Crit Care Clin 18 (2002) 915 929

Neuromuscular disorders in the intensive care unit

William A. Marinelli, MD*, James W. Leatherman, MD
Division of Pulmonary and Critical Care Medicine, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415, USA Department of Medicine, University of Minnesota, USA

Neuromuscular disorders leading to intensive care unit (ICU) admission Respiratory muscle impairment is the most common reason for admission to the ICU in patients with neuromuscular disorders. Because significant respiratory muscle impairment may exist despite a paucity of symptoms, objective measures of respiratory muscle function are necessary. The most important respiratory muscle function parameters to be followed are maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), vital capacity (VC), and an assessment of oropharyngeal function [1 4]. The MIP and MEP are the most sensitive measures of respiratory muscle strength and should be closely monitored. Measurement of MIP and MEP requires patients to offer a maximal effort at residual volume (MIP) and total lung capacity (MEP) using a bedside manometer fitted with a mouthpiece. The normal values for MIP and MEP are approximately 70 cm H2O and 100 cm H2O, respectively, for women and 100 cm H2O and 150 cm H2O, respectively, for men [3]. Hypercapnia is common when the MIP is less than 20 cm H2O, and an effective cough is unlikely when the MEP is below 40 cm H2O. In the early stages of respiratory muscle weakness, the arterial blood gas and VC measurements are commonly normal. Adults are normally able to generate a VC of approximately 50 mL/kg; elimination of secretions with coughing is impaired when the VC declines to below 30 mL/kg. When serial measurements of VC reveal a decline below 15 to 20 mL/kg, there is increased likelihood that mechanical ventilatory support will be necessary [5]. The least recognized respiratory complication of neuromuscular weakness is loss of upper airway protection in the setting of bulbar muscle involvement [6]. Effective oropharyngeal function requires an intact musculature involving the mouth, phar* Corresponding author. Division of Pulmonary and Critical Care Medicine, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415, USA E-mail address: marin005@tc.umn.edu (W.A. Marinelli). 0749-0704/02/$ see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 4 9 - 0 7 0 4 ( 0 2 ) 0 0 0 2 0 - 9

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ynx, palate, tongue, and larynx [2]. The assessment of oropharyngeal function is primarily based on clinical observation, and early consultation with an experienced speech pathologist is recommended. ` Guillain-Barre syndrome ` The Guillain-Barre syndrome (GBS) is an acute inflammatory demyelinating polyneuropathy that seems to be more common in young adults and in elderly persons [5,6]. A preceding infectious syndrome with respiratory or gastrointestinal symptoms, usually occurring 2 to 4 weeks before the onset of neurologic symptoms, has been identified in approximately two thirds of patients [5]. Patients typically present with progressive, ascending weakness over days to weeks that is usually symmetrical and is accompanied by depressed or absent reflexes, with preservation of bowel and bladder function. Sensory symptoms are commonly noted; many patients complain of peripheral paresthesias. In addition, myalgias causing an aching discomfort in the lower back and legs are frequently noted in the early phase of the syndrome. Autonomic dysfunction is common in patients with GBS; approximately 50% of patients demonstrate brady- or tachyarrhythmias, orthostatic hypotension, hypertension, ileus, bladder dysfunction, and abnormal sweating. The diagnosis of GBS is based on the clinical presentation and on electrodiagnostic studies, with the latter showing features indicative of an acquired demyelinating polyneuropathy [5]. Early diagnosis of GBS may be difficult when the patient presents only with subtle peripheral paresthesias and variable complaints of back or leg discomfort. 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) [5]. The differential diagnosis includes (1) pontine infarction; (2) myelopathy, including epidural abscess, cord compression, and transverse myelitis; (3) peripheral nerve disorders, including diphtheria; (4) disorders of neuromuscular transmission, including myasthenia gravis (MG), Eaton-Lambert syndrome, botulism, tick paralysis, and organophosphate poisoning; and (5) myopathic disorders, with the principal concern for inflammatory myopathy (dermatomyositis/polymyositis) [5]. A rapidly progressive spinal lesion is the most important concern to be excluded in patients who present with ascending weakness and hyporeflexia [7]. Diagnoses other than GBS should be more aggressively considered if reflexes remain intact despite significant weakness, if the distribution of weakness shows significant asymmetry, or if the characteristic electrodiagnostic features are not observed [5]. Respiratory failure occurs in approximately 10% of patients at initial presentation and eventually develops in approximately 30% of patients during the course of the disease [5]. The progressive ascending weakness characteristic of GBS may impair all elements of effective respiration, including inspiratory strength, expiratory strength, and upper airway protection [6]. Although the mortality rate is significantly higher (up to 20%) in patients requiring mechanical ventilation, the functional outcome of ventilated patients who survive is high,

