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.
Chronic Obstructive Pulmonary Disease
Energy Demands of Inspiration
Respiratory Pressure Generation
Surgery for COPD
Strength and Endurance
Chronic Heart Failure
Strength and Endurance
Acute Respiratory Failure
Increased Load: Mechanics and Ventilatory Requirements
Decreased Neuromuscular Capacity: Weakness
Decreased Neuromuscular Capacity: Fatigue
Central Nervous System
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
Collagen Vascular Diseases
Human Immunodeficiency Virus Infection
Consequences of Surgery
Thoracic and Cardiac Surgery
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.
In attempting to achieve adequate alveolar ventilation, patients with COPD must generate more negative intrathoracic pressures than normal because of abnormalities of gas exchange and mechanical load. The pressure output of the inspiratory muscles during resting breathing can be more than three times higher than in healthy subjects: average pressure–time product of 341 (6) versus 94 cm H2O · second/minute (7). Consequently, the oxygen cost of respiration is more and the efficiency of the respiratory muscles is less in patients with COPD than in healthy subjects. Several abnormalities of the airways and lung parenchyma contribute to the stress on the respiratory muscles. First, inspiratory flow resistance is increased more than fourfold (8). Second, loss of elastic recoil of the lungs causes the relaxation volume to move to a higher volume and causes closure of small airways in early exhalation (static hyperinflation). Third, resting minute ventilation is increased by 50% to compensate for impaired gas exchange (9, 10). Fourth, increases in time constants and breathing frequency cause dynamic lung compliance to fall below the static value (11). Five, expiratory flow limitation, which occurs in about 60% of ambulatory patients with COPD (12), delays lung emptying, with the result that inspiration begins before the respiratory system has returned to its relaxation volume (dynamic hyperinflation). Consequently, the inspiratory muscles have to offset a threshold load—termed auto or intrinsic positive end-expiratory pressure (PEEP)—before inspiratory flow can begin.
Patients with COPD not only have an increased load on the respiratory muscles, but the capacity of their respiratory muscles to generate pressure is also decreased. Hyperinflation impairs the capacity of the respiratory muscles to generate negative intrathoracic pressure through several mechanisms: worsening of the length–tension relationship, decrease in the zone of apposition, decrease in the curvature of the diaphragm, change in the mechanical arrangement of costal and crural components of the diaphragm, and increase in the elastic recoil of the thoracic cage.
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.
Patients with COPD generate less negative maximal inspiratory pressures than do healthy subjects (24). The smaller swings in airway and transdiaphragmatic pressures can be completely explained by hyperinflation-induced muscle shortening in some patients (13, 24–27). Similowski and coworkers (26) found that some patients with COPD had greater transdiaphragmatic pressure (in response to phrenic nerve stimulation) than did healthy subjects at equivalent lung volumes. The finding suggests that the inspiratory muscles had adapted to hyperinflation. The adaptation is probably secondary to shortening of diaphragmatic sarcomeres (reported in patients with mild-to-moderate COPD  and in a hamster model of emphysema ) and a decrease in sarcomere number (hamster model of emphysema [29, 30]), which cause a leftward shift of the length–tension relationship.
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.
Weight loss and muscle wasting are present in about 20% of stable outpatients with COPD (35), and 70% of patients requiring mechanical ventilation (36). A decrease in fat-free mass is accompanied by a decrease in muscle mass (33, 36), which can be depleted despite normal body weight (33). Weight loss is a predictor of increased mortality independent of the degree of airflow obstruction (37–39).
Inspiratory muscle strength is about 30% less in poorly nourished patients than in well-nourished patients with equivalent airway obstruction (33). In malnourished patients, inspiratory weakness, fatigability, and dyspnea are partially reversible with nutritional support (33). Short-term (40) and long-term malnutrition in otherwise healthy animals decreases diaphragmatic mass (41, 42). Short-term malnutrition causes atrophy of all fiber types: fatigue resistant (Type I, Type IIa) and fatigue sensitive (Type IIb) (40) (Table 1)
|Velocity of shortening||+||++||+++||++++|
|Mitochondrial volume density||+++||+++||++||+|
|ATP consumption rate||+||++||+++||++++|
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).
The interaction between weight loss, muscle wasting, and respiratory and nonrespiratory muscle function in patients with COPD probably results from an altered inflammatory profile (33, 44, 45). Patients with COPD who unintentionally lose weight have increased plasma levels of tumor necrosis factor-α (44, 45). Tumor necrosis factor-α can decrease diaphragmatic strength through several mechanisms: decrease in muscle anabolism, increase in muscle catabolism, and inhibition of contractility (Figure 1)(46, 47). An increase in tumor necrosis factor-α decreases muscle anabolism by causing anorexia (46, 48). Both anorexia and tumor necrosis factor-α decrease the content of messenger RNA for myofibrillar proteins (myosin light and heavy chains, and α-actin) (48). Chronic administration of tumor necrosis factor-α also interferes with the translational regulation of myofibrillar protein synthesis in the rat diaphragm; as a result, synthesis of myosin light and heavy chains and G-actin is inhibited (49).
Elevated tumor necrosis factor-α can also increase muscle catabolism. In differentiated skeletal muscle, administration of tumor necrosis factor-α 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-κB (50) (Figure 1). Activation of nuclear factor-κB involves phosphorylation of the inhibitory protein-κBα, which, in turn, is followed by ubiquitin conjugation and proteasomal degradation of the inhibitory protein (50). The activated nuclear factor-κB 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-κB 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-α, in concert with interferon-γ, can decrease protein expression of MyoD by activating the nuclear factor-κB system (51). MyoD is required to maintain stable skeletal muscle differentiation and to induce proliferation and repair by satellite cells in response to muscle injury. A decrease in MyoD could cause degeneration of newly formed myotubes (multinucleated young muscle cell not yet developed into mature myofibers) in the cachectic patient (51). Tumor necrosis factor-α can stimulate protein catabolism through pathways that target hormones involved in muscle growth. These pathways include the development of insulin resistance, decrease in thyroid hormones, and increases in glucagon, cortisol, corticosterone, and occasionally catecholamines (44, 45) (Figure 1). Tumor necrosis factor-α can also cause protein catabolism by stimulating the production of catabolic cytokines, such as prostaglandin E2 and interleukin-1 (44, 45).
Tumor necrosis factor-α can also decrease diaphragmatic contractility by inducing the production of reactive oxygen species through activation of the cyclooxygenase pathway and stimulation of mitochondria (46). Reactive oxygen species cause oxidative damage to the sarcoplasmic reticulum, regulatory proteins of the sarcolemma, and myofilaments (46, 47, 52). Oxidative damage to the myofilaments is thought to blunt the response of the myofilaments to calcium activation (47). This mechanism enables tumor necrosis factor-α to cause muscle weakness in the absence of overt protein loss (47). Generation of reactive oxygen species by the cyclooxygenase pathway probably mediates the impaired neuromuscular transmission that follows administration of tumor necrosis factor-α (46).
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 ) and increase (secondary to increase in protein synthesis and protein breakdown ). The conflicting data may reflect differences in patient selection (severely malnourished  versus well-nourished patients ) 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-α is thought to cause the skeletal muscle apoptosis (and thus muscle atrophy) in underweight patients with COPD (56, 57).
It can take months of refeeding for muscle mass to return to normal values (58). Refeeding of malnourished rats for 5 weeks resolves the atrophy of diaphragmatic Type IIa fibers (58). Refeeding for up to 9 weeks, however, does not resolve the atrophy of the Type IIb and IIx fibers (58). Growth hormone combined with refeeding can normalize atrophic fibers within 5 weeks in rats (58). The positive response is paralleled by a rise in the insulin-like growth factor (58).
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-α have not been conducted in malnourished patients with COPD.
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.
Steroid myopathy can present as an acute or chronic process (44). Glucocorticoids occasionally cause acute myonecrosis (62)—most commonly when combined with muscle relaxants (44). Steroid myopathy may be mediated by a decrease in local (diaphragm) and systemic (liver) expression of insulin growth factor, which reduces the production of contractile proteins and increases the turnover of biochemical substrates (63). Other potential mechanisms include increased catabolism of myofibrils (64), impaired glycolytic activity, slowing of cross-bridge kinetics (44), and decreased expression of the sarco-endoplasmic reticulum calcium-adenosine triphosphatase (SERCA)-type pumps (a key protein pump for calcium kinetics during muscle relaxation following contraction, which scavenges calcium from the cytosol) (65, 66). Atrophy may also result from activation of the ubiquitin–proteasome pathway through the release of ubiquitin ligases such as MuRF1 and MAFbx (64). Steroid myopathy affects mainly Type IIb fibers (44, 67, 68) (Table 1).
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.
The ability of the respiratory muscles to sustain an increased inspiratory load critically depends on two ratios: respiratory duty cycle (inspiratory time divided by the time of a total respiratory cycle) and mean transdiaphragmatic pressure per breath divided by maximum static transdiaphragmatic pressure (73). The product of these ratios is termed the tension–time index. When an inspiratory load causes the tension–time index of the diaphragm to exceed 0.15 (73) or that of the rib cage muscles to exceed 0.30 (74), the load cannot be sustained indefinitely (task failure). Healthy subjects breathing at rest have a diaphragmatic tension–time index of 0.02 (eightfold reserve before task failure) (73). Stable patients with COPD have a diaphragmatic tension–time index of 0.05 (range, 0.01 to 0.12) during resting breathing (73). Patients with COPD have nearly a twofold higher discharge frequency of phrenic nerve motor neurons (75) and fivefold greater diaphragmatic recruitment than do healthy subjects during resting breathing (76).
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).
Rib cage–abdominal motion is commonly abnormal in patients with COPD and appears to indicate a poor prognosis. Best recognized is the inward motion of the lateral rib cage during inspiration with normal anteroposterior expansion (80). The extent of lateral in-drawing of the rib cage (Hoover's sign) increases in proportion with inspiratory drive and disease severity (80). This paradoxic motion is greatest at the time that pleural pressure is most negative and transdiaphragmatic pressure is at its peak. The distortion appears to be primarily related to increased airway resistance, because acute hyperinflation alters rib cage–abdominal motion minimally in healthy subjects (81). Hoover's sign is probably caused by more negative intrathoracic pressure rather than direct traction by the flattened diaphragm on the lateral rib margins.
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).
More than half of patients with severe COPD actively recruit their transversus abdominis muscle during resting breathing (88). The resulting phasic rise in abdominal pressure contributes to the generation of intrinsic PEEP (84). Recruitment of the expiratory muscles is likely part of the constrained response of the respiratory centers to increased ventilatory demands. In healthy subjects, expiratory muscle recruitment helps inspiration because the active reduction in end-expiratory lung volume stores elastic energy in the diaphragm and abdomen. At the end of exhalation, the transversus abdominis relaxes and the release of stored energy causes intrathoracic pressure to fall and inspiratory flow to start before the diaphragm begins to contract. About 60% of patients with COPD have expiratory flow limitation (12), which hinders the expiratory muscles from lowering lung volume and, thus, patients cannot benefit from this effect on the expiratory muscles. Expiratory muscle recruitment might also aid inhalation by causing lengthening of the diaphragm, which improves its length–tension relationship. Yan and coworkers (89), however, reported that the pressure-generating capacity of the diaphragm was not influenced by 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).
The mechanism of the hypercapnia in patients with COPD is incompletely understood. Incriminating factors include respiratory muscle function (90), configuration of the diaphragm (91), respiratory mechanics (90), gas exchange (90), respiratory drive, and resetting of the carbon dioxide tension (Pco2) threshold (92). Progressive airflow obstruction (90) could cause hypercapnia despite a combination of preserved pressure output from the respiratory muscles and an increased drive (93).
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.
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).
An imbalance between oversized (hyperinflated) lungs and a relatively small rib cage is primarily responsible for abnormal respiratory muscle function in patients with COPD. Accordingly, reducing the volume of the lungs should improve the match between the lungs and the rib cage and the capacity of the respiratory muscles to generate pressure.
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 can improve quality of life and exercise capacity in patients with end-stage emphysema. It is not clear whether lung transplantation prolongs life in patients with end-stage emphysema (120) or not (121).
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 ), 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.
Airway resistance is twice the normal value in patients who stop bronchodilator therapy for at least 24 hours during a remission (8). Resistance is increased threefold or higher in patients with chronic persistent asthma (138), and it may be increased more than 10-fold during acute bronchoconstriction (8, 139). Increase in respiratory work contributes to the sense of effort but not to the sense of chest tightness that accompanies acute bronchoconstriction in patients with asthma (140, 141).
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.
The intermittent nature of the respiratory load may have a training effect and also allows the respiratory muscles to recover between exacerbations. Some patients display increases in inspiratory muscle strength and endurance (144). After histamine inhalation, an increase in end-expiratory volume by 112 to 123% of the prechallenge value (145) does not decrease inspiratory muscle strength (corrected for hyperinflation) or endurance (in absolute values) (145). A consistent effect on expiratory muscle strength has not been reported (146).
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 β2-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).
Inhaled and systemic glucocorticoids represent the mainstream therapy of patients with asthma. Although decreasing airway inflammation, inhaled glucocorticoids enhance the perception of inspiratory muscle effort during histamine-induced bronchoconstriction (154). The effect of glucocorticoids on respiratory muscle function is discussed in detail in the section on COPD.
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.
Maximal inspiratory pressure and transdiaphragmatic twitch pressure elicited by phrenic nerve stimulation are about 20 to 30% below normal in patients with chronic heart failure (32). Many (157), but not all (158), investigators have reported that the degree of respiratory muscle weakness parallels the severity of cardiac dysfunction in patients with chronic heart failure. Reductions in maximal inspiratory pressures often exceed reductions of maximal expiratory pressures (32, 158). Several mechanisms are responsible for the inspiratory muscle weakness. First, the total number of diaphragmatic actin–myosin cross-bridges is decreased in a hamster model of heart failure (159). Second, Type IIb fibers, which had been reported by some investigators to produce 1.5 to 2.0 times more force than Type I fibers (160), are fewer in patients (161). Third, the cross-sectional area of all types of fibers of the diaphragm and rib cage muscles is reduced in patients (162) and in a pig model of heart failure (163); potential mechanisms include decreased regional blood flow (164) and activation of the ubiquitin–proteasome proteolytic pathway by tumor necrosis factor (165) (Figure 1). Fourth, diaphragmatic fibers have structural abnormalities (162); these are more frequent in patients with idiopathic dilated cardiomyopathy than in patients with ischemic cardiomyopathy (162), explaining the greater respiratory muscle weakness of the former (158). Fifth, voluntary drive to the diaphragm during maximal inspiratory efforts is probably decreased in patients (166). The resting length of muscles (as indirectly quantified by the normal or decreased value of functional residual capacity) is not decreased and thus cannot explain the inspiratory muscle weakness. The last consideration must be viewed cautiously because the volume of the chest (which determines muscle length) may be greater than intrathoracic gas volume in heart failure.
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).
In patients with chronic heart failure, exercise increases the duty cycle (by decreasing expiratory time) and decreases lung compliance (173). As a result, the tension–time index of the diaphragm at peak exercise is 0.10 in patients with advanced heart failure versus 0.03 in healthy subjects (166). Maximal oxygen consumption during exercise correlates with maximal inspiratory pressure (174). At the end of maximal exercise, patients have decreases in maximal inspiratory (166, 174) and expiratory pressures (166) (all suggestive of fatigue). The decrease in maximal inspiratory pressure lasts longer (at least 10 minutes) in patients who display a lower oxygen consumption at peak exercise and slower decline in oxygen consumption just after exercise, suggesting decreased recovery of their energy stores (174).
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 muscle unloading, which helps to redistribute blood flow from respiratory muscles to limb muscles—as noted in healthy subjects during exercise (178). This redistribution of blood flow is likely mediated by a metabolic reflex (acidosis) from the contracting muscle (178).
Abnormalities of the respiratory muscles that cause acute respiratory failure can be divided into disorders causing an increased load or a decreased neuromuscular capacity.
Patients in acute respiratory failure usually experience an increased mechanical load (7). The patients typically have a 30 to 50% greater inspiratory resistance (7), 100% greater dynamic elastance (7), and 100 to 200% greater intrinsic PEEP (7, 179) than do similar patients who are not in acute respiratory failure. Inspiratory effort is almost equally divided in offsetting intrinsic PEEP, elastic recoil, and inspiratory resistance (7). Abnormal mechanics arise from bronchoconstriction, bronchial edema, pulmonary edema (7), and lung inflammation. Rapid shallow breathing can aggravate the abnormalities in lung elastance, intrinsic PEEP, and carbon dioxide clearance (7). Expiratory muscle recruitment can also increase intrinsic PEEP and breathing effort (116, 179). Increased ventilatory requirements can result from increased carbon dioxide production, increased deadspace ventilation, and elevated respiratory drive. An increase in either carbon dioxide production or in deadspace can be only contributory factors and not the sole causes of hypercapnic respiratory failure.
Respiratory muscle weakness leading to hypoventilation may result from hyperinflation, neuropathies, myopathies, metabolic abnormalities, decreased oxygen delivery, and medications. The myopathies are subdivided into several categories that include critical illness myopathy, sepsis-associated myopathy, ventilator-associated respiratory muscle damage, disuse atrophy, metabolic disturbances, and medications (180, 181).
Tachypnea and the associated shortening of expiratory time can prevent complete lung emptying, leading to dynamic hyperinflation (182, 183). Dynamic hyperinflation is common in patients experiencing an exacerbation of COPD, and it also occurs in patients with pneumonia, acute respiratory distress syndrome, and chest trauma (183, 184). The functional consequences of dynamic hyperinflation are probably the main causes of ventilatory failure in patients with COPD (184). Impairment of inspiratory muscle function, however, is less likely in patients with acute respiratory distress syndrome because these patients breathe at a low lung volume despite dynamic hyperinflation.
Neuromuscular Conduction Defect
|Compound muscle action potential, amplitude*||Reduced||Normal to slightly reduced||Normal†||Normal|
|Sensory nerve action potential, amplitude‡||Reduced||Normal to reduced||Normal||Normal|
|Conduction velocity||Normal to slightly reduced||Reduced||Normal||Normal|
|Spontaneous muscle depolarization§||Present||Absent||Absent||None to present|
|Amplitude of compound muscle action potential with stimulation at 3 Hz¶||Unchanged||Unchanged||Decreased||Unchanged|
|Motor unit activation||Decreased||Decreased||Normal||Increased|
In prospective studies, the electrophysiologic incidence of critical illness polyneuropathy was 76% in patients with septic shock (187), and it ranged from 63 to 75% in mechanically ventilated patients with sepsis and multiple organ dysfunction syndrome (188). Electrophysiologic evidence can appear as early as 3 days after the onset of septic shock (187). Critical illness polyneuropathy, defined as clinically significant muscle weakness in patients who achieve satisfactory awakening after at least 7 days of mechanical ventilation, has an incidence of 25% (186). Clinical signs of the polyneuropathy disappear or improve in about 60% (189) to 90% (186) of patients who survive intensive care. More than one-third of patients with severe involvement (quadriparesis and quadriplegia) display motor impairment after 2 years (190) (Table 3)
Critical Illness Polyneuropathy
Critical Illness Myopathy
Spinal Cord Lesion
|Progression||Days to weeks||Days to weeks||Days to weeks||Slow or immediate||Days to weeks||Hours to days||Days|
|Evolution of motor deficit||Usually ascending||Generalized||Generalized||Focal||Asymmetric||Ascending||Descending|
|Tendon reflexes||Absent||Reduced or absent||Reduced or absent||Variable||Absent||Absent||Reduced or absent|
|CSF: Protein||High||—||Normal||Normal or high||High||Normal||—|
|CSF: White cells (per mm3)||< 10||—||—||Variable||> 10||< 10||—|
|Recovery time||Weeks to
no recovery||Weeks to
no recovery||Weeks to
to etiology||Months to
years or no
recovery||< 24 h (North
> 2 wk
The axonal degeneration is thought to result from release of cytokines in patients with sepsis and multiple organ failure (180). Critical illness polyneuropathy, however, has also been reported in mechanically ventilated patients without evidence of sepsis or multiple organ failure (180, 181). Tight control of hyperglycemia reduces the risk of polyneuropathy and the duration of mechanical ventilation (191).
The importance of critical illness polyneuropathy in causing ventilatory failure is controversial. In nine mechanically ventilated patients who had features of critical illness polyneuropathy at death (192), mild axonal degeneration of the phrenic and intercostal nerves and denervation atrophy of the respiratory muscles were seen at autopsy. It is not clear that the polyneuropathy caused the respiratory failure because the patients also had other active pulmonary pathologies (pulmonary infarct, bronchopneumonia, abscess, and emphysema). In a prospective study of 73 septic patients with multiple organ dysfunction syndrome (188), the duration of mechanical ventilation was longer in patients with critical illness polyneuropathy (32 days) than in patients without the polyneuropathy (19 days).
Two large studies (193, 194) have raised questions about the impact of critical illness polyneuropathy on respiratory muscle function and ventilatory failure. Of 102 difficult-to-wean patients, 44 had critical illness polyneuropathy, and 24 of these patients had diaphragmatic denervation (193). In 15 of the 24 patients, however, diaphragmatic denervation was explained by disorders other than the polyneuropathy (193). In a study of 38 patients (194), duration of mechanical ventilation was greater in patients with critical illness polyneuropathy than in patients without the polyneuropathy. The clinical course, however, suggested that the severity of multiple organ failure, not the polyneuropathy, was responsible for the prolonged mechanical ventilation (194). Indeed, the polyneuropathy was present in two of four patients who sustained spontaneous respiration within 2 days of the first weaning attempt (194). In another study (195), the polyneuropathy was present in 3 of 13 patients who had no weaning difficulties. The risk of developing the polyneuropathy is 24 times greater in patients with severe encephalopathy (188), suggesting that the polyneuropathy is a manifestation of a more generalized neurologic impairment in patients with multiple organ dysfunction syndrome. It is controversial whether critical illness polyneuropathy increases length of stay (intensive care unit or hospital) or mortality by itself (189).
More than two-thirds of mechanically ventilated patients who receive glucocorticoids and neuromuscular blocking agents for more than 2 days develop prolonged weakness (quadriparesis) or paralysis (quadriplegia) in the absence of critical illness polyneuropathy (62, 196). Electrophysiology reveals features of myopathy (62) (Table 2). The condition is described by various names: critical illness myopathy, thick filament myopathy, acute quadriplegic myopathy, and acute necrotizing myopathy of intensive care (180). It is not known whether the prevalence of critical illness myopathy is greater or less than that of critical illness polyneuropathy (181, 186, 197). Both can coexist in the same patient (180, 181, 186, 198).
Critical illness myopathy is less strongly associated with sepsis and multiorgan dysfunction than is critical illness polyneuropathy (62, 180, 181, 198). Critical illness myopathy is most commonly reported in patients with severe asthma (62), but it also occurs in patients with COPD, solid organ transplants, leukemia, or lymphoma who received glucocorticoids and neuromuscular blocking agents (198, 199). Rarely, it occurs in patients receiving glucocorticoids alone, neuromuscular blocking agents alone, or neither agent (198–200).
Electromyography cannot always distinguish critical illness myopathy from critical illness polyneuropathy, and muscle biopsies may be needed (181, 197). Biopsies reveal a general decrease in myofibrillar protein content (196) and a selective loss of thick filaments (myosin) within Type I and Type II fibers in up to 79% of patients who receive glucocorticoids for more than 2 weeks (200). Other findings include patchy necrosis and regeneration (78%), mild myopathy (14%), and atrophy of Type I and Type II fibers (7%) (200). Serum creatine phosphokinase may be normal, probably because the myopathy has a gradual onset (198).
To study the underlying mechanism, Rouleau and coworkers (201) administered glucocorticoids to rats with denervated muscles. The rats developed muscle atrophy with loss of thick filaments (myosin); rats with denervation alone or receiving glucocorticoids alone did not. The results suggest that upregulation of glucocorticoid receptors in a paralyzed muscle increases the catabolic effect of glucocorticoids and contributes to critical illness myopathy (180).
Glucocorticoids can directly or indirectly cause proteolysis of myosin filaments by activating calpain (a calcium-activated protease), cathepsins, lysosomal acid proteases, and the ubiquitin–proteasome pathway (a cytosolic ATP-dependent protease system) (202) (Figure 5). During the acute phase of critical illness myopathy, a decrease in myosin content might also result from reduced myosin transcription (196). Although a decrease in thick-filament proteins may be important for prolonged weakness (196), it is probably not the cause of the acute paralysis (199), particularly in patients with compound motor action potentials of low amplitude (197). Impaired muscle membrane excitability is probably more important during the acute stage (199).
Some investigators (67) have reported that patients with clinical evidence of myopathy experience a longer duration of mechanical ventilation: 13 versus 3 days. Others report that prolonged mechanical ventilation is rare: less than 5%, even in patients with quadriparesis (62). Titrating the dose of neuromuscular blocking agents using train-of-four monitoring does not decrease the incidence of critical illness myopathy (62). The functional outcome is unclear. Some authors report that patients generally experience an improvement in strength, with half returning to normal over a period of 2 weeks to 6 months or longer (62, 196). Others report a worse outcome: only 2 of 10 patients left the hospital in one report (198).
Sepsis can produce ventilatory failure because of respiratory muscle dysfunction and increased metabolic demands (203). Septic animals develop failure of neuromuscular transmission (because of an elevated of muscle membrane potential), and failure of excitation–contraction coupling (203, 204). Mechanisms include the cytotoxic effect of nitric oxide and its metabolites, free radicals, and ubiquitin–proteasome proteolysis (203, 205).
