© 2003 American Thoracic Society
Disorders of the Respiratory MusclesDivision of Pulmonary and Critical Care Medicine, Edward Hines, Jr. Veterans Administration Hospital, and Loyola University of Chicago Stritch School of Medicine, Hines, Illinois Correspondence and requests for reprints should be addressed to Franco Laghi, M.D., Division of Pulmonary and Critical Care Medicine, Edward Hines, Jr. VA Hospital, 111 N. 5th Avenue and Roosevelt Road, Hines, IL 60141. E-mail: FLAGHI{at}lumc.edu
The act of breathing depends on coordinated activity of the respiratory muscles to generate subatmospheric pressure. This action is compromised by disease states affecting anatomical sites ranging from the cerebral cortex to the alveolar sac. Weakness of the respiratory muscles can dominate the clinical manifestations in the later stages of several primary neurologic and neuromuscular disorders in a manner unique to each disease state. Structural abnormalities of the thoracic cage, such as scoliosis or flail chest, interfere with the action of the respiratory muscles—again in a manner unique to each disease state. The hyperinflation that accompanies diseases of the airways interferes with the ability of the respiratory muscles to generate subatmospheric pressure and it increases the load on the respiratory muscles. Impaired respiratory muscle function is the most severe consequence of several newly described syndromes affecting critically ill patients. Research on the respiratory muscles embraces techniques of molecular biology, integrative physiology, and controlled clinical trials. A detailed understanding of disease states affecting the respiratory muscles is necessary for every physician who practices pulmonary medicine or critical care medicine.
Key Words: respiratory insufficiency • heart failure • nervous system diseases • neuromuscular diseases • sepsis
Chronic Obstructive Pulmonary Disease Energy Demands of Inspiration Hyperinflation Respiratory Pressure Generation Malnutrition Glucocorticoids Respiratory Endurance Clinical Manifestations Surgery for COPD Asthma Mechanics Strength and Endurance Glucocorticoids Chronic Heart Failure Strength and Endurance Exercise Acute Respiratory Failure Increased Load: Mechanics and Ventilatory Requirements Decreased Neuromuscular Capacity: Weakness Decreased Neuromuscular Capacity: Fatigue Neuromuscular Diseases General Concepts Central Nervous System Motor Neuron Peripheral Nerve: Diaphragmatic Paralysis Peripheral Nerve: Neuralgic Amyotrophy Peripheral Nerve: Guillain-Barré Syndrome Neuromuscular Junction: Lambert-Eaton Syndrome Neuromuscular Junction: Botulism Neuromuscular Junction: Myasthenia Gravis Neuromuscular Junction: Tick Paralysis Muscle Dystrophies Restrictive Diseases Thoracic Deformity Abdominal Distension Systemic Diseases Inflammatory Myopathies Collagen Vascular Diseases Sarcoidosis Endocrinopathy Human Immunodeficiency Virus Infection Consequences of Surgery Thoracic and Cardiac Surgery Abdominal Surgery Conclusion More than 20 years ago, Derenne, Macklem, and Roussos published a three-part State-of-the-Art review on the mechanics, control, and pathophysiology of the respiratory muscles (1–3). A large body of scientific information on the respiratory muscles has been published since that time. The purpose of this article is to present the accumulated knowledge with particular emphasis on research published in the last 5 to 10 years. The literature was evaluated using several approaches. A MEDLINE search of articles published on the respiratory muscles between 1978 and 2002 was undertaken. Searches of the bibliographies of articles resulted in several additional articles and book chapters. Retrieved material ranged from experiments of molecular mechanisms, through studies of integrative pathophysiology in animals and volunteers, to randomized controlled trials in patients. Information was selected on the basis of scientific quality and potential relevance to patients suffering from pulmonary disease or a disorder requiring admission to an intensive care unit. The article does not include technical details of diagnostic techniques because that is the subject of a Joint Statement of the American Thoracic Society and European Respiratory Society (4). An extended version of this article, with 553 additional references, is accessible as an online supplement. The abnormality of respiratory muscle function in patients with chronic obstructive pulmonary disease (COPD) is multifaceted. Because the involvement illustrates several pathophysiological principles, COPD serves as a suitable introduction for a discussion of respiratory muscle involvement in other disease states.
COPD has become the fourth leading cause of death in the United States (5), and its global impact on health is expected to double between 1990 and 2020. The most disabling symptom of COPD is dyspnea, which primarily results from a decrease in the capacity of the respiratory muscles to meet an increased mechanical load. Several mechanisms contribute to the imbalance between load and capacity and consequent respiratory muscle dysfunction.
