Clinical Exercise Testing, Idelle M. Weisman,R. Jorge Zeballos, vol 32

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Clinical Exercise Testing

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Progress in Respiratory Research Vol. 32 Series Editor Chris T. Bolliger, Cape Town ABC Basel W Freiburg W Paris W London W New York W New Delhi W Bangkok W Singapore W Tokyo W Sydney

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Clinical Exercise Testing Volume Editors Idelle M. Weisman, El Paso, Tex. R. Jorge Zeballos, El Paso, Tex. 83 figures, 10 in color, and 97 tables, 2002 ABC Basel W Freiburg W Paris W London W New York W New Delhi W Bangkok W Singapore W Tokyo W Sydney

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Idelle M. Weisman, MD Human Performance Laboratory Department of Clinical Investigation Pulmonary-Critical Care Service William Beaumont Army Medical Center El Paso, Tex. and Department of Medicine Pulmonary-Critical Care Division University of Texas Health Science Center at San Antonio San Antonio, Tex., USA R. Jorge Zeballos, MD, DMSc Department of Anesthesia Texas Tech Regional Health Science Center and Human Performance Laboratory Department of Clinical Investigation William Beaumont Army Medical Center El Paso, Tex., USA Library of Congress Cataloging-in-Publication Data Clinical exercise testing / volume editors, Idelle M. Weisman, R. Jorge Zeballos. 2002016243 p. ; cm. – (Progress in respiratory research, ISSN 1422-2140 ; v. 32) Includes bibliographical references and index. ISBN 3805572980 (hardcover : alk. paper) 1. Exercise tests. 2. Lungs – Diseases – Diagnosis. 3. Cardiopulmonary system – Diseases – Diagnosis. I. Weisman, Idelle M. II. Zeballos, R. Jorge. III. Series. [DNLM: 1. Exercise Test. WG 141.5.F9 C641 2002] RC734.E87.C554 2002 616.1)075–dc21 Bibliographic Indices. This publication is listed in bibliographic All rights reserved. No part of this publication may be translated services, including Current Contents® and Index Medicus. into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, Drug Dosage. The authors and the publisher have exerted every microcopying, or by any information storage and retrieval system, effort to ensure that drug selection and dosage set forth in this text are without permission in writing from the publisher. in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in govern- © Copyright 2002 by S. Karger AG, ment regulations, and the constant flow of information relating to drug P.O. Box, CH–4009 Basel (Switzerland) therapy and drug reactions, the reader is urged to check the package www.karger.com insert for each drug for any change in indications and dosage and for Printed in Switzerland on acid-free paper by added warnings and precautions. This is particularly important when Reinhardt Druck, Basel the recommended agent is a new and/or infrequently employed drug. ISBN 3–8055–7298–0, ISSN 1422–2140

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Contents VII Foreword IX Preface 1 Cardiovascular and Respiratory System Responses and Limitations to Exercise Rodman, J.R.; Haverkamp, H.C.; Gordon, S.M.; Dempsey, J.A. 18 Muscular Alterations in Chronic Obstructive Pulmonary Disease and Chronic Heart Failure at Rest and during Exercise Gosker, H.R.; Uszko-Lencer, N.H.M.K.; Wouters, E.F.M.; van der Vusse, G.J.; Schols, A.M.W.J. 30 Modalities of Clinical Exercise Testing Zeballos, R.J.; Weisman, I.M. 43 Methods for Cardiopulmonary Exercise Testing Beck, K.C.; Weisman, I.M. 60 Deconditioning, and Principles of Training Troosters, T.; Gosselink, R.; Decramer, M. 72 Mechanisms and Measurement of Exertional Dyspnea Mahler, D.A.; Fierro-Carrion, G.; Baird, J.C. 81 Cardiopulmonary Exercise Testing in Unexplained Dyspnea Gay, S.E.; Weisman, I.M.; Flaherty, K.R.; Martinez, F.J. 89 Respiratory System Responses to Exercise in Aging Johnson, B.D. 99 Evolving Role of Cardiopulmonary Exercise Testing in Heart Failure and Cardiac Transplantation Agostoni, P.; Guazzi, M. 109 Noninvasive Exercise Testing Modalities for Ischemia Strelich, K.; Bach, D.S. 120 Role of Cardiac Rehabilitation in Heart Failure and Cardiac Transplantation Braith, R.W.; Edwards, D.G. 138 Exercise Limitation and Clinical Exercise Testing in Chronic Obstructive Pulmonary Disease O’Donnell, D.E. 159 The Importance of Exercise Training in Pulmonary Rehabilitation Celli, B.R.

173 Functional Evaluation in Lung Volume Reduction Surgery Sciurba, F.C.; Patel, S.A. 186 Cardiorespiratory Responses during Exercise in Interstitial Lung Disease Krishnan, B.S.; Marciniuk, D.D. 200 Role of Cardiopulmonary Exercise Testing in Patients with Pulmonary Vascular Disease Systrom, D.M.; Cockrill, B.A.; Hales, C.A. 205 Asthma and Exercise Tan, R.A.; Spector, S.L. 217 Evaluation of Impairment and Disability: The Role of Cardiopulmonary Exercise Testing Sue, D.Y. 231 Role of Cardiopulmonary Exercise Testing in the Preoperative Evaluation for Lung Resection Diacon, A.H.; Bolliger, C.T. 242 The Role of Cardiopulmonary Exercise Testing for Patients with Suspected Metabolic Myopathies and Other Neuromuscular Disorders Flaherty, K.R.; Weisman, I.M.; Zeballos, R.J.; Martinez, F.J. 254 Role of Cardiopulmonary Exercise Testing in Lung and Heart-Lung Transplantation Williams, T.J.; Slater, W.R. 264 Exercise Responses in Systemic Conditions Obesity, Diabetes,Thyroid Disorders, and Chronic Fatigue Syndrome Sietsema, K.E. 273 Clinical Exercise Testing during Pregnancy and the Postpartum Period O’Toole, M.L.; Artal, R. 282 Clinical Exercise Testing in Children Fahey, J.; Nemet, D.; Cooper, D.M. 300 An Integrative Approach to the Interpretation of Cardiopulmonary Exercise Testing Weisman, I.M.; Zeballos, R.J. 323 Author Index 324 Subject Index VI Contents

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Foreword Clinical exercise testing has been an area of personal Dear Reader, when you look at the final product you interest for me for many years. It could therefore only will easily see what a high-powered book you are holding have been a matter of time until I would have liked to see in your hands. In 25 well-written chapters all the relevant a volume in the book series Progress in Respiratory information about CPET is covered, from the physiologic Research dedicated to this topic. Volume 32 is the result responses to exercise, the set-up of an exercise lab, the of this desire. The most important thing in the initial methodology of clinical exercise testing, the varying pat- planning phase was, as always, to find the ideal volume terns of response to exercise in different disease states, editor(s), respected scientists in the field who can deliver and very importantly to the clinical applications, every- the goods in time. Until now we have always been lucky in thing you might want to know has been covered. As you this respect. For this 32nd volume I did not have to think read the book you will easily understand why CPET is a long time who I was going to ask. Idelle Weisman, one of becoming increasingly more important to help in clinical the outstanding experts in Cardiopulmonary Exercise decision-making in the management of patients. The Testing (CPET), came to my mind almost immediately. I book is a must for anyone interested in clinical exercise have known her for some years now and have always testing. admired her knowledge but at least as much her contin- ued enthusiasm for both research in and teaching of Again, the publisher, S. Karger AG, Basel, Switzerland, CPET. When I approached her she immediately accepted has done a great job in bringing out a very attractive book the task, but asked me to do it together with her long-time with excellent quality of print. The appealing appearance colleague, Jorge Zeballos, a further name which does not of each single volume of Progress in Respiratory Research need introduction. Their choice of chapter authors united continues to be another key factor for the ever increasing a team of recognized specialists in their respective field. success of the ‘blue’ book series. I would like to express a sincere thank you to Idelle and Jorge, to all chapter con- The set was almost a guarantee for success. From there tributors, as well as to the staff at Karger. to the finished book, however, it took a lot of staying pow- er by everyone to get everything done on time. C.T. Bolliger, Series Editor VII

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Preface Clinical Exercise Testing is increasingly being used in lenged with keeping up with the remarkable information clinical medicine, as functional assessment has become an expansion in this area and the on-going need to assess integral component of patient evaluation; this reflects in clinical relevancy. part a growing awareness of the limitations of traditional resting cardiopulmonary measurements in reliably esti- The expert contributors to this issue have provided mating functional performance and outcome. A spectrum timely, clinically oriented, and practical updates/reviews, of clinical exercise testing modalities is available; which which together represent a well-balanced perspective of test to use depends on the question(s) being asked and the clinical exercise testing for the new millennium. In that available resources. In turn, Cardiopulmonary Exercise regard, we believe that this issue will be helpful to a wide Testing (CPET) has gained increasing popularity with a audience – pulmonologists, cardiologists, pediatricians, wide spectrum of clinical application over the last 25 exercise physiologists, rehabilitation specialists, respirato- years because of the valuable information it provides in ry therapists, etc. This issue begins with a state-of-the-art patient diagnosis and management. This issue of Progress review of exercise physiology and limitation to exercise in in Respiratory Research is testimony to the expanding list normal subjects and is followed by a chapter on skeletal of clinical applications. muscle function and energy metabolism during exercise which is currently a very ‘hot’ investigational topic. Mo- We were very excited about the Progress in Respiratory dalities of clinical exercise testing provides a low-tech to Research issue on Clinical Exercise Testing, as it would provide an opportunity for presentation of a comprehen- sive interdisciplinary update by well-respected experts that would focus on clinical application and highlight recent developments/practices based on current scientific knowledge and technologic advances. For CPET this would also reinforce the importance/value of the integra- tive exercise response in clinical assessment; that is, the ability to quantitate the patient’s whole exercise response as well as contributions and interactions of individual components and thereby provide answers to questions not possible from other clinical exercise testing modalities. This issue explores the most widely used clinical exercise testing modalities with an emphasis on CPET. Further- more, these comprehensive albeit succinct and cogent updates will be particularly useful to clinical readers chal- IX

high-tech functional assessment overview which concen- including pregnant/post-partum women and children, trates on the 6-minute walk test, the shuttle test, and stair which have been included in this issue. Importantly, the climbing, and addresses when these and more high-tech chapter on exercise in children will appeal not only to tests including graded exercise testing and CPET would be pediatricians and pediatric sub-specialists, but also to appropriately used. This is followed by a chapter provid- adult pulmonologists and cardiologists who will provide ing basic and practical information related to equipment, care for the increasing number of children surviving into methodology, protocols, conduct of the test, and also adulthood. addresses important quality control issues for CPET. An article on deconditioning and training highlights the phys- The subject of the last chapter is interpretation of car- iologic response to training and relates current knowledge diopulmonary exercise testing, which uses illustrative to practical considerations for clinical application. case studies to highlight the integrative approach to car- diopulmonary exercise testing and its role in the clinical Since exertional dyspnea is a common reason for decision-making process. Finally, it should be noted that referral for exercise testing, mechanisms and measure- most of these articles were written within the last 6 ment of dyspnea are also discussed. Another chapter months of 2001 and includes ‘hot-off-the-press’ informa- addresses the patient with unexplained dyspnea after ini- tion that will remain clinically relevant for some time. tial non-diagnostic work-up and emphasizes the role of CPET used as part of a step approach in the assessment of Our vision for this issue was to demonstrate how the these challenging cases. A chapter on the aging pulmonary information obtained from cardiopulmonary exercise system and exercise provides insight and information that testing impacts and enhances the clinical decision-making is extremely relevant as increasing numbers of senior process including diagnosis, prognosis, severity, progres- citizens exercise. sion, and response to treatment in different clinical set- tings. Furthermore, we wanted to demonstrate how CPET Subsequent discussions evaluate exercise testing in dif- complements and enhances other diagnostic modalities ferent patient populations. A trio of complimentary chap- and can be an integral component in the clinical decision- ters addresses important cardiovascular topics – the role making process. Enormous progress has been made but of CPET in heart failure and transplantation discusses CPET still remains underutilized. Hopefully, the contents physiologic responses and current drug therapies, the role of this issue will stimulate more widespread use and dis- of cardiac rehabilitation in heart failure and cardiac trans- cussion so that the full potential and limitations of cardio- plantation discusses exercise prescription and monitoring pulmonary exercise testing in the clinical decision-making and to complete the picture, non-invasive exercise testing process will be realized. modalities for ischemia discusses the most current tech- nologies and clinical decision analysis for their use. A trio Acknowledgements of chapters comprehensively evaluates important COPD topics including the role of CPET in evaluating exercise We are grateful to S. Karger AG, Switzerland and to Chris Bolli- intolerance, exercise response patterns, exercise limita- ger, Editor of the Progress in Respiratory Research series, for allowing tion, exercise training, and functional evaluation in lung us the opportunity to assemble this outstanding group of articles. We volume reduction surgery. The next two chapters address believe that they will be a valuable resource and will appeal to a broad the role of CPET in Interstitial Lung Disease and in Pul- spectrum of readers interested in clinical exercise testing – from those monary Vascular Disease and a third discusses asthma who order exercise tests to answer important clinical questions to and exercise. those who perform the testing. We would also like to express our appreciation to the expert contributors for their efforts to make this This is followed by articles evaluating the use of exer- an updated ‘state-of-the-art’ book in Clinical Exercise Testing. cise testing in specific clinical settings: in the evaluation of Impairment-Disability; in the Preoperative Evaluation Special thanks are extended to Raul Hernandez, David Lopez for lung resection; in the evaluation of patients with meta- and Luz Torres at William Beaumont Army Medical Center, El Paso, bolic myopathy and other neuromuscular disorders; in Texas, for their diligence and dedication in helping me complete this the evaluation of patients with Lung and Heart-Lung project. We would like to thank the command at William Beaumont Transplantation, and in the evaluation of patients with Army Medical Center for their support in completing this project, other systemic diseases including obesity, diabetes, hyper- and all colleagues who over the years have referred patients to the thyroidism and chronic fatigue syndrome. Human Performance Laboratory so that we might contribute to the clinical decision-making process. Finally, this issue is dedicated to Previous monographs on clinical exercise testing have our families for their patience, tolerance and ongoing support. not included chapters on important population cohorts Idelle M. Weisman, R. Jorge Zeballos, Volume Editors X Preface

Weisman IM, Zeballos RJ (eds): Clinical Exercise Testing. Prog Respir Res. Basel, Karger, 2002, vol 32, pp 1–17 OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Cardiovascular and Respiratory System Responses and Limitations to Exercise Joshua R. Rodman Hans C. Haverkamp Sinéad M. Gordon Jerome A. Dempsey The John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin at Madison., Wisc., USA Summary reach maximum levels, PO2 and PCO2 in blood leaving the lung remains near resting levels and we rarely become The design and dimensions of the healthy pulmonary system consciously aware of our breathing. These near perfect are nearly perfect to meet the considerable demands on O2 responses are universal in health and even small increases transport and CO2 elimination imposed by physical exercise. In in arterial PCO2 above resting levels or sensations of dys- our chapter, we briefly describe the features of the nervous pnea during exercise should be treated with great suspi- system pathways and the structure of the airways, lung surface cion of impending or underlying pathophysiology. This area and respiratory muscles which ensure both the complete- chapter describes the essential cardiovascular and respira- ness of gas exchange at the level of alveolar gas, pulmonary tory responses to exercise in health, discusses their un- capillaries and arterial blood and the high level of mechanical derlying mechanisms and also deals briefly with circum- efficiency with which the respiratory muscle pump operates. stances where the healthy respiratory system may fail We also discuss the absence of a physical training effect on regarding its homeostatic missions, thereby presenting a pulmonary vs. systemic structures which determine O2 deliv- potential limitation to exercise performance. ery and the implications of a relatively underbuilt lung and chest wall to exercise-induced arterial hypoxemia, diaphragm fatigue Neurochemical Control of Exercise Hyperpnea and the distribution of systemic vascular conductance and blood flow. The precision with which alveolar ventilation is in- creased during exercise can be appreciated by examining Introduction the near constancy of alveolar (and arterial) carbon diox- ide pressure (PACO2 (and PaCO2)) during steady-state Muscular exercise presents multiple challenges to the exercise of mild-to-moderate intensity (fig. 1). The alveo- cardiorespiratory system’s goals of maintaining adequate lar ventilation equation states that O2 and CO2 transport to meet increased metabolic de- mands while minimizing the increase in work performed PACO2 = V˙ CO2 W K by the heart and respiratory muscles. Despite marked O2 V˙ desaturation (! 10% SvO2) and CO2 retention (PvCO2 180 mm Hg) in mixed venous blood as V˙ O2 and V˙ CO2 The fact that PaCO2 (and arterial oxygen pressure (PaO2)) is maintained near constant during exercise means that alveolar ventilation (V˙ A) increases in proportion to

