Research 2-Carlson

研究2-卡尔森

• 批准号: 10468697
• 负责人: Andrew Phillip Carlson
• 金额: $ 26.08万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468697
• 关键词: Blood; Brain; Brain Injuries; Chronic; Clinical; Cognitive; Collection; Confusion; Data; Development; Dose; Drainage procedure; Electrodes; Ensure; Environment; Event; Functional disorder; Future; Goals; Human; Impaired cognition; Impairment; Ketamine; Knowledge; Language Disorders; Link; Liquid substance; Mediating; Memantine; Metabolic; Mission; Monitor; N-Methylaspartate; Nervous System Physiology; Nervous System Trauma; Neurologic; Neurologic Deficit; Neurologic Dysfunctions; Neurosurgeon; New Mexico; Operative Surgical Procedures; Outcome; Outcome Assessment; Outcome Measure; Patient Care; Patients; Pharmacotherapy; Phenotype; Physiology; Placebos; Play; Pneumonia; Postoperative Period; Prospective Studies; Randomized; Randomized Controlled Trials; Recovery; Research; Research Personnel; Risk; Role; Seizures; Stroke; Subdural Hematoma; Testing; Therapeutic; Time; Traumatic Brain Injury; United States National Institutes of Health; Universities; Work; aging population; antagonist; base; behavioral outcome; clinical outcome measures; cognitive performance; cost; disability; effective therapy; efficacy testing; efficacy trial; experience; improved; improved outcome; neurological recovery; neuropsychiatry; novel; novel therapeutic intervention; older patient; pilot trial; programs; prospective; randomized trial; repaired; socioeconomics; success; synergism; targeted treatment; therapeutic target

PROJECT SUMMARY/ ABSTRACT Chronic Subdural Hematoma (cSDH) is an extremely common problem, particularly in the aging population, where fluid like collections compress the brain, frequently requiring surgical drainage. After drainage, 25-50% of patients experience post operative neurologic deficits such as weakness or confusion that are often not explained by problems such as seizure, stroke, or mass effect from the fluid and blood. Recent subdural recordings have demonstrated that some of these neurological deficits may be related to waves of spreading depolarization (SD), which cause temporary neurological dysfunction. There is a fundamental gap in knowledge as to how commonly such events are related to neurologic deficits and if they could be targeted with pharmacotherapy to improve outcomes. This knowledge gap represents an important problem because cSDH is expected to be the most common condition treated by neurosurgeons by 2030 and postoperative neurological deficits in elderly patients can have a significant impact on outcomes and secondary risks such as pneumonia and delayed mobilization. Our long-term goal is to develop effective treatments to improve recovery in these patients by targeting SD. The overall objective of this application is to examine the relationship between neurological deficits and SD and to assess feasibility of a pilot trial to determine if a strategy of NMDA-R antagonism can effectively reduce SD and improve clinical recovery. We also plan to study detailed neuropsychiatric outcomes and if these are worse in patients with SD. The central hypothesis is that SD plays a causal role in some neurologic deficits after cSDH drainage. This hypothesis is based on our preliminary data where SD was observed in 15% of such patients. In one case, repeated waves of SD were exactly time locked to development of new language deficit. Guided by this promising preliminary data, we plan to rigorously examine the relationship between SD and neurologic deficits after cSDH drainage in additional subjects (Aim #1). We will then determine feasibility of performing a randomized trial to test if a strategy of NMDA-R antagonism with a brief course of memantine effectively reduces SD and improves neurologic function (Aim #2). Finally, we will determine the time course of neuropsychiatric recovery after cSDH evacuation at day 30, 90, and 180 and assess if this is worse in patients with SD (Aim#3). We expect that these studies will provide exciting new therapeutic approaches for a previously unrecognized pathophysiology in a very common problem. These data will provide the necessary groundwork for larger pivotal trials to test efficacy of such a targeted, physiology based approach.

项目概要/摘要 慢性硬膜下血肿（cSDH）是一个极其常见的问题，特别是在老龄化人口中， 液体等积聚物压迫大脑，经常需要手术引流。排水后25-50% 的患者经历术后神经功能缺陷，例如虚弱或意识模糊，而这些症状通常不是 可以用癫痫、中风或液体和血液的肿块效应等问题来解释。最近的硬膜下 记录表明，其中一些神经功能缺陷可能与传播波有关 去极化（SD），导致暂时的神经功能障碍。存在根本性差距 了解此类事件与神经系统缺陷相关的常见程度以及是否可以针对这些事件 通过药物治疗来改善结果。这种知识差距是一个重要的问题，因为 预计到 2030 年，cSDH 将成为神经外科医生及术后最常见的疾病 老年患者的神经功能缺陷可能对结果和次要风险产生重大影响，例如 肺炎和活动延迟。我们的长期目标是开发有效的治疗方法以改善康复 通过针对 SD 来治疗这些患者。该应用程序的总体目标是检查关系 神经功能缺陷和 SD 之间的关系，并评估试点试验的可行性，以确定是否采取策略 NMDA-R拮抗作用可有效降低SD并提高临床恢复。我们也计划详细研究一下 神经精神结局以及 SD 患者的神经精神结局是否更糟。中心假设是 SD 发挥 cSDH 引流后某些神经功能缺损的因果作用。这个假设是基于我们的初步数据 其中 15% 的此类患者观察到 SD。在一种情况下，重复的 SD 波被精确地时间锁定 发展新的语言缺陷。在这一有希望的初步数据的指导下，我们计划严格 检查其他受试者 cSDH 引流后 SD 和神经功能缺损之间的关系（目的 ＃1）。然后，我们将确定进行随机试验的可行性，以测试 NMDA-R 策略是否有效 美金刚短期疗程的拮抗作用可有效降低 SD 并改善神经功能（Aim ＃2）。最后，我们将确定第 30 天 cSDH 疏散后神经精神恢复的时间进程， 90 和 180 并评估 SD 患者的情况是否更糟（目标#3）。我们期望这些研究将提供 针对以前未被认识到的非常常见的病理生理学的令人兴奋的新治疗方法 问题。这些数据将为更大规模的关键试验提供必要的基础，以测试此类药物的功效 有针对性的、基于生理学的方法。