Lee T C, Charles B G, Harte G J, Gray P H, Steer P A, Flenady V J
School of Pharmacy, The University of Queensland, St. Lucia, Australia.
Anesthesiology. 1999 Feb;90(2):451-7. doi: 10.1097/00000542-199902000-00020.
Midazolam is used widely as a sedative to facilitate mechanical ventilation. This prospective study investigated the population pharmacokinetics of midazolam in very premature infants.
Midazolam (100 microg/kg) was administered as a rapid intravenous bolus dose every 4-6 h to 60 very premature neonates with a mean (range) gestational age of 27 weeks (24-31 weeks), a birth weight of 965 g (523-1,470 g), and an age of 4.5 days (2-15 days). A median (range) of four (one to four) blood samples, 0.2 ml each, were drawn at random times after the first dose or during continuous treatment, and concentrations of midazolam in serum were assayed by high-performance liquid chromatography. A population analysis was conducted using a two-compartment pharmacokinetic model using the NONMEM program.
Average parameter values (interpatient percent coefficient of variation) for infants with birth weights 1,000 g or less were total systemic clearance (Cl(T)) = 0.783 ml/min (83%), intercompartmental clearance (Cl(Q)) = 6.53 ml/min (116%), volume of distribution of the central compartment (V1) = 473 ml (70%), and volume of distribution of the peripheral compartment (V2) = 513 ml (146%). For infants with birth weights more than 1,000 g they were as follows: Cl(T) = 1.24 ml/min (78%), Cl(Q) = 9.82 ml/min (98%), V1 = 823 ml (43%), and V2 = 1,040 ml (193%). The intrapatient variability (percent coefficient of variation) in the data was 4.5% at the mean concentration midazolam in serum of 121 ng/mL.
Serum concentration-time data were used in modeling the population pharmacokinetics of midazolam in very premature, ventilated neonates. Clearance of midazolam was markedly decreased compared with previous data from term infants and older patients. Infants weighing less than 1,000 g at birth had significantly lower clearance than those weighing more than 1,000 g.
咪达唑仑作为一种镇静剂被广泛用于辅助机械通气。这项前瞻性研究调查了咪达唑仑在极早产儿中的群体药代动力学。
对60例极早产儿每4 - 6小时静脉快速推注一剂咪达唑仑（100μg/kg），这些极早产儿的平均（范围）胎龄为27周（24 - 31周），出生体重为965g（523 - 1470g），年龄为4.5天（2 - 15天）。在首剂给药后或持续治疗期间的随机时间抽取中位数为4次（1 - 4次）、每次0.2ml的血样，采用高效液相色谱法测定血清中咪达唑仑的浓度。使用NONMEM程序，采用二室药代动力学模型进行群体分析。
出生体重1000g及以下婴儿的平均参数值（患者间变异系数百分比）为：总全身清除率（Cl(T)）= 0.783ml/min（83%），隔室间清除率（Cl(Q)）= 6.53ml/min（116%），中央室分布容积（V1）= 473ml（70%），外周室分布容积（V2）= 513ml（146%）。出生体重超过1000g的婴儿参数值如下：Cl(T)= 1.24ml/min（78%），Cl(Q)= 9.82ml/min（98%），V1 = 823ml（43%），V2 = 1040ml（193%）。血清中咪达唑仑平均浓度为121ng/mL时，数据中的患者内变异（变异系数百分比）为4.5%。
血清浓度 - 时间数据用于建立咪达唑仑在极早产、机械通气新生儿中的群体药代动力学模型。与足月儿和年长患者的既往数据相比，咪达唑仑的清除率明显降低。出生体重小于1000g的婴儿清除率显著低于出生体重大于1000g的婴儿。
