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.

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.

Can functional electrical stimulation-assisted cycle ergometry replace insulin infusion in patients? A nested substudy in a randomized controlled trial with 6 months' follow-up.

BACKGROUND: Functional electrical stimulation-assisted cycle ergometry (FESCE) can deliver active exercise to critically ill patients, including those who are sedated. Aerobic exercise is known to stimulate skeletal muscle glucose uptake. We asked whether FESCE can reduce intravenous insulin requirements and improve insulin sensitivity in intensive care unit (ICU) patients. METHOD: We performed an a priori-planned secondary analysis of data from an outcome-based randomized controlled trial (NCT02864745) of FESCE-based early-mobility program vs standard of care in mechanically ventilated patients. We analyzed glucose profile, glucose intake, and insulin requirements during ICU stay in all enrolled patients. In a nested subgroup, we performed hyperinsulinemic (120 mIU/min/m2 ) euglycemic clamps at days 0, 7, and 180 (n = 30, 23, and 11, respectively). RESULTS: We randomized 150 patients 1:1 to receive intervention or standard of care. Seventeen (23%) patients in each study arm had a history of diabetes. During ICU stay, patients received 137 ± 65 and 137 ± 88 g/day carbohydrate (P = .97), and 31 vs 35 (P = .62) of them required insulin infusion to maintain blood glucose 8.61 ± 2.82 vs 8.73 ± 2.67 mM (P = .75, n = 11,254). In those treated with insulin, median daily dose was 53 IU (interquartile range [IQR], 25-95) vs 62 IU (IQR, 26-96) in the intervention and control arm, respectively (P = .44). In the subgroup of patients undergoing hyperglycemic clamps, insulin sensitivities improved similarly and significantly from acute and protracted critical illness to 6 months after discharge. CONCLUSION: The FESCE-based early-mobility program does not significantly reduce insulin requirements in critically ill patients on mechanical ventilation.

Functional electrical stimulation-assisted cycle ergometry-based progressive mobility programme for mechanically ventilated patients: randomised controlled trial with 6 months follow-up.

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

Effects of Rehabilitation Interventions on Clinical Outcomes in Critically Ill Patients: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: To assess the impact of rehabilitation in ICU on clinical outcomes. DATA SOURCES: Secondary data analysis of randomized controlled trials published between 1998 and October 2019 was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. STUDY SELECTION: We have selected trials investigating neuromuscular electrical stimulation or cycling exercises or protocolized physical rehabilitation as compared to standard of care in critically ill adults. DATA EXTRACTION: Mortality, length of stay in ICU and at hospital, days on mechanical ventilator, and adverse events. DATA SYNTHESIS: We found 43 randomized controlled trials (nine on cycling, 14 on neuromuscular electrical stimulation alone and 20 on protocolized physical rehabilitation) into which 3,548 patients were randomized and none of whom experienced an intervention-related serious adverse event. The exercise interventions had no influence on mortality (odds ratio 0.94 [0.79-1.12], n = 38 randomized controlled trials) but reduced duration of mechanical ventilation (mean difference, -1.7 d [-2.5 to -0.8 d], n = 32, length of stay in ICU (-1.2 d [-2.5 to 0.0 d], n = 32) but not at hospital (-1.6 [-4.3 to 1.2 d], n = 23). The effects on the length of mechanical ventilation and ICU stay were only significant for the protocolized physical rehabilitation subgroup and enhanced in patients with longer ICU stay and lower Acute Physiology and Chronic Health Evaluation II scores. There was no benefit of early start of the intervention. It is likely that the dose of rehabilitation delivered was much lower than dictated by the protocol in many randomized controlled trials and negative results may reflect the failure to implement the intervention. CONCLUSIONS: Rehabilitation interventions in critically ill patients do not influence mortality and are safe. Protocolized physical rehabilitation significantly shortens time spent on mechanical ventilation and in ICU, but this does not consistently translate into long-term functional benefit. Stable patients with lower Acute Physiology and Chronic Health Evaluation II at admission (<20) and prone to protracted ICU stay may benefit most from rehabilitation interventions.

