Neurol Clin 26 (2008) 507–520

Critical Illness Neuromuscular

Syndromes
Bernard De Jonghe, MDa,*,
Jean-Claude Lacherade, MDa,
Marie-Christine Durand, MDb,
Tarek Sharshar, MD, PhDc
a
Réanimation Médico-chirurgicale, Centre Hospitalier de Poissy, 10 rue du Champ-Gaillard,
78300 Poissy, France
b
Service de Physiologie et d’Explorations Fonctionnelles, Hôpital Raymond Poincaré,
104 Boulevard Raymond Poincaré, 92380, Garches, France
c
Re´animation Me´dicale, Hôpital Raymond Poincaré, 104 Boulevard Raymond Poincaré,
92380, Garches, France

Critical illness neuromyopathy (CINM) occurs often in patients with se-

vere acute illness requiring management in the ICU. This disorder involves
the peripheral nerves, muscles, or neuromuscular junction. It develops dur-
ing the ICU stay, in contrast to other neuromuscular diseases, such as Guil-
lain-Barré syndrome or myasthenia gravis, which are usually present on
admission to the ICU. CINM is increasingly recognized in ICU patients af-
ter several days of mechanical ventilation (MV) and organ failure and is
now the most common neuromuscular disorder encountered in the ICU.
The true incidence and prevalence of CINM have long been underesti-
mated. Bed confinement, impaired walking, and delayed recovery of physi-
cal autonomy were viewed as a nonspecific weakness accompanying critical
illness. Improvements in the treatment of acute respiratory, circulatory, and
neurologic failure over the last decades also may have increased the number
of patients who survive prolonged multiorgan failure (MOF), which is con-
sidered a major risk factor for the development of CINM.
Bolton and colleagues [1] were among the first to use the electroneuro-
myogram (ENMG) systematically in the investigation of patients with

This is an updated version of an article that originally appeared in Critical Care Clinics,
volume 22, issue 4.
* Corresponding author.
E-mail address: bdejonghe@chi-poissy-st-germain.fr (B. De Jonghe).

0733-8619/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ncl.2008.03.001 neurologic.theclinics.com
508 DE JONGHE et al

severe muscle weakness, allowing the identification and classification of an

authentic spectrum of peripheral neuromuscular diseases acquired during
the ICU stay. Since then, standardized evaluation of muscle strength using
simple clinical scores has facilitated early detection and quantification of
muscle weakness shortly after the acute phase of illness.
CINM has several implications for ICU patients and caregivers, includ-
ing intensivists, nurses, and physiotherapists. Involvement of the limbs car-
ries the risk of prolonged confinement to bed, delay in return to physical
autonomy after discharge from the ICU, and prolonged disability and reha-
bilitation needs. Respiratory involvement carries the risk of difficult weaning
and prolonged MV. This article summarizes the main features and causes of
CINM and addresses potential preventive interventions. The focus is on dif-
fuse neuromuscular abnormalities, excluding entrapment neuropathy.

Limb weakness
The cardinal locomotor sign of CINM is weakness. Assessment of limb
strength is feasible in extubated patients and in intubated patients provided
that they have regained wakefulness and can follow simple commands.
Various levels of quadriparesis can be encountered, whereas complete quad-
riplegia is less common. Muscle weakness usually predominates in the prox-
imal parts of the limbs (shoulders and ankles) and is grossly symmetric. It
can be quantified using the Medical Research Council (MRC) score [2].
The instrument is easy to use and has satisfactory reproducibility, even in
mechanically ventilated patients [3,4]. Three muscle functions are evaluated
in the upper limbs (shoulder abduction, elbow flexion, and wrist extension)
and three in the lower limb (hip flexion, knee flexion, and ankle flexion)
(Table 1). Each function score ranges from 0 (no movement) to 5 (normal
strength). The total score ranges from 0 to 60; a score less than 48 reflects
significant weakness. In CINM, face muscles usually are spared, and the pa-
tient is able to grimace during nursing care, such as side turning, in marked
contrast to the lack of limb muscle responsiveness. Other clinical signs

