Lung Biology in Health & Disease Volume 184 Lung Volume Reduction Surgery for Emphysema

LUNG VOLUME REDUCTION SURGERY FOR EMPHYSEMA Edited by Henry E. Fessler Johns Hopkins Medical Institutions Baltimore, ...

Author: Henry E. Fessler | Jr. | John J. Reilly | David Sugarbaker

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LUNG VOLUME REDUCTION SURGERY FOR EMPHYSEMA

Edited by

Henry E. Fessler Johns Hopkins Medical Institutions Baltimore, Maryland, CI. S.A.

John J. Reilly, Jr. David J. Sugarbaker Harvard Medical School and Brigham & Women’s Hospital Boston, Massachusetts, (J.S.A.

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Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material contained herein is not intended to provide speciﬁc advice or recommendations for any speciﬁc situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identiﬁcation and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-0897-0 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc., 270 Madison Avenue, New York, NY 10016, U.S.A. tel: 212-696-9000; fax: 212-685-4540 Distribution and Customer Service Marcel Dekker, Inc., Cimarron Road, Monticello, New York 12701, U.S.A. tel: 800-228-1160; fax: 845-796-1772 Eastern Hemisphere Distribution Marcel Dekker AG, Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright # 2004 by Marcel Dekker, Inc.

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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 anid 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. Sfaub 8. Extrapulmonary Manifestations of Respiratory Disease, edited by €. D. Robin 9. Chronic Obstructive Pulmonary Disease, edited by T. L. Pet'ty 10. Pathogenesis and Therapy of Lung Cancer, edited by C. C. Harris 11. Genetic Determinants of Pulmonary Disease, edited by S. 13.Litwin 12. The Lung in the Transition Between Health and Disease, edited by P. T. Macklem and S. Permuff 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. lmmunopharmacologyof 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. Pneumocysfis carinii Pneumonia: Pathogenesis, Diagnosis, and Treatment, edited by L. s. Young 23. Pulmonary Nuclear Medicine: Techniques in Diagnosis of Lung Disease, edited by N.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. Chretien, 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 0. P. Mathew and G. Sant'Ambrogio 36. Chronic Obstructive Pulmonary Disease: A Behavioral Perspective, edited by A. J. McSweeny and 1. 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. Weirand 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 Ah. 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 0. 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. 1. 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. 0. Trouth, R. M. Millis, H. F. Kiwull-Schone, and M. E. Schlafke 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. Szeflerand D. Y. M. Leung 87. Mycobacteriurn avium-Complex Infection: Progress in Research and Treatment, edited by J. A. Kowick and C. A. Benson 88. Alpha I-Antitrypsin Deficiency: Biology 0 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. Chretien and D. Dusser 94. Inhalation Aerosols: Physical and Biological Basis for Therapy, edited byA. 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. Putrnan 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. Beta,-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. 1. Said 113. Self-Management of Asthma, edited by H. Kotses and A. Hawer 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. lngbar 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. Dahlen, 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. Ka wakami 136. lmmunotherapy 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. 0. 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. Notfer 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. 6 . 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. Braffsand 164. IgE and Anti-igE Therapy in Asthma and Allergic Disease, edited by R. B. Fick, Jr., and P. M. Jardieu 165. Clinical Management of Chronic Obstructive Pulmonary Disease, edited by T. Sirnilowski, W. A. Whitelaw, and J.-P. Derenne 166. Sleep Apnea: Pathogenesis, Diagnosis, and Treatment, edited by A. 1. 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 0. 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 182. Pharmacotherapy in Chronic Obstructive Pulmonary Disease, edited by B. R. Celli 183. Acute Exacerbations of Chronic Obstructive Pulmonary Disease, edited by N. M. Siafakas, N. R. Anthonisen, and 0. Georgopoulos 184. Lung Volume Reduction Surgery for Emphysema, edited by H. E. Fessler, J. J. Reilly, Jr., and D. J. Sugarbaker 185. Idiopathic Pulmonary Fibrosis, edited by J. Lynch 111

ADDITIONAL VOLUMES IN PREPARATION

Therapy for Mucus-Clearance Disorders, edited by B. K. Rubin and C. P. van der Schans Pleural Disease, edited by D. Bouros lnterventional Pulmonary Medicine, edited by J. F. Beamis, P. N. Mathur. andA. C. Mehta OxygedNitrogen Radicals: Lung Injury and Disease, edited by Val Vallya than Lung Development and Regeneration, edited by D. J. Massaro, G. Massaro, and P. Chambon

The opinions expressed in these volumes do not necessari1,v represent the views of the National Institutes of Health.

INTRODUCTION

This volume, Lung Volume Reduction Surgery for Emphysema, is the culmination of a most challenging chapter in medical history. It reports the labors of many medical scientists to analyze and certify the role that this type of surgery can play in improving the quality of life—and perhaps even the fate—of many patients suffering from chronic obstructive pulmonary disease (COPD). However, the journey to get us where we are today was long, tedious, and tortuous. The Preface of editors Henry E. Fessler, John J. Reilly, and David J. Sugarbaker very nicely represents the unfolding of this odyssey, which began in 1930. From that time on, many new steps were taken and new routes were explored, sometimes with frustrating results. Then in 1995 came the report (1) of Joel Cooper and his colleagues on the ﬁrst signiﬁcant case series of lung volume reduction surgery (LVRS)—a remarkable account that created quite a sensation in the COPD community. But researchers and clinicians who had followed the story of LVRS knew that the path to this juncture had not been for the fainthearted. As the editors mention in their Preface, it took visionaries to light the way. Moreover, while this book ‘‘. . . collect[s] the current state of knowledge about this procedure . . . it can neither answer all questions nor stem all controversy.’’ It has been a long time since the ﬁrst step toward LVRS as we know it today was taken, but compared with the time that has passed since COPD was ﬁrst recognized, it is very short—70 years versus centuries! This contrast iii

iv

Introduction

in time illustrates the complexity of the problem: COPD is a difﬁcult disease. Knowledge and progress are advancing one step at a time, and the steps are often very small ones. Happily, this book documents a huge step that is likely to have signiﬁcant impact. There is no question that LVRS has stimulated a new wave of research and observations, amply covered herein, that will beneﬁt patients with COPD. As well, this volume presents a state-of-the-art report on what we know today about several other therapeutic approaches to COPD—pharmacological, rehabilitative, and surgical. Thus, it will assist the practitioner in reaching the best decision for each patient. As early as 1981, the Lung Biology in Health and Disease series presented its ﬁrst volume on COPD (vol. 9), edited by T. L. Petty. Since then, many more volumes have been published to keep pace with advances in the ﬁeld and increases in interest among the scientiﬁc and lay communities. This new volume is about a timely and important subject and is presented by the best in the ﬁeld. As the executive editor of the Lung Biology in Health and Disease series, I am grateful for the opportunity to introduce this work to the readership. Claude Lenfant, M.D. Bethesda, Maryland Reference 1.

Cooper JD, Trulock EP, Trianraﬁlou AN, Patterson GA, Pohl MS, Deloney PA, et al. Bilateral pneumonectomy (volume reduction) for chronic obstructive pulmonary disease. J Thoracic Cardiovasc Surg 1995; 109:106–119.

PREFACE

In our lifetimes in medicine, we have witnessed the discovery of treatments for many devastating diseases that allow their sufferers to lead normal, productive lives. For emphysema, however, such effective treatment has remained elusive. In its advanced stages, patients often become imprisoned by their dyspnea. Their seasons are marked by hospitalizations instead of holidays. Their excursions are limited to the radius of an oxygen tube or the capacity of a tank. The simplest exertions induce terrifying symptoms. As clinicians, we have often felt helpless or useless, with little to offer except sympathy. Little wonder, then, that the rediscovery of lung volume reduction surgery (LVRS) has excited patients and physicians alike. The best of our previous therapy could only slow the progression of emphysema or prolong a life of dyspnea. For the ﬁrst time, we can offer a treatment with the potential to substantially improve lung function. For patients, this is like an opportunity to turn back time and to be young again. For physicians, it is an opportunity to heal and to feel the satisfaction associated with the treatment of so many other diseases. Careful perusal of the medical therapy of emphysema reveals some lessons that foreshadowed LVRS. In the 1930s, abdominal compression belts were reported to relieve dyspnea in patients with emphysema. The stimulus for these devices was the observation that emphysema patients often lean forward when they breathe. Today, the common explanation is v

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that this allows more effective use of respiratory accessory muscles. However, it was hypothesized at the time that this was an attempt to increase abdominal pressure and thereby restore curvature to the diaphragm. Measurements of vital capacity after wearing the abdominal compression belt showed increases of nearly 40%, which was highly signiﬁcant in a group of 25 patients (1). In the 1950s, there were several reports of relief of dyspnea by pneumoperitoneum in patients with emphysema. Like abdominal belts, this was an attempt to restore diaphragmatic curvature. Case reports described resurrection from near moribund states (2). Physiological measurements in the roughly 50% of patients with symptomatic relief in case series demonstrated decreased total lung capacity, still greater decreases in residual volume, and a corresponding increase in vital capacity (3, 4). These are precisely the changes described after successful LVRS. Restoration of diaphragmatic curvature at end-expiration would not, however, be expected to cause any of these changes. In contrast, we speculate that these interventions induced atelectasis, reducing lung volume in a reversible and noninvasive way. It is likely that the most normal lung regions were the ﬁrst to become atelectatic because they emptied ﬁrst, so effects on gas exchange may have been deleterious. However, these concepts are receiving new attention as several groups explore noninvasive methods to achieve the beneﬁts of surgical lung volume reduction (5, 6). Lung volume reduction surgery holds great temptation for both the healers of and sufferers from emphysema. Its lure can be as compelling as breath itself. However, temptation must be tempered by commitment to proceed rationally. Medical history is littered with examples in which desperate or ill-conceived treatments have led to harm. For therapy of emphysema, discarded surgical interventions date back almost to the birth of thoracic surgery. Reasoning that the lungs had grown too large for the chest, costochondrectomy or transverse sternotomy was attempted to provide more room. Conversely, hypothesizing that the chest had grown too large led to attempts to shrink it with thoracoplasty. The theory that emphysema resulted from ischemia to alveolar walls inspired pleurodesis to increase pleural blood ﬂow. Phrenectomy was performed, based on the notion that overvigorous inspiration was ripping alveolar walls. This notion sounds ill-conceived today. However, it is completely consistent with the upper-lobe predominance of emphysema, attributed years later to essentially the same mechanism: excessive stress. Hilar denervation was attempted to decrease bronchoconstriction or mucus hypersecretion that was thought to be mediated by the parasympathetic nervous system. Whole-lung radiation

Preface

vii

was used to increase elastic recoil by inducing ﬁbrosis, and patients often reported relief (7). These treatments were all based on careful observation and reasoned physiological hypotheses. None is performed today. Their history teaches us just how desperate patients, their families, and often their physicians can be, and is a sober reminder to proceed cautiously. The lessons of the past remind us to evaluate objectively and critically this major surgical procedure. Similar reminders abound in other areas of medicine. Dramatic relief of angina pectoris was reported following internal mammary artery ligation, which is now known to be without physiological beneﬁt. Blinded, controlled trials of this treatment, which included a sham surgical arm, ﬁnally demonstrated the astounding power of the placebo effect (8, 9). Even truly effective, physiologically sound treatments such as coronary artery bypass grafting or organ transplantation matured only after long periods over which techniques and indications were reﬁned. A few visionaries lit the way, but hundreds of others took up the torch, carefully reviewed retrospective data, collected prospective series, executed randomized trials, and revised techniques in an iterative process that continues today. This process is just beginning in LVRS. The procedure shows great promise, but its ﬁnal place in the pantheon of emphysema therapies is unknown. It has been widely promoted, occasionally denounced, and generated as much confusion as enthusiasm. Lung Volume Reduction Surgery for Emphysema is an attempt to collect the current state of knowledge about this procedure into one reference but it can neither answer all questions nor stem all controversy. The ﬁeld is hampered by a lack of data that no amount of argument can overcome. We have, however, learned much about this operation in the few years that it has been widely performed, and LVRS has provided new insight into the nature of emphysema itself. To organize and interpret these new ﬁndings, we have assembled a group of world leaders in LVRS and emphysema. We have asked them to describe what is known, what is believed, and what is hoped for, and to distinguish clearly among the three. We hope that this book will be both stimulating and useful to the internists, pulmonologists, anesthesiologists, surgeons, nurses, and therapists who care for these patients, and to the inner scientist perched on each of their shoulders. We wish to thank our mentors, patients, and families for the inspiration they provide daily, and for keeping us, with only partial success, humble. We also note with pride and sadness the chapter on the physiology of emphysema written by our late colleague Joseph Rodarte. Dr. Rodarte

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was a friend and teacher to us as he was to hundreds of others, and his death is a great loss to science and to humankind. Henry E. Fessler John J. Reilly David J. Sugarbaker References 1. 2.

3. 4. 5.

6.

7. 8.

9.

Alexander HL, Kountz WB. Symptomatic relief of emphysema by an abdominal belt. Am J Med Sci 1934; 187:687–692. Callaway JJ, McKusick VA. Carbon dioxide intoxication in emphysema: Emergency treatment by artiﬁcial pneumoperitoneum. N Engl J Med 1950; 245:9–13. Carter MG, Gaensler EA, Kyllonen A. Pneumoperitoneum in the treatment of pulmonary emphysema. N Engl J Med 1950; 243(15):549–558. Gaensler EA, Carter MG. Ventilation measurements in pulmonary emphysema treated with pneumoperitoneum. J Lab Clin Med 1950; 35:945–959. Ingenito EP, Reilly JJ, Mentzer SJ, Swanson SJ, Vin R, Keuhn H, et al. Bronchoscopic volume reduction: a safe and effective alternative to surgical therapy for emphysema. Am J Respir Crit Care Med 2001; 164(2):295–301. Brenner M, Gonzalez X, Jones B, Ha R, Osann K, McKenna R, et al. Effects of a novel implantable elastomer device for lung volume reduction surgery in a rabbit model of elastase-induced emphysema. Chest 2002; 121(1):201–209. Axford AT, Cotes JE, Deeley TJ, Smith CW. Clinical improvement of patients with emphysema after radiotherapy. Thorax 1977; 32:35–39. Cobb LA, Thomas GI, Dillard DH, Merendino KA, Bruce RA. An evaluation of internal-mammary-artery ligation by a double-blind technic. N Engl J Med 1959; 260(22):1115–1118. Dimond EG, Kittle CF, Crockett JE. Comparison of internal mammary artery ligation and sham operation for angina pectoris. Am J Cardiol 1960; April:483– 486.

CONTRIBUTORS

Simon C. Body, M.B., Ch.B. Assistant Professor, Department of Anesthesia, Harvard Medical School, and Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women’s Hospital, Boston, Massachusetts, U.S.A. Bartolome R. Celli, M.D. Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Tufts University, and Chief, Department of Pulmonary and Critical Care Medicine, St. Elizabeth’s Medical Center, Boston, Massachusetts, U.S.A. Francis C. Cordova, M.D. Assistant Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A. Gerard J. Criner, M.D. Professor and Director, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, U.S.A. Henry E. Fessler, M.D. Associate Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, U.S.A. ix

x

Contributors

Alfred P. Fishman, M.D. Professor, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A. Philip M. Hartigan, M.D. Director, Division of Thoracic Anesthesia, Harvard Medical School, and Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women’s Hospital, Boston, Massachusetts, U.S.A. James C. Hogg, M.D., Ph.D., F.R.S.C. Professor Emeritus, Department of Pathology and Medicine, and McDonald Research Laboratory/ iCAPTUR4E Centre, The University of British Columbia, and St. Paul’s Hospital, Vancouver, British Columbia, Canada Larry R. Kaiser, M.D. Chairman, Department of Surgery, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, U.S.A. Ella A. Kazerooni, M.D. Associate Professor, Department of Radiology, University of Michigan, Ann Arbor, Michigan, U.S.A. Cesar A. Keller, M.D., F.C.C.P. Medical Director, Lung Transplant Program, Mayo Clinic, Jacksonville, Florida, U.S.A. Noah Lechtzin, M.D., M.H.S. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, U.S.A. Todd A. Lee, Pharm.D., Ph.D. Senior Investigator, Midwest Center for Health Services and Policy Research, and Hines VA Hospital, Hines, Illinois, U.S.A. Fernando J. Martinez, M.D., M.S. Professor, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, U.S.A. Robert J. McKenna, Jr., M.D., F.A.C.S. Head, Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Cedars Sinai Medical Center, Los Angeles, California, U.S.A. Jonathan B. Orens, M.D. Associate Professor and Director, Lung Transplantation Program, Johns Hopkins Medical Institutions, Baltimore, Maryland, U.S.A.

Contributors

xi

Scott Ramsey, M.D., Ph.D. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A. John J. Reilly, Jr., M.D. Associate Professor, Department of Medicine, Harvard Medical School, and Clinical Director, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham & Women’s Hospital, Boston, Massachusetts, U.S.A. Andrew L. Ries, M.D., M.P.H. Professor, Department of Medicine and Department of Family and Preventive Medicine, University of California, San Diego, San Diego, California, U.S.A. John R. Roberts, M.D. Tennessee, U.S.A.

Vanderbilt University Hospital, Nashville,

Joseph R. Rodarte, M.D.{ Professor and Chief, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Baylor College of Medicine, Houston, Texas, U.S.A. Steven M. Scharf, M.D., Ph.D. Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland, Baltimore, Maryland, U.S.A. K. Robert Shen, M.D. Clinical Fellow, Department of Surgery, Harvard Medical School, and Chief Resident, Division of Cardiothoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, U.S.A. Joseph B. Shrager, M.D., F.A.C.S., F.A.C.C.P. Chief, General Thoracic Surgery Section, Department of Surgery, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, U.S.A. Sean D. Sullivan, Ph.D. Professor, Departments of Pharmacy and Health Sciences, University of Washington, Seattle, Washington, U.S.A. Scott J. Swanson, M.D. Chief and Eugene Friedman Professor of Surgical Oncology, Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Mount Sinai Medical Center, New York, New York, U.S.A.

{

Deceased.

xii

Contributors

Ira L. Weg, M.D. Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, New York, U.S.A. Robert A. Wise, M.D. Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, U.S.A. Lambros Zellos, M.D., M.P.H. Division of Thoracic Surgery, Department of Surgery, Harvard Medical School, and Brigham & Women’s Hospital, Boston, Massachusetts, U.S.A.

CONTENTS

Introduction Preface Contributors

Claude Lenfant

1. Epidemiology of Chronic Obstructive Pulmonary Disease Robert A. Wise I. II. III. IV. V.

Deﬁnition of COPD Natural History of COPD Health Burden of COPD Health Costs of COPD Summary and Future Trends References

2. Pathology of Emphysema James C. Hogg I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII.

Introduction Terminology Centrilobular/Centriacinar Emphysema Panacinar/Panlobular Emphysema Distal Acinar Emphysema Miscellaneous Forms of Emphysema Measurement of Emphysema Grading Systems Quantitative Histology Computed Tomographic Estimates of Emphysema Combination of CT and Quantitative Histology Functional Consequences of Alveolar Destruction References

iii v ix 1 1 3 4 14 14 15 23 23 24 25 27 27 27 28 28 30 33 34 37 39

xiii

xiv

Contents

3. Physiology of Airﬂow Limitation in Emphysema Joseph R. Rodarte I. II. III. IV. V. VI. VII. VIII.

Introduction Pathophysiology of Respiratory Failure in COPD Other Effects of Emphysema Mechanisms of Flow Limitation Maximal Expiratory Flow Response to Lung Reduction Implications for Selection of Patients for LVRS Summary References

4. Cardiovascular Effects of Emphysema and Lung Volume Reduction Surgery Steven M. Scharf, Ira L. Weg, and Cesar A. Keller I. II. III. IV. V. VI.

Introduction Theoretical Effects of Emphysema on Cardiovascular Function Studies on the Effects of Emphysema on Cardiovascular Function Cardiovascular Function in Emphysematous Patients Undergoing Transplant or LVRS Pulmonary Vascular Disease in Emphysema: Chicken or Egg? Summary References

5. Medical Therapy for Chronic Obstructive Pulmonary Disease and Emphysema Bartolome R. Celli I. II. III. IV. V. VI. VII. VIII. IX.

Introduction Smoking Cessation Pharmacological Smoking Cessation Therapy Pharmacological Therapy of Airﬂow Obstruction Management of the Acute Exacerbation of COPD Long-Term Oxygen Therapy Hospitalization and Discharge Criteria Noninvasive Ventilation Summary References

43 43 44 45 46 49 55 57 61 63

65 65 66 68 78 91 92 92

99 99 100 101 102 109 110 113 116 117 117

Contents

xv

6. Pulmonary Rehabilitation and Lung Volume Reduction Surgery Andrew L. Ries I. II. III. IV. V. VI. VII.

Introduction Role of Pulmonary Rehabilitation in LVRS Patient Selection Patient Evaluation Program Content Results of Pulmonary Rehabilitation Summary References

7. Evaluation of Patients Considering Lung Volume Reduction Surgery John J. Reilly, Jr. I. Introduction II. Preoperative Risk Assessment: General Considerations III. Pulmonary Function Testing IV. Cardiac Issues V. Exercise Performance VI. Radiographic Studies VII. Summary References 8. Radiological Evaluation for Lung Volume Reduction Surgery Ella A. Kazerooni I. II. III. IV. V. VI. VII. VIII. IX.

Introduction Chest Radiography of Emphysema CT of Emphysema Chest Radiography and Patient Selection for LVRS CT and Patient Selection for LVRS Scintigraphy and Patient Selection for LVRS CT Versus Perfusion Scintigraphy Imaging Before and After LVRS Summary References

123 123 125 126 127 130 135 142 143

149 149 151 155 158 161 162 163 165 169 169 170 170 184 184 187 189 192 193 193

xvi

Contents

9. The Interface of Lung Volume Reduction Surgery and Lung Transplantation Jonathan B. Orens I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. XIV.

Introduction Candidate Selection for Transplantation Timing of Transplantation Type of Transplant Procedure Immunosuppression Survival Following Transplantation Functional Outcomes of Transplantation Quality of Life Following Transplantation LVRS and Transplantation Choosing LVRS Prior to Transplantation Type of LVRS Procedure Prior to Transplantation LVRS During and Following SLT Comparison of Costs for LVRS and Transplantation Summary References

10. Anesthetic Considerations for Lung Volume Reduction Surgery Philip M. Hartigan and Simon C. Body I. Introduction II. Adverse Respiratory Effects of Anesthesia, Thoracic Surgery, and COPD III. Physiology of One-Lung Ventilation IV. Positive-Pressure Ventilation and Intrinsic PEEP V. Anesthetic Management of Patients with Severe Emphysema for LVRS VI. Summary References 11. Technique of Lung Volume Reduction Surgery by Median Sternotomy Joseph B. Shrager and Larry R. Kaiser I. II. III. IV.

Introduction MS Versus VATS Technique of LVRS by MS Summary References

201 201 202 203 205 205 206 206 207 208 210 213 213 214 215 215 219 219 220 223 224 228 238 238

247 247 247 250 254 254

Contents

xvii

12. Thoracoscopic Approach for Lung Volume Reduction Surgery Robert J. McKenna, Jr.

257

I. Introduction II. Patient Selection III. Deﬁnition of Surgical Emphysema Versus Medical Emphysema IV. Patient Selection Unique to VATS V. Technique for VATS LVRS VI. Anesthesia VII. Positioning of the Patient VIII. Incisions IX. Lung Resection X. Buttressing XI. Resection or Plication? XII. Identiﬁcation and Control of Air Leaks XIII. Conversion to Open Procedure XIV. Postoperative Management XV. Results of LVRS via VATS XVI. Comparison of VATS and Open LVRS XVII. LVRS and Lung Transplant XVIII. Summary References 13. Perioperative Complications and Their Management K. Robert Shen and Scott J. Swanson I. II. III. IV. V. IX.

Introduction Preparation for Surgery Perioperative Management Postoperative Management Management of Postoperative Complications Summary References

14. Surgical Controversies in Lung Volume Reduction John R. Roberts I. II. III. IV.

Introduction Laser or Resection? Unilateral or Bilateral? Thoracoscopy or Median Sternotomy?

257 258 258 259 260 260 260 261 261 262 262 262 263 263 264 266 269 269 269 273 273 273 274 275 276 285 286 289 289 290 290 295

xviii

Contents V. Summary References

15. Giant Bullectomy Lambros Zellos I. II. III. IV. V. VI.

Introduction Pathophysiology and Classiﬁcation Indications for Surgery Surgical Techniques and Incisions Results Summary References

16. Outcomes from Lung Volume Reduction Surgery: Short-Term and Long-Term Results Fernando J. Martinez I. II. III. IV. V.

Introduction Short-Term Results Long-Term Results Patient Selection Summary References

17. Mechanisms of Improvement Following Lung Volume Reduction Surgery Noah Lechtzin and Henry E. Fessler I. II. III. IV. V. VI. VII. VIII. IX.

Introduction Spirometry Improvement in Respiratory Muscle Function Effects on Gas Exchange Symptoms Excercise Capacity Placebo Effect Accelerated Deterioration of Pulmonary Function Summary References

297 298 301 301 302 303 304 307 308 308

311 311 312 331 339 346 346

355 355 356 366 370 372 375 377 378 379 380

Contents

xix

18. Lung Volume Reduction Surgery in Unique Patient Populations Francis C. Cordova and Gerard J. Criner

385

I. II. III. IV.

Introduction LVRS and Pulmonary Nodules LVRS and Coronary Artery Disease Summary References

385 386 395 408 408

19. Financial Aspects of Emphysema and Emphysema Surgery Scott Ramsey, Todd A. Lee, and Sean D. Sullivan

413

I. II. III. IV. V.

Introduction Economic Burden of Disease Cost-Effectiveness Analysis Cost Effectiveness of Therapies for Emphysema Summary References

20. Not the Final Chapter: The National Emphysema Treatment Trial Henry E. Fessler, Alfred P. Fishman, and John J. Reilly I. Origins of the National Emphysema Treatment Trial II. Planning the NETT III. Rationale and Design IV. Recruitment V. Protocol Modiﬁcations VI. Main Study Results VII. Cost-Effectiveness Analysis VIII. Impact of the NETT References Author Index Subject Index

413 414 418 420 422 422

425

425 428 429 435 436 438 447 448 450 453 489

1 Epidemiology of Chronic Obstructive Pulmonary Disease

ROBERT A. WISE Johns Hopkins Medical Institutions Baltimore, Maryland, U.S.A.

I. Deﬁnition of COPD Chronic obstructive pulmonary disease (COPD) is a disorder that is characterized by progressive reduction in forced expiratory airﬂow in excess of the normal age-related decline. Eventually, the reduction in airﬂow leads to exercise impairment, increased susceptibility to respiratory infections and irritants, and reduced life expectancy. Obstructive ventilatory defects occur in a number of lung disorders, including asthma, bronchiectasis, cystic ﬁbrosis, immunoglobulin deﬁciency, lymphangioleiomyomatosis, and eosinophilic granuloma. In common practice, however, COPD is usually used to refer to the tobacco smoking–related diseases chronic bronchitis and emphysema. The presence of airﬂow obstruction is deﬁned based on the forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio. The threshold for a diagnosis of an obstructive ventilatory defect varies somewhat. The American Thoracic Society (ATS) deﬁnition is an FEV1/ FVC ratio less than 75%; The European Respiratory Society (ERS) deﬁnition is an FEV1/FVC ratio less than 88% predicted in men and less than 89% predicted in women, which approximates 70%. A ﬁxed threshold 1

2

Wise

of FEV/FVC ratio less than 70% is often used for clinical purposes because of simplicity and the ability to predict subsequent decline in pulmonary function. The criterion used for deﬁnition of airﬂow obstruction depends, to a large extent, on whether the goal is to establish a more sensitive or a more speciﬁc measure (1). The FEV1 is used as the standard measure of severity of airﬂow obstruction because of the ease and precision of measurement and because it is a good predictor of impairment and survival (2,3). Chronic bronchitis is a disorder of chronic inﬂammation and excess mucus production of the airways. For the purposes of epidemiological studies, it is deﬁned as daily cough and phlegm for 3 months per year for 2 successive years in the absence of other known cause (4). In the vast majority of cases, however, productive cough is present perennially. Thus, chronic bronchitis, also referred to as chronic mucus hypersecretion syndrome, is diagnosed on the basis of historical information alone. Although it is often associated with airﬂow obstruction, many individuals with chronic mucus hypersecretion do not manifest airﬂow limitation. Chronic bronchitis in the absence of signiﬁcant airﬂow limitation probably contributes little, if any, to shortened life expectancy (5,6). Patients with chronic mucus hypersecretion syndrome are, however, at greater risk for developing clinically important impairment of lung function than those without it (7,8). Emphysema, in contrast, is a disease that occurs as a result of the destruction of elastic tissue in the lung leading to a reduction in lung elasticity and enlargement of airspaces. The American Thoracic Society deﬁnition of emphysema is, ‘‘abnormal permanent enlargement of the airspaces distal to the terminal bronchioles accompanied by destruction of their walls and without obvious ﬁbrosis’’ (4). Strictly deﬁned, emphysema requires an anatomical diagnosis. Although gross pathological examination is the gold standard for diagnosis of emphysema, the use of radiological imaging methods, particularly highresolution computed tomography, have been employed to deﬁne anatomical emphysema. In clinical practice, however, emphysema is usually diagnosed on the basis of a constellation of clinical features such as airﬂow limitation, hyperinﬂation, air trapping, and reduced carbon monoxide diffusing capacity. In many epidemiological studies, however, emphysema is more loosely deﬁned, usually on the basis of a physician’s diagnosis of emphysema without strict criteria. Thus, one should be skeptical of epidemiological studies that purport to distinguish emphysema from other forms of COPD. In many cigarette smokers with airﬂow obstruction, there are elements of both emphysema and chronic bronchitis, making it difﬁcult to weight the contribution of each to the overall impairment of lung function. For this reason, survey studies of COPD do not attempt to

Chronic Obstructive Pulmonary Disease

3

distinguish between emphysema and chronic bronchitis. Thus, it is impossible to determine accurately from epidemiological surveys how many people might be candidates for lung volume reduction surgery on the basis of anatomical emphysema. Recently, however, Mannino and colleagues have analyzed the data from the Third National Health and Nutrition Survey (NHANES III) in the United States. They estimated that 2.6 million people in the United States have obstructive lung disease with an FEV1 less than 50% predicted, and 900,000 individuals have an FEV1 less than 35% predicted. It is reasonable to assume that the majority of these individuals have anatomical emphysema, but it is uncertain how many would be candidates for lung volume reduction surgery (9).

II.

Natural History of COPD

The natural history of COPD has been well deﬁned by the seminal work of Fletcher and Peto (10,11). Adult nonsmokers and smokers who are not susceptible to develop COPD show declines of about 30 mL of FEV1 per year as a consequence of aging. Smokers who are destined to develop COPD lose FEV1 two to four times more rapidly. Over the course of three to four decades, this eventually leads to symptomatic disease. Individuals with lower lung function at any age tend to show more rapid declines in lung function; the so-called ‘‘horse-race’’ effect (12). Over the age of 50 years, the decline in lung function accelerates until the disease becomes very severe (13,14). In those with far-advanced disease, lung function tends to stabilize as a result of survivor effect and smoking cessation in those with severe impairment (15). People with COPD who stop smoking early in the course of the disease have an initial improvement in lung function, and thereafter a decline in lung function that is similar to that of a nonsmoker (16–18). Individuals who quit smoking intermittently have declines in lung function intermediate between those of smokers and nonsmokers (16) (Fig. 1). The traditional view of COPD is that it is an insidiously progressive disease that eventually leads to disability and death. In recent years, this has been undergoing change with greater appreciation of the impact of exacerbations on morbidity and quality of life (19). An individual with clinically diagnosed COPD has a median of three exacerbations per year. Only half of these exacerbations come to medical attention. Factors that predict exacerbations of COPD include chronic cough and phlegm, worse pulmonary function, and poor nutritional status. About 50% of exacerbations can be attributed to bacterial infections. There is an increase in COPD exacerbations in the winter and on days with high ambient air pollution. The 10-year mortality for COPD patients with an FEV1 45–59% of predicted

4

Wise

Figure 1 Changes in FEV1 are shown for placebo participants in a smoking cessation treatment program in the Lung Health Study (SI-P group). Sustained quitters showed an initial improvement in pulmonary function followed by a normal age-related decline in FEV1. Continuing smokers exhibited a progressive decline in pulmonary function.

remains approximately 60% (37). After admission to an intensive care unit for treatment of an acute exacerbation of COPD, the 6-month mortality is 33–47% and the median survival is 8 months to 2 years (20,21). III.

Health Burden of COPD

There are several metrics for the burden that a chronic disease like COPD imposes on the U.S. population. Age-adjusted mortality is the most widely measured indicator of disease burden. COPD is the fourth most common disease causing death in the United States (Fig. 2) Among the ﬁve leading causes of death (cardiovascular, cancer, stroke, COPD, and accidents), COPD is the only disease that has shown increased death rates in recent decades (Fig. 3). Between 1979 and 1993, the age-adjusted COPDassociated mortality rate increased 47.3% from 52.6 per 100,000 to 79.5 per 100,000 and the COPD-speciﬁc mortality rate rose 46.6% from 14.6 to

Chronic Obstructive Pulmonary Disease

5

Figure 2 1993 Mortality, United States. COPD is the fourth leading cause of death in the United States (23).

21.4 deaths per 100,000 (22,23) (Figs. 3 and 4). The mortality rate was approximately three times greater in men than in women, although the relative increase was greatest in women. The mortality rate increased 17.1% in men, whereas the mortality rate increased 126.1% among women (22) (Fig. 5). In middle-aged and younger men, the mortality from COPD seems to be stable; however, there is a continued increase in mortality in men over the age of 75 years (24). The increase in mortality is present in women of all ages (25,26). Most evidence suggests that the full mortality burden of COPD is underestimated by vital statistics. Persons with abnormal lung function, particularly those with COPD, have increased mortality from all causes (27– 29). Only 38% of patients with COPD and chronic respiratory failure die of acute respiratory failure. Other important causes of death in these patients include cardiac disease, chest infection, and lung cancer (Fig. 6) (30). Of all

6

Wise

Figure 3 Percent change in mortality 1979 to 1993. Among the leading causes of death, COPD is the only disease that has shown substantial increases in age-adjusted mortality rates from 1979 to 1993 (23).

death statistics compiled by the National Center for Health Statistics, 8.3% of death certiﬁcates list COPD as a contributing cause, whereas only 3.5% of death certiﬁcates list COPD as the underlying cause of death (22). In the population study in Tecumseh, Michigan, COPD was listed on the death certiﬁcates of 11% of men and 13% of women, with 41% of the deaths listing COPD as the primary cause of death. The listing of COPD on death certiﬁcates is almost certainly underrepresentative of the prevalence of disease. In Tecumseh, among decedents with a clinical diagnosis of COPD, only 21% of men and 6% of women had the disease listed on their death certiﬁcate (31). An autopsy case-control series found that patients with anatomical evidence of chronic bronchitis or emphysema were often undiagnosed in life and contributed to increased risk of death from myocardial infarction and pulmonary embolism as well as respiratory failure (32). In a 20-year prospective study of Finnish hospitalized patients with COPD, COPD was listed as a contributing cause of death in only 33.3% of women and 29.4% of men (33). The NHANES III study found that

Chronic Obstructive Pulmonary Disease

7

Figure 4 COPD-related deaths are those where COPD is listed as the underlying cause or a contributing cause of death on the death certiﬁcate. Over the past 14 years, there has been a consistently increasing trend in the total number of deaths in the United States (22).

a clinical diagnosis of COPD was present in fewer than half of patients with clinically important airﬂow obstruction (9). Thus, it reasonable to conclude that COPD plays a role in as many as two to three times the number of deaths as are recorded in vital statistics. The reason for these rising trends in COPD mortality is only partially understood. In part, these trends in mortality reﬂect historical trends in smoking behavior delayed by 30–50 years. There was a large increase in smoking among young men in the 1940s during World War II, whereas the increase in cigarette smoking in women started a decade later. In recent years, the prevalence of cigarette smoking has decreased among men but is stable or increasing among women (see Fig. 4) There is also evidence that active smokers are more prone to die from COPD in recent decades. The landmark Cancer Prevention Study (CPS) conducted by the American Cancer Society has shown that even among cigarette smokers there has been a striking increase in COPD mortality (34,35) (Table 1). It has been postulated that this increase in mortality is the consequence of changes in the content of cigarettes. Filtered and lower tar and nicotine cigarettes may have contributed to the increased inhalation of toxic substances or changes in the pattern of smoking inhalation (25). Another contributing factor may

8

Wise

Figure 5 The age-adjusted mortality rate expressed as deaths per 100,000 people is higher in men than in women. In recent years, however, the mortality rate has stabilized in men but continues to rise in women (22).

be the dramatic reduction in competing mortality, particularly heart disease, which is the result of new modes of treatment of acute coronary syndromes (36). In contrast, there has been no appreciable improvement in survival among persons with moderate to severe COPD in the past 30 years (37). A. Geographic Distribution of COPD

Although information is limited, it appears that the global trends in mortality from COPD mirror those in the United States (38–43). The prevalence of COPD is particularly high in Eastern Europe and the United Kingdom, whereas it is lower in Japan and southern Europe (44,45). The mortality from COPD is four-fold greater in eastern Europe (Romania, Great Britain, Germany, Poland, and Hungary) than in southern Europe (Spain, Portugal, France, and Greece) (45,46). From a global perspective, the United States has a relatively low prevalence and mortality from COPD. It is projected that COPD will become a major cause of chronic illness and mortality in Third World countries where cigarette smoking is expanding rapidly (47). Geographic differences in the mortality from COPD, however,

Chronic Obstructive Pulmonary Disease

9

Figure 6 Causes of death in hypoxemic COPD patients. Prospective studies have demonstrated that patients with advanced COPD often die from causes other than respiratory failure. Thus, COPD is a likely contributing factor in many deaths attributed to other causes (30).

cannot be entirely explained by smoking behavior (48). Other factors such as diet or altitude may also explain geographical differences in mortality (49– 51). High levels of ﬁsh or fruits in the diet have been associated with a lower incidence of COPD, although it is not clear if this is causally related or a marker of other healthful behaviors (52–54). Within the United States, COPD mortality is two to three times greater in the Rocky Mountain states and Appalachia than in the rest of the country (55). This has led to the proposal that hypoxia at high altitude contributes to mortality from COPD.

Table 1

Deaths per 100,000 Smokers Adjusted for Age

Gender Men Women Source: Ref. 35.

1959–1965 73.6 17.6

1982–1988

% Change

103.9 61.6

41.2 250.0

10

Wise

Analysis of COPD death rates by county in the United States demonstrates that those counties with higher altitude show greater COPD mortality. The risk of a 3000-ft elevation in altitude is approximately equal to 54 packs of cigarettes per year, leading to an increment in one death per 100,000 people per year.

B. Prevalence of COPD in Ethnic and Gender Subgroups

Estimates of the prevalence of COPD in the United States may vary widely because of varying deﬁnitions of the disease, and because many people with mild or moderate disease are not under medical care. Undiagnosed obstructive lung disease, evidenced by spirometry, is more prevalent than diagnosed obstructive lung disease, particularly among those with mild impairment (56). Based on the National Health Interview Survey, it is estimated that 12.6 million Americans have symptoms of chronic bronchitis with a prevalence of 51.1 cases per 100 and with a preponderance in women (61.0 per 1000 in women and 40.6 per 1000 in men) (57,58). A physician’s diagnosis of emphysema is estimated to be present in about 2 million Americans with a prevalence of 8.2 per 1000. In contrast to chronic bronchitis, emphysema is more common among men than women (10.7 cases per 1000 in men and 5.9 cases per 1000 in women). It is likely, however, that the gender difference between chronic bronchitis and emphysema is due in part to diagnostic bias by physicians to consider emphysema as being more likely in men and chronic bronchitis as being more likely in women (59). The greatest prevalence of COPD, according to the National Health Interview Survey, reaches a peak in both men and women aged 65–74 years (136/1000 men and 118/1000 women) (60). Like mortality, it appears that age-adjusted prevalence rates of COPD have stabilized in men between 1980 and 1985, but that the prevalence in women showed an increase of more than 30% in the same interval (60). Earlier population studies have suggested that smoking men are at greater risk for airﬂow obstruction (61). However, more recent longitudinal studies have shown that women have a greater risk of developing COPD when initial levels of lung function and intensity of tobacco exposure are taken into account (62). In the Netherlands, models projecting the impact of COPD in an aging population over the next two decades show an increase in prevalence in men of 57% in contrast to an increase in women of 130%, assuming constant rates of smoking. Using projected rates of smoking behavior which is decreasing in men but increasing in women, the projected increase in COPD prevalence by 2020 is 38% in men but 150% in women (63).

Chronic Obstructive Pulmonary Disease

11

Minority populations, particularly African Americans, have less COPD mortality than whites in the United States, but mortality rates are rising proportionately faster (64). The reason for this is not known. Historical trends in smoking show higher smoking prevalence in African American men than white men (Fig. 7) and higher rates of other smoking related-diseases such as lung cancer and cardiovascular disease (65). Factors that have been proposed to explain this paradox include competing mortality risks, diagnostic bias, different tobacco brands, different smoking intensity, and differences in nicotine metabolism (66). African Americans start smoking at a later age than whites (Fig. 8). According to the 1989 Surgeon General’s report, only 34.5% of white smokers use less than 20 cigarettes per day, whereas 63.5% of African Americans use less than 20 cigarettes per day. African Americans also tend to use more mentholated cigarettes (75% vs. 23%) and more high-tar brands (78% vs. 56%). This may lead to differing patterns of smoke inhalation that alter the relative incidence of lung cancer and COPD. The National Health and Nutrition Examination Survey (NHANES) found that African Americans had higher

Figure 7 The percentage of adults smoking cigarettes has decreased over the past 30 years. This trend has been most prominent among men. Thus, the gender difference in smoking status is narrowing. (AA-F, African American females; AA-M, African American males; WF, white females; WM, white males.) (From United States Census Bureau; www.census.gov/statab/www/smoktb.txt.)

12

Wise

Figure 8 Among whites, smoking is most common in young adults (18–35 years), whereas in African Americans, smoking is most common among middle-aged individuals (35–64 years). Smoking onset is later among African-Americans. (AA-F, African American females; AA-M, African American males; WF, white females; WM, white males.) (From United States Census Bureau; www.census.gov/statab/ www/smoktb.txt.)

levels of serum cotinine, a nicotine metabolite, than whites with similar smoking intensity, suggesting lower metabolism of nicotine or differing patterns of cigarette inhalation (67). In Hispanics, COPD mortality as well as lung cancer mortality are about half that of whites for both men and women (66). Hispanic men have similar smoking prevalence to whites, but Hispanic women smoke about one-third less frequently than whites. Overall smoking intensity is lower in Hispanics than whites, but there are important subgroup differences (68). Smoking intensity is heaviest in Cuban and Puerto Rican men, but is substantially less in Mexican Americans (69). The increase in COPD mortality, however, in Hispanics is concerning. In the southwestern United States, COPD mortality rose sixfold between 1960 and 1980 (70). Asian Americans have the lowest rate of COPD mortality of any ethnic subgroup in the United States, which is less than half that of whites.

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This is likely the consequence of the lower smoking rates. In 1979, a survey in California showed a smoking rate of 21% in Asian Americans compared to 33% in whites, 40% in African Americans, and 29% in Hispanics. Among Asian women, only 8.9% were smokers compared to 22% in white women (66). Among Native Americans, smoking rates are highest in the Northern Plains and Alaska and lowest in the Southwest (66,68). Northern Plains Indians have a 48% smoking prevalence in men and 57% in women. In contrast, the southwestern Indians have smoking rates of 18 and 15% for men and women, respectively. Overall, Native Americans are lighter smokers than whites, which may be the explanation for the lower COPD mortality in that group. COPD mortality follows the distribution of smokers, however, with two-fold increases in COPD mortality in Northern Plains Indians compared to southwestern Indians. C. Risk Factors for COPD

Cigarette smoking is widely understood to be the major risk factor for the development of COPD. It is estimated that 85–90% of the cases of COPD occur in cigarette smokers (71). Because smoking cessation can halt the excessive decline in pulmonary function, and spirometry screening programs can detect airﬂow obstruction in approximately 25% of current smokers, some have advocated mass spirometric screening programs with aggressive smoking intervention programs (16,72). Other factors may also inﬂuence the extent that a susceptible smoker develops abnormal lung function. The role of gender is now controversial (73). Although COPD was thought to be more common among male smokers, it is likely that this was an effect of the later age of onset and lighter smoking habit in women accounted for part of this (62). More recent studies have shown an increased susceptibility to COPD in women when smoking duration and behavior are taken into account (74,75). This may be the result of smaller airways and greater tendency to bronchial reactivity (76). Nonspeciﬁc airways reactivity is present in nearly 70% of COPD patients, whereas similar degrees of airways responsiveness is found in only 15% or so of the general population. The socalled ‘‘Dutch’’ hypothesis is that the tendency to constrict airways is a constitutional factor that puts an individual at risk for developing COPD if they smoke. Among patients with COPD, those with greater levels of airways responsiveness show more rapid declines in FEV1 (77). Lower socioeconomic status is also a risk factor for abnormal lung function and COPD mortality (78). The reason for this has been postulated to be the consequence of exposure to respiratory infections and indoor air pollution. Passive smoke exposure is associated with lower levels of lung function and

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more respiratory symptoms in children, but it has not been established as an important cause of clinically apparent COPD in adults. Occupational exposure to organic and inorganic dusts are thought to interact with cigarette smoking to cause a measurable decline in lung function, although the effect is small (79,80). The most important occupational exposures leading to clinically important airﬂow obstruction include cadmium, silica dust, cotton dust, grain dust, and isocyanates (81). The role of air pollution as a cause of respiratory symptoms, COPD exacerbations, and cardiorespiratory mortality has been well established; however, there is little evidence to support the theory that outdoor air pollution is an important cause of clinically important airﬂow obstruction (82–84). There is, however, an increasing body of evidence that subtle defects in lung function occur among growing children as well as adults exposed to particulate matter, and this could theoretically augment susceptibility to cigarette smoking–related lung disease (85,86). Alpha1-antitrypsin deﬁciency is a genetic defect that inhibits hepatic secretion of alpha1-antitrypsin, thus presumably allowing inﬂammatory enzymes to damage lung tissue. Only people with the severest deﬁciencies of alpha1-antitrypsin, less than one-third of the normal level, are prone to develop premature emphysema, with much severer disease in those who smoke tobacco. Alpha1-antitrypsin deﬁciency accounts for about 1% of all cases of emphysema (87,88). IV.

Health Costs of COPD

In 1993, the estimated annual direct health care costs associated with COPD were estimated to be $24 billion, with direct medical expenditures accounting for 62% of the total (89). In 1991, COPD was the primary discharge diagnosis for 297,000 hospitalizations averaging 7 days. COPD ranks seventh among diseases in terms of hospitalization. Over 13 million physician visits were attributed primarily to COPD care (58,90). Persons enrolled in Medicare who have a diagnosis of COPD cost 2.4 times more for medical care than the average Medicare beneﬁciary. Among the Medicare COPD population, over half of the expenditures are directed toward only 10% of the recipients (91). Thus, COPD represents an important element in overall health care costs in the United States. V.

Summary and Future Trends

Chronic obstructive pulmonary disease is a common, important, and expensive chronic disease in the United States. The prevalence of the disease

Chronic Obstructive Pulmonary Disease

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and the number of deaths where COPD is an important contributing factor are underestimated by vital statistics. Optimistically, if current trends toward smoking cessation continue, the increasing burden of this disease in the past 50 years should stabilize and eventually decline. Based on trends in smoking, the demographics of this disease will change from a predominance of white men to one that affects women and minorities. Globally, we will likely see an increasing prevalence and mortality from COPD in developing countries where smoking levels are increasing (92,93). Although the introduction of long-term oxygen therapy may extend the lives of those with far-advanced disease, the introduction of this therapy has had little impact on overall morbidity and death rates.

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24. Rogot E, Hrubec Z. Trends in mortality from chronic obstructive pulmonary disease among U.S. veterans: 1954 to 1979. Am Rev Respir Dis 1989; 140:S69– 75. 25. Wise RA. Changing smoking patterns and mortality from chronic obstructive pulmonary disease. Prev Med 1997; 26:418–421. 26. Sunyer J, Anto JM, McFarlane D, Domingo A, Tobias A, Barcelo MA, Munoz A. Sex differences in mortality of people who visited emergency rooms for asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998; 158:851–856. 27. Speizer FE, Fay ME, Dockery DW, Ferris BG Jr. Chronic obstructive pulmonary disease mortality in six U.S. cities. Am Rev Respir Dis 1989; 140:S49–55. 28. Tockman MS, Comstock GW. Respiratory risk factors and mortality: longitudinal studies in Washington County, Maryland. Am Rev Respir Dis 1989; 140:S56–63. 29. Tockman MS, Pearson JD, Fleg JL, Metter EJ, Kao SY, Rampal KG, Cruise LJ, Fozard JL. Rapid decline in FEV1. A new risk factor for coronary heart disease mortality. Am J Respir Crit Care Med 1995; 151:390–398. 30. Zielinski J, MacNee W, Wedzicha J, Ambrosino N, Braghiroli A, Dolensky J, Howard P, Gorzelak K, Lahdensuo A, Strom K, Tobiasz M, Weitzenblum E. Causes of death in patients with COPD and chronic respiratory failure. Monaldi Arch Chest Dis 1997; 52:43–47. 31. Higgins MW, Keller JB. Trends in COPD morbidity and mortality in Tecumseh, Michigan. Am Rev Respir Dis 1989; 140:S42–48. 32. Janssens JP, Herrmann F, MacGee W, Michel JP. Cause of death in older patients with anatomo-pathological evidence of chronic bronchitis or emphysema: a case-control study based on autopsy ﬁndings. J Am Geriatr Soc. 2001; 49(5):571–576. 33. Vilkman S, Keistinen T, Tuuponen T, Kivela SL. Survival and cause of death among elderly chronic obstructive pulmonary disease patients after ﬁrst admission to hospital. Respiration 1997; 64:281–284. 34. Thun MJ, Day-Lally CA, Calle EE, Flanders WD, Health CW Jr. Excess mortality among cigarette smokers: changes in a 20-year interval. Am J Public Health 1995; 85:1223–1230. 35. Thun MJ, Heath CW Jr. Changes in mortality from smoking in two American Cancer Society prospective studies since 1959. Prev Med 1997; 26:422–426. 36. Scheidt S. Changing mortality from coronary heart disease among smokers and nonsmokers over a 20-year interval. Prev Med 1997; 26:441–446. 37. Burrows B. The course and prognosis of different types of chronic airﬂow limitation in a general population sample from Arizona: comparison with the Chicago ‘‘COPD’’ series. Am Rev Respir Dis 1989; 140(3 Pt 2):S92–S94. 38. Guidotti TL, Jhangri GS. Mortality from airways disorders in Alberta, 1927– 1987: an expanding epidemic of COPD, but asthma shows little change. J Asthma 1994; 31:277–290.

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39. Manfreda J, Mao Y, Litven W. Morbidity and mortality from chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 140(3 Pt 2):S19–26. 40. Wever-Hess J, Wever AM. Asthma statistics in the Netherlands 1980–94. Respir Med 1997; 91(7):417–422. 41. Crockett AJ, Cranston JM, Moss JR, Alpers JH. Trends in chronic obstructive pulmonary disease mortality in Australia. Med J Aust 1994; 161(10):600–603. 42. Viegi G, Scognamiglio A, Baldacci S, Pistelli F, Carrozzi L. Epidemiology of chronic obstructive pulmonary disease (COPD). Respiration 2001; 68(1):4–19. 43. Anto JM, Vermeire P, Vestbo J, Sunyer J. Epidemiology of chronic obstructive pulmonary disease. Eur Respir J 2001; 17(5):982–994. 44. Cooreman J, Thom TJ, Higgins MW. Mortality from chronic obstructive pulmonary diseases and asthma in France, 1969–1983. Comparisons with the United States and Canada. Chest 1990; 97:213–219. 45. Thom TJ. International comparisons in COPD mortality. Am Rev Respir Dis 1989; 140(3 Pt 2):S27–34. 46. Gulsvik A. Mortality in and prevalence of chronic obstructive pulmonary disease in different parts of Europe. Monaldi Arch Chest Dis 1999; 54:160–162. 47. Murray CJ, Lopez AD. Summary: The Global Burden of Disease. Cambridge, MA: Harvard University Press, 1997. 48. Brown CA, Crombie IK, Tunstall-Pedoe H. Failure of cigarette smoking to explain international differences in mortality from chronic obstructive pulmonary disease. J Epidemiol Commun Health 1994; 48:134–139. 49. Tabak C, Feskens EJ, Heederik D, Kromhout D, Menotti A, Blackburn HW Fruit and ﬁsh consumption: a possible explanation for population differences in COPD mortality (The Seven Countries Study). Eur J Clin Nutr 1998; 52:819–825. 50. Miedema I, Feskens EJ, Heederik D, Kromhout D Dietary determinants of long-term incidence of chronic nonspeciﬁc lung diseases. The Zutphen Study Am J Epidemiol 1993; 138:37–45. 51. Cote TR, Stroup DF, Dwyer DM, Horan JM, Peterson DE. Chronic obstructive pulmonary disease mortality. A role for altitude. Chest 1993; 103:1194–1197. 52. Tabak C, Feskens EJ, Heederik D, Kromhout D, Menotti A, Blackburn HW. Fruit and ﬁsh consumption: a possible explanation for population differences in COPD mortality (The Seven Countries Study). Eur J Clin Nutr 1998; 52(11):819–825. 53. Tabak C, Arts IC, Smit HA, Heederik D, Kromhout D. Chronic obstructive pulmonary disease and intake of catechins, ﬂavonols, and ﬂavones: the MORGEN Study. Am J Respir Crit Care Med 2001; 164(1):61–64. 54. Tabak C, Smit HA, Heederik D, Ocke MC, Kromhout D. Diet and chronic obstructive pulmonary disease: independent beneﬁcial effects of fruits, whole grains, and alcohol (the MORGEN study). Clin Exp Allergy 2001; 31(5):747– 755.

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55. Anonymous. Deaths from chronic obstructive pulmonary disease in the United States, 1987. Statistics Bulletin of the Metropolitan Insurance Co. 1990; 71:20– 26. 56. Coultas DB, Mapel D, Gagnon R, Lydick E. The health impact of undiagnosed airﬂow obstruction in a national sample of United States adults. Am J Respir Crit Care Med 2001; 164(3):372–377. 57. American Lung Association. Lung Disease Data, 1993. New York: American Lung Association, 1993:6. 58. National Heart Lung and Blood Institute. Morbidity and Mortality Chartbook Washington, DC: 1994. U.S. Department of Health and Human Services, 1994:48–54. 59. Dodge R, Cline MG, Burrows B. Comparisons of asthma, emphysema, and chronic bronchitis diagnoses in a general population sample. Am Rev Respir Dis 1986; 133:981–986. 60. Feinleib M, Rosenberg HM, Collins JG, Delozier JE, Pokras R, Chevarley FM. Trends in COPD morbidity and mortality in the United States. Am Rev Respir Dis 1989; 140(3 Pt 2):S9–18. 61. Beaty TH, Menkes HA, Cohen BH, Newill CA. Risk factors associated with longitudinal change in pulmonary function. Am Rev Respir Dis 1984; 129:660– 667. 62. Prescott E, Bjerg AM, Andersen PK, Lange P, Vestbo J. Gender difference in smoking effects on lung function and risk of hospitalization for COPD: results from a Danish longitudinal population study Eur Respir J 1997; 10:822–827. 63. Feenstra TL, van Genugten ML, Hoogenveen RT, Wouters EF, Rutten-van Molken MP. The impact of aging and smoking on the future burden of chronic obstructive pulmonary disease: a model analysis in the Netherlands. Am J Respir Crit Care Med 2001; 164(4):590–596. 64. Gillum RF. Chronic obstructive pulmonary disease in blacks and whites: mortality and morbidity. J Natl Med Assoc 1990; 82:417–428. 65. Gillum RF. Chronic obstructive pulmonary disease in blacks and whites: pulmonary function norms and risk factors. J Natl Med Assoc 1991; 83:393– 401. 66. Coultas DB, Gong H Jr, Grad R, Handler A, McCurdy SA, Player R, Rhoades ER, Samet JM, Thomas A, Westley M. Respiratory diseases in minorities of the United States Am J Respir Crit Care Med 1994; 149(3 Pt 2):S93–131. 67. Caraballo RS, Giovino GA, Pechacek TF, Mowery PD, Richter PA, Strauss WJ, Sharp DJ, Eriksen MP, Pirkle JL, Maurer KR. Racial and ethnic differences in serum cotinine levels of cigarette smokers: Third National Health and Nutrition Examination Survey, 1988–1991. JAMA 1998; 280:135–139. 68. Centers for Disease Control and Prevention. Tobacco use among U.S. racial/ ethnic minority groups, African-Americans, American Indians and Alaska Natives, Asian Americans and Paciﬁc Islanders, Hispanics: a report of the Surgeon General (Executive Summary). MMWR 1998;47:1–16.

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69. Haynes SG, Harvey C, Montes H, Nickens H, Cohen BH. Patterns of cigarette smoking among Hispanics in the United States: results from HHANES 1982– 84. Am J Public Health 1990; 80 (Suppl):47–53. 70. Samet JM, Wiggins CL, Key CR, Becker TM. Mortality from lung cancer and chronic obstructive pulmonary disease in New Mexico, 1958–82. Am J Publ Health 1988; 78:1182–1186. 71. U.S. Surgeon General. The Health Consequences of Smoking: Chronic Obstructive Lung Disease. Washington, DC: U.S. Department of Health and Human Services, DHHS Publication No. 84–50205. 72. Zielinski J, Bednarek M. Early detection of COPD in a high-risk population using spirometric screening. Chest 2001; 119(3):731–736. 73. Vollmer WM, Enright PL, Pedula KL, Speizer F, Kuller LH, Kiley J, Weinmann GG. Race and gender differences in the effects of smoking on lung function. Chest 2000; 117:764–772. 74. Gold DR, Wang X, Wypij D, Speizer FE, Ware JH, Dockery DW. Effects of cigarette smoking on lung function in adolescent boys and girls. N Engl J Med 1996; 335(13):931–937. 75. Chen Y, Horne SL, Dosman JA. Increased susceptibility to lung dysfunction in female smokers. Am Rev Respir Dis 1991; 143:1224–1230. 76. Kanner RE, Connett JE, Altose MD, Buist AS, Lee WW, Tashkin DP, Wise RA. Gender difference in airway hyperresponsiveness in smokers with mild COPD. The Lung Health Study. Am J Respir Crit Care Med 1994; 150:956– 961. 77. Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee WW, Wise RA. Methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. The Lung Health Study Research Group. Am J Respir Crit Care Med 1996; 153:1802–1811. 78. Cohen BH, Ball WC Jr, Brashears S, Diamond EL, Kreiss P, Levy DA, Menkes HA, Permutt S, Tockman MS. Risk factors in chronic obstructive pulmonary disease (COPD). Am J Epidemiol 1977; 105:223–232. 79. Becklake MR. Occupational exposures: evidence for a causal association with chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 140(3 Pt 2):S85–91. 80. Lapp NL, Morgan WK, Zaldivar G. Airways obstruction, coal mining, and disability. Occup Environ Med 1994; 51:234–238. 81. Hendrick DJ. Occupational and chronic obstructive pulmonary disease (COPD). Thorax 1996; 51(9):947–955. 82. Silverman EK, Speizer FE. Risk factors for the development of chronic obstructive pulmonary disease. Med Clin North Am 1996; 80:501–522. 83. Sunyer J, Schwartz J, Tobias A, Macfarlane D, Garcia J, Anto JM. Patients with chronic obstructive pulmonary disease are at increased risk of death associated with urban particle air pollution: a case-crossover analysis. Am J Epidemiol 2000; 151(1):50–56.

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2 Pathology of Emphysema

JAMES C. HOGG University of British Columbia and St. Paul’s Hospital Vancouver, British Columbia, Canada

I. Introduction Pulmonary emphysema was ﬁrst described by Laennec in 1834 from observations of the cut surface of postmortem human lungs that had been air dried in inﬂation (1). The lesions were attributed to the compression of capillaries by overinﬂation of the lung, interference with blood ﬂow, and atrophy of the tissue. This hypothesis persisted in major textbooks of pathology as late as 1940 (2), but it fell into disfavor as reports implicating infection and inﬂammation in the pathogenesis of emphysema began to appear. The concept that inﬂammation of the alveoli was an important cause of emphysema was advanced by McLean in Australia (3). Leopold and Gough (4) in the United Kingdom, and Andersen and Foraker in North America (5) in the 1950s and 1960s, but the theory was resisted, because the terminal bronchopneumonia complicated the histological picture in these postmortem studies. The fact that a cigarette smoke–induced inﬂammatory process is present in all smokers was established by subsequent studies based on careful postmortem examination of sudden deaths (6), examination of surgically resected lungs (7), and bronchoalveolar lavage (8). The current hypothesis is that a proteolytic imbalance within this inﬂammatory process 23

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is responsible for the lung destruction in emphysema (9), but there is no clear agreement as to which cells are involved (10–12) and even less agreement as to which proteolytic enzyme is responsible for the lung destruction (10,13,14). The fact that all smokers develop lung inﬂammation (6–8) and only a fraction develop emphysema (15–17) is similarly unexplained. The description of emphysematous lesions improved in the 1950s and 1960s, because pathologists returned to ﬁxing postmortem lung specimens in the inﬂated state, examined the cut surface of these specimens following barium sulphate-impregnation (18), and developed a method of mounting whole lung sections on paper in order to demonstrate the lesions outside the postmortem room (19). Differences between clinicians and pathologists concerning the meaning of the terms they used to describe emphysema led to a Ciba Guest Symposium where important, if not unanimous, agreement was produced on terminology, deﬁnitions, and classiﬁcation of emphysema and its related conditions (20). Subsequent conferences held under the auspices of the American Thoracic Society (21) and the U.S. National Institutes of Health (22) further modiﬁed and improved these deﬁnitions. Emphysema is currently deﬁned as ‘‘abnormal permanent enlargement of airspaces distal to terminal bronchioles, accompanied by destruction of their walls without obvious ﬁbrosis.’’ This deﬁnition presupposes knowledge of normal airspace size, which varies with lung inﬂation, making it difﬁcult to separate fully inﬂated normal lung tissue from mild emphysematous lung destruction. This problem restricted the diagnosis of emphysema to pathologists who were willing to ﬁx the postmortem lung in full inﬂation. This changed with the introduction of computed tomographic (CT) scanning and its morphology, which will be reviewed in more detail in a later section.

II.

Terminology

The terms used to describe the pathology of emphysema are well established. They are based on the anatomy of the normal lung where the secondary lobule is deﬁned as that part of the lung surrounded by connective tissue septae (Fig. 1A) and the acinus as the portion of the lung parenchyma supplied by a single terminal bronchiole (Fig. 1B). The terminal bronchioles are the last purely conducting airway with alveoli ﬁrst appearing in the respiratory bronchioles that arise from them. Each subsequent division of the respiratory bronchiole contains increasing numbers of alveoli and less conducting airway epithelium. The conducting epithelium is completely replaced by alveoli in the alveolar ducts, and these ducts branch

Pathology of Emphysema

25

Figure 1 (A) Connective tissue outlining the secondary lobule (solid arrow) where several terminal bronchioles (TB) are ﬁlled with contrast. (B) Histology of the terminal bronchiole (TB), respiratory bronchiole (RB), and alveolar duct (AD). (C) Diagram showing destruction of the respiratory bronchioles in a centrilobular lesion. (From Ref. 4.) (D) Bronchogram demonstrating the centrilobular lesion (CLE).

for several more generations until they end in alveolar sacs. Reid (23) was the ﬁrst to deﬁne the nature of the terminal bronchiole in radiological terms and establish that each secondary lobule contained several acini. III.

Centrilobular/Centriacinar Emphysema

Figure 1C and 1D show examples of the centrilobular form of emphysema caused by dilatation and destruction of the respiratory bronchioles. This form of emphysema was brieﬂy described by Gough in 1952 (24), by McLean in Australia in 1956 (25), and in a more detailed report by Leopold and Gough in 1957 (4). Dunnill (26) suggested that centriacinar emphysema

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Figure 2 (A) A paper-mounted whole lung section of a lung with mild centrilobular emphysema. Note that the lesions are larger and more numerous in the upper regions of the lung. (B) A paper-mounted whole lung section of severe panacinar emphysema. Note that only the upper part of the upper lobe looks normal and the lower lung regions are nearly destroyed by severe panacinar disease.

is a better term, because the disease is located in the acinus and not all of the acini in a lobule need be affected. However, as individual centriacinar lesions frequently coalesce, the term centrilobular emphysema has become ﬁrmly entrenched in the literature. The centrilobular form of emphysema (Fig. 2) affects the upper regions of the lung more commonly than the lower (27), and the individual lesions are larger and more numerous in the upper lung (27). Heppleston and Leopold emphasized that the parent airways supplying the centriacinar lesions were often narrowed owing to an inﬂammatory reaction that was peribronchiolar in location and involved both a polymorphonuclear and mononuclear leukocyte inﬁltration. They also showed that the lesions often contained carbonaceous pigment, and that fragmented strands of tissue within the lesions were inﬂamed (28). The same investigators described focal emphysema that involved the respiratory bronchioles, was less destructive than the centrilobular form, contained large quantities of pigment, and was supplied by airways that were neither inﬂamed nor stenosed (28). Wyatt challenged the view that there was any difference between focal and centrilobular emphysema (29), and Dunnill suggested that the separation of focal from centrilobular emphysema was

Pathology of Emphysema

27

based on semantic arguments that add little to our understanding of either the mechanism of the lung destruction or its functional consequences (26). The two conditions probably have a similar origin with focal emphysema being more widely distributed and less severe than the classic centrilobular form. IV.

Panacinar/Panlobular Emphysema

The term panacinar emphysema refers to dilatation and destruction throughout the acinus that results in uniform destruction of the entire lobule when all of the acini in it are involved. Wyatt et al. (29) provided a detailed account of this lesion in 1962, although it had been described under different names by earlier investigators. Thurlbeck’s review of this topic established that the mildest form of this disease is difﬁcult to discern unless slices of ﬁxed inﬂated lung are impregnated with barium sulfate and examined underwater using the low-power magniﬁcation provided by a dissecting microscope (27). The disease is said to be more severe in the lower lobe, but Thurlbeck found that this only becomes statistically signiﬁcant in advanced cases (27). Severe panacinar emphysema was associated with alpha1-antitrypsin deﬁciency, and reports of panacinar emphysema in young subjects with normal levels of alpha1-antitrypsin have prompted others to look for genetic deﬁciencies that make persons more susceptible to the development of emphysema (27). Indeed, the variable incidence of emphysema in the face of similar heavy cigarette smoking histories suggests that there may indeed be susceptibility genes (15–17). V. Distal Acinar Emphysema The terms distal acinar, mantle, or paraseptal emphysema are used to describe lesions that occur in the periphery of the lobule (27). This type of lesion is commonly found along the lobular septa, particularly in the subpleural region. It can occur in isolation where it has been associated with spontaneous pneumothorax in young adults and bullous lung disease in older individuals. However, isolated distal acinar destruction is often found in association with other forms of emphysema. VI.

Miscellaneous Forms of Emphysema

Several types of emphysema are only marginally relevant to the pathology of adult chronic obstructive pulmonary disease (COPD), which is fully

28

Hogg

described elsewhere (26,27). The emphysema that forms around scars lacks any special distribution in the lobule and is referred to as irregular emphysema. Bullous disease of the lung arises from the distal acinar form of emphysema described above. It can occur in isolation and create large cysts that interfere with lung function. Surgical removal of these isolated lesions can have a very positive effect on lung function. Unilateral emphysema, or McLeod’s syndrome, has been described following severe infections with measles and adenovirus and is associated with a severe bronchiolitis in the affected lung, and lobar emphysema is a developmental abnormality affecting newborn children (26,27). VII.

Measurement of Emphysema

A quantitative assessment of the extent and severity of emphysema present in the lung is the key to understanding both the natural history of the disease and measuring its response to treatment. The early attempts at quantitation were undertaken by pathologists and were based on qualitative grading systems that assessed the cut surface of lung slices. A smaller number of pathologists based their assessment on objective measurements of lung surface area, surface to volume ratio, and alveolar number. Clinical physiologists have used this methodology to assess emphysema and found that the diffusing capacity of the lung for carbon monoxide (DLCO) and the mechanical properties of the lungs, particularly the pressure volume relationship, provide useful information (30). The contributions of radiology to quantitation of emphysema which began with the CT scan are reviewed below. VIII.

Grading Systems

The previously most popular subjective grading system was based on comparing lung sections from patients of interest to a series of papermounted whole lung sections with increasing severity of emphysema (31). This system allowed a grade between 0 and 100 units to be assigned with knowledge of the magnitude and of the between observer and within observer errors (31). Wright et al. modiﬁed this technique and applied it to slices of lobes or whole lungs that had been surgically resected because they contained small peripheral tumors (32). They found that values assigned patients by assessing individual lobes were reproducible and compared favorably to values assigned when an entire pneumonectomy specimen was available. The results of the prospective study of 407 heavy smokers who underwent lung resection for tumor (Table 1) showed an average prevalence

148 (43)

175 (55)a 138 (19)

24 (14)

23.1 (14) (n ¼ 46) 32/65 (50%)

143 (39) 80 (15)

122 (28)

50/15 63 (9) 71 (41) 102 (17)

60–69 (n ¼ 65)

125 (33)

23 (15)

22.4 (8.3) (n ¼ 48) 37/71 (55%)

132 (35) 80 (19)

120 (26)

54/17 63 (9) 55 (33) 103 (17)

70–79 (n ¼ 71)

137 (19)

25 (14)

25.3 (8.5) (n ¼ 61) 29/88 (33%)

125 (41) 83 (26)

115 (30)

57/31 60 (12) 48 (34) 103 (14)

80–89 (n ¼ 88)

FEV1 (% predicted) categories

155 (21)

22 (9)

24.1 (9.3) (n ¼ 57) 25/75 (33%)

124 (33) 102 (34)

118 (25)

56/19 60 (10) 49 (33) 107 (15)

90–99 (n ¼ 75)

145 (17)

23 (13)

23.7 (8) (n ¼ 21) 8/30 (27%)

122 (34) 81 (18)

119 (22)

14/19 60 (8) 47 (33) 112 (14)

100–110 (n ¼ 30)

143 (32)

24 (19)

26.9 (7.8) (n ¼ 16) 2/24 (9%)

113 (26) 106 (53)

121 (21)

11/13 50 (13) 30 (30) 112 (15)

>110 (n ¼ 24)

TLC, total lung capacity; FRC, functional residual capacity; RV, residual volume; DLCO, carbon monoxide diffusing capacity; ALM, distance between alveolar walls. a Signiﬁcantly different (P < .05) from all categories. Source: Modiﬁed from Ref. 17.

29 (17)

32 (15)

151 (42) 72 (18)

175 (50) 78 (19) 18 (5.8) (n ¼ 24) 17/32 (55%)

127 (33)

141 (36)

17.3 (6.2) (n ¼ 7) 11/22 (50%)

24/8 61 (8) 56 (33) 102 (19)

50–59 (n ¼ 32)

16/6 66 (9) 52 (32) 107 (19)

<50 (n ¼ 22)

Mean (SD) Patient Data in Relation to FEV1

M/F Age Pack years TLC (% pred) FRC (% pred) RV (% pred) DLCO (% pred) PLmax (cm H2O) Emphysema prevalence Emphysema score ALM (mm) (n ¼ 5)

Table 1

Pathology of Emphysema 29

30

Hogg

of emphysema of 18% in patients with an FEV1 > 100% predicted that increased to 50% in patients with an FEV1 < 70% predicted (17). Somewhat surprisingly, fairly severe emphysema (24 + 19 units) was present in some smokers with a normal FEV1, DLCO, and normal elastic recoil properties of the lung. Wright et al. concluded that the reduction in elastic recoil that appeared as FEV1 declined was due to changes in the lung surrounding the grossly visible lesions rather than to the lesions themselves. This conclusion was supported by measurements of alveolar size in the surrounding lung in those cases and by subsequent studies that have shown that the earliest change in emphysema is an increase in the surface/volume ratio with relative preservation of the total surface area (33). Both of these observations suggest that earliest emphysematous change is an increase in alveolar volume with relative preservation of the surface area.

IX.

Quantitative Histology

The methods for quantitating lung structure in more precise physical terms was developed in the Cardiopulmonary Laboratory of the Department of Medicine in Bellevue Hospital in New York. The classic work on the normal lung was initiated by an anatomist, Weibel (34), and was followed by the application of this quantitative technique to emphysematous lung disease by the English pathologist Dunnill (35). Both investigators acknowledged the help they received from Dr. Domingo Gomez, a biologist, who was also a talented mathematician. The quantitative approach that they developed is based on a geological principle introduced by Delesse in 1848 and formally proven by Chayes 100 years later (36,37). The fundamental premise is that the fraction of the cut surface taken up by an item of interest is the same as the fraction of the volume that it takes up in the intact specimen. The surface proportions are determined by placing a grid of points randomly over the surface and determining the fraction of the total number of points present that fall on the item of interest. Linear integration is a substitute for point counting based on placing random lines on the surface and determining the proportion of the line taken up by the structure of interest (34,35). Histology provides a two-dimensional representation of three-dimensional objects where lines appear as points, surfaces as lines, and volumes as areas. A section through a container of spheres yields a collection of circles where the spheres and circles have interrelated parameters: 2pr ¼ circumference of the circle pr2 ¼ area of the circle 4pr2 ¼ surface area of the sphere

Pathology of Emphysema

31

4 3 3p

¼ volume of the sphere The constant, p, is a dimension deﬁned by the ratio of the circumference of a circle to its diameter. The volume of the sphere is linked to the area of the circle by the mean chord length (or LM), which turns out to be two-third of the diameter. LM ¼

sphere volume ð4=3Þpr3 4 2 ¼ diameter ¼ r or 2 circle area 3 3 pr

ð1Þ

The area of a circle is also linked to the surface area of the sphere by the factor 1/4: area of circle pr2 1 ¼ ¼ surface area of sphere 4pr2 4 surface area circle area ¼ 4

ð2Þ

Rearranging equations 1 and 2 to solve the area of the circle and then setting them equal to each other, yields: volume surface area ¼ Lm 4 46volume or surface area ¼ Lm

ð3Þ

Tomkeiff (38) showed that in the general case the calculated surface area of the small objects that appeared in cross section on the surface was independent of the shape of either the objects or their container and only required that they be randomly distributed within the container. Campbell and Tomkeiff (39) applied the method to the lung by projecting test lines on randomly selected ﬁelds of histological specimens. Division of the total length of the lines by the number of times the alveolar wall intersected them (using two intersections of the surface for each alveolar wall crossing) provides the Lm. This value represents the proportion of the line taken up by alveoli or the proportion of alveoli in a given volume. The reference volume for all the alveoli contained in a ﬁxed lung (tissue þ air) can be determined by water displacement, and the fraction of this lung volume made up of alveoli can be established by point counting the cut surface of the specimen. Lm must also be corrected for the shrinkage that occurs when fresh tissue is ﬁxed and when ﬁxed tissue is processed onto parafﬁn (34,35). The test lines shown in Figure 3 provide the advantage that the points on the end of each line can be used for point counting and the lines for linear

32

Hogg

Figure 3 Test lines of a point-counting grid where the total length of the lines is used to calculate the number of times alveolar walls intersect the lines and the points at the end of the line are used for point counting (see text for further explanation).

integration. The proportion of the points (P) that fall on tissue provide the fraction of the lung volume taken up by tissue and the number of times the alveolar surface intersects the test lines samples the alveolar surface (I). This information can be used in equation 4 to calculate the surface density (SD), which is a two-dimensional representation of the surface area/volume ratio of the lung. The lung surface area is found by multiplying this ratio by the volume (tissue þ air) of the lung. SD ¼

4 SI ‘ SP

ð4Þ

Pathology of Emphysema

33

Thurlbeck made an extensive study of the surface area of normal and emphysematous lungs obtained at postmortem examination and concluded that the measurements of surface area were too variable to be used to quantitate emphysema in any precise way (27,40). Subsequent studies of human emphysema showing that the SA/volume decreases before there is a signiﬁcant reduction in surface area suggests that SA/volume may be more useful in detecting early disease (33).

X. Computed Tomographic Estimates of Emphysema The Edinburgh group led by the late Professor David Flenley was the ﬁrst to use computed tomography (CT) to estimate the amount of emphysema in the lungs of a living patient (41). The Hounsﬁeld unit (HU) provided by the CT scan is a measure of the degree to which x-rays are attenuated by tissue. It varies between 1000 (air) and 0 (water) and can be converted to lung density by adding 1000 to the Hounsﬁeld units in each voxel and dividing the sum by 1000. The Edinburgh group found that the frequency distribution of the CT units in each voxel of the CT scan could be used to quantitate distal airspace enlargement (41). This concept was expanded by Muller and colleagues, who separated the CT voxels below a certain density (0.910 HU), and showed that the low-density units of lung were emphysematous (42). They referred to this method of separating normal and emphysematous lung as a density mask, and showed that it readily detects lesions larger than 5 mm in diameter but misses lesions less than 5 mm in diameter (43). The measurement of density (weight/volume) can be readily converted to speciﬁc volume (volume/weight), and subtraction of the speciﬁc volume of tissue from the speciﬁc volume of tissue plus air provides the volume of gas/gram of lung tissue (equation 5). mL of gas ¼ specific volume ðtissue þ gasÞ specific volumeðtissueÞ * ð5Þ gram tissue Some years ago we used this relationship to obtain measurements of regional lung volume in experimental animals that were frozen with the thorax intact (44). These measurements can be expressed as a percentage of total lung capacity (%TLC) by dividing the measured mL/g in each regional sample by the total mL/g obtained by dividing TLC (measured during life * Density of tissue assumed to be 1.065 g/mL.

34

Hogg

using a body plethysmograph) by the total lung weight (estimated from the average density and total volume of the lung). Coxson et al. (45) applied this method to CT measurement of human lung density to determine regional lung volume in both absolute terms milliliters of gas/gram tissue (mL/g) and as a %TLC. They were able to show the expected regional differences in normal lung expansion with the thorax intact and predict pleural pressure gradient from the CT estimates of regional lung volume. These measurements were in close agreement with earlier determinations of regional lung volume and the pleural pressure gradient based on the inhalation of radioactive gases (46). They also found that the summed weight of all of the voxels (density 6 volume) of a lung or lobe obtained using the preoperative CT compared favorably with the weight of the resected lung or lobe in patients undergoing surgical treatment for tumor. Measurements of the TLC by plethysmography and the weight of both lungs measured by CT showed that at TLC, the maximally expanded control lungs contained 6.0 + 1.1 mL air/g (33). An analysis of the frequency distribution of the volume of gas/gram tissue for all of the voxels in the CT scan of lungs from patients with normal lung function are normally distributed (Fig. 4). Mild emphysema shifts this distribution to the right and severe emphysema further to the right (33). Comparison of CT measurements of the lobe to the resected specimen conﬁrmed that lesions smaller than 5 mm were detected between normal TLC (6 mL/g) and 10.2 mL/g, which is the volume at the density cutoff (910 HU) used by Muller et al. to separate normal from emphysematous lung (42). Progressively larger emphysematous lesions were distributed between 10.2 and >20 mL/g in these cases (33). These results show that a quantitative assessment of the CT scan can separate maximally expanded normal lung from lung containing mild emphysema. Furthermore, this separation is based on the degree to which the lung is expanded beyond normal, which is the way in which the disease is deﬁned (20–22). Information about the severity of emphysema and its location within the lung can also be quantitated and mapped.

XI.

Combination of CT and Quantitative Histology

Although CT can measure lung overexpansion, it does not have the resolution to study the process of lung destruction. Quantitation at the histological level requires a process based on a sampling design developed by Cruz-Orive and Weibel (47). This procedure allows a random histological sample to be examined in a series of steps based on increasing magniﬁcation where structures observed at one level can be subdivided into their

Pathology of Emphysema

35

Figure 4 Comparison of the frequency distribution of the voxels of the CT scan of lungs from control patients with normal lung function to lungs from patients with mild and severe emphysema. Note that the data from control lungs are normally distributed compared to mild and severe disease where the curves are shifted progressively to the right. A voxel of a CT scan is a three-dimensional source of data compared to the pixel, which has two dimensions. The arrows on the X axis indicate the value for normal total lung capacity (TLC) and the value used to identify emphysema by the density mask (42). See text for further explanation. (Data from Ref. 33.)

components at the next highest level of magniﬁcation. By multiplying the volume fraction (Vv) of tissue taken up by a particular cell type at the highest level of magniﬁcation by volume fractions (Vv) of the tissue at successive lower levels of magniﬁcation, the fraction of the whole lung taken up by that cell can be determined. The total volume of cells of interest can then be obtained by multiplying this fraction by a reference lung volume, and the number of cells present can be calculated by dividing the total cell volume by the average volume of an individual cell. Coxson et al. were able to show that a reference volume determined by CT could be combined with histological samples obtained by open lung biopsy to quantitate the changes that occur in lungs with interstitial ﬁbrosis (48). They subsequently used the same approach in patients undergoing lung volume reduction surgery and developed an equation ðSA=V ¼ e6:480:326mL gas=g Þ that allowed the surface area of each voxel of

36

Hogg

the lung CT to be estimated (33). By using this equation to compute the surface area/volume and total surface area of the entire lung, they were able to show that the mild emphysema was associated with a reduction SA/V with preservation of the total surface area, whereas both parameters were reduced in severe disease (33). This approach can be used to compute the total number of cells present in the lung and express them per unit surface area, and in a recent study, we demonstrated an absolute increase in the number of inﬂammatory cells present in severe emphysema (49). These data suggest that the inﬂammatory response is ampliﬁed in emphysematous lung destruction but does not provide a clear idea of the kinetics involved in moving inﬂammatory cells from the circulation into the airspaces. A normal cardiac output of 5 L/min delivers 7200 L of blood to the lung in 24 h. A white blood cell count (WBC) count of approximately 5 6 109/L means that 36 6 1012 WBCs will ﬂow through the lung microvessels over this period of time. At an average lung weight of 1000 g, each gram of lung will see 36 6 109 leukocytes ﬂow through its capillaries in 24 h. The time spent by the WBCs in each transit through the lung capillaries is of the order of 60 s compared to the erythrocyte’s transit time of 1 s (50). This results in a concentration of polymorphonuclear neutrophils (PMNs) with respect to erythrocytes of about 60-fold in lung capillaries compared to peripheral blood (50,51). The slowing down and concentration of WBCs with respect to erythrocytes occurs because the maximum dimension of both the erythrocyte and WBC is larger than the maximum diameter of many segments of the capillary bed (52). The erythrocytes are much better able to negotiate this restriction because they are able to fold quickly, whereas the WBC must slowly deform (50,51). The delay that individual WBC experience with respect to the erythrocyte is roughly proportioned to their size, and their correlation in lung microvessels is further increased by acute cigarette smoke exposure (53). The lung capillary bed can accommodate this slower WBC trafﬁc, because it is made up of a large number of short interconnecting capillary segments that allow the fast-moving red blood cells (RBCs) to stream around segments ﬁlled with slower moving WBC (50,51). The number of cells that migrate out of the lung capillary bed is very small in relation to the number that ﬂow through it. Even with a strong stimulus such as acute streptococcal pneumonia, only 1–2% of cells delivered to the pneumonia migrate into the alveolar space (54). The number of cells that migrate into the alvcoli in cigarette smoke–induced inﬂammation is more difﬁcult to study, but the important point is that relatively few of the cells ﬂowing through the capillary bed will migrate through the alveolar wall tissue into the airspaces.

Pathology of Emphysema

37

Walker and his colleagues have provided important new information about the pathways that the PMN take through the alveolar wall during an acute inﬂammatory response (55–58). Their work shows that interstitial ﬁbroblasts extend projections that reach holes in the basement membrane of both the endothelium and epithelium. After PMN migrate out of capillaries (55,56), they negotiate the tiny holes in the basement membrane of the capillaries (57) and then use the surface of the ﬁbroblast as a guide to reach the holes in the basement membrane of the epithelium (58). They then migrate through these holes and exit into the alveolus between the type I and type II alveolar cells. Nothing is known about this process in cigarette smoke–induced inﬂammation, but it seems likely that the excess trafﬁc of cells in this chronic form of alveolitis provide the migrating cells with more opportunity to come in contact with the elastic network in the alveolar wall interstitial space. The steps by which this contact between inﬂammatory cell and elastic ﬁber cause the destruction of the network is poorly understood and not under very active investigation. An excellent early study provided some of the best information about the elastic network in normal and emphysematous lungs (59). Unfortunately, there is little direct morpholog-ical data about what happens to the elastin in the alveolar wall as it comes into contact with inﬂammatory cells in the early stages of emphysema, and most biochemical studies of elastin content are confounded by the changes in nonalveolar tissue such as arteries, airways, and pleura. Much more work remains to be done on the relationship between cells migrating through the interstitial space of the alveolar wall and the exact mechanism of the destructive process that results in emphysema. Boren (60) and Pump (61) suggested that alveolar destruction begins with enlargement of the normal pores (pores of Kohn) in the alveolar wall to form fenestrae. Just how the inﬂammatory process causes the fenestrae to form has not been determined.

XII.

Functional Consequences of Alveolar Destruction

The pressure required to inﬂate the lung is determined by the Laplace equation which relates distending pressure to the tension in the wall and the radius of curvature of the alveoli. The total tension in the alveolar walls is determined by both tissue and surface forces (equation 6). In the normal lung, the surface forces are low following a full inﬂation, and the maximum elastic recoil ðPLmax Þ measured at this point primarily reﬂects the elastic recoil of the tissue.

38

Hogg

Figure 5 Bronchogram comparing the same centrilobular emphysema (CLE) space at different transpulmonary pressures. Graph compares PV characteristics of CLE spaces to the PV curves of normal lungs. The spaces are nearly fully inﬂated at FRC (p ¼ 2.5 cm H2O) and there is little volume change with increasing pressure. The PV curve from one lung with emphysema is shown for comparison. Its nature suggests that its elastic properties have been decreased by changes in the lung surrounding the CLE lesions. See text for further explanation. (From Ref. 62.)

Pathology of Emphysema

39

Equation 6 shows that PLmax will fall with either an increase in the average dimension of surface tension tissue tension þ P¼2 ð6Þ R R the alveoli of the lung (R) or by a decrease in the tissue tension. Referral back to the data in Table 1 shows that PLmax fell about 10 cm H2O as FEV1 decreased from >100% predicted to <50% predicted in this group of cases. As stated earlier, we suspect that some, if not most, of this loss in recoil is due to an increase in airspace size in the lung surrounding the emphysematous lesions because of the fact that the earliest change in emphysema is a decrease in SA/V with a relatively preserved surface area (33). This suggests that the disease may be localized to the visible lesions when lung function is normal and involve the surrounding lung, which has not yet developed visible lesions as lung function deteriorates. Thurlbeck (personal communication) used a Swiss cheese analogy for the lung, which means it is the cheese, not the holes, that determine the loss in elastic recoil. Figure 5 shows measurements of the PV curves of well-developed centrilobular emphysematous spaces (61), indicating that the spaces are nearly fully inﬂated at modest transpulmonary pressure. This means that when the lung is at functional residual capacity (FRC), the spaces have a markedly reduced inspiratory capacity compared to the surrounding lung. Therefore, they take in less than their share of each inspiratory breath, and as more and more of the lung is taken up with these lesions, the total inspiratory capacity of the lung falls. This will interfere with the subject’s ability to increase tidal volume during exercise and eventually encroach on tidal volume at rest. The exact contribution of these changes to overall lung function is difﬁcult to determine with respect to the other factors such as reduced capillary surface area and ventilation/perfusion (V/Q) abnormality. However, it is clearly one of the deﬁcits that might be improved by lung volume reduction surgery.

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40

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6. 7. 8. 9. 10. 11.

12.

13.

14.

15. 16. 17. 18. 19. 20. 21.

22.

23.

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24. Gough J. Discussion on the diagnosis of pulmonary emphysema. Proc R Soc Med 1952; 45:576–577. 25. McLean KH. Macroscopic anatomy of pulmonary emphysema. Aust Ann Med 1958; 5:62–74. 26. Dunnill MS. Emphysema. In: Pulmonary Pathology. New York: Churchill Livingstone, 1982:81–112. 27. Thurlbeck WM. Chronic airﬂow obstruction. In: Pathology of the Lung. 2nd ed. New York: Theime, 1995:739–825. 28. Heppleston AG, Leopold JG. Chronic pulmonary emphysema anatomy and pathogenesis. Am J Med 1961; 31:279–291. 29. Wyatt JP, Fisher VW, Sweet AC. Panlobular emphysema: anatomy and pathogenesis. Dis Chest 1962; 41:239–259. 30. Bates DV, Macklem PT, Christie RV. Emphysema. In: Respiratory Function in Disease. Philadelphia: Saunders, 1996:156–218. 31. Thurlbeck WM, Dunnill MS, Hartung W, et al. A comparison of three methods of measuring emphysema. Hum Pathol 1970; 1(2):215–226. 32. Wright JL, Wiggs B, Pare PD, Hogg JC. Ranking the severity of emphysema on whole lung slices. Am Rev Respir Dis 1986; 133:930–931. 33. Coxson HO, Rogers RM, Whittal KP, D’Yachkova Y, Pare PD, Sciurba FC, Hogg JC. Quantiﬁcation of the lung surface area in emphysema using computed tomography. Am J Respir Crit Care Med 1999; 169:851–856. 34. Weibel ER. Morphometry of the Human Lung. Berlin: Springer-Verlag. 1963. 35. Dunnill MS. Quantitative methods for the study of pulmonary pathology. Thorax 1962; 17:320–328. 36. Delesse A. Ann Mines 1848; 13:378. 37. Chaynes F. Petrographic Model Analysis. New York: Wiley, 1956. 38. Tomkeiff SA. Linear intercepts, areas and volumes. Nature 1945; 155:24. 39. Campbell H, Tomkeiff SA. Calculation of the internal surface of the lung. Nature 1952; 170:117. 40. Thurlbeck WM. Internal surface area and other measurements of emphysema. Thorax 1967; 22:483–496. 41. Hayhurst MD, MacNee W, Flenley DC, et al. Diagnosis of pulmonary emphysema using computed tomography. Lancet 1984; 2:320–322. 42. Muller NL, Staples CA, Miller RR, Abboud RT. Density Mask. An objective method to quantitate emphysema. Chest 1988; 94:78787. 43. Miller RR, Muller NL, Vedal S, et al. Limitations of computed tomography in the assessment of emphysema. Am Rev Respir Dis 1989; 139:980–983. 44. Hogg JC, Nepszy S. Regional lung volumes and pleural pressure gradient measured from lung density in dogs. J Appl Physiol 1969; 27:198–203. 45. Coxson HO, Mayo JR, Behzad H, Moore BJ, Verburgt LM, Staples CA, Pare PD, Hogg JC. The measurement of lung expansion with computed tomography and comparison with quantitative histology. J Appl Physiol 1995; 79:1525–1530. 46. Milic-Emili J, Henderson JA, Dolovich MB, Trop D, Kaneko K. Regional distribution of inspired gas in the lung. J Appl Physiol 1966; 21:749–759.

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47. Cruz-Orive LM, Weibel ER. Sampling designs for stereology. J Microscop 1981; 122:235–257. 48. Coxson HO, Hogg JC, Mayo JR, et al. Quantiﬁcation of pulmonary ﬁbrosis using computed tomography and histology. Am J Respir Crit Care Med 1997; 155:1649–1656. 49. Ratemales I, Elliott WM, Meshi B, et al. Ampliﬁcation of inﬂammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med 2001; 164:469–473. 50. Hogg JC, Coxson HO, Brumwell ML. Erythrocyte and polymorphonuclear cell transit time and concentration in human pulmonary capillaries. J Appl Physiol 1994; 77:1995–1800. 51. Hogg JC. Neutrophil kinetics and lung injury. Physiol Rev 1987; 67:1249–1295. 52. Doerschuk CM, Bayers N, Coxson HO, Wiggs BR, Hogg JC. Comparison of neutrophil and capillary diameters and their relation to neutrophil sequestration in the lung. J Appl Physiol 1993; 74:3040–3045. 53. MacNee W, Wiggs B, Belzberg AS, Hogg JC. The effect of cigarette smoking on neutrophil kinetics in human lungs. N Engl J Med 1989; 321:924–928. 54. Doerschuk CM, Markos J, Coxson HO, English D, Hogg JC. Quantitation of neutrophil migration in acute bacterial pneumonia in rabbits. J Appl Physiol 1994; 77:2593–2599. 55. Walker DC, Brown LJ, MacDonell SD, Chu F, Burns AR. Serial section reconstruction of neutrophils, endothelium and tight junctions during diapedesis in capillaries of rabbit lung. FASEB J 1998; 12:A952. 56. Walker DC, MacKenzic A, Hosford S. The structure of the tricellular region of endothelial tight junctions of pulmonary capillaries analyzed by freeze-fracture. Microvasc Res 1994; 48:259–281. 57. Walker DC, Behzad AR, Chu F. Neutrophil migration through pre-existing holes in the basal laminac of alveolar capillaries and epithelium during streptococcal pneumonia. Microvasc Res 1995; 50:397–416. 58. Behzad A, Chu F, Walker DC. Fibroblasts are in a position to provide directional information to migrating neutrophils during pneumonia in rabbit lungs. Microvasc Res 1996; 51:303–316. 59. Wright RR. Elastin tissue of normal and emphysematous lungs. A tridimensional histologic study. Am J Pathol 1961; 39:355–367. 60. Boren HG. Alveolar fenestrae. Relationship to pathology and pathogenesis of emphysema. Am Rev Respir Dis 1968; 98:217–228. 61. Pump KK. Emphysema and its relation to age. Am Rev Respir Dis 1976; 114:5–13. 62. Hogg JC, Nepszy S, Macklem PT, Thurlbeck WM. The elastic properties of the centrilobular emphysematous space. J Clin Invest 1969; 48:1306–1312.

3 Physiology of Airﬂow Limitation in Emphysema

JOSEPH R. RODARTE{ Baylor College of Medicine Houston, Texas, U.S.A.

I. Introduction In the majority of patients with emphysema, pathological changes of emphysema coexist with chronic bronchitis. Furthermore, emphysema may exist in centrilobular or panlobular forms, may include large bullae, may be diffuse or relatively localized, and may predominate in upper or lower lobes. The impact of these pathological and anatomical variations on whole lung function is largely unknown. The pathology of emphysema is covered in detail in Chapter 2. In this chapter, we ﬁrst describe the pathophysiology of chronic obstructive pulmonary disease (COPD) of any cause, then differentiate airway disease from emphysema, and ﬁnally consider the possible signiﬁcance of different types of emphysema for the outcome of lung volume reduction surgery (LVRS). Because of the paucity of data from patients with end-stage emphysema, much of the following discussion is theoretical, being extrapolated from animal studies and data on patients with less severe disease. {

Deceased.

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Rodarte II.

Pathophysiology of Respiratory Failure in COPD

The cardinal abnormality of COPD is irreversible reduction in maximal expiratory ﬂow. In normal middle-aged and elderly humans, residual volume (RV) is determined by dynamic compression and perhaps closure of peripheral airways. As estimated from esophageal pressure, pleural pressure at RV may be from 20 to 50 cm H2O. This is associated with a minuscule but ﬁnite expiratory ﬂow, so that RV is, in part, determined by the length of the time that the patient is willing or able to maintain expiratory effort. Chronic obstructive pulmonary disease alters several features of the normal ﬂow volume curve. In normal subjects, maximal expiratory ﬂow is an approximately linearly increasing function of lung volume above RV up to peak ﬂow, which occurs within the ﬁrst 20% of expired vital capacity. In the healthy middle-aged and elderly, the ﬂow volume curve is slightly convex to the volume axis. With COPD, residual volume is increased and the maximal ﬂow at any volume above RV is less. The ﬂow volume curve becomes more convex to the volume axis. Total lung capacity (TLC), which is determined by the balance between the maximal inspiratory force produced by the inspiratory muscles and the expiratory recoil of the lung and chest wall, is also increased. Thus, the ﬂow volume curve is shifted to higher volume and downward to lower ﬂows. In normal men, maximal expiratory ﬂow near functional residual capacity (FRC) is high, so that maximum ﬂow is not achieved even during maximal exercise except in the highly aerobically ﬁt elderly (1–4). However, young women may utilize maximal ﬂow during heavy exercise (5). During resting breathing, inspiration takes about 45% of the total breathing cycle. Therefore, mean inspiratory ﬂow rate is about 20% higher than mean expiratory ﬂow rate. With exercise, inspiratory and expiratory ﬂow rates equalize as inspiratory time approaches 50% of the cycle. With even mild COPD, maximal expiratory ﬂow is required during modest levels of exercise. Patients maintain the timing of ventilation but increase mean expiratory ﬂow rate by increasing FRC (1). This phenomenon is termed dynamic hyperinﬂation. With more advanced disease, maximal ﬂow at normal FRC is less than normal tidal ﬂow, and dynamic hyperinﬂation occurs even at rest. Utilization of maximal ﬂow during quiet breathing is associated with dyspnea (6), although it is not clear whether it is dynamic airway compression during maximal ﬂow or accompanying hyperinﬂation that contributes to the symptom. During maximal exercise in patients with moderately severe disease, end-inspiratory lung volume approaches TLC and maximal ﬂow occurs throughout expiration. End-expiratory lung volume may be above the entire normal tidal breathing range. With advanced disease, this pattern occurs at

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rest. Such patients also use nearly maximal inspiratory ﬂow, which is determined by the strength and force–velocity relationships of the inspiratory muscles, with each tidal breath. These patients are no longer able to maintain normal respiratory timing. Mean inspiratory ﬂow rate may be three to four times mean expiratory ﬂow rate, subjects’ end-inspiratory lung volume is near TLC, and expiratory ﬂow is maximal throughout expiration. These patients are unable substantially to increase their ventilation, and their exercise capacity becomes markedly limited. Finally, even ventilation required to maintain a normal resting arterial CO2 content at rest cannot be sustained. Patients develop chronic respiratory failure, as deﬁned by the chronically elevated arterial CO2 pressure (PaCO2). This simple scenario is fully explained by the need to achieve certain ventilation to meet metabolic needs within the conﬁnes of the abnormal maximal inspiratory and expiratory ﬂow volume relationship.

III.

Other Effects of Emphysema

Many sequelae of airway obstruction are similar regardless of whether the reduced maximal ﬂows are due to reduced lung elastic recoil or to airway disease. The mechanism for the increase in TLC in patients with severe airway disease is not understood but may involve decreased lung recoil, disinhibition of maximal inspiratory effort, and chest wall remodeling. In general, patients with emphysema have more hyperinﬂation than those with predominantly airway disease. Emphysema is also characterized by reduction of the diffusing capacity of lung for carbon monoxide (DLCO) because of destruction of alveolar surface area. There is a reasonable correlation between lung elastic recoil and DLCO in mild to moderate disease (7). In patients with severe airway obstruction, DLCO may also be reduced because of ventilation/perfusion (V/Q) mismatch, and the patient may be too dyspneic to perform the test properly. Most emphysematous patients have an increased alveolar–arterial O2 pressure (Aa PO2) gradient, but characteristically they exhibit only mild hypoxia until the disease becomes extremely severe. They often have slight chronic alveolar hyperventilation. Chronic respiratory failure with an elevated PaCO2, and PaO2 below 50 mmHg generally occur later in the course of the disease than it does in patients with primarily airway disease. Alveolar destruction creates high ventilation/perfusion (V/Q) areas, which, although poorly ventilated, are even more poorly perfused. These high V/Q areas receive more ventilation than normal relative to CO2 production, thus compounding the demands on the inspiratory muscles. Because of the

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nonlinearity of oxyhemoglobin dissociation, these relatively hyperventilated regions decrease arterial CO2 tension without increasing arterial O2 tension. Emphysema has several cardiovascular consequences, which are discussed in detail in Chapter 4. With dynamic hyperinﬂation, expiratory pleural pressures are positive because of the high lung volumes and the elastic recoil of the chest wall. This positive pressure during the prolonged expiratory phase impedes venous return to the heart. Dynamic hyperinﬂation and high airway resistance also cause very negative pleural pressures during inspiration, which increases the afterload on the left ventricle. with marked hyperinﬂation, there may be obstruction of the inferior vena cava during inspiration (8), so that venous return only occurs during expiration. At high lung volumes, inspiratory muscles are operating at a very short length, which reduces force-generating capacity. The muscles are also at a mechanical disadvantage. The diaphragm is ﬂatter, so that muscle tension becomes less effective in generating a transdiaphragmatic pressure. Ultimately, the diaphragm pulls inward on the lower rib cage rather than producing caudal displacement of the dome; that is, it has an expiratory rather than an inspiratory effect. In summary, progressive reduction of maximal expiratory ﬂow as a function of volume produces dynamic hyperinﬂation and reduces sustainable ventilatory capacity. This initially limits exercise capacity and ultimately compromises the resting ventilation that sustains life. This sequence is independent of the cause of the decreased maximal expiratory ﬂow. IV.

Mechanisms of Flow Limitation

In order to differentiate the pathophysiology of emphysema from that of airway disease, it is helpful to review the determinants of maximal ﬂow. One important factor is the pressure that distends the airway at any given locus. This is the transmural airway pressure or the intraluminal pressure relative to pleural pressure. During expiration, this airway pressure decreases by several mechanisms, expressed in equation 1: P ¼ PEL V_ ð fRE Þ 1=2rU 2

ð1Þ

P is intraluminal pressure relative to pleural pressure; PEL is elastic recoil pressure of the lung; V_ is expiratory ﬂow rate; fRE is a frictional resistance; r is the gas density; and U is average molecular velocity in the airway, which is equal to V_ divided by the total cross-sectional area of the airway at that generation. The ﬂow rate in the alveolus is vanishingly small; therefore, alveolar pressure exceeds pleural pressure by the elastic recoil pressure of the

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lung at that volume. At any point downstream from the alveolus, the distending pressure is reduced below PEL by the two factors in equation 1. The ﬁrst factor describes pressure loss to friction, and the second describes loss to acceleration. In turn, the magnitude of the frictional loss component is dependent on the Reynolds number (RE). The Reynolds number is a dimensionless term describing ﬂow in pipes. It is the ratio of the kinetic energy of the ﬂow to viscous pressure losses: RE ¼

rUD ; m

ð2Þ

where r and U are density and velocity, as deﬁned above; D is the diameter of the tube; and m is the viscosity of the ﬂuid. The kinetic energy in a tube of ﬂowing gas is proportional to its density r and U2. The diameter of the tube appears, because for any mean velocity, the larger the diameter, the greater the difference in velocity between the wall of the tube and the center where velocity is highest. The denominator of the Reynolds number is U 6 m, a measure of the viscous forces which slow the ﬂow at the wall to zero. This drag is transmitted through the ﬂuid as more central cylinders slide within more peripheral ones. The U in the denominator cancels one in the numerator, yielding equation 2. In the lung periphery, there are a large number of small-diameter airways, so the cumulative cross-sectional area is huge. Therefore, the mean velocity and the kinetic energy are small. The Reynolds number is low, and the pressure losses are largely viscous. The pressure loss is linearly related to the ﬁrst power of gas viscosity and velocity, but increases in proportion to the fourth power of the airway radius. In more central airways, although the individual bronchial diameters are larger, the cumulative cross-sectional area is much smaller. Velocities are much higher, as are Reynolds numbers. The smooth velocity proﬁle that occurs at low Reynolds numbers is disrupted. Gas molecules collide with each other and ﬂow becomes chaotic, with individual molecular velocities in a region varying with time in both magnitude and direction. In this ﬂow regimen, pressure drop in the airway is independent of gas viscosity and is dependent instead on gas velocity squared and density. The last term in equation 1 derives from the Bernoulli equation, which describes the distending pressure losses due to convective acceleration in a frictionless system: P ¼ ðconstantÞ 1=2rU 2

ð3Þ

As gas ﬂows from the huge cross-sectional area in the periphery to a central airway, velocity increases and intraluminal distending pressure drops as

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potential energy is used to accelerate the gas. That is, in a frictionless system in which total energy is constant, the Bernoulli equation quantiﬁes the conversion between potential energy (represented by the distending pressure in the airway) and kinetic energy (proportional to the velocity of the ﬂowing gas). During quiet breathing in normal lungs, Reynolds numbers are low throughout the lung. Therefore, the pressure drop is linearly related to ﬂow and gas viscosity and largely independent of density. During maximal ﬂow from TLC to 60% of expired vital capacity, the pressure drop from the alveolus to the critical point in the airway that determines maximal ﬂow is almost completely due to convective acceleration. At lower volumes or in the presence of airway disease, frictional losses become increasingly important. Since the airways are elastic tubes, those factors that alter intraluminal pressure also alter luminal diameter. The magnitude of diameter change depends upon the intraluminal pressure, the pressure on the outer surface of the airways, and their pressure–area relationship. The bronchovascular sheath surrounding the airways is contiguous with the pleural space. Therefore, the lung can be considered as being an elastic organ pierced with tunnels, which expand and contract with the same pressure–volume relationship as the lung parenchyma. The conducting airways and vessels lie within these hypothetical tunnels. To the ﬁrst approximation, the pressure on the outside of the intraparenchymal airways is equal to the pleural pressure. The material properties of the lung allow it to change shape easily at constant volume. Therefore, if the bronchi narrow or enlarge at a ﬁxed lung volume, the pressure surrounding the airway still does not deviate greatly from pleural pressure. In the absence of ﬂow, the transmural pressure of the airway therefore equals the difference between alveolar and pleural pressure; that is, the elastic recoil pressure of the lung. Since the airways change their crosssectional area with transmural pressure, airways increase their diameter with lung inﬂation, and of course they must also lengthen. Since frictional resistance is directly proportional to the length but inversely proportional to the fourth power of the diameter, frictional resistance of the airway decreases as lung volume increases. In the presence of airﬂow, intraluminal pressure relative to pleural pressure decreases from the alveoli to the airway opening because of convective and frictional pressure losses. With increasing ﬂow at the same lung volume (obtained from a different expiration with more effort), pleural and alveolar pressure increase equally, and the pressure drop down the airway is greater. As transmural pressure decreases down the elastic airway, diameters decrease according to the elastic properties of the airway, and

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frictional and convective pressure losses increase further. Therefore, the pressure drop at each point in the airway is determined by the coupled equations of the mechanics of the ﬂow (which determine the distending pressure at any ﬂow) and the airway (which determines the area at any distending pressure).

V. Maximal Expiratory Flow It has long been appreciated that all terrestrial mammals exhibit a maximal expiratory airﬂow. To understand the mechanisms causing this phenomenon, it is useful to divide the airway into two segments upstream and downstream of the site of ﬂow limitation. In the upstream segment, the pressure drop down the airway increases with increasing effort and ﬂow until maximal ﬂow is reached. Once this occurs, further increases in effort increase pleural and intraluminal pressure equally. Therefore, transmural pressure and the pressure–ﬂow relationship in this segment does not change. Mouthward of the site of ﬂow limitation, resistance increases with effort. Further increases in pleural pressure compress the airway, increasing resistance such that any increased pressure at the entry to this downstream segment is dissipated to atmospheric pressure at the mouth. Once maximal ﬂow is reached, ﬂow is constant and independent of greater effort. During mechanical ﬂow, the pressure–ﬂow relationship given by equation 1 and the pressure–area relationship of the airway through which the ﬂow occurs must coincide. If one combines the equations describing the loss of distending pressure with increasing ﬂow, and the decreasing airway area with decreasing distending pressure, and solves for the unique maximal ﬂow, one obtains the following: 1=2 AdA _ ð4Þ Vmax ¼ A rdP This is the equation for wave speed, the speed of wave travel in a tube of compliance, dA/dP, expressed as a ﬂow rate (9). That ﬂow can never exceed this rate can be qualitatively understood as follows: imagine an isolated lung removed from the thorax. The lung can be inﬂated to TLC and maximal expiratory airﬂow generated by attaching the airway opening to a vacuum source. If pressure then suddenly decreases further at the airway opening, expired ﬂow will transiently increase, but the decrease in pressure will cause the cross-sectional area of the airway to decrease, and part of the increased ﬂow will come from that airway narrowing. This pressure wave and airway narrowing move upstream at the wave speed of the tube minus the

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downstream velocity of any preexisting expiratory ﬂow. Maximal expiratory ﬂow occurs when, at some point in the airway, gas velocity in the expiratory direction is equal to the wave speed. Any further decrease in transmural pressure of the tube downstream of that point propagates against the airﬂow until it reaches this critical locus at which downstream velocity is equal to the upstream velocity. There it can progress no further. Since the decreased pressure wave cannot traverse this critical point, the pressure upstream never decreases, and ﬂow does not change. In summary, at constant volume with increasing pleural pressure, there is increasing ﬂow and transmural pressure drops down the airway, according to equation 1. Airway area continuously changes according to the elastic properties of each generation of airway until at some point in the airway, wave speed is achieved. The airway generation in which the lowest ﬂow produces wave speed determines the maximal ﬂow for the entire lung at that volume. The wave speed equation shows that the maximal ﬂow for a given airway is determined by the area (1,10), and is inversely proportional to the square root of the airway compliance. At high lung volume and zero ﬂow, the initial transmural pressure of an airway that will become the ﬂowlimiting site is high, and the resistance between it and the alveoli is relatively low. Therefore, a very high ﬂow may occur before the condition of wave speed is met. At a lower lung volume where the transmural pressure at zero ﬂow is much smaller, wave speed is achieved at lower ﬂows. Therefore, maximal ﬂow decreases if the static elastic recoil pressure decreases. This explains the decreased ﬂow with decreasing lung volume on the maximal expiratory ﬂow–volume curve. Elastic recoil is reduced at all lung volumes in emphysema, which also causes decreased maximal ﬂow. Wave speed will also be reached at reduced ﬂows if there are increased upstream frictional losses because of airway narrowing. In the normal lung at lung recoils which occur above 50% of vital capacity, the ﬂow-limiting point is located in the ﬁrst few generations of the airway. Virtually all pressure losses upstream are due to convective acceleration. At lower recoils, the more peripheral generations become smaller and more compliant, so that the ﬂow-limiting points migrate to the periphery. Near RV, the most peripheral airways become the limiting airways. Although both maximal ﬂow and the location of the ﬂow-limiting segment vary with lung volume, volume per se is not a direct determinant of ﬂow. Rather it is the lung recoil pressure, which varies with lung volume, that is a determinant of ﬂow. Airway diameter varies with airway-distending pressure, which cannot exceed lung recoil pressure. Airway resistance, in turn, increases in inverse proportion to the fourth power of the diameter.

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Although increasing lung volume lengthens the airways, resistance is only linearly related to length. Lung volume per se, therefore, has a minor effect on resistance compared to the effect of airway diameter–pressure relations. The relationship between lung recoil pressure and airway resistive properties will distinguish between reduced forced expiratory volume in 1 s (FEV1) owing to emphysema or to airway disease. In theory, pure emphysema causes only loss of lung elastic recoil. Figure 1 shows a normal pressure–volume relationship of the lung and chest wall and the effects of emphysema. The pressure–volume curve of the emphysematous patient not only has its zero intercept shifted upward, increasing RV, but also has a change in shape with increased static compliance. However, studies in autopsied lungs and computed tomography (CT) scans at TLC and RV of patients with bullae suggest that change in bullae volume is very small, at least over the time course of a single expiration. It has been suggested that bullae are more like a cellophane sac, which has near inﬁnite compliance until it ﬁlls, and then becomes very stiff. If so, these bullous lesions are ﬁlled at FRC and may not expand more with inﬂation to TLC. However, patients with severe emphysema can exhale well below FRC if the expiratory effort is begun from FRC after a quiet breath. An example is shown in Figure 2. When patients inspire to TLC, they may have difﬁculty expiring below control FRC during a single expiration but can do so after several breaths. This suggests that there are areas of the lung that ﬁll during inspiration to TLC but empty very slowly. This can occur even when normal end inspiration is near TLC, as in the patient in Figure 2. A. Effect of Emphysema on Maximal Expiratory Flow

The classic work of Black et al. (11) studied the relationship between maximal expiratory ﬂow and lung elastic recoil in patients with emphysema due to alpha1-antitrypsin deﬁciency. They measured maximal ﬂow during a forced expiration and lung recoil during a static deﬂation pressure–volume curve (Fig. 3, left panel). They then plotted the maximal ﬂow against the corresponding recoil pressure at each lung volume (Fig. 3, right panel). This is termed the maximum ﬂow/static recoil (MFSR) relationship. The solid line shows data from normal individuals. In the patients with alpha1-antitrypsin deﬁciency emphysema who had never smoked and had no symptoms of airway disease, the relationship between recoil and maximal ﬂow was completely normal but truncated (Fig. 3, right panel, line a). Although both ﬂow and recoil were reduced at any lung volume, ﬂow at a given recoil was normal. Although not shown, pulmonary conductance, the reciprocal of resistance was also normal as a function of lung recoil. In contrast, patients

Figure 1 Idealized pressure–volume relationships of the respiratory system and its components. Lung volume as a percentage of a normal TLC is plotted versus the esophageal pressure (Pes) as an index of pleural pressure. The curved lines with entirely negative pressures are the esophageal pressure–volume relationships of a normal lung (PSTL) and a patient with emphysema (PSTLE). These curves could be obtained by measuring Pes during static breath holds with the glottis open and volume maintained by inspiratory muscle force. These curves are the mirror images of lung elastic recoil curves. They intersect the zero-pressure axis at residual volume, where lung recoil is zero. The straight lines are the static esophageal pressure measurements made with all respiratory muscles relaxed and the glottis closed. The chest wall curves for a normal (PW) and emphysema patient (PWE) are shown. The horizontal separation between the lung and chest wall pressure curves is the airway pressure required to maintain the respiratory system (lung and chest wall in series) at that volume. The intersection between the lung and chest wall curves is the volume of the respiratory system when muscles are relaxed and airway pressure is zero (FRC). In normal subjects, FRC occurs slightly above 50% TLC with an esophageal pressure of 3 to 5 cm H2O. With emphysema (PSTLE), the residual volume is increased. The intersection of lung and chest wall curves is also shifted to a higher volume. The lung recoil for the emphysematous patient at this volume is near zero, and maximal ﬂow may therefore be too low for the patient to breathe at this volume. The curve, PWE, reﬂects the upward shift of the static chest wall pressure volume curve which has been described in emphysema. This further increases FRC, but also increases recoil at FRC. However, the recoil may still not be sufﬁcient to allow end expiration to occur at this volume. The dashed line connecting the maximum volume of the two lung pressure–volume curves is a hypothetical relationship expressing the maximal negative static pleural pressure that the inspiratory muscles can generate. It could be the trajectory of TLC as the lung pressure volume changed from the normal to the emphysematous curve. However, it is probably not the relationship that existed either in the normal situation or in the fully developed emphysema, since the maximal negative inspiratory pressure at a given volume is almost certainly affected by the shift in the static chest wall curve.

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Figure 2 Air trapping in severe emphysema. Tracing is a spirogram of a patient with severe emphysema during quiet breathing in a volume displacement body plethysmograph. Volume is expressed relative to control FRC. Near the end of a quiet breath, the patient was instructed to exhale to residual volume. After about 3 s, he was still expiring at a steady rate of 0.2 L/s when he could no longer sustain the effort. He then inspired to TLC, relaxed, and made inspiration to approximately the same volume and then began another expiration. After about 6 s, he was expiring at only about 0.1 L/s when he could no longer maintain the effort. The residual volume during expiration from control FRC was approximately 0.5 L less than during the slow vital capacity maneuver. This is one measure of ‘‘air trapping.’’

with the same ﬂow–volume curves who had symptoms of bronchitis had reduced ﬂow at any recoil pressure (Fig. 3, right panel, line b). Among patients with reduced maximal airﬂow, the contribution of emphysema may be estimated clinically by the degree of hyperinﬂation, by the reduction in diffusing capacity, or by high-resolution CT scan (see Chap. 8). In research laboratories, additional measurements can help distinguish emphysema from airway disease. Increased static lung compliance, decreased lung elastic recoil, and normal relations between maximal expiratory ﬂow and lung recoil suggest that the airway obstruction is due

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Figure 3 Relationships between lung elastic recoil, maximal expiratory ﬂow, and lung volume in normal subjects and in airway obstruction from a1-antitrypsin deﬁciency (6). (Left panel) The vertical axis is absolute lung volume, as determined in a volume displacement body plethysmograph. On the left of the vertical axis, maximal ﬂow from a forced expiration is plotted. On the right, static lung elastic recoil as determined from a static interrupted deﬂation maneuver are plotted. Solid lines are of an age-matched normal subject. Patients (a) and (b) are a1-antitrypsindeﬁcient patients chosen to have the same degree of airway obstruction as judged by the ﬂow–volume curve. Both patient (a) and (b) are hyperinﬂated and their static lung elastic recoil is reduced. Patient (a) is a never smoker with no clinical symptoms of airway disease and has more reduction of recoil than subject (b), who is an exsmoker with symptoms of chronic bronchitis. (Right panel) Maximum ﬂow, static recoil (MFSR) curves from the same patients. Maximal expiratory ﬂow from selected volumes during the forced expiration is plotted against lung elastic recoil from the static pressure–volume curve. Patient (a) with reduction in both recoil and ﬂow is superimposed on the lower one-third of the normal relationship, suggesting that the reduced ﬂow is entirely due to reduction in recoil. Patient (b), who has equal ﬂow reduction but less reduction of recoil, has an MFSR curve well below the normal relationship. This suggests that ﬂow is reduced due to airway disease as well as loss of lung elasticity.

to emphysema. In patients with severe emphysema who are dynamically hyperinﬂated, resistance during expiration is quite high owing to dynamic compression of airways. However, inspiratory resistance may be near normal, especially if corrected for lung recoil (12). Inspiratory resistance, even if not corrected for lung recoil, has been shown to be a predictor of outcome in LVRS (13). Total lung capacity would be expected to increase with a loss of lung elastic recoil (see Fig. 1). However, in addition, there is remodeling of the chest wall (14), which is little appreciated but is a very important adaptive response. A patient with an FEV1 of about 30% predicted and a TLC of

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125% predicted has virtually zero ﬂow at a volume corresponding to 100% of predicted TLC. Patients who had been unable to increase TLC would have died before their lung disease reached its current severity. Virtually nothing is known about what determines how much a given individual can increase TLC. The relationship between maximal ﬂow and static recoil has not been measured in patients with mild to moderate centrilobular emphysema. Studies comparing lung function to resected tissue from patients with mild to moderate emphysema show that with panlobular emphysema, there is a good correlation between pathological emphysema severity and degree of airway obstruction. However, in centrilobular emphysema, the extent of emphysema correlates rather poorly with function. In these patients, function is better correlated with pathological abnormalities in the terminal airways (15,16). In this regard, centrilobular emphysema appears more like so-called small airway disease than emphysema. Whether this is the case in the far advanced emphysema considered for LVRS is not clear at the present time. In fact, the hypothesis that the response to LVRS will be best in patients who have the purest emphysema with the least airway disease has not been conclusively proven. VI.

Response to Lung Reduction

A. Theoretical Aspects

The response to the removal of lung tissue would theoretically depend highly on the region resected and the site of ﬂow limitation. One must also carefully distinguish between ﬂows compared at the same recoil pressure (but at differing preoperative and postoperative lung volume) or ﬂows compared at the same volume (but differing recoil pressure). Consider the removal of one lobe comprising 25% of the lung. Since ﬂow limitation occurs in central large airways at high lung volume, resection of the lobe in a normal individual would produce little or no decrease in ﬂow at any given high recoil pressure. However, since 25% of the lung was resected, recoil pressure at any volume would be greater, and therefore ﬂow would be increased if compared at the same absolute volume as before the operation. (The subject would not be able to reach the same TLC, however.) In contrast, at a low lung volume with the ﬂow-limiting site upstream from the lobar bronchi, resection of the lobe would reduce the ﬂow at equal recoil pressure by 25%. At equal preoperative and postoperative volumes, recoil would be 25% greater and ﬂow at comparable volume might be unchanged. The loss of one-quarter of the parallel conducting airways would be compensated by proportionally increased recoil in the lung that remains.

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Therefore, at the same recoil pressure, the effect of lobar resection will vary between extremes of no reduction and proportional reduction in ﬂow. LVRS resects only the most peripheral sections of the lung, and specimens usually contain no major airways. This is distal to the ﬂowlimiting site in emphysema. One would anticipate, therefore, no change in ﬂow at equal recoil (as in the normal case at high lung volume after lobar resection) but increased ﬂow at equal lung volumes. In contrast, in patients with bronchiolitis in whom LVRS resects both lung and ﬂow-limiting sites, one might anticipate decreased ﬂow at equal recoil pressure and unchanged ﬂow if compared at equal lung volume. This is like the case of a normal patient at low lung volume following lobar resection. B. Predictions of the Effect of Lung Volume Reduction

Another approach begins with examination of effects of LVRS on elastic properties of the lung rather than on airﬂow. The following simplistic graphical analysis is similar to the more complete algebraic model of Fessler and Permutt (17). For the sake of simplicity, the lung pressure volume curve, the maximal ﬂow static recoil curve, and the relationship between the pressure-generating capacity of the inspiratory muscles and volume are all treated as linear, as shown in Figure 4A. Resection of one-third of the lung tissue causes a one-third reduction in RV. At its extremes, LVRS is considered to remove either completely destroyed lung with no elastic recoil (bullae) or lung exactly like the lung left behind (diffuse emphysema). The operation is therefore considered to be either not to change lung compliance or to reduce it in proportion to the volume resected. In addition, maximal ﬂow as a function of recoil pressure is either unchanged if pure bullae are resected or reduced proportionately if one-third of the parallel conducting airways are resected. Chest wall remodeling is assumed not to occur. The response to resection would most likely fall between the bounds of no change in either compliance or the pressure–ﬂow relationship and proportionate changes in both (Fig. 4A). Despite the limitations of the linear model of a nonlinear system, this approach illustrates the range of mechanical effects that are likely to occur. In heterogeneous emphysema, the resection of bullae would not be expected to change the ﬂow at a given recoil pressure from the remaining lung. In contrast, when the tissue resected is equivalent to that remaining and contains the ﬂow-limiting airways, ﬂow at a given recoil pressure decreases. In either case, ﬂow at equal volumes will be increased, because the recoil at that volume will be greater. This analysis also shows how LVRS can increase vital capacity despite the removal of lung volume. Residential volume is decreased by the same

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fraction that the lung is reduced. The decrease in TLC is smaller, however, since TLC is determined by the interaction between lung elastic recoil and the maximal inspiratory pressure the muscles can generate. This interaction is improved by the surgery, which better matches the sizes of the lungs and thorax. Since RV decreases by more than TLC, the difference between them, vital capacity, increases. In this analysis, the increase in recoil is shown to be an unimportant factor in the increase in vital capacity. Indeed, the decrease in lung compliance following LVRS in diffuse emphysema causes a greater increase in recoil but subtracts from the increase in vital capacity.

