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

Risk Factors of Intraoperative Dysglycemia in Elderly Surgical Patients

BACKGROUNDː Dysglycemia is associated with adverse outcome including increased morbidity and mortality in surgical patients. Acute insulin resistance due to the surgical stress response is seen as a major cause of so-called stress hyperglycemia. However, understanding of factors determining blood glucose (BG) during surgery is limited. Therefore, we investigated risk factors contributing to intraoperative dysglycemia. METHODSː In this subgroup investigation of the BIOCOG study, we analyzed 87 patients of ≥ 65 years with tight intraoperative BG measurement every 20 min during elective surgery. Dysglycemia was defined as at least one intraoperative BG measurement outside the recommended target range of 80-150 mg/dL. Additionally, all postoperative BG measurements in the ICU were obtained. Multivariable logistic regression analysis adjusted for age, sex, American Society of Anesthesiologists (ASA) status, diabetes, type and duration of surgery, minimum Hemoglobin (Hb) and mean intraoperative norepinephrine use was performed to identify risk factors of intraoperative dysglycemia. RESULTSː 46 (52.9%) out of 87 patients developed intraoperative dysglycemia. 31.8% of all intraoperative BG measurements were detected outside the target range. Diabetes [OR 9.263 (95% CI 2.492, 34.433); p=0.001] and duration of surgery [OR 1.005 (1.000, 1.010); p=0.036] were independently associated with the development of intraoperative dysglycemia. Patients who experienced intraoperative dysglycemia had significantly elevated postoperative mean (p<0.001) and maximum BG levels (p=0.001). Length of ICU (p=0.007) as well as hospital stay (p=0.012) were longer in patients with dysglycemia. CONCLUSIONSː Diabetes and duration of surgery were confirmed as independent risk factors for intraoperative dysglycemia, which was associated with adverse outcome. These patients, therefore, might require intensified glycemic control. Increased awareness and management of intraoperative dysglycemia is warranted

a prospective clinical trial

Background Continuous glucose monitoring (CGM) has not yet been implemented in the intensive care unit (ICU) setting. The purpose of this study was to evaluate reliability, feasibility, nurse acceptance and accuracy of the Medtronic Sentrino® CGM system in critically ill patients. Methods Sensors were inserted into the subcutaneous tissue of the patient’s thigh, quantifying interstitial glucose concentration for up to 72 h per sensor. Reliability and feasibility analysis included frequency of data display, data gaps and reasons for sensor removal. We surveyed nurse acceptance in a questionnaire. For the accuracy analysis, we compared sensor values to glucose values obtained via blood gas analysis. Potential benefits of CGM were investigated in intra- individual analyses of factors, such as glycemic variability or time in target range achieved with CGM compared to that achieved with intermittent glucose monitoring. Results The device generated 68,655 real-time values from 31 sensors in 20 critically ill patients. 532 comparative blood glucose values were collected. Data were displayed during 32.5 h [16.0/62.4] per sensor, which is 45.1 % of the expected time of 72 h and 84.8 % of 37.9 h actual monitoring time. 21 out of 31 sensors were removed prematurely. 79.1 % of the nursing staff rated the device as not beneficial; the response rate was one- third. Mean absolute relative difference was 15.3 % (CI 13.5–17.0 %). Clarke error grid: 76.9 % zone A, 21.6 % zone B, 0.2 % zone C, 0.9 % zone D, 0.4 % zone E. Bland–Altman plot: mean bias +0.53 mg/dl, limits of agreement +64.6 and −63.5 mg/dl. Accuracy deteriorated during elevated glycemic variability and in the hyperglycemic range. There was no reduction in dysglycemic events during CGM compared to 72 h before and after CGM. If CGM was measuring accurately, it identified more hyperglycemic events when compared to intermittent measurements. This study was not designed to evaluate potential benefits of CGM on glucose control. Conclusions The subcutaneous CGM system did not perform with satisfactory accuracy, feasibility, or nursing acceptance when evaluated in 20 medical-surgical ICU patients. Low point accuracy and prolonged data gaps significantly limited the potential clinical usefulness of the CGM trend data. Accurate continuous data display, with a MARD < 14 %, showed potential benefits in a subgroup of our patients. Trial registration NCT02296372; Ethic vote Charité EA2/095/1

safety, feasibility, and metabolic response

Background Intensive care unit (ICU)-acquired weakness in critically ill patients is a common and significant complication affecting the course of critical illness. Whole-body vibration is known to be effective muscle training and may be an option in diminishing weakness and muscle wasting. Especially, patients who are immobilized and not available for active physiotherapy may benefit. Until now whole-body vibration was not investigated in mechanically ventilated ICU patients. We investigated the safety, feasibility, and metabolic response of whole-body vibration in critically ill patients. Methods We investigated 19 mechanically ventilated, immobilized ICU patients. Passive range of motion was performed prior to whole-body vibration therapy held in the supine position for 15 minutes. Continuous monitoring of vital signs, hemodynamics, and energy metabolism, as well as intermittent blood sampling, took place from the start of baseline measurements up to 1 hour post intervention. We performed comparative longitudinal analysis of the phases before, during, and after intervention. Results Vital signs and hemodynamic parameters remained stable with only minor changes resulting from the intervention. No application had to be interrupted. We did not observe any adverse event. Whole-body vibration did not significantly and/or clinically change vital signs and hemodynamics. A significant increase in energy expenditure during whole-body vibration could be observed. Conclusions In our study the application of whole-body vibration was safe and feasible. The technique leads to increased energy expenditure. This may offer the chance to treat patients in the ICU with whole-body vibration. Further investigations should focus on the efficacy of whole-body vibration in the prevention of ICU- acquired weakness. Trial registration Applicability and Safety of Vibration Therapy in Intensive Care Unit (ICU) Patients. ClinicalTrials.gov NCT01286610. Registered 28 January 2011

