Neuromuscular Disorders in Critically Ill Patients

Neuromuscular Disorders in Critically IllPatients: Review and Update

David Lacomis, MD

AbstractNeuromuscular disorders that are diagnosed in the

intensive care unit (ICU) usually cause substantial

limb weakness and contribute to ventilatory dys-

function. Although some lead to ICU admission,

ICU-acquired disorders, mainly critical illness my-

opathy (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 electro-

myography 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 degener-

ation 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;12:197–218)

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 pres-

sure 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 com-

monly 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 weak-

ness, often with ventilatory failure.

Bolton and colleagues first reported the

clinical, electrodiagnostic, and histopatho-

logic features of ICU patients with newly

acquired weakness primarily in the setting of

sepsis—defined as suspected or proven infec-

tion with a systemic inflammatory response

syndrome (SIRS)1,2—and multiorgan failure,

culminating in their seminal reports of critical

illness polyneuropathy (CIP).3–5 In Bolton’s

comments on the discovery of CIP, he credits

Osler’s 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 Neverthe-

less, it was really Bolton, Zochodne, and

colleagues who identified CIP and brought

attention to the field of ICU-acquired neuro-

muscular weakness.3–5

While Bolton and colleagues were

studying CIP, there were also reports of single

cases10–14 and eventually series15–21 of adult

and pediatric10 patients who developed acute

myopathy during treatment of status asthma-

ticus. Later, a similar acute myopathy was

noted to follow organ transplantation22–27 and

to occur in association with many other

critical illness states in children as well as

adults.28–35 Terminology was highly variable

Journal of

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From the Departments ofNeurology and Pathology(Neuropathology), University ofPittsburgh School of Medicine,Pittsburgh, PA.

Reprints: David Lacomis, MD,UPMC Presbyterian, 200 LothropStreet, F878, Pittsburgh, PA15213 (e-mail:[email protected]).

Copyright � 2011 byLippincott Williams & Wilkins

Review Article 197

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 neuromus-

cular junction (NMJ) blockade after receiving

paralytic drugs in high doses or for prolonged

periods in association with persisting drug

metabolites and organ failure.37–41 Some of

these patients also had myopathy or neurop-

athy.41–44 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 dis-

orders in the ICU while providing a detailed

update on the ICU-acquired conditions,

mainly CIM and CIP.

Spectrum of NeuromuscularDisorders in the Intensive Care Unit

Given the lack of prospective data, the

spectrum and relative frequency of occur-

rence of all neuromuscular disorders diag-

nosed 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 pre-

existing myopathy were reported. The major-

ity had newly acquired myopathy, mostly CIM,

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

collapse47–55 are shown in Table 1. These con-

ditions may be important causes of prolonged

ventilator dependency.56 In addition, some

pre-existing mild or subclinical neuromuscu-

lar 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 IntensiveCare 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 Weaknessin the Intensive Care Unit

MyopathyCritical illness myopathyRhabdomyolysis (toxins, infection, and so on)Cachectic myopathyPolymyositis, dermatomyositisMuscular dystrophiesAcid maltase deficiencyMitochondrial myopathyHypophosphatemic myopathyToxic myopathy, eg, hydroxychloroquine

Peripheral neuropathyCritical illness polyneuropathyGuillian Barre syndromesVasculitic polyneuropathyPorphyriaParaneoplastic polyneuropathyToxic polyneuropathyNutritional polyneuropathy

Neuromuscular junction disordersProlonged neuromuscular junction blockadeMyasthenia gravisLambert-Eaton myasthenic syndromeBotulismTick paralysis

Motor neuron disordersAmyotrophic lateral sclerosis and variantsSpinal muscular atrophyPoliomyelitis syndromes, eg, West Nile virusPostpolio syndrome

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� 2011 Lippincott Williams & Wilkins

Limitations may include encephalopathy,

tracheal intubation with limited patient com-

munication, and an unreliable sensory exam-

ination. The presence of encephalopathy

should not dissuade one from searching for

a neuromuscular disorder, especially when

the encephalopathy is improving and weak-

ness is not. Even hyperreflexia does not

exclude a coexisting lower motor neuron

disturbance in these complex patients. Fur-

thermore, a pre-existing neuromuscular dis-

order, 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 de-

myelination 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 local-

ize 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 reso-

nance 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 find-

ings. 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 men-

tioned, 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 myas-

thenic syndrome almost never present with

ventilatory failure. They usually have proxi-

mal 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.37–41

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The polyneuropathies that occur in the

ICU usually do not present like the typical

chronic length-dependent sensorimotor neu-

ropathies 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 pro-

totype demyelinating PN, the acute inflam-

matory 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

GBS—acute 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 un-

common 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 mono-

neuritis 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 PolyneuropathyThe major features of CIP are general-

ized 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 dystro-

phies, acid maltase deficiency, and mitochon-

drial myopathy may present in this fashion,

but usually their presence has been known

before ICU admission. Mitochondrial disor-

ders 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 antisynthe-

tase syndromes or cardiac involvement. Such

cardiac involvement is rare.63 Toxic myopa-

thies 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 myopa-

thies, 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-predomi-

nant 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 electro-

diagnostic evidence of a persistent defect in

NMJ transmission.34 Acute necrotizing myop-

athy in the ICU may be a subset of CIM,

because associated loss of thick filaments has

been described rarely66 or it may be consid-

ered a separate entity probably related to

certain medications, especially NMJ-blocking

agents, or possibly from sepsis. This syndrome

is distinct from the more typical rhabdomyol-

ysis 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

Critical Illness MyopathyCIM presents with flaccid, generalized,

or proximal weakness, often with failure to

wean from mechanical ventilation. There are

normal or reduced tendon reflexes.16–18,20,22,29

Rarely is the weakness asymmetric69 or

upper extremity predominant.70 Facial

weakness may be present,22,29 and extra-

ocular 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

(median, 1576 IU/L; range, 66–7430 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 theIntensive 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 interfer-

ence, 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, poly-

phasic motor unit potentials even if they are

hidden within the artifact. Sixty-Hertz artifact

may especially interfere with F-wave record-

ings 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 stimula-

tion.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

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If it is clinically helpful to determine if

a patient’s 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 re-

ported by Bolton and colleagues73–75 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 avail-

ability 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 conduc-

tion velocities support the diagnosis of an

axonal sensorimotor PN. In the ICU, we

usually do not search for side-to-side asymme-

tries 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 senso-

rimotor 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 dia-

phragm.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 later—or 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 encoun-

tered in ICU patients with diffuse neuromus-

cular weakness. In fact, monitoring the

peroneal motor amplitude has been advo-

cated 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 post-

exercise single shocks to assess for potentia-

tion of the compound muscle action

potentials (CMAPs); and, in patients who

cannot exercise, we perform 50 Hz stimula-

tion. 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

segments).80,81

In CIM, the characteristic electrodiag-

nostic 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.82–85

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 stimulation—discussed subsequently—

may be useful.