VII.

Implications for Selection of Patients for LVRS

Figure 4 shows that the biggest improvement in lung mechanics occurs when surgery does not change compliance or the MFSR curve (see Fig. 4B, line a or c) (On theoretical grounds, it is difﬁcult to imagine that ﬂow at a given recoil could be increased.) The optimal improvement is most likely to occur in heterogeneous emphysema with the resection of bullae. This is almost analogous to evacuation of a pneumothorax, which expands the remaining lung and improves the match between the mechanics of the lung and the chest wall. Resection of lung tissue in patients with diffuse emphysema would also increase ﬂow at the same lung volume. This would allow reduction in mean lung volume during tidal breathing, which would beneﬁt inspiratory muscle function. However, this would be at the cost of resecting functional tissue, attenuating the increase in vital capacity, reducing diffusing capacity, and increasing pulmonary vascular resistance. This model is consistent with the predominant current hypothesis that subjects who beneﬁt most from LVRS are those with heterogeneous disease. Ingenito et al. (13) also suggest that measurement of inspiratory pulmonary resistance is helpful in identifying candidates who would beneﬁt from LVRS. Their view is that in patients with low FEV1, a low inspiratory resistance may indicate obstruction is due to loss of recoil rather than to airway disease. In contrast, Gelb et al. (18) found that the slope of maximal ﬂow static recoil curves was not predictive of outcome. Both techniques depend on the measurement of esophageal pressure as an estimate of pleural pressure. In heterogeneous disease, however, pleural pressure adjacent to the esophageal balloon may not be representative of average pleural pressure throughout the lung. Interpretation of the MFSR curves also assumes that the lung elastic recoil pressure measured during a static maneuver is the same as during a forced expiration. In heterogeneous emphysema, more normal areas may empty very quickly so that ﬂow over most of the vital

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Figure 4 (A) Effects of LVRS on emphysema. The idealized, simpliﬁed pressure– volume curves of the normal (N) and emphysematous (E) lung are plotted with volume expressed as percentage of normal TLC. The pressure–volume curves intersect the y axis at RV. The uppermost end of each line is TLC on the y axis, and maximal elastic recoil on the x axis. The line connecting the TLC points is the most negative pleural pressure that the inspiratory muscles can generate as a function of thoracic volume. The normal RV is taken to be 30% and the emphysematous RV to be 60% of TLC. Resection of one-third of the emphysematous patient’s RV results in a new RV which is still 45% of normal TLC. Line a represents the linearized pressure–volume curves when the resection reduces RV but does not change compliance. Line b represents the postoperative curve when resection reduces both RV and compliance by one-third. In case a, TLC decreases from 132 to 128%, and vital capacity increases from 67 to 85% normal TLC. In condition b, TLC falls more, from 132 to 120%, and the vital capacity increases from 67 to only 77% normal TLC.

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The vital capacities may seem unreasonably large, but patients with emphysema can maintain a low but steady ﬂow as long as they can hold their breath, and what their ‘‘true’’ RV and thus VC might be is uncertain. (B) Effects of LVRS on emphysema. Flow–volume curves are constructed from the pressure–volume relationship in Figure 4A assuming that ﬂow is linearly related to pressure in all cases, where N and E represent normal and emphysema, respectively, and have the same pressure–ﬂow relationship. LVRS cases a and c also have a normal pressure–ﬂow relationship. Cases b and d have one-third the ﬂow at each recoil pressure. Cases b and c are highly unlikely to occur. Case a represents LVRS for heterogeneous disease and case d for homogeneous disease. If the chest wall muscle pressure curve had a steeper slope, the difference in TLC and thus maximal ﬂow between cases a and d would be greater.

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capacity comes from areas that empty more slowly. At the same volume during a static maneuver, the normal areas will be partially expanded. The net result is that maximal ﬂow at a given recoil will be artifactually low as compared to the same measurements from patients with homogeneous disease. This could bias a study of the MFSR as a predictor of outcome, since patients with airway disease and patients with heterogeneous emphysema would have similar curves. Another limitation of many published studies of LVRS is their dependence on FEV1 as a measure of disease severity and improvement of FEV1 as an indicator outcome. Although FEV1 has been traditionally used to assess severity of COPD and response to therapy, it correlates rather poorly with severity of emphysema on CT scans, maximal exercise capacity, and subjective response to LVRS. All these parameters are complex and multifactorial and therefore are unlikely to be closely correlated to any single physiological measure. There are two major deﬁciencies of the FEV1 as a single index of disease severity in this population. First, it does not indicate the degree of hyperinﬂation. A patient with an FEV1 of 30% predicted and a TLC of 130% predicted has worse lung function than a patient with the same FEV1 and a TLC of 110% predicted. The ﬁrst patient would be capable of no expiratory ﬂow whatsoever over most of the vital capacity range of the second patient. The ﬁrst patient would probably have more emphysema on CT scan and more impaired respiratory muscle function and gas exchange during exercise. In individual patients with progressive disease, the ability to remodel the chest wall to maintain ventilation is an important determinant of level of function and even survival, which is not assessed by FEV1. Following LVRS, patients who have reduced lung volumes but unchanged FEV1 may have symptomatic improvement because of improved respiratory muscle function. They have increased ﬂow at the same absolute lung volume, which permits them to maintain a lower FRC. Second, the FEV1 in severe COPD patients can be quite dependent on effort because of compression of gas within the lungs. Although it is a very reproducible measurement, it is nevertheless a poor measure of the ﬂow of which patients are actually capable. Figure 5 shows a forced vital capacity maneuver of a patient with severe emphysema. Flow at the mouth is plotted against both expired volume and actual lung volume determined from a volume displacement body plethysmograph. The horizontal difference between the two volume signals at the same ﬂow is due to compression of the intrathoracic gas. Within the ﬁrst few hundred milliseconds, this patient has compressed his lungs to below FRC, and ﬂow is correspondingly reduced. At the moment the patient has expired this FEV1 of 0.55 L, the actual lung volume is 1.75 L below TLC. The expired FEV1 is dominated by

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these ﬂows at low volumes. It is a poor measure of the maximal ﬂow that the subject has available at rest or for increased ventilation during exercise. Flow–volume curves whose volume axis is based on expired volume, therefore, cannot be used to generate MFSR curves, because they underestimate maximal ﬂow as a function of volume. Finally, none of the studies of the epidemiology or natural history of COPD has included the contribution of emphysema as determined by a CT scan. Therefore, there is virtually no epidemiological data on the radiological extent of emphysema in patients with moderate airway obstruction. Patients being evaluated for LVRS all have similarly severe airway obstruction but have great variability in the distribution and severity of emphysema by CT. Some patients with hyperinﬂation, reduced maximal expiratory ﬂow, and reduced lung elastic recoil have little or no emphysema detectable on high-resolution CT scans. Radiologists often interpret this ﬁnding as bronchiolitis. However, it is not currently known if these patients who appear to have less severe emphysema for a given degree of airway obstruction have small airway disease with respiratory bronchiolitis and mucus plugging, or instead have diffuse emphysema below the resolution of a CT scan. It is possible that disease of small airways that limits ﬂow during expiration could also cause low lung elastic recoil during a deﬂation pressure–volume curve. However, it is difﬁcult to imagine how such a patient could be inﬂated to 130% of predicted TLC by pressures less than 15 cm H2O and have a normal inspiratory pulmonary resistance unless emphysematous parenchymal changes were present and merely undetectable by CT.

VIII.

Summary

Patients with only airway disease may hyperinﬂate until their inspiratory muscle function is compromised and their maximal ﬂow at TLC is barely adequate to sustain life. Lung volume reduction surgery in such patients lacking emphysema, even if it reduced ﬂow at the same recoil, could allow subjects to have an increase in ﬂow at an achievable lung volume. This would produce some modest beneﬁt if it did not compromise perfusion or gas exchange. In contrast, patients whose lungs have become too large for their chest because of severely emphysematous regions behaving physiologically like a pneumothorax should beneﬁt tremendously from resection. Patients with diffuse emphysema also would beneﬁt, and because RV is reduced more than is TLC, they should have more beneﬁt than patients with airway disease. This theory has not been conﬁrmed, nor do we yet know the best way to differentiate these patients prior to surgery.

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Figure 5 (A) Maximal ﬂow–volume curves in emphysema. Maximal expiratory ﬂow measured at the mouth is plotted against expired volume (thin line) and absolute lung volume determined in the volume displacement body plethysmograph in an emphysematous patient with an FEV1 of 18% predicted. The volume displacement body plethysmograph measures both expired volume and intrathoracic gas compression. Since there is a single ﬂow measurement, the difference in volume at the two ﬂows is the amount of gas compression, which is a product of the alveolar pressure and TLC minus the expired volume. The thin vertical line, slightly above 8.5 L, is the FEV1 determined by American Thoracic Society criteria from the expired spirogram. The thick vertical bar is the actual lung volume and ﬂow at that same instant in time, which is about 2 L lower than TLC minus the FEV1. At the time of FEV1, the actual ﬂow at which the patient is capable is nearly four times that estimated from the expired volume ﬂow–volume curve. Note that gas compression continues to RV and the subject increases volume while expiratory ﬂow continues at the end of the expiratory effort.

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Figure 5 (B) Volume time curves. Expired (thin line) and plethysmograph (thick line) volume curves for the forced expiration in Figure 5A are plotted as a function of time. Note, after the initial rapid change of volume in the ﬁrst 250 ms that the expired volume is a virtually straight line with a slope of about 0.22 L/s. During the same time, the absolute volume has decreased to below RV predominately due to gas compression and decreases minimally during the rest of the maneuver. The minimal reduction in ﬂow with the modest changes in lung volume after the ﬁrst second are best appreciated in Figure 5A.

References 1.

2.

3.

Babb T, Viggiano R, Hurley B, Staats B, Rodarte JR. Effect of mild to moderate airﬂow limitation on exercise capacity and end-expiratory lung volume (EELV). J Appl Physiol 1991; 70:223–230. Johnson BD, Reddan WG, Pegelow DF, Seow KC, Dempsey JA. Flow limitation and regulation of functional residual capacity during exercise in a physically active aging population. Am Rev Respir Dis 1991; 143:960–967. Johnson BD, Reddan WG, Seow KC, Dempsey JA. Mechanical constraints on exercise hypernea in a ﬁt aging population. Am Rev Respir Dis 1991; 143:968– 977.

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Johnson BD, Saupe KW, Dempsey JA. Mechanical constraints on exercise hypernea in endurance athletes. J Appl Physiol 1992; 73:874–886. McClaran SR, Harms CA, Pegelow DF, Dempsey JA. Smaller lungs in women affect exercise hypernea. J Appl Physiol 1998; 84:1872–1881. Koulouris NG, Dimopoulou I, Valta P, Finkelstein R, Cosio MG, Milic-Emili J. Detection of expiratory ﬂow limitations during exercise in COPD patients. J Appl Physiol 1997; 82:723–731. Morrison NJ, Abboud RT, Ramadan F, Miller RR, Gibson NN, Evans KG, et al. Comparison of single breath carbon monoxide diffusing capacity and pressure-volume curves in detecting emphysema. Am Rev Respir Dis 1989; 139:1179–1187. Nakhjavan FK, Palmer WH, McGregor M. Inﬂuence of respiration on venous return in pulmonary emphysema. Circulation 1966; 33(1):8–16. Dawson SV, Elliot EA. Wave-speed limitations on expiratory ﬂow—a unifying concept. J Appl Physiol Respir Environ Exercise Physiol 1977; 43:498–515. Becker MD, Berkmen YM, Austin JH, Mun IK, Romney BM, Rozenshtein A, et al. Lung volumes before and after lung volume reduction surgery: quantitative CT analysis. Am J Respir Crit Care Med 1998; 157:1593–1599. Black LF, Hyatt RE, Stubbs SE. Mechanism of expiratory airﬂow limitation in chronic obstructive pulmonary disease associated with 1-antitrypsin deﬁciency. Am J Respir Dis 1972; 105:891–899. Ofﬁcer TM, Pellegrio R, Brusasco V, Rodarte JR. Measurement of pulmonary resistance and dynamic compliance with airway obstruction. J Appl Physiol 1998; 85:1982–1988. Ingenito EP, Evans RB, Loring SH, Kaczka DW, Rodenhouse JD, Body SC, et al. Relation between preoperative inspiratory lung resistance and the outcome of lung-volume-reduction surgery for emphysema. N Engl J Med 1998; 338:1181–1185. Sharp JT, Van Lith P, Nuchprayoon CV, et al. The thorax in chronic obstructive lung disease. Am Rev Respir Dis 1968; 44:39–46. Kim WD, Eidelman DH, Izquierdo JL, Ghezzo H, Saetta MP, Cosio MG. Centrilobular and panlobular emphysema in smokers. Two distict morphologic and functional entities. Am Rev Respir Dis 1991; 144:1385–1390. Saetta MP, Kim WD, Izquierdo JL, Ghezzo H, Cosio MG. Extent of centrilobular and panacinar emphysema in smokers’ lungs: pathological and mechanical implications. Eur Respir J 1994; 7:664–671. Fessler HE, Permutt S. Lung volume reduction surgery and airﬂow limitation. Am J Respir Crit Care Med 1998; 157:715–722. Gelb AF, Zamel N, McKenna RJ Jr, Brenner M. Mechanism of short-term improvement in lung function after emphysema resection. Am J Respir Crit Care Med 1996; 154:945–951.

5. 6.

7.

8. 9. 10.

11.

12.

13.

14. 15.

16.

17. 18.

4 Cardiovascular Effects of Emphysema and Lung Volume Reduction Surgery

STEVEN M. SCHARF

CESAR A. KELLER

University of Maryland Baltimore, Maryland, U.S.A.

Mayo Clinic Jacksonville, Florida, U.S.A.

IRA L. WEG Long Island Jewish Medical Center New Hyde Park, New York, U.S.A.

I. Introduction The recent reintroduction of lung volume reduction surgery (LVRS) for the treatment of severe emphysema has led to a reevaluation of the pathophysiology of this often debilitating condition. Severe shortness of breath is recognized as the most distressing of the symptoms of the emphysematous form of the chronic obstructive pulmonary disease (COPD) spectrum. The origin of this symptom is likely to be multifactorial, and hence the mechanisms by which LVRS may alleviate symptoms is also likely to be multifactorial. The intimate connection between the function of the respiratory and cardiovascular systems is well established. It is not surprising, therefore, that there should be interest in the effects of LVRS on cardiovascular function and how these effects are integrated into the overall response. Although the cardiovascular effects of COPD have been the subject of hundreds of scientiﬁc studies, the majority of these studies do not distinguish between the major subgroups of COPD; namely, chronic bronchitis and emphysema. The effects of the latter are not as well characterized as those of the former. This is in part due to the question of 65

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deﬁning emphysema on clinical, pathological, or physiological grounds. Some of these difﬁculties also inﬂuence the interpretation of studies purporting to assess the hemodynamic effects of emphysema. In this chapter, we will address a number of issues. We will describe the pathophysiological effects of emphysema that could, in theory, affect cardiovascular function. We will review some studies of the cardiovascular effects of emphysema in animal models and what is known about the cardiovascular effects of emphysema in humans. We will address the issue of whether or not there is a cardiovascular limitation to exercise tolerance in patients with emphysema. We will then review the cardiovascular changes in patients with end-stage emphysema referred for surgical treatment. Finally, we will try to draw some conclusions and suggest where emphasis should be placed in future studies.

II.

Theoretical Effects of Emphysema on Cardiovascular Function

Table 1 lists some of the theoretical mechanisms by which emphysema could adversely affect cardiovascular function. Emphysema leads to increased pulmonary vascular resistance (PVR) and hyperinﬂation. Hyperinﬂation could have a number of possible cardiovascular effects. The mechanisms for increased PVR in emphysema will be reviewed below. However, increased PVR can lead to structural changes in the right ventricle (RV); that is, cor pulmonale (1). Increased PVR, if severe enough, could theoretically limit cardiac output, especially during exercise. Further, since myocardial ﬁbers are a syncytium, it is possible that the biochemical events leading to structural changes in the RV as a result of chronic RV overload could affect ﬁbers around the left ventricle (LV) and change LV function. Indeed, following experimental banding of the pulmonary artery (PA) in animals, Laks et al. (2,3) found that pulmonary hypertension caused remodeling of LV as well as RV myocardium. This could affect LV systolic performance. In addition, acting via the interventricular septum as well as the pericardium, there are parallel interactions between the ventricles both in diastole (4) and in systole (5). During diastole, RV overload acts to stiffen the LV, whereas during systole, RV contraction against an increased afterload could actually aid LV systolic function. Hyperinﬂation with positive end-expiratory pressure (PEEP) may be a good model to study some of the effects of emphysema-induced hyperinﬂation. First, hyperinﬂation itself, because of compression of intra-alveolar pulmonary vessels, could contribute to increased PVR (6,7). In the presence of coexisting pathology that increases PVR, further increases in PVR due to

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Table 1 Theoretical Mechanisms by Which Emphysema Could Adversely Affect Cardiovascular Function Increased Pulmonary Vascular Resistance Hypoxia-induced vasospasm (acute) Hypoxia-induced vascular remodeling (chronic) Loss of cross-sectional area due to tissue (precapillary) destruction Compression of pulmonary capillaries (intra-alveolar vessels) by regional hyperinﬂation Sympathetic vasoconstriction Hyperinﬂation—Other Effects Compression of IVC due to ﬂattening and conﬁgurational change in the diaphragm Compression of the intrathoracic portion of the IVC Increased pleural pressure, especially at end expiration: could raise right atrial pressure atrial pressure Increased cardiac fossa pressure, inhibiting RV and LV diastolic ventricular ﬁlling Effects on Cardiac Function Increased load on the RV, leading to inhibition of LV diastolic ﬁlling (diastolic interdependence) Adverse affect of RV overload on LV myocardial ﬁbers (whole heart hypothesis of chronic RV overload)—adverse effects on systolic function Effects of chronic hypoxia on cardiac function—systolic and diastolic

high levels of PEEP have even been shown to lead to circulatory collapse due to acute cor pulmonale (8). Second, hyperinﬂation could affect venous return of blood to the right atrium via the inferior vena cava (IVC). This could occur at the level of the diaphragm or the intrathoracic IVC. Normally, during exercise, decreasing inspiratory intrathoracic pressure aids venous return to the right heart, thereby allowing increased cardiac output. Nakhjavan, et al. (9) demonstrated inspiratory collapse of the IVC at the level of the diaphragm in hyperinﬂated emphysematous patients. Because of IVC collapse during inspiration, the mechanism of increasing venous return by inspiratory decreases in intrathoracic pressure (thoracic pump) may be unavailable to patients with emphysema, thus constituting another mechanism whereby cardiac output is limited during exercise in these patients. It is unlikely that inspiratory collapse of the IVC would limit resting cardiac output, however. In dogs, Fessler et al. (10) demonstrated collapse of the IVC during PEEP-induced hyperinﬂation. This occurred in the supine posture and led to a rightward shift in the point of ﬂow limitation

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in the venous return curve. This means that venous return into the right atrium, normally increasing with decreasing right atrial pressure, becomes limited at higher than normal right atrial pressures with PEEP (11,12). Since emphysematous patients undergo hyperinﬂation during exercise, these mechanisms would be expected to be especially important in limiting cardiac output during exercise. In humans, as compared to dogs, the IVC is relatively short. Thus, it is expected that intrathoracic IVC collapse would be less likely than IVC closure at the level of the diaphragm. Finally, hyperinﬂation would be expected to lead to mechanical interactions between the heart and lungs. First, increased lung volume would be expected to increase end-expiratory pleural pressure. Second, hyperinﬂation with PEEP is known to increase pressure in the cardiac fossa (13,14) above that of the increase in pleural pressure. In COPD patients during exercise or voluntary hyperventilation, parallel increases in right atrial and pulmonary arterial wedge pressure (Pw) have been attributed to hyperinﬂation of the lower lobes with concomitant increases in cardiac fossa pressures (15,16). By ‘‘compressing’’ the heart, especially during exercise, the lungs would be expected to inhibit ventricular diastolic ﬁlling. This could further decrease LV stroke volume and cardiac output. We next consider what is known about the effects of emphysema (as opposed to chronic bronchitis) on cardiovascular function in experimental animals and in patients.

III.

Studies on the Effects of Emphysema on Cardiovascular Function

Emphysema is deﬁned as ‘‘a condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by the destruction of their walls, and with ﬁbrosis’’ (17). Because destruction of the airspaces includes the pulmonary vasculature, there is an association between the development of cor pulmonale and emphysema. Approximately 6% of patients with emphysema develop cor pulmonale each year (18), and the presence of cor pulmonale is the best predictor of mortality after adjusting for the forced expired volume in 1 s (FEV1) (19). Further, mortality rate is inversely related to PVR (20), with PVR values greater than 600 dyne-s/cm5 being associated with very low survival (Fig. 1). Since in humans there are often multiple factors present leading to the development of pulmonary hypertension, such as concomitant cardiac disease, bronchitis, or thromboembolic disease, the study of relatively ‘‘pure’’ animal models of emphysema offers some advantages for dissecting out those factors responsible for pulmonary hypertension in

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Figure 1 Plot of survival in years as a function of initial pulmonary vascular resistance (PVR) in chronic obstructive pulmonary disease patients. (From Ref. 20.)

emphysema. Many of the studies have centered around deciding whether chronic hypoxia or obliteration of the pulmonary vascular bed is primarily responsible for the development of pulmonary hypertension and cor pulmonale in emphysema.

A. Effects of Emphysema on Cardiovascular Function in Experimental Animal Models

In order to study the effects of emphysema on pulmonary mechanics, respiratory muscle function, and hemodynamics, animal models of emphysema have been developed, often involving intratracheal instillation of a protease (elastase or papain) (21). An animal model of emphysema has been deﬁned similarly to emphysema in humans as ‘‘an abnormal state of the lungs in which there is enlargement of the airspaces distal to the terminal bronchiole’’ (22). Most animal models of emphysema are of the panlobular type, and probably most relevant to human alpha1-antitrypsin (a1-ATD) deﬁciency. Most smoking-related emphysema in humans, in contrast, is

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usually centrilobular, and is typically associated with some degree of chronic bronchitis. Animal models produce increases in lung volumes, decreases in diffusion capacity, decreases in ﬂow rates, and decreased elastic recoil just as in human disease. The hemodynamic changes observed with animal models of emphysema may be relevant to human disease. Further, the longitudinal study of animal models enables one to determine the relationship between changes in lung mechanics and pulmonary hemodynamics. In 1991, Wright and Churg (23) investigated the effects of chronic (up to 12 months) exposure to cigarette smoke on the structure and function of pulmonary vasculature in guinea pigs. These workers found an increase in PA pressure after 1 month’s exposure even though at this time there was no histological evidence of emphysema. Pulmonary vascular pressures remained elevated over time, but did not continue to increase despite evidence of progressive lung destruction. Pulmonary hypertension was associated with muscularization of the small pulmonary vessels, but there was no hypoxia or hypercapnia. These workers believed that the dissociation between parenchymal and vascular changes indicated that emphysema per se with attendant obliteration of the pulmonary vascular bed does not cause pulmonary hypertension. Rather pulmonary hypertension was due to smoking-induced inﬂammation in the lung capillary bed, possibly due to release of proteolytic enzymes or vasoactive substances. Sato et al. (24) studied pulmonary hemodynamics in awake rats with elastase-induced emphysema over 4 weeks. There were no differences in arterial O2 saturations between elastase-treated rats and the control group. Although there was a trend toward increased PA pressures in the elastasetreated rats compared with the control group, this was not statistically signiﬁcant. However, the increase in PA pressures caused by inhalation of a hypoxic gas mixture was greater in the experimental group. Interestingly, the greater increase in PA pressure in the elastase group was related to greater increases in cardiac output, not PVR, on exposure to hypoxia in this group compared with the control group. Further, RV hypertrophy was observed in the elastase-treated group. Pulmonary hypertension was associated with greater thickness of medial arterial walls. These results suggest that the development of pulmonary hypertension may be associated with or preceded by increased pulmonary vascular reactivity. This in turn could be caused by loss of radial traction acting on blood vessels, pulmonary muscular hypertrophy, or increased intrinsic smooth muscle reactivity in the emphysematous group. On the other hand, the greater cardiac output response in the emphysematous group suggests that there may be a component of sympathetic hyperreactivity in this group.

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Tseng et al. (25) studied pulmonary hemodynamics and reactivity to hypoxia in isolated lungs for up to 8 months following instillation of elastase in hamsters. At 1 month, they found increased baseline PA pressure at a standard ﬂow, and as did Sato et al. (24), increased hypoxic vasoconstriction and RV hypertrophy. Unlike Sato et al. (24), they found that baseline hemodynamics were correlated with the development of parenchymal morphological changes in that neither parenchymal nor hemodynamic changes progressed between 1–8 months following exposure. Hypoxic vasoconstriction was maintained over the 8-month study period in elastasetreated animals. However, hypoxic vasoconstriction lessened with time in the control animals. Thus, heightened vascular reactivity did not precede the development of pulmonary hypertension and cor pulmonale. These investigators suggested that chronic hypoxia is not necessary for the development of cor pulmonale, but rather that pulmonary hypertension resulted from ‘‘direct destruction of connective tissue and pulmonary vessels’’ (25), with the development of emphysema. To study the relationship between parenchymal morphometry and pulmonary hemodynamics in emphysema, Martorana et al. (26) studied dogs for up to 6 months following the instillation of papain. The animals remained normoxic and normocapnic. They found that at 6 months, there was a correlation between indices of tissue destruction (mean linear intercept and internal surface area) and both PA pressure and PVR. This ﬁnding suggested that pulmonary hypertension was caused by tissue destruction not hypoxic vasoconstriction. Further, they observed increased heart rate at 3 and 6 months. At 3 months, they observed an inotropic effect in that cardiac output increased and Pw decreased in emphysematous relative to control animals. Thus, early in the course of emphysema, augmented cardiovascular performance was observed. This also argues for sympathetic activation early in the course of emphysema (27) that could contribute to pulmonary vasoconstriction. Further, although enhanced sympathoadrenal activity acutely increases cardiac output and maintains blood pressure, chronic sympathetic activation could lead to vasoconstriction, myocardial necrosis, depletion of myocardial b-receptors, and decreased myocardial catecholamine stores (28,29), thus diminishing cardiac function. Conceivably, this could account for some of the studies reporting decreased LV function in emphysema, especially over the long term (see further discussion). In a short-term study (3 months) following induction of emphysema in dogs, Mink et al. (30) observed pulmonary hypertension. Using plots of stroke volume against transmural ﬁlling pressure to characterize cardiac function (modiﬁed Starling curves), these investigators demonstrated a decreased function in the RV and normal function in the LV. These ﬁndings

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were consistent with the notion that RV afterload decreased RV function, but that there was no intrinsic change in myocardial contractile function. This group (31) later extended their studies to 1-year following emphysema induction in dogs. In an elegant paper characterizing LV systolic function using ejection fraction, maximum shortening velocity, and mean velocity of circumferential shortening, they demonstrated a decrease in LV systolic function in the emphysematous dogs. They also plotted LV end-systolic pressure against end-systolic volume (32) and demonstrated a parallel rightward shift in the curve, but no change in the slope of the endsystolic pressure/volume curve. This suggests that there was no change in intrinsic myocardial contractility but that there was a change in ventricular unstressed volume. Such a change could occur as a result of remodeling of the LV with time. These ﬁndings were consistent with previous results from the same group demonstrating increased diastolic stiffness in dogs 1 year following the induction of emphysema (33). In this study, the investigators demonstrated that although LV pressure/strain relations were decreased along the septal–lateral and anterior posterior axes in emphysema, a rightward shift of the interventricular septum did not occur. Although diastolic myocardial stiffness increased, this increase was not attributable to RV to LV interdependence due to cor pulmonale. Thus, there appear to be chronic changes in LV diastolic and systolic myocardial function with emphysema, suggesting changes in stress–strain relationships (stiffness). According to Laks et al. (2,3), RV strain leads to biventricular remodeling and global alterations in myocardial function. On the other hand, it is possible that the altered stress–strain relations observed by Gomez et al. (31,33) are the result of mechanical interactions between the heart and lungs (13–15). Because the pleural or esophageal pressures used by Mink et al. (30) and Gomez et al. (31,33) to calculate transmural ﬁlling or end-systolic transmural pressures may underestimate cardiac surface pressure in the case of lung inﬂation (13–16,34), the true transmural pressure could have been overestimated at any given cardiac volume, leading to the conclusion that stiffness was increased with emphysema. These possibilities remain speculative, and we agree with Gomez et al. that the mechanisms changing LV function in emphysema ‘‘must await future studies (33).’’ B. Effects of Emphysema on Cardiovascular Function: Human Disease

There are a number of problems in interpreting the clinical literature with regard to understanding the hemodynamic effects of emphysema in patients.

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One is that many studies of COPD do not distinguish between emphysema and the more common chronic bronchitis. Another is that the deﬁnition of emphysema may not be the same for all studies. Emphysema may be deﬁned physiologically and clinically as normal oxygenation and minimal hypercapnia (pink and pufﬁng), hyperinﬂation, decreased diffusion capacity, and perhaps decreased elastic recoil. Emphysema may also be deﬁned on the basis of the radiological picture. Finally, emphysema may be deﬁned pathologically on the basis of tissue destruction. Since most patients with COPD have, in fact, both emphysema and chronic bronchitis, the distinctions are often illusory. Filley et al. (35) described two clinical types of COPD. Patients with airﬂow limitation were described as ‘‘pink puffers’’ if they were thin and had a narrow cardiac silhouette with no history of heart failure and a normal hematocrit. ‘‘Blue bloaters’’ were described as patients with little weight loss, enlarged cardiac silhouettes, a history of heart failure, and polycythemia. It has often been thought that patients with the ‘‘blue and bloated’’ (hypoxic/hypercapnic) pattern of COPD have more severe pulmonary hypertension than those with the normoxic normocapnic (‘‘pink and pufﬁng’’) pattern (36,37). Polycythemia in the blue and bloated patients may contribute to this (38). Indeed, earlier clinicophysiological studies suggested that the pink and pufﬁng pattern was associated with more emphysema and the blue and bloated pattern with more chronic bronchitis (20,35,39). However, clinicopathological studies relating the extent of emphysema estimated pathologically with the clinical syndrome did not bear this out (40). In 1989, using a population with a spectrum of disease, Biernacki et al. (41) examined the correlation between the extent of emphysema radiologically by computed tomography (CT) and the clinical and pathological features of the pink and pufﬁng syndrome (mild hypoxia, no CO2 retention, no pulmonary hypertension) versus the blue and bloated syndrome (hypoxemia, CO2 retention, pulmonary hypertension). There were no signiﬁcant relationships between the CT-estimated extent of emphysema and either arterial blood gas tensions, mean PA pressure, cardiac output, and calculated PVR at rest or during exercise. These workers concluded that ‘‘to equate ‘pink puffers’ with emphysema, and ‘blue bloaters’ as having little or no emphysema, is no longer valid.’’ Of note in the study of Bienacki et al. (41) is the ﬁnding that there was a good correlation between carbon monoxide (CO) transfer coefﬁcient and the CT density histogram. This ﬁnding suggests that CO diffusion capacity is a good index of the extent of amputation of the pulmonary vascular bed in emphysema. This ﬁnding may be important in predicting the effects of LVRS on pulmonary hemodynamics, as will be discussed later.

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Burrows et al. (20) had found that COPD patients with emphysema have lower cardiac outputs and higher PVR than COPD patients without emphysema. However, in a later study in which emphysema was deﬁned as decreased CO diffusion capacity and pulmonary elastic recoil pressure, Boushy and North (42) failed to demonstrate a difference in cardiac output and PVR between emphysematous and nonemphysematous patients. They followed hemodynamic data over 25 months and found progressive decreases in cardiac output of 6–7% in both groups. Wright et al. (43) and later Schulman et al. (44) emphasized the importance of exercise in bringing out abnormalities of pulmonary hemodynamics in mild to moderate COPD even before abnormal PA pressure is detected at rest. Wright et al. (43) found that in patients with normal PA and wedge pressures at rest, with exercise both PA and wedge pressures increased more than in normal subjects. The more severe the disease, the greater was the exercise response. Because of parallel changes in PA and wedge pressures with exercise, they concluded that most likely gas trapping leads to increased alveolar and pleural pressure. Since the exercise response was abolished with O2 breathing, Wright et al. (43) concluded that simple destruction of the pulmonary capillary bed was not responsible for their ﬁndings but that lung inﬂation with increased intrathoracic pressures might have occurred. The later work of Butler et al. (15) demonstrating the role of direct mechanical heart–lung interactions with exercise is thus consistent with the original conclusion of Wright et al. (43). The reason for abolishing the response with O2 in the studies of Wright et al. (43) was not known. However, these workers speculated that O2 breathing might have shortened the time constants for ventilation in poorly ventilated lung units (possibly via bronchodilation), which would in turn have led to less hyperinﬂation and lesser increases in wedge and PA pressures. On the other hand, Schulman et al. (44) noted that, in COPD just as in interstitial lung disease, there was a correlation between CO diffusion capacity and the increase in PA pressures with exercise. They concluded that the analogous relationships suggested that, as in interstitial lung disease, mild pulmonary hypertension in mild to moderate emphysema was due to obliteration of pulmonary vascular bed. Oswald-Mammosser et al. (45) investigated pulmonary hemodynamics in a large series of 151 emphysematous patients. In general, the patients were normoxic, normocapnic at rest. Emphysema was moderate to severe (mean FEV1 1.2 L). Of the 151 patients, 31 (20.5%) had resting pulmonary hypertension, and 99 of the 151 (65.5%) had increased PA mean pressure, deﬁned as more than 20 mmHg, during exercise. Since these investigators had a large population, they could determine the correlates of pulmonary hypertension with emphysema. Pulmonary arterial (PA) pressures were well

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correlated with CO diffusion capacity and FEV1 but only poorly correlated with resting PO2 and PCO2. These ﬁndings suggested that pulmonary hypertension was not a feature of most patients with moderate to severe emphysema, and that hypoxemia and hypercapnia were not important determinants of pulmonary hypertension. The correlation between airﬂow obstruction and PA pressure could have been related to hyperinﬂation and increased alveolar pressures. The correlation between PA pressure and CO diffusion capacity were similar to those of Biernacki et al. (41), suggesting that CO diffusion capacity predicts the extent of capillary bed destruction in emphysema. Finally, Mise et al. (46) reported on a long-term (4.4 years) follow-up study of 103 emphysematous patients. They concluded that PA mean pressure greater than 30 mmHg, RV hypertrophy on electrocardiogram, and/or PVR index above 600 dynes-s/cm5 at the time of initial study were associated with poor prognosis. Thus, their studies were consistent with the earlier smaller study of Burrows et al. (40) showing that pulmonary hemodynamics are important predictors of outcome in emphysema.

C. Left Ventricular Function in Emphysema

As already noted, diastolic ventricular interdependence, mediated through the interventricular septum and pericardium, has been well described (4,5). Further, decreased compliance of the LV has been demonstrated in patients with chronic cor pulmonale due to COPD (47). Acutely, increasing RV systolic pressure should assist LV contraction, since the ﬁbers of the LV and RV contract toward the same center of gravity and systolic forces are transmitted through the septum (positive systolic interdependence). However, as the septum hypertrophies, its stiffness increases and the transmission of systolic forces decreases (5). There has been a good deal of debate in the literature concerning the effects of chronic cor pulmonale on LV function and as to whether chronic RV overload leads to structural and functional changes in patients. Rao et al. (48) ﬁrst reported depressed LV function in some patients with cor pulmonale and no other identiﬁable cause of LV failure. This was followed by other reports of decreased LV function measured by systolic time intervals or ejection fraction (49–51). However, other studies have failed to ﬁnd evidence of LV dysfunction in patients with COPD and cor pulmonale in the absence of other identiﬁable causes of LV failure (52–56). In a clinicopathological study, Kohama et al. (57) demonstrated myocardial ﬁbrosis and cellular hypertrophy in the LV in COPD patients dying of heart failure with no other identiﬁable cause of heart failure. They speculated that such changes might be related to

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hypoxemia, hypercarbia, acidosis, and possibly chronic sympathetic overload. Recently, Vizza et al. (58) performed a retrospective analysis of a 434 patients with severe pulmonary disease being evaluated for lung transplantation. Although the group contained a mix of diagnoses, including COPD, pulmonary ﬁbrosis, cystic ﬁbrosis, and pulmonary hypertension, there were some interesting ﬁndings regarding the relationship between RV and LV function in patients expected to have a high incidence of cor pulmonale. RV function (assessed from transthoracic echocardiography and radionuclide ventriculography) was impaired (RV ejection fraction <45%) in 66%. On the other hand, LV dysfunction (LV ejection fraction <45%) was present in only 6.4%, but was most common for the group with pulmonary hypertension (19.6%), with a very low incidence in patients with pulmonary parenchymal disease (3.6%). LV and RV ejection fraction were signiﬁcantly and directly correlated. In patients with biventricular dysfunction, RV and LV function pari passu after transplantation. These investigators concluded that LV and RV function could be related through ventricular interdependence (positive systolic interdependence). Finally, patients with COPD generate large negative swings in intrathoracic pressure during inspiration (45). Venous return normally increases with inspiration. Increased venous return to the RV would act to decrease LV preload during inspiration owing to the effects of ventricular interdependence (59). However, in emphysematous patients with hyperinﬂation, this effect would probably be minimal, as has been noted. Sustained decreases in intrathoracic pressure increase the afterload on the LV (60,61). The effects of transient decreases in intrathoracic pressure, such as are seen on inspiration in COPD, are not well known in humans and are the subject of considerable debate in animal studies (59). In one animal study, chronically exaggerated negative swings in intrathoracic pressure in a normoxic model of upper airway obstruction in rats failed to produce LV hypertrophy, which suggests that increasing negative intrathoracic swings per se are not sufﬁcient to affect LV function (62). In humans, there have been few studies of LV function in patients with the clinical presentation of emphysema as opposed to chronic bronchitis, so our understanding is even murkier there. However, in severe emphysema, Pw has been reported at times (in the minority of patients) to be elevated and to increase on exercise (37,41,45,46). It is possible that increased Pw signals the presence of LV dysfunction in severely ill emphysematous patients. On the other hand, there are several other reasons that Pw could be elevated in these patients, such as pulmonary hyperinﬂation, or it may be that Pw is a poor reﬂection of LV ﬁlling pressure in emphysematous patients.

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D. Exercise Tolerance in Chronic Obstructive Pulmonary Disease—Is There a Cardiovascular Component?

In patients with severe airﬂow limitation, it might be surmised that the most important mechanism limiting exercise tolerance is ventilatory limitation. The role of the cardiovascular system in limiting exercise tolerance in patients with COPD has been the subject of some investigation. Obviously, older patients with smoking-related COPD may also have coronary artery disease, which could limit exercise capacity. However, there is evidence that patients with severe COPD and no obvious cardiac disease may also have a cardiovascular contribution to their exercise limitation. Mithoefer et al. (63,64) demonstrated that COPD patients with the most functional limitation are not necessarily those with the greatest degree of airﬂow limitation or abnormal gas exchange but rather are those with the lowest mixed venous O2 tensions and the lowest resting cardiac output (63). These studies, however, did not separate emphysematous from bronchitic patients. As already noted, older studies (20,35) indicated that emphysematous patients actually had lower cardiac outputs during exercise than nonemphysematous patients. Figure 2 demonstrates the relationships between heart rate (ordinate) and O2 consumption (abscissa) in ﬁve normoxic patients at our institution with severe emphysema prior to undergoing LVRS. The predicted line is the diagonal dashed line. Three of the ﬁve patients demonstrated a heart rate that was increased more than

Figure 2 Plot of heart rate (ordinate) versus O2 consumption (VO2—abscissa) in ﬁve patients with severe emphysema who were candidates for lung volume reduction surgery. The dashed diagonal line is the predicted relationship between VO2 and heart rate. In three of these patients, heart rate is greater than or increases more than expected, suggesting an element of cardiovascular limitation. All of the patients were found to have normal LV function by echocardiogram and none had coronary artery disease by thallium scanning.

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predicted, which suggests a cardiovascular component to their exercise limitation. Stewart and Lewis (65) studied the hemodynamic response in 20 patients with COPD. They were divided into a low cardiac output group (cardiac output less than 80% of predicted) and a normal cardiac output group (cardiac output more than 80% of predicted). The low cardiac output group had greater exercise limitation than the high cardiac output group. However, this group also had greater PVR and lower FEV1 and elastic recoil than the normal cardiac output group. Interestingly, PA pressures were not different between the groups, which suggests that RV afterload per se was not the determining factor. Further, there were no differences in arterial oxygenation between the groups. These investigators concluded that by one of the mechanisms outlined previously (see Table 1), lung hyperinﬂation rather than hypoxic vasoconstriction, was responsible for the lower exercise cardiac output in the low-output group, and that cardiovascular limitation played a role in limiting exercise tolerance. Although data are lacking, cardiovascular limitation could also contribute indirectly to ventilatory limitation during exercise. Carbon dioxide production rises at the anaerobic threshold. Therefore, limitation of systemic blood ﬂow that lowers the anaerobic threshold would drive ventilation to its ceiling at reduced workloads. IV.

Cardiovascular Function in Emphysematous Patients Undergoing Transplant or LVRS

Several studies we have cited indicate that, in emphysema, cardiovascular function is more limited as airﬂow obstruction becomes more severe. If this were the case, one would expect the most severe limitation to occur in patients who are candidates for either lung transplantation or lung volume reduction, procedures generally reserved for the most severely ill. Here we review what is known about cardiovascular function in advanced emphysematous patients who are candidates for surgical intervention. A. Cardiovascular Function in Patients Undergoing Lung Transplantation

Recently published guidelines for selection of patients requiring single- or double-lung transplantation for COPD include subjects less than 65 years of age whose FEV1 is 25% of predicted or less. Other factors include the absence of signiﬁcant hypercapnia (PaCO2 < 55 mmHg) or of signiﬁcant secondary pulmonary hypertension (66). These patients should have no

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medical or surgical conditions that contraindicate transplantation, such as severe cor pulmonale with irreversible right heart failure. In that case, combined heart–lung transplantation would be indicated if the subject is younger than 55 years. Patients with end-stage obstructive lung disease who qualify for lung transplantation commonly have only mild to moderate pulmonary hypertension with variable degrees of RV dysfunction. Keller et al. (67) studied the hemodynamic proﬁle, at rest and during maximum exercise, in a group of 30 patients listed for lung transplantation. Pulmonary function studies, gas exchange, and hemodynamic variables are shown in Tables 2 and 3. Fifteen of these patients had COPD secondary to chronic smoking and the other 15 had alpha1-antitrypsin deﬁciency (A1-ATD). The patients with smoking-related COPD were signiﬁcantly older than A1-ATD patients. Pulmonary function was similar in both groups, with mean FEV1 less than 25% of predicted, severe hyperinﬂation, and severely reduced diffusion capacity. Hemodynamic responses were measured with the patients seated at rest and while pedaling to maximum tolerance on a bicycle ergometer. These patients had severe functional aerobic impairment, with mean maximal

Table 2 Pulmonary Function Tests of 30 Patients with COPD Listed for Lung Transplantationa N ¼ 30 Age FVC (L) FVC (% pred) FEV1 (L) FEV1 (% pred) FEV1/FVC (%) FEF25–75 (L/s) FEF25–75 (% pred) TLC (L) TLC (% pred) RV (L) RV (% pred) DLCO (% pred)

COPD (N ¼ 15 M:7 F:8) 53 + 4 (46–59) 2.01 + 0.8 (0.98–3.91) 51 + 18 (21–86) 0.63 + 0.2 (0.29–1.22) 22 + 8 (9–37) 33 + 5.4 (8–37) 0.24 + 0.1 (0.1–0.45) 6 + 3 (0.5–11) 6.17 + 1.4 (4.4–8.9) 105 + 17 (10–141) 4.38 + 1.4 (2.93–7.47) 219 + 51 (145–341) 27 + 14 (4–52)

A1-ATD (N ¼ 15; M:11 F:4) 45 þ 9b (31–58) 2.36 + 0.83 (1.22–3.73) 51 + 16 (22–78) 0.65 + 0.29 (0.27–1.35) 18 + 7 (9–31) 29 + 9 (16–47) 0.25 + 0.12 (0.1–0.52) 6 + 3 (3–16) 6.39 + 1.2 (4.15–8.14) 104 + 39 (71–109) 4.00 + 1.1 (2.14–6.02) 205 + 83 (115–369) 27 + 19% (5–74)

Range is given in parentheses. FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s. FEF25–75%, forced expiratory ﬂow between 25 and 75% of the FVC; TLC, total lung capacity; RV, residual volume; DLCO, lung diffusion for carbon monoxide. a 15 with COPD; 15 with A1-ATD. b P < .01 between the groups.

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Table 3 Hemodynamics and Gas Exchange at Rest and During Maximum Exercise in Patients with COPD and A1-ATD Listed for Lung Transplantation Variable HR beats/min BP mean mmHg CVP mmHg PAP systolic mmHg PAP diastolic mmHg PAP mean mmHg Pw mmHg CI (Fick) L/m/m2 SVi mL/beat/m2 PVRi dyne/s/cm5/m2 FiO2 (%) pH PaCO2 mmHg PaO2 mmHg (A-a)O2 mmHg CaO2 mLO2/dL CvO2 mLO2/dL O2Di mLO2/L/m/m2

COPD (N ¼ 15) Rest VO2 ¼ 560 + 137

A1-ATD (N ¼ 15) Rest VO2 ¼ 503 + 148

106 + 20 127 + 20 104 + 12 125 + 27 6 + 4 13 + 10 33 + 5 50 + 6 16 + 3 25 + 7 22 + 3 34 + 7 11 + 4 20 + 2 2.64 + 0.6 4.32 + 1.3 27 + 8 35 + 10 341 + 156 263 + 123 25 + 4 26 + 5 7.42 + 0.04 7.36 + 0.06 41 + 8 49 + 12 84 + 20 77 + 19 45 + 15 46 + 20 17.1 + 1.4 16.9 + 1.9 13.7 + 7.4 9.6 + 1.6 447 + 95 746 + 211

106 + 13 133 + 14 99 + 14 120 + 18 8 + 6 11 + 10 43 + 13** 58 + 12 23 + 5** 34 + 11* 31 + 6** 42 + 10* 17 + 5** 22 + 8 2.91 + 0.7 3.91 + 0.8 28 + 6 30 + 8 394 + 218 420 + 220 25 + 5 29 + 5 7.42 + 0.04 7.34 + 0.03 45 + 11 53 + 13 61 + 8 74 + 30 60 + 31 81 + 36** 17.1 + 2.6 16.9 + 2.9 10.9 + 2.3 9.6 + 2 492 + 121 663 + 191

HR, heart rate; BP, blood pressure; CVP, central venous pressure; PAP, pulmonary artery pressure; Pw, pulmonary artery occlusion wedge pressure; CI, cardiac index; SVi, stroke volume index; PVRi, pulmonary vascular resistance index; FiO2, fraction of inspired oxygen; PaCO2, partial pressure, carbon dioxide; PaO2, partial pressure, oxygen; (A-a)O2, alveolar–arterial oxygen gradient; CaO2, oxygen content, arterial blood; CvO2, oxygen content, mixed venous blood; O2Di, oxygen delivery index. For differences between groups (COPD versus A1-ATD): * ¼ P < .05 ** ¼ P < .01.

oxygen consumption (VO2max) under 600 mL O2/min in both groups. The COPD group showed normal resting cardiac index (CI), with the ability to increase heart rate and stroke volume indices (SVI) proportional to the increase in VO2. Both groups had elevated PVR and pulmonary hypertension at rest, although PA pressure was lower among the smoking-related COPD patients than among the A1-ATD patients. With exercise, both groups signiﬁcantly increased PA pressures. Because patients with obstructive airways disease develop increased intrathoracic pressures with exercise, this may have contributed to increased vascular pressures. The gas exchange pattern was characterized by relatively normal ventilation at rest and development of signiﬁcant respiratory acidosis at

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peak exertion. Supplementary O2 was administered to avoid signiﬁcant hypoxemia. Both groups showed increased alveolar–arterial oxygen gradients at rest and during exercise (signiﬁcantly worse among A1-ATD patients). B. Right Ventricular Function in Patients with Severe COPD Evaluated for Lung Transplantation

Several techniques have been described to evaluate RV function in patients selected for single- or double-lung transplantation. These include echocardiography, ultrafast CT, ﬁrst-pass multigated acquisition scan (MUGA), and direct measurement of RV ejection fraction, with RV end-diastolic and systolic volumes using a fast-thermistor–tipped PA catheter (68–70). Keller et al. (70) measured indices of RV function in 10 COPD patients listed for single-lung transplantation (SLT). Hemodynamic variables and measurements of RV function are described in Table 4. The exercise response was similar to that of the groups previously described. With exertion, the

Table 4 Right Ventricular Function in Patients with Severe COPD Evaluated for Lung Transplantation Variable

Rest

MUGA RVEF% PA catheter RVEF

57 + 10% 27 + 8%

CVP mmHg PAP mean mmHg CI L/min/m2 SVI mL/beat/m2 PVRi dyne-s/cm5/m2 RVEDV mL RVESV mL CaO2 mL O2/dL CvO2 mL O2/dL VO2 mL O2/min

6+4 24 + 4 2.34 + .4 21 + 5 339 + 182 146 + 40 110 + 38 17.3 + 2 1.9 + 2 253 + 55

Exercise

14 + 9 39 + 11 3.55 + .7 30 + 8 313 + 120 181 + 42 127 + 31 17.6 + 2 9.2 + 1.7 506 + 139

P value (2-tail) <.001 (compared to MUGA) <.002 <.001 <.001 <.005 NS NS NS NS <.01 <.001

MUGA, multigated acquisition scan; PA, pulmonary artery; RVEF, right ventricular ejection fraction; CVP, central venous pressure; PAP, pulmonary artery pressure; CI, cardiac index; SVI, stroke volume index; PVRi, pulmonary vascular resistance index; RVEDV, right ventricular end-diastolic volume; RVESV, right ventricular end-systolic volume. CaO2, arterial oxygen content; CvO2, mixed venous oxygen content; VO2, oxygen consumption. Except where noted, P value is for difference between rest and exercise.

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patients developed signiﬁcant elevations in central venous pressure (CVP) and PA pressure. Pulmonary vascular resistance was elevated at rest and failed to decrease with exertion. The mean VO2max was only 506 mL O2/min. Estimated RV ejection fraction (RVEF) was signiﬁcantly higher when measured by the single-pass MUGA technique than when measured by PA catheter (see Table 4). The differences between estimates of RVEF using MUGA versus thermodilution catheter are likely due to systematic differences in the techniques. The MUGA scan depends on injecting technetium 99 m intravenously followed by imaging and collection of data during RV transit only. Regions of interest calculated from counts at end diastole and end systole are obtained to calculate RVEF from the formula: RVEF ¼ (EDC ESC)/EDC, where EDC equals counts at end diastole and ESC equals counts at end systole. This technology essentially measures the capacity of the RV to empty during systole, whether blood is ejected forward into the PA or backward into the right atrium owing to tricuspid regurgitation. Therefore, patients with normal or elevated RVEF by MUGA could have either normal RV function or severely diminished RV function with concomitant tricuspid regurgitation (71,72), allowing total RV emptying to be preserved. On the other hand, RVEF measured by a fastthermistor–tipped PA catheter depends on sensing temperature changes in the PA over time to calculate cardiac output (CO) and stroke volume (SV) by thermodilution technique. Thus, whereas the MUGA RVEF better estimates the ‘‘total’’ volume ejected from the RV (forward volume plus the volume ejected backward through the tricuspid valve), the cathetermeasured RVEF best reﬂects effective ‘‘forward’’ volume ejected into the PA. Since many patients with advanced chronic lung disease and secondary pulmonary hypertension have right ventricular dilation and tricuspid regurgitation, the MUGA estimation of RVEF is expected to be larger than the catheter-measured RVEF. Indeed, in the studies of Spinale et al. (70,71), the difference between the MUGA EF and the catheter-determined EF directly estimated the degree of regurgitation. When SLT was ﬁrst used in the management of patients with COPD, there was concern that patients could only receive transplants if the RVEF was more than 25% (73). With experience, it was demonstrated that patients with restrictive lung disease requiring SLT on average have signiﬁcantly worse pulmonary hypertension than patients with COPD. Patients with COPD undergoing SLT rarely require cardiopulmonary bypass support. Most of these patients tolerate temporary clamping of the PA during surgery (74) regardless of baseline RV function or how low the RVEF becomes during clamping. Furthermore, even patients with primary pulmonary hypertension and severe RV dysfunction can undergo singlelung transplantation, with rapid and lasting recovery of right heart function

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(75). Therefore, in general, pulmonary hypertension per se is not considered a contraindication for lung transplantation. Only subjects with clinically obvious and refractory cor pulmonale, manifested by severe RV hypertrophy and increased jugular venous distention, with hepatomegaly and peripheral edema despite the use of oxygen therapy and diuretics, are considered for alternatives to SLT. Presumably, the reason that patients with severe pulmonary hypertension can undergo successful lung transplantation is that the transplanted lung decreases overall PVR and RV strain. C. Intraoperative and Postoperative Hemodynamics and Gas Exchange Associated with SLT Transplantation Recipients Compared with Unilateral Thoracoscopic LVRS

The intraoperative and postoperative hemodynamic proﬁle of patients with severe emphysema subjected to either SLT or unilateral LVRS has been studied and compared (76). Table 5 describes hemodynamic changes and gas exchange in 20 patients, half during SLT for COPD and half during LVRS. Baseline measurements were obtained with the patients anesthetized in the supine position, intubated with a double-lumen endotracheal tube, and ventilated with 100% O2. Subsequently, the same variables were measured after the patients were positioned in the lateral decubitus position while ventilating both lungs prior to surgery. A third set of measurements was obtained during surgery (Intraop column). Among SLT recipients, variables were measured after the PA and main bronchus were clamped and patients were receiving one-lung ventilation and one-lung perfusion. In the LVRS group, the intraoperative measurements were made while the lung being surgically reduced was collapsed and patients were receiving one-lung ventilation while both lungs were perfused. A fourth set of measurements was performed at the end of surgery (End OR column) in both groups while ventilating and perfusing both lungs. The ﬁnal measurements were obtained shortly after extubation. All LVRS patients were extubated immediately after surgery and SLT patients were all extubated within 48 h. At baseline, both groups showed mild to moderate pulmonary hypertension, increased PVR index, and decreased RVEF. While anesthetized, the patients showed mild baseline hypercapnia. The hemodynamic proﬁle remained basically unchanged in the lateral decubitus position. There was a small increase in shunt fraction in SLT patients. During surgery, the main difference in intraoperative management between the techniques resulted from the use of one-lung ventilation. In the SLT patients, both ventilation and perfusion shifted to the nonoperative lung. The LVRS patients had one-lung ventilation to the

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Table 5 Intraoperative and Postoperative Changes in Hemodynamics, Right Ventricular Function, and Gas Exchange in Patients Undergoing SLT Compared to Patients Undergoing Unilateral Thoracoscopic LVRS

CVP–SLT CVP–LVRS PA m–SLT PA m LVRS CI–SLT CI–LVRS PVRi–SLT PVRi–LVRS RVEF–SLT RVEF–LVRS PH–SLT PH–LVRS PaCO2–SLT PaCO2–LVRS FIO2–SLT FIO2–LVRS PaO2–SLT PaO2–LVRS Qs/Qt–SLT Qs/Qt–LVRS

Supine

Lat. decubitus

Intraop.

End OR

13 + 6 13 + 4 32 + 14 31 + 7 2.90 + 1 2.08 + 0.4 489 + 359 545 + 269 32 + 8 28 + 7 7.32 + .07 7.36 + .05 59 + 15 48 + 11 1.00 1.00 419 + 125 528 + 53* 13 + 8 9+6

14 + 6 13 + 3 34 + 11 33 + 5 3.08 + 1 2.83 + 1.1 519 + 319 438 + 160 33 + 8 33 + 5 7.29 + .07 7.35 + .04* 57 + 13 51 + 10 1.00 1.00 400 + 156 545 + 19* 17 + 10 9 + 6*

15 + 6 13 + 4 48 + 16 34 + 4* 3.86 + 1.4 2.79 + 0.7 649 + 408 442 + 130 34 + 9 33 + 3 7.12 þ .1 7.33 þ .05** 91 + 32 53 + 11** 1.00 1.00 370 + 176 128 + 74** 17 + 14 34 + 8*

11 + 4 12 + 4 28 + 4 31 + 3 3.46 + 0.8 2.78 + 0.6 324 + 80 411 + 125 35 + 11 37 + 5 7.22 þ .09 7.35 þ .03** 65 + 14 50 + 8** 1.00 1.00 478 + 88 341 + 170 11 + 6 13 + 7

Extubated 4+2 5+4 22 + 4 26 + 6 3.82 + 1 3.50 + 0.7 250 + 85 354 + 211 37 + 6 37 + 7 7.42 þ .02 7.40 þ .03 46 + 5 43 + 9 0.21 0.21 104 + 23 57 + 10** — —

SLT, single-lung transplant; CVP, central venous pressure (mmHg); PA m, mean pulmonary artery pressure (mmHg); CI, cardiac index (L/m/m2); PVRi, pulmonary vascular resistance (dyne/s/cm5/m2); RVEF, right ventricular ejection fraction; PaCO2, partial pressure arterial carbon dioxide (mmHg); PaO2, partial pressure arterial oxygen (mmHg); Qs/Qt, shunt fraction (%). For difference between SLT and LVRS: * ¼ P < .05; ** ¼ P < .01.

nonoperative lung, but the PA was not clamped, which favored an increased right-to-left shunt fraction while the lung was perfused but not ventilated. During the operative phase, SLT patients developed signiﬁcantly worse pulmonary hypertension than LVRS patients. One-lung ventilation and perfusion was also associated with development of more severe respiratory acidosis in transplant recipients than in LVRS patients. Thus, development of pulmonary hypertension and moderate to severe respiratory acidosis during surgery was typical but well tolerated. Excessive efforts to lower PCO2 require either increased tidal volume with peak inspiratory pressures or increased respiratory rate. Severe deleterious effects can follow both maneuvers. Increasing tidal volume to ventilate the only lung available for gas exchange can potentially produce life-

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threatening barotrauma and intraoperative pneumothorax. Increasing respiratory rate in patients with severe obstructive lung disease favors the development of signiﬁcant auto-PEEP which may cause serious hemodynamic decompensation. At the end of SLT and LVRS surgery (see Table 5), the hemodynamic proﬁle rapidly improved. Pulmonary vascular resistance, CVP, and PA pressures fell; more markedly in the SLT patients. RVEF signiﬁcantly increased after surgery in both groups. Likewise, ventilatory capacity improved and the intraoperative respiratory acidosis was fully corrected by the time patients were extubated. Thus, a substantial hemodynamic load is placed on the RV during surgery for SLT or unilateral LVRS, which is more severe in the SLT patients. However, this load appeared to be well tolerated. Over time, SLT transplant recipients who have pulmonary hypertension and RV dysfunction prior to transplantation achieve and preserve a normal hemodynamic proﬁle and demonstrate progressively improved RV function (77). Unloading of the RV occurs acutely after transplantation. Over time, this results in remodeling of the RV, producing a reduction in RV end-diastolic volume and sustained improvement in RVEF after surgery (78). The long-term effects of LVRS are less well understood. On one hand, improved gas exchange could improve arterial PO2 and lead to decreased PVR. On the other hand, removal of pulmonary vasculature during LVRS could exacerbate already existing pulmonary hypertension. What little is known about the effects of LVRS and pulmonary hemodynamics in these patients is reviewed in a later section.

D. Cardiovascular Function in Candidates for LVRS

Since candidates for LVRS have very severe disease, it might be expected that this group would have more cardiovascular dysfunction than emphysematous patients in general. Because there are few observations on large groups of patients with well-characterized emphysema, patients being evaluated for participation in the National Emphysema Treatment Trial (NETT) underwent right heart cardiac catheterization at three of the participating NETT centers (Temple University, St. Louis University, and Long Island Jewish Medical Center). All patients had FEV1 < 45% of predicted, residual volume 5150% of predicted, and moderate to severe emphysema on CT scanning of the chest. Table 6 summarizes the distribution of the commonly measured variables in 120 patients studied to date. The data suggest that moderate resting pulmonary hypertension, increased PVR, and elevated Pw are common in patients with severe emphysema.

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Table 6 Summary of Findings at Right Heart Catheterization in Patients Prior to Undergoing LVRS Mean pulmonary arterial pressure (PA) (mmHg): PA < 20 (normal to mildly elevated) PA > 20 435 (moderately elevated) PA > 35 (severely elevated)

13/120 (10.8%) 101/120 (84.2%) 6/120 (5.0%)

Resting cardiac index (CI) (L/min/M2) CI < 2.5 (low) CI 52.5 (normal)

38/118 (32.2%) 80/118 (67.8%)

PA occlusion (wedge) pressure (Pw) (mmHg) Pw 412 (normal) Pw > 12 (high)

46/120 (38.3%) 74/120 (61.7%)

Pulmonary vascular resistance (PVR) (dyne-sc/cm5) PVR < 200 (normal) PVR 5200 (high)

64/117 (54.7%) 53/117 (44.2%)

For each variable, the number of observations is in the denominator. Source: Data gathered at Long Island Jewish Medical Center, Temple University, and St. Louis University. Courtesy of S. M. Scharf, G. Criner, and C. Keller.

E.

Effects of LVRS on Pulmonary Hemodynamics

Although there substantial information regarding the effects of LVRS on pulmonary function, less is known about its effects on pulmonary hemodynamics. The disease itself may cause pulmonary hypertension, which excludes candidates from surgery (79). Theoretically, beneﬁcial hemodynamic effects could stem from decreased PVR caused by relief of hypoxia or reexpansion of compressed pulmonary vessels. Also, venous return might increase, augmenting RV preload. On the other hand, LVRS could result in deformation of pulmonary vessels and removal of a signiﬁcant amount of the pulmonary vascular bed. Furthermore, any increase in venous return might increase PA pressure. To date, there are few studies addressing the effects of LVRS on pulmonary hemodynamics. Sciurba et al. (80) demonstrated an increase in the echocardiographically determined fractional change in RV area after LVRS, suggesting an improvement in RV systolic function. They speculated

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that this was due to a reduction in PVR after LVRS and a decrease in RV afterload, and they hypothesized that capillaries that were compressed by hyperinﬂated alveoli may have been recruited after the resection of pulmonary parenchyma. Alternatively, the capillaries may have been recruited because of increased tethering of extra-alveolar vessels associated with increased elastic recoil. Right ventricular preload also may have been augmented by reduced intrathoracic pressure. Proceeding on the hypothesis that PA pressures would be reduced after LVRS and that improvements in symptoms and pressures would correlate, Weg et al. (81) studied nine consecutive patients with emphysema before and 3 months after bilateral LVRS. Contrary to expectations, systolic, mean, and diastolic pressures rose (Figs. 3 and 4). Patients with the highest initial PA pressures demonstrated the greatest increase in PA pressure postoperatively. Although the mean change in PVR (208.6 + 86.8 preoperatively to 251.8 + 149.4 dyne-s/cm5 postoperatively) did not reach statistical signiﬁcance, an increase in PVR were observed in six of the patients. Weg et al. (81) explored the relationship between the pulmonary hemodynamics and the patients’ symptoms. Preoperatively, a negative correlation was noted between PA systolic pressure (PAs) and the Mahler dyspnea index; that is, the greater the PAs, the greater the dyspnea (dyspnea score ¼ 6.6 0.1 [PAs], r ¼ .81, P ¼ .008). However, this relationship was not maintained from the presurgical to the postoperative period. That is, the degree of dyspnea did not worsen as the PAs rose after surgery. There was also no correlation between resting cardiac output and dyspnea preoperatively or between the change in cardiac output and change in dyspnea following surgery. Indeed, the data showed that despite no change in resting cardiac output, substantial improvement in dyspnea occurred after surgery. Others have not found increased resting PA pressures following LVRS (82– 84). In the studies of Oswald-Mammosser et al. (82), the ‘‘respiratory swing’’ (large variations in intrathoracic pressure) detected in the PA diastolic pressure prior to LVRS was decreased after surgery. As these swings are generated to compensate for altered lung mechanics, the narrowing of the respiratory variation suggests less vigorous inspiratory effort and less hyperinﬂation. Kubo et al. (85) compared pulmonary hemodynamics before and following LVRS both during exercise and at rest. Both before and following LVRS there was an approximate doubling of resting PA systolic pressure with exercise (nonsigniﬁcant difference in the PA systolic pressure response to exercise), although maximum exercise tolerance improved. However, cardiac output was greater at rest and during exercise following LVRS, suggesting an improvement in PVR. These ﬁndings are consistent with a

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Figure 3 Effect of LVRS on pulmonary arterial systolic (PAsystolic) and mean (PAmean) pressure in nine patients with emphysema. (From Ref. 80.)

cardiovascular limitation to maximum exercise performance in severe emphysema discussed above. The reason for the difference in ﬁndings regarding PA pressure between the studies of Weg et al. (80) and the others cited (82–85) is not clear. However, mean preoperative PA pressure was higher in the patients studied by Weg et al. (26 mmHg) than in the other series (17, 18, and 9 mmHg, respectively). Moreover, diffusion capacity was approximately

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Figure 4 Effect of LVRS on PA diastolic (PAdiastolic) and wedge pressure (Pw). (From Ref. 80.)

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25% of predicted (unpublished data) for the patients studied by Weg et al., whereas it was approximately 50 and 44% of predicted in other studies (82,85). Possibly, more severely reduced CO diffusion capacity and greater initial PA pressure reﬂect greater initial obliteration of the pulmonary vascular bed. Taken together, these studies may indicate that LVRS does, in fact, reduce pulmonary vascular surface area. However, this would only be reﬂected in increased postoperative PA pressure in patients in whom initial pulmonary vascular surface area was the most limited. Recent studies by Pawell et al. (86) on LVRS in emphysematous rabbits lend support to the idea that surgery compromises the pulmonary vasculature in the most severe cases. Emphysema was produced by endotracheal instillation of elastase of low doses (mild emphysema) or high doses (moderate emphysema). All animals had an immediate (1 week) increase in pulmonary vascular resistance following LVRS. However, in animals with mild emphysema, pulmonary pressures returned to normal with time, whereas remaining elevated in those with moderate emphysema. These workers concluded that ‘‘sustained increased PVR . . . is more likely to occur after LVRS in animals with more severe emphysema and larger volume resection.’’ Thus, the lung mechanical beneﬁts of LVRS in patients with severe disease need to be weighed against possible vascular compromise. Presumably, the larger the resection volume, the more likely vascular compromise would occur in severely ill patients. F.

Measurement of Pulmonary Arterial Wedge Pressure (Pw) in Emphysema and with LVRS

It is generally assumed that with a normal pulmonary vasculature, Pw reﬂects left atrial pressure and hence LV ﬁlling pressure. There are a number of well-known situations in which these assumptions are not true (84), including the scarred, nonhomogeneous lung characteristic of emphysema. Over 30 years ago, Jezek and Herles (88) found differences in Pw at various sites of ‘‘wedging’’ in patients with COPD or pulmonary ﬁbrosis, differences not found in normal subjects. In an earlier editorial, Herles (89) discussed the contribution to the Pw of other pressure sources such as bronchopulmonary shunts, which would increase the measured Pw. As previously noted, Butler et al. (15) emphasized how lower lobe gas trapping during exercise in COPD could increase the pressure surrounding the heart, leading to increased pulmonary vascular pressures. In the group of patients studied by Weg et al. (81), as is consistent with Table 6, there was a high prevalence of patients with increased Pw. Paired LVEF and Pw data were available in six patients, and there was no association of elevated Pw with LVEF either before or following LVRS. Diastolic LV dysfunction was suspected in at

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least one of the patients, but the data were not correlated with echocardiographic ﬁndings. Finally, in the studies of exercise hemodynamics, Kubo et al. (85) found that pulmonary occlusion pressure (Pw) increased with exercise both before and following LVRS. However, the exercise-induced increase was reduced following LVRS. Since increased Pw with exercise probably reﬂects lower lobe hyperinﬂation (15), it is logical that exercise-induced hyperinﬂation and increased Pw are both reduced by the surgery. G. Coronary Artery Disease in Candidates for LVRS

Most patients referred for LVRS have a long history of cigarette smoking. Thus, concomitant coronary artery disease could be a factor in the prognosis of these patients either in the perioperative period or over the long term. Thurheer et al. (90) prospectively studied the prevalence of coronary artery disease using coronary angiography in 41 candidates for LVRS who gave no history of coronary disease and had no coronary disease symptoms. Six of these patients (15%) were found to have signiﬁcant coronary stenosis (> 70% occlusion). In ﬁve of these, the clinical management was altered by the angiographic ﬁndings. Thus, there may be a relatively high prevalence of clinically silent coronary disease in LVRS candidates. V. Pulmonary Vascular Disease in Emphysema: Chicken or Egg? Observations made in the 1960s have formed the backbone of the currently accepted model for the pathogenesis of emphysema. The ﬁrst is that alpha1ATD, a natural protease inhibitor, leads to emphysema (91), and the second is that instillation of proteases leads to emphysema (92). These observations have formed the basis for the currently accepted protease–antiprotease balance theory of the genesis of emphysema. Under this theory, blood vessels could be mere ‘‘innocent bystanders’’ and be destroyed as part of the general inﬂammatory process leading to emphysema. The protease– antiprotease theory largely replaced Liebow’s speculation in the 1950s (93) that a reduction in blood supply to alveolar septa could induce their disappearance and lead to emphysema. According to this hypothesis, changes in the pulmonary microcirculation precede and lead to changes in pulmonary parenchyma. This speculation was given a rebirth by recent studies of Kasahara et al. (94) demonstrating that inhibition of vascular endothelial growth factor (VEGF) leads to both endothelial and epithelial apoptosis and emphysema in mice. Thus, obliteration of the pulmonary vascular bed in emphysema might be the ﬁrst pathogenetic step and could

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further lead to inﬂammatory (protease) damage and hypoxic vasoconstriction, thereby further increasing pulmonary vascular resistance. Thus, increased pulmonary vascular resistance, pulmonary hypertension, and eventually RV strain are all part and parcel of the original vascular damage leading to emphysema. Like all shifts in paradigm, many questions are raised by these speculations which require further in-depth research.

VI.

Summary

It must be clear to the reader that generalizations about the effects of what appears to be emphysema on pulmonary hemodynamics must be made with extreme caution. This is due to the variability of results found in different studies, which in turn often results from variability in the deﬁnition of chronicity and distribution of true emphysematous changes in the lung. However, it appears that severe emphysema is capable of producing pulmonary hypertension and limitation of peripheral O2 delivery, that this may be part of the reason for exercise limitation in these patients, and that pulmonary hypertension predicts a poor prognosis. It appears that pulmonary hypertension can be produced even if hypoxia is not a feature of the patient’s illness. Although pulmonary hypertension is relieved by lung transplantation, the effects of LVRS on pulmonary hemodynamics are not well known. The divergent preliminary results from different studies underscore the need for extensive evaluation of the effects of LVRS on pulmonary hemodynamics. We speculate that the extent of baseline pulmonary vascular obliteration, possibly as measured by the diffusion capacity and initial PA pressure or PVR, may predict the hemodynamic effects of LVRS. The opportunity to perform large-scale studies of the effects of emphysema and LVRS on pulmonary hemodynamic and cardiac function afforded by the National Emphysema Treatment Trial will add greatly to our understanding of this important problem.

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70. Keller CA, Ohar J, Ruppel G, Wittry MD, Goodgold HM. Right ventricular function in patients with severe COPD evaluated for lung transplantation. Chest 1995; 107:1510–1516. 71. Spinale FG, Smith AC, Carabello BA, Crawford FA. Right ventricular function computed by thermodilution and ventriculography. J Thorac Cardiovasc Surg 1990; 99:141–152. 72. Spinale FG, Mukherjee R, Ryunhei T, Tanaka R, Zile MR. The effects of valvular regurgitation on thermodilution ejection fraction measurements. Chest 1992; 101:723–731. 73. Morrison DL, Maurer JR, Grossman RF. Preoperative assessment for lung transplantation. Clin Chest Med 1990; 11:207–215. 74. deHoyos A, Demajo W, Snell G, Miller J, Winton T, Maurer J, Patterson GA. Preoperative prediction for the use of cardiopulmonary bypass in lung transplantation. J Thorac Cardiovasc Surg 1993; 106:787–796. 75. Pasque MK, Trulock EP, Cooper JD, Triantaﬁllon AN, Huddleston CB, Rosenbloom M, Sundaresan S, Cox JL, Patterson GA. Single lung transplantation for pulmonary hypertension. Circulation 1995; 92:2252–2258. 76. Keller CA, Naunheim KS, Osterloch J, Krucylak PE, Baundendistel L, McBride L, Hibbett A, Ruppel G. Hemodynamics and gas exchange after single lung transplantation and unilateral thoracoscopic lung reduction. J Heart Lung Transplant 1997; 16:199–208. 77. Bjortuft O, Simonsen S, Geiran OR, Fjeld JG, Skuvlund E, Boe J. Pulmonary haemodynamics after single lung transplantation for end-stage pulmonary parenchymal disease. Eur Respir J 1996; 9:2007–2011. 78. Rensing BJ, McDougall JC, Breen JF, Vigneswaran WT, McGregor CG, Rumberger JA. Right and left ventricular remodeling after orthotoic single lung transplantation for end-stage emphysema. J Heart Lung Transplant 1997; 16:926–933. 79. Cooper JD, Trulock EP, Triantaﬁllon AN, Patterson GA, Pohl MS, Deloney PA, Sundaresan RS, Roper CL. Bilateral pneumonectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995; 109:106–119. 80. Sciurba FC, Rogers RM, Keenan RI, Slivka WA, Gorcsan J, Ferson PF, Holbert JM, Brown ML, Landreneau RI. Improvement in pulmonary function and elastic recoil after lung-reduction surgery for diffuse emphysema. N Engl J Med 1996; 334:1095–1099. 81. Weg IL, L Rossoff, McKeon K, Graver LM, Steinberg HN, Scharf SM. Development of pulmonary hypertension following lung volume reduction surgery. Am J Respir Crit Care Med 1999; 159:552–556. 82. Oswald-Mammosser M, Kessler R, Massard G, Wihlm J-M, Weitzenblum E, Lonsdorfer J. Effect of lung volume reduction surgery on gas exchange and pulmonary hemodynamics at rest and during exercise. Am J Respir Crit Care Med 1998; 158:1020–1025. 83. Thurnheer R, Bingisser R, Stammberger U, Muntwyler J, Zollinger A, Block KE, Weder W, Russi EW. Effect of lung volume reduction surgery on

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Scharf et al. pulmonary hemodynamics in severe pulmonary emphysema. Eur J Cardiothorac Surg 1998; 13:253–258. Comparison of changes in hemodynamics between unilateral and bilateral lung volume reduction for pulmonary emphysema. Ann Thorac Cardiovasc Surg 2001; 7:266–272. Kubo K, Koizumi T, Fujimoto K, Matsuzawa Y, Yamanda T, Haniuda M, Takahashi S. Effects of lung volume reduction surgery on exercise pulmonary hemodynamics in severe emphysema. Chest 1998; 114:1575–1582. Powell LL, Serna DL, Brenner M, Gaon M, Jalal R, Stemmer E, Chen JC. Pulmonary vascular pressures increase after lung volume reduction surgery in rabbits with more severe emphysema. J Surg Res 2000; 92:157–164. Raper R, Sibbald W. Misled by the wedge? The Swan-Ganz catheter and left ventricular preload. Chest 1986; 89:427–434. Jezek V, Herles F. Uneven distribution of pulmonary arterial wedge pressure in chronic bronchitis and emphysema. Cardiologia 1969; 54:164–169. Herles F. The pulmonary artery wedge pressure: Its origin and value in assessing pulmonary hemodynamics in emphysema (editorial). Cor Vasa 1966; 8:161–166. Thurnheer R, Muntwyler J, Stammberger U, Block KE, Zollinger A, Weder W, Russi EW. Coronary artery disease in patients undergoing lung volume reduction surgery for emphysema. Chest 1997; 112:122–128. Laurell CB, Eriksson SE. The electrophoretic alpha-globulin pattern of serum in alpha-antitrypsin deﬁciency. Scan J Clin Lab Invest 1963; 15:132–140. Gross P, Pﬁtzer E, Tolker E, Babyak M, Kaschak M. Experimental emphysema: its production with papain in normal and silicotic rats. Arch Environ Health 1965; 11:50–58. Liebow A. Pulmonary emphysema with special emphasis to vascular changes. Am Rev Respir Dis 1959; 80:67–93. Kasahara Y, Tuder RM, Taraseviciene-Stewart L, LeCreas TD, Abman S, Hirth PK, Waltenberger J, Voelkel NF. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000; 106:1311–1319.

5 Medical Therapy for Chronic Obstructive Pulmonary Disease and Emphysema

BARTOLOME R. CELLI Tufts University and St. Elizabeth’s Medical Center Boston, Massachusetts, U.S.A.

I. Introduction The airﬂow obstruction of chronic obstructive pulmonary disease (COPD) is thought to be largely irreversible (1,2). Furthermore, emphysema is primarily a disease of the lung parenchyma, whereas most of our medical therapy is directed at abnormalities of the airways. These physiological truisms have unfortunately engendered nihilism in many health care providers. Abundant evidence suggests that this is unwarranted, and optimism toward these patients goes far in relieving their fears and misconceptions. In contrast to many other diseases, some interventions, such as smoking cessation (1,3) and long-term oxygen therapy in hypoxemic patients, improve survival (1,2), whereas others improve symptoms and quality of life. Table 1 shows the spectrum of available therapeutic options for patients with COPD. The overall goals of treatment are to prevent further deterioration in lung function, alleviate symptoms, and treat complications as they arise. Patients should be encouraged to actively participate in their management. This concept of collaborative management may improve self-reliance, esteem, 99

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Table 1

Therapy of Patients with Symptomatic Stable COPD

Interventions that improve survival

Interventions that improve symptoms

Smoking cessation

Pharmacotherapy

Oxygen therapy if hypoxemic

Rehabilitation: Education Training and exercise Psychological support Nutrition Surgery: LVRS Lung transplant

and compliance with treatment. Patients should be encouraged to lead a healthy life and exercise regularly. Preventive care should be stressed. Treatments have largely been studied in patients with COPD without distinguishing between those with emphysema and those with chronic bronchitis. Since both diseases usually coexist in patients, this chapter will address the treatment of COPD. Patients with predominantly emphysema being considered for lung volume reduction surgery (LVRS) should also have their airway disease optimally treated. The principles of such therapy are discussed here. Pulmonary rehabilitation, another cornerstone of medical management of COPD, is discussed in Chapter 6.

II.

Smoking Cessation

Since smoking is the major cause of COPD, smoking cessation is the most important intervention for patients who still smoke (1–3). Furthermore, continued smoking is generally an absolute contraindication to LVRS. Most patients recognize that smoking is dangerous, but often have failed multiple attempts to quit on their own. The spontaneous rate of quitting among patients with early COPD is only less than 5% per year (3). The factors that cause patients with lung disease to smoke include addiction to nicotine; conditioned responses to stimuli surrounding smoking; psychosocial problems such as depression, poor education, and low income; and forceful advertising campaigns. As the causes of smoking are multifactorial, the solutions for smoking cessation should also involve multimodal interventions.

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The clinician should consistently encourage smoking cessation, because a physician’s speciﬁc advice to quit smoking improves results (4–6). A strong social support system, including professionals, family, and friends, is also associated with cessation and long-term abstinence. The smoker should avoid circumstances likely to prompt relapse, including addressing sources of stress. It is useful for the patient to set a quit date, because stopping ‘‘cold turkey’’ is more effective than gradual withdrawal (7–9) It can be helpful to telephone the patient at follow-up intervals to encourage continued abstinence. Group smoking cessation clinics are offered by many hospitals, work sites, and voluntary agencies. They include programs such as the American Lung Association’s Freedom From Smoking clinics. These programs effectively integrate behavioral therapy, social support, counseling, and adjunctive pharmacological treatment. Practical guidelines for smoking cessation have recently been published by the U.S. Public Health Service (10).

III.

Pharmacological Smoking Cessation Therapy

Nicotine is the ingredient in cigarettes that is primarily responsible for the physical addiction of smoking (6). One to 2 mg of nicotine is delivered to the lungs with each cigarette smoked. Because of rapid absorption into the blood and a half-life of 2 h, regular daytime smoking can cause nicotine accumulation for an entire 24-h period. The concentration of nicotine receptors in the brain is genetically determined, but is upregulated by continued nicotine use (9). Nicotine is metabolized by the liver. Cotinine, a primary metabolite of nicotine, has a longer half-life and can be detected in the urine of smokers. Withdrawal from nicotine causes anxiety, irritability, difﬁculty concentrating, anger, fatigue, drowsiness, depression, and sleep disruption, especially during the ﬁrst week of cessation (9). Nicotine replacement reduces withdrawal symptoms and enhances abstinence in a dose-dependent fashion. Highly dependent nicotine smokers can be identiﬁed as those who smoke over one pack of cigarettes per day, who require their ﬁrst cigarette within 30 min of arising, and who ﬁnd it difﬁcult to refrain from smoking in places where it is forbidden (8). Physical dependence can also be assessed by a formal questionnaire such as the Fagerstrom tolerance questionnaire. Nicotine polacrilex gum (2 mg per piece) and nicotine nasal inhalers are effective when compared to placebo, especially in self-referred smokers who are highly addicted (9). Transdermal nicotine patches are more widely available, and may be prescribed for the patient who has failed smoking cessation efforts in the past or whose smoking cessation has been troubled

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by withdrawal symptoms (9). Short-term success rates have varied widely (18–77%), but in general nicotine patches are about twice as effective as placebo. Long-term success rates (6 months and longer) are considerably lower (22–42%), but are consistently better when compared with placebo patch (2–26%). The ideal duration of replacement therapy has not been established. It has been recommended that nicotine therapy beyond 6–8 weeks may not be necessary. However, some studies have shown greater efﬁcacy when nicotine replacement is continued for 10 weeks (11) or up to 9 months (12). Although nicotine patches are well tolerated, mild erythema or other local skin reactions may be seen in up to 50% of patients. However, these effects can be minimized by rotating the patch to different sites of the skin. The anxiolytic agent bupropion has also been show to be of great beneﬁt in producing abstinence. Several randomized trials have documented its effectiveness compared both with placebo and with nicotine replacement (13–15). In one study, a combination of nicotine patch and bupropion was more effective then either therapy alone (13). The doses of bupropion and nicotine are most effective when individualized for each patient. The smoking status (abstinence or continued smoking) during the ﬁrst 2 weeks of nicotine patch or bupropion therapy can serve as a predictor of smoking cessation, since smoking during this period is a powerful predictor of failure at the end of a 6-month trial. As with nicotine replacement, long-term therapy may improve long-term abstinence rates (14). Patients who fail during the ﬁrst 2 weeks of therapy should be offered more intense pharmacological or adjuvant therapy. Patients who fail at any time should be encouraged to try again, since many who achieve long-term abstinence do so only after several aborted attempts. Adjuvant programs such as individual or group therapy increase success rates when added to pharmacological intervention. Hypnosis may be an effective adjunct, but is of little value when offered as a single-session cure. There is little evidence that acupuncture contributes to smoking cessation beyond its placebo effect.

IV.

Pharmacological Therapy of Airﬂow Obstruction

The pharmacotherapy of COPD should be stratiﬁed according to the severity of the disease (16). In the outpatient setting, a step-wise approach (Table 2) similar in concept to that developed for asthma and systemic hypertension is recommended (1,2,16). There is currently no evidence that regular medication use alters the progression of COPD. However, medications relieve symptoms, improve exercise tolerance, decrease

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Pharmacological Step Care of COPD

1. For mild variable symptoms: Selective b2-agonist MDI aerosol 1–2 puffs q2–6h prn (not to exceed 8–12 puffs/ 24 h) or Long-acting b2-agonist 1–2 puffs q12h. 2. For mild-to-moderate continuing symptoms: Ipratropium MDI aerosol 2–8 puffs q6–8 h (not to be used more frequently) plus Selective b-agonist MDI aerosol 1–4 puffs prn qid (for rapid relief, when needed, or as regular supplement) 3. If response to Step 2 is unsatisfactory, or for a mild-to-moderate increase in symptoms: add Sustained-release theophylline 200–400 mg bid or 400–800 mg h.s. for nocturnal bronchospasm and/or Long-acting b2-agonist 1–2 puffs bid and/or Consider use of sustained-release albuterol 4–8 mg bid, or at night only. 4. If control of symptoms is suboptimal: Consider a course of oral steroids (e.g., prednisone) up to 40 mg/d for 10–14 days: If improvement occurs, wean down to low daily or alternate-day dosing, e.g., 7.5 mg. If no improvement occurs, stop. If steroid appears to help, consider possible use of aerosol MDI, particularly if patient has evidence of bronchial hyperreactivity and repeated exacerbations. 5. For severe exacerbation: Increase b2-agonist dosage e.g., MDI with spacer 4–6 puffs q1/2–2 h or inhalant solution, unit dose q1/2–2 h or subcutaneous administration of epinephrine or terbutaline, 0.1–0.5 mL and/or Increase ipratropium dosage e.g., MDI with spacer 6–8 puffs q3–4h or inhalant solution of ipratropium 0.5 mg q4–8h and Provide theophylline dosage IV with calculated amount to bring serum level to 10– 12 mmg/mL and Provide methylprednisolone dosage IV giving 50–100 mg stat then q6–8h. Taper as soon as possible (2 weeks) add An antibiotic, if indicated.

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frequency or severity of exacerbations, and improve quality of life, all worthwhile goals in COPD. It is important to remember that most COPD patients are older and therefore particularly susceptible to the side effects of some of these drugs. Since the goal of therapy is often symptomatic, relief of dyspnea must always be weighed against exacerbation of side effects. The bronchodilators used in COPD are similar to those used in asthma, with some noteworthy differences. b-Agonists produce less bronchodilation in COPD, and in some patients the acute spirometric changes may be insigniﬁcant. However, symptomatic beneﬁt may be experienced despite the lack of an acute bronchodilator response, perhaps through other mechanisms such as decreased dynamic hyperinﬂation. The older age of patients with COPD may result in less tolerance for sympathomimetic-induced tremor, nervousness, and cardiac side effects (17). Likewise, many older COPD patients cannot effectively activate or coordinate metered dose inhalers (MDIs), and may require training to achieve proper technique. If this is not possible, use of a spacer will facilitate inhalation of the medication. Spacers also reduce mucosal deposition in the mouth, minimizing local side effects (e.g., thrush with inhaled steroids) or systemic absorption and its consequences (e.g., tremor after b-agonists). The occasional patient may require bronchodilators to be administered by smallvolume nebulizer. A. b-Agonists

b-Agonist therapy decreases dyspnea and dynamic hyperinﬂation and improves exercise tolerance in COPD (18,19). In patients with intermittent symptoms, it is reasonable to initiate drug therapy with an MDI of a b-agonist as needed for relief of dyspnea (1). Albuterol, pirbuterol, metaproterenol, terbutaline, or isoetharine (each of which is preferable to the less selective drugs epinephrine, isoproterenol, and ephedrine) may be taken up to a maximum of six times a day or as prophylaxis before exercise. The rapid onset of action of b-agonist aerosols may cause dyspneic patients to favor them for regular use. The potential for arrhythmias necessitates careful dosing in patients with cardiac disease, although serious cardiac complications are rare with conventional doses. Levo-albuterol is available and has been suggested to decrease side effects by eliminating the slowly metabolized D-enantiomer from the usual racemic products. However, this has not been consistently documented to decrease cardiac effects (20). In more advanced disease requiring continuous therapy, one may add long-acting b-agonists (salmeterol, formoterol). At a dose of one or two puffs twice daily, they have been shown to prevent nocturnal bronchospasm, increase exercise endurance, and improve quality of life (21). The twice-daily

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administration may improve compliance. Patients must be warned not to exceed recommended doses or to use long-acting agents as rescue therapy because of the risk of cumulative dosing and cardiac complications. New b2-receptor agonists with simultaneous dopaminergic activity (which may decrease cough and sputum production) are in development. B. Anticholinergics

Once the patient suffers from persistent symptoms, an alternative therapy is regular use of inhaled ipratropium. This has a slower onset and longer duration of action than short-acting b2-agonists, and thus is less suitable for rescue use (22). The usual dose is two to four puffs three or four times a day, but some patients require larger dosages (up to eight puffs at a time). Ipratropium is effective in increasing exercise tolerance and decreasing dyspnea (23). There is little systemic absorption, and side effects are few. Inadvertent spraying of the medication into the eyes can cause prolonged mydriasis, which may be a problem in patients with glaucoma. A large multicenter controlled trial of therapy with ipratropium bromide conﬁrmed a signiﬁcant bronchodilator effect, but found no alteration in the rate of decline in lung function in the patients receiving the medication (3). There is no evidence that regular use of anticholinergic therapy, with or without a b2-agonist, leads to a worsening of spirometry or premature death in COPD. Thus, it is appropriate to begin regular therapy with ipratropium and to add a b2-agonist as often as needed for up to four treatments a day (24). A new long-acting quaternary ammonium compound (tiotropium) has been very effective in patients with once or twice daily administration (25–27). It is not yet available in the United States. Currently, there is one available ﬁxed-combination MDI of ipratropium and a b-agonist that has been proven to be effective in the management of COPD (24). This may increase convenience and compliance or reduce cost for patients requiring both agents. Furthermore, recent analysis of prospectively collected data suggests that the combination of b-agonists and ipratropium may decrease the incidence of acute COPD exacerbations and hospitalizations, and thereby decrease overall therapy cost (28). C. Phosphodiesterase Inhibitors

The potential for toxicity has relegated theophylline to a third-line agent in the therapy of COPD (1). However, it remains useful for less compliant or less capable patients who cannot use aerosol therapy optimally. Theophylline has been shown to improve the function of the respiratory muscles, stimulate the respiratory center, enhance activities of daily living, and

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decrease dyspnea (29,30). It also improves cardiac output, reduces pulmonary vascular resistance, and improves the perfusion of ischemic myocardial muscle. Recent evidence suggests an anti-inﬂammatory role for this drug as well. Thus, there are several advantages to theophylline therapy in patients with cardiac disease or cor pulmonale, but its use should be carefully followed and serum levels must be monitored (1,30). The previously recommended therapeutic serum range of 15–20 mg/dL is too close to the toxic range and is frequently associated with side effects. Therefore, a lower target range of 8–13 mg/dL is safer while still being therapeutic. The regular use of theophylline has not been shown to have a detrimental effect on the course of COPD. Combinations of theophylline, albuterol, and ipratropium can result in maximum beneﬁt in stable COPD (31,32). There are other phosphodiesterase inhibitors in development. A phosphodiesterase E4 inhibitor with an anti-inﬂammatory and bronchodilator effect, but less gastrointestinal irritation, could prove to be extremely useful if its theoretical advantages are clinically conﬁrmed. D. Anti-Inﬂammatory Therapy

In contrast to their central role in asthma management, anti-inﬂammatory drugs have not been documented to have signiﬁcant value in the routine treatment of patients with stable COPD (1). Corticosteroids may merit more thorough evaluation in individual patients who fail to improve on adequate bronchodilator therapy (32,33). Most studies suggest that only 10–30% of patients with COPD improve with chronic oral steroid therapy (32). Exacerbations often necessitate a course of oral steroids (34,35), but it is important to wean patients quickly, because the older COPD population is susceptible to complications such as skin damage, cataracts, diabetes, osteoporosis, and secondary infection. The dangers of steroids mandate careful documentation of the effectiveness of such therapy before a patient is committed to prolonged daily or alternate-day dosing. The latter regimen may be safer, but its effectiveness has not been adequately evaluated in COPD. The role of inhaled corticosteroids is even less certain. Several recent large multicenter, placebo-controlled long-term trials evaluated the effect of inhaled corticosteroids in slowing the progression symptomatic COPD in affected patients (36–39). The results showed no beneﬁts in slowing the rate of decline of lung function. However, secondary beneﬁts shown in these studies included better maintained health-related quality of life, reduced respiratory symptoms, fewer phisician visits due to respiratory symptoms, and reduced airway reactivity. More rapid loss of bone density was also seen

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in patients receiving inhaled triamcinolone (39). The addition of inhaled steroids to albuterol and ipratropium must be evaluated on an individual basis. Patients with moderate-to-severe COPD who have have repeated exacerbations and who respond to oral steroids may be the best candidates for this form of therapy. The role of other drugs used in asthma, such as leukotriene inhibitors, remains to be established in patients with COPD. Cromolyn and nedocromil are not useful agents, although they could possibly be helpful in patients with associated respiratory tract allergy. As the inﬂammatory nature of COPD is better understood, it is likely that anti-inﬂammatory agents that are more targeted and more effective than corticosteroids will become available. E.

Mucokinetic Agents

The only controlled study suggesting a symptomatic beneﬁt of mucokinetic agents in the long-term management of bronchitis was a multicenter evaluation of organic iodide (40). The value of other agents, including water, has not been clearly demonstrated. Some agents (such as oral acetylcysteine) are favored in Europe for their antioxidant effects in addition to their mucokinetic properties. Small controlled trials have shown some effect of these agents on FEV1 and in reduction of acute exacerbations (41). Genetically engineered ribonuclease seems to be useful in cystic ﬁbrosis, but is of no value in COPD. Furthermore, since excessive mucus production will exclude patients from LVRS, these medications have little practical role in patients typically considered for such surgery. F.

Antibiotics

In patients with evidence of respiratory tract infection, such as fever, leukocytosis, and a change in the chest radiograph, antibiotics have been proved to be effective (42). When an acute bacterial infection is suspected, antibiotic therapy is generally prescribed, but the decision is usually made clinically because culture of sputum is not cost effective. The major bacteria to be considered are Streptococcus pneumoniae, Haemophilus inﬂuenzae, and Moraxella catarrhalis. The antibiotic choice will depend on local experience, supported by sputum culture and sensitivities only if the patient is moderately ill or needs to be admitted to hospital. In prescribing treatment, ﬁscal concerns should be a factor, because older, less costly agents, for example, tetracycline, doxycycline, amoxicillin, or erythromycin, are often sufﬁcient (1,42). The recent introduction of oral ﬂuoroquinolones and macrolides has increased our capacity effectively to treat patients with acute respiratory tract infections. Quinolone medications may be favored in the

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more severe cases in which gram-negative bacteria with resistance to many antibiotics seem to be a growing problem (43,44). If recurrent infections occur, particularly in winter, continuous or intermittent prolonged outpatient courses of antibiotics may be useful (although beneﬁt is unproven).

G. Alpha1-Antitrypsin Replacement

Although replacement with alpha1-antitrypsin may be indicated in nonsmoking, younger patients with documented antitrypsin-deﬁciency emphysema, in practice such therapy is difﬁcult to initiate. Administration of alpha1-antitrypsin is relatively safe, but the selection of appropriate candidates for such therapy has not been well deﬁned (1). Patients either with very severe and crippling COPD or with quite good lung function are not ideal candidates for therapy. The high cost of therapy precludes its widespread use, and its safety and long-term effects, including efﬁcacy, remain unknown. There is currently a worldwide shortage of the only available formulation, making it difﬁcult to supply even the patients who are receiving regular therapy.

H. Respiratory Stimulants and Psychoactive Drugs

Respiratory stimulants such as doxapram or almitrine are not recommended (2), although they are used occasionally (32). Psychoactive drugs are often sought by older patients to treat depression, anxiety, insomnia, or pain. In general, these agents can be given with careful attention to their depressant effect on the respiratory center. Benzodiazepines do not have a marked effect on respiration in mild or moderate COPD, but can be suppressive in severe disease, particularly during sleep. The safer hypnotics for treatment of insomnia include sedating antihistamines and chloral hydrate. Depression is common in COPD, and tricyclic antidepressants taken at bedtime may also have the advantage of improving sleep. Newer antidepressant serotonin-reuptake inhibitors, on the other hand, are nonsedating and may be advantageous for patients with hypercapnia. Cardiovascular drugs, for example, diuretics, angiotensin-converting enzyme inhibitors, and calcium channel blockers, may be needed in severe COPD and cor pulmonale. Digoxin is occasionally useful, whereas badrenergic blockers are generally contraindicated. These drugs must be used cautiously to avoid dehydration, hypotension, myocardial ischemia, and arrhythmias. Since most patients requiring such therapy are elderly or have impaired drug clearance, the potential for side effects is exaggerated.

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I. Vaccination

Some infectious complications of the respiratory tract can be prevented by vaccination in patients with COPD (1). However, the currently available vaccines are not totally effective, and are not used as widely as recommended. Pneumococcal vaccine should be given once to patients under age 65 years and repeated every 5 years in patients who were ﬁrst immunized over age 65 years (45). Inﬂuenza vaccine should be given annually. V. Management of the Acute Exacerbation of COPD The most important components of therapy for acute exacerbation of COPD are anticholinergic and b-agonists aerosols. Aerosols may be administered via an MDI, with a spacer if the administration is erratic, or as an inhalant solution by nebulization. Although the upper limit of ipratropium dosage has not been established, the drug is safe, and higher dosages than usual can be given to a poorly responsive patient. However, the long half-life dictates that doses should not be repeated more often than every 4 h. An inhaled b2-agonist should also be administered. In contrast to ipratropium, these drugs have a reduced functional half-life in exacerbations of COPD, and thus may be given every 30–60 min if tolerated. The added value and safety of continuous nebulization have not been established, but in selected cases may be worth a trial. Subcutaneous or intramuscular dosing is only recommended if aerosol use is not feasible and it is associated with more cardiac side effects. Intravenous administration is not an acceptable practice. The addition of theophylline may be useful, and should be given as intravenous aminophylline in a severe exacerbation. Serum levels are needed as a guide to avoid toxicity, and in most patients a serum level of 8–12 mg/ mL is adequate. Aminophylline clearance is enhanced in active smokers and decreased in congestive heart failure and liver disease, and doses must be adjusted accordingly to avoid toxic levels. Clearance is also effected by a wide range of drugs. When the patient improves, oral long-acting theophylline can be substituted at doses equal to 80% of the daily dose of aminophylline. Systemic corticosteroids are often used during more severe exacerbations. Their usefulness has been demonstrated in one small (35) and one large randomized trial (46). The optimal dosage of corticosteroids has not been established, but is generally between 60 and 240 mg of prednisone or its equivalent per day. In addition, the large randomized trial compared 2 versus 8 weeks of steroids, and showed no advantage for the longer course

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(46). Rapid weaning may protect patients from serious complications such as psychosis, ﬂuid retention, accelerated osteoporosis, and avascular necrosis of bones. Antibiotics such as amoxicillin, doxycycline, erythromycin, quinolones, and macrolides are recommended in exacerbations of COPD regardless of the results of sputum culture, particularly when sputum is purulent (2). Mucokinetic agents have not been shown to be effective in exacerbations of COPD, although some patients report subjective improvement. Inhaled corticosteroids, cromolyn, and leukotriene antagonists have no role in the treatment of acute exacerbations.

VI.

Long-Term Oxygen Therapy

Therapeutic oxygen has been used systematically since ﬁrst Barach and then Petty et al. recognized the association between hypoxemia and right heart failure, and noted the beneﬁt of continuous oxygen delivery to patients with severe COPD (47). Since then much has been learned about the effects of oxygen and hypoxemia, and progress has been made in the design of mechanical oxygen-delivery devices. The Nocturnal Oxygen Therapy Trial (NOTT) and Medical Research Council (MRC) studies established that continuous home oxygen therapy improves survival in hypoxemic COPD, and that survival is related to the number of hours of supplemental oxygen use per day (48,49). Other beneﬁcial effects of long-term oxygen therapy (LTOT) include reductions in polycythemia, dyspnea, pulmonary artery pressure, and rapid eye movement–related hypoxemia during sleep. Oxygen also improves sleep and may reduce nocturnal arrhythmias. Oxygen can also improve neuropsychiatric testing and exercise tolerance (50–52). The latter effect has been attributed to central mechanisms causing reduced minute ventilation at the same workload. This delays the time until ventilatory limitation is reached. In addition, exercise capacity may be increased by improved arterial oxygenation, enabling greater oxygen delivery, reversal of hypoxemiainduced bronchoconstriction, and the effect of oxygen on respiratory muscle recruitment (53,54). It is recommended that measurement of PaO2, rather than pulse oximetry (SpO2), be the standard for initiating LTOT, particularly during rest (1). Oximetry may be used to adjust oxygen ﬂow settings over time or to assess requirements during exercise. If hypercapnia or acidosis is suspected, an arterial blood gas must be performed. Medicare guidelines cover domiciliary oxygen services for patients with a resting PaO2 of 55 mmHg or less, or saturation of 88% or less, or for patients with cor pulmonale,

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congestive heart failure, ischemic electrocardiographic changes, or polycythemia together with a PaO2 of 56–59 mmHg (or SpO2 of 89%). Portable systems are covered for ambulatory patients who meet these criteria with exercise. Oxygen therapy in normoxic patients has not been shown to improve survival. However, patients who desaturate only with exercise may have improved exercise capacity or may be able to participate more effectively in pulmonary rehabilitation. A Health Care Finance Administration (HCFA) certiﬁcate of medical necessity must be completed by a physician to prescribe LTOT. The HCFA form ensures that decisions concerning therapy remain under physician control. Some COPD patients may require home oxygen temporarily following an exacerbation. For patients ﬁrst starting home oxygen during an exacerbation, it is therefore recommended that the need for long-term oxygen be reassessed in 30–90 days when the patient is clinically stable. LTOT can be discontinued if the patient no longer meets blood gas criteria. Like any drug, oxygen has potential deleterious effects. The hazardous effects of oxygen therapy can be considered under three broad headings (54– 58). First, there are physical risks, such as ﬁre hazard or tank explosion, trauma from catheters or masks, and drying of mucous membranes owing to high ﬂow rates and inadequate humidiﬁcation. Second, cytotoxic effects are theoretically possible but have not clearly been demonstrated with the low ﬂow rates typically used for chronic home oxygen therapy in COPD. Third, there are functional effects related to increased carbon dioxide retention. Elevated PaCO2 in response to supplemental oxygen is a well-recognized complication occurring in a minority of patients. The mechanism has traditionally been ascribed to reductions in hypoxic ventilatory drive. However, in many patients, the increase in PaCO2 is out of proportion to the small decrease in minute ventilation. This indicates worsening of the pulmonary ventilation/perfusion distribution with an increase in the physiological dead space. A. Oxygen-Delivery Systems

Long-term home oxygen is available from three different delivery systems: oxygen concentrators, liquid systems, and compressed gas (1,59). Each has advantages and disadvantages, and the best system for a given patient depends on issues such as their level of activity, ﬂow requirements, convenience, and reliability of the local supplier. Compressed gas is stored in variably sized steel or aluminum cylinders weighing 200, 16, 9, or 4 lb and lasting 2.4 days, 5.2 h, 2.0 h, or 1.2 h, respectively, at 2 L/min ﬂow. The advantages of compressed gas oxygen are its low price, wide availability, and ability to be stored for long periods.

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Disadvantages are its weight (with the large cylinders), short oxygen supply time (with the smaller cylinders), potential hazard of creating a torpedolike missile if the regulator valve breaks from the compressed gas cylinder, and difﬁculty in transferring gas between tanks. Liquid oxygen is stored at cryogenic temperatures that reduce the volume to less than 1% of the room temperature equivalent. Portable containers weigh less than 10 lb and last up 8 h at 2 L/min ﬂow. A wheelmounted, 140-lb stationary unit is also available which can last up to 3.5 days at 2 L/min. Advantages of this system are its relative portability, longlasting portable supplies, and ease of reﬁlling portable units. Disadvantages are its higher cost and requirements for intermittent pressure venting. This results in oxygen loss even when the system is not being used. Oxygen concentrators are electrical devices that extract oxygen by passing air through a molecular sieve. The oxygen is delivered to the patient, and the nitrogen is returned to the atmosphere. The devices weigh about 35 lb and are not easily moved. They are typically used in a stationary capacity, while liquid or compressed gas is used to provide mobility. The major advantage of the oxygen concentrator is its relative cost effectiveness over the long term. The disadvantages are its need for a power source, regular servicing, and a backup system for portable oxygen or power outages, as well as the ability to deliver only up to 2–3 L/min of oxygen. B. Administration Devices

Oxygen is typically administered with continuous ﬂow by nasal cannula. However, because inspiration comprises only one-third to one-sixth of the respiratory cycle, the majority of continuously ﬂowing oxygen is wasted into the atmosphere (59,60). To improve efﬁciency and increase usable time for portable systems, several devices are available that limit delivery to early inspiration. These devices include reservoir cannulas, demand-type systems, and transtracheal catheters (59,60). Reservoir nasal cannulas and pendants store oxygen during expiration and deliver it as a bolus during early inspiration. Because respirable oxygen accumulates during expiration, ﬂows may be reduced proportionally. This has been shown to result in a two- to fourfold oxygen savings at rest and with exercise. Because the devices are somewhat bulky, cosmetic considerations have often limited patient acceptance. Demand valve systems have an electronic sensor that delivers oxygen only during early inspiration or provides an additional pulse early in inspiration as an adjuvant to the continuous ﬂow. This results in a two- to sevenfold oxygen savings. However, mouth breathing may interfere with efﬁcient sensing of inspiration.

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Transtracheal oxygen therapy employs a thin ﬂexible catheter placed into the lower trachea for delivery of continuous (or pulsed) oxygen via a percutaneous minitracheostomy (61–63) Because oxygen is delivered directly into the trachea, anatomical dead space is reduced and the upper trachea serves as a reservoir of undiluted oxygen. This provides a two- to threefold oxygen savings compared to use of a nasal cannula. In addition, the small tracheostomy catheter is easily hidden beneath the collar. However, the catheters require daily removal and cleaning, may cause intractable cough in some patients, and can become impacted with dried mucus in patients with excess sputum production.

VII.

Hospitalization and Discharge Criteria

Although acute exacerbations are difﬁcult to deﬁne and their pathogenesis is poorly understood, it is clear that acutely impaired lung function can lead to respiratory failure requiring intubation and mechanical ventilation. The purpose of inpatient treatment is to manage the patient’s decompensation and comorbid conditions to prevent further deterioration and readmission. Table 3 lists the components of the history, physical examination, and laboratory evaluation that should be obtained during a moderate-to-severe acute exacerbation to assist the formulation of therapy and the decision for hospital admission (1). Traditionally, the decision to admit derives from subjective interpretation of clinical features, such as the severity of dyspnea, the presence of respiratory failure, short-term response to emergency room therapy, and the presence of complicating features such as pneumonia, cor pulmonale, or comorbid conditions (1). However, this approach is quite imperfect. Up to 28% of patients with an acute exacerbation of COPD discharged from an emergency room have recurrent symptoms within 14 days. Additionally, 17% of patients discharged after emergency room management of COPD will relapse and require hospitalization. Few clinical studies have investigated objective clinical and laboratory features that identify COPD patients who require hospitalization. General consensus supports the need for hospitalization in patients with severe hypoxemia or acute hypercarbia. Less extreme arterial blood gas abnormalities, however, do not assist decision analysis. Other factors that identify ‘‘high-risk’’ patients include a previous emergency room (ER) visit within 7 days, need for many doses of nebulized bronchodilators, the use of home oxygen, previous relapse rate, administration of aminophylline, and the use of corticosteroids and antibiotics at the time of ER discharge.

114 Table 3

Celli Emergency Room Evaluation of Exacerbations of COPD

History

Baseline respiratory status, sputum volume, and characteristics, duration and progression of symptoms. Dyspnea severity, exercise limitations, sleep and eating difﬁculties, home care resources, home therapeutic regimen, symptoms of comorbid acute or chronic conditions.

Physical

Evidence of cor pulmonale, tachypnea, bronchospasm, pneumonia. Hemodynamic instability, altered mentation, respiratory muscle fatigue, excessive work of breathing. Acute comorbid conditions.

Laboratory

ABG, chest radiograph (PA, Lat), ECG, theophylline level (if outpatient theophylline used). Pulse oximetry monitoring, ECG monitoring. Post-ER treatment — spirometry (if FEV1 changes from baseline to be used as admission criteria), additional studies as clinically indicated.

FEV1, forced expiratory volume in 1 s; ECG, electrocardiogram; ER, emergency room; ABG, arterial blood gas; PA, posterior–anterior; Lat, lateral.

The indications for hospital admission are summarized in Table 4. Based on expert consensus but largely untested, they consider the severity of the respiratory dysfunction, progression of symptoms, response to outpatient therapies, comorbid conditions, anticipated surgical interventions that may affect pulmonary function, and the availability of adequate home care. Indications for intensive care unit (ICU) admission are shown in Table 5. Depending on the resources available within an institution, patients with severe exacerbations of COPD may be admitted to intermediate or special respiratory care units. Because of the complex management issues of patients with impending or frank respiratory failure, specialists with extensive experience in COPD should participate in the care of hospitalized patients with severe disease. These may include patients requiring invasive or noninvasive ventilation, those with refractory hypoxemia or new-onset hypercarbia, patients undergoing thoracoabdominal surgery, and those requiring specialized techniques to manage copious airway secretions. Suggested discharge criteria are given in Table 6, but they are supported by limited data.

Table 4

Indications for Hospitalization in COPD

1. Patient has an acute exacerbation of COPD characterized by increased dyspnea, cough, and sputum production with one or more of the following features: Symptoms that do not adequately respond to outpatient management. Inability of a previously mobile patient to walk between rooms. Inability to eat or sleep due to dyspnea. Family and/or physician assessment that the patient cannot manage at home, and supplementary home care resources are not immediately available. Presence of high-risk comorbid pulmonary (e.g., pneumonia) or nonpulmonary conditions. Prolonged, progressive symptoms before emergency room visit. Presence of worsening hypoxemia, new or worsening hypercarbia, or new or worsening cor pulmonale. 2. Acute respiratory failure characterized by severe respiratory distress, uncompensated hypercarbia, or severe hypoxemia. 3. Patient has new or worsening cor pulmonale that is unresponsive to outpatient management. 4. Invasive surgical or diagnostic procedures are planned requiring analgesics or sedatives that may worsen pulmonary function. 5. Comorbid conditions, such as severe steroid myopathy or acute vertebral compression fractures with severe pain, have worsened pulmonary function.

Table 5 Indications for ICU Admission of Patients with Acute Exacerbations of COPD 1. Severe dyspnea that does not respond to initial emergency room therapy. 2. Confusion, lethargy, or respiratory muscle fatigue characterized by paradoxical diaphragmatic motion. 3. Laboratory evidence demonstrating persistent/worsening hypoxemia despite supplemental oxygen or severe/worsening respiratory acidosis (e.g., pH < 7.30). 4. Assisted mechanical ventilation by means of an endotracheal tube or noninvasive technique is required.

Table 6 1. 2. 3. 4. 5. 6. 7.

Discharge Criteria After Treatment for Acute Exacerbations of COPD

Inhaled b-agonist therapy is required no more frequently than every 4 h. Previously ambulatory patient is able to walk across the room. Patient is able to sleep without frequent awakening by dyspnea. Any component of reactive airway disease is under stable control. Patient is stable off of parenteral therapy for 12–24 h. Patient or home caregiver is educated as to correct use of medications. Arrangements for follow-up care and home care (e.g., visiting nurse, home oxygen delivery, meal provisions) are completed.

Note: Patients who do not yet fulﬁll criteria for discharge to home may be successfully managed at nonacute care placement sites for observation during the ﬁnal resolution of symptoms.

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Celli VIII.

Noninvasive Ventilation

Noninvasive ventilation (NIV) refers to positive-pressure ventilation using a face or nasal mask as the interface between the patient and mechanical ventilator. Ventilation may be provided through either volume-cycled or pressure-cycled modes. Uncontrolled series (64,65) and controlled trials (66– 69) of NIV in acute-on-chronic respiratory failure have conﬁrmed its beneﬁt in COPD. NIV has been applied in settings ranging from the intensive care unit (68) to general respiratory wards (69). These trials evaluated various outcomes, including rate of intubation, length of ICU and hospital stay, dyspnea and mortality. Although not all studies showed decreases in mortality, noninvasive positive-pressure ventilation was consistently effective in improving arterial blood gases and in decreasing the need for intubation. The patients most likely to beneﬁt from NIV are those with dyspnea and respiratory acidosis who are cooperative and lack major other comorbidities (sepsis, severe pneumonia, cardiovascular collapse, arrhythmias). None of these trials evaluated respiratory muscle function per se, so it is impossible to determine if the beneﬁts were due to resting of the muscles or to the support provided to the whole system as the basic pathological process was treated. The use of NIV in a variety of diseases including COPD was the subject of a detailed recent review (70). The idea that the respiratory muscles of patients with severe COPD operate in a state of chronic fatigue has led several investigators to explore the effects of resting the muscles with long-term, intermittent or nocturnal NIV. Early studies reported improvement in symptoms, but were uncontrolled. (71) Furthermore, longer-term controlled trials using either positive- or negative-pressure ventilation showed no beneﬁt in most of the outcomes studied (72–74) One recent trial found nasal positivepressure mechanical ventilation improved quality of life and arterial blood gases in patients with stable COPD, although there was no change in pulmonary function. Unfortunately, respiratory muscle function was not evaluated (75). In the largest study to date, exercise tolerance, arterial blood gases, frequency of decompensation, and pulmonary functions were similar in treated and untreated patients (76). A recent study, which has only been reported as an abstract, found no difference in 1-year mortality, rate of exacerbation, and hospitalization between patients with chronic stable COPD randomized to noninvasive nasal ventilation or to usual care (77). In addition, no study showed improvement in respiratory muscle strength or endurance. Thus, there is little evidence that intermittent noninvasive ventilation for stable patients with COPD improves respiratory muscle function or any major clinical outcome. In contrast, when such a patient becomes unstable, a trial of NIV may help avert intubation.

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More studies are needed to deﬁne the population that best beneﬁts from these techniques.

IX.

Summary

Over the years, medical treatment for emphysema and COPD continues to be reﬁned. Smoking cessation efforts signiﬁcantly decreased smoking prevalence in the United States, although rates remain high in many other countries. The widespread use of LTOT for hypoxemic patients has increased their survival. During this time we have expanded our drug therapy armamentarium and have used it effectively to improve dyspnea and quality of life. Growing insight into the inﬂammatory basis of these diseases will provide new opportunities for intervention in the near future. Pulmonary rehabilitation is slowly being recognized for its symptomatic beneﬁts and incorporated into routine care. Noninvasive ventilation offers new options for the patient with acute on chronic failure. The revival of surgery for emphysema is yet another promising alternative for patients with severe COPD who are symptomatic despite maximal medical therapy. With all these new options, a nihilistic attitude toward the patient with COPD is simply archaic.

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6 Pulmonary Rehabilitation and Lung Volume Reduction Surgery

ANDREW L. RIES University of California, San Diego San Diego, California, U.S.A.

I. Introduction Rehabilitation programs for patients with chronic lung diseases are well established as a means of enhancing standard therapy in order to control and alleviate symptoms and optimize functional capacity (1–8). In recent years, the emergence of surgical options for patients with advanced chronic lung disease, such as lung volume reduction surgery (LVRS) and lung transplantation, has focused attention on the role of pulmonary rehabilitation in evaluating patients, preparing them for surgery, and maximizing their recovery after surgery (9–11). In fact, given the various treatment options available to such patients with symptoms of disabling dyspnea, pulmonary rehabilitation can help patients to understand better these options and to make more informed choices. The primary goal of any rehabilitation program is to restore the patient to the highest possible level of independent function. This goal is accomplished by helping patients and their friends and family learn more about their disease, treatment options, and coping strategies. Patients are encouraged to become actively involved in providing their own health care, to become more independent in daily activities and less dependent on health 123

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professionals and expensive medical resources. Rather than focusing solely on reversing the disease process, rehabilitation attempts to reduce disability from disease. Many rehabilitation strategies have been developed for patients with disabling chronic obstructive pulmonary disease (COPD). More recently, as mentioned, pulmonary rehabilitation has been incorporated into lung surgery programs for pulmonary patients, as well as applied successfully to patients with other chronic lung conditions such as interstitial diseases, cystic ﬁbrosis, bronchiectasis, and thoracic cage abnormalities (12,13). Pulmonary rehabilitation is appropriate for any patient with stable chronic lung disease who is disabled by respiratory symptoms. In 1974, the American College of Chest Physicians’ Committee on Pulmonary Rehabilitation adopted the following deﬁnition (1): Pulmonary rehabilitation may be deﬁned as an art of medical practice wherein an individually tailored, multidisciplinary program is formulated which through accurate diagnosis, therapy, emotional support, and education, stabilizes or reverses both the physio- and psychopathology of pulmonary diseases and attempts to return the patient to the highest possible functional capacity allowed by his pulmonary handicap and overall life situation.

This deﬁnition focuses on three important features of successful rehabilitation: 1.

2.

3.

Individual: Patients with disabling lung disease require individual assessment of needs, individual attention, and a program designed to meet realistic individual goals. Multidisciplinary: Pulmonary rehabilitation programs utilize expertise from various health care disciplines that is integrated into a comprehensive, cohesive program tailored to the needs of each patient. Attention to Physiopathology and Psychopathology: To be successful, pulmonary rehabilitation pays attention to psychological and emotional problems as well as helping to optimize medical therapy to improve lung function.

A newer deﬁnition proposed by an National Institute of Health Workshop on Pulmonary Rehabilitation Research emphasizes as key aspects the multidimensional services, interdisciplinary team, involvement of patients and families, and individual goals for independence and function in the community (14): Pulmonary rehabilitation is a multidimensional continuum of services directed to persons with pulmonary disease and their families, usually by an interdisciplinary team of specialists, with the goal of achieving and

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maintaining the individual’s maximum level of independence and functioning in the community.

The interdisciplinary team of health care professionals in pulmonary rehabilitation may include physicians, nurses, respiratory and physical therapists, psychologists, exercise specialists, and/or others with appropriate expertise. Speciﬁc team make-up depends upon the resources and expertise available, but usually includes at least one full-time staff member. Responsibilities of team members generally cross disciplines; the necessary skills have been delineated (15). Within this general framework, successful pulmonary rehabilitation programs have been established in both outpatient and inpatient settings and with different formats. The keys to success are a dedicated, enthusiastic staff familiar with the problems of pulmonary patients who can relate well to and motivate them. II.

Role of Pulmonary Rehabilitation in LVRS

Recently, there has been a resurgence of interest in LVRS for the treatment of patients with severe emphysematous obstructive lung disease (16–20). Pulmonary rehabilitation has been recommended as an important modality in the evaluation for and preparation of patients for this procedure as well as in the postoperative recovery phase (13,21). However, there are no published clinical trials that demonstrate the beneﬁts of pulmonary rehabilitation as part of LVRS programs. Not all centers have incorporated it routinely, and some have reported excellent surgical results without rehabilitation. In the National Emphysema Treatment Trial, designed to evaluate the role of LVRS in addition to maximal medical therapy in the management of patients with emphysema, all subjects are required to complete a comprehensive pulmonary rehabilitation program as part of their maximum medical care program prior to the decision to enroll in the randomized trial. Patients with disabling emphysema who are considering LVRS are excellent candidates for pulmonary rehabilitation. Many of these patients are severely dyspneic, depressed, dysfunctional, and desperate. Enrolling patients in rehabilitation prior to surgery has the advantage of optimizing their functional status, improving physical and psychological symptoms, helping them learn more about their disease and alternative treatment options, and improving their skills for coping and actively comanaging their disease. Patients can then make an informed decision about surgical treatment based upon their optimal level of baseline function. Some patients may improve sufﬁciently after rehabilitation that they choose to defer or

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delay the decision to pursue surgical options. Although there are currently no published data, our own experience suggests that approximately 10–15% of patients who initially desire LVRS will choose not to proceed with surgery after successfully completing a pulmonary rehabilitation program. Patients who do choose to undergo LVRS may be better prepared for surgery physically, mentally, and emotionally. Some patients, based on their response to rehabilitation and with the assistance and careful evaluation of the rehabilitation staff, may come to realize that they are poor candidates for surgery. After surgery, rehabilitation helps patients to adapt to new levels of function and to reassess symptoms and oxygenation needs. Such patients typically need several months to recover from the effects of surgery and to recondition themselves to optimal levels. Supervised rehabilitation sessions during this period help to guide the patient’s recovery, physical reconditioning, and readaptation to life. Moreover, the preoperative pulmonary rehabilitation program helps give patients the preparation, self-reliance, independence, and conﬁdence to continue their long-term daily care program.

III.

Patient Selection

Since programs can and should be tailored to the needs of individual patients, almost any patient with symptomatic chronic lung disease is a candidate for pulmonary rehabilitation. Appropriate patients are aware of disability from their disease and are motivated to be active participants in their own care in order to improve their health status. Patients with mild disease may not perceive their symptoms to be severe enough to warrant a comprehensive care program. On the other hand, patients with severe disease who are bed bound may be too limited to beneﬁt greatly, at least from an ambulatory, outpatient program. However, some centers have successfully incorporated rehabilitation strategies as adjuncts to weaning for patients with chronic mechanical ventilation and for inpatients recovering from episodes of respiratory failure. There are relatively few contraindications to pulmonary rehabilitation in patients with chronic lung diseases unless they have signiﬁcant comorbidities (e.g., cardiac disease, psychiatric disorders) that limit their ability to participate. The one group of pulmonary patients who may be excluded from exercise training in pulmonary rehabilitation are those with pulmonary hypertension due to primary pulmonary vascular diseases (e.g., primary pulmonary hypertension or chronic pulmonary thromboembolism). Although there are no data that speciﬁcally address the risk for such

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patients, many experienced practitioners advise such patients to avoid physical activity because of the potential risk of cardiac arrhythmias or sudden death. Criteria based on arbitrary lung function parameters or age alone should not be used in selecting patients for pulmonary rehabilitation (5,7). Pulmonary function is not a good predictor of symptoms, function, or improvement after rehabilitation in individuals (22). Older patients with chronic lung diseases may live many years with pulmonary disability. In general, selection should be based upon a person’s disability and functional limitation from respiratory symptoms, potential for improvement, and motivation to participate actively in a comprehensive self-care program. Other factors are also important in evaluating candidates. Pulmonary rehabilitation is not a primary mode of therapy. Patients should be evaluated and stabilized with standard therapy before beginning a program. They should not have other disabling or unstable conditions that might limit their ability to participate fully and to concentrate. The ideal patients for pulmonary rehabilitation, then, are those with functional limitation from moderate to severe lung disease who are stable while receiving standard therapy, not distracted or limited by other serious or unstable medical conditions, willing and able to learn about their disease, and motivated to devote the time and effort necessary to beneﬁt from a comprehensive care program.

IV.

