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Every day about 60,000 people have surgery under general anesthesia in the United States.
Often casually compared to falling into a deep sleep, going under is in fact wildly different from your everyday nocturnal slumber. Not only does a person lose the ability to feel pain, form memories, or move—they can’t simply be nudged back into conscious awareness.
But occasionally, people do wake unexpectedly—in about 1 out of every 1,000 to 2,000 surgeries, patients emerge from the fog of anesthesia into the harsh light of the operating room while still under the knife.
One question that has dogged researchers over the past several decades is whether women are more likely to find themselves in these unfortunate circumstances. A number of recent studies, including a 2023 meta-analysis, suggest that the answer is yes.
There seems to be something hardwired into the female brain that biases it more toward a state of wakefulness.
But the findings are controversial: Other studies have found no differences in waking frequency between the sexes and most of the studies were not designed specifically to identify sex differences. It’s also difficult to know whether other factors might have influenced the results: rates of metabolization of drugs by male and female bodies, as well as variation in kinds of surgeries and anesthetic regimens among study participants. No causal link had been established.
Now, a new study published in the Proceedings of the National Academy of Sciences helps untangle some of the mystery. In a series of experiments in mice and in humans, the researchers found that females do wake more easily from anesthesia and that testosterone plays an important role in how quickly and deeply we go under, and how easily we wake up.
“There seems to be something hardwired into the female brain that biases it more toward a state of wakefulness,” says University of Pennsylvania anesthesiologist Max Kelz, co-author of the study.
Kelz and his colleagues also learned that EEG, or electroencephalogram readings—which have been used to quantify the effects of anesthesia since the 1930s—do not accurately detect differences in anesthetic sensitivity between male and female humans or mice. The findings could influence clinical anesthesia dosing for women, which today is still largely guided by data disproportionally collected from males.
Despite the differences between sleep and anesthesia, a growing body of evidence across species suggests that anesthesia acts on a region of the brain that regulates sleep and arousal called the hypothalamus. This region is also known to be sensitive to sex hormones, so Kelz and his team decided to test the impact of hormones on anesthesia directly by removing the sex organs of a cohort of mice and comparing their responses to those with organs intact.
The male mice whose testicles were removed were more likely to resist the pull of sleep than male mice with testicles—their response times were similar to those of regular female mice. Meanwhile, the females whose ovaries were removed behaved no differently from those whose ovaries remained intact. Was testosterone the deciding factor? To further test this idea, they administered testosterone to both intact and castrated male mice and found it increased the responses to anesthesia in both—sensitivity rose with the dose and was stronger in the castrated mice.
Next, the scientists peered inside the brains of the mice to see if they could detect specific sex differences in hypothalamic activity under anesthesia. They flash-froze the brains of normal male and female mice immediately following four hours of general anesthesia and used fluorescent chemicals to tag neurons expressing a protein associated with brain cell activity. In male mice, the proteins lit up cells in crowded constellations around the sleep-promoting neurons of the hypothalamus, while the females had a sparser smattering of fluoresced cells in the same area.
To see if their findings about anesthetic sensitivity extended to humans, they took a fresh look at data from a small prior study they had conducted in which 12 female and 18 male adult volunteers underwent general anesthesia, without surgery. They wanted to compare brain activity and function in these individuals as they regained consciousness.
“We initially ignored any sex-based differences,” says Kelz, when they conducted the study in 2021. But a second look revealed a similar pattern to that found in mice: Female participants emerged in just under 30 minutes on average compared to about 45 minutes for the males after identical exposures to anesthesia. They also performed faster and more accurately on cognitive tests during their recoveries.
Having confirmed these behavioral differences in anesthetic response, the researchers turned to EEG. They analyzed EEG readings of not just male and female mice, but also humans to see if they could detect any differences in activity under a variety of doses of anesthesia. They could not.
Of course, none of this answers the question of why females might have evolved to resist the tug of anesthetic sleep more than males. But it does settle some puzzles about cause and effect. And it could, ultimately, lead to safer surgeries for women. 
Lead image: agsandrew / Shutterstock
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