RETURN OF THE ICE AGE:
THERAPEUTIC HYPOTHERMIA
IN EMERGENCY AND CRITICAL
CARE

BY SUSAN CONOVA

The only thing Zeyad Barazanji, Ph.D., remembers about the day he nearly died was that it was Election Day 2006 and he went to the gym near his Bronx home in the evening to run on the treadmill and watch the election returns.

hospital equipment
PHOTO CREDIT: ED ECKSTEIN
The 67-year-old semi-retired literature and language professor and English-Arabic translator, who likes to work up a sweat four or five times a week, speaks matterof- factly about what happened next: He collapsed suddenly as he stepped off the treadmill, hit his head on the machine as he fell, and lay unconscious on the floor.
     According to witnesses, trainers at the gym suspected a cardiac arrest and acted quickly to prevent the irreversible brain damage that starts when the brain goes two to four minutes without oxygen. Within a minute, a personal trainer grabbed the gym’s automated external defibrillator and placed the electrodes on Dr. Barazanji’s chest. The AED prompted the trainer to shock Dr. Barazanji, whose heart returned to a normal rhythm. EMS arrived and took Dr. Barazanji, still unconscious but alive, to the emergency department at the Allen Pavilion, part of New York-Presbyterian Hospital, in Upper Manhattan.
     By making it to the emergency department alive, Dr. Barazanji joined a small minority of cardiac arrest patients. The American Heart Association estimates that the vast majority — 95 percent — die before reaching the hospital. Of the 5 percent who get to the ER, only half are still alive 24 hours later.
     Statistics suggested a dismal prognosis for Dr. Barazanji: Very few patients leave the hospital with the same neurological capability as before; the others span the full spectrum of neurological function, from minor memory loss to a permanent vegetative state. Survival is slim not because the heart has been damaged, but because of irreversible damage to the brain.
     “The worst possible injury that anyone can have to their brain is prolonged deprivation of oxygen,” says Dr. Stephan Mayer, associate professor of clinical neurology and director of the neurological intensive care unit at the Neurological Institute. “It’s the worst cause of coma. It has the worst prospects of recovery than any other cause of brain injury. It’s your worst nightmare.”
     As a neurocritical care fellow at the University of California at San Francisco, Dr. Barazanji’s niece, Nobl Barazangi, a 2000 Ph.D. graduate and 2002 P&S graduate, knew precisely what her uncle’s odds were when her family contacted her later that night. (The two sides of the family spell their surname differently.) “When I heard he had a cardiac arrest and was unresponsive, I was concerned about hypoxic damage to the brain,” Dr. Barazangi remembers.
     Much of the brain damage after cardiac arrest actually occurs after circulation is restored. As blood starts flowing again, the influx of oxygen into the brain increases the activity of enzymes that destroy proteins, fats, and organelles within the neurons. Some neurons die immediately from the assault; others die hours and days later.
     Though several drugs have been tested in clinical trials, none have been successful in preventing the damage that comes from ischemia and reperfusion. Most hospitals around the country provide only supportive care.
     At places like Columbia and UCSF, though, neurocritical care physicians are starting to use a controversial treatment to minimize brain damage: cooling the brain. Therapeutic hypothermia is not available at the Allen Pavilion, which does not have a neurological intensive care unit, so Dr. Barazangi spent hours on the phone from San Francisco arranging for her uncle to be transferred to Columbia.
     “If he needed cooling, it had to be started ASAP,” Dr. Barazangi says.

Dr. Zeyad Barazanji and his wife, Rawaa Sadaat Barazanji Zeyad Barazanji and his niece, Nobl Barazangi
Dr. Zeyad Barazanji and his wife, Rawaa Sadaat Barazanji, in a December 2006 family photo. Dr. Barazanji says his wife not only made many sacrifices during his illness, but also was instrumental in his recovery: She woke him up from a coma by speaking to him in Arabic, his native language, after Dr. Mayer failed to wake him by speaking to him in English. Zeyad Barazanji and his niece, Nobl Barazangi, a P&S graduate, in May 2007. Nobl Barazangi’00 Ph.D./’02 M.D., a neurocritical care fellow at UCSF, was instrumental in getting her uncle transferred to Columbia for care after his cardiac arrest.