Patient Evaluation

The initial step in pulmonary rehabilitation is screening patients to ensure appropriate selection and to set realistic individual and program goals. The evaluation process includes the following components: interview, medical evaluation, psychosocial assessment, diagnostic testing, and goal setting. A. Interview

The screening interview is an important ﬁrst step. It serves to introduce the patient to the program as well as to review the medical history and identify psychosocial problems and needs. Other people who are important for the patient’s social support should be included. Communication with the primary care physician is also important, establishing the vital link for the rehabilitation staff in clarifying questions prior to the program and facilitating recommendations during and after treatment. Care and attention in this initial evaluation helps in setting goals that are compatible with everyone’s expectations as well as appropriate to program objectives.

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Reviewing the medical history helps identify the patient’s lung disease and assess its severity. Other medical problems that might preclude or delay participation may be identiﬁed. Available laboratory data should be reviewed, including pulmonary function and exercise tests, arterial blood gas measurements during rest and exercise, chest radiographs, electrocardiogram, and pertinent blood tests. Program staff can then determine the need for additional information or action before the program.

C. Diagnostic Testing

Planning an appropriate rehabilitation program requires accurate current information. The complexity of testing procedures performed depends on the individual patient and program goals, as well as on the facilities and expertise available. Pulmonary function testing is used to characterize lung disease and quantify impairment. Spirometry and lung volume measurements are most useful; other tests such as diffusing capacity, airway resistance, and maximal respiratory pressures to assess muscle strength can be added as needed. Exercise testing helps to assess the patient’s exercise tolerance and to evaluate blood gas changes (hypoxemia or hypercapnia) with exercise. This may also uncover coexisting diseases (e.g., heart disease). The exercise test is also used to establish a safe and appropriate prescription for subsequent training. Maximal exercise of patients with chronic lung disease is limited largely by their breathing reserve. Simple pulmonary function tests such as spirometry can be used to estimate a patient’s capacity for sustained breathing (maximum ventilation) during exercise. The forced expiratory volume in 1 s (FEV1) is most useful in this regard (23). However, an individual patient’s maximum work capacity can only be estimated from lung function (24). Exercise tolerance depends also on the patient’s perception and tolerance of the subjective symptom of breathlessness. Therefore, it is important to have patients exercise to assess their physical function and symptom tolerance. Exercise evaluation for rehabilitation is most easily performed with the type of activity planned for training (e.g., treadmill for a walking training program); however, test results from one type of exercise (e.g., cycle) can be translated to related activities (e.g., walking) (25). Variables measured or monitored during testing should include workload, heart rate, electrocardiogram, arterial oxygenation, and symptoms (e.g., breathlessness). Other measures, such as ventilation or expired gas analysis to calculate

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oxygen uptake (VO2) and related variables, may be obtained depending on the interest and expertise of the program staff and laboratory (23,26,27). Measurement of arterial blood gases at rest and during exercise is important because of the frequent but unpredictable occurrence of exerciseinduced hypoxemia (28). Blood gas sampling during exercise makes testing more complex. Noninvasive estimation of arterial oxygen saturation by cutaneous oximetry is useful for continuous monitoring, but has limited accuracy (e.g., 95% conﬁdence limits for cutaneous oximetry are +4–5% saturation) (28). D. Psychosocial Assessment

Successful rehabilitation requires attention not only to physical problems but also to psychological, emotional, and social ones. Patients with chronic illnesses experience psychosocial difﬁculties as they struggle to deal with symptoms they may not fully understand (29–31). Neuropsychological impairment is common in patients with chronic lung disease and cannot be accounted for solely on the basis of age, depression, and physical disease (32). Commonly, such patients become depressed, frightened, anxious, and more dependent on others to care for their needs. Progressive dyspnea is a frightening symptom and may lead to a vicious ‘‘fear–dyspnea’’ cycle: With progressive disease, less exertion results in more dyspnea which produces more fear and anxiety which, in turn, leads to more dyspnea. Ultimately, the patient avoids any physical activity associated with both of these unpleasant symptoms. Jensen (33) reported that high stress and low social support were better predictors of subsequent hospitalizations than severity of illness in patients with obstructive lung disease. In order to address these problems, the initial evaluation should include an assessment of the patient’s psychological state and close attention to psychosocial clues during screening interviews (e.g., family and social support, living arrangement, activities of daily living, hobbies, employment potential). Important clues in initial interviews may be obtained by paying attention to nonverbal communication such as facial expression, physical appearance, handshake, and ‘‘body space’’ (34). Cognitive impairment that may limit the ability to participate fully can be identiﬁed. Others who are close to the patient may provide valuable insight and should be included in the screening process and program whenever possible. E.

Goals

After evaluating a patient’s medical, physiological, and psychosocial state, it is important to set speciﬁc goals that are compatible with each individual’s

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disease, needs, and expectations. Goals should be realistic given the objectives of the program. Signiﬁcant others should be included in this process so that everyone understands what can, and cannot, be expected.

V.

Program Content

Comprehensive pulmonary rehabilitation programs typically include several key components: education, respiratory and chest physiotherapy instruction, psychosocial support, and exercise training. Often, the various components are provided simultaneously; for example, during an exercise session, a patient may learn and practice breathing techniques for symptom control while being encouraged and supported by staff or other patients.

A. Education

Successful pulmonary rehabilitation depends on the understanding and active involvement of patients and those important for their social support. Education is an integral component; even patients with severe disease can gain a better understanding of their disease and learn speciﬁc means to deal with problems (35,36). Instruction can be provided individually or in small groups, but should be adapted to different learning abilities. Typical topics covered include how normal lungs work, what chronic lung disease is, medications, nutrition, travel, stress reduction and relaxation, when to call one’s doctor, and planning a daily schedule. Individual instruction and coaching may be provided on the use of respiratory therapy equipment and oxygen, breathing techniques, bronchial drainage, chest percussion, energysaving techniques, and self-care tips. The general philosophy is to encourage patients to assume responsibility for and become partners with their physician in providing their own care (37). For the patient considering LVRS, the program should include education about the potential risks and beneﬁts of lung surgery. If the patient chooses to undergo LVRS, speciﬁc instruction about the surgical procedure and perioperative period can help to alleviate anxiety and facilitate the patient’s postoperative recovery. Despite the importance of education, it is unlikely that knowledge along will lead to improved health status. It is more difﬁcult to change attitudes and behaviors. Patients require speciﬁc, individualized strategies with instruction and reinforcement. Thus, education is a necessary, but not sufﬁcient, component of pulmonary rehabilitation.

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B. Respiratory and Chest Physiotherapy Techniques

Patients with chronic lung disease use, abuse, and are confused about respiratory and chest physiotherapy techniques. In pulmonary rehabilitation, each patient’s needs for respiratory care techniques can be assessed and instruction in proper use provided. These may include: chest physiotherapy techniques to control secretions; breathing retraining techniques to relieve and control dyspnea and improve ventilatory function; and proper use of respiratory care equipment including nebulizers, metered-dose inhalers, and oxygen (4,38). Bronchial Hygiene

Patients with chronic lung diseases have abnormal lung clearance mechanisms which make them more susceptible to problems with retained secretions and infection. Therefore, rehabilitation programs teach chest physiotherapy techniques for secretion control, such as controlled coughing, postural drainage, and chest vibration and/or percussion (37–41). These are important for patients with excess mucus production during exacerbations and as routine preventive measures for patients with chronic sputum secretion. Breathing Retraining Techniques

Pulmonary rehabilitation typically includes instruction in breathing techniques such as diaphragmatic and pursed-lip breathing aimed at helping patients relieve and control breathlessness, improve ventilatory pattern (i.e., slow respiratory rate, increase tidal volume), prevent dynamic airway compression, improve respiratory synchrony of abdominal and thoracic musculature, and improve gas exchange (2,3,37,39,42–45). Review of studies evaluating these techniques indicates that improvement in symptoms (e.g., dyspnea) is more consistent than measurable changes in physiological parameters (44). Oxygen

For patients who require chronic oxygen therapy, available methods of oxygen delivery can be reviewed to help select the best system for their needs. Supplemental oxygen is beneﬁcial for patients with severe resting hypoxemia. Long-term, continuous oxygen therapy has been shown to improve survival and reduce morbidity in hypoxemic patients with COPD (2,46–50). Beneﬁts of supplemental oxygen for nonhypoxemic patients or for patients with hypoxemia only under certain conditions (e.g., exercise, sleep) are less clearly deﬁned (46,47,51).

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Although continuous oxygen therapy is feasible and safe, maintaining patients on oxygen presents several challenges (50). Handling equipment is particularly difﬁcult for physically disabled and frail individuals. Therefore, it is important to assess each person’s oxygen needs and provide instruction in appropriate techniques. Several new developments have improved the efﬁciency of gas delivery and patient compliance with continuous therapy (50,52). Liquid oxygen provides more gas with less weight than tanks of compressed gas, particularly in portable systems. Also, transtracheal delivery may increase efﬁciency, reducing ﬂow rates and prolonging duration of portable sources, as well as improving compliance and avoiding problems with nasal catheters (53). However, patients need careful instruction in caring for and maintaining the catheter. C. Exercise

Exercise is important in pulmonary rehabilitation (1,4,6,7,54,55). There is considerable evidence of favorable responses to exercise training in patients with chronic lung diseases (5,54–57). Beneﬁts are both physiological and psychological. Patients may increase their maximum capacity and/or endurance for physical activity even though lung function does not usually change. Patients may also beneﬁt from learning to perform physical tasks more efﬁciently. Exercise training provides an ideal opportunity for patients to learn their capacity for physical work and to use and practice methods for controlling dyspnea (e.g., breathing and relaxation techniques). Of all the components in a comprehensive pulmonary rehabilitation program, exercise is probably the most difﬁcult in terms of personnel, equipment, and expertise. Principles of exercise testing and training for patients with lung disease differ from those derived in normal subjects or other patient populations because of differences in the limitations to exercise and the problems encountered in training (56). Many approaches have been used in rehabilitation to train the person with chronic lung disease. To be successful, the program should be tailored to the individual’s physical abilities, interests, resources, and environment. For general application, techniques should be simple and inexpensive. As in normal subjects and other patients, beneﬁts are largely speciﬁc to the muscles and tasks involved in training. Patients tend to do best on activities and exercises for which they are trained. Walking programs are particularly useful. They have the added beneﬁt of encouraging patients to expand their social horizons. In inclement weather, many can walk indoors (e.g., shopping malls). Other types of exercise (e.g., cycling, swimming) are also effective. Patients should be encouraged to incorporate regular exercise into

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daily activities they enjoy (e.g., golf, gardening). Since many persons with chronic lung disease have limited exercise tolerance, emphasis during training should be placed on increasing endurance. Changes in endurance are often greater than changes in maximal exercise tolerance (22,58). This allows patients to become more functional within their physical limits. Increase in maximum exercise is also possible as patients gain experience and conﬁdence with their exercise program. Exercise Prescription

Selection of training targets based on percentages of maximum heart rate or VO2 is well established in normal subjects or other patient groups. In persons with chronic lung diseases, however, the best method of choosing an appropriate training prescription is less clearly deﬁned. Exercise tolerance in pulmonary patients is typically limited by maximum ventilation and breathlessness. Such patients frequently do not approach limits of cardiac or peripheral muscle performance. There has been much controversy about the appropriate intensity target for training patients with chronic lung disease. Use of a target heart rate has been advocated by some workers (59), although it is recognized that such targets may not be reliable for patients with more severe disease (56,60). Many patients with lung disease can be trained at high percentages of maximum that approach or even exceed the maximum level reached on the initial exercise test. In a study of 52 patients with moderate-to-severe COPD, Punzal et al. reported that patients were able to perform endurance exercise testing at an average workload of 95% of baseline maximum exercise tolerance (61). After 8 weeks, these patients were training at 86% of the baseline maximum workload. In fact, many patients with severe COPD were exercising at levels exceeding their baseline maximum. Carter et al. trained 59 patients with moderate-to-severe COPD at levels near their ventilatory limits (62). At baseline, after training, and 3 months later, they reported mean peak exercise ventilation of 94–100% of measured maximum voluntary ventilation. These ﬁndings suggest that even patients with advanced disease can be successfully trained at or near maximal levels. Therefore, some pulmonary rehabilitation programs deﬁne exercise targets and progression during training more by symptom tolerance than by heart rate, work level, or other physiological measurements (56,60). Ratings of perceived symptoms (e.g., breathlessness) help teach patients to exercise to ‘‘target’’ levels of breathing discomfort (63,64). A typical approach is to begin training at a level that the patient can sustain with reasonable comfort for several minutes. Increase in time or level is then made according to the symptom tolerance. Patients are encouraged to exercise daily and to increase

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endurance up to 15–30 min of continuous activity. This helps them to achieve a goal of improved tolerance for tasks of daily living that often require a period of sustained activity. Blood Gas Changes

A major problem in planning a safe exercise program for patients with lung disease is the potential worsening of hypoxemia with exercise. Patients who may not be hypoxemic at rest can develop changes in arterial oxygenation that cannot be predicted reliably from resting measurements of pulmonary function or gas exchange. Normal individuals do not become hypoxemic with exercise. In patients with obstructive lung disease, PaO2 changes unpredictably during exercise (28). In patients with mild COPD, PaO2 typically does not change or may even improve with exercise. However, in patients with moderate to severe COPD, PaO2 may increase, decrease, or remain unchanged. In contrast, in patients with interstitial lung disease, oxygenation commonly worsens with exercise (65). Therefore, it is important to evaluate both rest and exercise oxygenation. Such testing is also used to prescribe oxygen therapy at rest and with physical activity. With the availability of convenient, portable systems for ambulatory oxygen delivery, hypoxemia is not a contraindication to safe exercise training. Other Types of Exercise Upper Extremity Training

Exercise programs for pulmonary patients typically emphasize lower extremity training (e.g., walking). However, many persons with chronic lung disease report disabling dyspnea for daily activities involving the upper extremities (e.g., lifting, grooming) at work levels much lower than those used for the lower extremities (66,67). Upper extremity exercise is accompanied by a higher ventilatory demand than is lower extremity exercise for the same level of work. Because training is speciﬁc to the muscles and tasks used, upper extremity exercises may be important in helping pulmonary patients cope better with common daily activities (54). Ventilatory Muscle Training (VMT)

The potential role of ventilatory muscle fatigue as a cause of respiratory failure and ventilatory limitation in patients with chronic lung disease has stimulated attempts to train the ventilatory muscles (68–71). Techniques of isocapnic hyperventilation, inspiratory resistive, and inspiratory threshold loading have been shown to improve function of these muscles in both normal subjects and in patients (70). In normal individuals, respiratory

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muscles do not limit exercise tolerance; therefore, speciﬁc respiratory muscle training is unlikely to be of clinical beneﬁt. In patients with COPD, who have been studied most extensively, improvement in general exercise performance from ventilatory muscle training alone has not been demonstrated consistently (71). Thus, the role of such training incorporated routinely in pulmonary rehabilitation has not been clearly established (54). D. Psychosocial Support

An important component of pulmonary rehabilitation is psychosocial support to help patients combat symptoms reﬂecting progressive feelings of hopelessness and an inability to cope with a chronic, progressive disease (2,4,29,72). Depression is common (30,31). Patients may also have symptoms of anxiety (particularly fear of dyspnea), denial, anger, and isolation. They may become sedentary and dependent upon family members, friends, and medical services to provide for their needs, and they may become overly concerned with other physical problems and psychosomatic complaints. Sexual dysfunction and fear are common, often unspoken consequences of chronic lung disease (73–75). Patients may also demonstrate cognitive and neuropsychological dysfunction, possibly related to or exacerbated by the effects of hypoxemia on the brain. Psychosocial support is provided best by a warm and enthusiastic staff that can communicate effectively with patients and devote the time and effort necessary to understand and motivate them. Family members or close friends should be included in activities so that they can understand and cope better with the patient’s disease. Support groups are also effective. Patients with severe psychological disorders may beneﬁt from individual counseling and therapy. Psychotropic drugs should generally be reserved for patients with more severe psychological dysfunction.

VI.

Results of Pulmonary Rehabilitation

Several comprehensive reviews have been published that substantiate the practices and expected results of pulmonary rehabilitation (2,4–6,8,54,55). Recently, a panel convened jointly by the American College of Chest Physicians and the American Association of Cardiovascular and Pulmonary Rehabilitation published an evidence-based guideline document that reviewed the scientiﬁc basis for pulmonary rehabilitation in patients with COPD (54). The panel made recommendations accompanied by grades (A, B, or C) for the strength of evidence supporting each recommendation (Table 1). They graded as strongest (A) the evidence supporting the beneﬁts

Pulmonary rehabilitation Pulmonary rehabilitation Pulmonary rehabilitation hospitalization. Pulmonary rehabilitation may improve survival.

improves the symptom of dyspnea. improves health-related QOL. has reduced the number of hospitalizations and days of

Lower extremity training improves exercise tolerance and is recommended as part of pulmonary rehabilitation. Strength and endurance training improves arm function; arm exercises should be included in pulmonary rehabilitation. Scientiﬁc evidence does not support the routine use of VMT in pulmonary rehabilitation; it may be considered in selected patients with decreased respiratory muscle strength and breathlessness. Evidence does not support the beneﬁts of short-term psychosocial interventions as singletherapeutic modalities; longer term interventions may be beneﬁcial; expert opinion supports inclusion of educational and psychosocial intervention components in pulmonary rehabilitation.

C

A B B

C

B

B

A

Gradea

VMT, ventilary muscle training; QOL, quality of life. a Strength of scientiﬁc evidence to support recommendations: A, well-designed, well-conducted controlled trials with consistent, signiﬁcant results; B, observational studies or controlled trials with less consistent results; C, expert opinion, available scientiﬁc evidence not consistent or controlled trials lacking. Source: Modiﬁed from Ref. 54.

Survival

Psychosocial, behavioral, and educational components and outcomes Dyspnea Quality of life Health care utilization

Ventilatory muscle training

Upper extremity training

Lower extremity training

Recommendations

Summary of Recommendations and Evidence Grades for Pulmonary Rehabilitation Guidelines for Patients with COPD

Component/outcome

Table 1

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of lower extremity exercise training and improvement in dyspnea after pulmonary rehabilitation. Scientiﬁc evidence was graded as moderately strong (B) for the beneﬁts from upper extremity training, improvement in quality of life, and reduction in health care utilization, as well as the lack of support for routine use of ventilatory muscle training in pulmonary rehabilitation. The weakest evidence (C) was found supporting the beneﬁts of short-term psychosocial interventions and possible improvement in survival. A. Randomized Clinical Trials

Several published randomized clinical trials demonstrate important and signiﬁcant beneﬁts of pulmonary rehabilitation for patients with COPD, including improvements in exercise performance, symptoms, and key elements of quality of life (54). In addition, in a meta-analysis of 14 randomized trials, Lacasse et al. (8) reported statistically signiﬁcant improvements for the outcomes examined including dyspnea, health-related quality of life, and exercise tolerance. The magnitude of changes observed in symptoms were considered clinically signiﬁcant, whereas for exercise tolerance, the clinical signiﬁcance was less clear. In a randomized clinical trial of rehabilitation versus an education program in 119 patients with COPD, Ries et al. (58) reported a highly signiﬁcant improvement in exercise endurance after rehabilitation which was maintained up to 18 months later (Fig. 1). This was associated with a signiﬁcant decrease in perceived symptoms of breathlessness and muscle fatigue (Fig. 1) during exercise as well as with improvement in maximum exercise tolerance, reported breathlessness with daily activities, and selfefﬁcacy for walking. Two other recently published randomized trials reported shorter term beneﬁts favoring pulmonary rehabilitation over conventional treatment. Several smaller randomized, controlled trials have also documented the beneﬁts of rehabilitation. Goldstein et al. (76) reported signiﬁcant improvement in exercise tolerance, dyspnea, and quality of life after 6 months in 45 patients receiving 8 weeks of inpatient pulmonary rehabilitation followed by 16 weeks of supervised outpatient care as compared to 44 patients who received conventional care from their own physicians. Wijkstra et al. (77) reported signiﬁcant improvement in exercise tolerance and quality of life in 28 patients who were randomly allocated to a home pulmonary rehabilitation program for 12 weeks compared to 15 patients who received no rehabilitation. Strijbos et al. (78) reported results of 18 months of followup in 45 patients randomly allocated to an outpatient or home rehabilitation program or a control group. They found improvements in exercise tolerance

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Figure 1 Beneﬁts of comprehensive pulmonary rehabilitation (Rehab) versus an education program (Education) in 119 subjects with COPD. Signiﬁcant increases in treadmill exercise endurance and corresponding decreases in ratings of perceived breathlessness and muscle fatigue were observed in up to 12 months of follow-up. (From Ref. 58.)

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and dyspnea in both rehabilitation groups. However, the beneﬁts were maintained better in the home exercise group. B. Hospitalizations and Medical Resources

Pulmonary rehabilitation has been shown to produce cost-effective beneﬁts for patients with chronic lung disease. Several studies have analyzed hospital and medical resource utilization before and after rehabilitation. Given the high costs of acute care hospitalizations for these often sick patients, the potential saving from a reduction in hospital days alone is signiﬁcant (54). C. Quality of Life

After rehabilitation, improvements have been noted in several aspects of quality of life, including respiratory and psychological symptoms, exercise tolerance, and social activity. Several quality of life instruments that incorporate aspects of physical, emotional, and psychological function into one or a small number of measures have been used increasingly in the evaluation of patients with chronic lung diseases. A disease-speciﬁc measure that has been used frequently for patients with chronic lung diseases is the Chronic Respiratory Questionnaire (CRQ) developed by Guyatt et al. (79). In a long-term study of multidisciplinary pulmonary rehabilitation in 31 consecutive patients, Guyatt et al. (80) reported improvement in all four measured dimensions of quality of life (dyspnea, fatigue, emotional function, and mastery). Similar ﬁndings were reported by Reardon et al. (81) in 44 patients completing a 6-week pulmonary rehabilitation program. Also, two of the randomized clinical trials mentioned previously that used the CRQ to assess changes in quality of life found signiﬁcant improvements in quality of life in the rehabilitation groups compared with the control groups (76,77). Another disease-speciﬁc measure of health-related quality of life with established reliability and validity is the St. George’s Respiratory Questionnaire (SGRQ). This 76-item, self-administered questionnaire produces three component scores; namely, symptoms, activity, and impacts on daily life, as well as a total score. In one study that evaluated 133 patients with COPD over 1 year, Jones and colleagues found good correlations between changes in the SGRQ and changes in other measures of disease severity, including spirometry, 6-min walk distance, anxiety, depression, dyspnea, and the Sickness Impact Proﬁle (82). The Quality of Well-Being Scale (QWB) is a comprehensive measure of health-related quality of life shown to have validity as an outcome measure for evaluating interventions that affect general health status (83). In

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one randomized, controlled trial of behavioral intervention on exercise in patients with COPD, Atkins et al. (84) reported greater changes in the QWB in three experimental groups compared to an untreated control group. Using these data to estimate and compare the cost-effectiveness of intervention strategies in producing a well-year of life, the investigators concluded that this treatment resulted in signiﬁcant cost beneﬁts for these patients. However, in a subsequent randomized clinical trial of pulmonary rehabilitation in 119 patients with COPD, no signiﬁcant changes were in QWB observed in either treated or control groups despite marked changes in exercise tolerance and breathlessness after rehabilitation (58). Another general health measure, the Rand Health Survey instrument (equivalent to the SF-36) developed as part of the Medical Outcomes Study, includes 36 items that can be combined into eight dimensions of health status (85). In one preliminary report in 21 patients after pulmonary rehabilitation, Make et al. (86) reported signiﬁcant changes on seven of the nine subscales. D. Exercise

Exercise is important and well established in pulmonary rehabilitation, producing both physiological and psychological beneﬁts (5,54–57). Casaburi reviewed 37 published studies of exercise training in more than 900 patients with COPD (55). Nearly unanimously, these studies demonstrated improvement in exercise endurance and/or maximum exercise tolerance. The mechanisms of improvement after exercise training in patients with lung disease are different than those observed in normal individuals or other patient populations and can include factors such as improved mechanical efﬁciency, improved ventilatory efﬁciency (e.g., increased tidal volume reduced respiratory rate), and/or improved symptom tolerance (e.g., ‘‘desensitization’’ to dyspnea). The contribution of the peripheral muscles to exercise limitation in patients with COPD has been highlighted recently (87). Several investigators have demonstrated skeletal muscles dysfunction in such patients. Endurance and strength training can improve function of these muscles, which may possibly translate to improvement in overall exercise performance (88). There have been several controlled trials of exercise training supporting the beneﬁcial effects of exercise in patients with chronic lung disease, including many randomized clinical trials (54). In the largest clinical trial of rehabilitation versus an education control program in 119 patients with COPD, Ries and coworkers reported highly signiﬁcant improvements in exercise endurance and maximum exercise tolerance after rehabilitation that were maintained up to 18 months (58).

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Pulmonary Function and Symptoms

Pulmonary rehabilitation does not result in any consistent changes in lung function in patients with chronic lung disease if patients are on good medical therapy prior to the program. Nevertheless, many patients report improvement in respiratory symptoms, particularly the troubling sensation of breathlessness. Improved dyspnea has been reported consistently in experimental studies (5,54). Improvement in psychological symptoms has also been demonstrated after rehabilitation (5,54). F.

Education

Pulmonary rehabilitation emphasizes educating patients to be actively involved in their own care, improve their understanding of the disease, and learn practical ways of coping with disabling symptoms. Studies that have examined the effects of education have shown that even patients with severe disease can learn to understand their disease better (5,36). However, education alone does not typically lead to improved health status. Patients also require speciﬁc, individual strategies for changing behavior along with encouragement, practice, and positive feedback. G. Survival

Studies of survival of patients with chronic lung disease after pulmonary rehabilitation have shown variable results. In the randomized trial with 6 years of follow-up evaluation, there was no statistically signiﬁcant difference in survival between the rehabilitation and education groups, although there was a nonsigniﬁcant trend of improved survival in the rehabilitation subjects (67 vs 56% survival) (58). More studies are needed to address the question of survival changes after pulmonary rehabilitation. The current published literature does not allow ﬁrm conclusions to be drawn (54). H. Longer Term Effects of Pulmonary Rehabilitation

Most published studies of pulmonary rehabilitation demonstrate beneﬁts that last at least 12–18 months after completion of short-term programs. Studies of longer term rehabilitation interventions in patients with COPD have shown promising but mixed results. Guell et al. (89) randomized 60 patients to either 12 months of intervention (6 months of daily rehabilitation, 6 months of weekly maintenance) or standard care, and followed them for 2 years. The experimental group showed improvement in exercise tolerance, dyspnea, and quality of life. Beneﬁts were present, but diminished, over the second year. Troosters et al. (90) randomized 100 patients to either 6 months of exercise training or usual care, and

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followed them for 18 months. In the 70 patients who completed the intervention and 6-month follow-up, exercise tolerance and quality of life improved in the training group at 6 months and persisted over the next year. Engstrom et al. (91) randomized 50 patients to a 12-month intervention (with a tapering exercise schedule) or usual care. Exercise tolerance improved signiﬁcantly more in subjects randomized to exercise, but they had no signiﬁcant improvement in quality of life. Wijkstra et al. (92) randomized 36 patients into three groups. Two experimental groups received 18 months of home rehabilitation with 3 months of twice weekly sessions followed by either weekly or monthly maintenance. The control group received no rehabilitation. All subjects were followed for 18 months. They reported improved quality of life in the experimental groups compared to controls, although the beneﬁts diminished over the 18-month study period. There were no signiﬁcant group differences in measured exercise tolerance. There is one published report of a small randomized trial of the effects of repeating a pulmonary rehabilitation program 1 or 2 years after an initial short-term program. Foglio et al. (93) randomized 61 patients to receive a repeat program after 1 year; all patients received a repeat program after 2 years. The results demonstrated beneﬁts in exercise and quality of life approximating gains from the initial program. Among 36 patients who completed the 2-year study, there were no statistically signiﬁcant differences in exercise or quality of life between groups. There were, however, signiﬁcantly fewer exacerbations in those who had been retreated after 1 year. Trends in the data suggested possible group differences. However, conclusions were limited by the small sample size and by the large numbers of patients who withdrew.

VII.

Summary

Pulmonary rehabilitation has been well established as a means of improving functional status and reducing the disability and economic burden of the growing number of patients with chronic lung diseases in our population. Adopting a broad rehabilitation medicine perspective, such programs provide interdisciplinary expertise directed toward the needs of individual, disabled pulmonary patients. Much of the experience in pulmonary rehabilitation has been with patients with COPD; however, it is clear that similar beneﬁts can result for persons with other disabling pulmonary conditions. Pulmonary rehabilitation may play an important role in the preoperative evaluation, selection,

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and preparation as well as postoperative recovery of patients undergoing LVRS and other surgical procedures.

References 1. 2.

3.

4. 5.

6. 7.

8.

9. 10.

11.

12. 13. 14.

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15. Kirilloff LH, Carpenter V, Kerby GR, Kigin C, Weimer MP. Skills of the health team involved in out-of-hospital care for patients with COPD. Am Rev Respir Dis 1986; 133:948–949. 16. Weinmann GC, Hyatt R. Evaluation and research in lung volume reduction surgery. Am J Respir Crit Care Med 1996; 154:1913–1918. 17. Sciurba FC. Early and long-term functional outcomes following lung volume reduction surgery. Clin Chest Med 1997; 18:259–276. 18. Benditt JO, Albert RK. Lung reduction surgery: great expectations and a cautionary note. Chest 1995; 107:297–298. 19. Fein AM. Lung volume reduction surgery: answering the crucial questions. Chest 1998; 113:277S–282S. 20. Cooper JD, Trulock EP, Triantaﬁllou AN, Patterson GA, Pohl MS, Deloney PA, Sndaresan RS, Roper CL. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995; 109:106–119. 21. Moser KM, Kerr KM, Colt HG, Ries AL. Lung reduction surgery: what role in emphysema? J Respir Dis 1996; 17:351–358. 22. Niederman MS, Clemente PH, Fein AM, Feinsilver SH, Robinson DA, Ilowite JS, Bernstein MG. Beneﬁts of a multi-disciplinary pulmonary rehabilitation program: improvements are independent of lung function. Chest 1991; 99:798– 804. 23. Ries AL. The role of exercise testing in pulmonary diagnosis. Clin Chest Med 1987; 8:81–89. 24. Carlson D, Ries A, Kaplan R. Prediction of maximum exercise tolerance in patients with chronic obstructive pulmonary disease. Chest 1991; 100:307–311. 25. Ries AL, Moser KM. Predicting treadmill/walking speed from cycle ergometry exercise in chronic obstructive pulmonary disease. Am Rev Respir Dis 1982; 126:924–927. 26. Jones NL. Clinical Exercise Testing. 4th ed. Philadelphia: Saunders, 1997. 27. Wasserman K, Hansen JE, Sue DY, Casaburi R, Whipp BJ. Principles of Exercise Testing and Interpretation. 3rd ed. In: Harris JM, Stead LS, DiRienzi D, eds. Philadelphia: Lippincott, Williams and Wilkins, 1999. 28. Ries AL, Farrow JT, Clausen JL. Pulmonary function tests cannot predict exercise-induced hypoxemia in chronic obstructive pulmonary disease. Chest 1988; 93:454–459. 29. Dudley DL, Glaser EM, Jorgenson BN, Logan DL. Psychosocial concomitants to rehabilitation in chronic obstructive pulmonary disease: Part 1. Psychosocial and psychological considerations; Part 2. Psychosocial treatment; Part 3. Dealing with psychiatric disease (as distinguished from psychosocial or psychophysiologic problems). Chest 1980; 77:413–420, 544–551, 677–684. 30. McSweeny AJ, Grant I, Heaton RK, Adams KM, Timms RM. Life quality of patients with chronic obstructive pulmonary disease. Arch Intern Med 1982; 142:473–478. 31. Sandhu HS. Psychosocial issues in chronic obstructive pulmonary disease. Clin Chest Med 1986; 7:629–642.

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32. Prigatano GP, Grant I. Neuropsychological correlates of COPD. In: Chronic Obstructive Pulmonary Disease: A Behavioral Perspective. McSweeny AJ, Grant I, eds. New York: Marcel Dekker, 1988:39–57. 33. Jensen PS. Risk, protective factors, and supportive interventions in chronic airway obstruction. Arch Gen Psychiatry 1983; 40:1203–1207. 34. Dudley DL, Sitzman J. Psychobiological evaluation and treatment of COPD. In: Chronic Obstructive Pulmonary Disease: A Behavioral Perspective. McSweeny AJ, Grant I, eds. New York: Marcel Dekker, 1988:183–235. 35. Gilmartin ME. Patient and family education. Clin Chest Med 1986; 7:619–627. 36. Neish CM, Hop JW. The role of education in pulmonary rehabilitation. J Cardiopulm Rehab 1988; 11:439–441. 37. Ries AL, Bullock PJ, Larson CA, Limberg TM, Myers R, Pﬁster T, SassiDambron D, Sheldon JB. Shortness of Breath: A Guide to Better Living and Breathing. 6th ed. St. Louis: Mosby, 2001. 38. Kirilloff LH, Owens GR, Rogers RM, Mazzocco MC. Does chest physical therapy work? Chest 1985; 88:436–444. 39. Rochester DF, Goldberg SK. Techniques of respiratory physical therapy. Am Rev Respir Dis 1980; 122(Suppl):133–146. 40. Sutton PP, Parker RA, Webber BA, Newman SP, Garland N, Lopez-Vidriero MT, Pavia D, Clarke SW. Assessment of the forced expiration technique, postural drainage and directed coughing in chest physiotherapy. Eur J Respir Dis 1983; 64:62–68. 41. Sutton PP, Pavia D, Bateman JRM, Clarke SW. Chest physiotherapy: a review. Eur J Respir Dis 1982; 63:188–201. 42. Barach AL. Breathing exercises in pulmonary emphysema and allied chronic respiratory disease. Arch Physical Med Rehab 1955; 36:379–390. 43. Campbell EJM, Friend J. Action of breathing exercises in pulmonary emphysema. Lancet 1955; 268:325–329. 44. Faling LJ. Pulmonary rehabilitation—physical modalities. Clin Chest Med 1986; 7:599–618. 45. Miller WF. Physical therapeutic measures in the treatment of chronic bronchopulmonary disorders: methods for breathing training. Am J Med 1958; 24:929–940. 46. Anthonisen NR. Long-term oxygen therapy. Ann Intern Med 1983; 99:519– 527. 47. Fulmer JD, Snider GL. ACCP-NHLBI national conference on oxygen therapy. Chest 1984; 86:234–247. 48. Medical Research Council Working Party. Long-term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; 1:681–686. 49. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 1980; 93:391–398. 50. Tiep BL. Long-term home oxygen therapy. Chest 1990; 11:505–521.

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51. Dean NC, Brown JK, Himelman RB. Oxygen may improve dyspnea and endurance in patients with chronic obstructive pulmonary disease and only mild hypoxemia. Am Rev Respir Dis 1992; 146:941–945. 52. Tiep BL, Lewis MI. Oxygen conservation and oxygen-conserving devices in chronic lung disease: a review. Chest 1987; 92:263–272. 53. Christopher KL, Spofford BT, Petrun MD, McCarty DC, Goodman JR, Petty TL. A program for transtracheal oxygen delivery: assessment of safety and efﬁcacy. Ann Intern Med 1987; 107:802–808. 54. ACCP/AACVPR Pulmonary Rehabilitation Guidelines Panel. Pulmonary rehabilitation: joint ACCP/AACVPR evidence based guidelines. Chest 1997; 112:1363–1396 and J Cardiopulm Rehabil 1997; 17:371–405. 55. Casaburi R. Exercise training in chronic obstructive lung disease. In: Principles and Practice of Pulmonary Rehabilitation. Casaburi R, Petty TL, eds. Philadelphia: Saunders, 1993:204–224. 56. Belman MJ. Exercise in chronic obstructive pulmonary disease. Clin Chest Med 1986; 7:585–597. 57. Hughes RL, Davison R. Limitations of exercise reconditioning in COLD. Chest 1983; 83:241–249. 58. Ries AL, Kaplan RM, Limberg TM, Prewitt LM. Effects of pulmonary rehabilitation on physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease. Ann Intern Med 1995; 122:823–832. 59. Hodgkin JE. Pulmonary rehabilitation: structure, components, and beneﬁts. J Cardiopulm Rehab 1988; 11:423–434. 60. Ries AL. The importance of exercise in pulmonary rehabilitation. Clin Chest Med 1994; 15:327–337. 61. Punzal PA, Ries AL, Kaplan RM, Prewitt LM. Maximum intensity exercise training in patients with chronic obstructive pulmonary disease. Chest 1991; 100:618–623. 62. Carter R, Nicotra B, Clark L, Zinkgraf S, Williams J, Peavler M, Fields S, Berry J. Exercise conditioning in the rehabilitation of patients with chronic obstructive pulmonary disease. Arch Phys Med Rehab 1988; 69:118–122. 63. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14:377–381. 64. Mahler DA. The measurement of dyspnea during exercise in patients with lung disease. Chest 1992; 101:242S–247S. 65. Keogh BA, Lakatos E, Price D, Crystal RG. Importance of the lower respiratory tract in oxygen transfer: exercise testing in patients with interstitial and destructive lung disease. Am Rev Respir Dis 1984; 129:S76–S80. 66. Celli BR, Rassulo J, Make BJ. Dyssynchronous breathing during arm but not leg exercise in patients with chronic airﬂow obstruction. N Engl J Med 1986; 314:1485–1490. 67. Couser JL, Martinez FJ, Celli BR. Pulmonary rehabilitation that includes arm exercise reduces metabolic and ventilatory requirements for simple arm elevation. Chest 1993; 103:37–41. 68. Celli BR. Respiratory muscle function. Clin Chest Med 1986; 7:567–584.

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69. Grassino A. Inspiratory muscle training in COPD patients. Eur Respir J 1989; 2(Suppl 7):581S–586S. 70. Belman MJ. Ventilatory muscle training and unloading. In: Principles and Practice of Pulmonary Rehabilitation. Casaburi R, Petty TL, eds. Philadelphia: Saunders, 1993:225–240. 71. Smith K, Cook D, Guyatt GH, Madhavan J, Oxman AD. Respiratory muscle training in chronic airﬂow limitation: a meta-analysis. Am Rev Respir Dis 1992; 145:533–539. 72. Light RW, Merrill EJ, Despars JA, Gordon GH, Mutalipassi LR. Prevalence of depression and anxiety in patients with COPD: relationship to functional capacity. Chest 1985; 87:35–38. 73. Curgian LM, Gronkiewicz CA. Enhancing sexual performance in COPD. Nurse Practitioner 1988; 13:34–38. 74. Fletcher EC, Martin RJ. Sexual dysfunction and erectile impotence in chronic obstructive pulmonary disease. Chest 1982; 81:413–421. 75. Timms RM. Sexual dysfunction and chronic obstructive pulmonary disease. Chest 1982; 81:398–400. 76. Goldstein RS, Gort EH, Avendano MA, Guyatt GH. Randomised controlled trial of respiratory rehabilitation. Lancet 1994; 344:1394–1397. 77. Wijkstra PJ, van Altena R, Kraan J, Otten V, Postma DS, Koeter GH. Quality of Life in patients with chronic obstructive pulmonary disease improves after rehabilitation at home. Eur Respir J 1994; 7:269–273. 78. Strijbos JH, Postma DS, van Altena R, Gimeno F, Koeter GH. A comparison between an outpatient hospital-based pulmonary rehabilitation program and a home-care pulmonary rehabilitation program in patients with COPD: a followup of 18 months. Chest 1996; 109:366–372. 79. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LW. A measure of quality of life for clinical trials in chronic lung disease. Thorax 1987; 42:773– 778. 80. Guyatt GH, Berman LB, Townsend M. Long-term outcome after respiratory rehabilitation. Can Med Assoc J 1987; 137:1089–1095. 81. Reardon J, Patel K, ZuWallack RL. Improvement in quality of life is unrelated to improvement in exercise endurance after outpatient pulmonary rehabilitation. J Cardiopulm Rehab 1993; 13:51–54. 82. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airﬂow limitation. Am Rev Respir Dis 1992; 145:1321–1327. 83. Kaplan RM, Anderson JP. The quality of well-being scale: rationale for a single quality of life index. In: Quality of Life: Assessment and Application. Walker SR, Rosser RM, eds. London: MTP Press 1988:51–77. 84. Atkins CJ, Kaplan RM, Timms RM, Reinsch S, Lofback K. Behavioral exercise programs in the management of chronic obstructive pulmonary disease. J Consult Clin Psychol 1984; 52:591–603. 85. Ware JE, Sherbourne CD. The MOS 36-item short form health survey (SF-36): I. Conceptual framework and item selection. Med Care 1992; 30:473–483.

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86. Make BJ, Glenn K, Ikle D, et al. Pulmonary rehabilitation improves the quality of life of patients with chronic obstructive pulmonary disease (COPD). Am Rev Respir Dis 1992; 145:A767–A767. 87. Casabur R. Anabolic therapies in chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 1998; 53:454–459. 88. Gosselink R, Decramer M. Peripheral skeletal muscles and exercise performance in patients with chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 1998; 53:419–423. 89. Guell R, Casan P, Belda J, et al. Long-term effects of outpatient rehabilitation of COPD: a randomized trial. Chest 2000; 117:976–983. 90. Troosters T, Gosselink R, Decramer M. Short- and long-term effects of outpatient rehabilitation in patients with chronic obstructive pulmonary disease: a randomized trial. Am J Med 2000; 109:207–212. 91. Engstrom CP, Persson LO, Larsson S, et al. Long-term effects of a pulmonary rehabilitation programme in outpatients with chronic obstructive pulmonary disease: a randomized controlled study. Scand J Rehab Med 1999; 31:207–213. 92. Wijkstra PJ, TenVergert EM, van Altena R, et al. Long term beneﬁts of rehabilitation at home on quality of life and exercise tolerance in patients with chronic obstructive pulmonary disease. Thorax 1995; 50:824–828. 93. Foglio K, Bianchi L, Ambrosino N. Is it really useful to repeat outpatient pulmonary rehabilitation programs in patients with chronic airway obstruction? A 2-year controlled study. Chest 2001; 119:1696–1704.

7 Evaluation of Patients Considering Lung Volume Reduction Surgery

JOHN J. REILLY, Jr. Harvard Medical School and Brigham & Women’s Hospital Boston, Massachusetts, U.S.A.

I. Introduction Most pulmonologists, internists, and thoracic surgeons have shared the challenges of caring for patients with advanced emphysema. Although oxygen therapy has had a substantial impact on the natural history of the disease (reviewed in Chap. 5), the clinician caring for patients with emphysema often feels that they are bailing a continuously leaking boat, just hoping to stem the tide of disease progression. The reintroduction of lung volume reduction surgery (LVRS), therefore, changes the perspectives of both physician and patient by introducing the hope of a substantial improvement beyond that expected from medical therapy. It also puts the patient and physician in the seemingly paradoxical position of contemplating elective major chest surgery in a patient whose lung disease is conventionally felt to be a contraindication to major surgical procedures of all types. Patients considering LVRS share the common feature of severe obstructive lung disease. By usual criteria, they are at high risk for perioperative complications after any type of procedure involving general 149

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anesthesia and/or thoracic or abdominal surgery. In the case of LVRS, it can reasonably be expected that the surgery, with its resection of pulmonary parenchyma from both lungs and subsequent placement of chest tubes to evacuate the pleural spaces, might transiently worsen pulmonary function. Once the patient has recovered from surgery, the (hopefully) beneﬁcial effects of volume reduction may manifest themselves. Surgeons and physicians evaluating patients for LVRS have a special responsibility to try to identify patients with sufﬁcient physical and psychological resilience to withstand the procedure, as well as the appropriate anatomy and physiology to make it likely that they will beneﬁt. As with all surgical procedures, there are risks associated with general anesthesia and the usual perioperative issues. In addition, there are risks speciﬁc to LVRS. This chapter will discuss both categories and present both the available data about risk and the current clinical practice when no data are available. As is true for many areas of medicine, current practice relating to LVRS is an amalgam of practices that come from experience with other procedures, recommendations based upon ﬁrst principles, personal prior experience, and the retrospective analysis of others’ experience with LVRS. There is a paucity of prospective trials examining many of the important issues related to LVRS. In this respect, it mirrors the history of lung transplantation. The early clinical experience in both areas was dominated by the goal of simply demonstrating the technical feasibility of the procedure. This is followed by a period during which indications, patient selection, and technical approach are more thoroughly explored. The current practice of LVRS is being driven by a desperate patient population and an often enthusiastic medical community that can draw upon extensive experience in performing thoracic surgery in ‘‘high-risk’’ patients and in lung transplantation. This can create temptations and pressures which bias one toward surgery. The challenge of patient selection is to identify patients who are physiologically likely to beneﬁt and who are sufﬁciently disabled to warrant the surgery, but who are not yet too ill to survive it. At the same time that a physician is deciding if a patient is appropriate for LVRS, the patient should be deciding if LVRS is appropriate for them. Their decision will be based on their perceived disability, their understanding of risks and beneﬁts, and their comfort level in the face of uncertainty. This requires patient education and time for questions and reﬂection. Often several meetings and discussions with family members are needed. Although a medical contraindication may disqualify a patient from further consideration instantly, the decision to proceed can rarely be made quickly. Although most patients present themselves with initial enthusiasm for surgery, sometimes even seemingly ideal candidates will elect not to

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proceed. Conversely, a patient’s willingness to proceed without any hesitation may indicate some misperceptions. II.

Preoperative Risk Assessment: General Considerations

Traditionally, resection of lung parenchyma results in a decrement in pulmonary function. A number of papers demonstrate that the amount of parenchymal resection and, more importantly, the predicted amount of pulmonary function with which the patient is left after resection, is an important predictor of postoperative morbidity and mortality (1–5). There have been attempts to reﬁne this assessment of risk by adding exercise testing (6–11). The applicability of this conventional approach to preoperative assessment is problematic, since LVRS is intended to improve pulmonary function. However, our ability accurately to predict postoperative improvement is limited. As a result, various investigators have examined a number of parameters in hopes of identifying factors that indicate patients at high risk for postoperative complications and also those likely to experience substantial beneﬁt from the procedure. These are shown in Table 1. The typical approach to evaluating a patient includes a complete history and physical examination, thoracic imaging studies, pulmonary function testing, cardiac testing, and some assessment of functional capacity. Although outcomes from LVRS are discussed in detail in Chapter 15, consideration of published results is closely linked to patient selection decisions, and is included in the discussion which follows.

Table 1

Factors Potentially Affecting Risk or Beneﬁt from LVRS

Increase risk Comorbid diseases Pulmonary hypertension Extreme age Pleural scarring Deconditioning Extreme severity of emphysema Hypercarbia Hypoxemia Low functional status Corticosteroid use

Increase beneﬁt Apical distribution of emphysema Choice of procedure Absence of airway disease

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Figure 1 Schema for the evaluation of the LVRS candidate. Some exclusionary characteristics may be reversible, such as pulmonary hypertension that improves with oxygen therapy. Others may change with disease progression, such as patients excluded because of too low residual volume or total lung capacity. Patients with these ﬁndings may undergo periodic reevaluation, and may become candidates at a later date. Other characteristics, such as severe diffuse emphysema not amenable to resection, cannot be corrected.

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A. History and Physical Examination

As is true in most aspects of medicine, this is a crucial step in the evaluation of potential candidates for LVRS. This is an opportunity for the physician to develop a sense of how limited the patient is by lung disease: the clinical manifestations of lung disease such as wheezing, cough or phlegm, the presence of comorbid conditions that may contribute to disability or increase the risk of postoperative complications; the patient’s emotional state, expectations, and support system; the presence of contraindications to surgery or areas that require further evaluation; and the appropriateness of the patient’s current medical regimen. Importantly, this is the ﬁrst opportunity for a face-to-face discussion of the risks and beneﬁts of LVRS, and for the physician to determine whether the patient has realistic expectations for the procedure. There are several aspects of the history and physical examination that deserve particular mention. Cigarette Smoking

It is well recognized that cigarette smoking is the major risk factor for the development of emphysema. It has also been clearly demonstrated that smoking cessation has a signiﬁcant positive impact on the rate of decline in FEV1 (12). Virtually every program that has published data concerning LVRS excludes patients who continue to smoke cigarettes (13–21). Corticosteroid Usage

Corticosteroids have well-recognized effects on immunity, body composition, and wound healing. They are commonly used as anti-inﬂammatory agents in patients with chronic obstructive lung disease to reduce airway inﬂammation and improve airﬂow obstruction, cough, and mucus production (22). Their use in patients considering LVRS raises concerns about a potential increase in the risk of postoperative complications. In particular, there is concern that the use of systemic corticosteroids will increase the duration of postoperative air leaks and, consequently, chest tube placement. A second area of concern about the requirement for continuous corticosteroid therapy centers on the etiology of airﬂow obstruction. In patients with airﬂow obstruction primarily due to emphysema, airway inﬂammation does not play a major role in symptoms or the pathophysiology of the obstruction. The requirement for signiﬁcant doses of corticosteroids may be a marker for a coexistent inﬂammatory disorder of the airways that is contributing to airﬂow obstruction and dyspnea. Our current concepts about LVRS focus on its effects on the physiology of the emphysematous lung (see Chap. 3). It is not expected that patients who

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suffer from disorders of airway inﬂammation will beneﬁt from LVRS. The requirement for ongoing high-dose systemic corticosteroid treatment should therefore prompt careful consideration of the degree to which underlying emphysema contributes to the patient’s dyspnea and disability. Many programs require that patients be on the equivalent of 20 mg/ day or less of prednisone (17,23). Yusen and colleagues require that patients be on less than 10 mg/day of prednisone (24). There is a limited experience in performing surgery on patients on higher doses of steroids. McKenna reported results of LVRS in four patients on 15–18 mg/day of prednisone, eight on 20 mg/day, and one patient on 40 mg/day and reported a perioperative course and beneﬁt comparable to patients not on corticosteroids (20). Argenziano reported that 26 patients on >10 mg/day prednisone had perioperative course and beneﬁt comparable to patients not taking corticosteroids (25).

Prior Thoracic Surgery

Prolonged air leak is among the most common complication after LVRS. It results from trauma to an abnormal lung parenchyma that is less resistant to mechanical stress than normal lung tissue. The presence of signiﬁcant pleural adhesions increases the likelihood that pleural tears will occur during mobilization of lung for LVRS, leading to air leaks. For this reason, extensive pleural disease or prior major thoracic surgery is considered to be a contraindication to LVRS (14,20,26–28)

Nutritional Status

The classic ‘‘pink puffer’’ patient with emphysema is described as being quite thin. Weight loss and malnutrition have been well described in patients with chronic obstructive lung disease. Mazolewski and colleagues performed a prospective study in 51 patients undergoing LVRS (29). Using the body mass index (BMI) as a measure of nutritional status, they found that 53% (27/51) had a low BMI (20.9 + 2.05). Preoperative pulmonary function testing, age, sex distribution, and arterial oxygen levels were not different between the normal and low BMI groups. Corticosteroid usage was higher in the normal BMI group (46 vs. 15%). Although postoperative mortality did not differ between the two groups, the low BMI cohort had a greater proportion of patients requiring mechanical ventilatory support for more than 24 h in the postoperative period (26 vs. 4%) and had a longer hospital length of stay (15.8 vs. 11.7 days).

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Alpha1-Antitrypsin Deﬁciency

This hereditary disorder is characterized by the development of panacinar emphysema with lower lobe predominance in some patients deﬁcient in the antiprotease alpha1-antitrypsin, particularly those with a smoking history. Patients often present at a younger age than typical smokers who develop emphysema. Although patients with alpha1-antitrypsin deﬁciency often have heterogeneous emphysema, the fact that it is sometimes most pronounced in the lower lobes has led some to question whether such patients are as likely to beneﬁt from LVRS. Cassina and colleagues reported their experience in 12 patients with alpha1-antitrypsin deﬁciency, comparing them with 18 patients with emphysema without such deﬁciency (30). They found that alpha1-antitrypsin–deﬁcient patients experience immediate improvement in spirometry, dyspnea, and 6-min walk distance comparable to that of controls. By 12 months after surgery, however, spirometric values, total lung capacity, and dyspnea had returned to preoperative baseline in patients with alpha1-antitrypsin deﬁciency, but not the control group. In contrast, an improvement in 6-min walk distance was noted at 12 and 24 months, although not as marked as that noted at 6 months. At the 12- and 24-month time points, the values of FEV1, total lung capacity (TLC), dyspnea, and 6min walk distance were signiﬁcantly lower in the patients with alpha1antitrypsin deﬁciency than in the control patients with emphysema. A Gelb and colleagues reported their results in six patients with alpha1-antitrypsin deﬁciency who underwent LVRS (31). In four patients who returned for follow-up at 22, 24, 27, and 36 months after surgery, the FEV1 had improved minimally from 30 to 33% of predicted. Changes in TLC (151– 127%), vital capacity (68–88%), and carbon monoxide diffuse in the lung (DLCO) (35 to 59%) were signiﬁcantly larger. They also reported improvement in dyspnea and 6-min walk distance at these time points, leading them to conclude that LVRS ‘‘provides modest physiological improvement for 2–3 years’’ in patients with alpha1-antitrypsin deﬁciency.

III.

Pulmonary Function Testing

A. FEV1

The population of patients selected for LVRS have signiﬁcant airﬂow obstruction that contributes to disability and a decreased quality of life. Although the criteria vary from series to series, the upper limit of FEV1 is usually between 35 and 45% predicted (32). Some investigators restrict LVRS to patients with an FEV1 > 15% predicted, whereas others do not have a lower limit of acceptability (33,34). McKenna and colleagues report

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that preoperative FEV1 does not correlate with the amount of improvement in FEV1 that occurs as a result of LVRS (20). This observation has also been reported by Ingenito, Yusen, Sciurba, and others (14,28,35). Recently, the investigators of the National Emphysema Treatment Trial reported that patients with an FEV1 < 20% predicted and a DLCO < 20% predicted and/or homogeneously distributed emphysema on computed tomographic (CT) scan are at high (*35%) risk for postoperative death after LVRS (36). B. Lung Volumes

An increase in TLC is characteristic of emphysema. Since the beneﬁcial effects of LVRS are believed to depend in large part on the restoration of more normal thoracic working volumes, most exclude patients who do not have an elevated TLC and residual volume. Theoretical analysis by Fessler and Permutt suggests that an important determinant of improvement in expiratory ﬂow rates after LVRS is an elevated residual volume (RV) to TLC ratio (RV/TLC) (37). The methodology used to measure lung volumes is important, as volumes measured by helium dilution are prone to underestimate lung volumes owing to incomplete equilibration of helium during the test. Volumes measured by plethysmography are felt to more accurately represent ‘‘thoracic gas volume.’’ Some investigators have used ‘‘trapped gas’’ volume, the difference in lung volumes measured by plethysmography and helium dilution, to select patients more likely to beneﬁt from surgery (38). Neither RV nor TLC alone have been shown to be predictive of the response to LVRS (20). C. Diffusing Capacity

A reduced DLCO is characteristic of patients with emphysema, reﬂecting the destruction of the alveolar capillary bed. Yusen and colleagues set an upper limit of 50% predicted and a lower limit of 10% predicted in their series (32). Keenan and colleagues reported that patients with a DLCO of <25% predicted had a 60% incidence of adverse outcomes after LVRS (23). D. Lung Resistance

Ingenito and colleagues reported that patients with a lower lung resistance during inspiration had more improvement in expiratory ﬂow rates than patients with higher inspiratory resistance (14). Lung resistance did not correlate with mortality or postoperative complications. Inspiratory resistance measurements combined with measurement of emphysema distribution from perfusion scans had still better utility in selecting suitable LVRS candidates (39). It should be noted that measurement of inspiratory

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resistance differs from the routine resistance measurements made during body plethysmography. It requires measurement of esophageal pressure and ﬂow during tidal breathing. The values during inspiration are then applied to the equation of motion using customized software. E.

PaO2

There are few data available concerning PaO2 as a predictor of either postoperative complications or beneﬁcial response to LVRS. Although McKenna reported no correlation between PaO2 and change in FEV1, he noted that patients with a resting oxygen requirements of greater than 4 L had little improvement (20). Gaissert and colleagues excluded patients with oxygen requirements >6 L/min from consideration for LVRS (34). Many other programs have adopted similar policies. F.

PaCO2

The data concerning the prognostic value of PaCO2 with respect to postoperative morbidity and mortality are particularly contradictory. An elevated PaCO2 has been viewed as a contraindication to pulmonary parenchymal resection, although several reports did not ﬁnd it to be an independent predictor of perioperative adverse events (3,40,41). Yusen and colleagues report that patients should have a PaCO2 < 55 mmHg to be considered candidates for LVRS (32). Kotloff and colleagues recommend that LVRS be performed only in patients with PaCO2 < 50 mmHg (27). Szekely and colleagues reported their initial experience with LVRS in a group of 47 patients (15). Overall mortality was 19%, and their retrospective analysis demonstrated that a strong predictor of prolonged hospital stay (> 21 days; P ¼ 0.0002) and mortality (P ¼ 0.012) was a PaCO2 > 45 mmHg. Keenan and colleagues reported that among six patients with PaCO2 > 50 mmHg and DLCO<25%, ﬁve experienced adverse outcomes (23). In a univariate analysis in the same series, patients with PaCO2 > 50 mmHg had a 60% incidence of adverse outcomes. However, when the they included patients with milder hypercarbia (> 45 mmHg) in the analysis, they found that the group of 12 patients had a mean decrease in PaCO2 of 5 mmHg as a result of LVRS (50– 45 mmHg). Other groups have had a different experience. O’Brien reported the ﬁndings at Temple University from LVRS in 15 patients with PaCO2 > 45 mmHg, with 31 patients with PaCO2 < 45 mmHg serving as a comparison group (42). They observed that the hypercapnic patients were more impaired preoperatively, but had a similar magnitude (expressed as a percentage of baseline values) of improvement in spirometric values,

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exercise performance, and health-related quality of life (HRQOL). Morbidity and mortality were similar between the groups. These workers concluded that hypercarbia alone should not disqualify a patient from consideration for LVRS. Another report from the same group concluded that patients with higher baseline PaCO2 experience the greatest reduction in PaCO2 postoperatively (43). McKenna reported his experience in performing LVRS on 10 patients with PaCO2 > 55 mmHg and found no correlation between hypercarbia and change in FEV1 or dyspnea (20). Wisser and colleagues reported their experience with LVRS in 22 patients with PaCO2 > 45 mmHg, comparing outcomes with 58 patients without hypercapnia (44). They found the hypercarbic group to be more impaired preoperatively, but at no greater risk for morbidity or mortality after the procedure. In contrast to O’Brien’s report, they found a greater magnitude of improvement in the hypercarbic group than in the controls, and they also concluded that chronic hypercarbia alone should not viewed as a contraindication to LVRS. Argenziano and colleagues reported their experience with LVRS in 85 patients (25). Of these, 36% had a PaCO2 > 45 mmHg and 11% had a PaCO2 > 55 mmHg. They reported no deaths in the severely hypercarbic patients and an improvement in dyspnea that was greater than the other patients in the series. These investigators also concluded that patients felt to be at ‘‘high risk’’ owing to hypercarbia should not be excluded from consideration for LVRS.

IV.

Cardiac Issues

Two cardiac issues are principal considerations in patients considering LVRS: and coronary artery disease and pulmonary hypertension. As presented by Goldman and colleagues, certain factors have been demonstrated to inﬂuence the perioperative risk of cardiac complications after surgery of all types (45). These include age, the presence of left ventricular dysfunction, recent myocardial infarction, arrhythmias, aortic stenosis. Most patients being considered for LVRS fall into Class II or higher in the Cardiac Risk Index presented in Goldman’s report (summarized in Table 2). These data were incorporated into more recent recommendations concerning perioperative cardiovascular evaluation published by the American College of Cardiology/American Heart Association Task Force (46). It is important to note that published reports of LVRS speciﬁcally exclude patients with signiﬁcant comorbid conditions that are likely to impact the

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Computation of Cardiac Risk Index

Criteria Age >70 years Myocardial infarction in prior 6 months S3 gallop or jugular venous distention Important aortic stenosis ECG with rhythm other than sinus or APCs >5 PVC’s / min documented preoperatively PaO2 < 60, PaCO2 > 50, K < 3, HCO3 < 20, BUN > 50, Creat >3, signs of chronic liver disease or patient bedridden Intraperitoneal, intrathoracic, or aortic operation Emergency operation Total possible points Cardiac risk index calculation Class I Class II Class III Class IV

Point value 5 10 11 3 7 7 3 3 4 53 Point total 0–5 6–12 13–25 > 26

Typical LVRS patient: 3 points for general condition, 3 points for intrathoracic operation. Source: Adapted from Ref. 43.

outcome adversely. The applicability of the Cardiac Risk Index or similar measures has not been systematically examined in LVRS. A. Coronary Artery Disease

Coronary artery disease (CAD) shares a common risk factor with emphysema—cigarette smoking. The evaluation of patients with advanced emphysema for the presence and extent of coronary artery disease presents a clinical challenge. Conventional evaluation for cardiac ischemia principally rely upon exercise to generate a physiological stress to demonstrate the presence of signiﬁcant coronary artery disease by electrocardiography or imaging. In patients with advanced emphysema, pulmonary mechanical limits to exercise preclude a sufﬁcient workload to reach the targets required for sensitive evaluation of ischemia. Consequently, exercise testing for this purpose is useless. One alternative approach is the use of transthoracic echocardiography to assess left ventricular function. The demonstration of regional wall motion abnormalities of the left ventricle, intracavitary thrombus, or globally decreased left ventricular function suggests underlying coronary

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artery disease and merits further evaluation (usually with coronary angiography). Bach and colleagues reported results of echocardiography in 207 patients being considered for LVRS (47). They found that images were adequate for assessment of chamber size and function in virtually all patients (206/207). Abnormalities of the right heart were found in 40.1% of the patients. Left heart abnormalities were signiﬁcantly less common, with only 3.9% of patients having decreased LV function and *10% with some evidence for coronary artery disease. No feature of the preoperative echocardiogram was found to be predictive of postoperative complications. The same group (47) examined dobutamine stress echocardiography in preoperative evaluation of LVRS candidates (48). They reported results in 46 patients, 45 of whom had interpretable results. Four patients (9%) had evidence of myocardial ischemia; one of these four patients had two major cardiac events in the postoperative period, the others did not. They concluded that a negative dobutamine stress echocardiogram has an excellent negative predictive value for adverse cardiac events. Dobutamine-thallium perfusion imaging may be a useful alternative to stress echocardiography, depending upon local expertise. Thurnheer and colleagues reported their experience with dipyridamole positron emission tomography (PET) in 20 patients with severe chronic obstructive pulmonary disease under consideration for LVRS (49). All were negative for signs of myocardial ischemia. Seventeen of the patients subsequently underwent LVRS, and none had cardiac complications. Nine (45%) of the patients developed ‘‘intolerable dyspnea’’ during the procedure and required intravenous aminophylline administration to relieve symptoms; the same number of patients experienced a 15% or greater reduction in FEV1 after dipyridamole administration. Although these effects were reversible, the investigators concluded that dipyridamole ‘‘cannot be recommended as a pharmacologic stress’’ in this patient population. These same investigators (49) also reported their experience with coronary angiography in 46 patients under consideration for LVRS (50). Three of 46 patients had a history of CAD and all 3 had signiﬁcant (> 70%) coronary artery stenoses demonstrated angiographically. Two of these patients had further intervention; one underwent coronary artery bypass grafting and the other had angiographic deployment of a vascular stent. One of these three patients died of ‘‘cardiopulmonary decompensation’’ without evidence of a myocardial infarction or ischemia. Forty-one of the other 43 patients underwent coronary angiography. Six of 41 patients had signiﬁcant CAD. Four of six patients were excluded from further consideration for surgery. One of the remaining two patients underwent percutaneous transluminal coronary angioplasty (PTCA). None of the 37 patients from

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this group who subsequently underwent LVRS had an adverse cardiac event in the perioperative period. B. Pulmonary Hypertension

Virtually every group reporting experience with LVRS considers ‘‘signiﬁcant’’ pulmonary hypertension to be a contraindication for the procedure. The deﬁnition of ‘‘signiﬁcant’’ varies from publication to publication, but is usually a pulmonary artery (PA) systolic pressure greater than 45–50 mmHg or a mean PA pressure greater than 30–35 mmHg. Although PA pressures are measured most accurately by placement of a PA catheter, most patients have pressures estimated noninvasively by continuous Doppler echocardiographic techniques. In patients with tricuspid regurgitation, RV systolic and, by inference, PA pressure may be estimated from the peak velocity of the regurgitant jet using the simpliﬁed Bernoulli equation (4[v2] þ estimated right atrial pressure). Right atrial pressure is estimated from the size and respiratory variation of the inferior vena cava. Investigators at the University of Michigan have compared such noninvasive estimates with directly measured pressures (47). In a group of patients being considered for LVRS, they found that echocardiographic estimates of PA pressure were higher than actual pressures in most patients. However, in many patients with emphysema, body habitus may preclude Doppler measurement of pulmonary artery pressure. Right heart catheterization is warranted when pressures cannot be estimated noninvasively, when echocardiographic measurements are close to the acceptable limit, or when pressures are below the limit by echocardiography but there are other signs of right ventricular overload or failure. In summary, patients considering LVRS should be carefully evaluated for CAD and/or pulmonary hypertension. Recent myocardial infarction or advanced congestive heart failure are contraindications for LVRS. Patients should undergo noninvasive pharmacological testing to screen for CAD. The presence of abnormalities on noninvasive tests should prompt consideration of more extensive testing prior to surgery. Current practices concerning pulmonary hypertension are that pulmonary artery systolic pressures greater than 45–50 mmHg are a contraindication to LVRS, although this has not been systematically studied. V. Exercise Performance A clinical maxim in evaluating patients for pulmonary resections of all types is that the exercise capability has important prognostic implications for postoperative complications and mortality. Various methods of assessing

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exercise capability have been used, including stair climbing and cardiopulmonary exercise testing with measurement of oxygen uptake (reviewed in Refs. 2 and 51). The same general principles apply to the evaluation of LVRS candidates, modiﬁed to account for the facts that these patients are very limited in their exercise capacity, and that the surgery is designed to result in an improvement in pulmonary function rather than the decrement seen after other parenchymal resection. Although there is widespread recognition of the importance of preoperative exercise performance, there are few data available to use to formulate guidelines comparable to those that exist for the evaluation of patients requiring parenchymal resection for lung cancer. In one retrospective analysis, Szekely and colleagues reported that patients with a preoperative 6-min walk distance of less than 200 m had an exceptionally high perioperative mortality (15). Geddes reported a high postoperative mortality in patients with a shuttle walk distance of less than 150 m or DLCO less than 30% predicted (52). Based on these considerations and the rationale that early postoperative mobilization reduces perioperative complications, many programs require candidates for LVRS undergo formal pulmonary rehabilitation prior to surgery (53,54). Others are less convinced of the need for preoperative rehabilitation and do not require it of all patients (20,52). There are no prospective data that address this issue. Investigators at Columbia University reported their experience in 35 patients who were unable to complete pulmonary rehabilitation. The average 6-min walk distance for this subset of patients was 477 + 347 ft. They reported mortality was no higher than ‘‘low-risk’’ patients in the same series, and that the magnitude of improvement in function was equivalent in the two groups (25). The group at Temple University has reported their experience in patients dependent on mechanical ventilation (see Chap. 17) and good outcomes despite signiﬁcant debilitation in operative candidates (56). One possible added value of rehabilitation in some patients is that it enforces a period of reﬂection prior to undergoing surgery, and ensures that maximal symptomatic relief has been obtained.

VI.

Radiographic Studies

Issues related to imaging the thorax are discussed in detail in Chapter 8. In brief, a CT scan of the chest should be obtained to (1) conﬁrm the diagnosis of emphysema, (2) demonstrate the distribution of emphysema within the parenchyma, and (3) demonstrate the presence of any nodules or masses in the lung in a patient at increased risk for lung cancer due to a history of

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smoking and chronic obstructive lung disease. As discussed more completely elsewhere within this monograph, upper lobe predominant or heterogeneous emphysema has been found by several groups to identify patients likely to beneﬁt from LVRS (39,57–59). VII.

Summary

The data presented in this chapter provide an approach to patients considering LVRS. A summary of the tests recommended for evaluation is given in Table 3. However, 60–90% of patients who present for consideration of LVRS are turned down after study. The most frequent reason is the assessment that the distribution of emphysema is not amenable to resection. The reader will have noted, however, that the data are insufﬁcient to support an inﬂexible set of rules, nor have many guidelines been subjected to prospective conﬁrmation. There is anecdotal experience in violating almost every rule that has been suggested. It is important to keep

Table 3

Recommended Testing for LVRS Candidates

History and Physical Examination Pulmonary function testing Spirometry Lung volumes by plethysmography Diffusing capacity Arterial blood gas Lung compliance and resistance measurements (depending on center expertise/ interest) Cardiac testing Electrocardiogram Pharmacological cardiac stress test Echocardiogram Radiographic studies Chest CT scan Radionuclide perfusion scan (optional) Functional assessment 6-min walk and/or exercise test Blood/urine testing Alpha1-antitrypsin level Metabolic panel Complete blood count Urinary cotinine or arterial carboxyhemoglobin

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in mind, however, that such ‘‘high-risk’’ patients who have had LVRS with good results represent a subset of patients who, despite having characteristics thought to increase the risk of surgery, have nevertheless passed the subjective assessment by a team experienced in LVRS. Very few patients who present with unfavorable characteristics are offered surgery. Despite this uncertainty, individual patients still require concrete decisions. A set of inclusion and exclusion guidelines is given in Table 4, provided with the caveat that any such set is untested and somewhat ﬂexible. For patients participating in clinical trials involving LVRS, the task is simpliﬁed by the fact that the evaluation and inclusion criteria are speciﬁed by the trial protocol. The decisions about the relative contraindications posed by hypoxemia, hypercarbia, corticosteroid usage, nutritional status, and various patterns of the distribution of emphysema have been made by the authors of the trial protocol. One goal of current clinical trials is to accrue the experience to enable evidence-based conclusions about LVRS for

Table 4

Inclusion and Exclusion Criteria for LVRS

Inclusion criteria Disabling dyspnea Airﬂow obstruction with FEV1 < 45% predicted Hyperinﬂation with TLC >100% predicted and RV >150% predicted Emphysema visible on high-resolution CT scan Compliance with optimal medical therapy Exclusion criteria Comorbidities limiting exercise (arthritis, myopathy, morbid obesity) Comorbidities increasing risk (coronary disease, congestive heart failure, obesity) Active smoking Clinically signiﬁcant chronic bronchitis or bronchiectasis Signiﬁcant ﬁbrotic or other nonemphysematous lung disease Extensive pleural ﬁbrosis Pulmonary artery pressure >45 mmHg (systolic) or 35 mmHg (mean) Cor pulmonale Emphysema distribution not surgically accessible Emphysema too advanced (FEV1 < 15% predicted or lung largely destroyed on CT scan, or PaCO2 > 60 mmHg) Documented high-risk group: FEV1 < 20% predicted and DLCO <20% predicted and/or homogeneously distributed emphysema on CT scan Very poor general functional status Personality disorder or poor social support system

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a given patient. For physicians counseling patients considering LVRS, careful consideration should be given to recommending that they participate in available clinical trials or seek treatment at a center that has a extensive experience in the procedure.

References 1. 2. 3.

4. 5.

6. 7.

8. 9.

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15. Szekely LA, Oelberg DA, Wright CD, et al. Preoperative predictors of operative morbidity and mortality in COPD patients undergoing bilateral lung volume reduction surgery. Chest 1997; 111:550–558. 16. Norman M, Hillerdal G, Orre L, et al. Improved lung function and quality of life following increased elastic recoil after lung volume reduction surgery in emphysema. Respir Med 1998; 92:653–658. 17. Kotloff RM, Tino G, Palevsky HI, et al. Comparison of short-term functional outcomes following unilateral and bilateral lung volume reduction surgery. Chest 1998; 113:890–895. 18. Ferguson GT, Fernandez E, Zamora MR, et al. Improved exercise performance following lung volume reduction surgery for emphysema. Am J Respir Crit Care Med 1998; 157:1195–1203. 19. Bagley PH, Davis SM, O’Shea M, et al. Lung volume reduction surgery at a community hospital: program development and outcomes. Chest 1997; 111:1552–1559. 20. McKenna RJ Jr. Patient selection criteria for lung volume reduction surgery. J Thorac Cardiovasc Surg 1997; 114:957–964. 21. Yusen RD. Evaluation of patients with emphysema for lung volume reduction surgery. Washington University Emphysema Surgery Group. Semin Thorac Cardiovasc Surg 1996; 8:83–93. 22. American Thoracic Society. ATS Statement on Standards for the Diagnosis and Care of Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 1995; 152:S77–S120. 23. Keenan RJ, Landreneau RJ, Sciurba FC, et al. Unilateral thoracoscopic surgical approach for diffuse emphysema. J Thorac Cardiovasc Surg 1996; 111:308–315; discussion 315–6. 24. Yusen RD. Evaluation and preoperative management of lung volume reduction surgery candidates. Clin Chest Med 1997; 18:199–224. 25. Argenziano M, Moazami N, Thomashow B, et al. Extended indications for lung volume reduction surgery in advanced emphysema. Ann Thorac Surg 1996; 62:1588–1597. 26. Yusen RD, Lefrak SS, Trulock EP. Evaluation and preoperative management of lung volume reduction surgery candidates. Clin Chest Med 1997; 18:199– 224. 27. Kotloff RM, Tino G, Bavaria JE, et al. Bilateral lung volume reduction surgery for advanced emphysema. A comparison of median sternotomy and thoracoscopic approaches. Chest 1996; 110:1399–1406. 28. Sciurba FC, Rogers RM, Keenan RJ, et al. Improvement in pulmonary function and elastic recoil after lung-reduction surgery for diffuse emphysema [see comments]. N Engl J Med 1996; 334:1095–1099. 29. Mazolewski P. The impact of nutritional status on the outcome of lung volume reduction surgery: a prospective study. Chest 1999; 116:693–696. 30. Cassina PC, Teschler H, Konietzko N, et al. Two-year results after lung volume reduction surgery in alpha1-antitrypsin deﬁciency versus smoker’s emphysema. Eur Respir J 1998; 12:1028–1032.

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31. Gelb AF. Lung function after bilateral lower lobe lung volume reduction surgery for alpha1-antitrypsin emphysema. Eur Respir J 1999; 14:928–933. 32. Yusen RD, Lefrak SS, Washington University Thoracic Surgery Group. Evaluation of patients with emphysema for lung volume reduction surgery. Semin Thorac Cardiovasc Surg 1996; 8:83–93. 33. Naunheim KS, Kaiser LR, Bavaria JE, et al. Long-term survival after thoracoscopic lung volume reduction: a multiinstitutional review. Ann Thorac Surg 1999; 68:2026–2031; discussion 2031. 34. Gaissert HA, Trulock EP, Cooper JD, et al. Comparison of early functional results after volume reduction or lung transplantation for chronic obstructive pulmonary disease (see comments). J Thorac Cardiovasc Surg 1996; 111:296– 306; discussion 306. 35. Yusen RD, Trulock EP, Pohl MS, et al. Results of lung volume reduction surgery in patients with emphysema. The Washington University Emphysema Surgery Group. Semin Thorac Cardiovasc Surg 1996; 8:99–109. 36. Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med 2001; 345:1075–1083. 37. Fessler HE, Permutt S. Lung volume reduction surgery and airﬂow limitation. Am J Respir Crit Care Med 1998; 157:715–722. 38. Cooper JD, Patterson GA. Lung-volume reduction surgery for severe emphysema. Chest Surg Clin North Am 1995; 5:815–831. 39. Ingenito EP, Loring SH, Moy MM, et al. Comparison of physiological and radiological screening for lung volume reduction surgery. Am J Respir Crit Care Med 2001; 163:1068–1073. 40. Preoperative pulmonary function testing. American College of Physicians. Ann Intern Med 1990; 112:793–794. 41. Reilly JJ. Preparing for pulmonary resection: preoperative evaluation of patients. Chest 1997; 112:206S–208S. 42. O’Brien GM, Furukawa S, Kuzma AM, et al. Improvements in lung function, exercise, and quality of life in hypercapnic COPD patients after lung volume reduction surgery. Chest 1999; 115:75–84. 43. Shade D, Jr., Cordova F, Lando Y, et al. Relationship between resting hypercapnia and physiologic parameters before and after lung volume reduction surgery in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159:1405–1411. 44. Wisser W, Klepetko W, Senbaklavaci O, et al. Chronic hypercapnia should not exclude patients from lung volume reduction surgery. Eur J Cardiothorac Surg 1998; 14:107–112. 45. Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med 1977; 297:845–850. 46. Eagle KA, Brundage BH, Chaitman BR, et al. Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). J Am Coll Cardiol 1996; 27:910–948.

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47. Bach DS, Curtis JL, Christensen PJ, et al. Preoperative echocardiographic evaluation of patients referred for lung volume reduction surgery. Chest 1998; 114:972–980. 48. Bossone E, Martinez FJ, Whyte RI, et al. Dobutamine stress echocardiography for the preoperative evaluation of patients undergoing lung volume reduction surgery. J Thorac Cardiovasc Surg 1999; 118:542–546. 49. Thurnheer R, Laube I, Kaufmann PA, et al. Practicability and safety of dipyridamole cardiac imaging in patients with severe chronic obstructive pulmonary disease. Eur J Nucl Med 1999; 26:812–817. 50. Thurnheer R, Muntwyler J, Stammberger U, et al. Coronary artery disease in patients undergoing lung volume reduction surgery for emphysema. Chest 1997; 112:122–128. 51. Reilly JJ. Evidence-based preoperative evaluation of candidates for thoracotomy. Chest 1999; 116:474S–476S. 52. Geddes D, Davies M, Koyama H, Hansell D, Pastorino U, Pepper J, Agent P, Cullinan P, MacNeill SJ, Goldstraw P. Effect of lung volume reduction surgery in patients with severe emphysema. N Engl J Med 2000; 343:239–245. 53. Cooper JD, Patterson GA, Sundaresan RS, et al. Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema. J Thorac Cardiovasc Surg 1996; 112:1319–1329; discussion 1329–. 54. Moy ML, Ingenito EP, Mentzer SJ, et al. Health-related quality of life improves following pulmonary rehabilitation and lung volume reduction surgery. Chest 1999; 115:383–389. 55. Benditt JO, Lewis S, Wood DE, et al. Lung volume reduction surgery improves maximal O2 consumption, maximal minute ventilation, O2 pulse, and dead space-to-tidal volume ratio during leg cycle ergometry. Am J Respir Crit Care Med 1997; 156:561–566. 56. Criner GJ, O’Brien G, Furukawa S, et al. Lung volume reduction surgery in ventilator-dependent COPD patients. Chest 1996; 110:877–884. 57. Wang SC, Fischer KC, Slone RM, et al. Perfusion scintigraphy in the evaluation for lung volume reduction surgery: correlation with clinical outcome. Radiology 1997; 205:243–248. 58. Gierada DS. Pulmonary emphysema: comparison of preoperative quantitative CT and physiologic index values with clinical outcome after lung-volume reduction surgery. Radiology 1997; 205:235–242. 59. Weder W, Thurnheer R, Stammberger U, et al. Radiologic emphysema morphology is associated with outcome after surgical lung volume reduction. Ann Thorac Surg 1997; 64:313–319.

8 Radiological Evaluation for Lung Volume Reduction Surgery

ELLA A. KAZEROONI University of Michigan Ann Arbor, Michigan, U.S.A.

I. Introduction The imaging of emphysema has received renewed attention since the resurgent interest in lung volume reduction surgery (LVRS). Prior to LVRS, the clinical imaging of emphysema extended little beyond the chest radiograph. Computed tomography (CT) had a narrow role. It was used to establish the diagnosis of emphysema in patients with dyspnea, normal chest radiographs, and isolated reduction in diffusing capacity on pulmonary function testing (1,2). More commonly, emphysema was reported as an incidental ﬁnding on CT examinations performed for other clinical indications, such as lung cancer. CT scans had not been used routinely in the evaluation of pulmonary emphysema itself. With recent evidence that the severity and distribution of emphysema within the lungs are useful predictors of patient outcome after LVRS, a new indication has arisen for the advanced imaging of emphysema with both CT and perfusion scintigraphy (3–9). Other techniques are being used investigationally, including magnetic resonance imaging (MRI) to evaluate the morphology and coordinated movements of the chest wall and diaphragm before and 169

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after LVRS (10) and xenon-enhanced CT to map the distribution of ventilation (11,12). This chapter deﬁnes the appearance of emphysema on chest radiographs, CT scans, and ventilation–perfusion scintigraphs, presents the available data on the use of these modalities in patient selection for LVRS, and describes the alterations in imaging features seen in patients studied before and after LVRS. II.

Chest Radiography of Emphysema

The radiographic evaluation of emphysema relies on signs of lung destruction and/or hyperinﬂation on the posteroanterior and/or lateral views (13,14). These signs include (1) radiolucency of the lungs, arterial depletion, or increased vascular markings; (2) ﬂattening or depression of the diaphragm; (3) enlargement of the retrosternal clear space; (4) increased lung height; (5) height of the right hemidiaphragm; and (6) the ‘‘sabersheath’’ trachea (Figs. 1 and 2) (13–15). These signs alone or in combination have 40–80% sensitivity for detecting emphysema (15). In general, moderate to severe emphysema is detectable radiographically, whereas mild emphysema is not. Furthermore, signs of pulmonary hyperinﬂation are not speciﬁc for emphysema, and are seen in patients with other forms of obstructive lung disease. The identiﬁcation of bullae is the only speciﬁc sign of pulmonary emphysema on chest radiographs. Thus, although chest radiographs provide supporting evidence of a diagnosis of emphysema, and are routinely used to evaluate for complications of emphysema, such as pneumonia or lung cancer, the insensitivity and nonspeciﬁcity of chest radiographs limits their use as a diagnostic tool (14,16,17). III.

CT of Emphysema

Although a thorough explanation of the operations of a CT scanner is complex and beyond the scope of this chapter, a familiarity with the basic principles and terminology is necessary to understand the CT material that follows. The cross-sectional depiction of the body on CT eliminates the superimposition of structures that occurs with chest radiography. In addition, CT detects differences in radiographic density of only 0.5% compared with the 10% difference required for conventional radiography. Conventional CT refers to the axial CT scanning mode in which individual or a few axial images are obtained in a single breath hold. The patient is then allowed to breathe before another individual image or cluster of images is obtained. Owing to variation in the size of each breath, inevitably areas of

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(A) Figure 1 (A) Posteroanterior radiograph of upper lobe–predominant emphysema in a 63-year-old woman as demonstrated on chest radiography, HRCT, and helical three-dimensional density mask.

the lung may be missed or scanned twice. Collimation refers to the slice thickness used or the thickness of the body that is scanned to generate an image. This is usually 5–10 mm for conventional chest CT. Images are obtained in contiguous fashion, say from lung apex through lung bases; in other words, there are no intentional skip areas in conventional CT. Each CT image is a 512 6 512 matrix of numbers or pixels in two-dimensions (x and y). Voxel refers to the added z-dimension when a volume of data is discussed, as in helical CT. Each number is assigned a value of 1000 (air) to þ3000 (metal, mineral) Hounsﬁeld Units (HU), with zero representing

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(B) Figure 1 (B) Lateral chest radiographs demonstrate pulmonary hyperinﬂation with ﬂat hemidiaphragms, increased anteroposterior chest dimension, and retrosternal clear space, increased height of the lungs, and a paucity of pulmonary vessels in the upper lobes.

water. CT scanners undergo regular quality control and calibration with water phantoms and calibration to air to make sure that there is no drift in CT numbers.

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(C) Figure 1

(C) Axial HRCT images through the upper lobes.

It is not possible to display the full range of CT numbers on a single image because the limited number of shades of gray on an electronic display, the human eye can only distinguish 30–90 levels of gray. CT images are therefore viewed on different window and level combinations, each designed for the depiction of speciﬁc structures. Chest CT images are usually viewed on at least two window and level setting combinations: one for evaluation of the lung parenchyma and the other for evaluation of the soft tissues that make up the mediastinum and chest wall. The terms level and window each refer to the Hounsﬁeld unit attenuation values. The level is best set midway between the attenuation value of the structure of interest and that of the surrounding tissue, whereas the width is chosen to include the entire range of attenuation values around the level that are present within the scanned tissue. For example, when viewing the soft tissues a window level of 20 HU and width of 450 HU may be used. The gray scale seen represents the pixel values that are 225 HU on either side of 20, or 205 to þ240 HU. All pixels with a value of less than 205 HU will appear black and all pixels greater than 240 HU will appear white. When viewing the lungs, a level of 700 HU

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(D) Figure 1 (D) Lower lungs demonstrate more severe anatomical destruction, separation, and thinning of pulmonary blood vessels at the lung apices than the lung bases.

and width of 1000 HU may be used; all pixels greater than 200 HU will appear white. High-resolution CT (HRCT) refers to scanning in axial mode with the thinnest possible slice thickness available, usually 1.0–1.5 mm, combined with the use of a high spatial frequency reconstruction algorithm that enhances the ability to see ﬁne lines and interfaces. This is in contrast to conventional chest CT which uses a reconstruction algorithm that smoothes interfaces. Helical CT refers to scanning that acquires a continuous volume of data, with the detector rotating continuously as the patient moves through the scanner gantry. When a scan is obtained with a pitch of 1, it means that the detector rotated 360 degrees as the patient moved the distance set as the collimation. At a pitch of 2, the patient has moved twice the collimation distance through the scanner gantry for one detector revolution. The larger the pitch, the larger the effective slice thickness; in other words, the actual images generated are thicker than the collimation set. Recently, Cederlund et al. demonstrated that readers prefer HRCT

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(E) Figure 1 (E) Anterior lateral projection from three-dimensional shaded surface display reconstructions shows the total lung volume in gray and emphysema volume of all pixels less than 900 HU superimposed in white.

images to helical CT images for evaluating advanced emphysema in the majority of cases (56%), whereas in some cases, the helical CT images were preferred (18%), and in 25% of patients studied both the HRCT and helical CT images were thought to be important for characterizing the lung abnormality (18). CT provides excellent anatomical detail for detecting, characterizing, and quantifying the severity of emphysema. As would be expected,

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(F) Figure 1 (F) Right lateral projections from three-dimensional shaded surface display reconstructions shows the total lung volume in gray and emphysema volume of all pixels less than 900 HU superimposed in white. Dividing the lung in half from apex to base, 54% of the upper half of the lungs and 9% of the lower half of the lungs represents emphysema, for a CT ratio of 6.

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(A) Figure 2 (A) Posteroanterior chest radiograph of diffuse emphysema in a 50-yearold woman as demonstrated on chest radiography, HRCT, axial two-dimensionaldensity mask HRCT and helical three-dimensional-density mask.

conventional CT is more accurate than chest radiography, and HRCT is more accurate than conventional CT (19,20). Emphysema is characterized by abnormal areas of low attenuation pulmonary parenchyma without deﬁnable walls (Figs. 1C, 2C and D, 3A and B), which decrease the mean attenuation value of the lung (15).

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(B) Figure 2 (B) Lateral chest radiograph demonstrates pulmonary hyperinﬂation with ﬂat hemidiaphragms, increased anteroposterior chest dimension and retrosternal clear space, increased height of the lungs, and diffuse paucity of pulmonary vascularity consistent with diffuse emphysema. Caution should be used in interpreting the heterogeneity of emphysema on the posteroanterior view, as increased opacity may be created by the chest wall tissue. In this case, note the increased opacity in the mid to lower thorax created by the superimposed breasts.

Figure 2 (C) Axial HRCT image through the upper lobes at the level of the aortic arch demonstrates abnormal low attenuation uniformly through the upper lobes. A similar appearance was present on images taken throughout the lungs.

(C)

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Figure 2 (D) Density mask of 900 HU applied to the same image shown in (C). The white pixels falling below the 900 HU threshold represent emphysema. Total lung volume on this single slice is 21,956 mm2 and emphysema volume 15,268 mm2, with 69% of the lung on this image representing emphysema. Mean lung attenuation at this level was 916 + 62 HU.

(D)

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Emphysema severity may be quantiﬁed either by using visual scoring systems or, because the image data are acquired digitally and are readily subjected to computerized analysis, by using threshold-based techniques. In the former, a human reader compares the images with standards to estimate severity and distribution of emphysema. In the latter, software can be used to mask off regions with attenuation below a threshold set to represent air. This method, known as density masking, identiﬁes all areas within a region of interest where lung parenchyma is lacking and divides the lung into ‘‘emphysema’’ and ‘‘other.’’ An example of this technique before and after masking is shown in Figures 2C and D. The strengths of visual scoring are its simplicity and intuitive familiarity to clinicians. However, its weakness is its wide interobserver variability unless readers are carefully trained to uniform standards comparable to the ‘‘B reader’’ training for pneumoconioses (17). Density-masking methods are extremely reproducible with uniform technique. However, thinner CT slices or higher attenuation thresholds will increase the area labeled as being emphysema. Many investigators have shown that CT is an accurate method for quantifying the severity of emphysema, using either visual scoring methods or threshold-based quantitative analysis (19,21–34). For example, the severity of emphysema present on HRCT and conventional CT has demonstrated excellent correlation with the pathological severity of emphysema (20,24,27,28,35). A radiologic–pathologic study by Hruban et al. demonstrated a correlation coefﬁcient of 0.91 (P < .005) between the visual estimation of emphysema on in vitro 2-mm collimation HRCT images of resected lung tissue and the severity of emphysema in the pathological specimens (22). Subsequently, Mu¨ller et al. compared a visual CT scoring system and axial density-masking technique (pixels between 910 and 1024 HU representing emphysema) applied to a single conventional 10-mm collimation image of the lung to inﬂation-ﬁxed lung specimen pathology scores in patients undergoing thoracotomy for tumor resection (23,24). A modiﬁcation of a grading system developed by Thurlbeck et al. was used to score the histological specimens (36). Pathology scores ranged from 0 to 100, with 0 representing no emphysema. Of 28 patients, 25 (89%) had pathology scores less than or equal to 50. Both the visual score (r ¼ 0.9; P < .001) and the density mask score (r ¼ 0.94) demonstrated excellent correlation with the pathology score. Using the visual score, one CT reader missed emphysema in six cases and the other CT reader missed it in three cases, all involving relatively mild disease by pathology scores. Each reader diagnosed emphysema in one scan of pathologically normal lung. By comparison, the density mask missed three cases of mild emphysema and read one

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normal case as being emphysema. The sensitivity for emphysema detection by reader 1, reader 2, and density-masking techniques were 71, 86, and 86% respectively; all had a speciﬁcity of 86%. Miller et al. later used a visual grid scoring system and compared 10-mm conventional CT and 1.5mm HRCT images of patients undergoing lung resection for malignancy to the severity of emphysema present in corresponding inﬂation-ﬁxed lung pathological specimens. The visual grid system is the superimposition of a cross-hair grid on an image, with emphysema scored in each box. A correlation with r ¼ 0.81 (P < .001) was found between the 10-mm CT visual score and the pathology score, which improved slightly to r ¼ 0.85 (P < .001) for the HRCT images (20). Because of volume averaging, these methods have been shown to underestimate the earliest and smallest lesions of emphysema cysts; that is, those less than 0.5 cm (20). A sliding thin-slab, minimum-intensity projection technique has recently been demonstrated to be more accurate than HRCT for the detection of mild emphysema when evaluating images only for the presence or absence of emphysema (21). Other quantitative tools have been applied investigationally to the evaluation of CT data in patients with emphysema. These include a method incorporating multiple advanced statistical and fractal texture features, which has not yet been widely used clinically (37,38). Furthermore, insensitivity to early changes of emphysema is usually not critical in the evaluation of patients for LVRS, because they generally have advanced disease. Studies of third- and fourth-generation CT scanners from different vendors have demonstrated that, with appropriate calibration for water and air, results are quite reproducible for lung densitometry measurements and measurement of the low-attenuation area of the lung (39,40). When imaging is gated to spirometrically measured lung volume, repeated density measurements on the same patient agree closely even in patients with severe respiratory insufﬁciency. Reproducibility is best at 90% of vital capacity and was worse by a factor of three at end expiration (40). The quantitative measurements described above were performed on inspiratory CT images. By using a computer-based method to determine the areas of emphysema (26), analysis of expiratory HRCT at 1-mm collimation was shown to be less accurate than analysis of inspiratory HRCT in a series of 89 patients undergoing lung resection. This was believed to be due to air trapping during expiration in the presence of reversible small airway disease (28). Mean lung attenuation has also demonstrated weak correlation with the pathological severity of emphysema. For example, in the study by Mu¨ller et al. of 10-mm collimation images, the correlation between mean lung density and the visual score with pathology scores was only moderate (r ¼ 0.44, P < .01, and r ¼ 0.46, P < .01, respectively) (24).

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The appropriate upper attenuation threshold to use for quantitative CT analysis varies with slice thickness and with inspiration versus expiration. For example, the optimum threshold for 10-mm collimation inspiratory CT is 910 HU (24) versus 950 HU for 1-mm collimation inspiratory CT (28) and 820 HU for 1-mm collimation expiratory CT (28). Using an incorrectly high threshold will overestimate emphysema, and using an incorrectly low threshold will underestimate it. The quantitative CT methods correlate well with diffusing capacity and pulmonary capillary blood volume, but correlate only moderately with measures of airﬂow obstruction such as the forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio (41,42). This has led some to speculation that the severity of expiratory airway obstruction is not directly related to the alveolar wall destruction that occurs in emphysema (34,41–44). In one study comparing inspiratory and expiratory CT to pulmonary function, the visual emphysema score correlated better with the FEV1 and diffusing capacity than with the ratio of residual volume to total lung capacity (RV/TLC). The ratio of the CT attenuation number at expiration to inspiration correlated well with RV/ TLC and FEV1 but less well with the diffusing capacity, which suggests that it reﬂects air trapping (45). Another study which quantiﬁed emphysema using regions of interest drawn in the central, intermediate, and peripheral lung, as well as in the upper, middle, and lower lung, concluded that central rather than peripheral emphysema has the greatest correlation with pulmonary function, and that the more uniform the emphysema between upper and lower lung, or the central and peripheral lung, the more severe the airway obstruction (46). Density masking was initially performed on selected axial twodimensional images (see Fig. 2D) (24). This technique requires that one manually draw a region of interest around the lung on each image, making study of the entire lungs cumbersome and time consuming. However, with automation, the same technique can be applied to three-dimensional helical CT volumetric data sets acquired during a single inspiration for evaluation of the entire lungs (see Figs. 2 and 3) (47,48). These analyses can be performed on commercially available scanner consoles or workstations from all CT scanner manufacturers. Static lung volumes, including TLC and RV, can also be calculated from inspiratory and expiratory helical CT data with excellent correlation to traditional techniques (49). Gierada et al. have demonstrated that quantitative CT measurements of emphysema in LVRS candidates are highly reproducible, and that the addition of spirometric gating in this setting does not signiﬁcantly improve these measurements (50).

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Chest Radiography and Patient Selection for LVRS

The data available on the use of chest radiographs to identify patients who will beneﬁt from LVRS are limited. In one series of 47 LVRS survivors, chest radiographic scores were more strongly correlated with outcome than CT scores, but this depended on the outcome variable (5). Emphysema severity was scored on chest radiographs and CT using a 5-point scale (0 ¼ normal, 4 ¼ severe). Emphysema heterogeneity was scored on a 5-point scale (0 ¼ uniform distribution, 4 ¼ extreme differences in regional severity, with clearly deﬁned target areas of severe emphysema). Hyperinﬂation and compression of normal lung were also scored. The scores were correlated with three post-LVRS outcomes 6 months after surgery: FEV1, 6-min walk test distance, and PaO2. Greater regional heterogeneity, lung compression, and upper lobe–predominant emphysema on both chest radiograph and CT correlated with postoperative improvements in all measures, whereas interobserver agreement was slightly greater for CT scores than for radiograph scores. Other investigators have cautioned against the use of plain chest radiographs without CT for patient selection, having found changes in emphysema distribution on CT from that determined on radiograph in approximately 20% of patients (51). This may be due to overlapping breast tissue, pectoralis muscles, or abundant chest wall soft tissue. Furthermore, in this population at risk for lung cancer because of prior cigarette smoking, small cancers may be missed without CT.

V.

CT and Patient Selection for LVRS

A. Deﬁning the Severity and Anatomical Distribution of Emphysema

Several investigators have demonstrated that the anatomical distribution of emphysema within the lungs on CT is a predictor of patient outcome after LVRS (3,5,6,47,52–56). This has been shown both with qualitative visual emphysema scoring systems (52–54) and quantitative analysis (3,5,6,47,55). In general, the more homogeneous the emphysema from lung apices to bases, the worse the outcome after surgery. Patients with either upper lobe– or lower lobe–predominant emphysema, that is, target areas for resection with other areas of relatively normal lung, experience the greatest improvements after LVRS. The best method for scoring or quantifying emphysema for LVRS selection has not yet been determined. Examples of some of the qualitative and quantitative CT investigations of LVRS outcome are described below.

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A qualitative assessment of preoperative HRCT and spiral CT images was performed in one series of 50 consecutive patients undergoing bilateral LVRS with video-assisted thoracoscopy. The patients with markedly heterogeneous pulmonary emphysema had signiﬁcantly greater improvement in FEV1 3 months after surgery, (81 + 17%) versus patients with intermediately heterogeneous emphysema (44 + 10%) and patients with homogeneous emphysema (34 + 6%) (53). In another study of 47 patients undergoing bilateral LVRS by either median sternotomy (n ¼ 15) or videoassisted thoracoscopy (n ¼ 32), a 4-point grading scheme for heterogeneity of emphysema and a 48-point scale for severity of lung parenchymal destruction was applied to HRCT and helical CT images. Four patients who died within 30 days of LVRS had signiﬁcantly greater parenchymal destruction scores than survivors (28.4 vs 21.3; P ¼ .003). The heterogeneity of emphysema correlated with postoperative improvements in FEV1 3 months after surgery (52). Similar results have been demonstrated using quantitative analysis. In a series of 46 patients undergoing bilateral LVRS, preoperative CT scans using 8- or 10-mm collimation in incremental mode (one scan was performed in helical mode) were compared to outcomes 6 months after surgery. Postoperative improvements in FEV1, PaO2, and 6-min walk distance were greater in patients with mean total lung attenuation values of more than 900 HU, an emphysema index with 75% or more of the upper half of the lung representing emphysema (threshold 900 to 1024 HU), a greater volume of lung in the normal attenuation range (701 to 850 HU), and a ratio of upper to lower lung emphysema indices of greater than 1.5, indicating greater regional heterogeneity of emphysema (6). Our work has demonstrated similar results with the three-dimensional density-masking technique applied to a single breath hold acquisition at 10-mm collimation with 2:1 pitch. This allows the entire lungs to be included in a single uninterrupted data set for interrogation with a commercially available CT workstation. It represents a compromise between resolution of detail and speed of acquisition (47,57). Although thinner collimation provides more detail, it would require several breath holds to complete, which the currently available analysis packages cannot readily evaluate as a single volume. Gierada et al. have demonstrated high repeatability of quantitative CT analysis of emphysema, with such measurements in LVRS candidates not signiﬁcantly improved by the addition of spirometric gating of the CT acquisition (50). By receiver operator curve analysis, we found that the emphysema ratio (percentage of emphysema in upper lungs divided by percentage of emphysema in the lower lungs) was the best single predictor of improvements in FEV1 and in 6-min walk distance 3, 6, 12, 18, and 24 months after bilateral apical LVRS performed through a median

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sternotomy. Our results extend the published CT outcome data from 3 to 6 months to 2 years after LVRS (58). We ﬁnd that the CT emphysema ratio correlates better with these outcomes than do measures of pulmonary hyperinﬂation (RV, TLC, RV/TLC), baseline FEV1, diffusing capacity, and other quantitative CT measures, such as the percentage of normal lower lung and the percentage of emphysema in the entire lungs. The prediction of outcome with the CT ratio is slightly improved when combined with either the RV, TLC, or RV/TLC. Rogers et al. have also demonstrated that CT measurements of emphysema severity are related to the improvement in maximal cardiopulmonary exercise after LVRS (59). Newer, multidetector helical CT scanners allow faster scanning at thinner collimation, acquiring images between 0.5- and 1.25-mm collimation of the entire lungs. These should improve the accuracy of helical CT quantitative assessment, and potentially improve the accuracy of predicting outcome after LVRS. B. Identiﬁcation of Incidental Lung Cancer

Patients with severe emphysema are at risk for developing lung cancer. Three different series of emphysematous patients being evaluated for LVRS or lung transplantation have reported a 5% incidence of bronchogenic carcinoma (60–62). These similar results have been reported with different scanning techniques, including both 10-mm contiguous axial images in two series (60,62) and HRCT with 1.0- to 1.5-mm collimation at 10-mm intervals in the third (61). In addition, 11–26% of patients have one or more pulmonary nodules suspicious for bronchogenic carcinoma identiﬁed during evaluation (60–64). Although the majority of such nodules prove to be benign, further evaluation with either follow-up serial CT, biopsy, or resection is warranted. Although positron emission tomography (PET) scanning shows promise in distinguishing malignant larger nodules, for many nodules, PET scanning is not an option because of their small size. Noncalciﬁed lung nodules were identiﬁed in 113 of 442 patients with severe emphysema being evaluated for LVRS in one series. Only 22% of the nodules exceeded 1 cm in size (63). It is important to note whether or not a nodule is within the area of lung that may be resected during LVRS. Some patients with insufﬁcient pulmonary function to tolerate conventional lung cancer surgery with lobectomy may be eligible for resection of the nodule during a combined LVRS procedure (64). Although the post-LVRS outcomes in patients undergoing combined nodule resection and LVRS have been reported to be poorer than after LVRS alone, in the past these patients were ineligible for potentially curative treatment of lung cancer (65).

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Scintigraphy and Patient Selection for LVRS

When emphysema is mild, perfusion and ventilation scintigraphy of the lungs demonstrates defects of perfusion in the absence of ventilation defects. With more severe emphysema, ventilation and perfusion defects are usually matched (66). Perfusion scintigraphy has been used to identify target areas for resection during LVRS (7–9,54,67–69). As with CT scanning, patients with heterogeneous upper lobe–predominant abnormality on perfusion scintigraphy, as demonstrated in Figure 3, have been shown to have greater improvements in FEV1 after surgery than patients with homogeneous perfusion scintigrams (68,69). Three-dimensional single-photon emission CT (SPECT) imaging performed in addition to planar perfusion imaging has not been shown to provide additional useful information in evaluating the size or severity of perfusion defects or in predicting outcome after LVRS (68).

(A) Figure 3 (A) A 72-year-old man with upper lobe–predominant emphysema demonstrated on HRCT and perfusion scintigraphy. HRCT image through the upper lobes at the level of the great vessels.

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(B) Figure 3 (B) The lower lungs demonstrate extensive upper lobe abnormal low attenuation and anatomical destruction with large geographical areas of normal lower lung.

Less attention has been given to ventilation scintigraphy. One investigator noted that half of the ventilation scans performed with a technetium 99 m diethylenetriaminepentacetate (DTPA) agent were not interpretable because of extensive central airway deposition of radiotracer (68). This problem does not occur when using a xenon 133 gas agent. However, technetium agents are replacing xenon for ventilation studies because of greater ease of administration. Since matched ventilation and perfusion defects are found when emphysema is severe, it is not surprising that ventilation scintigraphy has not been shown to be useful when added to perfusion scintigraphy in the evaluation of LVRS candidates (66).

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(C) Figure 3 (C) Anterior lateral projection from planar perfusion scintigraphy demonstrates large bilateral perfusion defects in the upper and middle portion of the lungs, with all perfusion to the lower third of the lungs. The relatively homogeneous perfusion at the lung bases masks the mild basilar emphysema identiﬁed on CT.

VII.

CT Versus Perfusion Scintigraphy

There are few published data that compare CT to lung perfusion scintigraphy for the selection of LVRS candidates, or correlate the CT ﬁndings with patterns of perfusion scintigraphy abnormality. Although the use of both modalities may provide complementary information, the importance of perfusion scanning has not yet been demonstrated. In a recent study of 70 patients undergoing bilateral LVRS with video-assisted

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(D) Figure 3 (D) Right lateral projection from planar perfusion scintigraphy demonstrate large bilateral perfusion defects in the upper and middle portion of the lungs, with all perfusion to the lower third of the lungs. The relatively homogeneous perfusion at the lung bases masks the mild basilar emphysema identiﬁed on CT.

thoracoscopy, both HRCT scans and technetium 99 m-labeled macroaggregated albumin (MAA) perfusion scintigrams were scored as either homogeneous, intermediately heterogeneous, or markedly heterogeneous. The functional improvement after LVRS correlated more closely with the degree of emphysema heterogeneity on HRCT and the severity of preoperative hyperinﬂation than with the degree of heterogeneity on

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perfusion scintigraphy (54). Of the 10 patients with homogeneous perfusion scintigrams, 3 were scored as intermediately heterogeneous and 1 as markedly heterogeneous on CT (54). Re-review of the imaging studies revealed that the peripheral boundaries of the upper lobes had been misinterpreted on perfusion images, and that a peripheral zone of decreased perfusion was present, correlating with the CT scan readings. Cleverley et al. recently demonstrated a strong correlation between lung perfusion, assessed by HRCT evaluation of the pulmonary vascularity, and lung perfusion on scintigraphy (r(s) ¼ 0.85, P < .00005), suggesting that perfusion scintigraphy may be superﬂuous in the preoperative evaluation of emphysematous patients for LVRS (70) In contrast, of the 22 patients in this series with homogeneous or diffuse emphysema on HRCT, 16 patients (73%) had heterogeneous perfusion scintigrams, 7 scored as intermediately heterogeneous and 9 scored as markedly heterogeneous (54). Two explanations were given for the disparity in HRCT and perfusion scintigram interpretations. First, whereas HRCT evaluates structure, scintigraphy evaluates regional perfusion. Because of regional differences in blood ﬂow, for example, due to hypoxic pulmonary vasoconstriction, abnormalities of structure and function need not coexist. Second, perfusion scintigraphy may be more sensitive to subtle differences in regional emphysema than is HRCT, as supported by the low prevalence of homogeneous perfusion scintigrams (10 of 70 or 14%) compared to homogeneous HRCT scans (22 of 70 or 31%). A comparison of HRCT and SPECT perfusion imaging in a porcine elastase-induced emphysema model supports this hypothesis (66). Mild emphysema produced decreased and impaired perfusion without detectable ventilation abnormalities. The SPECT perfusion studies were more sensitive than HRCT for the detection of these mild changes. This is consistent with the recognized insensitivity of HRCT for mild emphysema (20). During scintigraphic imaging, perfusion within the lungs is displayed relative to the rest of the lungs; that is, the perfusion agent has to be distributed somewhere in the lungs after injection of a ﬁxed amount of radiotracer. In contrast, the anatomical destruction of emphysema seen on CT is not dependent on whether the adjacent lung is normal or abnormal. If there is absent perfusion to the upper lobes, CT ﬁndings may demonstrate either upper lobe giant bullae or moderate to severe emphysema, whereas the lower lungs may be either normal or abnormal, as long as there is less vascular destruction in the lower lungs than in the upper lungs. Thus, although perfusion scintigrams may identify target areas for resection, they do not accurately depict the quality of the remainder of the lung parenchyma.

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Imaging Before and After LVRS

A. Computed Tomography

CT before and after LVRS has been used to evaluate the structural changes that occur following surgery. In one series of 28 patients undergoing video-assisted thoracoscopic unilateral LVRS, quantitative CT of lung volumes was performed before and after LVRS. Pixel values of 910 to 1024 HU were used to calculate the volume of emphysema; 5-mm collimation at 8-mm intervals was used in 21 patients and 10-mm collimation at 10-mm intervals in 7 patients. There was an average 22% decrease in lung volume, a 14% decrease in the percentage of emphysema and an increase in attenuation of 26 HU in the lung that had undergone resection without signiﬁcant changes in the contralateral lung (71). In a series of 10 patients undergoing bilateral LVRS via median sternotomy, CT scans were performed a mean of 4 months (range 2–12 months) after surgery. The CT scans were acquired with contiguous 10-mm axial images and a 5-s interscan delay. Emphysema volume was deﬁned with an upper boundary of 900 HU. The average inspiratory lung volume decreased 25%, from 7.5 Ls before surgery to 5.6 Ls after surgery. At full expiration, lung volumes decreased an average of 41%, from 6.4 to 3.8 Ls. The percentage of lung represented by emphysema on inspiratory images decreased from an average 60% prior to surgery to 38% (3). Finally, in a study of 28 patients undergoing LVRS (15 bilateral, 13 unilateral) using helical CT at 10-mm collimation with pitch 1:1, custom software with a seed growing algorithm and lung volume upper threshold of 500 HU, there was a 13% decrease in individual lung volume and a 20% reduction in individual lung RV in patients imaged an average of 6 months (range 73.2–8.4 months) after surgery (55) (The seed growing algorithm refers to selecting a pixel attenuation value in a structure and a range around that value that is to be included in the studied volume. The seed grows in all directions to form a volume as long as the attenuation value next to it falls within the selected range. If the next adjacent pixel is outside the desired range, the seed stops growing in that direction.) Lung attenuation increased an average of 9%. For patients undergoing unilateral LVRS, there was no signiﬁcant change in the RV of the contralateral lung after surgery, which implied no alteration in air trapping in the lung not undergoing reduction. Individual lung alterations in total and residual volume were independent of the contralateral lung. Several investigators have demonstrated changes in the morphology of the diaphragm after LVRS. For example, Quint et al. demonstrated that in

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patients with poor clinical outcome, surgery had little effect on diaphragm shape (72). They also demonstrated that the shape of the diaphragm in patients with a good clinical outcome differed from the preoperative shape of the diaphragm, and was similar to the shape of the diaphragm in normal patients. Cassart et al. demonstrated both an increased surface area of the diaphragm and a larger zone of apposition after LVRS using threedimensional CT reconstructions of the diaphragm in 11 patients before and after LVRS compared to 11 control subjects (73). B. Scintigraphy

Two investigations of perfusion and ventilation scintigraphy have compared the appearance before and after LVRS with similar ﬁndings. In these series of 11 and 29 patients each, perfusion scintigrams performed before and after LVRS demonstrated more uniform perfusion to the remaining lungs after surgery with disappearance of nonperfused areas (7,9).

IX.

Summary

LVRS has created a need and an opportunity for the advanced imaging of emphysema. Patients whose CT scans and/or perfusion scintigrams demonstrate a heterogeneous upper lobe or lower lobe predominant pattern of emphysema have better clinical outcomes after LVRS than patients with emphysema diffusely or homogeneously distributed throughout the lungs. Although some patients with diffuse or homogeneous emphysema often improve function or dyspnea after surgery, the magnitude of the improvement is less than in patients with heterogeneous emphysema. Care should also be taken to identify and anatomically describe the location of noncalciﬁed pulmonary nodules in this patient population, who are at high risk for bronchogenic carcinoma.

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Klein JS, Gamsu G, Webb WR, Golden JA, Mu¨ller NL. High-resolution CT diagnosis of emphysema in symptomatic patients with normal chest radiographs and isolated low diffusing capacity. Radiology 1992; 182(3):817–821. Chin NK, Lim TK. A 39-year-old smoker with effort dyspnea, normal spirometry results, and low diffusing capacity. Chest 1998; 113(1):231–233. Bae K, Slone R, Gierada D, Yusen R, Cooper J. Patients with emphysema: quantitative CT analysis before and after lung volume reduction surgery—work in progress. Radiology 1997; 203:705–714.

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19. Bergin C, Mu¨ller N, Nichols DM, Lillington G, Hogg JC, Mullen B, Grymaloski MR, Osborne S, Pare PD. The diagnosis of emphysema. A computed tomographic-pathologic correlation. Am Rev Respir Dis 1986; 133(4):541–546. 20. Miller RR, Mu¨ller NL, Vedal S, Morrison NJ, Staples CA. Limitations of computed tomography in the assessment of emphysema. Am Rev Respir Dis 1989; 139(4):980–983. 21. Remy-Jardin M, Remy J, Gosselin B, Copin MC, Wurtz A, Duhamel A. Sliding thin slab, minimum intensity projection technique in the diagnosis of emphysema: histopathologic-CT correlation. Radiology 1996; 200(3):665–671. 22. Hruban RH, Meziane MA, Zerhouni EA, Khouri NF, Fishman EK, Wheeler PS, Dumler JS, Hutchins GM. High resolution computed tomography of inﬂation-ﬁxed lungs. Pathologic-radiologic correlation of centrilobular emphysema. Am Rev Respir Dis 1987; 136(4):935–940. 23. Spouge D, Mayo JR, Cardoso W, Mu¨ller NL. Panacinar emphysema: CT and pathologic ﬁndings. J Comput Assist Tomogr 1993; 17(5):710–713. 24. Mu¨ller NL, Staples CA, Miller RR, Abboud RT. ‘‘Density mask.’’ An objective method to quantitate emphysema using computed tomography. Chest 1988; 94(4):782–787. 25. Gevenois PA, Yernault JC. Can computed tomography quantify pulmonary emphysema? Eur Respir J 1995; 8(5):843–848. 26. Gevenois PA, Zanen J, de Maertelaer V, De Vuyst P, Dumortier P, Yernault JC. Macroscopic assessment of pulmonary emphysema by image analysis. J Clin Pathol 1995; 48(4):318–322. 27. Gevenois PA, de Maertelaer V, De Vuyst P, Zanen J, Yernault JC. Comparison of computed density and macroscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med 1995; 152(2):653–657. 28. Gevenois PA, De Vuyst P, Sy M, Scillia P, Chaminade L, de Maertelaer V, Zanen J, Yernault JC. Pulmonary emphysema: quantitative CT during expiration. Radiology 1996; 199(3):825–829. 29. Sakai F, Gamsu G, Im JG, Ray CS. Pulmonary function abnormalities in patients with CT-determined emphysema. J Comput Assist Tomogr 1987; 11(6):963–968. 30. Sakai N, Mishima M, Nishimura K, Itoh H, Kuno K. An automated method to assess the distribution of low attenuation areas on chest CT scans in chronic pulmonary emphysema patients. Chest 1994; 106(5):1319–1325. 31. Sanders C, Nath PH, Bailey WC. Detection of emphysema with computed tomography. Correlation with pulmonary function tests and chest radiography. Invest Radiol 1988; 23(4):262–266. 32. Foster WL. Jr, Pratt PC, Roggli VL, Godwin JD, Halvorsen RA, Jr, Putman CE. Centrilobular emphysema: CT-pathologic correlation. Radiology 1986; 159(1):27–32. 33. Nishimura K, Murata K, Yamagishi M, Itoh H, Ikeda A, Tsukino M, Koyama H, Sakai N, Mishima M, Izumi T. Comparison of different computed

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47. Kazerooni E, Martinez F, Quint L, Whyte R. Quantitative helical CT indices of emphysema as predictors of outcome after lung volume reduction surgery. Radiology 1996; 201(P):298. 48. Kazerooni EA, Whyte RI, Flint A, Martinez FJ. Imaging of emphysema and lung volume reduction surgery. Radiographics 1997; 17(4):1023–1036. 49. Kauczor HU, Heussel CP, Fischer B, Klamm R, Mildenberger P, Thelen M. Assessment of lung volumes using helical CT at inspiration and expiration: comparison with pulmonary function tests. Am J Roentgenol 1998; 171(4):1091–1095. 50. Gierada DS, Yusen RD, Pilgram TK, Crouch L, Slone RM, Bae KT, Lefrak SS, Cooper JD. Repeatability of quantitative CT indexes of emphysema in patients evaluated for lung volume reduction surgery. Radiology 2001; 220(2):448–454. 51. Adusumilli S, Kazerooni E, Martinez F. Distribution of pulmonary emphysema: comparison of chest radiography to CT. Radiology 1998; 209(P):256– 257. 52. Wisser W, Klepetko W, Kontrus M, Bankier A, Senbaklavaci O, Kaider A, Wanke T, Tschernko E, Wolner E. Morphologic grading of the emphysematous lung and its relation to improvement after lung volume reduction surgery. Ann Thorac Surg 1998; 65(3):793–799. 53. Weder W, Thurnheer R, Stammberger U, Burge M, Russi EW, Bloch KE. Radiologic emphysema morphology is associated with outcome after surgical lung volume reduction. Ann Thorac Surg 1997; 64(2):313–9; discussion 319– 320. 54. Thurnheer R, Hermann E, Weder W, Stannberger U, Laube I, Russi E, Bloch K. Role of lung perfusion scintigraphy in relation to chest computed tomography and pulmonary function in the evaluation of candidates for lung volume reduction surgery. Am J Respir Crit Care Med 1999; 159:301–310. 55. Becker MD, Berkmen YM, Austin JH, Mun IK, Romney BM, Rozenshtein A, Jellen PA, Yip CK, Thomashow B, Ginsburg ME. Lung volumes before and after lung volume reduction surgery: quantitative CT analysis. Am J Respir Crit Care Med 1998; 157(5 Pt 1):1593–1599. 56. Gierada DS, Yusen RD, Villanueva IA, Pilgram TK, Slone RM, Lefrak SS, Cooper JD. Patient selection for lung volume reduction surgery: An objective model based on prior clinical decisions and quantitative CT analysis. Chest 2000; 117(4):991–998. 57. Kazerooni EA, Curtis JL, Paine R, Iannettoni MD, Lewis P, and Martinez FJ. Long-term outcome after bilateral apical lung volume reduction surgery (LVRS) via median sternotomy: predictive value of quantitative helical CT analysis (QCT) and physiologic severity of hyperinﬂation. Radiology 1998; 209(P):257. 58. Flaherty K, Kazerooni E, Curtis J, Iannettoni M, Lange L, Schork M, Martinez F. Short-term and long-term outcomes after bilateral lung volume reduction surgery. Prediction by quantitative CT. Chest 2001; 119:1337–1346.

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59. Rogers RM, Coxson HO, Sciurba FC, Keenan RJ, Whittall KP, Hogg JC. Preoperative severity of emphysema predictive of improvement after lung volume reduction surgery: use of CT morphometry. Chest 2000; 118(5):1240– 1247. 60. Rozenshtein A, White CS, Austin JH, Romney BM, Protopapas Z, Krasna MI. Incidental lung carcinoma detected at CT in patients selected for lung volume reduction surgery to treat severe pulmonary emphysema. Radiology 1998; 207(2):487–490. 61. Kazerooni EA, Chow LC, Whyte RI, Martinez FJ, Lynch JP. Preoperative examination of lung transplant candidates: value of chest CT compared with chest radiography. Am J Roentgenol 1995; 165(6):1343–1348. 62. Slone R, Gierada D, Lopes T. Unsuspected bronchogenic carcinoma in patients with severe pulmonary emphysema being evaluated for lung volume reduction surgery. Am J Roentgenol 1997; 168(A):112. 63. Adusumilli S, Kazerooni E, Ojo T. Screening CT for lung cancer: a study of emphysema patients being evaluated for lung volume reduction surgery. Radiology 1998; 209(P):222–223. 64. McKenna RJ. Jr, Fischel RJ, Brenner M, Gelb AF. Combined operations for lung volume reduction surgery and lung cancer. Chest 1996; 110(4):885– 888. 65. Ojo TC, Martinez F, Paine R. 3rd, Christensen PJ, Curtis JL, Weg JG, Kazerooni EA, Whyte RI. Lung volume reduction surgery alters management of pulmonary nodules in patients with severe COPD. Chest 1997; 112(6):1494– 1500. 66. Noma S, Moskowitz GW, Herman PG, Khan A, Rojas KA. Pulmonary scintigraphy in elastase-induced emphysema in pigs. Correlation with highresolution computed tomography and histology. Invest Radiol 1992; 27(6):429– 435. 67. Suga K, Nishigauchi K, Shimizu K, Kawamura T, Matsumoto T, Matsunaga N, Sugi K, Esato K. (Usefulness of 3-D dynamic pulmonary xenon-133 SPECT for thoracoscopic lung volume reduction surgery in patients with pulmonary emphysema.) Nippon Igaku Hoshasen Gakkai Zasshi–Nippon Acta Radiol 1997; 57(4):215–216. 68. Jamadar D, Kazerooni E, Martinez F, Wahl R. Semi-quantitative ventilationperfusion scintigraphy and single photon emission computed tomography for evaluation of lung volume reduction surgery candidates: description and prediction of clinical outcomes. Eur J Nucl Med 1999; 26:734–742. 69. McKenna RJ. Jr, Brenner M, Fischel RJ, Singh N, Yoong B, Gelb Af, Osann KE. Patient selection criteria for lung volume reduction surgery. J Thorac Cardiovasc Surg 1997; 114(6):957–964; discussion 964–967. 70. Cleverley JR, Desai SR, Wells AU, Koyama H, Eastick S, Schmidt MA, Charrier CL, Gatehouse PD, Goldstraw P, Pepper JR, Geddes DM, Hansell DM. Evaluation of patients undergoing lung volume reduction surgery: ancillary information available from computed tomography. Clin Radiol 2000; 55(1):45–50.

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71. Holbert J, Brown M, Sciruba F, Keenan R, Landreneau R, Holzer A. Changes in lung volume and volume of emphysema after unilateral lung reduction surgery: analysis with CT densitometry. Radiology 1996; 201:793– 797. 72. Quint LE, Bland PH, Walker JM, Kazerooni EA, Martinez FJ, Iannettoni MD, Bookstein FL. Diaphragmatic shape change after lung volume reduction surgery. J Thorac Imag 2001; 16(3):149–155. 73. Cassart M, Hamacher J, Verbandt Y, Wildermuth S, Ritscher D, Russi EW, de Francquen P, Cappello M, Weder W, Estenne M. Effects of lung volume reduction surgery for emphysema on diaphragm dimensions and conﬁguration. Am J Respir Crit Care Med 2001; 163(5):1171–1175.

9 The Interface of Lung Volume Reduction Surgery and Lung Transplantation

JONATHAN B. ORENS Johns Hopkins Medical Institutions Baltimore, Maryland, U.S.A.

I. Introduction The ﬁrst human lung transplant is credited to Hardy and colleagues (1), who performed this procedure in 1963. The patient suffered from emphysema and lung cancer and would not have survived resection without transplantation. Unfortunately, the patient died on the 18th postoperative day, raising questions about the utility of this procedure. Nearly 20 years passed before lung transplantation was ﬁnally successful. With signiﬁcant improvement in survival and functional outcomes since Hardy’s ﬁrst attempt, this procedure is now a widely accepted therapeutic option for patients with end-stage lung disease (2). As with other solid organ transplants, the success of lung transplantation followed the introduction of the immunosuppressive drug cyclosporine A in the early 1980s (3). Since then, with some modiﬁcations to the surgical technique, lung transplantation is now performed routinely to prolong the life and functional capabilities of patients with end-stage lung disorders. Given the high prevalence of emphysema, it is not surprising that this is the most common diagnosis for which lung transplantation is performed (2). For selected patients with severe end-stage emphysema, lung 201

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transplantation offers the possibility of improved survival and functional status (2,4,6). However, despite major strides in the ﬁeld, there are still numerous shortcomings associated with this procedure, including the lack of available donor lungs, requirement for lifelong immunosuppression, acute and chronic allograft rejection, infection, and extremely high ﬁnancial costs of the procedure and posttransplant care. Furthermore, waiting periods average 1.5–2.0 years. These problems have motivated clinical investigators to search for other treatments such as lung volume reduction surgery (LVRS) to alleviate emphysema’s devastating symptoms. Initially described in the 1950s, LVRS was reintroduced by Cooper et al. in part to help patients waiting extremely long periods of time for lung transplantation (7,10). Many centers now offer LVRS for selected patients with end-stage emphysema either as an alternative or ‘‘bridge’’ to transplantation (11,12). This chapter will review the potential utility of LVRS in the context of lung transplantation.

