June 13, 2008 — Hypothermia therapy initiated within 8 hours and continued for 24 hours in children with severe traumatic brain injury (TBI) to treat intracranial hypertension does not improve neurological outcome and may increase mortality, new research suggests.

In a randomized, multicenter trial, the largest study of its kind ever published and the first collaborative study of 225 children with head injury among international pediatric intensive care units, researchers found that at 6-month follow-up, 32 (31%) of the 102 children assigned to the hypothermia group had unfavorable outcomes, compared with 23 (22%) of 103 children in the normothermia group.

Mortality was also higher in subjects who received hypothermia compared with those in the normothermia group, with 23 deaths (21%) and 14 deaths (12%) respectively.

"We were surprised by this trend in increased mortality [in the hypothermia group]. It looks as though it is clinically significant, but the numbers are small and the study was not designed to look at this outcome," principal investigator James Hutchison, MD, from the Hospital for Sick Children, in Toronto, Ontario, told Medscape Neurology & Neurosurgery.

The study is published in the June 5 issue of the New England Journal of Medicine.

International Trial

According to Dr. Hutchison, the rationale for the study came from animal and human studies indicating hypothermia therapy improves survival and neurologic outcomes.

In particular, he said, a single randomized trial in adults published in 1997 that showed hypothermia therapy decreased the risk of a poor outcome in a subgroup of adults with TBI who had a Glasgow Coma Scale (GCS) score of 5 to 7 (Marion DW et al. N Engl J Med. 1997;336:540-546) provided the impetus for the current trial.

"This study had a small sample size, but it looked very promising and also at that time there hadn't been any good studies done in children," he said.

"We hypothesized that, as compared with normothermia, treatment with hypothermia for 24 hours started within 8 hours after severe TBI would reduce their risk of an unfavorable outcome at 6 months," the authors write.

The study included 225 children from 17 centers in Canada, France, and the United Kingdom. Children with severe TBI were randomly assigned to either hypothermia therapy (32.5°C for 24 hours) initiated within 8 hours after injury or to normothermia (37.0°C).

Primary Outcome

The primary outcome was the proportion of children who had an unfavorable outcome, which included severe disability, persistent vegetative state, or death, assessed by the Pediatric Cerebral Performance Category score at 6 months.

A total of 102 subjects were included in the hypothermia group and 103 were assigned to the normothermia group. Subjects were eligible if they were 1 to 17 years old and had a TBI and a GCS score of 8 or less at the accident scene or in the emergency department.

All patients had a need for mechanical ventilation and a computed tomographic (CT) scan that showed an acute brain injury.

Exclusion criteria included patients who were screened more than 8 hours after injury, those with refractory shock or with suspected brain death, nonaccidental injury, prolonged cardiac arrest at the accident scene, and high cervical spinal cord injury.

Study subjects were cooled with the use of surface cooling techniques. Esophageal temperature was maintained at a mean of 32.5°C for 24 hours. For rewarming, the temperature was increased at a rate of 0.5°C every 2 hours.

After rewarming in the hypothermia group and immediately in the normothermia group, temperature was maintained at 37°C until intracranial hypertension resolved.

More Research Required

The researchers found there was more hypotension and more vasoactive agents were administered in the hypothermia group during the rewarming period vs those in the normothermia arm.

"When your whole body is cooled and rewarmed, the blood vessels constrict and blood pressure drops, and that can be bad for the brain. Even though we had a very strict protocol that continuously monitored for this and administered boluses of fluid and medication to guard against it, it still occurred during rewarming. So I think we need to be more cautious and take a slower approach [to rewarming]," he said.

A study of hypothermia therapy in an adult TBI population published in 2001 also showed no beneficial impact on survival or functional outcomes and in fact demonstrated a higher complication rate (Clifton GL et al. N Engl J Med. 2001;344:556-563).

On the basis of these results, the investigators conclude this protocol is not warranted for the treatment of severe head injury in children, and Dr. Hutchison said more research is required.

