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Intensive-Care-Unit-Acquired Muscle Weakness

Steven Deem MD

Introduction
Definitions
Incidence
Pathology of ICU-Acquired Weakness
Risk Factors and Pathogenesis
Clinical Presentation and Outcomes
Diagnosis
Prevention and Therapy
Summary and the Future

Neuromuscular abnormalities culminating in skeletal-muscle weakness occur very commonly in


critically ill patients. Intensive-care-unit (ICU) acquired neuromuscular abnormalities are typically
divided into 2 discrete classes: polyneuropathy and myopathy. However, it is likely that these 2
entities commonly coexist, with myopathy being the most common cause of weakness. Major risk
factors for ICU-acquired neuromuscular abnormalities include sepsis, corticosteroid administra-
tion, and hyperglycemia, with other associated factors including neuromuscular blockade and
increasing severity of illness. The pathogenesis of these disorders is not well defined, but probably
involves inflammatory injury of nerve and/or muscle that is potentiated by functional denervation
and corticosteroids. ICU-acquired neuromuscular abnormalities are associated with multiple ad-
verse outcomes, including higher mortality, prolonged duration of mechanical ventilation, and
increased length of stay. The only intervention proven to reduce the incidence of ICU-acquired
neuromuscular abnormalities is intensive insulin therapy. Additional research is necessary to better
delineate the causes and pathogenesis of these disorders and to identify potential preventive and
therapeutic strategies. In addition, consensus guidelines for its classification and diagnosis are
needed. Key words: neuromuscular, weakness, polyneuropathy, myopathy, polyneuromyopathy, intensive
care, inflammation, mechanical ventilation, insulin, critical illness. [Respir Care 2006;51(9):10421052.
2006 Daedalus Enterprises]

Introduction important clinical problem. Weakness acquired in the in-


tensive care unit (ICU) and related acquired neuromuscu-
Weakness that is acquired during hospitalization for crit- lar dysfunction occur in a large percentage of critically ill
ical illness is increasingly recognized as a common and patients13 and are associated with increased morbidity
and mortality.4,5 In addition, it is estimated that the devel-
opment of ICU-acquired paresis may result in an average
Steven Deem MD is affiliated with the Departments of Anesthesiology
of $66,000 per patient in excess hospital charges (1996
and Medicine, Harborview Medical Center, University of Washington,
Seattle, Washington.

Steven Deem MD presented a version of this paper at the 37th RESPIRA-


TORY CARE Journal Conference, Neuromuscular Disease in Respiratory Correspondence: Steven Deem MD, Anesthesiology Department, Har-
and Critical Care Medicine, held March 1719, 2006, in Ixtapa, borview Medical Center, Box 359724, 325 Ninth Avenue, Seattle WA
Mexico. 98104. E-mail: sdeem@u.washington.edu.

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United States dollars).6 This review will discuss the inci- nitions of weakness for diagnosis, which may have re-
dence, causes, importance, pathogenesis, diagnosis, and sulted in overestimation of weakness, although the presence
prevention of ICU-acquired paresis and associated ICU- of electrophysiologic abnormalities may be an indepen-
acquired neuromuscular disorders. dently important predictor of outcome.4,13
Taking a different approach, De Jonghe et al prospec-
Definitions tively identified patients who were mechanically venti-
lated for 7 days, and evaluated them for weakness only
Because weakness in critically ill patients has been de- when they awakened and were able to cooperate with phys-
scribed in a variety of clinical situations and ascribed to ical examination.1 Clinically important weakness was de-
more than one etiology, several descriptive terms have fined as the inability to move against resistance and was
been coined to attempt to define and differentiate weak- quantitated using the Medical Research Council summa-
ness syndromes. These include critical-illness polyneurop- tion score of testing in 12 muscle groups (upper and lower
athy, critical-illness myopathy, and acute quadriplegic my- limbs).27 Ninety-five of 206 enrolled patients were evalu-
opathy. Unfortunately, these terms may be too restrictive able during their hospitalization; of these, 25% developed
in that they imply a single and distinct cause of weakness severe weakness.1 This study provides the most conserva-
for each patient or group of patients, when in fact the tive estimate of ICU-acquired paresis, but probably under-
pathology appears to be more complex, with considerable estimated the incidence of neuromuscular problems in the
overlap between the syndromes. For example, myopathy entire population of critically ill patients, including those
appears to be present in the majority of cases that might who die or are transferred from the hospital before they
once have been classified as polyneuropathy (discussed in can cooperate with a strength examination, or those with
detail later).7,8 In addition, these terms are not necessarily milder degrees of weakness. It is unclear how neuromus-
applied to patients with clinical evidence of weakness; for cular abnormalities contribute to morbidity and mortality
example, critical-illness polyneuropathy has been defined in this latter group of patients.
solely by abnormalities on electrophysiologic testing Certain groups of patients appear to be at high risk for
(nerve-conduction studies and electromyography [EMG]) developing ICU-acquired neuromuscular abnormalities,
in several studies.4,9 13 These factors create considerable undoubtedly due to the presence of specific risk factors, as
confusion when trying to read the literature on ICU-ac- discussed in a following section. In 5 prospective studies
quired weakness. Thus, additional terms have been coined of patients with sepsis and/or septic shock, electrophysi-
that reflect the complexity and uncertainty of the cause of ologic abnormalities were detected in 53%, 68%, 71%,
ICU-acquired weakness, including critical-illness neuro- 76%, and 100% of patients, although clinical evidence of
muscular abnormalities,14 critical illness myopathy and weakness was not reported in all the studies.4,10,11,13,28
neuropathy,15 critical illness polyneuropathy and myop- Berek et al prospectively evaluated 22 patients with
athy,2 and critical illness polyneuromyopathy.16 Lastly, sepsis or the systemic inflammatory response syndrome
a term that refers only to the presence of weakness, rather (SIRS) and multiple-organ-failure, and found electrophysi-
than cause, was recently suggested: ICU-acquired pare- ologic abnormalities in 82% of patients.25 Of note, only
sis. To reduce confusion, this review will avoid acro- half of these patients had clinical evidence of weakness,
nyms, and use the general terms ICU-acquired weakness although clinical examination was not performed in all
and neuromuscular abnormalities or disorders. patients.
In another prospective study of patients with failure of
Incidence 2 organs, 56% of patients developed electrophysiologic
abnormalities, 52% developed some focal or diffuse weak-
Only a few studies have rigorously and systematically ness, and 26% developed severe diffuse weakness.8 Fi-
studied the incidence of ICU-acquired weakness. Many of nally, in a retrospective analysis of 50 consecutive patients
the original reports on ICU-acquired neuromuscular dis- with acute respiratory distress syndrome and sepsis/SIRS,
orders were case reports or case series of retrospectively Bercker et al reported that 27 of 45 ICU survivors (60%)
identified patients, with no denominator available for mea- developed severe clinical weakness, with 25 patients ex-
surement of the frequency of this problem.1721 Several hibiting concomitant electrophysiologic abnormalities.29
subsequent prospective studies have suggested that the in- Thus, sepsis, SIRS, and multiple-organ-failure appear to
cidence of weakness combined with abnormalities on nerve- place patients at considerable risk for ICU-acquired neu-
conduction studies and/or EMG in patients mechanically romuscular disorders.
ventilated for more than 4 7 days is very high (33 ICU-acquired weakness is generally reported in patients
82%).2,3,2226 However, these studies included patients with who have been mechanically ventilated for 7 days. How-
altered levels of consciousness, so they relied on nerve- ever, there is evidence that nerve and/or muscle injury may
conduction studies and EMG testing or nonrigorous defi- begin early in the course of hospitalization, particularly in

