Pathophysiology and Pulmonary Function Testing

Weakness of the respiratory muscles leads to the inability to generate or maintain normal respiratory pressures. Pulmonary function testing in patients with neuromuscular weakness typically reveals a restrictive ventilatory defect even if the lungs are normal. Vital capacity (VC), forced expiratory volume in 1 second (FEV₁), and total lung capacity (TLC) are decreased. Residual volume (RV) is normal or decreased, and diffusing capacity corrected for alveolar volume is normal or near-normal but has been reported to be decreased.¹ Comparison of spirometric results obtained with the patient in seated and supine positions can be useful in showing that orthopnea is caused by neuromuscular weakness. A decrease in VC or FEV₁ of greater than 20% when a patient moves from the seated to the supine position suggests diaphragmatic weakness (Table 29-2 and Figure 29-2). The inability to generate normal respiratory pressures is reflected in a decreased maximal inspiratory pressure (PImax). Expiratory muscle weakness is characterized by a decreased maximal expiratory pressure (PEmax).

Arterial blood gases in the setting of a rapid, shallow breathing pattern may show a decreased PaCO₂, although progressive inspiratory muscle weakness leads to hypoventilation and hypercapnia. Hypoxemia can occur in patients unable to take deep breaths and may be caused by microatelectasis, which leads to ventilation/perfusion mismatching within the lung and a resulting decrease in PaO₂ (Figure 29-3). Chronic hypoxemia in this situation may be protective against acute respiratory muscle failure. Experimental data suggest that when hypoxemia is chronic, it may increase diaphragm muscle endurance.² Hypoventilation that occurs with progressive neuromuscular disease may be a protective mechanism that avoids acute respiratory muscle fatigue. However, when hypoxemia is acute, it potentiates respiratory muscle fatigue, hastening respiratory failure.³

Clinical Signs and Symptoms

In the early stages of neuromuscular disease, patients with respiratory muscle weakness initially report exertional dyspnea and fatigue. As the disease process progresses, patients may complain of orthopnea or symptoms of cor pulmonale. These symptoms occur because the muscles involved with respiration can no longer generate or maintain normal ventilation. The response to hypoxemia and respiratory drive, measured with airway occlusion pressure (P0.1), is preserved in most patients with neuromuscular weakness.⁴ Because these patients do not have the strength to take deep breaths, they increase minute ventilation by increasing respiratory rate and adopting a rapid, shallow breathing pattern, which uses less respiratory muscle strength but provides less efficient ventilation. Patients with poor inspiratory muscle function (especially diaphragm weakness) may have marked orthopnea and prefer to sleep in a seated position. They may also experience a decline in the volume and power of voice or voice quality. Progressive muscle weakness can progress to the point where adequate ventilation is no longer maintained, and hypercapnia occurs.

Monitoring and Assessing Patients With Muscle Weakness for Respiratory Insufficiency

If respiratory muscle weakness progresses and cannot be stopped, the eventual result is respiratory failure. The onset of respiratory failure is acute or chronic depending on the time course of the disease process and the circumstances of the patient. When this progression toward respiratory failure is noted, careful follow-up and monitoring of symptoms and pulmonary function are necessary for assessment of the need for mechanical ventilation.

Monitoring the ventilatory function of a patient with neuromuscular weakness can involve repeated measurement of inspiratory pressure, VC, and arterial blood gas values. Depending on the condition, the need for mechanical support can be signaled by reaching either a critical value on testing or an overall clinical condition that does not allow unassisted ventilation to continue. Additional measurements that have been suggested to be more indicative of early respiratory insufficiency, at least in amyotrophic lateral sclerosis (ALS), include maximal sniff nasal inspiratory force⁵ and nocturnal oximetry.⁶

At least two caveats to this general approach should be mentioned. First, patients with myasthenia gravis having an acute myasthenic crisis may have normal test results within minutes of acute ventilatory failure because of the nature of the disorder.⁷ Second, the need to protect the upper airway from secretions and aspiration may not be clearly reflected in results of pulmonary function tests, which evaluate only the mechanical function of the ventilatory pump. Neuromuscular weakness may not manifest uniformly in all muscle groups. Ventilation may be only moderately reduced in patients with gross oropharyngeal dysfunction leading to aspiration. Patients with ventilatory weakness can have a high risk of acute respiratory failure if upper respiratory tract infection or pneumonia develops. In these patients, inability to clear secretions can increase the work of breathing; the results are muscle fatigue, hypoventilation, and acute respiratory failure.

