Dyspnea: Mechanisms, Measurement and Management, 2nd Edition (Lung Biology in Health and Disease Vol 208) [2 ed.] 0824725778, 9780824725778

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DYSPNEA

LUNG BIOLOGY IN HEALTH AND DISEASE Executive Editor Claude Lenfant Former Director, National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland

1. Immunologic and Infectious Reactions in the Lung, edited by C. H. Kirkpatrick and H. Y. Reynolds 2. The Biochemical Basis of Pulmonary Function, edited by R. G. Crystal 3. Bioengineering Aspects of the Lung, edited by J. B. West 4. Metabolic Functions of the Lung, edited by Y. S. Bakhle and J. R. Vane 5. Respiratory Defense Mechanisms (in two parts), edited by J. D. Brain, D. F. Proctor, and L. M. Reid 6. Development of the Lung, edited by W. A. Hodson 7. Lung Water and Solute Exchange, edited by N. C. Staub 8. Extrapulmonary Manifestations of Respiratory Disease, edited by E. D. Robin 9. Chronic Obstructive Pulmonary Disease, edited by T. L. Petty 10. Pathogenesis and Therapy of Lung Cancer, edited by C. C. Harris 11. Genetic Determinants of Pulmonary Disease, edited by S. D. Litwin 12. The Lung in the Transition Between Health and Disease, edited by P. T. Macklem and S. Permutt 13. Evolution of Respiratory Processes: A Comparative Approach, edited by S. C. Wood and C. Lenfant 14. Pulmonary Vascular Diseases, edited by K. M. Moser 15. Physiology and Pharmacology of the Airways, edited by J. A. Nadel 16. Diagnostic Techniques in Pulmonary Disease (in two parts), edited by M. A. Sackner 17. Regulation of Breathing (in two parts), edited by T. F. Hornbein 18. Occupational Lung Diseases: Research Approaches and Methods, edited by H. Weill and M. Turner-Warwick 19. Immunopharmacology of the Lung, edited by H. H. Newball 20. Sarcoidosis and Other Granulomatous Diseases of the Lung, edited by B. L. Fanburg

21. Sleep and Breathing, edited by N. A. Saunders and C. E. Sullivan 22. Pneumocystis carinii Pneumonia: Pathogenesis, Diagnosis, and Treatment, edited by L. S. Young 23. Pulmonary Nuclear Medicine: Techniques in Diagnosis of Lung Disease, edited by H. L. Atkins 24. Acute Respiratory Failure, edited by W. M. Zapol and K. J. Falke 25. Gas Mixing and Distribution in the Lung, edited by L. A. Engel and M. Paiva 26. High-Frequency Ventilation in Intensive Care and During Surgery, edited by G. Carlon and W. S. Howland 27. Pulmonary Development: Transition from Intrauterine to Extrauterine Life, edited by G. H. Nelson 28. Chronic Obstructive Pulmonary Disease: Second Edition, edited by T. L. Petty 29. The Thorax (in two parts), edited by C. Roussos and P. T. Macklem 30. The Pleura in Health and Disease, edited by J. Chrétien, J. Bignon, and A. Hirsch 31. Drug Therapy for Asthma: Research and Clinical Practice, edited by J. W. Jenne and S. Murphy 32. Pulmonary Endothelium in Health and Disease, edited by U. S. Ryan 33. The Airways: Neural Control in Health and Disease, edited by M. A. Kaliner and P. J. Barnes 34. Pathophysiology and Treatment of Inhalation Injuries, edited by J. Loke 35. Respiratory Function of the Upper Airway, edited by O. P. Mathew and G. Sant’Ambrogio 36. Chronic Obstructive Pulmonary Disease: A Behavioral Perspective, edited by A. J. McSweeny and I. Grant 37. Biology of Lung Cancer: Diagnosis and Treatment, edited by S. T. Rosen, J. L. Mulshine, F. Cuttitta, and P. G. Abrams 38. Pulmonary Vascular Physiology and Pathophysiology, edited by E. K. Weir and J. T. Reeves 39. Comparative Pulmonary Physiology: Current Concepts, edited by S. C. Wood 40. Respiratory Physiology: An Analytical Approach, edited by H. K. Chang and M. Paiva 41. Lung Cell Biology, edited by D. Massaro 42. Heart–Lung Interactions in Health and Disease, edited by S. M. Scharf and S. S. Cassidy 43. Clinical Epidemiology of Chronic Obstructive Pulmonary Disease, edited by M. J. Hensley and N. A. Saunders 44. Surgical Pathology of Lung Neoplasms, edited by A. M. Marchevsky

45. The Lung in Rheumatic Diseases, edited by G. W. Cannon and G. A. Zimmerman 46. Diagnostic Imaging of the Lung, edited by C. E. Putman 47. Models of Lung Disease: Microscopy and Structural Methods, edited by J. Gil 48. Electron Microscopy of the Lung, edited by D. E. Schraufnagel 49. Asthma: Its Pathology and Treatment, edited by M. A. Kaliner, P. J. Barnes, and C. G. A. Persson 50. Acute Respiratory Failure: Second Edition, edited by W. M. Zapol and F. Lemaire 51. Lung Disease in the Tropics, edited by O. P. Sharma 52. Exercise: Pulmonary Physiology and Pathophysiology, edited by B. J. Whipp and K. Wasserman 53. Developmental Neurobiology of Breathing, edited by G. G. Haddad and J. P. Farber 54. Mediators of Pulmonary Inflammation, edited by M. A. Bray and W. H. Anderson 55. The Airway Epithelium, edited by S. G. Farmer and D. Hay 56. Physiological Adaptations in Vertebrates: Respiration, Circulation, and Metabolism, edited by S. C. Wood, R. E. Weber, A. R. Hargens, and R. W. Millard 57. The Bronchial Circulation, edited by J. Butler 58. Lung Cancer Differentiation: Implications for Diagnosis and Treatment, edited by S. D. Bernal and P. J. Hesketh 59. Pulmonary Complications of Systemic Disease, edited by J. F. Murray 60. Lung Vascular Injury: Molecular and Cellular Response, edited by A. Johnson and T. J. Ferro 61. Cytokines of the Lung, edited by J. Kelley 62. The Mast Cell in Health and Disease, edited by M. A. Kaliner and D. D. Metcalfe 63. Pulmonary Disease in the Elderly Patient, edited by D. A. Mahler 64. Cystic Fibrosis, edited by P. B. Davis 65. Signal Transduction in Lung Cells, edited by J. S. Brody, D. M. Center, and V. A. Tkachuk 66. Tuberculosis: A Comprehensive International Approach, edited by L. B. Reichman and E. S. Hershfield 67. Pharmacology of the Respiratory Tract: Experimental and Clinical Research, edited by K. F. Chung and P. J. Barnes 68. Prevention of Respiratory Diseases, edited by A. Hirsch, M. Goldberg, J.-P. Martin, and R. Masse 69. Pneumocystis carinii Pneumonia: Second Edition, edited by P. D. Walzer 70. Fluid and Solute Transport in the Airspaces of the Lungs, edited by R. M. Effros and H. K. Chang

71. Sleep and Breathing: Second Edition, edited by N. A. Saunders and C. E. Sullivan 72. Airway Secretion: Physiological Bases for the Control of Mucous Hypersecretion, edited by T. Takishima and S. Shimura 73. Sarcoidosis and Other Granulomatous Disorders, edited by D. G. James 74. Epidemiology of Lung Cancer, edited by J. M. Samet 75. Pulmonary Embolism, edited by M. Morpurgo 76. Sports and Exercise Medicine, edited by S. C. Wood and R. C. Roach 77. Endotoxin and the Lungs, edited by K. L. Brigham 78. The Mesothelial Cell and Mesothelioma, edited by M.-C. Jaurand and J. Bignon 79. Regulation of Breathing: Second Edition, edited by J. A. Dempsey and A. I. Pack 80. Pulmonary Fibrosis, edited by S. Hin. Phan and R. S. Thrall 81. Long-Term Oxygen Therapy: Scientific Basis and Clinical Application, edited by W. J. O’Donohue, Jr. 82. Ventral Brainstem Mechanisms and Control of Respiration and Blood Pressure, edited by C. O. Trouth, R. M. Millis, H. F. Kiwull-Schöne, and M. E. Schläfke 83. A History of Breathing Physiology, edited by D. F. Proctor 84. Surfactant Therapy for Lung Disease, edited by B. Robertson and H. W. Taeusch 85. The Thorax: Second Edition, Revised and Expanded (in three parts), edited by C. Roussos 86. Severe Asthma: Pathogenesis and Clinical Management, edited by S. J. Szefler and D. Y. M. Leung 87. Mycobacterium avium–Complex Infection: Progress in Research and Treatment, edited by J. A. Korvick and C. A. Benson 88. Alpha 1–Antitrypsin Deficiency: Biology • Pathogenesis • Clinical Manifestations • Therapy, edited by R. G. Crystal 89. Adhesion Molecules and the Lung, edited by P. A. Ward and J. C. Fantone 90. Respiratory Sensation, edited by L. Adams and A. Guz 91. Pulmonary Rehabilitation, edited by A. P. Fishman 92. Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease, edited by J.-P. Derenne, W. A. Whitelaw, and T. Similowski 93. Environmental Impact on the Airways: From Injury to Repair, edited by J. Chrétien and D. Dusser 94. Inhalation Aerosols: Physical and Biological Basis for Therapy, edited by A. J. Hickey 95. Tissue Oxygen Deprivation: From Molecular to Integrated Function, edited by G. G. Haddad and G. Lister

96. The Genetics of Asthma, edited by S. B. Liggett and D. A. Meyers 97. Inhaled Glucocorticoids in Asthma: Mechanisms and Clinical Actions, edited by R. P. Schleimer, W. W. Busse, and P. M. O’Byrne 98. Nitric Oxide and the Lung, edited by W. M. Zapol and K. D. Bloch 99. Primary Pulmonary Hypertension, edited by L. J. Rubin and S. Rich 100. Lung Growth and Development, edited by J. A. McDonald 101. Parasitic Lung Diseases, edited by A. A. F. Mahmoud 102. Lung Macrophages and Dendritic Cells in Health and Disease, edited by M. F. Lipscomb and S. W. Russell 103. Pulmonary and Cardiac Imaging, edited by C. Chiles and C. E. Putman 104. Gene Therapy for Diseases of the Lung, edited by K. L. Brigham 105. Oxygen, Gene Expression, and Cellular Function, edited by L. Biadasz Clerch and D. J. Massaro 106. Beta2-Agonists in Asthma Treatment, edited by R. Pauwels and P. M. O’Byrne 107. Inhalation Delivery of Therapeutic Peptides and Proteins, edited by A. L. Adjei and P. K. Gupta 108. Asthma in the Elderly, edited by R. A. Barbee and J. W. Bloom 109. Treatment of the Hospitalized Cystic Fibrosis Patient, edited by D. M. Orenstein and R. C. Stern 110. Asthma and Immunological Diseases in Pregnancy and Early Infancy, edited by M. Schatz, R. S. Zeiger, and H. N. Claman 111. Dyspnea, edited by D. A. Mahler 112. Proinflammatory and Antiinflammatory Peptides, edited by S. I. Said 113. Self-Management of Asthma, edited by H. Kotses and A. Harver 114. Eicosanoids, Aspirin, and Asthma, edited by A. Szczeklik, R. J. Gryglewski, and J. R. Vane 115. Fatal Asthma, edited by A. L. Sheffer 116. Pulmonary Edema, edited by M. A. Matthay and D. H. Ingbar 117. Inflammatory Mechanisms in Asthma, edited by S. T. Holgate and W. W. Busse 118. Physiological Basis of Ventilatory Support, edited by J. J. Marini and A. S. Slutsky 119. Human Immunodeficiency Virus and the Lung, edited by M. J. Rosen and J. M. Beck 120. Five-Lipoxygenase Products in Asthma, edited by J. M. Drazen, S.-E. Dahlén, and T. H. Lee 121. Complexity in Structure and Function of the Lung, edited by M. P. Hlastala and H. T. Robertson

122. Biology of Lung Cancer, edited by M. A. Kane and P. A. Bunn, Jr. 123. Rhinitis: Mechanisms and Management, edited by R. M. Naclerio, S. R. Durham, and N. Mygind 124. Lung Tumors: Fundamental Biology and Clinical Management, edited by C. Brambilla and E. Brambilla 125. Interleukin-5: From Molecule to Drug Target for Asthma, edited by C. J. Sanderson 126. Pediatric Asthma, edited by S. Murphy and H. W. Kelly 127. Viral Infections of the Respiratory Tract, edited by R. Dolin and P. F. Wright 128. Air Pollutants and the Respiratory Tract, edited by D. L. Swift and W. M. Foster 129. Gastroesophageal Reflux Disease and Airway Disease, edited by M. R. Stein 130. Exercise-Induced Asthma, edited by E. R. McFadden, Jr. 131. LAM and Other Diseases Characterized by Smooth Muscle Proliferation, edited by J. Moss 132. The Lung at Depth, edited by C. E. G. Lundgren and J. N. Miller 133. Regulation of Sleep and Circadian Rhythms, edited by F. W. Turek and P. C. Zee 134. Anticholinergic Agents in the Upper and Lower Airways, edited by S. L. Spector 135. Control of Breathing in Health and Disease, edited by M. D. Altose and Y. Kawakami 136. Immunotherapy in Asthma, edited by J. Bousquet and H. Yssel 137. Chronic Lung Disease in Early Infancy, edited by R. D. Bland and J. J. Coalson 138. Asthma’s Impact on Society: The Social and Economic Burden, edited by K. B. Weiss, A. S. Buist, and S. D. Sullivan 139. New and Exploratory Therapeutic Agents for Asthma, edited by M. Yeadon and Z. Diamant 140. Multimodality Treatment of Lung Cancer, edited by A. T. Skarin 141. Cytokines in Pulmonary Disease: Infection and Inflammation, edited by S. Nelson and T. R. Martin 142. Diagnostic Pulmonary Pathology, edited by P. T. Cagle 143. Particle–Lung Interactions, edited by P. Gehr and J. Heyder 144. Tuberculosis: A Comprehensive International Approach, Second Edition, Revised and Expanded, edited by L. B. Reichman and E. S. Hershfield 145. Combination Therapy for Asthma and Chronic Obstructive Pulmonary Disease, edited by R. J. Martin and M. Kraft

146. Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Disease, edited by T. D. Bradley and J. S. Floras 147. Sleep and Breathing in Children: A Developmental Approach, edited by G. M. Loughlin, J. L. Carroll, and C. L. Marcus 148. Pulmonary and Peripheral Gas Exchange in Health and Disease, edited by J. Roca, R. Rodriguez-Roisen, and P. D. Wagner 149. Lung Surfactants: Basic Science and Clinical Applications, R. H. Notter 150. Nosocomial Pneumonia, edited by W. R. Jarvis 151. Fetal Origins of Cardiovascular and Lung Disease, edited by David J. P. Barker 152. Long-Term Mechanical Ventilation, edited by N. S. Hill 153. Environmental Asthma, edited by R. K. Bush 154. Asthma and Respiratory Infections, edited by D. P. Skoner 155. Airway Remodeling, edited by P. H. Howarth, J. W. Wilson, J. Bousquet, S. Rak, and R. A. Pauwels 156. Genetic Models in Cardiorespiratory Biology, edited by G. G. Haddad and T. Xu 157. Respiratory-Circulatory Interactions in Health and Disease, edited by S. M. Scharf, M. R. Pinsky, and S. Magder 158. Ventilator Management Strategies for Critical Care, edited by N. S. Hill and M. M. Levy 159. Severe Asthma: Pathogenesis and Clinical Management, Second Edition, Revised and Expanded, edited by S. J. Szefler and D. Y. M. Leung 160. Gravity and the Lung: Lessons from Microgravity, edited by G. K. Prisk, M. Paiva, and J. B. West 161. High Altitude: An Exploration of Human Adaptation, edited by T. F. Hornbein and R. B. Schoene 162. Drug Delivery to the Lung, edited by H. Bisgaard, C. O’Callaghan, and G. C. Smaldone 163. Inhaled Steroids in Asthma: Optimizing Effects in the Airways, edited by R. P. Schleimer, P. M. O’Byrne, S. J. Szefler, and R. Brattsand 164. IgE and Anti-IgE Therapy in Asthma and Allergic Disease, edited by R. B. Fick, Jr., and P. M. Jardieu 165. Clinical Management of Chronic Obstructive Pulmonary Disease, edited by T. Similowski, W. A. Whitelaw, and J.-P. Derenne 166. Sleep Apnea: Pathogenesis, Diagnosis, and Treatment, edited by A. I. Pack 167. Biotherapeutic Approaches to Asthma, edited by J. Agosti and A. L. Sheffer 168. Proteoglycans in Lung Disease, edited by H. G. Garg, P. J. Roughley, and C. A. Hales

169. Gene Therapy in Lung Disease, edited by S. M. Albelda 170. Disease Markers in Exhaled Breath, edited by N. Marczin, S. A. Kharitonov, M. H. Yacoub, and P. J. Barnes 171. Sleep-Related Breathing Disorders: Experimental Models and Therapeutic Potential, edited by D. W. Carley and M. Radulovacki 172. Chemokines in the Lung, edited by R. M. Strieter, S. L. Kunkel, and T. J. Standiford 173. Respiratory Control and Disorders in the Newborn, edited by O. P. Mathew 174. The Immunological Basis of Asthma, edited by B. N. Lambrecht, H. C. Hoogsteden, and Z. Diamant 175. Oxygen Sensing: Responses and Adaptation to Hypoxia, edited by S. Lahiri, G. L. Semenza, and N. R. Prabhakar 176. Non-Neoplastic Advanced Lung Disease, edited by J. R. Maurer 177. Therapeutic Targets in Airway Inflammation, edited by N. T. Eissa and D. P. Huston 178. Respiratory Infections in Allergy and Asthma, edited by S. L. Johnston and N. G. Papadopoulos 179. Acute Respiratory Distress Syndrome, edited by M. A. Matthay 180. Venous Thromboembolism, edited by J. E. Dalen 181. Upper and Lower Respiratory Disease, edited by J. Corren, A. Togias, and J. Bousquet 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 D. 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. P. Lynch III 186. Pleural Disease, edited by D. Bouros 187. Oxygen/Nitrogen Radicals: Lung Injury and Disease, edited by V. Vallyathan, V. Castranova, and X. Shi 188. Therapy for Mucus-Clearance Disorders, edited by B. K. Rubin and C. P. van der Schans 189. Interventional Pulmonary Medicine, edited by J. F. Beamis, Jr., P. N. Mathur, and A. C. Mehta 190. Lung Development and Regeneration, edited by D. J. Massaro, G. Massaro, and P. Chambon 191. Long-Term Intervention in Chronic Obstructive Pulmonary Disease, edited by R. Pauwels, D. S. Postma, and S. T. Weiss 192. Sleep Deprivation: Basic Science, Physiology, and Behavior, edited by Clete A. Kushida

193. Sleep Deprivation: Clinical Issues, Pharmacology, and Sleep Loss Effects, edited by Clete A. Kushida 194. Pneumocystis Pneumonia: Third Edition, Revised and Expanded, edited by P. D. Walzer and M. Cushion 195. Asthma Prevention, edited by William W. Busse and Robert F. Lemanske, Jr. 196. Lung Injury: Mechanisms, Pathophysiology, and Therapy, edited by Robert H. Notter, Jacob Finkelstein, and Bruce Holm 197. Ion Channels in the Pulmonary Vasculature, edited by Jason X.-J. Yuan 198. Chronic Obstuctive Pulmonary Disease: Cellular and Molecular Mechanisms, edited by Peter J. Barnes 199. Pediatric Nasal and Sinus Disorders, edited by Tania Sih and Peter A. R. Clement 200. Functional Lung Imaging, edited by David Lipson and Edwin van Beek 201. Lung Surfactant Function and Disorder, edited by Kaushik Nag 202. Pharmacology and Pathophysiology of the Control of Breathing, edited by Denham S. Ward, Albert Dahan and Luc J. Teppema 203. Molecular Imaging of the Lungs, edited by Daniel Schuster and Timothy Blackwell 204. Air Pollutants and the Respiratory Tract: Second Edition, edited by W. Michael Foster and Daniel L. Costa 205. Acute and Chronic Cough, edited by Anthony E. Redington and Alyn H. Morice 206. Severe Pneumonia, edited by Michael S. Niederman 207. Monitoring Asthma, edited by Peter G. Gibson 208. Dyspnea: Mechanisms, Measurement, and Management, Second Edition, edited by Donald A. Mahler and Denis E. O'Donnell

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

DYSPNEA MECHANISMS, MEASUREMENT, AND MANAGEMENT SECOND EDITION

Edited by

Donald A. Mahler Dartmouth Medical School Hanover, New Hampshire, U.S.A.

Denis E. O’Donnell Queens University Kingston, Ontario, Canada

Boca Raton London New York Singapore

Published in 2005 by Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2005 by Taylor & Francis Group, LLC No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8247-2577-8 (Hardcover) International Standard Book Number-13: 978-0-8247-2577-8 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe.

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Introduction

The word dyspnea derives from two Greek words (difficult and breathing) and is present when a person becomes aware of labored respiration. There is no doubt that people have experienced difficult breathing since the beginning of time and thus it should be no surprise that the history of dyspnea, so well described in the first chapter of this volume Dyspnea: Mechanisms, Measurement, and Management, Second Edition, begins with Hippocrates, follows with the Middle Ages and then reaches current times. Today, dyspnea is recognized as a symptom, not a sign, and is the event that most often brings the patient to the physician who then must endeavor to determine the cause of this symptom—is it physiological or is it pathological? In either case, dyspnea results from the difficulty of getting sufficient air past the larynx. If the cause is pathological, in most instances it results from a lung disease and is called pulmonary dyspnea. In some other cases it will result from a variety of heart disease and is called cardiac dyspnea. One common distinction between these two types of dyspnea is that in general, pulmonary dyspnea is almost continuous, while in contrast cardiac dyspnea is most often paraxysmal.

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These considerations explain the complexity of dyspnea, especially pulmonary dyspnea. At the same time, it cannot be forgotten that in many chronic and dyspneic pulmonary patients there is the association of significant cardiovascular disease. Thus, major questions confront the physician, such as how to recognize the cause of dyspnea, how to treat it, and how to ensure that the patient can effectively cope with this symptom. Seven years ago, the series of monographs Lung Biology in Health and Disease presented a volume titled Dyspnea, edited by Dr. Donald A. Mahler. That volume was the state-of-the-art at that time. This new volume, edited by Dr. Donald A. Mahler and Dr. Denis O’Donnell, has a significantly expanded title, Dyspnea: Mechanisms, Measurement, and Management and represents the current state of knowledge. To put it simply, this volume is a tribute to the large body of research that has been performed since the first volume was published. This has resulted in what the editors call in their Preface ‘‘the new understanding.’’ Quite rightfully, they underscore that what we know today about dyspnea is the result of a synergistic approach between basic ‘‘investigators, physicians . . . industry representatives, and regulatory agencies.’’ Certainly, each of these groups must be commended for their efforts, but just as commendable is the work of Drs. Mahler and O’Donnell who together with a cadre of distinguished contributors have produced this new volume. It is written and structured to be an asset for practicing physicians treating dyspneic patients. In turn, these patients will benefit from a better quality of life and physical well being. It gives me great pride to present this new volume to the readership of the series Lung Biology in Health and Disease. Claude Lenfant, MD Gaithersburg, Maryland

Preface

Dyspnea, or breathing difficulty, is the primary complaint of patients with respiratory disease because it limits their ability to live. Frequently, such individuals consider that they are ‘‘getting older’’ as a likely explanation for their breathlessness; and, in an unconscious manner, they typically reduce occupational and/or recreational activities to avoid or minimize the discomfort of breathing. Over time, the problem of breathlessness may impact their ability to function at a desired or expected capacity. Yet, the person must perform certain daily activities that eventually become compromised by ‘‘shortness of breath.’’ The prevalence of dyspnea and the overall burden of chronic respiratory diseases, particularly asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung disease, have prompted the medical community to learn more about the complex nature of dyspnea. Why has this happened? The renewed interest in dyspnea has been a direct result of the scientific inquiry into the efficacy and effectiveness of different treatment options for our patients. What are the results? Two large randomized, controlled trials (RCTs) performed in the 1990s (Lung Health Study I and II) yielded negative findings as related to their hypotheses (neither regular v

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use of an inhaled short-acting bronchodilator (ipratropium bromide) nor an inhaled corticosteroid (triamcinolone) altered the progressive decline in lung function). Nevertheless, these results, combined with those from other studies, have led investigators, physicians, industry representatives, and regulatory agencies to re-examine the goals of treatment. For example, there is now wide recognition and acceptance (as reflected in the GOLD guidelines) that treatment of COPD should consider outcomes that are important to our patients (i.e., dyspnea, quality of life, exercise capacity, and exacerbations) rather than to focus predominantly on lung function, arterial blood gases, and radiographic imaging. Clearly, these clinical outcomes reflect the daily impact of the various chronic respiratory conditions that are important to individual patients. As part of this ‘‘new understanding’’ investigators have pursued three separate, but related, directions in the study of dyspnea. One approach examines the mechanism(s) contributing to breathlessness in patients with respiratory disease rather than the study of sensory physiology of breathing in healthy subjects under conditions of mechanical and chemical loading (as has been the focus of investigation in the past). A second approach considers the development and testing (validity, reliability, and responsiveness) of different instruments that could be used to measure dyspnea in clinical trials. For example, how can we know if a treatment is beneficial for the patient unless the individual’s experience can somehow be quantified? Using the principles of psychophysics (the study of the stimulus–response relationship), instruments have been developed, refined, and/or applied to measure the patient’s perception of dyspnea. The third approach investigates the efficacy and effectiveness of both old and new treatments for the relief of dyspnea as part of multicenter RCTs. These distinct but complementary approaches provide the framework for our book entitled Dyspnea: Mechanisms, Measurement, and Management. Although dyspnea affects almost all respiratory conditions as well as cardiac diseases and musculoskeletal disorders, most of the material presented in this book involves COPD. Why? it is because of the high prevalence of COPD worldwide, and because patients with COPD seek medical attention for relief of dyspnea in far greater numbers than do patients with other conditions. As a result, patients with COPD have participated as subjects in clinical investigations with the hope of achieving some improvement in their breathing. Certainly, patients who experience dyspnea due to other cardiorespiratory conditions also deserve the same attention and consideration. We are pleased that experts from various backgrounds and leaders in the study of dyspnea have contributed enthusiastically to this book. Our aim was to provide up-to-date practical information on how best to assess and

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alleviate respiratory discomfort across the spectrum of pulmonary diseases and at the end of life. Our collective hope and aspirations are that this book will provide both a ‘‘state of the art’’ review of the topics related to dyspnea, but will also serve to identify ‘‘new directions’’ in our understanding and treatment of this most important outcome for our patients. One of these emerging ‘‘new directions’’ is our realization that the past nihilism related to treating many chronic respiratory diseases, especially COPD, can be replaced with optimism by considering dyspnea, not lung function, as a major outcome in the treatment paradigm. Donald A. Mahler, MD Denis E. O’Donnell, MD

Contributors

John C. Baird Psychological Applications, Waterbury, Vermont and Dartmouth Medical School, Hanover, New Hampshire, U.S.A. Gisella Borzone Department of Respiratory Diseases, Pontificia Universidad Cato´lica de Chile, Santiago, Chile Virginia Carrieri-Kohlman Department of Physiological Nursing, UCSF, San Francisco, California, U.S.A. D. Dudgeon

Queen’s University, Kingston, Ontario, Canada

Roger S. Goldstein University of Toronto, West Park Healthcare Center, Toronto, Ontario, Canada Paul W. Jones

St. George’s Hospital Medical School, London, U.K.

Kieran Killian Ambrose Cardiorespiratory Department, McMaster University, Hamilton, Ontario, Canada Suzanne C. Lareau New Mexico VA Health Care System, Albuquerque, New Mexico, U.S.A. ix

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Contributors

Carmen Lisboa Department of Respiratory Diseases, Pontificia Universidad Cato´lica de Chile, Santiago, Chile M. Diane Lougheed Division of Respiratory and Critical Care Medicine, Department of Medicine, Queen’s University, Kingston, Ontario, Canada Donald A. Mahler Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School, Hanover, New Hampshire, U.S.A. Paula Meek College of Nursing, University of New Mexico, Albuquerque, New Mexico, U.S.A. Alexander S. Niven Texas Tech University of the Health Sciences E1 Paso, and William Beaumont Army Medical Center, E1 Paso, Texas, U.S.A. Denis E. O’Donnell Division of Respiratory and Critical Care Medicine, Department of Medicine, Queen’s University, Kingston, Ontario, Canada Sanjay A. Patel Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Richard M. Schwartzstein Division of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, U.S.A. Frank C. Sciurba Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Nha Voduc Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada Katherine A. Webb Respiratory Investigation Unit, Department of Medicine, Queen’s University, Kingston, Ontario, Canada Idelle M. Weisman University of Texas Health Sciences Center at San Antonio, San Antonio, and Human Performance Lab, Department of Clinical Investigation, Pulmonary/Critical Care Service, William Beaumont Army Medical Center, E1 Paso, Texas, U.S.A. Theodore J. Witek, Jr. Boehringer Ingelheim Portugal, Lisbon, Portugal Richard ZuWallack Section of Pulmonary and Critical Care, St. Francis Hospital and Medical Center, Hartford, Connecticut, U.S.A.

Contents

Introduction Claude Lenfant . . . . iii Preface . . . . v Contributors . . . . ix 1. History of Dyspnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Kieran Killian I. Introduction . . . . 1 II. Hippocrates . . . . 2 III. Middle Ages . . . . 3 IV. Morbid Anatomy . . . . 3 V. Physics . . . . 4 VI. Respiration . . . . 4 VII. Respiratory Center . . . . 5 VIII. Perception and Hypoxia . . . . 5 IX. Perception and Hypercapnia . . . . 6 X. Origins of Muscular Sensation . . . . 6 XI. Dyspnea and the Lung . . . . 8 XII. Dyspnea (1900–1950) . . . . 8 XIII. Clinical Contribution . . . . 9 XIV. Dyspnea and Fatigue . . . . 10 xi

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XV. XVI.

Sensory Neurophysiology . . . . 11 Psychophysics . . . . 11 References . . . . 14

2. Dyspnea in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . Donald A. Mahler and John C. Baird I. Introduction . . . . 19 II. Prevalence of Dyspnea in the Elderly . . . . 20 III. Aging and Lung Function . . . . 20 IV. Respiratory Sensation and Aging . . . . 22 V. Dyspnea During Exercise and the Aging . . . . 23 VI. Summary . . . . 24 References . . . . 26

19

3. Mechanisms of Dyspnea in COPD . . . . . . . . . . . . . . . . . Denis E. O’Donnell and Katherine A. Webb I. Pathophysiology of COPD . . . . 30 II. Dyspnea: Physiological Correlates . . . . 35 III. Neurophysiology of Dyspnea in COPD . . . . 44 IV. Putative Mechanisms of Dyspnea During Dynamic Hyperinflation . . . . 45 V. Summary . . . . 49 References . . . . 49

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4. Dyspnea in Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 M. Diane Lougheed and Denis E. O’Donnell I. Introduction . . . . 59 II. Historical Perspective . . . . 60 III. Factors Affecting Symptom Perception . . . . 67 IV. Quality of Dyspnea in Asthma . . . . 69 V. Mechanics of Asthma . . . . 70 VI. Mechanical Basis for Asthma Symptoms . . . . 72 VII. Summary . . . . 78 References . . . . 80 5. Mechanisms of Dyspnea in Restrictive Lung Disease . . . . . 87 Denis E. O’Donnell and Nha Voduc I. Introduction . . . . 87 II. Interstitial Lung Disease . . . . 88 III. Mechanisms of Dyspnea in ILD . . . . 92 IV. Other Forms of Restrictive Lung Disease . . . . 99 V. Conclusion . . . . 106 References . . . . 107

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6. Language of Dyspnea . . . . . . . . . . . . . . . . . . . . . . . . . 115 Richard M. Schwartzstein I. Introduction—A Problem of Communication . . . . 115 II. Developing a Vocabulary . . . . 116 III. Verbal Descriptors and the Physiology of Dyspnea . . . . 125 IV. The Language of Dyspnea in Specific Disease States . . . . 133 V. Distress and Breathing Discomfort—Affective Qualities of Dyspnea . . . . 137 VI. Use of the Language of Dyspnea in the Evaluation and Study of Patients with Breathing Discomfort . . . . 138 VII. Summary . . . . 140 References . . . . 141 7. Measurement of Dyspnea: Clinical Ratings . . . . . . . . . . . 147 Donald A. Mahler I. Introduction . . . . 147 II. Can Dyspnea be Measured? . . . . 149 III. Types of Instruments and Measurement Criteria . . . . 150 IV. Clinical Instruments Used to Measure Dyspnea . . . . 151 V. Validity . . . . 155 VI. Reliability (for a Discriminative Instrument) . . . . 155 VII. Responsiveness (for an Evaluative Instrument) . . . . 156 VIII. Minimal Clinically Important Difference . . . . 156 IX. What Is the MCID for Instruments that Measure Dyspnea? . . . . 157 X. Recommendations . . . . 159 References . . . . 161 8. Measurement of Dyspnea Ratings During Exercise . . . . . Donald A. Mahler I. Introduction . . . . 167 II. What Is the Stimulus for Dyspnea During Exercise? . . . . 168

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III. IV. V. VI. VII.

Types of Exercise Tests Used to Provoke Dyspnea . . . . 168 Instruments to Measure Dyspnea During Exercise . . . . 171 Dyspnea Ratings During Exercise Testing . . . . 173 Clinical Applications . . . . 177 Recommendations . . . . 178 References . . . . 179

9. Assessment of Dyspnea in Large-Scale Clinical Trials: Application to Clinical Development Programs in COPD . . . . . . . . . 183 Theodore J. Witek, Jr. I. Introduction . . . . 183 II. Measuring Dyspnea in the Context of Regulatory and Clinical Development . . . . 184 III. Selection and Application of Instrument . . . . 186 IV. Experience from Published Trials . . . . 192 V. Summary . . . . 200 References . . . . 202 10. Diagnosis of Unexplained Dyspnea . . . . . . . . . . . . . . . . Alexander S. Niven and Idelle M. Weisman I. Introduction . . . . 209 II. Causes of Dyspnea . . . . 210 III. Evaluation of Unexplained Dyspnea . . . . 210 IV. Summary . . . . 245 V. Case Studies . . . . 246 References . . . . 253

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11. Health Status, Health-Related Quality of Life, and Dyspnea in COPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 Paul W. Jones I. Introduction . . . . 265 II. Assessing the Overall Effect of COPD . . . . 267 III. Quality of Life Vs. Health Status Measurement . . . . 267 IV. Health Status Questionnaires . . . . 268 V. Determinants of Health Status Questionnaires . . . . 271 VI. Dyspnea and Health Status . . . . 271 VII. Changes in Health Status and Dyspnea . . . . 273 VIII. Health-Related Quality of Life and Dyspnea . . . . 275

Contents

IX.

xv

Summary . . . . 277 References . . . . 277

12. Effect of Bronchodilators and Inhaled Corticosteroids on Dyspnea in COPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 Denis E. O’Donnell and Donald A. Mahler I. Introduction . . . . 283 II. Assessment of Bronchodilator Efficacy . . . . 283 III. How do Bronchodilators Improve Dyspnea in COPD? . . . . 284 IV. Dyspnea Evaluation . . . . 286 V. Inhaled Beta-2-Agonists . . . . 287 VI. Anticholinergic Therapy . . . . 289 VII. Theophylline . . . . 291 VIII. Inhaled Corticosteroids . . . . 292 IX. What Are the Possible Mechanisms for Relief of Dyspnea with ICS? . . . . 292 X. Combination Therapy with Inhaled Corticosteroid and Long-Acting Beta-Agonist . . . . 294 XI. Summary . . . . 296 References . . . . 296 13. The Effect of Pulmonary Rehabilitation on Dyspnea . . . . 301 Richard ZuWallack, Suzanne C. Lareau, and Paula Meek I. Introduction . . . . 301 II. Definition and Goals of Pulmonary Rehabilitation . . . . 302 III. Patient Selection for Pulmonary Rehabilitation . . . . 302 IV. Components of Pulmonary Rehabilitation . . . . 302 V. The Rationale for Pulmonary Rehabilitation . . . . 303 VI. Outcome Assessment in Pulmonary Rehabilitation . . . . 304 VII. Dyspnea Assessment in Pulmonary Rehabilitation . . . . 305 VIII. Mechanism(s) by Which Pulmonary Rehabilitation Relieves Dyspnea . . . . 305 IX. Studies Showing the Effect of Pulmonary Rehabilitation on Dyspnea . . . . 309 X. Strategies to Improve the Effectiveness of Pulmonary Rehabilitation . . . . 313

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XI.

Summary . . . . 317 References . . . . 318

14. Inspiratory Muscle Training . . . . . . . . . . . . . . . . . . . . . 321 Carmen Lisboa and Gisella Borzone I. Introduction . . . . 321 II. Rationale for Training Inspiratory Muscles in COPD . . . . 323 III. Components of IMT . . . . 324 IV. Inspiratory Muscle Training in COPD . . . . 332 V. Patient Selection . . . . 337 VI. Conclusions . . . . 339 References . . . . 340 15. Oxygen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 Roger S. Goldstein I. Introduction . . . . 345 II. Rationale for Oxygen Therapy . . . . 346 III. Benefits Based on Exercise Testing . . . . 347 IV. Benefits Based on Clinical Instruments that Measure Dyspnea . . . . 353 V. Patient Selection . . . . 358 VI. Summary and Recommendations . . . . 359 References . . . . 360 16. Coping and Self-Management Strategies for Dyspnea Virginia Carrieri-Kohlman I. Introduction . . . . 365 II. Conceptual Approach . . . . 366 III. Selected Coping and Self-Management Strategies . . . . 368 IV. Summary . . . . 386 References . . . . 386

...

365

17. Management of Dyspnea: Lung Volume Reduction Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 Sanjay A. Patel and Frank C. Sciurba I. Introduction . . . . 397 II. Rationale . . . . 398 III. Components . . . . 402 IV. Benefits Based on Clinical Instruments . . . . 403 V. Benefits Based on Exercise Testing . . . . 407

Contents

VI. VII.

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Patient Selection . . . . 412 Summary . . . . 418 References . . . . 418

18. Management of Dyspnea at the End of Life . . . . . . . . . . 429 D. Dudgeon I. Introduction . . . . 429 II. Rationale for Management of Dyspnea at End of Life . . . . 430 III. Components of Management of Dyspnea at the End of Life . . . . 431 IV. Special Considerations in People Near the End of Life . . . . 433 V. Interventions for Management of Dyspnea . . . . 436 VI. Withdrawal of Life Support . . . . 441 VII. Patient Selection for End-of-Life Care . . . . 442 VIII. Communication . . . . 443 IX. Recommendations . . . . 445 X. Summary . . . . 446 Appendix A . . . . 446 References . . . . 453 Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463

1 History of Dyspnea

KIERAN KILLIAN Ambrose Cardiorespiratory Department, McMaster University, Hamilton, Ontario, Canada

I. Introduction Words describing discomfort associated with the act of breathing (dyspnea) can be found in the hieroglyphics of Mesopotamia (3300 B.C.), in the Harappa civilization in the Indus valley (2500 B.C.), and the Smith and Ebers papyri of ancient Egypt (1534 B.C.). These words were pragmatic, acquired meaning from common usage, and were destined to change with progressive understanding. Muscular exertion, consciously perceived as pleasant, recedes promptly with rest leaving us with a sense of well-being, described by Pavlov as a sense of muscular gladness. Strenuous physical activity was required for the survival of primitive man. If muscular exertion was experienced with breathing during modest exercise, concern was engendered or if it occurred at rest, outright fear. Lacking understanding, primitive man innately sought relief as best he could and blamed his symptoms on supernatural forces. Voluntary cessation of breathing brings on an unpleasant urge to breathe (breathlessness) while suffocation brings on both, breathlessness and progressive exertion

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of the respiratory muscles (dyspnea). The difference between muscular exertion and breathlessness was as obvious to primitive man as it is today. II. Hippocrates The role of the Gods faded as the Hippocratic School (460–360 B.C.) attributed symptom/disease to imbalance in four basic humors. Blood, associated with air, bestowed a sanguine temperament characterized by optimism, enthusiasm, and excitability. Phlegm, associated with water, arose from the brain accessing the lungs through the cribiform plate and bestowed a phlegmatic temperament characterized by apathy. Black bile, associated with earth, arose from the spleen and bestowed a melancholic temperament characterized by depression. Yellow bile, associated with fire, arose from the liver and bestowed a choleric temperament characterized by anger and irritability. Blood was hot and moist, phlegm was cold and moist, yellow bile was hot and dry, and black bile was cold and dry. Too much air made one sanguine, too much water phlegmatic, too much fire choleric, and too much earth melancholic. The practice of medicine was based on balancing the four humors. Fever, attributed to yellow bile (hot dry disease), could be counterbalanced with phlegm (cold moist disease) by prescribing cold baths. Colds, attributed to excess phlegm, could be counterbalanced with warmth and wine. To restore balance, blood letting, purgatives, cathartics, emetics, diuretics, alcohol, and opiates were widely used. Vomiting and diarrhea, induced with hellebore, were signs that balance was being restored. Evidence-based medicine would have thrived on the strictly limited causes of disease and the equally limited therapeutic possibilities. The recognition of labored breathing in the Hippocratic period is unmistakable. Inconsistencies arose until Erasistratos (304–250 B.C.) of the Alexandrian school identified breathing as a muscular act. Over the succeeding years, the Hippocratic system evolved and was restructured by Galen (129–210 A.D.) in an even more complex system. All matter consisted of air, water, earth, and fire alone or in combination. Ingested food was absorbed from the gastro-intestinal tract, transported to the liver, and converted into blood. Blood and a natural spirit, generated in the liver, were transported by the venous system to all parts of the body. A vital spirit, generated in the left heart, was transported to all parts of the body by the arterial system. An animal spirit, generated in the brain, was transported to the muscles through the nerves. The humoral theory of Hippocrates was extended to include the appropriate actions of the three spirits. Symptoms continued to be caused by an imbalance of the four humors (blood, phlegm, black bile, and yellow bile) grafted to a general system where specific spirits were essential for life. Therapeutics changed little and restoring the balance with blood letting, emetics, and laxatives continued. Breathing was thought to simply cool the heart. The pulmonary veins transported an

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element contained in the air from the lungs to the heart and transported the sooty vapors from the production of vital spirit from the heart back to the lungs. However, no direct communication occurred between the venous and the arterial systems.

III. Middle Ages The fall of the Roman Empire, the meteoric rise of the Moslem Empire with the continued presence of the Eastern Empire centered at Byzantium (Constantinople) led to no substantial advances in medicine. As contact between Moslems and Christians increased during the Crusades, approaches to medicine were inevitably contrasted and compared. Earlier concepts were modestly extended by a Moslem contribution. Around the turn of the millennium, the Canons of Avicenna (980–1037) together with the Hippocratic writings and the collected works of Galen reappeared in Salerno. Universities spread through the city states of Italy to France and England heralding the end of the dark ages.

IV. Morbid Anatomy To both the Christian and Moslem religions, understanding life was an unnecessary distraction from saving the soul. The integrity of the body after death was crucial for the resurrection of the soul. Postmortem dissection was proscribed until the emerging power of the city states of Italy limited the control of the Church. Dissection of executed prisoners, less likely to benefit from resurrection, led to the first accurate description of human anatomy since Galen. At the University of Bologna, Mondino De Luzzi (1275–1326) produced the first influential textbook on human anatomy. The revival of anatomy reached a crescendo in 1562 with the publication of De Humani Corporis Fabrica Libri Septem by Andreas Vesalius (1514–1564). Anatomical examination was to have a profound influence on dyspnea. Postmortem examinations allowed physicians to match clinical symptoms in life to morbid anatomy following death. Jan Baptista van Helmont (1577–1644) challenged the notion that disease was based on humoral imbalance and dismissed the notion that phlegm arose from the brain. Thomas Willis (1621–1675) identified chronic bronchitis with cough, serious filth (sputum arising from the lung) and a fixed inflated chest that could neither fill nor empty properly. Asthma identified by Maimonides (1135– 1204), Willis and John Floyer (1649–1734) a lifelong asthmatic. Asthma had no obvious pathology and was considered a neurogenic disease. Symptom and disease were no longer synonymous.

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At Leyden, Hermann Boerhaave (1668–1738) supplemented clinical teaching around patients with their postmortem examinations. Symptoms were matched to morbid anatomy allowing physicians to look for anatomical changes in life. The benefits of inspection, palpation, percussion, later introduced by Leopold Auenbrugger (1722–1809), and auscultation, introduced by Rene´ Lae¨nnec (1781–1826), proved crucial when combined with the growing knowledge of morbid anatomy. Concepts of cardiac dyspnea, pulmonary dyspnea, and renal dyspnea emerged. However, understanding dyspnea would not be achieved with these advances. V. Physics The role of physics was destined to promote further understanding. Rene´ Descartes (1596–1650) proposed that the body was composed of particles that obey the laws of physics. Galileo Galilei (1564–1642), Evangelista Torricelli (1608–1647), and Isaac Newton (1642–1734) introduced mechanics, the study of the relationships between force and displacement. In 1628, the heart, circulation, and the physical principles essential to support life were introduced by William Harvey (1578–1657) in De Moto Cordis. VI. Respiration In the Jesuit letters of 1590, Father Acosta reported dyspnea, profound fatigue, and headache in those traveling across the Andes during the Spanish exploitation of Peru. In the Philosophical Transactions of 1670, Robert Boyle reported similar symptoms climbing Mount Ararat, Tenerife and the Pyrenees. With interests overlapping physics, chemistry, and medicine, Boyle recognized that an element in the air was essential for combustion and essential for life after a lighted candle and a mouse expired in an airtight space; expiring one right after the other. Boyle knew these phenomena were somehow related to the symptoms experienced by individuals traveling to high places. Influenced by Boyle’s work, Richard Lower (1631–1691) recognized that blood was arterialized in the lung, John Mayow (1640– 1679) described a nitro-aerial spirit which was very close in concept to oxygen, and Robert Hooke (1635–1703) recognized that ventilation could be sustained artificially by continually passing air through the punctured lungs dismissing the notion that ventilation simply cooled the heart. The essential elements of life included the presence of heat, responsiveness, breathing, and pulse. Joseph Black (1728–1799), distinguished between temperature and heat, introduced calorimetry and isolated carbon dioxide. Joseph Priestley (1733–1804) and Carl Scheele (1742–1786) isolated ‘‘eminently respirable air.’’ Putting these elements together, Antoine Lavoisier (1743–1794) recognized that combustion and respiration

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were the same; body tissues burned just as a candle did, by consuming oxygen, producing carbon dioxide and generating heat in a stoichiometric manner. Quantitative chemistry, the elements of the periodic table, and the laws of thermodynamics followed. VII. Respiratory Center In the early 1800s, Julien Legallois (1770–1814) (1) demonstrated that breathing, vital for survival, was dependent on neural activity in the medulla oblongata (‘‘noeud vital’’). The activation of respiratory neurons, to drive the respiratory muscles, had a profound influence on dyspnea and engendered enormous confusion. Dyspnea was merely an expression of respiratory muscle activity where apnea depicted absence and dyspnea depicted intense contractile activity (2–5). Given the fundamentals of combustion and respiration, the notion that hypoxia and hypercapnia stimulate the respiratory neurons driving the respiratory muscles causing dyspnea was appealing (3,6,7). Later, as hypoxia might reasonably be expected to generate lactic acid, the respiratory neurons were thought sensitive to hydrogen ion concentration (8,9). Implicitly, without addressing mechanisms, the notion arose that the activation of the respiratory neurons or the stimuli arising as a consequence of their activation caused dyspnea. VIII. Perception and Hypoxia On April 15, 1875, Gaston Tissandier, Joseph Croce´-Spinelli, and Theodore Sivel ascended to 8600 m in the flight of the Zenith. At a height of 7000 m, Tissandier recorded ‘‘I breathed the mixture of air and oxygen and felt my whole being, already oppressed, revive under the influence of the cordial. Toward 7500 m, the numbness one experiences is extraordinary. The body and the mind weaken little by little, gradually, unconsciously, without one’s knowledge. One does not suffer at all; on the contrary, one experiences inner joy, as if it were an effect of the inundating flood of light. One becomes indifferent; one no longer thinks of the perilous situation or of the danger; one rises and is happy to rise. Vertigo of the lofty regions is not a vain word. But as far as I can judge by my personal impressions, this vertigo appears at the last moment; it immediately precedes annihilation, sudden, unexpected and irresistible. I soon felt so weak that I could not even turn my head to look at my companions.’’ On descent, even though their oxygen bags remained half full, both colleagues were dead. The increase in dyspnea and breathlessness during ascent was not sufficient to provoke using oxygen even though it was noted to have such an extreme effect. Profound weakness and altered consciousness were similar to the difficulties encountered by travelers to high places.

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Killian IX. Perception and Hypercapnia

In the early decades of the 20th century, hypercapnia was considered the dominant stimulus in the control of breathing. John Scott Haldane (1860–1936) and Joseph Barcroft (1872–1947) revisited Boyle’s experiment using humans in an airtight chamber. Breathlessness became noticeable with a rise in PCO2 of as little as 1–2 mm whereas PO2 had to drop as much as 68 mm (12%). In the practical course on human physiology, Claude Gordon Douglas (1882–1963) and John Gillies Priestley (1880–1941) had all medical students re-breathe from a spirometer (i) filled with expired air, to experience progressive hypoxia and hypercapnia; (ii) filled with oxygen, to experience progressive hypercapnia alone; and (iii) filled with expired air scrubbing the carbon dioxide produced with soda lime to experience progressive hypoxia and hypocapnia. Breathlessness was most intense with hypercapnic hypoxia; intense with hyperoxic hypercapnia; and modest with hypocapnic hypoxia. Over the succeeding years, ventilatory responses to hypoxia and hypercapnia were studied under steady-state conditions or during progressive re-breathing. Under hyperoxic conditions, ventilation varied from 1 to 7 L/ min for every 1 mm rise in PCO2. Under isocapnic conditions, ventilation varied from 1 to 3 L/min for every 1% decline in arterial oxygen saturation. During exercise, respiratory control was homeostatic maintaining constant arterial blood gases and hydrogen ion concentration. Ventilation increased with carbon dioxide production. Interestingly, ventilation, between subjects, varied very modestly despite many fold differences in responsiveness to PCO2 and PO2. The strength of the respiratory muscles and the forces opposing their contraction accounted for the variability in ventilatory responses. The role of pulmonary mechanics was generally understated. The notion that the effort associated with labored breathing gave rise to dyspnea while chemoreceptor activity gave rise to breathlessness (‘‘unpleasant urge to breathe’’) was not appreciated.

