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An oxygen-rich atmosphere or systemic fluoxetine extend the time to respiratory arrest in a rat model of obstructive apnea.
Neurobiology of Disease ( IF 6.1 ) Pub Date : 2019-11-20 , DOI: 10.1016/j.nbd.2019.104682
S Mooney 1 , R Kollmar 2 , R Gurevich 1 , J Tromblee 1 , A Banerjee 1 , K Sundaram 3 , J B Silverman 4 , M Stewart 5
Affiliation  

Audiogenic seizure-prone mice can be protected from seizure-associated death by exposure to an oxygen atmosphere or treatment with selective serotonergic reuptake inhibitors (SSRIs). We have shown previously in a rat model that epileptic seizure activity can spread through brainstem areas to cause sufficient laryngospasm for obstructive apnea and that the period of seizure-associated obstructive apnea can last long enough for respiratory arrest to occur. We hypothesized that both the oxygen-rich atmosphere and SSRIs function by prolonging the time to respiratory arrest, thus ensuring that seizure activity stops before the point of respiratory arrest to allow recovery of respiratory function. To test this hypothesis, we evaluated each preventative treatment in a rat model of controlled airway occlusion where the times to respiratory arrest can be measured. Adult male Sprague Dawley rats (median age = 66 days) were studied in the absence of any seizure activity. By directly studying responses to controlled airway occlusion, rather than airway occlusion secondary to seizure activity, we could isolate the effects of manipulations that might prolong respiratory arrest from the effects of those manipulations on seizure intensity. All group sizes were ≥ 8 animals per group. We found that both oxygen exposure and fluoxetine significantly increased the time to respiratory arrest by up to 65% (p < .0001 for 5 min oxygen exposure; p = .031 for 25 mg/kg fluoxetine tested 60 min after injection) and, given that neither treatment has been shown to significantly alter seizure duration, these increases can account for the protection of either manipulation against death in sudden death models. Importantly, we found that 30 s of exposure to oxygen produced nearly the same protection as 5 min exposure suggesting that oxygen exposure could start after a seizure starts (p = .0012 for 30 s oxygen exposure). Experiments with 50% oxygen/50% air mixtures indicate that the oxygen concentration needs to be above about 60% to ensure that times to respiratory arrest will always be longer than a period of seizure-induced airway occlusion. Selective serotonin reuptake inhibitors, while instructive with regard to mechanism, require impractical dosing and may carry additional risk in the form of greater challenges for resuscitation. We conclude that oxygen exposure or SSRI treatment prevent seizure associated death by sufficiently prolonging the time to respiratory arrest so that respiratory function can recover after the seizure abates and eliminates the stimulus for seizure-induced apnea.

中文翻译:

在阻塞性呼吸暂停的大鼠模型中,富氧气氛或全身性氟西汀会延长呼吸停止的时间。

可以通过暴露在氧气气氛中或使用选择性血清素能再摄取抑制剂(SSRIs)来保护易发源性癫痫发作的小鼠免受癫痫发作相关的死亡。先前我们在大鼠模型中显示,癫痫性癫痫发作活动可通过脑干区域传播,引起阻塞性呼吸暂停引起足够的喉痉挛,而与癫痫发作相关的阻塞性呼吸暂停可持续足够长的时间,以引起呼吸停止。我们假设,富氧气氛和SSRIs都可以通过延长呼吸停止时间来起作用,从而确保在呼吸停止点之前停止癫痫发作活动,以恢复呼吸功能。为了检验这个假设,我们在可控制气道阻塞的大鼠模型中评估了每种预防性治疗的方法,在该模型中可以测量呼吸停止的时间。在没有任何癫痫发作活动的情况下研究成年雄性Sprague Dawley大鼠(中位年龄= 66天)。通过直接研究对气道闭塞的反应,而不是继发于癫痫发作的气道闭塞,我们可以将可能延长呼吸暂停的操作的效果与这些对癫痫发作强度的效果进行隔离。每组所有大小均≥8只动物。我们发现,氧气暴露和氟西汀都显着增加了呼吸暂停时间,最多可延长65%(5分钟氧气暴露p <.0001; 25 mg / kg氟西汀注射后60分钟测试p = .031),并且 鉴于尚未显示出两种治疗均能显着改变癫痫发作持续时间,因此这些增加可解释为在猝死模型中针对死亡采取任何一种保护措施。重要的是,我们发现30 s的氧气暴露与5 min的暴露几乎具有相同的保护作用,这表明在癫痫发作开始后可以开始氧气暴露(30 s的氧气暴露p = .0012)。用50%氧气/ 50%空气混合物进行的实验表明,氧气浓度需要高于约60%,以确保呼吸停止的时间始终长于癫痫发作引起的气道阻塞的时间。选择性5-羟色胺再摄取抑制剂虽然对机制具有指导意义,但需要不切实际的剂量,并且可能以更大的复苏挑战形式带来额外的风险。
更新日期:2019-11-20
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