Pediatric Traumatic Brain Injury Consortium: Hypothermia

描述（由申请人提供）：尽管采取了预防措施，但创伤性脑损伤（TBI）仍然是儿童死亡和残疾的主要原因。虽然迄今为止大多数TBI的儿科治疗方案都来自成人研究，但没有治疗方案在改善儿童预后方面特别成功。已经有许多在成熟和未成熟动物中使用中度低温（HYPO）（32-33 ℃）的实验室研究，在成人患者TBI后24 - 48小时的成功II期和III期临床研究，以及在缺氧缺血性（HIE）脑损伤后HYPO儿童中的许多试验支持这种干预的有效性。最近发表的在6小时内用HYPO治疗HIE的试验显示，与严重残疾相比，结局显著改善，特别是死亡率。虽然成人中度HYPO的多中心III期随机对照临床试验（RCT）由于无效而不是缺乏疗效而提前停止，但次要分析确实强调了与老年受试者相比，年轻成人患者（< 40岁）倾向于改善结局。这一发现沿着早期冷却（< 6 h）改善结局的趋势，导致了一项资助的HYPO RCT，特别包括年龄16- 45岁的患者和最近开始的早期院前冷却。根据我们的先导性临床试验（PCT）的结果，在儿童严重TBI后使用中度HYPO，以下应用是一项多中心III期RCT，以确定与正常体温（37- 38 ℃）相比，儿童严重TBI后诱导早期冷却（6小时内）（32-33 ℃）并维持48小时是否会改善损伤后3个月的死亡率。再次基于PCT分析的次要假设是，儿童重度TBI后早期HYPO并维持48小时：1）将改善GOS/ GOS-扩展儿科测量的整体功能（GOS- E Peds）和神经认知状态，包括损伤后6和12个月的智力发育、学习和记忆以及行为; 2）与> 6岁的儿童相比，< 6岁的儿童更有效，3）将减轻颅内高压和控制ICP所需的治疗强度。

DESCRIPTION (provided by applicant): 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.