X. Origins of Muscular Sensation The conscious awareness of one’s surroundings arises through external sensory receptors associated with sight, hearing, olfaction, taste, and touch just as the conscious awareness of muscular activity arises through internal sensory receptors. The activation of these receptors is first relayed to the central nervous system where an impression of the conditions is made and is later interpreted in light of previous experience and learning. In an era where muscular sensory receptors were unknown, John Locke (1632– 1704), George Berkeley (1685–1753), and others recognized that the control of muscular activity was dependent on the awareness of both the

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outgoing motor command and its simultaneous consequences. Sensory information was not merely sensed but interpreted and if misinterpreted, led to sensory illusions. They reasoned that there must be a sense of the willed motor command and a sense of its achieved effects. Charles Bell (1774–1842) and Franc¸ois Magendie (1783–1855) recognized that afferent nerve fibers exclusively traverse the posterior horns of the spinal cord. By the end of the 19th century, Golgi tendon organs were recognized to mediate a sense of tension and joint receptors to mediate a sense of displacement (position and movement). Muscle spindles were not recognized to mediate a sense of displacement until the 1960s. Small nerve endings contributing to vasomotor control proved polymodal, responding to a wide range of mechanical and chemical stimuli. These influence the responsiveness of alpha-motor neurons and when intensely stimulated, generate muscular pain. Charles Sherrington (1857–1952) (10), a major figure in neurophysiology, considered that muscular sensations were entirely afferent. The ‘‘sense of innervation’’ lost favor only to reappear in the 1970s when the sense of effort could not be explained by afferents arising within the muscle. A sense of achieved tension and a sense of effort were easily separated under conditions of fatigue, of neuromuscular blockade, by altering the length and velocity of contraction, and by reflex stimulation or inhibition of alpha-motor neurons (11–18). Breathing stimulates muscle spindles, tendon organs, free nerve endings and stimulates joint and skin receptors in the chest cage (10,11,15,17–26). Hence, with the activation of respiratory muscles arise many different sensations, i.e., awareness of motor command intensity, awareness of the force generated, awareness of achieved displacement, and sometimes awareness of focal discomfort. This sensory information can be further interpreted to yield a sense of fatigue and weakness by comparing the motor output to the achieved effect over time; to recognize the nature (elastic, resistive, or threshold) of the loads opposing contraction by comparing the force relative to displacement and rate of displacement. Hence, the perceived sensation of muscular effort has qualitative and quantitative aspects. The sense of effort appears to be uniquely related to exertional discomfort independent of other afferent inputs. For example, high velocity contraction and high tension contraction are both distressing even though the afferent input from the muscle is widely different. Excessive effort is common to both contractions. In the face of varying metabolic demands, the respiratory muscles must work to maintain blood gases. Therefore, the respiratory muscles are susceptible to fatigue: (i) if the force generated is excessive, (ii) if the muscles are not adequately perfused, and (iii) if oxygen delivery or carbon dioxide excretion is impaired. Given the sustained necessity to breathe, it is critically important to avoid respiratory muscle fatigue. Dyspnea arises due

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to an increase in inspiratory muscle effort generating exertional discomfort under conditions of exercise, of respiratory loading, and with muscle weakness. One attempts to behaviorally minimize effort which coincidentally minimizes the propensity to fatigue. Dyspnea is relieved in acute respiratory failure with ventilation for as long as the respiratory muscles remain silent and gas exchange demands are met. Dyspnea arises with excessive effort and breathlessness with a rising PCO2. XI. Dyspnea and the Lung Pulmonary receptors are arguably the best studied receptors associated with the act of breathing (27). Stimulation of irritant receptors in the airway results in cough and in the substernal discomfort associated with tracheal inflammation. Afferents from the lung parenchyma, vasculature, and airways (stretch, irritant, and C fibers/j receptors) are well known to modify the control of breathing. The role of pulmonary stretch receptors in mediating a sense of displacement remains controversial (28–33). In the 1960s, J. M. Petit, following an experiment conducted on himself, reported that the sense of tightness experienced by chemically induced bronchoconstriction was abolished by vagal blockade. Based on this report, the sense of tightness is thought to be due to intrapulmonary receptor stimulation relayed by vagal afferents. Anand Paintal showed that breathing can be driven by the stimulation of juxta capillary receptors in the lungs (‘‘Paintal receptors’’) and went on to suggest that breathing during exercise is driven by their stimulation. Following heart/lung transplantation, even though the lungs are no longer a source of afferent activity, dyspnea still arises during exercise. The Paintal receptors are unlikely to play a primary role in generating dyspnea. In the middle of the 18th century, Ewald Hering (1834–1918) and Josef Breuer (1842–1925) (34) considered the control of breathing self steering. ‘‘The lung, when it becomes more expanded by inspiration, or by inflation, exerts an inhibitory effect on inspiration and promotes expiration, and this effect is greater the stronger the expansion. Every inspiration, therefore, in that it distends the lung brings about its own end by means of this distension, and thus initiates expiration.’’ Mechanical loading by limiting inspiration leads to intense activity in the medulla generating exertional discomfort and dyspnea. XII. Dyspnea (1900–1950) In the early part of the 20th century, Ronald Christie (35) summarized: ‘‘Though the conditions under which dyspnea occurs are various and manyfold, giving rise to an impression of complexity, the fundamental

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9

causes are few and relatively simple. They consist of chemical and reflex disturbances.’’ Jonathan Meakins, his colleague of many years, summarized the mechanisms of dyspnea: (1) want of oxygen; (2) carbon dioxide retention, absolute or relative (36), but later suggested that dyspnea was merely the perception of respiratory muscle effort. One might suggest that the respiratory neurons in the medulla control the activation of alpha-motor neurons driving the respiratory muscles generating the same sense of effort as the motor cortex generates in driving the limb muscles. The respiratory muscles are unique in that they are controlled by both, the respiratory neurons in the medulla and the motor cortex. Dyspnea arising in patients suffering from the ravages of poliomyelitis provided a valuable clue. The effort required to breathe was increased when the respiratory muscles were weak. The difference between the sense of achieved force and the sense of effort required to generate force was not appreciated in this era. McIlroy (37) suggested that the respiratory muscles incur an oxygen debt, and dyspnea is a consequence. Inadequate supply of oxygenated blood to the respiratory muscles similar to claudication was forwarded by Harrison (38). The oxygen cost of breathing increases in a positively accelerating manner as ventilation increases from 0.5 mL/L at low levels to >2 mL/L at high levels of ventilation (39–42). The oxygen cost of breathing is increased in patients with pulmonary and cardiac diseases (43). Afferent neural activity arising in small myelinated and unmyelinated fibers as a consequence of tissue hypoxia was the implied mechanism. Today dyspnea would be attributed to excessive effort due to fatigue resulting from inadequate perfusion.

XIII. Clinical Contribution In 1924, in an influential monograph on the physiology of breathing entitled Dyspnea, Means (44) inferred that dyspnea becomes intense as ventilation encroaches on the capacity to breathe. A maximal respiratory muscle effort was obviously required to achieve maximal ventilation. Hence, if expressed as a percent of maximal breathing capacity, ventilation should reflect the intensity of effort and the intensity of dyspnea. The ventilatory index (VE/MBC) was synonymous with dyspnea. Andre´ Cournand and Dickinson Richards from the Chest Service at Bellevue Hospital provided respiratory leadership for the following generation (45–47). They formalized physiological concepts of respiration in the following simplified manner: (1) ventilatory insufficiency is measured by VE/MBC and its cardinal symptom is dyspnea; (2) respiratory insufficiency is measured by gas exchange and its cardinal sign is cyanosis (arterial blood gas measurements were not broadly available until the 1960s); (3) cardiovascular insufficiency is measured by the cardinal signs of congestive failure. Although their views and aspirations have not survived, their

10

Killian

writings remain refreshing to this day. They measured ventilation, ventilatory capacity, blood volume, cardiac output, and invasive hemodynamics and showed that blood flow is critical to sustain muscular activity and that reduction in cardiac output (shock) resulted in profound skeletal and cardiac muscle weakness. Much greater effort is required to drive both the respiratory and peripheral muscles when fatigued by reduced blood flow. Vital capacity as a measurement of ventilatory capacity, introduced in 1846 by John Hutchinson and the maximum voluntary ventilation introduced in the 1920s were not broadly adopted. Later, Robert Tiffeneau measured the forced vital capacity on inspiration and on expiration by recording the volume displaced over 1–5 sec. The measurement of the forced expired volume in 1 sec (FEV1) has survived and assumed major clinical importance. For reasons that remain obscure, the maximum rate at which the FEV1 could be inspired was considered twice as high as the expiratory flow rate. Dyspnea increased with ventilation and maximum breathing capacity (MBC) was approximated by 40
FEV1, a practice which implicitly survives to the present day. In the 1960s, it became clear that the effort required for maximal expiration was modest due to dynamic compression of the airways while inspiratory flow rate increased with inspiratory muscle effort. With technological advances, an MBC could be measured by a single maximal forced inspiration and expiration by placing the tidal volume within the flow-volume loop. In COPD, even though the problem is predominantly expiratory, patients complain of difficulty in inspiration because greater inspiratory effort is required due to the prolongation of expiration. Expiratory muscle effort is modest.

XIV. Dyspnea and Fatigue The ventilatory index (VE/MBC) was puzzling in that many patients with known ventilatory insufficiency stopped exercise when their ventilation was below capacity. Maximal breathing capacity declines over time due to inspiratory muscle fatigue. The MBC drops to an average of 70% after 4 min when measured relative to that achieved over the first 15 sec (48). An increase in motor command is required to sustain the same force over time as muscles fatigue. Hence, the intensity of dyspnea increases, even if the ventilation remains the same over time. Obviously, expressing ventilation during sustained exercise relative to MBC measured at rest failed to consider the effects of fatigue. With high intensity exercise, fatigue occurs as high energy phosphates (Creatine Phosphate and Adenosine Triphosphate) are depleted but recovers promptly with rest as energy stores are quickly restored. This is known as high frequency fatigue. With low intensity exercise, fatigue occurs with prolonged

History of Dyspnea

11

exercise. This is known as low frequency fatigue. The mechanisms contributing to low frequency fatigue are complex and will not be discussed. As muscles fatigue, the intensity of the central motor command must increase to sustain the same power output. Hence, by influencing the relationship between the intensity of motor command and the force generated, fatigue contributes to dyspnea. XV. Sensory Neurophysiology The responses of sensory receptors to physical stimuli, interpreted by the central nervous system, generate a complex of perceptual experiences. During breathing, chemoreceptor stimulation, the central motor command, the respiratory muscle forces, the displacement achieved in the lungs and chest wall, elastance, resistance, and work of breathing generate distinct sensations (2,4,5,49–54). Excessive effort generates dyspnea; excessive chemoreceptor stimulation generates breathlessness. With surprising precision, one can rate the magnitude of a tidal volume, flow rate, respiratory pressure, added resistance, and/or elastance. The respiratory muscle effort and the magnitude of ventilation required for common tasks such as walking and climbing stairs give rise to sensations of appropriateness. One seldom focuses on breathing until changes in the inter-relationships of effort, tension, length, and velocity give rise to conscious inappropriateness. In the early 1960s, Campbell and Howell forwarded the notion that inappropriateness was central to the recognition of dyspnea. The relationship between inspiratory muscle tension and a given displacement in terms of volume and flow rate is the mechanism through which added loads are detected (55,56). The conscious recognition of ‘‘inappropriateness’’ is pervasive across all sensory systems (57). Day after day, the central nervous system is inundated with afferent information from all internal and external sensory receptors. Conscious perception requires focus which is suppressed by sleep and enhanced by the state of alertness dependent on the reticular activating system. On the one hand, total airway obstruction may fail to arouse sleeping individuals (58). On the other hand, normal sensory information may be perceived as excessive in zealous people. Psychological factors have long been appreciated as factors influencing the perception of dyspnea. XVI. Psychophysics No historical account of dyspnea would be complete without addressing the role of psychophysics. The study of psychophysics examines the quantitative relationship between the input (stimulus conditions) and the output parameters (perceptual responses). The principle is that the linkage between

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Killian

stimulus and perception consists of: (1) the receptor activated by the stimulus; (2) the sensory nerves transmitting the stimulus to the central nervous system; (3) the processing of this afferent information in the central nervous system; (4) the interpretation in light of previous experience and learning; and (5) the generation of conscious sensation. Due to technical difficulties, the intervening unit processes cannot always be identified and/or measured. In psychophysics, as in any other area, measurement is obtained by matching one continuum to another under preset rules (nominal; ordinal; interval; ratio). Open magnitude scaling, a ratio scale, can be useful in defining the parameters of stimulation contributing to perceptual magnitude (59). One selects a number to represent the magnitude of the stimulus while maintaining proportionality in the perceptual domain e.g., if one stimulus is perceived to be twice as intense as another, the magnitude selected is twice as big. Open magnitude scaling makes no measurement of absolute sensory intensity that is transferable across individuals or across time in the same individual. For such comparisons, a category scale is commonly used. One rates the perceptual magnitude by selecting from a range of numbers, length of line, or simple verbal expressions (60–65). Although ratio relationships may not be preserved, a category scale has distinct advantages: (1) allows a crude but very useful estimate of absolute magnitude; (2) allows comparison across individuals; and (3) is easy to use in practice. Using the Borg scale (66–71), one matches an absolute sensory magnitude to quantitative semantics (slight, moderate, severe, etc). The numbers tagged to these descriptors have crude ratio properties relative to each other. A two-fold increase in the number implies a two-fold increase in sensory magnitude. Therefore, the Borg scale is an attempt to combine the properties of open magnitude scaling with the properties of absolute magnitude. To better understand dyspnea, the perceptual responses to the same stimuli are measured in all individuals using the Borg scale. Differences in perceptual responses have to be, in some way, attributed to the stimulus or its handling by the central nervous system. A standardized incremental exercise test provides a stimulus common to all individuals. The rating of dyspnea, at rest and throughout the incremental exercise to capacity, establishes the perceptual responses in health and various disorders. In normal individuals, the magnitude of dyspnea can be expressed as follows (72): Dyspnea ¼ 1:8 þ 0:005 PO þ 0:02 Age  0:03 Ht þ 0:72 Sex ðr ¼ 0:71Þ Dyspnea increases with power output (PO) (kpm/min), increases with age (yr); decreases as stature increases (cm); and dyspnea is more intense in females (2) than males (1). The effort required to generate power depends on how much muscle mass is available. More effort is required to drive weak muscles; muscle mass is lower in females, increases with height and declines with age. The effort required to breathe increases with the power

History of Dyspnea

13

required to generate ventilation. With lung disease, the effort required to drive ventilation is greater because of weak respiratory muscles. When dyspnea or any other symptom reaches intolerable intensity, exercise is terminated due to unwillingness to bear such discomfort. Normal individuals or patients most commonly cite discomfort associated with breathing and/or peripheral skeletal muscles as limiting symptoms (72). Dyspnea and leg effort increase with intensity and duration of exercise as follows: Dyspnea ¼ k %MPO2:41 Time0:47 Leg effort ¼ k %MPO2:13 Time0:39 Doubling the intensity results in a four- to five-fold increase in symptoms whereas doubling the duration results in only 30–40% increase in symptoms (73,74). Reducing the intensity and increasing the duration of activity are extremely effective in minimizing symptoms. Typically, one stops exercise when leg effort, dyspnea, or both exceed 7, ‘‘very severe,’’ on the Borg scale. Tolerance in health and disease varies from 4 ‘‘somewhat severe’’ to 10 ‘‘maximal’’ (95% confidence limits) (72). In both health and disease, ventilatory, circulatory, and neuromuscular factors may limit exercise. An FEV1 and DLCO, commonly used to quantify ventilatory and gas transfer capacity, collectively account for 50% of the variability in maximum power output in chronic obstructive pulmonary disease (COPD). This is expressed in the following multiple regression equation: MPO ð%predictedÞ ¼13:6 þ 0:57 FEV1 ð%predÞ þ 0:28 DLCO ð%predÞ ðr ¼ 0:71Þ What is not appreciated is that limitation imposed by these factors is expressed through symptoms. Pathophysiological effects of disease contribute to symptom intensity and the limiting symptom intensity is experienced at lower workloads (75). In essence, exercise is dependent on muscle fiber shortening, under the control of the central nervous system, in both the respiratory and peripheral skeletal muscles. The responsiveness of the alpha-motor neurons, to activation by the central motor neurons, can be facilitated and/or inhibited by afferent feedback from muscle spindles (facilitate), tendon organs (inhibit), small myelinated and unmyelinated intramuscular fibers (inhibit), and from antagonist muscle groups. The responsiveness of the muscle to activation by the alpha-motor neuron depends on intramuscular homeostasis. Membrane charge, the amount of calcium released, and the availability of high energy phosphates are some of the factors that determine the responsiveness of muscle. To continue activity, an ATP must be regenerated from creatine phosphate, from the oxidation of glycogen to lactate and from the oxidation of carbohydrate

14

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and fats to carbon dioxide and water. The latter requires the delivery of oxygen through central cardiorespiratory and peripheral cardiovascular adaptations. Failure in any of these processes leads to weakness and fatigue and is perceptually expressed through an increase in the sense of effort via the sensory system. Chemical, neural, metabolic, and/or mechanical stimuli continue to compete as the fundamental stimulus. However, rating dyspnea under controlled conditions allows us to study perceptual responses and provides greater understanding of the mechanisms in individual patients. The ultimate answer will arise when description gives way to measurement and calculation replaces debate. No natural phenomenon can be adequately studied in itself alone, but to be understood must be considered as it stands connected with all of nature. Sir Francis Bacon (1561–1626)

References 1. LeGallois CJJ. Experiments on the principle of life, and particularly on the principle of the notions of the heart, and on the seat of this principle. In: Nancrede NC, Nancrede JG, trans. Philadelphia: M. Thomas, 1813. (Excerpts in Comroe JH Jr, ed. Pulmonary and Respiratory Physiology. Part II. Stroudsbourg, Pennsylvania: Dowden, Hutchinson & Ross, 1976:12–16). 2. Donders FC. Contribution to the mechanism of respiration and circulation in health and disease. (Beitra¨ge zum Mechanismus der Respiration und Circulation im gesunden und kranken Zustande. Zeitschrift fu¨r rationelle Medizin 1853; 3:287–319.). In: West JB, ed. Translations in Respiratory Physiology. Stroudsburg, Pennsylvania: Dowden, Hutchinson & Ross, 1975:298–318. 3. Pflu¨ger E. On the causes of respiratory movement, and of dyspnea and apnea. ¨ ber die Ursache der Atembewegungen, sowie der Dyspnoe¨ und Apnoe¨. (U Pfu¨ger’s Arch Ges Physiol 1868; 1:61–106). In: West JB, ed. Translations in Respiratory Physiology. Stroudsburg, Pennsylvania: Dowden, Hutchinson & Ross, 1975:404–434. 4. Rohrer F. The physiology of respiratory movements. (Physiologie der Atembewegung Handbuch der normalen und pathologischen Physiologie, 1925; 2: 70–127.). In: West JB, ed. Translations in Respiratory Physiology. Stroudsburg, Pennsylvania: Dowden, Hutchinson & Ross, 1975:93–170. 5. Rohrer F. The correlation of respiratory forces and their dependence upon the state of expansion of the respiratory organs. (Der Zusammenhang der Atemkra¨fte und ihre Abha¨ngigkeit vom Dehnungszustand der Atmungsorgane. Pflu¨gers Arch Ges Physiol 1916; 165:419–444.). In: West JB, ed. Translations in Respiratory Physiology. Stroudsburg, Pennsylvania: Dowden, Hutchinson & Ross, 1975:67–88. 6. Miescher-Ru¨sch F. Bemerkungen zur Lehre von den Atembewegungen. Arch Anat u Physiol 1885; 6:355–380.

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7. Haldane JS, Smith JL. Carbon dioxide and regulation of breathing. J Pathol Bact 1893; 1:168,318. 8. Winterstein H. The regulation of breathing by the blood (Die Regulierung der Atmung durch das Blut Pfu¨ger’s Arch Ges Physiol 1911; 138:167–184.). In: West JB, ed. Translations in Respiratory Physiology. Stroudsburg, Pennsylvania: Dowden, Hutchinson & Ross, 1975:529–542. 9. Winterstein H. The reaction theory of respiratory regulation (Die Reaktionstheorie der Atmungsregulation. Pflu¨gers Arch Ges Physiol 1921; 187:293–298.). In: West JB, ed. Translations in Respiratory Physiology. Stroudsburg, Pennsylvania: Dowden, Hutchinson & Ross, 1975:543–548. 10. Sherrington CS. The muscular sense. In: Shafer SA, ed. Textbook of Physiology. Vol. 2. Edingburgh: TJ Pentland, 1900:1002–1025. 11. Roland PE, Ladegaard-Pederson H. A quantitative analysis of sensations of tension and kinaesthesia in man. Evidence for a peripherally originating muscle and for a sense of effort. Brain 1977; 100:671–692. 12. Cafarelli E, Bigland-Ritchie B. Sensation of static force in muscles of different length. Exp Neurol 1979; 65:511–525. 13. Cafarelli E. Peripheral contributions to the perception of effort. Med Sci Sports Exerc 1982; 14:382–389. 14. Campbell EJM, Gandevia SC, Killian KJ, Mahutte CK, Rigg JRA. Changes in perception of inspiratory resistive loads during partial curarization. J Physiol 1980; 319:93–100. 15. Gandevia SC. The perception of motor commands or effort during muscular paralysis. Brain 1982; 105:151–195. 16. Gandevia SC, Killian KJ, Campbell EJM. The effect of respiratory muscle fatigue on respiratory sensations. Clin Sci 1981; 60:463–466. 17. Gandevia SC, McCloskey DI. Changes in motor commands, as shown by changes in perceived heaviness, during partial curarization and peripheral muscle anaesthesia in man. J Physiol (London) 1977; 272:673–689. 18. Gandevia SC, McCloskey DI. Sensations of heaviness. Brain 1977; 100: 345–354. 19. McCloskey DI. Kinesthetic sensibility. Physiol Rev 1978; 58:763–820. 20. Matthews PBC. Where does Sherrington’s ‘‘muscular sense’’ originate? Muscles, joints, corollary discharges? Ann Rev Neurosci 1982; 5:189–218 21. Gandevia SC, McCloskey DI. Interpretation of perceived motor commands by reference to afferent signals. J Physiol 1978; 283:493–499. 22. Gandevia SC, McCloskey DI. Joint sense, muscle sense, and their combination as position sense, measured at the distal interphalangeal joint of the middle finger. J Appl Physiol 1976; 260:387–407. 23. McCloskey DI, Ebeling P, Goodwin GM. Estimation of weights and tensions and apparent involvement of a ‘‘sense of effort’’. Exp Neurol 1974; 42:220–232. 24. Matthews PBC. Evolving views on the internal operation and functional role of the muscle spindle. J Physiol 1981; 320:1–30. 25. Burgess PR, Wei JY, Clark FJ, Simon J. Signaling of kinesthetic information by peripheral sensory receptors. Ann Rev Neurosci 1982; 5:171–187. 26. Matthews PBC, Simmonds A. Sensations of finger movement elicited by pulling upon flexor tendons in man. J Physiol (London) 1974; 239:27–28.

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27. Coleridge HM, Coleridge JCG. Reflexes evoked from tracheobronchial tree and lungs. In: Geiger SR, Widdicombe JG, Cherniack NS, Fishman AP, eds. The Handbook of Physiology. Section 3: The Respiratory System. Bethesda, Maryland: American Physiological Society, 1986:395–429. 28. Salamon M, Von Euler C, Franzen O. Perception of mechanical factors in breathing. Abstract presented at the National Symposium on ‘‘Physical Work and Effort’’, Wenner-Gren Centre, Stockholm, 1975. 29. Stubbing DG, Killian KJ, Campbell EJM. The quantification of respiratory sensations by normal subjects. Resp Physiol 1981; 44:251–260. 30. Wolkove N, Altose MD, Kelsen SG, Kondapalli PG, Cherniack NS. Perception of lung volume and Weber’s Law. J Appl Physiol Respir Environ Exerc Physiol 1982; 52:1679–1680. 31. Katz-Salamon M. Perception of mechanical factors in breathing. In: Borg G, ed. Physical Work and Effort (Wenner Gren Vol 28). Oxford: Pergamon Press, 1976:101–113. 32. Halttunen PK. The voluntary control in human breathing. Acta Physiol Scand 1974; 419(suppl):1–47. 33. West DWM, Ellis CG, Campbell EJM. Ability of man to detect increases in his breathing. J Appl Physiol 1975; 39:372–376. 34. Breuer J, Hering E. Self-steering of respiration through the nervous vagus. In: Comroe JH Jr, ed. Pulmonary and Respiratory Physiology. Part II. Stroudsburg, Pennsylvania: Dowden, Hutchinson & Ross, 1976:108–113. 35. Christie RV. Dyspnea. Q J Med 1938; 7:421–454. 36. Meakins JM. The cause and treatment of dyspnea in cardiovascular disease. Br Med J 1923; 1:1043–1055. 37. McIlroy MB. Dyspnea and the work of breathing in diseases of the heart and lungs. Prof Cardiovasc Dis 1958; 1:284–297. 38. Harrison TR. Shortness of breath. In: Beeson PB, Thorn GW, Resnik WH, Wintrobe MM, eds. Principles of Internal Medicine. Philadelphia: Blakiston, 1950:111–119. 39. Liljestrand G. Studies of the work of breathing. (Untersuchungen u¨ber die Atmungsarbeit. Skandinavisches Archiv fu¨r Physiologie (Leipzig) 1918; 35:199–293.). In: West JB, ed. Translations in Respiratory Physiology. Stroudsburg, Pennsylvania: Dowden, Hutchinson & Ross, 1975:438–513. 40. Bartlett RG, Brubach HF, Specht H. Oxygen cost of breathing. J Appl Physiol 1958; 12:413–424. 41. Campbell EJM, Westlake EK, Cherniack RM. The oxygen consumption and efficiency of the respiratory muscles of young male subjects. Clin Sci 1959; 18:55–64. 42. Cournand A, Richards DW, Bader RE, Bader ME, Fishman AP. The oxygen cost of breathing. Trans Ass Am Physiol 1954; 67:162–173. 43. Fritts HW, Filler J, Fishman AP, Cournand A. The efficiency of ventilation during voluntary hyperpnea: studies in normal subjects and in dyspneic patients with either chronic pulmonary emphysema or obesity. J Clin Invest 1959; 38:1339–1348. 44. Means JH. Dyspnea. In: Medicine Monograph. Vol. 5. Baltimore: Williams & Wilkins, 1924.

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45. Cournand A, Richards DW. Pulmonary insufficiency, Part I: Discussion of a physiological classification and presentation of clinical tests. Am Rev Tuberc 1941; 44:26–41. 46. Cournand A, Richards DW. Pulmonary insufficiency, Part II: the effects of various types of collapse therapy upon cardiopulmonary function. Am Rev Tuberc 1941; 44:123–172. 47. Cournand A, Richards DW. Pulmonary insufficiency, Part III: cases demonstrating advanced cardiopulmonary insufficiency following artificial pneumothorax and thoracoplasty. Am Rev Tuberc 1941; 44:272–287. 48. Freedman S. Sustained maximum voluntary ventilation. Respir Physiol 1970; 8:230–244. 49. Wirz K. Changes in the pleural pressure during respiration, and causes of its variability (Das Verhalten des Druckes im Pleuraraum bei der Atmung und die Ursachen seiner Vera¨nderlichkeit. Pflu¨gers Arch Ges Physiol 1923; 199:1–56). In: West JB, ed. Translations in Respiratory Physiology. Stroudsburg, Pennsylvania: Dowden, Hutchinson & Ross, 1975:174–226. 50. Von Neergard K, Wirz K. Method for measuring lung elasticity in living human ¨ ber eine Methode zur Messung der subjects, especially in emphysema (U Lungenelastizita¨t am lebenden Menschen, insbesondere beim Emphysem. Zeitschrift fur klinische Medizin 1927; 105:35–50). In: West JB, ed. Translations in Respiratory Physiology. Stroudsburg, Penn Sylvania: Dowden, Hutchinson & Ross, 1975:227–269. 51. Otis AB, Fenn WO, Rahn H. Mechanics of breathing in man. J Appl Physiol 1950; 2:592–607. 52. Otis AB. The work of breathing. In: Fenn WO, Rahn H, eds. Handbook of Physiology: The Respiratory System. Vol. 1. Part 3. Bethesda, MD: American Physiological Society, 1964:463–476. 53. Marshall R, McIlroy MB, Christie RV. The work of breathing in mitral stenosis. Clin Sci 1954; 13:137–146. 54. Marshall R, Stone RW, Christie RV. Relationship of dyspnea to respiratory effort in normal subjects, mitral mitosis and emphysema. Clin Sci 1954; 13:625–631. 55. Bennett ED, Jayson MIV, Rubenstein D, Campbell EJM. The ability of man to detect added non-elastic loads to breathing. Clin Sci 1962; 23:155–162. 56. Campbell EJM, Freedman S, Smith PS, Taylor ME. The ability of man to detect added elastic loads to breathing. Clin Sci 1961; 20:223–231. 57. Campbell EJM, Howell JBL. The sensation of breathlessness. Br Med Bull 1963; 19:36–40. 58. McNicholas WT, Bowes G, Zamel N, Phillipson EA. Impaired detection of added inspiratory resistance in patients with obstructive sleep apnea. Am Rev Respir Dis 1984; 129:45–48. 59. Marks LE. Sensory Processes: The New Psychophysics. New York: Academic Press, 1974. 60. Stevens SS. Psychophysics: Introduction to Its Perceptual, Neural, and Social Prospects. New York: John Wiley & Sons, 1975. 61. Stevens SS. Issues in psychophysical measurement. Psychol Rev 1971; 78: 426–450.

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62. Stevens SS. To honor Fechner and repeal his law. Science 1961; 133:80–86. 63. Stevens SS. Ratio scales, partition scales and confusion scales. In: Gulliksen H, Messick S, eds. Psychological Scaling: Theory and Applications. New York: John Wiley & Sons, 1960:49–66. 64. Stevens SS. Problems and methods of psychophysics. Psychol Bull 1958; 55:177–196. 65. Stevens SS. The surprising simplicity of sensory metrics. Am Psychol 1962; 17:29. 66. Borg GAV. A category scale with ratio properties and interindividual comparisons. In: Geissler HG, Petzold P, eds. Psychological Judgment and the Process of Perception. Amsterdam: North Holland Publishing, 1980:25–34. 67. Borg GAV. Interindividual scaling and perception of muscular force. K Fysiogr Sallsk Lund Forh 1961; 12:117–125. 68. Borg GAV. On quantitative semantics in connection with psychophysics. Educational and Psychological Research Bulletin, University of Umea, 1964; 3. 69. Borg GAV, Hosman J. The metric properties of adverbs. Institute of Applied Psychology Report, University of Stockholm, 1970; 7. 70. Borg GAV. A ratio scaling method for interindividual comparisons. Institute of Applied Psychology Report, University of Stockholm, 1972; 27. 71. Borg GAV, Lindblad I. The determination of subjective intensities in verbal descriptions of symptoms. Institute of Applied Psychology Report, University of Stockholm, 1976; 75. 72. Killian KJ, Summers E, Jones NL, Campbell EJM. Dyspnea and leg effort during incremental cycle ergometry. Am Rev Respir Dis 1992; 145:1339–1345. 73. Kearon MC, Summers E, Jones NL, Campbell EJM, Killian KJ. Breathing during prolonged exercise in man. J Physiol 1991; 442:477–487. 74. Kearon MC, Summers E, Jones NL, Campbell EJM, Killian KJ. Effort and dyspnea during work of varying intensity and duration. Eur Respir J 1991; 4:917–925. 75. Jones NL, Killian KJ. Limitation of exercise in chronic airflow obstruction. In: Cherniack NS, ed. Chronic Obstructive Pulmonary Disease. Philadelphia: WB Saunders, 1991:196–206.

2 Dyspnea in the Elderly

DONALD A. MAHLER

JOHN C. BAIRD

Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School, Hanover, New Hampshire, U.S.A.

Psychological Applications, Waterbury, Vermont and Dartmouth Medical School, Hanover, New Hampshire, U.S.A.

I. Introduction Exertional dyspnea is a frequent complaint that is commonly associated with a cardiac or respiratory disease, but may also be due to obesity and deconditioning. As the prevalence of these conditions increases with advancing age, dyspnea is an important cause of morbidity in the elderly (1). In an attempt to minimize or to avoid the unpleasant experience of breathing difficulty, many older individuals reduce or even stop certain physical activities (e.g., walking to the store; climbing stairs; doing yard or house work). This ‘‘adaptation’’ contributes to the downward spiral of deconditioning and eventually leads to more breathlessness. Studies of patients with chronic respiratory disease, many of whom are elderly, have demonstrated the major impact that dyspnea exerts on a person’s quality of life (2,3). In Chapter 11, Jones describes the important inter-relationship between dyspnea and health status.

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Mahler and Baird II. Prevalence of Dyspnea in the Elderly

The reported prevalence of dyspnea in different populations depends not only on the definitions used in questionnaires for patients to report dsypnea, but also on the differences in smoking status, general activity level, occupational history, geographical location, and possible exposure to environmental pollutants. In populations less than 65 years of age, the prevalence of dyspnea ranges from 10% to 18% (4–9). However, the reported prevalence clearly depends on the physical stimulus, or activity, which provokes the symptom. For example, Dow et al. (10) found that 21% of subjects
65 years of age experienced breathlessness ‘‘at rest during the day at any time in the past 12 months.’’ However, it appears that a more realistic estimate is that over 30% of elderly subjects (i.e.,
65 years of age) report breathlessness with various activities of daily living, including walking on a level surface or up an incline (11–15) (Table 1). The prevalence that up to one-third of communitydwelling older people report breathlessness with exertion is quite consistent in different countries such as France, the United Kingdom, and the United States (13–15). Moreover, studies in various countries have demonstrated that the complaint of breathlessness is more frequent in women than in men (8,9,13,16,17).

III. Aging and Lung Function The three phases of pulmonary function over an individual’s lifetime are growth, maturation, and decline. During the first 12 years of life, the lung grows progressively. Maturation then occurs until maximal function of the respiratory system is attained at approximately age 20 for women and at 25 for men. Throughout the remainder of adult life, the aging process causes a gradual deterioration in lung function. Three major factors contribute to the physiological changes in lung function (1,18,19):  decrease in lung elasticity;  increase in stiffness of the chest wall;  decrease in respiratory muscle strength. These structural alterations lead to changes in respiratory function with aging which are summarized in Table 2. The decrease in forced expiratory volume in one second (FEV1) may not be truly linear; there is an initial low rate of decline in FEV1 which accelerates with advancing years. Cigarette smoking accelerates the age-related decline in lung function. Aging of the lung also contributes to a decrease in the diffusing capacity for carbon

Dyspnea in the Elderly

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Table 1 Prevalence of Breathlessness in the Elderly

Author (year) a

Renwick (1999)


45

508

Boezen (1998) Dow (1991)

> 55
65

210 2,161

Horsley (1991)


65

1,803

Tessier (2001)


65

2,762

> 70 70–79

1,404 2,485

b a

a

c

d e

Number of subjects Prevalence Definitions of (%) breathlessness Age (years) surveyed

Ho (2001) Waterer (2001)

17

‘‘When walking on level surface/ walking in the house/sitting at rest’’ 24 ‘‘At rest’’ 21 ‘‘At rest during the day at any time in the past 12 months’’ 38 ‘‘When hurrying on the level ground or a slight hill’’ 21 men ‘‘Walking on flat surface 27 women at normal pace’’ 32 MRC grade 3þ 31 ‘‘Shortness of breath when hurrying on level surface, walking up a hill, or need to stop walking at own pace on level surface’’

a

Population survey from postal questionnaire using random sampling. Random sample of subjects who performed a physical fitness test. c Cohort study of general electoral list in Gironde area of France. d Random sample of people aged over 70 living at home in Wales. e Cohort study of well-functioning subjects contacted by mailed brochure and then telephoned in Memphis, Tennessee, and Pittsburg, PA, U.S.A. MRC ¼ Medical Research Council dyspnea scale. b

Table 2 Changes in Lung Function with Aging Increased

No change

Decreased

Functional residual capacity Residual volume Alveolararterial oxygen difference

Total lung capacity

Forced vital capacity Expiratory flow rates Diffusing capacity Arterial oxygen pressure Respiratory muscle strength

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Mahler and Baird

monoxide which results from a loss of lung tissue and alveolar-capillary surface area. Furthermore, there is a predictable reduction in arterial oxygen tension (PaO2) with aging which can be represented by the following equation (18): PaO2 ðmmHgÞ ¼ 100:1  0:325  ageðyearsÞ Aging, however, does not influence arterial pH or arterial carbon dioxide tension (PaCO2) values. Finally, the aging process produces morphologic and biochemical changes in skeletal muscles including the muscles of respiration. Both inspiratory (PImax) and expiratory (PEmax) mouth pressures remain relatively stable until 55 years of age, but then begin to decline (20). In several studies, respiratory muscle strength has been shown to correlate significantly with the severity of dyspnea (16,21,22). In addition, a reduction in respiratory muscle strength may not only contribute to breathlessness, but may also limit the ability of elderly individuals to inspire fully and to expectorate mucus in the airway (23).

IV. Respiratory Sensation and Aging A. Added Respiratory Loads

Sensory psychophysics examines the ability of individuals to detect changes in the intensity of a stimulus and to judge the magnitude of these changes (24). The technique of magnitude estimation, as reflected by the calculated exponent of the stimulus (e.g., an added respiratory load)—response (rating of breathlessness) relationship using Stevens’ Law (25), has been used primarily to investigate respiratory sensation in people of different ages. However, this psychophysical parameter is not synonymous with breathing difficulty as experienced by patients with respiratory disease during activities of daily living (26,27). Nevertheless, psychophysical testing has been used to consider the effects of aging on the sensations and evoked responses to added respiratory loads in the laboratory. In cross-sectional studies Tack et al. (28,29) demonstrate that the calculated exponent (the slope of the log–log plot of the added load and the subject’s rating of breathlessness) was significantly lower in the older healthy subjects compared to young healthy subjects. This observation applied both to elastic and resistive loads (28,29). By combining data from different studies using magnitude scaling for added resistive loads Manning et al. (1) reported decreased sensitivity to added resistive loads with advancing age in normal subjects and in patients with obstructive airway disease.

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B. Chemical Stimuli

With aging, there is a diminution in the ventilatory response to both hypoxia and hypercapnia at rest (30,31). Although ventilation is actually lower, Akiyama et al. (32) found that the dyspnea response to hypercapnia (arterial carbon dioxide levels of 45, 50, and 55 mmHg) was generally higher for an older group of healthy subjects (69  1 years) compared to a younger group (29  3 years). This occurred with or without inspiratory flowresistive loading of 17 cm H2O/LI/sec.

V. Dyspnea During Exercise and the Aging There is very little published information about the effects of aging on the intensity of breathlessness during exertion. In the cardiopulmonary exercise laboratory, we compared ratings of dyspnea during cycle ergometry in 28 healthy young subjects (age, 19  1 years; 14 females, 14 male) (33) and in 24 healthy elderly individuals (age, 66  10 years; 11 females, 13 males) (34). While pedaling on the cycle ergometer, subjects could move the position of a computer mouse (located on a platform attached to the handlebars) in order to adjust a vertical bar visible on monitor and adjacent to the 0–10 category-ratio (Borg) scale to indicate ‘‘a change in breathlessness’’ (33,34). We observed that the slope of power (W)–dyspnea ratings was higher for the older subjects compared to the younger subjects, whereas the intercept on the x-axis was similar between the two groups (Fig. 1). Although the numbers of subjects based on gender were small, the steeper slope for older subjects was evident in both women (Fig. 2A) and in men (Fig. 2B). Older subjects exhibit increased ventilation during exercise. For example, Briscetto et al. (35) have shown that the slope of the ventilatory response relative to carbon dioxide production (D VE/D VCO2) during exercise was substantially higher in elderly subjects (~ 30) compared with young subjects (~ 25). In a cross-sectional study of 474 healthy adults, Sun et al. (36) reported that the VE/VCO2 ratio during exercise increased with age based on the regression equation: V E =V CO2 ¼ 27:94 þ 0:108  age ðyearsÞ þ ð0:97 females; 0:0 malesÞ  0:0376  height ðcmÞ This increased ventilatory demand coupled with diminished ventilatory capacity (i.e., reduced respiratory muscle strength that occurs with advancing age) likely contribute to the relatively higher prevalence of dyspnea in the elderly (Table 1).

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Figure 1 Breathlessness ratings during incremental exercise on the cycle ergometer as a function of power production (W) in 28 healthy young subjects (age, 19  1 years; 14 females, 14 males) and in 24 healthy older subjects (age, 66  10 years; 11 females, 13 males). The functions represent the average parameters of the bestfitting linear regression for individual subjects. Source: Data from young subjects were taken from Ref. 33; and for old subjects from Ref. 34.

VI. Summary Elderly subjects exhibit reduced sensory psychophysics to various sensations including sight, sound, taste, and pain compared to younger adults. Therefore, it is likely that the reduced respiratory sensation (i.e., magnitude estimation of added respiratory loads) observed in older individuals reflects the aging process. Yet, epidemiology studies indicate that approximately one-third of healthy elderly individuals report breathlessness with daily activities when queried about this symptom (see Table 1). Although there are no longitudinal studies that have directly assessed the effect of aging on dyspnea, crosssectional comparisons reveal that older subjects report higher ratings of breathlessness for equivalent power produced during cycle ergometry (Figs. 1 and 2). Moreover, Johnson et al. (37) reported that healthy older subjects rated breathlessness greater than general fatigue during exertion, whereas healthy young people rated fatigue greater than breathlessness. These collective findings are

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Figure 2 Breathlessness ratings during incremental exercise on the cycle ergometer as a function of power (W) in young (n ¼ 14) and old (n ¼ 11) females (A), and in young (n ¼ 14) and old (n ¼ 13) males (B). These subjects are subgroups of the data displayed in Figure 1. The slopes of power–dyspnea are higher for older subjects compared with younger subjects regardless of gender.

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likely due to the higher level of ventilation observed in older individuals during exercise. However, it is unclear whether the higher ventilatory demand is a direct result of the aging process, or more a consequence of sedentary lifestyle, deconditioning, and/or weight gain, which typically occur with advancing age in those who reside in developed countries. However, ventilatory demand can be modulated with exercise training. Studies have shown that ventilation during exercise diminishes when elderly subjects participate in a physical training program (38,39). Thus, it is likely, although unproven, that breathlessness will be reduced as well in healthy elderly people who do exercise training. These changes would be similar to those observed in older patients with COPD who report decreased breathlessness and achieve enhanced exercise endurance after completion of a comprehensive pulmonary rehabilitation program (see Chapter 13 by ZuWallack et al.).

Acknowledgment Supported by the National Institutes of Health, Small Business Innovative Grant No.1 R43 HL68493–02 (Dr. Baird). References 1. Manning HL, Mahler DA, Harver A. Dyspnea in the elderly. In: Mahler DA, ed. Pulmonary Disease in the Elderly Patient. (Lung Biology in Health and Disease, Vol 63). New York: Marcel Dekker, 1993:81–112. 2. Jones PW. Quality of life measurement for patients with diseases of the airways. Thorax 1991; 46:676–682. 3. Mahler DA, Jones PW. Measurement of health status in advance respiratory diseases. In: Maurer JR, ed. Non-neoplastic Advanced Lung Disease. New York: Marcel Dekker, 2003:685–709. 4. Rijken B, Schouten JP, Weiss ST, Speizer FE, van der Lende R. The relationship of nonspecific bronchial responsiveness to respiratory symptoms in a random population sample. Am Rev Respir Dis 1987; 136:62–68. 5. Samet JM, Schrag SD, Howard CA, Key CR, Pathak DR. Respiratory disease in a New Mexico population of Hispanic and non-Hispanic whites. Am Rev Respir Dis 1982; 125:152–157. 6. Viegi G, Paoletti P, Carrozzi L. Prevalence rates of respiratory symptoms in Italian general population samples exposed to different levels of air pollution. Environ Health Perspect 1991; 94:95–99. 7. Woolcock AJ, Peat JK, Salome CM, Yan K, Anderson SD, Schoeffel RE, McCowage G, Killalea T. Prevalence of bronchial hyper-responsiveness and asthma in a rural adult population. Thorax 1987; 42:361–368.

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8. Lebowitz MD, Knudson RJ, Burrows B. Tucson epidemiologic study of obstructive lung diseases. I: Methodology and prevalence of disease. Am J Epidemiol 1975; 102:137–152. 9. Boezen HM, Rijcken B, Schouten JP, Postma DS. Breathlessness in elderly individuals is related to low lung function and reversibility of airway obstruction. Eur Respir J 1998; 12:805–810. 10. Dow L, Coggon D, Osmond C, Holgate ST. A population survey of respiratory symptoms in the elderly. Eur Respir J 1991; 4:267–272. 11. Renwick DS, Connolly MJ. Do respiratory symptoms predict chronic airflow obstruction and bronchial hyperresponsiveness in older adults? Gerontol 1999; 54A:M136–M139. 12. Horsley JR, Sterling IJN, Waters, Howell JBL. Respiratory symptoms among elderly people in the New Forest area as assessed by postal questionnaire. Age Ageing 1991; 20:325–331. 13. Tessier JF, Nejjari C, Letenneur L, Filleul L, Marty ML, Barberger Gateau P, Dartigues JF. Dyspnea and 8-year mortality among elderly men and women: the PAQUID cohort study. Eur J Epidemiol 2001; 17:223–229. 14. Waterer GW, Wan JY, Kritchevsky SB, Wunderink RG, Satterfield S, Bauer DC, Newman AB, Taaffe DR, Jensen RL, Crapo RO. Airflow limitation is underrecognized in well-functioning older people. J Am Geriatr Soc 2001; 49:1032–1038. 15. Ho SF, O’Mahoney MS, Steward JA, Breay P, Buchalter M, Burr ML. Dyspnoea and quality of life in older people at home. Age Ageing 2001; 30:155–159. 16. Foglio K, Carone M, Pagani M, Bianchi L, Jones PW, Ambrosino N. Physiological and symptom determinants of exercise performance in patients with chronic airway obstruction. Respir Med 2000; 94:256–263. 17. Yamada K, Kida K, Takasaki Y, Kudoh S. A clinical study of the usefulness of assessing dyspnea in healthy elderly subjects. J Nippon Med Sch 2001; 68: 246–252. 18. Knudson RJ. How aging affects the normal adult lung. J Respir Dis 1981; 2: 74–84. 19. Mahler DA, Rosiello RA, Loke J. The aging lung. Clin Geriatric Med 1986; 2(2):215–225. 20. Black LF, Hyatt RE. Maximal inspiratory pressures: normal values and relationship to age and sex. Am Rev Respir Dis 1969; 99:696–702. 21. Mahler DA, Wells CK. Evaluation of clinical methods for rating dsypnea. Chest 1988; 93:580–586. 22. Killian KJ, Jones NL. Respiratory muscles and dyspnea. Clin Chest Med 1988; 9:237–248. 23. Mahler DA, Fierro-Carrion G, Baird JC. Evaluation of dyspnea in the elderly. Clin Geriatr Med 2003; 19:19–33. 24. Baird JC, Noma E. Fundamentals of Scaling and Psychophysics. New York: John Wiley & Sons, 1978. 25. Stevens SS. Psychophysics. New York: John Wiley & Sons, 1975:1–62. 26. Mahler DA, Rosiello RA, Harver A, Lentine T, McGovern JF, Daubenspeck JA. Comparison of clinical dyspnea ratings and psychophysical measurements

28

27.

28. 29. 30.

31.

32.

33.

34.

35.

36.

37. 38.

39.

Mahler and Baird of respiratory sensation in obstructive airway disease. Am Rev Respir Dis 1987; 135:1229–1233. Mahler DA, Harver A, Rosiello RA, Daubenspeck JA. Measurement of respiratory sensation in interstitial lung disease: evaluation of clinical dyspnea ratings and magnitude estimation. Chest 1989; 96:767–771. Tack M, Altose MD, Cherniack NS. Effects of aging on respiratory sensations produced by elastic loads. J Appl Physiol 1981; 50:844–850. Tack M, Altose MD, Cherniack NS. Effects of aging on perception of resistive ventilatory loads. Am Rev Respir Dis 1982; 126:463–467. Kronenberg RS, Drage CW. Attentuation of the ventilatory and heart rate responses to hypoxia and hypercapnia with aging in normal men. J Clin Invest 1973; 52:1812–1819. Peterson DD, Pack AI, Silage DA, Fishman AP. Effects of aging on ventilatory and occlusion pressure responses to hypoxia and hypercapnia. Am Rev Respir Dis 1981; 124:387–391. Akiyama Y, Nishimura M, Kobayashi S, Yamamoto M, Miyamoto K, Kawakami Y. Effects of aging on respiratory load compensation and dyspnea sensation. Am Rev Respir Dis 1993; 148:1586–1591. Mahler DA, Mejia-Alfaro R, Ward J, Baird JC. Continuous measurement of breathlessness during exercise: validity, reliability, and responsiveness. J Appl Physiol 2001; 90:2188–2196. Fierro-Carrion G, Mahler DA, Ward J, Baird JC. Comparison of continuous and discrete measurements of dyspnea during exercise in patients with COPD and normals. Chest 2004; 125:77–84. Brischetto MJ, Millman RP, Peterson DD, Silage DA, Pack AI. Effect of aging on ventilatory response to exercise and CO2. J Appl Physiol 1984; 56: 1143–1150. Sun XG, Hansen JE, Garatachea N, Storer TW, Wasserman K. Ventilatory efficiency during exercise in healthy subjects. Am J Respir Crit Care Med 2002; 166:1443–1448. Johnson BD, Badr MS, Dempsey JA. Impact of the aging pulmonary system on the response to exercise. Clin Chest Med 1994; 15:229–246. Tzankoff SP, Robinson S, Pyke FS, Brawn CA. Physiological adjustments to work in older men as affected by physical training. J Appl Physiol 1972; 33:346–350. Yerg JE, Seals DR, Hagberg JM, Holloszy JO. Effect of endurance exercise training on ventilatory function in older individuals. J Appl Physiol 1985; 58:791–794.

3 Mechanisms of Dyspnea in COPD

DENIS E. O’DONNELL

KATHERINE A. WEBB

Division of Respiratory and Critical Care Medicine, Department of Medicine, Queen’s University, Kingston, Ontario, Canada

Respiratory Investigation Unit, Department of Medicine, Queen’s University, Kingston, Ontario, Canada

Dyspnea, the perception of breathing discomfort, is the most common symptom in patients with chronic obstructive pulmonary disease (COPD) and often progresses inexorably as the disease advances. The precise neurophysiological underpinnings of dyspnea are not completely understood, but our knowledge of the ‘‘pathophysiology of dyspnea’’ has increased considerably in recent years. Thus, the direct application of the scientific principles of psychophysics to the study of dyspnea in the clinical domain has increased our understanding of its source and mechanisms. The emergence of validated scales that measure dyspnea, during its provocation by exercise or external loading, has been an important advance. The use of stepwise multiple regression analysis, with dyspnea ratings (at a standardized stimulus) as the dependent variable vs. a number of relevant physiological parameters, has allowed us to identify consistent contributory factors. The strength of these associations has subsequently been tested by specific therapeutic manipulation. In fact, the study of mechanisms of dyspnea relief following a number of diverse therapeutic interventions (i.e., bronchodilators, oxygen therapy, etc.) has provided important new insights into causation. 29

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In this review we will first briefly consider the pathophysiology of COPD during rest and exercise, since this is necessary to understand the origin of the symptom. We will then examine the relationship between the intensity and quality of exertional dyspnea and the well-described derangements of ventilatory mechanics and gas exchange in COPD. Finally, we will speculate on possible underlying neurophysiological mechanisms.