II.

Candidate Selection for Transplantation

Appropriate candidates for lung transplantation have end-stage lung disease without concomitant illness that would adversely affect their survival following transplant (Table 1). In selecting candidates, several issues must be considered, including the patient’s pulmonary disability and projected survival without transplantation, comorbid conditions, and the ﬁnancial cost of the procedure. Although estimating survival without transplantation is difﬁcult, it is critical to selecting the appropriate timing for lung transplantation. This is because, after matching for ABO blood type and body size, the priority for obtaining a donor lung is based solely upon the duration of time accrued on the waiting list. This is unlike other solid organ

Table 1 General Selection Guidelines for Lung Transplantation (Johns Hopkins Hospital) End-stage pulmonary parenchymal and/or vascular disease (lung disease not responsive to any form of medical or surgical intervention) Projected life expectancy of less than 2 years Severely limited in activities of daily living due to lung disease Preserved left ventricular function without signiﬁcant coronary artery disease Acceptable nutritional status Satisfactory psychosocial proﬁle with adequate support systems (family or friends)

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transplants where consideration is given to the severity of the recipient’s disease. Therefore, in order to select the optimal time to list patients, one must carefully weigh the candidate’s projected survival without transplantation against the projected waiting period for a lung. To assure some consistency among lung transplant centers, four major societies have proposed disease-speciﬁc criteria to guide the selection of candidates. The American Thoracic Society (ATS), European Respiratory Society (ERS), International Society For Heart and Lung Transplantation (ISHLT), and the American Society of Transplant Physicians (ASTP) have each proposed selection guidelines for lung transplantation which have been published in a joint statement (13). Although these guidelines were proposed to develop standards and consistency across centers, individual programs continue to use their own selection criteria, which vary from center to center. Thus, a candidate who is unacceptable at one program may be considered to be acceptable elsewhere. We will present the criteria used at our center, which overlap with the proposed recommendations from each of these societies. There are both absolute and relative contraindications to transplantation (Table 2). These criteria are based upon the impact of coexisting problems on the potential for short- and long-term success following transplantation. It is also important to note that these criteria are utilized only as general guidelines to help select potential candidates. Thus, in special circumstances, individual patients may still be accepted for transplantation even if they do not meet all of the criteria in these guidelines.

III.

Timing of Transplantation

The transplantation must be carefully timed such that the transplant is performed when the patient is neither too well nor too ill. Furthermore, given the long waiting periods for transplantation, predictions must be made about a patient’s course prior to the time of transplantation. Unfortunately, despite the high prevalence of this disease, limited data exist regarding longterm survival with emphysema. Traver et al. (14) showed that the combination of a low FEV1 (forced expiratory volume in 1 s), advanced age, and a low arterial oxygen level had a negative impact on survival. In this population the overall 2-year survival was 44%. However, the 2-year survival in the subgroup of younger patients with a postbronchodilator FEV1 of 430% of predicted normal and less than aged 65 years was near 70%. In a similar group of patients with severe emphysema with hypoxemia, The Nocturnal Oxygen Treatment Trial (15) documented improvement in survival with the use of supplemental oxygen. Another large study of

204 Table 2

Orens Contraindications to Lung Transplantation (Johns Hopkins Hospital)

Relative contraindications Age: >65 for single lung transplantation (SLT) >60 for bilateral single lung transplantation (BLT) >55 for heart and lung transplantation (HLT) Psychosocial instability Mechanical ventilation Chest wall deformity Asymptomatic osteoporosis History of substance abuse Weight outside of acceptable range (morbid obesity or severely malnourished) Prednisone use >20 mg/day or 40 mg QOD Bilateral pleurodesis (for cardiopulmonary bypass candidates) Absolute contraindications HIV infection Bone marrow failure Cirrhosis of the liver or active hepatitis B or C infection Chronic renal failure (creatinine clearance <50 mL/min) Malignancy precluding long-term survival Other life-limiting conditions Active tobacco smoking or other substance abuse Signiﬁcant coronary artery or peripheral vascular disease Impaired left heart function unless considered for heart transplant Severe symptomatic osteoporosis Sputum growing antibiotic pan-resistant bacteria

nonhypoxemic patients with a postbronchodilator FEV1 of 430% of predicted and aged less than 65 years documented a 75% 2-year survival (16). Since the 2-year survival for lung transplantation is approximately 70% for recipients with emphysema (2), it would seem reasonable that these patients be offered lung transplantation when the postbronchodilator FEV1 is <25% of predicted provided there are no other extenuating issues. In practice, the mean FEV1 of emphysematous patients transplanted at most major centers is approximately 20% (3). At our center, however, problems such as advanced functional impairment, severe hypoxemia and hypercapnia, cor pulmonale, frequent hospitalizations, and recurrent infections may relax the FEV1 requirement. Conversely, negative factors such as

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concomitant illness, poor nutritional status, and psychosocial instability must also be considered. IV.

Type of Transplant Procedure

The type of transplant procedure for emphysema varies somewhat from center to center. Single-lung transplant (SLT) is most commonly performed, although some centers offer sequential double-lung transplantation (DLT) for this disease. Both procedures have advantages and disadvantages. The long-term survival is slightly better for DLT compared to SLT (2). Pulmonary function test (PFT) improvements are better with DLT, although the differences in exercise tolerance with DLT over SLT are not striking (17,19). Importantly with SLT, two patients may beneﬁt from a single donor. With single-lung procedures, native lung hyperinﬂation may occur in the immediate postoperative period. This may be very difﬁcult to manage, particularly while the patient remains on mechanical ventilation. This problem more commonly occurs in patients with severe bullous disease, and this is the group that is sometimes offered double-lung procedures (6). Recently, LVRS of the native lung has been suggested as a method to prevent this problem (see Sec. XII). V. Immunosuppression Following lung transplantation, recipients must remain on lifelong immunosuppression to prevent allograft rejection. Unfortunately, there are numerous side effects associated with immunosuppressive medications, and the long-term complications associated with these drugs is part of the stimulus to search for alternative treatment short of transplantation. The major consequence of long-term immunosuppression is an increased rate of infection. Following transplantation there is an increased risk for bacterial, viral (particularly cytomegalovirus [CMV]), and fungal infections (20,21). Risk of infection relates inversely to the duration of time from the transplant procedure (20,21). This is due in part to both mechanical factors and the intensity of immunosuppression (20,22). Although the risk of infection decreases as the amount of immunosuppression is reduced over time, the risk never returns to that of normal individuals. Other risks of immunosuppression relate speciﬁcally to each drug. Our center uses a triple drugbased regimen including cyclosporine A, azathioprine, and prednisone. Other commonly used agents include tacrolimus (FK-506) and mycophenolate mophetil (Cellcept), which may be substituted for cyclosporine and azathioprine, respectively. Both cyclosporine and tacrolimus may induce

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hypertension and nephrotoxicity, whereas azathioprine and mycophenolate produce leukopenia. Long-term corticosteroid use is associated with a litany of problems including osteoporosis, skin bruising, hyperglycemia, cataracts, and myopathy. In addition, long-term immunosuppression increases the risk of cancer, particularly posttransplant lymphoproliferative disorder. This has been reported at a rate of around 6% following solid organ transplants (23). VI.

Survival Following Transplantation

The ISHLT/UNOS lung transplant registry currently shows a 1- and 5-year actuarial survival of 71 and 45% respectively, for all lung transplants performed (2). Short- and long-term survival depends upon the underlying disease. Patients with emphysema have the best survival statistics, whereas patients who undergo retransplantation fare the worst. There are a number of factors responsible for early mortality (less than 90 days). These include infection (35%), primary graft failure/reperfusion injury (13%), heart failure (9%), acute rejection (5%), bleeding (6%), anastomotic dehiscence (5%), and other causes (27%) (24). The factors responsible for late mortality differ from the data for early mortality. Although infection remains the most common cause of death (30%), beyond 90 days, the rate of infection may be inﬂuenced by the presence of chronic rejection manifested pathologically as obliterative bronchiolitis (OB). This is due to a higher rate of pneumonia and bacterial colonization of the lungs in patients who develop OB. Obliterative bronchiolitis occurs in at least 40% of patients by 2 years, and is the cause of death in 50% of those affected. Other causes of late mortality include malignancy (6%), respiratory failure (5%), bleeding (4%), and other (26%). Although data from the early days of lung transplantation did not show a survival advantage for either SLT or DLT, recent data suggest a slight survival advantage for double-lung recipients (2). Possible explanations for the survival advantage include younger age of double-lung recipients, posttransplant complications related to the native lung in singlelung procedures, and more lung reserve to offset the deleterious effects of obliterative bronchiolitis in double-lung recipients. VII.

Functional Outcomes of Transplantation

Functional outcomes were recently analyzed in the 2001 ISHLT report representing data through March 2001 (2). At 3 years posttransplant, almost 90% of surviving recipients reported no activity limitations, whereas the majority of the remaining patients were able to perform activity with some assistance, and only a few required total assistance. Despite the functional

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improvements, only a minority of patients (<30%) were working full-time by 3 years posttransplant. Nearly 55% required repeat hospitalization during the ﬁrst year, although by the third postoperative year this fell to 40%. The most common reasons for hospitalization was allograft rejection and infection. Although data are limited, studies have assessed speciﬁc measurements of lung function and exercise tolerance following lung transplantation. Functional improvements may be limited by complications such as pleural scarring, chest wall changes, and phrenic nerve injury. Additionally, in single-lung transplantation, functional outcome is in part dependent upon the underlying disease, as the native lung contributes to overall lung function (3). Thus, in obstructive lung disease, a component of airﬂow obstruction may persist, whereas in interstitial lung disease, a component of restrictive change may persist. Following SLT, FEV1 is expected to rise to 50–57% of predicted for COPD patients and the forced vital capacity (FVC) to about 69% of predicted (5,17,18,25). DLT recipients enjoy a higher improvement in overall lung function with an FEV1 of 78–85% and FVC of 66–92% of predicted (17,25,26). Interestingly, during cardiopulmonary exercise testing, both work rate and maximal VO2 achieved are not signiﬁcantly different between recipients of SLT and DLT (17). In stable patients without additional complicating factors, there is no ventilatory limitation during exercise, assessed at 3 months and through the ﬁrst postoperative year regardless of whether a SLT or DLT is performed (17). Other studies conﬁrm a signiﬁcant rise in VO2max (19,27,30) and 6-min walk distance (31) and improvement in NYHA functional class (32,33) following all forms of lung transplantation.

VIII.

Quality of Life Following Transplantation

Despite widespread use of lung transplantation, few studies assess quality of life in recipients. Gross and colleagues (34) documented overall improvement in quality of life following lung transplantation assessed by the Medical Outcomes Health Survey (MOS)-20 health proﬁle. Over the long-term, the beneﬁt persists except in those patients who develop chronic rejection. Although exercise tolerance, pulmonary function, and quality of life improve following lung transplantation, only a minority of patients return to full-time work. The reason(s) that so few recipients return to work is not well known. Following transplantation the majority of patients reach functional levels that should not limit their physical ability to work in a variety of occupations. However, many transplant recipients are unable to work because of ﬁnancial constraints. For some, returning to work means

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giving up disability insurance beneﬁts that cover their long-term medications and posttransplant medical care. Increasingly, lung transplantation in emphysema is being questioned because of the morbidity and mortality of the procedure as it compares to the natural history of this disease. Although low FEV1 in emphysematous patients carries a high mortality in aggregate, some patients with severe emphysema may live for many years, albeit with signiﬁcant dyspnea and poor functional status. Furthermore, emphysematous patients are the least likely to die from their illness while awaiting transplantation when compared to those with diseases such as idiopathic pulmonary ﬁbrosis, pulmonary hypertension, and cystic ﬁbrosis (35). Thus, from a mortality standpoint alone, for a given patient with emphysema, the risk/beneﬁt ratio may not favor transplantation. However, the major argument in favor of transplantation is the superior functional beneﬁt that can be obtained with a successful transplantation. IX.

LVRS and Transplantation

Because of the extremely long waiting time for transplantation and the signiﬁcant disability of patients with severe emphysema, some centers now offer LVRS for selected patients being considered for transplantation. The procedure has also been applied to patients who have undergone SLT. In the former group, LVRS is suggested by some to serve as a bridge to transplantation. In the latter group, LVRS may be utilized to improve symptoms and lung function for patients with complications, such as native lung hyperinﬂation or chronic allograft rejection. A. LVRS as a Bridge to Transplantation

This term is a misnomer, as it implies that LVRS allows some patients to survive to transplant who would otherwise have died. No studies convincingly demonstrate improved survival for patients who undergo LVRS, nor is it intuitively obvious that interposing an elective operation with its own surgical mortality should improve survival. Indeed, the National Emphysema Treatment Trial investigators recently reported a group of emphysematous patients at excessive risk of mortality from LVRS. These constituted the patients with the most advanced emphysema, an FEV1 <20% predicted, and either a carbon monoxide diffusing capacity less than 20% predicted or homogeneous emphysema by computed tomographic (CT) scan. These features would describe many patients awaiting lung transplantation for COPD. The 30-day post-LVRS mortality in this group was 16%, and the mortality did not plateau (at about 35%) until 6 months

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after surgery (36). Although FEV1 correlates with survival in COPD and LVRS can increase FEV1, it has also not been shown that successful LVRS carries with it the survival advantage of the improved spirogram. This is an important consideration, since a major goal for transplantation is to prolong survival while also providing symptomatic relief. The current literature does support the potential of LVRS to improve symptoms such as dyspnea and to improve pulmonary function (10,37). However, there are limited studies of LVRS in patients awaiting transplant (12,38,40). In one short-term study, Zenati et al. (12) reviewed the University of Pittsburgh’s experience in LVRS for patients listed for lung transplantation. Ninety-ﬁve patients were evaluated for transplantation. Of this group, 45 patients were accepted for both LVRS and transplant and 35 patients underwent LVRS. Of the 35 patients in the LVRS group, there was no perioperative mortality. Only 30 patients had 3-month follow-up PFT data. In those, signiﬁcant increases in FEV1 and FVC were documented (0.64–0.97 L and 2.12–2.76 L, respectively). There were also signiﬁcant improvements in maximum voluntary ventilation, 6-min walk distance, Borg dyspnea index, and arterial carbon dioxide tension. Because of these clinical improvements by LVRS, 20 patients were placed on an inactive status for lung transplantation (no longer accruing time for transplant). The 10 patients who remained on the active transplant list had not achieved the same beneﬁt from LVRS in terms of improvement in FEV1 (27 vs. 70%) or FVC (18 vs. 41%). Of these 10 patients, 7 were ‘‘bridged to transplant’’ over an average period of 11 months. Although it is interesting that these investigators were able to use LVRS as an alternative to transplantation for a small group of patients (n ¼ 20), there are no further publications documenting the long-term outcome of this approach. Furthermore, what Zenati et al. meant by ‘‘bridged to transplant’’ is unclear. In this context the term bridge implies either prolonging survival or providing a marked improvement in symptoms or physiology while waiting for transplantation. Since this study lacked a control group, it remains uncertain if such patients could have fared as well without the extra procedure while awaiting transplantation. Gaissert et al. (38) documented the Washington University experience with LVRS in patients considered for transplant. They performed a retrospective study comparing the survival and functional outcomes after these procedures for patients with severe emphysema having a minimum of 6 months of follow-up. The three groups consisted of patients who underwent bilateral LVRS via median sternotomy (n ¼ 33), unilateral transplant (n ¼ 39), and bilateral transplant (n ¼ 25). All patients underwent supervised exercise rehabilitation prior to either procedure. Inclusion criteria for LVRS included severe dyspnea with hyperinﬂation, thoracic

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distention, ﬂattened diaphragms, and heterogeneous destruction of the lung by emphysema (usually upper lobes). Patients were excluded from LVRS if they were older than 80 years, had pulmonary artery hypertension (mean >35 mmHg, systolic >45 mmHg), severe kyphosis, chronic bronchitis, bronchiectasis, or asthma. Gaissert et al. also avoided LVRS in patients with very severe lung destruction marked by FEV1 <15% of predicted, the need for >6 L supplemental oxygen at rest, or severe carbon dioxide retention (PaCO2 >55 mmHg). However, it is not clear if all such patients were excluded from LVRS in this study. Candidates for lung transplantation were less than 65 years old and had severely limiting emphysema with an FEV1 of <20% of predicted. These patients also had to be free of signiﬁcant coronary artery disease, left ventricular dysfunction, or other signiﬁcant organ dysfunction. Although the mean age of the patients was similar (55 years for transplant vs. 57 years for LVRS), the patients in the LVRS group were less severely ill than those in the two transplant groups, as manifested by a higher FEV1 (18 and 16% for transplant vs. 25% for LVRS), PaO2 (52 and 56 mm Hg vs. 62 mmHg), and longer 6-min walk distance (703 and 830 ft vs. 917 ft). Thus, these groups were not equivalent from a clinical standpoint. Thirty-day mortality for LVRS, SLT, and DLT was 0, 2.5, and 8.0%, respectively. Late mortality (30 days to 1 year) for the same groups was 3.0, 10.2, and 16%, respectively. All three procedures provided signiﬁcant improvements in physiological parameters including lung function, exercise tolerance, and gas exchange. At 6 months after surgical intervention, FEV1 increased by 79% in the LVRS group, 231% in the SLT group, and 498% in the DLT group (Fig. 1). Six-minute walk distance at 6 months improved by 28, 47, and 79% for the LVRS, SLT, and DLT groups, respectively. Gaissert et al. (3) suggest that the improvement obtained by LVRS may provide selected patients with enough symptomatic relief to prolong the time until the need for transplantation. Thus, for the group of patients who are candidates for both LVRS and transplantation, LVRS may provide a therapeutic option without the long wait for transplantation and the risks associated with the transplant procedure and long-term immunosuppression. Despite this interesting perspective, there are no randomized studies assessing the long-term outcome of emphysematous patients eligible for both LVRS and transplantation.

X.

Choosing LVRS Prior to Transplantation

There are few patients with severe emphysema who will meet eligibility criteria for both LVRS and transplantation simultaneously. For example, a

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Figure 1 FEV1 3, 6, and 12 months after surgery for bilateral lung transplant (BLT), single lung transplant (SLT), or lung volume reduction (VR). (From Ref. 38, with permission.)

patient older than 65 years but who would otherwise have met criteria for both procedures would be eligible only for LVRS. Conversely, a younger patient with severe emphysema complicated by pulmonary hypertension, marked CO2 retention, or diffusely damaged lungs would be a candidate only for transplantation. The quandary arises with a young patient who has severely limiting symptoms with an FEV1 of less than 30% of predicted and otherwise meets the criteria for both procedures. Since prior uncomplicated LVRS does not preclude future transplantation, we will offer LVRS in an attempt to improve symptoms and quality of life while the patient awaits the transplant procedure. If the LVRS provides symptomatic and physiological beneﬁt, some patients may be placed on an inactive status for transplantation (no longer accruing time on the waiting list) until such time that their symptoms or physiology worsen. This approach may thereby delay the risks of transplantation and immunosuppression. Admittedly, this also incurs the risks of poor LVRS outcome and hastened death. In counseling patients about LVRS in this setting, it is important to recognize that lung transplantation cannot be offered emergently to a patient who has a bad outcome such as respiratory failure following LVRS. Currently, our center selects patients for these procedures based upon the results of a standard evaluation protocol. Patients are usually referred

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from an outside pulmonologist or internist. Based upon a review of their records, formal evaluation proceeds guided by a physician from the advanced lung disease team. Further testing is obtained if there are no obvious contraindications to transplantation or LVRS. Studies performed at our center include PFTs (spirometry, lung volumes by body plethysmography, and carbon monoxide diffusing capacity (DLCO), resting arterial blood gas breathing room air, chest imaging with standard posteroanterior (PA) and lateral chest radiograph, standard and high-resolution chest CT scans, quantitative V/Q scanning, echocardiogram, and dobutamine thallium stress testing). Right- and left-sided cardiac catheterization is performed if the noninvasive cardiac studies are abnormal or nondiagnostic. All health maintenance issues (e.g., rectal examination PSA level, mammography) must be up to date without signiﬁcant abnormalities. Patients with a heterogeneous distribution of emphysema by CT scanning and V/Q scanning, marked hyperinﬂation and air-trapping with a residual volume (RV) of >200% of predicted, pulmonary artery systolic pressure 445 mmHg, and a PaCO2 of 455 mmHg without exclusionary comorbidities are offered LVRS while awaiting transplantation. Importantly, patients are warned that there are limited data on the efﬁcacy of LVRS, and if the LVRS procedure results in signiﬁcant complications, this could hinder their chance of having a future transplant. Patients are offered transplantation alone if they do not meet the strict criteria for LVRS but are otherwise good candidates for transplantation (Table 3).

Table 3 Inclusion Criteria for Lung Transplantation and LVRS in COPD (Johns Hopkins Hospital) Transplant Age <65 years Postbronchodilator FEV1 425% predicted Resting PO2 <55 mmHg PCO2>55 mmHg Signiﬁcant pulmonary hypertension Clinical course: Declining FEV1 Life-threatening exacerbations Severe exercise limitation as measured by 6-min walk or cardiopulmonary exercise test

LVRS Age <75 years Postbronchodilator FEV1 <45% predicted RV >200% predicted PCO2<55 mmHg PA systolic <45 mmHg Heterogeneous emphysematous changes by high-resolution chest CT scan Severe exercise limitation as measured by 6-min walk or cardiopulmonary exercise test

The Interface of LVRS and Lung Transplantation XI.

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Type of LVRS Procedure Prior to Transplantation

The best surgical approach to LVRS in patients who are transplant candidates is unknown. Speciﬁcally, should the procedure be unilateral or bilateral, and should it be performed via median sternotomy or videoassisted thoracoscopy (VATS)? One approach is to perform only unilateral LVRS in this group, leaving one side of the chest free from surgery to allow an easier future implantation of a SLT. Although scarring in the chest from previous LVRS may present some technical problems during transplantation, our group still prefers to offer bilateral LVRS. This is because the functional outcomes appear to be superior for bilateral LVRS compared to the unilateral procedure, which increases the chances of successfully postponing transplantation. However, we prefer to perform the LVRS with VATS instead of median sternotomy in order to keep mediastinal structures free of scarring in anticipation of transplantation. Additionally, pleurodesis is avoided in order to facilitate future explanation of the native lungs.

XII.

LVRS During and Following SLT

Compared to SLT alone, combining simultaneous LVRS of one lung while transplanting the other is reported to achieve better pulmonary function (41). Despite this encouraging report, few transplant centers currently follow this practice. Unilateral LVRS of the native lung is performed at some centers when symptomatic native lung hyperinﬂation occurs. We performed lung volume reduction via VATS on the native lung in a 65-year-old patient who was 1 year posttransplant and had developed OB associated with modest dysfunction of the allograft combined with marked hyperinﬂation of the native lung. The surgery was performed without complications, and the patient realized marked improvement in shortness of breath, exercise tolerance, and pulmonary function (Table 4). Another such patient was ventilator dependent for nearly 6 months before undergoing LVRS of her native lung at our institution. Although her postoperative course and recovery were stormy, she was weaned from the ventilator and recently helped carry the Olympic torch as it passed through Baltimore on route to Salt Lake City. There have been a few published examples similar to ours (42,44). Venuta et al. (43) documents a 44-year-old female patient who underwent uncomplicated SLT for emphysema. At 1-year post transplant FEV1 was 1.6 L but fell to 0.53 L at 3 years. Following LVRS, the FEV1 rose to 1.8 L. Additionally, the patient’s 6-min walk distance increased from 230

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Table 4 Unilateral LVRS Following SLT in a Patient with Chronic Allograft

Rejection

Pretransplant 6 months posttransplant 9 months posttransplant (1 week prior to LVRS) 6 months post-LVRS

FEV1

FVC

TLC

RV

DLCO

1.04(27) 1.66(51) 1.07(33)

3.32(67) 3.37(68) 2.93(61)

10.2(138)

6.65(273)

12.9(57)

a

a

a

8.15(115)

5.24(202)

12.3(55)

1.89(63)

4.18(96)

7.55(119)

3.38(141)

13.1(62)

FEV1, forced expiratory volume in 1s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume; DLCO, carbon monoxide diffusing capacity. a Test not performed.

up to 590 m following LVRS. Anderson et al. (44) published three similar cases in which successful LVRS was performed on the hyperinﬂated native lung of recipients of SLT. Each of these patients had marked overdistention of the native lung with depression of the hemidiaphragm and displacement of the mediastinum to the side of the allograft. The patients in this series demonstrated a mean improvement of 35% in VO2max, 500 mL (63%) in FEV1, and 900 mL (67%) in FVC at 3 months following LVRS. These cases suggest a possible utility for LVRS in this setting; however, further studies are necessary to assess the true beneﬁt of this procedure in the short and long term for posttransplant patients. XIII.

Comparison of Costs for LVRS and Transplantation

The ﬁnancial impact of both LVRS and lung transplantation are not trivial. In fact, the high cost of lung transplantation has been a motivating factor for Medicare and other third-party payers to offer reimbursement for this procedure only to approved centers of excellence. Ramsey et al. (45) outlined the overall costs of lung transplantation for the University of Washington Medical Center. The average charges for the transplantation procedure and immediate postoperative care were $164,989 (median $152,071). The posttransplant average monthly charges during the ﬁrst 6 months were $16,628, in the second 6 months $5440, but fell to $4525 thereafter. This compared to the average monthly charges for patients on the waiting list of $3395. Although these ﬁgures come from a single center, they do not differ substantially from reports of other centers (46,47). The cost of LVRS seems to be less than for transplantation, although long-term analysis is lacking. The mean hospital costs associated with LVRS reported at one center is $30,976 with a range of $11,712–$121,829 (48). The

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wide variation in charges was related to complications and length of stay. Other reports estimate the charges for LVRS via median sternotomy to range from $30,000 to $45,000 (49,50). Data are not reported on the longterm care of patients following LVRS. However, much of the posttransplantation costs are for immunosuppressive medications and surveillance bronchoscopic biopsies that are unnecessary after LVRS. Therefore, barring the need for much more frequent hospitalizations, it is likely that the postprocedure costs are also lower for LVRS than for transplantation.

XIV.

Summary

As illustrated in this chapter, there are many questions lacking answers regarding the interplay between LVRS and lung transplantation. Both lung transplantation and LVRS have the potential to improve symptoms and functional abilities of patients with severe emphysema. These procedures are indicated only for highly selected individuals, and both carry signiﬁcant risks and costs. Further studies are needed to assess the utility of LVRS for patients who are either waiting for, or recovered from, lung transplantation. LVRS should only be offered in this context with great caution.

References 1. 2.

3. 4.

5.

6. 7. 8.

Hardy KJ, Webb D, Dalton M, et al. Lung homotransplantation in man. JAMA 1963; 186:1065–1074. Hosenpud J, Bennett L, Keck B, Boucek M, Novick R. The registry of The International Society for Heart and Lung Transplantation: Eighteenth Ofﬁcial Report 2001; 20(8):805–815. Trulock EP. Lung transplantation: State of the art. Am J Respir Crit Care Med 1997; 155:789–818. Low DE, Trulock EP, Kaiser LE. Morbidity, mortality, and early results of single versus bilateral lung transplanation for emphysema. J Thorac Cardiovasc Surg 1992; 103:1119–1126. Mal H, Sleiman C, Jebrak G, et al. Functional results of single-lung tranplantation for chronic obstructive lung disease. Am J Respir Crit Care Med 1994; 149:1476–1481. Trulock EP. Lung transplantation for COPD. Chest 1998; 113(4) (suppl):269s– 276s. Brantigan O, Mueller E. Surgical treatment of pulmonary emphysema. Am Surg 1957;789–804. Brantigan O, Mueller E, Kress MB. A surgical approach to pulmonary emphysema. Am Rev Respir Dis 1959; 80:194–202.

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26.

Orens Brantigan O, Kress MB, Mueller EA. The surgical approach to pulmonary emphysema. Chest 1961; 39:485–501. Cooper JD, Trulock EP, Taﬁllou A, et al. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995; 109:106–119. Zenati M, Keenan RJ, Landreneau R, et al. Lung reduction as bridge to lung transplantation in pulmonary emphysema. Ann Thorac Surg 1995; 59:1581– 1583. Zenati M, Keenan RJ, Sciurba F, et al. Role of lung reduction in lung transplant candidates with pulmonary emphysema. Ann Thorac Surg 1996; 62:994–999. American Thoracic Society: Medical Section of the American Lung Association. International guidelines for the selection of lung transplant candidates. Am J Respir Crit Care Med 1998; 158:335–339. Traver G, Cline M, Burrows B. Predictors of mortality in chronic obstructive pulmonary disease. Am Rev Respir Dis 1979; 119:895–902. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive pulmonary disease: a clinical trial. Ann Intern Med 1980; 93:391–398. Anthonisen NR. Prognosis in chronic obstructive pulmonary disease: Results from multicenter clinical trials. Am Rev Respir Dis 1989;s95–s99. Orens J, Martinez F, Becker F, et al. Cardiopulmonary exercise testing following lung transplantation for different underlying diseases. Chest 1995; 107(1):144–149. Patterson GA, Maurer JR, Williams TJ, et al. Comparison of outcomes of double and single lung transplantation for obstructive lung disease. J Thorac Cardiovasc Surg 1991; 101:623–632. Levy R, Ernst P, Levine S, et al. Exercise performance after lung transplantation. J Heart Lung Transplant 1993; 12:27–33. Chaparro C, Kesten S. Infections in lung transplant recipients. Clin Chest Med 1997; 18(2):339–351. Maurer JR, Tullis DE, Grossman RF, et al. Infectious complications following isolated lung transplantation. Chest 1992; 101:1056–1059. Dolonish M, Rossm C, Chambers C, et al. Mucociliary function in patients following single or lung-heart transplantation. Am Rev Respir Dis 1987; 135:A363. Armitage J, Kormos R, Stuart R, et al. Posttransplant lymphoproliferative disease in thoracic organ transplant patients: ten years of cyclosporine-based immunosuppression. J Heart Lung Transplant 1991; 10:877–887. St. Louis International Lung Transplant Registry Report. Washington University School of Medicine, St. Louis, 1996. Bando K, Paradis I, Keenan RJ, et al. Comparison of coutcomes after single and bilateral lung transplantation for obstructive lung disease. J Heart Lung Transplant 1995; 14:692–698. Williams TJ, Grossman RF, Maurer JR. Long-term functional follow-up of lung transplant recipients. Clin Chest Med 1990; 11:347–358.

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27. Gibbons W, Levine S, Bryan C, et al. Cardiopulmonary exercise responses after single lung transplantation for severe obstructive lung disease. Chest 1991; 100:106–111. 28. Banner N, Lloyd M, Hamilton R, et al. Cardiopulmonary response to dynamic exercise after heart and combined heart-lung transplantation. Br Heart J 1989; 61:215–223. 29. Myoshi S, Trulock EP, Shaefers H, et al. Cardiopulmonary exercise testing after single and double lung transplantation. Chest 1990; 97:1130–1136. 30. Williams TJ, Patterson GA, McClean P, et al. Maximal exercise testing in single and double lung transplant recipients. Am Rev Respir Dis 1992; 145:101–105. 31. Cooper JD, Patterson GA, Trulock EP. Results of single and bilateral lung transplantation in 131 consecutive recipients. J Thorac Cardiovasc Surg 1994; 107:460–470. 32. Pasque M, Trulock EP, Kaiser LE, Cooper JD. Single-lung transplantation for pulmonary hypertension. Three month hemodynamic follow-up. Circulation 1991; 84:2275–2279. 33. Barr M, Schenkel F, Cohen R, et al. Living-related lobar transplantation: recipient outcome and early rejection patterns. Transplant Proc 1995; 27:1995– 1996. 34. Gross C, Savik K, Bolman M, Hertz MI. Long-term health status and qualityof-life outcomes of lung transplant recipients. Chest 1995; 108:1587–1593. 35. Hayden AM, Robert R, Kriett J, et al. Primary diagnosis predicts prognosis of lung transplant candidates. Transplantation 1993; 55:1048–1050. 36. National Emphysema Treatment Trial. Patients at high risk of death after lung volume reduction surgery. N Engl J Med 2001; 345(15):1075–1083. 37. Sciurba F, Rogers RM, Keenan RJ, et al. Improvement in pulmonary function and elastic recoil after lung reduction surgery for diffuse emphysema. N Eng J Med 1996; 334(17):1095–1099. 38. Gaissert H, Trulock EP, Cooper JD, et al. Comparison of early functional results after volume reduction of lung transplantation for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1996; 111(2):296–307. 39. Zenati M, Keenan RJ, Courcoulas A, Grifﬁth BP. Lung volume reduction or lung transplantation for end-stage pulmonary emphysema? Eur J Cardiothorac Surg 1998; 14:27–31. 40. Bavaria JE, Pachettino A, Kotloff R, et al. Effect of volume reduction on lung transplant timing and selection for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1998; 115:9–18. 41. Todd T, Perron J, Winston T, Keshavjee S. Simultaneous single-lung transplantation and lung volume reduction. Ann Thorac Surg 1997; 63:1468– 1470. 42. Kroshus T, Bolman M, Kshettry VR. Unilateral volume reduction after singlelung transplantation for emphysema. Ann Thorac Surg 1996; 62:363–368. 43. Venuta F, Giacomo T, Rendina E, et al. Thorascopic volume reduction of the native lung after single lung transplantation for emphysema. Am J Respir Crit Care Med 1997; 156:292–293.

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44. Anderson M, Kriett J, Kapelanski D, et al. Volume reduction surgery in the native lung after single lung transplantation for emphysema. J Heart Lung Transplant 1997; 16(7):752–757. 45. Ramsey S, Patrick D, Albert R, et al. The cost effectiveness of lung transplantation. Chest 1995; 108(6):1594–1601. 46. Reemtsma K, Gelijns A, Sisk J, et al. Supporting future surgical innovation lung transplantation as a case study. Ann Surg 1993; 218:465. 47. Maurer JR. Costs of lung transplant in Canada. J Heart Lung Transplant 1996; 13:S70. 48. Elpern E, Behner K, Klontz B, et al. Lung volume reduction surgery: An analysis of hospital costs. Chest 1998; 113(4):896–899. 49. Cooper JD. Is lung volume reduction surgery appropriate in the treatment of emphysema? Am J Respir Crit Care Med 1996; 153:1201–1204. 50. Albert R, Lewis S, Wood D, et al. Economic aspects of lung volume reduction surgery. Chest 1996; 110:1068–1071.

10 Anesthetic Considerations for Lung Volume Reduction Surgery

PHILIP M. HARTIGAN and SIMON C. BODY Harvard Medical School and Brigham & Women’s Hospital Boston, Massachusetts, U.S.A.

I. Introduction Tailoring of anesthetic management to speciﬁc physiological goals is more important than are the speciﬁc agents or techniques utilized. Anesthesia for lung volume reduction surgery (LVRS) is no exception to this principle. Several investigations have reported their anesthetic approaches in case series (1–3), but to date, no studies have sought prospectively to compare anesthetic regimens for LVRS. Although consensus on optimal anesthetic techniques for such patients has not yet been established, there is general agreement on management goals. Paramount among those goals is rapid postoperative extubation, which is based on the appreciation that positivepressure ventilation (PPV) may lead to dynamic pulmonary hyperinﬂation, cardiovascular instability, alveolar barotrauma, disruption of surgical staple lines, impaired gas exchange, and chronic ventilator dependence. Opposing the goal of early extubation are the adverse respiratory effects of anesthesia, thoracic surgery, and severe chronic obstructive pulmonary disease (COPD). The intraoperative requirement for PPV (including single-lung ventilation) requires balancing those adverse effects against the goals of 219

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hemodynamic stability, adequate gas exchange, and the minimization of intrinsic positive end-expiratory pressure (PEEPI) and barotrauma. Equally important are the needs for excellent analgesia, prompt return of cerebral function, prevention of myocardial ischemia, and avoidance of other organ dysfunction. II.

Adverse Respiratory Effects of Anesthesia, Thoracic Surgery, and COPD

A. Effects of Anesthesia

General anesthesia has long been known to have multiple adverse effects on respiratory function (4–6) (see Table 1). Those effects, independent of underlying pulmonary disease or surgery, include reduction in functional residual capacity (FRC), depression of respiratory drive, an increased propensity for upper and lower airway obstruction, impaired mechanics of ventilation, and impaired gas exchange. FRC falls by 15–20%, or approximately 500 mL, abruptly following induction of anesthesia irrespective of the agents used (excepting ketamine) or the presence or absence of spontaneous breathing, controlled ventilation, or paralysis. The likely mechanism is a reduction in basal inspiratory muscle tone, an effect that persists for some hours after anesthesia (4,7). Consequences of FRC

Table 1 ; FRC?

: : ; ;

; : : :

Respiratory Effects of Anesthesia

Altered respiratory mechanics : Atelectasis/shunt ; Compliance ; Airway caliber/: airﬂow resistance : Work of breathing : Risk of air trapping Dead space VA/Q mismatch Hypoxic pulmonary vasoconstriction Respiratory drive in response to: Hypercarbia Hypoxemia Acidosis Upper airway muscle tone ? Upper airway obstruction Tendency for bronchospasm Volume of secretions Viscosity of secretions

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reduction include atelectasis, intrapulmonary shunt, increased airways resistance, and decreased pulmonary compliance (6). Atelectasis occurs when FRC falls below closing capacity, the volume at which small airways begin to close. The degree of intrapulmonary shunt during anesthesia strongly correlates with the degree of computed tomographically demonstrated atelectasis (5). Gas exchange during anesthesia is further hindered by broadening of the ventilation–perfusion (VA/Q) ratio distribution. Particularly in older patients, increased perfusion of lung regions of low VA/Q ratio signiﬁcantly contributes to the increased alveolar–arterial PO2 gradient during anesthesia (8). Carbon dioxide elimination is impaired during anesthesia by increased dead space, due to increased distribution of ventilation to areas of high VA/Q ratio (6), and anesthesia apparatus (e.g., endotracheal tube connectors). Hypoxic pulmonary vasoconstriction (HPV) is attenuated by clinical concentrations of vasodilating intravenous drugs and most inhaled volatile anesthetics (9). Recent evidence suggests that HPV may be preserved with the newer volatile agents desﬂurane and sevoﬂurane (10). Respiratory drive is impaired by all volatile inhalational anesthetic agents, opioids, and most intravenous anesthetic agents in a dose-dependent manner. Even subanesthetic concentrations of volatile agents will depress CO2 ventilation response and attenuate the ventilatory response to hypoxemia and acidemia. End tidal concentrations of volatile agents as low as 0.1 MAC (minimum alveolar concentration) have been shown markedly to attenuate the ventilatory response to hypoxemia (11). Anesthesia inhibits tonic and inspiratory phasic activity in pharyngeal dilator muscles, predisposing to upper airway obstruction after extubation. Distal airway obstruction is more likely during anesthesia due to the effect of the decreased FRC on small airway caliber, accumulated secretions, and bronchospasm. Inhalational agents and nitrous oxide suppress tracheal ciliary activity, whereas anesthetic gases, which bypass the nasopharyngeal mucosa, tend to dry secretions. Drugs with anticholinergic proﬁles increase the viscosity of secretions, whereas other drugs (notably ketamine) increase their volume. Bronchospasm during anesthesia is largely a reﬂex response to mechanical stimulation by laryngoscopy, endotracheal intubation, or surgical stimulation. Much has been written about potential pharmacological exacerbating factors (e.g., beta-adrenergic blocking drugs, histaminereleasing agents, anticholinesterases, H2 receptor antagonists), but these are rarely clinically important causes of bronchospasm. A history of reactive airways disease and/or chronic or recent (within the prior 2 weeks) acute respiratory infection strongly predispose to bronchospasm with airway stimulation.

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Whereas derangements of respiratory physiology during the intraoperative and early (hours) postoperative period are primarily attributable to anesthesia, later effects (day 1 to weeks) are thought to be caused primarily by the surgical intervention (4). In this respect, surgery of the thorax and upper abdomen are the worst offenders. Those effects are characterized by severe reductions in inspiratory and vital capacities, with smaller but more important reductions in FRC and PaO2. That such effects are speciﬁcally related to the surgical intervention per se rather than anesthesia or pain is suggested by the absence of such changes with superﬁcial or extremity surgery (12) and by the inability of complete pain relief to abolish those changes (13). Thoracic and upper abdominal surgery alter the mechanics of diaphragm and chest wall function, leading to a restrictive pattern of breathing which gradually normalizes after at least 10–14 days postoperatively. The applicability of such principles to modern thoracoscopic approaches to LVRS is uncertain, and is complicated by the fact that the surgery itself usually improves respiratory mechanics. C. Effects of Severe COPD

The pathophysiology of severe COPD compounds the derangements of respiratory physiology imposed by anesthesia and surgery. Historically, COPD imparts a 10-fold increase in the incidence of bronchospasm, intraoperative and postoperative pulmonary complications, and death in patents undergoing anesthesia and surgery compared to patients with normal pulmonary function (14,15). Anesthesia-associated increases in VA/Q mismatch and widened perfusion distribution are more profound in patients with COPD (16). Although gas trapping and reduced elastic recoil may protect against anesthesia-associated effects on functional residual capacity (FRC) and shunt during surgery, the degree to which this protective effect persists postoperatively is unclear. The respiratory depressant effects of inhalational agents are more profound in patients with COPD (17), and the duration of ventilatory depression by drugs such as barbiturates and benzodiazepines is prolonged (18). Spirometry values quoted as thresholds predictive of increased risk for postoperative respiratory complications and the need for postoperative mechanical ventilation (FEV1 <2 L, reserve volume/total lung capacity [RV/TLO] >50% of predicted) (19) are routinely violated in LVRS. Thus, the anesthesiologist is challenged to safely deliver anesthesia, including onelung ventilation (OLV) and rapid postoperative extubation, to a population of patients who less than a decade ago would have been rejected for elective surgery, much less thoracic surgery involving lung resection.

Anesthetic Considerations for LVRS III.

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Physiology of One-Lung Ventilation

The distribution of ventilation and perfusion, already disrupted by anesthesia and emphysema, is further disturbed by lateral decubitus positioning, positive-pressure ventilation, opening the pleural space to atmospheric pressure, and OLV. Important factors involved are gravity, HPV, and regional alveolar pressures. During OLV, residual perfusion of the atelectatic nonventilated lung becomes pure shunt. HPV is critical to reduce nonventilated lung shunt, the average effect being an approximately 50% reduction in nonventilated lung blood ﬂow (20). HPV is inhibited by inhaled volatile anesthetic agents and vasodilators. In healthy lungs with intact HPV, OLV with 100% oxygen to the ventilated lung results in an average PaO2 of 150–210 mmHg (21). Since pulmonary blood ﬂow is greater in dependent lung regions, shunt may also be attenuated during thoracoscopic surgery when the unventilated operative lung is nondependent. Oxygenation in the supine position, such as for a sternotomy approach, may be more impaired owing to the absence of this gravitational advantage of perfusion to the ventilated lung. Increased pulmonary vascular resistance (PVR) in the ventilated lung may counter the normal effects of both gravity and HPV and divert a higher fraction of pulmonary blood ﬂow to the atelectatic, nonventilated lung with detrimental effects on gas exchange. Important iatrogenic causes of increased PVR include elevated alveolar pressures due to inappropriate ventilator settings, excessive applied PEEP (PEEPE), or PEEPI due to dynamic hyperinﬂation. Excessive volumes and pressures in the nonoperative lung may also reduce PaO2 by reducing cardiac output and thereby mixed venous oxygen saturation. Although the predominant cause of hypoxemia during OLV is shunt in the deﬂated lung, shunt within the nonoperative lung may also contribute. Adequate ventilation and alveolar recruitment in the ventilated lung are impaired by circumferential restrictive forces (i.e., mediastinum, dependent hemidiaphragm, and chest wall). The paralyzed, dependent hemidiaphragm presses cephalad under the weight of the abdominal contents. In the lateral decubitus position, stabilizing anterior and posterior bolsters may further restrict dependent chest wall expansion. These forces, together with an anesthesia-related decline in FRC, may predispose to ventilated lung atelectasis and shunt. Large tidal volumes or PEEPE have been employed to counteract this, but PEEPI in severely emphysematous patients may obviate the need for such maneuvers. Optimal gas exchange requires balancing the beneﬁts of higher volumes and pressures in the ventilated lung against deleterious effects on nonventilated lung shunt and cardiac output.

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Traditional effective maneuvers to relieve hypoxemia during OLV are continuous positive airway pressure (CPAP) applied to the operative, nonventilated lung, PEEPE to the nonoperative lung, and transient or intermittent lung reinﬂation. CPAP and lung reinﬂation considerably disturb the conduct of thoracoscopic surgery, although low levels of CPAP are less intrusive when surgery is performed via sternotomy. Use of a 10 mL/kg tidal volume, as generally recommended for OLV (22), results in signiﬁcant intrinsic PEEP in patients with even moderate obstructive lung disease (23), and is excessive in the severely obstructed LVRS patient. Use of PEEPE is complicated by the unavoidable presence of PEEPI in this population during OLV. Attempts to improve blood ﬂow and VA/Q matching in the ventilated lung through the administration of inhaled nitric oxide or prostaglandin E (PGE) have failed to improve gas exchange (24,25) unless administered concomitantly with systemic vasoconstrictors (26).

IV.

Positive-Pressure Ventilation and Intrinsic PEEP

A. Positive-Pressure Ventilation

Positive-pressure ventilation (PPV) may adversely affect hemodynamics and gas exchange. The augmentation of systemic venous return by the ‘‘thoracic pump’’ is lost when spontaneous ventilation ceases. Additionally, positive pulmonary pressures during inspiration transmit to intrathoracic vascular spaces, further decreasing the transdiaphragmatic gradient for venous return and reducing left ventricular afterload (27,28). With normal biventricular function, the preload effect predominates resulting in a decreased cardiac output. The transmission of airway pressures to intrathoracic structures is more profound in patients with high pulmonary compliance, such as with emphysema. The use of ventilator settings which result in higher airway pressures, the use of PEEPE, and relative or absolute intravascular volume depletion exacerbate the effect on cardiac output. B. Intrinsic PEEP

The expiratory ﬂow limitation characteristic of emphysema mandates a longer expiratory duration to return to FRC. Patients with severe COPD may have maximal expiratory ﬂows of 200 mL/s or less at lung volumes between FRC and TLC (29). Dynamic pulmonary hyperinﬂation occurs when an inspiration is initiated prior to complete exhalation of the prior breath. End-expiratory volume and pressure within the lungs consequently increase, as does recoil pressure, until a new equilibrium is reached at higher lung volumes and airway pressures (Fig. 1). PEEPI is affected by the

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Figure 1 Schematic representation of dynamic hyperinﬂation. Inadequate exhalation time during mechanical ventilation of patients with severe airway obstruction results in progressive increases in lung volumes (and pressures) until a new equilibrium is reached, at which point the entire tidal volume (VT) is exhaled. The volume of gas trapped above FRC by dynamic hyperinﬂation (DFRC) increases airway pressures throughout the respiratory cycle and imposes intrinsic positive endexpiratory pressure (PEEPI). (Adapted from Tuxen D. Permissive hypercapnic ventilation. Am J Respir Crit Care Med 1994; 150:870–874.)

patient’s respiratory mechanics (resistance and compliance), ventilator settings, and extrinsic resistors (e.g., endotracheal tube, ventilator tubing, valves). The magnitude of PEEPI correlates with the severity of the COPD (30). PEEPI is increased by larger tidal volumes and shorter expiratory times; either absolute (high respiratory rate) or relative (high I:E ratio). During mechanical ventilation of patients with severe obstructive disease, dynamic hyperinﬂation and PEEPI are almost universally present, particularly during OLV, and may reach levels in excess of 20 cm H2O (30). During OLV, PEEPI is worsened by the increased ventilatory demands placed upon the single diseased lung (31,32). Excessive PEEPI may increase PVR in the ventilated lung and shunt blood ﬂow to the nonventilated lung, thereby causing hypoxemia. Attempts to eliminate PEEPI by decreasing the I:E ratio, tidal volume, and respiratory rate are generally constrained by the patient’s ventilatory requirements (CO2 excretion) before PEEPI can be reduced to zero. Consequences of PEEPI are hemodynamic instability, barotrauma, and altered gas exchange. PEEPI is occasionally referred to as ‘‘occult,’’ because it is not readily detected by standard anesthesia or intensive care unit (ICU) monitors, and may progress undetected until dire complications ensue (33). During OLV with an open chest, the best method to estimate dynamic hyperinﬂation is by measuring expiratory gas ﬂow. This can be achieved visually by observing ﬂow in a rotary expiratory ﬂowmeter, or by using pneumotachography to

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Figure 2 (A) Normal ﬂow–volume curve obtained by an on-line ﬂow sensor. Direction of ﬂow is marked by arrows. (B) Flow–volume curves during thoracic surgery obtained from patients with moderate (left) and severe (right) obstructive airways disease. Dynamic hyperinﬂation and PEEPI is indicated by the failure of end-expiratory ﬂow to return to zero. (Adapted from Bardoczky G, D’Hollander JD, Yernault A, et al. On-line expiratory ﬂow-volume curves during thoracic surgery: occurrence of auto-PEEP. Br J Anaesth 1994; 72:25–28.)

construct a ﬂow–volume loop (Fig. 2). Termination of expiratory ﬂow before it reaches zero by the next inspiration indicates PEEP (31). A mechanism for measuring expiratory ﬂow limitation is very useful when attempting to modify ventilatory parameters to minimize or eliminate PEEPI while maximizing ventilation. C. Cardiovascular Effects of PEEPI

PEEPI may compromise cardiovascular function by several mechanisms: (1) by increasing intrathoracic pressures beyond those of PPV alone, PEEPI further reduces the transdiaphragmatic gradient for venous return; (2) hyperexpanded lungs may also exert a tamponade-like effect on the

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heart, reducing diastolic compliance and preload, primarily in the thin walled, low-pressure right ventricle (RV), with secondary impact on the left ventricle (LV); (3) high alveolar pressures associated with PEEPI may also compress intra-alveolar vessels, thus increasing PVR and RV output impedance; (4) ventricular interdependence may additionally contribute to impaired cardiac output during conditions of high PEEPI, RV dysfunction, and extrinsic cardiac pressure from hyperexpanded lungs. Dilation of the RV reduces diastolic compliance and ﬁlling of the LV because of their shared pericardium and interventricular septum. A ﬂattened or left-shifted interventricular septum adversely alters the geometry and efﬁciency of LV systolic contraction. Whether the net primary mechanism for development of cardiac dysfunction during OLV is an underﬁlled RV (from reduced venous return to the heart) (35) or an underﬁlled LV with a dilated RV (from increased RV afterload) (36–38) depends on a number of variables, prominently including intravascular volume status and RV function. During OLV, the potential for diversion of blood ﬂow from the ventilated lung to the nonventilated lung likely protects against RV failure, although oxygenation may suffer. On the other hand, many patients undergoing LVRS have impaired RV function (although not frank cor pulmonale) from their advanced emphysema. This puts them at greater risk of RV dilatation and reduced cardiac output when RV afterload is increased by PEEPI. In addition to mechanical heart–lung interactions, reﬂex neural and humoral interactions occur with PPV and PEEPI (27,28). D. Gas Exchange Effects of PEEPI

PEEPI has both positive and negative effects on gas exchange and oxygen delivery. Many interdependent variables impact, making it difﬁcult to predict the net effect of a given level of PEEPI. Extrinsic PEEP has long been known to improve oxygenation and reduce intrapulmonary shunt in patients with adult respiratory distress syndrome (ARDS) (39) and in patients with normal lungs during anesthesia, through recruitment of previously unventilated (or poorly ventilated) alveolar units and improvement in VA/Q matching. By analogy, PEEPI is thought to beneﬁt oxygenation in COPD patients by preventing the FRC reduction and shunt associated with anesthesia (40). With increasing levels of PEEPI however, decreasing cardiac output and mixed venous oxygen saturation and increasing barotrauma risk outweigh these advantages. During OLV, high levels of PEEPI may divert pulmonary blood ﬂow to the operative lung, thereby increasing shunt. Pursuit of ventilator settings to optimize the beneﬁt to liability ratio of PEEP is a central challenge in the anesthetic management of LVRS patients.

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Anesthetic Management of Patients with Severe Emphysema for LVRS

No study has evaluated speciﬁc drugs, ventilatory strategies, or postoperative analgesic regimens for LVRS, yet remarkable consistency in principles and methods of anesthesia is seen in the thoracic anesthesia community. Although one might expect differences in the intraoperative anesthetic management and postoperative care of patients undergoing LVRS by the median sternotomy and bilateral thoracoscopic routes, the goals, physiology, and management are essentially identical. A. Preoperative Management

All reversible components contributing to the patient’s obstructive pulmonary disease should be aggressively addressed preoperatively, with smoking cessation, antibiotics, bronchodilators, and steroids as indicated. Fortunately, candidates for LVRS are all exsmokers or nonsmokers. Smoking cessation for 18 h produces substantial reductions in blood nicotine and carboxyhemoglobin levels, normalizes the oxyhemoglobin dissociation curve, and reduces tissue hypoxia (41). The beneﬁcial effects on mucus volume, mucociliary transport, and small airways resistance require long-term abstinence. Demonstrable reductions in morbidity require that smoking cease more than a month prior to surgery (42). Recent (within 4–6 weeks) upper respiratory tract infection (URI) is associated with airway hyperreactivity, increased secretions, and an increased incidence of intraoperative and postoperative pulmonary complications (43). Strong consideration should be given to postponing LVRS in patients with a recent history of URI. Prophylactic preinduction bronchodilators should be given to all LVRS patients whether or not wheezing is present. The patient’s medication regimen should otherwise remain unaltered. Preoperative optimization through pulmonary rehabilitation is discussed in Chapter 6. LVRS is a signiﬁcant cardiac stress due to the frequent occurrences of perioperative hypotension, tachycardia, and desaturation. Acute intraoperative myocardial infarction during LVRS has been reported (44). Pulmonary limitations on exercise confound standard preoperative screening techniques such as history and exercise stress testing, although pharmacological cardiac stress testing may be useful. Because of shared risk factors (age, gender, smoking), there is a high prevalence of angiographically signiﬁcant, but clinically silent, coronary artery disease among LVRS patients (45,46). The preoperative approach to these patients should therefore assume some risk of myocardial ischemia. Beta-adrenergic

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blocking or antianginal drugs should not be withheld for fear of bronchospasm or cardiac depression. Clinical assessment of the patient’s intravascular volume status is important to prevent unrecognized hypovolemia from exacerbating the hemodynamic effects of induction and PPV. A prophylactic preinduction ﬂuid bolus is usually indicated, as right ventricular ﬁlling is always reduced by PPV. B. Monitors

Invasive arterial pressure monitoring provides essential rapid-response blood pressure measurements as well as a source of blood gas samples, and is best established prior to induction. Central venous access can be justiﬁed as a conduit for central delivery of resuscitative drugs, but is of very limited value for intraoperative ﬂuid management, assuming that right heart function is relatively normal. Central venous pressure (CVP) rarely changes during LVRS despite a wide variety of insults, and is poorly predictive of intraoperative blood volume status. Although pulmonary hypertension may develop following LVRS (47,48), the routine use of pulmonary artery (PA) catheters is not supported by current experience (3). Both PA wedge pressure and CVP measurements are subject to false elevation by PEEPI (33). Even in the absence of PEEPI. PA diastolic and wedge pressures are poor monitors of myocardial ischemia. The interpretation of PA catheter data is subject to many pitfalls during OLV in the lateral decubitus position with an open chest (22). In addition to standard end-tidal capnography, pulse oximetry, and continuous electrocardiographic (ECG) recording, the use of a pneumotachograph or rotary ﬂow detector in the expiratory limb is an essential monitor for PEEPI. Because dead space is increased, the gradient between end-tidal and arterial PCO2 is increased by an unpredictable amount, and arterial blood gases are needed to measure PaCO2. C. Induction

The challenge on induction of the LVRS patient is to transition smoothly from the awake, anxious, spontaneously ventilating patient to the anesthetized state with PPV and inevitably a degree of PEEPI. Hypotension following induction presents a diagnostic dilemma. Causes or contributing factors to hypotension include loss of thoracic pump effect, PEEPI, tension pneumothorax, vasodilation from induction agents or the epidural test dose, exaggerated response to the epidural test dose due to subarachnoid or subdural catheter malposition, unrecognized hypovolemia, and myocardial ischemia. In all instances except myocardial ischemia, the common mechanism is diminished venous return to the heart. Vasopressors and judicious intravascular volume expansion are effective. However, because

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PEEPI is such a common cause of hypotension in these patients and may be difﬁcult to detect, a useful diagnostic routine is to open or disconnect the expiratory limb of the breathing circuit whenever signiﬁcant hypotension develops and allow lung volumes to decrease for 30–60 s, assessing the effect on blood pressure. Maintaining spontaneous breathing does not eliminate the possibility of PEEPI, which still may occur with tachypnea or the introduction of an endotracheal tube which further contributes to airﬂow resistance. If ﬁberoptic bronchoscopy is performed via an endotracheal tube, the increased airway resistance may profoundly impede expiration and increase PEEPI. Cardiac arrest during induction of severely obstructed patients has been reported (49). There are no data to support the use of any intravenous induction agent over another. From the standpoint of hemodynamic stability and prevention of bronchospasm, there are theoretical advantages to ketamine based on its sympathomimetic side effects. Other induction agents (propofol, thiopental) have been used with success so long as the vasodilatory effects are anticipated and compensated for. A spontaneously breathing inhalation induction with potent volatile agents would likely maintain greater hemodynamic stability, but only postpones the inevitable need to transition to PPV for OLV. D. Maintenance

The mainstay of maintenance for thoracic surgical cases has traditionally been volatile inhalational agents, based on their potent, dose-dependent bronchodilating effect, easy titration and elimination, and allowance for a high FIO2 (22). Inhalational agents ameliorate bronchospasm through depression of peripheral vagal airway reﬂexes (50) and by direct relaxation of airway smooth muscle (51). Currently used inhalational agents are of comparable clinical efﬁcacy in this regard. However, in the LVRS patient, the ability to titrate and eliminate volatile agents is impaired because of poor lung function. Maintenance of anesthetic depth and comparable protection against bronchospasm may also be achieved with a combination of intravenous agents. Ultrashort-acting narcotics (remifentanil) and propofol have potencies and elimination half-times that couple the provision of deep analgesia/anesthesia with a rapid recovery when used as a continuous infusion. Although lacking in direct bronchodilating action, these agents protect against reﬂex bronchoconstriction if adequate depth is maintained (52). In pursuit of the earliest possible extubation, protection against bronchospasm, and adequate anesthetic depth, the trend for anesthetic maintenance has been to reduce the use of volatile inhalational agents and

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long-acting or even intermediate-acting narcotics. These authors prefer to rely instead on combinations or intravenous agents, nonsteroidal antiinﬂammatory agents, ‘‘preemptive’’ or intraoperative local anesthetics to the wound(s), or thoracic epidural local anesthetics and/or narcotics. However, prospective blinded comparisons are as yet unavailable. Concerns that the sympathetic blockade of thoracic epidural analgesia (TEA) might predispose patients to bronchospasm has not been substantiated, although mild decreases in PaO2 have been reported in association with TEA (53). E.

Lung Isolation Techniques

OLV may be accomplished by use of a double-lumen tube (DLT), a tracheally positioned single-lumen tube (SLT) with a separately placed bronchial blocker, a SLT with an intrinsic bronchial blocker, or an endobronchially positioned SLT. Bronchial blockers have a tendency to dislodge from the short right mainstem bronchus, lack a central lumen to apply CPAP or suction to the operative lung, provide slower collapse of the lung due to lack of a central lumen for air egress, and need to be repositioned if bilateral surgery is performed. Similar disadvantages apply to an endobronchially positioned SLT. DLTs therefore tend to be favored for LVRS. Because right-sided DLTs are more difﬁcult to position and have a narrower margin of safety for malpositioning, left-sided DLTs are most commonly employed for LVRS. Flow resistance characteristics of modern, disposable double-lumen, single-lumen, and Univent (Fuji Systems Corp., Tokyo, Japan) tubes have recently been evaluated and reviewed (54,32). Although the slight resistance of left DLTs may worsen PEEPI, the advantages of DLT for lung isolation during LVRS outweigh the risk of slightly increased PEEPI. F.

Barotrauma

The term barotrauma reﬂects the historical presumption that the mechanism of alveolar disruption associated with mechanical ventilation is excessive airway pressure. Animal studies now suggest that volume (i.e., alveolar overdistension) rather than pressure is the critical variable (55). Since volume is imperfectly related to pressure, and since volume cannot be easily measured, clinical attention has continued to focus on minimizing airway pressures to prevent barotrauma. The effect of airway pressures on alveolar volume depends on pulmonary compliance, airways resistance (pressure drop), the distribution of the pressure/volume, and the net transpulmonary pressure gradient. The importance of transpulmonary gradient is evident when one considers that a Valsalva maneuver may produce airway pressures in excess of 280 cm H2O without barotrauma (56).

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LVRS patients are particularly vulnerable to barotrauma because of their abnormal pulmonary parenchyma with a fresh surgical staple line, their heterogeneous distribution of inspired volume, and because of their propensity to develop dynamic hyperinﬂation and PEEPI. Barotrauma during LVRS can result in acute tension pneumothorax if the chest is closed, deterioration in one-lung gas exchange, or a persistent air leak necessitating postoperative ventilatory support. There is no consensus as to the upper limit of safe airway pressures to prevent barotrauma. Reports of clinically safe airway pressures (in ARDS patients) range from 25 to 50 cm H2O (57). Yet, there are no safe pressure guidelines for patients with severe COPD. Intraoperative ventilated-lung tension pneumothorax is a known complication of OLV and LVRS. Precipitous hypotension should raise a very strong index of suspicion of pneumothorax. G. Ventilator Management Strategies

Particularly challenging among anesthetic management goals is the selection of ventilatory parameters that balance the competing aims of optimizing PEEPI, minimizing barotrauma, and maximizing CO2 excretion. Safe limits for permissive hypercapnia, acidosis, and airway pressures remain uncertain. Even if safe airway pressure limits were known, there currently is no way to measure pressures within distal lung units. Therefore, ventilator management for LVRS is extrapolated from the physiology of ventilation for OLV and of patients with severe COPD. Low levels of PEEPI may improve oxygenation during OLV (34,58). Such levels are likely to be present in patients with severe emphysema even with a strategy of permissive hypercapnia. In one study, ventilatory strategies to reduce PEEPI by 50% from baseline in mechanically ventilated patients with chronic airﬂow obstruction resulted in a left shift of the VA/Q distributions and small decreases in PaO2 and PaCO2 (59). These minor changes were accompanied by decreases in alveolar pressures (endinspiratory plateau pressures) and increases in cardiac output, causing a net increase in oxygen delivery. Rossi et al. (59) argue that as long as PaO2 remains at the upper, ﬂat region of the oxyhemoglobin dissociation curve by use of a high FIO2, the small decline in PaO2 which occurs with decreased PEEPI is offset by improved oxygen delivery and a reduced risk of barotrauma. Maneuvers to minimize intrinsic PEEP are reducing tidal volume, respiratory rate, and I:E ratio. Many permutations exist for the adjustments that can be made among those parameters, thus requiring an experimental approach and a means of monitoring PEEPI and PaCO2. The increase and variable degrees of dead space imposed by the patient’s obstructive disease,

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PPV, and PEEPI render end-expiratory CO2 unreliable as a measure of ventilation and mandate occasional blood gas measurements. Increasing peak inspiratory ﬂows or pressures to reduce inspiratory time and allow a longer expiratory time may actually reduce the alveolar pressures and risk of barotrauma despite increased peak inspiratory pressures measured at the circuit (60). A clinically useful method to balance these competing goals is to minimize measured end-expiratory ﬂow while measuring PaCO2 and arterial blood pressure. Ultimately, an experimental approach to optimize ventilation is recommended, with attention to airway pressures, PaCO2, and hemodynamics and an awareness of the uncertainty of airway pressure as a measure of barotrauma risk. Pressure-controlled ventilation (PCV) may offer more effective ventilation compared to volume-controlled ventilation (VCV) with similar barotrauma risk, with other factors being equal. Although this remains untested, some have demonstrated improved oxygenation during OLV with PCV compared to VCV at comparable tidal volumes (61). High-frequency jet ventilation is associated with lower peak airway pressures than conventional PPV, but the incidence of barotrauma is not reduced (62). Jet ventilation has not been used for LVRS. Despite optimal ventilator strategies for gas exchange during two- or one-lung ventilation for LVRS, there is often persistent hypotension due to PEEPI. This requires management with crystalloid ﬂuid boluses, inotropic agents, and vasopressors. H. Permissive Hypercapnia

Controlled hypoventilation (permissive hypercapnia), may be important in minimizing the risk of barotrauma and nonoperative lung shunt during OLV for LVRS. In a permissive hypercapnic ventilatory strategy, normal alveolar ventilation is compromised in deference to the prevention or limitation of dynamic pulmonary hyperinﬂation and barotrauma. Initially proposed for the management of patients with severe acute asthma (63,64), it has since been applied to patients with ARDS or severe COPD as well. Application of permissive hypercapnia requires cognizance of the effects of acidosis and hypercarbia. The potential adverse effects of hypercapnic acidosis are many and have been reviewed elsewhere (65). Depressant effects on myocardial contractility are effectively overcompensated by the increased adrenergic tone, such that with moderate hypercapnia, the net cardiovascular effect tends to be an increase in cardiac output and stroke volume. Sympathetic compensation is blunted by beta-adrenergic blockade, deep anesthesia, or limited myocardial reserve. CO2 is a potent coronary vasodilator, and

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patients with steal-prone coronary anatomy may theoretically be at risk for myocardial ischemia. Pulmonary vascular resistance also increases and may worsen right heart dysfunction. In extreme hypercapnic acidosis, the risk of malignant arrhythmias increases and the response to DC cardioversion is blunted. The contractility and endurance of skeletal muscle, particularly the diaphragm, is impaired with moderate acidosis, whereas bronchial smooth muscle tone increases. Hypercarbic acidosis shifts the oxyhemoglobin dissociation curve to the right, promoting the release of oxygen to tissues, whereas hypoxic pulmonary vasoconstriction is enhanced. The net effect of moderate hypercapnic acidosis on oxygen delivery is difﬁcult to predict, as it depends on both cardiovascular and respiratory effects and the underlying pathophysiology. Acidemia may also exert some cytoprotective effect from hypoxic injury (66). Although the application of permissive hypercapnia to patients with ARDS or severe airﬂow obstruction has been associated with improved outcome in some clinical trials (64,67,68), it has not been formally studied in the setting of LVRS. The degree of ‘‘permissible’’ permissive hypercapnia, beyond which the risks outweigh the beneﬁts, will no doubt remain a difﬁcult judgment for each patient and circumstance. Transient acute hypercapnia, up to a PaCO2 of 80 mm Hg with a pH of 7.15, has been shown to be well tolerated provided oxygenation is preserved (65). The patients of that study, however, did not require rapid extubation and return of spontaneous respiration in an immediate postthoracic surgical setting. The sedative effects of elevated PaCO2 are highly variable and depend on the rate of rise and duration as well as the level. The degree to which moderate hypercarbic acidosis interferes with rapid post-LVRS extubation deserves investigation in seeking the acceptable threshold for permissive hypercapnia during LVRS. I. Extrinsic PEEP

The addition of extrinsic PEEPE to ventilated COPD patients has historically been discouraged out of concern for excessive hyperinﬂation and barotrauma. However, in patients with PEEPI, the addition of low levels of PEEPE (up to approximately 85% of PEEPI) imposes no additional pressure or volume to the lungs of such patients (69–71). Effectively, PEEPE replaces PEEPI up to a certain ‘‘critical value,’’ after which PEEPI and PEEPE become roughly additive, to increase total pressures and volumes. The application of sub-PEEPI amounts of PEEPE may have respiratory advantages. During weaning from mechanical ventilation, patients must exert a certain inspiratory effort to overcome PEEPI before inspiratory ﬂow is initiated. Replacing PEEPI with PEEPE shifts this work from the patient

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to the ventilator and reduces the work of breathing (72). In addition, such low levels of PEEPE reduce expiratory ﬂow resistance (70,72) and may decrease the degree of air trapping (73). Recent evidence suggests that the replacement of PEEPI with equivalent amounts of PEEPE results in equivalent cardiovascular effects, but improvement in shunt reduction and PaO2 (74). It is possible that the distribution of ventilation (and pressure) may be more homogeneous with PEEPE, whereas PEEPI is preferentially distributed to lung regions with the longest time constants (74). Rossi (59) found that the addition of PEEPE in an amount equal to 50% of the baseline PEEPI in mechanically ventilated patients with severe airﬂow obstruction resulted in improved gas exchange (PaO2 increased 10 mmHg on average) and VA/Q matching without increasing total PEEP. Higher values of PEEPE (100% of PEEPI) in this study did not offer further gas exchange advantage. The effect of PEEPE on gas exchange during OLV has produced mixed results (40,59,75,76), probably because of failure to account for interactions between PEEPE and unrecognized levels of intrinsic PEEPI (23). Slinger et al. has shown that the net effect of PEEPE on one-lung oxygenation tends to be beneﬁcial if it results in a shift of the plateau end-expiratory pressure (EPP) toward the inﬂection point of the patient’s static compliance curve (77). Oxygenation will deteriorate, however, if PEEPE results in a shift of EPP beyond the inﬂection point. J.

Emergence Strategies

Prompt extubation of LVRS patients is challenging given the aforementioned respiratory effects of anesthesia, thoracic surgery, and the severity of preexisting lung disease and the fact that the purported ameliorating effects of the surgery in terms of respiratory function are not immediately manifest. Failure or delay of extubation may be caused by surprisingly small deviations from the optimum in terms of elimination of respiratory depressant or sedating drugs, residual neuromuscular paralysis, pain control, secretions, bronchospasm, or hypercarbia and acidosis. Postoperative respiratory failure following LVRS has been associated with a hospital mortality rate of 33% (78). Many practitioners advocate changing from a DLT to a SLT prior to emergence to facilitate a ‘‘toilet’’ bronchoscopy, to deliver more effectively aerosolized bronchodilators, and to reduce airﬂow resistance. When both lumens of a DLT are utilized, studies indicate that airﬂow resistance is only marginally increased compared to SLTs of comparable internal diameters (32). Even with deliberate attempts to minimize residual anesthetic–induced sedation and respiratory depression, a common ﬁnding is that LVRS patients exhibit a slow return of vigorous respiratory effort and alert mental

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status. Neither the prevalence nor cause of this has been systematically studied. The substantial dead space, ventilation–perfusion inequality, and air trapping of these patients’ pathophysiology causes end-tidal anesthetic agent levels to underestimate grossly the amount of residual volatile agent and to delay emergence. In our experience, however, total intravenous anesthetic techniques do not completely eliminate delayed emergence. The degree to which hypercarbia and/or acidosis contribute to emergence hypoventilation and somnolence is uncertain, since, as previously mentioned, the degree of narcosis is poorly correlated to the PaCO2. Although permissive hypercapnia may be strategic or necessary during the period of OLV, if severe respiratory acidosis results, two-lung ventilation during the preemergence period should be directed to correct the respiratory acidosis with attention to the risk of barotrauma. Some investigators advocate reduction of FIO2 to 0.3 prior to emergence (3) based on the belief that hyperoxia in COPD patients can cause CO2 retention through suppression of central chemoreceptor ventilatory drive (79). Recent work has challenged that premise and suggested that the observed rise in PaCO2 in such patients can be accounted for by an increase in dead space (80–82). Respiratory drive and minute ventilation have been shown not to be reduced by the administration of high FIO2 (82,83). On this basis, we do not recommend reducing the FIO2 to facilitate extubation, nor do we advocate withholding or reducing supplemental oxygen in the recovery room as a means to stimulate respiration in the somnolent, hypoventilating patient. Although arterial blood gases are essential for the intraoperative management of ventilation, they are less useful for determining readiness for extubation. Patients are typically extubated in the operating room while they still have a respiratory acidosis that, in other circumstances, would trigger intubation. However, delays in extubation in an attempt to achieve more normal pH during spontaneous breathing will often lead to prolonged ventilator dependency, and PPV after surgery can cause devastating air leaks. Early extubation is imperative, and respiratory acidosis will slowly resolve as residual anesthetic effects clear. K. Postoperative Pain Management

The need for postoperative analgesia to prevent splinting and hypoventilation must be met with minimal respiratory depression. Options for pain control after thoracic surgery have recently been reviewed (84). Although the pain from thoracoscopic or sternotomy incisions is generally considerably less than that for a full thoracotomy, TEA is favored by nearly all practitioners as a means to maximize analgesia with less systemic narcotic

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effect than patient-controlled, narcotic-based intravenous analgesia (84–86). TEA has been shown to improve diaphragmatic function (87) and overall pulmonary function (88,89) and may decrease the incidence of chronic chest wall pain syndromes (90). Although one center stated that the optimal epidural analgesia technique was the use of high concentrations of bupivacaine (1), this technique has not been widely accepted. Rather most practitioners favor the use of a mixture of low-dose (40.1% bupivacaine) local anesthetics and low-dose hydrophilic narcotics (such as morphine or hydromorphone). Low-dose bupivacaine yields effective analgesia with a low incidence of hypotension (91,92) or other side effects. Low-dose hydrophilic narcotics are favored because of their lesser systemic absorption compared to lipophilic narcotics (93) and reduced frequency of sedation and respiratory depression. TEA is superior to lumbar epidural analgesia for analgesia after thoracic surgery (95–98). TEA delivers drugs close to the site of nociceptive input to the spinal cord, and therefore is associated with superior analgesia, reduced drug requirements, and a lower incidence of side effects such as urinary retention and leg weakness compared to lumbar epidural analgesia. TEA may also be cardioprotective during thoracotomy (99–102). This may be advantageous in this population at high risk of myocardial infarction (44). A frequently useful adjunct to TEA is ketorolac, an intravenous nonsteroidal anti-inﬂammatory drug (NSAID). Ketorolac and other NSAIDs have been shown to improve the quality of analgesia with TEA (103), and are helpful for shoulder pain occurring after thoracic surgery. Ipsilateral shoulder pain after thoracic surgery is most likely referred pain mediated by the phrenic nerve, and thus not controlled by mid thoracic epidural blockade (104). NSAIDs have serious side effects that may be more important after surgery (notably, inhibition of platelet function, renal toxicity, and gastrointestinal ulceration). COX-2–inhibiting drugs are promising as an alternative, with a lower incidence of side effects, but have yet to be evaluated for this population. Other potential techniques exist for postoperative analgesia after LVRS. There are no published data on the efﬁcacy of parenteral narcotics, intercostal nerve blockade, interpleural analgesia, paravertebral nerve blockade, or cryoanalgesia upon analgesia after LVRS. For median sternotomy, parenteral narcotics are the only practical alternative to TEA. Their use may be associated with an unacceptable incidence of sedation and respiratory depression. All techniques are possible after bilateral thoracoscopy, although local anesthetic toxicity will likely limit the utility of most remaining techniques, and their overall effectiveness for unilateral thoracotomy has often been questioned.

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The management of TEA is often complicated by iatrogenic hypovolemia and poor cardiac function. TEA should be managed by a dedicated acute pain service team familiar with its use and complications in concert with the thoracic surgeon. L.

Postoperative Respiratory Management

The recently awakened and extubated LVRS patient requires close supervision in the immediate postoperative period. Prompt treatment of pain, bronchospasm, oversedation, obstruction, stridor, mucous plugging, and hypotension is important. Two sets of arterial blood gases following extubation are often useful to recognize a temporal trend toward impending respiratory failure. Should respiratory failure occur in the postanesthesia care unit (PACU) requiring reintubation, care must be exercised to avoid dynamic hyperinﬂation in the heat of the moment. The time of PACU reintubation and during manual ventilation for transport to the ICU are times of risk for barotrauma and exacerbation of air leaks. The use of noninvasive PPV devices have not been reported in this setting, but may be a useful means of avoiding reintubation of the marginal LVRS patient in the PACU.

VI.

Summary

Anesthetic management strategies and the physiological foundations for LVRS have been reviewed. The challenging physiological goals emphasized are to provide anesthesia, positive-pressure one-lung ventilation, and postoperative analgesia in a manner consistent with rapid postoperative extubation, hemodynamic stability, adequate single-lung gas exchange, and minimal barotrauma for this population of patients with end-stage obstructive lung disease undergoing LVRS.

References 1. 2.

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Hartigan and Body ventilation with and without PEEP5. Acta Anaesthesiol Scand 1975; 19:287– 295. Benumof J. Anesthesia for Thoracic Surgery. Philadelphia: Saunders, 1995. Slinger P, Hickey D. The interaction between applied and auto-PEEP during one-lung ventilation. J Cardiothorac Vasc Anesth 1998; 12:133–136. Hartigan P, Formanek V, Shernan S, et al. Inhaled NO fails to improve gas exchange during one-lung ventilation. Anesthesiology 1996; 85:A1165. Wilson WC, Kapelanski DP. Benumof, J.L. et al. Inhaled nitric oxide (40 ppm) during one-lung ventilation, in the lateral decubitus position, does not decrease pulmonary vascular resistance or improve oxygenation in normal patients (see comments). J Cardiothorac Vasc Anesth 1997; 11:172–176. Freden F, Wei S, Berglund J, et al. Nitric oxide modulation of pulmonary blood ﬂow distribution in lobar hypoxia. Anesthesiology 1995; 82:1216–1225. Miro A, Pinsky M. Heart-Lung Interactions. In: Principles and Practice of Mechanical Ventilation. Tobin M, ed. New York: McGraw-Hill, 1994:647– 672. Fessler HE. Heart-lung interactions: applications in the critically ill. Eur Respir J 1997; 10:226–237. Reinoso M, Gracey D, Hubmayr R. Interrupter mechanics of patients admitted to a chronic ventilator dependency unit. Am Rev Respir Dis 1993; 148:127–131. Ducros L, Moutaﬁs M, Castelain M-H, et al. Pulmonary air trapping during two-lung and one-lung ventilation. J Cardiothorac Vasc Anesth 1999; 13:35– 39. Bardoczky G, D’Hollander A, Cappello M, et al. Interrupted expiratory ﬂow on automatically constructed ﬂow-volume curves may determine the presence of intrinsic positive endexpiratory pressure during one-lung ventilation. Anesth Analg 1998; 86:880–884. Slinger P, Lesiuk L. Flow resistances of disposable double-lumen, singlelumen, and Univent tubes. J Cardiothorac Vasc Anesth 1998; 12:142–144. Pepe P, Marini J. Occult positive end-expiratory pressure in mechanically ventilated patients with airﬂow obstruction. The auto-PEEP effect. Am Rev Respir Dis 1982; 126:166–170. Myles P. Auto-PEEP may improve oxygenation during one-lung ventilation. Anesth Analg 1996; 83:1131. Huemer G, Kolev N, Kurz A, et al. Inﬂuence of positive end-expiratory pressure on right and left ventricular performance assessed by doppler twodimensional echocardiography. Chest 1994; 106:67–73. Jardin F, Brun-Ney D, Hardy A, et al. Combined thermodilution and twodimensional echocardiographic evaluation of right ventricular function during respiratory support with PEEP. Chest 1991; 99:162–168. Jardin F, Delorme G, Hary A, et al. Reevaluation of hemodynamic consequences of positive end-expiratory ventilation: Emphasis on cyclic right ventricular afterloading by mechanical lung inﬂation. Anesthesiology 1990; 72:966–970.

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38. Cheifetz I, Craig D, Quick G, et al. Increasing tidal volumes and pulmonary overdistension adversely affect pulmonary vascular mechanics and cardiac output in a pediatric swine model. Crit Care Med 1998; 26:710–716. 39. Suter P, Fairley B, Isenberg M. Optimum end-expiratory airway pressure in patients with acute pulmonary failure. New Engl J Med 1975; 292:284–289. 40. Cohen E, Eisenkraft J. Positive end-expiratory pressure during one-lung ventilation improves oxygenation in patients with low arterial oxygen tensions. J Cardiothorac Vasc Anesth 1996; 10:579–582. 41. Kambam J, Chen L, Hyman S. Effect of short-term smoking halt on carboxyhemoglobin levels and P50 values. Anesth Analg 1986; 65:1186–1188. 42. Egan T, Wong K. Perioperative smoking cessation and anesthesia: a review. J Clin Anesth 1991; 4:63–72. 43. DeSoto H, Patel R, Solimon I, et al. Changes in oxygen saturation following general anesthesia in children with upper respiratory infection signs and symptoms undergoing otolaryngological procedures. Anesthesiology 1988; 68:276–279. 44. Hogue CW Jr, Stamos T, Winters KJ, et al. Acute myocardial infarction during lung volume reduction surgery. Anesth Analg 1999; 88:332–334. 45. Thurnheer R, Muntwyler J, Stammberger U, et al. Coronary artery disease in patients undergoing lung volume reduction surgery for emphysema. Chest 1997; 112:122–128. 46. Bach D, Curtis J, Christensen P, et al. Preoperative echocardiographic evaluation of patients referred for lung volume reduction surgery. Chest 1998; 14:972–980. 47. Thurnheer R, Bingisser R, Stammberger U, et al. Effect of lung volume reduction surgery on pulmonary hemodynamics in severe pulmonary emphysema. Eur J Cardiothorac Surg 1998; 13:253–258. 48. Weg I, Rosoff L, McKeon K, et al. Development of pulmonary hypertension after lung volume reduction surgery. Am J Respir Crit Care Med 1999; 159:552–556. 49. Myles P, Madder H, Morgan E. Intraoperative cardiac arrest after unrecognised dynamic hyperinﬂarion. Br J Anaesth 1995; 74:340–342. 50. Brichant J, Gunst S, Warner D, et al. Halothane, enﬂurane and isoﬂurane depress peripheral vagal motor pathway in isolated canine tracheal smooth muscle. Anesthesiology 1991; 74:325–332. 51. Yamakage M, Kohro S, Kawamata T, et al. Inhibitory effects of four inhaled anesthetics on canine tracheal smooth muscle contraction and intracellular calcium concentration. Anesth Analg 1993; 77:67–72. 52. DeSouza G, deLisser E, Turry P, et al. Comparison of propofol with isoﬂurane for maintenance of anesthesia in patients with chronic obstructive pulmonary disease: use of pulmonary mechanics, peak ﬂow rates, and blood gases. J Cardiothorac Vasc Anesth 1995; 9:24–28. 53. Ignacio G, Quintana B, Olmedilla L, et al. Arterial oxygenation during onelung ventilation: combined versus general anesthesia. Anesth Analg 1999; 88:494–499.

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54. Hannallah M, Miller S, Kurzer S, et al. The effective diameter and airﬂow resistance of the individual lumens of left polyvinyl chloride double-lumen endotracheal tubes. Anesth Analg 1996; 82:867–869. 55. Hernandez L, Peeevy K, Moise A, et al. Chest wall restriction limits high airway pressure induced lung injury in young rabbits. J Appl Physiol 1989; 66:2364–2368. 56. Pierson D. Barotrauma and bronchopleural ﬁstula. In: Principles and Practice of Mechanical Ventilation. Tabin M, ed. New York: McGraw-Hill, 1994, pp 813–836. 57. Haake R, Schlichtig R, Ulstad D, et al. Barotrauma. Pathophysiology, risk factors, and prevention. Chest 1987; 91:608–613. 58. Yakota K, Toriumi T, Sari A, et al. Auto-positive end-expiratory pressure during one-lung ventilation using a double-lumen endobronchial tube. Anesth Analg 1996; 82:1007–1010. 59. Rossi A, Santos C, Roca J, et al. Effects of PEEP on VA/Q mismatching in ventilated patients with chronic airﬂow obstruction. Am J Respir Crit Care Med 1994; 149:1077–1084. 60. Gladwin M, Pierson D. Mechanical ventilation of the patient with severe chronic obstructive pulmonary disease. Intensive Care Med 1998; 24:898–910. 61. Tugrul M, Canci E, Karadeniz H, et al. Comparison of volume controlled with pressure controlled ventilation during one-lung anaesthesia. Br J Anaesth 1997; 79:306–310. 62. Carlon G, Howland W, Ray C, et al. High-frequency jet ventilation: a prospective randomized evaluation. Chest 1983; 84:551–559. 63. Menitove S, Goldring R. Combined ventilator and bicarbonate strategy in the management of status asthmaticus. Am J Med 1983; 74:898–901. 64. Darioli R, Perret C. Mechanical controlled hypoventilation in status asthmaticus. Am Rev Respir Dis 1984; 129:385–387. 65. Feihl F, Perret C. Permissive hypercapnia. How permissive should we be? Am J Respir Crit Care Med 1994;150:1722–1737. 66. Gores G, Nieminen A, Fleishman K, et al. Extracellular acidosis delays onset of cell death in ATP-depleted hepatocytes. Am J Physiol 1988; 255:C315– C321. 67. Hickling K, Henderson S, Jackson R. Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med 1990;16:372–377. 68. 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. 69. Guy P, Rodarte J, Hubmayr R. The effect of positive expiratory pressure on isovolume and dynamic hyperinﬂation in patients receiving mechanical ventilation. Am Rev Respir Dis 1987; 139:621–626.

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70. Rossi A, Brandolese R, Milic-Emili J, et al. The role of PEEP in patients with chronic obstructive pulmonary disease during assisted ventilation. Eur Respir J 1990; 3:818–822. 71. Ranieri M, Giuliani R, Cinnella G, et al. Physiologic effects of positive endexpiratory pressure in patients with chronic obstructive pulmonary disease during acute ventilatory failure and controlled mechanical ventilation. Am Rev Respir Dis 1993; 147:5–13. 72. Smith T, Marini J. Impact of PEEP on lung mechanics and work of breathing in severe airﬂow obstruction. J Appl Physiol 1988; 65:1488–1499. 73. Quinlan J, Bufﬁngton C. Deliberate hypoventilation in a patient with air trapping during lung transplantation. Anesthesiology 1993; 78:1177–1181. 74. Brandolese R, Broseghini C, Polese G, et al. Effects of intrinsic PEEP on pulmonary gas exchange in mechanically ventilated patients. Eur Respir J 1993; 6:358–363. 75. Capan L, Turndorf H, Chandrakant P, et al. Optimization of arterial oxygenation during one-lung anesthesia. Anesth Analg 1980; 59:847–851. 76. Katz J, Laverne R, Fairley H, et al. Pulmonary oxygen exchange during endobronchial anesthesia: effects of tidal volume and PEEP. Anesthesiology 1982; 56:164–171. 77. Slinger PD, Kruger M, McRae K, Winton T. Relation of the static compliance curve and positive end-expiratory pressure to oxygenation during one-lung ventilation. Anesthesiology 2001;95:1096–1102. 78. Chatila W, Furukawa S, Criner G. Acute respiratory failure after lung volume reduction surgery. Am J Respir Crit Care Med, 2000, 162:1292–1296. 79. Guyton A. Respiratory insufﬁciency. In: Guyton A, Hall J, eds. Textbook of Medical Physiology. Philadelphia: Saunders, 1996:531. 80. Aubier M, Murciano D, Fournier M, et al. Central respiratory drive in acute respiratory failure of patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1980; 122:191–199. 81. Aubier M, Murciano D, Milic-Emili J. Effects of administration of 02 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure. Am Rev Respir Dis 1980; 122:747– 754. 82. Hanson C, Marshall B, Frasch H, et al. Causes of hypercarbia with oxygen therapy in patients with chronic obstructive pulmonary disease. Crit Care Med 1996; 24:23–28. 83. Crossley D, McGuire G, Barrow P, et al. Inﬂuence of inspired oxygen concentration on deadspace, respiratory drive, and PaCO2 in intubated patients with chronic obstructive pulmonary disease. Crit Care Med 1997; 25:1522–1526. 84. Kavanagh B, Katz J, Sandler A. Pain control after thoracic surgery. A review of current techniques. Anesthesiology 1994; 81:737–759. 85. Schultz AM, Werba A, Ulbing S, et al. Peri-operative thoracic epidural analgesia for thoracotomy. Eur J Anaesthesiol 1997; 14:600–603.

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86. Myles PS. Lessons from lung transplantation for everyday thoracic anesthesia. Anesthesiol Clin North Am 2001; 19(7):581–590. 87. Polaner DM, Kimball WR, Fratacci MD, et al. Thoracic epidural anesthesia increases diaphragmatic shortening after thoracotomy in the awake lamb. Anesthesiology 1993; 79:808–816. 88. Miguel R, Hubbell D. Pain management and spirometry following thoracotomy: a prospective, randomized study of four techniques. J Cardiothorac Vasc Anesth 1993; 7:529–534. 89. Furrer M, Rechsteiner R, Eigenmann V, et al. Thoracotomy and thoracoscopy: postoperative pulmonary function, pain and chest wall complaints. Eur J Cardiothorac Surg 1997; 12:82–87. 90. Katz J, Kavanagh BP, Sandler AN, et al. Preemptive analgesia. Clinical evidence of neuroplasticity contributing to postoperative pain. Anesthesiology 1992; 77:439–446. 91. Etches RC, Gammer TL, Cornish R. Patient-controlled epidural analgesia after thoracotomy: a comparison of meperidine with and without bupivacaine. Anesth Analg 1996; 83:81–86. 92. Hansdottir V, Bake B, Nordberg G. The analgesic efﬁcacy and adverse effects of continuous epidural sufentanil and bupivacaine infusion after thoracotomy. Anesth Analg 1996; 83:394–400. 93. Bouchard F, Drolet P. Thoracic versus lumbar administration of fentanyl using patient-controlled epidural after thoracotomy. Reg Anesth 1995; 20:385–388. 94. Slinger P, Shennib H, Wilson S. Postthoracotomy pulmonary function: a comparison of epidural versus intravenous meperidine infusions. J Cardiothorac Vasc Anesth 1995; 9:128–134. 95. Benzon HT. Post-thoracotomy epidural analgesia: lumbar or thoracic placement? J Cardiothorac Vasc Anesth 1993; 7:515–516. 96. Grant GJ, Zakowski M, Ramanathan S, et al. Thoracic versus lumbar administration of epidural morphine for postoperative analgesia after thoracotomy. Reg Anesth 1993; 18:351–355. 97. Hurford WE, Dutton RP, Alﬁlle PH, et al. Comparison of thoracic and lumbar epidural infusions of bupivacaine and fentanyl for post-thoracotomy analgesia. J Cardiothorac Vasc Anesth 1993; 7:521–525. 98. Sawchuk CW, Ong B, Unruh HW, et al. Thoracic versus lumbar epidural fentanyl for postthoracotomy pain. Ann Thorac Surg 1993; 55:1472–1476. 99. Kock M, Blomberg S, Emanuelsson H, et al. Thoracic epidural anesthesia improves global and regional left ventricular function during stress-induced myocardial ischemia in patients with coronary artery disease. Anesth Analg 1990; 71:625–630. 100. Gramling-Babb P, Miller MJ, Reeves ST, et al. Treatment of medically and surgically refractory angina pectoris with high thoracic epidural analgesia: initial clinical experience. Am Heart J 1997; 133:648–655.

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101. Meissner A, Rolf N, Van Aken H. Thoracic epidural anesthesia and the patient with heart disease: beneﬁts, risks, and controversies. Anesth Analg 1997; 85:517–528. 102. Loick HM, Schmidt C, Van Aken H, et al. High thoracic epidural anesthesia, but not clonidine, attenuates the perioperative stress response via sympatholysis and reduces the release of troponin T in patients undergoing coronary artery bypass grafting. Anesth Analg 1999; 88:701. 103. Singh H, Bossard RF, White FF, et al. Effects of ketorolac versus bupivacaine coadministration during patient- controlled hydromorphone epidural analgesia after thoracotomy procedures. Anesth Analg 1997; 84:564–569. 104. Scawn NDA, Pennefather SH, Soorac A, et al. Ipsilateral shoulder pain after thoracotomy with epidural analgesia: The inﬂuence of phrenic nerve inﬁltration with lidocaine. Anesth Analg 2001; 93:260–264.

11 Technique of Lung Volume Reduction by Median Sternotomy

JOSEPH B. SHRAGER and LARRY R. KAISER University of Pennsylvania Medical Center Philadelphia, Pennsylvania, U.S.A.

I. Introduction Since the reintroduction of lung volume reduction surgery (LVRS) by Cooper et al. in 1995 (1), there has been resurgent interest in this approach for the palliation of severe emphysema. In both the early clinical application of LVRS and in ongoing trials, two surgical approaches for the procedure have been employed. Cooper (1), and many others who followed, have preferentially employed a median sternotomy (MS) for surgical access, whereas other surgeons favor a bilateral, sequential video-assisted thoracoscopic (VATS) approach. It is currently unclear if either of these approaches is superior. We have favored the MS approach in most patients, for reasons that will be discussed below. This chapter will compare MS and VATS and describe our technique of LVRS by MS.

II.

MS Versus VATS

A cursory examination of Table 1 suggests that both the MS and VATS approaches are reasonable; each has its advocates. A study from our 247

39 79 32 120 28 443 57 50 20 150 100 26 53 85 30 54 46 55 37 39

2 3 4b 5 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

0.70 (–) 0.69 (25) 0.68 (23) 0.73 (–) 0.68 (–) – (25) 0.82 (30) 0.73 (26) 0.80 (28) 0.70 (25) 0.60 (19) 0.73 (25) 0.56 (–) 0.55 (23) 0.64 (22) – (24) 0.70 (27) 0.70 (28) 0.68 (26) 0.74 (–)

5.40 (–) 4.80 (–) – 4.95 (–) 5.07(–) – (197) 5.10 (239) 5.13 (235) 5.80 (250) 5.91 (283) 5.50 (290) 6.10 (–) – 4.00 (–) 5.62 (265) – (317) 4.73 (237) 3.94 (192) – – (201)

Preop RV (% pred) – – – 1008 – – 754 864 1608 1125 1106 – 785 589 904 – 797 774 913 1083

Preop 6-min walk (ft) Uni-VAT Bi-VAT Both-Both Bi-Both Uni-VAT Uni-VAT Uni-VAT Uni-VAT Bi-VAT Bi-Open Bi-Open Bi-Open Both-Open Both-Open Both-Both Both-Both Bi-Both Bi-Openc Both-Open Bi-Open

Technique 2.5 1.0 0 10 0 5.6 5.3 4.0 0 5.0 5.2 3.8 5.2 7.1 0 9.8 8.7 5.0 6.7 0

Mortality (%) 13 11 7 20 – 18 17 13 15 15 – 14 – 17 18 12 – 18 16 –

LOS (days) 33 52 29 41 34 26 27 35 37 51 97 40 97 61 54 40 20 27 59 41

Increase FEV1 (%) – – – 26 12 12 16 33 24 28 – 30 – – 24 31 22 25 – 21

Decrease RV (%) – – – 26 – – 14 20 39 17 104 – 104 62 12 – 26 17 32 16

Increase 6-MW (%)

N, number of patients; FEV1, forced expiratory volume in 1 s; RV, residual volume; 6-MW, 6-min walk distance; Bi, bilateral; Uni, unilateral; VAT, video-assisted thoracoscopic surgery; LOS, length of stay. a Papers using solely laser techniques have been excluded. b Uses novel plication technique. c Except one patient.

N

Ref.

Preop FEV1 (% pred)

Table 1 Published Results of LVRSa

248 Shrager and Kaiser

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institution retrospectively reviewed 80 patients undergoing bilateral LVRS by MS and 40 by VATS and found that there were similar improvements in pulmonary function and exercise capacity regardless of the approach. There was a lower incidence of respiratory failure requiring reintubation in the VATS group and a trend, which did not reach statistical signiﬁcance, favoring VATS with regard to in-hospital mortality. In patients over the age of 65 years, there was a signiﬁcantly higher hospital mortality in the sternotomy group (5). Slightly different conclusions can be drawn regarding VATS versus MS from a later study published by our group encompassing patients operated upon more recently (6). There were no signiﬁcant differences between the VATS and MS patients with regard to length of stay, chest tube duration, or Heimlich valve requirement. Operating times were signiﬁcantly longer for the VATS group; blood loss was greater for the MS group. Most importantly, the MS patients had signiﬁcantly longer intensive care unit (ICU) stays, more days intubated, more respiratory complications, and more postoperative tracheostomy placements. However, when the analysis is restricted to only the most recent one-half of MS cases, only the number of ICU days and the number of respiratory complications were signiﬁcantly increased. Furthermore, the MS patients were a mean of 4.6 years older than the VATS patients, and, as established in the earlier publication discussed above (5), there is a signiﬁcantly greater mortality following LVRS by MS versus VATS in patients over age 65 years. Another group has addressed the issue of LVRS by MS versus VATS by direct retrospective comparison (7). This study also demonstrated that the VATS approach takes longer, but that there was a signiﬁcantly longer ICU stay in the MS group. Trends that did not reach statistical signiﬁcance included more ventilator days, air leak days, and total hospital days in the MS group. Again, the sternotomies were performed primarily early in this group’s experience, clouding the analysis of the data to some extent. Returning to Table 1, one can review the available literature to provide further information regarding the issue of VATS versus MS approaches. Focusing on the two studies reporting only bilateral VATS operations and the four studies reporting only bilateral open operations, we ﬁnd the following: (1) the improvement in pulmonary function following MS may be slightly greater than that following VATS (average increase in FEV1 58 vs. 49%); (2) the weighted average mortality rate with VATS is 1%, whereas that with MS is 4.4%; (3) the length of stay for VATS averages 12 days versus 15 days with MS. Of course, these data are merely suggestive and suffer from all the ﬂaws mentioned in the above discussion of the direct comparison studies plus several others.

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In the absence of hard data clearly to recommend one approach over the other, several clinical impressions continue to drive our tendency to perform most of our LVR procedures via MS. First, we feel that we are better able to visualize and therefore more precisely resect the areas of lung most involved by the emphysematous process during procedures conducted through an MS. Second, we feel that the VATS procedure, due to the limited ‘‘jaw’’ opening of currently available endoscopic staplers, tends to result in resection of less than the optimal amount of pulmonary tissue (compounding the natural tendency to perform too conservative a resection). Third, the MS approach allows us greater ﬂexibility in the performance of the procedure—for example, it allows performance of a right upper lobectomy in patients in whom there is virtually no functional parenchyma remaining in this lobe. The data suggesting increased mortality by the MS approach in patients over age 65 years has altered our approach to these patients. In the elderly, and in others who appear to be more severely compromised by a variety of clinical criteria, but who nevertheless remain candidates for the procedure, we currently favor a VATS approach.

III.

Technique of LVRS by MS

Preoperatively, a thoracic epidural catheter is placed for intraoperative and postoperative analgesia. Fiberoptic bronchoscopy is performed through a single-lumen endotracheal tube to rule out unexpected malignancy or active infection that would preclude proceeding with the operation. A sputum sample or bronchial washing is sent for microbiological study at this time even if there is not an excessive amount of secretions. These intraoperative cultures are used to guide initial antimicrobial therapy if the patient develops an inﬁltrate in the early postoperative period. An MS is performed with complete division of the bone from the sternal notch to the xyphoid process. The skin incision is kept somewhat shorter, from approximately the angle of Louis to 3 cm above the xyphisternal junction, with elevation of ﬂaps to expose the full extent of the bone incision. Care is taken throughout the procedure to handle the sternum gently. Cautery is not used widely for control of bleeding, but rather only on speciﬁc bleeding points in order to preserve sternal blood supply. The sternal edges are protected with laparotomy pads to avoid damage from the retractor. Furthermore, the retractor is spread slowly to allow progressive relaxation of attached soft tissues and cartilages, avoiding sternal and rib fractures. We have found these maneuvers to be useful in minimizing sternal complications, which can range from nuisance ‘‘clicks’’ to the very rare case (one in our experience with over 200 LVRS procedures)

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of mediastinitis. Certainly, these patients are at high risk for problems with sternal healing owing to their high work of breathing and the stress which this places on the sternal closure. The side to be operated upon ﬁrst—generally the side with the worst disease as demonstrated on preoperative studies—is collapsed before the skin incision is begun. This provides adequate time for the very slowly deﬂating diseased areas to fall to some extent by the time the surgeon is prepared to resect. The sternal edge on the side of interest is elevated with a sternal retractor (Buggie type—a hemisternal retractor such as a Favolaro can be used as an alternative, but we have found it cumbersome to have to replace these retractors on the opposite side of the table after the completion of surgery on the ﬁrst side.) The pleura on the side of interest is bluntly dissected off of the anterior chest wall for a width of approximately 5 cm along the entire length of the incision. This maneuver facilitates identiﬁcation and careful avoidance of injury to the phrenic nerve. The pleura is then carefully incised, exposing the lung. It is at the upper end of the pleural incision that the phrenic nerve is most at risk and must be most assiduously identiﬁed and avoided; cautery should not be used during the incision of this portion of pleura. Additionally, the incision in the pleural reﬂection is only carried as far superiorly as the internal mammary vein. Sternal retraction is gradually increased until sufﬁcient room has been created to insert a hand into the thorax. Many of the patients have scattered areas of ﬁlmy adhesions, presumably resulting from past inﬂammatory processes. Taking care not to tear any adhesions that may be present, the surgeon carefully retracts the lung, and the adhesions (which are often vascular) are divided with cautery as they are encountered. Overvigorous retraction at this point may cause the lung to tear, rather than the adhesion, and this may result in a prolonged postoperative air leak. On rare occasions, we have encountered severe, dense adhesions which had not been anticipated preoperatively and which caused us to abort the procedure on that side. Attempting to lyse dense adhesions may lead to prolonged air leaks and additional postoperative complications, so prudent judgment must be exercised in these situations. We do not, as a routine, incise the inferior pulmonary ligament, although some surgeons do. Once the lung is fully mobilized, the areas for resection are chosen. Ideally, a single, large strip of tissue from the upper lobe (in the patient who has upper lobe–predominant disease) can be resected with several ﬁrings of the stapler, creating a single continuous staple line from the most caudad portion of the upper lobe to the extreme apex. Filling the hemithorax with saline and rotating the table slightly to the side of interest (Fig. 1) ﬂoats the lung well up into the operative ﬁeld, making resection easier. The lung in the area where the disease appears to be most severe is grasped with Duvall

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Figure 1 Demonstration of the technique of partially ﬁlling the hemithorax with saline and rotating the table away from the operator. This ﬂoats the lung well up into the operative ﬁeld, facilitating lung volume reduction through a median sternotomy.

clamps—lung not to be resected is left undisturbed—and the staple line is begun beneath the clamps. The stapler we favor is a GIA 80 (U.S. Surgical, Norwalk, CT) with 4.8-mm staples, and we employ 0.35 mm polytetraﬂuoroethylene (PTFE) inserts for buttressing (Fig. 2). We are careful that as the staple line is created, the stapler is placed exactly at the ‘‘crotch’’ created by the previous stapler—we suspect that some postoperative air leaks occur at points where staple lines cross. In patients who have disease that by ventilation/perfusion scan is not localized primarily to the apices, we attempt to target the areas of resection to the areas of disease, often resecting portions of the middle or lower lobes. Areas with poor perfusion remain inﬂated for the longest period of time, facilitating their identiﬁcation as the lung collapses. In patients who have minimal function in the right upper lobe, we occasionally perform a formal right upper lobectomy. How much parenchyma to remove cannot be easily quantitated, but an average goal is 20–30% of the volume on each side. More is removed in hemithoraces containing more diseased lung; less is removed in hemithoraces which contain less severely diseased lung. The resection should

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Figure 2 A standard, 80 mm G.I.A. stapling instrument is used when performing lung volume reduction by median sternotomy, with buttresses as pictured here to minimize air leaks.

result in a residual apical space when the lung is reinﬂated. If no such space is visible after initial reinﬂation, more tissue should be removed. Once the resection is completed, the lung is gently reexpanded while the staple line is submerged in saline and evaluated for air leaks. We are extremely careful to keep peak inspiratory pressures at the time of lung reexpansion and from this point forward during the procedure to less than 25 cm H2O. Usually, no air leaks are identiﬁed at this time. Occasionally, leaks occur adjacent to the buttressed staple line. Small leaks are tolerated, if found, as attempts to repair them often lead to worse leaks. The rare large leak may often be repaired by restapling the area. Generally, 2 #28 chest tubes are placed and are left to water seal with no suction applied. Once the procedure on the ﬁrst side is completed, we check an arterial blood gas. If severe hypercarbia is identiﬁed (PaCO2 >70 mm Hg in patients without preoperative CO2 retention), we ventilate both lungs for several minutes to reduce this toward normal. The opposite lung is then collapsed, and the procedure described above is repeated. Peak pressures on the previously operated lung that is now being ventilated are minimized.

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At the termination of the procedure, the sternum is closed with three wires in the manubrium, and no less than four more in the body of the sternum. These are secured tightly but without tearing through the sternum. We extubate the patient in the operating room. Usually, this can be done promptly, but it sometimes requires up to an hour of waiting for narcotics to be metabolized and PaCO2 to be blown off. Rarely are formal ‘‘extubation criteria’’ met by these patients prior to extubation, yet if the analgesia is adequate, successful extubation can almost always be achieved despite hypercarbia.

IV.

Summary

We have reviewed the putative advantages and disadvantages of the VATS and MS surgical approaches. We have discussed our reasons for continuing to favor the sternotomy approach in patients who are less than 65 years old, reserving the VATS approach for the elderly and those who are more severely compromised. Certainly, the results with the two approaches are sufﬁciently similar to recommend that surgeons should use the technique with which they are most comfortable. Our speciﬁc technique of LVRS by MS is described in detail. Although signiﬁcant experience with LVRS has now been accrued, and although there is little doubt that a subgroup of patients beneﬁt from the operation with acceptable risks of morbidity and mortality, a broad array of questions remain to be answered. Areas of controversy that remain include issues of patient selection, surgical technique and approach, durability and extent of beneﬁt, and even the basic question of physiological mechanism of the effect. Ongoing studies may support application of this operation to selected emphysematous patients worldwide who have no other viable alternative.

References 1.

2.

Cooper JD, Trulock EP, Triantaﬁllou AN, Patterson GA, Pohl MS, Deloney PA, Sundaresan RS, Roper CL. Bilateral pneumonectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995; 109:106–119. McKenna RJ, Brenner M, Gelb AF, Mullin M, Singh N, Peters H, Panzera J, Calmese J, Schein MJ. A randomized, prospective trial of stapled lung reduction versus laser bullectomy for diffuse emphysema. J Thorac Cardiovasc Surg 1996; 111:317–322.

Lung Volume Reduction by Median Sternotomy 3.

4.

5.

6.

7. 8.

9. 10.

11. 12.

13.

14.

15.

16. 17.

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McKenna RJ, Brenner M, Fischel RJ, Gelb AF. Should lung volume reduction for emphysema be unilateral or bilateral? J Thorac Cardiovasc Surg 1996; 112:1331–1339. Swanson SJ, Mentzer SJ, DeCamp MM, Bueno R, Richards WG, Ingenito EP, Reilly JJ, Sugarbaker DJ. No-cut thoracoscopic lung plication: A new technique for lung volume reduction surgery. J Am Coll Surg 1997; 185:25–32. Kotloff RM, Tino G, Bavaria JF, Palevsky HI, Hansen-Flaschen J, Wahl PM, Kaiser LR. Bilateral lung volume reduction surgery for advanced emphysema: A comparison of median sternotomy and thoracoscopic approaches. Chest 1996; 110:1399–1406. Roberts JR, Bavaria JE, Wahl P, Wurster A, Friedberg JS, Kaiser LR. Comparison of open and thoracoscopic bilateral volume reduction surgery: Complications analysis. Ann Thorac Surg 1998; 66:1759–1765. Ko CY, Waters PF. Lung volume reduction surgery: A cost and outcomes comparison of sternotomy versus thoracoscopy. Am Surg 1998; 64:1010–1013. Eugene J, Ott RA, Gogia HS, Dos Santos C, Zeit R, Kayaleh RA. Videothoracic surgery for treatment of end-stage bullous emphysema and chronic obstructive pulmonary disease. Am Surg 1995; 61(10):934–936. Wakabayashi A. Thoracoscopic laser pneumoplasty in the treatment of diffuse bullous emphysema. Ann Thorac Surg 1995; 60:936–942. Keenan RJ, Landreneau RJ, Sciurba FC, et al. Unilateral thoracoscopic surgical approach for diffuse emphysema. J Thorac Cardiovasc Surg 1996; 111:308–316. Naunheim KS, Keller CA, Krucylak PE, Ruppel G, Singh A, Osterloh J. Unilateral VATS lung reduction. Ann Thorac Surg 1996; 61:1092–1098. Bingisser R, Zollinger A, Hauser M, Bloch KE, Russi EW, Weder W. Bilateral volume lung reduction surgery for diffuse pulmonary emphysema by videoassisted thoracoscopy. J Thorac Cardiovasc Surg 1996; 112(4):875–882. Cooper JD, Patterson GA, Sundaresan RS, Trulock EP, Yusen RD, Pohl MS, Lefrak SS. Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema. J Thorac Cardiovasc Surg 1996; 112:1319–1330. Miller DL, Dowling RD, McConnell JW, Skolnick JL. Effects of lung volume reduction surgery on lung and chest wall mechanics. Presented at the 23rd Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 25–31, 1996. Daniel M, Chan BK, Bhaskar V, et al. Lung volume reduction surgery: case selection, operative technique and clinical results. Ann Surg 1996; 223(5):526– 531. Miller JI. Jr, Lee RB, Mansour KA. Lung volume reduction surgery: lessons learned for emphysema. Ann Thorac Surg 1996; 61:1464–1469. Argenziano M, Moazimi N, Thomashaw B, et al. Extended indications for volume reduction pneumectomy in advanced emphysema. Ann Thorac Surg 1996; 62:1558–1597.

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18. Zenati M, Keenan RJ, Sciurba FC, Manzetti JD, Landreneau RJ, Grifﬁth BP. Role of lung reduction in lung transplant candidates with pulmonary emphysema. Ann Thorac Surg 1996; 62:994–999. 19. Wisser W, Tshernko E, Wanke T, Senbaclavaci O, Kontrus M, Wolner E, Klepetko W. Functional improvements in ventilatory mechanics after lung volume reduction surgery for homogeneous emphysema. Eur J Cardiothorac Surg 1997; 12:525–530. 20. O’Brien GM, Furukawa S, Kuzma AM, Cordova F, Criner GJ. Improvements in lung function, exercise, and quality of life in hypercapnic COPD patients after lung volume reduction surgery. Chest 1999; 115:75–84. 21. Bagley PH, Davis SM, O’Shea M, Coleman AM. Lung volume reduction surgery at a community hospital: Program development and outcomes. Chest 1997; 111:1552–1559. 22. Bousamra M, Haasler GB, Lipchik RJ, Henry D, Chammas JH, Rokkas CK, Menard-Rothe K, Sobush DC, Olinger GN. Functional and oximetric assessment of patients after lung reduction surgery. J Thorac Cardiovasc Surg 1997; 113:675–682. 23. Date H, Goto K, Souda R, Nagashima H, Togami I, Endou S, Aoe M, Yamashita M, Andou A, Shimizu N. Bilateral lung volume reduction surgery via median sternotomy for severe pulmonary emphysema. Ann Thorac Surg 1998; 65:939–942.

12 Thoracoscopic Approach for Lung Volume Reduction Surgery

ROBERT J. McKENNA, Jr. Cedars Sinai Medical Center Los Angeles, California, U.S.A.

I. Introduction Since the introduction of minimally invasive surgical techniques to thoracic surgery in 1990, video-assisted thoracic surgery (VATS) has become a common technique for many operative procedures. When Cooper rekindled interest in the surgical treatment of diffuse emphysema, he used the median sternotomy, because it offered good access to both lungs with minimal postoperative complications and pain (1). At several institutions, surgeons utilizing minimally invasive techniques have shown that bilateral VATS appears to produce results that are comparable with those of a median sternotomy for lung volume reduction surgery (LVRS). In certain situations, a VATS approach to LVRS may be preferable. This chapter will review the indications for LVRS, present the results for the various LVRS procedures, describe the VATS technique for LVRS, and compare the published data for the bilateral VATS and the median sternotomy approaches.

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Patient Selection

Regardless of the incision used to perform the procedure, the basic indications for LVRS are the same. Candidates for LVRS remain symptomatic despite maximal medical management for moderate to severe emphysema. Their quality of life is poor, because they have considerable dyspnea with simple activities, such as dressing, showering, and walking short distances. These patients are usually oxygen dependent. They are most often less than 75 years of age, but selected older patients may be candidates for this type of surgery. LVRS is generally contraindicated for patients who are too severely incapacitated (e.g., ventilator dependency, wheelchair dependency, and severe hypercarbia). Severe anxiety and depression are contraindications to LVRS, because they limit patient compliance with exercise programs. This in turn limits postoperative functional improvement, because maximal improvement requires extensive muscle conditioning in addition to the improvement in pulmonary mechanics provided by LVRS. The procedure is not indicted for patients with either asthma or signiﬁcant bronchitis. The patient evaluation process has been discussed in detail in Chapter 7.

III.

Deﬁnition of Surgical Emphysema Versus Medical Emphysema

Pulmonary function testing diagnoses and quantiﬁes the severity of emphysema, but it is not the most important selection factor for LVRS. Only a small percentage of patients with severe emphysema have an anatomical pattern of emphysema that is appropriate for LVRS. There is a poor correlation between pulmonary function tests and the degree or pattern of emphysematous parenchymal destruction as seen on computed tomography (CT) scanning. Gelb et al. (2) found that only 24 (30%) of 81 symptomatic patients with severe chronic obstructive pulmonary disease (COPD), hyperinﬂated lungs seen on chest radiography, and comparable pulmonary function tests had signiﬁcant amounts of parenchymal destruction on high-resolution chest CT scan. Patients who are candidates for LVRS at our institution have a heterogeneous pattern with severe parenchymal destruction in part of the lungs (usually the upper lobes) seen on the chest CT scan and markedly reduced blood ﬂow in the corresponding area on the lung perfusion scan. Other areas of the lungs are more normal. These patients are to be distinguished from those with only a few giant bullae, who may be considered for traditional bullectomy.

Thoracoscopic Approach for LVRS IV.

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Patient Selection Unique to VATS

Although the basic selection criteria for LVRS are not dependent on the operative approach, there are some clinical situations in which VATS may be preferable to a median sternotomy (Table 1); for example, when LVRS is indicated for only one lung, when surgery is contraindicated on the opposite side, or when a lateral approach is preferred to the midline bilateral approach of the median sternotomy. Some patients have a heterogeneous pattern of emphysema in only one lung; we limit LVRS to that side. Prior unilateral surgery (e.g., lung resection, LVRS, or lung transplant) or unilateral pleural disease (e.g., pleurodesis, empyema) precludes LVRS on that side and makes VATS a logical approach for the other lung. Some candidates for LVRS have signiﬁcant adhesions located posteriorly. Lysis of these adhesions is often easier with a lateral approach than with the anterior approach of the median sternotomy. The access to anterior and apical areas of emphysema is very good with a median sternotomy, but the access to lower lobe disease, especially the left lower lobe, is better with VATS. Finally, unilateral LVRS is beneﬁcial to lung transplant patients when hyperinﬂation of the native lung compresses the transplanted lung. Table 2 shows advantages and disadvantages of the VATS approach for LVRS. Table 1 Clinical Settings in Which VATS May Be the Preferred Approach for LVRS Rather than an Open Procedure 1. Only unilateral LVRS is indicated Prior contralateral surgery (e.g., lobectomy, LVRS) Contralateral pleural disease (e.g., pleurodesis) 2. Posterior pleural adhesions 3. Lower lobe disease 4. Contralateral lung transplant Table 2

Advantages and Disadvantages to a VATS Approach for LVRS

Advantages for a VATS approach to LVRS Better access for lower lobe disease Better access to posterior adhesions No risk of sternal infection Better access for mediastinal nodes if cancer is found

Disadvantages for a VATS approach to LVRS Requires good video skills Usually requires two skin preps Difﬁculty in identiﬁying air leaks Intercostal neuritis Limited access for palpation of lung masses

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Technique for VATS LVRS

The goal of LVRS is always to accomplish the same resection whether the operative approach is via median sternotomy, clamshell incision, thoracotomy, or VATS. This section will detail the technical aspects of LVRS by VATS.

VI.

Anesthesia

The procedure is performed under general anesthesia with a double-lumen tube. Despite severely compromised pulmonary function, patients undergoing LVRS tolerate one-lung anesthesia surprisingly well. During the operation, reduced oxygen saturation is usually related to endobronchial secretions or poor positioning of the endotracheal tube. Bronchoscopy is very important to conﬁrm proper positioning of the tube and to remove secretions. Because the elastic recoil of emphysematous lung is poor, bronchoscopic suctioning in the main stem bronchus is also frequently used to encourage atelectasis of the lung on which the surgeon is operating. The anesthesia should be planned carefully to allow extubation of the patient at the completion of the procedure. Details of anesthetic management have been covered in Chapter 10.

VII.

Positioning of the Patient

The patient is usually in the full lateral decubitus position for thoracoscopic LVRS. This allows access to all areas of the chest and is especially helpful in the presence of posteriorly located adhesions or resection of lower lobe emphysema. After the resection has been completed on one side, the patient is turned into the opposite lateral decubitus position for a second skin preparation. Alternatively, LVRS via VATS can be performed with the patient in the supine position. This approach provides access to both pleural spaces with one skin preparation and without the need to reposition the patient. One technique for the supine approach is to position the arms above the head and place inﬂatable bags under each half of the chest (3). Inﬂation of the bag under the side of the chest in which the surgeon is operating provides access further posteriorly on the chest wall. After completion of LVRS on the ﬁrst side, that bag is deﬂated and the contralateral bag is inﬂated. Alternatively, the patient may simply be elevated off the bed by a beanbag positioned posteriorly between the scapulae.

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The supine position provides the same access for upper lobe emphysema resection as the median sternotomy. Access to the lower lobes is poor, however, so the lateral decubitus position is the preferred VATS approach for patients with lower lobe disease. The supine VATS approach has many of the advantages of the median sternotomy approach (simultaneous access to both sides and the ability to go back to the ﬁrst side without having to repeat the skin preparation and reopen incisions). It also has some of the disadvantages of the median sternotomy approach (more difﬁculty with posterior adhesions and lower lobe disease). The identiﬁcation of air leaks is more difﬁcult with any VATS approach than with the median sternotomy. VIII.

Incisions

In the lateral decubitus position, the ﬁrst incision is made in the tenth intercostal space for the trocar and the thoracoscope. A ring forceps is placed through the fourth intercostal space in the midaxillary line for manipulation of the lung. The stapler is passed through the sixth intercostal space in the midclavicular line. In the supine position, the incision for the trocar and the thoracoscope is placed in the ﬁfth intercostal space in the midaxillary line. In the midclavicular line, the ring forceps is placed through an incision in the second intercostal space and the stapler through the sixth intercostal space. IX.

Lung Resection

The same resection for LVRS is performed with the open and VATS techniques. The target areas are primarily determined preoperatively by CT scanning and perfusion imaging. Absorptive atelectasis occurs more readily in areas where the emphysema is not as severe, so the target areas may also be identiﬁed intraoperatively as areas that stay hyperinﬂated. For upper lobe disease, the resection usually begins in the anterior segment of the upper lobe adjacent to the mediastinum. The stapler is ﬁred ﬁve or six times as the resection proceeds over the apex of the lung from anterior to posterior. If the anterior segment of the upper lobes is well perfused, the resection begins in the midaxillary line and proceeds over the apex of the lung from lateral to medial. Approximately 50–60% of each upper lobe is resected. Although the density of the tissue may vary from patient to patient, the average weight of the resected tissues is approximately 60 g per side. For lower lobe disease, the four basilar segments are almost entirely resected. The superior segment is preserved if it is well perfused on the lung

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scan or resected if it is poorly perfused. After the inferior pulmonary ligament is taken down, the stapler is serially ﬁred across the lower lobe adjacent to the ﬁssure. This continues until the entire lobe has been resected. If the emphysema is minimal in the superior segment, the staples are ﬁred horizontally at the junction of the superior segment and the basilar segments to preserve the superior segment. X.

Buttressing

When Cooper found that signiﬁcant air leaks occurred after the ﬁrst few procedures, he developed the use of bovine pericardium strips to buttress the staple line on emphysematous lung (4). Two studies have demonstrated that buttressed staples reduce the duration of the chest tube by approximately 2 days compared to staples without a buttress (5,6). The buttress material may be bovine pericardium (Peri-strips, Biovascular, Minneapolis, MN), Gortex (Core-guard, W.L.Gore, Flagstaff, AZ), or bovine collagen (Instat, Johnson and Johnson, Brunswick, NJ). Currently, we favor the Peri-strips, because they are attached to the stapler with a glue. When the other materials are used, the surgeon must remove additional materials that hold the buttress to the stapler, a procedure unnecessary with the dry Peri-strips. Despite the buttress, prolonged air leak still occurs in 40–50% of patients following LVRS, because the air leaks are usually not on the staple line. Some surgeons report reasonable hospital length of stay and postoperative results for LVRS without buttressed staples. The buttress is probably very beneﬁcial when stapling very thin lung tissue with subpleural emphysema and less important for thicker lung tissue. XI.

Resection or Plication?

An alternative to lung resection for LVRS is plication of the emphysematous lung parenchyma. A special clamp rolls the surface of the lung so that a stapler (with the knife blade removed) can plicate the folded tissue (7). There are currently not enough data to compare the results of plication to the results of excision. XII.

Identiﬁcation and Control of Air Leaks

The best approach for air leaks is to prevent them from occurring. The trocar should be inserted carefully to avoid puncturing the lung. Manipulation of the lung should be minimized, because air leaks may

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occur whenever the lung is touched. Air leaks may also occur during lysis of adhesions; therefore, careful extrapleural dissection is often helpful to avoid cutting or tearing lung parenchyma. If air leaks do occur, the surgeon should try to eliminate them prior to completion of the operation. When LVRS is performed via either median sternotomy or thoracotomy, the chest is ﬁlled with water, and the surgeon inspects for air leaks as the lung is inﬂated underwater. The water test is more difﬁcult with VATS. As an instrument holds the lung away from the chest wall, a suction–irrigator sprays the lung with water to help detect air bubbles. Visualization is difﬁcult because inﬂation of the lung obliterates the pleural space. Air leaks most often occur 1–2 cm lateral to the staple line. If possible, they are closed with another ﬁring of the stapler with buttressing material. Options are limited for these air leaks or other air leaks deep in the ﬁssure when they are not amenable to closure with a stapler. Suturing emphysematous lung is often unsuccessful, because the soft emphysematous lung tissue does not hold sutures well. Ethyl cyanoacrylate adhesive (instant glue, Krazy Glue) can be placed on the leak with some success (D. L. Miller, R. D. Dowling, and J. L. McConnell, personal communications). Tissue glue has not worked, because it does not adhere to the lung very well. Several companies are developing sealants, but these are not currently commercially available in the United States. XIII.