Dicey History of Ice
Columbia neurointensivists are among the few groups in the country who routinely chill patients. Dr. Mayer first started experimenting in the mid-1990s using therapeutic hypothermia to reduce fevers in stroke patients (see related article).

In 1996, when Dr. Mayer first started experimenting with hypothermia in the intensive care unit, covering patients with ice packs was the most effective way to reduce body temperature. But control wasn’t precise and body temperature often dropped to a level that can cause cardiac arrhythmia. Arrhythmia can now be avoided largely by using new cooling technology that strictly limits cooling to a range between 32 C and 34 C, where arrhythmia usually doesn’t occur.
     The history of the technique, however, goes back to the 1930s and possibly beyond. The first published accounts were reported by Philadelphia neurosurgeon Temple Fay, M.D., who cooled patients to treat cancer, infections, and head trauma. Fay put patients in cold rooms or packed ice around them, once bringing a patient down to an extremely low 24 C (75 F). His colleagues derided his “ridiculous experiments.”
     “By the 1950s, neurologists understood the protective effect of hypothermia, but they were literally putting people in bathtubs filled with ice,” Dr. Mayer says. “If you read the articles from that time, all the patients seem to improve at first when they’re cold, but then they die.”
     The deaths were caused by complications of hypothermia that can only be managed with modern critical care. Except for continued use in the operating room by heart surgeons (who had anesthesiologists by the patient’s side performing what later evolved into critical care), the technique was quickly abandoned.
     Some researchers, including the late Peter Safar, the father of cardiopulmonary resuscitation, kept experimenting, and their animal studies in the 1980s and 1990s sparked new interest in hypothermia as a way to reduce brain damage from stroke, trauma, and cardiac arrest.
     By the end of the 20th century, intensive care could resolve hypothermia’s side effects: If heart rate slows too much, the patient can be given atropine to boost it. If the patient develops pneumonia because hypothermia has suppressed the immune system, respirators and antibiotics can prevent death from respiratory failure. Improvements in cooling technology also helped to reduce complications.
     In 1996, when Dr. Mayer first started experimenting with hypothermia in the intensive care unit, covering patients with ice packs was the most effective way to reduce body temperature. But control wasn’t precise and body temperature often dropped to a level that can cause cardiac arrhythmia. Arrhythmia can now be avoided largely by using new cooling technology that strictly limits cooling to a range between 32 C and 34 C, where arrhythmia usually doesn’t occur.

Treatment for Dr. Barazanji
As soon as Dr. Barazanji arrived in the NYP/Columbia’s neurological ICU, Augusto Parra, M.D., assistant professor of neurology and neurological surgery, oversaw the standard protocol: wrapping blue pads of a cooling system, called the Arctic Sun, around Dr. Barazanji’s torso and upper legs.
     Unlike loose-fitting cooling blankets (another alternative to ice packs), the pads of the Arctic Sun system stick to the skin, which the manufacturer says draws heat out of the body more quickly. The pads are hooked up to a console that pumps cool water through them. In 2001, Dr. Mayer was the first physician to test the system, and it has now become the standard hypothermia device in the Columbia NICU.
     In just a couple of hours of the cooling system use, Dr. Barazanji’s temperature dropped from a normal 37 C to 33 C. He was kept at this temperature for two days and then slowly rewarmed. After cooling, Dr. Barazanji’s condition improved and he started purposefully moving his arms and legs.
     “When I heard that, I breathed a big sigh of relief,” his niece recalls. “He still had some other problems — he had a brain hemorrhage from the fall and his kidneys were not working well — but this was a good sign that he would
pull through.
     “And today, neurologically, he is back to normal. It is hard to tell for certain, but it’s very possible that the cooling is what saved him. I’ve seen other people arrive in a coma who walk out of the hospital after getting this treatment. It is very important to get the chance.”
     When Dr. Mayer speaks about the large number of people who don’t get the chance, you can hear the irritation in his voice. “It’s too new, it’s too hard, it’s too weird. The comfort isn’t there yet. Cooling people is not a normal thing that doctors do,” Dr. Mayer says.
     In a 2005 survey of emergency physicians, cardiologists, and critical care specialists, only 26 percent of the doctors had ever tried the technique (and the survey authors think the results were that high because doctors at academic medical centers were overrepresented in the study).