Energy Demands of Inspiration
Hyperinflation Hyperinflation decreases the resting length of the diaphragm and, less so, of the rib cage muscles. Using spiral computed tomography, Cassart and coworkers (13) found that the length of the diaphragm in the coronal plane (plane that divides the body between front and back) was shorter at functional residual capacity in 10 patients with severe COPD than in 10 healthy subjects: 45 versus 57 cm. The shortening was entirely due to a decrease in the length of the zone of apposition, which causes a decrease in the pressure generated by the diaphragm (14). The zone of apposition normally constitutes 60% of the diaphragm's total area, but only 40% in patients with COPD (13). The smaller zone of apposition means that less of the rib cage is exposed to the positive abdominal pressure produced by diaphragmatic contraction, and this further limits the capacity of the diaphragm to produce rib cage expansion. Investigators have used radiological techniques (15, 16) to study whether the configuration and dimensions of the thorax produce shortening of the rib cage muscles. Walsh and coworkers (15) found that the size of the rib cage and arrangement of the ribs were not different between severely hyperinflated patients with COPD and healthy subjects. Over the range of vital capacity (VC), however, Cassart and coworkers (16) found that the anteroposterior diameter of the rib cage was 2 to 3 cm greater in patients with severe COPD than in control subjects. The transverse diameter did not differ from healthy subjects in either study (15, 16). The discrepancy between the studies may have arisen from different imaging techniques, postures, degree of hyperinflation, and active contraction of inspiratory muscles at total lung capacity versus voluntary relaxation (15, 16). Irrespective of whether hyperinflation has some (16) or no effect (15) on rib cage dimensions, it has limited effect on the length–tension relationship of the intercostal muscles. As lung volume increases from functional residual capacity to total lung capacity, the parasternal intercostals shorten only by 2 to 8% (17) and the external intercostals shorten by no more than 11% (18). In contrast, the diaphragm shortens by 25% over the same change in volume (19). The influence of lung volume on the ability to generate pressure, however, is greater for the rib cage muscles than for the diaphragm (20). On going from a low lung volume to total lung capacity, the rib cage muscles experience an 80% decrease in inspiratory pressure generation, contrasted with a 60% decrease for the diaphragm (20). The rib cage muscles are less effective because of a shift in the ribs from their usual oblique orientation to a more horizontal position (20). This shift increases the impedance to rib cage expansion, and the disadvantage is greater for the rib cage muscles than for the diaphragm (20). Hyperinflation has traditionally been thought to cause flattening of the diaphragm and to increase its radius of curvature. According to Laplace's law, an increase in the radius of curvature causes an increase in the passive tension of the diaphragm and a decrease in the efficiency of transdiaphragmatic pressure generation. At resting functional residual capacity, however, the curvature of the diaphragm (coronal plane) is only 3.5% smaller in patients with severe COPD than in healthy subjects (21). The radius of curvature also changes little over the range of inspiratory capacity in either patients with severe COPD (21) or in healthy subjects (19). As such, a change in curvature is likely to be less important than a change in length of diaphragmatic fibers in determining contractile force at either functional residual capacity or over the range of inspiratory capacity. When the end-expiratory lung volume of dogs is increased by applying PEEP, the costal and crural diaphragms change from a parallel to a series arrangement (22). The series arrangement decreases the ability of the diaphragm to generate force, and the diaphragm has an expiratory rather than inspiratory action on the rib cage (22). The same limitation may apply in patients with COPD who are hyperinflated. End-expiratory lung volume is usually determined by the static equilibrium between inwardly directed elastic recoil of the lungs and outwardly directly recoil of the thoracic cage (relaxation volume). The outwardly directed forces help the inspiratory muscles to inflate the lungs. When end-expiratory lung volume lies above 70% of predicted total lung capacity (23), thoracic elastic recoil is directed inward. With such dynamic hyperinflation, the inspiratory muscles have to work not only against the elastic recoil of the lungs but also against that of the thoracic cage.
Respiratory Pressure Generation About half of patients with moderate-to-severe COPD exhibit parallel reductions in maximal expiratory and inspiratory pressures (23, 31). Because the expiratory muscles are not at a mechanical disadvantage, Rochester and Braun (23) inferred that some patients have generalized muscle weakness. This reasoning is supported by the correlation between maximal inspiratory and expiratory pressures (r = 0.73) in their 32 patients with COPD (23). Mechanisms contributing to generalized muscle weakness include electrolyte disturbances, blood gas abnormalities, cardiac decompensation (32), weight loss with muscle wasting (33), and steroid myopathy (31, 34). The last two mechanisms are probably the most important and are individually discussed.
Malnutrition
Strength and endurance.
Long-term malnutrition superimposed on emphysema produces a decrease in total force production, atrophy (more so of Type II fibers), and improved capillarity of the diaphragm in hamsters (43). Diaphragmatic endurance is increased in hamsters with emphysema, but the combination of long-term malnutrition and emphysema decreases endurance to the level of normal animals (43). The studies in animals are confounded by the use of semistarvation (40–43), which also decreases energy expenditure, to achieve weight loss. In patients with COPD, involuntary weight loss occurs without caloric restriction and energy expenditure is usually increased (33).
Metabolic pathways.
Elevated tumor necrosis factor-  can also increase muscle catabolism. In differentiated skeletal muscle, administration of tumor necrosis factor- induces a time- and concentration-dependent reduction in total protein content and loss of myosin heavy chains (46, 50). This catabolic action is transduced by activation of nuclear factor- B (50) (Figure 1). Activation of nuclear factor-B involves phosphorylation of the inhibitory protein-B, which, in turn, is followed by ubiquitin conjugation and proteasomal degradation of the inhibitory protein (50). The activated nuclear factor-B enters the nucleus and binds to a (not well-defined) promoter region in DNA. Because the last interaction does not decrease muscle protein synthesis, it is thought that nuclear factor-B binds to the promoter region of genes that regulate the ubiquitin–proteasome pathway (50). In turn, the activated ubiquitin–proteasome pathway may cause muscle catabolism (50).
