Clinical Features

As always, a detailed history will facilitate making a correct diagnosis (Table 64-1). Of particular importance is the rate of onset of symptoms. Acute respiratory muscle weakness tends to progress rapidly, culminating in a medical emergency requiring intubation and mechanical ventilation. Some causes of acute respiratory muscle weakness, such as an acute myasthenic crisis or Guillain-Barré disease, may be reversible, and it is important to facilitate invasive respiratory support in the acute setting until a diagnosis can be made and appropriate therapies initiated. In chronic respiratory failure, the onset may not be clear, but clues to the course of events can be gained from the history. Often patients will describe dyspnea on exertion, but if peripheral muscle weakness precedes respiratory muscle weakness, the consequent loss of significant locomotor function will not permit exertion of sufficient degree to produce dyspnea. Classic features of diaphragm weakness are not always present in patients with generalized neuromuscular disease but may include dyspnea on lying supine, on bending forward, or on immersion in water above the midchest level. If respiratory weakness is severe, patients also may describe symptoms of nocturnal hypoventilation, such as extensive daytime somnolence, reduced concentration, and morning headaches that typically resolve within 30 minutes of waking. Specifically, in the pediatric and adolescent populations, clinicians should be alerted to more subtle clinical features such as failing school performance, recurrent episodes of chest sepsis, reduction in appetite, and weight loss.

Table 64-1 Important Clinical Features in Diseases of the Thoracic Cage and Respiratory Muscles

In all cases of respiratory muscle weakness, an important aspect of the evaluation is to identify any symptoms that may suggest generalized neuromuscular weakness—in particular, decrements in the patient’s speech and swallowing function, as well as weakness of the arms and legs. Weakness of the abdominal muscles may result in difficulty achieving an effective cough to clear secretions and debris from the airways. This impairment leads to issues with sputum retention and increases the risk of chest infection. In the case of chest wall disease, the common causes kyphoscoliosis and obesity usually are self-evident. As highlighted earlier, certain drugs have effects that can accelerate respiratory decline, so attention should be given to the common offenders, such as benzodiazepines, opiates, and corticosteroids. More recently, in particular, in the Duchenne muscular dystrophy (DMD) population, corticosteroids are increasingly being used to maintain locomotor muscle function, and these agents are associated with substantial weight gain and consequent upper airway obstruction. Clinicians must be aware of this potential problem in this younger patient population.

Physical examination requires a careful and considered approach, which must include a thorough neurologic examination to observe for signs of tongue and peripheral muscle fasciculation, peripheral muscle wasting and weakness, and peripheral sensory loss. Other signs, such as pseudohypertrophy of the calf muscles, are observed in patients with muscular dystrophies. Scars of previous operations may indicate possible trauma to underlying neuromuscular structures or an imposed restrictive chest wall deformity, such as from a phrenic nerve crush, thoracoplasty, coronary artery bypass grafting, thyroidectomy, or thymoma resection. With severe diaphragm weakness, abdominal inspiratory paradox is observed: The anterior abdominal wall moves inward as a result of the failure of a weak or paralyzed diaphragm to descend against the force exerted by the abdominal contents. With more generalized weakness, global loss of thoracic expansion on inspiration is observed.

Arterial Blood Gas Analysis

Although arterial blood gas analysis is one of the most common first-line investigations to diagnose chronic respiratory failure, limitations associated with this technique have been recognized. In particular, the daytime partial pressure of carbon dioxide (PaCO₂) may be normal despite the presence of substantial inspiratory muscle weakness, nocturnal hypoventilation, and nocturnal hypercapnia. Measurement of arterial blood gas partial pressures is essential, however, to define the severity of respiratory failure. Most commonly, hypoventilation caused by neuromuscular respiratory weakness and chest wall disease manifests with a mild hypoxia, with a partial pressure of oxygen (PaO₂) less than 60 mm Hg, and hypercapnia, with a PaCO₂ greater than 45 mm Hg.

The respiratory failure associated with many neurologic and chest wall conditions frequently manifests insidiously, with hypercapnia triggering metabolic compensation and renal retention of bicarbonate to maintain the hydrogen ions and, consequently, arterial pH within the normal range.

In the event of rapid onset of neurologic symptoms, such as in Guillain-Barré syndrome and myasthenic syndrome, or with acute deterioration of chronic respiratory failure, there is less time for renal buffering, so hypercapnic respiratory acidosis will occur.

Pulmonary Function Tests

Patients with respiratory neuromuscular weakness and those with chest wall disease both are characterized by a reduced ability to expand the thoracic rib cage. In turn, this failure to expand the rib cage results in a lack of generation of sufficient negative intrathoracic pressure to facilitate adequate inspiratory airflow. As a result, these patients present with clinical features of a restrictive lung function pattern characterized by a reduced forced vital capacity (FVC) and an elevated ratio of forced expiratory volume in 1 second (FEV₁) to FVC (FEV₁/FVC greater than 80%). Although vital capacity (VC) is in widespread use and is relatively simple to determine, its utility is limited because it has low sensitivity. In particular, significant inspiratory muscle weakness is required before a significant fall in VC is observed. A fall in VC on adoption of the supine position is specific for respiratory muscle weakness, and a fall in VC of more than 20% suggests bilateral diaphragmatic weakness. Of importance, the VC can be preserved in persons with a moderate degree of global respiratory muscle weakness or hemidiaphragm weakness.

