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Brains On Ice

The coolest idea in stroke treatment is refrigeration. Yes, cold is hot.

Many doctors believe they can reduce permanent damage after a stroke by quickly dropping victims' body temperatures for a day or two, in effect, storing their brains on ice until the crisis passes.

"It's like putting food in the refrigerator. It doesn't go bad. You slow down all the processes," says Dr. David Tong of Stanford University.

The approach is new, but the insight behind it -- that cold protects the brain just as a fridge keeps grapefruit -- has been recognized for centuries.

Everyone knows a story of a child who falls into any icy pond, is fished out after 45 minutes and then is warmed up and found to be as good as ever. The chilly water suspends biological processes that ordinarily would kill brain cells almost immediately.

Though done occasionally during surgery, chilling the sick was regarded as too clumsy, risky and unpleasant to be routine, and flat-out impractical for the 700,000 or so strokes in the United States each year. Instead, researchers bet that medicines would be designed to work as well. But that goal has proven disappointingly elusive as dozens of supposedly brain-protecting drugs failed testing over the past decade.

Now, backed by fresh science and new technology, doctors are taking a serious second look at cold. They hope soon to prove it a workable and valuable first step for treating victims of strokes.

"When done carefully, there are strong early indications of effectiveness," says Dr. Jeffrey Saver of the University of California, Los Angeles.

Strokes typically occur when a blood clot lodges in the tree of arteries in the head, choking off the flow. Quickly giving the clot dissolver TPA can forestall much of the damage, but most patients do not get to the hospital soon enough for the medicine to do any good.

Even after TPA can no longer help, brain cells continue to die off for several more hours. The cells killed first are filled with proteins that ooze out as they die. These substances trigger a chemical chain reaction that kills neighboring cells.

In theory, doctors say, cooling the head should slow or even stop the destruction of these vulnerable bystanders. Several small experiments, intended largely to examine whether cooling stroke victims is even feasible, offer tantalizing hints of this.

At the Cleveland Clinic, doctors have cooled five victims of especially severe strokes, dropping their temperatures a few degrees for a day or two. Ordinarily, 80 percent of such people die or are seriously disabled. Against the odds, two of these five recovered completely.

Doctors at the University of Texas in Houston saw similar results cooling victims of cardiac arrest. Like a stroke, cardiac arrest wrecks the brain by shutting off its blood supply. Victims often suffer permanent brain damage, even if paramedics eventully restart their hearts.

The Houston doctors chilled seven patients who arrived at the hospital in comas after being resuscitated. After a day of cooling, two of them soon returned completely to normal, while another is nearly so.

Dr. James Grotta cautions that such examples prove little. Without carefully controlled studies, doctors can only guess how many would get better on their own.

Still, he says, "we have been very encouraged. I have seen results that in my mind are very dramatic."

Much as doctors would like to, there is no way of cooling just the head. They must chill the entire body. In all the experiments so far, this is done the old-fashioned way. Patients are covered in air-cooled blankets and sometimes packed in ice or rubbed with alcohol.

However, later this year, doctors will try something entirely new. Human studies are expected to begin with devices that cool the body from the inside out.

At least three small U.S. companies are working on these cold-tipped catheters. They are threaded from the groin up to the inferior vena cava, the big vein that runs down the center of the abdomen. There the catheter cools the blood flowing over it. Developers estimate they can lower an adult's temperature several degrees with pinpoint accuracy in an hour or less.

Dr. E. Sander Connolly of Columbia University uses baboons to test a cold catheter made by Innercool Therapies of San Diego. The scientists triggered the experimental equivalent of a stroke by temporarily clamping an artery in the animals' heads. To mimic the usual real-world delay getting to the hospital, they waited a few hours, then cooled the animals' blood for a day or more.

The results from the seven animals studied look good, Connolly says. "The strokes are smaller. Their neurological exams are better."

Innercool and two competitors - Radiant Medical of Redwood City, Calif. and Alsius Corp. of Irvine, Calif. - plan studies on victims of strokes and cardiac arrest, as well as on patients whose brain circulation must be stopped temporarily so doctors can fix broken blood vessels inside their heads.

Deep-cooling the traditional way is already sometimes used to help minimize damage during this kind of surgery. It was also routine in the early days of open-heart surgery, before the invention of circulation machines that pump the blood while the heart is stopped. For these operations, doctors typically plunged patients to such low temperatures that dangerous complications can occur, such as irregular heartbeats and blood clotting.

In these cases, the patients are unconscious, as were the few stroke and cardiac arrest victims treated with cooling in Cleveland, Houston and elsewhere. When patients are unconscious, doctors can easily control one of the most problematic ill effects of cold - violent shivering.

But many stroke patients remain conscious. Stopping deepl cooled, conscious patients from shivering would probably require knocking them out, paralyzing them and hooking them to breathing machines.

None of this appeals much to doctors. The treatment could be done only in intensive care, making it horrendously expensive. The risk of complications could be substantial. And physicians routinely check on stroke patients' progress by talking to them, something they certainly cannot do if their patients are out cold.

However, a chance discovery a decade ago suggests a way around much of this: It appears that much mild cooling may be nearly as good.

Dr. Myron Ginsberg of the University of Miami noticed that when scientists clamped arteries in rats' brains to study the amount of damage that resulted, no two experiments ever seemed to turn out the same.

In time, he figured out why. Slight differences in the temperature of the rats' brains, resulting from things like the lab temperature and air currents, had a huge impact on the extent of the animals' strokes. The cooler the brain, it turned out, the smaller the stroke. But even a modest drop in temperature seemed to be highly protective, while a little extra heat made things vastly worse.

In a cool head, enzymes stop working. Oxygen consumption slows. Glucose metabolism plummets. The processes of cell death shut down.

"Two or three degrees of temperature change every biological system known to man, often by 100 percent," says Dr. Alister Buchon of the University of Calgary. "We evolved at this temperature. We don't work if we lower it."

Ginsberg says his experiments suggest an ideal target for stroke treatment: Lower body temperature by about 5 degrees Celsius from the normal 37.5, start the treatment within three or four hours and hold down the temperature for 24 to 36 hours.

Doctors consider this to be mild hypothermia, and they hope patients will be able to stand it while conscious. Possibilities include giving them mild sedatives and warming their skin while catheters chill their blood.

However, the cold catheters have never been used on a person, so no one really knows how the human body will react to having its blood cooled. Some speculate that if the skin stays warm, the brain will be fooled into thinking all is balmy.

"It makes sense that some of the body's negative reaction to hypothermia would possibly not be seen if the cooling comes from within," says Connolly. "The body has no defense mechanism against that, because there is no environmental equivalent."

Many doctors agree that if cooling works, it will have to be done quickly, before the stroke runs its irreversible course. This will mean starting it as soon as suspected stroke patients arrive at the emergency room, or perhaps even before. Some suggest ambulance crews might insert a cooling catheter on the way to the hospital.

"It's going to turn out to be useul," predicts Dr. Steven Grannotta of the University of Southern California. "The problem is, how are we going to deliver the cooling in the quickest, safest and most efficient way?"

By Daniel Q. Haney

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