NHLBI Workshop Summary Respiratory Muscle Fatigue Report of the Respiratory Muscle Fatigue Workshop Group1-3 Introduction
The potential importance of respiratory, chiefly inspiratory, muscle fatigue has become well recognized in the last decade. If inspiratory muscles fail, so does ventilation and tissue respiration. There are theoretical reasons to postulate inspiratory muscle failure in chronic obstructive pulmonary disease (COPD), and there is some fairly good evidence that respiratory muscle fatigue is of importance in certain neuromuscular diseases such as polio, ALS, muscular dystrophies, and myopathies. In 1982, the Division of Lung Diseases issued a Request for Grant Applications in order to stimulate research in this field. Six grants were awarded, and substantial progress was made in understanding the basic physiology of respiratory muscle fatigue. In September 1988, a workshop was held at Kansas State University in Manhattan, Kansas, in order to reassess the state of research in the field and to define areas in which further research might be fruitful. The attendees included investigators specializing in basic muscle physiology as well as those with a specific interest in respiratory muscles, respiratory muscle fatigue, and the control of breathing. Definitions
The group attending the workshop felt that the term "muscle fatigue" needed careful definition, particularly in order that there be no confusion with the term "muscle weakness." Accordingly, the following definitions were discussed and agreed upon. Muscle fatigue is a condition in which there is a loss in the capacity for developing force and/or velocity of a muscle, resulting from muscle activ.ity under load and which is reversible by rest. Muscle weakness is a condition in which the capacity of a rested muscle to generate force is impaired. Summary of Workshop Sessions
Basic Properties of the Respiratory Muscles The respiratory muscles are embryologi474
cally, morphologically, and functionally skeletal muscles. They are mixed muscles made up of combinations of the three principal fiber types found in all skeletal muscles. Half of the fibers in the human diaphragm are slow oxidative (type I) fibers, and the remainder of the fibers consist of equal proportions of fast oxidative glycolytic (type IIA) fibers and fast glycolytic (type lIB) fibers. Among the mammalian species whose diaphragm fiber type distributions have been investigated, the percentages 0 f type I and type IIA vary widely from 93 and 707o, respectively, in the mouse and 39 to 16%, respectively, in the cat. Despite this variability among species, in all species studied, the oxidative, fatigue-resistant fibers (type I plus type IIA) exceed 55%. This composition is consistent with the fact that the diaphragm is denied the opportunity for sustained rest. Although extensive studies of fiber type distribution in other respiratory muscles are lacking, the intercostal muscles generally match the diaphragm in this respect. The contraction, relaxation, and shortening properties of the respiratory muscles are qualitatively and quantitatively within the range of other skeletal muscles located in the limbs. The velocity of shortening of the respiratory muscles, or more particularly the diaphragm, varies considerably depending upon the size and life-style of the species. Within a given species, the diaphragm appears to be consistently slower than the other respiratory muscles. Muscle fibers produce substantially less active force at shorter and longer lengths than at optimal length. For the diaphragm, the overall force length characteristics depend upon the force length characteristic of its two components, the costal and crural parts and how they are mechanically linked. For a parallel m~ chanicallinkage, the forces are additive, whereas for a series mechanical linkage, the displacements are additive. In vivo, the length-tension relationship of the whole diaphragm shows a rather broad effective length range, encompassing 30 to 40% of the in situ resting length. This
is greater than is the case for the rib cage inspiratory muscles such as the intercostal whose length-tension relationship encompasses less range and whose in vivo length change rarely exceeds 10% of the in situ resting length. Of interest is the observation that different inspiratory muscles appear to operate in vivo over different portions of their length-tension curves during resting tidal breathing; for instance, increases in lung volume (which shorten these muscles) cause a decrease in diaphragmatic tension, an increase in intercostal tension, and little change in the tension generated by the scalene and sternomastoid for a given degree of excitation. Despite these differences in operating length, the length-tension curve (Received in original form January 10, 1990) 1 The Workshop was held at Kansas State University in Manhattan, Kansas, September 14-17, 1988, sponsored by the Division of Lung Diseases (Structure and Function Branch), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Support from Kansas State University, including the use of their facilities, is gratefully acknowledged. 1 List of Participants: Michel Aubier, Clichy, France; Robert B. Banzett, Boston, MA; Francois Bellemare, Montreal, Quebec, Canada; Norma M. T. Braun, New York, NY; Neil S. Cherniack, Cleveland, OH; Thomas L. Clanton, Columbus, OH; Jerome A. Dempsey, Madison, WI; Andre De Troyer, Rochester, MN; Ludwig A. Engel, Westmead, NSW, Australia; Gaspar A. Farkas, Rochester, MN; John A. Faulkner, Ann Arbor, MI; Alejandro E. Grassino, Montreal, Quebec, Canada; Gabriel Haddad, New Haven, Cr, Frederic G. Hoppin, Jr., Pawtucket, RI; Rolf D. Hubmayr, Rochester, MN; Sabah Hussain, Montreal, Quebec, Canada; Steven G. Kelsen, Philadelphia, PA; Stephen H. Loring, Boston, MA; Franklin D. McCool, Pawtucket, RI; John Moxham, London, England; Michael B. Reid, Boston, MA; Brenda B. Ritchie, New Haven, CT; Dudley F. Rochester, Charlottesville, VA; Charalambos Roussos, Montreal, Quebec, Canada; John T. Sharp, Tampa, FL; Everett E. Sinnett, Bethesda, MD; Gerald Supinski, Cleveland, OH; Magdy K. Younes, Winnipeg, Manitoba, Canada. Chairman: Peter T. Macklem, Montreal, Quebec, Canada. Cochairmen: Nicholas R. Anthonisen, Winnipeg, Manitoba, Canada; David E. Leith, Manhattan, KS. 3 Correspondence and requests for reprints should be addressed to Dr. Dorothy Berlin Gail, Division of Lung Diseases, NHLBI, National Institutes of Health, Westwood Building, Room 6A07, 5333 Westbard Avenue, Bethesda, MD 20892.
AM REV RESPIR DIS 1990; 142:474-480
WORKSHOP SUMMARY
describes the maximal limits for the development of force. In situ, breathing results from submaximal activation of the respiratory muscles. Furthermore, because of the complexity of the thorax, the effective pressures generated by the various respiratory muscles will likely be altered because of changes in lung volume and body position, independent of muscle length. A muscle operating at less than optimallength not only generates less force, it also fatigues more rapidly. However, among the important properties of skeletal muscles, including the respiratory muscles, is their ability to adapt to altered conditions and regimens. When required to work chronically at shorter fiber length, sarcomeres at the ends of fibers in the diaphragm muscle are absorbed, and the resting in situ length is shortened to allow the remaining muscle to operate at near optimal length-tension conditions. This adaptation has been demonstrated in the hamster diaphragm when chronic shortening of its fibers occurs as a result of elastase-induced pulmonary emphysema. Metabolic and contractile characteristics also change in response to alterations in innervation and to changes in stimulus characteristics. Innervating a slow muscle fiber with a motor nerve from a fast muscle fiber will result in a transition of the characteristics of the slow fiber toward those of the fast fiber. Similarly, stimulating a mixed muscle at low frequencies will improve its endurance characteristics but decrease its capability to develop force. A practical application of this phenomenon is the clinical use of phrenic nerve pacing. Stimulation frequencies of 30 Hz permit stimulation of only one hemidiaphragm at a time while the other hemidiaphragm recovers, whereas stimulation of the diaphragm muscle at 10 Hz allows bilateral stimulation of the diaphragm for 24 h daily without requiring rest periods, resulting in the conditioning of the whole muscle. With the same principle of chronic low frequency stimulation, skeletal muscles have been conditioned to serve as an auxiliary or substitute heart. Such protocols offer the possibility that endurance characteristics of respiratory muscles may be improved in appropriate clinical situations. Skeletal muscles, including the respiratory muscles, are capable of improving their strength and endurance by appropriately designed training protocols. To be effective, training must take into account three principles: overload, spec-
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ificity, and reversibility. For an "overload," the training stimulus must be an increase in either the number of contractions performed or in the load on the muscle during contractions or both. High repetitions and low load activities produce endurance training, whereas low repetitions and high loads produce strength training. The specificity of the training stimulus is supported by the observation that only organelles within fibers in those motor units influenced by the training stimulus adapt to the stimulus and consequently improve their performance. The principle of reversibility requires that training be kept up if the gains achieved by the training are to be retained. "Use it or lose it" expresses this idea well. Data obtained by several observers suggest that inspiratory muscle resistance training may be of clinical benefit to some patients but not to all patients with COPD nor to other patients with respiratory insufficiency of neuromuscular origin.
