Mild intermittent hypoxia and CPAP: A multi-pronged approach to treat sleep apnea in intact and spinal cord injured humans

轻度间歇性缺氧和 CPAP：治疗完好和脊髓损伤人类睡眠呼吸暂停的多管齐下的方法

• 批准号: 9926308
• 负责人: Jason H. Mateika
• 金额: $ 38.5万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926308
• 关键词: Animals; Biological Markers; Blood Pressure; Brain Stem; Cardiovascular system; Chest wall structure; Continuous Positive Airway Pressure; Coupled; Couples Therapy; Diagnosis; Event; Exposure to; General Population; Gold; Health; Human; Hypoxia; Impairment; Incidence; Individual; Inflammatory; Innovative Therapy; Laboratories; Lead; Limb structure; Link; Measures; Metabolic; Metabolic dysfunction; Modification; Morphology; Motor; Motor Neurons; Neurocognitive; Neurologic; Obstructive Sleep Apnea; Outcome; Outcome Measure; Parasympathetic Nervous System; Participant; Prevalence; Recovery; Safety; Secondary to; Sleep; Sleep Apnea Syndromes; Spinal cord injury; Stimulus; Sympathetic Nervous System; Synapses; Therapeutic; Therapeutic Effect; Time; United States; Wakefulness; airway muscle; comorbidity; compliance behavior; design; improved; improved outcome; motor disorder; motor function recovery; novel; pressure; primary outcome; respiratory; response; standard care

Mild intermittent hypoxia (IH) initiates sustained increases in chest wall and upper airway muscle activity in humans. This sustained increase is a form of respiratory plasticity known as long-term facilitation (LTF). Repeated daily exposure to mild IH that leads to the initiation of LTF of upper airway muscle activity could lead to increased stability of the upper airway. In line with my laboratory’s mandate to develop innovative therapies to treat sleep apnea, this increased stability could ultimately reduce the continuous positive airway pressure (CPAP) required to treat obstructive sleep apnea (OSA) and improve compliance with this gold standard treatment. Improved compliance could ultimately serve to mitigate those co- morbidities linked to sleep apnea. Moreover, in addition to improving CPAP compliance numerous studies indicate that mild IH has many direct beneficial cardiovascular, neurocognitive and metabolic effects. Thus, mild IH could serve as a multipronged therapeutic approach to treat sleep apnea. In accordance with this postulation, Aim 1 of our proposal will determine if repeated daily exposure to mild IH serves as an adjunct therapy coupled with CPAP to mitigate associated co-morbidities via its direct effects on a variety of cardiovascular, metabolic and neurocognitive measures and indirectly by improving CPAP compliance. Modifications in autonomic (i.e. sympathetic nervous system activity) and cardiovascular (i.e. blood pressure) function will be the primary outcome measures coupled to secondary measures of metabolic and neurocognitive outcomes. Sleep is typically associated with a reduction in respiratory motoneuron excitability. This response is exacerbated and coupled to obstructive apneic events as a consequence of spinal cord injury induced morphological and neurological impairment of bulbospinal synaptic inputs to respiratory motoneurons, and adaptations in brainstem respiratory and upper airway motor function. These modifications are coupled to an incidence of sleep-disordered breathing (i.e. both central and obstructive sleep apnea) which is approximately 15 times higher in individuals with spinal cord injury than in the general population of the United States. Thus, exposure to this stimulus could improve CPAP compliance and enhanced outcome measures as outlined above. Additionally, repeated daily exposure to intermittent hypoxia promotes the recovery of respiratory and motor limb function in animals and humans. Thus, daily repeated exposure to IH could have significant therapeutic effects on respiratory and limb motor function in individuals with spinal cord injury accompanied by sleep apnea. Thus, Aim 2 of our proposal will serve to determine if IH can serve to mitigate co-morbidities linked to sleep apnea and promote the recovery of respiratory motor function during wakefulness and sleep, and motor limb function during wakefulness.

轻度间歇性缺氧（IH）引发胸壁和上气道肌肉持续增加 人类的活动。这种持续的增加是呼吸可塑性的一种形式，被称为长期易化 （LTF）。每日重复暴露于轻度IH，导致上气道肌肉活动的LTF启动 会增加上呼吸道的稳定性根据我实验室的任务， 治疗睡眠呼吸暂停的创新疗法，这种增加的稳定性最终可以减少持续的 治疗阻塞性睡眠呼吸暂停（OSA）和提高依从性所需的气道正压通气（CPAP） 这种黄金标准的治疗。改善遵守情况最终可有助于减轻这些共同-- 与睡眠呼吸暂停有关的疾病此外，除了改善CPAP依从性之外， 表明轻度IH具有许多直接有益心血管、神经认知和代谢作用。因此，在本发明中， 轻度IH可作为治疗睡眠呼吸暂停的多管齐下的治疗方法。根据本 假设，我们建议的目标1将确定每天重复暴露于轻度IH是否可作为辅助治疗 联合CPAP治疗，通过其对各种并发症的直接影响来减轻相关的并发症 心血管、代谢和神经认知测量，并间接通过改善CPAP依从性。 自主神经（即交感神经系统活动）和心血管（即血压）的变化 功能将是主要的结局指标，与代谢和 神经认知结果。 睡眠通常与呼吸运动神经元兴奋性的降低有关。这种反应 加重并伴有脊髓损伤引起的阻塞性呼吸暂停事件 呼吸运动神经元的球脊髓突触输入的形态学和神经学损伤，以及 脑干呼吸和上呼吸道运动功能的适应。这些修改与 睡眠呼吸障碍（即中枢性和阻塞性睡眠呼吸暂停）的发生率约为 脊髓损伤患者比美国普通人群高15倍。 因此，暴露于这种刺激可以改善CPAP依从性并增强所述的结果测量 以上此外，每天重复暴露于间歇性缺氧可促进呼吸和 动物和人类的运动肢体功能。因此，每天重复暴露于IH可能具有显著的 对脊髓损伤患者呼吸和肢体运动功能的治疗作用 睡眠呼吸暂停因此，我们建议的目标2将用于确定IH是否可以减轻合并症 与睡眠呼吸暂停有关，并促进清醒和睡眠期间呼吸运动功能的恢复， 和运动肢体的功能。