Table 1
Medical Research Council neuromuscular score
Movements tested (six on each side) Score for each movement
Arm abduction 0 ¼ no visible contraction
Elbow flexion 1 ¼ visible contraction but no limb movement
Wrist extension 2 ¼ active movement insufficient to overcome gravity
Hip flexion 3 ¼ active movement against gravity
Knee extension 4 ¼ active movement against gravity and resistance
Ankle dorsiflexion 5 ¼ normal power
Each limb is assigned a score from 0 to 15. The total score can range from 0 (complete quad-
riplegia) to 60 (normal muscle strength).
From Kleyweg RP, van der Meche FG, Meulstee J. Treatment of Guillain-Barre syndrome
with high-dose gammaglobulin. Neurology 1988;38:1639–41; with permission.
 CRITICAL ILLNESS NEUROMUSCULAR SYNDROMES 509

include sensory loss in some patients; decreased or absent deep tendon re-
flexes (although these might be preserved); and muscle atrophy. In patients
with frank asymmetric weakness, exaggerated deep tendon reflexes, or Ba-
binski’s sign, an alternative diagnosis should be considered.
After more than 1 week of MV, a quarter of ICU patients who recover
satisfactory consciousness have significant weakness lasting at least 1 week
after awakening [5]. The incidence of weakness is greater when patients
with symptoms that resolve within a few days are considered. Weakness
can last a few days to several weeks or months [6,7]. Twelve months after
admission to the ICU, survivors of severe acute respiratory distress syn-
drome have significant residual weakness, which is reflected in the difficulty
they encounter in performing a 6-minute walk test [8]. The median distance
walked in 6 minutes was 422 m, representing only 66% of the predicted
value. The presence of only slight alterations in respiratory function, includ-
ing carbon monoxide diffusion capacity and pulse oximetry, during the walk
test suggested that reduced performance on the walk test was caused mainly
by CINM. Chronic severe disability including quadriparesis, paraplegia, or
quadriplegia is observed in almost 30% of patients with CINM, and persist-
ing milder disabilities are common even in patients with complete functional
recovery [9].
Although the main diagnostic feature of CINM is weakness, electrophys-
iologic investigations can be undertaken to confirm the diagnosis; establish
the mechanism of neuromuscular involvement (mostly for research pur-
poses); or promote early diagnosis before awakening and muscle strength
evaluation. The most frequent pattern on standard ENMG investigation
is reduced compound muscle action potential with normal conduction veloc-
ity on motor nerve stimulation and spontaneous electrical activity on muscle
needle recording. This pattern is observed in 70% to 100% of ICU patients
with sepsis or MOF after 5 to 7 days of MV [10]. It reflects axonal or muscle
involvement or both. Sensory nerve action potentials can be reduced, sug-
gesting that at least part of the ENMG pattern is explained by an axonal
involvement. ENMG abnormalities can be identified in two thirds of pa-
tients within the first 72 hours of a severe sepsis and are predictive of hos-
pital mortality [11]. A recently developed investigation, direct muscle
stimulation, also can help differentiate between reduced muscle action po-
tential secondary to axonal disease (reduced muscle action potential on
nerve stimulation with normal action potential on direct muscle stimulation)
or loss of muscle membrane excitability (reduced muscle action potential on
nerve and direct muscle stimulation) [12]. Using this technique, several
authors have underlined the important contribution of muscle membrane in-
excitability to clinical weakness in CINM [11,13,14]. Analysis of the electro-
physiologic morphology and recruitment of motor unit potentials during
active muscle contraction, which could help identify a myopathic compo-
nent, is frequently impaired by the limited ability to perform muscle contrac-
tion in patients with paresis or paralysis. Muscle biopsy often reveals a true
510 DE JONGHE et al

