Intensive Care Med (2007) 33:1876–1891
DOI 10.1007/s00134-007-0772-2
Robert D. Stevens
David W. Dowdy
Robert K. Michaels
Pedro A. Mendez-Tellez
Peter J. Pronovost
Dale M. Needham
Received: 7 March 2007
Accepted: 15 June 2007
Published online: 17 July 2007
© Springer-Verlag 2007
R. D. Stevens (u) · R. K. Michaels ·
P. A. Mendez-Tellez · P. J. Pronovost
Johns Hopkins University School of
Medicine, Department of
Anesthesiology/Critical Care Medicine,
600 N Wolfe St, Meyer 8-140, Baltimore
21287, MD, USA
e-mail: rstevens@jhmi.edu
Tel.: +1-410-9557481
Fax: +1-410-6147903
R. D. Stevens
Johns Hopkins University School of
Medicine, Department of Neurology,
Baltimore MD, USA
R. D. Stevens
Johns Hopkins University School of
Medicine, Department of Neurosurgery,
Baltimore MD, USA
D. W. Dowdy
Johns Hopkins Bloomberg School of Public
Health, Department of Epidemiology,
Baltimore MD, USA
P. J. Pronovost
Johns Hopkins University School of
Medicine, Department of Surgery,
Baltimore MD, USA
SYSTEMATIC REVIEW
Neuromuscular dysfunction acquired in critical
illness: a systematic review
P. J. Pronovost
Johns Hopkins Bloomberg School of Public
Health, Department of Health Policy and
Management,
Baltimore MD, USA
D. M. Needham
Johns Hopkins University School of
Medicine, Department of
Pulmonary/Critical Care Medicine,
Baltimore MD, USA
Abstract Objective: To determine
the prevalence, risk factors, and
outcomes of critical illness neuro-
muscular abnormalities (CINMA).
Design: Systematic review. Data
sources and study selection: MED-
LINE, EMBASE, CINAHL, and the
Cochrane Library were searched for
reports on adult ICU patients who
were evaluated for CINMA clinically
and electrophysiologically. Studies
were included if they contained suffi-
cient data to quantify the association
between CINMA and relevant ex-
posures and/or outcome variables.
Measurements and results: CINMA
was diagnosed in 655 of 1421 [46%
(95% confidence interval 43–49%)]
adult ICU patients enrolled in 24
studies, all with inclusion criteria
of sepsis, multi-organ failure, or
prolonged mechanical ventilation.
Diagnostic criteria for CINMA were
not uniform, and few reports un-
equivocally differentiated between
polyneuropathy, myopathy, and mixed
types of CINMA. The risk of CINMA
was associated with hyperglycemia
(and inversely associated with tight
glycemic control), the systemic
inflammatory response syndrome,
sepsis, multiple organ dysfunction,
renal replacement therapy, and cat-
echolamine administration. Across
studies, there was no consistent rela-
tionship between CINMA and patient
age, gender, severity of illness, or use
of glucocorticoids, neuromuscular
blockers, aminoglycosides, or mida-
zolam. Unadjusted mortality was not
increased in the majority of patients
with CINMA, but mechanical ventila-
tion and ICU and hospital stay were
prolonged. Conclusions: The risk of
CINMA is nearly 50% in ICU patients
with sepsis, multi-organ failure, or
protracted mechanical ventilation.
The association of CINMA with
frequently cited CINMA risk fac-
tors (glucocorticoids, neuromuscular
blockers) and with short-term survival
is uncertain. Available data indi-
cate glycemic control as a potential
strategy to decrease CINMA risk.

Introduction
Many patients admitted to the intensive care unit (ICU)
develop a syndrome of neuromuscular dysfunction
characterized by generalized muscle weakness and an
inability to separate from mechanical ventilation [1].
Since this syndrome occurs in the absence of preex-
isting neuromuscular disease, it is believed to reflect
illnesses or treatments occurring in the ICU. Early re-
ports described two categories of acute neuromuscular
dysfunction, a polyneuropathy found in patients with
sepsis and multiple organ failure [2, 3] and a myopathy
in patients with acute respiratory failure who received
glucocorticoids and/or neuromuscular blocking drugs [4,
5]. More recent work has delineated subtypes of critical
illness polyneuropathy and myopathy, and has emphasized
that peripheral nerve and muscle involvement frequently
coexist [6–8]. The spectrum of neuromuscular disorders
acquired in the ICU, which also includes neuromuscular
junction dysfunction, has been collectively referred to as
“critical illness neuromyopathy” [9], “ICU-acquired pare-
sis” [7], “Critical illness myopathy and/or neuropathy”
(CRIMYNE) [10], or “critical illness neuromuscular
abnormalities” (CINMA) [11].
The rising incidence and societal burden of critical ill-
nesses such as sepsis and the acute respiratory distress syn-
drome [12–14], coupled with declining case fatality rates
and an aging population [14–16], suggest that the number
of patients with CINMA and its sequelae may be substan-
tial and likely to grow [17]. Many survivors of critical ill-
ness present with chronic morbidity linked to central and
peripheral neurological dysfunction [18–20], resulting in
diminished functional status and quality of life months and
years after the acute period [21].
Knowledge of CINMA has increased through stud-
ies exploring the relationship between CINMA and
selected risk factors, as well as the impact of CINMA
on short-term outcomes [7, 8, 22–25]. CINMA has
been incorporated as an outcome measure in recent
large-scale randomized trials of ICU patients [26–28].
Nevertheless, considerable uncertainty persists regarding
the epidemiology, pathogenesis, and natural history of
CINMA. We undertook a systematic review to syn-
thesize knowledge from published studies in this field
and to identify important areas for future research.
Specifically, our aims were threefold: first, to estimate
the prevalence of CINMA and its subsets using ex-
plicit diagnostic criteria; second, to identify variables
that are associated with an increased (or decreased)
risk of CINMA; and third, to evaluate the relationship
between CINMA and patient outcomes, including mor-
tality, duration of mechanical ventilation, and length of
hospitalization.
1877
Methods
Data sources and searches
Relevant publications were identified by searching Med-
line (1966–2006), EMBASE (1974–2006), CINAHL
(1982–2006) and the Cochrane Library (2006, Issue 2) on
29 April 2006, using the following terms: neuromuscular
diseases, muscular diseases, paresis, polyneuropathy,
myopathy, neuromyopathy, critical illness, critical care,
critically ill, intensive care, ICU, sepsis, septic, systemic
inflammatory response syndrome, acute lung injury,
acute/adult respiratory distress syndrome, ARDS, mul-
tiple organ dysfunction/failure, artificial ventilation,
mechanical ventilation. Terms were mapped to the ap-
propriate “Medical Subject Heading” (MeSH) term and
“title/abstract” (tiab) text word in Medline, and to the
EMTREE subject headings in EMBASE, and “exploded”.
Citations were not excluded on the basis of language. In
addition to the electronic search, references from selected
reports and review articles, as well as personal files,
were hand searched. Only full-length reports published
in peer-reviewed journals were included in this review. If
data were missing or unclear in published reports, authors
were contacted for additional information.
Study selection
We selected articles meeting the following inclusion
criteria. First, studies enrolled adults (> 16 years old)
admitted to the ICU who were evaluated for CINMA
using either diagnostic tests (nerve conduction velocities,
needle electromyography, direct muscle stimulation,
histopathology of muscle or nerve tissue) or a combination
of diagnostic tests and clinical findings (muscle weakness,
decreased or absent deep tendon reflexes, and/or failure
to liberate from mechanical ventilation), with diagnostic
tests obtained in at least all patients who had positive
clinical findings. Second, studies compared patients with
CINMA to a group of ICU patients without clinical
weakness and/or with negative diagnostic tests, such that
a quantitative estimate of the association between CINMA
and at least one relevant exposure and/or outcome variable
was possible. Relevant exposure variables were patient
demographics, admission diagnosis, severity of illness,
physiological and metabolic status, organ dysfunction
or failure, and the administration of pharmacological
agents. Relevant outcomes were the duration of mech-
anical ventilation, ICU and hospital mortality and length
of stay, and any reporting of long-term outcomes such
as muscle weakness or functional status. Third, studies
contained original data with a sample size of ≥ 10 patients.
1878
There are no universally accepted or consensus-derived
definitions of CINMA and its subtypes. For the purposes
of this review, we accepted the classification used by
study investigators provided that they explicitly met the
following minimum criteria. For critical illness polyneu-
ropathy (CIP), minimum criteria were the presence of
weakness acquired after admission to the ICU associated
Fig. 1 Flow diagram of study se-
lection process
with decreased amplitudes of compound muscle action
potentials or sensory nerve action potentials. For critical
illness myopathy (CIM), minimum criteria were the
presence of weakness acquired after admission to the
ICU and at least one of the following: demonstration
of short, low-amplitude motor unit potentials (requires
patient cooperation); decreased direct muscle stimula-

