Specific Diseases

The major neuromuscular diseases that can affect the muscles of respiration are listed in Table 19-1; several are discussed here.

Guillain-Barré syndrome is a disorder characterized by demyelination of peripheral nerves. It is thought to be triggered by exposure to an antigen (typically an infectious agent such as Campylobacter jejuni). The resulting immune response is misdirected to similar antigenic determinants (epitopes) on neural tissue or Schwann cells. Patients frequently have a history of a recent viral or bacterial illness followed by development of an ascending paralysis and variable sensory symptoms. Classically, weakness or paralysis starts symmetrically in the lower extremities and progresses or ascends proximally to the upper extremities and trunk. In up to one-third of cases, the disease is more severe, with respiratory muscle weakness or paralysis accompanying the more usual limb and trunk symptoms. When respiratory muscles are affected, respiratory failure often supervenes but usually is reversible over the course of weeks to months. Generally, the natural history of the disease leads to recovery, although 3% to 8% of patients die, and up to 10% of survivors have permanent sequelae.

In myasthenia gravis, patients experience weakness and fatigue of voluntary muscles, most frequently those innervated by cranial nerves, but peripheral (limb) and, potentially, respiratory muscles also are affected. The primary abnormality is found at the neuromuscular junction, where transmission of impulses from nerve to muscle is impaired by a decreased number of receptors on the muscle for the neurotransmitter acetylcholine and by the presence of antibodies against these receptors. Although myasthenia gravis is a chronic illness, the manifestations often can be controlled by appropriate therapy, and individual episodes of respiratory failure are potentially reversible.

Poliomyelitis is a viral disease in which the poliovirus attacks motor nerve cells of the spinal cord and brainstem. Both the diaphragm and intercostal muscles can be affected, with resulting weakness or paralysis and respiratory failure. Surviving patients generally recover respiratory muscle function, although some patients have chronic respiratory insufficiency from prior disease. Mass vaccination of the population in developed countries makes new cases rare. In postpolio syndrome, patients develop new or progressive symptoms of weakness that occur decades after the initial episode of poliomyelitis. Involvement occurs in muscles originally affected by the disease, so respiratory muscle involvement is more likely in patients who had respiratory failure with their initial disease.

Amyotrophic lateral sclerosis is a degenerative disease of the nervous system that involves both upper and lower motor neurons. Commonly, muscles innervated by either cranial nerves or spinal nerves are affected. Clinically, progressive muscle weakness and wasting develop, eventually leading to profound weakness of respiratory muscles and death. Although the time course of the disease is variable among patients, the natural history is one of irreversibility and progressive deterioration. As a result, patients and families must confront the difficult decision of whether to use mechanical ventilation either noninvasively or through a tracheostomy tube when the patient is in respiratory failure, knowing that no treatment will arrest the progressive neurologic deterioration.

Pathophysiology and Clinical Consequences

Weakness of respiratory muscles is the hallmark of respiratory involvement in the neuromuscular diseases. Depending on the specific disease, chest wall (intercostal) muscles, diaphragm, and expiratory muscles of the abdominal wall are affected to variable extents.

Impairment of inspiratory muscle strength may render patients unable to maintain sufficient minute ventilation for adequate CO₂ elimination. In addition, patients often alter their pattern of breathing, taking shallower and more frequent breaths. Although this pattern of breathing may require less muscular effort and be more comfortable, it is also less efficient because a greater proportion of each breath is wasted on ventilating the anatomic dead space (see Chapter 1). Therefore, even if total minute ventilation is maintained, alveolar ventilation (and thus CO₂ elimination) is impaired by the altered pattern of breathing.

The respiratory difficulty that develops in patients with neuromuscular disease is complicated by weakness of expiratory muscles and by an ineffective cough. Recurrent respiratory tract infections, accumulation of secretions, and areas of collapse or atelectasis contribute to the clinical problems seen in these patients.

Symptoms include dyspnea and anxiety. Patients may also have a feeling of suffocation. Often the presence of generalized muscle weakness severely limits patients’ activity and lessens the degree of dyspnea that would be present if they were capable of more exertion.