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high-risk patients. Electrophysiologic testing (nerve-con- copy.1,3335,48,49 The second variant presents as widespread
duction studies/EMG) of 9 patients with sepsis or SIRS muscle necrosis with vacuolization and phagocytosis of
who were in the ICU for 27 days (mean 3.9 d) found muscle fibers.31,42,43,50,51 Inflammatory infiltration has been
evidence of neuromuscular abnormalities in all.10 Strength described in some cases.52 Acute necrotizing myopathy
testing was not reported in that study. has been associated with renal failure and may be related
In another study of 25 patients with septic shock, 50% to reports of rhabdomyolysis in patients with severe acute
had developed diffuse weakness within 72 hours of diag- asthma.51,53,54 Atrophy, thick-filament loss, and necrosis
nosis, and 68% had concomitant electrophysiologic evi- have been described in single biopsy specimens, suggest-
dence of critical-illness polyneuropathy.28 Thus, although ing that there may be a spectrum of injury between these
the risk of an ICU-acquired neuromuscular disorder ap- variants.1,55,56 The risk factors and recovery pattern of these
pears to increase with the duration of critical illness, ab- 2 variants do not appear to differ.
normalities begin to develop early in the hospital course, Critical-illness polyneuropathy was originally and is
and it appears that the vast majority of patients admitted to most frequently described in patients with sepsis, SIRS,
the ICU with sepsis will exhibit electrophysiologic neuro- and multiple-organ-failure.18,20,23,26,57,58 However, motor
muscular abnormalities by day 10 of their ICU stay.4,28 neuropathy has also been described in patients with respi-
In patients with severe acute asthma undergoing me- ratory failure due to asthma.59 The presentation is similar
chanical ventilation, 2 retrospective studies reported the to acute quadriplegic myopathy, with diffuse weakness.
incidence of weakness attributed to myopathy at 10% and The diagnosis has typically been made by electrophysi-
18%.30,31 However, a small, prospective trial found a much ologic testing, with nerve-conduction studies revealing re-
higher incidence of clinically important weakness in pa- duced motor and often sensory nerve action potentials, and
tients with severe acute asthma (36%).32 Similar findings muscle fibrillation on EMG that is suggestive of denerva-
were reported in patients undergoing mechanical ventila- tion.20,58 Critical-illness polyneuropathy can be distin-
tion and receiving corticosteroids for exacerbations of guished from demyelinating diseases such as Guillain-Barre
chronic obstructive pulmonary disease.33 The high inci- syndrome by the preservation of nerve-conduction veloc-
dence of myopathy in these latter 2 studies probably re- ity.58 Nerve biopsies in some studies have shown axonal
flects the higher identification of cases when systematic degeneration,18,56,60 although in others no abnormalities
examination and reporting are used. were evident.49,61 However, nerve biopsies are rarely per-
formed or reported. Until very recently, critical-illness poly-
Pathology of ICU-Acquired Weakness neuropathy was thought to be the major cause of ICU-
acquired weakness.62
ICU-acquired weakness has been attributed to several The simultaneous presence of critical-illness polyneu-
underlying pathologies, although it is unclear if there are ropathy and myopathy has been described for many
in fact multiple distinct entities or, rather, one disease with years.15,16,24 However, the impracticality and infrequency
variable presentations. The major categories of ICU-ac- of muscle biopsy in many studies of ICU-acquired neuro-
quired neuromuscular dysfunction grew from descriptions muscular disorders have probably resulted in an underes-
of myopathy21,34 and then polyneuropathy20 in the 1970s timation of the incidence of myopathy. Several studies in
and 1980s. These categories and the case for their shared which muscle biopsies were performed found a high fre-
features will be discussed in the following section. quency of myopathic changes in unselected patients, in
So-called acute quadriplegic myopathy was originally those evaluated for weakness, and in patients with elec-
and has frequently since been reported in patients with trophysiologic evidence of neuropathy.1,24,42,49,61 In a study
severe acute asthma who were receiving high-dose corti- by De Jonghe et al of ICU-acquired weakness, 22 patients
costeroids and/or neuromuscular blocking agents.21,32,35 41 underwent electrophysiologic testing, and all had evidence
However, acute quadriplegic myopathy has also been re- of sensory and motor neuropathy. However, muscle biop-
ported in association with a variety of critical illnesses, sies from ten of those patients revealed primary myop-
including acute respiratory distress syndrome, sepsis, and athy.1 In a recent prospective study of 15 patients who
after heart, lung, and liver transplantation.34,42 48 Fre- underwent electrophysiologic testing and nerve and mus-
quently, but not always, corticosteroids and neuromuscu- cle biopsy for evaluation of ICU-acquired weakness, 13/15
lar blocking agents were implicated in the cause of these patients had myopathic changes in the form of muscle
cases (discussed in detail later). necrosis and/or myosin loss; the other two had muscle
Two major pathologic patterns have been described in atrophy.56 Seven patients also had evidence of axonal de-
muscle-biopsy specimens from patients with ICU-acquired generation; however, only 2 patients appeared to have neu-
myopathy. One variant is described as selective thick (my- ropathy as the primary cause of weakness.
osin) filament loss under electron microscopy, with gen- This infrequency of muscle biopsies is compounded by
eralized or selective Type II fiber atrophy on light micros- the imprecision of standard electrophysiologic studies

