ß-hydroxybutyrate exposure restores mitochondrial function in skeletal muscle satellite cells of critically ill patients.

BACKGROUND & AIM: Dysfunction of skeletal muscle satellite cells might impair muscle regeneration and prolong ICU-acquired weakness, a condition associated with disability and delayed death. This study aimed to elucidate the distinct metabolic effects of critical illness and ß-OH-butyrate on satellite cells isolated from these patients. METHODS: Satellite cells were extracted from vastus lateralis muscle biopsies of patients with ICU-acquired weakness (n = 10) and control group of healthy volunteers or patients undergoing elective hip replacement surgery (n = 10). The cells were exposed to standard culture media supplemented with ß-OH-butyrate to assess its influence on cell proliferation by ELISA, mitochondrial functions by extracellular flux analysis, electron transport chain complexes by high resolution respirometry, and ROS production by confocal microscopy. RESULTS: Critical illness led to a decline in maximal respiratory capacity, ATP production and glycolytic capacity and increased ROS production in ICU patients' cells. Notably, the function of complex II was impaired due to critical illness but restored to normal levels upon exposure to ß-OH-butyrate. While ß-OH-butyrate significantly reduced ROS production in both control and ICU groups, it had no significant impact on global mitochondrial functions. CONCLUSION: Critical illness induces measurable bioenergetic dysfunction of skeletal muscle satellite cells. ß-OH-butyrate displayed a potential in rectifying complex II dysfunction caused by critical illness and this warrants further exploration.

Assessment of Faecal Microbiota Transplant Stability in Deep-Freeze Conditions: A 12-Month Ex Vivo Viability Analysis.

BACKGROUND: Faecal microbiota transplantation (FMT) is an established treatment for Clostridioides difficile infection and is under investigation for other conditions. The availability of suitable donors and the logistics of fresh stool preparation present challenges, making frozen, biobanked stools an attractive alternative. AIMS: This study aimed to evaluate the long-term viability of bacterial populations in faecal samples stored at -80°C for up to 12 months, supporting the feasibility of using frozen grafts for FMT. METHODS: Fifteen faecal samples from nine healthy donors were processed, mixed with cryoprotectants and stored at -80°C. Samples were assessed at baseline and after 3, 6 and 12 months using quantitative culturing methods to determine the concentration of live bacteria. RESULTS: Quantitative analysis showed no significant decrease in bacterial viability over the 12-month period for both aerobic and anaerobic cultures (p = 0.09). At all timepoints, the coefficients of variability in colony-forming unit (CFU) counts were greater between samples (102 ± 21% and 100 ± 13% for aerobic and anaerobic cultures, respectively) than the variability between measurements of the same sample (30 ± 22% and 30 ± 19%). CONCLUSIONS: The study confirmed that faecal microbiota can be preserved with high viability in deep-freeze storage for up to a year, making allogenic FMT from biobanked samples a viable and safer option for patients. However, a multidonor approach may be beneficial to mitigate the risk of viability loss in any single donor sample.

Should New Data on Rehabilitation Interventions in Critically Ill Patients Change Clinical Practice? Updated Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: We published a meta-analysis in March 2020 to assess the impact of rehabilitation in the ICU on clinical outcomes. Since then, 15 new randomized controlled trials (RCTs) have been published; we updated the meta-analysis to show how the recent studies have tipped the scale. DESIGN: Systematic review and meta-analysis. SETTING: An update of secondary data analysis of RCTs published between January 1998 and July 2023 performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PATIENTS: Critically ill adults. INTERVENTIONS: Cycling exercises or neuromuscular electrical stimulation (NMES) or protocolized physical rehabilitation (PPR) or functional electrical stimulation-assisted cycle ergometry (FESCE) compared with standard of care. MEASUREMENTS AND MAIN RESULTS: Days on a mechanical ventilator, length of stay in ICU and at the hospital, and mortality. We found 15 RCTs (one on cycling, eight on NMES alone, four on PPR, and two on FESCE) into which 2116 patients were randomized. The updated meta-analysis encompasses a total of 5664 patients. The exercise interventions did not influence mortality (odds ratio, 1.00 [0.87-1.14]; n = 53 RCTs) but reduced the duration of mechanical ventilation (mean difference, -1.76 d [-2.8 to -0.8 d]; n = 46) and length of stay in ICU (-1.16 d [-2.3 to 0.0 d]; n = 45). The effects on the length of mechanical ventilation and ICU stay were only significant for the PPR subgroup by a median of -1.7 days (95% CI, -3.2 to -0.2 d) and -1.9 days (95% CI, -3.5 to -0.2 d), respectively. Notably, newly published trials provided consistent results and reduced the overall heterogeneity of these results. CONCLUSIONS: None of the rehabilitation intervention strategies being studied influence mortality. Both mechanical ventilation and ICU stay were shortened by PPR, this strengthens the earlier findings as all new RCTs yielded very consistent results. However, no early rehabilitation interventions in passive patients seem to have clinical benefits. Regarding long-term functional outcomes, the results remain inconclusive.