Fig.1. Alveolar ventilation, arterial PCO2, arterial lactate, and arteri- The feed-forward or ‘central command’ mechanism al pH during progressive exercise to maximum in a healthy young likely underlies the fast ventilatory response at exercise adult. As exercise intensity increases, a progressive lactic acidosis onset and remains the dominant stimulus to increase occurs which causes a decrease in arterial pH despite the concomi- respiratory motor output at each level of exercise. This tant hyperventilation (fall in PaCO2). Data compiled from the feed-forward ventilatory stimulation originates from authors’ laboratory. higher locomotor centers (diencephalon, mesencephalon, and/or hypothalamic regions) and rises in parallel with tissue CO2 production (V˙ CO2) (fig. 1). The complex ques- central command to locomotor spinal motor neurons thus tion is: ‘What powerful drives to breathe also change with stimulating phrenic, intercostal, and lumbar respiratory exercise so precisely and quickly in concert with the motor neurons via descending neural pathways through increase in muscle CO2 production?’ Despite 120+ years the dorsal and ventral medullary areas responsible for of debate and often ingenious experimentation of this generating respiratory motor output. There is no direct question, the exact mechanism(s) remain unresolved and experimental evidence supporting ventilatory stimulation intensely debated [see ref. 12 for recent review]. We have via the normally occurring increase in central locomotor chosen to summarize this vast literature with the follow- command. Rather, support for this hypothesis comes pri- ing generalizations, which we believe are supported by marily from electrical and pharmacological stimulation of most experiments in both humans and animals. As with motor areas in the supramedullary CNS to produce loco- the control of heart rate and cardiac output (CO) in exer- motion in decorticate cats. This stimulation increases cise, both feedback and feed-forward mechanisms operate ventilation (and cardiac output) even when the locomotor in concert to mediate the hyperpneic response. muscles are paralyzed [46]. Attempts have been made to increase central locomo- tor command (i.e., effort) in humans independently of muscle force output by using spinal blockade, partial mus- cle paralysis, studying patients with selected spinal cord lesions, or using hypnotic suggestion of exercise in normal intact subjects [78, 89, 91]. Inferences are then made about the role of central command during actual exercise based on the substantial hyperpnea and tachycardia ob- served under these conditions. However, we cannot be sure how closely, if at all, these changes in so-called ‘cen- tral locomotor command’ mimic those normally occur- ring during exercise. Does the increased locomotor ‘effort’ under these nonphysiologic conditions originate from the same motor areas of the higher CNS and travel the same descending neural pathways as normally occurs during whole body exercise? In summary, the available evidence in animal models and the descriptive evidence in humans points toward a feed-forward stimulus from higher locomotor centers that is sufficiently powerful and precisely in tune with locomo- tor needs to explain much of the immediate and perhaps even steady-state hyperpnea achieved during exercise. However, final proof of this hypothesis requires that we be capable of mimicking, in isolation, all of the important characteristics of a truly physiological central locomotor command. Certainly, this is not an easy requirement and will not be met with current experimental approaches. There is also a great deal of evidence supporting the view that feedback from unmyelinated metaboreceptors (type IV) and thinly myelinated mechanoreceptors (type 2 Rodman/Haverkamp/Gordon/Dempsey

Fig. 2. Schema of two sets of influences (loco- motor and respiratory) over autonomic con- trol of cardiac output and blood flow distribu- tion during exercise. Traditional central loco- motor command effects parasympathetic out- flow to the SA node for control of heart rate and sympathetic constrictor outflow to heart, skeletal muscle, and inactive vasculature. Feedback effects from working limb locomo- tor muscle effect sympathetic outflow. Aortic and carotid sinus baroreceptors undergo ‘re- setting’ during exercise which permit heart rate and blood pressure to rise concomitantly. Newer data on respiratory system influences is included depicting excitatory metaborecep- tor reflex effects from the diaphragm and expiratory muscles on vasoconstrictor sympa- thetic outflow (SNA), and an inhibitory feed- back effect of lung inflation on SNA. Two additional respiratory-related sympathetic vasoconstrictor effects may include the in- fluence of an increasing central respiratory motor output (which is strong in debuffered animals but may be masked by inhibitory feedback in intact humans) and the influence of carotid chemoreceptor stimulation, which likely occurs during heavy exercise. III) from contracting skeletal muscle contribute to regula- which changes in proportion to CO2 flow with exercise tion of the cardiorespiratory responses to exercise (fig. 2). [46]. However, these stimuli are not obligatory for the Until recently, these muscle receptors were only thought exercise hyperpnea to occur as shown by the normal venti- to increase their activity in response to experimental per- latory response to moderate exercise in humans with de- turbations such as ischemia, vessel distention, or elec- nervated lungs or carotid bodies, or in animal models trical stimulation of motor nerves [46]. However, Kauf- where cardiac output and/or venous CO2 concentrations man and Forster [46] have shown that locomotion in- can be controlled. duced by electrical stimulation of locomotor centers in the higher CNS increases type III and IV afferent nerve activ- The hyperventilation of heavy exercise occurs at work ity in response to the ‘exercise stimulus,’ per se. Presence rates requiring 1 70% V˙ O2max reducing PaCO2 as an of this feedback effect is much more difficult to demon- arterial lactic acidosis develops. Three types of ‘extra’ strate in humans although increases in ventilation can be stimuli to breathe appear to play a role here including: produced by local muscle ischemia, lower body positive (a) curvilinear increases in the feedback stimulus as lactic pressure, vascular distention, or electrical stimulation of acid and heat accumulate in working limb and respiratory muscle. Evidence suggests a synergistic effect on the ven- muscles; (b) curvilinear increases in the feed-forward cen- tilatory response between feed-forward and feedback ef- tral command stimulus as more and more motor units are fects, especially as exercise intensity increases [91]. recruited in an attempt to maintain force output as limb and respiratory muscles fatigue [12], and (c) the added ‘CO2 flow’ back to the lung has logically been proposed influence of carotid chemoreceptor stimulation in heavy as a regulating mechanism of hyperpnea primarily be- work due to the addition of large quantities of hydrogen cause of the tight correspondence between V˙ A and V˙ CO2 ions, norepinephrine, and potassium to arterial blood [12, during exercise. Receptors in the heart (mechanorecep- 46]. Controversy exists, however, as denervation of the tors) or lung (chemoreceptors) and magnified oscillations carotid bodies shows opposite effects on the hyperventila- of arterial pH and PCO2 stimulating carotid chemorecep- tory response to heavy exercise when tested in asthmatic tors have all been suggested as the ‘missing stimulus’ humans (who exhibit a markedly blunted ventilatory Cardiovascular and Respiratory Response 3 to Exercise

Fig. 3. Alveolar PO2, arterial PO2, and saturation of hemoglobin with O2 and CO2 remain constant (fig. 1, 3). As exercise pro- oxygen during progressive exercise to maximum in a healthy, young gresses from mild through moderate intensity, V˙ A is adult. In spite of the progressively widened A-aDO2, arterial PO2 is increased primarily through increases in tidal volume maintained at resting levels during all exercise intensities. SaO2 falls (VT) which: (1) reduces the dead space to tidal volume primarily because of a temperature and pH-mediated effect on the ratio (VD/VT), and therefore the ‘wasted’ portion of each oxyhemoglobin dissociation curve. Data compiled from the authors’ inspiration, and (2) minimizes the flow-resistive work of laboratory. breathing which is more closely related to breathing fre- quency (fb). The exercise-induced increases in VT are response following denervation) compared to animal achieved by encroaching into both the inspiratory and models (who show an enhanced ventilatory response fol- expiratory reserve lung volumes [33]. Encroachment into lowing denervation) [46]. We favor a combination of the the expiratory reserve volume (i.e. reducing end-expirato- aforementioned three mechanisms to explain the hyper- ry lung volume (EELV) below relaxation functional resid- ventilatory response to heavy exercise. ual capacity (FRC)) is accomplished by recruitment of expiratory muscles [2] and is beneficial as it: (1) provides Mechanics of Breathing during Exercise a passive contribution to the subsequent inspiration due to outward recoil of the rib cage upon termination of expi- During exercise, the respiratory control system func- ration; (2) lengthens the inspiratory muscles thereby plac- tions to increase ventilation of the alveoli sufficient to ing them at a more optimal position for generating force maintain alveolar O2 and CO2 at or near resting levels during the subsequent inspiration, and (3) keeps the oper- while minimizing the mechanical work performed by the ating lung volumes on the linear (high compliance) por- respiratory muscles [54, 57]. Minimizing the mechanical tion of the pressure-volume curve over a greater range work, and therefore the metabolic cost of breathing will (fig. 4). As exercise intensity progresses from moderate to allow for: (1) a greater amount of cardiac output to be higher levels, VT begins to impinge upon the flatter (stif- available for delivery to working limb muscle [28]; (2) a fer) portion of the pressure-volume curve (VT 175% TLC; reduction in respiratory muscle energy store depletion fig. 4). At this point of reduced lung compliance, VT pla- [17], and (3) minimize sensory input and discomfort from teaus and further increases in V˙ A are accomplished solely the chest wall and lung reducing the potential for develop- through increases in fb [34]. ment of dyspnea or sensations of increased respiratory effort. These effects will delay limb and respiratory mus- An implicit consequence of increasing fb is a reduction cle fatigue thereby maximizing exercise performance in both inspiratory (TI) and expiratory (TE) time, which [32]. means flow must increase if a given lung volume change is to be maintained. Figure 5 illustrates the maximal flow During submaximal exercise, the increase in V˙ A is pro- volume loop generated by subjects at rest and is indicative portional to the increase in metabolic rate so that arterial of the capacity of the airways and respiratory muscles to produce flow and volume. In the healthy untrained adult, it can be seen that the capacities of both the airways and respiratory muscles to produce flow and volume are well in excess of those achieved during maximal exercise. A portion of the system’s large capability to generate flow can be attributed to the coordinated efforts of numerous muscles that are recruited as exercise intensity increases including the diaphragm, scalenes, sternocleidomastoids, intercostals, abdominals, and pectorals. The metabolic capacities of these muscles are large and their biochemical properties quite heterogeneous [59], which provides for great functional versatility. Although most of the respira- tory muscles are highly fatigue-resistant compared to limb muscles [24], they are susceptible to fatigue (especially during prolonged exercise at intensities 180% V˙ O2max), which can effect sympathetic discharge, limb blood flow, and exercise performance (see ‘Cardiorespiratory Interac- 4 Rodman/Haverkamp/Gordon/Dempsey

Fig. 4. Relaxation pressure-volume curve of the lung and chest wall. Fig. 5. Flow-volume relationship before, during, and after exercise in The subject inspires (or expires) to a certain volume from the spirom- young adult males. The largest solid lined envelope is the mean maxi- eter, the tap is closed, he then relaxes his respiratory muscles. Modi- fied from Powers et al. [59]. Less of a volume change is achieved for a mal volitional effort for all subjects before exercise. The smallest loop given change in pressure generation at lower and higher lung volumes than compared to the mid-range volumes (decreased efficiency, i.e. is that obtained at rest. Note that all subjects show a reduced FRC compliance, at low and high lung volumes). Operating lung volumes at rest and during exercise are indicated by the short and long arrows, during mild-to-moderate exercise (middle loops). Untrained subjects respectively. These volumes lie on the linear portion of the curve. (V˙ O2max = 35–50 ml/kg/min) with a mean VE of 117 liters/min at Note the reduction in FRC during exercise due to abdominal expira- maximal exercise show no significant flow limitation (i.e. impinge- tory muscle recruitment. ment onto the maximal volitional loop), while highly trained subjects (V˙ O2max = 60–83 ml/kg/min) with a mean maximal VE of 150–190 liters/min but normal maximal flow-volume envelopes show signifi- cant expiratory flow limitation during strenuous and maximal exer- cise. The largest envelope (dotted line) represents the mean postexer- cise loop of all subjects and exceeds the maximal pre-exercise loop due to exercise-induced bronchodilation. Data compiled from Inbar et al. [42]. tions during Exercise and Respiratory Limitations to Ex- ‘braking’ due to reductions in laryngeal adductor [14] and ercise Performance’). postinspiratory diaphragm muscle activity, and (5) sym- pathetic nervous system-mediated constriction of the vas- Despite the large increases in both inspiratory and culature in pulmonary and nasal mucosa which increases expiratory flows during exercise, flow resistance remains airway diameter [64]. at or near resting levels due to a variety of precisely con- trolled mechanisms including: (1) a shift from predomi- The capabilities of the lung and respiratory muscles in nantly nasal to oro-nasal breathing routes (normally the healthy, untrained adult are well in excess of the occurs at levels of V˙ A equal to 20–40 liters/min [7]); demands placed on them during exercise. As mentioned (2) enhanced recruitment of laryngeal [14], tongue [88], above, the flow rates and volume changes seen during and nasal [88] inspiratory muscles which serves to stiffen maximal exercise are well within the maximal volitional the airway and prevent negative pressure-induced airway flow-volume loops obtained at rest (fig. 5). Similarly, the narrowing; (3) coordinated activation of thoracic and amount of force generation required of the inspiratory abdominal respiratory muscles preventing paradoxical muscles, as well as their velocity of shortening are only movement of the thorax [3]; (4) decreased expiratory 40–60% of capacity at maximal exercise in the untrained Cardiovascular and Respiratory Response 5 to Exercise

individual. However, these numbers approach 90% of nisms causing the increased A-aDO2 during exercise in- the system’s capacity in the endurance-trained athlete clude a worsening maldistribution of ventilation to perfu- [11] (see ‘Respiratory Limitations to Exercise Perfor- sion (V˙ A/Q˙ ), increased contributions from a fixed ana- mance’). tomical shunt, and/or a limitation for the diffusion of oxy- Dyspnea gen from alveoli to pulmonary capillary. The ratio of V˙ A to Q˙ can be partitioned into inter- A critical aspect of the feedback control of breathing during exercise is its influence on suprapontine brain (among regions) and intraregional (within a region) distri- structures including the cortex, which are manifested as butions for V˙ A and Q˙ . With respect to the interregional an ‘awareness’ of ventilatory effort and possibly even differences, both V˙ A and Q˙ are greater at the base and less unpleasant sensations known as ‘dyspnea’. Afferent fibers at the apex of the lung, a difference that has traditionally originating in the chest wall musculature and vagal affer- ents from the lung project all the way to the cerebellum been thought to be primarily a function of gravity. How- and cerebral cortex. Furthermore, medullary inspiratory and expiratory pattern generator neurons project to the ever, recent evidence in primates and horses suggests only mid-brain and higher CNS. These neural connections may provide the sensory information that allows mecha- a small role for gravity effects on the pulmonary blood no- and chemostimuli to be perceived consciously. flow distribution during resting [21, 22] and exercising Under what conditions does this cortical awareness of breathing and dyspnea occur during exercise? An in- conditions [15]. Rather, it is suggested that the geometry creased drive to breathe by itself does not cause dyspnea, at least under conditions of mild to moderate exercise of the pulmonary vascular tree is the principle determi- despite 10-fold increases in ventilation. Only in heavy exercise is the increased sensory input sufficient to engage nant of interregional pulmonary perfusion heterogeneity the higher CNS and produce awareness of ventilatory effort. However, an increased drive to breathe combined and, thus, both structural heterogeneity and gravity ef- with some form of mechanical impedance to flow or vol- ume (i.e. an imbalance between neuromuscular effort and fects result in the variability of resistances to blood flow lung volume change) results in dyspneic sensations. Dis- that cause unequal distributions of Q˙ vertically within the eases which increase airway resistance, reduced lung/ lung. Additionally, the rate of decline in Q˙ from base to chest wall compliance, or cause respiratory muscle weak- apex is greater than for V˙ A so that overall V˙ A/Q˙ is greater ness create discrepancies between neuromuscular effort than 1 at the top, and less than 1 at the base of the lung at and ventilatory output, even during moderate intensity exercise. Hyperinflation of the lung secondary to expira- rest. Thus, an unequal distribution between ventilation tory flow limitation during exercise gives rise to extreme dyspnea because above a certain threshold lung volume, and perfusion along the vertical plane of the lung also con- inspiratory efforts are opposed by inward recoil of the tributes to the interregional differences in V˙ A/Q˙ and some chest wall plus a stiffened lung (see fig. 4). of the A-aDO2 at rest and during exercise. Pulmonary Gas Exchange Intraregional differences in V˙ A distribution refer to the differences within a horizontal plane of the lung and arise The alveolar to arterial PO2 difference (A-aDO2) is a measure of gas exchange efficiency from the alveoli to the due to variations in resistance of the airways within a pulmonary capillaries. At rest in the healthy human, the region. Similarly, intraregional heterogeneity in Q˙ is a A-aDO2 is F5 mm Hg [11] and progressively widens dur- ing exercise of increasing intensity to values of F20 mm function of the complex nature of the pulmonary vessels, Hg during maximal exercise [80] (fig. 3). Potential mecha- which have random structural differences in diameter, length, and branching angles. At rest, the A-aDO2 is due almost entirely to a mis- match between V˙ A and Q˙ within the lung. During exercise of increasing intensity [20, 80] and duration [38], the overall distribution of ventilation and perfusion through- out the lung likely becomes progressively slightly more nonuniform. This increase in overall V˙ A/Q˙ nonuniformity (as measured by the multiple inert gas technique (MI- GET)) likely reflects the net effect of a more uniform topographical distribution (interregional) of V˙ A/Q˙ [5] and a less uniform intraregional V˙ A/Q˙ distribution. Despite this increase in nonuniformity of V˙ A/Q˙ , the overall mean V˙ A increases out of proportion to Q˙ with increasing exer- cise intensity. The resultant 3- to 4-fold higher overall V˙ A/ Q˙ for the lung in heavy exercise vs. rest means that ele- vated alveolar PO2s are present across all V˙ A/Q˙ units; thus, end-pulmonary-capillary PO2 is maintained despite 6 Rodman/Haverkamp/Gordon/Dempsey

