Neuromuscular Disorders in Critically Ill Patients

Review Article
Journal of
CLINICAL NEUROMUSCULAR DISEASE

Volume 12, Number 4 June 2011
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Neuromuscular Disorders in Critically Ill Patients: Review and Update

David Lacomis, MD
Abstract
Neuromuscular disorders that are diagnosed in the intensive care unit (ICU) usually cause substantial limb weakness and contribute to ventilatory dysfunction. Although some lead to ICU admission, ICU-acquired disorders, mainly critical illness myopathy (CIM) and critical illness polyneuropathy (CIP), are more frequent and are associated with considerable morbidity. Approximately 25% to 45% of patients admitted to the ICU develop CIM, CIP, or both. Their clinical features often overlap; therefore, nerve conduction studies and electromyography are particularly helpful diagnostically, and more sophisticated electrodiagnostic studies and histopathologic evaluation are required in some circumstances. A number of prospective studies have identified risk factors for CIP and CIM, but their limitations often include the inability to separate CIM from CIP. Animal models reveal evidence of a channelopathy in both CIM and CIP, and human studies also identified axonal degeneration in CIP and myosin loss in CIM. Outcomes are variable. They tend to be better with CIM, and some patients have longstanding disabilities. Future studies of well-characterized patients with CIP and CIM should refine our understanding of risk factors, outcomes, and pathogenic mechanisms, leading to better interventions. Key Words: critical illness myopathy, critical illness polyneuropathy, intensive care unit, myopathy, polyneuropathy, neuromuscular disorders
( J Clin Neuromusc Dis 2011;12:197218)
HISTORY
The study of neuromuscular disorders in critically ill patients has been evolving over the past 50 years. Patients with polio were the first to have neuromuscular weakness that often caused ventilatory dysfunction leading to admission to the earliest intensive care units (ICUs) that consisted of negative pressure ventilators. As modern ICUs arose and polio was mostly eradicated, patients with
other traditional neuromuscular disorders such as Guillain Barre syndrome (GBS) and myasthenia gravis with crisis more commonly benefited from ICU treatment of ventilatory dysfunction or airway collapse, and mortality rates declined. In the 1980s, it became evident that some patients, who were in the ICU for treatment of medical and surgical conditions, developed diffuse weakness, often with ventilatory failure. Bolton and colleagues first reported the clinical, electrodiagnostic, and histopathologic features of ICU patients with newly acquired weakness primarily in the setting of sepsisdefined as suspected or proven infection with a systemic inflammatory response syndrome (SIRS)1,2and multiorgan failure, culminating in their seminal reports of critical illness polyneuropathy (CIP).35 In Boltons comments on the discovery of CIP, he credits Oslers 1892 description of rapid loss of flesh with prolonged sepsis as the first possible observation of this association,6,7 and he notes reports of polyneuropathy (PN) after circulatory shock8 and burns.9 Nevertheless, it was really Bolton, Zochodne, and colleagues who identified CIP and brought attention to the field of ICU-acquired neuromuscular weakness.35 While Bolton and colleagues were studying CIP, there were also reports of single cases1014 and eventually series1521 of adult and pediatric10 patients who developed acute myopathy during treatment of status asthmaticus. Later, a similar acute myopathy was noted to follow organ transplantation2227 and to occur in association with many other critical illness states in children as well as adults.2835 Terminology was highly variable
From the Departments of Neurology and Pathology (Neuropathology), University of Pittsburgh School of Medicine, Pittsburgh, PA. Reprints: David Lacomis, MD, UPMC Presbyterian, 200 Lothrop Street, F878, Pittsburgh, PA 15213 (e-mail: lacomisd@upmc.edu).
Copyright 2011 by Lippincott Williams & Wilkins
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initially, but eventually the name critical illness myopathy (CIM) was accepted.36 Also, during the same period, it was noted that rare ICU patients developed prolonged neuromuscular junction (NMJ) blockade after receiving paralytic drugs in high doses or for prolonged periods in association with persisting drug metabolites and organ failure.3741 Some of these patients also had myopathy or neuropathy.4144 As treatment regimens shifted from the use of paralytic agents to sedatives such as propofol, persistent NMJ blockade has largely disappeared, whereas CIP and CIM persist. Zochodne et al also noted that biopsy or autopsy specimens from some of their patients with CIP exhibited muscle necrosis consistent with a component of myopathy.4 Since the last review of neuromuscular weakness in the ICU in this journal,45 there has been a substantial increase in reports that the disorders mentioned, especially CIM and CIP, occur together. The coexistence of CIM and CIP certainly complicates diagnosis. Lumping CIM and CIP together, when they cannot be differentiated, has also made it more difficult to interpret the results of clinical research on these two conditions. This article provides an overview of the approach to diagnosing neuromuscular disorders in the ICU while providing a detailed update on the ICU-acquired conditions, mainly CIM and CIP.
and most of the rest had CIP. Neuromuscular junction blockade was rarely noted.46 Other disorders causing neuromuscular weakness that sometimes leads to ICU admission resulting from ventilatory failure or airway collapse4755 are shown in Table 1. These conditions may be important causes of prolonged ventilator dependency.56 In addition, some pre-existing mild or subclinical neuromuscular disorders, including myasthenia gravis or Lambert-Eaton myasthenic syndrome, may be unmasked in the ICU by either the critical illness or treatment with medications such as aminoglycosides and magnesium.
Approach to the Weak Intensive Care Unit Patient

Clinical and Laboratory Features Like with all neurologic evaluations, localization of the disease process is first attempted from the history and examination.
TABLE 1. Neuromuscular Causes of Weakness in the Intensive Care Unit Myopathy Critical illness myopathy Rhabdomyolysis (toxins, infection, and so on) Cachectic myopathy Polymyositis, dermatomyositis Muscular dystrophies Acid maltase deficiency Mitochondrial myopathy Hypophosphatemic myopathy Toxic myopathy, eg, hydroxychloroquine Peripheral neuropathy Critical illness polyneuropathy Guillian Barre syndromes Vasculitic polyneuropathy Porphyria Paraneoplastic polyneuropathy Toxic polyneuropathy Nutritional polyneuropathy Neuromuscular junction disorders Prolonged neuromuscular junction blockade Myasthenia gravis Lambert-Eaton myasthenic syndrome Botulism Tick paralysis Motor neuron disorders Amyotrophic lateral sclerosis and variants Spinal muscular atrophy Poliomyelitis syndromes, eg, West Nile virus Postpolio syndrome
Spectrum of Neuromuscular Disorders in the Intensive Care Unit

Given the lack of prospective data, the spectrum and relative frequency of occurrence of all neuromuscular disorders diagnosed in the ICU is uncertain. One retrospective, electromyography (EMG)based series performed on 92 patients over 4 years noted that 28% of patients who underwent EMG in the ICU because of weakness had traditional neuromuscular disorders that led to ICU admission. Of these, GBS was most common, but motor neuron disease, myasthenia gravis, and rarely preexisting myopathy were reported. The majority had newly acquired myopathy, mostly CIM,
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Limitations may include encephalopathy, tracheal intubation with limited patient communication, and an unreliable sensory examination. The presence of encephalopathy should not dissuade one from searching for a neuromuscular disorder, especially when the encephalopathy is improving and weakness is not. Even hyperreflexia does not exclude a coexisting lower motor neuron disturbance in these complex patients. Furthermore, a pre-existing neuromuscular disorder, typically a PN, may make diagnosis of a new neuromuscular disturbance even more challenging. In the ICU, newly acquired central nervous system (CNS) disorders are rarely found to be the cause of acute flaccid quadriparesis with airway or ventilatory dysfunction. Considerations include high cervical myelopathy or brainstem disorders that may be the result of autoimmune demyelination or myelinolysis or from vascular diseases, including hemorrhage or infarction from thrombosis or hypoperfusion. If present in CNS disorders, pupillary or ocular motility abnormalities may help localize the process to the brainstem. If a sensory level and sphincter dysfunction are found, a spinal cord lesion should be sought. In the absence of these findings, magnetic resonance imaging of the brain or spinal cord may still be worth obtaining in patients with risk factors for vascular diseases or for osmotic or autoimmune demyelination. In diagnosing acute lower motor neuron disorders in the ICU, analysis of the following clinical features is most helpful: presence and pattern of weakness, pattern of tendon reflex alteration, fasciculations, and sensory findings. Acute motor neuron diseases such as poliomyelitis syndrome from West Nile virus may also have features of systemic illnesses, including fever, fatigue, and headache.57 Occasionally, patients with chronic motor neuron diseases are first diagnosed in the ICU if they present with ventilatory or bulbar dysfunction. They may or may not have subtle pre-existing symptoms, including limb and bulbar weakness. Fasciculations in the
tongue, paraspinal, intercostal, or limb muscles along with atrophy and upper motor neuron signs (in amyotrophic lateral sclerosis) are most diagnostically helpful if present. When limb weakness is present, it is often asymmetric and not length-dependent. This pattern of weakness with fasciculations and without sensory dysfunction is not seen in other groups of neuromuscular disorders occurring in the ICU. Neuromuscular junction disorders are rarely first diagnosed in the ICU. As mentioned, they may be unmasked by critical illness or by drugs such as magnesium and aminoglycosides, which interfere with NMJ transmission. Myasthenia gravis sometimes presents with crisis and is diagnosed in the ICU. Many of these patients have ptosis and pupil-sparing ophthalmoparesis with facial, bulbar, and proximal or generalized limb weakness that is fatigable. Tendon reflexes are usually normal. Although acetylcholine receptor binding antibodies are often present and anti-MuSK antibodies occur in many seronegative patients, finding a decrement on 2- to 3-Hz repetitive stimulation (discussed later) is a more timely way of supporting the diagnosis and is more objective and possibly more specific than a positive edrophonium test.58 Patients with Lambert- Eaton myasthenic syndrome almost never present with ventilatory failure. They usually have proximal weakness, hyporeflexia, and milder cranial muscle and autonomic involvement. Voltage-gated calcium channel antibodies are often present, and an underlying small cell lung cancer may be found in approximately half. Botulism, on the other hand, often leads to ICU admission and can be a difficult diagnosis without an obvious history of eating home-canned or spoiled food. Pupils are usually affected in addition to ventilatory, bulbar, and limb muscles. Tendon reflexes may be attenuated. Prolonged NMJ blockade is now rarely seen as a result of decreased use of high doses or continuous infusions of NMJ-blocking agents. Affected patients have tetraplegia and areflexia with or without ophthalmoplegia.3741
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The polyneuropathies that occur in the ICU usually do not present like the typical chronic length-dependent sensorimotor neuropathies seen in outpatients. They often affect phrenic or cranial nerve function and may be acute to subacute in onset. There are axonal and demyelinating subtypes. The prototype demyelinating PN, the acute inflammatory demyelinating polyneuropathy variant of GBS, may lead to ICU admission; it rarely develops in the ICU. The axonal neuropathies that may be diagnosed in the ICU include CIP, axonal variants of GBS, and porphyric as well as vasculitic neuropathies. In theory, some toxic and nutritional neuropathies may be diagnosed in the ICU. The axonal variants of GBSacute motor axonal neuropathy and acute motor sensory axonal neuropathy usually follow a diarrheal illness and present similarly to acute inflammatory demyelinating polyneuropathy clinically, but they are uncommon in North America. In all GBS variants, the cerebrospinal fluid protein is usually elevated.59 Vasculitic neuropathies usually begin before ICU admission and present as mononeuritis multiplex or asymmetric axonal sensorimotor polyneuropathies more often than symmetric PN. Systemic vasculitis or a predisposing connective tissue may be present. Laboratory studies may reflect the presence of an associated connective tissue disease or systemic vasculitis, for example, positive anti-c-antineutrophilic cytoplasmic, or antinuclear antibody. However, laboratory abnormalities may be absent or less specific such as an elevated erythrocyte sedimentation rate. Histopathologic evaluation of nerve and muscle is typically used to confirm the diagnosis. Porphyria could theoretically present in the ICU. It can be precipitated by stress or medications and cause a diffuse, severe, nonlength-dependent primarily motor axonal neuropathy with dysautonomia. There may be sensory symptoms without much sensory loss. Associated features often include abdominal pain, constipation, psychiatric manifestations, and sometimes brainstem
dysfunction. Urine assay for porphobilinogen is the initial screening test.60
Critical Illness Polyneuropathy

