Treatment of Sleep Apnea using a Positive Airway Pressure Rebreathing Modulator

描述(申请人提供)：尽管阻塞性睡眠呼吸暂停在研究和实践中得到了最大程度的认可和调查，但更令人担忧的睡眠呼吸暂停形式，如由化学反射不稳定引起的睡眠呼吸暂停，仍然存在并继续得不到适当的治疗。中枢性呼吸暂停和周期性呼吸(现在称为Cheyne Stokes呼吸模式)是强化学反射调节睡眠呼吸暂停的经典多导睡眠图标志。最近描述的一种变种，“复杂睡眠呼吸暂停”，表明在正压滴定期间持续诱导中枢性呼吸暂停或严重的周期性呼吸，诊断多导睡眠图上似乎是阻塞性疾病。受影响的人群数量很大，特别是当考虑到充血性心力衰竭等特定人群时。据估计，仅复杂睡眠呼吸暂停患者就占睡眠呼吸暂停患者总数的10%-15%，或超过150万患者(假设保守估计为睡眠呼吸暂停患者总数为1000万美元)。在那些具有显著的化学反射调节作用的患者中，传统的气道正压治疗失败的可能性很高。正压治疗往往能排出并降低二氧化碳(CO2)水平；在应用正压治疗期间预防这种低碳酸血症状态是化学反射调节型睡眠呼吸暂停综合征的重要稳定因素。正压气体调节器(PAPGAM)是一种新型的正压设备，旨在通过谨慎地将二氧化碳水平维持在略高于二氧化碳依赖呼吸暂停阈值的水平来防止化学反射不稳定，已显示出良好的急性效果。一种名为增强呼气重复呼吸空间的改良死腔方法显示出了一些成功的慢性效应，但不如直接控制二氧化碳水平精确。这项提案将研究使用呼出的空气来提供与正呼吸道压力装置的入口空气混合的二氧化碳。通过控制混合，我们希望完全消除对高压罐的需求，或至少显著提高其寿命。因此，其目的是获得PAPGAM治疗的精确度，但同时降低成本，显著改善易用性，并将技术故障造成的不良后果降至最低。第一阶段研究的目标包括：1)建立能够将患者呼出的空气转移或拉向正压设备入口的原型；2)确定是否需要被动或主动再呼吸机制；3)确定使用每种技术可能的最大浓度；以及4)对该系统进行临床评估。成功的实施将为化学反射调节型睡眠呼吸暂停带来一种强有力的新疗法。 与公共卫生相关：睡眠时对呼吸的异常控制会导致中枢性或混合性睡眠呼吸暂停，在心力衰竭和肾衰竭患者中尤其常见。阻塞性睡眠呼吸暂停的常用治疗方法-面罩和气压装置-在患有中枢性/混合性睡眠呼吸暂停的人身上效果不佳。最近的研究表明，空气加压装置降低了二氧化碳的正常水平，通过将二氧化碳水平提高到正常水平，已经取得了良好的处理效果。这项拟议的研究将开发利用患者呼出的二氧化碳来提供睡眠期间稳定的呼吸模式的方法。这种名为正压再呼吸调节器(PAPREM，将与气压疗法一起使用)设备的成功开发将显著改进复杂形式的睡眠呼吸暂停的治疗。

DESCRIPTION (provided by applicant): Although obstructive sleep apnea has received the lion's share of recognition and investigation in research and practice, more troubling forms of sleep apnea, like those that are mediated by chemoreflex instability, exist and continue to have inadequate treatment. Central apneas and periodic breathing (now called the Cheyne Stokes breathing pattern) are the classic polysomnographic markers of strong chemoreflex modulation of sleep apnea. A recently described variant, "complex sleep apnea", demonstrates sustained induction of central apneas or severe periodic breathing during positive pressure titration for what seems to be obstructive disease on the diagnostic polysomnogram. The number of the affected population is large, especially when specific populations such as congestive heart failure are considered. It is estimated that complex sleep apnea alone makes up 10%-15% of the overall sleep apnea patient population or over 1.5 million patients (assuming a conservative estimate of $10 million overall sleep apnea population). In those with significant chemoreflex modulatory effects, the probability of failure of conventional positive airway pressure therapy is high. Positive airway pressure therapies tend to flush out and reduce the level of carbon dioxide (CO2); prevention of this hypocapnia state during the application of positive airway pressure therapies is an important stabilizing factor for chemoreflex-modulated sleep apnea syndromes. The Positive Airway Pressure Gas Modulator (PAPGAM), a new class of positive airway pressure device designed to prevent chemoreflex instability by carefully maintaining CO2 levels just above the CO2-dependent apneic threshold, has shown excellent acute results. Chronic effects with a modified dead space approach, called Enhanced Expiratory Rebreathing Space, have shown some success, but are less precise than directly controlling the CO2 level. This proposal will investigate the use of exhaled air to provide the CO2 that is mixed with the inlet air of the positive airway pressure device. By controlled mixing, we hope to completely eliminate the need for the high pressure tank, or at a minimum markedly increase its life. Thus, the aim is to obtain the precision of PAPGAM treatment but with reduced cost, marked improvements in ease of use, and minimized adverse outcomes from technical failures. The goals of the phase I research include: 1) building prototypes capable of diverting or pulling the exhaled air from the patient to the inlet of the positive airway pressure device; 2) determining if a passive or an active rebreathing mechanism is required; 3) determining what maximum concentrations are possible using each technique; and 4) clinically assessing the system. Successful implementation will result in a poweful new treatment for chemoreflex-modulated sleep apnea. PUBLIC HEALTH RELEVANCE: Abnormal control of breathing during sleep causes central or mixed forms of sleep apnea and is especially common in heart failure and kidney failure patients. The usual treatment for obstructive sleep apnea, a mask and air pressure device, does not work well in those with central / mixed sleep apnea. Recent research indicates that the air pressure device decreases the normal level of carbon dioxide and excellent treatment results have been achieved by increasing carbon dioxide levels back to normal levels. The proposed research will develop methods to use carbon dioxide exhaled by the patient to provide stability of breathing patterns during sleep. Success in development of this device, called the Positive Airway Pressure Rebreathing Modulator (PAPREM, to be used with air pressure treatments) will markedly improve treatment of complicated forms of sleep apnea.