Skeletal Muscle Myokine Expression in Critical Illness, Association With Outcome and Impact of Therapeutic Interventions.

Context: Muscle expresses and secretes several myokines that bring about benefits in distant organs. Objective: We investigated the impact of critical illness on muscular expression of irisin, kynurenine aminotransferases, and amylase; association with clinical outcome; and impact of interventions that attenuate muscle wasting/weakness. Methods: We studied critically ill patients who participated in 2 randomized controlled trials (EPaNIC/NESCI) and documented time profiles in critically ill mice. Included in the study were 174 intensive care unit (ICU) patients (day 8 ± 1) vs 19 matched controls, and 60 mice subjected to surgery/sepsis vs 60 pair-fed healthy mice. Interventions studied included 7-day neuromuscular electrical stimulation (NMES), and withholding parenteral nutrition (PN) in the first ICU week (late PN) vs early PN. The main outcome measures were FNDC5 (irisin- precursor), KYAT1, KYAT3, and amylase mRNA expression in skeletal muscle. Results: Critically ill patients showed 34% to 80% lower mRNA expression of FNDC5, KYAT1, and amylases than controls (P < .0001). Critically ill mice showed time-dependent reductions in all mRNAs compared with healthy mice (P ≤ .04). The lower FNDC5 expression in patients was independently associated with a higher ICU mortality (P = .015) and ICU-acquired weakness (P = .012), whereas the lower amylase expression in ICU survivors was independently associated with a longer ICU stay (P = .0060). Lower amylase expression was independently associated with a lower risk of death (P = .048), and lower KYAT1 expression with a lower risk of weakness (P = .022). NMES increased FNDC5 expression compared with unstimulated muscle (P = .016), and late PN patients had a higher KYAT1 expression than early PN patients (P = .022). Conclusion: Expression of the studied myokines was affected by critical illness and associated with clinical outcomes, with limited effects of interventions that attenuate muscle wasting or weakness.

Early mobilization in clinical practice: the reliability and feasibility of the 'Start To Move' Protocol.

PURPOSE: The properties of a local Intensive Care Unit early mobilization protocol ('Start To Move As Soon As Possible') in critically ill patients, consisting of an objective diagnostic assessment linked to six treatment levels were evaluated. This study aimed to investigate whether the protocol can be reliably applied by different health-care providers (reliability), to examine the associations between prescribed and delivered treatments (feasibility) and to explore safety and patient satisfaction with the protocol. METHODS: Cross-sectional observational study evaluating the reliability of the protocol between physiotherapist was evaluated with Cohen's kappa, percentage of agreement, and intraclass correlation coefficients in 61 patients. Feasibility was analyzed as agreement between prescribed and delivered treatments with Spearman's rank correlation coefficients in 60 patients. A satisfaction survey was used to evaluate patient satisfaction with the protocol. RESULTS: Excellent agreement was observed between physiotherapists for diagnostic level assignment (Kappa = 0.92), while the majority of the treatment proposals per level showed moderate to substantial agreement between the physiotherapists (Kappa range: 0.40-0.89). Three hundred and thirteen treatments were prescribed. Perfect agreement was observed between prescribed and delivered treatments in level 0 (Spearman's rho 1.00) and excellent associations for levels 1-5 (0.941, 0.995, 0.951, 0.998, and 0.999), respectively. Unwanted safety events rate was 3%. Most patients (92%) were very satisfied with physiotherapy. CONCLUSION: Excellent inter-rater agreement for diagnostic level assignment and moderate to substantial agreement for proposed treatments support the reliability of the protocol. Perfect to excellent associations between prescribed and delivered treatments supports its feasibility. Complications were rare, and most patients were very positive regarding the care provided by physiotherapists during their stay in the ICU.

Early neuromuscular electrical stimulation reduces the loss of muscle mass in critically ill patients - A within subject randomized controlled trial.

PURPOSE: To investigate the effect of Neuromuscular Electrical Stimulation (NMES) on muscle thickness, strength and morphological and molecular markers of the quadriceps. MATERIALS AND METHODS: Adult critically ill patients with an expected prolonged stay received unilateral quadriceps NMES sessions for 7 consecutive days. Before and after the intervention period, quadriceps thickness was measured with ultrasound. After the intervention period, strength was assessed in cooperative patients and muscle biopsies were taken. Multivariable regression was performed to identify factors affecting muscle thickness loss. RESULTS: Muscle thickness decreased less in the stimulated leg (-6 ± 16% versus -12 ± 15%, p = 0.014, n = 47). Strength was comparable. Opioid administration, minimal muscle contraction and more muscle thickness loss in the non-stimulated muscle were independently associated with better muscle thickness preservation. Stimulated muscles showed a shift towards larger myofibers and higher MyHC-I gene expression. NMES did not affect gene expression of other myofibrillary proteins, MuRF-1 or atrogin-1. Signs of myofiber necrosis and inflammation were comparable for both muscles. CONCLUSIONS: NMES attenuated the loss of muscle mass, but not of strength, in critically ill patients. Preservation of muscle mass was more likely in patients receiving opioids, patients with a minimal muscle contraction during NMES and patients more prone to lose muscle mass. TRIAL REGISTRATION: clinicaltrials.govNCT02133300.

