Differential contractile response of critically ill patients to neuromuscular electrical stimulation

BACKGROUND: Neuromuscular electrical stimulation (NMES) has been investigated as a preventative measure for intensive care unit-acquired weakness. Trial results remain contradictory and therefore inconclusive. As it has been shown that NMES does not necessarily lead to a contractile response, our aim was to characterise the response of critically ill patients to NMES and investigate potential outcome benefits of an adequate contractile response. METHODS: This is a sub-analysis of a randomised controlled trial investigating early muscle activating measures together with protocol-based physiotherapy in patients with a SOFA score ≥ 9 within the first 72 h after admission. Included patients received protocol-based physiotherapy twice daily for 20 min and NMES once daily for 20 min, bilaterally on eight muscle groups. Electrical current was increased up to 70 mA or until a contraction was detected visually or on palpation. Muscle strength was measured by a blinded assessor at the first adequate awakening and ICU discharge. RESULTS: One thousand eight hundred twenty-four neuromuscular electrical stimulations in 21 patients starting on day 3.0 (2.0/6.0) after ICU admission were included in this sub-analysis. Contractile response decreased from 64.4% on day 1 to 25.0% on day 7 with a significantly lower response rate in the lower extremities and proximal muscle groups. The electrical current required to elicit a contraction did not change over time (day 1, 50.2 [31.3/58.8] mA; day 7, 45.3 [38.0/57.5] mA). The electrical current necessary for a contractile response was higher in the lower extremities. At the first awakening, patients presented with significant weakness (3.2 [2.5/3.8] MRC score). When dividing the cohort into responders and non-responders (> 50% vs. ≤ 50% contractile response), we observed a significantly higher SOFA score in non-responders. The electrical current necessary for a muscle contraction in responders was significantly lower (38.0 [32.8/42.9] vs. 54.7 [51.3/56.0] mA, p < 0.001). Muscle strength showed higher values in the upper extremities of responders at ICU discharge (4.4 [4.1/4.6] vs. 3.3 [2.8/3.8] MRC score, p = 0.036). CONCLUSION: Patients show a differential contractile response to NMES, which appears to be dependent on the severity of illness and also relevant for potential outcome benefits. TRIAL REGISTRATION: ISRCTN ISRCTN19392591 , registered 17 February 201

Impact of protocol‐based physiotherapy on insulin sensitivity and peripheral glucose metabolism in critically ill patients

Background: The impact of physiotherapy on insulin sensitivity and peripheral glucose metabolism in critically ill patients is not well understood. Methods: This pooled analysis investigates the impact of different physiotherapeutic strategies on insulin sensitivity in critically ill patients. We pooled data from two previous trials in adult patients with sequential organ failure assessment score (SOFA)>= 9 within 72 h of intensive care unit (ICU) admission, who received hyperinsulinaemic euglycaemic (HE) clamps. Patients were divided into three groups: standard physiotherapy (sPT, n = 22), protocol-based physiotherapy (pPT, n = 8), and pPT with added muscle activating measures (pPT+, n = 20). Insulin sensitivity index (ISI) was determined by HE clamp. Muscle metabolites lactate, pyruvate, and glycerol were measured in the M. vastus lateralis via microdialysis during the HE clamp. Histochemical visualization of glucose transporter-4 (GLUT4) translocation was performed in surgically extracted muscle biopsies. All data are reported as median (25th/75th percentile) (trial registry: ISRCTN77569430 and ISRCTN19392591/ethics approval: Charite-EA2/061/06 and Charite-EA2/041/10). Results Fifty critically ill patients (admission SOFA 13) showed markedly decreased ISIs on Day 17 (interquartile range) 0.029 (0.022/0.048) (mg/min/kg)/(mU/L) compared with healthy controls 0.103 (0.087/0.111), P < 0.001. ISI correlated with muscle strength measured by medical research council (MRC) score at first awakening (r = 0.383, P = 0.026) and at ICU discharge (r = 0.503, P = 0.002). Different physiotherapeutic strategies showed no effect on the ISI [sPT 0.029 (0.019/0.053) (mg/min/kg)/(mU/L) vs. pPT 0.026 (0.023/0.041) (mg/min/kg)/(mU/L) vs. pPT+ 0.029 (0.023/0.042) (mg/min/kg)/(mU/L); P = 0.919]. Regardless of the physiotherapeutic strategy metabolic flexibility was reduced. Relative change of lactate/pyruvate ratio during HE clamp is as follows: sPT 0.09 (-0.13/0.27) vs. pPT 0.07 (-0.16/0.31) vs. pPT+ -0.06 (-0.19/0.16), P = 0.729, and relative change of glycerol concentration: sPT -0.39 (-0.8/-0.12) vs. pPT -0.21 (-0.33/0.07) vs. pPT+ -0.21 (-0.44/-0.03), P = 0.257. The majority of ICU patients showed abnormal localization of GLUT4 with membranous GLUT4 distribution in 37.5% (3 of 8) of ICU patients receiving sPT, in 42.9% (3 of 7) of ICU patients receiving pPT, and in 53.8% (7 of 13) of ICU patients receiving pPT+ (no statistical testing possible). Conclusions: Our data suggest that a higher duration of muscle activating measures had no impact on insulin sensitivity or metabolic flexibility in critically ill patients with sepsis-related multiple organ failure

