Neuromuscular dysfunction acquired in critical illness: a ...

Intensive Care Med SYSTEMATIC REVIEW
DOI 10.1007/s00134-007-0772-2

Robert D. Stevens Neuromuscular dysfunction acquired in critical
David W. Dowdy illness: a systematic review
Robert K. Michaels
Pedro A. Mendez-Tellez
Peter J. Pronovost
Dale M. Needham

Received: 7 March 2007 P. J. Pronovost prolonged mechanical ventilation.
Accepted: 15 June 2007 Johns Hopkins Bloomberg School of Public Diagnostic criteria for CINMA were
Health, Department of Health Policy and not uniform, and few reports un-
© Springer-Verlag 2007 Management, equivocally differentiated between
Baltimore MD, USA polyneuropathy, myopathy, and mixed
R. D. Stevens (u) · R. K. Michaels · types of CINMA. The risk of CINMA
P. A. Mendez-Tellez · P. J. Pronovost D. M. Needham was associated with hyperglycemia
Johns Hopkins University School of Johns Hopkins University School of (and inversely associated with tight
Medicine, Department of Medicine, Department of glycemic control), the systemic
Anesthesiology/Critical Care Medicine, Pulmonary/Critical Care Medicine, inflammatory response syndrome,
600 N Wolfe St, Meyer 8-140, Baltimore Baltimore MD, USA sepsis, multiple organ dysfunction,
21287, MD, USA renal replacement therapy, and cat-
e-mail: [email protected] Abstract Objective: To determine echolamine administration. Across
Tel.: +1-410-9557481 the prevalence, risk factors, and studies, there was no consistent rela-
Fax: +1-410-6147903 outcomes of critical illness neuro- tionship between CINMA and patient
muscular abnormalities (CINMA). age, gender, severity of illness, or use
R. D. Stevens Design: Systematic review. Data of glucocorticoids, neuromuscular
Johns Hopkins University School of sources and study selection: MED- blockers, aminoglycosides, or mida-
Medicine, Department of Neurology, LINE, EMBASE, CINAHL, and the zolam. Unadjusted mortality was not
Baltimore MD, USA Cochrane Library were searched for increased in the majority of patients
reports on adult ICU patients who with CINMA, but mechanical ventila-
R. D. Stevens were evaluated for CINMA clinically tion and ICU and hospital stay were
Johns Hopkins University School of and electrophysiologically. Studies prolonged. Conclusions: The risk of
Medicine, Department of Neurosurgery, were included if they contained suffi- CINMA is nearly 50% in ICU patients
Baltimore MD, USA cient data to quantify the association with sepsis, multi-organ failure, or
between CINMA and relevant ex- protracted mechanical ventilation.
D. W. Dowdy posures and/or outcome variables. The association of CINMA with
Johns Hopkins Bloomberg School of Public Measurements and results: CINMA frequently cited CINMA risk fac-
Health, Department of Epidemiology, was diagnosed in 655 of 1421 [46% tors (glucocorticoids, neuromuscular
Baltimore MD, USA (95% confidence interval 43–49%)] blockers) and with short-term survival
adult ICU patients enrolled in 24 is uncertain. Available data indi-
P. J. Pronovost studies, all with inclusion criteria cate glycemic control as a potential
Johns Hopkins University School of of sepsis, multi-organ failure, or strategy to decrease CINMA risk.
Medicine, Department of Surgery,
Baltimore MD, USA

Introduction Methods

Many patients admitted to the intensive care unit (ICU) Data sources and searches

develop a syndrome of neuromuscular dysfunction

characterized by generalized muscle weakness and an Relevant publications were identified by searching Med-

inability to separate from mechanical ventilation [1]. line (1966–2006), EMBASE (1974–2006), CINAHL

Since this syndrome occurs in the absence of preex- (1982–2006) and the Cochrane Library (2006, Issue 2) on

isting neuromuscular disease, it is believed to reflect 29 April 2006, using the following terms: neuromuscular

illnesses or treatments occurring in the ICU. Early re- diseases, muscular diseases, paresis, polyneuropathy,

ports described two categories of acute neuromuscular myopathy, neuromyopathy, critical illness, critical care,

dysfunction, a polyneuropathy found in patients with critically ill, intensive care, ICU, sepsis, septic, systemic

sepsis and multiple organ failure [2, 3] and a myopathy inflammatory response syndrome, acute lung injury,

in patients with acute respiratory failure who received acute/adult respiratory distress syndrome, ARDS, mul-

glucocorticoids and/or neuromuscular blocking drugs [4, tiple organ dysfunction/failure, artificial ventilation,

5]. More recent work has delineated subtypes of critical mechanical ventilation. Terms were mapped to the ap-

illness polyneuropathy and myopathy, and has emphasized propriate “Medical Subject Heading” (MeSH) term and

that peripheral nerve and muscle involvement frequently “title/abstract” (tiab) text word in Medline, and to the

coexist [6–8]. The spectrum of neuromuscular disorders EMTREE subject headings in EMBASE, and “exploded”.

acquired in the ICU, which also includes neuromuscular Citations were not excluded on the basis of language. In

junction dysfunction, has been collectively referred to as addition to the electronic search, references from selected

“critical illness neuromyopathy” [9], “ICU-acquired pare- reports and review articles, as well as personal files,

sis” [7], “Critical illness myopathy and/or neuropathy” were hand searched. Only full-length reports published

(CRIMYNE) [10], or “critical illness neuromuscular in peer-reviewed journals were included in this review. If

abnormalities” (CINMA) [11]. data were missing or unclear in published reports, authors

The rising incidence and societal burden of critical ill- were contacted for additional information.

