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OBJECTIVES: An early diagnosis of intensive care unit-acquired weakness (ICU-AW) is often not possible due to impaired consciousness. To avoid a diagnostic delay, we previously developed a prediction model, based on single-center data from 212 patients (development cohort), to predict ICU-AW at 2 days after ICU admission. The objective of this study was to investigate the external validity of the original prediction model in a new, multicenter cohort and, if necessary, to update the model. METHODS: Newly admitted ICU patients who were mechanically ventilated at 48 hours after ICU admission were included. Predictors were prospectively recorded, and the outcome ICU-AW was defined by an average Medical Research Council score <4. In the validation cohort, consisting of 349 patients, we analyzed performance of the original prediction model by assessment of calibration and discrimination. Additionally, we updated the model in this validation cohort. Finally, we evaluated a new prediction model based on all patients of the development and validation cohort. RESULTS: Of 349 analyzed patients in the validation cohort, 190 (54%) developed ICU-AW. Both model calibration and discrimination of the original model were poor in the validation cohort. The area under the receiver operating characteristics curve (AUC-ROC) was 0.60 (95% confidence interval [CI]: 0.54-0.66). Model updating methods improved calibration but not discrimination. The new prediction model, based on all patients of the development and validation cohort (total of 536 patients) had a fair discrimination, AUC-ROC: 0.70 (95% CI: 0.66-0.75). CONCLUSIONS: The previously developed prediction model for ICU-AW showed poor performance in a new independent multicenter validation cohort. Model updating methods improved calibration but not discrimination. The newly derived prediction model showed fair discrimination. This indicates that early prediction of ICU-AW is still challenging and needs further attention.

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BACKGROUND: Intensive care unit-acquired weakness (ICU-AW) is a common complication of critical illness and is associated with increased mortality, longer mechanical ventilation and longer hospital stay. Little is known about the causes of mortality in patients with ICU-AW. In this study, we aimed to give an overview of the causes of death in a population diagnosed with ICU-AW during hospital admission. METHODS: Data from a prospective cohort study in the mixed medical-surgical ICU of the Academic Medical Center in Amsterdam were used. Patients were included when mechanically ventilated for more than 48 hours. Intensive care unit-acquired weakness was defined as a mean medical research council score <4. Baseline data and data on the time of death were collected. RESULTS: Fifty-three patients were included. Irreversible shock with multiple organ failure (MOF) was the most common cause of death (28/53 of patients; 26 patients with septic shock and 2 patients with hypovolemic shock). Most common site of sepsis was abdominal (38.5%) and pulmonary (19.2%). On admission to the ICU, 53% had a do-not-resuscitate code. In 74% of the patients, further treatment limitations were implemented during their ICU stay. CONCLUSION: In this cohort of patients with ICU-AW, most patients died of irreversible shock with MOF, caused by sepsis.

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BACKGROUND: Results from preclinical studies suggest that age-dependent differences in host defense and the pulmonary renin-angiotensin system (RAS) are responsible for observed differences in epidemiology of acute respiratory distress syndrome (ARDS) between children and adults. The present study compares biomarkers of host defense and RAS in bronchoalveolar lavage (BAL) fluid from neonates, children, adults, and older adults with ARDS. METHODS: In this prospective observational study, we enrolled mechanical ventilated ARDS patients categorized into four age groups: 20 neonates (< 28 days corrected postnatal age), 29 children (28 days-18 years), 26 adults (18-65 years), and 17 older adults (> 65 years of age). All patients underwent a nondirected BAL within 72 h after intubation. Activities of the two main enzymes of RAS, angiotensin converting enzyme (ACE) and ACE2, and levels of biomarkers of inflammation, endothelial activation, and epithelial damage were determined in BAL fluid. RESULTS: Levels of myeloperoxidase, interleukin (IL)-6, IL-10, and p-selectin were higher with increasing age, whereas intercellular adhesion molecule-1 was higher in neonates. No differences in activity of ACE and ACE2 were seen between the four age groups. CONCLUSIONS: Age-dependent differences in the levels of biomarkers in lungs of ARDS patients are present. Especially, higher levels of markers involved in the neutrophil response were found with increasing age. In contrast to preclinical studies, age is not associated with changes in the pulmonary RAS.

