Accelerometer-derived movement features as predictive biomarkers for muscle atrophy in neurocritical care: a prospective cohort study.

BACKGROUND: Physical inactivity and subsequent muscle atrophy are highly prevalent in neurocritical care and are recognized as key mechanisms underlying intensive care unit acquired weakness (ICUAW). The lack of quantifiable biomarkers for inactivity complicates the assessment of its relative importance compared to other conditions under the syndromic diagnosis of ICUAW. We hypothesize that active movement, as opposed to passive movement without active patient participation, can serve as a valid proxy for activity and may help predict muscle atrophy. To test this hypothesis, we utilized non-invasive, body-fixed accelerometers to compute measures of active movement and subsequently developed a machine learning model to predict muscle atrophy. METHODS: This study was conducted as a single-center, prospective, observational cohort study as part of the MINCE registry (metabolism and nutrition in neurointensive care, DRKS-ID: DRKS00031472). Atrophy of rectus femoris muscle (RFM) relative to baseline (day 0) was evaluated at days 3, 7 and 10 after intensive care unit (ICU) admission and served as the dependent variable in a generalized linear mixed model with Least Absolute Shrinkage and Selection Operator regularization and nested-cross validation. RESULTS: Out of 407 patients screened, 53 patients (age: 59.2 years (SD 15.9), 31 (58.5%) male) with a total of 91 available accelerometer datasets were enrolled. RFM thickness changed - 19.5% (SD 12.0) by day 10. Out of 12 demographic, clinical, nutritional and accelerometer-derived variables, baseline RFM muscle mass (beta - 5.1, 95% CI - 7.9 to - 3.8) and proportion of active movement (% activity) (beta 1.6, 95% CI 0.1 to 4.9) were selected as significant predictors of muscle atrophy. Including movement features into the prediction model substantially improved performance on an unseen test data set (including movement features: R2 = 79%; excluding movement features: R2 = 55%). CONCLUSION: Active movement, as measured with thigh-fixed accelerometers, is a key risk factor for muscle atrophy in neurocritical care patients. Quantifiable biomarkers reflecting the level of activity can support more precise phenotyping of ICUAW and may direct tailored interventions to support activity in the ICU. Studies addressing the external validity of these findings beyond the neurointensive care unit are warranted. TRIAL REGISTRATION: DRKS00031472, retrospectively registered on 13.03.2023.

Relationship between critical care nutrition and post-intensive care syndrome in surviving ventilated patients with COVID-19: a multicenter prospective observational study.

The impact of nutrition therapy in the acute phase on post-intensive care syndrome (PICS) remains unclear. We conducted a multicenter prospective study on adult patients with COVID-19 who required mechanical ventilation for more than three days. The questionnaire was mailed after discharge. Physical PICS, defined as less than 90 points on the Barthel index (BI), was assigned as the primary outcome. We examined the types of nutrition therapy in the first week that affected PICS components. 269 eligible patients were evaluated 10 months after discharge. Supplemental parenteral nutrition (SPN) >400 kcal/day correlated with a lower occurrence of physical PICS (10% vs 21.92%, p = 0.042), whereas the amounts of energy and protein provided, early enteral nutrition, and a gradual increase in nutrition delivery did not, and none correlated with cognitive or mental PICS. A multivariable regression analysis revealed that SPN had an independent impact on physical PICS (odds ratio 0.33, 95% CI 0.12-0.92, p = 0.034), even after adjustments for age, sex, body mass index and severity. Protein provision ≥1.2 g/kg/day was associated with a lower occurrence of physical PICS (odds ratio 0.42, 95% CI 0.16-1.08, p = 0.071). In conclusion, SPN in the acute phase had a positive impact on physical PICS for ventilated patients with COVID-19.

The rate and assessment of muscle wasting during critical illness: a systematic review and meta-analysis.