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 Study selection

of patients with CINMA and its sequelae may be substan-

tial and likely to grow [17]. Many survivors of critical ill- We selected articles meeting the following inclusion

ness present with chronic morbidity linked to central and criteria. First, studies enrolled adults (> 16 years old)

peripheral neurological dysfunction [18–20], resulting in admitted to the ICU who were evaluated for CINMA

diminished functional status and quality of life months and using either diagnostic tests (nerve conduction velocities,

years after the acute period [21]. needle electromyography, direct muscle stimulation,

Knowledge of CINMA has increased through stud- histopathology of muscle or nerve tissue) or a combination

ies exploring the relationship between CINMA and of diagnostic tests and clinical findings (muscle weakness,

selected risk factors, as well as the impact of CINMA decreased or absent deep tendon reflexes, and/or failure

on short-term outcomes [7, 8, 22–25]. CINMA has to liberate from mechanical ventilation), with diagnostic

been incorporated as an outcome measure in recent tests obtained in at least all patients who had positive

large-scale randomized trials of ICU patients [26–28]. clinical findings. Second, studies compared patients with

Nevertheless, considerable uncertainty persists regarding CINMA to a group of ICU patients without clinical

the epidemiology, pathogenesis, and natural history of weakness and/or with negative diagnostic tests, such that

CINMA. We undertook a systematic review to syn- a quantitative estimate of the association between CINMA

thesize knowledge from published studies in this field and at least one relevant exposure and/or outcome variable

and to identify important areas for future research. was possible. Relevant exposure variables were patient

Specifically, our aims were threefold: first, to estimate demographics, admission diagnosis, severity of illness,

the prevalence of CINMA and its subsets using ex- physiological and metabolic status, organ dysfunction

plicit diagnostic criteria; second, to identify variables or failure, and the administration of pharmacological

that are associated with an increased (or decreased) agents. Relevant outcomes were the duration of mech-

risk of CINMA; and third, to evaluate the relationship anical ventilation, ICU and hospital mortality and length

between CINMA and patient outcomes, including mor- of stay, and any reporting of long-term outcomes such

tality, duration of mechanical ventilation, and length of as muscle weakness or functional status. Third, studies

hospitalization. contained original data with a sample size of ≥ 10 patients.

There are no universally accepted or consensus-derived with decreased amplitudes of compound muscle action
definitions of CINMA and its subtypes. For the purposes potentials or sensory nerve action potentials. For critical
of this review, we accepted the classification used by illness myopathy (CIM), minimum criteria were the
study investigators provided that they explicitly met the presence of weakness acquired after admission to the
following minimum criteria. For critical illness polyneu- ICU and at least one of the following: demonstration
ropathy (CIP), minimum criteria were the presence of of short, low-amplitude motor unit potentials (requires
weakness acquired after admission to the ICU associated patient cooperation); decreased direct muscle stimula-

Fig. 1 Flow diagram of study se-
lection process

tion amplitude or prolonged direct muscle stimulation (0–2), and the description of dropouts and withdrawals

latency; or muscle histopathology consistent with an (0–1).

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 Data synthesis and analysis
studies which did not fully differentiate between CINMA

subtypes. Since an explicit differentiation between CIP, CIM, and

A diagram of the study selection process is given in mixed CINMA was not available in most studies, these
Fig. 1. Using the study inclusion criteria above, article subtypes were not analyzed separately. In most of the
titles were screened for potentially relevant papers; these included studies, comparisons of exposure and outcome
papers were reviewed in abstract form, and relevant variables between patients with and without CINMA were
abstracts were chosen for full-text analysis. Each of made without adjustment for potential confounders. For
these steps was performed independently by two authors univariable comparisons, we recorded p-values provided
(R. D. S., D. W. D.); any title or abstract selected by either in the articles, and if these were not reported we calculated
author as potentially relevant was included in the next them from the original data; for multivariable compar-
round of review. Full-text review and final selection of isons, we recorded odds ratios (OR) or relative risks (RR)
articles was performed independently by two authors along with the 95% confidence interval (95% CI), and if
(D. W. D., R. K. M.), with discrepancies adjudicated by these data were not given, we calculated them using the
a third author (R. D. S.). Agreement between reviewers original data. In light of inter-study heterogeneity in both
was estimated using the kappa statistic.
the number and type of covariates included in multivari-

able analyses, quantitative synthesis (i. e. meta-analysis)

Data extraction and quality assessment of study results was not undertaken.