I. Pathophysiology of COPD COPD is characterized by complex and diverse pathophysiological and clinical manifestations. Persistent inflammation of the small and large airways, with destruction of the lung parenchyma and its vasculature, occurs in highly variable combinations that differ from patient to patient. Expiratory flow limitation (EFL) is the pathophysiological hallmark of COPD (1,2). This arises because of intrinsic airway factors that increase resistance (i.e., mucosal inflammation/edema, airway remodeling and secretions) and extrinsic airway factors (i.e., reduced airway tethering from emphysema and regional extra-luminal compression by adjacent overinflated alveolar units) (1,2) (Fig. 1). Emphysematous destruction, particularly in patients with diffuse panacinar emphysema, also reduces elastic lung recoil and, thus, the driving pressure for expiratory flow, further compounding flow limitation. EFL with dynamic collapse of the airways compromises the ability of patients to expel air during both forced and quiet expiration (2–4). Therefore, during tidal expiration many alveolar units with slow time constants continue to empty even after the onset of neural inspiration. A. Exercise

Reduced lung recoil in emphysema alters the balance of forces between the lung and chest wall such that the relaxation volume at end-expiration is higher than in health (1) (Fig. 2). Moreover, in flow-limited patients with COPD, end-expiratory lung volume (EELV) is a continuous dynamic variable that varies with the prevailing ventilatory demand. In flow-limited COPD, inspiration usually begins before tidal expiration is complete. Since the time constant for emptying of the respiratory system is substantially delayed and the time available for tidal expiration is insufficiently long, alveolar air retention at end-expiration becomes inevitable (5). When breathing rate acutely increases (and expiratory time diminishes) above baseline values, or when tidal volume increases for a given expiratory time during exercise or hyperventilation, there is further ‘‘dynamic’’ lung hyperinflation (DH) as a result of air trapping (Figs. 1 and 3). This phenomenon, as we will see, has serious mechanical and sensory consequences (6–13).

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Figure 1 Schematic representations of alveolar units in health and in COPD. In COPD, EFL occurs because of the combined effects of increased airway resistance and reduced lung recoil: alveolar emptying is therefore critically dependent on expiratory time which if insufficiently long results in lung over-inflation (reduction in IC). The presence of EFL is suggested in COPD by the encroachment of tidal expiratory flows on the forced maximal expiratory flow envelope over the tidal operating lung volume range. In contrast to health, hyperinflation occurs in COPD during exercise as indicated by the shift in EELV to the left (i.e., reduced IC). Abbreviations: PL ¼ lung recoil pressure; V’ ¼ flow; V’max ¼ maximal expiratory flow; IC ¼ inspiratory capacity.

The respiratory system adjusts to lung overinflation over many years: the rib cage reconfigures to accommodate large over-distended lungs and there is temporal adaptation of the ventilatory muscles, particularly the diaphragm, to maintain an adequate pressure-generating capacity at rest, despite the mechanical disadvantage (14–16). Such adaptations, however, are quickly overwhelmed as a result of the effects of acute-on-chronic hyperinflation when ventilatory demand suddenly increases during exercise. Thus, tidal volume encroaches further on the upper alinear extreme of the respiratory system’s sigmoidal pressure–volume relationship where elastic work is greatly increased (Fig. 2). As a result of DH, the inspiratory muscles must first counterbalance the inward (expiratory-directed) combined recoil

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Figure 2 Pressure–volume (P–V) relationships of the total respiratory system in health and in COPD. Tidal pressure–volume curves during rest (filled area) and exercise (open area) are shown. Note that in COPD, because of resting and dynamic hyperinflation (a further decreased IC), exercise tidal volume (VT) encroaches on the upper, alinear extreme of the respiratory system’s P–V curve where there is increased elastic loading. In COPD the ability to further expand VT is reduced, i.e., IRV is diminished. In contrast to health, the combined recoil pressure of the lungs and chest wall in hyperinflated patients with COPD is inwardly directed during both rest and exercise: this results in an ITL on the inspiratory muscles.

of the chest wall and lungs before any inspired flow is initiated (i.e., inspiratory threshold load, ITL). The pattern and magnitude of DH during exercise is highly variable and depends on the extent of EFL and the ventilatory demand, and is inversely related to the level of resting lung hyperinflation (17). Serial inspiratory capacity (IC) measurements can be used to track dynamic changes in EELV since total lung capacity (TLC) is unaltered with exercise (11). At peak exercise, the IC diminishes by approximately 20% of its already reduced resting value in COPD. In flow-limited patients, the resting IC (percent predicted) has been shown to correlate well with peak symptom-limited oxygen uptake (VO2) (17). The resting IC represents the true operating limits for tidal volume (VT) expansion during

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Figure 3 Changes in operating lung volumes are shown as ventilation increases with exercise in COPD and in age-matched healthy subjects. EILV increases above the relaxation volume of the respiratory system (Rrs) in COPD, as reflected by a decrease in inspiratory capacity (IC), while EILV in health either remains unchanged or decreases. ‘‘Restrictive’’ constraints on tidal volume (VT, solid area) expansion during exercise are significantly greater in the COPD group from both below (increased EILV) and above (reduced IRV as EILV approaches TLC). Source: Data from Ref. 17.

exercise: the smaller the IC, the greater the constraints on VT expansion during exercise (17–20) (Figs. 1–3). Faced with this mechanical restriction, patients rely on increasing breathing frequency to increase ventilation, but this rebounds to cause even further DH in a vicious cycle. Resting IC has been shown to correlate well with the peak VT during exercise and this, in turn, correlates strongly with the peak ventilation and peak symptomlimited VO2 (17–20). The mechanical consequences of acute-on-chronic hyperinflation are well described. DH results in increased elastic and inspiratory threshold loading of inspiratory muscles already burdened with increased resistive work (1,13,21). The tidal volume response to exercise is markedly blunted in response to the increasing inspiratory effort during exercise (Figs. 3 and 4). Moreover, acute-on-chronic hyperinflation compromises the ability of the ventilatory muscles, particularly the diaphragm, to increase pressure generation in response to the increased drive to breathe during exercise (Fig. 3). The tachypnea, associated with early mechanical restriction during

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Figure 4 Mean exercise responses are shown in a group of patients with COPD (n ¼ 12) and in age-matched normal subjects (n ¼ 12). In COPD: exertional dyspnea intensity is increased; minute ventilation is increased; breathing pattern is relatively rapid and shallow; tidal volume (VT) does not expand appropriately as respiratory effort (Pes/PImax) increases. Due to mechanical constraints on the VT response to exercise, patients with COPD rely more on increasing breathing frequency (F) to generate increases in ventilation. Source: Data from Ref. 13. Abbreviations: VO2 ¼ oxygen consumption; Pes ¼ esophageal pressure; PImax ¼ maximal inspiratory esophageal pressure.

exercise, contributes to reduced dynamic lung compliance which has an exaggerated frequency dependency in COPD (1,13,21). B. Increased Ventilatory Demand During Exercise

The effects of the mechanical derangements in COPD outlined above are often amplified by concomitantly increased ventilatory demand (Fig. 4). The primary stimulus for increased submaximal ventilation is a high physiological dead space (VD/VT) that fails to decline with exercise as a result of worsening ventilation–perfusion (V/Q) abnormalities (22–25). Other contributing factors are: early metabolic (lactic) acidosis due to deconditioning, critical hypoxemia, high metabolic cost of breathing, lower set-points for arterial carbon dioxide (PaCO2), and other sources of ventilatory stimulation (i.e., anxiety and increased sympathetic system stimulation) (22–27).

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C. Gas Exchange Abnormalities in COPD

Arterial hypoxemia during exercise commonly occurs in patients with severe COPD as a result of the effects of a fall in mixed venous oxygen tension on lung units with low ventilation–perfusion ratios and shunting (24–27). In severe COPD, both the ability to increase lung perfusion and to distribute inspired ventilation throughout the lungs during exercise is compromised. In more advanced COPD, arterial hypoxemia during exercise occurs as a result of alveolar hypoventilation (28,29). An increase in arterial CO2 during exercise in COPD has been variously attributed to reduced central respiratory drive, altered breathing patterns to minimize respiratory discomfort, excessive inspiratory muscle loading relative to capacity, and inspiratory muscle fatigue (30–32). The extent of exercise hypercapnia cannot be predicted by measurement of FEV1.0, resting PaCO2, VD/VT, or tests of chemosensitivity (27–32). We have recently demonstrated that patients who retain CO2 during exercise have greater dynamic lung hyperinflation and earlier attainment of their peak alveolar ventilation than CO2 nonretainers (33). There was a good correlation between the EELV/TLC and the PaCO2 measured simultaneously during exercise (r ¼ 0.68, p < 0.005). Greater dynamic mechanical constraints on the expansion of VT, in the setting of a fixed high physiological dead space, was associated with CO2 retention as CO2 output increased during exercise (33). II. Dyspnea: Physiological Correlates Exertional dyspnea in COPD is complex and multifactorial. Several potential physiological contributory factors to exertional dyspnea intensity have been identified including: dynamic lung hyperinflation, increased ventilatory demand relative to capacity, critical hypoxemia and hypercapnia, inspiratory muscle weakness or any combination of the above. The evidence for each of these associations will be reviewed below. A. Mechanical Factors and Dyspnea

A number of studies have shown a close correlation between the reduction of IC during exercise and the intensity of exertional dyspnea (6,13). The relationship between dyspnea and lung hyperinflation is complex. The slope of the relationship between IC and Borg dyspnea ratings is alinear in COPD: when the IC [and inspiratory reserve volume (IRV)] reaches a critically reduced level, dyspnea rises steeply to intolerable levels (34). Thus, with increasing exercise, VT expands maximally to approach mechanical limitation at a minimal IRV of approximately of 0.5 L; thereafter, dyspnea rises rapidly as a function of the increasing drive to breathe (34). Close inter-correlations have been found between the intensity of exertional

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Figure 5 The relationship between respiratory effort (Pes/PImax) and tidal volume (VT) at peak exercise with simultaneous qualitative descriptors of exertional breathlessness in health and in COPD. Note the ITL, the disparity between effort and VT, and the different descriptor in COPD. Source: Adapted from Ref. 13.

dyspnea, the increase in EELV (i.e., reduction of IRV and IC), and the increased ratio of respiratory effort (represented as the ratio of esophageal pressure relative to the maximum inspiratory pressure, Pes/PImax) to tidal volume during exercise (13) (Fig. 5). This increased effort–displacement ratio is a crude measure of neuromechanical uncoupling of the respiratory system. As is the case in the restrictive disorders, the inability to expand VT appropriately in response to the increased central drive to breathe appears to contribute importantly to the intensity and quality of dyspnea in COPD. B. Quality of Exertional Dyspnea in COPD

An American Thoracic Society task force has defined dyspnea as ‘‘a term used to characterize the subjective experience of breathing discomfort and consists of qualitatively distinct sensations that vary in intensity’’(35). Qualitative descriptors of breathing discomfort vary across health and disease and different disease states appear to be characterized by distinctive descriptor choices (36,37). It is reasonable to assume that these qualitative descriptors may reflect different neurophysiological mechanisms. We recently compared qualitative differences in dyspnea during incremental

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cycle exercise tests in 12 patients (66
2 years, mean
SEM) with severe COPD (FEV1.0 37
5% predicted) and 12 age-matched normal subjects, and sought a physiological rationale for these differences (13). While both normals and COPD patients chose descriptors of increased work or effort of breathing, only COPD patients consistently chose descriptors denoting increased inspiratory difficulty (67%, i.e., ‘‘breathing in requires more effort’’ or ‘‘my breath does not go in all the way’’) and unsatisfied inspiration (92%, ‘‘I can’t get enough air in’’) (Fig. 6). While the sense of inspiratory muscle contractile effort undoubtedly contributes to exertional breathlessness both in health and disease, the distressing sensation of

Figure 6 Responses to exercise are shown in two COPD subgroups matched for FEV1: (A) with a low diffusion capacity (DLCO) 50% predicted (n ¼ 24). Group A had significantly (p < 0.05) greater exertional dyspnea, greater levels of lung hyperinflation, and earlier attainment of a limiting mechanical restriction (i.e., reduced IRV) than Group B. Source: Adapted from Ref. 17.

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unsatisfied inspiration is clearly important, if not predominant in COPD. At a VO2 equivalent to peak exercise in the COPD group (13 mL/kg/min), mean
SEM Borg ratings of inspiratory difficulty were 5.2
0.3 (‘‘severe’’) in COPD and 0.3
0.2 (‘‘very, very slight’’, or ‘‘just noticeable’’) in the normal subjects (p < 0.001, COPD vs. normals). Using stepwise multiple regression analysis, standardized Borg ratings of inspiratory difficulty related primarily to the concurrent EELV/TLC (n ¼ 24, r2 ¼ 0.61, p < 0.001). Not surprisingly, the reduction in IRV correlated strongly with the Pes/PImax (r ¼ 0.79, p < 0.001) and Pes/VT ratio (13). We speculated that the severe inspiratory difficulty and unsatisfied inspiration experienced by patients during exercise might, in part, have a pathophysiological basis in lung hyperinflation. Thus, while breathing close to TLC, the motion of the lung and thorax is markedly restricted despite increasing inspiratory efforts (and central drive) that approach the maximal possible effort that they can generate at that volume (13). Clearly, the intensity of inspiratory difficulty arises during exercise as tidal volume encroaches on the diminished IRV and the upper, alinear extreme of the respiratory system’s pressure–volume relationship (Figs. 2 and 3). Here, the muscles are naturally weakened and there is severe elastic and inspiratory threshold loading (21,28,33). Thus, the lower the dynamic IRV during exercise, the greater the disparity between inspiratory effort and the resultant volume displacement. When IRV diminishes to a critical value of 0.5 L or less, neuromechanical uncoupling of the respiratory system approaches a maximum value and there is simply ‘‘no more room to breathe.’’ The change in dynamic IRV during exercise serves as a noninvasive surrogate for measurement of neuromechanical dissociation (NMD). The contention that acute DH during exercise contributes to the intensity of exertional dyspnea has been bolstered by a number of studies which have shown that dyspnea relief following bronchodilator therapy or lung volume reduction surgery is closely associated with increases in the resting and exercise IC (34,39–43). These interventions that reduce resting lung hyperinflation and increase IRV, allow greater VT expansion for any given (or decreased) inspiratory effort throughout exercise. Improvement in exertional dyspnea after bronchodilator treatment correlates well with the increased VT and the perception of unsatisfied inspiration is significantly less (34,43). C. Dyspnea and Increased Ventilatory Demand in COPD

The effects of the mechanical derangements in COPD outlined above are amplified by concomitantly increased ventilatory demand. In flow-limited patients, the extent of DH and its negative sensory consequences will vary with ventilatory demand. There is abundant evidence that the intensity of dyspnea during exercise strongly correlates with change in ventilation, in

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absolute terms, or expressed as a fraction of maximal ventilatory capacity (38,39,44–46). Moreover, relief of exertional dyspnea and improved exercise endurance following interventions such as exercise training, oxygen therapy, and opiates, have been shown to result, in part, from the attendant reduction in submaximal ventilation (47–49). It must be remembered that reduction in ventilation from any cause will be associated with improved dynamic ventilatory mechanics and that this, in turn, may have additional salutary effects on respiratory sensation through enhanced neuromechanical coupling (47,49,50) (see below). D. Dyspnea and Reduced Diffusion Capacity

A common clinical observation is that patients with COPD who have a reduced diffusion capacity for carbon monoxide (DLCO), signifying a reduced surface area for gas exchange, often experience more severe dyspnea and disability than those with a preserved DLCO. In one study in two groups of COPD patients with a similar FEV1.0, those with a reduced DLCO ( 40% V predicted. Wide range of normal: 35 – 80%. Clinical validation is required

HR max > 90% age - predicted HRR

< 15 bpm

> 80%

> 8.3 mL/min/W (Continued)

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Table 7 Selected Peak Cardiopulmonary Exercise Testing Measurements (Continued ) Variables

Measurement caveats incremental cycle ergometry. ˙ O2 at ˙ O2peak–V (V min 3 unloaded)/ (W/ min  duration test – 0.75). Recently, simpler linear regression is also being used

Comments

Suggested guidelines

O2 delivery/ utilization by the muscle. Could be abnormal in patients with cardiovascular/ pulmonary vascular disease. Normal in patients with pulmonary disease ˙ Emax > MVV – V Potential ventilation in 11 L liters that could V ˙ Emax/MVV  100: be increased < 75%

˙ Emax or Ventilatory reserve MVV–V ˙ Emax/ V MVV  100 (widely used). MVV can be Wide normal range: measured directly Percentage of the 72  15% or calculated maximum (FEV1  40). breathing capacity used. No ExtFVL/MFVL gold standard for to visualize its determination ‘‘limitation’’; Quantitate: IC ¼ TLC – EELV; EILV/ TLC < 60 breaths/min Breathing frequency Different breathing Reflects abnormalities in strategies in the mechanics of COPD and breathing, control interstitial lung disease. Erratic in of breathing, and/or malingers. High hypoxemia or in psychogenic psychological disorders disorders ˙ E/V ˙ CO2 (at AT) Measured V < 34 Noninvasive measurement of throughout but efficiency of reported at AT ventilation (L of (or near nadir) (Continued)

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Table 7 Selected Peak Cardiopulmonary Exercise Testing Measurements (Continued ) Variables

˙ D/V ˙T V

PaO2

P(A-a)O2

Measurement caveats

Comments

Suggested guidelines

when PaCO2 is VE to eliminate ˙ CO2). steady, to avoid 1L of V Reflects increase the effect of ˙ T and/or ˙ D/V in V hyperventilation hyperventilation acidosis, etc. < 0.30 PaCO2 should be Reflects efficiency of CO2 exchange used in its determination. or lung units with PETCO2 produces proportionally ˙ A than Q higher V unreliable results ˙ D). (increased V Normally decreases with increased exercise intensity Careful anaerobic Ability to exchange > 80 mm Hg O2 is best assessed collection near by the maximal and measurement of peak exercise for PaO2 and not by consistency of pulse oximetry, results particularly in suspect cases Evaluates gas Arterial blood < 35 mm Hg transfer. should be collected slowly in Abnormal high the middle to end values may reflect ˙ /Q mismatching V of the respective (shunt type), interval diffusion limitation, shunt, or reduced PvO2

Source: Adapted from Ref. 117.

depend on the clinical reasons for exercise testing, selected key measurements necessary for CPET evaluation are discussed in further detail below. i. V˙O2max

Oxygen uptake measurements remain the best available index for assess˙ O2max) are most ment of exercise capacity. Maximal oxygen uptake values (V ˙ O2 values plateau despite further work rate increases, but reliable when V

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˙ O2peak) is the this is not often observed (111). Peak oxygen consumption (V ˙ maximum VO2 achieved, and represents the maximal achievable level of ˙ O2peak is modulated by dynamic exercise involving large muscle groups. V physical activity, and therefore provides a gold standard index for evalua˙ O2peak should always be measured directly and tion of level of fitness. V expressed in absolute values (L/min) and percent predicted. Normalized values for body mass should also be displayed, although the optimal method ˙ O2/kg (mL/kg/min) is the easiest to do this remains controversial. V normalized value to calculate and is also the most commonly used. For ˙ O2peak are used interchangeably (92). ˙ O2max and V practical purposes V ˙ A reduced VO2peak response to exercise reflects problems with oxygen delivery, peripheral utilization, or decreased patient effort. Abnormalities of the heart, lungs, systemic and pulmonary circulation, low hemoglobin levels, muscle dysfunction, and/or decreased oxygen utilization can all ˙ O2peak reflects a normal aerobic power and ˙ O2peak. A normal V reduce V exercise capacity and provides reassurance that no significant functional impairment exists, provided no other CPET abnormalities of diagnostic value are detected. ii. Carbon Dioxide Production

The volume of carbon dioxide (CO2) expired tends to be slightly less than the uptake of O2 at low levels of exercise, equimolar at anaerobic threshold (AT), and exceeds O2 uptake during moderate to severe exercise. The ˙ CO2 to respiratory exchange ratio (RER) reflects the relationship of V ˙ O2, which at steady-state exercise roughly approximates the respiratory V quotient. In heavy, non-steady-state exercise, the RER more accurately reflects transient changes in CO2 stores. iii. Anaerobic Threshold

The anaerobic threshold, also known as the lactate threshold (LT), is an estimator of the onset of metabolic acidosis caused predominantly by increased lactic acid output due to both an imbalance of oxygen supply and oxidative metabolism and the recruitment of muscle fibers during exercise (92). Although the physiologic significance of AT remains controversial, it appears to be related to increased anaerobic metabolism within exercising muscles and is affected by variations in oxygen delivery, consumption, and patterns of muscle fiber recruitment (112). The AT is usually ˙ O2max in sedentary individuals and higher in fit individuals 50–60% of V (97). The AT can be determined invasively by measurement of arterial lactate, or noninvasively using ventilatory or gas exchange variables (97). An approach that combines the modified V-slope and the ventilatory equivalents method is recommended (25). A current perspective containing a more thorough discussion on the clinical use of AT in the interpretation of CPET has recently been published (92).

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iv. Cardiovascular Measurements

Cardiac output (CO) is the best index of cardiac function during exercise. Since CO is not measured routinely in the exercise laboratory, heart rate ˙ O2 is used as a surrogate of cardiac output and function coupled with V during CPET (62,97). This value, otherwise known as the O2 pulse ˙ O2/HR), is equal to the product of stroke volume (SV) and the (V arterial-mixed venous oxygen difference [C(a-v)O2]. Increases in cardiac output during exercise are initially achieved by increases in both stroke volume and heart rate, and at higher work rates almost exclusively by increases in heart rate. The heart rate reserve (HRR) is the difference between the age-predicted maximal HR (See Table 7) and the maximum HR achieved during exercise. At maximal exercise, there is normally little or no HRR (113). An O2 pulse value < 80% predicted at maximal effort is abnormal (92,97). v. Ventilatory Measurements

˙ T) and respiratory ˙ E) is the product of tidal volume (V Minute ventilation (V frequency (f), and provides an assessment of the ventilatory demand of exer˙ E achieved durcise. Ventilatory reserve is the difference between maximal V ˙ ing exercise (VEmax) as an index of ventilatory demand, and maximal voluntary ventilation (MVV) as a practical index of ventilatory capacity ˙ Emax/MVV (62,97,114). ˙ Emax or V and is expressed as either MVV–V Normally at maximum exercise, this difference is greater than 20%, and a reduced or absent ventilatory reserve is one of the criteria often used to establish ventilatory limitation to exercise. Breathing pattern assessment can be helpful in both the diagnosis of respiratory disease (92) and psychogenic disorders (see Case 2) (115,116). In patients with abnormal breathing patterns, a more comprehensive assessment can be obtained by comparing the maximal volitional flow-volume envelope (MFVL) obtained at baseline with exercise tidal flow-volume loops (Fig. 1) (114). Exercise tidal flow-volume loops provide graphic insight into the degree of ventilatory constraint, mechanisms of compensation for ventilatory impairment, and a more precise measurement of ventilatory capacity. Further studies are needed to clarify the clinical role that this sensitive technique may play in exercise testing. vi. Pulmonary Gas Exchange Measurements

CPET can provide information on both ventilatory efficiency and oxygen transfer. Ventilatory efficiency is determined by how much ventilation is ˙ E/V ˙ CO2 and V ˙ E/V ˙ O2) achieved for a given level of metabolic demand (V ˙ E/V ˙ CO2 and V ˙ E/V ˙ O2 are generally similar until during moderate exercise. V ˙ CO2 tends to stay constant while ˙ E/V the onset of heavy exercise, when V ˙ O2 increases. Near the end of exercise, both V ˙ E/V ˙ CO2 and V ˙ E/V ˙ O2 ˙ E/V V ˙ E/V ˙ CO2 generally suggests increased increase. An inappropriately high V

Figure 1 Exercise flow-volume loop measurements demonstrating flow-volume loop responses in a normal subject and a patient with moderate COPD. Key differences in the ventilatory response to exercise: Normal subject: (1) drop in FRC, (2) encroachment equally on IRV and ERV, (3) little or no expiratory flow limitation, (4) available inspiratory flow reserve, and (5) significant volume reserve. Moderate COPD: (1) EELV increases from the onset of exercise due to dynamic hyperinflation resulting in a decrease in IC, (2) EILV is high ˙ T by peak exercise, (4) inspiratory flows approach relative to TLC, (3) expiratory flow limitation is present over more than 80% of the V maximum at higher lung volumes (4) little volume reserve to increase ventilation. Source: Adapted from Refs. 114, 116a.

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dead-space ventilation or hyperventilation, while a low value may imply ˙ CO2 values are gener˙ E/V inadequate ventilation for the level of exercise. V ally reported at AT (92,117). Blood gas measurements are necessary whenever specific information on pulmonary gas exchange is required. Combining PaO2 and PaCO2 values with the ventilatory measurements above allows an accurate assess˙ D/V ˙ T ratio (118). P(A-a)O2 usually ment of the P(A-a) O2 and the V/Q V increases with exercise but remains less than 35 mm Hg; and an abnormal widening can be seen in any state that decreases V/Q matching and/or ˙ D/V ˙ T to decrease reduces mixed venous oxygenation (119). Failure of V with exercise also suggests V/Q mismatch due to an inappropriately high physiologic dead space (62,97). 4. CPET Interpretation

There are several approaches to CPET interpretation (62,92,97,120). We recommend the following practical approach to the interpretation of cardiopulmonary exercise testing: (1) review the reason(s) for CPET and the pertinent clinical history; (2) note the overall quality of the test, assessment of subject effort, and reason for test cessation; (3) identify key variables and determine if they are normal or abnormal based on appropriate normal reference values; (4) identify and trend important relationships displayed in both the tabular and graphic presentation of data; (5) evaluate abnormal exercise response patterns and limitation(s) to exercise; (6) consider clinical conditions which may be associated with these patterns; and (7) correlate results with the patient’s clinical information in the final CPET report. A major factor in CPET interpretation is the selection of appropriate reference values (109). The selection of an appropriate reference set is a function of age, height, weight, sex, and physical activity, and should generally reflect the patient population seen in a given exercise laboratory. A full discussion of appropriate methods of reference value selection and validation has been recently reviewed (92). Guidelines to facilitate interpretation and clinical decisions have recently been established, and should serve as a valuable tool to standardize further research efforts in this area (92). The major mechanisms of exercise ˙ O2max are listed in Table 8 (92), and limitation in patients with reduced V individual subjects will frequently demonstrate multiple coexisting etiologies. Typical CPET response patterns used to focus further evaluation of unexplained dyspnea (Table 3, Fig. 3) appear in Table 9, and are outlined in further detail below. Normal Exercise Response

The physiologic responses of a healthy adult to maximal CPET are shown in Fig. 2. During an incremental protocol to volitional exhaustion on cycle

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Table 8 Major Mechanisms of Exercise Limitation Pulmonary Ventilatory (mechanical) Respiratory muscle dysfunction (dynamic hyperinflation) Gas exchange Cardiovascular Reduced stroke volume Abnormal HRR Abnormal systemic or pulmonary circulation Hemodynamic consequences of dynamic hyperinflation Abnormal blood (anemia, COHb) Peripheral limitation Inactivity (disuse) Loss of muscle mass (atrophy) Neuromuscular dysfunction Peripheral circulatory abnormalities Reduced skeletal muscle oxidative capacity (metabolic myopathy, COPD) Malnutrition Perceptual Motivational Environmental Source: Adapted from Ref. 121.

ergometer, VO2 increases linearly with increases in work rate, and at peak ˙ O2max values are >84% predicted and highly reproducible in a exercise V given individual. HR and O2 pulse both also increase linearly with increases in work rate. Late in exercise O2 pulse typically reaches a plateau, while increases in HR account for subsequent rises in cardiac output. Exercise in normal subjects appears to be limited by the diffusive capacity of oxygen transport into muscle (121) and oxygen delivery (92). Oxygen delivery is the product of cardiac output and arterial oxygen content. As arterial oxygen content is normally maintained even at peak exercise, it appears that cardiac output is ˙ O2max in normal subjects. HR and O2 pulse therethe limiting factor for V fore generally approximate maximal predicted values at peak exercise. ˙ T will progressively increase until V ˙T In a normal adult both f and V reaches approximately 50% of VC, after which increases in f primarily ˙ E at higher work rates. Exercise tidal flow-volume loops will augment V ˙ T increases by encroaching on both the inspiratory demonstrate that V ˙ E/V ˙ O2 and V ˙ E/V ˙ CO2 are freand expiratory reserve volumes (Fig. 1). V quently high at the beginning of exercise due to anxiety and use of the mouthpiece, and then decrease to levels proportional to the metabolic

Normal Normal or increased Normal Normal Normal/may increase May decrease

O2 pulse

˙ E/MVV)  100 (V

Normal

Normal Normal Normal

Normal

Decreased

Normal/slightly decreased

Normal or decreased

Decreased

Deconditioning

Decreased, normal, increased with respect to normal response. Source: Adapted from Ref. 92.

P(A-a)O2

˙ E/V ˙ CO2 (at AT) V ˙ D/V ˙T V PaO2

Normal/slightly decreased

Decreased for actual, normal for ideal weight Normal

Obesity

Peak HR

Anaerobic threshold

˙ O2 max or peak V

Measurements

Table 9 Usual Cardiopulmonary Exercise Response Patterns

Normal/ decreased/ indeterminate Decreased, normal in mild Normal or decreased Increased

Decreased

COPD

Usually normal

Variable, usually increased

Normal or decreased Increased Increased Increased Increased Normal Variable

Variable, usually normal Decreased

Decreased

Decreased

CHF

Decreased

Increased

Normal or decreased Normal or increased Increased Increased Decreased

Decreased

Increased

Increased Increased Decreased

Normal

Normal/ slightly decreased Decreased

Normal or Decreased decreased

Decreased

ILD

Pulmonary vascular disease

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Figure 2 Ref. 113.

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Normal cardiopulmonary responses to exercise. Source: Adpated from

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˙ CO2 and V ˙ E increase linearly until 50– demand during moderate exercise. V ˙ O2 (RER 60% of VO2max, when the slope of their rise increases relative to V > 1) to compensate for increases in lactic acid production above AT. The ˙ E increases above that of V ˙ CO2 at 70% of V ˙ O2max, likely rate of rise in V due to stimulation of hydrogen ions produced by lactic acid production on the respiratory center. During heavy exercise, there is relative hyperven˙ O2, then to both V ˙ O2 and V ˙ CO2 near the end of exercise. tilation first to V PETO2 increases and PETCO2 decreases towards peak exercise, resulting in an increase in PaO2 due to alveolar hyperventilation. P(A-a)O2 generally widens ˙ T normally ˙ D/V towards peak exercise but remains less than 35 mm Hg, while V decreases throughout incremental exercise (92). i. Hyperventilation/Psychogenic Disorders

Patients with psychogenic dysfunction will often have a normal or near nor˙ O2peak and work rate. Abnormal breathing patterns at rest and during mal V exercise should increase clinical suspicion, and in some circumstances can be diagnostic (see Case 2). In contrast to the gradual increase in respiratory frequency during progressive exercise in normal individuals, patients with hyperventilation syndrome may have an abrupt onset of regular, rapid, shallow breathing that is disproportionate to the level of metabolic stress (122). ˙ E, V ˙ E/V ˙ CO2, f, and an inappropriate respiratory Abnormal increases in V alkalosis at rest or during exercise may be observed (122,123). Hyperventilation and exercise have been associated with ECG changes resembling ischemia in patients with normal coronary arteries (124). ii. Obesity

˙ O2peak. V ˙ O2peak will Obese patients may demonstrate a normal or low V be progressively lower with increasing obesity when expressed per kilogram ˙ O2peak/kg), but may be normal when based on of actual body weight (V ˙ O2 may also be increased for a given work rate ideal body weight. V ˙ O2/DWR slope remains normal (125,126), reflecting the although the DV excessive metabolic requirements of moving excess weight during exercise. The excessive metabolic requirements also result in an increase in HR at submaximal work, with a normal or near normal HR at peak exercise with no HRR. AT is usually normal, although it may be reduced in obese individuals compared to normal subjects; this finding suggests that obese patients may have less efficient cardiac performance (127). ˙ E at a given work rate is disproportionately increased, while breathV ˙ Emax/MVV) can be normal or reduced due to increased metaing reserve (V bolic requirements and work of breathing (125). A trend toward increased f ˙ T is usually observed, and exercise tidal flow-volume loops and reduced V may show an inability to increase end-expiratory lung volume sufficiently during exercise, resulting in expiratory flow limitation (114,128). At rest obese patients may have an abnormal PaO2 and widened P(A-a)O2 due

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to basilar atelactasis, which may normalize with exercise as tidal volumes and ventilation–perfusion matching improves. iii. Cardiovascular Disease

Patients with a cardiovascular response pattern on CPET may have problems with the heart, the pulmonary or systemic circulation, or reduced ˙ O2max is low with evidence of oxygen delivery due to significant anemia. V an early onset lactic acidosis (decreased AT). HR is elevated with a leftward shift of the HR–VO2 relationship and low O2 pulse, reflecting the fact that cardiac output is almost exclusively maintained by increases in HR. ECG may show evidence of cardiac ischemia if the cardiac dysfunction is due to coronary artery disease. ˙ Emax is generally reduced with ample ventilatory reserve, although V exercise flow-volume loops in patients with left ventricular dysfunction will show a tendency to breath near residual volume on exercise tidal flow volume loops despite evidence of severe expiratory flow limitation and ample room to increase EELV. This breathing strategy may be adopted in order to reduce work of breathing due to decreased lung compliance from congestive heart failure combined with weak respiratory muscles from reduced oxygen delivery (92,129). Patients with a cardiovascular limitation due only to heart disease will ˙ D/V ˙ T and generally have normal PaO2 and P(A-a)O2; increases in V ˙ CO2 are often seen and are due to reduced pulmonary perfusion from ˙ E/V V a decreased cardiac output (92,109,130). Patients with primary or secondary pulmonary vascular disease will also demonstrate these abnormalities due to inefficient ventilation from increased dead space, in addition to arterial hypoxemia and widening of the P(A-a)O2 as exercise progresses (131,132). iv. Deconditioning

The CPET pattern seen with deconditioning has many similarities to early or mild heart disease; these two entities often co-exist and are difficult to distinguish (92). Although less common, patients with mitochondrial myopathy also have a similar exercise pattern (see Case 3) (63). Decondi˙ O2max and a tioned patients will demonstrate a low or low normal V normal or low AT suggesting a tendency towards early onset of metabolic acidosis. HR is increased disproportionately at low levels of exercise, with ˙ O2max. V ˙ Emax is low with sigminimal to no HRR and a low O2 pulse at V nificant ventilatory reserve, and there usually are no pulmonary gas exchange abnormalities. v. Respiratory Disease

Patients with evidence of respiratory disease on CPET can demonstrate a wide variety of exercise patterns depending on the predominant mechanism of exercise limitation and the severity of the abnormality. Ventilatory

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impairment due to mechanical derangements, respiratory muscle dysfunction due to dynamic hyperinflation, and pulmonary abnormalities of gas exchange can all cause a respiratory disease pattern on CPET. ˙ O2peak and work rate remain normal in patients with mild In general, V degrees of pulmonary impairment, while patients with moderate to severe lung disease will demonstrate progressive reductions in exercise tolerance. Patients with COPD may have a low, normal, or indeterminate AT response. Early onset metabolic acidosis (low AT) is generally due to deconditioning from physical inactivity and/or skeletal muscle dysfunction (92,109,134), and leg fatigue is a common contributing factor to exercise limitation along with dyspnea in patients with COPD. There is usually significant HRR and a low O2 pulse, reflecting a relatively understressed cardiovascular system. Reduction in O2 pulse has also been attributed to deconditioning, hypoxemia, and possibly the physiologic consequences of dynamic hyperinflation (134). Patients with severe obstructive lung disease will also frequently have increased submaximal HR responses but a reduced ˙ O2peak, making evaluation of patients peak HR and O2 pulse relative to V with concomitant cardiac disease more challenging. Abnormal exercise flow-volume loops with expiratory flow limitation but otherwise normal CPET responses can be seen in patients with mild COPD (135), and serial spirometry after CPET can identify postexercise bronchospam in patients with occult asthma or inadequate asthma therapy. Most patients with clinically significant ventilatory impairment, however, ˙ E with a reduced ventilawill demonstrate a disproportionately increased V ˙ Emax/MVV approaching or exceeding 100%). Patients with tory reserve (V moderate to severe COPD will frequently manifest a higher f and lower ˙ E compared to normal subjects, with exercise flow-volume ˙ T at the same V V loops that demonstrate dynamic hyperinflation, progressive reduction in inspiratory capacity, and severe expiratory flow limitation during exercise ˙ E/V ˙ CO2 is generally increased with an abnormal (Fig. 1) (136,137). V ˙ D/V ˙ T response due to increased dead-space ventilation, and PaCO2 will V remain constant or increase due to ventilation–perfusion mismatch with alveolar hypoventilation and dynamic hyperinflation (137). PaO2 and P(A-a)O2 will generally decrease during exercise in moderate to severe COPD (120). Patients with interstitial lung disease will generally have a reduced ˙ O2peak. AT will be normal or reduced, reflecting either destruction of V the pulmonary vascular bed with pulmonary circulatory impairment, skeletal muscle dysfunction, or deconditioning. Evidence of cardiovascular/pulmonary vascular limitation may be more common than previously recognized in diseases like idiopathic pulmonary fibrosis (138), with abnormal HRR and O2 pulse responses in a pattern more suggestive of cardiac limitation. Hypoxemia has been proposed as an important mechanism,

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although the exact mechanism behind this observation remains unclear (139). ˙ E and a reduced ventilatory reserve are commonly seen in Increased V ˙ T, and interstitial lung disease. Rapid shallow breathing with a high f, low V low inspiratory capacity is also common, as is evidence of inefficient venti˙ E/V ˙ O2 and V ˙ E/V ˙ CO2) and increased dead space (abnorlation (increased V ˙ ˙ mal VD/VT) (140,141). Patients will frequently manifest marked gas exchange abnormalities including reduced PaO2 and an abnormally wide P(A-a)O2 (92,93,140). vi. Limitations in Interpretation

It must be emphasized that significant overlap exists in the exercise responses of patients with different respiratory and cardiac diseases. Patients often have co-existing conditions (obesity, deconditioning) that may also contribute to exercise intolerance. Accurate interpretation requires appreciation of such overlap and variability. The sensitivity and specificity of CPET in diagnosing specific clinical entities based on exercise patterns requires further study. CPET can help distinguish between exercise limitation from cardiac and pulmonary diseases, but the distinction between deconditioning and mild or early heart disease may be very difficult. This problem is often complicated by the high co-existing prevalence of deconditioning in patients with chronic illness. Response to an aerobic training regimen may help to distinguish between these two clinical entities (142). D. Step IV: Specialized Tests for Unexplained Dyspnea Based on CPET Results

CPET has been shown to be a useful tool to focus the evaluation of patients with unexplained dyspnea (Fig. 3) (16). Focusing diagnostic efforts into one or several of these categories reduces costly, unnecessary testing and permits timely therapeutic intervention. Additional studies are still needed, however, to define the optimal sequence of subsequent testing within each category. 1. Normal

Normal CPET results provide reassurance that no significant functional abnormalities exist and frequently obviate the need for further testing. However, it is important to recognize patients with psychogenic factors will often have a normal CPET, and these findings should not discourage referral for psychiatric evaluation and treatment if suggested by the clinical history. Patients with gastroesophageal reflux disease (GERD) may also have a normal CPET, and will require either an empiric trial of antisecretory ther-

Figure 3 Clinical utility of cardiopulmonary exercise testing to focus diagnostic testing. Abbreviations: CPET, cardiopulmonary exercise test; HX, clinical history; PE, physical examination; CXR, chest radiograph; SpO2, noninvasive oxygen saturation measured by pulse oximetry; PFTs, pulmonary function tests; EKG, electrocardiogram; PVD, pulmonary vascular disease; V/Q, ventilation perfusion scan; ILD, interstitial lung disease; HRCT, high resolution computed tomography. Source: Adapted from Ref. 16.

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apy or appropriate evaluation with endoscopy or ambulatory esophageal pH monitoring (143). 2. Hyperventilation/Psychogenic Disorders

Hyperventilation syndrome, initially termed ‘‘irritable heart,’’ was first described in 1871 (144). Patients with this syndrome frequently have a variety of psychogenic disorders which may or may not be readily apparent at initial evaluation (116), and in one series were reported to have with a high prevalence of asthma symptoms (17 of 23 patients, 74%) and a history of marijuana or alcohol abuse (4 of 23, 17%) (146). Common complaints in all reported series include exertional dyspnea, chest pain, and lightheadedness, and many patients may report a ‘‘positive review of systems’’ (115). These symptoms may represent unrecognized hyperventilation due to anxiety and stress (115). Once a diagnosis of hyperventilation syndrome is made or suspected, the association between excessive breathing and the presenting symptoms can be demonstrated to the patient with a controlled hyperventilation trial. A variety of behavioral modification techniques, either alone or in combination with psychological evaluation and pharmacotherapy, can be very successful in this otherwise challenging disorder (115,116). 3. Obesity

A spectrum of exercise responses can be seen in obese patients. Many associated conditions place this population at risk for dyspnea, and obesity itself can be the major contributing factor to respiratory symptoms and reduced exercise tolerance. Cardiovascular limitation due to underlying coronary ischemia or to the diastolic dysfunction commonly seen in this population (146) must be carefully excluded during evaluation and development of an exercise prescription. Once other causes of dyspnea are excluded through CPET evaluation, these patients should be enrolled in a weight reduction/aerobic training program, with subsequent monitoring of response and symptom improvement. Exercise remains one of the most potent physiologic stimuli of lipolysis, exceeding even the effects of 84 hours of starvation (147). Women have been shown to exhibit less lipolysis than men during exercise (148), and weight loss from exercise may be accompanied by an increase in appetite (149). These and other factors must be taken into careful consideration when developing a conditioning program for obese individuals. Many experts advocate an intervention combining behavior therapy, a low-calorie diet, and high fre˙ O2max for a longer quency, low-intensity activity with a goal of 30–50% V duration (90–240 min) as the optimal method to lose body fat (150).

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4. Cardiac/Ischemia

Patients with diagnostic evidence or suspected ischemia on exercise electrocardiogram should be placed on empiric beta blocker and aspirin therapy unless clinically contraindicated while awaiting further evaluation. Further noninvasive functional assessment may be performed in low to moderate risk patients with stress echocardiography (151) or a variety of nuclear imaging modalities (152,153), while high risk patients should generally proceed directly to coronary angiography (153). Monitoring response to therapy after risk stratification and coronary intervention is completed is important, as continued symptoms of dyspnea may suggest another concurrent cause that would require further evaluation. 5. Cardiac/Deconditioning

Patients with a cardiac/deconditioning exercise pattern demonstrate a ˙ O2peak, low anaerobic threshold and work rate, and an inapproreduced V priately steep heart rate response (16). This pattern can be particularly challenging, as there are no clear distinguishing characteristics to define early or mild heart disease from deconditioning as a cause of patient symptoms. A similar exercise pattern has also been well described in patients with abnormal peripheral muscle oxygen utilization from mitochondrial myopathy (63,95,154). The vast majority of congestive heart failure in patients aged 60 years or younger is due to systolic dysfunction, but over later decades the prevalence of diastolic dysfunction progressively increases (21% of patients age 61–70, 41% of patients older than 70 years, 47% in a nursing home population with a mean age of 84 years) (156). Echocardiography therefore becomes an important tool to define an appropriate treatment strategy for individuals with congestive heart failure, in addition to identifying and stratifying the degree of pulmonary hypertension present. In patients with abnormal ECG findings, echocardiography can also serve as an initial screening tool to identify focal wall motion abnormalities that may prompt further evaluation for coronary artery disease. Patients with a cardiac/deconditioning pattern should therefore receive an echocardiogram with doppler flow estimation of pulmonary artery pressures to exclude cardiac dysfunction as the next step in their evaluation. Patients with a normal echocardiogram should begin a training program based on CPET results. Weight reduction should be considered when appropriate, and clinical monitoring with repeat CPET measurements should be considered. If there is no evidence of improvement or interval development of organic cardiopulmonary disease on follow-up, mitochondrial disease should be considered (see Case 3) (95). In one series of unexplained dyspnea referrals to a tertiary care specialty clinic, 8.5% (28 of 331 patients)

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were found to have a metabolic myopathy. It is important to note that many patients with mitochondrial myopathies are deconditioned, and demonstrate significant improvement in exercise capacity after participating in a pulmonary rehabilitation program (157). If a patient remains with significant activity limitation following completion of an intensive training program, further evaluation with a muscle biopsy may be considered to confirm a diagnosis of metabolic myopathy. 6. Pulmonary Vascular Disease

Patients with an exercise response pattern showing a pulmonary vascular limitation will need further evaluation to identify secondary causes of pulmonary hypertension. Effective treatment for the majority of these patients will be focused on the underlying disorder, such as chronic venous thromboembolism, obstructive sleep apnea, chronic valvular heart disease, or left ventricular dysfunction. Further investigations will need to be performed in patients at risk for primary or secondary causes of pulmonary arterial hypertension (PAH), including those with a history of connective tissue disease, liver cirrhosis, cocaine or metamphetamine use, and HIV. Echocardiography retains a central role as an effective screening tool, but PAH patients with clinically significant and/or progressive symptoms will need further invasive studies including a right heart catheterization and vasodilator study prior to being considered for medical treatment (158). 7. Obstructive Lung Disease

Growing evidence of increased metabolism due to systemic oxidative stress and release of inflammatory mediators in COPD has provided another plausible mechanism for the loss of skeletal muscle and limb muscle wasting frequently observed in these individuals (159). Many patients with COPD will stop exercising due to complaints of leg fatigue, and the high prevalence of deconditioning seen in this population emphasizes the fact that exercise limitation is usually multifactorial (90,92,160). Treatment for patients with exercise limiting obstructive lung disease should follow current practice guidelines (161), with careful consideration of the systemic nature of this disease. In addition to medical therapy with bronchodilators and oxygen, referral to a pulmonary rehabilitation program has been shown to improve exercise capacity, reduce health care utilization and improve quality of life in these patients (163). Patients with postexercise bronchospasm due to asthma should have their asthma regimen intensified. Treatment of exercise-induced asthma consists of administration of a variety of controller medications based on previously published guidelines for asthma management, with regular administration of a short-acting bronchodilator prior to exercise (163). Formoterol, a long-acting bronchodilator with rapid onset of action, shows

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promise as an effective therapy for exercise-induced asthma patients with breakthrough symptoms following pretreatment with albuterol (164). 8. Interstitial Lung Disease

The most recent classification of the idiopathic interstitial pneumonias by the American Thoracic Society/European Respiratory Society (ATS/ ERS) emphasizes an integrated clinical, radiological and pathological approach to systematically diagnose a causative clinical condition from the diverse and heterogeneous etiologies of interstitial lung disease (86). While careful clinical history and evaluation using HRCT can often arrive at a diagnosis with an acceptable level of clinical confidence, surgical lung biopsy remains the gold standard to definitively diagnose these interstitial lung diseases. Arterial desaturation or an abnormal increase in P(A-a)O2 were shown useful in one study to identify patients appropriate for lung biopsy consideration (10). Recommendations for the evaluation and treatment of interstitial lung disease are summarized elsewhere (86). IV. Summary Exertional dyspnea is a common, complex clinical problem. Many patients with common causes of dyspnea can be effectively diagnosed after a complete history and physical, chest radiograph, and screening spirometry and laboratory tests. The evaluation and diagnosis of patients with dyspnea unexplained by this initial evaluation can be considerably more complex, consuming significant time and medical resources. In the absence of rigorous evidence based practice guidelines, a stepwise approach to the patient with unexplained dyspnea is recommended using diagnostic tests with a high post-test predictive value based on disease prevalence and test characteristics. Younger patients should receive early bronchoprovocation challenge testing, followed by laryngoscopy if clinical suspicion for vocal cord dysfunction exists. Older adults should receive a screening electrocardiogram, more complete pulmonary function testing, and echocardiography if indicated by initial subjective and objective findings on clinical evaluation. If the diagnosis remains elusive or multiple diagnoses are identified, CPET should be performed to focus the differential diagnosis or identify the predominant limiting factor requiring treatment. CPET is a valuable tool in the efficient evaluation of dyspnea when initial test results are nondiagnostic, the degree of dyspnea is disproportionate to test results, and when psychological factors, deconditioning or obesity are suspected. When performed early, CPET can focus further testing to facilitate expeditious diagnosis and therapeutic outcomes without significant excess time and resource utilization.

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The following cases provide practical examples of how CPET may assist the clinician to resolve persistent questions in patients with unexplained dyspnea. CPET can identify disease patterns that are not readily apparent during diagnostic testing performed at rest (Cases 1–3). As many patients with dyspnea present with multiple contributing clinical conditions, CPET can also identify, prioritize, and quantify the limiting factors leading to exercise intolerance. CPET therefore enables the clinician to develop an effective management plan in a timely manner and minimize further expensive and invasive testing. A. Case 1 (Ref. 109)

A 26-year-old Caucasian female was referred for evaluation of shortness of breath on exertion. Her symptoms also occasionally developed at rest, but were most prominent with running without any other associated respiratory symptoms. Physical examination, chest radiograph, screening spirometry, and pulse oximetry measurements were normal. Methacholine bronchoprovocation testing was negative. Anthropometric data and peak CPET results are displayed in Table 10. CPET Interpretation. Subject effort was excellent, based on a nor˙ O2 peak (88% predicted), maximal heart rate achieved (93%) and mal V O2 pulse (95% predicted). Exercise was terminated due to complaints of shortness of breath and audible inspiratory stridor. Exercise flow-volume loops obtained near peak exercise showed an increase in end-expiratory lung volume (EELV) suggestive of hyperinflation but ample residual inspiratory reserve volume, along with large amounts of inspiratory and expiratory flow reserve. The remainder of measured CPET variables and relationships was normal. Laryngoscopy performed immediately after cessation of exercise demonstrated abnormal anterior vocal cord adduction with a residual posterior glottic ‘‘chink’’ during inspiration consistent with vocal cord dysfunction (Fig. 4). Although CPET is not considered a sensitive method to provoke signs and symptoms of vocal cord dysfunction, it can be effective in reproducing conditions in patients whose symptoms occur predominantly with running or cycling (74). The patient was referred for psychological evaluation and speech therapy, following which her symptoms improved. B. Case 2 (14a)

A 24-year-old African American female nonsmoker was referred for the evaluation of shortness of breath with exercise. The symptoms had progressed over the past 12 months, and she also complained of lightheadedness and weakness when running. Of note she had gained 11 kg

120 1.72 22.8 0.87 180 9.5 63 35 33 1.12 Shortness of breath

Power, W ˙ O2, L/min V ˙ O2, mL/kg/min V A.T., L/min H.R., bpm O2 Pulse, mL/beat ˙ E, L/min V f, br/min ˙ E/V ˙ CO2, at AT V RER Reason for stop

Ideal weight: 68 kg.

Peak

Variable 90% 88% 79% N ( > 0.85) 93% 95% 51% N N H 10/10

%Pred

Table 10 Maximal cardiopulmonary incremental exercise test in a 26-year-old female with unexplained exertional dyspnea. Height: 163 cm. Weight: 75 Kg. Protocol: maximal, symptom limited, incremental cycle ergometry, 15 W/min.