The pattern of respiratory muscle weakness must be considered in interpreting results of pulmonary function tests in patients with chest wall disease and respiratory muscle weakness. Although total lung capacity (TLC) and VC are reduced in patients with predominantly inspiratory muscle weakness and combined inspiratory and expiratory muscle weakness, the pattern of weakness influences functional residual capacity (FRC), residual volume (RV), overall gas transfer (DLCO), and gas transfer corrected for alveolar volume (Table 64-2).

Table 64-2 Pulmonary Function Tests for Patients with Predominantly Inspiratory Muscle Weakness and Combined Inspiratory/Expiratory Muscle Weakness

FEV₁, forced expiratory volume in 1 second FRC, functional residual capacity; FVC, forced vital capacity; KCO, gas transfer coefficient corrected for alveolar volume; N/A, not available; RV, residual volume; TLC, total lung capacity; TLCO, overall gas transfer; VC, vital capacity.

Tests of Respiratory Muscle Function

Because respiratory muscle contraction generates tension, the consequent pressure change that occurs can serve as an in vivo measure for the quantification of respiratory muscle strength. In addition, recent developments have expanded the current understanding of the mechanical actions and interactions of the respiratory muscles. A greater emphasis has been placed on assessing and quantifying respiratory muscle strength and pulmonary mechanics in a variety of patient groups, including children, adolescents, and adults (see Chapter 6 for a more detailed discussion).

Maximum Transdiaphragmatic Pressure Measurements

The previously described tests provide data only on global respiratory muscle function, rather than on diaphragm function itself. To specifically assess diaphragm function, transdiaphragmatic pressure (Pdi) is measured by placement of a pressure-monitoring catheter in both the esophagus and stomach, to provide measurement of the esophageal and gastric pressures (Figure 64-3).

Figure 64-3 Equipment required to measure transdiaphragmatic pressure.

(Courtesy of the patient.)

Although transdiaphragmatic pressure during a maximal static maneuver (Pdi_max) has been reported, this maneuver gives a wide normal range in naive (i.e., previously untested) subjects. An alternative is to obtain maximal sniff transdiaphragmatic pressure (Pdi_sn), which has gained recognition in clinical practice not only because it is a familiar maneuver but because it measures both Pes_sn and Pdi_sn, providing data on global inspiratory muscle and diaphragm strength (Figure 64-4).

Figure 64-4 Transdiaphragmatic pressure measurements during a sniff maneuver in a healthy subject (left) and a patient with diaphragm weakness (right). Note the negative deflection of the gastric pressure curve in the patient with diaphragm weakness. Pdi, transdiaphragmatic pressure; Pes, esophageal pressure; Pgas, gastric pressure; Pnasal, nasal pressure.

(From Mustfa N, Moxham J: Respiratory muscle assessment in motor neurone disease, Q J Med 94:497–502, 2001.)

Twitch Transdiaphragmatic Pressure

Faraday’s law states that in a conducting material, a changing magnetic field will induce an electric current. Magnetic stimulation stores electrical energy in a capacitor and then discharges this energy by way of a coil to generate a rapidly changing magnetic field. This magnetic field has advantages over the electrical stimulus in that it is less attenuated by distance and therefore can more easily penetrate the deep structures in the neck and stimulate the phrenic nerve. This stimulation produces a single “twitch” of the diaphragm that is well tolerated by patients.

Clinical magnetic stimulation to allow bilateral stimulation of the roots supplying the phrenic nerves was first reported in 1989. Subsequent work has demonstrated its clinical usefulness, and this technique provides a nonvolitional assessment of diaphragm strength in a number of patient groups, including children and adolescents, as well as critically ill patients in intensive care in whom motivation and cooperation to perform maximal volitional maneuvers are difficult to achieve. In addition to improved tolerability, magnetic stimulation has advantages over electrical stimulation in that it is easier to stimulate the phrenic nerves and reduces the technical difficulties involved in isolation of the nerve (Figure 64-5). Further details can be found in the recommended reading section.

Figure 64-5 An example of bilateral anterior magnetic phrenic nerve stimulation weakness. A, Equipment required to perform bilateral anterior magnetic phrenic nerve stimulation. B, Example of transdiaphragmatic pressure change generated after a phrenic nerve magnetic twitch stimulus. ICU, intensive care unit; Pdi, transdiaphragmatic pressure; Pes, esophageal pressure; Pgas, gastric pressure.

(From Harris ML, Moxham J: Measuring respiratory and limb muscle strength using magnetic stimulation, Br J Intensive Care 8:21–28, 1998.)

