Possible Pathogenic Mechanism of Propofol Infusion Syndrome Involves Coenzyme Q

AbstractAbstractIn eight rats sedated for up to 20 h with gradually increasing doses of propofol, succinate cytochrome c reductase (complex II+III) was the most sensitive to inhibition by propofol. The activities of complex II and complex III were not decreased when tested individually, suggesting propofol interferes with coenzyme Q, which transfers electrons from complex II to complex III.Supplemental Digital Content is available in the text.Background:Propofol is a short-acting intravenous anesthetic agent. In rare conditions, a life-threatening complication known as propofol infusion syndrome can occur. The pathophysiologic mechanism is still unknown. Some studies suggested that propofol acts as uncoupling agent, others suggested that it inhibits complex I or complex IV, or causes increased oxidation of cytochrome c and cytochrome aa3, or inhibits mitochondrial fatty acid metabolism. Although the exact site of interaction is not known, most hypotheses point to the direction of the mitochondria.Methods:Eight rats were ventilated and sedated with propofol up to 20 h. Sequential biopsy specimens were taken from liver and skeletal muscle and used for determination of respiratory chain activities and propofol concentration. Activities were also measured in skeletal muscle from a patient who died of propofol infusion syndrome.Results:In rats, authors detected a decrease in complex II+III activity starting at low tissue concentration of propofol (20 to 25 µM), further declining at higher concentrations. Before starting anesthesia, the complex II+III/citrate synthase activity ratio in liver was 0.46 (0.25) and in skeletal muscle 0.23 (0.05) (mean [SD]). After 20 h of anesthesia, the ratios declined to 0.17 (0.03) and 0.12 (0.02), respectively. When measured individually, the activities of complexes II and III remained normal. Skeletal muscle from one patient taken in the acute phase of propofol infusion syndrome also shows a selective decrease in complex II+III activity (z-score: −2.96).Conclusion:Propofol impedes the electron flow through the respiratory chain and coenzyme Q is the main site of interaction with propofol.