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BACKGROUND: The pathophysiology of intensive care unit-acquired weakness (ICU-AW), which affects peripheral nerves, limb muscles and respiratory muscles, is complex and incompletely understood. This illustrates the need for an ICU-AW animal model. However, a translatable and easily applicable ICU-AW animal model does not exist. The objective of this study was to investigate whether induction of a S. pneumoniae sepsis could serve as a model for ICU-AW. METHODS: A total of 24 C57BL/6J mice were infected intranasally with viable S. pneumoniae. Control mice (n=8) received intranasal saline and mice of the blank group (n=4) were not inoculated. Ceftriaxone was administered at 24 h (n=8) or at 48h after inoculation (n=8), or as soon as mice lost 10% of their body weight (n=8). The primary endpoint, in vivo grip strength, was measured daily. At the end of the experiment, at 120 h after inoculation, electrophysiological recordings were performed and diaphragm muscle was excised to determine ex vivo muscle fiber strength and myosin/action ratio. RESULTS: Grip strength over time was similar between experimental and control groups and electrophysiological recordings did not show signs of ICU-AW. Diaphragm fiber contractility measurements showed reduced strength in the group that received ceftriaxone at 48 h after S. pneumoniae inoculation. CONCLUSIONS: Ex vivo diaphragm weakness, but no in vivo limb weakness was found in the S. pneumoniae mouse model in which severe illness was induced. This does not reflect the full clinical picture of ICU-AW as seen in humans and as such this model did not fulfill our predefined requirements. However, this model may be used to study inflammation induced diaphragmatic weakness.

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BACKGROUND: The main risk factors for intensive care unit-acquired weakness (ICU-AW) are sepsis, the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction. These risk factors are associated with systemic complement activation. We hypothesized that critically ill patients who develop ICU-AW have increased systemic complement activation compared to critically ill patients who do not develop ICU-AW. METHODS: Complement activation products C3b/c, C4b/c and C5a were measured in plasma of ICU patients with mechanical ventilation for ≥48 hours. Samples were collected at admission to the ICU and for 6 consecutive days. ICU-AW was defined by a mean Medical Research Council (MRC) score <4. We compared the level of complement activation products between patients who did and who did not develop ICU-AW. RESULTS: Muscle strength measurements and complement assays were available in 27 ICU patients, of whom 13 patients developed ICU-AW. Increased levels of C4b/c were seen in all patients. Neither admission levels, nor maximum, minimum and mean levels of complement activation products were different between patients who did and did not develop ICU-AW. CONCLUSIONS: Complement activation is seen in critically ill patients, but is not different between patients who did and who did not develop ICU-AW.

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BACKGROUND: Neuromuscular ultrasound is a noninvasive investigation, which can be easily performed at the bedside on the ICU. A reduction in muscle thickness and increase in echo intensity over time have been described in ICU patients, but the relation to ICU-acquired weakness (ICU-AW) is unknown. We hypothesized that quantitative assessment of muscle and nerve parameters with ultrasound can differentiate between patients with and without ICU-AW. The aim of this cross-sectional study was to investigate the diagnostic accuracy of neuromuscular ultrasound for diagnosing ICU-AW. METHODS: Newly admitted ICU patients, mechanically ventilated for at least 48 h, were included. As soon as patients were awake and attentive, an ultrasound was made of four muscles and two nerves (index test) and ICU-AW was evaluated using muscle strength testing (reference standard; ICU-AW defined as mean Medical Research Council score <4). Diagnostic accuracy of muscle thickness, echo intensity and homogeneity (echo intensity standard deviation) as well as nerve cross-sectional area, thickness and vascularization were evaluated with the area under the curve of the receiver operating characteristic curve (ROC-AUC). We also evaluated diagnostic accuracy of z-scores of muscle thickness, echo intensity and echo intensity standard deviation. RESULTS: Seventy-one patients were evaluated of whom 41 had ICU-AW. Ultrasound was done at a median of 7 days after admission in patients without ICU-AW and 9 days in patients with ICU-AW. Diagnostic accuracy of all muscle and nerve parameters was low. ROC-AUC ranged from 51.3 to 68.0% for muscle parameters and from 51.0 to 66.7% for nerve parameters. CONCLUSION: Neuromuscular ultrasound does not discriminate between patients with and without ICU-AW at the time the patient awakens and is therefore not able to reliably diagnose ICU-AW in ICU patients relatively early in the disease course.