Using a standardized data collection form, two authors
(D. W. D., R. K. M.) independently abstracted data on Results
study design and quality, methods for diagnosing CINMA,
and patient demographic characteristics. The following Study search and selection
exposure variables were systematically recorded (when
available): severity of illness scores; organ dysfunction The initial search retrieved 9,299 citations. Sequential
scores; presence of the systemic inflammatory response review of titles, abstracts, and full-length articles ulti-
syndrome (SIRS), sepsis, or acute respiratory distress mately yielded 29 reports on 24 unique patient populations
syndrome; renal replacement therapy, parenteral nutrition (Fig. 1). Hereafter, unless otherwise noted, our findings
and hyperglycemia; glycemic control; and administration refer to these 24 patient populations. The included studies
of glucocorticoids, neuromuscular blockers, aminogly- had a mean sample size of 59 (range 10–405), and totaled
cosides, vasopressors or inotropic agents, metronidazole, 1,421 patients. Kappa statistics for inter-reviewer selection
furosemide, and midazolam. We also abstracted the of potentially relevant titles, abstracts, and full-text articles
following outcomes (when available): death in the ICU were 0.67, 0.72, and 0.79, respectively, demonstrating
and hospital, duration of mechanical ventilation, length of substantial agreement [33].
stay in the ICU and hospital, and long-term outcomes.

Methodological quality of individual observational
studies was assessed with the Newcastle–Ottawa Scale Study characteristics and quality
(NOS) [29], a validated instrument specifically designed to
evaluate the quality of observational studies in systematic Of the 24 studies, 19 were prospective cohorts [7, 8, 22,
reviews and meta-analyses [30, 31]. The NOS evaluates 24, 25, 34–46], 2 were retrospective cohorts [47, 48], 2
three domains of study methodology: the selection of were case–control studies [49, 50], and 1 was a random-
study groups (score range 0–4), the comparability of ized controlled trial [26] (Table 1). The criteria for enroll-
groups (score range 0–1), and the quality of ascertainment ment of ICU patients included mechanical ventilation in
of either the exposures (for case–control studies) or of 17 reports [median (range) duration of mechanical venti-
the outcomes of interest (for cohort studies) (score range lation 7 (2–10); in 14 reports, mechanical ventilation was
0–3). The composite NOS score ranges from 0 to 8, ≥ 7 days], sepsis or septic shock in 5 reports, and multi-
with a NOS > 5 indicating an acceptable methodological ple organ failure in 5. Patient exclusion criteria were stated
design. For the one randomized controlled trial included in in 20 studies and included presence or risk of prior neuro-
this review, methodological quality was assessed using the muscular disease in 19 reports and moribund status in 1.
Jadad scale [32]. This is a validated 3-item, 5-point scor- Patient follow-up extended beyond hospital discharge in 3
ing system evaluating trial randomization (0–2), blinding cohorts [7, 34, 43].

Table 1 Study characteristics

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

MOF (Goris score > 5 for > 5 days) In-hospital only

Cases: weakness after NMB In-hospital only

Septic shock ICU only

MV > 3 days, cardiac surgery ICU only

MV > 3 days, cardiac surgery ICU only

MV, EMG in subset with ICU LOS In-hospital only

ICU LOS > or = 7 days

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

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

Prevalence of CINMA
Diagnosis of CINMA

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

Table 3 Diagnosis of CINMA

Exclusion
of prior NMD
Documentation
of weakness
Repetitive
stimulation
CMAP
SNAP
60
Fibrillation
potentials
DMS
No. of patients (%)
with muscle biopsy
Reference Timing of first CINMA evaluation MUP

Amaya-Villar, 2005 [24] Median (range) 6 (2–12) days of MV ++–––+ –– 3 (12)
Bedoarik, 2003 [8] < 3 days after ICU admission
Bednarik, 2005 [22] < 3 days after ICU admission + + + + + + + + 11 (24)
Bercker, 2005 [48] NR
Berek, 1996 [34] 14–28 days after ICU admission + + + + + + + + 11 (18)
Campellone, 1998 [35] 2 weeks after liver transplantation
Coakley, 1998 [36] NR ++–––– –––
De Jonghe, 2002 [7] Mean (SD) 12.4 (6.8) of MV
De Letter, 2000 [52] 4 days MV ++–+++ +––
Druschky, 2001 [38] 4 days of MV
Garnacho-Montero, 2001 [25] 10 days of MV –+++++ +– 5 (7)
Garnacho-Montero, 2005 [51] Onset of weaning from MV
Hund, 1997 [50] 5–7 days of MV + + + + + – + – 24 (55)
Kupfer, 1992 [40] > 24 h after discontinuation of vecuronium infusion
Lefaucheur, 2006 [41] Mean (SD) 13.7 (7.8) days after awakening from coma + + + + + – + – 10 (11)
Leijten, 1995 [43] 7–9 days of MV
Leijten, 1996 [42] 7–9 days of MV + + + + + + + – 32 (33)
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
++–+–– +– 2 (7)

