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）启动胸壁和上呼吸道肌肉的持续增加 人类的活动。这种持续增长是一种称为长期设施的呼吸可塑性形式 （LTF）。每天反复暴露于温和的IH，导致上呼吸道肌肉活动的LTF主动性 可能导致上呼吸道的稳定性提高。符合我的实验室发展的任务 用于治疗睡眠呼吸暂停的创新疗法，这种提高的稳定性最终可以减少连续的 治疗阻塞性睡眠呼吸暂停（OSA）并提高合规性所需的正气道压力（CPAP） 使用这种黄金标准处理。提高的合规性最终可能有助于减轻这些共同的合规性 与睡眠呼吸暂停有关的病态。此外，除了改善CPAP合规性众多研究 表明温和的IH具有许多直接有益的心血管，神经认知和代谢作用。那， 温和的IH可以用作治疗睡眠呼吸暂停的多重治疗方法。按照这个 假设，我们的提案的目标1将确定是否每天重复暴露于轻度IH作为辅助 治疗与CPAP结合以减轻相关的合并症，直接影响各种 心血管，代谢和神经认知措施，并通过提高CPAP依从性间接。 自主神经（即交感神经系统活动）和心血管的修改（即血压） 功能将是与代谢的次级措施相连的主要结果度量 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。这个反应是 由于脊髓损伤诱导的结果加重并耦合到阻塞性呼吸暂停事件 呼吸道神经元的球囊突触输入的形态和神经系统障碍，以及 脑干呼吸道和上呼吸道运动功能的适应。这些修改与 睡眠呼吸呼吸的发生率（即中央和阻塞性睡眠呼吸暂停）大约 脊髓损伤患者的15倍，是美国普通人群的15倍。 这是这种刺激的暴露可以提高CPAP的合规性和增强的结果指标 多于。此外，每天反复暴露于间歇性缺氧会促进呼吸的恢复和 动物和人类的运动四肢功能。那，每天反复接触IH可能会有很大的意义 脊髓损伤患者对呼吸和肢体运动功能的治疗作用完成 通过睡眠呼吸暂停。这是我们的建议2将有助于确定IH是否可以减轻合并症 与睡眠呼吸暂停有关，并在清醒和睡眠期间促进呼吸运动功能的恢复， 在清醒期间的运动四肢功能。

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