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(nerve-conduction studies and EMG) in distinguishing be- patients with sepsis and/or neuromuscular abnormalities
tween motor neuropathy and myopathy in critically ill pa- exhibits neurotoxicity and effects on muscle membrane
tients who cannot cooperate with testing by voluntarily excitability and intracellular calcium release that could
contracting muscles.63 Direct stimulation of muscle may contribute to clinical neuromuscular abnormalities.72,73 The
overcome this inherent limitation of standard EMG, in that nature of the circulating mediator or mediators is not clear;
myopathic muscle shows reduced excitability, compared tumor necrosis factor has been suggested as a likely cul-
to normal or atrophied muscle.64 Studies that used direct prit,74,75 although one study found no evidence of elevated
muscle stimulation revealed a predominance of myopathic tumor necrosis factor or interleukin-6 in the serum of pa-
changes in patients with ICU-acquired weakness, whereas tients with critical-illness polyneuropathy.76 However, in
standard nerve-conduction studies and EMG may have led that study, tumor necrosis factor was measured after the
to a diagnosis of polyneuropathy in many of these pa- established diagnosis of polyneuropathy, whereas peak lev-
tients.61,64,65 Thus, myopathy may be the primary or a els and nerve or muscle injury probably occurred earlier in
contributing factor in a large percentage of patients with the course of illness.
ICU-acquired weakness. Moreover, it has become increas- Corticosteroid administration is another commonly
ingly apparent that neuropathy and myopathy are probably identified risk factor for ICU-acquired weakness. ICU-
interrelated organ dysfunctions related to SIRS, and po- acquired myopathy has been frequently described in
tentiated by other risk factors such as corticosteroids, as asthmatics and other patients who received high-dose
will be discussed in the next section. The relative contri- corticosteroids, often in association with other potential
butions of polyneuropathy and myopathy to ICU-acquired risk factors, such as sepsis or neuromuscular block-
weakness are difficult to ascertain. ade.21,30,31,3337,39,46,48,50,55,59,77 In a prospective study of
critically ill patients, De Jonghe et al found that corti-
Risk Factors and Pathogenesis costeroid administration was the strongest predictor of
ICU-acquired weakness (odds ratio 14.9, 95% confi-
As noted previously, sepsis and SIRS appear to be im- dence interval 3.2 69.8). 1 However, ICU-acquired
portant risk factors for the development of ICU-acquired weakness, myopathy, and polyneuropathy have also been
weakness. In addition to the previously discussed high described in the absence of corticosteroid administra-
incidence of ICU-acquired neuromuscular disorders in pa- tion, which once again emphasizes our incomplete un-
tients with sepsis, several prospective studies of mechan- derstanding of this syndrome.2,29,44
ically ventilated, critically ill patients have identified sep- The third major risk factor associated with ICU-acquired
sis as an important risk factor.12,23,33 In a prospective weakness is the administration of neuromuscular blocking
evaluation of a mixed population of 98 critically ill pa- drugs. Many of the early reports of ICU-acquired myop-
tients, 33% of whom developed neuromuscular disorders athy in asthmatics and other patients with respiratory fail-
while in the ICU, SIRS and severity of illness (as assessed ure in the 1970s, 1980s, and early 1990s occurred at a time
with the Acute Physiology and Chronic Health Evaluation when it was common practice to administer neuromuscu-
[APACHE III]) were identified as the only independent lar blocking drugs to facilitate mechanical ventilation. Be-
risk factors for the development of neuromuscular abnor- cause these patients often received both corticosteroids
malities.2 On the other hand, not all studies have found an and neuromuscular blocking drugs, it is difficult to distin-
independent association between sepsis and neuromuscu- guish the respective roles these agents played in the de-
lar abnormalities in the ICU, which reflects the complexity velopment of myopathy.41,50 However, several studies
of the pathogenesis of this problem.1,3 showed that neuromuscular blockade was clearly associ-
It has been proposed that ICU-acquired neuromuscular ated with increased risk of myopathy, particularly as the
abnormalities are an organ failure caused by inflamma- duration of drug administration increased beyond
tory mediators that are either systemically or locally pro- 24 hours.30,31,78,79 The enthusiasm for neuromuscular block-
duced in sepsis and SIRS.66,67 Analysis of muscle speci- ade in the ICU diminished considerably after the relation-
mens from patients with ICU-acquired neuromuscular ship to myopathy became clear. Despite this, ICU-acquired
abnormalities reveals macrophage and T-cell infiltration neuromuscular abnormalities continue to occur with alarm-
and expression of both pro- and anti-inflammatory cyto- ing frequency, and several recent studies found no rela-
kines.52 Furthermore, muscle from septic patients exhibits tionship between ICU-acquired weakness and neuromus-
over-expression of other pro- and anti-inflammatory en- cular blockade.1,2,29,33,44
zymes and activation of a key intracellular proteolytic path- The interaction between corticosteroids, neuromuscular
way (ubiquitin-proteasome).68,69 Animal models of sepsis blockade, and ICU-acquired neuromuscular abnormalities
confirm the presence of increased muscle proteolysis re- may be explained by the observation that denervation in-
lated to the ubiquitin-proteasome pathway, which is fur- creases steroid-receptor density in muscle.80 Administra-
ther activated by corticosteroids.68,70,71 Lastly, serum from tion of corticosteroids to animals with denervated muscle

