Positive Airway Pressure Gas Modulator - A Novel Method to Treat Central Sleep Ap

气道正压气体调节器 - 治疗中枢性睡眠呼吸暂停的新方法

• 批准号: 7537871
• 负责人: Hani Akram Kayyali
• 金额: $ 23.75万
• 依托单位: CLEVELAND MEDICAL DEVICES, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-19 至 2010-03-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537871
• 关键词: Affect; Agreement; Attention; Back; Behavioral; Body Weight decreased; Boston; Breathing; Carbon Dioxide; Central Sleep Apnea; Chronic; Class; Clinical; Clinical Trials; Comorbidity; Complex; Congestive; Continuous Positive Airway Pressure; Detection; Development; Device or Instrument Development; Devices; Diagnostic; Disease; Electrocardiogram; Ensure; Environmental air flow; Evaluation; Exhibits; Failure; Future; Gases; Goals; Hearing; Heart failure; Hypercapnia; Hypocapnia; Israel; Mediating; Mediation; Medical; Medical center; Medicine; Metabolic; Methods; Modality; Monitor; Muscle; Numbers; Obstruction; Obstructive Sleep Apnea; Operative Surgical Procedures; Oral; Oral Positive Airway Pressure; Patient Selection; Patients; Pattern; Phase; Phenotype; Polysomnography; Population; Prevention; Probability; Production; Public Health; Recommendation; Regulation; Research; Resistance; Safety; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Software Design; Standards of Weights and Measures; Syndrome; System; Techniques; Technology; Testing; Titrations; Toxic effect; Toxicity Tests; Treatment Efficacy; Universities; Variant; Week; Work; base; design; experience; hemodynamics; improved; innovative technologies; medical schools; novel; novel strategies; pressure; prevent; prototype; research clinical testing; research in practice; research study; respiratory; response

DESCRIPTION (provided by applicant): Sleep apnea is a major public health problem but traditional treatments have focused mostly on resolving obstructive sleep apnea (OSA) as demonstrated by the plethora of obstruction-motivated therapies like positive airway pressure, oral appliances, and others. However, more troubling forms of sleep apnea exist like those that are mediated by chemoreflex instability; yet, treatment for such disease states remain inadequate. Central apneas and periodic breathing are the classic polysomnographic markers of strong chemoreflex mediation of sleep apnea. Recently, another variation called "complex sleep apnea" has been described, which is characterized by sustained induction of central apneas or severe periodic breathing during positive pressure titration for what seems to be an obstructive disease on the diagnostic polysomnogram. The number of the affected population is large with Complex Sleep apnea alone estimated at over 1.5 million patients. We propose to develop a new class of positive airway pressure devices that will be based on preventing chemoreflex instability by carefully maintaining carbon dioxide (CO2) levels just above the CO2-dependent apneic threshold. We will call this technology: Positive Airway Pressure Gas Modulation (PAPGAM). We have conducted significant preliminary experiments demonstrating that prevention of hypocapnia during the application of positive airway pressure therapies can restore normal breathing to patients who were resistant to current therapies. The overarching goal of Phase I is to confirm the sustained efficacy and lack of toxicity of PAPGAM by testing more patients