Inspiratory muscle training in the patient with neuromuscular disease.

The maintenance of adequate alveolar ventilation depends in part on proper function of the inspiratory muscles (IM). The respiratory muscles are governed by a control system that consists of the brain, spinal cord, and peripheral nerves. The muscles act to displace a "bellows" that consists of the rib cage, abdomen, and lungs. In total, these disparate components make up the "inspiratory pump."[1] Neuromuscular diseases can result in dysfunction at any level of the inspiratory pump, including the central nervous system, peripheral nerves, neuromuscular junction, or the muscles themselves. As a consequence, respiratory failure, impaired cough, and pneumonia are leading causes of morbidity and mortality in patients with varied neuromuscular disorders such as muscular dystrophy, amyotrophic lateral sclerosis, and spinal cord injury.[2-7] This article will first discuss the effects of respiratory muscle weakness on pulmonary function, next review the effects of training on respiratory muscle function in individuals with neuromuscular disease, and finally discuss which inspiratory muscle training protocols may elicit the desired results.

Effects of Respiratory Muscle

Weakness on Pulmonary

Function

Regardless of the site of involvement, neuromuscular diseases weaken the respiratory muscles and predispose them to fatigue. inspiratory muscle weakness is defined as "a condition in which the capacity of the breathing muscles to generate force"[8(p474)] is impaired. In the respiratory system, the presence of IM weakness can be detected by assessing the maximal pressure generated at the airway opening during a maximal voluntary static inspiratory effort ([PI.sub.max]).[9] Alternatively, IM fatigue is defined as "a condition in which there is a loss, in the capacity for developing force and/or velocity of muscle resulting from muscle activity under load and which is reversible by rest."[8(p474)] In contrast to respiratory muscle force, a major limitation to the study of fatigue in the clinical setting is the lack of a readily applicable test for detecting the presence of fatigue. Respiratory muscle weakness will adversely affect lung volumes, respiratory system compliance, gas exchange, and alveolar ventilation.

Neuromuscular weakness reduces the capacity of the IM to expand the chest wall and inflate the lungs. Total lung capacity (TLC) is normally set by the balance between the elastic recoil of the respiratory system and the force of the inspiratory muscles. As one inhales to TIC, the inspiratory muscles grow weaker because of their length-tension properties and the respiratory system becomes stiffer, primarily because of a decrease in lung compliance (Fig. 1). Normally, the respiratory system does not become extraordinarily stiff until lung volume approaches 90% of TLC. Accordingly, the IM have to exert little force to achieve normal lung volumes. To reduce TLC, IM force is usually reduced to less than 50% of the predicted value. Krietzer et al,[10] for example, found that a 50% reduction in IM force resulted in only a 6% reduction in TIC in patients with amyotrophic lateral sclerosis. They reasoned that this was a consequence of the curvilinear shapes of the respiratory system compliance and the IM pressure-volume curves. Namely, a 50% reduction in IM force at all lung volumes would intersect the volume axis near 90% of TIC (Fig. 1). Thus, a patient with a moderate degree of IM weakness would still have the force reserve needed to achieve a normal inspiratory capacity. To reduce TIC below the range of normal, the IM must then be severely weakened.

The vital capacity (VC) is the difference between TLC and residual volume (RV) and can also be reduced in patients with neuromuscular disease. The reduction in VC seen with IM weakness is primarily a consequence of a reduction in TIC. In patients with profound expiratory muscle weakness, however, RV may be increased due to an inability of the expiratory muscles to decrease the volume of the thoracic cavity. The increase in RV would in turn decrease VC. Therefore, patients with combined IM and expiratory muscle weakness may have a more profound reduction in VC than patients with IM weakness alone.