Functional electrical stimulation-assisted cycle ergometry in the critically ill: protocol for a randomized controlled trial.

BACKGROUND: Intensive care unit (ICU)-acquired weakness is the most important cause of failed functional outcome in survivors of critical care. Most damage occurs during the first week when patients are not cooperative enough with conventional rehabilitation. Functional electrical stimulation-assisted cycle ergometry (FES-CE) applied within 48 h of ICU admission may improve muscle function and long-term outcome. METHODS: An assessor-blinded, pragmatic, single-centre randomized controlled trial will be performed. Adults (n = 150) mechanically ventilated for < 48 h from four ICUs who are estimated to need > 7 days of critical care will be randomized (1:1) to receive either standard of care or FES-CE-based intensified rehabilitation, which will continue until ICU discharge. PRIMARY OUTCOME: quality of life measured by 36-Item Short Form Health Survey score at 6 months. SECONDARY OUTCOMES: functional performance at ICU discharge, muscle mass (vastus ultrasound, N-balance) and function (Medical Research Council score, insulin sensitivity). In a subgroup (n = 30) we will assess insulin sensitivity and perform skeletal muscle biopsies to look at mitochondrial function, fibre typing and regulatory protein expression. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02864745. Registered on 12 August 2016.

Using pCO2 Gap in the Differential Diagnosis of Hyperlactatemia Outside the Context of Sepsis: A Physiological Review and Case Series.

INTRODUCTION: There is an inverse relationship between cardiac output and the central venous-arterial difference of partial pressures of carbon dioxide (pCO2 gap), and pCO2 gap has been used to guide early resuscitation of septic shock. It can be hypothesized that pCO2 gap can be used outside the context of sepsis to distinguish type A and type B lactic acidosis and thereby avoid unnecessary fluid resuscitation in patients with high lactate, but without organ hypoperfusion. METHODS: We performed a structured review of the literature enlightening the physiological background. Next, we retrospectively selected a series of case reports of nonseptic critically ill patients with elevated lactate, in whom both arterial and central venous blood gases were simultaneously measured and the diagnosis of either type A or type B hyperlactataemia was conclusively known. In these cases, we calculated venous-arterial CO2 and O2 content differences and pCO2 gap. RESULTS: Based on available physiological data, pCO2 can be considered as an acceptable surrogate of venous-arterial CO2 content difference, and it should better reflect cardiac output than central venous saturation or indices based on venous-arterial O2 content difference. In our case report of nonseptic patients, we observed that if global hypoperfusion was present (i.e., in type A lactic acidosis), pCO2 gap was elevated (>1 kPa), whilst in the absence of it (i.e., in type B lactic acidosis), pCO2 gap was low (<0.5 kPa). CONCLUSION: Physiological rationale and a small case series are consistent with the hypothesis that low pCO2 gap in nonseptic critically ill is suggestive of the absence of tissue hypoperfusion, mandating the search for the cause of type B lactic acidosis rather than administration of fluids or other drugs aimed at increasing cardiac output.

Kinetic characteristics of propofol-induced inhibition of electron-transfer chain and fatty acid oxidation in human and rodent skeletal and cardiac muscles.

