Pathogenesis of Sleep Disordered Breathing in Spinal Cord Injury Patients

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研究目的：脊髓损伤(SCI)与睡眠呼吸障碍(SDB)的发病率显著增加有关。超过60%的颈椎脊髓损伤患者在损伤后6个月出现SDB。然而，脊髓损伤患者发生SDB的潜在机制尚不清楚。最近的数据显示，颈髓损伤易导致呼吸运动输出的改变，提示呼吸不稳定在脊髓损伤患者SDB的发生发展中起重要作用。中心假设是颈椎脊髓损伤患者睡眠呼吸暂停的高发生率是由于中枢呼吸不稳定所致，这种呼吸不稳定是5-羟色胺依赖的，也是新治疗的靶点。B.研究计划：为此，研究建议旨在如下：具体目标(1)：确定SDB在颈椎和胸部脊髓损伤中的作用机制。假设(1a)：颈性脊髓损伤患者比胸部脊髓损伤患者更容易发生低碳酸性中枢性呼吸暂停。假设(1b)：颈髓损伤患者对低碳酸血症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的增加。具体目的(2)：检验与健全个体相比，脊髓损伤将增强长期促进作用(LTF)的假设。假设：与匹配的有能力的人相比，脊髓损伤患者的LTF更高。我们将测量LTF对睡眠中间歇性低氧的反应。具体目的(3)：探讨全身5-羟色胺受体激动剂对脊髓损伤患者睡眠时呼吸机能活动的刺激作用。假设(3a)：丁螺环酮(5-HT1a激动剂)可增加脊髓损伤患者的二氧化碳储备。假设(3b)：曲唑酮(5-HT2C激动剂)扩大了脊髓损伤患者的二氧化碳储备。具体目的(4)：在动物模型中确定导致呼吸不稳定的脊髓损伤的程度和程度。假设(4a)：脊髓损伤后的中枢性呼吸不稳定是由于大鼠颈部损伤造成的。假设(4b)：颈脊髓损伤后切除双侧颈动脉小体可改善大鼠睡眠期间的中枢呼吸不稳定。方法：研究对象为T6及以上脊髓损伤患者，均未接受人工呼吸机治疗。为了表征每个受试者的睡眠和呼吸状态，将在基线时测量多导睡眠图和上呼吸道塌陷程度。然后进行以下实验：首先，通过诱导低碳酸血症的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，将使用间歇性低氧方案与正常氧方案(SHAM)来确定通气性可塑性的存在(长期易化，血清素依赖的过程)。第三，为了确定5-羟色胺A1受体激动剂对脊髓损伤患者发生中枢性呼吸暂停的易感性的影响，将使用FDA批准的两种药物(1)丁螺环酮与安慰剂对照2周和(2)曲唑酮与安慰剂对照2周，然后是2周的洗脱期和交叉对照进行随机安慰剂对照试验。第四，为了评估颈椎脊髓损伤对呼吸和睡眠的影响，我们将用颈椎(C2)半横断的方法建立成年大鼠脊髓损伤模型，并与假手术进行比较。然后进行双侧颈总动脉切除术，以评估外周化疗敏感性在不稳定呼吸发生中的相对作用。D.与退伍军人的临床相关性：据估计，仅在美国就有1275,000人患有脊髓损伤，估计至少有100,000名退伍军人患有脊髓损伤，使退伍军人管理局成为世界上最大的脊髓损伤综合保健系统。SDB与脊髓损伤密切相关，影响生活质量，并可能增加呼吸系统和心血管疾病的发生率。对脊髓损伤患者SDB机制的识别将为进一步研究SCI患者SDB的新疗法，特别是在普通人群中的SDB奠定坚实的科学框架。

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.