Neuromuscular Disorders in the ICU

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37 Neuromuscular Disorders in the ICU

Abnormal neuromuscular function may precipitate a patient’s admission to an intensive care unit (ICU) or may develop as a consequence of another critical illness and its treatment. This chapter focuses primarily on respiratory failure due to neuromuscular disease but also addresses autonomic dysfunction occurring in this setting. To facilitate understanding of the concepts involved, a brief review of the motor unit and its physiology is provided and specific muscles critical to ventilation are identified.

The Motor Unit and Its Physiology

Central nervous system activity designated for motor output is ultimately conducted to lower motor neurons, also known as alpha motor neurons. A motor unit is composed of a lower motor neuron and its distal ramifications, its neuromuscular junctions, and the muscle fibers it innervates. The cell bodies of the lower motor neurons are located in the brainstem for cranial musculature and in the anterior horn of the spinal cord for somatic muscles. At the level of the brainstem or spinal cord, the motor neurons receive various excitatory and inhibitory inputs. Motor axons project through the subarachnoid space and penetrate the dura mater as nerve roots. They may join with other motor axons and with sensory and autonomic fibers in a plexus and then travel in peripheral nerves to the muscles they innervate. Alpha motor neurons are myelinated, a feature that accelerates nerve impulse propagation. The multiple terminal ramifications of the motor neuron synapse on individual muscle fibers.

The motor axon communicates with muscle via a specialized area termed the neuromuscular junction. On the presynaptic side of the neuromuscular junction, the neurotransmitter acetylcholine is synthesized, packaged in vesicles, and stored for release. Depolarization of the axon opens presynaptic voltage-gated calcium channels, which activate the molecular machinery responsible for drawing the vesicles to the presynaptic membrane. The vesicles then fuse with the membrane and release acetylcholine into the synaptic cleft. Acetylcholine molecules bind to receptors on the postsynaptic membrane and cause an influx of sodium, which in turn increases the muscle end-plate potential. When the end-plate potential exceeds the threshold level, the muscle membrane becomes depolarized. This depolarization releases calcium ions from the sarcoplasmic reticulum, and muscle contraction occurs through a process known as excitation-contraction coupling. After activating the acetylcholine receptor complex, the acetylcholine molecule is degraded by cholinesterase; the choline released by this reaction is then recycled by the presynaptic neuron.

Muscles of Respiration

Three muscle groups may be defined based on their importance for respiration (Figure 37-1):¹

1 Upper airway muscles: palatal, pharyngeal, laryngeal, and lingual

2 Inspiratory muscles: sternomastoid, diaphragm, scalenes, and parasternal intercostals

3 Expiratory muscles: internal intercostal muscles (except for parasternals) and abdominal muscles

Figure 37-1 Major respiratory muscles.

Inspiratory muscles are indicated on the left and expiratory muscles are indicated on the right.

(From Garrity ER. Respiratory failure due to disorders of the chest wall and respiratory muscles. In: MacDonnell KF, Fahey PJ, Segal MS, editors. Respiratory Intensive Care. Boston: Little, Brown; 1987, p. 313.)

The upper airway muscles receive their innervation from the lower cranial nerves. Sternomastoid innervation arrives predominantly from cranial nerve XI, with a small contribution from C2. The phrenic nerve originates from cell bodies located between C3 and C5, with a maximum contribution from C4, and innervates the diaphragm. Innervation to the scalenes arises from C4 to C8, whereas that of the parasternal intercostals is from T1 to T7. The intercostal muscles receive innervation from T1 to T12, and the abdominal musculature receives it from T7 to L1. Reference to this innervation scheme is important in understanding the effects of spinal cord and nerve root injuries on respiration and for the differential diagnosis of disorders producing apparently diffuse weakness.

Clinical Presentation of Neuromuscular Respiratory Failure

Patients experiencing respiratory dysfunction due to neuromuscular disease typically present with a combination of upper airway dysfunction and diminished tidal volume (VT). Difficulty with swallowing liquids, including respiratory secretions, is the most typical presentation of pharyngeal weakness, although some patients have an equal or greater degree of difficulty with solid food. A hoarse or nasal voice may also signal problems with the upper airway. These conditions are noted in patients who are at risk for aspiration and present with difficulty with attempts at negative-pressure ventilation (cuirass or iron lung), because the weakened muscles may not be able to keep the airway open as the pressure falls.² Paradoxical abdominal movement (inward movement of the abdomen during inspiration) is an important sign of diaphragmatic weakness.³

Loss of VT occurs most dramatically with diaphragmatic weakness but also follows insults that affect the ability of the parasternal intercostals to keep the chest wall expanded against negative intrapleural pressure. This is most apparent in lower cervical spinal cord injuries where atelectasis commonly develops despite preserved phrenic nerve function. This problem usually diminishes over weeks as the parasternal intercostal muscles develop spasticity.

Patients with progressive generalized weakness (e.g., Guillain-Barré syndrome) commonly begin to lose VT before developing upper airway weakness. To maintain minute ventilation, and therefore carbon dioxide excretion, a patient’s respiratory rate increases. Respiratory rate is thus one of the most important clinical parameters to monitor. As the vital capacity falls from the norm of about 65 to 30 mL/kg, a patient’s cough weakens, and clearing secretions becomes difficult. A further decrease of vital capacity to 20 to 25 mL/kg results in an impaired ability to sigh with progressive atelectasis. At this point, hypoxemia may be present because of ventilation-perfusion mismatching and because an increasing percentage of VT is used to ventilate dead space. Before the vital capacity reaches 18 mL/kg, a patient should be in an ICU, because respiratory failure is imminent and endotracheal intubation should be considered. The precise point at which mechanical ventilation is necessary varies with the patient, the underlying condition, and especially with the likelihood of a rapid response to treatment.

