Special Feature: Critical Illness Polyneuromyopathy: Risk Factors and Clinical Consequences
Special Feature
Critical Illness Polyneuromyopathy: Risk Factors and Clinical Consequences
By Karen L. Johnson PhD, RN, CCRN, Assistant Professor, School of Nursing, University of Maryland, is Associate Editor for Critical Care Alert.
Dr. Johnson reports no financial relationship to this filed of study.
More than 20 years ago, case reports appeared in the literature describing a neuromuscular abnormality that developed as a consequence of critical illness.1 Despite its slow acceptance, the description of a neuromuscular abnormality secondary to critical illness is now reasonably rooted in the literature, although its explanation remains unclear. This is a highly unrecognized complication of critical illness that is associated with prolonged mechanical ventilation, prolonged ICU stays, and increased hospital mortality. The potential economic impact of this complication has been estimated to cost more than $66,000 per patient (1996 dollars) in excess of hospital charges.2 At present, there is no treatment. A clearer understanding and appreciation of the risk factors may help to prevent and therefore treat this complication of critical illness.
Definition
Critical illness can be complicated by extreme neuromuscular weakness associated with a delay in weaning from mechanical ventilation, prolonged hospitalization and rehabilitation. Neuromuscular abnormalities have been found in a majority of patients within a week of admission to the ICU.3-6 These neuromuscular disorders develop in patients without previously known neuromuscular disorders. A clear classification of ICU acquired neuromuscular disorders is difficult because of inconsistent terminology in the literature. Terms used to describe this ICU-acquired neuromuscular disorder are listed in Table 1.
Two main clinical, pathological, and electrophysiological types of acquired neuromuscular involvement in critically ill patients have been described: critical illness polyneuropathy1,7 and critical illness myopathy.8 The differentiation between them is based on the assumption that most cases can be categorized as one or the other.9 However, there is evidence that these conditions co-exist.8 Therefore, until more data on the different pathogenesis of various pathological subtypes are available, the use of the term "critical illness polyneuromyopathy" (CIPNM) has been suggested.6
Diagnosis
Clinically, CIPNM manifests as sensory deficits and general weakness. These symptoms are usually not detected because ICU patients are intubated and sedated. The first sign of CIPNM may become apparent as a failure to wean from mechanical ventilation. Cranial nerves may be intact on clinical—but not electromyographic (EMG)—examination, an important clinical finding distinguishing this disorder from Guillain-Barré syndrome and other myopathies. Limbs have varying degrees of flaccid weakness and atrophy. Distal atrophy may be obscured by limb edema. The majority of patients have loss of previously normal deep tendon reflexes. Disappearance of these reflexes is an important sign that neuropathy has developed. Unfortunately, this simple neurologic test is routinely omitted in daily physical examinations. While loss of reflexes is commonly blamed on sedatives and analgesics, there is little evidence that these drugs eliminate them. Propofol may cloud the bedside neurologic examination by rendering flaccid areflexic paralysis. Sensory examination is often unreliable and may only become apparent if the patient has a clear sensorium.
Recently, the Medical Research Council (MRC) score,10 has been validated in the ICU patient population to evaluate muscle strength.11 Each muscle group score ranges from 0 (paralysis) to 5 (normal muscle strength), and the overall score from 0 to 60. In a recent study,11 patients with an MRC score less than 48 were diagnosed as having CIPNM, whereas those with a MRC score of 48 or higher, which indicated muscle strength of 5 (normal) or 4 (subnormal) in each limb segment were considered normal. The most important factor that limits a reliable clinical examination with the MRC is the alteration of consciousness frequently present in the ICU patient.
Electrophysiologic studies are the diagnostic standard for identifying CIPNM. Nerve conduction studies reveal declines of the amplitudes of compound muscle action potentials with relatively preserved motor conduction velocities, distal motor latencies, and F-wave latencies. There is variable loss of sensory nerve action potential amplitudes with preserved sensory nerve conduction velocities. One problem complicating interpretation of high-gain surface electrode recordings of sensory potentials is edema. Near-nerve needle recordings have been used to help with this problem. Needle EMG has identified fibrillation potentials and positive sharp waves.
Muscle biopsy may show loss of myosin documented by decreased or absent myosin ATP staining of atrophic fibers or selective loss of myosin filaments with relative sparing of actin filaments and Z discs on ultrastructural examination, degenerative-necrotic changes, and type II fiber atrophy detected by quantitative automatic morphometrical analysis of the mean cross sectional area of both types of muscle fibers.
