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To the Editor
The real cause of exercise limitation in COPD
Interpretation of exercise intolerance in COPD requires an integrated, multisystemic approach
Untitled
Exercise intolerance in COPD: putting the peaces of the puzzle together
Multiple mechanisms limit exercise in COPD
Missing pieces
"In medium stat virtus"
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John B. West, Distinguished Professor of Medicine and Physiology School of Medicine, University of California, San Diego
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jwest{at}ucsd.edu John B. West
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Two comments. 1. It is extremely unlikely that all patients with COPD have the same major limitation (1, 2, 4). 2. As regards the three choices, I would choose none of the above. I do not understand the term dynamic hyperinflation. Hyperinflation refers to a large lung volume which is a static not dynamic measurement. A major limitation to exercise performance in COPD is the inability of the patient to increase his ventilation. The basic mechanism for this is dynamic compression of the airways. This may lead to hyperinflation but the fundamental problem is that any increase in expiratory flow rate is impossible because the flow is independent of effort (3). Incidentally this year is the 50th anniversary of this landmark paper. References 1. Aliverti A, Macklem P. The major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor muscles. J Appl Physiol, in press 2008. 2. Debigare R, Maltais F. The major limitation to exercise performance in COPD is lower limb muscle dysfunction. J Appl Physiol, in press 2008. 3. Hyatt RE, Schilder DP, Fry DL. Relationship between maximum expiratory flow and degree of lung inflation. J Appl Physiol 13: 331-336, 1958. 4. ODonnell D, Webb K. The major limitation to exercise performance in COPD is dynamic hyperinflation. J Appl Physiol, in press 2008. |
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Peter D. Wagner, Professor University of California, San Diego
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pdwagner{at}ucsd.edu Peter D. Wagner
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The ménage à trois on exercise limitation in COPD (1, 3, 4) misses the point: Limitation is not ascribable to any single structural or functional abnormality, in health or in disease. Exercise depends on an in -series system wherein ventilation, gas exchange, blood flow, hemoglobin, muscle O2/CO2 transport and O2 utilization/CO2 production all contribute (6). Thus, having three articles each claiming that their mechanism rules unfortunately de-emphasizes this fundamental concept. However, certain steps in O2/CO2 transport may differently influence exercise in COPD versus health. Debigare & Maltais claim muscle dysfunction, but when one COPD leg is exercised alone, peak muscle VO2 is normal while in the same patient, it is reduced during cycling (5). This does not necessarily mean muscles function normally, nor that muscle training is pointless (2). But it does show that the muscles contribute little to limit whole body exercise in COPD. Aren’t the major contributors to exercise limitation in COPD mechanical derangements reducing maximal ventilation? Emphysema reduces airway radial traction and increases compliance, increasing dynamic compression. Chronic bronchitis aggravates this, increasing airway resistance by secretions, bronchomotor tone and thickened airway walls. Tidal volume and thus ventilation are limited, hyperinflation and early dyspnea ensue, and exercise therefore stops early - well before the heart (absent overt heart failure) and muscles have reached functional limits. O'Donnell and Webb come closest, but dynamic hyperinflation seems not to be the root cause. It is a consequence of the root cause: Structural abnormalities causing mechanical derangements (that limit maximal ventilation). 1. Aliverti A, Macklem P. The major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor muscles. J Appl Physiol, in press 2008. 2. Casaburi R, Patessio A, Ioli F, Zanaboni S, Donner CF and Wasserman K. Reductions in exercise lactic acidosis and ventilation as a result of exercise training in patients with obstructive lung disease. Am Rev Respir Dis 143: 9-18, 1991 3. Debigare R, Maltais F. The major limitation to exercise performance in COPD is lower limb muscle dysfunction. J Appl Physiol, in press 2008. 4. O’Donnell D, Webb K. The major limitation to exercise performance in COPD is dynamic hyperinflation. J Appl Physiol, in press 2008. 5. Richardson, RS, BT Leek, TP Gavin, LJ Haseler, SRD Mudaliar, R Henry, O Mathieu-Costello, PD Wagner. Reduced mechanical efficiency in chronic obstructive pulmonary disease but normal peak V. O2 with small muscle mass exercise. Am J Respir Crit Care Med 169(1): 89-96, 2004 6. Wagner PD. Determinants of maximal oxygen transport and utilization. Annu Rev Physiol 58: 21-30, 1996. |