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

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

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

Neuromuskuläres Organversagen auf der Intensivstation und perioperativ

Hintergrund und Zielsetzung dieser kummulativen Habiliationsschrift: Seit 2010 beschäftige ich mich mit dem Themengebiet der erworbenen Muskelschwäche. Meinen wissenschaftlichen Arbeiten liegen klinische Observations und Interventionsstudien zu Grunde, die sich klinisch und molekular mit der Entstehung eines erworbenen muskulären Organversagens beschäftigen. In den letzten Jahren stehen die Untersuchungen von Interventionsmöglichkeiten als mögliche Therapieoptionen und Präventionsstrategien im Fokus meiner Arbeit. Die in dieser Schrift eingebrachten wissenschaftlichen Originalarbeiten untersuchen die Anwendbarkeit und Wirksamkeit von Physiotherapie und erweiterten physiotherapeutischen Verfahren als Präventionsoption zur Vermeidung oder zumindest Reduktion der Ausprägung einer erworbenen Muskelschwäche auf dem Hintergrund pathophysiologischer Observationsstudien. Eigene und andere Arbeiten der letzten Jahre haben den sehr frühen Beginn eines neuromuskulären Organverfahrens gezeigt und widersprechen dem ursprünglich angenommen Erleiden einer Muskelschwäche erst bei mehrwöchigem Aufenthalt auf der Intensivstation. Mittlerweile sind Mechanismen bekannt, die innerhalb von Tagen, wenn nicht sogar Stunden, den übermäßigen Muskelabbaus initiieren. Gerade deshalb kann Prävention nur möglich sein, wenn Interventionen zügig nach Aufnahme auf die Intensivstation beginnen. Um dem Beginn einer muskulären Schwäche noch näher zu kommen haben wir erstmalig auch elektiv operative Patienten untersucht, um die Auswirkungen des perioperativen Ablaufs auf die Muskulatur zu beobachtet. Hier konnten wir erstmalig das Auftreten einer erworbenen Muskelschwäche im unmittelbaren perioperativen Verlauf sogar ganz ohne intensivmedizinische Behandlung zeigen

Intensive care unit acquired weakness is characterized by early and rapid myosin loss