It is possible, he added, that lowering body temperature earlier and rewarming patients at a slower rate may improve outcomes — a hypothesis that will be tested in 2 new pediatric trials that are currently enrolling patients.

In the meantime, he said, the treatment should be reserved for children with refractory intracranial hypertension.

The study was supported by the Canadian Institutes of Health Research, the Ontario Neurotrauma Foundation, the Rick Hansen Institute, the SickKids Foundation, the Physicians Services Incorporated, Fonds de la Recherche en Santé du Québec, and the Children's Hospital of Eastern Ontario Research Institute. One of the study authors has received consulting fees from Johnson & Johnson. The other study authors have disclosed no relevant financial relationships.

N Engl J Med. 2008;358:2447-2456.

Clinical Context

Study Highlights

• This trial took place at 17 centers in 3 countries.
• Eligibility criteria were 1 to 17 years of age, TBI, a GCS score of 8 or less at the scene where the injury occurred or in the emergency department, a CT scan that showed an acute brain injury, and need for mechanical ventilation.
• Exclusion criteria were screening more than 8 hours after injury, refractory shock, suspected brain death, nonaccidental injury, prolonged cardiac arrest at the scene of the injury, high cervical spinal cord injury, severe neurodevelopmental disability before the injury, a brain injury from a gunshot wound, acute isolated epidural hematoma, or pregnancy.
• From February 1999 to October 2004, a total of 1441 consecutive patients with TBI were admitted to the participating pediatric intensive care units; 327 (23%) met eligibility criteria.
• Of the 327 eligible patients, 225 (69% of eligible patients) were enrolled; 108 were randomized to hypothermia therapy (32.5°C for 24 hours) with 6 lost to follow-up, and 117 patients to normothermia (37.0°C) with 14 lost to follow-up.
• Patients in the hypothermia group were cooled with the use of surface cooling techniques. Mean time to initiation of hypothermia was 6.3 hours (< 8 hours in all patients).
• The main endpoint was the proportion of children with an unfavorable outcome.
• Unfavorable outcome was defined as severe disability, persistent vegetative state, or death, as assessed on the basis of the Pediatric Cerebral Performance Category score at 6 months.
• Mean temperatures achieved were 33.1 ± 1.2°C in the hypothermia group and 36.9 ± 0.5°C in the normothermia group.
• At 6 months, outcome was unfavorable in 31% of the patients in the hypothermia group and 22% of the patients in the normothermia group (relative risk [RR], 1.41; 95% CI, 0.89 - 2.22; P = .14).
• There were 23 (21%) deaths in the hypothermia group vs 14 (12%) deaths in the normothermia group (RR, 1.40; 95% CI, 0.90 - 2.27; P = .06).
• The hypothermia group also fared worse than the normothermia group because the hypothermia group had more hypotension (P = .047) and use of more vasoactive agents during the rewarming period (P < .001).
• Both groups had similar lengths of stay in the intensive care unit and in the hospital.
• Other adverse events were similar in both groups.
• At 12 months after injury, scores on assessments of long-term visual memory were significantly worse in the hypothermia vs the normothermia group (P = .05).
• There were no other differences in neuropsychological outcomes between the groups.
• The investigators concluded that in children with severe TBI, hypothermia therapy started within 8 hours after injury and continued for 24 hours does not improve the neurologic outcome and may increase the mortality rate and that use of this hypothermia protocol is not warranted for the treatment of severe head injury in children.
• Limitations of the study were inability to determine the effect of hypothermia initiated earlier or given for longer periods.

Pearls for Practice

• At 6 months, the outcome of hypothermia treatment in children with TBI was unfavorable in 31% of the patients in the hypothermia group and 22% of the patients in the normothermia group. There were 23 deaths in the hypothermia group vs 14 deaths in the normothermia group. In children with severe TBI, hypothermia therapy started within 8 hours after injury and continued for 24 hours did not improve the neurologic outcome and may increase the mortality rate.
• In children with severe TBI undergoing hypothermia treatment, the hypothermia group also fared worse than the normothermia group because the hypothermia group had more hypotension and use of more vasoactive agents during the rewarming period.

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