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Canadian Journal of Anesthesia 53:1148-1156 (2006)
© Canadian Anesthesiologists' Society, 2006
Neuroanesthesia and Intensive Care

Brief review: Nondepolarizing neuromuscular blocking drugs and critical illness myopathy

[Revue sommaire : les myorelaxants non dépolarisants et la myopathie de réanimation]

Michael J. Murray, MD PhD*, Sorin J. Brull, MD* and Charles F. Bolton, MD{dagger}

* From the Departments of Anesthesiology, Mayo Clinic Jacksonville, Jacksonville; and
{dagger} Neurology, Mayo Clinic Rochester, Minnesota, USA.

Address correspondence to: Dr. Michael J. Murray, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA. Phone: 904-296-5688; Fax: 904-296-3877; E-mail : murray.michael{at}mayo.edu


   Abstract
TOP
 Abstract
Introduction
 Clinical features
 Summary
 References
 
Purpose: Critically-ill patients who receive nondepolarizing neuromuscular blocking drugs (NMBDs) may be at risk of developing profound muscle weakness that may last for months after the NMBD is discontinued, especially when large cumulative doses of NMBDs and corticosteroids are co-administered to septic, mechanically ventilated patients. This review focuses on the etiology and clinical features of critical illness myopathy (CIM), summarizes specific risk factors for its development, and discusses strategies that might be used to attenuate or even prevent the development of this potentially devastating syndrome.

Clinical features: The etiology of CIM is unknown. Whether it can develop in at-risk patients who undergo lengthy operations during which they receive NMBDs is also unknown. In some patients following exposure to NMBDs their motor systems are impaired secondary to loss of thick (myosin) filaments that render the muscle unexcitable to direct electrical stimulation, while the sensory system is spared. Management of patients who develop NMBD myopathy is supportive, consisting of nutritional support, physical therapy, and daily trials of decreased ventilatory support.

Conclusion: Recent guidelines recommend that NMBDs be used in critically ill patients only when absolutely necessary, that the depth of muscle paralysis be monitored to avoid overdosing and metabolite accumulation, and that drug administration be curtailed periodically to allow interruption of sustained NMBD effect.


   Introduction
TOP
 Abstract
 Introduction
Clinical features
 Summary
 References
 
THE often devastating problem of neuromuscular dysfunction following a prolonged (> 28 days) critical illness has been well described previously.1 Muscle weakness, especially that involving the respiratory muscles, is a frequent finding in intensive care unit (ICU) patients and has particular implications in those patients who require mechanical ventilation. On one hand, weakness of respiratory muscles will require prolonged mechanical ventilation, while on the other hand, mechanical ventilation may itself contribute to impaired respiratory muscle function.2 There is increased awareness of the problem and increased recognition of the multiple etiologies that lead to weakness in patients who are critically ill.

Patients with systemic inflammatory response syndrome (SIRS), which often leads to multiple organ dysfunction syndrome (MODS), receive a variety of therapies including glucocorticoids, antibiotics, and neuromuscular blocking drugs (NMBDs). These drugs may interact with one another in a complex manner, and their side effects are increased by underlying illnesses. Muscle weakness is being reported in as many as 35% to 80% of ICU patients requiring prolonged mechanical ventilation3 and in approximately 70% of ICU patients with sepsis, with an overall mortality rate between 26% to 71%.4 Even amongst patients who survive a critical illness, but develop prolonged muscle weakness after nondepolarizing neuromuscular blockade to facilitate mechanical ventilation, the economic impact is significant: patients with post-ICU weakness have a significant increase in ICU and hospital length of stay, and incur disproportionate healthcare costs (in excess of $66,000 US per patient).5