BACKGROUND: Patients with critical illness can lose more than 15% of muscle mass in one week, and this can have long-term detrimental effects. However, there is currently no synthesis of the data of intensive care unit (ICU) muscle wasting studies, so the true mean rate of muscle loss across all studies is unknown. The aim of this project was therefore to systematically synthetise data on the rate of muscle loss and to identify the methods used to measure muscle size and to synthetise data on the prevalence of ICU-acquired weakness in critically ill patients. METHODS: We conducted a systematic literature search of MEDLINE, PubMed, AMED, BNI, CINAHL, and EMCARE until January 2022 (International Prospective Register of Systematic Reviews [PROSPERO] registration: CRD420222989540. We included studies with at least 20 adult critically ill patients where the investigators measured a muscle mass-related variable at two time points during the ICU stay. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and assessed the study quality using the Newcastle-Ottawa Scale. RESULTS: Fifty-two studies that included 3251 patients fulfilled the selection criteria. These studies investigated the rate of muscle wasting in 1773 (55%) patients and assessed ICU-acquired muscle weakness in 1478 (45%) patients. The methods used to assess muscle mass were ultrasound in 85% (n = 28/33) of the studies and computed tomography in the rest 15% (n = 5/33). During the first week of critical illness, patients lost every day -1.75% (95% CI -2.05, -1.45) of their rectus femoris thickness or -2.10% (95% CI -3.17, -1.02) of rectus femoris cross-sectional area. The overall prevalence of ICU-acquired weakness was 48% (95% CI 39%, 56%). CONCLUSION: On average, critically ill patients lose nearly 2% of skeletal muscle per day during the first week of ICU admission.

Quantitative muscle MRI displays clinically relevant myostructural abnormalities in long-term ICU-survivors: a case-control study.

BACKGROUND: Long-term data on ICU-survivors reveal persisting sequalae and a reduced quality-of-life even after years. Major complaints are neuromuscular dysfunction due to Intensive care unit acquired weakness (ICUAW). Quantitative MRI (qMRI) protocols can quantify muscle alterations in contrast to standard qualitative MRI-protocols. METHODS: Using qMRI, the aim of this study was to analyse persisting myostructural abnormalities in former ICU patients compared to controls and relate them to clinical assessments. The study was conducted as a cohort/case-control study. Nine former ICU-patients and matched controls were recruited (7 males; 54.8y ± 16.9; controls: 54.3y ± 11.1). MRI scans were performed on a 3T-MRI including a mDTI, T2 mapping and a mDixonquant sequence. Water T2 times, fat-fraction and mean values of the eigenvalue (λ1), mean diffusivity (MD), radial diffusivity (RD) and fractional anisotropy (FA) were obtained for six thigh and seven calf muscles bilaterally. Clinical assessment included strength testing, electrophysiologic studies and a questionnaire on quality-of-life (QoL). Study groups were compared using a multivariate general linear model. qMRI parameters were correlated to clinical assessments and QoL questionnaire using Pearson´s correlation. RESULTS: qMRI parameters were significantly higher in the patients for fat-fraction (p < 0.001), water T2 time (p < 0.001), FA (p = 0.047), MD (p < 0.001) and RD (p < 0.001). Thighs and calves showed a different pattern with significantly higher water T2 times only in the calves. Correlation analysis showed a significant negative correlation of muscle strength (MRC sum score) with FA and T2-time. The results were related to impairment seen in QoL-questionnaires, clinical testing and electrophysiologic studies. CONCLUSION: qMRI parameters show chronic next to active muscle degeneration in ICU survivors even years after ICU therapy with ongoing clinical relevance. Therefore, qMRI opens new doors to characterize and monitor muscle changes of patients with ICUAW. Further, better understanding on the underlying mechanisms of the persisting complaints could contribute the development of personalized rehabilitation programs.

Mitochondrial Dysfunction in Intensive Care Unit-Acquired Weakness and Critical Illness Myopathy: A Narrative Review.

Mitochondria are key structures providing most of the energy needed to maintain homeostasis. They are the main source of adenosine triphosphate (ATP), participate in glucose, lipid and amino acid metabolism, store calcium and are integral components in various intracellular signaling cascades. However, due to their crucial role in cellular integrity, mitochondrial damage and dysregulation in the context of critical illness can severely impair organ function, leading to energetic crisis and organ failure. Skeletal muscle tissue is rich in mitochondria and, therefore, particularly vulnerable to mitochondrial dysfunction. Intensive care unit-acquired weakness (ICUAW) and critical illness myopathy (CIM) are phenomena of generalized weakness and atrophying skeletal muscle wasting, including preferential myosin breakdown in critical illness, which has also been linked to mitochondrial failure. Hence, imbalanced mitochondrial dynamics, dysregulation of the respiratory chain complexes, alterations in gene expression, disturbed signal transduction as well as impaired nutrient utilization have been proposed as underlying mechanisms. This narrative review aims to highlight the current known molecular mechanisms immanent in mitochondrial dysfunction of patients suffering from ICUAW and CIM, as well as to discuss possible implications for muscle phenotype, function and therapeutic approaches.