+++–+– –––

++++++ ++–

+++++– +––

+++++– +––

++–++– +––

–+++++ +––

++–++– +––

–+–++– +––

–+–++– +––

–––––– +––

++–++– +––

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

Table 4 Prevalence of CINMA

Reference No. No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) with
of patients without with with with
enrolled CINMA CINMA CIP CIM with mixed with NMJ unclassified

8 (17%) CIP/CIM defect CINMA
14 (23%)
Amaya-Villar, 2005 [24] 26 17 (65%) 9 (35%) 7 (15%) 11 (24%) 9 (35%)
Bednarik, 2003 [8] 46 10 (43%) 26 (57%) 12 (20%) 12 (12%) 9 (15%) 27 (60%)
Bednarik, 2005 [22] 61 26 (43%) 35 (57%) 18 (82%)
Bercker, 2005 [48] 45 18 (40%) 27 (60%) 9 (30%) 7 (7%) 7 (9%)
Berek, 1996 [34] 22 4 (18%) 18 (82%) 11 (11%) 37 (84%)
Campellone, 1998 [35] 77 70 (91%) 7 (9%) 6 (30%) 2 (2%) 24 (25%)
Coakley, 1998 [36] 44 7 (16%) 37 (84%) 1 (3%) 16 (53%) 2 (2%)
De Jonghe, 2002 [7] 95 71 (75%) 24 (25%) 16 (57%)
De Letter, 2001 [52] 98 66 (67%) 32 (33%) 2 (10%) 1 (5%) 1 (5%) 50 (68%)
Druschky, 2001 [38] 28 12 (43%) 16 (57%) 34 (53%)
Garnacho-Montero, 2001 [25] 73 23 (32%) 50 (68%) 20 (71%)
Garnacho-Montero, 2005 [51] 64 30 (47%) 34 (53%) 5 (50%)
Hund, 1997 [50] 28 8 (29%) 20 (71%)
Kupfer, 1992 [40] 10 3 (30%) 7 (70%) 29 (58%)
Lefaucheur, 2006 [41] 30 4 (13%) 26 (87%) 18 (47%)
Leijten, 1995 [43] 50 21 (42%) 29 (58%) 7 (21%)
Leijten, 1996 [42] 38 20 (53%) 18 (47%)
Mohr, 1997 [44] 33 26 (89%) 7 (21%) 19 (86%)
Rudis, 1996 [49] 20 10 (50%) 10 (50%) 7 (16%)
Tepper, 2000 [45] 22 3 (14%) 19 (86%) 12 (63%)
Thiele, 1997 [50] 44 37 (84%) 7 (16%) 155 (38%)
Thiele, 2000 [46] 19 7 (37%) 12 (63%) 30 (70%)
Van den Berghe, 2005 [54] 405 250 (62%) 155 (38%)
Witt, 1991 [47] 43 13 (30%) 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 in one of these [7], renal replacement was associated with

six reports that differentiated between CIM, CIP and a 3.4-fold increase in the odds of developing CINMA

CIP/CIM [8, 22, 34, 41, 49, 52], the median (range) (95% CI 1.1–10.5), while the other study suggested

prevalence of these subsets within the study populations a reduction in risk [OR (95%CI) 0.27 (0.1–0.70)] [25].

were respectively 20% (0–30%), 13% (3–82%), and 9% In reports containing multivariable analyses, CINMA

(5–53%). 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];

Exposure variables and CINMA APACHE III score [55] 30 days after institution of

mechanical ventilation [5.2 (2.8–9.8)] [52]; SOFA

Non-pharmacological exposures score [56] 1 week after ICU admission [RR (95% CI)

2.4 (1.02–5.53)] [22]; SIRS 1 week after admission [RR

Data on patient characteristics and commonly cited (95% CI) 3.74 (1.37–10.20)] [22]; SIRS 30 days after

CINMA risk factors are provided in Tables 5 and 6. Two institution of mechanical ventilation [OR (95% CI) 2.5

of 3 studies reported a univariable relationship between (1.2–4.8)] [52]; blood glucose levels [OR (95% CI)

SIRS and CINMA [22, 52], while sepsis was evaluated 1.24 (1.14–1.36) per 20 mg/dl increment] [53]; and total

in 12 reports, with a significant unadjusted association parenteral nutrition (OR [95% CI] 5.1 [1.1–23.0]) [25].