Patients with significant weakness of the respiratory muscles can have a high risk of respiratory failure when any pulmonary process increases the work of breathing. Pulmonary edema, pneumonia, and mucous plugging are examples of clinical conditions that can precipitate respiratory failure rapidly in patients with significant neuromuscular weakness. Such patients may need observation of their respiratory status when they are in the hospital with these conditions. Although the underlying disease may not have progressed to the point that these patients need continual or routine ventilatory support, that support may be critical in the setting of acute, exacerbating illness.

Nocturnal oximetry or formal sleep testing with polysomnography may be suggested in some clinical settings when patients have cor pulmonale, sleep disturbance, or excessive daytime somnolence that is otherwise unexplained.

Management of Respiratory Muscle Weakness

Respiratory insufficiency and failure to clear secretions are the major consequences of inspiratory and expiratory muscle weakness. Treatment of these patients involves consideration of mechanical ventilation via face mask or other noninvasive interfaces or via tracheostomy. Although often overlooked, therapies to augment secretion clearance and assist with cough are important in these patients (see Chapters 39 and 40). Used together, these interventions can decrease hospitalizations secondary to respiratory complications in patients with neuromuscular disease.⁸ These measures may also be useful in delaying or preventing the need for intubation or tracheostomy, although severe bulbar muscle weakness may limit a patient’s ability to avoid invasive ventilatory support.⁹ In addition to these interventions, general rehabilitation focusing on aerobic conditioning, muscle strengthening, and respiratory muscle training can often delay the need for ventilatory support and improve the overall quality of life for patients with muscle weakness.¹⁰

Noninvasive ventilation is being used increasingly for short-term and intermittent ventilatory support of patients with neuromuscular disease.¹¹ Acute deterioration, such as during a pneumonia, and surgical procedures such as gastrostomy tube insertion are situations where noninvasive ventilation is safe and effective if used carefully.^9,12 If a patient needs long-term ventilatory support on an intermittent basis, such as at night only, noninvasive ventilation may be appropriate.¹³ Decisions to begin mechanical ventilation in some patients with neuromuscular weakness have varied greatly among physicians¹⁴ and may be motivated by many different patient factors.¹⁵ No uniform guidelines exist for the use of long-term mechanical ventilation for patients with neuromuscular weakness. However, it is considered a standard option for patients who have reached the point of respiratory failure. Starting a patient on long-term mechanical ventilation requires careful planning and consideration of various issues related to respiratory care in alternative settings. These issues have been addressed in consensus statements^16,17 and are discussed in Chapter 51.

Diaphragm pacing in patients with spinal cord injury has been described for some time using direct stimulation of an intact phrenic nerve to contract the diaphragm and produce negative intrathoracic pressure and inspiration.¹⁸ This technique usually requires a thoracotomy, with its associated risks and high cost, and carries some risk of phrenic nerve injury. These objections have led to the development of an alternative system for diaphragm pacing using direct pacing of the diaphragm employing intramuscular electrodes implanted laparoscopically.¹⁹ When the electrodes can be placed in the diaphragm muscle at an electrophysiologically mapped motor point, the result is often elimination of the need for mechanical ventilation in patients with spinal cord injury and delay in the need to start mechanical ventilation in patients with ALS and other neuromuscular diseases.²⁰

Duchenne Muscular Dystrophy and Becker Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a genetic muscle-wasting disorder caused by mutations in the dystrophin gene.²¹ Because it is an X-linked recessive disorder, it affects mostly males. The diagnosis is made when a dystrophin mutation is found in DNA from peripheral white blood cells or when dystrophin is found to be absent or abnormal in muscle biopsy tissue.