Tumor necrosis factor-
Tumor necrosis factor- Hypermetabolism contributes to weight loss and muscle wasting in patients with COPD (33, 53). Total daily energy expenditure is increased under both resting (33) and nonresting conditions (53). Increased oxygen cost of breathing and decreased efficiency of the peripheral skeletal muscles contributes to the increased energy expenditure. The alterations in anabolism, catabolism, and intermediate metabolism in patients with COPD have been reported to cause protein turnover to decrease (secondary to decrease in protein synthesis [54]) and increase (secondary to increase in protein synthesis and protein breakdown [55]). The conflicting data may reflect differences in patient selection (severely malnourished [54] versus well-nourished patients [55]) or a Type 2 error (8 and 14 patients) (54, 55).
In contrast to normal-weight patients with COPD, underweight patients show increased apoptosis in skeletal muscles (quadriceps) (56). The patients with apoptosis have impaired exercise tolerance despite no greater decrease in lung function (56). Release of cytochrome c from the mitochondria and tumor necrosis factor-
Refeeding. General physical training (treadmill, swimming, walking) and a 8-week course of nandrolone decanoate (an anabolic steroid) combined with nutritional supplementation (at 70% above resting energy expenditure) enhanced the gain in fat-free mass and respiratory muscle strength in patients with COPD who had a decreased muscle mass (33). No benefit, however, was seen in 50% of the patients (37). Patients who did not respond to diet and training were older, more anorectic, and had a greater systemic inflammatory response (59). Patients who gain more than 2 kg over 8 weeks in response to nutritional therapy, with or without anabolic steroids, have a lower mortality (37). Recombinant human growth hormone (plus nutritional supplementation) did not improve respiratory muscle strength of malnourished patients with COPD in the only randomized-controlled trial to date (60). Factors that may explain the lack of response include a redistribution of protein toward central organs rather than toward muscle—both of which are part of lean body mass measurement (60)—and insufficient dose and duration of therapy (3 weeks) (60). Megestrol acetate, a progestational appetite stimulant, increased the fat mass of malnourished patients with COPD, but it did not improve respiratory muscle endurance (61).
Nutritional supplementation produces an increase in fat-free mass in underweight patients with COPD without affecting inflammatory parameters (59). As such, the enhanced inflammatory response appears to be a cause, not the effect, of weight loss and muscle wasting in patients with COPD. Trials of pharmacological antagonists of tumor necrosis factor- In summary, patients with COPD are commonly malnourished and have decreased muscle mass. Several complex mechanisms, likely triggered by systemic inflammation, are responsible for the decreased anabolism and increased catabolism. In some patients, improved nutrition and exercise can partially reverse the processes.
Glucocorticoids Glucocorticoids may (34, 69) or may not (70, 71) decrease inspiratory muscle strength. In 19 patients with asthma receiving prednisone (21 mg/day for 5 years), maximal inspiratory pressure was equivalent to that of 16 patients with asthma not receiving glucocorticoids and who had similar pulmonary function (70). Endurance, however, was reduced in the glucocorticoid-dependent patients (70). Susceptibility to fatigue in glucocorticoid-dependent patients with asthma was equivalent to that in healthy subjects, but greater than that in patients with COPD (71). In patients with increased respiratory loads, the greater endurance in patients not receiving glucocorticoids suggests that glucocorticoids counterbalance the training effect of airway obstruction without causing overt muscle weakness. The minimum dose of glucocorticoids to cause a chronic myopathy is not known. Among 21 patients admitted to hospital for exacerbations of COPD or asthma, Decramer and coworkers (34) found that 8 had generalized muscle weakness. The average dose of methylprednisolone during the preceding 6 months exceeded 4 mg/day in 7 of the 8 patients; lower dosages were used in 10 of the 13 patients with normal muscle strength. The average dose of glucocorticoids over the preceding 6 months explained 40% of the variance of inspiratory muscle strength in the patients with COPD, and this relationship was independent of the degree of airway obstruction (34). Decramer and coworkers (31) also compared 8 patients with COPD who had steroid-induced myopathy (patients received methylprednisolone at 14 mg/day over the preceding 6 months) against 24 patients with COPD without steroid-induced myopathy. The quadriceps in all patients with steroid-induced myopathy contained diffuse atrophic and necrotic fibers, with increased connective tissue between fibers and increased subsarcolemmal and central nuclei. Because body mass index was lower in the patients with steroid-induced myopathy than in the control patients, malnutrition, rather than a direct action of glucocorticoids, cannot be excluded as the cause of the muscle atrophy. Four of the 8 patients with chronic steroid myopathy (31) died within 6 months of developing hypercapnic respiratory failure, but only 2 of the 24 control patients died over the same period. These data suggest that chronic steroid myopathy adversely affects survival. Although use of glucocorticoids might be no more than a marker of disease severity, the equivalent airway obstruction in these two groups argues against that possibility. Patients take 2 months (69) to 3 months (72) to recover from the chronic respiratory myopathy.