The major features of CIP are generalized or sometimes distal more than proximal flaccid weakness, often with ventilatory dysfunction from phrenic nerve involvement. Patients may develop muscle atrophy fairly soon after onset. Tendon reflexes are usually attenuated or absent. There may be distal sensory loss, but the sensory examination may be limited, and motor findings are usually predominant. Extraocular muscles are spared, but mild facial weakness may occur. In contrast to axonal GBS, cerebrospinal fluid protein is usually normal with CIP.3,4,61,62 Laboratory features are usually consistent with an underlying SIRS, sepsis, multiorgan failure, or a combination. Most myopathies that lead to ICU admission cause proximal-predominant weakness with normal tendon reflexes and sensation. ICU admission may be caused by diaphragm, cardiac, or sometimes airway muscle involvement. Some muscular dystrophies, acid maltase deficiency, and mitochondrial myopathy may present in this fashion, but usually their presence has been known before ICU admission. Mitochondrial disorders often affect extraocular muscles, and this may be a clue to diagnosis; in addition, serum lactate is sometimes elevated. Polymyositis and dermatomyositis rarely lead to ICU admission unless there is either interstitial lung disease as in the antisynthetase syndromes or cardiac involvement. Such cardiac involvement is rare.63 Toxic myopathies such as hydroxychloroquine myopathy rarely cause ventilatory muscle weakness. Histopathologic studies reveal a vacuolar myopathy with complex lipid and curvilinear inclusions.51 Serum creatine kinase (CK) is usually elevated in the inflammatory myopathies, many dystrophies, toxic myopathies, and acid maltase deficiency, and it may be elevated in some cases of mitochondrial myopathy.63
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Cachectic myopathy, which develops in chronically and critically ill patients, presents with muscle wasting and proximal-predominant weakness. Serum CK is normal. EMG does not reveal fibrillation potentials; normal or short duration motor unit potentials may be present. Type 2 myofiber atrophy is seen histologically.64,65 Acute necrotizing myopathy with or without myoglobinuria sometimes occurs in ICU patients. It is associated with generalized weakness, very high CK levels, irritable myopathy on EMG, and widespread necrosis histopathologically.34,66 There may be electrodiagnostic evidence of a persistent defect in NMJ transmission.34 Acute necrotizing myopathy in the ICU may be a subset of CIM, because associated loss of thick filaments has been described rarely66 or it may be considered a separate entity probably related to certain medications, especially NMJ-blocking agents, or possibly from sepsis. This syndrome is distinct from the more typical rhabdomyolysis related to other exogenous agents in which there is muscle pain and tenderness with variable degrees of weakness and normal or only mildly myopathic EMGs.67 It should be noted that some degree of subclinical muscle necrosis is probably present in many septic patients.68
(median, 1576 IU/L; range, 667430 IU/L); elevations lasted up to 16 days.20 Therefore, if patients are not evaluated during the first 2 weeks after onset, the CK elevation may be missed.
Electrodiagnostic Approach in the Intensive Care Unit

Because of the limitations in neurologic examination, electrodiagnostic testing is usually crucial for accurately localizing neuromuscular disorders in ICU patients. Unfortunately, it is also more difficult to perform EMGs in the ICU as a result of the frequent occurrences of electrical interference, edema, cool limbs, limited patient cooperation, and reduced access to sites of stimulation and recording resulting from catheters and dressings. It may be useful to address some of these issues briefly. Hot packs can be used for warming cool limbs. Shutting off unnecessary electrical equipment and using an isolated outlet may reduce electrical interference, but it is usually insufficient. Increasing the low-frequency filter during needle examination may also allow identification of fibrillation potentials, and the electromyographer can use sound to identify fibrillation potentials and small, polyphasic motor unit potentials even if they are hidden within the artifact. Sixty-Hertz artifact may especially interfere with F-wave recordings and sensory responses. Averaging may help identify sensory responses. Fortunately, motor nerve conductions are usually less affected. Attention to electrical safety is also more important in the ICU. Proper grounding is necessary. Stimulation in a region of fluid spill should be avoided to prevent current leak. Patients with external pacemakers cannot undergo nerve conduction studies (NCSs). Patients with implanted pacemakers can, but it may be prudent to avoid repetitive stimulation.72 As another precaution, we have not stimulated in the neck when intravenous catheters are present in the internal jugular or subclavian veins,72 but Bolton finds such stimulation safe.73
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Critical Illness Myopathy

CIM presents with flaccid, generalized, or proximal weakness, often with failure to wean from mechanical ventilation. There are normal or reduced tendon reflexes.1618,20,22,29 Rarely is the weakness asymmetric69 or upper extremity predominant.70 Facial weakness may be present,22,29 and extraocular muscle weakness is rare.71 There may be loss of muscle bulk.28 Sensation is normal, but it may impossible to test; thus, there is often clinical overlap with CIP. Creatine kinase levels are elevated in up to 50% or more of patients with CIM studied retrospectively. In a prospective study in status asthmaticus, CK levels were elevated in 19 of 25 (76%), and peaked 4 days after intravenous (IV) corticosteroid exposure
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If it is clinically helpful to determine if a patients ventilatory dysfunction is the result of neuromuscular weakness, phrenic NCSs are very useful, and diaphragm EMG may provide additional information. The best techniques have been summarized and reported by Bolton and colleagues7375 with an alternative phrenic nerve stimulation site reported by Resman-Gaspersc and Podnar.76 Our routine ICU NCS usually include at least one motor and sensory nerve from an arm and leg. Choices may depend on availability of stimulation and recording sites. If the sensory responses are abnormal or if PN is more likely on clinical grounds, we try to examine sural, superficial peroneal, median, ulnar, and radial sensory responses in addition to peroneal, tibial, median, and ulnar motor nerves. In the absence of significant edema, low sensory amplitudes usually indicate a component of axonal neuropathy. If edema is present in the legs only, the radial sensory response may be used as a more reliable indicator of diffuse sensory axon loss as may be seen with CIP. The combination of low motor and sensory amplitudes with normal latencies and normal or slightly slow conduction velocities support the diagnosis of an axonal sensorimotor PN. In the ICU, we usually do not search for side-to-side asymmetries unless vasculitis is suspected clinically or if there is intralimb disparity in amplitudes, for example, low superficial peroneal with normal sural sensory response. CIP and the axonal sensorimotor variant of GBS have features of a generalized sensorimotor axonal PN,3,4,61,62,77 whereas only the motor amplitudes are reduced with acute motor axonal neuropathy.59 In CIP, phrenic motor amplitudes may be reduced, and fibrillation potentials appear in the diaphragm.62 In the limbs, fibrillation potentials are usually seen diffusely within 2 to 3 weeks after onset, and findings of reinnervation are seen later. Mild denervation findings may also be seen in facial muscles.4 Early on, there is decreased motor unit potential (MUP) recruitment. Short-duration, polyphasic MUPs may be seen during the early phase of
reinnervation. Especially in this early phase, if sensory responses are spared, CIM needs to be excluded. Direct muscle stimulation discussed lateror muscle biopsy may be useful in further evaluating for CIM if necessary. Typical demyelinating GBS has the familiar features that may include conduction block or temporal dispersion, prolonged latencies, slowing of conduction velocity, and low amplitudes. Upper extremity sensory responses may be more affected than the sural response.78 F-wave prolongation is usually present but may be difficult to identify in the ICU as a result of 60-Hz artifact. Low motor responses are not only typical of CIP; they are commonly encountered in ICU patients with diffuse neuromuscular weakness. In fact, monitoring the peroneal motor amplitude has been advocated as a screening method for evolving CIM or CIP.79 If the sensory responses are normal or relatively spared, and the low motor responses affect several nerves, the most common cause is CIM, but anterior horn cell disease, motor axonopathy, NMJ disorders, and other myopathies may be considered. We perform 2- to 3-Hz repetitive stimulation of the ulnar or median motor nerve to exclude a defect in NMJ transmission, especially if paralytic agents were administered or if myasthenia gravis is suspected. If the rare instances when Lambert-Eaton syndrome or botulism is considered, we perform postexercise single shocks to assess for potentiation of the compound muscle action potentials (CMAPs); and, in patients who cannot exercise, we perform 50 Hz stimulation. In patients with anterior horn cell disease, the needle examination usually reveals fasciculation potentials along with features of denervation, reinnervation, or both in one or more body regions (bulbar, cervical, thoracic, or lumbosacral 80,81 segments). In CIM, the characteristic electrodiagnostic findings are diffusely low CMAPs with normal or minimally reduced sensory nerve action potentials.18,22,28,29,32 It has also been noted that slowing of muscle fiber conduction
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results in a broad, long-duration CMAP.8285 Although the CMAP duration has not been examined in CIP, it has been reported to be normal in neuropathy from diabetes.84 In milder cases of CIM, CMAPs may be normal. In all cases, distal latencies and conduction velocities are normal as is the number of motor units in a given muscle.86 Fibrillation potentials are seen in at least half of examined limb muscles and uncommonly in facial muscles19,29 They may be identified within 1 week of disease onset.19 Electrical myotonia in uncommon.22 If MUPs can be recorded, they are of short duration and low amplitude and typically recruit early. However, needle examination may be difficult in these patients. When MUPs cannot be assessed, direct muscle stimulationdiscussed subsequently may be useful. Nerve conductions are usually normal in other myopathies diagnosed in the ICU. If the needle examination reveals complex repetitive discharges or myotonia along with myopathic (short duration, low amplitude) MUP abnormalities, adult acid maltase deficiency should be suspected. The paraspinal muscles may be preferentially involved. Myotonic discharges may be also present in hydroxychloroquine myopathy.51 Inflammatory and dystrophic myopathies are usually associated with proximal-predominant or diffuse fibrillation potential activity with short-duration, low-amplitude MUPs. Muscle histopathologic analysis and sometimes genetic studies are required for definite diagnosis in most of these myopathies.
described, and it should be noted that DMS does have technical pitfalls, including the risk of end-plate stimulation.83 DMS is usually performed using a stimulating monopolar needle electrode with a surface or subdermal reference electrode placed away from the motor end plate, usually in the distal part of a muscle. The tibialis anterior is commonly studied. After causing a muscle twitch, a recording subdermal needle electrode pair or a concentric needle is placed in the center of the muscle proximal to the site of stimulation, and a maximal direct muscle stimulated CMAP (dmCMAP) is recorded.31,83 Alternatively, Trojaborg et al have used a surface stimulating electrode in their variation of DMS.33 In either scenario, the recording electrode pair is kept in place, and the appropriate nerve undergoes surface stimulation, recording a nerve-evoked CMAP (neCMAP). A neCMAP-to-dmCMAP (nerve to muscle) ratio can be calculated, and a value greater than 0.5, in the setting of a low dmCMAP, suggests that there is a disturbance in muscle membrane excitability consistent with CIM.31 A ratio of less than 0.5 is consistent with neuropathy.31 Allen et al also used DMS to demonstrate slowing of muscle fiber conduction and then confirmed reduced muscle fiber excitability using paired stimuli.83
Epidemiology of Critical Illness Myopathy and Critical Illness Polyneuropathy: Incidence and Risk Factors
The results of the first prospective study of CIP were reported in 1991.5 Of 43 patients in the ICU for more than 5 days with sepsis and multiorgan failure, 70% had electrodiagnostic evidence of axonal sensorimotor PN. Thirtyfive percent had clinical features of PN; 23% were moderately severe to severe. There was worsening PN with time in the ICU and a correlation with hyperglycemia, hypoalbuminemia, and the number of invasive procedures. Other studies revealed that 47% to 76% of ICU patients had electrophysiological evidence of CIP (Table 2).8993 Zifko et al studied 132 ICU patients referred for NCS/EMG found that 47% had CIP, and most had substantial
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Direct Muscle Stimulation