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 Pharmacological exposures

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 A number of studies investigated the relationship between

conventional (blood glucose target 180–200 mg/dl) versus pharmacological agents and CINMA. The majority of

intensive (blood glucose target 80–110 mg/dl) glycemic reports did not demonstrate a significant univariable

control resulted in an OR of CINMA of 2.6 (95% CI association between CINMA and glucocorticoids, amino-

1.6–4.2) [26]. Two of 3 studies found a univariable asso- glycosides, neuromuscular blocking agents, midazolam,

ciation between CINMA and renal replacement therapy; metronidazole, or furosemide. There was an unadjusted

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
Bednarik, 2005 [22] NR NR NR NR NR
Bercker, 2005 [48] 44 vs. 24, p = 0.01 NR
NR SOFA score 8 vs. 6, p = 0.04* NR
Berek, 1996 [34] 56 vs. 53, p = 0.44 17% vs. 50%, p = 0.41
Campellone, 1998 [35] NR NR SAPS2 35 vs. 32, SOFA score 5 vs. 5, p = 0.7 NR
Coakley, 1998 [36] NR 46% vs. 42%, p = 0.88
De Jonghe, 2002 [7] 68 vs. 59, p = 0.02** 50% vs. 20%, p < 0.004* p = 0.4

NR SAPS1 15 vs. 15, p = NS NR NR

38% vs. 33%, p = 0.82 AP2 24 vs. 16, p = 0.005 NR NR
NR
NR NR NR NR
NR
29% vs. 33%, p = 0.88 SAPS2 53 vs. 47, p = 0.15 ODIN score 3 vs. 2.5, p = 0.08 38% vs. 20%, p = 0.08
33% vs. 44%, p = 0.81
28% vs. 33%, p = 0.66 No. of days with dysfunction in

33 vs. 30%, p = 0.83 ≥ 2 organs 10 vs. 5, p < 0.001*
43% vs. 42%, p = 0.97
De Letter, 2001 [52] NR 70% vs. 70%, p = 1 AP3 independently NR NR
NR
NR predicted CINMA*
50% vs. 0%, p = 0.08
Druschky, 2001 [38] 70 vs. 64, p = 0.02 NR 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
Garnacho-Montero, 2005 [51] 61 vs. 62, p = 0.9 AP2 17 vs. 18, p = 0.94 SOFA score 12 vs. 11, p = 0.29 100% vs. 100%, p = 0.33
Hund, 1997 [50] NR
Kupfer, 1992 [40] 38 vs. 32, p = 0.51 AP2 19 vs. 18, p = 0.3 SOFA score 7.2 vs. 7.2, p = 1 100% vs. 100%, p = NS
Lefaucheur, 2006 [41] 63 vs. 46, p = 0.143
Leijten, 1995 [43] 59 vs. 54, p = 0.22 NR NR NR

NR NR NR

NR NR 100% vs. 100%, p = NS

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 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
Rudis, 1996 [49] 52 vs. 54, p = 0.97 AP2 22 vs. 21, p = 0.34 NR 100% vs. 35%, p = 0.0027
Tepper, 2000 [45] NR
Thiele, 1997 [50] 68 vs. 74, p = NS AP2 61 vs. 62, p = 0.65 NR 40% vs. 0%, p = 0.001
Thiele, 2000 [46] 66 vs. 68, p = NS
Van den Borghe, 2005 [54] NR NR NR NR
Witt, 1991 [47] NR
NR NR 86% vs. 11%, p < 0.01

NR NR 58% vs. 0%, p < 0.05

NR 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 Neuromuscular blockers Aminoglycosides
(Total dose or % patients) (% patients or dose)
(mg/dL or % patients) (MP total dose or % patients) CINMA vs. no CINMA CINMA vs. no CINMA

CINMA vs. no CINMA CINMA vs. no CINMA

Amaya-Villar, 2005 [24] NR 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
Bednarik, 2003 [8] NR NR NR NR
Bednarik, 2005 [22] NR NR
Bercker, 2005 [48] Peak, 166 vs. 144, p < 0.001 NS association with CINMA NS association with CINMA NR
Berek, 1996 [34] NR
Campellone, 1998 [35] 312 vs. 221, p = 0.007 74% vs. 66%, p = 0.7 NR 67% vs. 42%, p = 0.04**
Coakley, 1998 [36] NR
De Jonghe, 2002 [7] Peak, 360 vs. 259, p = 0.001** NR NR NS association with CINMA**
NR
2438 vs. 1674 mg, p = 0.02 NR 42% vs. 44%, p = 0.91
NR
24% vs. 29%, p = 1 62% vs. 71%, p = 1 NR
NR
54% vs. 18%, p = 0.001* 63% vs. 41%, p = 0.07** NR
NR
290 vs. 460 mg, p = 0.32 Vecuronium 13 vs. 16 mg, p = 0.11 NR
100% vs. 35%, p = 0.6
De Letter, 2001 [52] NR NS association with CINMA** NS association with CINMA** 70% vs. 80%, p = 1