myopathy with loss of thick myosin filaments sometimes combined with de-
nervation atrophy. Necrosis may be present in certain cases. Serum creatine
kinase levels may be elevated but the increase is often transient and can be
absent.
In clinical practice, CINM is suggested by the presence of symmetric
muscle weakness without upper motor neuron signs in patients having un-
dergone several days of MV for a nonneurologic severe acute illness. Addi-
tional investigations usually are not warranted, unless clinical examination
discloses asymmetric weakness or upper motor neuron signs, which should
prompt neuroimaging of the spinal cord and brainstem and ENMG.
ENMG also may prove useful when there is no improvement in the MRC
score over 1 or 2 weeks, because this is an unusual clinical feature for
CINM. Muscle biopsy rarely is performed in routine practice.
In clinical investigation, the question has emerged of whether clinical ex-
amination or standard ENMG should be used to detect CINM in large ep-
idemiologic or interventional studies. Both clinical findings and ENMG
abnormalities have been associated with important outcomes, such as dura-
tion of weaning from MV. Advantages of ENMG include early identifica-
tion of CINM in patients before awakening. Advantages of clinical
detection include widespread availability, simplicity, low cost, and repeat-
ability. Differences in detection methods may account for the important dis-
crepancies in risk factors reported in CINM studies to date. Studies of
interventions to prevent CINM may also have different effect depending
on whether ENMG abnormalities or relevant clinical outcomes, including
muscle weakness or inability to walk at ICU discharge, are being measured.

Respiratory involvement
Involvement of the respiratory muscles has a major implication for inten-
sivists because this may contribute to delayed weaning and prolonged MV.
Assessing respiratory involvement is challenging in the ICU, however, and
much evidence of respiratory neuromuscular involvement in CINM is based
on comparison of MV duration in patients with or without locomotor
CINM.
Total duration of MV in patients with and without CINM has been pro-
spectively compared in 10 cohort studies that included general ICU patients,
patients with sepsis and MOF, or more selected populations of cardiac sur-
gery patients [5,6,15–22]. All the studies reported a significant increase in du-
ration of MV (range 5–40 days depending on the study) in patients with
CINM. Although MV may be prolonged by the occurrence of neuromuscu-
lar abnormalities, neuromuscular involvement also may be facilitated by
prolonged MV. The duration of MV before awakening is an independent
predictor of ICU-acquired paresis detected at awakening [5], suggesting
that the consequence of CINM should be measured on duration of ventila-
tion after the diagnosis of CINM has been established. Two studies have
 CRITICAL ILLNESS NEUROMUSCULAR SYNDROMES 511

investigated the impact of CINM on the duration of MV after awakening or

on weaning time in general ICU patients and used multivariate analysis to
determine the role of potential confounders [21,23]. The authors’ study
was performed in 95 patients who required more than 7 days of MV and re-
covered normal consciousness [23]. As soon as standard prerequisite criteria
were met, patients underwent a short (30 minutes–2 hours) T-piece trial fol-
lowed by extubation if positive. The study showed that the presence of
chronic obstructive pulmonary disease on ICU admission (odds ratio 2.6;
95% confidence interval, 1.5–4.5) and presence of ICU-acquired paresis, de-
fined by an MRC score less than 48 persisting for 7 or more days after awak-
ening (odds ratio 2.4, 95% confidence interval, 1.4–4.2), were independently
associated with the duration of MV after awakening. In patients without
chronic obstructive pulmonary disease, the median duration of weaning
was 3.5 days longer in patients with ICU-acquired paresis than in patients
without ICU-acquired paresis. These results were confirmed in a Spanish
study of 64 ICU patients with severe sepsis or septic shock requiring MV
for at least 7 days [21]. The weaning method was daily T-piece trials in
most patients and gradually reduced pressure support in the others. Among
the 34 patients (53.1%) with CINM diagnosed by ENMG at onset of the
weaning period, the median duration of weaning was significantly longer
compared with patients without CINM (15 days versus 2 days: P!.001).
In addition, weaning failure, defined by failed extubation requiring reintu-
bation or need to perform a tracheostomy because of the impossibility to
discontinue MV, was significantly more frequent in patients with CINM
than in patients without CINM (27 [79.4%] versus 30 [20%]; P!.0001).
CINM was the only independent predictor of weaning failure in multiple lo-
gistic regression analysis. There is growing evidence that CINM is an inde-
pendent contributor to delayed weaning, weaning failure, and prolonged
MV in ICU patients.
Investigation of respiratory muscle in patients receiving MV involves
two approaches: ENMG investigation of the phrenic nerve and dia-
phragm, and functional testing of the respiratory muscles. In a retrospec-
tive study of 40 patients with difficult MV weaning secondary to suspected
neuromuscular disorder, 31 patients had ENMG abnormalities suggesting
CINM involving the extremities [24]. Of these, 15 (48.4%) had electro-
physiologic abnormalities involving the diaphragm (reduced or absent di-
aphragm compound muscle action potential and diaphragm spontaneous
electrical activity). Among the 21 patients with moderate ENMG abnor-
malities in the limbs, only six (28.6%) had diaphragmatic involvement,
whereas among the 10 patients with severe ENMG locomotor involve-
ment, nine (90%) had diaphragmatic involvement. In a prospective study
of 62 patients with CINM who were referred to an electrophysiology lab-
oratory (80.6% for difficult weaning), 51 (82%) had abnormal respiratory
electrophysiologic findings [25]. These results suggest that diaphragmatic
electrophysiologic abnormalities are common in patients with locomotor
512 DE JONGHE et al

