Treatment of Sleep Apnea using a Positive Airway Pressure Rebreathing Modulator

描述（由申请人提供）：尽管阻塞性睡眠呼吸暂停在研究和实践中得到了最大的认可和调查，但更令人不安的睡眠呼吸暂停形式，如由化学反射不稳定介导的那些，仍然存在并且仍然没有充分的治疗。中枢性呼吸暂停和周期性呼吸（现在称为Cheyne Stokes呼吸模式）是睡眠呼吸暂停强化学反射调节的经典多导睡眠图标记。最近描述的一种变体，“复杂性睡眠呼吸暂停”，在诊断性多导睡眠图上显示为阻塞性疾病的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。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，仅复杂性睡眠呼吸暂停就占总睡眠呼吸暂停患者人群的10%-15%或超过150万患者（假设保守估计总睡眠呼吸暂停人群为1000万美元）。在那些具有显著化学反射调节作用的患者中，常规气道正压通气治疗失败的可能性很高。 气道正压通气治疗往往会排出并降低二氧化碳（CO2）水平;在应用气道正压通气治疗期间预防这种低碳酸血症状态是化学反射调节的睡眠呼吸暂停综合征的重要稳定因素。气道正压气体调节器（PAPGAM）是一种新型气道正压装置，旨在通过小心地将CO2水平维持在略高于CO2依赖性呼吸暂停阈值来防止化学反射不稳定，已显示出出色的急性结果。使用改良的死腔方法（称为增强呼气再呼吸空间）的慢性效应已显示出一些成功，但不如直接控制CO2水平精确。本提案将研究使用呼出空气提供与气道正压通气装置的进气混合的CO2。通过控制混合，我们希望完全消除对高压罐的需求，或者至少显著增加其寿命。因此，目的是获得PAPGAM治疗的精度，但降低成本，显著改善易用性，并最大限度地减少技术故障的不良后果。 第一阶段研究的目标包括：1）构建能够将患者呼出的空气转移或拉至气道正压通气装置入口的原型; 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）临床评估系统。成功的实施将为化学反射调节的睡眠呼吸暂停提供一种强有力的新治疗方法。 公共卫生相关性：睡眠期间呼吸控制异常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通常治疗方法是面罩和气压装置，对中枢性/混合性睡眠呼吸暂停患者效果不佳。最近的研究表明，空气压力装置降低了二氧化碳的正常水平，并且通过将二氧化碳水平提高到正常水平来实现优异的处理结果。这项拟议中的研究将开发使用患者呼出的二氧化碳的方法，以提供睡眠期间呼吸模式的稳定性。这种名为气道正压再呼吸调节器（PAPREM，与气压治疗一起使用）的设备的成功开发将显着改善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.