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School of Clinical Sciences, University Hospital Aintree, Liverpool, United Kingdom
Correspondence and requests for reprints should be addressed to Peter M.A. Calverley, M.D., School of Clinical Sciences, Clinical Sciences Centre, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UK. E-mail: pmacal{at}liv.ac.uk
ABSTRACT
A reduced exercise capacity is an important determinant of health status and an independent prognostic marker in patients with chronic obstructive pulmonary disease. The inability to increase expiratory flow at the resting end-expiratory lung volume in the face of expiratory-flow limitation means that end-expiratory lung volume must increase if gas exchange is to be maintained near normal values. This phenomenon is usually referred to as dynamic hyperinflation. The change in operating lung volumes during exercise is related to the intensity of breathlessness. Treatments such as bronchodilators that increase inspiratory capacity or supplemental oxygen, which reduces ventilatory demand, decrease the degree of dynamic hyperinflation at any external workload. However, dynamic hyperinflation is not seen universally in patients with chronic obstructive pulmonary disease as some adopt different breathing patterns when they exercise, or respond to inhaled bronchodilators by changing their pattern of abdominal muscle activation, a behavior that can be counterproductive. Finally, dynamic hyperinflation can be reduced when, for example, breathing oxygen after exercise without changes in dyspnea, as other factors are more important determinants of this symptom in these circumstances. Dynamic hyperinflation can be reliably measured from the inspiratory capacity maneuver in many laboratories. Although knowledge about this variable gives great insight into the mechanisms of therapy, its routine measurement cannot currently be recommended as it does not appear to add additional clinical data beyond those available in present laboratory exercise testing protocols.
Key Words: activity limitation • dyspnea • exercise capacity • health status
Chronic obstructive pulmonary disease (COPD) is a highly prevalent condition (1) that usually attracts medical attention when patients become symptomatic. Although cough and sputum production appear early in the natural history of the disease, it is the development of breathlessness on exertion that most commonly alarms patients (2). This can be a difficult symptom to evaluate, as the patient may appear to be quite well under resting conditions but develop severe distress after relatively modest exertion. Breathlessness sufficient to limit normal daily activities was a significant problem in 29%, and a moderately severe problem in 26%, of the patients identified in a random-digit-dialing telephone survey that identified patients with COPD in eight countries (3). The limitation of everyday activities by breathlessness assessed by the Medical Research Council Dyspnea Scale was a better predictor than FEV1 of subsequent survival in a large prospective Japanese study (4). Further data from the same group established that the peak oxygen consumption was also a useful and independent marker of subsequent prognosis in patients with COPD (5). These data were in agreement with those derived from self-paced walking tests such as the 6-min walking distance test, which has also been proved important for prognosis independent of the severity of airflow obstruction (6, 7). More recently, exercise has proved to be an important predictive variable when included as part of a multidimensional scale to identify prognosis prospectively in COPD (8). Given the clinical importance of exercise, it is not surprising that, as well as being prognostically valuable, exercise capacity has been identified as an important determinant of overall health status in patients with usual COPD and those patients in whom COPD developed as a consequence of 
1-antitrypsin (9, 10). These data have led to renewed interest in the physiologic mechanisms that underlie breathlessness and have been paralleled by new insights into the nature of these processes.
PHYSIOLOGIC BASIS OF EXERCISE LIMITATION IN COPD
Many factors singly or in combination lead to a reduction in exercise performance in patients with COPD. The amount of daily activity of patients with established COPD is reduced compared with that of normal subjects (11), although how this relates to other indices of disease severity has yet to be established. There is general agreement that patients with more severe disease experience ventilatory limitation (12) rather than impaired cardiac performance. Also, the onset of leg fatigue limits exercise performance. The latter symptom appears to be more important in those with less severe COPD (13). At present, the interactions between cardiovascular and respiratory causes of exercise limitation remain relatively poorly understood and further studies using similar exercise-testing protocols over a greater range of disease severity will be needed to resolve this. The rather sedentary lifestyle of the patient with COPD contributes to peripheral muscle deconditioning and there is evidence that peripheral muscle function is impaired in moderately severe COPD (14, 15). Specific muscle weakness has been attributed to a possible "COPD peripheral myopathy" (16). This has been proposed on the basis of biochemical and histologic changes in the quadriceps muscle of patients with COPD, although there is debate about the adequacy of oxygen delivery during exercise in these circumstances and whether this rather than any intrinsic abnormality explains the poor performance (17–19).
