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Hypothermia for Traumatic Brain Injury in Children-A Phase II Randomized Controlled Trial
John Beca1, Brent McSharry, Simon Erickson
11Department of Pediatric Intensive Care at Starship Children's Hospital, Auckland, New Zealand. 2Department of Pediatric Intensive Care, Princess Margaret Hospital, Perth, Australia. 3Department of Pediatric Intensive Care, Women and Children's Hospital, Adelaide, Australia. 4Department of Pediatric Intensive Care, Mater Children's Hospital, Brisbane, Australia. 5Department of Pediatric Intensive Care, Royal Children's Hospital, Brisbane, Australia. 6Department of Pediatric Intensive Care, Children's Hospital at Westmead, Sydney, Australia. 7Department of Pediatric Neurosurgery, British Columbia Children's Hospital, Vancouver, BC, Canada. 8Department of Pediatric Intensive Care, Sydney Children's Hospital, Sydney, Australia. 9Department of Pediatric Intensive Care, Royal Children's Hospital, Melbourne, Australia.
Insights
Therapeutic hypothermia for severe pediatric traumatic brain injury did not improve outcomes. This study suggests early hypothermia should not be used outside clinical trials due to feasibility challenges.
Area of Science:
- Pediatric critical care medicine
- Neurotrauma research
- Clinical trial design
Background:
- Severe traumatic brain injury (TBI) in children presents significant management challenges.
- Therapeutic hypothermia is a potential neuroprotective strategy, but its efficacy in pediatric TBI requires further investigation.
Purpose of the Study:
- To assess the feasibility of a large-scale Phase III clinical trial for early therapeutic hypothermia in children with severe TBI.
- To evaluate the safety and potential efficacy of maintaining a temperature of 32-33°C for 72 hours compared to normothermia (36-37°C).
Main Methods:
- A multicenter, prospective, randomized controlled Phase II trial.
- Involved children aged 1-15 years with severe TBI, randomized within 6 hours of injury.
- Intervention group received therapeutic hypothermia; control group received strict normothermia for 72 hours.
Main Results:
- Recruitment was challenging, with only 7.2% of eligible children enrolled.
- Protocol violations occurred in 9% of cases, primarily related to recruitment and temperature management.
- No significant increase in complications (infections, bleeding, arrhythmias) was observed with hypothermia; no difference in 12-month outcomes between groups.
Conclusions:
- Early therapeutic hypothermia did not improve outcomes in children with severe TBI and should not be used outside clinical trials.
- Conventional randomized controlled trials for pediatric severe TBI face feasibility issues.
- Future research requires a large international collaboration and innovative trial designs.
Objectives:
To perform a pilot study to assess the feasibility of performing a phase III trial of therapeutic hypothermia started early and continued for at least 72 hours in children with severe traumatic brain injury.
Design:
Multicenter prospective randomized controlled phase II trial.
Setting:
All eight of the PICUs in Australia and New Zealand and one in Canada.
Patients:
Children 1-15 years old with severe traumatic brain injury and who could be randomized within 6 hours of injury.
Interventions:
The control group had strict normothermia to a temperature of 36-37°C for 72 hours. The intervention group had therapeutic hypothermia to a temperature of 32-33°C for 72 hours followed by slow rewarming at a rate compatible with maintaining intracranial pressure and cerebral perfusion pressure.
Measurements And Main Results:
Of 764 children admitted to PICU with traumatic brain injury, 92 (12%) were eligible and 55 (7.2%) were recruited. There were five major protocol violations (9%): three related to recruitment and consent processes and two to incorrect temperature management. Rewarming took a median of 21.5 hours (16-35 hr) and was performed without compromise in the cerebral perfusion pressure. There was no increase in any complications, including infections, bleeding, and arrhythmias. There was no difference in outcomes 12 months after injury; in the therapeutic hypothermia group, four (17%) had a bad outcome (pediatric cerebral performance category, 4-6) and three (13%) died, whereas in the normothermia group, three (12%) had a bad outcome and one (4%) died.
Conclusions:
Early therapeutic hypothermia in children with severe traumatic brain injury does not improve outcome and should not be used outside a clinical trial. Recruitment rates were lower and outcomes were better than expected. Conventional randomized controlled trials in children with severe traumatic brain injury are unlikely to be feasible. A large international trials group and alternative approaches to trial design will be required to further inform practice.
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