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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 175 2007

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DOI: 10.1164/rccm.200612-1800ED

Critical Illness Neuromyopathy

From Risk Factors to Prevention
Critical illness neuromyopathy (CINM) can signicantly delay
weaning from mechanical ventilation and impair physical recovery (1, 2). CINM is often unrecognized and, depending on the
population studied, may affect between 25 and 75% of longerstay intensive care unit (ICU) patients (3, 4). In this issue of
the Journal (pp. 480489), Hermans and colleagues report that
intensive insulin therapy prevented CINM in a subset of patients
enrolled in their medical ICU trial (5). That intensive insulin
therapy may prevent CINM is exciting, but the report highlights
the difculty of diagnosing CINM in a research context and
raises important issues of clinical trial methodology.
Hermans and colleagues diagnosed CINM solely on the presence of spontaneous electrical activity in muscle on electroneuromyography. They did not identify altered muscle membrane excitability, which is increasingly recognized as a cause of
muscle weakness in critically ill patients (6). Had they done so,
they may have reported a different result. In addition, they only
report outcomes in patients treated in the ICU for 7 days or
more and do not present an intention-to-treat analysis. The incidence of CINM in patients who received the study and control
treatments for up to 7 days goes unreported and this signicantly
reduces the certainty of the ndings (7). Furthermore, because
the subgroup studied could not be identied at the start of
treatment, clinicians do not know to which of their patients the
ndings apply (8).
Although selecting appropriate subgroups and reporting
intention-to-treat analyses are essential components of clinical
trial design, studying CINM presents particular difculties. CINM
can be detected by clinical examination or electroneuromyogra-

phy but usually not until patients have been treated with mechanical ventilation for several days. Clinical examination is focused
on detecting muscle weakness, which is a uniform manifestation
of CINM, regardless of whether the axon, muscle contractile
proteins, or muscle membrane excitability are involved alone or
in combination (4, 9). As the patient must be cooperative, daily
assessment from the beginning of mechanical ventilation is rarely
possible. Electroneuromyography is the alternative diagnostic
approach. Electroneuromyography allows earlier diagnosis but
its use requires considerable resources and can cause discomfort.
It is neither practical nor ethical to conduct repeat testing on a
daily basis for a clinical trial.
To date, only patients who remain in an ICU for 5 to 7 days
have been assessed for CINM, and because many patients will
have been discharged or will have died by this time, an intentionto-treat analysis of a clinical trial may appear impractical. However, the methodologic difculties can be overcome by asking the
right questions in the right population. We should ask whether a
treatment reduces the incidence of CINM and does that result
in better outcomes for patients. The study population should be
patients likely to receive at least 5 days of mechanical ventilation
and in whom the clinical diagnosis of CINM is feasible. This will
likely mean excluding patients with primary neurologic diseases
or brain injury. To determine if CINM is prevented, the outcome
measure could be the number of patients discharged alive from
ICU who were never diagnosed with CINM. To determine if
patients outcomes are improved, time to recovery from CINM
and long-term functional recovery of survivors should be reported.

Editorials

In our opinion, the diagnosis of CINM should be made by

clinical examination conducted by a blinded observer using a
recognized scoring system. For example, the Medical Research
Council scale is a simple and robust score that quanties muscle
weakness (10). It has satisfactory interobserver reproducibility in
ventilated patients with Guillain-Barre syndrome (10), and in
patients with acute stroke (11). Although not yet validated in the
general ICU population, it appears to be an ideal tool for the
diagnosis of CINM. The timing of clinical testing may be difcult
because patients must be sufciently recovered to cooperate;
the earliest this is likely is at the start of weaning from mechanical
ventilation. Serial testing should be conducted from the start of
weaning until the time of discharge from the ICU.
Having recognized the methodologic difculties inherent in
such research, what are the implications of Hermans and colleagues report for clinicians? Enthusiasm for intensive insulin
therapy arose from the reduction in mortality in Van den
Berghes rst trial (12). This enthusiasm has been tempered
somewhat by the ndings of the second trial (13), and because
the Efcacy of Volume Substitution and Insulin Therapy in
Severe Sepsis (VISEP) and Glucontrol studies have both
stopped early due to lack of efcacy and concerns about the
safety of intensive insulin therapy (1416). A fourth, multicenter
trial in Australasia and North America (the NICE-SUGAR
[Normoglycaemia in Intensive Care Evaluation and Survival
Using Glucose Algorithm Regulation] study) plans to recruit
6,100 patients and report its ndings in 2008 (17). If NICESUGAR shows a clear mortality benet, then intensive insulin
therapy will likely become a standard of care. If not, then effects
on secondary outcomes, such as the incidence of CINM and
duration of mechanical ventilation, will assume considerable importance. Data from the two European trials may conrm or
refute Hermans and colleagues ndings as the incidence of
CINM was assessed in the VISEP trial using electrophysiology
and in Glucontrol using clinical examination (F. Brunkhorst and
J.-C. Preiser, personal communications).
If intensive insulin therapy does prevent CINM, then the
benet to patients should be a reduction in the duration of
mechanical ventilation and more rapid recovery from critical
illness. From the patients perspective, these outcomes are valuable regardless of why they occur. Van den Berghe and colleagues have reported that intensive insulin therapy signicantly
reduced the time to weaning in their medical ICU trial (13), but
not the median duration of ventilation in their surgical ICU trial
(12). The VISEP, Glucontrol, and NICE-SUGAR trials will
report the impact of intensive insulin therapy on duration of
mechanical ventilation in a large population of patients treated
in different ICUs. The collective ndings should be broadly
applicable in ICUs around the world.
Hermans and colleagues report that a metabolic therapy may
prevent CINM is exciting. From the clinicians viewpoint, the
report presents those who have adopted intensive insulin therapy
with no reason to change their practice. Others may be concerned
about the methodologic issues and that intensive insulin therapy
has not yet been proven benecial in multicenter trials. Those
who remain skeptical may prefer to wait for the full reports of
the VISEP and Glucontrol trials and possibly for the results of
the NICE-SUGAR study.
It is hoped that other strategies to prevent CINM will be
developed and tested in randomized controlled trials. The difculties of conducting such research should not be underestimated
and Hermans and colleagues are to be congratulated on their
work. The results of future trials will be regarded with the greatest certainty if the outcomes most relevant to patients are reported in the intention-to-treat population.

425
Conflict of Interest Statement : Neither author has a financial relationship with a
commercial entity that has an interest in the subject of this manuscript.

Bernard De Jonghe, M.D.

Centre Hospitalier de Poissy-Saint-Germain
Poissy, France
Simon Finfer, F.R.C.P., F.J.F.I.C.M.
Royal North Shore Hospital
and
Northern Clinical School
University of Sydney
Sydney, Australia
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