Chapter 66. Neuromuscular Diseases Leading to Respiratory Failure

• Neuromuscular disorders (NMDs) in critical care may be divided into those that precipitate admission to the ICU and those that arise during ICU management; the latter are much more common and significantly influence the pace and extent of recovery from critical illness.
• The maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), vital capacity (VC), and qualitative judgment of oropharyngeal function are the most important parameters to follow in patients with NMDs.
• An effective cough is unlikely with a MEP <40 cm H2O or a VC <30 mL/kg.
• Sleep-related deterioration in hypoventilation and hypoxemia is common in patients with respiratory muscle impairment.
• Many patients with Guillain-Barré syndrome or myasthenia gravis of sufficient severity to precipitate ICU admission will benefit from treatment with plasmapheresis or intravenous immunoglobulin.
• Muscle biopsy is useful in the diagnosis of polymyositis, mitochondrial disease, and other myopathies, and should be considered when electrophysiologic and other testing does not offer a clear diagnosis of peripheral neuropathy or myoneural junction diseases.
• Critical illness myopathy and neuropathy should be considered in all patients with protracted critical illness, particularly when multisystem organ failure has been present; avoidance of paralytics, appropriate correction of the metabolic milieu, early physical therapy, and measures to shorten duration of mechanical ventilation may help ameliorate the impact of these acquired NMDs.

Neuromuscular weakness may result from disorders involving the peripheral nerves, neuromuscular transmission, or skeletal muscles.1–3 Neuromuscular disorders encountered in the critical care setting may be divided into those that result in ICU admission and those that are acquired during treatment of critical illness. In the first part of this chapter we will address neuromuscular disorders that lead to ICU admission, focusing on Guillain-Barré syndrome (GBS), myasthenia gravis (MG), and dermatomyositis/polymyositis (DM/PM), and concluding with a brief discussion of mitochondrial disease, a recently recognized metabolic myopathy. Subsequently, neuromuscular weakness that is acquired after admission to the ICU will be reviewed. However, before discussing the various causes of neuromuscular weakness, a brief review of respiratory muscle impairment is appropriate, since respiratory failure is the most common reason that patients with a primary neuromuscular disorder are admitted to an ICU.

Although respiratory muscle impairment may occasionally develop rapidly, more often its onset is gradual. Diaphragmatic weakness may be initially manifested by orthopnea or sleep disruption due to nocturnal hypoventilation, without prominent dyspnea.2 Because there may be a paucity of symptoms, objective testing is necessary. Maximal inspiratory pressure (MIP), maximum expiratory pressure (MEP), vital capacity (VC), and an assessment of oropharyngeal function are the most important respiratory muscle parameters to follow,4–6 and should be measured frequently in hospitalized patients who have an evolving neuromuscular disorder, with careful attention to serial changes.7 The most sensitive parameters of respiratory muscle strength are the MIP and MEP. Measurement of MIP and MEP requires a maximal effort at residual volume (MIP) and total lung capacity (MEP), using a bedside manometer fitted with a mouthpiece. Normal values for MIP and MEP are approximately –70 cm H2O and 100 cm H2O, respectively, for women, and approximately –100 cm H2O and 150 cm H2O, respectively, for men.5 An effective cough is unlikely when the MEP is <40 cm H2O, and there is risk of hypercapnia when the MIP is less negative than –20 cm H2O. In the early stages of respiratory muscle weakness, arterial blood gas and VC measurements are commonly normal. The normal VC in adults is approximately 50 mL/kg, and elimination of secretions with coughing is impaired when the VC declines to <30 mL/kg. Serial VC measurements that decline to <15 to 20 mL/kg increase the likelihood that ventilatory assistance will be necessary.1,8 Sleep-related deterioration in hypoventilation and hypoxemia are common in patients with respiratory muscle impairment, particularly during rapid eye movement sleep.2 When the supine VC is <60% of the predicted value, or the MIP is less negative than –34 cm H2O, sleep-disordered breathing is common.9

Bulbar muscle impairment may significantly increase the risk for aspiration-related respiratory failure. Unfortunately, bulbar muscle impairment is commonly unrecognized, resulting in increased risk of morbidity and mortality.8 Intact musculature involving the mouth, pharynx, palate, tongue, and larynx are necessary for effective oropharyngeal function.10 The assessment of oropharyngeal function is primarily based on clinical observation, and early consultation with an experienced speech pathologist is recommended to assess the patient's ability to perform the complex and coordinated action of swallowing.

Many patients who present to the ICU as a result of an underlying neuromuscular disorder will have a previously defined diagnosis. However, when a patient presents with recent onset of acute or subacute bilateral muscle weakness, a broad differential diagnosis must be considered (Table 66-1). An initial approach to differential diagnosis is based on the patient's history and a careful neurologic exam that attempts to define the principal level of abnormality (Table 66-2). Additional diagnostic tests such as nerve conduction studies and an electromyogram (EMG) are often needed to more reliably establish the underlying disorder. Although lesions involving the upper and lower motor neuron may occasionally be responsible for new-onset weakness that necessitates ICU admission, the latter is more often due to diseases that effect the peripheral nerves (e.g., GBS), neuromuscular junction (e.g., MG), or muscles (e.g., PM/DM).