Heat and emergency room admissions in the Netherlands.

BACKGROUND: Due to a global warming-related increase in heatwaves, it is important to obtain detailed understanding of the relationship between heat and health. We assessed the relationship between heat and urgent emergency room admissions in the Netherlands. METHODS: We collected daily maximum temperature and relative humidity data over the period 2002-2007. Daily urgent emergency room admissions were divided by sex, age group and disease category. We used distributed lag non-linear Poisson models, estimating temperature-admission associations. We estimated the relative risk (RR) for urgent hospital admissions for a range of temperatures compared to a baseline temperature of 21 °C. In addition, we compared the impact of three different temperature scenarios on admissions using the RR. RESULTS: There is a positive relationship between increasing temperatures above 21 °C and the RR for urgent emergency room admissions for the disease categories 'Potential heat-related diseases' and 'Respiratory diseases'. This relationship is strongest in the 85+ group. The RRs are strongest for lag 0. For admissions for 'circulatory diseases', there is only a small significant increase of RRs within the 85+ age group for moderate heat, but not for extreme heat. The RRs for a one-day event with extreme heat are comparable to the RRs for multiple-day events with moderate heat. CONCLUSIONS: Hospitals should adjust the capacity of their emergency departments on warm days, and the days immediately thereafter. The elderly in particular should be targeted through prevention programmes to reduce harmful effects of heat. The fact that this increase in admissions already occurs in temperatures above 21 °C is different from previous findings in warmer countries. Given the similar impact of three consecutive days of moderate heat and one day of extreme heat on admissions, criteria for activation of national heatwave plans need adjustments based on different temperature scenarios.

Feasibility of neuromuscular electrical stimulation in critically ill patients.

OBJECTIVE: Critically ill patients often develop intensive care unit-acquired weakness. Reduction in muscle mass and muscle strength occurs early after admission to the intensive care unit (ICU). Although early active muscle training could attenuate this intensive care unit-acquired weakness, in the early phase of critical illness, a large proportion of patients are unable to participate in any active mobilization. Neuromuscular electrical stimulation (NMES) could be an alternative strategy for muscle training. The aim of this study was to investigate the safety and feasibility of NMES in critically ill patients. DESIGN: This is an observational study. SETTING: The setting is in the medical and surgical ICUs of a tertiary referral university hospital. PATIENTS: Fifty patients with a prognosticated prolonged stay of at least 6 days were included on day 3 to 5 of their ICU stay. Patients with preexisting neuromuscular disorders and patients with musculoskeletal conditions limiting quadriceps contraction were excluded. INTERVENTION: Twenty-five minutes of simultaneous bilateral NMES of the quadriceps femoris muscle. This intervention was performed 5 days per week (Monday-Friday). Effective muscle stimulation was defined as a palpable and visible contraction (partial or full muscle bulk). MEASUREMENTS: The following parameters, potentially affecting contraction upon NMES, were assessed: functional status before admission to the ICU (Barthel index), type and severity of illness (Acute Physiology And Chronic Health Evaluation II score and sepsis), treatments possibly influencing the muscle contraction (corticosteroids, vasopressors, inotropes, aminoglycosides, and neuromuscular blocking agents), level of consciousness (Glasgow Coma Scale, score on 5 standardized questions evaluating awakening, and sedation agitation scale), characteristics of stimulation (intensity of the NMES, number of sessions per patient, and edema), and neuromuscular electrophysiologic characteristics. Changes in heart rate, blood pressure, oxygen saturation, respiratory rate, and skin reactions were registered to assess the safety of the technique. RESULTS: In 50% of the patients, an adequate quadriceps contraction was obtained in at least 75% of the NMES sessions. Univariate analysis showed that lower limb edema (P<.001), sepsis (P=.008), admission to the medical ICU (P=.041), and treatment with vasopressors (P=.011) were associated with impaired quadriceps contraction. A backward multivariate analysis identified presence of sepsis, lower limb edema, and use of vasopressors as independent predictors of impaired quadriceps contraction (R2=59.5%). Patients responded better to NMES in the beginning of their ICU stay in comparison with after 1 week of ICU stay. There was no change in any of the safety end points with NMES. CONCLUSIONS: Critically ill patients having sepsis, edema, or receiving vasopressors were less likely to respond to NMES with an adequate quadriceps contraction. Neuromuscular electrical stimulation is a safe intervention to be administered in the ICU.

Assessment of limb muscle strength in critically ill patients: a systematic review.