Nerve conductions are usually normal in

other myopathies diagnosed in the ICU. If the

needle examination reveals complex repeti-

tive discharges or myotonia along with

myopathic (short duration, low amplitude)

MUP abnormalities, adult acid maltase de-

ficiency should be suspected. The paraspinal

muscles may be preferentially involved. Myo-

tonic discharges may be also present in

hydroxychloroquine myopathy.51 Inflamma-

tory 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 ge-

netic studies are required for definite di-

agnosis in most of these myopathies.

Direct Muscle StimulationWhen the routine electrophysiological

studies do not distinguish CIM from CIP or if

there is suspected overlap, direct muscle

stimulation (DMS) may be useful in differen-

tiating these entities. Rich and colleagues first

suspected that muscle membrane inexcitabil-

ity 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

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 re-

cording 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 distur-

bance in muscle membrane excitability con-

sistent 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 IllnessMyopathy and Critical IllnessPolyneuropathy: Incidence andRisk 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. Thirty-

five 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, hypoalbu-

minemia, and the number of invasive proce-

dures. Other studies revealed that 47% to 76%

of ICU patients had electrophysiological evi-

dence of CIP (Table 2).89–93 Zifko et al studied

132 ICU patients referred for NCS/EMG found

that 47% had CIP, and most had substantial



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TABLE 2. Prospective Studies of Critical Illness Polyneuropathy

Reference Inclusion/Methods Incidence Risk Factors Comment

Witt et al, 19915 43 patients in ICU > 5 days; Sepsisand MOF; NCS/EMG; examination

70% CIP (NCS/EMG) 35%CIP clinically

Hyperglycemia; HypoalbuminemiaNo. of invasive procedures

First prospective series

Zifko et al, 199862 132 patients referred for NCS/EMG(performed Days 7–240); SIRS

47% CIP; approximatelytwo thirds of these withsubstantial weakness

No case–controls 40% diagnosed with CIPhad normal sensory responsessuggesting a component of CIM;overestimates frequency becausepatients were referred forelectrodiagnostic testing

Leijten et al, 199689 38 patients; ventilated for 7 or moredays; NCS/EMG

47% CIP (NCS/EMG) Multiorgan dysfunction No myopathies detected; no musclebiopsies

Tepper et al, 200092 25 patients with septic shock;NCS/EMG within 72 hours

76% CIP (NCS/EMG):At least 50% withsubstantial weakness

No additional factors described No myopathies detected

Garnacho-Monteroet al, 200191

73 patients sepsis; MOF; Ventilationgreater than 10 days; NCS/EMG

63% CIP (NCS/EMG) Parenteral nutrition; NMJ blockersHyperosmolality; Worsening CNSfunction

Used very broad range for normalsural sensory responses; did notdiagnose CIM

Druschky et al,200190

28 patients ventilated for 4 or moredays; EMG/NCS

57% CIP (NCS/EMG) MODS score; duration of ventilatorysupport; Sepsis and/or lung failure

Serum neurotoxicity assay: 12 of 16serum samples were toxic toin vitro cultures of rat spinal cordmotor neurons

Thiele et al, 200093 19 survivors from cohort of37 patients requiring ventilationfor 3–5 days after heart surgery;NCS/EMG

63% CIP (NCS/EMG) Sepsis; Amount of catecholaminesupport; plasma urea level

Enrolled 37 of 104 eligible patients

ICU, intensive care unit; MOF, multiorgan failure; NCS/EMG, nerve conduction studies/electromyogram; SIRS, systemic inflammatory response syndrome; CIP, critical illnesspolyneuropathy; 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 paren-

teral nutrition, NMJ blockers, hyperosmolal-

ity, 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 cortico-

steroids, and 23 received vecuronium. Se-

venty-six percent had elevated CK levels,

whereas 36% had clinical evidence of myop-

athy with weakness that was usually general-

ized. 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 develop-

ment of myopathy.20

Campellone et al monitored 100 consec-

utive critically ill patients after liver trans-

plantation. All received IV corticosteroids and

NMJ blockers. Patients underwent electro-

diagnostic 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).94–99 As a result of differing meth-

odologies, they are somewhat difficult to

compare. Some evaluated the incidence of

neuromuscular disorders in a population at TA

BLE

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.



June 2011

205

www.jcnmd.com

risk. Others evaluated the cause of weakness

in ICU patients. In some studies, comprehen-

sive 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 stud-

ies 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 in-

cluded patients, 25% were found to have

weakness. All had electrodiagnostic evidence

of sensorimotor axonal PN. Ten, who un-

derwent muscle biopsy, also had evidence of

myopathy, but myosin adenosine triphospha-

tase 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

disease—mostly mixed CIM and CIP—during

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 multi-

organ 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 ‘‘dysfunc-

tion.’’ 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 hemor-

rhages. 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 weak-

ness in 34%. Of those who underwent

electrodiagnostic testing, most had evidence

of CIM. The study had limitations, but there

was no definite relationship between de-

velopment 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 disor-

ders were evaluated secondarily, and the

authors were unable to diagnose CIM or

clearly separate CIP from CIM.102–105 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 fibrilla-

tion 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

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TABLE 4. Prospective Studies of Mixed Critical Illness Polyneuropathy and Myopathy

Reference Inclusion/Methods Incidence Risk Factors Comment

Coakley et al,199399

23 patients in ICU longer than7 days; muscle biopsy in all;electrodiagnostic studies in 10

