Central Sleep Apnea: Physiologic Mechanisms to Inform Treatment

中枢性睡眠呼吸暂停：指导治疗的生理机制

• 批准号: 10390291
• 负责人: M. Safwan Badr
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390291
• 关键词: Acetazolamide; Address; Agonist; Animals; Apnea; Arousal; Breathing; Buspirone; Carbon Dioxide; Caring; Central Sleep Apnea; Chemoreceptors; Chronic; Clinical Trials; Combined Modality Therapy; Complex; EFRAC; Ensure; Equilibrium; Event; Feedback; Future; Heart failure; Heterogeneity; Human; Hyperpnea; Hypocapnia; Hypoxia; Intervention; Laboratories; Literature; Motor output; Opioid Analgesics; Outcome; Oxygen; Pathway interactions; Patient Care; Patients; Peripheral; Pharmacology; Physiological; Placebos; Plants; Quality of life; Randomized; Recurrence; Resolution; Respiration; Sensory; Series; Serotonin; Serotonin Agents; Sleep; Testing; Therapeutic Intervention; Treatment Effectiveness; Veterans; Work; adverse outcome; arm; base; clinically relevant; design; effective therapy; experience; experimental study; hypnotic; improved; indexing; innovation; novel; opioid use; optimal treatments; positive airway pressure; preconditioning; pressure; prevent; receptor; respiratory; response; skills; supplemental oxygen; targeted treatment; zolpidem

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.

中央呼吸暂停的有效治疗仍然难以捉摸。该项目的重点是识别机械 基于强大的前提 多模式疗法 - 旨在使呼吸归一化的旨在减轻长期的必要途径 CSA的不利后果。我们的中心假设是CSA反映了生理的结合 扰动，可能需要针对通风反馈不同部位的组合方式疗法 环形。我们提出的研究将测试组合疗法，包括PAP和药理剂。这 由于PAP治疗通常被规定为 CSA的初始治疗。我们建议通过三种不同的生理途径修改CSA倾向：1） 通过氧气和/或乙唑胺的降低环的增益，2）通过降低通风过冲的降低 呼吸唤醒的催眠剂，3）用血清素能抬高通气电机输出 代理人。为了确保临床相关性，我们将重点关注两种最常见类型的CSA：1）心力衰竭与 减少射血分数（HFREF）和2）使用阿片类药物，使用分层随机化来平衡 每个实验的每个臂中的受试者。为了实现该提案的目标，我们将测试以下 三个具体目标。具体目的（1）是确定旨在抑制的组合疗法的影响 化学感受器的敏感性和植物增益降低。我们假设该疗法与PAP合并， 在减少CAHI和CO2储备中，乙酰唑胺和氧气将优于每种干预措施 中央睡眠呼吸暂停患者的睡眠期间。具体目的（2）是确定减少的效果 呼吸相关的唤醒倾向于发展中央呼吸暂停。我们假设管理 PAP和ZOLPIDEM将减少与呼吸有关的唤醒，Cahi和CO2储备在睡眠中 与安慰剂相比，CSA患者。具体目的（3）是确定增加5-羟色胺的效果 A1受体活动在睡眠期间呼吸。我们假设给予子宫颈脑和胰蛋白酶，一个 5-羟色胺A1受体激动剂；将减少在中央的退伍军人中睡眠期间中央呼吸暂停的倾向 睡眠呼吸暂停。这个新型项目旨在识别可以与PAP结合的生理途径 治疗，提高CSA患者治疗的有效性。拟议的研究是创新的， 可行，并将为将来的临床试验提供急需的路线图，这可能会改变护理 退伍军人中央呼吸暂停。