Dyspnea: Mechanisms, Measurement and Management, 2nd Edition (Lung Biology in Health and Disease Vol 208)

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DYSPNEA

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

Killian

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


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

Renwick (1999)

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

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27.

28. 29. 30.

31.

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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), and (B) with a better preserved 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 (<50% predicted) experienced greater chronic activity-related dyspnea measured by the Baseline Dyspnea Index than those with a better preserved DLCO (38,51). During exercise, a subset of these patients with reduced DLCO had a higher measured physiological dead space, greater arterial hypoxemia, and higher submaximal ventilations throughout exercise than the other group (38). Patients with clinical and physiological characteristics of emphysema appear to have greater EFL (reduced lung recoil and tethering) and greater ventilatory demand (more V/Q mismatching) which, together, would predispose them to greater acute-on-chronic hyperinflation. In this regard, it was recently determined that among patients with an identical FEV1.0, those with the lower DLCO had a more rapid rate of rise of DH (and reduction of IRV) early in exercise, with greater mechanical constraints on ventilation (reduced peak ventilation) and consequently, greater exertional dyspnea and lower symptom-limited VO2 compared with the preserved DLCO group (17) (Fig. 7). This latter group had similar restto-peak changes in DH during exercise, but hyperinflation occurred more towards the latter part of exercise as ventilation increased. E. Dyspnea and Blood Gas Abnormalities in COPD 1. Dyspnea and Hypoxia

Given that oxygen uptake and carbon dioxide elimination are among the most important functions of the respiratory system, it would not be unreasonable to assume that dyspnea is the result of increased chemoreceptor activity in response to arterial hypoxia or hypercapnia. Indeed, this assumption has prevailed since the 19th century. At that time, dyspnea was believed to result in one of two processes, ‘‘want of oxygen’’ and ‘‘carbon dioxide

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Figure 7 At a standardized level of exercise in COPD, significant correlations have been found among Borg ratings of dyspnea intensity, EELV, and NMD, i.e., the ratio of inspiratory effort (esophageal pressure relative to maximum, Pes/PImax) to the volume response (tidal volume standardized for vital capacity, VT/VC). Source: Data from Ref. 13.

retention’’ (52). The effects of arterial hypoxia on dyspnea are complex and poorly understood (53–58). The response to induced hypoxemia is also quite variable and appears to be closely related to the attendant increase in ventilation. In COPD, the level of arterial oxygen desaturation during activity correlates poorly with the intensity of dyspnea and the responses to supplemental oxygen are highly variable and cannot be predicted from pulmonary function or resting arterial oxygen saturation on room air (53–60). Critical arterial hypoxemia (PaO2 < 60 mmHg) acutely stimulates peripheral chemoreceptors, whose afferent activity may directly reach consciousness but the evidence to support this is presently inconclusive. Additionally, the resultant ventilatory stimulation, with increased central motor output and respiratory muscle activation, may contribute to breathing discomfort (61,62). Hypoxic effects on the cardiac pump and pulmonary vasculature may also have negative sensory consequences that are currently poorly understand (59,60). In the exercising subject, the sensory effects of hypoxia are even more complex (63–68). Low arterial oxygenation will alter the metabolic milieu and the level of sympathetic activation at the peripheral muscle level and consequently, influence ventilatory and sensory responses during exercise.

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Hypoxia may contribute to ventilatory muscle fatigue, which would require greater motor activation and effort for a given muscle contraction (62,69). This perception of heightened inspiratory effort may contribute to respiratory discomfort (61,62). The relative contribution of these multiple sensory inputs that arise as a consequence of hypoxia is difficult, if not impossible, to determine with precision. In order to determine the effects of hyperoxia on ventilatory mechanics and dyspnea during exercise, patients with COPD with widely varying arterial O2 tensions (PaO2 on room air, range 35–84 mmHg) were randomized to receive room air or 60% O2 (48,63). The Borg/IRV relationship remained unaltered despite large differences in PaO2 under the two conditions (Fig. 8). Added oxygen reduced submaximal ventilation by an average of 3 L/min and significantly affected the timing component of breathing (i.e., prolonged expiratory time) compared with room air. This, in turn, promoted greater lung emptying with each tidal breath, which deflated lung volumes to a level closer to the relaxation volume of the respiratory system. The net effect of this reduced hyperinflation was to increase IRV and to delay the attainment of critical mechanical limitation, NMD, and intolerable dyspnea. Somfay et al. (50) demonstrated a dosedependent relationship between added oxygen and an increase in dynamic

Figure 8 Exercise responses during hyperoxia (breathing 60% O2) and room air (RA) are shown in patients with advanced COPD. During hyperoxia, arterial oxygen saturation (SaO2) was maintained near 100% and dyspnea and exercise endurance were significantly improved during constant-load cycle exercise. The relationship between dyspnea intensity and IRV remained constant under both conditions. However, dyspnea intensity decreased and IRV increased significantly at a standardized exercise time during hyperoxia compared with RA (p < 0.05, difference at isotime). Source: Data from Ref. 63.

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IRV during exercise, with a plateau being reached at fractional inspiratory concentration of oxygen of 0.5. The mechanisms by which added oxygen influenced carotid chemoreceptor activity in normoxic COPD patients (who presumably lack an increased hypoxic drive) remain unexplained. Improved oxygenation at the peripheral muscle level delayed metabolic acidosis, which may have directly influenced chemoreceptor activation and reduced ventilation (48,63,64). Since hyperoxia has been shown to depress ventilation even in health, similar chemoreceptor influences may exist in normoxic COPD (48,65). The preservation of the Borg/IRV relationship within patients during exercise over a range of arterial oxygen tensions would support the idea that chemical drive affects dyspnea only insofar as it alters the rate of change of IRV and thus the extent of neuromechanical uncoupling. 2. Dyspnea and Hypercapnia

Hypercapnia is a powerful dyspneogenic stimulus in health (53,66–69). Many of the studies that have demonstrated a relationship between hypercapnia and dyspnea in health, did not control for the attendant increase in ventilation and respiratory muscle activation. When ventilation is controlled, the results for the research in this area are somewhat contradictory. Campbell et al. (70) observed that patients paralyzed with curare did not complain of air hunger after the inhalation of CO2. On the other hand, Banzett et al. (71) found that patients with high level quadriplegia and almost total respiratory muscle paralysis reported air hunger with increasing levels of carbon dioxide in the absence of any increase in ventilation. Most recently, Gandevia et al. (72) demonstrated that healthy subjects who were completely paralyzed with high doses of atracurium still reported severe dyspnea in response to a relatively mild hypercapnia change of 4 mmHg. Notwithstanding Campbell’s earlier results, it would seem that the existing evidence favors a direct central role for CO2 in the pathogenesis of dyspnea and, in particular, the perception of air hunger. The role of hypercapnia in dyspnea causation in COPD remains unknown. There is significant overlap in the relationship between arterial CO2 and dyspnea intensity in this population. Patients with advanced COPD often tolerate acute elevation of CO2 to high levels, presumably reflecting effective buffering. Traditionally, patients who retain CO2 are thought to be less breathless than those with a similar FEV1.0 who maintain the CO2 in the normal range (i.e., ‘‘pink puffers’’) (73–81). However, it remains unclear whether this apparent disparity in symptom intensity is the result of differences in ventilatory mechanics, chemosensitivity, or both. The bulk of evidence indicates that even patients with compensated hypercapnic respiratory acidosis have preserved, or amplified, central respiratory drive compared with emphysematous patients with normal arterial CO2

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(73–78). Many of the early studies that examined ventilatory responses to CO2 re-breathing in COPD did not specifically measure dyspnea intensity and did not account for the simultaneous changes in mechanics (i.e., dynamic hyperinflation) that were occurring (73–81). We recently examined the interaction between increases in chemical drive and mechanical loading in patients with airflow limitation (82,83). We used an airway closure analog to adjust inspiratory capacity to any desired level. Subjects completed symptom-limited testing of responses to incremental hyperinflation using this method, with or without CO2 re-breathing (84). As in the hyperoxia studies, Borg/IRV relationships were superimposed under all three conditions (Fig. 9). Dyspnea was amplified during combined chemical and mechanical loading compared with either intervention alone: this was explained by a more rapid decline in IRV with the combined interventions. The results of this study are again consistent with the notion that mechanical factors, particularly ‘‘high-end mechanics,’’ contribute importantly to respiratory discomfort, and that increases in chemical drive merely accentuate the

Figure 9 Stable patients with COPD (n ¼ 8) breathed on a customized breathing circuit that induced mechanical hyperinflation (HI). This circuit was an airway closure analog that permitted stepwise increases in EELV (decreases in IC) to the desired level, with or without addition of CO2. Tests continued to a symptom-limited endpoint. During HI and HI þ CO2 tests, EELV increased by 0.96
0.20 and 0.70
0.14 L, respectively. During HIþCO2 tests, arterial CO2 increased by 19
3 mmHg and patients stopped the test significantly earlier than with HI alone. Dyspnea–IRV relationships were similar in both tests despite differences in EELV (p < 0.01), ventilation (p < 0.05), tidal volume (p < 0.0005), arterial CO2 (p < 0.0005) and test duration (p < 0.05). During chemical and mechanical loading, alone or in combination, dyspnea intensity correlated best with the IRV decline. Source: Data from Ref. 84.

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dynamic mechanical abnormalities and, thus, intensify dyspnea by worsening neuromechanical coupling. F. The Influence of Co-Morbidities on Dyspnea

In its later stages, COPD becomes a complex multicomponent disease and raises the possibility that the expression of dyspnea is shaped by sensory inputs from a variety of additional sources that varies from patient to patient. Secondary pulmonary hypertension and its negative cardiac consequences may contribute to respiratory discomfort via mechanisms that are currently not understood (59,60,85–89). Moreover, coronary artery disease is a common disabling co-morbidity in COPD. During exercise, acute-onchronic lung hyperinflation may seriously impair cardiac performance with possible negative sensory consequences (88–90). Ventilatory muscle weakness as a result of nutritional problems, overuse of oral corticosteroids, or electrolyte imbalance has obvious implications for dyspnea causation (91– 93). The true prevalence of inspiratory muscle weakness in the COPD population is unknown and the response to specific inspiratory muscle training has been inconsistent (94). Nevertheless, a subset of patients do appear to have measurable weakness and derive symptomatic benefit from muscle training (95–97). Co-existent obesity or kyphosis (as a result of osteoporosis) would each compound restrictive ventilatory mechanics in COPD and likely amplify exertional dyspnea though this postulation requires experimental verification. Anxiety and depression are all too common in advanced COPD and can greatly influence the affective response to the symptom of dyspnea. III. Neurophysiology of Dyspnea in COPD In virtually all of the circumstances where dyspnea is encountered in COPD patients, the drive to breathe is increased and the mechanical response of the respiratory system is impaired. There appears to be no unique peripheral or central source for this complex, multidimensional symptom. An increased reflexic central drive in response to acute chemical changes certainly gives rise to respiratory discomfort, but this effect cannot easily be separated from sensory inputs arising from the attendant alterations in ventilation and muscle activity or overall mechanical output. There is a multitude of sensory receptors throughout the respiratory system: in the airway, lung parenchyma and its vasculature, as well as the ventilatory muscles and tendons, whose afferent inputs travel via the vagus, spinal, and phrenic nerves (68,98–108). All of these are potentially implicated in the genesis of unpleasant sensation. However, there is little current evidence of a direct dyspneogenic role for these peripheral respiratory receptors. Extensive vagal denervation does not modify sensory responses to chemical and

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mechanical loading or exercise in humans, suggesting that the role of the vagus in dyspnea causation is less important than previously thought (109–112). The main role of peripheral sensory receptors throughout the respiratory system appears to be to provide precise proprioceptive and kinesthetic feedback about change in respired airflow, lung and thoracic cage volumes, muscle tension, and displacement during each tidal breath (104–107). Muscle spindles and Golgi tendon organs would seem to be particularly well positioned to act as the proximate source of sensory feedback under conditions of acute mechanical loading (69,108,113,114). Mechanoreceptors in the chest wall are thought to play a pivotal role in the optimization of breathing pattern to minimize dyspnea during loading or during increased ventilation from whatever cause (105,106,113,114). Stimulation of chest wall mechanoreceptors by vibration has been shown to influence dyspnea in COPD (102). These receptors, whose afferent inputs travel directly to the cortex, are thought to provide information concerning tidal thoracic displacement and breathing pattern (104,107,113–115). Clearly, there is considerable redundancy in sensory systems that ensure that adequate feedback is preserved, even in the face of substantial attenuation (by disease or iatrogenically) of various sensory inputs. IV. Putative Mechanisms of Dyspnea During Dynamic Hyperinflation The neurophysiological mechanisms responsible for dyspnea caused by acute-on-chronic hyperinflation in COPD remain speculative. Possible explanations include increased contractile muscle effort and/or NMD of the ventilatory system. A. Inspiratory Muscle Effort and Dyspnea

Several investigators have suggested that dyspnea may reflect greater respiratory muscle activity or effort, and that the sensation arises from awareness of the efferent motor command from the central nervous system to the respiratory muscles (116–119). It has been hypothesized, based on electrophysiological studies in the decerebrate cat, that this awareness arises from a corollary discharge from respiratory neurons in the brainstem and motor cortex, to the sensory cortex (120,121). The sense of muscle effort reflects the magnitude of this corollary discharge and is dependant not only on the absolute magnitude of the load and its duration, but also on the relative magnitude of the load compared to the maximum capacity of the muscle (122,123). For example, the act of moving a light load may be perceived as requiring significant effort if muscle weakness is present (122,124). With regards to the respiratory muscles, inspiratory effort is proportional to the intrathoracic pressures generated during tidal breathing

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(which can be measured by esophageal balloon) and the peak pressures generated during a maximum inspiratory effort. This can be expressed as a ratio (Pes:PImax) (120–123). Increased contractile muscle effort would appear to explain the presence of dyspnea in a wide variety of clinical settings. Several studies have noted a correlation between dyspnea and indices of respiratory muscle effort when applying external loads to normal subjects (118,119). It has also been demonstrated that healthy subjects overestimate the magnitude of an inspiratory load in the setting of respiratory muscle fatigue (124). Patients with neuromuscular weakness may complain of dyspnea because the respiratory muscle load associated with tidal breathing may represent a much greater proportion of their respiratory muscle capacity (increased Pes:PImax ratio). Statistical correlations between intensity of dyspnea, measured by the Borg scale, and the increased Pes:PImax ratio support the notion that perceived heightened or disproportionate effort is pervasive as a contributor to dyspnea across health and disease. However, the perception of respiratory muscle effort is not always synonymous with dyspnea, which, as suggested by its definition, has a distressing or uncomfortable aspect. Several studies on respiratory muscle loading have shown that external loads can be sensed and quantified, but it is important to acknowledge that the respiratory sensations (including increased sense of effort) were not universally reported as distressing or uncomfortable. Furthermore, carefully controlled studies (71,72) have shown that dyspnea can occur even in the absence of increased muscle activation and respiratory effort. Studies conducted in asthmatics during acute bronchoconstriction, or in patients with COPD, have shown that some patients who receive mechanical ventilatory assistance (pressure support) may continue to experience severe dyspnea despite effective reduction in tidal esophageal pressure swings (i.e., reduced effort) (125–127). Clearly, in such patients there is another source of dyspnea not addressed by ventilatory muscle unloading. B. NMD and Dyspnea in COPD

The respiratory system has a remarkable capacity to optimize ventilatory output and to attenuate breathing discomfort under a number of intrinsic or experimentally imposed loading conditions (128–130). Poon (131,132) and Poon et al. (133) have demonstrated that breathing pattern responses to acute mechanical and chemical loading and exercise can be predicted from a model that incorporates conventional equations of steady-state gas exchange, as well as lung mechanics, measures of chemosensitivity and inspiratory neural drive. Thus, the ventilatory output selected under loading is directed toward minimizing the mechanical and metabolic cost of breathing and presumably the avoidance of unpleasant respiratory sensations. Breathing pattern and respiratory comfort are optimized under acute stress

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via integrated sensory feedback from an abundance of sensory receptors that convey precise information about change from the status quo in the chemical or metabolic milieu or in the mechanical and muscle pump performance characteristics of the ventilatory system. This ‘‘optimization’’ theory implies that under conditions of acute or chronic chemical or mechanical loading, the respiratory system has evolved to preserve, insofar as this is possible, a harmonious relation between the central drive to breathe and the mechanical/muscular response of the system (i.e., neuromechanical coupling). In chronic respiratory disease, temporal adaptation ensures that both breathing comfort and ventilatory output are optimized in the face of the persisting intrinsic mechanical and/or chemical derangements. Even patients with advanced gas exchange and mechanical abnormalities often do not experience dyspnea during quiet, resting breathing. However, during the acute physiological stress of exercise, these adaptive mechanisms are overwhelmed and a disparity (or disharmony) develops between central respiratory drive and the simultaneous mechanical response (i.e., NMD), and severe breathing discomfort is perceived. The theory of NMD is difficult to prove because we currently lack the ability to accurately measure the amplitude of central drive and afferent inputs from peripheral receptors. A number of studies, however, support the notion that NMD may form the basis, at least in part, for the perception of dyspnea (13,101,129,134–136). In healthy humans, when tidal volume expansion is constrained, either voluntarily or by externally imposed mechanical impedance (e.g., chest wall strapping), in the setting of an increased chemical drive to breathe, severe dyspnea is provoked. Combined chest wall strapping and dead-space loading in healthy subjects during exercise cause intense dyspnea that is qualitatively and quantitatively similar to that experienced by patients with COPD at the peak of exercise (i.e., unsatisfied inspiration) (137). Dyspnea intensity during exercise in COPD was found to correlate well with the high ratio of inspiratory muscle effort (measured by esophageal pressure) to tidal volume—a crude index of NMD. To the extent that esophageal pressure swings do not reflect the amplitude of neural drive in the setting of abnormal mechanic impedances, the calculated effort–displacement ratio is an underestimation of the true NMD. Relief of dyspnea in COPD patients who adopted a leaning forward position was shown by Sharp et al. (138) to be associated with more efficient conversion of electrical activation of the diaphragm to force generation by this muscle in this favored position. Recent studies have demonstrated that exertional dyspnea relief following bronchodilator treatment in COPD was associated with improved dynamic ventilatory mechanics (i.e., increased inspiratory capacity and increased dynamic IRV) (34,39,40,43). Pharmacological lung volume reduction at rest results in a delay in reaching the threshold for intolerable dyspnea during incremental hyperinflation imposed by exercise (Fig. 10) or by mechanical limitation using an airway

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Figure 10 Mean
SEM responses to bronchodilator therapy (salmeterol, 50 mg) are shown in 10 patients with COPD. Postbronchodilator (BD), resting IC increased by 0.40
0.08 L (p ¼ 0.001). Post-BD during exercise, patients were able to tolerate significantly larger decreases in IC before exceeding an IRV ‘‘threshold’’ (i.e., IRV <20% predicted TLC or <1 L) and developing intolerable dyspnea. Under both conditions, increased dyspnea was closely associated with a reduced IRV. Source: Data from Ref. 139.

closure analog (34,139). Thus, the dyspnea/IRV relationship during both of these interventions was unaltered by prior bronchodilatation and lung deflation. The reduced resting EELV means a delay in reaching a critically low IRV where NMD approaches the maximal level; intolerable dyspnea is therefore delayed.

C. Relieving Dyspnea: A Physiological Rationale

The NMD theory of dyspnea provides a useful construct for the development of therapeutic strategies in COPD. Thus, interventions that reduce central drive, improve the mechanical/muscular response for a given drive or achieve both of these effects in combination should alleviate dyspnea. Opiates, oxygen therapy, and exercise training (via reduced metabolic acidosis) all reduce central drive—the reduced ventilatory requirement has salutary effects in mechanically compromised patients (74–79). Pharmacological and surgical lung volume reduction improve the mechanical response of the respiratory system for a given drive (34,39,40,43,140– 144). Combination treatments that both reduce central drive and improve dynamic mechanics should, theoretically, have greater impact on dyspnea but this remains to be studied.

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V. Summary Our knowledge of the pathophysiological mechanisms of dyspnea in COPD continues to grow. Inspiratory difficulty and the sense of unsatisfied inspiration represent prominent qualitative dimensions of exertional dyspnea and likely have their origins in the derangements of dynamic ventilatory mechanics peculiar to this disease. Correlative analysis has shown that the intensity of dyspnea during exercise is closely associated with a number of inter-related physiological variables including the extent of dynamic hyperinflation, the ventilation (relative to capacity), inspiratory effort (relative to maximum), and the effort–displacement ratio. The validity of these associations is supported by studies that have shown that relief of dyspnea following a number of therapeutic interventions was found to be closely associated with reductions in DH, ventilation and inspiratory effort, and an increased ability to expand VT. Recent studies have indicated that the Borg/IRV relationship remains remarkably constant in COPD in the face of wide variations in the prevailing ventilation, the inspiratory capacity (postbronchodilator), PaO2, and PaCO2. This suggests that restrictive mechanical factors importantly shape the experience of respiratory discomfort during exercise in COPD. Thus, perceived inspiratory difficulty may arise during exercise, in part, because of an inability to expand VT appropriately in response to an increasing central drive to breathe. The neurophysiological underpinnings of dyspnea in COPD remain speculative. There is currently little evidence that peripheral sensory afferent inputs from the respiratory system directly give rise to breathing discomfort in COPD. Their primary role appears to be to provide precise, instantaneous, integrated feedback on the dynamic mechanical output of the ventilatory system in relation to neural drive. Similarly, there is inconclusive evidence that acute alterations in chemical stimuli (hypercapnia or hypoxia) directly influence dyspnea intensity, independent of the attendant simultaneous changes in dynamic mechanics and ventilatory muscle activation. Sense of heightened inspiratory effort is pervasive in COPD during exercise and likely contributes to this multidimensional symptom. Finally, the NMD hypothesis is intuitively appealing and states that inspiratory difficulty (unsatisfied inspiration) in COPD is not only a function of the amplitude of central neural drive, but is also importantly modulated by peripheral sensory feedback from multiple mechanoreceptors throughout the respiratory system. References 1. Pride NB, Macklem PT. Lung mechanics in disease. In: Fishman AP, ed. Handbook of Physiology, Section 3, Vol III, Part 2: The Respiratory System. Bethesda, MD: American Physiological Society, 1986:659–692.

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2. Hyatt RE. Expiratory flow limitation. J Appl Physiol 1983; 55:1–8. 3. O’Donnell DE, Sanii R, Anthonisen NR, Younes M. The effect of airway dynamic compression on breathing pattern and respiratory sensation in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1987; 135:912–918. 4. Leaver DG, Pride NB. Flow volume curves and expiratory pressures during exercise in patients with chronic airflow obstruction. Scand J Respir Dis 1971; 42(suppl):23–27. 5. Vinegar A, Sinnett EE, Leith DE. Dynamic mechanisms determine functional residual capacity in mice. J Appl Physiol 1979; 46:867–892. 6. O’Donnell DE, Webb KA. Exertional breathlessness in patients with chronic airflow limitation: the role of hyperinflation. Am Rev Respir Dis 1993; 148:1351–1357. 7. O’Donnell DE, Lam M, Webb KA. Measurement of symptoms, lung hyperinflation and endurance during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 158:1557–1565. 8. Grimby G, Bunn J, Mean J. Relative contribution of rib cage and abdomen to ventilation during exercise. J Appl Physiol 1968; 24:159–166. 9. Potter WA, Olafsson S, Hyatt RE. Ventilatory mechanics and expiratory flow limitation during exercise in patients with obstructive lung disease. J Clin Invest 1971; 50:910–919. 10. Dodd DS, Brancatisano T, Engel LA. Chest wall mechanics during exercise in patients with severe chronic airway obstruction. Am Rev Respir Dis 1984; 129:33–38. 11. Stubbing DG, Pengelly LD, Morse JLC, Jones NL. Pulmonary mechanics during exercise in subjects with chronic airflow obstruction. J Appl Physiol 1080; 49:511–515. 12. Yan S, Kaminski D, Sliwinski P. Reliability of inspiratory capacity for estimating end-expiratory lung volume changes during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1997; 156:55–59. 13. O’Donnell DE, Chau LKL, Bertley JC, Webb KA. Qualitative aspects of exertional breathlessness in chronic airflow limitation: pathophysiologic mechanisms. Am J Respir Crit Care Med 1997; 155:109–115. 14. Cassart M, Pettiaux N, Genevois PA, Paiva M, Estenne M. Effect of chronic hyperinflation on diaphragm length and surface area. Am J Respir Crit Care Med 1997; 156:504–508. 15. McKenzie DK, Gorman RB, Tolman J, Pride NB, Gandevia SC. Estimation of diaphragm length in patients with severe chronic obstructive pulmonary disease. Respir Physiol 2000; 123:225–234. 16. Similowski T, Yan S, Gauthier AP, Macklem PT, Bellemare F. Contractile properties of the human diaphragm during chronic hyperinflation. N Engl J Med 1991; 325:917–923. 17. O’Donnell DE, Revill S, Webb KA. Dynamic hyperinflation and exercise intolerance in COPD. Am J Respir Crit Care Med 2001; 164:770–777. 18. Tantucci C, Duguet A, Similowski T, Zelter M, Derenne JP, Milic-Emili J. Effect of salbutamol on dynamic hyperinflation in chronic obstructive pulmonary disease patients. Eur Respir J 1998; 12:799–804.

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19. Diaz O, Villafranca C, Ghezzo H, Borzone G, Leiva A, Milic-Emil J, Lisboa C. Role of inspiratory capacity on exercise tolerance in COPD patients with and without tidal expiratory flow limitations at rest. Eur Respir J 2000; 16: 269–275. 20. Eltayara L, Becklake MR, Volta CA, Milic-Emili J. Relationship between chronic dyspnea and expiratory flow limitation in patients with chronic obstructive pulmonary disease. Am J Crit Care Med 1996; 154:1726–1734. 21. Younes M. Determinants of thoracic excursions during exercise. In: Whipp BJ, Wasserman K, eds. Lung Biology in Health and Disease, Vol 42: Exercise, Pulmonary Physiology and Pathophysiology. New York: Marcel Dekker, 1991:1–65. 22. O’Donnell DE, Webb KA. Exercise. In: Calverley PMA, MacNee W, Pride NB, Rennard SI, eds. Chronic Obstructive Pulmonary Disease. Chapter 18, 2003:243–269. 23. O’Donnell DE. Ventilatory limitations in chronic obstructive pulmonary disease. Med Sci Sports Exer 2001; 33:S647–S655. 24. Barbera JA, Roca J, Ramirez J, Wagner PD, Usetti P, Rodriguez-Roisin R. Gas exchange during exercise in mild chronic obstructive pulmonary disease: correlation with lung structure. Am Rev Respir Dis 1991; 144:520–525. 25. Dantzker DR, D’Alonzo GE. The effect of exercise on pulmonary gas exchange in patients with severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1986; 134:1135–1139. 26. Dillard TA, Piantadosi S, Rajagopal KR. Prediction of ventilation at maximal exercise in chronic airflow obstructive. Am Rev Respir Dis 1985; 132: 230–235. 27. O’Donnell DE, Lam M, Webb KA. Measurement of exertional symptoms, dynamic hyperinflation and exercise endurance. Am J Respir Crit Care Med 1998; 158:1557–1565. 28. Begin P, Grassino A. Inspiratory muscle dysfunction and chronic hypercapnia in chronic obstructive pulmonary disease. Am Rev Respir Dis 1991; 143: 905–912. 29. Burrows B, Earle RH. Course and prognosis of chronic obstructive lung disease: a prospective study of 200 patients. N Engl J Med 1969; 280:397–404. 30. Altose MD, McCauley WC, Kelsen SG, Cherniack NS. Effects of hypercapnia and inspiratory flow-resistive loading on respiratory activity in chronic airways obstruction. J Clin Invest 1977; 59:500–507. 31. Light RW, Mahutte CK, Brown SE. Etiology of carbon dioxide retention at rest and during exercise in chronic airflow obstruction. Chest 1988; 84:61–67. 32. DeTroyer A, Leeper JB, McKenzie D, Gandevia S. Neural drive to the diaphragm in patients with severe COPD. Am J Respir Crit Care Med 1997; 155:1335–1340. 33. O’Donnell DE, D’Arsigny C, Fitzpatrick M, Webb KA. Exercise hypercapnia in advanced COPD: The role of lung hyperinflation. (Accompanying editorial by J. Dempsey. 634–635). Am J Respir Crit Care Med 2002; 166:663–668. 34. O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol on the ventilatory response to exercise in COPD. Eur Resp J 2004; 24:86–94.

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35. American Thoracic Society. Dyspnea. Mechanisms, assessment and management: a consensus statement. Am J Respir Crit Care Med 1999; 159:321–340. 36. Simon PM, Schwartzstein RM, Weiss JW, LaHive K, Fencl V, Teghtsoonian M, Weinberger SE. Distinguishable sensations of breathlessness induced in normal volunteers. Am Rev Respir Dis 1989; 140:1021–1027. 37. Simon PM, Schwartzstein RM, Weiss JW, Fencl V, Teghtsoonian M, Weinberger SE. Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 1990; 142:1009–1014. 38. O’Donnell DE, Webb KA. Breathlessness in patients with severe chronic airflow limitation: physiological correlates. Chest 1992; 102:824–831. 39. O’Donnell DE, Lam M, Webb KA. Spirometric correlates of improvement in exercise performance after anticholinergic therapy in COPD. Am J Respir Crit Care Med 1999; 160:424–449. 40. 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. 41. Martinez FJ, Montes de Oca M, Whyte RI, Stetz J, Gay SE, Celli BR. Lungvolume reduction improves dyspnea, dynamic hyperinflation and respiratory muscle function. Am J Respir Crit Care Med 1997; 155:1984–1990. 42. O’Donnell DE, Bertley J, Webb KA, Conlan AA. Mechanisms of relief of exertional breathlessness following unilateral bullectomy and lung volume reduction surgery in advanced chronic airflow limitation. Chest 1996; 110:18–27. 43. O’Donnell DE, Flu¨ge T, Gerken F, Hamilton A, Webb K, Aguilaniu B, Make B, Magnussen H. Effect of tiotropium on lung hyperinflation, dyspnea and exercise tolerance in COPD. Eur Resp J 2004; 23:832–840. 44. Jones N, Jones G, Edwards RHT. Exercise tolerance in chronic airway obstruction. Am Rev Respir Dis 1971; 103:477–491. 45. Levison H, Cherniack RM. Ventilatory cost of exercise in chronic obstructive pulmonary disease. J Appl Physiol 1968; 25:21–27. 46. Jones NL. Pulmonary gas-exchange during exercise in patients with chronic airway obstruction. Clin Sci 1966; 31:39–50. 47. O’Donnell DE, McGuire M, Samis L, Webb KA. The impact of exercise reconditioning on breathlessness in severe chronic airflow limitation. Am J Respir Crit Care Med 1995; 152:2005–2013. 48. 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. 49. Light RW, Muro JR, Sato RI, Stansbury DW, Fischer CE, Brown SE. Effects of oral morphine on breathlessness and exercise tolerance in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 139: 126–133. 50. Somfay A, Porszasz J, Lee SM, Casaburi R. Dose-response effect of oxygen on hyperinflation and exercise endurance in non-hypoxemic COPD patients. Eur Respir J 2001; 18:77–84. 51. O’Donnell DE. Assessment and management of dyspnea in chronic obstructive pulmonary disease. In: Lenfant C, Similowski T, Whitelaw WA, Derenne J-P.

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54.

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56. 57.

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61. 62. 63.

64.

65. 66.

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68. Zechman FR Jr, Wiley RL. Afferent inputs to breathing: respiratory sensation: In: Fishman AP, ed. Handbook of Physiology, Section 3, Vol II, Part 2: The Respiratory System. Bethesda, MD: American Physiological Society, 1986:449–474. 69. Gandevia SC. The perception of motor commands on effort during muscular paralysis. Brain 1982; 105:151–195. 70. Campbell EJM, Godfrey S, Clark TJH, Freedman S, Norman J. The effect of muscular paralysis induced by tubocurarine on the duration and sensation of breath-holding during hypercapnia. Clin Sci 1969; 36:323–328. 71. Banzett RB, Lansing RW, Reid MB, Brown R. ‘Air Hunger’ arising from increasing PCO2 in mechanically ventilated quadriplegics. Respir Physiol 1989; 76:53–68. 72. Gandevia SC, Killian K, McKenzie DK, Crawford M, Allen GM, Gorman RB, Hales JP. Respiratory sensations, cardiovascular control, kinaesthesia and transcranial stimulation during paralysis in humans. J Physiol 1993; 470:85–107. 73. Cherniack RM, Snidal DP. The effect of obstruction to breathing on the ventilatory response to CO2. J Clin Invest 1956; 35:1286–1290. 74. DeTroyer A, Leeper JB, McKenzie DK, Gandevia SC. Neural drive to the diaphgram in patients with severe COPD. Am J Respir Crit Care Med 1997; 155:1335–1340. 75. Lourenco RV, Miranda JM. Drive and performance of the ventilatory apparatus in chronic obstructive lung disease. N Engl J Med 1968; 279:53–59. 76. Gorini MD, Spinelli A, Duranti R, Gigliotti F, Scano G. Neural respiratory drive and neuromuscular coupling in patients with chronic obstructive pulmonary disease (COPD). Chest 1990; 98:1179–1186. 77. Scano G, Spinelli A, Duranti R, et al. Carbon dioxide responsiveness in COPD patients with and without chronic hypercapnia. Eur Respir J 1995; 8:78–85. 78. Lopata M, Onal E, Cromydas G. Respiratory load compensation in chronic airway obstruction. J Appl Physiol 1985; 59:1947–1954. 79. Costello R, Deegan P, Fitzpatrick M, McNicholas WT. Reversible hypercapnia in chronic obstructive pulmonary disease: a distinct pattern of respiratory failure with a favorable prognosis. Am J Med 1997; 102:239–244. 80. Gorini M, Misuri G, Corrado A, et al. Breathing pattern and carbon dioxide retention in severe chronic obstructive pulmonary disease. Thorax 1996; 51:677–683. 81. Haluszka J, Chartrand KA, Grassino A, Milic-Emili J. Intrinsic PEEP and arterial PCO2 in stable patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1990; 141:1194–1197. 82. Lougheed MD, Palumbo G, Lawson B, McBride I, Webb KA, O’Donnell DE. Blunted sensory responses to hyperinflation (HI) in patients with life threatening asthma (LTA). Am J Respir Crit Care Med 2002; 165:A266. 83. Palumbo G, Webb KA, O’Donnell DE. Mechanisms of dyspnea during lung hyperinflation in COPD. Am J Respir Crit Care Med 2002; 165:A503.

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84. O’Donnell DE, Webb KA, Verton LE. Effects of hypercapnia on dyspnea during acute lung hyperinflation in COPD (abs). Am J Respir Crit Care Med 2004; 169:A760. 85. Light RW, Mintz WM, Linden GS, Brown SE. Hemodynamics of patients with severe chronic obstructive pulmonary disease during progressive upright exercise. Am Rev Respir Dis 1984; 130:391–395. 86. Vissa CD, Lynch JP, Ochoa LL, Richardson G, Trulock EP. Right and left ventricular dysfunction in patients with severe pulmonary disease. Chest 1998; 113:576–583. 87. Oswald-Mammosser M, Apprill M, Bachez P, Ehrhart M, Weitzenblum E. Pulmonary hemodynamics in chronic obstructive pulmonary disease of the emphysematous type. Respiration 1991; 58:304–310. 88. Morrison DA, Adock K, Collins CM, Goldman S, Caldwell JH, Schwartz MI. Right ventricular dysfunction and the exercise limitation of chronic obstructive pulmonary disease. J Am Coll Cardiol 1987; 9:1219–1229. 89. Dimopoulou I, Tsintzas OK, Daganou M, Cokkinos DV, Tzelepis GE. Contribution of lung function to exercise capacity in patients with chronic heart failure. Respiration 1999; 66:144–149. 90. Koskolou MD, Calbet JA, Radegran G, Roach RC. Hypoxia and the cardiovascular response to dynamic knee-extensor exercise. Am J Physiol 1997; 272:H2655–H2663. 91. Rochester DF. The diaphragm in COPD: better than expected, but not good enough. N Engl J Med 1991; 325:961–962. 92. Rochester DF, Braun NMT. Determinants of maximal inspiratory pressure in chronic obstructive pulmonary disease. Am Rev Respir Dis 1970; 132:42–47. 93. Killian KJ, Jones NJ. Respiratory muscles and dyspnea. Clin Chest Med 1989; 2:37–48. 94. Smith K, Cook D, Guyatt GH, Madhoven J, Oxman AD. Respiratory muscle training in chronic airflow obstruction. Am Rev Respir Dis 1992; 145: 533–539. 95. Harver A, Mahler DA, Daubenspeck JA. Targeted inspiratory muscle training improves respiratory muscle function and reduces dyspnea in chronic obstructive pulmonary disease. Ann Intern Med 1989; 111:117–124. 96. Kim J, Larson J, Covery M, Vitalo C, Alex C, Patel M. Inspiratory muscle training in patients with chronic obstructive pulmonary disease. Nurs Res 1993; 42:356–362. 97. Lisboa C, Munoz 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. 98. Raj H, Singh VK, Anand A, Paintal AS. Sensory origin of lobeline-induced sensations: a correlative study in man and cat. J Physiol 1995; 482:235–246. 99. Guz A, Noble MIM, Widdicombe JG, Trenchard D, Mushin WW, Makey AR. The role of vagal and glossopharyngeal afferent nerves in respiratory sensation, control of breathing and arterial pressure regulation in conscious man. Clin Sci 1966; 30:161–170.

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100. Bradley GW, Hale T, Pimble J, Rowlandson R, Noble MIM. Effect of vagotomy on the breathing pattern and exercise ability in emphysematous patients. Clin Sci 1982; 62:311–319. 101. Fowler WS. Breaking point of breath-holding. J Appl Physiol 1954; 6: 539–545. 102. Sibuya M, Yamada M, Kanamara A, Tanaka K, Suzuki H, Noguchi E, Altose MD, Homma I. Effect of chest wall vibration on dyspnea in patients with chronic respiratory disease. Am J Respir Crit Care Med 1994; 149: 1235–1240. 103. Paintal AS. Vagal sensory receptors and their reflex effects. Physiol Rev 1973; 53:159–227. 104. Coleridge HM, Coleridge JCG. Reflexes evoked from tracheobronchial tree and lungs. In: Cherniack NS, Widdicombe JG, eds. Handbook of Physiology: Control of Breathing. Vol 2, Part 2, Section 3. Bethesda, MD: American Physiology Society, 1986:395–430. 105. Homma I, Obata T, Sibuya M, Uchida M. Gate mechanisms in breathlessness caused by chest wall vibration in humans. J Appl Physiol 1984; 56:8–11. 106. Shannon R. Reflexes from respiratory muscles and costovertebral joints. In: Cherniack NS, Widdicombe JG, eds. Handbook of Physiology: Control of Breathing. Vol. 2, Part 1, Section 3. Bethesda, MD: American Physiology Society, 1986:431–448. 107. Newsom-Davies J, Stagg D. Interrelationships of the volume and time components of individual breaths in normal man. J Physiol (Lond) 1975; 245:481–488. 108. Grodins FS. Analysis of factors concerned in regulation of breathing in exercise. Physiol Rev 1950; 30:220–239. 109. Sanders MH, Owens GR, Sciurba FC, et al. Ventilation and breathing pattern during progressive hypercapnia and hypoxia after human heart–lung transplantation. Am Rev Respir Dis 1989; 140:38–40. 110. Kagawa FT, Duncan SR, Theodore J. Inspiratory timing of heart–lung transplant recipients during progressive hypercapnia. J Appl Physiol 1991; 71:945–950. 111. Tapper DP, Duncan SR, Kraft S, Kagawa FT, Marshall S, Theodore J. Detection of inspiratory resistive loads by heart–lung transplant recipients. Am Rev Respir Dis 1992; 145:458–460. 112. Frost AR, Zamel N, McClean P, Grossman R, Patterson GA, Maurer JR. Hypercapnic ventilatory response in recipients of double-lung transplants. Am Rev Respir Dis 1992; 146:1610–1612. 113. Manning HL, Basner R, Ringler J, et al. Effect of chest wall vibration on breathlessness in normal subjects. J Appl Physiol 1991; 71:175–181. 114. Remmers JE. Inhibition of inspiratory activity by intercostals muscle afferents. Respir Physiol 1970; 10:358–383. 115. Gandevia SC, Macefield G. Projection of low threshold afferents from human intercostal muscles to the cerebral cortex. Respir Physiol 1989; 77:201. 116. Katz-Salamon M. Respiratory psychophysics: a methodological overview. In: von Euler C, Katz-Salamon M, eds. Respiratory Psychophysiology. New York: Stockton Press, 1988:65–78.

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117. Killian KJ, Bucens DD, Campbell EJM. The effect of patterns of breathing on the perceived magnitude of added loads to breathing. J Appl Physiol 1982; 52:578–584. 118. Killian KJ, Mahutte CK, Howell JBL, Campbell EJM. Effect of timing, flow, lung volume and threshold pressures on resistive load detection. J Appl Physiol 1980; 49:958–963. 119. Killian KJ, Gandevia SC, Summers E, Campbell EJM. Effect of increased lung volume on perception of breathlessness, effort and tension. J Appl Physiol 1984; 57:686–691. 120. Chen Z, Eldridge FL, Wagner PG. Respiratory-associated thalamic activity is related to level of respiratory drive. Respir Physiol 1992; 90:99–113. 121. Chen Z, Eldridge FL, Wagner PG. Respiratory-associated rhythmic firing of midbrain neurons in cats: relation to level of respiratory drive. J Physiol 1991; 37:305–325. 122. Bradley TD, Chartrand DA, Fitting JW, Killian KJ, Grassino A. The relation of inspiratory effort sensation to fatiguing patterns of the diaphragm. Am Rev Respir Dis 1986; 134:1119–1124. 123. el Manshawi A, Killian KJ, Summers E, Jones NL. Breathlessness during exercise with and without resistive loading. J Appl Physiol 1986; 61:896–905. 124. Gandevia SC, Killian KJ, Campbell EJM. The effect of respiratory muscle fatigue in respiratory sensations. Clin Sci 1981; 60:463–466. 125. O’Donnell DE, Webb KA, Revill SM. Mechanical ventilation during exercise in COPD. In: Jobin J, Maltais F, Poirier P, LeBlanc P, Simard C, eds. Advancing the Frontiers of Cardiopulmonary Rehabilitation. Champaign: Human Kinetics, 2002:91–105. 126. Shinder N, Webb KA, O’Donnell DE. Relief of exertional dyspnea during different modes of non-invasive ventilation in COPD (abs). Am J Respir Crit Care Med 1995; 152:A912. 127. Lougheed MD, Webb K, O’Donnell DE. Breathlessness during induced hyperinflation in asthma: role of the inspiratory threshold load. Am J Respir Crit Care Med 1995; 152(3):911–920. 128. Zechman FW, Muza SR, Davenport PW, Wiley RL, Shelton R. Relationship of transdiaphragmatic pressure and latencies for detecting added inspiratory loads. J Appl Physiol 1985; 58:236–243. 129. Xu F, Taylor RF, McLarney T, Lee L-Y, Frazier DT. Respiratory load compensation. 1 Role of the cerebrum. J Appl Physiol 1993; 74:853–858. 130. Oliven A, Kelsen SG, Deal EC, Cherniack NS. Respiratory pressure sensation. Relationship to changes in breathing pattern in patients with chronic obstructive lung disease. Am Rev Respir Dis 1985; 132:1214–1218. 131. Poon CS. Ventilatory control n hypercapnia and exercise: optimization hypothesis. J Appl Physiol 1987; 62:2447–2459. 132. Poon CS. Effects of inspiratory resistive load on respiratory control in hypercapnia and exercise. J Appl Physiol 1989; 66:2391–2399. 133. Poon CS, Lin S-L, Knudson OB. Optimization character of inspiratory neural drive. J Appl Physiol 1992; 72:2005–2017.

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134. Chonan T, Mulholland MB, Cherniack NS, Altose MD. Effect of voluntary constraining of thoracic displacement during hypercapnia. J Appl Physiol 1987; 63:1822–1828. 135. Campbell EJM, Howell JBL. The sensation of breathlessness. Br Med Bull 1963; 18:36–40. 136. Schwartzstein RM, Simon PM, Weiss JW, Fencl V, Weinberger SE. Breathlessness induced by dissociation between ventilation and chemical drive. Am Rev Respir Dis 1989; 139:1231–1237. 137. O’Donnell DE, Hong HH, Webb KA. Effects of chest wall restriction and deadspace loading on dyspnea and exercise tolerance in healthy normals. J Appl Physiol 2000; 88:1859–1869. 138. Sharp JT, Druz WS, Moisan T, Foster J, Machnach W. Postural relief of dyspnea in severe COPD. Am Rev Respir Dis 1980; 122:201–211. 139. O’Donnell DE, Webb KA. Pharmacological volume reduction delays the threshold for intolerable dyspnea during acute hyperinflation in COPD (abs). Am J Respir Crit Care Med 2003; 167(7):A293. 140. Young J, Fry-Smith A, Hyde C. Lung volume reduction surgery (LVRS) for chronic obstructive pulmonary disease (COPD) with underlying severe emphysema. Thorax 1999; 54:779–789. 141. Martinez FJ, de Oca MM, Whyte RI, Stetz J, Gay SE, Celli BR. Lung-volume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function. Am J Respir Crit Care Med 1997; 155:1984–1990. 142. Tschernko EM, Gruber EM, Jaksch P, et al. Ventilatory mechanics and gas exchange during exercise before and after lung volume reduction surgery. Am J Respir Crit Care Med 1998; 158:1424–1431. 143. Shade DJ, Cordova F, Lando Y, et al. Relationship between resting hypercapnia and physiologic parameters before and after lung volume reduction surgery in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159:1405–1411. 144. Laghi F, Jurban A, Topeli A, Fahey PJ, Garrity E Jr, Archids JM, DePinto DJ, Edwards LC, Tobin MJ. Effect of lung volume reduction surgery on neuromechanical coupling of the diaphragm. Am J Respir Crit Care Med 1998; 157:475–483.

4 Dyspnea in Asthma

M. DIANE LOUGHEED and DENIS E. O’DONNELL Division of Respiratory and Critical Care Medicine, Department of Medicine, Queen’s University, Kingston, Ontario, Canada

I. Introduction Symptoms of asthma are important parameters used by patients and health care providers to assess disease severity and control. Appropriate recognition of symptoms plays a pivotal role in guided self-management, as the accuracy of symptom perception may affect both morbidity and mortality from this condition. Patients with poor perception of episodic changes in lung function may underestimate the severity of an exacerbation, underutilize anti-inflammatory medication, and delay seeking care. Conversely, patients with heightened perception of airway narrowing may overutilize health care services and medication, and encounter deleterious side effects as a result. Dyspnea is one of the most common symptoms of asthma. Knowledge of the mechanisms of dyspnea in asthma is crucial for optimal individual patient management and may help identify patients at risk of fatal asthma (FA) or near-fatal asthma (NFA). This chapter provides a historical perspective on the evaluation of dyspnea in asthma, and explores current concepts of its pathophysioloical basis. In doing so, methods of studying symptoms in asthma and 59

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associations between poor perception and life-threatening asthma (LTA) are reviewed. Second, factors known or thought to affect symptom perception are summarized. Third, the quality of dyspnea in asthma is examined. Fourth, a detailed overview of the mechanics of asthma is provided. Finally, mechanisms of dyspnea are explored in detail by reviewing the relationship between pulmonary mechanics and respiratory sensations in asthma. II. Historical Perspective Dyspnea of status asthmaticus was eloquently described by Sir William Osler as (1): a distressing sense of want of breath and a feeling of great oppression in the chest. Soon the respiratory efforts become violent, all the accessory muscles are brought into play, and in a few minutes the patient is in a paroxysm of the most intense dyspnea . . . speech is impossible, and in spite of the most strenuous efforts, very little air enters the lungs. Expiration is prolonged and also wheezy . . .

Given the multitude of physiological aberrations that characterize an asthma attack, it is not surprising that it has taken centuries of clinical observation and decades of research to elucidate potential mechanisms for this common symptom. The episodic nature of asthma poses a challenge for evaluation of the pathophysiology of dyspnea of spontaneous asthma, as airflow rates may vary in an unpredictable manner from being completely normal at times to being severely compromised at other times. Furthermore, some patients are completely or relatively asymptomatic despite the presence of severe airway obstruction (2), while others appear to be ‘‘in extremis’’ with seemingly minor airway obstruction. Additionally, there are challenges in measuring perception of symptoms, and in defining ‘‘normal’’ and ‘‘abnormal’’ perception. A. Methods of Studying Dyspnea in Asthma

Dyspnea in asthma has historically been evaluated by examining the relation between symptoms and lung function as each varies either spontaneously, or under controlled, experimental conditions. Such experimental simulations include external resistive loading and induced bronchoconstriction. Various symptom rating scales have been employed to quantify asthma symptoms. The most widely used are the visual analogue scale (VAS) (3) and modified Borg scale (4), which are both reproducible and sensitive to change. Psychophysical domains evaluated have included magnitude estimation, discrimination, and thresholds of detection. More recently, qualitative aspects of dyspnea in asthma have been explored. The interpretation of much of the existing literature on symptom perception in asthma is limited

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by the use of small sample sizes, and inconsistent or poorly validated methods of evaluating symptom intensity and quality. Moreover, many studies either confined observations to mild bronchoconstriction, of only a 20% fall in FEV1, relied upon only one independent variable (FEV1 or PEFR), or failed to consider or reliably correct for breathing pattern and prevailing pulmonary mechanics. 1. Spontaneous Asthma

Early research in the area focused on the description of symptoms experienced by patients during periods of clinical stability or spontaneous asthma exacerbations. In a landmark publication, McFadden et al. (5) found marked discrepancies between symptoms (dyspnea and wheeze) and objective measures of airflow obstruction both during and after symptomatic recovery from a severe spontaneous asthma exacerbation. Notably, at symptom recovery, mean peak expiratory flow rates and FEV1 were only 40–50% of predicted values. These findings may reflect temporal adaptation to a certain level of chronic airflow obstruction (6) and/or differences in the rate of change in airway caliber (7), both of which have been shown to influence symptom perception. Alternatively, symptoms may parallel physiologic parameters other than expiratory flow rates more closely, such as concomitant alterations in lung mechanics. Population studies utilizing symptom diaries suggest indices other than expiratory flow rates play an important role in symptom generation in asthma. Symptoms of asthma are reported more frequently in individuals with more severe airway hyperresponsiveness (lower provocative concentration of agonist producing a 20% reduction in FEV1 (PC20) and absence of a plateau response on bronchoprovocation testing) (8,9). Yet, studies have shown only weak associations between chronic symptoms, including dyspnea, PEFR variability, FEV1% predicted, and airway sensitivity as measured by PC20 (10). 2. Simulated Asthma a. Hypoxic and Hypercarbic Challenges

The potential role of altered perception of hypoxemia, hypercarbia, and/or acidosis characteristic of acute severe bronchoconstriction in asthma has been evaluated by hypoxic and hypercarbic challenges, but studies have yielded conflicting results. Altered chemosensitivity in asthma was reported by Rebuck and Read in 1971 (11). They noted that asthmatics with a history of hypercapnia during an asthma exacerbation had blunted ventilatory responses to carbon dioxide when in remission. Subsequently, Kikuchi et al. (12) found reduced chemosensitivity to hypoxia, but not hypercarbia, in patients with prior NFA compared with normal subjects and patients

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who had not had NFA. The clinical relevance of these conflicting findings remains to be determined. Altered chemosensitivity to hypoxia and hypercarbia likely plays a minor role in dyspnea perception in most patients with mild-to-moderate asthma (13). b. External Mechanical Loading

External loading via the application of inspiratory resistive, elastic, and threshold loads has been used to study symptom perception in asthma (12,14–18). The landmark publication in this realm was by Burki et al. (14), who compared the ability of 12 subjects (6 normal and 6 with asthma) to detect inspiratory resistive loads. They reported wide variation in detection threshold in both groups and a nonstatistically significant increase in detection threshold in subjects with asthma. They and others (6,19) have suggested that psychological factors and the degree of baseline airflow obstruction (reflecting a principle of sensory physiology known as the Weber fraction, or temporal adaptation) play a role in detection thresholds. While such studies have been utilized to determine thresholds of perception and the ability to discriminate changes in the magnitude of stimuli, these experimental conditions do not reliably mimic the pulmonary mechanics of spontaneous asthma, in that lung volumes do not increase to the same extent (15). Furthermore, breathing pattern responses and dyspnea intensity also differ between external resistive loading and induced bronchoconstriction (15). As such, the generalizability of these studies is uncertain. Furthermore, the quality of respiratory sensations during external resistive loading appears to differ from induced bronchoconstriction (15,18). c. Induced Bronchoconstriction

Bronchoconstriction induced by allergens, histamine, methacholine, exercise, and leukotrienes is an additional method of simulating spontaneous asthma that has been used to study symptom perception in asthma experimentally. There are reports that symptom intensity varies with the bronchoconstrictor agent used. While allergen, exercise, and histamine appear to induce comparable dyspnea intensity (20), others have found that indirect agonists (such as adenosine monophosphate, which induces bronchoconstriction by causing mast cell degranulation, and sodium metabisulfite, which stimulates sensory nerves) cause more intense symptoms than a direct smooth muscle agonist (methacholine) (21). Nonetheless, in general, these experimental conditions mimic the physiologic and mechanical changes of spontaneous asthma more closely than does external loading (22). The advantage of this experimental condition over spontaneous asthma is the ability to examine stimulus–response relationships in detail, while controlling for known or potential confounders.

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Several epidemiologic surveys have shown that only 70–75% of subjects detect an acute decline in FEV1 of 10–20% (23,24), indicating a minority of individuals with or without asthma may have poor perception of changes in expiratory flow rates. These studies have also demonstrated higher dyspnea intensity in females than males at comparable degrees of bronchoconstriction. This interesting observation might contribute to the female predominance of a diagnosis of asthma in adults (24). There are conflicting data as to whether individuals with asymptomatic airway hyperresponsiveness are poor perceivers of airway narrowing (23,25,26). Studies utilizing induced bronchoconstriction have consistently demonstrated at least moderate associations between intensity of dyspnea and acute reductions in expiratory flow rates (6,27–29). These studies have also uniformly demonstrated large inter-subject variability in dyspnea intensity for a given level of bronchoconstriction, which has been the impetus for considerable research into potential mechanisms that account for this variation, discussed below. B. Methods of Analysis 1. Regression Analyses

The relationship between symptom intensity, scored by VASs or the modified Borg scale, and changes in lung function are often displayed graphically (6,27,28). Elements of the stimulus–response relationship are then analyzed to calculate measures of ‘‘perception’’ (30). Linear regression analysis, specifically the linear regression coefficient (slope), has been shown to be a valid method of assessing respiratory sensations during histamine challenge (31). In comparison with the gold standard exponential regression methodology, which describes the relationship between a stimulus and sensation (Stevens’ Law), the linear regression coefficient is simpler and may prove to be a practical index for interpreting a patient’s ‘‘sensitivity’’ or ‘‘perceptiveness’’ (31). In an attempt to determine the relative contribution of changes in numerous physiologic parameters to the genesis of respiratory sensations such as dyspnea, many have employed multiple linear regression techniques (27–29,32). This is a sound statistical method that permits one to stipulate the strength of interrelationships (tolerance) between potential explanatory independent variables being evaluated in relation to a dependent variable. This technique has enabled researchers to identify the statistical independence of relations between factors associated with dyspnea in univariate analyses. C. Normal, Excessive, and Poor Perception of Dyspnea in Asthma 1. Normal Perception

Any discussion of the clinical relevance of ‘‘abnormal’’ perception of symptoms must first define what is considered ‘‘normal.’’ Unfortunately, presently

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there is no consensus as to what constitutes ‘‘normal,’’ ‘‘excessive,’’ or ‘‘poor’’ perception of asthma symptoms (22). One approach used in the literature is to compare results of individuals with asthma to individuals who are healthy and do not have asthma (9,12,26). James et al. (26) found an increased perception of mild-to-moderate airflow obstruction during high-dose methacholine bronchoprovocation in subjects with a history of mild asthma or wheeze in the last 12 months, compared with those without asthma or wheeze. Boulet et al. (33) attempted to determine the range and distribution of respiratory sensations using lowdose bronchoprovocation testing. They found that Borg Scores at PC20 during histamine-induced bronchoconstriction (or perception score of breathlessness at PC20, PS20) were normally distributed (Fig. 1A), and arbitrarily defined normal perception as
1 SD from the mean. They found no differences in the clinical characteristics (age, gender, baseline FEV1, and PC20) between those with a PS20 under or over 1 SD from the mean. However, large, prospective studies would be required to determine the correlation between PS20 and clinical outcomes such as hospitalizations or LTA. In addition, mild bronchoconstriction may not be a sufficient stimulus to uncover perceptual abnormalities. To date, there are no published studies of the normal range and distribution of respiratory sensations during high-dose bronchoprovocation testing. We have performed high-dose methacholine challenges on 99

Figure 1 (A) Distribution of perception score for dyspnea on the modified Borg scale at the provocative concentration of histamine producing a 20% fall in FEV1 (PS20) in 150 subjects with asthma. Source: From Ref. 33. (B) Distribution of dyspnea intensity ratings (modified Borg scale) at maximum response during highdose methacholine challenge testing in 99 subjects with asthma (open bars), including five subjects with life-threatening asthma (LTA) (closed bars). Source: Courtesy of M. D. Lougheed.

