Zomorodi K, Donner A, Somma J, Barr J, Sladen R, Ramsay J, Geller E, Shafer S L
Department of Anesthesia, Stanford University, California, USA.
Anesthesiology. 1998 Dec;89(6):1418-29. doi: 10.1097/00000542-199812000-00020.
Midazolam is commonly used for short-term postoperative sedation of patients undergoing cardiac surgery. The purpose of this multicenter study was to characterize the pharmacokinetics and intersubject variability of midazolam in patients undergoing coronary artery bypass grafting.
With institutional review board approval, 90 consenting patients undergoing coronary artery bypass grafting were enrolled at three study centers. All subjects received sufentanil and midazolam via target-controlled infusions. After operation, midazolam was titrated to maintain deep sedation for at least 2 h. It was then titrated downward to decrease sedation for a minimum of 4 h more and was discontinued before tracheal extubation. Arterial blood samples were taken throughout the study and were assayed for midazolam and 1-hydroxymidazolam. Midazolam population pharmacokinetic parameters were estimated using NONMEM. Cross-validation was used to estimate the performance of the model.
The pharmacokinetics of midazolam were best described by a simple three-compartment mammillary model. Typical pharmacokinetic parameters were V1 = 32.2 l, V2 = 53 l, V3 = 245 l, Cl1 = 0.43 l/min, Cl2 = 0.56 l/min, and Cl3 = 0.39 l/min. The calculated elimination half-life was 15 h. The median absolute prediction error was 25%, with a bias of 1.4%. The performance in the cross-validation was similar. Midazolam metabolites were clinically insignificant in all patients.
The intersubject variability and predictability of the three-compartment pharmacokinetic model are similar to those of other intravenous anesthetic drugs. This multicenter study did not confirm previous studies of exceptionally large variability of midazolam pharmacokinetics when used for sedation in intensive care settings.
咪达唑仑常用于心脏手术患者的短期术后镇静。这项多中心研究的目的是描述冠状动脉旁路移植术患者中咪达唑仑的药代动力学及个体间变异性。
经机构审查委员会批准，三个研究中心招募了90例接受冠状动脉旁路移植术且同意参与研究的患者。所有受试者通过靶控输注接受舒芬太尼和咪达唑仑。术后，滴定咪达唑仑以维持深度镇静至少2小时。然后向下滴定以减少镇静至少4小时，并在气管插管前停药。在整个研究过程中采集动脉血样，检测其中咪达唑仑和1-羟基咪达唑仑的含量。使用NONMEM估算咪达唑仑群体药代动力学参数。采用交叉验证评估模型性能。
咪达唑仑的药代动力学最佳用简单的三室乳突模型描述。典型的药代动力学参数为V1 = 32.2升，V2 = 53升，V3 = 245升，Cl1 = 0.43升/分钟，Cl2 = 0.56升/分钟，Cl3 = 0.39升/分钟。计算得出的消除半衰期为15小时。中位绝对预测误差为25%，偏差为1.4%。交叉验证中的性能相似。咪达唑仑代谢产物在所有患者中临床意义不大。
三室药代动力学模型的个体间变异性和可预测性与其他静脉麻醉药物相似。这项多中心研究未证实先前关于咪达唑仑用于重症监护镇静时药代动力学存在异常大的变异性的研究结果。
