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Thorax 58:741-742 doi:10.1136/thorax.58.9.741
  • Editorial

Peripheral muscle weakness in COPD: where does it come from?

  1. M I Polkey
  1. Department of Respiratory Medicine, Royal Brompton Hospital and National Heart & Lung Institute, London SW3 6NP, UK; m.polkey{at}rbh.nthames.nhs.uk

    Do patients with frequent exacerbations of COPD have a more rapid rate of decline in quadriceps strength than those with stable disease?

    Exertional dyspnoea is usually the main complaint of a patient with chronic obstructive pulmonary disease (COPD). Although this is partly a result of impaired pulmonary mechanics, exercise performance remains substantially reduced even if both lungs are replaced,1 which suggests that the lungs alone cannot explain exertional dyspnoea. Quadriceps myopathy is a feature of COPD. Histological examination of quadriceps biopsy tissues shows a switch towards fatiguable type II fibres2 and reduced oxidative enzymes. This in turn leads to anaerobic metabolism at lower work rates than in normal subjects.3 Lactic acid, generated as a byproduct of anaerobic metabolism, is buffered by bicarbonate with the generation of carbon dioxide. Patients with severe COPD cannot clear carbon dioxide by increasing their ventilation and thus treadmill walking may result in transient hypercapnia and acidosis.4 It is perhaps not surprising therefore that quadriceps weakness is demonstrably related to the utilisation of healthcare resources.5

    The magnitude of quadriceps weakness is related to disease severity,6 but there is wide variation for a given forced expiratory volume in 1 second (FEV1) and a number of competing (though not mutually exclusive) theories have been proposed as contributors to quadriceps muscle weakness in COPD. The most straightforward suggestion is that the muscle changes are simply a local result of inactivity. This explanation is favoured by the preferential involvement of lower limb muscle (generally less active in COPD) over upper limb muscle,6,7 as well as the sparing of the diaphragm8 which, of course, shows increased activity. This argument is further supported by the observation that exercise training,9 and possibly externally applied nerve stimulation,10 can reverse disease induced changes in the muscle. Another explanation is that muscle wasting is the result of a systemic inflammatory response; this hypothesis is supported by data which show that patients who fail to gain weight during a refeeding programme have high levels of soluble tumour necrosis factor (TNF) receptor 55.11 In addition, skeletal muscle mass in COPD is inversely related to circulating levels of interleukin (IL)-6 and TNF-α.12

    Against this background, Spruit et al13 present new data which raise a new hypothesis—that recurrent exacerbations result in stepwise impairment of muscle function. They studied 34 men with moderately severe COPD admitted from an emergency department and measured indices of respiratory and peripheral muscle strength. Systemic levels of insulin-like growth factor I (IGF-I), TNF-α, and IL-6, IL-8 (the latter now known as CXCL8), and IL-10 were measured. Control data were obtained from men with stable COPD attending an outpatient clinic and from healthy elderly men. CXCL8 was highest in men admitted to hospital and statistically higher than for stable COPD patients. A similar trend was observed for IL-6, although this was not statistically significant. TNF-α levels were undetectable in all but two of the patients studied. Quadriceps strength was inversely correlated with levels of both CXCL8 and IL-6, as well as with indices of disease severity. Handgrip force correlated weakly with CXCL8 only in the patients admitted to hospital. Follow up data are also provided, although their interpretation is tempered by the fact that nine of the 34 patients dropped out between the first assessment (day 3) and the second assessment (day 8), and that a further 12 patients dropped out before the third assessment (day 90), leaving an available pool of just 13 of 34 subjects (38%). Quadriceps strength was observed to fall by 5% at day 8 but to have been regained by day 90.

    An important claim of the present study is that quadriceps strength was negatively correlated with CXCL8 on day 3 of admission. Proximal myopathy is a well known consequence of corticosteroid therapy14 and the Leuven group have stressed the importance of steroid myopathy in COPD.15 In fact, approximately 50% of the variation in quadriceps strength in patients admitted with COPD can be related to cumulative steroid dose,16 and one explanation of the findings in the study by Spruit et al is that preadmission steroid exposure (or factors giving rise to a need for courses of steroids) both increased CXCL8 and reduced quadriceps strength.

    Another exciting result is the demonstration that there is an acute loss of muscle force during an acute exacerbation of COPD. As with chronic muscle weakness, various pathophysiological mechanisms could be advanced to explain this. The authors correctly argue that steroids given during the admission are unlikely candidates because the magnitude of force loss is unrelated to steroid dosage, so it may be helpful to consider the physiological site of the weakness. Spruit et al used volitional tests of muscle strength so their results depend both on the contractile properties of the muscles studied and also on the maximality of the effort made during the test. In a study of the unaffected leg of patients admitted with acute hemiplegic stroke—that is, ipsilateral to the lesion—Harris et al17 used both non-volitional and volitional techniques to measure quadriceps strength. With the non-volitional technique she found a significant (16%) loss of strength in the first week after admission but a much greater loss (30%) when the patients were assessed using a volitional technique, suggesting that volitional techniques may overestimate weakness in acutely ill patients. Preliminary data from a small number of subjects suggest that motor cortex function may be altered (in fact to reduce intracortical inhibition) during acute exacerbations of COPD,18 and the present data should be confirmed using a non-volitional technique. The other possibility, which is consistent with the known histological myopathy in stable patients with COPD, is that the weakness is due to an acute myopathy. If so, the contractile properties of the muscle could have been directly impaired by inactivity,17,19 but the acute inflammatory response recognised to accompany acute exacerbations20 may also be relevant if an acute exacerbation could be shown to result in local skeletal muscle damage. Myopathy is known to contribute to neurological abnormalities in patients in critical care units21; a similar finding in acute exacerbations of COPD would be plausible

    It is now recognised that patients with frequent exacerbations of COPD have a more rapid rate of decline in lung function,22 and the study by Spruit et al raises the intriguing hypothesis that frequent exacerbators might have a more rapid decline in quadriceps strength. In future, therapeutic strategies aimed at reducing exacerbations (or their effects) might be valuable for maintaining exercise performance in patients with COPD.

    Do patients with frequent exacerbations of COPD have a more rapid rate of decline in quadriceps strength than those with stable disease?

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