the marked reduction in mixed venous O2 content and A third potential contributing factor to the increased increased nonuniformity of V˙ A/Q˙ distribution. A-aDO2 during exercise is failure of mixed venous blood in the pulmonary capillaries to equilibrate with alveolar The mechanisms accounting for the greater maldistri- oxygen pressure. Diffusion disequilibrium may occur be- bution of V˙ A/Q˙ during exercise remain largely unknown tween alveolar PO2 and blood leaving the pulmonary cap- although possibilities include: (a) minor structural varia- illaries if the time required for equilibration is greater tions in airway and/or lung blood vessels could become than the time a red blood cell spends in a gas exchanging further manifested during exercise as ventilatory and cir- portion of the lung. The average time a red blood cell culatory flows increase; (b) high flow rates could poten- (RBC) spends in a pulmonary capillary is known as transit tially irritate the airways resulting in airway secretions time and is determined by the ratio of pulmonary capil- that effect the distribution of ventilation; (c) vascular tone lary blood volume to pulmonary blood flow. At rest, tran- could be altered during exercise, and/or (d) mild intersti- sit time is approximately 0.75 s while only F0.40 s is tial edema could develop during exercise if the lymphatic required for the RBC to equilibrate with alveolar PO2. system does not adequately drain fluid leaking across the During high-intensity exercise, however, transit time may pulmonary capillary membrane into the interstitial space. be reduced to F0.40 s or less which may result in incom- Interstitial edema might be expected to effect the distribu- plete oxygenation of hemoglobin (see ‘Respiratory Limi- tions of V˙ A and Q˙ by increasing resistance to air and blood tations to Exercise Performance’). flow in affected areas. Additionally, if the fluid flux were to overwhelm the system so that it accumulated in the The rate of diffusion for O2 across the alveolar-capil- alveoli, gas exchange would be severely compromised. An lary membrane is determined by several factors that are increased transvascular fluid movement does occur dur- quantitatively expressed in Fick’s law of diffusion, ing exercise [10], and several mechanisms exist to explain this including: (1) increased recruitment and distension of Volume of gas = D ! A ! (P1 – P2) the pulmonary vasculature during exercise results in an T increased total vascular surface area; (2) high pulmonary capillary transmural pressures during intense exercise where D is a diffusion constant for the gas of interest, A is may cause capillary stress failure and subsequent fluid the surface area of the alveolar-capillary membrane, P1 – leakage, and/or (3) the release of inflammatory mediators P2 is the partial pressure difference between gas in the during exercise elicited by high flow rates and/or mechan- alveoli and red blood cell, and T is the thickness of the ical stress may increase vascular permeability resulting in blood-gas barrier membrane. The thickness and surface fluid exudation/transudation. In healthy individuals how- area depend on the structure of the blood-gas barrier, ever, the increased transcapillary flux does not result in which is well designed to maximize diffusion across the appreciable accumulation of fluid within the interstitial membrane. While it is extremely thin (0.2–0.3 Ìm) [19] space, primarily because of the lungs tremendous capacity which is extremely important (see Fick’s law of diffusion to increase lymph flow and thus fluid drainage during above), its design maintains the strength necessary to exercise [10]. Also, the decrease in pulmonary vascular withstand the high transmural pressures developed dur- resistance that occurs during exercise attenuates the rise ing exercise. The interface consists of three primary com- in pulmonary artery pressure minimizing the outward ponents including the capillary endothelium, alveolar epi- driving pressure for transcapillary fluid flux during exer- thelium, and extracellular matrix (which is further com- cise. prised of the alveolar and capillary basement mem- branes). Situated in the middle of the extracellular matrix The second contributing factor to the A-aDO2 is a is an ultrathin layer of type IV collagen, which probably right-to-left shunt of mixed venous blood (refers to blood provides most of the strength to the blood-gas barrier [84]. that enters the arterial system without passing through the The arrangement of type IV collagen is well designed to lungs). A fixed 1–2% extrapulmonary shunt exists in the withstand the large transmural pressures generated during normal human lung of which the thebesian veins are most exercise. Additionally, the tremendous total surface area important. Deoxygenated blood from these vessels emp- of the alveolar-capillary interface (approximately 50– ties directly into the left heart and mixes with oxygenated 100 m2) [19] maximizes diffusion potential (see Fick’s law blood leaving the lungs, thus lowering PaO2. The extra- of diffusion above). Thus, the extreme thinness and large pulmonary shunt becomes progressively more important surface area of the blood-gas barrier provide an optimal in determining the A-aDO2 during exercise of increasing environment for diffusion of oxygen from the alveoli to intensity as CvO2 falls. pulmonary capillary during exercise. The only suggestion Cardiovascular and Respiratory Response 7 to Exercise

Fig. 6. Total A-aDO2 (open symbols) and A-aDO2 due to V˙ A/Q˙ mis- During exercise, pulmonary artery pressure rises, pulmo- match predicted by MIGET (closed symbols) during exercise of nary vascular resistance falls, and a passive expansion of increasing intensity in four separate studies [20, 26, 62, 77]. Data the pulmonary capillary bed occurs mainly in lung regions from each study are represented by separate symbols. Also included that were under-perfused at rest with respect to V˙ A. This are average values of oxygen uptake (V˙ O2), cardiac output (CO), pul- expansion acts to maintain RBC transit time in the face of monary artery pressure (Ppa), pulmonary capillary blood volume an increased cardiac output. Thus, only when cardiac out- (PCBV), and pulmonary capillary transit time. Ppa was calculated put rises out of proportion to the pulmonary capillary from the regression equation of [60] and PCBV from [39]. To illus- blood volume does the possibility exist for a diffusion lim- trate, at a V˙ O2 of F3 liters/min, results from Hammond et al. [26] itation to occur. Given the maximal cardiac output of a (represented by circles) measured a total A-aDO2 of 18 mm Hg, while healthy, untrained person (F20 liters/min) and the great the A-aDO2 attributable to V˙ A/Q˙ mismatch was 9 mm Hg. This V˙ O2 capacity for expansion of the pulmonary capillary bed, a corresponds to a CO of F23 liters/min which brings Ppa, PCBV, and limitation for diffusion is unlikely. Thus, if diffusion dis- transit time to 30 mm Hg, 210 ml, and 0.54 s, respectively. equilibrium is involved in the increased A-aDO2, it will likely only contribute during near-maximal to maximal for a loss of blood-gas barrier integrity in humans comes exercise in the trained individual with a high cardiac out- from highly trained cyclists working at maximal intensity put and rarely be involved in the increased A-aDO2 dur- [37]; concentrations of red blood cells, total protein, and ing submaximal exercise [38]. leukotriene B4 measured in their broncho-alveolar lavage (BAL) fluid were significantly higher after a maximal 7- The MIGET (multiple inert gas elimination technique) min uphill bike ride compared to a group of untrained can be used to indirectly assess the contributions from dif- subjects who did not perform an exercise bout. Unfortu- fusion limitation and extra-pulmonary shunt to the wi- nately, the more appropriate test would have been to com- dened A-aDO2 during exercise. Since the MIGET quan- pare BAL fluid in the athletes before and after a maximal tifies V˙ A/Q˙ inequality, a predicted value for the A-aDO2 exercise bout as these results could have been due solely to (assuming complete diffusion equilibration and no extra- subject selection bias. pulmonary shunt) can be calculated and compared to the measured A-aDO2. If the measured A-aDO2 is greater The lung is further protected from significant diffusion than that predicted from the MIGET, a diffusion disequi- disequilibrium by virtue of its low resistance pulmonary librium and/or extrapulmonary shunt must account for vasculature, which possesses a great capacity to dilate. the difference although it is difficult to discern the relative contributions from each of the two. Using this technique, several authors have shown a significant difference be- tween predicted and measured A-aDO2 during exercise [26, 63, 80] and attribute this difference solely to diffusion disequilibrium. However, these studies found that the A- aDO2 due to ventilation-perfusion mismatch (predicted) was less than the total A-aDO2 during sub-maximal levels of exercise (V˙ O2 F2 liters/min) when cardiac output and pulmonary capillary blood volume are well below maxi- mal levels, transit time is F0.6 s, and pulmonary vascular pressures are well below those required for interstitial fluid accumulation due to capillary stress failure (fig. 6). Thus, it seems highly unlikely that alveolar-capillary dif- fusion disequilibrium actually occurs at these moderate exercise intensities. Alternatively, the extrapulmonary shunt may be responsible for a significant portion of the uncoupling between measured and predicted A-aDO2 that occurs during submaximal exercise. Indeed, it was determined that during moderate exercise, an extrapul- monary shunt of 1% of cardiac output could explain all of the A-aDO2 that remained after accounting for that due to V˙ A/Q˙ maldistribution [20]. It is important to emphasize 8 Rodman/Haverkamp/Gordon/Dempsey

that the MIGET technique is not free from error as shown SA node. As exercise intensity increases, further increases in studies which have predicted the A-aDO2 attributable in heart rate are caused by sympathetic stimulation of the to ventilation-perfusion inequality and found this value to SA node. The SA node is further stimulated by circulating be (impossibly) in excess of the actual total A-aDO2 [38, catecholamines, which are secreted into the plasma by the 77]. adrenal glands in response to sympathetic activation. Stroke volume increases during the early stages of upright In summary, the increased A-aDO2 during exercise exercise and reaches a plateau at submaximal workloads results from a maldistribution of V˙ A/Q˙ as well as contribu- equal to approximately 40% of V˙ O2max in healthy, un- tions from diffusion disequilibrium and/or extrapulmon- trained adults. The increase in stroke volume is due to the ary shunt as exercise intensity increases. The combined combined effects of increased venous return and the posi- effects of the latter two may comprise greater than 50% of tive ionotropic effects of sympathetic stimulation on the A-aDO2 during heavy exercise in trained individuals heart muscle. [38, 63] and may account for the occurrences of exercise- induced arterial hypoxemia (see ‘Respiratory Limitations Skeletal muscle contraction elicits a reflex increase in to Exercise Performance’). sympathetic outflow to several key vascular beds, which in turn causes widespread vasoconstriction contributing Cardiovascular System Responses to Exercise to the exercise-induced rise in blood pressure. This reflex is triggered by stimulation of mechano- and chemorecep- At rest, skeletal muscle receives less than 20% of total tors located within working muscle. Although the precise cardiac output. The fraction of cardiac output delivered nature of the stimulus is not known, exercise-induced to muscle increases during exercise, so that at maximal blood pressure increases are closely correlated with in- intensity, skeletal muscle receives approximately 80% of creases in muscle venous lactate concentration and de- total cardiac output. Although cardiac output increases creases in pH. Reflex sympathetic activation is the prima- roughly in proportion to V˙ O2, redistribution of flow from ry mechanism causing redistribution of cardiac output ‘inactive’ areas of the circulation (mainly the visceral away from nonworking muscle and inactive tissue to pro- organs) is necessary to supply the flow requirements of vide more blood flow to working muscle. It is important active muscle. Thus, blood flow to working muscle during to note that reflex increases in sympathetic outflow occur exercise depends on appropriate: (1) increases in cardiac to active, as well as inactive skeletal muscle. Although output; (2) increases in vascular resistance to skin, vis- sympathetic tone probably constrains the increase in limb cera, and other inactive tissues (including nonworking muscle blood flow during exercise, local mechanical and skeletal muscle), and (3) decreases in vascular resistance chemical factors provide strong vasodilator influences to working muscle. The underlying mechanisms are opposing the constrictor influence and are probably the shown in figure 2. most important regulators of flow during exercise. During contraction, the blood vessels within skeletal muscle are During exercise, cardiac output must increase to meet mechanically compressed to the extent that flow is im- the contracting muscle’s requirement for flow. The in- peded; subsequent relaxation of the muscle allows flow to crease in cardiac output occurs through increases in both increase. Thus, rhythmic contraction and relaxation of heart rate and stroke volume and is thought to be me- skeletal muscle (as occurs during activities such as walk- diated via feed-forward mechanisms. The concept of ‘cen- ing or running) imparts energy onto the blood vessels pro- tral command’ states that medullary cardiovascular cen- pelling blood out of the muscle vascular bed thereby facili- ters are activated in parallel with ·-motoneurons at the tating venous return. The ‘muscle pump’ is thought to be onset of and throughout exercise. Evidence for this mech- almost entirely responsible for the immediate increase in anism comes from experiments in which attempted mus- blood flow that occurs at the onset of exercise. The cle contraction raised cardiac output to nearly the same mechanical effects of rhythmic contraction also play an extent in subjects with temporary neuromuscular block- important role in exercise vasodilation. Specifically, the ade as did actual contractions observed in control condi- muscle pump intermittently increases and decreases tions. Additionally, cardiac output often increases in an extravascular pressure (i.e. within the muscle) resulting in anticipatory fashion (i.e. before exercise even begins). hyperemia. The increase in heart rate that begins prior to and dur- The search for specific chemical mediators of exercise ing mild and moderate intensity exercise is caused pri- vasodilation has been partially successful. Many by-prod- marily by withdrawal of parasympathetic outflow to the ucts of muscle contraction (e.g. potassium, adenosine, Cardiovascular and Respiratory Response 9 to Exercise

CO2, lactate, nitric oxide) are capable of producing vaso- Harms et al. [30] used proportional assist mechanical ven- dilation although none are obligatory for exercise hyper- tilation to unload the respiratory muscles and decrease emia to occur [46]. the negativity of intrathoracic pressure during inspira- tion. They observed a reduction in stroke volume and car- In summary, the cardiovascular system response to diac output at all exercise intensities up to maximum, exercise is regulated by interplay between neural, chemi- although a portion of the reduction was related to con- cal, and mechanical factors. Increases in sympathetic ner- comitant reductions in V˙ O2. vous system activity triggered by feedback and feed-for- ward mechanisms are responsible for the exercise-in- In addition to the aforementioned mechanical effects duced increase in cardiac output and redistribution of of intra-thoracic and abdominal pressure swings on car- blood flow from inactive to active tissue. In exercising diac function, respiratory muscle work leading to dia- muscle (including the heart), metabolic vasodilation is the phragm fatigue (which does occur during heavy exercise) predominant hemodynamic influence. Cerebral blood exerts significant effects on sympathetic nervous system flow remains constant during exercise, even in the face of outflow to skeletal muscle (MSNA) and limb muscle a small rise in systemic blood pressure; however, in heavy blood flow. Using microneurographic recordings from the exercise, hypocapnia (secondary to the hyperventilatory peroneal nerve of the resting limb, St. Croix et al. [71] response) will cause local cerebral vasoconstriction. demonstrated that repeated voluntary inspiratory efforts leading to diaphragm fatigue in otherwise resting subjects Cardiorespiratory Interactions during Exercise caused a time-dependent increase in MSNA (despite a coincident increase in MAP). Sheel et al. [68] subsequent- The heart of the healthy individual is very sensitive to ly demonstrated that this increased MSNA coincided changes in preload which means the mechanical effects of with an increase in limb vascular resistance (LVR) and a inspiration and expiration impact cardiac output and 20–40% reduction in limb blood flow (Q˙ L). This sympa- blood flow distribution during exercise, especially that of thetically-mediated limb vasoconstriction was not in- high intensity. These influences are complex and include duced by voluntary increases in central respiratory motor the following: (1) a more negative intrathoracic pressure output per se as voluntary increases in central respiratory during inspiration increases venous return and stroke vol- motor output without fatigue actually reduced MSNA ume (unless the negative pressure is too great and/or sus- and LVR and increased Q˙ L. The time-dependent effects tained too long during inspiration which could collapse of diaphragm fatigue on sympathetically-mediated limb the inferior vena cava, or unless an increased right atrial vasoconstriction parallel those caused by fatiguing rhyth- and ventricular volumes compromised left-ventricular mic handgrip or expiratory muscle contractions. These expansion due to interventricular dependence) [65]; data in humans support a physiological role for the type (2) active expiration during exercise causes large positive III and IV receptors in respiratory muscle [13] and are intra-thoracic and intra-abdominal pressures which may consistent with the activation of these receptors during counterbalance the potential positive influences of nega- fatiguing diaphragmatic contractions induced by phrenic tive intrathoracic pressure during inspiration on venous nerve stimulation in the anesthetized rat [35]. Further- return and stroke volume, and (3) if inspiration is accom- more, electrical or pharmacological stimulation of thin plished primarily with the diaphragm, diaphragmatic de- fiber phrenic nerve afferents in anesthetized animals scent will increase intra-abdominal pressure during inspi- causes constriction of coronary arterioles [74] and several ration reducing the pressure gradient from the limbs to other systemic vascular beds [41]. the abdomen thus impeding venous return [91]. How these isolated findings apply to normal whole Available evidence in the exercising human demon- body exercise in humans is not clear. We do know that in strates that the negative intrathoracic pressure normally humans performing heavy cycling exercise, unloading the generated during inspiration exerts enough of a preload normal work of breathing with a mechanical ventilator effect on the heart to account for a significant fraction of causes vasodilation and increased blood flow to the exer- the increase in stroke volume and cardiac output during cising limb [28]. These cardiovascular effects do not occur exercise. Wexler et al. [87] measured blood flow velocity if respiratory muscle unloading is applied during moder- in the inferior vena cava of humans during mild supine ate intensity exercise during which diaphragm fatigue exercise and found cyclical increases in venous return does not occur [85]. Considering all available data togeth- during inspiration and reductions during expiration. er, it is likely that an accumulation of metabolites in fatiguing respiratory muscle during exercise triggers an 10 Rodman/Haverkamp/Gordon/Dempsey

