Approach to neuromuscular disorders in the intensive care unit

Neuromuscular disorders increasingly are recognized as a complication in patients in the intensive care unit (ICU) and represent a common cause of prolonged ventilator dependency. The distinct syndromes of critical illness myopathy, prolonged neuromuscular blockade, and critical illness polyneuropathy (CIP) may arise as a consequence of sepsis, multi-organ failure, and exposure to various medications—notably, intravenous corticosteroids and neuromuscular blocking agents—but the pathophysiology of these disorders remains poorly understood. More than one syndrome may occur simultaneously, and the distinctions may be difficult in a particular patient, but a specific diagnosis usually can be established after careful clinical, electrodiagnostic, and, when necessary, histological evaluation. For example, asthmatics requiring treatment with corticosteroids and neuromuscular blocking agents may develop an acute myopathy characterized by generalized weakness, preserved eye movements, elevated creatine kinase levels, and myopathic motor units on electromyography (EMG). Muscle biopsy demonstrates distinctive features of thick (myosin) filament loss on ultrastructural studies. Conversely, those with a prolonged ICU course that is complicated by episodes of sepsis with failure to wean from the ventilator, distal or generalized flaccid limb weakness, and areflexia probably have CIP. EMG in these patients demonstrates reduced or absent motor and sensory potentials with neurogenic motor units. Prolonged neuromuscular blockade most commonly occurs in patients with renal failure who have received prolonged infusions of neuromuscular blockers. There is severe flaccid, areflexic paralysis with normal sensation, facial weakness, and ophthalmoparesis that persists for days or weeks after the neuromuscular blockers have been discontinued. Repetitive nerve stimulation shows a decrement of the compound muscle action potential and, in most cases, establishes a disorder of neuromuscular transmission. With the recent epidemic of West Nile virus infection, a clinical syndrome of acute flaccid paralysis with several features indistinguishable from poliomyelitis has emerged. This article critically examines the clinical, electrophysiological, and pathological features of these and other acute neuromuscular syndromes that arise in the context of ICU care and summarizes the current understanding of the pathophysiology and treatment of these disorders.     

Neuromuscular manifestations of critical illness

Critical illness, more precisely defined as the systemic inflammatory response syndrome (SIRS), occurs in 20%-50% of patients who have been on mechanical ventilation for more than 1 week in an intensive care unit. Critical illness polyneuropathy (CIP) and myopathy (CIM), singly or in combination, occur commonly in these patients and present as limb weakness and difficulty in weaning from the ventilator. Critical illness myopathy can be subdivided into thick-filament (myosin) loss, cachectic myopathy, acute rhabdomyolysis, and acute necrotizing myopathy of intensive care. SIRS is the predominant underlying factor in CIP and is likely a factor in CIM even though the effects of neuromuscular blocking agents and steroids predominate in CIM. Identification and characterization of the polyneuropathy and myopathy depend upon neurological examination, electrophysiological studies, measurement of serum creatine kinase, and, if features suggest a myopathy, muscle biopsy. The information is valuable in deciding treatment and prognosis.     

Weakness on the intensive care unit

Patients who are recovering from critical illness may be weak and difficult to wean from ventilatory support as a complication of their underlying disorder, intercurrent events or treatment given during prolonged intensive care. These patients are difficult to assess because of the severity of their weakness and any accompanying encephalopathy. It is essential to undertake a meticulous review, including assessment of any septic, hypoxic or metabolic derangements and a detailed look at the dosage and duration of medication including antibiotics, neuromuscular junction blocking agents and sedation. If a primary underlying neurological cause or an intercurrent event have been excluded, the likeliest cause of weakness is one of the neuromuscular complications of critical care such as: critical care polyneuropathy, an acute axonal neuropathy which develops in patients with preceding sepsis or multi-organ failure; the use of neuromuscular junction blocking agents or steroids; and critical illness myopathy, which is the most common cause of critical care related weakness.     

Critical illness myopathy and polyneuropathy

Neuromuscular weakness commonly develops in the setting of critical illness. This weakness delays recovery and often causes prolonged ventilator dependence. An axonal sensory-motor polyneuropathy, critical illness polyneuropathy (CIP), is seen in up to one third of critically ill patients with the systemic inflammatory response syndrome (usually due to sepsis). An acute myopathy, critical illness myopathy (CIM), frequently develops in a similar setting, often in association with the use of corticosteroids and/or nondepolarizing neuromuscular blocking agents. These patients are often difficult to evaluate due to the limitations imposed by the critical care setting and may be further complicated by the presence of both CIP and CIM in varying degrees. This paper reviews the clinical and electrophysiologic features of these disorders, as well as the putative pathophysiology. In the case of CIM, an animal model has provided evidence that weakness in this disorder is caused by muscle membrane inexcitability due to altered membrane sodium currents and loss of myosin thick filaments.     