DMD manifests early in life with proximal muscle weakness that leads to a waddling gait, exaggerated lumbar curvature (lordosis), and frequent falls. Most affected children need a wheelchair by 12 years of age. Death generally occurs by 20 years of age, usually as a result of declining respiratory muscle strength and subsequent infection. Becker muscular dystrophy, a milder form of DMD, also is associated with dysregulation of the dystrophin gene and manifests later in life.

Other systemic effects of DMD include scarring of the left ventricle and decreased bowel motility (intestinal pseudoobstruction). The progressive decline in respiratory function in patients with DMD parallels limb weakness and typically occurs at the point of wheelchair dependence. Respiratory weakness is primarily due to loss of muscle strength and leads to a lower PImax at all lung volumes than is present in healthy persons.

Progressive scoliosis is associated with DMD and can contribute further to respiratory insufficiency. Many patients undergo spine fusion surgery, and often the procedure allows greater comfort and ease in maintaining an upright posture. Although no randomized trials have proven any benefit of surgery on pulmonary function,²² observational data suggest that the rate of respiratory decline is slower after fusion surgery.²³

Obstructive sleep apnea has been described in a significant proportion of patients with DMD, prompting some authors to recommend formal polysomnography in patients with symptoms of obstructive sleep apnea or at the stage of becoming wheelchair-bound.²⁴ Institution of positive pressure ventilation (PPV) is a decision most patients face at some point in the disease. The point at which to begin different stages of ventilatory support depends on both test results and clinical condition. Nocturnal PPV is usually indicated when FVC reaches 30% of predicted with signs of hypoventilation.^25,26 It can be instituted in response to oxygen desaturation during sleep, which is common in patients with increased disability and scoliosis. Nocturnal ventilation seems to improve daytime ventilatory function in patients with DMD,²⁷ presumably through the prevention of fatigue of the affected respiratory muscles. Despite this improvement, results of studies of early “prophylactic” institution of PPV in the care of patients with DMD have shown that early PPV failed to delay the need for formal ventilatory support.²⁸ However, long-term inspiratory muscle training using resistive loading was shown in at least one study to improve PImax in patients with DMD and VC values greater than 27%,²⁹ theoretically delaying the need for ventilatory support. Although there are concerns that pulmonary rehabilitation could produce deleterious effects through overloading weak respiratory muscles, such concerns have not been confirmed in studies in Becker muscular dystrophy.³⁰

Myotonic Dystrophy

Myotonic dystrophy is the most common form of muscular dystrophy in adults, with an estimated frequency of 1 in 8000 persons.³¹ Myotonia, or delayed muscle relaxation, is the hallmark of this neuromuscular disorder but does not clearly occur in respiratory muscles or directly cause respiratory insufficiency.³² This autosomal dominant disorder causes progressive muscle weakness, abnormalities of the cardiac conduction system, endocrine dysfunction, and cataracts. There are two main types of myotonic dystrophy, both caused by an expansion of a repeated DNA sequence on chromosome 19.³³

Respiratory dysfunction in myotonic dystrophy is common, usually occurring late in the course of disease, and can include respiratory muscle weakness, obstructive sleep apnea, central sleep apnea, and bulbar muscle dysfunction leading to aspiration. Sleep-related disorders are particularly common, even at an early age.³⁴

Patients with myotonic dystrophy can be very sensitive to anesthesia and respiratory depressants. Both respiratory failure and prolonged neuromuscular blockade have been reported in patients with myotonic dystrophy given usual doses of these agents. For this reason, prolonged perioperative monitoring after surgery is important.35,36

Nocturnal ventilation by nasal mask often is effective for these patients and should be considered if the patient has declining oxygen saturation or hypercapnia. If present, central hypoventilation may necessitate tracheostomy and mechanical ventilation.