Oxygen therapy improves exercise performance in patients with COPD who desaturate during exercise, and arterial oxygen desaturation is recognized as a useful criterion in prescribing ambulatory oxygen (20). However, it is less clear whether the presence of the desaturation is merely a surrogate marker for the presence of disease or is itself the pathogenic mechanism (21). The lack of any clear relationship between changes in exercise performance and changes in oxygen saturation during exercise argues against a causal relationship between the severity of desaturation and the distance walked (22). On the other hand, there is a convincing literature supporting mechanical limitation as the primary abnormality limiting maximum exercise performance. The traditional analysis of this problem has focused on the inability of patients with COPD to achieve the same maximum ventilation during exercise as healthy subjects (23). The FEV1 is a reasonable predictor of peak ventilation during incremental exercise although the strength of the respiratory muscles is also important (24).
The inability of the respiratory muscles to sustain ventilation in the face of this airflow obstruction is due in part to the mechanical disadvantage associated with pulmonary hyperinflation that accompanies more severe lung disease (25). In these circumstances the inspiratory muscles are shortened and have a reduced force-generating capacity and this, together with a reduction of the area of apposition of the diaphragm, diminishes the effectiveness of the ventilatory pump. In addition, the increased respiratory rate that is necessary to enhance alveolar ventilation when a normal increase in tidal volume is not possible shortens the time for lung emptying in these patients in whom the mechanical time constant of the respiratory system is increased. As a result, inspiration begins before the elastic equilibrium volume of the respiratory system is reached and a threshold inspiratory load, usually described as positive end-expiratory pressure intrinsic, must be overcome (26). The resulting neuromechanical dissociation when an increasing level of ventilatory drive is associated with a reduced capacity of the respiratory muscles to develop force and hence effective ventilation is now recognized as the principal mechanism of breathlessness in these patients (27).
DYNAMIC HYPERINFLATION DURING EXERCISE IN COPD
The physiologically conventional model of ventilatory limitation to exercise in COPD has been challenged and expanded by observations made in the last 10 yr by Professor O'Donnell's group in Kingston, Ontario. These observations built on earlier studies that demonstrated that many patients with COPD exhibited expiratory-flow limitation during tidal breathing at rest. The technical issues related to the demonstration of flow limitation in these circumstances have recently been reviewed (28), but the initial methods used relied on body plethysmography or balloon catheterization and were relatively cumbersome and inaccurate. The development of the negative-expiratory-pressure test for flow limitation showed that patients who were flow limited were those most likely to report breathlessness (29) and were much more likely to allow their end-expiratory lung volume (EELV) to increase during exercise (30). This is not really surprising as the only way in which expiratory flow and hence minute ventilation can be increased when expiratory flow is limited would be for the respiratory system to operate at a higher EELV. Unlike healthy individuals who reduce EELV during exercise lung volume during exercise, patients with COPD maintain a relatively constant tidal volume (31). EELV changes progressively throughout exercise and as a result the end-inspiratory lung volume approaches the minimal inspiratory reserve volume when exercise stops (Figure 1). At this point, further increases in inspiratory muscle activation produce little or no additional ventilation and muscle contraction becomes more isometric. Presumably this is why similar increases in self-reported dyspnea occur at end-exercise irrespective of the time taken for EELV to reach this point (32).
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Although dynamic hyperinflation is usually considered in the context of exercise, it is worth noting that EELV can be dynamically regulated at rest, as has been shown in studies of patients in the intensive care unit (37). In these circumstances, dynamic hyperinflation is indicated by the fact that, when the patient is anaesthetized and paralyzed, EELV falls below the values observed during spontaneous breathing (26). The relationship between this form of dynamically regulated lung volume and the change in lung volume during exercise is yet to be established, but it is likely to be close.
