Hypothermia May Protect the Brain, Researchers Report

by Aalok Mehta

September 19, 2008

Hypothermia—a sometimes dramatic lowering of body temperature that can be deadly—has become something of a boon for scientists seeking better ways to curb brain damage after cardiac arrest and brain injury.

This is an exciting time for clinical applications of hypothermia, says Stephan Mayer, an associate professor of clinical neurology and neurological surgery at Columbia University.

Mayer was one of more than a dozen researchers to report their latest findings on the condition at a conference on Friday titled Hypothermia—From Threat to Cure, sponsored by Columbia University School of Medicine and the New York Academy of Sciences with partial support from the Dana Foundation.

At least two conditions are now regularly treated with hypothermia, which is administered either through surface pads, water blankets or special catheters, Mayer says. One is cardiac-arrest-induced coma, in which people are resuscitated after their hearts stopped beating for five to 30 minutes. Such extended periods of hypoxia—a shortage of oxygen in the body—causes major damage to the brain; survival rates hover around 15 percent, often with significant neurological impairment. The survival rate shoots up to 40 percent, and with much-improved neurological outcomes, when doctors apply hypothermia treatments.

“This is an incredibly powerful, proven, evidence-based treatment for the world’s worst kind of brain damage,” Mayer says.

However, many doctors have been reluctant to embrace the treatment because they lack training or proper equipment. That situation is beginning to change. Mayer, for example, is leading a program called New York City Project Hypothermia to ensure that all cardiac-arrest patients in New York are taken to hospitals equipped for hypothermia treatment.

Hypothermia also can be used to treat the brain swelling and intracranial pressure associated with trauma, stroke bleeding or occlusions, aneurysm and certain rare forms of brain infection, though how effective it is and when to apply it continue to be studied, Mayer says.

New targets

Hypothermia shows promise in treating several additional conditions as well. For example, H. Bart van der Worp of the University Medical Center in Utrecht, Netherlands, outlined the results of animal studies looking at hypothermia treatment of stroke. Results from more than 100 studies—some 3,300 animals total—showed improved outcomes in about one-third of animals treated with hypothermia under conditions achievable in hospitals, he says. Although some researchers express doubts about the validity of animal stroke models, van der Worp says the data are promising enough to warrant clinical trials in humans.

Abbot Laptook, a pediatrician at the Women and Infant’s Hospital of Rhode Island, outlined data from two clinical trials looking at hypothermia treatment of newborn encephalopathy, a neurological syndrome that is often caused by lack of oxygen during labor or gestation. Infants who survive this condition are at high risk of developing other, often fatal neurological disorders such as cerebral palsy.

“To date, no specific brain-oriented therapy has been available to reduce adverse outcomes,” Laptook says. But the trials, one that cooled just the newborns’ heads and one that cooled their entire bodies, were each “able to demonstrate reductions in both death and neurodevelopmental disorders,” he says. Scientists are awaiting results from three other trials before deciding whether to do more research or move to suggesting it be used as a treatment, Laptook says.

Hypothermia seems to achieve its neuroprotective effects in a variety of ways, such as reducing apoptosis, inflammation, microglia activation and excitatory neurotransmitter levels, Laptook says. Scientists aren’t yet sure why this is the case, but they suspect a combination of metabolic slowdowns and other changes in cell function.

Treat with caution

Hypothermia is not without its risks. Presenters pointed out that hypothermia can cause heart arrhythmias and increase the risk of infection. Doctors must take care to suppress the shivering reflex, which counters the effect of the treatment; to keep body temperatures from falling too low; and to ensure that rewarming is slow enough to prevent fatal complications.

Emmanuel Planel, a neuroscientist at Columbia University Medical School, notes at least one additional, unsuspected side effect of hypothermia-like conditions, particularly those caused during anesthesia. In mice, anesthetic hypothermia appears to directly decrease the activity of phosphatases, enzymes that remove phosphate groups from proteins. Buildup of phosphate groups in tau proteins can cause them to clump into the tangles thought to play a major role in Alzheimer’s. “What we see in the mouse model is due to the temperature decrease and not anesthesia,” Planel says.

His group has submitted a proposal to test cerebrospinal fluid in human surgery patients. If the findings follow the same pattern, he says, surgical teams may need to administer some sort of protective warming treatment along with anesthesia, at least for some patients, to reduce the risk or progression of Alzheimer’s.