Literature from the past decade is replete with reports of an association between critical illness and muscle weakness. There are many clinical scenarios that may contribute to muscle weakness including the use of NMBDs in the ICU to facilitate mechanical ventilation (leading to accumulation of NMBD metabolites), 6 critical illness polyneuropathy and myopathy which may be triggered by the patient’s immune response and tissue inflammation,3 and critical illness polyneuropathy (CIP) associated with sepsis.4,7 Other potential contributing factors include acute necrotizing myopathy of intensive care,8 the acute quadriplegic myopathy syndrome (AQMS) that may9 or may not be associated with administration of corticosteroids and/or NMBDs,10,11 Guillain-Barré syndrome,12 steroid-induced myopathy,13 or the deconditioning that follows prolonged bed rest (Table IGo). Bolton has very recently written an extensive review of the weakness that can also develop because of a neuropathy,14 a myopathy, or in some patients, because of a combined neuropathy and myopathy.


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  		TABLE I Differential diagnosis of neuromuscular complications in the ICU: arising de novo
 
Medical literature that spans over two decades describes the development of weakness following the use of NMBDs during mechanical ventilation.15 Despite this finding and the development of guidelines for the rational use of NMBDs in the critical care setting, administration of these drugs continues in up to 30% of ICU patients.16 Neuromuscular blocking drugs occasionally must be used to facilitate medical management, most commonly mechanical ventilation in patients with acute lung injury and acute respiratory distress syndrome, but they are also used in patients with tetanus and for patients in "hypothermia protocols" following cardiac arrest. Due to the difficulty in oxygenating such patients, unique modes of mechanical ventilation are often used, e.g., inverse ratio, highfrequency, or prone-position ventilation. Intensive care unit practice has changed in the last decade so that mechanically ventilated patients receive tidal volumes of 4 to 8 mL·kg–1, which frequently results in hypercapnia, leading to agitation, tachypnea, and ventilator asynchrony. To better coordinate the mode of ventilation with the patient, muscle paralysis with an NMBD may be achieved using an aminosteroidal or benzylisoquinolinium drug. Although intermittent bolus doses are occasionally used, prolonged need for relaxation (days) generally requires a continuous infusion of NMBDs. Once the lung injury and patient improve, the muscle relaxant infusion is stopped; however, over 50% of survivors will have motor deficits on clinical examination. When attempts are made to wean the patient from mechanical ventilation, up to 95% of these patients will have electromyographic evidence of chronic partial denervation that persists for years.1 This review will focus on the clinical features of one relatively common sequelae of critical illness, critical illness myopathy (CIM). This review will weigh and summarize specific risk factors, and discuss strategies that might be used to prevent or attenuate the development of this syndrome. We searched PubMed (National Library of Medicine in the United States) using the terms "myopathy," "muscle weakness," "weakness," "paralysis," "neuromuscular blocking drugs," and "intensive care units" for articles containing these terms in English. Thirty-six articles were retrieved and reviewed by us for new information on the etiology, pathophysiology, and therapy of CIM.


   Clinical features
TOP
 Abstract
 Introduction
 Clinical features
Summary
 References
 
Critical illness myopathy is known by many names such as AQMS, but CIM is preferred.8 The clinical setting is most helpful in establishing the diagnosis, but electromyography (EMG) and occasionally muscle biopsy and other laboratory tests are helpful. Electromyography demonstrates unexcitable muscle with markedly decreased or even absent compound muscle action potentials.17 Nerve conduction studies are normal, and there is no evidence of a sensory neuropathy. Muscle biopsy shows a selective thick (myosin) filament loss. Actin (thin myofilaments) and Z-discs are preserved,18 and nerve histology is normal. Denervated muscles of rats that have been treated with corticosteroids show similar pathology.18 Because of the muscle injury and necrosis, creatine phosphokinase blood concentrations are often profoundly elevated. There is no apparent predilection for bulbar weakness vs lower or upper extremity weakness.

