Science, Medicine, and the Anesthesiologist

Recent studies suggest an increased likelihood of intraoperative awareness in female patients. However, most investigations were not designed to identify sex differences in anesthetic sensitivity. Using experiments in mice and data from the ReCCognition trial (NCT01911195), this study tested whether sexually dimorphic responses to general anesthesia exist, and if so, how they could be mechanistically explained. The righting reflex was used to generate induction and emergence dose-response curves using four volatile anesthetics in male and female mice. Female mice took longer to become anesthetized and emerged faster. Female mice were more likely to exhibit righting reflex at equal steady-state anesthetic concentration measured in the brain. These experimental findings could be confirmed by data collected in the ReCCognition trial showing faster emergence from anesthesia in female volunteers corroborated by psychomotor vigilance tests. Lower concentrations of testosterone contributed to resistance to general anesthesia. Experiments in castrated male mice showed that anesthetic sensitivity was increased by application of testosterone acting on specific hypothalamic neurons, which are involved in the induction of natural sleep. Interestingly, conventional electroencephalogram used to measure brain activity during anesthesia did not detect sex-based differences. This suggests that standard clinical practice might not fully capture depth of anesthesia in humans.

Take home message: The female brain in mice and humans is more resistant to the hypnotic effects of volatile anesthetics, which may explain the higher incidence of awareness under anesthesia in females.