Association between potassium concentrations, variability and supplementation, and in‑hospital mortality in ICU patients: a retrospective analysis

BACKGROUND: Serum potassium concentrations are commonly between 3.5 and 5.0 mmol/l. Standardised protocols for potassium range and supplementation in the ICU are lacking. The purpose of this retrospective analysis of ICU patients was to investigate potassium concentrations, variability and supplementation, and their association with in-hospital mortality. METHODS: ICU patients ≥ 18 years, with ≥ 2 serum potassium values, treated at the Charité - Universitätsmedizin Berlin between 2006 and 2018 were eligible for inclusion. We categorised into groups of mean potassium concentrations:  3.5-4.0, > 4.0-4.5, > 4.5-5.0, > 5.0-5.5, > 5.5 mmol/l and potassium variability: 1st, 2nd and ≥ 3rd standard deviation (SD). We analysed the association between the particular groups and in-hospital mortality and performed binary logistic regression analysis. Survival curves were performed according to Kaplan-Meier and tested by Log-Rank. In a subanalysis, the association between potassium supplementation and in-hospital mortality was investigated. RESULTS: In 53,248 ICU patients with 1,337,742 potassium values, the lowest mortality (3.7%) was observed in patients with mean potassium concentrations between > 3.5 and 4.0 mmol/l and a low potassium variability within the 1st SD. Binary logistic regression confirmed these results. In a subanalysis of 22,406 ICU patients (ICU admission: 2013-2018), 12,892 (57.5%) received oral and/or intravenous potassium supplementation. Potassium supplementation was associated with an increase in in-hospital mortality in potassium categories from > 3.5 to 4.5 mmol/l and in the 1st, 2nd and ≥ 3rd SD (p < 0.001 each). CONCLUSIONS: ICU patients may benefit from a target range between 3.5 and 4.0 mmol/l and a minimal potassium variability. Clear potassium target ranges have to be determined. Criteria for widely applied potassium supplementation should be critically discussed. Trial registration German Clinical Trials Register, DRKS00016411. Retrospectively registered 11 January 2019, http://www.drks.de/DRKS00016411

Mobilisation of critically ill patients receiving norepinephrine: a retrospective cohort study

Background: Mobilisation and exercise intervention in general are safe and feasible in critically ill patients. For patients requiring catecholamines, however, doses of norepinephrine safe for mobilisation in the intensive care unit (ICU) are not defined. This study aimed to describe mobilisation practice in our hospital and identify doses of norepinephrine that allowed a safe mobilisation. Methods: We conducted a retrospective single-centre cohort study of 16 ICUs at a university hospital in Germany with patients admitted between March 2018 and November 2021. Data were collected from our patient data management system. We analysed the effect of norepinephrine on level (ICU Mobility Scale) and frequency (units per day) of mobilisation, early mobilisation (within 72 h of ICU admission), mortality, and rate of adverse events. Data were extracted from free-text mobilisation entries using supervised machine learning (support vector machine). Statistical analyses were done using (generalised) linear (mixed-effect) models, as well as chi-square tests and ANOVAs. Results: A total of 12,462 patients were analysed in this study. They received a total of 59,415 mobilisation units. Of these patients, 842 (6.8%) received mobilisation under continuous norepinephrine administration. Norepinephrine administration was negatively associated with the frequency of mobilisation (adjusted difference -0.07 mobilisations per day; 95% CI - 0.09, - 0.05; p 0.1). Higher compared to lower doses of norepinephrine did not lead to a significant increase in adverse events in our practice (p > 0.1). We identified that mobilisation was safe with up to 0.20 mu g/kg/min norepinephrine for out-of-bed (IMS >= 2) and 0.33 mu g/kg/min for in-bed (IMS 0-1) mobilisation. Conclusions: Mobilisation with norepinephrine can be done safely when considering the status of the patient and safety guidelines. We demonstrated that safe mobilisation was possible with norepinephrine doses up to 0.20 mu g/kg/min for out-of-bed (IMS >= 2) and 0.33 mu g/kg/min for in-bed (IMS 0-1) mobilisation