90% abnormal EMG: 6 axonal PN;2 PN and myopathy; 1 motorsyndrome; all muscle biopsieswere abnormal

None identified Muscle pathology included neurogenicatrophy, Type 2 fiber atrophy, andnonspecific myopathic changesincluding necrosis; myosin loss wasnot identified

Coakley et al,199894

44 patients; in ICU longer than7 days electrodiagnostic studies;muscle biopsies in 24

9% sensory PN 43% CIP;11% ‘‘motor process’’

No association with illnessseverity, sepsis, or drugs

Did not identify CIM; muscle biopsiesrevealed mixed (myopathic andneurogenic) changes

De Jonghe et al,200295

95 patients; multicenter;ventilated greater than 7 daysand improving LOC

25% weakness; all of these withPN (CIP); Myopathy inat least 11%

Female; duration ofventilation and organdysfunction; corticosteroids(not dose-related)

10 of 10 who underwent muscle biopsyalso had evidence of myopathy(myosin ATPase stains were notassessed)

Khan et al,200696

48 patients with sepsis; NCSwithin 72 hours; Follow-upNCS 6 EMG

63% abnormal NCS initially;at least 21% neuromusculardisorders clinically (majoritymixed CIM and CIP)

No association withcorticosteroids ofNMJ blockers

Abnormal initial NCS predictive of inhospital mortality. No muscle biopsies

Latronico et al,200779

92 patients; multicenter; NCS/EMGat 24 hours and daily peronealand sural NCS

30% CIM/CIP; Definite EMGdiagnosis in 13: CIM (6);CIP (4); mixed CIM/CIP (3)

MOF NO associated withSIRS, sepsis, drugs,nutrition

Did not fully differentiate CIM from CIP;no muscle biopsies Drop in peronealmotor amplitude of 25% predictive ofCIP/CIM

Berek et al,199661

22 patients with sepsis or SIRSand MOF; NCS/EMG

82% CIP by NCS/EMG;41% CIP clinically

No comparison group No myopathies identified

Hough et al,2009101

128 patients who were alive atDay 60 in study of acute lunginjury treated with IVcorticosteroids versus placebo;secondary analysis (chart review)

34% CIM/CIP; NCS/EMGperformed on 11; of these,9 had CIM

No risk from corticosteroids Not truly a prospective analysis; nomuscle biopsies; limited differentiationof CIP from CIM

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Patients who were in the ICU at and beyond

Day 7 were screened by weekly ‘‘electro-

neuromyography,’’ 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. Neuromus-

cular junction-blocking agents were a risk

factor for developing neuromuscular dysfunc-

tion, but corticosteroids were not. The

duration of mechanical ventilation was re-

duced 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 weak-

ness.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 con-

cluded 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 com-

monly 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 ofBed

nar

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al,

20

05

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IP/C

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ids

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LacomisJournal of



June 2011

208


46% overall.108 Compared with CIP, it is often

more difficult to diagnose CIM without

a muscle biopsy or sophisticated electrophys-

iological 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 Hyperglyce-

mia 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 associ-

ated CIM with the use of these drugs.10–

20,71,110–115 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 cortico-

steroids nor NMJ blockers were adminis-

tered.116–118 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 pro-

duced by activated leukocytes in muscle

specimens from patients with CIP/CIM.121

Hyperglycemia, increased capillary perme-

ability, 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, de-

creased sodium current was identified.126

Additional study of this model, in which there

are declines mixed sensory tail nerve record-

ings, revealed reduced excitability in dorsal

root sensory axons through intracellular

recordings. These experiments indicated that

sodium channels were inactivated,127 consis-

tent 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 biop-

sy may be obtained, especially if the



June 2011

209

www.jcnmd.com

electrodiagnostic findings are inconclusive or

if the differential diagnosis includes toxic or

inflammatory myopathy. The major histopath-

ologic 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 Ex-

cess 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 immu-

nohistochemical 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 disorgani-

zation, including abnormal basophilic stip-

pling with hematoxylin and eosin stains,

purplish staining with Gomori trichrome,

and irregular clumping of the reaction prod-

uct or core-like changes with NADH-TR

staining.

Additionally, evidence of abnormal deg-

radative pathway activation has been found.

There is upregulation of calpain118,131 along

with increased apoptosis.132 Results of ubiq-

uitin immunoreactivity are mixed.118,132

FIGURE 1. (A–C) 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 thanexpected differentiation in stain intensity in Type 1 (light) and Type 2 (dark) fibers. (See normal inset inC for comparison.) Rare fibers have a mild patchy reduction in reactivity (see arrows), whereas a rarefiber (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 thickfilaments. In comparison, an atrophic myofiber at the bottom has preservation of both thick and thinfilaments.

LacomisJournal of



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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 re-

ducing 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 peroxyni-

trate 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 preferen-

tially 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 com-

prehensive histopathologic study of the hu-

man diaphragm has not been undertaken.

However, studies of diaphragm from patients

who had undergone mechanical ventilation

for 18 to 69 hours showed atrophy of slow-

and fast-twitch fibers, increased caspase

activation, decreased glutathione, and in-

creased 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 chan-

nelopathy features of CIM.138–140 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 Further-

more, 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 immo-

bilization and systemic injections of Coryne-

bacterium 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

ubiquitin–proteasome 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 in-

fection 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 end-

plate involvement. Furthermore, it is conceiv-

able 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 hu-

man studies that include comprehensive

electrodiagnostic testing and muscle histopa-

thology will be necessary.

Treatment and OutcomesThere 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 in-

creased mortality rate with intensive treat-

ment of hyperglycemia.106 A prospective,

uncontrolled study of 33 patients with multi-

organ dysfunction syndrome (16 with Gram-

negative 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 prospec-

tive, controlled trial is necessary to make that

determination.

