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Purpose Critically ill patients requiring intensive care unit (ICU) admission suffer from muscle weakness that persists for years, compromising quality-of-life. The pathophysiology of this long-term weakness remains unclear. We hypothesized that former ICU-patients show a long-term abnormal RNA-expression profile, which may contribute to lower long-term strength and for which modifiable risk factors can be identified. Methods This pre-planned secondary analysis of the EPaNIC-trial compared muscle transcriptomes of 115 former ICU-patients 5 years after critical illness and 30 matched controls with RNA-sequencing, followed by pathway over-representation and differential co-expression analyses of the differentially expressed RNAs. We used multivariable linear regression analyses to identify which of the abnormal RNA-expressions associated with the long-term muscle strength of the patients and to identify potential risk factors for the abnormal RNA-expressions. Results In former patients, 234 down-regulated and 116 up-regulated RNAs were identified after adjustment for age, sex, and BMI. Pathway over-representation and further molecular and histological analyses indicated impaired mitochondrial energy metabolism, disturbed lipid metabolism, and increased collagen formation/fibrosis in former patients. Abnormal muscle RNA-expression in former patients correlated with lower long-term muscle strength. Several treatments given in-ICU and at 5-year follow-up associated with abnormal RNA-expression, most notably in-ICU early parenteral nutrition (early PN) and glucocorticoid use. Conclusion Abnormal RNA-expression profiles 5 years after critical illness suggest disrupted mitochondrial function, disturbed lipid metabolism, and fibrosis, associated with lower long-term muscle strength and partly attributable to possibly avoidable risk factors. These findings open perspectives for prevention and possibly treatment of long-term muscle weakness after critical illness. Trial registration number and date ClinicalTrials.gov-NCT00512122, July 31, 2007.

Background Intensive care unit acquired-weakness syndrome (ICUAWS) leaves several complications in functional movements of patients such as severe walking disability. Objective Assessment of functional outcomes of 1-month inspiratory muscle training (IMT) in elderly with ICUAWS and severe walking disability was our aim. The design, setting, participants, and intervention. This study is a randomized controlled trial. ICUAWS patients who complained of severe walking disability on the Modified Functional Ambulatory Category Test (MFACT) were randomly assigned into the IMT group or control group, n  = 20 for each group. Both groups received the traditional physical therapy program. Results The results showed that the post-therapy between-group comparison of ICUAWS sufferers/groups’ parameters showed a significant improvement toward the IMT group in six-minute walk test, inspiratory and expiratory muscle strength, forced vital capacity, time up and go test, 10-m walk test, forced expiratory volume in the first second, 30-s sit-to-stand test, partial pressure of arterial blood oxygen and carbon dioxide, MFACT, oxygen saturation of arterial blood, physical, and mental summary of short form 36. Conclusion In conclusion, IMT improves functional outcomes in ICUAWS patients with walking disability. Trial registration number The clinical trial ID of this ICUAWS trial is NCT06210763.

PurposeFunctional electrical stimulation-assisted cycle ergometry (FESCE) enables in-bed leg exercise independently of patients’ volition. We hypothesised that early use of FESCE-based progressive mobility programme improves physical function in survivors of critical care after 6 months.MethodsWe enrolled mechanically ventilated adults estimated to need >7 days of intensive care unit (ICU) stay into an assessor-blinded single centre randomised controlled trial to receive either FESCE-based protocolised or standard rehabilitation that continued up to day 28 or ICU discharge.ResultsWe randomised in 1:1 ratio 150 patients (age 61±15 years, Acute Physiology and Chronic Health Evaluation II 21±7) at a median of 21 (IQR 19–43) hours after admission to ICU. Mean rehabilitation duration of rehabilitation delivered to intervention versus control group was 82 (IQR 66–97) versus 53 (IQR 50–57) min per treatment day, p<0.001. At 6 months 42 (56%) and 46 (61%) patients in interventional and control groups, respectively, were alive and available to follow-up (81.5% of prespecified sample size). Their Physical Component Summary of SF-36 (primary outcome) was not different at 6 months (50 (IQR 21–69) vs 49 (IQR 26–77); p=0.26). At ICU discharge, there were no differences in the ICU length of stay, functional performance, rectus femoris cross-sectional diameter or muscle power despite the daily nitrogen balance was being 0.6 (95% CI 0.2 to 1.0; p=0.004) gN/m2 less negative in the intervention group.ConclusionEarly delivery of FESCE-based protocolised rehabilitation to ICU patients does not improve physical functioning at 6 months in survivors.Trial registration number NCT02864745.

