Toward Closed-Loop Control of Homeostatic Blood Pressure Following Spinal Cord Injury

脊髓损伤后稳态血压的闭环控制

• 批准号: 10311117
• 负责人: MATTHEW Anthony SCHIEFER
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311117
• 关键词: Abdomen; Acute; Address; Agreement; Alternative Therapies; Animals; Anxiety; Autonomic Dysreflexia; Bilateral; Blood; Blood Pressure; Blood Volume; Blood flow; Cardiac development; Cessation of life; Chemicals; Chest; Chronic; Clinical Trials; Custom; Dangerousness; Data; Dose; Drug usage; Electric Stimulation; Electrodes; Emergency Situation; Feasibility Studies; Frequencies; Future; Goals; Hand; Hyperreflexia; Hypertension; Hypotension; Impaired cognition; Impairment; Implant; Individual; Intervention; Lead; Left; Life; Maintenance; Measures; Mechanics; Medical Device; Mental Depression; Methodology; Modeling; Monitor; Multiple Sclerosis; Nerve; Nerve Block; Organ; Orthostatic Hypotension; Outcome; Output; Patients; Pelvis; Pharmaceutical Preparations; Pharmacological Treatment; Pilot Projects; Planning Techniques; Population; Preventive Medicine; Publications; Quality of life; Regimen; Research; Risk; Rodent; Seminal; Spinal; Spinal cord injury; Splanchnic Nerves; Stimulus; Stroke; System; Technology; Testing; Therapeutic Effect; Time; Translating; Translations; Traumatic Brain Injury; Traumatic CNS injury; Vasodilation; Veterans; Veterans Health Administration; blood pressure control; blood pressure elevation; blood pressure regulation; cardiac pacing; clinical practice; cognitive function; comorbidity; design; dosage; experience; experimental study; first-in-human; forgetting; hypoperfusion; innovation; military veteran; neurovascular; novel; preclinical trial; prevent; programs; response; side effect; stroke risk; success; vasoconstriction

Rationale: Approximately 42,000 Veterans have a spinal cord injury (SCI). For the 65% of these individuals with an SCI above thoracic (T) spinal level 6, both hypo- and hypertension are common comorbidities. SCI above T6 increases the risk for autonomic dysreflexia (AD) because the central descending control over the greater splanchnic nerves (GSNs) is lost, and with it the ability to control the abdominal splanchnic vasculature. Uncontrolled hyperreflexia in the GSNs can evolve to AD-induced hypertension, which is a significant risk in this population and increases the risk of stroke by up to 400%. Conversely, insufficient splanchnic tone leads to hypotension and 57% of this population experience orthostatic hypotension (OH). OH is associated with up to a 65% reduction in cognitive function. An implantable system that delivers the appropriate electrical stimulation or block to the splanchnic nerves could treat both conditions. Objective: The greater splanchnic nerves are primary targets for restoring healthy arterial blood pressure (BPart). Modulating activity in these nerves may provide a novel, immediate, and acute means to prevent both hypotension (Aim 1) and hypertension (Aim 2). Our long-term goal is to develop a closed-loop, implantable system that maintains BPart within a healthy range in individuals with SCI in which central control over the abdominal vasculature has been compromised. To advance this goal, we require a clearer understanding of splanchnic nerve control of the abdominal vasculature following loss of central control due to SCI. Research Plan and Methodology: We will conduct pre-clinical trials in an established rodent T3 spinal transection model that displays impaired regulation of BPart. In both aims, arterial blood pressure and abdominal blood flow (BFabd) will be monitored. During Aim 1, splanchnic nerve stimulation (SpNS) will be applied whereas during Aim 2, splanchnic nerve block (SpNB) will be applied. The effect of SpNS and SpNB on BPart and BFabd over a broad range of frequencies will be determined. A dosage-response curve will be developed that expresses the changes in BPart and BFabd as a function of SpNS and SpNB frequencies following SCI. This will be performed for both unilateral and bilateral SpNS and SpNB. The relative contribution of each nerve to overall changes in BPart and BFabd will be determined. Expected Outcomes: This proof-of-concept study is an important first step in developing a new intervention and preparing for the technical and regulatory activities necessary to move it into first-in-human trials and ultimately pivotal clinical trials. This study will generate sufficient data to create a Merit Review that will develop the real- time, closed-loop, and fully implantable system for controlling BPart during transient but large changes in BPart in animals with a chronic SCI, including older animals that capture the full Veteran population. It is our long-term goal to translate this system to Veterans who have sustained an SCI and experience recurring and severe hypotension and/or hypertension. We anticipate that this SPiRE will generate one publication. Benefits to Veterans: Several thousand Veterans have an SCI above T6 and experience hypo- and/or hypertension. Severe, acute hypo- or hypertension can be life-threatening without proper and immediate treatment. This proof-of-concept study is an important first step in developing a new intervention and preparing for the technical and regulatory activities necessary to move it into first-in-human trials and ultimately pivotal clinical trials. Success will mean that patients have an alternative therapy that may obviate the need for a chronic drug regimen.