ENMG abnormalities, especially in patients with severe extremity

involvement.
To date, very few studies have been performed directly assessing the re-
spiratory function component of CINM in ICU patients receiving MV.
Maximal inspiratory pressure and inspiratory airway occlusion pressure,
maximal expiratory pressure, and vital capacity are common markers of re-
spiratory neuromuscular strength, although the last two also are influenced
by bronchopulmonary conditions. During the last decade, they have largely
been used as indexes to predict immediate extubation success or failure [26].
In a recent multicentre study of patients requiring 7 or more days of MV,
maximal inspiratory pressure, maximal expiratory pressure, and vital capac-
ity measured at awakening, after ensuring an adequate response to simple
commands, revealed very low values, which were significantly correlated
to the MRC score measured the same day [27]. This finding strongly sug-
gested that limb and respiratory muscles are concomitantly and proportion-
ally involved in patients with CINM. Furthermore, maximal inspiratory
pressure and maximal expiratory pressure at awakening (and MRC score)
were predictors of delayed weaning, independent of markers of initial illness
severity or concomitant morbidities.
Several experimental studies have assessed respiratory muscle involve-
ment in sepsis or under MV, which are both frequently present in critically
ill patients. Animals exposed to experimental sepsis develop within a few
days a significant dramatic decrease in maximal diaphragmatic force
[28,29]. Similarly, compared with control animals maintained on spontane-
ous ventilation, animals subjected to controlled MV showed a 50% decrease
in maximal diaphragmatic force within 3 days, termed ‘‘ventilator-induced
diaphragmatic dysfunction’’ [30,31]. The decrease in diaphragmatic force
is prevented when animals are allowed to trigger the ventilator during as-
sist-controlled MV [32].
Another important question regarding weaning and extubation is the
level of involvement of the pharyngeal and laryngeal muscles in patients
with CINM. Involvement of these muscles could lead to orotracheal secre-
tion stasis, impaired swallowing, and repeated aspiration after extubation,
which can lead to failed extubation and reintubation. Pharyngeal and laryn-
geal involvement has not been evaluated, however, in CINM.

Risk factors for critical illness neuromyopathy

Eight prospective clinical studies on the incidence of CINM have in-
cluded a multivariate analysis of risk factors for CINM [5,19,33–38]. Two
analyses each included more than 400 patients from two large prospective
randomized controlled trials of intensive insulin therapy in surgical [39]
and medical [40] patients and represent the largest multivariate analyses
of risk factors for CINM to date.
 CRITICAL ILLNESS NEUROMUSCULAR SYNDROMES 513