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with most patients regaining independent ambulation [8]. The dysautonomic state characteristic of GBS increases the risk of intubation by exaggerating the hypotensive response to sedative agents and markedly increasing the risk of arrhythmias, most commonly bradyarrhythmias [2]. The natural history of GBS is fairly predictable, with at least 90% of patients reaching the nadir of impairment by 4 weeks [6]. Most patients recover from the monophasic illness, with two thirds experiencing mild residual deficits and 10% to 20% of patients recovering completely. Between 3% and 8% of patients with GBS do not survive the illness. Pneumonia, acute respiratory distress syndrome, sepsis, pulmonary emboli, and cardiac arrest are the principal causes of death [5,9,10]. Treatment of GBS involves either plasmapheresis or intravenous immune globulin (IVIg). Three multicenter trials conducted in the 1980s showed that in GBS plasma exchange improves strength and reduces the incidence of respiratory failure requiring intubation and mechanical ventilation [5]. Albumin seems to be as effective as fresh frozen plasma as a replacement fluid during plasma exchange [11]. Two exchanges may be needed in patients with mild impairment, and four exchanges seem to result in a maximal response in those with more severe impairment [12]. Intravenous immune globulin has been shown to be an effective therapy in GBS [13]. A recent international, randomized, multicenter trial compared plasmapheresis, IVIg, or plasmapheresis followed by IVIg in 379 patients with marked weakness and with symptoms of 14 days or less [10]. This trial did not find significant differences among these three treatment groups in the duration of mechanical ventilation or in outcome at 4 weeks after therapy as assessed by a disability scale. Secondary outcome measures followed for up to 48 weeks were also similar among the treatment groups. The study concluded that IVIg and plasmapheresis are effective therapies with equal efficacy, and their combined use offers no additional benefit. Intravenous immune globulin is often preferred because of its ease of administration and acceptable side effect profile [14]. Screening for IgA deficiency is recommended before treatment with IVIg to reduce the risk of anaphylaxis during infusion. Although previously used as standard therapy, corticosteroids are not effective in patients with GBS [5,14]. MG MG is an autoimmune disorder of the neuromuscular junction transmission resulting from antibodies targeted to the acetylcholine receptor [15]. MG occurs most often in younger women or older men. Ptosis and diplopia caused by ocular muscle involvement are common at presentation. Bulbar muscle impairment with dysphonia and difficulty with chewing and swallowing may also be noted. Generalized weakness with fatigability involving trunk and extremity muscles is noted in approximately 85% of patients and may be the dominant complaint. Muscle fatigability with repetitive use and improvement in strength with rest are characteristics of MG. Respiratory muscle impairment typically presents with generalized muscle weakness; however, isolated involvement of the respiratory muscles may occur

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[4,16]. Bulbar muscle involvement leads to impaired swallowing and speech. Upper airway obstruction with abnormal adduction of vocal cords during inspiration has also been described [17]. Lower respiratory muscle impairment commonly presents with reductions in VC, MIP, and MEP. Approximately 15% to 27% of patients exhibit myasthenic crisis, a rapid and severe decline in respiratory muscle function, with a mortality rate of 4% to 13% [18,19]. Cardiac dysrhythmias are a common cause of death in patients with myasthenic crises. Multiple heterogeneous triggers for myasthenic crises have been identified; these triggers include infection, electrolyte abnormalities, withdrawal of anticholinesterase drugs, and the use of drugs that may impair neuromuscular transmission. Studies used to diagnose MG include a positive antiacetylcholinesterase test (transient improvement in strength after administration of edrophonium), presence of acetylcholine-receptor antibodies in serum, a decremental response in compound action potentials (CMAPs) to repetitive stimulation, and an electromyogram (EMG) indicative of a disorder of the neuromuscular junction [15]. Antiacetylcholinesterase antibodies are identified in approximately 85% of patients and in approximately 50% of patients with symptoms limited to ocular muscle involvement. One diagnostic strategy that has been recommended in patients with compatible clinical presentations begins with an edrophonium test, followed by a repetitive nerve stimulation test and measurement of acetylcholine receptor antibodies [15]. An EMG may be obtained if the diagnosis remains undefined. Disorders of neuromuscular transmission that may mimic MG include a myasthenic syndrome induced by penicillamine, organophosphate toxicity, EatonLambert syndrome, botulism, and tick paralysis [15]. Conditions associated with MG are thymic hyperplasia, thymoma, and autoimmune conditions, including rheumatoid arthritis, lupus, thyroiditis, and Graves disease [15]. The association with thymic abnormalities has led to the use of a chest computed tomographic (CT) scan or MR imaging as a screening tool in patients with MG. Treatment of MG centers on three general approaches: anticholinesterase medications that increase the concentration of acetylcholine available for receptor binding, immunosuppressive therapy, and thymectomy [15,20]. Treatment with an anticholinesterase agent, most commonly pyridostigmine, is the first line of therapy. The anticholinesterase medications may produce muscarinic side effects such as abdominal cramping, fasiculations, and increased oral secretions. Cholinergic crisis is an uncommon complication with these agents, typically presenting with increased bulbar and lower respiratory muscle weakness during the early phase of treatment. Distinguishing a cholinergic crisis from a myasthenic crisis may be difficult, and withholding anticholinesterase medications for 4 to 10 days may be necessary. Several options are available for immunosuppressive therapy in patients with MG [15]. Corticosteroids have been the most commonly used agents, resulting in a remission or marked improvement in approximately 75% of patients. Azathioprine has a more delayed onset of action, usually requiring at least 3 months of therapy and thereby limiting its use as a primary agent for initial therapy. Cyclosporine reduces acetylcholine receptor antibody production, but toxicity

