Anesthesia is one of the most effective medical interventions, yet one of the least understood. Since the nature of consciousness is a fundamental mystery, perhaps it is not surprising that the art of rendering people unconscious also defies exact understanding.

These gaps in knowledge mean that anesthesiologists have no reliable ways to gauge when a person is unconscious. On rare occasions patients wake up during surgery.

"I came out of the anesthetic and couldn't understand why I wasn't in the ward," said one patient who was undergoing surgery in a British hospital, quoted in a recent book on anesthesia. "I could see the surgeons at the end of the operating table and I thought, 'Oh, my God, they're going to operate on me and I'm awake.' I tried to tell them, but I couldn't speak -- couldn't move. It was the worst experience of my life."

Fortunately, the vast majority of patients -- even those few who experience some level of awareness during operations -- feel no pain while under general anesthesia and tend not to remember anything afterward. But the fact that some people do regain consciousness during surgery, coupled with an inability to reliably measure or even define consciousness, has prompted a number of anesthesiologists to venture out of the operating room and into the research laboratory to find out just what anesthetics do to people's brains.

Only a handful of anesthesiologists are interested in this question, says Dr. Guy Weinberg, an assistant professor of anesthesiology at the University of Illinois College of Medicine in Chicago. But given advances in molecular biology and new ways of studying the brain, he said, more research is being done.

Earlier this month, Dr. Weinberg ran a weeklong, intensive session on the molecular mechanisms of anesthesia at the Telluride Summer Research Center in Telluride, Colo. Nine anesthesiologists were invited to discuss their theories and exchange ideas for new experiments.

Defining consciousness

Because the goal of general anesthesia is to render people unconscious, Dr. Weinberg said, understanding how the drugs work could shed light on the bigger question of the nature of consciousness and where it resides in the brain.

It may also lead to a clearer definition of consciousness, he said. For example, some anesthetics work by blocking memory. Patients, who are given other drugs to eliminate the pain, can walk, talk and follow directions, yet they do not remember any of their actions. Are they conscious or unconscious?

L Another major question is whether the major anesthetics work

through a single mechanism or multiple pathways, said Dr. Eric Moody, an anesthesiologist in the Laboratory of Neuroscience at the National Institutes of Health in Bethesda who attended the conference. Both complex compounds and simple gases can act as anesthetics, he said, yet they produce similar results.

Anesthetic cocktails

The issue is complicated by the fact that anesthesiologists mix as many as 15 drugs to produce desired effects. They use opiates to block pain, Valium-type drugs to reduce anxiety and induce amnesia, a muscle relaxant to paralyze the body and a dollop of volatile gases to promote unconsciousness.

These anesthetic cocktails are custom-designed for various kinds of procedures and to meet the needs of each patient, Dr. Moody said. For example, the goal in some Caesarean sections is to lightly anesthetize the mother so as to protect the baby, but also to blunt the mother's memory.

In earlier times, anesthesiologists only had volatile gases, such as ether and chloroform, to knock people out, Dr. Weinberg said. Such gases seemed to work on the whole brain and led, at the turn of the century, to a unitary hypothesis of anesthesia.

Researchers noted that as the fat solubility of an anesthetic increases, its potency rises in proportion, and they concluded that anesthetics work by altering fat in cell membranes, Dr. Weinberg said. When enough membranes are swollen or otherwise changed by an anesthetic gas, he said, a person would be rendered unconscious.

This theory was bolstered by the later observation that an anesthetized animal, placed in a pressure chamber, immediately regains consciousness, Dr. Weinberg said. The explanation was that pressure shrinks swollen cell membranes and causes the anesthetic to leach out, thus reversing anesthesia.

Evolving theories

This lipid hypothesis dominated the field until 15 years ago, Dr. Weinberg said, when researchers found that volatile anesthetics can act directly on proteins in the cell membrane. Although the exact site of action is not known, he said, the discovery has led to a search for new ideas about how anesthetics work.

One leading idea is that anesthetics bind to proteins at sites called hydrophobic pockets. Such water-repellent pockets are found on many proteins and help determine the protein's shape, said Dr. Stuart Hameroff, an anesthesiologist at the University of Arizona Health Sciences Center in Tucson. By occupying these pockets, he said, anesthetics might alter protein shape and temporarily stop them from functioning. The result would be loss of consciousness, he said.

Several researchers at the meeting said that it may be time to abandon the search for a unitary hypothesis and to focus instead on how each drug leads to different aspects of general anesthesia. In this view, there are many paths to unconsciousness, based on different subsystems in the brain.

For example, barbiturates seem to affect one subtype of brain receptor called GABA-alpha, whose action inhibits the firing of brain cells. Barbiturates may produce some of their effects by stepping up this inhibition, the scientists said.

But despite the evidence, Dr. Weinberg said, unitary hypotheses are not dead. "There may be a site in the brain no one has looked at," he said, where volatile anesthetics exert their effects.

When people are strangled or their hearts miss a beat, Dr. Weinberg said, they lose consciousness immediately, passing out long before a lack of blood flow could damage brain cells. He said this may be one of the brain's protective mechanisms to conserve energy during when disaster strikes.

"We know there are cells in the brain's carotid artery that are very sensitive to lack of oxygen," Dr. Weinberg said. "And while this is pure conjecture," he continued, similar cells could exist at a central site, possibly in the brain stem. If anesthetics impair a central oxygen sensor, they might trick the brain into thinking it has been strangled, Dr. Weinberg said. The effect would be

transient and reversible.

Until anesthesia is better understood, some researchers are looking for methods to gauge levels of consciousness and unconsciousness. A lot of things have been tried, said Dr. Christof Koch, a leading theorist on consciousness at the California Institute of Technology in Pasadena, Calif., but the most promising one seems to be a method of measuring brain-wave oscillations.

An awake, conscious brain produces 40-hertz signals, but during anesthesia, he said, this signal is attenuated or disorganized.

Anesthesiologists in Canada are using the method to determine when patients are unconscious, Dr. Koch said.

Any theory of anesthetic mechanisms and consciousness will have to be explained at several levels, said Dr. Robert Pearce, an anesthesiologist at the University of Wisconsin Medical Center in Madison.

"We'll need to understand what is going on with physical interactions between electron clouds; with biochemistry, cell physiology and networks; and how brain networks interact," he explained.

"Anesthetics could affect each of these levels differently," he added, "and a unitary hypothesis may exist at one level but not at another."

Meanwhile, Dr. Pearce and others said, it is general policy in all operating rooms not to talk about patients when they are anesthetized, in case they "overhear" comments.