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results in thick-filament (myosin) loss, similar to that seen of sepsis, thus leading to or exacerbating injury in multiple
in patients with ICU-acquired myopathy.81 Furthermore, organs, including muscle and nerves.96 In addition, insulin
denervated muscle in animals treated with corticosteroids increases mitochondrial adenosine-triphosphate production
loses membrane excitability, again similar to that seen in and protein synthesis in skeletal muscle, counteracting the
patients with ICU-acquired myopathy.64,82 This loss of effect of corticosteroids in this regard.97,98 This may pro-
membrane excitability may be due to inactivation of mem- vide some explanation for the protective effect of intensive
brane sodium channels.83 Thus, it is likely that neuromus- insulin therapy observed by Van den Berghe et al.93,94
cular blockade functionally denervates muscle, thereby However, further research is needed to elucidate the role
potentiating the direct muscle toxicity of corticosteroids. A that hyperglycemia plays in the development of ICU-ac-
direct toxic effect of neuromuscular blocking agents has quired neuromuscular abnormalities.
not been established. Additional but less consistently identified risk factors
It was originally proposed that the type of neuromus- for ICU-acquired neuromuscular abnormalities include ad-
cular blocking drug was related to the development of ministration of total parenteral nutrition, aminoglycosides,
myopathy, and that the aminosteroid agents vecuronium catecholamines, hyperosmolality, neurologic failure, fe-
and pancuronium were particularly harmful.78 However, male sex, greater quantity and longer duration of organ
there have since been many reports of myopathy develop- dysfunction, and greater severity of illness.1,2,4,12,23,33,73 Re-
ing after the use of structurally unrelated neuromuscular nal failure has been reported as a risk factor,26 whereas
blocking drugs (atracurium, cisatracurium, and doxa- renal-replacement therapy has been reported as protec-
curium),31,84 90 which suggests that the earlier reports were tive.4
related to the more frequent use of vecuronium and pan- In summary, the major identified risk factors for ICU-
curonium rather than to their specific toxic effect. acquired neuromuscular abnormalities include sepsis/SIRS,
Prolonged neuromuscular blockade after discontinua- corticosteroids and neuromuscular blocking drugs, and hy-
tion of the drugs can also present as prolonged weakness perglycemia. Experimental models and testing of muscle
in the ICU.19,91,92 This is more likely to occur with the use samples from patients with sepsis or myopathy provide
of vecuronium or pancuronium, particularly to patients some insight into the mechanisms by which muscle injury
with renal insufficiency, given that these agents and their occurs in critical illness, but the pathogenesis of nerve
active metabolites are cleared by the kidney.92 Prolonged injury remains unknown. Friedrich et al summarized the
neuromuscular blockade can be distinguished from other pathogenic factors leading to critical-illness myopathy as
causes of ICU-acquired neuromuscular abnormalities by predisposing factors such as sepsis or SIRS, priming
documentation of fade on repeated peripheral motor-nerve factors such as denervation (eg, neuromuscular blockade),
stimulation (train-of-4), or by evidence of a neuromuscular and triggering factors such as corticosteroids.67 This
transmission defect on formal electrophysiologic testing. model may well be applied to the entire spectrum of ICU-
Prolonged neuromuscular blockade can be minimized by acquired neuromuscular abnormalities and may involve
careful titration and monitoring of these drugs, and the use other predisposing factors such as genetics, and triggering
of non-renally-cleared agents, such as cisatracurium, in factors such as hyperglycemia, renal failure, and others. In
patients with renal insufficiency. the right combination, these factors lead to a syndrome of
Several retrospective and prospective studies have iden- weakness that is associated with poor outcome, as will be
tified hyperglycemia as a fourth major risk factor for the described in the next section.
development of ICU-acquired neuromuscular disor-
ders.1,22,29,93 It is not clear whether hyperglycemia is a Clinical Presentation and Outcomes
truly independent risk factor or merely associated with
others, such as sepsis or glucocorticoid administration. ICU-acquired neuromuscular disorders generally present
However, a large, prospective trial of tight glycemic con- as diffuse skeletal-muscle weakness, unless diagnosed by
trol using intensive insulin therapy in critically ill surgical electrophysiologic testing, as in the context of a research
patients dramatically reduced electrophysiologically diag- study. Muscles are generally flaccid and deep-tendon re-
nosed polyneuropathy.9 In post-hoc analysis of that trial, flexes absent, although spastic quadriplegia and isolated
the level of glycemic control (as opposed to other meta- limb weakness have also been described.8,32,99 It is also
bolic effects of insulin) appeared to account for the reduc- likely that a common initial presentation is failure to sep-
tion in polyneuropathy.93,94 arate from mechanical ventilation, given the evidence that
The mechanism by which hyperglycemia leads to mus- ICU-acquired neuromuscular disorders affect respiratory
cle and/or nerve injury is at this point unknown. There is as well as skeletal muscles. Spitzer et al found that 62% of
some evidence that aggressive glycemic control protects patients with prolonged ventilator dependence in associa-
hepatocytes from mitochondrial injury;95 it is possible that tion with critical illness had a possible neuromuscular cause
hyperglycemia potentiates the mitochondrial dysfunction of ventilatory failure, including critical-illness polyneu-

