The respiratory muscles: cellular and molecular physiology.

The respiratory muscles have been studied extensively during the last 20 yrs. This interest was triggered predominantly by the observation made by ROUSSOS and MACKLEM [1] that the respiratory muscles, like all other skeletal muscles, may fatigue. Subsequent research critically examined the significance of inspiratory muscle fatigue in clinical pulmonary medicine. The conclusion of this research was largely that inspiratory muscle fatigue was rarely, if ever, present [2, 3]. Respiratory muscle fatigue appeared to be effectively avoided by reduction of the duration of inspiration whenever the limits of respiratory muscle performance were approached [4]. This reduction in the duration of inspiration leads to an inappropriately small tidal volume, and, hence, to alveolar hypoventilation and consequent hypercapnia [4, 5]. Inspiratory muscle fatigue, therefore, appeared to occur only in exceptional circumstances, such as cardiogenic [6] or septic shock [7] and weaning from mechanical ventilation [8]. The limits of respiratory muscle performance are determined by respiratory muscle force and endurance capacity. At present, there are few data on the clinical significance of respiratory muscle endurance. There are, however, abundant data on respiratory muscle weakness. Indeed, the clinical significance of respiratory muscle weakness is now clearly established, not only conceptually (see above), but also through empirical observation. Although there are, without question, other circumstances in which it is important, it has been most extensively studied in patients with chronic obstructive pulmonary disease (COPD). The present Editorial, therefore, will focus primarily on COPD. Inspiratory muscle weakness was shown to be related to dyspnoea [9], fatigue, and exercise limitation in COPD patients [10]. Expiratory muscle weakness was shown to be related to cough efficiency [11, 12]. In addition, inspiratory muscle weakness is an important determinant of the development of hypercapnic respiratory failure [13]. As hypercapnic respiratory failure is the most important cause of death in COPD [14], inspiratory muscle weakness is, therefore, also expected to be related to mortality in these patients. At least two observations support the presence of such a relationship. Indeed, DECRAMER et al. [15] demonstrated that survival was severely reduced in patients with COPD and steroidinduced myopathy in comparison to control COPD patients, despite the fact that they had the same degree of airflow obstruction and hyperinflation, the known major determinants of survival in COPD. Moreover, GRAY-DONALD et al. [16], in a cohort study on 348 COPD patients, demonstrated that, in hospitalized COPD patients, maximal inspiratory pressure (PI,max) was an independent determinant of survival, besides hypercapnia, body mass index and transfer factor. There are numerous factors potentially contributing to respiratory muscle weakness in COPD patients. Inspiratory muscle weakness may be related to hyperinflation, which puts the inspiratory muscles at a less advantageous position of their length-tension curve [17], and causes geometrical alterations in the inspiratory muscles. Both factors curtail the force-generating capacity of the respiratory muscles. Moreover, hyperinflation increases the dimensions of the rib cage, such that the muscles at the periphery have to generate a greater tension to develop the same change in pleural pressure in order to produce the same tidal volume [18]. Although adaptations to chronic hyperinflation most probably occur, the overall effect of hyperinflation on the inspiratory musculature is likely to be detrimental [19]. This is confirmed by the observation that volume reduction surgery, which in essence reduces hyperinflation, improves inspiratory muscle function [18, 20–22]. In addition, generalized muscle weakness is present in COPD patients [23]. Both the inspiratory and expiratory muscles partake in this muscle weakness. There are several causes of this generalized muscle weakness. They include: malnutrition [24]; cardiac failure [25, 26]; hypoxaemia; hypercapnia [27]; steroid treatment [28, 29]; electrolyte disturbances, such as hypomagnesaemia [30]; and hypophosphataemia [31] etc. Clearly, the peripheral muscles also participate in this generalized muscle weakness, and a number of studies have recently underlined the significance of peripheral muscle weakness in COPD patients. Three studies have demonstrated a relationship between peripheral muscle force and exercise capacity in COPD patients, suggesting that exercise limitation is frequently associated with peripheral muscle dysfunction [10, 32, 33]. Two other studies have shown that peripheral muscle training resulted in beneficial effects. In the first study, strength training was applied. It resulted in improvements in muscle force and quality of life [34]. In the second study, low intensity endurance training was performed. The beneficial effects observed were: reductions in dyspnoea; and reduced ventilatory requirements [35]. Although, conceptually, it would be expected that, primarily, endurance training would be beneficial, at present it remains unclear whether strength or endurance training results in the greatest benefit to COPD patients. The mechanism of peripheral muscle dysfunction is likely EDITORIAL