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Breathlessness during exercise in COPD: how do the drugs work?
  1. P M A Calverley
  1. Correspondence to:
    Professor P M A Calverley
    Department of Medicine, Clinical Sciences Centre, University Hospital Aintree, Liverpool L9 7AL, UK;

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Salmeterol reduces breathlessness during exercise without necessarily changing exercise duration

The inability to exercise because of distressing breathlessness is one of the most frequent problems experienced by patients with chronic obstructive pulmonary disease (COPD)1 and is a major determinant of impaired quality of life.2 Our understanding of why this occurs and how best to treat it has improved significantly in the last decade. At one level the problem appears relatively straightforward. Exercise invariably involves an increase in whole body oxygen consumption and carbon dioxide production, which requires an appropriate rise in alveolar ventilation if arterial carbon dioxide tension is to remain constant. In patients with COPD the ability to increase minute ventilation is restricted as is the capacity to empty their lungs quickly, hence exercise limitation occurs at a lower workload than in age matched healthy subjects. Although there is much truth in this simple scheme, it does not do justice to the many complex adaptive responses that patients use to cope with their chronic airflow obstruction, nor does it explain the variability seen in both the duration of exercise and the intensity of breathlessness in patients with apparently similar levels of airflow obstruction.


Unsurprisingly, the general relationship of ventilatory capacity, commonly established indirectly from the forced expiratory volume in 1 second (FEV1),3 is not simple. While the 12 minute walking distance is broadly related to the severity of airflow obstruction,4 spirometric measurements are not very precise indicators of exercise capacity in the individual patient. Differences in ventilation-perfusion matching during exercise mean that individuals with more “wasted ventilation” achieve their maximum sustainable ventilation sooner for the same degree of alveolar ventilation.5 Differences in pre-morbid fitness are also relevant. Patients who are less fit progress to anaerobic metabolism (and hence increased carbon dioxide production) at lower levels of work than those who are fitter.6 More recently, differences in the dynamic behaviour of the respiratory system during exercise have been identified.7 Unlike healthy subjects, patients with severe COPD progressively increase their end expiratory lung volume rather than reducing it during exercise as occurs in healthy subjects. Since total lung capacity is constant, these patients have a restricted ability to increase tidal volume and their minute ventilation is increased predominantly by an increase in respiratory frequency. The ability to eliminate carbon dioxide is even worse in these circumstances and some patients become hypercapnic before stopping exercise.8 More recently, changes in end expiratory chest wall volume—which reflects changes in lung volume—have been shown to occur during uninstrumented exercise.9 This pattern of response is not universal as some patients appear to retain the more normal behaviour of trying to reduce end expiratory lung volume while exercising, which perversely may be a bad strategy when they are close to flow limitation at rest. Nonetheless, patients with the most severe COPD, and certainly those with the lower expiratory flow reserve, adopt a strategy of allowing dynamic hyperinflation to occur which further compromises their respiratory mechanics and increases their sensation of breathlessness.

Changes in lung volume with exercise provide an attractive explanation for the increase in breathlessness reported by patients with COPD as respiratory muscle activation, a key correlate of breathlessness in patients with a mechanically impaired lung function,10 is increased at any given workload. The higher the lung volume, the less effective is respiratory muscle contraction due to shortening of the respiratory muscles, particularly the diaphragm. Moreover, breathing occurs over a flatter part of the pressure-volume relationship of the respiratory system and is mechanically less efficient. These processes have been described as neuromechanical dissociation as there is an increase in respiratory drive that fails to produce effective ventilation.11 By analogy with the previously popular length-tension inappropriateness concept of Campbell and Howell, it is believed that neuromechanical dissociation is a major determinant of breathlessness in COPD. Certainly, there is increased respiratory muscle energy expenditure which can approach the levels where inspiratory muscle fatigue can occur.12 However, whether this actually happens during exercise in patients with COPD remains contentious.13


As mechanical factors appear to predominate, it is reasonable to try to alleviate these with drugs that improve lung emptying, principally by producing airway smooth muscle relaxation. Initial data were rather disappointing as they focused on the magnitude of change in FEV1 (modest at best) and whether individuals showed bronchodilator reversibility. This is not a particularly effective approach as the specificity of reversibility testing in stable COPD is poor,14,15 as is the relationship of acute changes in these variables to subsequent exercise performance.16 Studies with β agonists17 and anticholinergic drugs18 have shown that there is improvement in self-paced or treadmill exercise tests irrespective of the magnitude of lung function change or the presence of oxygen desaturation. O’Donnell and colleagues reported improvements in end expiratory lung volume during exercise in patients treated with ipratropium, which suggests that the bronchodilator delayed the onset of dynamic hyperinflation.19 Similar changes in end expiratory lung volumes at comparable workloads have been seen with β agonists, although in this case the duration of exercise did not change.20