Neuromuscular disease and respiratory failure

Neurologists should be able to anticipate and recognise the onset of respiratory failure in patients with neuromuscular disorders. Symptoms will differ depending on the speed of onset of the respiratory muscle weakness. Careful monitoring of respiratory function is particularly important in acute disorders such as Guillain-Barré syndrome. Patients with an unrecognised neuromuscular disorder may occasionally present with respiratory failure. Important investigations include vital capacity, mouth pressures, arterial blood gases, chest x ray and sometimes overnight respiratory monitoring. Patients with Guillain-Barré and other acute conditions may require short-term ventilatory support in the intensive care unit. Patients with some chronic disorders, such as motor neuron disease and Duchenne dystrophy, can be successfully treated with non-invasive ventilation, usually in collaboration with a respiratory physician. New-onset weakness of limb and respiratory muscles in the intensive care unit is usually due to critical illness myopathy or critical illness polyneuropathy, and treatment is supportive.     

Critical illness polyneuropathy and myopathy]

Critical Illness Polyneuropathy (CIP) and Myopathy (CIM), either singly or in combination, are a common complication of critical illness. Both disorders may lead to severe weakness and require mechanical ventilation. CIP, as initially described by Bolton et al., in 1984, is a sensorimotor polyneuropathy that is often a complication of sepsis and multiorgan failure. In Japan, Horinouchi et al., first reported a case in 1994. CIM has been referred to by a number of different terms (acute quadriplegic myopathy, thick filament myopathy, acute necrotizing myopathy of intensive care, rapidly evolving myopathy with myosin-deficiency fibers) in the literature. A variety of serious problems (e.g., pneumonia, severe asthma, and lung or liver transplantation) and the concomitant use of high-dose intravenous corticosteroids and nondepolarizing neuromuscular blocking agents predispose to CIM. In Japan, Kawada et al., reported a first case as acute quadriplegic myopathy in 2000. There is no specific treatment for CIP and CIM. Minimizing the use of corticosteroids and nondepolarizing neuromuscular blocking agents in a critical illness setting may prove helpful in preventing the occurrence of these disorders. The prognosis is directly related to the age of the patient and the seriousness of the underlying illness.     

Electrophysiologic studies of critically ill patients

Sepsis and critical illness occur as complications of illness, injury, or surgery in approximately 5% of patients in our critical care unit. Clinical evaluation of the nervous system is difficult in this clinical setting, and electrophysiologic studies are therefore quite valuable. Electroencephalography detects encephalopathy and electromyography (EMG) and nerve conduction studies detect neuromuscular disorders at early stages of their development. Thus, septic encephalopathy occurs in almost all patients and critically ill polyneuropathy in at least 50% of such patients. The polyneuropathy is a predominantly distal axonal degeneration of motor and sensory fibers. A catabolic myopathy is also present, but is difficult to detect electrophysiologically. No defect in neuromuscular transmission has so far been demonstrated. Both the encephalopathy and polyneuropathy may be quite severe, but with vigorous management of the sepsis and critical illness complete recovery may occur in the 40% of patients who survive.     

The neurological complications of sepsis

Encephalopathy and polyneuropathy occur in 70% of septic patients. The encephalopathy is diffuse, appears early, is often severe, but reverses quickly with successful treatment of the sepsis. The electroencephalogram is a sensitive indicator of the incidence and severity of the encephalopathy, but computed tomograms of the brain and cerebrospinal fluid findings are unremarkable. Critical-illness polyneuropathy develops later and in association with multiple-organ failure. Recovery is more gradual. Difficulty in weaning from the ventilator is an important early manifestation. Electromyography should be routinely performed to establish the diagnosis. The polyneuropathy is a primary axonal degeneration, predominantly of distal motor fibers. A persistent deficit may eventuate in severe cases. Whether muscle is affected as consistently as brain and peripheral nerve, and by the same process, has not been determined. Medications used in critical care units, notably sedatives and neuromuscular blocking agents, often confuse the clinical picture. The neurological pathophysiology is unknown but current evidence suggests that nervous system dysfunction arises through the same mechanisms as for systemic organs in the septic syndrome.     