Incidence
The incidence of CIPNM is larger than generally recognized: 33-80% depending on the group of critically ill patients evaluated and the timing of electrophysiologic and histologic study.7,12 In prospective, observational studies, electrophysiologic abnormalities ranged from 47% to 90% of patients7,13 and histologic abnormalities range from 71% to 96%.3,14
Risk Factors
While there is considerable debate as to the precise etiology of this neuromuscular disorder, multiple risk factors have been implicated (see Table 2).
SIRS and MODS
Several prospective studies have confirmed the association between the systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and CIPNM.4,6,11,15 When both factors are present, the risk is as high as 70%.15 As early as 1892, Osler described a condition of muscle wasting as a complication of prolonged sepsis.16 However, the association between sepsis and CIPNM in modern medicine did not become apparent until almost a hundred years later when Bolton and colleagues through a series of papers, hypothesized that a systemic inflammatory response/sepsis contributed to neuronal damage in critically ill patients.1,7,17,18 More recent studies offer experimental evidence that CIPNM is characterized by generalized axonal motor and/or sensory denervation.4,6,19 There is a significant association between the development of CIPNM and respiratory failure,20 neurologic failure, and renal failure.6 These associations raise questions as to whether neuromuscular involvement is a consequence of these organ failures, or whether it represents another organ failure.
Prolonged Mechanical Ventilation
Another risk factor associated with the development of CIPNM is prolonged mechanical ventilation. Duration of mechanical ventilation is significantly longer in patients with CIPNM.5,6,11,20 One recent study reported that CIPNM increased length of mechanical ventilation 11.6 days.5 Others postulate that readmission to the ICU for respiratory failure may be due to undetected CIPMN prior to discharge from the ICU.21
Drugs
Critical illness myopathy was originally reported as a complication of corticosteroid administration, either alone or in association with non-depolarizing neuromuscular blocking agents (NMBA).22,23 Prospective studies however, report conflicting data on the significant independent influence of corticosteroids or NMBA on development of CIPNM.11,15,20,24 There is evidence that ICU patients who receive corticosteroids are susceptible to developing histologic features of myopathy that include type 2 fiber atrophy and myosinolysis.11 It has been postulated that these lesions are the consequence of corticosteroid muscle receptor stimulation by exogenous corticosteroids25 that maybe enhanced by muscle denervation.26 However, in a recent prospective multi-center cohort study, De Jonghe and colleagues reported no significant difference in the duration or cumulative dose of corticosteroids in patients with and without CIPNM.11 They suggested 2 explanations: 1) the medical condition that prompts corticosteroid administration is responsible for the neuromuscular dysfunction, or 2) corticosteroids may act as a trigger for neuromuscular dysfunction.
Aminoglycosides have been linked to presynaptic neuromuscular transmission defects, implying that these agents may be toxic to distal motor terminals.27 However, recent prospective studies have not found electrophysiologic evidence of a neurotoxic effect of aminoglycosides on the neuromuscular junction.5,15
Hyperglycemia
Hyperglycemia has been associated with an increased risk of CIPNM.5,11,20 Van den Berghe demonstrated that tight glycemic control led to a reduction in the incidence of CIPNM.28 Possible explanations include the direct cytotoxic effects of hyperglycemia or the neuroprotective effects of insulin.28
Prevention and Treatment
At present, there are no definitive therapies to prevent or treat CIPNM. Current therapy is directed at supportive care. An understanding and appreciation of the risk factors identified here are essential in order to prevent this complication of critical illness.
Patients with initial high APACHE III score and development of SIRS should have regular assessments of muscle strength. As soon as CIPNM is suspected, an electromyogram should be done to confirm findings. Although evidence does not support the direct deleterious effects of NMBA and corticosteroids on development of CIPNM, their use should be restricted. De Jonghe suggests that until more evidence is available, clinicians should weigh the indications of corticosteroids in ICU patients and restrict their use to conditions, such as septic shock, unresolved acute respiratory distress syndrome, status asthmaticus, in which corticosteroids have been shown to have a significant impact on mortality and morbidity.11 Van den Berghe et al have shown that tight glycemic control reduces the incidence of CIPNM by half.28
The risk factor of prolonged mechanical ventilation on the development of CIPNM may likely represent another example of the deleterious effects of immobilization which raises the question of whether ICU patients are getting adequate range of motion exercises and/or physical therapy. In my own experience, bedside nurses say they are too busy to perform range-of-motion exercises and physical therapists say the patient is too sick to participate in physical therapy. Teaching family members to perform range-of-motion exercises has been successful in my experience. The patients get the therapy and the family members feel as though they are contributing to the patient’s recovery. Certainly, studies are needed to evaluate the effects of an aggressive range-of-motion exercise program on reducing CIPNM.