INTRODUCTION: Propofol causes a profound inhibition of fatty acid oxidation and reduces spare electron transfer chain capacity in a range of human and rodent cells and tissues-a feature that might be related to the pathogenesis of Propofol Infusion Syndrome. We aimed to explore the mechanism of propofol-induced alteration of bioenergetic pathways by describing its kinetic characteristics. METHODS: We obtained samples of skeletal and cardiac muscle from Wistar rat (n = 3) and human subjects: vastus lateralis from hip surgery patients (n = 11) and myocardium from brain-dead organ donors (n = 10). We assessed mitochondrial functional indices using standard SUIT protocol and high resolution respirometry in fresh tissue homogenates with or without short-term exposure to a range of propofol concentration (2.5-100 µg/ml). After finding concentrations of propofol causing partial inhibition of a particular pathways, we used that concentration to construct kinetic curves by plotting oxygen flux against substrate concentration during its stepwise titration in the presence or absence of propofol. By spectrophotometry we also measured the influence of the same propofol concentrations on the activity of isolated respiratory complexes. RESULTS: We found that human muscle and cardiac tissues are more sensitive to propofol-mediated inhibition of bioenergetic pathways than rat's tissue. In human homogenates, palmitoyl carnitine-driven respiration was inhibited at much lower concentrations of propofol than that required for a reduction of electron transfer chain capacity, suggesting FAO inhibition mechanism different from downstream limitation or carnitine-palmitoyl transferase-1 inhibition. Inhibition of Complex I was characterised by more marked reduction of Vmax, in keeping with non-competitive nature of the inhibition and the pattern was similar to the inhibition of Complex II or electron transfer chain capacity. There was neither inhibition of Complex IV nor increased leak through inner mitochondrial membrane with up to 100 µg/ml of propofol. If measured in isolation by spectrophotometry, propofol 10 µg/ml did not affect the activity of any respiratory complexes. CONCLUSION: In human skeletal and heart muscle homogenates, propofol in concentrations that are achieved in propofol-anaesthetized patients, causes a direct inhibition of fatty acid oxidation, in addition to inhibiting flux of electrons through inner mitochondrial membrane. The inhibition is more marked in human as compared to rodent tissues.

Mitochondrial Function in an In Vitro Model of Skeletal Muscle of Patients With Protracted Critical Illness and Intensive Care Unit-Acquired Weakness.

BACKGROUND: Functional mitochondria in skeletal muscle of patients with protracted critical illness and intensive care unit-acquired weakness are depleted, but remaining mitochondria have increased functional capacities of respiratory complexes II and III. This can be an adaptation to relative abundancy of fatty acid over glucose caused by insulin resistance. We hypothesized that the capacity of muscle mitochondria to oxidize fatty acid is increased in protracted critical illness. METHODS: We assessed fatty acid oxidation (FAO) and mitochondrial functional indices in vitro by using extracellular flux analysis in cultured myotubes obtained by isolating and culturing satellite cells from vastus lateralis muscle biopsy samples from patients with ICU-acquired weakness (n = 6) and age-matched healthy controls (n = 7). Bioenergetic measurements were performed at baseline and after 6 days of exposure to free fatty acids (FFAs). RESULTS: Mitochondrial density in myotubes from ICU patients was 69% of healthy controls ( P = .051). After adjustment to mitochondrial content, there were no differences in adenosine triphosphate (ATP) synthesis or the capacity and coupling of the respiratory chain. FAO capacity in ICU patients was 157% of FAO capacity in controls ( P = .015). In myotubes of ICU patients, unlike healthy controls, the exposure to FFA significantly ( P = .009) increased maximum respiratory chain capacity. CONCLUSION: In an in vitro model of skeletal muscle of patients with protracted critical illness, we have shown signs of adaptation to increased FAO. Even in the presence of glucose and insulin, elevation of FFAs in the extracellular environment increased maximal capacity of the respiratory chain.

Mitochondrial function in skeletal muscle of patients with protracted critical illness and ICU-acquired weakness.

