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CHAPTER 83: ICU-Acquired Weakness 769

and facial weakness. Train-of-four stimulation with a peripheral ICUAW as detected by chart review. There was no statistically signifi-
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nerve stimulator measures the decremental response semiquantita- cant association of ICUAW with randomization to methylprednisolone;
tively and may detect a major neuromuscular junction defect. Formal however, intervention patients were more likely to have evidence of
testing with repetitive nerve stimulation is the confirmatory test. In ICUAW in the first 28 days of the study, and were more likely to be
this test, a series of supramaximal stimuli are applied with a nerve clinically diagnosed with myopathy. It is plausible that some benefits
stimulator. Decreases in CMAP amplitude greater than 10% from the of corticosteroid treatment on lung function were offset by the adverse
first to fourth response indicate a postsynaptic defect in neuromus- effects on strength.
cular transmission, such as myasthenia gravis or prolonged NMBA The association of neuromuscular weakness with prolonged effect
effect. Transient improvement in muscle strength after administra- of neuromuscular blocking agents (NMBAs) has long been recognized
tion of an anticholinesterase reversing agent, such as pyridostigmine, and was the most prominent reason for a shift away from NMBA use
supports prolonged neuromuscular junction blockade as a cause in the critically ill. A typical scenario involves patients with severe
of weakness. acute asthma and ventilatory failure who undergo treatment with high-
The condition is reversible and recovery of motor function is dose corticosteroids in combination with NMBAs. These patients may
observed over a period of 2 to 10 days. Weakness beyond this dura- exhibit severe and protracted myopathy. 37,53,54 However, this relationship
tion should prompt consideration for alternative diagnoses, especially has not borne out in the general adult ICU population. 36,42 Concerns
other neuromuscular junction diseases such as myasthenia gravis. about NMBA use have been reduced by a recent multicenter RCT test-
Prolonged neuromuscular blockade can be prevented by avoiding ing the benefit of early neuromuscular blockade for severe ARDS.
23
aminosteroid blocking drugs in favor of benzylisoquinoline agents, Randomization to cisatracurium versus placebo significantly decreased
such as cisatracurium, which has no dependence on end organ 90-day mortality from 40.7% to 31.6%. Investigators included ICUAW as
function (metabolized by rapid nonenzymatic degradation in the a secondary outcome. At ICU discharge, there were neither differences
bloodstream, Hofmann elimination). Indeed, the routine use of cisa- in average muscle strength among patients tested nor any difference in
tracurium for neuromuscular blockade in the ICU has largely elimi- proportion of patients with ICUAW. These findings are a substantial
nated this problem. contribution, challenging the commonly held belief about the causal role
■ ICUAW EPIDEMIOLOGY AND RISK FACTORS of neuromuscular blockers in ICUAW. However, there are some impor-
tant limitations, including the use of manual muscle strength testing as
Several studies have attempted to establish the prevalence of ICUAW the gold standard for investigating nerve and muscle function in the
and its associated risk factors. Given the history of reliance upon ICU and lack of follow-up testing to answer questions about lingering
advanced testing to delineate phenotypes, large-scale epidemiology impairment.
studies have not been conducted. In this context, the best summary
data is a systematic review of 24 published studies that included both PREVENTION AND TREATMENT
clinical and electrophysiologic examination. Their end point was
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abnormal EP test findings (including CIP, CIM, and CIPNM), which Data supporting specific approaches to prevent or treat ICUAW are
they termed critical illness neuromuscular abnormalities (CINMAs), a limited. A Cochrane review identified only one successful interven-
label now interchangeable with ICUAW. Of the 1421 total patients with tion: insulin therapy with strict glycemic control. This evidence for
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sepsis, multiorgan failure, or prolonged mechanical ventilation, 46% had prevention comes from two trials studying “intensive” insulin therapy
ICUAW. The risk of ICUAW was associated with hyperglycemia (and (defined as maintenance of a blood glucose level between 80 and
inversely associated with tight glycemic control), the systemic inflam- 110 mg/dL) in critically ill patients who remain in the ICU for 7 or
matory response syndrome (SIRS), sepsis, multiple organ dysfunction, more days. The first trial, focused on surgical patients, demonstrated
renal replacement therapy, and catecholamine administration. Across a mortality benefit and a secondary end point of fewer cases of CIP
studies, there was no consistent relationship between ICUAW and detected by routine electrophysiologic testing after day 7 (29% vs 52%,
patient age, gender, severity of illness, or exposure to glucocorticoids, p < 0.001). The same investigators studied the effect of intensive
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neuromuscular blockers, aminoglycosides or midazolam. Unadjusted insulin therapy in medically critically ill patients. The prospective
mortality was not increased in the majority of patients with ICUAW, but subanalysis demonstrated a significant reduction in the incidence of
mechanical ventilation and ICU LOS were prolonged. critical illness polyneuropathy and myopathy (51% vs 39%, p = 0.02)
The cohort study that established the validity of the physical examination when similarly screened by weekly EP studies. Unfortunately, despite
for ICUAW had both complementary and different findings. For example, this protective effect on the development of ICUAW, intensive insulin
18
in the 95 ICU patients who underwent mechanical ventilation for 7 days therapy has been associated with an increased risk of severe hypogly-
or more, independent predictors of ICUAW included the number of days cemia and either increased mortality or had no effect on mortality
with dysfunction of two or more organs (OR: 1.28, 95% CI: 1.11-1.49) and when compared to more permissive blood glucose ranges (such as
the duration of mechanical ventilation (OR: 1.10, 95% CI: 1.00-1.22). In 140-180 mg/dL and 180-200 mg/dL). 57,58 Furthermore, because more
contrast to the systematic review, female sex (OR: 4.66, 95% CI: 1.19-18.30) recent data suggest an increased mortality with aggressive insulin
and administration of corticosteroids (OR: 14.90, 95% CI: 3.20-69.80) were therapy, this treatment option cannot be recommended as a means
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strong predictors. to prevent ICUAW.
In search of potentially modifiable risk factors for ICUAW, many For all forms of ICUAW, care is supportive. Measures to avoid second-
investigations have focused on exposure to corticosteroids and NMBAs. ary injury must be undertaken. These practices may span mechanical
These agents have been both implicated in animal research and ventilation (low tidal volume ventilation for ARDS; protocols to guide
observational trials in humans. Results have not been consistent or ventilator readiness testing and liberation), stress ulcer and venous
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conclusive, likely due to methodological limitations of these inves- thrombosis prophylaxis, titrated sedation and analgesia therapy, and
tigations. More recently, randomized controlled trials have included efforts to avoid nosocomial infection (head of bed elevation, early
secondary analyses for evidence of ICUAW to bypass the problem of discontinuation of central venous and urinary catheters). Because
confounding by indication. 23 prolonged immobilization and bed rest have been shown to acceler-
Although corticosteroids inhibit protein synthesis in type II muscle ate muscle loss, which may exacerbate ICUAW, mobility therapy has
fibers and contribute to severe protein catabolism, the relationship emerged as a potential preventive measure. 59
between corticosteroids and ICUAW has been inconsistent. In a second- A new framework for early mobilization during critical illness
ary analysis of a multicenter study of patients with severe and persistent has evolved. Rather than delay rehabilitation until the patient has
ARDS randomized to methylprednisolone or placebo, 34% developed left the ICU, studies of progressively earlier exercise have repeatedly

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