HOUSTON—Inducing moderate hypothermia is a promising therapy that markedly improved functional outcomes after acute brain injury in animal studies and phase II clinical trials. That is why researchers were surprised when the treatment proved less effective in a recent phase III trial.[1]

Six months after the brain injury, the rate of poor outcomes—severe disability, a vegetative state, or death—was the same (57%) in the patients who had been made hypothermic in the hours following injury and in those who had not. Mortality was also similar in the two groups. During the initial hospital stay, complications occurred more often in those who received hypothermia.

Lead investigator Guy L. Clifton, MD, said he is not yet ready to give up on hypothermia induction, though. “For most treatments, it takes two to three phase III trials to get it right,” pointed out Dr. Clifton, Professor and Chairman in the Department of Neurosurgery at the University of Texas-Houston Health Science Center.

Although the prospective, randomized, multicenter trial was originally going to include 500 patients with closed head injuries, only 392 were enrolled. The trial was discontinued when it became apparent that hypothermia was not effective. The enrollees were between ages 16 and 65 years and had a postresuscitation score of 3 to 8 on the Glasgow Coma Scale, signifying coma.

In the hypothermia group, the goal was to achieve a bladder temperature of 33°C within eight hours of injury. Induction of hypothermia, accomplished with ice application, gastric lavage with iced fluids, and room-temperature air in the ventilator circuit, was begun within six hours of brain injury. A bladder temperature of 32.5° to 34.0°C was maintained for 48 hours. The patients were subsequently rewarmed at a rate no faster than 0.5°C every two hours. In the normothermic group, body temperature was kept at 37.0°C.

All patients received standard care consistent with recent guidelines,[2] including continuous temperature monitoring using Foley catheters with thermistors, management of increased intracranial pressure, intravenous morphine for at least 72 hours, hydration, seven days of daily phenytoin administration, and enteral or parenteral nutrition. Potassium was given as needed.

Cerebral perfusion pressure was kept at 70 mm Hg or higher through intracranial pressure control and administration of intravenous fluids and vasopressors. Intravenous vecuronium was given to the normothermia group as needed for respiratory management and to the hypothermia group for 72 hours to prevent shivering.

The two groups were similar in terms of mean age and type and severity of brain injury. The mean time from injury to randomization was 4.1 hours in the normothermia group and 4.3 hours in the hypothermia group. In the latter group, the average interval between injury and the achievement of the target bladder temperature was 8.4 hours.

During the initial days of treatment, the use of hypothermia did appear to lower intracranial pressure. However, the complication rate was higher in the hypothermia group. For example, critical hypotension (mean arterial pressure below 70 mm Hg for two or more consecutive hours in association with organ failure) developed in 10% of the hypothermic patients but in only 3% of the normothermic patients. Combined bradycardia and hypotension occurred in 16% and 4% of patients, respectively. In addition, the percentage of hospital days on which any complication occurred was higher in the hypothermia group (78% vs 70% in the normothermia group).

Only a few of the patients in the study were older than 45 years. In these patients, the use of hypothermia was more likely to be associated with a poor outcome than it was when used in younger patients (Table 1).

Although its findings are disappointing, the trial still represents a landmark achievement, wrote Raj K. Narayan, MD, Professor and Chairman of the Department of Neurosurgery at Temple University Hospital in Philadelphia. In an accompanying editorial,[3] Dr. Narayan listed four lessons to be learned from this study:

• Older patients do not benefit from hypothermia, and they may actually have worse outcomes than may patients who remain normothermic.

• Patients who are hypothermic upon arrival at the emergency department appear to have more severe injuries.

• It may not be advisable to rewarm patients who are hypothermic upon arrival at the emergency department.

• The timing of the cooling may be an important variable.

Further, said Dr. Narayan, hypothermia induction significantly reduces the likelihood of developing very high intracranial pressure (above 30 mm Hg) during the 96 hours after brain injury. “It may be a useful therapy when intracranial pressure has failed to respond to simpler measures,” he said.

Despite the trial’s negative overall findings, Dr. Clifton maintains hope in the future of hypothermia induction. In fact, the procedure worked quite well in the subgroup of patients with hypothermia on admission. “In these cases, cooling occurred within moments of injury, and we maintained it,” Dr. Clifton told PULMONARY REVIEWS. “That is a big clue that our overall findings were negative because we cooled patients too late.” Hypothermia induction may therefore prove to be efficacious when started within a couple hours, rather than six hours, of acute brain injury, said Dr. Clifton. He plans to submit an application for another phase III trial to the National Institutes of Health on June 1.

--Timothy Begany

References
1. Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001;344:556-563.

2. Bullock R, Chesnut RM, Clifton G, et al. Guidelines for the management of severe traumatic brain injury. J Neurotrauma. 2000;17:451-553.

3. Narayan RK. Hypothermia for traumatic brain injury—a good idea proved ineffective. N Engl J Med. 2001;344:602-603.

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