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ropathy and/or myopathy.5 Several studies have found ab- abnormalities.4 Multivariate analysis found that neuromus-
normal phrenic-nerve and/or diaphragm function by elec- cular abnormalities independently predicted in-hospital
trophysiology in the presence of ICU-acquired mortality in that study (odds ratio 7.1, 95% confidence
neuromuscular disorders.18,22,45,100,101 In addition, several interval 1.54 32.75). De Jonghe et al found that, among
prospective studies have found that ICU-acquired neuro- patients who survived long enough to awaken and undergo
muscular disorders are associated with longer duration of clinical examination, death in the ICU occurred in 4/26
mechanical ventilation and length of stay,1,4,12,13,23,32,33 al- (17%) of patients with weakness, compared to 4/71 (4%)
though cause-and-effect cannot be proven, given that the of patients without weakness (p 0.20).1 Although that
severity of illness and neuromuscular abnormalities are difference is not statistically significant, the trend suggests
linked. ICU-acquired neuromuscular abnormalities have that weakness identified during early recovery from criti-
also been implicated in respiratory failure that develops cal illness may be associated with a high risk of death, as
after discharge from the ICU.102 is the presence of neuromuscular abnormalities by elec-
Three studies are of particular interest in regard to the trophysiologic testing early in the course of illness.
association between ICU-acquired neuromuscular disor- The rate of recovery of muscle strength among survi-
ders and prolonged mechanical ventilation. In their (above- vors with ICU-acquired neuromuscular disorders is highly
described) prospective study, De Jonghe et al1 found that variable, with some patients recovering fully in weeks and
the presence of ICU-acquired weakness by clinical exam- others remaining severely weak for years. Latronico et al
ination was associated with more than twice the mean recently summarized the results from 36 studies that re-
duration of mechanical ventilation (compared to controls ported long-term outcomes in 263 patients who were di-
without weakness) after patient awakening (18.2 36.3 d agnosed with ICU-acquired neuromuscular disorders.103
vs 7.6 19.2 d, p 0.03). There was also a trend toward The mean duration of follow-up was 3 6 months, although
longer ICU stay for patients with weakness (27.6 31.4 d some patients were followed for up to 8 years. Sixty-eight
vs 14.6 19.6 d, p 0.06). percent of the patients had complete functional recovery,
Garnacho-Montero et al prospectively evaluated a group whereas 28% had severe disability, with difficulty walking
of critically ill patients with sepsis.13 Of 64 included pa- and/or breathing. The interpretation of these data is limited
tients, 54% developed electrophysiologic evidence of neu- by the highly variable duration of follow-up. In addition,
romuscular abnormalities. Electrophysiologic abnormali- long-term follow-up in small studies is limited by the high
ties alone, without clinical confirmation of weakness, were ICU, post-ICU, and post-hospital mortality reported in pa-
associated with longer duration of mechanical ventilation tients with ICU-acquired neuromuscular disorders.56,104
(34 d vs 14 d, p 0.001), greater number of weaning days In their prospective study of ICU-acquired weakness,
(15 d vs 2 d, p 0.001), longer ICU and hospital length De Jonge et al found that nearly all evaluable patients
of stay, and higher hospital mortality (47.1% vs 20%, (16/24) had recovered some strength by 9 months of fol-
p 0.03). Multivariate analysis revealed that neuromus- low-up, with two thirds living at home.1 Zifko studied 13
cular disorders were the only independent risk factor as- patients with ICU-acquired weakness and electrophysi-
sociated with prolonged mechanical ventilation (odds ratio ologic evidence of polyneuropathy 1324 months after
15.4, 95% confidence interval 4.5552.3, p 0.001). Van discharge (mean 17 mo).100 All the patients had suffered
den Berghe et al used multivariate analysis and found that from SIRS during their ICU stay. At follow-up, 2 patients
the reduction in electrophysiologically diagnosed neuro- had normal physical examinations, 1 patient had persistent
muscular abnormalities that occurred with intensive insu- severe weakness, four had mild weakness, and the remain-
lin therapy was independently associated with a reduction der had sensory and/or focal motor abnormalities. All had
in prolonged mechanical ventilation.94 These 3 studies sug- electrophysiologic abnormalities. De Seze et al followed
gest that both ICU-acquired weakness and electrophysi- 19 patients who had been transferred from an ICU to a
ologic abnormalities are important predictors of relevant specialized neurologic rehabilitation unit for recovery from
patient outcomes. critical-illness polyneuropathy; all had diffuse weakness,
Several prospective studies, including the one described and six had severe weakness (quadriplegia).105 Complete
above, have found that ICU-acquired neuromuscular dis- recovery occurred in 4 patients (21%) at 3 months, 4 pa-
orders are associated with increased mortality. Leitjen et al tients at 6 months, and 3 patients (16%) at 12 months. Two
studied a mixed population of critically ill, mechanically patients died between 6 months and 9 months with quad-
ventilated patients and reported an ICU mortality of 48% riplegia, and four had persistent quadriplegia at 2 years of
in patients with ICU-acquired neuromuscular abnormali- follow-up. These latter 2 studies paint a relatively grim
ties, versus 19% in patients without abnormalities picture in terms of the long-term recovery from ICU-ac-
(p 0.03).23 In patients with sepsis and electrophysiologi- quired neuromuscular disorders.
cally-defined neuromuscular abnormalities, in-hospital Several studies have found that survivors of critical ill-
mortality was 84%, compared to 56.5% in patients without ness have sustained impairments in physical function and