An indirect consequence of IM weakness is a reduction in respiratory system compliance (CRS). This can be defined as the ratio of the change in respiratory system volume to a change in pressure (CRS=[delta]V/[delta]P). A reduction of CRS, in turn, will increase the work of breathing. The reduction in CRS is due to diminished chest wall compliance, lung compliance, or both[11-14] (Fig. 2). Inspiratory muscle weakness promotes these compliance changes by not allowing the respiratory system to be inflated to its predicted TLC. The inability of the IM to adequately expand the chest wall results m stiffening of the costovertebral joints.[12,15,16] Consequently, the chest wall becomes more rigid and its compliance is reduced. The compliance characteristics of the lung are also affected by the inability to breath deeply. Areas of atelectasis that are not radiographically visible and altered alveolar surface tension make the lung itself less distensible.[17,18] The areas of microatelectasis also promote hypoxemia due to ventilation perfusion mismatching and shunt. In addition, these areas may serve as a nidus for pulmonary infection. Microatelectasis can be reversed, in part, by periodic deep inspirations delivered by intermittent positive pressure breathing (IPPB) or with incentive spirometry.[19]

Inspiratory muscle weakness also affects the ability of these patients to maintain normal alveolar ventilation. When [PI.sub.max] is reduced, the change in esophageal pressure that occurs with each breath is a greater fraction of the maximal inspiratory force. Thus, die IM are working at a higher percentage of their maximal level and may eventually fatigue and lead to hypoventilation with carbon dioxide retention. Indeed, Rochester and Braun[20] noted that the risk of carbon dioxide retention increased when [PI.sub.max] is less than 50 cm [H.sub.2]O in patients with chronic obstructive pulmonary disease (COPD) (Fig. 3). In addition, when [PI.sub.max] is reduced, maximal inspiratory flow rates ([VI.sub.max]) are reduced. When [VI.sub.max] is reduced, die change in inspiratory flow that occurs with each breath becomes a greater fraction of [VI.sub.max] Once again, the IM will be working at a greater fraction of their maximal level and will be predisposed to fatigue.[21-23] Reductions in energy supplies related to either poor nutritional status or decreased diaphragmatic blood flow would further impair endurance.[24]

Inspiratory Muscle Force Training

in Neuromuscular Disease

To the extent that respiratory dysfunction in neuromuscular disease is directly related to IM weakness, one would predict that strengthening the inspiratory muscles may potentially reverse or delay the development of some of the complications of IM weakness. Although the IM can be trained for force and endurance in asymptomatic individuals,[23] the potential for IM training to improve IM force in individuals with diseased muscles must be viewed in the context of the general plasticity of diseased skeletal muscle.

The efficacy of strength training the limb muscles in patients with neuromuscular diseases is controversial.[25,26] One concern is die possibility that diseased and weakened skeletal muscle may not be able to adapt to a strength training stimulus. This concern was raised by early uncontrolled studies in which there was little or no improvement in muscle function.[27,28] The majority of these patients, however, were severely affected by their disease and were confined to wheelchairs.[25] Subsequent studies of less severely affected patients demonstrated that training could improve muscle force.[29-32] In addition, the slower the progression of the underlying myopathy, the better the likelihood of eliciting a training response.[29] Indeed, the lack of a training effect in some of the more severely affected individuals may be due to rapid progression of the underlying disease. A second concern is the possibility that strengthening exercises may overwork and damage the muscles. The anecdotal reports of exercise-induced injury, however, have not been confirmed subsequent studies.[29,33] Thus, from the studies to date, it appears that diseased muscles can be trained, with the less severely affected muscles showing the greatest response, and that training of limb skeletal muscles is safe. None of these studies, however, has shown that any increase in limb muscle force enhanced the patient's performance of daily living activities.

