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

直立性低血压(OH)是老年人的一种常见的致残状态，尤其是对那些有障碍的人 自主反射。仰卧位高血压是最常见的共病；它不仅增加了靶向高血压的风险 器官受损，但也会在夜间诱发压力性钠尿，导致夜尿症和容量衰竭 对OH有贡献。因此，夜间高血压会加重白天的OH值。不幸的是，人们不愿 治疗仰卧位高血压，以防病情恶化。仰卧(小屋)睡姿可以改善睡眠 夜间高血压通过减少静脉回流、每搏量和心输出量，但倾斜水平需要 产生这些效果在临床上是很难实现的。在这个应用中，我们建议增加胸腔内 在临床使用的水平上，持续气道正压(CPAP)的压力将产生类似的 通过诱导静脉淤积进入内脏循环而产生的血液动力学效应。事实上，我们初步的 研究表明，在临床使用的水平上，CPAP可引起急性和可逆的血压下降 在无阻塞性睡眠呼吸暂停(OSA)的自主神经衰竭患者中，通过直接血流动力学机制，以及 这种影响在夜间持续存在，并与夜尿症的减少有关。在正常受试者中，这种影响是 被代偿性交感神经激活所掩盖。这个应用程序的总体目标是检验假设 CPAP加压是治疗夜间高血压的有效方法 由于自主神经功能衰竭，通过减少压力利尿，它将改善白天的OH。在具体目标1中， 我们将研究自主神经衰竭患者CPAP的血流动力学机制，确定其疗效。 从胸段到腹段的容量转移，调节钠尿的激素，以及中央 血压和动脉僵硬指数。这些指标是心血管疾病阴性的更好的预测指标。 结果比臂血压，和这一独特的患者群体将使我们能够确定的影响 CPAP不受交感调制的阻碍。我们还建议彻夜进行概念验证研究，以测试 CPAP对控制夜间仰卧位高血压有效的假说(特异性目标2)和降低 夜间利尿，改善白天立位耐力(具体目标3)。对于这些首字母 我们排除OSA患者的概念验证性机制研究，因为我们的重点是新的 CPAP对血流动力学的影响而不是抑制呼吸暂停发作。我们相信拟议的研究 将为夜间高血压的管理带来一种具有临床意义的创新方法 自主神经衰竭患者，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 夜尿症，不仅会影响睡眠，还会使患者摔倒。更重要的是，它将改善白天 提高患者的立位耐受性和生活质量。我们的学习也将提高我们的基础 了解CPAP对心血管调节的影响，然后将其应用于其他情况。

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.