At least in CIM, injudicious use of IV

corticosteroids should be avoided, and seda-

tives 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 in-

fections. Prophylaxis for deep venous throm-

bosis, pulmonary toilet, padding of pressure

points, frequent turning, physiotherapy, and

appropriate orthotics are recommended. Re-

habilitation may be required.150

Regarding outcomes, there is growing

evidence that persistent neuromuscular dys-

function is a common consequence of critical

illness. There is evidence of partial denerva-

tion on electrodiagnostic testing performed

up to 5 years after the critical illness.151 Most

survivors of adult respiratory distress syn-

drome, 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 pre-

dictive 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 re-

habilitation 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 handi-

caps 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 weak-

ness.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 consider-

able 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 DirectionsIn 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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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 channel-

opathy may be predominant in both CIM and

CIP. Thus, it is also paramount that study

patients are monitored for onset by straight-

forward techniques such as serial peroneal

motor studies. It is desirable to have larger

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; and4. 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; and4. 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;23:1785–1788.36

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; and3. 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 morenerves

d Absence of conduction block or prolongation of F-wavesd 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; and4. 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:

140–16365 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 second-

ary end point. The role for such studies in

patients at risk for ICU-acquired neuromuscu-

lar disorders, the methods to use in these

studies, and the specific issues to address have

been thoughtfully discussed by Hough and

Needham.158

REFERENCES1. Russell JA. Management of sepsis. N Engl J Med.

2006;355:1699–1713.

2. Bone RC, Balk RA, Cerra FB, et al. Definitions forsepsis and organ failure and guidelines for the useof innovative therapies in sepsis. Chest. 1992;101:1644–1655.

3. Bolton CF, Gilbert JJ, Hahn AF, et al. Polyneuropathyin critically ill patients. J Neurol Neurosurg

Psychiatry. 1984;47:1223–1231.

4. Zochodne DW, Bolton CF, Wells GA, et al. Criticalillness polyneuropathy. A complication of sepsisand multiple organ failure. Brain. 1987;110:819–841.

5. Witt NJ, Zochodne DW, Bolton CF, et al. Peripheralnerve function in sepsis and multiple organ failure.Chest. 1991;99:176–184.

6. Bolton CF. The discovery of critical illness poly-neuropathy. Eur J Anaesthesiol. 2008;S42:66–67.

7. Osler W. The Principles and Practice of Medicine.New York: D Appleton; 1892.

8. Mertens HG. Disseminated neuropathy followingcoma. On the differentiation of so-called toxicpolyneuropathy. Nervenartz. 1961;32:71–79.

9. Henderson B, Koepke GH, Feller I. Peripheralpolyneuropathy among patients with burns. Arch

Phys Med Rehabil. 1971;52:149–151.

10. Kaplan PW, Rocha W, Sanders DB, et al. Acutesteroid-induced tetraplegia following status asthma-ticus. Pediatrics. 1986;78:121–123.

11. Knox AJ, Mascie-Taylor BH, Muers MF. Acutehydrocortisone myopathy in acute severe asthma.Thorax. 1986;41:411–412.

12. Van Marle W, Woods KL. Acute hydrocortisonemyopathy. BMJ. 1980;281:271–272.

13. Williams TJ, O’Hehir RE, Czarny D, et al. Acutemyopathy in severe acute asthma treated withintravenously administered corticosteroids. Am

Rev Respir Dis. 1988;137:460–463.

14. MacFarlane IA, Rosenthal FD. Severe myopathyafter status asthmaticus. Lancet. 1977;2:615.

15. Shee CD. Risk factors for hydrocortisone myopathyin acute severe asthma. Respir Med. 1990;84:229–233.

16. Blackie JD, Gibson P, Murree-Allen K, et al. Acutemyopathy in status asthmaticus. Clin Exp Neurol.1993;30:72–81.

17. Griffin D, Fairman N, Coursin D, et al. Acutemyopathy during treatment of status asthmaticuswith corticosteroids and steroidal muscle relaxants.Chest. 1992;102:510–514.

18. Leatherman JW, Fluegel WL, David WS, et al.Muscle weakness in mechanically ventilated pa-tients with severe asthma. Am J Respir Crit Care

Med. 1996;153:1686–1690.

19. Road J, Mackie G, Jiang TX, et al. Reversibleparalysis with status asthmaticus, steroids, andpancuronium: clinical electrophysiological corre-lates. Muscle Nerve. 1997;20:1587–1590.

20. Douglass JA, Tuxen DV, Horne M, et al. Myopathyin severe asthma. Am Rev Respir Dis. 1992;146:517–519.

21. Amaya-Villar R, Garnacho-Montero J, Garcia-Garmendia JL et al. Steroid-induced myopathy inpatients intubated due to exacerbation of chronicobstructive pulmonary disease. Intensive Care

Med. 2005;31:157–161.

22. Campellone JV, Lacomis D, Kramer DJ, et al. Acutemyopathy after liver transplantation. Neurology.1998;50:46–53.

23. Miro O, Salmeron JM, Masanes F, et al. Acutequadriplegic myopathy with myosin-deficient mus-cle fibres after liver transplantation: defining theclinical picture and delimiting the risk factors.Transplantation. 1999;67:1144–1151.

24. Subramony SH, Carpenter DE, Raju S, et al. Myo-pathy and prolonged neuromuscular blockade afterlung transplant. Crit Care Med. 1991:19:1580–1582.

25. Salviati L, Laverda AM, Zancan L, et al. Acutequadriplegic myopathy in a 17-month-old boy.J Child Neurol. 2000;15:63–66.

26. Chetaille P, Paut O, Fraisse A, et al. Acute myopathyof intensive care in child after heart transplantation.Can J Anaesth. 2000;47:342–346.

27. Perea M, Picon M, Miro O, et al. Acute quadriplegicmyopathy with loss of thick (myosin) filamentsfollowing heart transplantation. J Heart Lung

Transplant. 2001;20:1136–1141.

28. Hanson P, Dive A, Brucher JM, et al. Acutecorticosteroid myopathy in intensive care patients.Muscle Nerve. 1997;20:1371–1380.

29. Lacomis D, Giuliani MJ, Van Cott A, et al. Acutemyopathy of intensive care: clinical, electromyo-graphic, and pathological aspects. Ann Neurol.1996;40:645–654.

30. Faragher MW, Day, BJ, Dennett X. Critical caremyopathy: an electrophysiological and histologicalstudy. Muscle Nerve. 1996;19:516–518.

31. Rich MM, Bird SJ, Raps EC, et al. Direct musclestimulation in acute quadriplegic myopathy. Muscle

Nerve. 1997;20:665–673.