Quantifying pH-induced changes in plasma strong ion difference during experimental acidosis: clinical implications for base excess interpretation.

It is commonly assumed that changes in plasma strong ion difference (SID) result in equal changes in whole blood base excess (BE). However, at varying pH, albumin ionic-binding and transerythrocyte shifts alter the SID of plasma without affecting that of whole blood (SIDwb), i.e., the BE. We hypothesize that, during acidosis, 1) an expected plasma SID (SIDexp) reflecting electrolytes redistribution can be predicted from albumin and hemoglobin's charges, and 2) only deviations in SID from SIDexp reflect changes in SIDwb, and therefore, BE. We equilibrated whole blood of 18 healthy subjects (albumin = 4.8 ± 0.2 g/dL, hemoglobin = 14.2 ± 0.9 g/dL), 18 septic patients with hypoalbuminemia and anemia (albumin = 3.1 ± 0.5 g/dL, hemoglobin = 10.4 ± 0.8 g/dL), and 10 healthy subjects after in vitro-induced isolated anemia (albumin = 5.0 ± 0.2 g/dL, hemoglobin = 7.0 ± 0.9 g/dL) with varying CO2 concentrations (2-20%). Plasma SID increased by 12.7 ± 2.1, 9.3 ± 1.7, and 7.8 ± 1.6 mEq/L, respectively (P < 0.01) and its agreement (bias[limits of agreement]) with SIDexp was strong: 0.5[-1.9; 2.8], 0.9[-0.9; 2.6], and 0.3[-1.4; 2.1] mEq/L, respectively. Separately, we added 7.5 or 15 mEq/L of lactic or hydrochloric acid to whole blood of 10 healthy subjects obtaining BE of -6.6 ± 1.7, -13.4 ± 2.2, -6.8 ± 1.8, and -13.6 ± 2.1 mEq/L, respectively. The agreement between ΔBE and ΔSID was weak (2.6[-1.1; 6.3] mEq/L), worsening with varying CO2 (2-20%): 6.3[-2.7; 15.2] mEq/L. Conversely, ΔSIDwb (the deviation of SID from SIDexp) agreed strongly with ΔBE at both constant and varying CO2: -0.1[-2.0; 1.7], and -0.5[-2.4; 1.5] mEq/L, respectively. We conclude that BE reflects only changes in plasma SID that are not expected from electrolytes redistribution, the latter being predictable from albumin and hemoglobin's charges.NEW & NOTEWORTHY This paper challenges the assumed equivalence between changes in plasma strong ion difference (SID) and whole blood base excess (BE) during in vitro acidosis. We highlight that redistribution of strong ions, in the form of albumin ionic-binding and transerythrocyte shifts, alters SID without affecting BE. We demonstrate that these expected SID alterations are predictable from albumin and hemoglobin's charges, or from the noncarbonic whole blood buffer value, allowing a better interpretation of SID and BE during in vitro acidosis.

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).

Amiodarone but not propafenone impairs bioenergetics and autophagy of human myocardial cells.