over multiple nights, while Phase II will complete device development and conduct an extensive clinical trial. The extensive preliminary results, which demonstrated an appreciable level of safety and efficacy testing combined with the excellent investigative team and timeliness of the project have encouraged us to submit a Fast Track application instead of Phase I only. Phase I will assess in subjects with chemoreflex dependent sleep apnea: 1) The development of tolerance, or lack of, to the PAPGAM over a two-week period. 2) The safety profile of the PAPGAM in relation to hemodynamic, respiratory, autonomic and metabolic variables. Phase II will complete the development of PAPGAM hardware and software design including regulatory and medical standards testing and conduct extensive medium term efficacy and toxicity clinical testing. We believe, our approach will create a paradigm shift in the treatment of sleep-breathing disorders that will benefit patients with and without significant comorbidities such as heart failure. Our goal is in strong agreement with NIH's recommendation for future sleep disorders research as clearly indicated in the most recent National Center for Sleep Disorders Research Plan. We have assembled world renowned experts in the field to execute this project. Dr. Robert Thomas from Beth Israel Deaconess Medical Center, Boston and Dr. Safwan Badr from Wayne State University School of Medicine, Detroit, are experts not only in the field of sleep disordered breathing but have been leading the emerging field of chemoreflex dependent sleep apnea. PUBLIC HEALTH RELEVANCE: Sleep apnea is a major public health problem but traditional treatments have focused mostly on resolving obstructive sleep apnea (OSA) as demonstrated by the plethora of obstruction-motivated therapies like positive airway pressure, oral appliances, and others. However, more troubling forms of sleep apnea exist like those that are mediated by chemoreflex instability; yet, treatment for such disease states remain inadequate. Central apneas and periodic breathing are the classic polysomnographic markers of strong chemoreflex mediation of sleep apnea. Recently, another variation called "complex sleep apnea" has been described, which is characterized by sustained induction of central apneas or severe periodic breathing during positive pressure titration for what seems to be an obstructive disease on the diagnostic polysomnogram. The number of the affected population is large with Complex Sleep apnea alone estimated at over 1.5 million patients. We propose to develop a new class of positive airway pressure devices that will be based on preventing chemoreflex instability by carefully maintaining carbon dioxide (CO2) levels just above the CO2-dependent apneic threshold. We will call this technology: Positive Airway Pressure Gas Modulation (PAPGAM). We have conducted significant preliminary experiments demonstrating that prevention of hypocapnia during the application of positive airway pressure therapies can restore normal breathing to patients who were resistant to current therapies. The overarching goal of Phase I is to confirm the sustained efficacy and lack of toxicity of PAPGAM by testing more patients over multiple nights, while Phase II will complete device development and conduct an extensive clinical trial. The extensive preliminary results, which demonstrated an appreciable level of safety and efficacy testing combined with the excellent investigative team and timeliness of the project have encouraged us to submit a Fast Track application instead of Phase I only. Phase I will assess in subjects with chemoreflex dependent sleep apnea: 1) The development of tolerance, or lack of, to the PAPGAM over a two-week period. 