Oestrous cycle affects emergence from anaesthesia with dexmedetomidine, but not propofol, isoflurane, or sevoflurane, in female rats

Vincent, Kathleen; Mallari, Olivia G.; Dillon, Emmaline J.; Stewart, Victoria G.; Cho, Angel J.; Dong, Yuanlin; Edlow, Andrea G.; Ichinose, Fumito; Xie, Zhongcong; Solt, Ken

doi:10.1016/j.bja.2023.03.025

Cited by 7 publications

(5 citation statements)

References 37 publications

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“…The existence of sex differences in anesthetic sensitivity has been suggested by some previous clinical ( 23 , 37 ) and animal studies ( 43 , 44 , 46 ). However, a major limitation of the previous work was that the sex differences in anesthetic sensitivity were confounded by differences in drug absorption and elimination.…”

Section: Discussionmentioning

confidence: 82%

“…Conflicting results have been previously reported using rodents as a model organism for studying sex differences in anesthetic sensitivity ( 42 – 45 ). A common explanation for these disparities has been cyclic fluctuations of sex hormones ( 44 – 48 ). Despite recent efforts to elucidate sex and hormonal effects on anesthetic sensitivity, pharmacokinetic confounds complicate the interpretations of many studies.…”

mentioning

confidence: 99%

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Hormonal basis of sex differences in anesthetic sensitivity

Wasilczuk,

Rinehart,

Aggarwal

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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General anesthesia—a pharmacologically induced reversible state of unconsciousness—enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females.

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

Hormonal basis of sex differences in anesthetic sensitivity

Wasilczuk,

Rinehart,

Aggarwal

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…Gender disparities might affect the sensitivity to dexmedetomidine-associated sedation ( Vincent et al, 2023 ). Hence, we conducted subgroup analyses to examine the potential influence of gender on dexmedetomidine-associated adverse effects among men and women.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, descriptive baseline population data suggest proportional differences in the gender distribution of adverse effects. Basic studies have demonstrated that gender differences influence the anxiolytic and sedative effects of dexmedetomidine ( Jang et al, 2019 ; Vincent et al, 2023 ). Identifying biological or social factors associated with gender may provide guidance for monitoring dexmedetomidine adverse reactions.…”

Section: Discussionmentioning

confidence: 99%

Clinical adverse events to dexmedetomidine: a real-world drug safety study based on the FAERS database

Liu,

Zheng,

2024

Front. Pharmacol.

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ObjectiveAdverse events associated with dexmedetomidine were analyzed using data from the FDA’s FAERS database, spanning from 2004 to the third quarter of 2023. This analysis serves as a foundation for monitoring dexmedetomidine’s safety in clinical applications.MethodsData on adverse events associated with dexmedetomidine were standardized and analyzed to identify clinical adverse events closely linked to its use. This analysis employed various signal quantification analysis algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS).ResultsIn the FAERS database, dexmedetomidine was identified as the primary suspect in 1,910 adverse events. Our analysis encompassed 26 organ system levels, from which we selected 346 relevant Preferred Terms (PTs) for further examination. Notably, adverse drug reactions such as diabetes insipidus, abnormal transcranial electrical motor evoked potential monitoring, acute motor axonal neuropathy, and trigeminal cardiac reflex were identified. These reactions are not explicitly mentioned in the drug’s specification, indicating the emergence of new signals for adverse drug reactions.ConclusionData mining in the FAERS database has elucidated the characteristics of dexmedetomidine-related adverse drug reactions. This analysis enhances our understanding of dexmedetomidine’s drug safety, aids in the clinical management of pharmacovigilance studies, and offers valuable insights for refining drug-use protocols.

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“…Thus, these results suggest that the effect of KEMCT administration on the time required to recover from isoflurane anesthesia may be sex-dependent, likely through the adenosinergic system, at least in WAG/Rij rats. Nonetheless, it was demonstrated that the recovery time from isoflurane anesthesia was similar in male and female rats [49] and was not modulated by the estrus cycle [50].…”

Section: Discussionmentioning

confidence: 96%

Exogenous Ketone Supplement Administration Abrogated Isoflurane-Anesthesia-Induced Increase in Blood Glucose Level in Female WAG/Rij Rats

Rauch,

Ari,

D’Agostino

et al. 2024

Nutrients

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It has been demonstrated that isoflurane-induced anesthesia can increase the blood glucose level, leading to hyperglycemia and several adverse effects. The administration of a mix of ketone diester (KE) and medium-chain triglyceride (MCT) oil, named KEMCT, abolished the isoflurane-anesthesia-induced increase in blood glucose level and prolonged the recovery time from isoflurane anesthesia in a male preclinical rodent model, Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. While most preclinical studies use exclusively male animals, our previous study on blood glucose changes in response to KEMCT administration showed that the results can be sex-dependent. Thus, in this study, we investigated female WAG/Rij rats, whether KEMCT gavage (3 g/kg/day for 7 days) can change the isoflurane (3%)-anesthesia-induced increase in blood glucose level and the recovery time from isoflurane-evoked anesthesia using the righting reflex. Moreover, KEMCT-induced ketosis may enhance both the extracellular level of adenosine and the activity of adenosine A1 receptors (A1Rs). To obtain information on the putative A1R mechanism of action, the effects of an A1R antagonist, DPCPX (1,3-dipropyl-8-cyclopentylxanthine; intraperitoneal/i.p. 0.2 mg/kg), on KEMCT-generated influences were also investigated. Our results show that KEMCT supplementation abolished the isoflurane-anesthesia-induced increase in blood glucose level, and this was abrogated by the co-administration of DPCPX. Nevertheless, KEMCT gavage did not change the recovery time from isoflurane-induced anesthesia. We can conclude that intragastric gavage of exogenous ketone supplements (EKSs), such as KEMCT, can abolish the isoflurane-anesthesia-induced increase in blood glucose level in both sexes likely through A1Rs in WAG/Rij rats, while recovery time was not affected in females, unlike in males. These results suggest that the administration of EKSs as an adjuvant therapy may be effective in mitigating metabolic side effects of isoflurane, such as hyperglycemia, in both sexes.

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Oestrous cycle affects emergence from anaesthesia with dexmedetomidine, but not propofol, isoflurane, or sevoflurane, in female rats

Cited by 7 publications

References 37 publications

Hormonal basis of sex differences in anesthetic sensitivity

Hormonal basis of sex differences in anesthetic sensitivity

Clinical adverse events to dexmedetomidine: a real-world drug safety study based on the FAERS database

Exogenous Ketone Supplement Administration Abrogated Isoflurane-Anesthesia-Induced Increase in Blood Glucose Level in Female WAG/Rij Rats

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