Muscular myostatin gene expression and plasma concentrations are decreased in critically ill patients.

BACKGROUND: The objective was to investigate the role of gene expression and plasma levels of the muscular protein myostatin in intensive care unit-acquired weakness (ICUAW). This was performed to evaluate a potential clinical and/or pathophysiological rationale of therapeutic myostatin inhibition. METHODS: A retrospective analysis from pooled data of two prospective studies to assess the dynamics of myostatin plasma concentrations (day 4, 8 and 14) and myostatin gene (MSTN) expression levels in skeletal muscle (day 15) was performed. Associations of myostatin to clinical and electrophysiological outcomes, muscular metabolism and muscular atrophy pathways were investigated. RESULTS: MSTN gene expression (median [IQR] fold change: 1.00 [0.68-1.54] vs. 0.26 [0.11-0.80]; p = 0.004) and myostatin plasma concentrations were significantly reduced in all critically ill patients when compared to healthy controls. In critically ill patients, myostatin plasma concentrations increased over time (median [IQR] fold change: day 4: 0.13 [0.08/0.21] vs. day 8: 0.23 [0.10/0.43] vs. day 14: 0.40 [0.26/0.61]; p < 0.001). Patients with ICUAW versus without ICUAW showed significantly lower MSTN gene expression levels (median [IQR] fold change: 0.17 [0.10/0.33] and 0.51 [0.20/0.86]; p = 0.047). Myostatin levels were directly correlated with muscle strength (correlation coefficient 0.339; p = 0.020) and insulin sensitivity index (correlation coefficient 0.357; p = 0.015). No association was observed between myostatin plasma concentrations as well as MSTN expression levels and levels of mobilization, electrophysiological variables, or markers of atrophy pathways. CONCLUSION: Muscular gene expression and systemic protein levels of myostatin are downregulated during critical illness. The previously proposed therapeutic inhibition of myostatin does therefore not seem to have a pathophysiological rationale to improve muscle quality in critically ill patients. TRIAL REGISTRATION: ISRCTN77569430 -13th of February 2008 and ISRCTN19392591 17th of February 2011.

Novel protocol combining physical and nutrition therapies, Intensive Goal-directed REhabilitation with Electrical muscle stimulation and Nutrition (IGREEN) care bundle.

BACKGROUND: Although the combination of rehabilitation and nutrition may be important for the prevention of intensive care unit (ICU)-acquired weakness, a protocolized intervention of this combination has not yet been reported. We herein developed an original combined protocol and evaluated its efficacy. METHODS: In this single-center historical control study, we enrolled adult patients admitted to the ICU. Patients in the control group received standard care, while those in the intervention group received the protocol-based intervention. The ICU mobility scale was used to set goals for early mobilization and a neuromuscular electrical stimulation was employed when patients were unable to stand. The nutritional status was assessed for nutritional therapy, and target calorie delivery was set at 20 or 30 kcal/kg/day and target protein delivery at 1.8 g/kg/day in the intervention group. The primary endpoint was a decrease in femoral muscle volume in 10 days assessed by computed tomography. RESULTS: Forty-five patients in the control group and 56 in the intervention group were included in the analysis. Femoral muscle volume loss was significantly lower in the intervention group (11.6 vs 14.5%, p = 0.03). The absolute risk difference was 2.9% (95% CI 0.1-5.6%). Early mobilization to a sitting position by day 10 was achieved earlier (p = 0.03), and mean calorie delivery (20.1 vs. 16.8 kcal/kg/day, p = 0.01) and mean protein delivery (1.4 vs. 0.8 g/kg/day, p < 0.01) were higher in the intervention group. CONCLUSION: The protocolized intervention, combining early mobilization and high-protein nutrition, contributed to the achievement of treatment goals and prevention of femoral muscle volume loss. TRIAL REGISTRATION NUMBER: The present study is registered at the University Hospital Medical Information Network-clinical trials registry (UMIN000040290, Registration date: May 7, 2020).

