Central Sleep Apnea: Physiologic Mechanisms to Inform Treatment

中枢性呼吸暂停的有效治疗仍然是难以捉摸的。该项目的重点是确定机械 基于强有力的前提，指导未来中枢性睡眠呼吸暂停（CSA）治疗干预的途径 旨在使呼吸正常化的多模态治疗是减轻长期呼吸困难的必要途径。 CSA的不良后果。我们的中心假设是CSA反映了生理性 干扰，并且可能需要针对通气反馈的不同部分的联合模式治疗 循环.我们提出的研究将测试联合治疗，包括PAP加一种药物。这 还将增加拟议研究的临床相关性，因为PAP治疗通常被规定为 CSA的初步治疗。我们建议通过三种不同的生理途径来改变CSA倾向：1） 用氧和/或乙酰唑胺降低回路增益，2）通过阻尼降低补偿过冲 用催眠剂进行呼吸唤醒，以及3）用肾上腺素能神经递质升高呼吸运动输出。 剂为了确保临床相关性，我们将重点关注两种最常见的CSA类型：1）心力衰竭， 射血分数降低（HFrEF）和2）阿片类药物使用，使用分层随机化来平衡 每个实验中的每一组受试者。为了实现本建议的目标，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 化学感受器敏感性和降低植物增益。我们假设联合PAP治疗， 乙酰唑胺和氧气在降低CAHI和CO2储备方面优于单独的每种干预措施上级 中枢性睡眠呼吸暂停综合征患者的睡眠中。具体目标（2）是确定降低 麻醉相关性觉醒对中枢性呼吸暂停发生倾向的影响。我们假设， PAP和唑吡坦将减少睡眠中与麻醉相关的觉醒、CAHI和CO2储备， 与安慰剂相比，CSA患者。具体目的（3）是确定增加血清素的作用 A1受体在睡眠中对呼吸的影响我们假设，PAP和丁螺环酮， 5-羟色胺A1受体激动剂;将减少中枢性呼吸暂停退伍军人睡眠期间的倾向 睡眠呼吸暂停这个新的项目旨在确定可以与PAP结合的生理途径， 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急需的路线图，这些临床试验可能会改变 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.