Flint Robert B, Brouwer Carole N M, Kränzlin Anne S C, Lie-A-Huen Loraine, Bos Albert P, Mathôt Ron A A
Department of Hospital Pharmacy, Academic Medical Center, Amsterdam, The Netherlands.
Pediatric Intensive Care, Academic Medical Center, Amsterdam, The Netherlands.
Paediatr Anaesth. 2017 Nov;27(11):1098-1107. doi: 10.1111/pan.13239.
S-ketamine is the S(+)-enantiomer of the racemic mixture ketamine, an anesthetic drug providing both sedation and analgesia. In clinical practice, significant interpatient variability in drug effect of S-ketamine is observed during long-term sedation.
The aim of this study was to evaluate the pharmacokinetic variability of S-ketamine in children aged 0-18 years during long-term sedation. Twenty-five children (median age: 0.42 years, range: 0.02-12.5) received continuous intravenous administrations of 0.3-3.6 mg/kg/h S-ketamine for sedation during mechanical ventilation. Infusion rates were adjusted to the desired level of sedation and analgesia based on the COMFORT-B score and Visual Analog Scale. Blood samples were drawn once daily at random time-points, and at 1 and 4 hours after discontinuation of S-ketamine infusion. Time profiles of plasma concentrations of S-ketamine and active metabolite S-norketamine were analyzed using nonlinear mixed-effects modeling software. Clearance and volume of distribution were allometrically scaled using the ¾ power model.
A total of 86 blood samples were collected. A 2-compartment and 1-compartment model adequately described the PK of S-ketamine and S-norketamine, respectively. The typical parameter estimates for clearance and central and peripheral volumes of distribution were: CL =112 L/h/70 kg, V1 =7.7 L/70 kg, V2 =545L/70 kg, Q =196 L/h/70 kg, and CL =53 L/h/70 kg. Interpatient variability of CL and CL was considerable with values of 40% and 104%, respectively, leading to marked variability in steady-state plasma concentrations.
Substantial interpatient variability in pharmacokinetics in children complicates the development of adequate dosage regimen for continuous sedation.
S-氯胺酮是消旋混合物氯胺酮的S(+)-对映体，是一种兼具镇静和镇痛作用的麻醉药物。在临床实践中，长期镇静期间观察到S-氯胺酮的药物效应在患者间存在显著差异。
本研究旨在评估0至18岁儿童在长期镇静期间S-氯胺酮的药代动力学变异性。25名儿童（中位年龄：0.42岁，范围：0.02至12.5岁）在机械通气期间接受0.3至3.6mg/kg/h的S-氯胺酮持续静脉输注以进行镇静。根据COMFORT-B评分和视觉模拟量表将输注速率调整至所需的镇静和镇痛水平。每天在随机时间点采集血样，并在停止S-氯胺酮输注后1小时和4小时采集血样。使用非线性混合效应建模软件分析S-氯胺酮及其活性代谢物S-去甲氯胺酮的血浆浓度时间曲线。清除率和分布容积使用3/4幂模型进行异速缩放。
共采集了86份血样。二室模型和一室模型分别充分描述了S-氯胺酮和S-去甲氯胺酮的药代动力学。清除率以及中央和外周分布容积的典型参数估计值为：CL =112L/h/70kg，V1 =7.7L/70kg，V2 =545L/70kg，Q =196L/h/70kg，以及CL =53L/h/70kg。CL和CL的患者间变异性相当大，分别为40%和104%，导致稳态血浆浓度存在显著差异。
儿童药代动力学存在显著的患者间变异性，这使得制定连续镇静合适的给药方案变得复杂。