Incidence, Time Course and Influence on Quality of Life of Intensive Care Unit-Acquired Weakness Symptoms in Long-Term Intensive Care Survivors.

PURPOSE: Intensive care unit-acquired weakness (ICUAW) can manifest as muscle weakness or neuropathy-like symptoms, with diagnosis remaining a challenge. Uncertainties surround the long-term cause and sequelae. Therefore, the purpose was to assess incidence, time course and long-term influence on quality of life (QoL) of symptoms in ICU survivors. METHODS: After ethical approval and registration (www.drks.de: DRKS00011593), in a single-center cohort study all patients admitted to the ICU in 2007-2017 in a German university hospital were screened. Out of 1,860 patients (≥7d ICU care including ventilation support for ≥72 h, at least 6mo-10y after ICU) 636 were deceased, 912 survivors were contacted. RESULTS: 149 former patients (age: 63.5 ± 13.1y; males: 73%; duration in ICU: 20.8 ± 15.7d; duration of ventilation: 16.5 ± 13.7 h; time post-ICU: 4.4 ± 2.7y, 5-10y: 43%) consented to be interviewed concerning occurrence, duration, recovery and consequences of ICUAW-associated muscle weakness or neuropathy-like symptoms after ICU. In 75% at least 1 persistent or previous symmetrical symptom was reported (myopathy-like muscle weakness: 43%; neuropathy-like symptoms: 13%; both: 44%) and rated as incidence of ICUAW. However, only 18% of participants had received an ICUAW diagnosis by their physicians, although 62% had persistent symptoms up to 10y after ICU (5-10y: 46%). Only 37% of participants reported a complete recovery of symptoms, significantly associated with an initially low number of symptoms after ICU (p < 0.0001), myopathy-like symptoms (p = 0.024), and younger age at the time of ICU admission (55.7 ± 13.1 vs. 62.6 ± 10.6y, p < 0.001). ICUAW still impaired the QoL at the time of the interview in 74% of affected survivors, with 30% reporting severe impairment. CONCLUSION: ICUAW symptoms were disturbingly common in the majority of long-term survivors, indicating that symptoms persist up to 10y and frequently impair QoL. However, only a small number of patients had been diagnosed with ICUAW. Trial registry: Deutsches Register Klinischer Studien (DRKS), https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011593, registration number: DRKS00011593.

Clinical and neurophysiological characterization of muscular weakness in severe COVID-19.

OBJECTIVE: To report clinical and electroneuromyographic (ENMG) characteristics of patients affected by severe COVID-19 infection, evaluated for muscular weakness. MATERIALS AND METHODS: ENMGs performed for evaluation of diffuse weakness in patients who could not be discharged from semi-intensive care COVID unit because of difficulties in ventilation weaning were reviewed. Patients with severe COVID-19 infection who had undergone endotracheal intubation and able to co-operate were considered. ENMG protocol was focused on neurophysiological items that excluded or confirmed critical illness polyneuropathy (CIP), myopathy (CIM), or polyneuromyopathy (CIPM). Standardized clinical evaluation was performed using Medical Research Council (MRC) sum score. RESULTS: Eight patients were included in the study. All presented known risk factors for intensive care unit-acquired weakness (ICU-AW), and none of them had history of underlying neuromuscular disorders. ENMG findings were normal in two patients, while only two patients had an altered MRC sum score (< 48). Neuromuscular involvement was diagnosed in 6/8 patients (75%): 2 had CIP, 1 had possible CIM, 1 had CIPM, while 1 patient, with clinically evident weakness but equivocal ENMG findings, was classified as ICU-AW. Finally, 1 patient was diagnosed with acute demyelinating neuropathy. Patients with neuromuscular involvement were those with longer intubation duration and higher levels of IL-6 at admission. CONCLUSION: Neuromuscular complications are frequent in severe COVID-19 and cannot be excluded by MRC sum scores above 48. Standardized ENMG is helpful in guiding diagnosis when clinical evaluation is not reliable or possible. Elevated IL-6 at admission may be a predictor biomarker of ICU-AW in COVID-19.

