Effects of dexmedetomidine, propofol, sevoflurane and S-ketamine on the human metabolome : A randomised trial using nuclear magnetic resonance spectroscopy

BACKGROUND: Pharmacometabolomics uses large-scale data capturing methods to uncover drug-induced shifts in the metabolic profile. The specific effects of anaesthetics on the human metabolome are largely unknown. OBJECTIVE: We aimed to discover whether exposure to routinely used anaesthetics have an acute effect on the human metabolic profile. DESIGN: Randomised, open-label, controlled, parallel group, phase IV clinical drug trial. SETTING: The study was conducted at Turku PET Centre, University of Turku, Finland, 2016 to 2017. PARTICIPANTS: One hundred and sixty healthy male volunteers were recruited. The metabolomic data of 159 were evaluable. INTERVENTIONS: Volunteers were randomised to receive a 1-h exposure to 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 = 39), S-ketamine (0.75 μg ml-1; n = 20) or placebo (n = 20). MAIN OUTCOME MEASURES: Metabolite subgroups of apolipoproteins and lipoproteins, cholesterol, glycerides and phospholipids, fatty acids, glycolysis, amino acids, ketone bodies, creatinine and albumin and the inflammatory marker GlycA, were analysed with nuclear magnetic resonance spectroscopy from arterial blood samples collected at baseline, after anaesthetic administration and 70 min postanaesthesia. RESULTS: All metabolite subgroups were affected. Statistically significant changes vs. placebo were observed in 11.0, 41.3, 0.65 and 3.9% of the 155 analytes in the dexmedetomidine, propofol, sevoflurane and S-ketamine groups, respectively. Dexmedetomidine increased glucose, decreased ketone bodies and affected lipoproteins and apolipoproteins. Propofol altered lipoproteins, fatty acids, glycerides and phospholipids and slightly increased inflammatory marker glycoprotein acetylation. Sevoflurane was relatively inert. S-ketamine increased glucose and lactate, whereas branched chain amino acids and tyrosine decreased. CONCLUSION: A 1-h exposure to moderate doses of routinely used anaesthetics led to significant and characteristic alterations in the metabolic profile. Dexmedetomidine-induced alterations mirror α2-adrenoceptor agonism. Propofol emulsion altered the lipid profile. The inertness of sevoflurane might prove useful in vulnerable patients. S-ketamine induced amino acid alterations might be linked to its suggested antidepressive properties. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02624401. URL: https://clinicaltrials.gov/ct2/show/NCT02624401. CC BY 4.0September 15, 2021Correspondence to Aleksi J. Nummela, Department of Internal Medicine, Turku University Hospital, 20521 Turku, Finland E-mail: aljunu@utu.fiFinancial support and sponsorship: this work was supported by Academy of Finland, Helsinki, Finland (grant numbers 266467, 266434); Jane and Aatos Erkko Foundation, Helsinki, Finland; The Finnish Medical Foundation, Helsinki, Finland (JWL); The Emil Aaltonen Foundation, Tampere, Finland (JWL); and The Paulo Foundation, Espoo, Finland (LTL) and Orion Research Foundation, Espoo, Finland (LTL); Signe and Ane Gyllenberg Foundation, Helsinki, Finland (KJV); The Finnish Medical Foundation, Eero Matti Raninen Fund, Helsinki, Finland (AJN) and University of Turku, Finland (AJN).