When the routine electrophysiological studies do not distinguish CIM from CIP or if there is suspected overlap, direct muscle stimulation (DMS) may be useful in differentiating these entities. Rich and colleagues first suspected that muscle membrane inexcitability was the cause of the low CMAPs in CIM, and they used DMS to prove it in humans87 and to confirm it in an animal model that also revealed a sodium channelopathy.88 Slightly different DMS techniques have been
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TABLE 2. Prospective Studies of Critical Illness Polyneuropathy Reference Witt et al, 1991
5
Inclusion/Methods
Incidence
Risk Factors
Comment First prospective series 40% diagnosed with CIP had normal sensory responses suggesting a component of CIM; overestimates frequency because patients were referred for electrodiagnostic testing No myopathies detected; no muscle biopsies No myopathies detected
Zifko et al, 199862
43 patients in ICU > 5 days; Sepsis 70% CIP (NCS/EMG) 35% Hyperglycemia; Hypoalbuminemia and MOF; NCS/EMG; examination CIP clinically No. of invasive procedures 132 patients referred for NCS/EMG 47% CIP; approximately No casecontrols (performed Days 7240); SIRS two thirds of these with substantial weakness
Leijten et al, 199689 Tepper et al, 200092 Garnacho-Montero et al, 200191 Druschky et al, 200190 Thiele et al, 200093
38 patients; ventilated for 7 or more 47% CIP (NCS/EMG) days; NCS/EMG 25 patients with septic shock; 76% CIP (NCS/EMG): NCS/EMG within 72 hours At least 50% with substantial weakness 73 patients sepsis; MOF; Ventilation 63% CIP (NCS/EMG) greater than 10 days; NCS/EMG 28 patients ventilated for 4 or more days; EMG/NCS 19 survivors from cohort of 37 patients requiring ventilation for 35 days after heart surgery; NCS/EMG 57% CIP (NCS/EMG)
Multiorgan dysfunction No additional factors described
63% CIP (NCS/EMG)
Parenteral nutrition; NMJ blockers Used very broad range for normal Hyperosmolality; Worsening CNS sural sensory responses; did not function diagnose CIM MODS score; duration of ventilatory Serum neurotoxicity assay: 12 of 16 support; Sepsis and/or lung failure serum samples were toxic to in vitro cultures of rat spinal cord motor neurons Sepsis; Amount of catecholamine Enrolled 37 of 104 eligible patients support; plasma urea level
ICU, intensive care unit; MOF, multiorgan failure; NCS/EMG, nerve conduction studies/electromyogram; SIRS, systemic inflammatory response syndrome; CIP, critical illness polyneuropathy; NMJ, neuromuscular junction; CNS, central nervous system; MODS, multiorgan dysfunction syndrome; CIM, critical illness myopathy.
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weakness.62 Tepper et al showed that CIP could be diagnosed as early as 72 hours after admission for septic shock.92 Risk factors included multiorgan failure,89,90 use of parenteral nutrition, NMJ blockers, hyperosmolality, and worsening CNS function.91 Patients with CIP were on mechanical ventilation for a longer periods, had longer lengths of stay, and had higher mortality. There are three prospective studies of CIM (Table 3). Douglass et al reported the first in 1992. They studied 25 ICU patients with status asthmaticus; all received IV corticosteroids, and 23 received vecuronium. Seventy-six percent had elevated CK levels, whereas 36% had clinical evidence of myopathy with weakness that was usually generalized. Myopathy was confirmed by EMG and muscle biopsy in a subset, but myosin loss was not described. There was some correlation between doses of vecuronium and development of myopathy.20 Campellone et al monitored 100 consecutive critically ill patients after liver transplantation. All received IV corticosteroids and NMJ blockers. Patients underwent electrodiagnostic and histopathologic studies if they had severe weakness with less than antigravity muscle function, so milder cases were not detected in this ill patient population. The incidence of CIM was 7%. Five of seven underwent muscle biopsies that revealed patchy myonecrosis with myosin loss. Risk factors for development of CIM were severity of illness by Acute Physiology and Chronic Health Evaluation II (APACHE II) scores and renal failure requiring dialysis.22 Amaya-Villar et al noted a 34.6% incidence of CIM in patients with severe chronic obstructive pulmonary disease exacerbations. Biopsies in a subset confirmed CIM. Risk factors included total corticosteroid dose and illness severity as well as sepsis.21 A number of prospective studies have evaluated the incidence of CIM, CIP, or both (Table 4).9499 As a result of differing methodologies, they are somewhat difficult to compare. Some evaluated the incidence of neuromuscular disorders in a population at
25 patients status asthmaticus 76% elevated CK All received IV corticosteroids, Myopathy only series CK levels; examination 36% CIM clinically NMJ blockers and other drugs 7% CIM 0% CIP Severity of illness; renal failure Selected for severe cases because patients 100 patients postliver transplant; were already weak from liver failure; evaluated if on ventilator more than underestimates incidence of CIM 7 days or in hospital more than 14 days; NCS/EMG; muscle biopsy 34.6% CIM Illness severity; rate of sepsis; No nerve conductions; could not exclude CIP. 26 patients with COPD requiring total dose of corticosteroids Biopsy confirmed CIM in three (myopathy ventilation and high-dose with myosin loss and Type 2 fiber atrophy) corticosteroids; Needle EMG at Myopathy associated with increased weaning duration of ventilation Douglass et al, 1992
20
TABLE 3. Prospective Studies of Critical Illness Myopathy
Amaya-Villar et al, 200521
Campellone et al, 199822
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CK, creatine kinase; NCS/EMG, nerve conduction studies/electromyogram; COPD, chronic obstructive pulmonary disease; CIM, critical illness polyneuropathy; IV, intravenous; NMJ, neuromuscular junction.
Reference
Inclusion/Methods
Incidence
Risk Factors
Comment
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risk. Others evaluated the cause of weakness in ICU patients. In some studies, comprehensive electrodiagnostic studies were performed that allowed differentiation of CIM from CIP or at least weighed the various contributions of myopathy versus neuropathy. In other studies, differentiation between myopathy and neuropathy was not possible, and the processes were lumped together. Some studies did not confirm CIM histopathologically. They are summarized in Table 4, and some are discussed subsequently. Of note, De Jonghe et al performed a large, multicenter study.95 Of the 95 included patients, 25% were found to have weakness. All had electrodiagnostic evidence of sensorimotor axonal PN. Ten, who underwent muscle biopsy, also had evidence of myopathy, but myosin adenosine triphosphatase stains were not performed. This study is the only one in the group in which risk factors included corticosteroids. Khan et al studied patients with sepsis by NCS within 72 hours of ICU admission96 and examined them weekly, performing needle EMG if there was weakness or if the CMAPs were low. Sixty-three percent had abnormal NCS at enrollment, and 10 of 48 (21%) were felt to have a neuromuscular diseasemostly mixed CIM and CIPduring serial evaluations. Muscle biopsies were not performed.96 In a small study, Tennila et al also performed early electrophysiological studies on ICU Days 2 to 5 on nine ventilated ICU patients with either SIRS or sepsis and multiorgan deficiency syndrome. All had reduced median and ulnar CMAPs; four of five had fibrillation potentials. Motor and sensory conduction velocities were normal. Sensory amplitudes were not reported. These patients were said to have neuromuscular dysfunction. It is not clear if this was CIP or CIM.100 de Letter et al also performed a large prospective study, identifying neuromuscular dysfunction in 33% of patients with various disorders, including traumas, postsurgical states, and medical conditions.97 Bednarik et al performed a comprehensive study that included early NCS (Day 3), quantitative EMG,
and DMS. Muscle and nerve biopsies were performed in a subset. They completed clinical and electrophysiological evaluations over a 28-day period in 60 patients with medical and surgical conditions as well as cerebral infarction and intracranial hemorrhages. There was a 36.3% mortality rate. Of 27.9% of patients with clinical evidence of a neuromuscular disorder, 40% had myopathy, 34% had neuropathy, and 26% had mixed neuropathy and myopathy. In the subset that underwent muscle biopsy, it is uncertain if patients with myopathy had myosin loss. The major risk factors are shown in Table 4.98 Most recently, Hough et al reviewed data collected prospectively in ICU patients with acute respiratory distress syndrome treated with methylprednisolone versus placebo. One hundred twenty-eight survived 60 days. Chart review disclosed neuromuscular weakness in 34%. Of those who underwent electrodiagnostic testing, most had evidence of CIM. The study had limitations, but there was no definite relationship between development of CIM and corticosteroid treatment.101 Two large, prospective, randomized, controlled studies that are not listed in Table 4 addressed the influence of intensive insulin therapy in critically ill surgical and medical patients. Critical illness neuromuscular disorders were evaluated secondarily, and the authors were unable to diagnose CIM or clearly separate CIP from CIM.102105 Van den Berghe et al randomly treated intubated surgical patients with either intensive IV insulin therapy (765 subjects) or conventional insulin dosing (783 subjects). There was a 44% lower incidence of neuromuscular disease in the intensively treated group (28.7% versus 51.9% in the conventionally treated group).104 The diagnoses of CIP were based purely on the presence of positive sharp waves and fibrillation potentials. Motor unit potentials could not be assessed, and NCS was not performed; thus, myopathy could not be diagnosed.105 Next, this group performed a prospective study of 1200 medical ICU patients; 767 stayed in the ICU for 3 days or longer.102
TABLE 4. Prospective Studies of Mixed Critical Illness Polyneuropathy and Myopathy Reference Coakley et al, 199399 Inclusion/Methods 23 patients in ICU longer than 7 days; muscle biopsy in all; electrodiagnostic studies in 10 Incidence Risk Factors Comment
90% abnormal EMG: 6 axonal PN; None identified 2 PN and myopathy; 1 motor syndrome; all muscle biopsies were abnormal 9% sensory PN 43% CIP; 11% motor process 25% weakness; all of these with PN (CIP); Myopathy in at least 11%
44 patients; in ICU longer than 7 days electrodiagnostic studies; muscle biopsies in 24 De Jonghe et al, 95 patients; multicenter; 200295 ventilated greater than 7 days and improving LOC Khan et al, 200696 Latronico et al, 200779 Berek et al, 199661 Hough et al, 2009101 48 patients with sepsis; NCS within 72 hours; Follow-up NCS 6 EMG
Coakley et al, 199894
63% abnormal NCS initially; at least 21% neuromuscular disorders clinically (majority mixed CIM and CIP) 92 patients; multicenter; NCS/EMG 30% CIM/CIP; Definite EMG diagnosis in 13: CIM (6); at 24 hours and daily peroneal CIP (4); mixed CIM/CIP (3) and sural NCS 22 patients with sepsis or SIRS and MOF; NCS/EMG 82% CIP by NCS/EMG; 41% CIP clinically
Muscle pathology included neurogenic atrophy, Type 2 fiber atrophy, and nonspecific myopathic changes including necrosis; myosin loss was not identified No association with illness Did not identify CIM; muscle biopsies severity, sepsis, or drugs revealed mixed (myopathic and neurogenic) changes 10 of 10 who underwent muscle biopsy Female; duration of also had evidence of myopathy ventilation and organ (myosin ATPase stains were not dysfunction; corticosteroids assessed) (not dose-related) Abnormal initial NCS predictive of in No association with hospital mortality. No muscle biopsies corticosteroids of NMJ blockers MOF NO associated with SIRS, sepsis, drugs, nutrition No comparison group No risk from corticosteroids Did not fully differentiate CIM from CIP; no muscle biopsies Drop in peroneal motor amplitude of 25% predictive of CIP/CIM No myopathies identified Not truly a prospective analysis; no muscle biopsies; limited differentiation of CIP from CIM
34% CIM/CIP; NCS/EMG 128 patients who were alive at performed on 11; of these, Day 60 in study of acute lung 9 had CIM injury treated with IV corticosteroids versus placebo; secondary analysis (chart review)
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ICU, intensive care unit; LOC, level of consciousness; NCS, nerve conduction study; EMG, electromyography; SIRS, systemic inflammatory response syndrome; MOF, multiorgan function; IV, intravenous; PN, polyneuropathy; CIP, critical illness polyneuropathy; CIM, critical illness myopathy; NMJ, neuromuscular junction.
Degree of MOF and duration of SIRS during first week was predictive of CIP/CIM. Muscle biopsies (11 patients): myopathic changes in all, and neurogenic changes in 7; nerve biopsies (5): axon loss; Did not differentiate CIP from CIM in most cases Did not differentiate CIP from CIM; no muscle biopsies; Notable that authors did not include acute quadriplegic myopathy with loss of thick filaments
Patients who were in the ICU at and beyond Day 7 were screened by weekly electroneuromyography, but the details of this analysis were not provided. Again, there was no separation of CIP from CIM. Blood glucose levels, but not the insulin dose, independently correlated with the risk of developing CIP. There was also a protectant effect on the CNS.105 A total of 50.5% of conventionally treated patients developed neuromuscular dysfunction, versus 38.9% in the intensively treated group, a 20% reduction. Neuromuscular junction-blocking agents were a risk factor for developing neuromuscular dysfunction, but corticosteroids were not. The duration of mechanical ventilation was reduced in the intensively treated group.103 As a note of caution, a recent study of intensive treatment of hyperglycemia disclosed an increased mortality rate.106 Two studies in which comprehensive electrodiagnostic studies were performed on weak patients provided interesting results. Trojaborg et al evaluated 22 ICU patients who underwent EMG for evaluation of weakness.33 NCS, needle electrode examination, DMS, quantitative EMG, and motor unit number estimation were performed, and nine underwent muscle biopsies. All were found to have evidence of myopathy; a milder PN was present in five patients, usually with motor greater than sensory involvement. Lefaucher et al107 performed a somewhat similar study on 30 consecutive ICU patients with moderate to severe weakness. They underwent mechanical ventilation for 7 or more days and were evaluated by NCS, needle EMG, and DMS. The authors concluded that 25 of 30 (83%) had evidence of myopathy, whereas 16 (53%) had low sensory nerve action potentials consistent with a component of PN. What is the take-home message of these studies? First, neuromuscular weakness commonly occurs in ICU patients. Clinically significant weakness occurs in at least 25%, and subclinical neuromuscular dysfunction is much more common. A systematic review of CIP/CIM studies disclosed an incidence of
27.9% CIP/CIM (clinically); 57.4% CIP/CIM (NCS/EMG)
de Letter et al, 200197
Bednarik et al, 200598
98 patients on ventilator for 4 or more days; Clinical examination, NCS/EMG on Days 4, 11, and 25 minimum
60 patients with two or more failing organs; Extensive electrodiagnostic Testing
33% CIM/CIP
SIRS and severity of illness; no increased risk with corticosteroids or NMJ blockers
Presence and duration of SIRS and severity of MOF; no correlation with NMJ blockers or corticosteroids
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46% overall.108 Compared with CIP, it is often more difficult to diagnose CIM without a muscle biopsy or sophisticated electrophysiological testing. Therefore, it is difficult to separate CIM and CIP in studies that not did not use such measures, and CIM is probably underrepresented. In studies of mixed CIM and CIP in which these extensive studies were performed, it seemed that CIM was the predominant component. The weight of evidence confirms that SIRS109 and multiorgan failure are the major risk factors for CIP, although some studies did not note these associations.79,94 Hyperglycemia is another. There is probably a correlation with the severity of the underlying illness. The likelihood of developing CIP increases with the number of days in the ICU5; however, it may occur within 72 hours of onset of critical illness. There are no definite associations with pharmacologic treatments such as corticosteroids, but some debate exists. Risk factors for CIM are less certain as a result of prospective study designs that often did not differentiate CIM from CIP or assess for myosin loss. It does appear that IV corticosteroids and probably NMJ blockers are risk factors, especially when myosin loss is present. SIRS may be another. Earlier uncontrolled studies in asthmatics associated CIM with the use of these drugs.10 20,71,110115 There may be a dose relationship with NMJ blockers,21 but a dose relationship with corticosteroids is uncertain. There have been pathologically confirmed cases of CIM with myosin loss in which neither corticosteroids nor NMJ blockers were administered.116118 These patients all had sepsis or SIRS. In the reports of patients with status asthmaticus, many had SIRS, but some had only respiratory failure and did not meet criteria for SIRS, suggesting SIRS is a risk factor but not a prerequisite for CIM.18 In addition, the severity of the underlying illness does correlate with development of myopathy (Table 3), and the presence of renal failure also correlated in a transplant population.22
Pathology and Pathogenesis

