Circulating oxylipin and bile acid profiles of dexmedetomidine, propofol, sevoflurane, and S-ketamine: a randomised controlled trial using tandem mass spectrometry
Aleksi Nummela,
Lauri Laaksonen,
Annalotta Scheinin,
Kaike Kaisti,
Tero Vahlberg,
Mikko Neuvonen,
Katja Valli,
Antti Revonsuo,
Markus Perola,
Mikko Niemi,
Harry Scheinin,
Timo Laitio
Affiliations
Aleksi Nummela
Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland; Department of Internal Medicine, Turku University Hospital, Turku, Finland; Corresponding author. Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland.
Lauri Laaksonen
Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland; Department of Peri-operative Services, University of Turku and Turku University Hospital, Turku, Finland
Annalotta Scheinin
Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland; Department of Peri-operative Services, University of Turku and Turku University Hospital, Turku, Finland
Kaike Kaisti
Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland; Department of Peri-operative Services, University of Turku and Turku University Hospital, Turku, Finland
Tero Vahlberg
Department of Clinical Medicine, Biostatistics, Intensive Care and Pain Medicine, University of Turku and Turku University Hospital, Turku, Finland
Mikko Neuvonen
Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Katja Valli
Department of Peri-operative Services, University of Turku and Turku University Hospital, Turku, Finland; Department of Psychology and Speech-Language Pathology, and Turku Brain and Mind Center, University of Turku, Turku, Finland; Department of Cognitive Neuroscience and Philosophy, School of Bioscience, University of Skövde, Skövde, Sweden
Antti Revonsuo
Department of Psychology and Speech-Language Pathology, and Turku Brain and Mind Center, University of Turku, Turku, Finland; Department of Cognitive Neuroscience and Philosophy, School of Bioscience, University of Skövde, Skövde, Sweden
Markus Perola
Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Finnish Institute for Health and Welfare, Helsinki, Finland
Mikko Niemi
Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
Harry Scheinin
Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland; Department of Peri-operative Services, University of Turku and Turku University Hospital, Turku, Finland; Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland
Timo Laitio
Department of Peri-operative Services, University of Turku and Turku University Hospital, Turku, Finland
Background: This exploratory study aimed to investigate whether dexmedetomidine, propofol, sevoflurane, and S-ketamine affect oxylipins and bile acids, which are functionally diverse molecules with possible connections to cellular bioenergetics, immune modulation, and organ protection. Methods: In this randomised, open-label, controlled, parallel group, Phase IV clinical drug trial, healthy male subjects (n=160) received equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml−1; n=40), propofol (1.7 μg ml−1; n=40), sevoflurane (0.9% end-tidal; n=40), S-ketamine (0.75 μg ml−1; n=20), or placebo (n=20). Blood samples for tandem mass spectrometry were obtained at baseline, after study drug administration at 60 and 130 min from baseline; 40 metabolites were analysed. Results: Statistically significant changes vs placebo were observed in 62.5%, 12.5%, 5.0%, and 2.5% of analytes in dexmedetomidine, propofol, sevoflurane, and S-ketamine groups, respectively. Data are presented as standard deviation score, 95% confidence interval, and P-value. Dexmedetomidine induced wide-ranging decreases in oxylipins and bile acids. Amongst others, 9,10-dihydroxyoctadecenoic acid (DiHOME) –1.19 (–1.6; –0.78), P<0.001 and 12,13-DiHOME –1.22 (–1.66; –0.77), P<0.001 were affected. Propofol elevated 9,10-DiHOME 2.29 (1.62; 2.96), P<0.001 and 12,13-DiHOME 2.13 (1.42; 2.84), P<0.001. Analytes were mostly unaffected by S-ketamine. Sevoflurane decreased tauroursodeoxycholic acid (TUDCA) –2.7 (–3.84; –1.55), P=0.015. Conclusions: Dexmedetomidine-induced oxylipin alterations may be connected to pathways associated with organ protection. In contrast to dexmedetomidine, propofol emulsion elevated DiHOMEs, oxylipins associated with acute respiratory distress syndrome, and mitochondrial dysfunction in high concentrations. Further research is needed to establish the behaviour of DIHOMEs during prolonged propofol/dexmedetomidine infusions and to verify the sevoflurane-induced reduction in TUDCA, a suggested neuroprotective agent. Clinical trial registration: NCT02624401.