Guillain-Barré Syndrome

Guillain-Barré syndrome is an acute inflammatory demyelinating polyneuropathy that most often presents with ascending symmetrical weakness.1,8,11 Weakness typically evolves over days to weeks, although a subset of patients experience a rapid decline in function over hours. Excluding trauma, GBS is the most common cause for acute flaccid paralysis in previously healthy people.1 The ascending weakness is accompanied by depressed or absent reflexes. Sensory involvement is common, and many patients experience peripheral paresthesias as their initial symptom. In addition, an aching discomfort in the lower back and legs is common in the early phase of the syndrome. Autonomic dysfunction is common in patients with GBS, resulting in brady- or tachyarrhythmias, orthostatic hypotension, hypertension, or abnormal sweating.8 Although bowel and bladder function are usually preserved,12 ileus and bladder dysfunction can occur. Variants from the usual GBS presentation may be encountered, including the Miller-Fischer variant, with ataxia, ophthalmoparesis, and areflexia.1,11,13

For unclear reasons, GBS appears to be more common in young adults and in the elderly. A preceding infectious syndrome with respiratory or gastrointestinal symptoms, usually occurring 1 to 4 weeks prior to the onset of neurologic symptoms, has been noted in approximately two thirds of patients.1,11,14Campylobacter jejuni and cytomegalovirus infections are the most commonly identified triggers for GBS.11,14 However, a diverse and seemingly unrelated group of triggers have been identified, including infections, vaccination, general surgery, epidural anesthesia, thrombolytic agents, drugs, neoplastic disease (Hodgkin's disease), sarcoidosis, and connective tissue diseases.1,8

A diagnosis of GBS is based on the clinical presentation and electrodiagnostic studies compatible with a demyelinating polyneuropathy.1,11 Elevated cerebrospinal fluid protein levels are commonly noted after the first week of symptoms and may be associated with a limited mononuclear pleocytosis (<10 cells/cm3). Diagnoses other than GBS should be more aggressively considered if: (1) reflexes remain intact despite weakness (areflexia is present in ∼90% of patients when weakness is fully developed); (2) the distribution of weakness is highly asymmetric; (3) fever is present during the initial presentation; or (4) the electrodiagnostic features are not indicative of an acquired demyelinating polyneuropathy.1 A rapidly progressive spinal lesion is the most important potentially reversible process to be excluded in a patient who presents with ascending weakness.12

Respiratory failure occurs at the time of initial presentation in 10% of patients, and eventually develops in up to 43% of patients during the course of their disease.1,15 All aspects of respiratory muscle function—inspiratory strength, expiratory strength, and upper airway protection—may be impaired.8,16 Progression to respiratory failure was predicted in one retrospective study by the presence of a VC <20 mL/kg, MIP less negative than –30 cm H2O, and MEP <40 cm H2O (“20/30/40 rule”).17 Inability to cough markedly increases the risk for intubation.15 In addition, multivariate analyses have also indicated that a time from onset to admission of less than 7 days, inability to stand, and inability to lift the head or elbows are all associated with an increased risk for mechanical ventilation.15 The risk of intubation is increased by the dysautonomia of GBS, because of an exaggeration of the hypotensive response to sedative agents, and a markedly increased risk of arrhythmias, most often bradyarrhythmias.8,10

Guillain-Barré syndrome is a monophasic illness with a fairly predictable natural history; at least 90% of patients reach the nadir of their neuromuscular impairment by 4 weeks.8 Most patients recover from their illness, with two thirds experiencing mild residual deficits, and 10% to 20% of patients recovering completely.1 The remaining 3% to 8% of patients will die as a result of pneumonia, acute respiratory distress syndrome, sepsis, pulmonary emboli, and cardiac arrest.1,18,19 Deaths appear to be more common in the elderly, particularly in patients with pre-existing pulmonary disease.18 In addition, the mortality and morbidity of GBS is strongly associated with the need for and duration of mechanical ventilation. The mortality rate of patients with GBS who require mechanical ventilation may be as high as 20%.20 Mechanical ventilation for more than 2 weeks has been found to be the strongest predictor of major morbidity by multivariate analysis, with lower respiratory tract infection being the most common complication.21

Treatment of GBS involves either plasmapheresis or intravenous immune globulin (IVIg). Plasma exchange was demonstrated to improve strength and reduce the incidence of respiratory failure in three multicenter trials conducted in the 1980s.22–24 Two exchanges may be needed in patients with mild impairment, whereas four exchanges are optimal in those with more severe impairment.25Albumin is as effective as fresh frozen plasma as a replacement fluid during plasma exchange, and is associated with fewer adverse reactions.26 IVIg has also been shown to be an effective therapy for GBS.27 The mechanism by which IVIg benefits patients with GBS is not fully defined, but neutralizing neuromuscular blocking antibodies by a dose-dependent process appears likely.28 A randomized, multicenter, international trial compared plasma exchange, IVIg, or plasma exchange followed by IVIg in 379 GBS patients who had marked weakness and whose symptoms had been present for 14 days or less.21 There were no differences among the three treatment groups with regard to either the duration of mechanical ventilation or functional outcome 4 weeks after therapy. It was therefore concluded that IVIg and plasmapheresis are equally effective therapies, and that their combined use offered no additional benefit.21 Because of its ease of administration and acceptable side effect profile, IVIg is often preferred. In addition, IVIg may be superior to plasmapheresis in patients with Campylobacter jejuni infections and antibodies to peripheral nerve gangliosides.2,29 Screening for IgA deficiency is recommended prior to treatment with IVIg to reduce the risk of anaphylaxis during infusion. Although frequently used in the past, corticosteroids have not been shown to be beneficial in patients with GBS.1,11,13