OBJECTIVES: To determine the reliability of volitional and nonvolitional limb muscle strength assessment in critically ill patients and to provide guidelines for the implementation of limb muscle strength assessment this population. DATA SOURCES: The following computerized bibliographic databases were searched with MeSH terms and keywords or combinations: MEDLINE through PubMed and Embase through Embase.com. STUDY SELECTION: Articles were screened by two independent reviewers. Included studies were all performed in humans and were original articles. The research population exists of adult, critically ill patients or ICU survivors of either sex, and those admitted to a medical, surgical, respiratory, or mixed ICU. A study was included if reliability of muscle strength measurements was determined in this population. DATA EXTRACTION: Data on baseline characteristics (country, study population, eligibility, age, setting and method, and equipment of limb muscle strength assessment) and reliability scores were obtained by two independent reviewers. DATA SYNTHESIS: Data of six observational studies were analyzed. Interrater reliability of the Medical Research Council scale for individual muscle groups varied from "fair" or "substantial" (weighted κ, 0.23-0.64) to "very good" agreement (weighted κ, 0.80-0.96). Interrater reliability of the Medical Research Council-sum score was found to be very good in all four studies (intraclass correlation coefficients, 0.86-0.99 or Pearson product moment correlation coefficient = 0.96). Interrater reliability of handheld dynamometry was comparable between two studies (intraclass correlation coefficients, 0.62-0.96). Interrater reliability of handgrip dynamometry was very good in two studies (intraclass correlation coefficients, 0.89-0.97). Intrarater reliability of handheld dynamometry and handgrip dynamometry was assessed in one study, and results were very good (intraclass correlation coefficients > 0.81). No studies were obtained on reliability of nonvolitional muscle strength assessment. CONCLUSIONS: Voluntary muscle strength measurement has proven reliable in critically ill patients provided that strict guidelines on adequacy and standardized test procedures and positions are followed.

Interobserver agreement of Medical Research Council sum-score and handgrip strength in the intensive care unit.

INTRODUCTION: Muscle weakness often complicates critical illness and is associated with devastating short- and long-term consequences. For interventional studies, reliable measurements of muscle force in the intensive care unit (ICU) are needed. METHODS: To examine interobserver agreement, two observers independently measured Medical Research Council (MRC) sum-score (n = 75) and handgrip strength (n = 46) in a cross-sectional ICU sample. RESULTS: The intraclass correlation coefficient (ICC) for MRC sum-score was 0.95 (0.92-0.97). The kappa coefficient for identifying "significant weakness" (MRC sum-score <48, MRC subtotal upper limbs <24) and "severe weakness" (MRC sum-score <36) was 0.68 ± 0.09, 0.88 ± 0.07, and 0.93 ± 0.07, respectively. The ICC for left and right handgrip strength was 0.97 (0.94-0.98) and 0.93 (0.86-0.97), respectively. CONCLUSIONS: Interobserver agreement on MRC sum-score and handgrip strength in the ICU was very good. Agreement on "severe weakness" (MRC sum-score <36) was excellent and supports its use in interventional studies. Agreement on "significant weakness" (MRC sum-score <48) was good, but even better using the equivalent cut-off in the upper limbs. It remains to be determined whether this may serve as a substitute.

The interobserver agreement of handheld dynamometry for muscle strength assessment in critically ill patients.

OBJECTIVE: Muscle weakness often complicates critical illness and is associated with increased risk of morbidity, mortality, and limiting functional outcome even years later. To assess the presence of muscle weakness and to examine the effects of interventions, objective and reliable muscle strength measurements are required. The first objective of this study is to determine interobserver reliability of handheld dynamometry. Secondary objectives are to quantify muscle weakness, to evaluate distribution of muscle weakness, and to evaluate gender-related differences in muscle strength. DESIGN: Cross-sectional observational study. SETTING: The surgical and medical intensive care units of a large, tertiary referral, university hospital. PATIENTS: A cross-sectional, randomly selected sample of awake and cooperative critically ill patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Handheld dynamometry was performed in critically ill patients who had at least a score of 3 (movement against gravity) on the Medical Research Council scale. Three upper limb and three lower limb muscle groups were tested at the right-hand side. Patients were tested twice daily by two independent raters. Fifty-one test-retests were performed in 39 critically ill patients. Handheld dynamometry demonstrated good interobserver agreement with intraclass correlation coefficients >0.90 in four of the muscle groups tested (range, 0.91-0.96) and somewhat less for hip flexion (intraclass correlation coefficient, 0.80) and ankle dorsiflexion (intraclass correlation coefficient, 0.76). Limb muscle strength was considerably reduced in all muscle groups as shown by the median z-score (range, -1.08 to -3.48 sd units). Elbow flexors, knee extensors, and ankle dorsiflexors were the most affected muscle groups. Loss of muscle strength was comparable between men and women. CONCLUSIONS: Handheld dynamometry is a tool with a very good interobserver reliability to assess limb muscle strength in awake and cooperative critically ill patients. Future studies should focus on the sensitivity of handheld dynamometry in longitudinal studies to evaluate predictive values toward patients' functional outcome.