Guillain-Barre syndrome following cardiac surgery. Difficult diagnosis in the intensive care unit

Weakness of limb and respiratory muscles developing in the course of treatment in the intensive care unit (ICU) is commonly due to critical illness polyneuropathy, a complication of sepsis, or critical illness myopathy, a complication of the use of neuromuscular blocking agents and steroids. Guillain-Barre syndrome may rarely occur in this setting. We report 2 patients identified in our ICU in the last 20 years. Surgery was an apparent precipitating event in both patients. The clinical, electrophysiological, and cerebrospinal fluid features were consistent with this diagnosis. Both patients responded to treatment; the first case was treated with plasmapheresis while the other with intravenous immune globulin. Thus, while rare, it is important to identify this disorder in the ICU because of its response to specific treatment.     

Acute necrotizing myopathy of intensive care: Electrophysiological studies

A series of recent reports have identified cases of a quadriplegic myopathy characterized by myofiber necrosis and loss of myosin filaments associated with the use of nondepolarizing muscle blocking agents and glucocorticoids. We report electrophysiological findings in 7 intensive care unit patients who developed evidence of an acute myopathy in association with the use of nondepolarizing muscle blocking agents. Several important features were identified: (i) a neuromuscular transmission deficit was observed in 3 patients up to 7 days following withdrawal of vecuronium; (ii) motor M potentials were of low amplitude, there was mild abnormal spontaneous activity on needle electromyography, and sensory conduction was relatively preserved; (iii) not all patients received glucocorticoids or were asthmatic; (iv) 2 patients given vecuronium had very high creatine kinase levels and developed acute renal failure associated with myoglobinuria; and (v) rises in motor M potentials accompanied clinical recovery. This complication of intensive care may be severe, but is reversible and possibly avoidable. Our findings implicate nondepolarizing muscle blocking agents in the development of the myopathy. Electrophysiological studies provide important prognostic guidance. © 1994 John Wiley & Sons, Inc.     

Critical illness neuropathy in pediatric intensive care patients

Critical illness neuropathy is an axonal polyneuropathy recognized more frequently in adult intensive care patients with sepsis and multiple organ dysfunction. In children the diagnosis is rarely made. Within 1 year the authors observed two children with critical illness neuropathy. Both patients, a male 6 years, 6 months of age with a brain contusion and a male 2 years, 6 months of age who underwent craniectomy for Crouzon's disease, required prolonged mechanical ventilation and developed sepsis with multiple organ dysfunction. Three to 4 weeks after successful treatment of the sepsis, a flaccid tetraparesis was noticed in both patients. Laboratory investigations of blood and cerebrospinal fluid and spinal magnetic resonance imaging revealed normal results. Electrophysiologic examinations were indicative of an axonal polyneuropathy. Spontaneous improvement occurred within several months. It is likely that critical illness neuropathy occurs more often in critically ill children than previously thought. Careful neurologic examination and early electrophysiologic investigations are necessary to establish the diagnosis. Important differential diagnoses of acquired lower motor neuron weakness in pediatric intensive care medicine are discussed.     

Critical illness polyneuropathy: a case report

Critical illness polyneuropathy (CIP) is defined as a common complication of critically ilness patients who were admitted to the intensive care unit due to sepsis, multiple trauma and/or multi-organ failure. We aimed to present a patient who was diagnosed as CIP. He was admitted to our outpatient clinic due to weakness and pain in his lower extremities. He had been followed in an intensive care unit due to suicid five months ago. There were symmetrically and predominantly muscle weakness, sensory impairment, absence of deep tendon reflexes in his lower extremities. Electrophysiological evaluation demonstrated motor and sensory axonal distal polyneuropathy predominantly in lower extremities. At follow up, he had high fever, and elevated acute phase responses. Therefore source of infection was investigated and was suspected to a diagnosis of infective endocarditis. He was discharged to be hospitalized in cardiology clinic. With this case, we think that physiatrists should take into consideration a diagnosis of critical illness polyneuropathy in patients with symmetric motor weakness. In CIP, muscle weakness, sensory loss, neuropathic pain, and autonomic problems lengthened the rehabilitation period. Due to a diagnosis of infective endocarditis in our case, we point out that source of infection should be carefully investigated if there is acute phase responses in CIP patients even if during rehabilitation period.     

