Pediatric Traumatic Brain Injury Consortium: Hypothermia

描述（由申请人提供）：尽管采取了预防措施，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儿童TBI治疗方案来源于成人研究，但没有一种治疗方案在改善儿童预后方面特别成功。已有大量实验室研究在成熟和未成熟动物中使用中度低温（HYPO）（32-33°C），在成年患者TBI后24至48小时成功的II期和III期临床研究，以及在缺氧缺血性（HIE）脑损伤后出现中度低温（HYPO）的儿童中进行的大量试验，都支持了这种干预的有效性。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，结果有显著改善，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）由于无效而提前停止，但并非缺乏疗效，但次要分析确实强调，与老年受试者相比，年轻成人患者（< 40岁）倾向于改善结果。这一发现以及早期降温（< 6小时）改善预后的趋势导致了一项资助的HYPO RCT，特别包括16- 45岁的患者和最近开始的院前早期降温。根据我们的试点临床试验（PCT）的结果，在儿童严重TBI后使用中度高温降温，以下申请是一项多中心III期随机对照试验，以确定在儿童严重TBI后诱导早期降温（6小时内）（32-33°C）并维持48小时是否会比常温降温（37- 38°C）提高损伤后3个月的死亡率。第二个假设，同样基于PCT的分析，是儿童严重TBI后早期HYPO并维持48小时：1)将改善GOS/ GOS-扩展儿科（GOS- E Peds）测量的整体功能和损伤后6和12个月的智力发展、学习记忆和行为领域的神经认知状态；2)对于小于6岁的儿童比大于6岁的儿童更有效，并且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.