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, 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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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

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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

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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

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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

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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

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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

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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

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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,

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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).

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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.)

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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

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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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84. Samet JM, Dominici F, Curriero FC, Coursac I, Zeger SL. Fine particulate air pollution and mortality in 20 U.S. cities, 1987–1994. N Engl J Med 2000; 343(24):1742–1749. 85. Gauderman WJ, McConnell R, Gilliland F, London S, Thomas D, Avol E, Vora H, Berhane K, Rappaport EB, Lurmann F, Margolis HG, Peters J. Association between air pollution and lung function growth in southern California children. Am J Respir Crit Care Med 2000; 162(4):1383–1390. 86. Ackermann-Liebrich U, Leuenberger P, Schwartz J, Schindler C, Monn C, Bolognini G, Bongard JP, Brandli O, Domenighetti G, Elsasser S, Grize L, Karrer W, Keller R, Keller-Wossidlo H, Kunzli N, Martin BW, Medici TC, Perruchoud AP, Schoni MH, Tschopp JM, Villiger B, Wuthrich B, Zellweger JP, Zemp E. Lung function and long term exposure to air pollutants in Switzerland. Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) Team. Am J Respir Crit Care Med 1997; 155(1):122–129. 87. Hutchison DC. The epidemiology of alpha 1-antitrypsin deficiency. Lung 1990; 168 (suppl):535–42. 88. Silverman EK, Pierce JA, Province MA, Rao DC, Campbell EJ. Variability of pulmonary function in alpha-1-antitrypsin deficiency: clinical correlates. Ann Intern Med 1989; 111:982–991. 89. Sullivan SD, Ramsey SD, Lee TA. The economic burden of COPD. Chest 2000; 117:5S–9S. 90. Gross CP, Anderson GF, Powe NR. The relation between funding by the National Institutes of Health and the burden of disease. N Engl J Med 1999; 340:1881–1887. 91. Grasso ME, Weller WE, Shaffer TJ, Diette GB, Anderson GF. Capitation, managed care, and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 19981; 158:133–138. 92. Mackay J. The global tobacco epidemic. The next 25 years. Publ Health Rep 1998; 113:14–21. 93. Mackay JJ. US tobacco export to Third World: Third World War. Natl Cancer Inst Monogr 1992; (12):25–28.

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

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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

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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

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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)

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

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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

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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

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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.

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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

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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 e6:48
0:326mL gas=g Þ that allowed the surface area of each voxel of

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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.

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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 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

Evaluation of Patients Considering LVRS Table 2

159

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 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 5 days)

13 + 9.4

17 + 11.1

67 VATS 10.4%

(36)

278 Shen and Swanson

Perioperative Complications and Their Management

279

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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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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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.

294

Roberts

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

295

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

298

Roberts

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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Zellos

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); severe intercurrent diseases Right heart failure and cor pulmonale >10% Slowly progressive ‘‘Blue bloater’’ (sputum production, chronic bronchitis)

Markedly decreased 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

318

Martinez

*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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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

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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)

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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

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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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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

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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).

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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 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 200–250% Increased RV/TLC DLCO 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 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