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J Alberto Neder, Professor of Respiratory Medicine Federal University of São Paulo, Brazil
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albneder{at}pneumo.epm.br J Alberto Neder
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The notion that exercise intolerance in COPD is a multifactorial construct can be appreciated from a circumspect analysis of the points raised by the authors (1-3). Unfortunately, the issue is further complicated by the intervening effects of co-morbidities on individual patients which can differently impact upon physical impairment in specific disease phenotypes. Much of the ongoing controversy may also stem from inadequate patient comparisons as any of the discussed pathophysiological mechanisms can dominate the scene on a given moment in the natural history of COPD. Moreover, different conclusions can be drawn from distinct testing paradigms and modalities (e.g. maximum incremental vs. high intensity constant work rate or cycling vs. walking). The highest sustainable exercise work rate (“critical power”), for instance, has been associated with the rate of development of ventilatory limitation (4) and dynamic hyperinflation (5). However, the argument in favor of inadequate energy (O2) supply is also compelling and there is new evidence coming out suggesting that this is indeed a relevant limiting mechanism in patients with more advanced disease (6,7). In this context, a less biased interpretation of the available evidence indicates that the fundamental pulmonary-mechanical derangements associated with COPD are likely to produce perceptual (dyspnea) and physiological (DH, increased WOB) consequences that can modulate energy supply to the peripheral muscles. Resolution or amelioration of exercise intolerance in these patients, therefore, may also require a multifaceted approach aiming to increase energy supply (e.g. reducing DH and WOB, supplementing O2) and optimize energy utilization (e.g. training, improving mechanical efficiency). 1. Aliverti A, Macklem P. The major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor muscles. J Appl Physiol, in press 2008. 2. Debigare R, Maltais F. The major limitation to exercise performance in COPD is lower limb muscle dysfunction. J Appl Physiol, in press 2008. 3. O’Donnell D, Webb K. The major limitation to exercise performance in COPD is dynamic hyperinflation. J Appl Physiol, in press 2008. 4. Neder JA, Jones PW, Nery LE, Whipp BJ. Determinants of the exercise endurance capacity in patients with chronic obstructive pulmonary disease. The power-duration relationship.Am J Respir Crit Care Med;162:497 -504, 2000. 5. Puente-Maestu L, García de Pedro J, Martínez-Abad Y, Ruíz de Oña JM, Llorente D, Cubillo JM. Dyspnea, ventilatory pattern, and changes in dynamic hyperinflation related to the intensity of constant work rate exercise in COPD. Chest;128(2):651-656, 2005. 6. Chiappa GR, Borghi-Silva A, Ferreira LF, Carrascosa C, Oliveira CC, Maia J, Gimenes AC, Queiroga F, Berton D, Ferreira EM, Nery LE, Neder JA. Kinetics of muscle deoxygenation are accelerated at the onset of heavy intensity exercise in patients with COPD: relationship to central cardiovascular dynamics. J Appl Physiol Mar 20, 2008 [Epub ahead of print] 7. Borghi-Silva A, Carneiro Oliveira C, Carrascosa C, Maia J, Berton DC, Queiroga Jr F, Ferreira EMV, Ribeiro D, Nery LE, Neder JA. Respiratory muscle unloading improves leg muscle oxygenation during exercise in patients with COPD. Thorax, 2008 (in press) |
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Giorgio L. Scano, physician University of Florence
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gscano{at}unifi.it Giorgio L. Scano