Risk factors for CINM can be classified according to the level of suspi-
cion of their implication in the development of CINM (Fig. 1). The highest
level of suspicion is the severity and duration of systemic inflammatory re-
sponse syndrome or MOF. Although several conditions other than sepsis
can induce MOF (eg, multiple trauma, acute pancreatitis, cardiac arrest),
the main cause of MOF in the ICU is severe sepsis or septic shock. Sepsis
is consistently reported as a risk factor for CINM, although this association
does not clearly appear in all multivariate analyses, either because of a strong
statistical association with MOF or because many investigations have fo-
cused only on patients with septic shock. The strong link between MOF
and CINM has led some authors to consider that CINM was another
marker of MOF, in addition to renal, liver, central nervous system, or cir-
culatory failure. At a similar high level of suspicion is the length of stay
and MV before diagnosis of CINM. The fact that the effect of this factor
on CINM is independent of severity and duration of MOF strongly suggests
that prolonged muscle immobilization contributes to CINM.
Hyperglycemia, a common finding during the acute phase of critical ill-
ness, seems to increase the risk of CINM. In the early 1990s, a prospective
cohort study reported a significant association between hyperglycemia and
CINM (detected on routine ENMG) even after adjustment for potential
confounders, such as severity of the initial disease [33]. The most convincing
evidence comes from two large therapeutic trials comparing intensive with
conventional insulin therapy in surgical (mostly cardiothoracic) [39] and
medical [38,40] ICU patients. Intensive treatment was associated with

High Duration of ICU stay / MV

suspicion Persistent SIRS/MOF
Days on vasoactive drugs

Hyperglycemia

Corticosteroids
Neuromuscular blockers

Hypoalbuminemia
Parenteral nutrition
Low Hyperosmolarity
suspicion ERR

Fig. 1. Classification of risk factors for CINM identified from prospective studies with multi-
variate risk factor analysis, according to the level of suspicion of their implication in the devel-
opment of CINM. ERR, extrarenal replacement therapy; MOF, multiorgan failure; SIRS,
systemic inflammatory response syndrome.
514 DE JONGHE et al

a 50% (surgical patients) and 20% (medical patients) reduction in ENMG

abnormalities detected on routine electrophysiologic testing. These studies
represent major advances in the prevention of CINM, although several
questions remain unanswered, including the exact safety profile of intensive
insulin therapy especially in the subgroup of medical patients with a length
of stay in ICU less than 3 days (whose ICU mortality was slightly higher
when randomized to the intensive insulin therapy arm [40]), and the exact
relationship between ENMG abnormalities and relevant clinical outcomes,
such as muscle weakness or inability to walk or perform other activities of
daily life.
The role of corticosteroids in CINM is particularly controversial. Given
the increasing use of corticosteroids in the ICU, however, the question of the
association between corticosteroids and CINM is important. There is strong
evidence from experimental studies that supports the deleterious effect of
corticosteroids on muscle (see later). Clinical data in critically ill patients,
however, are contradictory. Among studies with a multivariate analysis of
risk factors for CINM, three concluded to a deleterious effect of corticoste-
roids [5,8,34], whereas two concluded to an absence of effect [37] or even
a protective effect [38]. Two factors might account for these discrepancies.
In the first three studies [5,8,34], blood glucose level was not measured,
whereas in the two latter [37,38], blood glucose level was measured and in-
cluded in the multivariate analysis. This suggests that the deleterious effect
of corticosteroids on neuromuscular function might not be direct but indi-
rect, mediated by corticosteroid-induced hyperglycemia, and that subse-
quently strict glucose control under corticosteroids might reduce their
neuromuscular effect. The other explanation relates to the criteria used to
diagnose CINM. Clinical detection was used in the first three studies
[5,8,34], whereas electrophysiologic detection (presence of muscle spontane-
ous electrical activity) was used in the latter two [37,38]. Because muscle
spontaneous electrical activity is only one aspect of the common electro-
physiologic pattern of CINM (the other being a reduced compound muscle
action potential on motor nerve stimulation), clinical examination assessing
the overall consequence of both axonal and muscle involvement on neuro-
muscular system might be more sensitive to detect corticosteroid-inducted
neuromuscular dysfunction. A high level of evidence regarding the deleteri-
ous effect of corticosteroids could arise from randomized trials of corticoste-
roids in critically ill patients. Although several trials of prolonged (O7 days)
low-dose corticosteroids in septic shock have been conducted [41,42], the
incidence of CINM was not reported. In a more recent prospective random-
ized double-blind controlled trial of corticosteroids in persistent acute respi-
ratory distress syndrome, 60-day and 180-day mortality were not lower
among patients who received corticosteroids, despite a significant improve-
ment in respiratory parameters [43]. In the absence of higher infection rate
in the corticosteroid group, one explanation for this discrepancy could be
the higher rate of CINM in the corticosteroid group. Although the overall
 CRITICAL ILLNESS NEUROMUSCULAR SYNDROMES 515