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subjects as part of a population survey of individuals with mild, moderate, and severe asthma. Preliminary analyses reveal that dyspnea intensity at maximal bronchoconstriction (mean
SEM% change in FEV1 48.9
1.0) appears also to be normally distributed (Fig. 1B). We have observed that a number of asthmatics clearly rate dyspnea intensity (relative to changes in % predicted FEV1) at the extremes of the confidence limits for the group mean data. Evaluation of an even larger sample size will help define the normal range and distribution of dyspnea during moderate bronchoconstriction, determine the prevalence of abnormal perception of dyspnea, and permit prospective evaluations of morbidity and mortality in those with abnormal perception. 2. Poor Perception as a Risk Factor for Life-Threatening Asthma

Underestimation of the severity of an exacerbation because of poor perception of symptoms may be an important risk factor for LTA (34–37). The notion of ‘‘poor perception’’ was first described in 1976 by Rubinfeld and Pain (38) in a classic study of symptom perception during methacholine challenge testing. They reported that 9 of 61 subjects with asthma were asymptomatic despite an FEV1 of < 50% predicted. It should be noted that in 6 of these subjects, the poor perception occurred at baseline; thus, only three subjects were unable to appreciate acute severe airflow obstruction. Although the ‘‘blunted perceiver’’ hypothesis has been the impetus for further investigations, a universally accepted definition of a ‘‘poor perceiver’’ and method of detecting such individuals are lacking. Furthermore, it is not known whether ‘‘poor perceivers’’ represent the lower end of a normal distribution of dyspnea intensity, or a distinct, skewed subgroup with inherent perceptual abnormalities of potential clinical importance. Kikuchi and coworkers found dyspnea intensity during resistive loading was lower in a small group of subjects with a history of NFA (n ¼ 11) than normal subjects (n ¼ 16), but not significantly different than patients with asthma without a history of NFA (n ¼ 11) (Fig. 2A, B). This study did not control for compensatory breathing pattern responses to resistive loads. A subsequent study, which did control for inspiratory flow rate, found reduced sensitivity to external resistive loads in children with a history of LTA compared with asthmatic children without LTA or normal children (17). To our knowledge, there is only one published prospective study comparing health outcomes of individuals with poor perception of external loading. Magadle et al. (39) found significantly greater hospitalizations, near fatal exacerbations, and deaths during a 24-month period in 29 subjects with poor perception of threshold loading compared with individuals with normal (n ¼ 67) or high (n ¼ 17) perception. Additional studies are required to determine whether patients with LTA or less severe asthma have impaired perception of intrinsic mechanical loads, present during

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Figure 2 (A) Dyspnea intensity (Borg Score) during breathing at six levels of resistance is significantly lower in 11 patients with near-fatal asthma (NFA) than in 12 normal subjects, but not significantly different than in 11 patients with asthma but no near-fatal attacks. (B) Dyspnea intensity (Borg Score) during breathing with a resistance of 20.0 cm of water per liter per second is significantly lower in subjects with NFA than in normal subjects, but not significantly different than in patients with asthma without near-fatal attacks. Horizontal and vertical bars represent mean
1 SD, respectively. Source: From Ref. 12.

spontaneous or induced bronchoconstriction. In preliminary studies comparing perception of methacholine-induced bronchoconstriction and hyperinflation to perception of mechanical hyperinflation in the absence of bronchoconstriction, we found that subjects with LTA (previous NFA, n ¼ 5) had blunted perception both of bronchoconstriction and mechanical hyperinflation compared with patients with asthma without LTA (n ¼ 16) (Fig. 3A, B) (40). Reduced voluntary drive to breathe has been reported in approximately 50% of unselected asthmatics (41) and may be a risk factor for LTA (42). Potential mechanisms include diminished reflex responses to airway occlusion (43), impaired central processing of inspiratory load information (44), and mood disorders such as depression (42) resulting in alveolar hypoventilation (45). 3. Overperception as a Risk Factor for Life-Threatening Asthma

Heightened perception of airflow obstruction is another theoretical risk factor for increased asthma morbidity and mortality (22), largely based upon the association between excess use of short-acting beta-2-agonists and FA or NFA (46). Prospective evaluations of clinical outcomes in

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Figure 3 (A) Slope of the relationship between dyspnea intensity (modified Borg scale) and change in inspiratory capacity (IC) (% predicted) during methacholine challenge testing is significantly lower in subjects with life-threatening asthma (LTA, n ¼ 5) compared with asthma without life-threatening episodes (n ¼ 15). (B) Dyspnea intensity (modified Borg scale) at a standardized reduction in IC of 40% during methacholine challenge testing is significantly lower in subjects with LTA (n ¼ 5) compared with subjects with asthma without LTA (n ¼ 15). Source: From Ref. 40.

individuals with apparently increased awareness of small changes in lung function are required. III. Factors Affecting Symptom Perception Perception of respiratory sensations in asthma may be affected by a number of factors, well summarized in previous reviews of this topic (13,47). The current literature suggests that advanced age (over 60 years), indices of asthma severity (such as airway hyperresponsiveness and diurnal peak flow variability), chronic baseline airflow obstruction, medication, and personality and psychological profile are key factors that need to be considered when studying perception of dyspnea in asthma. A. Demographics

In contrast to general population studies discussed previously, which included subjects without asthma, gender does not appear to affect symptom perception in individuals with a diagnosis of asthma (38,48).

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However, significant differences have been found with age, which may contribute to the higher mortality rate from asthma in the elderly (49). Connolly and colleagues found that elderly asthmatics (over 60 years of age) reported less intense dyspnea than younger individuals during induced bronchoconstriction. Conceivable mechanisms have been proposed (50) (including age-related impairment in sensory receptors, nerves and/or central processing) but not thoroughly evaluated. B. Disease Duration and Severity

Contrary to what one might expect, studies have not found a relationship between asthma duration and perception of asthma symptoms (48,51). Furthermore, studies of the impact of measures of asthma severity have yielded conflicting results. Burdon et al. (6) found an inverse relationship between the magnitude of induced breathlessness and airway hyperresponsiveness to histamine. Yet, increased diurnal peak flow variability typical of more severe or uncontrolled asthma has been associated with enhanced accuracy of symptom perception (48). C. Asthma Medication

Asthma medication may clearly affect symptoms by altering airflow rates, but could also modulate sensory afferents or central perception of obstruction (50). Inhibition of airway sensory nerves has been reported in vitro with beta-agonists, sodium cromoglycate, and nedocromil sodium (50). On the other hand, theophylline appears to increase symptom intensity (52), perhaps via central effects. It has been suggested that airway inflammation directly affects perception of bronchoconstriction (53–55). Most studies have observed enhanced perception of induced bronchoconstriction in subjects taking inhaled corticosteroids (53,56,57), but others have reported the opposite (52,54,55). Interpretation of this literature is hindered by differences in disease severity and duration of treatment. Furthermore, the potential for medication to alter dyspnea via effects on lung mechanics secondary to altered small airway function has not been addressed. D. Personality and Psychological Profile

The link between personality, psychological profiles, and symptom perception has been examined predominantly in individuals with severe, LTA. Notably, psychopathology appears more prevalent in this group (58–60). However, Chetta et al. (60) did not find any relationship between Minnesota Multiphasic Personality Inventory results and perception of breathlessness in individuals classified as either ‘‘hypoperceivers’’ or ‘‘hyperperceivers’’ of induced bronchoconstriction. Although the notion exists that anxiety is

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linked to overperception of symptoms with resultant overuse of betaagonists, consensus is lacking. Boulet et al. (61) did not find a difference in anxiety scores between asthmatics and normal subjects; nor was there a relationship between anxiety scores and perception of methacholineinduced bronchoconstriction. Similarly, we found no difference in anxiety scores between asthmatics with plateau responses vs. excessive airway narrowing (EAN) on bronchoprovocation testing (62). The extent to which emotional state and personality affect perception of airflow obstruction per se or alter behavioral responses to physiologic changes during asthma exacerbations remains uncertain (63). Psychological factors need to be examined under controlled experimental conditions and related to asthma severity and perceptual acuity in a large population sample.

IV. Quality of Dyspnea in Asthma Dyspnea of asthma is commonly, and erroneously, regarded by health care providers to be ‘‘expiratory’’ in nature (64). This misconception is presumably rooted in the relatively greater increase in expiratory as opposed to inspiratory resistance, and emphasis placed clinically on the magnitude of reduction in expiratory flow rates as a marker of severity of obstruction to airflow. The clinical observations of Woolcock and Read (65) that patients with asthma typically complain that it is harder to breathe in than out have been confirmed experimentally. We have consistently shown that Borg Scores for inspiratory difficulty exceed those for expiratory difficulty throughout methacholine-induced bronchoconstriction in asthma (Fig. 4) (27,28). Dyspnea of asthma is characterized by a number of different respiratory sensations, such as ‘‘chest tightness,’’ increased ‘‘effort’’ or ‘‘work,’’ and ‘‘difficult breathing.’’ It is well recognized that symptom quality varies with the level of bronchoconstriction, and presumed that specific qualitative dimensions have specific neurophysiologic underpinnings (22). For example, ‘‘tightness’’ is commonly regarded as a respiratory sensation characteristic of mild bronchoconstriction (66,67), attributed to stimulation of vagal receptors by increased airway resistance (18), not respiratory muscle work or hyperinflation (68). However, these inferences were drawn from experimental conditions (external mechanical loading) that do not reliably mimic spontaneous asthma. We have shown that high-dose methacholine bronchoprovocation reliably mimics the respiratory sensations of spontaneous asthma at peak bronchoconstriction (27). To better delineate qualitative dimensions of dyspnea throughout bronchoconstriction, we recently tracked the evolution of respiratory sensations throughout bronchoconstriction. We compared qualitative descriptors of breathlessness at the dose nearest to PC20 and

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Figure 4 In 13 subjects during high-dose methacholine challenge testing, Borg scale ratings of inspiratory difficulty were significantly greater than ratings of expiratory difficulty at maximum response.**p < 0.001. Values are means
SEM. Source: From Ref. 27.

at maximum response (69). Notably, the predominant quality throughout bronchoconstriction was ‘‘inspiratory difficulty.’’ ‘‘Chest tightness’’ was present in only 57% of subjects at PC20. Although ‘‘chest tightness’’ was present in 80% at maximum response (p ¼ 0.095 compared with PC20), ‘‘unsatisfied inspiration’’ was even more prevalent (90%) at maximum response compared with PC20 (57%, p ¼ 0.007).

V. Mechanics of Asthma The hallmark of asthma is widespread, typically acute, and reversible airflow obstruction in response to specific and nonspecific stimuli. As Osler hypothesized, the obstruction to airflow in acute asthma is typically due to a combination of airway inflammation and edema, mucous hypersecretion, and bronchoconstriction. Airway responsiveness to nonspecific stimuli can

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be quantified by constructing bronchoprovocation dose–response curves (70,71). The most commonly used measure of airway responsiveness is the strength of agonist that results in a given change in lung function, termed ‘‘sensitivity,’’ for example, the provocative concentration or dose which produces a 20% reduction in FEV1 (PC20 or PD20). Other dose– response characteristics include the slope or ‘‘reactivity,’’ presence or absence of a ‘‘plateau response’’ (less than 5% change in FEV1 over two or more dose steps) or ‘‘excessive airway narrowing’’ (EAN) (absence of a plateau response), and the magnitude of maximal change in lung function ‘‘maximum response.’’ Features of the airway hyperresponsiveness of asthma include increased sensitivity, increased slope, and an elevated maximum response plateau or lack of a measurable plateau (8,72). Search for the ‘‘cause’’ of asthma has in large part focused on the pathophysiologic mechanism(s) of EAN. Factors influencing airway narrowing have been extensively reviewed (73,74) and include the interaction between the agonist (stimulus) and receptor (airway smooth muscle, ASM), ASM contractility, geometry of the airway lumen, and flow regimen of the airway segments. The degree of ASM shortening depends upon the dose–response curve and length–tension characteristics of the muscle as well as the load the ASM must overcome. The effect ASM shortening has upon airway lumen caliber depends upon ASM and airway wall thickness as well as intralumenal secretions (74). Resistance to airflow in narrowed lumens is also affected by airflow rate, cross-sectional area, and gas density and velocity. Woolcock et al. (8), Macklem (75), and others have postulated that the fundamental abnormality in asthma is the absence of a factor that normally limits ASM shortening. Additional theories include decreased interdependence between the lung parenchyma and airway wall and increased ASM force (75), loss of the bronchoprotective effect of a deep inspiration (76,77), and altered ASM resting length and altered actin– myosin interactions leading to a latch state, particularly in the setting of reduced tidal excursions (78–83). Regardless of the mechanism of EAN, the inciting physiologic abnormality in asthma is an increase in airway resistance. It has long been recognized that FRC and RV increase in association with increases in airway resistance in asthma (65,84–86). As dynamic end-expiratory lung volume (EELV) increases progressively towards total lung capacity (TLC), the respiratory system is forced to operate on the upper nonlinear portion of the pressure– volume curve. Inspiratory reserve volume (IRV) is reduced, thoracic expansion is constrained, and tidal volume represents a greater percentage of inspiratory capacity (IC). At these lung volumes, the inspiratory muscles must generate enough pressure to overcome a substantial threshold load (ITL) created by the inward recoil pressure of the lung and chest wall at endexpiration, in order to initiate inspiratory flow (28,85). While inspiratory muscle strength and endurance do not appear to be altered during histamine-induced

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dynamic hyperinflation (DH) (87), DH does alter the length–tension relationships of the inspiratory muscles, producing functional muscle weakness (85,88). Thus, in addition to the initial resistive load, these functionally weakened inspiratory muscles encounter inspiratory threshold and elastic loads secondary to DH and reduced dynamic compliance. The inspiratory muscles must use a greater fraction of their maximum force-generating capacity (27,85). DH restricts thoracic expansion and increases the ratio of inspiratory effort [tidal esophageal pressure swings (Pes)/maximal inspiratory pressure (PImax)] to the tidal volume response, producing neuromechanical uncoupling of the respiratory system (27,28). Clearly, the main mechanical consequences of increased airway resistance in asthma are the results of DH (22). A Campbell diagram, illustrating pressure–volume changes in induced asthma, is presented in Figure 5. While airway closure is the accepted explanation for the increase in RV (85,89), the explanation for the rise in FRC has been quite controversial (90,91). The debate has been between whether FRC increases actively, due to persistent activity of inspiratory muscles during expiration (termed ‘‘inspiratory muscle braking’’) (91–93), or passively, due to expiratory flow limitation (EFL) (27,28,90,94,95). The former is thought to maintain airway patency, and minimize EFL (45). While postinspiratory contraction of the diaphragm could contribute to DH (93), we believe that sustained DH in asthma is due to EFL. We have documented overlap of the tidal and maximal expiratory flow–volume loops during bronchoprovocation testing in asthma (27) and quadriplegia (96). Furthermore, we have demonstrated increases in EELV in quadriplegic subjects, who lack the capacity for rib cage inspiratory muscle braking, comparable to those in neurologically intact subjects with asthma (96). Original reports of marked acute increases in TLC (65) were likely at least in part due to frequency-dependent overestimation of thoracic gas volume (97). When panting frequency is standardized (98), we and others have shown that TLC does not change (27,28,99). As a result, reductions in IC accurately reflect changes in FRC and may be used to track dynamic EELV during acute bronchoconstriction (27,28). Hyperinflation is also present in chronic persistent asthma, presumably because airway remodeling and resultant fixed obstruction as well as loss of elastic recoil increase the time constant of the respiratory system beyond the time available for exhalation (45,100,101).

VI. Mechanical Basis for Asthma Symptoms Detailed examination of pulmonary mechanics and sensory–mechanical relationships in asthma has shed new light on the mechanisms of dyspnea in asthma. Using high-dose methacholine bronchoprovocation testing, we

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Figure 5 Campbell diagram illustrating a typical response to induced asthma. Tidal Pes–volume loops were anchored at EELVdyn; Cw was positioned by passing a line through Pes at end-expiration at baseline with a predicted slope of 4% VC per cm H2O; CLdyn represents the slope of the line joining values of Pes at points of zero flow; ITL is the difference between Pes values at the onset of inspiratory flow and the Cw curve at isovolume. Work measurements were obtained through planimetry: WI, the area subtended by Cw and the inspiratory curve; WIEL, the shaded area between CLdyn and Cw; WIRES, the area to the left of CLdyn. Source: From Ref. 28.

have examined sensory responses over a range of physiologic stimuli from mild bronchoconstriction to moderate DH with attendant inspiratory threshold and elastic loading. Using multiple regression analysis, we determined that reduction in IC (% predicted) was the strongest independently significant factor related to the change in Borg ratings of dyspnea (Fig. 6) (27). The reduction in IC (% predicted) accurately reflected dynamic increases in FRC and accounted for 74% of the interindividual variance in Borg ratings for a given reduction in airflow rates. Furthermore, symptom

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Figure 6 Change in end-expiratory lung volume, as measured by change in inspiratory capacity (DIC), best predicted change in breathlessness (DBorg) during progressive induction of bronchoconstriction (n ¼ 193 data points, p < 0.001). Source: From Ref. 27.

recovery occurred when IC (% predicted) had returned to baseline levels, despite residual airflow obstruction. In comparing sensory responses of individuals with EAN to those with plateau responses to methacholine, we noted that dyspnea intensity at maximum response was similar despite differences in the level of bronchoconstriction (102). In addition, dyspnea intensity continued to increase when FEV1 reduction had reached a plateau. Furthermore, IC continued to decline, indicating hyperinflation does not plateau. In a subsequent study, we recorded esophageal pressure and breathing pattern responses. Stepwise

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multiple regression analysis revealed change in IC (% predicted) to be the strongest independently significant correlate of the increase in Borg dyspnea ratings from the onset of the FEV1 plateau to the end of the FEV1 plateau (partial R ¼ 0.906, p ¼ 0.002) (103). We have consistently found strong statistical interrelationships between dyspnea (or inspiratory difficulty), inspiratory effort, and DH (27,28,96,103). Our findings, duplicated by others (104–106), have confirmed earlier hypotheses (85,107) that DH is a major determinant of dyspnea intensity during acute bronchoconstriction. Dynamic hyperinflation may contribute to dyspnea in several ways. The mechanical load encountered requires an increase in central motor command output (medullary drive), which is thought to be perceived by corollary discharge from the medulla to the cerebral cortex as a sense of effort (108). However, this increased effort is not rewarded by the same mechanical response as would normally be achieved. This disparity between effort expended (Pes/PImax) and the anticipated mechanical response (i.e., change in inspiratory flow or volume) results in neuromechanical dissociation of the ventilatory pump (27,28). Additionally, DH may directly alter afferent feedback from chest wall, accessory muscles, lung parenchyma, and the diaphragm. Dynamic hyperinflation also accounts for the major qualitative dimension of respiratory distress throughout bronchoconstriction: ‘‘inspiratory difficulty’’ (27,69). In our study comparing the quality respiratory sensations at PC20 and maximum response during bronchoprovocation, ‘‘unrewarded inspiration’’ increased with progressive DH, and was associated with significantly greater reductions in IC. The ITL likely contributes to the sensation of ‘‘unrewarded inspiration’’ prevalent at maximum response during bronchoprovocation: as the ITL increases, greater effort must be expended to be rewarded by inspiratory airflow. We have examined potential mechanisms by which DH might contribute to dyspnea intensity and quality by (a) partitioning the effects of the ITL from resistive and elastic loads, (b) partitioning the effects of hyperinflation from bronchoconstriction, and (c) examining the role of afferent receptors in the ‘‘chest wall’’ (rib cage and intercostal muscles) in perception of respiratory sensations induced by bronchoconstriction. A. The Inspiratory Threshold Load

To isolate the effects of the ITL from resistive and elastic loading, we applied continuous positive airway pressure (CPAP) or inspiratory positive airway pressure (IPAP) to 12 subjects with asthma at maximum response during methacholine bronchoprovocation testing. The inspiratory pressure assist in both modes counterbalances resistive and elastic loads, but only CPAP (optimized to match intrinsic positive end-expiratory pressure, PEEPi) counterbalances the ITL. Although both CPAP and IPAP reduced

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inspiratory work of breathing and inspiratory effort (tidal esophageal pressure excursions relative to maximum, Pes/PImax) to comparable degrees, only CPAP significantly decreased inspiratory difficulty (Fig. 7). In a similar study, Chen and Yan (104) tried to isolate the effects of an imposed ITL and changes in operating lung volumes on inspiratory difficulty. They used CPAP to increase EELV in association with increased intrinsic PEEP (an ITL) and compared responses to the application of an ITL in the absence of a change in operating lung volume. They found that the imposed ITL alone accounted for 40% of the variation in inspiratory difficulty, while change in end-inspiratory lung volume (EILV) contributed an additional 24% to the regression model. Yan and Bates (105) demonstrated that an ITL as low as 2.5 cm H2O could be perceived as inspiratory difficulty. By inference, the ITL is a major determinant of dyspnea in asthma, particularly inspiratory difficulty. B. Hyperinflation Without Bronchoconstriction

Dynamic hyperinflation accompanies even mild bronchoconstriction (69), making it difficult to determine the relative importance of reductions in airflow rates and increases in lung volumes as stimuli for dyspnea. To partition the effects of DH from those of bronchoconstriction coupled with DH, we compared sensory responses of 16 asthmatics at a standardized level of lung hyperinflation (i.e., IC reduction) during hyperinflation induced by an airway closure analogue (modified from Ref. 109), and during high-dose methacholine bronchoprovocation. Qualitative descriptors of dyspnea were similar during mechanical hyperinflation and methacholine challenge, and alluded predominantly to inspiratory difficulty and unsatisfied inspiration (110). Stepwise multiple regression analysis revealed the change in IC (% predicted) was the strongest correlate of inspiratory difficulty during both mechanical hyperinflation (partial R ¼ 0.81, p < 0.001) and methacholine challenge (partial R ¼ 0.88, p < 0.001). For a given level of hyperinflation, the quality and intensity of dyspnea were similar despite differences in bronchoconstriction, ventilation, breathing pattern, and inspiratory effort. Thus, acute hyperinflation contributes importantly, if not predominantly, to the quality and intensity of dyspnea during asthma. C. Role of Chest Wall Afferents

The role of sensory (afferent) information from chest wall mechanoreceptors in the perception of external resistive and elastic loads and changes in thoracic volume has been controversial (111–117). Since airway hyperresponsiveness is present following cervical spinal cord injury (118), we were able to utilize high-dose bronchoprovocation testing to compare sensory and mechanical responses in spontaneously breathing low cervical quadriplegia (n ¼ 6) to asthma (n ¼ 12) (96). We hypothesized that if

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Figure 7 (A) For a given breath in the absence of expiratory airflow limitation (baseline), there is a harmonious relationship between inspiratory effort (Pes/PImax) and instantaneous change in volume (neuromechanical coupling). During bronchoconstriction (maximum response), intrinsic mechanical loading and functional muscle weakness disrupt this relationship (neuromechanical dissociation), and greater levels of inspiratory difficulty or breathlessness are experienced. (B) Optimized CPAP improves neuromechanical coupling, and therefore breathlessness, to a greater extent than does IPAP by reducing both the intercept (intrinsic PEEP, PEEPi) and the slope of the tidal Pes–volume relationship. Values are means
SEM. Source: From Ref. 28.

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afferent information from chest wall afferents were critically important to perception of dyspnea in asthma, there would be differences in intensity and/or quality of respiratory sensations between subjects with quadriplegia and neurologically intact subjects with asthma. The subjects with quadriplegia had mild airway hyperresponsiveness (PC20 7.8
3.0 mg/mL), and at maximum response, they were flow limited and had substantial dynamic increases in EELV of 1 L. Interestingly, the quality of respiratory sensations was similar to that reported by subjects with asthma. Furthermore, the relationship between induced dyspnea and hyperinflation (change in IC, % predicted) was consistent between groups (Fig. 8), despite differences in baseline mechanics, breathing pattern responses to bronchoprovocation, reduced expiratory muscle strength, and substantial chest wall and sympathetic deafferentation in quadriplegia. Thus, while afferent information from the chest wall and sympathetic system may normally contribute to dyspnea, a limited pool of sensory information (traveling via the vagus and/or phrenic nerves) can suffice to produce complex respiratory sensations during bronchoconstriction.

VII. Summary Dyspnea in asthma is the result of the conscious awareness of multiple, dynamic interrelated physiologic perturbations that in combination result in the perception of the uncomfortable sensation of unrewarded inspiration. Much insight in to the pathophysiologic basis for the quality and intensity of dyspnea has been gained by detailed examination of sensory–mechanical relationships using validated measurement instruments. The mechanical consequences of progressive increases in airway resistance in asthma, particularly DH and all it entails (including inspiratory threshold loading, reduced dynamic compliance, and functional inspiratory muscle weakness), result in neuromechanical dissociation of the ventilatory system. Many factors have been identified which modulate dyspnea in asthma, such as age, rate of development of airflow obstruction, medication use, psychological profile, and asthma severity (bronchial hyperresponsiveness, PEFR variability, baseline airflow obstruction, plateau responses). However, differences in symptom intensity and quality within and between individuals may be accounted for, in large part, by differences in dynamic mechanics. Knowledge of the nature and pathophysiologic basis of dyspnea in asthma should enable clinicians to better assess the severity of an exacerbation of asthma. Objective assessment of airflow rates must remain a fundamental aspect of assessing severity and control, but when there appear to be discrepancies between symptoms and objective measures, mechanical explanations, and abnormal symptom perception should be entertained. The clinical utility of ambulatory monitoring of IC as an objective measurement

Figure 8 Relationships between dyspnea intensity (Borg) and change in inspiratory capacity (IC) or change in FEV1 (each expressed as percentage of predicted normal) during methacholine-induced bronchoconstriction were similar in quadriplegia (Q) (n ¼ 6) and asthma (A) (n ¼ 12). When the change in FEV1 was expressed as percentage fall from baseline, slopes were slightly greater in subjects with asthma than in those with quadriplegia (p ¼ 0.07) due to bias from differences in group baseline measurements. Values shown are means
SEM. Source: From Ref. 96.

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51. Connolly MJ, Crowley JJ, Charan NB, Nielsen CP, Vestal RE. Reduced subjective awareness of bronchoconstriction provoked by methacholine in elderly asthmatic and normal subjects as measured on a simple awareness scale. Thorax 1992; 47:410–413. 52. Higgs CM, Laszlo G. Influence of treatment with beclomethasone, cromoglycate and theophylline on perception of bronchoconstriction in patients with bronchial asthma. Clin Sci 1996; 90:227–234. 53. Roisman GL, Peiffer C, Lacronique JG, Le Cae A, Dusser DJ. Perception of bronchial obstruction in asthmatic patients. Relationship with bronchial eosinophilic inflammation and epithelial damage and effect of corticosteroid treatment. J Clin Invest 1995; 96(1):12–21. 54. in’t Veen JCCM, Smits HH, Ravensberg AJJ, Hiefmstra PS, Sterk PJ, Bel EH. Impaired perception of dyspnea in patients with severe asthma. Relation to sputum eosinophils. Am J Respir Crit Care Med 1998; 158:1134–1141. 55. Ottanelli R, Rosi E, Romagnoli I, Grazzini M, Stendardi L, Duranti R, et al. Do inhaled corticosteroids affect perception of dyspnea during bronchoconstriction in asthma? Chest 2001; 120(3):770–777. 56. Boulet LP, Turcotte H, Cartier A, Milot J, Cote J, Malo JL, et al. Influence of beclomethasone and salmeterol on the perception of methacholine-induced bronchoconstriction. Chest 1998; 114(2):373–379. 57. Salome CM, Reddel HK, Ware SI, Roberts AM, Jenkins CR, Marks GB, et al. Effect of budesonide on the perception of induced airway narrowing in subjects with asthma. Am J Respir Crit Care Med 2002; 165(1):15–21. 58. Boulet LP, Deschesnes F, Turcotte H, Gignac F. Near-fatal asthma: clinical and physiologic features, perception of bronchoconstriction and psychologic profile. J Allergy Clin Immunol 1991; 88:838–846. 59. Campbell DA, Yellowlees PM, McLennan G, Coates JR, Frith PA, Gluyas PA, et al. Psychiatric and medical features of near fatal asthma. Thorax 1995; 50:254–259. 60. Chetta A, Gerra G, Foresi A, Zaimovic A, Del Donno M, Chittolini B, et al. Personality profiles and breathlessness perception in outpatients with different gradings of asthma. Am J Respir Crit Care Med 1998; 157(1):116–122. 61. Boulet L-P, Cournoyer I, Deschesnes F, Leblanc P, Nouwen A. Perception of airflow obstruction and associated breathlessness in normal and asthmatic subjects: correlation with anxiety and bronchodilator needs. Thorax 1994; 49:965–970. 62. Lougheed MD, Ross SE, O’Donnell DE. Clinical significance of the methacholine response plateau in asthma. Am J Respir Crit Care Med 2003; 167(7):A635. 63. Gibson GJ. Perception, personality, and respiratory control in life-threatening asthma. Thorax 1995; 50(suppl 1):S2–S4. 64. Morris MJ. Asthma—expiratory dyspnoea? Br Med J 1987; 283:838–839. 65. Woolcock A, Read J. Lung volumes in exacerbations of asthma. Am J Med 1966; 41:259–273. 66. Simon PM, Schwartzstein RM, Weiss JW, Fencl V, Teghtsoonian M, Weinberger SE. Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 1990; 142:1009–1014.

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67. Elliott MW, Adams L, Cockcroft A, MacRae KD, Murphy K, Guz A. The language of breathlessness. Use of verbal descriptors by patients with cardiopulmonary disease. Am Rev Respir Dis 1991; 144(4):826–832. 68. Binks AP, Moosavi SH, Banzett RB, Schwartzstein RM. ‘‘Tightness’’ sensation of asthma does not arise from the work of breathing. Am J Respir Crit Care Med 2002; 165:78–82. 69. Lougheed MD, O’Donnell DE. Respiratory symptoms during induced bronchoconstriction in asthma: comparison between PC20 and maximum response. Am J Respir Crit Care Med 2001; 163:A813. 70. Cockcroft DW, Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and a clinical survey. Clin Allergy 1977; 7:235–243. 71. American Thoracic Society. Guidelines for methacholine and exercise challenge testing—1999. Am J Respir Crit Care Med 2000; 161:309–329. 72. Sterk PJ, Daniel EE, Zamel N, Hargreave FE. Limited maximal airway narrowing in nonasthmatic subjects. Am Rev Respir Dis 1985; 132:865–870. 73. Moreno RH, Hogg JC, Pare PD. Mechanics of airway narrowing. Am Rev Respir Dis 1996; 133:1171–1180. 74. James AL, Pare PD, Hogg JC. The mechanics of airway narrowing in asthma. Am Rev Respir Dis 1989; 139:242–246. 75. Macklem PT. Mechanical factors determining maximum bronchoconstriction. Eur Respir J Suppl 1989; 6:516s–519s. 76. Skloot G, Permutt S, Togias A. Airway responsiveness in asthma: a problem of limited smooth muscle relaxation with inspiration. J Clin Invest 1995; 96:2393–2403. 77. King GC, Moore BJ, Seow CY, Pare PD. Airway narrowing associated with inhibition of deep inspiration during methacholine inhalation in asthmatics. Am J Respir Crit Care Med 2001; 164:216–218. 78. Fredberg JJ, Jones KA, Nathan M. Friction in airway smooth muscle: mechanism, latch and implications in asthma. J Appl Physiol 1996; 81: 2703–2712. 79. Fredberg JJ, Inouye D, Miller B, Nathan M, Jafari S, Raboudi SH, et al. Airway smooth muscle, tidal stretches, and dynamically determined contractile states. Am Rev Respir Crit Care Med 1997; 156:1752–1759. 80. Solway J, Fredberg JJ. Perhaps airway smooth muscle dysfunction contributes to asthmatic bronchial hyperresponsiveness after all. Am J Respir Cell Mol Biol 1997; 17:144–146. 81. Fredberg JJ. Airway smooth muscle in asthma: flirting with disaster. Eur Respir J 1998; 12:1252–1256. 82. Fredberg JJ, Inouye DS, Mijailovich SM, Butler JP. Perturbed equilibrium of myosin binding in airway smooth muscle and its implications in bronchospasm. Am J Respir Crit Care Med 1999; 159:959–967. 83. Fredberg JJ, Shore SA. The unbearable lightness of breathing [editorial; comment]. J Appl Physiol 1999; 86:3–4. 84. Cade JF, Woolcock AJ. Lung mechanics during provocation of asthma. Clin Sci 1971; 40:381–391.

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5 Mechanisms of Dyspnea in Restrictive Lung Disease

DENIS E. O’DONNELL

NHA VODUC

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

Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada

I. Introduction Restrictive lung disease is a broad term, encompassing a number of conditions in which lung volumes are reduced. The hallmark of many restrictive lung diseases is a decrease in the compliance of the lung and/or chest wall. Dyspnea is a common clinical manifestation of restrictive lung disease and frequently becomes a prominent and disabling symptom for patients with more advanced restriction. In recent decades, our understanding of the mechanisms of dyspnea in restrictive lung disease has been furthered by a small, but significant, body of research. This chapter will review the existing literature on this subject. The main focus will be on interstitial lung disease (ILD), because it is the prototypical restrictive disease. However, other causes of restriction will also be discussed, including pleural disease, neuromuscular disease, obesity, and congestive heart failure. Although the pathology of these conditions are clearly disparate, closer scrutiny suggests that they may share certain physiologic characteristics and that some mechanisms of dyspnea may be common to many, if not all, restrictive lung diseases. 87

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In order to understand the mechanisms of dyspnea, one must first appreciate the range of physiologic disturbances that are seen in ILD at rest and during exercise (1). As alluded to above, one of the characteristic features of ILD is a reduction in lung compliance and lung volumes (2,3). A reduction in vital capacity (VC) reflects the smaller number of functioning alveolar units (4). The reduction in functional residual volume (FRC) reflects a greater static recoil pressure of the lung, which forces the relaxation volume of the respiratory system to decline to a lower volume than in health. Gas exchange may be impaired to a varying degree in ILD. This impairment is, in part, a reflection of the decreased diffusion capacity caused by a smaller surface area available for gas exchange and an increased thickness of the alveolar–capillary membrane (5). Gas exchange may also be affected by increased ventilation–perfusion (V/Q) mismatching and increased right-to-left shunting. ILD generally involves the lungs in a heterogeneous manner, with marked interregional variations in matching of ventilation to perfusion (6). An important consequence of these gas-exchange abnormalities is an increase in the alveolar–arterial oxygen gradient [P(A–a)O2] during activity.

B. Exercise Physiology

The increased metabolic demands of exercise will often accentuate the physiologic abnormalities of ILD. Indeed, one of the earliest clinical manifestations of ILD may be exertional dyspnea and exercise intolerance. Although the extent of exercise limitation will depend on the nature and severity of the underlying disease as well as co-existent morbidities, many patients with ILD will share similar patterns of cardiopulmonary responses to exercise (7–15). Peak oxygen uptake (VO2) and work rate will typically be reduced. Many, but not all, patients will demonstrate evidence of ventilatory constraints at peak exercise (Fig. 1). Ventilatory responses will be abnormal, with a rapid and relatively shallow breathing pattern (12) (Fig. 2). Peak ventilation will be lower than normal, but submaximal ventilation will be increased in order to compensate for abnormally high physiologic deadspace and possibly for an early onset metabolic acidosis and arterial oxygen desaturation. Physiologic deadspace will be elevated at rest and often fails to decline normally during exercise (6,10,13). This persistent elevation in deadspace is due in part to smaller than normal tidal volumes. An early anaerobic threshold may be seen in some patients with ILD (17). Although hypoxia may predispose to lactic acidosis, deconditioning and concomitant heart disease may be important contributors as well.

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Figure 1 Tidal flow–volume loops at rest (inner solid line curve) and during exercise (dashed line curve) are shown in relation to their respective maximal flow– volume loops (outer solid line curve) in a normal healthy subject and a typical patient with ILD. Peak exercise in ILD was compared with exercise at a comparable metabolic load in the age-matched person. As a result of a decreased total lung capacity (TLC), inspiratory capacity (IC), and inspiratory resource volume (IRV) are reduced in ILD. Note expiratory flow limitation (tidal expiratory flow encroaching on the maximal curve) and An increase in dynamic end-expiratory lung volume (EELV) during exercise in the ILD patient. The dotted line represents the predicted maximal expiratory curve for the ILD patient. Source: From Ref. 19.

During exercise, there is typically a widening of the P(A–a) O2 and hypoxia is a relatively common finding (13). The contributors to hypoxia in ILD include V/Q mismatching, diffusion limitation, reduced mixed venous oxygenation and, less commonly, alveolar hypoventilation (13,17). Red blood cell transit times through the alveolar capillaries are reduced during exercise, magnifying the effects of impaired gas diffusion. Interestingly, alveolar hypoventilation is not a common finding in ILD, despite the high physiologic deadspace. Exceptions to this rule include patients with very severe disease or those with a second, superimposed condition (such as obstructive disease or neuromuscular involvement). C. Ventilatory Mechanics During Exercise

Lung compliance is reduced in ILD and, therefore, greater pressure generation is required by the inspiratory muscles for a given tidal volume, i.e., increased elastic loading (2,3,18) (Fig. 2). The resting inspiratory capacity (IC) and inspiratory reserve volume (IRV) are often diminished compared with health (20) (Fig. 3). This means significant mechanical constraints on tidal volume (VT) expansion during exercise, which results in a greater

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Figure 2 Responses to exercise in 12 patients with ILD and in 12 age-matched normal subjects. (A) dyspnea intensity measured by the Borg scale; (B) minute ventilation (VE); (C) breathing pattern; and (D) respiratory effort expressed as the ratio between esophageal pressure (Pes) and maximal inspiratory pressure (PImax). Values are means
SE. Abbreviations: VO2 ¼ O2 uptake; breathing frequency ¼ F and VT ¼ tidal volume. Pes measurements were obtained in 8 of 12 patients with ILD. All slopes are significantly greater (p < 0.05) in patients with ILD than in normal subjects. Source: From Ref. 20.

reliance on increasing breathing frequency to increase ventilation, i.e., a rapid and shallow breathing pattern. As a result of these restrictive mechanics, the ratio of inspiratory muscle effort (tidal esophageal pressure relative to maximum) to VT is consistently increased throughout exercise when compared with healthy individuals (19) (Fig. 4). Expiratory flow limitation, due to concomitant airways disease or reduced operating lung volumes (i.e., reduced end-expiratory lung volume (EELV)), has also been reported in some patients with ILD (Fig. 1). Evidence of flow limitation during exercise was reported by Marciniuk et al. (20) in a subset of ILD patients without evidence of obstructive physiology on resting pulmonary function tests. The mechanical consequence of this finding is not known given that, in contrast to patients with obstructive lung disease, it does not appear severe enough to result in dynamic lung hyperinflation during exercise (19). It may be that flow limitation in ILD does not allow further

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Figure 3 Operating lung volumes are shown relative to ventilation during exercise in 12 patients with ILD and in 12 age-matched normal subjects. Due to a reduced total lung capacity (TLC), there are greater volume constraints on VT expansion (solid area) during exercise in ILD. For a given ventilation, inspiratory capacity (IC) and inspiratory reserve volume (IRV) are significantly reduced in patients with ILD. EELV ¼ end-expiratory lung volume. Source: From Ref. 19.

encroachment on the expiratory reserve volume as an option for increasing VT. This would prevent effective expiratory muscle recruitment from occurring, thus forcing the inspiratory muscles to take on a greater share of the increased work of breathing. D. Characteristics of Dyspnea in ILD

Rampulla et al. (21) included 16 patients with ILD in their study of exercise responses in 88 patients with chronic pulmonary disease. The authors observed that 62% of patients with ILD stopped exercise due to dyspnea, 25% stopped because of fatigue and 12% stopped due to cardiac limitation. ln ILD, a correlation was noted between exertional dyspnea and ventilation (expressed as a fraction of maximum ventilatory capacity: VE/MVV). However, other potential contributors to dyspnea and exertional limitation, such as hypoxia, ventilatory mechanics, and airflow, were not studied in detail. Mahler et al. (22) undertook a qualitative analysis of dyspnea in patients with various cardiopulmonary diseases. Patients with ILD commonly selected descriptors denoting increased work/effort and rapid breathing. Patients in this study relied on their recall of more remote exertional symptoms. O’Donnell et al. (19) evaluated the quality and magnitude of dyspnea at exercise termination in 12 patients with ILD. They found that for a given level of oxygen uptake or ventilation, patients reported a substantially

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Figure 4 The ratio between tidal volume [as a percentage of predicted vital capacity (VC)] and the tidal swing of esophageal pressure Pes [as a percentage of maximal inspiratory pressure (PImax)] is an index of neuromechanical coupling. For a given respiratory effort (Pes/PImax), the tidal volume response is reduced in ILD and CHF. Source: From Ref. 19 and 90.

greater level of dyspnea than healthy control subjects (Fig. 2). The quality of the exertional dyspnea reported by ILD patients was also distinct. Both the healthy and ILD groups chose terms such as increased ‘‘work and/or effort’’ and ‘‘heaviness’’ of breathing to describe their dyspnea, but only patients with ILD chose the terms relating to ‘‘unsatisfied inspiratory effort,’’ ‘‘increased inspiratory difficulty’’ and ‘‘rapid breathing’’ (Fig. 5). III. Mechanisms of Dyspnea in ILD The mechanisms of exertional dyspnea in ILD remain unknown. Possible contributory factors include: (1) increased chemoreceptor activation secondary to hypoxia, (2) altered vagal afferent activity as a result of lung parenchymal abnormalities, (3) increased contractile muscle effort due to increased elastic loading and functional weakness of the ventilatory muscles, (4) restriction of thoracic volume displacement for a given or increased central medullary drive and (5) any combination of the above. The published evidence to date does not identify a single mechanism that fully explains the nature of dyspnea in ILD, however several plausible theories have been evaluated. A. Hypoxia and Dyspnea in ILD

Arterial oxygen desaturation during exercise is a common finding in ILD and although one may intuitively expect hypoxia to be an important

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Figure 5 The selection frequency for qualitative descriptors of exertional dyspnea are shown for normal subjects (n ¼ 12), ILD (n ¼ 12) and CHF (n ¼ 12).  p < 0.05, Significant difference from normal group. Source: From Ref. 19, 101.

determinant of dyspnea, the relationship between hypoxia and dyspnea in ILD has not been well established. Research involving healthy subjects has suggested that the relationship between hypoxia and dyspnea may be indirect and secondary to the attendant stimulation of ventilation (23,24). When changes in ventilation are taken into account, arterial oxygen levels actually correlate poorly with dyspnea. There are currently no studies, which specifically address the relationship between arterial oxygen levels and dyspnea in ILD, although some studies have examined the relationship between acute O2 administration and either ventilation or exercise capacity. Lourenco et al. (25) and Turino et al. (26) observed that resting ventilation in patients with ILD did not change significantly following administration of 40% oxygen. The conclusions that may be drawn from these studies are limited because the majority of the patients included did not have hypoxia at rest and the effects of oxygen were not evaluated during exercise. More recently, Bye et al. (27) evaluated the effect of supplemental oxygen on ventilation during exercise. They noted that exercise duration was increased with the addition of supplemental oxygen in patients with ILD. Lactic acid and oxygen saturation were not measured in all patients but appeared to improve in some with oxygen administration. Oxygen also clearly lowered ventilation measured at a given time-point during exercise. Other potential contributors to dyspnea relief during oxygen therapy

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include improved ventilatory and peripheral function, as well as cardiac performance. Finally, oxygen therapy may modify central processing of various dyspneogenic stimuli and thus influence respiratory sensation. Marciniuk et al. (20) evaluated the exercise responses of seven patients with ILD. Four of the seven patients were limited primarily by dyspnea while the remaining three was limited by leg fatigue. Patients limited by dyspnea had greater ventilation and demonstrated evidence of expiratory flow limitation during exercise. However, the average arterial oxygen saturation at peak exercise was equal in both groups (84%). Although the small sample size of this study prevents a definitive conclusion from being drawn, the results support the argument that hypoxia is not the primary mechanism for dyspnea in ILD. B. Role of the Vagus

The lung is innervated by a variety of receptors capable of responding to a wide range of stimuli. Of these receptors, the juxta-pulmonary receptors (unmyelinated pulmonary C-fibers) have been of particular interest in ILD (28–30). As their name implies, these ‘‘j-receptors’’ are located near the alveoli, close to the pulmonary capillaries. Experimentally, j-receptors may be stimulated by a variety of different chemicals, delivered by either inhalation or via pulmonary circulation. The resulting afferent signal is transmitted via the vagus nerve and has been shown to produce a shallow and rapid breathing response in animals. Of greater clinical relevance is the observation that j-receptor activation may also occur in cats following pulmonary congestion produced experimentally by aortic occlusion (31). Interestingly, it was noted that the onset of excitation was more closely related to the fall in lung compliance than the increase in pulmonary artery pressure associated with congestion. This observation prompted speculation that j-receptors may be responsible for the dyspnea related to interstitial edema. The role of the vagus nerves in the etiology of dyspnea in ILD has also been investigated. The vagi are responsible for transmitting afferent signals from a number of pulmonary receptors, (i.e., stretch receptors, rapidly adapting receptors, and bronchial j-receptors) (28). Earlier studies utilized artificially induced pneumonitis in dogs as a surrogate model for ILD (32). The presence of pneumonitis was associated with increases in lung recoil, ventilation, and respiratory frequency, as well as a reduced exercise tolerance. The investigators subsequently demonstrated that the changes in ventilatory pattern resulting from a restrictive process could be partially abolished by vagal blockade. Cervical blockade of the vagus nerves had no effect on healthy animals but lowered respiratory rate and increased tidal volume in dogs with pneumonitis. Obviously, the assessment of dyspnea was impossible in animal studies but the ‘‘normalization’’ of ventilatory

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responses following chemical vagotomy suggested that vagal afferents were involved in control of breathing in ILD, and may possibly influence the development of dyspnea. Unfortunately, subsequent experiments in human patients with ILD failed to support this hypothesis (36). The role of the vagus in human neuroregulatory control and respiratory sensation has not been determined with any precision. Total pulmonary denervation after heart/lung transplantation does not effect the ventilatory response to hypoxia, hypercapnia or exercise (33–35). Moreover, breathing pattern responses to external mechanical loading are unaffected by vagotomy (35). Arguably, the most conclusive work on this subject was published by Winning et al. (36). The authors used inhaled bupivicaine to produce airway anesthesia in six patients with ILD, based on previous work that suggested that this would provide blockade of pulmonary afferent receptors. Adequate anesthesia was confirmed by abolition of the cough reflex associated with inhalation of 5% citric acid. On subsequent exercise testing, bupivicaine inhalation was found to have no effect on either exercise capacity or cardiopulmonary responses, compared to placebo. Three of six patients actually reported an increase in dyspnea at the end of exercise following inhalation of bupivacaine, while one patient reported a reduction in dyspnea. These differences, however, were generally very modest and an overall analysis of variance failed to demonstrate a significant effect with airway anesthesia. The results of this study suggested that vagal stimulation was not the principle mechanism for dyspnea in ILD. C. Increased Effort and Dyspnea in ILD

Respiratory motor output is increased in ILD and indices of respiratory muscle effort have been shown to correlate with dyspnea in healthy subjects as well as in patients with a wide variety of lung diseases. Leblanc et al. (37) measured the intensity of breathlessness during exercise in 20 patients, 11 of whom had evidence of restriction on resting pulmonary function tests. A multiple regression analysis found that exertional dyspnea was significantly related to peak inspiratory pressure (as a fraction of maximum inspiratory pressures), tidal volume (as a fraction of VC), mean inspiratory flow rate, the inspiratory duty cycle and respiratory rate. Many of these variables would be adversely affected in the presence of ILD, thus explaining why these patients experience greater dyspnea. Inspiratory pressures are increased due to lower lung compliance, which also reduces VC. In order to meet ventilatory demands in the presence of reduced volumes, respiratory rate is often supranormal, particularly during exertion. Tachypnea will typically reduce expiratory time to a greater degree than inspiratory time, thus increasing the inspiratory duty cycle. Based on the above evidence, it would seem that inspiratory muscle effort influences dyspnea in ILD. However, this observation does not explain why the quality of dyspnea in ILD is

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distinct from exertional dyspnea experienced in health, even when increases in inspiratory muscle effort are comparable. The reduced lung volumes that characterize ILD would normally convey a mechanical advantage to the inspiratory muscles, particularly the diaphragm, thus enhancing their ability to generate pressure (38). Some interstitial diseases, such as those associated with connective tissue disorders, may be associated with concomitant ventilatory muscle weakness. Steroid myopathy and nutritional problems may additionally alter the load–capacity ratio of the inspiratory muscles and result in perceived heightened inspiratory effort. Baydur et al. (39) studied 36 patients with various stages of sarcoidosis. They found that dyspnea in this population correlated best with evidence of inspiratory muscle weakness. D. Neuromechanical Dissociation and Dyspnea in ILD

The underlying premise of the neuromechanical dissociation model is that dyspnea is the result of a ‘‘dissociation’’ between central motor command output (and corollary efferent signals) to the respiratory muscles, and afferent feedback from a multiple sensory receptors throughout the respiratory system (40–46). This general concept of dyspnea causation has previously been highlighted in various iterations by Campbell and has been put forward as a putative mechanism for this symptom in both asthma and COPD (40–46). A multitude of sensory receptors are believed to convey precise proprioceptive information regarding change ‘‘from the status quo’’ in the chemical or metabolic milieu or in the mechanical and muscle pump performance characteristics of the ventilatory system. Mechanoreceptors in the airways, lung, and chest wall (and its musculature), sense tidal alterations in airflow, lung volume and chest wall motion, as well as changes in the tension and length of the ventilatory muscles. This afferent information is transmitted via vagal, glossopharyngeal, spinal, and phrenic nerves and is conveyed to the medulla and central cortex where it is integrated (28). In health, increases in respiratory drive (for example, in response to increased oxygen consumption and carbon dioxide production during exercise) will result in proportional and appropriate increases in ventilation that, in turn, would be sensed by afferent receptors and ‘‘feedback’’ to the central nervous system (described above). When the relationship between efferent drive and afferent feedback is altered, the sensation of dyspnea is produced (41). Based on the pathophysiology of ILD described above, it is reasonable to expect this relationship between central drive and the mechanical response of the system to be compromised. Efferent drive is increased in ILD due to V/Q mismatching and elastic loading. V/Q mismatching increases physiologic deadspace, requiring a compensatory increase in ventilation (and efferent drive) in order to meet metabolic requirements

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of the body. Reduced lung compliance will also require an increase in efferent signaling to the respiratory muscles in order to maintain a given level of ventilation. The restriction in lung volume expansion caused by reductions in lung compliance will also alter the afferent feedback. It should be appreciated that, although the concept of neuromechanical dissociation may be appealing, it is also difficult to prove because comprehensive measurements of efferent and afferent signals are not currently possible. Nevertheless, the results of three experimental studies have supported this hypothesis. Harty et al. (47) investigated the possible contribution of pulmonary and chest wall mechanoreceptors in dyspnea by using external thoracic restriction in healthy subjects. They argued that previous models of restrictive lung disease that utilized an external elastic load, failed to reproduce the rapid and shallow breathing pattern which characterizes ILD. In this study, external restriction was produced by an inexpandable corset and responses to steady-state exercise were measured. (CWS) faithfully mimics many of the physiological abnormalities common to the restrictive disorders and is associated with reduced lung compliance (48). During exercise, this restriction produced a more shallow and rapid breathing pattern compared to placebo and was associated with greater dyspnea. These responses were similar to those observed in other studies for patients with ILD. The descriptors (quality) of dyspnea reported in this study were also similar to those reported by ILD patients in other studies. External restriction was associated with reports of inspiratory difficulty, tightness, and increased effort. This model suggests that the etiology of dyspnea in ILD may be due, at least in part, to the mechanical effects of restriction itself. It is important to acknowledge that the findings of Harty et al. (47) do not necessarily contradict previously mentioned attempts to link dyspnea with respiratory muscle effort, as the application of external chest wall restriction would have increased inspiratory muscle load. Instead, this study supports the concept that additional factors may be contributing to the dyspnea in ILD. O’Donnell et al. (46) employed a combination of external chest wall restriction and added deadspace to create a closer approximation of the physiologic disturbances caused by ILD. This study explored the contributions of tidal volume restriction as well as increased respiratory drive to the genesis of dyspnea. The exercise and ventilatory responses of 12 healthy men under various combinations of restriction and added deadspace were assessed. The latter was produced by the addition of 600 mL of volume to a breathing circuit. The added deadspace was intended as a crude reproduction of the increased physiologic deadspace seen in ILD and required the subjects to increase ventilation (and VT) in order to maintain adequate CO2 excretion, thus serving as added stimulus for ventilatory drive. The results of external restriction to 60% of VC were similar to those reported by Harty et al. Tidal volumes during exercise and exercise capacity were

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reduced and both dyspnea and indices of respiratory effort were increased (Fig. 6). Furthermore, inspiratory difficulty and/or unsatisfied inspiration were common descriptors chosen to qualify the dyspnea (Fig. 7). The addition of deadspace alone only modestly increased dyspnea and this increase was proportional to increases in ventilation; when the increase in VT is appropriate for a given increase in CO2, neuromechanical coupling is maintained. Dyspnea intensified dramatically when the tidal volume response to the added chemical load was physically constrained. The results of this study provide support for the neuromechanical dissociation hypothesis by demonstrating that, by changing both efferent drive (in response to added deadspace) and afferent feedback (by restricting chest wall expansion), one can incrementally increase dyspnea. In a study designed to examine contributory factors to inspiratory difficulty during exercise in patients with ILD, VT/IC (a measure of mechanical restriction at rest) correlated best with dyspnea (Borg)–VO2 slopes during exercise (r ¼ 0.58, p < 0.05) (19). Using a stepwise multiple regression analysis in 12 patients with ILD and 12 age-matched control subjects, the slope of esophageal pressure/VT (a crude measure of neuromechanical dissociation) over VO2, together with the group covariate, accounted for 60% of the variance in Borg–VO2 slopes during exercise. Collectively, these data support the notion that the inability to expand tidal volume appropriately in the face of an increased drive to breathe contributes to the intensity and quality of dyspnea in ILD.

Figure 6 In 12 healthy young males, dyspnea intensity (Borg scale) was increased while exercising with the combination of chest wall strapping (CWS to 60% of vital capacity) and added dead space (DS; 600 ml dead space was added to the breathing circuit) compared to control testing. During CWS þ DS, there was a reduced tidal volume response (VT expressed as a percentage of VC) for a given respiratory effort (esophageal pressure expressed as a percentage of maximal inspiratory pressure: Pes/ PImax), i.e., neuromechanical dissociation. Source: From Ref. 46.

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Figure 7 Qualitative descriptors of exertional dyspnea in 12 healthy young males while exercising with the combination of chest wall strapping (CWS) and dead space loading (DS) and during control testing. p < 0.05 Significant difference from control. Source: Data From Ref. 46.