Role of Imaging in Respiratory Muscle Weakness and Chest Wall Disease

An elevated hemidiaphragm on a plain chest radiograph often is considered to indicate diaphragmatic weakness or paralysis, but in fact this finding is confirmed by diaphragmatic testing in only approximately 24% of cases. The most recent data indicate that hemidiaphragm elevation on the chest radiograph has a 93% sensitivity but only a 44% specificity for predicting diaphragmatic weakness. Thus, elevation of the hemidiaphragm on the chest radiograph is likely to represent hemidiaphragmatic weakness; however, a normally positioned hemidiaphragm does not exclude weakness on that side.

The contraction of the diaphragm can be directly visualized by other techniques such as fluoroscopic screening, ultrasonography, and dynamic magnetic resonance imaging. Of these, ultrasonography has the advantage of being cheap and radiation-free; however, false positives may occur in approximately 6% of subjects, and even when correctly identifying weakness, this technique gives no functional information with regard to diaphragm strength. Accordingly, ultrasound imaging should not routinely be used in the assessment of patients with suspected hemidiaphragm or bilateral diaphragm weakness. For these purposes, unilateral and bilateral magnetic phrenic nerve stimulation should be used. Although computed tomography (CT) cross-sectional imaging may have particular value in the assessment of pleural causes of lung restriction, it is relatively unhelpful in obese patients, except to exclude coexisting thromboembolic disease and parenchymal lung disease.

Sleep Studies

Overnight oximetry and capnometry constitute an essential part of the assessment for the early detection of nocturnal hypoventilation. These are recommended investigations in patients with neuromuscular and chest wall disease who report symptoms of sleep-disordered breathing (see Table 64-1). Although some investigators advocate the use of polysomnography, including an electroencephalogram, to confirm and quantify arousals during respiratory events, this study is not necessary in the routine clinical management of these patients. Nocturnal hypoventilation can be managed simply with overnight titration of ventilatory support to a defined level of hypercapnia, irrespective of the sleep stage of the patient.

Stroke

Stroke (cerebrovascular accident) is one of the most common causes of acute neurologic deterioration. It is the third leading cause of death in both the United Kingdom and the United States affecting 150,000 and 795,000 patients, respectively, each year. The diaphragm has bilateral cortical representation, whereas the expiratory muscles have contralateral representation, similar to that in the limb muscles. Although hypercapnic respiratory failure is uncommon in stroke patients, chest infection is relatively frequent, and it is likely that impaired voluntary cough coupled with poor glottic coordination as well as swallowing difficulties contribute to the episodes of chest sepsis.

Cheyne-Stokes respiration breathing pattern often is observed as a feature associated with many different types of stroke. This pattern consists of a regular crescendo and decrescendo in breathing interspersed with periods of total apnea that cycles approximately every 30 seconds to 2 minutes. It commonly is observed in chronic heart failure and as a preterminal breathing pattern but also may be seen in healthy subjects at altitude.

Certain classic breathing patterns (Figure 64-7) are considered to reflect aspects of central nervous system pathology, though these are relatively rare in mainstream respiratory clinical practice. These include (1) central neurogenic hyperventilation resulting from a pontine lesion with hyperventilation present throughout both sleep and wakefulness; (2) cluster breathing caused by a mid–brain stem lesion, with periods of hyperventilation alternating with distinct periods of apnea; (3) apneustic breathing as a consequence of damage to the caudal pons with prolonged pauses after each inspiratory breath resulting in hypoventilation; and (4) ataxic breathing observed in patients with cortical lesions of the medulla, which is characterized by an erratic breathing pattern, which differs from the other breathing patterns in having no clear-cut cyclic nature.

Figure 64-7 Breathing patterns in central nervous system diseases.

(Modified from Plum F, Swanson AG: Central neurogenic hyperventilation in man, AMA Arch Neurol Psychiatry 81:535–549, 1959.)

Spinal Cord Injury

Spinal cord injury (SCI) commonly is a complication of trauma occurring predominantly in young adults, but it also may result from spinal artery infarction or tumor compression. The average age at insult is 34 years, and males are four times more likely to be affected. The extent of any neuromuscular weakness will be dependent on the site of injury, with higher cervical injuries resulting in more profound impairment. SCI at the level of C1 to C3 results in profound respiratory failure secondary to respiratory muscle denervation. Both voluntary and involuntary muscle control are lost. Unless neurologic recovery occurs, the patient will remain tracheostomy ventilator–dependent. SCI at the level of C3 to C6 results in a variable degree of diaphragmatic weakness, with more caudal lesions conferring a better prognosis. Patients may not have long-term ventilator dependence, and some improvement in respiratory muscle function often occurs over time as a consequence of reduction in inflammation and recruitment of other accessory muscles. SCI affecting the lower cervical and upper thoracic spinal cord carries a significantly better prognosis. The intercostal muscles and the abdominal muscles are affected, but the diaphragm is spared. Patients therefore rarely require long-term mechanical ventilation.

Custom-made corsets that are designed to provide both truncal stability and abdominal support are helpful in such patients. These garments reduce the sensation of respiratory effort by optimizing the operating lung volumes and decreasing abdominal compliance, which in turn enhances diaphragm performance. These patients are susceptible to respiratory tract infections, however, as with other neuromuscular disease, due to the impairment of cough function.

