Central Sleep Apnea: Physiologic Mechanisms to Inform Treatment

中枢性呼吸暂停的有效治疗仍然难以捉摸。这个项目的重点是识别机械 基于强有力的前提指导中枢性睡眠呼吸暂停(CSA)未来治疗干预的途径 旨在使呼吸正常化的多模式治疗是缓解长期 CsA的不良后果。我们的中心假设是CsA反映了生理学 干扰，可能需要针对呼吸反馈的不同部分的联合模式治疗 循环播放。我们提议的研究将测试联合疗法，包括PAP和一种药理学试剂。这 也将增加拟议研究的临床相关性，因为PAP治疗通常被指定为 CsA的初始治疗。我们建议通过三种不同的生理途径来改变CSA倾向：1) 用氧气和/或乙酰唑胺降低环路增益，2)通过抑制来减少通风超调 使用催眠剂进行呼吸唤醒，以及3)使用5-羟色胺能提高呼吸机能输出 探员。为了确保临床相关性，我们将重点介绍两种最常见的环孢素A：1)心力衰竭，包括 减少射血分数(HFrEF)和2)阿片类药物的使用，使用分层随机分组来平衡 每个实验的每一只手臂上都有受试者。为了实现这项提案的目标，我们将测试以下内容 三个具体目标。具体目的(1)是确定旨在抑制的综合治疗的效果 化学感受器的敏感性和植物增益的下降。我们假设与PAP联合治疗， 在降低CAHI和二氧化碳储备方面，乙酰唑胺和氧气将优于单独的每一种干预措施 睡眠期间中枢性睡眠呼吸暂停患者。具体目标(2)是确定减少的效果 与呼吸相关的觉醒有发展成中枢性呼吸暂停的倾向。我们假设美国政府 PAP和唑吡坦，将减少与呼吸相关的觉醒，CAHI和睡眠中的二氧化碳储备 服用环孢素A的患者与安慰剂进行比较。具体目的(3)是确定增加5-羟色胺的效果 睡眠时呼吸上的A1受体活性。我们假设PAP和丁螺环酮的用药是 5-羟色胺A1受体激动剂；将减少患有中枢性呼吸暂停的退伍军人在睡眠期间发生中枢性呼吸暂停的倾向 睡眠呼吸暂停。这一新的项目试图确定与PAP相结合的生理通路 治疗，提高CsA患者的治疗效果。拟议的研究是创新的， 可行，并将为未来的临床试验提供亟需的路线图，这些试验可能会改变对 退伍军人的中枢性呼吸暂停。

Effective treatment of central apnea remains elusive. This project is focused on identifying mechanistic pathways to guide future therapeutic interventions for central sleep apnea (CSA) based on the strong premise that multi-modality therapy - aiming to normalize respiration- is the requisite path to mitigating the long-term adverse consequences of CSA. Our central hypothesis is that CSA reflects a combination of physiologic perturbations and may require combined modality therapy targeting different parts of the ventilatory feedback loop. Our proposed studies will test combination therapies, including PAP plus a pharmacological agent. This will also increase the clinical relevance of the proposed studies since PAP therapy is typically prescribed as the initial treatment of CSA. We propose to modify CSA propensity via three distinct physiologic pathways: 1) decreasing loop gain with oxygen and/or acetazolamide, 2) decreasing ventilatory overshoot by dampening respiratory arousals with a hypnotic agent, and 3) elevating the ventilatory motor output with a serotonergic agent. To ensure clinical relevance, we will focus on the two most common types of CSA: 1) heart failure with reduced ejection fraction (HFrEF) and 2) opioid use, using stratified randomization to balance the number of subjects in each arm of each experiment. To achieve the objectives of this proposal, we will test the following three specific aims. Specific Aim (1) is to determine the effect of combination therapy aiming to dampen chemoreceptor sensitivity AND decreasing plant gain. We hypothesize that combined therapy with PAP, acetazolamide and oxygen will be superior to each intervention alone in reducing CAHI and the CO2 reserve during sleep in patients with central sleep apnea. Specific Aim (2) is to determine the effect of decreasing respiratory-related arousals on the propensity to develop central apnea. We hypothesize that administration of PAP and zolpidem, will decrease respiratory-related arousals, CAHI and the CO2 reserve during sleep in patients with CSA compared to placebo. Specific Aim (3) is to determine the effect of augmenting serotonin A1 receptor activity on breathing during sleep. We hypothesize that administration of PAP and buspirone, a serotonin A1 receptor agonist; will reduce the propensity to central apnea during sleep in Veterans with central sleep apnea. This Novel project seeks to identify physiologic pathways that can, in combination with PAP therapy, improve the effectiveness of treatment for patients with CSA. The proposed studies are innovative, feasible and will provide a much-needed roadmap for future clinical trials that are likely to transform the care of central apnea in Veterans.