IV. Other Forms of Restrictive Lung Disease A. Pleural Effusions

Pleural effusions can be viewed as a form of restrictive lung disease as they are typically associated with a reduction in lung volume. Unlike other restrictive conditions, however, effusions are also associated with distension of the chest wall. Indeed, the increase in chest wall volume produced by fluid in the pleural space is usually significantly greater than the reduction in lung volume (49–51). Dyspnea is a common complaint among patients with large pleural effusions. Estenne et al. (52) examined the mechanism of dyspnea in this population. They measured the respiratory mechanics of nine patients with large pleural effusions before and 2 hr after thoracentesis. Prior to thoracentesis, all patients had marked reductions in lung volumes, including both VC and functional residual capacity. Static compliance of the lungs was also significantly reduced. These changes are similar to those seen in ILD. However, a unique

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and important difference relates to inspiratory muscle length. In ILD, inspiratory muscle function is actually optimized because reductions in chest wall size are associated with a lengthening of the muscle fibres (53). In pleural effusions, overdistension of the chest wall is associated with shortening of inspiratory muscles, placing them at a functional disadvantage. Following thoracentesis, it was noted that despite an average fluid removal of 1.82 L, there were relatively small changes in either VC or functional residual capacity (0.3 and 0.46 L, respectively). It was suggested that these lung volume changes were too small to adequately explain the degree of dyspnea relief reported by the patients. Many patients experienced marked relief of dyspnea in the presence of minimal change in volumes or lung mechanics. Symptom improvement in this and previous studies could not be attributed to improvements in arterial oxygenation following the procedure (49–52). Rather, it was argued that the mechanism of dyspnea relief was related to the reduction in the size of the thoracic cage. By reducing the expansion of the chest wall, thoracentesis shifted the pressure–volume curve, such that a given change in pressure produced larger changes in volume. The reduction in chest wall volume also lengthened inspiratory muscles, allowing them to operate on the more advantageous portion of their length–tension curve. This resulted in a significant increase in the pressure generating capacity of the inspiratory muscles. Improvement in the operating characteristics of the diaphragm and intercostal muscles and in the compliance and mobility of the thoracic cage would be expected to restore better neuromechanical coupling during tidal breathing. Improved mechanical output for a given drive after chest wall volume reduction may be ‘‘sensed’’ through altered integrated afferent activity from multiple mechanoreceptors in the chest wall and its musculature, which projects to the cortex (54,55). B. Pleural Thickening

For many patients, the presence of pleural thickening will not be associated with any respiratory symptoms. A minority of patients, however, will report exertional dyspnea that cannot be explained by other processes. Picado et al. (56) attempted to explore possible mechanisms for dyspnea among a group of six symptomatic patients with asbestos-related pleural disease. Their study patients all complained of dyspnea and had evidence of pleural disease, without significant parenchymal disease on radiography and with a normal diffusing capacity for carbon monoxide. On average, resting pulmonary function tests revealed a mild reduction in VC. This was offset by an increase in residual volume, such that total lung capacity was within normal limits. Exercise testing revealed a reduction in exercise capacity in five of six patients. Ventilatory pattern during exercise was rapid and shallow, with a tidal volume that was reduced even when examined in proportion to an already reduced VC. Diaphragmatic EMG did not show evidence of

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muscle fatigue during exercise. A complete assessment of pulmonary mechanics was not performed, nevertheless, it was postulated that the reduction in resting VC and the shallow breathing pattern during exercise suggested the presence of an increased elastic load. Although definitive conclusions regarding the etiology of dyspnea cannot be drawn from this study, it does provide evidence that, in some cases, pleural thickening may produce a ‘‘restrictive’’ ventilatory pattern resembling that produced by ILD (or external chest wall restriction). In this circumstance, inability to expand tidal volume appropriately in response to the progressively increasing drive of exercise may contribute to respiratory discomfort. C. Neuromuscular Disease

Respiratory involvement in neuromuscular disease is highly variable and not always clinically recognized, in part because many patients will become limited by peripheral muscle weakness before exertional dyspnea is noticed. A restrictive ventilatory deficit may accompany neuromuscular weakness of the respiratory muscles. The degree of restriction will depend on the underlying condition and the respiratory muscles involved. Inspiratory muscle weakness will manifest primarily as a reduction in IRV and expiratory weakness will reduce the expiratory reserve volume (ERV) (57). Both conditions may potentially reduce VC. With longstanding neuromuscular weakness, lung and chest wall compliance will also diminish (57). The precise reasons for this change are not known but could possibly include chronic microatelectasis and chest wall rigidity due to remodeling. Exercise testing is often not possible for patients who have concomitant limb weakness but, if available, will typically demonstrate relative rapid and shallow breathing if respiratory muscle weakness is present. The mechanisms of dyspnea in patients with ventilatory muscle weakness have received little attention. Possible contributors include: (1) increased motor output and corollary discharge to the central cortex resulting in heightened sense of contractile muscle effort, (2) altered afferent activity of mechanoreceptors in the lung, chest wall, and respiratory muscles, (3) increased chemoreceptor activation as a result of arterial hypercapnia, hypoxia, or early metabolic acidosis (in patients with exercise deconditioning) or (4) a variable combination of all of the above factors culminating in neuromechanical dissociation. As previously mentioned, perception of inspiratory muscle effort and dyspnea is related to the ratio of tidal inspiratory pressure (Pes) to the maximum inspiratory pressure (PImax) (58). Inspiratory muscle weakness will increase this ratio (Pes/PImax) by decreasing the denominator. The effort expended during tidal breathing, therefore, represents a much higher fraction of the maximal possible effort than in health. Increased central motor output is thought to be present in patients with neuromuscular weakness, whether

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Figure 8 (A) Dyspnea (Borg scale) with increasing ventilation (VE) during CO2 rebreathing. a.u. ¼ arbitrary units. (B) Changes in respiratory effort (Pes sw/Pes sn) for a given tidal volume (VT). Closed circles are patients, open circles are mean for control subjects. Source: From Ref. 64.

the latter is intrinsically present or experimentally induced in the laboratory (59–63). It is reasonable to assume that the attendant corollary discharge contributes to the perception of increased breathing effort, but this theory is difficult to prove. Lanini et al. (64) evaluated the relationship between lung mechanics, respiratory motor output and dyspnea by comparing 11 patients with neuromuscular disease to 17 healthy control subjects during hypercapnic stimulation. The authors showed that the increase in motor output [as reflected by tidal esophageal pressure swings relative to maximum sniff pressure (Pes sw/Pes sn)] for every unit change in arterial CO2 was similar in neuromuscular disease and control subjects. However, in neuromuscular disease the mechanical output [as reflected by change in VT relative to VC (VT/VC)] was diminished for any given effort and the effort–displacement ratio was elevated (Fig. 8). Dyspnea was increased for any given ventilation (VE) during CO2 stimulation in neuromuscular patients (Fig. 8), in part because of the increased dynamic elastance of the lungs, possibly secondary to microatelectasis and a stiffer chest wall. They found that 46% of the variance in dyspnea ratings in patients during CO2-loading was explained by the increased ratio of (Pes sw/Pes sn) to VT/VC and postulated an important role for neuromechanical dissociation. D. Obesity

Obesity could arguably be considered the most common restrictive process. Early mechanical studies have demonstrated a reduction in chest wall

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compliance with increased work of breathing in resting obese patients (65–67). The reduced chest wall compliance is associated with a reduced FRC. TLC, VC, and ERV are frequently reduced in more severe obesity but RV is relatively preserved. Decreased static inspiratory strength has been reported in morbid obesity (body mass index 41 kg/m2) and may reflect the increased chest impedance to diaphragmatic contraction (68). During exercise, ventilation is often increased, especially at the higher submaximal work rates, when compared with lean age-matched subjects (69). This has been attributed to (1) increased metabolic demands from a greater body mass as well as an earlier anaerobic threshold reflecting attendant deconditioning, and (2) in some cases, increased physiologic deadspace due to V/Q mismatching from basal atelectasis (70–72). The VO2–work rate (efficiency) relationship is similar to lean subjects but is displaced upwards in obesity. Patients with severe obesity may also have a lower than normal peak ventilation, which may be related to lowered chest wall compliance (70–72). Expiratory flow limitation may be present at rest in obese patients, reflecting the proximity of VT to RV, i.e., reduced ERV (73–76). During exercise, the combination of flow limitation and higher than normal ventilatory demands may result in failure to decrease EELV as in normalweight (young) individuals, or in overt dynamic hyperinflation (74,75). As mentioned before, this may impose constraints on VT expansion and burden the inspiratory muscles (i.e., diminish work-sharing with the expiratory muscles). Alternatively, a normal VT expansion can be achieved but at the expense of a relatively lower IRV reflecting increased elastic work, i.e., the operating volume is closer to TLC and the ‘‘stiffer’’ upper extreme of the respiratory system’s pressure-volume curve. Anecdotally, it has been noted that obese patients tend to report increased exertional dyspnea but the amount of research addressing the etiology of dyspnea in obesity is surprising limited. Sahebjami and Gartside (77) found an association between resting dyspnea and reductions in maximum ventilatory capacity, which suggests that dyspnea may be related, in part, to the degree of restriction caused by obesity. In common with other restrictive disorders, the above outlined physiological derangements of obesity would be expected to increase central drive and diminished mechanical output during activity. This mismatching could theoretically give rise to respiratory discomfort that is qualitatively similar to that described by lean subjects during combined chest wall and chemical loading (see above) (21). E. Congestive Heart Failure

Many patients with congestive heart failure (CHF) demonstrate a restrictive ventilatory defect on resting pulmonary function testing (Fig. 9). Reductions in lung compliance have been described, even in the absence of overt pulmonary edema (78–81). Mechanical restriction is evident by reductions

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Figure 9 Tidal flow–volume loops at rest (inner solid) and during exercise (dashed) are shown in relation to their respective maximal flow–volume loops (outer solid) in a normal healthy subject and a typical patient with CHF. Peak exercise in CHF was compared with exercise at a comparable metabolic load in the age-matched person. Note expiratory flow limitation (tidal expiratory flow encroaching on the maximal curve) and an increase in dynamic end-expiratory lung volume (EELV) during exercise in the CHF patient. Inspiratory capacity (IC) and inspiratory reserve volume (IRV) are also reduced in CHF. The dotted line represents the predicted maximal expiratory curve for the CHF patient. Source: From Ref. 90.

of VC, IC, and ERV (78–81). Significant small airways obstruction is frequently present in CHF, even in nonsmokers (80–84). Airway dysfunction and expiratory flow limitation may be caused by bronchial mucosal edema that may, in turn, contribute to airway hyper-responsiveness (80–85). Reductions in static inspiratory and expiratory muscle strength have been reported in some studies (86–89) but not in others (90,91), and the exact prevalence of muscle weakness remains to be determined. A recent study by Nanas et al. (92) showed that resting IC (in L) predicted symptomlimited peak VO2 (in L/min) in CHF better than any other resting pulmonary function or hemodynamic parameter, confirming the importance of restrictive ventilatory mechanics. Peak ventilation is usually diminished in CHF, reflecting the reduced peak VO2. Submaximal ventilation is usually increased at higher work rates than in health, reflecting an earlier onset of metabolic acidosis due to reduced oxygen delivery/utilization and deconditioning (93–95). Increased central drive during exercise may also be related to increased metaboreceptor (and sympathetic system) activation in the poorly perfused and weakened peripheral muscles (96–99). Gas

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exchange is remarkably preserved during exercise in CHF and arterial oxygen desaturation during exercise is rare (83,86–89). However, V/Q abnormalities throughout exercise may give rise to a higher physiological dead space than in health. Dynamic lung hyperinflation has been described during exercise and VT responses may be relatively diminished (83,92). The majority of patients with stable CHF stop exercise because of leg discomfort but such patients also experience severe exertional dyspnea (15). Potential contributory factors to dyspnea in CHF include: (1) increased central ventilatory drive as a result of increased inspiratory muscle loading and/or functional weakness, increased chemical loading and sympathetic system activation; (2) impaired dynamic ventilatory mechanics and altered peripheral mechanoreceptor inputs; and (3) abnormal cardiovascular responses which remain poorly understood. Several investigators have attempted to elucidate the mechanisms underlying dyspnea in CHF. McParland et al. (86) assessed respiratory muscle strength at rest in nine patients with CHF. They found a significant inverse correlation between inspiratory muscle strength and chronic activity-related dyspnea, as assessed by a comprehensive questionnaire (Baseline Dyspnea Index). A weaker, but still significant, relationship was noted between expiratory muscle strength and dyspnea. As discussed above, respiratory muscle effort (efferent drive) is an important contributor to dyspnea and will clearly be increased in the setting of muscle weakness. There was no definitive explanation provided for the presence of respiratory muscle weakness in CHF, although it was postulated that it may be one manifestation of more generalized striated muscle abnormalities. Previous studies of peripheral muscle function in CHF noted alterations in muscle function, which were attributed to reduced aerobic activity and substrate utilization abnormalities (98). Cahalin et al. (99) assessed dyspnea and respiratory muscle strength in CHF patients before and after inspiratory muscle training. They found that inspiratory muscle training produced improvements in maximum inspiratory and expiratory pressures. Reductions in dyspnea during submaximal exercise were also noted following inspiratory muscle training. Although these results support a relationship between respiratory muscle weakness and dyspnea in CHF, its prevalence in this population is unknown. Russell et al. (100) evaluated dyspnea using cardiopulmonary exercise testing in 71 patients with CHF; however, no control group was used. Instead, patients were divided into two groups for analysis, depending on their primary reason for stopping exercise (leg fatigue or dyspnea). Fortyone patients stopped exercising because of dyspnea, while the remainder were limited by leg fatigue. There were no differences observed on exercise testing, i.e., similar ventilatory and metabolic responses were measured in both groups. Based on these results, it was concluded that exertional dyspnea in CHF was not related to differences in ventilatory responses to

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exercise. Unfortunately, no measurements of pulmonary mechanics were performed to support this hypothesis. Furthermore, it should be noted that significant dyspnea was also reported by the fatigue-limited group. O’Donnell et al. studied the contribution of mechanical factors to exertional dyspnea and exercise intolerance in 12 patients with advanced CHF, by performing detailed flow-volume loop analysis during exercise (101). These authors showed that both peak VO2 and the dyspnea (Borg)–VO2 slope correlated significantly with the resting VT/IC ratio, i.e., constraints on VT expansion. Fittingly, 75% of these patients selected qualitative descriptors of dyspnea pertaining to ‘‘unsatisfied inspiratory effort’’ during exercise (Fig. 5). In order to examine the role of the ventilatory muscles in the exertional dyspnea of CHF, O’Donnell et al. (90) examined the effects of inspiratory muscle unloading during symptom-limited constant-load exercise using a ventilator. Not surprisingly, during the unassisted control test, peak VO2 and ventilation were lower than normal in CHF patients. These patients also had a higher submaximal ventilation and experienced severe dyspnea. The ventilatory pattern was characterized by a relatively shallow VT and a high respiratory rate. No arterial oxygen desaturation occurred. Furthermore, exercise flow-volume loop analysis demonstrated dynamic hyperinflation: there was a progressive rise in EELV by an average of 0.26 L. ln turn, a higher lung volume at end-expiration would limit the ability of VT to expand. Indeed, at a peak work rate of only 41% predicted, endinspiratory lung volume comprised 92% of TLC, suggesting that further expansion of VT was not possible. Pressure support, which reduced the tidal inspiratory pleural pressure–time slope by an average of 44%, did not affect submaximal dyspnea ratings but, nevertheless, allowed patients to exercise for an additional 3 min (a 43% increase over the unassisted control test) at ventilation levels greater than 50 L/min without experiencing any significant rise in dyspnea. Pressure support also reduced perceived leg discomfort, which contributed importantly to the increased exercise endurance. The results of this study lend support to previous studies suggesting that abnormal ventilatory muscle function (either increased loading or weakness or both) contributes to exertional dyspnea in CHF. V. CONCLUSION Although our understanding of the mechanisms of dyspnea in restrictive lung disease remains incomplete, an overview of the existing literature reveals several common themes and provides new insights. All of these conditions are characterized by a reduction in the compliance of the respiratory system (lung and chest wall). The universal sequelae of this is a reduced ability to adequately expand tidal volume to normal levels in response to increases in central respiratory drive. The impairment of mechanical output

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in restrictive lung disorders is multifactorial: excessive elastic loading and inspiratory muscle weakness, either singly or in combination, appear to be important. The central reflexic drive to breathe is likely to be increased during activity compared with normal as a result of alterations in the metabolic load and gas exchange capabilities, both of which vary greatly between patients. There is no definitive evidence in the restrictive disorders that altered chemoreceptor activation per se, can directly give rise to dyspnea, independent of the increased ventilation and attendant mechanical changes. Similarly, there is little convincing evidence at present that sensory inputs arising from mechanoreceptors in the lungs, chest wall or ventilatory muscles directly give rise to dyspnea. The primary role of peripheral sensory receptors may be to provide precise, simultaneous, proprioceptive feedback concerning the integrated dynamic changes in thoracic volume, in inspired airflow and in the tension and length of the inspiratory muscles. These multiple peripheral receptors are well placed to detect mismatching between the central controller and the mechanical response during tidal respiration. One attractive theory is that conscious awareness of this central–peripheral mismatching may form the basis for some of the qualitative dimensions of dyspnea in the restrictive lung disorders. References 1. O’Donnell DE, Fitzpatrick M. Physiology of interstitial lung disease. In: Swartz M, King BC, eds. Interstitial Lung Disease. 4th ed. Dekker, 2003:54–75. 2. Macklem PT, Becklake MR. The relationship between mechanical and diffusing properties of the lung in health and disease. Am Rev Respir Dis 1963; 87:47–56. 3. Yearnult JC, deJonghe M, deCoster A, Englert M. Pulmonary mechanics in diffuse fibrosing alveolitis. Bull Eur Physiopathol Respir 1975; 22:231–244. 4. Gibson GJ, Pride NB. Pulmonary mechanics in fibrosing alveolitis: the effects of lung shrinkage. Am Rev Respir Dis 1977; 116:637–647. 5. Georges R, Saumon G, Lafosse JE, Turiaf J. Membrane-diffusing capacity and pulmonary capillary blood volume. Prog Respir Res 1975; 8:198–212. 6. Wagner PD, Dantzker DR, Dueck R. Distribution of ventilation–perfusion ratios in patients with interstitial lung disease. Chest 1976; 69:256–257. 7. Kaltreider NL, McCann WS. Respiratory response during exercise in pulmonary fibrosis and emphysema. J Clin Invest 1937; 16:23–40. 8. Austrian R, McClement JH, Renzetti AD, et al. Clinical and physiologic features of some types of pulmonary diseases with impairment of alveolar– capillary diffusion. Am J Med 1951; 2:267–285. 9. Keogh BA, Lakatos E, Price D, Crystal RG. Importance of the lower respiratory tract in oxygen transfer. Exercise testing in patients with interstitial and destructive lung disease. Am Rev Respir Dis 1984; 129:S76–S80.

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10. Spiro SG, Dowdeswell IRG, Clark TJH. An analysis of submaximal exercise responses in patients with sarcoidosis and fibrosing alveolitis. Br J Dis Chest 1981; 75:169–180. 11. Burdon JGW, Killian KJ, Jones NL. Pattern of breathing during exercise in patients with interstitial lung disease. Thorax 1983; 38:778–784. 12. Jones NL, Rebuck AS. Tidal volume during exercise in patients with diffuse fibrosing alveolitis. Bull Eur Physiopathol Respir 1979; 15:321–327. 13. Risk C, Epler GR, Gaensler EA. Exercise alveolar–arterial oxygen pressure difference in interstitial lung disease. Chest 1984; 5:69–74. 14. Johnson RL Jr, Spice WS, Bishop JM, Forster RE. Pulmonary capillary blood volume, flow and diffusing capacity during exercise. J Appl Physiol 1960; 15:893–902. 15. Hamilton AL, Killian KJ, Summers E, Jones NL. Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders. Am J Respir Crit Care Med 1995; 152:2021–2031. 16. Widimsky J, Riedel M, Stonek V. Central hemodynamics during exercise in patients with restrictive pulmonary disease. Bull Eur Physiopath Respir 1977; 13:369–379. 17. Jernudd-Wilhelmsson T, Homblad Y, Hedenstierna G. Ventilation–perfusion relationships in interstitial lung disease. Eur J Respir Dis 1986; 68:39–49. 18. DiMarco AF, Kelsen SG, Cherniack NS, Goethe B. Occlusion pressure and breathing pattern in patients with interstitial lung disease. Am Rev Respir Dis 1983; 127:425–430. 19. O’Donnell DE, Chau LKL, Webb KA. Qualitative aspects of exertional dyspnea in patients with interstitial lung disease. J Appl Physiol 1998; 84: 2000–2009. 20. Marciniuk DD, Sridhar G, Clemens RE, Zintel TA, Gallagher CG. Lung volumes and expiratory flow limitation during exercise in interstitial lung disease. J Appl Physiol 1994; 77:963–973. 21. Rampulla C, Baiocch S, Dacosto E, Ambrosino N. Dyspnea on exercise: pathological mechanisms. Chest 1992; 101:248S–252S. 22. Mahler DA, Harver AA, Lentine T, Scott JA, Beck K, Schwartzstein RM. Descriptors of breathlessness in cardiorespiratory diseases. Am J Respir Crit Care Med 1996; 154:1357–1363. 23. Lane R, Adams L, Guz A. The effects of hypoxia and hypercapnia on perceived breathlessness during exercise in humans. J Physiol (Lond) 1990; 428:579–593. 24. Lane R, Adams L, Guz A. Acidosis and breathlessness in normal subjects [abstr]. Eur Respir J 1990; 3:142S. 25. Lourenco RV, Turino GM, Davidson LAG, Fishman AP. The regulation of ventilation in diffuse pulmonary fibrosis. Am J Med 1965; 38:199–216. 26. Turino GM, Lourenco RV, Davidson LAG, Fishman AP. The control of ventilation in patients with reduced pulmonary distensibility. Ann NY Acad Sci 1963; 109:932–941. 27. Bye PTP, 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 1992; 126:1005–1012.

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28. Widdicombe JG. Nervous receptors in the respiratory tract and lung. In: Hornbein TD, ed. Regulation of Breathing. Lung Biology in Health and Disease, 17th edn. Vol. 1. New York: Marcel Dekker, 1981:429–472. 29. Paintal AS. Vagal sensory receptors and their reflex effects. Physiol Rev 1973; 53:159–227. 30. Guz A, Nobel MIM, Eisele JH, Trechard D. Experimental results in vagal block in cardio pulmonary disease. In: Porter R, ed. Breathing. Hering-Breuer Centenary Symposium. London: Churchill, 1970:315–328. 31. Paintal AS. Mechanism of stimulation of type J pulmonary receptors. J Physiol 1969; 203:511–532. 32. Philipson EA, Murphy E, Kozar LF, Schultze RK. Role of vagal stimuli in exercise ventilation in dogs with experimental pneumonitis. J Appl Physiol 1973; 39:76–85. 33. Sanders MH, Owens GR, Sciurba FC, et al. Ventilation and breathing pattern during progressive hypercapnia and hypoxia after human heart–lung transplantation. Am Rev Respir Dis 1989; 140:38–40. 34. Kagawa FT, Duncan SR, Theodore J. Inspiratory timing of heart–lung transplant recipients during progressive hypercapnia. J Appl Physiol 1991; 71: 945–950. 35. Tapper DP, Duncan SR, Kraft S, Kagawa FT, Marshall S, Theodore J. Detection of inspiratory resistive loads by heart–lung transplant recipients. Am Rev Respir Dis 1992; 145:458–460. 36. Winning AJ, Hamilton RD, Guz A. Ventilation and breathlessness on maximal exercise in patients with interstitial lung disease after local anaesthetic aerosol inhalation. Clin Sci 1988; 74:275–281. 37. Leblanc P, Bowie DM, Summers E, Jones NL, Killian KJ. Breathlessness and exercise in patients with cardiorespiratory disease. Am Rev Respir Dis 1986; 133:21–25. 38. DeTroyer A, Yernault JC. Inspiratory muscle force in normal subjects and patients with interstitial lung disease. Thorax 1980; 35:92–100. 39. Baydur A, Alsalek M, Louie SG, Sharma OP. Respiratory muscle strength, lung function and dyspnea in patients with sarcoidosis. Chest 2001; 210:102–108. 40. O’Donnell DE. The assessment and management of dyspnea in the clinical management of COPD. Chapter 7. In: Similowski T, Whitelaw WA, Derene J-P, eds. Management of COPD. Lung Biology in Health and Disease Series. Marcel Dekker, 2002:113–170. 41. O’Donnell DE. Exertional breathlessness in chronic respiratory diseases. In: Mahler D, ed. Dyspnea. Lung Biology in Health and Disease Series. : Marcel Dekker1998:11:97–147. 42. Campbell EJM, Freedman S, Smith PS, Taylor ME. The ability of man to detect added elastic loads to breathing. Clin Sci (Colch) 1961; 20:223–231. 43. Campbell EJM, Howell JBL. The sensation of breathlessness. Br Med Bull 1963; 19:36–40. 44. Lougheed MD, Webb K, O’Donnell DE. Breathlessness during induced hyperinflation in asthma: role of the inspiratory threshold load. Am J Respir Crit Care Med 1995; 152(3):911–920.

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45. O’Donnell DE, Bertley JC, Chau LKL, Webb KA. Qualitative aspects of exertional breathlessness in chronic airflow limitation: pathophysiological mechanisms. Am J Respir Crit Care Med 1997; 155:109–115. 46. O’Donnell DE, Hong HH, Webb KA. Respiratory sensation during chest wall restriction and dead space loading in exercising men. J Appl Physiol 2000; 88:1859–1869. 47. Harty HR, Corfield DR, Schwartzstein RM, Adams L. External thoracic restriction, respiratory sensation, and ventilation during exercise in men. J Appl Physiol 1999; 86:1142–4150. 48. Caro CG, Butler J, DuBois AB. Some effects of restriction of chest cage expansion on pulmonary function in man. An experimental study. J Clin Invest 1960; 39:53–583. 49. Yoo OH, Ting EY. The effect of pleural effusion on pulmonary function. Am Rev Respir Dis 1964; 89:55–63. 50. Neff TA, Buchanan BD. Tension pleural effusion. Am Rev Respir Dis 1975; 111:543–548. 51. Brown NE, Zamel N, Aberman A. Changes in pulmonary mechanics and gas exchange following thoracocentesis. Chest 1978; 74:540–542. 52. Estenne M, Yernault JC, DeTroyer A. Mechanism of relief of dyspnea after thoracentesis in patients with large pleural effusions. Am J Med 1982; 74: 813–819. 53. DeTroyer A, Yernault JC. Inspiratory muscle force in normal subjects and patients with interstitial lung disease. Thorax 1980; 35:92–100. 54. Shannon R. Reflexes from respiratory muscles and costovertebral joints. In: Chemiack NS, Widdicombe JG, eds. Handbook of Physiology: Control of breathing, Vol. 2 Part 1, Section 3. Bethesda: American Physiology Society 1986:2:431–448. 55. Homma I, Obata T, Sibuya M, Uchida M. Gate mechanisms in breathlessness caused by chest wall vibration in humans. J Appl Physiol 1984; 56:8–11. 56. Picado C, Laporta D, Grassino A, Cosio M, Thibodeau M, Becklake MR. Mechanisms affecting exercise performance in subjects with asbestos–related pleural fibrosis. Lung 1987; 165:45–57. 57. Gibson GJ, Pride MB, Newsom-Davis J, et al. Pulmonary mechanics in patients with respiratory muscle weakness. Am Rev Respir Dis 1977; 115:389–395. 58. Killian KJ, Jones NL. Respiratory muscle and dyspnea. Clin Chest Med 1988; 9:237–248. 59. Gandevia SC. Neural mechanisms underlying the sensation of breathlessness: kinesthetic parallels between respiratory and limb muscles. Aus N Z J Med 1988; 18:83–91. 60. Killian KJ, Bucens DD, Campbell EJM. The effect of patterns of breathing on the perceived magnitude of added loads to breathing. J Appl Physiol 1982; 52:578–584. 61. Gandevia SC, Killian KJ, Campbell EJM. The effect of respiratory muscle fatigue in respiratory sensations. Clin Sci 1981; 60:463–466.

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81. Guazzi M, Agostoni P, Matturri M, Pontone G, Guazzi MD. Pulmonary function, cardiac function, and exercise capacity in a follow-up of patients with congestive heart failure treated with carvedilol. Am Heart J 1999; 138: 460–467. 82. Duguet A, Tanucci C, Lozinguez O, Isnard R, Thomas D, Zelter M, Derenne JP, Milic-Emili J, Similowski T. Expiratory flow limitation as a determinant of orthopnea in acute heart failure. J Am Coll Cardiol 2000; 35:690–700. 83. Light RW, George RB. Serial pulmonary function in patients with acute heart failure. Arch Intern Med 1983; 143:429–433. 84. Collins JV, Clark TJH, Brown DJ. Airway function in healthy subjects and patients with left heart failure. Clin Sci Mol Med 1975; 49:217–228. 85. Cabanes LR, Weber SN, Matran R, Regnard J, Richard MO, Degeorges ME, Lockhart A. Bronchial hyper-responsiveness to methacholine in patients with impaired left ventricular function. N Engl J Med 1989; 320:1317–1322. 86. McParland C, Krishnan B, Wang Y, Gallagher CG. Inspiratory muscle weakness and dyspnea in chronic heart failure. Am Rev Respir Dis 1992; 146: 467–472. 87. Nanas S, Nanas J, Kassiotis C, et al. Respiratory muscles performance is related to oxygen kinetics during maximal exercise and early recovery in patients with congestive heart failure. Circulation 1999; 100:503–508. 88. Mancini DM, Henson D, LaManca J, Levine S. Respiratory muscle function and dyspnea in patients with chronic congestive heart failure. Circulation 1992; 86:909–918. 89. Hammond MD, Bauer KA, Sharp JT, Rocha RD. Respiratory muscle strength in congestive heart failure. Chest 1990; 98:1091–1094. 90. O’Donnell DE, D’Arsigny C, Raj S, Abdollah H, Webb KA. Ventilatory assistance improves exercise endurance in patients with stable congestive heart failure. Am J Resp Crit Care Med 1999; 160:1804–1811. 91. Hughes PD, Polkey MJ, Harris ML, Coats AJS, Moxham J, Green M. Diaphragm strength in chronic heart failure. Am J Respir Crit Care Med 1999; 160:529–534. 92. Nanas S, Nanas J, Papazachou O, Kassiotis C, Papamichalopoulos A, Milic-Emili J, Roussos C. Resting lung function and hemodynamic parameters as predictors of exercise capacity in patients with chronic heart failure. Chest 2003; 123:1386–1393. 93. Clark AL, Volterrani M, Swan JW, Coats AJ. The increased ventilatory response to exercise in chronic heart failure: relation to pulmonary pathology. Heart 1997; 77:138–146. 94. Clark AL, Volterrani M, Swan JW, Coats AJ. Ventilation-perfusion matching in chronic heart failure. Int J Cardiol 1995; 48:259–270. 95. Piepoli M, Clark AL, Volterrani M, Adamopoulos S, Sleight P, Coats AJS. Contribution of muscle afferents to the hemodynamic, autonomic, and ventilatory responses to exercise in patients with chronic heart failure: effects of physical training. Circulation 1996; 93:940–952. 96. Weber KT, Kinasewitz GT, Janicki JS, Fishman AP. Oxygen utilization and ventilation during exercise in patients with chronic heart failure. Circulation 1982; 65:1213–1223.

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97. Johnson BD, Beck KC, Olson LJ, O’Malley KA, Allison TG, Squires RW, Gau GT. Ventilatory constraints during exercise in patients with chronic heart failure. Chest 2000; 117:321–332. 98. Sullivan MJ, Green HJ, Cobb FR. Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 1990; 81: 518–527. 99. Cahalin LP, Semigran MJ, Dec GW. Inspiratory muscle training in patients with chronic heart failure awaiting cardiac transplantation: results of a pilot clinical trial. Phys Ther 1997; 77:830–838. 100. Russell SD, McNeer FR, Higginbotham MB. Exertional dyspnea in heart failure: A symptom unrelated to pulmonary function testing at rest or during exercise. Am Heart J 1998; 135:398–405. 101. D’Arsigny C, Webb KA, Raj S, Abdollah H, O’Donnell DE. Ventilatory constraints contribute to exercise limitation and dyspnea in stable congestive heart failure [abstr]. Am J Respir Crit Care Med 1999; 159:A418.

6 Language of Dyspnea

RICHARD M. SCHWARTZSTEIN Division of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, U.S.A.

I. Introduction—A Problem of Communication A patient comes to see his doctor with a complaint of shortness of breath. The probability is quite high that as the doctor begins to take her history, the focus of the questions will be on the intensity of the discomfort and the factors that precipitate the breathlessness. The quality of the breathing discomfort, what the patient actually feels, will be ignored. Contrast this with the experience of the same patient presenting to his physician with a complaint of abdominal or chest pain. Quickly, the doctor will ask about the quality of the pain—is it sharp, aching, cramping, or burning? What accounts for this difference in the approach to the assessment of two related symptoms? If a physician has a normal cardiopulmonary system, she likely experiences dyspnea only with exercise. If it is true that dyspnea, like pain, is a ‘‘private experience, and only through such experience’’ can it be defined (1), then the presumption may be that all dyspnea is characterized by this sensation and thus, there is little utility in probing for qualitative distinctions. Traditional texts used to instruct medical students on the art of 115

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patient interviewing do not discuss qualitative aspects of dyspnea (2,3) despite the fact that, as early as 1966, Comroe (4) summarized the prevailing work on dyspnea as showing six grades or types of dyspnea, and over 20 years ago, Campbell and Guz (5) enumerated four ‘‘elemental sensations’’ that ‘‘singly or in combination underlie breathlessness.’’ The patient may also be a bit unsure about the words to use to describe breathing discomfort the first time she experiences the sensation. Unlike painful experiences that are commonplace for all people, even when we are basically healthy, the first episode of asthma, or heart failure, or pulmonary embolism may have no counterpart. Even as the quality of the sensation becomes more evident to the patient, she may have difficulty communicating to her doctor if he has never had a similar experience and if, as maintained by Campbell and Howell (6) ‘‘we can only describe sensations to others who have experienced them.’’ Ultimately, our ability to conceptualize and communicate an idea depends upon our success at giving the idea life via language. We all marvel at the gifted writer who is able to describe a scene or emotional experience in words that enable others to fully appreciate what the characters in the story see and feel. Until recently, we have been limited in our ability to describe respiratory sensations by the absence of a common vocabulary. In the past 15 years, however, considerable work has been done to develop a language of dyspnea to assist patients and physicians in communicating about respiratory discomfort. This work has enabled us to gain greater appreciation of the multiple physiological mechanisms that underlie dyspnea in different disease states, as well as the presence of multiple sensations (and physiological derangements) that may coexist within a given patient. With the development of dyspnea questionnaires, doctors and their patients have a greater chance of communicating accurately about breathing symptoms, and researchers have added tools with which to dissect the mechanisms leading to respiratory discomfort.

II. Developing a Vocabulary Early efforts to characterize the qualitative aspects of dyspnea were confounded by a tendency to mix sensations with the activities associated with the sensations. Comroe (4), for example, in his list of six grades or types of sensations includes an activity or task, such as the sensation associated with a breath-hold, in addition to a specific sensation such as suffocating (Table 1). To some degree, this approach reflected the absence of well-defined descriptive terms; it was easier to merely allude to the sensation associated with an activity that was accessible to the patient and the doctor for reference purposes. In their four elemental sensations, Campbell and Guz (5) refined Comroe’s list and attempted to define actual sensations. Even here,

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Table 1 Early Categorizations of the Qualities of Dyspnea Comroe (4) Deep breathing associated with exercise Sensation associated with breath-hold Harder to get one’s breath Hindered breathing Sensation of suffocating Sensation of increased ventilation Campbell and Guz (5) Sensation of tightness Sensation of excessive ventilation Sensation of excessive frequency of breathing Sensation of difficulty of breathing

however, two of the ‘‘sensations,’’ rapid breathing and excessive ventilation, seem closer to physical signs than symptoms (Table 1). What was needed was a systematic effort to elicit descriptive terms used by patients to describe their breathing discomfort. Studies on the language of pain ultimately provided a template for similar investigations that led to the development of a vocabulary of dyspnea. A. Insights from the Language of Pain

Headaches, stomachaches, burns, contusions—these are all common experiences of virtually every individual over the course of a normal, essentially healthy life. We are used to thinking about and describing the quality of the sensations associated with these experiences. Nearly a century ago, Titchener (7) described four qualitatively distinct categories of pain: prick, clear pain, quick pain, and ache. Over the next several decades, researchers amplified these categories and the qualifying terms were grouped based upon the following characteristics: temporal features (palpitating, throbbing), spatial features, a ‘‘pressure’’ component (heavy, pressing), qualitative features (dull, sharp), or an affective component (8). By the 1970s, Melzack and Torgerson had (9) refined this approach further, added more terms, and regrouped them into three categories: sensory, affective, and evaluative. Subsequently, these terms were placed into a questionnaire that was administered to 297 patients with different pain syndromes (10). The patients were quite selective in their choice of terms to describe their pain experience, and the results suggested a potential specificity of some terms for particular conditions. The next step in this process was the administration of the pain questionnaire to 95 patients with eight different pain syndromes (11). When one examines the terms selected by the patients (Table 2), some patterns begin to

Intense Rhythmic

Rhythmic

Tiring Exhausting

Pounding Shooting Stabbing Sharp Cramping Aching

Labor pain

Annoying

Source: Modified from Ref. 11.

Evaluative Temporal Constant

Exhausting

Gnawing Aching

Sensory Cramping Aching

Affective Tiring Sickening

Arthritic pain

Menstrual pain

Constant Rhythmic

Unbearable

Tiring Exhausting

Throbbing Shooting Stabbing Sharp Cramping Aching Heavy Tender

Disc disease pain

Table 2 Descriptions Characteristic of Clinical Pain Syndromes

Constant Rhythmic

Annoying

Sickening

Throbbing Boring Sharp

Toothache

Constant Rhythmic

Unbearable

Exhausting

Shooting Sharp Gnawing Burning Heavy

Cancer pain

Constant Rhythmic

Tiring Exhausting Cruel

Throbbing Stabbing Sharp Cramping Burning Aching

Phantom limb pain

Constant Rhythmic

Exhausting

Sharp Pulling Aching Tender

Posttherapeutic pain

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emerge. Looking at the vertical columns on the table, each associated with a different pain syndrome, one finds a unique set of words. When one looks horizontally across categories of terms, one sees that some terms are used by more than one group, i.e., they are shared by more than one condition. Fully 77% of the patients in the study selected descriptive phrases that grouped them with other patients within their diagnostic category. These results suggested that pain questionnaires might be a useful diagnostic tool in the assessment of patients with pain. Variations of these questionnaires were employed with patients with chronic headache (12), toothache (13), and facial pain (14). In each case, diagnostic distinctions emerged from the terms selected by patients with different underlying pathology. Tension headaches were characterized by ‘‘tight’’ pain, whereas migraine headaches were described as ‘‘sharp, binding, or nauseating’’ (12). Toothache due to necrotic pulp was more intense pain than the discomfort associated with inflammation (13). Of patients with facial pain due to trigeminal neuralgia vs. atypical facial pain, 90% could be correctly classified based largely upon the affective components of the pain descriptors (14). Thus, the qualitative aspects of pain give insights into the physiologic mechanisms responsible for the symptom. B. Development of Dyspnea Questionnaires

The first attempt to gather systematically data on the qualitative aspects of respiratory sensations focused on normal subjects made breathless in a laboratory setting (15). Healthy subjects performed a series of eight respiratory tasks including breath-hold, breathing with resistive and elastic loads, breathing with an elevated end-expiratory lung volume, as well as with restricted tidal volumes, and exercise. Acute hypercapnia was also induced as a stimulus for respiratory discomfort. Utilizing a questionnaire composed of a list of phrases culled from patients with dyspnea who were asked to describe their breathing discomfort and from healthy individuals made breathless during pilot studies (Table 3), subjects selected the phrases that best described their respiratory sensations after each task. Without exception, each subject volunteered that the sensory experience associated with each task was different from the others. These reports were substantiated when the phrases selected were examined using a cluster analysis, a statistical method for assessing whether certain phrases tended to be chosen together. From this analysis, the investigators determined that nine groups or clusters of phrases best described the experiences of the subjects (Table 4). When one examines the association of various clusters with the tasks used to stimulate dyspnea (Table 5), patterns emerge that are quite reminiscent of what was seen when pain questionnaires were administered to patients with eight different pain syndromes (11). Looking at the table vertically, each stimulus is associated with a unique set descriptors (‘‘uniqueness’’)

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Schwartzstein Table 3 Dyspnea Questionnaire 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

My breath does not go in all the way My breathing requires effort I feel that I am smothering I feel a hunger for more air My breathing is heavy I cannot take a deep breath I feel out of breath My chest feels tight My breathing requires more work I feel that I am smothering I feel that my breath stops I feel I am gasping for breath My chest is constricted I feel that my breathing is rapid My breathing is shallow I feel that I am breathing more I cannot get a deep breath My breath does not go out all the way

Source: Modified from Ref. 15.

Table 4 Clusters of Descriptors of Dyspnea Cluster name

Descriptive phrase

Rapid Exhalation Concentration Shallow

I feel that my breathing is rapid My breath does not go out all the way My breathing requires more concentration My breath does not go in all the way I cannot take a deep breath My breathing is shallow My breathing requires effort My breathing requires work I feel that I am smothering My chest feels tight I feel that I am suffocating I feel that my breath stops My chest is constricted I feel a hunger for more air My breathing is heavy My breathing is heavy I feel that I am breathing more I feel out of breath I am gasping for air

Work Suffocating

Hunger Heavy Gasping

Source: Modified from Ref. 15.

X

BrHO

X

X

CO2

X

X

DTV

X

X

Res

X

Etas

Stimuli

X X

FRC

X X

X

VT

X

X

Exercise

Note: Each subject experienced eight respiratory tasks (BrHO, breath-holding; CO2, acute hypercapnia; DTV, suppressed ventilation during acute hypercapnia; Res, external resistive load; Elas, external elastic load; FRC, increased end-expiratory lung volume; VT, voluntary limitation of tidal volume) and selected phrases that best described the breathing sensations associated with the task. The phrases were found to group together into discrete clusters, and most clusters had a significant association with at least one of the respiratory tasks. Note that each task or stimulus has a unique set of clusters with which it is associated. Source: Modified from Ref. 15.

Rapid Exhalation Concentration Shallow Work Suffocating Hunger Heavy Gasping

Cluster

Table 5 Clusters of Descriptive Phrases in Association with Respiratory Tasks

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and is characterized by more than one sensation (‘‘multiplicity’’) (16). As one views the table horizontally, one sees that clusters are often associated with more than one stimulus (‘‘sharing’’). Because it is clear that the tasks performed by the subjects varied in the stresses imposed upon the ventilatory pump and in the stimulation provided to the central controller, i.e., the ‘‘drive to breathe,’’ the results of this study suggest that not only may the qualitative aspects of the discomfort provide clues as to the stimulus, but also they may inform us about the physiological mechanisms leading to the discomfort. Simon et al. (16) extended these observations by administering their questionnaire to 53 patients with a range of cardiopulmonary disorders, as well as to women in the early stages of pregnancy, who complained of breathing discomfort. A cluster analysis was utilized to examine the relationships among the phrases selected. Fourteen clusters emerged (Table 6). Again, as in the study of healthy subjects (15), the features of uniqueness, Table 6 Clusters of Phrases Emerging from Patients with Dyspnea Cluster name

Descriptive phrase

In

My breath does not go in all the way I cannot take a deep breath I feel that my breath stops I am gasping for breath I feel that my breathing is rapid I feel that I am breathing more My breath does not go out all the way My breathing requires concentration I feel that I am smothering I feel that I am suffocating I feel a hunger for more air I feel out of breath I cannot get enough air My breathing requires effort My breathing is heavy My breathing requires effort I feel out of breath My breathing requires more work My chest feels tight My breathing requires more work

Deep Stops Gasping Rapid More Exhalation Concentration Suffocating Hunger

Heavy Effort

Tight Shallow

Source: Modified from Ref. 16.

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multiplicity, and sharing are apparent. The dyspnea of different disease states appears to be characterized by different qualitative phrases. The reliability of dyspnea questionnaires, i.e., the likelihood that a descriptor chosen by a patient on 1 day will also be chosen at a subsequent time to characterize the same sensation, was examined in patients with chronic obstructive pulmonary disease (COPD) (17). Investigators administered a questionnaire, similar to that used by Simon et al. (16), to 16 patients with COPD on two occasions 1 week apart. The agreement among the descriptors chosen on the 2 days was highly significant; there was 79% agreement for all descriptors (r ¼ 0.82). This analysis was part of a larger investigation of the qualities of dyspnea in 218 patients with cardiopulmonary disease. Although the number and content of the clusters that emerged varied slightly from the study of Simon et al. (16), the essential elements were present and the concept that different disease states are associated with different qualities of dyspnea was confirmed. Retest reliability was also excellent in a study using a questionnaire with 45 descriptor phrases administered to
200 patients in the United Kingdom (18). To determine whether the use of descriptors from dyspnea questionnaires is similar in patients and healthy individuals, Harver et al. (19) tested the hypothesis that descriptors of breathlessness represent distinct and separable cognitive constructs. One hundred generally healthy individuals judged the dissimilarity between 120 pairs of descriptors of breathlessness created by the combination of 15 different descriptors chosen from questionnaires used previously in studies of patients with dyspnea (16,17). Seven of the eight clusters, as well as associated descriptors, derived from the study by Simon et al. (16) of patients with dyspnea were replicated by the healthy subjects examining the dissimilarity of the phrases. Similarly, nine of the 10 clusters that emerged from the study by Mahler et al. (17) were replicated by the healthy subjects. These results, evidence that cluster solutions for dissimilarity judgments about pairs of descriptors in healthy subjects are nearly identical to the clusters that emerge from the characterization of breathlessness by patients with cardiopulmonary disease, indicate that the use of these descriptors by healthy subjects is the same as that by patients. From these findings, one can conclude that the relations among descriptors of breathlessness that have become apparent from questionnaire studies are not dependent strictly upon the presence of a specific disease but represent distinct and separable cognitive constructs (19). These data support the notion that the qualitative aspects of dyspnea differ among patient groups because they represent different composites of sensations. C. Racial and Cultural Influences on the Language of Dyspnea

The studies previously cited, in which dyspnea questionnaires were developed and administered to patients with cardiopulmonary disease, included

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a range of individuals from the United States and no attempt was made to examine the effect of race or culture on the selection of descriptive phrases. To determine whether African-American patients with asthma differ from White patients in their characterization of breathlessness, Hardie et al. (20) compared the use of an ‘‘open-ended dyspnea questionnaire’’ in 32 individuals with asthma. Fifty percentage of the study population was White and half was African-American. The investigators gave the subjects a blank form on which to write, in their own words, the ‘‘sensations and/or symptoms’’ they experienced during the administration of nebulized methacholine. The subjects were not specifically asked to describe breathing discomfort. While there was considerable overlap in the descriptions of breathing discomfort associated with increased airflow obstruction as forced expiratory volume in one second (FEV1) dropped, AfricanAmericans were more likely to volunteer sensations localized to the throat, and White patients were more likely to use phrases related to an awareness of breathing at mild degrees of bronchoconstriction (Table 7). Although these data suggest that there may be important differences among Whites and African-Americans in how they perceive respiratory sensations, it is noteworthy that the investigators did not specifically instruct subjects to describe breathing discomfort and that the descriptors used were very similar when discomfort became more prominent. Thus, from the standpoint of dyspnea, there were more similarities than differences between the two groups. Investigators in the United Kingdom have also undertaken several studies of the qualitative aspects of dyspnea in patients with cardiopulmonary disease. Elliott et al. (18) examined 208 patients with asthma, COPD, cardiac disorders, interstitial fibrosis, and pulmonary inflammatory conditions. Utilizing a dyspnea questionnaire with 45 descriptive phrases, they Table 7 Qualities of Dyspnea Associated with Bronchoconstriction Racial differences in descriptors African-American

White

Tight throat Voice tight Itchy throat Tough breath Scared, agitated

Deep breath Out of air Aware of breathing Hurts to breathe Lightheaded

Note: Thirty-two subjects (16 African-American, 16 White) inhaled methacholine to provoke bronchoconstriction. The phrases offered by the subjects when FEV1 had dropped by 30% are listed above. Source: Modified from Ref. 20.

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instructed patients to select phrases that described their breathing discomfort during physical activity. A cluster analysis of the phrases selected produced 12 groupings of phrases that, like those of studies in the United States (16,17), varied among the different pathologic conditions. While the list of phrases employed in the British study varied slightly from the American questionnaires, the similarities were more striking than the differences. In a study of 33 patients from respiratory and oncology wards in the United Kingdom, patients described ‘‘in their own words’’ what it ‘‘felt like to be breathless’’ (21). A list of 63 phrases emerged. The list included not only phrases that are commonly seen in studies of American patients (e.g., tight, winded, short of breath, cannot get my breath, gasping), but also descriptors that are likely unique to British culture (e.g., fagged out, knotty, whacked). Attempts have been made to translate dyspnea questionnaires into languages quite disparate from English as well. To study the phrases used by children with asthma in Thailand, commonly used English words were translated into Thai and efforts were made to ascertain the local words that best represented the sensations associated with breathing discomfort from asthma (22). Over three-quarters of the 60 patients surveyed referred to rapid breathing and feeling tired when describing their dyspnea. Shortness of breath seemed to be described most commonly as not being able to catch a breath, too short a breath (which may reflect a sensation of inability to get a deep breath associated with hyperinflation), and feeling suffocated. The sensation chest tightness appeared to correlate with chest discomfort in two-thirds of patients. Although more work needs to be done to determine if the dyspnea questionnaires developed thus far need to be modified for different ethnic and racial groups within English speaking countries, as well as to determine how well they can be transformed for use in other languages, the data thus far suggest that there are qualitatively distinct sensations that characterize the dyspnea of different pathologic states (Table 8) and that these differences among sensations are not a unique phenomenon to American English or American culture. Application of these questionnaires to patients with different diseases has given us additional insights into the physiology of the breathing discomfort in these pathologic states.

III. Verbal Descriptors and the Physiology of Dyspnea The chapters in Section A of this volume outline the pathophysiologic mechanisms that account for dyspnea in a number of common cardiopulmonary disorders. It is not uncommon for more than one physiologic derangement to be present in a given patient at a particular point in time.

X

X

Vase

X

X

X X

X X X

X

X

Cardiac

X

X

X

Neuro

X

X

X

Preg

X

X

X X

Restrictive

X X

X

X X

X

Asthma

X

X X X

X

COPD

X

X X

Decond

Note: Not all patient group were included in each study. Patient groups: Vasc, pulmonary vascular disease; Neuro, neuromuscular disease; Cardiac, primary cardiac disease; Preg, pregnancy; Restrictive, ILD and chest wall disease; COPD, chronic obstructive pulmonary disease; Decond, cardiovascular deconditioning. Clusters as described in Ref. 16. Data derived from Refs. 16–18, 30, 33, 41, 43, 54.

