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)

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)

Figure 1. Metabolic pathways implicated in muscle wasting of malnourished patients with chronic obstructive pulmonary disease (COPD) and other diseases. Tumor necrosis factor-α (TNF-α), which is increased in several disease states, can decrease muscle contractile proteins by causing decreased muscle anabolism, structural damage, and increased muscle catabolism. Decreased anabolism secondary to anorexia and insulin resistance causes decreased protein synthesis and decreased messenger RNA for the synthesis of contractile proteins. Production of reactive oxygen species by the cyclooxygenase pathway (not shown) and by mitochondria damages contractile proteins. TNF-α causes muscle catabolism by activating the transcription factor, nuclear factor-κB (NF-κB), a heterodimeric complex, which typically consists of a 50-kD protein (p50) and a 65-kD protein (p65). NF-κB is usually sequestered in the cytoplasm, where it is bound to inhibitory proteins, such as inhibitor-κBα (I-κBα). I-κBα controls the transfer of NF-κB into the nucleus. The first step in release of NF-κB from the inhibitory protein is phosphorylation of I-κBα; I-κBα is subsequently degraded through the ubiquitin–proteasome pathway. Once freed from I-κBα, NF-κB enters the nucleus and binds to a DNA promoter region, whereby it induces translation and transcription of proteases. TNF-α also enhances catabolism by increasing catabolic cytokines (prostaglandin E₂, interleukin-1) and hormones that promote muscle catabolism (not shown).

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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 [54]) and increase (secondary to increase in protein synthesis and protein breakdown [55]). The conflicting data may reflect differences in patient selection (severely malnourished [54] versus well-nourished patients [55]) or a Type 2 error (8 and 14 patients) (54, 55).

In contrast to normal-weight patients with COPD, underweight patients show increased apoptosis in skeletal muscles (quadriceps) (56). The patients with apoptosis have impaired exercise tolerance despite no greater decrease in lung function (56). Release of cytochrome c from the mitochondria and tumor necrosis factor-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.

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)

Figure 2. Tracings of transdiaphragmatic pressure (Pdi) during bilateral phrenic nerve stimulation in a patient with COPD. During a forceful Mueller maneuver, stimulation produced a superimposed twitch pressure (arrow). Twitch pressure achieved by stimulation during resting breathing is seen on the right. The ratio of the amplitude of superimposed twitch pressure to resting twitch pressure (expressed as a percentage) measures the extent that muscle is not recruited by the central nervous system during the Mueller maneuver. The extent of muscle recruitment is usually expressed as the voluntary activation index, which is calculated as: 100 minus the superimposed twitch pressure to resting twitch pressure ratio. In the displayed example, the amplitude of the superimposed twitch pressure is 19% of the amplitude of resting twitch pressure, yielding a voluntary activation index of 81%; if the superimposed stimulus had evoked no increase in pressure, the activation index would have been 100%.

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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)

Figure 3. Flow, esophageal pressure, rib cage motion, gastric pressure, and abdominal motion in a patient with COPD before and during maximum cycle exercise. In both panels the first vertical line is the start of inhalation, the second vertical line is the end of inhalation, and the third vertical line is the end of exhalation. Before exercise (left), contraction of the diaphragm at the beginning of inhalation causes an increase in gastric pressure and outward abdominal motion. At the end of inhalation, relaxation of the diaphragm causes a decrease in gastric pressure and inward abdominal motion. During peak exercise (right), there is a delay between the rapid drop in esophageal (and gastric) pressure and the start of inspiratory flow, indicating the presence of intrinsic positive end expiratory pressure; before exercise, the beginning of inspiratory effort (rapid drop in esophageal pressure) coincides with the start of inspiratory flow, indicating the absence of intrinsic positive end expiratory pressure. Expiratory muscle recruitment causes a rise in gastric pressure during exhalation and inward abdominal motion. At the beginning of inhalation, expiratory muscle relaxation is accompanied by a precipitous fall in gastric pressure and outward abdominal motion. Later in inhalation, diaphragmatic contraction causes an increase in gastric pressure and continued outward motion of the abdomen.

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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)

Figure 4. Twitch transdiaphragmatic pressure elicited by phrenic nerve stimulation (top) and functional residual capacity (FRC; bottom) in a patient with COPD before (left) and after (right) lung volume reduction surgery. The higher pressure after surgery was in part due to a decrease in operating lung volume as demonstrated by a decrease in FRC. (Data from Laghi and coworkers [6]).

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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 [131]), which is probably a structural adaptation to pulmonary hyperinflation (129, 131).