Myasthenia Gravis

Myasthenia gravis is an acquired autoimmune disorder of neuromuscular junction transmission characterized by muscle weakness, progressive muscle fatigue with repetitive use, and improvement in strength after rest.3,30 The incidence of MG is highest in younger women or older men. Generalized weakness with fatigability involving the trunk and extremity muscles is noted in approximately 85% of patients and may be the dominant complaint.3 Ocular muscle involvement, including ptosis and diplopia, are common at presentation. Bulbar muscle impairment results in dysphonia and difficulty with chewing and swallowing. The immunopathogenesis of MG has been well defined, with identification of autoantibodies that bind to the acetylcholine receptor resulting in a significant reduction in the number of available receptors at the neuromuscular junction, thereby impairing neuromuscular transmission.3

Although isolated involvement of the respiratory muscles may occur, respiratory muscle impairment typically presents along with generalized muscle weakness.31,32 Upper airway obstruction with abnormal vocal cord adduction during inspiration has also been described.33 Lower respiratory muscle impairment is evidenced by a significant reduction in VC, MIP, and MEP. Approximately 15% to 27% of patients experience “myasthenic crises,” a rapid and severe decline in respiratory muscle function that is associated with a mortality of 4% to 13%.34–36 Multiple triggers for myasthenic crises have been identified, including infection, electrolyte abnormalities, withdrawal of anticholinesterase drugs, and the use of drugs that impair neuromuscular transmission, with infection being the most common identifiable precipitating factor. However, a trigger for the myasthenic crisis cannot be found in nearly a third of patients.35 In a retrospective study of 73 episodes of myasthenic crises progressing to intubation, 50% of patients were extubated within 2 weeks, and the median ICU and hospital stays were 14 and 35 days, respectively.35 Three independent predictors of prolonged intubation were identified in this study: (1) preintubation serum bicarbonate ≥30 mg/dL; (2) peak VC <25 mL/kg on day 1 to 6 postintubation; and, (3) age >50 years. Cardiac dysrhythmias are a common cause of death in patients with myasthenic crises, and continuous cardiac rhythm monitoring is strongly recommended.

In patients with a compatible clinical presentation, the diagnosis of MG centers on three principal studies: (1) a positive anticholinesterase test (rapid and transient improvement in strength after administration of edrophonium); (2) presence of acetylcholine receptor antibodies in the serum; and (3) electrophysiologic studies that are indicative of a disorder of the neuromuscular junction, with a decremental response in compound action potentials to repetitive nerve stimulation.3 Acetylcholine receptor–binding antibodies are identified in approximately 88% to 93% of patients with generalized MG, and in approximately 71% of patients with symptoms limited to ocular muscle involvement.37 One diagnostic strategy that has been recommended begins with an edrophonium test, followed by a repetitive nerve stimulation test and measurement of acetylcholine receptor antibodies.3 Single-fiber EMG may be obtained if the diagnosis remains undefined.

Conditions associated with MG include thymic hyperplasia or thymoma, and autoimmune conditions such as rheumatoid arthritis, lupus, thyroiditis, and Graves disease.3 Thyroid function testing should be obtained in all patients with MG. Thymic abnormalities are present in the majority of patients with MG, with thymic hyperplasia being most common and thymoma identified in 10% to 12% of patients.3 The association with thymic abnormalities has led to the use of a chest computed tomographic (CT) or magnetic resonance imaging (MRI) scan as a screening tool in patients with MG.

The treatment of MG includes anticholinesterase medications to increase the concentration of acetylcholine available for receptor binding, immunosuppressive therapy, and thymectomy.3,38,39 The first line of therapy is use of an anticholinesterase agent, most commonly pyridostigmine. Respiratory muscle function improves in approximately 50% of patients treated with anticholinesterase medications.2,40 Muscarinic side effects include abdominal cramping with frequent defecation, increased urinary frequency, bronchospasm, bradycardia, fasciculations, increased oral secretions, and excessive lacrimation. Less commonly, these agents produce a cholinergic crisis, with increased bulbar and lower respiratory muscle weakness during the early phase of treatment. The clinical manifestations of a cholinergic crisis may overlap with those of a myasthenic crisis, making a clear distinction difficult; withholding anticholinesterase medications for 4 to 10 days may be necessary.

Most patients respond to anticholinesterase therapy, but their response is usually incomplete and symptomatic relapse during therapy is common. Unfortunately, increasing the dose of drug often leads to significant side effects.3,38,39 Thus the majority of patients require additional therapy with immunosuppressive agents. Corticosteroid use results in a remission or marked improvement in approximately 75% of patients with MG, and these are the most commonly used agents. Azathioprine has a more delayed onset of action, usually requiring at least 3 months of therapy, thereby limiting its use as a primary agent for initial therapy. Cyclosporine reduces acetylcholine receptor antibody production, but toxicity limits its use. Cyclophosphamide has also been beneficial in patients who were refractory to other agents, but toxicity remains a significant concern.