Polymyositis

Polymyositis, dermatomyositis, and inclusion body myositis are inflammatory myopathies of unknown cause. Respiratory compromise is rare in inclusion body myositis but can be seen in both polymyositis and dermatomyositis. Clinical respiratory muscle weakness is uncommon but can lead to respiratory weakness or failure within weeks to months in the setting of rapidly progressing disease. Diagnosis of these diseases is based on clinical findings of myalgia, elevated muscle enzyme levels (creatine phosphokinase or aldolase), and compatible electromyographic or muscle biopsy results. Diagnostic criteria may apply to any inflammatory myopathy, and specific findings or antibody identification may be needed to differentiate the various diseases (Table 29-4).^37,38

Ventilatory insufficiency and failure caused by these inflammatory myopathies are unusual but tend to parallel the development of limb muscle weakness when they occur. In rare reported instances, diaphragmatic function is decreased disproportionately to the degree of limb weakness.³⁹

Corticosteroids are the mainstay of initial management of polymyositis and dermatomyositis, although other immunosuppressive and cytotoxic regimens are used to limit long-term steroid exposure; 35% to 40% of patients with inflammatory myopathy have interstitial lung disease associated with myopathy. This lung disease appears as diffuse interstitial infiltrates that may be caused by various lung processes, but the most common (56%) is nonspecific interstitial pneumonia.⁴⁰ Various antisynthetase antibodies (e.g., Jo-1) have been identified that are associated with polymyositis and dermatomyositis,^41–43 although the role of these antibodies in the pathogenesis of these diseases is unclear. Pulmonary vasculitis can occur with polymyositis and dermatomyositis and can lead to oxygen exchange abnormalities and pulmonary hypertension.

Critical Illness Myopathy

Critical illness myopathy is a heterogeneous entity that occurs commonly in intensive care units (ICUs) and in which patients develop flaccid weakness of proximal muscles. Patients are often very difficult to wean from mechanical ventilation. Risk factors for developing this myopathy include use of corticosteroids (likely dose-dependent); use of paralytic agents; hyperglycemia; hyperthyroidism; and possibly systemic inflammatory response syndrome, with or without sepsis.44,45 Weakness improves on its own in most cases but may take weeks or months to resolve. There is no specific therapy, and prevention by avoiding the aforementioned risk factors is the best approach.

Disorders of the Neuromuscular Junction

Disorders of the neuromuscular junction decrease conduction of nervous system impulses to the peripheral muscles, resulting in muscle weakness. Different clinical syndromes are caused by defects in different molecules or components of the neuromuscular junction, which is represented schematically in Figure 29-4. Disorders of the neuromuscular junction include the following:

Myasthenia Gravis

Myasthenia gravis (MG) is characterized by intermittent muscular weakness, which worsens on repetitive stimulation and improves with administration of anticholinesterase medications, such as edrophonium (Tensilon) or neostigmine. Most cases of MG arise from production of antibodies directed against the acetylcholine receptor (ACh-R). The antibodies inactivate the ACh-R and block transmission of electrical impulses from the nerve to the muscle.⁴⁶

Approximately 20% of patients with MG do not exhibit such antibodies but may have antibodies to alternative targets, such as muscle-specific kinase.⁴⁷ Abnormalities of the thymus gland are common in MG. Approximately 10% of patients with MG have a neoplastic growth within the thymus called thymoma, which can be malignant but usually is not. Patients without thymoma typically have some degree of thymic hyperplasia. Congenital or fetal myasthenic syndromes are caused by either autoantibodies or inherited defects in the ACh-R.

MG typically occurs earlier in life in women and later in men. As the population has aged, more patients are diagnosed with MG later in life, and now there are more men affected than women.⁴⁸ This disorder may be associated with other autoimmune diseases, such as endocrinopathies, rheumatoid arthritis, ulcerative colitis, sarcoidosis, and pernicious anemia.

MG is characterized by progressive loss of muscular function, which may affect only the eye muscles (ocular myasthenia) or may be more widespread. The initial symptom is diplopia (double vision) or ptosis (a drooping eyelid) in greater than 65% of patients (Figure 29-5).⁴⁹ The patient typically reports weakness of the affected muscles that may vary through the day or progress, especially with repetitive use. The diagnosis of MG is supported by the detection of anti–ACh-R antibodies in the blood, a characteristic fading of nerve impulses with repeated nerve stimulation testing during electromyography, and improvement of strength or symptoms in response to an anticholinesterase inhibitor drug (edrophonium) (Figure 29-6).

