右美托咪定在婴幼⼉原位肝移植术后的药代动⼒学研究
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Pharmacokinetics of Dexmedetomidine in Infants and Children After Orthotopic Liver Transplantation
背景与目的
右美托咪定是⼀种镇静和镇痛药物，在⼉童肝移植术后经常使⽤。肝移植术后⽴即发⽣肝功能不全，包括药物清除的改变，都是很常⻅的。 然⽽，该群体中右美托咪定的药代动⼒学是未知的。 本研究旨在确定⼉童肝移植后应⽤右美托咪定的药代动⼒学特征。
方 法
这是⼀项单中⼼、开放式的药代动⼒学研究，将右美托咪定以0.5μg/ kg的负荷剂量静脉注射，然后以0.5μg/ kg / h的剂量持续输注。纳⼊20名肝移植后⼊住⼉科重症监护病房的患⼉，年龄为1个⽉⾄18岁。 收集全⾎并使⽤⼲⾎斑法分析右美托咪定的浓度。采⽤⾮线性混合效应建模⽅法来描述右美托咪定的药代动⼒学特征。
结 果
右美托咪定药代动⼒学最好⽤具有⼀级消除动⼒学的双室模型来描述。 典型的肝移植后⼉童，国际标准化⽐率（INR）为1.8，发现全⾎右美托咪定清除率为52 L /h（95％置信区间[CI]，31-73 L / h）。 此外，室间隙清除率为246 L / h（95％CI，139-391 L / h），中⼼分布容积为186 L / 70 kg（95％CI，140-301 L / 70kg），外周分布容积为203L（95％CI，123-338L）。 所有参数的个体间变异范围为11％⾄111％。未发现清除与体重有关，但发现与INR成反⽐。 INR增加⾄3.2导致右美托咪定清除率降低50％。体重与中⼼容积呈线性相关。 所有其他相关变量，包括年龄、缺⾎时间、总胆红素和丙氨酸氨基转移酶，并未发现是右美托咪定处置的重要预测因⼦。
结 论
肝移植后接受右美托咪定的⼉童在清除过程中有很⼤的差异，未发现与体重有关，但受INR反映的潜在肝功能影响。 在该群体中，右美托咪定给药⾄临床效果的滴定可能是重要的，因为基于体重的剂量与⾎液浓度的相关性很差。 当INR值发⽣变化时，可能需要更加关注右美托咪定镇静的质量。
原始文献摘要
Damian MA, Hammer GB, Elkomy MH, Frymoyer A, Drover DR, Su F.Pharmacokinetics of Dexmedetomidine in Infants and Children After OrthotopicLiver Transplantation. Anesth Analg. 2018 Sep 5.doi:10.1213/ANE.0000000000003761
BACKGROUND:
Dexmedetomidine (DEX) is a sedative and analgesic medication that is frequently used postoperatively in childrenafter liver transplantation. Hepatic dysfunction, including alterations in drug clearance, is common immediately after liver transplantation. However, the pharmacokinetics (PK) of DEX in this population is unknown. The objective of this study was to determine the PK profile of DEX in children after liver transplantation.
METHODS:
This was a single-center, open-label PK study of DEX administered as an intravenous loading dose of 0.5 μg/kg followed by a continuous infusion of 0.5 μg/kg/h. Twenty subjects,1 month to 18 years of age, who were admitted to the pediatric intensive care unit after liver transplantation were enrolled. Whole blood was collected and analyzed for DEX concentration using a dried blood spot method. Nonlinear mixed-effects modeling was used to characterize the population PK of DEX.
RESULTS:
DEX PK was best described by a 2-compartment model with first-order elimination. A typical child after liver transplantation with an international normalized ratio (INR) of 1.8 was found to have a whole blood DEX clearance of 52 L/h (95% confidence interval [CI], 31-73 L/h). In addition, intercompartmental clearance was 246 L/h (95% CI, 139-391 L/h),central volume of distribution was 186 L/70 kg (95% CI, 140-301 L/70 kg), and peripheral volume of distribution was 203 L (95% CI, 123-338 L). Interindividual variability ranged from11% to 111% for all parameters. Clearance was not found to be associated with weight but was found to be inversely proportional to INR. An increase in INR to 3.2 resulted in a 50% decrease in DEX clearance. Weight was linearly correlated with central volume of distribution. All other covariates, including age, ischemic time, total bilirubin, and alanine aminotransferase, were not found to be significant predictors of DEX disposition.
CONCLUSIONS:
Children who received DEX after liver transplantationhave large variability in clearance,which was not found to be associated with weight but is influenced by underlying liver function, as reflected by INR. In this population, titration of DEX dosing to clinical effect may be important because weight-based dosing is poorly associated with blood concentrations. More attention to quality of DEX sedation may be warranted when INR values are changing.
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