Plasma exchange and IVIg are commonly used for intensive short-term therapy.41,42 Plasma exchange removes acetylcholine receptor antibodies rapidly, commonly resulting in an improvement in strength within several days. Typically, 2- to 4-liter exchanges are performed two to three times per week over a 10- to 14-day period. IVIg also results in a rapid improvement in most patients. Plasma exchange should be considered as an initial intervention in patients with myasthenic crisis, with IVIg reserved for possible use after a course of plasma exchange.38

Thymectomy has been associated with clinical improvement and remission in patients with MG, and is generally recommended for patients with thymomas between the ages of puberty and approximately 60 years.3,38,43 However, adequate prospective studies demonstrating a clear benefit from thymectomy are unavailable. Because postoperative decline in ventilatory function is common, thymectomy should not be performed as an emergency procedure in patients with significantly impaired ventilatory function (VC <2 L). Plasma exchange should be considered preoperatively in patients with significant ventilatory impairment.

Alternative therapeutic strategies should be considered in MG patients who are refractory to conventional therapy. For example, high-dose cyclophosphamide followed by granulocyte colony-stimulating factor therapy was reported to be effective in three patients with MG refractory to conventional immunosuppressive therapy, plasma exchange, and thymectomy.44 In addition, lymphocyte depletion therapy with the human-mouse chimeric monoclonal antibody rituximab was associated with clinical improvement and reduction in the acetylcholine receptor antibody titer in a patient who developed MG after bone marrow transplantation.45,46

Disorders of neuromuscular transmission that may mimic MG include Eaton-Lambert syndrome (usually associated with small-cell carcinoma), botulism, tick paralysis, organophosphate toxicity, and a myasthenic-like syndrome induced by penicillamine.3 Botulism results in a toxin-mediated irreversible inhibition of neuromuscular transmission, resulting in an acute symmetric descending paralysis beginning with bulbar impairment.2,47 The early bulbar involvement of botulism may initially be confused with the Miller-Fischer variant of GBS, which predominantly involves the bulbar musculature.1,13 Botulism is most commonly associated with food-borne and intestinal sources. Wound-related illness may also occur, especially in parenteral heroin users. Bioterroism remains a serious concern as another potential source of botulism. Tick paralysis typically affects children more than adults and is manifested by an ascending paresis or paralysis caused by a tick-borne neurotoxin.48 A high index of clinical suspicion is critical for establishing a diagnosis of tick paralysis. Treatment of tick paralysis is centered on a careful physical exam (including scalp, ears, axilla, buttocks, perianal skin, and labia) to identify and remove all ticks and their body parts, along with close observation and supportive care. In North American tick paralysis, significant improvement in neuromuscular strength usually occurs within several hours of tick identification and removal.

Dermatomyositis and Polymyositis

Dermatomyositis and polymyositis are idiopathic inflammatory disorders which usually present with progressive symmetrical muscle weakness over several months.49,50 Less commonly, there is an acute presentation with rapidly evolving muscle weakness. Of the major muscle groups, the shoulder and pelvic girdle muscles are most often affected. Neck flexion muscles are weakened in up to 50% of patients, but facial muscles are usually spared. Pharyngeal muscle involvement may present with dysphonia or dysphagia. Myalgias and muscle tenderness occur in up to 50% of patients. An immune-mediated mechanism is strongly supported by the association of PM/DM with other autoimmune diseases, and by the frequent presence of autoantibodies in serum.50

Diagnostic criteria for PM/DM include the presence of symmetrical proximal muscle weakness, elevated skeletal muscle enzymes, and compatible findings on electromyography and skeletal muscle biopsy.49–51 Characteristic dermatologic findings are present in dermatomyositis, including heliotropic changes of the eyelids and Gottron sign, a characteristic symmetric erythematous rash over the extensor surfaces of metacarpophalangeal, interphalangeal, elbow, and knee joints. Creatine phosphokinase (CK) elevation is the most consistent indicator of muscle inflammation. However, other muscle enzymes (aldolase, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase) may also be elevated. Electromyography typically reveals features of a generalized myopathic disorder, but findings may be normal in 10% to 15% of patients. Muscle biopsy is the most definitive test, demonstrating variable degrees of type I and II fiber necrosis and inflammation.

Respiratory and cardiovascular complications of DM/PM are the main concerns in the ICU.49,52,53 Respiratory complications with DM/PM include respiratory muscle weakness, interstitial lung disease, pneumonia resulting from aspiration or immunosuppression, and drug-induced lung disease. The presence of dysphagia suggests pharyngeal muscle dysfunction, which greatly increases the risk for aspiration, the most commonly reported pulmonary complication of DM/PM. Respiratory muscle dysfunction with inspiratory and expiratory muscle involvement has been reported in up to one third of patients. Interstitial lung disease has also been identified in nearly one third of patients with DM/PM,54 with nonspecific interstitial pneumonitis being the most common underlying histopathologic lesion.55 Typical findings on high-resolution chest CT include reticular and ground-glass opacities in the lower lung fields, variable presence of consolidation in the lung periphery, and the absence of a fibrotic honeycomb-like appearance.56 An analysis of 70 patients with DM/PM and diffuse interstitial lung disease found a musculoskeletal presentation in 36%, pulmonary presentation in 30%, and a combination of musculoskeletal and pulmonary symptoms in 21%.55 When presentation is with pulmonary disease alone, treatment with corticosteroids may suppress or obscure musculoskeletal symptoms, thereby delaying the diagnosis of DM/PM for weeks to years.55 Cardiac features include tachyarrhythmias, conduction abnormalities, myocarditis, or heart failure with a dilated cardiomyopathy. Chronic pulmonary hypertension may result from several mechanisms, including underlying cardiomyopathy, chronic hypoxia associated with either chronic hypercapnic respiratory failure or interstitial lung disease, or the development of a primary pulmonary hypertension–like syndrome.