Vecuronium-associated axonal motor neuropathy: a variant of critical illness polyneuropathy?

Neuromuscular blocking agents are routinely used as an adjunct therapy for critically ill patients. Unlike many neuromuscular blocking agents, vecuronium does not cause significant histamine release, which may lead to bronchoconstriction. Due to a short duration of action and limited accumulation, vecuronium has been widely used. Prolonged ventilatory dependence due to persistent neuromuscular blockade has been reported in patients treated with vecuronium. We report a case of an 8-year-old girl who had a primarily motor axonopathy presenting with weakness after extended vecuronium administration with prolonged course of recovery. This primarily motor neuropathy with axonal features may be a variant of critical illness polyneuropathy, a rarely reported condition in pediatric patients.     

Causes of neuromuscular weakness in the intensive care unit: A study of ninety-two patients

The spectrum of neuromuscular disorders among intensive care unit (ICU) patients has shifted toward disorders acquired within the ICU and away from “traditional” neuromuscular disorders that lead to ICU admission. We sought to assess this spectrum by determining the causes and relative frequencies of neuromuscular disorders that led to electromyography (EMG) examinations in our ICU population. Ninety-two patients were studied over a 4½-year period. Twenty-six (28%) had neuromuscular disorders (mainly Guillain–Barré syndrome, myopathy, and motor neuron disease) that led to ICU admission. Among patients who developed weakness in the ICU, there was a predominance of organ transplant patients and patients with the systemic inflammatory response syndrome and multiorgan dysfunction. Thirty-nine (42%) developed acute myopathy (consistent with critical illness myopathy in most), and 13% developed acute axonal sensorimotor polyneuropathy (mainly critical illness polyneuropathy). Patients with acute myopathy and acute axonal sensorimotor polyneuropathy had similar functional outcomes. We conclude that among patients who underwent EMG in our ICU population, acute myopathy is three times as common as acute axonal polyneuropathy, and the outcomes from acute myopathy and acute axonal polyneuropathy may be similar. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:610–617, 1998.     

Critical illness polyneuropathy and myopathy:a systematic review简

Critical illness polyneuropathy and critical illness myopathy are frequent complications of severe illness that involve sensorimotor axons and skeletal muscles, respectively. Clinically, they manifest as limb and respiratory muscle weakness. Critical illness polyneuropathy/myopathy in isolation or combination increases intensive care unit morbidity via the inability or difficulty in weaning these patients off mechanical ventilation. Many patients continue to suffer from decreased exercise capacity and compromised quality of life for months to years after the acute event. Substantial progress has been made lately in the understanding of the pathophysiology of critical illness polyneuropathy and myopathy. Clinical and ancillary test results should be carefully interpreted to differentiate critical illness polyneuropathy/myopathy from similar weaknesses in this patient population. The present review is aimed at providing the latest knowledge concerning the pathophysiology of critical illness polyneuropathy/myopathy along with relevant clinical, diagnostic, differentiating, and treatment information for this debilitat- ing neurological disease.     

Electrophysiologic studies in critical illness associated weakness: myopathy or neuropathy--a reappraisal.

OBJECTIVE: Unexplained weakness in critically ill patients is recognized with increasing frequency. However, it is debated whether the condition is a peripheral neuropathy or a myopathy. Diagnostic difficulties can arise from multiple sources that are not generally a factor in other neuromuscular conditions. Conventional electrodiagnostic techniques may provide only non-specific data, clinical examination is often hampered, and muscle biopsy is not a practical screening tool. METHOD: To improve diagnostic yield, we studied 22 consecutive patients with critical illness associated weakness with additional electrodiagnostic techniques, including direct muscle stimulation, quantitative electromyography, and motor unit number estimation. RESULTS: The applied techniques supported an underlying myopathy in all the patients examined. The diagnosis was confirmed by muscle biopsy in 9 patients. Additional lesser features of neuropathy were concomitantly present in one patient who also underwent sural nerve biopsy. CONCLUSIONS: The study suggests that myopathy is much more common than polyneuropathy in critical illness. Suspicion of this entity should be high in this setting even without exposure to corticosteroids or non-depolarizing blocking agents.     