Regardless of the vital capacity, however, indications for intubation and mechanical ventilation include evidence of fatigue, hypoxemia despite supplemental oxygen administration, difficulty with secretions, and a rising PaCO₂. In the absence of hypercapnia, occasional patients (e.g., those with myasthenia gravis) can be managed under very close observation in an ICU with less invasive techniques (e.g., bilevel positive airway pressure [BiPAP]).⁴

In addition to vital capacity, trended measurements of the maximum inspiratory pressure (PImax, more typically recorded as negative inspiratory force [NIF]), are useful indicators of ventilatory capacity. Inability to maintain a PImax greater than 20 to 25 cm H₂O usually indicates a need for mechanical ventilation. Although the maximum expiratory pressure (PEmax) is a more sensitive indicator of weakness,⁵ it has not proved to be as useful as an indicator of the need for mechanical ventilation. A more detailed discussion of these variables and their use may be found elsewhere.^6,⁷

Because a patient with neuromuscular respiratory failure has intact ventilatory drive,⁸ the fall in VT is initially matched by an increase in respiratory rate, keeping the PaCO₂ normal or low until the vital capacity becomes dangerously reduced. Many patients initially maintain their PaCO₂ in the range of 35 mm Hg because of either (1) a subjective sense of dyspnea at low VT or (2) hypoxia from atelectasis and increasing dead space. When the PaCO₂ begins to rise in this circumstance, abrupt respiratory failure may be imminent.

The modest degree of hypoxia in most of these patients worsens when the PaCO₂ begins to rise, displacing more oxygen from the alveolar gas. However, aspiration pneumonia and pulmonary embolism are also frequent causes of hypoxemia in these patients. To determine the relative contributions of these conditions to a patient’s hypoxemia, one can use a simplified version of the alveolar gas equation as follows (derived elsewhere)^6,⁷:

where PAO₂ is the alveolar partial pressure of oxygen, PIO₂ is the partial pressure of inspired oxygen (in room air, 150 mm Hg), and R is the respiratory quotient (on most diets, about 0.8). This allows estimation of the alveolar-arterial oxygen difference (PAO₂ − PaO₂). Under ideal circumstances in young people breathing room air, this value is about 10 mm Hg, but it rises to about 100 mm Hg when the fraction of inspired oxygen (FIO₂) is 1.0. The alveolar air equation allows one to factor out the contribution of hypercarbia to the decrease in arterial partial pressure of oxygen (PaO₂); it should be used to determine whether there is a cause of significant hypoxemia in addition to the displacement of oxygen by carbon dioxide.

Patients with orbicularis oris weakness may have artifactually low vital capacity and NIF measurements because they cannot form a tight seal around the spirometer mouthpiece. The need for nursing and respiratory therapy personnel who are experienced in the care of these patients is thus underscored. It is also important for physicians to observe these patients directly rather than relying solely on reported measurements. The physical findings associated with neuromuscular respiratory failure are reviewed elsewhere.^6,⁷ Among the most important findings are rapid, shallow breathing,⁹ the recruitment of accessory muscles, and paradoxical movement of the abdomen during the respiratory cycle. Fluoroscopy of the diaphragm is occasionally valuable for the diagnosis of diaphragmatic dysfunction.¹⁰

Autonomic dysfunction commonly accompanies some of the neuromuscular disorders requiring critical care, such as Guillain-Barré syndrome, botulism, and porphyria (Table 37-1). In Guillain-Barré syndrome (discussed later) dysautonomia is common and may arise in parallel with weakness or may follow the onset of the motor disorder after one week or more.

TABLE37-1 Neuromuscular Causes of Acute Respiratory Failure

Location	Disorder	Associated Autonomic Dysfunction?
Spinal cord	Tetanus¹¹²	Frequent
Anterior horn cell	Amyotrophic lateral sclerosis¹¹³	No
	Poliomyelitis	No
	Rabies	Frequent
	West Nile virus flaccid paralysis	No
Peripheral nerve	Guillain-Barré syndrome	Frequent
	Critical illness polyneuropathy	No
	Diphtheria	No, but cardiomyopathy and arrhythmias may occur
	Porphyria	Occasional
	Ciguatoxin (ciguatera poisoning)	Occasional
	Saxitoxin (paralytic shellfish poisoning)	No
	Tetrodotoxin (pufferfish poisoning)	No
	Thallium intoxication	No
	Arsenic intoxication^114,¹¹⁵	No
	Lead intoxication	No
	Buckthorn neuropathy	No
Neuromuscular junction	Myasthenia gravis	No
	Botulism¹¹⁶	Frequent
	Lambert-Eaton myasthenic syndrome¹¹⁷	Yes, frequent dry mouth and postural hypotension
	Hypermagnesemia¹¹⁸	No
	Organophosphate poisoning	No
	Tick paralysis	No
	Snake bite	No
Muscle	Polymyositis/dermatomyositis	No
	Acute quadriplegic myopathy	No
	Eosinophilia-myalgia syndrome¹¹⁹	No
	Muscular dystrophies¹²⁰	No, but cardiac rhythm disturbances may occur
	Carnitine palmitoyl transferase deficiency	No
	Nemaline myopathy¹²¹	No
	Acid maltase deficiency¹²²	No
	Mitochondrial myopathy¹²³	No
	Acute hypokalemic paralysis	No
	Stonefish myotoxin poisoning	No
	Rhabdomyolysis	No
	Hypophosphatemia¹²⁴	No