Neuromuscular weakness resulting in severe functional impairment is common in critical care survivors. This study aimed to evaluate effects of an early progressive rehabilitation intervention in mechanically ventilated adults at risk. This was a parallel, two-arm, assessor-blinded, randomised controlled trial with 6-months follow-up that was conducted in a mixed ICU of an academic centre in Switzerland. Previously independent, mechanically ventilated, critically ill adults with expected critical care stay ≥72 hours (n = 115) were randomised to a control group receiving standard physiotherapy including early mobilisation or to an experimental group with early endurance and resistance training combined with mobilisation. Primary endpoints were functional capacity (6-Minute Walk Distance) and functional independence (Functional Independence Measure) at hospital discharge. Secondary endpoints including muscle strength were assessed at critical care discharge. Safety was monitored closely by standard monitoring and predefined adverse events. Physiotherapy started within 48 hours of critical care admission while 97% of participants were still ventilated and 68% on inotropes. Compared to the control group (n = 57), the experimental group (n = 58) received significantly more physiotherapy (sessions: 407 vs 377, p<0.001; time/session: 25min vs 18min, p<0.001) and had less days with sedation (p<0.001). Adverse events were rare (0.6%) and without consequences. There were no significant between-group differences in 6-Minute Walk Distance (experimental 123m (IQR 25-280) vs control 100m (IQR 0-300); p = 0.542) or functional independence (98 (IQR 66-119) vs 98 (IQR 18-115); p = 0.308). Likewise, no differences were found for the secondary outcomes, except a trend towards improved mental health in the experimental group after 6 months (84 (IQR 68-88) vs 70 (IQR 64-76); p = 0.023). Early endurance and resistance training in mechanically ventilated, intensive care patients does not improve functional capacity or independence at hospital discharge compared to early standard physiotherapy but may improve mental health 6-months after critical care discharge. German Clinical Trials Register (DRKS): DRKS00004347, registered on 10 September 2012.

Background and aimsAnterior quadratus lumborum block is a truncal block, applied in close proximity to the lumbar plexus, potentially causing lower limb weakness. This trial aimed to evaluate whether a unilateral anterior quadratus lumborum block caused quadriceps muscle weakness compared with placebo.MethodsIn this randomized, non-inferiority, triple-blind trial, 20 healthy volunteers received an active unilateral anterior quadratus lumborum block with 30 mL ropivacaine 0.75% and a placebo block on the contralateral side. Primary outcome was change in maximal quadriceps muscle strength from baseline to 60 min postblock compared with placebo. Secondary outcomes were change in single-leg 6 m timed hop test, change in Timed-Up and Go test, change in mean arterial pressure from baseline to 30 min postblock and dermatomal affection.ResultsThere was no statistically significant difference in changes in maximal quadriceps muscle strength between active and placebo block; 15.88 N (95% CI −12.19 to +43.94), pnon-inf=0.003, indicating non-inferiority. Timed-Up and Go test was performed significantly faster 60 min postblock; −0.23 s (95% CI −0.38 to −0.08, p=0.005). Mean change in mean arterial pressure from baseline to 30 min postblock was 4.25 mm Hg (95% CI 0.24 to 8.26, p=0.04). Dermatome testing revealed an affection primarily of the lower abdomen (Th10-L1) with the active block.ConclusionIn this randomized controlled trial including healthy volunteers a unilateral anterior quadratus lumborum block does not cause statistical or clinical significant motor block of the quadriceps muscle compared with placebo. When administered correctly, the block can be used for procedures where early postoperative mobilization is essential.Trial registration number NCT05023343.