Respiratory Endurance Despite the greater load and inspiratory muscle recruitment (75, 76), respiratory muscle endurance is probably increased in patients with COPD (24). Potential adaptations that account for the increased endurance include muscle remodeling (28, 77) and a short respiratory duty cycle (10). Evidence of remodeling includes increased concentration of mitochondria (28) and changes in muscle fiber composition (77). The diaphragm of patients with COPD has a higher proportion of fatigue-resistant Type I fibers as compared with control subjects (61 versus 46%), a somewhat lower proportion of fatigue-resistant Type IIa fibers (31 versus 39%), and very few fatigue-sensitive Type IIb fibers (8 versus 15%) (77) (Table 1). The aforementioned changes together with increases in capillarity, mitochondrial volume density, and mitochondrial oxidative enzyme capacity (78) and an increase in respiratory muscle blood flow during exercise may contribute to the purported increased diaphragmatic endurance in patients with COPD (24). Similar to limb muscles of endurance athletes, the cross-sectional area of all types of diaphragmatic fibers is decreased in well-nourished patients with COPD (77). The decrease in area may enhance oxidative potential because of the shorter distance oxygen has to diffuse from the capillary to a fiber. In patients with COPD, inspiratory muscle training can increase the proportion of Type I fibers and the size of Type I and Type II fibers in the external intercostal muscles (79).
Clinical Manifestations For a given fall in pleural pressure during resting breathing, patients with COPD exhibit a smaller increase in abdominal pressure and less abdominal expansion than do healthy subjects (82). Two factors may explain this observation. First, the rib cage muscles make a greater contribution to tidal breathing in patients with COPD than in healthy subjects because of greater activity of the parasternal and scalene muscles (but not of the sternomastoid muscles [83, 84]) secondary to increased discharge frequency of their motor units (rate coding) and possibly increased number of active motor units (recruitment) (85). Second, the respiratory muscles of patients with severe COPD become less efficient in performing work on switching from natural breathing to deliberate diaphragmatic breathing (10 versus 40–50% diaphragmatic contribution to tidal breathing) (82). The capacity of the diaphragm to shorten and thus contribute to tidal volume, however, is not impaired in patients with COPD (80, 86). In fluoroscopic (86) and ultrasonographic studies (80), diaphragmatic excursion (86) and shortening (80) during tidal breathing was equivalent in patients with COPD and control subjects. The resting length of the diaphragm is shortened in patients with COPD because of hyperinflation. Accordingly, the proportional decrease in length of the diaphragm, as a fraction of its total length, is much greater during tidal breathing in patients with COPD than in control subjects (80). Mechanisms that help patients with COPD to defend the contribution of the diaphragm to tidal breathing include an increase in the discharge frequency of diaphragmatic motor units during resting breathing (75), and, possibly, chronic adaptations that reduce the length and number of sarcomeres in series (28, 29, 87).
Expiratory muscle recruitment. The inability of the expiratory muscles to help with generating inspiratory pressure fits with the finding that nearly 90% of patients with COPD who activate the transversus abdominis during exhalation stop this activity at the start of inhalation (88). In other words, the diaphragm starts to contract just after the abdomen starts to return to its relaxed configuration, regardless of whether the expiratory muscles were contracting during exhalation (88, 89). Yan and coworkers (89) reported that diaphragmatic recruitment (diaphragmatic electrical activity normalized to its maximal value) was less in patients who recruited their expiratory muscles than in patients who did not. Decreased diaphragmatic recruitment was paralleled by increased contribution of the rib cage muscles to tidal breathing (89). Whether more severe airway obstruction fosters expiratory muscle recruitment and increased rib cage muscle contribution to tidal breathing is disputed: some data support (88) and other data refute the association (84, 89).
Hypercapnia. In a study of 311 stable outpatients with COPD, hypercapnia was more common in patients who had a combination of inspiratory muscle weakness and a high inspiratory load (90). The tension–time index of the diaphragm was higher in hypercapnic than in normocapnic patients (90), although no patient exceeded the threshold for task failure (90). For the hypercapnic patients to achieve normocapnia, the investigators estimated they would need to increase their tension–time index by more than 20%. This may be an underestimate because it ignores the increase in carbon dioxide production secondary to increased ventilation and it assumes that the relationship between tension–time index and alveolar ventilation remains constant. On attempting to increase minute ventilation, patients typically develop dynamic hyperinflation and rapid shallow breathing. Accordingly, the tension–time index might reach a level that causes task failure and fatigue. On increasing tidal volume, hypercapnic patients experienced an increase in the oxygen cost of breathing whereas normocapnic patients did not (91). The increase in oxygen cost of breathing was correlated with the degree of diaphragmatic flattening (r2 = 0.74) (91). Hypercapnia can also decrease respiratory muscle contractility, leading to a vicious circle of carbon dioxide retention. The respiratory muscles of patients with chronic hypercapnia are at greatest risk during an acute exacerbation of COPD. To investigate the role of voluntary activation of the diaphragm, Topeli and coworkers (94) used the twitch interpolation technique. When the phrenic nerves are stimulated during a voluntary contraction, the increase in transdiaphragmatic pressure provides a measure of voluntary activation (Figure 2) . Voluntary activation was higher in six hypercapnic patients than in nine normocapnic patients, 95 versus 89%; the value in normocapnic patients was equivalent to that reported in healthy subjects (88%) (95). The extent of voluntary activation of the diaphragm and PaCO2 were both positively correlated with inspiratory muscle load (94), suggesting that patients with a high load may have learned how to fully activate their diaphragm on an intermittent basis (94). The ability to mount an increase in voluntary drive to the diaphragm may be especially important during an acute exacerbation of COPD. If patients have a low baseline level of voluntary activation, they may be unable to generate sufficient inspiratory pressure to avoid alveolar hypoventilation. The situation is analogous to patients with prior poliomyelitis who exhibit greater than normal fatigability of limb muscles, partly because of impaired voluntary activation of the limb muscles.