Critical Illness Polyneuropathy The main pathologic lesion is axonal degeneration of sensory and motor axons, but nerve biopsies are sometimes normal.3,4,98,119 The cause of axonal degeneration is not known, but peripheral nerve is considered to be one of the tissues that is injured by SIRS and multiorgan failure. A number of metabolic derangements and release of cytokines such as interleukins-1, -2, and -6, and tumor necrosis factor-a likely culminate in axonal injury from proinflammatory and vascular mediators as reviewed by Bolton.65,120 There is some supportive evidence of cytokines being produced by activated leukocytes in muscle specimens from patients with CIP/CIM.121 Hyperglycemia, increased capillary permeability, endothelial cell activation122 and possibly hypoalbuminemia could also impair delivery of oxygen and metabolic substrates to the endoneurium. A humoral factor (identity undetermined) has also been noted in patients with CIP, but its significance is unknown and warrants further investigation because it has been shown be toxic to rat spinal cord neurons.90,123,124 Several studies have also showed that ICU patients may exhibit transient reductions in motor and sensory responses consistent with a reversible neuropathy without axonal degeneration.125 A chronic sepsis animal model has been produced by cecal ligature and needle perforation. In this model, decreased sodium current was identified.126 Additional study of this model, in which there are declines mixed sensory tail nerve recordings, revealed reduced excitability in dorsal root sensory axons through intracellular recordings. These experiments indicated that sodium channels were inactivated,127 consistent with the hypothesis that a potentially reversible channelopathy also occurs early in the course of CIP. Critical Illness Myopathy When CIM is suspected, a muscle biopsy may be obtained, especially if the
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electrodiagnostic findings are inconclusive or if the differential diagnosis includes toxic or inflammatory myopathy. The major histopathologic findings include myofiber atrophy, which may affect Type 2 more than Type 1 fibers, along with myofibrillar disorganization. Occasionally, all Type 2 fibers are atrophic, regenerating, or both.128 A variable degree of necrosis and regeneration may occur.29 Excess lipid deposits have also been noted. However, the characteristic feature is the loss of myosin-thick filaments.22,29,32,35,110,111,115 Suspicion for myosin loss is raised when there is reduced or patchy reactivity on myosin adenosine triphosphatase-reacted sections. It may be present primarily in atrophic fibers,129 making it less noticeable. It can be subtle or obvious resulting in core-like lesions (Fig. 1). Myosin loss can be proven with immunohistochemical staining for myosin, by
ultrastructural studies (Fig. 1D), and by electrophoresis.130 Immunostains are more variable depending on the myosin isoforms that are examined.32 Myosin loss may be related to a decreased transcription rate or loss of myosin messenger RNA.32 Structural proteins, aside from myosin, are mostly unaffected.32,118,130 Myosin loss is often seen along with features of myofibrillar disorganization, including abnormal basophilic stippling with hematoxylin and eosin stains, purplish staining with Gomori trichrome, and irregular clumping of the reaction product or core-like changes with NADH-TR staining. Additionally, evidence of abnormal degradative pathway activation has been found. There is upregulation of calpain118,131 along with increased apoptosis.132 Results of ubiquitin immunoreactivity are mixed.118,132
FIGURE 1. (AC) Part of the spectrum of alterations in myosin-adenosine triphosphatase (ATPase) reactivity in critical illness myopathy (cryostat sections, pH 9.4). (A) There is a subtle, less than expected differentiation in stain intensity in Type 1 (light) and Type 2 (dark) fibers. (See normal inset in C for comparison.) Rare fibers have a mild patchy reduction in reactivity (see arrows), whereas a rare fiber (asterisk) has reduced reactivity that is also seen at pHs 4.3 and 4.6. (Other pHs are not shown.) There is also atrophy of Type 1 more than Type 2 fibers. (Bar = 30 mm.) (B) Type 2 fibers are atrophic, and many Type 1 and Type 2 fibers have a mild, patchy, and often central reduction in reactivity. (C) There are obvious core-like regions of absent myosin-ATPase reactivity in many fibers. (As mentioned, the inset reveals normal ATPase reactivity.) (D) An electron photomicrograph reveals a myofiber (top) with preservation of Z-bands and thin filaments with loss of the intervening A-bands containing thick filaments. In comparison, an atrophic myofiber at the bottom has preservation of both thick and thin filaments.
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There is also upregulation of the transforming growth factor-b/mitogen-activated protein kinase pathway,133 and oxidative stress may also play a role. It has been hypothesized that loss of sarcolemmal nitric oxide synthase 1 leads to muscle fiber inexcitability by reducing nitric oxide release at the muscle membrane.134 In septic patients, an increase in muscle nitric oxide synthase 2 mRNA and protein has been associated with peroxynitrate formation and reduced contractile strength.135 Myogenic differentiation factor D plays an important role in regulating muscle differentiation, and it may be involved in CIM and in cachectic myopathy. Myogenic differentiation factor D and other myogenic regulatory factors influence the activity of a number of muscle-specific genes, including myosin light chain and myosin heavy chain. Myogenic differentiation factor D is preferentially expressed in fast twitch fibers, and it is upregulated with denervation.136 Diaphragm dysfunction is presumably present in patients with CIM and failure to wean from mechanical ventilation, but a comprehensive histopathologic study of the human diaphragm has not been undertaken. However, studies of diaphragm from patients who had undergone mechanical ventilation for 18 to 69 hours showed atrophy of slowand fast-twitch fibers, increased caspase activation, decreased glutathione, and increased activity in the ubiquitin proteosome pathway. This study shows that the diaphragm muscle is susceptible to proteolysis in critical illness, disuse, or both.137
Animal Data A rodent model using intraperitoneal corticosteroids and denervation reproduces the histologic, electrophysiological, and channelopathy features of CIM.138140 It also suggests that this combination leads to selective depletion of myosin mRNA as detected in the animal model by Mozaffar et al141 and as shown in humans.32 Furthermore, a mouse neuropathy model suggests
that the state of innervation regulates myosin isoforms.142 Activity levels also influence myosin isoform expression.143 A recently developed septic rat model uses limb immobilization and systemic injections of Corynebacterium resulting in loss of body weight, muscle atrophy, reduced tetanic contraction, and inflammation with probable myofiber degeneration.144 Muscle specimens were not assessed for myosin loss, and this could be characterized as a model of necrotizing myopathy. Studies of the effects of high doses of intramuscular methylprednisolone on rabbit diaphragm muscle function revealed a decline in diaphragm maximum muscle tension, myofibrillar disarray, suppression of insulin growth factor Type 1, and overexpression of muscle atrophy F-box mRNA. The authors suggested that there was activation of the ubiquitinproteasome pathway.145 A recent review by Friedrich provides a comprehensive discussion of all of the pathways that may be affected in CIM.146 In summary, the animal models of CIM support a role for corticosteroids as well as neurogenic factors in leading to myosin loss and channelopathy. Immobilization and infection may play roles in muscle inflammation and necrosis. In some patients, CIP could be a neurogenic trigger for CIM. NMJ blockers or myasthenia gravis147 could also serve as neurogenic triggers as a result of motor endplate involvement. Furthermore, it is conceivable that there are two categories of CIM, one with myosin loss and one with myonecrosis only, and that the risk factors differ. To confirm that hypothesis, additional prospective human studies that include comprehensive electrodiagnostic testing and muscle histopathology will be necessary.
Treatment and Outcomes

There are no proven therapies that reverse CIP or CIM. The underlying systemic illness must be treated aggressively. As noted, there is a 20% to 44% lower incidence of neuromuscular disease in ICU patients who are intensively treated for hyperglycemia,102,104
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but there is concern about a possible increased mortality rate with intensive treatment of hyperglycemia.106 A prospective, uncontrolled study of 33 patients with multiorgan dysfunction syndrome (16 with Gramnegative septicemia) suggested that 0.9 g/kg of intravenous immunoglobulin given over 3 days may prevent CIP in patients with septicemia or SIRS,148 but a larger prospective, controlled trial is necessary to make that determination. At least in CIM, injudicious use of IV corticosteroids should be avoided, and sedatives should probably be used instead of NMJ blockers when possible. Based on the work of Latronico et al, patients at risk for CIM and CIP could be monitored by serial peroneal motor NCSs,79 and serial assessments of serum CK may also predict development of CIM.20 Once CIM is identified, corticosteroids should probably be tapered or discontinued if possible, but benefit from this intervention has not been proven. Rechallenge with IV corticosteroids should be avoided, if possible, because CIM may recur.13 If there is associated rhabdomyolysis, IV hydration with alkaline diuresis is recommended to avoid renal failure.149 Otherwise, treatment is largely supportive. Like with all critically ill patients, those with neuromuscular weakness should be provided with adequate nutritional intake, correction of underlying metabolic disorders such as hypokalemia and hypophosphatemia, and aggressive treatment of underlying infections. Prophylaxis for deep venous thrombosis, pulmonary toilet, padding of pressure points, frequent turning, physiotherapy, and appropriate orthotics are recommended. Rehabilitation may be required.150 Regarding outcomes, there is growing evidence that persistent neuromuscular dysfunction is a common consequence of critical illness. There is evidence of partial denervation on electrodiagnostic testing performed up to 5 years after the critical illness.151 Most survivors of adult respiratory distress syndrome, who were followed for 12 months after discharge, were found to have muscle wasting and weakness.152 Determining
whether these patients have CIM, CIP, or another neuromuscular problem is a challenge. In CIP, there is a high mortality rate (up to 50%) resulting from the underlying disease. In the acute period, abnormal NCS is predictive of in-hospital mortality.96,125 The majority of survivors tend to recover partially (severe PN) or fully (mild to moderate PN) over months, and milder symptoms and signs may resolve in weeks.153 Two-year follow up of 19 patients with CIP, who had severe enough weakness to be admitted to a rehabilitation facility, revealed that 58% had full recovery, 21% remained quadriplegic, 11% had milder residual weakness, and 11% died.154 Another study disclosed that 21% of patients with CIP have severe residual handicaps at one year.89 Guarneri et al reported worse outcomes in four patients with CIP seen at 1 year. One recovered, one was tetraplegic, and two had residual weakness.155 Like with most axonopathies, distal leg weakness and sensory disturbances are the most common residual effects.156 Patients with CIM, who do not die of their underlying disorder, usually recover over weeks to months, and most recover fully.18,29,150,155 However, there is considerable morbidity and increased medical costs associated with CIM. For example, the mean time to ambulation is approximately 8 weeks, and in one study of patients with CIM undergoing liver transplantation, the time in the ICU was 49 6 36 days (mean 6 standard deviation) versus 14 6 14 days for those without CIM.22 Although patients with CIM are generally in poorer health overall, failure to wean from CIM is a major contributor to prolonged ICU stays. However, CIM does appear to have a better prognosis than CIP.155
Future Directions
In prospective human studies, it is important to differentiate CIP from CIM as best as possible using diagnostic criteria such as those already suggested (Tables 5 and 6).36,65,157 Otherwise, clear identification of risk factors is very difficult. Matched case control subjects are also necessary. It would
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TABLE 5. Diagnostic Criteria for Critical Illness Myopathy (CIM) Major features: 1. Sensory nerve amplitudes greater than 80% of the lower limit of normal (LLN) in two or more nerves; 2. Needle electromyography with short duration, low amplitude motor unit potentials with early or normal full recruitment with or without fibrillation potentials; 3. Absence of a decremental response on repetitive nerve stimulation; and 4. Muscle histopathologic findings of myopathy with myosin loss. Supportive features: 1. Compound muscle action potential (CMAP) amplitudes less than 80% LLN without conduction block; 2. Elevated serum creatine kinase (best assessed in first week of illness); 3. Demonstration of muscle inexcitability by direct muscle stimulation; and 4. Prolonged duration of CMAPs. By definition, the patients are also critically ill. Definite CIM: All four major features. Probable CIM: Any three major features and one or more supportive features. Possible CIM: Either major features 1 and 3 or 2 and 3 and one or more supportive feature. Modified from Lacomis D, Zochodne D, Bird SJ. Critical illness myopathy [Editorial]. Muscle Nerve. 2000;23:17851788.36
also be of interest to determine if patients with CIM with myosin loss versus CIM with necrosis and no myosin loss have different risk factors such as corticosteroids or SIRS. Although there is a tendency to avoid open muscle biopsies in these patients, needle muscle biopsies have been used effectively in previous studies.29,32,94,99 Although there are considerable amounts of data on disease mechanisms,
especially in CIM, further study is necessary to identify specific factors that could be subjected to therapy that blocks or reverses symptoms. Such a treatment could be most effective in the earlier stages when channelopathy may be predominant in both CIM and CIP. Thus, it is also paramount that study patients are monitored for onset by straightforward techniques such as serial peroneal motor studies. It is desirable to have larger
TABLE 6. Diagnostic Criteria for Critical Illness Polyneuropathy (CIP) Major features: 1. The patient is critically ill; 2. Possible diffuse limb weakness, difficulty weaning from mechanical ventilation in the absence of a nonneuromuscular etiology, or both; and 3. Electrophysiological evidence of axonal motor and sensory polyneuropathy, including: d Sensory and motor nerve amplitudes less than 80% of the lower limit of normal in two or more nerves d Absence of conduction block or prolongation of F-waves d Needle electromyography with reduced recruitment of normal motor unit potentials (MUPs) (early), fibrillation potentials and reduced recruitment of long-duration, high-amplitude MUPs (after weeks) Supportive features: 1. Absence of a decremental response on repetitive nerve stimulation; 2. Absence of myopathy with myosin loss on muscle biopsy; 3. Presence of axonal degeneration on nerve biopsy; and 4. A nerve-evoked muscle action potential-to-direct muscle stimulated continuous muscle action potential (CMAP) (nerve to muscle) ratio of less than 0.5 with direct stimulation. Diagnosis of CIP should include all major features. If all of the elements of item 3 (electrophysiological evidence) are not present, supportive features 1 and 4, 1 and 2, or 1 and 3 should be present. Modified from Bolton CF. Neuromuscular manifestations of critical illness. Muscle Nerve.2005;32: 14016365 and Lacomis D. Neuromuscular weakness related to critical illness. In: Rose BD, ed. UpToDate.Wellesley, MA; 2007.157
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prospective studies that assess outcomes and interventions that may include specific and innovative physiotherapy techniques such as muscle stimulation. All prospective studies of critical illness states such as sepsis and lung injury should include neuromuscular sequelae as a secondary end point. The role for such studies in patients at risk for ICU-acquired neuromuscular disorders, the methods to use in these studies, and the specific issues to address have been thoughtfully discussed by Hough and Needham.158
16. Blackie JD, Gibson P, Murree-Allen K, et al. Acute myopathy in status asthmaticus. Clin Exp Neurol. 1993;30:7281. 17. Griffin D, Fairman N, Coursin D, et al. Acute myopathy during treatment of status asthmaticus with corticosteroids and steroidal muscle relaxants. Chest. 1992;102:510514. 18. Leatherman JW, Fluegel WL, David WS, et al. Muscle weakness in mechanically ventilated patients with severe asthma. Am J Respir Crit Care Med. 1996;153:16861690. 19. Road J, Mackie G, Jiang TX, et al. Reversible paralysis with status asthmaticus, steroids, and pancuronium: clinical electrophysiological correlates. Muscle Nerve. 1997;20:15871590. 20. Douglass JA, Tuxen DV, Horne M, et al. Myopathy in severe asthma. Am Rev Respir Dis. 1992;146: 517519. 21. Amaya-Villar R, Garnacho-Montero J, GarciaGarmendia JL et al. Steroid-induced myopathy in patients intubated due to exacerbation of chronic obstructive pulmonary disease. Intensive Care Med. 2005;31:157161. 22. Campellone JV, Lacomis D, Kramer DJ, et al. Acute myopathy after liver transplantation. Neurology. 1998;50:4653. 23. Miro O, Salmeron JM, Masanes F, et al. Acute quadriplegic myopathy with myosin-deficient muscle fibres after liver transplantation: defining the clinical picture and delimiting the risk factors. Transplantation. 1999;67:11441151. 24. Subramony SH, Carpenter DE, Raju S, et al. Myopathy and prolonged neuromuscular blockade after lung transplant. Crit Care Med. 1991:19:15801582. 25. Salviati L, Laverda AM, Zancan L, et al. Acute quadriplegic myopathy in a 17-month-old boy. J Child Neurol. 2000;15:6366. 26. Chetaille P, Paut O, Fraisse A, et al. Acute myopathy of intensive care in child after heart transplantation. Can J Anaesth. 2000;47:342346. 27. Perea M, Picon M, Miro O, et al. Acute quadriplegic myopathy with loss of thick (myosin) filaments following heart transplantation. J Heart Lung Transplant. 2001;20:11361141. 28. Hanson P, Dive A, Brucher JM, et al. Acute corticosteroid myopathy in intensive care patients. Muscle Nerve. 1997;20:13711380. 29. Lacomis D, Giuliani MJ, Van Cott A, et al. Acute myopathy of intensive care: clinical, electromyographic, and pathological aspects. Ann Neurol. 1996;40:645654. 30. Faragher MW, Day, BJ, Dennett X. Critical care myopathy: an electrophysiological and histological study. Muscle Nerve. 1996;19:516518. 31. Rich MM, Bird SJ, Raps EC, et al. Direct muscle stimulation in acute quadriplegic myopathy. Muscle Nerve. 1997;20:665673. 32. Larsson L, Li X, Edstrom L, et al. Acute quadriplegia and loss of muscle myosin in patients treated with nondepolarizing neuromuscular blocking agents and corticosteroids: mechanisms at the cellular and molecular levels. Crit Care Med. 2000;28:3445. 33. Trojaborg W, Weimer LH, Hays AP. Electrophysiologic studies in critical illness associated weakness:
REFERENCES
1. Russell JA. Management of sepsis. N Engl J Med. 2006;355:16991713. 2. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101: 16441655. 3. Bolton CF, Gilbert JJ, Hahn AF, et al. Polyneuropathy in critically ill patients. J Neurol Neurosurg Psychiatry. 1984;47:12231231. 4. Zochodne DW, Bolton CF, Wells GA, et al. Critical illness polyneuropathy. A complication of sepsis and multiple organ failure. Brain. 1987;110: 819841. 5. Witt NJ, Zochodne DW, Bolton CF, et al. Peripheral nerve function in sepsis and multiple organ failure. Chest. 1991;99:176184. 6. Bolton CF. The discovery of critical illness polyneuropathy. Eur J Anaesthesiol. 2008;S42:6667. 7. Osler W. The Principles and Practice of Medicine. New York: D Appleton; 1892. 8. Mertens HG. Disseminated neuropathy following coma. On the differentiation of so-called toxic polyneuropathy. Nervenartz. 1961;32:7179. 9. Henderson B, Koepke GH, Feller I. Peripheral polyneuropathy among patients with burns. Arch Phys Med Rehabil. 1971;52:149151. 10. Kaplan PW, Rocha W, Sanders DB, et al. Acute steroid-induced tetraplegia following status asthmaticus. Pediatrics. 1986;78:121123. 11. Knox AJ, Mascie-Taylor BH, Muers MF. Acute hydrocortisone myopathy in acute severe asthma. Thorax. 1986;41:411412. 12. Van Marle W, Woods KL. Acute hydrocortisone myopathy. BMJ. 1980;281:271272. 13. Williams TJ, OHehir RE, Czarny D, et al. Acute myopathy in severe acute asthma treated with intravenously administered corticosteroids. Am Rev Respir Dis. 1988;137:460463. 14. MacFarlane IA, Rosenthal FD. Severe myopathy after status asthmaticus. Lancet. 1977;2:615. 15. Shee CD. Risk factors for hydrocortisone myopathy in acute severe asthma. Respir Med. 1990;84: 229233. 2011 Lippincott Williams & Wilkins
Journal of

