Chen C, Yamaguchi N, Varin F
Faculté de pharmacie, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, QC, Canada H3C 3J7.
Br J Anaesth. 2008 Dec;101(6):788-97. doi: 10.1093/bja/aen308. Epub 2008 Oct 28.
Pharmacokinetic/pharmacodynamic (PK/PD) parameters of neuromuscular blocking agents (NMBAs) are generally assumed to be dose-independent. To our knowledge, there are very few clinical reports where the PK/PD parameters of a NMBA were derived separately for each dose group during a formal dose-ranging study. The primary objective of this study was to challenge a potential dose-dependency of cisatracurium PK/PD parameters by conducting a well-controlled experimental study.
Eight dogs were anaesthetized with pentobarbital and mechanically ventilated. Two doses of cisatracurium (1.5xED(95) and 6xED(95)) were administered in a randomized cross-over design after an appropriate washout period. Neuromuscular function was monitored using train-of-four (TOF) stimulation. Arterial blood was sampled continuously for the first minute after cisatracurium injection and at frequent intervals thereafter. Cisatracurium plasma concentrations were determined by high performance liquid chromatography analysis. PK/PD modelling of individual data sets was performed with NONMEM using a non-parametric approach and a descriptive sigmoid E(max) model.
Cisatracurium PKs were linear over the dose range studied. Using non-parametric PK/PD analysis, mean values for plasma-effect compartment equilibration delay (k(e0)) were 0.0600 vs 0.1278 min(-1) (P<0.05) and sensitivity (EC(50)) were 323 vs 235 ng ml(-1) (P<0.05) for the high and low doses, respectively.
A dose-dependent effect on the PK/PD parameters of cisatracurium has important clinical implications as an accurate estimate of the EC(50) is desirable. PK/PD parameters derived after intubating bolus doses of cisatracurium would be more reliable.
一般认为神经肌肉阻滞剂（NMBA）的药代动力学/药效学（PK/PD）参数与剂量无关。据我们所知，在正式的剂量范围研究中，很少有临床报告分别针对每个剂量组得出NMBA的PK/PD参数。本研究的主要目的是通过开展一项严格对照的实验研究，验证顺式阿曲库铵PK/PD参数是否存在潜在的剂量依赖性。
八只犬用戊巴比妥麻醉并进行机械通气。在适当的洗脱期后，采用随机交叉设计给予两剂顺式阿曲库铵（1.5倍95%有效剂量（ED(95)）和6倍ED(水平分隔符)95））。使用四个成串刺激（TOF）监测神经肌肉功能。在注射顺式阿曲库铵后的第一分钟持续采集动脉血样，此后定期采样。通过高效液相色谱分析测定顺式阿曲库铵的血浆浓度。使用非参数方法和描述性S型E(max)模型，通过NONMEM对各个数据集进行PK/PD建模。
在所研究的剂量范围内，顺式阿曲库铵的药代动力学呈线性。采用非参数PK/PD分析，高剂量和低剂量的血浆-效应室平衡延迟（k(e0)）平均值分别为0.0600和0.1278分钟(-1)（P<0.05），敏感性（EC(50)）分别为323和235纳克/毫升（P<0.05）。
顺式阿曲库铵的PK/PD参数存在剂量依赖性效应具有重要的临床意义，因为准确估计EC(50)是很有必要的。插管推注剂量的顺式阿曲库铵后得出的PK/PD参数会更可靠。