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limits its use. Plasmapheresis and IVIg are commonly used for intensive shortterm immunosuppression [21,22]. Plasmapheresis 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. Intravenous immune globulin also results in a rapid improvement in most patients. Plasmapheresis should be the initial intervention in patients with myasthenic crisis, with IVIg reserved for possible use after a course of plasmapheresis [20]. Although adequate prospective studies are lacking, thymectomy seems to be associated with clinical improvement and remission and is generally recommended for patients with thymomas between the ages of puberty and approximately 60 years [15,20]. Thymectomy should not be performed as an emergency procedure in patients with significantly impaired ventilatory function (VC < 2 L), because postoperative decline in ventilatory function is common. Plasmapheresis should be considered preoperatively in patients with significant ventilatory impairment. Dermatomyositis and polymyositis (DM/PM) DM/PM are idiopathic inflammatory disorders which usually present with progressive symmetrical muscle weakness over several months. An acute presentation is occasionally seen [23]. Shoulder and pelvic girdle muscles are usually the major muscle groups affected in DM/PM. Although facial muscles are spared, neck flexion muscles are weakened in up to 50% of patients. Pharyngeal muscle involvement may present with dysphonia or dysphagia. Myalgias and muscle tenderness are less common than in other inflammatory myopathies, such as infection and drug-related myositis, but may occur in up to 50% of patients. Criteria for the diagnosis of idiopathic inflammatory myopathies include symmetrical proximal muscle weakness, elevated skeletal muscle enzymes, and compatible findings on electromyography and skeletal muscle biopsy [23,24]. In addition, patients with dermatomyositis demonstrate characteristic dermatologic findings, including heliotropic changes of the eyelids and Gottrons sign, a characteristic symmetrical erythematous rash over the extensor surfaces of metacarpophalangeal, interphalangeal, elbow, and knee joints. Elevated skeletal muscle enzymes, reflecting muscle inflammation, are the principal laboratory abnormalities found in DM/PM. Although creatine phosphokinase (CK) elevation is the most consistent indicator of muscle inflammation, other enzyme levels, aldolase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH), are also useful. 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. Cardiac and respiratory complications of DM/PM are the main concerns for an intensivist. Cardiac involvement presents with tachyarrhythmias, conduction abnormalities, or heart failure with a dilated cardiomyopathy. Chronic pulmonary hypertension may result from several mechanisms, including underlying cardio-

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myopathy, hypoxia associated with either chronic hypercapnic respiratory failure or interstitial lung disease, or the development of a primary pulmonary hypertension like syndrome [25]. Respiratory complications with DM/PM include abnormal central respiratory drive, pharyngeal muscle impairment, respiratory muscle weakness, interstitial disease, pneumonia caused by aspiration or therapy-related immunosuppression, and drug-induced lung disease [25]. The presence of dysphagia should suggest 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. An analysis of 70 patients with DM/PM and diffuse interstitial lung disease revealed an initial musculoskeletal presentation (myalgias, arthralgias, weakness) in 25 patients (36%), pulmonary presentation in 21 patients (30%), and a combination of musculoskeletal and pulmonary symptoms in 15 patients (21%) [26]. Treatment with corticosteroids in patients who initially present with diffuse interstitial lung disease may suppress or obscure musculoskeletal symptoms, thereby delaying the diagnosis of DM/PM for weeks to years [26]. In a recent study of 22 patients with interstitial lung disease and DM/PM who underwent surgical lung biopsy, four histologic patterns were identified: nonspecific interstitial pneumonitis (NSIP) in 18 (82%), organizing diffuse alveolar damage in 2, bronchiolitis obliterans organizing pneumonia (BOOP) in 1, and usual interstitial pneumonitis in 1 [26]. The clinical course of DM/PM is variable, ranging from a relatively indolent course to a relentlessly progressive process that is unresponsive to therapy. Fortunately, 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. Corticosteroid therapy is usually initiated at a dosage of 0.5 to 1.5 mg/kg of prednisone, with gradual tapering after a complete response has been demonstrated. In patients with pulmonary disease, the response to corticosteroid therapy is greatest in those with a more inflammatory process (eg, BOOP, NSIP, pulmonary capillaritis). Predictors of poor outcome in DM/PM include symptoms of greater than 6 months duration before diagnosis, severe symptoms, and the presence of dysphagia [27,28]. Methotrexate, azathioprine, or cyclophosphamide may be initially considered, along with corticosteroids in patients with poor prognostic markers. These drugs may also used when there is corticosteroid intolerance and for long-term maintenance therapy. Alternative agents have been used in the small subset of patients with symptoms unresponsive to standard therapy. These agents include intravenous immune globulin, cyclosporine, tacrolimus, alkylating agents, and tumor necrosis factor inhibitors. Intravenous immune globulin has been recently reported to be beneficial in the management of life-threatening esophageal involvement in DM/PM [29]. 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. Cardiac complications are managed with appropriate pharmacologic therapy and insertion of a pacemaker or implantable defibrillator when necessary.