Fatigue of Respiratory Muscles Neuromuscular fatigue has previously been defined as the inability to maintain or repeat the required or expected force or power output. This widely accepted definition has two major drawbacks. First, it implies that fatigue is delayed in onset and can only be detected when the required force can no longer be generated by a maximal voluntary effort, neglecting the decline in force-generating capacity that occurs meanwhile. Second, it implies that force and power output necessarily change in parallel, and that these terms can be used synonymously, whereas it is now clear that during fatigue from dynamic contractions the maximum force and velocity of shortening often change independently. Moreover, the timing and extent of changes in both force or power output depend on the type of exercise being performed. According to the agreed definition, fatigue occurs before the required force or power can no longer be generated by a maximal effort. The point at which the required force can no longer be attained is then termed "exhaustion" or "task failure." The causes of fatigue are complex and involve simultaneous changes at various sites within both the muscle and the central nervous system (CNS). In practice, a reduced performance capacity often results from an inability or unwillingness to maintain sufficient central motor drive. However, under experimental
conditions, the drive to most human limb muscles can be kept adeq uate to activate all motor units to respond with maximal force throughout the exercise regime. In contrast, when fatigue of the diaphragm is induced by a similar intermittent contraction breathing protocol, about 500/0 of the force decline can be attributed to a mandatory reduction of central motor drive. However, it is not yet clear what role mandatory depression of CNS motor drive plays when the diaphragm or other respiratory muscles are fatigued under other, more normal, conditions. Further research in this area may provide significant advances. In limb muscles, the main eNS response to fatigue from sustained maximal contractions is a reduction in motoneuron firing rates. This has been attributed to reflex inhibition initiated by some fatigue-induced change within the muscle. However, because of a corresponding slowing of contractile speed, this reduction in motoneuron firing rates does not result in a reduction in muscle activation. In contrast, it may optimize force generation by reducing peripheral failure of both impulse propagation and excitation/contraction coupling. Ample evidence suggests that similar processes may operate during fatigue of respiratory muscles, but, in this case, the reflex may be more powerful so that maximal muscle activation becomes no longer possible once these muscles are fatigued. If so, perhaps this CNS depression provides a protective mechanism to prevent an undue reduction of intrinsic diaphragm muscle fiber strength. Major differences exist between events seen during fatigue induced by voluntary contractions and those from artificial nerve or muscle stimulation. During artificial stimulation, especially at high frequencies, muscle force declines rapidly in association with the decline in actionpotential amplitude. This response, known as "high frequency fatigue," is attributed to failure of impulse propagation across the neuromuscular junction and/or over the muscle surface membrane. However, the development of this type of failure during voluntary contraction is questionable. First, evoked muscle compound action potential (M-wave) amplitudes are generally found to remain unimpaired. Second, no unique relation between muscle force and electromyographic (EMG) activity has been observed. For example, the EMG activity recorded from single motor units may decline under conditions where the force remains unchanged,
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and EMG responses can potentiate during periods of force reduction. Thus, there is a large safety factor between the extent to which muscle membranes may become depolarized and the point where impaired activation results. A major difference between fatigue induced by voluntary contractions and by artificial stimulation is due to differences in the rates at which action potentials are delivered. In voluntary contractions, each motor unit is excited at a rate matched to its particular contractile properties. During artificial stimulation, only one rate can be used, and this is often selected arbitrarily. Thus, for any given rate, some units may be stimulated supratetanically (perhaps generating high frequency fatigue), whereas others are less than maximally activated. Caution should therefore be used when extrapolating results from experiments on isolated preparations or anesthetized animals to imply similar events during fatigue from voluntary contractions; this can pose a major difficulty when more detailed investigations require techniques inappropriate for use with intact human subjects. Most studies conclude that the major factors underlying neuromuscular fatigue occur within the muscle fibers and mainly result from depletion of muscle energy stores or pH changes from lactic acid accumulation. During sustained high force contractions, the intramuscular pressure generated impedes the muscle blood supply so that these changes are expected, and probably account for the corresponding force reduction. However, there is no quantitative relation between force reduction and metabolic changes with fatigue from different types of exercise. Moreover, results from fatigue induced by intermittent, submaximal, isometric contractions, where blood flow is minimally impeded, provides evidence that nonmetabolic factors are also involved. In these experiments, the force from brief, maximal test contractions declined by about 500/0 during a time when no significant metabolic changes were detectable. Because no evidence was found for insufficient motor drive or failure of peripheral impulse propagation, this must have been caused by impaired excitation/contraction coupling. Similar conclusions have been reached under other exercise conditions. Many of the factors contributing to neuromuscular fatigue can be measured most conveniently by twitch occlusion. This technique is particularly appropriate for clinical studies since it is relative-
WORKSHOP SUMMARY
ly painless, easy to apply, and can be used on muscles where the motor nerve is not readily accessible. Moreover, maximal muscle strength can be indirectly and accurately assessed under conditions where the patient is unable, or unwilling, to make a truly maximal effort. It has been used successfully during fatigue studies on the human diaphragm involving both patients and normal subjects. The decline in intrinsic muscle strength is measured from changes in the contractile response to electrical stimulation delivered to the relaxed muscle between voluntary contractions while changes in the degree to which the muscle is (or can be) activated by the CNS are assessed by comparing these values to the extra force that can be elicited when twitches are superimposed on the voluntary contractions. For this purpose, it is important to be certain that the intensity of the stimulus remains unchanged by, for example, monitoring the amplitude of the evoked M-wave, which also tests the integrity of neuromuscular transmission. One drawback when using this method to investigate fatigue of the diaphragm is that consistent supramaximal, bilateral, tetanic stimulation of the phrenic nerves has so far proved unreliable. Thus, changes in intrinsic muscle stength can so far only be assessed from changes in the twitch responses elicited from the relaxed muscle. These responses may be subject to fluctuations, e.g., substantial degrees of twitch potentiation or "low frequency fatigue," not seen when tetanic stimulation is applied. If this technique is to be developed for extensive clinical use, more work is needed to explore the relationship between changes in twitch and tetanic responses as fatigue develops. Other methods that have long been used to predict the onset of neuromuscular fatigue involve changes in the EMG power spectrum. However, power spectrum changes can result from conditions other than muscle fatigue and their quantitative relation to force or power reduction remains controversial. It is also suggested that promising techniques for assessing neurom uscular fatigue might be developed from more thorough investigations of the relationship between force or power loss and changes in muscle relaxation rates, and from exploration of the reliability of using sniffs as a means of generating maximal voluntary diaphragmatic contractions.
Control of Breathing with Mechanical Loads Many respiratory diseases alter the load
on the respiratory muscles. Defining the normal responses to loading and their mechanisms is essential for understanding the pathogenesis of respiratory failure in these diseases and for developing rational approaches to prevention and treatment of hypercapnia. Except with severe loads, conscious humans maintain a normal Pe02, at least in the short term, when a variety of loads are applied in the laboratory setting. This attests to the presence of powerful neural load compensatory mechanisms in conscious humans. Feedback through chemoreceptors is the mechanism that the body uses to adjust the activity of the respiratory pump so that arterial blood gas tensions of O 2 and CO 2 can be kept within acceptable limits. A different but related protective system maintains ventilation and defends the force-generating ability of the respiratory muscles and the respiratory pump against mechanical breakdown. This system, which is brought into play not only when breathing is mechanically impaired by pulmonary disease but whenever postural changes affect the mechanical advantage of the respiratory muscles, has three major components. These are (1) the intrinsic properties of the respiratory muscles; (2) the reflexes brought into play by stimulation of receptors in the airways, lung parenchyma, and the muscles; and (3) behavioral compensations, which occur presumably because of the conscious perception that excessive effort is required to bring air into and out of the lungs. This compensatory response is modified if loads to breathing are maintained for long periods of time. This occurs not only by changes in the muscular strength and endurance but also by adaptations in reflex response and by adjustments in behavioral responses, which become more automatic and are probably set into play by proprioceptor signals. In anesthetized animals, adjustments occuring immediately after load application are mainly the result of changes in vagal mechanoreceptor feedback related to lung volume. Subsequent adjustments are chemically mediated (i.e., P0 2 and Pe02). Unfortunately, responses of conscious humans are different and cannot be readily explained by either mechanism. In part, this may depend on the neural origin of the breath - cerebral cortex or brainstem. The response of anesthetized humans and of sleeping animals and sleeping humans is much closer to those of anesthetized animals than to those of conscious humans. Not enough
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information is available about the response of conscious animals to ascertain whether these responses are similar to those of conscious humans. More studies are needed with different types of loads: easily tolerated and non fatiguing loads, as well as more fatiguing loads. Although published results in conscious animals are not entirely the same as those in humans, animals allow the investigation of biochemical and anatomic components of the load response more readily than do humans. Nevertheless, progress in understanding compensation to the added loads in disease will have to come largely from studies on conscious humans. Although much work has been done to study the response of conscious humans to loads, the information available is largely descriptive and limited to loading conditions that can be easily carried out in short experiments in the laboratory. We are far from understanding the mechanisms of human responses, how chronicity affects the responses, the relevance of the documented responses to respiratory failure in the clinical setting, or the relative role of cortical versus brainstem control in the experimental setting. Because disease affects the respiratory system in a complex manner by actions on the lung, the ventilatory muscles themselves, and to a degree, on the CNS, investigators have resorted to a variety of techniques to produce simpler disturbances of muscle performance so that the elements of the compensatory responses can be better delineated and analyzed. On the other hand, there is some evidence that load responses, particularly in conscious humans, differ depending on the character of the load. The type of loads commonly used include external resistances, elastic loads, chest strapping, pressure breathing, inhalations of gases of different density and viscosity, and bronchoconstriction. The effects of loads will depend not only on the type of loads but also on whether they are applied continuously or for just a portion of a breath, as well as on the duration of load application. Measurements of ventilation and its components, of the respiratory muscle electromyogram, and of occlusion pressure have been used to measure the response to loads. However, the reaction of conscious subjects to loads must also depend in large part on the capacity to detect changes in the loading of the respiratory muscles and to quantitate the force produced during breathing and the