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

The Functional Trajectory in Frail Compared With Non-frail Critically Ill Patients During the Hospital Stay

Background: Long-term outcome is determined not only by the acute critical illness but increasingly by the reduced functional reserve of pre-existing frailty. The patients with frailty currently account for one-third of the critically ill, resulting in higher mortality. There is evidence of how frailty affects the intrahospital functional trajectory of critically ill patients since prehospital status is often missing. Methods: In this prospective single-center cohort study at two interdisciplinary intensive care units (ICUs) at a university hospital in Germany, the frailty was assessed using the Clinical Frailty Scale (CFS) in the adult patients with critical illness with an ICU stay >24 h. The functional status was assessed using the sum of the subdomains "Mobility" and "Transfer" of the Barthel Index (MTB) at three time points (pre-hospital, ICU discharge, and hospital discharge). Results: We included 1,172 patients with a median age of 75 years, of which 290 patients (25%) were frail. In a propensity score-matched cohort, the probability of MTB deterioration till hospital discharge did not differ in the patients with frailty (odds ratio (OR) 1.3 [95% CI 0.8-1.9], p = 0.301), confirmed in several sensitivity analyses in all the patients and survivors only. Conclusion: The patients with frailty have a reduced functional status. Their intrahospital functional trajectory, however, was not worse than those in non-frail patients, suggesting a rehabilitation potential of function in critically ill patients with frailty

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Der Effekt protokollbasierter Physiotherapie auf molekulare Mechanismen von Muskelatrophie bei Patienten mit intensivstationserworbener Schwäche in kritisch kranken Patienten

