Schnider T W, Gaeta R, Brose W, Minto C F, Gregg K M, Shafer S L
Department of Anesthesia, Stanford University School of Medicine, California, USA.
Anesthesiology. 1996 May;84(5):1043-50. doi: 10.1097/00000542-199605000-00005.
Lidocaine administered intravenously is efficacious in treating neuropathic pain at doses that do not cause sedation or other side effects. Using a computer-controlled infusion pump (CCIP), it is possible to maintain the plasma lidocaine concentration to allow drug equilibration between the plasma and the site of the drug effect. Pharmacokinetic parameters were derived for CCIP administration of lidocaine in patients with chronic pain.
Thirteen patients (mean age 45 yr, mean weight 66 kg) were studied. Eight subjects received a computer-controlled infusion, targeting four increasing lidocaine concentrations (1-7 micrograms.ml-1) for 30 min each, based on published kinetic parameters in which venous samples were obtained infrequently after bolus administration. From the observations in these eight patients, new lidocaine pharmacokinetic parameters were estimated. These were prospectively tested in five additional patients. From the complete data set (13 patients), final structural parameters were estimated using a pooled analysis approach. The interindividual variability was determined with a mixed-effects model, with the structural model parameters fixed at the values obtained from the pooled analysis. Internal cross-validation was used to estimate the residual error in the final pharmacokinetic model.
The lidocaine administration based on the published parameters consistently produced higher concentrations than desired, resulting in acute lidocaine toxicity in most of the first eight patients. The highest measured plasma concentration was 15.3 micrograms.ml-1. The pharmacokinetic parameters estimated from these eight patients differed from the initial estimates and included a central volume one-sixth of the initial estimate. In the subsequent prospective test in five subjects, the new parameters resulted in concentrations evenly distributed around the target concentration. None of the second group of subjects had evidence of acute lidocaine toxicity. The final parameters ( +/- population variability expressed as %CV) were estimated as follows: V1 0.101 +/- 53% 1.kg-1, V2 0.452 +/- 33% 1.kg-1, Cl1 0.0215 +/- 25% 1.kg-1.min-1, and Cl2 0.0589 +/- 35% 1.kg-1.min-1. The median error measured by internal cross-validation was +1.9%, and the median absolute error was 14%.
Pharmacokinetic parameters for lidocaine were derived and administration was prospectively tested via computer-controlled infusion pumps for patients with chronic neuropathic pain. The estimated parameters performed well when tested prospectively. A second estimation step further refined the parameters and improved performance, as measured using internal cross-validation.
静脉注射利多卡因在不引起镇静或其他副作用的剂量下对治疗神经性疼痛有效。使用计算机控制输注泵（CCIP），可以维持血浆利多卡因浓度，使药物在血浆和药物作用部位之间达到平衡。已得出慢性疼痛患者CCIP给药利多卡因的药代动力学参数。
研究了13名患者（平均年龄45岁，平均体重66千克）。8名受试者接受计算机控制输注，根据已发表的动力学参数，针对四个逐渐升高的利多卡因浓度（1 - 7微克/毫升）各输注30分钟，在静脉推注给药后很少采集静脉样本。根据这8名患者的观察结果，估算了新的利多卡因药代动力学参数。这些参数在前瞻性研究中对另外5名患者进行了测试。根据完整数据集（13名患者），采用合并分析方法估算最终结构参数。使用混合效应模型确定个体间变异性，结构模型参数固定为合并分析得出的值。采用内部交叉验证估算最终药代动力学模型中的残余误差。
根据已发表参数给药的利多卡因始终产生高于预期的浓度，导致前8名患者中的大多数出现急性利多卡因毒性。测得的最高血浆浓度为15.3微克/毫升。从这8名患者估算的药代动力学参数与初始估算值不同，包括中央室容积为初始估算值的六分之一。在随后对5名受试者的前瞻性测试中，新参数使浓度均匀分布在目标浓度周围。第二组受试者均无急性利多卡因毒性迹象。最终参数（以%CV表示的±总体变异性）估算如下：V1 0.101±53% 升/千克，V2 0.452±33% 升/千克，Cl1 0.0215±25% 升/千克·分钟-1，Cl2 0.0589±35% 升/千克·分钟-1。通过内部交叉验证测得的中位误差为 +1.9%，中位绝对误差为14%。
得出了利多卡因的药代动力学参数，并通过计算机控制输注泵对慢性神经性疼痛患者进行了前瞻性给药测试。前瞻性测试时，估算参数表现良好。如采用内部交叉验证测量，第二步估算进一步优化了参数并改善了性能。