Twitch and sniff transdiaphragmatic pressures are not affected (132) by the decrease in resting length and normalization of the radius of curvature of the diaphragm after transplanting one lung (122). These two factors (130, 132), however, probably contribute to the improved sniff pressure (132) and normalization of maximal inspiratory airway pressure after transplanting two lungs (133). Patients with end-stage cystic fibrosis who receive two lungs are capable of generating maximal esophageal pressures more negative than those recorded in healthy subjects (131), possibly reflecting a leftward shift of the pressure–volume curve of the chest wall (131). In 8 patients with COPD who received double lung transplantation, transdiaphragmatic twitch pressure elicited by phrenic nerve stimulation tended to be greater than that in 14 patients with COPD who had not undergone surgery (132).

Unlike the improvement in maximal inspiratory pressures (132, 133), maximal expiratory pressures reached only 70% of normal in nine patients who received two lungs (133). It is not known why transplantation improved inspiratory but not expiratory muscle strength. Weakness of the expiratory muscles and ankle dorsiflexors was equivalent (133), suggesting that these muscle groups are vulnerable to some factor that does not affect the diaphragm—perhaps because it is continually active (133). Possible factors include muscle atrophy (disuse or malnutrition), myopathy (steroid myopathy or mitochondrial myopathy associated with cyclosporine), or a deficit in motor activation.

Inspiratory muscle endurance does not change after single or double lung transplantation (134). The lack of effect may be secondary to the protocol used for testing endurance (imposed respiratory frequency and inspiratory time), adverse effects of the antirejection regimen, or a Type 2 error. Blunting of the voluntary activation of the inspiratory muscles (94) is another possibility. The improved respiratory muscle strength (132) and decreased drive under loaded conditions probably reduce the sensation of inspiratory effort and contribute to the improved quality of life.

In patients with one (124) and two transplanted lungs (133, 135, 136), maximal exercise capacity is about half the normal value. The reduced exercise capacity is not the result of ventilatory limitation, as is the case of patients with COPD who have not undergone lung transplantation. Ventilatory reserve during maximal exercise is equivalent in transplanted patients and control subjects (67 versus 58% of maximum voluntary ventilation) (136). Exercise limitation in patients with end-stage COPD who receive one or two lungs is probably caused by decreased strength (136) and endurance of the limb muscles (137). Compared with healthy subjects, transplant recipients have a shorter time to exhaustion (137), greater acidosis in the quadriceps during knee-extending exercise (137), reduced Type I muscle fibers (135), and severely reduced mitochondrial oxidative capacity (135).

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.

Some patients with sepsis and multiple organ failure develop weakness, reduced or absent tendon reflexes, and occasional loss of sensation (185). Electromyography (Table 2)

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)

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)

Figure 5. Ubiquitin–proteasome degradation of contractile proteins. The first step in degradation of actin and myosin is activation of ubiquitin (Ub) by a first enzyme, E1—a process requiring ATP. Activated ubiquitin interacts with a second enzyme, E2, a carrier protein. Ub and E2 join a third enzyme, E3. E3 transfers activated Ub to actin and myosin. The cycle is repeated until a chain of Ub is bound to the contractile proteins. The chain of Ub binds to one end of a proteasome complex in a process requiring ATP. The Ub chain is subsequently removed (allowing reuse of Ub), and actin and myosin are unfolded and pushed into the core of the proteasome. Multiple enzymes within the core degrade actin and myosin into small peptides. The peptides are extruded from the proteasome and degraded to amino acids by peptidases in the cytoplasm. The ubiquitin–proteasome pathway degrades many proteins other than actin and myosin.

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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)

Figure 6. (A) A strip of diaphragm obtained from a C57BL/6 mouse injected 12 hours earlier with normal saline. The strip was stimulated for 3 minutes (50 Hz, 300-millisecond duration) and then immersed for 90 minutes in Krebs solution containing a fluorescent probe, Procion orange 14 (0.15, wt/vol). (B) A strip of diaphragm obtained from a C57BL/6 mouse injected 12 hours earlier with Escherichia coli endotoxin (20 mg/kg). Stimulation and staining were conducted as described above. Sarcolemmal damage, indicated by yellow staining, was increased by endotoxin. The photomicrographs were provided by Dr. Sabah N. Hussain, Royal Victoria Hospital, Montreal, Canada.

