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

描述（由申请人提供）：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)解剖上狭窄或可折叠的上呼吸道，2)不稳定的通气控制系统，3)睡眠时呼吸唤醒阈值低，4)睡眠时上呼吸道肌肉反应差。这项研究的长远目标是更好地了解这些特征如何相互作用，在个别患者中产生OSA，然后利用这些信息来设计新的治疗方法。具体而言，该资助旨在验证一种用于测量和建模导致OSA的特征的新技术（目标1），然后确定非持续气道正压治疗在控制这些特征方面的有效性（目标2）。为了实现这些目标，将测试夜间和夜间测量和模型的可重复性，以及通气稳定性和唤醒阈值指标的有效性。注意：上呼吸道解剖/湿陷性测量先前已经过验证，不会重复。此外，由于方法简单，上气道（肌肉）反应测量将不被验证。通气稳定性指标（循环增益）将通过给个体低氧气体并将低氧循环增益与常氧循环增益进行比较（低氧提高循环增益）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环路增益的方向性变化来验证。新的唤醒阈值测量将通过将其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特征的影响。将测试的干预措施包括上呼吸道手术和口腔器械（操纵咽塌陷），乙酰唑胺和补充氧（操纵呼吸控制），以及艾司佐匹克隆（操纵唤醒阈值）。操纵上气道肌肉反应的干预措施将不会被测试，因为目前没有很好的候选药物来做这件事。所提出的研究不仅将提高我们对OSA病理生理的理解，而且可能实际地导致新的治疗方法。

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.