The impact of female sex on anaesthetic awareness, depth and emergence: A systematic review and meta-analysis

Background Accumulating evidence supports sex differences in pharmacodynamic and pharmacokinetic drug profiles. However, recommended anaesthetic drug doses are not sex-adjusted, likely due to limited studies comparing sexes. Our objective was to systematically synthesise studies of anaesthetic key performance indicators (anaesthesia awareness), and markers of relatively lighter anaesthesia, time to emergence and dosing to achieve adequate depth of anaesthesia, for females and males. Methods MEDLINE, Embase, and the Cochrane library databases. Studies were identified from inception of database to August 2 nd , 2022. Controlled clinical trials (randomised and non-randomised) and prospective cohort studies that reported outcomes by sex for awareness with post-operative recall, connected consciousness during anaesthesia, depth of anaesthesia, and emergence from anaesthesia. Two authors undertook search, review, selection, and data abstraction. Risk of bias was assessed using the Newcastle Ottawa Scale. Results were synthesized by random effects meta-analysis where possible, or narrative form. Results were expressed as odds ratios (ORs) and mean differences (MDs) with corresponding 95% confidence intervals (CIs). Results Of the 19,749 studies identified from literature search, 66 citations of 64 studies (98,243 participants; 53,143 females and 45,100 males) were eligible for inclusion, of which 44 contributed to meta-analysis. Females had a higher incidence of awareness with post-operative recall (33 studies, OR 1.37, 95%CI 1.09 to 1.75) and connected consciousness during anaesthesia (3 studies, OR 2.09, 95% CI 1.04 to 4.23) than males. Time to emergence was faster in females than in males, including time to eye-opening (10 studies, MD -2.28 min, 95% CI -3.58 to -0.98), and time to response to command (6 studies, MD - 2.84 min, 95% CI -4.07 to -1.62). Data on depth of anaesthesia were heterogenous limiting synthesis to a qualitative review which did not identify differences by sex. Conclusion Female sex was associated with a greater incidence of anaesthetic awareness, as well as faster emergence from anaesthesia. These data suggest reappraisal of anaesthetic care, including whether similar drug dosing for females and males represents best care. Equitable outcomes for females undergoing general anaesthesia warrants strategic focus in future research. Systematic review registration PROSPERO CRD42022336087.