Circulating Oxylipin and Bile Acid Profiles of Dexmedetomidine, Propofol, Sevoflurane, and S-ketamine: a Randomised Controlled Trial Using Tandem Mass Spectrometry

Overview

Journal BJA Open

Specialty Anesthesiology

Date 2023 Aug 17

PMID 37588789

Authors

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

Soon will be listed here.

Abstract

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 (=160) received equipotent doses (EC for verbal command) of dexmedetomidine (1.5 ng ml; =40), propofol (1.7 μg ml; =40), sevoflurane (0.9% end-tidal; =40), S-ketamine (0.75 μg ml; =20), or placebo (=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 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 -value. Dexmedetomidine induced wide-ranging decreases in oxylipins and bile acids. Amongst others, 9,10-dihydroxyoctadecenoic acid (DiHOME) -1.19 (-1.6; -0.78), <0.001 and 12,13-DiHOME -1.22 (-1.66; -0.77), <0.001 were affected. Propofol elevated 9,10-DiHOME 2.29 (1.62; 2.96), <0.001 and 12,13-DiHOME 2.13 (1.42; 2.84), <0.001. Analytes were mostly unaffected by S-ketamine. Sevoflurane decreased tauroursodeoxycholic acid (TUDCA) -2.7 (-3.84; -1.55), =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.

Citing Articles

The Octadecanoids: Synthesis and Bioactivity of 18-Carbon Oxygenated Fatty Acids in Mammals, Bacteria, and Fungi.

Revol-Cavalier J, Quaranta A, Newman J, Brash A, Hamberg M, Wheelock C Chem Rev. 2024; 125(1):1-90.

PMID: 39680864 PMC: 11719350. DOI: 10.1021/acs.chemrev.3c00520.

References

Thompson D, Hammock B . Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst. J Biosci. 2007; 32(2):279-91. PMC: 1904342. DOI: 10.1007/s12038-007-0028-x. View

Xiang H, Hu B, Li Z, Li J . Dexmedetomidine controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Inflammation. 2014; 37(5):1763-70. DOI: 10.1007/s10753-014-9906-1. View

Kawai T, Akira S . Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med. 2007; 13(11):460-9. DOI: 10.1016/j.molmed.2007.09.002. View

Krajcova A, Waldauf P, Andel M, Duska F . Propofol infusion syndrome: a structured review of experimental studies and 153 published case reports. Crit Care. 2015; 19:398. PMC: 4642662. DOI: 10.1186/s13054-015-1112-5. View

OConnell T, Mason R, Budoff M, Navar A, Shearer G . Mechanistic insights into cardiovascular protection for omega-3 fatty acids and their bioactive lipid metabolites. Eur Heart J Suppl. 2020; 22(Suppl J):J3-J20. PMC: 7537803. DOI: 10.1093/eurheartj/suaa115. View

Gabbs M, Leng S, Devassy J, Monirujjaman M, Aukema H . Advances in Our Understanding of Oxylipins Derived from Dietary PUFAs. Adv Nutr. 2015; 6(5):513-40. PMC: 4561827. DOI: 10.3945/an.114.007732. View

Imig J . Epoxides and soluble epoxide hydrolase in cardiovascular physiology. Physiol Rev. 2012; 92(1):101-30. PMC: 3613253. DOI: 10.1152/physrev.00021.2011. View

McReynolds C, Cortes-Puch I, Ravindran R, Khan I, Hammock B, Shih P . Plasma Linoleate Diols Are Potential Biomarkers for Severe COVID-19 Infections. Front Physiol. 2021; 12:663869. PMC: 8047414. DOI: 10.3389/fphys.2021.663869. View

Ackerman H, Gerhard G . Bile Acids in Neurodegenerative Disorders. Front Aging Neurosci. 2016; 8:263. PMC: 5118426. DOI: 10.3389/fnagi.2016.00263. View

10.

Liu J, Yang J, Inceoglu B, Qiu H, Ulu A, Hwang S . Inhibition of soluble epoxide hydrolase enhances the anti-inflammatory effects of aspirin and 5-lipoxygenase activation protein inhibitor in a murine model. Biochem Pharmacol. 2009; 79(6):880-7. PMC: 3285377. DOI: 10.1016/j.bcp.2009.10.025. View

11.

Dutta S, Lal R, Karol M, Cohen T, Ebert T . Influence of cardiac output on dexmedetomidine pharmacokinetics. J Pharm Sci. 2000; 89(4):519-27. DOI: 10.1002/(SICI)1520-6017(200004)89:4<519::AID-JPS9>3.0.CO;2-U. View

12.

Zheng J, Plopper C, Lakritz J, Storms D, Hammock B . Leukotoxin-diol: a putative toxic mediator involved in acute respiratory distress syndrome. Am J Respir Cell Mol Biol. 2001; 25(4):434-8. DOI: 10.1165/ajrcmb.25.4.4104. View

13.

Stanford K, Lynes M, Takahashi H, Baer L, Arts P, May F . 12,13-diHOME: An Exercise-Induced Lipokine that Increases Skeletal Muscle Fatty Acid Uptake. Cell Metab. 2018; 27(5):1111-1120.e3. PMC: 5935136. DOI: 10.1016/j.cmet.2018.03.020. View

14.

Clouet P, Niot I, BEZARD J . Pathway of alpha-linolenic acid through the mitochondrial outer membrane in the rat liver and influence on the rate of oxidation. Comparison with linoleic and oleic acids. Biochem J. 1989; 263(3):867-73. PMC: 1133511. DOI: 10.1042/bj2630867. View

15.

Bergmann C, McReynolds C, Wan D, Singh N, Goetzman H, Caldwell C . sEH-derived metabolites of linoleic acid drive pathologic inflammation while impairing key innate immune cell function in burn injury. Proc Natl Acad Sci U S A. 2022; 119(13):e2120691119. PMC: 9060469. DOI: 10.1073/pnas.2120691119. View

16.

Li Y, Wu B, Hu C, Hu J, Lian Q, Li J . The role of the vagus nerve on dexmedetomidine promoting survival and lung protection in a sepsis model in rats. Eur J Pharmacol. 2021; 914:174668. DOI: 10.1016/j.ejphar.2021.174668. View

17.

Langsjo J, Maksimow A, Salmi E, Kaisti K, Aalto S, Oikonen V . S-ketamine anesthesia increases cerebral blood flow in excess of the metabolic needs in humans. Anesthesiology. 2005; 103(2):258-68. DOI: 10.1097/00000542-200508000-00008. View

18.

Hildreth K, Kodani S, Hammock B, Zhao L . Cytochrome P450-derived linoleic acid metabolites EpOMEs and DiHOMEs: a review of recent studies. J Nutr Biochem. 2020; 86:108484. PMC: 7606796. DOI: 10.1016/j.jnutbio.2020.108484. View

19.

Hu A, Zhong X, Li Z, Zhang Z, Li H . Comparative Effectiveness of Midazolam, Propofol, and Dexmedetomidine in Patients With or at Risk for Acute Respiratory Distress Syndrome: A Propensity Score-Matched Cohort Study. Front Pharmacol. 2021; 12:614465. PMC: 8044880. DOI: 10.3389/fphar.2021.614465. View

20.

Lawrence C, Prinzen F, de Lange S . The effect of dexmedetomidine on nutrient organ blood flow. Anesth Analg. 1996; 83(6):1160-5. DOI: 10.1097/00000539-199612000-00005. View