In Deep Stops Gasping Rapid More Exhalation Concentration Suffocating Hunger Heavy Effort Tight Shallow

Clusters

Disease States

Table 8 Clusters of Phrases Associated with Different Disease States

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For example, a patient with COPD may experience an increase in resistance to airflow, may have a reduced inspiratory capacity due to hyperinflation, and may be hypoxemic while trying to walk up a hill. Sorting out which factor may be the predominant one in limiting a patient’s physical capabilities can be difficult. By identifying the qualitative phrases associated with particular physiologic derangements, one may be able to discern clues that will assist the physician in determining the primary problem at hand. A. Stimulation of the Ventilatory Controller—Increased Drive to Breathe

The chemoreceptors stimulate the respiratory centers when an individual becomes acutely hypoxemic or hypercapnic or when an academia is present. In the absence of major limitations in the mechanical capacity of the lungs and chest wall, this stimulation typically leads to increased ventilation manifest as a combination of an increase in respiratory rate and tidal volume. The cluster of phrases most commonly used in association with these conditions includes air hunger, urge to breathe, need to breathe (23–25). Although the acute development of hypoxemic and hypercapnia typically leads to increases in ventilation, the dyspnea associated with these changes is not dependent upon these changes. Furthermore, restriction of the normal ventilatory response to the gas-exchange derangement exacerbates the intensity of the breathing discomfort. When normal subjects exercise while breathing an hypoxic mixture of gases, the onset of dyspnea occurs more rapidly than when they are inspiring room air. Furthermore, under hypoxic conditions, the ‘‘uncomfortable need to breathe’’ did not track with minute ventilation as it did under normoxic conditions (23). Similarly, the respiratory discomfort associated with acute hypercapnia is not dependent on the development of increased ventilation as evidenced by the onset of air hunger in patients with spinal cord injury who are maintained on fixed ventilation via a mechanical ventilator (24) and in normal subjects in whom muscular paralysis was induced under conditions of hypercapnia (25). In addition, increased ventilation alone does not mimic the air hunger of hypercapnia. Children with congenital central hypoventilation syndrome, a rare disorder that appears to render the central chemoreceptor inoperative, do not develop breathing discomfort in the setting of a breath-hold or acute hypercapnia, nor do they demonstrate a usual ventilatory response to hypercapnia (26). They do, however, report other sensations similar to shortness of breath with exercise when performing physical tasks (26). The voluntary restriction of ventilation in spontaneously breathing subjects will exacerbate air hunger associated with acute hypercapnia (27,28), and breathing above the ventilation dictated by the chemical

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derangement also leads to an increase in dyspnea (28), although not necessarily air hunger (29). Other conditions in which the drive to breathe is increased are associated with air hunger despite the absence of hypoxia or hypercapnia (16,30). Acute pulmonary embolism, for example, leads to dyspnea unrelieved or only partially relieved by administration of supplemental oxygen, and the administration of thrombolytic agents directly into the pulmonary artery has been associated with near instant relief of breathing discomfort (J Markis personal communication). Moderate to severe bronchoconstriction can also provoke air hunger under normoxic conditions (30). In none of these situations was acute hypercapnia present. B. Stimulation of Pulmonary Receptors

Stimulation of irritant receptors, stretch receptors, and vascular receptors can affect the body’s minute ventilation, tidal volume, and/or respiratory rate. Data are emerging, primarily from studies of respiratory sensations in asthma, to suggest that afferent information from these receptors may also play a role in the generation of dyspnea independently of any changes in ventilation. A number of studies suggest that the quality and intensity of dyspnea are different when the work of breathing is increased by the induction of bronchoconstriction, as compared with the addition of external resistive loads to a breathing circuit (30–32), and that dyspnea persists in the setting of bronchoconstriction even when the work of breathing is relieved with institution of mechanical ventilation (33). Arguments for the role of pulmonary receptors in the formulation of at least part of the breathing discomfort in asthma derive from studies that suggest that dyspnea in the setting of bronchoconstriction can be dissociated from the work of breathing. Inhalation of lidocaine, a local anesthetic that can blunt the sensitivity of airway receptors, diminishes the intensity of dyspnea associated with bronchoconstriction but not that of external resistive loads (31). Breathing discomfort from bronchoconstriction begins, in some subjects, before significant airway obstruction or hyperinflation is observed (Fig. 1) (30). Finally, the institution of mechanical ventilation does not fully relieve the dyspnea of bronchoconstriction (33) (Fig. 2), but the administration of an inhaled bronchodilator may ameliorate at least one form of breathing discomfort in patients with acute asthma who present to the emergency department (34). In these last three studies, the sensation that appears to be independent of the mechanical load on the system, and thus, most likely is the consequence of stimulation of pulmonary receptors, is chest tightness. Further evidence that chest tightness arises from pulmonary receptors is seen in the preliminary observation that this discomfort is present in patients with cervical spinal cord injury, who do not have sensations from

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Figure 1 Verbal descriptors chosen from a dyspnea questionnaire in subjects with mild asthma in whom bronchoconstriction was induced with inhaled methacholine. Note that the relative frequency with which the phrases ‘‘chest tightness’’ and ‘‘increased effort to breathe’’ are chosen varies with the degree of airway obstruction. At the mildest degrees of obstruction, e.g., when the FEV1 is still within the normal range or marginally reduced, chest tightness predominates. As lung function declines farther, the sense of effort is chosen as frequently as tightness to describe the individual’s breathing discomfort. Source: Modified from Ref. 30.

the rib cage, when they are given methacholine to inhale with the consequent development of bronchoconstriction (35). As noted previously, the infusion of a thrombolytic agent into the pulmonary artery of a patient with acute pulmonary embolism results in almost instantaneous relief of dyspnea (J Markis personal communication). Patients with acute congestive heart failure (CHF) have been shown to benefit from the institution of nasal continuous positive airway pressure in terms of both reduced breathing discomfort (36) and decreased incidence of intubation (37). This intervention may work, in part, by reducing afterload and intracardiac pressures. In both of the clinical situations cited here, a component of the dyspnea relief may be secondary to changes in the stimulation of pulmonary vascular receptors. C. Mechanical Loads and Increased Work of Breathing

The most common cardiopulmonary disorders leading to dyspnea are characterized by an increase in the load on the ventilatory muscles. Asthma, COPD, and frequently pulmonary edema are associated with increased airway resistance. The hyperinflation resulting from airflow

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Figure 2 Ratings of the intensity of the sensations of ‘‘effort to breathe’’ (Left) and ‘‘chest tightness’’ (Right) in subjects with mild asthma in whom bronchoconstriction was provoked with inhaled methacholine. Utilizing a visual analog scale, subjects rated their sensations during spontaneous breathing and when being mechanically ventilated (with mouthpiece) following training to breathe passively on the ventilator. The sense of effort associated with acute bronchoconstriction was less when the subjects were on the mechanical ventilator than when they were breathing spontaneously (p < 0.01). In contrast, the sense of chest tightness was not significantly different during the two conditions (p ¼ 0.12) suggesting that this sensation is not the consequence of ventilatory muscle activity and the work of breathing. Source: Modified from Ref. 34.

obstruction imposes an elastic load on the inspiratory muscles as well. Patients with interstitial lung disease (ILD) and chest wall disorders such as kyphoscoliosis must work against the reduced compliance of the respiratory system. The physiology of the increased mechanical loads leads to discomfort typically described as an increased ‘‘effort or work of breathing.’’ To the extent that ventilation is under voluntary control and neural impulses are sent from the motor cortex to the ventilatory muscles, it is hypothesized that a ‘‘corollary discharge’’ is sent simultaneously to the sensory cortex (38). This corollary discharge is perceived as the ‘‘effort’’ expended to move the muscles (39) and can be conceived of as a means for the brain to assess the response of the muscles in the context of the workings of the respiratory system. The presence of muscle contraction does appear to be necessary for the sensation of effort to exist. In subjects who are paralyzed, there does not appear to be a sense of effort despite the

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subjects’ reports that they are attempting to move an unresponsive muscle (25). A sense of increased effort of breathing is associated with many diseases including COPD, asthma, ILD, chest wall disorders, and neuromuscular diseases (16–18) (Table 7). In the presence of muscle weakness or fatigue, the sense of increased effort or work of breathing may be present even in the absence of a mechanical load on the system. Interestingly, the sense of effort does not correlate solely with the output of the ventilatory muscles, typically expressed as a measure that reflects the work being performed by the muscle as a fraction of its maximal output. When subjects were asked to match a ventilatory target under two conditions, normocapnia and hypercapnia, the sense of effort was higher in the normocapnic state (29). These data suggest that when ventilation is the consequence primarily of automatic control centers, the sense of effort is less than when it is the result of voluntary neural activity. In the setting of an increase in the mechanical load on the respiratory system or in the presence of neuromuscular weakness or fatigue, the respiratory system does not respond normally to a given neurological output from the brain. The displacement of the lungs and chest wall is less than expected; the shortening of the ventilatory muscles and the flow of air into and out of the lungs are less than expected. This discrepancy between the neural stimulus and the resulting output of the respiratory system was originally hypothesized as ‘‘ultimately responsible for the unpleasant sensation’’ of dyspnea (6). We now know that this imbalance, termed efferent– reafferent dissociation (40) or neuromechanical dissociation (41), plays an important role in determining the intensity of dyspnea but does not appear to generate a specific quality of discomfort. Efferent–reafferent dissociation may increase the sense of effort associated with breathing at elevated lung volumes (42), for example, as well as the sense of air hunger in hypercapnic subjects whose tidal volume or ventilation is restricted (24,28). D. Hyperinflation—Breathing at Elevated Lung Volumes

Patients with expiratory airflow obstruction often develop air trapping and hyperinflation. As the end-expiratory lung volume increases, the inspiratory capacity is reduced because the volume available for inspiration is now limited by total lung capacity. This becomes a particular issue during exercise when individuals need to increase flow to achieve higher levels of ventilation. If flow is limited at usual lung volumes, patients must hyperinflate in order to achieve the necessary levels of ventilation to sustain the increased metabolic demands of exercise (41,43,44). Patients with moderate to severe asthma and COPD, who demonstrate significant hyperinflation, may report breathing discomfort as a sense of ‘‘an inability to get a deep breath’’ or an ‘‘unsatisfied inspiration’’ (41,43). These sensations are believed to reflect

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the actual inability of the patient to achieve the tidal volume desired because of the reduced inspiratory capacity associated with the elevated end-expiratory lung volume. The sense of ‘‘effort’’ or ‘‘increased work of breathing’’ is also associated with the mechanical load that results from hyperinflation in these patients (16,17). E. Cardiovascular Deconditioning

During maximal exercise, the normal individual is limited by the ability of the heart to pump blood to the active muscles and by the ability of the muscles to extract and utilize oxygen to support aerobic metabolism. Ultimately, this imbalance between the metabolic needs of the muscle and the ability of the heart to deliver oxygenated blood leads to anaerobic metabolism and the accumulation of metabolic byproducts in the muscle. This condition may lead to stimulation of receptors in the muscles, termed ‘‘metaboreceptors,’’ which are felt to play a role in the production of sensations that we perceive as dyspnea both in patients who are at the limits of their level of fitness and in patients with heart failure and reduced cardiac output (45,46). The descriptive phrases used by individuals who experience breathing discomfort as a result of reaching the limits of their cardiovascular performance include ‘‘breathing heavy,’’ ‘‘gasping,’’ and ‘‘breathing more’’ (17). It must be remembered that many patients with underlying cardiopulmonary diseases often limit their physical activities to avoid discomfort and become increasingly deconditioned over the course of months and years. Under these conditions, the quality of their dyspnea may change with time as the physiology of their limitation changes. F. Complex Physiology in Patients

Patients with cardiopulmonary diseases and dyspnea frequently have more than one physiological derangement that may contribute to their breathing discomfort, and the cause of the limitation may change over time. For example, a patient with asthma who experiences an acute attack of bronchoconstriction may experience chest tightness from the stimulation of pulmonary receptors, or an increased effort of breathing from the work against the elevated airway resistance, or a sense of an inability to get a deep breath if there is significant hyperinflation. At other times, when the asthma is well controlled, the individual may experience heavy breathing due to a low level of physical fitness. Studies in healthy subjects in whom dyspnea is induced demonstrate that individuals can discern different qualities of dyspnea that may be occurring simultaneously as a result of multiple physiological stimuli. Individuals who maintained a constant, targeted level of ventilation, for example, complained of an effort to breathe when PaCO2 was maintained at normal levels, and a sense of air hunger when the PaCO2 was elevated (29,47). Similarly, over the course of methacholine-induced

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bronchoconstriction, subjects report different sensations as lung function declines; the dyspnea evolves from chest tightness, to an increased effort to breathe, to a sensation of air hunger (30) (Fig. 1). Thus, the language of dyspnea offers clues to the underlying physiological derangements causing the breathing discomfort and may allow a physician to target interventions more accurately to alleviate symptoms. IV. The Language of Dyspnea in Specific Disease States As one examines the results of the studies of the qualitative aspects of dyspnea in patients with different disease states, it is apparent that most conditions are associated with more than one descriptive phrase (16–18) (Table 7). This is due, in part, to the fact that a given disease may be characterized by more than one physiological derangement, for example, a resistive load and hypoxia. Nevertheless, laboratory studies of patients have begun to reveal the identity of qualifiers that, while not entirely specific for a particular disease, can be very suggestive of a diagnosis. A. Asthma

Pathologically, asthma is characterized by airway inflammation and edema and an increased sensitivity of the bronchi to constrict. Physiologically, there is increased airway resistance and, in more severe disease, hyperinflation and gas-exchange abnormalities. Throughout an asthma attack, the drive to breathe is increased, even when gas exchange remains relatively normal. As might be expected, given the range of abnormalities apparent in the respiratory system during acute bronchoconstriction, the descriptions of the breathing discomfort associated with asthma evolve from mild to more severe disease. The qualitative aspects of dyspnea in asthma have been clarified by several studies that provoked bronchoconstriction in individuals who had a history of asthma but also had normal lung function at baseline. At the most mild degrees of bronchoconstriction, even when the FEV1 remains within the normal range, subjects note a sensation of ‘‘chest tightness’’ (30,33). As FEV1 drops further, a sense of ‘‘effort or work of breathing’’ emerges (Fig. 1) (30,33) followed by a sensation of ‘‘air hunger’’ and an ‘‘inability to get a deep breath’’ at the most extreme degrees of airflow obstruction (30,41). The language of dyspnea in asthma, as elicited during methacholine-induced bronchoconstriction, correlates very well with descriptions provided by patients as they recall spontaneous asthma attacks (16–18,33,48). The treatment of patients with asthma is frequently multifaceted, directed at the different pathophysiological derangements associated with the disease. Changes in the varying aspects of the breathing discomfort

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experienced by patients provide insight into what are often confusing clinical observations. For example, the administration of a beta agonist bronchodilator to a patient presenting to the emergency department in the midst of an acute asthma attack may relieve dyspnea while lung function remains essentially unchanged. A closer examination of the sensory experience of the patient in this setting, however, reveals that the sensation of chest tightness is relieved while the sensation of effort and work of breathing is unaltered (34). On the basis of our understanding of the physiological mechanisms responsible for these sensations, one may hypothesize that the beta agonist relieves bronchoconstriction (and hence, chest tightness) but does little to ameliorate airway inflammation, which may be the major determinant of airway resistance (and the sense of increased effort or work of breathing) in an acutely ill patient. Attention to the details of the language of dyspnea in the setting of acute asthma may assist physicians as they try to avoid fatal asthma episodes that are due, in part, to under-treatment of the disease in the setting of seemingly contradictory subjective and objective data. Familiarity with these sensations on the part of patients may be a marker of asthma prevalence (49) and may make them better observers of their own conditions. Similar confusion often exists in the management of patients with status asthmaticus and acute respiratory failure. In contrast to patients with COPD, who are usually very comfortable on mechanical ventilation when suffering an episode of acute respiratory failure, individuals with asthma remain distressed. A recent study of the dyspnea of asthma sheds light on this paradox (34). Individuals with asthma, who had been trained to breathe passively on a mechanical ventilator, were given inhaled methacholine to induce bronchoconstriction. Subjects rated their sense of effort of breathing and their sense of chest tightness both on and off the ventilator. As expected, when the ventilator was performing the work of breathing, the sense of effort was reduced. However, the intensity of chest tightness was unaffected by the ventilator (Fig. 2). In two patients with high cervical spinal cord injury and absent sensory information from the chest wall, methacholine-induced bronchoconstriction also led to a sensation of chest tightness (35). If the discomfort is not related to ventilatory muscle activity, relief of the work of breathing will not reduce the dyspnea. The principle of efferent–reafferent dissociation may also contribute to the persistent dyspnea of patients with status asthmaticus on ventilators. With a very high drive to breathe, an inappropriately low inspiratory flow rate from the ventilator may induce a sense of air hunger (50). B. Chronic Obstructive Pulmonary Disease

Patients with COPD must contend with expiratory airflow obstruction and, as their disease progresses or as they exercise, with an elastic load due to hyperinflation of the lungs and chest wall. As in asthma, varying degrees

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of hypoxia or hypercapnia may also contribute to breathing discomfort. Initial questionnaire studies of patients with COPD showed that the sense of increased ‘‘effort or work of breathing’’ was the most characteristic descriptive phrase chosen (16–18). This finding is consistent with the primary physiologic derangement, a mechanical load on the ventilatory muscles. Laboratory studies of patients with COPD have elicited an additional quality of dyspnea, the sensation of ‘‘an inability to get a deep breath’’ or an ‘‘unsatisfying breath or unsatisfied inspiratory effort’’ (43). These sensations are associated with significant dynamic hyperinflation during exercise and likely reflect the reduced inspiratory capacity that results from the hyperinflation (43,44). A number of studies have demonstrated that the intensity of dyspnea in COPD correlates with changes in inspiratory capacity (43,44,51,52). Although specific studies tracking the changes in the intensity of specific sensations under these conditions are lacking, it is likely that the sense of effort and the inability to get a deep breath will correlate with the worsening mechanical load and declining inspiratory capacity. C. Interstitial Lung Disease

Patients with ILD experience an increased mechanical load on their ventilatory muscles in association with reduced compliance of the lungs. Hypoxemia may be present, especially during exercise. Pulmonary receptors may also be stimulated as a result of inflammation, atelectasis, or altered interalveolar forces. Compared with the studies of asthma and COPD, there has been relatively little work examining the quality of respiratory sensations in patients with ILD. Questionnaire studies noted a sense of ‘‘gasping,’’ an increased ‘‘effort to breathe,’’ and ‘‘shallow breathing’’ as characteristic descriptors for the breathing discomfort of ILD (16–18). Laboratory studies of models of thoracic restriction (53) and exercise-induced dyspnea in patients with ILD (54) have yielded similar results with the added sensation of ‘‘unsatisfied inspiratory effort’’ in the latter. The sensation of an unsatisfied breath or shallow breathing likely correlates with the ratio of tidal volume to inspiratory capacity; with a reduction in total lung capacity, end-inspiratory lung volume begins to approximate total lung capacity and one’s ability to get a deeper breath is limited (54). D. Congestive Heart Failure

As with the other disease states discussed earlier, CHF is characterized by multiple physiological derangements. Interstitial edema and the resulting decrease in pulmonary compliance lead to a mechanical load on the ventilatory muscles and are postulated to stimulate receptors adjacent to pulmonary capillaries (J-receptors). Hypoxemia and, in severe cases, hypercapnia

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may be present. Narrowing of airways from edema fluid and bronchoconstriction increases airway resistance. Intracardiac and pulmonary vascular pressures are increased and may stimulate vascular receptors. Questionnaire studies of patients with CHF reveal a relatively unique descriptor, a sensation of ‘‘suffocating’’ for the breathing discomfort of this condition (16). This sensation is rarely selected by other patient groups assessed (16–18). It is not immediately evident which of the pathophysiologic derangements, or combination thereof, produces this sensation, but its apparent specificity can be useful in the evaluation of patients with acute dyspnea. The term suffocating, unlike the other descriptors we have been discussing, does connote a fairly severe intensity of sensation; it is not evident that one can be ‘‘mildly suffocating,’’ for example. It is possible, therefore, that the specificity of the term may also reflect, in part, the more intense breathing discomfort of pulmonary edema relative to other cardiopulmonary disorders.

E. Behavioral Dyspnea

Breathing is unique among essential bodily functions in that it is under both automatic and voluntary control. Fear, panic, anxiety, and pain may lead to increases in ventilation and a sense of breathing discomfort independent of underlying cardiopulmonary disorders (55). Alternatively, patients with a mechanical load on the respiratory system will experience increased breathing discomfort due to their altered physiology when ventilation is increased by emotional factors. A patient with COPD, for example, will develop dynamic hyperinflation if he becomes tachypneic due to psychological stress, and the hyperinflation may then lead to dyspnea. In cases such as these, behavioral factors will tend to increase the intensity of the breathing discomfort normally experienced by the patient but will not necessarily alter the quality of the discomfort. A vicious cycle may be established, however, as anxiety leads to tachypnea and increased ventilation that subsequently causes breathing discomfort, more anxiety, and further increases in ventilation. The hyperventilation syndrome is a condition characterized by a sensation of breathing discomfort, palpitations, chest pain, and paresthesias and is typically applied to patients presenting with anxiety and hyperventilation without underlying cardiopulmonary explanations for their dyspnea (55). These patients often complain of an ‘‘inability to get a deep breath’’ despite the fact that they may be exhibiting remarkably large tidal volumes (56). It remains unclear whether the etiology of this condition is strictly behavioral or reflects altered sensitivity to carbon dioxide or possibly misperception of changes in pulmonary and thoracic volume.

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V. Distress and Breathing Discomfort—Affective Qualities of Dyspnea In discussing the work on the development of the language of pain in the 1970s, we noted that Melzack and Torgerson (9) grouped the pain descriptors into three categories: sensory qualities, affective qualities, and evaluative qualities. Most of the works on the language of dyspnea have focused on the sensory qualities of the breathing experience. As the sensory vocabulary has become better delineated, however, more attention is being paid to the affective aspects of breathing discomfort and to the role of emotional and psychological factors in the modification of the sensory experience. Increasingly investigators and clinicians are asking not only ‘‘what does the breathing discomfort feel like?’’, but also ‘‘how unpleasant is the sensation?’’ and ‘‘does it cause you to be distressed?’’ Symptom lists developed in patients with asthma to describe the experience of an acute asthma attack yielded what were termed two ‘‘mood clusters’’ that encompassed sensations akin to panic, fear, and irritability (57,58). Comparable studies in patients with COPD yielded similar results. A category of affective terms emerged that represented sensations such as ‘‘helplessness, hopelessness, irritability, and anxiety’’ (59). There is a high prevalence of panic and anxiety as a manifestation of pulmonary disease (55), and between one-quarter and one-third of patients with COPD have been found to meet criteria for the diagnosis of anxiety or panic disorder (60). In addition to the effect that these psychological factors have on the affective qualities of breathing discomfort, they may also impact the intensity of the sensory experience. Patients with anxiety disorders, for example, have been shown to have a greater variability in their estimation of added resistive loads to a breathing circuit compared with normal controls (61). In addition, patients’ ratings of their breathlessness are significantly associated with self-ratings of depression (62,63). In the laboratory setting, subjects appear to be able to distinguish the intensity of the sensory experience of a given respiratory stimulus from the unpleasantness of the discomfort. Subjects asked to rate air hunger and work or effort of breathing while maintaining a ventilatory target under conditions of hypercapnia, were able to independently rate the intensity of each sensation, and also noted that the sensations differed in the degree of discomfort or unpleasantness (47). Similarly, five na€
ve subjects in whom partial paralysis was induced with a short-acting neuromuscular blocker were asked to rate their sense of air hunger and effort to breathe under conditions of hypercapnia. Again, subjects made independent ratings of the two sensory experiences, and air hunger was associated with a greater degree of unpleasantness than was the effort to breathe (64). Changes in the affective component of dyspnea may, in part, explain the improvement seen in exercise capacity despite the absence of changes in

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Figure 3 Ratings of the intensity of dyspnea (Left) and dyspnea distress (Right) during exercise before (dark lines) and after (light lines) a supervised exercise-training program. Subjects rated the intensity of the sensation with a 200 mm visual analog scale. Note that the intensity of ‘‘distress’’ was reduced to a greater degree by the exercise program than was the intensity of the dyspnea itself. Source: Modified from Ref. 65.

lung function in many patients with chronic lung disease who undergo pulmonary rehabilitation programs. Supervised exercise training, for example, has been shown to decrease anxiety and distress (Fig. 3) in patients with COPD (65,66). Psychotherapy without exercise training has also been demonstrated to improve exercise tolerance in COPD patients with significant anxiety (67). Others have found, however, no significant correlation between exercise tolerance, as assessed with a six min walk test, and measures of anxiety and depression (68). VI. Use of the Language of Dyspnea in the Evaluation and Study of Patients with Breathing Discomfort A. Clinical Applications

On the basis of the work of the last 15 years, the concept that there are multiple qualitatively distinct sensations that comprise the broad term ‘‘dyspnea’’ is well established. The links between specific descriptive phrases and underlying physiological mechanisms are being elaborated, although more study needs to be done in this area. The language of dyspnea can be a useful tool diagnostically in the evaluation of patients presenting with a complaint of shortness of breath and will allow us to tailor therapeutic interventions more finely than has been the case in the past.

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In a general study of the utility of the medical history and physical examination for determining the cause of dyspnea in patients presenting to a pulmonary clinic, the diagnosis could be made in
60% of patients without recourse to additional testing (69). Utilizing dyspnea questionnaires, the effectiveness of the medical history as a diagnostic tool can be greatly enhanced. In a preliminary study, 142 patients presenting with a complaint of breathing discomfort to pulmonary clinics at two academic medical centers were given a dyspnea questionnaire as part of their evaluation (70). The presence of a sensation of ‘‘chest tightness or constriction’’ had a specificity of 0.951 and a positive predictive value of 0.862 for the diagnosis of asthma. The combination of the phrases ‘‘effort or work of breathing and can’t get a deep breath’’ had a sensitivity of 0.744 for a diagnosis of COPD; the negative predictive value was similarly high at 0.776. In patients specifically referred for a diagnosis of asthma despite normal baseline lung function, the absence of a sensation of chest tightness greatly increases the likelihood that the bronchoprovocation study will be negative (71). Data from laboratory studies indicate that subjects can distinguish at least two qualitatively distinct dyspnea sensations occurring simultaneously (29,47). Many patients with cardiopulmonary disease may have more than one physiologic derangement present. Before deciding what therapy may be most appropriate for such patients, it is important to determine which factor is the cause of the patients’ physical limitation, i.e., at the point that patients cannot go any farther, what is stopping them? Cardiopulmonary exercise tests are frequently used to gather objective information on the nature of the physiological limitation. The descriptive phrases used by the patients at the time that they must stop (e.g., during a 6 min walk test) can more quickly give the physician similar information. If the patients describe a sensation of ‘‘huffing and puffing’’ or ‘‘breathing more’’ and are not complaining of ‘‘an inability to get a deep breath’’ or an ‘‘increased effort to breathe,’’ the limiting problem is likely to be cardiovascular deconditioning rather than COPD even if the patients have significant expiratory airflow obstruction. In this case, entry into a supervised exercise program would be indicated rather than an intensification of bronchodilator therapy. It is important to remember that deconditioning is a common accompaniment of cardiopulmonary disorders. When patients know they have a lung disease that can cause shortness of breath, they often begin to assume, without much thought, that their breathing is limiting their activities. Two large studies, however, have shown that normal subjects and patients with severe obstructive lung disease are limited frequently by general fatigue or leg fatigue rather than dyspnea (72,73).

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Schwartzstein B. Research Applications

If dyspnea is composed of multiple qualitatively distinct sensations that are the result of a range of physiologic abnormalities, then merely asking a subject to rate ‘‘dyspnea’’ may not be as informative as focusing on the specific sensation that is being produced by the stimulus used in the investigation. Similarly, in studies of patients, given the possibility of multiple simultaneous sensations, the greater the specificity in the instructions given to the subjects with respect to the sensations to be rated, the more likely the resulting data will be informative. If one is unsure about the specific sensation that is operative in a given experimental situation, it is best to instruct the subjects about the sensation to be rated with the most generic term possible, e.g., ‘‘breathing discomfort,’’ to avoid the possibility of biasing a subject toward a particular sensation. To use the term ‘‘difficult breathing’’ in the instructions, for example, may predispose the patient to think about the sense of effort or work of breathing and mask changes in other sensations such as air hunger. Open-ended debriefings, in which one asks the subjects to describe in their own words what sensations were being rated, and dyspnea questionnaires, used after the experiment is concluded, are important tools in these circumstances in determining exactly what the subject was experiencing and assessing. C. Use of Dyspnea Questionnaires

When employing a dyspnea questionnaire, either in the clinical or in the research environment, it is best to ask the patients first to examine all the descriptive phrases available and to put a mark next to any and all phrases that apply to the breathing discomfort they are experiencing (or have experienced at the time of interest to the physician). Frequently, multiple phrases are checked. One should then ask the patients to examine only the phrases that they checked and pick out the phrase that is the ‘‘best’’ descriptor of their breathing discomfort, the second best, and the third best. This process enables one to confirm which sensation(s) are the most prominent. Every list of phrases should include at least one blank line for the patients to add a phrase that they feel may not be represented in the formal questionnaire. VII. Summary The language of dyspnea has evolved significantly in the past two decades. Focus on the descriptive phrases used by patients with cardiopulmonary disease and by normal subjects made breathless in laboratory studies has given us important insights into the physiology of this frequently disabling symptom. As we gain more experience with dyspnea questionnaires in the

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clinical setting, our ability to use the medical history to sharpen our diagnosis of the factors limiting patients’ exercise capacity will undoubtedly improve. Ultimately, the goal is that these tools will enhance the specificity of our therapeutic interventions in the treatment of dyspnea. References 1. Reading AE. Testing pain mechanisms in persons with pain. In: Melzack R, Wall PD 2nd ed. Textbook of Pain. New York: Churchill Livingstone, 1989:269–280. 2. Degowin EL, DeGowin RL. Diagnostic Evaluation. New York: Macmillan, 1976. 3. Fairman RP, Glauser FL. Dyspnea. In: Glauser FL, ed. Signs and Symptoms in Pulmonary Medicine. Philadelphia: JB Lippincott, 1983:1–11. 4. Comroe J. Summing up. In: Howell JBL, Campbell EJM, eds. Breathlessness. London: Blackwell Scientific, 1966:233–238. 5. Campbell EJM, Guz A. Breathlessness. In: Hornbein TF, ed. Regulation of Breathing, Part II. New York: Dekker, 1981:1181–1195. 6. Campbell EJM, Howell JBL. The sensation of breathlessness. Br Med Bull 1963; 19:36–40. 7. Titchener EB. Notes from the psychology laboratory of Cornell University. Am J Psychol 1920; 31:212. 8. Dallenbach KM. Somesthesis. In: Boring EG, Langfield HS, Weld HP, eds. Introduction to Psychology. New York: Wiley and Sons, 1939:608–625. 9. Melzack R, Torgerson WS. On the language of pain. Anesthesiology 1971; 34:50–59. 10. Melzack R. The McGill pain questionnaire: major properties and scoring methods. Pain 1975; 1:277–299. 11. Dubuisson D, Melzack R. Classification of clinical pain descriptions by multiple group discriminate analysis. Exp Neurol 1976; 51:480–487. 12. Hunter M, Philips C. The experience of headache—an assessment of the qualities of tension headache pain. Pain 1981; 10:209–219. 13. Grushka M, Sessle BJ. Applicability of the McGill pain questionnaire to the differentiation of ‘‘toothache’’ pain. Pain 1984; 19:49–57. 14. Melzack R, Terrence C, Fromm G, Amsel R. Trigemmal neuralgia and atypical facial pain: use of the McGill pain questionnaire for discrimination and diagnosis. Pain 1986; 27:297–302. 15. Simon PM, Schwartzstein RM, Weiss JW, LaHive K, Fencl V, Teghtsoonian M, Weinberger SE. Distinguishable sensations of breathlessness induced in normal volunteers. Am Rev Respir Dis 1989; 140:1021–1027. 16. Simon PM, Schwartzstein RM, Weiss JW, Fencl V, Teghtsoonian M, Weinberger SE. Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 1990; 142:1009–1014. 17. Mahler DA, Harver A, Lentine T, Scott JA, Beck K, Schwartzstein RM. Descriptors of breathlessness in cardiorespiratory diseases. Am J Respir Grit Care Med 1996; 154:1357–1363.

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18. Elliott MW, Adams L, Cockroft A, MacRae KD, Murphy K, Guz A. The language of breathlessness: Use by patients of verbal descriptors. Am Rev Respir Dis 1991; 144:826–832. 19. Harver A, Mahler DA, Schwartzstein RM, Baird JC. Descriptors of breathlessness in healthy individuals. Chest 2000; 118:679–690. 20. Hardie GE, Janson S, Gold WM, Carreri-Kohlman V, Boushey HA. Ethnic differences: word descriptors used by African-American and White asthma patients during induced bronchoconstriction. Chest 2000; 117:935–943. 21. Skevington SM, Pilaar M, Routh D, Macleod RD. On the language of breathlessness. Psychol Health 1997; 12:677–689. 22. Phankingthongkum S, Daengsuwan T, Visitsunthorn N, Thamlikitkul V, Udompunthuruk S, Vichyanond P. How do Thai children and adolescents describe asthma symptoms? Pediatr Allergy Immunol 2002; 13:119–124. 23. Chronos N, Adams L, Guz A. Effect of hyperoxia and hypoxia on exerciseinduced breathlessness in normal subjects. Clin Sci 1988; 74:531–537. 24. Banzett RB, Lansing RW, Reid MB, Adams L, Brown R. ‘‘Air hunger’’ arising from increased PCO2 in mechanically ventilated quadriplegics. Respir Physiol 1989; 76:53–68. 25. Banzett RB, Lansing RW, Brown R, Topulos GP, Yager D, Steele SM, Londono B, Loring SH, Reid MB, Adams L, Nations CS. ‘‘Air hunger’’ from increased PCO2 persists after complete neuromuscular block in humans. Respir Physiol 1990; 81:1–18. 26. Shea SA, Andres LP, Guz A, Banzett RB. Respiratory sensations in subjects who lack a ventilatory response to CO2. Respir Physiol 1993; 93(2):203–219. 27. Chonan T, Mulholland MB, Cherniack NS, Altose MD. Effects of voluntary constraining of thoracic displacement during hypercapnia. J Appl Physiol 1987; 63:1822–1828. 28. Schwartzstein RM, Simon PM, Weiss JW, Fencl V, Weinberger SE. Breathlessness induced by dissociation between ventilation and chemical drive. Am Rev Respir Dis 1989; 139:1231–1237. 29. Demediuk BH, Manning H, Lilly J, Fencl V, Weinberger SE, Weiss JW, Schwartzstein RM. Dissociation between dyspnea and respiratory effort. Am Rev Respir Dis 1992; 146:1222–1225. 30. Moy ML, Weiss JW, Sparrow D, Israel E, Schwartzstein RM. Quality of dyspnea in bronchoconstriction differs from external loads. Am J Respir Crit Care Med 2000; 162:451–455. 31. Taguchi O, Kikuchi Y, Hida W, Iwase N, Satoh M, Chonan T, Takishima T. Effects of bronchoconstriction and external resistive loading on the sensation of dyspnea. J Appl Physiol 1991; 71:2183–2190. 32. Kelsen SG, Prestel TF, Cherniack NS, Chester EH, Deal EC. Comparison of the respiratory responses to external resistive loading and bronchoconstriction. J Clin Invest 1981; 67:1761–1768. 33. Binks AP, Moosavi SH, Banzett RB, Schwartzstein RM. ‘‘Tightness’’ sensation of asthma does not arise from the work of breathing. Am J Respir Crit Care Med 2002; 165:78–82.

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34. Moy ML, Lantin ML, Harver A, Schwartzstein RM. Language of dyspnea in assessment of patients with acute asthma treated with nebulized albuterol. Am J Respir Crit Care Med 1998; 158:749–753. 35. Cristiano LM, Klenz J, Shao A, Mourad I, Brown R, Schwartzstein RM. Rib cage innervation is not necessary for perception of chest tightness during methacholine induced bronchoconstriction. Am J Respir Crit Care Med 1994; 149:A1085. 36. Widger HN, Hoffman P, Mazzolini D, Stone A, Scholly S, Clark J. Pressure support noninvasive positive pressure ventilation treatment of acute cardiogenic pulmonary edema. Am J Emerg Med 2001; 19:179–181. 37. Masip J, Betbese AJ, Paez J, Vecilla F, Canizares R, Pedro J, Paz MA, de Otero J, Ballus J. Noninvasive pressure support ventilation vs. conventional oxygen therapy in acute cardiogenic pulmonary edema: a randomized trial. Lancet 2000; 356:2126–2132. 38. Sperry RW. Neural basis of the spontaneous optokinetic response produced by visual neural inversion. J Comp Physiol Psychol 1950; 45:482–489. 39. Gandevia SC. Neural mechanisms underlying the sensation of breathlessness: kinesthetic parallels between respiratory and limb muscles. Aust NZ J Med 1988; 18:83–91. 40. Schwartzstein RM, Manning HL, Weiss JW, Weinberger SE. Dyspnea: a sensory experience. Lung 1990; 168:185–199. 41. Lougheed MD, Lam M, Forkert L, Webb KA, O’Donnell DE. Breathlessness during acute bronchoconstriction in asthma. Am Rev Respir Dis 1993; 148:1452–1459. 42. Killian KJ, Gandevia SC, Summers E, Campbell EJM. Effect of increased lung volume on perception of breathlessness, effort and tension. J Appl Physiol 1984; 57:686–691. 43. O’Donnell DE, Bertley JC, Chau LKL, Webb K. Qualitative aspects of exertional breathlessness in chronic airflow obstruction. Am J Respir Crit Care Med 1997; 155:109–115. 44. O’Donnell DE, Revill SM, Webb K. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164:770–777. 45. Scott AC, Davies LC, Coats AJ, Piepoli M. Relationship of skeletal muscle metaboreceptors in the upper and lower limbs with the respiratory control in patients with heart failure. Clin Sci 2002; 102:23–30. 46. Clark A, Coats A. Mechanisms of exercise intolerance in cardiac failure: abnonnalities of skeletal muscle and pulmonary function. Curr Opin Cardiol 1994; 9:305–314. 47. Lansing RW, Im BS, Thwing JI, Legedza AT, Banzett RB. The perception of respiratory work and effort can be independent of the perception of air hunger. Am J Respir Crit Care Med 2000; 162:1690–1696. 48. Killian KJ, Watson R, Otis J, St Amand TA, O’Byrne PM. Symptom perception during acute bronchoconstriction. Am J Respir Crit Care Med 2000; 162:490–496.

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49. Devereux G, Hendrick DJ, Stenton SC. Perception of respiratory symptoms after methacholine-induced bronchoconstriction in a general population. Eur Respir J 1998; 12:1089–1093. 50. Manning HL, Molinary EJ, Leiter JC. Effect of inspiratory flow rate on respiratory sensation and pattern of breathing. Am J Respir Crit Care Med 1995; 151:751–757. 51. O’Donnell DE, Webb KA. Exertional breathlessness in patients with chronic airflow limitation. Am Rev Respir Dis 1993; 148:1351–1357. 52. O’Donnell DE, Lam M, Webb KA. Measurement of symptoms, lung hyperinflation, and endurance during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 158:1557–1565. 53. Harty HR, Corfield DR, Schwartzstein RM, Adams L. External thoracic restriction, respiratory sensation, and ventilation during exercise in men. J Appl Physiol 1999; 86:1142–1150. 54. O’Donnell DE, Chau LKL, Webb KA. Qualitative aspects of exertional dyspnea in patients with interstitial lung disease. J Appl Physiol 1998; 84:2000–2009. 55. Smoller JW, Pollack MH, Otto MW, Rosenbaum JF, Kradin RL. Panic anxiety, dyspnea, and respiratory disease. Am J Respir Crit Care Med 1996; 154:6–17. 56. Chevalier B, Schwartzstein RM. Hyperventilation syndrome: insights into a puzzling disorder. J Respir Dis 2000; 21:569–574. 57. Kinsman RA, Luparello TJ, O’Banion K, Spector SL. Multidimensional analysis of the subjective symptomatology of asthma. Psychosom Med 1973; 35:250–267. 58. Kinsman RA, O’Banion K, Resnikoff P, Luparello TJ, Spector SL. Subjective symptoms of acute asthma with a heterogeneous sample of asthmatics. J Allergy Clin Immunol 1973; 52:284–296. 59. Kinsman RA, Fernandez E, Shockef M, Dirks JF, Covino NA. Multidimensional analysis of the symptoms of chronic bronchitis and emphysema. J Behav Med 1983; 6:339–357. 60. Yellowlees PM, Alpers JH, Bowsen JJ, Bryant GD, Ruffin RE. Psychiatric morbidity in patients with chronic airflow obstruction. Med J Aust 1987; 146:305–307. 61. Tiller J, Pain M, Biddle N. Anxiety disorder and perception of inspiratory resistive loads. Chest 1987; 91:547–551. 62. Kellner R, Samet J, Pathak D. Dyspnea, anxiety, and depression in chronic respiratory impairment. Gen Hosp Psychiatry 1992; 14:20–28. 63. Mishima M, Oku Y, Muro S, Hirai T, Chin K, Ohi M, Nakagawa M, Fujita M, Sato K, Shimada K, Yamaoka S, Oda Y, Asai N, Sagawa Y, Juno K. Relationship between dyspnea in daily life and psycho-physiologic state in patients with chronic obstructive pulmonary disease during long-term domiciliary oxygen therapy. Intern Med 1996; 35:453–458. 64. Moosavi SH, Topulos GP, HaferA, Lansing RW, Adams L, Brown R, Banzett RB. Acute partial paralysis alters perceptions of air hunger, work and effort at constant PCO2 and VE. Respir Physiol 2000; 122:45–60.

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65. 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; 110:1526–1535. 66. Carrieri-Kohlman V, Gormley JM, Eiser S, Demir-Deviren S, Nguyen H, Paul SM, Stulbarg MS. Dyspnea and the affective response during exercise training in obstructive pulmonary disease. Nurs Res 2001; 50:136–146. 67. Eiser N, West C, Evans S, Jeffers A, Quirk F. Effects of psychotherapy in moderately severe COPD: a pilot study. Eur Respir J 1997; 10:1581–1584. 68. Borak J, Chodosowska E, Matuszewski A, Zielinski J. Emotional status does not alter exercise tolerance in patients with chronic obstructive pulmonary disease. Eur Respir J 1998; 12:370–373. 69. Pratter MR, Curley FJ, Dubois J, Irwin RS. Cause and evaluation of chronic dyspnea in a pulmonary disease clinic. Arch Intern Med 1989; 149:2277–2282. 70. Harver A, Mahler DA, Schwartzstein RM. Use of a descriptor model for prospective diagnosis of dyspnea. Am J Respir Grit Care Med 2000; 161:A705. 71. Chevalier B, Schwartzstein R. The role of the methacholine inhalation challenge: avoiding a misdiagnosis of asthma. J Respir Dis 2001; 22:153–160. 72. Killian KJ, Summers E, Jones NL, Campbell EJM. Dyspnea and leg fatigue during incremental cycle ergometry. Am Rev Respir Dis 1992; 145:1339–1345. 73. Killian KJ, Leblanc P, Martin DH, Summers E, Jones NL, Campbell EJM. Exercise capacity and ventilatory, circulatory, and symptom limitation in patients with chronic airflow limitation. Am Rev Respir Dis 1992; 146: 935–940.

7 Measurement of Dyspnea: Clinical Ratings

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

I. Introduction From the perspective of the patients with respiratory disease, the problem of breathlessness is clearly the most common symptom that limits their ability to perform daily activities. An expert panel representing the American Thoracic Society defined dyspnea as (1): A subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity.

Both the prevalence and impact of dyspnea, or breathlessness, have been quantified as part of a telephone survey of over 3000 individuals with chronic obstructive pulmonary disease (COPD) living in North America or Europe (2). On average, 54% of patients reported that they experienced dyspnea ‘‘every or most days’’ of their life. Moreover, the frequency of breathlessness is extremely common with various daily activities (Fig. 1). These collective data demonstrate the burden that symptom of breathlessness plays in the daily lives of patients with lung disease.

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Figure 1 The frequency of dyspnea with various activities as reported by more than 3000 patients with COPD in the Confronting COPD International Telephone Survey. Source: Adapted from Ref. 2.

In chronic respiratory disease, the typical approach in evaluating the efficacy of medical therapy has been to consider lung function as the major parameter. However, the airflow limitation in COPD has been defined in the past as ‘‘fixed’’ (3) or as ‘‘not fully reversible’’ (4). The focus on the forced expiratory volume in one second (FEV1) as the primary outcome measure by various investigators, industry, and regulatory agencies has made it both challenging and difficult to demonstrate the benefits of treatment, particularly with bronchodilators! Appropriately, there has been increased recognition and acceptance over the past decade that patient symptoms, as well as other clinical parameters (e.g., health status and exacerbations), are the more important outcomes (5,6). The consideration of dyspnea has been made possible by two related developments:
the development and validation of instruments to quantify breathlessness;
the application of these instruments in clinical trials to demonstrate that standard therapies relieve dyspnea in symptomatic patients. This two-part evolution has accomplished one of the objectives of the science of medicine that is to convert sensory experiences, such as pain or dyspnea, into quantitative information (7). In 2001, and again in the 2003 update, the Global Initiative for Obstructive Lung Disease guidelines

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emphasized the importance of symptoms, particularly dyspnea, along with health status and exacerbations as being primary metrics rather than dependence on lung function for assessing treatment efficacy (5,8). Additional reviews have explored and described these ‘‘key outcomes’’ in the evaluation of patients with COPD (9–11). Moreover, in recent studies, dyspnea scores have been shown to predict survival in patients with respiratory disease. Nishimura et al. (12) reported that the initial level of dyspnea [as recorded on the Medical Research Council (MRC) scale] was a more significant predictor of survival of 227 patients with COPD over five years than disease severity based on FEV1. Collard et al. (13) found that initial dyspnea scores (range: 0–20) predicted survival at six and 12 months, along with certain physiological parameters, in patients with idiopathic pulmonary fibrosis. These two studies illustrate that the severity of dyspnea, as measured with different clinical instruments, can predict survival in patients with respiratory disease.

II. Can Dyspnea be Measured? In 1946, Stevens (14) stated that: Measurement is defined as the assignment of numerals to objects or events according to rules.

The principles of psychophysics, which is the study of the relationship between a stimulus and the response, can be applied to quantify the severity of breathlessness (14,15). Although the exact mechanisms and precise stimuli for dyspnea have not been completely identified, three different psychophysical approaches have been used to measure dyspnea as a patientreported outcome (Table 1). Early investigations instructed subjects to estimate the magnitude of breathlessness when they breathed through added resistive or elastic loads (16,17). Such added respiratory loads were thought to mimic or to simulate what patients experienced when they had breathing difficulty. However, comparative studies have demonstrated that a patient’s estimation of the magnitude of external breathing loads does not relate to clinical ratings of dyspnea based on daily activities or tasks (18,19). Presently, added respiratory loads may be applied to explore possible mechanisms contributing to breathlessness. Another approach has been to consider that activities of daily living provoke breathlessness in patients with respiratory disease (6). Various clinical instruments have been developed and used in clinical trials on the basis of this premise. This methodology has been considered an ‘‘indirect’’ measurement because it depends on a person’s recall and description of daily tasks, ability to function, time and effort to complete an activity, etc.

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Table 1 Psychophysiological Approach for Measuring Dyspnea and Corresponding Clinical Applications Stimulus (Applications)

Response

Added respiratory loads (to study mechanisms)

!

Activities of daily living (clinical trials) Exercise testing (select clinical trials)a

! !

Open scale (0!1) Category-ratio scale Visual analog scale BDI and TDI Dyspnea component of the CRQ 0–10 category-ratio (CR-10) scale Visual analog scale

a

Exercise testing is not practical in large multicenter clinical trials.

Nevertheless, the use of clinical instruments to quantify dyspnea has been widely accepted for three important reasons. First, this approach measures dyspnea as reported by patients on the basis of their daily activities (i.e., a patient-reported outcome) (20). Second, certain scales or questionnaires have been tested extensively and fulfill established measurement criteria for validity, reliability, and responsiveness. Third, these instruments have demonstrated improvements in breathlessness with standard treatments (see Chapters 12–17 in Section 3 of this book). A third method considers exercise on the cycle ergometer or a treadmill as a direct stimulus in the laboratory to elicit both physiological and perceptual responses (21,22). This approach is reviewed in Chapter 8.

III. Types of Instruments and Measurement Criteria There are two general types of instruments used to measure dyspnea (6,23):
discriminative—to differentiate between people who have less dyspnea and those who have more dyspnea;
evaluative—to evaluate how dyspnea changes in response to a medical intervention. Several measurement criteria are important for establishing the utility of the instrument (Table 2). Validity concerns whether an instrument measures what it is intended to measure. For a discriminative instrument, validity is strengthened if different measures of dyspnea categorize patients in a similar manner. Moreover, scores from the different instruments should correlate highly with one another. For an evaluative instrument, validity is supported if changes in dyspnea scores correlate with expected changes

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Table 2 Measurement Criteria for Instruments Used to Measure Dyspnea Discriminative instrument—differentiates between people who have less dyspnea and those who have more dyspnea Reliability—stable patients should have only small changes in dyspnea scores with repeated testing when compared with differences in dyspnea scores between patients Validity—a dyspnea score from one instrument should correlate with the dyspnea score from another instrument Evaluative instrument—determines the magnitude of change in dyspnea Responsiveness—the ability to detect change if it has occurred Construct validity—any change in dyspnea scores should be expected to correlate with change in other variables, such as lung function or exercise performance, as a result of an intervention Source: Adapted from Ref. 6.

in other parameters (e.g., lung function and exercise performance) consistent with expectations. In addition, a satisfactory instrument should have a high ratio of the signal to the noise. For a discriminative instrument, reliability is the method for quantitating the signal to noise. An instrument is considered reliable if the variability in scores between patients (the signal) is considerably greater than the variability within subjects (the noise). For an evaluative instrument, responsiveness is the method for determining the signal-to-noise ratio. Physicians and/or investigators want to be confident that they can detect an important difference in dyspnea even if it is small. Responsiveness is related to the magnitude of the differences in scores in patients who have improved or deteriorated (the signal) compared with the extent to which patients who have not changed have more or less the same scores (the noise). Interpretability is another important criterion when considering a particular dyspnea score or rating. For an evaluative instrument, a specific change in the score could represent a trivial, small but important, moderate, or large improvement or deterioration in dyspnea. Furthermore, a threshold level, considered as the minimal clinically important difference (MCID), can be used to estimate whether the change in the dyspnea score is meaningful (24). Both anchor-based (25,26) and statistical (27) methods have been applied to establish the MCID for health-related instruments.

IV. Clinical Instruments Used to Measure Dyspnea A. Unidimensional Scales

The initial instruments developed to quantify dyspnea were category or analog scales that focused on a single dimension (i.e., daily tasks) that

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provoked breathlessness (Table 3). For example, in 1952, Fletcher (28) published a five-point scale that was used for patients with pneumoconiosis to rate the severity of dyspnea based on activities relative to healthy individuals of comparable age. Seven years later, Fletcher et al. (29) published a revised scale that considered the patient’s report of breathlessness while either walking on a level or climbing stairs. This five-point self-rating instrument was called the MRC scale because the British agency provided funding to the investigators. Although the MRC scale is an excellent discriminative instrument for categorizing patients according to the severity of their breathlessness, it has not been particularly useful as an evaluative instrument that can detect or measure change in response to an intervention. Subsequently, the American Thoracic Society (30), as well as other organizations, published different dyspnea scales or questionnaires that were actually quite similar to the MRC scale. Many of these instruments were developed for clinical research purposes; however, at the time of development, it was not standard practice to rigorously evaluate measurement characteristics (i.e., validity, reliability, and responsiveness) of the different scales. Although many of these questionnaires are appropriate discriminative instruments, they are limited by two factors:

Table 3 Clinical Instruments Used to Measure Dyspnea Name of instrument Unidimensional instruments Pneumoconiosis Dyspnea Questionnaire MRC Breathlessness Questionnaire Visual analog scale WHO Dyspnea Questionnaire ATS Dyspnea scale Oxygen-cost diagram Multidimensional instruments BDI and TDI Dyspnea component of the CRQ UCSD Shortness of Breath Questionnaire

Grades

Author (year of publication)

1–4

Schilling (1955)

1–5

Fletcher (1959)

0–10 cm 1–4

Aitken (1969) Rose (1982)

0–4 mm on a line

Brooks (1982) McGavin (1978)

0–12 9 to þ9 1–5

Mahler (1984) Guyatt (1987)

0–120

Eakin (1998)

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only one dimension (physical tasks) that provokes breathlessness is considered the broad grades make it difficult to detect small but important changes with various interventions (i.e., they are not satisfactory evaluative instruments)

B. Multidimensional Questionnaires

To improve the measurement of dyspnea, multidimensional instruments were developed that included additional components which influence the patient’s experience of dyspnea. The Baseline Dyspnea Index (BDI) and Transition Dyspnea Index (TDI) were published in 1984 and included three components:




functional impairment magnitude of task magnitude of effort

that contribute to breathing difficulty (31). The BDI and TDI are two separate instruments; the BDI was developed as a discriminative instrument to measure dyspnea at a single point in time, whereas the TDI was developed as an evaluative instrument to measure changes in dyspnea from the baseline state (Table 4). Ratings or scores for dyspnea are obtained from an interviewer (physician, nurse, or pulmonary function technician) as part of taking a medical history relating to respiratory disease; the interviewer selects a score for each of the three components on the basis of the patient’s answers using the specific criteria for the grades as described for the instruments. An interview approach was used rather than a self-administered questionnaire for two specific reasons. First, dyspnea could be graded as part of the process whereby a health-care provider obtains the medical history of a patient with respiratory disease. Second, the questions posed by the interviewer could uncover subtleties relating to dyspnea that might be missed by the patient simply checking a box on a self-administered questionnaire to indicate a dyspnea grade. In the Chronic Respiratory Questionnaire (CRQ) published in 1987, dyspnea was included as one of four components of a health-status instrument for use in patients with respiratory disease (32). The individual patient is asked to select the five most important activities that cause breathlessness over the past 2 weeks on the basis of recall and by reading from a list of 26 different activities. The patient then grades the severity of dyspnea by indicating a score on a Likert scale (range: 1–7) for each of the five activities (Table 5). The overall score can then be divided by the number of activities (usually five) selected by the patient. The CRQ was developed by Guyatt et al. (32) as an evaluative instrument to be used in clinical trials. A

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Table 4 Scoring System of the BDI and TDI Grades Baseline Dyspnea Index (BDI)a 0–4

0–4

0–4

0–12 Transition Dyspnea Index (TDI)b 3 to þ3 3 to þ3 3 to þ3 9 to þ9

Components Functional impairment—effect of dyspnea on ability to perform daily activities and to work Magnitude of task—range of various physical tasks (e.g., walking on a level, climbing stairs, etc.) Magnitude of effort—degree of effort required to perform activities and tasks (e.g., need to pause or rest) BDI total score Changes in functional impairment Changes in magnitude of task Changes in magnitude of effort TDI total score

a

Measures dyspnea at a baseline or at an initial time. Measures changes in dyspnea compared to the baseline or initial state.

b

self-administered CRQ has been described (33), and a preliminary report has standardized the various activities that can be selected by patients into five specific activities (34). Additional multidimensional questionnaires include the UCSD Shortness of Breath Questionnaire (35), the Pulmonary Functional Status and Dyspnea Questionnaire (36), and the Breathlessness, Cough, and Sputum Scale (37). The UCSD questionnaire requires patients to indicate how frequently they experience shortness of breath on a seven point scale during 21 activities of daily living. There are three additional questions about Table 5 Scoring System for the Dyspnea Component of the CRQ Score

Specific activity selected by the individual

1–7 1–7 1–7 1–7 1–7 5–35

Activity A Activity B Activity C Activity D Activity E CRQ dyspnea score

Note: (1–5) preferred scoring range obtained by dividing the final score (5–35) by the number of activities selected (typically five).

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limitations due to shortness of breath, fear of harm from overexertion, and fear of shortness of breath for a total of 24 items. The UCSD questionnaire was used to measure dyspnea in the National Emphysema Therapy Trial to evaluate the efficacy of lung volume reduction surgery in patients with emphysema (38). The dyspnea questionnaire developed by Lareau et al. (36) consists of a general dyspnea rating based on three general and three specific questions as well as the intensity of dyspnea [from 0 (none) to 10 (very severe)] experienced by the patient with each of 79 activities. The Breathlessness, Cough, and Sputum Scale reflects patient-reported daily symptom data in COPD (37). V. Validity A. Discriminative Instruments

Factor analyses have shown that scores from dyspnea instruments provide unique information that is distinct from measures of lung function, exercise performance, and health status (39–41). Moreover, dyspnea scores obtained from different instruments correlate significantly with each other in different populations of patients with respiratory disease (concurrent validity) (35,42,43). These studies, as well as other reports, have demonstrated the validity of unidimensional [MRC scale, the oxygen cost diagram (OCD), the World Health Organization (WHO) scale] and multidimensional (BDI and the UCSD Shortness of Breath Questionnaire) as discriminative instruments that are able to differentiate the severity of dyspnea between different individuals or groups. B. Evaluative Instruments

The validity of an evaluative instrument requires that changes in dyspnea scores correlate with changes in other parameters, such as lung function, exercise performance, albuterol rescue use, and health status (i.e., construct validity). Extensive testing has established the construct validity of both the TDI and the dyspnea component of the CRQ in different populations of patients with respiratory disease (6,9,32,43). For example, the TDI total score correlates significantly with changes in FEV1, inspiratory mouth pressure, number of puffs of supplemental use of albuterol, etc., in different populations of patients with COPD (44–47). VI. Reliability (for a Discriminative Instrument) Dyspnea scores obtained from a discriminative instrument should be similar in a stable patient upon repeat testing (test–retest and intra-rater reliability) and between different interviewers when the instrument requires an interview (inter-rater reliability). Guyatt et al. (32) measured dyspnea at

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six time periods at 2 week intervals in 43 symptomatic patients with respiratory disease. Both correlation coefficients and kappa values were statistically significant for dyspnea ratings obtained from the BDI, the OCD, and the WHO scale at the different visits. In 1995, Eakin et al. (35) reported that the BDI and the UCSD Shortness of Breath Questionnaire demonstrated the highest levels of reliability among six different measures of dyspnea (including the American Thoracic Society dyspnea scale, OCD, visual analog scale, and the CR-10 scale). In this cross-sectional study, the BDI exhibited consistently higher correlations with the 6-min walking distance, quality of well-being score, lung function, depression score, and anxiety score compared with the UCSD questionnaire (35). For the BDI, which requires an interviewer to ask questions to the patient in order to grade dyspnea, it is important that there is good agreement for the scores between different interviewers. Mahler et al. (31) have reported substantial congruence between different interviewers for the BDI total score on the basis of percentage agreement (range: 85–94%) and the weighted kappa value (range: 0.53–0.73). These overall results demonstrate satisfactory reliability for selected discriminative instruments used to measure dyspnea.

VII. Responsiveness (for an Evaluative Instrument) Responsiveness is an essential criterion for evaluation of the impact or efficacy of any treatment on the outcome of dyspnea. The characteristics of the TDI and the dyspnea component of the CRQ are compared in Table 6. In randomized controlled trials, bronchodilator medications, oxygen therapy, pulmonary rehabilitation, and inspiratory muscle training have been shown to relieve dyspnea in patients with COPD (6,9,11,44–53). The benefits of these specific interventions on the relief of dyspnea are reviewed in detail in subsequent chapters of this book.

VIII. Minimal Clinically Important Difference Although an experienced physician may be confident in interpreting the results of blood tests or the changes in lung function, any change in a breathlessness score or rating is not intuitively obvious. Accordingly, the concept of an MCID has been used to provide an estimate as to the clinical importance of the magnitude of the treatment effect. In addition, regulatory agencies have required that changes in clinical outcomes represent a value that is ‘‘clinically meaningful.’’ Jaeschke et al. (54) have defined the MCID as:

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Table 6 Comparison of TDI and Dyspnea Component of the CRQ as Evaluative Instruments Characteristic

TDI

Dyspnea—CRQ

Interviewer administered Self-administered version Components

Yes

Yes

Available

Available

Functional impairment Magnitude of task Magnitude of effort Specific criteria for each component 9 to þ9 3 min

Five activities

Grading scale Total score Time required to complete

Likert scale (1–7) for each activity 1–5 10–20 min (initial) 5–10 (follow-up)

Appropriate to compare dyspnea scores between studies Interviewer Yes administered Self-administered Yes

No Yes

The smallest difference in score in the domain of interest which patients perceive as beneficial and would mandate, in the absence of troublesome side-effects and excessive cost, a change in the patient’s management.

IX. What Is the MCID for Instruments that Measure Dyspnea? Evidence to support 1 unit as the MCID for the TDI total score is provided in Table 7 (55). Examination of the TDI reveals that a change of 1 unit (or more) in the total score is inherent in the instrument itself as representing meaningful change (improvement or deterioration) (31). From a patient’s perspective:


a 1-unit improvement in functional impairment represents: þ1 able to return to work at reduced pace or has resumed some customary activities with more vigor than previously due to improvement in shortness of breath; or




a 1-unit improvement in magnitude of task represents:

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Table 7 Supporting Evidence for the MCID of the TDI and the Dyspnea Component of the CRQ TDI total score

Dyspnea—CRQ

1.0 1.0 1.2a ND 1.0

0.6 ND 0.50–0.51b 0.43 0.5

Expert physician-based MCID Anchor-based MCID Distribution-based MCID Patient-based MCID Recommended MCID a

Based on 0.5 of the standard deviation (2.4). Based on standard error of the measurement. Abbreviation: ND, not determined. b

þ1 if patient was short of breath with light activities such as walking on the level or washing, now becomes short of breath with moderate or average tasks such as walking up a gradual hill or carrying a light load on the level; or


a 1-unit improvement in magnitude of effort represents: þ1 able to do things with distinctly greater effort without shortness of breath. May be able to carry out tasks somewhat more rapidly than previously.

These changes clearly represent benefits that are meaningful and important to an individual patient! Witek and Mahler (46,47) used the physician’s global evaluation (PGE) score (range: 1–8) of individual patients with COPD as an anchor to demonstrate that a change of 1 unit in the TDI focal score corresponded to a minimal improvement or decline in the PGE. Those patients who had a 1 unit improvement in the TDI score (responders) in two different randomized controlled trials evaluating a long-acting inhaled bronchodilator, tiotropium, used less albuterol as a rescue medication, had better health status, and had fewer exacerbations compared with those who had <1 unit improvement in the TDI score (nonresponders) (46,47). Using an anchorbased approach, a 1 unit change in the TDI total score represents the MCID. In addition, a distribution-based approach can be used to determine the MCID. Norman et al. (56) reviewed numerous studies that computed an MCID for health-related quality of life instruments and found the threshold was ‘‘very close to half a standard deviation.’’ In the 1-year triotropiumplacebo clinical trials, the standard deviation of the TDI total score was 2.4; one-half of the SD is 1.2 units. This number approximates closely the 1.0 value determined by other methods (Table 7).