The association between CIM and the use of NMBDs is controversial; two studies have not identified an association. In 2001, de Letter et al. studied 98 patients prospectively,19 using a multivariate analysis and found no significant relationship with the use of benzodiazepines, NMBDs, and corticosteroids. High APACHE III scores, coupled with SIRS, were significantly associated with the risk of developing CIM. In another study of 95 patients, De Jonghe et al. found that independent predictors of weakness in the ICU include female sex, the number of days with dysfunction of two or more organs, and the duration of mechanical ventilation. In their study, the authors also identified the administration of corticosteroids as having significant association with the development of weakness.20 However, Lacomis in 200221 and De Jonghe et al. in 200422 in more recent reviews of the literature, list NMBDs as risk factors for the development of prolonged weakness. Although initial reports of CIM implicated the use of aminosteroidal NMBDs (which have no glucocorticoid activity),6,15,23 benzylisoquinolinium compounds also have been associated with the development of CIM.24–28 Information presented to the Anesthesia Advisory Committee of the Food and Drug Administration in 1992,A which implicated aminosteroidal NMBDs, may have reflected the higher frequency with which aminosteroidal drugs were administered in the ICU, and not the true incidence of the syndrome nor the causative agents.27

Diagnosing CIM can be difficult because of the many possible and confounding causes of weakness in the ICU setting including neuropathies, other myopathies, neuromuscular diseases (myasthenia gravis, Guillain-Barré syndrome), electrolyte and acid-base abnormalities, use of corticosteroids, and immobilization atrophy (Table IIGo). Patients receiving corticosteroids, aminoglycoside antibiotics, and drugs that alter membrane depolarization (antiepileptics, antiarrhythmics) are at even higher risk for developing prolonged weakness. If these causes of weakness and other progressive neuromuscular diseases can be excluded, then the syndrome from which CIM most commonly must be differentiated is CIP, described initially by Charles Bolton.28 The latter syndrome is a polyneuropathy, seen more commonly in elderly patients with sepsis who develop SIRS or MODS (Figure 1Go).


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  		TABLE II
 

Figure 1
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  		FIGURE 1 The various factors associated with the development of the systemic inflammator y response syndrome (SIRS) and its ner vous system complications, septic encephalopathy, critical illness polyneuropathy, and other neuromuscular complications. (Reprinted with permission from: Bolton CF. Critical illness polyneuropathy. In: Thomas PK, Asbur y A (Eds): Peripheral Ner ve Disorders 2. Oxford: Butter worth-Heinemann; 1995: 262–70).

 
Critical illness polyneuropathy is an axonal degenerative process of motor and sensory fibres in which creatine phosphokinase levels are normal or only mildly elevated, and muscle biopsy reveals denervation atrophy. Early in the course of the disease, the EMG demonstrates a reduction of the compound muscle action potentials with minor changes in latency. Fibrillation potentials and positive sharp waves are common and rarely myotonic, and complex repetitive discharges appear, but not until two to three weeks later. In one study of 50 patients who were critically ill, 44% had signs of CIP, as evidenced by abnormal spontaneous muscle activity in more than one muscle group (due to muscle denervation).29 Motor unit potentials, if they can be voluntarily activated by the patient, will often appear normal or have slightly diminished amplitude and will be polyphasic, suggesting a primary involvement of muscle by SIRS. In contrast, in patients with CIM, the muscle is electrically unexcitable. Rich et al. have used direct muscle stimulation to differentiate between neuropathy and myopathy in critically ill patients.30 Using similar criteria, Latronico et al. examined 24 patients who had become quadriparetic or quadriplegic while in ICU.31 An axonal neuropathy was found in eight patients. The other 14 patients had received corticosteroids and NMBDs and, therefore, presumably had CIM.

