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

理由：大约42，000名退伍军人患有脊髓损伤（SCI）。对于65%的人来说， 胸（T）脊柱节段6以上的SCI，低血压和高血压都是常见的合并症。T6以上SCI 增加自主神经反射异常（AD）的风险，因为中枢下行控制更大的 内脏神经（GSN）丧失，并且随之丧失控制腹部内脏脉管系统的能力。 GSN中不受控制的反射亢进可演变为AD诱导的高血压，这是本研究中的一个重大风险。 中风的风险增加了400%。相反，内脏张力不足会导致 低血压和57%的这一群体经历直立性低血压（OH）。OH与高达 认知功能下降65%一种可植入系统，可提供适当的电刺激或 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的主要靶点。 调节这些神经的活动可能会提供一种新的，直接的，急性的手段，以防止这两个 低血压（目标1）和高血压（目标2）。我们的长期目标是开发一种闭环的、可植入的 在SCI患者中维持BPart在健康范围内的系统，其中中央控制 腹部血管系统已经受损为了实现这一目标，我们需要更清楚地了解 内脏神经控制的腹部脉管系统后，由于SCI的中央控制的损失。 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调节受损的横断模型。在这两个目标中，动脉血压和腹部 将监测血流量（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 将在宽的频率范围内确定。将绘制剂量-反应曲线， SCI后BPart和BFabd随SpNS和SpNB频率的变化。这将被执行 用于单侧和双侧SpNS和SpNB。每个神经对整体变化的相对贡献， 将确定BPart和BFabd。 预期结果：这项概念验证研究是开发新干预措施的重要第一步， 准备必要的技术和监管活动，以将其进入首次人体试验，并最终 关键临床试验本研究将生成足够的数据，以创建Merit Review，从而开发真实的- 时间、闭环和完全可植入的系统，用于在BPart中的瞬时但大的变化期间控制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 我的目标是把这个系统翻译给那些遭受SCI并经历反复发作和严重创伤的退伍军人。 低血压和/或高血压。我们预计该SPiRE将产生一份出版物。 对退伍军人的好处：数千名退伍军人的SCI高于T6，并经历了低血糖和/或高血糖。 高血压严重的急性低血压或高血压如果没有适当的和立即的治疗， 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。 进行必要的技术和监管活动，使其进入首次人体试验， 临床试验成功将意味着患者有一种替代疗法，可能会减少对慢性药物的需求。 药物疗法

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.