Maresh Scott, Prowting Joel, Vaughan Sarah, Kruppe Elizabeth, Alsabri Bander, Yarandi Hossein, Badr M Safwan, Sankari Abdulghani
Sleep Research Laboratory, John D. Dingell Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan.
Ascension Providence Hospital, Southfield, Michigan.
J Appl Physiol (1985). 2020 Oct 1;129(4):675-682. doi: 10.1152/japplphysiol.00435.2020. Epub 2020 Aug 20.
Spinal cord injury (SCI) is a risk factor for central sleep apnea (CSA). Previous studies in animal models with SCI have demonstrated a promising recovery in respiratory and phrenic nerve activity post-injury induced by the systemic and local administration of serotonin receptor agonists such as Buspirone and Trazodone. Human trials must be performed to determine whether individuals with SCI respond similarly. We hypothesized that Buspirone and Trazodone would decrease the propensity to hypocapnic CSA during sleep. We studied eight males with chronic SCI and sleep-disordered breathing (SDB) [age: 48.8 ± 14.2 yr; apnea-hypopnea index (AHI): 44.9 ± 23.1] in a single-blind crossover design. For 13 days, participants were randomly assigned either Buspirone (7.5-15 mg twice daily), Trazodone (100 mg), or a placebo followed by a 14-day washout period before crossing over to the other interventions. Study nights included polysomnography and induction of CSA using a noninvasive ventilation protocol. We assessed indexes of SDB, CO reserve, apneic threshold (AT), controller gain (CG), plant gain (PG), and ventilatory parameters. CO reserve was significantly widened on Buspirone (-3.6 ± 0.9 mmHg) compared with both Trazodone (-2.5 ± 1.0 mmHg, = 0.009) and placebo (-1.8 ± 1.5 mmHg, < 0.001) but not on Trazodone vs. placebo ( = 0.061). CG was significantly decreased on Buspirone compared with placebo (1.8 ± 0.4 vs. 4.0 ± 2.0 L/(mmHg·min), = 0.025) but not on Trazodone compared with placebo (2.5 ± 1.1 vs. 4.0 ± 2.0 L/(mmHg·min); = 0.065). There were no significant differences for PG, AT, or any SDB indexes (AHI, obstructive apnea index, central apnea index, oxygen desaturation index). The administration of Buspirone decreased the susceptibility to induced hypocapnic central apnea by reducing chemosensitivity and increasing CO reserve in chronic SCI patients. This research study is novel as it is the first study in a humans that we are aware of that demonstrates the ability of Buspirone to increase CO reserve and hence decrease susceptibility to hypocapnic central apnea in patients with spinal cord injury.
脊髓损伤（SCI）是中枢性睡眠呼吸暂停（CSA）的一个风险因素。先前在脊髓损伤动物模型中的研究表明，通过全身或局部给予5-羟色胺受体激动剂（如丁螺环酮和曲唑酮），损伤后呼吸和膈神经活动有望恢复。必须进行人体试验以确定脊髓损伤个体是否有类似反应。我们假设丁螺环酮和曲唑酮会降低睡眠期间低碳酸血症性CSA倾向。我们采用单盲交叉设计对8名患有慢性脊髓损伤和睡眠呼吸障碍（SDB）[年龄：48.8±14.2岁；呼吸暂停低通气指数（AHI）：44.9±23.1]的男性进行了研究。在13天内，参与者被随机分配服用丁螺环酮（每日两次，7.5 - 15毫克）、曲唑酮（100毫克）或安慰剂，随后有14天的洗脱期，之后再交叉接受其他干预措施。研究夜晚包括多导睡眠监测以及使用无创通气方案诱发CSA。我们评估了睡眠呼吸障碍、二氧化碳储备、呼吸暂停阈值（AT）、控制器增益（CG）、肺实质增益（PG）和通气参数的指标。与曲唑酮（-2.5±1.0毫米汞柱，P = 0.009）和安慰剂（-1.8±1.5毫米汞柱，P < 0.001）相比，丁螺环酮组的二氧化碳储备显著增加（-3.6±0.9毫米汞柱），但曲唑酮组与安慰剂组之间无显著差异（P = 0.061）。与安慰剂相比，丁螺环酮组的控制器增益显著降低（1.8±0.4对4.0±2.0升/（毫米汞柱·分钟），P = 0.025），但曲唑酮组与安慰剂组相比无显著差异（2.5±1.1对4.0±2.0升/（毫米汞柱·分钟）；P = 0.065）。在肺实质增益、呼吸暂停阈值或任何睡眠呼吸障碍指标（AHI、阻塞性呼吸暂停指数、中枢性呼吸暂停指数、氧饱和度下降指数）方面无显著差异。在慢性脊髓损伤患者中，丁螺环酮通过降低化学敏感性和增加二氧化碳储备，降低了诱发低碳酸血症性中枢性呼吸暂停的易感性。这项研究具有创新性，因为据我们所知，这是第一项在人体中证明丁螺环酮能够增加二氧化碳储备从而降低脊髓损伤患者低碳酸血症性中枢性呼吸暂停易感性的研究。