Etiology
The etiology of CIM has not been established, although both pharmacokinetic and pharmacodynamic factors have been implicated. Of note, sepsis has been associated independently as a risk factor for CIM.11 With respect to pharmacokinetic factors, metabolites of the nondepolarizing NMBDs are most likely responsible for the persistent weakness seen in up to 70% of patients after prolonged administration of a NMBD.32 Segredo et al. studied 16 patients who had received prolonged infusions of vecuronium.6 They found that plasma concentrations of the 3- desacetylvecuronium metabolite were elevated, and likely accounted for the persistent weakness that was observed. This metabolite accumulation would not have been unexpected as the depth of neuromuscular block was not monitored routinely in the ICU setting. Because of the past relatively liberal use of NMBDs in the critical care setting, often in the presence of organ (renal, hepatic) failure, the conditions for significant accumulation of NMBDs were not uncommon.

Even when the depth of neuromuscular block is monitored routinely in the ICU setting CIM may occur independently from excess drug metabolite activity.33 Other potential contributing etiologic factors include abnormalities of the nicotinic receptor, the muscle membrane, and the myosin-actin complex. With respect to neuromuscular blocking receptor pathology, the acetylcholine (ACh) receptor, one of the most extensively studied receptors, is comprised of five protein units, two of which ({alpha}) have the same amino acid sequence. The two {alpha} subunits, and the single ß beta, gamma and delta subunits are arranged in a pentameter with a central channel (Figure 2Go). In the presence of chronic neuromuscular block, the concentration of the ACh receptors in the neuromuscular cleft is significantly up-regulated.34 However, although the absolute number of receptors is increased, many of these up-regulated receptors have a different composition, in which the gamma subunit is replaced by an epsilon subunit. These ‘juvenile receptors’ as they are known, are two- to threefold less responsive to ACh. However, during normal neuromuscular transmission, even juvenile receptors respond to ACh because ACh is released in very large quantities, high enough to overcome any resistance.


Figure 2
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  		FIGURE 2 Neuronal axon with ner ve terminal abutting a motor unit, the neuromuscular junction. The axon contains storage vesicles containing many millions of molecules of acetylcholine. In the neuromuscular cleft, literally hundreds of thousands of neuromuscular receptors, comprised of five proteins, two alpha, one beta, one gamma, and one epsilon unit. Acetylcholine induces a conformational change in the neuromuscular receptor that opens the ion channel, resulting in activation of the motor unit. In patients who are critically ill, compounds circulating in the blood stream, i.e., cytokines, may damage the neuron (leading to critical illness) polyneuropathy or the membrane, leading to a predisposition to damage caused by corticosteroids and neuromuscular blocking drugs. How the corticosteroids or neuromuscular blocking drugs destroy myosin is unknown, but some form of chemically-induced dener vation must exist. One theor y is that the neuromuscular blocking compounds close the ion channels, leading to a chemical denervation, and then a toxic event affecting the myosin leads to destruction. Reproduced with permission from the Mayo Foundation for Medical Education and Research.

 
This observation might help explain diminished muscle activity in response to nerve stimulation, but would not explain the myopathy associated with CIM. Therefore, abnormalities of the muscle membrane might also be partly responsible. Recently, Mauch et al. discovered that cholesterol plays an important role in the formation of synapses.35 There is a high concentration of cholesterol in the phospholipid membrane immediately surrounding the neuromuscular junction. 36 The membrane lipid cholesterol is capable of modulating the action of anesthetic drugs on sodium channels.37 It is thus possible that the aminosteroidal NMBD compounds are associated with an increased incidence of CIM because of the high concentration of cholesterol in the plasma membrane surrounding the neuromuscular junction. Neuromuscular blocking drugs are known to have other actions at the neuromuscular junction, including a possible effect on presynaptic exocytosis that might inhibit the release of ACh into the presynaptic cleft.38

