Effect of Eythropoietin on Vascular Dysfunction in Human TBI

促红细胞生成素对人 TBI 血管功能障碍的影响

• 批准号: 7586626
• 负责人: CLAUDIA S ROBERTSON
• 金额: $ 25.59万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7586626
• 关键词: Accounting; Acute; Adult Respiratory Distress Syndrome; Adverse effects; Anemia; Behavior assessment; Blood Transfusion; Blood Vessels; Blood flow; Brain; Brain Injuries; Cardiovascular Diseases; Cause of Death; Cerebral perfusion pressure; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrum; Chronic; Clinical; Clinical Research; Clinical Trials; Complement; Contusions; Critical Illness; Data; Disease; Erythropoiesis; Experimental Models; Functional disorder; Funding; Goals; Grant; Hemoglobin; Homeostasis; Hospitals; Human; Hypertension; Incidence; Individual; Inflammatory Response; Injury; Ischemia; Laboratories; Laboratory Finding; Life; Logic; Malignant Neoplasms; Measures; Metabolic; Metabolism; Microdialysis; Modeling; Natural History; Neurologic; Neurological outcome; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Outcome; Oxygen; Pathology; Patients; Pharmaceutical Preparations; Physiological; Play; Population; Process; Production; Progress Reports; Protein Isoforms; Public Health; Range; Rate; Recovery; Regulation; Research Personnel; Risk; Role; Sampling; Secondary to; Severities; Spinal cord injury; Testing; Tissue Sample; Trauma; Traumatic Brain Injury; Unemployment; Up-Regulation; Venous; Work; age group; brain tissue; cerebrovascular; day; design; hemodynamics; human NOS3 protein; improved; injured; neuropathology; neuroprotection; neuropsychological; nitrate; pressure; prevent; programs; receptor; receptor expression; recombinant human erythropoietin; response; response to injury

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.

创伤性脑损伤（TBI）诱导一系列脑血管功能障碍，范围从 压力自动调节会导致TBI患者更容易受到继发性缺血性侮辱的影响 严重的全球性缺血。脑血流（CBF），尤其是在受伤后的前12小时内，强烈 预测神经系统结果，皮质CBF的每10ml/100g/min增加，导致3倍 增加了生存到医院出院的机会。在过去的研究中，TBI管理策略 在严重TBI患者中，保持脑灌注压力增加，以预防缺血 非常成功地降低颈效的发生率。但是，当这种管理策略 应用于所有严重TBI，不良反应的患者（尤其是成人发病率增加 呼吸窘迫综合征）似乎抵消了对长期结果的任何有益影响。目前，我们 正在研究动态压力自动调节测试可能在识别这些患者方面发挥作用的作用 患缺血的风险最大，因此可能从高血压中受益最大 管理策略。但是，我们发现在严重的TBI之后，几乎所有（87％）患者的患者具有 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 功能障碍必须应用于所有严重TBI患者。 创伤是1-44岁年龄段的最常见死亡原因，也是第三大的原因 对于整个美国人口。创伤占工作年寿命损失的损失比癌症和 心血管疾病的总和。需要有效治疗这种重要的公共卫生障碍。 TBI引起的脑血管功能障碍的治疗可能会显着改善神经系统 创伤后的恢复。 我们建议研究重组人红细胞生成素的生理影响 （RHEPO），一种被发现在实验性TBI和 脊髓损伤，这是刺激重症患者刺激红血病的额外好处。 初步数据表明，RHEPO神经保护机制的一部分可能是改善 脑血管功能障碍，可能是通过上调内皮一氧化氮合酶的上调。目标 该项目包括以下内容：1。通过研究EPO和EPO受体表达的自然史 受伤的大脑； 2。研究RHEPO给药对脑血液动力学的急性影响； 3 研究RHEPO给药对大脑对损伤的反应的慢性影响。