Druschky, 2001 [38] NR Daily dose, 0 vs. 32 mg, p = 0.47 NR NR
14% vs. 5%, p = NS
Garnacho-Montero, 2001 [25] 30% vs. 30%, p = NS 14% vs. 17%, p = 0.7 18% vs. 4%, p = 0.16* Total netilmycin
23 vs. 16 mg/kg
Garnacho-Montero, 2005 [51] NR NR 29% vs. 10%, p = 0.06 NR
NR
Hund, 1997 [50] NR NR NR

Kupfer, 1992 [40] NR NR Vecuronium 1352 vs. 528 mg, p = 0.05

Lefaucheur, 2006 [41] NR 58% vs. 25%, p = 0.31 19% vs. 25%, p = 0.78

Leijten, 1995 [43] NR NR NR

Leijten, 1996 [42] NR NR NR

Mohr, 1997 [44] NR NR 100% vs. 77%, p = 0.26

Rudis, 1996 [49] NR 70% vs. 50%, p = 0.65 70% vs. 90%, p = NS

Vecuronium or pancuronium

1080 vs. 1165 mg, p = 0.76

Tepper, 2000 [45] NR NR NR
Thiele, 1997 [50] NR
100% vs. 11%, p < 0.01 86% vs. 30%, p = NS

16 vs. 20 mg/kg, p < 0.01 Vecuronium or pancuronium

0.37 vs. 0.52 mg/kg, p = NS

Thiele, 2000 [46] 221 vs. 215, p = NS NR NR
Van den Berghe, 2005 [54] OR (95% CI) of CINMA
1.26 (1.09; 1.46) per mmol/l NR NR
Witt, 1991 [47] of AM blood glucose level*
NR NR NR 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

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
NR NR NR NR
Bednarik, 2003 [8] NR NR NR NR 16 vs. 3, p < 0.001
NR 38 vs. 26, p = 0.001 NR 20 vs. 13, p = 0.018
Bednarik, 2005 [22] NR NR NR NR NR
29% vs. 0%, p = 0.007 49 vs. 14, p = 0.002 NR NR
Bercker, 2005 [48] NR 24% vs. 14%, p = 1 NR NR NR
NR NR NR 38 vs. 18, p = 0.003*
Berek, 1996 [34] 39% vs. 0%, p = 0.26 NR NR NR NR
6% vs. 0%, p = 1 NR NR 15 vs. 8, p = 0.005
Campellone, 1998 [35] NR 84% vs. 57%, p = 0.01 * 53 vs. 32, p = 0.01 93 vs. 41, p = 0.01 32 vs. 19, p = 0.002*
47% vs. 20%, p = 0.03 46 vs. 23, p < 0.0001 85 vs. 33, p < 0.001 34 vs. 14, p < 0.0001 *
Coakley, 1998 [36] NR NR NR NR NR
NR NR NR NR
De Jonghe, 2002 [7] 17% vs. 6%, p = 0.2 NR NR NR NR
NR NR NR 25 vs. 20, p = 0.03
De Letter, 2001 [52] NR NR NR NR 11 vs. 8, p = 0.03
NR 27 vs. 21, p = 0.19 NR 23 vs. 17, p = 0.19
Druschky, 2001 [38] NR 50% vs. 60%, p = 1 42 vs. 8, p = 0.001 68 vs. 11, p = 0.001 41 vs. 3, p = 0.001
NR NR NR NR
Garnacho-Montero, 2001 [25] 66% vs. 52%, p = 0.26 NR 62 vs. 14, p < 0.01 NR 50 vs. 7, p < 0.01
NR 40 vs. 20, p < 0.05 NR 32 vs. 12, p < 0.05
Garnacho-Montero, 2005 [51] 21% vs. 10%, p = 0.31 NR NR NR NR
NR NR NR NR
Hund, 1997 [50] 50% vs. 100%, p = 0.025

Kupfer, 1992 [40] NR

Lefaucheur, 2006 [41] NR

Leijten, 1995 [43] 48% vs. 19%, p = 0.03

Leijten, 1996 [42] 44% vs. 20%, p = 0.11

Mohr, 1997 [44] NR

Rudis, 1996 [49] NS association with ClNMA

Tepper, 2000 [45] NR

Thiele, 1997 [50] 57% vs. 8%, p < 0.05

Thiele, 2000 [46] 33% vs. 0%, p = 0.24

Siroen, 2005 [67] NS association with ClNMA

Witt, 1991 [47] NR

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

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 6 5 2 1
Non-pharmacological 3 2 1 1
Blood glucose 3 2 2 2
Renal replacement therapy 12 6 0 0
SIRS 9 4 2 2
Sepsis 12 3 1 1
Multiple organ failure score 15 3 1 0
Severity of illness scores 12 1 1 1
Age 1 0 1 1
Gender
Total parenteral nutrition 3 3 0 0
Pharmacological 1 1 0 0
Catecholamines 12 4 2 1
Morphine 7 1 2 0
Glucocorticoids 12 1 3 1
Aminoglycosides 1 0 0 0
Neuromuscular blockers 1 0 0 0
Metronidazole 6 0 0 0
Furosemide
Midazolam 13 12 3 3
4 4 0 0
Outcomes 9 8 0 0
Duration of MV 3* 0 0
Hospital length of stay 12 3 1 1
ICU length of stay 7
Death in ICU
Death in hospital