increased sympathetic outflow increasing the total con- limit exercise performance by two different mechanisms strictor outflow to systemic vascular beds. We do not including: (1) the development of exercise-induced arteri- know, however, if this specific metaboreflex from respira- al hypoxemia, and (2) fatiguing levels of respiratory mus- tory muscle, by itself, is sufficiently powerful to override cle work. local vasodilator metabolites and impede blood flow to the exercising limb. We can only view these data as indic- Pulmonary gas exchange in the healthy, untrained per- ative of a respiratory-cardiovascular link during exercise son is usually adequate at all levels of exercise intensity as that deserves serious consideration along with the more arterial PO2 is maintained at resting levels (fig. 3). How- traditional feed-forward and feedback locomotor in- ever, significant decreases (3–13%) in the saturation of fluences within the grand scheme of autonomic control of hemoglobin with oxygen (SaO2) have been shown to occur the circulation during exercise (fig. 2). during exercise at sea level in healthy, habitually active humans [11, 31, 58]. These findings provide evidence that Respiratory Limitations to Exercise Performance the normal respiratory system is not always able to ade- quately accomplish its primary task of gas exchange. This The combined aerobic capacity of all the organ systems phenomenon is known as exercise-induced arterial hypox- involved in O2 transport and utilization is V˙ O2max. emia (EIAH) and results from a fall in arterial PO2 and a V˙ O2max is the plateau in V˙ O2 eventually achieved as pH or temperature-induced rightward shift of the oxy- work rate increases during a progressive exercise test. The hemoglobin dissociation curve. Individuals with greater Fick equation defines the determinants of V˙ O2max. aerobic capacity are far more likely to develop EIAH although there is marked variation within groups of simi- V˙ O2max = lar fitness levels [31]. COmax ! [arterial O2 content – mixed venous O2 content]max The causes of EIAH are multifactorial and may origi- Thus, V˙ O2max can be thought of as being limited by the nate from the observation that exercise training elicits capacity to transport O2 to working muscle (CaO2 ! adaptations in the cardiovascular and muscular systems COmax) or by the capacity of working muscle to extract without changing the gas exchange surface of the lung (see and utilize the available O2. ‘Effects of Endurance Training on the Respiratory Sys- tem’). The two primary variables with which EIAH most The majority of evidence indicates that exercise capac- often correlate are: (1) an excessively widened A-aDO2, ity in the healthy, untrained human at sea-level is limited and (2) an insufficient hyperventilatory response to the by the supply of O2 delivered to working muscles rather exercise stimulus. In a well-trained athlete with a high than by their capacity to oxidize it [81]. Specifically, maximal oxygen uptake, the A-aDO2 may reach values of V˙ O2max is increased: (a) in proportion to arterial O2 con- 40 mm Hg or greater at maximal exercise intensities com- tent when either O2 carrying capacity is augmented via pared with a maximal value of F25 mm Hg in a healthy added red cells (i.e. blood ‘doping’) or inspiring very high but untrained person. However, an excessively widened concentrations of O2 [79], or (b) when COmax is increased A-aDO2 does not necessarily predispose one to develop by adding total circulating blood volume [82] or surgically EIAH as PaO2 will be maintained if alveolar ventilation is removing the constraint of the pericardium [72]. In turn, increased in proportion to the widened A-aDO2. Thus, maximal stroke volume and cardiac output are believed individuals who have an excessively widened A-aDO2 in to be the major limiting factors to systemic O2 transport conjunction with a blunted hyperventilatory response to and therefore V˙ O2max in most healthy subjects exercising exercise are the most susceptible to EIAH. at sea level. Extremely sedentary humans (V˙ O2max !35 ml/kg/min) do not show this dependency of V˙ O2max The mechanisms responsible for the widened A-aDO2 on O2 transport and may be limited by the oxidative during exercise were discussed in detail above (see ‘Pul- capacity of skeletal muscle [66]. monary Gas Exchange’) and will not be rediscussed here except to mention that an excessively widened A-aDO2 The healthy pulmonary system is so well designed that (130 mm Hg) during exercise is likely due to a severe mal- it has traditionally been thought of as being ‘overbuilt’ distribution of V˙ A/Q˙ , diffusion limitation for O2, and/or a and able to provide adequate gas exchange during all greater contribution from extrapulmonary shunt than is types and intensities of exercise. However, this once pre- normally seen. In trained athletes at high exercise intensi- vailing view is no longer widely accepted. Evidence has ties, the possibility for a significant limitation for diffu- accumulated that indicates the respiratory system may sion cannot be discounted as their high COmax (25–30 liters/min) combined with a normal (untrained) maximal Cardiovascular and Respiratory Response 11 to Exercise

Fig. 7. Relationship between percent change in V˙ O2max when EIAH is important to remember that CO2 retention does not was prevented (with supplemental O2) and SaO2 during maximal occur during high-intensity exercise indicating that alveo- exercise in normoxia. The intercept of the regression line at zero lar ventilation is always adequate with regard to V˙ CO2. change in maximal oxygen consumption indicates that preventing Mechanical limitations to breathing during high-intensity EIAH began to have a significant effect on V˙ O2max when SaO2 was between 93 and 95% (i.e. a 3% reduction below resting levels). Data exercise may also prevent an increase in minute ventila- compiled from Harms et al. [31]. tion irrespective of respiratory motor output. Indeed, ven- pulmonary capillary blood volume of F220 ml [62] places their estimated average red blood cell transit time tilation increased and PaCO2 decreased when subjects at 0.35–0.40 s [36]. This puts these individuals at the limit who exhibited expiratory flow limitation during exercise needed for O2 equilibration between alveoli and red blood cell during maximal exercise. Indeed, total pulmonary breathing room air subsequently performed the same transit time (right to left ventricle) is significantly corre- lated with the magnitude of the A-aDO2 in trained ath- exercise bout while breathing heliox [53]. letes [36]. It is important to note that a substantial portion of the The degree of hyperventilation, as reflected by the decrease in PaCO2 from rest, is significantly correlated decreased SaO2 during exercise can be attributed to a pH with EIAH [11, 29] as women who hyperventilated more and/or temperature-induced rightward shift of the hemo- were less likely to develop EIAH at a given work rate com- pared to women who hyperventilated less [29]. The mech- globin dissociation curve. This was recently demonstrated anisms proposed to explain an inadequate hyperventila- tory response to exercise include: (1) a low hypoxic and/or in a group of runners during constant load high intensity hypercapnic drive related to blunted chemoreceptor sen- sitivity [27], and/or (2) a mechanical constraint to the treadmill exercise in which PaO2 rose progressively over exercise hyperpnea [43, 53]. Although the development of time while SaO2 fell progressively because of increasing EIAH has been shown to correlate with a reduced hypoxic temperature and acidosis [86]. and hypercapnic ventilatory response at rest and reduced ventilatory equivalent for CO2 during exercise [23, 27], it Evidence that EIAH limits exercise performance comes from studies where V˙ O2max increased in subjects when small amounts of supplemental inspired O2 were given just sufficient to prevent the decreases in arterial oxygen content that occurred during normoxic exercise [31, 58]. The magnitude of the increase in maximal oxy- gen consumption correlated with the severity of EIAH achieved during normoxic exercise (fig. 7). The likely mechanism for the increased V˙ O2max is a widened a- vO2 difference in proportion to the increased CaO2 [47]. Fur- ther, it has been demonstrated that hypoxemia begins to have a significant effect on V˙ O2max when SaO2 drops 3– 4% below resting levels [31]. SaO2 during maximal exer- cise in most healthy, untrained individuals is approxi- mately 94–95% [23, 27] placing them at a level of desatu- ration that would not be expected to compromise perfor- mance. However, many trained athletes commonly reach SaO2 levels of 87–92% during maximal exercise [11, 31], which would cause a 5–15% reduction in V˙ O2max. The second major cause of a respiratory limitation to exercise performance involves fatiguing levels of respira- tory muscle work. Fatiguing levels of respiratory muscle work are normally achieved during exercise in trained and untrained healthy people (180% V˙ O2max) and pre- sumably during lighter intensity work in patients with chronic pulmonary and/or heart disease. The degree of respiratory muscle work needed to sustain the hyperpnea of strenuous exercise in a trained athlete can account for up to 16% of maximal V˙ O2 [1] and cardiac output [30]. This significant demand for blood flow by the respiratory muscles does not influence the adequacy of ventilation, but may compromise perfusion of limb muscle thereby 12 Rodman/Haverkamp/Gordon/Dempsey

limiting its ability to perform work. Evidence of a compe- Fig. 8. Effects of respiratory muscle unloading on endurance exercise tition for blood flow between the respiratory and limb performance. Group mean data (n = 7) are shown for minutes 1–5 of muscles originates from data obtained in highly fit cyclists exercise and at exhaustion. * Significant difference from control, p ! exercising at 90% V˙ O2max who demonstrated decreases 0.05. Data compiled from Harms et al. [32]. in limb blood flow commensurate with respiratory muscle loading, and even more physiologically relevant, increases lar effort (both limb and respiratory). Results on the topic in limb blood flow when the normal work of breathing have been varied [4, 42, 70] and are likely due to differ- was unloaded using a proportional assist ventilator [28]. ences in training paradigms, subject populations, perfor- mance testing protocols, and/or placebo effects on tests of In subsequent work, Harms et al. [32] studied highly fit maximum volitional performance. cyclists, each of whom completed 11 randomized trials on a cycle ergometer at a workload requiring 90% V˙ O2max In summary, EIAH and the cardiovascular conse- under conditions of increased (loading), decreased (un- quences of respiratory muscle fatigue are two mechanisms loading), or normal (control) respiratory muscle work. They found that time to exhaustion was significantly increased with unloading the normal work of breathing in 76% of trials by an average of 1.3 min (14%) and signifi- cantly decreased with loading in 83% of the trials by an average of 1 min (15%) compared with control. Addition- ally, respiratory muscle unloading during exercise re- duced V˙ O2 and the rate of rise in dyspnea and limb dis- comfort (fig. 8). It was postulated that unloading the nor- mal work of breathing during heavy exercise improved performance due to a redistribution of blood flow to the working limb, which could delay fatigue and reduce the perception of limb muscle discomfort. Other studies have used assisted mechanical ventilation to reduce the normal work of breathing at lower exercise intensities in healthy subjects and found no effect on ventilation or endurance time [18, 48, 85], suggesting that respiratory muscle fatigue must occur for unloading to improve perfor- mance. On the other hand, respiratory muscle unloading during exercise in patients with chronic heart failure had marked effects on improving exercise performance, even during moderate intensity exercise [55]. This effect may reflect the enhanced ventilatory response to exercise and limited cardiac output available in these patients. Recent evidence has shown that fatiguing contractions of respiratory muscle in otherwise resting subjects in- crease efferent sympathetic nerve activity [71] and de- crease limb blood flow [68]. These findings suggest that respiratory muscle fatigue, which has been shown to occur in healthy humans during heavy exercise [44, 50] could negatively impact limb work capacity due to blood flow redistribution even when cardiac output is not near maxi- mal levels. It has thus been postulated that specific respi- ratory muscle training (either breathing against resistive loads or voluntary hyperpnea at rest) might improve exer- cise performance by: (1) delaying respiratory muscle fa- tigue and its subsequent effects on blood flow distribu- tion, and/or (2) reducing subjective perception of muscu- Cardiovascular and Respiratory Response 13 to Exercise

through which exercise performance and V˙ O2max are [67]. Also, highly trained human athletes show no differ- limited. However, these limitations do not generalize ence in diffusion capacity of the lung for carbon monox- equally to all humans or all conditions. Specifically, EIAH ide or pulmonary capillary blood volume at rest or any occurs during sub-maximal exercise (short or long dura- given exercise level compared to healthy, untrained sub- tion) only in the habitually active, while an increase in jects [62]. Exceptional cases have been found in competi- sympathetic outflow due to diaphragm fatigue can occur tive female swimmers who demonstrated significant in- in anyone. creases in vital capacity (F9%) and total lung capacity (F7%) following 12 weeks of intense endurance training Aging alters the way in which the respiratory system [9]. Larger than average vital and total lung capacities limits exercise. With normal healthy aging, the lung loses have also been shown in long distance swimmers com- elastic recoil, the chest wall and pulmonary arterioles pared to sprint trained and noncompetitive swimmers increase in stiffness, and the gas exchange surface dimin- [69] although the differences noted in this cross-sectional ishes. This results in greater dead-space ventilation, expi- study could have been solely due to subject selection bias. ratory flow limitation, and hyperinflation during exercise Longitudinal findings in elderly subjects demonstrated leading to dyspnea. EIAH occurs in many aged fit humans that habitual physical activity and high aerobic capacity with V˙ O2max in the 40- to 45-ml/kg/min range (which is do not prevent the normal deterioration in resting lung 50+% greater than normal at age 70 years) and pulmonary function (primarily reduced elastic recoil) or the high lev- vascular resistance during exercise is higher in older vs. els of expiratory flow limitation which occur during exer- young healthy subjects at any given V˙ O2. cise in the healthy pulmonary system over the sixth and seventh decades of life [52]. Hypoxia of high altitude makes the respiratory system the primary limiting factor to exercise because: (a) diffu- It is possible that exercise training is not an intense or sion limitation is enhanced and EIAH occurs much more specific enough stimulus to cause adaptation, as there are readily (even at !1,000 m altitude if the absolute work only a few chronic stimuli to which the structure and func- load is sufficiently high); (b) local hypoxic vasoconstric- tion of the healthy lung are known to adapt. One of these tion causes increased pulmonary vascular resistance stimuli is chronic hypoxia, which has been shown to which often precipitates edema formation during exer- increase alveolar and capillary number (expansion of the cise, and (c) carotid chemoreceptor stimulation causes a gas exchange surface area) in rats and dogs born and marked hyperventilatory response to exercise along with trained in hypoxia. Similarly, high-altitude residents of increases in inspiratory and expiratory muscle work mountains (such as the Peruvian Andes and North Amer- which enhance diaphragm fatigue and dyspnea. ican Rockies) show marked increases (30–50%) in pulmo- nary diffusion capacity at rest and during exercise [6]. A Effects of Endurance Training on the Respiratory second stimulus to which the lung is adaptable is pneu- System monectomy where compensatory growth of the remaining lung occurs [40, 75]. Daily stretching of the adult lung and Endurance training-induced structural adaptations respiratory muscles over a 5-week period as occurs during within the cardiovascular and muscular systems have programs of specific respiratory muscle training have been well documented [51, 83]. Whether training-induced been shown to elicit small but significant increases in vital changes in lung structure occur (i.e., lung diffusion surface capacity and peak flow [49]. area or parenchymal structure) is more controversial. Although exercise has been suggested to have an effect on In contrast to the lung, the respiratory muscles undergo lung development since the early 1900s, more recent data changes in histochemical [24, 73] and biochemical [24, comparing habitually active vs. sedentary animals of the 25, 59, 73] properties in response to whole-body training same body size but 3-fold differences in V˙ O2max (e.g. or a chronic overload stimulus [16, 76]. Whole body exer- horse vs. cow) reported little difference in the alveolar- cise training has been shown to promote a shift from gly- capillary interface despite significant differences in heart colytic to oxidative myosin heavy chain (MHC) isoforms and limb muscle mitochondrial volume and capillary [73] and significant increases (20–30%) in mitochondrial density [83]. Absence of an activity-induced effect on lung enzyme activity within the costal diaphragm of rodents structure is further supported by data showing that daily [24, 59, 73]. Interestingly, these training protocols did not exercise training is without effect on pulmonary diffusion elicit changes in the crural diaphragm unless 90-min surface area in the maturing lung of newborn guinea pigs training sessions of moderate-to-high intensity exercise were used, indicating that these two regions of the dia- 14 Rodman/Haverkamp/Gordon/Dempsey