Because IM weakness reduces VC, strengthening these muscles may reverse a detrimental change in VC. An observation that suggests this result is true has been made in patients with spinal cord injury. Following spinal cord injury, there are reductions m VC and IM force. Over the 6- to 9-month interval following the acute injury, there is a partial recovery of VC[34] (Fig. 4). In conjunction with the improvement in VC, there is a partial recovery of IM force, as assessed by maximal inspiratory mouth and transdiaphragmatic pressures ([Pdi.sub.max]). The improvements in VC were not related to changes in respiratory system compliance nor to changes in resting length of the IM as functional residual capacity did not change during the study. Thus, the time-related changes in VC, [PI.sub.max], and [Pdi.sub.max] strongly suggest that the improvement in VC is due to improvements in IM function. This improvement of IM function and consequently VC may be due either to a training effect on the accessory IM and diaphragm or to resolution of cervical spinal cord edema. Irrespective of mechanism, these findings indicate that strengthening the IM may improve VC in some patients with neuromuscular disease and IM weakness.

Respiratory muscle training has been applied to patients with quadriplegia, a group in whom the remaining intact IM are not diseased (Table).[33,35-41] Gross et al[35] evaluated the effects of IM training on diaphragm strength and endurance in six subjects with chronic quadriplegia. The training stimulus consisted of inspiratory resistive loaded breathing 30 minutes a day, 6 days a week, for 16 weeks. The authors found a progressive increase in [PI.sub.max] as well as the maximal pressure that could be sustained prior to developing fatigue, and they concluded that IM training would improve both force and endurance and potentially protect against IM fatigue. They did not report changes in VC in their study. The remaining expiratory muscles may also be strengthened in patient with quadriplegia. Estenne et al[41] found that strengthening the pectoralis major muscle unproved expiratory function. This improvement in expiratory force may prove to be clinically useful in increasing the effectiveness of cough and thus reducing the prevalence of respiratory infections in these patients.

[TABULAR DATA OMITTED]

The effects of IM training in patients with muscular dystrophy are varied.[33,36-40] DiMarco et al[36] evaluated the effects of inspiratory resistive training on IM function in 11 patients with Duchenne's, limb-girdle, and facioscapulohumeral muscular dystrophy. Following 6 weeks of IM training with inspiratory resistive loads, there were increases in indexes of endurance such as the maximum resistance that could be tolerated for 5 minutes and the patients' maximum sustainable ventilation. The authors found that the degree of improvement with training was directly related to the patients' baseline VC. Namely, the greatest improvements in endurance occurred in the patients with the best preserved VCs. DiMarco et al found, however, no improvements m IM force or VC following training. One criticism of this study was that the improvement in endurance may in part be due to learning to perform the breathing maneuvers more effectively. To minimize learning effects, Smith et al[39] subsequently evaluated inspiratory resistive training in eight subjects with Duchenne's muscular dystrophy who performed three baseline measurements prior to the training period. This study was designed as a single blind crossover trial of 5 weeks' training. Inspiratory muscle endurance was assessed as the maximal level of ventilation that could be sustained indefinitely. This level of ventilation is usually expressed as a fraction of the maximum voluntary ventilation. Smith et al39 found no change in VC, maximum static inspiratory pressures, or maximal sustainable ventilation following training. They concluded that the previously noted benefits of IM training may have been due to learning rather than to training itself.

Recently, Wanke et al[33] evaluated IM training in 15 patients with Duchenne's muscular dystrophy. The training protocol lasted for 6 months and consisted of breathing through an inspiratory resistive load, producing at least 700% of [Pdi.sub.max]. The authors found that the 10 patients who completed the training protocol had improvements in force, as assessed by measuring [Pdi.sub.max] and maximal esophageal pressures ([P.sub.es]max). In contrast, the control group and the 5 patients with severe puhmonary function impairment who did not complete the training protocol had no improvements in IM force (Fig. 5). Wanke et al found, however, no changes in VC, forced expiratory volume in 1 second, or maximum voluntary ventilation in either the control group or the training group. Similar to the findings of DiMarco et al,[36] the patients with the most severely reduced VCs responded less or did not respond to training. Five patients who had VCs of less than 25% of the predicted value and partial pressure of carbon dioxide values of more than 45 torr did not complete the training protocol and had no changes in [Pdi.sub.max] Because of the possibility that the weakened muscles in these individuals may be more susceptible to damage and fiber splitting, Wanke et al monitored serum creatine kinase; however, they noted no changes in this enzyme. Wanke and colleagues concluded, therefore, that IM training is useful in the early stages of Duchenne's muscular dystrophy when the VC is better preserved and that IM training had no deleterious effect on the IM even in patients who are extremely weak. These findings are in general agreement with what has been described for other skeletal muscle groups.

