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 EC50 was 46.3 ng/mL. At morphine concentrations below the EC50, the probability of oversedation was 2.9% (0.4& to 18%), whereas above the EC50 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.

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Keywords adverse effects, cardiac surgical procedures, intensive care unit, pediatrics, morphine, pharmacodynamics
Persistent URL dx.doi.org/10.1002/jcph.1620, hdl.handle.net/1765/127382
Journal Journal of Clinical Pharmacology
Valkenburg, A.J, Goulooze, S.C. (Sebastiaan C.), Ng, C.Y. (Chun Yin), Breatnach, C.V. (Cormac V.), Tibboel, D, van Dijk, M, … Krekels, E.H.J. (2020). Exploring the Relationship Between Morphine Concentration and Oversedation in Children After Cardiac Surgery. Journal of Clinical Pharmacology. doi:10.1002/jcph.1620