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OBJECTIVES: To investigate whether patients who develop ICU-acquired weakness have a different pattern of systemic inflammatory markers compared with critically ill patients who do not develop ICU-acquired weakness. DESIGN: Prospective observational cohort study. SETTING: Mixed medical-surgical ICU of a tertiary care hospital in the Netherlands. PATIENTS: Newly admitted critically ill patients, greater than or equal to 48 hours on mechanical ventilation with a nonneurologic ICU admission diagnosis, were included. INTERVENTIONS: A panel of systemic inflammatory markers and soluble vascular adhesion molecules were measured in plasma samples of day 0, 2, and 4 after ICU admission. ICU-acquired weakness was diagnosed by manual muscle strength testing as soon as patients were awake and attentive. MEASUREMENTS AND MAIN RESULTS: Ninety-nine of 204 included patients developed ICU-acquired weakness. Principal component regression analysis, adjusted for confounders, showed that principal component 1, mainly loaded with interleukin-6, interleukin-8, interleukin-10, and fractalkine, was significantly higher in patients who developed ICU-acquired weakness (odds ratio, 1.35 [95% CI, 1.18-1.55]). Partial least squares-discriminant analysis also showed that these markers were the most important discriminative markers. Mixed-effects models of these markers showed that ICU-acquired weakness was associated with an independent 1.5- to two-fold increase in these markers. CONCLUSIONS: Systemic inflammation is increased in patients who develop ICU-acquired weakness compared with patients who do not develop ICU-acquired weakness in the first 4 days after ICU admission. This finding is consistent when adjusted for confounders, like disease severity. A group consisting of interleukin-6, interleukin-8, interleukin-10, and fractalkine was identified to be the most important.

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INTRODUCTION: There are few reports of in vivo muscle strength measurements in animal models of ICU-acquired weakness (ICU-AW). In this study we investigated whether the Escherichia coli (E. coli) septic peritonitis mouse model may serve as an ICU-AW model using in vivo strength measurements and myosin/actin assays, and whether development of ICU-AW is age-dependent in this model. METHODS: Young and old mice were injected intraperitoneally with E. coli and treated with ceftriaxone. Forelimb grip strength was measured at multiple time points, and the myosin/actin ratio in muscle was determined. RESULTS: E. coli administration was not associated with grip strength decrease, neither in young nor in old mice. In old mice, the myosin/actin ratio was lower in E. coli mice at t = 48 h and higher at t = 72 h compared with controls. CONCLUSIONS: This E. coli septic peritonitis mouse model did not induce decreased grip strength. In its current form, it seems unsuitable as a model for ICU-AW.