Stephan Mayer, a self-proclaimed proselytizer about the use of therapeutic hypothermia in neurocritical care, being interviewed by CNN
PHOTO CREDIT: CHARLES MANLEY

Too Few Get the Chance
Dr. Mayer estimates that only 5 percent of hospitals in the country routinely employ hypothermia. As a self-described “do-er,” Dr. Mayer has set out to improve the statistics. He is armed with more than anecdotes. He promotes evidence that shows hypothermia works for patients whose cardiac arrests are caused by ventricular fibrillation.
     In 2002, two randomized studies published in the New England Journal of Medicine by two groups of researchers in Europe and Australia showed that cooling cardiac arrest patients increased their chances of leaving the hospital with mild or no neurological impairment. The Australian study used ice packs to lower temperature quickly, in a little more than two hours, and found that 49 percent of patients had a good outcome compared with 26 percent of patients left at normal body temperature.
     The European study, about four times larger with 275 subjects, cooled patients with cold air mattresses for 24 hours. Even though the technique took about eight hours to reduce body temperature to between 32 C and 34 C, 55 percent had a favorable outcome, significantly better than the 39 percent of normothermic patients.
     These two studies led the International Liaison Committee on Resuscitation in 2003 to recommend hypothermia in appropriate cases. In 2005, the American Heart Association gave hypothermia a level 2a recommendation — meaning it is reasonable to perform but not mandatory — for cardiac arrest patients who experience cardiac arrest outside of a hospital.
     The latest studies, using techniques that reduce temperature much more quickly, are showing the number of patients needed to treat to prevent one bad outcome — death or significant impairment — is six. “There is nothing more robust in medicine. This is a therapeutic grand slam,” Dr. Mayer says. “If this was a drug and it improved outcomes at the same rate, everyone would be prescribing it, but in the United States, very few people are getting this treatment.”

“Given how horrific this is, why wouldn’t you try it? At the very least, it won’t work. It won’t hurt anyone.”

Making a Difference
In surveys, the No. 1 reason doctors give for not using hypothermia is that they don’t believe the data. Dr. Mayer adamantly believes, though, that the real reasons are simply that doctors aren’t familiar with cooling techniques and cooling protocols can be difficult to implement.
     At CUMC, he has tried to make it easier for other physicians by setting up a 24-hour pager number (8-COOL) that they can call to transfer comatose cardiac arrest patients to the neurological ICU, where the nurses and doctors have experience with hypothermia.
     He’s also working with emergency physicians to kickstart the cooling process in the ER with cold intravenous fluids. “Maintenance of hypothermia is best achieved in the ICU, but the beneficial effects of cooling only happen if the cooling is started early,” Dr. Mayer says.
     To promote hypothermia in other hospitals, Dr. Mayer participates regularly in webcasts and is working with the American Academy of Neurology to release a position statement. “I may be a proselytizer, but given how horrific this is, why wouldn’t you try it?” Dr. Mayer asks. “At the very least, it won’t work. It won’t hurt anyone.”
     At the same time Dr. Barazanji was being cooled, another family camped out in the NICU around a young father who had suffered a cardiac arrest from a severe asthma attack. “He probably had a worse injury than Zeyad, but he wasn’t cooled,” Dr. Mayer says. “He deserved a better chance.
     “Neurocritical care is in a new era now. We have been completely underestimating the resilience and regenerative potential of the brain. We are rethinking everything about prognosis. We’re now much more cautious about writing people off. We need to wipe away decades of nihilism about these patients and give them a chance.”