Neuromuscular Disorders

Many chronic neuromuscular disorders and other central nervous system conditions affecting the suprasegmental innervation and control of respiratory muscles eventually compromise ventilation. In this chapter, however, we emphasize the more common acute and subacute neuromuscular disorders that precipitate or prolong critical illness due to ventilatory failure and autonomic dysfunction. A more complete listing of neuromuscular diseases appears in Table 37-1; reviews of this subject^11,¹² or the references listed in Table 37-1 may be consulted for details of the more rare disorders. Some of the diseases listed (e.g., Lambert-Eaton myasthenic syndrome) rarely cause respiratory failure in isolation but may be contributing causes in the presence of other conditions¹³ such as neuromuscular junction blockade intended only for the duration of a surgical procedure.¹⁴

Neuromuscular Diseases Precipitating Critical Illness

Guillain-Barré Syndrome

Guillain-Barré syndrome, or acute inflammatory demyelinating polyradiculoneuropathy, is typically a motor greater than sensory peripheral neuropathy with subacute onset, monophasic course, and nadir within 4 weeks. Although the precise etiology is unknown, Guillain-Barré syndrome is immune mediated and related to antibodies directed against peripheral nerve components. Approximately 1.7 cases occur per 100,000 population per year.¹⁵ Most patients suffer a demyelinating neuropathy, but in about 5% of cases the condition is a primary axonopathy.¹⁶ Numerous antecedents have been implicated¹⁷; the more frequent ones are listed in Box 37-1. The association with antecedent infections suggests that certain agents may elicit immune responses involving antibodies that cross-react with peripheral nerve gangliosides. In particular, the development of ganglioside antibodies has been observed in Guillain-Barré syndrome after Campylobacter jejuni infections, such as GM₁ antibodies in axonal forms of Guillain-Barré syndrome¹⁸ and GQ_1b antibodies in the Miller-Fisher variant of Guillain-Barré syndrome.¹⁹

The initial findings of patients with Guillain-Barré syndrome are subacute and progressive weakness, usually most marked in the legs, associated with sensory complaints but without objective signs of sensory dysfunction.²⁰ Deep tendon reflexes are often significantly reduced or absent at presentation, though this finding may take several days to develop. The cerebrospinal fluid (CSF) typically reveals an albuminocytologic dissociation or elevated protein content without pleocytosis; this may not evolve until the second week of illness. The major reason to examine the CSF is to preclude other diagnoses. Although mild CSF lymphocytic pleocytosis (10-20 cells/mm³) may suggest the possibility of associated human immunodeficiency virus (HIV) infection, in most patients, the nucleated cell count is less than 10 cells/mm³.²¹ Although they may be normal initially, results of electrodiagnostic studies (motor and sensory nerve conduction studies and needle electromyography) often reflect segmental nerve demyelination with multifocal conduction blocks, temporally dispersed compound muscle action potentials, slowed conduction velocity, and prolonged or absent F waves.²² Differential diagnostic considerations for patients with suspected Guillain-Barré syndrome are primarily those listed in the “Peripheral Nerve” section of Table 37-1.

The components of treatment for patients with Guillain-Barré syndrome are as follows:

• Management of ventilatory failure

• Management of autonomic dysfunction

• Meticulous nursing care

• Psychological support

• Physical and occupational therapy

• Prevention of deep venous thrombosis

• Nutritional support

• Early planning for rehabilitation

• Immunotherapy for the underlying autoimmune process

Patients with Guillain-Barré syndrome with evolving respiratory failure should generally be intubated when the vital capacity falls to about 15 mL/kg or when difficulty with secretions begins, because the response to treatment is slow. If a patient has been immobile for several days before intubation and neuromuscular junction blockade is needed, a nondepolarizing agent should be used to avoid transient hyperkalemia. Oral intubation is again being viewed as preferable to the nasal route, because the endotracheal tube is frequently required for a week or longer, raising the risk of sinusitis with nasal intubation.

Many patients are too weak to trigger the ventilator; in such cases, the assist/control or intermittent mandatory ventilation mode is initiated. Weaning patients with Guillain-Barré syndrome from mechanical ventilation must wait for adequate improvement in strength. We usually shift to pressure support ventilation for weaning, although evidence of its superiority over intermittent mandatory ventilation or synchronized intermittent mandatory ventilation modes is only anecdotal. Although the majority of patients require mechanical ventilation for less than 4 weeks, as many as one-fifth need 2 or more months of support before they can breathe without assistance. Improvement in vital capacity to greater than 15 mL/kg and in NIF to greater than 25 cm H₂O suggests that a patient has improved enough to begin weaning from the ventilator. A formula using a combination of ventilatory and gas exchange variables may allow more accurate determination of a patient’s ability to be weaned.²³

Autonomic dysfunction related to Guillain-Barré syndrome most typically presents as a hypersympathetic state and is often heralded by unexplained sinus tachycardia. The blood pressure may fluctuate wildly. Patients may rarely experience bradycardic episodes, which may require temporary pacing. Autonomic surges during tracheal suctioning or due to a distended viscus may be very dramatic and should be minimized. Autonomic failure and pulmonary embolism are now the major causes of mortality in Guillain-Barré syndrome.