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BACKGROUND: Enterococcal bacteremia has been associated with high case fatality, but it remains unknown to what extent death is caused by these infections. We therefore quantified attributable mortality of intensive care unit (ICU)-acquired bacteremia caused by enterococci. METHODS: From 2011 to 2013 we studied consecutive patients who stayed >48 hours in 2 tertiary ICUs in the Netherlands, using competing risk survival regression and marginal structural modeling to estimate ICU mortality caused by enterococcal bacteremia. RESULTS: Among 3080 admissions, 266 events of ICU-acquired bacteremia occurred in 218 (7.1%) patients, of which 76 were caused by enterococci (incidence rate, 3.0 per 1000 patient-days at risk; 95% confidence interval [CI], 2.3-3.7). A catheter-related bloodstream infection (CRBSI) was suspected in 44 (58%) of these, prompting removal of 68% of indwelling catheters and initiation of antibiotic treatment for a median duration of 3 (interquartile range 1-7) days. Enterococcal bacteremia was independently associated with an increased case fatality rate (adjusted subdistribution hazard ratio [SHR], 2.68; 95% CI, 1.44-4.98). However, for patients with CRBSI, case fatality was similar for infections caused by enterococci and coagulase-negative staphylococci (CoNS; adjusted SHR, 0.91; 95% CI, .50-1.67). Population-attributable fraction of mortality was 4.9% (95% CI, 2.9%-6.9%) by day 90, reflecting a population-attributable risk of 0.8% (95% CI, .4%-1.1%). CONCLUSIONS: ICU-acquired enterococcal bacteremia is associated with increased case fatality; however, the mortality attributable to these infections is low from a population perspective. The virulence of enterococci and CoNS in a setting of CRBSI seems comparable.

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BACKGROUND: An early diagnosis of ICU-acquired weakness (ICU-AW) is difficult because disorders of consciousness frequently preclude muscle strength assessment. In this study, we investigated feasibility and accuracy of electrophysiological recordings to diagnose ICU-AW early in non-awake critically ill patients. METHODS: Newly admitted patients, mechanically ventilated ≥2 days and unreactive to verbal stimuli, were included in this study. Electrophysiological recordings comprised nerve conduction studies (NCS) of three nerves and, if coagulation was normal, myography in three muscles. Upon awakening, strength was assessed (ICU-AW: average Medical Research Council score <4), blinded for electrophysiological recordings. Feasibility was expressed as the percentage of recordings that were both possible and had sufficient technical quality. Diagnostic accuracy of feasible (i.e., feasibility >75 %) recordings was analyzed based on cut-off values from healthy controls and from critically ill patients with and without ICU-AW. RESULTS: Thirty-five patients were included (17 with ICU-AW). Recordings were obtained on day 4 (IQR: 3-6). Feasibility was acceptable for ulnar and peroneal nerve recordings, and low for sural recordings and myography. Diagnostic accuracy based on cut-off values from healthy controls was low. When using cut-off values from critically ill patients with and without ICU-AW, the peroneal compound muscle action potential amplitude and ulnar sensory nerve action potential amplitude had good diagnostic accuracy. CONCLUSION: Nerve conduction studies of the ulnar and peroneal nerve are feasible in critically ill patients. The diagnostic accuracy is low using cut-off values from healthy controls. Cut-off values validated specifically for discrimination between critically ill patients with and without ICU-AW may improve diagnostic accuracy.

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INTRODUCTION: An early diagnosis of Intensive Care Unit-acquired weakness (ICU-AW) using muscle strength assessment is not possible in most critically ill patients. We hypothesized that development of ICU-AW can be predicted reliably two days after ICU admission, using patient characteristics, early available clinical parameters, laboratory results and use of medication as parameters. METHODS: Newly admitted ICU patients mechanically ventilated ≥2 days were included in this prospective observational cohort study. Manual muscle strength was measured according to the Medical Research Council (MRC) scale, when patients were awake and attentive. ICU-AW was defined as an average MRC score <4. A prediction model was developed by selecting predictors from an a-priori defined set of candidate predictors, based on known risk factors. Discriminative performance of the prediction model was evaluated, validated internally and compared to the APACHE IV and SOFA score. RESULTS: Of 212 included patients, 103 developed ICU-AW. Highest lactate levels, treatment with any aminoglycoside in the first two days after admission and age were selected as predictors. The area under the receiver operating characteristic curve of the prediction model was 0.71 after internal validation. The new prediction model improved discrimination compared to the APACHE IV and the SOFA score. CONCLUSION: The new early prediction model for ICU-AW using a set of 3 easily available parameters has fair discriminative performance. This model needs external validation.

