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.

中枢性呼吸暂停的有效治疗仍然难以实现。该项目的重点是识别机械 基于强有力的前提来指导中枢性睡眠呼吸暂停（CSA）未来治疗干预的途径 多模式治疗——旨在使呼吸正常化——是缓解长期症状的必要途径 CSA 的不良后果。我们的中心假设是 CSA 反映了生理学的结合 扰动，可能需要针对通气反馈不同部分的联合治疗 环形。我们提出的研究将测试联合疗法，包括 PAP 加药物制剂。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) 使用氧气和/或乙酰唑酰胺降低环路增益，2) 通过阻尼降低通气过冲 使用催眠剂引起呼吸唤醒，以及 3) 使用血清素能提高通气运动输出 代理人。为了确保临床相关性，我们将重点关注两种最常见的 CSA 类型：1) 伴有心力衰竭的心力衰竭 射血分数降低 (HFrEF) 和 2) 阿片类药物的使用，使用分层随机化来平衡 每个实验每组的受试者。为了实现本提案的目标，我们将测试以下内容 三个具体目标。具体目标 (1) 是确定联合治疗的效果，旨在抑制 化学感受器敏感性和植物增益降低。我们假设与 PAP 联合治疗， 乙酰唑胺和氧气在减少 CAHI 和二氧化碳储备方面优于单独的每种干预措施 中枢性睡眠呼吸暂停患者在睡眠期间。具体目标 (2) 是确定减少的效果 呼吸相关的唤醒对发生中枢性呼吸暂停的倾向的影响。我们假设管理 PAP 和唑吡坦将减少睡眠期间与呼吸相关的唤醒、CAHI 和 CO2 储备 CSA 患者与安慰剂患者进行比较。具体目标 (3) 是确定增加血清素的效果 A1 受体对睡眠期间呼吸的活动。我们假设给予 PAP 和丁螺环酮， 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。这个新项目旨在确定与 PAP 相结合的生理途径 治疗，提高 CSA 患者的治疗效果。所提出的研究具有创新性， 可行，并将为未来的临床试验提供急需的路线图，这些试验可能会改变对患者的护理 退伍军人中枢性呼吸暂停。