Exploring the Relationship Between Morphine Concentration and Oversedation in Children After Cardiac Surgery

The Journal of Clinical Pharmacology, vol. 60, pp. 1231–1236

Abstract

Abstract 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.

Authors 7

1. Abraham J. Valkenburg corresponding

   Erasmus MC

   Affiliation as printed

   Department of Intensive Care Erasmus University Medical Center Rotterdam the Netherlands

   Both authors contributed equally to this article

   Department of Intensive Care, Erasmus University Medical Center, Rotterdam, the Netherlands

2. Sebastiaan Camiel Goulooze Aachen Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research Leiden University Leiden the Netherlands

   Both authors contributed equally to this article

   Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands

3. Cormac Breatnach

   Children's Health Ireland at Crumlin

   Affiliation as printed

   Department of Anaesthesia and Critical Care Medicine Our Lady's Children's Hospital Dublin Ireland

   Department of Anaesthesia and Critical Care Medicine, Our Lady's Children's Hospital, Dublin, Ireland

4. Dick Tibboel

   Erasmus MC · Erasmus MC - Sophia Children’s Hospital

   Affiliation as printed

   Department of Pediatric Surgery Erasmus University Medical Center–Sophia Children's Hospital Rotterdam the Netherlands

5. Monique van Dijk

   Erasmus MC · Erasmus MC - Sophia Children’s Hospital

   Affiliation as printed

   Department of Pediatric Surgery Erasmus University Medical Center–Sophia Children's Hospital Rotterdam the Netherlands

   Division of Nursing Science Department of Internal Medicine Erasmus University Medical Center–Sophia Children's Hospital Rotterdam the Netherlands

6. Catherijne A. J. Knibbe Aachen Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research

   Leiden University · St. Antonius Ziekenhuis

   Affiliation as printed

   Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research Leiden University Leiden the Netherlands

   St. Antonius Hospital Department of Clinical Pharmacy Nieuwegein the Netherlands

   Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands

   St. Antonius Hospital, Department of Clinical Pharmacy, Nieuwegein, the Netherlands

7. Elke H. J. Krekels Aachen Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research Leiden University Leiden the Netherlands

   Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands