Neuromuscular dysfunction acquired in critical illness: a systematic review

Transcription

1 Intensive Care Med DOI /s SYSTEMATIC REVIEW Robert D. Stevens David W. Dowdy Robert K. Michaels Pedro A. Mendez-Tellez Peter J. Pronovost Dale M. Needham Neuromuscular dysfunction acquired in critical illness: a systematic review Received: 7 March 2007 Accepted: 15 June 2007 Springer-Verlag 2007 R. D. Stevens ( ) 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 rstevens@jhmi.edu Tel.: Fax: 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 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 neuromuscular 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 sufficient data to quantify the association between CINMA and relevant exposures 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 unequivocally 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 catecholamine administration. Across studies, there was no consistent relationship between CINMA and patient age, gender, severity of illness, or use of glucocorticoids, neuromuscular blockers, aminoglycosides, or midazolam. Unadjusted mortality was not increased in the majority of patients with CINMA, but mechanical ventilation 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 factors (glucocorticoids, neuromuscular blockers) and with short-term survival is uncertain. Available data indicate glycemic control as a potential strategy to decrease CINMA risk.

2 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 preexisting neuromuscular disease, it is believed to reflect illnesses or treatments occurring in the ICU. Early reports 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 paresis [7], Critical illness myopathy and/or neuropathy (CRIMYNE) [10], or critical illness neuromuscular abnormalities (CINMA) [11]. The rising incidence and societal burden of critical illnesses such as sepsis and the acute respiratory distress syndrome [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 substantial and likely to grow [17]. Many survivors of critical illness 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 studies 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 synthesize 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 explicit 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 mortality, duration of mechanical ventilation, and length of hospitalization. Methods Data sources and searches Relevant publications were identified by searching Medline ( ), EMBASE ( ), CINAHL ( ) 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, multiple organ dysfunction/failure, artificial ventilation, mechanical ventilation. Terms were mapped to the appropriate 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 mechanical 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.

3 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 polyneuropathy (CIP), minimum criteria were the presence of weakness acquired after admission to the ICU associated 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- Fig. 1 Flow diagram of study selection process

4 tion amplitude or prolonged direct muscle stimulation latency; or muscle histopathology consistent with an acute myopathy. Mixed CIP/CIM was defined as a combination 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, aminoglycosides, 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 scoring system evaluating trial randomization (0 2), blinding (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 comparisons, 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 multivariable 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 ultimately 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 ), 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 randomized controlled trial [26] (Table 1). The criteria for enrollment of ICU patients included mechanical ventilation in 17 reports [median (range) duration of mechanical ventilation 7 (2 10); in 14 reports, mechanical ventilation was 7 days], sepsis or septic shock in 5 reports, and multiple organ failure in 5. Patient exclusion criteria were stated in 20 studies and included presence or risk of prior neuromuscular disease in 19 reports and moribund status in 1. Patient follow-up extended beyond hospital discharge in 3 cohorts [7, 34, 43].

5 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 days after enrollment Neurological (1 unit) Bednarik, 2005 [22] Prospective cohort 61 Mixed (1 unit); > 2 organ failures with SOFA grade 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 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 < months Leijten, 1996 [42] Prospective cohort 38 Mixed MV > 7 days, age < 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

6 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] Bednarik, 2003 [8] Bednarik, 2005 [22] Bercker, 2005 [48] Berek, 1996 [34] Campellone, 1998 [35] Coakley, 1998 [36] De Jonghe, 2002 [7] De Letter, 2000 [52] Druschky, 2001 [38] Garnacho-Montero, 2001 [25] Garnacho-Montero, 2005 [51] Hund, 1997 [50] Kupfer, 1992 [40] Lefaucheur, 2006 [41] Leijten, 1995 [43] Leijten, 1996 [42] Mohr, 1997 [44] Rudis, 1996 [49] Tepper, 2000 [45] Thiele, 1997 [50] Thiele, 2000 [46] Witt, 1991 [47] 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] 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), representativeness 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 (adequate = 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 without adjustment for potential confounders. Multivariable regression analysis was available in 8 reports (Table 8) [7, 22 25, 34, 52, 53]. Diagnosis of CINMA Diagnosis of CINMA was confirmed with electrophysiological tests in all studies, and clinical findings were documented 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 disease as a cause of critical illness [35, 46, 49, 50, 54], indicating 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 analysis of motor unit potentials, direct muscle stimulation, or muscle histopathology. In all other studies, data were insufficient to make this distinction. 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,

7 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 (12) Bedoarik, 2003 [8] < 3 days after ICU admission (24) Bednarik, 2005 [22] < 3 days after ICU admission (18) Bercker, 2005 [48] NR + + Berek, 1996 [34] days after ICU admission Campellone, 1998 [35] 2 weeks after liver transplantation (7) Coakley, 1998 [36] NR (55) De Jonghe, 2002 [7] Mean (SD) 12.4 (6.8) of MV (11) De Letter, 2000 [52] 4 days MV (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 (7) Kupfer, 1992 [40] > 24hafterdiscontinuation ofvecuronium 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

8 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] (65%) 9 (35%) 9 (35%) Bednarik, 2003 [8] (43%) 26 (57%) 7 (15%) 8 (17%) 11 (24%) Bednarik, 2005 [22] (43%) 35 (57%) 12 (20%) 14 (23%) 9 (15%) Bercker, 2005 [48] (40%) 27 (60%) 27 (60%) Berek, 1996 [34] 22 4 (18%) 18 (82%) 18 (82%) Campellone, 1998 [35] (91%) 7 (9%) 7 (9%) Coakley, 1998 [36] 44 7 (16%) 37 (84%) 37 (84%) De Jonghe, 2002 [7] (75%) 24 (25%) 24 (25%) De Letter, 2001 [52] (67%) 32 (33%) 11 (11%) 12 (12%) 7 (7%) 2 (2%) Druschky, 2001 [38] (43%) 16 (57%) 16 (57%) Garnacho-Montero, 2001 [25] (32%) 50 (68%) 50 (68%) Garnacho-Montero, 2005 [51] (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] (42%) 29 (58%) 29 (58%) Leijten, 1996 [42] (53%) 18 (47%) 18 (47%) Mohr, 1997 [44] (89%) 7 (21%) 7 (21%) Rudis, 1996 [49] (50%) 10 (50%) 2 (10%) 6 (30%) 1 (5%) 1 (5%) Tepper, 2000 [45] 22 3 (14%) 19 (86%) 19 (86%) Thiele, 1997 [50] (84%) 7 (16%) 7 (16%) Thiele, 2000 [46] 19 7 (37%) 12 (63%) 12 (63%) Van den Berghe, 2005 [54] (62%) 155 (38%) 155 (38%) Witt, 1991 [47] (30%) 30 (70%) 30 (70%) CINMA, critical illness neuromuscular abnormality; CIP, critical illness polyneuropathy; CIM, critical illness myopathy; NMJ, neuromuscular 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 ( ) to 49 ( )] [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 mg/dl) versus intensive (blood glucose target mg/dl) glycemic control resulted in an OR of CINMA of 2.6 (95% CI ) [26]. Two of 3 studies found a univariable association 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 ), while the other study suggested a reduction in risk [OR (95%CI) 0.27 ( )] [25]. In reports containing multivariable analyses, CINMA was independently predicted by the following factors: female gender [OR (95% CI) 4.6 ( )] [7]; renal replacement therapy [OR (95% CI) 1.9 ( )] [26]; APACHE III score [55] 30 days after institution of mechanical ventilation [5.2 ( )] [52]; SOFA score [56] 1 week after ICU admission [RR (95% CI) 2.4 ( )] [22]; SIRS 1 week after admission [RR (95% CI) 3.74 ( )] [22]; SIRS 30 days after institution of mechanical ventilation [OR (95% CI) 2.5 ( )] [52]; blood glucose levels [OR (95% CI) 1.24 ( ) per 20 mg/dl increment] [53]; and total parenteral nutrition (OR [95% CI] 5.1 [ ]) [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, aminoglycosides, neuromuscular blocking agents, midazolam, metronidazole, or furosemide. There was an unadjusted

