Chilled to the bone

Why would Laurence Katz want to give patients hypothermia?

Chilled to the bone click to enlarge Laurence Katz, MD

This article originally appeared in Endeavors, a magazine that covers research and creative activity at UNC, here. Laurence Katz is an associate professor of emergency medicine in the School of Medicine and codirector of the Carolina Resuscitation Research Group. His work is funded by the National Institutes of Health.

The winter ice had just melted on a lake in the Alaskan interior, where a floatplane was humming across the water for takeoff. Inside were a pilot, a seven-year-old boy, and a thirty-one-year-old woman we’ll call Ann.

It happened fast. Water rushed into one of the floats. The plane rolled. Ann and the little boy toppled into the icy water and disappeared. The pilot dove in after them. Eventually he pulled up the little boy. Five or ten minutes of CPR revived him.

Ann was harder to find. The pilot had to dive in again and again. No one’s sure just how long she was in the water—at least thirty minutes, the pilot said, maybe sixty. He gave her CPR for an hour after he’d found her. Eight hours passed before a helicopter got her to a hospital. Her body temperature was only eighty-seven degrees Fahrenheit, but she was making small, jerking movements and her pupils responded to light.

Being without oxygen for half an hour is almost always a death sentence. “When a person drowns, they stop breathing, run out of oxygen, and then the heart stops,” says professor of emergency medicine Laurence Katz. “When the heart stops, blood flow to the entire body—including the brain—stops.” The brain becomes inflamed.

At the same time, the blood starts to accumulate toxins. If CPR can get the person’s heart started again, those toxins immediately flood the brain, causing catastrophic and irreversible damage. In fact, most of the brain damage occurs after blood flow is restored. Introducing blood that’s depleted of oxygen and full of high concentrations of acids is like pouring gasoline on a smoldering fire, Katz says. Near-drowning victims who are resuscitated often spend the rest of their lives in a vegetative state.

On the other hand, Katz says, the survival rate of cold water drowning victims is oddly high. There are plenty of case studies: The four-year-old found drifting under the clear, thin ice of a lake, who was revived and fully recovered. The sixty-nine-year-old crane operator who tumbled from a bridge and spent some forty-five minutes without a heartbeat before going back to work. There are some people who’ve been dead for over an hour, Katz says, who go on to lead normal lives.

It wasn’t until the 1980s that scientists made the connection. The sudden drop in temperature that causes hypothermia decreases the brain’s demand for oxygen. Because its need for oxygen is cut off, the brain doesn’t have a chance to suffocate. “Hypothermia is like an extinguisher,” Katz says. “It puts out the fire.” For decades now, doctors have used ice baths to cool patients down from the outside in, to put them into a kind of hibernation. But, Katz says, why couldn’t we do this from the inside out?

Two weeks after the pilot fished Ann out of the water, her doctors were running test after neurological test. All were coming back normal.

Katz was an undergrad when he wrote a letter to a scientist he greatly admired, a man named Peter Safar. Safar was the anesthesiologist who had introduced the world to CPR and founded the United States’ first intensive care unit and modern ambulance service. He was also one of the first to suspect that hypothermia could buy time for doctors in the emergency room. Safar had found that in treating acute brain injuries, lowering the patient’s body temperature by just a few degrees dramatically reduced the chance of neurological damage. Safar invited Katz to work with him in his lab at the International Resuscitation Research Center in Pittsburgh. Katz stayed there for years, working his way up from a technician to a faculty member, and helping Safar to bring therapeutic hypothermia out of their labs and into hospitals everywhere.

But even though Katz and other scientists have spent thirty years refining the treatment, he says, the technique is still crude.

For example, say doctors in an ER are using the therapy to treat a man who’s had a heart attack. The doctors give him a hefty dose of Fentanyl, a narcotic, and strap him into the modern version of an ice bath—a machine called the Arctic Sun, which pumps frigid water through pads wrapped around the patient’s torso and legs. The man’s body immediately starts fighting the cold, Katz says. It shivers, increases its metabolism, and sends blood up to the skin’s surface to help him retain heat. The docs use a chemical called vecuronium to paralyze his body and keep him from shivering. But paralysis also keeps the patient from breathing on his own, so in comes the breathing machine.