tion amplitude or prolonged direct muscle stimulation
latency; or muscle histopathology consistent with an
acute myopathy. Mixed CIP/CIM was defined as a com-
bination of features consistent with both CIP and CIM.
We use the term “unclassified CINMA” for patients in
studies which did not fully differentiate between CINMA
subtypes.
A diagram of the study selection process is given in
Fig. 1. Using the study inclusion criteria above, article
titles were screened for potentially relevant papers; these
papers were reviewed in abstract form, and relevant
abstracts were chosen for full-text analysis. Each of
these steps was performed independently by two authors
(R. D. S., D. W. D.); any title or abstract selected by either
author as potentially relevant was included in the next
round of review. Full-text review and final selection of
articles was performed independently by two authors
(D. W. D., R. K. M.), with discrepancies adjudicated by
a third author (R. D. S.). Agreement between reviewers
was estimated using the kappa statistic.
Data extraction and quality assessment
Using a standardized data collection form, two authors
(D. W. D., R. K. M.) independently abstracted data on
study design and quality, methods for diagnosing CINMA,
and patient demographic characteristics. The following
exposure variables were systematically recorded (when
available): severity of illness scores; organ dysfunction
scores; presence of the systemic inflammatory response
syndrome (SIRS), sepsis, or acute respiratory distress
syndrome; renal replacement therapy, parenteral nutrition
and hyperglycemia; glycemic control; and administration
of glucocorticoids, neuromuscular blockers, aminogly-
cosides, vasopressors or inotropic agents, metronidazole,
furosemide, and midazolam. We also abstracted the
following outcomes (when available): death in the ICU
and hospital, duration of mechanical ventilation, length of
stay in the ICU and hospital, and long-term outcomes.
Methodological quality of individual observational
studies was assessed with the Newcastle–Ottawa Scale
(NOS) [29], a validated instrument specifically designed to
evaluate the quality of observational studies in systematic
reviews and meta-analyses [30, 31]. The NOS evaluates
three domains of study methodology: the selection of
study groups (score range 0–4), the comparability of
groups (score range 0–1), and the quality of ascertainment
of either the exposures (for case–control studies) or of
the outcomes of interest (for cohort studies) (score range
0–3). The composite NOS score ranges from 0 to 8,
with a NOS > 5 indicating an acceptable methodological
design. For the one randomized controlled trial included in
this review, methodological quality was assessed using the
Jadad scale [32]. This is a validated 3-item, 5-point scor-
ing system evaluating trial randomization (0–2), blinding
1879
(0–2), and the description of dropouts and withdrawals
(0–1).
Data synthesis and analysis
Since an explicit differentiation between CIP, CIM, and
mixed CINMA was not available in most studies, these
subtypes were not analyzed separately. In most of the
included studies, comparisons of exposure and outcome
variables between patients with and without CINMA were
made without adjustment for potential confounders. For
univariable comparisons, we recorded p-values provided
in the articles, and if these were not reported we calculated
them from the original data; for multivariable compar-
isons, we recorded odds ratios (OR) or relative risks (RR)
along with the 95% confidence interval (95% CI), and if
these data were not given, we calculated them using the
original data. In light of inter-study heterogeneity in both
the number and type of covariates included in multivari-
able analyses, quantitative synthesis (i. e. meta-analysis)
of study results was not undertaken.
Results
Study search and selection
The initial search retrieved 9,299 citations. Sequential
review of titles, abstracts, and full-length articles ulti-
mately yielded 29 reports on 24 unique patient populations
(Fig. 1). Hereafter, unless otherwise noted, our findings
refer to these 24 patient populations. The included studies
had a mean sample size of 59 (range 10–405), and totaled
1,421 patients. Kappa statistics for inter-reviewer selection
of potentially relevant titles, abstracts, and full-text articles
were 0.67, 0.72, and 0.79, respectively, demonstrating
substantial agreement [33].
Study characteristics and quality
Of the 24 studies, 19 were prospective cohorts [7, 8, 22,
24, 25, 34–46], 2 were retrospective cohorts [47, 48], 2
were case–control studies [49, 50], and 1 was a random-
ized controlled trial [26] (Table 1). The criteria for enroll-
ment of ICU patients included mechanical ventilation in
17 reports [median (range) duration of mechanical venti-
lation 7 (2–10); in 14 reports, mechanical ventilation was
≥ 7 days], sepsis or septic shock in 5 reports, and multi-
ple organ failure in 5. Patient exclusion criteria were stated
in 20 studies and included presence or risk of prior neuro-
muscular disease in 19 reports and moribund status in 1.
Patient follow-up extended beyond hospital discharge in 3
cohorts [7, 34, 43].
 1880

