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.

Additional Metadata
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
Citation
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