Cardiac and extra-cardiac side effects of common antiarrhythmic agents might be related to drug-induced mitochondrial dysfunction. Supratherapeutic doses of amiodarone have been shown to impair mitochondria in animal studies, whilst influence of propafenone on cellular bioenergetics is unknown. We aimed to assess effects of protracted exposure to pharmacologically relevant doses of amiodarone and propafenone on cellular bioenergetics and mitochondrial biology of human and mouse cardiomyocytes. In this study, HL-1 mouse atrial cardiomyocytes and primary human cardiomyocytes derived from the ventricles of the adult heart were exposed to 2 and 7 µg/mL of either amiodarone or propafenone. After 24 h, extracellular flux analysis and confocal laser scanning microscopy were used to measure mitochondrial functions. Autophagy was assessed by western blots and live-cell imaging of lysosomes. In human cardiomyocytes, amiodarone significantly reduced mitochondrial membrane potential and ATP production, in association with an inhibition of fatty acid oxidation and impaired complex I- and II-linked respiration in the electron transport chain. Expectedly, this led to increased anaerobic glycolysis. Amiodarone increased the production of reactive oxygen species and autophagy was also markedly affected. In contrast, propafenone-exposed cardiomyocytes did not exert any impairment of cellular bioenergetics. Similar changes after amiodarone treatment were observed during identical experiments performed on HL-1 mouse cardiomyocytes, suggesting a comparable pharmacodynamics of amiodarone among mammalian species. In conclusion, amiodarone but not propafenone in near-therapeutic concentrations causes a pattern of mitochondrial dysfunction with affected autophagy and metabolic switch from oxidative metabolism to anaerobic glycolysis in human cardiomyocytes.

Propafenone versus amiodarone for supraventricular arrhythmias in septic shock: a randomised controlled trial.

PURPOSE: Acute onset supraventricular arrhythmias can contribute to haemodynamic compromise in septic shock. Both amiodarone and propafenone are available interventions, but their clinical effects have not yet been directly compared. METHODS: In this two-centre, prospective controlled parallel group double blind trial we recruited 209 septic shock patients with new-onset arrhythmia and a left ventricular ejection fraction above 35%. The patients were randomised in a 1:1 ratio to receive either intravenous propafenone (70 mg bolus followed by 400-840 mg/24 h) or amiodarone (300 mg bolus followed by 600-1800 mg/24 h). The primary outcomes were the proportion of patients who had sinus rhythm 24 h after the start of the infusion, time to restoration of the first sinus rhythm and the proportion of patients with arrhythmia recurrence. RESULTS: Out of 209 randomized patients, 200 (96%) received the study drug. After 24 h, 77 (72.8%) and 71 (67.3%) were in sinus rhythm (p = 0.4), restored after a median of 3.7 h (95% CI 2.3-6.8) and 7.3 h (95% CI 5-11), p = 0.02, with propafenone and amiodarone, respectively. The arrhythmia recurred in 54 (52%) patients treated with propafenone and in 80 (76%) with amiodarone, p < 0.001. Patients with a dilated left atrium had better rhythm control with amiodarone (6.4 h (95% CI 3.5; 14.1) until cardioversion vs 18 h (95% CI 2.8; 24.7) in propafenone, p = 0.05). CONCLUSION: Propafenone does not provide better rhythm control at 24 h yet offers faster cardioversion with fewer arrhythmia recurrences than with amiodarone, especially in patients with a non-dilated left atrium. No differences between propafenone and amiodarone on the prespecified short- and long-term outcomes were observed.

Mitragyna speciosa (Kratom) poisoning: Findings from ten cases.

Kratom is a mixture of compounds that are present in the leaves of the tropical tree Mitragyna speciosa. It is used as a psychoactive agent with both opiate and stimulant-like effects. In this case series we describe the signs, symptoms, and the management of kratom overdose in the prehospital setting and in intensive care. We retrospectively searched for cases in the Czech Republic. Over 36 months we found 10 cases of kratom poisoning, which healthcare records were analyzed and reported as per CARE guidelines. The dominant symptoms in our series were neurological and included quantitative (n = 9) or qualitative (n = 4) disorder of consciousness. Signs and symptoms of vegetative instability [hypertension (n = 3) and tachycardia (n = 3) vs. bradycardia/cardiac arrest (n = 2), mydriasis (n = 2) vs. miosis (n = 3)] were noticed. Prompt response to naloxone in two cases and lack of response in one patient were observed. All patients survived and the effect of intoxication wore off within two days. Kratom overdose toxidrome is variable and, in keeping with its receptor physiology, consists of signs and symptoms of opioid-like overdose, sympathetic overactivation and serotonin-like syndrome. Naloxone can help to avoid intubation in some cases.

