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.

• Keywords
• Critical illness, Mitochondrial dysfunction, Noradrenaline, Propofol infusion syndrome, Skeletal muscle,
• Publication type
• Journal Article MeSH

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.

• Keywords
• Critically ill, Early rehabilitation, Functional electrical stimulation-assisted cycle ergometry, Intensive care unit, Mobility, Physical therapy,
• MeSH
• Time Factors MeSH
• Bicycling * MeSH
• Electric Stimulation Therapy * adverse effects   MeSH
• Ergometry * MeSH
• Intensive Care Units MeSH
• Muscle, Skeletal innervation   MeSH
• Critical Illness MeSH
• Quality of Life MeSH
• Humans MeSH
• Recovery of Function MeSH
• Pragmatic Clinical Trials as Topic MeSH
• Muscle Contraction * MeSH
• Muscle Strength * MeSH
• Muscle Weakness diagnosis   physiopathology   rehabilitation   MeSH
• Treatment Outcome MeSH
• Exercise Test MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial Protocol MeSH
• Geographicals
• Czech Republic MeSH