Hypothermia in Children After Trauma

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).

Subjects assigned to the treatment arm will be cooled to 32-33 °C for 48 hours and then slowly warmed.

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.

To determine the effect of HYPO after severe TBI in children on global function and neurocognitive outcomes in the areas of intellectual ability/development, memory and learning, and behavior.

To determine the effect of HYPO after severe TBI in children of different age ranges (< 6y; 6-<16y; and 16-<18y) on mortality and 6 and 12 months functional and neurocognitive outcomes.

To determine the effect of HYPO after severe TBI in children on reducing intracranial hypertension and maintaining adequate cerebral perfusion pressure (CPP).

Inclusion Criteria: Patients with a GCS </= 8 Glasgow Motor Score < 6 Closed head injury Age 0 < 18 y Exclusion Criteria Unavailable to initiate cooling within 6 hours of injury Glasgow Coma Scale (GCS) score = 3 and abnormal brainstem function Normal initial CT scan (No blood, fracture, swelling, and/or shift) Penetrating brain injury No known mechanism of injury Unknown time of injury Uncorrectable coagulopathy (PT/PTT > 16/40 sec, INR > 1.7) Hypotensive episode (Systolic Blood Pressure <5th percentile for age>10 min) Documented Hypoxic episode (O2 saturation < 94% for > 30 min) Pregnancy

Meinert E, Bell MJ, Buttram S, Kochanek PM, Balasubramani GK, Wisniewski SR, Adelson PD; Pediatric Traumatic Brain Injury Consortium: Hypothermia Investigators. Initiating Nutritional Support Before 72 Hours Is Associated With Favorable Outcome After Severe Traumatic Brain Injury in Children: A Secondary Analysis of a Randomized, Controlled Trial of Therapeutic Hypothermia. Pediatr Crit Care Med. 2018 Apr;19(4):345-352. doi: 10.1097/PCC.0000000000001471.

Adelson PD, Wisniewski SR, Beca J, Brown SD, Bell M, Muizelaar JP, Okada P, Beers SR, Balasubramani GK, Hirtz D; Paediatric Traumatic Brain Injury Consortium. Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial. Lancet Neurol. 2013 Jun;12(6):546-53. doi: 10.1016/S1474-4422(13)70077-2. Epub 2013 May 8.