Neurological complications of sepsis: critical illness polyneuropathy and myopathy

Sepsis may cause not only failure of parenchymal organs but can also cause damage to peripheral nerves and skeletal muscles. It is now recognized that sepsis-mediated disorders of the peripheral nerves and the muscle, called critical illness polyneuropathy (CIP) and critical illness myopathy, are responsible for weakness and muscle atrophy occurring de novo in intensively treated patients. CIP represents an acute axonal neuropathy that develops during treatment of severely ill patients and remits spontaneously, once the critical condition is under control. The course is monophasic and self-limiting. Among the critical illness myopathies, three main types have been identified: a nonnecrotizing "cachectic" myopathy (critical illness myopathy in the strict sense), a myopathy with selective loss of myosin filaments ("thick filament myopathy") and an acute necrotizing myopathy of intensive care. Clinical manifestations of both critical illness myopathies and CIP include delayed weaning from the respirator, muscle weakness, and prolonging of the mobilization phase. The pathogenesis of these neuromuscular complications of sepsis is not understood in detail but most authors assume that the inflammatory factors that mediate systemic inflammatory response and multiple organ failure are closely involved. In thick filament myopathy and acute necrotizing myopathy, administration of steroids and neuromuscular blocking agents may act as triggers. Specific therapies have not been discovered. Stabilization of the underlying critical condition and elimination of sepsis appear to be of major importance. Steroids and muscle relaxants should be avoided or administered at the lowest dose possible.     

Role of endotoxin in the pathogenesis of critical illness polyneuropathy

Critical illness polyneuropathy (CIP) occurs in association with sepsis and multiple organ failure; however, little is known about the pathomechanisms of CIP and its therapy. In order to determine the parameters which interfere with development of CIP, electrophysiological investigations of peripheral nerves and biochemical measures were correlated to each other. The present study includes 20 consecutive patients in an intensive care unit developing severe sepsis or septic shock. Nerve conduction studies and electromyography were performed with occurring sepsis (day 1, 7, 14) and neurophysiological parameters were correlated with biochemical measures, especially indicators of infection and inflammation.It was found that all patients developed neurophysiological signs of axonal motor polyneuropathy. There was a significant correlation between serum concentrations of endotoxin and interleukin-2 receptors (IL2-R) and reduction of the amplitude of the compound motor action potentials. Other clinical and biochemical parameters showed no significant correlations with neurophysiological data.This finding apparently indicates that endotoxin damages nerve axons directly or indirectly, e.g. by activation of inflammatory cascades (IL2-R). Endotoxin appears to be an essential factor in the pathogenesis of CIP in sepsis, and therapeutic options neutralizing endotoxin may prevent development of CIP.     

Polyneuropathy in critically ill patients.

Five patients developed a severe motor and sensory polyneuropathy at the peak of critical illness (sepsis and multiorgan dysfunction complicating a variety of primary illnesses). Difficulties in weaning from the ventilator as the critical illness subsided and the development of flaccid and areflexic limbs were early clinical signs. However, electrophysiological studies, especially needle electrode examination of skeletal muscle, provided the definite evidence of polyneuropathy. The cause is uncertain, but the electrophysiological and morphological features indicate a primary axonal polyneuropathy with sparing of the central nervous system. Nutritional factors may have played a role, since the polyneuropathy improved in all five patients after total parenteral nutrition had been started, including the three patients who later died of unrelated causes. The features allow diagnosis during life, and encourage continued intensive management since recovery from the polyneuropathy may occur.     

A pediatric case of critical illness polyneuropathy: clinical and pathological findings

Critical illness polyneuropathy (CIP) is a sensorimotor polyneuropathy recognized in adult intensive care patients with sepsis and multiple organ dysfunction and only a few cases have been reported in children. Here we report a 13-year-old Japanese boy with CIP that developed during the course of encephalopathy. Two months after the onset of encephalopathy, he developed tetraplegia although consciousness had already recovered. Deep tendon reflex was absent. MRI of the brain and spinal cord was normal and no abnormality in the cerebrospinal fluid was detected. Motor and sensory nerve conduction velocities of the lower limbs and somatosensory evoked potential could not be detected. The motor activity subsequently showed gradual recovery, although standing and walking could not be achieved. Sural nerve biopsy performed 3 years after the onset showed severe reduction of the number of myelinated large-diameter fibers, thin myelin in almost all fibers and cluster formation of myelinated small-diameter fibers, indicating primary axonal degeneration with regeneration. We report here for the first time the neuropathological changes in peripheral nerves during the chronic stage of CIP in children.