Background & aim: Propofol is commonly used in ICUs, but its long-term effects have not been thoroughly studied. In vitro studies suggest it may harm mitochondrial function, potentially... Show moreBackground & aim: Propofol is commonly used in ICUs, but its long-term effects have not been thoroughly studied. In vitro studies suggest it may harm mitochondrial function, potentially affecting clinical outcomes. This study aimed to investigate the association between substantial propofol sedation and clinical outcomes in critically ill patients.Methods: We conducted a single-centre cohort study of critically ill, mechanically ventilated (>= 7 days) adults to compare patients who received a substantial dose of propofol (cumulative >500 mg) during the first week of ICU admission with those who did not. The primary outcome was the association between substantial propofol administration and 6-month mortality, adjusted for relevant covariates. Subanalyses were performed for administration in the early (day 1-3) and late (day 4-7) acute phases of critical illness due to the metabolic changes in this period. Secondary outcomes included tracheostomy need and duration, length of ICU and hospital stay (LOS), discharge destinations, ICU, hospital, and 3-month mortality.Results: A total of 839 patients were enrolled, with 73.7 % receiving substantial propofol administration (substantial propofol dose group). Six-month all-cause mortality was 32.4 %. After adjusting for relevant variables, we found no statistically significant difference in 6-month mortality between both groups. There were also no significant differences in secondary outcomes.Conclusion: Our study suggests that substantial propofol administration during the first week of ICU stay in the least sick critically ill, mechanically ventilated adult patients is safe, with no significant associations found with 6-month mortality, ICU or hospital LOS, differences in discharge destinations or need for tracheostomy.(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Martens, L.G.; Luo, J.; Wermer, M.J.H.; Dijk, K.W. van; Hagg, S.; Grassmann, F.; ... ; Heemst, D. van 2022
Background and aims: Mitochondrial dysfunction is associated with increased reactive oxygen species (ROS) that are thought to drive disease risk, including stroke. We investigated the association... Show moreBackground and aims: Mitochondrial dysfunction is associated with increased reactive oxygen species (ROS) that are thought to drive disease risk, including stroke. We investigated the association between mtDNA abundance, as a proxy measure of mitochondrial function, and incident stroke, using multivariable-adjusted survival and Mendelian Randomization (MR) analyses. Methods: Cox-proportional hazard model analyses were conducted to assess the association between mtDNA abundance, and incident ischemic and hemorrhagic stroke over a maximum of 14-year follow-up in European -ancestry participants from UK Biobank. MR was conducted using independent (R-2 < 0.001) lead variants for mtDNA abundance (p < 5 x 10(-8)) as instrumental variables. Single-nucleotide polymorphism (SNP)-ischemic stroke associations were derived from three published open source European-ancestry results databases (cases/ controls): MEGASTROKE (60,341/454,450), UK Biobank (2404/368,771) and FinnGen (10,551/202,223). MR was performed per study, and results were subsequently meta-analyzed. Results: In total, 288,572 unrelated participants (46% men) with mean (SD) age of 57 (8) years were included in the Cox-proportional hazard analyses. After correction for considered confounders (BMI, hypertension, cholesterol, T2D), no association was found between low versus high mtDNA abundance and ischemic (HR: 1.06 [95% CI: 0.95, 1.18]) or hemorrhagic (HR: 0.97 [95% CI: 0.82, 1.15]) stroke. However, in the MR analyses after removal of platelet count-associated SNPs, we found evidence for an association between genetically-influenced mtDNA abundance and ischemic stroke (odds ratio, 1.17; confidence interval, 1.03, 1.32). Conclusions: Although the results from both multivariable-adjusted prospective and basis MR analyses did not show an association between low mtDNA and increased risk of ischemic stroke, in-depth MR sensitivity analyses may suggest evidence for a causal relationship. Show less
This thesis describes several aspects of diagnostic and therapeutic possibilities of mitochondrial function in clinical pharmacological. During several clinical studies in healthy volunteers, pre... Show moreThis thesis describes several aspects of diagnostic and therapeutic possibilities of mitochondrial function in clinical pharmacological. During several clinical studies in healthy volunteers, pre-frail elderly and Huntington’s disease patients, we used phosphorous magnetic resonance spectroscopy as the main method to measure mitochondrial function in vivo. Other in vivo methods included Near Infrared Spectroscopy and the novel Protoporphorin-9 Triplet State Lifetime Technique, besides in vitro ELISA methods to measure activity of separate complexes of the mitochondrial electron transport chain. Using these modalities, we showed mitochondrial dysfunction in pre-frail elderly, emphasizing the importance of an active lifestyle in the prevention of sarcopenia and frailty. Using the mitotoxicity of simvastatin, and its reversibility by ubiquinol, we validated the first proof-of-pharmacology model in healthy volunteers to evaluate efficacy of novel mitochondrial function improving compounds. We also described the importance of measuring (mitochondrial) oxygen consumption as a means to measure mitotoxicity of commonly described medications. Lastly, we evaluated the safety and efficacy of the novel compound SBT-020 in a placebo-controlled, double-blinded, randomized controlled trial in mild to moderate Huntington’s disease patients and compared central to peripheral mitochondrial function for the first time, gaining inside into therapeutic possibilities in this complex and devastating disease. Show less