Nursing care for patients with Guillain-Barré syndrome is similar to that for other paralyzed and mechanically ventilated patients, but special care must be taken to remember that patients with Guillain-Barré syndrome are completely lucid. In addition to explaining any procedures carefully, arranging for distractions during the daytime (e.g., television, movies, conversation, visitors) and adequate sleep at right is very important. For the most severely affected patients, sedation should be considered. In concert with physical and occupational therapists, passive exercise should be performed frequently throughout the day.

Deep venous thrombosis is a significant danger for patients with Guillain-Barré syndrome. Episodic arterial desaturation is a common event, presumably owing to transient mucus plugging; submassive pulmonary emboli may therefore be overlooked. Adjusted-dose heparin (to slightly prolong the partial thromboplastin time) should be given, and sequential compression devices should be used on the legs; therapeutic anticoagulation may be considered. The risk of fatal pulmonary embolism extends through the initial period of improvement until patients are ambulatory.

Nutritional support should begin as soon as a patient is admitted, with appropriate concern for the risk of aspiration.²⁴ Most mechanically ventilated patients with Guillain-Barré syndrome can be fed via soft, small-caliber feeding tubes; autonomic dysfunction affecting the gut occasionally requires total parenteral nutrition.

Immunotherapy for Guillain-Barré syndrome includes removal of autoantibodies with plasma exchange or immune modulation with high-dose intravenous immunoglobulin (IVIg). The efficacy of plasma exchange has been evaluated in a Cochrane systematic review of six class II trials comparing plasma exchange alone with supportive care.²⁵ Most of the trials employed up to 5 plasma exchanges of 50 mL/kg over 2 weeks. In a large North American trial,²⁵ the time needed to improve one clinical grade (being weaned from the ventilator or being able to walk) was reduced by 50% in the plasma exchange group by comparison with the control group. There was no significant benefit when plasma exchange was begun later than 2 weeks after symptom onset. A meta-analysis demonstrated more rapid recovery in ventilated patients treated with plasma exchange within 4 weeks of onset.²⁶ The optimal number of plasma exchanges has been assessed in patients with mild (unable to run), moderate (unable to stand without assistance), and severe (requiring mechanical ventilation) Guillain-Barré syndrome by the French Cooperative Group.²⁷ On the basis of this trial, two exchanges are better than none in mild Guillain-Barré syndrome; four are better than two in moderate Guillain-Barré syndrome; and six are no better than four in severe Guillain-Barré syndrome. Albumin is the preferred replacement solution.²⁸ Treatment with IVIg for Guillain-Barré syndrome has also been examined in a Cochrane systematic review. Three randomized controlled trials demonstrated class I evidence that IVIg (2 g/kg over 2-5 days) is as effective as plasma exchange in Guillain-Barré syndrome patients with impaired walking.²⁹ Complication rates were somewhat higher in the plasma exchange groups. A large international multicenter randomized trial compared plasma exchange (50 mL/kg × 5 exchanges over 8-13 days), IVIg (0.4 g/kg × 5 days), and plasma exchange followed by IVIg.³⁰ No significant outcome differences between these therapies were found with respect to functional improvement at 4 weeks or at 48 weeks.

Evidence-based guidelines for Guillain-Barré syndrome immunotherapy have been published by the Quality Standards Subcommittee of the American Academy of Neurology.³¹ Plasma exchange is recommended for adult patients who cannot walk within 4 weeks of symptom onset. IVIg is recommended in these patients within 2 or possibly 4 weeks of symptom onset. Both treatments are deemed equivalent in efficacy, and combining treatment with plasma exchange and IVIg confers no additional benefit. In light of their therapeutic equivalence, the decision whether to employ plasma exchange or IVIg in treating acute Guillain-Barré syndrome may be determined by resource availability and by avoiding potential side effects related to a patient’s medical comorbidities. Patients with heart disease, renal insufficiency or failure, hyperviscosity, or IgA deficiency may be more susceptible to complications of treatment with IVIg, whereas plasma exchange may be complicated in patients with labile blood pressure, septicemia, and significant venous access problems.