incidence of CINM was similar (about 25%) in both treatment groups, severe
CINM was reported more frequently in the corticosteroid group (nine events)
than in the control group (no event). Unfortunately, no data on diagnostic
criteria or timing of CINM were given in this study, and blood glucose levels
were significantly higher in the corticosteroid group, which weakens the com-
parison between the corticosteroid and the placebo groups. Rigorous docu-
mentation of CINM using specific diagnostic and timing criteria should be
part of future trials of corticosteroids in critically ill patients. This approach
might provide reliable answers to the question of the contribution of cortico-
steroids to CINM. The question of strict blood glucose control in future trials
of corticosteroids also warrants consideration.
Neuromuscular blockers have been associated with weakness in ICU pa-
tients with renal failure receiving continuous infusions of pancuronium or ve-
curonium [44]. Weakness is attributed to accumulation of the neuromuscular
blocking drug and its active metabolites. The current trend to promote inter-
mittent bolus or, in the rare cases in which continuous infusion is still deemed
necessary, the use of neuromuscular blockers with metabolism independent
from renal or liver function, is likely to contribute to lowering the risk of pro-
longed neuromuscular blockade. In patients with severe acute asthma re-
quiring MV, a condition less frequently encountered in ICU, the use of
neuromuscular blockers (even in absence of renal failure) has been
associated with a higher rate of weakness at awakening and muscle biopsy–
proved myopathy [15,45,46], and patients treated with higher doses of
neuromuscular blockers are at higher risk of weakness compared with those
receiving lower doses [47]. The retrospective design of most of these studies
and the systematic coadministration of high doses of corticosteroids preclude
any firm conclusions, however, regarding the specific deleterious effect of neu-
romuscular blockers. Besides the use of corticosteroids, other potential con-
founders include sepsis; hyperglycemia; MOF resulting from right cardiac
failure; and, potentially, severe hypercapnia and the use of high doses of
b2-agonists. Despite these limitations, it is reasonable to consider that pa-
tients undergoing MV for severe acute asthma are at high risk for CINM.

Pathophysiology
Although series of CINM patients with exclusive axonal polyneuropathy
have been reported, many cases of CINM reflect combined polyneuropathy
and myopathy. Predominant or isolated muscle involvement is increasingly
reported [12,13,48]. The exact mechanism of CINM is unknown. Most ad-
vances in comprehension of pathophysiology of CINM concern the muscle
component of CINM, including muscle atrophy with loss of contractile pro-
teins and membrane inexcitability.
In animal models of sepsis [49,50] and in patients with severe sepsis [51],
early muscle atrophy is attributed to increased oxidative stress, increased
516 DE JONGHE et al