SARS-CoV-2/Renin-Angiotensin System: Deciphering the Clues for a Couple with Potentially Harmful Effects on Skeletal Muscle.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has produced significant health emergencies worldwide, resulting in the declaration by the World Health Organization of the coronavirus disease 2019 (COVID-19) pandemic. Acute respiratory syndrome seems to be the most common manifestation of COVID-19. A high proportion of patients require intensive care unit admission and mechanical ventilation (MV) to survive. It has been well established that angiotensin-converting enzyme type 2 (ACE2) is the primary cellular receptor for SARS-CoV-2. ACE2 belongs to the renin-angiotensin system (RAS), composed of several peptides, such as angiotensin II (Ang II) and angiotensin (1-7) (Ang-(1-7)). Both peptides regulate muscle mass and function. It has been described that SARS-CoV-2 infection, by direct and indirect mechanisms, affects a broad range of organ systems. In the skeletal muscle, through unbalanced RAS activity, SARS-CoV-2 could induce severe consequences such as loss of muscle mass, strength, and physical function, which will delay and interfere with the recovery process of patients with COVID-19. This article discusses the relationship between RAS, SARS-CoV-2, skeletal muscle, and the potentially harmful consequences for skeletal muscle in patients currently infected with and recovering from COVID-19.

Clinical Approaches to Assess Post-extubation Dysphagia (PED) in the Critically Ill.

Swallowing disorders and respective consequences (including aspiration-induced pneumonia) are often observed in extubated ICU patients with data indicating that a large number of patients are affected. We recently demonstrated in a large-scale analysis that the incidence of post-extubation dysphagia (PED) is 12.4% in a general ICU population and about 18% in emergency admissions to the ICU. Importantly, PED was mostly sustained until hospital discharge and independently predicted 28- and 90-day mortality. Although oropharyngeal/laryngeal trauma, neuromuscular ICU-acquired weakness, reduced sensation/sensorium, dyssynchronous breathing, and gastrointestinal reflux, are all considered to contribute to PED, little is known about the underlying pathomechanisms and risk factors leading to PED in critically ill patients. Systematic screening of all potential ICU patients for oropharyngeal dysphagia (OD) seems key for early recognition and follow-up, as well as the design and testing of novel therapeutic interventions. Today, screening methods and clinical investigations for dysphagia differ considerably. In the context of a recently proposed pragmatic screening algorithm introduced by us, we provide a concise review on currently available non-instrumental techniques that could potentially serve for non-instrumental OD assessment in critically ill patients. Following systematic literature review, we find that non-instrumental OD assessments were mostly tested in different patient populations with only a minority of studies performed in critically ill patients. Due to little available data on non-instrumental dysphagia assessment in the ICU, future investigations should aim to validate respective approaches in the critically ill against an instrumental (gold) standard, for example, flexible endoscopic evaluation of swallowing. An international expert panel is encouraged to addresses critical illness-related definitions, screening and confirmatory assessment approaches, treatment recommendations, and identifies optimal patient-centered outcome measures for future clinical investigations.

Which factors are associated with acquired weakness in the ICU? An overview of systematic reviews and meta-analyses.

RATIONALE: Intensive care unit-acquired weakness (ICUAW) is common in critically ill patients, characterized by muscle weakness and physical function loss. Determining risk factors for ICUAW poses challenges due to variations in assessment methods and limited generalizability of results from specific populations, the existing literature on these risk factors lacks a clear and comprehensive synthesis. OBJECTIVE: This overview aimed to synthesize risk factors for ICUAW, categorizing its modifiable and nonmodifiable factors. METHODS: An overview of systematic reviews was conducted. Six relevant databases were searched for systematic reviews. Two pairs of reviewers selected reviews following predefined criteria, where bias was evaluated. Results were qualitatively summarized and an overlap analysis was performed for meta-analyses. RESULTS: Eighteen systematic reviews were included, comprising 24 risk factors for ICUAW. Meta-analyses were performed for 15 factors, while remaining reviews provided qualitative syntheses. Twelve reviews had low risk of bias, 4 reviews were unclear, and 2 reviews exhibited high risk of bias. The extent of overlap ranged from 0 to 23% for the corrected covered area index. Nonmodifiable factors, including advanced age, female gender, and multiple organ failure, were consistently associated with ICUAW. Modifiable factors, including neuromuscular blocking agents, hyperglycemia, and corticosteroids, yielded conflicting results. Aminoglycosides, renal replacement therapy, and norepinephrine were associated with ICUAW but with high heterogeneity. CONCLUSIONS: Multiple risk factors associated with ICUAW were identified, warranting consideration in prevention and treatment strategies. Some risk factors have produced conflicting results, and several remain underexplored, emphasizing the ongoing need for personalized studies encompassing all potential contributors to ICUAW development.