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changes in lung volume that occur. Established methods and techniques in experimental psychology and psychophysics have been mainly used to quantitate respiratory sensations, and they have provided useful information. More recently, analysis of the electrical activity of the brain has been employed to obtain an objective measure of the effect of loads on the CNS. It has been suggested that higher brain centers receive some corollary input from respiratory motor neurons that allows them to assess output and possibly to compare effort to afferent signals from muscle and lung receptors so that muscular effort and its effect on breathing can be assessed. Evidence for such corollary discharge is incomplete and thus far pertains only to voluntary respiratory acts. Little is known about either the anatomic or biochemical basis of this corollary signal or how comparisons are made. Techniques such as PET scanning to evaluate regional changes in cerebral blood flow and metabolism may be useful in obtaining such data in conscious humans. In addition, more studies are needed with different types of loads: easily tolerated and nonfatiguing as well as more fatiguing loads. First, the majority of laboratory studies utilize linear or nearly linear inspiratory resistive loads. Because human responses tend to be load specific, attempts should be made to mimic as much as possible the abnormal mechanics of disease in which, in expiration in particular, resistance is grossly nonlinear, resulting in flow limitation. Second, most respiratory diseases that result in respiratory failure alter respiratory mechanics over a protracted period of time (months to years). The relevance of short-term responses (measured a few breaths or few minutes after load application) to the much more gradual and protracted disturbance produced by disease is not clear. The mechanisms involved in the short-term experiments in the laboratory, whether of neural or chemical origin, may adapt with time. This information is crucial. Third, it has been suggested that overworked respiratory muscles may contribute to respiratory failure by generating inhibitory signals that reduce the motor command in such a way that they are protected from fatigue. Although there is considerable indirect evidence that the machinery is there to effect inhibition under selected experimental conditions, it is not clear whether these conditions extend to the spontaneously breathing per-
son with chronic respiratory failure. Much critical animal and human work is needed before this important issue is resolved. Fourth, new approaches to load application, as well as the utilization of patients with selected neurologic deficits, are needed to define what it is about consciousness that enhances load compensation in conscious humans and by what means this is effected. Fifth, studies are needed to determine the effect of pharmacologic agents on load responses. Dyspnea is a major and often disabling symptom of lung disease and is related to loading of the respiratory muscles. It is important to ascertain whether there are agents that can alleviate dyspnea without impairing responses to loads. Finally, all current methods of evaluating respiratory motor output, except the phrenic neurogram, include measurements of the properties of the respiratory muscles. The use of occlusion pressure (P O• l ) is inappropriate in the face of changing mechanical loads and/or muscle contractibility; EMG recordings are difficult and sample only a few muscles. Noninvasive methods need to be developed by which the motor output can be separated from the muscular response. Criteria for Diagnosing Respiratory Muscle Fatigue Until now, the criteria for diagnosing respiratory muscle fatigue have been imprecise because of the lack of a definition, the limited knowledge regarding the processes leading to fatigue, and the lack of methods available to precisely measure this state. Differences in excitation patterns during voluntary activity from that during externally stimulated activity make the diagnosis more complicated. The working definition for muscle fatigue accepted at the conference (vide supra) should be of considerable help in establishing more precise criteria. Fatigue is likely to be the result of a dynamic process in which compensatory mechanisms are overwhelmed in a closed loop system consisting of central motor drive, peripheral impulse propagation, excitation/contraction coupling, depletion of energy substrates and/or metabolite accumulation, and feedback modulating reflexes. The bedside clinical diagnosis of fatigue is hampered by the inability to measure the baseline before fatigue. It may be possible only to infer fatigue retrospectively by its reversibility after a period of rest. The appropriate rest period, and readiness for re-
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spiratory weaning, remain clinical problems that require solutions. In order to understand fatigue mechanisms, several tests have been developed to measure the change from a nonfatigued, unloaded condition to a fatigued state after a load has been applied. Currently, there are tests that measure the pressures generated by the respiratory muscles (maximal inspiratory mouth pressure [PImax] and transdiaphragmatic pressure with respect to inspiratory time and respiratory rate [pressure-time index and Pdimax ]); tests that measure diaphragmatic or other inspiratory muscle electrical activity (power spectral analysis and integrated electrical acitivity [Edi] or some combination of electrical activity and pressure development [Edil Pdi)); other tests that aim to define the capacity of the diaphragm to generate pressure independent of central control mechanisms (bilateral phrenic nerve twitch stimulation and Pdilfrequency curves); and finally, tests that measure the increase in Pdi when a twitch is superimposed on the naturally activated diaphragm to assess the relative degree of motor unit recruitment through central pathways (twitch occlusion tests). Each of these tests has its own set of limitations. When interpreting PImax and Pdimax , submaximal efforts (inadequate motivation) cannot be distinguished from central fatigue; this represents a major limitation, particularly in critically ill and/or dyspneic patients. Tests that quantitate the electrical activity of inspiratory muscles are influenced by changes in the spatial relationships between the recording electrodes and the muscle. The cellular mechanisms responsible for shifts in the power spectrum remain unknown, which casts doubt upon the sensitivity and specificity of this technique. The measurement of Pdi requires the placement of esophageal and gastric balloon catheters and its magnitude is dependent on the geometry of the respiratory system (lung volume and thoracoabdominal shape) in addition to the contractile state of the diaphragm. When the diaphragm is activated electrically by stimulating the phrenic nerves, Pdi also varies in proportion with the resistance ofthe chest wall to deformation. Phrenic stimulation at fusion frequencies is not feasible in patients because of the associated discomfort. The only test from this series that may reliably separate central from peripheral fatigue is the twitch occlusion test. If all motor units of the diaphragm have been
recruited during a spontaneous breath or during a voluntary maximal inspiratory effort, twitch stimulation will not elicit an additional Pdi response. This test will have to be evaluated and compared with the other ones in order to determine the value and utility of each and so describe their specificity and sensitivity. Despite the drawbacks, it was felt that information obtained from bilateral transcutaneous supramaximal phrenic nerve twitch stimulation had the best potential of becoming a diagnostic test. The measurement of mouth pressure developed against an occluded airway can be done noninvasively and can potentially be used as a twitch occlusion test. From such a test, the time to peak tension, the dPdi/dt, the peak Pdi, and the Y2 relaxation time can also be computed. However, more rigorous evaluation of this test needs to be done before it can be recommended for general use.
Prevalence of Respiratory Muscle Fatigue The prevalence of respiratory muscle fatigue will remain unknown until a definition of fatigue is agreed upon and accepted diagnostic criteria are established. If the definitions proposed by this workshop are generally acceptable, they can be applied to patients to establish a base upon which prevalence studies can be developed. However, before such studies can be carried out, diagnostic criteria must also be developed as discussed above. Despite this lack of knowledge on prevalence, four groups of patients at high risk to develop fatigue can be identified: (1) premature and newborn populations; (2) patients with chronic respiratory loads or inspiratory muscle weakness (this latter group includes patients with neuromuscular disorders who appear to benefit from intermittent mechanical ventilation to put their muscles to rest); (3) patients with an inadequate supply of energy (cardiogenic shock, septicemia); and (4) asthmatics and COPD patients facing a sudden increase in load. In order to define the prevalence of respiratory muscle fatigue in a clinical setting, a "gold" standard is needed to diagnose respiratory muscle fatigue. There is no universally agreed upon objective physiologic or clinical test (or set of tests) that are unique indicators of fatigue. Despite the fact that it is necessary to develop diagnostic criteria before the prevalence of respiratory muscle fatigue can be assessed accurately, a small number of reports have been published in the past
several years that provide some evidence regarding the incidence of respiratory muscle fatigue in patients receiving mechanical ventilation. For example, 100010 of a small, highly select group of patients with chronic obstructive lung diseases had evidence of respiratory muscle fatigue shortly after the institution of mechanical ventilation, using the power spectral density of the diaphragm EMG as an index of fatigue. Inability to maintain an adequate alveolar ventilation was regarded as task failure from fatigue; according to the workshop definition, fatigue precedes task failure, and thus, if it occurs clinically, it should precede the development of hypercapnia. In a discussion about a suitable definition of respiratory muscle fatigue, it was initially suggested that the notion of an impaired ability to maintain adequate alveolar ventilation should be included. There was disagreement about this. It was generally felt that including some aspect of respiratory muscle task performance in the definition (in particular, the maintenance of adequate alveolar ventilation) was counter-productive. Furthermore, an impaired ability to maintain alveolar ventilation leading to respiratory failure may have causes other than respiratory muscle fatigue; its inclusion in the definition may therefore lead to confusion on the part of clinicians. Rather it was felt that the definition of respiratory muscle fatigue should focus on a description of the dysfunction that occurs in the muscles themselves. There was a general consensus that the definition should include the idea that the process of fatigue was reversible by rest or a decrease in the activity level of the muscle. It was felt that the incorporation of the concept of reversibility would have the advantage of distinguishing impaired muscle contractility related to neuromuscular disease, electrolyte disturbance, wasting, or other causes of weakness from that related to fatigue. It was also felt that inclusion of the concept of reversibility by rest, which has value as a diagnostic tool, also suggests a therapeutic approach. In general, however, the elements that were viewed by the majority of the session members as important components of the definition of respiratory muscle fatigue were: (1) fatigue is a condition in which the ability of the respiratory muscles to generate pressure or airflow is impaired; (2) impairment in muscle function is a result of heightened contractile activity relative to strength and/or a de-
WORKSHOP SUMMARY
crease in energy supply; and (3) the impairment in muscle function would be improved by rest or a decrease in the activity level of the muscles. The idea that a set of definitions on various aspects of respiratory muscle dysfunction should be put forward to cover some specific aspects of dysfunction was favorably received. For example, definitions of muscle weakness, task failure, chronic fatigue, and acute fatigue are needed. The definitions proposed by the workshop for skeletal muscle fatigue and weakness, which were not agreed upon until the final session, arose in large part from the discussions in the session on prevalence. It was strongly felt that: (1) further research leading to greater understanding of the process of respiratory muscle fatigue and failure is needed; (2) particular emphasis should be put on diagnostic methods and criteria for respiratory muscle fatigue so that prevalence can be determined; (3) this information is needed in order to assess the magnitude of the problem and its costs to the health care system. Research to obtain this information is urgently needed in order to establish priorities for funding.
