Department of Intensive Care, Erasmus University Medical Center, Rotterdam, the Netherlands.
Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
J Clin Pharmacol. 2020 Sep;60(9):1231-1236. doi: 10.1002/jcph.1620. Epub 2020 May 20.
Titrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study is to explore the concentration-effect relationship for morphine-associated oversedation after cardiac surgery in children aged 3 months to 3 years. Data on morphine dosing, as well as morphine plasma concentrations, were available from a previous study on the pharmacokinetics of morphine after cardiac surgery in children. Oversedation was defined as scores below 11 on the validated COMFORT-behavioral scale. Population pharmacokinetic-pharmacodynamic modeling was performed in NONMEM 7.3. The probability of oversedation as a function of morphine concentration was best described using a step function in which the EC was 46.3 ng/mL. At morphine concentrations below the EC , the probability of oversedation was 2.9% (0.4& to 18%), whereas above the EC percentages were 13% (1.9% to 52%) (median value [95% prediction interval from interindividual variability]). Additionally, the risk of oversedation was found to be increased during the first hours after surgery (P < .001) and was significantly lower during mechanical ventilation (P < .005). We conclude that morphine concentrations above approximately 45 ng/mL may increase the probability of oversedation in children after cardiac surgery. The clinician must evaluate, on a case-by-case basis, whether the analgesic benefits arising from dosing regimen associated with such concentrations outweigh the risks.
在儿科重症监护病房中，由于缺乏该人群的药效学知识，对医护人员来说，滴定镇痛和镇静药物仍然是一个挑战。本研究的目的是探讨 3 个月至 3 岁儿童心脏手术后与吗啡相关的过度镇静的浓度-效应关系。来自先前关于儿童心脏手术后吗啡药代动力学研究的吗啡剂量以及吗啡血浆浓度数据可用于本研究。过度镇静定义为经验证的 COMFORT 行为量表评分低于 11。在 NONMEM 7.3 中进行群体药代动力学-药效学建模。使用阶跃函数最佳描述了吗啡浓度与过度镇静概率之间的关系，其中 EC 为 46.3ng/ml。在 EC 以下的吗啡浓度下，过度镇静的概率为 2.9%（0.4&至 18%），而 EC 以上的概率为 13%（1.9%至 52%）（中位数[个体间变异性的 95%预测区间]）。此外，研究发现术后最初几小时内过度镇静的风险增加（P<0.001），机械通气期间的风险显著降低（P<0.005）。我们得出结论，心脏手术后儿童的吗啡浓度约为 45ng/ml 以上可能会增加过度镇静的概率。临床医生必须根据具体情况评估与这些浓度相关的剂量方案所带来的镇痛益处是否大于风险。
