Effect of Eythropoietin on Vascular Dysfunction in Human TBI

创伤性脑损伤（TBI）可引起一系列脑血管功能障碍，从受损 压力自动调节导致TBI患者更容易受到继发性缺血性损伤， 严重的全脑缺血脑血流量（CBF），特别是在受伤后的前12小时内， 预测神经系统结局，皮质CBF每增加10 ml/100 g/min， 增加存活出院的机会。在过去的研究中，TBI管理策略， 维持脑灌注压升高以防止严重TBI患者出现缺血 在降低颈静脉血氧饱和度下降方面非常成功。然而，当这种管理策略 应用于所有严重TBI患者，不良反应（尤其是成人TBI发生率增加） 呼吸窘迫综合征）似乎抵消了对长期结果的任何有益影响。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发挥的作用 发生缺血的风险最大，因此可能从高血压中获益最多 管理策略然而，我们发现，在严重的TBI后，几乎所有（87%）的患者 动态压力自动调节受损。我们现在认为，任何针对血管的有效疗法， 功能障碍将必须应用于所有严重TBI患者。 创伤是1-44岁年龄组中最常见的死亡原因， 为整个美国人口。创伤比癌症造成更多的工作寿命损失， 心血管疾病综合征需要对这种重要的公共卫生疾病进行有效治疗。 治疗脑损伤后脑血管功能障碍可明显改善神经功能 创伤后的恢复 我们建议研究重组人促红细胞生成素的生理作用 （rhEpo），一种已被发现在实验性TBI后具有有效的神经保护作用的药剂， 脊髓损伤，并具有刺激危重患者红细胞生成的额外益处。 初步数据表明，rhEpo的部分神经保护机制可能是改善 可能通过内皮型一氧化氮合酶的上调。的目标 包括以下内容：1.为了研究Epo和Epo受体表达的自然史， 受伤的大脑; 2。研究rhEpo对脑血流动力学的急性影响; 3.到 研究rhEpo给药对脑损伤反应的长期影响。

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.