Despite the autoimmune pathophysiology of Guillain-Barré syndrome and the efficacy of corticosteroids in more chronic forms of inflammatory neuropathy, corticosteroids have not demonstrated effectiveness in Guillain-Barré syndrome and are therefore not recommended for Guillain-Barré syndrome treatment.³¹ A large multicenter trial failed to demonstrate efficacy of high-dose intravenous methylprednisolone,³² and another large multicenter trial demonstrated no added clinical benefit in combined treatment with IVIg and methylprednisolone.³³

West Nile Virus Acute Flaccid Paralysis Syndrome

The large outbreak of West Nile virus encephalitis in the summer of 1999 in New York City marked the emergence of a relatively new cause for neuromuscular weakness with the potential for neuromuscular respiratory compromise. West Nile virus is a flavivirus transmitted between birds and mosquitoes. Humans may acquire West Nile virus from the bite of an infected Culex species mosquito, and a corresponding peak in human disease occurs in the late summer and fall. West Nile virus may also be transmitted to humans by organ transplantation,³⁴ blood and blood product transfusion,³⁵ transplacental exposure,³⁶ breast feeding,³⁷ and percutaneous laboratory injuries.³⁸ About 20% of humans experience a mild flulike illness lasting 3 to 6 days, and about 1 in 150 develop central nervous system disease, which usually presents as meningoencephalitis.³⁹

In the initial North American outbreak of West Nile virus, about 10% of infected patients experienced flaccid weakness with clinical features resembling Guillain-Barré syndrome.⁴⁰ In one report from the original outbreak, a patient developed electromyographic evidence for segmental demyelination compatible with Guillain-Barré syndrome.⁴¹ Although patients with West Nile virus infection exhibit a spectrum of clinical weakness,⁴² the most prominent and distinctive syndrome documented in several subsequent reports of West Nile virus infection is an acute “poliomyelitis-like” or acute flaccid paralysis syndrome with pathology localizing to the ventral horns of the spinal cord and/or ventral roots.⁴³^–⁴⁹ These patients developed acute, asymmetrical, flaccid weakness in the absence of sensory abnormalities, diffuse areflexia, or bowel/bladder dysfunction. Some of the patients experienced concurrent meningoencephalitis, and a few required mechanical ventilation.^44,⁴⁵ West Nile virus acute flaccid paralysis syndrome may occur in the absence of overt encephalitic signs (e.g., fever, confusion) or meningismus. Although the risk for West Nile virus encephalitis is significantly increased with age,⁵⁰ West Nile virus acute flaccid paralysis syndrome occurs in relatively younger patients.⁴³^–⁴⁹

Electrodiagnostic studies in patients with West Nile virus acute flaccid paralysis syndrome demonstrate normal sensory potentials, the absence of findings suggesting segmental demyelination (e.g., motor conduction block, reduced conduction velocities, prolonged distal and F-wave latencies), low-amplitude compound muscle action potentials in affected regions, and marked denervation changes in affected limb and in corresponding paraspinal muscles on needle electromyography. Corresponding magnetic resonance imaging (MRI) findings are sometimes observed and include abnormal signal in the spinal cord on T2-weighted images ^47,⁴⁸ and abnormal enhancement of the nerve roots and cauda equina.^46,⁴⁷ CSF analysis usually demonstrates mild pleocytosis with lymphocytic predominance, mild to moderate protein elevation, and normal glucose.⁵¹ Prognosis for recovery of strength in these patients appears poor.⁵²

West Nile virus infection may be diagnosed by demonstrating West Nile virus RNA in serum, CSF, or other tissues by reverse-transcriptase polymerase chain reaction, although this is insensitive.⁵³ More commonly, a diagnosis is made by demonstration of West Nile virus IgM in CSF or serum by antibody-capture enzyme-linked immunosorbent assay. When serum West Nile virus IgM is present, diagnosis is confirmed by a fourfold increase in West Nile virus IgG titers between acute and convalescent sera obtained 4 weeks apart. Positive IgM and IgG antibody titers should be confirmed by plaque-reduction viral neutralization assay to exclude false-positive results related to other flaviviral infections such as St. Louis encephalitis. Serology may not become positive until 8 days after symptom onset.³⁹

Particularly in the absence of a more typical encephalitic presentation of West Nile virus infection, a high index of clinical suspicion is needed to make a diagnosis of West Nile virus acute flaccid paralysis syndrome and to distinguish such cases from Guillain-Barré syndrome in patients presenting with acute weakness in the late summer or fall. Electrodiagnostic studies may help localize the pathology to the ventral horns of the spinal cord or ventral roots in West Nile virus cases and to exclude findings of segmental demyelination suggesting Guillain-Barré syndrome. CSF should also be evaluated to help discriminate between the albuminocytologic dissociation of Guillain-Barré syndrome and the lymphocytic pleocytosis observed in West Nile virus infection.

Although there is currently no specific treatment for West Nile virus acute flaccid paralysis syndrome, a multicenter study to evaluate the efficacy of Israeli IVIg in patients with West Nile virus meningoencephalitis or weakness began in the summer of 2003. The IVIg for this study contains high levels of West Nile virus antibodies because it was prepared from sera obtained after an Israeli West Nile virus epidemic in 2000.⁵⁴ Two candidate vaccines against West Nile virus are also being evaluated.⁵¹

Myasthenia Gravis

Myasthenia gravis is a consequence of autoimmune attack on the acetylcholine receptor complex at the postsynaptic membrane of the neuromuscular junction. This process results in clinical weakness with a fluctuating pattern that is most marked after prolonged muscle exertion. Myasthenia gravis occurs at a higher rate in early adulthood in women, but in later life the incidence rates for men and women become nearly equal. The reported prevalence is 14.2 cases per 100,000 population.⁵⁵ Myasthenia gravis typically involves ocular muscle weakness producing ptosis and diplopia, as well as bulbar muscle weakness resulting in dysphagia and dysarthria. This diagnosis should be considered in patients who have acute respiratory failure with these cranial nerve findings. A clinical diagnosis of myasthenia gravis may be supported by edrophonium testing, by electrophysiologic studies including repetitive nerve stimulation studies and single-fiber electromyography, and by acetylcholine receptor and muscle-specific receptor tyrosine kinase (MuSK) antibody testing.