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Figure 4 Baseline and post-exercise laryngoscopy images demonstrating normal vocal cord positioning (left) and paradoxical anterior adduction with a posterior glottic "chink" during inspiration (right) consistent with VCD.

over the past 18 months. Physical examination, chest radiograph, screening spirometry, and pulse oximetry measurements were normal. Methacholine bronchoprovocation testing was negative. CPET was performed to further delineate the cause of her exertional symptoms. Peak CPET results and graphical presentation are displayed in Table 11 and Fig. 5. CPET Interpretation. The patient provided an outstanding effort, with an RER of 1.19 and lactate of 8.4 mmol/L at peak exercise. Exercise was terminated due to dyspnea (8/10 on Borg scale). The aerobic capacity ˙ O2peak) was normal, but slightly reduced when normalized for body mass (V ˙ O2/kg). Cardiovascular and EKG responses were normal. There was a (V significant breathing reserve at peak exercise, and a marked abnormal respiratory pattern was observed. During unloaded exercise respiratory frequency abruptly increased from 16 to 50 breaths/min, then continued to escalate to 69 at peak exercise. Tidal volume increased in a somewhat flat˙ CO2 remained abnormally increased throughout ˙ E/V tened fashion, and V ˙ ˙ exercise. Normal VD/VT responses and the lack of hypoxemia further support the clinical impression of hyperventilation disproportionate to the level of metabolic acidosis present. The minimal change in pH associated with this excessive respiratory frequency and low PaCO2 at peak exercise

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Table 11 Maximal cardiopulmonary incremental exercise test in a 24-year-old black female with unexplained exertional dyspnea. Height: 170 cm. Weight: 79 kg. Protocol: maximal, symptom limited, incremental cycle ergometry, 15 W/min. Variable

Peak

%Pred

Variable

Rest

Peak

Power, W ˙ O2, L/min V ˙ O2, mL/kg/min V A.T., L/min H.R., bpm O2 Pulse, mL/beat ˙ E, L/min V f, br/min RER

150 1.84 23.3 0.97 167 11.0 93.5 69 1.19

103% 89% 76% N ( > 0.85) 86 103% 71% H H

SaO2, % PaO2, mm Hg PaCO2, mm Hg pH HCO3, mEq/L P(A-a)O2, mm Hg ˙ D/V ˙T V Lactate, mmol/L Reason for stop

94% 86 34 7.40 22 6 0.25 1.6 Dyspnea

95% 93 28 7.38 16 12 0.14 8.4 8/10

Ideal weight: 68 kg.

reflects physiologic compensation for a low CO2 set point due to chronic hyperventilation. ˙ O2/ Conclusions. Normal exercise capacity with a mildly reduced V kg reflecting the patient’s recent weight gain. The early and sustained increase in respiratory frequency disproportionate to the metabolic stress of exercise and resulting inefficient ventilation is consistent with primary hyperventilation. Psychogenic disorders are common in patients with unexplained dyspnea, and can easily be missed if the clinician relies on resting diagnostic testing alone. In this case, a maximal incremental exercise protocol without respiratory function measurements may have missed the diagnosis due to the patient’s normal exercise tolerance. The patient subsequently reported a history of significant childhood abuse, and responded well to psychiatric treatment counseling, and a regimented conditioning program.

C. Case 3 (Ref. 63)

A 36-year-old female presented for evaluation of progressive exertional dyspnea. She had formerly been a 100-mile/week cyclist, but had noted progressive decreasing exercise tolerance despite no other changes in her routine. Physical examination, chest radiograph, screening spirometry, and pulse oximetry measurements were all normal. Methacholine bronchoprovocation testing was negative. CPET was performed to focus further diagnostic testing efforts to determine the underlying cause of this patient’s unexplained dyspnea. Peak

Figure 5 Graphic presentation of CPET data (Case 2). The marked abnormal breathing pattern (Plot E, normal breathing pattern inset for comparison) and persistently increased VE/VCO2 observed throughout exercise without other significant abnormalities support a clinical impression of primary hyperventilation.

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Table 12 Maximal Cardiopulmonary Incremental Exercise Test in a 36-year Old Female Cyclist with Progressive Exertional Dyspnea. Protocol: maximal, symptom limited, incremental cycle ergometry, 20 W/min Variable

Peak

% Pred Variable

Rest

Peak

Power, W ˙ O2, L/min V ˙ O2, mL/kg/min V A.T., L/min H.R., bpm O2 Pulse, mL/beat ˙ E, L/min V f, br/min ˙ CO2, at AT ˙ E/V V

100 1.03 15.1 Indeterminate 171 6.0 61 69 65

79% 57% 55%

SaO2, %

94%

94%

92% 61% 75% H H

FVC FEV1 Ratio TLC MVV

110% predicted 123% predicted 0.88 123% predicted 101 L/min

RER

1.17

H

Reason for Dyspnea stop Leg fatigue

10/10 8/10

CPET results, graphical data presentation, maximal and exercise flowvolume loops appear in Table 12 and Figs. 6 and 7. CPET Interpretation. The patient provided an excellent effort, with obvious physical signs of exhaustion with maximal HR achieved (92% predicted). Exercise was terminated due to dyspnea and leg fatigue. The aero˙ O2–WR ˙ O2peak) was reduced with an abnormal V bic capacity (V ˙ O2 relationship was abnormal with an relationship (Fig. 7A). The HR–V ˙ O2 (Fig. 7B). The AT inappropriately high HR at submaximal levels of V was indeterminate using both the V-slope method and the ventilatory ˙ E–V ˙ O2 equivalents method due to hyperventilation (Fig. 7C, F). The V ˙ E for the level of V ˙ O2 relationship demonstrates an inappropriately high V (Fig. 7D), which is largely caused by a rapid abnormal increase in f ˙ O2 and V ˙ E/V ˙ CO2 were also increased at low levels of ˙ E/V (Fig. 7E). V ˙ O2, supporting other evidence of inefficient ventilation due to hyperventiV lation. Exercise tidal flow-volume loop measurements (Fig. 7) showed an abnormal increase in end-expiratory lung volume (EELV) with exercise, a reduction in inspiratory capacity (IC), and encroachment on the inspiratory flow envelope consistent with respiratory muscle dysfunction. Conclusions. Abnormal CPET with a hyperventilatory, hypercirculatory pattern, and reduced exercise capacity consistent with a cardiac/ deconditioning etiology; an exercise tidal volume loop (Fig. 6) suggested respiratory muscle fatigue. As this was a well-conditioned athlete who maintained a regular, rigorous exercise routine, deconditioning was unlikely and further training was considered low yield (Fig. 3). Subsequent cardiac work-up including an echocardiogram was negative. Due to the markedly discordant clinical presentation and CPET pattern, a muscle biopsy was performed that demonstrated histologic evidence of mitochondrial

Figure 6 Graphic presentation of CPET data showing the hyperventilatory, hypercirculatory pattern with reduced exercise capacity that can be associated with mitochondrial myopathy (case 3).

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Figure 7 Exercise tidal flow volume loop showing an abnormal increase in EELV with exercise, a reduction in the inspiratiory capacity, and encroachment on the inspiratory flow envelope consistent with respiratory muscle dysfunction.

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109. Weisman I, Zeballos R. An integrative approach to the interpretation of cardiopulmonary exercise testing. In: Weisman I, Zeballos R, eds. Clinical Exercise Testing. Basel: Karger, 2002:300–322. 110. Zeballos R, Weisman I, Connery S. Comparison of pulmonary gas exchange measurements between incremental and constant work exercise above the anaerobic threshold. Chest 1998; 113:602–611. 111. Howley E, Basett D, Welch H. Criteria for maximal oxygen uptake: review and commentary. Med Sci Sports Exerc 1995; 27:1292–1301. 112. Myers J, Ashley E. Dangerous curves: a perspective on exercise, lactate, and the anaerobic threshold. Chest 1997; 111:787–795. 113. Weisman I, Zeballos R. Clinical exercise testing. Clin Chest Med 2001; 22(4):679–701. 114. Johnson B, Weisman I, Zeballos R, Beck K. Emerging concepts in the evaluation of ventilatory limitation during exercise: the exercise tidal flow-volume loop. Chest 1999; 116(2):488–503. 115. Magarian G. Hyperventilation syndromes: infrequently recognized common expressions of anxiety and stress. Medicine 1982; 61:219–236. 116. Gardner W. The pathophysiology of hyperventilation disorders. Chest 1996; 109:516–534. 116a. Johnson BD, Badr MS, Dempsey JA. Impact of the aging pulmonary syatem on the responce to excrcise. . Clin Chest Med 1994; 15:229–246. 117. Johnson B, Weisman I. Clinical exercise testing. In: Crapo J, Glassroth J, Karlinsky J, King T, eds. Baum’s Textbook of Pulmonary Diseases. 7th ed. Philadelphia, Lippincott: Williams & Wilkins, 2004. 118. Anthonisen N, Fleetham J. Ventilation: total, alveolar, and dead space. In: Fishman A, ed. Handbook of Physiology, the Respiratory System: Gas Exchange. Bethesda, MD: American Physiological Society, 1987:113–117. 119. Hansen J, Sue D, Wasserman K. Predicted values for clinical exercise testing. Am Rev Respir Dis 1984; 129:S49–S55. 120. Jones N. Clinical Exercise Testing. Philadelphia: WB Saunders, 1988. 121. Wagner P. Determinants of maximal oxygen transport and utilization. Annu Rev Physiol 1996; 58:21–50. 122. Gardner W, Meah M, Bass C. Controlled study of respiratory responses during prolonged measurement in patients with chronic hyperventilation. Lancet 1986; 2:826–830. 123. Kinnula V, Sovijarvi A. Elevated ventilatory equivalents during exercise in patients with hyperventilation syndrome. Respiration 1993; 60:273–278. 124. Lary D, Goldschlager N. Electrocardiogram changes during hyperventilation resembling myocardial ischemia in patients with normal coronary arteriograms. Am J Heart 1974; 87:383–390. 125. Whipp B, Davis J. The ventilatory stress of exercise in obesity. Am Rev Respir Dis 1984; 129:S90–S92. 126. Dempsey J, Reddan W, Balke B, Rankin J. Work capacity determinants and physiologic cost of weight-supported work in obesity. J Appl Physiol 1966; 21:1815–1820.

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127. Salvadori A, Fanari P, Fontana M, Buontempi L, Saezza A, Baudo S, Miserocci G, Longhini E. Oxygen uptake and cardiac performance in obese and normal subjects during exercise. Respiration 1999; 66:25–33. 128. Babb T, Buskirk E, Hodgson J. Exercise end-expiratory lung volumes in lean and moderately obese women. Int J Obes 1989; 13:11–19. 129. Johnson B, Beck K, Olsen L, O’Malley K, Allison T, Squires R, Gau G. Ventilatory constraints during exercise in patients with congestive heart failure. Chest 2000; 117:321–332. 130. Chua T, Ponikowski P, Harrington D, Anker S, Webb-Peploe K, Clark A, Poole-Wilson P, Coates A. Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol 1997; 29:1585–1590. 131. Janicki J, Weber K, Likoff M, Fishman A. Exercise testing to evaluate patients with pulmonary vascular disease. Am Rev Respir Dis 1984; 129:S93–S95. 132. Sun X, Hansen J, Oudiz R, Wasserman K. Exercise pathophysiology in patients with primary pulmonary hypertension. Circulation 2001; 104:429–435. 133. Engelen M, Schols A, Does J, Gosker H, Deutz N, Wouters E. Exercise-induced lactate increase in relation to muscle substrates in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 162:1697–1704. 134. Montes de Oca M, Rassulo J, Celli B. Respiratory muscle and cardiopulmonary function during exercise in very severe COPD. Am J Respir Crit Care Med 1996; 154:1284–1289. 135. Babb T, Viggiano R, Hurley B, Staats B, Rodarte J. Effect of mild-to-moderate airflow limitation on exercise capacity. J Appl Physiol 1991; 70:223–230. 136. O’Donnell D. Breathlessness in patients with chronic airflow limitation: mechanisms and management. Chest 1994; 106:904–912. 137. O’Donnell D, Revill S, Webb K. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164:770–777. 138. Hansen J, Wasserman K. Pathophysiology of activity limitation in patients with interstitial lung disease. Chest 1996; 109:1566–1576. 139. Harris-Eze A, Sridhar G, Clemens R, Zintel T, Gallagher C, Marciniuk D. Role of hypoxemia and pulmonary mechanics in exercise limitation in interstitial lung disease. Am J Respir Crit Care Med 1996; 154:994–1001. 140. Krishnan B, Marciniuk D. Cardiopulmonary responses during exercise in interstitial lung disease. In: Weisman I, Zeballos R, eds. Clinical Exercise Testing. Basel: Karger, 2002:186–199. 141. Weisman I, Lynch J, Martinez F. Role of physiologic assessment in advanced interstitial lung disease. In: Maurer J, ed. Management of Non-Neoplastic Lung Disease. New York: Marcel Dekker, 2003:179–247. 142. Saltin B. Physiologic effects of physical conditioning. Med Sci Sports 1969; 1:50–56. 143. Howard P, Maher L, Pryde A, Heading R. Symptomatic gastro-oesophageal reflux, abnormal oesophageal acid exposure, and mucosal acid sensitivity are three separate, though related, aspects of gastro-oesophageal reflux disease. Gut 1991; 32:128–132.

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144. DaCosta J. On irritable heart: a clinical study of a form of functional cardiac disorder and its consequences. Am J Med Sci 1871; 61:517–552. 145. Saisch S, Wessely S, Gardner W. Patients with acute hyperventilation presenting to an inner-city emergency department. Chest 1996; 110:952–957. 146. Zarich S, Kowalchuk G, McGuire M, Benotti P, Mascioli E, Nesto R. Left ventricular filling abnormalities in asymptomatic morbid obesity. Am J Cardiol 1991; 68:377–381. 147. Klein S, Wolfe R. Carbohydrate restriction regulates the adaptive response to fasting. Am J Physiol 1992; 262:E631–E636. 148. Despres J, Bouchard C, Savard R, Tremblay A, Marcotte M, Theriault G. Effects of exercise-training and detraining on fat cell lipolysis in men and women. Eur J Appl Physiol 1984; 53:25–30. 149. Doucet E, Imbeault P, St-Pierre S, Almeras N, Mauriege P, Richard D, Tremblay A. Appetite after weight loss by energy restriction and a low-fat diet—exercise follow-up. Int J Obes Relat Metab Disord 2000; 24:906–914. 150. Poirier P, Despres J. Exercise in secondary prevention and cardiac rehabilitation: exercise in weight management of obesity. Cardiol Clin 2001; 19(3):459–470. 151. Marwick T, Nemec J, Pashkow F, Stewart W, Salcedo E. Accuracy and limitations of exercise echocardiography in a routine clinical setting. J Am Coll Cardiol 1992; 19:74–81. 152. Bonow R. Prognostic assessment in coronary artery disease: role of radionucleotide angiography. J Nucl Cardiol 1994; 1:280–291. 153. Gibbons R, Fyke FI, Clements I, Lapeyre AI, Zinsmeister A, Brown M. Noninvasive identification of severe coronary artery disease using exercise radionucleotide angiography. J Am Coll Cardiol 1988; 11:28–34. 154. Dandurand R, Matthews P, Arnold D, Eidelman D. Mitochondrial disease: pulmonary function, exercise performance, and blood lactate levels. Chest 1995; 108:182–189. 155. Kannel W, Belanger A. Epidemiology of heart failure. Am J Heart 1991; 121:951–957. 156. Wong W, Gold S, Fukuyama O, Blanchette P. Diastolic dysfunction in elderly patients with congestive heart failure. Am J Cardiol 1989; 63:1526–1528. 157. Taivassalo T, De Stefano N, Argov Z, Matthews P, Chen J, Genge A, Karpati G, Arnold D. Effects of aerobic training in patients with mitochondrial myopathies. Neurology 1998; 50:1055–1060. 158. McGoon M. The assessment of pulmonary hypertension. Clin Chest Med 2001; 22(3):493–508. 159. Barnes P. Chronic obstructive pulmonary disease. N Engl J Med 2000; 343(4):269–280. 160. Saey D, Debigare R, Leblanc P, Mador M, Cote C, Jobin J, Maltais F. Contractile leg fatigue after cycle exercise: a factor limiting exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 168:425–430. 161. American Thoracic Society/European Respiratory Society Task Force. Standards for the diagnosis and treatment of patients with COPD. Eur Respir J 2004; 23: 932–946.

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162. Griffiths T, Burr M, Campbell I, Lewis-Jenkins V, Mullins J, Shiels K, Turner-Lawlor P, Payne N, Newcombe R, Ionescu A, Thomas J, Tunbridge J, Lonescu A. Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomized controlled trial. Lancet 2000; 348:362–368. 163. NIH/NHLBI. Guidelines for the Diagnosis and Management of Asthma. Update on selected Topcis 2002. 02–5075. Bethesda: NIH, 2002:1–129. 164. Selroos O, Ekstrom T. Formoterol turbohaler 4.5 microg (delivered dose) has rapid onset and 12-hr duration of bronchodilation. Pulm Pharmacol Ther 2002; 15(2):175–183.

11 Health Status, Health-Related Quality of Life, and Dyspnea in COPD

PAUL W. JONES St. George’s Hospital Medical School, London, U.K.

I. Introduction The primary effects of COPD are in the lungs, and while breathlessness is a key link between lung pathophysiology and impaired health and well-being, there are others. It is now recognized that COPD is a multisystem disease and, in common with other chronic diseases, it has secondary effects on other organs and systems. These include the skeletal muscle, in which wasting can occur through disuse atrophy and cachexia. Cardiovascular disturbances include pulmonary hypertension and there may be effects on myocardial function and skeletal muscle circulation due to lack of physical exercise. Mechanisms of breathlessness are discussed in other chapters, but it should be recognized that fatigue is also a common, complex and illunderstood process in COPD (1). For reasons that are not clear, patients do not readily volunteer that fatigue is a problem until they are asked directly (2). Leg fatigue has been shown to be as important as breathlessness in limiting peak exercise performance (3). Muscle weakness particularly of the legs (4) but also the arms (5), is a feature of COPD. This may not be due entirely 265

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to disuse atrophy since nutritional depletion also occurs (6) and there is evidence of circulating inflammatory cytokines in COPD (7). Disturbed sleep appears to be a common feature. A recent survey carried out by the British Lung Foundation found that half of the respondents had regular sleep disturbance. Cognitive dysfunction may be present (8) and mood impairment may occur (9). This may be confined to subgroups within the COPD population who appear to have especially high scores for anxiety and depression (10). Depression scores are not uniformly elevated, even in patients with moderate–severe COPD (1). The importance of exacerbations is now recognized in COPD. The frequency of reported COPD exacerbations increases with disease severity (11), although patients appear to under-report them (12). In patients with moderate–severe COPD, prospective data collection with diary cards revealed a median exacerbation rate of 3 per year with a range of 1–8 (12). Lung function can take several weeks to recover following an exacerbation (13), so exacerbation frequency is clearly an important factor in this disease. It is very clear that the development of ill health due to chronic disease is complex and involves numerous mechanisms (Fig. 1). Not only are there multiple disease mechanisms, but there are also multiple

Figure 1 health.

Model of the pathways linking disease processes in the lungs to impaired

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mechanisms by which treatments may work. This means that an overall assessment of the impact of COPD, and an overall assessment of treatment, requires that all of these factors should be taken into account. The treatment of COPD is now multidimensional with a number of different modalities. This means that there is now an even greater need for outcomes that provide an unbiased estimate of therapeutic efficacy, independent of treatment type. II. Assessing the Overall Effect of COPD COPD assessment requires an integrative measure that sums the discrete effects of the disease into an overall summary score. This summary measure should bring together effects due to disturbances of lung function and those resulting from effects on other organs. Only two types of measurement currently provide this integrative function in COPD: cardiopulmonary exercise testing and questionnaires. From a physiological perspective, exercise tests provide a measure of overall cardiopulmonary function, they are objective, and they can be standardized. Their main disadvantage is that they do not address factors such as sleep disturbance, effects of cough and sputum production, impact of exacerbations and feelings of malaise and impaired wellbeing. To tackle all areas of impaired health, it is necessary to question the patient. This is the basis of clinical history taking, which is still the first clinical skill taught to medical students. Whilst medicine is now greatly reliant upon laboratory-based measurements, this has not invalidated the process of questioning patients to describe and quantify their symptoms. Clinical histories are largely qualitative and descriptive, but for scientific measurement, standardization is required. Health status measurement is a process that is essentially like taking a highly structured clinical history, although the end-product is not a clinical impression, but an objective and valid measurement. III. Quality of Life Vs. Health Status Measurement It is important to distinguish between ‘‘quality of life’’ which covers all aspects of an individual’s life and ‘‘health-related quality of life’’ which is limited to those areas of life disturbed specifically by disease. Health is only a minor factor in determining quality of life, even in patients with serious disease, but even the term ‘‘health-related quality of life’’ has disadvantages. People live very different lives, so its quality will be affected by disease in many different ways. It is useful to think of health-related quality of life as being unique to each patient. This concept comes into its own when making qualitative assessments of individual patients, and the effect of disease and treatment upon them.

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Standardized measurement means that all patients are assessed in exactly the same way. Questionnaires designed to measure the effect of COPD on symptoms, daily activities, and sense of well-being in groups of patients that must therefore be standardized. All items in the questionnaire must be relevant to all patients with the disease, at least potentially. Items that do not apply universally should not be included—for example, playing with grandchildren. Sophisticated scientific methodology is used for developing questionnaires, but this results in the construction of a questionnaire made up of items that are common to all patients. In this process, individuality is selected against. For these reasons, the term ‘‘health status measurement’’ may be a better description of the use of these questionnaires, to distinguish it from qualitative ‘‘health-related quality of life’’ assessment in individuals. Much of this chapter is concerned with health status measurement and what it can tell us about COPD and its treatment. The data discussed in this chapter present average results from studies carried out in groups of patients. Benefit to an individual’s health-related quality of life will depend on their circumstances and will vary among patients. IV. Health Status Questionnaires Health status questionnaires fall into two broad types: disease specific and general health. The major differences between them lie in terms of their content. As implied by the name, general health questionnaires are designed to assess the impact of any disease, whereas the content of disease-specific questionnaires is chosen for the disease in question. A. General Health Questionnaires

There are a number of these, and brief details of the most widely used are detailed below. 1. Medical Outcomes Study SF-36

The Medical Outcomes Study Short-Form 36-Item (SF-36) questionnaire covers eight dimensions of health: Physical Functioning, Physical Role Limitation, Social Functioning, Emotional Role Limitation, General Health, Vitality, Mental Health, and Bodily Pain (14,15). Each dimension is scored separately and transformed to a 0–100 scale. Two global scores are obtained for a Physical Component Summary and a Mental Component Summary. Patients can complete this instrument in 5–10 min. It has been validated in COPD and is used quite widely in COPD studies (16). Generic health instruments tend to be less sensitive than disease-specific questionnaires in clinical trials, although the SF-36 has shown responsiveness to change with treatment, both with rehabilitation (17) and inhaled

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corticosteroids (18). The disadvantage with the SF-36, as a general health measure, is that its scoring range does not include death, which limits its usefulness for health economic analyses. 2. Quality of Well-Being Scale

The Quality of Well-being (QWB) scale is a general health scale with utility properties—its scores ranges from perfect health (1) to death (0), so it can be used in cost–utility analyses. It contains 50 items with three components: Mobility, Physical activity, and Social activity. It is quite complex to use and takes approximately 10–15 min to be completed through an interview. It has been validated for use in obstructive airway disease (19), and has now been shown to respond to pulmonary rehabilitation (20). 3. EQ-5D (or EuroQol)

The EQ-5D is a utility scale that provides a simple and brief method for individuals to rate health status using a visual analog scale for five dimensions (Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression) (21). It is probable that this will be used increasingly in clinical trials, especially those sponsored by pharmaceutical companies. B. Disease-Specific Questionnaires

There are a number of questionnaires developed specifically for COPD. 1. Chronic Respiratory Disease Questionnaire

The Chronic Respiratory Disease Questionnaire (CRQ) was designed as an evaluative instrument to quantify changes in health (2,22). It consists of four components: Dyspnea (five items), Fatigue (four items), Mastery (four items), and Emotion (seven items). Each item is graded by the patient using a seven-point Likert scale. For the Dyspnea component, the subject is asked to describe the five most common activities that caused dyspnea over the past two weeks by recall and then by reading a list of 26 different activities. It takes 15–20 min for the first assessment. An interviewer is required to assist the patient in making these selections, but a standardized self-complete version is available. 2. St. George’s Respiratory Questionnaire

The St. George’s Respiratory Questionnaire (SGRQ) was developed for patients with asthma or COPD (23,24). Its three components are Symptoms (distress attributable to cough, wheeze, and acute exacerbations), Activity (disturbance of physical activity and mobility caused by dyspnea), and Impacts (psycho-social effects of the disease). It takes 10–15 min to

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complete. It was designed for supervised self-administration, but has also been validated for use by telephone and computer administration. The method of scoring differs from other disease-specific instruments because each item has its own empirically derived weight that is independent of age, gender, disease severity, and duration (25) and largely independent of country (26). 3. Other Disease-Specific Questionnaires

A number of other disease-specific questionnaires have been produced in recent years. Among them are the Breathing Problems Questionnaire (BPQ) (27,28) and the QOL-RIQ—a questionnaire developed originally in Dutch, but also available in English (29). Other questionnaires developed in the U.S.A. include the Seattle Obstructive Lung Disease Questionnaire (30) and two questionnaires that concentrate two functions limitation questionnaires that are similar in many respects to health status instruments: the Modified Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ-M) (31) and the Pulmonary Functional Status Scale (PFSS) (32). The latter questionnaires are in wide use in pulmonary rehabilitation programs in the U.S.A. All health status questionnaires tend to be rather long, which makes them largely unsuitable for use in the clinic. For this reason, a short questionnaire, the AQ20, was developed for routine use in asthma and COPD (33–35). It requires 2–3 min to complete and score. 4. Questionnaires for Severe Disease

Most of the disease-specific questionnaires were developed for patients who have at least some degree of mobility, but some patients particularly those with respiratory failure may have severe restriction of daily activity and be largely housebound. This may place them at one end of the scoring range of a questionnaire. Furthermore, a questionnaire designed for patients who are less severely restricted may not have enough items to discriminate well between different levels of very severe disease. The general health questionnaires, especially those that include death at one end of the scaling range may be more suitable. To meet the need for a disease-specific instrument for such patients, two different types of instrument have been developed. One, the LCADL, was designed specifically to assess limitations of activities of daily living in COPD patients (36). The other is a comprehensive measure of health status impairment for patients with respiratory failure irrespective of cause (37). There is evidence for the validity of these two questionnaires, although it is not yet clear whether either offers any distinct advantages over the existing instruments.

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V. Determinants of Health Status Questionnaires There is now a large body of evidence to demonstrate the links and strength of association between a wide range of aspects of COPD and health status scores. This has been summarized extensively elsewhere (38). In recent years, the important effect of exacerbations on health status has been established. A single exacerbation has a large effect on health that may persist for many months (39). Patients with frequent exacerbations have worse health (12). Recently, it has been shown that the health of COPD patients declines at a measurable rate (18). This is due, in part, to decline in FEV1, and partly due to exacerbations (40). Preventing exacerbations with inhaled corticosteroids reduces this rate of decline (40). Another recent finding is that health status predicts mortality when measured with the SGRQ (41,42) and SF-36 (42), but not the CRQ (43). The relationship between mortality and health status appears to be independent of FEV1, age, and Body Mass Index (41), but not exercise capacity (42). Dyspnea measured using the MRC is also a better predictor of mortality than airway obstruction (44).

VI. Dyspnea and Health Status There are a number of studies that show moderate correlations (r ¼ 0.46– 0.70) between dyspnea and health status (24,37,45,46). This association is present whether dyspnea is measured directly during an exercise test (e.g., using a Borg score), or indirectly through patient report of the effect of dyspnea on daily activities through the MRC Dyspnea Scale (Fig. 2). While the SGRQ correlated better with the MRC grade than the Borg score, both dyspnea measures were stronger correlates of health status than FEV1 (24). To set the impact of dyspnea on overall health into perspective, Figure 3 shows the proportion of variance in SGRQ Total score attributable to the MRC Dyspnea Grade, compared to other important determinants of health and well-being in COPD (24). About 20% of the variance in SGRQ score is attributable to variance in breathlessness measured in this way (this corresponds to an r value of
0.45). In that study, at least, dyspnea was the strongest correlate of impaired health of all the variables measured. The correlations described above are all cross-sectional, i.e., they reflect differences among patients. Health status questionnaires are also used to measure changes over time, but fewer studies have measured the correlation between changes in dyspnea and changes in health. One recent study reported a correlation between Transition Dyspnea Index (TDI) (the TDI is a change score) and change in SGRQ Total score of r ¼ 0.4 (47). This was slightly higher in English speaking countries (r ¼ 0.46) than nonEnglish speaking (r ¼ 0.38). In another study, it was possible to measure

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Figure 2 Correlations between St. George’s Respiratory Questionnaire (SGRQ) score and postbronchodilator FEV1 (as % of predicted normal), breathlessness measured using the Borg CR-10 scale at the end of paced stepping and MRC Dyspnea Grade. Source: Data are from Ref. 24.

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Figure 3 Partial correlations (as percentage of total variance) calculated from a multiple regression between SGRQ Total score and a number of COPD diseaserelated factors. Source: Data are from Ref. 24.

correlations between SGRQ score and MRC Dyspnea Grade both between patients, and within the same patients over one year (24). The longitudinal correlations were weaker than the cross-sectional comparisons, because changes within patients are smaller than the differences between them, but it is possible to make comparisons between the two by normalizing the data. These are plotted for two of the SGRQ components, the Activity and Impacts scores (Fig. 4). There is a different pattern of correlations between the two SGRQ components, but the relative contribution of dyspnea to each remains quite consistent, whether reflecting differences between or within patients. This is an important observation, since it suggests that differences in scores between patients reflect the same factors that determine changes within patients. Furthermore, it emphasizes the importance of dyspnea in determining health. VII. Changes in Health Status and Dyspnea COPD is usually a progressive disease, and changes in breathlessness over time have now been reported in COPD in terms of breathlessness, generic health, and disease-specific health status scores (18,48). Two large 6-month studies in COPD have compared the effect of salmeterol, fluticasone, the combination of both, or placebo on health status and dyspnea. The relative

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Figure 4 Partial correlations between a number of COPD disease-related factors and two components of the SGRQ: Activity and (psycho-social) Impacts. Data are both cross-sectional (between patients) and longitudinal (within patients). The proportion of variance is normalized to permit comparison of the relative contribution of each of the factors in each of the comparisons. Source: Data are from Ref. 24.

benefits of each of the treatments were somewhat inconsistent between studies (49,50), but there was a rank order correlation between improvement in TDI and improved CRQ score (Fig. 5). Data from a one-year study of tiotropium vs. ipratropium (51) provide a comparison of the patterns of change in dyspnea and health status with treatment over time (Fig. 6). For clarity, this figure shows the results only from those patients who received tiotropium. It can be seen that all of the improvement in FEV1 was present eight days after treatment was started. Thereafter, the only change was a very small drift down over the rest of the study. In terms of breathlessness, there was a clinically significant improvement, again within eight days of starting treatment. Following that there was a further small improvement, followed by a progressive deterioration. By Day 182, the TDI had fallen below the value at Day 8. The SGRQ scores showed a different pattern. They continued to improve to reach a maximum improvement at Day 182. Thereafter, they too began to worsen very slightly. Another study using tiotropium had a very similar design, but with a placebo control arm. The pattern of changes in the tiotropium treated patients was very similar to those shown in Figure 6 (52). The difference in speed of response to tiotropium between dyspnea and health

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Figure 5 Transition Dyspnea Index (TDI) scores and Total scores from the Chronic Respiratory Questionnaire (CRQ) measured at the end of 6 months treatment with salmeterol, fluticasone, the combination of both or placebo. Source: The data are from two trials, Refs. 49 (closed symbols) and 50 (open symbols).

status suggests that the drug is operating through more than one mechanism. The early improvement in dyspnea and health status is almost certainly attributable to improved lung function. The slower and more sustained improvement in health status may have been due to another mechanism such as prevention of exacerbations, since tiotropium treatment was associated with fewer exacerbations than either of the control treatments. VIII. Health-Related Quality of Life and Dyspnea As argued earlier in this chapter, the concept of health-related quality of life applies more to the individual than groups of patients. Standardized instruments can provide a very good estimate of the state of the patient’s health on a continuum from good to very poor health (or death), but they have limited value for assessing the response to changes with treatment in individuals. There are two main reasons for this. The first is individual specificity in terms of the impact of the disease. The second is statistical. The repeatability of questionnaire scores is usually very good (intraclass correlations typically 0.9), but this is still insufficient to permit the reliable detection of a clinically significant change in score. Health status and dyspnea instruments are not

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Figure 6 Trough FEV1 measurement (made in the morning predose), TDI scores and SGRQ scores in patients treated with the long-acting bronchodilator tiotropium. With the SGRQ a lower score means better health. With the TDI a higher score means less breathlessness. Note that the first estimate of TDI and SGRQ took place on Day 8. Source: Data are redrawn from the study by Vincken et al. (51).

unique in this respect. The response of FEV1 to bronchodilators in COPD is typically 100–160 mL, which is below the limits of between-day variability. The only effective way to detect change is through patient report and clinician assessment. There is good evidence that both patients’ and

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physicians’ subjective assessments of clinically detectable treatment effects correlate with a clinically significant change in health status score (53). There is also recent evidence that the minimum estimable change in clinician global assessments of COPD severity correlates with the threshold of change in TDI score (54). These associations provide us with confidence that clinicians and patients can detect a clinically worthwhile change, but they provide us with no insight into how they do this or what factors they take into account. In my own practice, I have tried to ascertain, from patients, what grounds they use for reporting symptomatic benefit from long-acting bronchodilators. This seems to be due, nearly always, to a perceived reduction in breathlessness, ‘‘easier breathing,’’ a longer duration of effect on breathlessness, or better exercise capacity because of the better breathing. It is also my impression that patients appear able to detect specific benefits after they occur, but are very poor at predicting what might improve. This means that goal-setting as a method of assessing clinical benefit from pharmacological therapies may have limited value.

IX. Summary Breathlessness is an important factor contributing to impaired health and quality of life. But it is not the only one, and it is clear that health status is determined by other factors that may be as important. In terms of individual patients, their subjective perception of change forms an essential component of the clinical assessment that is needed to judge whether they have had a worthwhile response to treatment. It is likely that aspects of breathlessness form a key component of that process. References 1. Breslin E, van der Schans C, Breukink S, Meek P, Mercer K, Volz W, Louie S. Perception of fatigue and quality of life in patients with COPD. Chest 1998; 114(4):958–964. 2. Guyatt GH, Townsend M, Berman LB, Pugsley SO. Quality of life in patients with chronic airflow limitation. Br J Dis Chest 1987; 81:45–54. 3. Killian KJ, Summers E, Jones NL, Campbell EJ. Dyspnea and leg effort during incremental cycle ergometry. Am Rev Respir Dis 1992; 145:1339–1345. 4. Gosselink R, Troosters T, DeCramer M. Peripheral muscle weakness contributes to exercise limitation in COPD. Am J Respir Crit Care Med 1996; 153:976–980. 5. Bernard S, Whittom F, Leblanc P, Jobin J, Belleau R, Berube C, Carrier G, Maltais F. Aerobic and strength training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159(3):896–901.

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6. Engelen MPKJ, Schols AMWJ, Baken WC, Wesseling GJ, Wouters EFM. Nutritional depletion in relation to respiratory and peripheral skeletal muscle function in out-patients with COPD. Eur Respir J 1994; 7:1793–1797. 7. Schols A, Buurman WA, Staal-van den Brekel AJ, Dentener MA, Wouters EFM. Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax 1996; 51(8):819–824. 8. Grant I, Prigatano GP, Heaton RK, McSweeny AJ, Wright EC, Adams KM. Progressive neuropsychologic impairment and hypoxemia. Relationship in chronic obstructive pulmonary disease. Arch Gen Psychiatry 1987; 44(11):999–1006. 9. Janssens JP, Rochat T, Frey JG, Dousse N, Pichard C, Tschopp JM. Healthrelated quality of life in patients under long-term oxygen therapy: a home-based descriptive study. Respir Med 1997; 91(10):592–602. 10. Engstrom CP, Persson LO, Larsson S, Ryden A, Sullivan M. Functional status and well being in chronic obstructive pulmonary disease with regard to clinical parameters and smoking: a descriptive and comparative study. Thorax 1996; 51(8):825–830. 11. Jones PW, Willits LR, Burge PS, Calverley PMA. Disease severity and the effect of fluticasone propionate on chronic obstructive pulmonary disease exacerbations. Eur Respir J 2003; 21:1–6. 12. Seemungal TAR, Donaldson GC, Paul EA, Bestall JC, Jefferies DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157:1418–1422. 13. Seemungal TA, Donaldson GC, Bhowmik A, Jefferies DJ, Wedzicha JA. Times course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161:1608–1613. 14. Stewart AL, Hays R, Ware JE. The MOS short-form general health survey. Reliability and validity in a patient population. Med Care 1988; 26:724–732. 15. Ware JE, Gandeck B. Overview of the SF-36 health survey and the International Quality of Life Assessment (IQOLA) Project. J Clin Epidemiol 1998; 51:903–912. 16. Mahler DA, Mackowiak JI. Evaluation of the short-form 36-item questionnaire to measure health-related quality of life in patients with COPD. Chest 1995; 107:1585–1589. 17. Griffiths TL, Burr ML, Campbell IA, Lewis-Jenkins V, Mullins J, Shiels K, Turner-Lawlor PJ, Payne N, Newcombe RG, Ionescu AA, Thomas J, Tunbridge J. Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial. Lancet 2000; 355(9201):362–368. 18. Spencer S, Calverley PMA, Burge PS, Jones PW. Health status deterioration in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163:122–128. 19. Kaplan RM, Atkins CJ, Timms R. Validity of a quality of well-being scale as an outcome measure in chronic obstructive pulmonary disease. J Chronic Dis 1984; 37:85–95.

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20. Ries AL, Kaplan RM, Myers R, Prewitt LM. Maintenance after pulmonary rehabilitation in chronic lung disease: a randomized trial. Am J Respir Crit Care Med 2003; 167:880–888. 21. EuroQol Group. EuroQol—a new facility for the measurement of healthrelated quality of life. Health Policy 1990; 20:329–332. 22. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LW. A measure of quality of life for clinical trials in chronic lung disease. Thorax 1987; 42: 773–778. 23. Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir Med 1991; 85(suppl B):25–31. 24. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure for chronic airflow limitation—the St George’s Respiratory Questionnaire. Am Rev Respir Dis 1992; 145:1321–1327. 25. Quirk FH, Jones PW. Patients’ perception of distress due to symptoms and effects of asthma on daily living and an investigation of possible influential factors. Clin Sci 1990; 79:17–21. 26. Quirk FH, Baveystock CM, Wilson RC, Jones PW. Influence of demographic and disease related factors on the degree of distress associated with symptoms and restrictions on daily living due to asthma in six countries. Eur Respir J 1991; 4:167–171. 27. Hyland ME, Bott J, Singh S, Kenyon CA. Domains, constructs and the development of the breathing problems questionnaire. Qual Life Res 1994; 3(4):245–256. 28. Hyland ME, Singh SJ, Sodergren SC, Morgan MP. Development of a shortened version of the Breathing Problems Questionnaire suitable for use in a pulmonary rehabilitation clinic: a purpose-specific, disease-specific questionnaire. Qual Life Res 1998; 7(3):227–233. 29. Maille AR, Koning CJ, Zwinderman AH, Willems LN, Dijkman JH, Kaptein AA. The development of the ‘Quality-of-life for Respiratory Illness Questionnaire (QOL-RIQ)’: a disease-specific quality-of-life questionnaire for patients with mild to moderate chronic non-specific lung disease. Respir Med 1997; 91(5):297–309. 30. Tu SP, McDonell MB, Spertus JA, Steele BG, Fihn SD. A new self-administered questionnaire to monitor health-related quality of life in patients with COPD. Chest 1997; 112:614–622. 31. Lareau SC, Breslin EH, Meek PM. Functional status instruments: outcome measure in the evaluation of patients with chronic obstructive pulmonary disease. Heart Lung 1996; 25(3):212–224. 32. Weaver TE, Narsavage GL, Guilfoyle MJ. The development and psychometric evaluation of the Pulmonary Functional Status Scale: an instrument to assess functional status in pulmonary disease. J Cardiopulm Rehabil 1998; 18(2):105–111. 33. Barley EA, Quirk FH, Jones PW. Asthma health status in clinical practice: validity of a new short and simple instrument. Respir Med 1998; 92:1207–1214. 34. Alemayehu B, Aubert RE, Feifer RA, Paul LD. Comparative analysis of two quality-of-life instruments for patients with chronic obstructive pulmonary disease. Value Health 2002; 5(5):436–441.

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35. Hajiro T, Nishimura K, Jones PW, Tsunkino M, Ikeda A, Koyama H, Izumi T. A novel, short and simple qustionnaire to measure health-related quality of life in patients with chronicobstructive pulmonary disease. AM J Respir Crit Care Med 1999; 159:1874–1878. 36. Garrod R, Bestall JC, Paul EA, Wedzicha JA, Jones PW. Development and validation of a standardized measure of activity of daily living in patients with severe COPD: the London Chest Activity of Daily Living Scale (LCADL). Respir Med 2000; 94:589–596. 37. Carone M, Bertolotti G, Anchisi F, Zotti AM, Donner CF, Jones PW. Analysis of factors that chraracterize health impairment in patients with chronic respiratory failure. Eur Respir J 1999; 13:1293–1300. 38. Jones PW. Health status measurement in chronic obstructive pulmonary disease. Thorax 2001; 56:880–887. 39. Spencer S, Jones PW. Time course of recovery of health status following an infective exacerbation of chronic bronchitis. Thorax 2003; 58:589–593. 40. Spencer S, Calverley PMA, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J 2004; 23:1–5. 41. Domingo-Salvany A, Lamarca R, Ferrer M, Garcia-Aymerich J, Alonso J, Fe´lez M, Khalaf A, Marrades RM, Monso´ E, Serra-Batlles J, Anto´ JM. Health-related quality of life and mortality in male patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166:680–685. 42. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T. Analysis of the factors related to mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 167:544–549. 43. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T, Ikeda A, Mishima M. Health status measured with the CRQ does not predict mortality in COPD. Eur Respir J 2002; 20:1147–1151. 44. Nishimura K, Izumi T, Tsukino M, Oga T. Dyspnea is a better predictor of 5year survival than airway obstruction in patients with COPD. Chest 2002; 121(5):1434–1440. 45. Hajiro T, Nishimura K, Tsukino M, Ikeda A, Oga T, Izumi T. A comparison of the level of dyspnea vs disease severity in indicating the health-related quality of life of patients with COPD. Chest 1999; 116(6):1632–1637. 46. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999; 54(7):581–586. 47. Witek TJ, Mahler DA. Minimal important difference of the transition dyspnoea index in a multinational clinical trial. Eur Respir J 2003; 21(2):267–272. 48. Mahler DA, Tomliinson D, Olmstead EM, Tosteson ANA, O’Connor GT. Changes in dyspnea, health status, and lung function in chronic airways disease. Am J Respir Crit Care Med 1995; 151:61–65. 49. Mahler DA, Wire P, Horstman D, Chang C-N, Yates J, Fischer T, Shah T. Effectiveness of fluticasone propionate and salmeterol combination delivered via the diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166:1084–1091.

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50. Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, Shah T. The efficacy and safety of fluticasone propionate (250 mcg)/salmeterol (50 mcg) combined in the Diskus inhaler for the treatment of COPD. Chest 2003; 124:834–843. 51. Vincken W, van Noord JA, Greefhorst AP, Bantje TA, Kesten S, Korducki L, Cornelissen PJ. Dutch/Belgian Tiotropium Study G. Improved health outcomes in patients with COPD during 1 yr’s treatment with tiotropium. Eur Respir J 2002; 19(2):209–216. 52. Casaburi R, Mahler DA, Jones PW, Wanner A, San Pedro G, ZuWallack RL, Menjonge SS, Serby CW, Witek T. A long-term evaluation of once daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002; 19:209–216. 53. Jones PW, Bosh TK. Changes in quality of life in COPD patients treated with salmeterol. Am J Respir Crit Care Med 1997; 155:1283–1289. 54. Witek TJ, Mahler DA. Meaningful effect size and patterns of response of the transition dyspnea index. J Clin Epidemiol 2003; 56:248–255.

12 Effect of Bronchodilators and Inhaled Corticosteroids on Dyspnea in COPD

DENIS E. O’DONNELL

DONALD A. MAHLER

Division of Respiratory and Critical Care Medicine, Department of Medicine, Queen’s University, Kingston, Ontario, Canada

Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School, Hanover, New Hampshire, U.S.A.

I. Introduction Dyspnea is the most common symptom in chronic obstructive pulmonary disease (COPD) and is a major contributor to poor health status (see Chapter 11). It follows that alleviation of this distressing symptom is one of the most important goals of management for this disease. Indeed, this objective has been highlighted in recent national and international guidelines (1,2). Bronchodilator therapy is the first step in the management of the dyspneic patient with COPD. Recent studies have confirmed that modern bronchodilator therapy is effective in achieving meaningful symptomatic improvement, even in patients with advanced disease. Moreover, there is evidence that the addition of inhaled corticosteroids (ICS) to long-acting beta-agonists provides enhanced benefit for relief of breathlessness than achieved with either agent alone. II. Assessment of Bronchodilator Efficacy In the past, exclusive reliance on an arbitrary increase in FEV1 as the primary outcome measure of interest in clinical trials in COPD has resulted 283

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in pervasive therapeutic nihilism. It has now become clear that clinically significant improvements in dyspnea and exercise capacity can occur in the presence of only minor changes in the FEV1. For this reason, there has recently been a move towards a more comprehensive evaluation of bronchodilator efficacy, which includes direct assessment of the trial drugs’ impact on dyspnea. A number of methods have been developed to examine the potential symptomatic benefits of bronchodilators (see Chapter 7). These include daily symptom diaries and a record of the subjective opinion of both the patients and their caregivers regarding the efficacy of the test drug. The documentation of a reduced requirement for reliever, short-acting bronchodilators (taken on a when-needed basis) has also been used as an indication of symptom control in clinical trials. Unidimensional instruments, such as the Medical Research Council scale (3), measure the magnitude of the task required to induce dyspnea; however, these questionnaires appear to lack sensitivity for assessment of bronchodilator therapy. Instead, multidimensional instruments such as the Baseline Dyspnea Index (BDI) and Transition Dyspnea Index (TDI) have provided greater refinement in measurement of the effects of the intervention on activity-related dyspnea over time (4). Exercise testing, which includes both field tests and cardiopulmonary exercise tests (incremental and constant work tests), has increasingly been used in dyspnea assessment. These tests are usually coupled with measurements of dyspnea intensity using validated scales such as the Borg and visual analog scales (see Chapter 8). In this review, we will confine our attention to the effects of inhaled bronchodilator medications and ICS on chronic dyspnea measured by multidimensional questionnaires and on tests of exercise performance and exertional dyspnea.

III. How do Bronchodilators Improve Dyspnea in COPD? Our understanding of the interface between pathophysiological impairment and disability has increased considerably in recent years (see Chapter 3). While the most obvious abnormality in COPD is expiratory flow limitation, the major mechanical consequence is evident in inspiration as a result of the negative effects of pulmonary hyperinflation. As ventilation increases during exercise in flow-limited patients, further acute-on-chronic dynamic hyperinflation (DH) occurs that further amplifies the derangements of ventilatory mechanics that are present at rest (5–10). DH restricts the ability to expand tidal volume (VT) appropriately during exercise because of the relatively reduced inspiratory reserve volume (IRV). Moreover, at high lung volumes, the inspiratory muscles are naturally weakened and are burdened with increased elastic and inspiratory threshold loading. The net effect of DH is an increased contractile muscle effort requirement for any given

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increase in ventilation during exercise compared with healthy individuals. In the hyperinflated COPD patient, there is, therefore, an increased disparity between the increased neural drive to breathe during exercise and the mechanical response of the respiratory system, which is blunted (i.e., neuromechanical uncoupling). The intensity of activity-related dyspnea in flowlimited patients has been found to be closely associated with the degree of DH during exercise (6–10). Bronchodilators reduce airway smooth muscle tone, thus, improving airway conductance during both expiration and inspiration. Significant improvements in dynamic small airway function can occur in the absence of change in FEV1, which mainly reflects large airway function. Improvements in tidal expiratory flow rates after bronchodilators promote lung emptying with each breath and allow the dynamically determined end-expiratory lung volume (EELV) to decline to a level closer to the relaxation volume of the respiratory system (Fig. 1). This means that after bronchodilators, patients can achieve the desired alveolar ventilation at a

Figure 1 Tidal flow-volume loops at rest (solid lines) and during exercise (dashed lines) are shown relative to the maximal loops in a typical patient with COPD. (Pre-dose) Owing to expiratory flow limitation, DH occurs during exercise and results in decreased inspiratory capacity (IC) and inspiratory reserve volume (IRV). (Post-dose) Maximal expiratory flow rates increase from pre- (dotted line) to post-bronchodilator, resulting in a decrease in EELV, as reflected by an increase in IC. A decrease in lung hyperinflation allows IC and IRV to increase, thus improving ventilatory capacity by increasing the limits for VT expansion during exercise.

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Figure 2 Operating lung volumes are shown as ventilation increases during exercise. Note the increased end expiratory lung volume (EELV) and constrained tidal volume (VT) responses to exercise in patients with COPD. Postbronchodilator testing in COPD shows a reduction in EELV with an increase in IC that, in turn, allows greater VT expansion and attainment of a higher peak ventilation during exercise.

lower operating lung volume and, therefore, at a lower oxygen cost. The reduction in EELV can be measured by body plethysmography or assessed indirectly by changes (increases) in spirometric inspiratory capacity (IC) measurements. Recent studies have confirmed that improvements in the resting IC allow greater (VT) expansion and, hence, greater submaximal and peak ventilation with exercise (9,10). Reduced dyspnea ratings following bronchodilators have been shown to be associated with an increased ability to increase VT (10) (Fig. 2). The increased resting IC at baseline means that patients can tolerate greater DH during exercise before having to stop because of intolerable dyspnea. Bronchodilators enhance neuromechanical coupling of the respiratory system, on the one hand, by increasing the ability to expand VT and, on the other, by improving the functional performance of the inspiratory muscles.

IV. Dyspnea Evaluation In clinical practice, the caregiver determines if a bronchodilator is effective by simply asking the question ‘‘has the new medication helped your breathing?’’ If the answer is affirmative, the caregiver will usually probe further to verify the patients’ subjective impression by asking if their ability to participate in a specific activity of daily living has increased. Should the patients

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report that they can now undertake a particular activity with less dyspnea or for a longer duration, the caregiver is convinced of the drugs’ benefit. However, in clinical trials, the same general principles apply except that:




the physical task is standardized; a possible placebo effect is taken into account; the impact of the drug on dyspnea intensity at a standardized stimulus is carefully quantified.

