Critical illness neuropathies

A number of patients admitted to intensive care units for non-neurological disorders develop neuromuscular complications. These patients present with an acute flaccid generalized weakness that may or may not be accompanied by sensory symptoms. There are two main conditions, namely critical illness polyneuropathy and neuromuscular disorder related to the use of neuromuscular blocking agents. These conditions differ in several ways. Critical illness polyneuropathy occurs usually after long stays (weeks) in intensive care units. It concerns patients presenting with a multiple organ dysfunction syndrome, and often sepsis. The polyneuropathy is axonal and implies both sensory and motor fibres. Its pathophysiology remains unclear. Mortality is as high as 60 p.cent and relates to the medical, rather than to the neurological condition. In survivors recovery may be complete, although over a period of months. Neuromuscular disorder related to the use of neuromuscular blocking agents occurs on average after 10 days. It most often concerns patients admitted to intensive care units for acute respiratory failure, mainly asthma or adult respiratory distress syndrome, that may require mechanical ventilation, use of neuromuscular blocking agents and steroids. A purely motor deficit is usually first noticed when curarisation is discontinued. Electromyography discloses fibrillation potentials in all muscles, as well as myopathic changes. Muscle biopsy demonstrates necrosis and a deficit in myosin filaments. In severe cases, injury to distal motor axons probably occurs. Recovery is usually excellent over a few weeks. Recently, replacement of neuromuscular blocking agents by sedatives has notably reduced the occurrence of this disorder. Critical illness neuropathies often cause difficulty in weaning patients from the respirator. They prolong the stay in the intensive care unit, thereby increasing the risks of complications for the patients. Course of these neuromuscular disorders is usually favorable, however sometimes with sequelae.     

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.     

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.     

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 non-necrotizing “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. Received: 12 April 2001, Accepted: 23 April 2001     

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.     

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 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.     

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.     

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.     

Neuromuscular disorders in critical illness

Neuromuscular disorders in the background of critical illness are under diagnosed. Standardized screening for weakness in the intensive care unit (ICU) setting is uncommon and persistent weakness as a sequel of critical illness is usually not recognized by physicians in the ICU for whom survival from acute illness is the primary outcome. The spectrum of illness ranges from isolated nerve entrapment with focal pain or weakness, to disuse muscle atrophy with mild weakness, and to severe myopathy or neuropathy with associated severe, prolonged weakness. This update focuses on neuromuscular disorders occurring in the critical care set up associated with diffuse and severe weakness.     

Neurologic Complications in the Intensive Care Unit

Complications involving the central and peripheral nervous system are frequently encountered in critically ill patients. All components of the neuraxis can be involved including the brain, spinal cord, peripheral nerves, neuromuscular junction, and muscles. Neurologic complications adversely impact outcome and length of stay. These complications can be related to underlying critical illness, pre-existing comorbid conditions, and commonly used and life-saving procedures and medications. Familiarity with the myriad neurologic complications that occur in the intensive care unit can facilitate their timely recognition and treatment. Additionally, awareness of treatment-related neurologic complications may inform decision-making, mitigate risk, and improve outcomes.     

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.     

Critical illness polyneuropathy

Over the past three decades, there has been an increasing interest in cases of profound muscle weakness in critically ill, mechanically ventilated patients. Potential causes for these acute weakness syndromes are multiple and include disorders of the peripheral nerves, the neuromuscular junction, and muscle (Sliwa, 2000). This article will provide an overview of one potential cause of an acute weakness syndrome affecting peripheral nerves, critical illness polyneuropathy (CIP). A case study concerning a 32-year-old male who suffered multiple traumatic injuries, and who was treated for more than two years, is presented to illustrate the course of the syndrome. He required extensive interdisciplinary involvement to achieve independence in spite of ongoing neurological impairments.     

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.     

Neuromuscular disease and anesthesia

Patients with neuromuscular disease pose many anesthetic challenges and are at greater risk for perioperative complications, including respiratory or cardiovascular dysfunction and pulmonary aspiration. Therefore, these patients require special precautions, including interdisciplinary communication between primary care physicians, neurologists, physiatrists, surgeons, and anesthesiologists. Preoperative evaluation and optimization of comorbid conditions is critical. These patients may have adverse response to neuromuscular blocking drugs and the reversal drugs (e.g., neostigmine). They should be used with caution and titrated based on objective neuromuscular monitoring. Drugs that potentiate neuromuscular blocking drugs should also be avoided or their doses limited if possible. The risk of malignant hyperthermia in certain neuromuscular diseases mandates avoidance of triggering agents such as succinylcholine and inhaled anesthetics. Patients with neuromuscular disease may also be sensitive to sedative‐hypnotics and opioids, which should be used judiciously. Finally, the postoperative period requires close monitoring due to increased risk of postoperative cardiorespiratory dysfunction. Muscle Nerve 48 : 451–460, 2013     

Prolonged myasthenic syndrome after one week of muscle relaxants

A child developed severe, generalized muscle weakness which persisted for 6 weeks, after receiving muscle relaxants for 1 week while requiring ventilator support. Electrodiagnostic studies indicated a presynaptic disorder of the neuromuscular junction which improved with high-frequency stimulation, similar to findings in Lambert-Eaton syndrome. Muscle specimens exhibited neurogenic targetoid fiber atrophy. Ultrastructure of the neuromuscular junction indicated terminal axon degeneration and atrophy with depletion of the secretory vesicles. Most reported patients with post-ventilator paresis have received steroids and muscle relaxants; muscle weakness commonly has been brief and attributed to steroids. We believe that this reversible myasthenic syndrome probably represents neurotoxicity due to high doses of steroidal nondepolarizing blocking agents; however, available data are insufficient to resolve this controversy.     