Exercise. During whole body exercise, healthy subjects decrease end-expiratory lung volume as a result of activating their abdominal and expiratory rib cage muscles (96). Although patients with COPD progressively recruit their expiratory muscles during whole body exercise (Figure 3) , end-expiratory lung volume usually increases (96–101) as a consequence of expiratory flow limitation (96). End-inspiratory volume during tidal breathing encroaches on total lung capacity. The dynamic hyperinflation reduces the capacity of the respiratory muscles to generate pressure (98) and increases their mechanical load (11). Dynamic hyperinflation (98) and quadriceps fatigue (102) are major causes of impaired exercise capacity. Exercise more than doubles the elastic work of inspiration because of decreased dynamic lung compliance and increased intrinsic PEEP (11). The increase in intrinsic PEEP is overcome by contraction of the diaphragm, commencing before the start of inspiratory flow (97). Once inspiratory flow commences, the contribution of diaphragmatic pressure to tidal breathing gradually decreases; the decrease parallels the increase in workload and is compensated by rib cage muscle recruitment (97). The rib cage muscles become the major determinant of inspiratory flow during exercise (97).
Two mechanisms may explain the limited diaphragmatic contribution to tidal breathing: exercise may induce central inhibition of the diaphragm, and dynamic hyperinflation may decrease the capacity of the diaphragm to generate pressure (98). In 10 patients with moderately severe COPD, Sinderby and coworkers (98) found that electrical activation of the diaphragm increased progressively during exercise. Tidal swings in transdiaphragmatic pressure increased only modestly and reached a plateau shortly after the onset of exercise (98). That electrical activation increased out of proportion to the tidal swings in transdiaphragmatic pressure indicates that hyperinflation rather than central inhibition of the diaphragm is responsible for the reduced diaphragmatic contribution to tidal breathing. The reason why most patients with COPD do not develop diaphragmatic fatigue when exercising to exhaustion (98, 102) is not known. Possible factors include constraints in ventilatory mechanics (96), increased diaphragmatic mitochondrial content (28), increased proportion of fatigue-resistant muscle fibers (77), unimpeded blood flow to the diaphragm because of the limited rise in transdiaphragmatic pressure, and redistribution of cardiac output from the lower limb exercising muscles to the respiratory muscles (103).
Surgery for COPD Most patients undergoing lung volume reduction surgery demonstrate an improvement in expiratory flow rates and less hyperinflation and air trapping. These effects partly result from an increase in lung elastic recoil and better matching of lung and rib cage size (104–107). The surgery leads to a decrease in the respiratory pressure requirement for tidal breathing (6, 108) and the energy cost for CO2 removal (6). Purported mechanisms for these benefits include improved alveolar ventilation, and decreases in operational lung volume, intrinsic PEEP, dynamic lung elastance, and chest wall elastance (105, 109). The surgery improves the length–tension relationship of the respiratory muscles (27, 110). Using spiral computed tomography to generate three-dimensional reconstruction of the diaphragm, Cassart and coworkers (27) found that surgery produced a 17% increase in the total surface area of the diaphragm in 11 patients with severe emphysema. The increase was completely accounted for by the increase in area of the zone of apposition (27). Diaphragmatic curvature was unaltered by surgery (27). The lengthening of the diaphragm after surgery may contribute to its improved pressure output (6, 110). Three months after surgery, maximal transdiaphragmatic pressure increased from 80 to 111 cm H2O and transdiaphragmatic twitch pressure in response to phrenic nerve stimulation increased from 17 to 26 cm H2O (Figure 4) (6). The greater pressure output can be explained, at least in part, by the improved length–tension relationship of the diaphragm (110). Considered as a group, the diaphragmatic surface area is linearly related to absolute lung volume in healthy subjects, chronically hyperinflated patients, and patients who have undergone the surgery (13, 27). These observations are compatible with a lack of adaptation of the diaphragm to hyperinflation—the differences in diaphragmatic length in the three groups of individuals may simply result from passive shortening of the muscle. Alternatively, the observations may be explained by adaptation to chronic hyperinflation, mediated by a reduction in the number or in the length of the sarcomeres. The relationship between diaphragmatic surface area and absolute lung volume was assessed only under static conditions (13, 27), which further confounds interpretation of the findings (111). The relationship between diaphragmatic surface area and a given (absolute) lung volume may be different during active breathing. Chronic hyperinflation might induce tonic recruitment of the rib cage muscles during active breathing (85), resulting in an elevated rib cage at a given lung volume. Elevation of the rib cage could stretch the diaphragm to a more favorable length and improve its mechanical advantage through an increase in the area and length of the zone of apposition (111). These considerations (111) underscore the possibility that the number and length of sarcomeres of the diaphragm (and possibly other inspiratory muscles) could increase after surgery, as reported in animal models of lung reduction surgery (112, 113); sarcomere number and length have not been measured in patients.
