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: 10445039
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445039
• 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）导致胸壁和上呼吸道肌肉持续增加 这种持续增加是呼吸可塑性的一种形式，称为长期促进。 (LTF) 每天重复接触轻度 IH，导致上呼吸道肌肉活动开始发生 LTF。 可以提高上呼吸道的稳定性，符合我实验室的开发任务。 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呼吸暂停 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) 通过这种黄金标准治疗，改善依从性最终可以缓解这些问题。 此外，除了改善 CPAP 依从性之外，还有大量研究表明与睡眠呼吸暂停相关的发病率。 表明轻度 IH 对心血管、神经认知和代谢有许多直接有益的影响。 据此，轻度 IH 可以作为治疗睡眠呼吸暂停的多管齐下的治疗方法。 假设，我们提案的目标 1 将确定每日重复接触轻度 IH 是否可以作为辅助手段 与 CPAP 联合治疗可通过其对多种疾病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，并通过改善 CPAP 依从性间接实现。 自主神经（即交感神经系统活动）和心血管（即血压）的改变 功能将是主要结果指标，与代谢和代谢的次要指标相结合。 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。 由于脊髓损伤引起的阻塞性呼吸暂停事件加剧并与之相关 呼吸运动神经元的球脊髓突触输入的形态和神经学损伤，以及 这些改变与脑干呼吸和上呼吸道运动功能相关。 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 脊髓损伤患者的患病率是美国普通人群的 15 倍。 因此，接触这种刺激措施可以提高 CPAP 的依从性并增强结果措施，如概述 此外，每天反复接触间歇性缺氧可促进呼吸和功能的恢复。 因此，每天重复接触 IH 可能会对动物和人类的运动肢体功能产生显着影响。 对伴有脊髓损伤的个体呼吸和肢体运动功能的治疗效果 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， 和清醒时的运动肢体功能。

项目成果

Longer Bouts of Intermittent Hypoxia Coupled with Increased Levels of Sustained Hypercapnia Lead to Increases in the Magnitude of Ventilatory Long-Term Facilitation in African Americans Compared to Caucasians.

与白人相比，较长时间的间歇性缺氧加上持续性高碳酸血症水平的增加，导致非洲裔美国人的通气长期便利程度增加。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Kissane,Dylan;Panza,Gino;Puri,Shipra;Lin,Ho-Sheng;Mateika,Jason
• 通讯作者: Mateika,Jason

15-Days of Therapeutic Mild Intermittent Hypoxia Improves Cardiovascular, Upper Airway and Motor Limb Function in Participants with Motor Incomplete Spinal Cord Injury and Severe Obstructive Sleep Apnea.

15 天的轻度间歇性缺氧治疗可改善运动不完全性脊髓损伤和严重阻塞性睡眠呼吸暂停参与者的心血管、上呼吸道和运动肢功能。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Panza,Gino;Kissine,Dylan;Puri,Shipra;Lin,Ho-Sheng;Matieka,Jason
• 通讯作者: Matieka,Jason

The Magnitude of Long-Term Facilitation is Influenced by Modifications to Mild Intermittent Hypoxia Protocols in Participants with OSA.

长期促进的程度受到 OSA 参与者轻度间歇性缺氧方案修改的影响。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Panza,Gino;Kissine,Dylan;Puri,Shipra;Lin,Ho-Sheng;Matieka,Jason
• 通讯作者: Matieka,Jason

Repeated Exposure to Mild Intermittent Hypoxia Mitigates the Severity of OSA, Reduces Blood Pressure and Improves Microvascular Function and Walking Endurance in Adults with OSA for 4 - 8 Weeks Post Therapy.

治疗后 4 - 8 周内，反复暴露于轻度间歇性缺氧可减轻 OSA 的严重程度、降低血压并改善患有 OSA 的成人的微血管功能和步行耐力。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Puri,Shipra;Kissane,Dylan;Panza,Gino;Lin,Ho-Sheng;Mateika,JasonH
• 通讯作者: Mateika,JasonH

Loop gain is Increased and the Arousal Threshold is Decreased in Caucasian Compared to African American Males with Obstructive Sleep Apnea.

与患有阻塞性睡眠呼吸暂停的非洲裔美国男性相比，白种人的循环增益增加，觉醒阈值降低。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Puri,Shipra;Kissane,Dylan;Panza,Gino;Lin,Ho-Sheng;Mateika,JasonH
• 通讯作者: Mateika,JasonH