Conversion to Open Procedure

Some surgeons have converted a VATS procedure to an open procedure to control difﬁcult air leaks or when extensive adhesions are found. The incidence of this is less than 5%. In our last 400 cases of LVRS, we have not found this to be necessary. XIV.

Postoperative Management

Patients are usually extubated at the end of the procedure and transferred to the intensive care unit. Aggressive pulmonary care is begun immediately. This includes the use of incentive spirometry, nebulizer treatments, chest physiotherapy, and early ambulation. Moderate hypercapnia and respiratory acidosis are well tolerated. A CO2 pressure of 55–70 mmHg is common postoperatively even in patients who had not retained CO2 preoperatively. One of our patients was awake and alert with an arterial PCO2 of 160 mmHg in the intensive care unit immediately following her operation. Aggressive nursing care has helped this patient and others to remain extubated and

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minimize the risk of pneumonia. Reintubation has been necessary in 16 of our last 400 cases (4%). In the operating room, all incisions are blocked with a long-acting local anesthetic. A continuous infusion of a narcotic through an epidural catheter provides postoperative pain relief for 2–3 days. We do not use local anesthetic through the epidural catheter, because it often causes vasodilation and hypotension. Indomethacin suppositories (50 mg q8h) for 2 days also help to reduce postoperative pain. The chest drainage system is usually left to water seal, because suction limits ambulation and may prolong air leaks. If an air leak is present on the third day following LVRS, we attach a Heimlich valve to the tubing and remove the chest drainage system. This increases the mobility of the patient and reduces the hospital length of stay by allowing discharge with an air leak (8).

XV.

Results of LVRS via VATS

The technique for LVRS can be any of the following: laser or staples, unilateral or bilateral, and open or VATS. The results of these various approaches (Tables 3–6) indicate that the bilateral staple operation is the procedure of choice. The results for VATS and open procedures appear to be comparable. In a randomized, prospective study of unilateral LVRS, we demonstrated the superiority of the resectional (staple) technique compared with the shrinkage (laser) technique (33 vs. 13.4% improvement in forced expiratory volume in 1 s (FEV1) at 6 months) (9). Two years after the laser treatment, only 1 of 33 patients (3%) had any residual beneﬁt from the procedure. In contrast, 11 of 39 staple-treated patients (28%) retained beneﬁt from the procedure. These results are consistent with the results of

Table 3 Ref. 10 5 11 31 Totals

Results with Unilateral Laser LVRS N

Mortality

LOS

D FEV1 (%)

33 141 55 20 249

0 8 (5.7%) 3 (5.5%) 1 (5.6%) 12 (5.6%)

9 NA 13 18 14

13 14 16 36 17

N, number of patients; LOS, length of stay.

Thoracoscopic Approach for LVRS Table 4 Ref. 18 26 12 14 Totals

265

Results with Unilateral Staple LVRS N

Mortality

LOS

D FEV1 (%)

87 50 57 11 205

3 (3.5%) 2 (4%) 2 (3.4%) 0 7 (3.4%)

11.4 13 17 29 14.3

31 35 27 66.7 32.7

N, number of patients; LOS, length of stay.

Table 5 Ref. 13 15 16 30 Totals

Results with Bilateral Staple LVRS Performed via VATS N

Mortality

LOS

D FEV1 (%)

154 40 20 42 256

6 (4%) 1 (2.5%) 0 0 7 (3.5%)

11.1 15 15 13 12.2

52 41.2 37 43 49.4

N, number of patients; LOS, length of stay.

Table 6 Results of 11 Series of Bilateral Staple LVRS Performed via Median Sternotomy Ref. 21 15 22 23 24 25 26 17 27 28 29 Totals

N

Mortality

LOS

D FEV1 (%)

150 80 85 26 53 37 100 15 39 8 17 610

6 (4%) 11 (13.8%) 6 (7%) 1 (3.8%) 3 (5.7%) 0 10 (10%) 2 (13%) 0 0 0 39 (6.4%)

13.5 22 17 13.6 NA NA NA 12.5 NA NA NA 16.2

51 41.4 61 49 96 57 91 59.7 41 32 46 60.8

N, number of patients; LOS, length of stay; NA, not available.

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nonrandomized series that used either the staple or laser procedures, and thus the staple procedure appears to be the technique of choice (9–16). To determine the roles of unilateral and bilateral procedures, we reported a nonrandomized comparison of 85 unilateral versus 79 bilateral staple operations (17). The morbidity, mortality (3.5 vs. 2.5%), and mean length of stay (11.4 vs. 10.9 days) were comparable for unilateral and bilateral procedures. The bilateral operation, however, showed greater improvement in the FEV1 (57 vs. 35%), oxygen independence (68 vs. 35%), and prednisone independence (85 vs. 56%). Postoperatively, signiﬁcant dyspnea (grade 3 or 4) remained in 44% of the patients after a unilateral procedure and in only 12% of the patients after a bilateral procedure. The 1-year mortality was signiﬁcantly higher for the unilateral compared with the bilateral procedure patients (17 vs. 5% P ¼ .005). This occurred in the highest-risk patients (older than 75 years, with a room air PaO2 < 50 mm Hg and an FEV1 < 500 mL) after a unilateral operation but not after a bilateral procedure. Furthermore, multivariate analysis failed to identify factors that could allow selection of patients who achieve enough beneﬁt from a unilateral procedure, so a bilateral procedure is recommended as the procedure of choice for patients with a bilateral pattern of heterogeneous emphysema. Results from other series of unilateral or bilateral procedures are consistent with these results (Tables 3–6).

XVI.

Comparison of VATS and Open LVRS

Cooper (1) originally proposed that bilateral staple LVRS should be performed through a median sternotomy, because that incision is less painful than bilateral thoracotomies (1). Bilateral VATS is also less painful than bilateral thoracotomies and provides access for bilateral staple LVRS, so other surgeons adopted this approach. A comparison of the data from largest single series of the median sternotomy and VATS approaches shows remarkably similar results (Table 7). Table 8 shows the experience of consecutive bilateral staple LVRS operations via median sternotomy (15 cases) followed by VATS (15 cases) at one institution (16). Although the mean intensive care unit stay was shorter for the VATS patients, the mean hospital length of stay was identical, and there was no difference in chest tube duration. Although the mortality was higher for patients who underwent the median sternotomy approach, the series is small, so this difference is not statistically signiﬁcant. The mean improvement in the percent age of predicted FEV1 was comparable for the median sternotomy (59.7%) and VATS (60.1%) groups, but the improvement was achieved earlier after the VATS operation (Table 9).

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Table 7 Comparison of the Current Largest Individual Series of LVRS by VATS and Median Sternotomy Factor

McKenna 1997

Patients Mean age Operation Preoperative FEV1 LOS Mortality DFEV1

Cooper 1996

154 67 VATS 0.64 (24%) 09.3 days 4.5% 52%

150 61 MS 0.70 (25%) 13.5 days 4% 51%

LOS, length of stay; MS, median sternotomy.

Table 8

Comparison of Median Sternotomy and VATS for LVRS Median sternotomy

VATS

15 6.5 12.3 2 (13%) 8.7 0

15 3.3 12.5 1 (7%) 8 5 (33%)

Patients ICU days LOS Mortality Chest tube days SC emphysema

ICU, days in intensive care unit; LOS, length of stay; SC emphysema, signiﬁcant subcutaneous emphysema. Source: Ref. 17.

Table 9 Comparison of the % Predicted FEV1 Preoperatively and at Various Time Intervals Following LVRS by Median Sternotomy and VATS Preop (%) Median sternotomy VATS

26 25

1 mo (%)

3 mo (%)

6 mo (%)

26 36.5

34.5 40.9

33.5 40.4

Source: Ref. 17.

Some complications were unique to the VATS group. Two of 15 VATS patients (13%) were converted to thoracotomy. Five of 15 VATS patients (33%) developed signiﬁcant subcutaneous emphysema, because the pleura remains open when a VATS incision is closed.

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In a nonrandomized series (14), one surgeon performed LVRS via VATS (40 patients) and another used the median sternotomy (80 cases). Table 10 shows that the length of stay and chest tube duration slightly favor the VATS approach. The 30-day mortality was the same for the two techniques. Reintubation was required for 14 of the median sternotomy patients and only 1 VATS patient. Eleven of the reintubated patients in the median sternotomy group became ventilator dependent and died. This made the total mortality for the median sternotomy approach signiﬁcantly higher than the mortality for the VATS approach. Table 11 shows that the difference in mortality for the two techniques is most pronounced in patients older than 65 years (20.9 vs. 9.1%). The improvement in pulmonary function was comparable for the two groups (see Table 10). As with other LVRS series, some patients had substantial improvement, whereas others hardly improved at all. There were no statistically signiﬁcant differences in these outcomes according to surgical approach.

Table 10 Nonrandomized Comparison of LVRS via Median Sternotomy and VATS at the University of Pennsylvania Median sternotomy Patients 30-day mortality Hospital mortality Reintubation Chest tube LOS DFEV1 < 20% DFEV1 > 60%

80 4.2% 13.8% 14 (17.5%) 16 22 34% 32%

VATS 40 2.5% 2.5% 1 (2.5%) 13 15 29% 42%

P value

P ¼ .02 P ¼ .41 P ¼ .13

LOS, length of stay. Source: Ref. 15.

Table 11 Mortality Following LVRS via Median Sternotomy and VATS in Patients Older and Younger Than 65 Years

Median sternotomy VATS Source: Ref. 15.

>65 years

<65 years

9/43 (20.9%) 1/11 (9.1%)

2/37 (5.4%) 0/29 (0%)

Thoracoscopic Approach for LVRS XVII.

269

LVRS and Lung Transplant

After a single-lung transplant for emphysema, further hyperexpansion of the native lung may compress the transplanted lung. Kroshus (18) reported the need for LVRS in the native lung in 3 of 66 patients at 12, 17, and 42 months after the transplant. The LVRS resulted in substantial relief of dyspnea and substantial improvement in pulmonary function tests and in the chest radiograph for all three patients (19). Further discussion of LVRS following unilateral transplantation is contained in Chapter 17. XVIII.

Summary

Current data suggest that the bilateral staple operation is the operation of choice for LVRS. The postoperative results for this procedure appear to be comparable whether the operation is performed with VATS or median sternotomy, although the postoperative improvement in pulmonary function may be achieved earlier with the VATS approach. Older patients may also have a lower mortality following a VATS operation. Preliminary results from nonrandomized series suggest that the overall morbidity and mortality might be slightly lower for the VATS approach, but a deﬁnitive statement regarding this cannot be made until the results from the ongoing randomized prospective trials are available. References 1.

2.

3. 4. 5. 6.

7.

Cooper JD, Trulock EP, Triantaﬁllou AN, et al. CL. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995; 109:106–116. Gelb AF, Schein M, Kuei J, et al. Limited contribution of emphysema in advanced chronic obstructive pulmonary disease. Am Rev Respir Dis 1993; 147:1157–1161. Vigneswaran WT, Podbielski FJ. Single-stage bilateral, video-assisted thoracoscopic lung volume reduction operation. Ann Thorac Surg 1997; 63:1807–1809. Cooper JD. Technique to reduce air leaks after resection of emphysematous lung. Ann Thorac Surg 1994;57:1038–1039. Hazelrigg SR, Naunheim K. Effect of pericardial strips on air leak after stapled pulmonary resection. Ann Thoracic Surg 1997; 63:1573–1575. Fischel RJ, McKenna RJ Jr. Bovine pericardium versus bovine collagen to buttress staples for lung reduction operations. Ann Thorac Surg 1998; 115:217– 219. Swanson SJ. No-cut thoracoscopic lung plication: A new technique for lung volume reduction surgery. J Am Coll Surg 1997; 185:25–32.

270 8.

9.

10. 11.

12. 13. 14. 15.

16.

17.

18. 19.

20. 21. 22.

23.

24.

McKenna McKenna RJ Jr, Fischel RJ, Brenner M, Gelb AF. Use of the Heimlich valve to shorten hospital stay after lung reduction surgery for emphysema. Ann Thorac Surg 1996; 61:1115–1117. McKenna R, Brenner M, Gelb AF, et al. A randomized, prospective trial of stapled lung reduction versus laser bullectomy for diffuse emphysema. J Thorac Cardiovasc Surg 1996; 111:310–322. Little AG, Swain JA, Nino JJ, et al. Pneumoplasty for emphysema: early results. Ann Surg 1995; 222:365–371. Keenen RJ, Landreneau RJ, Sciurba FC, et al. Unilateral thoracoscopic surgical approach for diffuse emphysema. J Thorac Cardiovasc Surg 1996; 111:308–315. McKenna RJ Jr, Brenner M, Singh N, et al. Patient selection for lung volume reduction surgery. J Thorac Cardiovasc Surg 1997; 114:957–967. Roue C, Mal H, Sleiman C, et al. Lung volume reduction in patients with severe diffuse emphysema. Chest 1996; 110:28–34. Kotloff RM, Tino G, Bavaria JE, et al. Bilateral lung volume reduction surgery for advanced emphysema. Chest 1996; 110:1399–1406. Bingisser R, Zollinger A, Hauser M, et al. W. Bilateral volume reduction surgery for diffuse pulmonary emphysema by video-assisted thoracoscopy. J Thorac Cardiovasc Surg 1996; 112:875–882. Wisser W, Tschernko E, Senbaklavaci O, et al. Functional improvement after volume reduction: Sternotomy versus videoendoscopic approach. Ann Thorac Surg 1997; 63:822–828. McKenna RJ Jr, Brenner M, Gelb AF, Fischel RJ. Should lung volume reduction surgery be unilateral or bilateral? J Thorac Cardiovasc Surg 1996; 112:1331–1339. Kroshus TJ. Unilateral volume reduction after single lung transplantation for emphysema. Ann Thoracic Surg 1996; 62:363–368. Kapelanski DP. Volume reduction of the native lung after single lung transplantation for emphysema. J Thorac Cardiovasc Surg 1996; 111:4898– 4899. Wakabayashi A, Wakabayashi A. Unilateral thoracoscopic laser pneumoplasty of diffuse bullous emphysema. Chest Surg Clin North Am 1995; 5:833–850. Naunheim KS. Ferguson MK. The current status of lung volume reduction operations for emphysema. Ann Thorac Surg 1996; 6:601–612. Stammberger U, Thurnheer R, Bloch KE, et al. Thoracoscopic bilateral lung volume reduction for diffuse pulmonary emphysema. Eur J Cardiothorac Surg 1997; 11:1005–1010. Cooper JD, Patterson GA, Sundaresan RS, et al. Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema. J Thorac Cardiovasc Surg 1996; 112:1319–1330. Argenziano M, Moazami N, Thomashaw B, et al. Extended indications for volume reduction pneumoplasty in advanced emphysema. Ann Thorac Surg 1996; 62:1588–1597.

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25. Daniel M, Chan BK, Bhaskar V, et al. Lung volume reduction surgery: case selection, operative technique, and clinical results. Ann Thorac Surg 1996; 61:526–532. 26. Miller JI, Lee RB, Mansour KA. Lung volume reduction surgery: lessons learned. Ann Thorac Surg 1996; 61:1464–1469. 27. Boussamra M, Haasler GB, Lipchik RJ, et al. Functional and oximetric assessment of patients after lung reduction surgery. J Thorac Cardiovasc Surg 1997; 113:675–681. 28. Date Hshimizu N, Andou A, et al. Bilateral lung volume reduction surgery via median sternotomy for severe pulmonary emphysema. Ann Thorac Surg 1998; 65:939–342. 29. Benditt JO, Wood ED, McCool FD, et al. Changes in breathing and ventilatory muscle recruitment patterns induced by lung volume reduction surgery. Am J Respir Crit Care Med 1997; 155:279–284. 30. Martinez FJ, de Oca MM, Whyte RI, et al. Lung volume reduction improves dyspnea, dynamic hyperinﬂation, and respiratory muscle function. Am J Respir Crit Care Med 1997; 55:1984–1990.

13 Perioperative Complications and Their Management

K. ROBERT SHEN

SCOTT J. SWANSON

Harvard Medical School and Massachusetts General Hospital Boston, Massachusetts, U.S.A.

Mount Sinai Medical Center New York, New York, U.S.A.

I. Introduction By virtue of age and smoking, the typical lung volume reduction surgery (LVRS) patient is at risk for numerous chronic medical problems in addition to emphysema. Long-term cigarette smoking increases risk for ischemic heart disease, cor pulmonale, pulmonary hypertension, diabetes, peripheral vascular disease, and gastrointestinal problems. Advanced age and chronic corticosteroid use also contribute to the higher potential complication rate in this patient population. These fragile patients require compulsive attention to prevent and manage the complications of anesthesia and thoracic surgery. Risks can be minimized by careful patient evaluation and selection, which are detailed in Chapter 7. However, even in ideal candidates, the risk of serious morbidity or mortality is substantial, especially for an elective surgical procedure. This chapter reviews the preparation of these patients for LVRS as well as the perioperative management and management of complications common to the technique. II.

Preparation for Surgery

At most centers, patients selected as candidates for LVRS are required to participate in a comprehensive pulmonary rehabilitation program both prior to surgery. Rehabilitation is quickly resumed postoperatively. Indeed, early experience with patients undergoing LVRS has convinced many 273

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centers that pulmonary rehabilitation is a critical part of preoperative preparation for LVRS, and that an inability to achieve targeted rehabilitation goals is sufﬁcient to exclude patients from this operation (1). Pulmonary rehabilitation, detailed in Chapter 6, consists of breathing exercises, pulmonary toilet, upper body strengthening, nutritional repletion, and overall conditioning. Descriptions of what the patient will experience in speciﬁc terms and the physical sensations associated with surgery are also provided and help reduce the patient’s perioperative anxiety. Before ﬁnal acceptance for surgery, some centers require that patients achieve speciﬁc functional goals such as the ability to walk continuously for 30 min on a treadmill or up two ﬂights of stairs, or a 20% improvement in 6-min walking distance (2,3).

III.

Perioperative Management

Meticulous anesthetic management is important for good postoperative outcome following LVRS. This is detailed more completely in Chapter 10. Several important points are reemphasized, as they impact directly on postoperative management. Anesthetic management begins with the preoperative bronchodilator pharmacotherapy. Humidiﬁers, systemic hydration, and mucolytic drugs are used to loosen secretions. Patients are maintained on their regular daily medication regimens and oxygen ﬂow rates prior to surgery. Given the high susceptibility of many of these patients to anxiety and panic attacks, patients should be kept informed and reassured about the surgical event. Premedication with anxiolytics or narcotics, which can cause respiratory depression, is avoided if possible. Our antibiotic prophylaxis consists of 1 g of cefazolin administered prior to induction of anesthesia. Antibiotic prophylaxis is continued every 8 h for at least 48 h postoperatively. Prophylaxis for thromboembolic complications includes both lower extremity compression boots and 5000 U of subcutaneous heparin just prior to induction. Heparin is continued every 12 h until the patient is fully ambulatory. Intraoperative monitoring of the patient is usually performed with a radial artery catheter and a central venous line. A thoracic epidural catheter for intraoperative and postoperative pain control is mandatory. Routine use of pulmonary artery catheters is not required. Other important monitoring includes pulse oximetry, capnography, and arterial blood gases when indicated. Continuous measurement of the patient’s temperature, usually by nasopharyngeal recording, is useful to prevent hypothermia. A transcutaneous nerve stimulator is used to adjust the degree of muscular relaxation,

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and is useful to assess neuromuscular recovery upon emergence from anesthesia prior to extubation. The main goals of the anesthesiological procedure are prevention of bronchospasm, optimal analgesia, and extubation of the patient on the operating table. Despite the diminished pulmonary function in these patients, there are compelling reasons to extubate patients immediately after LVRS, speciﬁcally the concern that intermittent positive-pressure ventilation will worsen postoperative air leaks. In a series of patients undergoing laser ablation, Fujita and Barnes reported a mortality rate of 22.7% in patients who required ventilation for longer than 24 h and a mortality rate of 45% in patients who were originally extubated immediately after surgery and developed respiratory failure requiring reintubation (4). Surgical techniques and intraoperative anesthetic considerations are detailed elsewhere and will not be repeated except to emphasize two points. First, complete reduction of target areas and meticulous avoidance of postoperative air leaks are critical to minimizing posoperative complications. Second, at the conclusion of the surgical procedure, it is essential that the patient is alert, following commands, breathing at a reasonable rate, and pain free prior to extubation.

IV.

Postoperative Management

Upon arrival in the postanesthesia care unit, patients are placed in an upright, sitting position to facilitate diaphragmatic excursion. Oxygen is administered via nasal canula at the lowest possible ﬂow to maintain arterial oxygen saturation just above 90% to preserve the patient’s respiratory drive. Patients are routinely monitored with pulse oximetry and continuous cardiac telemetry. A portable chest radiograph, 12-lead electrocardiogram, and a laboratory panel including electrolytes, complete blood counts, and arterial blood gases are obtained in the recovery room. At our center, chest tubes are placed to 10 cm of water pressure suction to maximize full expansion of the lung. Other centers use water seal only. If the postoperative chest radiograph shows a signiﬁcant pneumothorax (>30%), and the patient has hypoxemia, respiratory distress, or progressive subcutaneous emphysema, then the suction may be increased to 20 cm of water pressure. On the other hand, if there is no signiﬁcant air leak postoperatively, the chest tubes are placed to water seal. Postoperative pain is managed with epidural infusions of bupivacaine and a narcotic. Once patients have recovered from anesthesia and are stable, they are transferred to a thoracic intermediate care unit for observation. Their vital signs, urinary output, pulse oximetry, chest tube drainage, and cardiac

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rhythm are closely monitored. Nebulized treatments of albuterol and ipratropium are given every 4 h. Patients who are steroid dependent preoperatively are given intravenous hydrocortisone (100 mg every 8 h for 24 h) or methyl prednisolone (20 mg every 8 h for 24 h) and then returned to their baseline dose of prednisone. Intravenous ranitidine is used initially to protect against stress ulcers. Patients are allowed to take ice chips for comfort the night of surgery. It is important to document return of gastrointestinal function prior to initiating any substantial oral intake. With epidural analgesia that blunts the symptoms of a bloated stomach, aspiration can be a major problem in these patients. Total ﬂuid intake is restricted to 1500 mL/day. Docusate, suppositories, enemas, and occasionally lactulose (15 mL orally three times daily) are used to avoid impaction. Chest percussion is initiated the night of surgery and continued at 4-h intervals. Within 8–12 h after surgery, patients are helped to sit in a chair. By postoperative day 1, they begin ambulating several times a day. This may be one of the most critical components in avoiding postoperative complications. It promotes lung expansion, pulmonary toilet, and return of gastrointestinal function and helps prevent development of deep venous thrombosis. Patients have continuous pulse oximetry monitoring during ambulation, and oxygen is increased as necessary to avoid hypoxemia. Patients requiring chest tube suction ambulate using specially designed carts that hold oxygen, water seal chambers, pulse oximetry, and oxygen-powered portable suction devices. All patients have daily chest radiographs, and are evaluated closely for the presence of air leaks, pneumothorax, and subcutaneous emphysema. Chest tubes are removed when no air leaks during normal respiratory effort, forced expiration, or deep cough and drainage of ﬂuid is less than 150 mL over a 24-h period. The patients are then discharged home. In motivated patients with an uncomplicated recovery, hospitalization may be as short as 5 days. V.

Management of Postoperative Complications

A signiﬁcant portion of patients undergoing LVRS experience postoperative complications. Reported morbidity and mortality in various published series are shown in Table 1. Management of some of the common complications are reviewed in further detail below. A. Air Leaks

The most frequent and troublesome complication after LVRS is prolonged air leak. As seen in Table 1, up to 50% of patients in some series have an air

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leak persisting longer than 7 days regardless of whether the volume reduction was carried out via sternotomy or a thoracoscopic approach. Persistent air leaks extend the duration of intercostal drainage and immobility and increase risk of secondary complications (empyema formation, deep vein thrombosis, pulmonary emboli, and pneumonia). The results are prolonged hospitalization, delayed rehabilitation, and higher costs (5–7). In addition, patients often become quite distressed and depressed by the long periods of intercostal drainage. Several modiﬁcations of the original surgical technique for LVRS have been developed in an attempt to decrease the duration and severity of postoperative air leaks. Cooper and colleagues developed a technique using strips of bovine pericardium to buttress the areas of stapled resection (8). The effect of using this technique on air leaks after stapled volume reduction was reported by Hazelrigg and associates (9). One hundred twenty-three patients undergoing stapled thoracoscopic unilateral LVRS were prospectively randomized to receive either no buttressing of their staple lines or buttressing of all staple lines with bovine pericardial strips. Patients who had pericardial strips used to buttress their staples lines had chest tubes removed 2.5 days sooner than the group without buttressing (7.9 + 8.2 days vs 10.4 + 8.9, P < .04). As a result, this group of patients was also discharged from the hospital 2.8 days sooner than the nonbuttressed group (8.6 + 5.2 vs 11.4 + 8.1, P < .03). There was no difference in the two groups with respect to pneumonia, empyema, and wound infection. Cost data revealed that the savings accrued by 2 fewer days of hospitalization was offset by the cost of the pericardial sleeves, and overall hospital charges for the two groups of patients were almost identical ($22,108 buttressed group; $22,060 nonbuttressed group). The efﬁcacy of a less expensive product (INSTAT, bovine collagen, Specialty Products Division, Ethicon, Inc., Somerville, NJ) to buttress staple lines was reported by Fischel and McKenna (10). Fifty-seven consecutive patients underwent bilateral thoracoscopic stapled lung volume reduction procedures with bovine pericardial strips on one side and bovine collagen (INSTAT) on the contralateral side to buttress the staple lines. They concluded that there was no signiﬁcant difference in the efﬁcacy of the two materials in reducing the incidence or duration of air leaks. The average time to chest tube removal was not statistically different between the two groups (8.6 + 7.2 days for bovine pericardium group vs. 10.7 + 8.7 days for bovine collagen, P ¼ .16). There was, however, a considerable cost differential. Use of bovine collagen saved an average of $1800 per case (an 80% reduction compared to the cost of the pericardium). Several centers have begun using GORETEX sleeves (W.I. Gore, Flagstaff, AZ) to buttress their staple lines, but to date, the efﬁcacy and cost of this technique

NR 40% 17%

NR 17% NR NR

21% NR 15% NR

NR 46% 7%

8% 9% 1% NR

NR 1% 2% NR

14.2 + 14.5

6.3 + 0.5

NR

NR

10.9% NR

4.3% 4.3% NR 2.2%

6.5%

4.6%

11.6%

9.3% 1.2%

1.2% 10.5% 1.2% NR

NR

9.7%

23.7 + 36.3

8.2 + 0.5

8.7%

86 MS 12.8%

(29)

46 VATS 0%

(11)

NR, not reported; MS, median sternotomy; VATS, video-assisted thoracoscopic surgery.

Hospital length of stay (mean days) Chest tube duration (days) Prolonged air leak >7 days Respiratory failure requiring mechanical ventilation Reoperation Pneumonia Empyema Late pneumothorax requiring new chest tube Arrhythmia Myocardial infarction Gastrointestinal complication Urinary infection/ retention

53 MS 1.9% early, 7.5% late NR

100 MS 3% early, 2% late NR

Number of patients Technique Mortality

(1)

(35)

Ref.

Table 1 Reported Morbidity and Mortality in Patients Undergoing LVRS

6%

0%

12% 0%

0% 2% 0% NR

NR

6%

15.1 + 19.3

16.5 + 18

50 VATS 2%

(29)

NR

1.5%

6% NR

NR 3% 4.5% NR

10.4%

46.3% (>5 days)

13 + 9.4

17 + 11.1

67 VATS 10.4%

(36)

278 Shen and Swanson

Perioperative Complications and Their Management

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compared to bovine pericardial strips has not been studied in a prospective randomized study. The staple line can also be buttressed by fashioning a ﬂap of parietal pleura from the chest wall or mediastinum that can be placed over the resection margin for reinforcement. Another alternative to help obliterate apical airspaces and seal large apical air leaks is construction of a pleural tent by dissecting the parietal pleura free from the chest wall from the third or fourth rib up to the apex. The resulting pleural tent, which drapes over the lung to help seal it, is visible on the chest radiograph as a space above the lung and overlapping parietal pleura that ﬁlls with ﬂuid and subsequently disappears as the ﬂuid is reabsorbed. A number of novel surgical techniques and thoracoscopic instruments have been developed in an attempt to reduce the incidence and duration of prolonged air leaks. Swanson and colleagues have reported on a no-cut thoracoscopic lung plication approach (11). Utilizing a knifeless stapler and modiﬁed lung grasper, the target lung tissue is folded 180 degrees, resulting in a double layer of lung tissue and a staple line that is buttressed by four layers of visceral pleura. Thirty-two patients underwent 50 unilateral, staged bilateral or bilateral thoracoscopic lung plication procedures. Seventy-eight percent of the procedures resulted in improved pulmonary function, with a mean increase in the forced expiratory volume in 1 s (FEV1) of 43 + 7% at a mean follow-up of 3.8 + 0.5 months. There were no perioperative deaths, and postoperative morbidity occurred in 39% of procedures. The median length of hospital stay was 7 days (range 3–15 days), mean chest tube duration was 6.3 + 0.5 days, and 8.7% of patients had persistent (>7 days) air leak. These postoperative morbidity and mortality results compare favorably to those achieved in other studies using standard techniques, and suggest that preservation of visceral pleural integrity by plication may result in a reduction in the postoperative morbidity associated with LVRS. Iwasaki and colleagues have similarly reported on a group of 20 consecutive patients who underwent unilateral lung volume reduction using a similar but slightly modiﬁed thoracoscopic plication technique with improved pulmonary function and no persistent air leaks (12). Intraoperative application of ﬁbrin glue or synthetic sealants over resected lung tissue has also been proposed to reduce the incidence and duration of postoperative air leak. Although no data are yet available on its use in the setting of LVRS, a number of studies have been performed on patients undergoing pulmonary resections and pneumonectomies. The results published to date, primarily from centers in Europe, have been mixed. Several studies demonstrated some efﬁcacy for ﬁbrin glue in preventing prolonged air leaks (13–15). The majority of these studies, however, were not randomized and focused on the routine use of ﬁbrin glue

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after lung resection irrespective of whether an intraoperative air leak was present or how severe it was. Wong and Goldstraw found no statistically signiﬁcant difference in duration of intercostal drainage or hospital length of stay (16). When they studied 66 patients undergoing lobectomies, segmentectomies, or decortication who were judged intraoperatively to have moderate to severe air leaks and were then randomized to either a control group or to have ﬁbrin glue sprayed on the ‘‘raw’’ lung surface. Talc pleurodesis has also been used to seal persistent air leaks. This technique dilutes 2.5 g of asbestos-free talc in 60 mL of sterile normal saline. The resulting talc slurry is injected into the end of a chest tube with a 60-mL catheter-tip syringe. Extension tubing is then added to the end of the chest tube and draped over an intravenous pole which prevents the talc from leaving the pleural space but allows air to be evacuated. The inﬂammatory response to the talc facilitates apposition of the parietal and visceral pleura. Some investigators have shown this to be highly effective in sealing prolonged air leaks (17). One caveat, however, is that the technique should be reserved for patients who, because of either age or other criteria, are not candidates for future lung transplantation. If the patient is a potential lung transplantation candidate, talc pleurodesis should be avoided. There has also been a case report of pneumoperitoneum to treat air leaks and airspaces following LVRS. Hardy and colleagues describe a 63year-old woman who underwent bilateral LVRS via median sternotomy with pericardial buttressing whose postoperative course was complicated by large bilateral airspaces with air leaks. Since the patient had little pulmonary reserve after LVRS and could not tolerate further pulmonary parenchymal resection, she underwent placement of a peritoneal dialysis catheter. Large amounts of intraperitoneal air were instilled on the successive 2 days, with eventual resolution of her airspaces and air leaks after sclerosis with talc on both sides (18). Sometimes, despite these measures, patients develop major air leaks that can produce signiﬁcant respiratory distress as well as extensive subcutaneous emphysema. When the leaks fail to resolve with adequate chest tube drainage, reexploration is indicated to locate and repair the area of leakage. Patients who have undergone thoracoscopic LVRS can undergo repeat thoracoscopy. Air leaks can often be located by partially ﬁlling the hemithorax with saline while the affected lung is deﬂated. Once positive pressure is applied, air bubbles indicate the location of the leaks. Usually the defects are within 2 cm of the staple line; the result of new tension on the pleural surface produced by the nearby resection. If the patient has sufﬁcient pulmonary reserve and can tolerate additional resection of lung parenchyma, repair can sometimes be accomplished by placement of new buttressed staple lines. Often, however, staplers cannot be effectively or safely

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maneuvered into proper position, and repair requires an open technique. Once the leak has been localized, a mini-thoracotomy can be made immediately overlying the site. Since apical resections are the most common site for lung volume reduction, an axillary mini-thoracotomy about 5 cm in length sufﬁces for most patients. The parenchymal defect can be closed through that incision with Prolene suture reinforced with felt pledgets, GORTEX patches, or bovine pericardium. As previously discussed, a parietal pleural ﬂap or pleural tent can also be used to help eliminate air spaces and reinforce the repaired area. In patients who are well enough to be discharged except for their prolonged air leaks, McKenna and colleagues have demonstrated that use of the one-way Heimlich valve can shorten the mean hospital stay by 46% with minimal morbidity (19). In their study, Heimlich valves were used successfully in 25 patients with prolonged air leaks (>5 days) after LVRS even though 64% of the patients had apical airspaces that ranged from 1 to 7 cm, and 40% had air leaks that were graded as moderate to severe. These patients had a mean postoperative stay of 9.1 days and had their chest tubes removed an average of 7.7 days later. All apical airspaces resolved, and there were no deaths, empyemas, or pneumonias. No patients required a second operation for closure of an air leak, and one patient developed subcutaneous emphysema that required readmission to the hospital and reinstitution of suction drainage. B. Postoperative Pneumonia

The incidence of pneumonia reported after LVRS ranges from 2 to 30%, with the larger series reporting a 9–10% rate (see Table 1). This is signiﬁcantly higher than the 5–6% incidence of postoperative pneumonia reported in lung cancer patients undergoing thoracotomy (20,21). Many of the characteristics that have been identiﬁed as speciﬁc risk factors for the development of postoperative pneumonia are hallmarks of the patients undergoing LVRS. Low pulmonary reserve, poor FEV1, chronic obstructive pulmonary disease, poor nutritional status, prolonged hospitalization, and coexistent cardiovascular disease all pose an increase risk for the development of postoperative pneumonia in this patient population. In addition, LVRS patients have impaired cough reﬂexes from narcotic analgesia, decreased level of consciousness, pain, or large air leaks. As a result, the LVRS patient is at high risk for silent aspiration of oropharyngeal contents as well as the development of mucus plugs, which further decrease mucociliary clearance. Several strategies can be employed to reduce the inherent high risk of the LVRS patient developing postoperative pneumonia. Early ambulation

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and aggressive chest physiotherapy to mobilize pulmonary secretions and use of epidural analgesia are mandatory. Given the higher incidence of gastrointestinal complications (which will be discussed in greater detail later in this chapter), it is also crucial that each patient’s cough reﬂex, swallowing mechanism, and intestinal function be assessed carefully before initiating oral intake. Prophylactic antibiotics are also thought by some to prevent postoperative pneumonia. Although a common practice at some centers is the use of a single preoperative dose of the ﬁrst-generation cephalosporin cefazolin, recent data suggest that a longer antibiotic prophylaxis regimen of 48 h with a second-generation cephalosporin may decrease the rate of pulmonary infections. In a prospective randomized double-blind trial, Bernard and colleagues studied 203 patients undergoing lung resection (22). All patients were given 1.5 g of the second-generation cephalosporin cefuroxime intravenously at the time of the anesthetic induction and again 2 h later. Group 1 (n ¼ 102) received intravenous saline while group 2 (n ¼ 101) received additional intravenous cefuroxime every 6 h for 48 h. In the group that received 48 h of cefuroxime, there was a 20% reduction in the incidence of pneumonia and empyema compared to the control (46 vs. 65%, P ¼ .005). Postoperative pneumonias are notoriously difﬁcult to diagnose, particularly in patients who have undergone pulmonary resections. The usual clinical criteria of fever, leukocytosis, purulent sputum, pathogens growing from the sputum, and new or increasing inﬁltrates on chest radiograph are more speciﬁc in the ambulatory setting than the postoperative LVRS patient. There is often a lag between the clinical presentation and radiographic ﬁndings, and the postoperative radiographs of LVRS patients are difﬁcult to interpret. This is particularly so if a pleural tent has been created or the staple lines have been buttressed extensively. Respiratory failure in the postoperative LVRS patient should always raise the suspicion of pneumonia and prompt aggressive treatment. The pathogens are bacterial, and in decreasing order of frequency include Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus inﬂuenzae, Streptococcus pneumoniae, and gram-negative aerobes and anaerobes (23). Once the diagnosis is suspected, empiric antibiotic therapy should be initiated. This is often guided by clinical impressions, Gram stain, and knowledge of the bacterial pathogens common to the particular hospital. Selective use of ﬁberoptic bronchoscopy can aid in the diagnosis of postoperative pneumonia and help guide empiric antibiotic therapy. The protected brush catheter has been shown to be both sensitive (70–97%) and speciﬁc (95–100%) in the diagnosis of bacterial pneumonia in some studies (24–26). In some centers, cultures are routinely taken at the time of surgery,

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283

and if the LVRS patient is suspected of developing postoperative pneumonia, antibiotic therapy can be tailored based on these culture results (27). C. Postoperative Intrathoracic Bleeding

Most published series report a rate of about 5% of patients undergoing LVRS who require reoperation for intrathoracic bleeding (see Table 1). When this complication occurs in patients who have undergone thoracoscopic LVRS, the bleeding usually originates from the intercostal ports, causing bleeding of the thoracic wall. The diagnosis is suggested by increased density of the thoracic wall in chest radiographs, high chest tube outputs (>150 mL/h for more than 2 consecutive hours), systemic hypotension, tachycardia, and falling hematocrit levels. This also can present as excessive postoperative pain refractory to standard pain control maneuvers. A higher degree of suspicion is warranted if the patient required extensive dissection of pulmonary adhesions or had creation of a pleural tent. The treatment is prompt return to the operating room to explore, localize, and control the bleeding sites. Intrathoracic bleeding following LVRS also occurs after sternotomy; bleeding may occur into the pleural space from the raw chest wall surface above pleural tents or from the sternum itself. D. Respiratory Failure

Patients with severe emphysema undergoing LVRS who require mechanical ventilation postoperatively have a much higher morbidity and mortality rate than patients who are extubated immediately after surgery and do not require reintubation. In most published series, 5–10% of patients require reintubation and mechanical ventilation because of complications such as large air leaks, pneumonia, intrathoracic bleeding, severe gastrointestinal ileus compromising respiratory function, anxiety attacks, and patient fatigue. About half of patients reintubated require only a short period of ventilatory support while the primary complication is corrected (28). The remainder require prolonged ventilation and tracheostomy, and mortality is highest in this subgroup. These patients are at great risk for ventilatorassociated pneumonia, and often also develop persistent or worsened air leaks as a result of positive-pressure ventilation. In addition, because of their propensity to develop auto-positive end-expiratory pressure (auto-PEEP) when intubated, these patients can rapidly develop a catastrophic pulmonary tamponade syndrome. Auto-PEEP increases pleural pressure and causes a decrease in venous return and a tamponadelike effect. This manifests as a progressive increase in central venous pressure, pulmonary

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hypertension, and increased pulmonary capillary wedge pressure coupled with low cardiac output and systemic hypotension. If this condition is not recognized and rapidly corrected, the patient will die. E.

Cardiovascular Complications

Atrial ﬁbrillation and other supraventricular tachycardias are the most commonly reported cardiovascular complication. Myocardial infarction and ischemia are relatively rare (41%) in most series. The low incidence of myocardial ischemic complications thus far reported is likely a result of the rigorous screening process performed during patient selection, in which electrocardiograms, echocardiograms, cardiopulmonary stress tests, and right and left cardiac catheterization identify patients who may have underlying coronary artery disease, ventricular dysfunction, or pulmonary hypertension that disqualiﬁes them for surgery. F.

Gastrointestinal Complications

One of the unexpected observations is the much higher rate of serious gastrointestinal (GI) complications than typically seen after routine general thoracic surgery. Miller and colleagues reported major GI complications in 8 of 53 patients (15%) undergoing LVRS via median sternotomy (1). There was no mortality as a result of these complications, but there was signiﬁcant morbidity and prolonged hospitalization. Roberts and colleagues at the Hospital of the University of Pennsylvania reported that 5 of 86 (5.8%) patients undergoing LVRS via median sternotomy developed a perforated viscus (duodenum or colon) (29). Patients suffering these GI complications fared poorly and accounted for 45% of the total mortality in this group. In order to investigate this phenomena further, Centindag and colleagues retrospectively reviewed their experience in 287 patients who had LVRS to determine the frequency of GI complications and to attempt to identify risk factors (30). Using a broad deﬁnition of postoperative GI complications (nausea, vomiting, abdominal distension, gastroesophageal reﬂux, diarrhea, and constipation) they reported 137 complications in 67 of 287 patients (23%). More severe GI complications (bowel ischemia or perforation, bleeding, ulceration, ileus, colitis, cholecystitis, and pancreatitis) occurred 49 times in 27 of 287 patients (9.4%). Seven of the 27 patients required abdominal operations. In this subgroup of patients with severe GI complications, there were 6 of 27 (22%) hospital deaths compared with 5 of 260 (2%) in patients without GI complications (P ¼ .0001). Mortality from major GI complications accounted for 54% (6 of 11) of the 3.8% (11 of 287) mortality rate in the entire LVRS population studied.

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Corticosteroid usage, diabetes, oral narcotic pain medications, atrial ﬁbrillation, intravenous or intramuscular meperidine, and the duration of the chest tube were related to the development of minor GI complications. The use of prophylactic gastrointestinal-protecting agents (stool softeners, coating agents or H2 blockers) did not lead to a reduction in GI complications. Risk factors identiﬁed as being predictive of severe GI complications include diabetes (P ¼ .0003), lower preoperative hematocrit (P ¼ .01), steroid use (P ¼ .02), and use of parenteral meperidine analgesics (P ¼ .002). The association between long-term corticosteroid use and gastrointestinal perforation is well established (31,32). Patients on high-dose steroids may not manifest classic signs of an acute abdomen, and therefore a high level of suspicion needs to be maintained when these patients develop GI complaints. ReMine and colleagues have demonstrated that early diagnosis and surgical intervention after colonic perforation resulting from corticosteroid use reduced the mortality rate (33). Although diabetes has not been found to be a risk factor for GI problems after open heart surgery, in Cetindag’s analysis (30), diabetes was the most important risk factor for developing both minor and major GI complications after LVRS. Diabetic patients are predisposed to GI motility disorders, and the addition of epidural anesthesia and multiple narcotic pain medications increase their risk of developing postoperative ileus. Chronic hypoxia has also been shown to render the GI tract more vulnerable by lowering the gastric pH and the interstitial pH of the entire GI tract (34). In addition, because chronic diabetes adversely affects the microcirculation of all tissues including the GI tract, it has been suggested that this defective microcirculation might be the precipitating factor for developing GI events in patients with chronic hypoxia undergoing LVRS.

VI.

Summary

Data from the initial experience support LVRS as a means of improving pulmonary function in selected patients with severe emphysema. The majority of patients recover uneventfully following surgery. However, patients that develop respiratory failure requiring mechanical ventilation or serious gastrointestinal tract complications have a high mortality rate. Successful outcomes following surgery are derived from careful patient selection, preoperative preparation, and meticulous intraoperative and postoperative management of this fragile group of patients.

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1. 2. 3.

4. 5. 6. 7.

8. 9.

10.

11.

12.

13. 14. 15.

16. 17.

Miller J, Lee R, Mansour K. Lung volume reduction surgery: lessons learned. Ann Thorac Surg 1996; 61(5):1464–1469. Bird G, Macaluso S. Lung volume reduction surgery for emphysema. Crit Care Nurs North Am 1996; 8(3):323–331. Cahalin L. Preoperative and postoperative conditioning for lung transplantation and volume-reduction surgery. Crit Care Nurs Clin North Am 1996; 8(3):305–320. Fujita R, Barnes G. Morbidity and mortality after thoracoscopic pneumoplasty. Ann Thorac Surg 1996; 62(1):251–257. Kirsh M, Potman H, Behrendt D, et al. Complications of pulmonary resections. Ann Thorac Surg 1975; 20:215–236. Rice T, Kirby T. Prolonged air leak. Chest Surg Clin North Am 1992; 2:803– 811. Keagy B, Lores M, Starek P, et al. Elective pulmonary lobectomy: factors associated with morbidity and operative mortality. Ann Thorac Surg 1985; 40(4):349–352. Cooper J. Techniques to reduce air leaks after resection of emphysematous lung. Ann Thorac Surg 1994; 57:1038–1039. Hazelrigg S, Boley T, Naunheim, et al. Effect of bovine pericardial strips on air leak after stapled pulmonary resection. Ann Thorac Surg 1997; 63(6):1573– 1575. Fischel R, McKenna R. Bovine Pericardium versus bovine collagen to buttress staples for lung volume reduction operations. Ann Thorac Surg 1998; 65:217– 219. Swanson J, Mentzer S, DeCamp M, et al. No-cut thoracoscopic lung plication: a new technique for lung volume reduction surgery. J Am Coll Surg 1997; 185(1):25–32. Iwasaki M, Nishium N, Kaga K, et al. Application of the fold plication method for unilateral lung volume reduction in pulmonary emphysema. Ann Thorac Surg 1999; 67(3):815–817. Grunewald D. Intraoperative use of ﬁbrin sealant in pulmonary surgery. A prospective study on a series of 124 procedures. Ann Chir 1989; 43:147–150. Kjaergard H. Autologus ﬁbrin glue-preparation and clinical use in thoracic surgery. Eur J Cardiothorac Surg 1992; 6:52–54. Mouritzen C, Dromer M, Keinecke H. The effect of ﬁbrin glueing to seal bronchial and alveolar leakages after pulmonary resections and decortications. Eur J Cardiothorac Surg 1993; 7:75–80. Wong K, Goldstraw P. Effect of ﬁbrin glue in the reduction of postthoracotomy alveolar air leak. Ann Thorac Surg 1997; 64:979–981. Cerfolio R, Tummala R, Holman W, et al. A prospective algorithm for the management of air leaks after pulmonary resection. Ann Thorac Surg 1998; 66:1726–1731.

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18. Hardy J, Judson M, Zellner J. Pneumoperitonium to treat air leaks and spaces after a lung volume reduction operation. Ann Thorac Surg 1997; 64:1803–1805. 19. McKenna R, Fischel R, Brenner M, Gelb A. Use of the Heimlich valve to shorten hospital stay after lung reduction surgery for emphysema. Ann Thorac Surg 1996; 61:1115–1117. 20. Deslauriers J, Ginsberg RJ, Piantadosi S, Fournier B. Prospective assessment of 30-day operative morbidity for surgical resections in lung cancer. Chest 1994; 106(6):329S–330S. 21. Duque J, Ramos G, Castrodeza J, Cerezal J, Catanedo M, Yuste ML, Heras F. Early complications in surgical treatment of lung cancer: a prospective, multicenter study. Ann Thorac Surg 1997; 63(4):944–950. 22. Bernard A, Pillet M, Goudet P, Viard H. Antibiotic prophylaxis in pulmonary surgery. J Thorac Cardiovasc Surg 1994; 107(3):896–900. 23. Ferdinand B, Shennib H. Postoperative pneumonia. Chest Surg Clin North Am 1998; 8(3):529–539. 24. Hays D, McCarthy LC, Friedman M. Evaluation of two bronchoﬁberscopic methods of culturing the lower respiratory tract. Am Rev Respir Dis 1980; 122:319–329. 25. Higuchi J, Coalson JJ, Johanson WG. Evaluation of two bronchoﬁberscopic methods of culturing the lower respiratory tract. Usefulness of the protected specimen brush. Am Rev Respir Dis 1982; 125(1):53–57. 26. Wimberley N, Bass JB, Boyd BW, et al. Use of a bronchoscopic protected catheter brush for the diagnosis of pulmonary infections. Chest 1982; 81(5):556–562. 27. Russi E, Stammberger U, Weder W. Lung volume reduction surgery for emphysema. Eur Respir J 1997; 10:208–218. 28. Kellar C, Naunheim K. Perioperative management of lung volume reduction patients. Clin Chest Med 1997; 18(2):285–300. 29. Roberts J, Bavaria J, Wahl P, et al. Comparison of open and thoracoscopic bilateral volume reduction surgery: complications analysis. Ann Thorac Surg 1998; 66:1759–1765. 30. Centindag I, Boley T, Magee M, Hazelrigg S. Postoperative gastrointestinal complications after lung volume reduction operations. Ann Thorac Surg 1999; 68:1029–1033. 31. Beck J, Browne J, Johnson L. Occurance of peritonitis during ACTH administration. Can Med Assoc J 1950; 62:423–426. 32. Canter J, Shorb PJ. Acute perforation of colonic diverticula associated with prolonged adrenocorticosteroid therapy. Am J Surg 1971; 121:45–50. 33. ReMine S, McIlrath D. Bowel perforation in steroid-treated patients. Ann Surg 1980; 192:581–586. 34. Gutierrez G, Palizas F, Doglio G. Gastric intramucosal pH as a therapeutic index of tissue oxygenation in critically ill patients. Lancet 1992; 339:195–199. 35. Cooper J, Patterson G. Lung volume reduction surgery for severe emphysema. Semin Thorac Cardiovasc Surg 1996; 8(1):52–60.

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36. Keenan R, Landreneau R, Sciurba F, et al. Unilateral thoracoscopic surgical approach for diffuse emphysema. J Thorac Cardiovasc Surg 1996; 111(2):308– 315.

14 Surgical Controversies in Lung Volume Reduction

JOHN R. ROBERTS Vanderbilt University Hospital Nashville, Tennessee, U.S.A.

I. Introduction Perhaps no surgical innovation has ever deserved a chapter on controversies as much as lung volume reduction surgery (LVRS), which was ﬁrst described in 1959 by Brantigan et al. (1) from the University of Maryland. The method never caught on, because objective selection criteria, pulmonary function, and exercise testing were not reported, and perhaps in part because of opposition by prominent pulmonologists. Nonetheless, their patients appeared to demonstrate functional improvement, albeit at a fairly high perioperative mortality (16%). In the modern era of LVRS, there have been the typical debates about appropriate technique, approach, perioperative management, and selection of patients to undergo the procedure. However, there have also been extraordinary controversies about payment for the procedures, as well as about the mechanism by which surgical procedures are evaluated prior to application in clinical practice. Many of these issues are covered in other chapters. In this chapter, we will focus on issues speciﬁcally related to the surgical methodology. 289

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Roberts II.

Laser or Resection?

Wakabayashi ﬁrst reported thoracoscopic laser collapse in a mixed group of 22 patients with giant bullae and diffuse emphysema. He found signiﬁcant improvements in lung function and promoted the laser approach to emphysema surgery. However, in the original as well as subsequent series, selection criteria and physiological outcomes were poorly documented (2,3). Stapled resection in diffuse emphysema was ﬁrst formalized with the report of Cooper et al. (4) on 20 patients with diffuse emphysema who were treated with bilateral volume reduction through median sternotomy (MS). Several case series suggested that laser plication might not provide as substantial improvement as stapled LVRS. McKenna et al. (5) randomized patients between stapled and laser lung reduction. They found that laser volume reduction resulted in lesser improvement in forced expiratory volume in 1 s (FEV1) at 6 months (0.09 vs. 0.22 L, 13.4% vs. 32.9%) as compared to stapled LVRS. In addition, 18% of patients undergoing laser LVRS developed a delayed pneumothorax. Because of the results of this randomized comparison as well as the ﬁndings of series that examined either one technique or the other, the use of laser treatment for diffuse emphysema has largely been abandoned.

III.

Unilateral or Bilateral?

Table 1 summarizes the available data for the short-term results after unilateral LVRS. The improvement in FEV1 ranged from 16 to 35%, and the fall in residual volume (RV) from 11 to 28%. Although many studies did not report on 6-min walk distance, those that did found an improvement between 33 and 95 m. In general, those studies that used lasers exclusively had smaller increases in FEV1 (13–30%) than those with resection (23–35%). Perioperative mortality ranged from 0 to 9.1%. Table 2 summarizes the available data for the short-term functional and perioperative results after bilateral LVRS. In general, these data indicate equivalent functional results after bilateral LVRS no matter whether sternotomy or video-assisted thoracic surgery (VATS) was used. A tendency toward higher perioperative mortality is seen after MS (range 3.8–21.0%) as compared to VATS (range 0–7.5%). Table 3 summarizes those studies from institutions at which both unilateral and bilateral LVRS are performed, allowing direct comparison of patient data within an institution. Some of the approaches were thoracoscopic and some were by MS, which causes difﬁculties in interpretation. Nonetheless, some important points can be gleaned from the analysis.

1991 1995 1995 1995 1996 1996 1996 1996 1997 1997 1998

Year

DFVC (%) þ35 þ30 þ21 þ24 þ14 þ6 þ19 þ15 þ29 þ23 þ16

DFEV1 (%) þ30 þ18 þ31 þ34 þ16 þ13 þ27 þ35 þ28 þ31 þ24 — 10.5 13 12 14 — 16 33 — 14 17

DRV (%) — þ11 þ1 — þ2 — þ1 þ8 — þ9 —

PaO2 — — — — þ58 — þ33 — þ95 þ41 þ45

D6MWD

3.6 0.0 0.0

0.0 5.7 0.0 1.7

9.1 5.5

Mort (%) Laser Laser Laser Laser Laser Laser Resect Resect Resect Resect Resect

Tech

VATS Mixed VATS VATS VATS VATS VATS VATS Open VATS VATS

Surg

22 55 96 28 141 33 57 50 28 25 32

Pts

DFEV1, change in percent predicted FEV1 after LVRS; DFVC, change in percent predicted FVC; DRV, change in percent predicted RV; PaO2, change in arterial O2 pressure (mmHg); D6MWD, increase in 6-min walk distance (ft); Mort, perioperative mortality; Tech, resection or laser treatment; Surg, VATS or open thoracotomy; Pts, number of patients in the study.

2 17 3 18 19 5 20 10 8 21 6

Reference no.

Table 1 Results After Unilateral LVRS

Surgical Controversies in Lung Volume Reduction 291

1995 1996 1996 1997 1997 1997 1997 1998 2000 1996 1996 1996 1997 1998 1998 1999

Year

DFVC þ27% þ20% þ23% þ15% — þ0.37 L þ59% þ0.38 L NC þ14% þ12% þ17% þ48% — þ42.7%

DFEV1 þ82% þ51% þ49% þ10% — þ0.19 L þ37 þ0.24 L þ0.16 L þ42% þ57% þ41% þ70% þ34% þ55%

39% 28% 30% 69% — 0.97 L — 1.40 L 57% 61% — 32 — — 25.3%

DRV þ6 þ8 þ6.2 — — — — þ1 NC þ4 — þ7 — — þ6

PaO2 þ182 þ33 — þ140 — þ39.6 þ88.0 — þ50 þ193 — þ41 þ289 — þ87

D6MWD 0.0 4.0 3.8 — 19.1 5.0 11.1 4.0 21.0 0.0 0.0 1.7 7.4 8.5 — 4.5

Mort (%)

Open Open Open Open Open Open Open Open Open VATS VATS VATS VATS Both VATS VATS

Surg

20 150 28 26 47 55 37 27 24 20 70 35 68 47 40 101

Pts

DFEV1, percent change in FEV1 after LVRS; DFVC, percent change in FVC; DRV, percent change in RV; PaO2, change in mmHg arterial O2 pressure (mmHg); D6MWD, increase in 6-min walk distance (ft); Mort, perioperative mortality; Surg, VATS or open thoracotomy; Pts, number of patients in the study; NC, no change.

4 11 22 23 24 25 26 27 28 29 7 20 8 30 31 32

Reference no.

Table 2 Results After Bilateral LVRS

292 Roberts

Surgical Controversies in Lung Volume Reduction Table 3

293

Studies Comparing Results of Bilateral and Unilateral LVRS

Ref.

Approach

DFEV1 (L)

DFVC (L)

D6MWD

Mortality (%)

6

Unilateral Bilateral Unilateral Bilateral Unilateral Bilateral Unilateral Bilateral Unilateral Bilateral

0.16 + 0.22 0.25 + 0.31 0.21 0.33 0.15 0.30 0.15 + 0.03 0.39 + 0.02 — —

0.34 + 0.71 0.42 + 0.64 0.19 0.24 0.38 0.48 — — — —

147 ft 195 ft — — 315 ft 298 ft — — — —

0 10 3.5 2.5 3.6 7.4 4.0 4.0 5.2 7.0

7 8 9a 10

DFEV1, and DFVC, changes from preoperative to postoperative pulmonary function testing; D6MWT, change in 6-min walk distance; mortality results are the perioperative deaths; L, liter. a Brenner et al. did not differentiate unilateral from bilateral perioperative mortality; 3.98% was the overall perioperative mortality. However, they reported an 8.1% 90-day mortality for bilateral surgery patients and a 10.0% 90-day mortality for unilateral surgery patients.

Kotloff et al. (6), at the Hospital of the University of Pennsylvania, compared the functional results of their patients undergoing unilateral or bilateral LVRS. However, because of distinct surgical preferences about the approach used for the surgery, unilateral and bilateral operations were performed by separate surgeons. They found that bilateral LVRS resulted in greater improvement in FEV1, forced vital capacity (FVC), and RV than did unilateral surgery. However, the difference was much less than the twofold difference that one might expect. Further, that improvement came at the cost of a signiﬁcantly higher perioperative complication and mortality rate. Whereas no patients undergoing unilateral LVRS had to be reintubated, 15 patients (12.6%) undergoing bilateral LVRS were reintubated (P < .05). In addition, there was no perioperative mortality among the 32 patients undergoing unilateral LVRS, but there were 12 deaths among the 119 patients undergoing the bilateral approach (10%). This difference was also signiﬁcant (P < .5). Interpretation of the data of Kotloff et al. is complicated by the fact that many of the bilateral surgery patients underwent MS, whereas all of the unilateral patients underwent thoracoscopy, as well as the fact that the unilateral and bilateral operations were performed by two different surgeons. However, their ﬁndings suggest that the bilateral surgery patients had a greater perioperative risk but a better functional outcome.

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McKenna et al. (7) compared 87 patients undergoing unilateral thoracoscopic LVRS with 79 patients undergoing bilateral thoracoscopic LVRS. Unlike Kotloff et al., they found no signiﬁcant differences in operative mortality, mean length of hospital stay (11.4 + 1 vs 10.9 + 1 days), or morbidity between the two approaches. They did ﬁnd greater improvement in multiple parameters after bilateral LVRS, including postoperative oxygen dependence, prednisone requirement, and change in FEV1. They also found that especially compromised patients (age over 75 years, preoperative room air, arterial O2 pressure (PaO2) below 50 mmHg, or FEV1 below 500 mL) had the same morbidity and operative mortality with unilateral as with bilateral procedures, but they had signiﬁcantly higher 1year mortality (17 vs. 5%) after unilateral procedures. This was mostly due to respiratory failure. McKenna et al. concluded that the bilateral procedure is the procedure of choice, and speculated that very compromised patients needed maximal immediate improvement in function to avoid subsequent respiratory failure and death. Multivariate analysis was unable to identify a subset of patients for whom unilateral surgery was preferable. Argenziano et al. (8) compared 28 patients undergoing unilateral LVRS with 64 patients undergoing bilateral LVRS. Although the standard procedure was bilateral, several of their patients had a unilateral volume reduction because of a prior thoracic procedure or need for concomitant tumor resection. They also found that unilateral surgery gave less improvement in pulmonary function tests, but they found no difference in 6-min walk distance or in postoperative dyspnea. Although the perioperative mortality was higher after the bilateral procedure, they found, in contrast to McKenna et al., no difference in the actuarial survival out to 2 years. They concluded that unilateral LVRS provides functional and subjective beneﬁts of magnitude comparable with those of bilateral surgery. This interpretation is clouded by the nonrandomized allocation of patients to the unilateral procedure. For example, any intrinsically lower risk of the unilateral procedure would be obscured if it were performed on higher risk patients. Brenner et al. (9) evaluated the change in FEV1 with time after LVRS, but did not report in detail on other measures of outcome. They evaluated the rate of change in FEV1 for various thoracoscopic LVRS procedures in 376 patients at Chapman Medical Center over a 3-year period. Although they found a greater early improvement with the bilateral procedure, there was also a more rapid loss of improvement compared with the unilateral procedures. Like Kotloff et al. and McKenna et al., they found that the change in FEV1 after bilateral LVRS was not double that of unilateral LVRS. Although they did not report perioperative mortality rates for each procedure, they did ﬁnd a 90-day mortality of 11.9% for unilateral and 8.1% for bilateral surgery patients.

Surgical Controversies in Lung Volume Reduction

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Naunheim et al. (10) compared the results of unilateral and bilateral LVRS at multiple institutions. They did not analyze postoperative pulmonary function but instead evaluated perioperative and long-term mortality. They found slightly higher perioperative mortality in patients undergoing bilateral LVRS (7.0 vs. 5.2%) but slightly better long-term survival among the bilateral LVRS patients (1-, 2-, and 3-year survivals were 90, 81, and 74% vs. 86, 75, and 69% for unilateral LVRS). These differences were not statistically signiﬁcant, and Naunheim et al. concluded that bilateral LVRS offered no signiﬁcant long-term survival advantage over unilateral LVRS. To summarize, the question of whether to perform unilateral or bilateral operation is not entirely settled by the data. However, most studies have shown the bilateral operation to result in greater improvement in lung function with little increase in perioperative morbidity and mortality. There may be special patients for whom a unilateral operation is appropriate; for example, those with extensive pleural scarring on one side. For the typical patient with bilateral emphysema, however, a bilateral operation has become the procedure of choice.

IV.

Thoracoscopy or Median Sternotomy?

Whereas Brantigan et al. (1) used sequential thoracotomies to perform bilateral volume reduction surgery, the ﬁrst report of Cooper et al. (4) was on 20 patients undergoing MS. The standard for the open or median sternotomy approach is the subsequent report by Cooper et al. of their ﬁrst 150 patients (11). Their data and other open series data are summarized in Table 2. Table 4 summarizes the available published data in patients from the same institution who have undergone bilateral LVRS by both MS and thoracoscopy. Although no series are randomized, they at least represent a direct comparison of patients undergoing surgery at the same institution. Kotloff et al. (12) compared the functional outcomes of patients undergoing bilateral LVRS at the Hospital of the University of Pennsylvania. Although the MS patients were somewhat older, the VATS patients had somewhat worse preoperative pulmonary function. They found no difference in the improvements in pulmonary function or 6-min walk tests at 3 and 6 months. Roberts et al. (13) extended the analysis of those patients, focusing on the perioperative complications and postoperative mortality. More MS patients suffered life-threatening and major complications than did VATS patients (including pneumonia, reintubation, and emergency surgery). Further, the perioperative mortality was much greater in the MS patients (12.8 vs. 2.0%)

Median sternotomy Thoracoscopic Median sternotomy Thoracoscopic Median sternotomy Thoracoscopic 7 11

20.3 + 28.7 25.3 + 35.0

41.4 + 37.3 41.2 + 39.2

28 62

%DFVC

%DFEV1

— —

20.7 + 29.0 35.3 + 35.8

%D6MWD

13.8 2.5 12.8 2.0 15 4

Mortality (%)

DFEV1 and DFVC, changes from preoperative to postoperative pulmonary function testing; 6MWD, change in 6-min walk distance (ft); Mortality results are the perioperative mortality.

14

13

6

Approach

Studies Comparing Median Sternotomy and Thoracoscopic LVRS

Reference no.

Table 4

296 Roberts

Surgical Controversies in Lung Volume Reduction

297

than in the VATS patients. Ko and Waters (14) analyzed results from a series of patients at the University of California at Los Angeles, 19 of whom underwent MS and 23 VATS LVRS. Although VATS LVRS took longer to perform, the sternotomy patients had more days on the ventilator, more days in the intensive care unit, more days with an air leak, and longer hospital stays. Neither approach improved pulmonary function any more than the other, but the VATS approach was less costly ($27,178 for VATS vs $37,299 for MS). These data, taken together, suggest that VATS and MS offer similar beneﬁt in pulmonary improvement, but indicate that VATS may be less likely to result in perioperative complications and thus more likely to result in shorter hospital stays and less expense. Further, the perioperative mortality was, in general, 5–10% greater for LVRS via sternotomy than for VATS. Despite these suggestive data, outcomes from either technique are highly dependent on patient selection and the surgical team’s skill and experience.

V. Summary Lung volume reduction surgery appears to represent a breakthrough in the effort to improve pulmonary function and quality of life in patients with advanced emphysema. Based on early positive reports, it was quickly widely applied via a variety of methods. Some of the early approaches, such as routine use of laser or unilateral operations, have largely been abandoned. Other technical issues remain controversial. There is little debate that the operation causes short-term improvement in pulmonary function and symptoms in most patients. However, perhaps the greatest surgical controversy is whether this surgery should be widely available. This lingering and often acrimonious debate is sustained by the judgments intrinsic to an elective procedure with a signiﬁcant surgical mortality and temporary beneﬁt: How much operative risk is acceptable, how many patients must improve, how much improvement is necessary, how should we measure improvement, and how long must it last before a new procedure is considered routine care? The stakes are high for LVRS because of the potential costs involved. Huizenga et al. (15) estimated that performing the surgery for all current Medicare patients who meet the appropriate clinical criteria would cost $1 billion. The average Medicare reimbursement was $31,398 to both hospitals and physicians. Albert et al. (16) reported that the median charge at the University of Washington was $26,669. As the remaining surgical controversies are settled with further study, the outcomes will stabilize and the calculus will become clearer. The optimal techniques will minimize risk, maximize improvement, increase the percentage of

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patients who improve, and extend the duration of beneﬁt. This will only increase the value of LVRS to patients and make LVRS a better value for society.

References 1.

Brantigan OC, Mueller E, Kress M. A surgical approach to pulmonary emphysema. Am Rev Respir Dis 1959; 80:194–206. 2. Wakabayashi A, Brenner B, Kayaleh RA, Berns MW, Barker SJ, Rice SJ, Tadir Y, Bella LD, Wilson AF. Thoracoscopic carbon dioxide laser treatment of bullous emphysema. Lancet 1991; 337:881–883. 3. Wakabayashi A. Thoracoscopic laser pneumoplasty in the treatment of diffuse bullous emphysema. Ann Thorac Surg 1995; 60:936–942. 4. Cooper JD, Trulock EP, Triantaﬁllou AN, Patterson GA, Pohl MS, Deloney PA, Sundaresan RS, Roper CL. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995; 109:106–116. 5. McKenna RJ, Brenner M, Gelb AF, Mullin M, Singh N, Peters H, Panzera J, Calmese J, Schein MJ. A randomized, prospective trial of stapled lung reduction versus laser bullectomy for diffuse emphysema. J Thorac Cardiovasc Surg 1996; 111:317–322. 6. Kotloff RM, Tino G, Palevsky HI, Hansen-Flaschen J, Wahl PM, Kaiser LR, Bavaria JE. Comparison of short-term functional outcomes following unilateral and bilateral lung volume reduction surgery. Chest 1998; 113:890– 895. 7. McKenna RJ, Brenner M, Fischel RJ, Gelb AF. Should lung volume reduction for emphysema be unilateral or bilateral? J Thorac Cardiovasc Surg 1996; 112:1331–1339. 8. Argenziano M, Thomashow B, Jellen PA, Rose EA, Steinglass KM, Ginsburg ME, Gorenstein LA. Functional comparison of unilateral versus bilateral lung volume reduction surgery. Ann Thorac Surg 1997; 64:321–327. 9. Brenner M, McKenna RJ, Gelb AF, Fischel RJ, Wilson AF. Rate of FEV1 change following lung volume reduction surgery. Chest 1998; 113:652–659. 10. Naunheim KS, Kaiser LR, Bavaria JE, Hazelrigg SR, Magee MJ, Landreneau RJ, Keenan RJ, Osterloh JF, Boley TM, Keller CA. Long-term survival after thoracoscopic lung volume reduction: a multi-institutional review. Ann Thorac Surg 1999; 68:2026–2032. 11. Cooper JD, Patterson GA, Sundaresan RS, Trulock EP, Yusen RD, Pohl MS, Lefrak SS. Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema. J Thorac Cardiovasc Surg 1996; 112:1319–1330. 12. Kotloff RM, Tino G, Bavaria JE, Palevsky HI, Hansen-Flaschen J, Wahl PM, Kaiser LR. Bilateral lung volume reduction surgery for advanced emphy-

Surgical Controversies in Lung Volume Reduction

13.

14. 15. 16. 17. 18.

19.

20.

21.

22.

23.

24.

25. 26.

27.

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sema—a comparison of median sternotomy and thoracoscopic approaches. Chest 1996; 110:1399–1406. Roberts JR, Bavaria JE, Wahl P, Wurster A, Friedberg JS, Kaiser LR. Comparison of open and thoracoscopic bilateral volume reduction surgery: complications analysis. Ann Thorac Surg 1998; 66:1759–1765. Ko CY, Waters PF. Lung volume reduction surgery: a cost and outcomes comparison of sternotomy versus thoracoscopy. Am Surg 1998; 64:1010–1013. Huizenga HF, Ramsey SD, Albert RK. Estimated growth of lung volume reduction surgery among medicare enrollees. Chest 1998; 114:1583–1587. Albert RK, Lewis S, Wood D, Benditt JO. Economic aspects of lung volume reduction surgery. Chest 1996; 110:1068–1071. Little AG, Swain JA, Nino JJ, Rachakonda DP, Schlachter MD, Barcia TB. Reduction pneumoplasty for emphysema. Ann Surg 1995; 222:365–374. Eugene J, Ott RA, Gogia HS, Santos CD, Zeit R, Kayaleh RA. Video-thoracic surgery for treatment of end-stage bullous emphysema and chronic obstructive pulmonary disease. Am Surg 1995; 10:934–936. Hazelrigg SR, Boley T, Henkle J, et al. Thoracoscopic laser bullectomy: a prospective study with 3-month results. J Thorac Cardiovasc Surg 1996; 111:308–316. Keenan RJ, Landreneau RJ, Sciurba FC, Ferson PF, Holker JM, Brown ML, Fetterman LS, Bowers CM. Unilateral thoracoscopic surgical approach for diffuse emphysema. J Thorac Cardiovasc Surg 1996; 111:308–316. Keller CA, Ruppel G, Hibbett A, Osterloh J, Naunheim KS. Thoracoscopic lung volume reduction surgery reduces dyspnea and improves exercise capacity in patients with emphysema. Am J Respir Crit Care Med 1997; 156:60–67. Daniel TM, Chan BBK, Bhaskar V, Parekh JS, Walters PE, Reeder J, Truwit JD. Lung volume reduction surgery: case selection, operative technique, and clinical results. Ann Surg 1996; 223:526–533. Cordova F, O’Brien G, Furukawa S, Kuzma AM, Travaline J, Criner GJ. Stability of improvements in exercise performance and quality of life following bilateral lung volume reduction surgery in severe COPD. Chest 1997; 112:907– 915. Szekely LA, Oelberg DA, Wright C, Johnson DC, Wain J, Trotman-Dickenson B, Shepard J, Kanarek DJ, Systrom D, Ginns LC. Preoperative predictors of operative morbidity and mortality in COPD patients undergoing bilateral lung volume reduction surgery. Chest 1997; 111:550–558. Bagley PH, Davis SM, O’Shea M, Coleman A. Lung volume reduction surgery at a community hospital. Chest 1997; 111:1552–1559. Bousamra M, Haasler GB, Lipchik RJ, Henry D, Chammas JH, Rokkas CK, Menard-Rothe K, Sobush DC, Olinger GN. Functional and oximetric assessment of patients after lung reduction surgery. J Thorac Cardiovasc Surg 1997; 113:675–682. Ferguson GT, Fernandez E, Zamora MR, Pomerantz M, Buchholz J, Make BJ. Improved exercise performance following lung volume reduction surgery for emphysema. Am J Respir Crit Care Med 1998; 157:1195–1203.

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28. Geddes D, Davies M, Koyama H, Hansell D, Pastorino U, Pepper J, Agent P, Cullinan P, MacNeill SJ, Goldstraw P. Effect of lung-volume reduction surgery in patients with severe emphysema. N Engl J Med 2000; 343:239–245. 29. Bingisser R, Zollinger A, Hauser M, Bloch KE, Russi EW, Weder W. Bilateral volume reduction surgery for diffuse pulmonary emphysema by video-assisted thoracoscopy. J Thorac Cardiovasc Surg 1996; 112:875–882. 30. Wisser W, Klepetko W, Kontrus M, Bankier A, Senbaklavaci O, Kaider A, Wanke T, Tschernko E, Wolner E. Morphologic grading of the emphysematous lung and its relation to improvement after lung volume reduction surgery. Ann Thorac Surg 1998; 65:793–799. 31. Stammberger U, Bloch KE, Thurnheer R, Bingisser R, Weder W, Russi EW. Exercise performance and gas exchange after bilateral video-assisted thoracoscopic lung volume reduction for severe emphysema. Eur Respir J 1998; 12:785–792. 32. Hamacher J, Bloch KE, Stammberger U, Schmid RA, Laube I, Russi EW, Weder W. Two years’ outcome of lung volume reduction surgery in different morphologic emphysema types. Ann Thorac Surg 1999; 68:1792–1798.

15 Giant Bullectomy

LAMBROS ZELLOS Harvard Medical School and Brigham & Women’s Hospital Boston, Massachusetts, U.S.A.

I. Introduction Lung volume reduction surgery (LVRS) is, in many ways, an evolutionary step with its origins in classic surgical bullectomy. Surgical procedures for giant bullae and their complications were developed decades ago and used since the 1940s. These procedures have withstood the test of time much better than many other early procedures attempted for treatment of emphysema, such as thoracoplasties, glomectomies and sympathectomies (1,2). This likely reﬂects their more sound physiological basis, which is essentially the same basis as for LVRS. Although the procedures are related, there are important distinctions between LVRS and bullectomy. Candidates for bullectomy typically have only a small number of localized giant bullae with other, well preserved areas of normal lung (3). Such patients are quite rare. LVRS candidates have more generalized emphysema, albeit perhaps with a heterogeneous distribution. Unlike LVRS, surgery for giant bullous disease attempts resection only of the enlarged bullae and not of underlying lung parenchyma. LVRS targets the most diseased lung regions for resection, but derives its beneﬁt from resecting, not restoring, lung, and might beneﬁt patients even if the lung left behind were identical to the lung removed. 301

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Despite the much longer history of bullectomy, the experience and literature concerning that procedure has been quickly dwarfed by that describing LVRS, because of the vastly greater number of eligible candidates and operations that have been performed. This chapter will brieﬂy review the pathophysiology of bullae, patient selection, operative technique, and outcomes.

II.

Pathophysiology and Classiﬁcation

Giant bullae should be distinguished from large cysts or blebs. Cysts have an inner epithelial lining, while blebs are localized collections of air between visceral pleural layers with no underlying lung parenchymal disease. Bullae, on the other hand, are emphysematous projections from the surface of the lung characterized by destruction of the parenchyma and often by the appearance of compression of surrounding lung (2). Multiple classiﬁcation systems have been proposed which classify bullous disease into distinct categories, based on whether bullae are single or multiple, and on the degree of underlying lung parenchymal disease (4,5). Giant bullae can also be classiﬁed into three types based on their characteristics and location: Type I bullae are superﬁcial and with a narrow neck, type II bullae are superﬁcial with a broad neck, and type III are deep and with a broad neck (2). Giant bullae are initially formed due to local destruction of the lung parenchyma. Although it is commonly believed that bullae enlarge due to airway obstruction or air trapping (ball valve effect), there is little evidence to support this. Their bronchi are patent, and their volume usually changes in phase with lung volume. Furthermore, the pressure in a giant bulla is not greater than ambient pressure during inspiration, nor greater than pleural pressure during expiration (6). However, bullae are much more compliant than surrounding lung, up to their elastic limit (7). Hence less inspiratory force is required to inﬂate them than surrounding lung (2). The net effect is preferential ventilation of the bulla, and decreased ventilation of the nonbullous lung. This would suggest that the apparent ‘‘compression’’ of surrounding lung seen radiographically may be absorbtive atelectasis in those areas of decreased ventilation. This can also be manifest as various degrees of small airway obstruction, as well as reduction in both ventilation and perfusion of the lung tissue. Furthermore, although inspired air ventilates the bulla, this is almost entirely dead space ventilation because of the minimal surface area for gas exchange in the bulla.

Giant Bullectomy III.

303

Indications for Surgery

Indications for operative intervention in patients with giant bullae include the presence of symptoms such as dyspnea, chest pain, and hemoptysis or complications such as pneumothorax and infections. Whereas dyspnea and chest pain are common symptoms, hemoptysis and infection originating in the bulla are quite rare (8–10). Preventive surgery has been advocated for asymptomatic giant bullae that occupy most of the hemithorax to avoid future complications and symptoms. However, there are little data that can be used to predict the natural history of asymptomatic bullae. Enlargement remains unpredictable in any given patient, and studies supporting resection of asymptomatic giant bullae compared to postponing resection until symptoms develop are lacking (3). Although bleeding or infection may be suggested by the appearance of an air–ﬂuid level, these are rarely indications for surgery. An air–ﬂuid level is commonly seen in giant bullae, but is usually due to an inﬂammatory reaction from surrounding parenchymal infections. These air–ﬂuid levels have been shown to resorb at a mean duration of 11 weeks without interventions (10). If the bullae are truly infected and the patient does not respond to medical treatment, or complications arise despite medical therapy, such as rupture into the pleural space or hemoptysis, then operative intervention is required. Percutaneous drainage of the infected bullae can be reserved for patients who are not operative candidates. The most common scenario is that of a patient with dyspnea or chest pain and radiographic evidence of giant bullae. The issues are determining (1) the extent to which the symptoms are due to the bullae and (2) the extent to which bullectomy might be expected to relieve the symptoms. As with lung volume reduction surgery (LVRS), impressive results have been reported in properly selected patients. Resection of giant bullae has been shown to increase vital capacity, FEV1 (forced expiratory volume in 1 s), and PaO2 and decrease dead space ventilation (11–13). Resection has also resulted in improved diaphragmatic function, especially when resecting inferior lobe bullae (14). Dramatic reports include intubated and ventilated patients in acute respiratory failure who were extubated after giant bullectomy (15). Despite all these potential beneﬁts, preoperative selection remains difﬁcult, since no single test can deﬁnitively separate those with good outcomes from those with bad ones. As described in Section V, better results are often seen in patients with relatively normal surrounding lung rather than those in whom a few giant bullae are just the most prominent manifestation of widespread emphysema. Abnormalities of underlying lung may be suggested when pulmonary function impairment, exercise limitation, and symptoms appear out of

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proportion to the size of bullae seen radiographically. However, appropriate patients can rarely be identiﬁed by pulmonary function testing alone. A variety of other tests have been suggested to select the most appropriate patients for surgery (16,17). Computed tomographic (CT) scan of the chest yields the most detailed anatomical information. It can demonstrate large bullae and bullae at other sites, and it can provide an assessment of the degree of emphysema and pulmonary crowding in the rest of the lung. Angiography can also assess pulmonary crowding and is more sensitive than CT scan. In addition, the presence of pulmonary hypertension can be determined. In contrast to LVRS, pulmonary hypertension is not an exclusion criteria for bullectomy, since lung parenchyma is preserved. If pulmonary hypertension is due to tortuosity of vessels in compressed or atelectatic lung or to hypoxia, and if this is improved by surgery, then there is reason to expect pulmonary artery pressures to fall after surgery. However, this has not been systematically examined. Ventilation/perfusion scanning provides a functional assessment of the underlying lung and also helps to stratify patients. The presence of wellpreserved perfusion of the surrounding lung supports the CT impression of its normality. In a patient with the beneﬁt of longitudinal data, documented enlargement of a bulla coupled with deterioration in pulmonary function studies and symptoms provides presumptive causal evidence that the bulla is responsible for the disability. General guidelines for patient selection have been developed and are presented in Table 1.

IV.

Surgical Techniques and Incisions

Various techniques have been used for elimination of giant bullae. These include resection, plication, laser ablation, or intracavitary drainage. These procedures have also utilized a variety of incisions, including standard posterolateral thoracotomy, anterolateral muscle-sparing thoracotomy, median sternotomy, axillary thoracotomy, and video-assisted thoracic surgery (VATS). Although standard posterolateral thoracotomy provides the optimal exposure, it also has the highest morbidity. Therefore, other incisions have been proposed to minimize postoperative morbidity and respiratory muscle compromise. Incisions such as axillary thoracotomy, muscle-sparing thoracotomy, and anterior thoracotomy can provide good exposure and less morbidity as long as the bulla is in close proximity. If multiple bullae are present, or one is located further from the incision, exposure can be a problem. With experience, VATS can provide excellent exposure with minimal morbidity. Median sternotomy offers the advantage

Giant Bullectomy Table 1

305

Preoperative Selection for Bullectomy Improved by surgery

Clinical Presentation Age and medical status

Young age (<50 years); no comorbid illness

Cardiac status

Normal

Weight loss Dyspnea Other respiratory symptoms

None or <10% Rapidly progressive ‘‘Pink puffer’’

Pulmonary Function Studies FVC Normal or slightly decreased FEV1 >40% Normal DLCO PaO2 Normal PaCO2 Imaging Compression index Chest radiograph

CT scan

Angiography

Ventilation/perfusion scan

Source: Ref. 3.

Normal

High index (3/6) Bulla occupying greater than one-third of hemithorax, large bulla with vascular crowding, localized disease Large and localized bulla with evidence of vascular crowding and normal pulmonary density and architecture around the bulla Vascular crowding, preserved distal vascular branching Well-localized matching defect, normal uptake and washout from underlying lung

No improvement or worse outcome Old age (>50 years); severe intercurrent diseases Right heart failure and cor pulmonale >10% Slowly progressive ‘‘Blue bloater’’ (sputum production, chronic bronchitis)

Markedly decreased <35% Decreased Hypoxemia at rest or during exercise Increased

Low index (<3/6) Multiple small bullae, diffuse disease, vanishing lung syndrome Multiple bilateral bullae, evidence of emphysema in the underlying lung

Winter-tree appearance, no crowding Diffuse multiple defects, poor washout in restricted lung

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of bilateral exposure and minimal morbidity, and can be used when bilateral giant bullae are present (18–20). The goals of giant bullectomy are to resect the bulla while preserving lung parenchyma and avoiding excessive postoperative air leaks. For type I giant bullae that have a narrow neck, simple ligation and excision can be performed. However, when dealing with the type II bullae that have a broad base, plication is more appropriate. With this approach, the bulla is opened longitudinally. After debridement of the contents of the bulla, and division of any intracavitary adhesions, the edges of the pleura are grasped from inside the cavity near normal lung parenchyma. The walls of the bulla are folded over the lung and stapled over the lung parenchyma with a GI stapler (19). Several methods have been introduced to reduce the rate of postoperative leaks. The staple line and any raw lung parenchyma can be sprayed over with ﬁbrin glue to seal any small air leaks. However, excessive use of ﬁbrin glue may cause difﬁculties expanding the remaining lung. Teﬂon pledgets, bovine pericardium, or autologous parietal or visceral pleura have been incorporated to the staple lines to help reduce air leaks (19,21). Frequently after resection of a giant bulla, a space problem can be created if the remaining lung tissue fails to expand sufﬁciently. This can be treated with pleural tents, and chemical or mechanical pleurodesis can help provide good lung to pleura apposition. Chest tube suction can be minimized or the chest tubes can be placed on water seal alone to expedite resolution of the postoperative air leaks, as long as there is not a signiﬁcant pneumothorax. The VATS approach to resection of giant bullae offers good exposure with minimal morbidity. Except for the incision and thoracoscopic equipment, the technique is similar to that of open thoracotomy. Usually multiple ﬁrings of the GIA endostapler are required. This procedure is also complemented by mechanical or chemical pleurodesis. Laser (Nd:YAG, or CO2) has been used in conjunction with VATS in order either to resect or contract the bullous cavity and obliterate it (19). One technique reported by Wakabayashi uses laser to open the bulla and then ﬁgure-of-eight sutures to obliterate any bronchi that feed the bulla. Seventeen patients were successfully treated in this manner (22). Other surgeons have used the laser beam to contract the entire bulla thoracoscopically without cutting into it. Intracavitary suction and drainage of bullae with or without resection has been used since the 1940s. Intracavitary drainage was ﬁrst introduced in the 1930s for the management of tuberculous cavities. It later was applied to giant bullae. Goldstraw (23) reports the largest modern experience with this

Giant Bullectomy

307

method as follows: preoperative CT scan is used to select the best site for the surgical incision, which is directly over the bulla. The bulla is entered and any adhesions within the cavity are then divided. The cavity is sclerosed with instillation of talc, and a Foley catheter is inserted in the cavity and brought out through the wound. The lung can be inspected for other large bullae, and an intrapleural drain is placed after the pleural cavity is sclerosed with talc. The incision is then closed. The intracavitary Foley catheter is removed 8 days later. Persistent leaks will not cause a pneumothorax, since a controlled bronchocutaneous ﬁstula has been formed. This ﬁstula usually seals within few days. This technique is especially suitable for type III bullae that extend into the hilum, where resection would be difﬁcult without sacriﬁcing nonbullous lung parenchyma. Other surgeons have used intracavitary suction to collapse the bullae preoperatively, improve intrathoracic visualization, and increase the feasibility of a VATS-based resection (24).

V. Results Although most of the reported series include only a small number of patients, many of them include lengthy follow-up, sometimes up to 20 years. No randomized studies have been published, neither comparing medical to surgical management nor comparing different timing of bullectomy. Postoperative mortality rates reported range from 0 to 16%. The largest series, those involving more than 40 patients, show a mortality rate closer to 2% (25). Other procedures done at the same setting as giant bullectomy (segmentectomy or lobectomy) are associated with higher mortality rates. Low preoperative FEV1 also is associated with worse outcomes. To generalize from the results of several series, improved function sustained at 5-year follow-up has been shown in patients that, preoperatively, had an FEV1 greater than 35% predicted, quit smoking, and had giant bullae occupying more than one-third of the hemithorax (26–29). In three of the larger series, results were as follows: Nickoladze reported 46 patients in whom there were no operative deaths. Patients were followed for 5 years. Pulmonary function failed to improve in patients with bullae occupying less than one-third of the hemithorax, but no new bullae were found on follow-up (30). Barifﬁ et al. excised bullae in 60 patients with an operative mortality of 1.2%. However, few patients were followed beyond their operative hospitalization (31). Fitzgerald et al. reported bullectomies performed on 84 patients over 23 years. Operative mortality was 2.1%. Some patients were followed up as long as 20 years. Better outcomes at 5 years were seen in patients having undergone giant

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bullectomy rather than lobectomy, those with bullae occupying more than one-third of the hemithorax, and in those patients that did not have underlying chronic bronchitis or diffuse emphysema (32). In all of these series, there were very few patients in whom bullae recurred.

VI.

Summary

Giant bullectomy has endured the test of time and is a procedure that can offer signiﬁcant and prolonged improvement in selected patients. Based on limited numbers of patients, the best candidates are those with bullae occupying more than one-third of the hemithorax and relatively normal surrounding lung with moderately impaired overall pulmonary function and have symptoms or pulmonary compromise largely attributable to the giant bullae. Controversy will persist regarding bullectomy in asymptomatic patients owing to the unpredictable natural history of giant bullae. Although bullectomy shares some common concepts with LVRS, suitable subjects are much rarer, the procedures differ in their technical goals, and beneﬁts may be more long lasting.

References 1. 2. 3. 4. 5. 6. 7.

8. 9.

Naef AP. History of emphysema surgery. Ann Thorac Surg 1997; 64(5):1506– 1508. Deslauriers J. History of surgery for emphysema. Semin Thorac Cardiovasc Surg 1996; 8(1):43–51. Mehran RJ, Deslauriers J. Indications for surgery and patient work-up for bullectomy. Chest Surg Clin North Am 1995; 5(4):717–734. Witz JP, Roeslin N. La chirurgie de l’emphyseme bulleux chez l’adulte. Revue Francaise de Maladies Respiratoire 1980; 8:121. De Vries WC, Wolfe WG. The management of spontaneous pneumothorax and bullous emphysema. Surg Clin North Am 1980; 60:851. Morgan MD, Edwards CW, Morris J, Mathews HR. Origin and behaviour of emphysematous bullae. Thorax 1989; 44(7):533–538. Ting EY, Klopstock R, Lyons HA. Mechanical properties of pulmonary cysts and bullae. Am Rev Respir Dis 1963; 87:538. 7a. Oo AY, Page RD. Bullectomy for chronic obstructive pulmonary disease. Hosp Med 1998; 59(10):793–796. Benditt JO, Albert RK. Surgical options for patients with advanced emphysema. Clin Chest Med 1997; 18(3):577–593. Nakahara K, Nakaoka K, Ohno K, Monden Y, Maeda M, Masaoka A, Sawamura K, Kawashima Y. Functional indications for bullectomy of giant bulla. Ann Thorac Surg 1983; 35(5):480–487.

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10. Mahler DA, Gertstenhaber BJ, D’Esopo ND. Air-ﬂuid levels in lung bullae associated with pneumonitis. Am Rev Respir Dis 1979; 119(suppl):331. 11. O’Donnell DE, Webb KA, Bertley JC, Chau LK, Conlan AA. Mechanisms of relief of exertional breathlessness following unilateral bullectomy and lung volume reduction surgery in emphysema. Chest 1996; 110(1):18–27. 12. Teramoto S, Fukuchi Y, Nagase T, Matsuse T, Shindo G, Orimo H. Quantitative assessment of dyspnea during exercise before and after bullectomy for giant bulla. Chest 1992; 102(5):1362–1366. 13. Ohta M, Nakahara K, Yasumitsu T, Ohsugi T, Maeda M, Kawashima Y. Prediction of postoperative performance status in patients with giant bulla. Chest 1992; 101(3):668–673. 14. Travaline JM, Addonizio VP, Criner GJ. Effect of bullectomy on diaphragm strength. Am J Respir Crit Care Med 1995; 152(5 Pt 1):1697–1701. 15. Pacht ER. Emergent bullectomy in a patient with severe bullous emphysema receiving mechanical ventilatory assistance. Chest 1995; 108(5):1454–1456. 16. Slone RM, Gierada DS, Yusen RD. Preoperative and postoperative imaging in the surgical management of pulmonary emphysema. Radiol Clin North Am 1998; 36(1):57–89. 17. Gaensler EA, Jederlinic PJ, FitzGerald MX. Patient work-up for bullectomy. J Thorac Imaging 1986; 1(2):75–93. 18. Edelman JD, Kotloff RM. Surgical approaches to advanced emphysema. Respir Care Clin North Am 1998; 4(3):513–539. 19. Dartevelle P, Macchiarini P, Chapelier A. Operative technique of bullectomy. Chest Surg Clin North Am 1995; 5(4):735–749. 20. Vigneswaran WT, Townsend ER, Fountain SW. Surgery for bullous disease of the lung. Eur J Cardiothorac Surg 1992; 6(8):427–430. 21. Busetto A, Moretti R, Barbaresco S, Fontana P, Pagan V. Extrapleural bullectomy or lung volume reduction: air tight surgery for emphysema without strip-patch. Acta Chir Hung 1999; 38(1):15–17. 22. Wakabayashi A. Thoracoscopic technique for management of giant bullous lung disease Ann Thorac Surg 1993; 56:708–712. 23. Goldstraw P, Petrou M. The surgical treatment of emphysema. The Brompton approach. Chest Surg Clin North Am 1995; 5(4):777–796. 24. Shinonaga M, Yamaguchi A, Yoshiya K. VATS-stepwise resection of a giant bulla in an oxygen-dependent patient. Surg Laparosc Endosc 1999; 9(1):70–73. 25. Connolly JE. Results of bullectomy. Chest Surg Clin North Am 1995; 5(4):765– 776. 26. Verma RK, Nishiki M, Mukai M, Fujii T, Kuranishi F, Yoshioka S, Ohtani M, Dohi K. Intracavitary drainage procedure for giant bullae in compromised patients. Hiroshima J Med Sci 1991; 40(3):115–118. 27. Connolly JE, Wilson A. The current status of surgery for bullous emphysema. J Thorac Cardiovasc Surg 1989; 97(3):351–361. 28. Laros CD, Gelissen HJ, Bergstein PG, Van den Bosch JM, Vanderschueren RG, Westermann CJ, Knaepen PJ. Bullectomy for giant bullae in emphysema. J Thorac Cardiovasc Surg 1986; 91(1):63–70.

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29. Pearson MG, Ogilvie C. Surgical treatment of emphysematous bullae: late outcome. Thorax 1983; 38(2):134–137. 30. Nickoladze G. Results of surgery for bullous emphysema. Chest 1992; 101:119– 122. 31. Barifﬁ F, Rickler R, Tranfa C, et al. Clinical indications and results of surgery for bullous emphysema. Bronchopneumologie 1980; 30:228–235. 32. Fitzgerald M, Keelan P, Angell D, et al. Long-term results of surgery for bullous emphysema. Surgery 1974; 68:566–582.

16 Outcomes from Lung Volume Reduction Surgery Short-Term and Long-Term Results

FERNANDO J. MARTINEZ University of Michigan Ann Arbor, Michigan, U.S.A.

I. Introduction Chronic obstructive pulmonary disease (COPD) is a group of heterogeneous disorders with varying pathophysiological bases. They share the features of chronic airﬂow obstruction, hyperinﬂation, and depressed quality of life. Traditional management has emphasized smoking cessation and pharmacotherapy (1). A recent comprehensive review has also conﬁrmed objective and subjective functional improvements in patients with COPD following pulmonary rehabilitation (2). Unfortunately, despite these therapies, many patients continue to experience incapacitating breathlessness and impaired exercise capacity. This has led to numerous surgical approaches aimed at the chronic airﬂow obstruction and hyperinﬂation. This chapter will present the short- and long-term physiological and clinical outcomes reported after lung volume reduction surgery (LVRS) in the absence of giant bullae. In addition, the potential criteria that may predict patients most likely to beneﬁt from LVRS will be discussed on the basis of published literature.

311

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Martinez II.

Short-Term Results

Since the initial report of Cooper et al. and colleagues in 1995 (3), numerous reports of LVRS have appeared in the literature. Summaries of these studies have been provided by Utz et al. (4), Benditt and Albert (5), and Sciurba (6). It is evident from these reviews that major problems in the literature confound its interpretation. These include (1) variable surgical techniques and selection criteria; (2) short and often incomplete postoperative followup evaluations, (3) retrospective data collection in most series; and (4) the absence of a control group in most published reports. The major series published since 1994 are shown in Table 1. A. Mortality

A perusal of Table 1 reveals a wide range of 30-day LVRS mortality, a classic surgical benchmark of operative mortality, from 0 to 15%. The differences reported may relate to varied deﬁnitions of surgical mortality, different inclusion or exclusion criteria, and different surgical techniques or experience, as well as varied postoperative management (4,7). In part because of these inconsistencies, the Health Care Finance Administration in late 1995 decided to deny coverage for LVRS on the basis of two independent assessments of available data (8). A subsequent report to Congress included a supplemental analysis of Medicare claims identiﬁed by ICD-9 code for LVRS performed from October 1995 to January 1996 (9). This Medicare database totaled 722 patients, whose 3-month mortality was 14.4% and 6-month mortality was 16.9%. In addition, a marked rise was found in the number of acute care hospital days (11.8 days per patient in the year before surgery to 18.7 days per patient in the year after LVRS, exclusive of the surgical hospitalization). Similarly, long-term care facility days, rehabilitation hospital days, and skilled nursing facility days rose in the year after surgery (9). These data are ﬂawed by the lack of standardized reporting of the surgical procedure or patient characteristics. They may also reﬂect the early experience in numerous hospitals (138 total) just beginning to perform LVRS. However, they suggest a potentially signiﬁcant shortterm morbidity and mortality in this population that is not reﬂected in the selected experience published in the medical literature. More recently, the National Emphysema Treatment Trial has reported that certain patients are at high risk of death after LVRS (10). Such patients, identiﬁed by the characteristics of an FEV1 (forced expiratory volume in 1 s) < 20% predicted and a low diffusing capacity for carbon monoxide of < 20% predicted and/or a homogeneous distribution of emphysema on computed tomographic scan (CT) scan were found to have a mortality of

40 32 71

39 20 11

35

13

51

14 14

34

92 33 12

Reference

U and B MS staple U VATS staple U and B VATS staple; MS staple

U CO2 laser U laser + staple U VATS laser + staple; B VATS and MS staple + laser U VATS laser + staple U laser + staple U laser U VATS staple U laser þ staple; MS staple U thoracotomy B MS/ thoracosternotomy U and B MS staple U thoracotomy/ VATS staple U and B MS staple U VATS staple U and B VATS staple

Procedure

53/40 50/25 13/6–8

45/37 25/25 166/139

55/20–42

96/66

67/54 30/26 38/36 2020

141/91

24/19 28/28 44/38

Total patients/ follow-up

6–12 1–3 12–48

3–6 4 6

3–6

3–12

3

3 6

3

3 6 6–12

Duration of follow-up (months)

Table 1 Description of Lung Volume Reduction Studies

Yes Yes No

Yes Yes NA

Yes

Yes

No

No No

No

No No No

Preoperative rehabilitation

16 9 11 (U) 11 (B) NA 13 29

18

NA

17 11 14 NA

12

16 NA 12

LOS (days)

7/11.1 0/0 3.5/17 (U) 2.5/5.1 (B) 5.7/9.4 4/4 0/15

3/11

6.5/14.6

1.7/10.4 0/9 2.5/2.5 0

5.7/9.2

12.5/21 0/10.7% 2.3/27

Mortality (operative/ total)

62 60 68 (U) 68 (B) 67 62 55

65

64

62 69 66 60

65

62 66 66

Age (mean)

26 28 26 (U) 25 (B) NA 26 18

29

22

30 NA NA 32

25

NA NA NA

FEV1 % pred

89 74 NA

83 NA NA

75

69

80 76 69 NA

75

NA 82 100

O2 requirement (% patients)

Outcomes from LVRS 313

19

3 36 58 37 28 38 18

26 47

45 46 85 73 23 48 27 98 24 41

106

Reference B VATS staple B MS staple B VATS staple B VATS staple B VATS staple B VATS staple B VATS staple B VATS staple B VATS staple B VATS staple B MS staple B MS and thoracosternotomy B MS staple B MS staple B VATS staplea B MS staple B MS staple B MS staple B MS staple B MS staple MS staple B MS staple B VATS staple B MS staple B VATS staple

Procedure

Table 1 Continued

21/21 18/16 12/9 20/20 137/101 69/25 26/17 27/18 33/33 29/NA 50/NA 19/NA 23/NA

20/20 145/130 12/12 10/10 29/29 40/40 8/8 50/50 46/46 85/51

31/30

Total patients/ follow-up

NA

6 6–24 3–18 3 4 12 NA

3 24

3 9 6 12 6 3 3 3 3 3–6

3–6

Duration of follow-up (months)

NA

Yes Yes Yes Yes Yes Yes NA

No Yes

No No Yes Yes NA No Yes No No Yes

Yes

Preoperative rehabilitation

NA 16 18 15 14 NA 14 NA 16 15 21 14 10

15 9 10 NA NA NA NA 16 NA 17

NA

LOS (days)

5 0/11 0/0 0/0 4/8 NA 3.8/3.8 4/19 0/3 0/14 0/6 15/25 4/8

0/0 4.1/4.1 0/0 0/0 0/0 0/0 NA 0/0 0/0 7/17

3

Mortality (operative/ total)

NA 58 49 56 61 58 62 64 57 63 68 62 60

64 NA 68 67 60 63 60 66 59 64

53

Age (mean)

24 31 24 25 25 27 15 NA 25 25 23 25 29

29 25 29 24 21 29 24 28 23 23

23

FEV1 % pred

NA 78 75 70 93 74 35 100 88 59 62 86 85

NA NA NA 100 76 15 NA 12 NA NA

NA

O2 requirement (% patients)

314 Martinez

U/B VATS

B MS staple B MS staple B VATS staple

65

93 17

47/38 15/NA 15/NA

80/56 (MS) 40/34 (VATS) 17/17 14/14 48 (24 surgery)/ 48 15/14 (PaCO2 > 45) 31/ 27 (PaCO2 < 45) 60 (30 surgery)/ 60

Total patients/ follow-up

NA 6

6

3–6

4 3 6

3–6

Duration of follow-up (months)

No No

Yes

Yes

Yes No Yes

Yes

Preoperative rehabilitation

32 12 13

13.6

20 17

22 (MS) 15 (VATS) NA NA

LOS (days)

8.5/19.1 13.3 6.7

3.3/6.6%

7/7 0/10

4.2/13.8 2.5//2.5 0/0 0/0 5/24

Mortality (operative/ total)

U, unilateral; B, bilateral; MS, median sternotomy; VATS, video-assisted thoracic surgery; NA, not available. a a1-Antitrypsin deﬁciency.

60

22 62 63

MS staple VATS staple MS staple MS staple MS staple B VATS staple B MS staple B VATS staple

B B B B B

Procedure

Continued

16

Reference

Table 1

64 (M) 61 63

62 (S)

56 59

59 62 61 62 62

Age (mean)

NA 22 25

0.851

20 31

27 25 27 21 0.751

FEV1 %pred

56 80 67

18

NA

NA 43

NA

O2 requirement (% patients)

Outcomes from LVRS 315

40 32 71 45 46 85 73 23 48 27 98 24 41 26

35 39 20 11

51 13

34 15 14

92 33 12

Reference 44 34 45 (U) 82 (B) 16 27 13 (laser) 33 (staple) 28 28 (U) 70 (B) 30 59 31 31 (U) 57 (B) 96 34 51 42 62 68 34 33 55 38 34 to 81a 33 58 30

FEV1 (% change)

14 19 6 21 13 29 48 26 37 23 10 12 86 15 NA 29 40 18 13 18 42 24 37 to 60a 52 41 17

39 24 56

FVC (% change)

6 NA NA NA 1 NA

16 NA 9 NA 16 NA NA NA NA 16 19 18 11 NA 17 9 9 10 NA 7

7 6 NA

14 16 NA

NA 33 NA 23 28 30 19 NA 25 28 20 to 3a 22 NA 22

NA 20 23

TLC (% change)

20 12 30

RV (% change)

Table 2 Pulmonary Function Results of Lung Volume Reduction Studies

NA 5 NA NS 63 196 100 NA 0 NA 4 to 7a 24 NA NA

NA NA 23 NA

10 NA

5 NA NA

2 NA NA

DLCO (% change)

8 8 NA 4 1 NA NA NA 6 NA 2 to 4a 3 NA 5

NA NA 10 NA

2 NA

2 1 NA

NA NA 11

PaO2 (D mmHg)

3 NA 4

3 1 NA 2 1 NA NA NA 3 NA

NA NA 1 NA

4 NA

1 3 NA

NA NA 7

PaCO2 (D mmHg)

316 Martinez

19 (MS) 29 (VATSb) 82 51 37 49 32 85 40 (MS) 41 (VATS) 28 (MS) 62 (VATS) 41 (MS) 41 (VATS) 38 26 25 (PaCO2 > 45) 18 (PaCO2 < 45) 9.5 53 NA 60 (MS) 62 (VATS)

FEV1 (% change)

20 25 17 11 15 13 15 17 NA 33 35

NA

27 20 22 23 14 NA NA

NA

FVC (% change)

28 23 25 27 15 25 70 25 NA 22 29

14 5 39 28 27 14 28 NA 28 37 NA

RV (% change)

13 16 14 11 18 NA NA 11 8

7 11 NA

9 4.3 22 14 11 14 15 NA NA

TLC (% change)

10 NA 10 7.6 6 NA NA NA

NA

NA NA 14 NA 4 NA 15 10 NA

NA

DLCO (% change)

U, unilateral; B, bilateral; MS, median sternotomy; VATS, video-assisted thoracic surgery. NA, not available. a Stratiﬁed by emphysema heterogeneity on HRCT (see text for details). b a1-Antitrypsin deﬁciency.

63 65 93 17

22 62 60

16

19

3 36 58 37 28 38 18

47

Reference

Table 2 Continued

3 5 NA 3 3

NA 1 NA

1 1 6 8 NA 4 1 *6 9 2 11 2 NA

PaO2 (D mmHg)

NA 0 9 1 0 1 NA 6 1

0 0 1 4 2 2 3 *5 1 5 1 9 NA

PaCO2 (D mmHg)

Outcomes from LVRS 317

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*35% over the ﬁrst 3 months after randomization to surgery. This was markedly higher than the observed rate in patients with similar characteristics who were randomized to continued medical therapy. Thus, it is likely that perioperative mortality at any given center will be sensitive to both the experience of the surgical team and the speciﬁc selection criteria in use. B. Pulmonary Function

The initial report of Cooper et al. (3) documented an 82% improvement in FEV1 at a mean of 6.4 months of follow-up evaluation (3). Subsequent studies by that group and others conﬁrmed signiﬁcant mean improvements in spirometry, although less than the ﬁrst reports (4–6). These changes in pulmonary function are described in Table 2. The majority of these studies emphasized spirometric data, with statistically signiﬁcant mean improvements in FEV1 ranging from 13 to 96%. Unfortunately, in many studies, it is often not speciﬁed whether reported values are those obtained before or after administration of bronchodilators and optimization of medical therapy, which makes the improvement difﬁcult to attribute to LVRS alone. Nevertheless, given a preoperative FEV1 that ranges from 15 to 33% of predicted, the improvements appear to be clinically important. A close review of the data in Table 2 reveals additional ﬁndings. In general, bilateral procedures were associated with greater short-term improvements then unilateral operations. Of the studies in which a unilateral procedure was used exclusively, the improvement in FEV1 averaged 29%, whereas in those studies exclusively using a bilateral reduction procedure, the improvement was 46%. Head-to-head comparisons of unilateral versus bilateral reduction are rare (11–13). McKenna et al. described results in 166 consecutive patients undergoing volume reduction via thoracoscopic stapling (unilateral in 87 and bilateral in 79 patients). Those undergoing unilateral procedures experienced a 31% improvement in FEV1 6 months after surgery compared with 57% increases in those undergoing bilateral volume reduction. The mortality at 1 year was lower (5%) in the bilateral group compared with the unilaterally treated group (17%). Argenziano et al. (13) described results in 64 patients undergoing bilateral stapling procedures and 28 patients undergoing unilateral procedures. The indications for unilateral volume reduction included patients with asymmetrical disease, previous thoracic surgical procedures, or concomitant tumors. The improvement in FEV1 was higher in the bilaterally treated group (70 vs. 28%). Finally, Eugene et al. reported results of unilateral reduction in 34 patients compared with 10 patients undergoing bilateral procedures. The surgical procedures included a mixture of stapling and laser procedures. The improvement in FEV1 was much higher (82%) in

Outcomes from LVRS

319

those treated bilaterally compared with those treated unilaterally (45%). Although few randomized data exist, consistent ﬁndings from multiple series suggest better spirometric results in patients undergoing bilateral LVRS. Data comparing various surgical techniques are limited, as noted in Tables 1 and 2. The results of laser procedures appear to be worse than those utilizing stapling techniques. McKenna et al. (14) have reported the only prospective, randomized trial comparing stapled versus laser lung reduction. They compared results in 33 patients undergoing unilateral, video-assisted thoracic surgery (VATS) with Nd:YAG laser reduction and 39 patients undergoing unilateral VATS with stapled resection. The patients undergoing stapled resections experienced a greater short-term improvement in FEV1 (32.9%) than those undergoing laser reduction (13.4%). In addition, Keenan et al. (15) noted a much higher morbidity in a limited number of patients undergoing unilateral laser reduction (n ¼ 10) as compared with a group undergoing predominantly stapled resections (n ¼ 57). Pulmonary function results between the two groups were not reported. It is apparent that current laser technology has a limited role in LVRS. Several investigators have compared short-term physiological sequelae of bilateral volume reduction performed via VATS or median sternotomy (MS). Kotloff et al. (16) reported a retrospective series from two surgeons at the same institution, which included 59 patients who underwent bilateral LVRS via MS and 40 who underwent bilateral reduction via VATS. No difference in short-term spirometric outcomes was noted, but the total inhospital mortality was signiﬁcantly higher in the MS group (13.8 vs. 2.5%). Wisser et al. (17) described 15 patients undergoing bilateral LVRS via MS in comparison with 15 undergoing bilateral thoracoscopic LVRS. They noted little difference in all outcomes, including spirometry, between the two surgical groups. These data are consistent with the retrospective ﬁndings of Hazelrigg et al. (18). In contrast, Ko and Waters noted a much higher total mortality (25%) in 19 patients undergoing bilateral LVRS via MS as compared with 23 patients treated thoracoscopically (8%). In addition, the improvement in FEV1 was higher in the VATS group (62 vs. 28%). Unfortunately, none of these studies was randomized, which limits the conclusions that can be reached. The FEV1 data presented in Table 2 show the mean improvement. The variance around the mean is provided in remarkably few studies (15,19,20). Figure 1 illustrates the distribution of change in FEV1 in the retrospective comparison of bilateral LVRS via MS and VATS reported by Kotloff et al. (16). Approximately one-third of patients in both groups experienced an improvement in FEV1 of less than 20%. These data are qualitatively similar to those presented by others (15,21–23). That is, most investigators

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Martinez

Figure 1 Distribution of percentage increases in FEV1 after bilateral LVRS via median sternotomy (MS) or video-assisted thoracic surgery (VATS). (From Ref. 16.)

demonstrate a very wide variance around the mean improvement in FEV1. When the data are provided, 20–50% of patients show little short-term spirometric improvement after LVRS (7). However, many patients experiencing limited spirometric improvement obtain signiﬁcant reduction in breathlessness (22), which highlights the limitation of FEV1 as the sole measure of improvement. Although reported less frequently than FEV1, lung volumes have generally decreased during short-term follow-up periods. The decrease in total lung capacity (TLC) has varied from 2 to 23%, and residual volume (RV) has decreased by 3–39% (see Table 2). Changes in diffusing capacity for carbon monoxide (DLCO) have been more modest (see Table 2). Few data are available to compare the effects of different surgical techniques on lung volume and DLCO changes. Changes in resting arterial blood gases have been quite heterogeneous, ranging from signiﬁcant improvements in arterial O2 pressure (PaO2) and decreases in arterial CO2 pressure (PaCO2) to little change (5,6) (see Table 2). The retrospective data of Albert et al. (24) are the most detailed, showing signiﬁcant improvement in arterial blood

Outcomes from LVRS

321

gases in some patients with worsening in others. For the group as a whole, minimal mean changes were found. Furthermore, no correlation was seen between arterial blood gas changes and the changes in spirometry, lung volumes, or DLCO. They believed the effect of LVRS on blood gases resulted primarily from alterations in ventilation perfusion heterogeneity (24). C. Exercise Capacity

Improvement in exercise capacity may have greater relevance than FEV1 to patients undergoing LVRS. Most investigators have utilized simple measures of exercise capacity such as timed measures of walk distance. Table 3 demonstrates consistent improvements in walk distance ranging from 7 to 103%. Unfortunately, most investigators provide limited descriptions of the methodology employed. Six-minute walk distance, the most common test used, is highly dependent on the testing format and patient encouragement (25). In addition, pulmonary rehabilitation has been shown to improve walk distance (25). Given the limited methodological details provided by the majority of the investigators cited in Table 3 and the lack of blinding in all studies, it is difﬁcult to reach deﬁnite conclusions regarding the magnitude of improvement or its causal relationship to LVRS or aggressive rehabilitation. Several groups have examined additional measurements of exercise capacity, including cardiopulmonary exercise testing (CPET). The results included in Table 3 suggest consistent short-term increases in maximal workload, oxygen production (VO2), and minute ventilation (VE). Keller et al. (20) performed maximal CPET in 25 patients before and after unilateral LVRS. They found increases in maximal workload, VO2, and VE. The latter was achieved through increased tidal volume (VT) with little change in respiratory rate. Mean inspiratory and expiratory ﬂows increased signiﬁcantly in all patients, whereas PaO2 improved in 20 patients (20). Benditt et al. (26) extended these ﬁndings in a study of patients performing maximal CPET before and after bilateral LVRS. They conﬁrmed the improved aerobic capacity and also noted decreased heart rate at similar workloads. The primary limitation to exercise remained ventilatory, as the majority of patients developed an acute respiratory acidosis during maximal exercise both before and after LVRS. Martinez et al. (22) found similar results at isowork levels, but noted improved dyspnea that correlated best with decreased dynamic hyperinﬂation. In addition, Tschernko et al. (27) found a signiﬁcant decrease in the work of breathing during exercise after LVRS. Ferguson et al. (28) conﬁrmed similar improvements during maximal testing, and also showed improved VT at submaximal work loads during steady-state testing. In addition, they noted reduced physiological dead

6-Min walk distance only 34 19 15 14 51 12 13 58 (U) 55 (B) 35 7 39 32 40 96 32 20 98 27 to 47a 41 54 47 *32 (MS) *26 (VATSb) 3 *60 36 19 38 28 65 24% 18 26 (MS) 48 (VATS) 16 21 (MS) 35 (VATS) Cardiopulmonary exercise studies 20 15 45 59c 48 52

Reference

6-Min walk distance (% change) NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA

22 30 28

NA NA NA NA NA NA NA NA NA NA NA NA NA

41 52 43

Maximal VO2 (% change)

NA NA NA NA

Maximal work (% change)

Table 3 Studies Documenting Changes in Exercise Capacity After LVRS

17 31 31

NA

NA NA NA NA NA

NA NA NA NA NA NA NA

NA NA NA NA

Maximal VE (% change)

20 NA 39

NA

NA NA NA NA NA

NA NA NA NA NA NA NA

NA NA NA NA

VT (% change)

4 NA 4

NA

NA NA NA NA NA

NA NA NA NA NA NA NA

NA NA NA NA

fb (% change)

322 Martinez

NA NA 35 18 103 NA 39 (PaCO2 > 45) 23 (PaCO2 < 45) NA

6-Min walk distance (% change) Maximal VO2 (% change) 27 25 25 3 NA NA 25 11 NA

Maximal work (% change) * 100 46 48 20 NA 26 43 24 28 NA 27 29 30 NA NA 27 10 NA

Maximal VE (% change)

MS, median sternotomy; VATS, video-assisted thoracic surgery; fb, breathing frequency. a Stratiﬁed by emphysema heterogeneity on HRCT (see text for details). b 12-Min walk distance. c a1-Antitrypsin deﬁciency.

17

27 26 58 28 22 62 60

Reference

Table 3 Continued

25 43 34 25 20 NA 38 14 NA

VT (% change)

NA

15 0 12 4 22 NA NA

fb (% change)

Outcomes from LVRS 323

324

Martinez

space and PaCO2 during exercise. The improvement in exercise capacity correlated with the improvements in FEV1 and maximal inspiratory mouth pressure. Most recently, the short-term effects of LVRS on the pulmonary vascular response to exercise has been described by two groups (29,30). Neither noted signiﬁcant changes in pulmonary hemodynamics at rest or during exercise. However, Weg et al. (31) recently reported an elevation of resting pulmonary artery pressures in nine patients 3 months after bilateral LVRS. Clearly, further prospective data are required to better deﬁne these changes and their clinical signiﬁcance. D. Medication and Oxygen Requirements

Despite the variable effects on arterial blood gases, several groups have described improvements in oxygen requirement after surgery (4). Keenan et al. reported an elimination of oxygen requirement in 17% and a decrease in oxygen requirement in 25% of patients 3 months after unilateral LVRS. Similarly, Naunheim et al. (32) reported that 48% of patients had discontinued oxygen 3 months after unilateral LVRS. Others have reported similar data after unilateral LVRS (10,11,32–34). Cooper et al. (35) noted that 52% of patients were using oxygen continuously before surgery, but only 16% were doing so 6 months after bilateral LVRS; furthermore, 92% were using oxygen with exertion preoperatively, but only 44% were doing so postoperatively. Qualitatively similar data have been reported by other investigators (17,18,19,35,37–39). In the only randomized trial to examine bilateral versus unilateral LVRS, McKenna et al. (11) noted that 6 months after unilateral LVRS, 18 (36%) of the 50 patients requiring oxygen preoperatively did not require it postoperatively. In the bilaterally treated group, 30 (68%) of the 44 patients requiring oxygen preoperatively did not require it postoperatively. The difference between the two groups was signiﬁcant (P < .01). Unfortunately, these studies provide little description of the criteria for oxygen ‘‘requirement’’ before and after surgery. Furthermore, in many cases, follow-up study is incomplete, which could inﬂate the percentage of patients liberated from oxygen. Several groups have reported signiﬁcant rates of liberation from steroids after LVRS (3,12,18,32,33,35,36,40,41). Cooper et al. (36) examined the prednisone requirement in 56 of 76 patients eligible for 1-year follow-up study after bilateral LVRS. Preoperatively, 53% of patients required chronic steroid use, whereas the percentage decreased to 17% 6 months and 19% 1 year postoperatively. McKenna et al. (11) reported elimination of the steroid requirement in 54% of patients 6 months after unilateral LVRS and in 85% of patients after bilateral LVRS. The difference between the groups was signiﬁcant (P < .02). Unfortunately, the studies provide little detail

Outcomes from LVRS

325

regarding steroid reduction protocols or use of inhaled steroids, which limits the ability to interpret the data adequately. This is particularly true because objective improvement is seen in no more than 10% percent of COPD patients treated with chronic steroids (42). It is quite possible that many of these patients did not really need steroids before LVRS, but that an aggressive effort to wean them did not begin until after surgery. Further data must be prospectively collected before ﬁrm conclusions can be reached regarding the effect of LVRS on subsequent medication requirements. E.

Improvement in Dyspnea and Health-Related Quality of Life

Severe emphysema markedly impairs health-related quality of life (HRQL); in large part because of disabling dyspnea (43). Most investigators have reported improvements in dyspnea after LVRS, although only a few have used validated instruments to quantify the degree of improvement (Table 4). Using the Medical Research Council (MRC) dyspnea scoring system (44) to grade dyspnea, investigators have demonstrated signiﬁcant short-term improvements from a score of 2.9–4.1 before surgery to 0.8–1.8 after surgery (3,11–14,36,45–49). Other groups have used the transitional dyspnea index (TDI) of Mahler et al. (50). The range of improvement varies widely with TDI scores of 0.92–7.8 corresponding to decreases in dyspnea from minimal to dramatic (3,15,20,21,32,34,36,39,41,51). Data comparing varying surgical techniques are scant. Argenziano et al. (13) noted little change in dyspnea improvement as measured by the MRC scale after unilateral or bilateral LVRS. McKenna et al. (11) reported a greater percentage of patients with higher grade dyspnea (3–4 on the MRC scale) after unilateral (44%) compared with bilateral (12%) LVRS. In contrast, Wisser et al. (17) noted no difference in dyspnea improvement whether patients underwent LVRS via bilateral VATS or MS. Few groups have examined the independent effect of aggressive pulmonary rehabilitation as compared with LVRS. Cooper et al. (36) noted little change from baseline dyspnea (MRC grade 2.9) immediately after pulmonary rehabilitation (grade 2.8) compared with a signiﬁcant decrease after bilateral LVRS via MS (grade 1.2). As with spirometric data, the vast majority of dyspnea values have been reported only as mean improvements. Keller et al. (15) provided shortterm TDI scores in 25 patients after unilateral LVRS. Twenty-two of these patients demonstrated a change of þ3 or more; indicating consistent moderate improvement. The most detailed analysis of dyspnea after LVRS has been reported by Brenner et al. (46). These investigators measured the level of dyspnea using the MRC scale before and after thoracoscopic LVRS in 145 patients. The broad distribution of improvement in breathlessness is illustrated in

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Martinez

Table 4 Studies Quantifying Dyspnea or Health-Related Quality of Life Before and After LVRS Reference 3 11 41 36 15 71 32 51 45 34 38 39 12 13 17 46 35 20 26 58 22 18 47 48 28 62 60

Instrument used to quantify dyspnea TDI, MRC MRC MRC TDI, MRC TDI Fletcher TDI TDI TDI, MRC TDI TDI TDI MRC, Borg MRC TDI MRC NA TDI VAS NA TDI, VAS NA MRC MRC LOD NA NA

Instrument used to assess healthrelated quality of life SF-36, NHP SF-36 NA SF-36, NHP NA NA NA NA NA SF-36 NA NA NA NA NA NA CRQ NA NA SIP NA SF-36 NA NA SF-36 SG SIP

TDI, transitional dyspnea index (50); MRC, Medical Research Council (44); Fletcher (77); VAS, visual analog scale (107); LOD, level of dyspnea scale (108); SF-36, Medical Outcomes Study 36—Item Short-Form Health Survey (109); NHP, Nottingham Health Proﬁle (110); CRQ, Chronic Respiratory Disease Questionnaire (61); SG, St. George’s Respiratory Questionnaire (111); SIP, Sickness Impact Proﬁle (58); NA, Not available.