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Application of the BDI/TDI in randomized clinical trials has demonstrated that tiotropium (50,51,53), a combination of inhaled salmeterol and fluticasone (52), pulmonary rehabilitation (48,49,57), and inspiratory muscle training (58,59) have achieved and/or exceeded the 1 unit MCID in the TDI compared with placebo therapy in patients with COPD. Evidence to support 0.5 as the MCID for the dyspnea score of the CRQ is provided in Table 7 (60). For the dyspnea component of the CRQ, Redelmeier et al. (25) ‘‘found that scores, on average, needed to differ by about 0.5 per question for patients to stop rating themselves as ‘about the same’ and start rating themselves as either ‘a little bit better’ or ‘a little bit worse.’ Therefore, as there are five questions or activities related to dyspnea as part of the CRQ, the minimal important difference for the composite dyspnea score would be 0.5 (a total summation score of at least 2.5 divided by five activities) (25). Clinical trials of pulmonary rehabilitation in patients with COPD have shown consistent improvements of 0.5 units in the dyspnea component of the CRQ (61–65). At the present time, an MCID has not been established for the unidimensional MRC scale or for multidimensional instruments such as the UCSD Shortness of Breath Questionnaire and the Pulmonary Functional Status and Dyspnea Questionnaire. Leidy et al. (37) reported that a mean change in the Breathlessness, Cough, and Sputum Scale total score >1.0 represented ‘‘substantial symptomatic improvement,’’ whereas a change of 0.6 ‘‘can be interpreted as moderate.’’

X. Recommendations Unidimensional instruments can be used for discriminative purposes to measure dyspnea (Table 3). However, extensive experience has revealed that these types of instruments are generally insensitive to detect small but clinically important changes in dyspnea in response to various treatments. On the other hand, multidimensional instruments, particularly the BDI/TDI and the dyspnea component of the CRQ, have been used widely as evaluative tools and have demonstrated changes in breathlessness on the basis of activities of daily living. Although the vast majority of clinical trials that have measured dyspnea involve patients with COPD, these instruments are also being used in studies of other chronic respiratory diseases. For example, the BDI/TDI has been used to assess the efficacy of interferon gamma-1b therapy for patients with idiopathic pulmonary fibrosis (66). Several factors should be considered in selecting one of the clinical instruments for measuring breathlessness. These include the time required to administer the dyspnea scale, possible need for an interviewer or a person to supervise the measurement process, responsiveness of the instrument, available data on the MCID of the dyspnea score, overall

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experience with the instrument, and ability to compare scores among different populations in different studies. One concern raised about the BDI/TDI and the dyspnea component of the CRQ is the need for an interviewer to obtain or select the dyspnea score. For example, the interviewer asks the patient questions and then selects one of the possible grades on the basis of specific criteria. Both of these instruments were developed so that the interviewer could obtain dyspnea scores as part of a routine medical history. This process has enabled an interviewer to consider and probe any unique aspects of the patients’ breathlessness as part of their activities of daily living. Critics of the interview approach have commented that the process requires interpretation of the patients’ responses by the interviewer. To remedy this criticism, self-administered versions of the BDI/TDI (67,68) and the CRQ (33,34) have been developed. These instruments provide a standardized approach for the patients to rate or grade their dyspnea. Moreover, computerized versions of the BDI/TDI enable the patients to select a grade for each component of the BDI and also to indicate changes in dyspnea with a bidirectional visual analog scale (with descriptors positioned next to corresponding numbers for either improvement or deterioration) for each component of the TDI (self-reported dyspnea) (68). In a study of 25 patients with COPD, the BDI total score was 5.0  1.8 for the mean of two interviewers and 5.4  2.0 for the self-administered method; the correlation between these methods was 0.83 (p < ;0.0001). The TDI focal score was 0.1  3.0 for the interviewers and 0.4  3.0 for the self-administered method; the correlation between these methods was 0.94 (p < 0.0001) (68). The advantages of the self-administered versions include standardized methodology and computerized scoring. Further research will be needed in larger numbers of subjects to evaluate the measurement characteristics (Table 2) of the self-administered versions of the BDI/TDI and of the CRQ. Another issue is the validity of comparing dyspnea scores between or among different groups of patients. For example, it may be important to establish that the severity of breathlessness is similar for different groups at the start of a study. Moreover, it may be even more important to compare different interventions in different populations of patients with similar baseline characteristics to determine whether one treatment is more effective than another treatment. Because the dyspnea component of the interview-administered CRQ is individual specific (i.e., the patient selects the five most important activities that provoke dyspnea), it is not appropriate to compare dyspnea scores obtained from the CRQ between different individuals or different groups of subjects. On the other hand, a standardized version of the dyspnea component of the CRQ has been developed (five standard activities) and should allow comparison of the reported scores (34). With the BDI/TDI, it is acceptable to compare dyspnea scores

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between individuals or groups because specific criteria are used for each grade of each of the three components affecting dyspnea. At the present time, the BDI/TDI and the dyspnea component of the CRQ are the most widely used instruments to grade dyspnea in clinical trials of patients with respiratory disease. A comparison of the features of these instruments is detailed in Table 6. In 1995, the Outcomes Committee of the American Association of Cardiovascular and Pulmonary Rehabilitation reviewed the available clinical instruments to measure dyspnea and proposed that, ‘‘The recommended measure of overall dyspnea is the Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI),’’ for assessment of clinical outcomes in rehabilitation programs (69). Continued validation and testing of both current and new dyspnea instruments are expected and necessary. Computer administration (rather than use of paper and pencil) of patient-reported dyspnea should enhance the collection and analysis of a patient’s score. The self-administered computer (SAC) approach will likely be the method of choice to quantify dyspnea in clinical trials in the future. The SAC methodology may also be applied in the daily care of patients who experience breathlessness. References 1. American Thoracic Society. Dyspnea—assessment, mechanisms, and management. A consensus statement. Am J Respir Crit Care Med 1999; 159:321–340. 2. Rennard S, Decramer M, Calverly PM, Pride NB, Soriano JB, Vermeire PA, Vestbo J. The impact of COPD in North America and Europe in 2000: the subjects’ perspective of the Confronting COPD International Survey. Eur Respir J 2002; 20:799–805. 3. Pearson MG. BTS guidelines for the management of chronic obstructive pulmonary disease. Thorax 1997; 52:S1–S28. 4. Celli BR, MacNee W, and committee members. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004; 23: 932–946. 5. Pauwels RA, Busit AS, Calverly 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. 6. Mahler DA, Jones PW, Guyatt GH. Clinical measurement of dyspnea. In: Mahler DA, ed. Dyspnea. New York: Marcel Dekker, Inc., 1998:149–198. 7. Feinstein AR. ‘‘Clinical Judgment’’ revisited: the distraction of quantitative models. Ann Intern Med 1994; 120:799–805. 8. Fabbri LM, Hurd SS, for the GOLD Scientific Committee. Global strategy for the diagnosis, management and prevention of COPD: 2003 update. Eur Respir J 2003; 22:1–2.

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9. Mahler DA, Jones PW, eds. Key outcomes in COPD: exacerbations and dyspnoea. Eur Respir Rev 2002; 12:1–54. 10. Jones PW, Mahler DA, eds. Key outcomes in COPD: health-related quality of life. Eur Respir Rev 2002; 12:57–109. 11. Kesten S, Witek TJ. Providing evidence of therapeutic benefit in clinical drug development. In: Celli B, ed. Pharmacotherapy in COPD. New York: Marcel Dekker, 2003:1–18. 12. Nishimura K, Izumi T, Tsukino M, Oga T. Dyspnea is a better predictor of 5-year survival than airway obstruction in patients with COPD. Chest 2002; 121:1434–1440. 13. Collard HR, King TE, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003; 168:538–542. 14. Stevens SS. On the theory of scales of measurement. Science 1946; 103: 677–680. 15. Baird JC, Noma E. Fundamentals of Scaling and Psychophysics. New York: Wiley Interscience, 1978. 16. Killian KJ, Mahutee CK, Campbell EJM. Magnitude scaling of externally added loads to breathing. Am Rev Respir Dis 1981; 123:12–15. 17. Gottfried SB, Redline S, Altose MD. Respiratory sensation in chronic obstructive pulmonary disease. Am Rev Respir Dis 1985; 132:954–959. 18. Mahler DA, Rosiello RA, Harver A, Lentine T, McGovern JF, Daubenspeck JA. Comparison of clinical dyspnea ratings and psychophysical measurements of respiratory sensation in obstructive airway disease. Am Rev Respir Dis 1987; 135:1229–1233. 19. Mahler DA, Harver A, Rosiello RA, Daubenspeck JA. Measurement of respiratory sensation in interstitial lung disease: evaluation of clinical dyspnea ratings and magnitude scaling. Chest 1989; 96:767–771. 20. Patrick DL. Patient-reported outcomes (PROs): an organizing tool for concepts, measures, and applications. Qual Life Newslett 2003; 31:1–5. 21. Killian KJ. The objective measurement of dyspnea. Chest 1985; 85(suppl): 84S–90S. 22. Mahler DA, Fierro-Carrion G, Baird JC. Mechanisms and measurement of exertional dyspnea. In: Weisman IM, Zeballos RJ, eds. Clinical Exercise Testing. Progress in Respiratory Research. Vol. 32. Basel: Karger, 2002:72–80. 23. Guyatt GH, Feeny DH, Patrick DL. Measuring health-related quality of life. Ann Intern Med 1993; 118:622–629. 24. Guyatt GH, Feeny D, Patrick D. Proceedings of the international conference on the measurement of quality of life as an outcome in clinical trials: postscript. Control Clin Trials 1991; 12:266S–269S. 25. Redelmeier D, Guyatt GH, Goldstein RS. Assessing the minimal important difference in symptoms: a comparison of two techniques. J Clin Epidemiol 1996; 49:1215–1219. 26. Samsa G, Edelman D, Rothman ML, Wiliams GR, Lipscomb J, Matchar D. Determining clinically important differences in health status measures: a general approach with illustration to the health utilities index mark II. Pharmacoeconomics 1999; 15:141–155.

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27. Wyrwich KW, Tierney WM, Wolinsky FD. Further evidence supporting an SEM-based criterion for identifying meaningful intra-individual changes in health-related quality of life. J Clin Epidemiol 1999; 52:861–873. 28. Fletcher CM. The clinical diagnosis of pulmonary emphysema–an experimental study. Proc R Soc Med 1952; 45:577–584. 29. 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; 1:257–266. 30. Brooks SM (chairman). Task group on surveillance for respiratory hazards in the occupational setting. ATS News 1982; 8:12–16. 31. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea: contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest 1984; 85:751–758. 32. Guyatt GH, Berman LB, Townshend M, Pugsley SO, Chambers LW. A measure of quality of life for clinical trials in chronic lung disease. Thorax 1987; 42:773–778. 33. Williams JEA, Singh SJ, Sewell L, Guyatt GH, Morgan MDL. Development of a self-reported chronic respiratory questionnaire (CRQ-SR). Thorax 2001; 56:954–959. 34. Schunemann HJ, Goldstein R, Mador MI, McKim D, Stahl E, Puhan M, Griffith LE, Grant B, Austin P, Collins R, Guyatt GH. A randomized trial to evaluate the self-administered standardized chronic respiratory questionnaire. Eur Respir J 2005; 25:31–40. 35. Eakin EG, Resnikoff PM, Prewitt LM, Ries AL, Kaplan RM. Validation of a new dyspnea measure: the UCSD shortness of breath questionnaire. Chest 1998; 113:619–624. 36. Lareau SC, Carrieri-Kohlman V, Janson-Bjerklie, Ross PJ. Development and testing of the pulmonary functional status and dyspnea questionnaire. Heart Lung 1994; 23:242–250. 37. Leidy NK, Rennard SI, Schmier J, Jones MKC, Goldman M. The breathlessness, cough, and sputum scale. Chest 2003; 124:2182–2191. 38. 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. 39. Ries AL, Kaplan RM, Blumberg E. Use of factor analysis to consolidate multiple outcome measures in chronic obstructive pulmonary disease. J Clin Epidemiol 1991; 44:497–503. 40. Mahler DA, Harver A. A factor analysis of dyspnea ratings, respiratory muscle strength and lung function in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1992; 145:467–470. 41. Hajiro T, Nishimura K, Tsukino M, Ikeda A, Koyama H, Izumi T. Analysis of clinical methods used to evaluate dyspnea in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 158:1185–1189. 42. Mahler DA, Wells CK. Evaluation of clinical methods for rating dyspnea. Chest 1988; 93:580–586. 43. Guyatt GH, Thompson PJ, Berlan LB, Sullivan MJ, Townsend M, Jones NL, Pugsley SO. How should we measure function in patients with chronic heart and lung disease? J Chron Dis 1985; 38:517–524.

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44. Mahler DA. Therapeutic strategies. In: Mahler DA, eds. Dyspnea. Mount Kisco, NY: Futura Publishing Company Inc., 1990:231–263. 45. Mahler DA. Dyspnea. In: Celli BR, ed. Pharmacotherapy of COPD. New York: Marcel Dekker Inc., 2003:145–158. 46. Witek TJ Jr, Mahler DA. Meaningful effect size and patterns of response of the transition dyspnea index. J Clin Epidemiol 2003; 56:248–255. 47. Witek TJ Jr, Mahler DA. Minimal important difference of the transition dyspnea index in a multi-national clinical trial. Eur Respir J 2003; 21:267–272. 48. O’Donnell DE, McGuire MA, Samis L, Webb KA. The impact of exercise reconditioning on breathlessness in severe chronic airflow limitation. Am J Respir Crit Care Med 1995; 152:2005–2013. 49. 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. 50. Casaburi R, Mahler DA, Jones PW, Wanner A, San Pedro G, ZuWallack RL, Menjoge SS, Serby CW, Witek T Jr. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002; 19:217–224. 51. Brusasco V, Hodder R, Miravitlles M, Korducki L, Tlwse 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. 52. Mahler DA, Wire P, Horstman D, Chang CN, 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. 53. O’Donnell D, Fluge 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. 54. Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials 1989; 10:407–415. 55. Mahler DA, Witek TJ Jr, The MCID of the transition dyspnea index is a total score of one unit. J COPD 2005; 99–103. 56. Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in healthrelated quality of life. Med Care 2003; 41:582–592. 57. 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; 110:1526–1535. 58. Harver A, Mahler DA, Daubenspeck JA. Targeted inspiratory muscle training improves respiratory muscle function and reduces dyspnea in patients with chronic obstructive pulmonary disease. Ann Intern Med 1989; 111:117–124. 59. Lisboa C, Munoz 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. 60. Schunemann HJ, Puhan M, Goldstein R, Jaeschke R, Guyatt GH. Measurement properties and interpretability of the chronic respiratory disease questionnaire (CRQ). J COPD 2005; 81–89.

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61. Guell R, Casan P, Belda J, Sangenis M, Morante F, Guyatt GH, Sanchis J. Long-term effects of outpatient rehabilitation of COPD. Chest 2000; 117:1184–1191. 62. Behnke M, Taube C, Kirsten D, Lehnigk B, Jorrres RA, Magnussen H. Homebased exercise is capable of preserving hospital-based improvements in severe chronic obstructive pulmonary disease. Respir Med 2000; 94:1184–1191. 63. Goldstein RS, Gort EH, Stubbing D, Avendano MA, Guyatt GH. Randomised controlled trial of respiratory rehabilitation. Lancet 1994; 344:1394–1397. 64. Berry MJ, Rejeski WJ, Adair NE, Zaccaro D. Exercise rehabilitation and chronic obstructive pulmonary disease stage. Am J Respir Crit Care Med 1999; 160:1248–1253. 65. Ries AL, Kaplan RM, Myers R, Prewitt LM. Maintenance after pulmonary rehabilitation in chronic lung disease. Am J Respir Crit Care Med 2003; 167:880–888. 66. Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004; 350:125–133. 67. Mahler DA, Ward J, Baird JC. Validity of a self-administered computerized (SAC) baseline dyspnea index [abstr]. Am J Respir Crit Care Med 2003; 167:A312. 68. Mahler DA, Ward J, Fierro-Carrion G, Waterman LA, Lentine TF, MejiaAlfaro R, Baird JC. Development of self-administered versions of modified baseline and transition dyspnea indexes in COPD. J COPD 2004; 1:165–172. 69. AACVPR Outcomes Committee. Outcome measurement in cardiac and pulmonary rehabilitation. J Cardiopulm Rehabil 1995; 15:394–405.

8 Measurement of Dyspnea Ratings During Exercise

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

I. Introduction The principles of psychophysics can be applied to allow the patient or subject to report his/her intensity of dyspnea during the stimulus of a standard exercise test (1). As such, this method enables a direct measure of an individual’s breathlessness as opposed to the approach based on a patient’s responses to questions about the impact of activities of daily living on dyspnea (see Chapter 7 on Clinical Ratings of Dyspnea). Not surprisingly, Hajiro et al. (2) showed that dyspnea scores obtained at the end of exercise provide unique information that is different than that obtained from clinical scales such as the Medical Research Council (MRC) scale or the baseline dyspnea index (BDI). An exercise test is clearly different for patients than actual performance of daily activities. However, the rationale of using a standardized exercise testing as the stimulus to provoke breathlessness in the laboratory is that it mimics or simulates physical activities or work. Actual testing in the exercise laboratory enables the collection of physiological data that cannot be readily obtained in the home or work environment. One limitation of 167

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exercise testing is the requirement of appropriate equipment to collect and analyze the physiological exercise responses. Physiological variables such as power production, minute ventilation (VE), and oxygen consumption (VO2) are important in order to ‘‘match’’ the physiological with the perceptual responses of the patient so that the appropriate statistical analyses can be performed. II. What Is the Stimulus for Dyspnea During Exercise? There has been a long history of interest and study of the nature and mechanisms contributing to dyspnea (Ref. 3, and see Chapter 1). Attempts have been made by various investigators to predict the intensity of dyspnea based on physiological variables. However, statistical models show that different physiological parameters explain only 55–69% of the variability in breathlessness (4–7). Clearly, the exact mechanisms and precise stimuli for exertional breathlessness are not completely understood (8). Nevertheless, the principles of psychophysics have provided a framework to quantify the relationship between a physical stimulus and the consequent perceptual response (i.e., dyspnea). For measurement purposes, it is reasonable to consider that the power produced during exercise and/or the oxygen utilized by the exercising muscles (VO2) are physical stimuli for both physiological (e.g., heart rate and VE) and perceptual responses (9–11). This approach has led to a greater interest in using dyspnea as a metric to examine the efficacy of different treatments for dyspnea relief. III. Types of Exercise Tests Used to Provoke Dyspnea A. Walking Tests

The 6-min walk test (6MWT) measures the maximal distance that a patient can walk on a level surface for 6 min (12). It is a self-paced walk typically done in a corridor of a building such as clinic or hospital. In a recent American Thoracic Society statement, it is recommended that dyspnea be measured at baseline and at the end of the walking test using the 0–10 scale developed by Borg (13). Most patients are able to walk farther (6–7% increase) on a second 6MWT performed on a separate day indicating a learning effect (13,14). A distance of 54 m is considered the smallest difference in the 6MWT associated with a noticeable difference in the patient’s perception of exercise performance (15). There are three major problems or limitations using the 6MWT to quantify dyspnea. First, there is no standard physical stimulus. The test is self-paced and depends entirely on the individual’s motivation to walk as far as possible in the time period. Second, there are no published guidelines for interpreting the reported dyspnea scores obtained at the end of the

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6MWT (13). For example, patients with COPD walked farther after a 2-week trial of albuterol or theophylline, but also reported higher ratings of dyspnea at the end of the 6MWT (16). Although the higher scores suggest greater breathlessness, it is more likely that dyspnea ratings reflect the fact that the patient performed more work. Third, dyspnea ratings at the end of the 6MWT have not reflected the expected benefits of specific therapy. For example, in two multicenter randomized controlled trials, Mahler et al. (17) and Rennard et al. (18) reported no differences in the 6-min walking distance or in postwalk dyspnea scores after 12 weeks in patients receiving either salmeterol or ipratropium bromide compared with the placebo. These collective findings demonstrate that dyspnea scores obtained at the end of the 6MWT are both difficult to interpret and are not responsive to standard bronchodilator medications used to treat patients with COPD (19,20). An incremental shuttle-walking test was developed as a simple modality to measure maximal exercise capacity without the need for sophisticated monitoring such as an electrocardiogram or a metabolic cart (21). The protocol utilizes an audio signal from a cassette tape to direct the walking pace and requires the patient to walk at increasing speeds every minute until the patient is unable to maintain the speed. A constant work shuttle walk test was subsequently developed to more closely simulate the activities of daily living (22). An advantage of the constant work shuttle test is that the speed is controlled in contrast to the self-paced 6MWT. However, the shuttle test is more complicated and technically demanding than the 6MWT (23). In one study, Wadbo et al. (24) found no differences in the shuttle-walking test distance or in ratings of dyspnea at the end of the test after 12 weeks of formoterol, ipratropium bromide, and placebo treatments. B. Cardiopulmonary Exercise Testing

Cardiopulmonary exercise testing (CPET) has been used widely for both diagnostic and therapeutic purposes (23,25). Incremental exercise has been the traditional test used to diagnose coronary artery disease, ventilatory limitation, deconditioning, etc. Moreover, the primary interest of CPET has focused on physiological outcomes, such as heart rate response or maximal VO2. Incremental exercise (as the stimulus) and physiological outcomes (as the measured response) have been applied to investigate the efficacy of various therapies. However, the physiological outcomes measured during incremental CPET have not shown consistent benefits with various interventions in patients with COPD (19,26,27). These results prompted investigators to consider not only different types of exercise tests, but also nonphysiological outcome measures, particularly ratings of breathlessness. For example, in 1998, Franco et al. (28) observed that patients with COPD experience gradual increases in the

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intensity of dyspnea during 10 min of constant rate exercise at 50% and at 80% of peak VO2 (Fig. 1). In a study evaluating bronchodilator therapy, O’Donnell et al. (29) showed that patients with COPD increased their submaximal exercise time and reported lower ratings of dyspnea after nebulized ipratropium bromide (500 mcg) therapy compared with placebo at the same duration of exercise (exercise isotime). Oga et al. (30) found that the submaximal cycle endurance test was more sensitive in detecting the effects of bronchodilator therapy on exercise capacity than were either the 6MWT or incremental cycle ergometry to exhaustion. In 2003, Oga et al. (31) demonstrated that single doses of albuterol or ipratropium bromide improved exercise endurance time and reduced dyspnea ratings relative to endurance time compared with placebo therapy. These and other recent studies illustrate the benefits of measuring dyspnea during CPET for evaluative purposes (10,20,25,29–31).

Figure 1 Gradual increases in dyspnea ratings during constant work exercise on the cycle ergometer at 80% of peak VO2 in 20 patients with COPD. With constant work exercise, the measured VO2 was stable during 6–10 min of exercise. Source: From Ref. 28.

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IV. Instruments to Measure Dyspnea During Exercise A. 0–10 Category-Ratio (CR-10) Scale

Over the years, Borg (32) developed various scales for subjects to report their intensity of subjective experiences including perceived exertion during various stimuli including exercise. The CR-10 scale created by Borg (33) is the most widely used instrument to measure dyspnea during exercise testing for patients with respiratory disease (3–10,34,35). This scale consists of a vertical line with the numbers 0–10 and adjacent verbal descriptors positioned with nonlinear spacing (Fig. 2). The individual can select the appropriate number that corresponds to his/her current severity of breathlessness

Figure 2 The 0–10 category-ratio (CR-10) scale modified for use to measure dyspnea. The scale incorporates nonlinear spacing of verbal descriptors of severity that correspond to specific numbers and ratio properties of intensities. A number greater than 10 can be selected by the patient if his or her dyspnea exceeds ‘‘very, very severe (almost max).’’ Source: From Ref. 33.

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using the descriptors as a guide. Investigators have utilized the CR-10 scale to evaluate the efficacy of various therapies (20,29–31,36,37) and for exercise prescription (38–40). B. Visual Analog Scale (VAS)

The VAS is a continuous scale represented by either a vertical or a horizontal line typically 100 mm in length (41). Descriptors such as ‘‘no breathlessness’’ and ‘‘greatest breathlessness’’ may be positioned as anchors at the ends of the VAS (Fig. 3). The subject is instructed to place a mark on the VAS with a pen, or can adjust a cursor visible on a computer screen, to represent the intensity of breathlessness. C. Comparison of CR-10 Scale and VAS

In general, both healthy subjects (42) as well as patients with COPD (43) report comparable dyspnea ratings on the CR-10 and VAS during incremental CPET. However, the CR-10 scale has at least three advantages over the VAS (Table 1). First, the presence of descriptors on the CR-10 scale

Figure 3 VAS used to measure dyspnea. The VAS is typically 100 mm in length with descriptors of severity positioned as anchors. The patient marks the line at a point that corresponds to the intensity of dyspnea. Source: From Ref. 56.

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Table 1 Advantages of the CR-10 Scale Over the VAS for Measuring Dyspnea During Exercise Testing The presence of descriptors on the CR-10 permits direct comparison between individuals or groups; this is not appropriate with the VAS The VAS has a ‘‘ceiling effect,’’ whereas the CR-10 is an open magnitude scale (i.e., a number greater than 10 can be selected; see Fig. 2 ) A number and a corresponding descriptor on the CR-10 scale can be used by a patient as a ‘‘dyspnea target’’ for monitoring exercise training

permits direct comparisons between/among individuals or groups based on the assumption that the verbal descriptors on the scale correspond to the same subjective experience in different individuals or groups of subjects. As an example, two individuals may have different levels of cardiorespiratory fitness, but may select the same number (e.g., 7, or ‘‘very severe’’) on the CR10 scale as a reflection of their highest rating of breathlessness. Such comparisons of individuals or groups of subjects are not appropriate with the VAS. Second, the VAS has a ‘‘ceiling effect’’ (10,41). A subject is unable to provide a rating for dyspnea higher than the length of the line. In contrast, the CR-10 scale is an open magnitude scale such that the subject can give a rating above 10 on the scale (Fig. 2). Although this advantage of the CR-10 scale may appear more theoretical than practical, the author has observed subjects select a number above 10 if given appropriate instructions about using the scale prior to the CPET. Third, a number and corresponding descriptor on the CR-10 scale (e.g., 3, or ‘‘moderate’’) can be used by the patient as a ‘‘dyspnea target’’ for monitoring exercise training as opposed to using a target heart rate (38–40). From both conceptual and practical perspectives, it would be difficult for a patient to use a measured length in mm on the VAS for monitoring exercise training intensity of the patient. V. Dyspnea Ratings During Exercise Testing A comparison of the advantages and disadvantages of the different approaches (peak, discrete, and continuous) for patients to report dyspnea during exercise testing is provided in Table 2. A. Peak

Earlier investigations focused solely on the ratings of dyspnea reported by subjects on the CR-10 scale or the VAS at the end of CPET (i.e., peak values). For example, Killian et al. (34) reported that 320 healthy subjects had median dyspnea ratings of 6 at peak exertion [range of 5–9 (25–75th

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Table 2 Dyspnea Ratings During Exercise Testing Ratings

Advantages

Disadvantages

Peak

Easy to apply Can distinguish ‘‘limiting’’ symptom (dyspnea vs. leg discomfort) The calculated slope: Discriminates between healthy subjects and patients Is responsive to therapy

Do not discriminate between healthy subjects and patients Not responsive to therapy

Discrete

Continuous

More ratings provided spontaneously when patients experience a change in dyspnea The calculated slope discriminates between healthy subjects and patients Can calculate a threshold value

Ratings made ‘‘on cue’’ ratherthan spontaneously Only a few ratings in patients with severe exercise impairment Software required Additional testing required to establish psychometric properties

percentiles)]. Moreover, the peak dyspnea ratings were similar for patients with COPD despite different severities of airflow obstruction (34). As expected, the peak power production was almost twice as high on the cycle ergometer in the healthy subjects compared with patients with COPD (34). Mahler et al. (6) found that 15 patients with asthma gave ratings of 7.4
1.9 for dyspnea at peak exercise. On the other hand, O’Donnell et al. (36) observed that 30 patients with COPD reported peak values of 5.1
0.3 for dyspnea despite stopping exercise because of breathing difficulty. Overall, patients with respiratory disease provide peak ratings of dyspnea that range from 5 to 8 as reported in numerous studies (44). The most clinically useful purpose of obtaining peak ratings is to distinguish which symptom (dyspnea vs. leg discomfort for patients with respiratory disease) ‘‘limits’’ exercise performance. Of 40 patients with obstructive airway disease, Mahler and Harver (45) found that 18 patients reported higher ratings of ‘‘leg fatigue,’’ 14 reported dyspnea as the major complaint, and 8 patients indicated that leg fatigue and dyspnea were the same in the intensity at the end of CPET. In a study involving 578 patients, Hamilton et al. (35) reported that in 46% leg effort was higher, 38% described leg effort and dyspnea were equal, and 16% revealed that dyspnea was higher. However, patients with severe airflow obstruction complain of dyspnea as the most frequent ‘‘limiting’’ complaint (34).

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Man et al. (46) asked 84 patients with COPD to indicate the predominant symptom (dyspnea or leg effort) that limited incremental and endurance exercise tests. Breathlessness was cited more commonly as the ‘‘limiting symptom’’ after incremental walking compared with incremental cycling (81% vs. 34%; p < 0.001) and after endurance walking compared with endurance cycling (75% vs.29%; p < 0.001). In a subgroup of 12 patients, quadriceps fatigability was measured by twitch quadriceps tensions before and 30 min after exercise tests. Cycling, but not walking, produced significant reductions in twitch quadriceps tensions (46). Thus, the mode of the exercise test appears important in eliciting the primary symptom that limits exercise in patients with COPD. B. Discrete Ratings

As noted above, peak values of dyspnea do not discriminate between healthy subjects and patients with respiratory disease (34,47,48). Furthermore, peak ratings of symptoms at the end of CPET have not been helpful in evaluating the benefits of treatment (6,19,29,30). Thus, the next step in quantifying perceptual responses was for investigators to instruct patients to report ratings during CPET. As most progressive exercise tests incorporate increases in power output on the cycle ergometer each minute (incremental test) or by a continuous increase in power output (ramp test), subjects have been instructed to indicate ratings of dyspnea and/or leg discomfort each minute ‘‘on cue’’ (i.e., discrete method). With these instructions and methodology, patients typically provide anywhere from a few to several ratings depending on the individual’s exercise capacity. These results enable the ability to calculate a slope and intercept in order to describe the relationship between the putative stimulus (i.e., power production or VO2) and the reported dyspnea response on the CR-10 scale or VAS (8,9). Investigators have used both power and linear functions to analyze the watts ! dyspnea and VO2 ! dyspnea relationships during progressive exercise. As expected, both the exponent (power function) and slope (linear function) are higher in patients with respiratory disease compared with age-matched healthy individuals (8,10,34,47,48). C. Continuous

There are two major limitations of the discrete approach for having patients report breathlessness. First, the ratings are given at specific time periods (i.e., 1-min intervals) selected by the investigator or clinician rather than as spontaneously judged by the subject. However, patients likely experience changes in dyspnea at various times throughout the exercise test. Second, a patient may report only a few ratings of breathlessness if the patient has severely reduced exercise capacity. This small number of ratings makes it

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difficult to calculate accurately a slope and intercept of the power production, of VO2, and dyspnea relationship. In 1993, Harty et al. (49) described the continuous measurement of dyspnea in six healthy subjects who adjusted a potentiometer to provide spontaneous ratings of breathlessness during exercise on a VAS displayed on a monitor. Subsequently, in 2001, Mahler et al. (50) developed a computerized system for the continuous measurement of dyspnea whereby the subject moves a computer mouse that controls the length of a bar positioned adjacent to the CR-10 scale visible on a monitor (Fig. 4). The patient was instructed to move the mouse ‘‘when you experience a change in your breathlessness.’’ In 2004, Fierro-Carrion et al. (48) compared ratings of breathlessness using the continuous and discrete methods in 24 aged-matched healthy subjects and 24 patients with COPD. Both groups had more than twice the number of ratings with the continuous method than with the discrete method. Moreover, patients exhibited higher slopes, lower x-intercepts, and lower absolute thresholds [breathlessness rating that matched or exceeded 0.5 (‘‘just noticeable’’) on the CR-10 scale] for watts ! dyspnea compared with healthy subjects (48).

Figure 4 Schematic diagram of a subject pedaling on a cycle ergometer with computerized system to enable the subject to provide continuous ratings of dyspnea curing CPET. A mouse is positioned on a platform by the handlebars. The subject moves the mouse forward (increase in dyspnea) or backward (decrease in dyspnea) to position the vertical bar on the monitor that corresponds to the intensity of dyspnea as measured on the CR-10 scale. Source: From Ref. 48.

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Overall, the continuous measurement of dyspnea represents an important advance over the discrete method. Certainly, the perception of breathlessness during exercise changes throughout the course of CPET rather than only at arbitrary 1-min time intervals. Accordingly, discrete ratings obtained each minute will unlikely reflect the spontaneous changes in dyspnea. It is evident that some patients with respiratory disease have severe exercise impairment and may only be able to exercise for 3–4 min. Using the discrete method, these patients would provide only 3–4 ratings of dyspnea during CPET. Certainly, there are statistical considerations when fitting a quantitative function to such a small number of data points. In contrast, the continuous method enables numerous ratings regardless of the individual’s exercise capacity (48–50). A final advantage of the continuous method is the ability to calculate a threshold for the onset of dyspnea that corresponds to 0.5, or ‘‘just noticeable,’’ on the CR-10 scale (48–50). Such a threshold cannot be determined using the discrete method for measuring dyspnea.

VI. Clinical Applications CPET provides a standard stimulus to examine changes in the intensity of dyspnea in response to various interventions. In Chapters 12–17, various authors report on the effects of bronchodilator therapy and inhaled corticosteroids, pulmonary rehabilitation, inspiratory muscle training, supplemental oxygen, cognitive–behavioral strategies, and lung volume reduction surgery for the relief of dyspnea during CPET. Dyspnea ratings during exercise are complementary to the grades or scores obtained using clinical scales or questionnaires based on activities of daily living (see Chapter 7). A. Which Exercise Test(s) Should be Used to Evaluate Bronchodilator Therapy?

Dyspnea measured during both incremental and submaximal exercise tests has been shown to be responsive to various interventions (Table 3). However, to the best of my knowledge, only Oga et al. (30) compared different types of exercise tests (6MWT, incremental cycle ergometry, and cycle endurance test at 80% of the maximal workload) to evaluate the effects of an inhaled bronchodilator medication, oxitropium bromide. These investigators found that the ‘‘endurance test was the most sensitive in detecting the effects of inhaled anticholinergic agents on exercise performance.’’ However, their study was not ideal for examining dyspnea responses because patients rated the intensity of dyspnea on the CR-10 scale only at rest and at the end of exercise. Thus, it is difficult to determine from this study which exercise test is more responsive to examine dyspnea as an outcome measure during the stimulus of exercise.

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Table 3 Responsiveness of Dyspnea Ratings to Bronchodilator Therapy as Measured During Exercise Testing Author (reference) Incremental exercise Belman et al. (53) Oga et al. (30) Teramoto et al. (51) Tsukino et al. (52)

Submaximal exercise O’Donnell et al. (29) Oga et al. (30) Oga et al. (31) Ayers et al. (54)

Treatment

Dyspnea response

Albuterol Oxitropium Oxitropium Theo IB Theo and IB

# Borg Score at HEWL (p < 0.05 vs. P) No change in DBS–DVO2 (p ¼ NS) # DBS–DVO2 (p < 0.05 vs. P) # DBS–DVO2 (p < 0.05 vs. P) # DBS–DVO2 (p < 0.05 vs. P) # DBS–DVO2 (p < 0.05 vs. P)

IB Oxitropium Albuterol IB IB vs. Sal

# DBS–Dtime (p < 0.05 vs. P) # DBS–Dtime (p ¼ 0.003 vs. P) # DBS–Dtime (p < 0.001 vs. P) # DBS–Dtime (p < 0.001 vs. P) No difference in DBS–Dtime

Abbreviations: HEWL, highest equivalent work load; P, placebo; BS, Borg Score; Theo, theophylline; IB, ipratropium bromide; Sal, salmeterol.

At the present time, the medical literature supports the use of both incremental and submaximal exercise tests for evaluating the effects of bronchodilators on exertional breathlessness (Table 3). However, many clinical trials have focused on submaximal endurance exercise as the preferred method to provoke exertional dyspnea in order to assess bronchodilator effectiveness.

VII. Recommendations A. Stimulus

Available information indicates that CPET is a more appropriate stimulus to examine the dyspnea response compared with walking tests such as the 6MWT or the shuttle test. For example, in two multicenter randomized trials neither salmeterol nor ipratropium bromide (standard bronchodilators used as maintenance therapy in patients with COPD) reduced dyspnea ratings at the end of the 6MWT compared with placebo therapy (17,18). Moreover, CPET provides a measured stimulus (i.e., power production or VO2), whereas the walking tests depend largely on patient motivation and effort. In addition, it is difficult to know how to interpret dyspnea ratings relative to the distance walked during the 6MWT. What does a higher dyspnea score represent in a patient who is able to walk farther in 6 min after a specific intervention?

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Based on available studies both incremental and submaximal exercise tests are appropriate stimuli for provoking dyspnea responses during exercise. With incremental exercise the slope of watts, or VO2, ! dyspnea ratings, is reduced with different bronchodilators compared with placebo (19,29,51,52). During submaximal exercise or at equivalent levels of work intensity, dyspnea ratings are reduced with bronchodilator therapy compared with placebo (29,53). However, at the present time, it is not clear whether incremental or submaximal CPET is more responsive to therapy in order to assess relief in dyspnea. A prospective study to compare incremental and submaximal CPET would be useful to identify the merits of each test as a stimulus to evaluate dyspnea responses to various treatments.

B. Response The CR-10 scale is the standard instrument used for patients to report the intensity of the dyspnea response during CPET (10,19,28,29,34–37). Although the discrete method (i.e., ratings each minute) is currently the most widely used approach for patients to report dyspnea during CPET, the continuous method for measuring dyspnea using a computerized system offers several advantages over the discrete method. Additional testing will be required to examine the psychometric properties of this methodology.

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27. ACCP-AACVPR Pulmonary Rehabilitation Panel. Pulmonary rehabilitation: joint ACCP/AACVPR evidence based guidelines. Chest 1997; 112:1363–1396. 28. Franco MJ, Olmstead EM, Tosteson ANA, Lentine T, Ward J, Mahler DA. Comparison of dyspnea ratings during submaximal constant work exercise with incremental testing. Med Sci Sports Exerc 1998; 30:479–482. 29. O’Donnell DE, Lam M, Webb KA. Measurement of symptoms, lung hyperinflation, and endurance during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160:542–549. 30. 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. 31. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T, Mishima M. A comparison of the effects of salbutamol and ipratropium bromide on exercise endurance in patients with COPD. Chest 2003; 123:1810–1816. 32. Borg G. Borg’s Perceived Exertion and Pain Scales. Champaign, IL: Human Kinetics, 1998. 33. Borg GAV. Psychological bases of perceived exertion. Med Sci Sport Exerc 1982; 14:377–381. 34. Killian KJ, LeBlanc P, Martin DH, Summers E, Jones NL, Campbell EJM. Exercise capacity and ventilatory, circulatory, and symptom limitation in patients with chronic airflow limitation. Am Rev Respir Dis 1992; 146:935– 940. 35. Hamilton AL, Killian KJ, Summers E, Jones NL. Symptom intensity and subjective limitation to exercise in patients with cardiorespiratory disorders. Chest 1996; 110:1255–1263. 36. O’Donnell DE, McGuire MA, Samis L, Webb KA. The impact of exercise reconditioning on breathlessness in severe chronic airflow limitation. Am J Respir Crit Care Med 1995; 152:2005–2013. 37. Mahler DA. Measurement of dyspnea. In: Donner CF, Ambrosino N, Goldstein R, eds. Pulmonary Rehabilitation: Efficacy and Scientific Basis. London: Arnold, 2004, In press. 38. Horowitz MB, Littenberg B, Mahler DA. Dyspnea ratings for prescribing exercise intensity in patients with chronic obstructive pulmonary disease. Chest 1996; 109:1169–1175. 39. Mejia R, Ward J, Lentine T, Mahler DA. Target dyspnea ratings predict expected oxygen consumption as well as target heart rate values. Am J Respir Crit Care Med 1999; 159:1485–1489. 40. Mahler DA, Ward J, Mejia-Alfaro R. Stability of dyspnea ratings after exercise training in patients with COPD. Med Sci Sports Exerc 2003; 35:1083–1087. 41. Gift AG. Visual analogue scales: measurement of subjective phenomena. Nurs Res 1989; 38:286–288. 42. Wilson RC. A comparison of the visual analogue scale and modified Borg scale for the measurement of dyspnea during exercise. Clin Sci 1989; 76:277–282. 43. Muza SR, Silverman MT, Gilmore GC, Hellerstein HK, Kelsen SG. Comparison of scales used to quantitate the sense of effort to breathe in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1990; 141:909–913.

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44. Mahler DA, Fierro-Carrion G, Baird JC. Mechanisms and measurement of exertional dyspnea. In: Weisman IM, Zeballos RJ, eds. Clinical Exercise Testing. Progress in Respiratory Research. Basel: Karger, 2002:72–80. 45. Mahler DA, Harver A. Prediction of peak oxygen consumption in obstructive airway disease. Med Sci Sports Exerc 1988; 20:574–578. 46. Man WDC, Soliman MGG, Gearing J, Radford SG, Rafferty GF, Gray BJ, Polkey MI, Moxham J. Symptoms and quadriceps fatigability after walking and cycling in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 168:562–567. 47. O’Donnell DE, Chau LKL, Webb KA. Qualitative aspects of exertional dyspnea in patients with interstitial lung disease. J Appl Physiol 1998; 84:2000– 2009. 48. Fierro-Carrion G, Mahler DA, Ward J, Baird JC. Comparison of continuous and discrete measurements of dyspnea during exercise in patients with COPD and normal subjects. Chest 2004; 125:77–84. 49. Harty HR, Heywood P, Adams L. Comparison between continuous and discrete measurements of breathlessness during exercise in normal subjects using a visual anlogue scale. Clin Sci 1993; 85:229–236. 50. 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. 51. 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. 52. Tsukino M, Nishimura K, Ikeda A, Hajiro T, Koyama H, Izumi T. Effects of theophyloline and ipratropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease. Thorax 1998; 53:269–273. 53. 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. 54. Ayers ML, Mejia R, Ward J, Lentine T, Mahler DA. Effectiveness of salmeterol versus ipratropium bromide on exertional dyspnoea in COPD. Eur Respir J 2001; 17:1132–1137. 55. Mahler DA, Horowitz MB. Perception of breathlessness during exercise in patients with respiratory disease. Med Sci Sports Exerc 1994; 26:1078–1081. 56. Mahler DA. Dyspnea: diagnosis and management. Clin Chest Med 1987; 8:215–230.

9 Assessment of Dyspnea in Large-Scale Clinical Trials: Application to Clinical Development Programs in COPD

THEODORE J. WITEK, JR. Boehringer Ingelheim Portugal, Lisbon, Portugal

I. Introduction This book deals with the importance of dyspnea as a symptom of disease (and as a major cause of disability and handicap) as well as the measurement of dyspnea, including its worsening or improvement This chapter will identify and address issues as they relate to clinical trials. Most often, the measurement of dyspnea in clinical trials is in the context of evaluating therapeutic intervention for chronic dyspnea. These studies most often involve large numbers of patients (100–1000), large numbers of investigating centers (50–100), several countries (up to 20), and comparison to controls such as usual care (i.e., placebo added to stable standard medication) which allow true assessment of a drug effect on dyspnea. Drug development trials often consist of two replicate trials of similar or identical design in order to insure substantial evidence of clinical effectiveness. Among the various respiratory diseases which are accompanied by dyspnea, the prominent and persistent nature of breathlessness in chronic obstructive pulmonary disease (COPD) makes it an important condition to be able to measure dyspnea both in a discriminative as well as evaluative 183

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manner. The recognition of the importance of COPD as a public health problem and the recognition of dyspnea as its most troublesome symptom have resulted in several large-scale trials that have assessed dyspnea. Key findings and associated key learnings will be reviewed.

II. Measuring Dyspnea in the Context of Regulatory and Clinical Development As dyspnea is an important and troublesome symptom of COPD (1–4), establishing its presence and severity in a population and evaluating the degrees to which an intervention provides relief is a basic principle in clinical therapeutics. Despite this, assessment of chronic symptoms has received little attention in the development of bronchodilators over the last several decades—particularly relative to the importance placed on basic measures of airflow obstruction such as the FEV1. More recently, however, clinical development programs for respiratory drugs have put greater emphasis on the measurement of symptoms and health status (5). The evaluation of dyspnea in clinical trials of COPD has public health, clinical, regulatory, and, although less often discussed, commercial components. From a public health perspective, dyspnea is central to the triad of impairment, disability, and handicap impacts of a chronic disease such as COPD. Most patients and caregivers acknowledge breathlessness as troublesome and most impactful. From the clinicians’ perspective, this impact is mirrored in practice where breathlessness is often conveyed as the presenting symptom. Therefore, its characterization and change over time is central to clinical epidemiology and to the care of individual patients. Regulators who give an independent assessment of a drug’s benefits and risks have evolved in recent years to accept the importance of integrating both physiologic and outcome measures. In 1999, for example, the European Agency for the Evaluation of Medicinal Products (EMEA) clearly stated in a "Points to Consider" document concerning the design of clinical programs in COPD that major efficacy studies should include the FEV1 as a measure of lung function, but should also include a measure of symptomatic benefit (6). Expanded points to consider as proposed by the EMEA are listed in Table 1. One particularly relevant regulatory point is the recommendation that in major studies, the primary endpoint should reflect the clinical benefit the applicant wishes to claim in the future summary of product characteristics, or SPC. In the United States, the FDA would not consider a formal indication for a drug to relieve dyspnea in COPD unless it was stated a priori as a primary endpoint (or co-primary endpoint with appropriate statistical rigor) and was measured with a validated tool. The FDA and its scientific advisors have debated whether relief of dyspnea should be recognized as an

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Table 1 Points to Consider on Clinical Investigation of Medicinal Products in the Treatment of COPD Duration of at least 6 months . . . is benefit of treatment prolonged? Rapidity and extent of treatment benefit loss. The most useful comparison is placebo. Primary endpoint should reflect the clinical benefit the applicant wishes to claim in the future SPC. It should include the FEV1 as a measure of lung function and include a measure of symptomatic benefit. The primary, symptomatic benefit endpoint should be justified by referencing published data which support its validity. Examine time profile. A number of secondary endpoints may provide useful information. Consider statistical multiplicity if secondary endpoints become the basis for specific claims. Derived from Ref. 6.

indication for prescribing a bronchodilator. While this specific regulatory point might not matter for many prescribers of bronchodilators, it can be argued that it is an important feature to highlight in the product label if there is sufficient evidence to support the effect. Thus, the ultimate goal for including such an assessment in a clinical trial (e.g., label statement, promotional claim, and exploratory) should be clear at onset. Two interesting case studies have come in the form of the clinical/ regulatory approach to characterize dyspnea in the clinical development programs in the USA for two long-acting bronchodilators, salmeterol, and tiotropium. Both programs used the baseline (BDI) and transition (TDI) dyspnea index to measure changes in dyspnea (TDI focal score) prospectively as a co-primary endpoint in pivotal trials. In the salmeterol trials, no meaningful benefit in dyspnea over placebo was demonstrated (7,8). Despite the failure of this co-primary endpoint, salmeterol was appropriately approved as a bronchodilator based on FEV1 improvements of the drug over placebo. In two pivotal trials in the tiotropium clinical development program, improvements in TDI were acknowledged in the review. However, as the TDI focal score was changed to a primary endpoint only before unblinding in these two trials and not prospectively in the clinical trial protocol, there was concern that the execution of the TDI did not get the detailed attention required for a primary endpoint. Thus, a major conclusion from these experiences is that endpoints should be established in the final protocol prior to clinical trial initiation with prospective identification of an effect size that would be deemed clinically meaningful.

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Another key regulatory component of dyspnea measurement is instrument validation. For example, the EMEA guidance states that the symptomatic benefit endpoint should be justified by referencing published data that support its validity. Such data had been developed for the BDI/TDI (9–11). In our work with the TDI, we further demonstrated the robustness of the instrument in our own hands in a multicenter trial setting by demonstrating both its concurrent and construct validity (12,13). Similarly assessment of reliability, validity, and responsiveness in a drug development program has been reported for the breathlessness, cough, and sputum scale (BCSS) used in the evaluation of the dual D2 dopamine receptor and (b2-adrenoceptor agonist sibenadet HCl (14). These data are discussed below. Should a new instrument be selected to be used in a clinical development program, it should be validated early in the program prior to Phase III trials, as it is optimal that the primary instrument validation work be independent from the trial used to establish the primary evidence of effect. Such a process depends on the scope and rigor of validation, but can be lengthy (e.g., one to two years).

III. Selection and Application of Instrument A. Basic Concepts

In general terms, an instrument used to measure dyspnea in a clinical trial should be easy to administer whether this is done by the patient (as in the UCSD Shortness of Breath Questionnaire) (15) or completed via an interview assessment (as in the BDI/TDI). The instrument needs to be incorporated into the data management flow, most often starting with its transfer into the case record form used in the trial with subsequent data entry of the variables outlined in the statistical analysis plan. Care should be taken when transforming the instrument to maintain the same format that was used during its developmental validation. As described in Chapter 7, instruments can be both discriminative (i.e., present or absent, mild or severe) and evaluative (i.e., changes over time). It is helpful to include a related dyspnea instrument to accompany the primary tool in order to insure concurrent validity in practice. Also, some instruments will solely evaluate a grade of dyspnea (e.g., VAS) while others are more focused on evaluating the consequence of breathlessness on activities of daily living (e.g., TDI). There are important elements of clinical development trials that impact measurement. As trials are often required to be large to have sufficient power to detect real changes and evaluate safety, they are often conducted across multiple clinical centers as well as across multiple countries. This increases the importance of uniform training of study staff as well as adequate translation procedures from a given instrument’s native language to multiple

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additional languages. Also, the length of clinical trials for drug development has expanded in the recent past, particularly for diseases with chronic dyspnea such as COPD. Longer trials can add complexity in the form of turnover of study staff, recall of previous events when referring changes to baseline, and proper statistical analysis plans for dealing with patients who have withdrawn from the trial. B. Validation

The concepts of reliability, validity, and responsiveness are discussed in the general context of dyspnea measurement in Chapter 7. Large-scale clinical trials provide a unique opportunity to establish an instrument’s features in practice. For example, the ability to include more than one assessment of dyspnea allows for evaluation of concurrent validity both at baseline (cross sectionally) and with change over time (longitudinally). For example, Leidy et al. (14) reported a moderate correlation between Borg scale at rest and the breathlessness component of the Breathlessness, Cough, and Sputum Scale (BCSS) (r ¼ 0.48) with the expected lower correlation of Borg with the cough (r ¼ 0.13) and sputum (r ¼ 0.20) components. We found similarly moderate correlations between the BDI and a simple dyspnea diary measure in a single country (r ¼
0.50) and in a multinational setting (r ¼
0.34) (12,13). For the response to therapy, correlations between TDI and change in dyspnea diary assessment (r ¼
0.24 and r ¼
0.29) were also significant, with the weaker correlations likely due in part to the tighter distribution of drug response values relative to the broader distribution found at baseline. The association of dyspnea measures with related measures is also afforded in clinical drug trials as there are often several variables that have a logical relationship with dyspnea. These include physiologic tests as well as measures of health status, many of which have a dyspnea or symptomatic component. Figure 1 illustrates this construct validity reported in the tiotropium development program. These correlations range from weak to moderate, are statistically significant, and the changes are in the expected direction, e.g., improved dyspnea is associated with improved health status. Expected or logical associations should also be evaluated such as those detailed by Leidy et al. (14) in the sibenadet development trials. Here, sputum volume correlated more strongly with cough (r ¼ 0.27) and sputum (r ¼ 0.30) symptoms than with breathlessness (r ¼ 0.16) while breathlessness, as noted above, correlated more strongly with Borg rating (r ¼ 0.48) than did cough (r ¼ 0.13) or sputum (r ¼ 0.20). Measures in clinical trials also allow evaluations of potential biases. For example, the observation that patients who responded positively in the TDI utilized less supplemental albuterol confirms that their improved breathlessness was not driven by the use of more albuterol, but related to

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Figure 1 Correlation coefficients describing the association of dyspnea measures with other outcomes. Source: Data derived from Refs. 12, 13.

tiotropium treatment (12,13). Also, the global patient and physician measures have been used to assess responsiveness and meaningful effect size. For example, patient and physician determinations of improvement have been used to demonstrate the responsiveness of the BCSS (14). Patients classified as improved (vs. stable) reported significant improvement in BCSS scores from baseline to end of treatment, with scores significantly better than those in the stable group (Fig. 2). We have used changes in Physician’s Global Evaluation to assist in determination of the meaningful effect size in TDI (12,13, see below).

C. Translation

As more clinical trials are initiated on a multinational level, the requirements for instruments that are valid and responsive across nations and across cultures increase as well. The major component of useful instruments at a multinational level is one of linguistic validation, a process that can include translations forward and back, review by clinicians, patient testing (particularly for patient self-administered questionnaires), and harmonization across participating countries. General concerns associated with language and translation issues are reviewed by Acquadro et al. (16) while a specific approach around the generic SF-36 instrument is detailed by Bullinger et al. (17). One can appreciate the need for such international harmonization when considering practical aspects such as the relevance of a question on shoveling snow in Sydney or mowing a lawn in Tokyo. If a questionnaire is to be modified for multinational use, one must then pay attention not only to

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Figure 2 Mean BCSS change score by change group (improved vs. stable): withingroup and between-group differences. Source: Re-drawn from Ref. 14.

the relevance of questions for a given country, but also to such details as keeping consistency in the number and numbering of items. The details of the linguistic validation process will depend on the type of instrument (e.g., self-administered vs. interview-based), but follow some basic procedural steps as outlined in Figure 3. It is common practice to obtain agreement and permission from the developers of the questionnaire before the process begins. Depending on the scope of the exercise, linguistic validation can take as long as three to four months; therefore, proper planning is required in order to minimize impact on clinical trial timelines while optimizing the instrument used to assess important outcomes such as dyspnea in COPD. D. Statistical Analysis Plan

As with all critical endpoints evaluated in a clinical trial, a statistical analysis plan should be compiled in order to consistently address the issues that can arise when making statistical inference of data. These include such issues as justification of sample size, data presentation to be evaluated (e.g., means vs. proportions or both), statistical test(s) to be used, issues of multiplicity, and handling of missing data. It is well known that in most instances sample size determination is driven by the differences in the expected population means, the variability of the measure, and the risks of falsely accepting or rejecting a hypothesis. Providing these numbers is easier when a body of literature exists and when

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Figure 3 A scheme of steps to consider in the translation of instruments used to assess health outcomes (see text for perspective). (From I. MEAR. Difficulties of international clinical trials: cultural adaptation of Quality of Life Questionnaires. In: Health-Related Quality of Life and Patient-Reported Outcomes: Scientific and Useful Outcome criteria, first edition, edited by O. Chassany, C. Caulin. SpringerVerlag France. Paris 2003: 55–62.)

there is a basis for determining the magnitude of difference that can be considered important to evaluate. The early large-scale studies, that evaluated the TDI, powered for a treatment difference of 1 unit in TDI focal score (7,8). As will be explained, this magnitude of change can be justified as having clinical relevance. Based on current knowledge from existing studies over six-month and one-year periods, where the TDI focal score had a standard deviation of 2.5–3.5 units, an estimate of approximately 135–260 patients per treatment group would be necessary in order to have

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90% power with a two-sided significance level of 5% and under the assumptions of a normal distribution of the TDI in the population to detect a mean 1-unit focal score difference from placebo should such a difference exist. While evaluating a mean response in TDI in a population has value, it may be more clinically relevant to evaluate the proportion of patients who achieve a prespecified meaningful threshold—such as a one unit focal score change in the TDI. If one powers a study to evaluate a 15% point difference in responder rate (50% increase over placebo), which can arguably be within the range of being meaningful to practice, a sample size of 170 (227) patients per treatment group will be needed [to achieve 80% (90%) power]. Another important aspect of an analysis plan is handling of missing data or drop-outs. This is particularly important with respect to chronic dyspnea involving long-term evaluations where the practical nature of such trials may result in missing data as well as the practical aspect of COPD where individuals can deteriorate in long-term enrollment necessitating discontinuation from the study. For missing data in general, it is not uncommon to carry the last observation forward for inclusion in the analysis relaying on the assumptions on missingness at random. For drop-outs due to worsening of the condition under study (e.g., worsening respiratory status), we have utilized the concept of carrying the worst observation forward, whatever assessment point that might have been.