In this way, we can determine whether a new treatment consistently improves dyspnea and exercise performance in a population compared with placebo. In this review, we will primarily confine our attention to the impact of various bronchodilators and of ICS on the TDI total score and on exertional dyspnea during exercise testing. A 1-unit change is considered to be the minimal clinically important difference in the TDI total score (11,12). However, there is no consensus as to what constitutes a clinically important improvement in dyspnea ratings during exercise or in exercise duration following a therapeutic intervention. V. Inhaled Beta-2-Agonists A. Short-Acting

There is no information about the effects of short-acting beta-2-agonists on relief of dyspnea using multidimensional instruments. A detailed mechanistic study of the effects of albuterol was performed by Belman et al. (13) in 13 patients with severe COPD. The results showed significant reductions in breathlessness at a standardized exercise stimulus as assessed by the Borg scale (4.5 for placebo vs. 3.1 for albuterol; p < 0.01). The improvement in dyspnea with albuterol correlated with a decrease in end-inspiratory lung volume (EILV) that, in turn, correlated with an improvement in the effort:displacement ratio. The impact of albuterol on exercise endurance time was not measured in that study. In addition, Oga et al. (14) reported a decrease in the DdyspneaDtime slope during constant workload ergometry with albuterol (400 mg) compared with placebo. Guyatt et al. (15) examined the effects of 2 weeks of albuterol therapy on dyspnea by measuring Borg ratings at the end of the 6-min walk but failed to show a positive benefit for albuterol vs. placebo. B. Long-Acting

Seven placebo-controlled studies have examined the effects of salmeterol on the TDI total score (10,16–21) (Table 1). In a 2-week study by O’Donnell et al. (10), the treatment difference was þ2.7 units on the TDI total score

Salmeterol 50 mg bid Salmeterol 50 mg bid Salmeterol 50 mg bid Formoterol 4.5 mg bid 9 mg bid 18 mg bid Salmeterol 50 mg bid Salmeterol 42 mg bid Salmeterol 42 mg bid Salmeterol 42 mg bid

O’Donnell, 2004 (10) Hananin, 2003 (20) Brusased, 2003 (21) Aalbers, 2002 (22)

Mahler, 2002 (19) ZuWallack, 2001 (18) Rennard, 2001 (17)

Mahler, 1999 (16)

1.30 1.22 1.30 1.28

135 pl 132 salm 143 pl 135 salm

12 weeks, parallel

1.29 1.24 1.09 1.07 1.47 1.44 1.49 1.51 1.32 1.24 1.20

185 177 400 405 173 171 166 177 136 103 313

pl salm pl salm pl form4.5 form9 form18 pl salm salm

1.08

Baseline FEV1 (L)

23

n

24 weeks, parallel 12 weeks, parallel 12 weeks, parallel

2 weeks, cross-over 24 weeks, parallel 6 months, parallel 12 weeks, parallel

Study design

Significantly different from placebo. Abbreviation: pl, placebo; salm, salmeterol; form, formoterol; NS, not significant.

a

Dose

First author year

Table 1 Effects of Long-Acting beta-2-Agonists on Activity-Related Dyspnea as Measured by the TDI

D vs. pl week 2 ¼ salm > pla weeks 6 and 10 ¼ NS D vs. pl At weeks 2, 4, 8, 10a

D from baseline ¼ 1.3

D vs. pl form4.5 ¼ 0.7 form9 ¼ 0.5 form18 ¼ 1.1a D vs. pl ¼ 0.5

D vs. pl ¼ 0.7a

D vs. pl ¼ 0.7a

D vs. pl ¼ 2.7a

TDI

288 O’Donnell and Mahler

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compared with placebo (p < 0.001). In a 12-week study by Mahler et al. (16), there was minimal improvement (0.2 units in the TDI total score) after 2, 4, 8, and 10 weeks vs. placebo (p < 0.05). Rennard et al. (17) performed a 12-week study that showed a significant improvement (p < 0.005) in the TDI total score after 2 weeks of treatment with salmeterol compared with placebo; however, this effect was lost by week 6 of the study. In the 12-week study by ZuWallack et al. (18), those patients who received salmeterol had a mean improvement in the TDI total score of þ1.3 units. However, there was no placebo group in this study for comparison. In a 6-month study by Mahler et al. (19), the TDI total score increased by þ0.5 in the salmeterol group compared with placebo (p > 0.05). In 6-month studies by Hanania et al. (20) and Brusasco et al. (21), there was a difference of þ0.7 in the TDI total score with salmeterol. In a 12-week study, Aalbers et al. (22) showed a þ1.2 unit improvement in the TDI total score with formoterol (18 mg) compared with placebo (p < 0.002). In two of four placebo-controlled studies, there was a reduction in Borg dyspnea ratings at the end of the 6-min walking test after 4 and 16 weeks of salmeterol treatment compared with placebo, although there were no consistent benefits with long-acting beta-2-agonists on walking distance (16,17,23,24). In a recent cross-over trial in 23 patients with COPD, the use of salmeterol was associated with significantly improved exercise endurance time by 58% during constant work cycle ergometry at 75% of the peak work capacity and a corresponding significant reduction (0.9 units on the Borg scale) in dyspnea intensity at a standardized exercise time (10) (Fig. 3). Although the investigators did not include a placebo arm in their study design, Ayers et al. (25) showed that 42 mg salmeterol and 72 mg ipratropium bromide (four puffs) had similar effects at 1- and 6-hr postdose on dyspnea intensity (Borg ratings were 2) during steady-state cycle exercise at 60% of the peak VO2.

VI. Anticholinergic Therapy A. Short-Acting

In a 12-week study by Mahler et al. (16), the TDI total score improvement (range of difference: þ0.5 to þ1.0 units) was greater in the group receiving ipratropium bromide compared with the group receiving placebo at weeks 2, 4, 6, 8, 10, and 12 (p < 0.05). However, in a similar 12-week study by Rennard et al. (17), the positive treatment effect in the TDI score shown at week 2 (p < 0.005) with ipratropium bromide compared with placebo was lost by week 6 of treatment. O’Donnell et al. (26) conducted a 3-week cross-over study in 29 patients with severe COPD to examine the effects of this drug on exercise

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endurance and dyspnea. Nebulized ipratropium bromide (500 mg) was compared with nebulized saline as placebo. This study showed consistent improvements in the Borg dyspnea ratings by 0.5 units at a standardized time during exercise (p < 0.01). This was associated with a 37% improvement in exercise endurance time when compared with placebo. The decrease in dyspnea intensity correlated with the increase in resting IC. During incremental cardiopulmonary exercise testing, Teramoto et al. (27) demonstrated that dyspnea intensity, as measured by the slope of Borg ratings VO2, was reduced following one dose of oxitropium (15.4 vs. 29.7 for placebo; p < 0.05) indicating a positive effect of the drug. Oga et al. (28) showed that oxitropium (400 mg) reduced the Ddyspnea Dtime ratio during constant work exercise but did not change the Ddyspnea DVO2 during incremental exercise. In another study, Oga et al. (14) found a decrease in the Ddyspnea Dtime slope during constant workload ergometry with ipratropium bromide (80 mg) compared with placebo. B. Long-Acting

Four studies have reported the beneficial effects of tiotropium as measured with the TDI total score (9,21,29,30) (Table 2). In the 1-year study by Casaburi et al. (29), TDI averaged þ1.1 units greater than placebo (p < 0.001). In the 1-year study by Vincken et al. (30), the TDI score improved by þ0.9 compared with ipratropium bromide (p ¼ 0.001). Brusasco et al. (21) also reported a significant improvement by þ1.1 after 6 months treatment with tiotropium compared with placebo, but there was no significant difference in the TDI total scores between the tiotropium and salmeterol groups. O’Donnell et al. (9) showed that the TDI total score

Table 2 Effects of Long-Acting Anticholinergics (Tiotropium Bromide 18 mg/day) on Activity-Related Dyspnea as Measured by the TDI First author year

Study design

O’Donnell, 2004 (9) Brusasco, 2003 (21) Casaburi, 2002 (29) Vincken, 2002 (30)

6 weeks, parallel vs. placebo 6 months, parallel vs. placebo 1 year, parallel vs. placebo 1 year, parallel vs. ib 40 mg qid

a

n

Baseline FEV1 (L)

96 tio 91 pl 402 tio 400 pl 550 tio 371 pl 356 tio 179 ib

1.22 1.27 1.09 1.12 1.01 0.99 1.25 1.18

TDI D vs. pl ¼ 1.6a D vs. pl ¼ 1.1a D vs. pl ¼ 1.1a D vs. ib ¼ 0.90a

Significantly different from placebo except for study by Vincken et al. (30). Abbreviation: tio, tiotropium bromide; pl, placebo; ib, ipratropium bromide.

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improved by þ1.6 units compared with placebo after 6 weeks of treatment with tiotropium (p < 0.01). O’Donnell et al. (9) also examined the mechanisms for improvement in dyspnea with tiotropium in a multicenter, placebo-controlled study conducted in 187 patients with moderately severe COPD. After 6 weeks of treatment, endurance time was 21% greater in those taking tiotropium compared with placebo. Dyspnea, measured by Borg units at isotime (Fig. 3), decreased by an average of 0.9 units compared with placebo (p < 0.001) on day 42. The improvements in dyspnea and exercise performance were closely correlated with improvements in resting IC (Fig. 3). VII. Theophylline Three studies have evaluated the effects of theophylline on the TDI total score (17,29,30). In a 4-week cross-over study Mahler et al. (31) demonstrated a þ2.8 improvement with theophylline vs. þ0.7 with placebo (p < 0.05). In a

Figure 3 Schematic diagram showing when dyspnea ratings (or other cardiopulmonary measurements) can be collected as part of a constant-load exercise test conducted at a standardized work rate set between 50% and 80% of the maximal work capacity. Comparisons between pre- and postintervention measurements can then be made at rest (‘‘preexercise’’), at a standardized time during exercise (‘‘isotime’’), and at peak exercise (‘‘end-exercise’’). If exercise responses are linear, then linear regression analyses may also be performed to evaluate slopes and intercepts for the data collected during each test.

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non-placebo-controlled study, ZuWallack et al. (18) demonstrated a þ1.1 increase in the TDI score after 12 weeks of treatment with theophylline. The addition of salmeterol to theophylline increased this score significantly to þ1.9 units. Kirsten et al. (32) demonstrated a deterioration in the TDI by
0.9 units in a group of 20 patients who had their theophylline therapy withdrawn compared with a TDI total score of þ0.4 in a group of 20 patients who were permitted to continue their therapy (p < 0.05). Guyatt et al. (15) failed to demonstrate an improvement in dyspnea at the end of a 6-min walk distance in patients taking oral theophylline compared with placebo (i.e., Borg rating was 3.6 on oral theophylline vs. 2.4 on placebo at the end of the walking test). Tsukino et al. (33) reported a reduction in the slope of Borg dyspnea ratings
VO2 in those taking theophylline compared with placebo (p < 0.05). As observed with the anticholinergic therapy, greater improvement in exercise performance tended to occur with higher dosages of theophylline. VIII. Inhaled Corticosteroids Randomized controlled trials show that ICS generally reduce the severity of breathlessness in patients with COPD (Table 3) (19,20,34–38). In 1996, Renkema et al. (34) reported that budesonide (800 mg twice daily) improved combined scores for dyspnea and wheeze at 2 years on the basis of selfreported ratings on a 0–4 scale. In the Lung Health Study II, there was a significant decrease (p ¼ 0.02) in the percentage of participants reporting ‘‘highest dyspnea level at 36 months’’ on the American Thoracic Dyspnea Questionnaire in patients who received triamcinolone (600 mg twice daily) compared with placebo therapy (35). Although Calverly et al. (36) observed that patients who were treated with fluticasone (500 mg twice daily) reported a decrease (
0.08  0.03) in dyspnea scores on a 0–4 scale, these investigators did not report whether the difference was statistically significant. Using the TDI to measure changes in dyspnea, both Mahler et al. (19) and Hanania et al. (20) observed that patients had significantly less breathlessness related to activities of daily living after 6 months of fluticasone. However, only the 500 mg dose of fluticasone achieved a difference of 1.0 unit in the TDI total score considered to be clinically meaningful (Table 3). To the best of our knowledge, there are no reports evaluating the effect of ICS on dyspnea ratings during exercise. IX. What Are the Possible Mechanisms for Relief of Dyspnea with ICS? Examination of peak flows measured by patients at home reveals that patients with COPD experience modest improvements in lung function

Budesonide 320 mg bid Fluticasone 250 mg bid Fluticasone 00 mg bid Fluticasone 500 mg bid Triamcinolone 600 mg bid Budesonide 800 mg bid

Calverly, 2003 (38) Hanania, 2003 (20) Calverly, 2003 (36) Mahler, 2002 (19) LHS II, 2000 (18)

Renkema, 1996 (34)

21 bud 18 pl

2.16 1.90

0.99 0.98 1.31 1.29 1.30 1.26 1.23 1.32 2.16 2.10

257 bud 256 pl 183 flut 185 pl 374 flut 361 pl 168 flut 181 pl 559 triam 557 pl

1 year, parallel 24 weeks, parallel 1 year, parallel 24 weeks, parallel 3 years, parallel 2 years, parallel

Baseline FEV1 (L)

n

Study design

p ¼ 0.02 on ATS questionnaire for triam vs. pl p < 0.05 for dyspnea and wheeze score for bud vs. pl

D vs. pl ¼ 0.08 (0–4 scale) DTDI vs. pl ¼ 1.0a

D vs. pl ¼ 0.09a (0–4 scale) DTDI vs. pl ¼ 0.7a

Dyspnea measure

a Significantly different from placebo. Abbreviation: bud, budesonide; flut, fluticasone propionate; triam, triamcinolone; pl, placebo; TDI, transition dyspnea index.

Dose

First author year

Table 3 Effects of ICS on Dyspnea

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within days of starting ICS therapy (19,20,36,38). This increase in expiratory airflow is likely a result of some reduction in the airway edema/inflammation and/or enhanced beta-2-activity on bronchial smooth muscle. As a result, hyperinflation at rest and/or with exercise would be expected to decrease as has been observed with bronchodilator therapy. Such changes would improve respiratory mechanics, diminish elastic recoil, and increase the length of the vertical muscles of the diaphragm—all of which would be expected to reduce the severity of breathlessness. In addition, in the Lung Health Study II, inhaled triamcinolone was shown to reduce airway reactivity in response to methacholine in patients with mild COPD (35). These patients ‘‘had fewer respiratory symptoms during the course of the study’’ compared with placebo group. Any reduction in airway reactivity with ICS in patients with COPD would also be expected to improve breathlessness.

X. Combination Therapy with Inhaled Corticosteroid and Long-Acting Beta-Agonist Inhaled corticosteroids have been approved by regulatory agencies in combination with long-acting beta-agonists for the treatment of patients with COPD in various countries throughout the world. At the present time, the specific approved combinations and doses are fluticasone propionate and salmeterol inhalation powder (Advair DiskusÕ 250/50 and 500/50) and budesonide and eformoterol inhalation powder (SymbicortÕ 400/12 TurbohalerÕ ). The beneficial effects of combination therapy on the relief of dyspnea are displayed in Table 4. In all five studies, there were significant improvements in the severity of dyspnea with ICS/LABA therapy compared with placebo. In three of these studies, the addition of the ICS to the long-acting beta-2-agonist provided significantly greater relief of breathlessness than with the LABA alone (19,36,37). Moreover, these findings are supported by reduced albuterol use as rescue medication (19,20,36). Comparison of the results in studies by Mahler et al. (19) and the Hanania et al. (20), which had the same study designs and inclusion/exclusion criteria, showed that the higher dose of ICS (fluticasone 500 mg) provided greater relief of dyspnea (DTDI ¼ 1.7 units) compared with a moderate dose (fluticasone 250 mg; DTDI ¼ 0.8 units). When ICS are combined with LABA, these agents target both the airway edema/inflammation and the bronchial smooth muscle constriction considered to be the major components causing airflow limitation in this disease. To the best of our knowledge, there are no reports evaluating the effect of combining an ICS with a long-acting beta-agonist on dyspnea ratings during exercise.

Budesonide 320 mg bid Formoterol 9 mg bid Fluticasone 250 mg bid Salm 50 mg bid Fluticasone 500 mg bid Salm 50 mg bid Budesonide 320 mg bid formoterol 9 mg bid Fluticasone 500 mg bid

Calverly, 2003 (38)

178 flut/salm 185 pl

358 flut/salm 361 pl

208 bud/form 205 pl

24 weeks, parallel

1 year, parallel

1 year, parallel

168 flut 181 pl

254 bud/form 256 pl

1 year, parallel

24 weeks, parallel

n

Study design

1.23 1.32

0.96 0.98

1.30 1.26

1.25 1.29

0.98 0.98

Baseline FEV1, (L)

a Significantly different from placebo. Abbreviation: flut, fluticasone propionate; bud, budesonide; form, formoterol; pl, placebo; TDI, transition dyspnea index.

Mahler, 2002 (19)

Szafranski, 2003 (37)

Calverly, 2003 (36)

Hanania, 2003 (20)

Dose

First author, year

Table 4 Effects of Combination Therapy with ICS and Long-Acting beta-2-Agonist on Dyspnea

D TDI vs. pl ¼ 1.7a

D vs. pl ¼ 0.36a (0–4 scale)

D vs. pl ¼ 0.19a (0–4 scale)

DTDI vs. pl ¼ 0.8a

D vs. pl ¼ 0.21a (0–4 scale)

Dyspnea measure

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In summary, all three classes of bronchodilators have been shown to improve dyspnea as measured by the TDI total score and/or during exercise testing compared with placebo. However, these overall effects are modest when compared with the benefits of pulmonary rehabilitation (see Chapter 13) or inspiratory muscle training (see Chapter 14). Certainly, variations in results from studies are likely multifactorial and relate to differences in the clinical characteristics of the study population, dosage and mode of administration of the drug, the choice of the stimulus (activities of daily living or type of exercise test), etc. Studies examining therapies with either more than one bronchodilator with the addition of an ICS to a LABA generally show enhanced benefits for relief of dyspnea. These randomized controlled trials support the approach commonly used by clinicians who prescribe multiple bronchodilators and/or ICS in an attempt to achieve optimal symptomatic response for the individual patient. It will be important to determine the threshold for improvement (i.e., minimal clinically important difference) for dyspnea responses during exercise testing. In addition, further studies are needed to evaluate the putative benefits of combining medical therapy with other modalities, such as pulmonary rehabilitation (39). References 1. Pauwels RA, Buist SA, Calverley PMA, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop Summary. Am J Respir Crit Care Med 2001; 163:1256–1276. 2. O’Donnell DE, Aaron S, Bourbeau J, Hernandez P, Marciniuk D, Balter M, Ford G, Gervais A, Goldstein R, Hodder R, Maltais F, Road J. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease—2003. Can Respir J 2003; 10(suppl A):11A–65A. 3. Fletcher CM, Elmes PC, Wood CH. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. Br Med J 1959; 2:257–266. 4. Mahler DA, Weinberg DH, Wells C, Feinstein AR. The measurements of dyspnea. Contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest 1984; 85(6):751–758. 5. O’Donnell DE, Webb KA. Chapter 3: exercise testing. In: Celli B, ed. Pharmacotherapy in Chronic Obstructive Pulmonary Disease. Vol. 182. Marcel Dekker, 2004:45–71. 6. O’Donnell DE, Webb KA. Exertional breathlessness in patients with chronic airflow limitation. The role of lung hyperinflation. Am Rev Respir Dis 1993; 148:1351–1357.

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7. O’Donnell DE, Bertley JC, Chau LKL, Webb KA. Qualitative aspects of exertional breathlessness in chronic airflow limitation. Pathophysiologic mechanisms. Am J Respir Crit Care Med 1997; 155:109–115. 8. O’Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and exercise intolerance in COPD. Am J Respir Crit Care Med 2001; 164:770–777. 9. O’Donnell DE, Flu¨ge T, Gerken F, Hamilton A, Webb K, Aguilaniu B, Make B, Magnussen H. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004; 23:832–840. 10. O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol on the ventilatory response to exercise in chronic obstruction pulmonary disease. Eur Respir J 2004; 23:832–840. 11. Witek TJ Jr, Mahler DA. Meaningful effect size and patterns of response of the transition dyspnea index. J Clin Epidemiol 2003; 56:248–255. 12. Witek TJ Jr, Mahler DA. Minimal important difference of the transition dyspnoea index in a multinational clinical trial. Eur Respir J 2003;21:267–272. 13. Belman MJ, Botnick WC, Shin JW. Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 153:967–975. 14. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T, Mishima M. A comparison of the effects of salbutamol and ipratropium on exercise endurance in patients with COPD. Chest 2003; 123:1810–1816. 15. Guyatt GH, Townsend M, Pugsley SO, Keller JL, Short HD, Taylor DW, Newhouse MT. Bronchodilators in chronic airflow limitation. Effects on airway function, exercise capacity, and quality of life. Am Rev Respir Dis 1987; 135:1069–1074. 16. Mahler DA, Donohue JF, Barbee RA, Goldman MD, Gross NJ, Wisniewski ME, Yancey SW, Zakes BA, Rickard KA, Anderson WH. Efficacy of salmeterol zinafoate in the treatment of COPD. Chest 1999; 115:957–965. 17. Rennard SI, Anderson W, ZuWallack R, Broughton J, Bailey W, Friedman M, Wisniewski M, Rickard K. Use of a long-acting inhaled b2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163:1087–1092. 18. ZuWallack RL, Mahler DA, Reilly D, Church N, Emmett A, Rickard K, Knobil K. Salmeterol plus theophylline combination therapy in the treatment of COPD. Chest 2001; 119:1661–1670. 19. Mahler DA, Wire P, Horstman D, Chang C-N, Yates J, Fischer T, Shah T. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166:1084–1091. 20. Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, Shah T. The efficacy and safety of fluticasone propionate (250 mg)/salmeterol (50 mg) combined in the Diskus inhaler for the treatment of COPD. Chest 2003; 124:834–843. 21. Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003; 58:399–404.

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22. Aalbers R, Ayres J, Backer V, Decramer M, Lier PA, Magyar P, Malolepszy J, Ruffin R, Sybrecht GW. Formoterol in patients with chronic obstructive pulmonary disease: a randomized, controlled, 3-month trial. Eur Respir J 2002; 19:936–943. 23. Boyd G, Morice AH, Pounsford JC, Siebert M, Peslis N, Crawford C, on behalf of an international study group. An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD). Eur Respir J 1997; 10:815–820. 24. Grove A, Lipworth BJ, Reid P, Smith RP, Ramage L, Ingram CG, Jenkins RJ, Winter JH, Dhillon DP. Effects of regular salmeterol on lung function and exercise capacity in patients with chronic obstructive airways disease. Thorax 1996; 51:689–693. 25. Ayers ML, Mejia R, Ward J, Lentine T, Mahler DA. Effectiveness of salmeterol vs. ipratropium bromide on exertional dyspnea in COPD. Eur Respir J 2001; 17:1132–1137. 26. O’Donnell DE, Lam M, Webb KA. Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160:542–549. 27. Teramoto S, Fukuchi Y, Orimo H. Effects of inhaled anticholinergic drug on dyspnea and gas exchange during exercise in patients with chronic obstructive pulmonary disease. Chest 1993; 103:1774–1782. 28. Oga T, Nishimura K, Tsukino M, Hajiro T, Ikeda A, Izumi T. The effects of oxitropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease. A comparison of three different exercise tests. Am J Respir Crit Care Med 2000; 161:1897–1901. 29. Casaburi R, Briggs DD Jr, Donohue JF, Serby CW, Menjoge SS, Witek TJ, for the US Tiotropium Study Group. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD. A 13-week multicenter trial. Chest 2000; 188:1294–1302. 30. Vincken W, van Noord JA, Greefhorst APM, Bantje TA, Kesten S, Korducki L, Cornelissen PJG, on behalf of the Dutch/Belgian Tiotropium Study Group. Improved health outcomes in patients with COPD during 1 yr’s treatment with tiotropium. Eur Respir J 2002; 19:209–216. 31. Mahler DA, Matthay RA, Snyder PE, Wells CK, Loke J. Sustained-release theophylline reduces dyspnea in nonreversible obstructive airways disease. Am Rev Respir Dis 1985; 131:22–25. 32. Kirsten DK, Wegner RE, Jorres RA, Magnussen H. Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest 1993; 104:1101–1107. 33. Tsukino M, Nishimura K, Ikeda A, Hajiro T, Koyoma H, Izumi T. Effects of theophylline and ipratropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease. Thorax 1998; 53:269–273. 34. Renkema TE, Schouten JP, Koeter GH, Postma DS. Effects of long-term treatment with corticosteroids in COPD. Chest 1996; 109:1156–1162. 35. The Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. New Engl J Med 2000; 343:1902–1909.

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36. Calverly P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2003; 361:449–456. 37. Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, Peterson S, Olsson H. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003; 21:74–81. 38. Calverly PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003; 22:912–919. 39. Casaburi R, Kufafka D, Cooper CB, Kesten S. Improvements in exercise endurance with the combination of tiotropium and rehabilitative exercise training in COPD patients [abstr]. Am J Respir Crit Care Med 2004; 169:A606.

13 The Effect of Pulmonary Rehabilitation on Dyspnea

RICHARD ZUWALLACK

SUZANNE C. LAREAU

Section of Pulmonary and Critical Care, St. Francis Hospital and Medical Center, Hartford, Connecticut, U.S.A.

New Mexico VA Health Care System, Albuquerque, New Mexico, U.S.A.

PAULA MEEK College of Nursing, University of New Mexico, Albuquerque, New Mexico, U.S.A.

I. Introduction Pulmonary rehabilitation has been accepted as a component of the comprehensive care of individuals with chronic lung disease since the 1970s (1). However, it was not until the 1990s that its benefits were unequivocally demonstrated by randomized, controlled trials (2). Documented gains from this intervention include reductions in exertional dyspnea and dyspnea associated with daily activities, increased exercise tolerance, and improvements in health-related quality of life (2). Other evidence suggests that this intervention may reduce medical resource utilization (3,4). The usefulness of pulmonary rehabilitation is underscored by the fact that it was chosen as the gold standard of medical care with which to compare surgical therapy in a recent multicenter trial of lung volume reduction surgery for emphysema (5). This chapter first provides a brief review of pulmonary rehabilitation then discusses randomized clinical trials evaluating its effectiveness in reducing the predominant symptom of advanced lung disease—dyspnea.

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Pulmonary rehabilitation is defined as ‘‘a multidisciplinary program of care for patients with chronic respiratory impairment that is individually tailored and designed to optimize physical and social performance and autonomy’’ (6). Its principal goal is to improve health-related quality of life (health status) through decreasing bothersome symptoms such as dyspnea and fatigue, increasing exercise tolerance, and improving activity levels. Pulmonary rehabilitation or some of its components have also been shown to improve other areas such as nutritional status, disease self-management, mastery/ self-efficacy, and mood.

III. Patient Selection for Pulmonary Rehabilitation Pulmonary rehabilitation is indicated for the individual with chronic lung disease who, despite standard medical management, remains symptomatic, or has reduced functional or health status. In patients with chronic obstructive pulmonary disease (COPD), dyspnea may be reported as severe, even with mild-to-moderate airway obstruction. In view of this, it is difficult to establish a specific pulmonary function threshold for referral for pulmonary rehabilitation. Historically, the majority of patients referred for pulmonary rehabilitation have had COPD, and most clinical trials on the effectiveness of this intervention have involved COPD patients. However, patients with other chronic respiratory diseases may share similar comorbidity, and should stand to benefit from this treatment. Frequently, despite ongoing bothersome dyspnea and a pattern of decreasing activity, individuals with COPD often are not routinely referred to pulmonary rehabilitation, despite the clear indications and comprehensive nature of the treatment that they will receive. However, if the health care provider believes that the persisting symptomatology may be due to an increase in metabolic load due to deconditioning, nutritional depletion and muscle wasting, or even a lack of self-management skills, there are no treatments that could address these as completely as comprehensive pulmonary rehabilitation.

IV. Components of Pulmonary Rehabilitation Comprehensive pulmonary rehabilitation has four essential components: education, exercise training, nutritional therapy, and psychosocial/behavioral intervention. While there is clinical rationale for incorporating each component into pulmonary rehabilitation, their relative, individual effects on outcomes (such as dyspnea) need further investigation.

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An important goal of education is to enhance the patient’s selfmanagement skills, through improving understanding of the disease and its treatment. Education typically includes didactic sessions related to the anatomy of the lung, discussions about medications, advance directives, demonstrations of breathing strategies, and energy conservation techniques to reduce dyspnea (6). Exercise training involves both upper and lower extremities, with a prominent goal of improving strength and endurance. This conditioning process is directed at improving activity levels and reducing dyspnea (6). A large percentage of individuals with COPD have nutritional depletion, manifested either as low body weight or reduced lean body mass (7,8). Nutritional depletion in COPD is associated with reduced functional exercise capacity (9) and increased dyspnea (10). Nutritional support includes education on proper nutrition, dietary supplements in nutritionally depleted individuals, and diet counseling in overweight individuals. Nutritional repletion for depleted patients has not been particularly successful (11), while pharmacologic therapy with anabolic steroids may be considered on an individual basis. Psychosocial problems, including anxiety, depression, and problems with coping are common in individuals with chronic lung disease and often contribute to its morbidity, including increasing dyspnea. Intervention in this area may include educational sessions or support groups focusing on specific problems such as stress management, or instructions in progressive muscle relaxation, stress reduction, panic control, and antidepressants. Each patient comes to pulmonary rehabilitation with a unique combination of physiologic, functional, and psychologic limitations caused by the underlying disease, or its treatment, along with associated morbidity, and comorbidities. In addition, each patient has unique learning needs, influenced by education level, cultural factors, and cognitive impairment, to name a few. These factors require a patient-centered approach, administered by a multidisciplinary team of health care professionals. This team is supervised by a physician and co-ordinated by an experienced health care professional, such as a registered nurse, physical therapist, or respiratory therapist.

V. The Rationale for Pulmonary Rehabilitation Pulmonary rehabilitation has little or no effect on the underlying pathophysiology of chronic lung disease. Despite this, rehabilitation usually leads to substantial improvements in multiple outcome areas of importance to the patient, including, dyspnea, activity levels, exercise tolerance, and health-related quality of life. Improvement in these areas reflects the beneficial effects of pulmonary rehabilitation on secondary morbidity and

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Table 1 Consequences of Respiratory Disease Types of secondary morbidity

Mechanism(s)

Peripheral muscle dysfunction

Deconditioning, steroid myopathy, ICU neuropathy, malnutrition, decreased lean body mass, fatigue, effects of hypoxemia, acid–base disturbance, electrolyte abnormalities Mechanical disadvantage secondary to hyperinflation, malnutrition, diaphragmatic fatigue, steroid myopathy, electrolyte abnormalities Obesity, cachexia, decreased lean body mass Deconditioning, cor pulmonale Osteoporosis, kyphoscoliosis Medications (e.g., steroids, diuretics, antibiotics) Anxiety, depression, guilt, panic, dependency, cognitive deficit, sleep disturbance, sexual dysfunction

Respiratory muscle dysfunction

Nutritional abnormality Cardiac impairment Skeletal disease Sensory deficits (impaired vision, hearing, etc.) Psychosocial

Source: From Ref. 6

comorbidities associated with chronic lung disease. Examples are listed in Table 1 (6). Unlike the underlying lung disease, much of this morbidity is treatable—if recognized and addressed. For example, pulmonary rehabilitation has virtually no effect on airflow limitation of COPD. Nevertheless, following this intervention, patients walk farther with reduced dyspnea, are able to pace themselves more efficiently, cope better with their disease, and have less anxiety associated with their symptoms. These positive outcomes result from attention to and treatment of these secondary and comorbidities.

VI. Outcome Assessment in Pulmonary Rehabilitation Outcome assessment of rehabilitation includes evaluation of symptoms, exercise performance, and health-related quality of life. This provides quality assurance information to the pulmonary rehabilitation staff. In addition, with direct feedback to the patient, outcome assessment can help reinforce the gains the patient made through his or her efforts. Outcome measurement of multiple areas is necessary to capture the full impact of the pulmonary rehabilitation intervention; however, the extent of the outcomes measured often depends on the resources of the program. Examples of

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outcome areas in pulmonary rehabilitation include measurements of exertional dyspnea during exercise testing, overall dyspnea using questionnaires, exercise performance, functional performance, health-related quality of life, and health resource utilization. Since outcome areas of importance to the patient usually correlate poorly with respiratory physiologic abnormalities such as the FEV1, the latter cannot be used as a surrogate for their measurement (12).

VII. Dyspnea Assessment in Pulmonary Rehabilitation Dyspnea is a subjective symptom, and therefore must be evaluated by selfreport. Self-report is measured using standardized scales or questionnaires (13,14). See Chapters 7 (Measurement of Dyspnea: Clinical Ratings) and 8 (Measurement of Dyspnea: Ratings During Exercise) for a comprehensive review of available instruments and supporting data for measuring dyspnea. Briefly, in the rehabilitation setting, dyspnea measurement usually falls into two general categories: 1.

2.

The real-time patient assessment of dyspnea during a specific exercise or task. These are called exertional measures and are usually evaluated with a scale such as a Borg scale (15) or a visual analog scale (VAS) (16). Questionnaire-rated dyspnea. These questionnaires are either designed to rate dyspnea as their primary purpose (called standard measures of dyspnea), or measure dyspnea as a component or domain of the questionnaire (called broad measures of dyspnea). Another feature of questionnaires (and therefore how these measures can vary) is that dyspnea may either be evaluated independent of activities or associated with activities. Dyspnea questionnaires can be one-dimensional, such as a simple VAS rating of overall dyspnea, or multidimensional, such as the baseline and transition dyspnea indexes (BDI and TDI).

VIII. Mechanism(s) by Which Pulmonary Rehabilitation Relieves Dyspnea In 1999, the ATS identified the key pathophysiologic mechanisms associated with dyspnea and currently known treatments (17). Based on this document, interventions that target dyspnea mechanisms can be categorized into the following: 1.

Reduce ventilatory demand, through decreasing metabolic load or central drive.

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3.

4.

Increase muscle function, through nutritional intervention, inspiratory muscle training, positioning, or partial ventilatory support. Reduce ventilatory impedance, through lung volume reduction surgery, counteracting intrinsic positive airway pressure (using continuous positive airway pressure), and reducing resistive load (using bronchodilators). Alter central perception, through educational approaches, desensitization mechanisms, and medications.

Table 2 identifies interventions common to pulmonary rehabilitation that target dyspnea mechanisms. While it is clear that pulmonary rehabilitation relieves dyspnea, it is not clear which components of this complex intervention are responsible for this positive outcome. This is due to the fact that comprehensive Table 2 Interventions in Pulmonary Rehabilitation that Target Dyspnea Mechanisms Mechanism to reduce dyspnea Reduce ventilatory demand Reduce metabolic load Decrease central drive

Interventions

Targeted by rehabilitation

Exercise training O2 therapy O2 therapy Medications (opiates) Altered afferent signal

X X X — —

Nutrition Inspiratory muscle training Positioning Partial ventilatory support

X X X —

Surgery CPAP Medications (bronchodilators)

— — X

Education Cognitive-behavioral approaches Desensitization Medications (opiates)

X X

Improve muscle function

Reduce ventilatory impedance Reduce/counterbalance Hyperinflation Reduce resistive load Alter central perception

Source: Modified from Ref. 17.

X X

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pulmonary rehabilitation by its very nature involves multiple therapeutic interventions occurring almost simultaneously. Indeed, most of the studies in this area have evaluated the entire process, not the individual components. Consequently, it is difficult to determine which are responsible for a specific outcome, such as a reduction in dyspnea. Making this analysis even more daunting, dyspnea mechanisms are remarkably integrated. For example, any reduction in metabolic load has the potential for reducing drive, altering central perception, and improving respiratory muscle function.

A. Reduction in Ventilatory Demand

The individualized exercise conditioning incorporated into the pulmonary rehabilitation of persons with chronic lung disease may produce a true physiologic training effect and/or an improvement in exercise efficiency. A study by Casaburi et al. in 1991 (18) demonstrated that COPD patients are often severely deconditioned, and this contributes substantially to their exercise intolerance. Furthermore, these patients stand to derive a true physiological training effect from relatively high levels of exercise training. This effect is more likely in those with mild-to-moderate respiratory disease. However, even those with more severe disease and ventilatory limitation improve following exercise training. In these, the increase in exercise performance appears to be more likely from improved efficiency. Whether improvement in exercise performance is from a true physiologic training effect or from improved efficiency (or both), the result is a decreased ventilatory demand because of a decreased metabolic load. This is probably responsible, in large part, for the reduction in exertional dyspnea following the exercise training component of pulmonary rehabilitation. Controlled trials by O’Donnell et al. (19) in COPD patients provide some evidence supporting the concept of reduced ventilatory demand as a mediator of reduced dyspnea following pulmonary rehabilitation. They evaluated the effects of multimodality upper and lower extremity endurance training targeted to a specific dyspnea level on physiologic variables and dyspnea ratings. Exertional breathlessness was significantly improved following exercise training, with the Borg Score at peak exercise on a cycle ergometer dropping from 5.3 to 3.8. The best correlate of improved exertional dyspnea was a fall in ventilatory demand, as evidenced by a reduced respiratory rate during peak exercise. The authors postulate that this was a result of enhanced mechanical efficiency from the exercise training. In a subsequent study by this group (20), exercise training in COPD resulted in increased ventilatory and peripheral muscle strength and endurance in addition to reduced breathlessness. Improvement in Borg-scale rated exertional dyspnea following exercise training, however, was related

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only to a decreased ventilatory demand—decreased respiratory rate (but not tidal volume) at isotime exercise following exercise training. Neither improved peripheral muscle nor respiratory muscle endurance correlated with the reduction in dyspnea. Pulmonary rehabilitation may reduce ventilatory demand through other mechanisms. One educational objective is to foster pacing during exercise, allowing the patient to do more with less peak energy expenditure. This should also decrease dyspnea through reducing ventilatory demand. Additionally, heretofore undetected oxygen desaturation during exercise is often discovered in pulmonary rehabilitation during exercise testing or training. The subsequent addition of supplemental oxygen during exercise should also reduce ventilatory demand. B. Improved Muscle Function

Strength training of peripheral muscles, which is now incorporated into most pulmonary rehabilitation programs, has been found to be associated with a reduction in breathlessness (21). Nutritional education, through maximizing the energy supply and limiting (or occasionally reversing) muscle wasting due to weight loss will augment the effects of exercise training and may improve respiratory muscle function. Since nutritional intervention alone has had only limited success (11), anabolic steroids have been used to augment these effects (22). Optimal body positioning and breathing strategies, which are included in the education component of pulmonary rehabilitation, enhance respiratory muscle function. Respiratory muscle training leads to increased strength and endurance of these muscles (23,24). To date, there has not always been a consistent link between improvement in inspiratory muscle performance and increases in functional exercise capacity. However, a recent meta-analysis of inspiratory muscle training in COPD did find that this therapy did lead to significant reductions in exertional (–1.5 Borg scale units) and TDI-rated (2.7 units) dyspnea (25). C. Reduced Ventilatory Impedance

The optimal use of bronchodilator medications that often accompanies comprehensive pulmonary rehabilitation will reduce the resistive load to breathing and may allow for higher levels of exercise training. This, in turn, will promote higher levels of general functioning and increased participation in activities of daily living. Dynamic hyperinflation is common in individuals with COPD and contributes substantially to the exertional dyspnea of these patients through its effect on increasing elastic work of breathing (19). Since a prominent effect of exercise training in COPD is the reduction in respiratory rate at comparable levels of work, a reduction in dynamic hyperinflation should

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be an added benefit of this intervention. This should augment the beneficial effect of exercise training on exertional dyspnea. D. Altered Central Perception

Although a decreased ventilatory demand is probably the most important factor related to the reduction in dyspnea following pulmonary rehabilitation, an alteration in the perception of this distressing symptom is probably also important, although less substantiated by scientific studies. Several components of comprehensive pulmonary rehabilitation may lead to a decreased perception of dyspnea. Detection of hypoxemia during exercise and the subsequent administration of supplemental oxygen will help to maintain an optimal balance between metabolic load and central drive to breathe. Repeated exercise training sessions in a supportive environment will probably lead to some desensitization to exertional dyspnea (26), mediated through decreased central drive. Finally, the self-management education that is central to pulmonary rehabilitation will enhance the patients’ ability to manage their breathing as they carry out their daily activities and deal with unexpected episodes of severe breathlessness (27). While self-management education would probably work in several areas to reduce dyspnea, including proper pacing and breathing techniques, it probably would also reduce the affective component of dyspnea and dyspnea-producing activities (28), and thereby favorably alter the central perception of this symptom. IX. Studies Showing the Effect of Pulmonary Rehabilitation on Dyspnea A. Exertional Dyspnea

Several randomized, controlled trials of pulmonary rehabilitation have demonstrated its effectiveness in reducing exertional dyspnea. A summary of these trials is given in Table 3. The following discussion highlights the results of some of these controlled trials. A study by Reardon et al. (16) evaluated the effectiveness of 6 weeks outpatient pulmonary rehabilitation on exertional dyspnea. Twenty patients with COPD were randomized into either comprehensive outpatient pulmonary rehabilitation or to a 6-week waiting period where standard medical care was given. Pulmonary rehabilitation included 12 three-hour sessions including education, breathing retraining, energy conservation techniques, relaxation therapy, and upper and lower physical conditioning. Incremental treadmill exercise testing was performed at baseline and 6 weeks. Dyspnea was assessed at 1-min intervals during exercise testing and at peak work rate using a 300-mm vertical VAS. In the control group, no significant change in dyspnea occurred following the 6-week waiting period. Following rehabilitation, exertional dyspnea decreased significantly. Improvement

8 weeks OPR

6 weeks multimodality exercise endurance

12 weeks home-care rehabilitation program (15) 6 weeks multimodality exercise (20)

(29)

(19)

(38)

(3)

(39)

8 weeks interval training at 45% and 90% of peak (10) 6 weeks OPR (99)

6 weeks OPR (10)

(16)

(20)

Treatment group (n)

References

Outcome

Borg at isotime near end of cycle exercise

No change in dyspnea in either group

Dyspnea improved postintervention and correlated with a reduced respiratory rate but not with ventilatory or peripheral muscle function No significant change in dyspnea in either group

Significant post-OPR reduction in dyspnea beginning early in exercise Significant reduction in exertional dyspnea following OPR compared to education only (–1.5 vs. 0.2 units); effect lasted 1 year Borg dyspnea during Exercise training led to significant cycle ergometry reductions in Borg Scores related to VO2 and VE Borg dyspnea at isowork Treatment resulted in significantly during cycle ergometry reduced exertional dyspnea

VAS during incremental treadmill exercise Borg dyspnea at the end of treadmill endurance testing

Dyspnea measure

8 weeks continuous VAS during incremental training at 60% of peak cycle ergometry rate (11) Standard medical Borg at end of management (101) incremental SWT

Stratified and randomized control group (15) Nonintervention period (20)a

Standard medical management

Standard medical care (10) Education only

Control group (n)

Table 3 Controlled Clinical Trials of Pulmonary Rehabilitation on Exertional Dyspnea in COPD

310 ZuWallack et al.

12 weeks continuous exercise training (18)

8 weeks high-intensity training (20)

12 weeks interval exercise training (18)

8 weeks low-intensity training (20)

(32)

(40)

(36)

Borg at end cycle Small reduction in exertional dyspnea ergometry and endurance measured during constant workload SWT testing only Both interval and continuous exercise Borg during incremental training resulted in significant and cycle ergometry similar decreases in exertional dyspnea Both levels of training led to significant decreases in exertional dyspnea, VAS at 50% and 80% of although the effect was greater in the high-intensity group peak treadmill exercise

Abbreviations: SWT, shuttle walk test; VO2, oxygen consumption; VE, minute ventilation; OPR, outpatient pulmonary rehabilitation; VAS, visual analog scale. a Crossover trial.

Standard medical care (17)

12 weeks walking exercise at or near home (20)

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was discernable in the first few minutes of incremental exercise, indicating that this was probably at a level of work common to usual daily activities. The study did not address the mechanisms for improvement in dyspnea. In a study of 119 patients with COPD, Ries et al. (29) evaluated the effect of 12 four-hour sessions of comprehensive outpatient pulmonary rehabilitation on multiple outcomes, including exertional dyspnea. Rehabilitation included education, exercise training predominately on a treadmill to a symptom-limited maximum of 30 min per session, and psychosocial support. Outcomes from the rehabilitation group were compared to a control group that was given education only. Exertional dyspnea, rated with a 10 point Borg scale, was measured at the end of a treadmill endurance exercise test at a constant workload of approximately 95% of a maximal value determined earlier. Following the 6-week intervention, breathlessness in the rehabilitation group decreased significantly compared to the education control group (–1.5 vs. 0.2 units, p < 0.001) despite a substantially increased exercise performance in the rehabilitation group. This beneficial effect on exertional dyspnea persisted up to 48 months following pulmonary rehabilitation, as depicted in Figure 1.

Figure 1 Changes in exertional dyspnea following pulmonary rehabilitation. Data from the first 48 months after pulmonary rehabilitation are given. Outpatient pulmonary rehabilitation led to significant reductions in Borg-scale rated exertional dyspnea for up to 24 months following beginning therapy.* p < 0.05; **p < 0.001. Source: Adapted from Ref. 29.

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B. Dyspnea with Daily Activities

In addition to the above-described reduction in exertional dyspnea measured during exercise testing, pulmonary rehabilitation improves dyspnea associated with activity. Table 4 lists controlled trials of pulmonary rehabilitation on this variable. The majority of these studies used the dyspnea subscale of the health status instrument, the Chronic Respiratory Disease Questionnaire (CRQ). Other questionnaires included the BDI/TDI and the University of California at San Diego Shortness of Breath Questionnaire (SOBQ). In all studies listed in this table, dyspnea was improved regardless of the measure used. In the earlier described trial by Ries et al. (29), the SOBQ was used to assess dyspnea. By the end of pulmonary rehabilitation, this score decreased by 6.8 units (i.e., less dyspnea) vs. no significant change in the education-only control group. The effect persisted for at least 6 months, as depicted in Figure 2. Interestingly, the reduction in questionnaire-rated dyspnea with daily activities—which lasted only approximately 6 months—was of shorter duration than the reduction in perceived breathlessness during exercise testing, which lasted approximately 24 months. A recent meta-analysis that used many of these same studies examined the benefit of pulmonary rehabilitation looking closely at the CRQ and confirmed that there were important improvements in dyspnea following rehabilitation (30). Across all studies examined in this meta-analysis, the total weighted mean difference between the treatment and control was 5.06 (confidence interval, 4.04–6.09) for the dyspnea total score. This number represents an average of a one-point change per item, which substantially exceeds the reported clinically important difference cutoff of 0.5 unit change per item. X. Strategies to Improve the Effectiveness of Pulmonary Rehabilitation The decade of the 1990s witnessed the documentation of the overall effectiveness of pulmonary rehabilitation on multiple outcomes, including dyspnea. What remains to be determined are the most efficient approaches to this labor-intensive treatment. The following briefly discusses some of these approaches. A. Site of Pulmonary Rehabilitation

Pulmonary rehabilitation can be offered in an inpatient, outpatient (hospital, office, or community), or in the home setting. The optimal setting has not been determined, but realistically depends on the characteristics and needs of the individual patient plus the availability of the type of program.

8 weeks upper and lower extremity weight training (14) 6 weeks OPR (10)

8 weeks inpatient rehabilitation, followed by 16 weeks outpatient supervision (45) 8 weeks OPR

6 weeks multimodality exercise endurance

6 weeks multimodality exercise (20)

12 weeks combined aerobic and strength training (21)

(21)

(41)

(19)

(20)

(42)

(29)

(16)

Treatment group (n)

References

BDI/TDI

CRQ dyspnea

Dyspnea measure

BDI/TDI, OCD

BDI/TDI

SOBQ

12 weeks aerobic training CRQ dyspnea alone (15)

Nonintervention period (20a)

Standard medical management

Education only

Conventional community CRQ dyspnea, care (44) BDI

Standard medical care (10)

No exercise training

Control group (n)

Significant improvement in CRQ dyspnea following treatment compared to control period The TDI significantly increased following OPR compared to control (2.3 vs. 0.2 units) The treatment–control in CRQ dyspnea was 3.0 units, which exceeded the MCID; the BDI increased by 2.7 units compared to control Dyspnea was significantly reduced following OPR, but the effect disappeared by the 12 months assessment The TDI increased by 2.8 units following exercise training indicating a significant improvement in chronic breathlessness The TDI was significantly greater following treatment period than nonintervention period: 3.2 vs. 0.0 units. There was a corresponding improvement in the OCD Both groups had significant but similar improvements in CRQ dyspnea that exceeded the MCID

Outcome

Table 4 Controlled Clinical Trials of Pulmonary Rehabilitation on Questionnaire-Measured Dyspnea

314 ZuWallack et al.

Standard care (30) Standard medical care (17) 12 weeks continuous exercise training (18)

8 weeks high-intensity training (20)

12 months of OPR (components given sequentially) (30) 12 weeks walking exercise at or near home (20) 12 weeks interval exercise training (18)

8 weeks low-intensity training (20)

(43)

Abbreviations: CRQ, Chronic Respiratory Questionnaire; SOBQ, University of California San Diego Shortness of Breath Questionnaire; BDI, Baseline Dyspnea Index; TDI, Transitional Dyspnea Index; OCD, Oxygen Cost Diagram; OPR, outpatient pulmonary rehabilitation; VAS, visual analog scale. a Crossover trial.

(36)

(40)

(32)

Standard medical management (101)

6 weeks OPR (99)

(3)

Treatment–control difference in CRQ dyspnea was 6.1 units after 6 weeks and 1.9 units after 1 year. The former exceed the MCID CRQ dyspnea Significant improvement in favor of rehabilitation in all areas of dyspnea CRQ dyspnea, measurement. Improvement in CRQ MRC, VAS for dyspnea exceeded the MCID daily activities Exercise training led to significant CRQ dyspnea, improvement in the TDI, MRC, and CRQ BDI/TDI, dyspnea MRC Both groups had significant but similar CRQ dyspnea increases in CRQ dyspnea Both groups had significant improvement in CRQ dyspnea (4.6 and 6.1 units, respectively) and the TDI (2.9 and 3.2 units, CRQ dyspnea, respectively); between-group differences were not significant BDI/TDI

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Figure 2 Changes in questionnaire-rated dyspnea following pulmonary rehabilitation. Data from the first 48 months after pulmonary rehabilitation are given. Outpatient pulmonary rehabilitation led to significant reductions in questionnairerated dyspnea (SOBQ) for approximately 6 months following beginning therapy. * p < 0.01. Abbreviation: SOBQ, Shortness of Breath Questionnaire. Source: Adapted from Ref. 29.

There are few studies comparing inpatient with outpatient or home-based pulmonary rehabilitation. Inpatient pulmonary rehabilitation is often optimal for patients with severe respiratory impairment, severe comorbidities, or major functional limitation. Patients too ill to regularly attend outpatient sessions could be considered for inpatient or home-based rehabilitation. It appears that pulmonary rehabilitation given exclusively in the home for individuals house bound with severe dyspnea (a Medical Research Council dyspnea score of 5) does not lead to an equivalent improvement in dyspnea or other outcomes as an outpatient-based facility (31). However, a homebased program for individuals with less severe disease has led to impressive gains in exercise performance, dyspnea relief, and quality of life (32). Home-based programs, which can be supplemented with visits to community-based centers, have advantages of convenience for the patient and family members and a familiar environment for training and the acquisition of techniques. The latter has the potential for producing sustained patient

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motivation, with prolonged maintenance of an optimal level of function. Indirect evidence for this effect comes from a study by Strijbos et al. (33), who compared outcome results from hospital-based outpatient vs. home-based pulmonary rehabilitation in a randomized trial of 45 patients with COPD lasting 18 months. Improvement in exercise performance appeared to initially slightly favor those given hospital-based rehabilitation (although between-group statistics were not given), but long-term gains were clearly superior in the home-based group. B. Duration of Exercise Training

The optimal number of exercise training sessions for pulmonary rehabilitation has yet to be determined. This is reflected by the wide variability in duration of pulmonary rehabilitation programs, with most ranging from 6 to 12 weeks. Green et al. (34) showed that four weeks of formal exercise training with directions to continue exercising at home following rehabilitation was less effective than seven weeks of formal training. Recent Global Initiative for Obstructive Lung Disease (GOLD) guidelines (35) recommend at least 8 weeks of rehabilitation, although the evidence backing this is meager. C. High- Vs. Low-Intensity Exercise Training

As in individuals without disease, the positive effect of exercise training on exercise variables is clearly dose dependent in COPD (18). The dosedependent effect of exercise training intensity on exertional dyspnea was also demonstrated by Normandin et al. (36), who compared high- with low-intensity exercise training in pulmonary rehabilitation. However, programs with less intense levels of exercise training have had impressive results in exercise variables (37). It should be emphasized that the goals of pulmonary rehabilitation are to reduce dyspnea, improve function, and enhance quality of life, not merely to improve exercise performance on a stationary bicycle or treadmill. Little evidence is present linking superior performance on the treadmill to greater improvement in dyspnea associated with daily activities or improvement in health status. For example, in the above-cited study by Normandin et al., improvements in the TDI and the CRQ-rated health status were similar in high- and low-intensity trained COPD patients despite the greater increases in exercise performance in the former group. Long-term adherence might be enhanced with a lower intensity regimen, although this has not been proven. XI. Summary Dyspnea is the major symptom in most patients with advanced lung disease and is the predominant reason for referral to pulmonary rehabilitation.