Hintergrund: Intensivpatienten erleiden häufig einen massiven Muskelschwund. Dieser ist mit auf der Intensivstation erworbener Muskelschwäche (Intensive Care Unit Acquired Weakness (ICUAW)) assoziiert und stellt eine schwerwiegende, intensivmedizinische Komorbidität dar, welche den Krankheitsverlauf negativ beeinflusst. Die Inzidenz wird zwischen 25% bei beatmeten Intensivpatienten und mehr als 70% bei Patienten mit schwerer Sepsis angegeben. Das klinische Symptom Muskelschwäche wird erst im Verlauf der kritischen Erkrankung gegenwärtig, wenn betroffene Patienten aus der Analgosedierung erwachen. Wann es jedoch zum eigentlichen Verlust des kontraktilen Muskelproteins Myosin kommt und welchen zeitlichen Verlauf der Abbau nimmt, wurde bisher nicht untersucht. Zielsetzung: Wir untersuchten zweizeitig Veränderungen des Myosingehaltes des schnellen und langsamen Subtyps im Skelettmuskel während des intensiv-medizinischen Krankheitsverlaufes und verglichen diesen mit gesunden Kontrollen. Methode: Kontrollierte, prospektive Beobachtungsstudie. Wir schlossen 29 beatmete Intensivpatienten mit einem SOFA score ≥ 8 an mindestens 3 von 5 Tagen nach Aufnahme auf die Intensivstation ein. Offen chirurgische Muskelbiopsien (M. vastus lateralis) wurden an median Tag 5 (4/7) und 15 (14/19) des intensivmedizinischen Aufenthaltes, sowie einmalig von gesunden Kontrollen (n=4), während einer elektiven Operation entnommen. Es erfolgte die Quantifizierung des skelettmuskelfaserspezifischen Myosingehaltes des schnellen (MyHC-fast) und langsamen (MyHC-slow) Subtyps im Western Blot. Am ersten Tag des adäquaten Erwachens - falls geschehen - erhoben wir den Kraftgrad mittels Medical-Research-Council (MRC) score. Zur statistischen Auswertung wurden nicht-parametrische Tests durchgeführt. Ethikvotum (Charite EA2/061/06). Ergebnis: Von den 29 Patienten konnten wir bei 22 Patienten eine zweizeitige Biopsie gewinnen, von 7 Patienten nur eine Biopsie, bevor sie die Station verließen oder verstarben. 16 der 22 Patienten wurden während des Aufenthaltes auf der Intensivstation am Tag 14 (12/20) adäquat wach und zeigten einen Kraftgrad von 3,1(2,9/3,4) und erfüllten damit die Kriterien der ICUAW. Die Quantifizierung im Western Blot ergab schon in der ersten frühen Biopsie, verglichen zu gesunden Kontrollen, einen signifikanten Myosinverlust von ca. 50% des langsamen (MyHC-slow) und ca. 90% des schnellen (MyHC-fast) Subtyps. Des Weiteren zeigte sich kein signifikanter Unterschied des Myosingehaltes zwischen der ersten und zweiten Biopsie der Intensivpatienten. Tabelle 1: Densometrische Messung. Der Mittelwert der Kontrollen entspricht = 1,0 Erste Biopsie Zweite Biopsie Kontrollen p (a) p (b) p (c) MyHC-slow 0,53(0,25/0,83) 0,37(0,13/0,92) 1,01(0,98/1,02) 0,026 0,009 n.s. MyHC-fast 0,10(0,08/0,13) 0,08(0,04/0,13) 1,03(0,96/1,04) <0,001 <0,001 n.s. Ergebnisse dargestellt als Median(25./75. Perzentile). n.s. = nicht signifikant p(a)=1.Biopsien vs. Kontrollen, p(b)=2.Biopsien vs. Kontrollen, p(c)=1. vs. 2.Biopsien Schlussfolgerung: Eine sehr frühe und massive Abnahme des Myosingehaltes, besonders der schnellen Muskelfasern, charakterisiert die auf der Intensivstation erworbene Muskelschwäche. Dieser rapide Myosinverlust, ohne weitere Veränderungen des geringen Gehaltes zwischen erster und zweiter Biopsie, konzentriert das Zeitfenster der pathophysiologischen Mechanismen der ICUAW auf Tage, wenn nicht sogar Stunden nach Auftreten der kritischen Erkrankung. Dies macht im Besonderen klar, dass, wenn es eine Präventionsmöglichkeit gibt, diese Maßnahmen dementsprechend früh beginnen müssen.Introduction: Often critically ill patient suffer muscle wasting which is associated with intensive care unit (ICU) acquired weakness (ICUAW). This is a serious complication in critically ill patients affecting the disease course. The incidence is given as 25% for mechanically ventilated patients and up to 70% for patients with severe sepsis. Weakness becomes clinically present when patients awake from sedation. The beginning and the time course of myosin loss have not been investigated yet. Objectives: To investigate changes in myosin content in skeletal muscle for slow and fast type myosin during the disease course of critically ill patients and to compare with healthy controls. Methods: Controlled, prospective observational study. We included 29 mechanically ventilated, critically ill patients with a SOFA score ≥ 8 at 3 within 5 days after ICU admission. A surgical muscle biopsy (M. vastus lateralis) was obtained at median day 5 (4/7) and 15 (14/19) during ICU stay and once from healthy controls (n=4) during an elective surgery. We quantified skeletal muscle specific myosin content of fast (MyHC-fast) and slow type (MyHC-slow) by Western blotting. On the first day patients got adequately awake we investigated muscle strength by Medical-Research-Council (MRC) score. Non-parametric tests were performed. Ethic vote (Charité EA2/061/06). Results: We got sequential muscle biopsies of 22 out of our 29 patients while 7 left the ICU or died before the second biopsy. 16 out of the 22 patients got adequately awake for the first time during ICU stay at median day 14(12/20) and revealed ICU-acquired weakness with a median MRC-score of 3.1(2.9/3.4). The quantification of the western blot showed a significant decrease of myosin content of approximately 50% for slow (MyHC-slow) and approximately 90% for fast (MyHC-fast) myosin already in the first, early biopsy in critically ill patients compared to healthy controls. Furthermore between the first and the second biopsy myosin contents did not change significantly any more. Table 1: Densometric Analysis. Values of controls are set to 1.0 first biopsy second biopsy controls p (a) p (b) p (c) MyHC-slow 0.53(0.25/0.83) 0.37(0.13/0.92) 1.01(0.98/1.02) 0.026 0.009 n.s. MyHC-fast 0.10(0.08/0.13) 0.08(0.04/0.13) 1.03(0.96/1.04) <0.001 <0.001 n.s. Results shown as median (25th/75th percentile). n.s. = not significant p(a)=1st biopsy vs. controls, p(b)= 2nd biopsy vs. controls, p(c)=1st vs. 2nd biopsy Conclusion: A very early and massive myosin loss, especially of the fast type myosin, characterizes ICUAW. Rapid myosin loss and unchanged low levels of myosin between the first and the second biopsies concentrates the time course of important pathophysiological mechanisms of ICUAW within days or even hours after onset of critical illness. These results demonstrate that if there are preventive interventions, they have to start accordingly early