Pathogenesis of Sleep Disordered Breathing in Spinal Cord Injury Patients

脊髓损伤患者睡眠呼吸障碍的发病机制

• 批准号: 8666539
• 负责人: Abdulghani Sankari
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666539
• 关键词: Acute; Address; Adult; Affect; Agonist; Animal Model; Animals; Area; Arousal; Award; Bilateral; Breathing; Buspirone; Carbon Dioxide; Cardiovascular Diseases; Cardiovascular system; Carotid Body; Central Sleep Apnea; Cervical; Cervical spinal cord injury; Chest; Chronic; Cross-Over Studies; Data; Development; Device Designs; Disabled Persons; Doctor of Philosophy; Environmental air flow; Excision; FDA approved; Future; General Population; Genetic Crossing Over; Heart Diseases; High Prevalence; Human; Hyperventilation; Hypoxia; Impaired cognition; Impairment; Incidence; Individual; Injury; Integrated Health Care Systems; Investigation; Lead; Life; Link; Measures; Mechanics; Methods; Mission; Modeling; Motor Activity; Motor output; Muscle Weakness; Obstruction; Pathogenesis; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Polysomnography; Predisposition; Prevalence; Procedures; Process; Protocols documentation; Quality of life; Randomized; Rattus; Relative (related person); Reporting; Research; Research Proposals; Respiration Disorders; Respiratory Muscles; Role; Serotonin; Serotonin Agonists; Sleep; Sleep Apnea Syndromes; Societies; Spinal; Spinal cord injury; Spinal cord injury patients; Stroke; Study Subject; Synapses; Testing; Therapeutic Intervention; Thoracic Injuries; Thoracic spinal cord structure; Training; Trazodone; United States; Veterans; Work; adverse outcome; base; clinically relevant; improved; innovation; lung volume; novel; programs; public health relevance; receptor; research study; respiratory; response; serotonin receptor

DESCRIPTION (provided by applicant): Pathogenesis of Sleep Disordered Breathing in Spinal Cord Injury Patients PI: AG Sankri-Tarbichi, MD, PhD ABSTRACT A. Objective: Spinal cord injury (SCI) is associated with significant increase in the sleep- disordered breathing (SDB) prevalence. More than 60% of cervical SCI patients suffer from SDB at six months post-injury. However the underlying mechanisms responsible for the development of SDB in SCI patients are not known. Recent data showed that cervical SCI predispose to alterations in ventilatory motor output suggesting important role for breathing instability in the development of SDB in SCI patients. The central hypothesis is that the high prevalence of sleep apnea in cervical SCI patients is due to central breathing instability that is serotonin dependent and a target for new treatments. B. Research Plan: To this end the research proposal is aimed as the followings: Specific Aim (1): To determine the mechanism of SDB in cervical vs. thoracic SCI. Hypothesis (1a): Cervical SCI patients are more susceptible to hypocapnic central apnea than thoracic SCI patients. Hypothesis (1b): Increased susceptibility to hypocapnic central apnea in cervical SCI is due to increased peripheral chemoreflex sensitivity. Specific Aim (2): To test the hypothesis that SCI will have enhanced long-term facilitation (LTF) compared to able-bodied individuals. Hypothesis: LTF is higher in SCI patients compared to matched able individuals. We will measure the LTF in response to intermittent hypoxia during sleep. Specific Aim (3): To determine the stimulatory effect of systemic serotonin receptors agonists on ventilatory motor activity in SCI patients during sleep. Hypothesis (3a): Buspirone (5-HT1A agonist) widens the CO2 reserve in SCI patients. Hypothesis (3b): Trazodone (5-HT2C agonist) widens the CO2 reserve in SCI patients. Specific Aim (4): To determine in an animal model the extent and level of SCI responsible for breathing instability. Hypothesis (4a): central breathing instability post SCI is due to cervical injury in a rat model. Hypothesis (4b): bilateral carotid body excision aftr cervical SCI improves central breathing instability during sleep in rats. C. Methods: We will study subjects with SCI at T6 or above who are not on artificial ventilation. To characterize the sleep and breathing state of each subject, polysomnography and upper airway collapsibility will be measured at baseline. Then the following experiments will be conducted: First, the susceptibility to develop central apnea will be determined by inducing hypocapnic central apnea to measure the apneic threshold. Second, an episodic hypoxia protocol vs. normoxia (sham) will be used to determine the presence of ventilatory plasticity (long-term facilitation, a serotoin dependent process). Third, to determine the effect of serotonin A1 receptor agonists on the susceptibility to develop central apnea in SCI, randomized placebo controlled cross-over study will be conducted using two FDA approved drugs (1) Buspiron vs. placebo for 2 weeks and (2) Trazodone vs. placebo for 2 weeks, followed by 2 weeks wash out period and crossed-over. Fourth, to assess the effect of cervical SCI on breathing and sleep, SCI will be induced in adults' rats by cervical (C2) hemisection and compared to sham procedure. Then bilateral carotids excisions will be performed to assess the relative contribution of peripheral chemosensitivity on the development of unstable breathing. D. Clinical Relevance to the Veterans: It is estimated that 1,275,000 people in the United States alone are living with SCI with an estimated at least 100,000 veterans with SCI making VA the largest integrated health care system in the world for SCI. SDB is strongly linked to SCI and affects the quality of life an may increase incidence of respiratory and cardiovascular disorders. The identification of the mechanism of SDB in SCI patients will establish a strong scientific frame work for further investigations using novel therapies for SDB in SCI patients in particular and potentially in the general population.

