OTTAWA—Although hypothermia for patients with severe traumatic brain injury is not a new idea, the negative results and increased risk for infection observed with some cooling protocols have tempered enthusiasm for this approach. Yet some clinical trials do show benefit. In a recent systematic review that included 1,069 head-injury patients from 12 studies, moderate therapeutic hypothermia for one day or longer reduced both the risk for mortality by 19% and the risk for a poor neurological outcome by 22%.[1] Cooling for more than 48 hours reduced the risk of death by 35% and the risk of a poor neurological outcome by 30%.

“We compiled 12 randomized controlled trials from around the world that included patients with severe traumatic brain injury … defined by a Glasgow Coma Scale [score] of 8 or less,” reported primary author Lauralyn A. McIntyre, MD, FRCPC. In each of the studies, researchers had aimed to maintain body temperatures between 32°C and 35°C for at least 24 hours. “If you cool patients for at least a 24-hour period, you may be able to reduce the risk of death, as well as reduce the risk of poor neurological outcome,” said Dr. McIntyre, a clinical scholar in the University of Ottawa Department of Medicine and an intensivist at the Ottawa Hospital.

However, differences in cooling protocols between the studies hint at ways to improve the results achieved with hypothermia. Unexpectedly, rewarming within a 24-hour period yielded better neurological outcomes than approaches employing a more gradual return to normothermia, although because stratification may have introduced bias, Dr. McIntyre advises caution in the interpretation of these results.

PROMISING, BUT NOT YET FIRST-LINE

Moreover, Dr. McIntyre warned that “this is not a primary randomized controlled trial; it’s a systematic review of the literature.” Thus, these observations require further testing before cooling protocols can be recommended as standard care for severe head trauma.

Nevertheless, a number of centers, including the ICU at the Vancouver General Hospital in which Dr. McIntyre trained, frequently use hypothermia for patients with severe traumatic brain injuries. “They’ve been cooling patients for over a decade,” she noted. “But in Vancouver, they only tend to cool once conventional management has failed—if the brain injury is severe and the intracranial pressure is still difficult to control after instituting conventional care, then they may go on to cooling the patient,” she stressed, “but not as a first-line therapy.”

HOW DOES COOLING WORK?

Animal work suggests that hypothermia reduces the metabolic rate within the brain to minimize damage. “It can also modulate the release of mediators and substances within the brain that contribute to secondary brain injury,” Dr. McIntyre said. Furthermore, lowering body temperature can help control brain swelling and intracranial pressure, which can also exacerbate secondary injury if left unchecked.

COOLING NOT WITHOUT RISK

The meta-analysis found that the risks of death or poor neurological outcome were optimally reduced when patients were cooled for more than 48 hours to a temperature between 32°C and 33°C. Cooling for 24 hours to a temperature between 32°C and 33°C and restoring normothermia within 24 hours after this cooling period also reduced the risk of a poor neurological outcome. However, “there are risks associated with hypothermia,” Dr. McIntyre again emphasized. “The major risk associated when you cool to these levels is infection.” She explained, “By cooling, you reduce the inflammatory response that goes on within the brain, but because you cool the whole patient, you also reduce the inflammatory response everywhere else as well.” Reduced inflammatory responses may result in impaired immune function.

Furthermore, colder temperatures can impair blood clotting and trigger cardiac arrhythmias. Said Dr. McIntyre, “When you get into lower temperatures, that’s when coagulation and bleeding risks and the heart-conduction abnormality risk become something to worry about.”

HOT QUESTIONS IN HYPOTHERMIA

Heterogeneity in results and protocols between the studies included in the meta-analysis raised important questions that need to be addressed by randomized controlled trials. “We think the time to initiate cooling is really important,” Dr. McIntyre remarked. “That’s one area that I think deserves future investigation.” Accordingly, she noted that an ongoing study will assess outcome in brain trauma patients who arrive cool at the hospital. “Another area that I think we need to think about is how long we want to cool these patients,” said Dr. McIntyre. Given that brain trauma patients cooled for more than two days showed better improvement in risk for death or poor neurological outcome than did patients cooled for 24 hours, she asked, “Is 48 hours a long enough duration for all patients with severe traumatic brain injury, or may some patients benefit from longer cooling periods?” Specifically, she queried, “If their injury is particularly severe—based on clinical and radiological findings, serum, and brain markers, as well as their intracranial pressure—would those types of patients, who may be at greatest risk of a poor outcome, benefit from even longer cooling?”

—Mimi Zucker, PhD

Reference
1. McIntyre LA, Fergusson DA, Hébert PC, et al. Prolonged therapeutic hypothermia after traumatic brain injury in adults: a systematic review. JAMA. 2003;289:2992-2999.

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