Figure 2. The baseline FEV1 correlated weakly with baseline dyspnea, and the change in FEV1 correlated poorly with the change in dyspnea (r ¼ 0.3). A better, inverse correlation was noted between improvement in dyspnea after LVRS and preoperative hyperinﬂation. Nevertheless, there were

Outcomes from LVRS

327

Figure 2 Distribution of improvement in MRC dyspnea score during short(acute) and long-term (>6 months, late) follow-up in 145 consecutive patients undergoing bilateral thoracoscopic stapled LVRS. The left axis demonstrates the proportion of patients demonstrating improvement in dyspnea while the right axis enumerates the total number. (From Ref. 46.)

several patients with severe hyperinﬂation (RV/TLC ratio above 0.7) who noted improved breathlessness after surgery (8 of 36 patients). In addition, although 37 patients (28%) had minimal or no improvement in FEV1 after surgery, 10 of these 37 noted an improvement by two or more dyspnea scores. This discrepancy between improvement in breathlessness and in FEV1 has been described by others. For example, Martinez et al. (22) found improved breathlessness in 17 patients after bilateral LVRS via MS, although 6 patients experienced a less than 20% improvement in FEV1 after surgery. A signiﬁcant correlation was noted between decreased breathlessness and decreased dynamic hyperinﬂation during exercise. Quantifying HRQL provides important additional information on the impact of COPD (52). These measurements add incremental information to

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the quantiﬁcation of breathlessness (53) and appear to be loosely correlated with increasingly severe disease (54). Because HRQL measures how a person enjoys life, it may be the most important of all functional measurements after LVRS. Only a few investigators have reported formal measurement of HRQL, as shown in Table 4. Furthermore, optimal information is obtained with the use of both a generic instrument and a disease-speciﬁc instrument (55). The generic instrument allows comparison with other illnesses, whereas the disease-speciﬁc instrument is more sensitive to changes in the prominent symptoms of that disease. However, no group has reported these data before and after LVRS. Cooper and colleagues (3,36) reported short-term improvements using the Medical Outcomes Survey—Short Form 36 (SF-36) and the Nottingham Health Proﬁle, generic instruments that have been validated in patients with COPD (52,53,56). Baseline values were in the range reported by others for patients with severe COPD. Improvements after LVRS were found in measures of vitality, social functioning, physical functioning, general health, and increased ability to perform various social roles. Although details were not reported, Hazelrigg et al. (34) noted improved HRQL measured with the SF-36 in 80% of patients after LVRS. The same group also found a similar short-term improvement after bilateral LVRS via VATS or MS (18). Ferguson et al. (28) reported improvement in HRQL measured by SF-36 after bilateral LVRS. The improvement in social functioning correlated well with the improvement in FEV1, and the improvement in exercise capacity correlated directly with improvement in physical functioning and inversely with dyspnea. The most detailed analysis has been published by Moy et al. (57). These investigators measured HRQL with the SF-36 before and after comprehensive pulmonary rehabilitation and again after bilateral LVRS via VATS in 19 patients. No signiﬁcant change was noted in any of the domains after pulmonary rehabilitation, although signiﬁcant improvement was noted in vitality after LVRS. When compared with the prerehabilitation scoring, the combination of rehabilitation and bilateral LVRS resulted in signiﬁcant improvement in four of the eight domains (physical functioning, role limitations due to physical problems, social functioning, and vitality). Pulmonary rehabilitation accounted for most of the improvement in role limitations, whereas LVRS accounted for most of the improvement in physical functioning, vitality, and social functioning. Cordova et al. (58) utilized the Sickness Impact Proﬁle (SIP) (59) before and after LVRS. They conﬁrmed signiﬁcant improvements in overall, physical, and social scores 3, 6, and 12 months after surgery. In a subsequent analysis by the same group, a similar degree of improvement in HRQL was noted in patients with hypercapnia as compared with those who were normocapnic before surgery (60).

Outcomes from LVRS

329

Disease-speciﬁc questionnaires may be more sensitive to changes than are general quality of life instruments. Reports of HRQL measured with disease-speciﬁc instruments are more limited. Bagley et al. (35) described changes measured with the Chronic Respiratory Questionnaire. This disease-speciﬁc questionnaire was the ﬁrst developed for use in patients with COPD (61) and has demonstrated responsiveness in therapeutic trials (52). During short-term follow-up, evaluation improvements were noted in the four domains of dyspnea, fatigue, emotional function, and mastery. Recently, Norman et al. (62) reported disease-speciﬁc measurement of HRQL using the St. George’s Respiratory Questionnaire. Large improvements were noted in scores within all sections, with a mean reduction in the total score of 31 points 3 months after bilateral LVRS via MS. F.

Randomized Studies

Geddes et al. (63) randomized 48 patients to continued medical therapy or LVRS (by MS or VATS) at a single hospital. All patients underwent pulmonary rehabilitation prior to randomization. Entry criteria were modiﬁed after 15 patients because of high early mortality (in both surgical and medical patients). There were ﬁve deaths in the surgical group and three in the medical group. Five of the 19 surviving surgical patients ‘‘had no beneﬁt after surgery.’’ Six medical patients crossed over to LVRS after 6 or more months and were excluded from analysis thereafter. During the ﬁrst 6 months before crossovers took place, the medical patients lost a median of 80 mL in their FEV1. The surviving LVRS patients gained 70 mL (P ¼ .02 medical vs. LVRS changes). Improvements compared with the medically treated patients also occurred in FVC, shuttle-walking distance, SF-36 quality of life scores, TLC, and RV. The study was not designed to demonstrate long-term effects, reﬁne selection criteria, or compare surgical methods. The beneﬁts seen in the LVRS patients as a group must also be weighed against the 10 of 24 surgical patients who either died or failed to beneﬁt from surgery (63). Criner et al. (64) enrolled 37 patients in a prospective randomized trial comparing LVRS by MS with 3 months of continued pulmonary rehabilitation at Temple University Hospital. All subjects began with 8 weeks of pulmonary rehabilitation. This produced a nonsigniﬁcant trend toward increased 6-min walk distance, signiﬁcant increases in maximal exercise test duration (5.8 + 1.7 to 7.4 + 2.1 min, P < .0001), and reduction in elements of the SIP scores. Among the 15 patients who then completed 3 additional months of rehabilitation, there were trends toward a further increase in 6-min walk distance but no further improvements in exercise time or SIP. There were no changes in pulmonary function at either time point.

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In contrast, 3 months after surgery, the patients undergoing LVRS had signiﬁcant increases in FEV1 (0.65 + 0.16 to 0.85 + 0.3 L) and FVC, decreased lung volumes, and decreased PaCO2. There were signiﬁcant further improvements in SIP as compared with the end of 8 weeks of rehabilitation. Positive trends in 6-min walk distance and exercise time did not reach statistical signiﬁcance. At 3 months, 11 of 15 medical patients elected to cross over to surgery. When they are included in the analysis of surgical results, changes in 6-min walk distance (282 + 100 to 337 + 99 ft) and exercise time (7.8 + 2 to 8.6 + 1.8 min) became statistically signiﬁcant. Overall surgical mortality was 9.4%. There were no increased hospitalization requirements in the 3-month follow-up period (64). Finally, Pompeo et al. (65) randomized 60 patients to LVRS or pulmonary rehabilitation in a multicenter trial. Patients with bullous emphysema were included, although those with giant bullae were excluded. The LVRS patients underwent either unilateral or bilateral operations by VATS. Importantly, patients were excluded if they had recently completed pulmonary rehabilitation, and rehabilitation was only offered to the medical arm. The medical arm saw signiﬁcant improvements in dyspnea, 6-min walk distance, and peak treadmill exercise workload. However, all of these improvements were signiﬁcantly greater in the surgical group (e.g., an increase of 93 + 24 vs. 31 + 8 m 6-min walk distance). The number of patients requiring oxygen decreased from 16 to 8 in only the surgical arm. Between 6 months and up to 24 months of follow-up study, 12 patients crossed over to LVRS. Only four surgical and ﬁve medical patients died in the 24-month follow-up period (65). These randomized trials conﬁrm the obvious; namely, that surgery improves pulmonary function, whereas pulmonary rehabilitation does not. However, the studies are important, because they clarify that the improvements in symptoms and exercise capacity following LVRS exceed those of rehabilitation alone. Furthermore, they provide some data on the natural history of the small subset of emphysematous patients who are candidates for LVRS. Their interpretation is highly constrained by the short follow-up period and large number of crossovers. The largest prospective randomized trial to date (n ¼ 140) is that of outcome from the high-risk subgroup of the National Emphysema Treatment Trial whose mortality ﬁgures were previously discussed (10). Because the analysis is limited to this high-risk group, the ﬁndings cannot be extended to other LVRS candidate pools. However, in patients with highrisk characteristics, the 30-day mortality was 16% in the surgical arm and zero in the medical arm (P < .001). Although statistical comparison is not provided, mortality at 6 months was *35% in the surgical arm and *8% in the medical arm. Surviving LVRS patients had greater improvements in

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exercise capacity, 6-min walk distance, and FEV1 than medically treated patients. There were no differences in Quality of Well-Being scores (P ¼ .51) Moreover, when death (more common in LVRS patients) and inability to complete testing (more common in the medical arm patients) were included as unfavorable outcomes, there were no differences between groups in exercise capacity, FEV1, 6-min walk, or Quality of Well-Being score. III.

Long-Term Results

A. Mortality

Data on long-term mortality are limited (see Table 1). The reported mortality during extended follow-up periods varies from 0 to 27%. The data presented by the Health Care Finance Administration (HCFA) to Congress in 1998 reported a 23% 12-month mortality and a 28% 18-month mortality (9). Brenner et al. (66) reported a prospective survival study of 256 consecutive patients with severe emphysema (mean FEV1 *25% of predicted) who underwent bilateral LVRS via VATS or MS. Standard survival analysis techniques indicated 1-year survival of 85%, whereas 2-year survival was 81%. Interestingly, patients with the greatest short-term improvement in FEV1 had the best long-term survival after surgery, as did those who were younger (70 years or less) and had a baseline FEV1 above 0.5 L and PaO2 above 54 mmHg. Comparison of these mortality ﬁgures with expected mortality in similar patient populations is difﬁcult, as discussed by Fessler and Wise (7). The majority of published data regarding survival in COPD have been collected in large epidemiological studies that include individuals with pulmonary hypertension, chronic bronchitis, bronchiectasis, and reactive airways disease, who would be excluded from LVRS. There may be a better prognosis in patients with predominantly ‘‘asthmatic bronchitis’’ as compared with those primarily with emphysema (67). However, the mean FEV1 in the emphysema group in that study was 47% of predicted, which is better than in patients considered for LVRS (see typical inclusion criteria enumerated in Table 5). The Nocturnal Oxygen Therapy Trial (NOTT) examined 203 patients with chronic airway obstruction, a mean FEV1 *30% of predicted, hypoxemia, and no other comorbid factor expected to inﬂuence survival (68). A total of 64 patients (31.5%) died during a mean of 19 months of follow-up study. The 1-year mortality was 11.9% in the group treated with continuous oxygen therapy. In the Intermittent Positive Pressure Breathing (IPPB) Trial, 985 nonhypoxemic patients with a postbronchodilator FEV1 of approximately 41% were followed for a mean of 34.7 months (69). Patient age and postbronchodilator FEV1 were the best predictors of mortality with 228

332 Table 5

Martinez Potential Indications and Contraindications for LVRS

Features

Indications Age < 75 yrs

Clinical Disability despite maximal medical treatment including pulmonary rehabilitation

Ex-smoker (>6 mo)

Physiological

FEV1 after bronchodilator <35–40% predicted

Contraindications Age >75–80 yrs Comorbid illness with 5-yr mortality >50% Severe coronary artery disease

Pulmonary hypertension (PA systolic >45, PAS mean >35 mmHg) Severe obesity or cachexia Surgical constraints: Previous thoracic procedure Pleuradesis Chest wall deformity FEV1 >50% predicted RV <150% predicted TLC <100% predicted

Hyperinﬂation TLC >120% predicted RV >200–250% Increased RV/TLC DLCO <50% predicted

Imaging

CXR: Hyperinﬂation CT: Marked emphysema with heterogeneity (upper lobe predominance is ideal) Isotope scan: Target areas for resection

DLCO <10% predicted PaCO2 >60 mmHg 6-Min walk <400 ft. after rehabilitation : Inspiratory resistance CXR: No hyperinﬂation CT: Minimal emphysema; homogeneous, severe emphysema Isotope scan: Absence of target zones

Source: Adapted from Refs. 4, 23, 78, and 98.

deaths (23%) at 3 years. Those patients older than 65 years with an FEV1 between 30 and 39% predicted experienced an annual mortality of approximately 12%. This increased to almost 20% if the FEV1 was below 30% of predicted. Unfortunately, only the study of Burrows et al. (67) examined prognosis speciﬁcally in patients with emphysema, and these

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patients had much milder cases than patients considered for LVRS. In the only study addressing patients considered to be appropriate candidates for LVRS, Meyers et al. (70) retrospectively compared a group of 22 patients denied surgery purely because of the withdrawal of Medicare funding with a group of 65 Medicare patients who underwent bilateral LVRS. There was no difference in baseline age, clinical status, or pulmonary function. During up to 3 years of follow-up evaluation, actuarial survival was 64% in the denied group compared with 83% of the LVRS patients. This difference in survival was not statistically signiﬁcant; however, and there was no 30-day surgical mortality reported. Minor deterioration was seen in spirometry in the denied group, whereas the LVRS experienced an *60% increase in FEV1 24 months after surgery. The limited sample size, lack of prospective data collection, and potential differences in other medical aspects of care limit interpretation. B. Pulmonary Function

Limited long-term (longer than 12 months) follow-up results after LVRS have been published, as shown in Table 1. Roue et al. (71) reported the results in 13 patients treated with varying surgical techniques (unilateral in 11 patients). Symptomatic improvement was noted in 12 of the 13 patients at 6 months, and FEV1 improved in the same 12 patients. Although data collection was incomplete, four of six patients for whom data were available maintained a >20% improvement in FEV1 at 2 years, but neither of two patients maintained improvement at 4 years. Cooper et al. (36) reported results of spirometry in their original 20 patients 24 months after bilateral LVRS. The baseline FEV1 had risen from 27% of predicted to 45% of predicted by 1 year and 42% of predicted 2 years after surgery. This group recently presented 3-year follow-up data on this same cohort of patients (72). Although data collection was not complete, a trend toward declining pulmonary function was conﬁrmed for the cohort as a whole by the second and third year. Nevertheless, the mean FEV1 at 3 years remained elevated compared with baseline values (1.04 + 0.54 vs. 0.83 + 0.26 L). Gelb et al. reported pulmonary function in 10 patients undergoing bilateral thoracoscopic stapling. Their FEV1 increased from 0.71 to 1.15 L at 6 months but decreased to 0.95 L 1 year postoperatively. In a slightly different group of patients from the same institution, a further slight drop in FEV1 was noted 24 months after surgery (74). Cassina et al. (47) reported 24-month follow-up data on a group of 12 patients with a1-antitrypsin related emphysema undergoing bilateral LVRS via thoracotomies and a group of 18 patients with non–a1-antitrypsin related emphysema undergoing LVRS via MS. Figure 3 demonstrates the time course of change in FEV1 for

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both groups. A decrement in pulmonary function was seen in both groups, although at a much faster rate in the a1-antitrypsin deﬁcient patients. Cordova et al. (58) reported follow-up data to 18 months after bilateral stapling via MS. The improvement in FEV1 appeared to be maintained in the six patients with 18-month data (baseline, mean FEV1 0.69 L compared with 0.91 L at 18 months), although signiﬁcant variability was noted. Gelb and colleagues (74) subsequently reported 5-year follow-up in a cohort of 26 patients who had undergone bilateral thoracoscopic LVRS. They reported clinically signiﬁcant (FEV1 >200 mL and/or FVC >400 mL) spirometric improvement in 73% at 1 year, 46% at 2 years, 35% at 3 years, 27% at 4 years, and 8% at 5 years. Mortality at these time points was 4, 19, 31, 46, and 58%. The largest and most detailed cohort reported is that of Brenner et al. (75), who published the rate of FEV1 change greater than 6 months after LVRS in a retrospective analysis of 376 patients undergoing LVRS over a

Figure 3 Serial change in FEV1 before and after bilateral LVRS in patients with a1-antitrypsin related emphysema (closed circles) and patients with smoker-related emphysema (open circles). *P < .05 versus corresponding baseline; {P < .05 versus alpha1-antitrypsin emphysema. (From Ref. 47.)

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2-year period at a single institution. Patients underwent unilateral laser resection via thoracoscopy (n ¼ 46), unilateral stapling via thoracoscopy (n ¼ 111), bilateral thoracoscopic stapling (n ¼ 184), bilateral stapling via MS (n ¼ 14), and the remainder a combination of unilateral thoracoscopic stapling and laser resection. Although the follow-up period was variable and a signiﬁcant amount of data were missing, Figure 4 illustrates the time course of improvement in FEV1. As numerous others have reported, the peak improvement in FEV1 was noted between 3 and 6 months after surgery. The greater improvement with bilateral procedures is also clear. These investigators noted a faster rate of fall in FEV1 (0.255+0.057 L/year) in those patients experiencing the greatest improvement in the initial 6 months after surgery (those treated with bilateral stapling). The lowest rate of decline in FEV1 appeared in those with the least initial improvement (those treated unilaterally). Fessler and Wise (7) have recently addressed the rapid annualized rate of decline in FEV1 after LVRS in comparison with

Figure 4 Serial FEV1 measurements in patients undergoing LVRS with varying surgical techniques. The dotted lines show the slope of deterioration in FEV1 from the 6-month average FEV1 based on the type of procedure. (From Ref. 79.)

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that expected in previously reported groups of patients with COPD (Fig. 5). The cause of the accelerated decline illustrated in Figure 5 remains speculative. These investigators highlight the difﬁculty in identifying a cohort of well-described COPD patients to serve as appropriate control subjects for this analysis. The need for a randomized trial of LVRS is strongly supported by these data. Similar limitations exist when examining the time course of response in lung volumes and DLCO. Cooper et al. (36) have reported 24-month followup data on their initial cohort of 20 patients. The initial decrease in RV and TLC appeared to have been maintained at 2 years of follow-up evaluation. Cordova et al. (58) reported decreases in RV and TLC 6 and 12 months after bilateral LVRS. These decreases appeared be maintained in the six patients in whom data were collected 18 months after surgery. Similarly, Gelb et al. (73) noted maintenance of the initial decrease in RV and TLC for up to 12 months after surgery, although a mild increase in both parameters

Figure 5 Annual loss of FEV1 (FEV1 slope) in patients with COPD or following LVRS. (From Ref. 7.)

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was shown between 18 and 24 months after surgery. The data of Cassina et al. (47) support these ﬁndings, with a nadir in RV and TLC 3–6 months after surgery, and a rise by 12 months and a further rise by 24 months after surgery. These latter data are limited by the missing follow-up evaluation in signiﬁcant numbers of patients. Given the importance of hyperinﬂation in the genesis of breathlessness in patients with COPD (22,77), further longterm data are required to deﬁne the potential clinical signiﬁcance of these rising lung volumes. C. Exercise Capacity

Limited data are available regarding long-term maintenance of improvements in exercise capacity. Cooper et al. (36) suggested maintenance of improvement in 6-min walk distance 24 months after surgery despite decrements in spirometry. Cordova et al. (58) found longer 6-min walk distance in six patients 18 months after surgery compared with preoperative values. On the other hand, Cassina et al. (47) suggest a gradual, albeit small, decline in 6-min walk distance 24 months after LVRS (Fig. 6). Little description is provided in these studies regarding continued participation in pulmonary rehabilitation after surgery. As a result, the long-term data regarding hall walk distance are difﬁcult to interpret given the known improvement in 6-min walk distance after rehabilitation (25). Similar limitations exist in examining long-term data regarding cardiopulmonary exercise testing (CPET). Cordova et al. (58) describe improvements in VO2 and VE over baseline in the 10 patients studied 12 months after surgery. Gelb et al. (74) describe a decrease in maximal VO2 and VE from 12 to 24 months after surgery in seven patients, although the 24-month values remained above the preoperative values (74). These data are limited by small numbers and varying or undescribed postoperative rehabilitation schedules. D. Medication and Oxygen Requirements

Few data exist regarding DLCO, arterial blood gas values, or oxygen requirements during long-term follow-up periods. The group at Washington University has reported data on a group of patients with up to 12 month postoperative follow-up periods (21). The results are illustrated in Figure 7. They found that 26% had a continuous oxygen requirement at baseline compared with no patients 12 and 24 months after bilateral LVRS. Also, 84% of patients at baseline required oxygen with exertion; this decreased to 5% 12 months after surgery and rose to 32% 24 months postoperatively. Gelb et al. (74) reported that two of seven patients still did not require oxygen 24 months after LVRS. These data are hampered by the uncertainty

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Figure 6 Serial change in 6-min walk distance (meters) before and after bilateral LVRS in patients with a1-antitrypsin related emphysema (closed circles) and patients with smoker-related emphysema (open circles). *P < .05 vs. corresponding baseline; {P < 0.05 vs. a1-antitrypsin emphysema. (From Ref. 47.)

of how oxygen requirements were determined by the investigators. Similar difﬁculties are encountered when examining steroid requirements after surgery. Cooper et al. (36) noted that 42% of their original cohort were steroid dependent at baseline. This percentage dropped to 6% 12 months after surgery and rose slightly to 11% 24 months after bilateral LVRS. E.

Improvement in Dyspnea and Health-Related Quality of Life

Data regarding long-term change in dyspnea after LVRS are quite limited. Using the Fletcher scale (77), Roue et al. (71) described improved dyspnea in 12 of 13 patients 6 months after LVRS. Eleven of the 13 patients maintained improvement for 12 months, 7 (54%) 18 months, 4 (31%) 24 months, and 4 (31%) 36 months after surgery. None of three eligible patients maintained an improvement in dyspnea 48 months after surgery. In the analysis detailed earlier, Brenner et al. (46) noted a similar distribution of improved dyspnea during long-term (>6 months after bilateral LVRS) and short-term follow-

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Figure 7 Supplemental oxygen requirement at rest and with exercise before (preop) and after bilateral LVRS. *P < .05 for all postoperative data versus preoperative data. (From Ref. 21.)

up study (see Fig. 2). A similar result was reported by Gelb et al. (74), who noted an improvement in dyspnea of one grade or more in 12 patients 1 year after LVRS and in 10 of 12 patients 2 years postoperatively. In contrast, Cassina et al. (47) noted an initial improvement in MRC dyspnea grade 3 months (grade 1.6) and 6 months (grade 1.5) after bilateral LVRS in non–a1antitrypsin related emphysema. The improvement in dyspnea waned 12 months (grade 1.7) and 24 months (grade 2.2) after surgery (47). In a cohort of 26 patients, Gelb (74) reported improvement in dyspnea 51 grade in 88% of patients at 1 year, 69% at 2 years, 46% at 3 years, 27% at 4 years, and 15% at 5 years. The worsening dyspnea was more pronounced in patients with lower lobe, a1-antitrypsin related emphysema. Data regarding long-term improvement in HRQL are few. Cordova et al. (58) reported maintenance of improvement in the Sickness Impact Proﬁle (SIP) in ﬁve of six patients with an 18-month follow-up period.

IV.

Patient Selection

Since the main beneﬁt from LVRS is believed to be related to the surgical relief of hyperinﬂation by removal of nonfunctioning lung, investigators have attempted to identify patients with lungs divisible into two anatomical

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compartments. One compartment comprises destroyed lung that takes up space but is nonfunctional and surgically accessible (79). The other compartment comprises emphysematous lung with relatively preserved function. Potential criteria to identify such patients are listed in Table 5, although none of these criteria have been prospectively validated and many remain controversial. A. Clinical Features

Medical and radiological evaluation for LVRS is described in Chapters 7 and 8. This chapter will focus on preoperative characteristics as predictors of outcome. As with classic bullectomy, the evaluation of the patient for LVRS aims to identify patients with emphysematous parenchymal destruction rather than primary airway disease. This can often be quite difﬁcult, although the presence of frequent respiratory infections and chronic, copious sputum production may be useful in identifying patients with primarily airway disease (1). In addition, the history and physical examination should attempt to identify features that could predict a higher mortality or a high likelihood of poor functional result. Although controversial, advanced age has been suggested as a predictor of increased mortality (10,21,34,79,80). However, other investigations have not conﬁrmed a higher risk in patients older than 75 years of age (80). Signiﬁcant comorbidity that will independently limit survival seems a reasonable contraindication (see Table 5). This could include advanced cancer or multiorgan disease. The presence of signiﬁcant coronary artery disease is frequently seen in this patient population (81), although it may not be an absolute contraindication to surgery. Preliminary data from our group suggest successful combined LVRS and cardiac surgery in a patient with signiﬁcant valvular disease and severe emphysema (82). Similarly, pulmonary hypertension has been reported to be a relative contraindication (79). Prohibitive pulmonary hypertension is infrequent in this patient population (83), and the impact of milder pulmonary vascular abnormality has not been prospectively studied (4). a1-Antitrypsin deﬁciency emphysema has been recently reported to be associated with less favorable outcome. Cassina et al. (47) compared 12 patients with a1-antitrypsin deﬁciency with 18 patients with typical smoking-related emphysema. Although short-term clinical and physiological responses were similar, the long-term response (12–24 months) was clearly poorer in a1-antitrypsin deﬁciency. Whether this is due to the presence of lower lobe emphysema or deﬁciency in a1-antitrypsin remains unclear. Clinical severity of disease has not proved to be an absolute contraindication. Patients who were prednisone-dependent (more than 10 mg/day, mean dose 24 mg/day) or

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who had failed pulmonary rehabilitation (the majority secondary to frailty) did not experience a poorer outcome in a study by Argenziano et al. (41). In fact, two groups have reported acceptable results in patients undergoing LVRS despite requiring mechanical ventilation because of acute respiratory failure (35,84). B. Physiological Factors

Most investigators have used pulmonary function testing to help identify optimal candidates for surgery. In contrast to classic bullectomy, most investigators agree that a postbronchodilator FEV1 greater than 40–45% of predicted does not justify the risks of LVRS (see Table 5). However, a lower limit of FEV1 that identiﬁes individuals at prohibitive risk has not been agreed upon. Indeed, some groups have demonstrated acceptable short-term results in patients with severely decreased FEV1. Argenziano et al. (41) noted acceptable spirometric and functional improvements in patients with an FEV1 below 500 mL (mean 368 mL), which is similar to data of others (12,81). If the mechanism of improvement in spirometry relates to improvement in elastic recoil (85), those patients with airﬂow obstruction from structural emphysema should be among the ones most likely to beneﬁt from LVRS. Although a marked bronchodilator response has been touted by some as a spirometric method of identifying primarily airway disease, this has not been rigorously tested. In fact, a signiﬁcant bronchodilator response has been found in a substantial proportion of patients with emphysema (86). Izquierdo-Alonzo et al. (87) compared bronchoreversibility in patients with normal DLCO and in those with a low DLCO. In the latter group, less reversibility was noted, which suggests a different pathophysiological lesion. In an effort to identify better individuals with airway disease, Ingenito et al. (23) measured inspiratory resistance in patients undergoing thoracoscopic LVRS. In a multivariate analysis, only those patients with low inspiratory resistance demonstrated short-term improvements in FEV1. A linear correlation could be demonstrated between resistance and the change in FEV1 during short-term follow-up observation (Fig. 8). This suggests that LVRS should not be offered to patients when the pathophysiological basis of obstruction is primarily airway in nature. However, in individual patients, this clinical distinction may be quite difﬁcult. Since LVRS reduces hyperinﬂation, some investigators have advocated its performance only in those patients with a signiﬁcant elevation of TLC (78), although the RV and RV/TLC ratio may be better theoretical predictors of response (88). Indeed, preliminary data have suggested that an elevated RV/TLC ratio may be the best physiological parameter to identify

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Figure 8 The correlation between preoperative inspiratory lung resistance and the change in FEV1 6 months after bilateral LVRS is illustrated. (From Ref. 23.)

patients who may be expected to obtain improved quality of life (8), pulmonary function, and exercise capacity after bilateral LVRS (89,91). Thurnheer et al. (49) have recently conﬁrmed the importance of physiological hyperinﬂation at baseline in predicting improvement in FVC after bilateral LVRS. Given the importance of hyperinﬂation in the genesis of dyspnea in patients with COPD, these ﬁndings would be expected (76). Several investigators have suggested that an extremely low DLCO increases surgical risk (15,34,93). Keenan et al. (15) found an unfavorable outcome (death or length of stay longer than 30 days) in those patients with a DLCO 25% of predicted or lower, particularly if associated with hypercapnia (PaCO2 above 50 mmHg) (15). Hazelrigg et al. (34) noted a

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lower DLCO (26.5 vs. 38.1% of predicted) in those patients dying after LVRS. However, other investigators have not conﬁrmed these ﬁndings (80). As noted above, a recent report from the National Emphysema Treatment Trial documented increased postoperative mortality with patients with an FEV1 <20% predicted and either a DLCO <20% predicted or homogeneously distributed emphysema on CT scan. McKenna et al. have suggested poor outcomes in patients with severe hypoxia (14). However, a subsequent analysis by the same group noted no worse outcome in patients with a PaO2 below 50 mmHg (80). Several groups have found worse outcome and higher mortality in patients with hypercapnia (15,28,34,93). As mentioned earlier, Keenan et al. (15) noted a poor outcome in those patients with a PaCO2 above 50 mmHg (6 of 10 patients died or experienced prolonged hospital stay compared with 5 of 28 normocapnic patients). This was particularly likely if both an elevated PaCO2 and low DLCO were present (ﬁve of six patients experiencing a bad outcome). Similarly, Hazelrigg et al. (34) noted a higher PaCO2 (mean 48 mmHg) in those patients dying after LVRS compared with those surviving (mean PaCO2 42.5 mmHg). Szekely et al. (93) compared a group of patients experiencing a bad outcome after LVRS (length of stay more than 3 weeks or death within 6 months) with a group experiencing an acceptable outcome. If either PaCO2 was above 45 mmHg or 6-min walk distance was less than 200 m before surgery, a poor outcome was more likely (6 of 16 patients died vs none of the 25 patients in the second group). On the other hand, Argenziano et al. (41) noted an acceptable surgical outcome in a group of nine patients with a PaCO2 >55 mmHg (mean 67 mmHg). Likewise, O’Brien et al. (60) compared results after bilateral LVRS in 15 patients with a PaCO2 >45 mmHg (mean 58 mmHg) normocapnic patients (mean 41 mmHg). They found no difference in clinical or physiological outcomes during short or longer term follow-up evaluation. Preoperative exercise capacity has been examined as a predictor of outcome in a limited number of investigations. Hazelrigg et al. (34) conﬁrmed a lower 6-min walk distance in those patients dying after thoracoscopic laser LVRS (356 vs. 714 ft). As mentioned earlier, Szekely et al. (93) noted a greater likelihood of poor outcome after bilateral LVRS if the initial 6-min walk distance was <200 m, particularly if this was associated with hypercapnia. Maximal VO2 has demonstrated only a loose correlation with the change in aerobic capacity after LVRS (48). It has not proved to be a reliable predictor of LVRS outcome, although there are data suggesting that maximal VO2 may predict complications after thoracotomy for resection of suspected lung cancers (94).

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Martinez C. Imaging

Thoracic imaging has assumed a primary role in the evaluation of patients for LVRS. Most authorities consider topographical heterogeneity to be a prerequisite for optimal response from LVRS (4). In an early study, Brenner et al. (92) noted greater spirometric improvement in patients with upper lobe predominant emphysema. Similar results were reported by McKenna et al. (11) in patients undergoing unilateral LVRS. In a more detailed analysis, McKenna’s group examined results in 138 patients surviving bilateral LVRS (80), of whom 106 of the patients (77%) had upper lobe predominant emphysema, whereas 10 (7%) had lower lobe predominant emphysema and 22 (16%) had diffusely homogeneous emphysema. The greatest improvement in FEV1 was noted in those patients with upper-lobe emphysema (73 percent), although those patients with homogeneous emphysema experienced a 38% improvement. More detailed, CT data have been provided by the group at Washington University in St. Louis. Slone et al. (95) used a semiquantitative scoring system to characterize the upper-lobe predominance of emphysema, lung compression, and the percentage of normal or mildly emphysematous lung. In the 47 surviving patients of 50 total, greater postoperative improvement was found in those patients with upper lobe predominant emphysema and in patients with more heterogeneous emphysema, more compressed lung, and a larger percentage of normal and mildly emphysematous lung. The combination of upper-lobe severity and the percentage of mildly emphysematous or normal lung were the best predictors of improved FEV1 (r2 ¼ 0.49). The same group has conﬁrmed qualitatively similar results using a quantitative high resolution CT measure of emphysema heterogeneity (96). A quantitative, computerized scoring system based on helical CT has been shown by our group (97) to provide an accurate index of emphysema heterogeneity. A high index indicating upper lobe predominant emphysema was the single best predictor of short- and long-term physiological improvement after bilateral LVRS in one preliminary report (90). Using a qualitative emphysema scoring system, Weder et al. (98) conﬁrmed the value of emphysema heterogeneity but also noted improvement in patients with homogeneous disease. Figure 9 illustrates the 34% improvement in FEV1 noted in patients with homogeneous emphysema compared with a 44% improvement in those patients with intermediately heterogeneous emphysema and an 81% improvement in those with markedly heterogeneous emphysema. However, a similar improvement in dyspnea was noted in all three groups. Similar ﬁndings have been reported by Wisser el al. (99). These data are in contrast to the theoretical model

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Figure 9 Change in FEV1 3 months after bilateral thoracoscopic LVRS. The patients are grouped by the qualitative distribution of emphysema on high-resolution CT. Group A had predominantly homogeneous disease; group B had intermediately heterogeneous disease; group C had markedly heterogeneous disease. The P values correspond to comparisons of preoperative with postoperative values. (From Ref. 99.)

described by Fessler and Permutt (88), which would indicate that disease heterogeneity is a relatively unimportant factor in spirometric improvement after LVRS. Isotope studies have been used to identify areas of decreased perfusion, which represent potential surgical ‘‘target zones’’ (100). Some investigators have suggested that functional heterogeneity can be assessed by this technique (101–103). Wang et al. (101) reported the results of qualitative scoring of perfusion in 103 patients undergoing bilateral LVRS. In the 96 survivors, short-term improvement in FEV1 correlated best with the extent of upper-lobe predominance of decreased perfusion, although the correlation was weak (r ¼ 0.38). Ingenito et al. (104) characterized 48 patients as having heterogeneous upper lobe, homogeneous, or heterogeneous lower lobe emphysema based on the ratio of upper to lower lobe perfusion. Patients with heterogeneous upper lobe disease tended to increase FEV1 more, but there was substantial overlap with patients with homogeneous disease. Heterogeneous lower lobe patients did poorly, but there were only 4 patients among the 48 studied. Recently, Thurnheer et al. (49) have compared qualitative assessment of emphysema heterogeneity on high-resolution CT with qualitative assessment of impaired perfusion on

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lung scanning. Those patients with homogeneous perfusion experienced less short-term improvement in FEV1 (23%) compared with those demonstrating intermediately heterogeneous perfusion (38%) and markedly heterogeneous perfusion (57%). Importantly, in multivariate analysis, preoperative hyperinﬂation and emphysema heterogeneity on high-resolution CT proved to be more powerful predictors of improvement after bilateral LVRS than perfusion scanning. A potential role for scintigraphy in identifying surgical target zones for resection in patients with more homogeneous emphysema on high-resolution CT could not be excluded. V.

Summary

Over the past decades, extensive literature has been published regarding surgical therapies for advanced COPD (103). The most widely accepted have been directed at surgical relief of hyperinﬂation; namely, bullectomy and LVRS. Bullectomy is an established surgical technique for a very limited number of patients, whereas LVRS in the absence of giant bullae could be an option for a signiﬁcantly larger number of patients. The initial enthusiasm has been tempered by major questions regarding the optimal surgical approach, safety, selection criteria, and conﬁrmation of long-term beneﬁts (105). In fact, the long-term follow-up reports on patients undergoing classic bullectomy should serve to caution against unbridled enthusiasm for the indiscriminate application of LVRS. The patients with the poorest long-term outcome despite favorable short-term improvements after bullectomy have consistently been those with the worst pulmonary function and signiﬁcant emphysema in the remaining lung. These patients appear to be remarkably similar to those currently being operated on for LVRS. It is hoped that data collected from ongoing randomized trials will place the role of LVRS in a clear perspective for the physician caring for patients with advanced COPD. References 1. 2.

3.

Martinez F. Diagnosing chronic obstructive pulmonary disease. Postgrad Med 1998; 103:112–125. ACCP/AACVPR Pulmonary Rehabilitation Guidelines Panel. Pulmonary rehabilitation. Joint ACCP/AACVPR evidence-based guidelines. Chest 1997; 112:1363–1396. Cooper J, Trulock E, Triantaﬁllou A, et al. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995; 109:106–116.

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5. 6. 7. 8.

9.

10. 11.

12.

13.

14.

15.

16.

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18.

19.

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90. Flaherty KR, Kazerooni EA, Curtis JL, Iannottoni M, Lange L, Schork A, Martinez FJ. Short-term and long-term outcomes after bilateral lung volume reduction surgery. Prediction by quantitative CT. Chest 2001; 119:1337–1346. 91. Kurosawa H, Hida W, Kikuchi Y, Okabe S, Ogawa H, Ebihara S, Wu D, Oikawa M, Takahashi T, Shirato K. Hyperinﬂation estimated by residual volume can predict beneﬁt of lung volume reduction surgery in patients with emphysema. Am J Respir Crit Care Med 1997; 155(suppl):A605. 92. Brenner M, Kayaleh R, Milne E, Della Bella L, Osann K, Tadir Y, Berns M, Wilson A. Thoracoscopic laser ablation of pulmonary bullae: radiographic selection and treatment response. J Thorac Cardiovasc Surg 1994; 107:883– 890. 93. Szekely L, Oelberg D, Wright C, Johnson D, Wain J, Trotman-Dickenson B, Shepard J, Kanarek D, Systrom D, Ginns L. Preoperative predictors of operative morbidity and mortality in COPD patients undergoing bilateral lung volume reduction surgery. Chest 1997; 111:550–558. 94. Martinez F, Paine R, Pass H, Mitchell J, Johnson D, Turrisi A. Medical evaluation of the patient with potentially resectable lung cancer. In: Lung Cancer: Principles and Practice. Philadelphia: Lippincott-Raven 1996, pp 511– 534. 95. Slone R, Pilgram T, Gierada D, Sagel S, Glazer H, Yusen R, Cooper J. Lung volume reduction surgery: Comparison of preoperative radiologic features and clinical outcome. Radiology 1997; 204:685–693. 96. Gierada D, Slone R, Bae K, Yusen R, Lefrak S, Cooper J. Pulmonary emphysema: comparison of preoperative quantitative CT and physiologic index values with clinical outcome after lung-volume reduction surgery. Radiology 1997; 205:235–242. 97. Kazerooni E, Whyte R, Flint A, Martinez F. Imaging of emphysema and lung volume reduction surgery. Radio Graphics 1997; 17:1023–1036. 98. Weder W, Thurnheer R, Stammberger U, Burge M, Russi E, Bloch K. Radiologic emphysema morphology is associated with outcome after surgical lung volume reduction. Ann Thorac Surg 1997; 64:313–320. 99. Wisser W, Klepetko W, Kontrus M, Bankier A, Senbaklavaci O, Kaider A, Wanke T, Tschernko E, Wolner E. Morphologic grading of the emphysematous lung and its relation to improvement after lung volume reduction surgery. Ann Thorac Surg 1998; 65:793–799. 100. Naunheim K, Ferguson M. The current status of lung volume reduction operations for emphysema. Ann Thorac Surg 1996; 62:601–612. 101. Wang S, Fischer K, Slone R, et al. Perfusion scintigraphy in the evaluation for lung volume reduction surgery: correlation with clinical outcome. Radiology 1997; 205:243–248. 102. Jamadar D, Kazerooni E, Martinez F, Whyte R, Wahl R. Semi-quantitative ventilation/perfusion scintigraphy and single photon emission computed tomography for evaluation of lung volume reduction surgery candidates: Description and prediction of clinical outcome. Eur J Nucl Med 1999; 26(7):734–742.

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17 Mechanisms of Improvement Following Lung Volume Reduction Surgery

NOAH LECHTZIN and HENRY E. FESSLER Johns Hopkins Medical Institutions Baltimore, Maryland, U.S.A.

I. Introduction In the earliest reports of lung volume reduction surgery (LVRS) for emphysema, Brantigan et al. (1) claimed short-term symptomatic beneﬁts but reported no objective ﬁndings. They cited Laennec, who had speculated that a procedure that could diminish alveolar distension would lessen the problems of hyperinﬂation (2). Brantigan suggested three mechanisms to explain the improvement after LVRS: increased radial traction on the airways, restoration of more normal conﬁguration of respiratory muscles, and increased recoil of the lung. Forty years of research have not proved Laennec was incorrect, but have expanded greatly on his speculations. Contemporary studies have shown numerous beneﬁcial effects from LVRS. These include improvements in spirometry, respiratory muscle function, gas exchange, symptoms, exercise capacity, and quality of life (3–9). Although these outcomes have generated much enthusiasm, this is tempered by the wide variability of outcomes between centers and between patients at the same institution. Additionally, the few long-term follow-up studies have shown a relatively rapid decline in pulmonary function following the initial improvement. This chapter will review the mechanisms 355

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Table 1

Selected Reported Outcomes Following LVRS

Variable

Range of reported mean change

Reference

Spirometry FEV1 FVC

33–82% increase 13–27% increase

3,16 3,50

Respiratory muscle function PDImax

38–53% increase

7,29

Gas exchange PaO2 PaCO2 DCO

1–8 mmHg increase 1–6 mmHg decrease 0–2-fold increase

9,3 8,29 4,6,9,44

Symptoms Dyspnea

3.6 decrease Borg scale

6

Exercise capacity Work 6-Min walk

20–41% increase in watts 15–18% increase in distance

8,9 8,9

that have been proposed to explain the beneﬁts of LVRS as well as the variability of beneﬁt between patients. A detailed review of the reported outcomes following LVRS can be found in Chapter 15. A brief summary of these ﬁndings is presented in Table 1. This is not meant to be a comprehensive review of all studies, but will serve as framework for the discussion that follows. II.

Spirometry

A. Traditional Paradigm

Although emphysema is deﬁned histologically, its functional hallmark is expiratory airﬂow limitation. Many of the complications of emphysema such as air trapping, hyperinﬂation, respiratory muscle dysfunction, dyspnea, and hypoventilation stem from progressive ﬂow limitation. Destruction of lung parenchyma and elastic elements in emphysema decreases elastic recoil of the lung. Airﬂow limitation in emphysema is traditionally explained, at least in part, by this loss of elastic recoil (10). Pride et al. (11) described a model of ﬂow limitation in which the airways are divided into two segments. The S segment represents the conducting airways from the alveoli up to and including the collapsible site

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at which ﬂow limitation occurs. P0TM is the transmural pressure at which the collapsible segment closes. A higher P0TM indicates an airway with greater tendency to close; that is, one requiring a higher transmural pressure to prevent closure. Maximal airﬂow during forced expiration (Vmax) is determined by the pressure difference between the transmural alveolar pressure (equal to lung elastic recoil pressure, PEL) and P0TM, divided by the resistance upstream of the locus of P0TM (RS): Vmax ¼

PEL P0TM Rs

ð1Þ

Since lung elastic recoil (PEL) is reduced in emphysema, it follows that maximal ﬂow will be reduced. Furthermore, airway caliber is dependent in part on the radial traction from the lung parenchyma in which the airways are invested (12). The decrease in this radial traction in emphysema increases airway resistance at any lung volume and increases the lung volume at which the airways close (increased P0TM). In addition to decreases in elastic recoil, patients with emphysema frequently have coexisting intrinsic airway disease (13). Finally, the destroyed lung parenchyma includes small airways, so that the number of parallel pathways for airﬂow is decreased. The physiology of airﬂow limitation in emphysema has been discussed in greater detail in Chapter 3. The most frequently cited mechanism for improvement in expiratory airﬂow after LVRS is increased elastic recoil (4,5,14–16). As will be detailed in Section II.B, we believe this simple explanation is incorrect. However, we begin by reviewing the data in its support. The role of elastic recoil in LVRS was ﬁrst investigated by Gelb et al. in 1996 (4). They studied 12 patients who underwent LVRS by bilateral video-assisted thoracoscopy (VATS) and applied the concepts of airﬂow limitation of Pride et al. (11) and Mead et al. (13) to the data. Using plethysmography to measure lung volume and esophageal balloons to estimate lung elastic recoil, they plotted the relationship between maximum expiratory ﬂow and static elastic recoil pressure before and after surgery (termed the maximal ﬂow/static recoil relation, MFSR). The slope of this relationship represents the conductance of the segment upstream from the ﬂow-limiting site (the S segment), and its zero-ﬂow intercept on the pressure axis indicates P0TM. Following surgery, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) increased. The MFSR curves extended further to the right after surgery, indicating greater maximal recoil pressure (Fig. 1). Elastic recoil at total lung capacity (TLC) was normalized to lung volume and expressed as the coefﬁcient of retraction: the elastic recoil at TLC divided by TLC. Multiple linear regression revealed correlation between the improvement in FEV1 and

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Figure 1 Idealized maximum ﬂow–static recoil (MFSR) curve drawn from data in reference 4. These relations are determined by separately measuring static recoil/lung volume and maximal airﬂow/lung volume. Prior to surgery, maximal airﬂow is reduced at any recoil pressure. After LVRS, the relationship improves toward normal.

postoperative increases in the coefﬁcient of retraction (r ¼ 0.70; P < .05). In an intraoperative study with patients under anesthesia and paralysis, Gelb et al. (14) demonstrated similar improvements in elastic recoil and associated reductions in airway resistance. This ﬁnding supports the concept that increases in elastic recoil cause the improvements in airﬂow. Further support for this conclusion came from a study by Ingenito et al. (16). This study sought preoperative predictors of successful outcome from LVRS: deﬁned by improvement in FEV1. They divided their 29 consecutive patients into 15 responders whose FEV1 increased by 0.2 L or 12% above baseline (the American Thoracic Society deﬁned bronchodilator response) and 14 whose improvement did not meet this threshold. The groups had similar baseline FEV1, FVC, TLC, and residual volume (RV). By univariate analysis, the responders were found to have lower static recoil pressure at TLC (8.1 + 3.1 vs 10.6 + 2.3). Since patients with lower baseline elastic recoil improved more from surgery, this suggests improvement in FEV1 is at least partially due to increases in elastic recoil. However, recoil pressure was not an independent predictor of FEV1 improvement by regression analysis, whereas low airway resistance was. This could indicate that, rather than being a determinant of outcome, low recoil pressure at a

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given FEV1 is merely closely associated with other favorable factors such as low airway resistance. Another frequent ﬁnding following LVRS that can contribute to improved expiratory ﬂow is decreased airway resistance. In the already cited study by Gelb et al. (4) P0TM and conductance of the S segment (Gs) was determined from the MFSR plot. The value of P0TM was estimated by extrapolation of the slope of the MFSR curve between 30 and 50% of vital capacity (VC) to the pressure axis intersection, at which Vmax is zero. Gs, the reciprocal of resistance, was calculated from Equation 1. Gelb et al. found a signiﬁcant increase in Gs and decrease in P0TM following LVRS. This is shown in Figure 1, respectively, by the counterclockwise rotation and leftward shift of the MFSR curve after LVRS. Multiple linear regression analysis revealed correlation between the improvements in FEV1 and in Gs (r ¼ 0.7; P ¼ .05). The decrease in P0TM (less collapsible airways) suggests that airways may be tethered open by radial traction. The decrease in P0TM could also reﬂect movement of the collapsible segment further upstream; this is, more distally in the airway. This would shorten the S segment and thereby increase Gs. Ingenito et al. (16) measured lung resistance prior to surgery using the equation of motion, which divides the resistive component of esophageal pressure during tidal breathing by inspiratory ﬂow. They found that preoperative inspiratory resistance correlated inversely with the postoperative change in FEV1 (r ¼ 0.63; P < .001). If inspiratory resistance reﬂects intrinsic airway disease, this ﬁnding indicates that those with more substantial airways disease are less likely to beneﬁt from LVRS than are those with only emphysematous parenchymal changes. Hoppin (17) used ﬂow–volume and pressure–volume data from himself (normal control) and an emphysematous patient as a baseline from which to predict mathematically the results after hypothetical LVRS. This analysis predicted increased expiratory ﬂows after surgery at equal lung volume. It also predicted greater improvement in ﬂows in the patient than in Hoppin, and somewhat better results if nonventilating lung (i.e., bullae) was removed than if diffusely diseased lung was removed. Improved inspiratory muscle function was speculated upon but not explicitly included in the mathematical model. Furthermore, the model predicted decreased VC, peak ﬂows, and FEV1 after surgery. This contrasts with the empirical ﬁndings. In a follow-up study, Ingenito et al. measured the determinants of maximal expiratory ﬂow from Pride et al. (11) in 37 patients before and 6 months after bilateral LVRS (18). For the group as a whole, there was a signiﬁcant increase in maximal recoil pressure but no change in resistance of the upstream segment, P0TM, lung compliance, or the product of lung compliance and upstream resistance, the time constant of lung emptying.

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About half of their patients had a positive response to LVRS: deﬁned as an increase in FEV1 of at least 150 mL or 12%. Among these responders, there was a signiﬁcant increase in maximal recoil pressure and decrease in time constant (although no change in the components of the time constant, resistance, and compliance). The failure upstream resistance and P0TM to improve contrasts with the ﬁndings of Gelb et al. (4). B. An Alternative Paradigm

Although elastic recoil sometimes increases and resistance sometimes decreases following LVRS, these changes cannot, in themselves, fully explain the reported improvements in spirometry. Likewise, resecting lung, even in an excised lung, will inevitably increase recoil and expiratory airﬂow at the same lung volume. Consideration of these lung properties alone will not explain why only some patients improve after LVRS. One spirometric ﬁnding which has been consistently demonstrated but little noted is an increase in VC. It is not obvious how removing lung could increase the amount of air that can be exhaled. Furthermore, the relationship between increased elastic recoil and increased VC is complex. For example, removing 30% of lung tissue from a patient with interstitial ﬁbrosis would certainly increase elastic recoil, but would also certainly decrease the VC. Therefore, there must be characteristics of emphysema that allow the removal of lung to increase the VC. A comprehensive analysis of the spirometric effects of LVRS must identify those characteristics and account for increases in both FEV1 and FVC. This requires consideration of both the lung and chest wall properties. Fessler and Permutt (19) have proposed an alternative model in which mechanisms other than loss of recoil may be responsible for airﬂow limitation in emphysema and its improvement following LVRS. Analyzing a series of patients with alpha1-antitrypsin deﬁciency reported by Black et al. (20), they found that FEV1 was not correlated at all with the loss of elastic recoil. Instead, FEV1 correlated closely with RV/TLC. The nonsmoking patients with early a1-antitrypsin deﬁciency already had low recoil, but FEV1 and VC were well preserved. It was only with age and accumulated smoking history that FEV1 fell, and the RV/TLC ratio rose, unaccompanied by any further change in recoil. The increased RV/TLC ratio is due to destruction of normal lung tissue which is replaced by cysts and bullae. These act as space-ﬁlling holes within the lungs. They do not contribute to elastic recoil, and their volume changes minimally between RV and TLC. These space-ﬁlling holes enlarge the lung and create a mismatch between the size of the lung and the size of the chest wall. It is to this mismatch, rather than to the decrease in elastic recoil per se,

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that Fessler and Permutt largely attribute the decreased VC and FEV1 in emphysema. This recalls the view of Brantigan et al., who had described emphysema as the state of a 7-L lung being forced into a 5-L chest (1). Since VC is the volume between TLC and RV, analysis of the determinants of those volumes will lend insight into how LVRS can increase the difference between them. Residual volume in adults is the volume when all airways are closed. In emphysema, this occurs when elastic recoil is near zero, and includes the volume of cysts and bullae incapable of emptying. Total lung capacity is not determined solely by lung properties, but is the volume at which the pleural pressure generated by maximal inspiratory muscle activity balances the inward recoil of the lung and bony thorax. The interaction between lung recoil and inspiratory muscle capacity can be expressed graphically as in Figure 2, in which pleural pressure is plotted on the abscissa against lung volume on the ordinate. The lines in Figure 2A represent a hypothetical patient with emphysema. Line AX is the lung elastic recoil, and its intercept on the volume axis (point A) is RV. Line BX reﬂects the inspiratory muscle and chest wall properties, and has been linearized for simplicity. It indicates the maximal negative pleural pressure that can be achieved at any lung volume, as measured with the airway occluded and a patient making maximal inspiratory efforts at that volume. This pressure is strongly dependent on volume because of the impediments to inspiratory muscle action caused by increased lung volume. Total lung capacity (point X) is reached where the declining pressure that inspiration can generate intersects the increasing recoil of the lungs. Figures 2B and 2C show the effects of LVRS in this patient with resection of one-third of the lung. LVRS could be performed in one of two ways. First, the patient could have perfect target areas for resection that are completely cystic and do not contribute to lung recoil, like the ‘‘nonventilating lung’’ in the model of Hoppin (17). The operation would then decrease lung volume but would not change lung compliance. The slope of the lung elastic recoil versus pleural pressure curve would not change, but it would be shifted downward by the loss of volume, as in Figure 2B. At the other extreme, the patient with diffuse emphysema undergoing LVRS would have lung removed that had mechanical properties identical to those of the lung left behind. In addition to the reduction in residual volume, the slope of the relationship between lung volume and pleural pressure (static compliance) would be proportionally depressed. This is shown in Figure 2C. Note that elastic recoil at TLC, the horizontal distance from the ordinate, increases in both cases. Although it increases even more in the latter situation, VC rises somewhat less. The coefﬁcient of retraction (PTLC/TLC) rises in both cases. Although recoil must increase when lung is removed, the increase is largely irrelevant to the increase in VC.

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Figure 2 (A) Relationship between lung recoil and recoil of the chest wall during maximal inspiratory efforts. Line AX represents the static negative pleural pressure necessary to inspire to a given lung volume. This is the mathematical inverse of lung recoil pressure, and the slope is the inverse of lung compliance. Point A is residual volume. Line BX represents the maximal static negative pleural pressure that the inspiratory muscles are capable of generating. These lines intersect at total lung capacity (X), where the maximal outward recoil of the chest wall equals the inward recoil of the lungs. Vital capacity (VC) is indicated. For simplicity and clarity, these lines have been linearized and there is no airway tone. (B) Dotted line shows the theoretical effects of LVRS with removal of pure ‘‘target areas,’’ cysts which contribute no elastic recoil. There is a decrease in residual volume, increase in elastic recoil pressure at total lung capacity and in vital capacity, and no change in lung compliance (slope). (C) Dotted line shows the theoretical effects of LVRS with removal of lung whose characteristics are exactly like those of the lung left behind. There is a decrease in both residual volume and lung compliance. Elastic recoil pressure at total lung capacity increases more than in 2(B), but VC increases less. (D) Theoretical effects of LVRS in a patient lacking characteristics of emphysema; baseline residual volume and lung compliance are low, chest wall function is unchanged. In this ‘‘patient,’’ LVRS reduces VC.

Indeed, ‘‘improvement’’ in lung compliance detracts from any increase in VC that would be obtained. Finally, Figure 2D shows the effects of LVRS in a patient with the same chest wall properties, but different baseline lung properties. In this patient, removal of the same one-third of lung decreases vital capacity.

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Figure 2 Continued.

Mathematical analysis reveals two characteristics of the lung that favor an increase in VC when lung is resected: an elevated RV and elevated lung compliance. These, of course, are prominent features of emphysema. Of the two lung factors, increased RV is by far the more inﬂuential.

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Figure 2 Continued.

The improvement in FEV1 following LVRS is attributable, in whole or in part, to this increase in VC. This may be seen more clearly by restating FEV1 in the terms of this simple equation: FEV1 ¼

FEV1 6VC VC

ð2Þ

Increases of either factor in Equation 2 will increase FEV1. The ﬁrst factor, FEV1/VC, describes the rate of lung emptying, and the second describes the volume that can be emptied. The determinants of the rate of emptying are the compliance of the lung and the resistance of the airways, which constitute the time constant. Removal of a portion of the lung could change these determinants in opposing directions: The decreased compliance (from removal of the parenchyma) may be accompanied by increased resistance (from removal of parallel conducting airways). Alternatively, as demonstrated by Gelb et al. (4), LVRS may change compliance and resistance in the same direction and decrease the time constant (18). This could occur if increased radial traction distended remaining airways in excess of the effects of loss of parallel channels. Application of Equation 2 allows one to partition the change in FEV1 following LVRS into its components. Some series have found increases in FEV1 that are proportionally greater than the changes in FVC (3,16). In that case, both

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the rate and volume factors are contributing to the change in FEV1. In other series, however, the FEV1/VC ratio is unchanged after surgery, and improvement in FEV1 is attributable only to the increased VC (7,18). Thus, this model provides a theoretical framework that explains how the interactions of the lungs and chest wall inﬂuence airﬂow limitation before and after LVRS. It leads to the hypothesis that improvement in VC will be limited to patients with a high RV/TLC ratio. In patients with a low RV/TLC ratio, FEV1 may still increase after LVRS. However, this increase will almost entirely be due to increased FEV1/FVC. Changes in FEV1/FVC are less predictable, depending on the potentially opposing changes in the time constant factors, compliance, and resistance. These hypotheses were recently tested in patients who underwent LVRS at Columbia Presbyterian Medical Center. Two groups of patients were studied. One group of 13 patients had detailed measures of lung mechanics made before and after surgery. Another group of 78 patients had routine pulmonary function measures. Patients underwent unilateral or bilateral LVRS by sternotomy or VATS at the surgeons’ discretion (21). Consistent with the predictions of the model, multivariate analysis found that preoperative RV/TLC was the sole predictor of improvement in FVC. Furthermore, in both groups of patients, about two-thirds of the improvement in FEV1 was attributable to increased FVC. However, RV/ TLC did not correlate with improvement in FEV1. This was because, although it correlated directly with improvement in FVC, it correlated inversely with improvement in FEV1/FVC. Since those two factors contribute multiplicatively to FEV1 [see Equation (2)], the inﬂuence of RV/TLC was obscured. The implications of this analysis are as follows: emphysema decreases FEV1 by two mechanisms. The predominant mechanism is the increase in RV, which decreases the total volume that can be exhaled. The secondary mechanism is the decrease in FEV1/FVC, due to increased compliance and/ or increased resistance, which together increase the time constant of emptying. Lung volume reduction surgery increases FEV1 primarily by increasing VC, which it achieves by better matching the size of the lungs to the capacity of the thorax (18,21). A secondary mechanism is increased FEV1/FVC in some patients. This results from decreases in compliance that are proportionally larger than any accompanying increase in airway resistance. We would expect that the best candidates for LVRS would be those with elevated RV/TLC. Patients with low RV/TLC may beneﬁt though improved FEV1/FVC, but their improvement would be less predictable.

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Improvement in Respiratory Muscle Function

Improvement in respiratory muscle performance has been a nearly uniform ﬁnding after LVRS (6,7,22). To understand respiratory muscle dysfunction in emphysema, a brief review of normal respiratory muscle physiology is necessary. When the diaphragm contracts, it lowers the ﬂoor of the thoracic cavity and also expands the lower rib cage. It acts on the ribs through two actions. First, a caudal–cranial vector of force at the sites of costal diaphragmatic insertion elevates the lower ribs. Second, diaphragmatic contraction increases abdominal pressure. Acting through the zone of apposition where the muscular diaphragm is closely applied to the inner surface of the rib cage, the increase in abdominal pressure spreads the lower ribs. If the diaphragm is modeled as a thin hemisphere, the pressure difference that it generates between the thoracic cavity and the abdominal cavity (transdiaphragmatic pressure, PDI) is related to its tension by LaPlace’s law: PDI ¼ tension/radius. That is, for the same tension, the smaller the radius of curvature of the diaphragm, the larger the pressure difference. Like other skeletal muscle, the maximally stimulated ﬁbers of the diaphragm can generate greatest tension from a speciﬁc preexcitation length that corresponds, in situ, to normal FRC. Respiratory muscle dysfunction occurs for a number of reasons in emphysema (23). Hyperinﬂation shortens the diaphragm at end expiration, decreasing the maximal tension it can develop. Hyperinﬂation decreases the area of apposition between the diaphragm and the lower rib cage and orients the muscle ﬁbers more radially, impairing the diaphragm’s ability to expand the ribs. At extremes of hyperinﬂation, the radius of curvature increases, reducing the transdiaphragmatic pressure at any level of muscle tension. In addition to these abnormalities, patients with emphysema face increased respiratory muscle loads due to increased airway resistance and intrinsic positive end-expiratory pressure. When sufﬁciently hyperinﬂated, patients breathe along a portion of the chest wall pressure–volume relationship at which its elastic recoil is directed inwardly rather than outward. Increased dead space increases the total ventilation necessary to maintain normocapnia. With increased respiratory drive, patients with emphysema recruit abdominal expiratory muscles. This elevates expiratory abdominal pressure. Canine studies suggest that this respiratory pattern may impair diaphragmatic blood ﬂow (24). Recruitment of the abdominal wall muscles on expiration also serves to decrease the circumference of the lower rib cage. This increases the curvature of the diaphragm and stores elastic energy in the lower ribcage, which can then assist inspiration (25). In the face of these impediments, there is evidence that the diaphragm adapts to chronic hyperinﬂation. Studies of animal models of emphysema

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and human autopsy series have shown absorption of sarcomeres with reduction in the muscular portion of the diaphragm. This would decrease the resting length of the muscle ﬁbers to better match the hyperinﬂated FRC (23,26,27). Similowski et al. demonstrated inspiratory muscle adaptation in patients with chronic hyperinﬂation. In eight patients with chronic obstructive pulmonary disease, transdiaphragmatic pressure generated during electrical stimulation of the phrenic nerve exceeded that of normal control subjects at equivalent lung volume (28). Given the respiratory muscle impairment associated with hyperinﬂation, it is understandable that a procedure that returns the thorax to a more normal conﬁguration would improve inspiratory force. Although several studies have shown improvements in global inspiratory muscle and diaphragmatic strength following LVRS, there are others that have not. It has also been difﬁcult to show associations between increased diaphragmatic strength and changes in lung volumes. Improved breathing patterns with less accessory muscle use has been demonstrated, as well as decreases in inspiratory loads and work of breathing following LVRS. Teshcler et al. (20) measured maximal inspiratory pressure (MIP) at the mouth and PDI with snifﬁng before and 1 month after LVRS in 17 patients. The mean MIP increased 52% from 4.8 + 0.4 to 7.3 + 0.6 kPa. The PDI increased 28% from 6.0 + 0.6 to 7.7 + 0.8 kPa. These changes were both statistically signiﬁcant. There was no association between improvement in either MIP or PDI and changes in lung volume. The greater change in MIP than in PDI may be due to the fact that MIP assesses strength of all the inspiratory muscles rather than just the diaphragm. Additionally, only 12 of 17 patients had PDI measured, and there was greater variability in the PDI measurements. No information about pulmonary rehabilitation was provided. Because pulmonary rehabilitation often includes respiratory muscle training, it is possible that a training effect, a learning effect after repeated testing, and motivational factors could have been present. Some of these issues were clariﬁed in a more recent study by Criner et al. (7), who assessed respiratory muscle strength in 20 patients before and after rehabilitation and then 3 months after LVRS. They measured MIP and PDI during a maximal sniff (PDIsniff), as well as with electrophrenic stimulation (PDItwitch) and with a combined expulsive–Mueller maneuver (PDIcombined). The PDIsniff was measured before and after LVRS in 14 patients and the PDItwitch was measured in 11 patients. After rehabilitation, total exercise time increased, but there were no changes in any of the measures of respiratory muscle strength. After LVRS, FEV1 increased 34%, TLC decreased 13%, FRC decreased 23%, and RV decreased by 28%. The MIP increased from 50 + 18 to 74 + 28 cm H2O (P < .002). The PDIsniff increased from 46 + 27 to 71 + 7 cm H2O (P < .01). The PDIcombined and the

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PDItwitch also improved signiﬁcantly after LVRS (P < .01). Maximal expiratory pressure (MEP) did not change. By multiple regression analysis, the increase in MIP, but not that in PDI, correlated with decreases in RV and FRC (r ¼ 0.67, P < .03). This study provided further evidence that respiratory muscle strength improves following LVRS. There were signiﬁcant improvements in every parameter of inspiratory strength measured. The correlation between increased MIP and decreased lung volumes supports decreased hyperinﬂation as a mechanism for improved inspiratory muscle function. The investigators note that corticosteroid use decreased following surgery, which may have improved muscle function. However, there were no signiﬁcant changes in patient weight or expiratory muscle strength following surgery, which suggests that the inspiratory muscle gains were not due to generalized improvements in muscle function. Finally, the improvement in PDItwitch argues against learning effects or motivational factors being important. In a follow-up study, Lando et al. (29) found that the decrease in AP diameter of the chest correlated with the increase in PDI. The above positive ﬁndings have not been seen in all series. Martinez et al. (6) evaluated 17 patients who underwent LVRS. Their subjects improved spirometry and lung volumes as expected. Maximal inspiratory pressure increased from 52.3 + 6.0 to 63.9 + 4.4 cm H2O (P ¼ .02), but the increase in PDIsniff was not statistically signiﬁcant (63.9 + 4.8 to 78.0 + 7.8 cm H2O). This may be due to the small number of subjects and variability in the measurement. Keller et al. (30) studied 25 patients who underwent unilateral thoracoscopic LVRS. The MIP changed minimally (71.5 + 41 to 72.5 + 35 mmHg, P ¼ .35). However, these patients had smaller reductions in TLC and RV than those reported in other series that used bilateral LVRS. This may account for the lack of improvement in respiratory muscle function. These two examples demonstrate the problems inherent in comparing multiple small studies. It is difﬁcult to know whether the differences in their results are due to differences in measurement technique, small numbers of patients, differences in patient selection, or surgical techniques. In spite of these inconsistencies, the majority of evidence suggests that LVRS improves inspiratory muscle strength by reducing chest wall volume. A few studies in animals have attempted to overcome some of the limitations to study of diaphragmatic function in humans. Marchand et al. (in hamsters) and Shrager et al. (in rats) showed that LVRS restored the length–tension relationship of the diaphragm with elastase-induced emphysema toward normal (26,27). Elastase-induced emphysema caused atrophy of the diaphragm and shift from type IIx/b to IIa muscle ﬁber types. The atrophy and ﬁber composition was unaltered by LVRS (27).

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The act of breathing requires not only respiratory muscle strength but also the coordinated activity of multiple muscle groups. In addition to increasing inspiratory muscle strength, LVRS may also improve respiratory muscle recruitment and respiratory patterns. Benditt et al. evaluated eight patients at rest and while exercising before and after LVRS (31). Preoperatively at rest, the patients had elevated esophageal (PES) and gastric (PGA) pressures at end expiration. Gastric pressure decreased with inspiration, which suggests that abdominal muscles were relaxing and/or the rib cage and accessory muscles were contracting more than the diaphragm. Following LVRS, the resting end-expiratory PES and PGA decreased signiﬁcantly (from 6 to 0 cm H2O and from 18 to 13 cm H2O, respectively). The end-inspiratory PES and PGA did not change. During isowatt exercise, end-expiratory PES and PGA also decreased signiﬁcantly (median fell from 29 to 6 cm H2O and from 40 to 18 cm H2O, respectively). The investigators calculated DPES and DPGA as the difference between end-expiratory and end-inspiratory pressures; that is, the magnitude of change during inspiration. DPES decreased at rest and at isowatt exercise. DPGA did not change at rest but decreased at isowatt exercise. DPGA/DPES was used to quantify the relative contribution of the diaphragm to inspiration. After LVRS, DPGA/DPES was more negative, which is consistent with reduced abdominal and intercostal muscle recruitment. Linear regression of DPGA/ DPES versus various pulmonary function ﬁndings showed the strongest correlation with the decrease in FRC (r ¼ 0.75, P < .05). This suggests that improved utilization of the diaphragm and decreased recruitment of accessory muscles results from decreased hyperinﬂation. Further evidence for changes in muscle recruitment following LVRS was provided by Bloch et al. (32). They used calibrated inductance plethysmography to monitor changes in rib cage and abdominal volume in 19 patients before and after LVRS. The surgery reduced TLC and RV and increased FEV1. There were no signiﬁcant changes in tidal volumes, respiratory rates, minute ventilation, or PaCO2 after surgery. The contribution of abdominal volume change to tidal volume increased from 43% to 58% (P ¼ .03); reﬂecting increased use of the diaphragm. Several measures of paradoxical abdominal movement also decreased postoperatively. These included the fraction of time with abdominal paradox and the phase shift between rib cage and abdominal motion. These changes reﬂect a decrease in inspiratory muscle loading and/or in hyperinﬂation. Laghi et al. (33) demonstrated decreased pressure output of the respiratory muscles, quantiﬁed by the pressure time product (PTP). This was calculated as the time integral of the difference between PES and the estimated chest wall relaxation pressure during inspiration. PTP/min was calculated as the product of the PTP and the frequency. The PTP/min

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decreased by 22% after surgery from 341 + 35 to 259 + 35 cm H2O/min (P ¼ .03). The decrease in PTP/min correlated with the change in TLC, intrinsic PEEP, and dyspnea. This is also consistent with improvement in respiratory muscle function due to decreased hyperinﬂation and inspiratory muscle loading. Since PTP correlates with oxygen consumption of the diaphragm (34), decreased oxygen costs of breathing may also be inferred. Thus, the weight of evidence supports the ﬁnding that diaphragmatic function improves after LVRS and accessory muscle use decreases. The inspiratory load on the respiratory muscles is decreased and their oxygen requirement may be lower. There is some evidence that links these ﬁndings to decreased hyperinﬂation, and there is certainly sound theoretical basis for this linkage. One study showed that increased strength was not attributable to rehabilitation. Other nonmechanical factors that are less easily dismissed are decreases in steroid use, decreases in PaCO2, and increased motivation following LVRS. Another factor that is not yet known is whether there is true remodeling of the respiratory muscles and chest wall following LVRS, or simply reduction in end-expiratory lung volume. Cassart et al. performed three-dimensional reconstruction of the diaphragm from computed tomographic (CT) images obtained before and after LVRS in 11 patients and in 11 normal controls. They found that LVRS elevated the diaphragm and expanded the zone of apposition. However, there was no change in conﬁguration of the diaphragm suggesting that the muscle changed its operating length without remodeling (35,36).

IV.

Effects on Gas Exchange

The changes in gas exchange after LVRS are complicated and variable. Many investigators have noted mean increases in PaO2 and decreases in PaCO2, but with wide ranges including numerous patients who worsen. The following section will address possible mechanisms for changes in PaCO2 and PaCO2 after LVRS. Although the effects of LVRS on PaCO2 are quite variable, mean changes are generally downward. There are several mechanisms to explain how this could occur. Total ventilation could increase, dead space ventilation could decrease, or CO2 production could decrease. Four studies measured total ventilation at rest preoperatively and postoperatively (9,31,32,37). Three of these studies documented signiﬁcant mean decreases in PaCO2, but none found an increase in total ventilation. Two of these studies showing decreased PaCO2 also measured the ratio of dead space to total ventilation, Vd/Vt. Benditt et al. (37) reported a small but signiﬁcant decrease in Vd/Vt from 0.50 to 0.48, whereas Ferguson et al. (9) found a nonsigniﬁcant change

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after LVRS. These small effects on dead space resemble the minimal changes reported decades ago after classic bullectomy, which were shown to be due to the quantitatively trivial ventilation of the bullae (38). The removal of the bullae does not reduce dead space ventilation, because they were virtually unventilated. No data have been published on the effect of LVRS on CO2 production, but there are at least two studies suggesting that work of breathing is decreased by LVRS (34,39). If work of breathing is decreased, CO2 production from the respiratory muscles will decrease. Since the metabolic activity of respiratory muscles is a substantial fraction of the total metabolic rate in patients with severe emphysema (40,41), this could produce a noticeable reduction in total CO2 production. Shade et al. (42) found a small (2 mmHg) but statistically signiﬁcant decrease in PaCO2 in a series of 33 patients after LVRS. There was wide interindividual variability, with the patients having the highest preoperative PaCO2 demonstrating the greatest fall. By multiple linear regression, the change in PaCO2 correlated with the change in FEV1, diffusing capacity, rapid shallow breathing index during exercise, and maximal inspiratory pressure. These ﬁndings suggest that the decrease in PaCO2 is attributable to improved total ventilation, decreased dead space ventilation, and improved ventilation–perfusion matching. At this point, the evidence for any speciﬁc cause of decreased PaCO2 following LVRS is weak, largely due to the small numbers of patients that have been studied and the additive inﬂuence of multiple factors which, individually, show small changes. As is the case with PaCO2, reported changes in PaO2 following LVRS have ranged widely but typically improve. Wagner et al. (43) found that patients with classic emphysema generally have large areas of high ventilation/perfusion (V/Q) ratios and V/Q mismatch, without hypoxemia attributable to shunt or diffusing abnormalities. Based on this, LVRS could not improve PaO2 by eliminating shunt or improving diffusing capacity. Possible explanations for increased PaO2 postoperatively include increased alveolar ventilation and decreased V/Q heterogeneity. Some studies have found improved oxygenation without improvements in PaCO2 (3,44). In these series, the improvement in PaO2 is attributable to decreased V/Q mismatch. Other studies have found quantitatively similar changes in both PaO2 and PaCO2 (39,45) and have attributed the oxygenation changes to increased alveolar ventilation. Improvement in PaO2 following bullectomy has been attributed to reduced venous admixture both from recruitment of previously compressed lung regions and improved V/Q matching (38). Wagner (46), in an editorial analyzing LVRS data published by Oswald-Mammosser et al. (47), found good correlation between the changes in alveolar–arterial gradient and pulmonary artery pressure at peak exercise. There was also good correlation

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between the changes in FEV1 and exercise capacity. However, there was no correlation between changes in FEV1 and peak exercise alveolar–arterial gradient. Wagner concluded that the determinants of increased exercise capacity and increased oxygenation are independent, and that improvement in perfusion is the key to the latter. Albert et al. (48) studied gas exchange in 46 patients undergoing LVRS. In their series, the PaO2 increased by 3 mmHg, which was not statistically signiﬁcant. The alveolar–arterial gradient increased by 1 mmHg, which was also not signiﬁcant. Emphasizing the heterogeneity of individual patient responses, these investigators used the CO2–O2 diagram (49) to explain how changes in ventilation and perfusion could explain the changes in oxygenation that have been reported. LVRS resects air spaces that may or may not have been ventilated and vessels that may or may not have been perfused. Presumably, both ventilation and perfusion of the resected lung are less than that of the lung left behind. The effects on PaO2 depend on the V/Q ratio of resected regions, the preoperative V/Q ratio of nonresected regions, and the ways in which ventilation and perfusion from the resected regions redistribute to the lung left behind. For example, if hypoxemia is due to low V/Q areas, then PaO2 will increase if ventilation is redistributed from high V/Q areas to low V/Q areas or if perfusion is redistributed from low V/Q areas toward high V/Q areas. The strength of this analysis is that it provides a theoretical framework to understand the often seemingly random changes in blood gases following LVRS. Its weakness is that it offers little hope of predicting individual responses. Although there are little data for or against these concepts, it is likely that changes in V/Q ratio are responsible for the changes in PaO2 following LVRS. Diffusing capacity has occasionally been reported to increase after LVRS (4). However, more typically, changes are not signiﬁcant (6,9,47,50), as previously shown following bullectomy (38). Improved perfusion of the remaining lung would be expected to increase carbon monoxide diffusing capacity (DCO). Improved perfusion after LVRS is suggested by increased right ventricular ejection indices (51). However, resection of functional lung would decrease DCO. These opposing effects may act in concert to yield the nonsigniﬁcant changes generally reported.

V.

Symptoms

Breathlessness is a common, disabling feature of emphysema. Dyspnea in patients with emphysema stems primarily from hyperinﬂation (52). This causes an imbalance between neuromuscular output and sensory information from mechanoreceptors throughout the respiratory system (53).

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Recruitment of accessory muscles such as occurs in hyperinﬂated states may also increase dyspnea; correlation between dyspnea and electrical activity in the rib cage and accessory muscles has been demonstrated (54). Abnormalities in airﬂow may contribute to dyspnea via airway mechanoreceptors (55). Hypercapnia and hypoxemia, both common in emphysema, can cause dyspnea through chemoreceptors (53). Breathlessness can be quantiﬁed by administering standardized scales to patients. In the Medical Research Council (MRC) scale, patients are asked to indicate the level of activity that produces dyspnea (56). One limitation of the MRC scale is that it can be difﬁcult to assess changes in dyspnea following a therapeutic intervention. For that reason, many investigators of LVRS have used the Baseline Dyspnea Index (BDI) and the Transitional Dyspnea Index (TDI) (57). The BDI combines ratings of several different components of dyspnea, such as functional impairment and magnitude of effort, into a composite score. The TDI tracks changes in the BDI categories over time. Two frequently used scales for rapid measurement of exertional symptoms are the visual analog scale (VAS) and the Borg scale. In the VAS, patients indicate their dyspnea by striking a line on a 100 mm scale where zero is not at all uncomfortable and 100 is extremely uncomfortable. In the Borg scale, dyspnea is graded on a 10-point scale with verbal descriptors of severity anchored to values between 1 and 10. Although the VAS is simpler, it produces greater variability when different subjects are exposed to the same external load, and a doubling or tripling of the load does not result in proportional increases in perceived exertion. All of these scales are limited by their subjectivity. One objective surrogate for breathlessness is central respiratory drive, which can be estimated by using the mouth occlusion pressure. This has been used to quantify respiratory center output in normal individuals and patients with chronic obstructive lung disease (COPD) (58,59). It is measured by surreptitiously occluding the inspiratory circuit while a subject exhales through a mouthpiece and a valve that separates inspired and expired ﬂow. With the next inspiration, airway pressure will begin to fall, but it takes a few hundred milliseconds before the occlusion is recognized by the subject. The mouth occlusion pressure 0.1 s after inspiration begins, P0.1, is related inversely to respiratory drive (greater drive corresponds to more negative pressure). Mean inspiratory ﬂow rate has also been used to estimate respiratory drive. However, a fall in mean ﬂow can be due either to a decrease in respiratory drive or worsened pulmonary mechanics. Many studies have shown improvements in patients’ ratings of breathlessness after LVRS (3,6,30,33,50,60). O’Donnell et al. (60) studied a group of eight patients who had underwent bullectomy or unilateral LVRS. The patients were evaluated at baseline and postoperatively with the

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MRC dyspnea scale, a Borg scale for exercise-induced symptoms, and the TDI and BDI. The subjects showed signiﬁcant improvements in all of the dyspnea indices. The TDI improved by 112 + 47% and the MRC improved 38 + 14%. By multivariate analysis, the improvement in Borg rating was explained almost entirely by a decrease in end-expiratory lung volume (as a percentage of predicted TLC), decrease in frequency, and change in tidal volume (as a percentage of predicted VC). The improvement in TDI was highly correlated with the change in FVC (r ¼ 0.88) and less so to the change in FEV1. In order to explore further the mechanics underlying these changes, one ‘‘representative’’ subject was more extensively evaluated. The patient was found to have smaller tidal PES excursions despite larger tidal volume as a percentage of VC. These ﬁndings are consistent with changes in breathlessness occurring as a response to decreases in hyperinﬂation and associated improvements in respiratory muscle function. Unfortunately, these results are difﬁcult to generalize, because the study numbers are small and include patients who underwent bullectomy as well as LVRS. Other studies have supported ﬁnding of O’Donnell’s et al. Martinez et al. (6) evaluated 17 patients with the BDI and the TDI as well as with an exertional Borg scale and a VAS. There was improvement after surgery in all scales. There was also a signiﬁcant decrease in the slope of the dyspnea (VAS) versus work rate relationship during exercise. There was a strong correlation between the change in Borg scale and the change in endexpiratory lung volume (r ¼ 0.75) or end-expiratory PES at equivalent work levels (r ¼ 0.78). There was a weaker association between the change in Borg scale and change in FEV1 (r ¼ 0.65). Laghi et al. (33) provided further support for the link between hyperinﬂation, respiratory muscle function, and breathlessness. They quantiﬁed neuromechanical coupling of the diaphragm as the quotient of tidal volume (normalized to TLC) to tidal change in PDI (normalized to maximal PDI). This ratio increased from 0.49 + 0.06 to 0.61 + 0.04 after surgery. The changes correlated well with the improvement in dyspnea (VAS), (r ¼ 0.76, P ¼ .08). Two studies emphasize the independence of changes in FEV1 and dyspnea (15,50). In both, there were signiﬁcant improvements in dyspnea after LVRS, but they correlated poorly with change in FEV1 (r ¼ 0.3). Only one study showed a modest correlation between change in PaO2 and dyspnea (r ¼ 0.5) (30). Most evidence thus supports decreases in lung volume and improvements in the coupling between respiratory muscle effort and tidal volume as the cause of improvements in dyspnea rather than improvement in airﬂow or oxygenation. Several studies have analyzed respiratory drive in patients before and after LVRS. Two report decreased P0.1. Celli et al. (58) measured mouth occlusion pressure in eight subjects breathing room air and also plotted P0.1

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against end-tidal CO2 during CO2-stimulated hyperventilation. There were signiﬁcant decreases in P0.1 and in the ratio of P0.1 to end-tidal CO2 pressure following LVRS. They found no signiﬁcant correlation between change in P0.1 and PaO2, PaCO2, FVC, FEV1, FRC, or TLC. These investigators suggest that the decrease in central drive may contribute to relief of dyspnea. Furthermore, these ﬁndings indicate that heightened hypercarbic drive could not be the cause of lower PaCO2 after LVRS. Teschler et al. (22) found similar reductions in P0.1 and improvement in dyspnea by the MRC scale. Laghi et al. (33) also demonstrated a decrease in mean inspiratory ﬂow in patients who underwent LVRS (472 + 56 to 372 + 49 mL/s). These studies provide objective evidence that LVRS leads to decreases in central respiratory drive. These changes are likely due to improved neuromechanical coupling as a result of improved chest wall–diaphragm conﬁguration and function.

VI.

Exercise Capacity

Patients with severe emphysema have ventilatory limitation to exercise, often with respiratory acidosis. As previously described, they are impaired by expiratory ﬂow limitation, inspiratory muscle dysfunction, and limited tidal volumes due to hyperinﬂation. The normal decrease in the dead space to tidal volume ratio during exercise also fails to occur in emphysema. In addition to these problems with respiratory mechanics, there are several other factors that may contribute to exercise limitation. Because these patients are so debilitated and dyspneic, they rarely exercise and become deconditioned. Cardiac function may be compromised owing to increased right ventricular afterload from increased pulmonary vascular resistance or impaired right ventricular ﬁlling due to compression of the inferior vena cava (see Chap. 4). Additionally, patients may simply be limited by their sensation of breathlessness. Given the multiple beneﬁcial effects of LVRS on these determinants of exercise tolerance, it is not surprising that the surgery has been shown to improve exercise capacity as measured by oxygen consumption (VO2), maximal workload, and 6-min walk distance (8,9,30,33,37). Although it is appealing to conclude that these improvements are solely due to improvements in airﬂow following LVRS, other factors may contribute. These include improved conditioning, improved respiratory muscle function, decreased dyspnea, improved cardiac function, decreased oxygen cost of breathing, improved efﬁciency, or even placebo effects in a highly motivated subject. Ferguson et al. (9) evaluated 27 patients with cycle ergometry and 6min walks. Maximal work increased from 40 to 48 W (P < .05), peak VO2 increased from 733 to 758 (P < .05), and 6-min walk distance increased from

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1081 to 1273 ft (P ¼ .02). They also compared exercise performance at equal workloads and found that tidal volume and total and alveolar ventilation was increased, whereas the ratio of dead space to total ventilation decreased. There was also a signiﬁcant fall in PaCO2 and an increase in pH at equal workloads. The improvements in exercise performance were signiﬁcantly correlated with the change in ventilation at peak exercise (r ¼ 0.8). These ﬁndings support the logical assumption that improved airﬂow following LVRS leads directly to an increase in ventilatory and exercise capacity. Although improvement in ventilatory capacity is an important factor in improved exercise performance, there are probably other determinants. Benditt et al. also evaluated exercise performance before and after LVRS (37). They found increases in maximal work rate, oxygen consumption, and ventilation that were similar to the ﬁndings already discussed. However, they found a poor correlation between the changes in peak VO2 or workload and maximal ventilation, and speculated that there were other factors contributing to exercise limitation. Interestingly, they noted an increase in oxygen pulse at maximal exercise and a decrease in heart rate at isowatt exercise. These ﬁndings suggest larger stroke volume and are consistent with improved right ventricular function. Support for improved right ventricular function after LVRS also comes from Sciurba et al., who documented an increase in right ventricular ejection fraction following LVRS (51). Laghi et al. (33) provided evidence that improved diaphragmatic function increase exercise tolerance. In their study, 6-min walk distance increased from 808 + 115 to 1198 + 99 ft (P < .01). They quantiﬁed neuromechanical coupling of the diaphragm as previously described. There was a signiﬁcant correlation between neuromechanical coupling and the increase in 6-min walk distance (r ¼ 0.86). Lando et al. (29) also demonstrated a correlation between reduction in anteroposterior chest diameter and increase in 6-min walk distance following LVRS. These correlations suggest that inspiratory muscle function, not just expiratory airﬂow, contribute to improved exercise capacity after this surgery. Several studies have found the maximum VO2 increased to a lesser extent than did the maximal workload after LVRS (9,30,37). This apparent increase in muscular efﬁciency could reﬂect a decrease in the oxygen cost of ventilation. Alternatively, the disproportionate increase in workload compared to VO2 may indicate more efﬁcient exercise mechanics, such as could occur from training. Although pulmonary rehabilitation is often required of LVRS candidates, Criner et al. found that rehabilitation alone did little to improve exercise performance compared to surgery. They evaluated patients at baseline, after 8 weeks of pulmonary rehabilitation, and again 3 months after LVRS (7). Rehabilitation resulted in a signiﬁcant increase in exercise time, but did not change 6-min walk distance, peak VO2,

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maximal ventilation, or tidal volume at peak exercise. After LVRS, however, all of these variables increased signiﬁcantly. LVRS improves exercise tolerance. The most important mechanism is probably through improvement in FEV1 and ventilatory capacity. Improved diaphragmatic function, decreased oxygen cost of breathing, and improved cardiac function may also all play a role. Although exercise training alone can cause modest beneﬁts, training does not appear to be responsible for the improved exercise tolerance documented after LVRS. However, there may be synergy between the mechanical effects of surgery and training, such that improved ventilatory capacity allows higher intensity exercise. Other factors that may play a role are motivational or placebo effects.

VII.

Placebo Effect

Patients who have endured months of rehabilitation and risky surgery are likely to be strongly motivated to prove to themselves and others that it has been beneﬁcial. Additionally, the personnel performing tests on these subjects are not blinded to their procedure, and may give them more encouragement and assistance than they would otherwise. It is obvious that this expectation bias could have a serious impact on dyspnea ratings and other subjective measures. More objective tests such as spirometry, respiratory muscle testing, and exercise capacity could also be inﬂuenced by effort and motivation. It is generally accepted that 35% of patients with a wide variety of disorders will beneﬁt from treatment with placebos. There are even reports of 70–100% of patients being ‘‘cured’’ by placebo treatment (61). One surgical procedure that appeared to be beneﬁcial in uncontrolled trials is bilateral internal mammary artery (IMA) ligation for angina pectoris. It was reasoned that occluding the IMA in patients with atherosclerotic heart disease would shunt blood to the coronaries via anastomotic channels. Battezzati et al. reported a series of 304 patients who underwent IMA ligation. Ninety-ﬁve percent of the subjects reported improvement in their symptoms, and the electrocardiogram improved in 64% (62). Two double-blinded studies were subsequently performed in which patients were randomized to either IMA ligation or sham surgery. Since IMA ligation is now understood not to improve coronary ﬂow, these studies may be viewed as having two placebo arms. Cobb randomized 17 patients to ligation or sham surgery; the surgeon was handed an envelope assigning the treatment group after the patient was prepped, and the cardiologists were also blinded. The physicians and most of the subjects were aware of enthusiastic reports in the lay press of the success of uncontrolled series. Both ligated and

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sham patients had striking improvements in angina. Two patients were now able to complete a full 10-min treadmill exercise test and one returned to work. Both were in the sham surgery group (63). In another double-blinded randomized trial of 18 patients with angina, 15 reported substantial and sustained improvement in symptoms, although there was no change in the duration of exercise necessary to provoke electrocardiographic changes (64). Studies of LVRS have used well-validated dyspnea scales and carefully administered pulmonary function tests. There are sound physiological explanations for the ﬁndings reported. Nevertheless, one must use caution when interpreting the results, as all reported series have been both uncontrolled and unblinded. The bias introduced in patients, technicians, and physicians by knowledge of who has undergone surgery cannot be avoided, but must be respected.

VIII.

Accelerated Deterioration of Pulmonary Function

One of the perceptions of Brantigan et al. (1) was that progression of emphysema was arrested by LVRS. They reported that one patient showed no signs of disease progression after 8 years. Although limited long-term follow-up data are available, the results of more recent surgery have contradicted this assertion. The data that are available suggest that pulmonary function deteriorates at an unusually rapid rate following LVRS. In nonsmoking patients with COPD, FEV1 declines by 30–40 mL/ year (65,66). In contrast, long-term follow-up evaluation of patients after LVRS has shown rates of FEV1 loss of 100–400 mL/year (67). As with the degree of initial improvement, there is likely to be wide interindividual variability in the rate of functional loss. Brenner et al. reported that the patients with the greatest initial improvement in FEV1 showed the most rapid subsequent decline (68). One series compared long-term follow-up of 12 patients with a1-antitrypsin deﬁciency emphysema (AAT) to 18 patients with smoking-induced emphysema after bilateral LVRS. Despite similar degrees of baseline impairment and of initial improvement, and ongoing human a1-antitrypsin replacement therapy, the AAT group showed much more rapid decline after surgery. By 12 months, they had returned to their preoperative function and by 24 months they were signiﬁcantly worse (69). At present, the longest term follow-up reported after LVRS in the modern era is 5 years. Among a cohort of 26 patients, 11 remained alive and only 2 had lung function still improved over baseline. Data to calculate an annualized rate of FEV1 loss are not provided (70). The reasons for accelerated decline in lung function after LVRS remain speculative. There may be gradual expansion of existing bullae with

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compression of more normal lung. Alternatively, there may be accelerated destruction of alveolar elements. This could result from the increased stress accompanying increased elastic recoil, and is consistent with the ﬁnding that patients with the greatest initial beneﬁt suffer the most rapid loss (68). This was the explanation suggested in a case report in which successful LVRS was followed by development of a giant bulla, loss of pulmonary function improvement, and eventual death during bullectomy (71). This imbalance between the tensile strength of the lung and the daily stress of ventilation has long been part of the pathophysiological explanation of emphysema. Early animal models of emphysema increased stress in normal lung by extensive lung resection (72). It is a small leap to hypothesize that increased stress in lung damaged by smoking would be more prone to stress failure. Increased stress in alveolar septa was the explanation proposed for the apical predominance of typical smoker’s emphysema (73). In animals with elastaseinduced emphysema, saline-ﬁlled lung pressure volume relations were more abnormal in animals subjected to daily exercise than in rested animals (74). Understanding the mechanism of the accelerated decline in lung function after LVRS may be essential in order to select patients least likely to experience it.

IX.

Summary

Lung volume reduction surgery is a promising therapy for patients with advanced emphysema. Improvements in spirometry, respiratory muscle function, gas exchange, breathlessness, and exercise capacity have been well documented. However, virtually every series has some patients who improve and others that worsen as assessed by almost every outcome variable. Although this variability provides a window into mechanisms, the view is clouded, because variations may be due to intrinsic patient factors, perioperative technical factors, or the vagaries of unpredictable postoperative complications. Nevertheless, some conclusions can be drawn. Spirometry improves because of improved ﬁt between the size of the lungs and that of chest wall, increases in elastic recoil, and perhaps decreased airway resistance. Decreases in hyperinﬂation and respiratory muscle load are largely responsible for the changes in diaphragmatic function following LVRS. Reduced dyspnea is similarly linked to decreased hyperinﬂation and improved respiratory muscle function. Changes in exercise capacity are closely associated with improvement in airﬂow limitation, but improved inspiratory muscle function and cardiovascular and training factors may also be important. The role of a placebo effect in subjective and objective changes is unknown. The determinants of long-term outcome are also

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unknown. Although LVRS appears to be promising, there is clearly much to be discovered about its mechanisms.

References 1. 2.

3.

4.

5.

6.

7.

8.

9.

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11. 12.

13.

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59. Whitelaw W, Derenne J, Milic-Emili J. Occlusion pressure as a measure of respiratory center output in conscious man. Respir Physiol 1975; 23:192–199. 60. O’Donnell DE, Webb KA, Bertley JC, Chau LKL, Conlan AA. Mechanisms of relief of exertional breathlessness following unilateral bullectomy and lung volume reduction surgery in emphysema. Chest 1996; 110:18–27. 61. Keinle GS, Kiene H. Placebo effect and placebo concept: a critical methodological and conceptual analysis of reports on the magnitude of the placebo effect. Altern Ther Health Med 1996; 2(6):39–54. 62. Battezati M, Tagliaferro A, Cattaneo AD. Clinical evaluation of bilateral internal mammary artery ligation as treatment of coronary heart disease. Am J Cardiol 1959; 4:180–183. 63. Cobb LA, Dillard TGI, Merendino KA, Bruce RA. An evaluation of internalmammary artery ligation by double blind technique. N Engl J Med 1959; 260:1115–1118. 64. Dimond EG, Kittle CF, Crockett JE. Comparison of internal mammary artery ligation and sham operation for angina pectoris. Am J Cardiol 1960; 5:483–486. 65. Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled bronchodilator on the rate of decline of FEV1. JAMA 1994; 272:1497–1505. 66. Fletcher C, Peto R. The natural history of chronic airﬂow obstruction. BMJ 1977; 1:1645–1648. 67. Fessler HE, Wise R. Lung volume reduction surgery: Is less really more? Am J Respir Crit Care Med 1999; 159:1031–1035. 68. Brenner M, McKenna RJ, Gelb AF, Fischell RJ, Wilson AF. Rate of FEV1 changes following lung volume reduction surgery. Chest 1998; 113:652–659. 69. Cassina PC, Teshler H, Konietzko N, Theegarten D, Stamatis G. Two-year results after lung volume reduction surgery in a1-antitrypsin deﬁciency versus smoker’s emphysema. Eur Respir J 1998; 12:1028–1032. 70. Gelb AF, McKenna RJ, Brenner M, Epstein JD, Zamel N. Lung function 5 years after LVRS for emphysema. Am J Respir Crit Care Med 2001; 163:1562– 1566. 71. Iqbal M, Rossoff L, Mckeon K, Graver M, Scharf SM. Development of a giant bulla after lung volume reduction surgery. Chest 1999; 116:1809–1811. 72. Adams WE, Livingstone HM. Lobectomy and pneumectomy in dogs. Arch Surg 1932; 25:898–908. 73. West JB. Distribution of mechanical stress in the lung, a possible factor in localization of pulmonary disease. Lancet 1:1971; 839–841. 74. Sahebjami H, Vassallo CL. Exercise stress and enzyme-induced emphysema. J Appl Physiol 1976; 41:332–335.

18 Lung Volume Reduction Surgery in Unique Patient Populations

FRANCIS C. CORDOVA and GERARD J. CRINER Temple University School of Medicine Philadelphia, Pennsylvania, U.S.A.

I. Introduction Since the initial reported success of lung volume reduction surgery (LVRS) in improving lung function, exercise performance, and quality of life in selected patients with emphysema (1–4), its application has been occasionally expanded to include chronic obstructive pulmonary disease (COPD) patients who have: (1) signiﬁcant cardiovascular disease (5,6); (2) lung nodules (7–12), and sometimes those who are ventilator dependent (13–15). In addition, LVRS has also been applied successfully in surgical reduction of hyperinﬂation of the native lung in COPD patients after single-lung transplantation (16–19). All of these highly selective group of patients were considered for LVRS despite the presence of signiﬁcant comorbidities, because their underlying prognosis was considered to be dismal without surgical treatment. In this chapter, we will review the extended indications for LVRS in these highly selective groups of COPD patients who receive LVRS under unique circumstances.

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LVRS and Pulmonary Nodules

A. Incidence of Solitary Pulmonary Nodules in Patients Evaluated for LVRS

Cigarette smoking is a common risk factor for both the development of emphysema and lung cancer. Thus, it comes as no surprise that early epidemiological studies showed a higher incidence of lung cancer in patients with bullous lung disease (20). In addition, the histopathological type of emphysema (centrilobular emphysema) commonly associated with cigarette smoking has been reported to increase the risk of lung cancer compared to other types of emphysema (21). Because of the strong association of emphysema with lung cancer and cigarette smoking, solitary pulmonary nodules are frequently encountered during LVRS evaluation. Both benign and malignant nodules have been detected in patients referred for LVRS either during routine preoperative work-up (chest radiograph and conventional or high-resolution computed tomographic [CT] scan) (8–12) or in some circumstances during surgery or only after resected tissue histopathological review (9,22). The overall incidence of pulmonary nodules in patients who are referred for LVRS evaluation is between 11 and 40% (8,10–12). The incidence of lung cancer in patients who undergo simultaneous LVRS and lung nodule resection is reported to be between 5 and 6% (8,10–12,23). In one of the largest case series reported to date, McKenna and Fischel et al. (10) reported 53 lung masses in 51 of 325 patients who underwent LVRS. After histological review, 43 lesions (in 42 patients) were benign and 11 lesions were non-small-cell lung cancer. The benign lesions included 20 calciﬁed nodules, 17 granulomas, 4 ﬁbrotic nodules, and 1 hamartoma. Two patients had both a granuloma and lung cancer. Of the 11 patients with clinical stage I lung cancer, 3 patients were referred for combined lung cancer surgery and LVRS, 7 patients were diagnosed by CT scan during LVRS evaluation, and 1 patient was diagnosed after histopathological analysis. Thus, the incidence of lung cancer by routine chest CT scan in the course of LVRS evaluation was 2%. CT is the single best ancillary test to diagnose unsuspected pulmonary nodules in patients who are undergoing LVRS evaluation. In one study involving 148 LVRS candidates, preoperative CT scan detected 18 pulmonary nodules that were suspicious for primary lung cancer (12). Sixteen of these lesions were resected during LVRS. Nine non-small-cell carcinomas were detected in eight patients, yielding a 5% incidence of lung cancer. The median size of the malignant lesions was 1.6 cm (range 1.0– 3.8 cm), whereas the benign lesion was 1.0 cm (range 0.7–2.0 cm).

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In another study involving 281 patients who underwent LVRS, 147 nodules were identiﬁed in 111 (40%) patients (8). The majority of lung nodules were identiﬁed preoperatively by chest CT. However, 14 nodules were identiﬁed intraoperatively, and another 14 nodules were only identiﬁed postoperatively during histological analysis. Fifty-seven of these nodules were calciﬁed and were though to be benign. Twelve nodules were resected, and pathological analysis conﬁrmed the benign nature of the lesions. The other remaining nodules were followed clinically and were reported to be stable in size with a mean follow-up of 23 months. On the other hand, there were 20 noncalciﬁed lesions on CT scan which were also followed clinically. Nineteen of these nodules remained radiographically stable after 18.5 months of follow-up, and one nodule was eventually diagnosed as squamous cell carcinoma resulting in the patient’s death 18 months after the nodule was initially identiﬁed. Overall, a total of 78 nodules were resected in this study, of which 61 (78.2%) were benign and 17 (21.8%) were neoplastic. The most common benign diagnoses was granuloma (29), ﬁbrosis (17), and hamartoma (5). Among the neoplastic lesions, adenocarcinoma (7), squamous cell carcinoma (3), and large cell carcinoma (2) topped the list. One case each of bronchoalveolar carcinoma, B-cell lymphoma, carcinoid, mesothelioma, and renal cell metastasis were found. The overall incidence of malignancy in the 281 patients was 6.4% (18 patients). The size of the primary lung cancer ranged from 0.5 to 3.2 cm with a mean size of 1.6 cm. The average size of the primary lung cancer not detected radiographically was 0.76 cm. This study emphasizes that chest CT is not capable of diagnosing all lung lesions, especially those less than 0.75 cm in size. Based on the above studies involving 829 patients, the incidence of pulmonary nodules in the course of LVRS work-up was 14%, 4.7% of which was unsuspected primary lung cancer (Table 1). The majority of the diagnosed lung cancers were in their early stages and potentially resectable

Table 1 LVRS

Incidence of Pulmonary Nodules in Severe COPD Patients Referred for

Reference Patients (n) 10 8

325 281

12 11

148 75

Total nodules 53 nodules in 51 patients 147 nodules in 111 patients; 78 nodules were resected 18 in 17 patients 11

Benign (%) Malignant (%) 43 (13) 61 (22)

11 (3) 17 (6)

7 (5) 8 (11)

8 (5) 3 (4)

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with curative intent. Thus, the utility of preoperative CT scan may serve a dual role, not only to characterize the pattern of parenchymal destruction due to emphysema but also to detect early potentially surgically curable lung cancer. The wide range in the reported incidence of pulmonary nodules may reﬂect different study populations, varying deﬁnitions of pulmonary nodules among investigators, different methods of detection, and the variable incidence of benign pulmonary nodules based on geographical location. Further investigation is required. B. Preoperative Evaluation of Lung Nodule Resection in LVRS

Before LVRS was made possible by advances in thoracic surgical techniques and modern cardiothoracic anesthesia, the majority of severe COPD patients with pulmonary nodules would have been deemed to be inoperable using standard preoperative criteria for lung resection owing to limited pulmonary reserve. For example, one recent study showed successful postoperative recovery and short-term improvement in lung function in 11 patients who underwent combined LVRS and resection of pulmonary nodules (11). If two of the standard preoperative criteria for lung resection were applied in these patients (postoperative for expiratory volume in 1 s [FEV1] of <40% and oxygen desaturation with exercise to <89%), all 11 patients would have been classiﬁed as very high risk for lung resection, and surgical resection would not have been considered. If an FEV1 of <0.6 L and a predicted postoperative carbon monoxide diffusion in the lung (DLCO) of <40%, were applied to the same patient group, 4 of 11 and 4 of 9 patients would have been deemed to be inoperable surgical candidates. Thus, current experience suggests that standard preoperative criteria for pulmonary nodule resection may not predict postoperative respiratory insufﬁciency in highly selective severe COPD patients if resection of the lung nodule is combined with LVRS. Moreover, several studies have shown no increase in mortality and morbidity in patients who undergo combined pulmonary nodule surgery and LVRS compared to LVRS alone (8,10–12,23). During preoperative evaluation, patients who are considered for pulmonary nodule resection and LVRS should have the following questions answered: (1) Is the patient a good candidate for LVRS? (2) Is the tumor accessible via bronchoscopy or transthoracic needle biopsy for preoperative histologic diagnosis? (3) Is the nodule located in an area of the lung with the worst emphysema or not? (4) Are there any hilar or mediastinal nodes that are suspicious for metastasis on CT scan? These questions should be answered during the preoperative evaluation period to optimize lung cancer surgery and to preserve residual lung function. Figure 1 shows the approach to the treatment of LVRS candidates with unsuspected pulmonary nodules.

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Figure 1 Approach to the evaluation and treatment of LVRS candidates with unsuspected pulmonary nodules. See text for explanation.

It is important to remember that all of the severe COPD patients who were reported to have pulmonary nodule resection and LVRS were initially referred for LVRS evaluation. Although preoperative clinical criteria that predicts improvement in lung function and exercise performance after LVRS still remains to be deﬁned, the generally accepted criteria for LVRS (Table 2) provides useful guidelines for optimal patient selection. Patients with chest CT scans demonstrating heterogeneous destruction of lung parenchyma due to emphysema may be expected to do better compared to a more diffuse distribution of emphysema (24). This is important to bear in mind, since the expected improvement in lung function after LVRS would counterbalance the loss of more functional lung tissue due to lung nodule resection. The majority of reported patients who have undergone lung nodule resection and LVRS have not undergone preoperative bronchoscopy or transthoracic needle biopsy. This is due to the fact that most of the nodules are small and located in the periphery of the lung, making the yield of bronchoscopy very low. Additionally, the presence of signiﬁcant bullous lung disease increases the risk of pneumothorax, a severe consequence rendering transthoracic needle biopsy an infrequently used technique in these patients. The usefulness of these two procedures needs to be evaluated

390 Table 2

Cordova and Criner Inclusion and Exclusion Criteria for LVRS

Inclusion Criteria A. New York Heart Association Class III–IV B. Evidence of airﬂow obstruction and hyperinﬂation by pulmonary function studies (i.e., FEV1<30% of predicted, postbronchodilator administration, RV >150% of predicted, TLC <110% of predicted) C. Hyperinﬂation documented by chest x-ray and emphysema documented by high-resolution CT scan D. Hypoperfusion documented in planned resected lung tissue by quantitative perfusion lung scan Exclusion Criteria A. Patients with severe and refractory hypoxemia (PaO2/FIO2 ratio <150) B. Severe hypercapnic respiratory failure requiring mechanical ventilation C. Presence of signiﬁcant cardiovascular disease D. Presence of severe pulmonary hypertension (mean pulmonary artery pressure >35 mmHg) E. Severe debilitated state with total body weight <70% of ideal body weight F. Presence of signiﬁcant extrapulmonary end-organ dysfunction expected to limit survival F. Presence of signiﬁcant extrapulmonary end-organ dysfunction expected to limit survival G. Psychosocial dysfunction H. Continued smoking

on a case by case basis. In certain clinical situations, a preoperative histological diagnosis may be required. Moreover, a preoperative diagnosis of lung cancer should prompt a complete staging evaluation to look for unsuspected metastases or other signiﬁcant medical problems (i.e., cardiac dysfunction). The location of the pulmonary nodule is very important in planning the type of thoracic surgery. Ideally, lobectomy with hilar node sampling is the preferred surgical technique for stage I lung cancer compared to simple wedge resection. Previous studies have shown that lobectomy for stage I non–small cell lung carcinoma improves survival and decreases the incidence of local recurrence (25). However, if the lung cancer is located in an area of relatively normal lung parenchyma, lobectomy may lead to postoperative respiratory insufﬁciency. In this circumstance, wedge resection may be the procedure of choice to avoid loss of remaining functioning lung tissue (26). If the lung cancer is located in the area of the lung that is

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extensively destroyed by emphysema, then a lobectomy, the surgical choice for optimal lung cancer surgery, is the preferred surgical procedure (7,25). An accurate assessment of hilar and mediastinal lymph nodes for metastatic disease is important both for the treatment and prognosis of primary lung cancer. This is even more important in this group of patients who are undergoing LVRS and clinical stage I lung cancer surgical resection, since mediastinal and subcarinal lymph nodes are inadequately exposed when median sternotomy is used. Although chest CT has good negative predictive accuracy in the evaluation of mediastinal lymph node metastasis, it does not completely rule out mediastinal metastasis in patients with stage I disease. In a recent study involving 575 patients with clinical stage I non–small cell lung carcinoma, who underwent lobectomy and systematic mediastinal lymphadenectomy, 79 patients (14%) had positive mediastinal lymph metastasis on pathological examination (27). In addition, 54 of the 79 patients (68%) who have pathological evidence of mediastinal metastasis had intraoperatively normal-appearing mediastinal lymph nodes. The investigators concluded that systematic staging of the mediastinal lymph nodes is necessary for all patients with resectable clinical stage I lung cancer. To avoid this dilemma, preoperative mediastinoscopy should be considered, especially if median sternotomy is the planned surgical approach. C. Outcome of Combined Pulmonary Nodule Resection and LVRS

Based on the basic guidelines of lung cancer surgery and LVRS previously discussed, several investigators have reported encouraging early results in severe COPD patients who underwent combined solitary pulmonary nodule resection and LVRS. McKenna and associates reported 51 patients who underwent combined LVRS and pulmonary nodule resection from a larger series of 325 patients who underwent LVRS (10). The clinical outcome of 11 patients with clinical stage I non-small-cell lung cancer who underwent either wedge resection (8) or lobectomy with lymph node dissection combined with LVRS was reported in detail. There were no perioperative deaths or major complications. The average length of hospital stay was 8.7 days. Despite substantial lung resection in addition to the standard LVRS procedure (20– 30% of each lung was resected), the group mean FEV1 signiﬁcantly increased to 1079 mL after surgery compared to a baseline value of 654 mL. No patients showed any decline in FEV1 postoperatively. In four cancer patients who underwent lobectomy (three patients with right upper lobe [RUL] and 1 patient with right middle lobe [RML]) substantial increases in

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FEV1 were also observed. Using the Medical Outcome Study—Short Form 36, the investigators reported that 7 of 11 patients experienced a signiﬁcant decline in perceived dyspnea postoperatively. The range of follow up was between 2 and 22 months with a mean of 9.7 months. In ﬁve patients who had >12 months of follow-up, no tumor recurrences were documented. In another large series of 281 severe COPD patients who underwent LVRS, Hazelrigg et al. (8) identiﬁed 148 nodules, 78 of which were resected. Seventeen of the resected nodules were found to be neoplastic on histopathological examination. Interestingly, 9 of the 17 resected neoplastic lesions were not diagnosed preoperatively, 2 of which turned out to be primary lung cancer. Thirteen of the 17 nodules were primary lung cancer. Among the 13 patients with lung cancer, 10 had pathological stage I disease, 2 had stage II, and 1 had stage IV disease. All patients underwent wedge resection and nodal dissection if malignancy was recognized intraoperatively. The reported overall in-hospital mortality for the 281 patients was 5%. There were ﬁve deaths in the neoplastic group during follow-up: one with metastatic renal cell carcinoma, one with unresectable mesothelioma, two with progression of primary lung carcinoma, and one with a stroke 10 months after surgery. Twelve patients were disease free with a mean followup of 14.3 months. No lung function data were provided in this study. Do patients who undergo combined LVRS and lung nodule resection have higher perioperative morbidity and mortality? This question was answered in part by a retrospective study reported by Ojo and Martinez (11), who compared the clinical outcome of 11 patients who had combined lung nodule resection and LVRS (LVRS group), with a cohort of age- and sex-matched lung cancer patients who had undergone standard lobectomy during the same period (control group). The rate of postoperative complications and the length of hospital stay between the two study groups were comparable. The LVRS group had very limited lung reserve prior to surgical resection, whereas the control group had normal baseline lung function. In the LVRS group, mean FEV1 was 26 + 2% of predicted, and all patients had oxygen desaturation on 6-min walk test. In addition, two patients had PaCO2 > 45 mmHg. At 3 months follow-up, the LVRS and nodule resection groups had 47 and 25% increases in FEV1 and forced vital capacity (FVC), respectively. Moreover, all study patients reported less dyspnea after surgery as measured by the Transitional Dyspnea Index. The study was limited by the small number of patients and by its retrospective design. In addition, the study groups may not have been comparable, since only three patients from the LVRS group had stage I non-small-cell lung carcinoma who underwent tumor wedge resection. The issue of whether hypoxemia, hypercapnia (PaCO2 > 45 mmHg), and preoperative steroid dependence would preclude combined lung nodule

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resection surgery and LVRS was recently addressed by a study in 21 patients with severe emphysema and concomitant pulmonary nodules (23). Seven patients were deemed to be inappropriate candidates for combined LVRS and pulmonary nodule resection based on inclusion and exclusion criteria previously discussed. Mediastinoscopy was performed only if suspicious lymph nodes (>1 cm) were detected on CT scan. The surgical approach was tailored to the anatomical distribution of the lesion in relation to the preoperatively determined worst emphysematous zones of the lung. Seven patients underwent unilateral resection through a posterolateral thoracotomy and one through video-assisted thoracoscopy. Three patients had bilateral LVRS via median sternotomy and three via bilateral anterior thoracosternotomy. Owing to the concern for the development of persistent air leaks and bronchopleural ﬁstula, routine intraoperative hilar nodal sampling was not routinely performed. Twelve of the pulmonary nodules were within the target areas of emphysema resection, whereas the remaining four nodules required separate wedge resections. In 14 patients with severe emphysema (mean FEV1 24 + 5%) who underwent combined LVRS and pulmonary nodule resection, 10 patients were oxygen dependent, 5 patients had hypercapnia, and 5 patients were steroid dependent. The mean age of the study group was 69 + 2 years old, with 7 patients older than 70 years old, with the oldest being 80 years old. Sixteen lesions were resected and nine lesions were diagnosed as non-smallcell carcinoma. All patients were extubated in the operating room. Three patients had prolonged air leaks (>14 days), one of whom required surgical repair. One patient had postoperative ileus, and another patient experienced a transient neurological event. There was one postoperative death which was attributed to a large bronchopleural ﬁstula in a patient who had prior ipsilateral lung operation. At 6 months follow-up, signiﬁcant improvements in FEV1 (886 + 141 vs. 676 + 106 mL), dyspnea index (1.9 + 0.3 vs. 3.6 + 0.3), and 6-min walk test (1100 + 103 vs. 817 + 100 ft) were documented. Moreover, there was a signiﬁcant decrease in PaCO2 after surgery from a baseline of 46.8 + 2.9 to 39.6 + 1.7 mmHg postoperatively. One patient had mediastinal recurrence 12 months after surgery from two separate lesions found to be bronchoalveolar carcinoma. The remainder of the patients were alive and well at a mean follow-up of 22.6 months (range 12–35 months). In most of the patients described above, limited resection or segmentectomy was utilized for fear of further loss of lung function. However, in a randomized trial comparing surgical outcome of lobectomy versus segmentectomy in stage I non-small-cell lung cancer, segmentectomy or limited resection was associated with an increased risk of local recurrence and a reduction in both overall and disease-free survival (25). Whether

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patients with advanced emphysema can tolerate optimal surgery for stage I non-small-cell lung cancer is not clear. This problem is compounded by the fact that the degree of improvement in lung function after LVRS is poorly predicted by preoperative static lung function and cardiopulmonary exercise testing. In an attempt to determine outcome following combined lobectomy for lung cancer treatment and LVRS, Demeester et al. (7) recently reported their experience with ﬁve patients who underwent combined lobectomy and LVRS. The mean age of the ﬁve patients was 62 years (range 53–70); three of the patients were male. Two patients were oxygen dependent, and one patient was on prednisone 30 mg/day. Four patients had preoperative diagnoses of lung cancer. Two patients were found to have concomitant cardiac disease on noninvasive cardiac evaluation. One patient required angioplasty before LVRS and lobectomy; the other patient had low cardiac ejection fraction, but no active ischemia was identiﬁed. Except for one patient, all patients underwent 6–8 weeks of pulmonary rehabilitation prior to surgery. All patients underwent intraoperative bronchoscopy, and four patients with a preoperative diagnosis of lung cancer also underwent mediastinoscopy. A median sternotomy was used in four patients, and one patient underwent bilateral staged thoracotomy because of prior pleurectomy on the left for treatment of recurrent spontaneous pneumothorax. Two patients had RML lobectomy in addition to LVRS. After surgery, all patients were reported to have a signiﬁcant improvement in lung function. There were no mortality; however, three of ﬁve patients had postoperative complications. One patient developed pneumothorax and retained airway secretions requiring reintubation and mechanical ventilation for 24 h. Two patients had postoperative bleeding into the extrapleural space created by pleural tents. Both patients improved with conservative management and did not require further surgical intervention. Four patients had pathological stage I lung cancer, and one patient had stage II lung cancer and received adjuvant radiation therapy. No recurrence was detected in any patients with a mean follow-up of 19 months. Overall, all prior studies showed that combined pulmonary nodule resection and LVRS can be done in a highly select group of COPD patients who are deemed good candidates for LVRS. Although most of the studies are small, and limited by retrospective design, it appears that perioperative morbidity and mortality are acceptable and not different than in patients who undergo LVRS alone. Since untreated lung cancer confers a 100% mortality, and since there is no other treatment that can potentially cure stage I non-small-cell lung cancer, surgery seems to be a rationale approach to consider in selected severe COPD patients who are deemed to be good LVRS candidates. However, it is premature to conclude whether wedge

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resection with limited nodal dissection offers a survival advantage comparable to standard lobectomy with hilar and mediastinal dissection in the surgical treatment of lung cancer. Additional studies are needed to compare the various surgical types of treatment with/or without the use of neoadjuvant chemotherapy or radiotherapy.

III.

LVRS and Coronary Artery Disease

A. Incidence of Coronary Artery Disease in Patients with Emphysema

Since LVRS candidates are typically males in their sixth decade of life with greater than 50 pack years of smoking history, it is not uncommon to uncover signiﬁcant concomitant cardiac disease in the course of LVRS evaluation. However, the diagnosis of coronary artery disease may not be readily apparent, since most patients with severe COPD are forced to live a sedentary life style due to incapacitating breathlessness brought on by a limited ventilatory reserve. Thus, these patients may either have asymptomatic cardiac disease that is masked by severe lung disease, or they may present with atypical cardiac symptoms such as frequent COPD exacerbations not readily amenable to standard medical therapy. Indeed, the incidence of asymptomatic but signiﬁcant coronary artery disease (CAD) in patients who undergo LVRS evaluation has been estimated to be as high as 15% in one study (28). Our data conﬁrm the same high prevalence of silent ischemic heart disease in COPD patients as reported by others. Since the inception of our LVRS and lung transplant program, we have screened 336 patients with severe COPD between June, 1993 and August, 1998. A total of 115 patients underwent left heart catheterization as part of their routine evaluation. Of 115 patients, 105 were asymptomatic for coronary artery disease, 6 patients had a previous history of coronary artery disease, 2 patients had symptoms of coronary artery disease, and 2 patients had abnormal exercise stress tests. Thirty-three patients (30%) had angiographic evidence of signiﬁcant coronary artery disease. Twenty of the 34 patients had severe coronary artery disease (17%). Ten of the 20 patients were completely asymptomatic and underwent only routine cardiac catheterization. The true incidence of CAD in patients with COPD is probably higher, since patients who have a history of myocardial infarction or congestive heart failure are often excluded from LVRS evaluation.

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Because both cardiac and lung diseases have many common clinical symptoms (e.g., dyspnea, chest pain, exercise intolerance), as well as risk factors (advanced age, smoking), CAD may not be appreciated during the initial evaluation of COPD patients who are otherwise considered LVRS candidates. In a recent study comparing the cardiovascular risk factors of COPD patients with and without CAD who underwent angiography as a part of LVRS evaluation, Thurnbeer and associates (28) showed that COPD patients who had CAD tended to smoke longer and have higher cholesterol levels, and about a third of them had other additional atherosclerotic risk factors such as diabetes mellitus and arterial hypertension. Table 3 illustrates the differences between the two groups in detail. This study seems to suggest that the presence of certain risk factors may be a useful guide in selecting which subset of LVRS patients may require more detailed cardiovascular work-up during LVRS evaluation. In a study involving 77 lung transplant candidates, Leibowitz et al. (29) found that a subset of patients with coronary risk factors may beneﬁt from routine coronary angiography. They concluded that routine angiography in lung transplant candidates with history of smoking but without additional coronary risk factors is unwarranted. Noninvasive Cardiac Evaluation

The goal of cardiac evaluation in LVRS candidates is twofold: to decrease perioperative mortality related to undiagnosed cardiac disease and, in patients with already diagnosed cardiac disease, to evaluate for possible

Table 3 Comparison of Cardiovascular Risk Factors in COPD Patients with and Without CAD Risk factor Smoking (pk/yrs) Diabetes mellitus (%) Arterial hypertension (%) Cholesterol mmol/L (mean + SD) Cholesterol >6.2 mmol/L (%)

COPD with CAD (n ¼ 35)

COPD without CAD (n ¼ 6)

P value

43 + 27 2.9 2.9 5.5 + 1.1 21.2

59 + 27 16.7 16.7 7.6 + 0.9 100

<.09 .27 .27 <.01 <.01

CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease. Source: Ref. 28.

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combined LVRS and cardiac surgery. At the present time, there is no standard work-up to detect the presence of signiﬁcant cardiac disease in patients who are undergoing LVRS evaluation. Common cardiac preoperative work-up may include: 12-lead electrocardiogram, two-dimensional echocardiogram, and a symptom-limited cardiopulmonary exercise test. Dobutamine echocardiography, dipyridamole thallium 210 scintigraphy, and coronary angiography are tests commonly reserved for patients with a strong clinical suspicion of CAD. Currently, the literature is not consistent in recommending a formal evaluation of CAD in the preoperative LVRS patient. Cooper and Patterson used left and right heart catheterization only when clinically indicated (30). In contrast, Millers and associates utilized dobutamine stress echocardiography and right heart catheterization in all their LVRS patients (31). Coronary angiography was only performed in patients with abnormal dobutamine stress echocardiography. Other investigators used dobutamine stress echo or left heart catheterization preoperatively only in LVRS patients suspected of having CAD (32). Preoperative cardiac risk assessment for noncardiac surgery has been published (33). However, since patients with severe emphysema are not commonly thought of as surgical candidates, preoperative cardiac work-up for LVRS is not speciﬁed. As previously discussed, patients with severe emphysema with concomitant coronary artery disease may pose a diagnostic challenge apart from the fact that a signiﬁcant number of them are asymptomatic. Standardized cardiac exercise stress testing is not a sensitive way to detect myocardial ischemia, because almost all of the patients with severe airﬂow obstruction stop exercise testing prematurely owing to ventilatory limitation before achieving the targeted heart rate (34). In addition, two-dimensional echocardiography is often reported as a suboptimal study because of inadequate viewing window secondary to hyperinﬂation. In a study involving 23 lung transplant candidates with a variety of end-stage lung diseases, dobutamine thallium stress test had high sensitivity but low speciﬁcity for the detection of coronary artery disease (35). The patient population studied, however, was much younger than that of LVRS candidates. Based on epidemiological data, it is not surprising for a test to have a low predictive value if the incidence of a particular disease is low. In a recent meta-analysis, dypyridamole–thallium 201 imaging has been shown to have high prognostic value for preoperative ischemic events in patients with a high prevalence of coronary artery disease (36). Thus, it appears that noninvasive cardiac testing such as dobutamine or dipyridamole stress thallium 201 scintigraphy is a safe and useful screening test in LVRS candidates who are suspected of having signiﬁcant coronary artery disease. We recommend left heart catheterization only if noninvasive cardiac testing is suspicious of coronary artery disease. Figure 2 describes an

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Figure 2

Preoperative cardiac evaluation of LVRS candidates.

algorithm for preoperative cardiac evaluation in patients who are LVRS candidates. Once detailed anatomy of the coronary arteries is elucidated, treatment options as such as coronary angioplasty prior to LVRS or combined LVRS and coronary artery bypass grafting can be entertained.

B. Combined LVRS and Coronary Artery Bypass Grafting

The technical feat of combined pulmonary resection and cardiac surgery has been successfully previously performed in only a small number of patients. In the pre-LVRS era, the majority of combined cardiothoracic surgeries involving coronary artery bypass with resection of lung tissue were only reported in a few cases suspected of having malignant pulmonary nodules. Since the reintroduction of LVRS, several investigators, including our group, have reported the feasibility of combined LVRS and coronary artery bypass grafting (5). The concept of combined major thoracic and cardiac surgery is appealing, because a single combined procedure avoids the risk of a second major operation, and may result in reduced overall hospitalization and medical costs, and improved patient survival. In addition, LVRS may make coronary artery bypass possible in patients with severe emphysema by

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signiﬁcantly improving lung function postoperatively, thus decreasing postoperative morbidity and mortality due to respiratory failure. Furukawa et al. (5), reported a 60-year-old male with peripheral vascular disease and triple-vessel coronary artery disease with greater than 90% blockage with severe COPD (FEV1 29%) who underwent bilateral LVRS and four-vessel coronary artery bypass grafting. Ten months after surgery, the patient was oxygen independent, his FEV1 increased to 1.3 L, he had no further angina, and all bypass grafts were patent. Successful coronary artery bypass grafting 32 months after bilateral LVRS has also been reported (37). However, cardiopulmonary bypass can potentially contribute to postoperative morbidity. There is a danger of pulmonary hemorrhage due to anticoagulation during cardiopulmonary bypass. Some investigators recommend resection after reversal of anticoagulation with protamine sulfate (38). In a recent review from the University of Toronto, only 1 of 19 patients who underwent LVRS during cardiopulmonary bypass suffered bleeding requiring reexploration (39). The greater application of bypass coronary artery grafting may avoid the risk of perioperative hemorrhage and extend the application of combined coronary artery revascularization with LVRS in selected candidates. Currently, there are no comprehensive data that allow one to evaluate the true risk beneﬁt of combined LVRS and coronary artery revascularization in patients with severe lung and heart disease.