32. Larsson L, Li X, Edstrom L, et al. Acute quadriplegiaand loss of muscle myosin in patients treated withnondepolarizing neuromuscular blocking agentsand corticosteroids: mechanisms at the cellular andmolecular levels. Crit Care Med. 2000;28:34–45.

33. Trojaborg W, Weimer LH, Hays AP. Electrophysio-logic studies in critical illness associated weakness:

LacomisJournal of



June 2011

214


myopathy or neuropathy—a reappraisal. Clin

Neurophysiol. 2001;112:1586–1593.

34. Zochodne DW, Ramsay DA, Saly V, et al. Acutenecrotizing myopathy of intensive care: electro-physiological studies. Muscle Nerve. 1994;17:285–292.

35. Sander HW, Golden M, Danon MJ. Quadriplegicareflexic ICU illness: selective thick filament lossand normal nerve histology. Muscle Nerve. 2002:26;499–505.

36. Lacomis D, Zochodne D, Bird SJ. Critical illnessmyopathy [Editorial]. Muscle Nerve. 2000;23:1785–1788.

37. Segredo V, Caldwell JE, Matthay MA, et al. Persistentparalysis in critically ill patients after long-termadministration of vecuronium. N Engl J Med. 1992;327:524–528.

38. Segredo V, Matthay MA, Sharma ML, et al. Prolongedneuromuscular blockade after long-term adminis-tration of vecuronium in two critically ill patients.Anesthesiology. 1990;72:566–570.

39. Partridge BL, Abrams JH, Bazemore C, et al.Prolonged neuromuscular blockade after long-terminfusion of vecuronium bromide in the intensivecare unit. Crit Care Med. 1990;18:1177–1179.

40. Shanks AB, Long T, Aitkenhead AR. Prolongedneuromuscular blockade following vecuronium.Br J Anaesth. 1985;57:807–810.

41. Kupfer Y, Namba T, Kaldawi E, et al. Prolongedweakness after long-term infusion of vecuroniumbromide. Ann Intern Med. 1992;117:484–486.

42. Gooch JL, Suchyta MR, Balbierz, JM, et al. Pro-longed paralysis after treatment with neuromuscu-lar junction blocking agents. Crit Care Med. 1991,19:1125–1131.

43. Op de Coul AA, Lambregts PC, Koeman J, et al.Neuromuscular complications in patients givenPavulon (pancuronium bromide) during artificialventilation. Clin Neurol Neurosurg. 1985;87:17–22.

44. Barohn RJ, Jackson CE, Rogers SJ, et al. Prolongedparalysis due to nondepolarizing neuromuscularblocking agents and corticosteroids. Muscle Nerve.1994;17:647–654.

45. Campellone JV. Clinical approach to neuromuscularweakness in the critically ill patient. J Clin Neuro-

muscul Dis. 2000;1:151–158.

46. Lacomis D, Petrella JT, Giuliani MJ. Causes ofneuromuscular weakness in the intensive care unit:a study of ninety-two patients. Muscle Nerve. 1998;21:610–617.

47. Rosenow EC III, Engel AG. Acid maltase deficiencyin adults presenting as respiratory failure. Am J

Med. 1978;64:485–491.

48. Hughes RA, Bihari D. Acute neuromuscular re-spiratory paralysis. J Neurol Neurosurg Psychiatry.1993;56:334–343.

49. Kelly BJ, Luce JM. The diagnosis and managementof neuromuscular diseases causing respiratoryfailure. Chest. 1991;99:1485–1494.

50. O’Donohue WJ Jr, Baker JP, Bell GM, et al. Re-spiratory failure in neuromuscular disease. Manage-ment in a respiratory intensive care unit. JAMA.1976;235:733–735.

51. Abdel-Hamid H, Oddis CV, Lacomis D. Severehydroxychloroquine myopathy. Muscle Nerve.2008;38:1206–1210.

52. Souayah N, Sander HW, Menkes DL, et al. HepatitisC virus acute quadriparetic vasculitic neuropathyresponsive to cyclophosphamide. Neurol Neuro-

physiol Neurosci. 2006;18:5.

53. Newman JH, Neff TA, Ziporin P. Acute respiratoryfailure associated with hypophosphatemia. N Engl

J Med. 1997;296:1101–1103.

54. Bruno C, Sacco O, Santorelli FM, et al. Mitochon-drial myopathy and respiratory failure associatedwith a new mutation in the mitochondrial transferribonucleic acid glutamic acid gene. J Child Neurol.2003;18:300–303.

55. Gorson KC, Ropper AH. Nonpoliovirus poliomyeli-tis simulating Guillain-Barre syndrome. Arch Neu-

rol. 2001;58:1460–1464.

56. Spitzer AR, Giancarlo T, Maher L, et al. Neuromus-cular causes of prolonged ventilator dependency.Muscle Nerve. 1992;15:682–686.

57. Davis LE, DeBiasi R, Goade DE, et al. West Nile virusneuroinvasive disease. Ann Neurol. 2006;60:286–300.

58. Seybold ME. Diagnosis of myasthenia gravis. In:Engel AG, ed. Myasthenia Gravis and Myasthenic

Disorders. New York: Oxford University Press;1999:146–166.

59. McKhann GM, Cornblath DR, Griffin JW, et al.Acute motor axonal neuropathy: a frequent causeof acute flaccid paralysis in China. Ann Neurol.1993;33:333–342.

60. Albers JW, Fink JK. Porphyric neuropathy. Muscle

Nerve. 2004;30:410–422.

61. Berek K, Margreiter J, Willeit J, et al. Polyneuropa-thies in critically ill patients: a prospective evalua-tion. Intensive Care Med. 1996;22:849–855.

62. Zifko UA, Zipko HT, Bolton CF. Clinical andelectrophysiological findings in critical illness poly-neuropathy. J Neurol Sci. 1998;159:186–193.

63. Mastaglia FL, Garlepp MJ, Phillips BA, et al. Inflam-matory myopathies: clinical, diagnostic, and thera-peutic aspects. Muscle Nerve. 2003;27:407–425.