Approximately 20% of patients with myasthenia gravis develop myasthenic crisis with respiratory failure requiring mechanical ventilation.⁵⁶ Intensivists may also encounter myasthenic patients for management of complications of immunomodulating treatment or for postoperative care after thymectomy The most common precipitating factors for myasthenic crisis include bronchopulmonary infections (29%) and aspiration (10%).⁵⁷ Other precipitating factors include sepsis, surgical procedures, rapid tapering of immune modulation, beginning treatment with corticosteroids, pregnancy, and exposure to drugs that may increase myasthenic weakness (Box 37-2).⁵⁸ Patients with myasthenia gravis are exceptionally sensitive to nondepolarizing neuromuscular blocking agents but are resistant to depolarizing agents.⁵⁹ Thymomas are associated with more fulminant disease and have been identified in about one third of patients in myasthenic crisis.⁵⁷

Although sometimes less appreciated than respiratory muscle weakness, upper airway muscle weakness is a common mechanism leading to myasthenic crisis.⁶⁰ Oropharyngeal and laryngeal muscle weakness may result in upper airway collapse with obstruction, along with inability to swallow secretions that may also obstruct the airway and become aspirated. Because direct assessment of oropharyngeal muscle strength is impractical, a focused history and examination to assess surrogate muscles in the head and neck region is important. Findings of bulbar myasthenia associated with upper airway compromise include flaccid dysarthria with hypernasal, staccato, or hoarse speech, dysphagia (sometimes associated with nasal regurgitation), and chewing fatigue. Patients may exhibit facial weakness with difficulty holding air within the cheeks. Jaw closure is often weak and cannot be maintained against resistance. Patients with myasthenic tongue weakness may be unable to protrude the tongue into either cheek. Although neck flexors are often weaker, a dropped head syndrome due to neck extensor weakness may occur. Vocal cord abductor paralysis may produce laryngeal obstruction with associated stridor.^61,⁶²

Patients with features of impending myasthenic crisis including severe bulbar weakness, marginal vital capacity (less than 20 to 25 mL/kg), weak cough with difficulty clearing secretions from the airway, or paradoxical breathing while supine should be admitted to an ICU and made NPO to prevent aspiration.⁶³ Serial vital capacity and NIF measurements may be used to monitor ventilatory function in impending myasthenic crisis. However, with significant bulbar weakness, these measurements are often inaccurate if the patient has difficulty sealing the lips around the spirometer mouthpiece or is unable to seal the nasopharynx. Vital capacity measurements may not reliably predict respiratory failure in myasthenia gravis, owing to the fluctuating nature of myasthenic weakness.⁶⁴ The criteria for intubation and mechanical ventilation are similar to those discussed earlier for Guillain-Barré syndrome. If the upper airway is competent and there is no difficulty handling secretions or gross hypercapnia (PaCO₂ > 50 mm Hg), intermittent nasal BiPAP may be a useful temporizing measure.⁴ The majority of patients who develop hypercapnia in myasthenic crisis require intubation, as do those who are becoming fatigued.

Plasma exchange is an effective short-term immunomodulating treatment for myasthenic crisis and for surgical preparation in symptomatic myasthenic patients. Significant strength improvement in myasthenic crisis is well documented in several series,⁶⁵^–⁶⁹ although there have been no controlled clinical trials. We perform a series of five to six exchanges of 2 to 3 L every other day. Onset of improved strength is variable but generally occurs after two to three exchanges.

IVIg may represent an alternative short-term treatment for myasthenic exacerbations or crises in patients who are poor candidates for plasma exchange because of difficult vascular access or septicemia. Comparable efficacy for plasma exchange and IVIg was demonstrated in myasthenic exacerbations and crises in a relatively small randomized controlled trial of IVIg at 1.2 and 2 g/kg over 2 to 5 days.⁷⁰ However, in a retrospective multicenter study of myasthenic crisis, plasma exchange proved more effective than IVIg in ability to extubate at 2 weeks and in 1-month functional outcome.⁶⁹ Treatment failures to IVIg subsequently responding to plasma exchange have also been reported.⁷¹ Recent experience with preoperative IVIg for thymectomy in myasthenia gravis suggests that the time course of maximal response may be considerably delayed in some patients.⁷²

Corticosteroids (e.g., prednisone, 1 mg/kg/day) are occasionally used in prolonged myasthenic crises that fail to respond to treatment with plasma exchange or IVIg. If begun early in the course of myasthenic crisis, the transient increase in myasthenic weakness associated with initiating corticosteroids may prolong mechanical ventilation. When preceded by unequivocal improvement in strength after plasma exchange or IVIg treatment, long-term treatment with corticosteroids may begin, with reduced risk for corticosteroid-related exacerbations.

In the context of myasthenic crisis, excessive dosing of cholinesterase inhibitors may superimpose a cholinergic crisis due to depolarization blockade and result in increased weakness. Other symptoms of cholinergic crisis include muscle fasciculations and prominent muscarinic symptoms including miosis, excessive lacrimation and salivation, abdominal cramping, nausea, vomiting, diarrhea, thick bronchial secretions, diaphoresis, and bradycardia. Cholinergic crisis is rare in contemporary series of myasthenic crisis,⁵⁷ and it is now common practice to avoid repeated dose escalations of cholinesterase inhibitors in impending myasthenic crisis and to discontinue the use of cholinesterase inhibitors after intubation to reduce muscarinic complications. When there is a question of cholinergic excess contributing to respiratory insufficiency, it is most prudent to discontinue all cholinesterase inhibitors, protect the airway, and support respiration as necessary.