C. LVRS In Ventilator-Dependent Patients

Prolonged mechanical ventilation and difﬁculty weaning from ventilator support often results from an acute exacerbation of airﬂow obstruction despite optimal medical therapy. The incidence of ventilator dependency in patients with severe emphysema is unclear, but correlates with several factors such as advanced lung disease, the severity of deconditioning, respiratory muscle weakness, and degree of undernutrition, as well as the patient’s level of motivation. Approximately one-third of patients who were referred to our ventilator rehabilitation unit were patients with advanced emphysema who failed initial weaning trials. The prognosis of ventilatordependent COPD patient is poor, with several studies reporting a 30–49% 2- to 3-year survival rate (40,41). In addition to increased mortality, ventilator-dependent COPD patients also have an increased number of comorbidities associated with the process of mechanical ventilation (i.e., limited mobility, inability to communicate, recurrent respiratory tract infections, swallowing dysfunction, and discomfort from ventilator–patient dyssynchrony).

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Ventilator-dependent COPD patients are often excluded from LVRS evaluation because of preexisting respiratory failure, signiﬁcant pulmonary hypertension, and deconditioning. We recently reported three ventilatordependent COPD patients who were successfully weaned from mechanical ventilation after LVRS (15). All three patients had severe COPD (FEV1 0.41 L in two patients), chronic hypercapnia (PaCO2 55 mmHg in two patients and 70 mmHg in one patient), and signiﬁcant respiratory muscle weakness (mean maximum inspiratory muscle strength of 29 cmH2O). In addition, all three patients had evidence of cor pulmonale by echocardiogram. These patients had had multiple episodes of intubation and mechanical ventilation owing to acute exacerbations of their underlying COPD, and at the time of LVRS evaluation, they had been on mechanical ventilation between 11 and 16 weeks. They showed evidence of hyperinﬂation with heterogeneous involvement of the lung parenchyma as demonstrated by chest CT scan and ventilation–perfusion scanning (Fig. 3). All three patients had been on oral steroids which were weaned to the lowest possible dose prior to LVRS. They were admitted to our Ventilator Rehabilitation Unit, which is a noninvasive respiratory care unit which emphasizes respiratory and whole-body reconditioning to maximize the condition of patients weaning from prolonged mechanical ventilation. However, despite aggressive medical care, all three patients failed multiple weaning attempts. After LVRS, there was a signiﬁcant improvement in gas exchange parameters as shown by increases in PaO2/FIO2 and reduction in PaCO2. In addition, signiﬁcant increases in FVC and MIP after surgery were noted

Table 4 Lung Function Before and 12–20 Weeks After LVRS in VentilatorDependent COPD Patients FVC (L)

PaCO2 (mmHg)

MIP (cmH2O)

Baseline Case 1 Case 2 Case 3

1.04 1.08 1.15

70 55 55

32 16 40

12–20 weeks postoperatively Case 1 Case 2 Case 3

2.89 1.80 2.04

42 43 40

70 32 70

FVC, forced vital capacity; MIP, maximum inspired pressure. Source: Ref. 15.

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(Table 4). Postoperative complications included persistent air leaks and one tension pneumothorax. All patients were successfully weaned from mechanical ventilation after 10–21 days and were discharged home. Since this initial report, we have performed LVRS in three additional ventilator-dependent COPD patients and have reported their clinical outcome on prolonged follow-up (mean 12 months) (14). One of six patients died from sepsis 3 months after surgery. Of the remaining ﬁve patients, none has required mechanical ventilation or corticosteroids. Three patients require no supplemental oxygen and two have returned to work. FEV1 of the ﬁve survivors increased from 0.39 + 0.05 to 0.68 + 0.35 at 3 months. Arterial CO2 decreased from 65 + 15 mmHg to 48 + 18 mmHg at 3 months and 47 + 8 mmHg at 5–23 months after surgery. Schmid and others (13) reported a patient with severe emphysema and mitral stenosis who was originally scheduled to undergo combined LVRS and mitral valve replacement. However, owing to intraoperative complications, LVRS was postponed. The postoperative course was complicated by cardiac tamponade, bilateral pneumothoraces, and a large left bronchopleural ﬁstula. Based on this stormy postoperative course, Schmid et al. concluded that extubation was impossible. The patient subsequently underwent LVRS on the third postoperative day and tracheostomy on the ﬁfth postoperative day. The patient was decannulated 18 days after LVRS. Hansson et al. (42) described a dramatic case of a 51-year-old male who developed bilateral pneumothoraces, respiratory failure requiring mechanical ventilation, and massive bilateral air leaks who underwent LVRS as an ‘‘emergency and life saving procedure.’’ Not only did the patient survive, his FEV1 at 3 months had increased by almost 100%. Similar to our case series, the patient in this report showed a substantial improvement in respiratory function 3 months after LVRS. Unlike our case series, the patient in this report was on mechanical ventilator for only a short period of time and therefore may not have been deconditioned or undernourished as typically are patients on prolonged mechanical ventilation. Nevertheless, these investigators concluded that LVRS facilitated successful weaning in their patient. More recently, Murtuza (43) reported a patient with severe emphysema who was admitted with acute respiratory failure. The patient had two previous episodes of intubation and mechanical ventilation, and had been on nocturnal nasal intermittent positive-pressure ventilation for 12 months. During her hospital stay, the patient became increasingly difﬁcult to ventilate. Chest CT showed emphysema predominantly affecting both upper lobes, and she underwent bilateral LVRS via a clam shell incision. Within 12 days, she was able to sustain spontaneous ventilation for an extended period of time, and was successfully extubated on postoperative

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Figure 3 (A) Lung perfusion scan of patient 3 prior to surgery showing attenuation of the perfusion density in both upper lung ﬁelds. (B) Cross-sectional CT scan image of the upper lung ﬁelds in the same patient showing evidence of diffuse bullous emphysema and decreased pulmonary vasculature.

day 19. She was discharged on postoperative day 30 with oxygen therapy and nocturnal noninvasive positive-pressure ventilation. Based on our experience and that of other investigators, LVRS in a select group of ventilator-dependent COPD patients may improve gas exchange, spirometry, and respiratory muscle function so as to improve functional status and the ability to wean from ventilator support. We believe that only patients with a heterogeneous distribution of emphysema

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Figure 3 Continued.

predominantly affecting both upper lobes as evidenced by CT scan and lung perfusion scan should be considered for LVRS. Patients with mild to moderate hypercapnia may undergo LVRS without an increase in morbidity or mortality. We would like to emphasize, however, that our series of patients described above were treated in a special unit geared toward reconditioning the ventilated patients. Therefore, we recommend that surgery in ventilator-dependent COPD should only be done in centers with a multidisciplinary team that includes pulmonologists; respiratory, physical, occupational, and speech therapists; psychologists; and nutritionists skilled in the care of ventilator-dependent patients in order to optimize the patient’s overall condition prior to LVRS. D. LVRS After Single-Lung Transplantation in Severe COPD

The interface between LVRS and lung transplantation is explored in greater detail in Chapter 9. Emphysema has become the leading indication for single-lung transplantation (44,45). However, hyperinﬂation of the native lung during the late posttransplant period has been reported. It is currently unclear as to whether this is due to progression of emphysema or to allograft

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dysfunction. Measurement of lung volumes of native and transplanted lungs after single-lung transplantation for COPD has shown that the transplanted lung has smaller than predicted lung volumes with native lung volume size increasing up to 6 months after transplantation (46). Other investigators have not shown signiﬁcant restriction of the transplanted lung (47). Clearly, hyperinﬂation of the native lung may be promoted by a decrease in compliance of the transplanted lung due to infection or rejection, especially in patients who develop bronchiolitis obliterans. The incidence of clinically signiﬁcant hyperinﬂation of the native lung after single-lung transplantation in COPD patient is not known but has been reported to be as high as 5% (17). The most common clinical presentation is worsening dyspnea and exercise intolerance. The chest radiograph typically shows hyperinﬂation of the native lung and herniation of the native lung via the anterior mediastinum with shift of the mediastinum to the contralateral side, thereby compressing the donor lung as shown in Figure 4. Native lung hyperinﬂation can be divided into early- and late-onset based on the presumed pathophysiology and therapy.

Figure 4 CT of the chest of a patient with severe COPD 14 months after left transplantation showing severe hyperinﬂation of the contralateral native lung with ipsilateral shift of the mediastinum and compression of the transplanted lung.

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Hyperinﬂation of the native lung that occurs during the perioperative period is most likely due to decreased compliance of the donor lung from variety of reasons such as noncardiogenic pulmonary edema, acute rejection, graft malfunction, or infection. Therapy is directed at improving the function of the transplanted lung, and speciﬁc decompressive maneuvers usually consist of proper patient positioning to ensure that the native lung is in a dependent position when the patient is in the lateral decubitus position. Because lung infection, acute rejection, or bronchiolitis obliterans may occur anytime during the posttransplant period, careful investigation (usually lung biopsy) is needed to rule out these disease entities. In patients who experience deteriorating lung function during the late posttransplant period, retransplantation is usually the only recourse left if the patient does not respond to treatments for concurrent infection or augmentation of immunosuppressive agents. If hyperinﬂation of the native lung is thought to be a signiﬁcant contributing factor in decreasing lung function, LVRS of the native lung to improve allograft function should be considered. Several case reports using a variety of surgical techniques have shown success in unilateral LVRS of the native lung after single-lung transplantation despite the fragile nature of these patients (16–18). After successful unilateral LVRS, patients usually experience symptomatic improvement and increase in exercise tolerance. Similarly, objective lung function testing shows substantial improvements in airﬂow and decreases in total lung capacity and residual volume. Anderson and coworkers (16) showed that in three patients who underwent LVRS 36–55 months after single-lung transplant for emphysema pulmonary function tests done 3 months after surgery demonstrated increases in mean FEV1 and FVC by 63 and 67%, respectively. Moreover, the functional residual and total lung capacities decreased by a mean of 38 and 26%, respectively. Additionally, exercise testing showed a modest but signiﬁcant increase in maximal oxygen consumption of 3.7 mL/kg/min. All patients had uneventful postoperative courses except for continuous lowvolume air leaks that eventually healed 2–3 weeks after surgery. The chest radiograph after unilateral LVRS showed the mediastinum returning to midline with resolution of native lung herniation across the midline into the contralateral chest. Recently, encouraging preliminary data from the University of Toronto showed that simultaneous single-lung transplantation and LVRS may result in a further improvement in lung function and exercise tolerance beyond the level of improvement usually seen after singlelung transplantation alone (48).

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LVRS as a Bridge to Lung Transplantation

End-stage lung disease due to emphysema remains the leading indication for lung transplantation. However, with the scarcity of organ donors prolonging the waiting period up to 18–24 months, the need for immunosuppression, and the constant risk of opportunistic infections, some investigators proposed to consider LVRS as an alternative to lung transplantation, so as to at least delay the time for eventual lung transplantation in a highly select cohort of patients with emphysema who meet criteria for both LVRS and lung transplantation (19,49). In a recent study from the University of Pittsburgh, 45 of 95 (47%) patients with end-stage emphysema who were evaluated for lung transplantation met dual criteria for lung transplantation or LVRS (19). Thirty of the 45 patients underwent LVRS. Three months after LVRS, there was a signiﬁcant increase in FEV1, maximum voluntary ventilation, and FVC, as well as a signiﬁcant decreased in hyperinﬂation and air trapping (Table 5). However, in subgroup analysis, 20 patients (group A) had signiﬁcant improvements in static lung function and exercise capacity compared to 10 other patients (group B) who had less than optimal improvement in lung function 3 months after LVRS (Table 6). Analysis of preoperative data between groups and the type of surgical techniques employed suggested that hypercapnia and unilateral LVRS may be predictors of poor outcome in these patients following LVRS. For example, all 10 patients in group B underwent unilateral thoracoscopic LVRS, whereas 6 of 29 in group A patients had bilateral LVRS. In 7 patients in group B who eventually required lung transplantation, 6 had preoperative hypercarbia compared to

Table 5 Lung Function Tests Before and 3 Months After LVRS in 30 Severe COPD Patients Who Were Also Lung Transplant Candidates Variable FEV1 (L) (% predicted) FVC (L) RV (L) TLC (L) MVV (L/min) 6-Min walk (ft)

Before LVRS (%) 0.64 + 0.22 (22) 2.12 + 0.68 (53) 5.62 + 1.67 (265) 7.8 + 1.8 (139) 28.1 + 9.7 904 + 282

3 Months after LVRS (%) P value 0.97 + 0.38 (35) 2.76 + 0.79 (71) 4.26 + 1.2 (214) 7.2 + 1.5 (128) 38.5 + 12.8 1012 + 229

<.0001 <.001 <.001 .07 <.01 <.05

FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity; MVV, maximum voluntary ventilation. Source: Ref. 19.

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Table 6 Comparison of Improvements in Lung Function Between Group A and Group B COPD Patients Who Underwent LVRS as an Alternative to Lung Transplantation Variable

Group A

Group B

% increase in FEV1 % increase in FVC % decrease in RV Transitional dyspnea index

70.6 + 38 40.8 + 18 26.4 + 12 1.82 + 0.6

29.4 + 45 21.3 + 34 1.5 + 13 1.17 + 0.3

P value <.01 <.05 <.0001 <.05

FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; RV, residual volumes. Source: Ref. 19.

8 of 20 patients in group A. All group A patients were deactivated from the transplant list. There was no reported increase in perioperative morbidity and mortality. A follow-up study by the same investigators showed that LVRS is an effective palliative alternative to lung transplantation in 75% of selected patients (50). In a similar study evaluating the impact of LVRS on timing and selection of lung transplant candidates, Bavaria and coworkers (49) showed that 77% (24 of 31) patients with end-stage emphysema who underwent LVRS were deactivated from the transplant list owing to substantial improvement in lung function 6 months after surgery. However, 4 of the 24 patients had more rapid decline in lung function and had to be relisted for lung transplantation. Perhaps more importantly, 23% (7 of 31) of the patient in this series either showed no improvement or, in fact, experienced a decline in lung function after LVRS. In contrast to the study from the University of Pittsburgh, seven patients who completed only unilateral LVRS had a signiﬁcant improvement in lung function after surgery. Bavaria et al. further concluded that the number of COPD patients listed for lung transplantation has decreased in part due to their LVRS program. Based on the current available studies, LVRS appears to be a viable alternative to lung transplantation in select patients with end-stage emphysema. Those patients who do not have substantial improvement in lung function after LVRS can undergo lung transplantation without added additional surgical morbidity and mortality. Whether LVRS decreases mortality in patients who are waiting for lung transplant remains to be elucidated.

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Summary

Lung volume reduction surgery has been shown to improve lung function, exercise capacity, and quality of life in short-term follow-up in a select group of patients with end-stage emphysema and other life-threatening co-morbid conditions. In addition, LVRS has redeﬁned the standard preoperative criteria for lung resection. Speciﬁcally, LVRS has made lung resection or complex cardiac surgery possible in patients with very poor pulmonary reserve. Improvement in lung mechanics following LVRS may help facilitate weaning in ventilator-dependent COPD patients. Based on preliminary data, LVRS may be useful as a bridge or as an alternative to lung transplantation in the treatment of end-stage COPD. Future investigations are needed to address the long-term outcome of LVRS in these special patient groups.

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39. Rao V, Todd TRJ, Weisel RD, et al. Results of combined pulmonary resection and cardiac operation. Ann Thorac Surg 1996; 62:342–347. 40. Moser KM, Shibel EM, Beamon AJ. Acute respiratory failure in obstructive lung disease: long-term survival after treatment in an intensive care unit. JAMA 1973; 225:705–707. 41. Asmundssen T, Kilburn KH. Survival of acute respiratory failure:a study 239 episodes. Ann Intern Med 1969; 70:471–485. 42. Hansson B, Jorens PG, van Schil P, van Kerckhoven W, van den Brande F, Eyskens E. Lung volume reduction surgery as an emergency and life-saving procedure. Eur Respir J 1997; 10:2650–2652. 43. Murtuza B, Keogh BF, Simonds AK, Pepper JR. Lung volume reduction surgery in a ventilated patient with severe pulmonary emphysema. Ann Thorac Surg 2001; 71:1037–1038. 44. Marinelli WA, Hertz MI, Shumway SJ, et al. Single lung transplantation for severe emphysema. J Heart Lung Transplant 1992; 11:577–583. 45. Trulock EP, Egan TM, Kouchoukos NT, et al. Single lung transplantation for severe chronic obstructive pulmonary disease. Chest 1989; 96:738–742. 46. Cherijan AF, Garrity ER, Pifarre R, Fahey PJ, Walsh JM. Reduced transplant lung volumes after single lung transplantation for chronic obstructive lung disease. Am J Respir Crit Care Med 1995; 151:851–853. 47. Brunsting LA, Lupinetti FM, Cascade PN, et al. Pulmonary function in single lung transplantation for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1994; 107:1337–1345. 48. Todd R, Perron J, Winston TL, Keshavjee SH. Simultaneous single-lung transplantation and lung volume reduction. Ann Thorac Surg 1997; 63:1468– 1470. 49. Bavaria JE, Pochettino A, Kotloff RM, Rosengard BR, Wahl PM, Roberts JR, Palevskey HI, Kaiser LR. Effect of volume reduction on lung transplant timing and selection for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1998; 115:9–18. 50. Zenati M, Keenan R, Courcoulas AP, Grifﬁth BP. Lung volume reduction or lung transplantation for end-stage pulmonary emphysema? Eur J Cardiothorac Surg 1998; 14:27–31.

19 Financial Aspects of Emphysema and Emphysema Surgery

SCOTT RAMSEY

SEAN D. SULLIVAN

Fred Hutchinson Cancer Research Center Seattle, Washington, U.S.A.

University of Washington Seattle, Washington, U.S.A.

TODD A. LEE Midwest Center for Health Services and Policy Research and Hines VA Hospital Hines, Illinois, U.S.A.

I. Introduction As health care costs continue to escalate, more emphasis is being placed on the economic implications of diseases and their treatments. Emphysema affects approximately 1.9 million Americans and is one of the fastest growing causes of morbidity and mortality in the United States (1,2). Given the prevalence of the disease and duration of illness for those affected, the impact of emphysema on the U.S. health economy is substantial. More importantly, because emphysema is highly prevalent, new treatments that are widely adopted for this condition, even if inexpensive at the individual level, can have a tremendous impact on the overall economic burden of the disease. Thus, in today’s cost-conscious environment, evaluating the economic impact of new therapies has become nearly as important as understanding their clinical impact. Emphysema and chronic bronchitis are the two primary components that constitute the condition commonly referred to as chronic obstructive pulmonary disease (COPD). Because patients with COPD suffer from varying degrees of both emphysema and bronchitis, determining the economic burden associated with each of the separate disease processes is 413

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difﬁcult. Therefore, most economic studies do not focus on the individual components of COPD; rather, they analyze the entire disease process. The current trend in health care is to focus on controlling costs, as many believe the amount of money spent on medical care is excessive. The managed care industry was the leader within the health care industry in determining effective ways to control costs. Medicare and Medicaid also now offer most beneﬁciaries an option to enroll in a managed care organization. Because emphysema is most prevalent in the population that is eligible for Medicare beneﬁts, economic analyses of emphysema and its treatments are of great interest for policymakers. Nevertheless, no study has yet quantiﬁed the overall economic burden of this disease at the level of the individual, and few studies have analyzed the economic impact of the individual treatments of emphysema. The goal of this chapter is to review the economic issues surrounding the treatment of emphysema.

II.

Economic Burden of Disease

The economic burden of a disease is deﬁned as the ﬁnancial impact the particular condition has on society. Economic burden, or cost of illness, studies provide insight into the economic impact that emphysema has on society as well as individuals and families. This approach separates the costs into direct and indirect costs of the disease. The direct costs are those associated with the intervention or treatment, whereas the indirect costs are those attributable to output losses that can be attributed to the disease (loss of work time, productivity). Economic burden studies can be useful for gauging the importance of the disease when making policy decisions. It is important to note that these studies are not used to assess the impact of individual treatment strategies on the costs of care. Evaluations of the economic impact of a particular treatment are made using cost-beneﬁt and cost-effectiveness analyses. The economic burden of COPD was estimated using data from the National Medical Expenditures Survey (NMES) (3). Based upon the 1987 NMES, it was estimated that total direct expenditures incurred by persons in the United States treated for COPD was nearly $8 billion. Approximately 23% of these expenditures were related directly to the treatment of COPD; the remainder was for treatment of comorbid conditions in persons with COPD, such as hypertension or other diseases prevalent in this population. The largest proportion of the total expenditures was for inpatient hospitalization—estimated at $5 billion a year. Outpatient clinic and ofﬁce

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visits accounted for over $900 million and $800 million, respectively. Prescription drug costs were responsible for 8.4% ($677 million) of the total direct medical expenditures. Expenditures for Medicare beneﬁciaries with COPD have been shown to be nearly 2.5 times higher than per capita total expenditures of those without COPD ($8482 vs. $3511) (4). As with other serious chronic conditions, the most severely affected individuals incur a disproportionate share of all costs associated with the condition in the population. Nearly 50% of the total Medicare payments for those with COPD were incurred by approximately 10% of the Medicare beneﬁciaries with COPD (4). Hospitalization-related costs—the largest portion of all expenditures for patients with COPD—commonly occur in the later stages of the disease. The NMES study estimated that per capita expenditures for inpatient hospitalizations in the COPD cohort were 2.7 times the per capita expenditures of the non-COPD cohort ($5409 vs. $2001). Treatments that prevent or limit hospitalizations could substantially impact the overall burden of this disease. In addition to direct costs, the economic burden of COPD also includes the costs associated with loss of productivity and underemployment. A recent analysis by Sin and colleagues estimates that COPD was responsible for work loss of approximately $9.9 billion in the United States in 1994 (5).

A. Costs of Treatments

When considering the impact of alternative therapies for emphysema on the economic burden of the disease, it is most useful to examine the costs of an individual treatment in relation to the best alternative therapy or therapies. Medical treatments include supplemental oxygen and bronchodilating and anti-inﬂammatory medications. Adjunct interventions include patient education and pulmonary rehabilitation programs. Surgical therapies include lung transplantation and the lung volume reduction surgery (LVRS). Although these treatment alternatives are used in different places along the disease continuum, several are often used in combination as complementary treatments. For example, when an individual is placed on medical management, they are often referred to an educational program to learn more about their disease. Because of this complementary nature of interventions for emphysema, it is difﬁcult to separate the treatments for emphysema and analyze their economic impact individually. This is an important limitation of most reported economic analyses of emphysema therapies, as most usually focus on a single therapy in relation to ‘‘placebo’’ or a single alternative.

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Sclar et al. analyzed the health service expenditures of COPD patients treated with pharmacotherapy (6). Their study estimated newly diagnosed COPD patients’ expenditures for prescription, physician, laboratory, and hospital services over 15 months. The results were adjusted for age, gender, comorbid diseases, forced expiratory volume in 1s (FEV1) percentage of predicted, and type of pharmacotherapy. The average estimated costs of health care for an individual over a 15-month period ranged from $596 to $954 in 1994 dollars. Since the largest share of expenditures in newly diagnosed patients with emphysema are for prescription drugs and physician visits, the results of this study may be a reasonable estimate of the initial cost of pharmacological intervention. However, as noted above, the greatest percentage of health care expenditures for emphysema occur late in the disease process. Therefore, although this analysis may provide information regarding the economic impact of treatment for early-stage emphysema, the overall impact of medical therapy on emphysema may be relatively small, particularly in later stages where the greatest proportion of costs are incurred for hospitalizations. Supplemental home oxygen is usually the most costly component of outpatient therapy for adults with emphysema who require this therapy (7). Reviews of the cost effectiveness of alternative outpatient oxygen delivery methods suggest that oxygen concentrator devices may be cost saving compared to cylinder delivery systems (8,19). C. Education and Pulmonary Rehabilitation

Educational and pulmonary rehabilitation programs have been shown to have beneﬁcial effects in patients with COPD (9). Educational programs have been promoted as an economically attractive intervention for individuals with COPD (10). A Canadian study found that the incremental cost of pulmonary rehabilitation at $11,597 (CDN) per person. Statistically signiﬁcant improvements in dyspnea, fatigue, emotional health, and mastery were observed (11). An observational study with a small number of subjects found that patients in a pulmonary rehabilitation program utilized fewer health care services compared to those without rehabilitation (12). Because of study design limitations, it is unclear whether these results are generalizable to a larger, more diverse group of patients. The initial costs of the rehabilitation program may be offset if urgent care and emergency room visits or hospitalizations are subsequently reduced. A lingering question regarding pulmonary rehabilitation programs is whether the physiological and psychological beneﬁts from the program

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decay over time. The beneﬁts of rehabilitation programs have been observed to diminish as time from the intervention increases (7). If the beneﬁts of rehabilitation programs are short lived or rehabilitation requires frequent reintervention to maintain a given level of beneﬁt, then it is possible that the costs of these programs will not offset savings from reduced use of other COPD-related health care services. D. Lung Volume Reduction Surgery

Since being reintroduced in the early 1990s, lung volume reduction surgery (LVRS) has become a widely available option for treating severely disabling emphysema (13). Considerable debate has surrounded the role of LVRS in treating emphysema, since evidence from controlled studies is lacking. The potential economic impact of LVRS on the health economy has been an integral but often unspoken part of the controversy surrounding this procedure. Given the prevalence of the disease and the proportion of patients who are potentially eligible, it has been projected that widespread adoption of this procedure could cost the U.S. health economy more than $6 billion in the ﬁrst few years that the procedure is widely used (14). The Health Care Financing Administration (HCFA) has added to the controversy by stating that Medicare will no longer provide reimbursement for LVRS until sufﬁcient evidence exists regarding the safety and efﬁcacy of the treatment. A number of studies have estimated costs for LVRS. Elpern and colleagues analyzed the hospital costs associated with LVRS in 52 consecutive patients (15). Total hospital costs ranged from $11,712 to $121,829, and were signiﬁcantly associated with length of stay, both in the intensive care unit and total length of stay in the hospital. A small number of individuals incurred extraordinary costs because of complications such as difﬁculty being weaned from the ventilator after the procedure. The mean cost in this study was $30,976 and the median cost was $19,771. Advanced age was a signiﬁcant factor leading to higher than expected total hospital costs. The Agency for Health Care Policy and Research circulated an open query regarding costs to centers performing LVRS. Only three centers provided information. Costs ranged from $29,000 to $48,666 for hospitalization plus surgeons’ fees (16). Albert and colleagues also evaluated the hospital charges in 23 consecutive patients admitted for LVRS at a single institution (17). Charges ranged from $20,032 to $75,561. Again, the distribution of charges was skewed, as a small number of patients were responsible for the highest charges. The median charge in their analysis was $26,669. As with the Elpern study, total charges were highly correlated with duration of stay. In

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both studies, the largest expenditure component was for professional fees and room charges. An important limitation of the Albert study is that charges may correlate poorly with either true medical care costs or reimbursements by the health insurer. However, both studies suggest that the costs of LVRS may fall when complication rates and average length of stay decreases over time as caregivers gain experience with the procedure. E.

Lung Transplantation

Lung transplantation is a costly but often effective therapy for severe emphysema. Ramsey and colleagues examined the hospitalization costs associated with lung transplantation (18). Other studies of lifetime expenditures for lung transplantation have ranged from $110,000 to well over $200,000 (22,23). Unlike LVRS, the costs associated with lung transplantation remain elevated for months to years after surgery. This is due to the high cost of immunosuppression and managing infections and other complications such as bronchiolitis obliterans that commonly occur posttransplant.

III.

Cost-Effectiveness Analysis

Although treatment costs are an important element of the economic impact of therapies for emphysema, they can provide a misleading picture when viewed without reference to the level of beneﬁt or comparison to the costs and beneﬁts of the best alternative therapy. For example, the costs and beneﬁts associated with LVRS must be compared to the costs and beneﬁts afforded from maximal medical therapy. Simultaneous evaluation of costs and beneﬁts of competing therapies is most commonly performed using cost-effectiveness analyses (CEA). CEA is now a widely accepted means by which to evaluate new technologies or treatments in the health care industry. This analytic technique is designed to compare two competing alternatives for a given health condition. It is important to note that the results of CEA are greatly affected by changes in the effectiveness of the intervention. Therefore, it is essential that the effectiveness of the interventions being compared are clearly understood or are analyzed prior to undertaking a CEA. Inherent in CEA is its comparative nature. That is, interventions can never be evaluated alone, but must be compared to an alternative, because CEA relies on making decisions based upon the opportunity costs associated with the competing alternatives. At the very least, an intervention must be compared to usual care or ‘‘no treatment.’’

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The bottom line of CEA shows the ‘‘extra’’ or incremental cost of one procedure in relation to the ‘‘extra’’ or incremental beneﬁt when compared to the best alternative treatment. This result is shown as a ratio of costs over beneﬁts for the two alternatives: Incremental Cost Effectiveness; Treatment A CostA CostB ¼ EffectivenessA EffectivenessB

ð1Þ

Essentially, there are three types of CEAs performed to analyze medical interventions. The ﬁrst, known as cost-minimization analysis, seeks to determine the least expensive treatment among competing alternatives. Cost minimization can only be performed when the health outcomes for each alternative are so similar that there are no clinical or signiﬁcant differences between the treatment groups. In Equation (1) above, this implies that the denominator is not relevant, because the beneﬁts are considered to be equal for all interventions. However, in most cases, there are differences in the outcomes associated with alternative treatments, and thus cost comparison studies are only a portion of the important factors used when comparing treatments. A second type of CEA used to compare treatment alternatives is a cost-beneﬁt analysis. In cost-beneﬁt analysis, both the costs and consequences are valued in monetary units. These costs and beneﬁts are then adjusted for time preference to provide a measure of net present value. In this special case of CEA, a single program can be viewed in isolation. Total costs (which may include ‘‘downstream’’ savings in health care resource expenditures) and beneﬁts are tallied for the program. If costs exceed beneﬁts, the program is not adopted. If costs are less than or equal to beneﬁts, the treatment or intervention is considered to be cost beneﬁcial. Many believe that the cost-beneﬁt analysis methodology is difﬁcult to apply to health care. Cost-beneﬁt analysis usually requires asking individuals to assign a dollar value to the health beneﬁts gained from health care program or intervention. Assigning dollar values to health improvements is technically difﬁcult, and has been challenged as unethical. Because of these limitations and concerns, cost-beneﬁt analyses are performed less commonly in health care. The third type of CEA values beneﬁts in natural units. For example, in emphysema, the value of the beneﬁt could be in terms of life years saved or distance walked in the 6-min walk test. Here the CEA yields an incremental cost-effectiveness ratio comparing two competing interventions. The ratio provides a means to compare the incremental beneﬁt seen with one program as compared to a competing program or intervention. As with other

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economic evaluations, the costs are evaluated comprehensively and are not limited to the costs of the intervention. Both the direct and indirect costs are included in the cost portion of the ratio. Cost-utility analysis is a special subset of CEA in which the beneﬁts of the program or intervention are valued in terms of quality adjusted life years (QALYs). QALYs are a measure of life expectancy adjusted for quality of life as perceived by the individual over that lifetime. For example, if life expectancy after LVRS was 2 years on average, and quality of life was found to be 0.7 on a 0 (death) to 1 (optimal health) on average over this time period, then LVRS would have 1.4 QALYs. This value would be compared to the QALYs afforded by other interventions such as medical therapy. The advantage of using QALYs in economic evaluations of health care is that it takes into account the morbidity, mortality, and patient preferences associated with a disease and its intervention. This methodology is particularly useful in emphysema, as many of the interventions are not associated with signiﬁcant differences in overall mortality.

IV.

Cost Effectiveness of Therapies for Emphysema

Very little information exists concerning the cost effectiveness of the competing alternatives available for the treatment of emphysema (19). This may stem in part from the difﬁculty of identifying the population on clinical grounds. No studies have analyzed the cost effectiveness of treatments speciﬁcally for a cohort of emphysematous patients. However, a small number of studies have been conducted that look at the cost effectiveness of various treatments in cohorts with lung disease that included patients with emphysema. For pharmacotherapy, Rutten-van Mo¨lken and associates investigated the costs and effects of adding inhaled anti-inﬂammatory therapy to inhaled b2-agonist by analyzing data from a randomized trial of 274 adult participants aged 18–60 years (20). Patients were selected for inclusion if they met the age criteria and had diagnosed moderately severe obstructive airway disease deﬁned by pulmonary function criteria. Patients were eligible if they had either asthma or COPD. Each was randomized to either ﬁxeddose inhaled terbutaline plus inhaled placebo, inhaled terbutaline plus 800 mg of inhaled beclomethasone per day, or inhaled terbutaline plus inhaled ipratropium bromide 160 mg per day. Patients were followed for up to 2.5 years or until premature withdrawal. The economic objective of this study was to determine the relative cost per unit of beneﬁt for the three therapeutic arms. The clinical results indicated that addition of the inhaled corticosteroid to ﬁxed-dose terbuta-

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line led to a signiﬁcant improvement in pulmonary function (FEV1 and PC20) and symptom-free days, whereas addition of the inhaled ipratropium bromide to ﬁxed-dose terbutaline produced no signiﬁcant clinical beneﬁts over placebo. The average annual monetary savings associated with the use of inhaled corticosteroid were not offset by the increase in costs from the average annual price of the inhaled product. The incremental cost effectiveness for inhaled corticosteroid was $201 per 10% improvement in FEV1 and $5 per symptom-free day gained. The incremental cost effectiveness of ipratropium bromide was not evaluated because of the lack of clinical beneﬁt relative to placebo. Jubran and colleagues performed a retrospective, chart-based costminimization analysis of theophylline versus ipratropium bromide for patients with COPD (21). They found that patients treated with ipratropium had lower costs and a greater number of complication-free months than those taking theophylline. No studies using the standard accepted methodologies noted above have directly assessed the cost effectiveness of educational programs or pulmonary rehabilitation programs for people with emphysema. Several small studies have examined the cost effectiveness of lung transplantation (18,22,23). Although no study focused exclusively on patients with a diagnosis of emphysema, this cohort represents the largest single diagnostic group undergoing lung transplantation today. The studies ﬁnd that quality-adjusted life expectancy can increase substantially in the transplant groups, but that costs are very high even by the standards of other organ transplants. Thus, these studies ﬁnd that lung transplantation is not particularly cost effective compared to other common transplant technologies. Further work will be needed to deﬁne better the cost effectiveness of lung transplantation in patients with severe emphysema. Although no data yet exist regarding the cost effectiveness of LVRS for severe emphysema, some have argued that it is reasonable to consider the costs and outcomes for LVRS relative to costs and outcomes for other medical procedures given the potential impact that this technology might have on the nation’s health care bill (24–26). The National Emphysema Treatment Trial (NETT), a multicenter, randomized controlled trial of LVRS versus maximal medical therapy for patients with severe emphysema, includes a parallel economic analysis (27). The purpose of the economic analysis is to determine the costs and cost effectiveness of LVRS versus medical therapy for this patient group. In addition, analyses will be performed to determine whether the cost effectiveness of LVRS is particularly high in certain patient subgroups. The NETT is one of the largest clinical trials to include a cost-effectiveness analysis component, and the only prospective clinical surgical trial to include economic endpoints. As

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such, it represents an important advance in the effort to produce timely, highly valid economic data alongside the clinical data for a new intervention for emphysema. A similar trial of LVRS versus standard therapy with ‘‘piggyback’’ economic endpoints is also being conducted in Canada.

V.

Summary

Because emphysema is highly prevalent and can be severely disabling for many years, medical expenditures for treating emphysema and its complications carry a substantial economic burden for societies and health plans worldwide. Nevertheless, very little economic information concerning emphysema is available in the literature today. In particular, very few costeffectiveness studies compare costs and outcomes of alternative treatments for emphysema. As options for treating this disease grows, more research will be needed to help guide caregivers and health plans regarding the most efﬁcient and effective ways of managing this disease.

References 1. 2. 3.

4.

5.

6.

7.

8.

American Lung Association, 1993. Staton GW Jr, Ingram RH Jr. Chronic obstructive diseases of the lung. Sci Am Med 1995; 3:1–25. Sullivan SD, Strassels S, Smith DH. Characterization of the incidence and cost of COPD in the U.S. European Respiratory Society, Stockholm, September, 1996. Grasso ME, Weller WE, Shaffer TJ, Diette GB, Anderson GF. Capitation, managed care, and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 158:133–138. Sin DS, Saﬁnski T, Ng YC, Bell NR, Jacobs, P. The impact of chronic obstructive pulmonary disease on work loss in the United States. Am J Respir Crit Care Med 2002; 165:704–707. Sclar DA, m Leff RF, Skaer TL, Robison LM, Nemic NL. Ipratropium bromide in the management of chronic obstructive pulmonary disease: effect on health service expenditures. Clin Ther 1994; 16:595–601. Petty TL, O’Donohue WJ Jr. Further recommendations for prescribing, reimbursement, technology development, and research in long-term oxygen therapy. Summary of the Fourth Oxygen Consensus Conference, Washington, DC, October 15–16, 1993. Am J Respir Crit Care Med 1994; 150:875–877. Pelletier-Fleury N, Lanoe JL, Fleury B, Fardeau M. The cost of treating COPD patients with long-term oxygen therapy in a French population. Chest 1996; 110:411–416.

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10. 11. 12.

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Ries AL, Kaplan RM, Limberg TM, Prewitt LM. Effects of pulmonary rehabilitation on physiologic and psychological and psychosocial outcomes in patients with chronic obstructive pulmonary disease. Ann Intern Med 1995; 122:823–832. Folgering H, Rooyakkers J, Herwaarden C. Education and cost/beneﬁt ratios in pulmonary patients. Monaldi Arch Chest Dis 1994; 49:166–168. Goldstein RS, Gort EH, Guyatt GH, Feeny D. Economic analysis of respiratory rehabilitation. Chest 1997; 112:370–379. Ries AL. Position paper of the American Association of Cardiovascular and Pulmonary Rehabilitation: scientiﬁc basis of pulmonary rehabilitation. J Cardiopulm Rehabi 1990; 10:418–441. Huizenga HF, Ramsey SD, Albert RA. Estimated growth of lung volume reduction surgery among Medicare enrollees: 1994–1996. Chest. In press. Second Opinion. Why Medicare covers a new lung surgery for just a few patients. Gentry C. Wall Street Journal, June 29, 1998. Elpern EH, Behner KG, Klontz B, et al. Lung volume reduction surgery. An analysis of hospital costs. Chest 1998; 113:896–899. Lung Volume Reduction Surgery for End-Stage Chronic Obstructive Pulmonary Disease. Health Technology Assessment: Number 10. U.S. Department of Health and Human Services Public Health Service, Agency for Health Care Policy and Research. Rockville, MD, September 1996. AHCPR Pub. No. 960062. Albert RK, Lewis S. Wood D, Benditt JO. Economic aspects of lung volume reduction surgery. Chest 1996; 110:1068–1071. Ramsey SD, Patrick DL, Albert RK, et al. The cost-effectiveness of lung transplantation: a pilot study. Chest 1995; 108:1594–1601. Molken MP, Van Doorslaer EK, Rutten FF. Economic appraisal of asthma and COPD care: a literature review 1980–1991. Soc Sci Med 1992; 35:161–175. Rutten-van Mo¨lken MP, Van Doorslaer EK, Jansen MC, Kerstjens HA, Rutten FF. Costs and effects of inhaled corticosteroids and bronchodilators in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 151(4):975–982. Jubran A, Gross N, Ramsdell J, Simonian R, Schuttenhelm K, Sax M, Kaniecki DJ, Arnold RJ, Sonnenberg FA. Comparative cost-effectiveness analysis of theophylline and ipratropium bromide in chronic obstructive pulmonary disease. A three-center study. Chest 1993; 103(3):78–84. Gartner SH, Sevick MA, Keenan RJ, Chen GJ. Cost-utility of lung transplantation: a pilot study. J Heart Lung Transplant 1997; 16(11):129–134. Al MJ, Koopmanschap MA, van Enckevort PJ, Geertsma A, van der Bij W, de Boer WJ, TenVergert EM. Cost-effectiveness of lung transplantation in The Netherlands: a scenario analysis. Chest 1998; 113(1):124–130. Snider GL. Health-care technology assessment of surgical procedures: the case of reduction pneumoplasty for emphysema (comment). Am J Respir Crit Care Med 1996; 154(3 Pt 1):824.

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25. Make BJ, Fein AM. Is volume reduction surgery appropriate in the treatment of emphysema? No (editorial). Am J Respir Crit Care Med 1996; 153(4 Pt 1):1205–1207. 26. Utz JD, Hubmayr RD, Deschamps C. Lung volume reduction surgery for emphysema: out on a limb without a NETT (see comments). Mayo Clin Proc 1998; 73(6):552–566. 27. Ramsey SD, Sullivan SD, Kaplan RM, Wood DE, Chiang YP, Wagner JL. Economic analysis of lung volume reduction surgery as part of the National Emphysema Treatment Trial. Ann Thorac Surg 2001; 71:995–1002.

20 Not the Final Chapter: The National Emphysema Treatment Trial

HENRY E. FESSLER

ALFRED P. FISHMAN

Johns Hopkins Medical Institutions Baltimore, Maryland, U.S.A.

University of Pennsylvania School of Medicine Philadelphia, Pennsylvania, U.S.A.

JOHN J. REILLY, JR. Harvard Medical School and Brigham & Women’s Hospital Boston, Massachusetts, U.S.A.

I. Origins of the National Emphysema Treatment Trial In 1995, Medicare faced a dilemma. Shortly following the publication of the ﬁrst contemporary case series of lung volume reduction surgery (LVRS) by Cooper et al. (1), there was a remarkable increase in the number of lung resections being performed in patients with chronic obstructive pulmonary disease (COPD) (2). Outcome and cost data for these operations were not readily available, because the absence of a speciﬁc Medicare billing code made it impossible to distinguish resections for cancer or lung nodules from those for LVRS. Nevertheless, the expense of a major thoracic resection, coupled with the high prevalence of emphysema, threatened to produce a Medicare cost estimated as high as $47 billion (3). In October 1995, the Health Care Financing Administration (HCFA; now the Centers for Medicare and Medicaid Services, CMS) published an International Classiﬁcation of Disease code for LVRS. This facilitated tracking of the procedure, although the extent to which other codes continued to be used for this operation remained uncertain. 425

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Faced with this uncertain efﬁcacy and potentially enormous cost, Medicare requested the Center for Health Care Technology (CHCT) branch of the Agency for Health Care Policy and Research (AHCPR) to undertake a review of the available data as a basis for a decision regarding Medicare coverage of the procedure. The CHCT reviewed the published series of LVRS, including related operations reported in the 1950s. The agency also wrote to organizations and medical institutions known or believed to be performing these operations in order to obtain any unpublished experience, and placed a notice in the Federal Register soliciting data. Twenty-seven hospitals provided additional data, selection criteria, cost information, and opinions. These data are published in detail in the public record (4). They report a wide variety of different selection criteria, operative approaches, and follow-up. The CHCT concluded: In considering all of the published and unpublished information obtained for this assessment, it cannot reasonably be concluded at this time that the objective data permit a logical and a scientiﬁcally defensible conclusion regarding the risks and the beneﬁts of LVRS as currently provided (4).

Furthermore: Notwithstanding, the data suggest that an as-yet undeﬁnable proportion of patients with severe COPD may have realized some beneﬁt from the procedure. If the surgery could be accomplished without undue morbidity or mortality, a prospective trial of LVRS under uniform protocol requirements with comprehensive long-term postoperative followup data is both ethically supportable and scientiﬁcally essential (4).

In early January 1996, HCFA adopted a noncoverage policy for LVRS. The considerations leading to the noncoverage policy were reviewed by Bruce Vladek, the HCFA Administrator at the time, in testimony before Congress in April of 1997 (5). He reported that published data on LVRS were limited to a relatively small group of case series. Moreover, these reports were based on a variety of surgical procedures with differing inclusion criteria, and as a rule, short-term and often incomplete follow-up. Vladek’s testimony included 1-year follow-up of the patients who had LVRS performed under its Medicare code during the last 3 months of 1995. Analysis of Medicare claims identiﬁed 711 patients who underwent LVRS during this period. By January 1997, 26% had died. Forty percent of patients had required acute care hospitalization in the 12 months after LVRS, with an average of 2.1 hospitalizations and 20 hospital days. Sixteen percent had required long-term care or rehabilitation hospitalization. Among these patients who had surgery, the number of patients requiring hospitalization, the number of hospitalizations per patient, and the number

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of hospital days (exclusive of the LVRS itself) were all greater in the year following the operation than in the year before (5). These data may well reﬂect the early experience at a large number of hospitals who were ill prepared to perform this procedure. Alternatively, they may reﬂect the natural history of such severe emphysema. Nevertheless, the data are representative of the general experience in the United States at the time; more so than are the more favorable published results from a few select centers. The results of the CHCT assessment provided justiﬁcation for the noncoverage policy, although the ﬁndings were not publicly available until April 1996, 3 months after the noncoverage policy had been announced. Meanwhile, coverage for this procedure was being provided by many private health insurers, including Blue Cross/Blue Shield, Aetna, and Kaiser Permanente. Reports in numerous lay publications, such as USA Today, the Boston Globe, and the New York Times (6–8), were generally positive and fueled demand for LVRS. Consequently, the Medicare decision left many emphysema patients uncertain about Medicare’s motivation and angry that the operation would only be available to those with ﬁnancial means or other insurance coverage. Some of this frustration was vented in hundreds of postings to Internet forums devoted to emphysema and thoracic surgery. The medical and scientiﬁc community was both excited and concerned by the rapid and potentially unsystematic spread of this procedure. A workshop was convened by the National Heart, Lung, and Blood Institute (NHLBI) in September 1995 at which experts in thoracic surgery, pulmonary medicine, physiology, and outcomes research debated the merits of the surgery. The workshop statement emphasized the need for more research to deﬁne the role of LVRS in the treatment of emphysema. Their ﬁnal recommendations advocated a prospective trial with a control, nonoperative arm (9). The noncoverage policy decision, coupled with the independent recognition of the need for a controlled trial of LVRS, led to an unprecedented collaboration between HCFA and the NHLBI. This was formalized in a Memorandum of Understanding to conduct a trial in which the National Institute of Health (NIH) was authorized to award and oversee the trial and Medicare would pay for the clinical services. In addition, the Agency for Health Care Policy and Research (AHCPR, now the Agency for Healthcare Research and Quality, AHRQ) also agreed to support a costeffectiveness study in parallel with the clinical trial. The studies were intended to deﬁne the role of LVRS in emphysema therapy and help set guidelines for Medicare coverage. In June 1996, a Request for Proposals (RFP) was announced by the NIH, and by December 1996, 18 clinical centers and a data coordinating center had been selected. The Steering

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Committee meeting held its ﬁrst meeting in Bethesda, Maryland, on January 27–28, 1997, and enrollment was scheduled to begin in early July 1997.

II.

Planning the NETT

Study design began in the midst of controversy. J.D. Cooper, while participating in the National Emphysema Treatment Trial (NETT) planning, remained a vocal advocate of the surgery. During the same April 1997 hearing at which Dr. Vladek testiﬁed, Cooper testiﬁed before the Health Subcommittee of the House Ways and Means Committee (10) that LVRS was of proven effectiveness for a well-deﬁned group of patients if performed at experienced centers. He argued that forcing Medicare recipients to agree to randomization effectively discriminated against them, and took treatment decisions out of the hands of their physicians. He criticized the torpid pace of HCFA coverage decisions. He also concluded, ‘‘If, for example, as is the case for LVRS, there is a well-deﬁned patient population for whom the beneﬁt is certain, randomization is not scientiﬁcally valid or ethically defensible.’’ Cooper was not alone in his criticisms. A patient advocacy group, The Coalition for Pulmonary Patient Care, obtained 65 physician’s signatures on a letter to Congress asking that the nonpayment decision be reversed. Numerous articles outlining the controversy appeared in the lay press (11,12). Planning for the trial proceeded carefully and with a healthy degree of internal debate. Participating investigators came from a variety of backgrounds in pulmonology, surgery, biostatistics, and physiology, and brought a range of opinions about LVRS and study design. Although the RFP set the outline of the trial, that is, that it would be prospective, randomized, and would compare LVRS by median sternotomy and thoracoscopic surgery to continued medical therapy, it fell to the investigators to reach consensus on the details. These included the speciﬁc inclusion and exclusion criteria, the testing and evaluation processes, the primary and secondary outcome variables, the deﬁnition of optimal medical therapy, and details of the surgical techniques. They had to write manuals of the procedures and patient consents, design the pulmonary rehabilitation component, hire and certify personnel and rehabilitation programs, and guide the protocol through each of the local institutional review boards. Among the investigators, substantial debate was engendered by the decision that the NETT surgeons and the principal pulmonologist at each center would be prohibited from performing LVRS or advising patients about LVRS outside of the conﬁnes of this clinical trial. It was argued, on one hand, that this would avoid conﬂict of interest or inconsistent actions in

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a setting of clinical equipoise. Furthermore, it mirrored the approach toward investigational drug therapy, in which the agent is not simultaneously offered to some patients as part of a randomized trial and to others at the investigator’s discretion. On the other hand, it was argued that this policy deprived patients of their free access to the physician of their choice, and might restrict their access to those best qualiﬁed to offer objective advice or skilled surgery. In April and December 1997, the NIH consulted with an independent ethical and legal panel, which concurred with the original policy. The panel reasoned that the study physicians had agreed to this restriction by their contractual agreement with the NHLBI. Moreover, the panel felt it would be impractical, unenforceable, and possibly unethical to require all patients at a participating institution (even if treated by a physician not involved in the NETT) to agree to be randomized. Nevertheless, Barnes/Jewish Hospital withdrew from the trial in April 1998 when its institutional review board refused to approve the protocol. Although HCFA had agreed to pay the study-related patient care costs, new or modiﬁed billing procedures had to be developed at both Medicare and the participating hospitals. Most of the hospitals also provided institutional support for ancillary personnel, since this essential component was funded neither by Medicare nor by the NIH. In October 1997, the ﬁrst patients were registered and the National Emphysema Treatment Trial (NETT) was ﬁnally underway.

III.

Rationale and Design

The NETT compared conventional medical therapy alone to medical therapy plus LVRS. Its goal for patient enrollment was 2500 randomized 1:1 to LVRS or medical therapy. The trial was to last for 5 years, with enrollment being staggered over the ﬁrst 4.5 years and follow-up ranging from 6 months to 5 years. Two surgical options were available. At some centers, surgeons would perform LVRS only by median sternotomy, at others, only by video-assisted thoracoscopic surgery (VATS), and at some, by either operation. At centers where both procedures were available, the surgical approach would be randomly allocated. Detailed inclusion and exclusion criteria have been published elsewhere (13). Major inclusion and exclusion criteria are shown in Table 1. The protocol speciﬁed two primary outcome variables: mortality and change in exercise capacity. The study size was based on power calculations using mortality as the outcome variable, which requires a larger sample size than the exercise outcome. The protocol speciﬁed a sample size of 2500 to

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Table 1 Inclusion 1. 2. 3. 4.

5. 6. 7.

Major Inclusion and Exclusion Criteria for the NETT History and physical exam consistent with emphysema Bilateral emphysema on CT scan Hyperinﬂation (TLC 5100% and RV 5150% predicted) FEV1 445% predicted (there was no lower limit of FEV1 except for patients older than 70 years, in whom FEV1 also had to be 515% predicted) PaCO2 460 mmHg and PaO2 545 mmHg on room air Approval by a cardiologist if any of a set of cardiac abnormalities was found Completion of the pulmonary rehabilitation program and all required assessments

Exclusion 1. Smoking within 6 months of randomization date (veriﬁed with cotinine measurement) 2. Previous major thoracic surgery 3. CT evidence of diffuse, severe emphysema judged ‘‘unsuitable for LVRS’’ 4. Giant bullae 5. Clinically signiﬁcant bronchiectasis or excessive sputum production 6. Obesity (body mass index >31.1 for males or 32.3 for females) 7. Pulmonary nodule requiring surgery 8. Signiﬁcant cardiac dysrhythmias 9. Pulmonary hypertension (mean pulmonary artery pressure 535 or systolic pressure 545 mmHg; screened by echocardiogram and conﬁrmed by right heart catheterization) 10. Cancer or systemic disease that would limit survival independent of emphysema 11. Myocardial infarction or congestive heart failure within the preceding 6 months and ejection fraction <45% 12. Postrehabilitation 6MWD 4140 ms 13. Oxygen requirements >6 L/min while walking at 1 mph Source: Modiﬁed from Ref. 13.

detect a 4% absolute difference in 4.5-year mortality with a type I error of 0.05 and 80% power. This assumed 8% annual mortality in the medical group, 5.6% loss to follow-up, 33% crossover from the medical group to surgery, and 6% crossover from the surgical group owing to refusal of surgery or late disqualiﬁcation from surgical eligibility. The second major outcome variable was change in exercise capacity. Exercise capacity was chosen over a pulmonary function measure, because it

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was thought to be more closely related to ability to perform daily activities, and it integrates cardiovascular, pulmonary, and psychomotor axes. There was considerable debate over what form of exercise test to use. Functional testing such as the 6-min walk distance (6MWD) was considered but not chosen as a primary outcome. Its advantages are that it uses a natural activity relevant to daily life, is simple to perform, and has been used in numerous studies of cardiac and pulmonary disease. However, the 6MWD has the disadvantage of being sensitive to motivation, variations in track layout, and experience (14–16). Maximal, symptom-limited cycle ergometry, although more complicated, was chosen as the main exercise parameter, because it could be better standardized and was felt to be more reproducible. The study size had a high power (93%) to detect a standardized between group difference of 0.15 standard deviations in exercise capacity. The 6MWD was retained as a secondary outcome variable, requiring two walks at each visit to reduce the learning effect (later changed to one walk). Finally, an oxygen titration test was designed speciﬁcally for the NETT. This test was intended to detect changes in oxygen requirements with exercise that might not be apparent by examining resting requirements alone. During the oxygen titration test, subjects walked on a level treadmill at 1 mph while the ﬂow of nasal oxygen was adjusted to maintain a minimum pulse oximeter saturation of at least 90%. Symptomatology was assessed using both general and disease-speciﬁc questionnaires. These were chosen based in part on their simplicity and speed of administration; the written questionnaires could be mailed and self-administered by the subjects. The general health instruments facilitated comparisons to other disease states. The Medical Outcomes Study 36-Item Short Form (SF-36) was chosen because of its wide usage and extensive validation (17). The Quality of Well-Being Scale (QWB) was chosen because it was necessary to calculate Quality Adjusted Life Years, an important element of cost-effectiveness analysis (18,19). Pulmonary disease–speciﬁc instruments are more sensitive to changes in pulmonary symptoms. The St. George’s Respiratory Questionnaire (SGRQ) was chosen because it has been widely used in patients with COPD (18). The Shortness of Breath Questionnaire was selected because it has been used to study response to pulmonary rehabilitation (20). The modiﬁed Borg Scale (21) was used to quantify dyspnea during exercise and 6MWD testing. Finally, attention and psychomotor function was measured over time with the Trail Making Test (22), and baseline screening for depression and anxiety was performed with the Self-Evaluation Questionnaire and the Beck Depression Inventory (23).

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Pulmonary function testing included spirometry before and after bronchodilators, plethysmographic lung volumes, single-breath carbon monoxide diffusing capacity, resting arterial blood gases on room air, and maximal inspiratory and expiratory mouth pressures. Cardiovascular assessment of all patients included a resting electrocardiogram, a dobutamine radionuclide stress test, and an echocardiogram, with a Doppler estimate of right ventricular systolic pressure. Patients with elevated pressures underwent right heart catheterization. Additional testing or cardiac consultation was obtained on an individual basis. Radiological studies included standard chest radiographs, helical computed tomographic (CT) scans during full inspiration and expiration, high-resolution CT scans, and a perfusion lung scan. The helical scan served to detect lung nodules and regional air trapping, and the high-resolution and perfusion scans were used to assess the distribution of emphysema. The CT scans were scored on a semiquantitative 0–4 scale, representing normal, 1– 25%, 26–50%, 51–75%, and 76–100% emphysema (airspace) in each of six lung zones (upper, middle, lower on the right and left). Radiologists were certiﬁed in the scoring system after reviewing and scoring a series of test scans. A centralized image analysis center was established by competitive application at the University of Iowa. All CT scans were electronically transferred there for quality control and for computerized analysis utilizing a variety of parameters based on CT density of voxels. Pulmonary rehabilitation for the NETT was planned to encourage lasting lifestyle change. It was divided into three phases: Prerandomization, postrandomization (consolidation), and maintenance. The prerandomization phase began with a 1-week core program administered at each of the clinical centers. This included the cognitive and psychosocial evaluation, goal setting, daily exercise sessions, and NETTspeciﬁc educational sessions. Thereafter, patients could enter rehabilitation at a local (‘‘satellite’’) center provided its program had been certiﬁed by NETT personnel. This program included 5–9 weeks of exercise and educational sessions (a minimum of 12 sessions), with weekly progress reports to the clinical center. Patients were then reevaluated at the core site to determine if goals had been met. The consolidation, or postrandomization, phase was begun immediately after randomization to medical therapy or as soon as possible after hospital discharge in patients randomized to the surgical arm. This consisted of two sessions at the core site followed by weekly sessions at the satellite center for 8 weeks. Its purpose was to reinforce the importance of life-long exercise as a new lifestyle. Maintenance therapy was to be continued indeﬁnitely, comprising regular, unsupervised exercise in the home, rehabilitation center, or ﬁtness

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center. This was reinforced by regular phone contacts and at follow-up visits. If the patient was found to have become sedentary, reenrollment in the comprehensive rehabilitation program was strongly encouraged. Costs of rehabilitation were also covered by Medicare. The NETT studies were of three types: (1) The main protocol performed at all centers; (2) substudies, which enrolled all willing participants at selected centers; and (3) ancillary studies, which could involve some or all centers. The main protocol, in addition to comparing mortality, quality of life, and exercise capacity of the two groups, sought to identify clinical criteria helpful in choosing the best or excluding the worst candidates for surgery, to compare the outcomes from the thoracoscopic and median sternotomy approaches, and to learn how long the improvements, if any, would last. Separately, the cost-effectiveness study was intended formally to assess the trade-off between the economic costs and the potential gains in clinical outcomes associated with the study interventions. The substudies focused on speciﬁc questions which required more intensive patient evaluation. These included detailed investigations of hemodynamics, lung mechanics, gas exchange during exercise. Ancillary studies, which used patients, data, or materials from the NETT, could be undertaken by independently funded outside or participating investigators with approval of the Steering Committee. Recruitment was initially left to the ingenuity and resources of the local centers. The initial screening was to be done by telephone. For those without contraindications by telephone screen, records were to be obtained from their referring physicians and reviewed by NETT personnel. Promising candidates would then be scheduled for an on-site evaluation. The evaluation and enrollment process was thorough but, consequently, also quite arduous. Potential subjects, all of whom were severely disabled by emphysema, underwent an exhaustive series of tests and interviews over several days. This was followed by a week of core pulmonary rehabilitation and by 5–9 weeks of prerandomization rehabilitation. Much of the initial testing was then repeated to conﬁrm eligibility and measure the impact of rehabilitation. Only at that point would participants be randomized. It was estimated that only 10–25% of candidates seen on-site would be found to be eligible. Most of the reasons for ineligibility were discovered during the initial series of tests. However, this extensive evaluation often revealed medical issues that required additional testing, such as lung nodules or cardiac abnormalities. If these issues could not be resolved in a way that permitted study participation, patients would become ineligible later in the process, and some even completed pulmonary rehabilitation before a ﬁnal decision could be made. All patients who began evaluation were entered into a

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registry with plans to follow them for mortality using the Medicare database. Medical therapy for both arms was to be managed by the patients’ referring physicians with review and oversight by the NETT investigators. It consisted of reinforcement of smoking cessation, inhaled b-agonists and ipratropium (using a spacer if appropriate), oxygen therapy if indicated, and vaccinations for pneumococcal pneumonia and inﬂuenza. The use of systemic corticosteroids, theophylline, and antibiotics for exacerbations was individualized. LVRS was to be performed by excision and stapling of emphysematous regions of both lungs at a single operation. Speciﬁc emphysematous lung regions were targeted for resection based on preoperative CT and perfusion images and intraoperative inspection. The goal was removal of 20–30% of both lungs. Buttressing of the lung resection incisions was allowed but not required. Detailed recommendations for perioperative, intraoperative, and complications management were provided in a manual. Consent was obtained in three stages which corresponded to the progressive risks of the study. The ﬁrst consent allowed the collection of registry data and the initial testing. The second consent was for the program of pulmonary rehabilitation and the repeat testing that followed. The ﬁnal consent covered randomization and possible surgery. In addition, the standard institutional surgical consent used by each hospital was obtained prior to LVRS. Advantages to this staged consent were that it provided multiple opportunities for discussion and questions, and served as a ‘‘test’’ of the subject’s commitment to return for follow-up. A Data and Safety Monitoring Board (DSMB) reviewed the data quarterly and made recommendations for early stoppage or modiﬁcation of the trial. In addition to outcomes data, the DSMB was provided with periodic reports of adverse events and synopses of all relevant literature published between their meetings. The DSMB reviewed recruitment progress and data quality and explored the data for evidence of efﬁcacy or concerns about safety in the overall trial as well as in subgroups. By consensus, the Steering Committee had prospectively deﬁned one subgroup that it believed had the greatest likelihood of beneﬁt. This consisted of patients aged 70 years or less, with an FEV1 from 15 through 35% predicted, PaCO2 450 mm Hg, residual volume >200% predicted, hyperinﬂation on chest radiography, and a heterogeneous distribution of emphysema as deﬁned by CT scan and perfusion scanning. The DSMB reviewed outcomes by these criteria as well as other subsets of their own design.

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Recruitment

The NETT was planned during a heady period of widespread enthusiasm about LVRS. The investigators set an optimistic goal of 4700 patients (providing a type I error of 0.01 and 90% power); in part so as not to have to turn patients away. However, when enrollment opened, it soon became apparent that this goal would not be met. This may have been due to several factors. The rates of LVRS, even among non-Medicare patients, were declining nationally (24). This may have resulted from belief that only a small fraction of emphysema patients were good candidates for surgery. There may have been spreading disenchantment when the outcomes reported in the literature could not be replicated at less experienced centers. Referring physicians and potential patients may have been dissuaded after seeing patients who did poorly or whose initial improvement was short lasting. Many physicians may have wanted to delay referring patients until more data were available. The protocol also held many disincentives for patients. The enrollment process was lengthy and strenuous. Medicare has no mechanism to forgive copayment requirements for patients lacking secondary insurance, so participants were potentially liable for signiﬁcant out-of-pocket expenses. An application to the Ofﬁce of the Inspector General eventually yielded an advisory opinion that waiver of the copayment requirement would not subject NETT investigators or their institutions to legal sanctions under the Social Security Act. However, this waiver proved administratively difﬁcult or impossible to carry out at many of the clinical centers. Funding from the NHLBI to help defray the costs of travel or accommodations during the several days required for each evaluation and follow-up visit was applied differently among the centers. The participating centers had been selected on technical criteria without consideration of their geographical distribution. As a result, there were two centers in Philadelphia competing over the same patient base. There was only one in the South, which has a high prevalence of COPD, and none in Florida despite its large Medicare population. Finally, from a patient’s perspective, the idea of being randomized between the two arms of this study with their vastly different risks may have been quite frightening. Initially, the study did not provide funds for advertising and recruitment, which were left to the resources of the participating centers. The resulting efforts varied widely from sophisticated radio and television campaigns to humble posters and letters to physicians. The optimistic initial recruitment goal of 4700 was lowered to 2500, which reduced the power of the study to the level speciﬁed in the RFA. When enrollment still lagged behind targets, supplemental funding was obtained to hire a ﬁrm

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specializing in medical research marketing to coordinate a national marketing campaign. They staffed a toll-free telephone center for patient screening and referral, produced television and news media advertising, and arranged press conferences and appearances. This marketing effort cost $2 million, but generated only about 50 new enrolled subjects. In response to a survey of the investigators about their recruitment needs, in 1999, the NHLBI began providing capitation payments for randomization and follow-up visits. V.

Protocol Modiﬁcations

Early in the study, the Steering Committee made several modiﬁcations to the inclusion and exclusion criteria. These were motivated by the belief among the participating physicians that candidates suitable for surgery were being found to be ineligible on the basis of imprecise or clinically unimportant test results. Modiﬁcations included allowing a right heart catheterization to conﬁrm pulmonary hypertension estimated from the echocardiogram. (Originally, patients were excluded based on echocardiographic ﬁndings alone.) In addition, the requirements that the diffusing capacity be 70% predicted or less and that there be a 30% or less FEV1 bronchodilator response were dropped; the total lung capacity (TLC) threshold was lowered from 5110% to 5100% predicted. The CT exclusion criteria were made more subjective, with patients being excluded if the NETT physicians felt the distribution and severity of emphysema were inappropriate for surgery rather than on the basis of the semiquantitative CT scores. After 1033 subjects had been recruited, the criteria were again modiﬁed when a separate subgroup at high risk of mortality after surgery was identiﬁed. A. High-Risk Subgroup

In April 2001, the DSMB became concerned that a subgroup of patients were suffering a 30-day surgical mortality that convincingly exceeded the stopping criterion of 8%. Enrollment of new patients ﬁtting this subgroup was suspended while more detailed analyses were performed. These conﬁrmed the excessive mortality and better deﬁned the identifying characteristics of the subgroup (25). The patients identiﬁed as being at high risk were those with the most severe emphysema, as indicated by an FEV1 420% predicted, in combination with either a diffusing capacity 420% predicted, homogeneous emphysema by CT scan, or both. These thresholds were conﬁrmed by sensitivity analysis.

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One hundred and forty high-risk patients had been enrolled, with 70 being randomized to LVRS (one of whom refused surgery). The 69 patients who underwent LVRS had a mortality rate of 16% at 30 days after surgery, with a lower conﬁdence limit of 8.2%. In contrast, none of the patients randomized to medical therapy had died at 30 days after randomization. Furthermore, mortality at 6 months after randomization was 35% in the surgical arm but less than 5% in the medical arm (Fig. 1). Examination of other outcomes revealed that more patients in the surgical arm had gains in maximal workload, 6MWD, and FEV1 than in the medical arm. However, the magnitude of those gains was often small. Considering the groups as a whole and accounting for the number of deaths and patients too ill to return for follow-up, there were no signiﬁcant differences in functional or symptomatic outcomes between the medical and surgical arms. The QWB score at 6 months decreased 0.01 unit in both groups. Thus, the surgical group had a greater mortality without signiﬁcant improvement in outcome. In May 2001, the local institutional review boards were notiﬁed about these ﬁndings, letters were sent to NETT subjects, notices were sent to

Figure 1 Kaplan-Meier estimates of mortality for patients in the high-risk subgroup. Mortality 30 days after surgery is 16% in the LVRS group, and 30 days after randomization, is zero in the medical group. At 6 months, the mortality is approximately 35 and 5%, respectively. (From Ref. 25.)

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pulmonary and thoracic surgery societies, and the ﬁndings were published in August 2001 (25). The ﬁndings were reported quickly by the lay media, with stories appearing in major newspapers by the following day (26–28). Unfortunately, the message perceived by much of the public appeared not to be that one particular group of patients was at excessive risk but rather that LVRS was excessively risky surgery. This high-risk group comprised only 13.6% of NETT subjects. Nevertheless, referral and enrollment suffered further and did not recover before the trial closed. This publication also stimulated a fresh round of accusations by opponents of the trial. For example, it was suggested that these patients were clearly inappropriate candidates for LVRS (29). However, these patients were among the most disabled and therefore had the most to gain. They had been included in the hopes of ﬁnding beneﬁt of surgery in as broad a range of patients as possible, and there were strong theoretical reasons to believe they would beneﬁt. Recruitment of eligible patients, after excluding this high-risk group, continued for another year.

VI.

Main Study Results

The NETT closed to new enrollment in July 2002 to allow a minimum of 6 months of follow-up after randomization. Its main results and the accompanying cost-effectiveness analysis were published in May 2003 (30,31). A total of 1218 patients were randomized. Although this was less than half the target enrollment, several assumptions originally used to calculate necessary study size were found to be overly generous. For example, crossover to LVRS from the medical arm was only 5.4% compared to the anticipated 33%, and refusal of or unsuitability for surgery among patients randomized to the LVRS arm was only 4.6%, not 6%. Had these actual ﬁgures been used for the initial power calculation instead of the original projections, the required study size would have been 1190. Thus, the study retained its statistical power despite lower than anticipated enrollment. Primary analysis was based on mortality and maximal exercise capacity. Exercise capacity was measured by cycle ergometry with all patients on 30% oxygen. After 3 min of unloaded pedaling, the ramp was advanced at either 5 or 10 watts each minute (based on maximum voluntary ventilation; 5–watt/min ramp if 440 L, otherwise a 10–watt/min ramp). Numerous secondary outcomes were analyzed, such as pulmonary function, symptoms, and quality of life ratings. Since a major goal of the NETT was to attempt to identify baseline patient characteristics that would predict extremes of outcome (good or poor), multiple subgroup analyses were also performed. Many of these subgroups had been speciﬁed in the trial protocol,

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others were suggested by the DSMB, and others were suggested by the investigators after trial initiation but well before data collection was complete. Six hundred and eight patients were randomized to LVRS and 610 to medical therapy. Salient baseline characteristics are shown in Table 2. Except for a slightly greater proportion of males in the medical arm, there were no signiﬁcant differences between groups. Mean age was about 67 years. Two-thirds of the subjects had an upper lobe–predominant distribution of emphysema. Postbronchodilator FEV1 averaged about 27% predicted, maximum work capacity averaged approximately 39 watts, and both groups had substantial respiratory symptoms and impaired quality of life. At the completion of the trial, 99% of surviving participants continued to receive follow-up either by telephone or through scheduled clinic visits. In the surgical arm, 95.4% of patients received LVRS at a median of 10 days after randomization. About two-thirds of LVRS patients had their surgery performed by median sternotomy and the remainder by VATS. Analysis

Table 2 Baseline Characteristics of All Randomized Patients (n ¼ 1218) After Completion of Pulmonary Rehabilitation LVRS (N ¼ 608) Age (years) Sex no. (%) Female Male Postbronchodilator pulmonary function FEV1 (% predicted) TLC (% predicted) RV (% predicted) DLCO (% predicted) PaO2 (mmHg, on room air) PaCO2 (mmHg, on room air) Maximum work (watts) 6-Min walk (feet) St. George’s Respiratory Questionnaire total score Quality of Well-Being score Mean + SD. Source: Ref. 30.

66.5 + 6.3 253 (42) 355 (58)

Medical (N ¼ 610) 66.7 + 5.9 219 (36) 391 (64)

26.8 + 7.4 128.0 + 15.3 220.5 + 49.9 28.3 + 9.7 64.5 + 10.5 43.3 + 5.9 38.7 + 21.1 1216.5 + 312.6 52.5 + 12.6

26.7 + 7.0 128.5 + 15.0 223.4 + 48.9 28.4 + 9.7 64.2 + 10.1 43.0 + 5.8 39.4 + 22.2 1219.0 + 316.0 53.6 + 12.7

0.58 + 0.12

0.56 + 0.11

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comparing those approaches has not been completed at the time of this writing. Among medical arm patients, 5.4% received LVRS outside of the study and 2.5% received a lung transplant at some time during followup. As would be anticipated, mortality 90 days after randomization was higher in the LVRS group (7.9%, 95% CI 5.9–10.3%) than it was in the medical patients (1.3%, 95% CI 0.6–2.6%; P < .001). Excluding the high-risk subgroup of patients, 30- and 90-day mortality in the surgical arm was 2.2 and 5.2%, compared to 0.2 and 1.5% in the medical group (both P < .001). There was also substantial short-term morbidity due to surgery. One month after randomization, 28.1% of the LVRS patients compared to only 2.2% of medical patients were either hospitalized or in rehabilitation or nursing facilities. (This includes patients unavailable for interview but not known to have died.) However, these differences in institutionalization rates diminished with time, and rates were similar in both groups by 8 months after randomization (3.3 and 3.7%, respectively). Over a longer time frame, mortality rates for LVRS and medical groups were also similar. For all participants during a mean follow-up of 29.2 months, mortality was 0.11 deaths per person-year in both groups (P ¼ .90). Mortality (and outcomes) after excluding the high-risk patients may be more clinically informative, since patients with the high-risk characteristics would no longer be likely to be offered surgery. Among the 1078 non–high-risk patients, mortality rates were 0.09 and 0.10 deaths per person-year for LVRS and medical arms, respectively (risk ratio 0.89, P ¼ .31). Thus, excess early mortality in the surgical group was compensated by lower mortality among those who survived the ﬁrst several postoperative months. This is shown in Figure 2. The 30-day mortality rate compared favorably with rates reported in the literature (see Chap. 16), and the 1-year mortality is notably lower than the rate of 26% in the ﬁrst year following surgery that early Medicare data had suggested (5). Analysis of functional outcomes could be complicated by the patients who did not return for in-person follow-up visits. This form of loss to follow-up has confounded most other studies of LVRS. In a randomized trial such as the NETT, there may be differences between the arms in the numbers of patients lost to follow-up or in their reasons for not returning. Most importantly, no statistical analysis can fully adjust for the possibility that patients lost to follow-up had different outcomes than did the patients who continued to return to the clinic. To minimize this problem, the NETT analysis used outcomes that could be deﬁned for every patient. Each outcome variable was divided into 10–12 categories of increase or decrease, which were ranked in order of desirability. For each variable, death was the least desirable outcome, and

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Figure 2 Kaplan-Meier estimates of mortality after randomization for patients exclusive of those in the high-risk subgroup. In patients receiving surgery, increased mortality in the early months is compensated by decreased mortality in later months. (From Ref. 30.)

missing data the next least favorable. This assumes that living patients with missing data were too disabled to complete that aspect of follow-up testing. To the extent that these patients were merely no longer interested in participating actively in the study, the low ranking of missing data may bias that group toward less desirable outcomes. Losses or gains of each outcome variable, relative to its baseline value, were ranked categorically above death or missing data. Selected outcomes at 6, 12, and 24 months for the non–high-risk patients are shown in this format in Figure 3. In each panel, the histogram on the left indicates the LVRS patients, and that on the right indicates the medical patients. Changes below the dashed line indicate progressively worse outcomes, and changes above the dashed line, progressively better outcomes. For either group, a symmetrical distribution about the dashed line indicates little mean change; a skew upward indicates overall beneﬁt and a skew downward indicates net deleterious effects. The width of the distribution reﬂects the overall range of outcomes. The percentages indicate the percentage of subjects in each quadrant. Comparing the two groups, a predominance of patients in the upper left and lower right quadrants favors LVRS, and a predominance in the upper right and lower left quadrants favors medical therapy.

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Figure 3 Outcomes at 6, 12, and 24 months among the randomized patients exclusive of the high-risk subgroup. LVRS patients are shown to the left and medical patients to the right. Gain or loss, including death or missing data, has been divided into 10–12 ranked categories. At each time point, LVRS and medical groups are compared by Wilcoxon rank sum tests. See text for details. (From Ref. 30 and its associated on-line data supplement.)

Several features are apparent in these plots. First, even at 6 months, there is a wide range of changes from baseline in both groups. With the

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Figure 3 Continued

passage of time, many of the outcomes tend to worsen, which are indicated by a downward movement of the histograms. Several of the variables show a distinct skew to the upper left. This is most apparent in the respiratory symptom scales, where many more LVRS patients than medical patients reported the highest category of symptom improvement. It can also be seen in the change in FEV1, where the majority of LVRS patients had

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improvement (of wide-ranging magnitude) at 6 months, whereas the majority of medical patients had either small loss or missing data. The percentage of patients with missing data is lower for the symptoms and quality of life assessment, which required only a mail-in questionnaire compared to pulmonary function or exercise testing, which required a clinic visit and signiﬁcant effort. By Wilcoxon rank sum testing, the LVRS group differed signiﬁcantly from the medical group for all variables and at all time points (P < .001). Thus, one may summarize the average effects of LVRS in this large group as producing symptomatic and functional relief compared to baseline and to medical therapy, which is sustained for at least 2 years. There is no increase in mortality over this time period. However, the outcomes after LVRS are extremely variable and improvement is often modest. An examination of subgroups is necessary to enrich the likelihood of a good outcome. This analysis was performed using the primary outcomes, mortality and change in maximal exercise, and the change in SGRQ score as the dependent variables. Two baseline patient characteristics were found independently to predict either differences in mortality rates and/or changes in maximal exercise capacity: the presence or absence of upper lobe– predominant emphysema (ULPE) as determined from the high-resolution CT scan and a (relatively) high or low baseline maximal exercise capacity (BMEC). The latter was deﬁned as 425 watts in females or 40 watts in males after completion of pulmonary rehabilitation. It is important to note that the methods for acquiring and interpreting the CT scan and for performing the exercise test were quite speciﬁc for the NETT, and therefore the same NETT thresholds may not apply if other CT or exercise protocols are used. However, with that qualiﬁcation, these two characteristics divide the study population into four groups: 1. 2. 3. 4.

ULPE and low BMEC ULPE and high BMEC Non-ULPE and low BMEC Non-ULPE and high BMEC

For the ﬁrst group, those with combined low baseline exercise capacity and upper lobe emphysema, both mortality and exercise outcomes favored LVRS. This group comprised about one-quarter of the non–high risk patients (290 total). Compared to patients treated medically, these patients undergoing LVRS had a risk ratio for mortality of 0.47 over the followup period (P ¼ .005) and a higher proportion with >10-watt improvement in exercise capacity (30 vs. 0%; P < .001) or substantial improvement (>8 points) in the SGRQ at 2 years (48 vs. 10%; P < .001).

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At the opposite extreme, patients with both non-ULPE and high BMEC (220 patients) had over twice the risk of death (RR 2.06, P ¼ .02) after LVRS. Only 3% of both medical and surgical patients in this subgroup had >10-watt improvement in maximal exercise at 24 months. Similarly, low percentages of patients improved SGRQ scores at 2 years by more than 8 points (15% LVRS, 12% medical; P ¼ .61). In the remaining two groups (totaling 568 patients), the mortality risks of medical and LVRS therapy did not differ from each other signiﬁcantly. Changes in maximal work, although also favoring LVRS, were generally quantitatively small or not statistically signiﬁcant between groups. The most striking differences were in symptom scores, where 37 and 41% of the LVRS patients in these two subgroups improved by more than 8 points on the SGRQ scale compared to 7 and 11% of medical patients in the respective subgroup (P 4 .001 for both comparisons). Although not a hypothesis speciﬁcally tested by the NETT, patients with low baseline exercise capacity treated medically had a high mortality compared to the other medical patients. The medical arms of the two subgroups with low BMEC had mortality rates of 0.15 and 0.18 deaths per person-year. Over the course of the study, the total deaths in the combined medical arms of those groups were 77 of 216 patients (35.6%; 95% CI 29.3– 42.4%). This compares with 53 deaths of 324 medical patients with high BMEC (16.3%; 95% CI 12.5–20.8%). Low BMEC therefore may be a marker for poor survival in advanced emphysema. In some patients, those with ULPE, survival can be improved by LVRS. Thus, this subgroup analysis clariﬁes the role of LVRS for at least certain patients. Those with upper lobe–predominant emphysema and very low baseline exercise capacity have reasonable indications for surgery: improved mortality and greater likelihood of improved symptoms and exercise capacity. It should be noted that this is the ﬁrst intervention since continuous oxygen therapy which has been shown to improve survival in COPD, albeit in the very small fraction of patients who meet these strict criteria. In contrast, there is little reason to recommend LVRS for patients lacking upper lobe–predominant emphysema and with better preserved exercise capacity. These patients would be more likely to die following surgery, and no more likely to feel better. For patients who are otherwise appropriate candidates but do not fall into either of these categories, LVRS is unlikely substantially to alter their mortality risk, and it also offers only a less than 50:50 chance of substantial improvement in symptoms. A ﬂow diagram illustrating how these ﬁndings can be applied to an individual patient is shown in Figure 4.

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Figure 4 Decision algorithm for LVRS candidates. The NETT provides no information regarding patients who do not meet the inclusion and exclusion criteria listed in Table 1. For those who do meet these criteria, the risks and beneﬁts of LVRS compared to medical therapy alone can be categorized into one of three groups. For patients in Class A, LVRS would increase their short- or long-term mortality risk with little likelihood of functional beneﬁt. These include the high-risk subgroup patients, as well as patients lacking upper lobe–predominant emphysema but with preserved exercise capacity. For patients in Class B, LVRS would have no effect on their mortality risk, and would be modestly more likely than medical therapy to improve their exercise capacity or symptoms. Class C patients are those with both upper lobe–predominant emphysema and poor maximal exercise capacity. They would have a lower long-term mortality risk after LVRS, and have a much greater likelihood of increased exercise capacity and/or decreased symptoms with surgery than with medical therapy alone. For these purposes, the distribution of emphysema is determined from the high-resolution CT scan and low exercise capacity is deﬁned as less than or equal to 25 watts for women and 40 watts peak maximal exercise for men using the cycle exercise protocol described in the text.

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Cost-Effectiveness Analysis

Because of the large numbers of patients with emphysema and the expense of this procedure, a cost-effectiveness study was performed concurrently with the medical outcomes aspects of the NETT (31). The outcome measure for this analysis was the cost per Quality-Adjusted Life Year (QALY). A QALY is based on the QWB score, which provides a global self-rating of a subject’s satisfaction with his or her state of health from 0 (death) to 1 (perfect heath). The utility scores used in the QWB were derived and validated in population studies, and have been applied in numerous diseases (18,19). A patient with a score of 0.5 would be in a condition half as satisfying as perfect health. If that patient remained in that condition for a year, they would have had one-half QALY. The use of the QALY may be insensitive to improvement in a disease-speciﬁc symptom, such as cough, but it provides a global measure of quality of life that facilitates comparison between diseases and is suitable for economic valuation. The QWB questionnaire was completed at each scheduled follow-up. Costs included all Medicare claims after randomization, pharmacy costs estimated from reported medication use, patient and caregiver (family or friend) time at standard rates, travel time, and expenses. Analysis was performed based on the time frame of the study, and also after extrapolating the ﬁndings in the study to a 10-year time horizon. For the 10-year estimate, costs and QWB scores were based on the extrapolated trend lines from the third-year data. Cost effectiveness was also calculated in patients in the subgroups as described above. Patients in the high-risk subgroup were excluded from the cost-effectiveness analyses, because they would not be appropriate candidates for surgery. Twelve additional patients were excluded because of incomplete Medicare claims data. For the remaining 1066 patients, the LVRS patients accrued 1.46 QALYs at 3 years compared to 1.27 QALYs in the medical patients (P < .001). In the ﬁrst year after surgery, the LVRS group had more inpatient hospital days, ambulatory care days, and higher costs. For example, the mean total per-patient costs in year one were $71,515 in the LVRS group and $23,371 in the medical group (P < .001). However, they had signiﬁcantly fewer hospital days and lower total costs than medical patients after 12 months ($13,222 vs $21,319 in year 2; P < .001). At 3 years, the cost effectiveness of LVRS was $190,000 per QALY. Extrapolated to 10 years, the cost effectiveness of LVRS for the overall group was about $53,000 per QALY. Owing to greater gains in mortality or QALYs, LVRS was more cost effective for some of the subgroups at 3 years than it was for the overall group and most cost effective for the group with ULPE and low BMEC. Extrapolated to 10 years, LVRS cost $21,000 per QALY for that

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group. That places LVRS favorably in the range of cost effectiveness demonstrated for heart transplantation, coronary bypass surgery, or implantable deﬁbrillators in deﬁned patient populations. The conclusions of the NETT have been criticized, because they have been based in part on subgroups deﬁned during data analysis. Given the large number of subgroups that were examined, there is always a possibility that statistically signiﬁcant differences were found by chance alone. In the NETT, the subgroup analysis is supported by the biological plausibility of the ﬁndings and the fact that heterogeneous emphysema was hypothesized to be a predictor of outcome from the beginning of the trial (32). Ideally, another prospective trial would be undertaken to conﬁrm the differences between subgroups. However, it seems unlikely that will occur. To summarize the major ﬁndings of the NETT: 1.

2. 3.

4.

5.

In this carefully deﬁned population and under the care of experienced personnel, LVRS does not increase mortality over the 2–3 years after surgery. Compared to medical therapy alone, LVRS is more likely to improve symptoms and exercise capacity. Patients with upper lobe–predominant emphysema and very low baseline maximal exercise capacity have lower mortality and the greatest likelihood of improvement with LVRS compared to medical therapy. Patients with better-preserved exercise capacity and lacking upper lobe–predominant emphysema have little symptomatic or functional beneﬁt compared to medical therapy and increased mortality following surgery. For all patient groups, individual results vary widely.

It bears reemphasis that these patients were determined to be eligible for surgery and characterized into subgroups based on a detailed evaluation with standardized methodology. All underwent comprehensive preoperative pulmonary rehabilitation and continued postoperative exercise. All were operated upon at centers with prior experience in LVRS. The quantitative and qualitative ﬁndings are unlikely to generalize to other settings unless these conditions are also replicated. VIII.

Impact of the NETT

The NETT was an enormous and controversial undertaking involving thousands of subjects, hundreds of investigators, and three government

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agencies. What has been learned? First, in regard to LVRS, we have only scratched the surface of what this study may teach us. The major ﬁndings have only just been published, and the wealth of data will spawn multiple hypotheses and analyses for many years. This study provides the most precise and robust estimates of what may be expected from LVRS and the ﬁrst long-term comparisons to medical therapy in well-screened candidates for LVRS. Although the ﬁndings will likely fuel debate, they will also guide physician and patient decisions for the foreseeable future. Second, in regard to clinical investigation, the NETT was ground breaking in several respects, and its lessons may be more far reaching. This was one of the rare examples where the meteoric ascendancy of a procedural intervention was interrupted early in its adaptation and subjected to systematic and controlled evaluation. It contrasts starkly to the history of coronary bypass surgery or percutaneous dilation, pulmonary artery catheterization, arthroscopic surgery, carotid endarterectomy, and numerous other procedures which became standards of care long before their indications and utility were deﬁned. This was the ﬁrst randomized trial in which the costs of clinical care were paid by Medicare, and it was an unprecedented collaboration between the NIH, CMS, AHRQ, and the research community. This introduced numerous bureaucratic hurdles and added to the complexity of the study. However, it is a model that may serve patients and society well in investigations of other promising therapies that share features with LVRS: undeﬁned risks and beneﬁts, study costs too great for the NIH budget alone, no obvious industry support, and outcomes of interest to Medicare. The NETT was also the ﬁrst large surgical trial to incorporate a prospective cost-effectiveness analysis from the onset. This is also likely to become an increasingly important evaluation of expensive new therapies. In many regards, therefore, the NETT provides a new paradigm for large clinical trials that utilize the infrastructure of government and science to address issues of clinical care and policy. The ﬁnal lesson of the NETT is its reminder of the cost of medical progress. The NETT has been a remarkable undertaking which brought together clinical scientists with a broad range of expertise and often widely divergent opinions. Consensus was achieved only at great effort, and enormous resources and determination were required to complete this project. Much more inspiring, however, were the contributions of our patients. Over 1200 severely disabled patients agreed to accept random allocation which might send them to major surgery, invested hundreds of hours of time and exhausting effort to provide follow-up, and became committed partners in the scientiﬁc quest. They are the quiet heroes without whom medical progress would cease.

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Fessler et al. Disclaimer

The authors are members of the NETT Research Group, and one (APF) was its chairman. Any opinions that have been expressed in this chapter are those of the authors and not of the NETT Research Group or its sponsoring agencies.

References 1.

2.

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

14. 15. 16.

Cooper JD, Trulock EP, Triantaﬁllou AN, Patterson GA, Pohl MS, Deloney PA, et al. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995; 109:106–119. Huizenga H, Ramsey S, Albert RK. Estimated growth of lung volume reduction surgery among Medicare enrollees: 1994 to 1996. Chest 1998; 114(6):1583–1587. Make B, Fein AM. Is volume reduction surgery appropriate in the treatment of emphsyema: No. Am J Respir Crit Care Med 1996; 153:1205–1206. Holohan TV, Handelsman H. Lung-volume reduction surgery for end-stage chronic obstructive pulmonary disease. Hlth Technol Assess 1996; 10:1–30. Vladeck B. Testimony before the House Ways and Means Health Subcommittee. 4–17–1997. Foreman J. Lung surgery makes ﬁght for breath easier. The Boston Globe Apr 25:3, 1996. Friend T. Surgery may offer emphysema relief. USA Today May 14; Sect. D:5, 1996. Leary W. Debating the beneﬁts and costs of major surgery for emphysema. New York Times May 14; Sect. C:3, 1996. Weinmann CG, Hyatt R. Evaluation and research in lung volume reduction surgery. Am J Respir Crit Care Med 1996; 154:1913–1918. Cooper JD. Testimony before the House Ways and Means Health Subcommittee. 4–17–1997. Knox R. Push is on to widen access to costly lung surgery. The Boston Globe Apr 29; Sect. A:4, 1998. Gentry C. Why Medicare covers a new lung surgery for just a few patients. Wall Street Journal Jun 29; A1–A10, 1998. National Emphysema Treatment Trial Research Group. Rationale and design of the National Emphysema Treatment Trial: a prospective randomized trial of lung volume reduction surgery. J Thorac Cardiovasc Surg 1999; 118:518–528. Knox A, Morrison J, Muers M. Reproducibility of walking test results in chronic obstructive airways disease. Thorax 1988; 43:388–392. Mungall I, Hainsworth R. Assessment of respiratory function in patients with chronic obstructive pulmonary disease. Thorax 1979; 34:254–258. Guyatt G, Pugsley S, Sullivan M, Thompson P, Berman L, Jones N et al. Effect of encouragement on walking test performance. Thorax 1984; 39:818–822.

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17. McHorney C, Ware J, Lu J, Sherbourne C. The MOS 36-item short form health survey: tests of data quality, scaling assumptions, and reliability across diverse patient groups. Medical Care 1994; 32(1):40–66. 18. Curtis J, Deyo R, Hudson L. Health-related quality of life among patients with chronic obstructive pulmonary disease. Thorax 1994; 49:162–170. 19. Kaplan R, Atkins C, Timms R. Validity of a quality of well-being scale as an outcome measure in chronic obstructive pulmonary disease. J Chronic Dis 1984; 37(2):85–95. 20. Eakin E, Resnikoff P, Prewitt L, Ries A, Kaplan R. Validation of a new dyspnea measure: the UCSD Shortness of Breath Questionnaire. Chest 1998; 113(3):619–624. 21. Borg G. Perceived exertion as an indicator of somatic stress. Scan J Rehab Med 1970; 2:92–98. 22. Sherman C, Kern D, Richardson E, Hubert M, Fogel B. Cognitive function and spirometry performance in the elderly. Am Rev Respir Dis 1993; 148(1):123–126. 23. Richter P, Werner J, Heerlein A, Kraus A, Sauer H. On the validity of the Beck Depression Inventory: a review. Psychopathology 1998; 31(3):160–168. 24. Berger R, Celli BR, Meneghetti A, Bagley P, Wright C, Ingenito EP et al. Limitations of randomized clinical trials for evaluating emerging operations: the case of lung volume reduction surgery. Ann Thorac Surg 2001; 72:649–657. 25. National Emphysema Treatment Trial Research Group. Patients at high risk of death after lung volume reduction surgery. N Engl J Med 2001; 345(15):1075– 1083. 26. Atkins K. Study ﬁnds surgery risky for severe emphysema. The Boston Globe Aug 15; Sect. A:21, 2001. 27. Brown D. Emphysema study curtailed; surgical death rate ﬁndings disqualify one group of patients. The Washington Post Aug 15; Sect. A:2, 2001. 28. Kolata G. Questions raised on lung operation. New York Times Aug 15; Sect. A:1, 2001. 29. Cooper JD, Lefrak SS. Surgery for emphysema. N Engl J Med 2002; 346:860. 30. National Emphysema Treatment Trial Research Group. A randomized trial comparing lung volume reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003; 348(21):2059–2073. 31. National Emphysema Treatment Trial Research Group. Cost effectiveness of lung volume reduction surgery for patients with severe emphysema. N Engl J Med 2003; 348(21):2092–2102. 32. Ware J. The National Emphysema Treatment Trial—How strong is the evidence? N Engl J Med 2003; 348(21):2055–2056.

AUTHOR INDEX

Italic numbers give the page on which the complete reference is listed.

A Aalto-Setala M, 223, 239 Abboud R, 183, 197 Abboud RT, 45, 64, 182, 183, 195, 197 Abman S, 91, 98 Abreu I, 116, 122 Ackermann-Liebrich U, 14, 21 Acosta O, 116, 122 Adams KM, 129, 135, 144 Adams WE, 379, 384 Addis GJ, 106, 119 Addonizio VP, 303, 309, 385, 398, 399, 408 Adomian G, 66, 72, 92 Adusumilli S, 185, 187, 197, 198 Agent P, 162, 168, 292, 300, 315, 318, 329, 351 Aguar C, 328, 350 Akamatsu H, 391, 410 Akkermans R, 106, 119 Al MJ, 418, 421, 423 Albert R, 106, 109, 119, 214, 215, 218, 312, 314, 316, 317, 320, 321, 323, 326, 341, 347, 348, 352, 385, 408 Albert RA, 417, 423 Albert RK, 68, 72, 74, 90, 91, 93, 125,

[Albert RK] 144, 297, 299, 303, 308, 369, 370, 372, 375, 376, 382, 383, 417, 418, 421, 423, 425, 450 Alcala R, 357, 380 Alderson PO, 75, 95 Alﬁlle PH, 237, 244 Ali J, 222, 239 Alleyne W, 105, 118 Alonso J, 328, 350 Alpers JH, 8, 18 Altose MD, 3, 7, 13, 16, 20, 99, 100, 117 Amaro P, 116, 121 Ambrosino N, 5, 17, 116, 121, 142, 148 Andersen PK, 10, 19 Anderson AE, 386, 409 Anderson GF, 14, 21, 415, 422 Anderson JA, 106, 120 Anderson JP, 139, 147 Anderson MB, 213, 218, 385, 405, 409 Anderson P, 102, 118 Andou A, 248, 256, 265, 271 Angell D, 302, 310 Annesi I, 2, 15 Anthonisen NR, 3, 7, 16, 99, 100, 107,

453

454

Author Index

[Anthonisen NR] 117, 120, 131, 145, 204, 216, 313, 317, 321, 326, 341, 351, 352, 378, 384 Anto JM 5, 8, 14, 17, 18, 20, 328, 350 Aoe M, 248, 256 Aouate P, 67, 93 Appleyard M, 2, 15 Apprill M, 74, 76, 95 Araki A, 182, 196 Arcidi JM, 369, 373, 374, 375, 376, 382 Argenziano M, 154, 158, 166, 248, 255, 265, 270, 291, 292, 293, 294, 298, 313, 314, 316, 317, 319, 322, 324, 325, 326, 341, 343, 347, 349, 386, 388, 393, 410 Arisaka Y, 70, 94 Armitage J, 206, 216 Armstrong W, 340, 352 Arnold RJ, 421, 423 Arts IC, 10, 18 Asmundssen T, 399, 411 Atkins CJ, 140, 147, 431, 447, 451 Atkins K, 438, 451 Aubier M, 111, 121, 236, 243 Austin JHM, 50, 64, 185, 187, 198, 385, 386, 387, 388, 409 Avendano MA, 137, 139, 147 Avol E, 14, 21

B Babb T, 44, 50, 63 Babyak M, 91, 98 Bach DS, 160, 161, 168, 228, 241, 340, 352 Bachez P, 74, 76, 95 Bae K, 169, 185, 194, 344, 351 Bae TK, 169, 184, 185, 186, 194, 197 Baffa G, 73, 95 Bagley PH, 153, 166, 248, 256, 292, 299, 313, 317, 322, 324, 326, 329, 341, 349, 435, 451 Bailey WC, 3, 7, 16, 99, 100, 102, 117, 118, 182, 196 Bakalar K, 72, 94

Bake B, 237, 244 Baker TB, 101, 117, 118 Baldacci S, 2, 8, 15, 18 Baldeyrou P, 314, 317, 333, 338, 351 Ball WC Jr, 14, 20 Bando K, 207, 216 Bankier A, 185, 197, 292, 300, 332, 344, 345, 351 Banner N, 207, 217 Bantje TA, 105, 119 Barach AL, 131, 145 Barbaresco S, 306, 309 Barbera JA, 151, 165 Barcelo MA, 5, 17 Barcia TB, 291, 299 Bardoczky G, 225, 226, 240 Barifﬁ F, 307, 310 Barker SJ, 290, 291, 298 Barnes G, 275, 286 Barr M, 207, 217 Barrow P, 236, 243 Barter CE, 371, 372, 382 Bass JB, 283, 287 Bateman JRM, 131, 145 Battezati M, 377, 384 Battista RN, 101, 117 Baundendistel L, 83, 97 Bautz W, 170, 195 Bavaria JE, 154, 155, 157, 166, 167, 209, 217, 248, 249, 255, 265, 266, 268, 270, 278, 284, 287, 291, 293, 295, 296, 298, 299, 315, 318, 319, 320, 322, 346, 347, 354, 406, 407, 411 Baveystock CM, 139, 147, 326, 354 Baydur A, 357, 358, 381 Beamon AJ, 399, 411 Beaty TH, 10, 19 Beck J, 285, 287 Beck KC, 69, 94 Becker F, 205, 207, 216 Becker MD, 50, 64, 185, 198 Becker TM, 13, 20 Becklake MR, 14, 20 Beckwitt HJ, 73, 77, 94 Bednarek M, 13, 20 Bedu M, 151, 165

Author Index Behner KG, 214, 218, 417, 423 Behrendt D, 277, 286 Belda J, 140, 148 Bell NR, 415, 422 Bella LD, 290, 291, 298 Bellamy P, 4, 16 Bellemare F, 367, 373, 381, 383 Belman MJ, 104, 118, 132, 133, 134, 140, 146, 147 Benditt JO, 113, 121, 125, 144, 162, 168, 265, 271, 297, 299, 303, 308, 312, 314, 316, 317, 320, 321, 323, 326, 341, 347, 348, 352, 369, 370, 372, 375, 376, 382, 383, 385, 408, 417, 423 Benumof JL, 224, 229, 230, 240 Benzon HT, 237, 244 Berger HJ, 73, 76, 95 Berger R, 435, 451 Bergin C, 177, 182, 195 Berglund E, 66, 93 Berglund J, 224, 240 Bergner M, 318, 323, 326, 328, 350 Bergstein PG, 307, 310 Bergstrand L, 176, 195 Berhane K, 14, 21 Berkmen YM, 50, 64, 185, 198 Berman LB, 139, 147, 329, 351, 431, 450 Bernard A, 282, 287 Berns MW, 290, 291, 298, 315, 318, 340, 342, 351, 352 Bernstein MG, 127, 133, 144 Berry J, 133, 146 Bertley JC, 303, 309, 373, 383, 384 Bertone P, 116, 121 Bestall JC, 3, 7, 16 Bhaskar V, 248, 255, 265, 271, 292, 299, 314, 318, 322, 324, 349, 356, 371, 383 Bianchi L, 142, 148 Bianco JA, 76, 96 Biernacki W, 73, 76, 95 Biggar DG, 123, 143, 318, 333, 340, 348, 351 Bindslev L, 221, 223, 239

455 Bingisser R, 87, 88, 90, 97, 229, 241, 248, 255, 265, 266, 268, 270, 292, 300, 317, 322, 325, 326, 343, 349, 350, 369, 370, 382 Bird G, 274, 286 Bishop JM, 73, 95, 123, 131, 143 Bjerg AM, 10, 19 Bjortuft O, 85, 97 Black LF, 51, 64, 360, 381 Blackburn HW, 9, 10, 18 Bland PH, 193, 199 Blank M, 170, 195 Bloch KE, 185, 187, 188, 198, 248, 255, 265, 270, 292, 300, 317, 322, 325, 326, 344, 349, 353, 369, 370, 382, 395, 396, 410 Block AJ, 110, 121 Block KE, 87, 88, 90, 91, 97, 98, 322, 325, 326, 342, 343, 350 Block MI, 399, 410 Blomberg S, 237, 244 Bloom J, 321, 332, 351 Bobbitt R, 318, 323, 326, 328, 350 Body SC, 54, 57, 64, 314, 318, 332, 342, 348, 356, 357, 358, 359, 365, 381 Boe J, 85, 97 Boiselle P, 356, 376, 382 Boley TM, 277, 284, 286, 287, 291, 293, 295, 298, 299, 313, 314, 318, 319, 322, 324, 326, 328, 340, 342, 343, 347, 349, 385, 386, 387, 388, 391, 392, 408 Bolliger CT, 151, 165 Bolling S, 340, 352 Bolman M, 207, 213, 217 Bolman RM III, 385, 404, 405, 409 Bolognini G, 14, 21 Bolton JW, 151, 165 Bone RC, 68, 93 Bongard JP, 14, 21 Bookstein FL, 193, 199 Borg G, 431, 451 Borg GA, 133, 146 Borst MC, 66, 93 Bosh T, 105, 118 Bossard RF, 237, 245

456 Bossone E, 160, 168 Botnick WC, 104, 118 Bott J, 116, 121 Bouchard F, 237, 244 Bousamra M, 248, 256, 265, 271, 292, 299 Bousamra M II, 313, 317, 322, 324, 326, 349 Boushy SF, 74, 95 Bowers C, 317, 319, 326, 342, 343, 347 Bowers CM, 291, 299 Boyd BW, 283, 287 Boysen P, 222, 239 Brack T, 314, 317, 321, 323, 348 Braghiroli A, 5, 17 Brandli O, 14, 21 Brandolese R, 234, 235, 243 Brantigan O, 202, 215, 216 Brantigan OC, 289, 295, 298, 355, 361, 380 Brashears S, 14, 20 Braun N, 116, 122 Braunwald E, 71, 94 Brazier J, 328, 350 Breen JF, 81, 85, 96, 97 Brenner B, 290, 291, 298 Brenner M, 57, 64, 90, 98, 187, 198, 199, 248, 254, 264, 265, 266, 270, 281, 287, 290, 291, 292, 293, 294, 298, 313, 315, 316, 317, 318, 319, 321, 324, 325, 326, 327, 333, 334, 336, 337, 338, 339, 340, 341, 342, 343, 344, 347, 349, 351, 352, 355, 356, 357, 358, 359, 360, 364, 365, 372, 373, 374, 378, 379, 380, 381, 383, 384, 385, 386, 387, 388, 389, 391, 409, 410 Bria W, 340, 352 Brichant J, 230, 241 Briggs DD Jr, 105, 119 Bright J, 123, 143 Brix A, 106, 120 Brochard L, 116, 121, 122 Bromberger-Barnea B, 356, 357, 359, 380 Broseghini C, 235, 243

Author Index Brower RG, 67, 68, 93 Brown C, 5, 6, 7, 8, 17 Brown CA, 9, 18 Brown D, 438, 451 Brown JK, 131, 146 Brown M, 192, 199, 317, 319, 326, 342, 343, 347 Brown ML, 86, 88, 89, 97, 291, 299, 372, 383 Brown R, 72, 76, 94, 96 Browne J, 285, 287 Bruce RA, 378, 384 Brun-Buisson C, 116, 121 Brun-Ney D, 227, 240 Brundage BH, 158, 167 Brunet FP, 67, 93 Brunsting LA, 404, 411 Brusasco V, 54, 64 Bryan C, 207, 217 Buchholz J, 292, 299, 318, 321, 323, 326, 328, 343, 348, 355, 356, 370, 372, 375, 376, 380, 385, 408 Bueno R, 248, 254 Bufﬁngton C, 235, 243 Buist AS, 3, 7, 13, 16, 20, 99, 100, 102, 110, 117, 118 Buist S, 102, 118 Bullock PJ, 130, 145 Burge M, 185, 198, 344, 353 Burge PS, 106, 120 Burrows B, 3, 7, 8, 10, 16, 18, 19, 68, 69, 73, 74, 77, 94, 203, 216, 321, 332, 351 Busetto A, 306, 309 Butler C, 341, 352 Butler J, 68, 72, 74, 90, 91, 93, 357, 380

C Cahalin L, 274, 286 Calcagni AM, 107, 120 Caldera DL, 158, 167 Caldwell EN, 75, 95 Caldwell J, 68, 72, 93

Author Index Callahan C, 106, 119, 325, 349 Calle EE, 6, 7, 17 Calmese J, 248, 254, 290, 291, 298, 313, 317, 319, 325, 343, 347 Calverley PMA, 99, 100, 102, 106, 110, 117, 120 Camilli AE, 3, 7, 16 Campbell EJM, 14, 21, 131, 145 Canci E, 233, 242 Canter J, 285, 287 Capan L, 235, 243 Capel LH, 123, 131, 143 Caplin M, 123, 131, 143 Cappello M, 193, 199, 225, 226, 240, 370, 382 Caputo AL, 396, 410 Caraballo RS, 12, 19 Carabello BA, 82, 97 Cardoso W, 182, 195 Carel W, 222, 239 Carillo A, 341, 352 Carlisle C, 116, 122 Carlon G, 233, 242 Carlson D, 128, 144 Caro GC, 357, 380 Carpenter V, 125, 144 Carretta A, 385, 408 Carroll MP, 116, 121 Carrozzi L, 2, 8, 15, 18 Carter R, 133, 146 Carter W, 318, 323, 326, 328, 350 Casaburi R, 105, 119, 129, 132, 135, 140, 144, 146, 148, 397, 410 Casan P, 140, 148 Casanova C, 116, 122 Cascade PN, 404, 411 Cassart M, 193, 199, 370, 382 Cassina PC, 155, 166, 314, 318, 322, 325, 326, 333, 334, 337, 338, 339, 340, 343, 349, 378, 384 Castelain MH, 225, 240 Castelao N, 341, 352 Castrodeza J, 281, 287 Catanedo M, 281, 287 Cattaneo AD, 377, 384 Cece R, 116, 121

457 Cederlund K, 176, 195, 315, 318, 323, 326, 329, 351 Celli BR, 104, 110, 113, 116, 118, 121, 122, 123, 132, 134, 135, 143, 146, 315, 318, 321, 322, 326, 327, 337, 348, 355, 356, 366, 368, 372, 373, 374, 380, 383, 435, 451 Centindag I, 284, 287 Cerezal J, 281, 287 Cerfolio R, 280, 287 Cerfolio RJ, 385, 408, 408385 Cesar KA, 355, 356, 372, 375, 380 Chaitman BR, 158, 167 Chalker R, 104, 118 Chambers C, 205, 216 Chambers LW, 139, 147 Chaminade L, 182, 183, 196 Chammas J, JH, 248, 255, 256, 265, 271, 292, 299, 313, 317, 322, 324, 326, 349 Chan BBK, 248, 255, 265, 271, 292, 299, 314, 318, 322, 324, 349, 356, 371, 383 Chandrakant P, 235, 243 Chaparro C, 205, 216 Chapman KR, 102, 118 Charrier CL, 188, 199 Chatila W, 235, 243 Chau LKL, 303, 309, 373, 383, 384 Cheifetz I, 227, 241 Chen GJ, 418, 421, 423 Chen J, 317, 318, 321, 325, 327, 338, 349, 351, 356, 372, 373, 374, 383 Chen JC, 90, 98 Chen L, 228, 241 Chen Y, 13, 20 Cherijan AF, 404, 411 Cherniack R, 326, 354, 371, 382 Cherniack RM, 106, 119, 123, 131, 132, 135, 143 Chevarley FM, 10, 19 Chiang YP, 421, 424 Chiesa R, 385, 408 Chin K, 183, 196 Chin NK, 169, 194 Chin W, 153, 165

458 Chipps BE, 75, 95 Chow LC, 187, 198 Christensen P, 228, 241, 340, 352 Christensen PJ, 160, 161, 168, 187, 198, 385, 386, 387, 388, 392, 409 Christiansen WR, 170, 195 Christopher KL, 112, 113, 121, 132, 146 Churg A, 70, 94 Cinnella G, 234, 243 Clark L, 133, 146 Clarke SW, 131, 145 Clausen JL, 129, 134, 144, 371, 383 Clement J, 221, 239 Clemente PH, 127, 133, 144 Cleverley JR, 188, 199 Cline M, 3, 7, 16, 203, 216, 321, 332, 351 Cline MG, 10, 19, 68, 94 Coalson JJ, 283, 287 Cobb LA, 378, 384 Cochrane AL, 2, 15 Cohen BH, 10, 12, 14, 19, 20 Cohen E, 110, 121, 227, 235, 241 Cohen R, 207, 217 Cohn KE, 75, 95 Coleman A, 292, 299, 313, 317, 322, 324, 326, 329, 341, 349 Coleman AM, 248, 256 Collins JG, 10, 19 Colt HG, 125, 144 Compear R, 68, 72, 93 Comstock GW, 5, 17 Conlan AA, 303, 309, 373, 384 Connett JE, 3, 7, 13, 16, 20, 99, 100, 117, 378, 384 Connolly JE, 307, 309 Connors AF Jr, 4, 16 Connors GL, 123, 132, 135, 143 Conway JH, 116, 121 Conway WA, 99, 100, 117 Conway WA Jr, 3, 7, 16 Cook D, 134, 135, 147 Cook DJ, 123, 135, 143 Cook W, 77, 96 Cooper J, 169, 185, 194, 277, 278, 286,

Author Index [Cooper J] 288, 312, 314, 316, 318, 320, 322, 324, 326, 328, 333, 336, 338, 341, 343, 344, 346, 349, 351, 352, 385, 399, 408, 410 Cooper JD, 83, 86, 97, 123, 125, 143, 144, 155, 156, 157, 162, 167, 168, 169, 184, 185, 186, 194, 197, 198, 202, 207, 209, 211, 215, 216, 217, 218, 247, 248, 254, 255, 257, 262, 265, 266, 269, 270, 290, 292, 295, 298, 355, 356, 371, 373, 380, 385, 387, 391, 394, 397, 408, 410, 425, 428, 438, 450, 451 Cooreman J, 8, 18 Copin MC, 182, 195 Corcsan J III, 313, 317, 322, 325, 326, 350 Cordova F, 158, 159, 167, 248, 256, 292, 299, 314, 315, 317, 318, 323, 326, 328, 334, 336, 337, 339, 340, 343, 350, 351, 352, 371, 382, 385, 400, 401, 409 Cordova FC, 329, 351, 355, 356, 366, 367, 376, 380 Cornelissen PJ, 105, 119 Cornish R, 237, 244 Corris P, 325, 349 Cosio MG, 44, 54, 55, 64 Costabel U, 366, 375, 381 Cote TR, 9, 18 Cotes JE, 123, 131, 143 Cottrell JJ, 151, 165 Coultas DB, 10, 11, 12, 19 Courcoulas A, 209, 217 Courcoulas AP, 407, 411 Coursac I, 14, 21 Couser JL, 134, 146 Coxson HO, 186, 198 Craig D, 220, 222, 227, 239, 241 Cranston JM, 8, 18 Craven JL, 123, 143 Crawford FA, 82, 97 Creagh E, 75, 96 Criner G, 116, 122, 235, 243, 314,

Author Index

459

[Criner G] 315, 317, 318, 323, 326, 328, 334, 336, 337, 339, 340, 343, 350, 351, 352, 355, 356, 366, 367, 376,380 Criner GJ, 162, 168, 248, 256, 292, 299, 303, 309, 329, 351, 356, 371, 376, 382, 385, 398, 399, 400, 401, 408, 409 Crockett AJ, 8, 18 Crockett JE, 378, 384 Crombie IK, 9, 18 Crossley D, 236, 243 Crouch L, 184, 197 Crouch R, 124, 143 Cruise LJ, 5, 17 Crystal RG, 134, 146 Cullinan P, 162, 168, 292, 300, 315, 318, 329, 351 Cunningham HS, 371, 382 Curigan LM, 135, 147 Curriero FC, 14, 21 Curtis J, 186, 198, 228, 241, 340, 352, 385, 386, 387, 388, 392, 409, 431, 447, 451 Curtis JL, 160, 161, 168, 186, 187, 198, 341, 353

D Dajee A, 313, 316, 317, 325, 326, 341, 347 D’Alonzo G, 385, 400, 409 Dalton M, 201, 215 Daly PA, 71, 94 Daniel M, 248, 255, 265, 271 Daniel T, 314, 318, 322, 324, 349 Daniel TM, 292, 299, 356, 371, 383 Dantzker DR, 371, 383 Darioli R, 233, 234, 242 Dart S, 73, 95 Dartevelle P, 306, 309 Date H, 248, 256 Date Hshimizu N, 265, 271 Dauber JH, 113, 121 Davies H, 75, 96

Davies M, 162, 168, 292, 300, 315, 318, 329, 351 Davis S, 221, 239, 313, 317, 322, 324, 326, 329, 341, 349 Davis SM, 153, 166, 248, 256, 292, 299 Davison R, 132, 140, 146 Dawson NV, 4, 16 Dawson SV, 49, 64 Day-Lally CA, 6, 7, 17 de Bock V, 367, 368, 381 de Boer WJ, 418, 421, 423 de Francquen P, 193, 199, 370, 382 De Leyn P, 367, 368, 381 de Maertelaer V, 182, 183, 196 de Oca M, 315, 318, 321, 322, 326, 327, 337, 348 de Oca MM, 265, 271, 373, 374, 383 de Pinto DJ, 369, 373, 374, 375, 376, 382 De Vries WC, 302, 308 De Vuyst P, 182, 183, 196 Dean NC, 131, 146 Dear CL, 123, 143 DeCamp M, 278, 279, 286, 314, 318, 332, 342, 348 DeCamp MM, 248, 254 DeCamp MW, 356, 357, 358, 359, 365, 381 Decramer M, 140, 148, 367, 368, 381 DeFriese GH, 101, 117 DeGraw S, 104, 118 deHoyos A, 82, 97 deLisser E, 230, 241 Della Bella L, 315, 318, 342, 351 Deloney PA, 86, 97, 125, 144, 247, 254, 290, 292, 295, 298, 425, 450 Delorme G, 227, 240 Delozier JE, 10, 19 Demajo W, 82, 97 DeMeester SR, 385, 387, 391, 394, 408 Dempsey JA, 44, 63, 64 Derenne J, 373, 384 Derenne JP, 104, 118 DeRose JJ, 386, 388, 393, 410

460 Desai SR, 188, 199 Desbiens N, 4, 16 Deschamps C, 69, 94, 312, 316, 324, 332, 340, 344, 347, 421, 424 Deslauriers J, 281, 287, 301, 302, 303, 305, 308, 345, 354 D’Esopo ND, 303, 309 DeSoto H, 228, 241 DeSouza G, 230, 241 Despars JA, 135, 147 Deupree RH, 109, 110, 120 Deyo R, 431, 447, 451 Dhainaut JF, 67, 93 D’Hollander A, 225, 226, 240 Di Pede Francesco, 2, 15 Di Tullio MR, 396, 410 Diamond EL, 14, 20 Diaz O, 151, 165 Diener CF, 68, 69, 73, 74, 77, 94 Diette GB, 14, 21, 415, 422 Dillard TGI, 378, 384 Dimond EG, 378, 384 Dimopoulou I, 44, 54, 64 Dirksen A, 2, 15 Dittus R, 106, 119, 325, 349 Dockery DW, 5, 13, 17, 20 Dodge R, 10, 19 Doglio G, 285, 288 Dohi K, 307, 309 Dolensky J, 5, 17 Dolonish M, 205, 216 Dom R, 367, 368, 381 Domenighetti G, 14, 21 Domingo A, 5, 17 Dominici F, 14, 21 Dompeling E, 106, 119 Don H, 222, 239 Donaldson GC, 3, 7, 16 Donohue JF, 105, 119 Dos Santos C, 248, 255, 313, 316, 317, 325, 326, 341, 347 Dos Santos R, 313, 317, 324, 348 Dosman JA, 13, 20 Dowling RD, 248, 255 Drent M, 183, 197 Drolet P, 237, 244

Author Index Dromer M, 280, 286 Duarte IG, 386, 409 DuBois AB, 357, 380 Duchatelle J, 314, 317, 333, 338, 351 Ducros L, 225, 240 Dudley DL, 129, 135, 144, 145 Dueck R, 371, 383 Duguet A, 104, 118 Duhamel A, 182, 195 Dumler JS, 182, 195 Dumortier P, 182, 183, 196 Dunn WF, 111, 121, 151, 165 Dunnill MS, 182, 196 Duque J, 281, 287 Durcan MJ, 102, 118 Dutton RE, 110, 121 Dutton RP, 237, 244 Dwyer DM, 9, 18

E Eagle KA, 158, 167 Eakin E, 431, 451 Eastick S, 188, 199 Ebihara S, 313, 317, 342, 351 Eda S, 184, 197 Edelman JD, 306, 309 Edwards CW, 302, 308 Edwards LC, 369, 373, 374, 375, 376, 382 Egan T, 228, 241 Egan TM, 403, 411 Ehrhart M, 74, 76, 95, 110, 120 Eidelman D, 373, 383 Eidelman DH, 55, 64 Eigenmann V, 237, 244 Eisenkraft J, 227, 235, 241 El-Amir N, 386, 388, 393, 410 Eland ME, 105, 119 Eldridge FL, 75, 95 Elliot EA, 49, 64 Elliott MW, 116, 122 Elliott WM, 183, 197 Ellis JH Jr, 75, 96 Elmes PC, 373, 383

Author Index

461

Elpern E, 214, 218 Elpern EH, 417, 423 Elsasser S, 14, 21 Emanuelsson H, 237, 244 Endou S, 248, 256 Engel H, 325, 342, 350 Engstrom CP, 142, 148 Enright P, 3, 7, 16 Enright PL, 3, 7, 13, 16, 20, 99, 100, 117 Enroth P, 71, 94 Enson Y, 74, 95 Epstein J, 333, 336, 351 Epstein JD, 183, 197, 333, 334, 337, 339, 352, 355, 356, 357, 378, 380, 384 Erbland ML, 109, 110, 120 Eriksen MP, 12, 19 Eriksson SE, 91, 98 Ernst P, 116, 122, 205, 207, 216 Esato K, 169, 187, 193, 194, 195, 199 Espiritu J, 385, 386, 387, 409 Espiritu JD, 79, 96 Estenne M, 193, 199, 370, 382 Etches RC, 237, 244 Eugene J, 248, 255, 291, 299, 313, 316, 317, 325, 326, 341, 347 Eugene JR, 313, 317, 324, 348 Evans K, 183, 197 Evans KG, 45, 64, 183, 197 Evans R, 314, 318, 332, 342, 348 Evans RB, 54, 57, 64, 153, 156, 165, 356, 357, 358, 359, 365, 381 Eyskens E, 401, 411

F Fahey PJ, 369, 373, 374, 375, 376, 382, 404, 411 Fahri LE, 372, 383 Fairley B, 227, 241 Fairley H, 235, 243 Faling LJ, 131, 145 Fallahnejad M, 385, 400, 409 Fardeau M, 416, 422 Farhat El-Raouf AA, 366, 375, 381

Farkas GA, 69, 94 Farrow JT, 129, 134, 144 Farrow S, 222, 239 Fay ME, 5, 17 Federman E, 116, 122 Feenstra TL, 11, 19 Feeny D, 416, 423 Feihl F, 233, 242 Fein A, 346, 354 Fein AM, 125, 127, 133, 144, 421, 424, 425, 450 Feinleib M, 10, 19 Feins R, 313, 322, 324, 326, 328, 340, 342, 343, 349 Feinsilver SH, 127, 133, 144 Feinstein A, 325, 350 Feinstein AR, 373, 383 Ferdinand B, 282, 287 Ferguson G, 318, 321, 323, 326, 328, 343, 348 Ferguson GT, 106, 119, 153, 166, 292, 299, 355, 356, 370, 372, 375, 376, 380, 385, 408 Ferguson M, 344, 351 Ferguson MK, 265, 270 Fernandez E, 153, 166, 292, 299, 318, 321, 323, 326, 328, 343, 348, 355, 356, 370, 372, 375, 376, 380, 385, 408 Fernandez F, 341, 352 Fernandez M, 116, 122 Ferrer M, 328, 350 Ferris BG Jr, 5, 17 Ferson P, 313, 317, 319, 322, 325, 326, 342, 343, 347, 350 Ferson PF, 86, 88, 89, 97, 113, 121, 151, 165, 291, 299, 372, 383 Feskens EJ, 9, 10, 18 Fessler HE, 56, 64, 67, 68, 93, 156, 167, 224, 227, 240, 312, 320, 331, 335, 336, 341, 347, 352, 360, 365, 366, 378, 381, 384 Fetterman LS, 291, 299, 317, 319, 326, 342, 343, 347 Fields S, 133, 146, 370, 371, 382 Filaire M, 151, 165

462 Filley GF, 73, 77, 94 Finigan MM, 110, 120 Finkelstein R, 44, 54, 64 Fiore MC, 101, 117, 118 Fischel RJ, 187, 198, 199, 248, 254, 262, 264, 265, 266, 269, 270, 277, 281, 286, 287, 292, 293, 294, 298, 313, 316, 317, 318, 321, 324, 325, 326, 327, 333, 334, 336, 337, 338, 339, 340, 344, 347, 349, 351, 352, 355, 356, 357, 358, 372, 373, 374, 378, 379, 380, 381, 383, 384, 385, 386, 387, 388, 389, 391, 409, 410 Fischer B, 184, 197 Fischer KC, 163, 168, 345, 351 Fishman AP, 75, 95, 124, 143 Fishman EK, 182, 195 Fitzgerald MX, 302, 304, 309, 310 Fjeld JG, 85, 97 Flaherty KR, 186, 198, 341, 353 Flaishman I, 385, 405, 409 Flanders WD, 6, 7, 17 Fleg JL, 5, 17 Flege JB, 399, 410 Fleishman K, 234, 242 Flenley DC, 73, 76, 95, 123, 131, 143 Fletcher CM, 2, 3, 7, 15, 16, 332, 337, 352, 373, 378, 383, 384 Fletcher EC, 135, 147 Fleury B, 416, 422 Flint A, 184, 197, 314, 317, 344, 353 Fogel B, 431, 451 Foglio K, 142, 148 Folgering H, 106, 119, 416, 423 Fontana P, 306, 309 Foraker AG, 386, 409 Foreman J, 427, 450 Formanek V, 224, 240 Foster S, 124, 125, 143 Foster WL Jr, 182, 196 Fountain SW, 306, 309 Fournier B, 281, 287 Fournier M, 314, 317, 333, 338, 351 Fowkes F, 222, 239 Fozard JL, 5, 17

Author Index Fracchia C, 116, 121 Frasch H, 236, 243 Fratacci MD, 237, 244 Freden F, 224, 240 Freilich A, 397, 410 Friedberg JS, 249, 255, 295, 296, 299 Friedman M, 105, 119, 283, 287 Friend J, 131, 145 Friend T, 427, 450 Fujii T, 307, 309 Fujimoto K, 87, 88, 90, 91, 98, 184, 197, 324, 348 Fujita N, 169, 187, 193, 195 Fujita R, 275, 286 Fukuchi Y, 303, 309 Fulkerson WJ, 4, 16 Fulmer JD, 131, 145 Furrer M, 237, 244 Furukawa S, 157, 162, 167, 168, 235, 243, 248, 256, 292, 299, 314, 315, 317, 318, 323, 326, 328, 329, 334, 336, 337, 339, 340, 343, 350, 351, 352, 355, 356, 366, 367, 371, 376, 380, 382, 385, 398, 399, 400, 401, 408, 409

