It was closing in on 5pm and Pamela Barco was getting antsy. Only half an hour left until her shift at the Children's Hospital of Philadelphia ended, and she had a date to look forward to. First, though, Barco—a 46-year-old ER clerk—had to finish setting up equipment in the trauma room for an incoming patient. When she was done, she walked back to her desk to chat with her friend and colleague Sharon Pryce.
As soon as Barco sat down, she felt the room begin to spin. Suddenly the ER was blurry, out of control. She mumbled to Pryce that she felt dizzy and put her head down on her desk. Just as quickly, Pryce was up, standing behind her, concerned. She put her hand on Barco's shoulder. "Pam, you ok? What's wrong?"
That's when Pryce felt her friend take her last breath. Barco's heart had stopped. More precisely, it was in V-fib—or ventricular fibrillation—meaning that it stopped pumping out blood, but was still quivering like a spoonful of Jell-O. Pryce grabbed Barco's arms to keep her from falling out of her chair. She glanced around; the normally bustling ER was empty. She considered screaming for help but didn't want to scare the patients. "Staff emergency," she hollered as calmly as she could. Two nurses at the other end of the hall came running.
Minutes later, a dozen doctors and nurses surrounded Barco's lifeless body. Only one of out 16 patients survives sudden cardiac arrest—every minute that the heart isn't pumping is a minute closer to death, as the body becomes more and more deprived of oxygen, its main source of fuel. Doctors shocked Barco with a defibrillator, which electrically jolts the heart into normal rhythm. Didn't work. They shocked her again. Twice. A few seconds of silence. Then: Beep. Beep. Beep. Barco was alive again.
But perhaps not for long. Post-cardiac arrest patients have a nasty habit of dying after their hearts re-start, a consequence of the shock the brain and heart cells endure when blood flow stops and then starts back up again. Even if the shock isn't bad enough to kill, few patients recover without noticeable brain damage, because after a couple of minutes, oxygen-starved brain cells begin to die. Barco, however, was exceptionally lucky. Not only did she collapse in a hospital, but she collapsed next door to the Hospital of the University of Pennsylvania, where a cadre of researchers is pioneering a controversial treatment that mitigates the aftermath of cardiac arrest.
Called therapeutic hypothermia, the technique is just like it sounds: doctors lower patients' body temperatures to 91˚F for 24 hours by pumping cold saline through their IVs and covering them with cold blankets and wraps—hell, even ice packs, sometimes. Two clinical trials from 2002 suggest that cooling saves one out of five cardiac arrest patients who would have otherwise died—patients like Barco, who, though alive, was unconscious and having serious trouble breathing. Barco was the perfect candidate for therapeutic hypothermia, so as soon as she was stable enough, the doctors wheeled her next door.
On May 20, 1999, 29-year-old medical student Anna Bagenholm went skiing with friends near Narvik, Norway, one of the most northerly towns in the world. A little after 6pm, she skied a favorite path down a waterfall gully and fell headfirst into a river. Her body wedged between some rocks and overlying ice; luckily, she found an air pocket so she could breathe. Although she was almost fully immersed underwater, Bagenholm's friends found her and tried to get her out. They couldn't.
Immediately, they called for help. Ten minutes went by as Bagenholm struggled in the icy water. Twenty. Thirty. After forty, her body went limp—either she had drowned, or the extreme cold had stopped her heart. When the rescue team finally arrived at 7:39, they cut a hole in the ice and took Bagenholm's body out, but she was dead. They measured her body temperature. 56.7˚F. They started performing CPR.
An hour-long helicopter ride brought Bagenholm to the Tromso University Hospital, where she was put on a heart-lung machine that breathed for her and pumped blood through her as she slowly re-warmed. Nine hours later, her body was back up to normal body temperature. They sedated her for another 72 hours and then slowly took her off the sedative. The doctors watched and waited. A little while later, she opened her eyes. Bagenholm was alive and responsive, her brain virtually undamaged despite a full hour without oxygen. After a long period of recovery, she went on to graduate from medical school.
Many doctors—including Mads Gilbert, the head of the ER at the Tromso University hospital—believe that the freezing temperatures that stopped Bagenholm's heart also saved her ("Hypothermia is a true double-edged sword: it protects you or it kills you," Gilbert says.) At lower temperatures, our organs slow down and need less fuel. By the time Bagenholm's heart had stopped pumping, her brain was so cold it needed little oxygen anyway. Even so, she was lifeless in the river for an hour before rescue teams began CPR, which means that her brain was oxygen-deprived for at least that long. How she did survive without any brain damage?