In summary, investigators have used either inspiratory resistive loads or isocapnic hyperpnea as a training stimulus. With the exception of one study, which used VC as the sole outcome, all studies have shown improvement in at least one of the indexes of respiratory muscle performance, either [Pl.sub.max] or the maximal sustainable pressure (Table). The variability of outcome may reflect the type of protocol used rather than the impaired capacity of the muscles to respond to a given protocol. Thus, in some studies in which inspiratory resistive loaded breathing was used, both force and endurance increased,[33,35,38] whereas in other studies, only endurance to high-flow tasks increased.[36,37] In a study by Smith et al,[39] in which no improvement in force or endurance was found, a single blind crossover trial was used in an attempt to minimize the effects of learning, but this study had the briefest training period. The lack of response may be related to the relatively short (5-week) training protocol. Although some studies demonstrated an increase in IM force, no controlled study demonstrated an improvement in VC with IM training. The studies by Wanke et al[33] and DiMarco et al[36] suggest that the lack of improvement in IM function may be, in part, related to the severity of disease. In those patients with muscular dystrophy who were so severely affected that they already are retaining carbon dioxide, IM training had little effect on IM force.33 In these individuals, the IM may already be working against loads sufficiently severe (ie, greater than 500% of their maximum) to provide a training stimulus with each breath or to actually result in fatigue. Thus, when comparing outcomes of various studies, information about seventy of disease should be considered.

Inspiratory Muscle Training

Protocols and Desired Results

Despite several studies evaluating respiratory muscle training in the past decade, a number of clinically relevant issues remain unresolved. Are chronically loaded muscles trainable? What are the benefits of IM training? Does IM training enhance activity? Does this t" of training provide a buffer for developing respiratory failure? Does such training relieve dyspnea? Because nonrespiratory factors usually limit exercise m patients with neuromuscular diseases, any clinical benefit to IM training may be manifested as a reduction in respiratory morbidity rather than as an improvement in exercise capacity. The training stimulus needed to elicit such a clinical benefit is not known in patients with neuromuscular diseases, but a better understanding of the loads faced by the IM in these patients will enable therapists to design more effective training protocols.

The loads imposed on the respiratory muscles can be characterized as pressure, flow, and volume loads.[42] A pressure load occurs with any process that increases the transpulmonary pressure required to inhale. These loads can be experimentally imposed by inhaling through an external resistance or by inhaling from an incompressible chamber. In contrast, a flow load is imposed by any process that increases the level of ventilation needed to remain normocapnic. Flow loads can be experimentally imposed by increasing the level of ventilation either voluntarily or with exercise. A volume load is a process that results in hyperinflation and decreases the operational length of the IM. This load is imposed by shortening the time to exhale, thereby causing dynamic hyperinflation, or by the application of continuous positive airway pressure.

In neuromuscular diseases, elastic pressure loads can be imposed on the IM by any process that reduces lung or chest wall compliance, such as atelectasis, obesity, or kyphoscoliosis. In addition, resistive pressure loads can be imposed by any process that increases airway resistance, such as bronchospasm or retention of airway secretions. Flow loads can be seen in patients with increased dead-space ventilation, such as occurs with rapid shallow breathing. Volume loads are imposed by disease processes that are accompanied by hiperinflation, such as acute exacerbations of COPD or asthma. As lung volume increases, IM endurance is further impaired.[43] Volume loads, however, are less likely to be of concern in patients with neuromuscular diseases than pressure or flow loads.