Endotoxemia (206, 207) and septic (207) or aseptic (208) peritonitis can increase the expression of constitutive and inducible forms of nitric oxide synthase in the diaphragm (203, 207). Endotoxemia and sepsis also induce mitochondrial dysfunction, sarcolemmal injury (Figure 6), and weakness and fatigability of the diaphragm (203, 207–209). This dysfunction and sarcolemmal injury can be largely prevented by nitric oxide synthase inhibitors, such as N-monomethyl l-arginine (206, 207) or S-methylisothiourea (209), or by pretreatment with dexamethasone, which prevents the expression of inducible nitric oxide synthase (206) (Figure 7) .
To determine whether the inducible nitric oxide synthase pathway contributes to impaired skeletal muscle contractility in sepsis, Lanone and coworkers (210) obtained samples of the rectus abdominis in 16 septic patients and 21 control subjects. The muscles of the patients had lower contractile force, and increases in inducible nitric oxide synthase expression (mRNA and protein) and activity. Immunohistochemical studies revealed the generation of peroxynitrite (a highly reactive oxidant formed by the reaction of nitric oxide with superoxide anion). Exposure of control muscles to the amount of peroxynitrite found in patients caused an irreversible decrease in force generation. These data suggest that sepsis decreases muscle force through the production of nitric oxide and its toxic by-products.
Production of nitric oxide in sepsis may be protective and not solely deleterious (211–213). In mice deficient in inducible (211) or constitutive (neuronal) nitric oxide synthase (212), endotoxin caused a greater decline in diaphragmatic contractility than in nondeficient mice. This finding contrasts with the observation that nitric oxide synthase inhibitors prevent muscle dysfunction in septic rats (206, 207, 209). Although the results may be species dependent (212), the data underscore that nitric oxide has both antioxidant and prooxidant actions.
Diaphragmatic contractions enhance sepsis-induced sarcolemmal injury in animals (212). Early mechanical ventilation decreases the sarcolemmal injury (214) and associated diaphragmatic dysfunction (214). The production of reactive oxygen species is also increased during diaphragmatic contractions (215), although mechanical ventilation does not decrease oxidative stress in the septic diaphragm (214) or expression of inducible nitric oxide synthase (214).
In addition to nitric oxide and its derivatives, several other oxygen-derived free radicals (superoxide anion, hydroxyl radicals, hydrogen peroxide) contribute to the decreased contractility of the diaphragm in sepsis (213, 216, 217). Sepsis is also associated with the enhanced activity of the antioxidant enzyme superoxide dismutase (216) and with the increased expression of the heme oxygenase-1 pathway (217). The heme oxygenase-1 pathway is a powerful cellular system that protects against oxidative stress and contractile fatigue during sepsis (217). Administration of an inhibitor (zinc protoporphyrin IX) or an inducer (hemin) of heme oxygenase activity, respectively, enhances or reduces the oxidative stress and contractile failure of the diaphragm in an animal model of sepsis (217). Decreased diaphragmatic contractility can also be improved by the administration of specific scavengers of superoxide ions, hydrogen peroxide, and hydroxyl radicals (216).
Muscle catabolism is a hallmark of sepsis and results from accelerated breakdown of myofibrillar proteins, such as actin and myosin (165). This catabolism occurs primarily in Type II muscle fibers (202, 218). The breakdown probably results from activation of the ubiquitin–proteasome proteolytic pathway (Figure 5) secondary to release of tumor necrosis factor (Figure 1), interleukin-1, and interleukin-6 (165, 202). The protein breakdown is almost prevented by pretreatment with a glucocorticoid receptor antagonist (RU 38,486) (202), suggesting that endogenous glucocorticoids regulate sepsis-induced proteolysis (165). Threefold to fourfold increases in messenger RNAs of the ubiquitin–proteasome proteolytic pathway were found in the rectus abdominis muscle of septic patients (218).
Rats ventilated for 1 day (219) to 2 days (220, 221) have a 50% or greater decrease in diaphragmatic force generation. The reduction in force is out of proportion to the decrease in diaphragmatic mass (10 to 20%) (220, 221) and cross-sectional area of muscle fibers (23 to 28%) (221). Similarly, 3 to 4 days of controlled ventilation decreases diaphragmatic force by more than 50% in rats (221) and rabbits (222). The decrease in force is related to the extent of myofibril damage (r = 0.82) (222). In rats, the decrease in force is associated with a decrease in fibers expressing Type I myosin isoform and an increase in hybrid fibers coexpressing Type I and Type II myosin isoforms (221). In rabbits, the decrease in force is associated with increased expression of Type IIa myosin heavy chains and mitochondrial swelling (222) (Figure 8). Five days of mechanical ventilation produces a 20% decrease in diaphragmatic strength in piglets and a 30% decrease in the amplitude of compound action potentials evoked by phrenic nerve stimulation (223).
Studies of the effect of mechanical ventilation on respiratory muscle function suffer from the relatively short periods of mechanical ventilation (219, 220, 222, 223), tonic shortening of muscle secondary to external PEEP (219, 221), passive shortening during tidal ventilation, use of neuromuscular blocking agents (221, 224), and development of pneumonia (224). Nevertheless, the emerging data suggest that mechanical ventilation can damage respiratory muscle (225). Likely mechanisms for the damage include activation of ubiquitin–proteasome proteolysis (226), calpain proteolysis (non-ubiquitin–proteasome system) (226), and oxidative stress (226, 227). Use of dantrolene to prevent an increase in intracellular calcium (which is necessary for calpain-mediated proteolysis) or use of antioxidants might prevent the muscle damage resulting from mechanical ventilation (227).
Few data exist on the effects of prolonged mechanical ventilation on the human diaphragm. In a retrospective study of 13 infants who received uninterrupted ventilator assistance for at least 12 days before death, most diaphragmatic fibers appeared atrophic (228). The development of atrophy was suggested by a smaller diaphragmatic muscle mass in these infants than in 26 infants who died after receiving mechanical ventilation for 7 days or less (228).
Weakness can result from medications that have a direct myotoxic effect, such as blockade of myocyte glycoprotein synthesis and electron transport caused by inhibitors of the hydroxymethylglutaryl coenzyme A reductase or nucleoside analogs in patients with human immunodeficiency virus (229). Weakness can also result with neuromuscular blocking agents and aminoglycosides, which interfere with neuromuscular transmission (230).
Paralysis, including the respiratory muscles, can persist after discontinuation of neuromuscular blocking agents (230–232). Prolonged neuromuscular blockade has been defined as 2 hours (230), 4 hours (232), or 6 hours (231) of paralysis after discontinuation of neuromuscular blocking agents. Prolonged blockade is estimated to occur in 12 to 44% of patients receiving pancuronium or vecuronium for one or more days (230–232). The risk with vecuronium is increased in patients with renal failure (230, 232). Accumulation of metabolites of the neuromuscular blocking agents is responsible for the prolonged blockade (230). Recovery begins within 2 days of the last dose (230, 231), in contrast to the prolonged course of critical illness myopathy or neuropathy (62, 190, 196). Train-of-four monitoring of the dose of a neuromuscular blocking agent with a peripheral nerve stimulator may hasten recovery (232).
Contractile fatigue occurs when a sufficiently large respiratory load is applied over a sufficiently long period (14, 233–235). Contractile fatigue can be brief or prolonged. Short-lasting fatigue results from accumulation of inorganic phosphate (236), failure of the membrane electrical potential to propagate beyond T-tubes, and to a much lesser extent intramuscular acidosis (237, 238). Short-lasting fatigue appears to have a protective function, because it can prevent injury to the sarcolemma caused by forceful muscle contractions (239). Long-lasting fatigue (234) is consistent with the development of, and recovery from, muscle injury (239, 240). Load-induced injury occurs in two phases: an acute injury immediately after muscle contraction (239) and a delayed or secondary injury (241).
Immediately after intense loading, muscles display apoptosis (242), vacuolization of the sarcoplasmic reticulum, sarcoplasmic damage, loss of the normal alignment between adjacent myofibrils, sarcomeric disruption (243, 244), and Z-band streaming (244) (Figure 9). Z-band streaming is attributed to a loss of protein elements in the Z-band, such as α-actinin and vimentin (244). Several mechanisms may contribute to the acute injury. These include eccentric contractions (contraction of a muscle while it is stretched by external forces) (239, 245–247), activation of calpain (a calcium-dependent nonlysosomal protease) (241, 244), increased muscle temperature (248), and excessive production of reactive oxygen species (52, 215, 235, 244, 249). Reactive oxygen species are, however, essential for normal force production (52), probably because they maintain an adequate redox state of sarcoplasmic reticulum proteins (52). Hypercapnia, a decrease in diaphragmatic length (hyperinflation), and a decrease in inspiratory muscle force can reduce superoxide release, and thus protect the diaphragm from excessive damage and fatigue (215). Strenuous muscle contractions also activate heme oxygenase (250) (a microsomal enzyme of the inducible heat-stress protein family), which has a defensive role against oxidative stress (217). The role of nitric oxide derivatives in oxidative stress and fatigue is controversial (52).
Delayed or secondary injury of the diaphragm is characterized by focal necrosis, flocculent degeneration of the sarcoplasm, influx of inflammatory cells (resistive loading in rabbits [240, 251]), and sarcolemma disruption (resistive loading in dogs ). The injury occurs days after exposure to a high-intensity load sustained over a couple of hours (240, 251), or moderate-intensity loading applied intermittently over several days (252). Delayed diaphragmatic injury is proportional to the load (240) and peaks 3 days after applying the load (threshold loading in rats ). The injury involves 7 to 9% of the diaphragm (240, 251), and it is accompanied by disruption of the sarcolemma (252) and sarcomeres (252). Delayed injury decreases diaphragmatic force production at rest and it increases fatigability (240, 251). The decrease in force production depends on the intensity of the preceding load (240). Free radicals, already present during acute injury, are still being produced 3 days after loading (251). Free radical scavengers, however, do not completely prevent the loss of diaphragmatic force associated with delayed injury (251), indicating that other mechanisms are involved.
In limb muscles, a repair process begins within 12 hours of the muscle injury that results from excessive load (253). Satellite cells proliferate, differentiate, and fuse with existing myofibers (253). Insulin-like growth factor I, hepatocyte growth factor, and fibroblast growth factor appear to modulate this response (253). Repair may explain the lessening of diaphragmatic injury between the third and fourth day after loading (threshold loading in rats) (241).
Modest intermittent resistive loading (2 hours/day over 4 days) can disrupt sarcomeres and the sarcolemma of diaphragmatic fibers in dogs (252). The sarcolemma disruption involves more Type I than Type II fibers (252). This mechanism may occur in patients. The proportion of abnormal fibers in the diaphragm was correlated with airflow obstruction in 21 patients with FEV1 ranging from 16 to 122% of predicted (254). Abnormalities consisted of myofibers with internally located nuclei, lipofuscin pigmentation (sign of oxidative stress), small angulated fibers, inflammation, and necrosis; these abnormalities occupied 4 to 34% of the diaphragm (254) (Figure 10). Sarcomere disruption has been reported in 18 patients with COPD (243). The density and area of disruptions in the patients were twice that seen in 11 control subjects, and they were correlated with FEV1 and hyperinflation (243). Diaphragmatic damage has been reported in patients dying of asphyxia, sudden infant death syndrome, and status asthmaticus (67, 255).
Whether or not critically ill patients develop either short-lasting or long-lasting contractile fatigue of the respiratory muscles has not been clear. Patients who fail a trial of weaning from mechanical ventilation are at particular risk of developing fatigue because they experience marked increases in respiratory load (7, 256, 257). The addition of a new injury to the respiratory muscles (secondary to the development of contractile fatigue) might be the ultimate determinant of whether or not some patients are ever successfully weaned.
Laghi and coworkers (179) measured the contractile response of the diaphragm to phrenic nerve stimulation in nine patients who failed a weaning trial; seven patients who were successfully weaned served as control subjects. The weaning failure patients experienced a greater respiratory load and developed greater diaphragmatic effort than did the weaning success patients. Nevertheless, not a single patient developed a decrease in transdiaphragmatic twitch pressure elicited by phrenic nerve stimulation. The failure to develop fatigue is surprising because seven of the nine weaning failure patients had a tension–time index above 0.15.
The most likely reason that patients did not develop fatigue is because physicians reinstituted mechanical ventilation before there was enough time for its development. The relationship between tension–time index and the length of time that a load can be sustained until task failure follows an inverse-power function. Bellemare and Grassino (258) expressed the relationship as: time to task failure = 0.1 (tension–time index)–3.6. The increase in tension–time index over the course of the weaning trial (179) and predicted time to task failure (258) are shown in Figure 11. At the point that the physician reinstituted mechanical ventilation, patients were predicted to be an average of 13 minutes away from task failure. In other words, patients display clinical manifestations of severe respiratory distress for a substantial time before they would develop fatigue. In an intensive care setting, these clinical signs will lead attendants to reinstitute mechanical ventilation before fatigue has time to develop.
Respiratory muscle weakness frequently goes undetected in patients with neuromuscular disease until ventilatory failure is precipitated by aspiration pneumonia or cor pulmonale. Diagnosis is delayed because limb muscle weakness prevents patients from exceeding their limited ventilatory capacity (259). A few patients develop severe respiratory muscle weakness despite little or no peripheral muscle weakness (260).
Severe weakness of the inspiratory muscles produces a restrictive pattern: decreases in VC, total lung capacity, and functional residual capacity, with a relatively normal FEV1/FVC ratio. Provided the expiratory muscles are not weak, residual volume remains relatively normal. Diffusing capacity, corrected for alveolar ventilation, is normal in patients with respiratory muscle weakness, but it can also be normal in patients with pulmonary fibrosis (261) and is of limited value in differentiating the two conditions. VC is normal, or only minimally reduced, if respiratory muscle strength is more than 50% of predicted (262). This finding results from the sigmoid shape of the pressure–volume relationship of the respiratory system. When strength is less than 50% of predicted, however, the loss in VC is greater than expected (262, 263). The decrease is secondary to the associated decrease in compliance of the chest wall and lungs (263, 264). The latter has been attributed to diffuse microatelectasis. Evidence of atelectasis on high-resolution computed tomography, however, was found in only 2 of 14 patients with neuromuscular disorders who had a 30% decrease in lung compliance (263). The decreased chest wall compliance probably results from stiffening of tendons and ligaments of the rib cage, and ankylosis of the costosternal and thoracovertebral joints.
Patients with respiratory muscle weakness take rapid shallow breaths (264), possibly as a result of afferent signals in weakened respiratory muscles, intrapulmonary receptors, or both (264, 265). PaCO2 may be reduced early in the disease (266), but hypercapnia is likely when respiratory muscle strength falls to 25% of predicted (267). Reduction in strength, however, does not consistently predict alveolar hypoventilation, because factors such as elastic load and breathing pattern also contribute (264). Abnormalities in respiratory muscle performance and in alveolar ventilation may initially be evident only during exercise (268) or sleep (269, 270). When inspiratory strength and VC are 50% of predicted, hypoventilation can occur with minor upper respiratory tract infections.
Patients with neuromuscular diseases, irrespective of the primary pathology (269, 271, 272), commonly develop abnormalities during sleep: frequent arousals, increased Stage 1 sleep, decreased rapid eye movement sleep, hypoventilation, and hypoxemia (273). Patients with diaphragmatic weakness or diaphragmatic paralysis are at particular risk of developing hypoventilation during rapid eye movement sleep (270, 273–275). To decrease this likelihood, the central nervous system can adopt two strategies: phasic recruitment of inspiratory muscles other than the diaphragm during rapid eye movement sleep (269), or suppression of rapid eye movement sleep (269, 270, 276). The failure of all patients to develop these adaptive strategies may explain discrepancies among reports on oxygenation during sleep in patients with isolated diaphragmatic paralysis (270, 275, 277).
Sleep-disordered breathing usually precedes, and probably contributes to, daytime ventilatory failure (92, 271, 272, 276, 278–281). Patients commonly report symptoms of nocturnal hypoventilation and sleep disruption (insomnia, morning headache, daytime somnolence, decreased intellectual performance) (281, 282). Sleep-disordered breathing usually develops when VC in the supine position is less than 60% of the predicted value (280) or maximal inspiratory pressure is less than 34 cm H2O (280). The degree of abnormality parallels the extent of respiratory weakness (280). Hypopneas and apneas in neuromuscular disorders can be central, pseudo-central (inspiratory effort too weak to be identified), or obstructive (276, 278, 283–285). The central events result from involvement of the central nervous system. Obstructive events typically result from weakness of the upper airway musculature (270, 286). Hypoventilation and daytime hypercapnia may be aggravated by resetting of the chemoreceptors during sleep, which is reversible with chronic nocturnal ventilation (92).
Hypopneas predominate in the early stage of a neuromuscular disease (280). As the respiratory muscle weakness progresses, hypopneas tend to be replaced by more prolonged episodes of hypoventilation that are not captured by the apnea–hypopnea score (280). Accordingly, apnea–hypopnea scores can underestimate the effect of nocturnal hypoventilation on quality of life or functional status (276). Sleep disruption in patients with neuromuscular diseases may also result from an inability to change position during sleep, muscle twitches, and leg jerks (272).
Noninvasive ventilation improves sleep-disordered breathing, quality of life, and survival in nonprogressive or slowly progressive neuromuscular diseases, such as myotonic dystrophy and Duchenne's muscular dystrophy (271, 282). It is probably also beneficial in more rapidly progressive diseases, such as amyotrophic lateral sclerosis (287–290). The optimal time for initiating noninvasive ventilation and the role of polysomnography or nocturnal oximetry in guiding management are not known (273, 291).
Some authors recommend sleep studies when abnormalities of spirometry or daytime arterial blood gases are first seen (271, 272, 279–281, 292). Data do not exist to support the use of sleep studies as compared with symptoms and daytime respiratory function in selecting patients for noninvasive ventilation (273, 284, 293, 294). For example, orthopnea is a better predictor of benefit from noninvasive ventilation in patients with amyotrophic lateral sclerosis than is the apnea–hypopnea index and sleep disruption (293). These observations are consistent with the knowledge that nocturnal saturation is a less accurate predictor of survival as compared with daytime lung function (284, 294).
The following discussion of specific neuromuscular disorders is arranged by the level of anatomical involvement.
Two main descending pathways control the lower motor neurons that innervate the respiratory muscles: the corticospinal (pyramidal) and bulbospinal tracts (Figure 12)(295). The pyramidal tract is responsible for voluntary control of breathing. Because the pyramidal motor neurons for respiration are spread over a large area of the cortex, most vascular accidents of the cortex do not cause significant diaphragmatic impairment (295, 296). On reaching the internal capsule, the pyramidal fibers become densely aggregated, and even a small capsular infarct can cause extensive damage to the pyramidal respiratory fibers (295, 296). Using cranial magnetic stimulation, Similowski and coworkers (295) and Khedr and coworkers (296) found that patients with capsular lesions had asymmetrical latencies for each hemidiaphragm (responses were markedly delayed or absent on the paralyzed side). The results indicate that each hemidiaphragm is separately represented in the opposite cortex. De Troyer and coworkers (297), however, found that patients with hemiplegia have a reduced, although not absent, electromyogram of the diaphragm and intercostal muscles on the paralyzed side during voluntary inhalation. Some diaphragmatic depolarization may have arisen because the patients may have had a hemispheric rather than true capsular infarct or secondary to activation of an excitatory phrenic-to-phrenic reflex, which mirrors the well-known inhibitory phrenic-to-phrenic reflex (298). The existence of nondecussating fibers originating within the pyramidal system contralateral to the capsular lesion (299) is a less likely explanation (295).
During resting (automatic) breathing, the hemidiaphragm on the paralyzed side of patients with a dense hemiplegia (compatible with a capsular infarct) moves normally (300). During voluntary inhalation, excursion on the paralyzed side is less than normal (300). Half of the patients display greater excursion of the unaffected hemidiaphragm during voluntary breathing than during resting breathing (300). The increased excursion may result from compensatory increases in neuronal activity in the unaffected side of the brain or from decreased impedance to diaphragmatic descent on the unaffected side. Maximal inspiratory and expiratory pressures in patients with dense hemiplegia are, respectively, 40 and 60% less than in healthy subjects (301). This respiratory muscle weakness is responsible for the decreases in VC and total lung capacity (301) and the increase in residual volume in some patients with capsular stroke (296, 300). Stroke-induced diaphragmatic paralysis per se does not typically cause elevation of the paralyzed hemidiaphragm on a chest radiograph (295, 300).
About one-quarter of patients with an acute hemispheric infarction require mechanical ventilation (302), usually because of impaired consciousness, impaired airway protection, or hypoxemia (302). More than 80% of intubated patients die, mostly because of midbrain herniation (302).
The second descending pathway that innervates the lower motor neurons of respiration is the bulbospinal tract. It is thought to originate in the paramedian reticular formation of the medullary tegmentum and to decussate at or near the upper cervical cord. The bulbospinal tract governs the cyclical contraction of the respiratory muscles responsible for automatic breathing. Brainstem lesions can eliminate automatic control but leave voluntary control intact (Ondine's curse). Brainstem lesions, particularly lateral medullary strokes, can also cause hypoventilation, apneustic breathing, ataxic breathing, and hyperventilation (see Howard and coworkers ).
Although multiple sclerosis commonly causes severe inspiratory and expiratory muscle weakness (304), patients rarely complain of dyspnea (259, 305). The lack of dyspnea may reflect the limited capacity of patients to exert themselves; difficulty in communicating symptoms because of cognitive impairment is a factor later in the course. The expiratory muscles are often weaker than the inspiratory muscles because paralysis ascends from the lower to upper body (259, 304, 306). Demyelination delays the transmission of neural impulses to the diaphragm even before demonstrable respiratory muscle dysfunction. Central fatigue occurs in other skeletal muscles (307), and it may also affect the respiratory muscles. Other causes of respiratory muscle weakness include deconditioning, which decreases the size and oxidative capacity of muscle fibers, steroid myopathy, and the release of tumor necrosis factor-α during exacerbations (308) (Figure 1).
Respiratory muscle weakness parallels systemic functional impairment (305), and contributes to nighttime desaturation (259, 303). During a relapse, respiratory muscle weakness can precipitate hypoxemia and hypercapnia of rapid onset (303). The first episode of respiratory failure is typically about 6 years after the onset of multiple sclerosis (range, 1 to 12 years) (303). Before overt respiratory failure, most patients report progressive dyspnea, orthopnea, and sleep disturbance (303). Hiccups signal medullary involvement in the region of the tractus solitarius, which is intimately associated with respiratory control (303). Respiratory failure can also occur as part of a gradual irreversible decline in respiratory muscle function (303).
Respiratory muscle weakness may result from involvement of the descending respiratory pathways, lower respiratory motor neurons (303), and anterior roots. Because the phrenic motor neurons are in the cervical cord, more than half of patients developing respiratory failure (cervical cord involvement) become quadriplegic during a relapse (303). Other contributors to respiratory failure include conduction block (fever decreases conduction in partially demyelinated fibers), bulbar dysfunction (associated with aspiration), and abnormal control of breathing (apneustic breathing, Ondine's curse, and apnea) (303). Of patients requiring mechanical ventilation during a relapse, about half can be weaned over 1 to 6 weeks (303).
Few treatments are specific for the serious respiratory complications. Intravenous glucocorticoids, plasma exchange, and interferon-β-1a have beneficial effects on the acute disorder, but their effects on respiratory muscle function have not been clearly delineated. Two randomized controlled trials of respiratory muscle training have been reported. Three months of expiratory muscle training produced an increase in expiratory muscle strength of 19 cm H2O as compared with a decrease of 1 cm H2O in a control group (306). In patients with longer lasting (24 versus 14 years) and more severe disease (304), expiratory muscle training tended to enhance the strength of the expiratory muscles and improve cough at 3 months. The improvement in cough lasted more than 6 months (304). Whether respiratory muscle training can decrease respiratory disability and affect clinical outcome is not known.
Inspiratory muscle strength is preserved in early Parkinson's disease (309), but decreases with progression of the disease (310, 311). It falls to about 30% of predicted in patients with advanced disease (310, 311). Inspiratory muscle strength improves during an infusion of apomorphine, a direct stimulant of dopamine receptors, suggesting that inspiratory muscle weakness results from impaired neural drive to the muscles (310).
In contrast to inspiratory muscle strength, inspiratory muscle endurance is decreased in early Parkinson's disease (309). Several factors are likely: one, impaired activation of the motor cortex for the respiratory muscles, limiting performance of repetitive motor tasks; two, a shift in fiber composition from fatigue-resistant Type IIa to more fatigable (and moderately atrophic) Type IIb (312) (Table 1); three, mitochondrial abnormalities; four, lack of coordination between inspiratory and expiratory muscles, involving phasic activity of scalene and intercostals (but not of the diaphragm) throughout the respiratory cycle (313). Phasic activity of these muscles over the entire respiratory cycle increases energy expenditure, contributing to decreased efficiency of breathing (309).
Patients also present with expiratory muscle weakness (311, 314), which is strongly correlated with the degree of clinical disability (314). Among patients with advanced disease, maximal expiratory pressure is about 35% of predicted (310, 311). The weakness results from decreased recruitment of the expiratory muscles (314), and it may contribute to ineffective cough and the high incidence of aspiration pneumonia (314).