That's a question that's now been partially answered thanks to Lance Becker, the director of the Penn Center for Resuscitative Medicine. Bald, wiry, and mischievous, Becker is the kind of guy you'd more easily picture in a jester's costume than a doctor's coat. When he was a medical resident in Chicago in the early 80s, he found himself oddly attracted to the ER—to the "really really sick patients," he says—because he was more interested in figuring out what was wrong with them than in actually treating them. (He's like a friendlier, funnier, and shorter version of House. And, no limp.)
After working in the ER of Chicago's Michael Reese Hospital for several years, Becker started questioning the published statistics about cardiac arrest. He'd read that 20 percent of cardiac arrest patients survive, but "I knew after working in the emergency department for a while that that wasn't anything close to reality," he says. He decided to perform his own study and found that the rates were off by more than a factor of ten—only 1.8 percent of cardiac arrest patients in Chicago lived. "That was a major wake-up call," he says.
But why did people die after cardiac arrest, even when their hearts had re-started? The question nagged at Becker. To answer it, he thought it best to start small—by looking at cells. Up until that point, scientists believed that when the heart stopped pumping oxygen, cells started to die. If that were true, then cells should fare better when the heart starts pumping again. "What we saw was almost the opposite," Becker recalls.
Becker watched heart cells under a microscope as he deprived them of oxygen for an hour. Then he gave them oxygen, or reperfused them, for another three hours. He couldn't believe what he saw: only four percent of the cells were damaged by the lack of oxygen, but 17 percent started showing signs of injury immediately after the oxygen reperfusion. That suggested to Becker that perhaps what killed cardiac arrest patients wasn't the heart stopping, but the heart re-starting—and the sudden recirculation of oxygen. Totally counterintuitive, but auspicious, he thought. "If we could get on top of and understand this reperfusion injury, we could drastically alter the way people live or die," Becker realized.
Becker has since learned why reperfusion injury occurs. Tiny organelles inside our cells called mitochondria use oxygen to produce energy, but these powerhouses are kind of like nuclear power plants—"very useful, generate a lot of power, but a little bit on the dangerous side," says Ben Abella, the clinical research director of the Center for Resuscitation Science and Becker's right hand man. (Abella decided to start working with Becker after a fateful day in 1999 when, as a resident team leader at the University of Chicago Hospital, he saw a whopping eight cardiac arrest patients in one day.)
Mitochondria have back-up systems in place to prevent dangerous oxygen chain-reactions, but when cells are deprived of oxygen, these systems break down. Then, when oxygen flow returns, the mitochondria go nuts and start producing reactive molecules called free radicals, which damage the cell and other nearby cells. The problem is most pronounced in the brain, which uses more oxygen than any other organ. The injured cells start killing themselves, and the body's immune system, alerted to the impending chaos, releases chemicals that make the problem worse.
Soon after performing his first lab experiments, Becker noticed something else odd. As all scientists do, he kept his cells in incubators at 98.6°F. But when he left them out for a few hours to do experiments, "we found that there were differences in rates of cell death," he says. When the cells had cooled a little, they didn't suffer as much reperfusion injury, perhaps because the mitochondria and the immune system don't work as well at low temperatures. Cold, in other words, appeared to temper the mitochondrial meltdown that occurs after cardiac arrest. It explained why Bagenholm recovered. Becker knew what he had to do next—try it on others.
It was 2001, and anesthesiologist Markus Födisch was an on-call physician for the Advanced Life Support unit in Bonn, Germany. His unit received a call from a local supermarket: A 37-year-old man had collapsed from cardiac arrest. Födisch and his team rushed over. By the time they got there, another unit had already arrived and re-started his heart, albeit after 37 minutes of cardiac arrest. Födisch knew the man would sustain some serious brain damage.
Several supermarket employees approached Födisch and asked him if he needed any help. Sure, he said. How about some ice packs? Födisch was familiar with the concept of therapeutic hypothermia, and thought it might be better to start cooling the patient now than to wait for him to get to the hospital, which was 45 minutes away.
The employee came back a couple minutes later, but not with ice packs. They didn’t have any. Instead, he arrived with a bunch of frozen pizza boxes. Födisch shook his head. "We told him we can't use pizza because it's too stiff," Födisch says. "We can't cover the body with them."
The employee rushed back to the freezer. A minute later, he was back, his arms full of packages of frozen french fries. Födisch figured, why not? He grabbed them and covered the patient's body with as many packages has he could, then transferred him to the ambulance. "So we transported him covered with french fries," Födisch says.
When they arrived at the hospital, doctors took the man's temperature. It was 91°F—the target for therapeutic hypothermia. And although everyone expected him to have serious brain damage, the patient recovered completely—rumor has it, he even decided to enroll in medical school. Födisch is well aware that his supermarket therapy was a little unconventional. "It's really crazy," he admits. "But nevertheless, sometimes science is crazy."