E. Meaningful Effect Size

While a statistical inference on a dyspnea measure allows one to judge a real or chance effect, it has been increasingly realized that an effect size should be established that has clinical importance. Both statistical (18) and anchorbased (19,20) techniques have been put forward to assist in this determination. Certain descriptors in given instruments practically dictate a recorded change is meaningful. For example, in the TDI, the instrument’s descriptor of a one-unit change in the functional impairment component describes a patient who is ‘‘able to return to work at reduced pace or has resumed some customary activities with more vigor than previously due to improvement in shortness of breath.’’ It is hard to describe this as not having clinical importance, particularly when it is considerate of a specific effect on an individual. A one-unit change is also supported by an anchor-based approach using a physician’s global assessment (12,13), but there are no published data using patient scales. One of the theoretical difficulties in selecting one unit of the
9 to þ9-unit TDI focal score as a minimal meaningful difference is that it is the mrnimal response on this particular scale. Nevertheless, there is growing evidence and acceptance that a one-unit change is meaningful.

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The time point of administration of a dyspnea assessment needs to be consistent from study visit to study visit being considerate of the duration a patient has ‘‘equilibrated’’ at the study center, the time of day, and the timing of the assessment relative to the administration of therapy both at the site and prior to coming to the clinic. As certain side effects (e.g., tremor or dry mouth) can be a potential signal to treatment group as could viewing spirometric test results, a separate study staff member ideally should be utilized for evaluation of dyspnea. This, however, would not avoid potential biases in patients’ response. Biases also have the potential to be introduced if the assessor and/or patient witness other assessments (e.g., adverse events, health status measures) that might cause speculation on what intervention the patient may be receiving. Also, minimizing the number of staff involved in dyspnea assessment over the duration of a study may help minimize variability. The fact that different instruments used in a series of evaluations can impose biases must be considered. On the one hand, it can be argued that completing an instrument such as the St. George’s Respiratory Questionnaire prior to the TDI can assist in recall of daily activity events. On the other hand, one may wish to avoid any influences all together by having as much distinction as possible (temporal, staff, etc.). It may be optimal that any instrument that measures a primary endpoint variable should be administered first. Provision of optimal training and consistent administration of instruments such as the BDI/TDI are in the best interest of the trial sponsor and investigator as they minimize nondifferential misclassification (i.e., noise) of recorded responses. The effect of such biases is to tend to attenuate any real association that might be present (21). This can have practical consequences when interpreting the effect size, as significant noise can mask a true effect and reduce the magnitude of an important association below a value that therefore is regarded as meaningful. While complete control of such measurement factors may not always be practical or possible, all efforts should be made to minimize any potential biases, particularly when such measures involve primary endpoints.

IV. Experience from Published Trials A. Experience with Various Instruments

Modern day clinical development programs over recent decades have used a variety of discriminative and evaluative instruments in trials of respiratory therapeutics. Most often, these were used to capture variables stated as secondary endpoints but more recently, dyspnea relief has been more of a focus as an intended benefit of therapy, particularly bronchodilators.

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Perhaps the first trials with focus on evaluation of pharmacotherapy for dyspnea relief (from diazepam, promethazine, and dihydrocodeine) involved simple visual analogue scales (22–24). Among the most frequently used evaluative instruments in current programs is the TDI, having been the primary instrument in the tiotropium and salmeterol programs. Simple number scales have also been used both alone and in conjunction with otiier instruments. The CRQ, which contains a dyspnea component (25) and, albeit to a lesser extent, the UCSD Shortness of Breath Questionnaire (15,26) has also been incorporated into programs. Table 2 summarizes the utilization of dyspnea instruments, related measures, and their primary results based on the observed drug effect (i.e., statistical significance of drug effect or intervention greater than that of placebo) (7,8,27–38). B. Basic Discriminative Patterns

Discriminative instruments allow a characterization of dyspnea severity. For example, patients with stable COPD who volunteer for pharmacologic intervention trials (7,8,28–31,39) have mean BDI scores in a narrow range of 5.8–6.6; thus, patients report moderate dyspnea as a cohort on average, regardless of test drug, study sponsor, or geography of trial site. In a study of patients with severe pulmonary hypertension (40) (PAP 53 mmHg; CO 3.8 1/m) more severe dyspnea was reported at study entry as evidenced by a mean (SD) BDI score of approximately 4.2 (1.8). Furthermore, Aaron et al. (41) reported a BDI score of 4.5 (0.26) units in patients presenting to the emergency room with an acute exacerbation of COPD (control patients ¼ 9 units). These observations, by themselves, provide yet another element of the validity of the BDI. The distribution of the BDI scores from two separate study programs with tiotropium (28,29) are illustrated in Figures 4A,B. It can be seen that very few patients in these trials report no breathlessness. This is despite not having a specific entry criterion for the presence of dyspnea in these specific protocols. C. Basic Evaluative Patterns 1. Temporal Patterns

Temporal patterns in dyspnea measures are an important feature in clinical trials. First, for a chronic symptom such as dyspnea, it is important to know when one would expect a benefit after start of therapy as well as if effects are maintained. Also, the pattern of response in those assigned to usual care and matched placebo is important for evaluation of true drug effects. As illustrated in Fig. 5, the placebo response has not been consistent across major trials (7,8,28,29,31,42); thus, inclusion of placebo remains an important feature to determine true drug effects.

Ipratropium Albuterol Tiotropium Salmeterol Combivent MDI Tiotropium

Bone (27)

Combivent inhalation Combivent SVN solution study group (33) Hanania (38) Salmeterol Fluticasone Salm/Fl Mahler (31) Salmeterol Fluticasone Salm/Fl Mahler (7) Salmeterol Ipratropium

Campbell (32) Casaburic (28)

Brusascoc (29)

Formoterol

Intervention

Aalbersa (30)

Author



&

 

&



&





&



 (0–4)



&e(0–4)

e,f

&b (unspecified)

b (0–3) d (0–3)

&b (0–3)

Numbered (e.g., 0–3) scales

TDI

& &

&

Borg

Dyspnea measures UCSD BS ATS

 

CRDQ& &



& CBSQ & & &



& CBSQ & & &

6 mw Test & &

CDRQ

CDRQ

SGRQ  Physician global  Quality of life questionnaire

&

Days with no breathlessness  SWT &

Other endpoints

Table 2 The Assessment of Dyspnea in Multicenter Therapeutic Intervention Trials. Statistical Significant Effects based on End of Study Assessment vs. Placebo

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Salmeterol Ipratropium Formoterol Ipratropium

Triamcinolase Iodinated glycerol

LVRS

& &

& – Measured.  – Effect vs. placebo observed. a 18 mcg/bid. b Comparisons limited to combo vs. individual (i.e., no placebo). c Reports two combined studies. d Clinical assessment. e Patient self-assessment. f For self-assessment night-time breathlessness.

Wadbo (35)

Rennard (8)

National emphysema treatment trial research group (34) Pauwels (LHS2) (36) Petty (37)

&e &e (0–4)  (0–4) (
14)

&a,b,d,e–f

&

&





SWT & SGRQ & & &

Other symptoms (1–5) & Patient global (1–7)  Physician global (1–7) & CRDQ & &

SGRQ

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Figure 4 Distribution of BDI focal scores in two sets of replicate studies of the tiotropium clinical development program. (A) Source: From Ref. 13. (B) Source: From Ref. 12.

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Figure 5 The temporal pattern of dyspnea as measured by the TDI focal score in patients receiving placebo in larger-scale clinical trials. Dashed lines are for reference to a focal score of 0 at baseline which, in practice, is a reference point to the BDI. Source: Data derived from Refs. 7,8.28,29,31,42.

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Another temporal aspect relevant to clinical trials is recall of a baseline state when such referral is required, as in the TDI. Here, referral notes of the baseline state may be helpful, but should be consistently used within and across study centers. In longer-term (i.e., >6 months) trials where a usual care (e.g., placebo) arm is included, one does see a slight increase in dyspnea over time. For example, in a two year prospective study of a cohort of 110 patients, Mahler et al. (42) reported that dyspnea slightly worsened as reflected by a TDI mean focal score of
0.1 (n ¼ 93) units after 1 year and
0.7 units (n ¼ 76) after two years. In 1-year study of stable COPD patients, there were slight improvements in TDI focal score of approximately 0.33 units in those remaining on usual care while tiotropium-treated patients showed improvements at the first assessment (1.2 Units) that was maintained throughout the treatment period (28). An atypical pattern of improvement and decline was also observed in the tiotropium comparative studies with ipratropium. Here, while greater improvements were seen with tiotropium, the study was limited by lack of placebo group (39). In an additional tiotropium study with an earlier assessment visit, the TDI focal score improved relative to placebo by approximately 1.8 units, as early as three weeks (43). Three-month trials using the TDI in salmeterol registration trials showed an unexplained reduction in dyspnea (i.e., increased focal score) in the placebo groups which contributed to lack of demonstration of drug effect (7,8). In a 24-week study evaluating salmeterol and fluticasone and their combination, the placebo group exhibited a TDI mean score of 0.4 focal score units (31). The authors noted that significant differences in treatment groups were seen as early as one week (8), but there was no significant difference between salmeterol and placebo at the study endpoint. Finally, in the Lung Health Study II (36), which used the ATS symptom scoring, it was reported that dyspnea was present in 58% of patients, assigned placebo at baseline and 61.5% some 40 months later. While this temporal group change was small and showed a ‘‘benefit’’ using this variable, this cohort was relatively mild with an entry predicted normal FEV1 of 63%. In two development trials with iodinated glycerol, Petty (37) utilized a 1–5 activity descriptor scale and noted only a trend in mean improvements. Dyspnea was subsequently not evaluated in the replicate trial (44). 2. Effect Size

The effect sizes observed for dyspnea measures may depend on several factors, with the nature of the intervention being the most important. Factors associated with the nature of the intervention include the type (e.g., pharmacologic vs. other), the intensity (e.g., dose), and perhaps the degree of

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interaction among the trial personnel and study subject. Specific examples using the TDI can be found in the literature. The largest body of data comes from bronchodilator trials in COPD which utilized the TDI. In the first study to use the TDI in a drug development trial, Mahler et al. (7) reported that ipratropium bromide improved mean TDI focal score by approximately 1 unit over placebo at 3-month endpoint; salmeterol improvements over placebo were minimal and not significant. Neither ipratropium nor salmeterol improved TDI scores over placebo in a replicate trial (8). In two additional 24-week trials, mean TDI score differences between salmeterol and placebo were 0.5 units (31) and 0.7 (38). Formoterol given at doses of 4.5, 9, and 18 mcg improved TDI focal scores over placebo by 0.67, 0.54, and 1.15 units, respectively (30). The most consistent drug effect sizes have been observed in the tiotropium program, where multicenter studies have reported drug effect sizes of 1.14 focal score units (28) (1.15 in one trial, 1.13 in replicate), and 1.1 focal score units (29) (1.02 in one trial, 1.21 in replicate) and 1.8 focal score units (43) (Fig. 6). Whether the sustained bronchodilation offered by tiotropium contributes to these consistent effects remains an attractive, but unproven hypothesis. Thus, for bronchodilator trials, it is not uncommon to observe mean effect sizes of the TDI focal score at or below the regarded meaningful

Figure 6 Mean TDI scores reported from clinical trials of bronchodilators. Scores indicate drug effect, i.e., difference between drug and placebo response. Numbers beneath the horizontal axis represent the reference number of the study. The dashed lines represent the data from the individual studies as the referenced papers reported combined data.

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threshold of one unit. A review of the literature has demonstrated that TDI can improve several units with other patient-intensive interventions such as inspiratory muscle training (45,46) (mean TDI focal scores 3.5 and 3.8), or exercise training (47,48) (TDI focal score approximately 2.1–2.8), or lung volume reduction surgery (49) (mean TDI focal score 7.8 units). Ten days following an exacerbation, TDI was shown to improve by 5.02 units (41) (see below). Although only speculative, it may be that more patient-intensive interactions with a higher frequency of instrument administration could result in larger effects being judged. Also, these studies tend to be shorter term, involve a single center, and are challenged by difficulties in insuring an optimal control group. 3. Response upon Withdrawal of Therapy and Relapse of Disease

Responsiveness of an instrument can also be evaluated by observing the reported responses with change or withdrawal of therapy as well as following an acute worsening of disease. In the tiotropium bronchodilator trials, the TDI returned to baseline state after withdrawal of tiotropium, while the parallel placebo group’s TDI focal score remained constant (12). A fall in TDI upon withdrawal of theophylline has also been observed (50). In a clinical trial evaluating maintenance after pulmonary rehabilitation, Ries et al. (51) noted improvements in dyspnea from an 8-week rehabilitation program in both the TDI (2.7 focal score units) as well as in the UCSD SOBQ (55.5  20.8 to 45.5  20.3). In a follow-up to the rehabilitation, there was deterioration of breathlessness, regardless if enrolled in a telephone-based maintenance program. Yet further increases in dyspnea were noted in a 12 and 24-month postintervention follow-up visit (Table 3, maintenance vs. control). Furthermore, a unique application of the BDI/TDI reported by Aaron et al. (41) noted that in patients with an exacerbation of COPD, the TDI score reflected significantly more breathlessness in the cohort who suffered a relapse (TDI focal score ¼
3.06) as opposed to an improvement (TDI ¼ 5.02) in those who did not suffer relapse. There was no significant change (
0.2 units) in controls (Table 4). This is the first trial noting good performance characteristics of the instrument in a setting of exacerbations. V. Summary Measures of efficacy in clinical trials of COPD have evolved beyond spirometry to recognize the importance of patient symptoms and health status. Experiences to date have increased our understanding of the application of instruments to measure such outcomes from both the regulatory viewpoint as well as their ultimate value to caregivers who incorporate these

45.5  20.3 — — þ2.7  2.3 — —

55.5  20.8 — — 5.0  2.0 — —

USCD SOBQ Maintenance Control

BDI/TDI Maintenance Control



p  0.05. Time: p  0.05. Source: Data based on Ref. 51.



Post-rehabilitation

Pre-rehabilitation

— þ2.9  2.4 þ2.7  2.2

— 44.1  19.4 43.3  20.9

Baseline

— þ1.5  2.8 þ1.0  2.9

— 45.9  20.4 46.5  22.9

6 months

Intervention

— þ0.8  2.8 þ1.0  2.8

— 51.1  23.4 50.4  23.7

12 months

— þ0.9  2.8 þ0.9  2.8

— 49.6  23.1 48.5  23.1

12 months

— þ0.2  3.4
0.1  3.4

— 51.4  23.0 53.9  24.4

24 months

Postintervention follow-up

Table 3 Dyspnea Measures Evaluating Rehabilitation, a Post-rehabilitation Maintenance Program and Post-Intervention Follow-up

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Table 4 BDI and TDI Mean (SD) Focal Scores in the Setting of Exacerbations of COPD BDI, day 0 All patients (n ¼ 66) Relapsing patients (n ¼ 17) Nonrelapsing patients (n ¼ 49) Control patients (n ¼ 10) TDI, day 10 or relapse day All patients (n ¼ 66) Relapsing patients (n¼ 17) Nonrelapsing patients (n ¼ 49) Control patients (n ¼ 10)

4.47  0.26 4.06  0.52 4.61  0.30 9.00  0.33 2.94  0.66
3.06  1.14 5.02  0.55
0.20  0.13

Source: Data based on Ref. 41.

data in their treatment decisions. Several instruments have been utilized in the past decade, with the most extensive experience found with the BDI/TDI. Improvements in its application as well as the development and validation of newer instruments are expected as drug developers, regulators, clinical researchers, and caregivers continue to investigate such measures in the overall assessment of a drug’s utility. References 1. Official Statement of the ATS. Dyspnea. Mechanisms, assessment, and management: a consensus statement. American Thoracic Society. Am J Respir Crit Care Med 1999; 159(1):321–340. 2. Rennard SI, Decramer M, Calverley PMA, et al. Impact of COPD in North America and Europe in 2000: subjects’ perspective of Confronting COPD International Survey. Eur Respir J 2002; 20:799–805. 3. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. GOLD Scientific Committee. 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. 4. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med 1995; 152:S77–S120. 5. Kesten S, Witek T. Providing Evidence of Therapeutic Benefit in Clinical Drug Development. In: Celli BR, Lenfant C, exec., ed. Pharmacotherapy in Chronic Obstructive Pulmonary Disease. Lung Biology in Health and Disease. Vol. 182. New York: Marcel Dekker, Inc., 2004:1–18. 6. Committee For Proprietary Medicinal Products (CPMP). Points to consider on Clinical investigation of medicinal products in the chronic treatment of

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patients with chronic obstructive pulmonary disease (COPD). Period CPMP/ EWP/562/98. London, 19 May, 2002. Mahler DA, Donohue JF, Barbee RA, Goldman MD, Gross NJ, Wisniewski ME, Yancey SW, Zakes BA, Rickard KA, Anderson WH. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 1999; 115:957–965. Rennard SI, Anderson W, ZuWallack R, Broughton J, Bailey W, Friedman M, et al. Use of 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. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea: contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest 1984; 85:751–758. Mahler DA, Guyatt GH, Jones PW. Clinical measurement of dyspnea. In: Mahler DA, ed. Dyspnea. New York: Marcel Dekker, 1998:149–198. Eakin EG, Sassi-Dambron DE, Ries AL, Kaplan RM. Reliability and Validity of dyspnea measures in patients with obstructive lung disease. Int J Behavioral Med 1995; 2:118–134. 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. Witek TJ Jr, Mahler DA. Meaningful effect size and patterns of response of the transition dyspnea index. J Clin Epidemiol 2003; 56:248–255. Leidy NK, Schmier JK, Jones MKC, Lloyd J, Rocchiccioli K. Evaluating symptoms in chronic obstructive pulmonary disease: validation of the breathlessness, cough and sputum scaleÕ. Respir Med 2003; 97(suppl A):S59–S70. Eakin EG, Resnikoff PM, Prewitt LM, Ries AL, Kaplan RM. Validation of a new dyspnea measure: the UCSD Shortness of Breath Questionnaire. Chest 1998; 113:619–624. Acquadro C, Jambon B, Ellis D, Marquis P. Language and translation issues. In: Spiker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. Philadelphia: Lippincott-Raven Publishers, 1996:575–585. Bullinger M, Alonso J, Apolone G, Leple`ge A, Sullivan M, Wood-Dauphinee S, et al. Translating health status questionnaires and evaluating their Quality: the IQOLA project approach. J Clin Epidemiol 1998; 51(11):913–923. Cohen J. Statistical Power Analysis for the Behavioral Sciences. New York: Academic Press, 1977:8. Samsa G, Edelman D, Rothman ML, Williams GR, Lipscomb J, Matchar D. Determining clinically important differences in health status measures: a general approach with illustration to the health utilities index mark II. Pharmacoeconomics 1999; 15(2):141–155. Redelmeier D, Guyatt GH, Goldstein RS. Assessing the minimal important difference in symptoms: a comparison of two techniques. J Clin Epidemiol 1996; 49(11):1215–1219. Rothman KJ, Greenland S, eds. Modern Epidemiology. Philadelphia: LippincottRaven 1998:130–131. Johnson MA, Woodcock AA, Geddes DM. Dihydrocodeine for breathlessness in ‘‘pink puffers.’’ Br Med J 1983; 286:675–677.

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23. Woodcock AA, Gross ER, Geddes DM. Drug treatment of breathlessness: contrasting effects of diazepam and promethazine in pink puffers. Br Med J 1981; 283:343–346. 24. Mitchell-Heggs P, Murphy K, Minty K, Guz A, Patterson SC, Minty PSB, et al. Diazepam in the treatment of dyspnoea in the ‘Pink Puffer’ syndrome. Q J Med 1980; 193:9–20. 25. Guyatt GH, Berman LB, Townshend M, Pugsley SO, Chambers LW. A measure of quality of life for clinical trials in chronic lung disease. Thorax 1987; 42:773–778. 26. Ries AL, Kaplan RM, Limberg TM, Prewitt LM. Effects of pulmonary rehabilitation on physiologic and psychosocial and psychosocial outcomes in patients with chronic obstructive pulmonary disease. Ann Intern Med 1995; 122:823–832. 27. Bone R, Boyars M, Braum S, et al. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: An 85-day multicenter trial. Chest 1994; 105:1411–1419. 28. Casaburi R, Mahler DA, Jones PW, Wanner A, San Pedro G, ZuWallack RL, Menjoge SS, Serby CW, Witek TJ Jr. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Resp J 2002; 19:217–224. 29. 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. 30. Aalbers R, Ayres J, Backer V, Decramer M, Lier PA, Magyar P, et al. Formoterol in patients with chronic obstructive pulmonary disease: a randomized, controlled, 3-month trial. Eur Respir J 2002; 19:936–943. 31. Mahler DA, Wire P, Horstman D, Chang C-N, Yates, J, Fischer T, et al. 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. 32. Campbell S. For COPD a Combination of ipratropium bromide and albuterol sulfate is more effective than albuterol base. Arch Intern Med 1999; 159: 156–160. 33. The COMBIVENT inhalation solution study group. Routine nebulized ipratropium and albuterol together are better than either alone in COPD. Chest 1997; 112:1514–1521. 34. 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. 35. Wadbo M, Lo¨fdahl C.-G, Larsson K, et al. Effects of formoterol and ipratropium bromide in COPD: a 3-month placebo-controlled study. Eur Respir J 2002; 20:1138–1146. 36. The Lung Health Study Research Group. Effect of Inhaled Triamcinolone on the Decline in Pulmonary Function in Chronic Obstructive Pulmonary Disease. N Engl J Med 2000; 343(26):1902–1909.

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37. Petty TL. The national mucolytic study: results of a randomized, double-blind, placebo-controlled study of iodinated glycerol in chronic obstructive bronchitis. Chest 1990; 97(1):75–83. 38. Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, et al. The Efficacy and Safety of Fluticason Propionate (250 mg)/Salmeterol (50 mg) Combined in the diskus inhaler for the treatment of COPD. Chest 2003; 124(3):834–843. 39. Vincken W, van Noord JA, Greefhorst APM, Bantje ThA, 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 Resp J 2002; 19:209–216. 40. Olschewski H, Simonneau G, Galie` N, Higenbottam T, Naeije R, Rubin LJ, et al. Inhaled Iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347(5):322–329. 41. Aaron SD, Vandenheen KL, Clinch JJ, Ahuja J, Brison RJ, Dickinson G, He´rbert PC. Measurement of short-term changes in dyspnea and disease-specific qualit of life following an acute COPD exacerbation. Chest 2002; 121(3):688–696. 42. Mahler DA, Tomlinson D, Olmstead EM, Tosteson NA, O’Conner GT. Changes in dyspnea, health status, and lung function in chronic airway disease. Am J Respir Crit Care Med l995; 151:61–65. 43. O’Donnell D, Flu¨ge T, Gerken F, Hamilton A, Make B, Magnussen H. Effects of tiotropium on lung hyperinflation, dyspnea and exercise tolerance in COPD. Eur Respir J 2004; 23:832–840. 44. Rubin BK, Ramirez O, Ohar JA. Iodinated glycerol has no effect on pulmonary function, symptom score, or sputum properties in patients with stable chronic bronchitis. Chest 1996; 109(2):348–352. 45. Lisboa C, Munoz 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. 46. Harver A, Mahler DA, Daubenspeck JA. Targeted inspiratory muscle training improves respiratory muscle function and reduces dyspnea in patients with chronic obstructive pulmonary disease. Ann Intern Med 1989; 111:117–124. 47. O’Donnell DE, McGuire MA Samis L, Webb, KA. The impact of exercise reconditioning on breathlessness in severe chronic airflow limitation. Am J Respir Crit Care Med 1995; 152:2005–2013. 48. 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. 49. Martinez FJ, Montez de Oca M, Whyte RI, Stetz J, Gay SE, Celli BR. Lungvolume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function. Am J Respir Crit Care Med 1997; 155:1984–1990. 50. Kirsten DK, Wegner RE, Jo¨rres RA, Magnussen H. Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest 1993; 104: 1101–1107. 51. Ries AL, Kaplan RM, Myers R, Prewitt LM. Maintenance after pulmonary rehabilitation in chronic lung disease. Am J Respir Crit Care Med 2003; 167:880–888.

10 Diagnosis of Unexplained Dyspnea


ALEXANDER S. NIVEN

IDELLE M. WEISMAN

Texas Tech University of the Health Sciences El Paso, and William Beaumont Army Medical Center, El Paso, Texas, U.S.A.

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, El Paso, Texas, U.S.A.

Index of Terms ABG AMP AT BDI/TDI BP C(a-v) O2 CF CHF CKD CO CO2 COPD

Arterial blood gas Adenosine 50 -monophosphate Anaerobic threshold Baseline and Transition Dyspnea Index Blood pressure Arterial-mixed venous oxygen difference Cystic fibrosis Congestive heart failure Chronic kidney disease Cardiac output Carbon dioxide Chronic obstructive pulmonary disease




The views expressed herein are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.

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208 COHb CPET CXR DLCO EBCT ECG EELV EILV EVH ExtFVL f FEV1 FVL FVC GERD GFR HCO3 HIV HR HRCT HRR IET IC ILD MEP MFVL MIP MVV O2 O2 pulse PAH PaO2 P(A-a) O2 PETCO2 PETO2 PVO2 RER RV SaO2 SpO2 SV TLC VCD

Niven and Weisman Carboxyhemoglobin Cardiopulmonary exercise testing Chest radiograph Carbon monoxide diffusing capacity Electron beam computed tomography Electrocardiogram End-expiratory lung volume (EELV ¼ TLC – IC) End inspiratory lung volume (EILV ¼ TLV – IRV) Eucapneic voluntary hyperventilation Exercise tidal flow-volume loop Respiratory frequency Forced expiratory volume in first second of exhalation Flow-volume loop Forced vital capacity Gastroesophageal reflux disease Glomerular filtration rate Serum bicarbonate Human immunodeficiency virus Heart rate High resolution computed tomography Heart rate reserve Incremental cardiopulmonary exercise test Inspiratory capacity Interstitial lung disease Maximum expiratory pressure Maximal volitional flow-volume envelope Maximum inspiratory pressure Maximum voluntary ventilation Oxygen VO2/HR, a noninvasive estimate of stroke volume Pulmonary arterial hypertension Arterial partial pressure of oxygen Alveolar–arterial difference in partial pressure of oxygen Partial pressure of end tidal CO2 Partial pressure of end tidal O2 Venous partial pressure of oxygen Respiratory exchange ratio Residual volume Arterial oxygen saturation Noninvasive oxygen saturation measured by pulse oximetry Stroke volume Total lung capacity Vocal cord dysfunction

Diagnosis of Unexplained Dyspnea ˙ CO2 V ˙ D/V ˙T V ˙E V ˙ Emax V ˙ E/V ˙ CO2 V ˙ E/V ˙ O2 V ˙ O2 V ˙ O2/kg V ˙ O2max V ˙ O2peak V V/Q VR V-slope ˙T V VTE WR

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Carbon dioxide output Dead space to tidal volume ratio Minute ventilation ˙ E achieved during exercise Maximal V Minute ventilation over carbon dioxide output, a marker of ventilatory efficiency Minute ventilation over oxygen uptake, a marker of ventilatory efficiency Oxygen uptake Oxygen uptake normalized for body mass Maximal oxygen uptake value Peak oxygen consumption Ventilation/Perfusion ˙ Emax/MVV; MVV – V ˙ Emax) Ventilatory reserve (V ˙ CO2 vs. V ˙ O2, used to determine anaerobic threshold Plot of V Tidal volume Venous thromboembolism Work rate

I. Introduction Dyspnea is a common complaint. An estimated 3–25% of the general community has been reported to complain of shortness of breath (1). Dyspnea is the presenting complaint for 3.7% of ambulatory medicine visits (2), 2.7% of emergency department visits (3), and 15–25% of all hospital admissions (4,5). The American Thoracic Society defines dyspnea as ‘‘a subjective experience of breathing discomfort that . . . derives from interactions among multiple physiological, psychological, social and environmental factors (6).’’ Dyspnea is therefore a broad term that encompasses a wide variety of clinical conditions, with symptoms that vary based both on the pathophysiologic mechanism and on the psychosocial factors involved. The evaluation of a patient presenting with acute dyspnea requires a focused clinical assessment designed to rapidly identify and treat potential life-threatening conditions. Chronic dyspnea is generally defined by symptoms that persist at rest or with exertion for at least three weeks (7). An underlying cause of dyspnea can frequently be determined in these patients following a comprehensive medical history, physical examination, and the results of screening tests. Patients without a unifying diagnosis after this preliminary evaluation are often referred to as having ‘‘unexplained dyspnea.’’ The purpose of this chapter is to provide a systematic, timely

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and cost-effective approach to the diagnosis of this latter challenging subgroup of patients. II. Causes of Dyspnea A wide variety of clinical conditions can cause symptoms of dyspnea (Table 1) (8). In three commonly cited studies, pulmonary disease was the most commonly identified cause of chronic dyspnea, followed by deconditioning, cardiac, and psychogenic disorders (Table 2) (7,9,10). Of these three series only Martinez et al. (10) reported patients with more than one diagnosis (5 of 50, 10%), but other authors have reported that multiple causes can be found in 27–33% of patients with chronic dyspnea (5,11,12). The three studies detailed above (Table 2) also provide an excellent illustration of the clinical heterogeneity of patients presenting with dyspnea. The prevalence of pulmonary disease, while common in all three studies, ranged from 36% to 75%; the frequency of deconditioning and psychogenic disorders also varied widely. The stable prevalence of cardiovascular disease (14%) in the two studies that reported detailed patient demographics can be attributed to the age of the study populations [median 55 years with a range of 26–82 years in Martinez et al. (10), mean 52 years old with range of 17–86 years in DePaso et al.]. In contrast, another published case series detailing the evaluation of 98 young active duty military patients with exertional dyspnea (mean age 25.4  4.3 years) found no cardiovascular disease and a predominance of asthma (56%) and vocal cord dysfunction (VCD) (10%) (13). An effective diagnostic approach to the patient with unexplained dyspnea must therefore consider the prevalence of specific clinical conditions within a population of similar characteristics and select tests with a high post-test predictive value. Older age, lower socioeconomic status, smoking, morbid obesity, and the female gender have all been associated with an increased prevalence of dyspnea (3,14). Co-morbid conditions commonly associated with these demographics and the prevalent diagnoses detailed in the above studies must be heavily weighted in the development of a general diagnostic algorithm. III. Evaluation of Unexplained Dyspnea Several investigators have proposed stepwise approaches to the patient with chronic dyspnea (8,15,16). A method that combines elements from these authors with available evidence from the medical literature is summarized in Table 3. While most patients with chronic dyspnea referred to a pulmonary specialist have already received some level of prior evaluation, the initial

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Table 1 Common Causes of Chronic Dyspnea Pulmonary Chronic obstructive pulmonary disease Asthma Upper airway obstruction Interstitial lung disease Pulmonary vascular disease Pleural effusion and other pleural disorders Other causes of ventilation–perfusion mismatch Cardiovascular Coronary artery disease Cardiomyopathy Valvular disease Arrhythmias Pericardial disease Psychogenic Hyperventilation syndrome Psychogenic disorders Neuromuscular Central nervous system disorders Neuromuscular disorders Chest wall abnormalities Others Deconditioning Obesity Gastroesophageal reflux Anemia (severe) Metabolic acidosis Thyroid disease Pregnancy Ascites Drugs Source: Adapted from Ref. 14a.

assessment should include review and elaboration of these elements through a comprehensive history and physical examination. A chest radiograph, screening spirometry, and pulse oximetry measurements should also be performed if not already completed during prior evaluation. If no diagnosis is evident after this initial assessment, then the patient truly has unexplained dyspnea. Focused follow-on testing should be selected based on the demographic characteristics of the patient and the pretest probability of common diseases. Young individuals should undergo bronchoprovocation testing, followed by laryngoscopy if clinical suspicion for VCD exists. Older individuals with risk factors for heart or structural lung disease should receive a screening electrocardiogram and more

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Table 2 Top Four Etiologies of Chronic Dyspnea in Three Published Studies Pratter et al. Asthma Chronic obstructive pulmonary disease Interstitial lung disease Cardiomyopathy DePaso et al. Hyperventilation syndrome Unexplained Asthma Cardiac disease Martinez et al. Deconditioning Asthma Psychogenic Cardiac disease

29% 14% 14% 9% 19% 19% 17% 14% 28% 24% 18% 14%

Source: Adapted from Ref. 16.

complete pulmonary function testing. Select older candidates should also be considered for bronchoprovocation testing (see section B1 below). Older individuals, women, and African-Americans should also be considered more strongly for laboratory testing for anemia, thyroid dysfunction, and renal disease. All individuals with an abnormal chest radiograph should receive further evaluation, which may include computed tomography (CT) of the chest, bronchoscopy, and other invasive biopsy techniques. If the cause of dyspnea remains elusive or if multiple abnormalities are identified without a clear principle limiting cause, cardiopulmonary exercise testing (CPET) should be performed to focus further diagnostic testing and treatment efforts. Subsequent specialized testing should be performed based on the focused differential generated from the exercise response pattern. The rationale for this diagnostic approach along with the supporting available medical evidence is detailed below. A. Step I: Initial Assessment

The initial assessment of a patient presenting with unexplained dyspnea should include a comprehensive medical history, physical examination, chest radiograph, screening spirometry, and pulse oximetry measurements. 1. Medical History

A comprehensive medical history should focus on a detailed description of the patient’s complaint, including the duration and progression of dyspnea,

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Table 3 Step Approach to the Evaluation of Unexplained Dyspnea Step I: Initial assessment Medical history and physical examination Chest radiograph Spirometry Pulse oximetry Step II: Focused testing Bronchoprovocation testing Electrocardiogram Further pulmonary function testing in older individuals and high-risk groups Laboratory tests: hemoglobin, thyroid function tests, and renal panel in high-risk groups Laryngoscopy if clinical history or flow volume loop suggestive of VCD CT imaging, bronchoscopy if CXR abnormal Step III: Cardiopulmonary exercise testing Protocols/measurements Study interpretation Exercise response patterns Step IV: Specialized tests for unexplained dyspnea based on CPET results Normal Reassurance Gastroesophageal reflux evaluation and treatment Hyperventilation/psychogenic Behavioral therapy Psychiatric medication Cardiac/deconditioning Echocardiogram, cardiac functional assessment Exercise training program Muscle biopsy Obesity Weight loss and exercise training program Cardiac/ischemia Cardiac functional assessment Cardiac catheterization Pulmonary Obstructive lung disease: treatment Pulmonary vascular disease: VTE evaluation, sleep study, echocardiogram Interstitial lung disease: HRCT, lung biopsy

frequency and severity, exacerbating factors, and associated symptoms. Because of the diverse and multifactorial nature of chronic dyspnea, attempts to qualify and quantify patient symptoms can provide valuable clues to potential etiologies of their condition and provide a baseline for comparison once therapy is initiated. Classical associations between

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Table 4 Classic Clinical Associations in Patients with Dyspnea Slowly progressive symptoms COPD ILD CHF Abrupt onset of symptoms Pulmonary embolism Inadvertent aspiration of foreign body Cardiac event Vocal cord dysfunction Waxing and waning symptoms Asthma Dyspnea with chronic cough Airways disease GERD ILD Wheezing Asthma Exacerbations of COPD CHF Nocturnal symptoms COPD Asthma CHF GERD Abbreviations: COPD, chronic obstructive pulmonary disease; ILD, interstitial lung disease; CHF, congestive heart failure; GERD, gastroesophageal reflux disease.

components of the clinical history and diagnoses in patients with dyspnea are listed in Table 4. Although few would dispute the importance of a complete medical history, scientific studies addressing its discriminative power are lacking. Pratter et al. (7) noted that history taking was most effective at excluding certain common clinical diagnoses. Absence of cigarette smoking, for example, had a 100% negative predictive value for the diagnosis of chronic obstructive pulmonary disease (COPD); a history of cigarette smoking, on the other hand, had only a 20% positive predictive value for finding the same diagnosis. Isolated components of the clinical history that are not supported by other objective findings, therefore, should be interpreted with caution. There are numerous examples of the lack of specificity of time honored historical complaints. Orthopnea is common in patients with congestive heart failure (CHF) and left ventricular dysfunction, but can also be seen in patients with cor pulmonale, ascites, obesity, anterior mediastinal masses,

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and respiratory muscle weakness. Dyspnea with platypnea has been reported with right-to-left shunting through a patent foramen ovale, intraparenchymal pulmonary shunts, advanced liver disease, and the hepatopulmonary syndrome, but can also be seen with other causes of ventilation–perfusion mismatch and pericarditis. Trepopnea, or dyspnea in one lateral position but not the other, can be seen in patients with unilateral lung disease, pleural effusion, or paralyzed hemidiaphragm, but is most commonly seen in COPD (17). The differential diagnosis of dyspnea (Table 1) should focus other elements of the medical history and review of systems. Questions concerning baseline level of activity and changes in weight may increase clinical suspicion of deconditioning. Past medical history, previous surgeries, and medications can suggest potential co-morbidities or confounding conditions to consider. Smoking history, social and occupational history can identify risk factors for COPD, occupational or interstitial lung disease (ILD). Menstrual history in women may increase clinical suspicion for symptomatic anemia. As psychogenic causes figure prominently in all four case series outlined above (7,9,10,13) and in other studies, psychosocial factors must also be carefully considered in a detailed evaluation of unexplained dyspnea (16). 2. Physical Examination

Most authors advocate a thorough physical exam focused on the heart, lungs, and other areas of interest based on the clinical history (18). Although generally accepted, the scientific evidence behind this recommendation again remains limited. Pratter et al. (7) found that the finding of crackles on physical exam had a high positive predictive value for ILD, but the presence of wheezing was not useful in predicting asthma. Another study reported that the presence of peripheral edema, jugular venous distension, and heart gallops or murmurs were not helpful in discriminating cardiac from pulmonary causes of dyspnea in a population-based cohort of Swedish men (19). An abnormal blood pressure response following valsalva manoever has been shown in one case series (20) and subsequent clinical review (1) to increase the probability of CHF [sensitivity 0.88, specificity 0.90, likelihood ratio 8.8 (95% CI 2.3, 33.2)]. Marantz et al. (21) also demonstrated that an abnormal hepatojugular reflux manoever is highly specific for CHF in patients presenting to the emergency room with acute dyspnea [sensitivity 0.24, specificity 0.96, positive likelihood ratio 6.4 (95% CI 0.8, 5.9)]; however, this exam finding has not been evaluated in patients with chronic respiratory symptoms. 3. Chest Roentgenograph, Spirometry, and Pulse Oximetry

The initial evaluation should include a chest radiograph to evaluate for occult parenchymal lung disease, adenopathy, evidence of hyperinflation

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or volume loss, cardiomegaly or pleural disease. Previous studies have found that diagnoses made on clinical impression alone (history, physical examination, and findings on chest radiograph) arrived at an incorrect cause of dyspnea in one-third of cases; however, common diagnoses like asthma, COPD, ILD, and cardiomyopathy were diagnosed with a much higher degree of accuracy (47 of 58 cases, 81%) than less common causes of dyspnea (9 of 27 cases, 33%) (7). Screening spirometry is also a valuable part of the initial assessment due to the high prevalence of pulmonary disease in this population. Spirometry provides a rapid assessment of lung mechanics, and is most effective at identifying obstructive lung disease in young adults with a clinical suspicion of asthma and older individuals with risk factors for COPD. Examination of the flow-volume loop for evidence of variable or fixed airway obstruction is a necessary and important part of this study, especially if stridor is detected on physical exam (22); although uncommon, clinical conditions associated with these abnormalities can otherwise go undiagnosed despite extensive subsequent testing. Pulse oximetry at rest and/or during ambulation should be included in the initial assessment to rapidly and noninvasively evaluate pulmonary gas exchange. It is most useful in patients at low risk of reduced diffusing capacity (age less than 40, no history of smoking or prior cardiopulmonary disease) and to risk stratify higher risk individuals for severity of illness and need for supplemental oxygen. It is important to emphasize that although pulse oximetry is noninvasive and convenient, SaO2 and can vary 4% from SpO2 (23). Since pulse oximeters measure functional rather than fractional hemoglobin, SpO2 will also be artifactually elevated in smokers with significant levels of COHb, and has been shown to be significantly less accurate in African-Americans compared to Caucasians (24). Arterial blood gas measurements (ABGs) remain the gold standard for determination of pulmonary gas exchange (25), and are the only means of measuring actual PaO2 and P(A-a)O2 to objectively quantify the degree of respiratory dysfunction in pulmonary parenchymal and vascular abnormalities. B. Step II: Focused Testing for Unexplained Dyspnea

If the cause of dyspnea remains unexplained after initial assessment, the next step is to perform further focused testing. The goal of focused testing is to evaluate patients for common causes of unexplained dyspnea based on their demographic characteristics and confirm or eliminate other conditions added to the differential diagnosis from the initial evaluation. The following diagnostic tests and descriptions outline the available evidence to assist the practicing clinician to select further testing using these criteria. Because the majority of young adults have a limited number of potential causes of dyspnea, we favor a more focused approach for the younger

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patient that is clinically appropriate and cost-effective. As patients age, the differential diagnosis broadens, with cardiovascular diseases becoming a more significant concern. Because of the increased clinical risk associated with these and other conditions, the clinical approach to the patient over 40 years old with dyspnea must be more systematic and complete. 1. Bronchoprovocation Testing

The majority of young patients with dyspnea will have asthma, vocal cord dysfunction, deconditioning, or psychiatric disorders (9,13). Because of the high prevalence of occult asthma in this population, our group favors bronchoprovocation testing as the next appropriate diagnostic step in young individuals. As new asthma cases develop at all ages, testing should also be strongly considered in older individuals with suggestive clinical symptoms. Bronchoprovocation testing has become increasingly important in clinical practice over the past decade with the establishment of clear standardized approaches to methodology and interpretation (26,27). The advantage of performing Bronchoprovocation testing early in the diagnostic scheme for unexplained dyspnea is its high post-test probability to detect occult asthma, in many cases eliminating the need for additional testing. Had Bronchoprovocation testing been performed prior to CPET in one case series detailed above, for example, approximately 25% of all CPETs performed may not have been necessary (10). Bronchoprovocation testing is both effective and safe, even in older individuals. Thousands of methacholine challenge tests have been performed in various pulmonary laboratories with minimal sequelae and no fatalities (26,28), while a single fatality has been reported with use of both specific antigen (29) and distilled water (30) challenges. Current guidelines recommend that a trained individual, resuscitation equipment and medications to treat bronchospasm be available during testing to minimize the risk identified by these rare occurrences (26). Survey data from the Cardiovascular Health Study demonstrate that asthma remains an underdiagnosed and undertreated condition in patients over the age of 65 (31). 3.9 percent of a community sample of 4561 persons were being actively treated for ‘‘definitive asthma,’’ but an additional 11.4% of untreated individuals were found to have possible asthma and 4.1% probable asthma based on symptoms of episodic wheezing or chest tightness, symptoms brought on by allergic exposures, or nocturnal symptoms. The latter two groups had significantly lower quality of life scores and higher morbidity than patients without symptoms. These sobering data emphasize the importance of considering asthma on the differential diagnosis of older individuals, and bronchoprovocation testing should also be considered in these individuals provided no cardiovascular contraindications exist.

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Table 5 Stimuli Causing Bronchial Responsiveness Nonselective stimuli

Selective stimuli

Chemical–direct acting Cholinergic agonists (methacholine) Histamine

Immunologically mediated Allergens Low molecular weight compounds (isocyanate)

Leukotrienes C4, D4, and E4 Chemical–indirect acting b-Adrenergic blockers a-Adrenergic agonists Prostaglandin D2 Adenosine 50 -monophosphate Acetaldehyde Platelet activating factor Bradykinin Tachykinins Serotonin Physical–Indirect acting Cold air Exercise Hyperventilation Nonisotonic aerosols

Nonimmunologic mediated NSAIDs Acetylsalicylic acid Food Food additives

Source: Adapted from Ref. 33.

One of the challenges of bronchoprovocation testing is selecting the most appropriate agent and method for the patient and clinical setting in question. Stimuli used to provoke bronchial responsiveness are listed in Table 5. No guidelines exist to help identify which bronchoprovocation challenge stimulus is most appropriate for the individual patient. Our group prefers methacholine because it is the best studied agent, and is probably the most effective at excluding the diagnosis of asthma (26). Indirect agents like adenosine 50 -monophosphate (AMP), have been shown to better reflect airway inflammation (32) and more effectively differentiate asthma from other chronic airway conditions (33). AMP may well become the preferred agent to confirm the diagnosis of reactive airways disease and monitor response to treatment once further protocol development and testing is performed. EVH is also a practical clinical tool, especially for patients with symptoms occurring predominantly during exercise or cold weather (34,35). 2. Electrocardiogram

Patients with known coronary artery disease, multiple cardiac risk factors, or symptoms suggestive of cardiac disease should receive a screening

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electrocardiogram (ECG). Coronary artery disease remains one of the principal causes of mortality and long-term morbidity in the Western world, and several studies have demonstrated that resting ECG changes in combination with clinical factors are of predictive value (36,37). Although the exact prevalence of clinically significant coronary disease in younger age groups is largely unknown, some guidance for screening criteria can be extrapolated from current developing noninvasive screening strategies. Detection of coronary calcification by electron beam computed tomography (EBCT) has been shown to be highly sensitive and specific for the angiographic presence of coronary disease (sensitivity 81–94%, specificity 72–86%) (38,39). The prevalence of coronary calcification has been shown to more than double from the fourth to fifth decades of life (21% of men and 11% of women 30–39 years old, 44% of men and 23% of women 40–49 years old) (40). Although detection of calcium by EBCT is still sensitive (85–100%) but somewhat less specific (< 50%) for diagnosis of hemodynamically significant coronory stenosis (41), this evidence provides a reasonable rationale to include a screening ECG as part of the evaluation for dyspneic patients over age 40. Echocardiography and/or stress testing should be considered if EKG abnormalities are identified, evidence of congestive heart failure is present on physical exam, or if patient symptoms remain out of proportion to objective findings from other diagnostic testing. 3. Pulmonary Function Testing

Practical guidelines for pulmonary function testing in the dyspneic patient must again consider demographics and likely clinical conditions. The majority of young adults will not need lung volume or diffiusing capacity measurement if screening spirometry is normal. For young patients with baseline airway obstruction, simple postbronchodilator spirometry may identify reversible airway obstruction and diagnose asthma without the time, expense, and risk of bronchoprovocation testing. Rosi et al. (42) demonstrated that reversible airway obstruction and bronchial hyperreactivity represent nonoverlapping descriptors of chronic asthma, making a bronchodilator response an independent clinical tool for the diagnosis of this disease. After reaching maximal respiratory function at age 20 in women and 25 in men, the aging process causes a gradual deterioration of lung function throughout the remainder of adult life, with an accelerated rate of decline in the later years (43). Decreased lung elasticity, increased chest wall stiffness, and decreased respiratory muscle strength are the three predominant factors that result in this decline, and can cause significant changes in pulmonary function measurements (44,45). These changes may also be accelerated by tobacco consumption or other inhalation exposures.

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Due to the increased risk of multiple physiologic abnormalities, pulmonary function testing in older dyspneic patients must be more complete. In our pulmonary function laboratory, these patients receive pre- and postbronchodilator spirometry, lung volumes, diffusing capacity, and ABG as part of a standard dyspnea evaluation. Patients with a clinical history or pulmonary function testing suggestive of neuromuscular weakness are also considered for maximum voluntary ventilation (MVV) and maximum inspiratory and expiratory pressure (MIP, MEP) measurements. A comprehensive review and update on pulmonary function testing was recently published, and provides an excellent reference for a more detailed discussion on this topic (46). A few issues commonly encountered in clinical practice are emphasized below. i. Lung Volumes

Lung volumes are essential to confirm the etiology of a restrictive pattern on spirometry, preferably using body plethysmography (47). The prevalence of obesity increases with age (43), underscoring the importance of performing lung volume measurements before other diagnostic testing in elderly individuals with a restrictive pattern on screening spirometry. Restrictive disorders in young patients include parenchymal lung disease from sarcoidosis, thoracic cage abnormalities, obesity, congenital pulmonary abnormalities, and neuromuscular disease. In healthy young adults the position of residual volume (RV) is totally dependent on the balance between the outward recoil of the respiratory system and the force generated by the expiratory muscles (48), and should be normal or low in a properly performed test. ii. Diffusing Capacity

The carbon monoxide diffusing capacity (DLCO) is helpful to evaluate oxygen transfer across the lungs, and may be reduced in parenchymal lung or pulmonary vascular disease. The DLCO should be corrected for hemoglobin and carboxyhemoglobin (when COHb > 4%) (49). Reference values should also be corrected for race, as DLCO measurements in AfricanAmericans average 1.96 mL/min/mm Hg less than Caucasians (50). In young women, interpretation of results should be tempered by the fact that DLCO can vary up to 9% during the menstrual cycle, with the highest level occurring before and the lowest level occurring 5–10 days after the onset of menses (51). Measurement of DLCO is important both in the detection of occult pulmonary hypertension and interstitial lung disease, and to complete the evaluation of chronic airflow obstruction. Although DLCO is almost always reduced in the setting of advanced obstructive lung disease (52), the degree of DLCO reduction has been shown in prospective studies to predict both functional impairment and a rapid deterioration in FEV1 (53). DLCO is a

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specific but relatively insensitive predictor of the degree of oxygen desaturation during exercise (54), and may have predictive value for survival. Dubois et al. (55) demonstrated that hypoxemic patients with COPD on long-term home oxygen therapy had a 2-year survival of 79% when DLCO was greater than 70% predicted, but only 37% when DLCO was <70% predicted. FEV1, on the other hand, had no prognostic value in this same group of patients (55). Due to the higher prevalence of pulmonary gas exchange and P(A-a)O2 abnormalities, arterial blood gas measurements should accompany the DLCO. A normal or increased DLCO in a patient with severe airflow obstruction suggests a diagnosis of asthma (56). iii. Respiratory Muscle Testing

Screening spirometry is of limited value in the identification of neuromuscular disease. A restrictive pattern is generally not seen until muscle strength, measured by maximum static mouth pressures, approaches 50% predicted (57). Flow-volume loops can demonstrate diminished peak expiratory flow, decreased slope of the ascending limb of the maximal expiratory curve, a drop in the forced expiratory flow near residual volume, and a reduced forced inspiratory flow at 50% of vital capacity (58). Vinken et al. (59) designed a flow-volume loop scoring system based on these patterns that predicted neuromuscular weakness with 90% sensitivity and 80% specificity. Inspiratory plateaus and flow oscillations in the inspiratory limb can also be seen in 90% of patients with bulbar dysfunction (60). Lung volume measurements may increase clinical suspicion for neuromascular weakness, but are too nonspecific; additional diagnostic studies are usually required. Maximal voluntary ventilation is an early and sensitive predictor of neuromuscular respiratory impairment (61), especially when disproportionately reduced compared to FEV1  35 or 40 (62,63). Results must be interpreted cautiously, however, as problems with airway resistance, respiratory system compliance, and patient effort can artificially lower measurements (58,64). Maximal inspiratory and expiratory pressures (MIP, MEP) are another useful but relatively insensitive measure for detecting neuromuscular weakness, as submaximal efforts can significantly influence results (65). MIP and MEP values can predict carbon dioxide retention if values fall below 50% predicted (66), and an MEP of greater than 40 cm H2O is also considered necessary for effective cough and clearance of secretions (58,67). 4. Serum Hemoglobin

U.S. populations with a high prevalence of anemia include African-Americans, Alaska natives and native Americans, immigrants from developing countries, and individuals of low socioeconomic status (68,69). Although less than 2% of nonpregnant women aged 20–44 years have iron-deficiency anemia (68), a

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low hemoglobin and/or hematocrit is present in between 6% and 25% of white and 17–46% of African American women during pregnancy (69). Among older individuals, the risk for anemia is based on co-morbid conditions such as chronic kidney disease (CKD), and colon cancer screening should be updated in any individual over 50 in whom a low hemoglobin is identified. 5. Thyroid Function Studies

Multiple epidemiologic studies have demonstrated that the majority of outpatient thyroid disease is due to hypothyroidism, and presents almost exclusively in women (70). The prevalence of overt thyroid disease in the general community in the United States is 1.1% for adult women over the age of 18, and 1.7% for women older than age 40 (71). Thyroid disease is much more common in geriatric units, acute hospital medical and psychiatric wards, postpartum women, and patients with autoimmune antibodies. Although the evidence remains poor that screening asymptomatic individuals in these high-risk groups improves clinically important outcomes (72), symptoms of dyspnea coupled with these demographics should prompt consideration of thyroid function testing. 6. Renal Panel

A renal panel may be added as clinically appropriate to screen for metabolic acidosis or chronic kidney disease with resulting volume overload. The prevalence of CKD in the U.S. adult population is 11% (19.2 million), almost 5% of whom possess a glomerular filtration rate (GFR) of less than 60 mL/ min/m2. Hypertension, diabetes, and age are the three major risk factors for CKD, and are also more prevalent in the African-American population (73). Metabolic acidosis will develop when the GFR falls to less than 50% of normal. Other causes of symptomatic metabolic acidosis in outpatients include low grade diabetic or alcoholic ketoacidosis, alcohol and salicylate poisoning, renal tubular acidosis, hypoaldosteronism, ‘‘potassium-sparing’’ diuretics, large volume diarrhea, and bicarbonate loss from a ureterosigmoidostomy. 7. Laryngoscopy

Vocal cord dysfunction (VCD) is a condition that frequently mimics or confounds asthma, and is characterized by paradoxical adduction of the vocal cords during inspiration (74). Although the exact prevalence of this disorder is unknown, it has been shown to be present in 10–15% of young patients evaluated for exertional dyspnea (13,75) and 40% of patients seeking evaluation of asthma unresponsive to aggressive therapy (76). In the largest published series to date, 56% of VCD patients were also found to have concomitant airflow limitation or airway hyper-reactivity consistent with

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asthma, underscoring that these conditions are not mutually exclusive (77). VCD has been characterized as a form of conversion disorder (78), and has been most commonly associated with single women between the ages of 20– 40 and a variety of psychiatric conditions including obsessive–compulsive personality disorder, depression, and anxiety (79). Flattening, truncation, or ‘‘fluttering’’ of the inspiratory limb of the flow volume loop (FVL) is a characteristic finding in VCD (78,80), but is absent in the majority of patients without acute symptoms (sensitivity 23%) (77). FVL evidence of VCD can be precipitated by bronchoprovocation testing (81), with 60% of VCD patients manifesting characteristic changes after methacholine bronchoprovocation testing in one series (75). It is also useful to attempt to reproduce inciting activities (see Case 1) or exposures (perfumes, cold air, occupational agents) (74). The gold standard for the diagnosis of VCD is rhinolaryngoscopy. Although clear clinical criteria for VCD have not been established, evidence of anterior vocal cord adduction during inspiration alone or in both the inspiratory and expiratory phases accompanied by a residual posterior glottic ‘‘chink’’ is diagnostic for the condition. A systematic protocol for the procedure is outlined in detail elsewhere (74). 8. CT Imaging and Bronchoscopy

Abnormalities of the chest radiograph are relatively uncommon in young otherwise healthy adults presenting with dyspnea. In one series abnormal chest x-ray findings were present in only 7 of 105 patients (13). Of these individuals, two were found to have sarcoidosis (one with increased interstitial markings, one with bilateral hilar adenopathy on chest x-ray), two had pectus excavatum (one of which was clinically significant), and one had an elevated hemidiaphragm and was subsequently found to have neuromuscular weakness. Computed tomography (CT) is recommended for young patients with a clinical suspicion of sarcoidosis prior to initiating therapy if there are atypical clinical or radiographic findings, evidence suggesting complications of lung disease (aspergilloma, superimposed infection), or a high clinical suspicion for disease without definitive radiographic abnormalities (82). Bronchoscopy is associated with a high yield for definitive diagnosis of sarcoidosis (71.4% from endobronchial biopsy, 64.5% from transbronchial biopsy), especially in African-American subjects (p ¼ 0.00081 compared to Caucasians) (83). Other CT imaging and invasive diagnostic techniques to evaluate for rare conditions that occur in young individuals (i.e., lymphangiomyomatosis, congenital lung disorders, hypersensitivity pneumonitis) should be determined individually based on the clinical presentation. Young patients who present with infiltrates and symptoms suggestive of a chronic

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infectious process should be carefully screened for tuberculosis, nontuberculous mycobacterial disease, and endemic fungi. Although its incidence is falling due to aggressive prophylaxis and highly active antiretroviral therapy, Pneumocystis carninii pneumonia remains a presenting condition for individuals infected with the human immunodeficiency virus (HIV) (84), and screening for HIV risk factors and other immunodeficiency states should be performed in the setting of unusual or atypical infection. The diagnostic yield of chest radiograph increases with age as the prevalence of obstructive and interstitial lung diseases, primary pulmonary and metastatic malignancies and their complications increase. High resolution CT scanning has proven very useful to further characterize many diffuse lung diseases and to assist in the localization and planning of further invasive diagnostic efforts (85,86). CT scanning also plays a valuable role in the evaluation of solitary pulmonary nodules and is the initial screening method of choice for the evaluation of mediastinal lymph nodes in patients with lung cancer (87). Common clinical indications for bronchoscopy (88) and recommendations for the use of bronchoalveolar lavage (89) have been reviewed elsewhere. C. Step III: Cardiopulmonary Exercise Testing

There are several limitations to the initial assessment and focused diagnostic evaluation outlined above. Exertional symptoms are common in unexplained dyspnea, but correlate poorly with resting cardiopulmonary measurements (90,91). One-third of patients with chronic dyspnea will have multiple contributing clinical conditions (5,11,12), leaving the physician to determine the predominant cause to treat. As guidelines for the selection and sequence of subsequent diagnostic tests have not been developed, the risk of expending significant time and resources on expensive and invasive follow-on testing is significant. For patients with unexplained dyspnea who remain without a clear diagnosis after focused diagnostic evaluation, incorporating cardiopulmonary exercise testing (CPET) into the clinical decision making process is a cost-effective and useful method to identify the exercise response pattern and focus further diagnostic testing to target the predominant organ system involved (8,92). CPET can provide reassurance and limit further testing in patients with normal exercise tolerance, and can effectively identify cardiac and pulmonary disease (10,93,94), psychogenic etiologies, deconditioning (7,10), and even rare disorders including mitochondrial myopathy (16,63,95). It can determine the predominant cause of functional limitation when multiple diagnoses exist, along with providing detailed information on disease severity, progression, response to treatment, and prognosis through objective measurements of symptoms and performance indices (62,92,96). CPET has been proven effective in the early detection of disease (93,97), and exercise

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tolerance measurements have been shown to have stronger correlations with subjective measures of patient quality of life than spirometry or oxygenation measurements (98). 1. Methodology

Comprehensive CPET improves upon the diagnostic potential of standard exercise testing through concurrent measurements of respiratory gas exchange. Current commercially available automated systems process four primary signals—airflow, oxygen (O2), carbon dioxide (CO2), and heart rate (HR)—that form the basis for all measured and derived cardiopulmonary variables. Modern CPET systems commonly provide on-lineanalysis of respiratory gas exchange using a breath-by-breath technique (99), with 30- or 60-sec interval averaging to minimize breath-to-breath measurement artifact (92,100). Proper calibration and quality assurance procedures are essential to ensure reproducible measurements (92,100,101). An electronically braked cycle ergometer is generally preferred to a treadmill for clinical CPET testing. The cycle ergometer offers direct measurement of work rate, minimizes ECG artifact, allows for easier blood sample collection during exercise, and has a better cost and safety profile ˙ O2max (92,100). One disadvantage of the cycle ergometer is that the V achieved is generally 5–11% less than the level achieved with a treadmill (102,103). It is presumed that the cycle ergometer causes more local muscle fatigue, while patients using a treadmill are able to use more muscle mass and may be pushed beyond usual comfort levels because of the nature of the electronically propelled exercise. 2. Protocols

There are several standardized protocols commonly used with CPET (92,100). The symptom-limited, incremental CPET (IET) consists of three min of rest, three min of unloaded pedaling, an incremental exercise phase during which the work rate is increased by 5–25 W per minute until peak exercise is reached, and a 10 min recovery (including three min of unloaded cycling). The introduction of computer-controlled cycle ergometers has provided the option of an alternate ramp protocol, which increases the work rate continuously every 1–2 sec at an incremental rate that is similar to an IET (5–25 W per min). Both protocols should be programmed to reach maximum aerobic capacity in 8–12 min, and both have been well established as comparable methods for metabolic and cardiopulmonary measurements (104,105). ˙ O2), carbon dioxide output (V ˙ CO2), minute ventilaOxygen uptake (V ˙ E), and pulse oximetry are all monitored during a symptom-limited tion (V exercise tolerance test in addition to standard interval 12-lead electrocardiograms (ECG), blood pressure, and heart rate. A full description of signs

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and symptoms limiting exercise coupled with objective measurements using Borg (106) or other standardized dyspnea rating scales must also be collected for appropriate interpretation. Arterial blood gas measurements can be added to provide more accurate information on pulmonary gas exchange. Exercise flow-volume loop analysis is an evolving technology that can also give important insight into breathing strategies when correlated with clinical symptoms of dyspnea during exercise. Constant work exercise is gaining popularity, and has been shown to be more sensitive than a 6-min walk test in determining therapeutic efficacy of pharmacological interventions (107,108). Constant work is also an excellent method to evaluate the presence and degree of dynamic hyperinflation during exercise. It is a useful alternative approach to measure partial pressure of arterial O2 (PaO2), alveolar–arterial difference in partial pressure of ˙ D/V ˙ T), avoiding plaO2 (P(A-aO2) and dead space to tidal volume ratios (V cement of an arterial line during maximal IET (109,110). The constant work protocol is commonly performed about 1 hr after IET, and consists of 6–10 min of continuous exercise using 70% of the maximum work rate achieved during IET. Arterial blood gas measurements are performed at rest and at minute five (92). A more complete discussion of this method is detailed elsewhere (100). 3. Measurements

CPET generates a number of measurements in a variety of different functional areas that are important for an accurate exercise interpretation (Tables 6 and 7) (92). Although the number of variables required will Table 6 Measured Variables During Cardiopulmonary Exercise Testing Variables

Noninvasive

Work Metabolic

Work rate ˙ O2, V ˙ CO2, RER, V AT HR, HRR, ECG, BP, O2 pulse ˙ E, V ˙ T, f, VR, PETO2, V PETCO2 ˙ E/V ˙ CO2, V ˙ E/V ˙ O2 SpO2, V

Cardiovascular Ventilatory Pulmonary gas exchange Acid–base Symptoms

Dyspnea, leg fatigue, chest pain

a Requires arterial blood sampling. Source: Adapted from Ref. 113.