Surgery increases diaphragmatic pressure output by about 20% more than is expected for the decrease in lung volume and improves the length–tension relationship (6). Factors contributing to the additional improvement include increases in oxygenation, right ventricular function (114, 115), cardiac output, number of sarcomeres (87), and muscle mass, and a decrease in glucocorticoid use. Fiber composition of the diaphragm does not change, at least after surgery in a hamster model of emphysema (113). In patients, coupling between inspiratory effort and diaphragmatic output improves after surgery (6). The improved neuromechanical coupling was correlated with improvement in the distance walked in 6 minutes (r = 0.86) and tended to correlate with decrease in dyspnea (r = 0.76) (6). The ratio of swings in gastric pressure to swings in transdiaphragmatic pressure during tidal breathing increased by more than one-third after surgery (6). An increase in this ratio can result from increases in the diaphragmatic contribution to tidal breathing or lessening of expiratory muscle recruitment (116). The latter cannot be the primary explanation because a fall in gastric pressure during early inhalation was uncommon (6). A more likely explanation for the increase in the ratio is a decrease in the activity of the intercostal-accessory muscles relative to that of the diaphragm. The increase in the ratio of swings in gastric pressure to swings in transdiaphragmatic pressure was related to improvement in diaphragmatic neuromechanical coupling (r = 0.91). A decrease in rib cage muscle recruitment after surgery may also account for the decreased dyspnea at rest (6, 108). Surgery improves diaphragmatic function during exercise. On a plot of esophageal pressure against gastric pressure during tidal breathing, the slope shifts to the right in patients performing whole body exercise after surgery (105, 108). This rightward shift suggests an increased diaphragmatic contribution to tidal breathing (108). Surgery lessens exercise-associated dynamic hyperinflation (105), which may contribute to the increased diaphragmatic contribution to tidal breathing and reduced abdominal recruitment after surgery (105, 108). Improvements in exercise performance and diaphragmatic contractility cannot be ascribed to preoperative pulmonary rehabilitation. The long-term benefits of lung volume reduction surgery on lung function, respiratory muscle function, exercise capacity, dyspnea, and quality of life do not follow a uniform course. Improvement in forced expiratory volume in 1 second (FEV1) peaks at 3 to 6 months after surgery and declines by 100 to 150 ml or more over the subsequent year (117, 118). Improvements in total lung capacity and residual volume appear to be more stable during the first year (117). Data on quality of life are conflicting: some investigators report substantial and persistent improvement at 1 year (117), others report no improvement at 6 months (119). Among 26 patients with severe COPD (118), surgery achieved clinical and physiological improvements in nine patients for up to 3 years, in seven patients at 4 years, and in two patients at 5 years.
Lung transplantation. After single lung transplantation, Cassart and coworkers (122) found that the radius of curvature of the dome of the diaphragm and the area of the zone of apposition on the side of the graft returned to normal. The surface area of the dome was also smaller on the transplanted side than in healthy subjects (122). This effect was secondary to mediastinal displacement toward the graft (122), which, in turn, was due to the lesser elastic recoil of the native emphysematous lung combined with the relatively greater elastic recoil of the graft. The uneven elastic recoil of the two lungs may be even greater if the graft is infected or is being rejected. A shift of the mediastinum toward the graft could also result from dynamic hyperinflation of the native lung (123). Such dynamic hyperinflation is unlikely because recipients of a single lung transplant usually do not exhibit flow limitation during tidal exhalation, except during maximal exercise (124). Mediastinal displacement is usually counterbalanced by an equal expansion of the rib cage on the side of the graft, such that functional residual capacity of the transplanted side remains within normal limits (125). Estenne and coworkers (125) reported that the volume of the graft tends to be greater in patients who had more severe hyperinflation of the native lung. Nevertheless, the compensatory expansion of the rib cage on the side of the graft is not always sufficient to accommodate the expansion of the contralateral hyperinflated lung. In rare instances, mediastinal displacement can be sufficient to compromise the function of the graft and cause hemodynamic instability up to 3 years after surgery (123). The risk of developing symptomatic mediastinal shift and compression of the transplanted lung after surgery is proportional to the severity of obstruction and air trapping before surgery (123). When recipients of a single lung inhale to total lung capacity, the transplanted lung reaches only about 78% of the volume attained by healthy subjects (122, 125). The smaller volume probably arises because of a shift of the mediastinum toward the transplanted side (125), a mismatch between the sizes of the native lung and the rib cage (106), and a decreased capacity of the inspiratory muscles to generate pressure (126). Esophageal pressure at total lung capacity is less negative than normal (126). The smaller inspiratory pressure may be caused by the shorter operating length of the inspiratory muscles resulting from hyperinflation of the contralateral lung (125) or by myopathy secondary to glucocorticoids or cyclosporine; the vehicle, cremophor (a derivative of castor oil used as solubilizer for lipophilic medications that can alter mitochondrial respiration), is the most likely culprit (127, 128). In contrast to transplanting a single lung, transplanting two lungs normalizes total lung capacity in patients with chronic hyperinflation (129–131). Bilateral transplantation, however, leaves functional residual capacity about 1 L above the predicted value (129, 131). The persistent hyperinflation is secondary to an increase in the anteroposterior diameter of the rib cage (about 3 cm [131]), which is probably a structural adaptation to pulmonary hyperinflation (129, 131). Twitch and sniff transdiaphragmatic pressures are not affected (132) by the decrease in resting length and normalization of the radius of curvature of the diaphragm after transplanting one lung (122). These two factors (130, 132), however, probably contribute to the improved sniff pressure (132) and normalization of maximal inspiratory airway pressure after transplanting two lungs (133). Patients with end-stage cystic fibrosis who receive two lungs are capable of generating maximal esophageal pressures more negative than those recorded in healthy subjects (131), possibly reflecting a leftward shift of the pressure–volume curve of the chest wall (131). In 8 patients with COPD who received double lung transplantation, transdiaphragmatic twitch pressure elicited by phrenic nerve stimulation tended to be greater than that in 14 patients with COPD who had not undergone surgery (132). Unlike the improvement in maximal inspiratory pressures (132, 133), maximal expiratory pressures reached only 70% of normal in nine patients who received two lungs (133). It is not known why transplantation improved inspiratory but not expiratory muscle strength. Weakness of the expiratory muscles and ankle dorsiflexors was equivalent (133), suggesting that these muscle groups are vulnerable to some factor that does not affect the diaphragm—perhaps because it is continually active (133). Possible factors include muscle atrophy (disuse or malnutrition), myopathy (steroid myopathy or mitochondrial myopathy associated with cyclosporine), or a deficit in motor activation. Inspiratory muscle endurance does not change after single or double lung transplantation (134). The lack of effect may be secondary to the protocol used for testing endurance (imposed respiratory frequency and inspiratory time), adverse effects of the antirejection regimen, or a Type 2 error. Blunting of the voluntary activation of the inspiratory muscles (94) is another possibility. The improved respiratory muscle strength (132) and decreased drive under loaded conditions probably reduce the sensation of inspiratory effort and contribute to the improved quality of life. In patients with one (124) and two transplanted lungs (133, 135, 136), maximal exercise capacity is about half the normal value. The reduced exercise capacity is not the result of ventilatory limitation, as is the case of patients with COPD who have not undergone lung transplantation. Ventilatory reserve during maximal exercise is equivalent in transplanted patients and control subjects (67 versus 58% of maximum voluntary ventilation) (136). Exercise limitation in patients with end-stage COPD who receive one or two lungs is probably caused by decreased strength (136) and endurance of the limb muscles (137). Compared with healthy subjects, transplant recipients have a shorter time to exhaustion (137), greater acidosis in the quadriceps during knee-extending exercise (137), reduced Type I muscle fibers (135), and severely reduced mitochondrial oxidative capacity (135).
Patients with asthma are exposed to airway obstruction and hyperinflation, but unlike patients with COPD the load is often intermittent.
Mechanics The portion of the rib cage in contact with the lungs and diaphragm largely accommodates the hyperinflation of acute bronchoconstriction (139). An increase in the abdominal compartment is limited by abdominal muscle recruitment (139). The portion of the rib cage in contact with the lungs at end exhalation and the portion in contact with the diaphragm move along the relaxation configuration of the rib cage, sharing proportionally in the hyperinflation (139). The lack of volume distortion at end exhalation probably results from coordinated action of the respiratory muscles. In particular, postinspiratory contraction of the rib cage inspiratory muscles is probably responsible for the increase in volume of the rib cage apposed to the lungs (139). By acting on the zone of apposition, postinspiratory contraction of the diaphragm and contraction of the expiratory muscles are likely responsible for the increase in volume of the rib cage apposed to the diaphragm (139). Postinspiratory activity of the diaphragm and rib cage inspiratory muscles together with expiratory muscle recruitment can brake expiratory airflow (139). As a result, lung volume does not fall to the level achieved by complete muscle relaxation (even in the absence of expiratory flow limitation) (142). The active increase in end-expiratory lung volume may maintain airway patency and minimize flow limitation during bronchoconstriction. Expiratory muscle recruitment during acute hyperinflation may also limit the shortening of the diaphragm and the associated reduction in the zone of apposition. This possible effect of the expiratory muscles on diaphragmatic dimensions could limit the effects of hyperinflation on the capacity of the diaphragm to generate pressure at the beginning of inhalation. In contrast to coordinated recruitment of the diaphragm and rib cage muscles on exhalation during acute hyperinflation, the rib cage muscles are recruited more than the diaphragm during inhalation (139). The consequent distortion of the chest wall (139) wastes energy. The greater recruitment of the rib cage muscles places them at risk of fatigue. Because their threshold for fatigue is higher than that for the diaphragm (74) however, greater recruitment of rib cage muscles may help prevent alveolar hypoventilation during an exacerbation. Patients with chronic persistent asthma display chronic hyperinflation (138, 143). The hyperinflation may be explained completely by the time constant of the respiratory system exceeding the time available for tidal exhalation. The increased time constant results from fixed airway obstruction (airway remodeling) and loss of elastic recoil (138). The loss of elastic recoil accounts for up to half of the decrease in maximal expiratory flow (138), but the mechanism is unclear. Some investigators found emphysema on high-resolution computed tomography (143), but others did not (138). Differentiating emphysema from air trapping on computed tomography is imperfect, which confounds the interpretation (143); decreased lung density does not correlate with diffusing capacity (143), which further confounds the association. The contribution of inspiratory muscle recruitment during exhalation to chronic hyperinflation is not clear.