Bilateral diaphragmatic pacing can be considered as an alternative method of ventilatory support in a select group of patients who have high SCI and preserved function of the phrenic nerve–diaphragm unit. The most suitable candidates for pacing are considered to be those patients with a preserved response to peripheral phrenic nerve stimulation but lacking a response to transcranial stimulation of the diaphragm motor area.

Tetanus

Tetanus toxin is produced by the anaerobic bacillus Clostridium tetani, which commonly resides in soil. The bacillus enters the human through a wound in the skin, and the toxin travels along peripheral nerves to the central nervous system. Hypertonicity and generalized severe muscular spasms develop when the tetanus toxin blocks the release of inhibitory neurotransmitters at the neuromuscular junction. These spasms often are protracted and can cause death by means of severe resistant laryngospasm and respiratory muscle failure. Potential treatments include wound débridement, penicillin, tetanus antitoxin, neuromuscular blocking agents, sedatives, tracheostomy, intubation, and mechanical ventilation. Preventive vaccination is now common, so this has become a rare condition for which the astute physician needs to maintain an awareness.

Drugs

Opiates, benzodiazepines, and anesthetic agents affect neural drive to the respiratory muscle and, consequently, the tone and coordination of the upper airway, diaphragm, and chest wall muscular contraction. These drugs should be used with caution in patients with underlying respiratory muscle weakness to avoid precipitating life-threatening respiratory failure.

Multiple Sclerosis

Multiple sclerosis is an inflammatory demyelinating condition that can affect any part of the central nervous system. Respiratory manifestations of this condition vary with the anatomic location of the demyelinating lesions. The most common finding is a difficulty performing voluntary tests, but because the central control of breathing depends on connections from the brain stem, respiratory failure is uncommon. More usual practical problems include difficulty with voluntary cough secondary to lesions causing paraplegia and complications such as obstructive sleep apnea arising from the weight gain that results from enforced reduction in physical activity and steroid therapy.

Arnold-Chiari Malformation

Arnold-Chiari malformation is a congenital condition characterized by caudal herniation of the cerebellum and medulla through the foramen magnum. The malformation commonly blocks the flow of cerebrospinal fluid out of the posterior fossa, leading to hydrocephalus. It also may be associated with a syringomyelia where it can often interrupt ventilatory control to cause both apnea and apneustic breathing patterns. Whether deterioration can be prevented to some extent by surgical decompression has not yet been established.

Parkinson Disease

Parkinson disease is the most common movement disorder observed in developed countries and frequently is associated with fatal respiratory complications related to infection. Inspiratory muscle weakness occurs late in the progression of the disease, when maximal inspiratory pressures can fall to approximately 30% predicted. Expiratory muscle weakness also is seen; patients are unable to generate a rapid rise in peak expiratory flow. This impairment is akin to the generalized hypokinesia that is a common feature in Parkinson disease and has a deleterious effect on cough function.

Patients with this disease have significant difficulty in coordinating succinct respiratory muscle recruitment, which may partly explain the breathlessness associated with many of the dystonias. Of interest, early in the course of the disease, when no respiratory muscle weakness is evident from objective lung function parameters, the patients are still less able to perform repetitive respiratory muscle contractions than healthy age-matched control subjects. L-Dopa and apomorphine therapy have been shown to reverse these phenomena, suggesting that the defect is one of a central control and coordination of the respiratory muscles.

Patients with Parkinson disease commonly exhibit involuntary movements affecting the upper airways. A saw-tooth flutter wave often is present on the flow-volume loop trace (Figure 64-8); this aberration results from repetitive adduction of the vocal cords, occurring at the same frequency as a tremor of 4 to 8 Hz. It can cause significant difficulties if tracheal intubation is required. Obstructive sleep apnea is observed more frequently in patients with Parkinson disease, although patients also may experience sleep fragmentation because of pain or dystonias. Finally, the related condition of multisystem atrophy is characterized by features of Parkinson disease and autonomic failure. It has been associated with irregular breathing patterns and life-threatening upper airway obstruction related to glottis and vocal cord dysfunction narrowing during sleep.

Figure 64-8 Characteristic flow-volume loop in Parkinson disease (left) compared with a normal flow-volume loop (right).

(From Laghi F, Tobin MJ: Disorders of the respiratory muscles, Am J Respir Crit Care Med 168:10–48, 2003.)

Rabies

Rabies is a ribonucleic acid viral disease that has one of the highest fatality rates worldwide. It is transmitted through an infected mammalian bite, primarily from dogs. When the spinal cord is involved an ascending paralysis with clinical features similar to those of Guillain-Barré syndrome is seen, which can ultimately paralyze the respiratory muscles. The condition is now preventable with the rabies vaccination, and rarely seen in industrialized nations.