THERAPEUTIC INTERVENTIONS AND DYNAMIC HYPERINFLATION
The effects of commonly used treatments on dynamic hyperinflation have been explored with relatively consistent results. Studies have differed in the exercise protocol examined with the largest changes always being evident when endurance exercise has been reported. However, the influence of therapy on lung mechanics during exercise appears to be independent of the testing regime. The short-acting inhaled anticholinergic bronchodilator ipratropium bromide was the first to be shown to reduce exercise-related dynamic hyperinflation (38). The reductions were independent of those in FEV1, the absolute increase in FEV1 with ipratropium being unrelated to the change in exercise performance, an observation made previously with this class of therapy (39). Subsequently, the effects of a bronchodilator on dynamic hyperinflation were confirmed when the effect on exercise performance of long-term treatment with a long-acting inhaled bronchodilator, tiotropium, was studied (40). In both of these studies a change in resting inspiratory capacity and hence a reduction in EELV was the best predictor of a subsequent response to treatment. More recent data with the long-acting inhaled ß-agonist drug salmeterol show that these effects are common to all bronchodilators but also emphasize that the rate of increase of breathlessness during exercise is not modified after administration of the bronchodilator drug, but is merely offset on line with the changing resting inspiratory capacity (32) (Figure 2).
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The impact of pulmonary rehabilitation on dynamic hyperinflation is less clear and currently only limited data are available. Pulmonary rehabilitation produces significant increases in exercise performance (45) in patients with COPD when clinically stable. The ventilatory demand for any degree of exercise is improved after rehabilitation, which helps explain the reduction in dyspnea at any given workload, although a change in individual perception of dyspnea after rehabilitation cannot be excluded (46). One study has suggested that patients adapt to higher EELV after rehabilitation (47) but this finding requires confirmation.
EXERCISE IN COPD WITH PRESERVATION OF LUNG VOLUMES
Although there is much evidence for an increase in EELV during exercise in many patients with COPD, several more recent studies also indicate that this is not always the case. This is in keeping with earlier data suggesting that patients with COPD could also be limited by fatigue of their leg muscles when they exercised rather than simply by ventilatory factors (13). In addition, in the original physiologic studies of lung volume change during exercise in patients with COPD, divergent patterns of response were noted (48). In the study by Diaz and colleagues, the initial inspiratory capacity was found to be more predictive of the subsequent maximum oxygen consumption and maximum work rate than was the percent-predicted FEV1 (30). The authors suggested that the presence of tidal expiratory-flow limitation under resting conditions was associated with hyperinflation during exercise (see above) whereas the severity of airflow obstruction expressed as the FEV1/FVC ratio was a better predictor of exercise performance in those who did not show tidal expiratory-flow limitation. Other studies in which the total chest wall volume was measured noninvasively using optoelectronic plethysmography (OEP) have also identified patients with significant airflow obstruction who did not appear to change their end-expiratory chest wall volume during exercise. The initial report used incremental protocol, and the patients in whom dynamic hyperinflation did not appear to occur tended to have better preserved midexpiratory flow rates on their resting flow–volume loop (49). Indirect estimates of the presence of expiratory-flow reserve suggested that those patients in whom EELV was maintained at or below resting values during exercise (euvolumics) had more resting expiratory-flow reserve. The behavior of their chest wall muscles was very different from the chest wall behavior of those who exhibited dynamic hyperinflation as they exercised, the latter group being a majority in this study. Euvolumic patients reduced end-expiratory chest wall volume largely by a reduction in the volume of their abdominal compartment as a result of increased activation of their abdominal muscles during expiration. In contrast, in those who demonstrated hyperinflation, the abdominal compartment expanded to accommodate the increased volume of gas remaining at the end of each breath as exercise proceeded. These changes were also accompanied by evidence of intrathoracic gas compression and blood shifts away from the thoracic compartment, which could, at least theoretically, reduce cardiac output and impair peripheral muscle function.
Subsequent data during endurance exercises have confirmed that there is a range of response among patients with COPD with some showing an early onset of change in end-expiratory chest wall volume whereas others continue to maintain their end-expiratory chest wall volume relatively constant until quite late during the exercise protocol (35). These differences may explain some of the apparent conflicts observed between previous studies where EELV was established using inspiratory capacity as opposed to the global assessment of chest wall volume that OEP provides.