Other factors may also play a role. Critical illness myopathy may have its highest incidence in patients with MODS receiving a combination of NMBDs and corticosteroids.23,27 Corticosteroid use, multi-organ dysfunction, prolonged duration of mechanical ventilation, and female gender are significant risk factors for the development of ICU-acquired paresis.20 Corticosteroids have been shown to induce myopathy through any one of at least three mechanisms. These drugs alter the electrical excitability of muscle fibres, decreasing their responsiveness to stimuli by inactivation of sodium channels,39 steroids induce loss of thick (myosin) filaments, decreasing the ability of the muscle fibres to contract; and steroids inhibit protein synthesis in the muscle, leading to an increased rate of muscle catabolism that results in loss of muscle strength.13 Corticosteroids also have an effect at the presynaptic and postsynaptic junction, decreasing the mini-end plate potentials that are constantly being elicited by leakage (tonic release) of ACh into the synapse.

Reports continue to ascribe an association between status asthmaticus, corticosteroid use, and CIM.13,40–42 Seven patients with CIM who had received highdose corticosteroids in combination with NMBDs of variable dosages and chronicity underwent muscle biopsy.43 The patients had a decrease in myofibrillar protein content, a partial or complete loss of myosin and myosin-associated proteins, a decrease in thick-filament to thin-filament protein ratios, absence of myosin messenger ribonucleic acid, and a decreased muscle cell force-generating capacity. Clinical improvement correlated with an increase in myosin-messenger ribonucleic acid. The authors concluded in a paper published in 2000 that the associated myopathy was due to several factors, amongst which corticosteroid use was predominant, an effect that was potentiated by NMBDs.43 In a retrospective study of 86 patients with asthma, the authors found that myopathy developed in nine of 30 (30%) patients who received NMBDs.44 In their multiple logistic regression model, the myopathy was significantly associated with the duration of muscle paralysis; the incidence increasing with each additional day of NMBD use.

For the reasons mentioned previously, corticosteroids can independently produce a profound myopathy. Furthermore, immobilization per se associated with NMBD use also can produce fibre atrophy.45 Corticosteroids may well potentiate the myopathy associated with NMBD use. Kindler et al.46 studied the effects of corticosteroids and vecuronium on adult ({alpha}2ß{delta}{varepsilon}) and fetal ({alpha}2ß {gamma}{delta}) nicotinic acetylcholine receptors (nAChR), which had been expressed in Xenopus laevis oocytes. Corticosteroids produced non-competitive antagonism of the nAChR. Vecuronium was even more potent in inhibiting the receptors through a competitive mechanism; the interaction nature of the two drugs was additive. The authors speculated that the combination may cause enhanced pharmacologic denervation which may lead to myopathy.46 As has long been suspected, patients receiving corticosteroids and NMBDs are at particularly high risk for development of CIM.

Another possible etiology of CIM is NMBDinduced channel block. Normally, NMBDs have an affinity for ACh receptors, typically binding to one of the two {alpha} subunit receptors. For normal neuromuscular transmission to occur, both of the {alpha} subunits must be bound by ACh; once ACh binding occurs, a conformational change in the receptor is induced, which results in opening (activation) of the central receptor channel, allowing ion (sodium and potassium) exchange and membrane depolarization. The binding of the NMBD to the {alpha} site prevents the normal binding of ACh to this subunit, rendering the receptor inactive. However, with long-term use of NMBDs, a receptor may be exposed to sufficiently high concentrations of NMBD for sufficient periods of time that the nicotinic ACh receptor number increases significantly (up-regulation),34 and true ion channel block does occur, requiring increased doses of NMBDs to maintain blockade.47

The role of SIRS in the development of CIM must also be considered. Certainly some patients in the operating room may undergo complete neuromuscular paralysis for many hours, even up to a day. Yet, reports of CIM in this subacute setting are rare. While the duration of muscle paralysis intraoperatively may be relatively short compared with the duration of neuromuscular block in ICU patients, CIM seems to develop preferentially in those patients who are critically ill (and who develop SIRS) and who are exposed to both NMBDs and corticosteroids. Systemic inflammatory response syndrome may contribute to myonecrosis and to a neuronal defect, leading to axonal damage and muscle denervation,8 while the elevated cytokines associated with SIRS may damage the muscle membrane allowing greater entry of NMBDs/corticosteroids into the sarcolemma.