理由：大约 42,000 名退伍军人患有脊髓损伤 (SCI)。对于其中 65% 的人来说 胸椎 (T) 脊髓 6 级以上的 SCI，低血压和高血压都是常见的合并症。 SCI T6以上 增加自主神经反射异常（AD）的风险，因为中枢下行控制更大 内脏神经（GSN）丧失，控制腹部内脏脉管系统的能力也随之丧失。 GSN 中不受控制的反射亢进可能演变成 AD 诱发的高血压，这是该疾病的一个重大风险 人群中，中风的风险增加高达 400%。相反，内脏张力不足会导致 低血压，57% 的人群患有直立性低血压 (OH)。 OH 与最多一个相关 认知功能下降 65%。一种可提供适当电刺激或 阻断内脏神经可以治疗这两种情况。 目的：内脏大神经是恢复健康动脉血压（BPart）的主要目标。 调节这些神经的活动可能提供一种新颖的、直接的、急性的方法来预防这两种情况 低血压（目标 1）和高血压（目标 2）。我们的长期目标是开发闭环、植入式 系统将 SCI 患者的 BPart 维持在健康范围内，其中集中控制 腹部血管系统已受到损害。为了实现这一目标，我们需要更清晰地了解 SCI 导致中枢控制丧失后，内脏神经对腹部脉管系统的控制。 研究计划和方法：我们将在已建立的啮齿动物 T3 脊柱中进行临床前试验 显示 BPart 调节受损的横断面模型。在这两个目标中，动脉血压和腹部血压 将监测血流（BFabd）。在目标 1 期间，将应用内脏神经刺激 (SpNS)，而 在目标 2 期间，将应用内脏神经阻滞 (SpNB)。 SpNS和SpNB对BPart和BFabd的影响 在很宽的频率范围内的频率将被确定。将开发一条剂量反应曲线，表示 SCI 后 BPart 和 BFabd 的变化作为 SpNS 和 SpNB 频率的函数。这将被执行 适用于单侧和双侧 SpNS 和 SpNB。每条神经对整体变化的相对贡献 BPart 和 BFabd 将被确定。 预期成果：这项概念验证研究是开发新干预措施和治疗方法的重要第一步。 准备必要的技术和监管活动，使其进入首次人体试验并最终 关键的临床试验。这项研究将产生足够的数据来创建一个优点审查，该审查将开发真实的 时间、闭环、完全植入式系统，用于在 BPart 短暂但较大变化期间控制 BPart 患有慢性 SCI 的动物，包括捕获全部退伍军人群体的老年动物。这是我们的长期 目标是将这个系统应用到遭受过 SCI 并经历过反复出现的严重损伤的退伍军人身上 低血压和/或高血压。我们预计该 SPiRE 将出版一份出版物。 对退伍军人的好处：数千名退伍军人的 SCI 高于 T6 并经历过低和/或 高血压。如果没有立即采取适当的措施，严重、急性低血压或高血压可能会危及生命 治疗。这项概念验证研究是开发新干预措施和准备的重要第一步 进行首次人体试验并最终发挥关键作用所需的技术和监管活动 临床试验。成功将意味着患者有一种替代疗法，可以消除慢性病的需要 药物治疗方案。