To Becker and Abella, who both moved from Chicago to Penn in 2006 to set up the Center for Resuscitation Science, Födisch's story embodies the future of cooling. In fact, they say, it may have even been better if Födisch had cooled the patient before he was resuscitated. Although it helps to start cooling even six hours after resuscitation—these patients are up to 20 percent more likely to walk out of the hospital than patients who aren't cooled at all, according to the two landmark trials published in 2002—Becker and Abella are convinced that cooling before or during resuscitation will help even more. "We're only seeing the tip of the proverbial iceberg in terms of what cooling could do," Becker says.
Indeed, in a study they published in 2007, they showed that mice in cardiac arrest were more likely to survive if the experimenters waited to resuscitate them until after cooling had started—even if that meant the mice spent longer with their hearts stopped. It was a provocative finding, because it suggested that the damage caused by a few extra minutes of oxygen deprivation is mitigated by cooling—and then some. "If you apply hypothermia during cardiac arrest itself, survival and neurologic outcomes are much better than if you apply it after resuscitation," Abella claims.
A smooth-talking, handsome guy who resembles a young Andy Garcia, Abella says he was destined for resuscitation research. His mother was born with third degree heart block, a defect of the heart's electrical system, which gave her a resting heart rate around 30 beats per minute (normal is 70). "They told her she could never give birth, her heart couldn't take it," Abella explains in his office at Penn, which is cluttered with empty computer boxes, dozens of packs of microwave popcorn and a life-size resuscitation doll he calls Annie. Abella's mother was stubborn, he says, so she got pregnant anyway, and one of the grandfathers of resuscitation research at the time, Richard Langendorf, came to the hospital to help with the birth. "He was in the room when I first came into the world. So in some really weird karmic way, I was meant to go into resuscitation," Abella says.
Cooling isn't happening as quickly as Becker and Abella want, though, partially because it's counterintuitive for doctors to delay resuscitation for any reason. (The mantra has always been to re-start the heart as soon as possible.) What's more, cooling technology isn't designed to bring on ambulances or trek around emergency rooms. Even for a patient like Barco—who collapsed within a few feet of the Penn hospital—the cooling process didn't begin until three and a half hours after her cardiac arrest, because doctors waited until her vitals were totally stable.
Becker and Abella are, however, trying to change that. With the help of postdoctoral engineer Josh Lampe, they have designed a cooling "slurry" machine that uses IVs to flush an ice-water saline mixture through the body, cooling patients faster. The machine makes its saline slurry— "like a slushee, a slurpee, a margarita," Lampe says—on demand, and two and a half liters is all that's needed get patients down to target temperature. Cooling someone using refrigerated saline requires more than four times the volume, and therefore a lot more time.
If all goes well with their first machine prototype, which was built earlier this year and is currently being tested on pigs, Becker and Lampe will apply for FDA approval to use the machine on cardiac arrest patients in a clinical trial. "Dream comes true, we hit the grand slam, it's in an ambulance and the EMT does it," Lampe says.
Becker is also organizing a national trial to test a new technology that cools by way of the nose. The aptly named Rhinochill, made by New York-based biotech Benechill, blows out a mist of liquid perfluorocarbons—the same stuff that cools refrigerators—and oxygen. The perfluorocarbons evaporate into the oxygen, a phase change that requires a lot of energy. And energy, of course, is heat. "With that evaporation, there's intense cooling," explains Becker. It cools down the back of the nose, the nasal hairs, and the base of the brain—causing the body to cool very quickly.
Thanks in part to Becker and Abella, who joke that their job is to "spread the gospel of hypothermia," the American Heart Association added therapeutic hypothermia to its Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care in 2005, which doctors around the world follow as protocol. Even so, not that many doctors seem to be using it yet. According to a physician survey that Abella conducted in 2006, only 26 percent of U.S. emergency room and cardiology doctors had ever cooled a patient after cardiac arrest. "It's taught me a lot about the inertia of American medicine," Abella laments.
He speculates that some doctors are afraid of cooling and what it entails. Cooling equipment is expensive, and although hospitals can cool a lot more cheaply with ice packs, it's much harder to control temperature that way. And the body is temperamental—if you cool it below about 86°F, the risk for cardiac arrest goes up drastically. (Plus, nurses hate ice packs. "Big puddles," Abella jokes.)
Hypothermia also requires hospital-wide collaboration. "It's not like one doctor can say, I'm going to start giving the blue pill as opposed to the red pill," Abella says. "Patients come into the ER, they then go to the intensive care unit, and the care needs to be coordinated. Cooling is a 24 hour process." That also means that everyone needs to know how to do it. Penn set up a cooling hotline so that anytime day or night, Penn doctors and nurses could send a page to 4233—that spells out ICEE—and get a call back from one of Penn's cooling experts who answers any questions.