Table 1 Study characteristics

Reference Study design No. of patients ICU Setting Patient enrollment criteria Follow up
enrolled
Amaya-Villar, 2005 [24] Prospective cohort 26 Mixed MV > 48 h, COPD, high-dose steroids In-hospital only
Bednarik, 2003 [8] Prospective cohort 46 Mixed (1 unit); > 2 organ failures with SOFA grade 3–5 28 days after enrollment
Neurological (1 unit)
Bednarik, 2005 [22] Prospective cohort 61 Mixed (1 unit); > 2 organ failures with SOFA grade 3–5 28 days after enrollment
Neurological (1 unit)
Bercker, 2005 [48] Retrospective cohort 45 Mixed ARDS and MV 29 days after enrollment
Berek, 1996 [34] Prospective cohort 22 Not reported SIRS or sepsis and MOF 60–90 days after enrollment
Campellone, 1998 [35] Prospective cohort 77 Surgical MV > 7 days or hospital LOS NR
> 14 days following OLT
Coakley, 1998 [36] Prospective cohort 44 Mixed MV and ICULOS > 7 days In-hospital only
De Jonghe, 2002 [7] Prospective cohort 95 Medical (3 units); MV > 7 days and evidence of wakefulness 45 days after enrollment
Surgical (2 units)
De Letter, 2001 [52] Prospective cohort 98 NR MV > 3 days 30 days after intubation
Druschky, 2001 [38] Prospective cohort 28 Neurological MV > 4 days 14 days of MV
Garnacho-Montero, 2001 [25] Prospective cohort 73 Mixed MV > 10 days, sepsis, MOF In-hospital only
Garnacho-Montero, 2005 [51] Prospective cohort 64 Mixed MV > 7 days, severe sepsis or septic shock In-hospital only
Hund, 1997 [50] Prospective cohort 28 Surgical “Prolonged” MV, sepsis ICU only
Kupfer, 1992 [40] Prospective cohort 10 Medical MV, vecuronium infusion ICU only
Lefaucheur, 2006 [41] Prospective cohort 30 Medical MV > 7 days, diffuse weakness NR
Leijten, 1995 [43] Prospective cohort 50 Mixed MV > 7 days, age < 75 12 months
Leijten, 1996 [42] Prospective cohort 38 Mixed MV > 7 days, age < 76 12 months
Mohr, 1997 [44] Prospective cohort 33 Mixed MOF (Goris score > 5 for > 5 days) In-hospital only
Rudis, 1996 [49] Case–control study 20 Mixed Cases: weakness after NMB In-hospital only
Tepper, 2000 [45] Prospective cohort 22 Mixed Septic shock ICU only
Thiele, 1997 [50] Case–control study 44 Surgical MV > 3 days, cardiac surgery ICU only
Thiele, 2000 [46] Prospective cohort 19 Surgical MV > 3 days, cardiac surgery ICU only
Van den Berghe, 2005 [54] Randomized 405 Mixed (mostly MV, EMG in subset with ICU LOS In-hospital only
controlled trial cardiac surgical) ICU LOS > or = 7 days
Witt, 1991 [47] Retrospective cohort 43 Mixed ICU LOS > 5 days, sepsis 6 months

MV, mechanical ventilation; COPD, chronic obstructive pulmonary disease; ARDS, acute respiratory distress syndrome; SIRS, systemic inflammatory response syndrome; MOF,
multiple organ failure; NR, not reported; LOS, length of stay; OLT, orthotopic liver transplantation; Goris score, see [66]; NMB, neuromuscular blockers; EMG, electromyogram
 1881

Table 2 Quality of CINMA studies

Newcastle-Ottawa Scale [27]

Selection (0–4) Comparability (0–1) Outcome/Exposure (0–3) Total
Amaya-Villar, 2005 [24] 3 0 2 5
Bednarik, 2003 [8] 3 0 1 4
Bednarik, 2005 [22] 3 1 2 6
Bercker, 2005 [48] 4 0 2 6
Berek, 1996 [34] 3 0 2 5
Campellone, 1998 [35] 3 0 1 4
Coakley, 1998 [36] 3 0 2 5
De Jonghe, 2002 [7] 2 1 2 5
De Letter, 2000 [52] 3 1 2 6
Druschky, 2001 [38] 3 0 2 5
Garnacho-Montero, 2001 [25] 3 1 3 7
Garnacho-Montero, 2005 [51] 3 1 3 7
Hund, 1997 [50] 1 0 2 3
Kupfer, 1992 [40] 1 0 3 4
Lefaucheur, 2006 [41] 2 0 2 4
Leijten, 1995 [43] 3 0 3 6
Leijten, 1996 [42] 3 0 2 5
Mohr, 1997 [44] 1 0 1 2
Rudis, 1996 [49] 4 0 3 7
Tepper, 2000 [45] 3 0 1 4
Thiele, 1997 [50] 3 0 2 5
Thiele, 2000 [46] 2 0 2 4
Witt, 1991 [47] 1 0 1 2
Median (range) 3 (1–4) 0 (0–1) 2 (1–3) 5
Mean (SD) 2.6 (0.9) 0.2 (0.5) 2.0 (0.65) 4.80

Jadad scale [30] Randomization Blinding Follow up Total

Van den Berghe, 2001 [54] 2 0 1 3

For cohort studies “selection” refers to the representativeness of the exposed cohort (yes = 1, no = 0), selection of the non exposed cohort
(adequate = 1, not adequate = 0), ascertainment of exposure (clear = 1, unclear = 0), demonstration that outcome of interest was not present
at start of study (yes = 1, no = 0); “comparability” refers to adjustment for bias/confounding (yes = 1, no = 0); “outcome” refers to outcome
assessment, i.e. independent blind assessment (yes = 1, no = 0), appropriate duration of follow up (yes = 1, no = 0), adequacy of follow-up
(> 90% = 1, ≤ 90% = 0). For case control studies, “selection” refers to the case definition (adequate = 1, inadequate = 0), representative-
ness of the cases (yes = 1, no = 0), selection of controls (adequate = 1, inadequate = 0), definition of controls (adequate = 1, inadequate = 0);
“comparability” refers to adjustment for bias/confounding (yes = 1, no = 0); Exposure assessment refers to ascertainment of exposure (ad-
equate = 1, inadequate = 0); identical method of ascertainment for cases and controls (yes = 1, no = 0), non-response rate (same rate for both
groups = 1, other = 0). Maximum score = 8, minimum = 0. Adapted from [29]