Balance function in critical illness survivors and evaluation of psychometric properties of the Mini-BESTest.

Critical illness survivors commonly face impairments, such as intensive care unit-acquired weakness (ICUAW) which is characterized by muscle weakness and sensory deficits. Despite these symptoms indicating potential balance deficits, systematic investigations and validated assessments are lacking. Therefore, we aimed to assess balance function using the Mini-BESTest, evaluate its psychometric properties, and identify associated variables. Balance was assessed post-ICU discharge (V1) and at discharge from inpatient neurorehabilitation (V2) in patients with ≥ 5 days of invasive ventilation. Mini-BESTest measurement characteristics were evaluated in an ambulatory subgroup. A multiple linear regression was conducted. The prospective cohort study comprised 250 patients (34% female, 62 ± 14 years, median ICU stay 55 days). Median Mini-BESTest scores improved significantly from V1 (5 (IQR 0-15)) to V2 (18.5 (10-23)) with a large effect size. Excellent inter-rater and test-retest reliabilities of the Mini-BESTest were observed (ICC = 0.981/0.950). Validity was demonstrated by a very high correlation with the Berg Balance Scale (ρ = 0.90). No floor or ceiling effects were detected. Muscle strength, cognitive function, cerebral disease, critical illness polyneuropathy/myopathy, and depression were significantly associated with balance. Despite significant improvements during the rehabilitation period, balance disorders were prevalent in critical illness survivors. Ongoing therapy is recommended. Due to its excellent psychometric properties, the Mini-BESTest is suitable for use in critical illness survivors.Registration: The study was registered at the German Clinical Trials Register (DRKS00021753, date of registration: 2020-09-03).

Predictors of postoperative physical functional decline at hospital discharge in elderly patients with prolonged intensive care unit stay after cardiac surgery.

BACKGROUND: A prolonged stay in the intensive care (ICU) is associated with physical function decline following cardiac surgery. To predict physical function decline after cardiac surgery, it may be important to evaluate physical function in the ICU. OBJECTIVES: This study aimed to determine that physical function examination at ICU discharge was independently associated with physical functional decline at hospital discharge in elderly patients who had undergone cardiac surgery and prolonged the ICU stay. METHODS: We assessed physical function before and after cardiac surgery in elderly patients who had spent ≥72 h in the ICU in this retrospective cohort study using the short physical performance battery (SPPB). At hospital discharge, a decrease of at least 1 point on the SPPB was considered a postoperative physical functional decline. Postoperative physical functional decline at hospital discharge was predicted using multiple logistic regression. RESULTS: We revealed postoperative physical functional deterioration in 28.0% of patients who spent ≥72 h in the ICU following cardiac surgery. The Medical Research Council sum score (MRC-SS) (OR: 0.96, 95% CI: 0.82-0.99) and mechanical ventilation days (OR: 1.27, 95% CI: 1.01-1.64) were independently associated with physical functional decline at hospital discharge. CONCLUSIONS: Physical function at ICU discharge and mechanical ventilation days were predictors of postoperative physical functional decline at hospital discharge in patients. MRC-SS was more accurate in predicting postoperative physical functional decline at hospital discharge when performed at the time of ICU discharge.

Roles of programmed death-1 and muscle innate lymphoid cell-derived interleukin 13 in sepsis-induced intensive care unit-acquired weakness.