phragm have different patterns of recruitment. Studies of A more recent question regarding possible training the expiratory muscles also indicate significant increases effects on the lung involves pulmonary vascular reactivi- (10–26%) in their oxidative capacity highlighting their ty, or more specifically, enhanced vasodilation of pulmo- recruitment during exercise [25, 59]. When training- nary arteries in response to acetylcholine (ACh). Aug- induced changes in the metabolic capacity of the respira- mented pulmonary vasorelaxation could allow for a great- tory muscles are compared to those in locomotor muscles er drop in pulmonary vascular resistance at any given car- of similar fiber type, locomotor muscles display a notably diac output during exercise, which would presumably higher increase (40–80%) [24, 25, 73]. These between- represent a favorable adaptation as the decreased pulmo- muscle differences are probably related to differences in nary arterial pressure would reduce the chance of develop- the metabolic demand placed on these muscles during ing pulmonary edema during heavy intensity exercise. A exercise and/or differences in the pre-training levels of recent study in this area demonstrated that short-term oxidative enzymes across limb and respiratory muscle. training (7 days) increased endothelial nitric oxide syn- Voluntary wheel running has shown that a volitional thase (eNOS) protein and endothelium-dependent relax- training stimulus can induce significantly greater adapta- ation in porcine conduit pulmonary arteries [45]. These tions in the oxidative capacity of inspiratory and expirato- findings on pulmonary vascular reactivity are consistent ry rat muscle than the aforementioned fixed-load tread- with studies reporting training-induced effects on limb mill training protocols [25], possibly because the animals vascular reactivity [51]. These data from pigs confirm in can either: (1) perform intermittent high intensity bouts part a previous training study in male rabbits that re- of exercise for many weeks, and/or (2) reach daily running ported enhanced endothelium-dependent relaxation in distances that are more than those of treadmill exercise pulmonary arteries following 8 weeks of training [8]. The models. It appears that the more intense the training exact mechanisms leading to these changes have not yet regime the greater the adaptations, although there appears been determined but it has been suggested in the porcine to be a threshold beyond which adaptation fails to occur model that acute exercise increases the shear stress im- as demonstrated by severe endurance training [56]. posed upon the endothelial lining of blood vessels leading to increased upregulation of eNOS protein. Surprisingly, To date there are no published reports regarding the much longer training periods (16 weeks) in pigs failed to effects of whole-body endurance training upon cellular change endothelium-dependent relaxation in pulmonary alterations in human respiratory muscle as biopsies are or systemic arteries [45] and no satisfactory explanation is extremely difficult to obtain. However, costal diaphragm forthcoming to explain the apparent discrepancy between samples from chronic heart failure patients, who exhibit short- and long-term training. We know of no human data persistently elevated levels of minute ventilation at rest that speaks for this proposed training effect and, as dis- and during exercise in the face of reduced cardiac outputs, cussed previously, there is no evidence that pulmonary have shown significantly elevated oxidative (64%) and capillaries respond to physical training. In short, these lipolytic (41%) capacities [76]. This illustrates the ability findings point to a previously unappreciated and poten- of the human diaphragm to change its metabolic proper- tially beneficial effect of physical training on the pulmo- ties in response to chronic overload. nary circulation. References 4 Boutellier U: Respiratory muscle fitness and 7 Chadha TS, Birch S, Sackner MA: Oro-nasal exercise endurance in healthy humans. 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J Shoukas AA, Bromberger-Barnea B: Left ven- 989–995. Appl Physiol 1984;57:971–976. tricular hemodynamics during respiration. J Appl Physiol 1979;47:1295–1303. 78 Victor RG, Secher NH, Lyson T, Mitchell JH: 91 Winchester PK, Williamson JW, Mitchell JH: Central command increases muscle sympathet- Cardiovascular responses to static exercise in 66 Roca J, Agusti AGN, Alonso A, Poole DC, Vie- ic nerve activity during intense intermittent patients with Brown-Séquard syndrome. J gas C, Barbera JA, Rodriguez-Roisin R, Ferrer isometric exercise in humans. Circ Res 1995; Physiol 2000;527.1:193–202. A, Wagner PD: Effects of physical training on 76:1710–1717. muscle O2 transport at V˙ O2max. J Appl Physiol Joshua Rodman 1992;73:1067–1976. 79 Wagner PD: New ideas on limitations to John Rankin Laboratory of V˙ O2max. Exer Sport Sci Rev 2000;28:10–14. Pulmonary Medicine 67 Ross KA, Thurlbeck WM: Lung growth in new- Department of Preventive Medicine born guinea pigs: Effects of endurance exercise. 80 Wagner PD, Gale GE, Moon RE, Torre-Bueno 504 North Walnut Street Respir Physiol 1992;89:353–364. JR, Stolp BW, Saltzman HA: Pulmonary gas University of Wisconsin at Madison exchange in humans exercising at sea level and Madison WI 53705 (USA) 68 Sheel AW, Derchak PA, Morgan B, Pegelow D, simulated altitude. J Appl Physiol 1986;61: Tel. +1 608 262 9499, Fax +1 608 262 8235 Jacques AJ, Dempsey JA: Fatiguing inspiratory 260–270. E-Mail [email protected] muscle work causes reflex reductions in resting leg blood flow. J Physiol 2001;537:277–289. 81 Wagner PD: Determinants of maximal oxygen transport and utilization. Annu Rev Physiol 1996;58:21–50. Cardiovascular and Respiratory Response 17 to Exercise

Weisman IM, Zeballos RJ (eds): Clinical Exercise Testing. Prog Respir Res. Basel, Karger, 2002, vol 32, pp 18–29 OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Muscular Alterations in Chronic Obstructive Pulmonary Disease and Chronic Heart Failure at Rest and during Exercise Harry R. Goskera Nicole H.M.K. Uszko-Lencerb Emiel F.M. Woutersa Ger J. van der Vussec Annemie M.W.J. Scholsa Departments of aPulmonology, bCardiology and cPhysiology, Maastricht University, Maastricht, The Netherlands Summary tions of exercise performance, respectively; but recent research has shown that skeletal muscle function is im- Reduced skeletal muscle performance contributes to exer- paired in moderate to severe COPD and CHF and also is cise intolerance in COPD and CHF patients, independent of an important predictor of exercise limitation in both dis- the severity of local organ dysfunction. Striking similarities are eases [2–4]. Muscle function depends, among others, on observed in morphological and metabolic abnormalities in perfusion, muscle mass, fibre composition and energy peripheral skeletal muscle between these two disorders, point- metabolism [5]. It can be inferred that alterations in one ing towards a decreased oxidative capacity. Both diseases also or more of these determinants play a role in reduced mus- share striking differences between peripheral muscles and the cle performance. Indeed, both in COPD and in CHF such diaphragm, which may therefore require a different therapeuti- changes have been found and striking similarities be- cal approach. The following possible underlying factors of mus- tween the two etiologically distinct disorders appear to be cular alterations in COPD and CHF are discussed: hypoxia, present. oxidative stress, disuse, weight loss and altered substrate metabolism. In this paper we will first present an overview of clini- cal studies that have investigated impaired muscle func- According to the definitions of the World Health Orga- tion with special emphasis on muscle morphology and nization chronic diseases are not only characterized by energy metabolism in COPD and CHF. In the second part their primary impairments, but also by the resulting dis- of the paper, potential causes will be discussed including abilities or even handicaps [1]. Although the primary hypoxia, oxidative stress, disuse, weight loss and altered impairments in chronic obstructive pulmonary disease substrate metabolism. (COPD) and chronic heart faulure (CHF) clearly differ, there is a striking resemblance in the systemic conse- Muscular Alterations in COPD and CHF quences of these diseases and their effect on exercise capacity and health status. Skeletal muscle function in Muscle Performance COPD and CHF has long been ignored as potential con- Muscle performance is largely characterized by tributor by focusing on the ventilatory and cardiac limita- strength and endurance. Strength is defined as the capaci- ty of the muscle to develop maximal force and endurance as the capacity of the muscle to maintain a certain force in

time, thus to resist fatigue. Loss of either one of these studies are required to clarify the individual roles of aspects results in muscle weakness and, hence, in im- strength and endurance limitation in peripheral and respi- paired muscle performance. Numerous studies have now ratory muscles in COPD and CHF. convincingly demonstrated that COPD and CHF are commonly associated with muscle weakness [6–8]. Ham- Muscle Morphology ilton et al. [3] found significantly reduced strengths of In both CHF [10, 23] and COPD [2, 24–27] marked both peripheral and respiratory muscles in patients suffer- loss of muscle mass or decline in cross-sectional area is ing from respiratory failure, heart failure, or a combina- observed. This muscle wasting plays an important role in tion of both as compared to healthy subjects. However, the loss of exercise tolerance in these patients. Morpholog- strength and endurance seem not to be affected in the ical alterations may also be related to muscle function same way in respiratory and peripheral muscles. This is impairment, although direct relationship with exercise illustrated by the poor correlation between the strengths performance have not (yet) been shown. Some histologi- of both muscle groups in both disorders [7, 8], compared cal information is available on abnormalities in skeletal to a much stronger correlation in healthy subjects [9]. It muscle in CHF but hardly any on COPD. Recently, implies that the strength component of muscle weakness reduced fibre cross-sectional area has been demonstrated is affected differently in peripheral and respiratory mus- in the vastus lateralis of COPD [28] and CHF [29]. Gertz cles. In healthy subjects, as well as in patients, exercise et al. [30] found no sings of increased fibrosis or other limiting symptoms are the sense of leg effort (exertional alterations in intercostal muscles from patients with respi- discomfort) and/or breathlessness (exertional dyspnoea) ratory failure, whereas endomyosal fibrosis has been [10, 11]. Despite correlations between peripheral muscle found in skeletal muscle of a limited number of CHF strength and performance in COPD and CHF [7, 10], patients [31]. Increased acid phosphatase activity, a lyso- reduced endurance (Ffatigue) seems to be the dominat- somal enzyme contributing to protein degradation, has ing limiting factor in peripheral muscles in these patients, been found in the quadriceps of some patients with CHF since the sense of leg effort was one of the main reasons to [32] or respiratory failure [27]. Increased lipid deposits stop exercise [3, 11–13]. Recently, it has been shown that have been found in the quadriceps, biceps and deltoids of early lactic acidosis occurs in COPD during exercise [14] some patients with CHF [27, 32]. Very contradicting and that this is largely the result of lactate release from the results have been obtained with respect to capillary densi- lower exercising limb [15]. In CHF reports lactate release ty in peripheral skeletal muscle in CHF. A normal capil- is thought to be a result of decreased blood flow to the lary density has been found [27], which is in confirmation peripheral muscles. Muscle acidosis is a contributing fac- with other studies where both a reduced capillary/fibre tor to muscle fatigue [16]. ratio and atrophy resulted in an unchanged capillary den- sity [32]. An unaltered capillary/fibre ratio has also been Fatigue probably is not the main limiting factor in reported; however, capillary density increased due to fibre respiratory muscle function. Morrison et al. [17] found atrophy [34]. In contrast, reduced capillary density in that COPD subjects have decreased respiratory muscle combination with a reduced capillary/fibre ratio has been strength and endurance. Fatigue of the respiratory muscle shown in CHF patients [35] and even in heart transplan- may indeed occur during exercise, but it is not certain tation recipients [36]. Thus, there is an overall tendency whether this is an independent determinant of exercise for a reduced capillary/fibre ratio, but depending on the capacity [12, 18, 19]. In addition, it is unlikely that the degree of atrophy the capillary density may even be respiratory muscles from exercising COPD patients con- increased. This has recently been confirmed for COPD tribute to the lactate response mentioned earlier [20]. It [25]. In a few studies morphometry of mitochondria has also should be emphasized that the respiratory muscles been performed using electron microscopy, showing that must operate against the mechanical airway impedances mitochondrial volume densities in skeletal muscle are in this specific disorder [21], for which the force compo- lower in CHF patients compared to control subjects [35, nent of respiratory muscle function is most likely of great 37], which was still the case 10 months after heart trans- importance. For CHF it was found that respiratory mus- plantation [36]. Histochemical alterations reflecting mito- cle strength and not respiratory muscle fatigability corre- chondrial abnormalities have also been reported in biceps lated with the degree of dyspnoea [22]. It thus seems that muscle biopsies of COPD patients [27]. These results sug- strength is the limiting aspect of muscle performance in gest that oxidative capacity in peripheral skeletal muscles the respiratory muscle, whereas endurance limitation may be altered. dominates in peripheral muscles. However, more detailed Muscular Alterations in COPD and CHF 19

Muscle Fibre Type Distribution fatique-resistant, but less strength adapted muscle. This The most remarkable muscle alteration in COPD and too is in line with our notion that strength and not fatigue CHF is a relative shift in fibre composition which seems seems to be the main limiting factor for respiratory mus- to occur in opposite direction in peripheral and respirato- cle function. ry muscle. Fibre typing is mainly performed histochemi- cally, based on the differences in myosin ATPase activi- Muscle Energy Metabolism ties, or immunocytochemically [38]. Adult mammalian skeletal muscle contains four myosin heavy chain Considerable amounts of data are available on skeletal (MyHC) isoforms, namely type I, IIa, IIb and IIx [39]. In muscle metabolism in CHF and COPD, partly because of most older studies fibre typing is limited to determining the applicability of 31P-nuclear magnetic resonance (31P- fibre types I, IIa and IIb. Furthermore, human fibres for- NMR) which has enabled a direct and non-invasive merly identified as being IIb with myosin ATPase stain- assessment of tissue levels of high-energy phosphates and ing are probably IIx fibres [40]. Therefore the notation pH. High levels of adenosine triphosphate (ATP), crea- IIb/x will be used in the subsequent text. Fibre type I has a tine phosphate (CrP) and nicotinamide adenine dinucleo- slow-twitch and develops a relative small tension, but tide in the reduced form (NADH) reflect a high energy since it depends mainly on aerobic metabolism it is state, whereas elevated levels of adenosine diphosphate fatigue resistant. In contrast, fibre type IIb/x has a fast- (ADP), adenosine monophosphate (AMP), inorganic twitch and develops large tensions, but it is susceptible for phosphate (Pi) and oxidized nicotinamide adenine dinu- fatigue, since in type IIb/x fibres energy conversion is cleotide (NAD+) commonly reflect a low energy state. based on anaerobic, glycolytic metabolism. Fibre type II Lactate and glycogen levels are often measured, but it has intermediate properties in that it also has a fast must be noted that low levels may reflect either increased twitch, develops a moderate tension, is relatively resistant clearance or reduced formation and vice versa for high to fatigue and is apt to work under both aerobic and levels. Although activities of enzymes involved in muscle anaerobic conditions [5, 38]. A decrease of the percentage energy metabolism do not reflect the physiological situa- of type I fibres and a corresponding increase in type II tion since only maximal activities are obtained under the (mainly type IIb/x) fibres compared to normal subjects optimal circumstances of in vitro measurements, they do has been reported for COPD [25, 41, 42] and for CHF provide an indication for adaptations in expressions of [32–35, 43] in limb muscles. In addition, recently we proteins involved in metabolic pathways. Typical oxida- demonstrated increased proportions of I/IIa and IIa/IIx tive enzymes are citrate synthase (CS), succinate dehydro- hybrid fibres in COPD [44]. These fibres may represent genase (SDH) and ß-hydroxyacyl-CoA dehydrogenase transformation intermediates in the I→IIx shift. In con- (HAD). Typical glycolytic enzymes are hexokinase (HK), trast to peripheral muscles, a shift from type IIb/x to type I phosphofructokinase (PFK) and lactate dehydrogenase fibres has been reported in the diaphragm in both COPD (LDH), the latter catalysing the last step of anaerobic gly- and CHF patients. Despite some variation in the results colysis. Measurements of substrate and cofactor levels in obtained till now, there is most likely a I→IIb/x shift in peripheral skeletal muscle of COPD and CHF patients peripheral muscles and a IIb/x→I shift in the respiratory indicate impaired energy metabolism (see table 3). Most muscle. It is feasible that these shifts have functional con- striking are the observed reduced levels of the high-energy sequences in the affected muscles, since the distinct fibre phosphates in rest. Pouw et al. [46] observed higher Pi/ types have different contractile properties with respect to Crp and ADP/ATP ratios associated with slightly, but sta- twitch and fatigue resistance. Therefore, in COPD and tistically significantly elevated inosine monophosphate CHF, a I→IIb/x shift accompanied by more glycolytic and (IMP) levels. The latter may be due to increased degrada- less oxidative capacity in peripheral muscles implies loss tion of accumulating AMP by deamination, which proba- of fatigue resistance. This change might contribute to the bly reflects reduced aerobic capacity [47]. The situation observed loss of exercise tolerance, since peripheral mus- becomes even worse during exercise: greater increase of cle fatigue is the main limiting factor in these patients. the Pi/CrP ratio and a faster drop in pH were found in the This is confirmed by a study in which a faster twitch calf muscle of COPD patients [48, 49] and of CHF response in combination with less resistance to fatigue patients [34, 50, 51] performing exercise. Similar results was observed in leg muscles of CHF patients [45]. Accord- have been obtained for the forearm muscle [51, 52] (ta- ingly, a IIb/x→I shift towards more oxidative metabolism ble 1). In addition, a slower recovery of CrP was observed in the respiratory muscle implies a shift towards a more 20 Gosker/Uszko-Lencer/Wouters/ van der Vusse/Schols

Table1. Changes in muscle energy Disorder Ref. Muscle Variables of NMR spectroscopy metabolism during exercise PCr Pi/PCr PCr/(PCr+Pi) ATP relATP pH COPD 54 calf ↓ ↓ ↓ 53 calf ↑ = ↓ ↑ ↓ = 55 calf = = ↑ ↓ 56 quadriceps ↓ NS == ↑↓ =↑ = 57 forearm ↓ == ↓ 58 forearm ↑ ↓ ↓ CHF 60 calf* = = = 60 calf** 59 calf ↓ NS 34 calf 61 calf 57 forearm Pi = Inorganic phosphate; PCr = phosphocreatine; ATP = adenosime triphosphate; relATP = ATP corrected for Pi/PCr; ↑ significantly increased compared to controls; ↓ signifi- cantly decreased compared to controls; = means in patients not significantly different from controls; * compared to sedentary controls; ** compared to trained controls. Table 2. Muscle energy metabolism in the recovery phase after exercise Disorder Ref. Muscle Variables of NMR spectroscopy PCr/RT1/2 PCr/(PCr+Pi)/RT1/2 Pi/PCr RT1/2 pH pH/RT1/2 COPD 53 calf ↑ ↑ ↑ CHF 54 calf = ↑ ↓↑ 55 calf ↑ 58 forearm = 57 forearm ↑ = ↑ 60 calf* ↓ ↑ ↓ NS 60 calf** 61 calf 57 forearm Pi = Inorganic phosphate; PCr = phosphocreatine; RT1/2 = recovery halftime; ↑ significantly increased compared to controls; ↓ significantly decreased compared to controls; = means in patients not significantly different from controls; * compared to sedentary controls; ** compared to trained controls. after exercise [34, 49–52]. COPD patients also show a found no difference between patients and sedentary con- prolonged half-time (RT½) for pH [53–55, 57, 58] (ta- trols and concluded deconditioning being an important ble 2). These results suggest that rephosphorylation of factor for the abnormalities. In addition, glycogen con- high-energy phosphates is less efficient in these patients tents in patients tend to be lower, whereas lactate levels both during and after muscular exercise. In CHF patients, are higher (table 3). It thus seems that anaerobic energy Chati et al. [60] compared NMR spectra of calf muscles metabolism is enhanced and since this process yields far during exercise with sedentary and trained controls. They less ATP compared to complete oxidative degradation of Muscular Alterations in COPD and CHF 21