About 12% (311) to 24% (315) of patients with Parkinson's disease develop upper airway dysfunction. Dysfunction results from rhythmic or irregular adduction of the vocal cords and supraglottic structures with occasional sudden and intermittent airway closure (316). Irregular adduction can be superimposed on a fixed reduction of the glottic area caused by tonic adduction of the vocal cords (316). The frequency of contraction mirrors that of tremor: 4 to 8 Hz (316). These contractions produce the sawtooth pattern on the flow–volume loop with occasional complete cessation of flow (Figure 13)(316). As much as 40% of patients with a sawtooth pattern present with stridor and develop dyspnea necessitating intubation (316). A sawtooth pattern is found in patients who are more disabled by extrapyramidal involvement (316). Peak expiratory flow may be decreased and delayed (rounding off) (Figure 13) (311) in up to 58% of patients (311). It probably results from impairment of ballistic movements, lack of coordination, and tonic adduction of the vocal cords in some patients. Apomorphine (310) or levodopa (315) can decrease the sawtoothing and rounding off on the flow–volume loop. Upper airway dysfunction may predispose to obstructive sleep apnea in patients with Parkinson's disease. Vocal cord dysfunction, and even frank vocal cord paralysis, has also been reported in multiple system atrophy (Shy-Drager syndrome), a Parkinson-like syndrome that causes progressive degenerative disease of the central nervous system. In patients with multiple system atrophy, vocal cord dysfunction can cause stridor and sudden death during sleep (317).
Chronic levodopa therapy, the mainstream therapy for Parkinson's disease, commonly leads to choreoathetoid movements of the face, mouth, limbs, and trunk (318, 319). An unknown proportion of patients with dyskinesia develop dyspnea and abnormal breathing patterns (rapid shallow breathing, irregular breathing, apneic episodes) (319). Dyskinesia is less common among patients treated with ropinirole, a dopamine D2-receptor agonist, as compared with levodopa, the dopamine precursor (318). Whether the incidence of respiratory dyskinesia is less with the use of ropinirole remains to be determined.
See online supplement.
Spinal cord injuries are common in the industrialized world, especially in young men. Some 250,000 to 400,000 people in the United States are estimated to have a spinal cord injury, with about 10,000 new injuries every year. Spinal cord injury is considered the most common cause of chronic ventilatory failure in young adults (Table 3).
Respiratory muscle impairment depends on the level of the lesion. High cervical cord lesions (C1 to C2) and middle cervical cord lesions (C3 to C5) cause paralysis of the diaphragm, intercostal, scalene, and abdominal muscles. Low cervical cord lesions (C6 to C8) and upper thoracic cord lesions (T1 to T6) denervate the intercostal and abdominal muscles, but leave the diaphragm and neck muscles intact; ventilatory endurance is not a problem and few patients require prolonged mechanical ventilation because the diaphragm is functional. Prognosis improves as a lesion moves downward: ventilator dependency occurs in 40, 14, and 11% of patients with C3, C4, and C5 lesions, respectively (320). Despite extensive chest wall deafferentation, the intensity and quality of dyspnea are not altered in patients with spinal cord injury in whom work of breathing is increased by bronchoconstriction (321).
During the first week after denervation, the diaphragm undergoes hypertrophy of fatigue-resistant Type I fibers, a 20% increase in the number of sarcomeres, and transformation of the myosin heavy-chain phenotype of fatigable Type II fibers to Type I fibers (Table 1) (322). Despite the increase in protein level for Type I myosin heavy chain, its messenger RNA is decreased in the denervated diaphragm (322). Thus, the increase in protein results from posttranscriptional modulation (322). The hypertrophy of Type I fibers and increased expression of Type I myosin heavy chain is sufficient to increase endurance of the denervated hemidiaphragm (322).
Denervation of more than 4 weeks causes muscle atrophy (323) and predominance of Type II myosin heavy chains in the denervated diaphragm. Such remodeling could explain the greater fatigability of the diaphragm in patients with spinal cord injury (268, 324). Sinderby and coworkers (268) found early signs of diaphragmatic fatigue (a reduction in center frequency of the electromyogram) in 7 of 10 patients with complete C5 to C8 injuries who were performing arm exercise. Susceptibility to diaphragmatic fatigue is increased by the increased inspiratory elastic load on the chest wall and lung and by expiratory muscle paralysis. Training with an inspiratory resistor decreases the susceptibility to diaphragmatic fatigue (325).
The neuromuscular junction of Type IIb/x fibers of the diaphragm undergoes remodeling after a spinal cord injury (326), with increases in the pre- and postsynaptic branches and an increase in the planar area of the neuromuscular junction. It is not known whether the improvement in neuromuscular transmission (326) contributes to recovery from diaphragmatic paralysis, which occurs in about one-quarter of patients with injuries at C4 (or higher) within 40 days (327).
For patients with high cervical spinal cord lesions and patients with selected middle cervical spinal cord lesions who have both intact phrenic motor neurons and intact phrenic nerves, bilateral phrenic nerve pacing provides a means of avoiding mechanical ventilation in 34% (328) to 80% (329). Patient selection depends on two criteria: one, proof that the phrenic nerves are intact, as demonstrated by a normal response to phrenic nerve stimulation, in terms of conduction time and, more controversially, the amplitude of the diaphragmatic compound action potential (329); two, predicting that the patient is unlikely to recover the ability to breathe spontaneously. This criterion is more difficult to resolve. Similowski and coworkers (330) reported that spontaneous respiration recovered in all of three patients who had a normal diaphragmatic response to stimulation of the cerebral cortex. In other words, demonstrating an intact corticospinal tract may indicate that the second criterion is not satisfied. The proximity of the pathways for voluntary breathing (corticospinal tract) to the pathways for automatic breathing (bulbospinal tract) helps explain why assessing the corticospinal tract provides useful information about likely recovery of the bulbospinal tract. To avoid damage to the diaphragm and to allow time for a previously paralyzed muscle to become conditioned, the duration of pacing should be increased slowly over 3 to 4 months (329). Pacing can induce expression of fatigue-resistant Type I muscle fibers (331) and prevent muscle atrophy (323). Some patients derive considerable benefit from pacing (periodic closure of tracheostomy stoma, improved speech, restored olfactory sensation), but it is expensive, invasive, and can cause infections, phrenic nerve damage, and hypoventilation (328, 329). Laparoscopic placement of electrodes in the diaphragm may become a reliable (and safer) alternative to thoracotomy in patients with spinal cord injury and intact phrenic nerves (332).
The expiratory muscles are often involved more than the inspiratory muscles (333). A decrease of tone in the paralyzed expiratory muscles dissipates the increase in abdominal pressure that normally accompanies diaphragmatic contraction. As a result, the lifting effect of the diaphragm, mediated through the zone of apposition, is decreased (334). In the first week of injury, expiratory reserve volume approaches zero. With time, it increases to about 500 ml (334), because of contraction of the clavicular portion of the pectoralis major (innervated by C5–C7) during exhalation (334). Contraction of this muscle fails to generate a pleural pressure sufficient to achieve dynamic compression of the intrathoracic airways (a critical requirement for effective cough) in half of patients with C5–C8 tetraplegia (335).
Three strategies can be used to augment expiratory muscle function and the cough: training the pectoralis major muscle, strapping the abdominal muscles, and stimulation (electrical or magnetic) of the abdominal muscles. Repetitive, strenuous, isometric contractions of the pectoralis major muscle over 6 weeks produced about a 50% increase in strength and expiratory reserve volume, and a 14% decrease in residual volume in six patients with tetraplegia (336). Strapping the abdomen was believed to augment intrathoracic pressure by preventing the outward abdominal displacement during forced exhalation (334). In eight tetraplegic patients, however, strapping produced small and inconsistent change in intrathoracic pressure during cough, and only four patients exhibited a small plateau in flow during exhalation (indicating dynamic airway collapse) (337). Strapping is therefore unlikely to substantially improve the efficiency of cough (337). Stimulation of the expiratory muscles (electrical  or magnetic ) increases intrathoracic pressure over that produced by voluntary exhalation (35 versus 19 cm H2O) (333). The pressure is sufficient to initiate dynamic airway compression and possibly clearance of secretions, even in patients with longstanding muscle atrophy (333). The primary aim of the preceding three strategies is to enhance cough by augmenting expiratory muscle function. Cough can also be enhanced by manual assistance and mechanical insufflation–exsufflation devices (339). Outcome comparisons of the different techniques of cough assistance have not been conducted.
Motor neuron disease encompasses pure upper motor disorders (primary lateral sclerosis), pure lower motor neuron disorders (postpolio syndrome, postirradiation radiculopathy), and a combination of the two (amyotrophic lateral sclerosis, paraneoplastic encephalomyelitis/sensory neuropathy associated with anti-Hu antibodies).
New cases of poliomyelitis have decreased, but the number of patients with postpolio syndrome is rising (340). Postpolio syndrome is characterized by new weakness, generalized fatigue, and muscle pain (341). About half of patients who recover (partially or completely) from paralytic poliomyelitis develop the syndrome over the subsequent 25 to 30 years. More than 300,000 patients are considered at risk for postpolio syndrome in the United States (340). The syndrome is thought to result from increased metabolic stress on the lower motor neurons, which undergo massive compensatory sprouting in the years after the initial infection (340).
Postpolio syndrome may result in progressive respiratory muscle weakness (342) and bulbar muscle dysfunction (340). Pulmonary problems account for most of the morbidity and mortality (341). Respiratory motor deficits, combined with a high incidence of scoliosis and obesity, cause dyspnea, sleep-disordered breathing, and respiratory failure (340). Respiratory compromise is more likely in patients who had required ventilator support during acute poliomyelitis, and in patients who contracted poliomyelitis after 10 years of age (343). Respiratory failure is usually caused by respiratory muscle weakness, but may also result from central hypoventilation (residual damage from earlier bulbar poliomyelitis) or late progressive scoliosis (341). Postpolio syndrome is a frequent indication for noninvasive ventilation among slowly progressive neuromuscular disorders. In a study of patients not requiring ventilator support just after acute poliomyelitis, however, only 3.7% of survivors (or an estimated 7.4% of patients with postpolio syndrome) subsequently received domiciliary noninvasive (54%) or invasive (46%) ventilation (281).
Inspiratory muscle training can increase respiratory muscle endurance in patients with postpolio syndrome who use part-time assisted ventilation (344). The use of inspiratory muscle training, however, may be imprudent in these patients. The syndrome is thought to result from increased metabolic stress on the lower motor neurons (340) and initial gains from training may lead to subsequent deterioration.
Amyotrophic lateral sclerosis is a progressive disease affecting both upper and lower motor neurons (345). Although disease progression varies among patients, half are dead within 3 years of the first symptoms—making it one of the most severe chronic neurological diseases (345).
Development of dyspnea is associated with inspiratory muscle weakness (346) and abnormal electromyographic responses of the diaphragm to stimulation of the phrenic nerve (lower motor neuron disorder) and the cortex (upper motor neuron disorder) (347). Inspiratory muscle weakness predicted survival in 25 patients monitored for 45 months: about 85% of patients who generated a maximal inspiratory pressures less negative than –30 cm H2O died as compared with about 10% of patients who generated a more negative pressure (348). All patients with amyotrophic lateral sclerosis develop expiratory muscle weakness (346) sufficient to impair cough (346). Impaired cough may also result from involuntary closure of the vocal cords during rapid exhalation secondary to bulbar involvement (346).
With disease progression, the tension–time index of the inspiratory muscles increases from 0.05 to 0.17 (348), which is below the threshold (0.30) for task failure of the rib cage muscles of healthy subjects (74). Gas exchange is largely maintained despite severe respiratory muscle involvement (348, 349). Of 81 patients, more than half of patients with a VC of 19 to 50% of predicted were normocapnic (349). Most patients with a maximal inspiratory or expiratory pressure of less than 25% of predicted were not hypercapnic (349). Measurements of arterial blood gasses alone are of little value in monitoring disease progression (349, 350) until the last 4 to 5 months of life. At that point, patients may show a precipitous fall in serum chloride (an indirect marker of respiratory acidosis), making it a more promising indicator of patient outcome than measurements of respiratory muscle strength during the terminal phase of the disease (350).
Patients commonly experience diaphragmatic weakness (347, 351), which can have a negative impact on rapid eye movement sleep (269) (when the diaphragm is almost the only active muscle). About half of patients with diaphragmatic weakness achieve partial or full preservation of rapid eye movement sleep through phasic activity of inspiratory muscles other than the diaphragm (269). Median survival is less in the patients with diaphragmatic dysfunction that in those with normal function: 7 versus 21 months; survival tends to be shorter in patients with the least duration of rapid eye movement sleep (269).
Noninvasive ventilation (290, 291) relieves dyspnea in patients without bulbar involvement (352), but is often ineffective and poorly tolerated in patients with bulbar symptoms (352). Although controversial, many consider severe bulbar involvement a contraindication to noninvasive ventilation (291, 352), and it is not clear when to use it in patients with mild or absent bulbar involvement. Among 2,357 patients (from 20 centers in the United States), noninvasive ventilation was being used in 360 (15%) (291). It was most often instituted when FVC fell to 20–40% of predicted and clinical features of hypoventilation appeared (291). Maximal nasal sniff pressure of less than 32% of predicted detects hypercapnia with a specificity and sensitivity of about 80% in patients without bulbar involvement (349). Nasal sniff pressures might help in deciding when to institute noninvasive ventilation.
Ventilator support can improve cognitive function (289) and the sense of vitality (one of eight domains in a quality of life questionnaire) despite disease progression (290). Most patients with advanced amyotrophic lateral sclerosis live in a functional locked-in state. Ventilator support prolongs this existence and may not be in a patient's best interest. About 30% of patients agree to noninvasive ventilation and less than 10% agree to a tracheostomy (353). Of patients who agree to tracheostomy and mechanical ventilation, however, 90% are satisfied with their decision and would repeat it (353).
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Damage to the phrenic nerves leading to diaphragmatic paralysis can occur with trauma, mediastinal malignancies, herpes zoster, diphtheria, Lyme disease, malnutrition, alcoholism, diabetes, lead toxicity, vasculitis (354), porphyria, neuralgic amyotrophy, and the Guillain-Barré syndrome. The differential diagnosis of weakness and paralysis of the diaphragm (unilateral or bilateral) includes disorders located in the upper motor neurons (cerebral infarction or hemorrhage), respiratory centers (infectious processes, Arnold-Chiari II malformation, parkinsonism ), lower motor neurons (spinal cord injury, poliomyelitis, amyotrophic lateral sclerosis), phrenic nerve, neuromuscular junction (myasthenia gravis, botulism), and muscle fibers (myotonic dystrophy, adult onset maltase deficiency).
In patients with unilateral paralysis, maximal inspiratory pressure is reduced to about 60% of predicted and maximal transdiaphragmatic pressure to about 40% of predicted (356). In patients with bilateral paralysis, maximal inspiratory pressure is reduced to less than 30% of predicted and maximal transdiaphragmatic pressure to about 5% of predicted (357). Transdiaphragmatic pressure is not zero because pressure is generated by passive stretching of the diaphragm (357).
Maximal expiratory pressure measured from total lung capacity is normal with unilateral paralysis (356), and between normal and 70% of predicted in patients with bilateral paralysis (277, 357). The decrease in patients with bilateral paralysis is secondary to a 30 to 50% decrease in total lung capacity (277, 357), causing the expiratory muscles to contract at a shorter than ideal length. Total lung capacity is virtually unchanged in patients with unilateral paralysis (356). Maximal voluntary ventilation, VC, and FEV1 are each decreased by about 50% with bilateral paralysis (270, 277) and by about 25% with unilateral paralysis (358). The decrease in lung volumes varies widely among patients with unilateral (358–360) and bilateral paralysis (360, 361); some patients with bilateral paralysis have normal or near normal values. About half of patients with bilateral or unilateral paralysis have decreased respiratory muscle endurance (362). The decrease is associated with a shorter duration of disease and less output of the expiratory muscles. The findings suggest that patients compensate by recruiting their expiratory muscles over time.
Most patients with unilateral and bilateral paralysis maintain adequate ventilation and gas exchange at rest (277, 361) and during exercise (277). Ventilation is probably maintained by a compensatory increase in motor output to the intercostal muscles and increased output to the normal hemidiaphragm (298) in patients with unilateral paralysis. Despite compensatory changes, patients with unilateral paralysis have about a 20% decrease in ventilation and perfusion of the affected lung (358).
The ratio of the tidal swing in gastric pressure to the tidal swing in esophageal pressure is a useful way of assessing the relative contribution of the diaphragm, rib cage, and expiratory muscles to tidal breathing (363). In healthy subjects, the ratio is equal to or more negative than –1 (360). A less negative ratio indicates an ever-increasing contribution of the rib cage and expiratory muscles, as compared with the diaphragm, to tidal breathing. With complete diaphragmatic paralysis, the ratio becomes equal to 1. Ratios more positive than 1 occur in 20% to 25% of patients with bilateral diaphragmatic paralysis (359, 362). In these patients, the rise in gastric pressure due to expiratory muscle recruitment in the preceding exhalation may be incompletely transmitted to the thorax because of the generation of passive diaphragmatic tension during the preceding exhalation; this explanation, however, has not been proven. Contraction of the expiratory muscles displaces the abdomen inward and the diaphragm upward into the thorax during exhalation. Relaxation of the abdominal muscles at the onset of inhalation causes outward abdominal motion and passive descent of the diaphragm (270) (Figure 14). Contraction of the abdominal muscles during exhalation can ablate the inward motion of the abdomen during inhalation (abdominal paradox, the cardinal sign of diaphragmatic paralysis). In the supine posture, relaxation of contracted abdominal muscles has little influence on abdominal motion because of the effect of gravity on the abdominal contents (359). Many patients also appear to recruit their expiratory muscles when erect and sitting, but not when supine; in the latter situation, the inward motion of the abdomen during inhalation will become obvious.
Abdominal paradox occurs during resting breathing in 10 (359) to 100% (277) of patients with bilateral paralysis when standing or sitting and in 50 to 100% when supine (364). In patients with diaphragmatic weakness rather than paralysis, the severity of the weakness determines the occurrence of paradox—paradox (and orthopnea) occurs only when maximal transdiaphragmatic pressure is less than 30 cm H2O (365). Abdominal paradox is rarely seen in patients with unilateral paralysis when upright or supine (359, 360). Patients occasionally display abdominal paradox on the affected side alone (360). In contrast to unilateral paralysis, bilateral paralysis can cause orthopnea even in patients without other pulmonary or nonpulmonary conditions.
Dyspnea during daily activities has been reported in patients with unilateral paralysis (356, 360). In a series of 40 patients with a diagnosis of lone unilateral paralysis made by fluoroscopy, dyspnea on exertion was reported by 10% on presentation and by 30% during follow-up of 4 months to 19 years (366). In more recent but smaller series, 40 to 100% of patients developed dyspnea during moderate exercise (356, 359, 360). Interpretation is confounded by selection bias: most patients with an elevated hemidiaphragm were referred because they had respiratory symptoms (356). Another confounding factor is the limited specificity of fluoroscopy for diagnosing unilateral hemidiaphragmatic paralysis (367).
Bilateral paralysis can cause dyspnea during mild to moderate exertion even in patients without pulmonary or nonpulmonary comorbidities (277, 357) or without desaturation during exercise (277). Bilateral paralysis can also cause dyspnea on immersion in water (361). Patients with unilateral or bilateral paralysis have subnormal exercise capacity (362), and oxygen consumption (normalized by minute ventilation) at peak exercise is increased (362). Patients with bilateral paralysis often complain of dyspnea when bending or lifting—activities that require expiratory muscle recruitment. These symptoms may arise because the paralyzed diaphragm cannot prevent the rise in intrathoracic pressure, and thus the cessation of inhalation, caused by expiratory muscle recruitment. The variability of symptoms, loss of lung volume, and inspiratory strength among reports is probably related to coexisting weakness of other inspiratory and expiratory muscles in some patients but not in others. Cor pulmonale is rare in patients with isolated bilateral paralysis. Its rarity may be the result of the common recruitment of rib cage and expiratory muscles during wakefulness and sleep (277, 362), which prevents the derangement in gas exchange necessary for the development of cor pulmonale.
Checking for an elevated hemidiaphragm on a chest radiograph is of little value because it lacks sensitivity and specificity in the diagnosis of unilateral paralysis (367). Fluoroscopy during a sniff is a time-honored method of diagnosing diaphragmatic paralysis, particularly for unilateral paralysis. The diaphragm normally descends during a sniff, whereas the paralyzed hemidiaphragm ascends in patients with unilateral paralysis. At least 2 cm of upward motion is considered abnormal (358, 367). The test is not specific. Fluoroscopy in the upright posture (posteroanterior view) revealed unilateral paradoxic motion in 9% and bilateral paradoxic motion in 2% of 776 subjects without diaphragmatic paralysis (367). False-positive results can be reduced in half by using an oblique view (367). Paradoxic motion during a sniff occurs in subjects without diaphragmatic paralysis because they strongly recruit their rib cage muscles or less likely because they recruit their expiratory muscles. Fluoroscopy is even less helpful when the hemidiaphragm is not completely paralyzed, and is particularly misleading in patients with bilateral paralysis. In a classic study, only one of six patients with bilateral paralysis displayed paradoxic motion (364). Patients contracted their abdominal muscles during exhalation, displacing the abdomen inward and the diaphragm upward into the rib cage. The abdominal muscles relaxed at the onset of inspiration, causing outward recoil of the abdominal wall and diaphragmatic descent, giving the misleading picture of normalcy (Figure 14).
On switching from upright to supine, the upper 95% confidence limits of the decrease in FVC was 19% in healthy subjects, 24% in patients with restrictive disease, and 38% in patients with obstructive disease (368). FVC decreases by as much as 55% when patients with bilateral paralysis become supine (364). The greater fall in volume may be the result of abdominal contents being moved into the chest, decreased effectiveness of the intercostal muscles (which are relatively shortened by the expanded rib cage), and an increase in chest wall elastance (caused by rib cage expansion).
Demonstrating a delayed phrenic nerve conduction time is more specific than fluoroscopy (363). Conduction time may be normal, however, if some viable axons are preserved. Sensitivity can be improved by using a multipolar esophageal electrode to record the amplitude of the diaphragmatic electromyogram elicited by phrenic nerve stimulation (369).
Diaphragmatic ultrasonography is a new method of assessing diaphragmatic function (370, 371). In 30 patients with suspected diaphragmatic paralysis, diaphragmatic motion was abnormal in 22 patients (370). Fluoroscopy (with sniff) was technically impossible in four patients and it missed the motion abnormalities in another five patients. Ultrasonography can also be used to measure diaphragmatic thickness in the zone of apposition (371). Diaphragmatic thickness at functional residual capacity of less than 2 mm combined with a less than 20% increase in thickness during inspiration provided perfect discrimination between a paralyzed and normal diaphragm (371).
Patients with diaphragmatic paralysis experience symptomatic benefit from the use of noninvasive ventilation at night. A cuirass ventilator, rocking bed, and pneumobelt are less commonly used (364). When diaphragmatic paralysis is caused by phrenic nerve damage, phrenic nerve pacing has no role in the management. Plication of both hemidiaphragms improved ventilation, gas exchange, and resolved orthopnea in three patients with persistent bilateral paralysis who developed cor pulmonale (372).
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Guillain-Barré syndrome is the most common cause of acute paralysis of the respiratory muscles. It is caused by a demyelinating process (80 to 90% of patients) or axonal degeneration (10 to 20% of patients) of the peripheral nerves, which can be preceded by bacterial infection (Campylobacter jejuni in up to 66% of patients) or viral infection (cytomegalovirus in up to 22% of patients) (373). Guillain-Barré syndrome accounts for more than half of patients with a primary neuromuscular disorder admitted to an intensive care unit. The disease may progress over a few hours to respiratory failure (373). Because the course is highly variable, all patients should be admitted to hospital (373). About one-third of the patients require either mechanical ventilation because of ventilatory failure or intubation for airway protection (patients with bulbar involvement) (373, 374).
In a prospective study, 15 of 18 patients with prolonged phrenic nerve conduction times developed ventilatory failure at some stage, whereas none of 10 patients with a normal conduction time required admission to the intensive care unit (374). VC was a much less sensitive marker, being abnormal in only 11 of 18 patients with a prolonged phrenic nerve conduction time. Serial studies showed progressive improvement in phrenic nerve conduction times: 78% of patients reached full recovery after 12 weeks, and 94% after 16 weeks (374). Diaphragmatic electromyograms obtained within 3 days of admission to hospital (2 to 28 days after symptom onset) were abnormal in 83% of 40 patients (375). A normal electromyogram suggests that a patient will not develop respiratory failure (375). An abnormal electromyogram, however, does not necessarily mean that a patient will develop respiratory failure—all patients requiring mechanical ventilation and 79% of patients not requiring ventilation had abnormal electromyograms (375).
In patients with severe disease, instituting plasma exchange or intravenous immune globulin within 2 weeks of symptoms decreases disability (376). The combination of plasma exchange and intravenous immune globulin is not superior to either alone (376). Intravenous immune globulin is superior to plasma exchange in patients with Campylobacter jejuni infection and antibodies directed against the GM1 and GM1b gangliosides (gangliosides in human peripheral nerves) (377). In patients with severe disease, instituting plasma exchange before respiratory failure reduces the need for mechanical ventilation (378). In those patients requiring mechanical ventilation, plasma exchange reduces its duration by 2 weeks (378).
