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Los Angeles Times, May, 2007

May 3, 2007

Some worry about brain cell death in studies of young animals. Human trials are planned. Anesthesia has been ranked in the top five medical advances of recent times. (LAT)

You are asleep on the table, surrounded by beeping monitors and people in white, unaware of the tube down your throat and the slice of the surgeon’s knife. You wake a few hours later, as if from deep slumber — and, thanks to the miracle of anesthesia, remember nothing.

Back to normal — or so it has long been assumed.

The use of anesthetics dates back at least 150 years to when a traveling dentist reported using laughing gas on a patient. Today, anesthesia is an integral part of modern medicine: A survey by the British Medical Journal earlier this year ranked it among the five most important medical advances in recent times.

But recently, a few scientists and clinicians have raised concerns about its possible long-term effects. They suspect, based on studies in animals and lab dishes as well as some preliminary human data, that for patients who are very young, old or sick, anesthesia might have longer-term consequences.

“Anesthesia was thought to be something that lasted a few hours, and any consequences would be gone within a day,” says Dr. Daniel Sessler, an anesthesiologist and chair of the outcomes research department at the Cleveland Clinic in Ohio. “There is increasing evidence that it is not the case.”

It is a minority viewpoint: Most anesthesiologists and surgeons, citing the millions of people the world over who live long, healthy lives after surgery, say there is no call for worry.

But the possibility has led Sessler and others to start human trials to examine the issue. The Food and Drug Administration is also taking notice. In March, it convened a panel of experts to look into the long-term safety of pediatric anesthesia.

Those worried about long-term effects cite several possible risks. Sessler suggests that general anesthesia might weaken the body’s ability to kill tumor cells released into the bloodstream during cancer surgery, making the disease more likely to return. Other researchers fear that anesthesia could trigger an inflammatory response in the body, eventually leading to atherosclerosis and other serious conditions.

But the biggest concern is the effect of anesthetic drugs upon brain cells, especially in infants.

In 2003, Dr. John Olney, professor of psychiatry and neuropathology at the Washington University School of Medicine in St. Louis, reported that an anesthetic mix commonly used on children caused significant loss of brain cells in infant rats. (The cause: a sharp increase in a kind of cell death that naturally occurs during brain development.) Olney and other researchers have also found that anesthetized baby rodents develop memory and learning problems — as measured by skills such as maze navigation — in adulthood.

“The chances are pretty strong that the same effect can occur in humans,” Olney says.

Researchers at the FDA have repeated Olney’s experiments with rhesus monkeys, which live longer than rats — about 20 years — and are biologically more similar to humans. They also found that 24 hours of anesthesia caused unborn and 5-day-old rhesus monkeys to lose brain cells, although not as many as the rats did. The cell death didn’t happen, however, with shorter periods of anesthesia or in older monkeys.

Gregory Crosby, associate professor of anesthesia at Harvard Medical School and Brigham and Women’s Hospital in Boston, has found effects on older animals. In 2004, he reported that aged rats given two hours of general anesthesia did more poorly in a maze-running test two weeks later. He also detected abnormalities in the rats’ hippocampus — the part of the brain linked to spatial reasoning and memory formation.

Mental confusion after surgery has been reported in humans: For example, in 1998, a study in Lancet found that about 10% of elderly surgery patients had a worse score in cognitive tests three months after the operation. But it’s not clear if the real culprit for this condition, called post-operative cognitive dysfunction, is anesthesia or the surgery itself.

Many clinical anesthesiologists question the relevance of the animal studies. “Human babies are not large rat pups,” says Dr. Sulpicio Soriano, associate professor of anesthesia at Harvard Medical School and senior associate in anesthesia at Children’s Hospital Boston. In his own experiments, he says, he had to anesthetize the baby rodents for at least six hours to trigger brain cell death: equivalent to giving several weeks-worth of anesthesia to a human patient. “That is a very artificial condition,” he says.

If human infants need major surgery, “we should not be delaying that because of this very preliminary result in rats,” says Dr. Roger Moore, first vice president of the Park Ridge, Ill.-based American Society of Anesthesiologists and chair emeritus of the Deborah Heart and Lung Center in Brown Mills, N.J.

A group of researchers including anesthesiologist Dr. Andrew Davidson of the Royal Children’s Hospital in Melbourne, Australia, is planning a multinational study of the long-term outcomes of infants undergoing hernia surgery. The patients will get either general anesthesia or spinal anesthesia, which, in theory, has less effect on the brain. The researchers will assess the mental development of the children at two and five years after surgery to see if those who got general anesthesia suffered any long-term effects.

“The study can be regarded as a safety trial,” Davidson says. “We’d like to show that anesthesia is safe in babies and doesn’t cause injuries.”

If any of the concerns turns out to be true, what then? Some researchers suggest postponing elective surgery for infants — such as cleft lip repair — until about 3 years of age. Most surgeries on newborns, however, are emergency life-saving operations. “We are not giving anesthesia for fun,” Soriano says.

Olney suggests developing a drug that interrupts the cascade of biochemical changes by which anesthetics might destroy brain cells. By giving this hypothetical drug along with the anesthetic, “you can have the benefits of anesthesia” without the unwelcome side effects, he says.

Crosby says he has found, in as-yet-unpublished work, that one commonly used anesthetic is less harmful to lab animals than the others he has tested. Maybe, he says, some of the potentially harmful effects of anesthesia could be avoided by changing the cocktail of anesthetic drugs administered to patients.

An already available option is regional anesthesia — in which only a region of the body is numbed instead of making the patient fully unconscious. In February, Sessler started a clinical trial to compare the cancer recurrence rate of about 1,100 women undergoing breast cancer surgery with either general or regional anesthesia. He hopes to show the latter is more benign.

In another clinical trial, he’s investigating the long-term outcomes of patients undergoing vascular surgery whose dose of general anesthetic is optimized based on their level of consciousness, as measured by a brain monitor. The idea is to give just enough medication to keep the patient unconscious, he says. A preliminary study of 1,064 patients published in 2005 suggested that this technique could reduce the likelihood of death in the year after vascular surgery.

Results of such studies are likely to be subtle, all agree. “Obviously,” Crosby says, “we are not rotting out people’s brains in a big way or you’d have known that a hundred years ago.”