Machine learning determination of motivators of terminal extubation during the transition to end-of-life care in intensive care unit.

Procedural aspects of compassionate care such as the terminal extubation are understudied. We used machine learning methods to determine factors associated with the decision to extubate the critically ill patient at the end of life, and whether the terminal extubation shortens the dying process. We performed a secondary data analysis of a large, prospective, multicentre, cohort study, death prediction and physiology after removal of therapy (DePPaRT), which collected baseline data as well as ECG, pulse oximeter and arterial waveforms from WLST until 30 min after death. We analysed a priori defined factors associated with the decision to perform terminal extubation in WLST using the random forest method and logistic regression. Cox regression was used to analyse the effect of terminal extubation on time from WLST to death. A total of 616 patients were included into the analysis, out of which 396 (64.3%) were terminally extubated. The study centre, low or no vasopressor support, and good respiratory function were factors significantly associated with the decision to extubate. Unadjusted time to death did not differ between patients with and without extubation (median survival time extubated vs. not extubated: 60 [95% CI: 46; 76] vs. 58 [95% CI: 45; 75] min). In contrast, after adjustment for confounders, time to death of extubated patients was significantly shorter (49 [95% CI: 40; 62] vs. 85 [95% CI: 61; 115] min). The decision to terminally extubate is associated with specific centres and less respiratory and/or vasopressor support. In this context, terminal extubation was associated with a shorter time to death.

Non-carbonic buffer power of whole blood is increased in experimental metabolic acidosis: An in-vitro study.

Non-carbonic buffer power (ßNC) of blood is a pivotal concept in acid-base physiology as it is employed in several acid-base evaluation techniques, including the Davenport nomogram and the Van Slyke equation used for Base excess estimation in blood. So far, ßNC has been assumed to be independent of metabolic acid-base status of blood, despite theoretical rationale for the contrary. In the current study, we used CO2 tonometry to assess ßNC in blood samples from 10 healthy volunteers, simultaneously analyzing the electrolyte shifts across the red blood cell membrane as these shifts translate the action of intracellular non-carbonic buffers to plasma. The ßNC of the blood was re-evaluated after experimental induction of metabolic acidosis obtained by adding a moderate or high amount of either hydrochloric or lactic acid to the samples. Moreover, the impact of ßNC and pCO2 on the Base excess of blood was examined. In the control samples, ßNC was 28.0 ± 2.5 mmol/L. In contrast to the traditional assumptions, our data showed that ßNC rose by 0.36 mmol/L for each 1 mEq/l reduction in plasma strong ion difference (p < 0.0001) and was independent of the acid used. This could serve as a protective mechanism that increases the resilience of blood to the combination of metabolic and respiratory acidosis. Sodium and chloride were the only electrolytes whose plasma concentration changed relevantly during CO2 titration. Although no significant difference was found between the electrolyte shifts in the two types of acidosis, we observed a slightly higher rate of chloride change in hyperchloremic acidosis, while the variation of sodium was more pronounced in lactic acidosis. Lastly, we found that the rise of ßNC in metabolic acidosis did not induce a clinically relevant bias in the calculation of Base excess of blood and confirmed that the Base excess of blood was little affected by a wide range of pCO2.

Effect of noradrenaline on propofol-induced mitochondrial dysfunction in human skeletal muscle cells.