The methodological quality of the studies was fair, with
7 studies achieving a NOS > 5 [22, 25, 37, 43, 48, 49,
51] (Table 2). The quality of reports published after 2000
was not significantly higher than in the older studies [mean
(SD) NOS 5.5 (1.0) versus 4.6 (1.3), p = 0.08]. Statistical
comparisons in the majority of studies were made with-
out adjustment for potential confounders. Multivariable re-
gression analysis was available in 8 reports (Table 8) [7,
22–25, 34, 52, 53].
ease as a cause of critical illness [35, 46, 49, 50, 54], in-
dicating possible enrollment of patients with non-CINMA
conditions. Six studies met minimum criteria to adequately
discriminate between cases of CIP, CIM, and CIP/CIM [8,
22, 34, 37, 41, 49]; these reports all contained either an-
alysis of motor unit potentials, direct muscle stimulation,
or muscle histopathology. In all other studies, data were
insufficient to make this distinction.

Diagnosis of CINMA
Diagnosis of CINMA was confirmed with electrophysio-
logical tests in all studies, and clinical findings were docu-
mented in all but three reports [24, 25, 54] (Table 3). Five
studies did not explicitly exclude patients with pre-existing
neuromuscular disease or patients with neuromuscular dis-
Prevalence of CINMA
Of the 1421 subjects included in this review, a total
of 655 (46%; 95% CI 43–49%) were diagnosed with
CINMA, with a median (range) prevalence of CINMA
in the studies of 57% (9–87%) (Table 4). Of the 655
patients diagnosed with CINMA, 51 (7.8%) had CIP,
49 (7.5%) had CIM, 44 (6.7%) had mixed CIM/CIP,
 1882

Table 3 Diagnosis of CINMA

Exclusion
of prior NMD
Documentation
of weakness
Repetitive
stimulation
CMAP
SNAP
MUP
Fibrillation
potentials
DMS
No. of patients (%)
with muscle biopsy

Reference Timing of first CINMA evaluation

Amaya-Villar, 2005 [24] Median (range) 6 (2–12) days of MV + + – – – + – – 3 (12)
Bedoarik, 2003 [8] < 3 days after ICU admission + + + + + + + + 11 (24)
Bednarik, 2005 [22] < 3 days after ICU admission + + + + + + + + 11 (18)
Bercker, 2005 [48] NR + + – – – – – – –
Berek, 1996 [34] 14–28 days after ICU admission + + – + + + + – –
Campellone, 1998 [35] 2 weeks after liver transplantation – + + + + + + – 5 (7)
Coakley, 1998 [36] NR + + + + + – + – 24 (55)
De Jonghe, 2002 [7] Mean (SD) 12.4 (6.8) of MV + + + + + – + – 10 (11)
De Letter, 2000 [52] 4 days MV + + + + + + + – 32 (33)
Druschky, 2001 [38] 4 days of MV + + + + + – + – –
Garnacho-Montero, 2001 [25] 10 days of MV + – + + + – + – –
Garnacho-Montero, 2005 [51] Onset of weaning from MV + – + + + – + – –
Hund, 1997 [50] 5–7 days of MV + + – + – – + – 2 (7)
Kupfer, 1992 [40] > 24 h after discontinuation of vecuronium infusion + + + – + – – – –
Lefaucheur, 2006 [41] Mean (SD) 13.7 (7.8) days after awakening from coma + + + + + + + + –
Leijten, 1995 [43] 7–9 days of MV + + + + + – + – –
Leijten, 1996 [42] 7–9 days of MV + + + + + – + – –
Mohr, 1997 [44] 1–2 days before discharge from ICU + + – + + – + – –
Rudis, 1996 [49] Median 6.5 days after discontinuing NMB – + + + + + + – –
Tepper, 2000 [45] < 3 days of septic shock + + – + + – + – –
Thiele, 1997 [50] 5–7 days of MV – + – + + – + – –
Thiele, 2000 [46] 5–7 days of MV – + – + + – + – –
Van den Berghe, 2005 [54] 1 week after ICU admission – – – – – – + – –
Witt, 1991 [47] 20 days after ICU adnrission + + – + + – + – –

CINMA, critical illness neuromuscular abnormality; NMD, neuromuscular disease; CMAP, compound muscle action potential; SNAP, sensory nerve action potential; MUP, motor
unit potential; DMS, direct muscle stimulation; MV, mechanical ventilation; NMB, neuromuscular blockers; + = information available in report; – = information not available in
report
 1883

Table 4 Prevalence of CINMA

Reference No. No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) with
of patients without with with with with mixed with NMJ unclassified
enrolled CINMA CINMA CIP CIM CIP/CIM defect CINMA
Amaya-Villar, 2005 [24] 26 17 (65%) 9 (35%) 9 (35%)
Bednarik, 2003 [8] 46 10 (43%) 26 (57%) 7 (15%) 8 (17%) 11 (24%)
Bednarik, 2005 [22] 61 26 (43%) 35 (57%) 12 (20%) 14 (23%) 9 (15%)
Bercker, 2005 [48] 45 18 (40%) 27 (60%) 27 (60%)
Berek, 1996 [34] 22 4 (18%) 18 (82%) 18 (82%)
Campellone, 1998 [35] 77 70 (91%) 7 (9%) 7 (9%)
Coakley, 1998 [36] 44 7 (16%) 37 (84%) 37 (84%)
De Jonghe, 2002 [7] 95 71 (75%) 24 (25%) 24 (25%)
De Letter, 2001 [52] 98 66 (67%) 32 (33%) 11 (11%) 12 (12%) 7 (7%) 2 (2%)
Druschky, 2001 [38] 28 12 (43%) 16 (57%) 16 (57%)
Garnacho-Montero, 2001 [25] 73 23 (32%) 50 (68%) 50 (68%)
Garnacho-Montero, 2005 [51] 64 30 (47%) 34 (53%) 34 (53%)
Hund, 1997 [50] 28 8 (29%) 20 (71%) 20 (71%)
Kupfer, 1992 [40] 10 3 (30%) 7 (70%) 2 (2%) 5 (50%)
Lefaucheur, 2006 [41] 30 4 (13%) 26 (87%) 1 (3%) 9 (30%) 16 (53%)
Leijten, 1995 [43] 50 21 (42%) 29 (58%) 29 (58%)
Leijten, 1996 [42] 38 20 (53%) 18 (47%) 18 (47%)
Mohr, 1997 [44] 33 26 (89%) 7 (21%) 7 (21%)
Rudis, 1996 [49] 20 10 (50%) 10 (50%) 2 (10%) 6 (30%) 1 (5%) 1 (5%)
Tepper, 2000 [45] 22 3 (14%) 19 (86%) 19 (86%)
Thiele, 1997 [50] 44 37 (84%) 7 (16%) 7 (16%)
Thiele, 2000 [46] 19 7 (37%) 12 (63%) 12 (63%)
Van den Berghe, 2005 [54] 405 250 (62%) 155 (38%) 155 (38%)
Witt, 1991 [47] 43 13 (30%) 30 (70%) 30 (70%)