With severe neuromuscular disease, pulmonary function tests show a restrictive pattern of impairment. Although muscle weakness is the primary cause of restriction, compliance of the lung and chest wall may be secondarily affected, further contributing to the restrictive pattern. The decrease in pulmonary compliance presumably is due to microatelectasis (i.e., multiple areas of alveolar collapse) resulting from the shallow tidal volumes. At the same time, stiffening of various components of the chest wall (e.g., tendons, ligaments, and joints) over time is thought to be responsible for decreased distensibility of the chest wall. Functional residual capacity (FRC) is normal or decreased, depending on how much respiratory system compliance is altered. Total lung capacity is decreased primarily as a result of inspiratory muscle weakness, but changes in respiratory system compliance may contribute as well. Residual volume (RV) frequently is increased as a result of expiratory muscle weakness (Fig. 19-1). The degree of muscle weakness can be quantified by measuring the maximal inspiratory and expiratory pressures the patient is able to generate with maximal inspiratory and expiratory efforts against a closed mouthpiece. Both maximal inspiratory pressure (MIP) and maximal expiratory pressure may be significantly depressed.

In the setting of severe muscle weakness, arterial blood gases are most notable for the presence of alveolar hypoventilation (i.e., hypercapnia). Hypoxemia due to alveolar hypoventilation and the associated depression in alveolar PO₂ also occurs. When hypoventilation is the sole cause of hypoxemia, the alveolar-arterial oxygen difference (AaDO₂) is normal. However, complications such as atelectasis, respiratory tract infections, and inadequately cleared secretions may add a component of ventilation-perfusion mismatch or shunt that further depresses PO₂ and increases AaDO₂.

Diaphragmatic Fatigue

Excluding cardiac muscle, the diaphragm is the single muscle used most consistently and repetitively throughout the course of a person’s lifetime. It is well suited for sustained activity and aerobic metabolism, and under normal circumstances the diaphragm does not become fatigued.

However, if the diaphragm is required to perform an excessive amount of work or if its energy supplies are limited, fatigue may develop and may contribute to respiratory dysfunction in certain clinical settings. For example, if a healthy individual repetitively uses the diaphragm to generate 40% or more of its maximal force, fatigue develops and prevents this degree of effort from being sustained indefinitely. For patients with diseases that increase the work of breathing, particularly obstructive lung disease and diseases of the chest wall (described in the section on diseases affecting the chest wall), the diaphragm works at a level much closer to the point of fatigue. When a superimposed acute illness further increases the work of breathing or when an intercurrent problem (e.g., depressed cardiac output, anemia, or hypoxemia) decreases the energy supply available to the diaphragm, diaphragmatic fatigue may contribute to the development of hypoventilation and respiratory failure.

Inefficient diaphragmatic contraction is another factor that may contribute to diaphragmatic fatigue, especially in patients with obstructive lung disease. When the diaphragm is flattened and its fibers are shortened as a result of hyperinflated lungs, the force or pressure developed during contraction is less for any given level of diaphragmatic excitation (see Chapter 17). Therefore, a higher degree of stimulation is necessary to generate comparable pressure by the diaphragm, and increased energy consumption results.

Diaphragmatic fatigue is often difficult to detect because the force generated by the diaphragm cannot be measured conveniently. Ideally, diaphragmatic fatigue is documented by measuring the pressure across the diaphragm (i.e., the difference between abdominal and pleural pressure, called the transdiaphragmatic pressure) during diaphragmatic stimulation or contraction. As an alternative to measurement of transdiaphragmatic pressure, the strength of the inspiratory muscles in general can be assessed by measuring the pressure that a patient can generate with a maximal inspiratory effort against a closed mouthpiece (i.e., MIP). A useful finding on physical examination is the pattern of motion of the abdomen during breathing when the patient is supine. If diaphragmatic contraction is especially weak or absent, pleural pressure falls during inspiration, mainly as a result of contraction of other inspiratory muscles. The negative pleural pressure is transmitted across the relatively flaccid diaphragm to the abdomen, which then moves paradoxically inward during inspiration.

Along with investigation of the role of diaphragmatic fatigue in respiratory failure have been attempts to improve or reverse fatigue. Use of assisted ventilation with a mechanical ventilator to rest the diaphragm is the main method for reversing fatigue. Alternatively, use of theophylline has been shown experimentally to increase the strength of diaphragmatic contraction. However, whether this type of pharmacologic therapy produces a clinically beneficial effect has yet to be proven.

Unilateral Diaphragmatic Paralysis

Paralysis of the diaphragm on one side of the thorax (also called a hemidiaphragm) typically results from disease affecting the ipsilateral phrenic nerve. A particularly common cause of unilateral diaphragmatic paralysis is invasion of the phrenic nerve by malignancy. The underlying tumor is frequently lung cancer that has invaded or metastasized to the mediastinum, and either the primary tumor itself or mediastinal lymph nodes affected by tumor invade the phrenic nerve somewhere along its course through the mediastinum. With treatment, some diaphragmatic function may return, but frequently diaphragmatic paralysis resulting from malignancy is irreversible.