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Neuromuscular weakness acquired in the ICU Neuromuscular weakness that is acquired in the ICU has been increasingly recognized as a major cause of morbidity for survivors of critical illness [30]. Although reversible, ICU-acquired muscle weakness often markedly prolongs the total duration of hospitalization and subsequent care, because of the need for physical rehabilitation and the patient s inability to perform even the most basic activities of daily living. If respiratory muscles are affected, the duration of mechanical ventilation may also be prolonged, increasing the risk for ventilatorrelated pneumonia. The economic cost attributable to ICU acquired muscle weakness is unknown but is likely to be substantial. Perhaps of greater importance, the psychologic and emotional cost to patients and their families may be considerable. Although there may be an initial sense of relief when the patient survives the critical illness, this relief is typically followed by considerable frustration over the patients nearly total dependence on others for simple tasks of daily living. The medical, economic, and psychosocial costs of neuromuscular weakness acquired in the ICU represent a major problem in the present practice of critical care medicine. Three basic causes of acquired neuromuscular weakness in the ICU have been identified: (1) a sensorimotor polyneuropathy, ( 2) an acute myopathy, and (3) persistent blockade of the neuromuscular junction [31 33]. Residual blockade of the neuromuscular junction after discontinuation of a neuromuscular blocking agent (NMBA) is rarely responsible for persistent neuromuscular weakness in the ICU. Recovery from paralysis almost always occurs within hours of discontinuing the commonly used NMBAs, with the exception of vecuronium administration in renal failure [33]. Therefore, ICU acquired muscle weakness is nearly always caused by a sensorimotor polyneuropathy or by acute myopathy. Critical-illness polyneuropathy In 1984, and later in 1987, Bolton and colleagues described a group of critically ill patients who developed neuromuscular weakness that was attributed to an acquired sensorimotor polyneruopathy [31,34]. Affected patients typically underwent neurologic evaluation because of difficulty in weaning from mechanical ventilation or because of evidence of diffuse limb weakness at bedside examination. Muscle weakness was generally noted only after several weeks in the ICU but could have been present earlier. Clinical evaluation revealed weakness that was typically diffuse and often severe, with distal muscles usually affected most prominently. Although detailed investigations of respiratory muscles were not undertaken, in several cases respiratory muscle involvement was believed to be a major factor in difficulty in weaning from the ventilator. Sensory examination was difficult to perform, but deep tendon reflexes were either reduced or absent in most cases. Cranial nerves did not seem to be involved [31,34]. A diagnosis of polyneuropathy as the cause of muscle weakness was based primarily on electrophysiologic studies [31,34]. The cardinal findings included

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a reduction in both compound muscle and sensory nerve action potentials and both spontaneous fibrillations and positive sharp waves on needle electromyography, with the latter findings being attributed to denervation. In two patients with severe neuropathy, compound muscle action potentials (CMAPs) of the diaphragm were absent bilaterally. Serial studies of 14 patients showed improved electrophysiologic findings that paralleled clinical recovery, as evidenced by increased limb strength, return of deep tendon reflexes, and weaning from the ventilator. Improvement was often documented several months after the initial study and became normal 6 months to a year after diagnosis, even in cases of severe neuropathy. Again, these findings paralleled the prolonged time required for resolution of weakness in those patients who survived the initial critical illness [34]. Histopathologic changes in peripheral nerves were documented at autopsy in several cases [34]. The key findings were axonal degeneration with loss of myelin in peripheral nerves and grouped fiber atrophy in skeletal muscle, with the latter finding again being attributed to denervation. Distal nerve segments were affected most severely. There was no evidence for inflammation in either nerves or muscles [34]. The pathogenetic mechanism responsible for acquired polyneuropathy in critical illness is not understood. In the studies of Bolton and colleagues, affected patients had clinical sepsis with multiorgan dysfunction [31,34]. It is generally believed that the peripheral nervous system may represent one of the many target sites for tissue damage that occurs in the setting of sepsis with the systemic inflammatory response syndrome (SIRS). It has been postulated that the lack of effective vascular autoregulation and increased microvascular permeability during the period of clinical sepsis could result in neural edema and capillary occlusion, thereby damaging peripheral nerves [31,35]. As with other types of organ dysfunction in SIRS, it is believed that neuronal injury might be cytokinemediated [35]. Myopathy acquired in the ICU (critical-illness myopathy) Severe myopathy acquired in the ICU was first reported 25 years ago [36]. Numerous individual case reports and case series have been published subsequently [37 39]. In most reported cases, acute myopathy has occurred in patients receiving mechanical ventilation for severe airflow obstruction. Affected individuals typically have been treated with corticosteroids and NMBAs, but myopathy has also been documented in patients with airflow obstruction without paralysis who received corticosteroids and in critically ill patients with sepsis who received neither corticosteroids nor NMBAs [32,40 43]. Numerous terms have been used to designate the acute myopathy acquired in the ICU, usually reflecting the suspected underlying cause or certain clinical or pathologic features. Some of the appellations that have been applied to this entity include acute corticosteroid (or hydrocortisone) myopathy, acute corticosteroid and pancuronium associated myopathy, acute neuromyopathy of intensive care, thick filament myopathy, and