Poliomyelitis

Poliomyelitis is a rare condition in the Western world consequent to the introduction of the “polio vaccine,” which is routinely administered during childhood, although the disease occasionally can occur as a result of the live attenuated vaccine itself. For this reason, since 2000 only the inactive polio vaccine has been used in the United States. In the epidemics in the early 20th century, however, it was the commonest neuromuscular cause of respiratory failure. In fact, the high incidence of acute neuromuscular respiratory failure was directly responsible for the development of and advances in invasive mechanical ventilation and critical care as a specialty. In developed countries, physicians continue to encounter a diminishing number of patients who present with late respiratory failure after having suffered poliomyelitis in youth. This phenomenon is more common in those who received mechanical ventilation, usually in an “iron lung,” at the time of the acute illness and in those in whom scoliosis developed subsequently. These so-called postpolio patients respond well to treatment of their chronic respiratory failure with home noninvasive ventilation.

Motor Neuron Disease

Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), has a European annual incidence of approximately 2 to 3 cases per 100,000 population. Only 1% to 3% of MND cases manifest with respiratory muscle weakness and acute respiratory failure. It is uncommon for patients to describe the classical signs of respiratory muscle weakness (see Table 64-1) as a presenting complaint, but respiratory physicians should consider this diagnosis in patients with coexisting muscle wasting and weakness. A more common presentation is one of exertional and positional dyspnea, ineffective cough, and low speech volume in a patient who has already received the diagnosis. Bulbar features, notably aspiration, are common in advanced disease. When muscle weakness is severe, the patient may report disrupted sleep and excessive fatigue, morning headaches and confusion. Physical findings may include tachypnea at rest, inability to complete full sentences, use of accessory muscles, and abdominal inspiratory paradox.

Respiratory muscle weakness may be present in the context of other generalized muscle involvement without chronic respiratory failure. Early detection of respiratory muscle involvement may facilitate appropriate timing of ventilatory support to prevent respiratory crises. Studies have shown that Pn_sn is easier to obtain in patients with MND and can be used to predict prognosis. Routine monitoring of Pn_sn has been recommended; if the Pn_sn is less than 40 cm H₂O, referral for home noninvasive ventilation should be considered. The median survival is 3 to 5 years from onset of symptoms; home noninvasive ventilation has been shown to prolong survival in non-bulbar MND and to enhance health-related quality of life in bulbar MND.

Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) includes a group of genetic autosomal recessive disorders. These disorders are characterized by degeneration of the anterior horn cells and the motor nuclei in the brain stem. Patients with SMA exhibit a progressive symmetric proximal muscular weakness.

The SMAs are classified clinically as types 1 to 4, depending on the age at onset and the progression of symptoms. SMA type 1 is the most aggressive form with rapidly progressive muscular weakness; infants usually develop severe respiratory failure and do not survive longer than a year. SMA type 4 is more indolent and may manifest in the second to third decades of life. The mainstay of treatment is supportive therapy, with a focus on nutritional needs and ventilatory support as symptoms arise.

Guillain-Barré Syndrome

Guillain-Barré syndrome is an acute inflammatory demyelinating motor polyneuropathy. Patients characteristically present with a symmetric ascending motor weakness with associated depressed reflexes. Symptoms usually progress over a 2-week period, with 90% of patients reaching the peak of the disease course within 4 weeks. Severe respiratory weakness is a common associated feature, and ventilatory support is required at some point in approximately 10% to 30% of cases. Despite many effective immunomodulatory treatments, the mortality rate for Guillain-Barré syndrome requiring intubation is around 5%.

Inflammatory demyelination starts at the nerve root and progresses in a patchy fashion along the nerve sheath, resulting in weakness and paralysis of the distal muscles. This is confirmed by nerve conduction tests whereby conduction velocity of the signal is slowed or absent. A reduction in the amplitude of the action potential obtained through diaphragm needle electromyelography in response to phrenic nerve stimulation has been correlated with the requirement for invasive ventilation. In view of the risk of respiratory failure, it is essential that respiratory muscle strength is monitored in patients with confirmed or suspected Guillain-Barré syndrome. Predictive indicators for requirement of invasive ventilation are cranial nerve involvement, infection in the preceding 8 days, time from onset of weakness to admission less than 7 days, inability to stand, inability to lift elbow above head, inability to lift head off the pillow, and ineffective cough. Respiratory muscle strength commonly is assessed by serial VC and mouth pressure measurements, for which a declining trend is indicative of impending ventilator failure.

The “20-30-40” rule often is applied in clinical practice, with the combination of a VC less than 20 mL/kg, a maximum inspiratory pressure above −30 cm H₂O, and maximum expiratory pressure below +40 cm H₂O indicating the onset of respiratory failure. A clinical challenge is in maintaining an adequate mouth seal in patients with bulbar involvement, and a full face mask can be attached to the spirometer or pressure monitor to ensure optimal delivery of ventilatory support. A minority of patients, mainly those in their seventh and eighth decade of life with significant bulbar involvement, fail to wean from invasive mechanical ventilation, and these patients will require long-term tracheostomy ventilation.

Critical Illness Neuromyopathy

Diaphragm weakness is observed in animals exposed to prolonged mechanical ventilation with concomitant use of neuromuscular blocking agents, and a similar observation has been reported in humans, albeit with complete denervation as a result of brain stem death. The importance of ventilator-induced diaphragm dysfunction more generally in critically ill patients remains unclear, although most studies have observed that the nonvolitional twitch transdiaphragmatic pressures are low compared with those obtained in healthy normal subjects. Although no direct correlation has been found between twitch transdiaphragmatic pressure and duration of mechanical ventilation, previous studies have shown that weaning failure was observed in patients who undergo changes in pulmonary mechanics during a weaning trial such that the respiratory muscle load exceeds the capacity.

