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

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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.