Strength and Endurance Increases in the energy cost of breathing combined with possible impaired function of the respiratory muscles (hyperinflation, acute and chronic steroid myopathy, malnutrition) puts patients with asthma at risk of respiratory muscle fatigue. Four strategies decrease the likelihood of fatigue. One, the duty cycle is decreased in patients with asthma (10), which tends to decrease the tension–time index. Two, endurance of the respiratory muscles is enhanced in patients with frequent exacerbations of asthma (144), perhaps secondary to a training response. Patients with asthma have a thicker diaphragm than do healthy subjects: 2.2 versus 1.7 mm (146). Three, inspiratory muscle training can increase muscle strength, decrease dyspnea, and decrease ß2-agonist consumption (147). Four, about half of unselected patients with asthma have a reduced voluntary drive to breathe (95), which will decrease respiratory muscle recruitment and the risk of fatigue during an exacerbation–albeit with attendant risk of alveolar hypoventilation. Three mechanisms may account for the decreased voluntary drive to breathe. First, patients with asthma have a decrease in reflex facilitation during forceful voluntary contraction (148); reflex facilitation–afferent feedback from a contracting muscle that increases the firing rate of motor neurons during a voluntary contraction–accounts for as much as one-third of the total activation in healthy subjects (149). Second, cortical processing of inspiratory information generated by load is reduced in patients with asthma who have not suffered life-threatening attacks (150) and is absent in about half of patients with asthma who have a history of life-threatening attacks (151). Third, depressed mood contributes in some patients (152). A decrease in voluntary activation concurs with the observation that patients with a history of near-fatal asthma have a reduced chemosensitivity to hypoxia, blunted perception of dyspnea, and reduced sensitivity to added inspiratory resistive loads (153).
Glucocorticoids
Exertional fatigue and dyspnea limit the activities of daily living of patients with chronic heart failure. Mechanisms include abnormalities of limb muscle fibers, such as atrophy, an increase in easily fatigable Type IIb fibers, a decrease in oxidative enzymes, and a decrease in size and number of mitochondria (155). A decrease in limb muscle perfusion is disputed (156). Impairment of respiratory muscle function contributes to the dyspnea and exercise limitation.
Strength and Endurance Dyspnea during submaximal exercise testing and during daily activities is related to respiratory muscle strength, and any improvement in strength will help (166). Strength is increased by selective respiratory muscle training (167, 168), nasal continuous positive airway pressure (157), and angiotensin-converting enzyme inhibitors. These studies (157, 167, 168), however, are marred by small numbers of patients, varying etiology and severity of heart failure, and occasional lack of control groups (168). The improvement may result from increased size of muscle fibers, increased number of cross-bridges, improved perfusion, and enhanced recruitment during voluntary efforts (157, 159). Respiratory muscle endurance in patients with chronic heart failure is about half that in healthy subjects (169), and the decrease is disproportionate to the decrease in inspiratory and expiratory strength (169). Several mechanisms may be involved. First, the circulatory supply of energy substrates during diaphragmatic loading increases less in animals with heart failure than in healthy animals (164). Second, hyperpnea during endurance testing (169) could predispose to hyperinflation (170) as a consequence of expiratory flow limitation (171). Third, work of the diaphragm is increased threefold (166) because of decreased static lung compliance in patients with heart failure and pulmonary congestion (172) or pleural effusions. The diaphragm of patients with chronic heart failure has an increased proportion of fatigue-resistant Type I muscle fibers and increased oxidative capacity (161). Moreover, respiratory muscle oxygenation does not decrease during endurance testing (169). Therefore, decreased endurance does not arise from an intrinsic defect in the contractile machinery or oxygenation (169), but rather demands overwhelm the mechanisms trying to enhance respiratory muscle endurance. Chronic hyperpnea and abnormal mechanics may serve as training stimuli and explain why some but not all investigators report less weakness of respiratory muscles than of limb muscles in patients with chronic heart failure (161). Decreased respiratory muscle strength and endurance contribute to dyspnea (166) and decreased exercise capacity (168) in patients with chronic heart failure. A link between dyspnea and respiratory muscle weakness is supported by the observation of Mancini and coworkers (168) that selective training of the respiratory muscles reduces dyspnea, improves respiratory muscle strength and endurance, and increases exercise capacity. The benefits of training may result from improved intrinsic properties of the respiratory muscles, a learning effect, and desensitization to dyspnea. In the only randomized controlled trial, however, Johnson and coworkers (167) found that domiciliary inspiratory muscle training improved inspiratory strength but not exercise capacity. The results of Mancini and coworkers (168) may have been positive because of the more intense supervision (hospital-based program) and training protocol (including expiratory muscle training), and more severe baseline inspiratory muscle weakness than was the case for the patients of Johnson and coworkers (167).
Exercise The limited energy supply to the respiratory muscles probably accounts for the fatigue after exercise (164). This possibility is supported by the decrease in oxygenation of the accessory muscles during whole body exercise (175), the association between recovery of strength and oxygen kinetics (174), the redistribution of blood flow from respiratory to limb muscles, and the decrease in strength at the end of exercise despite a tension–time index of the diaphragm below the threshold for task failure (166). Patients also develop dynamic hyperinflation (170), possibly from airway narrowing secondary to vasodilation of airway vessels (176) and expiratory flow limitation—similar to that reported in patients with acute left heart failure (171). Whether expiratory flow limitation is more severe in patients with an enhanced ventilatory response to exercise, expressed as ventilation per unit of carbon dioxide production, is unknown. Exercise capacity is improved by unloading the respiratory muscles with a helium–oxygen mixture (175), bronchodilator (177), pressure support (170), or methoxantine, a vasoconstrictor that may prevent bronchial vasodilation (176). Improved exercise capacity probably results from a better balance between oxygen demands and supply to the respiratory muscles (175) and respiratory </ |
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, can decrease protein expression of MyoD by activating the nuclear factor-