BACKGROUND: Intensive care unit-acquired weakness (ICU-AW) is a syndrome characterized by a long-term muscle weakness often observed in sepsis-surviving patients during the chronic phase. Although ICU-AW is independently associated with increased mortality, effective therapies have yet to be established. Programmed death-1 (PD-1) inhibitors have attracted attention as potential treatments for reversing immune exhaustion in sepsis; however, its impact on ICU-AW remains to be elucidated. Here, we study how PD-1 deficiency affects sepsis-induced skeletal muscle dysfunction in a preclinical sepsis model. METHODS: Chronic sepsis model was developed by treating wild-type (WT) and PD-1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15-17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL-13) and PD-1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow-twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). In an in vitro study, C2C12 myotubes were treated with lipopolysaccharide (LPS) and recombinant IL-13 followed by gene expression measurements. RESULTS: WT septic mice exhibited decreased muscle weight (quadriceps, P < 0.01; gastrocnemius, P < 0.05; and tibialis anterior, P < 0.01) and long-term muscle weakness (P < 0.0001), whereas PD-1 KO septic mice did not exhibit any reduction in muscle weights and strengths. Slow-twitch specific mRNAs, including myoglobin (Mb), troponin I type 1 (Tnni1), and myosin heavy chain 7 (Myh7) were decreased in WT skeletal muscle (Mb, P < 0.0001; Tnni1, P < 0.05; and Myh7, P < 0.05) after sepsis induction, but mRNA expressions of Tnni1 and Myh7 were increased in PD-1 KO septic mice (Mb, not significant; Tnni1, P < 0.0001; and Myh7, P < 0.05). Treatment of C2C12 myotube cells with LPS decreased the expression of slow-twitch mRNAs, which was restored by IL-13 (Mb, P < 0.0001; Tnni1, P < 0.001; and Myh7, P < 0.05). IL-13 production was significantly higher in ILC2s compared to T cells in skeletal muscle (P < 0.05). IL-13-producing ILC2s in skeletal muscle were examined and found to increase in PD-1 KO septic mice, compared with WT septic mice (P < 0.05). ILC2-derived IL-13 was increased by PD-1 KO septic mice and thought to protect the muscles from experimental ICU-AW. CONCLUSIONS: Long-term muscle weakness in experimental ICU-AW was ameliorated in PD-1 KO mice. ILC2-derived IL-13 production in skeletal muscles was increased in PD-1 KO mice, thereby suggesting that IL-13 alleviates muscle weakness during sepsis. This study demonstrates the effects of PD-1 blockade in preserving muscle strength during sepsis through an increase in ILC2-derived IL-13 and may be an attractive therapeutic target for sepsis-induced ICU-AW.

Coagulopathy correlates with muscle titin injury in critically ill patients.

PURPOSE: We hypothesized that coagulopathy independently contributes to muscle injury focusing to titin fragmentation, and investigated their correlations. MATERIAL AND METHODS: We conducted a post-hoc analysis of an observational study, in which we evaluated muscle injury with the biomarker titin. Coagulopathy was assessed on the first day using the Japanese diagnostic criteria of acute-phase disseminated intravascular coagulopathy (JAAM-DIC). Mean N-titin/Cre measured on days 1, 3, 5, and 7 was assigned as the primary outcome. RESULTS: Overall, 111 eligible patients were included. Mean N-titin/Cre were significantly higher in the JAAM-DIC group. A multivariable analysis identified JAAM-DIC as independent risk factors for mean N-titin/Cre while other severity scores were not. CONCLUSIONS: Coagulopathy correlated with muscle titin fragmentation, as an independent risk factor. TRIAL REGISTRATION NUMBER: The present study is registered at the University Hospital Medical Information Network-clinical trials registry (UMIN000040290, Registration date: May 7, 2020).

Targeting NAT10 protects against sepsis-induced skeletal muscle atrophy by inhibiting ROS/NLRP3.

AIMS: To identify N-acetyltransferase 10 (NAT10) and its downstream signaling pathways in myocytes and skeletal muscle, and to investigate its role in inflammation-induced muscle atrophy. MATERIALS AND METHODS: Cecal ligation and puncture models were used to induce sepsis in C57BL/6 mice, which were treated with either a NAT10 inhibitor or a control agent. The therapeutic effect of NAT10 inhibitor was investigated by evaluating the mass, morphology, and molecular characteristics of mouse skeletal muscle. C2C12 cells were stimulated with LPS, and the expression of the NAT10 gene, downstream protein content, and atrophy phenotype were analyzed using a NAT10 inhibitor, to further explore the atrophic effect of NAT10 on C2C12 differentiated myotubes. RESULTS: Gene set enrichment analysis revealed that NAT10 expression was elevated in the Lateral femoris muscle of patients with ICUAW. In vitro and in vivo experiments showed that sepsis or LPS induced the upregulation of NAT10 expression in skeletal muscles and C2C12 myotubes. Skeletal muscle mass, tissue morphology, gene expression, and protein content were associated with atrophic response in sepsis models. Remodelin ameliorated the LPS-induced skeletal muscle weight loss, as well as muscular atrophy, and improved survival. Remodelin reversed the atrophy program that was induced by inflammation through the downregulation of the ROS/NLRP3 pathway, along with the inhibition of the expression of MuRF1 and Atrogin-1. CONCLUSION: NAT10 is closely related to skeletal muscle atrophy during sepsis. Remodelin improves the survival rate of mice by improving the systemic inflammatory response and skeletal muscle atrophy by downregulating the ROS/NLRP3 signaling pathway.