In this issue of Thorax Man et al provide further insight into this problem.21 They studied 16 patients selected as having “irreversible” COPD with a mean change in FEV1 after an inhaled bronchodilator of only 10 ml, although it is not clear what dose of bronchodilator was used and how long after the measurement was made. However, treatment with regular salmeterol produced an improvement in FEV1 of only 40 ml, so the patients must be assumed to be relatively unresponsive, at least as judged spirometrically. Patients were randomised into a double blind, placebo controlled, crossover study where the change in transdiaphragmatic pressure-time product and end expiratory lung volume were compared while taking either a placebo or twice daily salmeterol in conventional doses. When compared at the same time point during exercise, the long acting β agonist significantly reduced the transdiaphragmatic pressure-time product, the degree of dynamic hyperinflation, and the severity of breathlessness. However, patients treated with salmeterol did not walk further, even though they were less breathless.

The reduction in respiratory muscle pressure-time product is in keeping with earlier data showing that the resting EMG, an index of respiratory muscle activation, was reduced after an inhaled β agonist.22 The reduction in transdiaphragmatic pressure-time product was largely the result of a fall in the gastric pressure, emphasising the importance of activation of the abdominal muscles during exercise in COPD. Resting inspiratory capacity fell by approximately 160 ml while the degree of dynamic hyperinflation was about 110 ml less after salmeterol. The similarity in magnitude of these changes suggests that the bronchodilator operates by shifting the starting point from which dynamic hyperinflation begins rather than changing its rate of evolution. The change in the relationship of tidal volume to oesophageal pressure at isotime was a good predictor of the change in breathlessness after treatment, as was the change in end expiratory lung volume. These findings are in keeping with earlier variables known to influence breathlessness at rest in COPD, particularly respiratory timing and tidal volume.23 It is a pity that more detail of the breathing pattern at the isotime comparison points was not provided.

These new data give further support to the idea that mechanical factors are the major determinants of breathlessness during exercise in COPD, certainly in patients with this severity of disease. The change in inspiratory capacity produced by salmeterol was similar to that produced at rest by nebulised salbutamol,24 although whether any further improvement in lung function could have been produced by adding in a different anticholinergic bronchodilator is not addressed here. The reduction in activation of the abdominal muscles produced by the bronchodilator is similar to the change seen by unloading the respiratory system mechanically with non-invasive ventilatory support,25 and such strategies might be synergistic. These improvements were seen after regular use of the long acting bronchodilator and suggest that there is no immediate tachyphylaxis in the effects of this treatment, at least spirometrically. Lack of improvement in exercise duration may reflect the severity of the patients studied or the complexity of the protocol adopted. It does emphasise the need to evaluate both the breathlessness and distance walked, particularly with current treatments which have only modest effects on reducing the mechanical limitations associated with exercise and COPD. Whether similar benefits are seen in individuals who are not flow limited at rest and are therefore less likely to exhibit dynamic hyperinflation26 remains to be tested, although at least one study suggests that this may not be the case.27


These relatively complex physiological investigations do have clinical implications. Current treatment can produce small changes in easily measured indices of lung function such as FEV1, which translate into more important improvements in respiratory muscle energy consumption and perceived breathlessness. The mean changes in Borg scale reported by Man et al represent a change from severe to somewhat severe, which may not appear important to fit people but is certainly noticed by patients with COPD. Why apparently similar individuals fail to obtain these benefits while others report marked improvement remains to be established, as does the consistency of changes in breathlessness. It is encouraging that changes in dynamic lung volume are as predictive as more invasive balloon catheter measurements in determining those who felt less breathless as this may make it easier to study these problems in future using less intrusive methodologies. The findings of Man et al reinforce the need to ask patients how they feel when they have been taking treatment and give us more confidence that their responses are likely to be physiologically meaningful, an approach endorsed recently in the NICE guidelines on COPD management.28

Salmeterol reduces breathlessness during exercise without necessarily changing exercise duration


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