64. Bolton CF. Sepsis and the systemic inflammatoryresponse syndrome: neuromuscular manifestations.Crit Care Med. 1996;24:1408–1416.

65. Bolton CF. Neuromuscular manifestations of criticalillness. Muscle Nerve. 2005;32:140–163.

66. Ramsay DA, Zochodne DW, Robertson DM, et al.A syndrome of acute severe muscle necrosis inintensive care unit patients. J Neuropathol Exp

Neurol. 1993;52:387–398.

67. Al-Shekhlee A, Hachwi R, Jaberi MM, et al. Theelectromyographic features of acute rhabdomyoly-sis. J Clin Neuromuscul Dis. 2005;6:114–118.

68. Helliwell TR, Wilkinson A, Griffiths RD, et al.Muscle fibre atrophy in critically ill patients isassociated with the loss of myosin filaments and thepresence of lysosomal enzymes and ubiquitin.Neuropathol Appl Neurobiol. 1998;24:507–517.

69. Sun DY, Edgar M, Rubin M. Hemiparetic acutemyopathy of intensive care progressing to triplegia.Arch Neurol. 1997;54:1420–1422.



June 2011

215

www.jcnmd.com

70. Vattemi G, Tonin P, Filosto M, et al. Reversibleupper limb muscle weakness with selective loss ofthick filaments. Neurology. 2003;61:863–864.

71. Sitwell LD, Weinshenker BG, Monpetit V, et al.Complete ophthalmoplegia as a complication ofacute corticosteroid- and pancuronium-associatedmyopathy. Neurology. 1991;41:921–922.

72. Al-Shekhlee A, Shapiro BE, Preston DC. Iatrogeniccomplications and risks of nerve conduction stud-ies and needle electromyography. Muscle Nerve.2003;27:517–526.

73. Bolton CF. Phrenic nerve conduction studies: tech-nical aspects and normative data. Muscle Nerve.2008;38:1658–1659.

74. Chen R, Collins S, Remtulla H, et al. Phrenic nerveconduction study in normal subjects. Muscle

Nerve. 1995;18:330–335.

75. Bolton CF. AAEM Minimonograph #40: clinicalneurophysiology of the respiratory system. Muscle

Nerve. 1993;16:809–818.

76. Resman-Gaspersc A, Podnar S. Phrenic nerve con-duction studies: technical aspects and normativedata. Muscle Nerve. 2008;37:36–41.

77. Chowdhury D, Arora A. Axonal Guillain-Barre syn-drome: a critical review. Acta Neurol Scand. 2001;103:267–277.

78. Van den Bergh PY, Pieret F. Electrodiagnostic cri-teria for acute and chronic inflammatory demyelin-ating polyradiculoneuropathy. Muscle Nerve. 2004;29:565–574.

79. Latronico N, Bertolini G, Guarneri B, et al. Simpli-fied electrophysiological evaluation of peripheralnerves in critically ill patients: the Italian multi-centre CRIMYNE study. Crit Care. 2007;11:R11.

80. Daube JR. Electrodiagnostic studies in amyotrophiclateral sclerosis and other motor neuron disorders.Muscle Nerve. 2000;23:1488–1502.

81. Makki AA, Benetar M. The electromyographic diag-nosis of amyotrophic lateral sclerosis: does theevidence support the El Escorial criteria? Muscle

Nerve. 2007;35:614–619.

82. Park EJ, Nishida T, Sufit RL, et al. Prolonged com-pound muscle action potential duration in criticalillness myopathy. Report of nine cases. J Clin

Neuromuscul Dis. 2004;5:176–183.

83. Allen DC, Arunachalam R, Mills KR. Critical illnessmyopathy: further evidence from muscle–fiberexcitability studies of an acquired channelopathy.Muscle Nerve. 2008;37:14–22.

84. Trojaborg W. Electrophysiologic techniques in criti-cal illness-associated weakness. J Neurol Sci. 2006:242:83–85.

85. Case Records of the Massachusetts General Hospi-tal. Weekly clinicopathological exercises. Case 11—1997. A 51-year-old man with chronic obstructivepulmonary disease and generalized muscle weak-ness. N Engl J Med. 1997:336:1079–1088.

86. Trojaborg W, Kaufmann P, Gooch CL. Motor unit esti-mate number in the anterior tibial muscle: normativedata versus findings in critically ill patients in intensivecare units. J Clin Neuromuscul Dis. 2002;3:139–142.

87. Rich MM, Teener JW, Raps EC, et al. Muscle iselectrically inexcitable in acute quadriplegic myop-athy. Neurology. 1996;46:731–736.

88. Rich MM, Pinter MJ, Kramer SD, et al. Loss ofelectrical excitability in an animal model of acutequadriplegic myopathy. Ann Neurol. 1998;43:171–179.

89. Leijten FS, De Weerd AW, Poortvliet DC. Criticalillness polyneuropathy in multiple organ dysfunc-tion syndrome and weaning from the ventilator.Intensive Care Med. 1996;22:856–861.

90. Druschky A, Herkert M, Radespiel-Troger M, et al.Critical illness polyneuropathy: clinical findings andcell culture assay of neurotoxicity assessed bya prospective study. Intensive Care Med. 2001;27:686–693.

91. Garnacho-Montero J, Madrazo-Osuna J, Garcıa-Garmendia JL, et al. Critical illness polyneuropathy:risk factors and clinical consequences. A cohortstudy in septic patients. Intensive Care Med. 2001;27:1288–1296.

92. Tepper M, Rakic S, Haas JA, et al. Incidence andonset of critical illness polyneuropathy in patientswith septic shock. Neth J Med. 2000;56:211–214.

93. Thiele RI, Jakob H, Hund E, et al. Sepsis andcatecholamine support are the major risk factorsfor critical illness polyneuropathy after open heartsurgery. Thorac Cardiovasc Surg. 2000;48:145–150.

94. Coakley JH, Nagendran K, Yarwood GD, et al.Patterns of neurophysiological abnormality inprolonged critical illness. Intensive Care Med.1998;24:801–807.

95. De Jonghe B, Sharshar T, Lefaucheur, JP, et al.Paresis acquired in the intensive care unit: a pro-spective multicenter study. JAMA. 2002;288:2859–2867.