CINMA, critical illness neuromuscular abnormality; CIP, critical illness polyneuropathy; CIM, critical illness myopathy; NMJ, neuromus-
cular junction

and 508 (77.6%) had unclassified CINMA. In the
six reports that differentiated between CIM, CIP and
CIP/CIM [8, 22, 34, 41, 49, 52], the median (range)
prevalence of these subsets within the study populations
were respectively 20% (0–30%), 13% (3–82%), and 9%
(5–53%).
Exposure variables and CINMA
Non-pharmacological exposures
Data on patient characteristics and commonly cited
CINMA risk factors are provided in Tables 5 and 6. Two
of 3 studies reported a univariable relationship between
SIRS and CINMA [22, 52], while sepsis was evaluated
in 12 reports, with a significant unadjusted association
with CINMA noted in 6 [OR (95% CI) ranged from 2.4
(0.8–6.8) to 49 (4.7–519)] [24, 38, 46, 49, 50, 52]. Patients
with CINMA had significantly higher blood glucose levels
in 5 of 6 studies [7, 26, 35, 48, 53], and in a subset of
405 patients enrolled in a randomized trial, a strategy of
conventional (blood glucose target 180–200 mg/dl) versus
intensive (blood glucose target 80–110 mg/dl) glycemic
control resulted in an OR of CINMA of 2.6 (95% CI
1.6–4.2) [26]. Two of 3 studies found a univariable asso-
ciation between CINMA and renal replacement therapy;
in one of these [7], renal replacement was associated with
a 3.4-fold increase in the odds of developing CINMA
(95% CI 1.1–10.5), while the other study suggested
a reduction in risk [OR (95%CI) 0.27 (0.1–0.70)] [25].
In reports containing multivariable analyses, CINMA
was independently predicted by the following factors:
female gender [OR (95% CI) 4.6 (1.2–18.3)] [7]; renal
replacement therapy [OR (95% CI) 1.9 (1.0–3.8)] [26];
APACHE III score [55] 30 days after institution of
mechanical ventilation [5.2 (2.8–9.8)] [52]; SOFA
score [56] 1 week after ICU admission [RR (95% CI)
2.4 (1.02–5.53)] [22]; SIRS 1 week after admission [RR
(95% CI) 3.74 (1.37–10.20)] [22]; SIRS 30 days after
institution of mechanical ventilation [OR (95% CI) 2.5
(1.2–4.8)] [52]; blood glucose levels [OR (95% CI)
1.24 (1.14–1.36) per 20 mg/dl increment] [53]; and total
parenteral nutrition (OR [95% CI] 5.1 [1.1–23.0]) [25].
Pharmacological exposures
A number of studies investigated the relationship between
pharmacological agents and CINMA. The majority of
reports did not demonstrate a significant univariable
association between CINMA and glucocorticoids, amino-
glycosides, neuromuscular blocking agents, midazolam,
metronidazole, or furosemide. There was an unadjusted
 1884

Table 5 Patient characteristics

Reference Age (years) Females (%) Severity of illness score Multiple organ failure score Sepsis (%)
CINMA vs. no CINMA CINMA vs. no CINMA CINMA vs. no CINMA CINMA vs. no CINMA CINMA vs. no CINMA
Amaya-Villar, 2005 [24] 62 vs. 66, p = 0.2 NR AP2 23 vs. 14, p < 0.001 NR 67% vs. 6%, p = 0.002
Bednarik, 2003 [8] NR 54% vs. 25%, p = 0.09 NR NR NR
Bednarik, 2005 [22] NR NR NR SOFA score 8 vs. 6, p = 0.04* NR
Bercker, 2005 [48] 44 vs. 24, p = 0.01 NR SAPS2 35 vs. 32, SOFA score 5 vs. 5, p = 0.7 NR
p = 0.4
Berek, 1996 [34] 56 vs. 53, p = 0.44 17% vs. 50%, p = 0.41 SAPS1 15 vs. 15, p = NS NR NR
Campellone, 1998 [35] NR NR AP2 24 vs. 16, p = 0.005 NR NR
Coakley, 1998 [36] NR 46% vs. 42%, p = 0.88 NR NR NR
De Jonghe, 2002 [7] 68 vs. 59, p = 0.02** 50% vs. 20%, p < 0.004* SAPS2 53 vs. 47, p = 0.15 ODIN score 3 vs. 2.5, p = 0.08 38% vs. 20%, p = 0.08
No. of days with dysfunction in
≥ 2 organs 10 vs. 5, p < 0.001*
De Letter, 2001 [52] NR NR AP3 independently NR NR
predicted CINMA*
Druschky, 2001 [38] 70 vs. 64, p = 0.02 38% vs. 33%, p = 0.82 NR Goris score 1 vs. 0, p = 0.009 94% vs. 50%, p = 0.05
Garnacho-Montero, 2001 [25] 62 vs. 62, p = 0.92 NR AP2 17 vs. 18, p = 0.94 SOFA score 12 vs. 11, p = 0.29 100% vs. 100%, p = 0.33
Garnacho-Montero, 2005 [51] 61 vs. 62, p = 0.9 NR AP2 19 vs. 18, p = 0.3 SOFA score 7.2 vs. 7.2, p = 1 100% vs. 100%, p = NS
Hund, 1997 [50] NR NR NR NR NR
Kupfer, 1992 [40] 38 vs. 32, p = 0.51 29% vs. 33%, p = 0.88 NR NR NR
Lefaucheur, 2006 [41] 63 vs. 46, p = 0.143 33% vs. 44%, p = 0.81 NR NR 100% vs. 100%, p = NS
Leijten, 1995 [43] 59 vs. 54, p = 0.22 28% vs. 33%, p = 0.66 AP2 22 vs. 23. p = 0.74 22 vs. 11 patients 48% vs. 43%, p = 0.7
had MOF, p = 0.08
Leijten, 1996 [42] 58 vs. 55, p = 0.49 33 vs. 30%, p = 0.83 AP2 22 vs. 23, p = 0.66 MODS 5.3 vs. 3.6, p = 0.003 56% vs. 40%, p = 0.34
Mohr, 1997 [44] 48 vs. 52, p = 0.82 43% vs. 42%, p = 0.97 AP2 22 vs. 21, p = 0.34 NR 100% vs. 35%, p = 0.0027
Rudis, 1996 [49] 52 vs. 54, p = 0.97 70% vs. 70%, p = 1 AP2 61 vs. 62, p = 0.65 NR 40% vs. 0%, p = 0.001
Tepper, 2000 [45] NR NR NR NR NR
Thiele, 1997 [50] 68 vs. 74, p = NS NR NR NR 86% vs. 11%, p < 0.01
Thiele, 2000 [46] 66 vs. 68, p = NS 50% vs. 0%, p = 0.08 NR NR 58% vs. 0%, p < 0.05
Van den Borghe, 2005 [54] NR NR NR NR NR
Witt, 1991 [47] NR NR NR NR NR

