A method for measuring and modeling the physiologic traits causing sleep apnea

描述(申请人提供)：阻塞性睡眠呼吸暂停(OSA)是一种多因素疾病，可能有四个主要原因或生理特征：1)解剖学上较小或可折叠的上呼吸道，2)呼吸控制系统不稳定，3)睡眠呼吸唤醒阈值低，以及4)睡眠期间上呼吸道肌肉反应不良。这项研究的总体目标是更好地了解这些特征是如何在个体患者中相互作用产生OSA的，然后利用这些信息来设计新的治疗方法。具体地说，这笔赠款旨在验证一种新的技术，用于测量和建模导致阻塞性睡眠呼吸暂停综合征的特征(目标1)，然后确定非连续性气道正压疗法在操纵这些特征方面的有效性(目标2)。为了实现这些目标，将测试测量和模型的夜间和夜间重复性，以及通风稳定性和唤醒阈值指标的有效性。注意：上呼吸道解剖/塌陷性测量先前已经过验证，不会重复。此外，上呼吸道(肌肉)反应测量将不会得到验证，因为方法很简单。呼吸稳定性指标(循环增益)将通过给个体注射低氧气体并将低氧循环增益与正常氧循环增益(低氧增加循环增益)进行比较来验证。由于没有测量环路增益的黄金标准，新方法正在通过确定它是否可以检测到环路增益的方向性变化来进行验证。新的觉醒阈值测量将通过与食道压力监测确定的唤醒阈值进行比较来验证。在目标2中，将测量几种干预措施对每个性状的影响。将接受测试的干预措施包括上呼吸道手术和口腔用具(用于操纵咽部塌陷)、乙酰唑胺和补充氧气(用于操纵呼吸控制)，以及埃佐匹克隆(用于操纵觉醒阈值)。由于目前还没有很好的候选药物来实现这一点，因此不会对操纵上呼吸道肌肉反应的干预措施进行测试。提出的研究不仅将提高我们对OSA病理生理学的理解，而且可能实际地导致新的治疗方法。 公共卫生相关性：这项拨款描述了一种测量和模拟导致睡眠呼吸暂停的一些重要致病特征的技术。还将测试非CPAP治疗对每种性状的有效性。这些研究可能有助于更好地了解睡眠呼吸暂停的发病机制，并有可能找到新的治疗方法。

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) is a multifactorial disorder with probably four main causes or physiologic traits: 1) an anatomically small, or collapsible, upper airway, 2) an unstable ventilatory control system, 3) a low respiratory arousal threshold from sleep, and 4) a poor upper airway muscle response during sleep. The broad term objective of this research is to better understand how these traits interact to produce OSA in individual patients, and then to use this information to design new treatments. Specifically, this grant aims to validate a novel technique for measuring and modeling the traits causing OSA (Aim 1), and then determine how effective non-continuous positive airway pressure therapies are at manipulating the traits (Aim 2). To achieve these objectives, the within-night and between-night repeatability of the measurements and model will be tested, along with the validity of the ventilatory stability and arousal threshold metrics. Note: the upper airway anatomy/collapsibility measurement has been previously validated and will not be repeated. Also, the upper airway (muscle) response measurement will not be validated because the methodology is straightforward. The ventilatory stability metric (loop gain), will be validated by administering hypoxic gas to individuals and comparing the hypoxic loop gain to the normoxic loop gain (hypoxia raises the loop gain). As there is not a gold standard for measuring loop gain, the new method is being validated by determining if it can detect a directional change in loop gain. The new arousal threshold measurement will be validated by comparing it to the arousal threshold determined from esophageal pressure monitoring. In Aim 2, the effect of several interventions on each trait will be measured. The interventions that will be tested include upper airway surgery and oral appliances (to manipulate pharyngeal collapsibility), acetazolamide and supplemental oxygen (to manipulate the control of breathing), and eszopiclone (to manipulate the arousal threshold). Interventions to manipulate the upper airway muscle response will not be tested since currently there are not good candidate drugs for doing this. The studies proposed will not only improve our understanding of OSA pathophysiology, but could realistically lead to new therapeutic approaches. PUBLIC HEALTH RELEVANCE: This grant describes a technique for measuring and modeling some of the important pathogenic traits causing sleep apnea. The effectiveness of non-CPAP treatments on each trait will also be tested. These studies could lead to a better understanding of sleep apnea pathogenesis and potentially new treatments.