Most recently, data from our laboratory have shown that bronchodilators can produce unpredictable effects in ventilatory response to exercise. When we conducted a randomized double-blind trial of the effect of high-dose nebulized salbutamol in exercise performance, we observed no overall improvement in endurance time on the cycle ergometer, a finding noted previously with this class of drugs (50). However, our patients clearly divided into some whose endurance was improved and others in whom there appeared to be deterioration in exercise performance after the active bronchodilator. These changes might be attributed to random variation in the measurements but further analysis of the OEP data suggested that there was a difference in the physiologic behavior during exercise (51). In those individuals whose exercise performance improved, dynamic hyperinflation was still present after the bronchodilator but at a lower end-expiratory chest wall volume. These data correspond to the data on large groups of subjects after short- and long-acting inhaled anticholinergic drugs. However, those patients whose exercise performance worsened had adopted a different ventilatory strategy, and when they exercised on the second occasion, they tried to reduce their EELV in a fashion analogous to the euvolumic subjects described in the original study using incremental exercise (49). In these circumstances, exercise performance was shorter than normal as has been seen previously in euvolumic patients with COPD studied without a bronchodilator drug. This suggests that in the face of fixed airflow obstruction any attempt to diminish end-expiratory chest wall volumes is an inefficient breathing strategy.
Inspiratory capacity has also been studied during the recovery period from exercise when a different set of circumstances applies. In a randomized trial of the effects of oxygen on the severity of breathlessness after a standardized exercise challenge, Stevenson and Calverley (52) saw no difference in the rate of recovery from breathlessness between patients randomized to receive compressed air or oxygen. This was true whether the oxygen was given via a facemask or with a noseclip and mouthpiece. In this trial, inspiratory capacity was also measured. Almost all patients had increased their lung volume by the end of the exercise test and there was evidence that inspiratory capacity returned to normal more rapidly in patients who received oxygen, in keeping with a reduction in the ventilatory drive that oxygen breathing produces. These data show that, although changes in inspiratory capacity could be physiologically manipulated, other factors were more important in determining the intensity of breathlessness in this setting. Hence, the degree of dynamic hyperinflation may not always be the most relevant outcome to study.
CONCLUSIONS
Although dynamic hyperinflation is an important variable determining the intensity of breathlessness and the ability to exercise in patients with stable COPD, it is not the only factor operating in these circumstances. The presence of dynamic hyperinflation is not a universal finding during exercise. Some patients may try to avoid a change in their operating lung volume or this may develop as exercise progresses in keeping with the tendency for expiratory-flow limitation to increase (53). The degree of airflow obstruction and loss of maximal midexpiratory flow over the normal range of operating lung volume seem to be the best way of identifying those patients in whom dynamic hyperinflation is most likely. Many other factors will influence exercise capacity in COPD; these include the prior level of fitness and physical activity undertaken, peripheral muscle function, and the patient's cardiovascular reserve. Identification of dynamic hyperinflation during exercise provides powerful evidence for an impact of treatment on exercise performance in COPD and helps provide a scientific rationale for using specific therapies. However, this is a post hoc explanation and the absence of large changes in dynamically regulated lung volumes does not mean that a treatment such as pulmonary rehabilitation is ineffective. The measurement of dynamic hyperinflation relies on the assumption that total lung capacity is unchanged, which appears to be reasonable during most forms of exercise. However, the technical expertise required to measure dynamic hyperinflation reliably is currently present in only a few laboratories. The test itself is relatively simple and reproducible with appropriate standardization but it cannot be recommended at present in institutions where progressive exercise testing is not part of the routine patient evaluation. In general, it is simpler, and probably more reliable clinically, to inquire about the consequences of dynamic hyperinflation rather than of establishing an objective increment. Thus, changes in the intensity of self-reported breathlessness with exercise are likely to prove to be a more robust clinical endpoint than investigation of this particular factor that leads to breathlessness and exercise limitation in the first place.
FOOTNOTES
Conflict of Interest Statement: P.M.A.C. has received funding for consultancy services and honoraria for speaking at conferences organized by AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim. He has also served on advisory boards for AstraZeneca, GlaxoSmithKline, and Altana.
(Received in original form August 2, 2005; accepted in final form December 6, 2005)
REFERENCES
1-antitrypsin deficiency. Am J Respir Crit Care Med 2001;163:936–941.
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