Two and a half years ago Susan Baker spent three hours under general anesthesia as surgeons fused several vertebrae in her spine. Everything went smoothly, and for the first six hours after her operation, Baker, then an 81-year-old professor at the Johns Hopkins Bloomberg School of Public Health, was recovering well. That night, however, she hallucinated a fire raging through the hospital toward her room. Petrified, she repeatedly buzzed the nurses' station, pleading for help. The next day she was back to her usual self. “It was the most terrifying experience I have ever had,” she says.

Baker's waking nightmare was a symptom of postoperative delirium, a state of serious confusion and memory loss that sometimes follows anesthesia. In addition to hallucinations, delirious patients may forget why they are in the hospital, have trouble responding to questions and speak in nonsensical sentences. Such bewilderment—which is far more severe than the temporary mental fog one might expect after any major operation that requires general anesthesia—usually resolves after a day or two.

Although physicians have known about the possibility of such confusion since at least the 1980s, they had decided, based on the then available evidence, that the drugs used to anesthetize a patient in the first place were unlikely to be responsible. Instead, they concluded, the condition occurred more often because of the stress of surgery, which might in turn unmask an underlying brain defect or the early stages of dementia. Studies in the past four years have cast doubt on that assumption, however, and suggest that a high enough dose of anesthesia can in fact raise the risk of delirium after surgery. Recent studies also indicate that the condition may be more pernicious than previously realized: even if the confusion dissipates, attention and memory can languish for months and, in some cases, years.

In Too Deep
Anesthesia comes in three main types. Local anesthesia, the mildest form, merely numbs a very small area, such as a single tooth. Regional anesthesia desensitizes a large section of someone's body by injecting drugs into the spine that block nerve signals to the brain. Often a patient getting regional anesthesia also takes a relatively small dose of a powerful sedative drug, such as propofol—not enough to put them under but enough to alter brain activity in a way that makes the person less aware and responsive.

General anesthesia relies on a cocktail of drugs that renders patients completely unconscious, prevents them from moving and blocks any memories of the surgery. Although anesthetic drugs have been around since 1846, many questions remain as to how exactly they work. To date, the strongest evidence suggests that the drugs are effective in part because they bind to and incapacitate several different proteins on the surface of neurons that are essential for regulating sleep, attention, learning and memory. In addition, it seems that interrupting the usual activity of neurons may disrupt communication between far-flung regions of the brain, which somehow triggers unconsciousness.

When postoperative delirium was first recognized, researchers wondered whether certain anesthetic drugs—but not others—deserved the blame. Yet studies comparing specific drugs and rates of delirium in patients after surgery have always been scant and inconclusive. “No particular anesthetic has been exonerated in patients,” says Roderic G. Eckenhoff, a professor of anesthesiology at the University of Pennsylvania. But “we can't say yet that there is an anesthetic that patients should not get.”

One reason scientists struggled to say whether sedative drugs were at fault was the difficulty of separating them from other major hospital stresses, such as surgery itself. Indeed, many of the things that make being hospitalized so unpleasant—poor sleep, restricted movement and a regimen of medicines—can also cause confusion, forgetfulness and even delusions.

In spite of these difficulties, researchers hit on two other factors that increased the chances a patient would become dramatically confused after an operation: being older than about 70 and having preexisting mental deficits, such as regularly forgetting appointments or severe dementia. Delirium is also more common after major surgeries—which can last at least a few hours and require patients to stay one night or longer in the hospital. Among patients above age 60 about 50 percent become seriously disoriented after heart bypass or valve replacement surgery, according to one study, yet the same is true for only 15 percent or so of patients in the same age range who have elective hip joint surgery—a shorter and less risky procedure.

Research over the past several years has revived anesthesia as a potential culprit in delirium: instead of focusing on the type of anesthetic drug, scientists are now concerned about the amount of overall anesthesia. Researchers suspect that the more anesthesia someone receives—and, consequently, the deeper someone slips into unconsciousness—the greater the risk of delirium. In one study, for example, Frederick E. Sieber of the Johns Hopkins University School of Medicine and his colleagues gave 57 elderly hip surgery patients enough propofol to achieve regional anesthesia and another 57 patients enough propofol to induce general anesthesia. Eleven of the lightly anesthetized patients became delirious after the operation, compared with 23 of the patients under general anesthesia.

