HYPOTHERMIA AND TRAUMATIC BRAIN INJURY

体温过低和创伤性脑损伤

• 批准号: 3100808
• 负责人: Donald W. Marion
• 金额: $ 32.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 1994-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3100808
• 关键词: brain injury; head /neck injury; induced hypothermia

In this feasibility proposal we are seeking support for the development of a comprehensive clinical and basic science head-injury research center. We will study the therapeutic value and potential mechanisms of action of moderate hypothermia administered after head injury. Data from our laboratories suggest that mild to moderate cerebral hypothermia used after global cerebral ischemia in dogs improves outcome and reduces mortality. Recent studies in a rodent fluid percussion model also suggest that hypothermia improves outcome, and that hypothermia may be more effective than many other types of therapy. In our clinical projects we will randomize adult victims of severe closed-head-injury to a normothermia group or a group cooled to 32-33 degree centigrade for 24 hours after their injury. Emphasis will be placed on cooling as soon as possible following the injury. Physiologic, metabolic and blood flow measurements will be made at frequent intervals during the first five days after injury, and the influence of hypothermia on these parameters will be assessed through statistical comparison of values from the experimental and control groups. Clinical outcome in both groups will also be carefully assessed and recorded. In our basic science projects we will define potential mechanisms through which hypothermia may be effective, determine the time interval following injury during which hypothermia might be expected to be effective, and determine if the use of high-dose steroids might enhance the efficacy of moderate hypothermia. These projects will complement the clinical projects by systematically analyzing ventricular cerebrospinal fluid (CSF) and brain tissue specimens obtained from human head-injured subjects for interleukin-1, glutamate and aspartate to define their role as mediators of secondary brain injury, and the effect of hypothermia on their concentration in CSF and brain tissue. In a rodent focal cerebral contusion model we will use microdialysis to investigate the time course of appearance of these neurochemicals in the extracellular space, and the effect of hypothermia on suppression of their production. In this same experimental paradigm we also will investigate the effects of hypothermia on nerve growth factor concentrations, and density and function of NMDA receptors. Using behavioral and histological analysis we will define the time interval after blunt head injury in rats and epidural compression injury in dogs during which hypothermia might still be efficacious. Finally, we will determine if a combination of high-dose steroids and moderate hypothermia will prolong the therapeutic window during which treatment can be administered. The projects submitted in this head-injury center proposal are designed to answer fundamental questions about the mechanisms of action of hypothermia in head injury, and its effect on cerebral physiology, metabolism and blood flow. Our results will provide the groundwork for a multicenter clinical trial of moderate hypothermia.

在此可行性建议中，我们正在寻求支持的发展 全面的临床和基础科学负责人研究中心。 我们 将研究的治疗价值和潜在的作用机理 头部受伤后施用中等温度。 来自我们的数据 实验室表明，在 狗的全球脑缺血改善了预后并降低死亡率。 在啮齿动物打击乐模型中的最新研究也表明 体温过低会改善预后，而体温过低可能更有效 比许多其他类型的疗法。 在我们的临床项目中，我们将 将严重闭合伤害的成年受害者随机与正常炎 小组或一组冷却至32-33度摄氏度，持续24小时 受伤。 重点将尽快放置冷却 受伤。 生理，代谢和血流测量将是 在受伤后的前五天，以频繁的间隔制作 体温过低对这些参数的影响将通过 实验组和对照组的值的统计比较。 两组的临床结果也将仔细评估，并且 记录。 在我们的基础科学项目中，我们将定义潜力 低温可能有效的机制，确定时间 受伤后的间隔可能预期体温过低 有效，并确定使用高剂量类固醇是否会增强 中度低温的功效。 这些项目将补充 临床项目通过系统地分析心室脑脊 流体（CSF）和脑组织标本从人头受伤的 白介素-1，谷氨酸和天冬氨酸的受试者将其作用定义为 继发性脑损伤的介体，以及体温过低的影响 CSF和脑组织的浓度。 在啮齿动物局部脑大脑中 挫伤模型我们将使用微透析研究时间过程 这些神经化学物质在细胞外空间中的外观， 体温过低对抑制其生产的影响。 同样 实验范式我们还将研究体温过低的影响 在神经生长因子浓度以及NMDA的密度和功能上 受体。 使用行为和组织学分析，我们将定义 大鼠钝性头部受伤和硬膜外压缩后的时间间隔 低温可能仍有效的狗受伤。 最后，我们将确定高剂量类固醇和 中度的体温过低将延长治疗窗口 可以进行治疗。 在此遭受损害中提交的项目 中心建议旨在回答有关 体温过低在头部受伤中的作用机制及其对 脑生理，代谢和血流。 我们的结果将提供 中等体温过低的多中心临床试验的基础。