Most patients with DM/PM respond to corticosteroids, with normalization in muscle enzymes by 4 to 6 weeks and improvement in muscle strength within 2 to 3 months.38,49,50 Therapy with corticosteroids is usually initiated at a dosage of 0.5 to 1.5 mg/kg prednisone, with gradual tapering after a complete response has been demonstrated. However, the clinical course of DM/PM is quite variable, ranging from a relatively indolent course to a relentlessly progressive process that is unresponsive to therapy. Symptom duration of greater than 6 months before diagnosis, severe symptoms, and the presence of dysphagia are clinical predictors of poor outcome in DM/PM.57,58

Alternative immunosuppressive agents, including methotrexate, azathioprine, or cyclophosphamide, should be considered in patients with poor prognostic markers or a limited response to corticosteroids.58 These immunosuppressive agents, particularly methotrexate or azathioprine, may also be used if there is corticosteroid intolerance and for long-term maintenance therapy. Alternative therapy with IVIg, cyclosporine, tacrolimus, alkylating agents, and tumor necrosis factor inhibitors has been used for patients whose symptoms are unresponsive to standard treatment. In one study of 35 patients with PM who were refractory to therapy with prednisone and at least one additional immunosuppressive agent, significant improvement in strength was noted in 71% of patients after treatment with IVIg; all patients had a significant reduction in CK values.59 IVIg has also been reported to be beneficial in the management of life-threatening esophageal involvement in DM/PM.60 Pharyngeal muscle involvement in DM/PM usually responds to corticosteroid therapy. However, surgical division of the cricopharyngeal muscle may be necessary for severe cricopharyngeal achalasia that is refractory to immunosuppressive therapy. Cardiac complications are managed with appropriate pharmacologic therapy and insertion of a pacemaker-defibrillator should be considered in the event of serious conduction abnormalities or ventricular dysrhythmias.

Mitochondrial Disease

Mitochondrial disease may present with diverse manifestations in the critical care setting, including respiratory muscle impairment. This increasingly recognized metabolic myopathy appears to result from acquired mutations of genes coding for critical proteins in glycolysis, fatty acid oxidation, or oxidative phosphorylation.61–63 Clues to the possible presence of this interesting disorder include unexplained dyspnea progressing to respiratory failure, sedative-related respiratory failure out of proportion to the sedative dose administered, respiratory failure with persistent unexplained lactic acidosis, prolonged paralysis following use of neuromuscular blockade, and unexplained difficulty with weaning from mechanical ventilation.61,64,65 An elevation in the lactate:pyruvate ratio of greater than 20 is frequently present in patients with abnormalities in glycolysis. Reduction in carnitine levels may be identified in patients with a disorder in fatty acid oxidation, reflecting abnormalities in carnitine palmitoyl transferase enzymes. Muscle biopsies are usually diagnostic, demonstrating characteristic findings on light and electron microscopy. Care for patients with these unique disorders is primarily supportive, including treatment of precipitating infections and withholding sedatives and neuromuscular blockers. A diet high in carbohydrates may be of benefit in patients with abnormal carnitine palmitoyl transferase enzyme function.

Acquired neuromuscular disorders have become increasingly recognized over the last two decades as a major cause of morbidity related to critical illness. Currently, acquired disorders are a much more common cause of severe generalized weakness in the ICU than are primary neuromuscular disorders.66 Although ICU-acquired muscle weakness is usually reversible, respiratory muscle involvement may lead to prolonged mechanical ventilation and delayed weaning. Once patients are successfully extubated, they often require prolonged physical rehabilitation and may be unable to perform basic activities of daily living for weeks to months.67 Of greater concern, recent studies have documented the persistence of significant weakness up to several years after hospital discharge, indicating that in some cases severe ICU-acquired weakness may result in permanent disability.68–71 Without question, the medical, economic, and psychosocial costs of ICU-acquired neuromuscular weakness represent a major problem in the current practice of critical care medicine.

Causes of Intensive Care Unit–Acquired Weakness

Three basic causes of ICU-acquired neuromuscular weakness have been identified: (1) persistent blockade of the neuromuscular junction after discontinuing a neuromuscular blocking agent (NMBA), (2) a sensorimotor axonal polyneuropathy, and (3) an acute myopathy.72–74 Although the clinical setting and physical examination may be of some help in elucidating the underlying cause of muscle weakness, in most cases diagnosis has been made by electrophysiologic studies, sometimes supplemented by biopsy of muscle or nerve. As will be discussed below, elucidation of the underlying cause of weakness is not always easy, and combined disorders of muscle and nerve may occur.75

Persistent Neuromuscular Junction Blockade

Residual blockade of the neuromuscular junction after discontinuation of an NMBA is rarely responsible for persistent neuromuscular weakness in the ICU.66 One possible exception is the use of vecuronium in patients with renal failure, in which case accumulation of the active metabolite 3-desacetylvecuronium may result in paralysis that is prolonged for several days.74 If residual neuromuscular paralysis is a consideration, a repetitive nerve stimulation protocol should be performed to see if there is a progressive decrement in the compound muscle action potential (CMAP) that would indicate residual blockade at the neuromuscular junction.

