CEREBRAL ISCHEMIA--MINIMIZING DAMAGE DURING ANESTHESIA

脑缺血——最大限度地减少麻醉期间的损伤

基本信息

批准号：
2180020
负责人：
DAVID WARNER
金额：
$ 20.66万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-04-01 至 1997-03-31
项目状态：
已结题

项目摘要

Cerebral ischemia remains a major problem for patients requiring anesthesia and surgery. This is particularly true for some procedures including carotid endarterectomy, cardiopulmonary bypass, and intracranial aneurysm surgery. Our work is devoted to improving knowledge of the effects of anesthetics on ischemic brain damage so as to reduce perioperative neurologic morbidity. To this end, we have developed several rat models of cerebral ischemia which allow us to mimic intraoperative events and examine the roles of anesthetic agents in these processes. This proposal contains two conceptual components. The first is to further define roles and limitations for existing anesthetic agents as cerebral protectants against both global and focal ischemic insults. Our work has allowed us to predict that anesthetics, which reduce cerebral metabolic rate, will provide improved outcome from brief episodes of global ischemia of varying magnitudes of severity. We also believe that some anesthetics, barbiturates in particular, reduce focal ischemic brain damage by mechanisms other than simple reduction in energy requirements. If so, then substantially lower doses of drug may be as beneficial as the very deep anesthetic states previously found to be protective. We thus intend to examine a dose-response relationship between depth of barbiturate anesthesia during focal ischemia and ultimate histologic/neurologic outcome. Finally, the simple possibility has not been directly addressed as to whether the anesthetic state itself is protective. Recent advances in rat models of cerebral ischemia now allow us to compare and explain outcome differences between groups of animals undergoing ischemia while anesthetized vs awake. The second component of this proposal is to improve understanding concerning a new class of drugs that could serve as neuroprotective anesthetics. These drugs inhibit excitatory neurotransmission by selectively antagonizing postsynaptic glutamate receptors. Although originally developed as anti-ischemic drugs, these compounds also produce anesthesia. We have shown that such drugs potentiate one another if given simultaneously. The experiments proposed herein have been designed to further define functional relationships between different glutamate receptors in the postischemic brain by examining anesthetic and anticonvulsant properties of glutamate antagonists. This work will be supplemented by quantification of ischemia/anesthetic effects on glutamate receptor binding kinetics and glutamate dependent synthesis of nitric oxide. Because glutamate antagonists provide both cerebral protection and anesthesia, this work may allow an entirely new mechanistic approach for anesthesia to emerge which possesses major neuroprotective properties.

对于需要的患者来说，脑缺血仍然是一个主要问题麻醉和手术。对于某些程序尤其如此包括颈动脉内膜切除术，心肺旁路和颅内动脉瘤手术。我们的工作致力于改善了解麻醉药对缺血性脑损伤的影响减少围手术期神经系统发病率。为此，我们有开发了几种大鼠缺血模型，使我们能够模仿术中事件并检查麻醉剂在这些事件中的作用过程。该建议包含两个概念组成部分。第一个是为了进一步定义现有麻醉剂的角色和局限性作为防止全球和局灶性缺血性损伤的脑保护物。我们的工作使我们能够预测麻醉药，从而减少脑代谢率将提供简短的改善结果全球缺血的发作的严重程度不同。我们也是相信某些麻醉剂尤其会减少焦点通过简单减少能量以外的机制，缺血性脑损伤要求。如果是这样，那么大幅降低剂量的药物可能是有益，因为先前发现的非常深的麻醉状态是保护的。因此，我们打算检查剂量反应关系在局灶性缺血期间巴比妥酸盐麻醉深度之间最终的组织学/神经系统结果。最后，简单的可能性尚未直接解决麻醉状态本身是否直接解决具有保护性。现在的大鼠缺血模型的最新进展允许我们比较并解释两组之间的结果差异麻醉与清醒的动物进行缺血。第二个该提案的组成部分是提高有关新的理解可以用作神经保护麻醉药的药物类别。这些药物通过选择性拮抗而抑制兴奋性神经传递突触后谷氨酸受体。尽管最初是作为抗缺血药物，这些化合物也会产生麻醉。我们有表明，如果同时给出，这种药物会互相增强。本文提出的实验旨在进一步定义不同谷氨酸受体之间的功能关系通过检查麻醉和抗惊厥性特性，疾病后大脑谷氨酸拮抗剂。这项工作将由量化缺血/麻醉对谷氨酸受体的影响一氧化氮的结合动力学和谷氨酸依赖性合成。因为谷氨酸拮抗剂既可以提供脑保护，又提供麻醉，这项工作可能允许一种全新的机械方法出现的麻醉，具有主要的神经保护特性。