BACKGROUND With current recommendation for phenobarbitone dosing, we have noted that babies are extremely sedated with elevated serum phenobarbitone levels. We postulate that asphyxiated neonates with hypoxic liver injury have impaired drug metabolism and renal injury affects drug elimination, thus elevating serum drug levels. Therapeutic hypothermia (TH) could further affect the drug levels. OBJECTIVE To determine the serum levels of the phenobarbitone in babies receiving different loading doses of phenobarbitone for neonatal seizures and to study the effect of asphyxia and TH on drug levels. DESIGN Prospective observational cohort study. MATERIAL AND METHODS Term neonates with seizures of any cause were given phenobarbitone up to a maximum loading of 40 mg/kg followed by maintenance dose of 5 mg/kg/day. Serum phenobarbitone levels were assessed after 4 h of the initial loading dose and subsequently at 24, 48 and 72 h from the time after maximum loading dose. Babies were divided into three groups Group 1 (HIE + TH-hypoxic ischemic encephalopathy undergoing TH), Group 2 (HIE - TH-hypoxic ischemic encephalopathy without TH) and Group 3 (non-HIE group). RESULTS A total of 47 babies completed the study. Twenty-three (49%) received 20 mg/kg, 14 (30%) received 30 mg/kg and 10 (21%) received 40 mg per kg of phenobarbitone as loading dose. HIE was the major cause of seizures 28 (59%) followed by hypoglycemia 7 (14%), cerebral malformations 4 (8%), inborn errors of metabolism 2 (4%) and hypocalcemia 1 (2%) while the cause of seizures was not known in 6 (13%). Median (IQR) Phenobarbitone levels at 72 h in babies who received 20 mg/kg loading dose of phenobarbitone was 46.72 (44.02-50.49) mcg/ml in HIE + TH group, 40.53 (28.66-65.09) mcg/ml in HIE - TH group and 49 (37-65) mcg/ml in non-HIE group. After a loading dose of 30 mg/kg, phenobarbitone level was 63.76 (59.5-65.94) mcg/ml in HIE + TH group, 42.5 (34.75-48.75) mcg/ml in HIE - TH group and 42.07 (40-49.05) mcg/ml in non-HIE group. After 40 mg/kg loading dose, it was 62.3 (60.2-64.9) mcg/ml in HIE + TH group, 57.0 (49.8-60.2) mcg/ml in HIE - TH group and 48.15 (40.8-50.97) mcg/ml in non-HIE group. In babies who received >20 mg/kg loading dose, 100% of HIE + TH, 80% of HIE - TH and 60% of non-HIE had supratherapeutic levels of phenobarbitone. CONCLUSION At higher loading doses of 30 and 40 mg/kg, steady state concentration of serum phenobarbitone is higher in babies with hypoxic ischemic encephalopathy who underwent TH than in babies with non-HIE causes of seizures. Loading dose beyond 20 mg/kg should be used with close monitoring of serum drug level.

中文翻译：

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比较不同负荷剂量的苯巴比妥对新生儿惊厥婴儿血清苯巴比妥水平的影响以及低温治疗对苯巴比妥水平的影响。

背景 根据目前对苯巴比妥剂量的推荐，我们注意到婴儿因血清苯巴比妥水平升高而极度镇静。我们推测伴有缺氧性肝损伤的窒息新生儿药物代谢受损，肾损伤影响药物清除，从而升高血清药物水平。治疗性低温 (TH) 可能会进一步影响药物水平。目的测定接受不同负荷剂量苯巴比妥治疗新生儿惊厥婴儿的血清苯巴比妥水平，并研究窒息和TH对药物水平的影响。设计前瞻性观察队列研究。材料和方法 对任何原因引起癫痫发作的足月新生儿给予最大负荷为 40 mg/kg 的苯巴比妥，然后维持剂量为 5 mg/kg/天。在初始负荷剂量 4 小时后以及随后在最大负荷剂量后 24、48 和 72 小时评估血清苯巴比妥水平。婴儿分为三组：第 1 组（HIE + TH-接受 TH 的缺氧缺血性脑病）、第 2 组（HIE - TH-无 TH 的缺氧缺血性脑病）和第 3 组（非 HIE 组）。结果 共有 47 名婴儿完成了研究。23 例 (49%) 接受 20 mg/kg，14 例 (30%) 接受 30 mg/kg，10 例 (21%) 接受 40 mg/kg 苯巴比妥作为负荷剂量。HIE 是癫痫发作的主要原因 28 例 (59%)，其次是低血糖 7 例 (14%)、脑畸形 4 例 (8%)、先天性代谢错误 2 例 (4%) 和低钙血症 1 例 (2%)，而癫痫发作的原因在 6 个 (13%) 中不为人所知。接受 20 mg/kg 负荷剂量苯巴比妥的婴儿在 72 小时时的中位 (IQR) 苯巴比妥水平在 HIE + TH 组中为 46.72 (44.02-50.49) mcg/ml，在 HIE - TH 中为 40.53 (28.66-65.09) mcg/ml组和非 HIE 组中的 49 (37-65) mcg/ml。在 30 mg/kg 的负荷剂量后，HIE + TH 组的苯巴比妥水平为 63.76 (59.5-65.94) mcg/ml，HIE - TH 组为 42.5 (34.75-48.75) mcg/ml 和 42.07 (40-49.05) mcg /ml 在非 HIE 组中。40mg/kg负荷剂量后，HIE+TH组为62.3（60.2-64.9）mcg/ml，HIE-TH组为57.0（49.8-60.2）mcg/ml，HIE-TH组为48.15（40.8-50.97）mcg/ml非 HIE 组。在接受 >20 mg/kg 负荷剂量的婴儿中，100% 的 HIE + TH、80% 的 HIE - TH 和 60% 的非 HIE 具有超治疗水平的苯巴比妥。结论 在 30 和 40 mg/kg 的较高负荷剂量下，接受 TH 治疗的缺氧缺血性脑病婴儿的血清苯巴比妥稳态浓度高于非 HIE 癫痫发作婴儿。负荷剂量超过 20 mg/kg 时应密切监测血清药物水平。