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- in patients with CINMA. CINMA independently pre-

tration and CINMA in the three cohorts in which it was dicted duration of mechanical ventilation in two reports

reported (Table 8) [26, 46, 50]. Multivariable analysis sug- [OR (95% CI) for prolonged mechanical ventilation 2.4

gested a relationship between CINMA and glucocorticoids (1.4–4.2) [23]; and mean increase in duration of mechan-

in one of two studies [OR (95% CI) 14.9 (3.2–69.8)] [7], ical ventilation, 11.6 days (95% CI 2.6–20.5)] [25]. In

and between CINMA and neuromuscular blockers in one one report, CINMA was the only independent predictor

out of three studies [OR (95% CI) 16.32 (1.34–199)] [25]. of failure to wean from mechanical ventilation [OR (95%

CI) 15.4 (4.6–52.3)] [51].

Patient outcomes after hospital discharge were reported

Outcomes and CINMA in three studies [7, 34, 43]. In one, clinically relevant re-

covery of motor function was noted in 15 of 16 CINMA

Univariable and multivariable relationships between patients evaluated at 9 months (94%) [7]. In another ICU

CINMA and selected outcomes are given in Tables 7 cohort followed up at 1 year, 4 of 11 (36%) CINMA pa-

and 8. Nine of the 12 studies which reported on un- tients had severe functional disability [43]. The third study

adjusted ICU mortality found no difference between evaluated 15 CINMA survivors at 3 months, finding clin-

patients with and without CINMA. Hospital mortality was ical and electrophysiological signs of polyneuropathy in

higher in CINMA patients in three of seven reports [24, respectively 7 (47%) and 11 (73%) patients [34].

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 Discussion
(1.5–32.6)] [25].

The influence of CINMA on mechanical ventilation There are four major findings of this systematic review.

was assessed in 13 studies, which with one exception [44] First, evidence of neuromuscular dysfunction is found in

all showed increased duration of mechanical ventilation approximately 50% of adult ICU patients who receive

prolonged mechanical ventilation, have sepsis or multiple populations, including patients not receiving mechanical

organ failure. Second, five of six reports found an as- ventilation or without multiple organ failure, in order to

sociation between CINMA and higher serum glucose delineate the scope of CINMA and achieve generalizable

levels, yet existing studies do not consistently support results.

several other generally accepted risk factors for CINMA A second implication of this review is the charac-

such as exposure to glucocorticoids or neuromuscular terization of risk factors for CINMA. Existing studies

blocking drugs. Third, although CINMA does not reliably suggest a positive association between blood glucose

predict ICU mortality in unadjusted models, it consis- levels and the incidence of CINMA, and two large ran-

tently and significantly increased duration of mechanical domized trials enrolling surgical [26] and medical [27]

ventilation and hospitalization, and it may be linked with ICU patients demonstrated that intensive insulin therapy

long-term neuromuscular weakness. Last, in the published substantially lowered the incidence of neuromuscular

studies, there is considerable heterogeneity in the way complications [54, 58]. These data support glycemic

CINMA is diagnosed, and CINMA subtypes are not well control as one potential strategy to decrease the risk of

differentiated. CINMA. On the other hand, the relationship between

In a prior systematic review, De Jonghe et al. syn- several other risk factors (e. g., neuromuscular blockers,

thesized data from eight prospective cohorts of CINMA glucocorticoids) and CINMA is unclear and needs to be

patients published between 1980 and 1997 [57]. Of the critically reevaluated; this was an unexpected finding, as

242 patients in these studies, 145 (60%) were diagnosed these drugs are widely viewed as having a direct or causal

with CINMA (the total number of patients included in relationship to CINMA. Since many of the available

this review was uncertain since, as the authors acknow- studies enrolled small numbers of patients and did not

ledge, there was possible duplication of patient samples properly adjust for covariates, more robust inferences

between at least two of the publications). The authors regarding CINMA risk factors and causation will require

recommended additional prospective studies to delin- larger patient cohorts incorporating predetermined multi-

eate CINMA risk factors and examine the contribution variable models. These studies will complement basic and

of CINMA to clinically relevant endpoints, including translational research into the etiology and pathogenesis

long-term outcomes. Our systematic review builds on of CINMA.

this earlier work and includes studies published up to Third, available data suggest there is a relationship

2006 with a total of 1421 patients, 655 (46%) of whom between CINMA and long-term patient outcomes [20].

were diagnosed with CINMA. Over half (13 of 24) of the Persistent weakness and residual motor and sensory

studies in our review were published after the study by neurological deficits are common findings in survivors

