Reiter P D, Stiles A D
Department of Pediatric Pharmacy, School of Medicine, University of North Carolina, Chapel Hill 27514.
Ann Pharmacother. 1993 Jun;27(6):727-9. doi: 10.1177/106002809302700611.
To report a case of lorazepam toxicity in a premature infant and discuss the importance of altered pharmacodynamics and pharmacokinetics in the neonatal population.
A 2025-g, 33-weeks' gestation infant was born with respiratory distress syndrome that required mechanical ventilation. Lorazepam was used to establish sedation and prevent asynchronous breathing while the infant was on the ventilator. Shortly after the first dose of lorazepam, the infant experienced a seizure and was subsequently given a loading dose of phenobarbital. Lorazepam therapy was continued for sedation. The patient was transferred to our tertiary care center on day 2 of life for evaluation of possible cardiac disease. Upon arrival, the infant was extremely hypotonic and unresponsive; therefore, all sedative medications were discontinued. Two days after admission, the infant continued to exhibit very little spontaneous activity and a lorazepam serum concentration was obtained (63 h after the last dose). Analysis revealed a toxic lorazepam serum concentration of 4453 nmol/L. The patient eventually was weaned to room air and was transported back to the referring hospital.
Lorazepam is commonly prescribed in the pediatric population for sedative, anticonvulsant, anxiolytic, antiemetic, and amnestic activity. Few data exist regarding the safety of long-term lorazepam therapy in the neonatal subpopulation. There have been some reports of neurologic toxicity secondary to lorazepam in preterm infants. Its metabolism depends on glucuronidation, an enzymatic process that is very depressed in the premature infant. Accumulation of the drug in the neonate accompanied by clinical toxicity is highly likely.
The inability to establish a clear pharmacokinetic-pharmacodynamic relationship, along with the increased incidence of reported adverse events of lorazepam in neonates, is concerning. Clinicians should be aware of the altered metabolism and elimination of lorazepam in the premature infant.
报告一例早产儿劳拉西泮中毒病例，并探讨新生儿群体中药物动力学和药效学改变的重要性。
一名孕33周、体重2025克的婴儿出生时患有呼吸窘迫综合征，需要机械通气。在婴儿使用呼吸机期间，使用劳拉西泮来建立镇静并防止呼吸不同步。首次给予劳拉西泮后不久，婴儿发生惊厥，随后给予苯巴比妥负荷剂量。继续使用劳拉西泮进行镇静治疗。患儿在出生后第2天被转至我们的三级医疗中心，以评估可能的心脏疾病。到达时，婴儿极度肌张力低下且无反应；因此，停用了所有镇静药物。入院两天后，婴儿仍表现出极少的自发活动，并检测了劳拉西泮血清浓度（最后一剂后63小时）。分析显示劳拉西泮血清浓度为4453 nmol/L，呈中毒水平。患儿最终脱机并被转运回转诊医院。
劳拉西泮常用于儿科人群，具有镇静、抗惊厥、抗焦虑、止吐和遗忘作用。关于新生儿亚群中长期劳拉西泮治疗安全性的数据很少。有一些关于早产儿因劳拉西泮继发神经毒性的报道。其代谢依赖于葡萄糖醛酸化，这一酶促过程在早产儿中非常低下。药物在新生儿体内蓄积并伴有临床毒性的可能性很高。
无法建立明确的药代动力学-药效学关系，以及新生儿中报道的劳拉西泮不良事件发生率增加，令人担忧。临床医生应意识到早产儿中劳拉西泮代谢和消除的改变。