Treatment of MG is generally effective, although it is largely empiric because clinical trials are rare. Long-term management includes thymectomy⁵⁰ and administration of anticholinesterases (edrophonium, neostigmine, pyridostigmine) with or without corticosteroids or other immunosuppressants, such as azathioprine or cyclosporine.⁴⁹ For patients in acute myasthenic crisis, who often are in respiratory failure on mechanical ventilation, circulating antibodies can be removed by plasmapheresis, which results in clinical improvement^51,52 usually after five or six treatments and has been used to facilitate weaning from mechanical ventilation in the care of patients with myasthenic crisis.⁵³ Intravenous IgG has also been used and can improve muscle strength and hasten recovery from respiratory failure. Neither apheresis nor intravenous IgG is generally used for long-term management of MG. The effect of both treatments is temporary but may last several months.⁴⁹ Clinical trials comparing these treatments have shown a slight efficacy advantage of plasmapheresis but at the cost of a higher complication rate.^54,55

The pulmonary complications of MG depend on the magnitude and location of the affected muscle groups and tend to occur in patients most severely disabled with the disease. Upper airway obstruction, exertional dyspnea, and overt ventilatory failure all are reported in MG. Pulmonary function testing of MG patients who have respiratory muscle weakness shows decreased TLC, VC, PImax, and PEmax similar to other neuromuscular disorders, with PImax and PEmax being more sensitive markers of early respiratory muscle weakness.⁵⁶

Myasthenic crisis is an acute event in MG and is characterized either by respiratory failure or by inability to maintain a patent airway. Myasthenic crisis can occur acutely in response to worsening of disease, intercurrent infection, or surgery or when excess anticholinesterase inhibitors have been given. Endotracheal intubation and mechanical ventilation are required immediately and may be prolonged.⁵⁷

Disorders of the Nerves

The peripheral nerves may be affected by toxic agents, inflammatory processes, vascular disorders, malignant diseases, and metabolic or nutritional imbalances. Hundreds of conditions have been associated with neuropathies leading to respiratory muscle dysfunction. Representative conditions are listed in Box 29-1.

Phrenic Nerve Damage and Diaphragmatic Paralysis

Each hemidiaphragm is supplied by its own phrenic nerve. The phrenic nerves emerge from the spinal cord at level C3-5 and descend through the mediastinum along the great vessels of the chest and pericardium. Damage to or interruption of either phrenic nerve leads to paralysis of the ipsilateral hemidiaphragm. Bilateral interruption is seen in high spinal cord injury and causes complete diaphragmatic paralysis. Unilateral diaphragmatic paralysis can be seen in various disease processes. Reversible unilateral diaphragmatic paralysis is a rare complication of acute pneumonia, but it can occur in 10% of patients who undergo cardiac surgery with cardiopulmonary bypass, usually secondary to cold cardioplegia or traction on the nerve during surgery or ischemic nerve injury.⁷⁰

Patients with unilateral diaphragmatic paralysis may have a 15% to 20% reduction in VC and TLC in the upright position and a further reduction while supine. If they have no other diseases, patients with unilateral diaphragmatic paralysis may have no symptoms. Athletes, musicians, and others who use their lungs more fully are more likely to notice the decreased ventilatory capacity caused by unilateral diaphragm weakness. Diaphragmatic paralysis is diagnosed most often with chest radiography. The paralyzed side retains its contour but is displaced upward (Figure 29-7, A). At fluoroscopy, the paralyzed hemidiaphragm paradoxically rises into the thorax during a sudden forceful inspiration (sniff test). This paradoxical motion dampens the effect of the normal diaphragm on the opposite side.

For patients with unilateral diaphragm paralysis, surgical plication of the weak side can move the diaphragm downward to a more normal position (Figure 29-7, B) and minimize paradoxical motion and improve overall lung function.^71,72 Historically, results of diaphragm plication procedures have been disappointing, but newer laparoscopic techniques are more promising.⁷³ Appropriate patient selection is crucial to avoid operating on patients whose diaphragms would recover their strength in time and patients whose weakness is due to primary neuromuscular disorders, which would not be improved by plication.