De Jonghe et al., with eight of these reports containing of critical illness, and electrophysiological testing can

statistical modeling to adjust for confounding of CINMA demonstrate residual neuromuscular dysfunction years

risk factors and outcomes. In addition to summarizing after the initial presentation [59]. In a seminal report on

results from a larger number of patients, our review has 109 acute respiratory distress syndrome survivors evalu-

several important new implications. ated at 1 year, patient-reported muscle weakness, rather

While the overall prevalence of CINMA in ICU than pulmonary dysfunction, was the most important fac-

patients remains unknown, we found that that this tor contributing to functional impairment (this study did

complication is remarkably common in patients with not include formal neuromuscular testing) [19]. A separate

prolonged mechanical ventilation, sepsis or multi-organ clinical and electrophysiological study of 22 patients who

failure. There are no known therapies for CINMA, yet the had a prolonged (> 28 days) critical illness and were

contribution of CINMA must be weighed when making assessed a median of 43 months after ICU discharge found

predictions about durations of mechanical ventilation that 13 (59%) had motor or sensory deficits on clinical

and hospitalization, the need for a tracheostomy, and examination and 21 (95%) had chronic partial denervation

anticipated long-term functional status [17]. CINMA on EMG [60]. Building on these observations, new cohort

should be entertained in all patients who fail to wean from studies are needed that are powered to quantify the impact

mechanical ventilation, even when other factors have been of CINMA on functional status, quality of life, and social

implicated in weaning failure. The relationship between and work-related reintegration in the months and years

CINMA and mechanical ventilation is complex, since following the acute illness [61].

mechanical ventilation may be a surrogate marker for Fourth, there is a need to apply standardized diagnostic

factors that are causally related to CINMA, while CINMA criteria of CINMA and its subtypes. Existing studies

in turn prolongs mechanical ventilation. More studies are heterogeneous in the use of diagnostic criteria. For

are needed to unravel these relationships, and to assess instance, in the largest patient sample within this re-

the relative contribution of CINMA and other factors, view [26, 62], there was no documented exclusion of

such as coexisting cardiac and pulmonary dysfunction, prior neuromuscular disease, no reporting of clinical

in patients who fail to wean from mechanical ventilation. findings, and the diagnosis of CIP was based exclusively

Future studies should also be directed to broader ICU on EMG results that are non-specific in differentiating

CIP and CIM [1]. Uniform use of diagnostic criteria outcome characteristics specific to CINMA, and therefore

will enhance communication between clinicians and help we disqualified studies that did not independently confirm

investigators design studies to understand the epidemiol- clinical findings. Another limitation is that the majority

ogy, risk factors, and impact of specific CINMA subsets. of reported CINMA risk factors and outcome analyses

These criteria should integrate physical examination were univariable and prone to confounding due to the

findings with valid and reliable bedside neurophysio- observational study designs. An additional limitation

logical tests (e. g., nerve conduction velocities, needle is that it was not possible to standardize the way that

electromyography), recognizing that CINMA preva- exposure variables were defined or modeled in individual

lence is likely to be underestimated when only physical studies, likely contributing to heterogeneity in our results

findings are relied upon [8], while clinically relevant (for instance, several studies included in this review

disease may be overestimated with electrophysiolog- provided either no definition or non-validated definitions

ical tests [7]. Clinicians should also understand that of terms such as sepsis or multiple organ failure). Study

conventional electrophysiological techniques may not heterogeneity precluded any quantitative pooling of

reliably identify CINMA subtypes [8, 63], and in selected risk estimates into a formal meta-analysis. Finally, the

circumstances specific methods such as direct muscle quality of included studies was only fair, potentially

stimulation [41, 64, 65] might be helpful, for example in influencing the direction and magnitude of the observed

unconscious patients, who are unable to voluntarily effects.

contract muscles and in whom the contribution of CIM is In conclusion, this systematic review reveals that

likely to be overlooked [6]. CINMA is a common complication in critically ill patients

This review has several limitations. By excluding with mechanical ventilation, sepsis or multiple organ

reports that lacked electrophysiological or histopatho- failure. Existing studies do not reliably confirm certain

logical confirmation of physical examination findings, widely cited CINMA risk factors, while new data indicate

we may have omitted data on patients with clinically that intensive glycemic control might decrease the risk

significant CINMA. It has been argued that a perti- of CINMA. Large prospective studies are needed to

nent history and detailed neurological examination may substantiate these findings and to identify new factors

be sufficient to establish a diagnosis of CINMA, and which might contribute to CINMA and its long-term

that additional tests are of little practical value or may consequences, with the goal of preventing and treating

even overestimate clinically relevant CINMA; others these disorders in vulnerable populations.

have countered that electrophysiological confirmation is

essential to accurately identify CINMA [1]. While elec- Acknowledgements. The authors wish to thank Ahmet Hoke, MD,
trophysiological results may have little impact on clinical Department of Neurology, Johns Hopkins University, for his atten-
decision-making, our intent was to identify exposure and tive manuscript review and helpful comments.

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