215
myopathy or neuropathya reappraisal. Clin Neurophysiol. 2001;112:15861593. 34. Zochodne DW, Ramsay DA, Saly V, et al. Acute necrotizing myopathy of intensive care: electrophysiological studies. Muscle Nerve. 1994;17: 285292. 35. Sander HW, Golden M, Danon MJ. Quadriplegic areflexic ICU illness: selective thick filament loss and normal nerve histology. Muscle Nerve. 2002: 26;499505. 36. Lacomis D, Zochodne D, Bird SJ. Critical illness myopathy [Editorial]. Muscle Nerve. 2000;23:1785 1788. 37. Segredo V, Caldwell JE, Matthay MA, et al. Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med. 1992; 327:524528. 38. Segredo V, Matthay MA, Sharma ML, et al. Prolonged neuromuscular blockade after long-term administration of vecuronium in two critically ill patients. Anesthesiology. 1990;72:566570. 39. Partridge BL, Abrams JH, Bazemore C, et al. Prolonged neuromuscular blockade after long-term infusion of vecuronium bromide in the intensive care unit. Crit Care Med. 1990;18:11771179. 40. Shanks AB, Long T, Aitkenhead AR. Prolonged neuromuscular blockade following vecuronium. Br J Anaesth. 1985;57:807810. 41. Kupfer Y, Namba T, Kaldawi E, et al. Prolonged weakness after long-term infusion of vecuronium bromide. Ann Intern Med. 1992;117:484486. 42. Gooch JL, Suchyta MR, Balbierz, JM, et al. Prolonged paralysis after treatment with neuromuscular junction blocking agents. Crit Care Med. 1991, 19:11251131. 43. Op de Coul AA, Lambregts PC, Koeman J, et al. Neuromuscular complications in patients given Pavulon (pancuronium bromide) during artificial ventilation. Clin Neurol Neurosurg. 1985;87: 1722. 44. Barohn RJ, Jackson CE, Rogers SJ, et al. Prolonged paralysis due to nondepolarizing neuromuscular blocking agents and corticosteroids. Muscle Nerve. 1994;17:647654. 45. Campellone JV. Clinical approach to neuromuscular weakness in the critically ill patient. J Clin Neuromuscul Dis. 2000;1:151158. 46. Lacomis D, Petrella JT, Giuliani MJ. Causes of neuromuscular weakness in the intensive care unit: a study of ninety-two patients. Muscle Nerve. 1998; 21:610617. 47. Rosenow EC III, Engel AG. Acid maltase deficiency in adults presenting as respiratory failure. Am J Med. 1978;64:485491. 48. Hughes RA, Bihari D. Acute neuromuscular respiratory paralysis. J Neurol Neurosurg Psychiatry. 1993;56:334343. 49. Kelly BJ, Luce JM. The diagnosis and management of neuromuscular diseases causing respiratory failure. Chest. 1991;99:14851494. 50. ODonohue WJ Jr, Baker JP, Bell GM, et al. Respiratory failure in neuromuscular disease. Management in a respiratory intensive care unit. JAMA. 1976;235:733735.
51. Abdel-Hamid H, Oddis CV, Lacomis D. Severe hydroxychloroquine myopathy. Muscle Nerve. 2008;38:12061210. 52. Souayah N, Sander HW, Menkes DL, et al. Hepatitis C virus acute quadriparetic vasculitic neuropathy responsive to cyclophosphamide. Neurol Neurophysiol Neurosci. 2006;18:5. 53. Newman JH, Neff TA, Ziporin P. Acute respiratory failure associated with hypophosphatemia. N Engl J Med. 1997;296:11011103. 54. Bruno C, Sacco O, Santorelli FM, et al. Mitochondrial myopathy and respiratory failure associated with a new mutation in the mitochondrial transfer ribonucleic acid glutamic acid gene. J Child Neurol. 2003;18:300303. 55. Gorson KC, Ropper AH. Nonpoliovirus poliomyeli tis simulating Guillain-Barre syndrome. Arch Neurol. 2001;58:14601464. 56. Spitzer AR, Giancarlo T, Maher L, et al. Neuromuscular causes of prolonged ventilator dependency. Muscle Nerve. 1992;15:682686. 57. Davis LE, DeBiasi R, Goade DE, et al. West Nile virus neuroinvasive disease. Ann Neurol. 2006;60: 286300. 58. Seybold ME. Diagnosis of myasthenia gravis. In: Engel AG, ed. Myasthenia Gravis and Myasthenic Disorders. New York: Oxford University Press; 1999:146166. 59. McKhann GM, Cornblath DR, Griffin JW, et al. Acute motor axonal neuropathy: a frequent cause of acute flaccid paralysis in China. Ann Neurol. 1993;33:333342. 60. Albers JW, Fink JK. Porphyric neuropathy. Muscle Nerve. 2004;30:410422. 61. Berek K, Margreiter J, Willeit J, et al. Polyneuropathies in critically ill patients: a prospective evaluation. Intensive Care Med. 1996;22:849855. 62. Zifko UA, Zipko HT, Bolton CF. Clinical and electrophysiological findings in critical illness polyneuropathy. J Neurol Sci. 1998;159:186193. 63. Mastaglia FL, Garlepp MJ, Phillips BA, et al. Inflammatory myopathies: clinical, diagnostic, and therapeutic aspects. Muscle Nerve. 2003;27:407425. 64. Bolton CF. Sepsis and the systemic inflammatory response syndrome: neuromuscular manifestations. Crit Care Med. 1996;24:14081416. 65. Bolton CF. Neuromuscular manifestations of critical illness. Muscle Nerve. 2005;32:140163. 66. Ramsay DA, Zochodne DW, Robertson DM, et al. A syndrome of acute severe muscle necrosis in intensive care unit patients. J Neuropathol Exp Neurol. 1993;52:387398. 67. Al-Shekhlee A, Hachwi R, Jaberi MM, et al. The electromyographic features of acute rhabdomyolysis. J Clin Neuromuscul Dis. 2005;6:114118. 68. Helliwell TR, Wilkinson A, Griffiths RD, et al. Muscle fibre atrophy in critically ill patients is associated with the loss of myosin filaments and the presence of lysosomal enzymes and ubiquitin. Neuropathol Appl Neurobiol. 1998;24:507517. 69. Sun DY, Edgar M, Rubin M. Hemiparetic acute myopathy of intensive care progressing to triplegia. Arch Neurol. 1997;54:14201422. www.jcnmd.com
216
Journal of