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Although pulmonary rehabilitation has no significant effect on the underlying pulmonary physiologic abnormalities, it often leads to significant and clinically meaningful improvement in this symptom. The physiologic mechanisms underlying the effectiveness of comprehensive pulmonary rehabilitation on this symptom are probably multifactorial, and vary among patients. Improved mechanical efficiency during exercise is undoubtedly important. The reduced respiratory rate associated with this may lead to a reduced tendency for dynamic hyperinflation as an added benefit. Other factors may also contribute to a reduction in breathlessness, including a physiologic training effect in some individuals, better pacing, desensitization to dyspnea, reduced anxiety for dyspnea-producing situations, and improved feelings of self-efficacy. Optimization of the pulmonary rehabilitation intervention remains a challenge for the discipline. References 1. Lertzman MM, Cherniack RM. Rehabilitation of patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1976; 114:1145–1165. 2. Pulmonary rehabilitation: joint ACCP/AACVPR evidence-based guidelines. J Cardiopulm Rehabil 1997; 17:371–405. 3. Griffiths TL, Burr ML, Campbell IA, Lewis-Jenkins V, Mullins J, Shiels K, Turner-Lawlor PJ, Payne N, Newcombe RG, Lonescu AA, Thomas J, Tunbridge J. Results of a 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial. Lancet 2000; 355:362–368. 4. Griffiths TL, Phillips CJ, Davies S, Burr ML, Campbell IA. Cost effectiveness of an outpatient multidisciplinary pulmonary rehabilitation programme. Thorax 2001; 56:779–784. 5. National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003; 348:2059–2073. 6. American Thoracic Society. Pulmonary rehabilitation—1999. The official statement of the American Thoracic Society. Am J Respir Crit Care Med 1999; 159:1666–1682. 7. Gray-Donald K, Gibbons L, Shapiro SH, Macklem PT, Martin JG. Nutritional status and mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 153:961–966. 8. Wouters EFM, Schols AMWJ. Prevalence and pathophysiology of nutritional depletion in chronic obstructive pulmonary disease. Respir Med 1993; 87(suppl B):45–47. 9. Schols AMWJ, Mostert R, Soeters PB, Wouters EFM. Body composition and exercise performance in patients with chronic obstructive pulmonary disease. Thorax 1991; 46:695–699. 10. Shoup R, Dalsky G, Warner S, Davies M, Connors M, Khan M, Khan F, ZuWallack RL. Body composition and health-related quality of life in patients with obstructive airways disease. Eur Respir J. 1997; 10:1576–1580.

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11. Ferreira IM, Brooks D, Lacasse Y, Goldstein RS. Nutritional intervention in COPD. A systematic overview. Chest 2001; 119:353–363. 12. Mahler DA, Faryniarz K, Tomlinson D, Colice GL, Robins AG, Olmstead EM, O’Connor GT. Impact of dyspnea and physiologic function on general health status in patients with chronic obstructive pulmonary disease. Chest 1992; 102:395–401. 13. Guyatt GH, Feeny DH, Patrick DL. Measuring health related quality of life. Ann Intern Med 1993; 118:622–629. 14. Mahler D, Guyatt G, Jones P. Clinical measurement of dyspnea. In: Mahler D, ed. Lung Biology in Health and Disease: Dyspnea. Vol. 111. New York: Marcel Decker Inc., 1998:149–198. 15. Borg GAV. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14:377–381. 16. Reardon J, Awad E, Normandin E, Vale F, Clark B, ZuWallack RL. The effect of comprehensive outpatient pulmonary rehabilitation on dyspnea. Chest 1994; 105:1046–1052. 17. American Thoracic Society. Dyspnea: mechanisms, assessment, and management: a consensus statement. Am J Respir Crit Care Med 1999; 159:321–340. 18. Casaburi R, Patessio A, Ioli F, Zanaboni S, Donner CF, Wasserman K. Reductions in exercise lactic acidosis and ventilation as a result of exercise training in patients with obstructive lung disease. Am Rev Respir Dis 1991; 143:9–18. 19. O’Donnell DE, McGuire M, Samis L, Webb KA. The impact of exercise reconditioning on breathlessness in severe airflow limitation. Am J Respir Crit Care Med 1995; 152:2005–2013. 20. O’Donnell DE, McGuire M, Samis L, Webb KA. General exercise training improves ventilatory and peripheral muscle strength and endurance in chronic airflow limitation. Am J Respir Crit Care Med 1998; 157:1489–1497. 21. Simpson K, Killian K, McCartney N, Stubbing DG, Jones NL. Randomised controlled trial of weightlifting exercise in patients with chronic airflow limitation. Thorax 1992; 47:70–75. 22. Schols AMWJ, et al. Physiological effects of nutritional support and anabolic steroids in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152:1268–1274. 23. Leith DE, Bradley M. Ventilatory muscle strength and endurance training. J Appl Physiol 1976; 41:508–516. 24. Weiner P, Rasmi M, Berar-Yanay R, Berar-Yaney N, Davidovich A, Weiner M. The cumulative effect of long-acting bronchodilators, exercise, and inspiratory muscle training in patients with advanced COPD. Chest 2000; 118:672–678. 25. Lotters F, van Tol B, Kwakkel G, Gosselink R. Effects of controlled inspiratory muscle training in patients with COPD: a meta-analysis. Eur Respir J 2002; 20:570–576. 26. Belman MJ, Brooks LR, Ross DI, Mohasifar Z. Variability of breathlessness measurements in patient with COPD. Chest 1991; 99:566–571. 27. Scherer YK, Schmieder LE. The effect of a pulmonary rehabilitation program on self-efficacy, perception of dyspnea, and physical endurance. Heart Lung 1997; 26:15–22.

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28. Carrieri-Kohlman V, Gormley JM, Douglas MK, Paul SM, Stulbarg MS. Exercise training decreases dyspnea and the distress and anxiety associated with it. Chest 1996; 110:1526–2535. 29. Ries AL, Kaplan RM, Limberg TM, Prewitt LM. Effects of pulmonary rehabilitation on physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease. Ann Intern Med 1995; 122:823–832. 30. Lacasse Y, Brosseau L, Milne S, Martin S, Wong E, Guyatt GH, Goldstein RS. Pulmonary rehabilitation for chronic obstructive pulmonary disease (Cochrane Review). In: The Cochrane Library, Issue 3. Oxford: Update Software, 2002. 31. Wedzicha JA, Bestall JC, Garrod R, Garnham R, Paul EA, Jones PW. Randomized controlled trial of pulmonary rehabilitation in severe chronic obstructive pulmonary disease patients, stratified with the MRC dyspnea scale. Eur Respir J 1998; 12:363–369. 32. Hernandez MTE, Rubio TM, Ruiz FO, Riera HS, Gil RS, Gomez JC. Results of a home-based training program for patients with COPD. Chest 2000; 118:106–114. 33. Strijbos JH, Postma DS, van Altena R, Gimeno F, Koeter GH. A comparison between an outpatient hospital-based pulmonary rehabilitation program and a home-care pulmonary rehabilitation program in patients with COPD. A followup of 18 months. Chest 1996; 109:366–372. 34. Green RH, Singh SJ, Williams J, Morgan MDL. A randomised controlled trial of four weeks versus seven weeks of pulmonary rehabilitation in chronic obstructive pulmonary disease. Thorax 2001; 56:143–145. 35. www.goldcopd.org. 36. Normandin EA, McCusker C, Connors ML, Vale F, Gerardi D, ZuWallack RL. An evaluation of two approaches to exercise conditioning in pulmonary rehabilitation. Chest 2002; 121:1085–1091. 37. Clark CJ, Cochrane L, Mackey E. Low intensity peripheral muscle conditioning improves exercise tolerance and breathlessness in COPD. Eur Respir J 1996; 9:2590–2596. 38. Strijbos JH, Postma DS, van Altena R, Gimeno F, Koeter GH. Feasibility and effects of a home-care rehabilitation program in patients with chronic obstructive pulmonary disease. J Cardiopulm Rehabil 1996; 16:386–393. 39. Coppoolse R, Schols AMWJ, Baarends EM, Mostert R, Akkermans MA, Janssen PP, Wouters EFM. Interval versus continuous training in patients with severe COPD: a randomized clinical trial. Eur Respir J 1999; 14:258–263. 40. Vogiatzis I, Nanas S, Roussos C. Interval training as an alternative modality to continuous exercise in patients with COPD. Eur Respir J 2002; 20:12–19. 41. Goldstein RS, Gort EH, Stubbing D, Avendano MA, Guyatt GH. Randomised controlled trial of respiratory rehabilitation. Lancet 1994; 344:1394–1397. 42. Bernard S, Whittom F, LeBlanc P, Jobin J, Belleau R, Berube C, Carrier G, Maltais F. Aerobic and strength training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159:896–901. 43. Guell R, Casan P, Belda J, Sangenis M, Morante F, Guyatt GH, Sanchis J. Long-term effects of outpatient rehabilitation of COPD. A randomized trial. Chest 2000; 117:976–983.

14 Inspiratory Muscle Training

CARMEN LISBOA and GISELLA BORZONE Department of Respiratory Diseases, Pontificia Universidad Cato´lica de Chile, Santiago, Chile

I. Introduction Inspiratory muscle training (IMT), first applied by Leith and Bradley in 1976 (1), has been used in several pathological conditions in which respiratory muscle function is impaired. Although there are data regarding the effects of IMT in neuromuscular diseases, asthma, and cystic fibrosis, the largest experience refers to patients with COPD. Even though the effects of IMT in these patients have been studied for more than 20 years, the role of this intervention in pulmonary rehabilitation remains controversial. Thus, in the Global Initiative for Chronic Obstructive Lung Disease (2), IMT is not considered a component of rehabilitation programs, and the ACCP/AACVPR guidelines recommend it only for patients who remain symptomatic in spite of optimal bronchodilator therapy (3). This position may be related in part to the meta-analysis by Smith et al. (4) published in 1992 showing no significant effects of IMT on respiratory muscle function and functional status. The conclusions of this metaanalysis had a negative impact, discouraging new investigations on the effects of IMT, mainly in North America. However, very few of the studies 321

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included in that meta-analysis controlled the inspiratory load, and in the vast majority of them, clinically relevant outcomes such as dyspnea were not considered. In a recent meta-analysis by Lo¨tters et al. (5) in which load control was a feature in all of the studies included, a significant improvement in inspiratory muscle strength, endurance, and the sensation of dyspnea with IMT was recognized. Another factor that has negatively affected IMT prescription in patients with several diseases derives from the studies of Reid et al. (6), showing diaphragm sarcomere injury in hamsters with tracheal banding. This type of experiment, unlike IMT, implies a high and constant load that affects both inspiration and expiration. It is then difficult to extrapolate the results of these experiments to IMT. Functional improvement induced by IMT may be explained, at least in part, by intrinsic structural adaptations of the inspiratory muscles, similar to those found with limb muscle training (7). Although Bisschop et al. (8) showed that intermittent IMT using mild loads induces changes in rat diaphragm fibers and Gea et al. (9), using in situ hybridization, found that dogs breathing with a moderate inspiratory resistance experience changes in diaphragm myosin expression, little is known about structural changes in human respiratory muscles with training. Recently, Ramı´rez-Sarmiento et al. (10) studied for the first time the structural changes in human inspiratory muscles induced by IMT in severe COPD. They used a training load of 40–50% PImax and found a significant increase in the proportion of type I fibers and in the size of type II fibers in the external intercostal muscles after 5 weeks of training, a response that would be predicted from findings in trained limb muscles. These results provide support for the safety of IMT as a treatment modality. Another piece of evidence that supports IMT safety comes from measurements of oxygen saturation during training maneuvers using loads ranging from 10% to 50% PImax (11). In this study, no desaturation was seen and, indeed, oxygen saturation improved with training maneuvers. As discussed in the following sections of this chapter, several investigators have shown that IMT not only improves inspiratory muscle function but also alleviates dyspnea, thus improving exercise tolerance. This is the main desirable goal of IMT in COPD, since dyspnea is the major limiting symptom in patients with this disease. Since previous studies have clearly demonstrated that control of the inspiratory load is crucial to assure training effects, we focus on the results of investigations in which the inspiratory load was quantified and a control group was included. Although some data exist that suggest beneficial effects of IMT in conditions such as chronic heart failure (12–14), cystic fibrosis (15), and asthma (16–18), we have restricted our review to analyze the effect of IMT on dyspnea in COPD.

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II. Rationale for Training Inspiratory Muscles in COPD In patients with COPD, pulmonary hyperinflation secondary to expiratory flow limitation leads to mechanical disadvantage of the diaphragm, impairing its capability for tension generation, mainly at the high lung volumes that are characteristic of tidal ventilation in COPD. This diaphragmatic weakness is considered to be relative, since patients with COPD are capable of generating normal or greater tension at a shorter length, due to compensatory cellular mechanisms contributing to offset the detrimental effects of hyperinflation (19). Nevertheless, in patients with advanced disease, diaphragmatic tension generation is not sufficient to cope with the increased ventilatory loads either at rest or with physical activity. A number of other factors are known to contribute to ventilatory muscle dysfunction in these patients, such as malnutrition (20), hypoxemia (21), hypercarbia (22), comorbid conditions, generalized muscle weakness (23), and electrolyte disturbances (24). A. Mechanisms Underlying Dyspnea

The increased respiratory impedance in patients with COPD requires greater motor command to achieve adequate ventilation. Since an important component of the sensation of dyspnea is the sense of effort when contracting the inspiratory muscles (25,26), dyspnea is related to the increased percentage of PImax employed to overcome disturbed impedance. Along the same lines, Patessio et al. (27) have shown that the sensation of dyspnea is related to the inspiratory muscle pressure generated during an inspiratory resistive loading test, both in normal subjects and in patients with COPD. They found a close relationship between Borg Score (28) and mouth pressure developed to overcome the progressively increasing loads, with more dyspnea for a given load in COPD patients than in controls. In the same study, in addition to improvement in inspiratory muscle function, patients with COPD submitted to IMT showed a significant reduction in Borg Score for all the loads during the loading test. Mangelsdorff et al. (29) in our laboratory found a similar relationship between dyspnea score and the percentage of PImax generated in an incremental threshold loading test in patients with COPD and in patients with chronic heart failure. Both types of patients had reduced inspiratory muscle strength and experienced a higher sense of dyspnea for a given load than normal subjects (Fig. 1). Furthermore, O’Donnell et al. (30) have shown that dyspnea during exercise in patients with COPD correlates with ventilatory effort, defined by them as the Pbreath/PImax/VT/VC ratio. Since the increased respiratory impedance in this disease is only partially reversible, it is unlikely that the percentage of PImax employed for breathing (Pbreath) could decrease

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Figure 1 Relationship between dyspnea (Borg Score) and % PImax employed during breathing against progressive threshold loads in normal subjects, in patients with COPD, and in patients with chronic heart failure (CHF). For each of the loads, patients reported higher dyspnea scores than their normal counterparts. Source: From Ref. 29.

significantly even after optimal pharmacologic treatment. Inspiratory muscle training by improving maximal strength decreases the Pbreath/PImax ratio, alleviating dyspnea. Figure 2 summarizes the mechanical factors involved in the genesis of dyspnea in patients with COPD and the proposed mechanisms by which IMT alleviates this symptom. III. Components of IMT The ventilatory muscles respond to the same conditioning stimuli as have been described for other skeletal muscles. In this respect, it has been traditionally postulated that in order to obtain a training response it is necessary: (a) to apply a sufficiently large stimulus; (b) to use a specific stimulus either to obtain strength or for endurance training; and (c) to maintain the stimulus for a long period of time, since the effect of training declines after its cessation. Available training methods differ with respect to the contraction pattern used to overcome the loads, the particular muscles recruited, and the potential for strength or endurance training. Belman et al. (31) have

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Figure 2 Diagram illustrating the mechanical factors involved in the genesis of dyspnea in COPD patients (panel A) and the effects of IMT (panel B). (a) Expiratory flow limitation by inducing dynamic hyperinflation (DH) impairs respiratory impedance with consequent increment in Pbreath to maintain VE. Dynamic hyperinflation also lowers inspiratory muscle strength, increasing the Pbreath/PImax ratio, ventilatory effort, and dyspnea. Inspiratory muscle training ameliorates dyspnea through improvement in strength, which lowers the Pbreath/PImax ratio.

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shown that patients allowed to adjust their own breathing pattern against a resistance eventually adopt a strategy that lowers their inspiratory work rate sufficiently to eliminate any training effect. However, when the load is controlled, training-induced changes in inspiratory muscle function are similar in different studies despite the training modality used (5). The first meta-analysis on the efficacy of IMT, published by Smith et al. (4), found no significant effects on inspiratory muscle strength, endurance, or dyspnea. However, in that meta-analysis, only 5 out of the 17 studies had load control. When the analysis takes into consideration studies with load control, as has been done in the recent meta-analysis by Lo¨tters et al. (5), there is a significant reduction in dyspnea, in association to IMT effects. Table 1 summarizes studies that meet the criteria of having both load control and a control group. Most of them include changes in dyspnea as one of the outcomes measured. A. Training Modalities

The most frequently employed methods for training inspiratory muscles are the following. 1. Normocapnic Hyperpnea

With this method, subjects breathe sustaining the highest possible level of minute ventilation for 10–15 min, training both the inspiratory and expiratory muscles. Since the rebreathing circuit required to maintain normocapnia is rather complex, this training method has mainly been used in laboratory settings. Recently, Scherer et al. (32) have developed a system that, once adjusted in the laboratory, allows the patient to train at home, keeping normocapnia by breathing at 60% MVV. 2. Inspiratory Resistive Breathing

(a) Resistive loads: Subjects inspire through the mouth using devices with simple resistive orifices of progressively decreasing diameter. With these types of devices, the load varies with inspiratory flow and is highly dependent on the pattern of breathing adopted by the subject during the training maneuvers. To assure the maintenance of a constant load, it is necessary to control both the breathing pattern and the target pressure. (b) Target flow resistive breathing: Subjects are instructed to generate a target inspiratory flow rate in a flow meter set so that they have to generate a percentage of their PImax while maintaining the target inspiratory flow. For this type of training, the duration of inspiration and that of the respiratory cycle need to be controlled.

15% PImax High load Low load 50% PImax

12 controls 10 subjects 8 controls 8 subjects

Home based Resistive controlled Home based Resistive controlled 8 controls 8 subjects

7 controls 10 subjects

10 controls

Laboratory Threshold device

Laboratory Threshold device

Home based

Flynn et al. (40)

Lisboa et al. (41)

Patessio et al. (27)

Harver et al. (52)

10% PImax

Sham 30% PImax

Sham High intensity

30% PImax

10 subjects

Threshold device

Training load

Larson et al. (38)

Sample size

Training type

References

5

6

8

8

8

Duration (weeks)

" VT/TI " PImax, IMPO, SIP, Vimax

" PImax " external work

" PImax and endurance

" PImax

" PImax and endurance

Effects on inspiratory muscle function

Table 1 Inspiratory Muscle Training in COPD: Review of Studies with Clinically Relevant Outcomes

(Continued)

# Dyspnea, " 6MWD

No changes in 12MWD and in maximal exercise capacity

# Dyspnea during loaded breathing

# Dyspnea

# 12MWD, no changes in HRQL

Clinical outcomes

Inspiratory Muscle Training 327

12 subjects

8 controls 10 subjects

10 controls 10 subjects

10 controls 20 subjects

15 controls

Threshold device

Home based Threshold device

Home based Threshold device

Home based Target flow

Home based

Preusser et al. (34)

Lisboa et al. (53)

Lisboa et al. (39)

de Lucas et al. (36)

Sample size

Training type

References

None

10% PImax 30% PImax

10% PImax 30% PImax

22% PImax 30% PImax

52% PImax

Training load

16

10

10 weeks and crossover

12

Duration (weeks)

" PImax

" PImax

" PImax, IMPO, SIP. Deterioration when lowering the load

" PImax. No effect on endurance

Effects on inspiratory muscle function

Improvement in exercise tolerance and # dyspnea. No changes in Wmax

# Dyspnea. No changes in Wmax. # Metabolic cost of exercise

" 6MWD, # dyspnea. Mild deterioration when lowering the load

No differences in 12MWD between groups

Clinical outcomes

Table 1 Inspiratory Muscle Training in COPD: Review of Studies with Clinically Relevant Outcomes (Continued )

328 Lisboa and Borzone

10 subjects

10 controls

Home based

15 controls

Hyperpnea Target flow

15 subjects

Normocapnic

No load

30% PImax

60% MVV Breathing exercises 24

8

" PImax

" Endurance

# Dyspnea, " 6MWD " HRQL. No changes in Wmax

PImax: maximal inspiratory pressure; MVV: maximal voluntary ventilation; IMPO: inspiratory muscle power output; SIP: sustainable inspiratory pressure; VI: inspiratory flow; VT/TI: mean inspiratory flow; 12MWD: 12-min walking distance; 6MWD: 6-min walking distance; HRQL: health related quality of life; Wmax: maximal work rate.

Sa´nchez Riera et al. (37)

Scherer et al. (32)

" 6MWD, no differences in dyspnea and HRQL between groups

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With this method, the training stimulus is a combination of pressure and flow loads applied through devices in which the subject must develop a given pressure to open the valve and thereby initiate inspiratory flow. Once the valve is opened by the subject’s effort, inspiration becomes unhindered. The advantage of these devices is that the pressure developed at the airway opening is relatively fixed and nearly independent of the patient’s inspiratory flow rate (33). B. Load Used for Training: High Vs. Low

Most of the studies in Table 1 have used a percentage of patient’s PImax for training. The most frequently used load is 30% PImax, since this load has been shown to lead to improvement in inspiratory muscle function and in several clinically relevant parameters. However, there are still insufficient data to evaluate the relationship between the magnitude of the load and the improvement in clinical parameters. Loads higher than 30% PImax (10,27,34,35) have also been used (Fig. 3). Although they seem to show a larger effect on PImax, only one of these studies (27) had analyzed the effect

Figure 3 Relationship between the magnitude of the load employed for IMT and the mean percent increase in PImax for most of the studies in Table 1, including loads employed in control groups. With higher loads, there is a larger improvement in PImax. The high variability in PImax response with a load of 30% PImax is related to differences in training duration (5–24 weeks).

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on dyspnea and found amelioration of this symptom during loaded breathing. Studies in Table 1 in which transition dyspnea index (TDI) was measured show a similar improvement of TDI independent of the magnitude of the load. C. Training Duration

It is not known for how long patients should be trained. Most of the studies have empirically used two daily sessions lasting 15 min each, for five or six days a week. In the literature, training duration is highly variable and ranges from five weeks to six months (Table 1). Data from studies using 30% PImax for long periods of time show larger improvements in both PImax and clinical outcomes at the end of the training protocol compared with studies in which training duration is shorter (36,37). Only a few studies have made measurements consistently during the training period, in order to evaluate performance over time. Unfortunately, only outcomes related to inspiratory muscle function have been measured. Since the increase in PImax shows a plateau after four weeks of training (38,39), it has been suggested that training protocols should not last less than 4 weeks. More studies are needed in order to have recommendations based on evidence of clinical benefit such as alleviation of dyspnea. D. Where should IMT be Implemented?

Most of the studies on IMT have been done at home, with frequent supervision in the laboratory. No significant differences were found in the effect of IMT on inspiratory muscle function when those studies were compared with the three studies entirely performed in the laboratory (10,27,40). Training at home has the advantages of lower cost and better patient compliance than training in the laboratory. The likelihood of achieving a lower training effect can be overcome with periodic supervision in the laboratory. In our experience, weekly testing in the laboratory in order to adjust the load allows for adequate monitoring of training and patient cooperation. E. What Outcomes Should be Measured?

The vast majority of the studies have focused on training-induced changes in inspiratory muscle function (strength and/or endurance). This seems reasonable, since changes in these parameters indicate training effects similar to the way in which training is assessed in limb skeletal muscles (7). Less frequently measured are changes induced by IMT on breathing pattern both at rest and during loaded breathing. Training-induced Ti

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shortening without changes in breathing frequency might be relevant to the effects of IMT on dyspnea sensation, since a larger Te reduces dynamic hyperinflation. An increase in the VT/Ti ratio also found with training suggests an improvement in shortening velocity of inspiratory muscles (40,41). The effects of IMT on inspiratory muscle tension–time index or inspiratory muscle power output have scarcely been studied (41,42). Very few studies have included clinical outcomes such as dyspnea scores, exercise tolerance, and quality of life. Since dyspnea is the most important and limiting symptom in patients with COPD, evaluation of this condition should be done routinely in IMT trials, using validated instruments with the capacity to detect mild to moderate changes (28,43). The effect of IMT on exercise tolerance has been evaluated in several studies by measuring maximal exercise capacity using either a symptomlimited progressive exercise test, the 12MWD (44), the 6MWD (45), or a submaximal exercise, but in only a few of them was dyspnea measured at the end of exercise. The effect of IMT on disease specific quality of life questionnaires (46,47) that include dyspnea during day-to-day activities, an outcome that in our opinion should also be measured, still need evaluation.

IV. Inspiratory Muscle Training in COPD Table 1 shows studies applying different training modalities and, independent of the training system used, in practically all of the studies, inspiratory muscle strength and/or endurance improved. Highly variable loads ranging from 0% (sham) to 22% PImax were used for the control groups, resulting in PImax increase not only in the experimental group but also in several control groups. Thus, in some studies, differences in PImax between groups at the end of IMT did not reach statistical significance. This observation suggests that loads traditionally considered to be negligible can induce some degree of functional change. As an example, a training load of approximately 10% PImax was able to induce a significant improvement in PImax in the control group in the study of Lisboa et al. (39). This improvement cannot be attributed to a learning effect with repeated measurements, since PImax maneuvers performed one week apart on four occasions during the run-in period did not result in a significantly larger PImax.

A. Benefits Based on Clinical Instruments

Next, we analyze the studies in Table 1 that have shown significant changes in clinical parameters with IMT.

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1. Reduction in Dyspnea During Daily Activities

Although early investigators reported subjective improvement and an increment in patients’ daily activities with resistive training (48–51), Harver et al. (52) were the first to evaluate dyspnea during day-to-day activities using a known and validated scale (43). Patients used a resistive trainer (P Flex), and after 8 weeks of training, the study group showed a significant improvement in dyspnea evaluated with the transitional dyspnea index (TDI) as compared with the control group (þ3.5
2.5 points vs. þ0.3
1.0). The investigators also found a significant correlation between the increment in PImaxRV, and the improvement in both the magnitude of the task (r ¼ 0.54; p < 0.018) and the magnitude of the effort (r ¼ 0.046; p < 0.047). A similar degree of improvement in TDI focal score as that described by Harver et al. (52) was found by Lisboa et al. (41) after 5 weeks of training. They also found a significant correlation between the percentage change in PImax after training and TDI (r ¼ 0.53; p < 0.05). These results suggest that amelioration of dyspnea is related to the increase in PImax with training and the subsequent reduction in Pbreath/PImax ratio. This concept is also supported by a crossover study by the same authors (53), in which a group of patients was first trained with 30% PImax for 10 weeks followed by another 10 weeks with 10% PImax. A different group was initially trained with a 10% PImax load, which was later increased to 30% PImax (Fig. 4). At

Figure 4 Inspiratory muscle training protocol applied to 20 patients with severe COPD. After a run-in period of 4 weeks, 10 patients were trained with a load of 30% PImax (Group 1), while the other 10 patients were trained with a load of 10% PImax (Group 2). After 10 weeks of training, the loads were crossed. Source: From Ref. 53.

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the end of the first 10 weeks, TDI focal score was significantly greater in the group trained with the highest load as compared with the group trained with the lowest load (þ3.7
0.6 vs. þ1.7
0.6; p ¼ 0.036). Since PImax increased in both groups, the difference between groups was not statistically significant. When loads diminished from 30% to 10% PImax, deterioration was seen in both dyspnea and PImax. In contrast, those patients initially trained with 10% PImax showed a significant increase in both PImax (81
5.6 to 89
5.6 cm of H2O) and TDI (þ1.7
0.6 to þ4.15
0.5) when the load was increased (Figs. 5 and 6). Another study showing an improvement in dyspnea using TDI is that of Sa´nchez Riera et al. (37), who found that the trained group reached a mean of þ4.7 points (4.2–5.2; 95% CI) after target flow training. They also found that the dyspnea component of the Chronic Respiratory Questionnaire (CRQ) disclosed an increase greater than the minimum clinically important difference (0.5 points) after training. The only study showing no significant differences in TDI after training compared with the control group was the study of Scherer et al. (32). They found that TDI after training with isocapnic hyperventilation reached

Figure 5 Mean PImax values
1 SE in COPD patients according to the protocol described in Figure 4. Group 1 (30% PImax followed by 10% PImax) is represented by closed squares and Group 2 (10% PImax followed by 30% PImax) by closed circles. After the first 10 weeks, a significant increment in PImax was observed in both groups. When the loads were crossed over, PImax fell in Group 1, whereas it continued to improve in Group 2. Source: Modified from Ref. 53.

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Figure 6 Changes in the transition dyspnea index (TDI) in both groups according to the protocol in Figure 4. Patients in Group 1 exhibited a nonsignificant deterioration in TDI when the load was decreased, whereas patients in Group 2 continued to improve TDI. Source: From Ref. 53.

þ4.8 points in the study group, and þ2 points in the control group. The lack of statistical significance was interpreted by the authors as the result of some level of IMT secondary to the breathing exercises used in the control group. Recently, Weiner et al. (54) have shown that IMT, either alone or combined with expiratory muscle training, improves dyspnea during daily activity. They used loads up to 60% and the BDI to assess dyspnea. The same investigators also showed a significant reduction in dyspnea perception during loaded breathing using Borg’s Score. Taken together, these results clearly show that IMT leads to improvement in dyspnea during daily activities. B. Reduction in Dyspnea During Exercise Testing

Exercise performance after IMT has been evaluated using different approaches. The vast majority of the studies evaluated changes in the six or 12 min walking distance (six or 12MWD tests). Other studies have measured maximal work rate during a progressive incremental exercise test limited by symptoms or exercise tolerance during a submaximal exercise (10,36,37,39,40). In the following section, we refer to studies in which changes in dyspnea have been measured.

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Lisboa and Borzone 1. Changes in Dyspnea at the End of Walking Distance Tests

Five studies (10,32,37,41,53) have evaluated the effect of IMT on the 6MWD, but the effect on dyspnea was assessed in only two of them. Lisboa et al. (53) found a 37% increment in the 6MWD (114 m) in a group of COPD patients trained for 10 weeks with 30% PImax, while the control group trained with 10% PImax only showed a 12% improvement (36 m). The improvement in walking distance in the group trained with the highest load was associated with a reduction in Borg Score of 3.2 points (Table 2), whereas no change was found in the group trained with the lower load. When the training load was reduced from 30% to 10% PImax, there was no deterioration in Borg Score or the 6MWD. On the other hand, when the low load group was subsequently trained with 30% PImax, there was a 66 m increase in 6MWD, with no significant reduction in Borg Score. In the study by Sa´nchez Riera et al. (37), target flow trained COPD patients had a mean increase of 93 m in walking distance using the shuttle test, whereas patients in the control group decreased their walking distance by 58 m. The Borg Score measured at the end of the test did not change with training. Unfortunately, Borg Score was not normalized by the increased walking distance achieved by the trained group. According to these results, we speculate that after IMT, COPD patients improve performance in 6 or 12MWD tests mainly because dyspnea sensation decreases. Reduction in dyspnea allows them to partially reassume day-to-day activities that they had abandoned and in turn provides for some level of whole body exercise. 2. Changes in Dyspnea During Maximal and Submaximal Exercise Tests After IMT

It is difficult to postulate that patients with COPD could improve performance during a progressive exercise test after IMT since ventilatory limitation curtails exercise and does not allow them to reach a plateau in VO2. Table 2 Effect of Crossing Over the IMT Loads on the Distance Walked in 6 min and on Borg Score at the End of Exercise in COPD Patients

Group 1

Group 2

a

Prior to IMT IMT with 30% IMT with 10% Prior to IMT IMT with 10% IMT with 30%

Significant difference from baseline.

PImax PImax PImax PImax

6MWD (m)

Borg’s Score (points)

303
38 417
34a 425
20a 316
31 354
30 420
15a

6.6
0.7 3.4
0.6a 3.0
0.4a 6.1
0.6 5.8
0.8 4.3
0.6

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Several investigators have evaluated the performance of patients with COPD during a progressive symptom-limited exercise test (10,36,37,39). None of the studies have demonstrated an increase in either maximal workload, maximal VO2, or maximal ventilation. Not all the studies looking at maximal exercise capacity have evaluated changes in dyspnea with exercise. Whereas trained patients in the study of de Lucas Ramos et al. (36) performed exercise with less dyspnea, trained patients in the study of Sa´nchez Riera et al. (37) performed exercise with a similar level of dyspnea. De Lucas-Ramos et al. (36) have been the only investigators who have evaluated the effect of IMT on submaximal exercise. They reported longer exercise duration with an accompanying reduction in the sense of dyspnea (Borg Score) after IMT training, an effect that was not seen in the control group. 3. Inspiratory Muscle Training as Part of a Global Exercise Rehabilitation Program

The effect of adding IMT to pulmonary rehabilitation has been studied using several different protocols, with results that are contradictory, mainly due to the fact that the control groups are highly heterogeneous (55–60). Berry et al. (56) employed progressive inspiratory loads ranging from 30% to 80% PImax combined with general exercises. They found no differences in exercise performance or dyspnea score measured at the same level of exercise as compared with control groups trained with 15% PImax alone or in addition to general exercises. Furthermore, training loads of 30–60% PImax did not improve dyspnea rating using either Borg’s Score or the dyspnea domain of the CRQ. In contrast, three studies (58–60) have shown improvement in exercise performance combining IMT with different exercise protocols, but in only one of them was dyspnea at the end of exercise measured. Wanke et al. (60) reported an increase in maximal exercise capacity with no significant change in dyspnea rating at the end of exercise. As mentioned in the previous section, differences in Borg’s Score could have been significant if the authors had normalized their results by workload and/orVO2 max. More studies using similar exercise and IMT protocols are required in order to clarify the role of IMT in combination with pulmonary rehabilitation on dyspnea and exercise performance. V. Patient Selection Criteria for selecting patients for IMT are not defined. From a theoretical point of view, if a patient with COPD has few or no symptoms and his or her respiratory muscle function is preserved, IMT may not be required. Although several studies, including those of Leith and Bradley (1) in normal subjects, Clanton et al. in athletes (61), and the study by Redline et al. (26),

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all show improvement in normal respiratory muscle function with IMT, the role of this improvement in the absence of symptoms is not clear. On the other hand, if there is severe inspiratory muscle dysfunction, IMT can be detrimental, especially if the Pbreath/PImax ratio is high or if the Ti/Ttot ratio is increased, since it could precipitate inspiratory muscle fatigue. It is not yet known what combination of patient’s symptoms and disturbed physiology will allow better prediction of the response to IMT. Some recommendations can be extracted from the ACCP/AACVPR guidelines (3) and the meta-analysis of Lo¨tters et al. (5). The ACCP/AACVPR guidelines (3) recommend IMT for patients with dyspnea despite optimal bronchodilator therapy, and Lo¨tters et al. (5) concluded that IMT is indicated for patients with inspiratory muscle weakness (PImax < 60 cm H2O). Studies in Table 1 reveal beneficial clinical effects in patients with a wide range of disease severity based on percentage predicted FEV1 values and muscle strength measurements. PImax at baseline in those studies ranges from 30 to 77 cm H2O. Figure 7 summarizes data from studies in Table 1 and illustrates that there is an inverse relationship between percentage change in PImax and

Figure 7 Relationship between the percentage change in PImax after training and mean baseline PImax reported in several studies, most of them included in Table 1. Patients with the largest disturbance in baseline PImax improved PImax most significantly.

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baseline PImax, taking into consideration mean data from several studies. This suggests that patients with the largest impairment in strength are those with the largest improvement in PImax with training. Since, in COPD, both the relative diaphragm weakness and dyspnea relate to the level of hyperinflation, one could speculate that recommendations should take into account the level of hyperinflation. In line with this, Clanton and Diaz (62), in a recent review reanalyzing data from Preusser et al. (34), concluded that patients with more hyperinflation were those with the largest improvement in PImax and 12MWD with high intensity training. When COPD patients allocated to IMT were selected on the basis of ventilatory limitation during exercise, Dekhuijzen et al. (58) found that the combination of exercise training plus IMT resulted in an improvement in 12MWD without improvement in ventilatory limitation. Lastly, the contributions of generalized muscle weakness, cardiac failure, and drug use, among others, need to be taken into account when evaluating responses to IMT, since all these factors contribute to dyspnea and exercise limitation in COPD. In conclusion, patients who benefit the most with IMT seem to be those who are dyspneic, exhibit poor tolerance to exercise, and have low inspiratory muscle strength. From data analyzed here, more disabled patients should not be denied the opportunity of an IMT trial, since reduced muscle strength is likely not due to structural muscle changes but due to geometrical thoracic changes that affect the tension generating capacity of the diaphragm that could at least in theory be partially modified with IMT by shortening Ti and allowing Te to be prolonged, thus reducing pulmonary hyperinflation. More research is needed on the effects of IMT on the breathing cycle to test this hypothesis. VI. Conclusions Current data support the role of IMT in reducing dyspnea in patients with COPD. A number of different factors contributed to the early inconsistent results: (a) studies using resistive devices without adequate control of the load; (b) training effects induced by loads thought to be negligible and used in control groups; (c) nonrandom allocation of patients to control groups; and (d) small sample size. There is evidence of beneficial clinical effects that can be achieved independent of the training modality provided pressure development is controlled using appropriate methods. Although the mechanisms by which IMT can improve exercise tolerance in COPD are not yet clear, there is evidence that the reduction in dyspnea secondary to the improvement in inspiratory muscle strength is related to the reduction in the Pbreath/PImax ratio. By reducing the sensation

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of dyspnea, patients are capable of undertaking day-to-day activities they had abandoned, preventing further deconditioning. More research is needed focusing on the mechanisms underlying clinical benefits elicited by IMT, mainly directed at analyzing changes in the breathing cycle that can affect the degree of hyperinflation and reduce dyspnea. Another area in which more research is needed relates to the minimum stimulus needed to maintain the beneficial effects obtained with IMT. Regarding the training regime, there is not enough information to recommend one in particular, but we believe that protocols using commercially available threshold devices with intermediate loads can be effectively used for home training 15 min twice a day. Applied this way, IMT is a low cost treatment that is safe and can be used as a modality of rehabilitation in very severe COPD patients who cannot perform whole body exercise, since in our opinion, improvement in dyspnea and exercise tolerance with IMT is similar to that obtained with full body exercise in severe COPD patients. IMT may also represent a low cost alternative for rehabilitation strategies in developing countries.

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37. Sa´nchez Riera H, Montemayor Rubio T, Ortega Ruiz F, Cejudo Ramos P, Del Castillo Otero D, Elias Hernandez T, Castillo Gomez J. Inspiratory muscle training in patients with COPD. Effect on dyspnea, exercise performance, and quality of life. Chest 2001; 120:748–756. 38. Larson JL, Kim MJ, Sharp JT, Larson DA. Inspiratory muscle training with a pressure threshold breathing device in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1988; 138:689–696. 39. Lisboa C, Villafranca C, Leiva A, Cruz E, Pertuze´ J, Borzone G. Inspiratory muscle training in chronic airflow limitation: effect on exercise performance. Eur Respir J 1997; 10:537–542. 40. Flynn MG, Barter CE, Nosworthy JC, Pretto JJ, Rochford PD, Pierce RJ. Threshold pressure training, breathing pattern, and exercise performance in chronic airflow obstruction. Chest 1989; 95:535–540. 41. Lisboa C, Mun˜oz V, Beroiza T, Leiva A, Cruz E. Inspiratory muscle training in chronic airflow limitation: comparison of two different training loads with a threshold device. Eur Respir J 1994; 7:1266–1274. 42. Villafranca C, Borzone G, Leiva A, Lisboa C. Effect of inspiratory muscle training with an intermediate load on inspiratory power output in COPD. Eur Respir J 1998; 11:28–33. 43. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea. Contents, interobserver agreement and physiologic correlate of two new clinical indexes. Chest 1984; 85:751–758. 44. Mc Gavin CR, Gupta SP, McHardy GJR. Twelve-minute walking test for assessing disability in chronic bronchitis. Br Med J 1976; 1:822–823. 45. Butland RJA, Pang J, Gross ER, Woodcock AA, Gedes DM. Two, six, and 12 minute walking tests in respiratory disease. Br Med J 1982; 284:1607–1608. 46. Guyatt GH, Townsend M, Berman LB, Pugsley SO. Quality of life in patients with chronic airflow limitation. Br J Dis Chest 1987; 81:45–54. 47. Jones PW, Quirck FH, Baveystock CM. A self-complete measure of health status for chronic airflow limitation. Am Rev Respir Dis 1992; 145:1321–1327. 48. Andersen JB, Falk P. Clinical experience with inspiratory resistive breathing training. Int Rehabil Med 1984; 6:183–185. 49. Andersen JB, Dragsted L, Kann T, et al. Resistive breathing training in severe chronic obstructive pulmonary disease: a pilot study. Scand J Respir Dis 1979; 60:151–156. 50. Falk P, Eriksen AM, Kolliker K, Andersen JB. Relieving dyspnea with an inexpensive and simple method in patients with severe chronic airflow limitation. Eur J Respir Dis 1985; 66:181–186. 51. Moreno R, Giugliano C, Lisboa C. Entrenamiento muscular inspiratorio en pacientes con limitacio´n cro´nica del flujo ae´reo. Rev Med Chile 1983; 111:647–653. 52. Harver A, Mahler DA, Daubenspeck A. Targeted inspiratory muscle training improves respiratory muscle function and reduces dyspnea in patients with chronic obstructive pulmonary disease. Ann Int Med 1989; 111:117–124. 53. Lisboa C, Villafranca C, Pertuze´ J, Leiva A, Repetto P. Efectos clı´nicos del entrenamiento muscular inspiratorio en pacientes con limitacio´n cro´nica del flujo ae´reo. Rev Med Chile 1995; 123:1108–1115.

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54. Weiner P, Magadle R, Beckerman M, Weiner M, Berar-Yanay N. Comparison of specific expiratory, inspiratory and combined muscle training programs in COPD. Chest 2003; 124:1357–1364. 55. Goldstein R, De Rosie J, Long S, Dolmage T, Avendano MA. Applicability of a threshold loading device for inspiratory muscle testing and training in patients with COPD. Chest 1989; 96:564–571. 56. Berry MJ, Adair NE, Sevensky KS, Quinby A, Lever HM. Inspiratory muscle training and whole-body reconditioning in chronic obstructive pulmonary disease. A controlled randomized trial. Am J Respir Crit Care Med 1996; 153:1812–1816. 57. Larson JL, Covey MK, Wirtz SE, Berry JK, Alex G, Langbein WE, Edwards L. Cycle ergometer and inspiratory muscle training in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160:500–507. 58. Dekhuijzen PNR, Folgering HTM, van Herwaarden CLA. Target-flow inspiratory muscle training during pulmonary rehabilitation in patients with COPD. Chest 1991; 99:128–133. 59. Weiner P, Azgad Y, Ganam R. Inspiratory muscle training combined with general exercise reconditioning in patients with COPD. Chest 1992; 102:1351–1356. 60. Wanke Th, Formanek D, Lahrmann H, Branth H, Wild M, Wagner Ch, Zwick H. Effects of combined inspiratory muscle and cycle ergometer training on exercise performance in patients with COPD. Eur Respir J 1994; 7:2205–2211. 61. Clanton TL, Dixon J, Drake J, Gadek JE. Inspiratory muscle conditioning using a threshold loading device. Chest 1985; 87:62–66. 62. Clanton Tl, Diaz Ph. Respiratory muscle training in chronic obstructive pulmonary disease. In: Similowski T, Whitelaw WA, Derenne JP, eds. Clinical Management of Chronic Obstructive Pulmonary Disease. New York, Basel: Marcel Dekker Inc., 2002:759–780.

15 Oxygen

ROGER S. GOLDSTEIN University of Toronto, West Park Healthcare Center, Toronto, Ontario, Canada

I. Introduction The role of supplemental oxygen in the relief of dyspnea is both physiologically interesting and clinically important. Despite the almost parallel advances in our understanding of the mechanisms of dyspnea (1) and the pathophysiology of hypoxemia, the precise relationship between them remains unclear. The extent to which an increase in inspired oxygen concentration will improve the PaO2 will vary depending on the magnitude of the mismatch between ventilation and perfusion. Understanding the significance of an increase in PaO2 as part of the management of dyspnea is all the more challenging as many profoundly dyspneic patients have only minimal hypoxemia. Most countries have developed programs for domiciliary oxygen therapy in which supplemental oxygen is funded according to established criteria, derived mainly from two well designed multicenter randomized controlled trials involving chronic obstructive pulmonary disease (COPD) patients with resting hypoxemia (2,3). Although resting hypoxemia is a clearly stated criterion for domiciliary oxygen therapy, some clinicians 345

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prescribe supplemental oxygen for patients with only minimal resting hypoxemia in an effort to alleviate their incapacitating dyspnea, increase their functional exercise capacity and improve their health status. Oxygen delivery systems have developed to the point of enabling many individuals to maintain mobility while benefiting from home oxygen therapy. However, the need for cost containment, together with the emphasis on evidence based medicine, has presented new challenges to those who administer, fund and deliver health care, to use oxygen therapy only when it is likely to be of benefit and to apply it in the most cost-effective way. The role of oxygen in the management of dyspnea must be placed within the context of a continuum of care for patients with chronic respiratory conditions, which includes cessation of smoking, maximal pharmacological therapy, prompt attention to infectious exacerbations and supervised programs in respiratory rehabilitation. The following comments relate to the role of supplemental oxygen in alleviating dyspnea and increasing exercise tolerance among patients with chronic respiratory conditions. The information presented comments on the rationale for oxygen as a life saving therapy in COPD patients with resting hypoxemia, followed by the laboratory measures of the influence of oxygen on dyspnea and exercise capacity, concluding with the few studies in which instruments that measure dyspnea have been applied to the clinical setting.

II. Rationale for Oxygen Therapy Survival benefit from oxygen therapy has been documented by randomized controlled trials from the Medical Research Council and Nocturnal Oxygen Therapy Trial study groups (2,3). Although the subjects with advanced COPD enrolled in these trials almost certainly experienced dyspnea, this symptom was neither a primary nor a secondary outcome measure in either of these important clinical trials. Given the observation that oxygen therapy was life saving and that continuous therapy was clearly of greater benefit than nocturnal therapy, it is unlikely that subjects with dyspnea and resting hypoxemia will ever be enrolled in an RCT in which the control group breathes only ambient air. Most patients with advanced COPD, who do not meet the major life saving criteria by which oxygen is funded (Table 1), do nevertheless experience oxygen desaturation during activities of daily living and during walking tests (4). Reports describing the application of long-term oxygen therapy for patients with milder degrees of resting hypoxemia, concluded that oxygen was not associated with a survival benefit. Unfortunately, these studies also did not address the possible effects of LTOT on dyspnea (5,6).

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Table 1 Entry Criteria for Nocturnal Oxygen Therapy Trial Clinical diagnosis of chronic obstructive lung disease Hypoxemia PaO2  55 mm Hg PaO2  59 plus one of the following: Edema Hematocrit  55% P pulmonale on ECG: 3 mm in leads II, III, aVf Lung function FEV1/FVC < 70% after inhaled bronchodilator TLC  80% precited Age > 35 FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity; TLC, total lung capacity. Source: From Ref. 3.

A. Oxygen Desaturation does not Predict Dyspnea or Exercise Capacity in Patients with Airflow Limitation

Although patients with airflow limitation experience dyspnea during exercise and although they also desaturate, breathlessness during exercise cannot be predicted from changes in oxygen saturation. In a study of 42 patients with COPD and 28 patients with severe asthma, mean saturation levels did not correlate with ratings of dyspnea at rest or after walking. Nor did they correlate with the six-minute walking distance (7). Although the severity of desaturation on walking was related to the severity of lung function impairment, no single measure of pulmonary function predicted either walking distance or dyspnea scores. Broadly, patients with the most dyspnea had the shortest six-minute walk distances, but they did not necessarily have appreciable desaturation (Fig. 1). Therefore, oxygen saturation during exercise cannot be used as a surrogate measure of dyspnea. The latter must be measured directly in any studies that seek to clarify the role of oxygen therapy in the relief of dyspnea. III. Benefits Based on Exercise Testing A. Oxygen, Dyspnea, and Endurance

Supplemental oxygen can result in marked improvements in dyspnea and exercise tolerance even in the absence of exercise-induced desaturation. Woodcock et al. (8) evaluated the effect of air vs. oxygen (4 L/min by nasal cannulae) on dyspnea and exercise tolerance in 10 ‘‘pink puffers’’ with fixed airway obstruction (FEV1 0.71
0.29). Arterial PaO2 at rest and on exercise, while breathing ambient air, was 71
11 and 61
12 mmHg, respectively. When breathing oxygen, the patients were less breathless

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Figure 1 Scatterplot of 6 minute walk distance related to minimum saturation during walking (r ¼ 0.28, p < 0.05). Note the wide scatter of walking distances for any given saturation. Source: From Ref. 7.

despite increasing their six-minute walking distance by 12% (289
105 to 324
87 m, p < 0.05). At submaximal treadmill speeds, breathlessness was reduced, with four of 10 patients reducing their dyspnea scores by more than 30%. The degree of improvement did not correlate with lung function, resting arterial blood gases, or baseline (room air) exercise tolerance. For some subjects, predosing with oxygen for five or 15 min prior to exercise resulted in improvements in exercise tolerance, although subsequent studies have shown that the effects of short burst oxygen therapy for dyspnea are inconsistent (9,10). When 40% oxygen was administered to 12 patients with severe COPD (FEV1 0.89
0.09 L), in whom the room air PaO2 was 71
3 mmHg at rest and 63
5 mmHg at end exercise, the duration of constant power exercise increased from 10
2 to 14
2 min (p ¼ 0.005), and the rise in dyspnea score was delayed (11). Oxygen also delayed the rise in right ventricular systolic pressure during incremental exercise and lowered the mean right ventricular systolic pressure at maximum exercise from 71
8 to

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Figure 2 Decreased dyspnea with oxygen, at the time point equal to end exercise (isotime) on compressed air, correlated with increased exercise duration. r2 ¼ 0.66, p ¼ 0.001. Source: From Ref. 11.