Paralysis of the left hemidiaphragm may be seen following cardiac surgery, attributable to either a stretch injury or a cooling injury to the phrenic nerve. In these cases, a cold solution is instilled in the pericardium during the procedure to stop cardiac contraction (cold cardioplegia) and allow surgery on a nonbeating heart while circulation is maintained by cardiopulmonary bypass. However, the cold solution causes temporary paralysis of the left phrenic nerve, leading to diaphragmatic paralysis of variable duration. With changes in surgical techniques, phrenic nerve injury is becoming less common following cardiac surgery. When it does occur, function usually recovers within 1 year.

In some patients with unilateral diaphragmatic paralysis, no underlying reason for the paralysis can be identified, and the problem is considered idiopathic. A viral infection affecting the phrenic nerve may be responsible in such cases. Many but not all of these patients recover some function over time.

The possibility of unilateral diaphragmatic paralysis is usually first suggested by a characteristic appearance on the chest radiograph (Fig. 19-2). The affected hemidiaphragm is elevated above its usual position in the absence of any associated lobar atelectasis or other reason for volume loss on the affected side. Standard chest radiographs taken during a full inspiration (to total lung capacity) reveal that the normal hemidiaphragm descends during inspiration, whereas the paralyzed hemidiaphragm cannot. Patients may or may not be symptomatic with dyspnea as a result of the paralyzed hemidiaphragm, often depending on the presence or absence of additional underlying lung disease.

Because an elevated diaphragm may result from causes other than diaphragmatic paralysis (e.g., processes below the diaphragm, such as a subphrenic abscess), it is generally useful to confirm objectively that diaphragmatic paralysis is the cause of diaphragmatic elevation. This can be achieved relatively easily by real-time observation of diaphragmatic movement during a “sniff test.” With this technique, the radiologist observes diaphragmatic motion under fluoroscopy while the patient sniffs. During the act of sniffing, which is a rapid inspiratory activity, the normal diaphragm contracts and therefore descends, but the paralyzed diaphragm moves passively (and paradoxically) upward as a result of rapid development of negative intrathoracic pressure during the sniff.

For appropriate patients who are dyspneic due to hemidiaphragmatic paralysis, a treatment option is diaphragmatic plication; in this surgical procedure, the hemidiaphragm is fixed in a flattened position. Although the hemidiaphragm does not move, the lung is maintained at a higher volume, and the hemidiaphragm can no longer move paradoxically upward during inspiration.

Bilateral Diaphragmatic Paralysis

Paralysis of both diaphragms has much more serious clinical implications than unilateral paralysis, because the patient must depend on the accessory muscles of inspiration to maintain minute ventilation. The causes of bilateral diaphragmatic paralysis are the neuromuscular diseases listed in Table 19-1, with bilateral diaphragmatic paralysis being the most severe consequence of respiratory involvement by these disorders.

A characteristic clinical manifestation of bilateral diaphragmatic paralysis is dyspnea that is significantly exacerbated when the patient assumes the recumbent position (i.e., severe orthopnea). When the patient is supine, the abdominal contents push on the flaccid diaphragm as the beneficial effects of gravity on abdominal contents and on lowering the position of the diaphragm are lost. On physical examination, patients typically demonstrate paradoxical inward motion of the abdomen during inspiration while they are supine, as described in the discussion on diaphragmatic fatigue. The deleterious effect of assuming the recumbent position is also seen with pulmonary function testing, in that the vital capacity measured in the supine position is significantly lower than that measured in the upright position.

Kyphoscoliosis

Kyphoscoliosis is an abnormal curvature of the spine in both the anterior (kyphosis) and lateral (scoliosis) directions (Fig. 19-3). This deformity causes the rib cage to become stiffer and more difficult to expand (i.e., chest wall compliance is decreased). Respiratory difficulties are common in patients with significant kyphoscoliosis. In particularly severe cases, chronic respiratory failure is the consequence. Although some cases of kyphoscoliosis actually are secondary to neuromuscular disease such as poliomyelitis, the majority of severe cases associated with respiratory impairment are idiopathic.

Several pathophysiologic features contribute to respiratory dysfunction in patients with kyphoscoliosis. A crucial underlying problem is the increased work of breathing resulting from the poorly compliant chest wall. To maintain even a normal minute ventilation, the work expenditure of the respiratory muscles is greatly increased. In addition, patients decrease their tidal volume and increase respiratory frequency because of difficulty expanding the abnormally stiff chest wall. Consequently, the proportion of wasted ventilation rises, and alveolar ventilation falls unless total ventilation undergoes a compensatory increase. Hence, the increased work of breathing acts together with the altered pattern of breathing to decrease alveolar ventilation and increase PCO₂. Chest wall compliance further decreases with age, and respiratory complications of uncorrected kyphoscoliosis become increasingly prevalent as the patient grows older.

