Phenobarbital and midazolam suppress neonatal seizures in a noninvasive rat model of birth asphyxia, whereas bumetanide is ineffective
Phenobarbital and midazolam suppress neonatal seizures in a noninvasive rat model of birth asphyxia, whereas bumetanide is ineffective
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DOI：
10.1111/epi.16778
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发表时间：
2020-12-01
期刊：
影响因子：
5.6
通讯作者：
Loescher, Wolfgang
中科院分区：
文献类型：
--
作者：
Johne, Marie;Roemermann, Kerstin;Loescher, Wolfgang
目的：新生儿癫痫发作是新生儿最常见的神经系统急症，通常是长期围产期窒息的结果。苯巴比妥是目前治疗新生儿癫痫发作最广泛使用的抗癫痫药物，但在50%的病例中未能阻止癫痫发作。在基于11日龄（P11）大鼠的新生儿缺氧模型中，据报道NKCC 1抑制剂布美他尼可增强苯巴比妥的抗癫痫活性，而在新生儿人体试验中无效。本研究的目的是评估临床相关剂量的布美他尼作为苯巴比妥的添加剂对P11大鼠出生窒息的非侵入性模型中新生儿癫痫发作的影响，旨在更好地翻译为人类足月新生儿。通过将大鼠幼崽暴露于恒定20%CO2下9%和5%O-2的三个7 + 3分钟循环，诱导间歇性窒息30分钟。药物治疗前或后立即给药intraperitoneal窒息。结果：所有未经处理的大鼠幼崽有癫痫发作后10分钟内终止窒息。在窒息前以30 mg/kg而非15 mg/kg剂量给药时，苯巴比妥可显著阻断癫痫发作。窒息后给予苯巴比妥无效，而咪达唑仑（0.3或1 mg/kg）在窒息前或窒息后给药时具有显著的抗癫痫作用。一般而言，局灶性癫痫发作比全身性惊厥性癫痫发作对治疗更耐药。布美他尼（0.3 mg/kg）单独或与苯巴比妥（15或30 mg/kg）组合对癫痫发作发生率无显著影响：数据表明布美他尼不会增加苯巴比妥在出生窒息模型中的疗效，这与最近人体试验的负面数据一致。用新生儿窒息的新大鼠模型获得的翻译数据表明，它是评估新生儿癫痫发作的新治疗方法的有用工具。
Objective: Neonatal seizures are the most frequent type of neurological emergency in newborn infants, often being a consequence of prolonged perinatal asphyxia. Phenobarbital is currently the most widely used antiseizure drug for treatment of neonatal seizures, but fails to stop them in similar to 50% of cases. In a neonatal hypoxia-only model based on 11-day-old (P11) rats, the NKCC1 inhibitor bumetanide was reported to potentiate the antiseizure activity of phenobarbital, whereas it was ineffective in a human trial in neonates. The aim of this study was to evaluate the effect of clinically relevant doses of bumetanide as add-on to phenobarbital on neonatal seizures in a noninvasive model of birth asphyxia in P11 rats, designed for better translation to the human term neonate.Methods: Intermittent asphyxia was induced for 30 minutes by exposing the rat pups to three 7 + 3-minute cycles of 9% and 5% O-2 at constant 20% CO2. Drug treatments were administered intraperitoneally either before or immediately after asphyxia.Results: All untreated rat pups had seizures within 10 minutes after termination of asphyxia. Phenobarbital significantly blocked seizures when applied before asphyxia at 30 mg/kg but not 15 mg/kg. Administration of phenobarbital after asphyxia was ineffective, whereas midazolam (0.3 or 1 mg/kg) exerted significant antiseizure effects when administered before or after asphyxia. In general, focal seizures were more resistant to treatment than generalized convulsive seizures. Bumetanide (0.3 mg/kg) alone or in combination with phenobarbital (15 or 30 mg/kg) exerted no significant effect on seizure occurrence.Significance: The data demonstrate that bumetanide does not increase the efficacy of phenobarbital in a model of birth asphyxia, which is consistent with the negative data of the recent human trial. The translational data obtained with the novel rat model of birth asphyxia indicate that it is a useful tool to evaluate novel treatments for neonatal seizures.