Background: Up to 50% of critically ill patients develop a severe muscle weakness during their intensive care treatment which leads to increased mortality and morbidity. Characteristic for this intensive care unit acquired weakness is a rapidly progressing muscle atrophy, which is the results of a decrease muscle protein synthesis as well as an increased muscle protein degradation. Our aim was to investigate the effect of therapeutic and preventatives interventions such as protocol-based physiotherapy and muscle activating measures on molecular mechanisms leading muscle atrophy during intensive care unit acquired weakness are unknown. Methods: 50 patients with a Sepsis-related Organ Failure Assessment ≥ 9 within the first 72 hours after admission to one of two ICUs within the Charité – Universitätsmedizin Berlin were randomised to receive either protocol-based physiotherapy alone (control) or protocol-based physiotherapy with additional muscle activating measures, such as neuromuscular electrical stimulation or whole body vibration (intervention). 15 days after admission to the ICU an open surgical muscle biopsy of the m. vastus lateralis was performed to assess the effect of protocol-based physiotherapy and muscle activating measures on muscle protein synthesis and degradation via real-time PCR and Western Blot. Patients receiving common physiotherapeutic practice from an earlier observational trial fulfilling the same inclusion criteria were included as a comparison group. Healthy patients undergoing elective orthopaedic surgery were similarly included for reference values. Ethical approval was granted by the institutional review borad (Charité EA 2/041/10). Results: Patients in the intervention group presented significantly increased mRNA expression values for MYH1, MYH2 and MYH4 in comparison to baseline values as well as for MYH1 and MYH4 in comparison to the common physiotherapeutic practice group. Relative mRNA expression for FBXO32 and TRIM62 as key components of the ubiquitine-proteasome system were increased above baseline values for all groups of critically ill patients. While TRIM63 mRNA expression was increased above baseline values and common physiotherapeutic practice for both the intervention and control group. The increase in myosin heavy chain mRNA expression is accompanied by a significantly increased protein content for total, slow and fast myosin in the intervention group as opposed to the common physiotherapeutic practice group. Protein content for Atrogin-1 and MuRF-1 was higher in the control and intervention groups in comparison to baseline values and values from the common physiotherapeutic practice group. Conclusion: Protocol-based physiotherapy and muscle activating measures increase myosin gene expression as well as protein content and do not suppress the ubiquitine-proteasome system.Kritisch kranke Patienten entwickeln regelhaft während der Therapie auf der Intensivstation eine ausgeprägte Muskelschwäche, welche zum einen mit einer erhöhten Mortalität und Morbidität, sowohl kurz- als auch langfristig, sowie zum anderen auch mit einer schnell fortschreitenden Muskelatrophie einhergeht. Die Muskelatrophie zeichnet sich durch eine Reduktion der Myosinsynthese und eine Induktion der Proteindegradation aus. Wir haben in dieser Arbeit untersucht, welchen Effekt therapeutische Ansätze, wie Protokoll-basierte Physiotherapie und Muskel aktivierende Maßnahmen auf die molekularen Mechanismen der Muskelatrophie bei der auf der Intensivstation erworbenen Muskelschwäche haben. Methodik: 50 Patienten mit einem Sepsis-related Organ Failure Assessment Score ≥ 9 innerhalb der ersten 72 Stunden nach Aufnahme auf eine von zwei Intensivstationen der Charité – Universitätsmedizin Berlin wurden randomisiert Protokoll-basierte Physiotherapie alleine (Kontrollen) oder in Kombination mit frühen Muskel aktivierenden Maßnahmen (Intervention), wie neuromuskuläre Elektrostimulation oder Ganzkörpervibrationstherapie, zu erhalten. Am fünfzehnten Liegetag wurde eine offen-chirurgische Muskelbiopsie am M. vastus lateralis vorgenommen, um den Effekt der Protokoll-basierten Physiotherapie mit und ohne Muskel aktivierende Maßnahmen auf die Proteinsynthese und -degradation mittels quantitativer Echtzeit-Polymerase-Kettenreaktion und Western Blot zu untersuchen. Patienten aus einer vorangehenden Observationsstudie, welche Standardphysiotherapie erhalten haben und alle Einschlusskriterien erfüllten, wurden als Vergleichsgruppe mit einbezogen. Muskelbiopsien, welche gesunden Patienten im Rahmen einer elektiven orthopädischen Operation entnommen wurden, wurden für Referenzwerte mit eingeschlossen. Das Ethikvotum wurde von der Ethikkommission der Charité – Universitätsmedizin Berlin eingeholt (Charité EA 2/041/10). Ergebnisse: Patienten in der Interventionsgruppe zeigten eine signifikant erhöhte mRNA-Expression für MYH1, MYH2 und MYH4 im Vergleich zu Referenzwerten sowie für MYH1 und MYH4 im Vergleich zur Standardphysiotherapie. Die relative mRNA-Expression für FBXO32 und TRIM62, als Schlüsselkomponenten des Ubiquitin-Proteasom-Systems, waren über Referenzwerte für alle Gruppen von kritisch kranken Patienten erhöht. Im Gegensatz dazu war die TRIM63 mRNA-Expression in der Interventions- und Kontrollgruppe gegenüber der Standardphysiotherapiegruppe sowie gegenüber den Referenzwerten erhöht. Der Anstieg der Myosingenexpression spiegelt sich auch auf Proteinebene in einem signifikant erhöhten Myosinproteingehalt für gesamtes, langsames und schnelles Myosin in der Interventionsgruppe im Vergleich zur Standardphysiotherapiegruppe wieder. Der Proteingehalt für Atrogin-1 und MuRF-1 war sowohl in der Interventions- als auch in der Kontrollgruppe oberhalb der Referenzwerte und der Werte der Standardphysiotherapiegruppe. Schlussfolgerung: Protokoll-basierte Physiotherapie und additive Muskel aktivierende Maßnahmen erhöhen die Myosingenexpression sowie den Proteingehalt, ohne das Ubiquitin-Proteasom-System zu hemmen