Prevention of CIM
Several strategies have been used in patients at risk, with varying degrees of success. In one study of critically ill patients (that included patients with multiple trauma, sepsis, and multiple organ failure), the clinical investigators used a peripheral nerve stimulator to avoid overdosing of NMBDs, and adequate sedation and analgesia to decrease the depth of neuromuscular block. In this study of 60 critically-ill patients, none experienced prolonged paralysis, muscle weakness or other neuromuscular dysfunction after tracheal extubation. 48 Because sepsis may induce CIM,11 specific therapies to eliminate or decrease the incidence of nosocomial infections and, therefore, sepsis have been reported to be of major importance.7

Patients with severe asthma (or status asthmaticus) who require mechanical ventilation are at particular risk for CIM, because the usual treatment includes anti-inflammatory therapy with corticosteroids and NMBDs to facilitate mechanical ventilation. In this group of high-risk patients, low ventilator respiratory rates, long expiratory times, and small tidal volumes help to prevent lung hyperinflation, and the use of volatile anesthetics may produce bronchodilation in patients refractory to ß-agonists.49 Other investigators have found that even in ICU patients who required mechanical ventilation for management of severe asthma, lower-dose steroid therapy (< 400 mg·day–1 hydrocortisone), permissive hypercapnia, and mechanical ventilation with minimal paralysis achieved excellent therapeutic results.50 Finally, in patients who required muscle paralysis for mechanical ventilation, bolus administration of NMBDs was associated with less total drug administered, and recovery was faster in comparison with patients receiving a continuous infusion of the drug.51

Supportive care
Once the syndrome develops, the management of patients with CIM is supportive. These patients are typically very weak and, therefore, may remain ventilator-dependent for prolonged periods, independently of any intrinsic lung pathology. During this supportive period, care for CIM patients should follow the principles for any chronic, ventilator-dependent patient, consisting of nutritional support, physical therapy, and daily trials of decreased ventilatory support. The weaning and extubation criteria will depend mainly on the local ICU or respiratory care unit protocols.


   Summary
TOP
 Abstract
 Introduction
 Clinical features
 Summary
References
 
Critically ill patients who receive NMBDs for extended periods of time are at risk of developing profound motor weakness for hours to months after the NMBD is discontinued, especially if corticosteroids are coadministered. This weakness is clearly a motor system problem that spares the sensory system, and is most likely secondary to a loss of the thick filaments (myosin) in the muscle fibres. Because many of these patients may be septic or have SIRS or MODS, a polyneuropathy may coexist, in which case the patient may have critical illness polyneuropathy. The muscle is inexcitable even to direct electrical stimulation. The myopathy resolves over several days to months, generally without any apparent long-term sequelae.

The etiology of CIM is unknown but most likely multifactorial. Current guidelines from the American College of Critical Care Medicine52 recommend that ICU patients should receive NMBDs only when absolutely necessary, and particular care should be exercised when corticosteroid co-administration is necessary in these patients. The steroid doses should be minimized, and NMBDs should be discontinued as soon as clinical indications allow. Daily trials to manage the patient without NMBDss are warranted. If CIM develops, patients require supportive care. This syndrome should be suspected in any patient with weakness in an ICU setting who has received an NMBD for a prolonged period of time.


   Footnotes
 
Assessed September 15, 2005. Accepted for publication July 4, 2006. Revision accepted July 18, 2006.

Competing interests: None declared.

A U.S. Food and Drug Administration’s Center for Drug Evaluation and Research: Report of the Anesthetic and Life Support Drugs Advisory Committee Meeting. Rockville, MD, November 23, 1992 (202-234-4433). Back


   References
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 Abstract
 Introduction
 Clinical features
 Summary
 References
 
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