ubiquitin proteasome and calpain activities, and subsequent proteolysis with

glutamine release from muscle. In experimental models, these findings are
prevented by concomitant administration of RU38486, a muscle steroid re-
ceptor antagonist [52], suggesting that sepsis-induced muscle changes are at
least partly mediated by endogenous corticosteroids. Another sepsis-in-
duced change is muscle mitochondrial dysfunction and decreased adenosine
triphosphate concentration, which has been shown in critically ill patients
with sepsis [53]. It is likely that mitochondrial energy failure in skeletal mus-
cles could lead to muscle failure and weakness. Identified mediators of sep-
sis-induced muscle changes include nitric oxide, tumor necrosis factor-a,
interleukin-1, and interleukin-6.
In rats exposed to corticosteroids, muscle structural changes are similar
to those observed in critically ill patients, including muscle atrophy and
loss of thick filaments of myosin [54,55]. These experimental lesions are sig-
nificantly enhanced by limb denervation before exposure to corticosteroids,
suggesting that, in ICU patients, the axonal component of CINM or a chem-
ical denervation, such as induced by neuromuscular blockers, could increase
muscle susceptibility to corticosteroids. Increased ubiquitin proteasome ac-
tivity and glutamine synthase activity have been identified and likely con-
tribute to the muscle changes [56,57]. In the same animal model, complete
muscle membrane inexcitability on direct muscle fiber stimulation, similar
to that increasingly identified in critically ill patients, also is observed [58].
The electrophysiologic feature is related to a modification of sodium chan-
nel fast inactivation, which might be caused by a corticosteroid-induced in-
crease in an embryonic sodium channel isoform [59].
Compared with patients with strict blood glucose level control under in-
tensive insulin therapy, patients with conventional insulin therapy exhibit
a significantly higher rate of hepatic mitochondrial structural and functional
abnormalities, suggesting a particularly deleterious role for hyperglycemia
in this organ [60]. Despite the implication of muscle mitochondrial dysfunc-
tion in sepsis [53], however, the deleterious effects of hyperglycemia or a pro-
tective effect of intensive insulin on mitochondrial function have not been
shown in muscle from critically ill patients. Nevertheless, there is a higher
protein content in skeletal muscle from intensive insulin therapy patients
compared with conventional insulin therapy patients, suggesting an ana-
bolic response to insulin [60].
There is no experimental model of the axonal component of CINM. Axons
are considered to be one of the targets of cytokines and other mediators re-
leased during severe systemic inflammatory response syndrome and septic
shock, although no correlation has been found between blood cytokine levels
and electrophysiologic abnormalities [61]. Microcirculatory disturbances are
thought to be involved [62], which is supported by an increased level of endo-
thelial cell activation in the microvessels of the endoneurium of peripheral
nerves in septic patients with CINM [63]. The short-term effect of blood glu-
cose control on nerve function and structure remains to be investigated.
 CRITICAL ILLNESS NEUROMUSCULAR SYNDROMES 517

Prevention
Strict blood glucose control is the only factor to date that has been eval-
uated in two randomized therapeutic trials [39,40] and has been discussed
previously. Apart from strict blood glucose control, very little is known
about the prevention and treatment of CINM. Several preventive measures
derived from knowledge of risk factors for CINM could be considered. Cor-
ticosteroid therapy is commonly prescribed in septic shock requiring vasoac-
tive drugs [41,42] or severe acute asthma. In other conditions, including
exacerbation of chronic obstructive pulmonary disease or persistent acute
respiratory distress syndrome, the expected beneficial effects of corticoste-
roids must be weighed against the risk of potential side effects, which include
CINM. Although neuromuscular blocking agents have not been definitely
proved to contribute to the genesis of CINM, it is reasonable to minimize
patient exposure to these drugs. Although other preventive measures may
seem attractive, these remain speculative. Considering that prolonged im-
mobilization likely contributes to CINM, mobilization or electrostimulation
may be a useful preventive measure. Passive stretching reduces histologic
markers of muscle atrophy [64], but impact on motor function has not
been assessed. Sedation protocols designed to minimize the use of sedatives
and analgesics, probably diminishing the time spent immobile, reduce MV
in ICU patients [65–67]. Whether this beneficial effect is explained by
a shorter time to awakening, by faster weaning from MV because of reduced
severity of CINM, or by both remains unclear. Modulation of the inflamma-
tory cascade of sepsis or MOF also conceptually could reduce the incidence
and severity of CINM. In an analysis of 33 survivors of sepsis and MOF,
a lower incidence of CINM was observed in patients who had been treated
with intravenous immunoglobulins as part of the treatment of MOF com-
pared with patients who had not received immunoglobulins [68]. These re-
sults, however, have not been confirmed in a randomized trial.
Severe hyperkalemia, with cardiorespiratory arrest in some instances, has
been reported after succinylcholine injection for reintubation of patients
who had spent several days in the ICU and had risk factors for CINM
[69–72]. Up-regulation of postsynaptic acetylcholine receptors induced by
ICU-acquired axonopathy is the most likely explanation for these events,
the risk of which remains underestimated by intensivists [73]. Succinylcho-
line should be used with utmost caution in this setting.

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