Invasivea Lactate

SaO2, PaO2, P(A-a)O2, ˙ D/V ˙T V pH, PaCO2, HCO3

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Table 7 Selected Peak Cardiopulmonary Exercise Testing Measurements Variables

Measurement caveats

Comments

˙ O2peak Max: when plateau Global assessment ˙ O2max or V V is achieved of respiratory, ˙ O2 at cardiovascular, Peak: V blood, and muscle maximum function exercise, but no plateau Direct: lactate in Estimator of the Anaerobic onset of threshold ( lactate arterial blood Indirect: modified metabolic threshold) ˙ CO2 V -slope (V acidosis during ˙ O2) and vs. V exercise. Not an conventional effective ˙ E/V ˙ O2, V ˙ E/ (V discriminator ˙ CO2, PETO2, V among different PETCO2). No exercise entities. noninvasive Appears not method is essential for consistently exercise superior prescription for COPD. 50 – 60% ˙ O2max in V average persons; higher in fit persons Heart rate reserve Predicted HR max: Age - related 210 – (age  0.65) variability in HR max predicted. Normal subjects usually have no HRR HRR: age predicted HR max – HR max achieved O2 pulse (VO2/HR) Determined at Reflects stroke volume assuming plateau, when O2 that O2 extraction maximum extraction and is normal. Its use stroke volume in COPF/CHF have been remains achieved unvalidated DVO2/DWR Measured during Used as an index of

Suggested guidelines > 84% predicted

˙ O2max > 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. ˙ O2peak–V ˙ O2 at (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 ˙ D/V ˙ T and/or in V hyperventilation hyperventilation acidosis, etc. < 0.30 Reflects efficiency PaCO2 should be 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 maximal and by the peak exercise for measurement of consistency of PaO2 and not by results pulse oximetry, 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 ˙ O2max and V ˙ O2peak are used interchangeably (92). 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. A normal V ˙ O2peak reflects a normal aerobic power and 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

˙ E) is the product of tidal volume (V ˙ T) and respiratory 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 or V ˙ Emax/MVV (62,97,114). 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 ˙ E/V ˙ CO2 tends to stay constant while the onset of heavy exercise, when V ˙ E/V ˙ O2 increases. Near the end of exercise, both V ˙ E/V ˙ CO2 and V ˙ E/V ˙ O2 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 ˙ E/V ˙ CO2 values are generinadequate 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 ˙ D/V ˙ T normally 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 ˙ E/V ˙ CO2 are often seen and are due to reduced pulmonary perfusion from 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 ˙ CO2 is generally increased with an abnormal ˙ E/V (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 ˙ E/V ˙ CO2, at AT 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˙ O2peak) was reduced with an abnormal V ˙ O2–WR 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 ˙ E/V ˙ O2 and V ˙ E/V ˙ CO2 were also increased at low levels of (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.

myopathy (‘‘ragged red fiber’’ disease). This case provides an excellent example of the clinical value of the exercise flow-volume loop, which along with the observed exercise patterns provided objective evidence for a neuromuscular process as the primary cause of the exercise limitation. References 1. Mulrow C, Lucey C, Farnett L. Discriminating causes of dyspnea through clinical evaluation. J Gen Intern Med 1993; 8:383–392. 2. Kronke K, Manglesdorff D. Common symptoms in ambulatory care: incidence, evaluation, therapy and outcome. Am J Med 1989; 86:262–266.

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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)

12 weeks, parallel

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

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

Study design

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

Dose

First author year

143 pl 135 salm

135 pl 132 salm

1.30 1.28

1.30 1.22

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

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

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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

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

a 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)

2 years, parallel

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

Study design

21 bud 18 pl

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

n

2.16 1.90

0.99 0.98 1.31 1.29 1.30 1.26 1.23 1.32 2.16 2.10

Baseline FEV1 (L)

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

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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

12 weeks aerobic training CRQ dyspnea alone (15)

BDI/TDI, OCD

BDI/TDI

Standard medical management Nonintervention period (20a)

SOBQ

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

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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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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.

Acknowledgment The author’s research in this article was supported by Fondecyt Grants 90/ 715, 92/96, 195/1149. References 1. Leith DE, Bradley M. Ventilatory muscle strength and endurance training. J Appl Physiol 1976; 41:508–516. 2. 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. 3. Ries AL, Carlin BW, Carrieri-Kolhman, Casaburi R, Celli BR, Emery CF, Hodgkin JE, Mahler DA, Make B, Skolnick J. Pulmonary rehabilitation: joint ACCP/AACVPR evidence-based guidelines. ACCP/AACVPR Pulmonary Rehabilitation Guidelines Panel. American College of Chest Physicians. American Association of Cardiovascular and Pulmonary Rehabilitation. Chest 1997; 112:1363–1396. 4. Smith K, Cook D, Guyatt GH, Madhavan J, Oxman AD. Respiratory muscle training in chronic airflow limitation: a meta-analysis. Am Rev Respir Dis 1992; 145:533–539. 5. Lo¨tters 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.

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6. Reid WD, Huang J, Bryson S, Walker DC, Belcastro AN. Diaphragm injury and myofibrillar structure induced by resistive loading. J Appl Physiol 1994; 76:176–184. 7. Faulkner JA. Structural and functional adaptations of skeletal muscle. In: Roussos C, ed. The Thorax. Part A. New York, Basel, Hong Kong: Marcel Dekker Inc., 1995:269–289. 8. Bisschop A, Gayan-Ramirez G, Rollier H, Gosselink R, Dom R, Bock V, Decramer M. Intermittent inspiratory muscle training induces fiber hypertrophy in rat diaphragm. Am J Respir Crit Care Med 1997; 155:1583–1589. 9. Gea J, Hamid Q, Czaika G, Zhu E, Mohan-Ram V, Goldspink G, Grassino A. Expression of myosin heavy-chain isoforms in the respiratory muscles following inspiratory resistive breathing. Am J Respir Crit Care Med 2000; 161:1274–1278. 10. Ramı´rez-Sarmiento A, Orozco-Levi M, Gu¨ell R, Barreiro E, Hernandez N, Mota S, Sangenis M, Broquetas JM, Casan P, Gea J. Inspiratory muscle training in patients with chronic obstructive pulmonary disease. Structural adaptation and physiologic outcomes. Am J Respir Crit Care Med 2002; 166:1491–1497. 11. Reid R, Leiva A, Colima R, Borzone G. Effects of inspiratory muscle training manoeuvres on oxygen and CO2 exchange in patients with COPD. Am J Respir Crit Care Med 2000; 161:A753. 12. Mancini DM, Henson D, La Manca J, Donchez L, Levine S. Benefit of selective respiratory muscle training on exercise capacity in patients with chronic congestive heart failure. Circulation 1995; 91:320–329. 13. Cahalin LP, Semigran MJ, Dec GW. Inspiratory muscle training in patients with chronic heart failure awaiting cardiac transplantation: results of a pilot clinical trial. Phys Ther 1997; 77:830–838. 14. Martinez A, Lisboa C, Jalil J, Mun˜oz V, Dı´az O, Casanegra P, Corbala´n R, Va´squez AM, Leiva A. Entrenamiento selectivo de los mu´sculos respiratorios en pacientes con insuficiencia cardı´aca cro´nica. Rev Me´d Chile 2001; 129:133–139. 15. Keens TG, Krastins IRB, Wannamaker EM, Levison H, Crozier DN, Bryan AC. Ventilatory muscle endurance training in normal subjects and patients with cystic fibrosis. Am Rev Respir Dis 1977; 116:853–860. 16. Weiner P, Azgad Y, Ganam R, Weiner M. Inspiratory muscle training in patients with bronchial asthma. Chest 1992; 102:1357–1361. 17. Weiner P, Berar-Yanay N, Davidovich A, Magadle R, Weiner M. Specific inspiratory muscle training in patients with mild asthma with high consumption of inhaled b2-agonist. Chest 2000; 117:722–727. 18. Weiner P, Maggadle R, Massarwa F, Beckerman M, Berar-Yanay N. Influence of gender and inspiratory muscle training on the perception of dyspnea in patients with asthma. Chest 2002; 122:197–201. 19. Similowski T, Yan S, Gauthier AP, Macklem PT, Bellemare F. Contractile properties of the human diaphragm during chronic hyperinflation. N Engl J Med 1991; 325:917–923. 20. Arora NS, Rochester DF. Effect of body weight and muscularity on human diaphragm muscle mass, thickness and area. J Appl Physiol 1982; 52:64–70.

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21. Jardim J, Farkas G, Prefaut C, Thomas D, Macklem PT, Roussos C. The failing inspiratory muscles under normoxic and hypoxic conditions. Am Rev Respir Dis 1981; 124:274–279. 22. Juan G, Calverley P, Talamo C, Roussos C. Effects of carbon dioxide on diaphragmatic function in humans. N Engl J Med 1984; 310:874–879. 23. Decramer M, Lacquet LM, Fagard R, Rogiers P. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med 1994; 150:11–16. 24. Aubier M, Murciano D, Lecocguic Y, Viires N, Jacquens Y, Squara P, Pariente R. Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. N Engl J Med 1985; 313:420–424. 25. Gandevia SC, Killian KJ, Campbell EJM. The effect of respiratory muscle fatigue on respiratory sensations. Clin Sci Lond 1981; 60:463–466. 26. Redline S, Gottfried SB, Altose MD. Effects of changes in inspiratory muscle strength on the sensation of respiratory force. J Appl Physiol 1991; 70:240–245. 27. Patessio A, Rampulla C, Fracchia C, Ioli F, Majani U, De Marchi A, Donner CF. Relationship between the perception of breathlessness and inspiratory resistive loading: report on a clinical trial. Eur Respir J 1989; 2:587s–591s. 28. Borg GAV. Psychophysical basis of perceived exertion. Med Sci Sport Exerc 1982; 14:377–381. 29. Mangelsdorff G, Borzone G, Leiva A, Martı´nez A, Lisboa C. Potencia de los mu´sculos inspiratorios en insuficiencia cardiaca cro´nica. Rev Me´d Chile 2001; 129:51–59. 30. 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. 31. Belman MJ, Botnick WC, Nathan SD, Chon KH. Ventilatory load characteristics during ventilatory muscle training. Am J Respir Crit Care Med 1994; 149:925–929. 32. Scherer TA, Spengler CM, Owassapian D, Imhof E, Boutellier U. Respiratory muscle endurance training in chronic obstructive pulmonary disease. Impact on exercise capacity, dyspnea, and quality of life. Am J Respir Crit Care Med 2000; 162:1709–1714. 33. Gosselink R, Wagenaar RC, Decramer M. Reliability of a commercially available threshold loading device in healthy subjects and in patients with chronic obstructive pulmonary disease. Thorax 1996; 51:601–605. 34. Preusser BA, Winningham ML, Clanton TL. High- vs. low-intensity inspiratory muscle interval training in patients with COPD. Chest 1994; 106:110–117. 35. Heijdra YF, Dekhuijzen RPN, van Herwaarden CLA, Folgering HTM. Nocturnal saturation improves by target-flow inspiratory muscle training in patients with COPD. Am J Respir Crit Care Med 1996; 153:260–265. 36. de Lucas Ramos P, Rodrı´guez Gonza´lez-Moro JM, Garcı´a de Pedro J, Santacruz Semimiani A, Tatay Martı´ E, Cubillo Marcos JM. Entrenamiento de los mu´sculos inspiratorios en la enfermedad pulmonar obstructiva cro´nica. Su impacto sobre las alteraciones funcionales y sobre la tolerancia al ejercicio. Arch Bronconeumol 1998; 34:64–70.

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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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Goldstein A. Oxygen, Dyspnea, and Pulmonary Rehabilitation

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

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 <3 >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%

LVRS and Dyspnea

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(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)

LVRS and Dyspnea

411

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)

412

Patel and Sciurba

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 13.0  2.3 11.8  3.0 D  0.16 (L/min) 0.76 (L/min) 12.8  0.3 14.7  3.3

17.02  4.6

10.0  2.5 9.7  2.0

0.73 (L/min) 10.0  0.4 11.7  1.9

14.6  3.3

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

—

—

—

48.9  2.4

34.3  2 —

48

52  21 D þ 17.5

47  14

40

3719

31  12

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 <45 mmHg

Surgical approach

LVRS and Dyspnea 413

21 45 32

Rogers (95) Sciurba (87)

Longer-Term Studies Cordova (88) 10

3 27

12

42

Leyenson (59)

Gelb (32) Sciurba unpublished

3 3 3

33

Shade (89)

24.8

60 3

3

3–6

n

Author

5.53 11.6  2.1

12.6  3.9

— 10.9  1.9 11.3  2.1

35% 10% 3%

11.9  2.4

12%

— 8% 10%

45%

11%

DVO2

7.47 12.8  2.9

14.1  3.5

— 11.8  2.8 12.4  2.5

0.82  0.21 (L/ 0.91  0.2 (L/ min) min) 11  2 16  3

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

Non-randomized Studies

—

—

—

40.8  28.1

— — 26.9  24.2 44.4  25.8

—

26  23 44  27 20.2  30.0 30.6  24.6 25.2  22.0 42.3  24.6

—

—

Work pre- Work postLVRS LVRS

Table 4 Studies Evaluating Maximal Exercise Response Following LVRS (Continued )

52%

— 65%

—

69% 51% 68%

—

—

Dwatts

16 Unilateral

11 Bilateral

Treadmill CPX, Bilateral MS

Bilateral MS Bilateral MS Bilateral Unilateral Bilateral

Surgical approach

414 Patel and Sciurba

6

24 6

781

348 55

NETT (20)

Dolmage (44)

3

28

Criner (42)

Follow up (months)

n

Author

— þ0.38

— þ0.65

—

þ1.9

þ0.7

—

DVO2 (LVRS)

DVO2 (control)

— < 0.05

—

< 0.01

p value

Randomized Studies

—

Dwatts (LVRS)

Comments

Analyzed with crossovers
4.4  10.8 þ5.5  14.7 Bilateral MS and VATS
9.2  13.3 þ1.7  7.7
3 þ7 Constantwork exercise also improved

—

Dwatts (control)

LVRS and Dyspnea 415

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Furthermore, an acceptable outcome is dependent on the patient’s preferences concerning lifestyle and their willingness to incur the risk of surgery. Two contrasting patient perspectives exemplify this concept. One woman who had lived a very active life was willing to risk a 50% chance of mortality to have a 33% chance of playing golf again. Another, a classical music lover and avid reader had an acceptable lifestyle and was not willing to risk even a 5% chance of mortality. While techniques designed to directly evaluate response in the context of patient values are available (96), none have yet been reported in the LVRS population (97). As such, studies evaluating the predictive role of various measures in predicting surgical mortality and the magnitude of response are reviewed here. A. Predictors Elucidated by the NETT

An important goal of the NETT was to identify characteristics of emphysema subjects who are most likely to benefit or be harmed by LVRS. An interim analysis of the NETT data revealed a subgroup (approximately 14% of accrued subjects) with high postoperative mortality. This subgroup had an FEV1 20% predicted and either a DLCO 20% predicted or homogeneous emphysema by computed tomography. The subsequent NETT publication further reported that the presence of upper lobe predominant emphysema (ULPE) was predictive of differences in mortality and differential improvement in exercise capacity at 24 months. Similarly, a low baseline exercise capacity (based upon a gender specific 40th percentile: 40 W for males and 25 W for females), was predictive of differential in mortality between the surgical and medical groups. Creation of subgroups based upon the four permutations of these two prognostic characteristics revealed strong evidence of a differential effect between groups (Fig. 2). Those with ULPE and a low exercise capacity benefited most with a decreased mortality, a high likelihood of improved exercise capacity and improved quality of life compared to the medical group. Conversely, those with non-ULPE and high exercise capacity had increased mortality and were not likely to realize an improvement in exercise capacity or quality of life. In the remaining two groups (those with only one of the two beneficial characteristics—ULPE or low exercise capacity), results were mixed. Mortality was equivalent between medical and surgical arms in both groups. Maximal exercise capacity was significantly improved by LVRS in the ULPE/high exercise capacity group but not in the non-ULPE/low exercise capacity group (Fig. 2). Despite the important insights provided by the NETT related to selection criteria, it is important to keep in mind that a modest proportion of patients in the favorable risk groups still have a poor functional response to surgery, and a small proportion of patients in the high risk group have

LVRS and Dyspnea

417

a good response. Further detailed analyses of the data collected from the NETT should aid in further refining LVRS selection criteria with respect to surgical mortality as well as the magnitude of symptomatic and functional improvement. B. Preoperative Physiologic Assessments

Pulmonary function testing has typically been used to identify optimal candidates for LVRS. Early studies focusing upon predicting mortality in patients with a very low FEV1 (62,98–100) or a very low DLCO (75,101) were conflicting. While the NETT more clearly confirmed that subjects with an FEV1  20% of predicted and a DLCO  20% of predicted are a highrisk group (22), a recent report highlights the potential for uniquely selected patients with these high-risk criteria to still have a successful outcome (102). Similarly, prior to the NETT, studies evaluating the predictive value of walk tests (101,103,104) or CPX performance (63,103) for mortality were difficult to interpret due to the lack of a control group. Although the NETT more clearly defined mortality risks based upon exercise performance, further detailed analyses in subgroups of patients who had even more detailed preoperative physiologic measurements (e.g., exercise blood gases, pulmonary hemodynamics) should yield further insights into optimizing selection criteria with respect to mortality. In contrast, other studies have focused on the magnitude of beneficial response. Theoretical work (28) suggesting a predictive role for RV/TLC is supported by reports of greater improvements in spirometry (30,31) in patients with greater preoperative RV/TLC. More complex physiologic measures such as inspiratory lung resistance (105), mean airway resistance and intrinsic PEEP (106) have also been associated with greater spirometric response. Again, future studies using such detailed physiologic measures may further refine selection criteria with respect to the magnitude of improvement in exercise capacity and dyspnea. C. Preoperative Imaging

Many early studies documented a relationship between outcome following LVRS and the preoperative volume or distribution of emphysema on chest computed tomography. The NETT further confirmed the value of assessing emphysema distribution in predicting both mortality and magnitude of functional response. Unfortunately, terms describing disease distribution such as heterogeneous and homogeneous are subjective, difficult to standardize, and vary from center to center. Furthermore, subjective scoring has been shown to over-estimate the volume of emphysema and exhibit poor inter-observer agreement (107). Thus, investigators have used quantitative analysis methods based on density mask threshold values to categorize disease severity and pattern

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(108–110). Such quantitative analysis techniques demonstrate significantly better correlation with tissue morphometric quantification of disease (r ¼ 0.59) compared to subjective assessments (r ¼ 0.44) (107). While such measures should be more accurate discriminators of LVRS response, it is not clear that currently available measures are better than qualitative scoring techniques (111). Thus, more innovative quantitative algorithms mimicking subjective assessments of emphysema distribution, such as proportion of emphysema in the upper vs. lower lung zones, proportion of disease in the peripheral (rind) vs. the central (core) lung or emphysema hole size have been utilized with some success (112–114). Alternatively, algorithms that define density patterns without known subjective equivalents may have independent predictive power (115). Ongoing advances such as comparison of thin section vs. thick section techniques, airway wall thickness assessment (116), lobar isolation, expiratory scanning and more advanced dynamic CT analyses highlight the potential for this technology to aid in further optimizing patient selection.

VII. Summary The need for integrative outcome measures that reflect the symptomatic and functional improvements following an intervention has never been more apparent than with LVRS. Because numerous physiologic parameters can be affected independently and may even change in conflicting directions, integrative tools such as dyspnea ratings and exercise tests should serve as more meaningful outcome measures. Ongoing detailed analyses of the NETT data, along with continued refinements in imaging and physiologic testing will further refine patient selection criteria and lead to more favorable outcomes. References 1. Sullivan SD, Ramsey SD, Lee TA. The economic burden of COPD. Chest 2000; 117:5S–9S. 2. Trulock EP, Cooper JD. Reduction pneumoplasty for COPD (abstr). Chest 1994; 106:52S. 3. Cooper JD, Trulock EP, Triantafillou AN, Patterson GA, Pohl MS, Deloney PA, Sundaresan RS, Roper CL. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995; 109:106–116; discussion 116–109. 4. Sciurba FC, Rogers RM, Keenan RJ, Slivka WA, Gorcsan J III, Ferson PF, Holbert JM, Brown ML, Landreneau RJ. Improvement in pulmonary

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35. Bellemare JF, Cordeau MP, Leblanc P, Bellemare F. Thoracic dimensions at maximum lung inflation in normal subjects and in patients with obstructive and restrictive lung diseases. Chest 2001; 119:376–386. 36. Lahrmann H, Wild M, Wanke T, Tschernko E, Wisser W, Klepetko W, Zwick H. Neural drive to the diaphragm after lung volume reduction surgery. Chest 1999; 116:1593–1600. 37. Tschernko EM, Wisser W, Wanke T, Rajek MA, Kritzinger M, Lahrmann H, Kontrus M, Benditte H, Klepetko W. Changes in ventilatory mechanics and diaphragmatic function after lung volume reduction surgery in patients with COPD. Thorax 1997; 52:545–550. 38. Laghi F, Jubran A, Topeli A, Fahey PJ, Garrity ER Jr, Arcidi JM, de Pinto DJ, Edwards LC, Tobin MJ. Effect of lung volume reduction surgery on neuromechanical coupling of the diaphragm. Am J Respir Crit Care Med 1998; 157:475–483. 39. Criner G, Cordova FC, Leyenson V, Roy B, Travaline J, Sudarshan S, O’Brien G, Kuzma AM, Furukawa S. Effect of lung volume reduction surgery on diaphragm strength. Am J Respir Crit Care Med 1998; 157:1578–1585. 40. Bellemare F, Cordeau MP, Couture J, Lafontaine E, Leblanc P, Passerini L. Effects of emphysema and lung volume reduction surgery on transdiaphragmatic pressure and diaphragm length. Chest 2002; 121:1898–1910. 41. Teschler H, Stamatis G, el-Raouf Farhat AA, Meyer FJ, Costabel U, Konietzko N. Effect of surgical lung volume reduction on respiratory muscle function in pulmonary emphysema. Eur Respir J 1996; 9:1779–1784. 42. Criner GJ, Cordova FC, Furukawa S, Kuzma AM, Travaline JM, Leyenson V, O’Brien GM. Prospective randomized trial comparing bilateral lung volume reduction surgery to pulmonary rehabilitation in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160:2018–2027. 43. Stammberger U, Thumheer R, Bloch KE, Zollinger A, Schmid RA, Russi EW, Weder W. Thoracoscopic bilateral lung volume reduction for diffuse pulmonary emphysema. Eur J Cardiothorac Surg 1997; 11:1005–1010. 44. Dolmage TE, Waddell TK, Maltais F, Guyatt GH, Todd TR, Keshavjee S, van Rooy S, Krip B, LeBlanc P, Goldstein RS. The influence of lung volume reduction surgery on exercise in patients with COPD. Eur Respir J 2004; 23:269–274. 45. O’Donnell DE, Webb KA, Bertley JC, Chau LK, Conlan AA. Mechanisms of relief of exertional breathlessness following unilateral bullectomy and lung volume reduction surgery in emphysema. Chest 1996; 110:18–27. 46. Bumbalo TS, Sciurba FC, Rogers RM, Silfies LA, JKR. Reduction in dyspnea and leg fatigue during exercise after lung volume reduction surgery. Am J Respir Crit Care Med 1998; 157:A338. 47. Benditt JO, Wood DE, McCool FD, Lewis S, Albert RK. Changes in breathing and ventilatory muscle recruitment patterns induced by lung volume reduction surgery. Am J Respir Crit Care Med 1997; 155:279–284. 48. Sciurba FC, Rogers RM. Lung reduction surgery for emphysema. Curr Opin Pulm Med 1996; 2:97–103. 49. Haniuda M, Kubo K, Fujimoto K, Aoki T, Yamanda T, Amano J. Different effects of lung volume reduction surgery and lobectomy on pulmonary circulation. Ann Surg 2000; 231:119–125.

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50. Weg IL, Rossoff L, McKeon K, Michael Graver L, Scharf SM. Development of pulmonary hypertension after lung volume reduction surgery. Am J Respir Crit Care Med 1999; 159:552–556. 51. Thurnheer R, Bingisser R, Stammberger U, Muntwyler J, Zollinger A, Bloch KE, Weder W, Russi EW. Effect of lung volume reduction surgery on pulmonary hemodynamics in severe pulmonary emphysema. Eur J Cardiothorac Surg 1998; 13:253–258. 52. Haniuda M, Kubo K, Fujimoto K, Honda T, Yamaguchi S, Yoshida K, Amano J. Effects of pulmonary artery remodeling on pulmonary circulation after lung volume reduction surgery. Thorac Cardiovasc Surg 2003; 51: 154–158. 53. Oswald-Mammosser M, Kessler R, Massard G, Wihlm JM, Weitzenblum E, Lonsdorfer J. Effect of lung volume reduction surgery on gas exchange and pulmonary hemodynamics at rest and during exercise. Am J Respir Crit Care Med 1998; 158:1020–1025. 54. Donahoe MP, Landreneau R, Sciurba FC. The effect of volume reduction surgery on body composition in patients with end-stage emphysema. Am J Respir Crit Care Med 1996; 153:451. 55. Christensen PJ, Paine R III, Curtis JL, Kazerooni EA, Iannettoni MD, Martinez FJ. Weight gain after lung volume reduction surgery is not correlated with improvement in pulmonary mechanics. Chest 1999; 116: 1601–1607. 56. Oey IF, Morgan MD, Singh SJ, Spyt TJ, Waller DA. The long-term health status improvements seen after lung volume reduction surgery. Eur J Cardiothorac Surg 2003; 24:614–619. 57. National Emphysema Treatment Trial Research Group. Rationale and design of the National Emphysema Treatment Trial (NETT): A prospective randomized trial of lung volume reduction surgery. J Thorac Cardiovas Surg 1999; 118:518–528. 58. Moy ML, Ingenito EP, Mentzer SJ, Evans RB, Rally JJ Jr. Health-related quality of life improves following pulmonary rehabilitation and lung volume reduction surgery. Chest 1999; 115:383–389. 59. Leyenson V, Furukawa S, Kuzma AM, Cordova F, Travaline J, Criner GJ. Correlation of changes in quality of life after lung volume reduction surgery with changes in lung function, exercise, and gas exchange. Chest 2000; 118():728–735. 60. Fletcher CM, Elmes PC, Fairbairn AS, Wood CH. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. Br Med J 1959; 5147:257–266. 61. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea. Contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest 1984; 85:751–758. 62. Argenziano M, Moazami N, Thomashow B, Jellen PA, Gorenstein LA, Rose EA, Weinberg AD, Steinglass KM, Ginsburg ME. Extended indications for lung volume reduction surgery in advanced emphysema. Ann Thorac Surg 1996; 62:1588–1597.

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63. Stammberger U, Bloch KE, Thurnheer R, Bingisser R, Weder W, Russi EW. Exercise performance and gas exchange after bilateral video-assisted thoracoscopic lung volume reduction for severe emphysema. Eur Respir J 1998; 12:785–792. 64. Yusen RD, Trulock EP, Pohl MS, Biggar DG. Results of lung volume reduction surgery in patients with emphysema. The Washington University Emphysema Surgery Group.. Semin Thorac Cardiovasc Surg 1996; 8:99–109. 65. Cassina PC, Teschler H, Konietzko N, Theegarten D, Stamatis G. Two-year results after lung volume reduction surgery in alpha 1-antitrypsin deficiency versus smoker’s emphysema. Eur Respir J 1998; 12:1028–1032. 66. Hamacher J, Bloch KE, Stammberger U, Schmid RA, Laube I, Russi EW, Weder W. Two years’ outcome of lung volume reduction surgery in different morphologic emphysema types. Ann Thorac Surg 1999; 68:1792–1798. 67. Fujimoto T, Teschler H, Hillejan L, Zaboura G, Stamatis G. Long-term results of lung volume reduction surgery. Eur J Cardiothorac Surg 2002; 21:483–488. 68. Hamacher J, Buchi S, Georgescu CL, Stammberger U, Thurnheer R, Bloch KE, Weder W, Russi EW. Improved quality of life after lung volume reduction surgery. Eur Respir J 2002; 19:54–60. 69. Appleton S, Adams R, Porter S, Peacock M, Ruffin R. Sustained improvements in dyspnea and pulmonary function 3 to 5 years after lung volume reduction surgery. Chest 2003; 123:1838–1846. 70. Yusen RD, Lefrak SS, Gierada DS, Davis GE, Meyers BF, Patterson GA, Cooper JD. A prospective evaluation of lung volume reduction surgery in 200 consecutive patients. Chest 2003; 123:1026–1037. 71. Pompeo E, Marino M, Nofroni I, Matteucci G, Mineo TC. Reduction pneumoplasty versus respiratory rehabilitation in severe emphysema: a randomized study. Pulmonary Emphysema Research Group. Ann Thorac Surg 2000; 70:948–953; discussion 954. 72. Brenner M, McKenna RJ, Gelb AF, Fischel RJ, Yoong B, Huh J, Osann K, Chen JC. Dyspnea response following bilateral thoracoscopic staple lung volume reduction surgery. Chest 1997; 112:916–923. 73. Bingisser R, Zollinger A, Hauser M, Block KE, Weder W. Bilateral volume reduction surgery for diffuse pulmonary emphysema by video-assisted thoracoscopy. J Thorac Cardiovasc Surg 1996; 112:875–882. 74. 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. 75. Keenan RJ, Landreneau RJ, Sciurba FC, Ferson PF, Holbert JM, Brown ML, Fetterman LS, Bowers CM. Unilateral thoracoscopic surgical approach for diffuse emphysema. J Thorac Cardiovasc Surg 1996; 111:308–315; discussion 315–306. 76. Ojo TC, Martinez F, Paine R III, Christensen PJ, Curtis JL, Weg JG, Kazerooni EA, Whyte R. Lung volume reduction surgery alters management of pulmonary nodules in patients with severe COPD. Chest 1997; 112:1494–1500. 77. Roue C, Mal H, Sleiman C, Fournier M, Duchatelle JP, Baldeyrou P, Pariente R. Lung volume reduction in patients with severe diffuse emphysema. A retrospective study. Chest 1996; 110:28–34.

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78. Eakin EG, Resnikoff PM, Prewitt LM, Ries AL, Kaplan RM. Validation of a new dyspnea measure: the UCSD Shortness of Breath Questionnaire. University of California, San Diego. Chest 1998; 113:619–624. 78a. Argenziano M, Thomashow B, Jelln PA, Rose EA, Steinglass KM, Ginsburg ME, Gorenstein LA. Functional comparison of unilateral versus bilateral lung volume reduction surgery. Ann Thorac Surg 1997; 64(2):321–6; discussion 326–7. 78b. MCKenna RJ, Jr., Brenner M, Fischel Rj, Gelb AF. Should lung volume reduction for emphysema be unilateral or bilateral? J Thorac Cardiovasc Surg 1996; 112(5):1331–8; discussion 1338–9. 78c. Quint LE, Bland PH, Walker Jm, Kazerooni EA, Martinez FJ, Lannettoni MD, Bookstein FL. Diapharagmatic shape change after lung volume reduction surgery. J Thorac Imaging 2001; 16(3):149–155. 79. Norman M, Hillerdal G, Orre L, Jorfeldt L, Larsen F, Cederlund K, Zetterberg G, Unge G. Improved lung function and quality of life following increased elastic recoil after lung volume reduction surgery in emphysema. Respir Med 1998; 92:653–658. 80. Bagley PH, Davis SM, O’Shea M, Coleman AM. Lung volume reduction surgery at a community hospital: program development and outcomes. Chest 1997; 111:1552–1559. 81. Goldstein RS, Todd TR, Guyatt G, Keshavjee S, Dolmage TE, van Rooy S, Krip B, Maltais F, LeBlanc P, Pakhale S, Waddell TK. Influence of lung volume reduction surgery (LVRS) on health related quality of life in patients with chronic obstructive pulmonary disease. Thorax 2003; 58:405–410. 82. O’Brien GM, Furukawa S, Kuzma AM, Cordova F, Criner GJ. Improvements in lung function, exercise, and quality of life in hypercapnic COPD patients after lung volume reduction surgery. Chest 1999; 115:75–84. 83. Geddes D, Davies M, Koyama H, Hansell D, Pastorino U, Pepper J, Agent P, Cullinan P, MacNeill SJ, Goldstraw P. Effect of lung-volume-reduction surgery in patients with severe emphysema. N Engl J Med 2000; 343:239–245. 84. Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, Weinmann G, Wood DE. Online supplement to: a randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003; 348:2059–2073. 85. 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. 86. Date H, Goto K, Souda R, Nagashima H, Togami I, Endou S, Aoe M, Yamashita M, Andou A, Shimizu N. Bilateral lung volume reduction surgery via median sternotomy for severe pulmonary emphysema. Ann Thorac Surg 1998; 65:939–942. 87. Sciurba FC, Patel SA. Functional evaluation in lung volume reduction surgery. Prog Respir Res 2002; 32:186–189. 88. Cordova F, O’Brien G, Furukawa S, Kuzma AM, Travaline J, Criner GJ. Stability of improvements in exercise performance and quality of life following bilateral lung volume reduction surgery in severe COPD. Chest 1997; 112:907–915.

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89. Shade D Jr, Cordova F, Lando Y, Travaline JM, Furukawa S, Kuzma AM, Criner GJ. Relationship between resting hypercapnia and physiologic parameters before and after lung volume reduction surgery in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159:1405–1411. 90. Bloch KE, Georgescu CL, Russi EW, Weder W. Gain and subsequent loss of lung function after lung volume reduction surgery in cases of severe emphysema with different morphologic patterns. J Thorac Cardiovasc Surg 2002; 123:845–854. 91. Appleton S, Adams R, Porter S, Peacock M, Ruffin R. Sustained improvements in dyspnea and pulmonary function 3 to 5 years after lung volume reduction surgery. Chest 2003; 123:1838–1846. 92. Ciccone AM, Meyers BF, Guthrie TJ, Davis GE, Yusen RD, Lefrak SS, Patterson GA, Cooper JD. Long-term outcome of bilateral lung volume reduction in 250 consecutive patients with emphysema. J Thorac Cardiovasc Surg 2003; 125:513–525. 93. ATS Statement: Guidelines for the Six-Minute Walk Test. Am J Respir Crit Care Med 2002; 166:111–117. 94. Sciurba F, Criner GJ, Lee SM, Mohsenifar Z, Shade D, Slivka W, Wise RA. Six-minute walk distance in chronic obstructive pulmonary disease: reproducibility and effect of walking course layout and length. Am J Respir Crit Care Med 2003; 167:1522–1527. 95. Rogers RM, Coxson HO, Sciurba FC, Kennan RJ, Whittall KP, Hogg JC. Preoperative severity of emphysema predictive of improvement after lung volume reduction surgery: use of CT morphometry. Chest 2000; 118: 1240–1247. 95a. Miller JI, Jr., Lee RB, and Mansour KA. Lung volume reduction surgery: lessons learned. Ann Thorac Surg 1996; 61(5):1464–8; discussion 1468–9. 96. Pauker SG, McNeil BJ. Impact of patient preferences on the selection of therapy. J Chronic Dis 1981; 34:77–86. 97. Torrance GW. Utility approach to measuring health-related quality of life. J Chronic Dis 1987; 40:593–603. 98. Fujita RA, Barnes GB. Morbidity and mortality after thoracoscopic pneumonoplasty. Ann Thorac Surg 1996; 62:251–257. 99. McKenna RJ Jr, Brenner M, Fischel RJ, Singh N, Yoong B, Gelb AF, Osann KE. Patient selection criteria for lung volume reduction surgery. J Thorac Cardiovasc Surg 1997; 114:957–964; discussion 964–957. 100. Eugene J, Dajee A, Kayaleh R, Gogia HS, Dos Santos C, Gazzaniga AB. Reduction pneumonoplasty for patients with a forced expiratory volume in 1 second of 500 milliliters or less. Ann Thorac Surg 1997; 63:186–190; discussion 190–182. 101. Hazelrigg S, Boley T, Henkle J, Lawyer C, Johnstone D, Naunheim K, Keller C, Keenan R, Landreneau R, Sciurba F, Feins R, Levy P, Magee M. Thoracoscopic laser bullectomy: a prospective study with three-month results. J Thorac Cardiovasc Surg 1996; 112:319–326; discussion 326–317. 102. Meyers BF, Yusen RD, Guthrie TJ, Patterson GA, Lefrak SS, Davis GE, Cooper JD. Results of lung volume reduction surgery in patients meeting a

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18 Management of Dyspnea at the End of Life

D. DUDGEON Queen’s University, Kingston, Ontario, Canada

I. Introduction Modern medicine has markedly changed the way people die. In the early 1900s people usually had a short period of illness prior to a rapid decline and death. Advances in public health and medical care have enabled people to live longer and to survive many life-threatening events. Today, we have an expanding number of people living with chronic diseases and experiencing prolonged illness and disability. Modern technology and innovative medical treatments have made it possible not only to prolong life, but also to prolong the dying process when little hope for a meaningful recovery exists. Most people, however, want more than just a longer life. We have no cure for any of the five major conditions that mark the end of most people’s lives: cancer, stroke, heart disease, lung disease, and dementia (1). Most of these deaths are anticipated and occur after prolonged periods of debility and suffering. This makes these disease states ideal for interventions to improve the end-of-life care. As breathlessness is so common and disabling in each of these diseases, good end-of-life care requires knowledge and skill in the management of dyspnea. 429

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Dyspnea is a very common symptom in people with advanced disease who are approaching the end of their lives. Its prevalence varies according to the stage and type of underlying disease. Approximately 50% of a general out-patient cancer population described some breathlessness (2) with this number rising up to 70% in the terminal phases of the disease (3–8). The prevalence of dyspnea is even more common in patients with lung cancer where almost 90% of them complain of breathlessness just prior to death (9). In a study of patients with end-stage chronic obstructive pulmonary disease (COPD), extreme breathlessness was experienced by 95% of the participants and was the most distressing and debilitating symptom (10). Dyspnea is also quite prevalent in the last year of life of people with congestive heart failure (CHF)—61–72% having suffered with it for six months or more (11); cerebrovascular accident—37–57% for more than six months (12); amyotrophic lateral sclerosis (ALS)—47–50%; and dementia—70% (13). B. Effect on Quality of Life

Studies have demonstrated that dyspnea severely impairs the quality of life of patients with advanced COPD and cancer (10,14,15). In patients living with end-stage COPD, 98% were unable to perform strenuous activities, 87% were unable to take a short walk around the house, 57% required help with washing, dressing, and getting to the toilet (10). In a similar study in advanced cancer patients, dyspnea was intensified with climbing stairs (95.6%), walking slowly (47.8%), getting dressed (52.2%), talking or eating (56.5%), and 26.1% were dyspneic at rest. Patients in this study universally responded by decreasing their activity to whatever degree they would relieve their breathlessness (15). Other studies found that patients had socially isolated themselves from friends and outside contacts to cope with their dyspnea (10,14). Depression, fatigue, generalized dissatisfaction with life (16), and a high degree of emotional distress (10) were very common. In one study, when patients with severe COPD were compared with patients with inoperable nonsmall cell lung cancer (NSCLC), the out-patients with COPD were significantly more depressed and anxious than the cancer patients (17). Eighty-two percent of the patients with COPD were housebound and 36% largely chairbound compared with 36% and 10%, respectively, of the patients with an NSCLC. Studies in patients with cerebral vascular accidents or end-stage heart and neurological diseases have also demonstrated the presence of significant dyspnea and other symptoms, functional disability, and impaired quality of life in the last year of their lives (11–13). Others have found (15) that the majority of patients had received

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no direct medical or nursing assistance with their dyspnea leaving them to cope with this debilitating symptom in isolation. C. Distress

Patients with advanced disease typically experience chronic shortness of breath with intermittent acute episodes (14,18). Acute attacks of breathlessness are usually accompanied by feelings of anxiety, fear, panic, and when severe enough a sensation of impending death (18). Patients and family members who were participants of a qualitative study using narrative analysis described two kinds of acute dyspneic episodes in patients with COPD: a near-death story with a distinct moment in time when they thought the person had died and then been resuscitated, and a shadow-of-death story where they feared dying or witnessing a death event (19). For some patients and family caregivers, these near-death events acted as a watershed among patients’ previous level of health, present experience of living with COPD, and ultimate death (19). These episodes of dyspnea were the events, which heralded the beginning of the ‘‘end-of-life’’ phase for these people. These patients and caregivers consistently expressed fear of dying during a future acute episode of breathlessness or of watching helplessly as a loved one became increasingly breathless and died before receiving any help. Many dying persons are terrified of waking in the middle of the night with intense air hunger (20). They need providers who will anticipate their fears and provide symptomatic relief of their breathlessness and anxiety as they approach death (19,20). III. Components of Management of Dyspnea at the End of Life Management of breathlessness of patients at the end of their lives requires expertise that includes an understanding and assessment of the multidimensional components of the symptom, a knowledge of the pathophysiological mechanisms and clinical syndromes that are common in people with advanced disease, and the indications and limitations of the available therapeutic approaches. A. Multidimensional Nature

Dyspnea, like pain, is a subjective experience that involves not only physical, but also affective components (21,22). The neuropathways responsible for the sensation of breathlessness are poorly understood (23) and no simple physiologic mechanism or unique peripheral site can explain the varied circumstances, which lead to a person feeling short of breath (21,24). Stimulation of a number of different receptors (Fig. 1) and the conscious perception

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Figure 1 Schematic diagram of the neuroanatomic elements involved in the control of ventilation.

this invokes can alter ventilation and result in the person feeling breathlessness. The quality and intensity of the breathlessness that the person perceives are affected by the person’s previous experience (21,22). This has particular relevance to the person near the end of life when acute episodes of breathlessness induce fear of ‘‘impending death.’’ B. Pathophysiology

An understanding of the pathophysiologic mechanisms that cause breathlessness is necessary to adequately assess and treat this distressing symptom. Exertional dyspnea is caused by: (1) increased ventilatory demand, (2) impaired mechanical responses, or (3) a combination of the two (25). The effects of abnormalities of these mechanisms can also be additive. 1. Increased Ventilatory Demand

Ventilatory demand is increased because of: increased physiological dead space due to reduction in the vascular bed (from thrombo-emboli, tumour emboli, vascular obstruction, due to radiation or chemotherapy toxicity, or concomitant emphysema); hypoxemia and severe deconditioning with early metabolic acidosis (with excessive hydrogen ion stimulation); alterations in carbon dioxide output (VCO2) or in the arterial PCO2 set point;

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and nonmetabolic sources such as increased neural reflex activity or psychological factors such as anxiety and depression. 2. Impaired Mechanical Response/Ventilatory Pump Impairment

Impaired mechanical responses result in restrictive ventilatory deficits due to inspiratory muscle weakness from cachexia, electrolyte imbalances, peripheral muscle weakness, neuromuscular abnormalities, neurohumoral causes and steroid use (26), pleural or parenchymal disease, or reduced chest wall compliance; airway obstruction from co-existent asthma or COPD, or tumour obstruction. Patients may also have a mixed obstructive and restrictive disorder. IV. Special Considerations in People Near the End of Life A. Psychological Factors

Individuals with comparable degrees of functional lung impairment may experience considerable differences in the intensity of dyspnea they perceive (21). This lack of correlation and predictability may be due to any one or a combination of factors including adaptation, differing physical characteristics, and psychological conditions (21). Anxious, obsessive, depressed, and dependent persons appear to experience dyspnea that is disproportionately severe relative to the extent of pulmonary disease (21). Gift et al. (27) found that anxiety was higher during episodes of high or medium dyspnea levels when compared with low dyspnea. Others have found that anxiety and depression seem to perpetuate episodes of disproportionate breathlessness (Campbell Symposium) (28). In another study, Kellner et al. (29) found that, in multiple regression analyses, depression was predictive of breathlessness. Studies in patients with advanced cancer have shown that anxiety is significantly correlated with the intensity of dyspnea (8,26,30,31). These correlations are significant but low, with anxiety explaining only 9% of the variance in the intensity of dyspnea. These studies were done in cancer patients who had a chronic level of dyspnea and therefore had adapted to the sensation. In episodes of acute shortness of breath, anxiety is a much more prominent factor and, as stated earlier, induces fears of dying in people with advanced disease. B. Skeletal and Respiratory Muscle Weakness

Asthenia and generalized muscle weakness are common in patients with advanced COPD and other end-stage diseases (32–35). Studies have demonstrated that exercise capacity is limited by abnormalities in either endurance or weakness of the skeletal muscles in patients with CHF (36), COPD (37), and cancer (38). Other investigators have found that both

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peripheral muscle and respiratory muscle strength are reduced in patients with cardiorespiratory diseases and cancer (38,39) with muscle strength, a significant contributor to the intensity of exercise-induced dyspnea (39). Studies have shown that patients with chronic heart failure have abnormal skeletal muscle metabolism during exercise and significant ultrastructural skeletal muscle abnormalities affecting both the respiratory and peripheral muscles (40,41). Respiratory muscle weakness and dysfunction can cause acute and chronic respiratory failure and lead to dyspnea and even death, on occasion. If respiratory muscle strength is reduced to less than 30% of predicted, respiratory failure may occur (42). Causes of respiratory and skeletal muscle dysfunction include neuromuscular diseases; malnutrition and cachexia; deficiencies of potassium, magnesium, and inorganic phosphate; poor oxygenation; neurohormonal changes in levels of cortisol, catecholamines, and tumor necrosis factor alpha (TNF-a); chronic steroid administration; and deconditioning (34,43–46). 1. Cachexia

Cachexia is a common final scenario of several chronic conditions including cancer, COPD, chronic heart failure, acquired immunodeficiency syndrome (AIDS), and renal failure (32). Cachexia differs from simple nutritional imbalance as there are modifications in the metabolism of proteins, lipids, and carbohydrates with a preferential loss of muscle tissue over fat, enhanced protein degradation, and unresponsiveness to nutritional interventions (32). Both respiratory and peripheral muscle weakness can result from an impaired nutritional status (47). The diaphragmatic mass is reduced in undernourished individuals, and contractile force per unit of muscle cross-sectional area is diminished as well (myopathy) (43). Although no studies have been conducted in cancer patients, there is evidence in COPD patients that re-feeding, exercise re-conditioning, and anabolic steroids improve exercise tolerance (48–50). 2. Neurological Paraneoplastic Syndromes

Neurological paraneoplastic syndromes can contribute to the development of dyspnea in cancer patients. Thirty percent of patients with malignant thymoma have myasthenia gravis that can weaken respiratory muscles and cause respiratory failure (51,52). The diagnosis is confirmed by the Tensilon test, by electromyography that reveals a decrementing motor response with repetitive nerve stimulation, or by radioimmunoassay for antibody to the acetylcholine receptor (52). A few patients with polymyositis develop cardiac conduction abnormalities and interstitial lung disease (52). Eaton–Lambert syndrome associated with lung, rectal, kidney, breast,

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stomach, skin, and thymic cancers can also produce respiratory muscle weakness, resulting in dyspnea (52,53). Neurophysiological studies which demonstrate that the amplitude of the action potential of muscle evoked by nerve stimulation increases by more than 200% after the muscle has exercised for 10–15 sec help confirm the diagnosis (52). Dyspnea in patients with neuromuscular disease probably results from a perception of increased respiratory muscle effort because of the increased neural drive required to activate weakened respiratory muscles (54). C. Clinical Assessment

As dyspnea is an unpleasant awareness of breathing, and therefore a subjective experience, it may not be evident to an observer. Tachypnea, a rapid respiratory rate, is not dyspnea. Medical personnel must learn to ask and accept the patient’s assessments as the groups often do not agree on the presence or intensity of breathlessness a person is experiencing (8). Studies have shown that patients universally respond to dyspnea by decreasing their activity to whatever degree necessary to relieve their breathlessness (15). It is therefore helpful to ask about shortness of breath in relation to activities such as ‘‘walking at the same speed as someone of your age,’’ ‘‘stopping to catch your breath when walking upstairs,’’ or ‘‘eating.’’ Gift et al. (27) found that the use of accessory muscles in subjects with COPD was significantly different with high, medium, and low levels of breathlessness. There were no significant differences in respiratory rate, depth of respiration or peak expiratory flow rates at the three levels of dyspnea. This would suggest that the use of accessory muscles might be helpful in assessing the level of discomfort of breathing in patients who are dying and unable to tell us. Clinical assessment of dyspnea should include a complete history of the symptom, including its temporal onset (acute or chronic), whether it is affected by positions, its qualities, associated symptoms, precipitation and relieving events, or activities and response to medications. A past history of smoking, underlying lung or cardiac disease, concurrent medical conditions, allergy history, and details of previous medications or treatments should be elicited (55,56). A careful physical examination focused on possible underlying causes of dyspnea should be performed. Particular attention should be directed at signs associated with certain clinical syndromes that are associated with common causes of dyspnea in people with the person’s particular underlying disease. An example of this would be the dullness to percussion, decreased tactile fremitus, and absent breath sounds associated with a pleural effusion in a person with lung cancer. Another example would be the findings of CHF with an elevated jugular venous pressure, an S3 heart sound and bilateral crackles audible on chest examination (55,56).