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acute quadriplegic myopathy. The last term reflects the profound degree of muscle weakness that is often seen. Some authors have attempted to subdivide the acute myopathy that develops in the ICU into critical-illness myopathy associated with hypercatabolic (generally septic) states, thick filament myopathy related to use of corticosteroids and (usually) NMBAs, and necrotizing myopathy characterized by prominent myonecrosis [32]. It is not clear that these are really distinct entities, and there is considerable overlap in the clinical, electrophysiologic, and pathologic features of the myopathy that is seen in the setting of sepsis with SIRS and in patients treated with corticosteroids and NMBAs. A recent editorial suggested the term criticalillness myopathy be used as the sole descriptor for all instances of ICU acquired myopathy [44]. The diagnosis of acute myopathy has been based primarily on EMG findings, although some patients also underwent muscle biopsy. Typical findings on EMG included the presence of an abundance of low-amplitude, short-duration polyphasic units with early recruitment. Fibrillation potentials and positive sharp waves are found in most, but not all, cases [45]. In keeping with a myopathic origin of weakness, sensory nerve conduction studies are either normal or minimally diminished. Evoked motor responses are almost always obtainable, with motor CMAP amplitudes being either normal or decreased, and nerve conduction velocities and latencies being normal [45]. Pathologic findings in acute myopathy have been variable. Fiber atrophy and vacuolization are common, but there is no inflammation [32]. Necrosis is generally minimal or absent but on occasion may be severe [32]. Electron microscopy may reveal selective loss of myosin, with relative sparing of actin and Z bands [32]. As noted earlier, most published reports of acute acquired myopathy in the ICU have focused on patients with status asthmaticus. The pathogenesis of myopathy in status asthmaticus is not fully understood, but certain factors are present in almost all cases. In keeping with standard treatment of status asthmaticus, all affected individuals have been treated with corticosteroids. It is clear, however, that corticosteroids alone are not the sole factor responsible for the development of acute myopathy in status asthmaticus. Almost all hospitalized patients with acute asthma receive corticosteroids, but only those who undergo mechanical ventilation seem to be at risk for myopathy. Furthermore, in almost all instances, affected patients had undergone neuromuscular paralysis to facilitate mechanical ventilation, usually for several days [37 39]. Thus it has been suggested that the use of systemic corticosteroids combined with prolonged exposure to NMBAs is the key risk factor for acute myopathy in status asthmaticus. A prospective study found a striking relationship between number of days of paralysis and the incidence of myopathy but no relationship between myopathy and numerous other factors, such as the dose of corticosteroids, degree of hypercapnia, or electrolyte disturbance [37]. All patients in this study received vecuronium, a NMBA that contains a steroid nucleus, leading to speculation that the chemical structure of the NMBA could influence the risk of myopathy.

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A subsequent report, however, found that the incidence of myopathy is similar whether atracurium, a nonsteroidal NMBA, or vecuronium was used, indicating that the type of paralytic agent is probably not relevant [38]. This latter report, a retrospective analysis of risk factors for myopathy, did suggest that duration of paralysis is a critical factor in development of myopathy, because none of the patients who received sedation without paralysis developed myopathy, and the risk of myopathy was minimal in those who were paralyzed for less than 24 hours [38]. These reports and numerous additional publications suggest that, in mechanically ventilated patients with status asthmaticus who are of necessity being treated with corticosteroids, the risk of developing acute myopathy can be minimized by employing only minimal exposure to NMBA (or even better, a complete avoidance of paralysis). This concept, although reasonable and consistent with published literature, was nonetheless based almost entirely on retrospective observational data. In the single prospective study of myopathy in status asthmaticus, patients were uniformly paralyzed [37]. More recently, myopathy has been reported in mechanically ventilated patients with airflow obstruction who received sedation without paralysis [41]. Furthermore, the authors unpublished clinical experience over the past few years has included a number of patients who developed severe myopathy despite minimal or no exposure to NMBAs. Therefore, although prolonged paralysis clearly seems to increase the risk of myopathy in status asthmaticus, simply avoiding the use of NMBAs in this setting does not seem to eliminate the risk of neuromuscular weakness completely. Although prolonged neuromuscular paralysis may not be the sine qua non for the development of acute myopathy in corticosteroid-treated patients who undergo mechanical ventilation for status asthmaticus, there is little doubt that it markedly increases risk for this complication. When patients undergo neuromuscular paralysis, an interruption of neuromuscular transmission leads to pharmacologic denervation of skeletal muscles. This denervation of necessity leads to total muscle inactivity. A critical question is whether it is the loss of neuromuscular transmission per se or the subsequent muscle inactivity that places the muscle at risk of injury when exposed to corticosteroids. Although this issue is difficult to resolve based on current data, the previously mentioned occurrence of severe myopathy in some mechanically ventilated asthmatic patients who were deeply sedated, but exposed to only minimal or no paralysis, suggests that prolonged nearly total muscle inactivity may be the key risk factor for myopathy in corticosteroid-treated patients [32]. The apparent lesser risk associated with sedation alone could be explained because, in the absence of paralysis, there is at least the possibility for some muscle activity, but no activity is possible with use of NMBAs. Prolonged deep sedation to the point of complete absence of any movement, even during routine procedures as suctioning or turning, could possibly be associated with a risk of myopathy that approaches that of prolonged paralysis. This suggestion is admittedly speculative, and clarification of this important issue can be firmly answered only by a prospective study that would