Peripheral skeletal muscle weakness associated with critical illness, or intensive care unit–acquired weakness, is beyond the scope of this chapter, but an increasingly abundant literature is accumulating in this important clinical area.

Phrenic Nerve Injury

Anatomically, the phrenic nerve is a long nerve measuring 30 to 40 cm and follows a tortuous path from the cervical spine to the diaphragm, predisposing the nerve to injury. In clinical practice, the most common cause of injury is cardiac surgery, particularly when iced slush has been used for cardioplegia. Other causes of phrenic nerve injury must be considered in patients who have undergone anterior cervical surgery (e.g., thymectomy), internal jugular line central venous access cannulation, and cervical radiotherapy.

Neuralgic Amyotrophy

Neuralgic amyotrophy is a syndrome that classically manifests with a relatively sudden onset of muscle weakness and wasting, which may involve the upper limbs or the diaphragm, or both. In addition to the symptoms of dyspnea on exertion, dyspnea on leaning forward, dyspnea on immersion in water, and orthopnea, there can be associated pain in the appropriate dermatome—in particular, shoulder tip or shoulder blade pain. Previous data have shown that one third of patients with diaphragm paralysis will recover completely, one third will have a partial recovery, and one third will have no recovery at all. This recovery can take between 2 and 5 years. A rare familial syndrome exists, and the clinician should consider this as a cause as well as the rare presentation of a more generalized neurologic condition, such as motor neuron disease, or phrenic nerve palsy due to mediastinal compression from some other cause, such as lymphadenopathy.

Hereditary Motor and Sensory Neuropathy (Charcot-Marie-Tooth Disease)

Hereditary motor and sensory neuropathy (i.e., Charcot-Marie-Tooth disease) is a spectrum of disorders resulting from a genetic mutation in one of many myelin genes. The condition is inherited in an autosomal dominant or recessive pattern, depending on the disorder. It is a chronic degenerative process of the peripheral nerves that results in distal weakness. Phrenic nerve involvement with consequent respiratory failure is a recognized complication but is relatively infrequent.

Botulism

Botulism is caused by the neurotoxin produced by the gram-positive anaerobic bacteria, Clostridium botulinum. The toxin is absorbed after ingestion, through infantile colonization of the gastrointestinal tract, or through a skin wound, commonly in association with intravenous or subcutaneous drug abuse. The toxin results in an acute presynaptic blockade of the cholinergic neuromuscular junction, leading to a life-threatening generalized paralysis. Mortality is reduced with rapid initiation of invasive ventilatory support, which may be prolonged over many months. Most patients achieve a full recovery, but the respiratory muscles can be slow to recover, and mild respiratory muscle weakness may persist indefinitely.

Myasthenia Gravis

Myasthenia gravis is the most common condition associated with interruption of neuromuscular signaling, but the disorder remains rare, with a prevalence of approximate 15 to 20 cases per 100,000 population. It is caused by antibodies against the acetylcholine receptor in the post synaptic nerve terminal. Patients typically present with a fluctuating muscular weakness that progresses with fatigue of the muscles, which classically is described as most pronounced toward the end of the day. Ocular and bulbar symptoms are the most common manifestations, but respiratory weakness also can occur and occasionally may be a presenting symptom of the condition. Acute respiratory failure can occur in a myasthenic crisis that may be precipitated by factors such as infection and surgery.

The mainstay of treatment is immunosuppression and use of cholinesterase inhibitors, although care must be taken to achieve an optimal balance, because excessive cholinergic blockade can result in issues with increased bronchial secretions or frank cholinergic block of the respiratory muscles. Despite appropriate treatment, a proportion of patients exhibit nocturnal hypoventilation, which will be exacerbated by steroid-induced weight gain.

Thymoma commonly is associated with the myasthenic syndrome, and clinicians must be aware that after thymectomy, acute respiratory failure may occur. Diagnostic considerations in this setting include both postoperative myasthenic syndrome, although risk for this syndrome should be much less after surgery, and phrenic nerve damage incurred during the procedure, because the nerve can be embedded in the tumor, with consequent intentional or unintentional resection.

Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome is a rare condition that affects the release of acetylcholine and reduces neuromuscular signaling at the neuromuscular junction. The disease is caused by antibodies directed against voltage-gated calcium channels. These channels regulate the flow of calcium required for the release of acetylcholine in the presynaptic nerve terminals. The condition is suggested by the presence of proximal muscular weakness, reduced or absent reflexes, and autonomic signs and symptoms such as a dry mouth. A unique feature is the recovery of reflexes and muscle strength with maximal isometric muscular activity and an increase in muscle action potential amplitude observed on repetitive nerve stimulation. Respiratory muscle weakness is uncommon as a presenting feature; more frequently, it occurs late in the disease process. The condition has a strong association with malignancy—in particular, small cell lung cancer, which coexists in up to 50% of cases.