Management oj Respiratory Muscle Fatigue Although experimental muscle fatigue develops when the demands on the respiratory pump are excessive in relation to pump capacity, it is, as yet, not clear whether in the clinical setting of ventilatory failure overt peripheral muscle fatigue develops or whether an adaptive feedback reduction of central drive avoids such fatigue, albeit at the cost of hypoventilation. The three components of the system (demand, capacity, and drive) are closely linked, and for the patient approaching ventilatory failure, a small alteration in one variable may determine outcome. It is rational, therefore, to direct therapeutic efforts at minimizing demand, maximizing capacity, and optimizing drive. However, specific therapy of respiratory muscle fatigue will only become possible when reliable criteria for the diagnosis and monitoring of fatigue are available. In the clinical setting, the distinction between respiratory muscle weakness and fatigue, both of which may cause respiratory muscle failure, is often difficult. Weak muscles are susceptible to fatigue, and an increase in muscle strength protects from fatigue. Important treatable or avoidable causes of weakness include
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hypercapnia, acidosis, electrolyte disturbances, and hypophosphatemia, as well as thyroid, alcohol, steroid, drug-induced, and inflammatory myopathies. The respiratory muscles of wasted patients are weak, and the strength of the ventilatory pump can be improved by nutritional repletion. Such nutritional therapy can facilitate weaning. Specific training of the respiratory muscles can enhance strength and endurance, the latter being of most relevance to patients with chronic ventilatory loads or weaning difficulties. The literature on respiratory muscle training leaves many clinically important questions unanswered. It is clear that training produces improvements in the task being trained for, with little crossover benefit to other tasks; further, such programs may also have a substantial placebo effect. Which patients are likely to benefit from training and what are the best protocols are questions that remain, for the most part, to be determined. We still do not know how much training, in terms of intensity and duration, produces maximal results, which training devices are most effective, and how much long-term training is required to avoid de-training. Furthermore, although training of respiratory muscles with spare capacity may improve performance, training of muscles already being driven at the limit of their capacity may produce myopathic changes, well recognized in overtrained athletes, recovery from which can be prolonged. Experimentally, fatigue develops when the pressure-time index of the respiratory muscles exceeds a critical value; it may therefore be avoided by therapy that reduces the load on the ventilatory pump below the fatiguing threshold. In the clinical situation, this is most often achieved by treatment directed at reducing airway resistance and increasing pulmonary compliance. A second experimental setting in which fatigue has been studied is that of reduced oxygen and substrate delivery to respiratory muscle, as occurs clinically in septic or cardiogenic shock; thus, therapy aimed at restoring oxygenation and muscle blood flow may enhance contractility and avoid fatigue in such situations. Fatigued muscle benefits from rest. If respiratory muscle fatigue is indeed of clinical importance, rest therapy should be beneficial to patients. Attractive as this hypothesis appears, clinical advancement in this field will be slow until reliable techniques become available for the diagnosis of respiratory muscle fatigue.
Available data clearly demonstrate long-term benefit to patients with chronic chest wall disorders and neuromuscular disease from the use of assisted ventilation, usually nocturnal, using both positive and negative pressure-ventilating devices. The recent development of nasal positive-pressure ventilation is likely to make it possible to apply respiratory muscle rest therapy to a wider group of patients, including some with COPD. Although such assisted ventilation rests the respiratory muscles, the mechanism whereby respiratory function, ventilatory failure, and symptoms are improved is not yet clear. The hypothesis that the improvement in these patients is a result of respiratory muscle rest reversing muscle fatigue remains speculative. In the critical balance between the demands made of the respiratory muscles and the capacity of the pump, the possibility of enhancing muscle contractility by drug therapy deserves careful assessment. Methyl xanthines have been extensively studied to determine whether or not they have a positive inotropic action in humans. The results of these studies are controversial, and any enhancement of contractility that results from their administration is likely to be small at therapeutic blood levels. However, this does not necessarily mean that their effects are therapeutically insignificant. Drug-induced increased peripheral contractility may not necessarily be beneficial if achieved at the cost of excessive energy utilization and consequent increased fatigability. Similarly, excessive central 'itimulation may overcome the usual feedback control mechanism and drive peripheral muscle into fatigue. On the other hand, if a drug improves muscle efficiency so that more external work can be performed at less energy cost, such pharmacotherapy would be beneficial. In the present state of knowledge, we must conclude that rational therapy of respiratory muscle fatigue, whether by training, nutritional repletion, rest, or muscle pharmacotherapy, will only become possible when fatigue can be accurately diagnosed and monitored in our patients. Priorities for Future Research
Basic Research Much research is needed on the relationship between respiratory muscle fatigue and the control of breathing. The following questions need to be answered. (1) In naturally occurring physiologic or pathophysiologic conditions, is there feed-
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back inhibition of motor output from the brainstem respiratory centers or of the respiratory motor neurons? (2) Do higher brain centers receive corollary input from the respiratory centers in the brainstem and/or the respiratory motor neurons that allows them to assess motor drive? (3) Are there afferent signals from muscles and/or lung receptors that allow assessment of the effort developed? (4) Is a comparison made centrally between the effort demanded and that which is developed? (5) If the effort demanded and that which is developed are assessed centrally, what are the pathways? (6) What are the load compensatory mechanisms that operate when the loads mimic as much as possible the mechanical abnormalities that result from disease? (7) What is the relationship between the acute responses to a load and the longterm adaptations that might result from chronic disease? (8) What is it about consciousness that enhances load compensation? (9) Are there pharmacologic agents that alleviate symptoms but do not influence load compensation? In addition to these questions concerning the relationship between load, fatigue, and central control of breathing, there was a consensus that there is great need for the development of methods to evaluate and quantify central respiratory motor output. In addition, we need to know more about the basic properties of respiratory muscles and how these are altered as a result of fatigue. The following questions require answers. (1) To what extent can the results of experiments performed on isolated muscles or intact muscles using external stimuli or, in anesthetized animals, be applied to fatigue resulting from
voluntary or subcortically endogenously driven muscle contractions? (2) To what extent does twitch potentiation occurring in low frequency fatigue impair the usefulness of twitch Pdi from bilateral, transcutaneous, supramaximal phrenic nerve shocks as a method to quantify diaphragmatic function? (3) What is the relationship between changes in diaphragmatic twitch and tetanic responses as fatigue develops?
ratory muscle training carries the risk of producing chronic fatigue, a condition well described in overtrained athletes, from which it takes substantial time to recover. Thus, there is a need for separate diagnostic criteria for acute and chronic fatigue, separate prevalence studies for the two types of fatigue, and separate studies to determine which therapeutic measures reverse which type of fatigue.
Clinical Research There was a consensus that the development of acceptable criteria to establish the diagnosis of fatigue was essential. In this regard, it was felt that assessment of twitch Pdi and twitch occlusion during diaphragmatic contraction held the most promise as a diagnostic test. The definition accepted by the workshop for skeletal muscle fatigue allowed the possibility of therapeutic trials to be used as diagnostic methods. There was also consensus that the prevalence of respiratory muscle fatigue could not be determined in the absence of acceptable diagnostic criteria but that prevalence studies were necessary in order to assess the magnitude of the problem and its costs to the health care system and thus to establish priorities for funding. Although there are a number of potential approaches to treating respiratory muscle fatigue, it was agreed that all of them need further research. Much more needs to be known about the role of rest, training, pharmacotherapy, and nutritional repletion in the therapy of respiratory muscle fatigue. In all these clinical studies, it was felt to be important to distinguish between acute and chronic fatigue. Indeed, res pi-
Recommendations
1. A high priority should be given to the support of basic research to: (1) further elucidate the relationship between fatiguing respiratory muscles and the central control of ventilation; (2) explore in greater detail the mechanisms of load compensation as it applies to human disease; (3) develop methods to quantify the central respiratory motor drive; (4) assess the basic properties of the respiratory muscles and how they change as a result of fatigue. 2. An equally high priority should be given to clinical research in order to: (1) establish criteria by which acute and chronic respiratory muscle fatigue can be diagnosed; (2) determine the prevalence of acute and chronic respiratory muscle fatigue using accepted diagnostic criteria; (3) assess the magnitude of the problem of acute and chronic respiratory muscle fatigue and its cost to the health care system; (4) establish priorities for funding in the field of acute and chronic respiratory muscle fatigue; (5) determine the efficacy of various therapeutic interventions in acute and chronic respiratory muscle fatigue.