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randomly assign corticosteroid-treated patients with severe airflow obstruction to either deep sedation alone or sedation plus paralysis. Animal studies conducted during the 1980s that explored the myotoxic effects of corticosteroids, although designed primarily to investigate chronic corticosteroid-induced myopathy, may have relevance to the problem of acute myopathy that occurs in the setting of status asthmaticus. One study found that the number of cytosolic corticosteroid receptors increases markedly after surgical denervation [46]. Interestingly, similar results were obtained when the muscle was immobilized by casting and pinning rather than by denervation [47], a finding consistent with the concept that muscle inactivity rather than denervation per se could be the key risk factor for acute myopathy. Other studies also explored the effects of corticosteroids and denervation on skeletal muscle. One elegant study found that absolute twitch amplitude of skeletal muscle was minimally affected when animals underwent denervation alone or were exposed only to corticosteroids, but it was markedly diminished when corticosteroids and denervation were combined [48]. Similarly, ultrastructural studies and biochemical evaluation showed that animals that received corticosteroids and denervation had a dramatic reduction in myosin (thick filament) without a significant change in actin (thin filament) content [48]. In contrast, myosinolysis was minimal in animals treated with either corticosteroids or denervation alone. As mentioned earlier, this selective loss of myosin a highly unusual abnormality in the myopathies has been described in humans who developed acute myopathy after exposure to corticosteroids and prolonged paralysis and in the setting of myopathy associated with septic critical illness [41,49 52]. The acute myopathy that occurs in the setting of septic, hypercatabolic critical illness is similar in many respects to the myopathy associated with mechanical ventilation for status asthmaticus, including the finding of selective myosin loss in skeletal muscle. Although not clearly reported in the published reports, it is likely that individuals with myopathy associated with severe sepsis were sedated and had minimal muscle activity for prolonged periods of time, as would be expected in the course of sepsis with multiorgan failure. Although admittedly speculative, it is possible that circulating cytokines, or even endogenous release of corticosteroids during the stress response to critical illness, could have effects on inactive skeletal muscle similar to those of exogenous corticosteroids. A basic question regarding acute myopathy relates to the actual mechanism of muscle weakness. Commonly, affected patients have a nearly quadriplegic degree of muscle weakness that cannot be explained by muscle atrophy. In addition, although muscle architecture is abnormal, widespread muscle necrosis is atypical, as evidenced by findings on muscle biopsy and by only modestly elevated or even normal serum CK levels [32]. Furthermore, some patients require many weeks for recovery, but others have a remarkably rapid improvement in muscle strength and may go from a state of nearly quadriplegic weakness to ambulation within 10 to 14 days [45]. This latter paradox could not be readily explained if the cause of weakness was massive disruption of the muscle intrinsic contractile apparatus.

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Temporary muscle inexcitibility has been proposed as an alternative mechanism for the often profound weakness seen in acute ICU acquired myopathy. In a study of patients who developed myopathy related to corticosteroids and neuromuscular paralysis, Rich and colleagues found that they were unable to induce an action potential even when the muscle was stimulated directly [53]. Subsequently, the muscle regained its ability to generate an action potential on stimulation, paralleling clinical recovery. In a later study, the same investigators found similar inability to induce an action potential in a heterogeneous group of patients with ICU acquired weakness, including a number of patients who were septic and had not received corticosteroids or NMBAs [42]. The investigators suggested that using direct muscle stimulation to differentiate myogenic from neurogenic muscle weakness might be especially applicable to the investigation of severe weakness in the ICU, because the stimulation can be used even in the setting of coma or deep sedation [42]. In contrast, the standard EMG may be unable to differentiate myopathy and neuropathy when patients are unable to attempt voluntary muscle contractions. In this regard, a recent prospective study used a variety of techniques, including direct muscle stimulation, quantitative electromyography, and motor unit number estimation, to investigate the cause of muscle weakness in a heterogeneous group of 22 critically ill patients, including many with sepsis and multiorgan failure [54]. A myopathy was diagnosed in all patients, and the results of muscle biopsy performed in 9 of these individuals were also uniformly consistent with myopathy. In contrast, only 1 patient had evidence of a concurrent neuropathy. The authors concluded that myopathy is far more common than neuropathy as a cause of muscle weakness in the ICU, raising the question of whether a number of cases diagnosed as critical-illness polyneuropathy by standard electrophysiologic studies may in fact have had an underlying myopathy. There is no specific treatment for ICU acquired muscle weakness other than physical rehabilitation. Unfortunately, it may not be possible to prevent this complication in patients with severe sepsis and multiorgan failure or with severe, protracted status asthmaticus that requires use of corticosteroids and either prolonged deep sedation or neuromuscular paralysis. In essence, the risk of myopathy may be largely determined by the severity and duration of the underlying illness, whether it is sepsis syndrome or status asthmaticus. Nonetheless, to the extent that nearly total muscle inactivity contributes to myopathy, it may be possible to mitigate to some degree the risk and severity of muscle injury by permitting as much muscle activity as can be done safely. In this regard, a recent study found that mandated withdrawal of sedatives to determine ongoing need helped avoid oversedation and shortened total time of mechanical ventilation, without increasing the risk of complications [55]. Although such an approach may not be appropriate for all patients, and the potential risk of inadequate sedation must be considered on an individual basis, mandated periods of sedation withdrawal might decrease risk of myopathy by permitting increased muscle activity, avoiding oversedation, and shortening the duration of ventilatory support. Whether such an approach would materially decrease the incidence of