Corticosteroid-Induced Respiratory Myopathy

Corticosteroid-induced myopathy involving the quadriceps is relatively commonly encountered as a consequence of extensive use of corticosteroid treatment for any of various inflammatory and autoimmune conditions. Current available evidence, however, suggests that this is rarely a problem with the respiratory muscles.

Rarer Causes of Acute Myopathy

Myopathy may be associated with many different endocrine and biochemical abnormalities. Commonly, severe hypokalemia causes a rapidly progressive myopathy predominantly affecting proximal muscles. Malabsorption of essential vitamins, such as vitamin D and vitamin E, also may result in a milder generalized myopathy. Hypothyroidism and hyperthyroidism, adrenal insufficiency, and Cushing disease also are associated with myopathy. This can occur at any point in the disease course but occasionally are the presenting manifestation, although such disorders generally are identified in the context of other systemic features. These myopathies rarely involve the respiratory muscles, but if ventilatory failure does occur, their management is supportive while the underlying abnormality is corrected.

Duchenne Muscular Dystrophy

DMD is an X-linked inherited condition arising from a mutation in the dystrophin gene. It affects males from early childhood, with an incidence of 1 in 3000 births. The decline in function in DMD manifests as a proximal to distal limb muscle weakness, leading to wheelchair dependency by the early teenage years and to respiratory muscle weakness with progression. Respiratory failure is the major cause of death in this group of patients, although mortality also may be associated with the dilated cardiomyopathy that can occur in the absence of respiratory muscle weakness.

As with other progressive neuromuscular conditions, respiratory muscle weakness progresses gradually. The deterioration in respiratory function within these groups manifests initially as nocturnal hypoventilation in REM sleep and progresses to hypoventilation in REM and non-REM sleep and finally to daytime hypercapnia and chronic respiratory failure. This progression in chronic respiratory failure is associated with increasing sleep disturbance, frequency of chest infections, hospital admissions, and deteriorating quality of life. The monitoring of respiratory muscle strength and VC in these patients is a key clinical assessment. VC decreases from the age of 10 years, and a VC of less than 1 L confers a poor prognosis, with mean survival of approximately 2 years without ventilatory support. The presence of scoliosis in these patients may accelerate this process. Mean survival with the onset of chronic respiratory failure is 9.7 months if home nocturnal noninvasive ventilation is not initiated. Although the prophylactic use of home nocturnal noninvasive ventilation before the onset of chronic respiratory failure is controversial, most authorities support the view that noninvasive ventilation brings improvements in gas exchange, normalization of sleep patterns, enhanced quality of life, and prolonged survival. A more recent study indicates that nocturnal ventilatory support should be considered when patients develop nocturnal hypoventilation, and without home noninvasive ventilation, progression to chronic diurnal hypercapnic respiratory failure occurs within 18 months.

Respiratory support also will include secretion clearance, specifically during any episode of pneumonia, with the introduction of a mechanical insufflation-exsufflation device to enhance cough function and secretion management (see earlier under “Cough Peak Flow”). As bulbar function declines, in addition to a reduction in effective cough, patients will be at increased risk for aspiration, and these swallowing problems reduce nutritional intake, resulting in weight loss. Early gastrostomy feeding tube insertion, accomplished with endoscopic or radiologic guidance, is recommended, although evidence supporting this practice is limited. It is possible, with appropriate expertise, to do such procedures with sedation using noninvasive ventilation alone in patients with established respiratory failure.

Other Muscular Dystrophies

Becker muscular dystrophy follows a clinical course similar to that for DMD but typically is of much later onset, with much milder clinical effects. Patients remain ambulatory until the late teenage years, and the degree of respiratory muscle involvement is less. Toward the later stages of the disease, in the fourth decade of life, respiratory failure can develop, and noninvasive ventilation may be required. Facioscapulohumeral muscular dystrophy also is a slowly progressive condition of autosomal dominant inheritance that affects muscles of the face, arms, and shoulders. In approximately 20% of the patients, chest wall and diaphragm involvement may result in respiratory decline necessitating ventilatory support.

Myotonic Dystrophy

Myotonic dystrophy is inherited as an autosomal dominant trait that exhibits generational anticipation. It is a multisystem disorder characterized by features of myotonia (delayed muscle relaxation), progressive skeletal muscle weakness, cardiac conduction deficits and cardiomyopathy, cataracts, frontal baldness, ptosis, testicular failure, hypogammaglobulinemia, and diabetes mellitus. Sleep-disordered breathing is common, with nocturnal hypoventilation and progressive hypercapnia resulting from respiratory muscle weakness and impaired neural respiratory drive. Central and obstructive sleep apnea also may occur as a consequence of upper airway muscular weakness and myotonia. Ventilatory support should be offered on the basis of patient symptoms and arterial carbon dioxide levels. Unfortunately, patients frequently find it difficult to use nocturnal ventilatory support, in part because only a limited symptomatic response is obtained, with persisting daytime somnolence as a consequence of the primary hypersomnolence that accompanies this condition.

