Hemodynamic Effects of Positive Airway Pressure to Treat Supine Hypertension and Improve Neurogenic Orthostatic Hypotension

气道正压通气治疗仰卧位高血压和改善神经源性直立性低血压的血流动力学效应

• 批准号: 10532156
• 负责人: Italo Biaggioni
• 金额: $ 67.16万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532156
• 关键词: Abdomen; Acute; Blood Pressure; Buffers; Cardiac Output; Cardiovascular system; Chest; Clinical; Continuous Positive Airway Pressure; Diuresis; Elderly; Electric Capacitance; Exclusion; Failure; Fright; Goals; Head; Hormones; Hypertension; Impairment; Knowledge; Masks; Multiple System Atrophy; Natriuresis; Nerve Degeneration; Nocturia; Nocturnal Hypertension; Obstructive Sleep Apnea; Organ; Orthostatic Hypotension; Outcome; Output; Parkinson Disease; Patients; Positioning Attribute; Pure Autonomic Failures; Quality of life; Regulation; Risk; Risk Factors; Sleep; Sleep disturbances; Splanchnic Circulation; Stroke Volume; Supination; Testing; Trimethaphan; Venous; Weight; arterial stiffness; autonomic reflex; clinically significant; comorbidity; disability; effective therapy; fall risk; falls; hemodynamics; improved; indexing; innovation; insight; mortality; neurogenic orthostatic hypotension; novel; novel strategies; novel therapeutic intervention; patient population; positive airway pressure; pressure; public health relevance; urinary

Orthostatic hypotension (OH) is a common disabling condition in the elderly, particularly in those with impaired autonomic reflexes. Supine hypertension is the most common comorbidity; it not only increases the risk for target organ damage but also induces pressure natriuresis during nighttime causing nocturia and volume depletion that contributes to OH. Thus, nocturnal hypertension worsens daytime OH. Unfortunately, there is reluctance to treat supine hypertension for fear of worsening OH. Sleeping in a head-up tilt (HUT) position can improve nocturnal hypertension by reducing venous return, stroke volume and cardiac output, but tilt levels needed to produce these effects are difficult to achieve clinically. In this application, we propose that increasing intrathoracic pressure with continuous positive airway pressure (CPAP), at levels used clinically, will produce similar hemodynamic effects as HUT, by inducing venous pooling into the splanchnic circulation. Indeed, our preliminary studies show that CPAP, at levels used clinically, induces an acute and reversible decrease in blood pressure in autonomic failure patients without obstructive sleep apnea (OSA) by a direct hemodynamic mechanism, and this effect is sustained during the night and associated with decreased nocturia. In normal subjects this effect is masked by compensatory sympathetic activation. The overall goal of this application is to test the hypothesis that increasing intrathoracic pressure with CPAP is an effective treatment for nocturnal hypertension in patients with autonomic failure and that, by reducing pressure diuresis, it will improve daytime OH. In Specific Aim 1, we will characterize the hemodynamic mechanisms of CPAP in autonomic failure patients, determine its effects on volume shifts from the thoracic to abdominal segments, on hormones that regulate natriuresis, and on central blood pressure and indices of arterial stiffness. These indices are better predictors of negative cardiovascular outcomes than brachial blood pressure, and this unique patient population will allow us to determine the effects of CPAP unencumbered by sympathetic modulation. We also propose overnight proof-of-concept studies to test the hypotheses that CPAP is effective in controlling nocturnal supine hypertension (Specific Aim 2) and reduces nighttime diuresis, resulting in improvement of daytime orthostatic tolerance (Specific Aim 3). For these initial proof-of-concept mechanistic studies we exclude patients with OSA because our focus is on the novel hemodynamic effects of CPAP rather than suppression of apneic episodes. We believe the proposed studies will lead to a clinically significant and innovative approach for the management of nocturnal hypertension in patients with autonomic failure, changing the way we manage patients, and eliminating the controversy of whether to treat, or not to treat, supine hypertension. If successful, lowering nighttime blood pressure will reduce nocturia, which not only impairs sleep but also exposes patients to falls. More importantly, it will improve daytime orthostatic tolerance and improve the quality of life of our patients. Our studies will also improve our basic knowledge about the effects of CPAP on cardiovascular regulation, that can then be applied to other conditions.

直立性低血压（OH）是老年人常见的致残性疾病，特别是在那些受损的 自主神经反射仰卧位高血压是最常见的合并症;它不仅增加了目标风险， 器官损伤，而且还在夜间引起压力性尿钠排泄，引起尿量过多和血容量不足， 贡献于OH因此，夜间高血压超过白天OH。不幸的是， 治疗仰卧位高血压，以免OH恶化。以头朝上倾斜（HUT）的姿势睡觉可以改善 通过减少静脉回流、每搏输出量和心输出量来降低夜间高血压，但需要倾斜水平， 产生这些效果在临床上是很难达到的。在本申请中，我们建议增加胸腔内 持续气道正压通气（CPAP）的压力，在临床上使用的水平，将产生类似的 血液动力学效应，如HUT，通过诱导静脉汇集到内脏循环。事实上，我们的初步 研究表明，在临床使用的水平下，CPAP诱导血压的急性和可逆降低， 在无阻塞性睡眠呼吸暂停（OSA）的自主神经功能衰竭患者中，通过直接血流动力学机制， 这种作用在夜间持续，并与降低的尿量有关。在正常受试者中， 被代偿性交感神经激活所掩盖本应用程序的总体目标是检验假设 CPAP增加胸内压是治疗夜间高血压的有效方法， 与自主神经功能衰竭，并通过减少压力利尿，它将改善白天的OH。具体目标1、 我们将描述CPAP在自主神经功能衰竭患者中的血流动力学机制， 对从胸段到腹段的容积转移、调节尿钠排泄的激素和中枢神经系统的影响。 血压和动脉硬度指数。这些指标是阴性心血管疾病的更好预测指标。 这一独特的患者人群将使我们能够确定 不受交感神经调节的影响。我们还建议进行夜间概念验证研究， 假设CPAP可有效控制夜间仰卧位高血压（具体目标2）， 夜间利尿，导致日间立位耐受性改善（具体目标3）。对于这些初始 在概念验证机制研究中，我们排除了OSA患者，因为我们的重点是新的 CPAP的血流动力学效应，而不是抑制呼吸暂停发作。我们认为，拟议的研究 将为夜间高血压的治疗提供一种具有临床意义的创新方法， 自主神经功能衰竭的患者，改变我们管理患者的方式，消除 是否治疗仰卧位高血压。如果成功，降低夜间血压将减少 这不仅会影响睡眠，而且会使患者福尔斯。更重要的是，它将改善白天 立位耐力和提高我们的病人的生活质量。我们的研究也将提高我们的基本 了解CPAP对心血管调节的影响，然后可以应用于其他条件。