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health status, even after one year of recovery.106 109 Mus- firm or exclude myopathy as a cause of weakness, but is
cle weakness appears to contribute substantially to disabil- not recommended as a routine course, given its invasive
ity after critical illness,107,110 and it is likely that ICU- nature and the lack of evidence that the information gained
acquired neuromuscular disorders play an important role will influence prognosis or therapy.
in this weakness. Fletcher et al studied 22 patients who had As discussed earlier, routine screening of patients by
been cared for in the ICU for 28 days.110 All patients electrophysiologic testing will identify more patients with
had sepsis and at least 2-organ failure during their ICU neuromuscular abnormalities than will clinical examina-
stay; two had been diagnosed with critical-illness polyneu- tion, particularly if performed early in the course of ill-
ropathy, and one with necrotizing myopathy. Subjects were ness. In a prospective evaluation of critically ill, mechan-
a year or more removed from ICU discharge (median 42.5 ically ventilated patients, abnormal electrophysiologic test
mo) at the time of follow-up, and yet all still complained results at ICU days 4, 8, and 14 were associated with
of extreme weakness. Although only one third of the pa-
severe weakness in 0/5, 6/14 (43%), and 6/10 (60%) of
tients had weakness on physical examination, all but one
patients, respectively (drop-out occurred due to death).73
had electrophysiologic evidence of critical-illness poly-
Milder degrees of weakness were not reported in this study,
neuropathy. Of note is that 25 patients initially contacted
and it is unclear if electrophysiology correlates with clin-
for this study refused to participate; thus, the results reflect
the findings from a highly motivated and perhaps more ical findings across a broad spectrum of disease. However,
functional subgroup of patients, and may underestimate outside the context of research, it is not clear that early
the true weakness-associated morbidity among survivors electrophysiologic testing provides sufficient information
of critical illness. Nonetheless, this study provides persua- to justify the cost, given that there are no known therapies
sive evidence that ICU-acquired neuromuscular disorders for ICU-acquired abnormalities at this point.
are a major contributor to long-term disability after critical
illness. Prevention and Therapy
It is unclear whether the primary underlying pathology
of ICU-acquired weakness (neuropathy vs myopathy) af-
fects long-term recovery. In part, this differentiation is The only intervention thus far shown to reduce the in-
complicated by the aforementioned deficiencies in elec- cidence of ICU-acquired neuromuscular disorders is inten-
trophysiologic testing and the lack of muscle biopsies in sive insulin therapy.9 Maintenance of serum glucose at
the majority of studies, in that many patients once thought 80 110 mg/dL, compared to a conventional glucose goal
to have critical-illness polyneuropathy probably had my- of 180 200 mg/dL, reduced electrophysiologically diag-
opathy as the primary or a contributing cause of weakness. nosed polyneuropathy by 49% in patients in the ICU for
In one study of patients evaluated for neuromuscular weak- 7 days.9,94 Unfortunately, polyneuropathy was not a
ness during their ICU stay, patients diagnosed with criti- reported end point in a more recent study of intensive
cal-illness myopathy (many confirmed by biopsy) had a insulin therapy in medical ICU patients.111
similar course of recovery to those with critical-illness Experience from one small series of patients suggests
neuropathy, with the vast majority of patients ambulatory that intravenous immunoglobulin may reduce the likeli-
by 12 months in each group.45 Of note, 3 patients with hood of developing critical-illness polyneuropathy.112 Fur-
myopathy were not ambulatory at 12 months, which con- ther study is needed prior to recommending this interven-
firms that the course of this entity is not always benign. tion, however.
It is likely that avoidance of potentially triggering or
Diagnosis
priming factors, such as corticosteroids and neuromuscular
blocking drugs, will reduce the incidence of ICU-acquired
The clinical diagnosis of ICU-acquired neuromuscular
neuromuscular abnormalities, as will avoidance of ICU-
disorders is suspected in the presence of unexplained weak-
ness in patients recovering from critical illness; weakness associated infections and prompt treatment of sepsis. If the
can be so severe as to be confused with coma. Metabolic, previous statement is true, advances in ICU care will be
pharmacologic, and central-nervous-system causes of associated with a reduction in ICU-acquired neuromuscu-
weakness must be ruled out prior to establishing the diag- lar disorders.
nosis. Electrophysiologic testing is useful primarily to ex- There is no established treatment for patients with ICU-
clude other (possibly treatable) causes of severe weakness, acquired weakness. Avoidance of drugs that may further
including prolonged neuromuscular blockade and Guil- perpetuate injury is obviously warranted. Physical therapy
lain-Barre syndrome.5,7,101 As noted earlier, polyneurop- and rehabilitation may be helpful in accelerating recovery,
athy can be difficult to distinguish from myopathy, unless but there is a lack of rigorous evidence to support this
direct muscle stimulation is used. Muscle biopsy can con- practice.113