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Skeletal muscle dysfunction, dynamic hyperinflation and excessive expiratory muscle activity may play independent roles in limiting exercise in COPD. However, the following consideration should be made :(i) Evidence has been provided of skeletal muscle metabolic reserve in COPD similar to that seen in fit healthy subjects (1). Moreover, the contractile properties of vastus lateralis are preserved, and muscle strength per unit cross sectional area is not impaired in COPD patients (2), (ii) The increase in expiratory muscle pressure is twice the increase in inspiratory muscles pressure, suggesting the major role played by the expiratory muscles in increasing dyspnea sensation in exercising flow-limited healthy humans (3). An expiratory muscle fatigue-induced metaboreflex results in sympathetic vasoconstrictor outflow, reduced blood flow and locomotor muscle fatigue (4).We might also expect the work of expiratory muscles to the point of fatigue in exercising COPD patients. However, might an imbalance between energy supplies and demands, or a plateau in the limb blood flow curtail incremental exercise in Gold stage I COPD patients as in those with severe airflow narrowing and more intense dyspnea at a lower work rate (5)? On the other hand, does activation of limb muscle metaboreflex influence blood flow to the respiratory muscles? (iii) Changes in intrathoracic and intra abdominal pressures influence venous return, ventricular pre load and after load, and stroke volume. However, how does this respiratory pressure influence cardiac output in exercising humans? A peripheral imbalance between energy supply and demand might be demonstrated if specific measure were employed (6). References 1 Richardson RS, Sheldon J, Poole DC, Hopkins SR, Ries AL, Wagner PD. Evidence of skeletal muscle metabolic reserve during whole body endurance exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med: 159;881-885,1999 2 Bernard S, LeBlanc P, Whittom F, Carrier G, Jobin J, Belleau R, Maltais Fl. Peripheral muscle weakness in patients with chronic obstructive pulmonary disease Am J Respir Crit Care Med; 158: 629-34,1988 3 Duranti R, Bonetti L, Vivoli P, Binazzi B, PA Laveneziana, Scano G. Dyspnea during exercise in hyperbaric conditions Med Sci Sport Exer; 38: 1932-38,2006 4 Derchak PA, Sheel AW, Morgan BJ, Dempsey JA. Effect of expiratory muscle work on muscle sympathetic nerve activity. J Appl Physiol 92; 1539-52,2002 5 Simon M, LeBlanc P, Jobin J, Desmeules M, Sullivan MJ, Maltais F. Limitation ol lower limbV0(2) during cycling exercise in COPD patients. J Appl Physiol 90. 1013-1019, 2001 6 Dempsey JA Challenges for future research in exercise physiology as applied to the respiratory system. Exerc.Sport.Sci.Rev 34; 92-98,2006 |
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Spyros G Zakynthinos, Associate Professor, National & Kapodistrian University of Athens, Greece Evangelismos Hospital, Athens, Greece, Ioannis Vogiatzis
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szakynthinos{at}yahoo.com Spyros G Zakynthinos, et al.
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The Point:Counterpoint articles (1-3) highlight the complex mechanisms underlying exercise intolerance in COPD. Recent studies (4, 5) suggest that the major limitation to exercise is largely dependent on lung disease severity classified by GOLD. Accordingly, although patients of all GOLD stages exhibited pulmonary mechanical derangements and dynamic hyperinflation (DH) at the limit of exercise tolerance, and this DH increased with increasing lung disease severity (4, 5), the predominant limiting symptom in stages I and II was leg fatigue (4, 5), whereas in stages III and IV it was dyspnoea (5). Naturally, exercise capacity was higher in stages I and III compared to stages II and IV, respectively (4, 5). However, in stages II and III exercise capacity was similar (5). Since most of stage II patients did not exhibit expiratory flow limitation (EFL) during exercise, substantial expiratory muscle activity resulted in higher expiratory flow rates compared to stage III, thereby attenuating DH and the intensity of dyspnoea (5); however, high expiratory pressures possibly caused adverse circulatory events, thus limiting energy supply to locomotor muscles and inducing leg fatigue (1, 5). This mechanism might also be involved in stage I. In stage III, EFL was more severe, expiratory abdominal muscle activity was minimal and DH was greater, thus restricting tidal volume expansion which intensified dyspnoea (5). Although stages III and IV exhibited similar DH, exercise capacity in the latter was more impaired than in the former owing to the fact that DH in stage IV occurred in lower minute ventilation (5). REFERENCES 1. Aliverti A, Macklem P. The major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor muscles. J Appl Physiol, in press 2008. 