描述（由申请人提供）： 脊髓损伤患者的睡眠呼吸发病机理PI：AG Sankri-Tarbichi，MD，PhD摘要A摘要A。目的：脊髓损伤（SCI）与睡眠无序呼吸（SDB）患病率显着增加有关。伤害后六个月后，超过60％的宫颈SCI患者患有SDB。但是，尚不清楚导致SCI患者SDB发展的基本机制。最近的数据表明，宫颈SCI倾向于改变通气运动输出的改变，这表明SCI患者在SDB发展中呼吸不稳定的重要作用。中心假设是宫颈SCI患者的睡眠呼吸暂停的高患病率是由于中枢呼吸不稳定是5-羟色胺依赖性的，并且是新治疗的靶标。 B.研究计划：为此，研究建议的目的是以下内容：特定目的（1）：确定颈椎与胸腔科学中SDB的机制。 假设（1A）：宫颈SCI患者比胸科SCI患者更容易受到低碳酸腹膜呼吸呼吸症的影响。 假设（1B）：宫颈SCI中低碳中心呼吸暂停的敏感性增加是由于外周化学反射敏感性提高所致。 具体目的（2）：检验以下假设：与健全的个体相比，SCI将增强长期促进（LTF）。假设：SCI患者的LTF比匹配的个体高。我们将在睡眠过程中响应间歇性缺氧而响应LTF。 具体目的（3）：确定睡眠期间SCI患者的全身性羟色胺受体激动剂对通气运动活动的刺激作用。假设（3A）：胰蛋白酶（5-HT1A激动剂）在SCI患者中扩大了CO2储备。假设（3B）：曲唑酮（5-HT2C激动剂）在SCI患者中扩大了CO2储备。 特定目的（4）：在动物模型中确定造成呼吸不稳定的SCI的程度和水平。假设（4A）：SCI后中央呼吸不稳定是由于大鼠模型中的宫颈损伤。假设（4B）：双侧颈动脉切除AFTR宫颈SCI可改善大鼠睡眠期间的中央呼吸不稳定。 C.方法：我们将研究未进行人工通气的T6或更高的SCI受试者。 为了表征每个受试者的睡眠和呼吸状态，将在基线时测量多肌仪和上呼吸道可折叠性。然后将进行以下实验：首先，开发中央呼吸暂停的敏感性将通过诱导低含量中央呼吸暂停来测量呼吸暂停阈值来确定。其次，将使用情节性缺氧方案与常氧（假）（假）来确定通气可塑性的存在（长期促进，依赖于5-血清素的过程）。第三，为了确定5-羟色胺A1受体激动剂对在SCI中开发中央呼吸暂停的敏感性的影响，将使用两种FDA认可的药物（1）Buspiron vs.安慰剂与安慰剂2周，（2）曲替酮与安慰剂2周一起进行2周，随后2周，将使用两种FDA批准的药物进行随机安慰剂控制的跨界研究，然后进行2周的洗涤。第四，为了评估宫颈SCI对呼吸和睡眠的影响，SCI将通过宫颈（C2）半分裂诱导成人大鼠，并与假手术相比。然后将进行双侧颈动脉切除术，以评估外周化学敏感性对不稳定呼吸发展的相对贡献。 D.与退伍军人的临床相关性：据估计，仅美国的1,275,000人就有SCI的生活，估计至少有100,000名退伍军人具有SCI，使VA成为世界上最大的SCI综合医疗保健系统。 SDB与SCI密切相关，并影响生活质量可能会增加呼吸道和心血管疾病的发病率。 SCI患者中SDB机制的鉴定将建立强大的科学框架工作，以进一步研究SCI患者的SDB新疗法，尤其是在一般人群中。