BACKGROUND: Mitochondrial damage occurs in the acute phase of critical illness, followed by activation of mitochondrial biogenesis in survivors. It has been hypothesized that bioenergetics failure of skeletal muscle may contribute to the development of ICU-acquired weakness. The aim of the present study was to determine whether mitochondrial dysfunction persists until protracted phase of critical illness. METHODS: In this single-centre controlled-cohort ex vivo proof-of-concept pilot study, we obtained vastus lateralis biopsies from ventilated patients with ICU-acquired weakness (n = 8) and from age and sex-matched metabolically healthy controls (n = 8). Mitochondrial functional indices were measured in cytosolic context by high-resolution respirometry in tissue homogenates, activities of respiratory complexes by spectrophotometry and individual functional capacities were correlated with concentrations of electron transport chain key subunits from respiratory complexes II, III, IV and V measured by western blot. RESULTS: The ability of aerobic ATP synthesis (OXPHOS) was reduced to ~54% in ICU patients (p<0.01), in correlation with the depletion of complexes III (~38% of control, p = 0.02) and IV (~26% of controls, p<0.01) and without signs of mitochondrial uncoupling. When mitochondrial functional indices were adjusted to citrate synthase activity, OXPHOS and the activity of complexes I and IV were not different, whilst the activities of complexes II and III were increased in ICU patients 3-fold (p<0.01) respectively 2-fold (p<0.01). CONCLUSIONS: Compared to healthy controls, in ICU patients we have demonstrated a ~50% reduction of the ability of skeletal muscle to synthetize ATP in mitochondria. We found a depletion of complex III and IV concentrations and relative increases in functional capacities of complex II and glycerol-3-phosphate dehydrogenase/complex III.

Assessing the function of mitochondria in cytosolic context in human skeletal muscle: adopting high-resolution respirometry to homogenate of needle biopsy tissue samples.

Using skeletal muscle homogenates for respirometry has many advantages, but the main challenge is avoiding the damage to outer mitochondrial membrane (OMM) and complex I. By optimising the amount of muscle and careful titration of substrates and inhibitors we developed a new protocol and compared it to isolated mitochondria. We found acceptable damage to OMM (~10-15% increment of oxygen flux after addition of cytochrome c) and to complex I (~70% of electron flux). Homogenate retained ~90% of phosphorylation capacity of isolated mitochondria. The use of fresh homogenate was crucial as mitochondrial function declined rapidly after 2-3h of cold storage.

Normalizing glutamine concentration causes mitochondrial uncoupling in an in vitro model of human skeletal muscle.

BACKGROUND: Glutamine has been considered essential for rapidly dividing cells, but its effect on mitochondrial function is unknown. MATERIALS AND METHODS: Human myoblasts were isolated from skeletal muscle biopsy samples (n = 9) and exposed for 20 days to 6 different glutamine concentrations (0, 100, 200, 300, 500, and 5000 µM). Cells were trypsinized and manually counted every 5 days. Seven days before the end of exposure, half of these cells were allowed to differentiate to myotubes. Afterward, energy metabolism in both myotubes and myoblasts was assessed by extracellular flux analysis (Seahorse Biosciences, Billerica, MA). The protocol for myoblasts was optimized in preliminary experiments. To account for different mitochondrial density or cell count, data were normalized to citrate synthase activity. RESULTS: Fastest myoblast proliferation was observed at 300 µM glutamine, with a significant reduction at 0 and 100 µM. Glutamine did not influence basal oxygen consumption, anaerobic glycolysis or respiratory chain capacity. Glutamine significantly (P = .015) influenced the leak through the inner mitochondrial membrane. Efficiency of respiratory chain was highest at 200-300 µM glutamine (~90% of oxygen used for adenosine triphosphate synthesis). Increased glutamine concentration to 500 or 5000 µM caused mitochondrial uncoupling in myoblasts and myotubes, decreasing the efficiency of the respiratory chain to ~70%. CONCLUSION: Glutamine concentrations, consistent with moderate clinical hypoglutaminemia (300 µM), bring about an optimal condition of myoblast proliferation and for efficiency of aerobic phosphorylation in an in vitro model of human skeletal muscle. These data support the hypothesis of hypoglutaminemia as an adaptive phenomenon in conditions leading to bioenergetic failure (eg, critical illness).