Multiple Medical Therapies for Pediatric TBI; Comparative Effectiveness Approach

描述(申请人提供)：创伤性脑损伤(TBI)是2005年美国报告的超过7000例儿童死亡的头号杀手。除了这一生命损失之外，在美国，脑外伤每年给儿童的健康和福利造成的急性护理成本超过20亿美元，100多万人的生命年可能面临风险。严重脑外伤儿童的护理进展缓慢，令人失望。新的治疗药物和方法的随机对照试验(RCT)在多个中心应用时普遍失败。以证据为基础的指南不足以产生有意义的建议，因为文献未能证明脑损伤护理的大多数方面的最佳实践。在当代临床实践中，如控制颅内压、减轻二次胰岛素和代谢支持等实践的差异很大，导致患者预后的巨大差异，并最终可能压倒设计良好的随机对照试验中可能观察到的治疗效果。我们建议对1000名患有严重脑外伤的儿童进行一项观察性队列研究，以比较来自美国、英国和欧盟的国际财团内儿童脑损伤治疗的有效性。我们将测试3个具体目标，包括总共6种脑损伤疗法--(I)颅内高压策略--脑脊液分流 二次损伤检测--预防性过度换气和脑组织氧监测(PbO2)；(3)代谢支持--营养支持和血糖管理。将采用几种统计方法，包括倾向分数调整、回归分析和新颖的统计建模，这些方法经常用于比较有效性研究(CER)以控制混杂因素。这项提案的成功完成将为改变临床实践提供令人信服的证据，为未来指南的几项新建议提供证据，并导致改进研究方案，以限制脑外伤治疗的可变性--通过更好的临床实践并最终通过更有效的研究立即帮助儿童。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the leading killer of children with over 7000 deaths reported in the US in 2005. In addition to this loss of life, the yearly costs of TBI on the health and welfare of children in the US is over $2 billion for acute care along and more than a million life-years are potentially at risk. Advances in care for children with severe TBI have been disappointingly slow. Randomized controlled trials (RCTs) of novel therapeutic agents and approaches have universally failed when applied in multiple centers. Evidenced-based guidelines are not sufficiently robust to generate meaningful recommendations because the literature has failed to demonstrate best practices for most aspects of TBI care. Variations in practices such as intracranial hypertension control, mitigation of secondary insults and metabolic support are substantial in contemporary clinical practice, leading to wide variations in patient outcomes and may ultimately overwhelm treatment effects that might be observed in a well-designed RCT. We propose an observational cohort study of 1000 children with severe TBI to compare the effectiveness of pediatric TBI therapies within an international consortium from the US, UK and EU. We will test 3 specific aims that encompass a total of 6 TBI therapies - (i) intracranial hypertension strategies - cerebrospinal fluid diversion and hyperosmolar therapies; (ii) secondary insult detection - prophylactic hyperventilation and brain tissue oxygen monitoring (PbO2); (iii) metabolic support - nutritional support and glucose management. Several statistical approaches, often used in comparative effectiveness research (CER) to control for confounders, will be employed including propensity score adjustments, regression analyses and novel statistical modeling. Successful completion of this proposal would provide compelling evidence to change clinical practices, provide evidence for several new recommendations for future guidelines and lead to improved research protocols that would be limit variability in TBI treatments - helping children immediately through better clinical practices and ultimately through more effective investigation.