2. Debigare R, Maltais F. The major limitation to exercise performance in COPD is lower limb muscle dysfunction. J Appl Physiol, in press 2008. 3. O’Donnell D, Webb K. The major limitation to exercise performance in COPD is dynamic hyperinflation. J Appl Physiol, in press 2008. 4. Ofir D, Laveneziana P, Webb KA, Lam YM, O’Donnell DE. Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD Stage I chronic obstructive pulmonary disease. Am J Respir Crit Care Med 177: 622- 629, 2008. 5. Vogiatzis I, Stratakos G, Athanasopoulos D, Georgiadou O, Golemati S, Koutsoukou A, Weisman I, Roussos C, Zakynthinos S. Chest wall volume regulation during exercise in COPD patients with GOLD stages II to IV. Eur Respir J, in press 2008. |
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Peter M Calverley, Physician University of Liverpool UK
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pmacal{at}liverpool.ac.uk Peter M Calverley
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This stimulating Point-Counterpoint has marshalled persuasive arguments in support of dynamic hyperinflation [5], inadequate energy supply to exercising muscle (both respiratory and locomotor) [1] and lower limb muscle dysfunction [4] as the principal cause of exercise limitation in COPD. Most data are derived from patients with severe or very severe disease and in this setting multiple mechanisms are likely to operate. Thus reducing operating lung volume can be associated with a reduced peak work rate if the chest wall volume change is inappropriate [2] while Pepin et al have shown that COPD patients developing quadriceps fatigue on exercise do not increase their exercise performance after a bronchodilator [6]. Thus different mechanisms limit performance in advanced disease in different patients. O’Donnell and Aliverti appear to be referring to different phenomena when considering dynamic hyperinflation, with the former focussing on changes in lung volume and the latter on chest wall volume. Thus ‘passive’ increases in EELV can occur in the face of active chest wall volume reduction which can produce substantial gas compression and blood shifts. Changes in cardiac output secondary to this process are compatible with data describing a relative slowing of central oxygen uptake kinetics compared to peripheral muscle oxygen extraction during heavy exercise in severe COPD [3]. More data about the time course of individuals change in EELV would be welcome as would studies in milder COPD testing each mechanism in the same person to establish when in the natural history of COPD exercise limitation begins and why. 1.Aliverti A, Macklem P. The major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor muscles. J Appl Physiol, in press 2008. 2. Aliverti A, Rodger K, Dellacà RL, Stevenson N, Lo Mauro A, Pedotti A, Calverley PM. Effect of salbutamol on lung function and chest wall volumes at rest and during exercise in COPD. Thorax 60: 916-24, 2005. 3. Chiappa GR, Borghi-Silva A, Ferreira LF, Carrascosa C, Oliveira CC, Maia J, Gimenes AC, Queiroga F, Berton D, Ferreira EM, Nery LE, Neder JA. Kinetics of Muscle Deoxygenation are Accelerated at the Onset of Heavy Intensity Exercise in Patients with COPD: Relationship to Central Cardiovascular Dynamics. J Appl Physiol. in press 2008. 4. Debigare R, Maltais F. The major limitation to exercise performance in COPD is lower limb muscle dysfunction. J Appl Physiol, in press 2008. 5. O’Donnell D, Webb K. The major limitation to exercise performance in COPD is dynamic hyperinflation. J Appl Physiol, in press 2008. 6. Pepin V, Saey D, Whittom F, LeBlanc P, Maltais F. Walking versus cycling: sensitivity to bronchodilation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 172:1517-22, 2005 |
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Harry R. Gosker, Assistent Professor Department of Respiratory Medicine, Maastricht University, The Netherlands, Annemie M.W.J. Schols
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h.gosker{at}pul.unimaas.nl Harry R. Gosker, et al.