The IM are usually confronted by combinations of pressure and flow loads. McCool et al[21] Studied the effects of combinations of such loads on IM endurance in asymptomatic subjects and found that the sustainable pressure load decreases as inspiratory flow increases (Fig. 6). Thus, for a given endurance, there is a trade-off between the pressure load and the flow load that can be sustained. with neuromuscular diseases in which [PI.sub.max] and [VI.sub.max] are reduced, any pressure and flow loads would be a large fraction of the pressure- and flow-generating capability of the IM. Thus, both types of loads may predispose the respiratory muscles to fatigue in patients with neuromuscular diseases. Furthermore, because of the adverse effects of increasing flow on sustainable pressure,[21] any increase in minute ventilation would reduce the fatiguing pressure threshold in these patients. Therefore, a training stimulus that increases both maximal pressure and flow may be better suited for patients with neuromuscular weakness than a training stimulus that increases pressure only.

The IM can be trained to increase [Pl.sub.max] or [VI.sub.max] (Fig. 7). Training the respiratory muscles to increase force ([PI.sub.max]) may enable the IM to work more effectively against pressure loads. Strength training can be accomplished by performing repetitive maximum static inspiratory or expiratory efforts against a closed glottis. With this type of training maneuver, increases in IM force as great as 500% can be anticipated. Training the IM to increase maximal inspiratory flow rates can be accomplished by performing repetitive maximal inspiratory efforts or voluntary hyperpnea.[44] if improved exercise capacity or sustainable ventilation alone is desired, then a flow load may provide the optimal training stimulus. The flow loads may be imposed by die hyperpnea that accompanies exercise, or by voluntarily increasing ventilation (ie, hyperventilating). When ventilation is voluntarily increased, the partial pressure of carbon dioxide is lowered. To raise the partial pressure of carbon dioxide back to a normal level, it can be increased by partially rebreathing expired gas or by titrating a mixture of carbon dioxide into the inspired gas. Thus, end-expired carbon dioxide must be assessed when using flow loads to train the respiratory muscles. Although there is general agreement that the maximal sustainable ventilation can be increased following this type of training, whether exercise performance improves is still debatable.

Training the IM to increase both [Pl.sub.max] and [VI.sub.max] may be accomplished by inhaling through an external resistance that is intermediate to a severe pressure or flow load. This type of training has been shown to increase [Pl.sub.max] and [VI.sub.max] nearly as much as specifically training for each alone.[44] An alternate approach is to use threshold loads. Threshold loads have been used to train the IM[45] and provide a combination of pressure and flow loads as a training stimulus. With this type of load, the subject must exert enough pressure to open a valve to initiate inspiratory flow. Once die valve is opened, inspiration is unimpeded. Thus, the IM initially work against a pressure load and later against a flow load.

Whether IM training improves exercise performance or lessens dyspnea in patients with lung disease remains controversial. Patients who may benefit from IM training would be those m whom IM fatigue contributes to exercise limitation, whereas those who would not benefit would be those in whom exercise is limited by cardiovascular or limb muscle performance. Discrepancies among studies may, in part, be due to lack of control groups, differences among patient populations studied, or differences in the training stimulus used. Because training with "pure" flow or pressure loads will improve flow or pressure performance,[44] training with pressure loads may not improve flow performance. Consequently, because exercise hyperpnea represents a flow load, exercise performance would not be improved. Training with flow loads, therefore, may be a more logical training stimulus for improving exercise performance. Few studies, however, have used voluntary isocapnic hyperpnea as a training stimulus. Training with threshold loads may provide a training stimulus that increases both the pressure- and flow-generating capacities of these muscles and therefore may provide a practical approach to IM training in neuromuscular disease, where it is desirable to increase both capacities.

Summary

The effects of IM weakness in patients with neuromuscular disease are to reduce VC; to decrease chest wall and lung compliance; to increase the work of breathing; and to promote atelectasis, hypoxemia, and IM fatigue. The IM can be safely trained for either force or endurance in these patients. The most severely affected individuals, however, are least likely to benefit from training. The effects of IM training on morbidity and mortality in this patient population remain unknown.

References

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