Critical Illness Polyneuropathy

In the 1980s Bolton and colleagues reported on a group of critically ill patients who developed generalized weakness after several weeks in the ICU.72,76 Affected patients, most of whom had underlying sepsis, often underwent neurologic evaluation because of difficulty in weaning from mechanical ventilation or because of diffuse limb weakness. Distal muscles were often affected most prominently, but cranial nerves did not appear to be involved. Sensory examination was difficult to perform, but deep tendon reflexes were either reduced or absent in most cases.72,76 Electrophysiologic evaluation with electroneurography (ENG) and EMG suggested that weakness was due to an axonal sensorimotor polyneuropathy. Key findings included a reduction in the CMAP in response to stimulation of motor nerves, often accompanied by a decrease in the sensory action potential (SAP) when sensory nerves were stimulated. The EMG revealed spontaneous fibrillations and positive sharp waves that were attributed to denervation. Survivors had improvement in their electrophysiologic studies over several months that paralleled clinical recovery. Autopsy findings included grouped fiber atrophy in muscle and axonal degeneration with loss of myelin in nerves, with distal segments most severely affected.76 Neither muscle nor nerve showed inflammation.76

Numerous additional studies dealing with critical illness polyneuropathy have been published in the last 20 years, and the reported findings have been similar to those initially described, including the diffuse distribution of weakness (other than the facial muscles), frequent difficulties with weaning, and occurrence in the setting of sepsis and systemic inflammatory response syndrome (SIRS), often with multiorgan dysfunction. The pathogenetic mechanism of acquired polyneuropathy in critical illness is not understood. It has been suggested that the peripheral nervous system may be one of the many target sites for tissue damage in the setting of sepsis, and that lack of effective vascular autoregulation and increased microvascular permeability could result in neural edema and capillary occlusion, thereby damaging peripheral nerves.72,77 As with other types of organ dysfunction in SIRS, neuronal injury may be cytokine-mediated.77

Intensive Care Unit–Acquired Myopathy (Critical Illness Myopathy)

Severe ICU-acquired myopathy was first reported 25 years ago,78 with numerous individual case reports and case series having been published subsequently.79–81 Myopathy most often occurred in the setting of mechanical ventilation for severe airflow obstruction, and affected individuals had typically been treated with concomitant corticosteroids and NMBAs. However, myopathy has also been documented in patients treated with corticosteroids without paralysis, and in critically ill septic patients who received neither corticosteroids nor NMBAs.73,82–85 Some authors have attempted to subdivide the acute myopathy that develops in the ICU into a “critical illness myopathy” associated with hypercatabolic (generally septic) states, a “thick filament myopathy” related to corticosteroids and (usually) NMBAs, and a “necrotizing myopathy” characterized by prominent myonecrosis.73 However, it is not clear that these are really distinct entities, and a recent editorial suggested the term critical illness myopathy be used as the sole descriptor for all instances of ICU-acquired myopathy.86

Like critical illness polyneuropathy, acute myopathy is usually manifested by generalized muscle weakness that becomes apparent once withdrawal of sedation allows an assessment of neuromuscular function. Although reflexes may be depressed or absent if myopathy is severe, sensation is intact. In severe cases, patients are unable to move their limbs, resulting in the commonly used descriptor “acute quadriplegic myopathy.” On occasion, patients may not open their eyes in response to verbal commands, giving the impression of coma. When less severe, patients may have predominantly distal weakness, and both foot drop and wrist drop are common. In contrast to the frequent diaphragmatic involvement in critical illness polyneuropathy, asthmatic patients who develop myopathy often have relatively well-preserved inspiratory muscle function despite near-quadriplegic limb weakness.80

Serum creatine kinase (CK) levels may be elevated or normal, and can neither establish nor exclude an underlying myopathy as the cause of muscle weakness. The EMG reveals either normal or decreased CMAP amplitudes, depending on the degree of muscle involvement. Like critical illness polyneuropathy, needle EMG often reveals spontaneous fibrillations and positive sharp waves in resting muscle. However, with voluntary contractions there is a characteristic myopathic pattern of abundant low-amplitude, short-duration polyphasic units with early recruitment.87 Pathologic findings in acute myopathy have been variable, with fiber atrophy and vacuolization in the absence of inflammation being the most common finding.73 Although necrosis may be prominent, more often it is minimal or absent.73 A key finding on electron microscopy is a selective loss of myosin, with relative sparing of actin and Z bands.73 This pattern is very characteristic of ICU-acquired myopathy and is rarely seen in other disorders of muscle. A reduction in the myosin:actin ratio has also been documented by electrophoresis of needle aspirates of muscle, potentially offering a minimally invasive technique of diagnosing acute ICU-acquired thick filament myopathy.88

The underlying reason for the often near-quadriplegic muscle weakness in ICU-acquired myopathy is uncertain. Although myosin loss may interfere with normal contractility, another potential mechanism of weakness may be temporary muscle inexcitability. In a study of patients with severe ICU-acquired myopathy related to corticosteroids and NMBAs, Rich and colleagues found that they were unable to induce an action potential even when the muscle was stimulated directly.89 Muscles later regained their ability to generate an action potential during clinical recovery.89 In a subsequent study, inability to induce an action potential by direct muscle stimulation was also documented in a more heterogenous group of patients with ICU weakness, including a number of patients who were septic and had not received corticosteroids or NMBAs.90 Studies in experimental animals suggest that muscle inexcitability may be due to impairment of sodium fast channels.91

Polyneuropathy, Myopathy, or “Polyneuromyopathy”

Differentiation of an axonal motor polyneuropathy and severe myopathy by EMG often rests upon the pattern of recruitment seen with voluntary muscle contraction, and inability to cooperate with the voluntary portion of the needle EMG may preclude reliable diagnosis. Marked reduction in sensory nerve amplitudes would indicate neuropathy, but tissue edema may limit the accuracy of sensory ENG, and it has been claimed that 40% to 60% of patients with critical illness polyneuropathy have normal sensory exams. Furthermore, the routine histopathologic findings in muscle biopsy specimens may be similar in myopathy and critical illness polyneuropathy. Therefore, a diagnostic dilemma is presented by patients who have a normal sensory ENG (or in whom sensory evaluation cannot be performed) and are unable to perform voluntary muscle contractions.

