Correction Appended: November 9, 2009
General anesthesia — the enabler of modern surgery and medical intervention — is one of the great triumphs of the scientific method. Ether, the compound from which almost all modern anesthetics are derived, was discovered largely by luck and its derivatives through trial and error. As a result, however, much about these drugs remains mysterious. Even today, doctors are baffled as to why exactly anesthetics cause unconsciousness in patients.
For the most part, however, doctors are happy that anesthetics indeed work and seem to be safe. Used at the right doses in healthy people, the drugs rarely cause serious complications or side effects; the risk of death in patients undergoing general anesthesia, for example, is 1 in 250,000. But recent inquiries into how these strange chemicals act on the cellular level have uncovered a troubling long-term possibility: that general anesthetics may potentially contribute to cognitive impairment in vulnerable patients such as the very young and very old.
In 2007, Dr. Zhongcong Xie, now an associate professor of anesthesia at Massachusetts General Hospital, and colleagues published the first in a series of studies demonstrating that commonly used general anesthetics can cause cell death and plaque accumulation in brain cells — both potential hallmarks of dementia and Alzheimer's disease. More recently, at the Mayo Clinic, in Minnesota, anesthesiologist Dr. Robert Wilder published a study that found a link between exposure to anesthesia and surgery in infancy and learning disabilities later in life. Both doctors have since been approached with inquiries from concerned patients — but armed only with early data, neither can offer much reassuring advice. "What can I say? We don't have any answers," says Xie. "We have some troubling warning signs, but we cannot conclude that these drugs are causing brain damage in people."
It has been a similarly frustrating situation for Wilder. "All we can say to parents, at the moment, is that you shouldn't do unnecessary procedures on kids — but we knew that already," he says.
Fittingly, the initial discovery of the potentially neurotoxic effect of anesthesia occurred by accident. In the 1990s, scientists discovered that the brain cells of patients in the midst of a stroke were flooded with calcium. Doctors wishing to treat these patients hypothesized that blocking the receptor that enables calcium to enter cells could protect stroke patients from severe brain damage. But in the course of researching this possibility, they found that switching off the receptor in a healthy brain cell led to the death of that cell — an unexpected and troubling result, given that many common anesthetics block the same receptor. At first this made little sense, but other researchers began to speculate that preventing calcium entry might be the cause of injury.
The role of calcium in the healthy brain is critical, particularly in young children, whose brains undergo rapid neural development from the last trimester in utero up through ages 1 to 2. Infants' brains expand quickly, then ruthlessly prune back brain cells — a process of orderly cell death, known as apoptosis. In an experiment in young rats undergoing this crucial stage of neural development, Christopher Turner, an assistant professor of neurobiology and anatomy at Wake Forest University School of Medicine, witnessed out-of-control apoptosis in the brains of rats treated with drugs that mimicked the action of the general anesthetic ketamine. Starved of calcium, whole portions of the rats' brains died off — enough to cause significant cognitive impairment. In adult rats, the effect was much less severe. "There is something about the young brain that makes it exquisitely sensitive to the loss of calcium," says Turner, who was the first to propose that calcium depletion is a critical first step in drug-induced brain-cell injury.
In a separate area of research, Xie at Massachusetts General tested another anesthetic, isoflurane, on a culture of human brain cells. (Isoflurane had already been shown to cause cognitive impairment in rats.) He saw a vicious cycle of apoptosis and the accumulation of beta-amyloid protein — the sticky plaques that build up in Alzheimer's patients' brains — among the cells. But in this case, it may have been an excess of calcium that led to cell death. Xie and his colleagues have since found that the Alzheimer's drug memantine, which works by reducing calcium levels inside cells, can slow the rate of isoflurane-induced cell death. "That certainly suggests that Dr. Turner and we could be looking at the different sides of the same coin," Xie says.
Whether these two areas of research are related was a topic of debate at the annual convention of the American Society of Anesthesiologists (ASA) in New Orleans in late October. So too was their clinical significance. No population study has ever conclusively linked anesthetic drugs to Alzheimer's or dementia. (Although doctors have long noted that about 10% of patients who receive anesthetics for major surgery experience a temporary period of "post-operative cognitive decline" after coming out of anesthesia, the condition is not limited to elderly patients, and it could be the result of inflammation or other stress responses to major surgery, rather than the anesthetic.) The only research to associate surgical anesthesia in infancy to cognitive impairment later in life was Wilder's study earlier this year, but the literature on the whole in this area remains inconclusive. So far, the bulk of the evidence comes from studies in lab animals, rather than the human population. "The animal data is convincing," says Wilder. "But we need further studies to see if it's true in humans too."
Some researchers, including Lisa Wise-Faberowski, an assistant professor of anesthesiology and pediatric cardiology at the University of Colorado, Denver, think the effect in humans won't be easy to show. At the ASA conference, Wise-Faberowski devoted her presentation to chiding researchers for worrying prematurely about "anesthesia-induced neurotoxicity," pointing out that it has been seen only in "cell cultures and lab animals." If anesthetics have always been neurotoxic, one slide in her presentation asked, "Why is it only an issue now?" She and others point out that non-human testing of anesthetic safety has an unreliable history. Ten years ago, for instance, lab researchers found evidence that isoflurane protected brain cells during surgery and trauma, only to be contradicted by more recent lab findings.
Every doctor interviewed for this article urged patients not to avoid necessary surgery or forgo required anesthesia. To understand the consequences of going without anesthesia, Wilder points to certain surgical trends in the 1960s. Believing that babies were still too underdeveloped to feel pain, many doctors at the time advocated only light anesthesia or none at all for infants undergoing surgery. "The morbidity and indeed mortality levels were much higher [in these babies]. The stress response to the pain of the surgery proved dangerous," Wilder explains. It is also important to remember how primitive surgical painkilling mechanisms were before the invention of ether, Wilder adds. According to the medical historian Paul Strathern, for example, the greatest French surgeon of the early 19th century, Guillaume Dupuytren, once reported that the best method he had discovered for anesthetizing his female patients was to make a "brutal remark" and hope they fell into a faint.
Several large population studies into anesthetics are now under way among both young children and elderly patients. Wilder anticipates that "we are about five years away from getting to the bottom of this." If anesthetics do prove to be neurotoxic, it could be a regulatory and ethical nightmare to decide how best to continue using them. For Xie's part, he thinks researchers must come up with alternative drugs for vulnerable patients if such a scenario unfolds. "Science doesn't always tell us what we want to hear. If certain drugs are dangerous to use, then we should not use them," he says.
In the originally published version of this story it was incorrectly stated that the most recent annual meeting of the American Society of Anesthesiologists took place in Chicago. In fact, the meeting took place in New Orleans.