Fiset P, Mathers L, Engstrom R, Fitzgerald D, Brand S C, Hsu F, Shafer S L
Department of Anaesthesia, McGill University, Montréal, Canada.
Anesthesiology. 1995 Nov;83(5):944-55. doi: 10.1097/00000542-199511000-00006.
Cardiopulmonary bypass (CPB) induces changes in the pharmacokinetics of drugs. The purpose of this study was to model the pharmacokinetics of alfentanil in children undergoing cardiac surgery to provide accurate dosage titration intraoperatively as well as in the postoperative period.
Fourteen children (aged 3 months to 8 yr) undergoing cardiac surgery with CPB were administered alfentanil via a computer-controlled infusion pump. During surgery, the computer-controlled infusion pump was set to target plasma alfentanil concentrations of 500-2500 micrograms/ml. After surgery, the computer-controlled infusion pump was set to target plasma concentrations of 200-500 micrograms/ml. Parameters for children previously published by Goresky et al. were programmed into the device. Arterial blood samples were taken throughout the infusion. Plasma samples were assayed by radioimmunoassay. Alfentanil pharmacokinetics were estimated using a pooled-data approach with a simple weight-proportional, three-compartment mamillary model with parameters expressed in volumes and clearances as well as a CPB-adjusted, three-compartment model in which the parameters were allowed to change before, during, and after CPB. The accuracy of the three models was compared using cross-validation.
Plasma alfentanil concentrations during computer-controlled infusion pump administration exceeded target concentrations for the first 10 min of drug administration, and from 300 min to the end of the study. The median absolute performance error was 33%. Pharmacokinetic modeling estimated a set of parameters for a simple three-compartment model with a median absolute weighted residual of 18.4%. A CPB-adjusted model nominally decreased the median absolute weighted residual to 17.0%. The performance of these models as measured by cross-validation performance was 18.9% median absolute performance error for the simple model and 18.4% median absolute performance error for the CPB-adjusted model. Parameters for the simple three-compartment model are: V1 = 19.2 ml.kg-1; V2 = 99 ml.kg-1; V3 = 2344 ml.kg-1; Cl1 = 2.5 ml.kg-1.min-1; Cl2 = 38 ml.kg-1.min-1; and Cl3 = 15 ml.kg-1.min-1. In the CPB-adjusted model V1, V2, and Cl2 changed with the onset of CPB. After CPB, V1 and Cl2 returned to the initial values, while V2 was described by a third value.
The population pharmacokinetics of alfentanil in children undergoing cardiac surgery were well described by both a simple weight-proportional, three-compartment model and a weight-proportional, CPB-adjusted three-compartment model. Cross-validation estimated an expected median inaccuracy of approximately 18-20% with the estimated models in identical experimental circumstances. The flexible CPB-adjusted pharmacokinetic model could be used for modeling any drug with linear pharmacokinetics given in the context of CPB.
体外循环（CPB）会引起药物药代动力学的变化。本研究的目的是建立接受心脏手术儿童中阿芬太尼的药代动力学模型，以便在术中及术后提供准确的剂量滴定。
14名接受CPB心脏手术的儿童（年龄3个月至8岁）通过计算机控制输注泵给予阿芬太尼。手术期间，计算机控制输注泵设定为使血浆阿芬太尼浓度目标为500 - 2500微克/毫升。术后，计算机控制输注泵设定为使血浆浓度目标为200 - 500微克/毫升。将Goresky等人先前发表的儿童参数编入该设备。在整个输注过程中采集动脉血样本。血浆样本通过放射免疫测定法进行检测。阿芬太尼药代动力学采用汇总数据方法，使用简单的重量比例三室乳突模型进行估计，其参数以体积和清除率表示，以及一个CPB调整的三室模型，其中参数在CPB之前、期间和之后允许变化。使用交叉验证比较这三种模型的准确性。
在计算机控制输注泵给药期间，血浆阿芬太尼浓度在给药的前10分钟以及从300分钟至研究结束时超过目标浓度。中位绝对性能误差为33%。药代动力学建模估计了一个简单三室模型的一组参数，中位绝对加权残差为18.4%。一个CPB调整模型名义上使中位绝对加权残差降至17.0%。通过交叉验证性能测量，这些模型的性能对于简单模型为中位绝对性能误差18.9%，对于CPB调整模型为中位绝对性能误差18.4%。简单三室模型的参数为：V1 = 19.2毫升·千克⁻¹；V2 = 99毫升·千克⁻¹；V3 = 2344毫升·千克⁻¹；Cl1 = 2.5毫升·千克⁻¹·分钟⁻¹；Cl2 = 38毫升·千克⁻¹·分钟⁻¹；Cl3 = 15毫升·千克⁻¹·分钟⁻¹。在CPB调整模型中，V1、V2和Cl2随CPB的开始而变化。CPB后，V1和Cl2恢复到初始值，而V2由第三个值描述。
简单重量比例三室模型和重量比例CPB调整三室模型均能很好地描述接受心脏手术儿童中阿芬太尼的群体药代动力学。交叉验证估计在相同实验情况下，估计模型的预期中位不准确性约为18 - 20%。灵活的CPB调整药代动力学模型可用于对CPB背景下具有线性药代动力学的任何药物进行建模。