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Patients with myasthenia gravis typically present with weakness, developing with or aggravated by exertion (379). Weakness can be localized to one group of muscles for years (commonly the eye muscles) or spread to other muscles (379). Onset can be acute or subacute, and relapses and remissions occur in about 20% (379). Patients are particularly susceptible to muscle relaxants, and weakness may be first noticed after general anesthesia (379). β-Blockers, verapamil, and aminoglycosides exacerbate poorly controlled myasthenia, and penicillamine can induce a syndrome that is indistinguishable from myasthenia gravis (379). Respiratory muscle involvement (even respiratory failure) occurs in 1 to 4% of patients with early disease, but becomes troublesome later in 50 to 60% of patients.
The neurophysiological hallmark is a decrease of at least 10% in the compound muscle action potential evoked by repetitive stimulation of peripheral nerves at 3 Hz (379) (Table 2). About 40 to 50% of patients with mild-to-moderate myasthenia gravis display the same response in the diaphragmatic compound muscle action potential (decrease in amplitude  or area  of more than 10%). Edrophonium, a short-acting anticholinesterase, produces a rapid (within 2 minutes) and short-lived (less than 5 minutes) improvement in strength (379). More than 80% of patients display a normal transdiaphragmatic twitch pressure in response to stimulating the phrenic nerve at 1 Hz (382). Edrophonium did not increase the twitch pressure in 14 patients with a normal response (382), although it increased twitch pressure in 1 of 3 patients with a reduced or absent response (382). Edrophonium fails to increase twitch pressure in all patients because the transmission failure across the neuromuscular junction is occurring at stimulation frequencies above 1 Hz (usually above 3 to 5 Hz) (382).
After patients with generalized myasthenia gravis suspend their anticholinesterase medications for 10 hours or more, inspiratory muscle strength is about 30 to 50% below normal (382, 383); expiratory muscle strength (382, 383) and respiratory muscle endurance (383) are about 50% below normal. Cholinesterase inhibitors, neostigmine (383) or edrophonium (382), increase maximal airway pressure by 20 (383) to 37% (382) and maximal transdiaphragmatic pressure by 29% (382). Maximal expiratory pressure responds variably to cholinesterase inhibitors: no improvement (383) and an increase of about 30% (382) have been reported. Cholinesterase inhibitors produce an increase in respiratory muscle endurance in about half the patients (383). Impaired excitation–contraction coupling may explain the failure of anticholinesterase medications to correct respiratory muscle endurance in some patients. The impairment may result from antibodies to titin (384, 385), a giant filamentous protein of striated muscle that contributes to muscle assembly and the ability of muscles to spring back after they are stretched (386), or antibodies to the ryanodine receptor, a calcium-release channel in the sarcoplasmic reticulum of striated muscles (386).
Diaphragmatic weakness is often detectable even when therapy achieves normal or near normal functional activity (387). Five patients with normal functional activity had maximal transdiaphragmatic pressures of 7 to 49 cm H2O (387), indicating respiratory weakness out of proportion to weakness of the limb muscles (382, 388).
Thymectomy, immunosuppressive treatment, short-term immunotherapies, and anticholinesterase agents (379) improve respiratory muscle function when administered alone or in combination. In an uncontrolled study of patients with moderate-to-severe myasthenia gravis (389), training (with threshold load) increased respiratory muscle strength and endurance and decreased dyspnea.
Myasthenic crises are life-threatening episodes of respiratory or bulbar paralysis (379). About 10% of patients with myasthenic crises die (388, 390). The incidence is about 2.5% per year per patient (390). One-third of crises have no obvious precipitating cause (388, 390), another one-third are precipitated by infection (often respiratory), and the rest are secondary to medication (underdosing or overdosing), surgery (thymectomy or other), or pregnancy (388, 390). During a myasthenic crisis, ventilatory failure typically develops within 3 days of a patient noticing worsening of bulbar, skeletal, or respiratory weakness (388). Limb weakness is absent in 20% of patients (388). The median duration of mechanical ventilation is 13 days (range, 1 to 159 days) (388). In a study of 63 episodes of myasthenic crisis in 44 patients, three regimens—pyridostigmine, pyridostigmine and prednisolone, or pyridostigmine and plasma exchange—had equivalent effects on duration of mechanical ventilation, complications, and outcome (390).
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Myotonic dystrophy Type 1 is an autosomal dominant disorder. All myotonic dystrophies are characterized by myotonia, that is, a delayed relaxation after a contraction whether voluntary, automatic, or induced (electrically or mechanically) (391). The electromyographic equivalent of myotonia is a rapid burst of action potentials when a muscle is expected to be relaxed. All myotonic dystrophies are characterized by progressive muscle weakness, wasting, and Type I muscle fiber atrophy (391). Despite the name, myotonic dystrophies affect several organs: heart, smooth muscle, eye, brain, endocrine system, and other tissues (391).
In 25 patients, needle electrodes (392) revealed myotonic discharges—sustained runs of either positive sharp waves or negative spikes with a small initial positivity—in 68% of the recordings from the diaphragm and intercostal muscle; the number of active motor units was decreased in 36% of the recordings (392). Longer duration of the disease is associated with smaller amplitude of diaphragmatic compound motor action potentials (392), smaller VC (392), and greater prevalence of myotonic discharges of the intercostal muscles (266). When the proximal limb muscles become weak, inspiratory pressure declines markedly and hypercapnia becomes more likely (393). Early in the disease, weakness of the expiratory muscles exceeds that of the inspiratory muscles, leading to a weak cough and frequent respiratory infections (393).
Impairment of the central inspiratory pathways, occurring in about one-third of patients, also contributes to the respiratory weakness (392). The impairment is recognized by the high excitability threshold and the small amplitude of the diaphragmatic compound action potentials in response to cortical (magnetic) stimulation (392). The abnormal conduction is compatible with recruitment of fewer spinal motor neurons by corticospinal tract volleys (392). The small recruitment may be secondary to cortical atrophy and lesions of white matter that occur in up to 80% of patients (394). The central impairment may explain the tendency for hypercapnia to be disproportionate to the degree of respiratory muscle weakness in patients with myotonic dystrophy (266) and the earlier onset of sleep-related symptoms than in patients with Duchenne's muscular dystrophy. Many patients display a highly irregular pattern of breathing while awake, which is thought to result from abnormal afferent information from the muscle spindles.
Mortality among patients with myotonic dystrophy is about seven times that of the general population (395). Patients with proximal muscle involvement and early onset disease have a higher mortality than do patients with distal muscle involvement and late onset disease (395). Death usually results from respiratory failure, pneumonia, and, less commonly, cardiovascular and neoplastic disease (395).
Duchenne's muscular dystrophy is the most common muscle dystrophy of childhood, occurring in 1 of 3,500 to 1 of 5,000 boys (396, 397). It is an X-linked recessive disorder caused by a defect in the gene that produces dystrophin, a large cytoskeletal protein (Figure 15). Impaired function of the sarcoplasmic reticulum calcium pumps and of the myosin molecule may contribute to the impaired muscle performance in muscular dystrophy (398).
Respiratory muscle weakness causes a progressive decrease in lung volumes from 7 to 12 years of age onward (396). When VC falls below 1 L, median survival is 3 years (399). Death typically occurs between 20 and 23 years of age (396), and is respiratory in origin in more than 80% of cases. Hypercapnia is uncommon until the terminal stage, when its development predicts a rapidly fatal course. Studies in a mouse model of muscular dystrophy suggest that some diaphragmatic function is preserved until late in the disease (397). Progressive muscle degeneration produces a fast-to-slow shift in the isoform profile of the myosin heavy chain of the diaphragm. This shift is associated with both a reduction in power output and an increase in muscle endurance (397). By decreasing cellular energy requirements, these changes may preserve contractile function and promote greater survival of remaining muscle fibers (397).
Inspiratory muscle training can improve inspiratory and expiratory muscle function (400). When VC falls below 20% of predicted, ventilatory failure is almost inevitable. In patients who developed ventilatory failure, noninvasive ventilation increased survival from less than 1 year to more than 5 years (401). In asymptomatic patients with normal daytime gas exchange and VC of 20–50% of predicted, Raphael and coworkers (396) reported that use of noninvasive ventilation to delay the onset of respiratory failure caused an increase in mortality. The findings, however, are confounded by the failure of the investigators to standardize ventilator use, type of nasal interface, and patient training (402). Left-ventricle hypokinesia was more common in the ventilated patients, although adjusting for this abnormality did not alter the findings of the study (403). Another confounding factor was the difference in use of invasive ventilation when patients developed respiratory infections and retention of secretions: 26% of patients in the control group versus 9% of patients managed by noninvasive ventilation (396). The latter observation together with more frequent deaths in the home than in hospital suggests that noninvasive ventilation led to a false sense of security and may have contributed to suboptimal medical management (396).
Scoliosis is characterized by lateral displacement of the spine. It is usually idiopathic. Less frequently, it is caused by neuromuscular diseases, such as cerebral palsy, poliomyelitis, Duchenne's muscular dystrophy, vertebral diseases (spinal osteomyelitis due to tuberculosis, brucellosis, or trauma), Marfan's syndrome, or thoracic cage abnormalities (pleural retraction from empyema or thoracoplasty). The severity of scoliosis is quantified by Cobb's method of measuring the angle between the upper and lower portions of the spinal curve. Among 37,019 children aged 6 to 14 years, the prevalence of scoliosis (defined as a Cobb angle of greater than 10 degrees) was 0.5 to 1.7% (404, 405). The thoracic and thoracolumbar regions are, respectively, involved in 48 and 30% of patients with idiopathic scoliosis (404). Of thoracic cage deformities, scoliosis produces the most severe reductions in total lung capacity and VC. When the Cobb angle exceeds 100 degrees (severe scoliosis), VC falls to about 50% of predicted (406).
Lung and chest wall compliances are about 25 to 50% of predicted in children and adults with scoliosis (407–409). Chest wall compliance is inversely proportional to the Cobb angle in stable patients. Applying 25 cm H2O of pressure on inspiration for 5 minutes produces a 34% increase in compliance and a 15% increase in functional residual capacity (407). It is not known whether the improvement results from resolution of microatelectasis, surfactant activation, or some other mechanism.
The spinal deformity produces inefficient coupling between the respiratory muscles and the thoracic cage, with consequent reduction in maximal inspiratory and expiratory pressures (407, 410, 411). In adolescents with mild-to-moderate scoliosis (Cobb angles of 30 to 60 degrees), maximal inspiratory pressure is about 70 to 80% of predicted (407, 411). In adults with more severe scoliosis (Cobb angles of 66 to 136 degrees), maximal inspiratory pressure is about 50 to 76% of predicted (408, 412). Despite these findings, the extent of inspiratory muscle weakness is not linearly related to the degree of spinal deformity (410), and may be affected by impaired body growth, including muscle mass. An unknown proportion of patients with scoliosis develop central hypopneas, particularly during rapid eye movement sleep. The degree of nocturnal desaturation is related to daytime saturation and not the Cobb angle. To meet the mechanical load, most patients with severe scoliosis exhibit increased transdiaphragmatic pressure during tidal breathing (410), increased rib cage contribution to tidal breathing (410), and transversus abdominis recruitment during exhalation (408). Expiratory muscle recruitment decreases the anteroposterior diameter of the abdomen, increases gastric pressure during exhalation, and assists inhalation (408). The pattern is essentially the same as that seen in patients with severe COPD (83, 84), supporting the belief that the respiratory centers recruit the respiratory muscles in the same order irrespective of the challenge.
Exercise capacity is reduced by 14% in patients with mild to moderate scoliosis (Cobb angle of 45 degrees) (411). Exercise capacity is not determined by respiratory muscle strength or the spinal angle (411), but by VC, muscularity, and cardiovascular conditioning (411). When the Cobb angle exceeds 100 degrees, pulmonary hypertension may also contribute to decreased exercise capacity.
Patients with scoliosis and a Cobb angle of less than 70 degrees are usually asymptomatic. With an angle between 70 and 100 degrees, patients often experience dyspnea on exertion. When the angle exceeds 100 degrees, patients are at risk for chronic respiratory failure (408). About 3 per million of the general population require domiciliary ventilator or oxygen therapy because of thoracic deformity. Interindividual variation is large, and patients with angles of 105 to 135 degrees can have only mild to moderate cardiorespiratory impairment. When respiratory failure occurs in a patient with an angle of less than 100 degrees, another cause of respiratory failure should be suspected. In patients with idiopathic or postpolio scoliosis, corrective surgery can prevent the development of respiratory failure, but spinal surgery should not be performed once chronic respiratory failure is established (409, 413). On long-term follow-up of patients with scoliosis, surgery rarely improves lung function (413) and can cause it to deteriorate (409, 413). In patients with chronic respiratory failure, nocturnal mechanical ventilation can reverse cor pulmonale, improve gas exchange and maximum inspiratory and expiratory pressures, and reduce hospital admissions (412).
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In patients with ankylosing spondylitis, ankylosis of the costovertebral and sternoclavicular joints leads to decreased rib cage movement, a compensatory increase in diaphragmatic excursion during tidal breathing, and increased expiratory muscle recruitment during hyperventilation (414). Despite severely curtailed rib cage expansion (less than 14 mm), patients can still have a VC of over 60% of predicted because of compensation by the diaphragm (414). Unique among disorders of the thoracic cage, about half of patients with ankylosing spondylitis have an elevated functional residual capacity. The stiff rib cage is thought to move the equilibrium point of the respiratory system closer to the resting point of the rib cage, which is about 1 L higher than normal functional residual capacity.
The effect of ankylosing spondylitis on respiratory muscle strength is not well defined. Some investigators report decreases in maximal inspiratory pressure to 56% and in expiratory pressures to 76% of predicted (414). Others report normal values (415). Patients with normal respiratory muscle strength can exhibit impaired inspiratory muscle endurance (415). A decrease in exercise capacity is usually not related to reduced respiratory muscle function or VC (415). Exercise performance is related to limb muscle strength and lean body mass, indicating that impaired exercise capacity is the result of deconditioning and not pulmonary impairment (415). Patients with ankylosing spondylitis rarely if ever develop ventilatory failure without superimposed lung disease.
A flail chest arises when a segment of the rib cage is disconnected from the rest of the chest wall because of multiple rib fractures. It is common with blunt chest trauma, and pulmonary contusion is present in almost half of the patients (416). Distortion of the rib cage in patients with a flail chest does not correlate with the location of the fractures (416). Patients with lateral rib fractures display paradoxic motion of that location, but also display paradoxic motion of the ventral rib cage and occasionally of the abdomen (416). The additional motion abnormalities result from chest pain (interferes with respiratory muscle recruitment ) and lung contusion (increases lung elastance), rather than the flail alone (416).
To investigate the effect of isolated flail chest on rib cage motion and muscle activity, Cappello and coworkers conducted several studies in dogs (417, 418). When the ribs were fractured, the flail portion moved inward during inspiration (417). Cranial displacement of the flail portion, however, was normal (417). Although the dogs displayed a three- to fourfold increase in activity of the external (inspiratory) intercostal muscles, the normal cranial displacement resulted from (unaltered) inspiratory contraction of the parasternal intercostals (418). The aponeuroses and muscles connecting the fractured ribs to the nonfractured ribs probably play a major role in transmitting the inspiratory force of the contracting parasternal intercostals to the flail portion of the chest (418). In dogs with an isolated flail chest, cranial motion of the ribs is normal as is minute ventilation and gas exchange.
Respiratory muscle work normally accounts for about 1 to 3% of total body oxygen consumption, but it increases to 16% in patients with morbid obesity (body mass index greater than 40 kg/m2) (419). The increased oxygen cost of breathing results from a respiratory system compliance that is half to one-third of normal (420), a doubling of total respiratory resistance (secondary to smaller operating lung volume rather than increased chest wall resistance ), and expiratory flow limitation (particularly when supine) (421).
Morbidly obese patients without hypoventilation (simple obesity) compensate for the respiratory load by doubling respiratory drive and diaphragmatic pressure output (421), and increasing the rib cage contribution to tidal breathing. They breathe rapidly and shallowly. In morbidly obese patients, electrical activity of the diaphragm persists longer into early exhalation than in healthy subjects. Activity can persist for half of expiratory time and it correlates with the extent of obesity. Expiratory flow limitation is common in obese patients (421). Persistent diaphragmatic activity in early exhalation may provide a braking action, ensuing a minimum level of expiratory flow.
Inspiratory and expiratory muscle strength are normal in seated patients with simple morbid obesity (420). Maximal inspiratory pressure decreases by about half when patients are supine. The decrease probably results from overstretching of the diaphragm (secondary to cephalad displacement by weight of the abdomen), causing it to operate on the descending limb of its length–tension curve. Obesity causes a fast-to-slow shift in the isoform profile of the myosin heavy chain in animals (422) (Table 1). The shift from a fatigue-sensitive to a fatigue-resistant phenotype may result from the chronically increased work of breathing. Despite the fast-to-slow shift, respiratory muscle endurance is decreased in massively obese patients (423). The decrease in endurance may result from the increase in load (423) and incompleteness of the shift to fatigue-resistant fibers. Weight loss after gastroplasty is followed by a 13% improvement in endurance (423), and the improvement is closely related to the loss of weight (423).
In the last weeks of pregnancy, the diaphragm is about 2 to 3 cm higher than normal. Despite cranial displacement, the diaphragm moves normally during tidal breathing up to the end of pregnancy. Pregnancy alters neither maximal inspiratory nor expiratory pressure (424, 425). Increased demands on the respiratory muscles result from a 30% increase in minute ventilation and produce a 30% increase in the tension–time index of the diaphragm (424). The increase in minute ventilation is achieved through a rise in tidal volume (424, 425) without any change in respiratory rate. The increase in tidal volume is achieved solely by increased rib cage displacement (425), which may (425) or may not (424) result from increased rib cage muscle recruitment or improved capacity of the diaphragm to displace the rib cage (425). The latter effect might result from an increase in the zone of apposition or a fulcrum effect of the gravid uterus on the diaphragm (425). The lack of change in tidal swings in gastric pressure (424) or displacement of the abdominal compartment (425) suggests that abdominal compliance is not decreased. Thus, better lifting of the rib cage by the diaphragm is unlikely to result from a fulcrum effect of the gravid uterus. Preservation of maximal expiratory pressure is critical for the expulsive phase of labor. During this phase, the diaphragm and abdominal muscles generate intraabdominal pressures of 150 cm H2O or more. Diaphragmatic contraction during an expulsive effort minimizes the rise in intrathoracic pressure (and adverse hemodynamic effects) that occurs when the abdominal muscles contract. These pressures are sufficient to induce diaphragmatic fatigue (426).
Tense ascites poses an elastic and threshold load on the respiratory muscles (427). The elastic load results from an increase in lung water and a shift in operating lung volume to the lower portion of the volume–pressure curve (427). Tense ascites causes about 4 cm H2O of intrinsic PEEP probably secondary to early closure of the small airways (427). To overcome the increased load, patients display increased swings of intrathoracic pressure during tidal breathing (427). Patients do not recruit their expiratory muscles during resting breathing (427). An increase in intraabdominal fluid has been reported to increase (428), decrease (427), or have no effect (427) on maximal inspiratory pressure.
See online supplement.
See online supplement.
Patients with systemic lupus erythematosus can develop dyspnea, reduced lung volumes, and an elevated hemidiaphragm (unilateral or bilateral) without radiographic involvement of the interstitium or pleura. This “shrinking lung” syndrome occurs in up to 25% of patients (429). Several mechanisms may be involved. In 12 patients, Laroche and coworkers (430) recorded normal maximal transdiaphragmatic pressures in nine patients and subnormal pressures in three patients because of incomplete voluntary activation of the diaphragm. The investigators concluded that chest wall restriction, rather than diaphragmatic weakness, was mainly responsible for the syndrome. In nine patients with systemic lupus erythematosus, six of whom had the syndrome, Wilcox and coworkers (431) reported a reduction in maximal transdiaphragmatic pressure (mean, 50 cm H2O). Significant phrenic neuropathy was excluded by electromyographic studies (431). The investigators did not exclude the possibility of incomplete diaphragmatic recruitment versus diaphragmatic weakness per se. An autopsy study revealed atrophy and diffuse fibrosis of the diaphragm (432), suggesting that the syndrome results from diaphragmatic weakness.
Even without the shrinking lung syndrome, patients with systemic lupus erythematosus can exhibit mild decreases in maximal inspiratory pressure, increased respiratory drive, and rapid shallow breathing (433). Glucocorticoids lessen symptoms and improve pulmonary function in more than 80% of patients with the shrinking lung syndrome. Prognosis is generally good, and most patients show gradual improvement or stabilization of pulmonary function (429).
See online supplement.
Patients with insulin-dependent diabetes mellitus exhibit a 20% decrease in global inspiratory strength (434) and a 30 to 50% decrease in diaphragmatic strength (434). In rare instances, diaphragmatic weakness results from diabetic neuropathy of the phrenic nerves, which can occur despite the absence of peripheral neuropathy. Weakness might also result from nonenzymatic glycosylation of the diaphragm (435). Thickening of the basal laminae of pulmonary capillaries may contribute to increase work of breathing and dyspnea in patients with diabetes mellitus (436).
Hyperthyroidism causes both inspiratory and expiratory muscle weakness (437). In rare cases, involvement causes respiratory failure. Respiratory muscle weakness is proportional to the severity of hyperthyroidism and is associated with a decrease in lung volume (437). Three months of treatment produced a twofold increase in maximal inspiratory and expiratory pressures (a return to normal) (437). Animal models indicate that respiratory muscle weakness is caused by enhanced proteolysis through the activation of a proteasome-dependent pathway (Figure 5). The decreased expression of Type I and Type IIa myosin heavy chains of the diaphragm suggests that respiratory muscle endurance may be reduced in hyperthyroidism. Hypothyroidism causes inspiratory and expiratory muscle weakness (438). Diaphragmatic weakness can increase the tension–time index above the threshold for task failure during tidal breathing (438). Weakness is proportional to the severity of hypothyroidism and reverses with replacement therapy. The weakness might result from decreased expression of Type IIb myosin heavy chains, or decreased neuromuscular transmission secondary to a decrease in the planar areas of nerve terminals and end-plates of Type I and IIa fibers (439). Although neuromuscular transmission is decreased at rest, transmission is increased during repetitive contractions (439); the mechanism is unknown.
Patients infected with human immunodeficiency virus (HIV) but free of AIDS-related pulmonary complications experience dyspnea (440). Severity of dyspnea is related to respiratory muscle strength, rather than to lung volume or diffusing capacity (441). Patients seropositive for HIV but without a history of AIDS-associated pulmonary complications exhibit a 20 to 30% decrease in inspiratory and expiratory muscle strength (441). These patients achieve about a 40% smaller load during inspiratory endurance testing than do healthy subjects (441). Impaired respiratory muscle function might result from activation of the ubiquitin–proteasome proteolytic system (Figure 5) (165), zidovudine-associated myopathy, decreased l-carnitine, or deficiency of glutathione (441).
An incision of the thoracic cage impairs the ability of the respiratory muscles to generate pressure, and it occasionally impairs lung and chest wall mechanics (442). A posterolateral thoracotomy through the fifth or sixth intercostal space is a common approach in noncardiac surgery. The approach has three detrimental effects on respiratory muscle function (442): it transects the trapezius, latissimus dorsi, serratus anterior, and intercostal muscles; it may damage the long thoracic and intercostal nerves; and it may induce profound diaphragmatic inhibition (442).
Thoracic surgery can temporarily increase respiratory load. At the end of coronary bypass surgery, lung compliance is less and lung resistance is greater after chest closure than before surgery (443). An increase in lung water after cardiopulmonary bypass, especially if the lungs remain collapsed during surgery, contributes to the worsening mechanics. In eight patients undergoing valvular surgery, compliances of the chest wall and lung were less at 4 hours after surgery that before surgery (444). By 7 hours, chest wall compliance was back to baseline and lung compliance was higher than before surgery (444). The investigators speculated that the initial decrease in lung compliance is caused by interstitial fluid secondary to increased vascular permeability (444). The subsequent increase in lung compliance may result from mobilization of fluid that had accumulated before surgery (as a consequence of valvular disease) and with extracorporeal circulation (increased permeability). An increase in gastric pressure (from 2 to 6 cm H2O) at 4 hours after surgery (444) suggests that the decreased chest wall compliance might have resulted from increased intestinal permeability, a known complication of cardiopulmonary bypass. These data clarify why chest wall mechanics are most abnormal when fluid balance is most positive (4 hours after surgery), and why some investigators failed to detect abnormalities immediately after surgery (443).
Diaphragmatic dysfunction may result from phrenic nerve damage complicating cardiac surgery. The injury is usually attributed to the use of ice slush to promote cardiac preservation (445). In a prospective study of 63 patients, 13 patients (21%) developed prolonged phrenic nerve conduction times: the left nerve for 12 patients and both nerves for 1 patient (445). More frequent involvement of the left phrenic nerve probably results from slush accumulating in the left posterolateral pericardium (445). Damage involves the myelin sheath, which resolves in 12 weeks or less, or the axon, which takes much longer to recover (446), or both.
The precise incidence of the injury is unclear because of limitations in diagnostic techniques. A raised hemidiaphragm or reduced lung volumes are not specific, and overestimate its incidence. A prolonged phrenic nerve conduction time had been considered specific and sensitive, but latency can be normal with incomplete nerve injury (447). In a prospective study of 59 patients undergoing cardiac surgery (447), the amplitude and area of diaphragmatic evoked potentials were more sensitive than latency in detecting phrenic nerve paresis. Only the failure of phrenic nerve stimulation to produce a diaphragmatic action potential can be considered specific for complete phrenic nerve damage.