A related study offers a clue as to why previous research failed to see a difference in rates of delirium between patients receiving general and regional anesthesia. Sieber tracked 15 patients aged 65 years and older who were all undergoing surgery to repair fractured hips. The team gave the patients regional anesthesia consisting of propofol and an anesthetic that disabled nerves in the spinal cord. Based on standard practice, the team monitored blood pressure and heart rate as a proxy for depth of anesthesia to determine the appropriate dose. Meanwhile a computer, which the team could not see, also determined the depth of anesthesia based on a more direct but less commonly used measurement: electrical activity in the patients' brain, as gauged by electrodes attached to their forehead. The fewer electrical impulses crackling through their brains, the deeper the anesthesia. Eighty-seven percent of patients' brain activity dipped low enough to qualify as general anesthesia during at least part of the surgery.

“I was flabbergasted,” Sieber says. Because of this study and similar findings, he suspects that it is common for patients getting regional anesthesia to receive so much sedative drug that they are actually in a state of general anesthesia.

Lasting Effects
Deep anesthesia has also been linked to subtler but longer-lasting cognitive problems. In a 2013 study, doctors at a Hong Kong hospital monitored the brain activity of 462 patients undergoing major surgery, keeping the electrical activity as high as possible while still inducing general anesthesia. For another 459 patients receiving general anesthesia, the doctors monitored only blood pressure and heart rate. Patients received either propofol or one of several anesthetic gases. The morning after surgery, 16 percent of patients who had received light anesthesia displayed confusion, compared with 24 percent of the routine care group. Likewise, 15 percent of patients who received typical anesthesia had postoperative mental setbacks that lingered for at least three months—they performed poorly on word-recall tests, for example—but only 10 percent of those in the light anesthesia group had such difficulties.

In some cases, these mental handicaps persist longer than a few months. Jane Saczynski, an assistant professor of medicine at the University of Massachusetts Medical School, and her colleagues tracked the mental abilities of patients 60 years and older in the Boston area for up to one year after heart bypass or valve surgery. Based on tests of memory and attention in which patients repeated phrases and named everyday objects, those who did not develop any delirium generally regained their presurgery mental capabilities within a month, whereas patients with postoperative delirium took between six months and a full year to recuperate. Patients whose mental fog lasted more than three days after surgery had still not regained their full acumen a year after the operation.

Although researchers remain uncertain about how anesthetic drugs might usher in a state of postoperative delirium, they have some ideas. The drugs may have an easier time overwhelming neurons in older adults because the proteins that anesthetic drugs are thought to target on the surface of neurons become less abundant with age. Some experts have suggested that in elderly patients, the brain may also have a harder time refashioning the connections between different regions that could break down during anesthesia.

Preliminary Protections
As researchers continue to look for more precise answers about postoperative delirium, clinicians are adopting a number of strategies to minimize risk. Doctors at John Hopkins and other hospital settings now constantly talk with elderly patients during regional anesthesia, making sure they can respond to their name. Sieber thinks this practice could be at least as effective a gauge of the depth of anesthesia as brain activity and could be superior to blood pressure and heart rate measurements.

Other precautions include making sure patients are well hydrated and nourished before surgery, which likely improves blood flow to the brain. After surgery, experts recommend orienting patients to their hospital stay by encouraging family and friends to visit, getting them up and out of bed during the day, encouraging a good night's sleep, and discontinuing any medications that could further alter brain activity. Although it remains unclear exactly how these interventions help, physical and mental activities stimulate communication between nerve cells, which could reestablish vital connections between brain regions.

For her part, Susan Baker has always made an effort to be as active as possible and to spend time with loved ones following the various surgeries in her life, just because it has seemed like a good way to spur recovery. But when she had to have another procedure after her delirious episode, she took a couple of extra precautions—asking her son to stay in her hospital room that night, for example. And before her operation, she made a special request: to keep the anesthesia as light as possible.