Department of Anesthesiology and Intensive Care, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
Clinic of Paediatrics, Tallinn Children's Hospital, Tallinn, Estonia.
Pediatr Crit Care Med. 2019 Jul;20(7):621-629. doi: 10.1097/PCC.0000000000001879.
The postoperative course of patent ductus arteriosus ligation is often complicated by postligation cardiac syndrome, occurring in 10-45% of operated infants. Milrinone might prevent profound hemodynamic instability and improve the recovery of cardiac function in this setting. The present study aimed to describe the population pharmacokinetics of milrinone in premature neonates at risk of postligation cardiac syndrome and give dosing recommendations.
A prospective single group open-label pharmacokinetics study.
Two tertiary care neonatal ICUs: Tallinn Children's Hospital and Tartu University Hospital, Estonia.
Ten neonates with postmenstrual age of 24.6-30.1 weeks and postnatal age of 5-27 days undergoing patent ductus arteriosus ligation and at risk of postligation cardiac syndrome, based on echocardiographic assessment of left ventricular output of less than 200 mL/kg/min 1 hour after the surgery.
Milrinone at a dose of 0.73 μg/kg/min for 3 hours followed by 0.16 μg/kg/min for 21 hours. Four blood samples from each patient for milrinone plasma concentration measurements were collected.
Concentration-time data of milrinone were analyzed with nonlinear mixed-effects modeling software (NONMEM Version 7.3 [ICON Development Solutions, Ellicott City, MD]). Probability of target attainment simulations gave a dosing schedule that maximally attains concentration targets of 150-250 μg/L. Milrinone pharmacokinetics was described by a one-compartmental linear model with allometric scaling to bodyweight and an age maturation function of glomerular filtration rate. Parameter estimates for a patient with the median weight were 0.350 (L/hr) for clearance and 0.329 (L) for volume of distribution. The best probability of target attainment was achieved with a loading dose of 0.50 μg/kg/min for 3 hours followed by 0.15 μg/kg/min (postmenstrual age < 27 wk) or 0.20 μg/kg/min (postmenstrual age ≥ 27 wk).
Population pharmacokinetic modeling and simulations suggest a slow loading dose followed by maintenance infusion to reach therapeutic milrinone plasma concentrations within the timeframe of the postligation cardiac syndrome.
动脉导管未闭结扎术后的病程常伴有结扎后心脏综合征，发生率为 10%-45%。米力农可预防严重的血液动力学不稳定，并改善这种情况下的心脏功能恢复。本研究旨在描述有结扎后心脏综合征风险的早产儿中米力农的群体药代动力学，并给出剂量建议。
一项前瞻性、单组、开放标签的药代动力学研究。
爱沙尼亚塔林儿童医院和塔尔图大学医院的两个三级新生儿重症监护病房。
24.6-30.1 周胎龄和 5-27 天日龄的 10 名新生儿，根据心脏超声左心室输出量评估，术后 1 小时小于 200ml/kg/min，有结扎后心脏综合征风险。
米力农 0.73μg/kg/min 剂量 3 小时，然后 0.16μg/kg/min 剂量 21 小时。对每位患者采集 4 份血样，用于米力农血药浓度测定。
米力农的浓度-时间数据采用非线性混合效应模型软件（NONMEM 版本 7.3 [ICON 发展解决方案，马里兰州埃利科特市]）进行分析。基于目标浓度的概率达到模拟给出了一个剂量方案，该方案最大限度地达到 150-250μg/L 的目标浓度。米力农的药代动力学采用一室线性模型描述，采用体质量的比例缩放和肾小球滤过率的年龄成熟函数。中位体重患者的参数估计值为 0.350（L/hr）的清除率和 0.329（L）的分布容积。负荷剂量为 0.50μg/kg/min 3 小时，随后维持剂量为 0.15μg/kg/min（胎龄＜27 周）或 0.20μg/kg/min（胎龄≥27 周）时，达到目标的概率最大。
群体药代动力学模型和模拟表明，缓慢的负荷剂量后，维持输注，可在结扎后心脏综合征的时间框架内达到治疗性米力农的血药浓度。
