing lung necrosis through ischemia. Classic wedge-shaped hemorrhagic infarcts may be seen in ARDS, but frequently infarcts assume unusual patterns such as subpleural band-like or intermittent lobular necrosis (50, 63). Lung tissue that is adjacent to the visceral pleura is particularly susceptible to the development of ischemic necrosis because of reduced collateral blood flow (50). Postmortem studies using indocyanine green instilled into the airways indicate preferential ventilation of hypoperfused areas (50). These peripheral necrotic regions are thus susceptible to barotrauma and infection, resulting in lung cavitation, pneumothorax, or bronchopleural fistula (50, 64). Communicating pleural arcade vessels that fill from pulmonary artery to pulmonary artery frequently bridge peripheral hypoperfused areas, but the ability of these arcades to provide collateral blood flow is unknown (50, 63) (Fig. 22). In the proliferative and fibrotic stages of DAD, fibrocellular intimal proliferation is a response to endothelial injury in arteries, veins and lymphatics (52) (Fig. 23). Vascular lumens are narrowed by concentrically or eccentrically layered fibrin, proliferating myointimal cells, hyperplastic endothelial cells, and fibromyxoid connective tissue. Obstruction of venous and lymphatic channels potentially further increases intracapillary pressure, contributing to the accumulation of interstitial edema as well as impeding the removal of extra vascular fluid from the lung (52). In the late proliferative and fibrotic phases of ARDS, postmortem arteriograms show narrow preacinar arteries stretched about fibrous-walled cysts and dilated airspaces (52) (Fig. 22). Serpentine arterial branches have thickened fibromuscular walls (Fig. 20). Arterial tortuosity occurs as a result of distortion by irregularly contracting fibrous tissue. Dilated pulmonary capillaries permit the passage of barium-gelatin injection medium, which is normally restricted to vessels greater than 15 µm in diameter, into pulmonary veins. This produces a dense, ground-glass background haze in the postmortem arteriogram (52) (Fig. 22). Capillary proliferation has been ascribed to angiogenesis associated with granulation tissue formation or possibly to a direct effect of oxygen toxicity (65, 66). An increased concentration of blood vessels in patients in the late stages of ARDS probably reflects the combined effects of abnormally dilated vessels, crowding of vessels, and increased profiles of tortuous vessels rather than a restoration or regrowth of normal arteries (50, 52). Hypermuscularization of pulmonary arteries is frequently associated with pulmonary hypertension and has been demonstrated morphometrically in the intermediate and late stages of ARDS (52, 67, 68). With increasing duration of lung injury, the thickness of the media relative to the arterial diameter increases (Fig. 24). The percentage of muscular thickness of

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Figure 22 Postmortem arteriographic patterns in ARDS, Visceral pleura is at bottom. (A) Normal adult lung. (B) Extensive reduction of filled peripheral arteries. Subpleural branches are stretched about dilated airspaces with “picket fence” appearance (16 days

Pulmonary pathology of the acute respiratory distress syndrome

after toxic inhalation). (C) Marked arterial tortuosity, increased background haze, and fine arteries stretched about honeycomb “cysts” (26 days after aspiration). (D) Intense background haze and venous filling (arrow) resulting from capillary dilation (55 days after viral pneumonia). In B, C, and D there are fine arcade vessels in the visceral pleura. (From Ref. 52.)

85

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Figure 23 Severe fibrocellular intimal proliferation in a nonmuscular alveolar wall artery. Note cell in mitosis (arrow). The interstitium is widened by collagen, edema, and a mononuclear cell infiltrate. Hyperplastic epithelial cells partially line alveolar surface (toluidine blue; original magnification×400). (From Ref. 52.) preacinar and intraacinar arteries has been shown to be significantly lower in patients surviving fewer than 9 days than in those who survive at least 20 days. The variability in medial thickness of muscular arteries also increases with the duration of ARDS (Fig. 25). Increased medial thickness also correlates with the extent of parenchymal honeycombing and hemorrhage (67). Evidence of peripheral extension of smooth muscle into normally nonmuscularized arteries and arterioles is reflected in the decreased mean external diameter of fully and partially muscular arteries in patients in the later stages of ARDS (52, 68) (Fig. 26). Potential causes of arterial muscularization in ARDS include hypoxia, pulmonary hypertension, and oxygen toxicity (69–74).

VI. Localization of Lesions: Regional Alveolar Damage As originally defined, ARDS is considered to be a generalized lung process characterized roentgenographically by diffuse bilateral alveolar

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Figure 24 Variation in the percentage of medial wall thickness of muscularized pulmonary arteries at different levels with duration of ARDS. The early (exudative phase) group differs significantly from the late fibrotic group at the alveolar duct (p