Table 3. Muscle metabolite concentrations in COPD and CHF Table 4. Muscle enzyme activities Metabolite Muscle Disorder Direction References Enzyme Muscle Disorder Direction References CrP QF COPD ↓ 30, 124, 125, 126* CS QF COPD ↓ 130, 131 ATP QF CHF ↓ 127, 128* HAD QF CHF ↓ 32, 34, 129, 132 IMP SDH DIA CHF ↑ 133 Glycogen QF COPD ↓ 30, 124, 125, 126* LDH Lactate QF CHF ↓ 127, 128* QF COPD ↓ 130, 131 Pyruvate HK QF CHF ↓ 32, 34, 129, 132 TA COPD ↑ 46 PFK DIA CHF ↑ 133 QF CHF ↓ 32, 127, 128 QF COPD ↓ 131 QF COPD ↓ 124, 125* QF CHF ↓ 32, 132 QF COPD ↑ 30, 126 QF COPD ↑ 131 QF CHF ↑ 129 QF CHF ↑ 129* DIA CHF ↓ 133 QF CHF ↑ 32 DIA COPD ↓ 134 QF COPD ↑ 14 QF CHF ↓ 132 ATP = Adenosine triphosphate; CrP = creatine phosphate; IMP = DIA COPD ↓ 134 inosine monophosphate; QF = quadriceps femoris; TA = tibialis anterior; * nearly reached significance. QF COPD ↑ 131 CS = Citrate synthase; HAD = ß-hydroxyacyl-CoA dehydroge- nase; SDH = succinate dehydrogenase; HK = hexokinase; PFK = phosphofructokinase; LDH = lactate dehydrogenase; QF = quadri- ceps femoris; DIA = diaphragm. glucose this could explain the reduced high-energy phos- muscle tissue may become hypoxic and this could lead to phate levels. the adaptive changes in skeletal muscle as those described above. In this respect relevant information is now avail- Analysis of enzyme activities too suggest an overall able from mountaineering expeditions (lasting at least 6 increase of glycolytic and an overall decrease of oxidative weeks above 5,000 m), since oxygen is limited at this alti- activities in peripheral muscles of both COPD and CHF tude. Under these conditions reductions in mitochondrial patients (table 4). Since these enzyme activities depend volume densities, in oxidative enzyme activities and in largely on the fibre type [62], it is likely that this shift in cross sectional areas of muscle fibers were found in the activities is related to the shift in fibre distribution men- quadriceps [63, 64]. But such expeditions are accompa- tioned above. Whether enzyme activities adapt to the nied by strenuous physical activity, which also causes fibre type redistribution or the other way around remains muscular adaptations other than those caused by hypoxia. unclear. Due to technical difficulties with 31P-NMR and In fact, the effect of training in combination with hypoxia muscle biopsies of the diaphragm and accessory respirato- may even cause a shift towards more oxidative metabo- ry muscles, very little is known about energy metabolism lism [65]. in these muscles. However, the observed alterations for enzyme activities (table 4) are in confirmation with the More information about the effect of hypoxia on mus- morphological data, in that oxidative enzyme activities cle has been obtained from animal studies. Several of are reduced and glycolytic enzyme activities are in- these studies have shown that hypoxia can indeed lead to creased. As in peripheral muscles, this shift probably the muscular alterations as described for limb muscles in results from the shift in fibre type distribution. COPD and CHF: (1) Reduced fibre diameters in combi- nation with unaffected numbers of capillaries, resulting in Possible Underlying Factors increased capillary densities, have been reported in rats exposed to hypoxia [66, 67]. (2) Some studies revealed Hypoxia that hypoxia depresses protein synthesis [68, 69], includ- In COPD and CHF oxygen delivery to peripheral and respiratory muscles may be insufficient, caused by either hypoxemia and/or reduced blood supply. In both cases 22 Gosker/Uszko-Lencer/Wouters/ van der Vusse/Schols

ing in muscle tissue [68]. Chronic hypoxia inhibits the ulating trigger resulting in a reduced antioxidant status. normal conversion of type IIa to type I fibres in growing Chronic hypoxia probably acts in the same way, since lim- rats, resulting in a predominating proportion of type IIa itations of oxygen supply are indeed found to be associat- fibres compared to control rats [70]. So hypoxia does not ed with reductions in SOD activity in mammalian tissues directly cause a type I → II fibre shift, but causes an like brain, lungs and heart, although this change was not abnormal fibre type distribution from alterations in mus- found in skeletal muscle tissue [87, 88]. In addition, in cular development. It is feasible that in COPD and CHF a myocytes (obtained from chronic hypoxic human myo- similar mechanism underlies the abnormal fibre type dis- cardium) cultured at low oxygen tension, antioxidant tribution in the regeneration of damaged muscle or the enzyme activities were lower than in myocytes cultured at adaptation of muscles to consequences of the disease. a higher oxygen tension, illustrating the direct modulatory (3) There is evidence that hypoxia causes a shift towards effect of oxygen [89]. In vivo and in vitro hypoxia-reoxy- glycolytic metabolism, resulting in an increased lactate- genation studies revealed that oxygen oversupply follow- to-pyruvate ratio [71, 72] and reduced malate dehydroge- ing a period of oxygen shortage may give rise to free radi- nase, a citric acid enzyme [73]. (4) Hypoxia causes stimu- cal formation in myocytes [87, 90]. Accordingly, in lation of glucose transport [74] and increased levels of COPD and CHF chronic hypoxia may result in a reduced membrane-associated glucose transporters (GLUT1 and antioxidant status and occasional bouts of exercise may GLUT4) in rat muscle [75]. cause a boost of free radicals exceeding the capacity of the defence system [78]. It is also feasible that the reduced It should be noted, however, that in COPD and CHF oxidative capacity in the patients itself leads to enhanced this reduction of oxidative capacity does not occur in the oxidative stress, since the sudden oversupply of oxygen diaphragm. It is feasible that hypoxia causes an endur- during exercise is inefficiently metabolised. ance training effect in the diaphragm due to increased ventilation, which overrides its direct effect ultimately Reactive oxygen species are well capable of damaging resulting in a shift towards more aerobic metabolism. lipids and proteins [78, 79, 86, 91]. Radicals that react with fatty acyl moieties in membrane phospholipids cause Oxidative Stress a chain reaction of peroxidations increasing the mem- Oxidative stress may be another factor contributing brane permeability [91]. Maintenance of membrane in- via reactive oxygen species to muscle damage. In both tegrity is crucial for: (1) Adequate functioning of the respi- COPD and CHF increased plasma levels of lipid peroxi- ratory chain, since the driving force for oxidative ATP dation products have been found [76, 77]. Sources of free synthesis is the electrochemical proton gradient over the oxygen radicals are: (1) Mitochondria, since 2–5% of the inner membrane of the mitochondrion, which is gener- total oxygen consumed is not fully reduced in the electron ated during the electron transfer from NADH to oxygen transport chain and may leak away as superoxide radicals [92]. (2) To prevent intracellular calcium overload, [78, 79]. (2) Immune cells activated during inflammation caused by damaged sarcoplasmatic reticulum membrane, [80]. Monocytes and macrophages produce cytokine tu- in combination with impaired activity of calcium mor necrosis factor-· (TNF·) which may in turn induce ATPases, which accompanies oxidative stress in animal oxidative stress in myocytes [81]. Elevated TNF· blood myocytes [78, 87, 90, 93], and may further uncouple res- levels have indeed been found in both COPD [82, 83] and piration from ATP production through extensive depolar- CHF [84, 85], in particular in those patients characterized isation of the inner membrane [94]. by weight loss and/or muscle wasting. (3) Xanthine oxi- dase, in case of a low energy state, is involved in the degra- Protein oxidation by oxygen free radicals leads to for- dation of AMP [79]. The above-mentioned elevated IMP mation of carbonyl groups on amino acid residues, which levels in COPD [46] indeed suggest enhanced AMP may modify the structure and/or chemical properties of breakdown. Susceptibility to these free radicals largely the proteins affected [95]. These alterations may cause depends on the antioxidant status of tissue [79]. The main decline in function or even complete protein unfolding. antioxidant scavengers and enzymes are, amongst others, The latter gives rise to enhanced susceptibility to protein- reduced glutathione, vitamin E (in cell membranes), su- ases. These modified proteins may also be recognized as peroxide dismutase (SOD), glutathione peroxidase and foreign substances and, hence, be attacked by the immune catalase [79, 86]. Long-term training stimulates the de- system. Whether radical induced protein damage plays a fense system against oxygen free radicals [78, 79, 86] and role in the abnormalities in muscles of COPD and CHF the disuse of muscles thus may lack this antioxidant stim- patients is unclear. It has been shown in animal studies that in vivo induced oxidative stress caused myofibrillar Muscular Alterations in COPD and CHF 23

muscle protein modification and that these proteins were weight loss can be distinguished: predominant loss of fat rapidly degraded by proteases [96]. Thus theoretically, mass, predominant loss of fat-free mass or a combination muscle atrophy can be enhanced by radical induced pro- of both. Predominant loss of fat mass involves an im- tein damage. Indeed, it has been shown that a calcium paired balance between energy requirement and energy overload is involved in muscle atrophy [97] and that vita- intake. Although limited information is available in CHF min E deficiency facilitates muscle wasting and necrosis patients, a negative energy balance commonly occurs in [98], both probably mediated by oxidative damage to pro- COPD as a result of either a decreased dietary intake, ele- teins. Also, in human skeletal muscle it has been shown vated energy requirements or a combination of both. that mitochondria and mitochondrial proteins were more Total daily energy metabolism (TDE) can be divided in 3 susceptible to oxidative damage compared to other sub- components: resting energy expenditure (REE), measured cellular components [99], which suggests that protein under fasting conditions in the early morning, diet in- damage may cause impaired oxidative metabolism. duced thermogenesis (DIT) and physical activity induced (PAI) thermogenesis. REE comprises the major part of As opposed to necrosis, which is the result of exoge- TDE, DIT on average only 10–15% and PAI can be highly nous damage as described above, apoptosis of muscle cells variable. While in many chronic wasting diseases, REE is is an active process of cell death, which recently also has increased, probably related to an enhanced systemic in- been associated with oxidative stress [100]. In this study flammation, TDE is not different from healthy control the exposure of rat myoblasts to nitric oxide or hydrogen subjects due to a compensatory decrease in daily activi- peroxidase led to apoptotic cell death. Since these chemi- ties. In contrast, TDE in COPD was found to be increased cal stimuli are also released by immune cells, it cannot be as a result of an increased PAI [110]. It is yet unclear to excluded that apoptosis underlies muscle wasting during what extent an increased PAI is related to a decreased inflammation. mechanical or a decreased metabolic efficiency and what the contributing role is of peripheral skeletal muscles ver- Disuse sus the diaphragm. Disuse (low level of physical exercise because of their disease) of skeletal muscle is also a factor that most likely In a situation of semistarvation, either primarily due to contributes to the observed muscle alterations in COPD increased energy requirements or due to decreased dietary and CHF. This results in: (1) Muscle weakness, due to intake, loss of both fat mass and fat-free mass occurs, but reduced motor neuron activity and muscle wasting [38, the loss of fat-free mass is relatively preserved. Therefore, 101]. (2) Relative reduction in the percentage of type I intrinsic muscle abnormalities besides loss of muscle fibres and an increase in the percentage of type IIb/x mass must account for impaired muscle performance. fibres [38, 102]. (3) A decline in activity of enzymes Studies on muscle function and histology in anorexia ner- involved in oxidative energy conversion, which occurs vosa patients provide strong data on the effect of under- both in type I and type II fibres [102], suggesting that it nutrition per se on muscles. Muscle performance is mark- can occur even without any change in fibre composition. edly impaired in these patients [111–113] and is associat- (4) A negative effect on the antioxidant status enhances ed with weight loss, loss of muscle mass and fibre atrophy the risk of oxidative damage. As mentioned above, the (particularly of type II fibres) [114, 115]. We recently diaphragm is probably not disused and a kind of endur- demonstrated selective fibre type IIx atrophy in COPD ance training effect may even occur. This may not only be patients associated with a reduced fat-free mass, suggest- true for COPD, but for CHF as well, since especially in ing a role for undernutrition in this disease too [44]. Data severe CHF dyspnoea and elevated ventilation occur from animal studies confirm these effects of undernutri- already at rest [13, 103]. tion. Decreased activities of enzymes involved in glycolyt- ic and mitochondrial pathways have been reported from Weight Loss and Altered Substrate Metabolism muscle biopsies of patients with anorexia nervosa [99, Weight loss commonly occurs in COPD [104, 105] and 111], with glycolytic capacity being affected the most in CHF [23, 106] and is an independent determinant of [111]. The contribution of nutritional depletion to a shift mortality [107, 108]. In both disorders in particular loss of from oxidative to glycolytic metabolism in COPD and FFM is an important determinant for exercise capacity [2, CHF patients needs further investigation. 24, 109]. Determination of body composition, and not only weight, with respect to nutritional depletion is very Disproportionate loss of fat-free mass often referred as important since at least in COPD different patterns of cachexia, involves an impaired balance between protein anabolism and catabolism. Protein depletion itself may 24 Gosker/Uszko-Lencer/Wouters/ van der Vusse/Schols

impair skeletal muscle performance as reflected by re- muscle GLU [14]. Not only at rest, but also during 20 min duced maximum voluntary handgrip strength, reduced of submaximal constant cycle exercise a different re- respiratory muscle strength and an increased fatigability sponse in amino acid status was found in skeletal muscle of in vivo electrically stimulated adductor pollicis muscle and plasma of COPD patients as compared with healthy [116]. Predominant loss of fat-free mass with relative age-matched controls [123]. A significant reduction of preservation of fat mass also points towards alterations in most muscle amino acids was present postexercise, where- substrate metabolism. Partly independent of pulmonary as several plasma amino acids were increased, suggesting or cardiac cachexia, other disease characteristics like hyp- an enhanced amino acid release from muscle in COPD oxia or hypercapnia may alter substrate metabolism. during exercise. The increase in plasma alanine and gluta- Insulin has a central role in substrate metabolism. Hyper- mine was even higher postexercise, suggesting enhanced insulinemia has been described in COPD and insulin nitrogen efflux. Although investigation of substrate me- resistance commonly occurs in CHF. While nearly no tabolism in COPD and CHF is still in its infancy, the data are available regarding carbohydrate and fat metabo- available studies clearly point towards therapeutic per- lism in fasting, fed or stressed states, protein metabolism spective, not only in cachectic patients, but also as ana- has been subject of recent investigations in COPD. In bolic stimulus to enhance muscle and exercise perfor- nondepleted COPD patients, an increased whole-body mance. In frail elderly it has indeed been observed that protein turnover was observed at rest and specifically in oral amino acid intake stimulates the transport of amino emphysema a suppressed whole body protein turnover acids into muscle, and that there is a direct link between was observed during and immediately after exercise [118, amino acid transport and protein synthesis when ingested 119]. Whole-body protein turnover, however, does not before exercise or some time after exercise. necessarily reflect muscle protein turnover. A study in underweight patients with emphysema reported a re- Conclusions duced muscle protein synthesis [117], while protein deg- radation was not increased [119, 120]. It is feasible that This review underscores that reduced skeletal muscle amino acids are required in other processes than muscular performance markedly contributes to exercise intolerance protein synthesis, such as gluconeogenesis. Besides, recent in COPD and CHF patients. Morphologic and metabolic data also showed intrinsic alterations in the amino acid abnormalities occur in the skeletal muscles of these pa- profile of peripheral skeletal muscles. Most consistent tients which, in both disorders, probably are determined results were found with respect to the amino acid gluta- by the same set of contributing factors. Both diseases also mate (GLU). Intracellular GLU has various important share striking differences between peripheral muscles and functions, as it plays an important role in preserving high- the diaphragm which, therefore, may require a different energy phosphates in muscle through different metabolic therapeutical approach. mechanisms. GLU concentration is high in the free ami- no acid pool of human skeletal muscle. Intracellular GLU is known as an important precursor for the antioxidant glutathione (GSH) and glutamine synthesis in the muscle. Muscle GLU is indeed highly associated with muscle GSH, and patients with emphysema suffer from de- creased muscular GLU and GSH levels [122]. Studies have shown that in healthy human muscle, the GLU pool functions to generate tricarboxylic acid (TCA) interme- diates during the first minutes of exercise, which is achieved via the alanine aminotransferase reaction (pyru- vate + GLU → alanine + ·-ketoglutarate) at the cost of GLU. Moreover, this reaction can shunt the pyruvate accumulated during exercise towards alanine instead of lactate, suggesting a possible role of the intracellular GLU level in the lactate response to exercise. In line with this hypothesis early lactic acidosis during exercise in patients with COPD was indeed associated with a reduction in Muscular Alterations in COPD and CHF 25

