Hallik Maarja, Tasa Tõnis, Starkopf Joel, Metsvaht Tuuli
Department of Anaesthesiology and Intensive Care, University of Tartu, Tartu, Estonia.
Neonatology. 2017;111(1):8-11. doi: 10.1159/000447049. Epub 2016 Aug 5.
Milrinone has been suggested as a possible first-line therapy for preterm neonates to prevent postligation cardiac syndrome (PLCS) through decreasing systemic vascular resistance and increasing cardiac contractility. The optimal dosing regimen, however, is not known.
To model the dosing of milrinone in preterm infants for prevention of PLCS after surgical closure of patent ductus arteriosus (PDA).
Milrinone time-concentration profiles were simulated for 1,000 subjects using the volume of distribution and clearance estimates based on one compartmental population pharmacokinetic model by Paradisis et al. [Arch Dis Child Fetal Neonatal Ed 2007;92:F204-F209]. Dose optimization was based on retrospectively collected demographic data from neonates undergoing PDA ligation in Estonian PICUs between 2012 and 2014 and existing pharmacodynamic data. The target plasma concentration was set at 150-200 ng/ml.
The simulation study used demographic data from 31 neonates who underwent PDA ligation. The median postnatal age was 13 days (range: 3-29) and weight was 760 g (range: 500-2,351). With continuous infusion of milrinone 0.33 μg/kg/min, the proportion of subjects within the desired concentration range was 0% by 3 h, 36% by 6 h, and 61% by 8 h; 99% of subjects exceeded the range by 18 h. The maximum proportion of total simulated concentrations in the target range was attained with a bolus infusion of 0.73 μg/kg/min for 3 h followed by a 0.16-μg/kg/min maintenance infusion.
Mathematical simulations suggest that in preterm neonates the plasma time-concentration profile of milrinone can be optimized with a slow loading dose followed by maintenance infusion.
米力农被认为可能是治疗早产儿的一线药物，通过降低体循环血管阻力和增强心肌收缩力来预防结扎后心脏综合征（PLCS）。然而，最佳给药方案尚不清楚。
模拟米力农在早产儿中预防动脉导管未闭（PDA）手术闭合后PLCS的给药情况。
采用Paradisis等人[《儿童疾病档案：胎儿和新生儿版》2007年；92：F204 - F209]基于单室群体药代动力学模型的分布容积和清除率估计值，对1000名受试者的米力农时间 - 浓度曲线进行模拟。剂量优化基于2012年至2014年爱沙尼亚重症监护病房（PICU）中接受PDA结扎的新生儿的回顾性收集的人口统计学数据以及现有的药效学数据。目标血浆浓度设定为150 - 200 ng/ml。
模拟研究使用了31名接受PDA结扎的新生儿的人口统计学数据。出生后中位年龄为13天（范围：3 - 29天），体重为760 g（范围：500 - 2351 g）。持续输注米力农0.33 μg/kg/min时，在期望浓度范围内的受试者比例在3小时时为0%，6小时时为36%，8小时时为61%；99%的受试者在18小时时超过该范围。通过先以0.73 μg/kg/min的负荷剂量输注3小时，然后以0.16 μg/kg/min的维持剂量输注，可使模拟总浓度在目标范围内的比例达到最大值。
数学模拟表明，在早产儿中，米力农的血浆时间 - 浓度曲线可通过缓慢负荷剂量后维持输注来优化。
