Despite preventative measures, traumatic brain injury (TBI) remains the leading cause of death and disability in children. While most pediatric treatment regimens for TBI to date are derived from adult studies, no therapeutic regimen has been particularly successful in improving outcome in children. There have been numerous laboratory studies utilizing moderate hypothermia (HYPO) (32-33?C) in mature and immature animals, successful Phase II and III clinical studies in adult patients for 24 to 48 h after TBI, and a number of trials in children of HYPO following hypoxia-ischemic (HIE) brain injuries that have supported the efficacy of this intervention. The most recently published trial of treatment with HYPO for HIE within 6 hours showed significant improvement in outcome, particularly in mortality, as compared to severe disability. While the multi-center Phase III randomized controlled clinical trial (RCT) of moderate HYPO in adults was stopped early due to futility but not lack of efficacy, the secondary analysis did highlight that younger adult patients (< 40 y) tended toward improved outcome compared to older subjects. This finding along with a trend toward improved outcomes with early cooling (< 6 h) has resulted in a funded HYPO RCT specifically inclusive of patients ages 16- 45 y and early pre-hospital cooling that has recently begun. Based on the results from our Pilot Clinical Trial (PCT) utilizing moderate HYPO following severe TBI in children, the following application is for a multicenter Phase III RCT to determine whether induced early cooling (within 6 h) (32-33?C) after severe TBI in children and maintained for 48 h will improve mortality at 3 mos post injury as compared to normothermia (37- 38?C). The Secondary Hypotheses, again based on the analysis of the PCT, are that early HYPO after severe TBI in children and maintained for 48 h: 1) will improve global function as measured by the GOS/ GOS- Extended Pediatrics (GOS- E Peds) and neurocognitive status across the domains of intellectual development, learning and memory, and behavior at 6 and 12 mos after injury; 2) will be more effective in younger children < 6 y compared to older children, > 6y, and 3) will lessen intracranial hypertension and the intensity of therapy necessary for control of ICP. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS052478-02
Application #
7419012
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Hicks, Ramona R
Project Start
2007-05-15
Project End
2009-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
2
Fiscal Year
2008
Total Cost
$1,000,000
Indirect Cost
Name
University of Pittsburgh
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Meinert, Elizabeth; Bell, Michael J; Buttram, Sandra et al. (2018) 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 19:345-352
Rosario, Bedda L; Horvat, Christopher M; Wisniewski, Stephen R et al. (2018) Presenting Characteristics Associated With Outcome in Children With Severe Traumatic Brain Injury: A Secondary Analysis From a Randomized, Controlled Trial of Therapeutic Hypothermia. Pediatr Crit Care Med 19:957-964
Miller Ferguson, Nikki; Shein, Steven L; Kochanek, Patrick M et al. (2016) Intracranial Hypertension and Cerebral Hypoperfusion in Children With Severe Traumatic Brain Injury: Thresholds and Burden in Accidental and Abusive Insults. Pediatr Crit Care Med 17:444-50
Chin, Katherine H; Bell, Michael J; Wisniewski, Stephen R et al. (2015) Effect of administration of neuromuscular blocking agents in children with severe traumatic brain injury on acute complication rates and outcomes: a secondary analysis from a randomized, controlled trial of therapeutic hypothermia. Pediatr Crit Care Med 16:352-8
Bell, Michael J; Adelson, P David; Hutchison, James S et al. (2013) Differences in medical therapy goals for children with severe traumatic brain injury-an international study. Pediatr Crit Care Med 14:811-8
Empey, Philip E; Velez de Mendizabal, Nieves; Bell, Michael J et al. (2013) Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury. Crit Care Med 41:2379-87
Adelson, P David; Wisniewski, Stephen R; Beca, John et al. (2013) Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial. Lancet Neurol 12:546-53
Fink, Ericka L; Kochanek, Patrick M; Clark, Robert S B et al. (2012) Fever control and application of hypothermia using intravenous cold saline. Pediatr Crit Care Med 13:80-4
Exo, Jennifer; Kochanek, Patrick M; Adelson, P David et al. (2011) Intracranial pressure-monitoring systems in children with traumatic brain injury: combining therapeutic and diagnostic tools. Pediatr Crit Care Med 12:560-5
Adelson, P David; Srinivas, Ravi; Chang, Yuefang et al. (2011) Cerebrovascular response in children following severe traumatic brain injury. Childs Nerv Syst 27:1465-76

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