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ICU acquired muscle weakness is, of course, unknown and can be answered definitively only by a prospective investigation.

References
[1] Rochester DF, Esau SA. Assessment of ventilatory function inpatients with neuromuscular disease. Clin Chest Med 1994;15:751 63. ` [2] Teitelbaum JS, Borel CE. Respiratory dysfunction in Guillain-Barre syndrome. Clin Chest Med 1994;15:705 14. [3] Ward NS, Hill NS. Pulmonary function testing in neuromuscular disease. Clin Chest Med 2001; 22:769 81. [4] Zulueta JJ, Fanburg BL. Respiratory dysfunction in myasthenia gravis. Clin Chest Med 1994; 15:683 91. ` [5] Ropper AH. The Guillain Barre syndrome. N Engl J Med 1992;326:1130 6. ` [6] Fulgham JR, Wijdicks EFM. Guillain Barre syndrome. Crit Care Clin 1997;13:1 15. ` [7] Bleck TP. Treatment strategies for patients with Guillain Barre syndrome. Crit Care Med 1993; 21:641 3. ` [8] Fletcher DD, Lawn ND, Wolter TD, et al. Long term outcome in patients with Guillain Barre syndrome requiring mechanical ventilation. Neurology 2000;54:2311 5. ` [9] Lawn ND, Wijdicks EFM. Fatal Guillain Barre syndrome. Neurology 1999;52:635 8. ` [10] Plasma Exchange/Sandoglobulin Guillain Barre Syndrome Trial Group. Randomized trial of ` plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain Barre syndrome. Lancet 1997;349:225 30. ` [11] Bouget J, Chevret S, Chastang C, et al. Plasma exchange morbidity in Guillain Barre syndrome: results from the French prospective, double blind, randomized, multicenter study. Crit Care Med 1993;21:651 8. ` [12] Raphael JC, Chevret S, Auriant I, et al. Treatment of adult Guillain Barre syndrome: indications for plasma exchange. Transfus Sci 1999;20:53 61. ` ` [13] van der Merche FGA, Schmitz PIM, and the Dutch Guillain Barre Study Group. A random` ized trial comparing intravenous immune globulin and plasma exchange in Guillain Barre syndrome. N Engl J Med 1992;326:1123 9. ` [14] Lindenbaum Y, Kissel JT, Mendell JR. Treatment approaches for Guillain Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Neurol Clin 2001;19:187 204. [15] Drachman DB. Myasthenia gravis. N Engl J Med 1994;330:1797 810. [16] Dushay KM, Zibrak JD, Jensen WA. Myasthenia gravis presenting as isolated respiratory failure. Chest 1990;97:232 4. [17] Putman MT, Wise RA. Myasthemia gravis and upper airway obstruction. Chest 1996;109: 400 4. [18] Berrouschot J, Baumann I, Kalischewski P, et al. Therapy of myasthenia gravis. Crit Care Med 1997;25:1228 35. [19] Thomas CE, Mayer SA, Gungor Y, et al. Myasthenic crisis: clinical features, mortality, complications, and risk factors for prolonged intubation. Neurology 1997;48:1253 60. [20] Younger DS, Raksdawan N. Therapy in neuromuscular disease. Neurol Clin 2001;19:205 15. [21] Gajdos P, Chevret S, Clair B, et al. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Ann Neurol 1997;41:789 96. [22] Qureshi AI, Choudhry MA, Akbar MS, et al. Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis. Neurology 1999;52:629 32. [23] Dalakas MC. Polymyositis, dermatomyositis, and inclusion-body myositis. N Engl J Med 1991; 325:1487 98. [24] Tymms KE, Webb J. Dermatopolymyositis and other connective tissue diseases. A review of 105 cases. J Rheumatol 1985;12:1140 8.