96. Khan J, Harrison TB, Rich MM, et al. Earlydevelopment of critical illness myopathy andneuropathy in patients with severe sepsis. Neurol-

ogy. 2006;67:1421–1425.

97. de Letter MA, Schmitz PI, Visser LH, et al. Riskfactors for the development of polyneuropathy andmyopathy in critically ill patients. Crit Care Med.2001;29:2281–2286.

98. Bednarik J, Vondracek P, Dusek L, et al. Risk factorsfor critical illness polyneuromyopathy. J Neurol.2005;252:343–351.

99. Coakley JH, Nagendran K, Honavar M, et al.Preliminary observations on the neuromuscularabnormalities in patients with organ failure andsepsis. Intensive Care Med. 1993;19:323–328.

100. Tennila A, Salmi T, Pettila V, et al. Early signs ofcritical illness polyneuropathy in ICU patients withsystemic inflammatory response syndrome orsepsis. Intensive Care Med. 2000;26:1360–1363.

101. Hough CL, Steinberg KP, Thompson BT, et al.Intensive care unit-acquired neuromyopathy andcorticosteroids in survivors of persistent ARDS.Intensive Care Med. 2009;35:63–68.

102. Van den Berghe G, Wilmer A, Hermans G, et al.Intensive insulin therapy in the medical ICU. N

Engl J Med. 2006;354:449–461.

103. Hermans G, Wilmer A, Meersseman W, et al. Impactof intensive insulin therapy on neuromuscularcomplications and ventilator dependency in themedical intensive care unit. Am J Respir Crit Care

Med. 2007;175:480–489.

LacomisJournal of



June 2011

216


104. Van den Berghe G, Wouters P, Weekers F, et al.Intensive insulin therapy in the critically illpatients. N Engl J Med. 2001;345:1359–1367.

105. Van den Berghe G, Schoonheydt K, Becx P, et al.Insulin therapy protects the central and peripheralnervous system of intensive care patients. Neurol-

ogy. 2005;64:1348–1353.

106. The NICE-SUGAR Study Investigators. Intensiveversus conventional glucose control in critically illpatients. N Engl J Med. 2009;360:1283–1297.

107. Lefaucher JP, Nordine T, Rodriguez P, et al. Origin ofICU acquired paresis determined by direct musclestimulation. J Neurol Neurosurg Psychiatry. 2006;77:500–506.

108. Stevens RD, Dowdy DW, Michaels RK, et al.Neuromuscular dysfunction acquired in criticalillness: a systematic review. Intensive Care Med.2007;33:1876–1891.

109. American College of Chest Physicians/Society ofCritical Care Medicine Consensus Conference:definitions for sepsis and organ failure and guide-lines for the use of innovative therapies in sepsis.Crit Care Med. 1992;20:864–874.

110. Lacomis D, Smith TW, Chad DA. Acute myopathyand neuropathy in status asthmaticus: case reportand literature review. Muscle Nerve. 1993;16:84–90.

111. Danon MJ, Carpenter S. Myopathy with thickfilament (myosin) loss following prolonged paraly-sis with vecuronium during steroid treatment.Muscle Nerve. 1991;14:1131–1139.

112. De Smet Y, Jaminet M, Jaeger U, et al. Acutecorticosteroid myopathy in patient with asthma [inFrench]. Rev Neurol (Paris). 1991;147:682–685.

113. De Smet Y. Status asthmaticus. Acute myopathyinduced by cortisone and neuropathy duringresuscitation [in French]. Rev Neurol (Paris).1993;149:573–576.

114. Hirano M, Ott BR, Raps EC, et al. Acute quadriple-gic myopathy: a complication of treatment withsteroids, nondepolarizing blocking agents, or both.Neurology. 1992;42:2082–2087.

115. Waclawik AJ, Sufit RL, Beinlich BR, et al. Acutemyopathy with selective degeneration of myosinfilaments following status asthmaticus treated withmethylprednisolone and vecuronium. Neuromus-

cul Disord. 1992;2:19–26.

116. Hoke A, Rewcastle NB, Zochodne DW. Acutequadriplegic myopathy unrelated to steroids orparalyzing agents: quantitative EMG studies. Can J

Neurol Sci. 1999;26:325–239.

117. Deconinck N, Van Parijs V, Beckers-Bleukx G, et al.Critical illness myopathy unrelated to corticoste-roids or neuromuscular blocking agents. Neuro-

muscul Disord. 1998;8:186–192.

118. Showalter CJ, Engel AG. Acute quadriplegic myop-athy: analysis of myosin isoforms and evidence forcalpain-mediated proteolysis. Muscle Nerve. 1997;20:316–322.

119. Latronico N, Fenzi F, Recupero D, et al. Criticalillness myopathy and neuropathy. Lancet. 1996;347:1579–1582.

120. Bolton CF, Young GB, Zochodne DW. The neuro-logical complications of sepsis. Ann Neurol. 1993;33:94–100.

121. de Letter MA, van Doorn PA, Savelkoul HF, et al.Critical illness polyneuropathy and myopathy(CIPNM): evidence for local immune activationby cytokine-expression in the muscle tissue.J Neuroimmunol. 2000;106:206–213.

122. Fenzi F, Latronico N, Refatti N, et al. Enhancedexpression of E-selectin on the vascular endothe-lium of peripheral nerve in critically ill patientswith neuromuscular disorders. Acta Neuropathol.2003;106:75–82.

123. Hund E, Herkert M, Becker CM, et al. A humoralneurotoxic factor in sera of patients with criticalillness polyneuropathy. Ann Neurol. 1996;40:539.

124. Friedrich O, Fink RA, Hund E. Understandingcritical illness myopathy: approaching the patho-mechanism. J Nutr. 2005;135:1813S–1817S.

125. Khan J, Harrison TB, Rich MM. Mechanisms ofneuromuscular dysfunction in critical illness. Crit

Care Clin. 2008;24:165–177.

126. Rossignol B, Gueret G, Pennec JP, et al. Effects ofchronic sepsis on the voltage-gated sodium channelin isolated rat muscle fibers. Crit Care Med. 2007;35:351–357.