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The choice of appropriate diagnostic tests should be guided by the stage of disease, the prognosis, the risk/benefit ratios of any proposed tests or interventions, and the desires of the patient and family. If the person is actively dying or wants no further investigations or invasive or diseaseoriented interventions, then it is totally appropriate to palliate the symptom without further testing. If they are at an earlier phase of their illness, diagnostic tests helpful in determining the etiology of dyspnea include chest radiograph, EKG, pulmonary function tests, arterial blood gases, complete blood counts, serum potassium, magnesium and phosphate levels, cardiopulmonary exercise testing, and tests specific for the suspected underlying pathologies (i.e., echocardiogram for suspected pericardial effusion) (55). V. Interventions for Management of Dyspnea The optimal treatment of dyspnea is to treat the underlying disease and any reversible causes. Unfortunately, as a person’s disease progresses and he/ she approaches the end of his/her life, this is often no longer possible or successful and palliation becomes the goal. Table 1 lists the potentially treatable causes of dyspnea. As with choosing appropriate diagnostic tests, the choice of treating or not treating a particular underlying cause of breathlessness should be guided by the stage of disease, prognosis, risk/benefit taken, and desire of the patient and family. This section outlines nonpharmacological and pharmacological interventions that are helpful in alleviating breathlessness without addressing the underlying cause. A. Nonpharmacological Interventions

Many patients obtain relief of dyspnea by leaning forward while sitting and supporting their upper arms on a table. This technique has demonstrated efficacy in patients with emphysema (57), probably because of increased efficiency of the diaphragm due to an improved length-tension state (58). Another simple technique is pursed-lip breathing, which slows the respiratory rate and increases intra-airway pressures, thus decreasing small airway collapse during periods of increased dyspnea (59). Mueller et al. (60) found that pursed-lip breathing led to an increase in tidal volume and decrease in respiratory rate at rest and during exercise with seven of the 12 COPD patients experiencing an improvement in dyspnea. Others contend that pursed-lip breathing reduces dyspnea in about 50% of patients with COPD (61). People who are short of breath often obtain relief by sitting near an open window or in front of a fan. Cold directed against the cheek (62) and through the nose (63,64) can alter ventilation patterns and reduce the perception of breathlessness, perhaps by affecting receptors in the

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Table 1 Potentially Treatable Causes of Dyspnea A. Increased ventilatory demand 1. Increased physiological dead space (a) Thrombo-emboli (b) Acute radiation pneumonitis (c) Acute chemotherapy pneumonitis (d) Pulmonary edema (e) Pneumonia (f) Pneumothorax 2. Hypoxemia 3. Arrhythmias 4. Pericardial effusion 5. Superior vena cava obstruction 6. Severe deconditioning 7. Psychological factors: (a) Anxiety (b) Depression B. Impaired mechanical response/ventilatory pump impairment 1. Restrictive ventilatory deficits (a) Inspiratory muscle weakness secondary to cachexia, electrolyte imbalances, deconditioning, or steroids (b) Pleural effusions (c) Ascites (d) Pain 2. Obstructive ventilatory deficits (a) Asthma (b) COPD (c) Tumor obstruction

distribution of the trigeminal nerve that are responsive to both thermal and mechanical stimuli (62,63). Nursing actions which intubated patients thought helpful included friendly attitudes, empathy, providing physical support, staying at their bedside and being reminded or allowed to concentrate on changing their breathing pattern, and providing information about the possible cause of the breathlessness and possible interventions (65). Randomized-controlled trials support the use of acupuncture and acupressure to relieve dyspnea in patients with moderate-to-severe COPD (66,67). Acupuncture provided marked symptomatic benefit in breathlessness and respiratory rate in patients with cancer-related breathlessness (68). Other randomized-controlled trials support using muscle relaxation with breathing retraining to reduce breathlessness in COPD patients (69,70). In patients with advanced lung cancer, a combined approach with breathing retraining, exercise counseling, relaxation, and coping and

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adaptation strategies significantly improved breathlessness and the ability to perform activities of daily living compared to the control group (71). Guided imagery (72) and therapeutic touch (73) have resulted in significant improvements in quality of life and sense of well-being in COPD and terminal cancer patients, respectively, without any significant improvement in breathlessness. 1. Noninvasive Ventilation (NIV)

Noninvasive ventilation uses a mask or other device to provide ventilatory support through the patient’s upper airway, as opposed to bypassing the airway with an endotracheal tube, laryngeal mask, or tracheostomy tube used with invasive ventilation (74). Unlike invasive ventilation, an NIV enables communication, feeding and drinking, and some mobility. No sedation or analgesia is required and an NIV delivery can be intermittent. Randomized-controlled trials have shown that an NIV reduces the need for intubation, decreases in-hospital mortality, and improves arterial blood gases, respiratory rate, and dyspnea. The role of an NIV in terminal breathlessness is unclear. The British Thoracic Society Standards of Care Committee states that an NIV is not appropriate in well-documented endstage disease or when several co-morbidities are present, however, there are no absolute contraindications. Shee and Green suggest that an NIV is appropriate in some people with end-stage disease and can be used to provide time to clarify the diagnosis or response to treatment, to enable a person to get well enough to return home or to give patients and families extra time to come to terms with dying and achieve ‘‘closure.’’ B. Pharmacological Interventions 1. Opioids

Since the late 19th century, opioids have been used to relieve breathlessness in patients with asthma, pneumothorax, and emphysema (75). Although most trials have demonstrated the benefit of opioids for the treatment of dyspnea (60,76–85), some have been negative (86–89) and/or produced undesirable side effects (78,86). When interpreting studies regarding the effectiveness of opioids in management of dyspnea, there are some lessons to be learned from use of opioids in management of pain. Firstly, some of the studies used suboptimal dosing intervals (82,86,87). Most oral opioids have a duration of action of 3–4 hr. In two negative studies, the dosing interval was every 6 hr and in one positive study it was three times per day (82). It is possible that the effect would have been greater, had the people received more appropriate dosing intervals. Bruera et al. (76) also observed that in their study the opioid effect for dyspnea was of shorter duration than the effect

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for pain, so perhaps even more frequent dosing or higher doses are required for treatment of breathlessness. Secondly, in all negative studies, morphine (88,89) or morphine-like (86,87) medications were used. In each of the studies, subjects were older and many developed intolerable side effects from the opioids (86–89). Of the 11 positive studies, eight were single dose studies (76,77,79,80,83,84) and all of the negative studies involved chronic dosing (86–89). It is known that morphine has active metabolites, morphine-3-glucuronide and morphine-6-glucuronide, which are excreted renally. These metabolites accumulate in patients with renal failure or in the elderly, due to the decrease in their glomerular filtration rate, and can cause intolerable side effects such as drowsiness, confusion, nausea and vomiting, myoclonus, and potentially respiratory depression. Opioids other than morphine should be considered in the elderly people with renal failure or people who develop intolerable side effects. A recent systemic review examined the effectiveness of oral or injectable opioid drugs for the palliative treatment of breathlessness (90). The authors identified 18 randomized double-blind controlled trials comparing the use of any opioid drug against placebo for the treatment of breathlessness in patients with any illness. In the studies (77,82,83,87,89,91–93) involving the nonnebulized route of administration, there was statistically strong evidence for a small effect of oral and parenteral opioids for the treatment of breathlessness (90). Opioid receptors are located throughout the respiratory tract and it is hypothesized that if the receptors are interrupted directly, lower doses, with fewer systemic side effects would be required to control breathlessness (94). The recent systemic review (90) identified nine randomized double-blind controlled trials comparing the use of nebulized opioids or placebo for the control of breathlessness (95–103). The authors concluded that there was no evidence that nebulized opioids were more effective than nebulized saline in relieving breathlessness (90). It is hard to justify the continued use of nebulized opioids. In the 1950s, the potential for respiratory failure after opioid administration was recognized, especially in patients with pre-existing respiratory impairment (104), and ever since then physicians have been reluctant to employ opioids for dyspnea, even in terminally ill cancer patients (105). The recent systemic review of opioids for breathlessness identified 11 studies that contained information on blood gases or oxygen saturation after intervention with opioids (90). Only one study reported a significant increase in PACO2 , but it did not rise above 40 mmHg (91). In studies of cancer patients, morphine did not compromise respiratory function as measured by respiratory effort and oxygen saturation (76,77,106) or respiratory rate and PACO2 (76). Whether clinically significant hypoventilation and respiratory depression develop from opioids is now known to depend on the rate of change of the dose, the history of previous exposure to opioids,

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and possibly the route of administration (107). Early use of opioids improves quality of life and allows the utilization of lower doses while tolerance to the respiratory depressant effects develops (108). Twycross (109) suggests that early use of morphine or another opioid, rather than hastening death in dyspneic patients, might actually prolong survival by reducing physical and psychological distress and exhaustion. At this time, the evidence supports the safe use of oral and parenteral opioids for control of dyspnea. If intolerable side effects develop to one opioid, then a trial with another opioid should be initiated. Appendix A outlines medical guidelines regarding the initiation and titration of opioids for the management of dyspnea. 2. Sedatives and Tranquilizers

Chlorpromazine decreases breathlessness without affecting ventilation or producing sedation in healthy subjects (110). Woodcock et al. found that promethazine, a phenothiazine antihistamine, reduced dyspnea and improved exercise tolerance in patients with severe COPD (111). Others did not find promethazine improved breathlessness in healthy people (110) nor in patients with stable COPD (86). In an open-labeled trial McIver et al. (112) found chlorpromazine effective for relief of dyspnea in advanced cancer. In a double-blind placebo-controlled randomized trial, Light et al. (92) studied the effectiveness of morphine alone, morphine and promethazine, and morphine and prochlorperazine for the treatment of breathlessness in COPD patients (92). The combination of morphine and promethazine significantly improved exercise tolerance without worsening dyspnea compared to placebo, morphine alone, or the combination of morphine and prochlorperazine (92). Ventafridda et al. (113) have also found the combination of morphine and chlorpromazine to be effective. Evidence supports the usefulness of promethazine or chlorpromazine alone or in combination with morphine for treatment of dyspnea. Appendix A outlines when phenothiazines could be considered as an adjunct to opioids in the management of dyspnea. Clinical trials to determine the effectiveness of anxiolytics for the treatment of breathlessness have had conflicting results (111,114–118) and therefore their use for the treatment of chronic breathlessness has little support in the literature. Anecdotal evidence supports the use of anxiolytics for episodes of acute breathlessness. Buspirone, a nonbenzodiazepine anxiolytic, had no effect on pulmonary function tests or arterial blood gases in patients with COPD but improved exercise tolerance and decreased dyspnea (119). This drug warrants further study. 3. Other Medications

Studies of the usefulness of indomethacin (120–122) and inhaled bupivacaine (123,124) for relief of breathlessness have been contradictory. Inhaled

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lidocaine (125) and dextromethorphan did not improve breathlessness (126). None of these medications can be recommended for the treatment of dyspnea at this time. 4. Oxygen

The usefulness of oxygen for management of chronic dyspnea associated with cancer has been questioned in the literature (127,128). Most authorities currently recommend oxygen for dyspneic hypoxic patients, even in the face of increasing hypercapnea to achieve and maintain a PaO2 of 55–60 mmHg and oxygen saturation of 88–90% (129,130). Bruera et al. (131,132) have demonstrated the benefit of oxygen therapy in 20 hypoxic patients with terminal cancer (131,132). Patients’ rating of dyspnea, their respiratory rate, oxygen saturation, respiratory effort all improved with oxygen to a statistically significant greater degree than with air. The role of oxygen in the treatment of nonhypoxic dyspneic patients is less clear. Woodcock et al. (133) studied the effect of oxygen on breathlessness in nonhypoxic patients with COPD. Oxygen not only reduced breathlessness, but also increased the distance that the patients could walk. In another study conducted in patients with advanced cancer, improvements in dyspnea with oxygen were quantitatively greater than with air in both the hypoxic and nonhypoxic patients (134). Unfortunately, the effect of chronic oxygen therapy on chronic activity-related dyspnea and quality of life have not be systematically studied (135). In many jurisdictions, reimbursement for oxygen therapy requires that certain physiological criteria are met. In other places, supplemental oxygen costs will be reimbursed for people who meet certain prognositc criteria. Some terminally ill patients report a marked improvement in both their breathlessness and quality of life with supplemental oxygen and, therefore, most palliative care physicians would suggest a therapeutic trial. VI. Withdrawal of Life Support Withdrawal or withholding life support in critically ill patients is a common and accepted practice. In a study of two university-affiliated intensive care units (ICU), 90% of all ICU deaths were preceded by a decision to limit treatment and in 71% life support was withdrawn (136). The decision to withdraw life-sustaining therapies is usually made after extensive discussions between the health care team and the patient (if possible) and family. Withdrawal of mechanical ventilation is viewed as more problematic than withdrawal of other interventions (137). It is recommended that the health care team discuss the procedure, strategies for assessing and ensuring comfort, and the patient’s expected length of survival with the family and patient (if possible) (137).

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There are two options for ventilator withdrawal: immediate extubation or terminal weaning where ventilation is slowly reduced prior to extubation. In both cases, ensuring patient comfort is essential. Protocols are available (138–140) and include the use of continuous infusions of opioids and at times benzodiazepines (139). Recommendations include starting a continuous hourly infusion of the same opioid at the same dose they were previously receiving. An example is if the current dose of morphine was 5 mg IV every hour as needed, start a continuous intravenous infusion of morphine at 5 mg per hour; if they were not on an opioid then start at morphine 1 mg per hour. Bolus doses of 50–100% of the hourly dose should be available on an as needed (prn) basis to maintain/ensure comfort. One protocol also recommends initiation of a midazolam or lorazepam infusion prior to ventilator withdrawal (139). If the person has problems with bronchial secretions, then scopolamine 0.6 mg can be administered. If distress ensues, then aggressive and immediate symptom control is needed. The ‘‘prn’’ opioid and/or midazolam 2–4 mg IV push every 10 min until distress is relieved is recommended (139). If symptoms are refractory to these measures then pentobarbital, methotrimeprazine, or propofol should be initiated (139).

VII. Patient Selection for End-of-Life Care In the early 1900s, the period for end-of-life care was short and well defined: people became seriously ill and because there were no effective treatments, they died a short time later. Today, because of advances in medical treatments, despite sophisticated models to predict prognosis for survival, estimates are often grossly inaccurate. Levenson et al. (141) demonstrated that even within 3 days of death of seriously ill patients with CHF, the estimated chance of living 6 months was greater than 50%. The ability to predict survival accurately is also dependent on the underlying disease. Authors of the SUPPORT study showed that there were significant differences between estimates of survival for COPD patients and estimates of survival for patients with Stage III or IV nonsmall cell carcinoma of the lung. For patients with lung cancer, the median 6-month survival estimate was as high as 20% during the last week, but generally declined to approach 0% on the day before death. Patients with COPD, however, had median 6month survival estimates of 40% or greater on 5 of the last 7 days of life (142). Today, it is recognized that different diseases are associated with different trajectories of functional decline at the end of life. Four trajectories are described which differ in the length and slope of functional decline and appear to account for most persons’ last phase of life (143). The first trajectory is when people die suddenly progressing from normal function to death

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in a brief period of time. The second trajectory has a distinct terminal phase of illness with people functioning well for a long time before the disease progresses and becomes nonresponsive to treatment. This is typical of the cancer patient where functional impairment begins as late as 5 months prior to death (144). The third trajectory of functional decline is exemplified by patients with COPD or CHF who have a gradual decrease in functional status with periodic traumatic exacerbations of their illness. Each exacerbation could cause death, but usually a person has many such episodes before they eventually do die. The prognosis for survival in this group is unpredictable and makes the identification of patients who are at the end of their lives difficult. The fourth trajectory group has a very gradual decline associated with progressive disability and death from complications of their underlying disease. This would be typical of people with dementia. It is important to differentiate among expected disease trajectories and related needs to recognize that there is not a ‘‘one-size-fits-all’’ model for end of life care (143). Claessens et al. (142) showed that despite the fact that COPD patients had more activity of daily living dependencies, worse cardiopulmonary reserve, and worse Acute Physiology Scores they survived markedly longer (23.9 mos vs. 3.3 mos, p ¼ 0.0001) than patients with lung cancer (142). The COPD patients were more likely to receive mechanical ventilation, tube feeding, and CPR than the lung cancer patients. The results would suggest that in most circumstances this was appropriate as 76% of the COPD patients who received mechanical ventilation vs. 38% of the cancer patients survived to leave the hospital. The unpredictable course of many illnesses renders the identification of a cohort of patients at the end-of-life difficult. If you limit end-of-life care until the prognosis is certain, then many people will suffer needlessly without the care they need. Due to the unpredictable nature of the end of most people’s lives, an integrated approach should provide disease-modifying and comfort-enhancing treatments simultaneously (1). When, then, should end-of-life care begin? Lynn et al. (145) have suggested that the best way to identify patients who would benefit from end-oflife services is to ask the question ‘‘Which patients are sick enough today that it would not be surprising to find they had died within the next year.’’ This question identifies people who might live many months but are sick enough to benefit from the interventions. Good end-of-life care must allow for the unpredictable timing of death.

VIII. Communication In a study of patients with COPD, AIDS, and cancer, communication was one of the skills that all groups thought physicians required for high quality

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end-of-life care (146). Patients with COPD identified education as qualitatively and quantitatively the most important. They wanted education to include information regarding diagnosis and disease process, treatment, prognosis, advanced care planning, and what dying might be like. A. Information Regarding Diagnosis, Disease Process, Treatment, and Prognosis

Knowledge is an essential tool for people living and dying with a serious chronic disease. Knowledge forms the basis of a coping strategy by decreasing uncertainty and increasing the person’s sense of control. People should be encouraged to have a family member or friend present when discussions occur. It not only provides them with emotional support but also helps ensure that they hear, understand, and remember what has been discussed. People should be encouraged to write their questions down so that the questions can be addressed on the next visit. Discussions about the end-of-life care should begin early in the course of the disease, as this will help set the stage for open discussions later. Early in the course of care, discussions may focus on the disease process, treatment options, goals of therapy, the prognosis, and patient’s values and attitudes toward medical treatment (147). Throughout the course of an illness, when discussing goals of treatment, it is helpful to establish a time limit to a trial of therapy after which the merits of continuing, changing, or stopping will be assessed. This type of discussion helps to ensure people understand what the potential benefits and limits of treatment are and allows one to more easily discontinue therapies when they are no longer providing meaningful benefit to the patient. In one study, 9.5% of terminally ill cancer patients within weeks of death denied awareness of both their terminal prognosis and foreshortened life expectancy. Depression was nearly three times greater in this group of patients, as compared to those who demonstrated partial or complete acknowledgment of their prognosis. The authors felt that the co-existence of denial and depression suggested that the depressed patients had overwhelming psychological distress and emotional turmoil. The fact that prognostic awareness was not related to hopelessness among the dying also suggested that hope and awareness of prognosis are not mutually exclusive. Today, full disclosure of diagnosis and prognosis is the standard of practice across North America and Western Europe. When discussing prognosis, it is important to provide honest information without discouraging hope. Information should be given as to what treatment options are possible and measures that are available to maximize quality of life and minimize suffering. Estimates of prognosis are often wrong and therefore it is important to convey the uncertainty associated with them. It is useful to speak in terms of hours to days, days to weeks, weeks to months, and months

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to years. This conveys information that helps patients and families plan for the future, and does not presuppose an accuracy that is not possible. B. Advanced Care Planning

Advanced care planning is an important part of communication with people as they approach the end of their lives. This involves ongoing discussion with patients, family members, and providers to establish a broad set of goals and knowledge of the patients’ wishes, so that the patients’ wishes can be followed when they become too ill to speak for themselves. Advanced planning also should involve responses to anticipated emergencies. Such planning might include discussions about not calling the ambulance if there is an anticipated death at home, or how to cope with uncontrolled symptoms. This planning can help to decrease stress, improve the response to the emergency, and helps people acknowledge the impending death. In a cross-sectional descriptive questionnaire study in two pulmonary rehabilitation programs, 80% of the patients felt that the physician should initiate discussions about mechanical ventilation (148). Most subjects wanted to actively participate in decisions about their life support and the majority preferred that the discussions about advanced directives and life support issues occur in the out-patient setting. Unfortunately, studies have shown that less than 5% of patients are able to communicate with clinicians at the time that decisions are made about withholding or withdrawing life-sustaining therapies in the ICU (5 out of 956) and the average time from the writing of a ‘‘Do-Not-Resuscitate’’ order to death was only 2 days (149). C. What Dying Might Be Like

As people approach death, they and their families also need information as to what dying might be like. Most people have seen traumatic death on television; a few have been present at a dying person’s bedside. It is important to stress that symptoms can be well controlled, that dying is not a painful process, and usually people just fall asleep. Describing the signs of approaching death also helps families and caregivers prepare and recognize its approach. It is important to mention things such as changes in breathing patterns, the possible build up of bronchial secretions, decreased level of consciousness, and discoloration and cooling of the limbs. Information about what occurs after death can also decrease some of the distress. IX. Recommendations Appendix A outlines guidelines for the management of dyspnea in palliative care patients. These guidelines were developed by a multidisciplinary team

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and based on the literature that is referenced in the text of this chapter. When using the guidelines, it is important to use clinical judgement and determine their appropriateness for a given patient. X. Summary Dyspnea is a very common, disabling, and distressing problem for many people near the end of their lives. Breathlessness needs to be recognized and managed early in the course of disease so that the individual’s quality of life can be maximized. Appendix A

DYSPNEA MANAGEMENT GUIDELINES FOR PALLIATIVE CARE PATIENTS Considerations:


Identify and treat common exacerbating medical conditions underlying dyspnea or shortness of breath, e.g., COPD, CHF, pneumonia.
Drug treatments listed are not intended to represent a comprehensive treatment. Other treatments should be considered such as fan, open window, etc.
Evaluate impact of anxiety and fear on dyspnea and treat appropriately.
Use Edmonton Symptom Assessment Scale (ESAS) and Oxygen Cost Diagram to measure outcome. Level of dyspnea

Treatment

Mild dyspnea ESAS (0–3)


Usually can sit and lie quietly
May be intermittent or persistent
Worsens with exertion
No anxiety or mild anxiety during








Ensure access to fresh air or use a fan directing cold air on the face. Start humidified oxygen prn if the patient is hypoxic (SaO2 < 92%) or if deemed helpful by the patient. (Up to 6 L/min by nasal prongs.) If the patient is not taking an opioid, initiate short-acting morphine 2.5– 5.0 mg PO q4h & 2.5 mg PO q2h prn (Continued)

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Level of dyspnea







shortness of breath Breathing not observed as labored No cyanosis

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Treatment














for breakthrough or hydromorphone 0.5–1.0 mg PO q4h & 0.5 mg PO q2h prn for breakthrough (If the SC route is needed, divide the PO dose by half.) Titrate up by 25% every 3–5 doses until dyspnea is relieved. (see titration guide.) If the patient is taking an opioid with q4h dosing, increase this dose by 25%. If the patient is taking a long-acting opioid, change back to q4h dosing and increase this dose by 25% (see conversion guide), alternatively, increase both the long-acting and breakthrough dose by 25%. Titrate short-acting opioid by 25% every 3–5 doses until dyspnea is relieved. (see titration guide.) If significant opioid side effects are present (e.g., nausea, drowsiness, and myoclonus), consider switching to another opioid (see conversion tables), and re-titrate.

Moderate dyspnea (ESAS 4–6)












Usually persistent May be new or chronic Shortness of breath worsens if walking or with exertion; settles partially with rest Pauses while talking every 30 sec Breathing mildly labored


Ensure access to fresh air or use a fan directing cold air on the face.
Start humidified oxygen prn if the patient is hypoxic (SaO2 < 92%) or if deemed helpful by the patient. (Up to 6 L/min by nasal prongs.)
If the patient is NOT taking an opioid, initiate short-acting morphine 2.5–5.0 mg PO q4h & 2.5 mg PO q1h prn or hydromorphone 0.5–1.0 mg PO q4h & 0.5 mg PO q1h prn. (If the SC route is needed, divide the PO dose (Continued)

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Level of dyspnea

Treatment



















Progressive severe dyspnea (ESAS 7–10)


Often acute on chronic
Worsening over days/weeks
Anxiety present
Often awakes




by half, and the prn dose can be as frequent as q30 min). Titrate the dose by 25% every 2–3 doses until dyspnea is relieved (see titration guide). If the patient is taking an opioid with q4h dosing, increase the dose by 25%, (this applies to SC or PO dosing) and continue with breakthrough dosing at 50% of the regular dose q1h prn (or q30 min prn if it is SC). If the patient is taking a long-acting opioid, change back to q4h dosing and increase this dose by 25%, (see conversion guide), alternatively, increase both the long-acting and breakthrough doses by 25%. Give breakthrough q1h prn. Titrate the dose by 25% every 2–3 doses until dyspnea is relieved (see titration guide). If opioids provide only a limited effect, consider adding chlorpromazine 12.5 or 25 mg q4–6h PO or methotrimeprazine 2.5–5.0 mg PO/SC q4–6h as an adjuvant. If significant opioid side effects are present (e.g., nausea, drowsiness, myoclonus), consider switching to another opioid (see conversion tables), and re-titrate.

Start humidified oxygen, up to 6 L/ min by nasal prongs or even higher flow rate with mask, as tolerated (even if not hypoxic). Consider nebulized saline 1–3 mL by mask, prn. (Continued)

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Level of dyspnea







suddenly with shortness of breath cyanosis onset of confusion Labored breathing awake and asleep Pauses while talking q 5–15 sec

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Treatment


If the patient is NOT taking an opioid, initiate short-acting opioid. Consider: Oral: Morphine 5–10 mg PO q4h & 5 mg PO q1h prn or hydromorphone 1.0– 2.0 mg PO q4h & 1.0 mg PO q1h prn or Subcutaneous: Morphine 2.5–5 mg SC q4h & 2.5 mg SC q30 min prn or hydromorphone 0.5–1.0 mg SC q4h & 0.5 mg SC q30 min prn.
Titrate dose by 25% every 1–2 doses until dyspnea is relieved (see titration guide).
If the patient is taking an opioid with q4h dosing, increase the regular and breakthrough doses by 25%. Change frequency of the breakthrough to q1h prn if PO and q30 min prn if SC.
If the patient is taking a long-acting opioid, switch back to q4h dosing and increase this dose by 25% (see conversion guide). Do not try to manage severe dyspnea with a longacting opioid. Change the breakthrough dose to half of the regular dose, either q1h prn PO or q30 min prn SC.
Titrate the dose by 25% increments every 1–2 doses until dyspnea is relieved (see titration guide).
If opioids provide a limited effect only, consider adding chlorpromazine 12.5 or 25 mg q4–6h PO or methotrimeprazine 2.5–5.0 mg PO/SC q4–6h as an adjuvant.
If unmanageable opioid-limiting side effects are present (e.g., nausea, drowsiness, myoclonus), consider (Continued)

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Level of dyspnea

Treatment

switching to another opioid (see conversion tables), and re-titrate. Acute exacerbation or very severe dyspnea


Start humidified oxygen, up to 6 L/
Sudden onset min by nasal prongs or even higher (minutes to hours) flow rate with mask, face tent if
High anxiety and tolerated (even if not hypoxic). fear If the patient is NOT taking an opioid:
Agitation with very labored
If IV access is present, stat morphine respirations 5–10 mg IV q10 min until settled.
Air hunger
If NO IV access is available, stat
Pauses while morphine 5–10 mg SC q20–30 min talking or unable until settled. to speak
Exhausted
When settled: morphine 10–20 mg
Total PO q4h and q1h prn or morphine 5– concentration on 10 mg SC or IV q4h and q30–60 min breathing prn and titrate vigilantly.
Cyanosis usually If the patient is taking an opioid and has IV access:
May be cold/ clammy
Stat opioid administration, dosed as
respiratory follows: congestion
If taking a PO opioid, give the same
acute chest pain dose IV, and repeat q10 min until
diaphoresis settled (e.g., if on 15 mg PO q4h
confusion usually, then give 15 mg IV q10 min


until settled). If taking a SC opioid, give double the SC dose IV, as often as, q10 min until settled.When settled: continue q4h dosing with breakthrough q30– 60 min prn (will likely need a higher dose than previous) and titrate vigilantly. (Continued)

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Treatment If the patient is taking an opioid and has no IV access:


Stat opioid administration, dosed as follows:
If taking a PO opioid, give the usual PO dose SC q 20–30 min until settled (e.g., if usually takes 15 mg PO q4h, then give 15 mg SC q20–30 min until settled).
If taking a SC opioid, give the usual dose (or double it) q20–30 min until settled (e.g.) if on 15 mg SC q4h usually, then give 15–30 mg SC q20– 30 min until settled).When settled: continue q4h dosing with breakthrough q30–60 min prn (will likely need a higher dose than previous) and titrate vigilantly. To treat agitation: For all patients, consider methotrimeprazine 5 mg, PO/SC q4–6h prn and titrate to a maximum of 25 mg q4–6h prn. For all patients, if significant anxiety is present, consider lorazepam 0.5–1.0 mg PO/IV/SC/SL q30 min prn for anxiety. (Carefully!) If the patient is already taking a higher dose of lorazepam or another benzodiazepine, then dose appropriately. Monitor for paradoxical agitation or excessive somnolence. For all patients with very congested breathing, consider glycopyrrolate 0.1–0.2 mg SC q4h prn or scopolamine 0.3–0.6 mg SC q2–3h prn.

Some reminders





It is usually best to use one opioid only. If the patient has been prescribed a fentanyl patch, then another opioid will be used for breakthrough. Some patients will be taking multiple opioids and care must be taken when determining the total opioid dose in the past 24 hr. If there any questions about dosage equivalencies, please contact a pharmacist.

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Titration Guide General principles: 1. 2. 3. 4.

5.

Calculate the total opioid dose taken by the patient in 24 hr (regular q4h dose  6 PLUS the total number of breakthrough doses given  breakthrough dose). Divide this 24-hr total by 6 for the equivalent q4h dose. Divide the newly calculated q4h dose by 2 for the breakthrough dose. Use clinical judgement regarding symptom control as to whether to round up or down the obtained result (both breakthrough and regular dosing). Remember to consider available doses (in the case of PO medications especially). If the patient is very symptomatic, a review of how many breakthrough doses have been given in the past few hours might be more representative of his/her needs.

Example: A patient is ordered morphine 20 mg q4h PO and 10 mg PO q2h prn, and has taken three breakthrough doses in the past 24 hr. 1.

Add up the amount of morphine taken in the past 24 hr:

6  20 mg of regular dosing, plus 3  10 mg prn doses equals a total of 150 mg morphine in 24 hr 2.

Divide this total by 6 to obtain the new q4h dose:

150 divided by 6 ¼ 25 mg q4h 3.

Divide the newly calculated q4h dose by 2 to obtain the new breakthrough dose:

25 mg divided by 2 ¼ 12.5 mg q1–2h prn 4.

If this dose provided reasonable symptom control, then order 25 mg PO q4h, with 12.5 mg PO q1–2h prn. (It would also be reasonable to order 10 or 15 mg PO q2h for breakthrough.)

Conversion Guide (To convert from long-acting preparations to short-acting preparations) General principles in converting from long- to short-acting preparations (for the same drug). 1. 2. 3. 4. 5.

Add up the total amount of opioid used in the past 24 hr, including breakthrough dosing. Divide this total by 6 to obtain equivalent q4h dosing. Divide the q4h dose by 2 to obtain breakthrough dosing. Use clinical judgement to adjust this dose up or down depending on symptom control. Consider available tablet sizes when calculating doses.

Example: A patient is ordered a long-acting morphine preparation at a dose of 60 mg PO q12h, with 20 mg PO q4h for breakthrough, and has taken four breakthrough doses in 24 hr.

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Add up the amount of opioid taken in 24 hr: 2  60 mg of long-acting morphine plus 4  20 mg of breakthrough is 200 mg of morphine in 24 hr

2.

Divide this total by 6 to obtain the equivalent q4h dosing: 200 divided by 6 is approximately 33 mg PO q4h

3.

Divide this q4h dose by 2 for the breakthrough dose 33 mg divided by 2 is 16.5 mg

4.

If the patient had reasonable symptom control with the previous regimen, then a reasonable order would be: 30 mg PO q4h and 15 mg q1–2h PO prn

EQUIANALGESIC CONVERSIONS DRUG Morphine Codeine Oxycodone Hydromorphone

SC

PO

Ratio

10 mg 120 mg N/A 2 mg

20 mg 200 mg 10–15 mg 4 mg

2:1 ¼ PO:SC 12:1 (codeine:morphine) 1:2 (oxycodone:morphine) 1:5 (hydromorphone:morphine)

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Index

6MWD, 332, 336 6-min walking test (6MWT), 168^170, 177, 178, 289

ACCP=AACVPR guidelines, 338 Acidosis, 34, 42, 48, 61, 88, 101, 104, 222, 230, 238, 239, 248, 432 Acupuncture, 381, 437 Acute distraction, 377, 378 Aerobic metabolism, 132 A¡erent signal, 94 African-Americans, 124, 212, 216, 220, 221, 223 Age (e¡ect of ) diastolic dysfunction, 243 dyspnea, 12, 19, 20, 67, 78 obesity, 220 teaching of symptom recognition, 385 ventilatory response, 23 Aggressive therapy, 222

Air hunger, 42, 127, 128, 131^134, 137, 140, 367, 431, 450 Air£ow limitation, 43, 148, 222, 294, 304, 347 Air£ow obstruction, 61, 62, 64^67, 69, 70, 74, 78, 124, 130, 131, 133, 134, 139, 174, 220, 221 Airway factors, 30 Airway hyperresponsiveness, 61, 63, 67, 68, 71, 76, 78 Airway in£ammation, 68, 70, 133, 134, 218, 376 Airway narrowing, 59, 63, 71 Airway occlusion, 66 Airway smooth muscle (ASM), 71 Albuterol, 155, 158, 169, 170, 187, 245, 287, 294 Alinear slope, 9 Alveolar units, 30, 88 Alveolar ^ arterial oxygen gradient, 88 Ambulation, 216, 370

463

464 Amyotrophic lateral sclerosis (ALS), 430 Anabolic steroids, 308, 434 Anaerobic threshold, 88, 103, 207, 209, 230, 243 Anemia, 212, 215, 221, 222, 238 Anxiety scores, 69 Anxiolytics, 373, 440 Aortic occlusion, 94 Arterial blood gas measurement, 9, 216, 221, 226 Arterial oxygen levels, 93 Arterial oxygen tension, 22, 361 Asbestos-related pleural disease, 100 Aspirin therapy, 243 Asthma characteristic, 133 fatal, 134 Life threatening (LTA), 65 management, 384 mild-to-moderate, 62, 64 mortality rate, 68 occult, 217, 239 perception of respiratory sensations (in), 67 physiological aberrations (of ), 60 symptoms, 61, 137 treatment of exercise induced, 244 Atrophy, 266, 455

Bacon, Sir Francis, 14 Baseline Dyspnea Index (BDI), 39, 105, 153, 161, 185, 193, 284, 305 Baseline walking distance, 358 Behavior therapy, 242 Benzodiazepines, 357 Beta-agonists, 68, 283, 294 Biofeedback, 379 Blood letting, 2 Blood pressure, 207, 215, 225 Body fat, 242 Body mass index, 103, 271 Borg scale, 12, 13, 23, 46, 60, 63, 70, 90, 98, 187, 248, 287, 289, 305, 308, 312, 382, 404

Index Borg score, 64, 69, 271, 307, 323, 336, 337, 354, 406 Brantigan s hypothesis, 399 Breath-by-breath technique, 225 Breathing circuit, 43, 97, 128, 137 Breathing discomfort, 29, 36, 40, 46, 47, 49, 115^117, 119, 122, 124, 125, 127^129, 131^133, 135^140, 147, 209 Breathing frequency, 33, 90, 228, 332, 350, 353 Breathing pattern, 34, 45, 46, 61, 62, 65, 74, 76, 78, 88, 90, 95, 97, 101, 231, 237, 326, 331, 357, 375, 379, 380, 437, 445 Breathing strategies, 226, 303, 308, 370, 371 Breathlessness, cough, and sputum, scale (BCSS), 186^188 Breathlessness improved, 187, 274, 307, instruments to quantify, 148 neuropathways (responsible for), 431 palliative treatment, 439 ratings, 24, 25, 137, 169, 176, 351, relief, 283 rest (at), 20 variance, 271 Bronchial mucosal edema, 104 Bronchoconstriction, 8, 46, 60^66, 68^70, 72^76, 78, 124, 128, 129, 132^134, 136, 353 Bronchodilator therapy, 38, 48, 139, 170, 177, 179, 284, 294, 321, 338 Bronchodilator trials, 199, 200 Bronchoprovocation testing, 61, 64, 69, 72, 75, 76, 211, 212, 217^219, 223, 246, 248, 249

Cachexia, 433, 434 Campbell diagram, 72 Cardiac dysfunction, 238, 243 Cardiac pump, 40 Cardiac output (CO), 10, 132, 193, 231, 234, 238, 358

Index Cardiopulmonary exercise testing (CPET), 169, 170, 172^175, 177^179, 208, 212, 217, 224^226, 229^231, 233, 238^240, 242, 243, 245, 246, 248, 249, 251 Caregiver, 286, 287 Case record, 186 Caucasians, 216, 220, 223 Cervical spinal cord injury, 76, 128, 134 Chemical load, 98 Chemoreceptors, 40, 127 Chest pain, 115, 136, 242, 450 Chest radiograph, 208, 211, 212, 215, 216, 223, 224, 245, 246, 248, 249, 436 Chest tightness, 69, 70, 125, 128, 130, 132^134, 139, 217 Chest wall mechanoreceptors, 45, 76, 97 Chronic kidney disease (CKD), 207, 222 Chronic pulmonary obstructive disease (COPD) air £ow limitation (in), 148 assessment of (integrative), 267 atypical pattern of improvement & decline, 198 chronic, 302 clinical trials for drug development, 187 decline in health, 271 exercise intolerance, 307 exercise mode: eliciting symptoms limiting exercise (in), 175 frequency of exacerbations, 266 genesis of dyspnea, 325 IMT (in), 327 increase in arterial CO2, 35 mechanical ventilation (a relief ), 134 nutritional depletion, 303 qualities of dyspnea, 123, 135 questionnaires, 269 release of in£ammatory mediators (in), 244 respiratory impedance, 323 responses to exercise, 37, 49 rest (at), 30^32

465 [Chronic pulmonary obstructive disease (COPD)] severity, 277, 287 symptom, 184, 269, 322, 332 Clinical development program, 185, 186 Clinical trials, 148, 149, 153, 158, 159, 161, 178, 184, 187, 188, 190, 193, 197^199, 268, 269, 283, 284, 287, 302, 346, 403, 440 Cluster analysis, 119, 122, 125 Comorbidity, 302 Congestive heart failure (CHF), 87, 103^106, 129, 135, 136, 207, 214, 215, 219, 238, 243, 324, 383, 430, 433, 435, 442, 443, 446 Constant power exercise, 348, 349, 351, 359 Constant work exercise (method to evaluate hyperin£ation), 226 Continuous method (measuring dyspnea), 176, 177 Corollary discharge, 45,75,101,102,130 Coronary angiography, 243 Coronary calci¢cation, 219 Corticosteroids, 44, 68, 177, 269, 271, 283, 292, 294 Cost ^ utility analyses, 269 CR-10 scale, 156, 171^173, 175^177, 179 Cross-over study, 289, 291, 354 CTscanning, 224 Cycle ergometry, 23, 24, 170, 177, 249, 251, 289, 401, 408, 409

De Humani Corporis Fabrica Libri Septem, 3 De Luzzi, Mondino (1275^1326), 3 Dead-space loading, 47 Deadspace, 88, 89, 96^98, 103 Death, 3, 269, 429, 434 approaching, 445 index (objective social security), 403 trajectories, 442 Dementia, 430 Demographic characteristics, 211, 216

466 Depression, 2, 44, 66, 137, 138, 156, 223, 266, 269, 303, 367, 381, 430, 433, 439, 444 Detect bene¢ts, 277 Diagnostic algorithm, 210 Diagnostic distinctions, 119 Diagnostic tool, 119, 139 Dietary supplements, 303 Di¡usion capacity for carbon monoxide (DLCO), 39, 220, 402, 416, 417 Discrete method (measuring dyspnea), 175^177, 179 Disease awareness, 444 Disease-speci¢c instrument, 270 Diurnal peak £ow, 67, 68 Domiciliary oxygen therapy, 345 Dose ^ response curves, 71 Dying process, 429 Dynamic hyperin£ation (DH), 43, 45, 49, 72, 75, 76, 103, 106, 135, 136, 226, 239, 284, 308, 318, 332, 350, 351, 370, 375, 400 Dyspnea ^ time slope, 287 Dyspnea a¡ective feelings (associated with), 367 alleviation, 48, gender (and), 20, 23, 63, 210 anxiety (and), 68, 136, 223, 367, 373, 379, 433 assessment, 192, 209, 353, ATS symptom scoring, 198 cancer patients (in), 430 causal clinical conditions, 210 cognitive ^ behavioral perspective (management of ), 368, 376 de¢nition by American Thoracic Society (ATS), 36, 147 during exercise, 13, 23, 29, 38, 41, 47, 49, 62, 226, 369, 404 measurement, 171, 177 educational interventions, 385 e¡ect of exertion (on), 20, 88 energy conservation: relationship, 303, 309, 372

Index [Dyspnea] evaluation, 305 exertional, 95, 178, 222, 242, 249, 284, 301, 307, 312, 432 frequency, 148 health status: interrelationship, 19 hypoxia (important determinat of ), 93 in ILD (cause of ), 96 intensity, 38, 62, 65^67, 75, 98, 128, 138, 168, 170, 285, 290 at rest, 379 language of, 133, 134, 137, 138 MRC dyspnea grade, 272 pathogenesis (of ), 42 pathophysiologic mechanisms, 305 perception score, 64 prevalence, 20, 23, 210, 430 qualitative analysis, 91 quality aspects (of ), 116, 133 quality of life, 19, 430 quantify, 150, 151, 161, 168 questionnarie, 116, 120, 140, 305 ratings, 29, 35, 73, 153, 155, 169, 174, 178, 286, 291, 307, 398, at rest, 347 relief, 29, 38, 47, 49, 93, 100, 129, 156, 168, 192, 316, 359, 440 cold air (role of ), 374, 436 IMT, 322, 331, 339, 347 music, 380 oxygen, 350, 355 posture, 376 role of pulmonary receptors, 128 scores, 149^151, 155, 157, 160, 168, 178, 323, 332, 337, 347, 351, 354, 358 self-management, 366, 377 sensations perceived as, 132 severity, 39, 149, 153, 193, 213, 302 sexual activity (during), 373 subjects with ILD, 357 symptom of asthma, 59 temporal pattern, 197 unexplained, 211, 216, 240, 249 vocabulary (of ), 117

Index E¡erent motor command, 45 E¡erent ^ rea¡erent disassociation, 131, 134 E¡ort ^ displacement ratio, 36, 287 Elastic loading, 73, 75, 89, 92, 96, 107 Electrocardiogram, 169, 208, 211, 218, 219, 225, 243, 245 Electron beam computed tomography (EBCT), 208, 219 Emotional responses to symptoms, 368 Emphysema, 30, 39, 155, 195, 301, 398, 402, 406, 412, 416^418, 432, 436 End-expiratory lung volume (EELV), 30, 32, 35, 36, 38, 48, 71, 72, 76, 78, 90, 103, 106, 119, 131, 132, 208, 237, 238, 246, 251, 285, 286, 398 End-inspiratory lung volume (EILV), 33, 76, 208, 232, 287 End-of-life care, 429, 444 Endurance test, 170, 177 EQ-5D utility scale, 269 Esophageal pressure swings, 46, 47, 72, 102 European agency for the evaluation of medicinal products (EMEA), 184, 186 Exacerbation(s), 158, 200, 271, 275, 346, 376, 443 acute, 193, 269, 450 asthma, 61, 69, clinical parameter, 148 importance in COPD, 266 life-threatening, 80 severe, 59, 65, 78, treatment, 383 Exercise capacity, 93, 95, 97, 100, 137, 141, 169, 170, 175, 177, 229, 230, 244, 249, 251, 271, 277, 284, 303, 308, 332, 337, 346, 347, 349, 350, 358, 359, 397, 400, 409, 416, 417, 433 endurance, 26, 39, 106, 170, 287, 289, 290, 349, 351, 380 response, 34, 41, 91, 168, 212, 224, 233, 244

467 [Exercise] testing, 95, 100, 101, 105, 150, 167^169, 171, 173, 174, 208, 212, 224, 225, 229, 231, 233, 267, 284, 287, 290, 296, 305, 308, 309, 313, 335, 347, 354, 359, 398, 402, 403, 407, 436 Expiration, 8, 10, 30, 60,71,72, 106, 285, 322, 375, 380 Expiratory £ow limitation (EFL), 30, 32, 39, 72, 90, 94, 103, 104, 237^239, 284, 323 Expiratory £ow rate, 10, 398 Expiratory reserve volume (ERV), 91, 101, 103, 104 Expiratory time, 30, 41, 95, 374, 375, 380

FDA, 184 Fessler and Permutt’s mathematical model, 399 Flow ^ volume loops, 72, 89, 104, 106, 216, 221, 226, 231, 238, 246, 251, 285 Fluticasone, 159, 198, 273, 292, 294 Focal score, 158, 160, 185, 190, 191, 198^200, 333, 334 Forced expiratory volume in one second (FEV1), 20, 61, 71, 75, 124, 133, 155, 198, 220, 347 (and) mortality prediction, 417 clinical importance, 10, 64, decline and health of COPD patients, 271 improvements, 399 measure of lung function, 184 primary outcome measure, 148, 283 quantify MPO, 13

Gas exchange, 8, 46, 107, 216, 238^240, 374, 399 analysis, 225 derangement, 127 (in) asthma, 133 (in) COPD, 30, 35, 39

468 [Gas exchange] (in) ILD, 88 (to) measure respiratory insu⁄ciency, 9 Gastroesophageal re£ux disease (GERD), 214, 240 Goal-setting, 277 Gold standard exponential regression methodology, 63

Health status, 158, 187, 192, 200, 274, 302, 317, 356, 359 component of questionnaire, 153, 270 measurement, 267 part of clinical development program, 184 poor, 283 scores, 271, 273, 277 treatment measure, 148 Health-related quality of life, 158, 267 Heart failure, 116, 132, 322, 323, 341, 357, 358, 367, 434 High frequency fatigue, 10 Hippocratic school, 2 Humoral theory, 2 Hypercapnia, 5, 6, 23, 35, 39, 42, 49, 61, 95, 101, 119, 127, 128, 131, 135, 137 Hyperventilation, 30, 136, 208, 233, 237, 242, 248, 249, 251, 334 Hypnosis, 380 Hypothyroidism, 222 Hypoventilation syndrome, 127 Hypoxemia, 34, 35, 39, 40, 61, 135, 238, 239, 248, 309, 323, 345, 346, 349, 354, 355, 357, 373, 398, 432

Index Inspiratory £ow, 10, 23, 65, 71, 75, 95, 134, 221, 251, 326, 330, 351, 353, 400 Inspiratory load, 46, 66, 322, 353 Inspiratory muscle braking, 72 Inspiratory muscle function, 100, 322, 323, 326, 330, 331, 353, 399 Inspiratory muscle tension ^ time index, 332 Inspiratory reserve volume (IRV), 35^39, 41^43, 47^49, 71, 89, 101, 103, 284 Instrument to measure dyspnea, 186, Instrument validation, 186 Interstitial edema, 94, 135 Interstitial lung disease (ILD), 130, 215, 357 characteristic features, 88, 96 £ow limitation, 90 increased e¡ort for breathing, 131, 135 inspiratory muscle function, 100 mechanism for dyspnea in ILD, 94, 95 physiologic deadspace, 97 tidal volume response, 92 Intubation, 129, 438 Inward recoil pressure, 71 Ipratropium bromide,169,170,178,199, 289, 290 Ischemia, 237, 238, 242, 243 Iso-watt exertion, 400

Juxta-pulmonary receptors, 94

Kyphoscoliosis, 130 Kyphosis, 44 Idiopathic pulmonary ¢brosis, 149, 159, 239 Ill health, 266 IMT protocol, 333 Inspiratory capacity (IC), 32, 43, 47, 71, 89, 127, 131, 132, 135, 239, 240, 251, 286, 350, 380 Inspiratory duty cycle, 95

Language of pain, 117 Lean body mass, 303 Leg discomfort, 105, 106, 174, 175 Leg fatigue, 94, 105, 139, 174, 239, 244, 251, 265, 406 Length ^ tension curve, 100

Index Life support: physical principles, 4 Likert scale, 153, 269 Linguistic validation, 188 Lipolysis, 242 Load control, 322, 326 Long-acting anticholinergics, 290 Lung elastic recoil pressure, 399 Lung function decline, 129, 133, e⁄cacy of medical therapy (evaluate), 148 episodic changes (in), 59 gradual deterioration, 20, 219 improved, 275 phases, 20 recovery (of ), 266 Lung volume reduction surgery (LVRS), 38, 155, 177, 200, 301, 306

Magnitude of dyspnea, 12, 91 Magnitude scale, 173 Magnitude scaling, 12, 22 Mast cell degranulation, 62 Maximal expiratory pressure (MEP), 220, 221 Maximal inspiratory pressure (MIP), 220, 221 Maximum breathing capacity (MBC), 9, 10 Mechanical vibration of chest wall, 374 Medical Outcomes Study Short-Form 36-Item (SF-36), 268, 407 Medical=patient history (importance in diagnoses), 139, 160, 209, 211, 212, 214, 215 Menstrual cycle, 220 Meta-analysis, 308, 313, 321, 322, 326, 338, 385 Metabolic cost, 34, 46 Metabolic load, 107, 302, 305, 307, 309, 353, 369 Microatelectasis 101, 102 Minimal clinically important di¡erence (MCID), 151, 156^159

469 Mitochondrial myopathy, 224 Morbidity, 19, 44, 59, 65, 66, 217, 219, 303, 304 Mortality, 59, 65, 66, 68, 219, 271, 398, 402, 403, 416, 417, 438 MRC scale, 152, 155, 159 Muscle activation, 40, 42, 46, 49 Muscle dysfunction, 230, 239, 251, 304, 323, 338, 434 Muscle fatigue, 7, 10, 35, 41, 46, 101, 225, 251, 304, 338, 358 Muscle paralysis, 42 Muscle wasting, 244, 302, 308 Muscle weakness, 8, 10, 35, 44, 45, 72, 78, 96, 101, 104, 105, 107, 131, 215, 265, 323, 338, 339, 433^ 435 Muscular paralysis, 127 Myocardial function, 265

National EmphysemaTreatment Trial (NETT), 398, 403, 408, 417 Neuromechanical coupling, 39, 44, 47, 92, 98, 100, 286, 400 Neuromechanical dissociation (NMD), 38, 75, 78, 97, 98, 101, 102, 131 Neuromuscular disease, 87, 101, 102, 131, 220, 221, 321, 435 Neuromuscular weakness, 46, 101, 131, 220, 221, 223 Noninvasive ventilation, 438 Normocapnia, 131, 326 Normoxic condition, 127, 128 Nutritional depletion, 266, 302, 303 Nutritional therapy, 302

Obesity, 19, 44, 87, 102, 103, 210, 214, 220, 237, 240, 242, 245 Open median sternotomy, 402 Opioid drugs, 439 Optimization theory, 47 Osler, Sir William 60 Outcome assessment, 304, 398 Outcome measure, 148, 169, 177, 184, 283, 346, 356, 398, 412

470 Oxygen cost diagram, 155, 446 Oxygen delivery systems, 346 Oxygen desaturation, 40, 88, 92, 105, 106, 221, 308, 346, 347, 375 Oxygen pulse, 402 Oxygen saturation, 6, 40, 93, 94, 322, 347, 439, 441 Oxygen therapy, 39, 48, 93, 94, 156, 221, 345^348, 357, 359, 373, 441 Oxygen uptake (VO2), 32^34, 38, 39, 91, 225, 229

P ^ Vcurve, 32 Pain syndromes, 117, 119 ‘‘Paintal receptors’’, 8 Panic disorder, 137 Panting frequency, 72 Pathophysiologic derangements, 136 Patient interviewing, 116 Patient questioning (quantifying symptoms), 267 Patient scales, 191 Patient selection, 302, 337, 358, 402, 412, 418, 442 Patient symptoms, 148, 200, 213, 219, 243 Patients’ physical limitation, 139 Patient s self-management skills, 303 Pattern of breathing, 326, 370, 371, 375 Peak oxygen uptake, 88, 357 Peripheral muscle function, 105, 353, 402 Pharmacologic therapy, 303 Physical examination, 139, 209, 211^213, 215, 216, 246, 248, 249, 435 Physical exercise, 265 Physical ¢tness, 132 Physiological dead space, 34, 35, 39, 105, 432 Physiotherapy, 371 Placebo therapy, 159, 170, 178, 292 Placebo-controlled study, 287, 289, 291, 440 Plethysmography, 220, 286 Pleural e¡usions, 99, 100

Index Product label, 185 Prophylaxis, 224 Psychiatric disorders, 217 Psychogenic disorders, 210, 231, 237, 242, 249 Psychological stress, 136 Psychophysics, 11, 12, 22, 24, 29, 149, 167, 168 Pulmonary embolism, 116, 128, 129 Pulmonary function testing, 103, 212, 219, 220, 245, 417 Pulmonary gas exchange, 216, 221, 226, 231, 233, 238 Pulmonary hypertension, 44, 193, 220, 243, 244, 265 Pulmonary perfusion, 238 Pulmonary rehabilitation, 26, 138, 156, 159, 161, 177, 200, 244, 269, 270, 296, 337, 354, 356, 357, 378, 382, 384, 386, 403, 409, 445 Pulse oximetry, 211, 212, 215, 216, 225, 246, 248, 249 Pursed-lips breathing (PLB), 370, 374, 386, 436 Putative stimulus, 175

Quadriplegia, 42, 72, 76, 78 Quality of life e¡ective measurement (of ), 225 health-related, 267, 268, 275, 301^305 improvement, 244, 316, 317, 375, 379, 382, 385, 408, 416, 438, 440 questionnaires, 190, 332, 406, 412 scores, 217 Quality of Well-being scale (QWB), 269, 407 Questionnaire(s), American, 125 assessing COPD. See under COPD health status, 270 multidimensional, 284 pain, 117, 119 scores, 275 self-administered, 153, 188 study, 123, 135, 445

Index [Questionnaire(s)] UCSD shortness of breath, 156 usefulness, 150 (with) multinational use, 188, 189

Rank order correlation, 274 Red blood cell transit times, 89 Reduced peak ventilation, 39 Reference set, 233 Regression analysis, 29, 38, 63, 73, 75, 76, 95, 98 Regression equation, 23 Relaxation therapy, 309 Resistive breathing, 326 Resistive loads, 22, 62, 65, 128, 137, 326 Resource utilization, 245, 301, 305, 375, 383, 385 Respiratory cycle, 326 Respiratory discomfort, 35, 41, 43, 44, 49, 101, 103, 116, 119, 127, 374 Respiratory failure, 8, 54, 134, 257, 270, 280, 342, 350, 434, 439, 457, 460, 461 Respiratory load, 22, 24 Respiratory malignancies, 357 Respiratory muscle strength, 20, 22, 23, 105, 219, 376, 434 Rest (role of ), 10, 12, 23, 31, 47, 93, 103, 177, 187, 209, 216, 226, 237, 246, 284, 291, 323, 331, 372, 400, Resting hypoxemia, 345, 346, 349, 357 Reversible air£ow obstruction, 70 Rhinolaryngoscopy, 223 Risk ^ bene¢t ratio, 397 Robert Boyle, 4

Salmeterol, 159, 169, 178, 185, 193 evaluation/drug e¡ect, 198, 199, 273, 287, 292 Sarcoidosis, 96, 220, 223 Sarcomere injury, 322 Shuttle walk test, 336, 354, Sickness impact pro¢le, 407 Sleep disturbance, 266, 304 Smoking (role of ), 20, 210, 346, 377

471 Speech therapy, 246 Spirometric test results, 192 Spirometry, 211, 212, 215, 216, 219^221, 225, 246, 412, 417 Starvation, 242 Statistical analysis plan, 186, 189 Steady-state cycle exercise, 289 Stevens’ law, 22, 63 Su¡ocating, 116, 136 Supplemental oxygen, 40, 93, 128, 177, 216, 308, 309, 345^347, 349, 354, 356^359, 373, 441 Surgical therapy, 301 Symptom diaries, 61, 284 Symptom diaries, 383 Systolic dysfunction, 243

Tachypnea, 33, 95, 136, 435 Tai Chi, 371 Tensilon test, 434 Tension generation, 323 Terminal weaning, 442 Theophylline therapy, 292 Theophylline, 68, 169, 200, 291, 292 Therapeutic nihilism, 284 Thoracentesis, 99, 100 Threshold training, 330 Thrombolytic agent, 129 Tidal volume, 38, 71, 97, 127 (and) minute ventilation, 231, 400 expansion, 47, 101, 284 (in) shallow breathing, 135 increase, 30, 374, 379, 436 operating limit, 32 (role in) elevation in deadspace, 88 standard, 40 use in measuring MBC, 10 Tiotropium, 158, 159, 185, 187, 188, 193, 198^200, 274, 275, 290, 291 Tissandier, Gaston, 5 Total lung capacity (TLC), 21, 32, 71, 89, 100, 131, 135, 350, 399 Tracheal banding, 322 Transition Dyspnea Index. (TDI), 153, 161, 271, 305, 331, 333, 403 Treatment e⁄cacy, 149

472 Ventilation, (e¡ect of ) supplemental oxygen, 93 feedback, 380 increase, 6, 23, 33, 40, 90, 96, 103, 117, 127, 284 causal factors, 136 ine¡ecient, 238, 240, 249 magnitude, 11 maximum voluntary (MVV), 220, 231, 326 mechanical, 128, 134, 441, 445 minute (VE), 168, 225, 231, 326, 349, 358, 400 peak, 88, 104, 286 reduced, 42, 350 tidal, 323 Ventilatory demand, 23, 26, 30^32, 34, 35, 38, 39, 95, 103, 231, 305, 307^309, 368, 369, 372, 432 Ventilatory index, 9, 10

Index Ventilatory loads, 323 Ventilatory mechanics during exercise, 89 Verbal descriptors, 125, 171, 173 Ventilation ^ perfusion ratios, 35, 88, 211, 215, 238, Visual analog scale (VAS), 60, 172, 173, 175, 176, 186, 305, 309, 350, 372, 382, 385 Vocal cord dysfunction (VCD), 210, 211, 222, 223

Walking pace, 169 Weber fraction, 62 Weight gain, 26, 249 Withdrawal of therapy, 200

Yoga, 371, 375