928

W.A. Marinelli, J.W. Leatherman / Crit Care Clin 18 (2002) 915929

[25] Schwartz M. The lung in polymyositis. Clin Chest Med 1998;19:701 12. [26] Douglas WW, Tazelaar HD, Hartman TE, et al. Polymyositis dermatomyositis associated interstitial lung disease. Am J Respir Crit Care Med 2001;164:1182 5. [27] Fafalak RG, Peterson MGE, Kagen LJ. Strength in polymyositis and dermatomyositis: best outcome in patients treated early. J Rheumatol 1994;21:643 8. [28] Joffe MM, Love LA, Leff R, et al. Drug therapy of idiopathic inflammatory myopathies: predictors of response to prednisone, azathioprine and methotrexate and a comparison of their efficacy. Am J Med 1993;94:379 87. [29] Marie I, Hachulla E, Leveesque H, et al. Intravenous immunoglobulins as treatment of life threatening esophageal involvement in polymyositis and dermatomyositis. J Rheumatol 1999; 26:2706 9. [30] Hund E. Neurological complications of sepsis: critical illness polyneuropathy and myopathy. J Neurol 2001;248(11):929 34. [31] Bolton CF, Gilbert JJ, Hahn AF, et al. Polyneuropathy in critically ill patients. J Neurol Neurosurg Psychiatry 1984;47:1223 31. [32] Hund E. Myopathy in critically ill patients. Crit Care Med 1999;27(11):2544 7. [33] Segredo V, Caldwell JE, Matthay MA, et al. Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med 1992;327(8):524 8. [34] Zochodne DW, Bolton CF, Wells GA, et al. Critical illness polyneuropathy. A complication of sepsis and multiple organ failure. Brain 1987;110:819 41. [35] Bolton CF, Young GB, Zochodne DW. The neurological complications of sepsis. Ann Neurol 1993;33(1):94 100. [36] MacFarlane I, Rosenthal F. Severe myopathy after status asthmaticus. Lancet 1977;ii:615. [37] Douglass J, Tuxen D, Horne M, et al. Myopathy in severe asthma. American Review of Respiratory Disease 1992;146:517 9. [38] Leatherman J, Fluegel W, David W, et al. Muscle weakness in mechanically ventilated patients with severe asthma. Am J Respir Crit Care Med 1996;153:1686 90. [39] Shapiro JM, Condos R, Cole RP. Myopathy in status asthmaticus: relation to neuromuscular blockade and corticosteroid administration. J Intens Care Med 1993;8(3):144 52. [40] Deconinck N, Van Parijs V, Beckers-Bleukx G, et al. Critical illness myopathy unrelated to corticosteroids or neuromuscular blocking agents. Neuromuscul Disord 1998;8(3 4):186 92. [41] Hanson P, Dive A, Brucher J-M, et al. Acute corticosteroid myopathy in intensive care patients. Muscle Nerve 1997;20:1371 80. [42] Rich MM, Bird S, Raps EC, et al. Direct muscle stimulation in acute quadriplegic myopathy. Muscle Nerve 1997;20:665 73. [43] Williams T, OHehr R, Czarny D, et al. Acute myopathy in severe acute asthma treated with intravenously administered corticosteroids. American Review of Respiratory Disease 1988;137: 460 3. [44] Lacomis D, Zochodne DW, Bird SJ. Critical illness myopathy. Muscle Nerve 2000;23(12): 1785 8. [45] David WS, Roehr CL, Leatherman JW. EMG findings in acute myopathy with status asthmaticus, steroids and paralytics. Clinical and electrophysiologic correlation. Electromyogr Clin Neurophysiol 1998;38(6):371 6. [46] Dubois DC, Almon RR. A possible role for glucocorticoids in denervation atrophy. Muscle Nerve 1981;4:370 3. [47] Dubois DC, Almon RR. Disuse atrophy of skeletal muscle is associated with an increase in number of glucocorticoid receptors. Endocrinology 1980;XX:1649 51. [48] Rouleau G, Karpati G, Carpenter S, et al. Glucocorticoid excess induces preferential depletion of myosin in denervated skeletal muscle fibres. Muscle Nerve 1987;10:428 38. [49] Al-lozi MT, Pestronk A, Yee WC, et al. Rapidly evolving myopathy with myosin-deficient muscle fibers. Ann Neurol 1994;35:275 9. [50] Danon MJ, Carpenter S. Myopathy with thick filament (myosin) loss following prolonged paralysis with vecuronium during steroid treatment. Muscle Nerve 1991;14:1131 9.

W.A. Marinelli, J.W. Leatherman / Crit Care Clin 18 (2002) 915929

929

[51] Sher JH, Shafiq SA, Schutta HS. Acute myopathy with selective lysis of myosin filaments. Neurology 1979;29:100 6. [52] Waclazwik AJ, Sufit RL, Beinlich BR, et al. Acute myopathy with selective degeneration of myosin filaments following status asthmaticus treated with methylprednisolone and vecuronium. Neuromuscul Disord 1992;2:19 26. [53] Rich M, Teener J, Raps E, et al. Muscle is electrically unexcitable in acute quadriplegic myopathy. Neurology 1996;46:731 6. [54] Trojaborg W, Weimer LH, Hays AP. Electrophysiologic studies in critical illness associated weakness: myopathy orneuropathya reappraisal. Clin Neurophysiol 2001;112(9):1586 93. [55] Kress JP, Pohlman AS, OConnor MF, et al. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000;342(20):1471 7.