Hypothermia in Pediatric Critical Care

Cardiac arrest doesn’t happen often in children, but should doctors use therapeutic hypothermia when it does?
     “The same organizations that recommend hypothermia for adults specifically state that currently there is insufficient evidence to recommend the technique in children,” says Charles Schleien, M.D., director of pediatric critical care medicine and professor of pediatrics and anesthesiology at P&S.
     “This is the major reason we decided to embark on our new study.”
     Dr. Schleien (and colleagues from the University of Michigan and 15 other pediatric medical centers) just finished a phase I study that tested the feasibility of cooling young patients who suffered a cardiac arrest. The researchers are now in the process of planning a clinical trial.
     As in adults, hypothermia in children initially seemed promising but was subsequently abandoned in the 1990s. Up through the 1980s, ice packs and cooling blankets were frequently used in an attempt to reduce brain injury in children who had suffered a serious deprivation of oxygen. However, subsequent experience showed that children treated with deep hypothermia were more likely to die or be left with severe neurologic consequences than untreated children.
     Dr. Schleien says hypothermia has reemerged in pediatrics, as it has in adult critical care, because of animal studies that show that a mild temperature reduction is beneficial to the brain without causing complications associated with more severe levels of hypothermia.
     “We used to cool to below 30 C,” Dr. Schleien says, “but the children frequently had ventricular fibrillation, coagulopathy (their blood wouldn’t clot), or their immune system became compromised and so they developed infections and septic shock.”
     A series of animal studies in Dr. Schleien’s lab completed in the late 1980s and early 1990s showed that cooling the brain mildly to between 33 C and 35 C could improve neurological outcomes without the side effects.
     “Based on our laboratory work and my experience with patients, I feel cooling is beneficial,” Dr. Schleien says. “We use it here in our PICU about once a month or so.”
     Still, not enough published evidence is available to recommend cooling for every child after a cardiac arrest. One difference that must be considered is the effect of hypothermia on a child’s still developing brain. “We don’t know if the outcomes will be the same as in adults, but the trial should begin to address many of these questions.”

Cooling for Stroke

Therapeutic hypothermia has been shown to help people after a cardiac arrest, but it is also under investigation for other conditions, including stroke.
      “The most common problem in my unit is all the stroke victims who develop high fevers,” Dr. Mayer says. Fever occurs in about 40 percent of patients who have suffered an ischemic stroke or intracerebral hemorrhage, and fevered patients are more likely to die or have more disability than normothermic patients.
     When Dr. Mayer was completing his residency at Columbia in the early 1990s, neurointensivists tried to eliminate fevers with nonsteroidal antiinflammatory drugs and cooling blankets, though they had no evidence that the approach — alone or in combination — improved outcomes.
     “All the guidelines say to control fever, but no one ever did because we didn’t have the tools to control body temperature,” Dr. Mayer says. “As a resident, I remember watching stroke patients fade off into a state of lethargy. Their brains were burning and dying. These patients really motivated me to find better ways to eliminate fever.”
     After experimenting with ice packs in some of the first studies to test hypothermia in stroke patients, Dr. Mayer was approached by the makers of the Arctic Sun cooling system. His first study with Arctic Sun, published in 2003, showed that the system could reduce body temperature more rapidly and more effectively than cooling blankets. However, the study wasn’t large enough to determine if more rapid and effective cooling improved patient outcomes.
     Despite that, Dr. Mayer says his experiences with the cooling system have opened up new avenues for investigation. “One day, I had a guy who had suffered a subdural hemorrhage, he had been feverish and comatose for a week, and when we started cooling him, he starting making eye contact and talking a little bit,” Dr. Mayer recalls. “I wondered if we really needed to continue cooling, so we turned off the machine. That evening, he was 102 F and totally comatose. We turned it back on, and the next morning he was awake.
     “We had always thought that when people develop fever, they may get a little less responsive, but not completely fall into a coma. This patient showed us how powerful temperature is on the level of consciousness. Now we think that by cooling the brain, we can keep people out of coma.”
     Dr. Mayer is planning a pilot study in comatose victims of brain aneurysms, the condition with the greatest incidence of fever. If cooling improves coma scores in patients and quickens their transition to recovery, he plans to progress to a multicenter study to see if cooling reduces mortality or severe neurological deficits.
     “Neurointensivists dream about waking up people from comas,” Dr. Mayer says. “If cooling works, it will be nothing short of amazing.”


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