Marked distortion of the chest wall causes underventilation of some regions of the lung, microatelectasis, ventilation-perfusion mismatch, and hypoxemia. Therefore, two frequent causes of hypoxemia in kyphoscoliosis are hypoventilation and ventilation-perfusion mismatch.

A common complication of severe kyphoscoliosis is pulmonary hypertension and cor pulmonale. Hypoxemia and, to a lesser extent, hypercapnia are important for the development of pulmonary hypertension. However, increased resistance of the pulmonary vessels also results from compression and possibly from impaired development in regions where the chest wall is especially distorted. Long-standing pulmonary hypertension itself also causes structural changes in the vessels, with thickening of the walls of pulmonary arteries. This thickening is not acutely reversible, even with correction of the hypoxemia.

Exertional dyspnea is probably the most common symptom experienced by patients with severe kyphoscoliosis and respiratory impairment. Unlike patients with neuromuscular disease, those with a chest wall deformity such as kyphoscoliosis have normal muscle strength and therefore are capable of normal levels of exertion. Unlike patients with neuromuscular disease, patients with kyphoscoliosis are not subject to the same difficulty in generating an effective cough. Expiratory muscle function is preserved, an effective cough is maintained, and problems with secretions and recurrent respiratory tract infections are not prominent clinical features.

Pulmonary function tests in patients with kyphoscoliosis are notable for a restrictive pattern of impairment with a decrease in total lung capacity. Vital capacity is significantly decreased, whereas RV tends to be relatively preserved. FRC, determined by the outward recoil of the chest wall balanced by the inward recoil of the lung, is decreased because the poorly compliant chest wall has a diminished propensity to recoil outward (see Fig. 19-1).

Severe cases of kyphoscoliosis are generally characterized by hypercapnia and hypoxemia. The latter usually is due to both hypoventilation and ventilation-perfusion mismatch. Chronic respiratory insufficiency and cor pulmonale are the end results of severe kyphoscoliosis, and the level of respiratory difficulty appears to correlate with the severity of chest wall deformity.

Surgical therapy aimed at improving or correcting the spinal deformity may be useful in children or adolescents but rarely is effective in adults. Supportive therapy that may be beneficial includes a variety of measures that provide ventilatory assistance to the patient. Treatments with an intermittent positive pressure breathing machine augment tidal volume by delivering positive pressure to the patient during inspiration. The increase in tidal volume improves microatelectasis and lung compliance, affording the patient several hours with decreased work of breathing after each treatment. At night, ventilatory assistance with either inspiratory positive pressure delivered via a mask or through a tracheostomy tube or negative pressure around the chest wall allows the respiratory muscles to rest. Nocturnal ventilatory support may provide sufficient rest for the inspiratory muscles to diminish daytime respiratory muscle fatigue. These types of ventilatory support are discussed further in Chapter 29.

Obesity

Obesity has many consequences for health, and respiratory symptoms are one aspect. Obesity can produce a wide spectrum in severity of respiratory impairment, ranging from no symptoms to marked limitation in function. Surprisingly, the degree of obesity does not appear to correlate with the presence or severity of respiratory dysfunction. Some patients who are massively obese have no difficulty in comparison with much less obese patients who may be severely limited. This may be partially explained by the distribution of body fat: central distribution of fat is more associated with decreased lung function as measured by pulmonary function testing. A full explanation of the discrepancies in symptoms among different patients is based on several factors, including smoking history, underlying lung disease, effects of obesity on the cardiovascular system, and underlying physical deconditioning.

The problem of respiratory impairment in obesity was popularly known for years as the pickwickian syndrome or obesity-hypoventilation syndrome. The term pickwickian was applied because of the description of Joe, the “fat boy” in Dickens’ Pickwick Papers, who had many of the characteristics described in this syndrome. Specifically, Joe had features of massive obesity, somnolence, and peripheral edema, the latter presumably related to cor pulmonale and right ventricular failure. With the accumulation of knowledge about the pathogenesis of respiratory impairment in obesity, the term pickwickian syndrome has become less meaningful.

Obesity appears to exert two mechanical effects on the respiratory system. As a result of excess soft tissue, the chest wall becomes stiffer or less compliant, so more work is necessary for expansion of the thorax. In addition, the massive accumulation of soft tissue in the abdominal wall exerts pressure on abdominal contents, forcing the diaphragm up to a higher resting position.