The potential importance of respiratory, chiefly inspiratory, muscle fatigue has become well recognized in the last decade. If inspiratory muscles fail, so does ventilation and tissue respiration. There are theoretical reasons to postulate inspiratory muscle failure in chronic obstructive pulmonary disease (COPD), and there is some fairly good evidence that respiratory muscle fatigue is of importance in certain neuromuscular diseases such as polio, ALS, muscular dystrophies, and myopathies. In 1982, the Division of Lung Diseases issued a Request for Grant Applications in order to stimulate research in this field. Six grants were awarded, and substantial progress was made in understanding the basic physiology of respiratory muscle fatigue. In September 1988, a workshop was held at Kansas State University in Manhattan, Kansas, in order to reassess the state of research in the field and to define areas in which further research might be fruitful. The attendees included investigators specializing in basic muscle physiology as well as those with a specific interest in respiratory muscles, respiratory muscle fatigue, and the control of breathing. Definitions
The group attending the workshop felt that the term "muscle fatigue" needed careful definition, particularly in order that there be no confusion with the term "muscle weakness." Accordingly, the following definitions were discussed and agreed upon. Muscle fatigue is a condition in which there is a loss in the capacity for developing force and/or velocity of a muscle, resulting from muscle activ.ity under load and which is reversible by rest. Muscle weakness is a condition in which the capacity of a rested muscle to generate force is impaired. Summary of Workshop Sessions
Basic Properties of the Respiratory Muscles The respiratory muscles are embryologi474
cally, morphologically, and functionally skeletal muscles. They are mixed muscles made up of combinations of the three principal fiber types found in all skeletal muscles. Half of the fibers in the human diaphragm are slow oxidative (type I) fibers, and the remainder of the fibers consist of equal proportions of fast oxidative glycolytic (type IIA) fibers and fast glycolytic (type lIB) fibers. Among the mammalian species whose diaphragm fiber type distributions have been investigated, the percentages 0 f type I and type IIA vary widely from 93 and 707o, respectively, in the mouse and 39 to 16%, respectively, in the cat. Despite this variability among species, in all species studied, the oxidative, fatigue-resistant fibers (type I plus type IIA) exceed 55%. This composition is consistent with the fact that the diaphragm is denied the opportunity for sustained rest. Although extensive studies of fiber type distribution in other respiratory muscles are lacking, the intercostal muscles generally match the diaphragm in this respect. The contraction, relaxation, and shortening properties of the respiratory muscles are qualitatively and quantitatively within the range of other skeletal muscles located in the limbs. The velocity of shortening of the respiratory muscles, or more particularly the diaphragm, varies considerably depending upon the size and life-style of the species. Within a given species, the diaphragm appears to be consistently slower than the other respiratory muscles. Muscle fibers produce substantially less active force at shorter and longer lengths than at optimal length. For the diaphragm, the overall force length characteristics depend upon the force length characteristic of its two components, the costal and crural parts and how they are mechanically linked. For a parallel m~ chanicallinkage, the forces are additive, whereas for a series mechanical linkage, the displacements are additive. In vivo, the length-tension relationship of the whole diaphragm shows a rather broad effective length range, encompassing 30 to 40% of the in situ resting length. This
is greater than is the case for the rib cage inspiratory muscles such as the intercostal whose length-tension relationship encompasses less range and whose in vivo length change rarely exceeds 10% of the in situ resting length. Of interest is the observation that different inspiratory muscles appear to operate in vivo over different portions of their length-tension curves during resting tidal breathing; for instance, increases in lung volume (which shorten these muscles) cause a decrease in diaphragmatic tension, an increase in intercostal tension, and little change in the tension generated by the scalene and sternomastoid for a given degree of excitation. Despite these differences in operating length, the length-tension curve (Received in original form January 10, 1990) 1 The Workshop was held at Kansas State University in Manhattan, Kansas, September 14-17, 1988, sponsored by the Division of Lung Diseases (Structure and Function Branch), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Support from Kansas State University, including the use of their facilities, is gratefully acknowledged. 1 List of Participants: Michel Aubier, Clichy, France; Robert B. Banzett, Boston, MA; Francois Bellemare, Montreal, Quebec, Canada; Norma M. T. Braun, New York, NY; Neil S. Cherniack, Cleveland, OH; Thomas L. Clanton, Columbus, OH; Jerome A. Dempsey, Madison, WI; Andre De Troyer, Rochester, MN; Ludwig A. Engel, Westmead, NSW, Australia; Gaspar A. Farkas, Rochester, MN; John A. Faulkner, Ann Arbor, MI; Alejandro E. Grassino, Montreal, Quebec, Canada; Gabriel Haddad, New Haven, Cr, Frederic G. Hoppin, Jr., Pawtucket, RI; Rolf D. Hubmayr, Rochester, MN; Sabah Hussain, Montreal, Quebec, Canada; Steven G. Kelsen, Philadelphia, PA; Stephen H. Loring, Boston, MA; Franklin D. McCool, Pawtucket, RI; John Moxham, London, England; Michael B. Reid, Boston, MA; Brenda B. Ritchie, New Haven, CT; Dudley F. Rochester, Charlottesville, VA; Charalambos Roussos, Montreal, Quebec, Canada; John T. Sharp, Tampa, FL; Everett E. Sinnett, Bethesda, MD; Gerald Supinski, Cleveland, OH; Magdy K. Younes, Winnipeg, Manitoba, Canada. Chairman: Peter T. Macklem, Montreal, Quebec, Canada. Cochairmen: Nicholas R. Anthonisen, Winnipeg, Manitoba, Canada; David E. Leith, Manhattan, KS. 3 Correspondence and requests for reprints should be addressed to Dr. Dorothy Berlin Gail, Division of Lung Diseases, NHLBI, National Institutes of Health, Westwood Building, Room 6A07, 5333 Westbard Avenue, Bethesda, MD 20892.
AM REV RESPIR DIS 1990; 142:474-480
WORKSHOP SUMMARY
describes the maximal limits for the development of force. In situ, breathing results from submaximal activation of the respiratory muscles. Furthermore, because of the complexity of the thorax, the effective pressures generated by the various respiratory muscles will likely be altered because of changes in lung volume and body position, independent of muscle length. A muscle operating at less than optimallength not only generates less force, it also fatigues more rapidly. However, among the important properties of skeletal muscles, including the respiratory muscles, is their ability to adapt to altered conditions and regimens. When required to work chronically at shorter fiber length, sarcomeres at the ends of fibers in the diaphragm muscle are absorbed, and the resting in situ length is shortened to allow the remaining muscle to operate at near optimal length-tension conditions. This adaptation has been demonstrated in the hamster diaphragm when chronic shortening of its fibers occurs as a result of elastase-induced pulmonary emphysema. Metabolic and contractile characteristics also change in response to alterations in innervation and to changes in stimulus characteristics. Innervating a slow muscle fiber with a motor nerve from a fast muscle fiber will result in a transition of the characteristics of the slow fiber toward those of the fast fiber. Similarly, stimulating a mixed muscle at low frequencies will improve its endurance characteristics but decrease its capability to develop force. A practical application of this phenomenon is the clinical use of phrenic nerve pacing. Stimulation frequencies of 30 Hz permit stimulation of only one hemidiaphragm at a time while the other hemidiaphragm recovers, whereas stimulation of the diaphragm muscle at 10 Hz allows bilateral stimulation of the diaphragm for 24 h daily without requiring rest periods, resulting in the conditioning of the whole muscle. With the same principle of chronic low frequency stimulation, skeletal muscles have been conditioned to serve as an auxiliary or substitute heart. Such protocols offer the possibility that endurance characteristics of respiratory muscles may be improved in appropriate clinical situations. Skeletal muscles, including the respiratory muscles, are capable of improving their strength and endurance by appropriately designed training protocols. To be effective, training must take into account three principles: overload, spec-
475
ificity, and reversibility. For an "overload," the training stimulus must be an increase in either the number of contractions performed or in the load on the muscle during contractions or both. High repetitions and low load activities produce endurance training, whereas low repetitions and high loads produce strength training. The specificity of the training stimulus is supported by the observation that only organelles within fibers in those motor units influenced by the training stimulus adapt to the stimulus and consequently improve their performance. The principle of reversibility requires that training be kept up if the gains achieved by the training are to be retained. "Use it or lose it" expresses this idea well. Data obtained by several observers suggest that inspiratory muscle resistance training may be of clinical benefit to some patients but not to all patients with COPD nor to other patients with respiratory insufficiency of neuromuscular origin.