1048 RESPIRATORY CARE SEPTEMBER 2006 VOL 51 NO 9


INTENSIVE-CARE-UNIT-ACQUIRED MUSCLE WEAKNESS

Summary and the Future systemic inflammatory response syndrome or sepsis. Intensive Care
Med 2000;26(9):13601363.
11. Hund E, Genzwurker H, Bohrer H, Jakob H, Thiele R, Hacke W.
Unfortunately, our understanding of the causes of ICU- Predominant involvement of motor fibres in patients with critical
acquired neuromuscular abnormalities remains limited by illness polyneuropathy. Br J Anaesth 1997;78(3):274278.
the lack of basic science and translational studies. There 12. Thiele RI, Jakob H, Hund E, Tantzky S, Keller S, Kamler M, et al.
have been a few animal models that adequately repro- Sepsis and catecholamine support are the major risk factors for
critical illness polyneuropathy after open heart surgery. Thorac Car-
duced the clinical conditions that predispose to ICU-ac- diovasc Surg 2000;48(3):145150.
quired weakness, and although existing animal models do 13. Garnacho-Montero J, Amaya-Villar R, Garcia-Garmendia JL, Madrazo-
provide some insight into myopathic processes, the nature Osuna J, Ortiz-Leyba C. Effect of critical illness polyneuropathy on the
of the nerve injury remains unclear. Preventive and ther- withdrawal from mechanical ventilation and the length of stay in septic
apeutic strategies cannot be logically pursued without a patients. Crit Care Med 2005;33(2):349354.
14. Bolton CF. Sepsis and the systemic inflammatory response syn-
better understanding of the basic science of ICU-acquired
drome: neuromuscular manifestations. Crit Care Med 1996;24(8):
neuromuscular disorders. In addition, larger and more sys- 14081416.
tematic long-term studies of patients with ICU-acquired 15. Latronico N, Fenzi F, Recupero D, Guarneri B, Tomelleri G, Tonin
weakness are needed to better guide rehabilitative strate- P, et al. Critical illness myopathy and neuropathy. Lancet 1996;
gies. Given the high incidence and potential costs of ICU- 347(9015):15791582.
acquired neuromuscular disorders, the need for and the 16. Op de Coul AA, Verheul GA, Leyten AC, Schellens RL, Teepen
JL. Critical illness polyneuromyopathy after artificial respiration.
likely benefits of further research in this area are evident. Clin Neurol Neurosurg 1991;93(1):2733.
In the interim, preventive strategies are limited to the pro- 17. Olsen CW. Lesions of peripheral nerves developing during coma.
vision of excellent ICU care in an effort to limit duration J Am Med Assoc 1956;160(1):3941.
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sepsis and multiple organ failure. Brain 1987;110(Pt 4):819841.
insulin therapy.
19. Op de Coul AA, Lambregts PC, Koeman J, van Puyenbroek MJ,
Ter Laak HJ, Gabreels-Festen AA. Neuromuscular complications
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Discussion phragm weakness are really what have volvement, which should not be im-
the most impact in the ICU. portant, but the patient started becom-
Rajiv Dhand: I have 2 comments. Over the last couple of years Ive ing more and more symptomatic.
One is related to hyperglycemia. In become very conscious of the fact that There was objective evidence of loss
the literature that you reviewed, did you can find a lot of weakness in the of pulmonary function, and the dia-
you find that diabetes was an inde- diaphragm and involvement of the phragm elevation went on getting
pendent risk factor for development phrenic nerve without having much higher. Phrenic-nerve testing showed
of this problem? And the related com- peripheral muscle weakness, or very that this was an idiopathic unilateral
ment was that we always think of cor- gradually progressive peripheral- involvement of the phrenic nerve on
ticosteroids as causing myopathy, but muscle weakness. In fact, we recently that side. And because she was pro-
is it also possible that corticosteroids had a patient with obstructive sleep gressively getting worse, we gave her
are having the effect through causing apnea, congestive heart failuremul- a trial of intravenous immunoglobulin
hyperglycemia? tiple comorbiditiesand he was ad- for 5 days. Upinder did that. And, lo
mitted because he had an olecranon and behold, the patient improved
Deem: I havent come across any- bursitis. He would not take a nonin- symptomatically; she improved her
thing that relates diabetes to critical ill- vasive mask and so on. But to cut a pulmonary function, and actually the
ness polyneuropathy, although, given long story short, we found that the elevation of the diaphragm got better
that diabetics have neuropathy, you reason that he had the olecranon bur- too. There is a possibility that by dis-
might think itd be a risk factor. Its sitis was that he had to use his elbow tinguishing whether this is a nerve in-
mainly just hyperglycemia that shows to support his chin, and over the years, volvement or a muscle involvement
up. I think only the studies by Van den this problem had progressed very grad- we may be able to better target our
Berghe et al1,2 have really addressed the ually. When we tested him, we found treatment for these patients.
independence of corticosteroids and hy- that he had profound respiratory-mus-
perglycemia. They suggested that it was cle weakness. Deem: I agree entirely. Few studies
glycemic control and not other factors So there may be an expanded role have looked at diaphragm and phren-
that related to the risk of developing
for electrophysiological studies, be- ic-nerve function in these syndromes,
polyneuropathy per se.
cause you may not find much weak- and theyve only looked at a few pa-
ness in the peripheral muscles, yet have tients. But it does appear to be a real
REFERENCES significant weakness in the respiratory entity. And electrophysiologic abnor-
1. Van den Berghe G, Schoonheydt K, Becx muscles. One of the reasons for dis- malities are much more common than
P, Bruyninckx F, Wouters PJ. Insulin ther- tinguishing between polyneuropathy weakness per se, but that doesnt nec-
apy protects the central and peripheral ner-
and myopathy would be to figure out essarily mean that there arent actu-
vous system of intensive care patients. Neu-
rology 2005;64(8):13481353. whether this was primarily a problem ally functional abnormalities that are
2. Van den Berghe G, Wouters PJ, Bouillon related to the phrenic nerves, or was it just too subtle for us to detect by ex-
R, Weekers F, Verwaest C, Schetz M, et al. a problem primarily related to the di- amination. About the intravenous im-
Outcome benefit of intensive insulin ther- aphragm itself? munoglobulin: did that patient have
apy in the critically ill: insulin dose versus
glycemic control. Crit Care Med 2003;
In this respect, IVIG [intravenous evidence of demyelination?
31(2):359366. immunoglobulin] may actually play a
very important role, because about a Upinder Dhand: Actually, the elec-
Rajiv Dhand: And my second com- couple of years ago we saw a patient trophysiologic study was remarkable
ment is that peripheral muscle weak- who presented with one hemidia- for demyelination changes. The distal
ness is obviously a problem, but I think phragm elevation, and, actually, Up- latency of the phrenic nerve, instead
the weakness that we are most con- inder [Dhand] played a very impor- of being 7 ms, was 22 ms, so it was
cerned about is the phrenic-nerve di- tant role in the treatment of that patient. markedly prolonged. It improved af-
aphragm weakness. As you know, So, first of all, we thought that this ter treatment; it came down to 14 ms,
phrenic-nerve involvement and dia- was just a unilateral diaphragm in- with higher amplitude of motor po-