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Figure 7. (A) A sample of gastrocnemius muscle obtained from an adult Sprague-Dawley rat injected 12 hours earlier with E. coli endotoxin (20 mg/kg). The section was stained with an antibody to inducible nitric oxide synthase. Positive staining (brown coloration, arrows) is evident inside the fibers. (B) A sample of gastrocnemius muscle obtained from a rat injected 12 hours earlier with normal saline. No positive staining is evident. The photomicrographs were provided by Dr. Sabah N. Hussain, Royal Victoria Hospital, Montreal, Canada.

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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)

Figure 8. Electron microscopy of the diaphragm (longitudinal section) of a rabbit under control conditions (left; specimen processed with 1,100-mOsm fixative) and after 3 days of controlled mechanical ventilation (right; specimen processed with 500-mOsm fixative). The control rabbit has an intact ultrastructure. The mechanically ventilated rabbit shows several areas of disrupted myofibrils (short thick arrows), the mitochondria are swollen (long thick arrow) and have abnormal cristae, and the intermyofibril space contains lipid droplets (long thin arrow), indicating decreased lipid uptake by the mitochondria. The electron micrographs were provided by Dr. Catherine S. H. Sassoon, Long Beach VA Hospital and University of California, Irvine, California.

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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).

Two main descending pathways control the lower motor neurons that innervate the respiratory muscles: the corticospinal (pyramidal) and bulbospinal tracts (Figure 12)

Figure 12. Voluntary (corticospinal tract) and automatic (bulbospinal tract) pathways that control breathing. Motor fibers of the corticospinal tract originate in the cerebral cortex, cross over in the medulla, and descend in the spinal cord. Motor fibers of the bulbospinal tract originate in the respiratory neurons of the medulla, cross over at or near the upper cervical cord, and descend in the spinal cord. The fibers synapse with the phrenic motor neurons that innervate the diaphragm.

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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 [303]).

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)

Figure 13. Two patterns of maximal flow–volume loops in patients with Parkinson's disease. Left: A sawtooth pattern, characterized by oscillations. Right: A rounded pattern, characterized by a slowing of the initial expiratory flow and a shift of the peak to a lower volume.

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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.

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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 [338] or magnetic [333]) 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.

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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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)

Figure 14. Schematic representation of sagittal section of thorax and abdomen in two patients with diaphragmatic paralysis during apnea at functional residual capacity (left), quiet exhalation (middle), and quiet inhalation (right). In the drawings, the continuous thin lines represent relaxed muscles, thick lines represent contracted muscles, and interrupted lines represent the relaxed configuration. Patient A: During apnea (left), all muscles are relaxed and all signals remain steady at the relaxed configuration (functional residual capacity). During exhalation (middle), the muscles are relaxed and the signals for volume, esophageal pressure, rib cage motion, gastric pressure, abdominal motion, and transdiaphragmatic pressure return to the relaxed configuration. During inhalation (right), contraction of the rib cage muscles (thick line) generates a negative esophageal pressure, outward rib cage motion, and increase in volume; the negative intrathoracic pressure sucks the diaphragm and abdominal contents cephalad, resulting in a negative gastric pressure and inward motion of the abdomen (paradox). Transdiaphragmatic pressure does not change. Patient B: During apnea (left), the pattern is identical to that described for Patient A. During exhalation (middle), the rib cage muscles relax and the rib cage moves inwards; contraction of the abdominal muscles (thick line) generates an increase in gastric pressure, inward motion of the abdominal wall, and forces lung volume to fall to below FRC at end exhalation. The smaller end-expiratory lung volume causes elastic recoil to be smaller and esophageal pressure to be less negative than at FRC. During inhalation (right), contraction of the rib cage muscles (thick line) causes outward motion of the rib cage, and relaxation of the expiratory muscles causes a rapid fall in gastric pressure and outward abdominal motion (no paradox). The transdiaphragmatic pressure does not change.

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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).

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 [380] or area [381] 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).

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)

Figure 15. Dystrophin–glycoprotein complex. The structural integrity of the sarcomere of a muscle is thought to be secured by a complex bridge binding F-actin within the cell cytoplasm to the extracellular matrix. The intracellular portion of this bridge is dystrophin (a rod-shaped molecule), the transmembrane portion of the bridge is the sarcoglycan (α, β, γ, δ subunits) and dystroglycan (β subunit) complex, and the extracellular portion of the bridge is anchored to the basal lamina (extracellular matrix) by the laminin complex. Patients with Duchenne's muscular dystrophy lack dystrophin. Lack of dystrophin in skeletal and cardiac muscles is thought to predispose to stress-induced rupture of a weakened sarcolemma and excessive influx of calcium.

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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 [416]) 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 [420]), 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.

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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).