Efficacy of Hypothermia in Pediatric TBI

在儿科人群中，创伤性脑损伤(TBI)的治疗一直完全依赖于成人的治疗模式，无论是在实验上还是在临床上，很少关注损伤后发育中的脑的潜在独特反应。利用未成熟动物进行的实验研究很少，利用儿童脑外伤后治疗干预的临床研究就更少了(例如)。低体温(低体温)。虽然有令人印象深刻的实验证据表明，Hypo在各种不同的脑外伤模型中具有神经保护作用，但在儿童中或利用不成熟的脑外伤模型进行的研究一直很缺乏。很明显，尽管在成人中有证据可用，但对Hypo对实验性和临床儿童脑外伤后的影响知之甚少，因此需要进一步研究。尽管最近使用低温的成人临床试验的结果令人失望，但有迹象表明，年轻患者的预后可能会扩大到儿科人群。这项研究的疗效不能转化为对儿童的护理，因为在这项试验中，没有一个患者是儿童，在没有进一步研究的情况下，儿童脑外伤后的Hypo既不能过早放弃，也不能用作治疗干预措施。根据以前的文献和我们的初步数据，与成人相比，Hypo在儿童中可能更有益。这一初步数据为进一步研究潜在的儿童提供了令人信服的证据，目前尚不清楚儿童脑外伤后Hypo治疗对后续神经发育的潜在年龄相关性影响或限制。我们对这一建议的总体假设是，虽然Hypo在治疗儿童脑外伤中将是有益的，但它将对不同受伤和治疗年龄的发育产生与年龄相关的影响。受伤时的年龄和治疗效果将反过来取决于发育中的大脑对神经递质释放和/或随后的阻断的敏感性。虽然儿童实验性和临床性脑损伤后的缺氧将对所有成熟年龄的神经递质释放的减弱产生积极影响，但由于不能充分阻断过度的神经递质释放或神经递质阻断对正常发育的负面影响，与年龄相关的效应将在损伤后的细胞死亡、突触连接和认知功能的标志物中得到证实。具体目标将包括确定Hypo治疗后的神经递质释放反应，以及随后损伤和组织损伤的治疗、早期和延迟性神经细胞死亡、突触形成和功能结果的年龄相关影响，使用不同年龄的脑损伤实验模型。平行的临床特定目标将确定Hypo治疗对神经递质释放的影响，以及Hypo对儿童早期和延迟细胞死亡的年龄相关影响。

Treatment of traumatic brain injury (TBI) in the pediatric population has been totally dependent on adult paradigms, both experimentally and clinically with little attention paid to the potential unique responses of the developing brain after injury. There has been few experimental studies utilizing immature animals and even fewer clinical studies utilizing treatment interventions following pediatric TBI (e.g.) Hypothermia (HYPO). While there is over-whelming experimental evidence that HYPO is neuroprotective in a wide spectrum of different models of TBI, studies in children or utilizing immature models of TBI have been lacking. It is obvious that despite the evidence available in the adult, so little is known of the effect of HYPO following experimental and clinical pediatric TBI that it necessitates further study. Despite the recent disappointing results from the adult clinical trials using hypothermia, there was a suggestion of improved outcome in younger patients that may extend to the pediatric population. Efficacy from this study through cannot be translated to care of children since none of the patients in this trial were children and HYPO following pediatric TBI cannot be either prematurely discarded or utilized as a therapeutic intervention without further study. Based on the previous literature and our Preliminary Data, HYPO may be potentially more beneficial in children as compared to the adult. This initial data is compelling evidence for further study as to the potential children, there is currently no understanding of the potential age dependent impact nor limitations of HYPO treatment following pediatric TBI on subsequent neural development. Our Overall Hypothesis for this proposal is that while HYPO will be beneficial in the treatment of pediatric TBI, it will have an age related impact on development at different ages of injury and treatment.. This age at injury and treatment effect will in turn be governed by the sensitivity of the developing brain to neurotransmitter release and/or subsequent blockade. While HYPO following experimental and clinical pediatric TBI will positively impact on the attenuation of neurotransmitter release in all maturational ages, an age related effect, due to either inadequate blockade of excessive neurotransmitter release or the negative impact of neurotransmitter blockade on normal development, will be evidenced in post-injury markers of cell death, synaptic connectivity, and cognitive function. The Specific Aims will include defining the neurotransmitter release response following treatment with HYPO and the subsequent age related impact of injury and treatment of histologic damage, both early and delayed neuronal cell death, synaptogenesis, and functional outcome using different age at injury experimental models of TBI in the immature rat. Parallel clinical specific aims will define the effect of neurotransmitter release in response to treatment with HYPO and the age-related impact of HYPO on early and delayed cell death in children.