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Weisman IM, Zeballos RJ (eds): Clinical Exercise Testing. Prog Respir Res. Basel, Karger, 2002, vol 32, pp 30–42 OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Modalities of Clinical Exercise Testing R. Jorge Zeballosa Idelle M. Weismanb aDepartment of Internal Medicine, Texas Tech University Health Sciences Center and Department of Clinical Investigation, Human Performance Laboratory, William Beaumont Army Medical Center, El Paso, Tex.; b Human Performance Laboratory, Department of Clinical Investigation, Pulmonary-Critical Care Service, William Beaumont Army Medical Center, El Paso, Tex., and Department of Medicine, Pulmonary-Critical Care Division, University of Texas Health Science Center at San Antonio, San Antonio, Tex., USA Summary 5]. Furthermore, exertional symptoms correlate poorly with resting cardiopulmonary measurements [4, 6]. Currently, clinical exercise testing is increasingly utilized in clinical practice in order to optimize patient management and There are several modalities of clinical exercise testing provide answers to questions not available from resting cardio- used in clinical practice. Some provide basic information, pulmonary tests. There are several modalities of clinical exer- are low tech, and simple to perform, while others provide cise testing designed to evaluate and to answer different clinical a more complete assessment of all the physiological sys- question(s). The selection of clinical exercise testing modality tems involved in exercise and require more complex tech- should be based on the clinical question, facilities and expertise nology. Table 1 shows the most popular clinical exercise available including consideration of the cost effectiveness of the tests in order of increasing complexity. different tests. The most popular clinical exercise tests are the 6-minute walk test, exercise-induced bronchospasm test, car- Modality selection should be based on the clinical diac stress test and cardiopulmonary exercise test. The main question(s) to be addressed and on the available equip- applications of clinical exercise testing include the evaluation of ment and facilities. Some examples of clinical scenarios exercise intolerance and unexplained dyspnea; early diagnosis that can be encountered and the appropriate clinical exer- of cardiopulmonary diseases; evaluation of coronary artery dis- cise modality to be used follow. A test for exercise- ease and exercise-induced asthma; assessment of functional induced bronchospasm would be appropriate for a patient capacity; preoperative surgical evaluation; prognosis of cardio- who is young and complains of breathing difficulties post- pulmonary diseases; evaluation of therapeutic interventions; exercise. However, asthma has a bimodal distribution oxygen prescription, and prescription for pulmonary rehabilita- and exercise-induced bronchoconstriction as a cause of tion. unexplained dyspnea occurs commonly in older patients [7]. For a patient over 40 years old with chest tightness Clinical exercise tests are utilized in a variety of clini- and/or chest pain triggered by exercise, a cardiac stress cal situations [1]. They provide functional information test on a treadmill would be the first choice, although the useful for patient management which cannot be obtained use of a cycle ergometer would also be acceptable. If these from resting pulmonary and/or cardiac measurements [2– modalities were not available, a Master two-step test could be another less frequently used alternative. If the The opinions or assertions contained herein are the private views of reason for testing is the diagnosis of unexplained dyspnea the authors and are not to be construed as official or as reflecting the or exercise intolerance, early cardiopulmonary exercise views of the Department of the Army or the Department of De- testing (CPET) would be most beneficial in clinical deci- fense. sion-making [8]. CPET is also most appropriate in situa- tions in which it is important to differentiate between car- diac and pulmonary etiologies for exercise limitation; to answer questions related to underlying mechanisms of

Table1. Modalities of clinical exercise testing Modalities Technical Intensity Evaluation Standar- Repro- Cost requirement dization ducibility Stair climbing 0 Near max/max Postoperative risk 0 0 0 Functional capacity Master two-step + Near max + ++ $ test Ischemia 6MWT + Submax/near max Functional capacity ++ ++ $ Shuttle test ++ Max +++ ++ $ EIB +++ Submax Functional capacity ++ ++ $$ GXT +++ Submax +++ +++ $$$ Functional capacity CPET ++++ Max ++ +++ $$$$ Airway hyperreactivity Ischemia Arrhythmias Functional capacity Global/individual system function 6MWT = 6-min walk test; EIB = exercise-induced bronchospasm; GXT = cardiac stress test; CPET = cardiopul- monary exercise test. exercise limitation, and when it is necessary to objectively used stair climbing to assess postoperative risk before determine aerobic capacity (V˙ O2 peak) as in patients more advanced techniques like CPET were available. being evaluated for cardiac transplantation. When the Stair climbing is still used in some clinical centers for its reason for the test is to evaluate the functional response to practicality in the evaluation of postoperative complica- a medical intervention, the six-minute walk test (6MWT) tions. This test imposes a progressive stress on the cardio- would probably be the more cost effective; alternatively, a pulmonary system and skeletal muscles, providing a basic shuttle test could also be used, but is technically more assessment of functional capacity. demanding. Recent work, however, has demonstrated that a constant work CPET is more sensitive than 6MWT Methodology in detecting responses to treatment [9]. For evaluation of There is no standardized procedure or consensus on heart and/or lung transplantation, either the cardiopul- how to perform the test. Variations in methodology and in monary (preferable) or the 6MWT can be used. Often the reporting of results among different authors make they are used together as they provide complementary comparisons of results difficult. information. Interpretation of CPET results may be more In essence, the test consists of asking the patients to complex, but in turn provide more insight into the differ- climb as many stairs as possible until they are limited by ent etiologies for exercise intolerance [10]. In hospitals symptoms including dyspnea, exhaustion, leg fatigue, that do not have facilities or equipment to perform chest pain and dizziness [11]. Some authors instruct the sophisticated exercise tests, stair climbing could be used patients to climb at their own pace [12] and others at a in the preoperative evaluation of patients for lung resec- brisk pace [11]. Also, some authors ask the patients to use tion. the railing for balance [13] while others ask them to climb without rail holding [11]. To improve reproducibility and Stair Climbing safety it would be better to let the patients choose their own pace (as in the 6MWT) and to use the railing for bal- This is the simplest and most basic of all clinical exer- ance. cise testing modalities, which does not require costly or Optional measurements include the timing of the test sophisticated equipment. Historically, surgeons have and the use of pulse oximetry [12]. In addition, heart rate and dyspnea index have been reported at rest and at the Modalities of Clinical Exercise Testing 31

end of the test in some studies [14]. However, these values tomy demonstrated a mortality of 50% in patients who were not used in the interpretation of the tests. were unable to climb two flights of stairs and that the mor- tality rate decreased to 11% in patients who were able to Another source of variability is the form in which the climb two flights of stairs. In another retrospective study results are reported. The majority of studies report the in patients who had undergone lung resection, the authors results by the number of flights of stairs climbed. How- observed that patients unable to climb three flight of stairs ever, there is no uniformity of the basic definition of one had a higher number of complications compared to pa- ‘flight of stairs’. Some papers include all the stairs be- tients who were able to climb three flights of stairs [16]. In tween floors as one flight and in others they describe two a study of 16 patients at high risk for pulmonary resection, flights of stairs with a landing on the middle between the authors reported that the patients who were unable to floors. Since the number of stairs per flight and the height climb 44 steps had a higher risk of medical complications of the stairs is not the same in all the health centers, it [12]. Girish et al. [13] in a prospective study in patients would be advisable to report the number of stairs climbed undergoing thoracotomy or upper abdominal laparotomy and also the height of the stairs. This information would demonstrated that the inability to climb two flights of allow a better comparison of results among different stud- stairs was associated with a positive predicted value of ies. Another practical approach would be to report the 82% for the development of postoperative complications. results as the number of floors climbed instead of flights The results of the cited studies appear to support the con- of stairs. cept that the inability to climb two flights of stairs may be associated with a higher risk of postoperative complica- For safety reasons, it would be advisable to have a tech- tions. nician trained in cardiopulmonary resuscitation conduct- ing the test. Also, a physician and a resuscitation cart Most recently, stair climbing has been used in other should be available in the proximity were the test is being clinical settings including evaluation of functional capaci- performed. ty in patients with COPD [11, 14]. There are several studies that have measured the ener- Master Two-Step Test gy cost of stair climbing (expressed in kcal and V˙ O2) which are discussed in the paper of Bassett et al. [15] The stress step tests consist of the subject walking up However, some studies cited for measurement of V˙ O2 and down on a stool or bench at an established rate. This during stair climbing in reality were performed during is one of the oldest, most basic and simplest exercise tests. bench stepping or during exercise on the Stair Master. Several variations of the original concept have been done Limited data exist in measurement of V˙ O2 during actual in regard to the step height, rate of step-ups per minute stair climbing. In the study of Pollock et al. [11], V˙ O2 was and number of steps. These different protocols were measured during stair climbing and during a maximal called the Harvard step test, the Master step test, progres- incremental cardiopulmonary exercise test on a cycle sive step test, the graded step test, etc. [18]. The Master ergometer in 31 patients with chronic obstructive pulmo- two-step test is the one that has become the most popular nary disease (COPD). The authors reported a good corre- [19]. lation (r = 0.7) between the number of steps climbed and V˙ O2. Also, the investigators reported that the V˙ O2, heart This test had been widely accepted and used in the past rate and blood pressure were higher at stair climbing peak for the diagnosis of ischemic heart diseases. Its popularity than during peak cycle ergometry. began to decline in the 1970s, although it continues to be used sporadically [20]. The advantages of the test are its Several studies have reported calculated V˙ O2 during simplicity, low-tech equipment, and that it is fairly inex- stair climbing [12, 16], but as has been discussed pre- pensive. The disadvantages include difficulty in measur- viously the calculations have a significant margin of error ing work rate, safety issues related to the risk of stumbling, and also they complicate unnecessarily the test. and difficulty in cardiac monitoring, and in performing cardiopulmonary measurements. This step test is suitable Applications of the Stair Climbing Test for office and field studies. With the step tests it is possible The main application of stair climbing is in the preop- to reach V˙ O2max or near V˙ O2max [21]. erative evaluation of postoperative complications of pa- tients undergoing thoracic or upper abdominal surgery. It is unclear when stair climbing began to be utilized in the evaluation of surgical patients. Van Nostrand et al. [17] in a retrospective study in patients undergoing pneumonec- 32 Zeballos/Weisman

Methodology Table 2. Applications of the 6MWT The equipment consists of three steps (benches) in a row: the first one is 9 in high, the middle is 18 in, and the Evaluation of medical interventions last is 9 in. The subject walks up and down the three steps. Pharmacological After going up and over, the patient then turns and repeats the procedure for a determined number of times Patients with heart disease [76] to be completed in 1.5 min [19]. The number of ascents is Patients with pulmonary disease [9] chosen from tables established for men and women based Surgical on age and weight [22]. ECG is monitored before and Lung transplantation [77] immediately after the test or continuously during the Lung resection [12] test. Lung volume reduction surgery [78, 79] Pulmonary rehabilitation [80] Six-Minute Walk Test Prediction of morbidity and mortality The 6MWT is gaining popularity because it is a practi- Patients with heart failure [77, 81] cal, simple test to perform that does not require high-tech Patients with COPD [82] equipment or advanced technical training and because it Primary pulmonary hypertension [83] provides an objective assessment of exercise tolerance/ functional status (capacity). Also, walking is an activity Evaluation of functional capacity familiar to almost everyone [23]. Patients with heart disease [56, 84] Patients with pulmonary disease Traditionally, the qualitative evaluation of functional capacity has been done by clinicians questioning their COPD [85] patients about the amount of physical activity performed. ILD [86] Based on this concept, Balke [24] developed a simple test Patients with peripheral vascular disease [87] to evaluate functional capacity measuring the distance Patients with cystic fibrosis [37] run in a 15-min best effort. Cooper [25] used a 12-minute Normal subjects [46] walk test (12MWT) for evaluation of the level of physical As predictor of VO˙ 2 peak [30, 81] fitness of healthy individuals. This test was subsequently adapted to assess disability in patients with chronic bron- CPET. Also, contrary to CPET in which the maximal chitis [26]. In order to accommodate patients with respi- exercise capacity is determined, the 6MWT assesses the ratory disease for whom walking 12 min was too exhaust- submaximal level of functional capacity. ing, Butland et al. [27] shortened the time to 2 and 6 min. They compared the results of these two tests with the stan- Indications dard 12MWT and concluded that: (1) 12 min is an unne- The 6MWT has been used successfully as an outcome cessarily long duration, (2) that the 2-min walk is less pow- measure of different types of interventions, including erful in discriminating between subjects, and (3) that the pharmacological, surgical and pulmonary rehabilitation. 6MWT appeared to be the best option for patients with Also, it is often used for functional assessment in a wide respiratory disease. spectrum of clinical entities. In addition, it had been used with promising results to predict morbidity and mortality This test consists of measuring the maximal distance in patients with cardiopulmonary diseases. A detailed list that a patient can walk on a flat hard surface in a period of of the indications of the 6MWT appears in table 2. 6 min. It is a self-paced walk in a measured corridor [28]. Solway et al. [29] have published a very complete and It evaluates the global and integrated responses of all the comprehensive review of the applications of the walking systems involved during exercise, which includes the pul- tests, including the 6MWT. monary and cardiovascular systems, systemic circulation, peripheral circulation, blood, neuromuscular units, mus- Important Factors That Impact the Results of the cle metabolism, etc. However, this test does not provide 6MWT specific information on the function of each one of the Length and Shape of the Course. Although most studies different organs and systems involved in exercise and of have used courses of approximately 30 m, there are others the mechanism of exercise limitation as is possible with that have used 20 m [30] and 50 m [31]. It is possible that in a shorter corridor, the distance walked could be less because more turns are involved. However, in a recent study, Wiese [32] did not find significant differences in Modalities of Clinical Exercise Testing 33

Fig. 1. Mean distance walked in the 6MWT by encouraged (d) and encouragement to obtain better results. The encourage- nonencouraged ([) groups of patients. From Guyatt et al. [26], with ment should be consistent for all patients. permission. Supplemental Oxygen. The beneficial effect of O2 sup- the distance walked in straight tracks ranging from 50 to plementation on walking distance has clearly been shown 64 ft. Also, it appears that in a continuous track (round) [36, 38]. If during the first practice test, SpO2 drops below the patients walk longer than in a straight track. 85%, supplemental O2 should be prescribed for subse- quent 6MWT. If O2 supplementation is indicated, all the Training Effect. Walking distance in patients with pul- 6MWT should be performed using the same modality of monary and heart disease can increase significantly with delivery and the same O2 flow. repeated tests; however, no significant changes were dem- onstrated after the third test (fig. 1) [27, 28, 33–36]. In a Medications. A significant improvement in the dis- study in which 24 patients with chronic bronchitis per- tance walked after administration of bronchodilators in formed a 5-minute walk test three times in a day and COPD patients has been demonstrated [39]. Therefore, it repeated it every week for 4 weeks, the distance walked is important to be consistent in the administration of increased continuously from the first test of the first day to medication(s) before the 6MWT. The administration of the last test of the fourth week, even though the mean medication will be determined by the objective of the increase in distance was of 21 m only [34]. Nevertheless, in test. a study in children with cystic fibrosis, no differences were reported between two 6MWTs performed 1 week apart Recommended Methodology for the 6MWT [37]. The observed training effect appears to be related to One of the shortcomings of the 6MWT is the lack of a coordination, stride length, overcoming of anxiety, etc. As widely accepted standardized protocol [40]. This repre- such, it is recommended that two practice tests be per- sents a potential source of intra- and inter-subject vari- formed before baseline measurements are obtained (third ability of an important functional outcome variable. A test). In many clinical situations, it is difficult and imprac- well-performed 6MWT requires attention to several tical to perform two practice tests before the valid one (third methodological issues as recommended by Guyatt et al. test). Since at this time the clinical relevance of the practice [28]. Since the main use of the 6MWT is to follow up med- tests is not clear, it appears that a reasonable approach ical interventions, it is critical that the 6MWT protocol be would be to perform two 6MWTs with at least 1 h of rest applied consistently in all the subjects. The American between them and to report the highest 6MWT. Thoracic Society (ATS) is in the process of publishing a statement with guidelines for the 6MWT [41]. The meth- Encouragement. Guyatt et al. [28, 33] have clearly odology presented in this chapter will incorporate the demonstrated that encouragement significantly increases most popular techniques and procedures actually in use the distance walked by patients (fig. 1). Since the repro- and the recommendations obtained from the draft of the ducibility for tests with and without encouragement was ATS document on the 6MWT [41]. similar, it would be advisable to perform the 6MWT with Track for 6MWT. The 6MWT should be performed indoors, preferably along a long, flat, straight, enclosed corridor (environmental conditions are more comfortable and consistent). The walking course should be 30 m (100- foot corridor) [28]. The extremes of the course should be marked on the floor with colored tape or with traffic cones and the length of the track should be marked every 3 m with pieces of tape stuck to the lower part of the wall. Patient Preparation. Patient instructions for the 6MWT should include wearing comfortable clothing and shoes (sneakers) and avoid vigorous exercise 2 h before the test. In order to minimize intra-individual variability, the 6MWT should be performed at the same time each testing day. A light breakfast is permitted before morning tests. The usual medication regimen should be main- tained the day of the walking test. 34 Zeballos/Weisman