Other Rarer Myopathies

Congenital myopathies are a group of inherited disorders of muscle that typically manifest with generalized muscle weakness in infancy. A muscle biopsy is required to characterize the type of myopathy. All patients present with hypotonia and a predominant proximal muscular weakness. The severity of the muscle impairment depends on the individual genetic mutation. A majority of the patients require mechanical ventilation from early life and do not survive childhood.

Metabolic myopathies constitute a heterogenous group of disorders that are related to a deficit in the metabolic pathways of the muscle. Among such disorders, the most common are the glycogen storage diseases. From a respiratory perspective, the most important metabolic myopathy is acid maltase deficiency, because respiratory muscle weakness can be the primary presentation of the condition in the adult-onset form. Treatment is supportive, as with the other myopathic conditions, although enzyme replacement therapy may have a role in slowing the onset of chronic respiratory failure.

Mitochondrial myopathies result from dysfunction of mitochondrial ability to release energy form adenosine triphosphate (ATP). The clinical manifestations are highly variable but can include respiratory failure.

Idiopathic inflammatory myopathies, including dermatomyositis and polymyositis, manifest with muscular weakness due to inflammatory destructive processes directly affecting the muscle fibers and their blood supply. Dermatomyositis is characterized by typical skin manifestations such as Gottron’s papules on the hands and feet and a heliotropic rash over the eyelids and can be associated with malignancy. The muscular weakness may rarely result in respiratory failure. These inflammatory myopathies are associated with interstitial parenchymal lung disease in approximately 20% of cases. Such disease can be rapidly progressive and frequently is fatal.

Clinical Consequences of Obesity

Within the Western world, a well-recognized major public health problem is the growing epidemic of obesity. Although the definition of obesity includes a requirement for a body mass index (BMI) greater than 30 kg/m², clinicians are now encountering increasing numbers of patients who are morbidly obese (i.e., with a BMI greater than 40 kg/m²), and more recently, the term superobese (BMI greater than 50 kg/m²) has been adopted to further characterize this patient group. In the United Kingdom, an estimated 25% of the population is obese, with superobesity increasing dramatically over the past decade. By current estimates, superobesity affects 1 in 230 adults in the United States.

With this obesity epidemic, patients are presenting more frequently to respiratory medicine departments and chest clinics with exercise-induced dyspnea, obstructive sleep apnea, and nocturnal hypoventilation necessitating ventilatory support. Observational data on hospitalized obese patients indicate that up to one third of those with a BMI greater than 35 kg/m² have hypercapnic respiratory failure.

Respiratory Muscle Pump in Obese Patients

It is hypothesized that breathlessness and alveolar hypoventilation in obese patients result from an imbalance between respiratory muscle load and/or capacity and neural respiratory drive, although the exact pathophysiologic details are yet to be determined. Respiratory muscle capacity, albeit estimated using volitional PImax and PEmax measurements, was found to be reduced in hypercapnic obese patients compared with eucapnic obese patients. However, direct measurement of diaphragm strength, using Pdi_max, demonstrated no difference between eucapnic and hypercapnic obese patients, indicating that diaphragm weakness does not contribute to the development of ventilatory failure in obese patients. By contrast, a difference is seen in respiratory muscle load between hypercapnic obese patients and eucapnic obese subjects with greater upper airway resistance in both sitting and supine positions and reduced respiratory system compliance. This increasing load on the respiratory muscles results in a reduction in lung volumes, with a reduction in FEV₁ and FVC and an elevated FEV₁/FVC ratio confirming a restrictive defect. In addition, TLC, expiratory reserve volume (ERV), and FRC are all reduced. Of interest, these reductions are more marked in obese patients with hypercapnic respiratory failure than in eucapnic obese subjects with a matched BMI. It is appreciated that in addition to absolute fat load, the distribution of the fat is important in determining the severity of lung restriction.

The obese patient breathes at a lower lung volume, which reduces chest wall and lung compliance. Breathing at a lower lung volume also results in closure of the small airways during early expiration, causing expiratory airflow limitation and development of intrinsic positive end-expiratory pressure (PEEPi). This phenomenon is exacerbated by adoption of a supine position, such as occurs during sleep. It has been shown that in obese patients, moving from a sitting to supine posture is associated with an increase in neural respiratory drive, as measured by the diaphragm electromyogram, with a corresponding increase in diaphragm pressure generation, as measured from transdiaphragmatic pressure swings, but without a corresponding increase in tidal volume. Furthermore, these patients develop PEEPi on change in position, indicating expiratory flow limitation, although it is difficult to separate whether this is a consequence of early airway closure during expiration or upper airway obstruction, or a combination of both mechanisms. More studies in this area are required to confirm the previous data demonstrating changes in hypercapnic ventilatory response in obese hypercapnic patients. These previous studies have shown that obese hypercapnic patients, compared with eucapnic obese subjects, have reduced hypercapnic ventilatory response as a consequence of an inadequate ability to increase tidal volume, resulting in dead space ventilation. Such research will allow investigators to define the pathophysiologic cause of alveolar hypoventilation in obese patients.