Critical illness polyneuropathy. A 2-year follow-up study in 19 severe cases

Critical illness polyneuropathy (CIP) is a reported cause of varying degrees of neuromuscular weakness in patients with multiple organ failure. Little is known concerning predictive factors of neurological recovery. The critical care conditions, neurological explorations and 2-year clinical follow-up of 19 patients who suffered from severe forms (quadriplegia or quadriparesis) of CIP were analyzed. Characteristics of patients who recovered clinically were compared with those of patients who did not. Two patients died within 2 months, 11 recovered completely, 4 remained quadriplegic and 2 remained quadriparetic. All patients suffered from sepsis, multiple organ dysfunction syndrome and a catabolic state before the onset of CIP. Outcome appears difficult to predict with clinical or electrophysiological data. Three parameters were significantly correlated with poor recovery: longer length of stay in the critical care unit, longer duration of sepsis and greater body weight loss. A relationship seems to exist between the severity of CIP and that of sepsis and its associated hypercatabolism. The favorable outcome usually attributed to CIP must be reconsidered. The authors recommend aggressive measures against sepsis to limit CIP and its sequelae.     

Prolonged paralysis due to nondepolarizing neuromuscular blocking agents and corticosteroids

The long-term use of nondepolarizing neuromuscular blocking agents (ND-NMBA) has recently been implicated as a cause of prolonged muscle weakness, although the site of the lesion and the predisposing factors have been unclear. We report 3 patients (age 37–52 years) with acute respiratory insufficiency who developed prolonged weakness following the discontinuation of ND-NMBAs. Two patients also received intravenous corticosteroids. Renal function was normal but hepatic function was impaired in all patients, and all had acidosis. Electrophysiologic studies revealed low amplitude compound motor action potentials, normal sensory studies, and fibrillations. Repetitive stimulation at 2 Hz showed a decremental response in 2 patients. The serum vecuronium level measured in 1 patient 14 days after the drug had been discontinued was 172 ng/mL. A muscle biopsy in this patient showed loss of thick, myosin filaments. The weakness in these patients is due to pathology at both the neuromuscular junction (most likely due to ND-NMBA) and muscle (most likely due to corticosteroids). Hepatic dysfunction and acidosis are contributing risk factors. © 1994 John Wiley & Sons, Inc.     

Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis

Critical illness polyneuropathy (CIP) and myopathy (CIM) are complications of critical illness that present with muscle weakness and failure to wean from the ventilator. In addition to prolonging mechanical ventilation and hospitalisation, CIP and CIM increase hospital mortality in patients who are critically ill and cause chronic disability in survivors of critical illness. Structural changes associated with CIP and CIM include axonal nerve degeneration, muscle myosin loss, and muscle necrosis. Functional changes can cause electrical inexcitability of nerves and muscles with reversible muscle weakness. Microvascular changes and cytopathic hypoxia might disrupt energy supply and use. An acquired sodium channelopathy causing reduced muscle membrane and nerve excitability is a possible unifying mechanism underlying CIP and CIM. The diagnosis of CIP, CIM, or combined CIP and CIM relies on clinical, electrophysiological, and muscle biopsy investigations. Control of hyperglycaemia might reduce the severity of these complications of critical illness, and early rehabilitation in the intensive care unit might improve the functional recovery and independence of patients.     

Late profound muscle weakness following heart transplantation due to danon disease

Introduction: Postoperative muscle weakness is a serious complication in surgical intensive care patients. It is mostly described as critical illness polyneuromyopathy. Risk factors include intensive care length of stay, sepsis, poor glycemic control, and combined use of corticosteroids and neuromuscular blocking agents, malnutrition, and electrolyte imbalance. Methods: We report a case of late‐progressive, profound weakness after heart transplantation for noncompaction cardiomyopathy which required prolonged mechanical ventilation. The patient's muscle strength recovered completely after prolonged rehabilitation. Results: Electromyographic assessment showed myopathy. Muscle biopsy revealed Danon disease, a genetic disorder affecting the lysosomal‐associated membrane protein 2 gene (LAMP2). Conclusions: The finding of this genetic disorder was unexpected, because the preoperative echocardiographic diagnosis of noncompaction cardiomyopathy has not been reported in Danon disease. This report underlines the need for early availability of pathology results from the explanted heart, which showed the same disorder. Muscle Nerve, 2013