In a fashion similar to that of kyphoscoliosis, the stiff chest wall results in lower tidal volumes and increased wasted or dead space ventilation. To maintain adequate alveolar ventilation, overall minute ventilation must increase in the face of increased work of breathing. Some patients are able to compensate appropriately by increasing their overall minute ventilation, and PCO₂ remains normal. Other patients do not compensate fully, and hypercapnia is the necessary consequence.

Exactly what distinguishes these two types of patients is not really known. Perhaps patients in the latter group, for whom the term obesity-hypoventilation syndrome can be applied, started out with a central nervous system respiratory controller that was relatively hyporesponsive. Output of the controller might not have responded sufficiently to keep pace with increased ventilatory requirements, and CO₂ retention resulted. After hypercapnia actually develops, it is much more difficult to assess the innate responsiveness of the patient’s ventilatory controller because chronic hypercapnia (i.e., chronic respiratory acidosis with a compensatory metabolic alkalosis) blunts the responsiveness of the central chemoreceptor.

Another distinguishing feature between normocapnic and hypercapnic obese patients may relate to inspiratory muscle strength. Whereas inspiratory muscle strength is normal in obese patients with normal PCO₂, it is reduced by approximately 30% in patients with obesity-hypoventilation syndrome, perhaps as a result of respiratory muscle fatigue.

The high resting position of the diaphragm in obesity, occurring as a result of pressure from the obese abdomen, is associated with decreased expansion of the lung and closure of small airways and alveoli at the bases. Thus, the dependent regions are hypoventilated relative to their perfusion, and this ventilation-perfusion mismatch contributes to arterial hypoxemia.

Another factor that contributes to the overall clinical picture in many massively obese patients is upper airway obstruction during sleep (i.e., the obstructive form of sleep apnea syndrome). Soft tissue deposition in the neck and tissues surrounding the upper airway presumably predisposes the person to episodes of complete upper airway obstruction during sleep (see Chapter 18). In a large percentage of cases, somnolence that occurs in patients who supposedly have obesity-hypoventilation syndrome is related to the presence of obstructive sleep apnea.

Although obesity, depressed respiratory drive, respiratory muscle weakness, and sleep apnea syndrome contribute to respiratory dysfunction, exactly how they interact in individual patients is often difficult to assess. Because sleep apnea syndrome and depressed respiratory drive also occur in patients who are not obese, it is reasonable to view some of the contributing pathophysiologic factors in terms of a Venn diagram (Fig. 19-4). Probably the most marked symptoms and respiratory dysfunction are seen in patients who are represented at the intersection of the three circles.

The symptoms that may occur in obese patients can be associated with increased work of breathing (e.g., dyspnea) or sleep apnea syndrome (e.g., daytime somnolence and disordered sleep with profound snoring). Patients may have clinical manifestations related to the complications of pulmonary hypertension, cor pulmonale, and right ventricular failure. These complications are largely related to arterial hypoxemia both during the day and at night, particularly if patients have sleep apnea syndrome.

Pulmonary function tests frequently demonstrate a restrictive pattern of dysfunction, with a decrease in total lung capacity. The diaphragm is pushed up in massively obese patients, reducing FRC, which in these patients is much closer to RV; thus, spirometric examination shows the expiratory reserve volume is greatly reduced. This pattern of functional impairment is shown in Figure 19-1.

In most obese patients, arterial blood gases show a decrease in PO₂ and an increase in AaDO₂ as a consequence of high diaphragms, airway and alveolar closure, and ventilation-perfusion mismatch. If PCO₂ is not elevated, these patients are sometimes said to have “simple obesity.” When PCO₂ is elevated, the term obesity-hypoventilation syndrome is often used, and in these cases superimposed hypoventilation is another factor contributing to hypoxemia. If patients have sleep apnea syndrome, arterial blood gas values become even more deranged at night during episodes of apnea.

Weight loss is crucial in the treatment of obese patients with respiratory dysfunction. If weight loss is successfully achieved by either diet or bariatric surgery, respiratory problems may resolve in some patients. Unfortunately, attempts at significant and sustained weight loss are often unsuccessful, and some patients who successfully lose weight do not manifest respiratory benefits. Thus in most patients, other modes of therapy must be instituted. Nocturnal positive pressure ventilation is generally helpful in improving daytime sleepiness, particularly if the patient has concomitant obstructive sleep apnea syndrome (see Chapter 18). In some patients who hypoventilate, respiratory stimulants, especially progesterone (a centrally acting respiratory stimulant), have been used with limited success.

Neuromuscular Disease Affecting the Muscles of Respiration

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