9 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 < NR 67% vs. 6%, p = 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 = % vs. 50%, p = 0.41 SAPS1 15 vs. 15, p =NS NR NR Campellone, 1998 [35] NR NR AP2 24 vs. 16, p = 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 = % vs. 20%, p =0.08 No. of days with dysfunction in 2organs10vs.5,p < 0.001* De Letter, 2001 [52] NR NR AP3 independently NR NR predicted CINMA* Druschky, 2001 [38] 70 vs. 64, p = % vs. 33%, p = 0.82 NR Goris score 1 vs. 0, p = % 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 = % 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 = % vs. 33%, p =0.88 NR NR NR Lefaucheur, 2006 [41] 63 vs. 46, p = % vs. 44%, p = 0.81 NR NR 100% vs. 100%, p = NS Leijten, 1995 [43] 59 vs. 54, p = % vs. 33%, p = 0.66 AP2 22 vs. 23. p = vs. 11 patients 48% vs. 43%, p =0.7 had MOF, p =0.08 Leijten, 1996 [42] 58 vs. 55, p = vs. 30%, p = 0.83 AP2 22 vs. 23, p = 0.66 MODS 5.3 vs. 3.6, p = % vs. 40%, p =0.34 Mohr, 1997 [44] 48 vs. 52, p = % vs. 42%, p = 0.97 AP2 22 vs. 21, p = 0.34 NR 100% vs. 35%, p = Rudis, 1996 [49] 52 vs. 54, p = % vs. 70%, p =1 AP261vs.62,p = 0.65 NR 40% vs. 0%, p = 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 assessment; SAPS2, simplified acute physiology score 2; ODIN, organ dysfunction and/or infection score; AP3, Acute Physiology and Chronic Health Evaluation III score; MODS, multiple organscore; Goris score, see ref. [66]; MOF, multipleorganfailure; * Significantassociation withcinmaafter multivariable adjustment; ** Non-significant association with CINMA after multivariable adjustment

10 Table 6 CINMA risk factors Reference Serum glucose or hyperglycemia Glucocorticoids Neuromuscular blockers Aminoglycosides (mg/dl or % patients) (MP total dose or % patients) (Total dose or % patients) (% patients or dose) 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 = % vs. 18%, p = % vs. 0%, p = 0.1 Vecuronium 13 vs. 11 mg, p =0.19 Bednarik, 2003 [8] NR NR NR NR Bednarik, 2005 [22] NR NS association with CINMA NS association with CINMA NR Bercker, 2005 [48] Peak, 166 vs. 144, p < % vs. 66%, p = 0.7 NR NR Berek, 1996 [34] NR NR NR Campellone, 1998 [35] 312 vs. 221, p = vs mg, p =0.02 NR NR Coakley, 1998 [36] NR 24% vs. 29%, p = 1 62% vs. 71%, p =1 NR De Jonghe, 2002 [7] Peak, 360 vs. 259, p = 0.001** 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 De Letter, 2001 [52] NR NS association with CINMA** NS association with CINMA** NS association with CINMA** Druschky, 2001 [38] NR Daily dose, 0 vs. 32 mg, p =0.47 NR NR Garnacho-Montero, 2001 [25] 30% vs. 30%, p = NS 14% vs. 17%, p = % vs. 4%, p = 0.16* 42% vs. 44%, p =0.91 Garnacho-Montero, 2005 [51] NR NR 29% vs. 10%, p = 0.06 NR Hund, 1997 [50] NR NR NR NR Kupfer, 1992 [40] NR NR Vecuronium 1352 vs. 528 mg, p = 0.05 NR Lefaucheur, 2006 [41] NR 58% vs. 25%, p = % vs. 25%, p =0.78 NR Leijten, 1995 [43] NR NR NR NR Leijten, 1996 [42] NR NR NR NR Mohr, 1997 [44] NR NR 100% vs. 77%, p = % vs. 35%, p = 0.6 Rudis, 1996 [49] NR 70% vs. 50%, p = % vs. 90%, p = NS 70% vs. 80%, p = 1 Vecuronium or pancuronium 1080 vs mg, p =0.76 Tepper, 2000 [45] NR NR NR NR Thiele, 1997 [50] NR 100% vs. 11%, p < % 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 mg/kg, p = NS 23 vs. 16 mg/kg Thiele, 2000 [46] 221 vs. 215, p =NS NR NR NR Van den Berghe, 2005 [54] OR (95% CI) of CINMA NR NR NR 1.26 (1.09; 1.46) per mmol/l of AM blood glucose level* Witt, 1991 [47] 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