Thymectomy may result in long-term improvement in patients with a suspected thymoma or with a life expectancy of more than 10 years. However, a patient in acute respiratory failure is generally considered a poor operative risk, and thymectomy is generally delayed until the patient’s condition has improved.⁷³ Post-thymectomy pain control and ventilatory function may be improved by postoperative administration of epidural morphine.⁷⁴

Neuromuscular Diseases Secondary to Critical Illness and Its Treatment

Critical Illness Polyneuropathy

Critical illness polyneuropathy is a widespread axonal peripheral neuropathy that develops in the context of multiple organ failure and sepsis. This entity was recognized by several investigators in 1983 ⁷⁵^–⁷⁷ and has been further characterized in large part by Bolton and colleagues.^78,⁷⁹ In a prospective series of 43 consecutive patients with sepsis and multiorgan failure, 70% developed electrophysiologic evidence of a sensorimotor axonal neuropathy, and 15 patients developed difficulty weaning from mechanical ventilation as a consequence of the neuropathy.⁸⁰ Critical illness polyneuropathy is possibly the most common neuromuscular cause of prolonged ventilator dependency in patients without prior known neuromuscular disease.⁸¹ Given the limitations to detailed clinical motor and sensory examinations in the setting of critical illness, the clinical features of critical illness polyneuropathy (extremity muscle weakness and wasting, distal sensory loss, and paresthesias) may not be recognized. Deep tendon reflexes are generally reduced or absent. In the setting of superimposed central nervous system insult with pyramidal tract dysfunction, however, deep tendon reflexes may be normal or increased.⁸²

Electrodiagnostic studies are important in establishing a diagnosis of critical illness polyneuropathy, because the clinical findings may be unobtainable or indeterminate in this setting.⁸² Nerve conduction findings include normal or near-normal conduction velocity and latency values and significantly reduced compound muscle action potential and sensory nerve action potential amplitudes. Needle electrode examination reveals denervation changes that are most marked in distal muscles, including fibrillation potentials, positive sharp waves, and reduced recruitment of motor unit potentials.⁸³ With recovery over time, the denervation potentials abate, and the motor unit potentials become polyphasic and enlarged. Peripheral nerve histopathology has revealed widespread primary axonal degeneration in distal motor and sensory fibers, and skeletal muscle has exhibited fiber-type grouping.⁷⁹

Although the clinical history is usually adequate to distinguish between critical illness polyneuropathy and Guillain-Barré syndrome, the latter has developed in the context of recent surgery complicated by infection.⁸⁴ In some such instances, it may be necessary to differentiate between these two peripheral neuropathic disorders in a patient with extremity weakness and inability to wean from mechanical ventilation. Although only a few severe cases of critical illness polyneuropathy have been associated with facial weakness,⁸⁵ facial and oropharyngeal weakness are common in Guillain-Barré syndrome.⁸⁴ Dysautonomia and occasionally external ophthalmoplegia are also observed in Guillain-Barré syndrome but have virtually never been attributed to critical illness polyneuropathy.⁸⁵

Electrophysiologic findings are also helpful in distinguishing these two disorders. Features of segmental demyelination may be observed in Guillain-Barré syndrome on nerve conduction studies (e.g., reduced conduction velocity, prolonged distal and F-wave latencies, conduction block, and temporal dispersion of compound muscle action potentials); these findings are not observed in critical illness polyneuropathy. Needle electromyographic findings may differ in that relatively less spontaneous activity is observed in clinically weak muscles within the first few days in Guillain-Barré syndrome.⁸³ Although electrophysiologic studies are quite helpful in demonstrating the classic demyelinating form of Guillain-Barré syndrome, an electrophysiologic distinction between axonal forms of Guillain-Barré syndrome and critical illness polyneuropathy may not be reliable. The mean CSF protein level in Guillain-Barré syndrome is significantly higher than in critical illness polyneuropathy, although there is overlap between these populations.⁸³ Peripheral nerve histopathology may also distinguish between these two groups, because segmental demyelination and inflammatory changes may be observed in Guillain-Barré syndrome and are not seen in critical illness polyneuropathy.⁷⁹

Although overall prognosis in critical illness polyneuropathy is dependent on recovery from the underlying critical illness, most patients who survive experience a functional recovery from the neuropathy within several months.⁷⁹ Critical illness polyneuropathy may prolong ventilator dependence, but it does not worsen long-term prognosis.⁸² Proper positioning and padding are important to prevent compression neuropathies, because prognosis from superimposed compression neuropathies in the context of critical illness polyneuropathy is less favorable.⁸²

The pathophysiology of critical illness polyneuropathy is unknown. No clear metabolic, drug, nutritional, or toxic factors have been identified,⁷⁹ although the severity of critical illness polyneuropathy has been correlated with the amount of time in the ICU, the number of invasive procedures, an increased glucose level, a reduced albumin level,⁸⁰ and the severity of multiple organ failure.⁸⁶ Given the common antecedents of multiple organ failure and sepsis in which significant release of various cytokines occurs, increased microvascular permeability has been postulated to ultimately result in axonal hypoxia and degeneration as a consequence of endoneurial edema.⁸⁷

