From the Department of Pediatrics, Pediatric Critical Care Medicine.
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California.
Anesth Analg. 2020 Jan;130(1):209-216. doi: 10.1213/ANE.0000000000003761.
Dexmedetomidine (DEX) is a sedative and analgesic medication that is frequently used postoperatively in children after 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.
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.
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 from 11% 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.
Children who received DEX after liver transplantation have 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.
右美托咪定（DEX）是一种镇静和镇痛药物，常用于儿童肝移植后的术后。肝移植后，肝功能障碍包括药物清除率的改变很常见。然而，DEX 在该人群中的药代动力学（PK）尚不清楚。本研究的目的是确定 DEX 在肝移植后的儿童中的 PK 特征。
这是一项单中心、开放标签的 DEX 药代动力学研究，静脉推注负荷剂量 0.5μg/kg，随后以 0.5μg/kg/h 的速度持续输注。20 名年龄在 1 个月至 18 岁之间的儿童，在肝移植后被收入儿科重症监护病房。使用干血斑法采集全血并分析 DEX 浓度。使用非线性混合效应模型对 DEX 的群体 PK 进行描述。
DEX PK 最好用具有一级消除的两室模型来描述。发现国际标准化比值（INR）为 1.8 的典型肝移植后儿童，DEX 的全血清除率为 52 L/h（95%置信区间 [CI]，31-73 L/h）。此外，隔室间清除率为 246 L/h（95%CI，139-391 L/h），中央分布容积为 186 L/70 kg（95%CI，140-301 L/70 kg），外周分布容积为 203 L（95%CI，123-338 L）。所有参数的个体间变异性范围为 11%-111%。清除率与体重无关，但与 INR 呈反比。INR 增加到 3.2 时，DEX 清除率降低 50%。体重与中央分布容积呈线性相关。其他所有协变量，包括年龄、缺血时间、总胆红素和丙氨酸氨基转移酶，均未被发现是 DEX 处置的显著预测因子。
接受 DEX 治疗的肝移植后儿童清除率的个体间差异较大，与体重无关，但受潜在肝功能的影响，反映在 INR 上。在该人群中，DEX 剂量滴定至临床效果可能很重要，因为基于体重的剂量与血药浓度相关性较差。当 INR 值发生变化时，可能需要更加注意 DEX 镇静的质量。