CINMA, critical illness neuromuscular abnormality; NR, not reported; AP2, Acute Physiology and Chronic Health Evaluation II score; SOFA, sequential organ function assess-
ment; SAPS2, simplified acute physiology score 2; ODIN, organ dysfunction and/or infection score; AP3, Acute Physiology and Chronic Health Evaluation III score; MODS,
multiple organ score; Goris score, see ref. [66]; MOF, multiple organ failure; * Significant association with CINMA after multivariable adjustment; ** Non-significant association
with CINMA after multivariable adjustment
Table 6 CINMA risk factors
Reference Serum glucose or hyperglycemia Glucocorticoids
(mg/dL or % patients)
CINMA vs. no CINMA
Amaya-Villar, 2005 [24] NR
Bednarik, 2003 [8] NR
Bednarik, 2005 [22] NR
Bercker, 2005 [48] Peak, 166 vs. 144, p < 0.001
Berek, 1996 [34]
Campellone, 1998 [35] 312 vs. 221, p = 0.007
Coakley, 1998 [36] NR
De Jonghe, 2002 [7] Peak, 360 vs. 259, p = 0.001**
De Letter, 2001 [52] NR
Druschky, 2001 [38] NR
Garnacho-Montero, 2001 [25] 30% vs. 30%, p = NS
Garnacho-Montero, 2005 [51] NR
Hund, 1997 [50] NR
Kupfer, 1992 [40] NR
Lefaucheur, 2006 [41] NR
Leijten, 1995 [43] NR
Leijten, 1996 [42] NR
Mohr, 1997 [44] NR
Rudis, 1996 [49] NR
Tepper, 2000 [45] NR
Thiele, 1997 [50] NR
Thiele, 2000 [46] 221 vs. 215, p = NS
Van den Berghe, 2005 [54] OR (95% CI) of CINMA
1.26 (1.09; 1.46) per mmol/l
of AM blood glucose level*
Witt, 1991 [47] NR
CINMA, critical illness neuromuscular abnormality; MP, methylprednisolone; NR, not reported; NS, not significant or non significant; HT, intensive insulin therapy; * Significant
association with CINMA after multivariable adjustment; ** Non-significant association with CINMA after multivariable adjustment
Neuromuscular blockers Aminoglycosides
(MP total dose or % patients) (Total dose or % patients) (% patients or dose)
CINMA vs. no CINMA CINMA vs. no CINMA CINMA vs. no CINMA
1649 vs. 979 mg, p = 0.05 44% vs. 18%, p = 0.19 22% vs. 0%, p = 0.1
Vecuronium 13 vs. 11 mg, p = 0.19
NR NR NR
NS association with CINMA NS association with CINMA NR
74% vs. 66%, p = 0.7 NR NR
NR NR NR
2438 vs. 1674 mg, p = 0.02 NR NR
24% vs. 29%, p = 1 62% vs. 71%, p = 1 NR
54% vs. 18%, p = 0.001* 63% vs. 41%, p = 0.07** 67% vs. 42%, p = 0.04**
290 vs. 460 mg, p = 0.32 Vecuronium 13 vs. 16 mg, p = 0.11
NS association with CINMA** NS association with CINMA** NS association with CINMA**
Daily dose, 0 vs. 32 mg, p = 0.47 NR NR
14% vs. 17%, p = 0.7 18% vs. 4%, p = 0.16* 42% vs. 44%, p = 0.91
NR 29% vs. 10%, p = 0.06 NR
NR NR NR
NR Vecuronium 1352 vs. 528 mg, p = 0.05 NR
58% vs. 25%, p = 0.31 19% vs. 25%, p = 0.78 NR
NR NR NR
NR NR NR
NR 100% vs. 77%, p = 0.26 100% vs. 35%, p = 0.6
70% vs. 50%, p = 0.65 70% vs. 90%, p = NS 70% vs. 80%, p = 1
Vecuronium or pancuronium
1080 vs. 1165 mg, p = 0.76
NR NR NR
100% vs. 11%, p < 0.01 86% vs. 30%, p = NS 14% vs. 5%, p = NS
16 vs. 20 mg/kg, p < 0.01 Vecuronium or pancuronium Total netilmycin
0.37 vs. 0.52 mg/kg, p = NS 23 vs. 16 mg/kg
NR NR NR
NR NR NR
NR NR NR
1885
 1886

