Futility

The primary hypothesis for this application for a multicenter phase III randomized clinical trial (RCT) is that induced moderate hypothermia (HYPO) (32-33 °C) after severe traumatic brain injury (TBI) in children and maintained for 48 hours will improve mortality at 3 months and 12 month functional outcome as assessed by the Glasgow Outcome Scale (GOS).

The primary specific aim of this RCT is to determine the effect of induced moderate HYPO (32-33 °C) after severe TBI in children on mortality at 3 months post injury. The primary outcome measure will be the GOS; the primary time point for evaluation is 3 months. Further secondary functional outcome measures will include the GOS - Extended Pediatrics (GOS - E Peds), and Vineland Adaptive Behavior Scale (VABS) and will be assessed in conjunction with the GOS at 6 and 12 months post injury.

The secondary hypotheses are based on the results and analysis of the Pilot Clinical Trial (completed and recently published [Adelson et al. NEUROSURGERY. 56 (4): 740-754, 2005]). These secondary hypotheses include that induced moderate hypothermia (HYPO) (32-33 °C) after severe TBI in children and maintained for 48 h:

• will improve other outcome assessments including neurocognitive status on performance-based neuropsychological testing across the domains of intellectual development, learning and memory, language, motor and psychomotor skills, visuo-spatial abilities, attention and executive function, and behavior at only 6 and 12 months after injury;
• HYPO will improve long term outcome of all age ranges and across genders in infants, young, preadolescent, and adolescent children; AND
• HYPO will lessen intracranial hypertension and lessen the intensity of therapy necessary for control of ICP.

Based on these hypotheses, further secondary specific aims are proposed:

• Specific Aim 2: To determine the effect of early induced moderate HYPO (32-33°C) after severe TBI in children on global function and neurocognitive outcomes in the areas of intellectual ability/ development, memory and learning, and behavior at 6 and 12 months post injury.
• Specific Aim 3: To determine the effect of early induced moderate HYPO after severe TBI in children of different age ranges (< 6 y and 6- < 16 y) on mortality and 6 and 12 months functional and neurocognitive outcomes.
• Specific Aim 4: To determine the effect of early moderate HYPO after severe TBI in children on reducing intracranial hypertension and maintaining adequate cerebral perfusion pressure (CPP).

Inclusion Criteria:

1. Patients with a GCS </= 8
2. Glasgow Motor Score < 6
3. Closed head injury
4. Age 0 < 18 y

Exclusion Criteria

1. Unavailable to initiate cooling within 6 hours of injury
2. Glasgow Coma Scale (GCS) score = 3 and abnormal brainstem function
3. Normal initial CT scan (No blood, fracture, swelling, and/or shift)
4. Penetrating brain injury
5. No known mechanism of injury
6. Unknown time of injury
7. Uncorrectable coagulopathy (PT/PTT > 16/40 sec, INR > 1.7)
8. Hypotensive episode (Systolic Blood Pressure <5th percentile for age>10 min)
9. Documented Hypoxic episode (O2 saturation < 94% for > 30 min)
10. Pregnancy