This goes on for between twelve and twenty-four hours. (Any less, and the benefits are only temporary.) All the while, the patient is in a delicate state of hibernation. The doctors have to be careful not to cool him too much or too fast, Katz says, or lower his blood pressure too much. When they return his temperature to a normal 98.6°F using heating pads and warm water, they have to be precise—overheating him could cause fever or brain damage.

Before 2007, when Katz created the hypothermia program at UNC, heart attack patients who were brought to UNC Hospitals comatose (but still with a pulse) had less than a 5 percent chance of leaving the hospital alive. Today, 50 percent go home without any neurological damage.

Everyone knows this therapy works, Katz says. Therapeutic hypothermia has been clinically proven to help patients who’ve been resuscitated after cardiac arrest—there are some 250,000 of those a year. But the method is far from perfect. It takes too long and it’s too complicated. Only a few hospitals across the country have the resources and expertise to do it.

Katz wants to change that. There’s a good chance the therapy could help more than just 250,000 people a year, he says. It could help millions. Therapeutic hypothermia may actually work for all acute brain injuries, including traumatic brain injuries (1.7 million a year), strokes (795,000 a year), and spinal cord injuries (12,000 a year).

Katz has spent the last ten years looking for a better way to use therapeutic hypothermia, one that’s less traumatic for patients and faster and easier for hospitals. There has to be a way to lower body temperature without using an Arctic Sun or plunging into a lake like Ann did, he says: a way to fool the brain into cooling the body.

No one knows exactly how it happens, but every winter, bears manage to lower their body temperature when they hibernate, from 98.6°F to 93°F. Their bodies cool, their metabolisms slow down, and they snooze comfortably—without the shivering and other signs of resistance doctors see from therapeutic hypothermia patients. Bears and humans—and all mammals, from elephants to field mice—maintain about the same body temperature, Katz says. And they regulate that temperature in similar ways. So he started studying all the data he could find on bears, thinking that if he could simulate their hibernation mechanism in humans, he might find the key to a better treatment.

Katz theorized that bears can reset their brains’ thermostats using a chemical that occurs naturally in their bodies. When it comes time for the bear to hibernate, the chemical triggers a reaction in the bear’s brain that convinces it that 93°F is the normal body temperature. “So their bodies do everything they can to reach that new temperature,” Katz says.

Now he’s working to figure out what that chemical is. Certain chemicals in bears’ brains increase during hibernation, he says, and so he began by testing compounds that had a similar chemical structure. He’s found some likely suspects, and has developed two different drugs that induce a hibernation-like state in small animals, lowering their body temperatures and even protecting them from brain injuries. The drugs are going through the patent process.

Just think, Katz says: Paramedics could administer a rapid infusion of the meds even before the ambulance gets to the hospital. Hospitalization times could plummet, and so could the costs of rehab after heart attacks and strokes. Therapeutic hypothermia could save billions of dollars.

In 2010 Katz formed Hibernaid, a company dedicated to creating new drugs for therapeutic hypothermia, testing them on humans, and getting them on the market. He and his partners are looking for funding to start clinical trials. It could take up to ten years before the drugs are available, Katz says, but he hopes to move fast. Hibernaid could save hundreds of thousands of lives in hospitals everywhere, he says. Even in remote pockets of the Alaskan bush.

Ann was released from the hospital eighteen days after she fell in the lake. She’d suffered kidney failure, depression, and sinusitis so severe it required surgery. But her brain was fine. She had absolutely no neurological damage.

Going so long without oxygen did leave her with some temporary amnesia. At first she couldn’t remember the accident itself. She could barely muster memories from six weeks before that. But slowly it came back to her. She eventually remembered details, she said, such as being outside her house the morning of the accident and briefly locking eyes with a passing grizzly bear.

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