Table 7 CINMA outcomes

References ICU mortality (%) Hospital mortality (%) ICU length of stay (days) Hospital length of stay (days) Duration of MV (days)
CINMA vs. no CINMA CINMA vs. no CINMA CINMA vs. no CINMA CINMA vs. no CINMA CINMA vs. no CINMA
Amaya-Villar, 2005 [24] 33% vs. 18%, p = 0.6 56% vs. 24%, p = 0.2 23 vs. 11, p < 0.003 33 vs. 21, p < 0.03 15 vs. 6, p = 0.006
Bednarik, 2003 [8] NR NR NR NR NR
Bednarik, 2005 [22] NR NR NR NR 16 vs. 3, p < 0.001
Bercker, 2005 [48] NR NR 38 vs. 26, p = 0.001 NR 20 vs. 13, p = 0.018
Berek, 1996 [34] 39% vs. 0%, p = 0.26 NR NR NR NR
Campellone, 1998 [35] NR 29% vs. 0%, p = 0.007 49 vs. 14, p = 0.002 NR NR
Coakley, 1998 [36] NR 24% vs. 14%, p = 1 NR NR NR
De Jonghe, 2002 [7] 17% vs. 6%, p = 0.2 NR NR NR 38 vs. 18, p = 0.003*
De Letter, 2001 [52] NR NR NR NR NR
Druschky, 2001 [38] NR 6% vs. 0%, p = 1 NR NR 15 vs. 8, p = 0.005
Garnacho-Montero, 2001 [25] 66% vs. 52%, p = 0.26 84% vs. 57%, p = 0.01 * 53 vs. 32, p = 0.01 93 vs. 41, p = 0.01 32 vs. 19, p = 0.002*
Garnacho-Montero, 2005 [51] 21% vs. 10%, p = 0.31 47% vs. 20%, p = 0.03 46 vs. 23, p < 0.0001 85 vs. 33, p < 0.001 34 vs. 14, p < 0.0001 *
Hund, 1997 [50] 50% vs. 100%, p = 0.025 NR NR NR NR
Kupfer, 1992 [40] NR NR NR NR NR
Lefaucheur, 2006 [41] NR NR NR NR NR
Leijten, 1995 [43] 48% vs. 19%, p = 0.03 NR NR NR 25 vs. 20, p = 0.03
Leijten, 1996 [42] 44% vs. 20%, p = 0.11 NR NR NR 11 vs. 8, p = 0.03
Mohr, 1997 [44] NR NR 27 vs. 21, p = 0.19 NR 23 vs. 17, p = 0.19
Rudis, 1996 [49] NS association with ClNMA 50% vs. 60%, p = 1 42 vs. 8, p = 0.001 68 vs. 11, p = 0.001 41 vs. 3, p = 0.001
Tepper, 2000 [45] NR NR NR NR NR
Thiele, 1997 [50] 57% vs. 8%, p < 0.05 NR 62 vs. 14, p < 0.01 NR 50 vs. 7, p < 0.01
Thiele, 2000 [46] 33% vs. 0%, p = 0.24 NR 40 vs. 20, p < 0.05 NR 32 vs. 12, p < 0.05
Siroen, 2005 [67] NS association with ClNMA NR NR NR NR
Witt, 1991 [47] NR NR NR NR NR

CINMA, critical illness neuromuscular abnormality; MV, mechanical ventilation; NR, not reported; * Significant association with CINMA after multivariable adjustment
 1887

Table 8 Exposure and outcome variables in CINMA studies

Univariable analysis Multivariable analysis

Comparisons of patients No. of studies No. of studies No. of studies No. of studies
with and without CINMA with comparison with association with comparison with association
Exposures
Non-pharmacological
Blood glucose 6 5 2 1
Renal replacement therapy 3 2 1 1
SIRS 3 2 2 2
Sepsis 12 6 0 0
Multiple organ failure score 9 4 2 2
Severity of illness scores 12 3 1 1
Age 15 3 1 0
Gender 12 1 1 1
Total parenteral nutrition 1 0 1 1
Pharmacological
Catecholamines 3 3 0 0
Morphine 1 1 0 0
Glucocorticoids 12 4 2 1
Aminoglycosides 7 1 2 0
Neuromuscular blockers 12 1 3 1
Metronidazole 1 0 0 0
Furosemide 1 0 0 0
Midazolam 6 0 0 0
Outcomes
Duration of MV 13 12 3 3
Hospital length of stay 4 4 0 0
ICU length of stay 9 8 0 0
Death in ICU 12 3* 0 0
Death in hospital 7 3 1 1

CINMA, critical illness neuromuscular abnormality; MV, mechanical ventilation; SIRS, systemic inflammatory response syndrome;
* Two studies showing higher hospital mortality in CINMA patients; one study showing higher hospital mortality in patients without
CINMA

