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There are sex differences in anesthetic sensitivity. Females recover from anesthesia faster than males. Two recent papers document this.
Should anesthesiologists change their clinical care based on these studies?
I.
A recent study, “Hormonal basis of sex differences in anesthetic sensitivity,” published in 2024 in the journal Neuroscience, presented data that females recover from general anesthesia faster than males. Andrzej Z. Wasilczuk from the Department of Anesthesiology and Critical Care at the University of Pennsylvania led the study. His team demonstrated that female brains in both mice and humans were more resistant to the effects of the potent volatile anesthetic gas isoflurane. The researchers postulated that this resistance to anesthetics could explain the higher incidence of awareness under anesthesia in female patients.
The experiments in mice: Twenty mice (10 male and 10 female) were exposed to 1.2% isoflurane in 100% oxygen in a hermetically sealed rotating chamber, and the time to the loss of the righting reflex was measured. The “righting reflex” refers to the innate ability of a mouse, when placed in a rotating drum, to automatically flip itself back onto its feet if the mouse is placed on its back. A loss of the righting reflex can indicate impairment in the mouse’s vestibular system or central nervous system. Starting from the onset of anesthetic delivery, the mice in Wasilczuk’s experiments were continuously rotated until they were unable to reorient themselves to a prone position. The time to loss of this righting reflex was measured, After the loss of the righting reflex, the rotation of the chamber was stopped, and mice were continuously exposed to 1.2% isoflurane for 2 additional hours. To study emergence, the isoflurane delivery was stopped and the time to spontaneous return of the righting reflex was recorded.
The averaged expired concentration for the induction of general anesthesia (the loss of the righting reflex) was significantly higher in females. The dose–response curve for emergence was also significantly faster in females. Similar differences in sensitivity were observed for all tested potent volatile gas anesthetics, including sevoflurane, the most used volatile anesthetic in America today.
The researchers also studied the effect of sex hormones on anesthetic sensitivity. They tested castrated male and ovariectomized female mice, and compared their anesthetic sensitivity to that of normal control mice. Castration eliminated all sex differences in anesthetic sensitivity. Oophorectomy had no effect on anesthetic sensitivity. These results suggested that sex differences in anesthetic sensitivity were primarily due to the presence of testosterone in male rats, and that sex hormones modulate anesthetic sensitivity.
The experiments in humans: The same researchers reanalyzed data collected from the ReCCognition trial, a study in which 30 healthy human volunteers (12 women and 18 men, 22 to 40 years old) were given isoflurane at 1.7% to 1.9% for 3 hours. Their EEGs were recorded throughout. Serial neurocognitive exams were performed prior to the anesthetic, immediately upon emergence, and every 30 minutes over the following 3 hours. At the end of the anesthetic an auditory cue was played for the volunteers and repeated every 30 seconds, asking them to squeeze either hand twice. Females regained the ability to follow auditory cues sooner, signifying emergence from anesthesia faster than males (p = 0.0017). The researchers also used the psychomotor vigilance test, which measures cognitive awareness and sustained attention. Females performed faster and more accurately on this test upon recovery from anesthesia. The test results offered evidence of significant increased anesthetic resistance in females.
Lack of EEG differences: The authors performed spectral analysis on the EEGs of female and male mice exposed to steady-state 0.6% isoflurane. Even though female mice woke more rapidly from isoflurane anesthesia, the EEGs of the female and male sexes recorded during the wakeup from steady-state anesthesia did not differ. In the human volunteers, the researchers found that during uniform 1.3 MAC steady-state isoflurane anesthetics, just as in mice, there were no sex differences were observed in the human EEGs. While sex corelated with clear differences in anesthetic sensitivity in both mice and humans, EEG measures of anesthetic depth did not reveal sex differences in either species.
In their conclusions the authors stated, “We directly demonstrated that the female brain is more resistant to the hypnotic effects of volatile anesthetics. Sex differences in anesthetic sensitivity are predominantly due to testosterone. We demonstrated that sex differences in anesthetic sensitivity are conserved between mice and humans.”
II.
A related paper, “Impact of female sex on anaesthetic awareness, depth, and emergence: a systematic review and meta-analysis,” by lead author Hannah E. Braithwaite from the Department of Anaesthetics, Royal Prince Alfred Hospital in Sydney, Australia, was published in 2023 in the British Journal of Anaesthesia. This study concluded that the “female sex was associated with a greater incidence of awareness under general anaesthesia, and faster emergence from anaesthesia. These data suggest reappraisal of anaesthetic care, including whether similar drug dosing for females and males represents best care.” This publication was a meta-analysis of 44 previous studies on anesthetic awareness, depth, and emergence, including a total of 98,243 participants (53,143 females and 45,100 males). Analysis of the data showed that 1) females had a higher incidence of awareness with postoperative recall than males, and 2) the time to emergence was faster in females, including time to eye-opening and time to response to command. The data in this meta-analysis was consistent with the Wasilczuk study.
Should anesthesiologists change their clinical care based on these two important publications? Here are my impressions on how these studies may affect clinical practice:
- For decades prior to these studies, when anesthesiologists utilized potent volatile gas anesthetics such as sevoflurane or isoflurane, the administered dose has been the same whether the patient was female or a male. The dose of the volatile anesthetic was titrated up or down based on the patient’s blood pressure and heart rate, and the potent volatile gas was tapered off at the conclusion of the anesthetic. For decades we were never aware, we were never taught, nor did we teach, that females recovered from volatile anesthetic faster than males. Both female and male patients eventually woke up, were sent to the Post Anesthesia Care Unit, and were ultimately discharged to their hospital room or to their home. Now that convincing data show that females are associated with faster emergence from volatile anesthesia and a greater incidence of awareness under general anesthesia, one may infer that we should administer a higher depth of volatile anesthesia to female patients. How much higher should the depth of volatile anesthesia be? This will require further study of volatile anesthetic potency in both sexes, and revisiting experiments to determine any difference in the minimum anesthetic concentration (MAC) in female and male patients.
- Most modern anesthetics are administered using a combination of volatile and intravenous drugs. Currently most general anesthetics include an IV benzodiazepine such as Versed, followed by IV fentanyl, IV propofol, and maintenance anesthesia with sevoflurane. At the conclusion of surgery the IV drugs are tapered off, the volatile anesthetic is turned off, and ventilation is continued to remove the anesthetic gas from the patient’s lungs, bloodstream, and brain. The Wasilczuk study shows that females wake more quickly from volatile anesthesia, but does not pertain to the depth of anesthesia from the potpourri of IV anesthetic drugs administered in modern operating rooms. Further investigations to determine whether there are differing responses to intravenous anesthetic drugs in females and males are needed.
- If an anesthesia professional is utilizing a continuous EEG monitor such as a BIS monitor, the Wasilczuk study affirmed that there is no EEG difference between females and males for an identical dose of volatile anesthesia, and BIS monitoring will not solve this problem.
- The data from these two publications are both interesting and unexpected. In 40 years of personally administering general anesthesia to more than 30,000 patients, I’ve had no suspicion that females woke more quickly than males. Contrary to the data in these studies, the most obvious difference between female and male wakeups has been that petite patients—most often petite females—were more sensitive to identical doses of IV drugs such as fentanyl, Versed, and propofol, and these petite females were more likely to have a prolonged recovery time.
- The data from these two publications is evidence that adequate anesthetic depth in female patients likely requires an increased concentration of volatile gas. The degree of that concentration increase is to be determined from future studies in both males and females.
- Note that the data from these two publications does not apply to injections of local anesthesia. There is no known data that females and males differ in sensitivity to lidocaine or other injected local anesthetics.
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