127. Novak KR, Nardelli P, Cope TC, et al. Inactivation ofsodium channels underlies reversible neuropathyduring critical illness in rats. J Clin Invest. 2009;119:1150–1158.

128. Gutmann L, Blumenthal D, Schochet SS. Acute typeII myofiber atrophy in critical illness. Neurology.1996;46:819–821.

129. Al-Lozi M, Pestronk A, Yee WC, et al. Rapidlyevolving myopathy with myosin-deficient fibers.Ann Neurol. 1994;35:273–279.

130. Matsumoto N, Nakamura T, Yasui, Y, et al. Analysisof muscle proteins in acute quadriplegic myopathy.Muscle Nerve. 2000;23:1270–1276.

131. Waclawik AJ, Selcen D, Keegan BM. A 46-year-oldwoman with severe weakness following acuterespiratory distress syndrome. Neurology. 2007;68:1529–1535.

132. Di Giovanni S, Mirabella M, D’Amico A, et al.Apoptotic features accompany acute quadriplegicmyopathy. Neurology. 2000;55:854–858.

133. Di Giovanni S, Molon A, Broccolini A, et al. Consti-tutive activation of MAPK cascade in acute quad-riplegic myopathy. Ann Neurol. 2004:55:195–206.

134. Capasso M, Di Muzio A, Pandolfi A, et al. Possiblerole for nitric oxide dysregulation in critical illnessmyopathy. Muscle Nerve. 2008;37:196–202.

135. Lanone S, Mebazaa A, Heymes C, et al. Muscularcontractile failure in septic patients. Role of theinducible nitric oxide synthase pathway. Am J

Respir Crit Care Med. 2000;162:2308–2315.

136. Legerlotz K, Smith HK. Role of MyoD in de-nervated, disused, and exercised muscle. Muscle

Nerve. 2008;38:1087–1100.

137. Levine S, Nguyen T, Talyor N, et al. Rapid disuseatrophy of diaphragm fibers in mechanicallyventilated humans. N Engl J Med. 2008;358:1327–1335.

138. Rouleau G, Karpati G, Carpenter S, et al. Glucocor-ticoid excess induces preferential depletion ofmyosin in denervated skeletal muscle fibers.Muscle Nerve. 1987;10:428–438.



June 2011

217

www.jcnmd.com

139. Massa R, Carpenter S, Holland P, et al. Loss andrenewal of thick myofilaments in glucocorticoid-treated rat soleus after denervation and reinnerva-tion. Muscle Nerve. 1992;15:1290–1298.

140. Rich MM, Kramer SD, Barchi RL. Altered geneexpression in an animal model of acute quad-riplegic myopathy [Abstract]. Ann Neurol. 1998;40:461.

141. Mozaffar T, Haddal F, Zeng M, et al. Molecular andcellular defects of skeletal muscle in an animalmodel of acute quadriplegic myopathy. Muscle

Nerve. 2006;35:55–65.

142. Maggs AM, Huxley C, Hughes SM. Nerve-dependentchanges in skeletal muscle myosin heavy chain afterexperimental denervation and cross-reinnervationand in a demyelinating mouse model of Charcot-Marie-Tooth disease type 1A. Muscle Nerve. 2008;38:1572–1584.

143. Talmadge RJ. Myosin heavy chain isoform expres-sion following reduced neuromuscular activity:potential regulatory mechanisms. Muscle Nerve.2000;23:661–679.

144. Fink H, Helming M, Unterbuchner C, et al. Systemicinflammatory response syndrome increases immo-bility-induced neuromuscular weakness. Crit Care

Med. 2008;36: 910–916.

145. Sassoon CS, Zhu E, Pham HT, et al. Acute effects ofhigh-dose methylprednisolone on diaphragm mus-cle function. Muscle Nerve. 2008;38:1161–1172.

146. Friedrich O. Critical illness myopathy: sepsis-mediated failure of the peripheral nervous system.Eur J Anaesthesiol. 2008;42:73–82.

147. Panegyres PK, Squier M, Mills KR, et al. Acutemyopathy associated with large parenteral dose ofcorticosteroid in myasthenia gravis. J Neurol Neu-

rosurg Psychiatry. 1993;56:702–702.

148. Mohr M, Englisch L, Roth A, et al. Effects of earlytreatment with immunoglobulin on critical illnesspolyneuropathy following multiple organ failure

and Gram-negative sepsis. Intensive Care Med.1997;23:1144–1149.

149. Slater MS, Mullins RJ. Rhabdomyolysis and myoglo-binuric renal failure in trauma and surgical patients:a review. J Am Coll Surg. 1998;186:693–716.

150. Apte-Kakade S. Rehabilitation of patients withquadriparesis after treatment of status asthmaticuswith neuromuscular blocking agents and high-dosecorticosteroids. Arch Phys Med Rehabil. 1991;72;1024–1028.

151. Fletcher SN, Kennedy DD, Ghosh IR, et al. Persis-tent neuromuscular and neurophysiologic abnor-malities in long-term survivors of prolonged criticalillness. Crit Care Med. 2003;31:1012–1016.

152. Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of the acute respiratorydistress syndrome. N Engl J Med. 2003;348:683–693.

153. Bolton CF. Critical illness polyneuropathy. Muscle

Nerve. 1999;22:419–424.

154. de Seze M, Petit H, Wiart L. Critical illnesspolyneuropathy. A 2-year follow-up study in 19severe cases. Eur Neurol. 2000;43:61–69.

155. Guarneri B, Bertolini G, Latronico N. Long-termoutcome in patients with critical illness myopathyor neuropathy: the Italian multicentre CRIMYNEstudy. J Neurol Neurosurg Psychiatry. 2008;79:838–841.

156. Latronico N, Shehu I, Seghelini E. Neuromuscularsequelae of critical illness. Curr Opin Crit Care.2005;11:381–390.

157. Lacomis D. Neuromuscular weakness related tocritical illness. In: Rose BD, ed. UpToDate. Wellesley,MA; 2007.

158. Hough CL, Needham DM. The role of futurelongitudinal studies in ICU survivors: understand-ing determinants and pathophysiology of weaknessand neuromuscular dysfunction. Curr Opin Crit

Care. 2007;13:489–496.

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Neuromuscular Disorders in Critically Ill Patients