Unilateral injury is rarely life threatening. Some (446, 448) but not all investigators (445) report that weaning is difficult in the first 2 to 3 days after surgery. Less than 2% of patients develop bilateral diaphragmatic paralysis resulting in prolonged ventilator dependency (445). Integrity of the phrenic nerve, assessed by conduction studies, is first established within 2 to 12 months and continues for at least 20 months (446). About 30% of patients never recover diaphragmatic function (449).
Diaphragmatic plication has been used to treat symptomatic patients (450, 451). Unilateral plication of a paralyzed hemidiaphragm decreases work of breathing and improves the efficiency of the respiratory muscles (including the nonparalyzed hemidiaphragm) in generating tidal volume (452). With bilateral paralysis, bilateral plication improves the efficiency of the rib cage muscles in generating tidal volume (452). Because phrenic nerve function recovers over time, plication should be reserved for the minority of patients with persistent symptoms (450). Noninvasive ventilation may be a more attractive option (92, 445).
Patients undergoing upper abdominal surgery commonly develop marked reductions in lung volumes, elevations of both hemidiaphragms, and lower lobe atelectasis. Dysfunction of the diaphragm is incriminated by several pieces of evidence: decreases in tidal swings in transdiaphragmatic pressure (453, 454); decreases in the ratio of tidal changes in gastric pressure over tidal changes in esophageal or transdiaphragmatic pressure (453) (not accountable by change in abdominal compliance); and decreases in the ratio of abdominal to rib cage diameter (453). The reduction in diaphragmatic activity is maximal between 2 and 8 hours after surgery, returning to normal over 24 hours (453). The reduction in diaphragmatic activity contributes to lower lobe atelectasis and other respiratory complications (455).
Several factors may contribute to diaphragmatic dysfunction after upper abdominal surgery. First, phrenic nerve output may be inhibited by stimulation of visceral or somatic afferent pathways during surgery (454, 456). Second, pain causing submaximal voluntary contractions is probably important (457), despite previous reports to the contrary. It is not clear whether alteration in the contractility of the diaphragm per se contributes or not to postoperative diaphragmatic dysfunction (458). Diaphragmatic dysfunction is not caused by general anesthesia (halothane and thiopental) because it does not arise after lower abdominal surgery.
Administration of aminophylline immediately after upper abdominal surgery lessens the decrease in maximum inspiratory pressure and tends to improve maximum expiratory pressure (459). Administration of digoxin 48 hours after upper abdominal surgery produced a 15% increase in maximum inspiratory pressure and a 12% increase in maximum expiratory pressure (458). The increases in pressures are not sufficient to improve lung volumes after surgery (458, 459). In a double-blind trial, pulmonary complications were decreased from about 60% in high-risk patients treated with placebo to about 20% in patients treated with doxapram, a respiratory stimulant (455).
A considerable body of research has been published since the last State-of-the-Art review on respiratory muscles (1–3). Information about respiratory muscle dysfunction in critically ill patients was almost nonexistent at that time; several new syndromes have since been described and research on the effect of sepsis has become one of the fastest growing areas. Research on the molecular basis of neuromuscular disorders had hardly commenced at the time of the preceding review, and understanding in this field has accelerated rapidly. Significant advances have also occurred in the staple entities of obstructive lung disease, heart failure, and spinal cord injury. Better understanding of pathophysiologic mechanisms, however, has not been accompanied by significant improvements in everyday diagnostic techniques. The approach for assessing respiratory muscle function in a pulmonary function laboratory has not changed over the last 25 years (only its limitations have been better delineated). Respiratory muscle function is monitored at a rudimentary level in routine critical care practice. Stagnation in diagnostic and monitoring techniques may have stemmed from the paucity of new therapies directed at the respiratory muscles. The mechanisms whereby cytokines cause respiratory muscle dysfunction are rapidly unfolding and new pharmacologic agents have been developed. Together, these advances should motivate the introduction of more advanced diagnostic and monitoring techniques into everyday clinical practice. Disappointingly, the gap between basic understanding of pathophysiologic mechanisms and the translation of this knowledge into improvements in patient outcome has widened over the last 25 years. It is hoped that this gap will be narrowed by the time of the next State-of-the-Art review on respiratory muscles.
The authors gratefully thank Mr. Yoon-Sub Choi for assistance with many of the figures.
|1.||Derenne JP, Macklem PT, Roussos C. The respiratory muscles: mechanics, control, and pathophysiology. Part I. Am Rev Respir Dis 1978;118:119–133.|
|2.||Derenne JP, Macklem PT, Roussos C. The respiratory muscles: mechanics, control, and pathophysiology. Part II. Am Rev Respir Dis 1978;118:373–390.|
|3.||Derenne JP, Macklem PT, Roussos C. The respiratory muscles: mechanics, control, and pathophysiology. Part III. Am Rev Respir Dis 1978;118:581–601.|
|4.||American Thoracic Society, European Respiratory Society. ATS/ERS statement on respiratory muscle testing. Am J Respir Crit Care Med 2002;166:518–624.|
|5.||Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256–1276.|
|6.||Laghi F, Jubran A, Topeli A, Fahey PJ, Garrity ER Jr, Arcidi JM, de Pinto DJ, Edwards LC, Tobin MJ. Effect of lung volume reduction surgery on neuromechanical coupling of the diaphragm. Am J Respir Crit Care Med 1998;157:475–483.|
|7.||Jubran A, Tobin MJ. Pathophysiologic basis of acute respiratory distress in patients who fail a trial of weaning from mechanical ventilation. Am J Respir Crit Care Med 1997;155:906–915.|
|8.||Officer TM, Pellegrino R, Brusasco V, Rodarte JR. Measurement of pulmonary resistance and dynamic compliance with airway obstruction. J Appl Physiol 1998;85:1982–1988.|
|9.||Tobin MJ, Chadha TS, Jenouri G, Birch SJ, Gazeroglu HB, Sackner MA. Breathing patterns. 1. Normal subjects. Chest 1983;84:202–205.|
|10.||Tobin MJ, Chadha TS, Jenouri G, Birch SJ, Gazeroglu HB, Sackner MA. Breathing patterns. 2. Diseased subjects. Chest 1983;84:286–294.|
|11.||Sliwinski P, Kaminski D, Zielinski J, Yan S. Partitioning of the elastic work of inspiration in patients with COPD during exercise. Eur Respir J 1998;11:416–421.|
|12.||Eltayara L, Becklake MR, Volta CA, Milic-Emili J. Relationship between chronic dyspnea and expiratory flow limitation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;154:1726–1734.|
|13.||Cassart M, Pettiaux N, Gevenois PA, Paiva M, Estenne M. Effect of chronic hyperinflation on diaphragm length and surface area. Am J Respir Crit Care Med 1997;156:504–508.|
|14.||Laghi F, Harrison MJ, Tobin MJ. Comparison of magnetic and electrical phrenic nerve stimulation in assessment of diaphragmatic contractility. J Appl Physiol 1996;80:1731–1742.|
|15.||Walsh JM, Webber CL Jr, Fahey PJ, Sharp JT. Structural change of the thorax in chronic obstructive pulmonary disease. J Appl Physiol 1992;72:1270–1278.|
|16.||Cassart M, Gevenois PA, Estenne M. Rib cage dimensions in hyperinflated patients with severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;154:800–805.|
|17.||De Troyer A, Legrand A, Gevenois PA, Wilson TA. Mechanical advantage of the human parasternal intercostal and triangularis sterni muscles. J Physiol 1998;513:915–925.|
|18.||Wilson TA, Legrand A, Gevenois PA, De Troyer A. Respiratory effects of the external and internal intercostal muscles in humans. J Physiol 2001;530:319–330.|
|19.||Gauthier AP, Verbanck S, Estenne M, Segebarth C, Macklem PT, Paiva M. Three-dimensional reconstruction of the in vivo human diaphragm shape at different lung volumes. J Appl Physiol 1994;76:495–506.|
|20.||Brancatisano A, Engel LA, Loring SH. Lung volume and effectiveness of inspiratory muscles. J Appl Physiol 1993;74:688–694.|
|21.||McKenzie DK, Gorman RB, Tolman J, Pride NB, Gandevia SC. Estimation of diaphragm length in patients with severe chronic obstructive pulmonary disease. Respir Physiol 2000;123:225–234.|
|22.||Zocchi L, Garzaniti N, Newman S, Macklem PT. Effect of hyperinflation and equalization of abdominal pressure on diaphragmatic action. J Appl Physiol 1987;62:1655–1664.|
|23.||Rochester DF, Braun NM. Determinants of maximal inspiratory pressure in chronic obstructive pulmonary disease. Am Rev Respir Dis 1985;132:42–47.|
|24.||Newell SZ, McKenzie DK, Gandevia SC. Inspiratory and skeletal muscle strength and endurance and diaphragmatic activation in patients with chronic airflow limitation. Thorax 1989;44:903–912.|
|25.||Topeli A, Laghi F, Tobin MJ. Can diaphragmatic contractility be assessed by twitch airway pressures in patients with chronic obstructive pulmonary disease? Am J Respir Crit Care Med 1999;160:1369–1374.|
|26.||Similowski T, Yan S, Gauthier AP, Macklem PT, Bellemare F. Contractile properties of the human diaphragm during chronic hyperinflation. N Engl J Med 1991;325:917–923.|
|27.||Cassart M, Hamacher J, Verbandt Y, Wildermuth S, Ritscher D, Russi EW, de Francquen P, Cappello M, Weder W, Estenne M. Effects of lung volume reduction surgery for emphysema on diaphragm dimensions and configuration. Am J Respir Crit Care Med 2001;163:1171–1175.|
|28.||Orozco-Levi M, Gea J, Lloreta JL, Felez M, Minguella J, Serrano S, Broquetas JM. Subcellular adaptation of the human diaphragm in chronic obstructive pulmonary disease. Eur Respir J 1999;13:371–378.|
|29.||Farkas GA, Roussos C. Diaphragm in emphysematous hamsters: sarcomere adaptability. J Appl Physiol 1983;54:1635–1640.|
|30.||Supinski GS, Kelsen SG. Effect of elastase-induced emphysema on the force-generating ability of the diaphragm. J Clin Invest 1982;70:978–988.|
|31.||Decramer M, de Bock V, Dom R. Functional and histologic picture of steroid-induced myopathy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;153:1958–1964.|
|32.||Hughes PD, Polkey MI, Harrus ML, Coats AJ, Moxham J, Green M. Diaphragm strength in chronic heart failure. Am J Respir Crit Care Med 1999;160:529–534.|
|33.||Schols AM, Soeters PB, Mostert R, Pluymers RJ, Wouters EF. Physiologic effects of nutritional support and anabolic steroids in patients with chronic obstructive pulmonary disease: a placebo-controlled randomized trial. Am J Respir Crit Care Med 1995;152:1268–1274.|
|34.||Decramer M, Lacquet LM, Fagard R, Rogiers P. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med 1994;150:11–16.|
|35.||Engelen MP, Schols AM, Baken WC, Wesseling GJ, Wouters EF. Nutritional depletion in relation to respiratory and peripheral skeletal muscle function in out-patients with COPD. Eur Respir J 1994;7:1793–1797.|
|36.||Laaban JP, Kouchakji B, Dore MF, Orvoen-Frija E, David P, Rochemaure J. Nutritional status of patients with chronic obstructive pulmonary disease and acute respiratory failure. Chest 1993;103:1362–1368.|
|37.||Schols AM, Slangen J, Volovics L, Wouters EF. Weight loss is a reversible factor in the prognosis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:1791–1797.|
|38.||Marquis K, Debigare R, Lacasse Y, LeBlanc P, Jobin J, Carrier G, Maltais F. Midthigh muscle cross-sectional area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:809–813.|
|39.||Mador MJ. Muscle mass, not body weight, predicts outcome in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:787–789.|
|40.||Lewis MI, Feinberg AT, Fournier M. IGF-I and/or growth hormone preserve diaphragm fiber size with moderate malnutrition. J Appl Physiol 1998;85:189–197.|
|41.||Ameredes BT, Watchko JF, Daood MJ, Rosas JF, Donahoe MP, Rogers RM. Growth hormone restores aged diaphragm myosin composition and performance after chronic undernutrition. J Appl Physiol 1999;87:1253–1259.|
|42.||Lewis MI, Lorusso TJ, Zhan WZ, Sieck GC. Interactive effects of denervation and malnutrition on diaphragm structure and function. J Appl Physiol 1996;81:2165–2172.|
|43.||Lewis MI, Monn SA, Zhan WZ, Sieck GC. Interactive effects of emphysema and malnutrition on diaphragm structure and function. J Appl Physiol 1994;77:947–955.|
|44.||American Thoracic Society, European Respiratory Society. Skeletal muscle dysfunction in chronic obstructive pulmonary disease: a statement of the American Thoracic Society and European Respiratory Society. Am J Respir Crit Care Med 1999;159:S1–40.|
|45.||Debigare R, Cote CH, Maltais F. Peripheral muscle wasting in chronic obstructive pulmonary disease: clinical relevance and mechanisms. Am J Respir Crit Care Med 2001;164:1712–1717.|
|46.||Li X, Moody MR, Engel D, Walker S, Clubb FJ Jr, Sivasubramanian N, Mann DL, Reid MB. Cardiac-specific overexpression of tumor necrosis factor-α causes oxidative stress and contractile dysfunction in mouse diaphragm. Circulation 2000;102:1690–1696.|
|47.||Reid MB, Lannergren J, Westerblad H. Respiratory and limb muscle weakness induced by tumor necrosis factor-α: involvement of muscle myofilaments. Am J Respir Crit Care Med 2002;166:479–484.|
|48.||Fong Y, Moldawer LL, Marano M, Wei H, Barber A, Manogue K, Tracey KJ, Kuo G, Fischman DA, Cerami A. Cachectin/TNF or IL-1β induces cachexia with redistribution of body proteins. Am J Physiol 1989;256:R659–R665.|
|49.||Cheema IR, Hermann C, Postell S, Barnes P. Effect of chronic excess of tumour necrosis factor-α on contractile proteins in rat skeletal muscle. Cytobios 2000;103:169–176.|
|50.||Li YP, Reid MB. NF-κB mediates the protein loss induced by TNF-α in differentiated skeletal muscle myotubes. Am J Physiol Regul Integr Comp Physiol 2000;279:R1165–R1170.|
|51.||Guttridge DC, Mayo MW, Madrid LV, Wang CY, Baldwin AS Jr. NF-κB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 2000;289:2363–2366.|
|52.||Reid MB. Redox modulation of skeletal muscle contraction: what we know and what we don't [invited review]. J Appl Physiol 2001;90:724–731.|
|53.||Baarends EM, Schols AM, Pannemans DL, Westerterp KR, Wouters EF. Total free living energy expenditure in patients with severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1997;155:549–554.|
|54.||Morrison WL, Gibson JN, Scrimgeour C, Rennie MJ. Muscle wasting in emphysema. Clin Sci (Lond) 1988;75:415–420.|
|55.||Engelen MP, Deutz NE, Wouters EF, Schols AM. Enhanced levels of whole-body protein turnover in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:1488–1492.|
|56.||Agusti AG, Sauleda J, Miralles C, Gomez C, Togores B, Sala E, Batle S, Busquets X. Skeletal muscle apoptosis and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:485–489.|
|57.||Lewis MI. Apoptosis as a potential mechanism of muscle cachexia in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:434–436.|
|58.||Lanz JK Jr, Donahoe M, Rogers RM, Ontell M. Effects of growth hormone on diaphragmatic recovery from malnutrition. J Appl Physiol 1992;73:801–805.|
|59.||Creutzberg EC, Schols AM, Weling-Scheepers CA, Buurman WA, Wouters EF. Characterization of nonresponse to high caloric oral nutritional therapy in depleted patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:745–752.|
|60.||Burdet L, de Muralt B, Schutz Y, Pichard C, Fitting JW. Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease: a prospective, randomized, controlled study. Am J Respir Crit Care Med 1997;156:1800–1806.|
|61.||Weisberg J, Wanger J, Olson J, Streit B, Fogarty C, Martin T, Casaburi R. Megestrol acetate stimulates weight gain and ventilation in underweight COPD patients. Chest 2002;121:1070–1078.|
|62.||Leatherman JW, Fluegel WL, David WS, Davies SF, Iber C. Muscle weakness in mechanically ventilated patients with severe asthma. Am J Respir Crit Care Med 1996;153:1686–1690.|
|63.||Gayan-Ramirez G, Vanderhoydonc F, Verhoeven G, Decramer M. Acute treatment with corticosteroids decreases IGF-1 and IGF-2 expression in the rat diaphragm and gastrocnemius. Am J Respir Crit Care Med 1999;159:283–289.|
|64.||Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 2001;294:1704–1708.|
|65.||Gayan-Ramirez G, Vanzeir L, Wuytack F, Decramer M. Corticosteroids decrease mRNA levels of SERCA pumps, whereas they increase sarcolipin mRNA in the rat diaphragm. J Physiol 2000;524:387–397.|
|66.||Aubier M, Viires N. Calcium ATPase and respiratory muscle function. Eur Respir J 1998;11:758–766.|
|67.||Douglass JA, Tuxen DV, Horne M, Scheinkestel CD, Weinmann M, Czarny D, Bowes G. Myopathy in severe asthma. Am Rev Respir Dis 1992;146:517–519.|
|68.||Nava S, Gayan-Ramirez G, Rollier H, Bisschop A, Dom R, de Bock V, Decramer M. Effects of acute steroid administration on ventilatory and peripheral muscles in rats. Am J Respir Crit Care Med 1996;153:1888–1896.|
|69.||Nava S, Fracchia C, Callegari G, Ambrosino N, Barbarito N, Felicetti G. Weakness of respiratory and skeletal muscles after a short course of steroids in patients with acute lung rejection. Eur Respir J 2002;20:497–499.|
|70.||Perez T, Becquart LA, Stach B, Wallaert B, Tonnel AB. Inspiratory muscle strength and endurance in steroid-dependent asthma. Am J Respir Crit Care Med 1996;153:610–615.|
|71.||Mak VH, Bugler JR, Spiro SG. Sternomastoid muscle fatigue and twitch maximum relaxation rate in patients with steroid dependent asthma. Thorax 1993;48:979–984.|
|72.||Decramer M, Stas KJ. Corticosteroid-induced myopathy involving respiratory muscles in patients with chronic obstructive pulmonary disease or asthma. Am Rev Respir Dis 1992;146:800–802.|
|73.||Bellemare F, Grassino A. Force reserve of the diaphragm in patients with chronic obstructive pulmonary disease. J Appl Physiol 1983;55:8–15.|
|74.||Zocchi L, Fitting JW, Majani U, Fracchia C, Rampulla C, Grassino A. Effect of pressure and timing of contraction on human rib cage muscle fatigue. Am Rev Respir Dis 1993;147:857–864.|
|75.||De Troyer A, Leeper JB, McKenzie DK, Gandevia SC. Neural drive to the diaphragm in patients with severe COPD. Am J Respir Crit Care Med 1997;155:1335–1340.|
|76.||Sinderby C, Beck J, Spahija J, Weinberg J, Grassino A. Voluntary activation of the human diaphragm in health and disease. J Appl Physiol 1998;85:2146–2158.|
|77.||Levine S, Kaiser L, Leferovich J, Tikunov B. Cellular adaptations in the diaphragm in chronic obstructive pulmonary disease. N Engl J Med 1997;337:1799–1806.|
|78.||Levine S, Nguyen T, Kaiser LR, Shrager JB. Evaluating respiratory muscle adaptations: a new approach. Am J Respir Crit Care Med 2002;166:1418–1419.|
|79.||Ramirez-Sarmiento A, Orozco-Levi M, Guell R, Barreiro E, Hernandez N, Mota S, Sangenis M, Broquetas JM, Casan P, Gea J. Inspiratory muscle training in patients with chronic obstructive pulmonary disease: structural adaptation and physiologic outcomes. Am J Respir Crit Care Med 2002;166:1491–1497.|
|80.||Gorman RB, McKenzie DK, Pride NB, Tolman JF, Gandevia SC. Diaphragm length during tidal breathing in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:1461–1469.|
|81.||Jubran A, Tobin MJ. The effect of hyperinflation on rib cage-abdominal motion. Am Rev Respir Dis 1992;146:1378–1382.|
|82.||Gosselink RA, Wagenaar RC, Rijswijk H, Sargeant AJ, Decramer ML. Diaphragmatic breathing reduces efficiency of breathing in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;151:1136–1142.|
|83.||De Troyer A, Peche R, Yernault JC, Estenne M. Neck muscle activity in patients with severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1994;150:41–47.|
|84.||Ninane V, Yernault JC, De Troyer A. Intrinsic PEEP in patients with chronic obstructive pulmonary disease: role of expiratory muscles. Am Rev Respir Dis 1993;148:1037–1042.|
|85.||Gandevia SC, Leeper JB, McKenzie DK, De Troyer A. Discharge frequencies of parasternal intercostal and scalene motor units during breathing in normal and COPD subjects. Am J Respir Crit Care Med 1996;153:622–628.|
|86.||Kleinman BS, Frey K, VanDrunen M, Sheikh T, DiPinto D, Mason R, Smith T. Motion of the diaphragm in patients with chronic obstructive pulmonary disease while spontaneously breathing versus during positive pressure breathing after anesthesia and neuromuscular blockade. Anesthesiology 2002;97:298–305.|
|87.||Shrager JB, Kim DK, Hashmi YJ, Stedman HH, Zhu J, Kaiser LR, Levine S. Sarcomeres are added in series to emphysematous rat diaphragm after lung volume reduction surgery. Chest 2002;121:210–215.|
|88.||Ninane V, Rypens F, Yernault JC, De Troyer A. Abdominal muscle use during breathing in patients with chronic airflow obstruction. Am Rev Respir Dis 1992;146:16–21.|
|89.||Yan S, Sinderby C, Bielen P, Beck J, Comtois N, Sliwinski P. Expiratory muscle pressure and breathing mechanics in chronic obstructive pulmonary disease. Eur Respir J 2000;16:684–690.|
|90.||Begin P, Grassino A. Inspiratory muscle dysfunction and chronic hypercapnia in chronic obstructive pulmonary disease. Am Rev Respir Dis 1991;143:905–912.|
|91.||Pitcher WD, Cunningham HS. Oxygen cost of increasing tidal volume and diaphragm flattening in obstructive pulmonary disease. J Appl Physiol 1993;74:2750–2756.|
|92.||Mehta S, Hill NS. Noninvasive ventilation. Am J Respir Crit Care Med 2001;163:540–577.|
|93.||Montes de Oca M, Celli BR. Respiratory muscle recruitment and exercise performance in eucapnic and hypercapnic severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:880–885.|
|94.||Topeli A, Laghi F, Tobin MJ. The voluntary drive to breathe is not decreased in hypercapnic patients with severe COPD. Eur Respir J 2001;18:53–60.|
|95.||Allen GM, McKenzie DK, Gandevia SC, Bass S. Reduced voluntary drive to breathe in asthmatic subjects. Respir Physiol 1993;93:29–40.|
|96.||Koulouris NG, Dimopoulou I, Valta P, Finkelstein R, Cosio MG, Milic-Emili J. Detection of expiratory flow limitation during exercise in COPD patients. J Appl Physiol 1997;82:723–731.|
|97.||Yan S, Kaminski D, Sliwinski P. Inspiratory muscle mechanics of patients with chronic obstructive pulmonary disease during incremental exercise. Am J Respir Crit Care Med 1997;156:807–813.|
