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 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 shock 8 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 cases 10–14 and eventually series 15–21 of adult and pediatric 10 patients who developed acute myopathy during treatment of status asthma- ticus. Later, a similar acute myopathy was noted to follow organ transplantation 22–27 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 CLINICAL NEUROMUSCULAR DISEASE Volume 12, Number 4 June 2011 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: [email protected]). Copyright Ó 2011 by Lippincott Williams & Wilkins Review Article 197
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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
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
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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.
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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
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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.
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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.
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
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