Background and ObjectivesFemoral nerve block (FNB), a commonly used postoperative pain treatment after total knee arthroplasty (TKA), reduces quadriceps muscle strength essential for mobilization. In contrast, adductor canal block (ACB) is predominately a sensory nerve block. We hypothesized that ACB preserves quadriceps muscle strength as compared with FNB (primary end point) in patients after TKA. Secondary end points were effects on morphine consumption, pain, adductor muscle strength, morphine-related complications, and mobilization ability.MethodsWe performed a double-blind, randomized, controlled study of patients scheduled for TKA with spinal anesthesia. The patients were randomized to receive either a continuous ACB or an FNB via a catheter (30-mL 0.5% ropivacaine given initially, followed by a continuous infusion of 0.2% ropivacaine, 8 mL/h for 24 hours). Muscle strength was assessed with a handheld dynamometer, and we used the percentile change from baseline for comparisons. The trial was registered at clinicaltrials.gov (Identifier: NCT01470391).ResultsWe enrolled 54 patients, of which 48 were analyzed. Quadriceps strength as a percentage of baseline was significantly higher in the ACB group compared with the FNB group: (median [range]) 52% [31–71] versus 18% [4–48], (95% confidence interval, 8–41; P = 0.004). There was no difference between the groups regarding morphine consumption (P = 0.94), pain at rest (P = 0.21), pain during flexion of the knee (P = 0.16), or adductor muscle strength (P = 0.39); neither was there a difference in morphine-related adverse effects or mobilization ability (P > 0.05).ConclusionsAdductor canal block preserved quadriceps muscle strength better than FNB, without a significant difference in postoperative pain.

Purpose This study investigated the effect of eicosapentaenoic and docosahexaenoic acids-rich fish oil (EPA + DHA) supplementation on eccentric contraction-induced muscle damage. Methods Twenty-four healthy men were randomly assigned to consume the EPA + DHA supplement (EPA, n  = 12) or placebo (PL, n  = 12) by the double-blind method. Participants consumed EPA + DHA or placebo supplement for 8 weeks prior to exercise and continued it until 5 days after exercise. The EPA group consumed EPA + DHA-rich fish oil containing 600 mg EPA and 260 mg DHA per day. Subjects performed five sets of six maximal eccentric elbow flexion exercises. Changes in the maximal voluntary contraction (MVC) torque, range of motion (ROM), upper arm circumference, muscle soreness as well as serum creatine kinase, myoglobin, IL-6, and TNF-α levels in blood were assessed before, immediately after, and 1, 2, 3, and 5 days after exercise. Results MVC was significantly higher in the EPA group than in the PL group at 2–5 days after exercise ( p  < 0.05). ROM was also significantly greater in the EPA group than in the PL group at 1–5 days after exercise ( p  < 0.05). At only 3 days after exercise, muscle soreness of the brachialis was significantly greater in the PL group than in the EPA group ( p  < 0.05), with a concomitant increase in serum IL-6 levels in the PL group. Conclusion Eight-week EPA + DHA supplementation attenuates strength loss and limited ROM after exercise. The supplementation also attenuates muscle soreness and elevates cytokine level, but the effect is limited.

Rationale Strength training and neuromuscular electrical stimulation (NMES) improve lower-limb muscle function in dyspnoeic individuals with chronic obstructive pulmonary disease (COPD). However, high-frequency NMES (HF-NMES) and strength training have never been compared head-to-head; and effects of low-frequency NMES (LF-NMES) have never been studied in COPD. Therefore, the optimal training modality to improve lower-limb muscle function, exercise performance and other patient-related outcomes in individuals with severe COPD remains unknown. Objectives To study prospectively the efficacy of HF-NMES (75 Hz), LF-NMES (15 Hz) or strength training in severely dyspnoeic individuals with COPD with quadriceps muscle weakness at baseline. Methods 120 individuals with COPD (FEV1: 33±1% predicted, men: 52%, age: 64.8±0.8 years) were randomised to HF-NMES, LF-NMES or strength training as part of a comprehensive inpatient pulmonary rehabilitation programme. No treadmill walking or stationary cycling was provided. Measurements and main results Groups were comparable at baseline. Quadriceps muscle strength increased after HF-NMES (+10.8 Newton-metre (Nm)) or strength training (+6.1 Nm; both p<0.01), but not after LF-NMES (+1.4 Nm; p=0.43). Quadriceps muscle endurance, exercise performance, lower-limb fat-free mass, exercise-induced symptoms of dyspnoea and fatigue improved significantly compared with baseline after HF-NMES, LF-NMES or strength training. The increase in quadriceps muscle strength and muscle endurance was greater after HF-NMES than after LF-NMES. Conclusions HF-NMES is equally effective as strength training in severely dyspnoeic individuals with COPD and muscle weakness in strengthening the quadriceps muscles and thus may be a good alternative in this particular group of patients. HF-NMES, LF-NMES and strength training were effective in improving exercise performance in severely dyspnoeic individuals with COPD and quadriceps weakness. Trial registration NTR2322

