Respiratory Muscle Failure: Fatigue or Weakness?: The Role of Theophylline

Abstract

SUMMARY COMMENTS Dr. Edwards: I believe we have achieved a considerable degree of agreement over what is meant by fatigue and weakness. Of the two, we are probably better able to define fatigue. Weakness may predispose to fatigue under certain circumstances, but it may also be associated with conditions where fatigue is less. The differences between fatigue and weakness require the development of new techniques to identify in the individual patient which mechanism is dominant. If there is clear evidence of fatigue, as expressed by failure of excitation-contraction coupling or incomplete activation of the muscle, then theophylline would probably be a useful intervention. On the other hand, if the muscle is not generating force because there is too little of it present, the therapeutic strategy must be an attempt to increase the mass of muscle. To help us separate fatigue from weakness, we need careful observations which are time-based in terms of force generation. Dr. Bryant: From the perspective of drug-muscle interaction and theophylline in particular, there is a clear problem with dosage levels used for in vivo and in vitro experiments. The differences are somewhere in the order of several hundredfold. This emphasizes the fact that mechanisms by which theophylline affects muscle function are not really understood well. There may be a number of other drugs that improve muscle function, particularly the so-called twitch potentiators, which may prove more useful than theophylline in improving muscular tension. Antagonizing the effects of theophylline with a calcium-blocking agent is an interesting phenomenon and needs to be verified. We need to better coordinate the efforts of the clinical and experimental laboratories to help explain some of the differences we have discussed today. Dr. Faulkner: For clinical purposes, weakness may imply either muscle atrophy or an impairment in activation. Although we are in fair agreement that low-frequency fatigue is caused by some process in excitation-contraction coupling, we are at a loss to explain the exact mechanism. This makes it difficult to interpret how theophylline affects the process of fatigue, but it appears to have some effect. We will need to know much more about the basic physiology of fatigue, as well as the pharmacologic effects of theophylline, before the drug can be used effectively. Dr. Roussos: I think it is inescapable to say that theophylline, both at high doses and therapeutic doses, does increase the contractility of respiratory muscles, reverse fatigue, and perhaps prevent fatigue. Certainly, the mechanism is not known, and this is an area that needs much more work.