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Missing pieces In a nutshell the question addressed here is whether lower limb muscle, either through muscle dysfunction (3) or reduced energy supply to that muscle (1), or dynamic hyperinflation (5) causes exercise intolerance in COPD. However, we must realize that there is a huge gap in our understanding regarding the origin and progression of limb muscle impairment in COPD simply due to the fact that the majority of studies focused on patients with severe COPD. The result of this being that hardly any literature is available on patients with mild to moderate COPD (GOLD stages I and II) (6) let alone in subjects at risk (i.e. smokers). We clearly demonstrated the lack of such data in early COPD for lower limb muscle abnormalities (4). To really understand whether limb muscle dysfunction is the cause or consequence (or neither) of reduced exercise capacity in COPD, future studies should incorporate the earlier stages of COPD as well as the effects of smoking. A longitudinal study design would be ideal for this. Another approach would be to evaluate exercise capacity after interventions targeted at the suspected mechanisms, for example after lung volume reduction surgery or lung transplantion (target: hyperinflation). Likewise, Calvert et al recently showed that exercise performance improved in COPD after a pharmacological intervention known to activate muscle pyruvate dehydrogenase complex in rest thereby improving energy supply to muscle mitochondria (target: muscle energy supply) (2). These are the kind of studies that we need to solve this puzzle. References 1. Aliverti A, and Macklem P. The major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor muscles. J Appl Physiol in press: 2008. 2. Calvert LD, Shelley R, Singh SJ, Greenhaff PL, Bankart J, Morgan MD, and Steiner MC. Dichloroacetate Enhances Performance and Reduces Blood Lactate during Maximal Cycle Exercise in COPD. Am J Respir Crit Care Med 2008 in press. 3. Debigare R, and Maltais F. The major limitation to exercise performance in COPD is lower limb muscle dysfunction. J Appl Physiol in press: 2008. 4. Gosker HR, Zeegers MP, Wouters EF, and Schols AM. Muscle fibre type shifting in the vastus lateralis of patients with COPD is associated with disease severity: a systematic review and meta-analysis. Thorax 62: 944-949, 2007. 5. O’Donnell D, and Webb K. The major limitation to exercise performance in COPD is dynamic hyperinflation. J Appl Physiol in press: 2008. 6. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, and Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 163: 1256-1276, 2001. |
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Paolo Palange, Associate Professor of Medicine Department of Clinical Medicine, University of Rome
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paolo.palange{at}uniroma1.it Paolo Palange
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The points raised by the authors (1-3) certainly support the hypothesis that the origin of exercise intolerance in COPD is multifactorial, reflecting a combination of “peripheral” and “central” factors. When examining the causes of reduced exercise tolerance in COPD, however, it is important first to clarify whether one is referring to exercise performance on a classical rapid-incremental exercise test or on a high-intensity constant work-rate test (Tlim) for which the characteristics of the power-duration relationship (i.e. critical power and W’) are important (4). Exercise modality should also be considered, significant differences having been reported in the ventilatory and gas exchange responses to cycle ergometry and free walking in COPD patients, for example (5). Furthermore, making judgements about the normalcy or otherwise of the ventilatory response to an exercise challenge requires an appropriate frame of reference (e.g. as is provided by factors such as the pulmonary CO2 output (V’CO2), the set-point level at which arterial PCO2 is regulated and the level of gas exchange inefficiency (i.e. the physiologic dead space fraction of the breath (VD/VT)). This, however, is a shortcoming of several of the studies cited by the authors (1, 3). Regardless, there would seem to be little question that exercise tolerance in COPD, particularly in patients with emphysema, is compromised because of severe dyspnea and ventilatory limitation: the improvements in Tlim engendered by supplemental oxygen (6) and heliox administration (7) clearly support this hypothesis. References 1. Aliverti A, Macklem P. The major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor muscles. J Appl Physiol, in press 2008. 2. Debigare R, Maltais F. The major limitation to exercise performance in COPD is lower limb muscle dysfunction. J Appl Physiol, in press 2008. 3. O’Donnell D, Webb K. The major limitation to exercise performance in COPD is dynamic hyperinflation. J Appl Physiol, in press 2008. 4. Poole DC, Ward SA, Whipp BJ The effects of training on the metabolic and respiratory profile of high-intensity cycle ergometer exercise. Eur J Appl Physiol Occup Physiol. 1990;59(6):421-9. 5. Palange P, Forte S, Onorati P, Manfredi F, Serra P, Carlone S. Ventilatory and metabolic adaptations to walking and cycling in patients with COPD. J Appl Physiol. 2000 May;88(5):1715-20. 6. O'Donnell DE, D'Arsigny C, Webb KA. Effects of hyperoxia on ventilatory limitation during exercise in advanced chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001 Mar;163(4):892-8. 7. Palange P, Valli G, Onorati P, Antonucci R, Paoletti P, Rosato A, Manfredi F, Serra P. Effect of heliox on lung dynamic hyperinflation, dyspnea, and exercise endurance capacity in COPD patients. J Appl Physiol. 2004 Nov;97(5):1637-42. |
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