|98.||Sinderby C, Spahija J, Beck J, Kaminski D, Yan S, Comtois N, Sliwinski P. Diaphragm activation during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:1637–1641.|
|99.||O'Donnell DE, D'Arsigny C, Webb KA. Effects of hyperoxia on ventilatory limitation during exercise in advanced chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:892–898.|
|100.||O'Donnell DE, D'Arsigny C, Fitzpatrick M, Webb KA. Exercise hypercapnia in advanced chronic obstructive pulmonary disease: the role of lung hyperinflation. Am J Respir Crit Care Med 2002;166:663–668.|
|101.||Dempsey JA. Exercise carbon dioxide retention in chronic obstructive pulmonary disease: a case for ventilation/perfusion mismatch combined with hyperinflation. Am J Respir Crit Care Med 2002;166:634–635.|
|102.||Mador MJ, Kufel TJ, Pineda LA, Sharma GK. Diaphragmatic fatigue and high-intensity exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:118–123.|
|103.||Simon M, LeBlanc P, Jobin J, Desmeules M, Sullivan MJ, Maltais F. Limitation of lower limb Vo2 during cycling exercise in COPD patients. J Appl Physiol 2001;90:1013–1019.|
|104.||Fessler HE, Permutt S. Lung volume reduction surgery and airflow limitation. Am J Respir Crit Care Med 1998;157:715–722.|
|105.||Martinez FJ, Montes de Oca M, Whyte RI, Stetz J, Gay SE, Celli BR. Lung-volume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function. Am J Respir Crit Care Med 1997;155:1984–1990.|
|106.||Loring SH, Leith DE, Connolly MJ, Ingenito EP, Mentzer SJ, Reilly JJ Jr. Model of functional restriction in chronic obstructive pulmonary disease, transplantation, and lung reduction surgery. Am J Respir Crit Care Med 1999;160:821–828.|
|107.||Fessler HE, Scharf SM, Permutt S. Improvement in spirometry following lung volume reduction surgery: application of a physiologic model. Am J Respir Crit Care Med 2002;165:34–40.|
|108.||Benditt JO, Wood DE, McCool FD, Lewis S, Albert RK. Changes in breathing and ventilatory muscle recruitment patterns induced by lung volume reduction surgery. Am J Respir Crit Care Med 1997;155:279–284.|
|109.||Jubran A, Laghi F, Mazur M, Parthasarathy S, Garrity ER Jr, Fahey PJ, Tobin MJ. Partitioning of lung and chest wall mechanics before and after lung volume reduction surgery. Am J Respir Crit Care Med 1998;158:306–310.|
|110.||Lando Y, Boiselle PM, Shade D, Furukawa S, Kuzma AM, Travaline JM, Criner GJ. Effect of lung volume reduction surgery on diaphragm length in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159:796–805.|
|111.||Hoppin FG Jr. Hyperinflation and the (passive) chest wall. Am J Respir Crit Care Med 2001;163:1042–1043.|
|112.||Shrager JB, Kim DK, Hashmi YJ, Lankford EB, Wahl P, Stedman HH, Levine S, Kaiser LR. Lung volume reduction surgery restores the normal diaphragmatic length–tension relationship in emphysematous rats. J Thorac Cardiovasc Surg 2001;121:217–224.|
|113.||Marchand E, De Leyn P, Gayan-Ramirez G, Palecek F, de Bock V, Dom R, Decramer M. Lung volume reduction surgery does not improve diaphragmatic contractile properties or atrophy in hamsters with elastase-induced emphysema. Am J Respir Crit Care Med 2000;162:1052–1057.|
|114.||Mineo TC, Pompeo E, Rogliani P, Dauri M, Turani F, Bollero P, Magliocchetti N. Effect of lung volume reduction surgery for severe emphysema on right ventricular function. Am J Respir Crit Care Med 2002;165:489–494.|
|115.||Scharf SM, Iqbal M, Keller C, Criner G, Lee S, Fessler HE. Hemodynamic characterization of patients with severe emphysema. Am J Respir Crit Care Med 2002;166:314–322.|
|116.||Parthasarathy S, Jubran A, Tobin MJ. Cycling of inspiratory and expiratory muscle groups with the ventilator in airflow limitation. Am J Respir Crit Care Med 1998;158:1471–1478.|
|117.||Geddes D, Davies M, Koyama H, Hansell D, Pastorino U, Pepper J, Agent P, Cullinan P, MacNeill SJ, Goldstraw P. Effect of lung volume reduction surgery in patients with severe emphysema. N Engl J Med 2000;343:239–245.|
|118.||Gelb AF, McKenna RJ Jr, Brenner M, Epstein JD, Zamel N. Lung function 5 years after lung volume reduction surgery for emphysema. Am J Respir Crit Care Med 2001;163:1562–1566.|
|119.||National Emphysema Treatment Trial Research Group. Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med 2001;345:1075–1083.|
|120.||De Meester J, Smits JM, Persijn GG, Haverich A. Listing for lung transplantation: life expectancy and transplant effect, stratified by type of end-stage lung disease, the Eurotransplant experience. J Heart Lung Transplant 2001;20:518–524.|
|121.||Hosenpud JD, Bennett LE, Keck BM, Edwards EB, Novick RJ. Effect of diagnosis on survival benefit of lung transplantation for end-stage lung disease. Lancet 1998;351:24–27.|
|122.||Cassart M, Verbandt Y, de Francquen P, Gevenois PA, Estenne M. Diaphragm dimensions after single-lung transplantation for emphysema. Am J Respir Crit Care Med 1999;159:1992–1997.|
|123.||Yonan NA, el Gamel A, Egan J, Kakadellis J, Rahman A, Deiraniya AK. Single lung transplantation for emphysema: predictors for native lung hyperinflation. J Heart Lung Transplant 1998;17:192–201.|
|124.||Murciano D, Ferretti A, Boczkowski J, Sleiman C, Fournier M, Milic-Emili J. Flow limitation and dynamic hyperinflation during exercise in COPD patients after single lung transplantation. Chest 2000;118:1248–1254.|
|125.||Estenne M, Cassart M, Poncelet P, Gevenois PA. Volume of graft and native lung after single-lung transplantation for emphysema. Am J Respir Crit Care Med 1999;159:641–645.|
|126.||Cheriyan AF, Garrity ER Jr, Pifarre R, Fahey PJ, Walsh JM. Reduced transplant lung volumes after single lung transplantation for chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;151:851–853.|
|127.||Sanchez H, Zoll J, Bigard X, Veksler V, Mettauer B, Lampert E, Lonsdorfer J, Ventura-Clapier R. Effect of cyclosporin A and its vehicle on cardiac and skeletal muscle mitochondria: relationship to efficacy of the respiratory chain. Br J Pharmacol 2001;133:781–788.|
|128.||Sanchez H, Bigard X, Veksler V, Mettauer B, Lampert E, Lonsdorfer J, Ventura-Clapier R. Immunosuppressive treatment affects cardiac and skeletal muscle mitochondria by the toxic effect of vehicle. J Mol Cell Cardiol 2000;32:323–331.|
|129.||Pinet C, Estenne M. Effect of preoperative hyperinflation on static lung volumes after lung transplantation. Eur Respir J 2000;16:482–485.|
|130.||Martinez FJ, Orens JB, Whyte RI, Graf L, Becker FS, Lynch JP III. Lung mechanics and dyspnea after lung transplantation for chronic airflow obstruction. Am J Respir Crit Care Med 1996;153:1536–1543.|
|131.||Guignon I, Cassart M, Gevenois PA, Knoop C, Antoine M, Yernault JC, Estenne M. Persistent hyperinflation after heart–lung transplantation for cystic fibrosis. Am J Respir Crit Care Med 1995;151:534–540.|
|132.||Wanke T, Merkle M, Formanek D, Zifko U, Wieselthaler G, Zwick H, Klepetko W, Burghuber OC. Effect of lung transplantation on diaphragmatic function in patients with chronic obstructive pulmonary disease. Thorax 1994;49:459–464.|
|133.||Pantoja JG, Andrade FH, Stoki DS, Frost AE, Eschenbacher WL, Reid MB. Respiratory and limb muscle function in lung allograft recipients. Am J Respir Crit Care Med 1999;160:1205–1211.|
|134.||Brath H, Lahrmann H, Wanke T, Wisser W, Wild M, Schlechta B, Zwick H, Klepetko W, Burghuber OC. The effect of lung transplantation on the neural drive to the diaphragm in patients with severe COPD. Eur Respir J 1997;10:424–429.|
|135.||Wang XN, Williams TJ, McKenna MJ, Li JL, Fraser SF, Side EA, Snell GI, Walters EH, Carey MF. Skeletal muscle oxidative capacity, fiber type, and metabolites after lung transplantation. Am J Respir Crit Care Med 1999;160:57–63.|
|136.||Pellegrino R, Rodarte JR, Frost AE, Reid MB. Breathing by double-lung recipients during exercise: response to expiratory threshold loading. Am J Respir Crit Care Med 1998;157:106–110.|
|137.||Evans AB, Al Himyary AJ, Hrovat MI, Pappagianopoulos P, Wain JC, Ginns LC, Systrom DM. Abnormal skeletal muscle oxidative capacity after lung transplantation by 31P-MRS. Am J Respir Crit Care Med 1997;155:615–621.|
|138.||Gelb AF, Zamel N. Unsuspected pseudophysiologic emphysema in chronic persistent asthma. Am J Respir Crit Care Med 2000;162:1778–1782.|
|139.||Gorini M, Iandelli I, Misuri G, Bertoli F, Filippelli M, Mancini M, Duranti R, Gigliotti F, Scano G. Chest wall hyperinflation during acute bronchoconstriction in asthma. Am J Respir Crit Care Med 1999;160:808–816.|
|140.||Binks AP, Moosavi SH, Banzett RB, Schwartzstein RM. “Tightness” sensation of asthma does not arise from the work of breathing. Am J Respir Crit Care Med 2002;165:78–82.|
|141.||Davenport PW. What caused the screech, whamity, bang, and thump? Am J Respir Crit Care Med 2002;165:2–3.|
|142.||Boczkowski J, Murciano D, Pichot MH, Ferretti A, Pariente R, Milic-Emili J. Expiratory flow limitation in stable asthmatic patients during resting breathing. Am J Respir Crit Care Med 1997;156:752–757.|
|143.||Mitsunobu F, Mifune T, Ashida K, Hosaki Y, Tsugeno H, Okamoto M, Harada S, Takata S, Tanizaki Y. Influence of age and disease severity on high resolution CT lung densitometry in asthma. Thorax 2001;56:851–856.|
|144.||McKenzie DK, Gandevia SC. Strength and endurance of inspiratory, expiratory, and limb muscles in asthma. Am Rev Respir Dis 1986;134:999–1004.|
|145.||Gorman RB, McKenzie DK, Gandevia SC, Plassman BL. Inspiratory muscle strength and endurance during hyperinflation and histamine induced bronchoconstriction. Thorax 1992;47:922–927.|
|146.||de Bruin PF, Ueki J, Watson A, Pride NB. Size and strength of the respiratory and quadriceps muscles in patients with chronic asthma. Eur Respir J 1997;10:59–64.|
|147.||Weiner P, Berar-Yanay N, Davidovich A, Magadle R, Weiner M. Specific inspiratory muscle training in patients with mild asthma with high consumption of inhaled β2-agonists. Chest 2000;117:722–727.|
|148.||Butler JE, McKenzie DK, Gandevia SC. Impaired reflex responses to airway occlusion in the inspiratory muscles of asthmatic subjects. Thorax 1996;51:490–495.|
|149.||Macefield VG, Gandevia SC, Bigland-Ritchie B, Gorman RB, Burke D. The firing rates of human motoneurones voluntarily activated in the absence of muscle afferent feedback. J Physiol 1993;471:429–443.|
|150.||Webster KE, Colrain IM. P3-specific amplitude reductions to respiratory and auditory stimuli in subjects with asthma. Am J Respir Crit Care Med 2002;166:47–52.|
|151.||Davenport PW, Cruz M, Stecenko AA, Kifle Y. Respiratory-related evoked potentials in children with life-threatening asthma. Am J Respir Crit Care Med 2000;161:1830–1835.|
|152.||Allen GM, Hickie I, Gandevia SC, McKenzie DK. Impaired voluntary drive to breathe: a possible link between depression and unexplained ventilatory failure in asthmatic patients. Thorax 1994;49:881–884.|
|153.||Kikuchi Y, Okabe S, Tamura G, Hida W, Homma M, Shirato K, Takishima T. Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 1994;330:1329–1334.|
|154.||Salome CM, Reddel HK, Ware SI, Roberts AM, Jenkins CR, Marks GB, Woolcock AJ. Effect of budesonide on the perception of induced airway narrowing in subjects with asthma. Am J Respir Crit Care Med 2002;165:15–21.|
|155.||Drexler H, Riede U, Munzel T, Konig H, Funke E, Just H. Alterations of skeletal muscle in chronic heart failure. Circulation 1992;85:1751–1759.|
|156.||Okita K, Yonezawa K, Nishijima H, Hanada A, Ohtsubo M, Kohya T, Murakami T, Kitabatake A. Skeletal muscle metabolism limits exercise capacity in patients with chronic heart failure. Circulation 1998;98:1886–1891.|
|157.||Granton JT, Naughton MT, Benard DC, Liu PP, Goldstein RS, Bradley TD. CPAP improves inspiratory muscle strength in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1996;153:277–282.|
|158.||Daganou M, Dimopoulou I, Alivizatos PA, Tzelepis GE. Pulmonary function and respiratory muscle strength in chronic heart failure: comparison between ischaemic and idiopathic dilated cardiomyopathy. Heart 1999;81:618–620.|
|159.||Lecarpentier Y, Coirault C, Lerebours G, Desche P, Scalbert E, Lambert F, Chemla D. Effects of angiotensin converting enzyme inhibition on crossbridge properties of diaphragm in cardiomyopathic hamsters of the dilated bio 53–58 strain. Am J Respir Crit Care Med 1997;155:630–636.|
|160.||Sieck GC, Fournier M. Diaphragm motor unit recruitment during ventilatory and nonventilatory behaviors. J Appl Physiol 1989;66:2539–2545.|
|161.||Tikunov B, Levine S, Mancini D. Chronic congestive heart failure elicits adaptations of endurance exercise in diaphragmatic muscle. Circulation 1997;95:910–916.|
|162.||Lindsay DC, Lovegrove CA, Dunn MJ, Bennett JG, Pepper JR, Yacoub MH, Poole-Wilson PA. Histological abnormalities of muscle from limb, thorax and diaphragm in chronic heart failure. Eur Heart J 1996;17:1239–1250.|
|163.||Howell S, Maarek JM, Fournier M, Sullivan K, Zhan WZ, Sieck GC. Congestive heart failure: differential adaptation of the diaphragm and latissimus dorsi. J Appl Physiol 1995;79:389–397.|
|164.||Supinski G, DiMarco A, Dibner-Dunlap M. Alterations in diaphragm strength and fatiguability in congestive heart failure. J Appl Physiol 1994;76:2707–2713.|
|165.||Mitch WE, Goldberg AL. Mechanisms of muscle wasting: the role of the ubiquitin–proteasome pathway. N Engl J Med 1996;335:1897–1905.|
|166.||Mancini DM, Henson D, LaManca J, Levine S. Respiratory muscle function and dyspnea in patients with chronic congestive heart failure. Circulation 1992;86:909–918.|
|167.||Johnson PH, Cowley AJ, Kinnear WJ. A randomized controlled trial of inspiratory muscle training in stable chronic heart failure. Eur Heart J 1998;19:1249–1253.|
|168.||Mancini DM, Henson D, La Manca J, Donchez L, Levine S. Benefit of selective respiratory muscle training on exercise capacity in patients with chronic congestive heart failure. Circulation 1995;91:320–329.|
|169.||Mancini DM, Henson D, LaManca J, Levine S. Evidence of reduced respiratory muscle endurance in patients with heart failure. J Am Coll Cardiol 1994;24:972–981.|
|170.||O'Donnell DE, D'Arsigny C, Raj S, Abdollah H, Webb KA. Ventilatory assistance improves exercise endurance in stable congestive heart failure. Am J Respir Crit Care Med 1999;160:1804–1811.|
|171.||Duguet A, Tantucci C, Lozinguez O, Isnard R, Thomas D, Zelter M, Derenne JP, Milic-Emili J, Similowski T. Expiratory flow limitation as a determinant of orthopnea in acute left heart failure. J Am Coll Cardiol 2000;35:690–700.|
|172.||Lenique F, Habis M, Lofaso F, Dubois-Rande JL, Harf A, Brochard L. Ventilatory and hemodynamic effects of continuous positive airway pressure in left heart failure. Am J Respir Crit Care Med 1997;155:500–505.|
|173.||Agostoni P, Pellegrino R, Conca C, Rodarte JR, Brusasco V. Exercise hyperpnea in chronic heart failure: relationships to lung stiffness and expiratory flow limitation. J Appl Physiol 2002;92:1409–1416.|
|174.||Nanas S, Nanas J, Kassiotis C, Alexopoulos G, Samakovli A, Kanakakis J, Tsolakis E, Roussos C. Respiratory muscles performance is related to oxygen kinetics during maximal exercise and early recovery in patients with congestive heart failure. Circulation 1999;100:503–508.|
|175.||Mancini D, Donchez L, Levine S. Acute unloading of the work of breathing extends exercise duration in patients with heart failure. J Am Coll Cardiol 1997;29:590–596.|
|176.||Cabanes L, Costes F, Weber S, Regnard J, Benvenuti C, Castaigne A, Guerin F, Lockhart A. Improvement in exercise performance by inhalation of methoxamine in patients with impaired left ventricular function. N Engl J Med 1992;326:1661–1665.|
|177.||Uren NG, Davies SW, Jordan SL, Lipkin DP. Inhaled bronchodilators increase maximum oxygen consumption in chronic left ventricular failure. Eur Heart J 1993;14:744–750.|
|178.||Harms CA, Babcock MA, McClaran SR, Pegelow DF, Nickele GA, Nelson WB, Dempsey JA. Respiratory muscle work compromises leg blood flow during maximal exercise. J Appl Physiol 1997;82:1573–1583.|
|179.||Laghi F, Cattapan SE, Jubran A, Parthasarathy S, Warshawsky P, Choi YS, Tobin MJ. Is weaning failure caused by low-frequency fatigue of the diaphragm? Am J Respir Crit Care Med 2003;167:120–127.|
|180.||Faragher MW, Day BJ. A practical approach to weakness in the intesive care unit. In: Cros D, editor. Peripheral neuropathy: a practical approach to diagnosis and management. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 370–386.|
|181.||Latronico N, Fenzi F, Recupero D, Guarneri B, Tomelleri G, Tonin P, De Maria G, Antonini L, Rizzuto N, Candiani A. Critical illness myopathy and neuropathy. Lancet 1996;347:1579–1582.|
|182.||Laghi F, Segal J, Choe WK, Tobin MJ. Effect of imposed inflation time on respiratory frequency and hyperinflation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:1365–1370.|
|183.||Tobin MJ, Perez W, Guenther SM, Semmes BJ, Mador MJ, Allen SJ, Lodato RF, Dantzker DR. The pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 1986;134:1111–1118.|
|184.||Coussa ML, Guerin C, Eissa NT, Corbeil C, Chasse M, Braidy J, Matar N, Milic-Emili J. Partitioning of work of breathing in mechanically ventilated COPD patients. J Appl Physiol 1993;75:1711–1719.|
|185.||Bolton CF, Laverty DA, Brown JD, Witt NJ, Hahn AF, Sibbald WJ. Critically ill polyneuropathy: electrophysiological studies and differentiation from Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry 1986;49:563–573.|
|186.||De Jonghe B, Sharshar T, Lefaucheur JP, Authier FJ, Durand-Zaleski I, Boussarsar M, Cerf C, Renaud E, Mesrati F, Carlet J, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 2002;288:2859–2867.|
|187.||Tepper M, Rakic S, Haas JA, Woittiez AJ. Incidence and onset of critical illness polyneuropathy in patients with septic shock. Neth J Med 2000;56:211–214.|
|188.||Garnacho-Montero J, Madrazo-Osuna J, Garcia-Garmendia JL, Ortiz-Leyba C, Jimenez-Jimenez FJ, Barrero-Almodovar A, Garnacho-Montero MC, Moyano-Del-Estad MR. Critical illness polyneuropathy: risk factors and clinical consequences: a cohort study in septic patients. Intensive Care Med 2001;27:1288–1296.|
|189.||Leijten FS, Harinck de Weerd JE, Poortvliet DC, De Weerd AW. The role of polyneuropathy in motor convalescence after prolonged mechanical ventilation. JAMA 1995;274:1221–1225.|
|190.||de Seze M, Petit H, Wiart L, Cardinaud JP, Gaujard E, Joseph PA, Mazaux JM, Barat M. Critical illness polyneuropathy: a 2-year follow-up study in 19 severe cases. Eur Neurol 2000;43:61–69.|
|191.||Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359–1367.|
|192.||Zochodne DW, Bolton CF, Wells GA, Gilbert JJ, Hahn AF, Brown JD, Sibbald WA. Critical illness polyneuropathy: a complication of sepsis and multiple organ failure. Brain 1987;110:819–841.|
|193.||Sander HW, Saadeh PB, Chandswang N, Greenbaum D, Chokroverty S. Diaphragmatic denervation in intensive care unit patients. Electromyogr Clin Neurophysiol 1999;39:3–5.|
|194.||Leijten FS, De Weerd AW, Poortvliet DC, De Ridder VA, Ulrich C, Harink-De Weerd JE. Critical illness polyneuropathy in multiple organ dysfunction syndrome and weaning from the ventilator. Intensive Care Med 1996;22:856–861.|
|195.||Druschky A, Herkert M, Radespiel-Troger M, Druschky K, Hund E, Becker CM, Hilz MJ, Erbguth F, Neundorfer B. Critical illness polyneuropathy: clinical findings and cell culture assay of neurotoxicity assessed by a prospective study. Intensive Care Med 2001;27:686–693.|
|196.||Larsson L, Li X, Edstrom L, Eriksson LI, Zackrisson H, Argentini C, Schiaffino S. Acute quadriplegia and loss of muscle myosin in patients treated with nondepolarizing neuromuscular blocking agents and corticosteroids: mechanisms at the cellular and molecular levels. Crit Care Med 2000;28:34–45.|
|197.||Rich MM, Bird SJ, Raps EC, McCluskey LF, Teener JW. Direct muscle stimulation in acute quadriplegic myopathy. Muscle Nerve 1997;20:665–673.|
|198.||Faragher MW, Day BJ, Dennett X. Critical care myopathy: an electrophysiological and histological study. Muscle Nerve 1996;19:516–518.|
|199.||Rich MM, Teener JW, Raps EC, Schotland DL, Bird SJ. Muscle is electrically inexcitable in acute quadriplegic myopathy. Neurology 1996;46:731–736.|
|200.||Lacomis D, Giuliani MJ, Van Cott A, Kramer DJ. Acute myopathy of intensive care: clinical, electromyographic, and pathological aspects. Ann Neurol 1996;40:645–654.|
|201.||Rouleau G, Karpati G, Carpenter S, Soza M, Prescott S, Holland P. Glucocorticoid excess induces preferential depletion of myosin in denervated skeletal muscle fibers. Muscle Nerve 1987;10:428–438.|
|202.||Tiao G, Fagan J, Roegner V, Lieberman M, Wang JJ, Fischer JE, Hasselgren PO. Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids. J Clin Invest 1996;97:339–348.|
|203.||Hussain SN. Respiratory muscle dysfunction in sepsis. Mol Cell Biochem 1998;179:125–134.|
|204.||Callahan LA, Nethery D, Stofan D, DiMarco A, Supinski G. Free radical-induced contractile protein dysfunction in endotoxin-induced sepsis. Am J Respir Cell Mol Biol 2001;24:210–217.|
|205.||Laghi F. Curing the septic diaphragm with the ventilator. Am J Respir Crit Care Med 2002;165:145–146.|
|206.||Boczkowski J, Lanone S, Ungureanu-Longrois D, Danialou G, Fournier T, Aubier M. Induction of diaphragmatic nitric oxide synthase after endotoxin administration in rats: role on diaphragmatic contractile dysfunction. J Clin Invest 1996;98:1550–1559.|
|207.||Lin MC, Ebihara S, El Dwairi Q, Hussain SN, Yang L, Gottfried SB, Comtois A, Petrof BJ. Diaphragm sarcolemmal injury is induced by sepsis and alleviated by nitric oxide synthase inhibition. Am J Respir Crit Care Med 1998;158:1656–1663.|
|208.||Krause KM, Moody MR, Andrade FH, Taylor AA, Miller CC III, Kobzik L, Reid MB. Peritonitis causes diaphragm weakness in rats. Am J Respir Crit Care Med 1998;157:1277–1282.|
|209.||El Dwairi Q, Comtois A, Guo Y, Hussain SN. Endotoxin-induced skeletal muscle contractile dysfunction: contribution of nitric oxide synthases. Am J Physiol 1998;274:C770–C779.|
|210.||Lanone S, Mebazaa A, Heymes C, Henin D, Poderoso JJ, Panis Y, Zedda C, Billiar T, Payen D, Aubier M, et al. Muscular contractile failure in septic patients: role of the inducible nitric oxide synthase pathway. Am J Respir Crit Care Med 2000;162:2308–2315.|