64
7 mmHg (p < 0.03). Improvements in the duration of exercise correlated with the decrease in dyspnea at isotime (the timepoint equal to end exercise on compressed air) (Fig. 2). Dyspnea scores at isotime fell by 25% and ventilation at isotime decreased from 36 to 33 L/min (p < 0.05). Clinical experience supports the notion that the response of dyspnea to oxygen varies among individuals. Therefore, the utility of oxygen therapy for dyspnea in patients with mild or borderline resting hypoxemia is unclear, and this form of therapy is often not covered by third party payers (12,13). B. Dyspnea Relief and Hyperoxia

In patients with severe COPD (FEV1 39
3% predicted) and mild resting hypoxemia (PaO2 74
3 mmHg, PaCO2 41
2 mmHg), supplemental oxygen (60%) administered during constant power exercise at approximately 50% of maximal incremental exercise capacity, increased exercise endurance time and reduced the intensity of exertional breathlessness as well as leg effort (14) (Fig. 3). At the time of exercise cessation, the PaO2 was 65
3 mmHg in those breathing ambient air and 226
12 mmHg in those receiving oxygen. Under laboratory conditions, moderate hyperoxia during submaximal exercise increased exercise time, reduced exercise lactate, and reduced exercise minute ventilation. Slopes of perceived breathlessness and

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Figure 3 Response to exercise over time in 11 patients with severe COPD and mild resting hypoxemia, breathing ambient air or 60% oxygen. Values are mean
SEM.  p < 0.05, differences between values at isotime. Source: From Ref. 14.

leg effort against time were significantly reduced when subjects breathed 60% oxygen compared with ambient air. Of note, the relationship between dyspnea and ventilation was maintained whether breathing air or oxygen (Fig. 4). Subsequent reports have confirmed that hyperoxia has been associated with modest (10%), variable improvements in exercise capacity and improved dyspnea scores among patients with COPD (15–20). C. Oxygen Dyspnea and Dynamic Hyperinflation

When 60% oxygen was administered during exercise to patients with chronic respiratory failure (PaO2 52
2 mmHg, PaCO2 48
2 mmHg), relief of dyspnea was associated with reduced ventilation, reduced breathing frequency, increased dynamic inspiratory capacity (ambient air 1.07
0.13 L, oxygen 1.25
0.16 L), and increased inspiratory reserve volume (ambient air 0.3
0.04 L, oxygen 0.45
0.08 L) (21). Given that patients with COPD breathe at lung volumes close to their total lung capacity, any small improvement in operational lung volume could translate into quite marked improvements in dyspnea. The acute effects of hyperoxia on dyspnea and inspiratory capacity, at rest, were recently described by Alvisi et al. (22). Ten patients with severe COPD (FEV1 0.71
0.08 L) were studied at rest before and after 5, 15, and 25 min breathing 30% oxygen. The visual analog scale (VAS) scores decreased significantly, associated with a concurrent increase in inspiratory capacity of 11%. There were significant reductions in minute ventilation

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Figure 4 The exponential relationship between Borg breathlessness ratings and ventilation is not different during air (solid line) and oxygen (dotted line). Within this relationship, exertional breathlessness decreased significantly (p < 0.005) in proportion to the fall in ventilation at isotime during hyperoxia. Values shown are the means of data at every 10% of room air endurance, among 11 subjects with severe COPD. Source: From Ref. 14.

(11%) and tidal volume (12%) due to significant decreases in mean inspiratory flow (Fig. 5). There was an almost significant correlation (p ¼ 0.07) between the reduction in dyspnea scores and the hypoxic ventilatory drive (change in ventilation divided by the change in saturation). In nonhypoxemic (resting SaO2 96
1%, exercise SaO2 92
3%), dyspneic COPD patients, oxygen supplementation during high-intensity constant power exercise-induced dose dependant improvements in dyspnea and endurance time, related at least in part to decreased hyperinflation and reduced respiratory frequency (23). Increasing the FiO2 attenuated dynamic hyperinflation [IC (FiO2 0.21) 1.39
0.14 L, (0.30) 1.59
0.14 L, and (0.5) 1.72
0.14 L], resulting in marked improvements in constant power exercise endurance time [(FiO2 0.21) 4.2
0.5 min, (0.30) 7.8
1 min, and (0.5) 10.3
1.9 min]. Borg ratings of breathlessness at isotime fell [(FiO2 0.21) 6.7
6, (0.30) 4.4
4, and (0.5) 4.0
4 units].

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Figure 5 Average values for dyspnea, measured using a visual analog scale (VAS) (upper panel), tidal volume (VT) (middle panel), and inspiratory capacity (IC) (lower panel) in 10 patients with severe COPD, breathing room air and after 5, 15, and 25 min of breathing 30% oxygen. Bars indicate SEM.p < 0.05 relative to air. Source: From Ref. 22.

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Changes in endurance correlated with changes in end inspiratory and end expiratory lung volumes (r ¼ 0.432, p ¼ 0.005 and r ¼ 0.48, p ¼ 0.002, respectively).

D. Mechanisms of Dyspnea Relief with Oxygen

The precise mechanism by which hyperoxia reduces dyspnea remains unclear and is likely to be multifactorial, reflecting alterations in ventilatory drive, dynamic ventilatory mechanics (24), metabolic load, dyspnea perception, and respiratory as well as peripheral muscle function (25,26). The mechanism is unlikely to be related to a nonspecific effect of gas flow on nasal mucosa (27). Swinburn et al. (28) attributed the decrease in dyspnea and ventilation to a reduction in the hypoxic drive to breathe. This in turn would be expected to reduce dynamic pulmonary hyperinflation with a concurrent reduction in inspiratory load due to a decrease in elastic work, a decrease in intrinsic positive end expiratory pressure and improvements in inspiratory muscle function. Reduced ventilation has been associated with a reduced resting inspiratory flow (22) and a reduced breathing frequency during exercise (21). Although it is possible that a component of hypoxic bronchoconstriction is relieved by oxygen, resulting in a decrease in resistive work, since the degree of resting hypoxia was often minimal (14,22,23), this mechanism is likely to provide only a minor contribution to the reduction in dyspnea. Given the decreased inspiratory work of breathing and improved mechanical advantage to the inspiratory muscles, it is not surprising that some patients with COPD experience a marked improvement in dyspnea when breathing oxygen. Whether the primary mechanism is one of reduced chemoreceptor activation or improved oxygen delivery to exercising muscles (25,29), including respiratory muscles (30) (reduced lactate and therefore reduced acid buffering), remains to be established. The contribution of additional mechanisms, such as improved cardiovascular function and alterations in the perception of symptom intensity will provide exciting research opportunities for those interested in this area.

IV. Benefits Based on Clinical Instruments that Measure Dyspnea In the clinical studies described below, instruments that measure dyspnea have been included in the outcome measures. Although dyspnea during exercise was usually assessed using a visual analog scale (31,32), in some studies (33,34) health status measures have included the domain of dyspnea.

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Given the reduction of dyspnea and the improvement in exercise tolerance with oxygen under laboratory conditions, it is reasonable to investigate whether supplemental oxygen during exercise will enhance the effects of training, compared with training while breathing ambient air. Rooyackers et al. (31) randomized 24 patients with severe COPD who developed hypoxemia during incremental cycle exercise (SaO2 < 90% at peak exercise) to train for 10 weeks breathing ambient air or supplemental oxygen, as part of an inpatient pulmonary rehabilitation program. During incremental exercise testing before and after training, dyspnea scores fell similarly in both the room air trained group (7.3
2.4 to 5.8
1.9) and those who received oxygen for training (6.6
2.1 to 5.3
1.2), with no between group differences. Although supplemental oxygen reduced dyspnea scores in both groups, during exercise testing before and after training, supplemental oxygen during general exercise training did not confer any advantage over training while breathing room air. In both groups, the 6 minute walking distance, stair climbing, weight lifting, and health status improved, with no between group differences (Fig. 6, Table 2). Garrod et al. (32) evaluated the influence of training with oxygen (OT) or air (AT) at a flow rate of 4 L/min, by nasal prongs, in 25 patients with stable COPD (FEV1 OT: 0.77
0.26 L, AT: 0.84
0.26 L, baseline oxygen tension OT: 63
10 mmHg, AT 63
9 mmHg, end exercise (shuttle walk) SaO2 OT: 80
10%, AT 85
5%), enrolled in a 6-week out-patient rehabilitation program. When provided acutely, oxygen increased the shuttle walk test by 27 m (95% CI 15–40) (p < 0.001), and reduced dyspnea by 0.68 units (95% CI 0.3–1.05) (p < 0.001). The OT group showed a significant reduction in postshuttle walk dyspnea following rehabilitation, compared to the AT group [mean between group difference in Borg Score of 1.46 (95% CI 2.72 to 0.19)]. The rehabilitation program was effective in showing improvements in health status and exercise tolerance in the group as a whole, but failed to identify any additional between group benefits in other outcome measures, including the shuttle walking distance, health status, mood state, and activities of daily living, beyond a small improvement in postshuttle walk dyspnea score, in the oxygen-trained group [D Borg 1.5 (95% CI 2.7 to 0.2) p ¼ 0.02]. B. Exertional Oxygen for Domiciliary Activities

An alternate approach to breathing supplemental oxygen during exercise rehabilitation is to provide it for activities during which the patient would normally experience dyspnea. In a 12-week pilot double blind cross-over study, McDonald et al. (33) adapted, small portable cylinders to provide intranasal oxygen or air, at 4 L/min, to 26 patients with COPD (mean age 73
6 years, mean FEV1 0.9
0.4 L, resting PaO2 69
8.5 mmHg,

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Figure 6 Exercise performance on room air before (open columns) and after (hatched columns) general exercise training breathing room air (GET/RA) and general exercise training breathing oxygen (GET/O2). The acute effects of oxygen are shown in the cross-hatched blocks above all four columns. Error bars represents standard deviation. The 6 minute walk increased with training in both groups. Oxygen increased the 6 minute walk distance before training in both groups (p < 0.01). After training, no further improvements were noted. There were no between group differences. Source: From Ref. 31.

resting SaO2 94
2.1%). They were asked to use these cylinders at home for any activities that they associated with dyspnea. The authors reported only trivial changes in 6 minute walk tests when oxygen was provided acutely, with no change in dyspnea scores. Health status, measured using the chronic respiratory questionnaire, showed significance only when the oxygen breathing group was compared to baseline, with no between group differences in dyspnea, fatigue, emotional function or mastery. This small negative pilot study did not support providing home oxygen for dyspnea relief among patients with mild hypoxemia who do not improve when oxygen is administered acutely. In a subsequent 12-week double blind crossover study, to identify whether the acute response to ambulatory oxygen was predictive of a

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Table 2 Quality of Life (CRQ) Before and After Pulmonary Rehabilitation When Training with Ambient Air or Supplemental Oxygen Air training

Dyspnea Fatigue Emotional function Mastery Total score

Oxygen training

Before

After

Before

After

15
6 17
5 32
7

22
5 20
5 35
9

16
5 16
4 30
7

22
6 19
4 35
6

20
4 85
16

23
4 100
17

18
6 79
18

22
3 98
16

 p < 0.01 within-group comparison before vs. after rehabilitation Source : From Ref. 31.

subsequent improvement in health status, Eaton et al. (34) provided lightweight portable cylinders to patients with COPD who had completed pulmonary rehabilitation. Patients were randomly assigned to oxygen or air with a crossover at six weeks. Results were reported for 41 patients (FEV1 26
8% predicted, resting PaO2 68
7 mmHg, post-6MW SaO2 82
5%), 39 of whom completed the study. Acceptable responses were related to the minimum clinically important difference of the outcome measure (35). There were 28 (68%) acute responders to cylinder oxygen (defined as an increase in 6MW > 54 m or a decrease in Borg dyspnea of > 1 unit) (36,37) and 23 (56%) short-term responders in health status (CRQ dyspnea > 3, fatigue > 2, emotional function > 4, and mastery > 2 units) (38). Unfortunately, the acute response and short-term response to oxygen did not correlate (Table 3). At study completion, 14 (41%) of Table 3 The Acute Response (6 min Walk and Dyspnea Score) to Supplemental Oxygen does not Correlate with the Short-Term Response (Dyspnea, Fatigue, Emotional Function and Mastery) in Patients with COPD Acute response

Short-term response Yes No Total Chi-squared test: p ¼ 0.382. Source: From Ref. 35.

Total

Yes

No

17 11 28

6 7 13

23 18 41

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the subjects defined as having either an acute or short-term response to oxygen did not wish to continue with ambulatory oxygen, citing poor acceptability as the reason. The authors concluded that ambulatory oxygen afforded modest improvements in health status, beyond those achievable by pulmonary rehabilitation alone, for patients with exertional desaturation who did not fulfill criteria for long-term oxygen therapy. Acute improvements with oxygen were not predictive of short-term improvements in health status. C. Oxygen and Dyspnea in Conditions Other than COPD

Although frequently associated with COPD, dyspnea is not restricted to this condition. Dyspnea is often present in respiratory malignancies, reaching a prevalence of 70% during the terminal weeks of advanced respiratory cancer (39). Oxygen is not infrequently prescribed for such individuals, on compassionate grounds. Booth et al. (40) administered oxygen or air in a single blind manner to 38 hospice patients with terminal respiratory malignancies who complained of dyspnea. Baseline dyspnea scores were reduced with either air or oxygen, with no between group differences or treatment order effects. Although the use of opiates or benzodiazepines did not affect the baseline dyspnea scores, they did potentiate the effect of oxygen in reducing dyspnea. Subjects with interstitial lung disease (ILD) experience incapacitating dyspnea. They also commonly demonstrate impaired exercise performance, resting hypoxemia, and further desaturation with exertion. Studies of supplemental oxygen in patients with ILD have yielded conflicting results (41,42) depending on the extent to which they desaturated while breathing room air. In one study (41) in which subjects desaturated by 11
1% (range 71–84%) during room air exercise, the relief of exercise hypoxemia was associated with an increase in peak oxygen uptake and maximum workload, with no alterations in breathing pattern. Despite the increased exercise duration (458
24 vs. 390
21 sec, p < 0.001), dyspnea measured at end exercise did not change. Although it is possible that at lower workloads, the dyspnea score may have been reduced by oxygen administration, mechanisms other than hypoxemia are likely to be responsible for the rapid shallow breathing pattern adopted by patients with ILD. The role of oxygen in the relief of dyspnea among patients with ILD requires further clarification. Dyspnea is a principle complaint of patients with heart failure. Although supplemental oxygen is used routinely to relieve dyspnea associated with acute left ventricular dysfunction, its role in the management of dyspnea associated with chronic heart failure is less clear. In a study of cardio-respiratory responses to exercise among 12 consecutive patients with chronic heart failure, the administration of 50% oxygen prolonged

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incremental exercise (548
275 to 632
288 sec, p < 0.05) (43). Visual analog measures of dyspnea were consistently lower for each workload when the patients breathed oxygen enriched air (Fig. 7). Constant power exercise was also associated with reductions in minute ventilation, cardiac output, and dyspnea scores. The mechanisms that limit exercise in chronic heart failure remain to be clarified. However, as both dyspnea and muscle fatigue are commonly voiced symptoms at the end of exercise, supplemental oxygen may have an important role in providing relief from dyspnea among patients with chronic heart failure. V. Patient Selection Jolly et al. (17) extended the observations of Mak et al. (7), noting that supplemental oxygen administered during walking tests to patients with COPD lowered dyspnea scores, irrespective of the extent to which the patients desaturated during exercise. Response to oxygen could not be predicted from baseline saturation or baseline walking distance. Although patients with the greatest exercise desaturation experienced the greatest improvements in walking distance, significant ( > 10%) improvements in exercise capacity and dyspnea scores (2 units) were occasionally observed among nondesaturating patients. Clinical comment: Although there is poor predictability of improvement with oxygen, the clinical observation that for some patients with

Figure 7 Effect of incremental exercise on dyspnea scores in patients with chronic heart failure breathing air (open circles) and 50% oxygen (closed triangles). Results show mean values plus standard deviation. Note that at each minute of exercise the dyspnea scores were lower when breathing supplemental oxygen. Source: From Ref. 43.

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severe COPD the modest reductions in ventilation and operational lung volumes, when breathing supplemental oxygen, are associated with dramatic improvements in dyspnea and exercise capacity is important. The optimistic findings of the influence of oxygen therapy on dyspnea, under laboratory conditions, have not been followed by unequivocal evidence of an improvement in health status when oxygen has been provided for dyspnea relief. The multifactorial mechanism of dyspnea relief, trial size and design, the dose and duration of oxygen therapy as well as the system used for oxygen delivery might all contribute to this apparent disparity. Until further trials clarify which individuals are most likely to benefit, those who do not meet current funding criteria based on the life saving benefits of oxygen should be individually tested to establish whether oxygen may be of benefit in the relief of dyspnea. Such a test should include constant power exercise with at least a single blinded randomized assignment to either ambient air or supplemental oxygen. A representative positive test result is shown in (Fig. 8). Whereas test protocols will likely vary among centers, it is suggested that the evaluation of an oxygen prescription for dyspnea relief be carried out by respiratory specialists familiar with exercise testing. Professional societies that provide guidelines for the management of patients with chronic respiratory conditions (5,44–47) should be encouraged to participate, together with healthcare professionals and third party payers in the standardization of tests used for such evaluations.

VI. Summary and Recommendations Dyspnea is arguably the single most important symptom among patients with COPD. Therefore, even if supplemental oxygen were to result in only small improvements to this disabling symptom, there is value in identifying which patients might be most likely to benefit from it. There is evidence that under laboratory conditions, supplemental oxygen will decrease dyspnea and increase exercise capacity among some patients with COPD in whom the resting SaO2 > 88% (48). Unfortunately, there is equivocal evidence that oxygen prescribed for dyspnea relief results in important improvements in health status. Therefore, potential benefit should be assessed under laboratory conditions to identify who might derive a meaningful reduction in dyspnea score or a meaningful improvement in exercise capacity. The prescription of oxygen for the relief of dyspnea among patients in whom the resting should be limited to individuals with documented (at least single blinded) acute improvements in dyspnea and exercise performance with oxygen. Although supplemental oxygen might enable such individuals to increase their ambulatory activities, there is currently insufficient evidence of this occurring to justify more widespread provision of ambulatory

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Figure 8 A representative study of constant power exercise at 15 W in which the subject was randomized to receive room air or supplemental oxygen through nasal cannulae at 3 L/min. Note when receiving oxygen, saturation (upper panel) is well maintained, dyspnea and leg sensation are reduced in comparison with room air, despite the increase in endurance time.

oxygen for patients with transient exercise desaturation or with profound dyspnea on activity. Given the high likelihood of a placebo effect of oxygen on dyspnea (49), it is essential that dyspnea be assessed using a standardized reproducible and interpretable oxygen protocol, to establish the acute response. The relationship between an acute reduction of dyspnea in response to oxygen and a longer-term improvement in health status remains to be determined. References 1. American Thoracic Society (ATS). Dyspnea. Mechanisms, assessment, and management: a consensus statement. Am J Respir Crit Care Med 1999; 159:321–340.

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2. Report of the Medical Research Council Working Party. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; 1:681–686. 3. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med 1980; 93:391–398. 4. D’Urzo AD, Mateika J, Bradley DT, Li D, Contreras MA, Goldstein RS. Correlates of arterial oxygenation during exercise in severe chronic obstructive pulmonary disease. Chest 1989; 95:13–17. 5. Crockett AJ, Moss JR, Cranston JM, Alpers JH. Domicilary oxygen for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2000; 4:CD001744. 6. Chaouat A, Weitzenblum E, Kessler R, et al. A randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease patients. Eur Respir J 1999; 14:1002–1008. 7. Mak VH, Bugler JR, Roberts CM, Spiro SG. Effect of arterial oxygen desaturation on six minute walk distance, perceived effort, and perceived breathlessness in patients with airflow limitation. Thorax 1993; 48:33–38. 8. Woodcock AA, Gross ER, Geddes DM. Oxygen relieves breathlessness in ‘‘pink puffers’’. Lancet 1981; 1:907–909. 9. Evans TW, Waterhouse JC, Carter A, Nicholl JF, Howard P. Short burst oxygen treatment for breathlessness in chronic obstructive airways disease. Thorax 1986; 41:611–615. 10. Killen JW, Corris PA. A pragmatic assessment of the placement of oxygen when given for exercise induced dyspnoea. Thorax 2000; 55:544–546. 11. Dean NC, Brown JK, Himelman RB, Doherty JJ, Gold WM, Stulbarg MS. Oxygen may improve dyspnea and endurance in patients with chronic obstructive pulmonary disease and only mild hypoxemia. Am Rev Respir Dis 1992; 146:941–945. 12. OMOH<C. Ontario Ministry of Health and Long Term Care Home Oxygen Program Information for Physicians, 2003. www.gov.on.ca:80/english/public/ pub/adp/oxyphys.html. 13. CM&MS. Centers for Medicare and Medicaid Services National Coverage Determinations (NCDs). Home Use of Oxygen. http://cms.hhs.gov/ncd/ searchdisplay.asp?NCD_ID¼169&NCD_vvsn_num¼1 1999; 6. 14. O’Donnell DE, Bain DJ, Webb KA. Factors contributing to relief of exertional breathlessness during hyperoxia in chronic airflow limitation. Am J Respir Crit Care Med 1997; 155:530–535. 15. Matsuzawa Y, Kubo K, Fujimoto K, et al. Acute effects of oxygen on dyspnea and exercise tolerance in patients with pulmonary emphysema with only mild exercise-induced oxyhemoglobin desaturation. Nihon Kokyuki Gakkai Zasshi 2000; 38:831–835. 16. Ishimine A, Saito H, Nishimura M, Nakano T, Miyamoto K, Kawakami Y. Effect of supplemental oxygen on exercise performance in patients with chronic obstructive pulmonary disease and an arterial oxygen tension over 60 Torr. Nihon Kyobu Shikkan Gakkai Zasshi 1995; 33:510–519.

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17. Jolly EC, Di Boscio V, Aguirre L, Luna CM, Berensztein S, Gene RJ. Effects of supplemental oxygen during activity in patients with advanced COPD without severe resting hypoxemia. Chest 2001; 120:437–443. 18. Bradley BL, Garner AE, Billiu D, Mestas JM, Forman J. Oxygen-assisted exercise in chronic obstructive lung disease. The effect on exercise capacity and arterial blood gas tensions. Am Rev Respir Dis 1978; 118:239–243. 19. Light RW, Mahutte CK, Stansbury DW, Fischer CE, Brown SE. Relationship between improvement in exercise performance with supplemental oxygen and hypoxic ventilatory drive in patients with chronic airflow obstruction. Chest 1989; 95:751–756. 20. Davidson AC, Leach R, George RJ, Geddes DM. Supplemental oxygen and exercise ability in chronic obstructive airways disease. Thorax 1988; 43:965–971. 21. O’Donnell DE, D’Arsigny C, Webb KA. Effects of hyperoxia on ventilatory limitation during exercise in advanced chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163:892–898. 22. Alvisi V, Mirkovic T, Nesme P, Guerin C, Milic-Emili J. Acute effects of hyperoxia on dyspnea in hypoxemia patients with chronic airway obstruction at rest. Chest 2003; 123:1038–1046. 23. Somfay A, Porszasz J, Lee SM, Casaburi R. Dose–response effect of oxygen on hyperinflation and exercise endurance in nonhypoxaemic COPD patients. Eur Respir J 2001; 18:77–84. 24. Criner GJ, Celli BR. Ventilatory muscle recruitment in exercise with O2 in obstructed patients with mild hypoxemia. J Appl Physiol 1987; 63:195–200. 25. Maltais F, Simon M, Jobin J, et al. Effects of oxygen on lower limb blood flow and O2 uptake during exercise in COPD. Med Sci Sports Exerc 2001; 33:916– 922. 26. Somfay A, Porszasz J, Lee SM, Casaburi R. Effect of hyperoxia on gas exchange and lactate kinetics following exercise onset in nonhypoxemic COPD patients. Chest 2002; 121:393–400. 27. Liss HP, Grant BJ. The effect of nasal flow on breathlessness in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1988; 137: 1285–1288. 28. Swinburn CR, Mould H, Stone TN, Corris PA, Gibson GJ. Symptomatic benefit of supplemental oxygen in hypoxemic patients with chronic lung disease. Am Rev Respir Dis 1991; 143:913–915. 29. Simon M, LeBlanc P, Jobin J, Desmeules M, Sullivan MJ, Maltais F. Limitation of lower limb VO(2) during cycling exercise in COPD patients. J Appl Physiol 2001; 90:1013–1019. 30. Bye PT, Esau SA, Levy RD, et al. Ventilatory muscle function during exercise in air and oxygen in patients with chronic air-flow limitation. Am Rev Respir Dis 1985; 132:236–240. 31. Rooyackers JM, Dekhuijzen PN, Van Herwaarden CL, Folgering HT. Training with supplemental oxygen in patients with COPD and hypoxaemia at peak exercise. Eur Respir J 1997; 10:1278–1284. 32. Garrod R, Paul EA, Wedzicha JA. Supplemental oxygen during pulmonary rehabilitation in patients with COPD with exercise hypoxaemia. Thorax 2000; 55:539–543.

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33. McDonald CF, Blyth CM, Lazarus MD, Marschner I, Barter CE. Exertional oxygen of limited benefit in patients with chronic obstructive pulmonary disease and mild hypoxemia. Am J Respir Crit Care Med 1995; 152:1616–1619. 34. Eaton T, Garrett JE, Young P, et al. Ambulatory oxygen improves quality of life of COPD patients: a randomised controlled study. Eur Respir J 2002; 20: 306–312. 35. Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials 1989; 10: 407–415. 36. Redelmeier DA, Bayoumi AM, Goldstein RS, Guyatt GH. Interpreting small differences in functional status: the Six Minute Walk test in chronic lung disease patients. Am J Respir Crit Care Med 1997; 155:1278–1282. 37. Wilson RC, Jones PW. Long-term reproducibility of Borg scale estimates of breathlessness during exercise. Clin Sci (Lond) 1991; 80:309–312. 38. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LW. A measure of quality of life for clinical trials in chronic lung disease. Thorax 1987; 42: 773–778. 39. Reuben DB, Mor V. Dyspnea in terminally ill cancer patients. Chest 1986; 89:234–236. 40. Booth S, Kelly MJ, Cox NP, Adams L, Guz A. Does oxygen help dyspnea in patients with cancer? Am J Respir Crit Care Med 1996; 153:1515–1518. 41. Harris-Eze AO, Sridhar G, Clemens RE, Gallagher CG, Marciniuk DD. Oxygen improves maximal exercise performance in interstitial lung disease. Am J Respir Crit Care Med 1994; 150:1616–1622. 42. Bye PT, Anderson SD, Woolcock AJ, Young IH, Alison JA. Bicycle endurance performance of patients with interstitial lung disease breathing air and oxygen. Am Rev Respir Dis 1982; 126:1005–1012. 43. Moore DP, Weston AR, Hughes JM, Oakley CM, Cleland JG. Effects of increased inspired oxygen concentrations on exercise performance in chronic heart failure. Lancet 1992; 339:850–853. 44. American Thoracic Society (ATS). Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152:S77–S121. 45. Wedzicha JA. Domiciliary oxygen therapy services: clinical guidelines and advice for prescribers: summary of a report of the Royal College of Physicians. J R Coll Physicians Lond 1999; 33:445–447. 46. CTS. Guidelines for the management of COPD. Can Respir J 2003; 10: 1A–65A. 47. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop Summary. Am J Respir Crit Care Med 2001; 163:1256–1276. 48. Snider GL. Enhancement of exercise performance in COPD patients by hyperoxia: a call for research. Chest 2002; 122:1830–1836. 49. Guyatt GH, McKim DA, Austin P, et al. Appropriateness of domiciliary oxygen delivery. Chest 2000; 118:1303–1308.

16 Coping and Self-Management Strategies for Dyspnea

VIRGINIA CARRIERI-KOHLMAN Department of Physiological Nursing, UCSF, San Francisco, California, U.S.A.

I. Introduction Despite optimal medical and pharmacological therapy, at one time or another, most individuals with cardiopulmonary disease will experience either acute or chronic progressive dyspnea (shortness of breath). Whether experiencing acute dyspnea during a limited period or consistently with activities of daily living, people need interventions or strategies that they are confident will help them reduce and control this life-threatening, distressing symptom. The purpose of this chapter is to review the theoretical foundations for ‘‘coping’’ and ‘‘self-management’’ strategies to reduce shortness of breath, to present the evidence from controlled studies for the effectiveness of these strategies, and to discuss clinical and patient experiences that suggest efficacy of strategies when a scientific foundation is not available.

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Carrieri-Kohlman II. Conceptual Approach A. Coping and Self-Management Strategies

Theorists differentiate coping and self-management by the following definitions. ‘‘Coping’’ is constantly changing cognitive and behavioral efforts used to manage external and internal demands that are appraised as exceeding the person’s resources. It is a response to a new or different situation that requires modification of old or development of new strategies and includes the processes of primary and secondary appraisal (1,2). In contrast, ‘‘self-care’’ or ‘‘self-management’’ is defined as the repetitive use of strategies that have proven effective in the past (3). ‘‘Self-management’’ is defined as ‘‘ . . . the individual’s ability to manage the symptoms, treatment, physical, and psychosocial consequences and life style changes inherent in living with a chronic condition . . . ’’ (4). Successful self-management requires that people with acute and chronic shortness of breath have the knowledge, skills, willingness to learn and participate in their care, and the potential to change their behavior. Specifically, self-management requires that patients: (1) engage in activities that promote health and prevent adverse sequelae; (2) interact with health care providers and develop a ‘‘mutually agreed upon’’ treatment plan with their adherence to recommended treatment protocols; (3) monitor physical and emotional status and make appropriate management decisions on the basis of the results of monitoring; and (4) manage the effects of their illness on emotions, self-esteem, relationships with their family and others, and their ability to function in important roles (3,5). Support for collaborative self-management has been recognized as a vital component in chronic illness care. Indeed, health consumers are willing and beginning to accept greater responsibility for their own care (6,7). B. Multidimensional Definition of Dyspnea

The theoretical perspectives guiding the self-management strategies for dyspnea discussed in this chapter are congruent with the most recent definition of dyspnea that includes the multidimensional characteristics of the symptom. ‘‘ . . . The experience derives from interactions among multiple physiological, psychological, social, and environmental factors, and may induce secondary physiological and behavioral responses’’ (8). This definition acknowledges that dyspnea is not only a physiological phenomenon, but has affective components similar to pain that are shaped by psychological, social, and environmental factors (9–11). It is proposed that the coping and self-management strategies presented here may alter any or all of these factors with subsequent modification of the nature of the perception and interpretation of the physiological state, and in turn, the response to the symptom and the strategies patients use to control it (12). Psychosocial

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factors that have been found to influence the perception of dyspnea are cognitive variables, such as, personality (13), emotions, including anxiety (14,15) and depression (16–18), attention to the symptom (19), the meaning of the symptom for the person (20), and beliefs in coping strategy effectiveness (21,22). Social–environmental influences, such as, an prior history with the symptom, the social context in which it is experienced (23), family conflict (24), and co-morbidities, such as fatigue (25), also influence the perception of shortness of breath.

C. Affective Dimensions of Dyspnea

The strategies presented herein are grounded in the belief that dyspnea, like pain, is associated with affective feelings, such as anxiety, unpleasantness, panic, and depression, as well as sensory components such as intensity, duration, location, and quality (26–28). It should be noted that laboratory studies of mechanisms and clinical studies of treatments for dyspnea, thus far, have placed greater emphasis on the sensory than the affective dimension. Patients with pulmonary disease have described affective emotions, such as anger and anxiety, when experiencing dyspnea (29). Healthy subjects (30) and patients with chronic obstructive pulmonary disease (COPD) (11) differentiated shortness of breath and distress during exercise. Price (31) has suggested a sequential model for the affective components of pain that may have application to the future study of dyspnea. The first stage is related to the immediate appraisal and emotional feelings, such as, unpleasantness, distress, and possible annoyance that are associated with the sensory features of pain and with the immediate context. A secondary stage of affect is associated with the long-term implications of having pain and is based on more reflection, concern for the future, and memories and imagination about the implications of having pain. Positron emission tomography (PET), used for decades to map pain pathways, has only recently been used to map the cortical activations associated with dyspnea and has demonstrated strong activation of the anterior insular cortex, a limbic structure, when normal volunteers experienced air hunger in the laboratory (32–34). This is the first neurological evidence that emotions are activated when normal subjects experience ‘‘air hunger’’ and that there is an affective dimension to the sensation. Although evidence that there is an affective response to dyspnea is accumulating with studies with COPD patients, one investigator reported that patients with heart failure were unable to differentiate between the intensity and distress of shortness of breath in the emergency department (35). This controversy indicates the need for ongoing study of the measurement and mechanism of the affective dimension of dyspnea.

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Strategies discussed in this chapter are based on a cognitive–behavioral perspective that suggests that individuals can be taught new patterns of thinking, feeling, and behaving to cope with and manage their symptoms. Cognition is the mental process by which knowledge is acquired, manipulated, and changed and is made up of thoughts, knowledge, and assigned meaning (36). Cognitive strategies involve attempts to modify thought processes, thinking, feeling, and knowledge in order to modulate an unpleasant symptom. Expectations, beliefs, attitudes, and the meaning a person assigns to a physical sensation can have a profound effect on the perception of the symptom as well as the behavioral and emotional responses to symptoms (20). A major tenet of this approach is that symptoms occur in a social context. The behavior of a patient with dyspnea not only is reinforced and shaped by others, but also influences and changes the behavior of others (37). Behaviors are defined as performances, activities, or responses and are believed to change environmental conditions, provide mastery experiences, increase self-efficacy and affect physiological processes (38). Environment is the aggregate of conditions or circumstances within which a symptom is perceived, including physical, social, and cultural variables (39). Other major concepts within the cognitive–behavioral perspective are that of self-efficacy and control. Increasing perceived confidence for coping can reduce symptoms in several ways (40). People who believe they can alleviate a symptom try management strategies they have learned and persevere in their attempts to decrease the symptom. On the other hand, those patients who do not feel confident in their ability to decrease their breathlessness by some means give up readily if they do not get quick results. If individuals have confidence that they can cope with an increasing symptom, they also may have less negative anticipatory emotions about the symptom, and therefore, the symptom may not be as intense or enhanced by anxiety and panic. For example, if a person believes he or she can cope with the amount of dyspnea they will experience while climbing the stairs, his or her anxiety about climbing stairs may be less, which may result in a lower level of dyspnea while climbing the stairs. People who believe they can exercise control over their symptoms are more likely to tolerate unpleasant bodily sensations than those who believe there is nothing they can do to alleviate the symptom (41). III. Selected Coping and Self-Management Strategies The American Thoracic Society (ATS) Position Statement (8) proposes physiological mechanisms causing dyspnea and appropriate therapeutic interventions. These interventions are categorized as (1) reducing ventilatory demand, (2) reducing ventilatory impedance, (3) improving muscle

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Table 1 Cognitive–Behavioral and Complementary Strategies for Managing Dyspnea Activity modification Social support Exercise desensitization Fresh air Relaxation exercises Breathing exercises Biofeedback Music Hypnosis Guided imagery Acupuncture and acupressure Knowledge about triggers and strategies Symptom monitoring Action plans Self-control of medications

function, and/or (4) altering the central perception of dyspnea. Focus in this chapter is on the last intervention category of cognitive–behavioral strategies that may alter the central perception when shortness of breath persists after optimal medical therapy (Table 1). Strategies that people report they use to manage their chronic dyspnea have been described (24,42–45). These strategies will be discussed under the appropriate intervention category, vary across genders (Tables 2 and 3), ethnic and illness groups (45), and span all ATS intervention categories (46). A. Reducing Ventilatory Demand

Strategies can reduce the demand for ventilation by either reducing the metabolic load or by decreasing the central respiratory drive. 1. Reducing Metabolic Load a. Strength or Endurance Exercise Training

One of the most powerful strategies for managing dyspnea is exercise. Although some authors have suggested ‘‘high intensity’’ exercise training, approximately 80% of peak VO2 to promote ‘‘conditioning,’’ (47) others have found improvement in dyspnea with lower levels of intensity (48–51). Other investigators have found reductions in dyspnea despite the lack of changes in variables that reflect a physiological training effect, such as improvements in peak VO2 or AT (52–54). Decreases in dyspnea after exercise training that are not accompanied by changes indicative of greater ‘‘conditioning’’ may be due to other physiological factors, such as

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Table 2 Strategies Reported by a 68-Year-Old Female When Asked ‘‘What Things Do You Do to Manage Your Shortness of Breath?’’ Stop what I’m doing Think of something else Take pulse for reassurance Relax and meditate Use PLB Slow down Visualization Sit up straight Exercise Commit myself to less activity

Have groceries in light bags Stand with arms on hips Lie down Play bridge Do not bend over Try to get fresh air Drink water Use proventil Read

improvement in respiratory and peripheral muscle strength (55), or changes in the pattern of breathing resulting in less severe dynamic hyperinflation with exercise (52). Alternative theoretical perspectives have been suggested as possible reasons for a decrease in dyspnea following exercise training. One frequently proposed alternative is desensitization or a decrease in dyspnea relative to work resulting from exposure to greater than usual dyspnea in a safe monitored environment. This exposure gives the patient an opportunity to use coping strategies and develop more effective ones (56). This experience increases the person’s control or self-efficacy for managing the symptom and changes the appraisal of dyspnea, or heightens the ‘‘perceptual threshold’’ for dyspnea (21). Clinically, one approach to decreasing a patient’s perceived dyspnea for a certain activity level has been to encourage ambulation to the point that greater than usual dyspnea occurs, while coaching the patient to use breathing strategies such as pursed-lips breathing (PLB). If this procedure is performed in a supportive environment with someone the patient trusts, the patient’s fear of dyspnea may decrease while Table 3 Strategies Reported by a 67-Year-Old Male When Asked ‘‘What Things Do You Do to Manage Your Shortness of Breath?’’ Write Take vitamins Cook Use a fan Pray Take a shower Shop Go driving Get cool Watch TV

Walk in the zoo Sleep Go fishing Get on internet Listen to music Use PLB Drink water Talk to a friend Read Take meds

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confidence is gained in the ability to control the symptom through his/her own actions (57). Exercise training is also a situation which provides people with all proposed sources for increasing self-efficacy including; performance or enactive accomplishments (mastery), the vicarious experience of learning from observing others, social persuasion, and re-interpretation of physiological signs and symptoms (58). Typical ‘‘coaching’’ maneuvers used by health care providers while patients are exercising might include development of short-term goals, modeling of breathing strategies and relaxation techniques, small increases in workload and duration of exercise, demonstration of breathing strategies, distraction, encouragement, and feedback of physiologic parameters (59). People who have chronic dyspnea become skilled in knowing their exercise tolerance relative to the amount of dyspnea they will experience and seem to regulate their activity to keep the level of perceived breathlessness at the same intensity (12,60). These patients should be encouraged to increase their intensity of exercise while slowly experiencing higher levels of dyspnea with reminders that it is ‘‘OK’’ to be breathless while exercising. Other explanations for a decrease in dyspnea after exercise without concomitant physiological changes include: a placebo response (61), prior ventilatory experience (62), a more relaxed stride (63), a practice effect (64), adaptation to the sensation (65) or a type of placebo response labeled ‘‘response shift’’ defined as a change in the patient’s self-assessed health perception without changes in biological and physiological effects, or a change in the meaning of a person’s self-evaluation of a target construct, such as a symptom (66,67). b. Yoga and Tai Chi Exercise

Exercises that are of Eastern origin and viewed as ‘‘complementary,’’ such as Yoga and Tai Chi, may be alternatives to aerobic or strength and endurance training for people who are limited by shortness of breath. These exercises are proposed to bring about relaxation, calmness, balance, and may promote changes in the pattern of breathing, including slow and deep breathing and enhanced feelings of control of one’s breathing. Although Tai Chi has been studied primarily for its effect on balance in the elderly, two investigators have measured some type of measurement of dyspnea in their study of yoga exercise. Tandon (68) trained 11 males with COPD in yoga abdominal and thoracic breathing exercises and 10 postures. A matched group received physiotherapy, including relaxation exercises for respiratory muscles, diaphragmatic breathing, and lower extremity exercises. Treatments for both groups were 1 hr three times a week for 4 weeks gradually decreased to once a week for the last 7 months for a total of 9 months. Significantly, more subjects in the yoga group stated that they had ‘‘easier control’’ of their dyspnea attacks. More recently, a single group

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pre-post test design was used to study 15 males with chronic bronchitis (69) who practiced eight body postures and five breathing exercises in the laboratory 30 min daily for 1 week and then continued in the home for 3 weeks with reinforcement. There were significant reductions in dyspnea measured by a visual analog scale (VAS) from baseline to week 4. These two studies are the only published reports of the effect of yoga training on shortness of breath. Although both studies included a small number of subjects and used non-validated measures of dyspnea, these findings indicate that yoga may be an alternative exercise that could be used to decrease the intensity or the frequency of dyspnea in moderate-to-severe COPD patients. c. Energy Conservation

i. Strategies for Decreasing Shortness of Breath During Activities of Daily Living. Ventilatory demand is diminished by reducing the patient’s work of breathing. There is little scientific study of the relationship between energy conservation and dyspnea. Clinical practice and descriptive studies suggest that patients who are short of breath use strategies that incorporate energy conservation (24,42,45). Some of the most difficult tasks for patients are to learn to pace their activities, to slow down, and to conserve energy. Patients need help with planning for almost any activity. Trips should be organized early to allow time to anticipate the availability of oxygen, the altitude, the potential for triggers/irritants, the amount of energy needed, and the scheduling of rest periods. Daily walks, restaurant lunches, and activities need to be planned ahead of time with anticipated ‘‘breathing stations.’’ Patients can be instructed that there is a crucial balance between pacing or resting and appropriate exercise. Graduated exercise and activity to stay physically conditioned have to be stressed, while at the same time emphasizing the need for a slower pace. Teaching can include contrasting the energy used for unnecessary tasks with energy that is used for a daily exercise program and leisure activities that will enhance the efficiency of the muscles and the body. There are published recommendations to help patients conserve energy and minimize shortness of breath during homemaking chores by the American Lung Association and others (70–72). Specific guidelines for completing activities of daily living such as grooming, bathing, showering, and dressing are available to use as visual aids when teaching patients and family. These energy conservation techniques gain greater importance for the patient and the family nearing the terminal phases of illness when small amounts of activity increase shortness of breath (73,74). ii. Strategies for Decreasing Shortness of Breath During Sexual Activity. Patients who are comfortable confiding in a health professional frequently complain of experiencing shortness of breath during sexual

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activity. As with other activities, patients can be taught strategies to decrease energy expenditure and dyspnea during sexual activity. Suggestions include: learning and practicing relaxation techniques; planning a rest period and inhaled bronchodilators before intimacy; use of massage to relax tense muscles; alternative expressions of love; supplemental oxygen; appropriate timing of sexual relations before meals and after resting; choosing less active positions for the partner with lung disease that do not require supporting body with arms or do not put pressure on the chest or abdomen, such as, sitting up, elevating head, and shoulders; and using other positions that provide a restful position with no pressure on the chest and a less ‘‘smothering sensation’’ (71,75). 2. Decrease Chemical or Neurological Central Respiratory Drive a. Oxygen Therapy

Oxygen therapy is an example of a medical strategy designed to decrease respiratory drive that has been shown to decrease dyspnea in patients with hypoxemia. Patients need to be supported in the therapeutic, behavioral, and emotional tasks needed to manage an oxygen prescription. Despite similarities in medical prescriptions, there is often wide variability in how patients use their oxygen. The patient should be asked about their current regimen to assess proper adherence to flow changes with activities. Health care providers need to teach patients home safety measures, such as keeping oxygen tubing out of major traffic pathways, and not using oxygen near an open flame or in areas where others are smoking. They need to learn to vary the dose depending on activity and level of symptom. Available resources, such as portable smaller equipment, and American Lung Association published guidelines and tips for traveling with oxygen will promote acceptance and adherence to oxygen therapy. In end of life and acute dyspnea situations, optimizing ventilator and oxygen settings or using anxiolytics and opiates are examples of medical strategies designed to reduce the central respiratory drive and improve dyspnea. b. Opioids and Anxiolytics

Opioids and anxiolytics as treatments for dyspnea are described in Chapter 18 on end of life. An important principle in the self-management of these treatments is that the patient understands the escalating effect of anxiety on dyspnea and that a plan for the use of opioids to control dyspnea is a joint decision between the health provider and patient. c. Alter Pulmonary Afferent Information

People who suffer from chronic dyspnea have identified ‘‘fresh air’’ or the use of fans as one strategy that they found successful in reducing their shortness of breath (8). The stimulation of a flow of cold air directed against the cheek caused a decrease in dyspnea in normal subjects in the laboratory,

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providing support for patients’ experience (76). It could be hypothesized that the most powerful non-pharmacological strategy today available for acute dyspnea or dyspnea at end of life is the provision of a fan that allows the person to direct the air to themselves in the most comfortable position. In-phase mechanical vibration of the chest wall (77,78) also has decreased respiratory discomfort in people with chronic lung disease. At the present time, vibration remains a strategy used only in the research laboratory, however, the findings related to acupressure (79) would suggest that vibration or a relaxing massage may be an alternative strategy that may help certain individuals with acute persistent dyspnea. d. Improve Efficiency of CO2 Elimination

i. Pursed-Lips Breathing. Clinically some patients report that using PLB is the most effective strategy they have for controlling their shortness of breath. PLB has been found to increase tidal volume and vital capacity, decrease respiratory rate, duty cycle, and functional residual capacity, cause changes in respiratory muscle recruitment, improve gas exchange, increase efficiency of ventilation and reduce dyspnea (80–83). Most notably, a group of investigators recently measuring lung volumes non-invasively found that PLB decreased end expiratory volume by decreasing RR and lengthening expiratory time, therefore, modulating dyspnea (84) (Fig. 1). Patients need to be taught the method of correct PLB, emphasizing a deeper slow breath and practicing a long exhalation.

Figure 1 Volume (V) Changes of the CW compartments [RC and abdomen (Ab)] in a patient with severe obstruction during quiet breathing followed by pursed lips breathing.