association between inotropic/vasopressor drug adminis-
tration and CINMA in the three cohorts in which it was
reported (Table 8) [26, 46, 50]. Multivariable analysis sug-
gested a relationship between CINMA and glucocorticoids
in one of two studies [OR (95% CI) 14.9 (3.2–69.8)] [7],
and between CINMA and neuromuscular blockers in one
out of three studies [OR (95% CI) 16.32 (1.34–199)] [25].
Outcomes and CINMA
Univariable and multivariable relationships between
CINMA and selected outcomes are given in Tables 7
and 8. Nine of the 12 studies which reported on un-
adjusted ICU mortality found no difference between
patients with and without CINMA. Hospital mortality was
higher in CINMA patients in three of seven reports [24,
25, 35]. Only one study evaluated hospital mortality in
a multivariable model, identifying CINMA as an inde-
pendent predictor of hospital death [OR (95% CI) 7.1
(1.5–32.6)] [25].
The influence of CINMA on mechanical ventilation
was assessed in 13 studies, which with one exception [44]
all showed increased duration of mechanical ventilation
in patients with CINMA. CINMA independently pre-
dicted duration of mechanical ventilation in two reports
[OR (95% CI) for prolonged mechanical ventilation 2.4
(1.4–4.2) [23]; and mean increase in duration of mechan-
ical ventilation, 11.6 days (95% CI 2.6–20.5)] [25]. In
one report, CINMA was the only independent predictor
of failure to wean from mechanical ventilation [OR (95%
CI) 15.4 (4.6–52.3)] [51].
Patient outcomes after hospital discharge were reported
in three studies [7, 34, 43]. In one, clinically relevant re-
covery of motor function was noted in 15 of 16 CINMA
patients evaluated at 9 months (94%) [7]. In another ICU
cohort followed up at 1 year, 4 of 11 (36%) CINMA pa-
tients had severe functional disability [43]. The third study
evaluated 15 CINMA survivors at 3 months, finding clin-
ical and electrophysiological signs of polyneuropathy in
respectively 7 (47%) and 11 (73%) patients [34].
Discussion
There are four major findings of this systematic review.
First, evidence of neuromuscular dysfunction is found in
approximately 50% of adult ICU patients who receive
1888
prolonged mechanical ventilation, have sepsis or multiple
organ failure. Second, five of six reports found an as-
sociation between CINMA and higher serum glucose
levels, yet existing studies do not consistently support
several other generally accepted risk factors for CINMA
such as exposure to glucocorticoids or neuromuscular
blocking drugs. Third, although CINMA does not reliably
predict ICU mortality in unadjusted models, it consis-
tently and significantly increased duration of mechanical
ventilation and hospitalization, and it may be linked with
long-term neuromuscular weakness. Last, in the published
studies, there is considerable heterogeneity in the way
CINMA is diagnosed, and CINMA subtypes are not well
differentiated.
In a prior systematic review, De Jonghe et al. syn-
thesized data from eight prospective cohorts of CINMA
patients published between 1980 and 1997 [57]. Of the
242 patients in these studies, 145 (60%) were diagnosed
with CINMA (the total number of patients included in
this review was uncertain since, as the authors acknow-
ledge, there was possible duplication of patient samples
between at least two of the publications). The authors
recommended additional prospective studies to delin-
eate CINMA risk factors and examine the contribution
of CINMA to clinically relevant endpoints, including
long-term outcomes. Our systematic review builds on
this earlier work and includes studies published up to
2006 with a total of 1421 patients, 655 (46%) of whom
were diagnosed with CINMA. Over half (13 of 24) of the
studies in our review were published after the study by
De Jonghe et al., with eight of these reports containing
statistical modeling to adjust for confounding of CINMA
risk factors and outcomes. In addition to summarizing
results from a larger number of patients, our review has
several important new implications.
While the overall prevalence of CINMA in ICU
patients remains unknown, we found that that this
complication is remarkably common in patients with
prolonged mechanical ventilation, sepsis or multi-organ
failure. There are no known therapies for CINMA, yet the
contribution of CINMA must be weighed when making
predictions about durations of mechanical ventilation
and hospitalization, the need for a tracheostomy, and
anticipated long-term functional status [17]. CINMA
should be entertained in all patients who fail to wean from
mechanical ventilation, even when other factors have been
implicated in weaning failure. The relationship between
CINMA and mechanical ventilation is complex, since
mechanical ventilation may be a surrogate marker for
factors that are causally related to CINMA, while CINMA
in turn prolongs mechanical ventilation. More studies
are needed to unravel these relationships, and to assess
the relative contribution of CINMA and other factors,
such as coexisting cardiac and pulmonary dysfunction,
in patients who fail to wean from mechanical ventilation.
Future studies should also be directed to broader ICU
populations, including patients not receiving mechanical
ventilation or without multiple organ failure, in order to
delineate the scope of CINMA and achieve generalizable
results.
A second implication of this review is the charac-
terization of risk factors for CINMA. Existing studies
suggest a positive association between blood glucose
levels and the incidence of CINMA, and two large ran-
domized trials enrolling surgical [26] and medical [27]
ICU patients demonstrated that intensive insulin therapy
substantially lowered the incidence of neuromuscular
complications [54, 58]. These data support glycemic
control as one potential strategy to decrease the risk of
CINMA. On the other hand, the relationship between
several other risk factors (e. g., neuromuscular blockers,
glucocorticoids) and CINMA is unclear and needs to be
critically reevaluated; this was an unexpected finding, as
these drugs are widely viewed as having a direct or causal
relationship to CINMA. Since many of the available
studies enrolled small numbers of patients and did not
properly adjust for covariates, more robust inferences
regarding CINMA risk factors and causation will require
larger patient cohorts incorporating predetermined multi-
variable models. These studies will complement basic and
translational research into the etiology and pathogenesis
of CINMA.
Third, available data suggest there is a relationship
between CINMA and long-term patient outcomes [20].
Persistent weakness and residual motor and sensory
neurological deficits are common findings in survivors
of critical illness, and electrophysiological testing can
demonstrate residual neuromuscular dysfunction years
after the initial presentation [59]. In a seminal report on
109 acute respiratory distress syndrome survivors evalu-
ated at 1 year, patient-reported muscle weakness, rather
than pulmonary dysfunction, was the most important fac-
tor contributing to functional impairment (this study did
not include formal neuromuscular testing) [19]. A separate
clinical and electrophysiological study of 22 patients who
had a prolonged (> 28 days) critical illness and were
assessed a median of 43 months after ICU discharge found
that 13 (59%) had motor or sensory deficits on clinical
examination and 21 (95%) had chronic partial denervation
on EMG [60]. Building on these observations, new cohort
studies are needed that are powered to quantify the impact
of CINMA on functional status, quality of life, and social
and work-related reintegration in the months and years
following the acute illness [61].
Fourth, there is a need to apply standardized diagnostic
criteria of CINMA and its subtypes. Existing studies
are heterogeneous in the use of diagnostic criteria. For
instance, in the largest patient sample within this re-
view [26, 62], there was no documented exclusion of
prior neuromuscular disease, no reporting of clinical
findings, and the diagnosis of CIP was based exclusively
on EMG results that are non-specific in differentiating
 1889

CIP and CIM [1]. Uniform use of diagnostic criteria
will enhance communication between clinicians and help
investigators design studies to understand the epidemiol-
ogy, risk factors, and impact of specific CINMA subsets.
These criteria should integrate physical examination
findings with valid and reliable bedside neurophysio-
logical tests (e. g., nerve conduction velocities, needle
electromyography), recognizing that CINMA preva-
lence is likely to be underestimated when only physical
findings are relied upon [8], while clinically relevant
disease may be overestimated with electrophysiolog-
ical tests [7]. Clinicians should also understand that
conventional electrophysiological techniques may not
reliably identify CINMA subtypes [8, 63], and in selected
circumstances specific methods such as direct muscle
stimulation [41, 64, 65] might be helpful, for example in
unconscious patients, who are unable to voluntarily
contract muscles and in whom the contribution of CIM is
likely to be overlooked [6].
This review has several limitations. By excluding
reports that lacked electrophysiological or histopatho-
logical confirmation of physical examination findings,
we may have omitted data on patients with clinically
significant CINMA. It has been argued that a perti-
nent history and detailed neurological examination may
be sufficient to establish a diagnosis of CINMA, and
that additional tests are of little practical value or may
even overestimate clinically relevant CINMA; others
have countered that electrophysiological confirmation is
essential to accurately identify CINMA [1]. While elec-
trophysiological results may have little impact on clinical
decision-making, our intent was to identify exposure and
outcome characteristics specific to CINMA, and therefore
we disqualified studies that did not independently confirm
clinical findings. Another limitation is that the majority
of reported CINMA risk factors and outcome analyses
were univariable and prone to confounding due to the
observational study designs. An additional limitation
is that it was not possible to standardize the way that
exposure variables were defined or modeled in individual
studies, likely contributing to heterogeneity in our results
(for instance, several studies included in this review
provided either no definition or non-validated definitions
of terms such as sepsis or multiple organ failure). Study
heterogeneity precluded any quantitative pooling of
risk estimates into a formal meta-analysis. Finally, the
quality of included studies was only fair, potentially
influencing the direction and magnitude of the observed
effects.
In conclusion, this systematic review reveals that
CINMA is a common complication in critically ill patients
with mechanical ventilation, sepsis or multiple organ
failure. Existing studies do not reliably confirm certain
widely cited CINMA risk factors, while new data indicate
that intensive glycemic control might decrease the risk
of CINMA. Large prospective studies are needed to
substantiate these findings and to identify new factors
which might contribute to CINMA and its long-term
consequences, with the goal of preventing and treating
these disorders in vulnerable populations.
Acknowledgements. The authors wish to thank Ahmet Hoke, MD,
Department of Neurology, Johns Hopkins University, for his atten-
tive manuscript review and helpful comments.

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