A recent study evaluated eight critically ill patients in whom a standard ENG/EMG and muscle histopathology could not differentiate a pure motor axonal neuropathy and a primary myopathy.92 In all cases electron microscopy revealed a profound selective loss of myosin and normal sural nerve histology, indicating the presence of a primary myopathy rather than motor neuropathy as the cause of weakness.92 A similar conclusion was reached when direct muscle stimulation was used to differentiate motor neuropathy and myopathy.93 As noted earlier, muscle inexcitability has been documented in acute myopathy, but a motor neuropathy should not preclude generation of a normal CMAP in response to direct muscle stimulation. In a study of 22 consecutive patients in whom standard ENG/EMG was nondiagnostic, all but 1 patient had evidence of myopathy by direct muscle stimulation and quantitative EMG.93 Another group has noted that with use of direct muscle stimulation they have never been able to document a single case of pure axonal motor neuropathy, and suggest that previously reported patients given the latter diagnosis almost certainly had a myopathy.94 Direct muscle stimulation could eventually prove to be useful in the investigation of severe weakness in the ICU, because coma or deep sedation does not preclude its use.84 It should be appreciated, however, that this technique is not as well-standardized as the routine EMG, and individual laboratories may need to establish their own normative data.

Recently, it has been suggested that some patients with ICU-acquired weakness have both an axonal polyneuropathy and myopathy. In one study muscle and nerve biopsies were performed in 24 patients with ICU-acquired weakness, all of whom had ENG/EMG evidence suggestive of polyneuropathy.95 All but one had pathologic evidence of a myopathy and one third also had an axonal lesion. The authors concluded that polyneuropathy and myopathy often coexist. A recent prospective study of ICU-acquired paresis found that 22 patients in whom ENG/EMG could be performed uniformly had evidence of a sensorimotor axonal neuropathy, but each of the 10 patients who also underwent muscle biopsy had evidence of myopathy (type II fiber atrophy with myosinolysis).96 This again suggested that both polyneuropathy and myopathy may coexist and together contribute to ICU-acquired weakness.

Although clarification of the underlying mechanisms of ICU-acquired weakness may be important from a research perspective, it is uncertain how it will affect individual patients in the ICU since there is no specific therapy. Indeed, it has been suggested that electrophysiologic and pathologic studies are of little practical value in the evaluation of weakness that is clearly acquired after the onset of critical illness, and that a purely clinical approach is adequate to define the presence of a critical illness weakness syndrome.97 From a practical standpoint, the primary concern with omission of electrophysiologic studies would be missing a rare case of the Guillain-Barré syndrome, a disorder with specific therapy that may be triggered by acute nonneurologic critical illness (see above). In addition, the prognosis for recovery may be different with a pure myopathy and a severe axonal polyneuropathy (see below).

Intensive Care Unit–Acquired Weakness: Incidence and Risk Factors

A number of studies have attempted to define the incidence of ICU-acquired weakness and the risk factors for its development. In general, two types of patient cohorts have been examined: those with status asthmaticus, and a more general ICU population in which sepsis, SIRS, and multiorgan failure were dominant.

Status Asthmaticus

Asthmatic patients who developed acute myopathy have uniformly received systemic corticosteroids while undergoing mechanical ventilation, and in the great majority of cases neuromuscular paralysis had been used to facilitate mechanical ventilation.79–81 Two large retrospective studies found an identical 30% incidence of myopathy among mechanically ventilated asthmatic patients who had received an NMBA.80,98 The risk of myopathy increases with the duration of paralysis. One prospective study found a striking relationship between the duration of paralysis and incidence of myopathy.79 In a second retrospective study the mean duration of paralysis for patients who developed myopathy was 3.2 days, and 90% of patients had been paralyzed for more than 24 hours.80 A third study also reported a mean duration of paralysis of 3 days among asthmatic patients who developed myopathy.98 Although it was initially believed that myopathy may be related to use of steroidal NMBAs (vecuronium and pancuronium), the incidence of myopathy is similar with atracurium (a nonsteroidal NMBA) and vecuronium.80

These reports, as well as numerous additional publications, have suggested that mechanically ventilated patients with status asthmaticus who are treated with corticosteroids should be at minimal risk of developing acute myopathy as long as they have minimal or no exposure to NMBAs. Unfortunately, the data linking use of NMBAs with acute myopathy has been based almost entirely on retrospective analyses. In the single prospective study of myopathy in status asthmaticus, patients were uniformly paralyzed.79 More recently, myopathy has been reported in mechanically ventilated patients with airflow obstruction who received corticosteroids and deep sedation, without paralysis.83 Furthermore, our recent unpublished clinical experience has included a number of patients who developed severe myopathy despite minimal or no exposure to NMBAs. Therefore, while prolonged paralysis appears to increase the risk of myopathy in status asthmaticus, avoidance of NMBAs does not eliminate the risk of neuromuscular weakness.