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ii. Changing the Pattern of Breathing. With the increasing evidence that dynamic hyperinflation with resulting restriction of tidal volume is the primary contributor to dyspnea (52,85,86), helping the patient to change their breathing pattern takes on increased importance. Recently, investigators have found that patients can change their rate and depth of breathing through biofeedback (87). Others have suggested that the traditional yoga pranayama technique of 4-4-8 can be modified for COPD patients to a 4-2-7-0 pattern, i.e., a count of 4 during inhalation, a count of 2 while holding the breath, with exhalation to a count of 7 while exhaling (V. Sharma, personal communication, 2004). This pattern of breathing can be practiced in walking and stair climbing to pace inspiration and expiration and has been suggested as a helpful exercise to reduce dynamic hyperinflation at rest. Continual practice of this new breathing pattern, which includes reducing the respiratory rate, prolonging the expiratory time and using a gentle forced expiration, may ultimately become unconscious and automatic for the patient. B. Decrease Ventilatory Impedance by Reducing Resistive Load 1. Medications

In order to assure the greatest benefit from medications, the patient must take an active role in manipulation of complex medical regimens and action plans. The dosage and frequency of medications may need to be altered without prior contact with their health care provider. Using a combination of written action plans, medical review, and self-monitoring, with the support of the physician and nurse and an objective physiological measure of lung function, such as a peak flow meter, patients can learn to manipulate their dose of bronchodilators, medication regimens, and corticosteroid therapy until they are able to contact their clinician. Controlled studies of medication self-management with asthma patients have resulted in a decrease in symptoms (88), decreased resource utilization (89), and improved quality of life (90). Recent studies of self-management programs for patients with COPD that have included either a prescription or a supply of antibiotics have decreased health care utilization, which might be assumed to be a result of decreased symptoms (91,92). C. Improve Muscle Function 1. Nutrition

Approximately one-third of patients with COPD are underweight (93). Many patients who are chronically short of breath lose their appetite and desire to eat especially if they live alone and ‘‘cook for one.’’ Dyspnea may be increased during meal preparation and eating due to energy requirements for chewing and arm movements, the reduction in airflow while swallowing, or oxygen desaturation (93). Nutrition repletion can improve

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respiratory function (94). Dyspnea in patients who are malnourished may decrease with supplementary oral nutrition presumably related to the increases in respiratory muscle strength (95,96). Patients should be taught to eat smaller more frequent meals, plan a positive environment, use oxygen before eating, and limit excess carbohydrates. In contrast, many patients with chronic respiratory diseases are overweight and this may contribute to restriction of the lungs and cause breathlessness. Increased appetite due to corticosteroid use and decreased mobility are two reasons for weight gain. Helping patients to plan meals, constant encouragement to lose weight, weighing the patient each visit, and referral to a weight loss program and/or dietitian will help motivate patients to lose weight. 2. Positioning

One of the first descriptions of people with shortness of breath changing their positions to decrease dyspnea was a study in which people with COPD described using ‘‘breathing stations.’’ These stations were places where they can rest when they are short of breath in their attempts to carry out normal daily activities (97). During an acute episode of dyspnea, adults and children with chronic lung disease have described standing still, being ‘‘motionless,’’ ‘‘keeping still,’’ ‘‘staying quiet,’’ or finding a ‘‘breathing station to sit or lean on’’ (29). A position that is often helpful in reducing dyspnea for patients is the leaning forward position either standing or sitting. This postural relief is thought to be due to an improvement in the mechanical efficiency of the diaphragm and optimal functioning of the inspiratory accessory muscles (98). Patients should be encouraged to assume the position that is the most comfortable for them. The head down and leaning forward position with arms supported may be the most comfortable during acute episodes (99). 3. Minimizing Use of Steroids

Steroids are used to reduce ventilatory impedance from airway inflammation and to increase vital capacity in interstitial lung diseases. However, the deleterious effects of muscle wasting and weakness must be considered when prescribing steroids for the symptom of dyspnea. As part of an education program, the consequences of steroids should be stressed and an action plan introduced that acknowledges the order in which medications should be added as the intensity of dyspnea and related symptoms increase during an exacerbation. D. Alter Central Perception of Dyspnea 1. Theoretical Perspective

As suggested earlier in the chapter, the cognitive–behavioral strategies presented below are theorized to alter the perception of dyspnea without a

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concomitant change in physiological mechanisms. The primary theoretical perspectives that are integrated to provide the foundation for these strategies include social cognitive learning theory (41), self-management principles (3), social support (2), and pathophysiological (100) theories. Cognitive– behavioral strategies may work through a number of different pathways or mechanisms. An information and decision-support pathway may empower patients with safe and effective self-management strategies for the symptom. A lifestyle or behavior change pathway may support successful behavior change strategies to decrease health-damaging behaviors and increase health-promoting behaviors. A social support pathway is another mechanism by which complementary interventions to increase perceived levels of social support and reduce social isolation may change symptoms or health status. Being a member of a group or attending an educational program may support the patient’s change in behavior, such as smoking cessation or adherence to an exercise program (101). Another theoretical process that supports change in the perception of symptoms with cognitive–behavioral strategies is that of the placebo effect or non-specific effects (102,103). The placebo response has been studied extensively in the treatment of pain, and it has been suggested that this response to non-specific treatment effects can be used effectively with other symptoms (104). Several possible mechanisms have been suggested as underlying the placebo effect, including expectancy that the treatment will be effective, suggestion, classical conditioning, motivation, anxiety reduction, and endorphin release (102). Investigators have recently proposed that other processes that can change the perception of a symptom after treatment may be understood as a phenomenon labeled ‘‘response shift.’’ Similar to earlier studies that documented a change in the scaling behaviors of individuals (105), or a change in the frame of reference from which the patient perceives the symptom (106) response shift, defined above (67,107), is proposed to cause a change in an individual’s perception of a symptom from one of three processes: a change in a person’s internal standards of measurement with scale recalibration as originally proposed by Hoogstraten (105); reconceptualization, or giving new meaning to the symptom; or a change in the person’s value system, where an intervention causes the person to believe that he or she has more control over a symptom. 2. Cognitive Behavioral Therapies

If the symptom is relatively brief, acute distraction may be more effective for alleviating distress and increasing tolerance than attention to the stressor (1,108). However, in long-term studies, attention becomes more beneficial when the individual may be more able to actively and successfully confront the situation (108). In general, using attentional coping strategies,

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e.g., symptom monitoring and information seeking to cope with chronic symptoms, is associated with better illness adjustment, while avoidant coping strategies or distraction, e.g., hoping, ignoring, and attention-diversion, result in higher levels of physical and psychological disability, and a poorer adjustment to illness (37). a. Distraction Strategies

Active distraction from a noxious physical sensation, such as a symptom, can increase tolerance and decrease both physiological arousal and psychological distress (20). During acute dyspnea, distraction is often effective in the short term as it is difficult to focus on two demands at once. Adults with asthma report using television and other stimuli to distance themselves from a trigger and to distract themselves (22). Children report various types of distraction including music and ‘‘ . . . walking anywhere and looking at things that are good, like flowers and trees . . . ’’ (109). i. Social Support. The provision of emotional and informational support (education) is proposed to buffer stress in chronic diseases (110), influence self-management and adaptation to the illness, improve functioning (111,112), and may even decrease the number of exacerbations in patients with COPD through improved immune functioning (113). The positive effects of social support are determined by an individual’s preference for the type, amount, source, timing, and control of support sources (110,114). The same tangible assistance, emotional interactions, or social groups may be helpful for one individual but not for another. In one cross-sectional interview survey, the level of recalled dyspnea was related to the number of persons in the social support network and the frequency of contact with others. The amount of material aid, affirmation, and affection was related to the intensity of dyspnea (115). Specific social support for a task is more powerful than general support. For example, social support focused on initiation or maintenance of exercise has been found to predict adherence to exercise (116,117) and impact motivational readiness for exercise more than general social support (118). People with chronic dyspnea sometimes develop extensive networks and resources that provide a high level of social support (119). Vicarious learning from other people, who have experienced the same symptom and tested successful strategies to decrease the symptom, is a powerful self-efficacy enhancing experience that allows individuals to develop a shared sense of commonality, acceptance, and normalization (120,121). In an early study of 64 patients with COPD, Ashikaga et al. (122) found that a group workshop increased self-help skills at home, encouragement, and support that increased confidence and motivation. At the present time, structured support groups, such as ALA Better Breathers Clubs or pulmonary rehabilitation programs, give patients the opportunity to see that they are not alone and to learn strategies from others who have been coping with their

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dyspnea. It may be that the component of social support provided in PR programs is one of the major contributors to symptom reduction and quality of life improvement (123). Some patients with dyspnea prefer to isolate themselves, and they begin to limit their interactions with friends and family (14). Patients may actually benefit from isolating themselves from others in certain situations. Dudley (14) reported that failure of patients with COPD to adequately use withdrawal during acute episodes of shortness of breath was associated with an increase in symptoms and psychological deterioration. People with COPD have suggested that health care providers and family permit them to withdraw and isolate themselves when experiencing severe dyspnea (124). ii. Relaxation Exercises. It has long been a clinical observation that dyspnea and anxiety levels are related and synergistic. Only recently, it has been shown that state anxiety is high during high levels of dyspnea in asthma patients in an emergency room (125) and that anxiety associated with dyspnea does increase as the intensity of perceived dyspnea increases during treadmill exercise (126). Affect and anxiety is related to dyspnea in cancer patients (127). If dyspnea is escalated and enhanced by anxiety or panic, strategies that decrease this anxiety or modulate the level of distress might be expected to reduce dyspnea. Relaxation may also improve dyspnea by reducing respiratory rate and increasing tidal volume thus improving breathing efficiency (128). One investigator studied the effect of relaxation on dyspnea in 10 COPD patients compared with a control group that was instructed to relax but not given specific instructions. Although dyspnea was significantly reduced for the relaxation group during treatment sessions, the scores were similar after 4 weeks (129). Another study found that the use of relaxation techniques by patients with COPD decreased state anxiety as well as the perception of dyspnea intensity at rest (130). These preliminary studies found that immediate significant decreases in dyspnea did not persist outside the experimental session, however, they do provide beginning evidence that relaxation may reduce dyspnea. Relaxation can take many forms depending on what method works for the patient. Most relaxation methods include the use of a quiet environment, a comfortable position, loose clothing, some type of word or imagery repeated in a systematic fashion, slow abdominal breathing with deep breaths and slow expirations, systematic tensing or relaxing of all muscles, and gentle massage if desired. Individualized tape recordings with a therapist can be used to coach patients throughout a session in the home (131). iii. Biofeedback. Using a patient’s own respiratory parameters as feedback to help change his/her breathing pattern has been shown to reduce respiratory rate and paradoxical breathing, increase tidal volume, decrease weaning time, and increase airway diameter (132–134). Most recently, a group of investigators compared the efficacy of a 6-week 18session program of ventilation-feedback combined with cycle exercise

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(VFþEX), ventilation-feedback only (VFONLY), or exercise only (EXONLY) on exercise endurance and breathlessness in 39 COPD patients (87). The ventilation-feedback was a visual and auditory presentation of an indicator of inhalation and exhalation (moving horizontal bar) presented on a screen with an audible alert when time of expiration was met. The purpose of the feedback was to train patients to prolong the expiratory time and maintain tidal volume during exercise. After 6 weeks, there was a significantly greater change in the exercise duration in the VFþEX than the VFONLY. There were impressive significant positive changes in the breathing pattern parameters including minute ventilation, tidal volume, and expiratory time in the VFþEX group. Only the VFþEX and EXONLY reported less dyspnea and these changes were associated with an increase in inspiratory capacity. iv. Music. Thornby et al. (135) found that at every level of treadmill exercise perceived ‘‘respiratory effort’’ was lower in patients with COPD while listening to music than while listening to grey noise or silence. Patients also performed significantly more exercise while listening to music. A more recent study investigated the effect of listening to music i.e, distractive auditory stimuli on dyspnea and anxiety during a home walking program in 24 COPD patients. There was a significant decrease in dyspnea following the use of music as reported in the music diary and a significant decrease in dyspnea and anxiety following the use of music in Week 2. However, over the total 5-week period, there were no significant changes in anxiety or dyspnea (136) (Fig. 2). Other investigators used a crossover design to measure the effect of music on dyspnea and anxiety experienced by 30 subjects with COPD while walking in their home. Dyspnea was measured after a pre-6 MW. Subjects then walked by random order for 10 min without music and for 10 min while listening to music selected. There were no differences in the change in dyspnea or anxiety measured before and after the walk between those who walked with or without music (137). v. Hypnosis. Hypnosis is a trance state that combines a heightened inner awareness with a diminished awareness of one’s surroundings. It has been suggested that hypnosis may bring about a type of ‘‘desensitization’’ by modifying the cortical centers and the perception of dyspnea. In one case study, dyspnea decreased in a patient with severe COPD who received hypnotically induced relaxation and biofeedback in an attempt to reduce dyspnea during periods of anxiety (138). Another 16 patients with asthma had a decrease in their dyspnea that was sustained from pre to 30 min after hypnosis (139). Instruction in self-hypnosis was given to 17 children and adolescents with normal lung function, but with chronic stable dyspnea that was not responsive to medical therapy (140). For nine of the 17 patients, a potential psychosocial association with their dyspnea was identified. Thirteen patients were taught to use self-hypnosis in one session. A second session was provided to three patients within 2 months. Thirteen patients reported

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Figure 2 UCSD-SOB scores. Lower scores indicate less perception of dyspnea during ADL. DAS = Distractive Auditory Stimuli.

their dyspnea and associated symptoms had resolved within 1 month of their final hypnosis session. Eleven believed that resolution of their dyspnea was attributable to hypnosis, because their symptoms cleared immediately after they received hypnosis or with its regular use. The author attributes the reduction in dyspnea to physiologic effects of hypnosis, changes in anxiety, and/or vocal cord dysfunction (140). vi. Guided Imagery. In an observational study, 19 COPD patients met weekly for 4 weeks for 1 hr of practice with guided imagery (141). As a standard guided imagery script was read, subjects were asked to visualize the scene described and audiotapes of the script were provided for practice. In this uncontrolled study, neither dyspnea nor depression, quality of life, anxiety, functional status changed significantly. vii. Acupuncture and Acupressure. Because studies have shown that opiates relieve dyspnea and acupuncture is thought to cause release of endogenous opiates, Jobst (142) hypothesized that acupuncture may relieve dyspnea and compared the effects of ‘‘traditional’’ and ‘‘placebo’’ acupuncture in 24 COPD patients with ‘‘disabling breathlessness.’’ Treatments were administered for 13 sessions over 3 weeks. Traditional acupuncture needles were inserted according to ‘‘traditional acupuncture points,’’ while the placebo needles were inserted in non-acupuncture ‘‘dead points.’’ Subjects from each group were paired for age, sex, severity of breathlessness, and lung function. Both groups did improve their dyspnea on two different scales and at the end of the 6 MW, with the acupuncture group having significantly greater improvement than the placebo. Filshie et al. (143) studied acupuncture in 20 patients with cancerrelated breathlessness. Twenty patients received four needles (two in the upper sternum and one in each hand) for 10 min by an experienced

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acupuncturist. Needles were left in place for 90 min. Seventy percent of the patients reported significantly improved relief in breathlessness, anxiety, and relaxation that peaked at 90 min and lasted up to 6 hr. In this uncontrolled study, it is not known whether this relief was due to the treatment or the reassurance of the nurse. Using a single-blind crossover design, investigators added an acupressure treatment to a pulmonary rehabilitation program to determine if there was added improvement in dyspnea. Thirty-one COPD patients were taught to apply pressure to seven acupoints that are believed to give minimum relief to patients with dyspnea. Patients were taught acupressure to be practiced daily at home for 6 weeks alternating with a sham acupressure for 6 weeks. Dyspnea on the VAS was significantly less during the acupressure than the ‘‘sham,’’ however, there were no significant differences between the treatments in dyspnea measured by the Borg scale or the 6-MW distance (144). Maa et al. (145) later compared the effect of standard care plus supplemental acupressure or acupuncture to a standard care treatment in patients with ‘‘chronically obstructed’’ asthma patients. The acupuncture group received 20 treatments using five points previously shown to provide relief for dyspnea and improve immune function (146), the other group selfadministered their acupressure daily for 8 weeks. Acupressure, a selfadministered, short-acting, and more accessible treatment was theorized to increase relaxation and reduce a patient’s fear of dyspnea. Although slightly improved, there were no significant differences in the groups in dyspnea measured by the VAS and modified Borg scale after 8 weeks. It is not clear whether dyspnea was measured at rest or after provoked exercise during the 6 MW. Although greater for the acupuncture group, both treatment groups had clinically significant improvements in quality of life measured by the St George’s Respiratory Questionnaire (SGRQ). More positive results were found by a group of Taiwanese investigators who matched and randomly assigned 44 patients with COPD to a program of true acupoint acupressure or sham pressure points (79). The sham pressing acupoints were different from the meridians and ganglionic section of the true acupoints to avoid confounding effects due to overlap. Both programs consisted of five 16-min weekly sessions for 4 weeks. The true acupoint group had significantly greater improvement than the sham group in dyspnea, measured by the Pulmonary Functional Status and Dyspnea Questionnaire-Modifed scale (147), 6 MW, state anxiety, and O2 saturation. The true effect of acupuncture and acupressure on dyspnea cannot be understood from these few studies using small samples. Future studies are needed to judge the true effect of ‘‘complementary’’ treatments on chronic symptoms.

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b. Attention Strategies

Over time, it may be just as important to allow patients to concentrate on their breathing and shortness of breath. Especially, during acute episodes patients reported they needed to concentrate on their breathlessness and were frustrated with suggestions of distraction (124). i. Symptom Monitoring. Regular monitoring of symptoms coupled with a clear individualized action plan negotiated with a primary health provider are essential components of a symptom management program for early recognition and treatment of exacerbations, possibly averting hospitalization. A few studies have shown that if COPD patients monitor their symptoms and/or use an action plan there is earlier initiation of medical therapy and reduced resource utilization. Patients, who were provided an education booklet, action plan, and a supply of prednisone and antibiotics, initiated medical treatment for their exacerbations earlier than usual care (148). Gallefoss et al. (149) compared the effects of a self-treatment plan with PEFR and symptom monitoring for exacerbations to usual care in patients with COPD. Treatment subjects used less short-acting beta agonists (149) had an 85% reduction in number of visits to their primary care provider (150) and less overall costs (151). Experience with asthma and congestive heart failure patients supports the use of symptom monitoring and/or action plans (90,152,153). Symptom or activity diaries may improve adherence to a treatment regimen because they provide the patient with patterns of triggers and symptoms as well as response to therapies (154). Daily symptom monitoring also provides more accurate reflection of symptoms than recall during a weekly or monthly visit (155). To the extent that monitoring a symptom provides information about actual physiological status (i.e., PEFR is added to the rating of shortness of breath), monitoring dyspnea may result in more appropriate self-regulatory behaviors (43). Examples of diaries are published and can be used to develop an ongoing monitoring system for patients (154). ii. Increasing Knowledge About Symptom Management. Acute dyspnea: In the hospital teaching patients strategies to reduce their breathlessness needs to begin early when the patient either is comfortable on ventilator assistance or during rest periods on the medical surgical unit. Hospitalized patients often have had previous experience with strategies that they have learned from others or developed themselves. The hospitalized patient with unrelenting shortness of breath should be asked to describe or write down the strategies they typically use at home. Often a family or significant other can provide a list of the patient’s previous adaptations for dealing with dyspnea and these strategies can be practiced and reinforced during hospitalization. Demonstration and modeling and ‘‘staying with the patient to help them breath slowly and deeply’’ may be the most

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important teaching and care the clinician can do while the patient is experiencing acute dyspnea (124,138). The COPD subjects reported their fear was relieved and breathing became less difficult when the nurse demonstrated proper breathing and encouraged them to model the techniques. During acute dyspnea, breathing techniques that required patients only to imitate the nurse were preferred and the most effective (124). Chronic dyspnea: Education for chronic dyspnea should focus on symptom management vs. the disease process. A structured program of strategies that the patient can use at home when their shortness of breath increases can be discussed with the patient (Table 4). The specific effect of knowledge on the perception of dyspnea is difficult to determine since education typically is offered within a multifaceted self-management programs or comprehensive pulmonary rehabilitation programs. Asthma: Content specific to the teaching of asthma management and symptoms for children and adults is presented in the Guidelines for the Diagnosis and Management of Asthma (156). Optimal self-management components in an asthma education program include: information and facts about asthma including correct inhaler use; self-monitoring of peak flow and/or symptoms; written action plan allowing self-adjustment of medications (individual); and regular clinician review of asthma control and medications (43). Developmental factors affect the recognition of Table 4 General Strategies for Managing Dyspnea at Home Know and monitor your baseline intensity and pattern of shortness of breath. You can use a scale from 0 (not at all) to 10 (worst possible you can imagine) to rate your shortness of breath with various activities and at different times of the day. If you have a way to measure your lung function at home, such as with a peak flowmeter or spirometer, measure how your long function varies by time of day and response to medications. If you can, keep a record of your lung function and symptoms. Have a crisis plan. Discuss with your health care provider what steps you should take in case of an episode of increased shortness of breath. Plan together if and how you should adjust medications and when you should contact him or her. If you have acute episodes of shortness of breath, you should develop an action plan with your health care provider. This plan should include symptoms and peak flow assessment, use of bronchodilators and corticosteroids, and contacting your health care provider. Anticipate! Plan ahead for activities. Keep medications and other resources handy. Imagine beforehand what you would do in a situation in which you are extremely short of breath. Identify and prioritize strategies for managing chronic shortness of breath that work for you. Teach these strategies to your family, friends and health care providers so that they can help you use them during an episode of acute shortness of breath.

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symptoms and, therefore, the teaching of symptom recognition must differ depending on the age (88). Education about symptoms in asthma is integrated into a self-management program. A meta-analysis of 12 studies of asthma self-management programs found that asthma self-management programs that included ‘‘education only’’ significantly improved knowledge of facts and improved perceived symptoms (90). However, these ‘‘education only’’ programs had no effect on hospitalizations, ER visits, unscheduled MD visits, lung function, medication use, or days lost from work. In contrast, a more recent meta-analysis found that self-management programs that included not just education, but also medical review, self-monitoring of PEFR and symptoms, and a written action plan allowing self-management of medications resulted in decreased resource utilization (89), days off work (152), nocturnal asthma (157), symptoms (88), and improved quality of life (89) when compared to usual controls. Lung Cancer: One of the most successful educational interventions for dyspnea is a nurse clinic for cancer patients who completed the ‘‘first line of treatment’’(158,159). The weekly clinic visit consisted of assessment of dyspnea, teaching effective ways of coping with dyspnea, exploration of the meaning of dyspnea, breathing control, activity pacing, relaxation techniques, and psychosocial support. The intervention was compared to a supportive care group that received standard treatment for breathlessness and breathing assessments. Worst and best breathlessness and distress on a VAS were measured at rest, at baseline, and at 8 weeks and were found to be decreased significantly more for the intervention group. It is noteworthy that this nursing intervention did improve dyspnea without exercise. This finding is similar to that of a much earlier study with COPD patients that compared teaching and counseling by a nurse to three psychotherapy groups (non-specific surveillance with psychotherapy, analytic psychotherapy, and supportive psychotherapy) and found that the group treated by the nurse was the only one that experienced a ‘‘sustained relief in breathlessness’’ (160). COPD: There has been much less study of educational or selfmanagement programs for COPD patients. The programs for COPD that included only education and limited skills training have not significantly improved dyspnea (148,151,161–164). However, a dyspnea self-management program that included supervised exercise sessions or just a home walking prescription with biweekly phone reinforcement improved dyspnea with activities of daily living (51). More recent programs for patients with COPD that have provided self-management education, action plans, and prescriptions for antibiotics and steroids coupled with home visits, a limited exercise program, and regularly scheduled follow-up phone calls (91,92,150,165) reported significant reductions in health care utilization compared to usual care groups. This decrease in health care utilization

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might be presumed to mirror a reduction in symptoms, however, which component of these multitreatment programs had the primary effect on the outcomes is unknown. E. Comprehensive Pulmonary Rehabilitation Programs (see Chapter 13)

Structured pulmonary rehabilitation programs typically target several causes of dyspnea and include most or all of the therapeutic interventions discussed above including exercise training, education about coping strategies, breathing retraining, nutritional assessment, behavioral modification, support, and group interaction (166). With little exception, these multicomponent programs have shown a clinically and statistically significant reduction in dyspnea with laboratory exercise and activities of daily living measured by the Chronic Respiratory Disease Questionnaire in the short and long term. It remains difficult to determine the effect of each of the individual components, however, exercise training is the critical component for improving dyspnea (151,162). IV. Summary The content of this chapter is grounded in the belief that dyspnea, like pain, is not only a physiological phenomenon, but also has affective components similar to pain that are shaped by psychological, social, and environmental factors. It is proposed that the coping and self-management strategies presented here may alter any or all of these factors with subsequent modification of the nature of the perception and interpretation of the physiological state, and in turn, the response to the symptom and the strategies that patients use to control it. The primary theoretical perspectives integrated in this chapter to provide the foundation for these strategies include social cognitive learning theory, self-management principles, social support, and pathophysiological theories. The non-pharmacological strategies, including cognitive–behavioral strategies, can be targeted at one or more of the proposed mechanisms for dyspnea. Examples of strategies that have been shown to reduce dyspnea include attention strategies, such as, education and exercise, fans or fresh air, and PLB, and biofeedback and distraction strategies, such as, music, relaxation, and social support. References 1. Lazarus RS, Folkman S. Stress, Appraisal and Coping. New York: Springer, 1984. 2. Tobin DL, Reynolds RVC, Holroyd KA, Creer TL. Self-management and social learning theory. In: Holroyd KA, Creer TL, eds. Self-Management of Chronic Disease. Orlando: Academic Press, 1986:29–58.

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17 Management of Dyspnea: Lung Volume Reduction Surgery

SANJAY A. PATEL and FRANK C. SCIURBA Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

I. Introduction Lung volume reduction surgery (LVRS) has been the most controversial topic in the management of patients with emphysema over the past decade. Given the modest efficacy of medical therapies for emphysema, the limited availability and drawbacks of lung transplantation and the significant economic burden of emphysema (1), the great enthusiasm that the reintroduction of LVRS (2,3) created in the medical and surgical communities was justifiable. The early enthusiasm for this procedure was bolstered by a number of optimistic publications suggesting that LVRS improves lung function (4), exercise capacity (5–9), dyspnea (7,10), and even survival (11). Unfortunately, these early clinical reports were limited by their nonrandomized design, small study size, incomplete follow-up (12), focus on short-term results and their use of nonobjective or inconsistent selection criteria. As a result, the rising popularity of LVRS was paralleled by a growing unease about its true efficacy, risk–benefit ratio and cost-effectiveness. These concerns were articulated in a number of reviews (13,14), editorials (15–17), and two federal reports (18,19). Ultimately, this encouraged the development 397

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of the National Emphysema Treatment Trial (NETT) (20), a unique collaborative effort between the National Heart, Lung and Blood Institute of the National Institutes of Health and the Health Care Financing Administration (HCFA). The results of the NETT, published in two key manuscripts to date have provided significant progress toward answering important questions about LVRS relating to operative mortality, procedural efficacy, and subject selection criteria, which could only have been answered adequately using such a large randomized controlled clinical trial design (21,22).

II. Rationale A. Need for Integrative Tools

Unfortunately, as with other interventions for emphysema, the assessment of outcome following LVRS is complicated by the absence of a gold standard (23). Indeed, the need for outcome measures that represent the integrated impact upon patients has never been more apparent than with this intervention. Following LVRS, various physiologic parameters, including expiratory flow rate, end-expiratory lung volume, pulmonary vascular resistance, gas exchange, and peripheral muscle conditioning can be affected independently and may even respond in conflicting directions (24). Thus, integrative measurement tools such as dyspnea ratings and exercise testing should best reflect the complexity of physiologic changes and thereby, the overall clinical response, following surgery. The following case highlights the difficulties in assessing therapeutic response following this procedure: A 78-year-old man with an FEV1 of 22% predicted, diffuse but mildly heterogeneous upper lobe dominant disease, and a diffusing capacity of 18% predicted underwent bilateral LVRS. At his six-month follow-up evaluation, he had significant improvements in his FEV1, residual volume and resting dyspnea. However, he had a significant decrease in exercise tolerance and worsening of exertional hypoxemia and dyspnea. On examination, he no longer used accessory muscles at rest and was able to speak in full sentences for the first time in years. On the other hand, he had developed symmetric leg edema and his echocardiogram revealed new right ventricular dilation. This patient experienced the mixed physiologic results of significant improvements in pulmonary mechanics and lung hyperinflation with worsening pulmonary vascular function and subsequent cor pulmonale. The clinical result was an improvement in resting dyspnea, associated with a paradoxical worsening of exercise tolerance and exertional symptoms. This patient highlights the need for integrative tools in outcome assessment and the potential advantages of using multiple tools or multiple domains within a given tool to adequately assess the full scope of response.

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B. Mechanisms of Improvement in Dyspnea and Exercise Tolerance

An understanding of the complex physiologic changes induced by LVRS provides insight into (a) the mechanisms of symptomatic and functional improvement, (b) the selection of appropriate outcome parameters for assessing the clinical response to LVRS and (c) the sources of variability in symptomatic and functional responses. These mechanisms can be classified into general categories including improvements in (i) lung mechanics, (ii) respiratory muscle function, (iii) exercise ventilation, (iv) gas exchange, (v) pulmonary hemodynamics, and (vi) peripheral muscle conditioning, each discussed in turn below. (i) Lung mechanics. The early hypothesis of Brantigan which suggested that LVRS results in partial restoration of diminished lung elastic recoil pressure and renewed airway tethering forces was corroborated by early experiments documenting improvements in the airway conductance to volume ratio following bullectomy (25). More recent reports documenting increases in maximal static recoil pressure and the coefficient of retraction after LVRS (4,26,27), further support Brantigan’s hypothesis. These changes should improve the effective pressure driving expiratory flow which should increase air flow at all thoracic volumes, thereby reducing lung hyperinflation and improving dyspnea. Thus ‘‘volume reduction’’ is, in part, due to increased expiratory flow and consequent reduced hyperinflation due to a global increase in lung elastic recoil. However, regions of lung ‘‘heterogeneity’’ are often specifically targeted for resection because they have such long time constants that they simply act as space occupying residual volume. Resection of these lung units should result in disproportionately greater improvements in expiratory flow by enabling the relatively preserved remaining lung units to more fully expand within the thorax. This concept is highlighted in Fessler and Permutt’s mathematical model (28) which attributes improvements in FEV1 following LVRS to a more appropriate resizing of the lung relative to the chest wall. In this model, the dominant impact of LVRS lies in the relatively greater reduction in residual volume (RV) compared to total lung capacity (TLC), and a consequent increase in vital capacity. This increase in vital capacity is the dominant factor affecting an increase in FEV1. Consistent with this model is the minimal change in FEV1/FVC observed in most patients following LVRS (29). This model exemplifies the importance of elucidating mechanisms of improvement, as it predicts that the greatest spirometric improvement will occur in those with the highest preoperative RV/TLC, a finding which has subsequently been confirmed (29–31). (ii) Respiratory muscle function. While the primary effect of LVRS is an alteration in lung mechanics, the consequent ‘‘volume reduction’’ and secondary improvement in inspiratory muscle function also likely contri-

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bute significantly to reduced dyspnea and functional improvement. Indeed, a less hyperinflated chest wall returns to a more compliant region of its pressure–volume curve and reduces the work of the respiratory muscles (32). This is at least in part due to improvements in respiratory muscle efficiency via partial normalization of end-expiratory diaphragmatic curvature and restoration of the normal bucket handle configuration of the rib cage (33–35). In addition, decreases in intrinsic positive end-expiratory pressure following LVRS (4,32,36,37) and improved neuromechanical coupling of the diaphragm (38–40), may further decrease the oxygen cost of breathing. Accordingly, large increases in maximal inspiratory and transdiaphragmatic pressures of 25–50% have been documented following LVRS (24,38,39,41). (iii) Exercise ventilation. The impact of LVRS on exercise minute ventilation and respiratory timing has been documented by many investigators (7,10,24,37,42–44). At iso-workloads, following LVRS, patients have a slower respiratory rate with significantly greater tidal volumes and associated higher inspiratory flow rates. This results in significantly lower Borg dyspnea ratings at a given workload (45,46) (Fig. 1). At maximal exertion, respiratory rate is similar before and after surgery, but tidal volume and minute ventilation are significantly increased (8,9). This may be due to reduced dynamic hyperinflation attributable to significantly greater inspiratory and expiratory flow rates. In addition, the improvements in diaphragm function described above aid in increasing exercise tidal volumes and contribute to improved exercise capacity and dyspnea (10,38,47). (iv) Gas exchange. While resting arterial oxygenation has been shown to improve following bilateral LVRS, the improvement is variable and the precise mechanisms of improvement are unclear. During exercise, following LVRS, arterial oxygenation is higher during iso-watt exertion, but there may be no significant differences at maximal exertion. Potential mechanisms include global increases in alveolar ventilation, regional improvements in V/Q matching due to reexpansion of less diseased but previously poorly ventilated lung units, and improved mixed venous saturation from improved right or left heart function. The significant improvement in arterial CO2 at rest, submaximal and maximal exercise (7,8,44,48) may be attributed to increased alveolar ventilation from improvements in pulmonary mechanics, but reductions in dead space ventilation from removal of partially ventilated bullae and increases in capillary flow to high V/Q units are likely, as well. (v) Pulmonary hemodynamics. The theoretical impact of LVRS on pulmonary vascular function is controversial. On one hand, resection of perfused lung could further decrease vascular reserve. On the other hand, a decrease in vascular resistance could occur through recruitment of vessels in re-expanding lung tissue or through increased radial traction on extraalveolar vessels due to improved elastic recoil.

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Figure 1 Changes in dyspnea and leg fatigue following LVRS. In 23 subjects performing incremental cycle ergometry before (black lines) and 3 months (gray lines) after bilateral LVRS. Subjects demonstrate lower mean modified Borg dyspnea (top panel) and leg fatigue (bottom panel) ratings at any given time point during 4 min of unloaded (UNL) pedaling (left panels) or at any given workload (right panels) (46).

Likewise, clinical studies have demonstrated mixed results following LVRS with respect to changes in pulmonary vascular function. In one study, significant increases in right ventricular fractional area of contraction have

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been reported following LVRS using echocardiography, suggesting improvements in pulmonary vascular function at rest (4). Similarly, during exercise, LVRS mediated reductions in exercise-induced dynamic hyperinflation (10) may mitigate increases in intrathoracic pressure and pulmonary vascular resistance. Indeed, noninvasive cardiopulmonary exercise testing reveals a reduction in heart rate and thus an increased oxygen pulse (9) at iso-workloads following LVRS. Conversely, other reports, including a study evaluating patients with more diffuse emphysema, demonstrate increases in pulmonary vascular resistance both at rest and with exertion (49,50). Lastly, three studies have concluded that LVRS has no significant effect on resting or exercise pulmonary artery pressure (51–53). Clearly, further studies delineating the mechanisms for this variability are needed to refine patient selection criteria with respect to pulmonary hemodynamics. (vi) Peripheral muscle conditioning. Another potentially important mechanism of functional and symptomatic improvement is facilitation of peripheral muscle training by improvements in pulmonary mechanics. Significant increases in thigh muscle cross-sectional area and patient weight occur following LVRS, and these changes correlate with improvements in 6-min walk (6 MW) distance and diffusion capacity for carbon monoxide (DLCO) (54,55). Indeed, prior to LVRS, patients may have profound deconditioning from chronic inactivity. With a successful surgical outcome, this deconditioning may become the limiting factor to exertion if ventilatory mechanical limitation no longer exists. The extent to which these patients can enhance peripheral muscle function with aggressive rehabilitation is uncertain. Further, the magnitude of improvement in exercise tolerance and dyspnea may lag behind improvements in pulmonary mechanics, as the abrogation of the mechanical ventilatory limitation re-potentiates peripheral muscle training and weight gain over a longer period of time (56).

III. Components LVRS involves the removal of 20–30% of each lung, whereby surgeons direct resection to regions of disproportionate emphysema guided by nuclear computed tomography, nuclear perfusion studies or intraoperative appearance. Initial attempts at unilateral or laser only resection yielded disappointing results (24). In contrast, the choice between an open median sternotomy vs. bilateral video assisted thoracic surgery approach does not impact functional response or mortality (6,21). A successful outcome from LVRS requires not only an experienced surgical team, but strong support from pulmonary medicine and radiology services to assist in preoperative evaluation and selection, anesthesiology, and critical care physicians dedicated to managing patients with advanced

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lung disease as well as respiratory care and pulmonary rehabilitation services to provide pre- and postoperative education and conditioning. The importance of a comprehensive, interdisciplinary program is reflected by differences in mortality rate between the published literature and an analysis from the broader U.S. experience (18). Indeed, while most published series before the NETT reported mortality rates of less than 10% at one year following surgery, a report issued by the Center for Health Care Technology determined the 1 year mortality rate using the objective social security death index for all Medicare recipients nationwide to be 23% (18). Following the release of the results of the NETT, the Centers for Medicare and Medicaid Services (CMS) has agreed to reinstate coverage for this procedure in the United States. It is expected that other insurance companies will follow the lead of CMS. The guidelines for inclusion and exclusion are based very closely on the original entry criteria for NETT (57) as well as the risk group stratification based on the two key NETT publications (21,22) discussed later. 6 MW testing will be required and patients unable to walk 140 m will be excluded. Cardiopulmonary exercise testing will be required to exclude patients unable to complete 3 min of unloaded pedaling and to risk stratify patients based on the NETT results. The complete CMS inclusion criteria can be found online at www.cms.hhs.gov/manuals/pm_trans/R3NCD.pdf. IV. Benefits Based on Clinical Instruments Studies of LVRS report improvements in dyspnea that are significantly greater in magnitude in comparison to those seen with pharmaceutical or rehabilitation interventions. As with other interventions, these improvements are only modestly correlated with changes in pulmonary function measures (58,59). Further, there are unique aspects of LVRS which may impact the validity and responsiveness of the utilized clinical instruments. For example, since subjects and investigators in LVRS trials cannot ethically be blinded to the intervention and because subjects have substantial investment in their treatment given the risk they have accepted, greater variability and a larger placebo effect may be expected. Nonetheless, in this section we review studies measuring dyspnea following LVRS. A. Dyspnea Ratings

The Medical Research Council dyspnea scale (MRC) (60) and the transitional dyspnea index (TDI) (61) were the most commonly used tools in the evaluation of response to LVRS in uncontrolled clinical trials. In general, most studies consistently report substantial clinically and statistically significant responses which worsen over time, but are maintained above baseline at up to 5 years.

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MRC dyspnea scores consistently improve following LVRS (Table 1) (3,45,62–73) with short term improvements ranging from
0.5 to
2.4. Two uncontrolled trials are noteworthy for their relatively large size and the documentation of the proportion of patients who improve rather than simply reporting the mean response. Yusen et al. (70) reported on 200 patients, in whom 81% were improved at 6 months and 40% remained improved at 5 years following bilateral LVRS. Only 26% had a worsening MRC score at 5 years. Brenner et al. (72) reported that, of 84 patients, nearly 90% of patients had at least a 1 unit improvement in their MRC score and 60% improved by 2 units or more, at 6 months following LVRS. Of note, there was a poor relationship between improvement in dyspnea and improvement in either FEV1 or reduction in RV. Further, a significant proportion (27%) of patients with minimal improvements in FEV1 had a 2 unit or greater improvement in MRC score. Two reports have assessed the impact of disease phenotype upon improvements in dyspnea. Hamacher et al. (66) demonstrated that patients with homogeneous disease had similar improvements in MRC dyspnea score compared to patients with heterogeneous disease, even though the latter group had greater improvements in walk performance. Cassina et al. (65) reported that improvements in MRC dyspnea scores are similar in smoker’s emphysema and alpha-1-antitrypsin emphysema patients 3 months after LVRS. However, by 24 months, the MRC score in the alpha-1-antitrypsin group deteriorated more rapidly than in the smoker’s emphysema group. TDI is also consistently reported to improve following LVRS, with changes ranging from 1.7 to 6.9, exceeding the minimal clinically important difference (74), in all three measured domains (functional impairment, magnitude of effort, and magnitude of task) (Table 2) (3,4,7,10,27,31,50,64,73,75,76). Flaherty et al. (31) report changes in TDI over a 3 year period, and noted maintenance of near peak levels in the 6–7 unit range at 3–12 months but deterioration to approximately 2.5 units by 36 months. Notably, dyspnea improved in all patients, including those with no improvement in FEV1. In contrast, the greatest improvements in TDI were associated with the greatest changes in FEV1. Other dyspnea scales showing improvement following LVRS include the visual analog scale (9), Fletcher’s scale (77), the Borg scale (45) and the University of California San Diego shortness of breath questionnaire (UCSD-SOBQ) (21,78). For example, in the NETT, there were large differences relative to control at 6 and 24 months in DUCSD-SOBQ (
16.0 vs. þ2.5 and
10.8 vs. þ4.6, respectively). As a result, at 6 months, significantly more subjects in the LVRS group had improvements in UCSD-SOBQ (66% vs. 34%) compared to controls. Unfortunately, dyspnea during exercise is not as widely reported (45) as measures of chronic breathlessness, such as the MRC and the TDI. At our institution, in 23 bilateral LVRS patients (Fig. 1), subjects demonstrated

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Table 1 Studies Evaluating MRC Dyspnea Following LVRS Nonrandomized Studies Author Short-Term Studies Cooper (3) Argenziano (62) Bingisser (73) O’Donnell (45) Argenziano (78a) Brenner (72) Stammberger (63) Longer-Term Studies Yusen (64)

McKenna (78b) Cassina (65)

Hamacher (66)

n

Follow-up (months)

Baseline MRC

Follow-up MRC

DMRC

11 51 20 8 28 64 130 84 40

3 3–6 3 3 6 6 6 3

2.9 4.1  0.8 3.9  0.7 3.3  0.5 4.1  0.8 4.0  0.8 3.00.7

0.8 1.8  1.2 1.8  0.9 1.1  0.5 1.5  1.2 1.3  0.8 1.7  0.8 1.3  0.9 1.40.1


2.1
2.3
2.1
2.2
2.6
2.7
1.3
1.7
2.1

3 6 12 12 12 3 6 12 24 3 6 12 24 3 24 3 24 3 24 6 12 24 36 3 6 12 18 24

2.5 2.5 2.5 2.89 2.9 3.2  0.6

1.33 0.88 0.64 2.14 1.8 1.8  0.8 1.9  0.4 2.2  0.5 3.1  0.6 1.6  0.5 1.5  0.3 1.7  0.5 2.2  0.5 1.6  0.4 2.0  0.3 1.4  0.5 2.0  0.6 1.5  0.2 1.9  0.2 1.5  0.1 2.0  0.1 2.1  0.2 2.5  0.2 1.5  0.0 1.5  0.1 1.7  0.2 1.8  0.2 2.0  0.2


1.17
1.62
1.86
0.75
1.1
1.4
1.3
1.0
0.1
1.6
1.5
1.3
0.8
1.9
1.5
2.3
1.7
1.9
1.5
1.3
0.8
0.7
0.3
2.4
2.4
2.2
2.1
1.9

45 30 17 87 79 12a 12a 12a 9a 18b 18b 17b 16b 12c 7d 18e

Fujimoto (67)

Hamacher (68)

57 57 46 26 39

3.5  0.1

3.00.6

3.5  0.2 3.70.2 3.4  0.2 2.8  0.1

3.90.1

(Continued)

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Table 1 Studies Evaluating MRC Dyspnea Following LVRS (Continued ) Nonrandomized Studies Author Longer-Term Studies Appleton (69) Yusen (70)

n

Follow-up (months)

28 109 92 35

36
66 6 36 60

Baseline MRC

Follow-up MRC

2.88  0.14 2.19  0.19 2.4  0.8 1.2  1.0 1.9  1.1 2.1  1.1

DMRC


0.69
1.2
0.5
0.3

Randomized Studies Author Pompeo (71)

n

Follow-up (months)

55

6

a

DMRC (control)

DMRC (LVRS)

p value


0.12


0.46

—

b

Type of emphysema: alpha-1-antitrypsin deficiency, smoker’s emphysema morphologic groups: chomogeneous, dintermediate heterogeneous, emarkedly heterogeneous.

a significantly lower modified Borg score for both dyspnea and leg fatigue following surgery during both unloaded pedaling and iso-watt incremental workloads (46).

B. Health Related Quality of Life

Two popular disease-specific quality of life instruments, the Saint George’s Respiratory Questionnaire (SGRQ) and the Chronic Respiratory Questionnaire (CRQ), incorporate domains related primarily to dyspnea. For example, in the NETT, there were greater improvements relative to control in total SGRQ score at 6 and 24 months (LVRS vs. control:
11.3 vs. þ2.1 and
7.2 vs. þ3.8, respectively). As a result, significantly more subjects in the LVRS group had improvements in SQRQ at 6 months (65% vs. 36%), though fewer maintained gains at 24 months (33% vs. 9%). However, in the subgroup with upper lobe predominant emphysema and low exercise tolerance, improvements were more durable at 24 months (48% vs. 10%) (Fig. 2). Unfortunately, scores for individual domains of the SGRQ were not reported. One uncontrolled study does, however, report improvements in all three assessed domains of the SGRQ (symptoms, activity, and impact) (79). The CRQ also demonstrated clinically important improvements in all four of its measured domains (dyspnea, emotional function, fatigue, and mastery) after LVRS in uncontrolled (40,80) trials and in one randomized controlled trial (81).

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Table 2 Studies Evaluating BDI/TDI Following LVRS Nonrandomized Studies Author

n

Follow-up (months)

Short-Term Studies Cooper (3) Bingisser (73) Keenan (75) Seiurba (4) Keller (7)

11 20 40 18 25

3 3 3 3 6

Martinez (10) Scharf (27) Weg (50) Quint (78C) Longer-Term Studies Ojo (76) Yusen (64)

Flaherty (31)

a

17 9 9 41

3 3 3

11 45 30 17 79 74 69 61 51 34

8–20 3 6 12 3 6 12 18 24 36

Domain

BDI

TDI

Mean Mean Mean Sum Functional impairment Magnitude of effort Magnitude of task Sum Sum Sum Sum

1.2 — 1.3 — 1.0  0.63

2 2 1.7 5.1 1.72  0.7

1.16  0.54

2.12  0.8

1.2  0.57

2.28  0.7

— 0.7  1.1 3.1  0.9 —

7.8  0.4 3.22  2.22 2.4  2.5 3

Sum Mean

1.8a 0.86

Sum

—

5.6a 1.68 2.5 2.4 6.4a 6.5a 6.9a 5.7a 5.5a 2.5a

estimated from figures.

General health related quality of life measures such as the sickness impact profile (SIP) (42,59,82), the Medical Outcomes Survey SF-36 (58,64,66,68,83), and the Quality of Well Being scale (84) also are reported to consistently improve following LVRS. However, these instruments do not explicitly include a dyspnea-related domain. V. Benefits Based on Exercise Testing Improvements in exercise performance are commonly used in studies of LVRS since they are good proximate surrogates of the integrated physiolo-

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Figure 2 NETT results summary. Odds of improved survival (black bars), improved exercise capacity [ >10 watts increase in maximal cycle ergometry workload] (light gray bars) and improved quality of life [ >8 point decrease in St Georges’s Respiratory Questionnaire (SGRQ)] (dark gray bars) are represented for all non high-risk (22) subjects in the NETT and for sub-groups based upon presence or absence of upper lobe predominant emphysema (ULPE) and low vs. high exercise capacity [maximal workload  25 watts (females) or 40 watts (males)]. Survival data are based upon complete follow-up of 1218 subjects, while exercise and HRQL data are based upon 643 subjects with follow-up data at 24 months. Odds ratios are logarthmically transformed. The inverse of the risk ratios for mortality (i.e., likelihood of survival) are plotted so that all values greater than one suggest LVRS benefit and values less than one suggest a detrimental effect of LVRS. p < 0.05, y log odds ratio >10.

gic response to LVRS. Indeed, improvements in exercise ventilation are closely tied to improvements in dyspnea during exercise (85). However, studies measuring dyspnea after LVRS generally report on chronic dyspnea and not on dyspnea during exercise tests (45,46). Thus, in this section, we summarize studies assessing walking test and cardiopulmonary exercise test performance following LVRS, presuming that improvements in these tests reflect improvements in dyspnea with exercise and daily activities. Future studies of LVRS should directly assess dyspnea during exercise, as these measures would serve to complement measures of chronic breathlessness. A. Improvement in Walk Distance

Short-term improvements in 6 MW distance have been widely reported after LVRS, with mean improvements ranging from 12% to 57%

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409

(Table 3) (5,6,8,31,32,59,63,64,66–68,70,73,80,82,86–92). Unfortunately, few studies report detailed methodology of their walk testing. Given that 6 MW is highly dependent upon methodological factors (93,94), results among centers are difficult to generalize. Nonetheless, uncontrolled studies suggest that this short-term improvement in walk distance is maintained at 12 months (32,64) and beyond (31,66,88). Five randomized controlled trials have assessed improvement in walk distance after LVRS as compared to pulmonary rehabilitation control arms. Pompeo et al. (71) demonstrated 2.1 times greater improvement in 6 MW (þ180 vs. þ85 ft) after LVRS as compared to 6 weeks of comprehensive pulmonary rehabilitation. Similarly, Criner et al. (42) reported 3 times greater 6 MW increase (þ305 vs. þ102 ft) following LVRS as compared to 12 weeks of rehabilitation. Geddes et al. (83), using the related incremental shuttle-walk test, also reported greater improvements in walk distance with LVRS as compared to 6 weeks of pulmonary rehabilitation and further documented sustained differences at 1 year. Goldstein et al. (81) identified no difference in 6 MW at 3 months between 28 subjects randomized to LVRS vs. 27 control subjects. However, by one year, there were clinically and statistically significant differences (66 m) due almost exclusively to deterioration in the control group with stability in the LVRS group. Finally, the NETT demonstrated 136 ft greater change in walking distance in the LVRS group relative to the control group at 6 months (þ47 vs.
89 ft) and 166 ft greater change at 24 months (
43 vs.
209 ft). At 6 months, a larger proportion of subjects (50% vs. 21%) had an increased walk distance, with fewer subjects maintaining improvements at 24 months (30% vs. 8%) (84). B. Improvement in Cardiopulmonary Exercise Test Parameters

Improvements in cardiopulmonary exercise test (CPX) parameters are also widely reported following LVRS (Table 4) (7–9,21,32,42,44,59,63,73,82,87– 89,95). Short term increases in maximal workload at 3–6 months have ranged from 20% to 69% and increases in peak oxygen consumption (VO2) have ranged from 3.4% to 30%. Further, at least a subset of patients maintain these improvements at 1 year (88) and further (32,87). Besides the NETT, three randomized trials, have confirmed these improvements in maximal exercise capacity (measured by maximal VO2 (42), maximal cycle ergometry workload (44) and incremental treadmill exercise (71)). In the NETT, maximal exercise watts (W), rather than VO2, was chosen as a primary outcome parameter for a number of theoretical and practical reasons beyond the scope of this review. In the non-high risk (22) group there was a 9.9 W greater change in workload in the LVRS group relative to the control group at 6 months (þ5.5 vs.
4.4 W) and 10.9 W greater change at 2 years (þ1.7 vs.
9.2 W). The NETT further analyzed the data with respect

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Table 3 Studies Evaluating 6 MW Distance Following LVRS Nonrandomized Studies

Author

n

6 MW 6 MW Follow Surgical pre-LVRS post-LVRS up (ft) D6 MW(%) approach (ft) (months)

Short-Term Studies Miller (95a)

40

1020

101 46 26

3 6 6 6 6

Cooper (5) Kotloff (6)

Bingisser (73)

20

Bagler (80)

Ferguson (8) Date (86) Stammberger (63) O’Brien (82)

Shade (89) Leyenson (59) Sciurba (87) Yusen (70)

1125 999  241 969  305

1250 1600 1311 1181  287 1244  331

23 57 17 18 28

33 Bilateral 7 Unilateral Bilateral MS Bilateral MS Bilateral VATS Bilateral VATS Bilateral MS and VATS

3

1624a

2257a

39

41

3

774

904

17

18 33 40

6 4 3 3

1164 1081  109 1273  101 1184  46 1407  52 915  46 120139

50 18 19 31

14

3–6

646  364

899  344

39

27

3
6

984  325

1214  276

23

33 42

3
6 3

948298 892  138

1128  269 1027  121

19 15

Bilateral MS Bilateral MS Bilateral VATS Bilateral MS and VATS PaCO245 mmHg Bilateral MS and VATS PaCO2 < 45 mmHg Bilateral MS Bilateral MS

56 55 171

3 3 6

862  279 968  316 863  258 1006  253 1141  285 1315  351

12 17 15

Unilateral Bilateral Bilateral

53 37 19 26

3 6 12 6

1122  336 1288  331 1403  274 1478  261 824  374 1115  276

15 25 32 35

Bilateral MS

12 6

12 18

1269  269 1187  253

54 44

Longer-Term Studies Yusen (64)

Cordova (88)

Treadmill CPX Bilateral MS

(Continued)

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Table 3 Studies Evaluating 6 MW Distance Following LVRS (Continued ) Nonrandomized Studies

Author

n

Hamacher (66) 12b

Follow 6 MW 6 MW up pre-LVRS post-LVRS Surgical (months) (ft) (ft) D6 MW(%) approach 3

12

24 3 24 3 24 6

51 34 115

12 24 36 3

65 40 57

24 36 6

46 26 39

24 36 3

Sciurba (87)

32

Appleton (91) Ciccone (92)

30

6 24 3 24 33–66

231 225 106

6 12 60

7c 18d Gelb (32)

Flaherty (31) Bloch (90)

Fujimoto (67)

Hamacher (68)

899  85

1214  85

35

1040  118 1030  115 1161  108 1082  213 827  69 1197  59 1155  82 823  374 1269  269

16 13 5 45 40 54

886

1187  253 1371 1390 1181

44 57 60 33

935  46

1181 1322 1328  43

33 49 42

899  53

1145  75 1096  148 1210  49

23 17 35

1220  53 1122  62 1020  216 889  254 1502  79

36 25 14 NS 38

1142  291 1345  316 1341  310 1154  348

18 17 1

871

896  208 1092  82

Bilateral VATS

Bilateral VATS Bilateral Bilateral VATS

Bilateral MS and VATS

Bilateral VATS

11 Bilateral 16 Unilateral Bilateral VATS Bilateral MS

(Continued)

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Table 3 Studies Evaluating 6 MW Distance Following LVRS (Continued ) Randomized Studies

Author

n

Criner (42)

28

3

85

Geddes (83)

24

6


66  66e

Pompeo (71)

55

12 6

Goldstein (81)

55

3


53  39


46  43

782

6 9 12 6

361

24


89  39
105  39
161  39
89.4  188.1
209.1  226.3

þ53  43 þ43  43 þ7  43 þ47.3  232.7
42.7  285.1

NETT (20)

D6 MWT (control)

D6 MWT (LVRS arm)

Follow up (months)

p value

Comments

180

0.001

164  131e

0.02

Significant with crossovers analyzed Shuttle walk test;


246  66b 72  299b 102 305

0.05 < 0.0002 17 Bilateral 13 Unilateral Bilateral VATS < 0.05 < 0.05 < 0.05 — Bilateral MS and VATS —

a

12 Minute walk test. Morphologic groups: b = homogeneous; c = intermediate heterogeneous; d = markedly heterogeneous. e Estimated from figures. Abbreviations: MS, median sternotomy; VATS, video-assisted thoracoscopic surgery.

to proportion of subjects with clinically important responses ( > 10 W increase) and showed markedly greater improvements relative to controls in patients with upper lobe predominant emphysema (Fig. 2).

VI. Patient Selection As discussed, it is uncertain which outcome measures most meaningfully measure response to LVRS (e.g., spirometry, 6 MW distance, maximal watts, dyspnea ratings, and quality of life questionnaires). This is an important question, since different outcomes may have differing preoperative predictors. For example, predictors of short-term response may differ from those of a long-term response, and predictors of spirometric improvement may differ from predictors of functional response.

3–6

3–6

20 25 21 18 40 14

27

Short-Term Studies Bingisser (73)

Keller (7) Benditt (9)

Ferguson (8)

Stammberger (63)

O’Brien (82)

3

4

4.2 3

3

n

Author

14.6  3.3

11.7  1.9

0.73 (L/min) 10.0  0.4

9.7  2.0

10.0  2.5

17.02  4.6

14.7  3.3

11.8  3.0 D  0.16 (L/min) 0.76 (L/min) 12.8  0.3

13.0  2.3

VO2 VO2 post-LVRS Follow up pre-LVRS (months) (mL/kg/min) (mL/kg/min)

17%

26%

28%

3.4%

27% 25%

30%

DVO2

Non-randomized Studies

Table 4 Studies Evaluating Maximal Exercise Response Following LVRS

—

—

34.3  2

40

3719

31  12

—

—

48.9  2.4

48

52  21 D þ 17.5

47  14

Work pre- Work postLVRS LVRS

—

—

43%

20%

41% 46%

52%

Dwatts

(Continued)

Bilateral VATS Unilateral Bilateral MS Bilateral MS Bilateral VATS Bilateral MS and VATS PaCO2 > 45 mmHg Bilateral MS and VATS PaCO2