Prolonged Effects of Neuromuscular Blocking Agents

Prolonged neuromuscular blockade may occur with most depolarizing and nondepolarizing agents, particularly when hepatic or renal function is impaired.⁸⁸ In one study, administration of vecuronium for 2 or more consecutive days resulted in prolonged neuromuscular blockade and paralysis lasting from 6 hours to 7 days.⁸⁹ Although vecuronium is hepatically metabolized, patients with renal failure were susceptible to prolonged effects due to delayed excretion of the active 3-desacetyl metabolite. Acidosis and elevated serum magnesium levels were also associated with prolonged paralytic effects of vecuronium. A peripheral nerve stimulator may be used to monitor muscle twitch responses to a train-of-four stimulus during use of neuromuscular blocking agents. Drug dosage should be titrated to preserve one or two twitches to avoid overdosing. Two- to 3-hertz repetitive nerve stimulation studies may also be used to confirm neuromuscular blockade when it is suspected. Since atracurium and cisatracurium do not require organ metabolism for clearance, they are rarely associated with this problem.

Acute Quadriplegic Myopathy

The syndrome known as acute quadriplegic myopathy⁹⁰ or acute myopathy of intensive care⁹¹ was originally described in 1977 in a young woman who developed severe myopathy after treatment of status asthmaticus with high doses of corticosteroids and pancuronium.⁹² Subsequent to that report, there have been numerous citations of an acute myopathy developing in critically ill patients without preexisting neuromuscular disease. Acute quadriplegic myopathy has developed most frequently in the setting of severe pulmonary disorders in which neuromuscular blockade is used to facilitate mechanical ventilation, and high doses of corticosteroids are concurrently administered. In a majority of reported cases, myopathy developed when nondepolarizing neuromuscular blocking agents were used for more than 2 days.⁹⁰^–¹⁰⁰ The development of acute, necrotizing myopathy with myosin loss also occurs in patients receiving high doses of corticosteroids and hypnotic doses of propofol and benzodiazepines to induce paralysis.¹⁰¹ This observation highlights the significance of high-dose corticosteroid exposure in the development of this syndrome and suggests that paralyzed muscles may be generally susceptible to the toxic effects of corticosteroids. The mechanism of this myosin abnormality appears to lie at the level of transcriptional regulation of protein synthesis.¹⁰² The occurrence of acute quadriplegic myopathy after organ transplantation may be caused by the use of high doses of corticosteroids to prevent graft rejection, along with perioperative exposure to neuromuscular blocking agents.¹⁰³ Although most cases of acute quadriplegic myopathy have been associated with critical illness, high doses of corticosteroids, and paralytic agents, acute quadriplegic myopathy has developed after isolated corticosteroid exposure,^90,¹⁰⁴^–¹⁰⁷ isolated nondepolarizing neuromuscular blocking agent use,^100,^104,¹⁰⁸ or neither.¹⁰⁹ Factors that may impair neuromuscular transmission (e.g., hypermagnesemia, aminoglycoside exposure), factors that may slow the elimination of nondepolarizing neuromuscular blocking agents (e.g., hepatic or renal failure), and factors associated with critical illness (e.g., sepsis and acidosis) have also been associated with acute quadriplegic myopathy.⁹³

In typical cases, a diffuse flaccid quadriparesis with involvement of respiratory muscles and muscle wasting evolves after several days of induced paralysis. External ophthalmoparesis has rarely been noted.¹¹⁰ Sensation remains intact, but deep tendon reflexes are reduced or absent. The creatine kinase level is commonly elevated, but this may not be observed if creatine kinase is measured well after the myopathy has developed. Although the paralysis may be quite severe and may necessitate or prolong mechanical ventilation, the prognosis from the myopathy itself is good, with functional recovery over several weeks to months.⁹⁵ Electromyographic findings include reduced amplitude of compound motor action potentials with normal sensory nerve action potentials and normal nerve conduction velocities. M-wave amplitude improvement accompanies clinical recovery.¹⁰⁰ Repetitive nerve stimulation studies may yield significant decremental responses while residual effects of nondepolarizing neuromuscular blocking agents or their active metabolites persist.^93,¹⁰⁰ Needle electromyography often reveals small, low-amplitude, polyphasic motor unit potentials exhibiting early recruitment, sometimes along with positive sharp waves and fibrillation potentials.

A spectrum of muscle histologic changes may be observed, ranging from type II fiber atrophy and loss of adenosine triphosphatase (ATPase) reactivity in atrophic fibers to fiber necrosis in severe cases. However, the distinctive finding in most cases of acute quadriplegic myopathy is an extensive loss of thick filaments corresponding to myosin loss.^90,^94,^99,^104,¹⁰⁹ This finding may be demonstrated with immunohistochemical staining or electron microscopy. The increased expression of steroid receptors in denervated and immobilized muscle¹¹¹ may render these muscles susceptible to toxic catabolic effects of steroids.⁹⁰ Given the growing recognition of acute quadriplegic myopathy, the use of high doses of corticosteroids should be avoided if possible when neuromuscular blockade or induced paralysis is required.