Fatigue of Respiratory Muscles Neuromuscular fatigue has previously been defined as the inability to maintain or repeat the required or expected force or power output. This widely accepted definition has two major drawbacks. First, it implies that fatigue is delayed in onset and can only be detected when the required force can no longer be generated by a maximal voluntary effort, neglecting the decline in force-generating capacity that occurs meanwhile. Second, it implies that force and power output necessarily change in parallel, and that these terms can be used synonymously, whereas it is now clear that during fatigue from dynamic contractions the maximum force and velocity of shortening often change independently. Moreover, the timing and extent of changes in both force or power output depend on the type of exercise being performed. According to the agreed definition, fatigue occurs before the required force or power can no longer be generated by a maximal effort. The point at which the required force can no longer be attained is then termed "exhaustion" or "task failure." The causes of fatigue are complex and involve simultaneous changes at various sites within both the muscle and the central nervous system (CNS). In practice, a reduced performance capacity often results from an inability or unwillingness to maintain sufficient central motor drive. However, under experimental
conditions, the drive to most human limb muscles can be kept adeq uate to activate all motor units to respond with maximal force throughout the exercise regime. In contrast, when fatigue of the diaphragm is induced by a similar intermittent contraction breathing protocol, about 500/0 of the force decline can be attributed to a mandatory reduction of central motor drive. However, it is not yet clear what role mandatory depression of CNS motor drive plays when the diaphragm or other respiratory muscles are fatigued under other, more normal, conditions. Further research in this area may provide significant advances. In limb muscles, the main eNS response to fatigue from sustained maximal contractions is a reduction in motoneuron firing rates. This has been attributed to reflex inhibition initiated by some fatigue-induced change within the muscle. However, because of a corresponding slowing of contractile speed, this reduction in motoneuron firing rates does not result in a reduction in muscle activation. In contrast, it may optimize force generation by reducing peripheral failure of both impulse propagation and excitation/contraction coupling. Ample evidence suggests that similar processes may operate during fatigue of respiratory muscles, but, in this case, the reflex may be more powerful so that maximal muscle activation becomes no longer possible once these muscles are fatigued. If so, perhaps this CNS depression provides a protective mechanism to prevent an undue reduction of intrinsic diaphragm muscle fiber strength. Major differences exist between events seen during fatigue induced by voluntary contractions and those from artificial nerve or muscle stimulation. During artificial stimulation, especially at high frequencies, muscle force declines rapidly in association with the decline in actionpotential amplitude. This response, known as "high frequency fatigue," is attributed to failure of impulse propagation across the neuromuscular junction and/or over the muscle surface membrane. However, the development of this type of failure during voluntary contraction is questionable. First, evoked muscle compound action potential (M-wave) amplitudes are generally found to remain unimpaired. Second, no unique relation between muscle force and electromyographic (EMG) activity has been observed. For example, the EMG activity recorded from single motor units may decline under conditions where the force remains unchanged,
476
and EMG responses can potentiate during periods of force reduction. Thus, there is a large safety factor between the extent to which muscle membranes may become depolarized and the point where impaired activation results. A major difference between fatigue induced by voluntary contractions and by artificial stimulation is due to differences in the rates at which action potentials are delivered. In voluntary contractions, each motor unit is excited at a rate matched to its particular contractile properties. During artificial stimulation, only one rate can be used, and this is often selected arbitrarily. Thus, for any given rate, some units may be stimulated supratetanically (perhaps generating high frequency fatigue), whereas others are less than maximally activated. Caution should therefore be used when extrapolating results from experiments on isolated preparations or anesthetized animals to imply similar events during fatigue from voluntary contractions; this can pose a major difficulty when more detailed investigations require techniques inappropriate for use with intact human subjects. Most studies conclude that the major factors underlying neuromuscular fatigue occur within the muscle fibers and mainly result from depletion of muscle energy stores or pH changes from lactic acid accumulation. During sustained high force contractions, the intramuscular pressure generated impedes the muscle blood supply so that these changes are expected, and probably account for the corresponding force reduction. However, there is no quantitative relation between force reduction and metabolic changes with fatigue from different types of exercise. Moreover, results from fatigue induced by intermittent, submaximal, isometric contractions, where blood flow is minimally impeded, provides evidence that nonmetabolic factors are also involved. In these experiments, the force from brief, maximal test contractions declined by about 500/0 during a time when no significant metabolic changes were detectable. Because no evidence was found for insufficient motor drive or failure of peripheral impulse propagation, this must have been caused by impaired excitation/contraction coupling. Similar conclusions have been reached under other exercise conditions. Many of the factors contributing to neuromuscular fatigue can be measured most conveniently by twitch occlusion. This technique is particularly appropriate for clinical studies since it is relative-
WORKSHOP SUMMARY
ly painless, easy to apply, and can be used on muscles where the motor nerve is not readily accessible. Moreover, maximal muscle strength can be indirectly and accurately assessed under conditions where the patient is unable, or unwilling, to make a truly maximal effort. It has been used successfully during fatigue studies on the human diaphragm involving both patients and normal subjects. The decline in intrinsic muscle strength is measured from changes in the contractile response to electrical stimulation delivered to the relaxed muscle between voluntary contractions while changes in the degree to which the muscle is (or can be) activated by the CNS are assessed by comparing these values to the extra force that can be elicited when twitches are superimposed on the voluntary contractions. For this purpose, it is important to be certain that the intensity of the stimulus remains unchanged by, for example, monitoring the amplitude of the evoked M-wave, which also tests the integrity of neuromuscular transmission. One drawback when using this method to investigate fatigue of the diaphragm is that consistent supramaximal, bilateral, tetanic stimulation of the phrenic nerves has so far proved unreliable. Thus, changes in intrinsic muscle stength can so far only be assessed from changes in the twitch responses elicited from the relaxed muscle. These responses may be subject to fluctuations, e.g., substantial degrees of twitch potentiation or "low frequency fatigue," not seen when tetanic stimulation is applied. If this technique is to be developed for extensive clinical use, more work is needed to explore the relationship between changes in twitch and tetanic responses as fatigue develops. Other methods that have long been used to predict the onset of neuromuscular fatigue involve changes in the EMG power spectrum. However, power spectrum changes can result from conditions other than muscle fatigue and their quantitative relation to force or power reduction remains controversial. It is also suggested that promising techniques for assessing neurom uscular fatigue might be developed from more thorough investigations of the relationship between force or power loss and changes in muscle relaxation rates, and from exploration of the reliability of using sniffs as a means of generating maximal voluntary diaphragmatic contractions.
Control of Breathing with Mechanical Loads Many respiratory diseases alter the load
on the respiratory muscles. Defining the normal responses to loading and their mechanisms is essential for understanding the pathogenesis of respiratory failure in these diseases and for developing rational approaches to prevention and treatment of hypercapnia. Except with severe loads, conscious humans maintain a normal Pe02, at least in the short term, when a variety of loads are applied in the laboratory setting. This attests to the presence of powerful neural load compensatory mechanisms in conscious humans. Feedback through chemoreceptors is the mechanism that the body uses to adjust the activity of the respiratory pump so that arterial blood gas tensions of O 2 and CO 2 can be kept within acceptable limits. A different but related protective system maintains ventilation and defends the force-generating ability of the respiratory muscles and the respiratory pump against mechanical breakdown. This system, which is brought into play not only when breathing is mechanically impaired by pulmonary disease but whenever postural changes affect the mechanical advantage of the respiratory muscles, has three major components. These are (1) the intrinsic properties of the respiratory muscles; (2) the reflexes brought into play by stimulation of receptors in the airways, lung parenchyma, and the muscles; and (3) behavioral compensations, which occur presumably because of the conscious perception that excessive effort is required to bring air into and out of the lungs. This compensatory response is modified if loads to breathing are maintained for long periods of time. This occurs not only by changes in the muscular strength and endurance but also by adaptations in reflex response and by adjustments in behavioral responses, which become more automatic and are probably set into play by proprioceptor signals. In anesthetized animals, adjustments occuring immediately after load application are mainly the result of changes in vagal mechanoreceptor feedback related to lung volume. Subsequent adjustments are chemically mediated (i.e., P0 2 and Pe02). Unfortunately, responses of conscious humans are different and cannot be readily explained by either mechanism. In part, this may depend on the neural origin of the breath - cerebral cortex or brainstem. The response of anesthetized humans and of sleeping animals and sleeping humans is much closer to those of anesthetized animals than to those of conscious humans. Not enough
WORKSHOP SUMMARY
information is available about the response of conscious animals to ascertain whether these responses are similar to those of conscious humans. More studies are needed with different types of loads: easily tolerated and non fatiguing loads, as well as more fatiguing loads. Although published results in conscious animals are not entirely the same as those in humans, animals allow the investigation of biochemical and anatomic components of the load response more readily than do humans. Nevertheless, progress in understanding compensation to the added loads in disease will have to come largely from studies on conscious humans. Although much work has been done to study the response of conscious humans to loads, the information available is largely descriptive and limited to loading conditions that can be easily carried out in short experiments in the laboratory. We are far from understanding the mechanisms of human responses, how chronicity affects the responses, the relevance of the documented responses to respiratory failure in the clinical setting, or the relative role of cortical versus brainstem control in the experimental setting. Because disease affects the respiratory system in a complex manner by actions on the lung, the ventilatory muscles themselves, and to a degree, on the CNS, investigators have resorted to a variety of techniques to produce simpler disturbances of muscle performance so that the elements of the compensatory responses can be better delineated and analyzed. On the other hand, there is some evidence that load responses, particularly in conscious humans, differ depending on the character of the load. The type of loads commonly used include external resistances, elastic loads, chest strapping, pressure breathing, inhalations of gases of different density and viscosity, and bronchoconstriction. The effects of loads will depend not only on the type of loads but also on whether they are applied continuously or for just a portion of a breath, as well as on the duration of load application. Measurements of ventilation and its components, of the respiratory muscle electromyogram, and of occlusion pressure have been used to measure the response to loads. However, the reaction of conscious subjects to loads must also depend in large part on the capacity to detect changes in the loading of the respiratory muscles and to quantitate the force produced during breathing and the