G Gaensler EA, 304, 309 Gagnon R, 10, 19 Gagnon RC, 3, 7, 16 Gaissert H, 209, 211, 217, 314, 318, 320, 322, 324, 349 Gaissert HA, 155, 157, 167 Gal AA, 386, 409 Gallardo C, 341, 352 Gammer TL, 237, 244 Gamsu G, 169, 182, 194, 196 Gaon M, 90, 98 Garcia I, 116, 122 Garcia J, 14, 20 Garland N, 131, 145 Garrity ER, 369, 373, 374, 375, 376, 382, 404, 411 Gartner SH, 418, 421, 423 Gatehouse PD, 188, 199

Author Index Gauderman WJ, 14, 21 Gauthier AP, 367, 381 Gay S, 315, 318, 321, 322, 326, 327, 337, 348 Gay SE, 355, 356, 366, 368, 372, 373, 374, 380, 385, 408, 408385 Gayan-Ramirez G, 367, 368, 381 Gazzaniga A, 313, 316, 317, 325, 326, 341, 347 Geddes D, 162, 168, 292, 300, 315, 318, 329, 351 Geddes DM, 188, 199 Geertsma A, 418, 421, 423 Geiran OR, 85, 97 Gelb A, 281, 287, 313, 316, 317, 318, 319, 321, 324, 325, 326, 327, 333, 334, 336, 337, 338, 339, 340, 341, 343, 344, 347, 349, 351, 352, 385, 386, 387, 388, 391, 409 Gelb AF, 57, 64, 155, 167, 183, 187, 197, 198, 199, 248, 254, 258, 264, 265, 266, 269, 270, 290, 291, 292, 293, 294, 298, 333, 334, 337, 339, 352, 355, 356, 357, 358, 359, 360, 364, 365, 372, 373, 374, 378, 379, 380, 381, 383, 384, 389, 410 Gelijns A, 214, 218 Gelissen HJ, 307, 310 Gentry C, 428, 450 George MS, 73, 95 Gertstenhaber BJ, 303, 309 Gevenois PA, 182, 183, 196 Ghafouri M, 105, 119 Ghezzo H, 55, 64 Giacomo T, 213, 217 Giacomo TD, 385, 405, 409 Gibbons W, 207, 217 Gibson N, 183, 197 Gibson NN, 45, 64, 183, 197 Gierada D, 187, 198, 343, 344, 351 Gierada DS, 163, 168, 169, 170, 184, 185, 186, 194, 195, 197, 198, 304, 309 Gilliland F, 14, 21 Gilliland J, 2, 15 Gillum RF, 11, 19 Gilmartin ME, 130, 145

463 Gilmore G, 314, 354 Gimeno F, 137, 139, 147 Ginns L, 342, 344, 351 Ginns LC, 292, 299 Ginsburg M, 313, 314, 316, 317, 319, 322, 324, 325, 326, 341, 343, 347, 349 Ginsburg ME, 185, 198, 291, 292, 293, 294, 298 Ginsburg RJ, 281, 287, 390, 391, 393, 410 Giovino GA, 5, 6, 7, 8, 12, 17, 19 Giuliani R, 234, 243 Giuntini C, 2, 15 Gladwin M, 233, 242 Glaser EM, 129, 135, 144 Glazer H, 343, 351 Glazer HS, 169, 184, 185, 194 Glenn K, 140, 148 Gobel H, 71, 94 Godwin JD, 182, 196 Gogia C, 313, 317, 324, 348 Gogia H, 313, 316, 317, 325, 326, 341, 347 Gogia HS, 248, 255, 291, 299 Gold DR, 13, 20 Goldberg SK, 131, 145 Golden JA, 169, 194 Goldman L, 4, 16, 158, 167 Goldring R, 233, 242 Goldstein MG, 101, 117 Goldstein RS, 123, 135, 137, 139, 143, 147, 416, 423 Goldstraw P, 162, 168, 188, 199, 280, 287, 292, 300, 307, 309, 315, 318, 329, 351 Gomez A, 71, 72, 94 Gong H Jr, 11, 12, 19 Gonzales D, 102, 118 Goodgold HM, 81, 97 Goodman J, 112, 121 Goodman JR, 113, 121, 132, 146 Gorcsan J, 372, 383 Gorcscan J, 86, 88, 89, 97 Gordon GH, 135, 147 Gorenstein L, 313, 314, 316, 317, 319, 322, 324, 325, 326, 341, 343, 347, 349

464 Gorenstein LA, 291, 292, 293, 294, 298 Gores G, 234, 242 Gort EH, 137, 139, 147, 416, 423 Gorzelak K, 5, 17 Gosselin B, 182, 195 Gosselink R, 140, 148 Goto K, 248, 256 Goudet P, 282, 287 Gould GA, 73, 76, 95 Gracey D, 224, 240 Grad R, 11, 12, 19 Gramling-Babb P, 237, 244 Grant GJ, 237, 244 Grant I, 129, 135, 144, 145 Grassino A, 134, 147, 370, 371, 382 Grasso ME, 14, 21, 415, 422 Graver L, 318, 324, 348 Graver LM, 87, 90, 97 Graver M, 379, 384 Gray-Donald K, 116, 122 Gray RG, 2, 15 Green RH, 183, 197 Grifﬁn JP, 151, 165 Grifﬁth BP, 209, 217, 248, 255, 385, 406, 407, 409, 411 Grimby G, 366, 381 Grize L, 14, 21 Gronkiewicz CA, 135, 147 Gross C, 207, 217 Gross CP, 14, 21 Gross J, 222, 239 Gross N, 421, 423 Gross P, 91, 98 Grossman RF, 82, 97, 205, 207, 216 Gruber E, 314, 317, 321, 323, 348 Grunewald D, 280, 286 Grymaloski MR, 177, 182, 195 Guarino E, 385, 405, 409 Gude JK, 108, 120 Guell R, 140, 148 Gueret P, 75, 95 Guidet B, 73, 95 Guidotti TL, 8, 18 Gulsvik A, 8, 18 Gumbhir-Shah K, 104, 118 Gunnarsson L, 222, 239

Author Index Gunst S, 230, 241 Gutierrez G, 285, 288 Guy P, 234, 242 Guyatt G, 329, 351, 431, 450 Guyatt GH, 123, 134, 135, 137, 139, 143, 147, 416, 423 Guyton A, 236, 243

H Haake R, 232, 242 Haasler G, 313, 317, 322, 324, 326, 349 Haasler GB, 248, 256, 265, 271, 292, 299 Hadjiaghai L, 183, 197 Hainsworth R, 431, 450 Hajiro T, 327, 328, 350 Hakimian S, 170, 195 Halvorsen RA Jr, 182, 196 Hamacher J, 193, 199, 292, 300 Hamilton R, 207, 217 Hammacher J, 370, 382 Hanbraeus-Jonzon K, 223, 239 Hancock HW, 75, 95 Handelsman H, 312, 342, 347, 426, 450 Handler A, 11, 12, 19 Haniuda M, 87, 88, 90, 91, 98, 324, 348 Hannallah M, 231, 242 Hansdottir V, 237, 244 Hansell D, 162, 168, 292, 300, 315, 318, 329, 351 Hansell DM, 188, 199 Hansen EF, 2, 15 Hansen-Flaschen J, 248, 249, 255, 291, 293, 295, 296, 298, 315, 318, 319, 320, 322, 347 Hansen JE, 129, 144, 397, 410 Hanson C, 236, 243 Hansson B, 401, 411 Hara PO, 99, 100, 117 Haraguchi M, 184, 197 Harding GKM, 107, 120 Hardy A, 227, 240 Hardy J, 280, 287 Hardy KJ, 201, 215

Author Index Harf A, 116, 121 Harms CA, 44, 64 Harper R, 328, 350 Harrell FE Jr, 4, 16 Hartigan P, 224, 240 Hartung W, 182, 196 Harvey C, 12, 20 Hary A, 227, 240 Hashmi YJ, 367, 368, 381 Hauser M, 248, 255, 265, 266, 268, 270, 292, 300, 317, 322, 325, 326, 349 Hayden AM, 208, 217 Haynes SG, 12, 20 Hays D, 283, 287 Hays JT, 102, 118 Hazelrigg S, 277, 284, 286, 287, 313, 314, 318, 319, 322, 324, 326, 328, 340, 342, 343, 347, 349 Hazelrigg SR, 262, 264, 269, 291, 293, 295, 298, 299, 385, 386, 387, 388, 391, 392, 408 Health CW Jr, 6, 7, 9, 17 Heard BE, 182, 196 Heaton RK, 129, 135, 144 Hedenstierna G, 220, 221, 239 Heederik D, 9, 10, 18, 19 Heerlein A, 431, 451 Heinonen J, 223, 239 Hellestein H, 314, 354 Henderson S, 234, 242 Hendrick DJ, 14, 20 Henkle J, 291, 299, 313, 314, 318, 319, 322, 324, 326, 328, 340, 342, 343, 347, 349 Henriquez A, 68, 72, 74, 90, 91, 93 Henry D, 248, 256, 292, 299, 313, 317, 322, 324, 326, 349 Henzlowa MJ, 397, 410 Hepplestn AG, 182, 196 Heras F, 281, 287 Herles F, 90, 98 Herman PG, 187, 189, 199 Hermann E, 185, 187, 188, 198 Hermans J, 201, 202, 204, 205, 206, 215

465 Hernandez C, 116, 122 Hernandez L, 231, 242 Herrmann F, 6, 17 Hershﬁeld ES, 107, 120 Hertz MI, 207, 217, 403, 411 Herwaarden C, 416, 423 Hess O, 75, 76, 95 Heussel CP, 184, 197 Hibbett A, 83, 97, 291, 299, 313, 317, 318, 322, 326, 339, 348, 355, 356, 368, 372, 373, 374, 375, 376, 380, 382 Hickey D, 224, 235, 240 Hickey R, 222, 239 Hickling K, 234, 242 Hida W, 184, 197, 313, 317, 342, 351 Higgins IT, 2, 15 Higgins MW, 6, 8, 17, 18 Higuchi J, 283, 287 Hildebrandt J, 314, 317, 320, 321, 348, 372, 383 Hill NS, 116, 121, 122 Hilleman D, 105, 119 Hillerdal G, 153, 166, 315, 318, 323, 326, 329, 351 Himelman RB, 131, 146 Hirai T, 183, 196 Hirth PK, 91, 98 Hlastala M, 314, 317, 320, 321, 348 Hlastala MP, 372, 383 Hodgkin J, 313, 317, 321, 326, 351 Hodgkin JE, 2, 15, 123, 132, 133, 135, 143, 146 Hofer S, 371, 382 Hoffman EA, 183, 196 Hoffman LA, 113, 121 Hogberg S, 176, 195 Hogg J, 356, 380 Hogg JC, 74, 95, 177, 182, 186, 195, 198 Hogue CW Jr, 228, 241 Holberg CJ, 3, 7, 16 Holbert J, 192, 199, 317, 319, 326, 342, 343, 347 Holbert JM, 86, 88, 89, 97, 372, 383 Holford FD, 77, 96

466 Holker JM, 291, 299 Holman W, 280, 287 Holohan T, 312, 342, 347 Holohan TV, 426, 450 Holzer A, 192, 199 Homma S, 396, 410 Hoogenveen RT, 11, 19 Hooper RG, 75, 95 Hooper RO, 74, 95 Hop JW, 130, 141, 145 Hoppin FG, 359, 361, 370, 381, 382 Horan JM, 9, 18 Hori M, 75, 96 Horne SL, 13, 20 Howard P, 5, 17, 123, 131, 143, 328, 350 Howell JBL, 66, 93 Howie CA, 106, 119 Howite JS, 105, 119 Howland W, 233, 242 Hruban RH, 182, 195 Hrubec Z, 5, 17 Hubbell D, 237, 244 Hubert M, 431, 451 Hubmayr R, 224, 234, 240, 242, 312, 316, 324, 332, 340, 344, 347 Hubmayr RD, 111, 121, 421, 424 Hudson L, 431, 447, 451 Huemer G, 227, 240 Hugh-Jones P, 371, 372, 382 Hughes RL, 132, 140, 146 Huh J, 317, 318, 325, 327, 338, 349, 356, 372, 373, 374, 383 Huizenga H, 425, 450 Huizenga HF, 297, 299, 417, 423 Hunsacker A, 345, 354 Hunt S, 326, 354 Hurd SS, 99, 100, 102, 110, 117 Hurford WE, 237, 244 Hurley B, 44, 50, 63 Hurt RD, 102, 118 Hutchins GM, 182, 195 Hutchison DC, 14, 21 Hyatt R, 125, 144, 427, 450 Hyatt RE, 51, 64, 69, 94, 360, 381 Hyman S, 228, 241

Author Index I Iannettoni M, 186, 198, 340, 341, 352, 353 Iannettoni MD, 186, 193, 198, 199 Ignacio G, 231, 241 Ikeda A, 182, 196 Ikeda T, 182, 196 Ikezoe J, 170, 195 Ikle D, 140, 148 Ilowite JS, 127, 133, 144 Im JG, 182, 196 Ingenito E, 314, 318, 328, 332, 342, 348, 350 Ingenito EP, 54, 57, 64, 153, 156, 162, 163, 165, 167, 168, 248, 254, 345, 354, 356, 357, 358, 359, 364, 365, 381, 435, 451 Ingram RH Jr, 413, 422 Iqbal M, 379, 384 Isabey D, 116, 121 Isenberg M, 227, 241 Ishida T, 182, 196 Isidori P, 107, 120 Itagaki S, 75, 76, 95 Itoh H, 182, 183, 196 Iwasaki M, 279, 286 Izquierdo-Alonso J, 341, 352 Izquierdo JL, 55, 64 Izumi T, 182, 196

J Jackson R, 234, 242 Jackson RM, 111, 121 Jacobs P, 415, 422 Jaksch P, 314, 317, 321, 323, 348 Jalal R, 90, 98 Jamadar D, 187, 188, 199, 345, 351 Jamerson B, 102, 118 Jamieson SW, 385, 405, 409 Jandrasits O, 314, 317, 321, 323, 348 Janicki JS, 66, 75, 93 Jansen MC, 420, 423 Janssens JP, 6, 17 Jantsch U, 314, 317, 321, 323, 348

Author Index

467

Jardin F, 75, 95, 227, 240 Jebrak G, 202, 215 Jederlinic PJ, 304, 309 Jedrychowski W, 2, 16 Jeevanandam JB, 385, 398, 399, 408 Jeffries DJ, 3, 7, 16 Jellen P, 313, 314, 316, 317, 319, 322, 324, 325, 326, 341, 343, 347, 349 Jellen PA, 185, 198, 291, 292, 293, 294, 298 Jenkins CR, 99, 100, 102, 110, 117 Jensen G, 2, 15 Jensen PS, 129, 145 Jezek V, 90, 98 Jhangri GS, 8, 18 Jin Z, 183, 196 Johanson WG, 283, 287 Johnson BD, 44, 63 Johnson D, 342, 343, 344, 351 Johnson DC, 292, 299 Johnson JM, 73, 95 Johnson JT, 113, 121 Johnson L, 285, 287 Johnson PA, 105, 119 Johnston A, 102, 118 Johnstone D, 313, 322, 324, 326, 328, 340, 342, 343, 349 Jones N, 328, 350, 431, 450 Jones NL, 73, 95, 129, 144 Jones P, 105, 116, 118, 122, 326, 354 Jones PW, 106, 120, 139, 147 Jordan P, 151, 165 Jorenby DE, 101, 102, 117, 118 Jorens PG, 401, 411 Jorfeldt L, 315, 318, 323, 326, 329, 351 Jorgenson BN, 129, 135, 144 Jubran A, 369, 373, 374, 375, 376, 382, 421, 423 Judson M, 280, 287 Judson MA, 81, 96 Jusko WJ, 104, 118

K Kachel RB, 75, 96

Kaczka D, 314, 318, 332, 342, 348 Kaczka DW, 54, 57, 64, 356, 357, 358, 359, 365, 381 Kaga K, 279, 286 Kaider A, 185, 197, 292, 300, 332, 344, 345, 351 Kaiser L, 315, 318, 319, 320, 322, 346, 347, 354 Kaiser LE, 202, 207, 215, 217 Kaiser LR, 155, 167, 248, 249, 255, 291, 293, 295, 296, 298, 299, 367, 368, 381, 406, 407, 411 Kajitani M, 170, 195 Kalendar W, 170, 195 Kambam J, 228, 241 Kanarek D, 342, 344, 351 Kanarek DJ, 292, 299 Kaneda Y, 169, 187, 193, 195 Kanford SL, 101, 118 Kaniecki DJ, 421, 423 Kanner R, 102, 118 Kanner RE, 3, 7, 13, 16, 20, 99, 100, 117, 153, 165 Kao SY, 5, 17 Kapelanski D, 213, 218 Kapelanski DP, 224, 240, 269, 270, 385, 405, 409 Kaplan R, 128, 144, 431, 447, 451 Kaplan RM, 133, 137, 138, 139, 140, 141, 146, 147, 416, 421, 423, 424 Kaplan V, 369, 370, 382 Karadeniz H, 233, 242 Karpel JP, 105, 118 Karrer W, 14, 21 Kasahara Y, 91, 98 Kaschak M, 91, 98 Kato S, 70, 94 Katz B, 325, 349 Katz BP, 106, 119 Katz J, 235, 236, 237, 243, 244 Kauczor HU, 184, 197 Kauffmann F, 2, 15 Kavanagh B, 236, 243 Kavanagh BP, 237, 244 Kawagoe Y, 366, 381 Kawakami K, 183, 196

468 Kawakami Y, 169, 187, 193, 194 Kawamata T, 230, 241 Kawamura T, 187, 199 Kawashima Y, 303, 309 Kayaleh R, 313, 315, 316, 317, 318, 324, 325, 326, 341, 342, 347, 348, 351 Kayaleh RA, 248, 255, 290, 291, 298, 299 Kazerooni E, 185, 186, 187, 188, 197, 198, 199, 314, 317, 340, 344, 345, 351, 352, 353 Kazerooni EA, 184, 185, 186, 187, 193, 197, 198, 199, 341, 353, 385, 386, 387, 388, 392, 409 Keagy B, 277, 286 Kearney DJ, 151, 157, 165 Keelan P, 302, 310 Keenan R, 192, 199, 278, 288, 313, 317, 319, 322, 324, 325, 326, 328, 340, 342, 343, 347, 349, 350, 385, 406, 407, 409, 411 Keenan RI, 86, 88, 89, 97 Keenan RJ, 154, 156, 157, 166, 186, 198, 202, 207, 209, 216, 217, 248, 255, 264, 266, 270, 291, 293, 295, 298, 299, 372, 383, 418, 421, 423 Keighley JF, 77, 96 Keinecke H, 280, 286 Keinle GS, 377, 384 Keistinen T, 6, 7, 17 Keller C, 219, 236, 238, 283, 287, 313, 317, 318, 322, 324, 326, 328, 339, 340, 342, 343, 348, 349 Keller CA, 79, 81, 83, 96, 97, 248, 255, 291, 293, 295, 298, 299, 368, 373, 374, 375, 376, 382, 385, 386, 387, 397, 409, 410 Keller JB, 6, 17 Keller R, 14, 21 Keller-Wossidlo H, 14, 21 Kellerman DJ, 104, 118 Kelsen S, 314, 354 Kemerink GJ, 183, 197 Kenford SL, 101, 117 Keogh BA, 134, 146 Keogh BF, 401, 411

Author Index Kerby GR, 125, 144 Kern D, 431, 451 Kerr KM, 125, 144 Kerstjens HA, 420, 423 Keshavjee S, 213, 217 Keshavjee SH, 405, 411 Kessler R, 87, 88, 90, 97, 324, 348, 371, 383 Kesten S, 205, 216 Kettel LJ, 68, 69, 73, 74, 77, 94 Key CR, 13, 20 Khalaf A, 328, 350 Khan A, 187, 189, 199 Khayrallah M, 102, 118 Khouri NF, 182, 195 Khuri S, 72, 94 Kiene H, 377, 384 Kigin C, 125, 144 Kikuchi Y, 313, 317, 342, 351 Kilburn KH, 399, 411 Kiley J, 13, 20 Kiley JP, 3, 7, 16, 99, 100, 117, 378, 384 Kim DK, 367, 368, 381 Kim WD, 55, 64 Kimball WR, 237, 244 Kindred MK, 68, 72, 93 King D, 123, 135, 143 King T, 326, 354 Kirby T, 277, 286 Kirilloff LH, 125, 131, 144, 145 Kirsh M, 277, 286 Kittle CF, 378, 384 Kivela SL, 6, 7, 17 Kjaergard H, 280, 286 Kjekshus J, 71, 94 Klamm R, 184, 197 Klein JS, 169, 194 Kleinerman J, 68, 93 Klepetko W, 158, 167, 185, 197, 248, 255, 292, 300, 314, 315, 317, 318, 319, 321, 323, 325, 326, 332, 344, 345, 347, 348, 351, 371, 382 Klima L, 314, 317, 321, 323, 326, 348, 370, 375, 376, 382, 385, 408 Klontz B, 214, 218, 417, 423 Klopstock R, 302, 308

Author Index Knaepen PJ, 307, 310 Knaus WA, 4, 16 Knill R, 221, 239 Knox A, 431, 450 Knox R, 428, 450 Knudson RJ, 3, 7, 16 Ko CY, 249, 255, 296, 297, 299, 314, 318, 319, 347 Koch P, 104, 118 Kocher A, 371, 382 Kock M, 237, 244 Koespell T, 68, 72, 93 Koeter GH, 137, 139, 147 Kohama A, 75, 96 Kohro S, 230, 241 Koike T, 391, 410 Koizumi T, 87, 88, 90, 91, 98, 324, 348 Kok-Jensen A, 2, 15 Kolata G, 438, 451 Kolev N, 227, 240 Kollin J, 183, 197 Konietzko N, 155, 166, 314, 318, 322, 325, 326, 333, 334, 337, 338, 339, 340, 343, 349, 366, 375, 378, 381, 384 Kontrus M, 185, 197, 248, 255, 292, 300, 315, 318, 319, 323, 325, 326, 332, 344, 345, 347, 351 Koopmanschap MA, 418, 421, 423 Korducki L, 105, 119 Kormos R, 206, 216 Kotch A, 105, 118 Kotloff RM, 153, 154, 157, 166, 209, 217, 248, 249, 255, 265, 266, 268, 270, 291, 293, 295, 296, 298, 306, 309, 315, 318, 319, 320, 322, 346, 347, 354, 406, 407, 411 Kottke TE, 101, 117 Kouchoukos NT, 403, 411 Koulouris NG, 44, 54, 64 Koyama H, 162, 168, 182, 188, 196, 199, 292, 300, 315, 318, 329, 351 Kraan J, 137, 139, 147 Kramer N, 116, 121 Krasna MI, 187, 198 Krasna MJ, 385, 386, 387, 388, 409 Kraus A, 431, 451

469 Krayenbuehl HP, 75, 76, 95 Kreimer DT, 385, 401, 409 Kreiss P, 14, 20 Kress M, 289, 295, 298 Kress MB, 202, 215, 216, 355, 361, 380 Kriett JM, 208, 213, 217, 218, 385, 405, 409 Kritzinger M, 371, 382 Kromhout D, 9, 10, 18, 19 Krop AD, 110, 121 Kroshus TJ, 213, 217, 265, 269, 270, 385, 404, 405, 409 Krucylak PE, 83, 97, 219, 236, 238, 248, 255, 313, 317, 322, 324, 326, 348, 397, 410 Kruger M, 235, 243 Krzyzanowski M, 2, 16 Kshettry VR, 213, 217, 385, 404, 405, 409 Kubo K, 87, 88, 90, 91, 98, 184, 197, 324, 348 Kuei J, 183, 197, 258, 269 Kuller LH, 13, 20 Kume N, 169, 187, 193, 194 Kuno K, 182, 183, 196 Kunzli N, 14, 21 Kuranishi F, 307, 309 Kurita Y, 391, 410 Kurosawa H, 313, 317, 342, 351 Kurz A, 227, 240 Kurzer S, 231, 242 Kussin P, 4, 16 Kuwano K, 182, 196 Kuzma A, 314, 315, 318, 323, 326, 328, 334, 336, 337, 339, 343, 350, 351 Kuzma AM, 157, 167, 248, 256, 292, 299, 329, 351, 355, 356, 366, 367, 371, 376, 380, 382, 385, 398, 399, 401, 408, 409

L Lacasse Y, 123, 135, 143 Laennec RTH, 355, 380 Laghi F, 369, 373, 374, 375, 376, 382

470 Lahdensuo A, 5, 17 Lahrmann H, 314, 317, 321, 323, 348 Laitinen L, 106, 119 Lakatos E, 134, 146 Laks M, 66, 72, 92 Lamers RJ, 183, 197 Lando Y, 158, 159, 167, 356, 371, 376, 382 Landreneau R, 192, 199, 202, 216, 278, 288, 313, 317, 319, 322, 324, 326, 328, 340, 342, 343, 347, 349 Landreneau RI, 86, 88, 89, 97 Landreneau RJ, 154, 157, 166, 248, 255, 264, 266, 270, 291, 293, 295, 298, 299, 372, 383, 385, 390, 406, 407, 409, 410 Lane DJ, 123, 131, 143 Lange L, 186, 198, 341, 353 Lange P, 2, 10, 15, 19, 106, 120 Lankford EB, 367, 368, 381 Lanoe JL, 416, 422 Lapp NL, 14, 20 Laros CD, 307, 310 Larsen F, 315, 318, 323, 326, 329, 351 Larson CA, 130, 145 Larsson S, 142, 148 Laube I, 185, 187, 188, 198, 292, 300, 325, 342, 350 Laurell CB, 91, 98 Laursen LC, 2, 15 Laverne R, 235, 243 Lawson L, 74, 95 Lawyer C, 313, 322, 324, 326, 328, 340, 342, 343, 349 Lawyer V, 314, 318, 319, 322, 324, 326, 328, 347 Layug A, 222, 239 Leary W, 427, 450 Lebowitz MD, 3, 7, 16 LeCreas TD, 91, 98 Lee H, 116, 122 Lee R, 274, 278, 284, 286, 313, 317, 322, 324, 349 Lee RB, 248, 255, 265, 271, 371, 383, 386, 397, 409, 410 Lee TA, 14, 21

Author Index Lee TH, 151, 157, 165 Lee WW, 13, 20 Leff RF, 416, 422 Lefrak S, 314, 318, 322, 324, 326, 328, 333, 336, 338, 341, 344, 349, 351, 352 Lefrak SS, 154, 155, 156, 157, 166, 167, 169, 184, 185, 186, 194, 197, 198, 248, 255, 292, 295, 298, 438, 451 Leibowitz DW, 396, 410 Leischow SG, 101, 102, 118 Lemaire F, 116, 121 Lennon PF, 74, 95 Lertzman MM, 123, 131, 132, 135, 143 Lesitsky M, 221, 239 Lesiuk L, 225, 231, 235, 240 Leuenberger P, 14, 21 Levine S, 205, 207, 216, 217, 367, 368, 381 Levison H, 371, 382 Levy DA, 14, 20 Levy P, 313, 322, 324, 326, 328, 340, 342, 343, 349 Levy R, 205, 207, 216 Lewis CM, 78, 96 Lewis MI, 132, 146 Lewis P, 186, 198, 340, 352 Lewis S, 106, 109, 119, 162, 168, 215, 218, 297, 299, 314, 317, 321, 323, 326, 341, 348, 352, 369, 370, 375, 376, 382, 385, 408, 417, 423 Leyenson V, 329, 351, 355, 356, 366, 367, 376, 380 Li Y, 369, 370, 382 Liebow A, 91, 98 Light RW, 135, 147 Lillington G, 177, 182, 195 Lim TK, 169, 194 Limberg TM, 130, 133, 137, 138, 140, 141, 145, 146, 416, 423 Liopyris P, 399, 410 Lipchik R, 313, 317, 322, 324, 326, 349 Lipchik RJ, 248, 256, 265, 271, 292, 299 Little AG, 264, 266, 270, 291, 299 Little JB, 357, 380

Author Index

471

Littlejohns P, 139, 147, 326, 354 Littner MR, 105, 119 Litven W, 8, 18 Livingstone HM, 379, 384 Lloyd M, 207, 217 Lloyd TC, 68, 72, 93 Lofback K, 140, 147 Lofdahl C, 106, 119 Logan DL, 129, 135, 144 Loick HM, 237, 245 London S, 14, 21 Lonsdorfer J, 87, 88, 90, 97, 324, 348, 371, 383 Lopes T, 187, 198 Lopez AD, 9, 18 Lopez-Majano V, 110, 121 Lopez-Vidriero MT, 131, 145 Lores M, 277, 286 Loring S, 314, 318, 332, 342, 348 Loring SH, 54, 57, 64, 153, 156, 163, 165, 167, 345, 354, 356, 357, 358, 359, 364, 365, 381 Low DE, 202, 215 Lu J, 431, 451 Lucey EC, 69, 94 Lundquist H, 222, 239 Lunn J, 222, 239 Lupinetti FM, 404, 411 Lurmann F, 14, 21 Lydick E, 3, 7, 10, 16, 19 Lyle SK, 3, 7, 16 Lynch JP, 76, 96, 187, 198 Lyons HA, 302, 308

M Macaluso S, 274, 286 Macchiarini P, 306, 309 Macey SL, 112, 121 Macfarlane D, 14, 20 MacGee W, 6, 17 MacIntyre NR, 124, 143 Mack MJ, 390, 410 Mackay J, 15, 21 Mackay JJ, 15, 21

Macklem PT, 357, 367, 373, 380, 381, 383 Mackowiak J, 328, 350 MacNee W, 5, 17 MacNeill SJ, 162, 168, 292, 300, 315, 318, 329, 351 Madder H, 230, 241 Madhavan J, 134, 135, 147 Maeda M, 303, 309 Magee M, 284, 287, 313, 314, 318, 319, 322, 324, 326, 328, 340, 342, 343, 347, 349 Magee MJ, 291, 293, 295, 298, 385, 386, 387, 388, 391, 392, 408 Mahler D, 325, 328, 350 Mahler DA, 133, 146, 303, 309, 373, 383 Make B, 318, 321, 323, 326, 328, 343, 348, 385, 408, 425, 450 Make BJ, 134, 140, 146, 148, 292, 299, 355, 356, 370, 372, 375, 376, 380, 421, 424 Mal H, 202, 215, 265, 266, 270, 314, 317, 333, 338, 351 Malen JF, 123, 143 Mammosser M, 110, 120 Mancebo J, 116, 121, 122 Manfreda J, 8, 18, 107, 120 Manninen P, 221, 239 Manning HE, 372, 383 Mannino DM, 3, 5, 6, 7, 8, 16, 17 Mansour K, 274, 278, 284, 286, 313, 317, 322, 324, 349 Mansour KA, 248, 255, 265, 271, 371, 383, 386, 397, 409, 410 Manzetti JD, 248, 255, 385, 406, 407, 409 Mao Y, 8, 18 Mapel D, 10, 19 Marchand E, 367, 368, 381 Margolis HG, 14, 21 Marinelli WA, 403, 411 Marini J, 225, 229, 235, 240, 243 Marino M, 315, 318, 322, 330, 351 Marino W, 116, 122 Marrades R, 328, 350

472 Marshall B, 236, 243 Martin BW, 14, 21 Martin RJ, 135, 147 Martin T, 106, 109, 119 Martinez F, 184, 185, 186, 187, 188, 197, 198, 199, 205, 207, 216, 311, 312, 314, 315, 317, 318, 321, 322, 326, 327, 337, 340, 343, 344, 345, 346, 348, 351, 352, 353, 385, 386, 387, 388, 392, 409 Martinez FJ, 134, 146, 160, 168, 184, 186, 187, 193, 197, 198, 199, 265, 271, 341, 353, 355, 356, 366, 368, 372, 373, 374, 380, 385, 408 Martorana PA, 71, 94 Masaoka A, 303, 309 Maslen TK, 106, 120 Massard G, 87, 88, 90, 97, 324, 348, 371, 383 Mathews HR, 302, 308 Matsuba K, 182, 196 Matsuda T, 170, 195 Matsumoto T, 169, 187, 194, 199 Matsunaga N, 169, 187, 193, 194, 199 Matsuoka T, 169, 187, 193, 195 Matsuse T, 303, 309 Matsuzawa Y, 87, 88, 90, 91, 98, 184, 197, 324, 348 Matteucci G, 315, 318, 322, 330, 351 Matthay RA, 73, 76, 95 Maurer J, 82, 97 Maurer JR, 82, 97, 205, 207, 214, 216, 218 Maurer KR, 12, 19 Mayo JR, 182, 195 Mazolewski P, 154, 166 Mazzocco MC, 131, 145 McBride L, 83, 97 McCarthy LC, 283, 287 McCarty DC, 113, 121, 132, 146 McClaran SR, 44, 64 McClean P, 207, 217 McClurken JB, 385, 398, 399, 408 McConnell JW, 248, 255 McConnell R, 14, 21 McCool D, 369, 370, 382

Author Index McCool FD, 265, 271 McCurdy SA, 11, 12, 19 McDonald JW, 385, 386, 387, 409 McDougall JC, 81, 85, 96, 97 McEwan J, 326, 354 McFadden ER Jr, 71, 94 McFarlane D, 5, 17 McGregor CG, 81, 85, 96, 97 McGregor GC, 396, 410 McGregor M, 46, 64, 66, 67, 93 McGuire G, 236, 243 McHardy GRJ, 123, 131, 143 McHorney C, 431, 451 McIlrath D, 285, 287 McKay SE, 106, 119 McKee CC, 345, 354 McKenna R, 264, 266, 270, 277, 281, 286, 287, 313, 317, 318, 319, 325, 327, 338, 343, 347, 349 McKenna R Jr, 313, 316, 317, 321, 324, 325, 326, 333, 334, 336, 337, 339, 340, 341, 344, 347, 351, 352 McKenna RJ, 248, 254, 290, 291, 292, 293, 294, 298, 333, 334, 337, 339, 352, 355, 356, 357, 358, 359, 360, 364, 365, 372, 373, 374, 378, 379, 380, 381, 383, 384, 385, 386, 387, 388, 391, 409 McKenna RJ Jr, 57, 64, 153, 154, 156, 157, 158, 166, 187, 198, 199, 262, 264, 265, 266, 269, 270, 389, 410 McKenna S, 326, 354 McKeon K, 87, 90, 97, 229, 241, 318, 324, 348, 379, 384 McLennan G, 183, 196 McRae K, 235, 243 McSweeny AJ, 129, 135, 144 Mead J, 357, 380 Medici TC, 14, 21 Meecham-Jones J, 116, 122 Meharg J, 116, 121 Mehran RJ, 302, 303, 305, 308 Mehta S, 116, 122 Meissner A, 237, 245 Mellgard A, 223, 239

Author Index Menard-Rothe K, 248, 256, 292, 299, 313, 317, 322, 324, 326, 349 Mendez R, 373, 374, 383 Meneghetti A, 435, 451 Menitove S, 233, 242 Menjoge S, 105, 119 Menjoge SS, 105, 119 Menkes HA, 10, 14, 19, 20 Menotti A, 9, 10, 18 Mentzer S, 278, 279, 286, 314, 318, 328, 332, 342, 348, 350 Mentzer SJ, 151, 162, 165, 168, 248, 254, 345, 354, 356, 357, 358, 359, 364, 365, 381 Merendino KA, 378, 384 Merrill EJ, 135, 147 Messadi A, 116, 121 Metter EJ, 5, 17 Meyer FJ, 366, 375, 381 Meyer T, 116, 121 Meyers B, 333, 351 Meziane MA, 182, 195 Michel JP, 6, 17 Miedema I, 9, 18 Miguel R, 237, 244 Mikkelsen KL, 102, 118 Mildenberger P, 184, 197 Milic-Emili J, 44, 54, 64, 104, 118, 234, 235, 236, 243, 373, 384 Milic-Emili M, 111, 121 Miller D, 397, 410 Miller DL, 248, 255 Miller J, 82, 97, 274, 278, 284, 286, 313, 317, 322, 324, 349 Miller JI, 265, 271, 371, 383, 386, 397, 409, 410 Miller JI Jr, 248, 255 Miller MJ, 237, 244 Miller R, 183, 197 Miller RD, 386, 409 Miller RR, 45, 64, 177, 182, 183, 190, 195, 197 Miller S, 231, 242 Miller WF, 131, 145 Millman RP, 116, 122 Milne E, 315, 318, 342, 351

473 Mineo TC, 315, 318, 322, 330, 351 Mink S, 71, 94 Mink SN, 71, 72, 94 Miro A, 224, 227, 240 Mise J, 75, 76, 95 Mishima M, 182, 183, 196 Mitchell AS, 73, 95 Mitchell J, 343, 351 Mitchell RS, 73, 77, 94 Mithoefer JC, 77, 96 Mitsa T, 183, 196 Mitzner W, 71, 94 Moazami N, 154, 158, 166, 248, 255, 265, 270, 314, 317, 322, 324, 326, 341, 343, 349 Moise A, 231, 242 Molema J, 106, 119 Molken MP, 416, 420, 423 Monden Y, 303, 309 Monn C, 14, 21 Montes de Oca M, 355, 356, 366, 368, 372, 373, 374, 380, 385, 408 Montes H, 12, 20 Moore F, 2, 15 Morady F, 66, 72, 92 Morera J, 328, 350 Moretti R, 306, 309 Morgan E, 230, 241 Morgan MD, 302, 308 Morgan WK, 14, 20 Morice RC, 151, 165 Moriyama K, 75, 76, 95 Morris J, 302, 308 Morrison DL, 82, 97 Morrison J, 431, 450 Morrison NJ, 45, 64, 177, 182, 183, 190, 195, 197 Moser KM, 125, 128, 144, 399, 411 Moskowitz GW, 187, 189, 199 Moss JR, 8, 18 Mouritzen C, 280, 286 Moutaﬁs M, 225, 240 Mowery PD, 12, 19 Moy M, 328, 350 Moy ML, 162, 168, 345, 354, 359, 364, 365, 381

474

Author Index

Moy MM, 156, 163, 167 Mueller E, 202, 215, 289, 295, 298, 355, 361, 380 Muers M, 431, 450 Mukai M, 307, 309 Mukherjee R, 82, 97 Mullen B, 177, 182, 195 Muller NL, 169, 170, 177, 181, 182, 183, 190, 194, 195, 196, 197 Mullin M, 248, 254, 290, 291, 298, 313, 317, 319, 325, 343, 347 Mun IK, 50, 64, 185, 198 Mungall I, 431, 450 Munoz A, 5, 17 Muntwyler J, 87, 88, 90, 91, 97, 98, 160, 168, 228, 241, 343, 344, 352, 395, 396, 410 Murakami J, 182, 196 Muramoto A, 68, 72, 93 Murata K, 182, 196 Murciano D, 111, 121, 236, 243 Murphy ML, 68, 93 Murray CJ, 9, 18 Murray P, 221, 239 Murtuza B, 401, 411 Mutalipassi LR, 135, 147 Muza S, 314, 354 Myers R, 130, 145 Myles P, 227, 230, 232, 240, 241 Myles PS, 237, 244 Myoshi S, 207, 217

N Naamee A, 151, 165 Naef AP, 301, 308 Nagase T, 303, 309 Nagashima H, 248, 256 Nakahara K, 303, 309 Nakano Y, 183, 196 Nakaoka K, 303, 309 Nakhjavan FK, 46, 64, 67, 93 Nath PH, 182, 196 Naunheim K, 219, 236, 238, 262, 264, 269, 277, 283, 286, 287, 313, 317,

[Naunheim K] 318, 322, 324, 326, 328, 339, 340, 342, 343, 344, 348, 349, 351 Naunheim KS, 83, 97, 155, 167, 248, 255, 265, 270, 291, 293, 295, 298, 299, 355, 356, 368, 372, 373, 374, 375, 376, 380, 382, 385, 386, 387, 388, 391, 392, 397, 408, 409, 410 Nava S, 116, 121 Nawata K, 169, 187, 193, 195 Neish CM, 130, 141, 145 Nelems B, 183, 197 Nelems JM, 74, 95 Nelson NA, 107, 120 Nelson SB, 111, 121 Nemic NL, 416, 422 Newill CA, 10, 19 Newman SP, 131, 145 Ng YC, 415, 422 Niaura R, 102, 118 Nichols DM, 177, 182, 195 Nickens H, 12, 20 Nicklaus TM, 170, 195 Nickoladze G, 307, 310 Nicotra B, 133, 146 Niden AH, 68, 69, 73, 74, 77, 94 Nides M, 102, 118 Nides MA, 102, 118 Niederman MS, 127, 133, 144 Nieminen A, 234, 242 Niewoehner DE, 109, 110, 120 Nino JJ, 264, 266, 270, 291, 299 Nishigauchi K, 169, 187, 193, 194, 199 Nishiki M, 307, 309 Nishimura K, 182, 196, 327, 328, 350 Nishitani H, 182, 196 Nishium N, 279, 286 Noma S, 187, 189, 199 Nordberg G, 237, 244 Norman M, 153, 166, 315, 318, 323, 326, 329, 351 Norman-Smith B, 2, 15 North LB, 74, 95 Nowak R, 102, 118 Nuchprayoon CV, 54, 64 Nunn J, 220, 221, 239

Author Index

475

Nussbaum SR, 158, 167 Nyboe J, 2, 15

O O’Brien G, 162, 168, 292, 299, 314, 315, 317, 318, 323, 326, 328, 334, 336, 337, 339, 340, 343, 350, 351, 352, 355, 356, 366, 367, 376, 380, 385, 398, 399, 400, 401, 408, 409 O’Brien GM, 157, 167, 248, 256, 329, 351 Ochoa LL, 76, 96 Ocke MC, 10, 19 O’Donnell D, 335, 352, 372, 383 O’Donnell DE, 303, 309, 373, 383, 384 O’Donohue WJ, 110, 111, 121 O’Donohue WJ Jr, 416, 417, 422 Oelberg D, 342, 344, 351 Oelberg DA, 153, 157, 162, 166, 292, 299 Offenstadt G, 73, 95 Ofﬁcer TM, 54, 64 Offord KP, 386, 409 Ogawa H, 313, 317, 342, 351 Ogilvie C, 307, 310 Ohar J, 79, 81, 96, 97 O’Hara P, 3, 7, 16 Ohi M, 183, 196 Ohlson S, 106, 119 Ohno K, 303, 309 Ohsugi T, 303, 309 Ohta M, 303, 309 Ohtani M, 307, 309 Oikawa M, 313, 317, 342, 351 Ojo T, 187, 198 Ojo TC, 187, 198, 385, 386, 387, 388, 392, 409 Okabe S, 313, 317, 342, 351 Oku Y, 183, 196 Olinger GN, 248, 256, 292, 299 Olmedilla L, 231, 241 Olsen GN, 151, 165 Olson LJ, 81, 96 Olsson G, 222, 239

Ong B, 237, 244 Onlinger G, 313, 317, 322, 324, 326, 349 Orens J, 205, 207, 216 Orimo H, 303, 309 Orre L, 153, 166, 315, 318, 323, 326, 329, 351 Osann K, 315, 317, 318, 321, 325, 327, 338, 340, 342, 349, 351, 352, 356, 372, 373, 374, 383 Osann KE, 187, 199, 389, 410 Osborne S, 177, 182, 195 O’Shea M, 153, 166, 248, 256, 292, 299, 313, 317, 322, 324, 326, 329, 341, 349 Osterloh J, 79, 83, 96, 97, 248, 255, 291, 299, 313, 317, 318, 322, 324, 326, 339, 348, 355, 356, 368, 372, 373, 374, 375, 376, 380, 382, 385, 386, 387, 409 Osterloh JF, 291, 293, 295, 298 Oswald-Mammosser M, 74, 76, 87, 88, 90, 95, 97, 324, 348, 371, 383 Ott H, 313, 317, 324, 348 Ott RA, 248, 255, 291, 299 Otten V, 137, 139, 147 Owen JL, 116, 122 Owens GR, 131, 145 Oxman AD, 134, 135, 147

P Pachettino A, 209, 217 Pacht ER, 303, 309 Padilla ML, 397, 410 Pagan V, 306, 309 Paine R, 186, 198, 343, 351 Paine R III, 187, 198, 385, 386, 387, 388, 392, 409 Palecek F, 367, 368, 381 Palevsky H, 315, 318, 319, 320, 322, 346, 347, 354 Palevsky HI, 153, 154, 166, 248, 249, 255, 291, 293, 295, 296, 298, 406, 407, 411 Palizas F, 285, 288

476 Palmer SM, 123, 143 Palmer WH, 46, 64, 67, 93 Panzera J, 248, 254, 290, 291, 298, 313, 317, 319, 325, 340, 343, 347, 352 Paradis I, 207, 216 Pare PD, 74, 95, 177, 182, 195 Parekh J, 314, 318, 322, 324, 349 Parekh JS, 292, 299, 356, 371, 383 Pariente R, 314, 317, 333, 338, 351 Parisi AF, 76, 96 Parker RA, 131, 145 Pasque M, 207, 217 Pasque MK, 83, 97 Pass H, 343, 351 Pastorino U, 162, 168, 292, 300, 315, 318, 329, 351 Pate P, 151, 165 Patel K, 139, 147 Patel MK, 102, 118 Patel R, 228, 241 Patrick D, 214, 218 Patrick DL, 418, 421, 423 Patterson A, 338, 341, 352 Patterson G, 278, 288, 314, 318, 320, 322, 324, 326, 328, 333, 336, 349, 351 Patterson GA, 82, 86, 97, 125, 144, 156, 162, 167, 168, 205, 207, 216, 217, 247, 248, 254, 255, 265, 270, 290, 292, 295, 298, 385, 387, 391, 394, 397, 408, 410, 425, 450 Paul E, 116, 122 Paul EA, 3, 7, 16 Pauwels RA, 99, 100, 102, 110, 117 Pavia D, 131, 145 Pawels R, 106, 119 Pearson JD, 5, 17 Pearson MG, 307, 310 Peavler M, 133, 146 Pechacek TF, 12, 19 Pedreschi M, 2, 15 Pedula KL, 13, 20 Peevy K, 231, 242 Pegelow DF, 44, 63, 64 Pela R, 107, 120 Pellegrio R, 54, 64 Pelletier A, 110, 120

Author Index Pelletier-Fleury N, 416, 422 Pennefather SH, 237, 245 Pepe P, 225, 229, 240 Pepper J, 162, 168, 292, 300, 315, 318, 329, 351 Pepper JR, 188, 199, 401, 411 Peretz DW, 74, 95 Permutt S, 14, 20, 56, 64, 66, 67, 68, 93, 156, 167, 341, 352, 356, 357, 359, 360, 365, 366, 380, 381 Perret C, 233, 234, 242 Perricone A, 385, 405, 409 Perron J, 213, 217, 405, 411 Perruchoud AP, 14, 21 Persson LO, 142, 148 Pesin J, 105, 118 Peters EJ, 151, 165 Peters H, 248, 254, 290, 291, 298, 313, 317, 319, 325, 343, 347 Peters J, 14, 21 Peterson DE, 9, 18 Peto R, 2, 3, 7, 15, 16, 378, 384 Petrou M, 307, 309 Petrun MD, 113, 121, 132, 146 Petty TL, 3, 7, 16, 107, 110, 113, 120, 121, 132, 146, 416, 417, 422 Pﬁster T, 130, 145 Pﬁtzer E, 91, 98 Phanareth K, 2, 15 Piantadosi S, 281, 287 Pierce JA, 14, 21 Pierson D, 231, 233, 242 Pietak S, 222, 239 Pifarre R, 404, 411 Pilgram T, 343, 351 Pilgram TK, 169, 184, 185, 194, 197, 198 Pillet M, 282, 287 Pinsky M, 224, 227, 240 Piquet J, 116, 121 Pirkle JL, 12, 19 Pistelli F, 2, 8, 15, 18 Pitcher WD, 371, 382 Plant PK, 116, 122 Player R, 11, 12, 19 Plaza V, 328, 350

Author Index Pochettino A, 346, 354, 406, 407, 411 Podbielski FJ, 260, 269 Pohl M, 314, 318, 322, 324, 326, 328, 333, 336, 338, 340, 341, 348, 349, 351, 352 Pohl MS, 86, 97, 125, 144, 156, 167, 247, 248, 254, 255, 290, 292, 295, 298, 425, 450 Pokras R, 10, 19 Polaner DM, 237, 244 Polese G, 235, 243 Pollock M, 113, 121 Polu JM, 68, 72, 74, 90, 91, 93 Pomerantz M, 292, 299, 318, 321, 323, 326, 328, 343, 348, 355, 356, 370, 372, 375, 376, 380, 385, 408 Pompeo E, 315, 318, 322, 330, 351 Postma D, 106, 119 Postma DS, 137, 139, 147 Potman H, 277, 286 Powe NR, 14, 21 Powell L, 321, 351 Powell LL, 90, 98 Pratt PC, 170, 182, 195, 196 Prescott E, 10, 19 Prewitt L, 431, 451 Prewitt LM, 133, 137, 138, 140, 141, 146, 416, 423 Price D, 134, 146 Pride N, 106, 119, 356, 357, 359, 380 Pride NB, 371, 372, 382 Prieto L, 328, 350 Prigatano GP, 129, 145 Primeau P, 111, 121 Prochaska JO, 101, 117 Proctor D, 66, 93 Prost JF, 75, 95 Protopapas Z, 187, 198, 385, 386, 387, 388, 409 Province MA, 14, 21 Pugsley JA, 106, 119 Pugsley S, 431, 450 Pugsley SO, 139, 147 Punzal PA, 133, 146 Putman CE, 182, 196

477 Q Qian S, 71, 94 Quick G, 227, 241 Quinlan J, 235, 243 Quint L, 184, 185, 186, 197 Quint LE, 193, 199 Quintana B, 231, 241 Quirk F, 326, 354 Quirk FH, 139, 147

R Rabinowitz M, 68, 69, 73, 74, 77, 94 Rachakonda DP, 291, 299 Ramadan F, 45, 64, 183, 197 Ramanathan S, 237, 244 Ramirez C, 77, 96 Ramos G, 281, 287 Ramos RR, 385, 386, 387, 409 Rampal KG, 5, 17 Rampulla C, 116, 121 Ramsdell J, 421, 423 Ramsey SD, 14, 21, 214, 218, 297, 299, 417, 418, 421, 423, 424, 425, 450 Ranieri M, 234, 243 Rao BS, 75, 95 Rao DC, 14, 21 Rao V, 399, 411 Raper R, 90, 98 Rappaport EB, 14, 21 Rasmussen E, 176, 195 Rassulo J, 134, 146 Rauss A, 116, 121 Ray CS, 182, 196, 233, 242 Reardon J, 139, 147 Rechsteiner R, 237, 244 Reddan WG, 44, 63 Reder I, 76, 96 Reeder J, 292, 299, 314, 318, 322, 324, 349, 356, 371, 383 Reemtsma K, 214, 218 Reeves JT, 73, 77, 94 Reeves ST, 237, 244 Reilly JJ Jr, 151, 157, 162, 165, 167, 168, 248, 254, 314, 318, 328, 332,

478 [Reilly JJ Jr] 342, 345, 348, 350, 354, 356, 357, 358, 359, 364, 365, 381 Reinoso M, 224, 240 Reinsch S, 140, 147 ReMine S, 285, 287 Remy J, 182, 195 Remy-Jardin M, 182, 195 Rendina EA, 213, 217, 385, 405, 409 Rennard SI, 105, 119 Rensing BJ, 85, 97 Renzetti AD Jr, 170, 195 Resnikoff P, 431, 451 Rhoades ER, 11, 12, 19 Ribas J, 151, 165 Ricci C, 385, 405, 409 Rice SJ, 290, 291, 298 Rice T, 277, 286 Richards SM, 2, 15 Richards WG, 248, 254 Richardson E, 431, 451 Richardson G, 76, 96 Richardson V, 333, 351 Richter PA, 12, 19, 431, 451 Rickler R, 307, 310 Ries AL, 123, 128, 129, 130, 132, 133, 134, 135, 137, 138, 140, 141, 143, 144, 145, 146, 416, 423, 431, 451 Rigotti NA, 102, 118 Riley RL, 66, 93, 356, 357, 359, 380 Ritscher D, 193, 199, 370, 382 Robert R, 208, 217 Roberts JR, 249, 255, 278, 284, 287, 295, 296, 299, 406, 407, 411 Robinson DA, 127, 133, 144 Robison LM, 416, 422 Robotham JL, 68, 72, 93 Roca J, 232, 235, 242 Rocca GD, 385, 405, 409 Rochester DF, 131, 145 Rodarte JR, 44, 50, 54, 63, 64, 234, 242 Rodenhouse JD, 54, 57, 64, 314, 318, 332, 342, 348, 356, 357, 358, 359, 365, 381 Rodnick JE, 108, 120 Roeslin N, 302, 308

Author Index Rogers RM, 86, 88, 89, 97, 131, 145, 154, 156, 166, 186, 198, 209, 217, 313, 317, 322, 325, 326, 350, 372, 383 Roggli VL, 182, 196 Rogot E, 5, 17 Rojas KA, 187, 189, 199 Rokkas CK, 248, 256, 292, 299, 313, 317, 322, 324, 326, 349 Roland JA, 75, 95 Rolf N, 237, 245 Romney BM, 50, 64, 185, 187, 198, 385, 386, 387, 388, 409 Rone C, 265, 266, 270 Rooyakkers J, 416, 423 Roper CL, 86, 97, 125, 144, 247, 254, 290, 292, 295, 298 Rose E, 313, 314, 316, 317, 319, 322, 324, 325, 326, 341, 343, 347, 349 Rose EA, 291, 292, 293, 294, 298 Rosenberg HM, 10, 19 Rosengard B, 346, 354 Rosengard BR, 406, 407, 411 Roser H, 151, 165 Rosoff L, 229, 241 Rossi A, 232, 234, 235, 242, 243 Rossm C, 205, 216 Rossoff L, 87, 90, 97, 318, 324, 348, 379, 384 Roue C, 314, 317, 333, 338, 351 Roy B, 355, 356, 366, 367, 376, 380 Rozenstein A, 50, 64, 185, 187, 198, 385, 386, 387, 388, 409 Rubinstein LV, 390, 391, 393, 410 Rumberger JA, 81, 85, 96, 97 Ruppel G, 79, 81, 83, 96, 97, 248, 255, 291, 299, 313, 317, 318, 322, 324, 326, 339, 348, 355, 356, 368, 372, 373, 374, 375, 376, 380, 382 Russi E, 185, 187, 188, 198, 283, 287, 317, 322, 325, 326, 342, 343, 344, 349, 350, 353 Russi EW, 87, 88, 90, 91, 97, 98, 185, 193, 198, 199, 248, 255, 292, 300, 369, 370, 382, 385, 395, 396, 401, 409, 410 Rutten FF, 416, 420, 423

Author Index

479

Rutten-van Molken MP, 11, 19, 420, 423 Ryan MB, 151, 165 Ryder RC, 182, 196 Ryunhei T, 82, 97

S Sachs DP, 101, 102, 118 Saetta MP, 55, 64 Saﬁnski T, 415, 422 Sagawa K, 72, 94 Sagel S, 343, 351 Sagel SS, 169, 184, 185, 194 Sahebjami H, 379, 384 Sakai F, 182, 184, 196, 197 Sakai H, 183, 196 Sakai N, 182, 183, 196 Sakano H, 169, 187, 193, 195 Salejee I, 76, 96 Salorinne Y, 223, 239 Samet JM, 11, 12, 13, 14, 19, 20, 21 Sanchez-Hernandez I, 341, 352 Sanci S, 370, 371, 382 Sanders C, 182, 196 Sandhu HS, 129, 135, 144 Sandler A, 236, 243 Sandler AN, 237, 244 Sanguinetti CM, 107, 120 Santesson J, 221, 239 Santos C, 232, 235, 242 Santos CD, 291, 299 Sari A, 232, 242 Sase S, 170, 195 Sassi-Dambron D, 130, 145 Sato S, 70, 94 Sauer H, 431, 451 Saupe KW, 44, 63 Sautegeau A, 110, 120 Savik K, 207, 217 Sawa T, 183, 196 Sawamura K, 303, 309 Sawchuk CW, 237, 244 Sax M, 421, 423 Scanlon DP, 99, 100, 117

Scanlon PD, 151, 165 Scawn NDA, 237, 245 Schaper J, 71, 94 Scharf S, 318, 324, 348 Scharf SM, 66, 68, 72, 75, 76, 87, 90, 93, 94, 96, 97, 365, 379, 381, 384 Scheidt S, 8, 17 Schein M, 183, 197, 258, 269, 313, 317, 319, 325, 340, 343, 347, 352 Schein MJ, 248, 254, 290, 291, 298, 357, 374, 381 Schenkel F, 207, 217 Schindler C, 14, 21 Schlachter MD, 291, 299 Schlichting R, 232, 242 Schlick W, 108, 120 Schmelzer V, 399, 410 Schmid RA, 292, 300, 385, 401, 409 Schmidt C, 237, 245 Schmidt MA, 188, 199 Schnohr P, 2, 15 Schoni MH, 14, 21 Schork A, 341, 353 Schork M, 186, 198 Schouten J, 106, 119 Schrijen F, 68, 72, 74, 90, 91, 93 Schroeder MA, 69, 94 Schulman LL, 74, 95, 396, 410 Schultz AM, 237, 243 Schulzer M, 74, 95 Schuttenhelm K, 421, 423 Schwartz A, 396, 410 Schwartz J, 14, 20, 21 Schwartz JL, 101, 118 Schwartz M, 326, 354 Schwartzstein R, 372, 383 Scillia P, 182, 183, 196 Sciurba F, 192, 199, 202, 209, 216, 217, 278, 288, 312, 313, 316, 317, 319, 320, 321, 322, 324, 325, 326, 328, 337, 340, 342, 343, 347, 348, 349, 350 Sciurba FC, 86, 88, 89, 97, 113, 121, 125, 144, 154, 156, 157, 166, 186, 198, 248, 255, 264, 266, 270, 291, 299, 372, 383, 385, 406, 407, 409 Sclar DA, 416, 422

480 Scognamiglio A, 8, 18 Seemungal TA, 3, 7, 16 Sekiguchi M, 184, 197 Senbaklavaci O, 158, 167, 185, 197, 248, 255, 265, 266, 270, 292, 300, 315, 318, 319, 323, 325, 326, 332, 344, 345, 347, 351 Seneff MG, 4, 16 Seow KC, 44, 63 Serby C, 105, 119 Serby CW, 105, 119 Serna DL, 90, 98 Sevick MA, 418, 421, 423 Shade D, 356, 371, 376, 382 Shade D Jr, 158, 159, 167 Shaefers H, 207, 217 Shaffer TJ, 14, 21, 415, 422 Shalala D, 312, 347 Shapiro EP, 67, 93 Shapiro GC, 396, 410 Shapiro S, 116, 122 Sharp DJ, 12, 19 Sharp JT, 54, 64, 366, 367, 381 Shaw LJ, 397, 410 Sheldon JB, 130, 145 Shennib H, 237, 244, 282, 287 Shepard J, 292, 299, 342, 344, 351 Sherbourne C, 326, 354, 431, 451 Sherbourne CD, 140, 147 Sherman C, 431, 451 Shernan S, 224, 240 Sherrill DL, 3, 7, 16 Shibel EM, 399, 411 Shiffman S, 102, 118 Shigematsu N, 182, 196 Shimada K, 183, 196 Shimizu K, 170, 187, 195, 199 Shimizu N, 248, 256 Shimura S, 184, 197 Shin JW, 104, 118 Shindo G, 303, 309 Shinonaga M, 307, 309 Shirato K, 184, 197, 313, 317, 342, 351 Shorb PJ, 285, 287 Shoukas A, 72, 94

Author Index Shrager JB, 367, 368, 381 Shumway SJ, 403, 411 Sibbald W, 90, 98 Silverman EK, 14, 20, 21 Silverman M, 314, 354 Silvers GW, 73, 95 Similowski T, 104, 118, 367, 381 Simon G, 170, 195 Simonds AK, 401, 411 Simonian R, 421, 423 Simonsen S, 85, 97 Sin DS, 415, 422 Singh A, 248, 255, 313, 317, 322, 324, 326, 348 Singh H, 237, 245 Singh N, 187, 199, 248, 254, 265, 266, 270, 290, 291, 298, 313, 317, 319, 325, 343, 347, 389, 410 Sisk J, 214, 218 Sitzman J, 129, 145 Skaer TL, 416, 422 Skillrud DM, 386, 409 Skolnick JL, 248, 255 Skuvlund E, 85, 97 Sleiman C, 202, 215, 265, 266, 270, 314, 317, 333, 338, 351 Slinger PD, 224, 225, 231, 235, 237, 240, 243, 244 Slivka WA, 86, 88, 89, 97, 313, 317, 321, 322, 325, 326, 337, 348, 350, 372, 383 Slone RM, 163, 168, 169, 170, 184, 185, 186, 187, 194, 195, 197, 198, 304, 309, 343, 344, 345, 351 Smit HA, 10, 18, 19 Smith AC, 82, 97 Smith CM, 385, 405, 409 Smith CR, 396, 410 Smith DH, 414, 422 Smith K, 134, 135, 147 Smith SS, 101, 118 Smith T, 235, 243 Snell G, 82, 97 Snell GI, 153, 165 Snider GL, 68, 69, 93, 94, 131, 145, 421, 423

Author Index Sobush DC, 248, 256, 292, 299, 313, 317, 322, 324, 326, 349 Sole MJ, 71, 94 Soler M, 151, 165 Solimon I, 228, 241 Solin P, 153, 165 Sonka M, 183, 196 Sonnenberg FA, 421, 423 Soorac A, 237, 245 Sorensen T, 106, 120 Soriano E, 116, 122 Souda R, 248, 256 Speizer F, 13, 20 Speizer FE, 2, 3, 5, 7, 13, 14, 15, 16, 17, 20 Spencer S, 106, 120 Spinale FG, 82, 97 Spofford BT, 112, 113, 121, 132, 146 Spouge D, 182, 195 Staats B, 44, 50, 63 Stamatis G, 314, 318, 322, 325, 326, 333, 334, 337, 338, 339, 340, 343, 349, 366, 375, 378, 381, 384 Stammberger U, 87, 88, 90, 91, 97, 98, 160, 163, 168, 185, 198, 228, 229, 241, 265, 270, 283, 287, 292, 300, 322, 325, 326, 342, 343, 344, 350, 352, 353, 395, 396, 410 Stamos T, 228, 241 Stanford RE, 73, 95, 326, 354 Stannberger U, 185, 187, 188, 198 Staples CA, 177, 182, 183, 190, 195 Starek P, 277, 286 Staton GW Jr, 413, 422 Stedman HH, 367, 368, 381 Steele P, 75, 96 Steinberg HN, 87, 90, 97 Steinglass KM, 291, 292, 293, 294, 298, 313, 314, 316, 317, 319, 322, 324, 325, 326, 341, 343, 347, 349 Stemmer E, 90, 98 Stetz J, 315, 318, 321, 322, 326, 327, 337, 348, 355, 356, 366, 368, 372, 373, 374, 380, 383, 385, 408 Stewart JH, 106, 119 Stewart RI, 78, 96

481 Stocker R, 385, 401, 409 Stone PJ, 69, 94 Stowell DW, 170, 195 Strassels S, 414, 422 Strauss WJ, 12, 19 Strijbos JH, 137, 139, 147 Striksa J, 366, 381 Strom K, 5, 17 Stroup DF, 9, 18 Struehn R, 170, 195 Strumpf D, 116, 122 Stuart R, 206, 216 Stubbing DG, 373, 383 Stubbs SE, 51, 64, 360, 381 Subiaco S, 107, 120 Sudarshan S, 355, 356, 366, 367, 376, 380 Sue DY, 129, 144, 397, 410 Suess C, 170, 195 Suga H, 72, 94 Suga K, 169, 187, 193, 194, 199 Sugarbaker DJ, 151, 162, 165, 248, 254, 314, 318, 332, 342, 348, 356, 357, 358, 359, 365, 381, 390, 410 Sugi K, 169, 187, 193, 194, 195, 199 Sullivan M, 431, 450 Sullivan SD, 14, 21, 414, 421, 422, 424 Sundaresan RS, 86, 97, 125, 144, 162, 168, 247, 248, 254, 255, 265, 270, 290, 292, 295, 298, 314, 318, 320, 322, 324, 326, 328, 336, 349, 385, 387, 391, 394, 408 Sundt III TM, 399, 410 Sunyer J, 5, 8, 14, 17, 18, 20 Suter P, 227, 241 Sutton F, 75, 96 Sutton PP, 131, 145 Svane B, 176, 195 Swain JA, 264, 266, 270, 291, 299 Swan J, 66, 72, 92 Swanson J, 278, 279, 286 Swanson SJ, 248, 254, 262, 269, 345, 354, 359, 364, 365, 381 Swartz M, 385, 400, 409 Swedberg K, 71, 94 Sy M, 182, 183, 196

482

Author Index

Systrom D, 292, 299, 342, 344, 351 Szekely LA, 153, 157, 162, 166, 292, 299, 342, 344, 351

T Tabak C, 9, 10, 18, 19 Tadir Y, 290, 291, 298, 315, 318, 342, 351 Taﬁllou A, 202, 209, 216 Tagliaferro A, 377, 384 Takahashi H, 70, 94 Takahashi S, 87, 88, 90, 91, 98, 324, 348 Takahashi T, 313, 317, 342, 351 Takizawa T, 391, 410 Tanaka R, 82, 97 Tanaka T, 169, 187, 193, 195 Tanouchi J, 75, 96 Tantucci C, 104, 118 Tapson VF, 123, 143 Taraseviciene-Stewart L, 91, 98 Tarasiuk A, 76, 96 Tarpy S, 110, 121 Tashkin DP, 13, 20, 102, 105, 118, 119, 183, 197 Tashkin RA, 99, 100, 117 Tenholder MF, 151, 165 TenVergert EM, 142, 148, 418, 421, 423 Teramoto S, 303, 309 Terashima M, 391, 410 Teschler H, 155, 166, 314, 318, 322, 325, 326, 333, 334, 337, 338, 339, 340, 343, 349, 366, 375, 381 Teshler H, 378, 384 Theegarten D, 314, 318, 322, 325, 326, 333, 334, 337, 338, 339, 340, 343, 349, 378, 384 Thelen M, 184, 197 Thom TJ, 8, 18 Thomas A, 11, 12, 19 Thomas C, 4, 16 Thomas D, 14, 21 Thomas HM, 124, 125, 143

Thomas P, 106, 119 Thomashow B, 154, 158, 166, 185, 198, 248, 255, 265, 270, 291, 292, 293, 294, 298, 313, 314, 316, 317, 319, 322, 324, 325, 326, 341, 343, 347, 349 Thompson P, 431, 450 Thomson AH, 106, 119 Thun MJ, 6, 7, 9, 17 Thurlbeck WMK, 68, 93, 170, 181, 182, 183, 195, 196 Thurnheer R, 87, 88, 90, 91, 97, 98, 160, 163, 168, 185, 187, 188, 198, 228, 229, 241, 265, 270, 292, 300, 322, 325, 326, 342, 343, 344, 350, 352, 353, 395, 396, 410 Tiep BL, 111, 112, 121, 131, 132, 145, 146 Timms RM, 129, 135, 140, 144, 147, 431, 447, 451 Ting EY, 302, 308 Tinker CM, 2, 3, 7, 15, 16 Tino G, 153, 154, 157, 166, 248, 249, 255, 265, 266, 268, 270, 291, 293, 295, 296, 298, 315, 318, 319, 320, 322, 347 Tobias A, 5, 14, 17, 20 Tobiasz M, 5, 17 Tobin MJ, 369, 373, 374, 375, 376, 382 Tockman MS, 5, 14, 17, 20 Todd R, 405, 411 Todd T, 213, 217 Todd TRJ, 399, 411 Togami I, 248, 256 Tokics L, 221, 222, 239 Tolker E, 91, 98 Tomoike H, 70, 94 Tonnesen P, 102, 118 Topeli A, 369, 373, 374, 375, 376, 382 Toriumi T, 232, 242 Torre P, 106, 120 Tos L, 116, 122 Tow DE, 76, 96 Townsend ER, 306, 309 Townsend M, 139, 147, 329, 351 Tranfa C, 307, 310 Trappe F, 170, 195

Author Index Travaline JM, 292, 299, 303, 309, 314, 328, 329, 334, 336, 337, 339, 350, 351, 355, 356, 366, 367, 371, 376, 380, 382, 385, 401, 409 Traver GA, 68, 94, 203, 216, 321, 332, 351 Trello C, 79, 96 Triantaﬁllou AN, 86, 97, 125, 144, 219, 237, 238, 247, 254, 257, 266, 269, 290, 292, 295, 298, 312, 314, 316, 322, 326, 328, 346, 385, 399, 408, 410, 425, 450 Troosters T, 140, 148 Trotman-Dickenson B, 292, 299, 342, 344, 351 Trulock EP, 76, 83, 86, 96, 97, 123, 125, 143, 144, 154, 155, 156, 157, 166, 167, 201, 202, 204, 205, 207, 209, 211, 215, 216, 217, 247, 248, 254, 255, 257, 266, 269, 290, 292, 295, 298, 312, 314, 316, 318, 322, 324, 326, 328, 333, 336, 338, 340, 341, 346, 348, 349, 351, 352, 355, 356, 371, 373, 380, 385, 403, 408, 411, 425, 450 Trulock I, 314, 318, 320, 322, 324, 349 Truwit J, 314, 318, 322, 324, 349 Truwitt JD, 292, 299, 356, 371, 383 Tschernko EM, 185, 197, 265, 266, 270, 292, 300, 314, 315, 317, 318, 319, 321, 323, 325, 326, 332, 344, 345, 347, 348, 351, 371, 382 Tschopp JM, 14, 21 Tseng SM, 71, 94 Tshernko E, 248, 255 Tsingh N, 340, 352 Tsukino M, 182, 196, 327, 328, 350 Tubaldi A, 107, 120 Tuder RM, 91, 98 Tugrul M, 233, 242 Tullis DE, 205, 216 Tummala R, 280, 287 Tunstall-Pedoe H, 9, 18 Turino J, 75, 76, 95 Turndorf H, 235, 243 Turner JM, 357, 380

483 Turrisi A, 343, 351 Turry P, 230, 241 Tuuponen T, 6, 7, 17

U Ueda K, 169, 187, 193, 195 Ulbing S, 237, 243 Ulicny KS Jr, 399, 410 Ulstad D, 232, 242 Unge G, 315, 318, 323, 326, 329, 351 Unruh H, 71, 72, 94 Unruh HW, 237, 244 Uppaluri R, 183, 196 Utz J, 312, 316, 324, 332, 340, 344, 347 Utz JD, 421, 424

V Valta P, 44, 54, 64 Van Aken H, 237, 245 van Altena R, 137, 139, 142, 147, 148 van Bockel JH, 201, 202, 204, 205, 206, 215 Van den Bosch JM, 307, 310 van den Brande F, 401, 411 van der Bij W, 418, 421, 423 Van Doorslaer EK, 416, 420, 423 Van Dyke D, 75, 96 van Enckevort PJ, 418, 421, 423 Van Engelshoven JM, 183, 197 van Es A, 201, 202, 204, 205, 206, 215 Van Evan P, 71, 94 van Genugten ML, 11, 19 Van Grunsven PM, 106, 119 Van Herwaarden CLA, 106, 119 van Kerckhoven W, 401, 411 Van Lith P, 54, 64 Van Noord JA, 105, 119 Van Schayek CP, 106, 119 van Schil P, 401, 411 Van Weel C, 106, 119 Vanderschueren RG, 307, 310 Vassallo CL, 379, 384 Vedal S, 177, 182, 190, 195

484

Author Index

Venuta F, 213, 217, 385, 405, 409 Verbandt Y, 193, 199, 370, 382 Verma RK, 307, 309 Vermeire P, 8, 18 Vestbo J, 8, 10, 18, 19, 106, 120 Viard H, 282, 287 Viegi G, 2, 8, 15, 18 Viggiano R, 44, 50, 63 Vigneswaran WT, 81, 85, 96, 97, 260, 269, 306, 309 Vilkman S, 6, 7, 17 Villanueva IA, 185, 198 Villiger B, 14, 21 Viskum K, 106, 120 Vizza CD, 76, 96 Vladeck B, 426, 427, 440, 450 Voelkel NF, 91, 98 Vogt P, 385, 401, 409 Vollmer WM, 13, 20 Vora H, 14, 21

W Wagner DP, 4, 16 Wagner P, 371, 383 Wagner PD, 371, 383 Wagner RP, 4, 16 WagnerJL, 421, 424 Wahba R, 220, 239 Wahba W, 222, 239 Wahl P, 249, 255, 278, 284, 287, 295, 296, 299, 315, 318, 319, 320, 322, 346, 347, 354, 367, 368, 381 Wahl PM, 248, 249, 255, 291, 293, 295, 296, 298, 406, 407, 411 Wahl R, 187, 188, 199, 345, 351 Wain J, 292, 299, 342, 344, 351 Wakabayashi A, 248, 255, 269, 270, 290, 291, 298, 306, 309 Waldron J, 326, 354 Walker JM, 193, 199 Wallis TW, 68, 72, 93 Walsh JM, 404, 411 Waltenberger J, 91, 98 Walters P, 314, 318, 322, 324, 349

Walters PE, 292, 299, 356, 371, 383 Walters S, 328, 350 Wang S, 345, 351 Wang SC, 163, 168 Wang X, 13, 20 Wanke T, 185, 197, 248, 255, 292, 300, 314, 315, 317, 318, 319, 321, 323, 325, 326, 332, 344, 345, 347, 348, 351 Ward ME, 373, 383 Ware J, 431, 448, 451 Ware J Jr, 326, 354 Ware JE, 140, 147 Ware JH, 13, 20 Warner D, 230, 241 Warner KG, 72, 94 Warren CPW, 107, 120 Wasserman K, 129, 144, 397, 410 Waterhouse J, 328, 350 Waters P, 314, 318, 319, 347 Waters PF, 249, 255, 296, 297, 299 Watters L, 326, 354 Watzinger U, 371, 382 Webb D, 201, 215 Webb K, 372, 383 Webb KA, 303, 309, 373, 383, 384 Webb WR, 169, 170, 177, 194, 195 Webber BA, 131, 145 Weber D, 385, 386, 387, 388, 391, 392, 408 Weber KT, 66, 75, 93 Weder W, 87, 88, 90, 91, 97, 98, 163, 168, 185, 187, 188, 193, 198, 199, 219, 238, 248, 255, 283, 287, 292, 300, 317, 322, 325, 326, 342, 343, 344, 349, 350, 353, 369, 370, 382, 385, 395, 396, 401, 409, 410 Wedzicha J, 5, 17, 116, 122 Wedzicha JA, 3, 7, 16 Weening C, 222, 239 Weg I, 229, 241, 318, 324, 348 Weg IL, 87, 90, 97 Weg JG, 187, 198, 385, 386, 387, 388, 392, 409 Wei S, 224, 240 Weiman DS, 151, 165 Weimer MP, 125, 144

Author Index Weinberg A, 314, 317, 322, 324, 326, 341, 343, 349 Weinberg D, 325, 350, 373, 383 Weinmann CG, 427, 450 Weinmann GC, 125, 144 Weinmann GG, 13, 20 Weisel R, 222, 239 Weisel RD, 399, 411 Weisse AB, 75, 96 Weitzenblum E, 5, 17, 74, 76, 87, 88, 90, 95, 97, 110, 120, 324, 348, 371, 383 Weller WE, 14, 21, 415, 422 Wells AU, 188, 199 Wells C, 325, 350, 373, 383 Werba A, 237, 243 Werner J, 431, 451 Wesmiller SW, 113, 121 West GA, 111, 121 West JB, 371, 379, 383, 384 Westermann CJ, 307, 310 Westley M, 11, 12, 19 Wetter D, 101, 118 Wever AM, 8, 18 Wever-Hess J, 8, 18 Wheeler PS, 182, 195 Whipp BJ, 129, 144, 397, 410 White CS, 187, 198, 385, 386, 387, 388, 409 White FF, 237, 245 White JD, 102, 118 Whitecomb ME, 75, 95 Whitelaw W, 373, 384 Whiting B, 106, 119 Whittall KP, 186, 198 Whittenberger JL, 66, 93 Whyte KF, 73, 76, 95 Whyte R, 184, 185, 186, 197, 314, 315, 317, 318, 321, 322, 326, 327, 337, 340, 344, 345, 348, 351, 352, 353, 385, 386, 387, 388, 392, 409 Whyte RI, 160, 168, 184, 187, 197, 198, 265, 271, 355, 356, 366, 368, 372, 373, 374, 380, 385, 408, 408, 385 Wiggins CL, 13, 20

485 Wihlm J, 324, 348 Wihlm JM, 87, 88, 90, 97, 371, 383 Wijkstra PJ, 137, 139, 142, 147, 148 Wildermuth S, 193, 199, 370, 382 Wilhelmsen L, 71, 94 Williams J, 133, 146 Williams TJ, 205, 207, 216, 217 Wilson A, 307, 309, 315, 318, 321, 333, 334, 337, 339, 340, 342, 351, 352 Wilson AF, 290, 291, 293, 294, 298, 378, 379, 384 Wilson D, 105, 119 Wilson S, 237, 244 Wilson WC, 224, 240 Wimberley N, 283, 287 Winston T, 213, 217 Winston TL, 405, 411 Winters KJ, 228, 241 Winton T, 82, 97, 235, 243 Wise R, 312, 320, 331, 335, 336, 347, 378, 384 Wise RA, 5, 13, 17, 20, 68, 93 Wislocki W, 371, 382 Wisser W, 158, 167, 185, 197, 248, 255, 265, 266, 270, 292, 300, 315, 318, 319, 323, 325, 326, 332, 344, 345, 347, 351, 371, 382 Witek T, 105, 119 Witek TJ, 105, 119 Witek TJ Jr, 105, 119 Wittry MD, 81, 97 Witz JP, 302, 308 Wolfe WG, 302, 308 Wolner E, 185, 197, 248, 255, 292, 300, 315, 318, 319, 323, 325, 326, 332, 344, 345, 347, 351 Wong E, 123, 135, 143 Wong H, 340, 352 Wong K, 228, 241, 280, 287 Wood CH, 373, 383 Wood D, 215, 218, 297, 299, 314, 317, 320, 321, 323, 326, 341, 348, 352, 417, 423 Wood DE, 162, 168, 369, 370, 372, 375, 376, 382, 383, 385, 408, 421, 424 Wood ED, 265, 271

486

Author Index

Wood JA, 74, 95 Worley PD, 112, 121 Wouters EF, 11, 19 Wright C, 292, 299, 342, 344, 351, 435, 451 Wright CD, 153, 157, 162, 166 Wright E, 313, 317, 321, 326, 341, 351, 352 Wright JL, 70, 74, 94, 95 Wu D, 313, 317, 342, 351 Wurster A, 249, 255, 295, 296, 299 Wurtz A, 182, 195 Wusten B, 71, 94 Wuthrich B, 14, 21 Wypij D, 13, 20 Wyser C, 151, 165 Wysocki M, 2, 16, 116, 122

Y Yakota K, 232, 242 Yamagishi M, 182, 196 Yamaguchi A, 307, 309 Yamaguchi K, 183, 196 Yamakage M, 230, 241 Yamanda T, 87, 88, 90, 91, 98, 324, 348 Yamashita M, 248, 256 Yan S, 367, 381 Yasuhara Y, 170, 195 Yasumitsu T, 303, 309 Yasumoto K, 182, 196 Yernault JC, 182, 183, 196 Yip CK, 185, 198 Yokoyama A, 391, 410 Yoon B, 340, 352 Yoong B, 187, 199, 317, 318, 325, 327, 338, 349, 356, 372, 373, 374, 383, 389, 410 Yoshioka S, 307, 309 Yoshiya K, 307, 309 Yusen R, 169, 185, 194, 314, 318, 322, 324, 326, 328, 333, 336, 338, 340, 341, 343, 344, 348, 349, 351, 352

Yusen RD, 154, 155, 156, 157, 166, 167, 169, 170, 184, 185, 186, 194, 195, 197, 198, 248, 255, 292, 295, 298, 304, 309 Yusen RD LS, 153, 166 Yusen RD LSTE, 154, 166 Yuste ML, 281, 287

Z Zakowski M, 237, 244 Zaldivar G, 14, 20 Zalunardo M, 385, 401, 409 Zame N, 183, 197 Zamel N, 57, 64, 333, 334, 336, 337, 339, 341, 351, 352, 355, 356, 357, 358, 359, 360, 364, 365, 372, 374, 378, 380, 381, 384 Zamora M, 318, 321, 323, 326, 328, 343, 348 Zamora MR, 153, 166, 292, 299, 355, 356, 370, 372, 375, 376, 380, 385, 408 Zanen J, 182, 183, 196 Zannini P, 385, 408 Zaugg M, 219, 238 Zebrowski M, 222, 239 Zeger SL, 14, 21 Zeit R, 248, 255, 291, 299, 313, 317, 324, 348 Zellner J, 280, 287 Zellweger JP, 14, 21 Zelter M, 104, 118 Zemp E, 14, 21 Zenati M, 202, 209, 216, 217, 248, 255, 385, 406, 407, 409, 411 Zerhouni EA, 182, 195 Zetterberg G, 315, 318, 323, 326, 329, 351 Zhang J, 369, 370, 382 Zibrak J, 116, 122 Zielinski J, 5, 13, 17, 20 Zile MR, 82, 97 Ziment I, 106, 108, 119 Zimmerman JE, 4, 16

Author Index Zinkgraf S, 133, 146 Zinny M, 105, 118 Zollinger A, 87, 88, 90, 91, 97, 98, 219, 238, 248, 255, 265, 266, 268, 270,

487 [Zollinger A] 292, 300, 317, 322, 325, 326, 349, 395, 396, 410 ZuWallack RL, 139, 147

SUBJECT INDEX

A Aa PO2, 45 AAT, 378 Acute exacerbation management, 109– 110 Adenocarcinoma, 387 African Americans and COPD, 11–12 Age and lung volume reduction surgery (LVRS), 273 Agency for Health Care Policy and Research, 417, 426 AHCPR, 417, 426 Airﬂow limitation, 43–63 air trapping, 53 bronchovascular sheath, 48 chronic bronchitis, 43 connective and frictional pressure losses, 48 elastic recoil pressure, 48 intraparenchymal airways, 48 maximal ﬂow-volume curves mechanisms, 46–49

[Airflow limitation] intraluminal pressure, 46 transmural airway pressure, 46 vital capacities, 59 volume time curves, 62 Airﬂow obstruction, 153 therapy, 102–108 Air leaks, 277–281 Airway inﬂammation, 153–154 Albuterol and postoperative management, 276 Alpha1-antitrypsin deﬁciency, 360 lung volume reduction surgery (LVRS), 155 panacinar emphysema, 155 replacement, 70, 108 Alpha-antitrypsin-deﬁciency emphysema (AAT), 378 Alpha-antitrypsin-related emphysema, 333, 339 Alveolar-arterial O2 pressure (Aa PO2), 45 Alveoli

489

490 [Alveoli] destruction and functional consequences, 38–39 inﬂammation, 23 American Association of Cardiovascular and Pulmonary Rehabilitation, 135 American College of Cardiology/ American Heart Association Task Force, 158 American College of Chest Physicians, 135 Committee on Pulmonary Rehabilitation, 124 American Lung Association Freedom From Smoking clinics, 101 American Thoracic Society, 358 Anesthesia adverse respiratory effects, 220–221 barotrauma, 231–232 emergency strategies, 235–236 emphysema patient management, 228–238 extrinsic positive end-expiratory pressure (PEEP), 234–235 induction, 229–230 agent comparison, 230 intrinsic positive end-expirate pressure (PEEP1), 224–226 lumbar epidural analgesia, 237 lung isolation techniques, 231 maintenance, 230–231 inhalation agents, 230 intravenous agents, 230–231 management goals, 219–220 monitors, 229 one-lung ventilation (OLV), 223–224 patient management, 228–238 permissive hypercapnia controlled hypoventilation, 233 hypercapnic acidosis, 233–234 positive-pressure ventilation (PPV), 219 postoperative extubation, 219 postoperative pain management, 236–238

Subject Index [Anesthesia] postoperative respiratory management, 238 thoracic epidural analgesia (TEA), 236–238 ventilator management strategies, 232–233 pressure-controlled ventilation (PCV), 233 volume-controlled ventilation (VCV), 233 Antibiotics, 107–108 prophylactic, 282–283 Anticholinergics, 105 Anti-inﬂammatory therapy, 106–107 Antitrypsin, 155 Antitrypsin deﬁciency, 51, 360 lung volume reduction surgery (LVRS), 155 panacinar emphysema, 155 replacement, 70, 108 Antitrypsin-related emphysema, 333, 339 Arterial carbon dioxide pressure (PaCO2), 320 Arterial oxygen pressure (PaO2), 320 Asian Americans chronic obstructive pulmonary disease (COPD), 13 Auto-positive end-expiratory pressure (auto-PEEP), 284

B Barotrauma anesthesia, 231–232 Baseline Dyspnea Index (BDI), 373– 374 Baseline maximal exercise capacity (BMEC), 444 B-cell lymphoma, 387 BDI, 373–374 Beck Depression Inventory, 431 Beclomethasone

Subject Index

491

[Beclomethasone] inhaled, 420 Bernoulli equation, 47 Beta-agonists, 104–105 BMEC, 444 Body mass index (BMI), 156 Borg scale, 373–374, 431 Bovine collagen air leaks, 277 buttressing, 262 Bovine pericardium air leaks, 277 buttressing, 262 Bronchoalveolar carcinoma, 387 Bronchogenic carcinoma emphysema, 187 positron emission tomography (PET), 187 Bronchoplethal ﬁstula, 401 Bullous disease, 28 Buttressing and lung volume reduction surgery (LVRS), 262

C CAD [see Coronary artery disease (CAD)] Carbon dioxide pressure (PaCO2), 324, 370, 371 pulmonary function testing, 157 Carbon monoxide diffusing capacity (DCO), 372 Carcinoid, 387 Cardiac output (CO), 82 Cardiac Risk Index, 158 computation, 159 Cardiac tamponade, 401 Cardiopulmonary exercise testing (CPET), 321, 337 Cardiovascular complications, 284 Cardiovascular function animal models, 69–72 emphysema effects, 67–78 human disease, 72–75 hypertension, 68

[Cardiovascular function] left ventricle function, 75–77 lung volume reduction surgery (LVRS) candidates, 85–86 positive end-expiratory pressure (PEEP), 66–68 PVR, 66 theoretical effects, 66–68 theoretical mechanisms, 67 transplant and lung volume reduction surgery (LVRS), 78–92 CEA [see Cost-effectiveness analysis (CEA)] Cefazolin anesthetic management, 274 postoperative pneumonia, 282 Cefuroxime postoperative pneumonia, 282 Center for Health Care Technology (CHCT), 426 Center for Medicare and Medicaid Services (CMS), 425 Central venous pressure (CVP), 82 Centrilobular/centriacinar emphysema, 25–27 CHCT, 426 Chest radiology lung volume reduction surgery (LVRS) patient selection, 184–185 Chest recoil lung recoil, 362–364 Chronic bronchitis deﬁned, 2 Chronic obstructive pulmonary disease (COPD), 425 adverse respiratory effects, 222 African Americans, 11–12 age-adjusted mortality rate, 6 b-agonist therapy, 104–105 airﬂow obstruction therapy, 102–108 alpha1-antitrypsin replacement, 108 anticholinergics, 105 anti-inﬂammatory therapy, 106–107 Asian Americans, 13 cardiac index (CI), 80

492 [Chronic obstructive pulmonary disease (COPD)] cardiovascular effects, 65–92 causes of death, 9 clinical types, 73 CT density histogram, 73 deﬁned, 1–2 dynamic hyperinﬂation, 44 epidemiology, 1–15 ethnic groups, 10–13 exercise response, 74 exercise tolerance, 77–78 functional residual capacity (FRC), 44 future, 15 gender, 10–13 geographical distribution, 8–10 health burden, 4–14 health costs, 14 Hispanics, 12–13 hospitalization and discharge criteria, 113–115 discharge criteria, 115 emergency room evaluation, 114 hospitalization indications, 115 ICU admission indications, 115 left ventricle function, 75–77 long-term oxygen therapy (LTOT), 110–113 mucokinetic agents, 107 Native Americans, 13 natural history, 3–4 noninvasive ventilation (NIV), 116– 117 phosphodiesterase inhibitors, 105– 106 polycythemia, 73 psychoactive drugs, 108 pulmonary function tests, 79 pulmonary rehabilitation clinical tests, 137–139 exercise, 140 rehabilitation guidelines, 136 rehab versus education, 138 residual volume (RV), 44 respiratory failure, 44–45 respiratory stimulants, 108

Subject Index [Chronic obstructive pulmonary disease (COPD)] right ventricular function, 81 risk factors, 13–14 step care, 103 stroke volume indices (SVI), 80 symptomatic stable therapy, 100 therapy, 99–117 total lung capacity (TLC), 44 vaccination, 109 wedge pressure (Pw), 68 Chronic Respiratory Questionnaire (CRQ), 139, 326, 329 Cigarette smoking, 70, 378, 386 animal exposure, 70 cessation, 4, 100–101 bupropion, 102 chronic obstructive pulmonary disease (COPD), 3, 13–14 coronary artery disease (CAD), 159 forced expiratory volume in 1s (FEV1), 153 lung volume reduction surgery (LVRS), 153, 273 nicotine role, 101 pharmacological therapy, 101–102 CMS, 425 CO, 82 Collimation computed tomography (CT), 171 Committee on Pulmonary Rehabilitation American College of Chest Physicians, 124 Computed tomography (CT), 344, 346 accuracy comparison, 176–177 collimation, 171 conventional, 170 diffuse emphysema, 172–177 emphysema, 170–184 helical, 175 high resolution, 175 inspiratory and expiratory comparisons, 183 lung volume reduction surgery (LVRS), 169

Subject Index [Computed tomography (CT)] before and after, 191–193 patient selection, 185–187 patient selection, 185–187 anatomical distribution as predictor, 185 incidental lung cancer identiﬁcation, 187 qualitative assessment, 185 quantitative assessment, 186 versus perfusion scintigraphy, 187– 191 quantitative measurements, 183 correlations, 183 xenon enhanced, 170 Conducting epithelium, 24 COPD [see Chronic obstructive pulmonary disease (COPD)] Coronary artery bypass grafting combined with lung volume reduction surgery (LVRS), 398–399 Coronary artery disease (CAD) alpha1-ADT, 91 cigarette smoking, 159 emphysema, 395 lung volume reduction surgery (LVRS), 159–161, 395–408 preoperative assessment, 396–398 risk assessment, 397–398 dypyridamole-thallium 201 imaging, 397 risk factors, 396 Corticosteroids cost effectiveness, 420–421 inhaled, 421 lung volume reduction surgery (LVRS), 153–154 Cost-beneﬁt analysis, 414, 419 Cost-effectiveness analysis (CEA), 414, 418–420 cost-beneﬁt analysis, 419 cost-minimalization analysis, 419 cost-utility analysis, 420 incremental beneﬁts, 419 incremental costs, 419

493 [Cost-effectiveness analysis (CEA)] natural units beneﬁts, 419–420 quality adjusted life years (QALYs), 420 use in health care industry, 418 Cost-minimalization analysis, 419 Cost of illness studies, 414 Cost-utility analysis, 420 CPET, 321, 337 CRQ, 139, 326, 329 CT [see Computed tomography (CT)] CVP, 82 Cycle ergometry, 375, 431

D Data and Safety Monitoring Board (DSMB), 434 DCO [see Diffusing capacity for carbon monoxide (DCO)] Density masking, 178, 181–182, 184 Diaphragmatic functions, 376 animal studies, 368 improvements, 370 Diffusing capacity, 372 Diffusing capacity for carbon monoxide (DCO), 45, 320, 336, 337, 341, 342, 343, 371 Dipyridamole positron emission tomography, 160 Distal acinar emphysema, 27 DLCO, 155 DLT lung transplantation, 205 Dobutamine stress echocardiography, 160 Double-lung transplantation (DLT) lung transplantation, 205 DSMB, 434 Dutch hypothesis, 13 Dynamic hyperinﬂation, 44 Dypyridamole-thallium 201 imaging, 397 Dyspnea, 372 versus exercise work rate, 374

494

Subject Index

[Dyspnea] lung volume reduction surgery (LVRS), 155, 325–328 long-term improvement, 338–339

E Economic burden, 414–418 deﬁnition, 414 education and pulmonary rehabilitation, 416–417 lung transplantation, 418 lung volume reduction surgery (LVRS), 417–418 medical/pharmaceutical, 416 treatment costs, 415 Electrophrenic stimulation (PDI twitch), 367 Emphysema airﬂow limitation, 43–63 air trapping, 53 alpha-antitrypsin-deﬁciency, 378 alpha1-antitrypsin deﬁciency, 51, 91 alpha-antitrypsin-related, 333, 339 alveolar-arterial O2 pressure (Aa PO2), 45 alveolar destruction, 45–46 anesthesia patient management, 228–238 animal models, 69–72 animal model studies, 366–367 bronchogenic carcinoma, 187 cardiovascular effects, 65–92 cellular hypertrophy, 75 centrilobular, 55 chest radiology, 170 computed tomography (CT), 34–35, 170–184, 258 anatomical distribution as predictor, 185 computed tomography (CT) with quantitative histology, 35–38 coronary artery disease (CAD), 395 cost effectiveness, 420–422 lung transplantation, 421

[Emphysema] lung volume reduction surgery (LVRS), 421 pharmacotherapy, 420 standard therapy versus LVRS, 420 deﬁned, 2 density masking, 178, 181–182, 184 diastolic myocardial stiffness, 72 diffuse, 361 elastic-induced, 368 end-stage, 66 ﬂow to pressure relationships, 54 gas exchange, 80 grading systems, 29–31 heart rate versus O2 consumption, 77 heterogeneous, 155 human autopsy, 367 human disease, 72–75 hypoxia, 71 incidental lung cancer identiﬁcation, 187 left ventricle function, 75–77 lung elastic recoil (PEL), 357 lung reduction effects, 58 lung transplantation, 201–202 mortality, 208 lung volume reduction surgery (LVRS) reversible components, 228–229 lung volume reduction surgery (LVRS) bridge to lung transplantation, 406–407 lung volume reduction surgery (LVRS) pressure effect, 88 maximal expiratory ﬂow effect, 51– 55 measurement, 29 median sternotomy (MS), 247 minimum-intensity projection technique, 182 myocardial ﬁbrosis, 75 oxyhemoglobin dissociation, 46 panacinar, 155 panlobular, 55 parenchymal morphometry, 71

Subject Index [Emphysema] pathology, 23–39 terminology, 24–25 positive end-expiratory pressure (PEEP), 66–68 protease-antiprotease balance theory, 91 pulmonary hemodynamics, 70–71, 74–75 pulmonary vascular disease, 91–91 PVR, 66 Pw measure with lung volume reduction surgery (LVRS), 90–91 quantitative histology, 31–33 RV to LV interdependence, 72 single-lung transplantation, 403–404 surgery cost-effectiveness analyses (CEA), 418–420 economic burden, 414–415 ﬁnancial aspects, 413–422 surgical versus medical deﬁnition, 258 theoretical mechanisms, 67 therapy, 99–117 cost-effectiveness, 420–422 threshold-based techniques, 178 transplant and lung volume reduction surgery (LVRS), 78–92 upper respiratory tract infection (URI), 228 vascular endothelial growth factor (VEGF), 91 VAT, 247 visual scoring system, 178, 181 V/Q, 45 Esophageal pressure (PES), 369 Ethnic groups chronic obstructive pulmonary disease (COPD), 10–13 Ethyl cyanoacrylate adhesive air leaks, 263 Europe chronic obstructive pulmonary

495 [Europe] disease (COPD), 8–9 Exercise, 74, 321, 337 capacity, 375 National Emphysema Treatment Trial (NETT), 429–430 capacity studies, 322–323 chronic obstructive pulmonary disease (COPD) tolerance, 77–78 lung volume reduction surgery (LVRS), 343 long-term results, 337 short-term results, 321–325 performance lung volume reduction surgery (LVRS), 161–162 Exercise testing, 151 Expiratory ﬂow rates, 156 Expulsive-Mueller maneuver (PDI combined), 367 Extrinsic positive end-expiratory pressure (PEEP) anesthesia, 234–235

F FEV [see Forced expiratory volume (FEV)] Fibrin glue air leaks, 279–280 Fibrosis, 387 Forced expiratory volume (FEV), 1, 290, 293, 294, 316, 319–320, 324, 326, 327, 328, 334–335, 341, 343, 344, 345, 346, 358, 365, 371, 374, 416, 421 correlation with residual volume (RV)/total lung capacity (TLC), 360 emphysema decrease mechanisms, 365 improvement, 364–365 lung resistance correlation, 342 serial change, 334

496

Subject Index

[Forced expiratory volume (FEV)] serial measurements, 335 slope, 336 Forced expiratory volume in 1 (FEV1), 51 BLT, SLT LVRS comparison, 211 cigarette smoking, 153 lung volume reduction surgery (LVRS), 155 patient data, 30 pulmonary function testing, 155–156 smoking cessation, 4 Forced vital capacity (FVC), 293, 329, 365, 374 FRC, 44 Freedom From Smoking clinics American Lung Association, 101 Functional residual capacity (FRC), 44 FVC [see Forced vital capacity (FVC)]

G Gastric pressure, 369 Gastrointestinal-protecting agents prophylactic, 285 Gender chronic obstructive pulmonary disease (COPD), 10–13 Gortex air leaks, 279 buttressing, 262 Gram-negative aerobes postoperative pneumonia, 282 Gram-negative anaerobes postoperative pneumonia, 282 Granuloma, 387 Gs, 359

H Haemophilus inﬂuenzae, 107 postoperative pneumonia, 282 Hamartoma, 387 Health Care Finance Administration (HCFA), 111, 312, 331, 417, 426

[Health Care Finance Administration] [see also Center for Medicare and Medicaid Services (CMS)] Health costs of COPD, 14 Health insurers, 427 Health-related quality of life (HRQL), 158 Chronic Respiratory Questionnaire (CRQ), 329 lung volume reduction surgery (LVRS), 325–329 long-term results, 338–339 Heimlich valve air leaks, 281 Heparin preoperative management, 274 Heterogeneous emphysema, 155 Hispanics chronic obstructive pulmonary disease (COPD), 12–13 Horse-race effect, 3 Hospitalization-related costs, 415 Hounsﬁeld Units (HU) computed tomography (CT), 173 level, 174 window, 174 HPV [see Hypoxic pulmonary vasoconstriction (HPV)] HRQL [see Health-related quality of life (HRQL)] HU [see Hounsﬁeld Units (HU)] Hydrocortisone postoperative management, 276 Hypercabia, 157 Hypercapnia, 373 Hypercapnic acidosis anesthesia, 233–234 Hyperinﬂation, 66–68, 366 Hypoxemia, 373 one-lung ventilation (OLV), 223– 224 Hypoxemic chronic obstructive pulmonary disease (COPD) causes of death, 9 Hypoxia lung volume reduction surgery

Subject Index

497

[Hypoxia] (LVRS) outcome predictor, 343 Hypoxic pulmonary vasoconstriction (HPV) one-lung ventilation (OLV), 223

[Japan] chronic obstructive pulmonary disease (COPD), 8

K I Ice chips postoperative management, 276 IMA ligation, 377–378 Immunosuppression lung transplantation, 205 Indomethacin suppositories postoperative management, 264 Inferior vena cava (IVC), 67 Inspiratory resistance, 156–157 Intermittent Positive Pressure Breathing (IPPB) Trial, 331 Internal mammary artery (IMA) ligation, 377–378 Intrathoracic bleeding postoperative, 283 Intrinsic positive end-expirate pressure (PEEP1) anesthesia, 224–226 cardiovascular effects, 226–227 gas exchange effects, 227 occult, 225 IPPB Trial, 331 Ipratropium cost-effectiveness, 421 inhaled, 420 postoperative management, 276 versus theophylline, 421 Isotope studies lung volume reduction surgery (LVRS), 345–346 Isowatt exercise, 369, 376 IVC, 67

J Japan

Klebsiella pneumoniae postoperative, 282

L Lactulose postoperative management, 276 LaPlace’s law, 366 Laser procedures, 319 versus resection, 290 Lobectomy, 390, 393 and lymphadenectomy, 391 Long-term oxygen therapy (LTOT), 110–113 LTOT, 110–113 Lumbar epidural analgesia anesthesia, 237 Lung carbon monoxide diffusion, 155 Lung elastic recoil, 357–359 emphysema, 357 lung volume reduction surgery (LVRS), 357–359 Lung isolation techniques anesthesia, 231 Lung nodule resection lymphadenectomy, 391 lymph nodes assessment, 391 nodule location, 390 preoperative evaluation, 388–391 criteria, 390 Lung parenchyma resection, 151 Lung recoil chest recoil, 362–364 interaction with inspiratory muscle capacity, 361–362 Lung reduction, 55–61 effect predictions, 56–57 preoperative and postoperative

498 [Lung reduction] volumes, 53 theoretical aspects, 55–56 Lung resistance pulmonary function testing, 156 Lung transplantation, 201–218, 418 bilateral lung transplant (BLT), 211 central venous pressure (CVP), 82 CO, 82 course predictions, 203 double-lung transplantation (DLT), 205 emphysema, 201–202 mortality, 208 forced expiratory volume in 1s (FEV1) BLT, SLT, LVRS comparison, 211 functional outcomes, 206–207 hyperinﬂation, 403–405 immunosuppression, 205 inclusion criteria, 212 life quality, 207–208 Medical Outcome Health Survey (MOS)-20 health proﬁle, 207 lung volume reduction surgery (LVRS) bridge candidates lung function, 406 candidates timing and selection, 407 lung function improvement, 407 lung volume reduction surgery (LVRS) interface, 208–210 cost comparisons, 214–215 median sternotomy versus videoassisted thoracoscopy (VATS), 213 prior to transplantation, 210–212 SLT combination, 213–214 transplantation bridge, 208 unilateral versus bilateral, 213 mortality factors, 206 patient selection, 202–203 contraindications, 203, 204

Subject Index [Lung transplantation] disease-speciﬁc criteria, 203 pulmonary function testing (PFT), 205 pulmonary function tests, 79 right ventricular function, 81 RV ejection fraction (RVEF), 82 selection guidelines, 202 single lung transplantation (SLT), 81, 205 standard evaluation protocol, 212 stroke volume (SV), 82 survival, 206 SLT versus DLT, 206 timing, 203–205 unilateral lung volume reduction surgery (LVRS), 405 Lung volume reduction surgery (LVRS), 55–63 after single-lung transplantation, 403–406 age, 273 anecdotal experience, 163 anesthetic management, 274–275 beneﬁts, 151, 355–356 bilateral and unilateral results comparison, 293 bilateral or unilateral, 290–295 bilateral results, 290, 292 buttressing, 262 candidates, 91 cardiac evaluation, 398 decision algorithm, 446 evaluation, 152, 163 cardiac issues, 158–161 cardiovascular function, 78–81, 85– 86 chest radiology bullae identiﬁcation, 170 emphysema, 170 patient selection, 184–185 cigarette smoking, 273 combined with coronary artery bypass grafting, 398–399 combined with pulmonary nodule resection

Subject Index [Lung volume reduction surgery (LVRS)] inappropriate candidates, 393 lobectomy versus segmentectomy, 393–394 morbidity and mortality, 392 outcome, 391–395 computed tomography (CT), 191– 193 patient selection, 185–187 controversies, 289–298 coronary artery disease (CAD), 159– 161, 395–408 corticosteroid usage, 153–154 demand for, 427 diastolic and Pw pressure effects, 89 diffuse emphysema, 361 emphysema, 58 reversible components, 228–229 wedge pressure (Pw) measure, 90– 91 estimated costs, 417–418 exercise performance, 161–162 forced expiratory volume (FEV) change, 345 lung resistance correlation, 342 serial change, 334 serial measurements, 335 slope, 336 gastrointestinal (GI) complications, 284–285 hemodynamics and gas exchange, 83–85 history and physical examination, 153–155 improvement mechanisms, 355–380 inclusion and exclusion criteria, 164 indications and contraindications, 332 isotope studies, 345–346 laser or resection, 290 limitations, 56 long-term results, 331–339 dyspnea, 338–339 exercise capacity, 337 HRQL, 338–339

499 [Lung volume reduction surgery (LVRS)] medication and oxygen, 337–338 mortality, 331–333 pulmonary function, 333–337 lung elastic recoil (PEL), 357–359 lung nodule resection, 388–391 lung transplantation, 269 bridge, 406–407 cost comparisons, 214–215 interface, 208–210 median sternotomy versus videoassisted thoracoscopy (VATS), 213 prior to transplantation, 210–212 single lung transplantation (SLT) combination, 213–214 unilateral versus bilateral, 213 maximal ﬂow/static recoil relation (MFSR), 358 maximum ﬂow static recoil curve, 56 median sternotomy (MS), 247–254, 295–297 studies, 296 morbidity and mortality rates, 278 outcomes, 311–346, 356 patient preparation, 272 patient selection, 57–63, 258, 339– 346 clinical features, 340–341 imaging, 344–346 physiological factors, 341–344 patients’ evaluation, 149–168 perioperative complications, 149– 150, 273–285 perioperative management, 274–275 postoperative complications, 276– 285 postoperative management, 275–276 preoperative risks, 151–155 pressure volume curve, 56 pulmonary function testing, 155–158 pulmonary hemodynamics effects, 86–90 pulmonary rehabilitation, 123–143 blood gas changes, 134

500 [Lung volume reduction surgery (LVRS)] breathing retraining techniques, 131 bronchial hygiene, 131 contraindications, 126 deﬁned, 124 diagnostic testing, 128–129 education, 130, 141 exercise, 132–133 exercise intensity target, 133 exercise prescription, 133–134 forced expiratory volume in 1 (FEV1), 128 function and symptoms, 141 goals, 129–130 long-term effects, 141–142 medical evaluation, 128 oxygen, 131–132 patient evaluation, 127–130 patient selection, 126–127 physiotherapy techniques, 131– 132 psychosocial assessment, 129 psychosocial support, 135 quality of life, 139–140 resources, 139 results, 135–142 role, 125–126 screening, 127 survival, 141 upper extremity training, 134 ventilatory muscle training, 134– 135 walking programs, 132 versus pulmonary rehabilitation, 330 radiographic studies, 161–162 radiological evaluation, 169–200 right heart catheterization, 86 scintigraphy patient selection, 187–188 short-term results, 312–331 dyspnea, 325–328 exercise capacity, 321–325 health-related quality of life (HRQL), 325–329

Subject Index [Lung volume reduction surgery (LVRS)] medication and oxygen, 324–325 mortality, 312–316 pulmonary function, 316–321 randomized studies, 329–331 versus SLT, 83–85 solitary pulmonary nodules, 386–388 spirometry, 356–372 steroid, 324–325 study descriptions, 313–315 systolic and mean pressure effects, 88 thorascopic approach, 257–269 unilateral laser results, 264 unilateral results, 290–291 unilateral staple results, 265 unilateral thorascopic, 83–85 unique patient populations, 385–408 ventilator-dependent patients, 399– 403 video-assisted thoracoscopy surgery (VATS), 247–250, 295–297 versus median sternotomy (MS), 257–269 xenon-enhanced computed tomography (CT), 170 LVRS [see Lung volume reduction surgery (LVRS)]

M Magnetic resonance imaging (MRI) lung volume reduction surgery (LVRS), 169 Maintenance therapy emphysema, 432–433 Mantle emphysema, 27 Maximal airﬂow during forced expiration (VMAX), 357 Maximal expiratory ﬂow, 49–55 computed tomography (CT), 51 emphysema’s effect, 51–55 forced expiratory volume in 1s (FEV1), 51

Subject Index [Maximal expiratory flow] maximal ﬂow/static recoil relation (MFSR), 51 pressure volume relationship idealized, 52 pressure volume relationship normal, 51, 52 upstream and downstream, 49 wave speed equation, 49–50 Maximal expiratory pressure (MEP), 368 Maximal ﬂow/static recoil relation (MFSR), 51, 357 Maximal sniff (PDI sniff), 367 Maximum ﬂow/static recoil (MFSR), 51 Maximum workload, 375–376 McLeod’s syndrome, 28 Median sternotomy (MS), 257–269, 290, 439–440 bilateral staple results, 265 emphysema, 247 forced expiratory volume (FEV) predicted versus VATS, 267 individual series versus VATS, 267 lung volume reduction surgery (LVRS), 247–254, 250–254 nonrandomized comparison, 268 mortality rates, 268 versus thoracoscopy, 295–297 versus VATS, 247–250, 257–269, 295–297 age difference, 254 clinical impressions, 250 literature review, 249 lung volume reduction surgery (LVRS) published results, 248 patient review, 249 retrospective comparison, 249 Medical emphysema versus surgical emphysema, 258 Medical Outcomes Survey-Short Form 36, 140, 326, 328, 329, 392, 431 Medical Research Council (MRC), 325, 326

501 [Medical Research Council (MRC)] dyspnea scale, 325, 373–374 Medicare expenditures, 415 Medication lung volume reduction surgery (LVRS), 337–338 MEP, 368 Mesothelioma, 387 Methyl prednisolone postoperative management, 276 MFSR, 51, 357 6-Min walk distance (6MWD), 290, 294, 295, 321–323, 329–330, 337, 338, 343, 375, 431 lung volume reduction surgery (LVRS), 155 Minimum-intensity projection technique emphysema, 182 Minute ventilation, 321–323 Moraxella catarrhalis, 107 Morbidity, 294 Mortality, 5, 290, 293, 294, 297 change in, 6 lung volume reduction surgery (LVRS), 312–316, 331–333 National Emphysema Treatment Trial (NETT), 429 MRC, 325, 326 dyspnea scale, 325, 373–374 MRI lung volume reduction surgery (LVRS), 169 MS [see Median sternotomy (MS)] Mucokinetic agents, 107 MUGA, 81 Multigated acquisition scan (MUGA), 81 Muscle recruitment changes, 369

N National Emphysema Treatment Trial (NETT), 85, 125, 156, 208, 312, 330, 343, 421, 425–450

502 [National Emphysema Treatment Trial (NETT)] cost-effectiveness analysis, 447–448 high-risk subgroup, 436–438 impact, 448–449 inclusion and exclusion criteria, 451 ineligibility, 433–434 mortality, 440 origins, 425–426 outcome variables, 440–443 planning, 428–429 protocol modiﬁcations, 436–438 pulmonary rehabilitation, 439 rationale and design, 429–434 recruitment, 433, 435–436 results, 438–446 types, 433–434 National Heart, Lung and Blood Institute (NHLBI), 427 National Institute of Health Workshop on Pulmonary Rehabilitation, 124 National Medical Expenditures Survey (NMES), 414, 424 Native Americans chronic obstructive pulmonary disease (COPD), 13 Nd:YAG, 319 Neoplastic lesions, 387 NETT [see National Emphysema Treatment Trial (NETT)] NHLBI, 427 NHP, 326, 328 NIV, 116–117 NMES, 414, 424 Nocturnal Oxygen Therapy Trial (NOTT), 110, 203, 331 Noncoverage policy decision, 427 Noninvasive Ventilation (NIV), 116– 117 Nonventilating lung, 361 NOTT, 110, 203, 331 Nottingham Health Proﬁle (NHP), 326, 328

Subject Index Nutritional status lung volume reduction surgery (LVRS), 154

O One-lung ventilation (OLV) anesthesia, 223–224 hypoxemia, 223–224 continuous positive airway pressure (CPAP), 224 hypoxic pulmonary vasoconstriction (HPV), 223 pulmonary vascular resistance (PVR), 223 shunt, 223 Oxygen lung volume reduction surgery (LVRS), 324 long-term results, 337–338 requirements, 339 postoperative management, 275–276 Oxygen pressure, 294, 320, 321, 343, 370, 371, 372 pulmonary function testing, 157 Oxygen production, 321–323, 337, 343, 375–376 Oxygen therapy, 149

P PaCO2, 320 [see also Carbon dioxide pressure (PaCO2)] Panacinar emphysema, 153 Panacinar/panlobular emphysema, 27 PaO2 (see Oxygen pressure) Paraseptal emphysema, 27 PCV, 233 PDI, 366, 367 PEEP [see Positive end-expiratory pressure (PEEP)] PEL, 357–359 Percutaneous transluminal coronary angioplasty (PTCA), 160

Subject Index Perfusion scanning, 346 Permissive hypercapnia controlled hypoventilation, 233 PES, 369 PET, 160, 187 bronchogenic carcinoma, 187 PFT [see Pulmonary function testing (PFT)] PGA, 369 Pharmacological therapy acute exacerbation management, 109–110 alpha1-antitrypsin replacement, 108 antibiotics, 107–108 anticholinergics, 105 anti-inﬂammatory therapy, 106–107 chronic oral steroid therapy, 106– 107 chronic obstructive pulmonary disease (COPD) step care, 103 long-term oxygen therapy (LTOT), 110–113 mucokinetic agents, 107 noninvasive ventilation (NIV), 116– 117 oxygen delivery systems, 111–112 devices, 112–113 phosphodiesterase inhibitors, 105– 106 psychoactive drugs, 108 respiratory stimulants, 108 vaccination, 109 Phosphodiesterase inhibitors, 105– 106 Physiological sequelae, 319 Pink puffer patient, 154 Pixel, 172 Placebo effect spirometry, 377–378 Plethysmography, 369 Pneumonia postoperative, 281–283 Pneumoperitoneum air leaks, 280 Pneumothorax, 290, 389, 401

503 Positive end-expirate pressure (PEEP1) intrinsic anesthesia, 224–226 cardiovascular effects, 226–227 gas exchange effects, 227 occult, 225 Positive end-expiratory pressure (PEEP), 66–68 automatic, 284 cardiovascular function, 66–68 emphysema, 66–68 induced hyperinﬂation, 67 IVC, 67–68 Positive-pressure ventilation (PPV), 219 adverse effects, 224 Positron emission tomography (PET), 187 bronchogenic carcinoma, 187 PPV, 219 adverse effects, 224 Prednisone, 154 lung volume reduction surgery (LVRS), 324 postoperative management, 276 Pressure-controlled ventilation (PCV), 233 Pressure time product (PTP), 369 Productivity, 415 Pseudomonas aeruginosa postoperative pneumonia, 282 Psychoactive drugs, 108 PTCA, 160 PTP, 369 Pulmonary function, 297 lung volume reduction surgery (LVRS), 316–321, 333–337 median sternotomy (MS) or videoassisted thoracic surgery (VATS), 295–297 Pulmonary function testing (PFT), 155–158 carbon dioxide pressure (PaCO2) prognostic value, 157 diffusing capacity, 156 emphysema, 432

504 [Pulmonary function testing (PFT)] forced expiratory volume in 1 (FEV1), 155–156 lung resistance, 156 lung transplantation, 205 lung volume reduction surgery (LVRS), 155–158 oxygen pressure ( PaO2), 157 total lung capacity (TLC), 156 Pulmonary hemodynamics lung volume reduction surgery (LVRS) effects, 86–90 Pulmonary hypertension lung volume reduction surgery (LVRS) cardiac issues, 161 Pulmonary nodules computed tomography (CT), 386– 387 lung volume reduction surgery (LVRS), 386–391 studies, 386–388 Pulmonary rehabilitation blood gas changes, 134 breathing retraining techniques, 131 bronchial hygiene, 131 clinical tests, 137–139 contraindications, 126 diagnostic testing, 128–129 education, 130, 141 emphysema, 432 exercise, 132–133, 140 exercise intensity target, 133 exercise prescription, 133–134 forced expiratory volume in 1 (FEV1), 128 function and symptoms, 141 goals, 129–130 long-term effects, 141–142 lung volume reduction surgery (LVRS), 123–143 versus lung volume reduction surgery (LVRS), 330 medical evaluation, 128 oxygen, 131–132 patient evaluation, 127–130 patient selection, 126–127

Subject Index [Pulmonary rehabilitation] physiotherapy techniques, 131–132 psychosocial assessment, 129 psychosocial support, 135 quality of life, 139–140 rehabilitation guidelines, 136 rehab versus education, 138 resources, 139 results, 135–142 role, 125–126 screening, 127 survival, 141 upper extremity training, 134 ventilatory muscle training, 134–135 walking programs, 132 Pulmonary vascular resistance (PVR), 66 survival rates, 69 PVR, 66 survival rates, 69 Pw [see Wedge pressure (Pw)]

Q Quality-Adjusted Life Year (QALY), 420, 447 cost-effectiveness analysis (CEA), 420 Quality of Well-Being Scale (QWB), 139, 431

R Radiological evaluation, 169–200 emphysema, 432 minimum-intensity projection technique, 182 Rand Health Survey, 140 Ranitidine postoperative management, 276 Renal cell metastasis, 387 Resection versus laser, 290 Residual volume (RV), 156, 320, 329, 336, 337, 341

Subject Index

505

[Residual volume (RV)] lung volume reduction surgery (LVRS), 293 Residual volume ejection fraction (RVEF), 82 Residual volume (RV)/total lung capacity (TLC), 327, 341, 360 FVC improvement predictor, 365 Respiratory failure, 283–284 Respiratory muscle dysfunction, 366 Respiratory muscles decreased pressure output, 369 Respiratory stimulants, 108 Reynolds number (RE), 47 RV [see Residual volume (RV)] RVEF, 82

S Scintigraphy, 187–188, 346 lung volume reduction surgery (LVRS) before and after, 193 patient selection, 187–188 patient selection, 187–188 perfusion, 187 versus computed tomography (CT), 187–191 radiological evaluation, 187–188 ventilation, 188 Segmentectomy, 394 Self-Evaluation Questionnaire, 431 SF-36, 326, 328, 329, 392, 431 (see also Medical Outcomes SurveyShort Form 36) SGRQ [see St. George’s Respiratory Questionnaire (SGRQ)] Shortness of Breath Questionnaire, 431 Shuttle-walking distance, 329 Sickness Impact Proﬁle (SIP), 139, 326, 328, 339 Single lung transplantation (SLT), 81, 205

[Single lung transplantation (SLT)] after lung volume reduction surgery (LVRS), 403–406 improvements, 405 unilateral, 405 hyperinﬂation, 404–405 lung volume reduction surgery (LVRS), 83–85 retransplantation, 405 SIP [see Sickness Impact Proﬁle (SIP)] SLT [see Single lung transplantation (SLT)] Smoking (see Cigarette smoking) Smoking cessation, 100–101 forced expiratory volume in 1s (FEV1), 4 Spirometry alternative paradigm, 360–365 exercise capacity, 375–377 gas exchange effects, 370–372 placebo effect, 377–378 pulmonary function accelerated deterioration, 378–379 respiratory muscle function improvement, 366–370 symptoms, 372–375 traditional paradigm, 356–360 Squamous cell carcinoma, 387 S segment (Gs), 359 St. George’s Respiratory Questionnaire (SGRQ), 139, 326, 329, 431 Staphylococcus aureus postoperative pneumonia, 282 Stapling techniques, 319 Steroids chronic use, 324–325 inhaled, 325 liberation lung volume reduction surgery (LVRS), 324–325 Streptococcus pneumoniae, 107–108 postoperative pneumonia, 282 Stroke volume (SV), 82 Surgical emphysema versus medical emphysema, 258 SV, 82

506

Subject Index

Symptomatic stable chronic obstructive pulmonary disease (COPD), 100

T Talc pleurodesis air leaks, 280 Target zones, 345–346 TDI, 325, 326, 373–374 TEA, 236–238 Terbutaline cost-effectiveness, 421 inhaled, 420 Terminal bronchiole, 24, 25 Theophylline cost-effectiveness, 421 versus ipratropium bromide, 421 Thoracic epidural analgesia (TEA), 236–238 Thoracic gas volume, 156 Thoracic surgery adverse respiratory effects, 222 lung volume reduction surgery (LVRS), 154 Thoracoscopic surgery, 257–269 Thoracoscopy versus median sternotomy, 295–297 Tidal volume (VT), 321–323 Total lung capacity (TLC), 44, 320, 327, 329, 336, 337, 341, 360 FVC improvement predictor, 365 lung volume reduction surgery (LVRS), 155, 156 Trail Making Test, 431 Transdiaphragmatic pressure (PDI), 366, 367 Transitional Dyspnea Index (TDI), 325, 326, 373–374 Transthoracic echocardiography, 159– 160 Trapped gas volume, 156

U ULPE, 444 Unilateral emphysema, 28 United Kingdom chronic obstructive pulmonary disease (COPD), 8 Upper lobe-predominant emphysema (ULPE), 444 Upper respiratory tract infection (URI) emphysema, 228

V Vaccination, 109 VAS, 326, 373–374 Vascular endothelial growth factor (VEGF), 91 VATS [see Video-assisted thoracic surgery (VATS)] VC, 360–365 VCV anesthesia, 233 Vd/Vt, 370 VEGF, 91 Ventilation/perfusion (V/Q), 45, 371, 372 Ventilator-dependent patients lung volume reduction surgery (LVRS), 399–403 improvements, 402 lung function, 400 mitral valve replacement, 402 Video-assisted thoracic surgery (VATS), 1, 213, 247–250, 257– 269, 290, 429, 439–440 advantages and disadvantages, 259 air leaks, 262–263 anesthesia, 260 bilateral staple results, 265 buttressing, 262 chest drainage system, 264

Subject Index [Video-assisted thoracic surgery (VATS)] clinical settings, 259 forced expiratory volume (FEV) predicted versus MS, 267 incisions, 261 individual series versus MS, 267 lung resection, 261–262 lower lobe disease, 261–262 upper lobe disease, 261 versus median sternotomy (MS), 247–250, 257–269 mortality rates, 268 open procedure conversion, 263 or median sternotomy (MS), 295– 297 comparison studies, 296 patient position, 260–261 patient selection, 259 postoperative management, 263– 264 resection versus plication, 262 results, 264–266 comparison, 266–268 technique, 260 unilateral and bilateral roles, 266 Visual analog scale (VAS), 326, 373– 374

507 Vital capacity (VC), 360–365 Vladek, Bruce, 426 VMAX, 357 VO2 (see Oxygen production) Volume-controlled ventilation (VCV) anesthesia, 233 Voxel, 173 V/Q, 45, 371, 372 VT, 321–323

W Wave speed equation, 49–50 Wedge pressure (Pw), 68 bronchopulmonary shunts, 90 fossa pressures, 68 lung volume reduction surgery (LVRS), 89, 90–91 Wedge resection, 390 Wilcoxon rank sum testing, 444

X Xenon-enhanced computed tomography lung volume reduction surgery (LVRS), 170

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