Lacomis
70. Vattemi G, Tonin P, Filosto M, et al. Reversible upper limb muscle weakness with selective loss of thick filaments. Neurology. 2003;61:863864. 71. Sitwell LD, Weinshenker BG, Monpetit V, et al. Complete ophthalmoplegia as a complication of acute corticosteroid- and pancuronium-associated myopathy. Neurology. 1991;41:921922. 72. Al-Shekhlee A, Shapiro BE, Preston DC. Iatrogenic complications and risks of nerve conduction studies and needle electromyography. Muscle Nerve. 2003;27:517526. 73. Bolton CF. Phrenic nerve conduction studies: technical aspects and normative data. Muscle Nerve. 2008;38:16581659. 74. Chen R, Collins S, Remtulla H, et al. Phrenic nerve conduction study in normal subjects. Muscle Nerve. 1995;18:330335. 75. Bolton CF. AAEM Minimonograph #40: clinical neurophysiology of the respiratory system. Muscle Nerve. 1993;16:809818. 76. Resman-Gaspersc A, Podnar S. Phrenic nerve conduction studies: technical aspects and normative data. Muscle Nerve. 2008;37:3641. 77. Chowdhury D, Arora A. Axonal Guillain-Barre syndrome: a critical review. Acta Neurol Scand. 2001; 103:267277. 78. Van den Bergh PY, Pieret F. Electrodiagnostic criteria for acute and chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve. 2004; 29:565574. 79. Latronico N, Bertolini G, Guarneri B, et al. Simplified electrophysiological evaluation of peripheral nerves in critically ill patients: the Italian multicentre CRIMYNE study. Crit Care. 2007;11:R11. 80. Daube JR. Electrodiagnostic studies in amyotrophic lateral sclerosis and other motor neuron disorders. Muscle Nerve. 2000;23:14881502. 81. Makki AA, Benetar M. The electromyographic diagnosis of amyotrophic lateral sclerosis: does the evidence support the El Escorial criteria? Muscle Nerve. 2007;35:614619. 82. Park EJ, Nishida T, Sufit RL, et al. Prolonged compound muscle action potential duration in critical illness myopathy. Report of nine cases. J Clin Neuromuscul Dis. 2004;5:176183. 83. Allen DC, Arunachalam R, Mills KR. Critical illness myopathy: further evidence from musclefiber excitability studies of an acquired channelopathy. Muscle Nerve. 2008;37:1422. 84. Trojaborg W. Electrophysiologic techniques in critical illness-associated weakness. J Neurol Sci. 2006: 242:8385. 85. Case Records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 11 1997. A 51-year-old man with chronic obstructive pulmonary disease and generalized muscle weakness. N Engl J Med. 1997:336:10791088. 86. Trojaborg W, Kaufmann P Gooch CL. Motor unit esti, mate number in the anterior tibial muscle: normative data versus findings in critically ill patients in intensive care units. J Clin Neuromuscul Dis. 2002;3:139142. 87. Rich MM, Teener JW, Raps EC, et al. Muscle is electrically inexcitable in acute quadriplegic myopathy. Neurology. 1996;46:731736. 2011 Lippincott Williams & Wilkins
88. Rich MM, Pinter MJ, Kramer SD, et al. Loss of electrical excitability in an animal model of acute quadriplegic myopathy. Ann Neurol. 1998;43:171 179. 89. Leijten FS, De Weerd AW, Poortvliet DC. Critical illness polyneuropathy in multiple organ dysfunction syndrome and weaning from the ventilator. Intensive Care Med. 1996;22:856861. 90. Druschky A, Herkert M, Radespiel-Troger M, et al. Critical illness polyneuropathy: clinical findings and cell culture assay of neurotoxicity assessed by a prospective study. Intensive Care Med. 2001;27: 686693. 91. Garnacho-Montero J, Madrazo-Osuna J, GarcaGarmendia JL, et al. Critical illness polyneuropathy: risk factors and clinical consequences. A cohort study in septic patients. Intensive Care Med. 2001; 27:12881296. 92. Tepper M, Rakic S, Haas JA, et al. Incidence and onset of critical illness polyneuropathy in patients with septic shock. Neth J Med. 2000;56:211214. 93. Thiele RI, Jakob H, Hund E, et al. Sepsis and catecholamine support are the major risk factors for critical illness polyneuropathy after open heart surgery. Thorac Cardiovasc Surg. 2000;48:145 150. 94. Coakley JH, Nagendran K, Yarwood GD, et al. Patterns of neurophysiological abnormality in prolonged critical illness. Intensive Care Med. 1998;24:801807. 95. De Jonghe B, Sharshar T, Lefaucheur, JP, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA. 2002;288:2859 2867. 96. Khan J, Harrison TB, Rich MM, et al. Early development of critical illness myopathy and neuropathy in patients with severe sepsis. Neurology. 2006;67:14211425. 97. de Letter MA, Schmitz PI, Visser LH, et al. Risk factors for the development of polyneuropathy and myopathy in critically ill patients. Crit Care Med. 2001;29:22812286. 98. Bednarik J, Vondracek P, Dusek L, et al. Risk factors for critical illness polyneuromyopathy. J Neurol. 2005;252:343351. 99. Coakley JH, Nagendran K, Honavar M, et al. Preliminary observations on the neuromuscular abnormalities in patients with organ failure and sepsis. Intensive Care Med. 1993;19:323328. 100. Tennila A, Salmi T, Pettila V, et al. Early signs of critical illness polyneuropathy in ICU patients with systemic inflammatory response syndrome or sepsis. Intensive Care Med. 2000;26:13601363. 101. Hough CL, Steinberg KP, Thompson BT, et al. Intensive care unit-acquired neuromyopathy and corticosteroids in survivors of persistent ARDS. Intensive Care Med. 2009;35:6368. 102. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354:449461. 103. Hermans G, Wilmer A, Meersseman W, et al. Impact of intensive insulin therapy on neuromuscular complications and ventilator dependency in the medical intensive care unit. Am J Respir Crit Care Med. 2007;175:480489.
Journal of