11 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 = % vs. 24%, p = vs. 11, p < vs. 21, p < vs. 6, p = Bednarik, 2003 [8] NR NR NR NR NR Bednarik, 2005 [22] NR NR NR NR 16 vs. 3, p < Bercker, 2005 [48] NR NR 38 vs. 26, p = NR 20 vs. 13, p = Berek, 1996 [34] 39% vs. 0%, p =0.26 NR NR NR NR Campellone, 1998 [35] NR 29% vs. 0%, p = vs. 14, p = 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 = Garnacho-Montero, 2001 [25] 66% vs. 52%, p = % vs. 57%, p = 0.01 * 53 vs. 32, p = vs. 41, p = vs. 19, p = 0.002* Garnacho-Montero, 2005 [51] 21% vs. 10%, p = % vs. 20%, p = vs. 23, p < vs. 33, p < vs. 14, p < * Hund, 1997 [50] 50% vs. 100%, p = 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 = vs. 11, p = vs. 3, p = 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

12 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 Renal replacement therapy SIRS Sepsis Multiple organ failure score Severity of illness scores Age Gender Total parenteral nutrition Pharmacological Catecholamines Morphine Glucocorticoids Aminoglycosides Neuromuscular blockers Metronidazole Furosemide Midazolam Outcomes Duration of MV Hospital length of stay ICU length of stay DeathinICU 12 3* 0 0 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 administration and CINMA in the three cohorts in which it was reported (Table 8) [26, 46, 50]. Multivariable analysis suggested a relationship between CINMA and glucocorticoids in one of two studies [OR (95% CI) 14.9 ( )] [7], and between CINMA and neuromuscular blockers in one out of three studies [OR (95% CI) ( )] [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 unadjusted 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 independent predictor of hospital death [OR (95% CI) 7.1 ( )] [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 predicted duration of mechanical ventilation in two reports [OR (95% CI) for prolonged mechanical ventilation 2.4 ( ) [23]; and mean increase in duration of mechanical ventilation, 11.6 days (95% CI )] [25]. In one report, CINMA was the only independent predictor of failure to wean from mechanical ventilation [OR (95% CI) 15.4 ( )] [51]. Patient outcomes after hospital discharge were reported in three studies [7, 34, 43]. In one, clinically relevant recovery 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 patients had severe functional disability [43]. The third study evaluated 15 CINMA survivors at 3 months, finding clinical 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

13 prolonged mechanical ventilation, have sepsis or multiple organ failure. Second, five of six reports found an association 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 consistently 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. synthesized 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 acknowledge, there was possible duplication of patient samples between at least two of the publications). The authors recommended additional prospective studies to delineate 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 characterization of risk factors for CINMA. Existing studies suggest a positive association between blood glucose levels and the incidence of CINMA, and two large randomized 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 multivariable 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 evaluated at 1 year, patient-reported muscle weakness, rather than pulmonary dysfunction, was the most important factor 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 review [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

14 CIP and CIM [1]. Uniform use of diagnostic criteria will enhance communication between clinicians and help investigators design studies to understand the epidemiology, risk factors, and impact of specific CINMA subsets. These criteria should integrate physical examination findings with valid and reliable bedside neurophysiological tests (e. g., nerve conduction velocities, needle electromyography), recognizing that CINMA prevalence is likely to be underestimated when only physical findings are relied upon [8], while clinically relevant disease may be overestimated with electrophysiological 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 histopathological confirmation of physical examination findings, we may have omitted data on patients with clinically significant CINMA. It has been argued that a pertinent 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 electrophysiological 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. 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