In experimental animals a thick filament myopathy analogous to that seen in humans with status asthmaticus can be produced by combined denervation and corticosteroids, but not by either intervention alone.99 Denervation results in a marked increase in the number of cytosolic corticosteroid receptors, but a similar effect is seen after limb immobilization by pinning and casting.100,101 It is possible that the apparent enhancement of corticosteroid myotoxicity by prolonged paralysis in individuals with status asthmaticus is related to the induction of total muscle inactivity rather than denervation per se. This could explain the occurrence of severe myopathy in corticosteroid-treated patients who underwent deep sedation for many days.83

A number of studies have attempted to identify the incidence and risk factors for ICU-acquired weakness among populations of medical and surgical patients who had prolonged critical illness, usually as a result of sepsis and SIRS. The reported incidence of ICU-acquired weakness has varied widely due to differences in diagnostic criteria and case mix. A recent study prospectively screened 95 consecutive patients who had remained mechanically ventilated for 7 days and subsequently became sufficiently awake that they could answer simple questions.96 Based on a complete clinical and electrophysiologic neuromuscular evaluation 1 week after awakening, clinically significant ICU-acquired paresis was diagnosed in 25% of patients.96 Another prospective study found an incidence of 33% among patients who had been mechanically ventilated for more than 4 days.102 When focusing on patients with sepsis and multiorgan failure, the incidence of clinically significant ICU-acquired neuromuscular disease appears to be much higher (70% to 82%).103,104

A variety of risk factors have been associated with risk for the development of weakness during critical illness. Sepsis is believed to be a major risk factor for ICU-acquired weakness. Although some studies found Acute Physiology and Chronic Health Evaluation (APACHE) II scores to be of no prognostic utility, a recent study found higher APACHE III score and presence of SIRS increased the risk of neuromuscular complications.102 Duration of mechanical ventilation has also been associated with increased risk, as has the presence of multiorgan dysfunction.96

Despite their putative role in status asthmaticus–related myopathy, the contribution of corticosteroids and NMBAs to weakness that occurs in a mixed ICU population, in which sepsis, SIRS, and multiorgan dysfunction predominate, is uncertain.105 Although one multicenter prospective study found corticosteroid therapy to be a strong risk factor for ICU-acquired paresis,96 most studies have not found a relationship between corticosteroid use and ICU-acquired weakness.105 Similarly, most studies involving mixed ICU populations have found no relationship between NMBA use and persistent muscle weakness.95,102

Outcome

The rate of recovery from ICU-acquired weakness has varied greatly in different series. When weakness occurs in the setting of severe asthma treated with corticosteroids and NMBAs, recovery may require several weeks, but near-normal muscle function is sometimes evident within 10 to 14 days after severe quadriparesis.87 A much longer recovery time has been found in studies involving a more diverse group of critically ill patients. In the first large study of critical illness polyneuropathy, survivors recovered over 3 to 6 months.76 A recent prospective study of ICU-acquired paresis reported a median recovery time of 21 days, and a number of patients did not achieve near-normal muscle function for 2 to 3 months.96 Another prospective study found that all survivors had recovered by 2 to 3 months.104

Although earlier studies suggested that ICU-acquired weakness is nearly always reversible, more recent studies have found that long-term, perhaps permanent, disability does occur. An evaluation of 109 survivors of acute respiratory distress syndrome found significant functional limitation at 1 year that was attributed in large part to muscle wasting and weakness.71 A second study found that one third of patients who had spent more than a month in the ICU had persistent muscle weakness 1 to 5 years after discharge.68 An evaluation of 19 patients who had been admitted to a rehabilitation unit due to severe ICU-acquired weakness found that one-third had persistent quadriparesis 2 years after discharge.69 Finally, 11 of 13 patients in one study had incomplete recovery by clinical and electrophysiologic criteria 1 to 2 years after ICU discharge.70 Together, these studies suggest the disturbing possibility that some patients with severe ICU-acquired weakness may never fully recover, and that the persistent muscle weakness may have a profound impact on overall function and quality of life.

Treatment and Prevention

There is no specific treatment for ICU-acquired muscle weakness other than physical rehabilitation. Unfortunately, it may not be possible to easily prevent this complication in patients with either severe sepsis and multiorgan failure or severe, protracted status asthmaticus that requires use of corticosteroids and either prolonged deep sedation or neuromuscular paralysis. In essence, the risk of neuromuscular weakness may be largely determined by the severity and duration of the underlying illness, whether it be sepsis syndrome or status asthmaticus. Nonetheless, to the extent that near-total muscle inactivity may contribute to myopathy, it is possible that risk of the latter might be decreased by maintaining as much muscle activity as is safely possible. A group of researchers recently found that mandated withdrawal of sedatives to determine ongoing need helped avoid oversedation and shortened the total time of mechanical ventilation, without increasing the risk of complications.106 It is possible that periods of sedation withdrawal could decrease the incidence of myopathy by permitting increased muscle activity, avoiding oversedation, and shortening the duration of ventilatory support. Finally, one large randomized study found that tight glycemic control improved overall outcome among surgical critically ill patients, including a significant reduction in the incidence of muscle weakness,107 suggesting an additional strategy for prevention of ICU-acquired neuromuscular weakness.