217
104. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345:13591367. 105. Van den Berghe G, Schoonheydt K, Becx P, et al. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology. 2005;64:13481353. 106. The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360:12831297. 107. Lefaucher JP, Nordine T, Rodriguez P, et al. Origin of ICU acquired paresis determined by direct muscle stimulation. J Neurol Neurosurg Psychiatry. 2006; 77:500506. 108. Stevens RD, Dowdy DW, Michaels RK, et al. Neuromuscular dysfunction acquired in critical illness: a systematic review. Intensive Care Med. 2007;33:18761891. 109. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864874. 110. Lacomis D, Smith TW, Chad DA. Acute myopathy and neuropathy in status asthmaticus: case report and literature review. Muscle Nerve. 1993;16: 8490. 111. Danon MJ, Carpenter S. Myopathy with thick filament (myosin) loss following prolonged paralysis with vecuronium during steroid treatment. Muscle Nerve. 1991;14:11311139. 112. De Smet Y, Jaminet M, Jaeger U, et al. Acute corticosteroid myopathy in patient with asthma [in French]. Rev Neurol (Paris). 1991;147:682685. 113. De Smet Y. Status asthmaticus. Acute myopathy induced by cortisone and neuropathy during resuscitation [in French]. Rev Neurol (Paris). 1993;149:573576. 114. Hirano M, Ott BR, Raps EC, et al. Acute quadriplegic myopathy: a complication of treatment with steroids, nondepolarizing blocking agents, or both. Neurology. 1992;42:20822087. 115. Waclawik AJ, Sufit RL, Beinlich BR, et al. Acute myopathy with selective degeneration of myosin filaments following status asthmaticus treated with methylprednisolone and vecuronium. Neuromuscul Disord. 1992;2:1926. 116. Hoke A, Rewcastle NB, Zochodne DW. Acute quadriplegic myopathy unrelated to steroids or paralyzing agents: quantitative EMG studies. Can J Neurol Sci. 1999;26:325239. 117. Deconinck N, Van Parijs V, Beckers-Bleukx G, et al. Critical illness myopathy unrelated to corticosteroids or neuromuscular blocking agents. Neuromuscul Disord. 1998;8:186192. 118. Showalter CJ, Engel AG. Acute quadriplegic myopathy: analysis of myosin isoforms and evidence for calpain-mediated proteolysis. Muscle Nerve. 1997; 20:316322. 119. Latronico N, Fenzi F, Recupero D, et al. Critical illness myopathy and neuropathy. Lancet. 1996; 347:15791582. 120. Bolton CF, Young GB, Zochodne DW. The neurological complications of sepsis. Ann Neurol. 1993; 33:94100.
121. de Letter MA, van Doorn PA, Savelkoul HF, et al. Critical illness polyneuropathy and myopathy (CIPNM): evidence for local immune activation by cytokine-expression in the muscle tissue. J Neuroimmunol. 2000;106:206213. 122. Fenzi F, Latronico N, Refatti N, et al. Enhanced expression of E-selectin on the vascular endothelium of peripheral nerve in critically ill patients with neuromuscular disorders. Acta Neuropathol. 2003;106:7582. 123. Hund E, Herkert M, Becker CM, et al. A humoral neurotoxic factor in sera of patients with critical illness polyneuropathy. Ann Neurol. 1996;40:539. 124. Friedrich O, Fink RA, Hund E. Understanding critical illness myopathy: approaching the pathomechanism. J Nutr. 2005;135:1813S1817S. 125. Khan J, Harrison TB, Rich MM. Mechanisms of neuromuscular dysfunction in critical illness. Crit Care Clin. 2008;24:165177. 126. Rossignol B, Gueret G, Pennec JP, et al. Effects of chronic sepsis on the voltage-gated sodium channel in isolated rat muscle fibers. Crit Care Med. 2007; 35:351357. 127. Novak KR, Nardelli P, Cope TC, et al. Inactivation of sodium channels underlies reversible neuropathy during critical illness in rats. J Clin Invest. 2009; 119:11501158. 128. Gutmann L, Blumenthal D, Schochet SS. Acute type II myofiber atrophy in critical illness. Neurology. 1996;46:819821. 129. Al-Lozi M, Pestronk A, Yee WC, et al. Rapidly evolving myopathy with myosin-deficient fibers. Ann Neurol. 1994;35:273279. 130. Matsumoto N, Nakamura T, Yasui, Y, et al. Analysis of muscle proteins in acute quadriplegic myopathy. Muscle Nerve. 2000;23:12701276. 131. Waclawik AJ, Selcen D, Keegan BM. A 46-year-old woman with severe weakness following acute respiratory distress syndrome. Neurology. 2007; 68:15291535. 132. Di Giovanni S, Mirabella M, DAmico A, et al. Apoptotic features accompany acute quadriplegic myopathy. Neurology. 2000;55:854858. 133. Di Giovanni S, Molon A, Broccolini A, et al. Constitutive activation of MAPK cascade in acute quadriplegic myopathy. Ann Neurol. 2004:55:195206. 134. Capasso M, Di Muzio A, Pandolfi A, et al. Possible role for nitric oxide dysregulation in critical illness myopathy. Muscle Nerve. 2008;37:196202. 135. Lanone S, Mebazaa A, Heymes C, et al. Muscular contractile failure in septic patients. Role of the inducible nitric oxide synthase pathway. Am J Respir Crit Care Med. 2000;162:23082315. 136. Legerlotz K, Smith HK. Role of MyoD in denervated, disused, and exercised muscle. Muscle Nerve. 2008;38:10871100. 137. Levine S, Nguyen T, Talyor N, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;358: 13271335. 138. Rouleau G, Karpati G, Carpenter S, et al. Glucocorticoid excess induces preferential depletion of myosin in denervated skeletal muscle fibers. Muscle Nerve. 1987;10:428438. www.jcnmd.com
218
Journal of

Lacomis
139. Massa R, Carpenter S, Holland P, et al. Loss and renewal of thick myofilaments in glucocorticoidtreated rat soleus after denervation and reinnervation. Muscle Nerve. 1992;15:12901298. 140. Rich MM, Kramer SD, Barchi RL. Altered gene expression in an animal model of acute quadriplegic myopathy [Abstract]. Ann Neurol. 1998; 40:461. 141. Mozaffar T, Haddal F, Zeng M, et al. Molecular and cellular defects of skeletal muscle in an animal model of acute quadriplegic myopathy. Muscle Nerve. 2006;35:5565. 142. Maggs AM, Huxley C, Hughes SM. Nerve-dependent changes in skeletal muscle myosin heavy chain after experimental denervation and cross-reinnervation and in a demyelinating mouse model of CharcotMarie-Tooth disease type 1A. Muscle Nerve. 2008; 38:15721584. 143. Talmadge RJ. Myosin heavy chain isoform expression following reduced neuromuscular activity: potential regulatory mechanisms. Muscle Nerve. 2000;23:661679. 144. Fink H, Helming M, Unterbuchner C, et al. Systemic inflammatory response syndrome increases immobility-induced neuromuscular weakness. Crit Care Med. 2008;36: 910916. 145. Sassoon CS, Zhu E, Pham HT, et al. Acute effects of high-dose methylprednisolone on diaphragm muscle function. Muscle Nerve. 2008;38:11611172. 146. Friedrich O. Critical illness myopathy: sepsismediated failure of the peripheral nervous system. Eur J Anaesthesiol. 2008;42:7382. 147. Panegyres PK, Squier M, Mills KR, et al. Acute myopathy associated with large parenteral dose of corticosteroid in myasthenia gravis. J Neurol Neurosurg Psychiatry. 1993;56:702702. 148. Mohr M, Englisch L, Roth A, et al. Effects of early treatment with immunoglobulin on critical illness polyneuropathy following multiple organ failure
and Gram-negative sepsis. Intensive Care Med. 1997;23:11441149. 149. Slater MS, Mullins RJ. Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review. J Am Coll Surg. 1998;186:693716. 150. Apte-Kakade S. Rehabilitation of patients with quadriparesis after treatment of status asthmaticus with neuromuscular blocking agents and high-dose corticosteroids. Arch Phys Med Rehabil. 1991;72; 10241028. 151. Fletcher SN, Kennedy DD, Ghosh IR, et al. Persistent neuromuscular and neurophysiologic abnormalities in long-term survivors of prolonged critical illness. Crit Care Med. 2003;31:10121016. 152. Herridge MS, Cheung AM, Tansey CM, et al. Oneyear outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med. 2003;348: 683693. 153. Bolton CF. Critical illness polyneuropathy. Muscle Nerve. 1999;22:419424. 154. de Seze M, Petit H, Wiart L. Critical illness polyneuropathy. A 2-year follow-up study in 19 severe cases. Eur Neurol. 2000;43:6169. 155. Guarneri B, Bertolini G, Latronico N. Long-term outcome in patients with critical illness myopathy or neuropathy: the Italian multicentre CRIMYNE study. J Neurol Neurosurg Psychiatry. 2008;79: 838841. 156. Latronico N, Shehu I, Seghelini E. Neuromuscular sequelae of critical illness. Curr Opin Crit Care. 2005;11:381390. 157. Lacomis D. Neuromuscular weakness related to critical illness. In: Rose BD, ed. UpToDate. Wellesley, MA; 2007. 158. Hough CL, Needham DM. The role of future longitudinal studies in ICU survivors: understanding determinants and pathophysiology of weakness and neuromuscular dysfunction. Curr Opin Crit Care. 2007;13:489496.

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CLINICAL NEUROMUSCULAR DISEASE