Gut-muscle axis and sepsis-induced myopathy: The potential role of gut microbiota.

Sepsis is described as an immune response disorder of the host to infection in which microorganisms play a non-negligible role. Most survivors of sepsis experience ICU-acquired weakness, also known as septic myopathy, characterized by skeletal muscle atrophy, weakness, and irreparable damage/regenerated or dysfunctional. The mechanism of sepsis-induced myopathy is currently unclear. It has been believed that this state is triggered by circulating pathogens and their related harmful factors, leading to impaired muscle metabolism. Sepsis and its resulting alterations in the intestinal microbiota are associated with sepsis-related organ dysfunction, including skeletal muscle wasting. There are also some studies on interventions targeting the flora, including fecal microbiota transplants, the addition of dietary fiber and probiotics in enteral feeding products, etc., aiming to improve sepsis-related myopathy. In this review, we critically assess the potential mechanisms and therapeutic prospects of intestinal flora in the development of septic myopathy.

[Robotic-assisted mobilization for an effective mobilization in a COVID-19 patient with ECMO treatment]. / Robotik für eine qualitativ hochwertige Mobilisation: Verbesserte Regeneration eines COVID-19-Patienten mit ECMO-Therapie.

An effective (early) mobilization in COVID-19 intensive care patients with ECMO treatment is very important. Sedation, extracorporeal procedures with the danger of circuit malfunction, large lumen ECMO cannulas with a risk of dislocation and a very severe neuromuscular weakness are factors that could deem mobilization beyond stage 1 of the ICU mobility score (IMS) in some cases difficult or impossible; however, early mobilization is a key point of the ABCDEF bundle to counteract pulmonary complications, neuromuscular dysfunction and enable recovery. The case of a 53-year-old, previously healthy and active male patient with a severe and complicated course of COVID-19 and pronounced ICU-acquired weakness is described. While receiving ECMO the patient could be mobilized using a robotic system. Due to severe and rapidly progressing pulmonary fibrosis, additional low-dose methylprednisolone therapy (Meduri protocol) was implemented. Under this multimodal treatment the patient was successfully weaned from the ventilator and decannulated. Robotic assisted mobilization has the potential to be a novel and safe therapeutic option for a customized and highly effective mobilization in ECMO patients.

Development and validation of a nomogram for predicting persistent inflammation, immunosuppression, and catabolism syndrome in trauma patients.

Background: Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PIICS) is a significant contributor to adverse long-term outcomes in severe trauma patients. Objective: The objective of this study was to establish and validate a PIICS predictive model in severe trauma patients, providing a practical tool for early clinical prediction. Patients and methods: Adult severe trauma patients with an Injury Severity Score (ISS) of ≥16, admitted between October 2020 and December 2022, were randomly divided into a training set and a validation set in a 7:3 ratio. Patients were classified into PIICS and non-PIICS groups based on diagnostic criteria. LASSO regression was used to select appropriate variables for constructing the prognostic model. A logistic regression model was developed and presented in the form of a nomogram. The performance of the model was evaluated using calibration and ROC curves. Results: A total of 215 patients were included, consisting of 155 males (72.1%) and 60 females (27.9%), with a median age of 51 years (range: 38-59). NRS2002, ISS, APACHE II, and SOFA scores were selected using LASSO regression to construct the prognostic model. The AUC of the ROC analysis for the predictive model in the validation set was 0.84 (95% CI 0.72-0.95). The Hosmer-Lemeshow test in the validation set yielded a χ2 value of 14.74, with a value of p of 0.098. Conclusion: An accurate and easily implementable PIICS risk prediction model was established. It can enhance risk stratification during hospitalization for severe trauma patients, providing a novel approach for prognostic prediction.