 Rule of Thumb

Diaphragm weakness resulting from phrenic nerve injury (not transection) often improves very slowly, sometimes over years, so plication should be delayed until serial testing shows that no further improvement is occurring, usually at least 1 to 2 years from the onset of weakness.

Disorders of the Spinal Cord

Upper motor neurons arise from cell bodies in the motor areas of the brain and terminate at the anterior horn cells in the spinal cord, which constitute the lower motor neurons because it is axons from these cells that extend out of the central nervous system to the skeletal muscles. Disorders in this group (e.g., ALS) can affect specific parts of this chain or nonspecifically disrupt these tracts (e.g., spinal cord injury). Other examples of lesions in this anatomic location include transverse myelitis, syringomyelia, poliomyelitis, and spinal cord tumors.

Disorders of the Brain

Traumatic brain injury, stroke, hemorrhage, and infection can lead to abnormality of respiration through various mechanisms. The motor cortex contains voluntary centers for control of the upper airway and pharynx (see Chapter 14). The pons and medulla, located in the brainstem, contain (1) chemoreceptors for automatic control of ventilation in response to increasing pH and hypercapnia and (2) centers that generate and modify patterns of automatic ventilation in response to visceral and chemical afferent information (see Figure 29-1). Both stroke and traumatic brain injury can lead to disordered patterns of breathing, which are listed in Table 29-6, and abnormalities in the lungs themselves, such as neurogenic pulmonary edema. This section describes the clinical entities of stroke and traumatic brain injury and their effects on the respiratory system.

Disorders of the Thoracic Cage

The thoracic cage contains the lungs and supports the muscles of respiration. Normal ventilatory mechanics depend on a compliant thoracic cage with free excursion throughout the respiratory cycle.

Kyphoscoliosis

Kyphosis is posterior angulation of the thoracic cage. Scoliosis is lateral curvature of the spine (Figure 29-8). These two deformities often occur together (called kyphoscoliosis) as a result of the compensatory effects of the spine in response to the primary lateral curve in scoliosis.

Scoliosis is typically noticed during childhood and progresses during adolescence, although idiopathic adult kyphoscoliosis has been reported. The degree of scoliosis is measured by the Cobb angle, which is determined by the intersection of lines drawn between the upper and lower limbs of the primary curve in scoliosis (Figure 29-9). Severe kyphoscoliosis (Cobb angle >90 to 100 degrees) can lead to hypoventilation, hypercapnia, and, if untreated, complications of pulmonary hypertension. However, the degree of pulmonary dysfunction cannot be predicted from the Cobb angle alone.^90,91 Respiratory dysfunction is probably multifactorial in most patients. Compliance of the chest wall and lung is decreased in patients with significant kyphoscoliosis. The result is a restrictive ventilatory defect with decreased TLC and VC in pulmonary function testing. Maximal transdiaphragmatic pressure also is decreased, a sign of impaired diaphragmatic function in the pathogenesis of respiratory dysfunction in severe kyphoscoliosis.

Anterior or posterior spinal fixation can stabilize kyphoscoliosis and restore the thoracic curvature to a condition close to normal. Fixation prevents complications secondary to progressive curvature, loss of compliance, and subsequent ventilatory dysfunction. Few options are available to restore pulmonary function to older patients with established kyphoscoliosis. Surgery to correct the deformity can be undertaken, but this treatment generally does not improve pulmonary function.⁹² Better long-term results are seen when surgery or brace therapy to correct the angulation are undertaken in adolescence.⁹³

Both noninvasive and invasive ventilation are used in some patients with severe kyphoscoliosis, with improvement in blood gas values, respiratory muscle strength, symptoms of dyspnea,⁹⁴ and exercise capacity.⁹⁵ Both negative pressure⁹⁶ and positive pressure⁹⁷ ventilation have been reported to stabilize respiratory function in patients with severe kyphoscoliosis.