477
changes in lung volume that occur. Established methods and techniques in experimental psychology and psychophysics have been mainly used to quantitate respiratory sensations, and they have provided useful information. More recently, analysis of the electrical activity of the brain has been employed to obtain an objective measure of the effect of loads on the CNS. It has been suggested that higher brain centers receive some corollary input from respiratory motor neurons that allows them to assess output and possibly to compare effort to afferent signals from muscle and lung receptors so that muscular effort and its effect on breathing can be assessed. Evidence for such corollary discharge is incomplete and thus far pertains only to voluntary respiratory acts. Little is known about either the anatomic or biochemical basis of this corollary signal or how comparisons are made. Techniques such as PET scanning to evaluate regional changes in cerebral blood flow and metabolism may be useful in obtaining such data in conscious humans. In addition, more studies are needed with different types of loads: easily tolerated and nonfatiguing as well as more fatiguing loads. First, the majority of laboratory studies utilize linear or nearly linear inspiratory resistive loads. Because human responses tend to be load specific, attempts should be made to mimic as much as possible the abnormal mechanics of disease in which, in expiration in particular, resistance is grossly nonlinear, resulting in flow limitation. Second, most respiratory diseases that result in respiratory failure alter respiratory mechanics over a protracted period of time (months to years). The relevance of short-term responses (measured a few breaths or few minutes after load application) to the much more gradual and protracted disturbance produced by disease is not clear. The mechanisms involved in the short-term experiments in the laboratory, whether of neural or chemical origin, may adapt with time. This information is crucial. Third, it has been suggested that overworked respiratory muscles may contribute to respiratory failure by generating inhibitory signals that reduce the motor command in such a way that they are protected from fatigue. Although there is considerable indirect evidence that the machinery is there to effect inhibition under selected experimental conditions, it is not clear whether these conditions extend to the spontaneously breathing per-
son with chronic respiratory failure. Much critical animal and human work is needed before this important issue is resolved. Fourth, new approaches to load application, as well as the utilization of patients with selected neurologic deficits, are needed to define what it is about consciousness that enhances load compensation in conscious humans and by what means this is effected. Fifth, studies are needed to determine the effect of pharmacologic agents on load responses. Dyspnea is a major and often disabling symptom of lung disease and is related to loading of the respiratory muscles. It is important to ascertain whether there are agents that can alleviate dyspnea without impairing responses to loads. Finally, all current methods of evaluating respiratory motor output, except the phrenic neurogram, include measurements of the properties of the respiratory muscles. The use of occlusion pressure (P O• l ) is inappropriate in the face of changing mechanical loads and/or muscle contractibility; EMG recordings are difficult and sample only a few muscles. Noninvasive methods need to be developed by which the motor output can be separated from the muscular response. Criteria for Diagnosing Respiratory Muscle Fatigue Until now, the criteria for diagnosing respiratory muscle fatigue have been imprecise because of the lack of a definition, the limited knowledge regarding the processes leading to fatigue, and the lack of methods available to precisely measure this state. Differences in excitation patterns during voluntary activity from that during externally stimulated activity make the diagnosis more complicated. The working definition for muscle fatigue accepted at the conference (vide supra) should be of considerable help in establishing more precise criteria. Fatigue is likely to be the result of a dynamic process in which compensatory mechanisms are overwhelmed in a closed loop system consisting of central motor drive, peripheral impulse propagation, excitation/contraction coupling, depletion of energy substrates and/or metabolite accumulation, and feedback modulating reflexes. The bedside clinical diagnosis of fatigue is hampered by the inability to measure the baseline before fatigue. It may be possible only to infer fatigue retrospectively by its reversibility after a period of rest. The appropriate rest period, and readiness for re-
WORKSHOP SUMMARY
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spiratory weaning, remain clinical problems that require solutions. In order to understand fatigue mechanisms, several tests have been developed to measure the change from a nonfatigued, unloaded condition to a fatigued state after a load has been applied. Currently, there are tests that measure the pressures generated by the respiratory muscles (maximal inspiratory mouth pressure [PImax] and transdiaphragmatic pressure with respect to inspiratory time and respiratory rate [pressure-time index and Pdimax ]); tests that measure diaphragmatic or other inspiratory muscle electrical activity (power spectral analysis and integrated electrical acitivity [Edi] or some combination of electrical activity and pressure development [Edil Pdi)); other tests that aim to define the capacity of the diaphragm to generate pressure independent of central control mechanisms (bilateral phrenic nerve twitch stimulation and Pdilfrequency curves); and finally, tests that measure the increase in Pdi when a twitch is superimposed on the naturally activated diaphragm to assess the relative degree of motor unit recruitment through central pathways (twitch occlusion tests). Each of these tests has its own set of limitations. When interpreting PImax and Pdimax , submaximal efforts (inadequate motivation) cannot be distinguished from central fatigue; this represents a major limitation, particularly in critically ill and/or dyspneic patients. Tests that quantitate the electrical activity of inspiratory muscles are influenced by changes in the spatial relationships between the recording electrodes and the muscle. The cellular mechanisms responsible for shifts in the power spectrum remain unknown, which casts doubt upon the sensitivity and specificity of this technique. The measurement of Pdi requires the placement of esophageal and gastric balloon catheters and its magnitude is dependent on the geometry of the respiratory system (lung volume and thoracoabdominal shape) in addition to the contractile state of the diaphragm. When the diaphragm is activated electrically by stimulating the phrenic nerves, Pdi also varies in proportion with the resistance ofthe chest wall to deformation. Phrenic stimulation at fusion frequencies is not feasible in patients because of the associated discomfort. The only test from this series that may reliably separate central from peripheral fatigue is the twitch occlusion test. If all motor units of the diaphragm have been
recruited during a spontaneous breath or during a voluntary maximal inspiratory effort, twitch stimulation will not elicit an additional Pdi response. This test will have to be evaluated and compared with the other ones in order to determine the value and utility of each and so describe their specificity and sensitivity. Despite the drawbacks, it was felt that information obtained from bilateral transcutaneous supramaximal phrenic nerve twitch stimulation had the best potential of becoming a diagnostic test. The measurement of mouth pressure developed against an occluded airway can be done noninvasively and can potentially be used as a twitch occlusion test. From such a test, the time to peak tension, the dPdi/dt, the peak Pdi, and the Y2 relaxation time can also be computed. However, more rigorous evaluation of this test needs to be done before it can be recommended for general use.
Prevalence of Respiratory Muscle Fatigue The prevalence of respiratory muscle fatigue will remain unknown until a definition of fatigue is agreed upon and accepted diagnostic criteria are established. If the definitions proposed by this workshop are generally acceptable, they can be applied to patients to establish a base upon which prevalence studies can be developed. However, before such studies can be carried out, diagnostic criteria must also be developed as discussed above. Despite this lack of knowledge on prevalence, four groups of patients at high risk to develop fatigue can be identified: (1) premature and newborn populations; (2) patients with chronic respiratory loads or inspiratory muscle weakness (this latter group includes patients with neuromuscular disorders who appear to benefit from intermittent mechanical ventilation to put their muscles to rest); (3) patients with an inadequate supply of energy (cardiogenic shock, septicemia); and (4) asthmatics and COPD patients facing a sudden increase in load. In order to define the prevalence of respiratory muscle fatigue in a clinical setting, a "gold" standard is needed to diagnose respiratory muscle fatigue. There is no universally agreed upon objective physiologic or clinical test (or set of tests) that are unique indicators of fatigue. Despite the fact that it is necessary to develop diagnostic criteria before the prevalence of respiratory muscle fatigue can be assessed accurately, a small number of reports have been published in the past
several years that provide some evidence regarding the incidence of respiratory muscle fatigue in patients receiving mechanical ventilation. For example, 100010 of a small, highly select group of patients with chronic obstructive lung diseases had evidence of respiratory muscle fatigue shortly after the institution of mechanical ventilation, using the power spectral density of the diaphragm EMG as an index of fatigue. Inability to maintain an adequate alveolar ventilation was regarded as task failure from fatigue; according to the workshop definition, fatigue precedes task failure, and thus, if it occurs clinically, it should precede the development of hypercapnia. In a discussion about a suitable definition of respiratory muscle fatigue, it was initially suggested that the notion of an impaired ability to maintain adequate alveolar ventilation should be included. There was disagreement about this. It was generally felt that including some aspect of respiratory muscle task performance in the definition (in particular, the maintenance of adequate alveolar ventilation) was counter-productive. Furthermore, an impaired ability to maintain alveolar ventilation leading to respiratory failure may have causes other than respiratory muscle fatigue; its inclusion in the definition may therefore lead to confusion on the part of clinicians. Rather it was felt that the definition of respiratory muscle fatigue should focus on a description of the dysfunction that occurs in the muscles themselves. There was a general consensus that the definition should include the idea that the process of fatigue was reversible by rest or a decrease in the activity level of the muscle. It was felt that the incorporation of the concept of reversibility would have the advantage of distinguishing impaired muscle contractility related to neuromuscular disease, electrolyte disturbance, wasting, or other causes of weakness from that related to fatigue. It was also felt that inclusion of the concept of reversibility by rest, which has value as a diagnostic tool, also suggests a therapeutic approach. In general, however, the elements that were viewed by the majority of the session members as important components of the definition of respiratory muscle fatigue were: (1) fatigue is a condition in which the ability of the respiratory muscles to generate pressure or airflow is impaired; (2) impairment in muscle function is a result of heightened contractile activity relative to strength and/or a de-
WORKSHOP SUMMARY
crease in energy supply; and (3) the impairment in muscle function would be improved by rest or a decrease in the activity level of the muscles. The idea that a set of definitions on various aspects of respiratory muscle dysfunction should be put forward to cover some specific aspects of dysfunction was favorably received. For example, definitions of muscle weakness, task failure, chronic fatigue, and acute fatigue are needed. The definitions proposed by the workshop for skeletal muscle fatigue and weakness, which were not agreed upon until the final session, arose in large part from the discussions in the session on prevalence. It was strongly felt that: (1) further research leading to greater understanding of the process of respiratory muscle fatigue and failure is needed; (2) particular emphasis should be put on diagnostic methods and criteria for respiratory muscle fatigue so that prevalence can be determined; (3) this information is needed in order to assess the magnitude of the problem and its costs to the health care system. Research to obtain this information is urgently needed in order to establish priorities for funding.
