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）： 脊髓损伤患者睡眠呼吸障碍的发病机制PI：AG Sankri-Tarbichi，MD，PhD摘要A。目的：脊髓损伤（Spinal cord injury，SCI）与睡眠呼吸障碍（sleep disordered breathing，SDB）的患病率显著增加有关.超过60%的颈脊髓损伤患者在伤后6个月时发生SDB。然而，SCI患者发生SDB的潜在机制尚不清楚。最近的数据表明，颈椎脊髓损伤易发生呼吸运动输出的改变，这表明呼吸不稳定在脊髓损伤患者SDB的发展中起着重要作用。中心假设是，颈部SCI患者睡眠呼吸暂停的高患病率是由于中枢呼吸不稳定造成的，这种不稳定是血清素依赖性的，并且是新治疗的目标。 B。研究计划：具体目的（1）：明确颈、胸段脊髓损伤后SDB的发生机制。 假设（1a）：颈脊髓损伤患者比胸脊髓损伤患者更易发生低碳酸血症性中枢性呼吸暂停。 假设（1b）：颈脊髓损伤患者对低碳酸血症性中枢性呼吸暂停的易感性增加是由于外周化学反射敏感性增加。 具体目标（2）：检验SCI与健全个体相比具有增强的长时程易化（LTF）的假设。假设：SCI患者的LTF高于匹配的个体。我们将测量LTF对睡眠期间间歇性缺氧的反应。 具体目标（三）：确定全身性5-羟色胺受体激动剂对SCI患者睡眠期间的运动活动的刺激作用。假设（3a）：丁螺环酮（5-HT 1A激动剂）扩大了SCI患者的CO2储备。假设（3b）：曲唑酮（5-HT 2C激动剂）扩大了SCI患者的CO2储备。 具体目标（4）：在动物模型中确定导致呼吸不稳定的SCI的程度和水平。假设（4a）：脊髓损伤后中枢性呼吸不稳定是由于大鼠模型中的颈部损伤所致。假设（4 b）：颈脊髓损伤后双侧颈动脉体切除改善了大鼠睡眠时的中枢呼吸不稳定性。 C.方法：我们将研究T6或以上未接受人工通气的SCI受试者。 为了表征每例受试者的睡眠和呼吸状态，将在基线时测量多导睡眠图和上气道通气性。然后进行以下实验：首先，通过诱导低碳酸血症性中枢性呼吸暂停来测量呼吸暂停阈值，以确定发生中枢性呼吸暂停的易感性。其次，将使用间歇性缺氧方案与常氧（假手术）来确定是否存在诱导可塑性（长期易化，一种血清妥英依赖性过程）。第三，为了确定5-羟色胺A1受体激动剂对SCI中发生中枢性呼吸暂停的易感性的影响，将使用两种FDA批准的药物进行随机安慰剂对照交叉研究（1）Buspiron对比安慰剂2周和（2）曲唑酮对比安慰剂2周，随后是2周洗脱期和交叉。第四，为了评估颈部SCI对呼吸和睡眠的影响，将通过颈部（C2）半切在成年大鼠中诱导SCI并与假手术进行比较。然后将进行双侧颈动脉切除术，以评估外周化疗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，仅在美国就有1，275，000人患有SCI，估计至少有100，000名退伍军人患有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，影响生活质量，可能增加呼吸系统和心血管疾病的发病率。SCI患者SDB机制的确定将建立一个强有力的科学框架，用于进一步研究SCI患者SDB的新疗法，特别是在一般人群中。