References
- Bolton CF, et al. Polyneuropathy in critically ill patients. J Neurol Neurosurg Psychiatry. 1984;47:1223-1231.
- Rudis MI, et al. Economic impact of prolonged motor weakness complicating neuromuscular blockade in the intensive care unit. Crit Care Med. 1996;24:1749-1756.
- Coakley JH, et al. Patterns of neurophysiological abnormality in prolonged critical illness. Intensive Care Med. 1998;24:801-807.
- Tennila A, et al. Early signs of critical illness polyneuropathy in ICU patients with systemic inflammatory response syndrome or sepsis. Intensive Care Med. 2000;26:1360-1363.
- Garnacho-Montero J, et al. Critical illness polyneuropathy: risk factors and clinical consequences: A cohort study in septic patients. Intensive Care Med. 2001;27:1288-1296.
- Bednarik J, et al. Critical illness polyneuropathy: the electrophysiological components of a complex entity. Intensive Care Med. 2003;29:1505-1514.
- Witt NJ, et al. Peripheral nerve function in sepsis and multiple organ failure. Chest. 1991;99:176-184.
- Latronico N, et al. Critical illness myopathy and neuropathy. Lancet. 1996;347:1579-1582.
- Lacomis D, et al. Critical illness myopathy. Muscle Nerve. 2000; 23:1785-1788.
- Kleyweg R, et al. Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barre syndrome. Muscle Nerve. 1991;14:1103-1109.
- De Jonghe B, et al. Paresis acquired in the intensive care unit. JAMA. 2002;288:2859-2867.
- Leijten FS, et al. The role of polyneuropathy in motor convalescence after prolonged mechanical ventilation. JAMA. 1995;274:1221-1225.
- Berek K, et al. Polyneuropathies in critically ill patients: a prospective evaluation. Intensive Care Med 1996;22:849-855.
- Helliwell TR, et al. Necrotizing myopathy in critically ill patients. J Pathol. 1991;164:307-314.
- deLetter MA, et al. Risk factors for the development of polyneuropathy and myopathy in critically ill patients. Crit Care Med. 2001;29:2281-2286.
- Osler W. The principles and practice of medicine: Designed for the use of practitioners and students of medicine. New York: D. Appleton & Co., 1892.
- Zochodne DW, et al. Critical illness polyneuropathy. A complication of sepsis and multiple organ failure. Brain. 1987;110(Pt 4):819-841.
- Bolton CF. Sepsis and the systemic inflammatory response syndrome: Neuromuscular manifestations. Crit Care Med. 1996;24:1408-1416.
- Bolton CF. Evidence of neuromuscular dysfunction in the early stages of the systemic inflammatory response syndrome. Intensive Care Med. 2000;26:1179-1180.
- Bercker S, et al. Critical illness polyneuropathy and myopathy in pateints with acute respiratory distress syndrome. Crit Care Med. 2005;33:711-715.
- Latronico N, et al. Acute neuromuscular respiratory failure after ICU discharge. Intensive Care Med. 1999;25:1302-1306.
- Hirano M, et al. Acute quadriplegic myopathy: a complication of treatment with steroids, nondepolarizing blocking agents, or both. Neurology. 1992;42:2082-2087.
- MacFarlane IA, Rosenthal FD. Severe myopathy after status asthmaticus. Lancet. 1977;2:615.
- Bednarik J, et al. Risk factors for critical illness polyneuromyopathy. J Neurol. 2005;252:343-351.
- Konagaya M, et al. Blockade of glucocorticoid receptor binding and inhibition of dexamethasone-induced muscle atrophy in the rate by RU38486, a potent glucocorticoid antagonist. Endocrinology. 1986;119:375-380.
- DuBois BC, Almon BR. A possible role for glucocorticoids in denervation atrophy. Muscle Nerve. 1981;4:370-373.
- Sokoll MD, Gergis SD. Antibiotics and neuromuscular function. Anesthesiology. 1981;55:148-159.
- van den Berghe G, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345:1359-1367.
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