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BACKGROUND: Intensive care unit-acquired weakness (ICU-AW) is an important complication of critical illness. The main risk factors, sepsis and the systemic inflammatory response syndrome, suggest an inflammatory pathogenesis. In this systematic translational review we summarize current knowledge on inflammation in muscle and nerve tissue in animal models of ICU-AW and in critically ill patients with ICU-AW. METHODS: We conducted a systematic search in the databases of MEDLINE, EMBASE and Web of Science using predefined search and selection criteria. From the included studies we extracted data on study characteristics and on inflammation in muscle and nerve tissue. RESULTS: The literature search yielded 349 unique articles, of which 12 animal studies and 20 human studies fulfilled the in- and exclusion criteria. All studies had important shortcomings in methodological quality. In the animal studies, inflammation of muscle tissue was found, represented by cellular infiltration and increased local levels of various inflammatory mediators. In human studies, high levels of various inflammatory mediators were found in muscle and nerve tissue of ICU-AW patients. CONCLUSION: This systematic translational review suggests a role for local inflammation in ICU-AW, but the available evidence is limited and studies have severe methodological limitations.

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INTRODUCTION: Early diagnosis of intensive care unit - acquired weakness (ICU-AW) using the current reference standard, that is, assessment of muscle strength, is often hampered due to impaired consciousness. Biological markers could solve this problem but have been scarcely investigated. We hypothesized that plasma levels of neurofilaments are elevated in ICU-AW and can diagnose ICU-AW before muscle strength assessment is possible. METHODS: For this prospective observational cohort study, neurofilament levels were measured using ELISA (NfHSMI35 antibody) in daily plasma samples (index test). When patients were awake and attentive, ICU-AW was diagnosed using the Medical Research Council scale (reference standard). Differences and discriminative power (using the area under the receiver operating characteristic curve; AUC) of highest and cumulative (calculated using the area under the neurofilament curve) neurofilament levels were investigated in relation to the moment of muscle strength assessment for each patient. RESULTS: Both the index test and reference standard were available for 77 ICU patients. A total of 18 patients (23%) fulfilled the clinical criteria for ICU-AW. Peak neurofilament levels were higher in patients with ICU-AW and had good discriminative power (AUC: 0.85; 95% CI: 0.72 to 0.97). However, neurofilament levels did not peak before muscle strength assessment was possible. Highest or cumulative neurofilament levels measured before muscle strength assessment could not diagnose ICU-AW (AUC 0.59; 95% CI 0.37 to 0.80 and AUC 0.57; 95% CI 0.32 to 0.81, respectively). CONCLUSIONS: Plasma neurofilament levels are raised in ICU-AW and may serve as a biological marker for ICU-AW. However, our study suggests that an early diagnosis of ICU-AW, before muscle strength assessment, is not possible using neurofilament levels in plasma.

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Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes progressive muscle weakness, eventually resulting in death because of respiratory failure. Genetic variants are thought to predispose to the disease. A recent, large, genome-wide association study identified 2 loci that increase susceptibility to ALS. These 2 loci on chromosomes 9 and 19 consist of 4 genes: UNC13a, IFNK, MOBKL2b, and C9ORF72. A hexanucleotide repeat expansion in the noncoding region of C9ORF72 was recently identified as the cause of chromosome 9-linked ALS-FTD (frontotemporal dementia). In this study, our aim was to determine whether the coding regions of these genes harbor rare, nonsynonymous variants that play a role in ALS pathogenesis. In DNA from 1019 sporadic ALS patients and 1103 control subjects of Dutch descent, we performed a mutation screening analysis in the coding region of these 4 genes by resequencing the exons. A total of 16 amino acid-changing rare variations were identified, 11 in UNC13a and 5 on chromosome 9. Some of these were unique to ALS, but were detected in a single patient. None of the genes showed significant enrichment of rare variants in the coding sequence. Rare variants in the coding region of UNC13a, IFNK, MOBKL2b, and C9ORF72 are unlikely to be a genetic cause of ALS.

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