|211.||Comtois AS, El Dwairi Q, Laubach VE, Hussain SN. Lipopolysaccharide-induced diaphragmatic contractile dysfunction in mice lacking the inducible nitric oxide synthase. Am J Respir Crit Care Med 1999;159:1975–1980.|
|212.||Comtois AS, Barreiro E, Huang PL, Marette A, Perrault M, Hussain SN. Lipopolysaccharide-induced diaphragmatic contractile dysfunction and sarcolemmal injury in mice lacking the neuronal nitric oxide synthase. Am J Respir Crit Care Med 2001;163:977–982.|
|213.||Javesghani D, Magder SA, Barreiro E, Quinn MT, Hussain SN. Molecular characterization of a superoxide-generating NAD(P)H oxidase in the ventilatory muscles. Am J Respir Crit Care Med 2002;165:412–418.|
|214.||Ebihara S, Hussain SN, Danialou G, Cho WK, Gottfried SB, Petrof BJ. Mechanical ventilation protects against diaphragm injury in sepsis: interaction of oxidative and mechanical stresses. Am J Respir Crit Care Med 2002;165:221–228.|
|215.||Stofan DA, Callahan LA, DiMarco AF, Nethery DE, Supinski GS. Modulation of release of reactive oxygen species by the contracting diaphragm. Am J Respir Crit Care Med 2000;161:891–898.|
|216.||Fujimura N, Sumita S, Aimono M, Masuda Y, Shichinohe Y, Narimatsu E, Namiki A. Effect of free radical scavengers on diaphragmatic contractility in septic peritonitis. Am J Respir Crit Care Med 2000;162:2159–2165.|
|217.||Taille C, Foresti R, Lanone S, Zedda C, Green C, Aubier M, Motterlini R, Boczkowski J. Protective role of heme oxygenases against endotoxin-induced diaphragmatic dysfunction in rats. Am J Respir Crit Care Med 2001;163:753–761.|
|218.||Tiao G, Hobler S, Wang JJ, Meyer TA, Luchette FA, Fischer JE, Hasselgren PO. Sepsis is associated with increased mRNAs of the ubiquitin–proteasome proteolytic pathway in human skeletal muscle. J Clin Invest 1997;99:163–168.|
|219.||Powers SK, Shanely RA, Coombes JS, Koesterer TJ, McKenzie M, Van Gammeren D, Cicale M, Dodd SL. Mechanical ventilation results in progressive contractile dysfunction in the diaphragm. J Appl Physiol 2002;92:1851–1858.|
|220.||Le Bourdelles G, Viires N, Boczkowski J, Seta N, Pavlovic D, Aubier M. Effects of mechanical ventilation on diaphragmatic contractile properties in rats. Am J Respir Crit Care Med 1994;149:1539–1544.|
|221.||Yang L, Luo J, Bourdon J, Lin MC, Gottfried SB, Petrof BJ. Controlled mechanical ventilation leads to remodeling of the rat diaphragm. Am J Respir Crit Care Med 2002;166:1135–1140.|
|222.||Sassoon CS, Ciaozzo VJ, Manka A, Sieck GC. Altered diaphragm contractile properties with controlled mechanical ventilation. J Appl Physiol 2002;92:2585–2595.|
|223.||Radell PJ, Remahl S, Nichols DG, Eriksson LI. Effects of prolonged mechanical ventilation and inactivity on piglet diaphragm function. Intensive Care Med 2002;28:358–364.|
|224.||Anzueto A, Peters JI, Tobin MJ, de los Santos R, Seidenfeld JJ, Moore G, Cox WJ, Coalson JJ. Effects of prolonged controlled mechanical ventilation on diaphragmatic function in healthy adult baboons. Crit Care Med 1997;25:1187–1190.|
|225.||Sassoon CS. Ventilator-associated diaphragmatic dysfunction. Am J Respir Crit Care Med 2002;166:1017–1018.|
|226.||Shanely RA, Zergeroglu MA, Lennon SL, Sugiura T, Yimlamai T, Enns D, Belcastro A, Powers SK. Mechanical ventilation-induced diaphragmatic atrophy is associated with oxidative injury and increased proteolytic activity. Am J Respir Crit Care Med 2002;166:1369–1374.|
|227.||Hussain SN, Vassilakopoulos T. Ventilator-induced cachexia. Am J Respir Crit Care Med 2002;166:1307–1308.|
|228.||Knisely AS, Leal SM, Singer DB. Abnormalities of diaphragmatic muscle in neonates with ventilated lungs. J Pediatr 1988;113:1074–1077.|
|229.||Cote HC, Brumme ZL, Craib KJ, Alexander CS, Wynhoven B, Ting L, Wong H, Harris M, Harrigan PR, O'Shaughnessy MV, et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 2002;346:811–820.|
|230.||Segredo V, Caldwell JE, Matthay MA, Sharma ML, Gruenke LD, Miller RD. Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med 1992;327:524–528.|
|231.||de Lemos JM, Carr RR, Shalansky KF, Bevan DR, Ronco JJ. Paralysis in the critically ill: intermittent bolus pancuronium compared with continuous infusion. Crit Care Med 1999;27:2648–2655.|
|232.||Rudis MI, Sikora CA, Angus E, Peterson E, Popovich J Jr, Hyzy R, Zarowitz BJ. A prospective, randomized, controlled evaluation of peripheral nerve stimulation versus standard clinical dosing of neuromuscular blocking agents in critically ill patients. Crit Care Med 1997;25:575–583.|
|233.||Laghi F, Topeli A, Tobin MJ. Does resistive loading decrease diaphragmatic contractility before task failure? J Appl Physiol 1998;85:1103–1112.|
|234.||Laghi F, D'Alfonso N, Tobin MJ. Pattern of recovery from diaphragmatic fatigue over 24 hours. J Appl Physiol 1995;79:539–546.|
|235.||Travaline JM, Sudarshan S, Roy BG, Cordova F, Leyenson V, Criner GJ. Effect of N-acetylcysteine on human diaphragm strength and fatigability. Am J Respir Crit Care Med 1997;156:1567–1571.|
|236.||Dahlstedt AJ, Katz A, Westerblad H. Role of myoplasmic phosphate in contractile function of skeletal muscle: studies on creatine kinase-deficient mice. J Physiol 2001;533:379–388.|
|237.||Radell PJ, Eleff SM, Nichols DG. Effects of loaded breathing and hypoxia on diaphragm metabolism as measured by 31P-NMR spectroscopy. J Appl Physiol 2000;88:933–938.|
|238.||Westerblad H, Bruton JD, Lannergren J. The effect of intracellular pH on contractile function of intact, single fibres of mouse muscle declines with increasing temperature. J Physiol 1997;500:193–204.|
|239.||Zhu E, Comtois AS, Fang L, Comtois NR, Grassino AE. Influence of tension time on muscle fiber sarcolemmal injury in rat diaphragm. J Appl Physiol 2000;88:135–141.|
|240.||Jiang TX, Reid WD, Road JD. Delayed diaphragm injury and diaphragm force production. Am J Respir Crit Care Med 1998;157:736–742.|
|241.||Reid WD, Belcastro AN. Time course of diaphragm injury and calpain activity during resistive loading. Am J Respir Crit Care Med 2000;162:1801–1806.|
|242.||Podhorska-Okolow M, Sandri M, Zampieri S, Brun B, Rossini K, Carraro U. Apoptosis of myofibres and satellite cells: exercise-induced damage in skeletal muscle of the mouse. Neuropathol Appl Neurobiol 1998;24:518–531.|
|243.||Orozco-Levi M, Lloreta J, Minguella J, Serrano S, Broquetas JM, Gea J. Injury of the human diaphragm associated with exertion and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1734–1739.|
|244.||Reid WD, Huang J, Bryson S, Walker DC, Belcastro AN. Diaphragm injury and myofibrillar structure induced by resistive loading. J Appl Physiol 1994;76:176–184.|
|245.||Martin J, Powell E, Shore S, Emrich J, Engel LA. The role of respiratory muscles in the hyperinflation of bronchial asthma. Am Rev Respir Dis 1980;121:441–447.|
|246.||Sampson MG, Grassino AE. Load compensation in obese patients during quiet tidal breathing. J Appl Physiol 1983;55:1269–1276.|
|247.||Wakai Y, Leevers AM, Road JD. Regional diaphragm shortening measured by sonomicrometry. J Appl Physiol 1994;77:2791–2796.|
|248.||Armstrong RB. Initial events in exercise-induced muscular injury. Med Sci Sports Exerc 1990;22:429–435.|
|249.||Vassilakopoulos T, Katsaounou P, Karatza MH, Kollintza A, Zakynthinos S, Roussos C. Strenuous resistive breathing induces plasma cytokines: role of antioxidants and monocytes. Am J Respir Crit Care Med 2002;166:1572–1578.|
|250.||Essig DA, Borger DR, Jackson DA. Induction of heme oxygenase-1 (HSP32) mRNA in skeletal muscle following contractions. Am J Physiol 1997;272:C59–C67.|
|251.||Jiang TX, Reid WD, Road JD. Free radical scavengers and diaphragm injury following inspiratory resistive loading. Am J Respir Crit Care Med 2001;164:1288–1294.|
|252.||Zhu E, Petrof BJ, Gea J, Comtois N, Grassino AE. Diaphragm muscle fiber injury after inspiratory resistive breathing. Am J Respir Crit Care Med 1997;155:1110–1116.|
|253.||Adams GR, Haddad F, Baldwin KM. Time course of changes in markers of myogenesis in overloaded rat skeletal muscles. J Appl Physiol 1999;87:1705–1712.|
|254.||Macgowan NA, Evans KG, Road JD, Reid WD. Diaphragm injury in individuals with airflow obstruction. Am J Respir Crit Care Med 2001;163:1654–1659.|
|255.||Silver MM, Smith CR. Diaphragmatic contraction band necrosis in a perinatal and infantile autopsy population. Hum Pathol 1992;23:817–827.|
|256.||Purro A, Appendini L, De Gaetano A, Gudjonsdottir M, Donner CF, Rossi A. Physiologic determinants of ventilator dependence in long-term mechanically ventilated patients. Am J Respir Crit Care Med 2000;161:1115–1123.|
|257.||Vassilakopoulos T, Zakynthinos S, Roussos C. The tension–time index and the frequency/tidal volume ratio are the major pathophysiologic determinants of weaning failure and success. Am J Respir Crit Care Med 1998;158:378–385.|
|258.||Bellemare F, Grassino A. Effect of pressure and timing of contraction on human diaphragm fatigue. J Appl Physiol 1982;53:1190–1195.|
|259.||Buyse B, Demedts M, Meekers J, Vandegaer L, Rochette F, Kerkhofs L. Respiratory dysfunction in multiple sclerosis: a prospective analysis of 60 patients. Eur Respir J 1997;10:139–145.|
|260.||Hughes PD, Polkey MI, Moxham J, Green M. Long-term recovery of diaphragm strength in neuralgic amyotrophy. Eur Respir J 1999;13:379–384.|
|261.||King TE Jr, Tooze JA, Schwarz MI, Brown KR, Cherniack RM. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med 2001;164:1171–1181.|
|262.||De Troyer A, Borenstein S, Cordier R. Analysis of lung volume restriction in patients with respiratory muscle weakness. Thorax 1980;35:603–610.|
|263.||Estenne M, Gevenois PA, Kinnear W, Soudon P, Heilporn A, De Troyer A. Lung volume restriction in patients with chronic respiratory muscle weakness: the role of microatelectasis. Thorax 1993;48:698–701.|
|264.||Misuri G, Lanini B, Gigliotti F, Iandelli I, Pizzi A, Bertolini MG, Scano G. Mechanism of CO2 retention in patients with neuromuscular disease. Chest 2000;117:447–453.|
|265.||Brack T, Jubran A, Tobin MJ. Dyspnea and decreased variability of breathing in patients with restrictive lung disease. Am J Respir Crit Care Med 2002;165:1260–1264.|
|266.||Rimmer KP, Golar SD, Lee MA, Whitelaw WA. Myotonia of the respiratory muscles in myotonic dystrophy. Am Rev Respir Dis 1993;148:1018–1022.|
|267.||Braun NM, Arora NS, Rochester DF. Respiratory muscle and pulmonary function in polymyositis and other proximal myopathies. Thorax 1983;38:616–623.|
|268.||Sinderby C, Weinberg J, Sullivan L, Lindstrom L, Grassino A. Electromyographical evidence for exercise-induced diaphragm fatigue in patients with chronic cervical cord injury or prior poliomyelitis infection. Spinal Cord 1996;34:594–601.|
|269.||Arnulf I, Similowski T, Salachas F, Garma L, Mehiri S, Attali V, Behin-Bellhesen V, Meininger V, Derenne JP. Sleep disorders and diaphragmatic function in patients with amyotrophic lateral sclerosis. Am J Respir Crit Care Med 2000;161:849–856.|
|270.||White JE, Drinnan MJ, Smithson AJ, Griffiths CJ, Gibson GJ. Respiratory muscle activity and oxygenation during sleep in patients with muscle weakness. Eur Respir J 1995;8:807–814.|
|271.||Hukins CA, Hillman DR. Daytime predictors of sleep hypoventilation in Duchenne muscular dystrophy. Am J Respir Crit Care Med 2000;161:166–170.|
|272.||Labanowski M, Schmidt-Nowara W, Guilleminault C. Sleep and neuromuscular disease: frequency of sleep-disordered breathing in a neuromuscular disease clinic population. Neurology 1996;47:1173–1180.|
|273.||Bourke SC, Gibson GJ. Sleep and breathing in neuromuscular disease. Eur Respir J 2002;19:1194–1201.|
|274.||Skatrud J, Iber C, McHugh W, Rasmussen H, Nichols D. Determinants of hypoventilation during wakefulness and sleep in diaphragmatic paralysis. Am Rev Respir Dis 1980;121:587–593.|
|275.||Stradling JR, Warley AR. Bilateral diaphragm paralysis and sleep apnoea without diurnal respiratory failure. Thorax 1988;43:75–77.|
|276.||Bourke SC, Shaw PJ, Gibson GJ. Respiratory function vs sleep-disordered breathing as predictors of QOL in ALS. Neurology 2001;57:2040–2044.|
|277.||Laroche CM, Carroll N, Moxham J, Green M. Clinical significance of severe isolated diaphragm weakness. Am Rev Respir Dis 1988;138:862–866.|
|278.||Kimura K, Tachibana N, Kimura J, Shibasaki H. Sleep-disordered breathing at an early stage of amyotrophic lateral sclerosis. J Neurol Sci 1999;164:37–43.|
|279.||Smith PE, Calverley PM, Edwards RH. Hypoxemia during sleep in Duchenne muscular dystrophy. Am Rev Respir Dis 1988;137:884–888.|
|280.||Ragette R, Mellies U, Schwake C, Voit T, Teschler H. Patterns and predictors of sleep disordered breathing in primary myopathies. Thorax 2002;57:724–728.|
|281.||Midgren B. Lung function and clinical outcome in postpolio patients: a prospective cohort study during 11 years. Eur Respir J 1997;10:146–149.|
|282.||Nugent AM, Smith IE, Shneerson JM. Domiciliary-assisted ventilation in patients with myotonic dystrophy. Chest 2002;121:459–464.|
|283.||Ferguson KA, Strong MJ, Ahmad D, George CF. Sleep-disordered breathing in amyotrophic lateral sclerosis. Chest 1996;110:664–669.|
|284.||Gay PC, Westbrook PR, Daube JR, Litchy WJ, Windebank AJ, Iverson R. Effects of alterations in pulmonary function and sleep variables on survival in patients with amyotrophic lateral sclerosis. Mayo Clin Proc 1991;66:686–694.|
|285.||Khan Y, Heckmatt JZ. Obstructive apnoeas in Duchenne muscular dystrophy. Thorax 1994;49:157–161.|
|286.||Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002;165:1217–1239.|
|287.||Pinto AC, Evangelista T, Carvalho M, Alves MA, Sales Luis ML. Respiratory assistance with a non-invasive ventilator (Bipap) in MND/ALS patients: survival rates in a controlled trial. J Neurol Sci 1995;129:19–26.|
|288.||Kleopa KA, Sherman M, Neal B, Romano GJ, Heiman-Patterson T. Bipap improves survival and rate of pulmonary function decline in patients with ALS. J Neurol Sci 1999;164:82–88.|
|289.||Newsom-Davis IC, Lyall RA, Leigh PN, Moxham J, Goldstein LH. The effect of non-invasive positive pressure ventilation (NIPPV) on cognitive function in amyotrophic lateral sclerosis (ALS): a prospective study. J Neurol Neurosurg Psychiatry 2001;71:482–487.|
|290.||Lyall RA, Donaldson N, Fleming T, Wood C, Newsom-Davis I, Polkey MI, Leigh PN, Moxham J. A prospective study of quality of life in ALS patients treated with noninvasive ventilation. Neurology 2001;57:153–156.|
|291.||Melo J, Homma A, Iturriaga E, Frierson L, Amato A, Anzueto A, Jackson C. Pulmonary evaluation and prevalence of non-invasive ventilation in patients with amyotrophic lateral sclerosis: a multicenter survey and proposal of a pulmonary protocol. J Neurol Sci 1999;169:114–117.|
|292.||Bye PT, Ellis ER, Issa FG, Donnelly PM, Sullivan CE. Respiratory failure and sleep in neuromuscular disease. Thorax 1990;45:241–247.|
|293.||Bourke SC, Shaw PJ, Bullock R, Gibson GJ. Criteria for initiating non-invasive ventilation in motor neurone disease [abstract]. Am J Respir Crit Care Med 2001;163:A153.|
|294.||Phillips MF, Smith PE, Carroll N, Edwards RH, Calverley PM. Nocturnal oxygenation and prognosis in Duchenne muscular dystrophy. Am J Respir Crit Care Med 1999;160:198–202.|
|295.||Similowski T, Catala M, Rancurel G, Derenne JP. Impairment of central motor conduction to the diaphragm in stroke. Am J Respir Crit Care Med 1996;154:436–441.|
|296.||Khedr EM, El Shinawy O, Khedr T, Aziz Ali YA, Awad EM. Assessment of corticodiaphragmatic pathway and pulmonary function in acute ischemic stroke patients. Eur J Neurol 2000;7:323–330.|
|297.||De Troyer A, Zegers DB, Thirion M. Function of the respiratory muscles in acute hemiplegia. Am Rev Respir Dis 1981;123:631–632.|
|298.||Teitelbaum J, Borel CO, Magder S, Traystman RJ, Hussain SN. Effect of selective diaphragmatic paralysis on the inspiratory motor drive. J Appl Physiol 1993;74:2261–2268.|
|299.||Maskill D, Murphy K, Mier A, Owen M, Guz A. Motor cortical representation of the diaphragm in man. J Physiol 1991;443:105–121.|
|300.||Cohen E, Mier A, Heywood P, Murphy K, Boultbee J, Guz A. Diaphragmatic movement in hemiplegic patients measured by ultrasonography. Thorax 1994;49:890–895.|
|301.||Fugl-Meyer AR, Linderholm H, Wilson AF. Restrictive ventilatory dysfunction in stroke: its relation to locomotor function. Scand J Rehabil Med Suppl 1983;9:118–124.|
|302.||Berrouschot J, Rossler A, Koster J, Schneider D. Mechanical ventilation in patients with hemispheric ischemic stroke. Crit Care Med 2000;28:2956–2961.|
|303.||Howard RS, Wiles CM, Hirsch NP, Loh L, Spencer GT, Newsom-Davis J. Respiratory involvement in multiple sclerosis. Brain 1992;115:479–494.|
|304.||Gosselink R, Kovacs L, Ketelaer P, Carton H, Decramer M. Respiratory muscle weakness and respiratory muscle training in severely disabled multiple sclerosis patients. Arch Phys Med Rehabil 2000;81:747–751.|
|305.||Smeltzer SC, Skurnick JH, Troiano R, Cook SD, Duran W, Lavietes MH. Respiratory function in multiple sclerosis: utility of clinical assessment of respiratory muscle function. Chest 1992;101:479–484.|
|306.||Smeltzer SC, Lavietes MH, Cook SD. Expiratory training in multiple sclerosis. Arch Phys Med Rehabil 1996;77:909–912.|
|307.||Sheean GL, Murray NM, Rothwell JC, Miller DH, Thompson AJ. An electrophysiological study of the mechanism of fatigue in multiple sclerosis. Brain 1997;120:299–315.|
|308.||Gosselink R, Kovacs L, Decramer M. Respiratory muscle involvement in multiple sclerosis. Eur Respir J 1999;13:449–454.|
|309.||Tzelepis GE, McCool FD, Friedman JH, Hoppin FG Jr. Respiratory muscle dysfunction in Parkinson's disease. Am Rev Respir Dis 1988;138:266–271.|
|310.||de Bruin PF, de Bruin VM, Lees AJ, Pride NB. Effects of treatment on airway dynamics and respiratory muscle strength in Parkinson's disease. Am Rev Respir Dis 1993;148:1576–1580.|
|311.||Bogaard JM, Hovestadt A, Meerwaldt J, van der Meche FG, Stigt J. Maximal expiratory and inspiratory flow–volume curves in Parkinson's disease. Am Rev Respir Dis 1989;139:610–614.|
|312.||Edstrom L, Gremski W, Wroblewski R. Sulphur and phosphorus content in relation to fibre composition and atrophy of skeletal muscle in patients with Parkinson's disease. J Neurol Sci 1979;41:311–323.|
|313.||Estenne M, Hubert M, De Troyer A. Respiratory muscle involvement in Parkinson's disease. N Engl J Med 1984;311:1516–1517.|
|314.||Fontana GA, Pantaleo T, Lavorini F, Benvenuti F, Gangemi S. Defective motor control of coughing in Parkinson's disease. Am J Respir Crit Care Med 1998;158:458–464.|
|315.||Herer B, Arnulf I, Housset B. Effects of levodopa on pulmonary function in Parkinson's disease. Chest 2001;119:387–393.|
|316.||Vincken WG, Gauthier SG, Dollfuss RE, Hanson RE, Darauay CM, Cosio MG. Involvement of upper-airway muscles in extrapyramidal disorders: a cause of airflow limitation. N Engl J Med 1984;311:438–442.|
|317.||Iranzo A, Santamaria J, Tolosa E. Continuous positive air pressure eliminates nocturnal stridor in multiple system atrophy. Barcelona Multiple System Atrophy Study Group. Lancet 2000;356:1329–1330.|
|318.||Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000;342:1484–1491.|
|319.||Zupnick HM, Brown LK, Miller A, Moros DA. Respiratory dysfunction due to l-dopa therapy for parkinsonism: diagnosis using serial pulmonary function tests and respiratory inductive plethysmography. Am J Med 1990;89:109–114.|
|320.||Wicks AB, Menter RR. Long-term outlook in quadriplegic patients with initial ventilator dependency. Chest 1986;90:406–410.|
|321.||Lougheed MD, Flannery J, Webb KA, O'Donnell DE. Respiratory sensation and ventilatory mechanics during induced bronchoconstriction in spontaneously breathing low cervical quadriplegia. Am J Respir Crit Care Med 2002;166:370–376.|
|322.||Yang L, Bourdon J, Gottfried SB, Zin WA, Petrof BJ. Regulation of myosin heavy chain gene expression after short-term diaphragm inactivation. Am J Physiol 1998;274:L980–L989.|
|323.||Ayas NT, McCool FD, Gore R, Lieberman SL, Brown R. Prevention of human diaphragm atrophy with short periods of electrical stimulation. Am J Respir Crit Care Med 1999;159:2018–2020.|
|324.||Nava S, Rubini F, Zanotti E, Caldiroli D. The tension–time index of the diaphragm revisited in quadriplegic patients with diaphragm pacing. Am J Respir Crit Care Med 1996;153:1322–1327.|
|325.||Gross D, Ladd HW, Riley EJ, Macklem PT, Grassino A. The effect of training on strength and endurance of the diaphragm in quadriplegia. Am J Med 1980;68:27–35.|
|326.||Prakash YS, Miyata H, Zhan WZ, Sieck GC. Inactivity-induced remodeling of neuromuscular junctions in rat diaphragmatic muscle. Muscle Nerve 1999;22:307–319.|
|327.||Oo T, Watt JW, Soni BM, Sett PK. Delayed diaphragm recovery in 12 patients after high cervical spinal cord injury: a retrospective review of the diaphragm status of 107 patients ventilated after acute spinal cord injury. Spinal Cord 1999;37:117–122.|
|328.||Weese-Mayer DE, Silvestri JM, Kenny AS, Ilbawi MN, Hauptman SA, Lipton JW, Talonen PP, Garcia HG, Watt JW, Exner G, et al. Diaphragm pacing with a quadripolar phrenic nerve electrode: an international study. Pacing Clin Electrophysiol 1996;19:1311–1319.|
|329.||Garrido-Garcia H, Mazaira AJ, Martin EP, Romero GJ, La Banda F, Gambarrutta C, Garcia ME, Labarta C, Arroyo O, de la Cruz S, et al. Treatment of chronic ventilatory failure using a diaphragmatic pacemaker. Spinal Cord 1998;36:310–314.|
|330.||Similowski T, Straus C, Attali V, Duguet A, Jourdain B, Derenne JP. Assessment of the motor pathway to the diaphragm using cortical and cervical magnetic stimulation in the decision-making process of phrenic pacing. Chest 1996;110:1551–1557.|
|331.||Baer GA, Kalimo H, Exner G, Talonen PP, Jaakkola S. Nerves and muscles of patients after multipolar sequential phrenic nerve stimulation. Muscle Nerve 1996;19:1169–1170.|
|332.||DiMarco AF, Onders RP, Kowalski KE, Miller ME, Ferek S, Mortimer JT. Phrenic nerve pacing in a tetraplegic patient via intramuscular diaphragm electrodes. Am J Respir Crit Care Med 2002;166:1604–1606.|
|333.||Estenne M, Pinet C, De Troyer A. Abdominal muscle strength in patients with tetraplegia. Am J Respir Crit Care Med 2000;161:707–712.|
|334.||De Troyer A, Estenne M, Heilporn A. Mechanism of active expiration in tetraplegic subjects. N Engl J Med 1986;314:740–744.|
|335.||Estenne M, Van Muylem A, Gorini M, Kinnear W, Heilporn A, De Troyer A. Evidence of dynamic airway compression during cough in tetraplegic patients. Am J Respir Crit Care Med 1994;150:1081–1085.|
