Effect of Eythropoietin on Vascular Dysfunction in Human TBI

创伤性脑损伤引起一系列脑血管功能障碍，从受损到 导致脑外伤患者更容易受到继发性脑缺血损害的压力自动调节 严重的全球缺血。脑血流量(CBF)，尤其是在受伤后12小时内 预测神经结果，皮质CBF每增加10ml/100g/min，导致3倍 存活到医院出院的机会增加。在过去的研究中，TBI管理战略 维持升高的脑灌流压预防重型颅脑损伤患者的脑缺血 在减少颈静脉不饱和的发生率方面非常成功。然而，当这个管理策略 适用于所有重型颅脑损伤患者，不良反应(特别是成人发病率增加 呼吸窘迫综合征)似乎抵消了对长期结果的任何有利影响。目前，我们 正在研究动态压力自动调节测试在识别这些患者中可能起到的作用 罹患脑缺血的风险最大，因此谁可能从高血压中获益最多 管理战略。然而，我们发现，在严重的颅脑损伤后，几乎所有(87%)的患者都有 动压自动调节功能受损。我们现在相信，任何针对血管的有效疗法 功能障碍将不得不应用于所有严重颅脑损伤的患者。 在1-44岁年龄组中，创伤是最常见的死亡原因，也是第三大常见原因 对整个美国人口来说。创伤造成的工作寿命损失比癌症和 心血管疾病加在一起。需要对这一重要的公共卫生疾病进行有效的治疗。 治疗颅脑损伤所致脑血管功能障碍可明显改善神经功能 创伤后的康复。 我们建议研究给予重组人促红细胞生成素的生理效应。 重组人促红细胞生成素(RhEPO)，已被发现在实验性脑损伤和 此外，它还能刺激危重病人的红细胞生成。 初步数据表明，rhEpo的神经保护机制的一部分可能是改善的。 脑血管功能障碍，可能是通过内皮型一氧化氮合酶上调。目标 本课题的主要研究内容包括：1.研究EPO及其受体表达的自然历史 2.研究重组人红细胞生成素对脑血流动力学的急性影响； 研究rhEpo给药对脑损伤反应的慢性影响。

Traumatic brain injury (TBI) induces a spectrum of cerebrovascular dysfunction, ranging from impaired pressure autoregulation which causes TBI patients to be more vulnerable to secondary ischemic insults to severe global ischemia. Cerebral blood flow (CBF), especially within the first 12 hr after injury, is strongly predictive of neurological outcome, with each 10ml/100g/min increase in cortical CBF resulting in a 3-fold increase in the chances of surviving to hospital discharge. In past studies, a TBI management strategy that maintained an increased cerebral perfusion pressure to prevent ischemia in patients with severe TBI was very successful at reducing the incidence of jugular desaturation. However, when this management strategy was applied to all patients with severe TBI, adverse effects (especially increased incidence of adult respiratory distress syndrome) appeared to offset any beneficial effect on long-term outcome. Currently, we are studying the role that testing of dynamic pressure autoregulation might play in identifying those patients at greatest risk for developing ischemia and who might therefore benefit most from a hypertensive management strategy. However, we have found that after severe TBI, almost all (87%) patients have impaired dynamic pressure autoregulation. We now believe that any effective therapy directed at vascular dysfunction will have to be applied to all patients with severe TBI. Trauma is the most common cause of death in the 1-44 yr age group, and the third most common cause for the entire US population. Trauma accounts for more loss of work life-years than cancer and cardiovascular diseases combined. Effective treatments for this important public health disorder are needed. Treatment of the cerebrovascular dysfunction caused by TBI could significantly improve neurological recovery following trauma. We propose to study the physiological effects of administration of recombinant human erythropoietin (rhEpo), an agent that has been found to have potent neuroprotective effects after experimental TBI and spinal cord injury and that has the added benefit of stimulating erythropoiesis in critically ill patients. Preliminary data suggests that part of the mechanism of neuroprotection by rhEpo is likely to be amelioration of cerebrovascular dysfunction, possibly through upregulation of endothelial nitric oxide synthase. The goals of this project include the following: 1. To study the natural history of Epo and Epo receptor expression by the injured brain; 2. To study the acute effects of rhEpo administration on cerebral hemodynamics; 3. To study the chronic effects of rhEpo administration on the brain's response to injury.