Efficacy of Hypothermia in Pediatric TBI

儿童创伤性脑损伤（TBI）的治疗一直完全依赖于成人的治疗模式，无论是实验还是临床，都很少关注损伤后发育中的大脑潜在的独特反应。很少有利用未成熟动物的实验研究，甚至更少的临床研究利用儿童TBI后的治疗干预措施（如低温治疗（HYPO））。虽然有大量的实验证据表明，HYPO在各种不同的创伤性脑损伤模型中具有神经保护作用，但在儿童或未成熟的创伤性脑损伤模型中的研究一直缺乏。很明显，尽管在成人中有证据，但对实验和临床儿童脑外伤后HYPO的效果知之甚少，因此需要进一步研究。尽管最近使用低温疗法的成人临床试验结果令人失望，但有迹象表明，在年轻患者中改善的结果可能会扩展到儿科人群。本研究的疗效不能转化为对儿童的护理，因为本试验中没有患者是儿童，儿科TBI后的HYPO既不能过早放弃，也不能在没有进一步研究的情况下用作治疗干预。根据先前的文献和我们的初步数据，与成人相比，HYPO可能对儿童更有益。这一初步数据为进一步研究潜在儿童提供了令人信服的证据，目前尚不清楚儿童TBI后HYPO治疗对随后神经发育的潜在年龄依赖性影响和局限性。我们的总体假设是，虽然HYPO在儿童TBI的治疗中是有益的，但它会对不同年龄的损伤和治疗的发育产生年龄相关的影响。损伤的年龄和治疗效果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。虽然实验和临床儿童脑损伤后的HYPO会对所有成熟年龄的神经递质释放衰减产生积极影响，但由于过度神经递质释放阻断不足或神经递质阻断对正常发育的负面影响，年龄相关的影响将在损伤后细胞死亡、突触连通性和认知功能的标志物中得到证明。具体目标将包括使用不同年龄的未成熟大鼠创伤性脑损伤实验模型，确定使用HYPO治疗后的神经递质释放反应，以及随后与年龄相关的损伤和组织学损伤治疗的影响，包括早期和延迟的神经元细胞死亡、突触发生和功能结果。平行的临床特定目标将确定神经递质释放对HYPO治疗反应的影响，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.