|336.||Estenne M, Knoop C, Vanvaerenbergh J, Heilporn A, De Troyer A. The effect of pectoralis muscle training in tetraplegic subjects. Am Rev Respir Dis 1989;139:1218–1222.|
|337.||Estenne M, Van Muylem A, Gorini M, Kinnear W, Heilporn A, De Troyer A. Effects of abdominal strapping on forced expiration in tetraplegic patients. Am J Respir Crit Care Med 1998;157:95–98.|
|338.||Laghi F, Lanbein EW, Jaeger RJ, Fehr LS, Bammert C, Choi YA, Tobin MJ. Can electrical stimulation of abdominal muscles assist cough in patients with spinal cord injury? [abstract]. Am J Respir Crit Care Med 2003;167:A416.|
|339.||Sivasothy P, Brown L, Smith IE, Shneerson JM. Effect of manually assisted cough and mechanical insufflation on cough flow of normal subjects, patients with chronic obstructive pulmonary disease (COPD), and patients with respiratory muscle weakness. Thorax 2001;56:438–444.|
|340.||Jubelt B, Agre JC. Characteristics and management of postpolio syndrome. JAMA 2000;284:412–414.|
|341.||Howard RS, Wiles CM, Spencer GT. The late sequelae of poliomyelitis. Q J Med 1988;66:219–232.|
|342.||Sinderby C, Weinberg J, Sullivan L, Borg J, Lindstrom L, Grassino A. Diaphragm function in patients with cervical cord injury or prior poliomyelitis infection. Spinal Cord 1996;34:204–213.|
|343.||Dean E, Ross J, Road JD, Courtenay L, Madill KJ. Pulmonary function in individuals with a history of poliomyelitis. Chest 1991;100:118–123.|
|344.||Klefbeck B, Lagerstrand L, Mattsson E. Inspiratory muscle training in patients with prior polio who use part-time assisted ventilation. Arch Phys Med Rehabil 2000;81:1065–1071.|
|345.||Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med 2001;344:1688–1700.|
|346.||Polkey MI, Lyall RA, Green M, Nigel LP, Moxham J. Expiratory muscle function in amyotrophic lateral sclerosis. Am J Respir Crit Care Med 1998;158:734–741.|
|347.||Similowski T, Attali V, Bensimon G, Salachas F, Mehiri S, Arnulf I, Lacomblez L, Zelter M, Meininger V, Derenne JP. Diaphragmatic dysfunction and dyspnoea in amyotrophic lateral sclerosis. Eur Respir J 2000;15:332–337.|
|348.||Vitacca M, Clini E, Facchetti D, Pagani M, Poloni M, Porta R, Ambrosino N. Breathing pattern and respiratory mechanics in patients with amyotrophic lateral sclerosis. Eur Respir J 1997;10:1614–1621.|
|349.||Lyall RA, Donaldson N, Polkey MI, Leigh PN, Moxham J. Respiratory muscle strength and ventilatory failure in amyotrophic lateral sclerosis. Brain 2001;124:2000–2013.|
|350.||Stambler N, Charatan M, Cedarbaum JM. Prognostic indicators of survival in ALS. ALS CNTF Treatment Study Group. Neurology 1998;50:66–72.|
|351.||Attali V, Mehiri S, Straus C, Salachas F, Arnulf I, Meininger V, Derenne JP, Similowski T. Influence of neck muscles on mouth pressure response to cervical magnetic stimulation. Am J Respir Crit Care Med 1997;156:509–514.|
|352.||Cazzolli PA, Oppenheimer EA. Home mechanical ventilation for amyotrophic lateral sclerosis: nasal compared with tracheostomy-intermittent positive pressure ventilation. J Neurol Sci 1996;139:123–128.|
|353.||Moss AH, Casey P, Stocking CB, Roos RP, Brooks BR, Siegler M. Home ventilation for amyotrophic lateral sclerosis patients: outcomes, costs, and patient, family, and physician attitudes. Neurology 1993;43:438–443.|
|354.||Hardy K, Herry I, Attali V, Cadranel J, Similowski T. Bilateral phrenic paralysis in a patient with systemic lupus erythematosus. Chest 2001;119:1274–1277.|
|355.||Tobin MJ, Gardner WN. Monitoring of the control of breathing. In: Tobin MJ, editor. Principles and practice of intensive care monitoring. New York: McGraw-Hill; 1998. p. 415–464.|
|356.||Laroche CM, Mier AK, Moxham J, Green M. Diaphragm strength in patients with recent hemidiaphragm paralysis. Thorax 1988;43:170–174.|
|357.||Mills GH, Kyroussis D, Hamnegard CH, Wragg S, Polkey MI, Moxham J, Green M. Cervical magnetic stimulation of the phrenic nerves in bilateral diaphragm paralysis. Am J Respir Crit Care Med 1997;155:1565–1569.|
|358.||Arborelius M Jr, Lilja B, Senyk J. Regional and total lung function studies in patients with hemidiaphragmatic paralysis. Respiration 1975;32:253–264.|
|359.||Hillman DR, Finucane KE. Respiratory pressure partitioning during quiet inspiration in unilateral and bilateral diaphragmatic weakness. Am Rev Respir Dis 1988;137:1401–1405.|
|360.||Lisboa C, Pare PD, Pertuze J, Contreras G, Moreno R, Guillemi S, Cruz E. Inspiratory muscle function in unilateral diaphragmatic paralysis. Am Rev Respir Dis 1986;134:488–492.|
|361.||Mulvey DA, Aquilina RJ, Elliott MW, Moxham J, Green M. Diaphragmatic dysfunction in neuralgic amyotrophy: an electrophysiologic evaluation of 16 patients presenting with dyspnea. Am Rev Respir Dis 1993;147:66–71.|
|362.||Hart N, Nickol AH, Cramer D, Ward SP, Lofaso F, Pride NB, Moxham J, Polkey MI. Effect of severe isolated unilateral and bilateral diaphragm weakness on exercise performance. Am J Respir Crit Care Med 2002;165:1265–1270.|
|363.||Tobin MJ, Laghi F. Monitoring respiratory muscle function. In: Tobin MJ, editor. Principles and practice of intensive care monitoring. New York: McGraw-Hill; 1998. p. 497–544.|
|364.||Davis J, Goldman M, Loh L, Casson M. Diaphragm function and alveolar hypoventilation. Q J Med 1976;45:87–100.|
|365.||Mier-Jedrzejowicz A, Brophy C, Moxham J, Green M. Assessment of diaphragm weakness. Am Rev Respir Dis 1988;137:877–883.|
|366.||Douglas BE, Clagett TO. The prognosis in idiopathic diaphragmatic paralysis. Chest 1960;37:294–297.|
|367.||Alexander C. Diaphragm movements and the diagnosis of diaphragmatic paralysis. Clin Radiol 1966;17:79–83.|
|368.||Allen SM, Hunt B, Green M. Fall in vital capacity with posture. Br J Dis Chest 1985;79:267–271.|
|369.||Luo YM, Lyall RA, Lou HM, Rafferty GF, Polkey MI, Moxham J. Quantification of the esophageal diaphragm electromyogram with magnetic phrenic nerve stimulation. Am J Respir Crit Care Med 1999;160:1629–1634.|
|370.||Houston JG, Fleet M, Cowan MD, McMillan NC. Comparison of ultrasound with fluoroscopy in the assessment of suspected hemidiaphragmatic movement abnormality. Clin Radiol 1995;50:95–98.|
|371.||Gottesman E, McCool FD. Ultrasound evaluation of the paralyzed diaphragm. Am J Respir Crit Care Med 1997;155:1570–1574.|
|372.||Stolk J, Versteegh MI. Long-term effect of bilateral plication of the diaphragm. Chest 2000;117:786–789.|
|373.||Hahn AF. Guillain-Barré syndrome. Lancet 1998;352:635–641.|
|374.||Gourie-Devi M, Ganapathy GR. Phrenic nerve conduction time in Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry 1985;48:245–249.|
|375.||Zifko U, Chen R, Remtulla H, Hahn AF, Koopman W, Bolton CF. Respiratory electrophysiological studies in Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry 1996;60:191–194.|
|376.||Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet 1997;349:225–230.|
|377.||Yuki N, Ang CW, Koga M, Jacobs BC, van Doorn PA, Hirata K, van der Meche FG. Clinical features and response to treatment in Guillain-Barré syndrome associated with antibodies to GM1b ganglioside. Ann Neurol 2000;47:314–321.|
|378.||French Cooperative Group on Plasma Exchange in Guillain-Barré Syndrome. Efficiency of plasma exchange in Guillain-Barré syndrome: role of replacement fluids. Ann Neurol 1987;22:753–761.|
|379.||Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis. Lancet 2001;357:2122–2128.|
|380.||Mier A, Brophy C, Moxham J, Green M. Repetitive stimulation of phrenic nerves in myasthenia gravis. Thorax 1992;47:640–644.|
|381.||Zifko UA, Nicolle MW, Grisold W, Bolton CF. Repetitive phrenic nerve stimulation in myasthenia gravis. Neurology 1999;53:1083–1087.|
|382.||Mier-Jedrzejowicz AK, Brophy C, Green M. Respiratory muscle function in myasthenia gravis. Am Rev Respir Dis 1988;138:867–873.|
|383.||Keenan SP, Alexander D, Road JD, Ryan CF, Oger J, Wilcox PG. Ventilatory muscle strength and endurance in myasthenia gravis. Eur Respir J 1995;8:1130–1135.|
|384.||Romi F, Skeie GO, Aarli JA, Gilhus NE. The severity of myasthenia gravis correlates with the serum concentration of titin and ryanodine receptor antibodies. Arch Neurol 2000;57:1596–1600.|
|385.||Romi F, Skeie GO, Vedeler C, Aarli JA, Zorzato F, Gilhus NE. Complement activation by titin and ryanodine receptor autoantibodies in myasthenia gravis: a study of IgG subclasses and clinical correlations. J Neuroimmunol 2000;111:169–176.|
|386.||Aarli JA, Skeie GO, Mygland A, Gilhus NE. Muscle striation antibodies in myasthenia gravis: diagnostic and functional significance. Ann N Y Acad Sci 1998;841:505–515.|
|387.||Quera-Salva MA, Guilleminault C, Chevret S, Troche G, Fromageot C, Crowe MC, Stoos R, de Lattre J, Raphael JC, Gajdos P. Breathing disorders during sleep in myasthenia gravis. Ann Neurol 1992;31:86–92.|
|388.||Thomas CE, Mayer SA, Gungor Y, Swarup R, Webster EA, Chang I, Brannagan TH, Fink ME, Rowland LP. Myasthenic crisis: clinical features, mortality, complications, and risk factors for prolonged intubation. Neurology 1997;48:1253–1260.|
|389.||Weiner P, Gross D, Meiner Z, Ganem R, Weiner M, Zamir D, Rabner M. Respiratory muscle training in patients with moderate to severe myasthenia gravis. Can J Neurol Sci 1998;25:236–241.|
|390.||Berrouschot J, Baumann I, Kalischewski P, Sterker M, Schneider D. Therapy of myasthenic crisis. Crit Care Med 1997;25:1228–1235.|
|391.||Meola G. Clinical and genetic heterogeneity in myotonic dystrophies. Muscle Nerve 2000;23:1789–1799.|
|392.||Zifko UA, Hahn AF, Remtulla H, George CF, Wihlidal W, Bolton CF. Central and peripheral respiratory electrophysiological studies in myotonic dystrophy. Brain 1996;119:1911–1922.|
|393.||Begin P, Mathieu J, Almirall J, Grassino A. Relationship between chronic hypercapnia and inspiratory-muscle weakness in myotonic dystrophy. Am J Respir Crit Care Med 1997;156:133–139.|
|394.||Censori B, Provinciali L, Danni M, Chiaramoni L, Maricotti M, Foschi N, Del Pesce M, Salvolini U. Brain involvement in myotonic dystrophy: MRI features and their relationship to clinical and cognitive conditions. Acta Neurol Scand 1994;90:211–217.|
|395.||Mathieu J, Allard P, Potvin L, Prevost C, Begin P. A 10-year study of mortality in a cohort of patients with myotonic dystrophy. Neurology 1999;52:1658–1662.|
|396.||Raphael JC, Chevret S, Chastang C, Bouvet F. Randomised trial of preventive nasal ventilation in Duchenne muscular dystrophy. French Multicentre Cooperative Group on Home Mechanical Ventilation Assistance in Duchenne de Boulogne Muscular Dystrophy. Lancet 1994;343:1600–1604.|
|397.||Petrof BJ, Stedman HH, Shrager JB, Eby J, Sweeney HL, Kelly AM. Adaptations in myosin heavy chain expression and contractile function in dystrophic mouse diaphragm. Am J Physiol 1993;265:C834–C841.|
|398.||Coirault C, Lambert F, Pourny JC, Lecarpentier Y. Velocity of actomyosin sliding in vitro is reduced in dystrophic mouse diaphragm. Am J Respir Crit Care Med 2002;165:250–253.|
|399.||Phillips MF, Quinlivan RC, Edwards RH, Calverley PM. Changes in spirometry over time as a prognostic marker in patients with Duchenne muscular dystrophy. Am J Respir Crit Care Med 2001;164:2191–2194.|
|400.||Wanke T, Toifl K, Merkle M, Formanek D, Lahrmann H, Zwick H. Inspiratory muscle training in patients with Duchenne muscular dystrophy. Chest 1994;105:475–482.|
|401.||Simonds AK, Muntoni F, Heather S, Fielding S. Impact of nasal ventilation on survival in hypercapnic Duchenne muscular dystrophy. Thorax 1998;53:949–952.|
|402.||Muntoni F, Hird M, Simonds AK. Preventive nasal ventilation in Duchenne muscular dystrophy. Lancet 1994;344:340.|
|403.||Bach JR. Misconceptions about nasal ventilation. Lancet 1994;344:752–753.|
|404.||Koukourakis I, Giaourakis G, Kouvidis G, Kivernitakis E, Blazos J, Koukourakis M. Screening school children for scoliosis on the island of Crete. J Spinal Disord 1997;10:527–531.|
|405.||Stirling AJ, Howel D, Millner PA, Sadiq S, Sharples D, Dickson RA. Late-onset idiopathic scoliosis in children six to fourteen years old: a cross-sectional prevalence study. J Bone Joint Surg Am 1996;78:1330–1336.|
|406.||Kearon C, Viviani GR, Kirkley A, Killian KJ. Factors determining pulmonary function in adolescent idiopathic thoracic scoliosis. Am Rev Respir Dis 1993;148:288–294.|
|407.||Cooper DM, Rojas JV, Mellins RB, Keim HA, Mansell AL. Respiratory mechanics in adolescents with idiopathic scoliosis. Am Rev Respir Dis 1984;130:16–22.|
|408.||Estenne M, Derom E, De Troyer A. Neck and abdominal muscle activity in patients with severe thoracic scoliosis. Am J Respir Crit Care Med 1998;158:452–457.|
|409.||Baydur A, Swank SM, Stiles CM, Sassoon CS. Respiratory mechanics in anesthetized young patients with kyphoscoliosis: immediate and delayed effects of corrective spinal surgery. Chest 1990;97:1157–1164.|
|410.||Lisboa C, Moreno R, Fava M, Ferretti R, Cruz E. Inspiratory muscle function in patients with severe kyphoscoliosis. Am Rev Respir Dis 1985;132:48–52.|
|411.||Kearon C, Viviani GR, Killian KJ. Factors influencing work capacity in adolescent idiopathic thoracic scoliosis. Am Rev Respir Dis 1993;148:295–303.|
|412.||Ferris G, Servera-Pieras E, Vergara P, Tzeng AC, Perez M, Marin J, Bach JR. Kyphoscoliosis ventilatory insufficiency: noninvasive management outcomes. Am J Phys Med Rehabil 2000;79:24–29.|
|413.||Graham EJ, Lenke LG, Lowe TG, Betz RR, Bridwell KH, Kong Y, Blanke K. Prospective pulmonary function evaluation following open thoracotomy for anterior spinal fusion in adolescent idiopathic scoliosis. Spine 2000;25:2319–2325.|
|414.||Vanderschueren D, Decramer M, Van den Daele P, Dequeker J. Pulmonary function and maximal transrespiratory pressures in ankylosing spondylitis. Ann Rheum Dis 1989;48:632–635.|
|415.||Carter R, Riantawan P, Banham SW, Sturrock RD. An investigation of factors limiting aerobic capacity in patients with ankylosing spondylitis. Respir Med 1999;93:700–708.|
|416.||Tzelepis GE, McCool FD, Hoppin FG Jr. Chest wall distortion in patients with flail chest. Am Rev Respir Dis 1989;140:31–37.|
|417.||Cappello M, Yuehua C, De Troyer A. Rib cage distortion in a canine model of flail chest. Am J Respir Crit Care Med 1995;151:1481–1485.|
|418.||Cappello M, De Troyer A. Actions of the inspiratory intercostal muscles in flail chest. Am J Respir Crit Care Med 1997;155:1085–1089.|
|419.||Kress JP, Pohlman AS, Alverdy J, Hall JB. The impact of morbid obesity on oxygen cost of breathing (VO2RESP) at rest. Am J Respir Crit Care Med 1999;160:883–886.|
|420.||Yap JC, Watson RA, Gilbey S, Pride NB. Effects of posture on respiratory mechanics in obesity. J Appl Physiol 1995;79:1199–1205.|
|421.||Pankow W, Podszus T, Gutheil T, Penzel T, Peter J, von Wichert P. Expiratory flow limitation and intrinsic positive end-expiratory pressure in obesity. J Appl Physiol 1998;85:1236–1243.|
|422.||Powers SK, Farkas GA, Demirel H, Coombes J, Fletcher L, Hughes MG, Hodge K, Dodd SL, Schlenker EH. Effects of aging and obesity on respiratory muscle phenotype in Zucker rats. J Appl Physiol 1996;81:1347–1354.|
|423.||Weiner P, Waizman J, Weiner M, Rabner M, Magadle R, Zamir D. Influence of excessive weight loss after gastroplasty for morbid obesity on respiratory muscle performance. Thorax 1998;53:39–42.|
|424.||Contreras G, Gutierrez M, Beroiza T, Fantin A, Oddo H, Villarroel L, Cruz E, Lisboa C. Ventilatory drive and respiratory muscle function in pregnancy. Am Rev Respir Dis 1991;144:837–841.|
|425.||Gilroy RJ, Mangura BT, Lavietes MH. Rib cage and abdominal volume displacements during breathing in pregnancy. Am Rev Respir Dis 1988;137:668–672.|
|426.||Nava S, Zanotti E, Ambrosino N, Fracchia C, Scarabelli C, Rampulla C. Evidence of acute diaphragmatic fatigue in a “natural” condition: the diaphragm during labor. Am Rev Respir Dis 1992;146:1226–1230.|
|427.||Duranti R, Laffi G, Misuri G, Riccardi D, Gorini M, Foschi M, Iandelli I, Mazzanti R, Mancini M, Scano G, et al. Respiratory mechanics in patients with tense cirrhotic ascites. Eur Respir J 1997;10:1622–1630.|
|428.||Prezant DJ, Aldrich TK, Karpel JP, Lynn RI. Adaptations in the diaphragm's in vitro force–length relationship in patients on continuous ambulatory peritoneal dialysis. Am Rev Respir Dis 1990;141:1342–1349.|
|429.||Gibson CJ, Edmonds JP, Hughes GR. Diaphragm function and lung involvement in systemic lupus erythematosus. Am J Med 1977;63:926–932.|
|430.||Laroche CM, Mulvey DA, Hawkins PN, Walport MJ, Strickland B, Moxham J, Green M. Diaphragm strength in the shrinking lung syndrome of systemic lupus erythematosus. Q J Med 1989;71:429–439.|
|431.||Wilcox PG, Stein HB, Clarke SD, Pare PD, Pardy RL. Phrenic nerve function in patients with diaphragmatic weakness and systemic lupus erythematosus. Chest 1988;93:352–358.|
|432.||Rubin LA, Urowitz MB. Shrinking lung syndrome in SLE: a clinical pathologic study. J Rheumatol 1983;10:973–976.|
|433.||Scano G, Goti P, Duranti R, Misuri G, Emmi L, Rosi E. Control of breathing in a subset of patients with systemic lupus erythematosus. Chest 1995;108:759–766.|
|434.||Wanke T, Formanek D, Auinger M, Popp W, Zwick H, Irsigler K. Inspiratory muscle performance and pulmonary function changes in insulin-dependent diabetes mellitus. Am Rev Respir Dis 1991;143:97–100.|
|435.||Polotsky VY, Wilson JA, Haines AS, Scharf MT, Soutiere SE, Tankersley CG, Smith PL, Schwartz AR, O'Donnell CP. The impact of insulin-dependent diabetes on ventilatory control in the mouse. Am J Respir Crit Care Med 2001;163:624–632.|
|436.||Guazzi M, Brambilla R, De Vita S, Guazzi MD. Diabetes worsens pulmonary diffusion in heart failure, and insulin counteracts this effect. Am J Respir Crit Care Med 2002;166:978–982.|
|437.||Siafakas NM, Milona I, Salesiotou V, Filaditaki V, Tzanakis N, Bouros D. Respiratory muscle strength in hyperthyroidism before and after treatment. Am Rev Respir Dis 1992;146:1025–1029.|
|438.||Martinez FJ, Bermudez-Gomez M, Celli BR. Hypothyroidism: a reversible cause of diaphragmatic dysfunction. Chest 1989;96:1059–1063.|
|439.||Prakash YS, Gosselin LE, Zhan WZ, Sieck GC. Alterations of diaphragm neuromuscular junctions with hypothyroidism. J Appl Physiol 1996;81:1240–1248.|
|440.||Mitchell DM, Fleming J, Pinching AJ, Harris JR, Moss FM, Veale D, Shaw RJ. Pulmonary function in human immunodeficiency virus infection: a prospective 18-month study of serial lung function in 474 patients. Am Rev Respir Dis 1992;146:745–751.|
|441.||Schulz L, Nagaraja HN, Rague N, Drake J, Diaz PT. Respiratory muscle dysfunction associated with human immunodeficiency virus infection. Am J Respir Crit Care Med 1997;155:1080–1084.|
|442.||Fratacci MD, Kimball WR, Wain JC, Kacmarek RM, Polaner DM, Zapol WM. Diaphragmatic shortening after thoracic surgery in humans: effects of mechanical ventilation and thoracic epidural anesthesia. Anesthesiology 1993;79:654–665.|
|443.||Barnas GM, Watson RJ, Green MD, Sequeira AJ, Gilbert TB, Kent J, Villamater E. Lung and chest wall mechanical properties before and after cardiac surgery with cardiopulmonary bypass. J Appl Physiol 1994;76:166–175.|
|444.||Ranieri VM, Vitale N, Grasso S, Puntillo F, Mascia L, Paparella D, Tunzi P, Giuliani R, de Luca TL, Fiore T. Time-course of impairment of respiratory mechanics after cardiac surgery and cardiopulmonary bypass. Crit Care Med 1999;27:1454–1460.|
|445.||Dimopoulou I, Daganou M, Dafni U, Karakatsani A, Khoury M, Geroulanos S, Jordanoglou J. Phrenic nerve dysfunction after cardiac operations: electrophysiologic evaluation of risk factors. Chest 1998;113:8–14.|
|446.||Wilcox PG, Pare PD, Pardy RL. Recovery after unilateral phrenic injury associated with coronary artery revascularization. Chest 1990;98:661–666.|
|447.||Chroni E, Patel RL, Taub N, Venn GE, Howard RS, Panayiotopoulos CP. A comprehensive electrophysiological evaluation of phrenic nerve injury related to open-heart surgery. Acta Neurol Scand 1995;91:255–259.|
|448.||Markand ON, Moorthy SS, Mahomed Y, King RD, Brown JW. Postoperative phrenic nerve palsy in patients with open-heart surgery. Ann Thorac Surg 1985;39:68–73.|
|449.||Katz MG, Katz R, Schachner A, Cohen AJ. Phrenic nerve injury after coronary artery bypass grafting: will it go away? Ann Thorac Surg 1998;65:32–35.|
|450.||Kunovsky P, Gibson GA, Pollock JC, Stejskal L, Houston A, Jamieson MP. Management of postoperative paralysis of diaphragm in infants and children. Eur J Cardiothorac Surg 1993;7:342–346.|
|451.||Simansky DA, Paley M, Refaely Y, Yellin A. Diaphragm plication following phrenic nerve injury: a comparison of paediatric and adult patients. Thorax 2002;57:613–616.|
|452.||Takeda S, Nakahara K, Fujii Y, Matsumura A, Minami M, Matsuda H. Effects of diaphragmatic plication on respiratory mechanics in dogs with unilateral and bilateral phrenic nerve paralyses. Chest 1995;107:798–804.|
|453.||Ford GT, Whitelaw WA, Rosenal TW, Cruse PJ, Guenter CA. Diaphragm function after upper abdominal surgery in humans. Am Rev Respir Dis 1983;127:431–436.|
|454.||Sharma RR, Axelsson H, Oberg A, Jansson E, Clergue F, Johansson G, Reiz S. Diaphragmatic activity after laparoscopic cholecystectomy. Anesthesiology 1999;91:406–413.|
|455.||Jansen JE, Sorensen AI, Naesh O, Erichsen CJ, Pedersen A. Effect of doxapram on postoperative pulmonary complications after upper abdominal surgery in high-risk patients. Lancet 1990;335:936–938.|
|456.||Rovina N, Bouros D, Tzanakis N, Velegrakis M, Kandilakis S, Vlasserou F, Siafakas NM. Effects of laparoscopic cholecystectomy on global respiratory muscle strength. Am J Respir Crit Care Med 1996;153:458–461.|
|457.||Vassilakopoulos T, Mastora Z, Katsaounou P, Doukas G, Klimopoulos S, Roussos C, Zakynthinos S. Contribution of pain to inspiratory muscle dysfunction after upper abdominal surgery: a randomized controlled trial. Am J Respir Crit Care Med 2000;161:1372–1375.|
|458.||Siafakas NM, Stathopoulou M, Tzanakis N, Mitrouska I, Tsoumakidou M, Georgopoulos D. Effect of digoxin on global respiratory muscle strength after cholecystectomy: a double blind study. Thorax 2000;55:497–501.|
|459.||Siafakas NM, Stoubou A, Stathopoulou M, Haviaras V, Tzanakis N, Bouros D. Effect of aminophylline on respiratory muscle strength after upper abdominal surgery: a double blind study. Thorax 1993;48:693–697.|
|460.||Sieck GC, Prakash YS. Cross-bridge kinetics in respiratory muscles. Eur Respir J 1997;10:2147–2158.|