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INTENSIVE-CARE-UNIT-ACQUIRED MUSCLE WEAKNESS

tential, so it improved both clinically Mehta: They are conducting a trial tually a positive trial. It did show lower
and electrophysiologically. with the Australians to evaluate the morbidity and no difference in mor-
effects of aggressive insulin therapy, tality, certainly, and there was a trend
Deem: Right. That illustrates how with adult and pediatric patients, on toward lower mortality in the inten-
electrophysiologic testing might be adrenal function in the ICU. tion-to-treat group. And in the patients
useful in patients with ICU-acquired who were there longer, there were even
weakness syndromes. Deem: OK, well, I think we really more benefits. I have no reason to be-
need more data, because Im confused lieve that intensive insulin therapy wont
Upinder Dhand: I want to point out by the results of that study. I do give reduce polyneuropathy in the medical
that we should not mix up just the steroids to patients with septic shock, ICU population. And in their study the
phrenic-nerve conduction abnormality and then I stop them if they turn out to reported incidence of electrophysiologi-
with the ICU neuropathy. It could be be responders. But thats not what they cally-diagnosed polyneuropathy was
important, because were not sure if did in that study, and I dont know about 50% in the control group, which
the critical illness neuropathy will ben- that what Im doing actually results in is in the range reported throughout the
efit from intravenous immunoglobu- better short-term patient outcomes, literature on this subject. So I dont think
lin. There are a few reports, but we and they really didnt look at long- the way they treated patients with, for
still dont know. Whereas this patient term outcomes in those patients. I think instance, total parenteral nutrition, was
was possibly a variant of multifocal thats an important end point that we contributing to a higher risk of polyneu-
motor neuropathy. So she was com- need to start including in our studies ropathy. I take your point, that it is dif-
pletely different etiologically. of interventions that we do in the ICU, ficult to generalize the results from the
because we may find out that in the first study, but I still think the evidence
Deem: Wijdicks et al, from the Mayo long run were actually harming more is convincing enough, at least for me, to
Clinic, reported on a small group of patients than we help. continue with that approach in the gen-
patients with polyneuropathy who re- eral ICU population.
ceived intravenous immunoglobulin Jubran: Steve, I think we have to
and it had no effect on their course.1 be careful of generalizing too much Rajiv Dhand: While we continue
from the data from the Van den Berghe using intensive insulin therapy for our
REFERENCE
et al study1 about using insulin for patients, I think I completely agree
1. Wijdicks EF, Fulgham JR. Failure of high- polyneuropathy. The first study in with Amal; I was quite disappointed
dose intravenous immunoglobulins to alter which they found benefits from inten- by the most recent study, in which
the clinical course of critical illness poly- sive insulin therapy was done in a sur- there was no difference in the primary
neuropathy. Muscle Nerve 1994;17(12):
14941495.
gical ICU. Also, they are more ag- outcome, and in the secondary out-
gressive in providing nutrition to the comes. 1 All the differences were
Benditt: I couldnt agree more. I patients than we routinely are in our shown, but no Bonferroni correction
think a lot of physiologic testing turns ICUs. In fact, when the investigators was applied for those outcomes. So,
up some things that you might not have repeated the study in medical ICU pa- really, this appears to be a totally neg-
expected, so I agree with that. Con- tients, they did not find a difference in ative study.
cerning the recent increase in use of mortality. I dont think they looked at
corticosteroids in the ICU,1 and rela- critical-illness polyneuropathy in the REFERENCE
tive or absolute adrenal insufficiency, second study, but hypoglycemia was
1. Van den Berghe G, Wilmer A, Hermans G,
do you think its overall a good thing an independent predictor of death. Meersseman W, Wouters PJ, Milants I, et al.
or a bad thing that were using ste- Intensive insulin therapy in the medical
roids more commonly? REFERENCE ICU. N Engl J Med 2006;354(5):449461.

1. Van den Berghe G, Wilmer A, Hermans G,


REFERENCE Deem: Of course, we really arent
Meersseman W, Wouters PJ, Milants I, et
1. Annane D. Resurrection of steroids for sep- al. Intensive insulin therapy in the medical here to debate that study, but I think it
sis resuscitation. Minerva Anestesiol 2002; ICU. N Engl J Med 2006;354(5):449461. depends on which data you look at,
68(4):127131. because the hazard ratios of various
Deem: I agree that its all so con- complications were reduced, and I
Deem: I wish I knew the answer to fusingmuch like the literature on ste- dont think those have to be corrected
that question. I think some Canadians roids for septic shock. On the other in any fashion.
are doing another trial of steroids for hand, I think we shouldnt look at their
sepsis, or am I confusing that with an follow-up study as being a negative Rajiv Dhand: Youre right about
insulin? trial, because in some ways it was ac- that.

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