Monitor. The monitor must have a stopwatch or a Measurements. The main outcome of the 6MWT is the countdown timer, a tape measure, a sphygmomanometer, maximal distance walked by the patient in 6 min. Other a worksheet on a clipboard to annotate the results of the measurements including HR, blood pressure, SpO2 and test, and a chair. Optionally, and only when additional perceived dyspnea have been shown not to be useful information is requested, a Borg dyspnea scale and a port- indices of functional capacity; however, they are usually able pulse oximeter would be required. The monitor measured for safety reasons as well as for providing a should be standing near the starting line (do not walk with more complete characterization of patient performance. the patient) keeping track of the time, counting the num- During serial evaluations of medical interventions, it is ber of laps walked and telling the patient the time and possible that improvement may be manifested by reduced words of encouragement. The monitor should stop the symptoms despite no change in the distance walked. test if the patient presents one of the medical complica- Recently, a new approach to the interpretation of the tions described in the ‘Safety Considerations’ section. 6MWT in the assessment of functional exercise tolerance, using a multivariable assessment that includes HR, oxy- 6MWT Protocol. Before beginning the test and prior to gen desaturation, perceived dyspnea and effort has been taking the resting measurements, the patient should be at proposed [43]. rest, sitting on a chair, for at least 10 min. Heart rate (HR) and blood pressure should be measured to check for con- Practice Test. As discussed previously, the need of a traindications. Optionally, the patient’s rate of perceived practice tests to evaluate the functional status of the dyspnea and overall fatigue using the Borg scale [42] and/ patient will be determined for the reason of the test. If it is or SpO2 could be assessed. Measurements should be per- a one time evaluation or the repeated tests are more than formed (standing) before and immediately after the test. 1 month apart, 6MWT evaluation with only one test may be acceptable, but if the medical intervention requires The instructions must be literally the same for all more frequent evaluations, at least two tests would be patients tested and for each test: ‘The object of this test is required with at least 1 h between them. The highest to walk as far as possible for six minutes. You will walk 6MWT should be used as the baseline for the post-inter- back and forth between the marks of the course. Six min- vention tests. utes is a long time to walk, so you will be exerting yourself. You will probably get out of breath or become exhausted. Safety Considerations You are permitted to slow down, to stop, and to rest as Contraindications for the 6MWT are similar to those necessary. You may lean against the wall while resting, described elsewhere for CPET [44]. However, it is un- but resume walking as soon as you are able to do so in known if medical complications would occur if such order to complete the 6MWT. During the test, you will be patients would perform the 6MWT, therefore the suggest- regularly informed of the elapsed time and you will be ed contraindications are dictated by the experience of the encouraged to do your best. Remember that your goal is to investigators and by the need of being prudent. The rea- walk as far as possible in 6 min’ [23, 41]. sons for stopping the 6MWT are similar to the ones rec- ommended for CPET [44]; the most important are [23]: The words of encouragement and notification of time chest pain, intolerable dyspnea, mental confusion or lack should be also consistent for all the patients. Each minute of coordination, leg cramps, sudden onset of pallor, sweat- of the test, the monitor will provide the same encourage- ing, evolving lightheadedness and SpO2 !85% (if moni- ment telling the patient ‘You are doing well’ or ‘keep up tored). the good work’ (do not use other words of encouragement) It appears that the exercise risks are less than for and will also tell the patient the minutes left to the end of CPET, since in the 6MWT, the patients determine the the test, in order to help adjust and maintain a good pace intensity of exercise that ‘they know they can tolerate safe- [33, 41]. For example, ‘you are doing well, you have four ly’. The 6MWT has been used safely in 800 patients with minutes to go’. cardiomyopathy or primary pulmonary hypertension [45]. Enright and Sherrill [46] performed this test in thou- At the end of the 6 min, the monitor must instruct the sands of elderly persons without untoward events. patient to stop and mark the place with a tape. He/she The technician performing the test must have training must immediately perform the pertinent measurements in cardiopulmonary resuscitation. The presence of a phy- (HR, blood pressure, Borg scale, SpO2). The distance sician is not necessary, however it would be advisable if walked is measured using the number of completed laps he/she is available in the same building where the test is (60 m) plus the distance to the start point, using as a guide the markers placed on the wall and a tape measure. The distance should be reported in meters. Modalities of Clinical Exercise Testing 35

being performed in case of an emergency. A resuscitation Comparison with Other Clinical Evaluators of cart must be available in close proximity to the area where Functional Capacity the 6MWT is being administered. A 6MWT is often used in lieu of CPET when the latter is either unavailable or impractical. Compared to CPET, Reference Values and Clinical Significance the 6MWT represents more of a submaximal and motiva- Scarce literature is available on normal reference values tional test. A good correlation, however, has been re- for the 6MWT. Recently, Enright and Sherrill [46] pub- ported between the 6MWT and maximal oxygen con- lished a set of reference equations for the 6MWT in sumption (V˙ O2max) in patients with end-stage lung dis- healthy adults (aged 40–80 years). In this study, the ease (r = 0.73) [51]. In some clinical situations, the 6MWT median distance walked was 576 m for healthy men and provides physiologic information that may be more realis- 494 m for healthy women. Trooster et al. [31] evaluated 51 tic than V˙ O2max in the evaluation of daily activities. The healthy 50- to 85-year-old subjects and reported a mean of information provided by a 6MWT is complimentary to 631 m. The average distance walked by males was 84 m CPET, but does not replace it. greater than females. As a ball park reference of 6MWT In almost all clinical exercise tests, the work rate inten- results to be expected, Redelmeier et al. [47] reported that sity is imposed on subjects. Considering that in the for patients with COPD, the average distance achieved 6MWT, patients choose their own intensity of exercise during the 6MWT was 371 m (range 119–705 m). In that (self-paced) and also that most activities of daily living are study, the authors estimate that the smallest difference in performed at submaximum levels of exertion, the 6MWT 6MWT distances associated with a noticeable clinical dif- appears to better reflect the functional exercise level for ference in patients’ perception of exercise performance daily physical activities. was 54 m [47]. However, in the same paper, the authors Some have suggested that endurance testing (constant reported that in 68% of the reviewed literature on statisti- work exercise) on the treadmill or cycle ergometer may be cal significant differences due to medical interventions, more helpful in the evaluation of functional capacity in the differences in the 6MWT were less than 54 m. In addi- COPD patients compared to maximal incremental exer- tion, a meta-analysis demonstrated that the best estimate cise testing; however, the constant work test requires an of the beneficial effect of pulmonary rehabilitation for initial maximal incremental exercise test to determine the COPD patients on the 6MWT was 56 m [48]. It appears level of constant work rate. This may be time consuming that differences between 6MWT of approximately 55 m and appear to be more motivationally dependent and less may have clinical significance. However, more studies are reproducible than the 6MWT [49]. However, in more needed to validate this number; additionally, it would recent work comparing different exercise modalities, a probably be better if clinical significant changes were cycle endurance constant work exercise protocol was expressed in percentage change from baseline. more sensitive than conventional 6MWT in detecting the effects of therapeutic interventions (inhaled anticholiner- Reproducibility gic agents) on exercise performance in patients with The 6MWT has good reproducibility, which is compa- COPD [9]. rable or better to other lung function and exercise tests. The shuttle-walking test (discussed in detail below) Noseda et al. [49] studied the reproducibility of lung func- requires the patient to walk at speeds which increase every tion and exercise testing over a long interval in 20 COPD minute until the patient cannot maintain the required patients. They showed that the coefficient of variation of walking speed. This test would be more comparable to a patients tested on four occasions at 1-month intervals was maximal symptom-limited incremental treadmill test. (mean and range) 5% (1.0–8.9) for HRmax; 9.0% (2.4– Not surprisingly, the ‘shuttle test’ has been reported to 19.5) for V˙ O2max; 9.0% (1.5–21.4) for 12 MWT; 10.2% have a better correlation with V˙ O2max compared to the (2.3–26.4) for FEV1. Although in this study the 12 MWT standard 6MWT. However, the shuttle test is more com- was used, the results can be extrapolated to the 6MWT plicated and more difficult to perform. The potential for because of the high correlation that has been shown cardiovascular problems may be greater, especially in between both walking tests. Other authors have reported elderly COPD, since patients are pushed to exercise more similar results [27, 34]. Also, it has been reported that the intensely without ECG monitoring. questionnaires for the subjective evaluation of functional A better correlation has been reported between the status have larger variability (22–33%) than the 6MWT 6MWT with several questionnaires on quality of life than (8–9%) [50]. with V˙ O2max [50]. It has been also shown that the 6MWT 36 Zeballos/Weisman

correlates well with subjective evaluation after different requires the patient to walk at speeds, which increase ev- interventions [52, 53]. ery minute, up and down a 10-meter course. The test ends when the patient cannot maintain the required walking 6MWT on the Treadmill speed. This test would be more comparable to a maximal The 6MWT can be performed on a treadmill and has symptom-limited incremental treadmill test. Although a been proposed in situations in which a long (30-meter) good correlation with 6MWT has been reported [58], the hallway or corridor may not be available. During this test, shuttle-walking test, not surprisingly, correlates better the patient walks on the treadmill for 6 min continuously with V˙ O2max than the 6MWT [59, 60]. However, the self-adjusting the speed of the treadmill in order to set the shuttle test is more complicated and more difficult to per- pace [54]. The advantages of a treadmill 6MWT include form. The shuttle-walking test probably does not reflect the availability of continuous cardiovascular and oxime- daily activities, as does the 6MWT, which is a submaxi- try monitoring, the ease of supplemental O2 device car- mal test. The shuttle-walk test can have a potentially riage, and the avoidance/inconvenience of performing the greater risk of medical complications than the CPET test outside the laboratory. However, a treadmill 6MWT because an ECG is not monitored. Presently, this test is may undermine the basic principles of the 6MWT, which less popular than the 6MWT, with its main use reported are low tech and self-paced. Furthermore, a treadmill in the UK. 6MWT may be difficult for the elderly because of coordi- nation problems of walking on the treadmill while simul- Constant Work Shuttle-Walking Test taneously controlling the speed. Recently, an externally controlled, constant-paced, In a recent study in lung disease patients, which com- walking test has been developed to evaluate the endur- pared treadmill 6MWT vs. conventional 6MWT, the dis- ance capacity of patients [61]. This test was designed to tance walked on the treadmill was, not surprisingly, 14% complement the incremental shuttle-walk test. The ra- less than corridor walking. This most probably reflects tionale for this test is that most activities of everyday liv- less familiarity with treadmill walking. The authors con- ing represent sustained submaximal levels of exercise. cluded that both test results were not interchangeable The advantage of this test over the 6MWT is that, since [54]. Similarly, Swerts et al. [55] reported longer distances this is an externally controlled constant walking test, the for the corridor as compared to the treadmill 6MWT in 11 variability would be less than for the 6MWT (which is a patients with severe COPD. In contrast, other authors self-paced test). The disadvantage would be that it is more have reported similar distances walked on the treadmill as complicated and technically demanding than the 6MWT compared to the corridor 6MWT in controls, patients and that this test would require an incremental shuttle- with chronic heart failure [56], and in severe COPD [57]. walk test to determine the walking speed. However, it is interesting to note that in the study in The methodology is the same as for the incremental chronic heart failure patients [56], 22% participants were shuttle test, that is a 10-meter course and an audio signal unable to perform the treadmill test and 17% covered to control the pace. The walking speed is selected based on very short distances on the treadmill as compared to the the percentage (75–95%) of the maximal speed reached corridor. More studies are needed to clarify if the 6MWT during the incremental shuttle test. Several cassette tapes on the treadmill is comparable to the corridor 6MWT. with speeds that range between 1.80 and 6.00 km/h are Alternatively, if treadmill testing were available/desired, available. The patients are instructed to walk for as long as an endurance constant work protocol at 0% elevation and possible until reaching exhaustion following the audio sig- at a steady speed comfortable for the patient might be nal from the cassette tape with the walking speed select- preferable. This approach is practical, simple and has ed. been extensively used in the past, but requires more rigor- It appears that very few studies using this methodology ous prospective comparative investigation. have been published, one of them by the same authors who developed this field test [62]; it was used to evaluate Shuttle-Walking Test the effect of ambulatory oxygen and an ambulatory venti- lator on endurance exercise in COPD. At the present A newer modality of walking tests is the ‘shuttle-walk- time, it is too premature to comment about the clinical ing test’ which uses an audio signal from a cassette tape to significance of this constant walking test. direct the walking pace of the patient [58]. The protocol Modalities of Clinical Exercise Testing 37

Exercise-Induced Bronchospasm Testing II: 2.5 mph and 12% grade, stage III: 3.4 mph and 14% grade, stage IV: 4.2 mph and 16% grade, and stage V: Exercise-induced bronchospasm (EIB) is defined as a 5.0 mph and 18% grade. The single most reliable indica- bronchospastic event that occurs after vigorous exercise. tor of exercise-induced ischemia is ST-segment depres- It is usually self-limited and remits spontaneously. It gen- sion [70]. Other ECG abnormalities are also used as sup- erally reaches its peak about 5–10 min after cessation of plementary indicators of ischemia. In general, however, exercise and usually resolves in another 20–30 min. It is and ischemia notwithstanding, the Bruce protocol cannot seldom life-threatening. Common symptoms of EIB are define underlying pathophysiology. For more complete wheezing, shortness of breath, chest pain or tightness, information about the topic of this section, please see the cough and deterioration in exercise performance [63, 64]. chapter on ‘Ischemic Heart Disease’. It is generally established that EIB is caused by a loss of heat, water, or both from the lung during exercise caused Cardiopulmonary Exercise Testing by the hyperventilation that accompanies exercise [64]. Exercise is one of the most common precipitants of acute CPET is the most complete of all the clinical exercise asthma encountered in clinical practice [65]. tests. CPET involves the measurement of oxygen uptake (V˙ O2), carbon dioxide output (V˙ CO2), minute ventilation EIB testing is primarily useful in the diagnosis of air- (V˙ E), and other variables, in addition to the monitoring of way hyperreactivity, particularly in patients who com- 12-lead ECG, blood pressure, and pulse oximetry (SpO2) plain of exercise intolerance and unexplained dyspnea. during a maximal symptom-limited incremental exercise test on the cycle ergometer or on the treadmill. When Bronchodilators and other inhaled agents should be appropriate, the additional measurement of arterial blood withheld prior to testing. Spirometry (FVC and FEV1) is gases provides important information on pulmonary gas measured before (baseline) and at 5, 15 and 30 min post- exchange. An evaluation, using the Borg scale, of the exercise. A positive test is reflected as a reduction of FEV1 symptoms limiting exercise is also necessary [42]. or FVC of 15% after exercise [64, 66]. A widely used pro- tocol involves constant work exercise on the treadmill or Maximal exercise testing can be safely performed in on the cycle ergometer for 6–8 min at an intensity neces- the vast majority of patients with respiratory disease with sary to elicit a HR of \"80% of the maximum predicted, so careful monitoring of the ECG and arterial oxygen satura- that V˙ E will increase sufficiently to trigger bronchocon- tion (SaO2) [71, 72]. striction in those with hyperreactive airways [67]. Exer- cise-induced bronchoconstriction is observed in 70–80% Why Perform CPET? of patients with clinically recognized asthma. However, CPET provides information not available from the this test is less sensitive than a methacholine challenge previously described clinical exercise testing modalities. test for the evaluation of airway hyperreactivity [68], CPET permits: objective determination of functional ca- especially in patients with unexplained dyspnea [69]. For pacity (V˙ O2max) and impairment; evaluation of the a more comprehensive explanation of exercise-induced mechanisms of exercise limitation, such as the contribu- asthma the reader is referred to the corresponding chapter tion of different organ systems involved in exercise (i.e., of this book (‘Asthma and Exercise’). heart, lungs, blood and/or skeletal muscles); differentia- tion between heart and lung disease; diagnosis of the Cardiac Stress Test or Graded Exercise Test causes of exercise intolerance/dyspnea on exertion; moni- toring of disease progression and response to treatment; This test is used primarily for the diagnosis of coronary early diagnosis of several clinical disorders, and determi- artery disease (myocardial ischemia), arrhythmias, and to nation of the appropriate intensity and duration of exer- assess therapeutic interventions (medications, interven- cise for cardiopulmonary rehabilitation (prescription) [5, tional techniques, surgery). It is the most widely used clin- 18]. ical exercise testing modality in the United States with In addition, resting cardiopulmonary measurements extensive literature documenting its efficacy [70]. This do not provide an adequate prediction of functional test is performed on a treadmill. During the test, ECG and capacity. Spirometry only estimates a patient’s ventilato- blood pressure are monitored. The Bruce protocol is the ry capacity and not the ventilatory requirements for exer- most popular and consists of five progressive stages, each cise. Although many studies have demonstrated a correla- 3 min in duration. Stage I: 1.7 mph and 10% grade, stage 38 Zeballos/Weisman

tion between FEV1 and V˙ O2max in patients, with COPD, Table 3. Clinical applications of cardiopulmonary exercise testing the variability of the prediction would limit its applicabil- ity for the individual patient [2, 73]. Similarly, for pa- Evaluation of exercise intolerance [5, 70, 88] tients with interstitial lung disease, spirometry and total Assessment of functional capacity (VO˙ 2 peak) lung capacity have been inconsistent predictors of Determination of exercise limitation V˙ O2max. However, patients with significantly low resting DLco are likely to experience abnormal gas exchange Evaluation of unexplained dyspnea [8, 89] response during exercise [74]. The predictive value of less Assessing contribution of cardiac and pulmonary etiology in severe resting DLco is less certain [3]. Finally, resting ECG and systolic performance variables (i.e., left ventric- coexisting disease ular ejection fraction) cannot reliably predict exercise per- Symptoms disproportionate to resting pulmonary and cardiac tests formance and functional capacity [75]. When initial resting cardiopulmonary testing is nondiagnostic Clinical Applications Evaluation of patients with cardiovascular disease The spectrum of clinical applications for CPET has Heart failure [90] broadened and increased significantly during the last few Prognosis of morbidity and mortality [91, 92] years. Comprehensive CPET is useful in a wide variety of Evaluation of therapeutic interventions [93] clinical settings (table 3). Its impact can be appreciated in all phases of clinical decision-making including diagnosis, Evaluation of patients with respiratory diseases assessment of severity, disease progression, prognosis, Assessment of functional impairment and response to treatment. In practice, CPET is consid- COPD [94, 95], ILD [96], PVD [83], cystic fibrosis [97] ered when specific questions persist following consider- Detection of gas exchange abnormalities [10, 74] ation of basic clinical data including history, physical Determination of magnitude of hypoxemia for O2 prescription [98] examination, CXR, PFTs and resting ECG. Please see Evaluation of therapeutic interventions [99] other chapters in the present issue which provide a more comprehensive explanation of methodology, normal exer- Surgical evaluation cise response and CPET results interpretation, as well as Lung resectional surgery, [100, 101] lung volume reduction surgery the application of CPET in different clinical entities. 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