2) The safety profile of the PAPGAM in relation to hemodynamic, respiratory, autonomic and metabolic variables. Phase II will complete the development of PAPGAM hardware and software design including regulatory and medical standards testing and conduct extensive medium term efficacy and toxicity clinical testing. We believe, our approach will create a paradigm shift in the treatment of sleep-breathing disorders that will benefit patients with and without significant comorbidities such as heart failure. Our goal is in strong agreement with NIH's recommendation for future sleep disorders research as clearly indicated in the most recent National Center for Sleep Disorders Research Plan. We have assembled world renowned experts in the field to execute this project. Dr. Robert Thomas from Beth Israel Deaconess Medical Center, Boston and Dr. Safwan Badr from Wayne State University School of Medicine, Detroit, are experts not only in the field of sleep disordered breathing but have been leading the emerging field of chemoreflex dependent sleep apnea.

描述（由申请人提供）：睡眠呼吸暂停是一个主要的公共卫生问题，但传统治疗主要集中在解决阻塞性睡眠呼吸暂停（OSA）上，如大量阻塞动机疗法所证明的，例如积极的气道压力，口服器具等。但是，像化学反射不稳定性介导的那样，更令人不安的睡眠呼吸暂停存在。然而，这种疾病状态的治疗仍然不足。中央呼吸暂停和周期性呼吸是强烈的化学反射呼吸呼吸中介导的经典多呼吸术标记。最近，已经描述了另一种称为“复杂睡眠呼吸暂停”的变体，其特征是在正压滴定期间持续诱导中央呼吸暂停或严重的周期性呼吸，这似乎是诊断性多发性疾病的阻塞性疾病。受影响人群的数量很大，仅复杂的睡眠呼吸暂停估计超过150万。我们建议开发一类新的正气道压力设备，这些设备将基于通过仔细维持二氧化碳（CO2）水平在CO2依赖性的呼吸暂停阈值上方来防止化学反射不稳定性。我们称这项技术为：正气道压力气体调制（PAPGAM）。我们已经进行了重要的初步实验，证明在阳性气道压力疗法中预防低核心可以恢复对当前疗法有抵抗力的患者的正常呼吸。第一阶段的总体目标是通过在多个晚上测试更多的患者来确认持续的疗效和缺乏木偶木皮毒性的毒性，而第二阶段将完成设备开发并进行广泛的临床试验。广泛的初步结果表明，安全和效力测试的水平相结合，结合了出色的调查团队和该项目的及时性，这鼓励我们仅提交快速轨道应用，而不是仅第一阶段。第一阶段将在具有化学反射依赖性睡眠呼吸暂停的受试者中评估：1）在为期两周的时间内，对帕帕姆的耐受性或缺乏耐受性的发展。 2）木偶木瓜与血液动力学，呼吸道，自主和代谢变量有关的安全性。第二阶段将完成木瓜硬件和软件设计的开发，包括监管和医疗标准测试，并进行广泛的中期功效和毒性临床测试。我们相信，我们的方法将在睡眠呼吸障碍的治疗中会产生范式转变，这将使有或没有明显合并症（例如心力衰竭）的患者受益。我们的目标是与NIH对未来睡眠障碍研究的建议非常同意，如最新的国家睡眠障碍研究中心所表明的那样。我们已经组建了该领域的世界知名专家，以执行该项目。来自贝斯顿贝丝（Beth Israel Deacones）医学中心的罗伯特·托马斯（Robert Thomas）博士和底特律韦恩州立大学医学院的Safwan Badr博士不仅是睡眠失调的呼吸领域的专家，而且一直领导着ChemoreFlex依赖性睡眠呼吸暂停的新兴领域。公共卫生相关性：睡眠呼吸暂停是一个主要的公共卫生问题，但传统治疗主要集中在解决阻塞性睡眠呼吸暂停（OSA）上，如大量阻塞动机疗法（如阳性气道压力，口腔用具等）所证明的那样。但是，像化学反射不稳定性介导的那样，更令人不安的睡眠呼吸暂停存在。然而，这种疾病状态的治疗仍然不足。中央呼吸暂停和周期性呼吸是强烈的化学反射呼吸呼吸中介导的经典多呼吸术标记。最近，已经描述了另一种称为“复杂睡眠呼吸暂停”的变体，其特征是在正压滴定期间持续诱导中央呼吸暂停或严重的周期性呼吸，这似乎是诊断性多发性疾病的阻塞性疾病。受影响人群的数量很大，仅复杂的睡眠呼吸暂停估计超过150万。我们建议开发一类新的正气道压力设备，这些设备将基于通过仔细维持二氧化碳（CO2）水平在CO2依赖性的呼吸暂停阈值上方来防止化学反射不稳定性。我们称这项技术为：正气道压力气体调制（PAPGAM）。我们已经进行了重要的初步实验，证明在阳性气道压力疗法中预防低核心可以恢复对当前疗法有抵抗力的患者的正常呼吸。第一阶段的总体目标是通过在多个晚上测试更多的患者来确认持续的疗效和缺乏木偶木皮毒性的毒性，而第二阶段将完成设备开发并进行广泛的临床试验。广泛的初步结果表明，安全和效力测试的水平相结合，结合了出色的调查团队和该项目的及时性，这鼓励我们仅提交快速轨道应用，而不是仅第一阶段。第一阶段将在具有化学反射依赖性睡眠呼吸暂停的受试者中评估：1）在为期两周的时间内，对帕帕姆的耐受性或缺乏耐受性的发展。 2）木偶木瓜与血液动力学，呼吸道，自主和代谢变量有关的安全性。第二阶段将完成木瓜硬件和软件设计的开发，包括监管和医疗标准测试，并进行广泛的中期功效和毒性临床测试。我们相信，我们的方法将在睡眠呼吸障碍的治疗中会产生范式转变，这将使有或没有明显合并症（例如心力衰竭）的患者受益。我们的目标是与NIH对未来睡眠障碍研究的建议非常同意，如最新的国家睡眠障碍研究中心所表明的那样。我们已经组建了该领域的世界知名专家，以执行该项目。来自贝斯顿贝丝（Beth Israel Deacones）医学中心的罗伯特·托马斯（Robert Thomas）博士和底特律韦恩州立大学医学院的Safwan Badr博士不仅是睡眠失调的呼吸领域的专家，而且一直领导着ChemoreFlex依赖性睡眠呼吸暂停的新兴领域。