Management oj Respiratory Muscle Fatigue Although experimental muscle fatigue develops when the demands on the respiratory pump are excessive in relation to pump capacity, it is, as yet, not clear whether in the clinical setting of ventilatory failure overt peripheral muscle fatigue develops or whether an adaptive feedback reduction of central drive avoids such fatigue, albeit at the cost of hypoventilation. The three components of the system (demand, capacity, and drive) are closely linked, and for the patient approaching ventilatory failure, a small alteration in one variable may determine outcome. It is rational, therefore, to direct therapeutic efforts at minimizing demand, maximizing capacity, and optimizing drive. However, specific therapy of respiratory muscle fatigue will only become possible when reliable criteria for the diagnosis and monitoring of fatigue are available. In the clinical setting, the distinction between respiratory muscle weakness and fatigue, both of which may cause respiratory muscle failure, is often difficult. Weak muscles are susceptible to fatigue, and an increase in muscle strength protects from fatigue. Important treatable or avoidable causes of weakness include
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hypercapnia, acidosis, electrolyte disturbances, and hypophosphatemia, as well as thyroid, alcohol, steroid, drug-induced, and inflammatory myopathies. The respiratory muscles of wasted patients are weak, and the strength of the ventilatory pump can be improved by nutritional repletion. Such nutritional therapy can facilitate weaning. Specific training of the respiratory muscles can enhance strength and endurance, the latter being of most relevance to patients with chronic ventilatory loads or weaning difficulties. The literature on respiratory muscle training leaves many clinically important questions unanswered. It is clear that training produces improvements in the task being trained for, with little crossover benefit to other tasks; further, such programs may also have a substantial placebo effect. Which patients are likely to benefit from training and what are the best protocols are questions that remain, for the most part, to be determined. We still do not know how much training, in terms of intensity and duration, produces maximal results, which training devices are most effective, and how much long-term training is required to avoid de-training. Furthermore, although training of respiratory muscles with spare capacity may improve performance, training of muscles already being driven at the limit of their capacity may produce myopathic changes, well recognized in overtrained athletes, recovery from which can be prolonged. Experimentally, fatigue develops when the pressure-time index of the respiratory muscles exceeds a critical value; it may therefore be avoided by therapy that reduces the load on the ventilatory pump below the fatiguing threshold. In the clinical situation, this is most often achieved by treatment directed at reducing airway resistance and increasing pulmonary compliance. A second experimental setting in which fatigue has been studied is that of reduced oxygen and substrate delivery to respiratory muscle, as occurs clinically in septic or cardiogenic shock; thus, therapy aimed at restoring oxygenation and muscle blood flow may enhance contractility and avoid fatigue in such situations. Fatigued muscle benefits from rest. If respiratory muscle fatigue is indeed of clinical importance, rest therapy should be beneficial to patients. Attractive as this hypothesis appears, clinical advancement in this field will be slow until reliable techniques become available for the diagnosis of respiratory muscle fatigue.
Available data clearly demonstrate long-term benefit to patients with chronic chest wall disorders and neuromuscular disease from the use of assisted ventilation, usually nocturnal, using both positive and negative pressure-ventilating devices. The recent development of nasal positive-pressure ventilation is likely to make it possible to apply respiratory muscle rest therapy to a wider group of patients, including some with COPD. Although such assisted ventilation rests the respiratory muscles, the mechanism whereby respiratory function, ventilatory failure, and symptoms are improved is not yet clear. The hypothesis that the improvement in these patients is a result of respiratory muscle rest reversing muscle fatigue remains speculative. In the critical balance between the demands made of the respiratory muscles and the capacity of the pump, the possibility of enhancing muscle contractility by drug therapy deserves careful assessment. Methyl xanthines have been extensively studied to determine whether or not they have a positive inotropic action in humans. The results of these studies are controversial, and any enhancement of contractility that results from their administration is likely to be small at therapeutic blood levels. However, this does not necessarily mean that their effects are therapeutically insignificant. Drug-induced increased peripheral contractility may not necessarily be beneficial if achieved at the cost of excessive energy utilization and consequent increased fatigability. Similarly, excessive central 'itimulation may overcome the usual feedback control mechanism and drive peripheral muscle into fatigue. On the other hand, if a drug improves muscle efficiency so that more external work can be performed at less energy cost, such pharmacotherapy would be beneficial. In the present state of knowledge, we must conclude that rational therapy of respiratory muscle fatigue, whether by training, nutritional repletion, rest, or muscle pharmacotherapy, will only become possible when fatigue can be accurately diagnosed and monitored in our patients. Priorities for Future Research
Basic Research Much research is needed on the relationship between respiratory muscle fatigue and the control of breathing. The following questions need to be answered. (1) In naturally occurring physiologic or pathophysiologic conditions, is there feed-
WORKSHOP SUMMARY
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back inhibition of motor output from the brainstem respiratory centers or of the respiratory motor neurons? (2) Do higher brain centers receive corollary input from the respiratory centers in the brainstem and/or the respiratory motor neurons that allows them to assess motor drive? (3) Are there afferent signals from muscles and/or lung receptors that allow assessment of the effort developed? (4) Is a comparison made centrally between the effort demanded and that which is developed? (5) If the effort demanded and that which is developed are assessed centrally, what are the pathways? (6) What are the load compensatory mechanisms that operate when the loads mimic as much as possible the mechanical abnormalities that result from disease? (7) What is the relationship between the acute responses to a load and the longterm adaptations that might result from chronic disease? (8) What is it about consciousness that enhances load compensation? (9) Are there pharmacologic agents that alleviate symptoms but do not influence load compensation? In addition to these questions concerning the relationship between load, fatigue, and central control of breathing, there was a consensus that there is great need for the development of methods to evaluate and quantify central respiratory motor output. In addition, we need to know more about the basic properties of respiratory muscles and how these are altered as a result of fatigue. The following questions require answers. (1) To what extent can the results of experiments performed on isolated muscles or intact muscles using external stimuli or, in anesthetized animals, be applied to fatigue resulting from
voluntary or subcortically endogenously driven muscle contractions? (2) To what extent does twitch potentiation occurring in low frequency fatigue impair the usefulness of twitch Pdi from bilateral, transcutaneous, supramaximal phrenic nerve shocks as a method to quantify diaphragmatic function? (3) What is the relationship between changes in diaphragmatic twitch and tetanic responses as fatigue develops?
ratory muscle training carries the risk of producing chronic fatigue, a condition well described in overtrained athletes, from which it takes substantial time to recover. Thus, there is a need for separate diagnostic criteria for acute and chronic fatigue, separate prevalence studies for the two types of fatigue, and separate studies to determine which therapeutic measures reverse which type of fatigue.
Clinical Research There was a consensus that the development of acceptable criteria to establish the diagnosis of fatigue was essential. In this regard, it was felt that assessment of twitch Pdi and twitch occlusion during diaphragmatic contraction held the most promise as a diagnostic test. The definition accepted by the workshop for skeletal muscle fatigue allowed the possibility of therapeutic trials to be used as diagnostic methods. There was also consensus that the prevalence of respiratory muscle fatigue could not be determined in the absence of acceptable diagnostic criteria but that prevalence studies were necessary in order to assess the magnitude of the problem and its costs to the health care system and thus to establish priorities for funding. Although there are a number of potential approaches to treating respiratory muscle fatigue, it was agreed that all of them need further research. Much more needs to be known about the role of rest, training, pharmacotherapy, and nutritional repletion in the therapy of respiratory muscle fatigue. In all these clinical studies, it was felt to be important to distinguish between acute and chronic fatigue. Indeed, res pi-
Recommendations
1. A high priority should be given to the support of basic research to: (1) further elucidate the relationship between fatiguing respiratory muscles and the central control of ventilation; (2) explore in greater detail the mechanisms of load compensation as it applies to human disease; (3) develop methods to quantify the central respiratory motor drive; (4) assess the basic properties of the respiratory muscles and how they change as a result of fatigue. 2. An equally high priority should be given to clinical research in order to: (1) establish criteria by which acute and chronic respiratory muscle fatigue can be diagnosed; (2) determine the prevalence of acute and chronic respiratory muscle fatigue using accepted diagnostic criteria; (3) assess the magnitude of the problem of acute and chronic respiratory muscle fatigue and its cost to the health care system; (4) establish priorities for funding in the field of acute and chronic respiratory muscle fatigue; (5) determine the efficacy of various therapeutic interventions in acute and chronic respiratory muscle fatigue.
