Central and Peripheral Mechanisms of Sleep Apnea

描述(申请人提供)：根据我们最近在睡眠中的人和狗的研究结果，我们认为真呼吸暂停以下的二氧化碳的呼吸反应性是高度不稳定的，这取决于主要的呼吸驱动的类型和方向，并且是许多类型的呼吸不稳定和呼吸暂停的关键决定因素。我们提出了五个主要目标来研究二氧化碳储备中不稳定的呼吸暂停阈值的原因和后果(即PETCO2 EUPNEA--PETCO2APNEA；通风不稳定的倾向指数)。首先，我们将使用睡狗模型和我们的压力支持通气法(PSV)来确定二氧化碳储备和因左房压力升高而引起的呼吸暂停易感性的变化，如充血性心力衰竭。AIMS 2和3将利用我们完整的睡狗制剂，其中颈动脉化学感受器被分离并通过体外循环灌流。我们将确定中枢和外周化学感受器对一过性PaCO2降低的敏感性，以及它们在呼吸暂停发生中的相对贡献。我们分离完整睡眠动物的中枢和外周化学感受器的能力也将被用来确定外周化学感受器低氧和中枢低氧在确定二氧化碳储备和呼吸不稳定倾向方面的相对重要性。在目标4中，我们将利用睡眠中的人来研究在低氧条件下睡眠时伴随周期性呼吸的脑血流动态变化对呼吸稳定性的原因和后果。最后，我们将检验这一假设，即阻塞性睡眠呼吸暂停患者由于长期暴露于夜间低氧血症，有不稳定的呼吸运动输出和敏感的呼吸暂停阈值(即，缩小的二氧化碳储备)的倾向。我们将通过将狗暴露在慢性间歇性低氧中来进一步检验这一假设，以确定它们的呼吸不稳定倾向是否随着慢性间歇性低氧暴露的持续时间而增加。

DESCRIPTION (provided by applicant): Based on our recent findings in sleeping humans and dogs we propose that the ventilatory responsiveness to CO2 below eupnea is highly labile depending on the type and direction of prevailing ventilatory drive and is a critical determinant of many types of breathing instability and apnea. We propose five major aims to study causes and consequences of a labile apneic threshold on the CO2 reserve (i.e., PETCO2 EUPNEA -- PETCO2APNEA ; an index of propensity for ventilatory instability). First, we will use the sleeping dog model and our pressure support ventilation (PSV) method to determine the CO2 reserve and change in the susceptibility to apnea caused by raised left atrial pressure, as occurs in congestive heart failure. Aims 2 & 3 will utilize our intact sleeping dog preparation in which the carotid chemoreceptor is isolated and perfused via extracorporeal circulation. We will determine the sensitivities of the central vs. peripheral chemoreceptors to transient reductions in PaCO2 and their relative contributions to the genesis of apnea. Our capability for isolating central from peripheral chemoreceptors in the intact sleeping animal will also be used to determine the relative importance of peripheral chemoreceptor hypoxia vs. CNS hypoxia in determining CO2 reserve and the propensity for ventilatory instability. In Aim 4, we will use sleeping humans to study the causes and consequences to ventilatory stability of the dynamic changes in cerebral blood flow which accompany periodic breathing during sleep in hypoxia. Finally, we will test the hypothesis that obstructive sleep apnea patients have a propensity for unstable respiratory motor output and a sensitive apneic threshold (i.e., narrowed CO2 reserve) because of their chronic exposure to nocturnal hypoxemia. We will test this hypothesis further by exposing dogs to chronic intermittent hypoxia to determine if their propensity for ventilatory instability increases over the duration of chronic intermittent hypoxic exposure.