BACKGROUND: Mitochondrial dysfunction is a hallmark of both critical illness and propofol infusion syndrome and its severity seems to be proportional to the doses of noradrenaline, which patients are receiving. We comprehensively studied the effects of noradrenaline on cellular bioenergetics and mitochondrial biology in human skeletal muscle cells with and without propofol-induced mitochondrial dysfunction. METHODS: Human skeletal muscle cells were isolated from vastus lateralis biopsies from patients undergoing elective hip replacement surgery (n = 14) or healthy volunteers (n = 4). After long-term (96 h) exposure to propofol (10 µg/mL), noradrenaline (100 µM), or both, energy metabolism was assessed by extracellular flux analysis and substrate oxidation assays using [14C] palmitic and [14C(U)] lactic acid. Mitochondrial membrane potential, morphology and reactive oxygen species production were analysed by confocal laser scanning microscopy. Mitochondrial mass was assessed both spectrophotometrically and by confocal laser scanning microscopy. RESULTS: Propofol moderately reduced mitochondrial mass and induced bioenergetic dysfunction, such as a reduction of maximum electron transfer chain capacity, ATP synthesis and profound inhibition of exogenous fatty acid oxidation. Noradrenaline exposure increased mitochondrial network size and turnover in both propofol treated and untreated cells as apparent from increased co-localization with lysosomes. After adjustment to mitochondrial mass, noradrenaline did not affect mitochondrial functional parameters in naïve cells, but it significantly reduced the degree of mitochondrial dysfunction induced by propofol co-exposure. The fatty acid oxidation capacity was restored almost completely by noradrenaline co-exposure, most likely due to restoration of the capacity to transfer long-chain fatty acid to mitochondria. Both propofol and noradrenaline reduced mitochondrial membrane potential and increased reactive oxygen species production, but their effects were not additive. CONCLUSIONS: Noradrenaline prevents rather than aggravates propofol-induced impairment of mitochondrial functions in human skeletal muscle cells. Its effects on bioenergetic dysfunctions of other origins, such as sepsis, remain to be demonstrated.

Video Emergency Calls in Medical Dispatching: A Scoping Review.

BACKGROUND: Video emergency calls (VCs) represent a feasible future trend in medical dispatching. Acceptance among callers and dispatchers seems to be good. Indications, potential problems, limitations, and directions of research of adding a live video from smartphones to an emergency call have not been reviewed outside the context of out-of-hospital cardiac arrest (OHCA). OBJECTIVE: The main objective of this study is to examine the scope and nature of research publications on the topic of VC. The secondary goal is to identify research gaps and discuss the potential directions of research efforts of VC. DESIGN: Following PRISMA-ScR guidelines, online bibliographic databases PubMed, Web of Science, SCOPUS, Google Scholar, ClinicalTrials.gov, and gray literature were searched from the period of January 1, 2012 through March 1, 2022 in English. Only studies focusing on video transfer via mobile phone to emergency medical dispatch centers (EMDCs) were included. RESULTS: Twelve articles were included in the qualitative synthesis and six main themes were identified: (1) cardiopulmonary resuscitation (CPR) guided by VC; (2) indications of VCs; (3) dispatchers' feedback and perception; (4) technical aspects of VCs; (5) callers' acceptance; and (6) confidentiality and legal issues. CONCLUSION: Video emergency calls are feasible and seem to be a well-accepted auxiliary method among dispatchers and callers. Some promising clinical results exist, especially for video-assisted CPR. On the other hand, there are still enormous knowledge gaps in the vast majority of implementation aspects of VC into practice.

Perimortem dynamics of blood potassium concentration in patients dying in intensive care unit: A prospective nested cohort study.

To enable diagnosis of hyperkalemia from the perimortem blood sample, we aim to describe the natural dynamics of blood potassium [K+ ] in patients dying after withdrawal of care while in an intensive care unit. In a nested sub-study of international Death Prediction and Physiology after Removal of Therapy (DePPaRT) project, we obtained serial whole-blood samples and analyzed ions and acid-base parameters in 23 patients just before life-sustaining treatment withdrawal, at the time of death, and after 5 and 30 min after death. Of the 631 patients in the DePPaRT study, we obtained consent and enrolled 23 subjects in the [K+ ] sub-study (12 M, 11F, aged 73 ± 14 years), mostly dying from irreversible brain damage or multi-organ failure. Blood [K+ ] rose from the median 4.3 (IQR 3.9; 4.8) mEq/L at treatment withdrawal to 5.2 (IQR 5.0; 6.8) mEq/L at death and then to 5.85 (IQR 5.2; 6.8) mEq/L after 30 min (mean rise of +0.64 mEq.L-1 .h-1 ). These changes were associated with progressive lactic and hypercapnic acidemia. After correcting the measured [K+] for pH by subtracting 0.6 mEq/L from [K+] for every 0.1 pH decrease from 7.40, the calculated [K+] remained normal or decreased from that measured at treatment withdrawal. In contrast to the late autolysis phase, the early changes of blood [K+ ] after death are slow and can be fully explained by progressive acidemia. Our data suggest that the diagnosis of hyperkalemia at death from a blood sample obtained within 30 min after death can be made by adjusting the [K+] concentration to a pH 7.40.