Background Intensive care unit-acquired weakness (ICUAW) is a prevalent secondary disorder in critically ill patients, characterized by significant loss of muscle mass and strength, often leading to prolonged ICU stays, increased mortality, and reduced post-discharge quality of life. Despite guidelines recommending early mobilization, logistical challenges and inconclusive efficacy have limited its impact on ICUAW prevalence. This study aims to assess the feasibility, safety, and clinical efficacy of exclusively passive physiotherapeutic interventions, including blood flow restriction/ischemic preconditioning (BFR/IPC) and electromyostimulation (EStim), as potential alternatives for muscle preservation in ICU patients who are often sedated or unable to participate in active rehabilitation. Methods This prospective, randomized controlled trial will recruit 120 patients from the surgical ICU at the University Hospital Bonn, who meet the inclusion criteria of a > 48-h ICU stay. Patients will be randomized into four groups: Sham-Control, BFR/IPC, EStim, and combined BFR/IPC + EStim. The study’s primary endpoints include feasibility and safety metrics, such as patient compliance and stress response, alongside secondary endpoints related to clinical outcomes like ICU length of stay, ICUAW prevalence, muscle mass preservation, and rehabilitation efficacy. Measurements include non-invasive assessments of muscle mass, intramuscular microdialysis to monitor metabolic and inflammatory markers, and health-related quality of life evaluations post-discharge. Discussion Preliminary literature and a systematic review underscore the need for resource-efficient, non-invasive interventions in ICU settings. BFR/IPC and EStim present promising results, but existing data on their efficacy in ICU populations are limited. This study’s findings will provide foundational data on the viability of passive physiotherapy techniques in ICU settings, potentially improving patient outcomes and reducing healthcare costs associated with prolonged ICU stays. If successful, these results will inform a multicenter randomized trial to further evaluate these interventions. This research represents a crucial step in developing feasible rehabilitation protocols to mitigate ICUAW, addressing a critical gap in critical care management and rehabilitation. Trial registration ClinicalTrials.gov DRKS00033592. Registered on March 05, 2024.

Purpose Respiratory muscle weakness frequently develops in critically ill patients and is associated with adverse outcome, including difficult weaning from mechanical ventilation. Today, no drug is approved to improve respiratory muscle function in these patients. Previously, we have shown that the calcium sensitizer levosimendan improves calcium sensitivity of human diaphragm muscle fibers in vitro and contractile efficiency of the diaphragm in healthy subjects. The main purpose of this study is to investigate the effects of levosimendan on diaphragm contractile efficiency in mechanically ventilated patients. Methods In a double-blind randomized placebo-controlled trial, mechanically ventilated patients performed two 30-min continuous positive airway pressure (CPAP) trials with 5-h interval. After the first CPAP trial, study medication (levosimendan 0.2 µg/kg/min continuous infusion or placebo) was administered. During the CPAP trials, electrical activity of the diaphragm (EA di ), transdiaphragmatic pressure ( P di ), and flow were measured. Neuromechanical efficiency (primary outcome parameter) was calculated. Results Thirty-nine patients were included in the study. Neuromechanical efficiency was not different during the CPAP trial after levosimendan administration compared to the CPAP trial before study medication. Tidal volume and minute ventilation were higher after levosimendan administration (11 and 21%, respectively), whereas EA di and P di were higher in both groups in the CPAP trial after study medication compared to the CPAP trial before study medication. Conclusions Levosimendan does not improve diaphragm contractile efficiency.