Pediatric Traumatic Brain Injury Consortium: Hypothermia

描述(申请人提供)：尽管采取了预防措施，但创伤性脑损伤(TBI)仍然是导致儿童死亡和残疾的主要原因。虽然到目前为止，大多数儿童脑损伤的治疗方案都来自成人研究，但没有一种治疗方案在改善儿童预后方面特别成功。已有大量的实验室研究在成熟和未成熟的动物中使用中低温(Hypo)(32-33℃)，在成人患者脑损伤后24至48小时内成功地进行了II期和III期临床研究，以及在儿童缺氧缺血(HIE)脑损伤后进行的一些试验，这些试验支持了这种干预的有效性。最近发表的Hypo在6小时内治疗HIE的试验显示，与严重残疾相比，结果显著改善，特别是死亡率。虽然成人中中度缺氧的多中心III期随机对照临床试验(RCT)因无效但并非缺乏疗效而提前停止，但二次分析确实强调，与年长的受试者相比，年轻的成年患者(40岁)倾向于改善结果。这一发现以及早期降温(&lt；6小时)改善预后的趋势导致了一项由基金资助的Hypo RCT，特别包括16-45岁的患者和最近开始的早期院前降温。基于我们对儿童重型颅脑损伤后使用中度低氧的试点临床试验(PCT)的结果，以下应用于多中心III期随机对照试验，以确定与常温(37-38摄氏度)相比，儿童重型颅脑损伤后早期诱导降温(6小时内)(32-33℃)并维持48小时是否会提高损伤后3个月的死亡率。第二个假设，同样基于PCT的分析，是儿童重型颅脑损伤后早期低氧并维持48小时：1)将改善GOS/GOS-E扩展儿科(GOS-E PEDS)测量的全球功能，以及在受伤后6个月和12个月的智力发展、学习和记忆以及行为领域的神经认知状态；2)与较大的儿童相比，更小的儿童将更有效；6)与较大的儿童相比，5)将降低颅内高压和控制颅内压所需的治疗强度。

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.