Maria Xiberras 1, Rob C. van Wijk 1, Elke H.J. Krekels 1,2, J.G. Coen van Hasselt 1, Gerdien Zeilmaker-Roest 3, Dick Tibboel 3, A.J. (Bram) Valkenburg 4, Enno D. Wildschut 3, Catherijne A.J. Knibbe 1,5, Sebastiaan C. Goulooze 1,6
1 Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University (Leiden, The Netherlands), 2 Certara Inc, (Princeton, USA), 3 Intensive Care and Department of Paediatric Surgery, Erasmus University Medical Center–Sophia Children’s Hospital (Rotterdam, Netherlands), 4 Department of Anesthesiology and Intensive Care, Isala (Zwolle, Netherlands), 5 Department of Clinical Pharmacy, St. Antonius Hospital (Nieuwegein, Netherlands), 6 LAP&P Consultants (Leiden, Netherlands)
Introduction and Objectives:
Morphine is widely used as an analgesic after paediatric cardiac surgery, with morphine dosage regimens varying widely across hospitals [1]. The Paediatric Analgesia after Cardiac Surgery (PACS) study [2], a multi-centre randomised controlled trial, investigated intermittent paracetamol as an alternative to continuous maintenance morphine infusions in children under three years after cardiac surgery and showed similar rescue morphine use in both groups [2]. The current study aimed to quantify how morphine and paracetamol exposure relate to the need for rescue morphine in children after cardiac surgery.
Methods:
In this analysis, we used data from the PACS study [2], wherein patients received a morphine loading dose at the end of surgery after which they were randomised to either continuous intravenous (IV) morphine or intermittent IV paracetamol as standard pain treatment. Rescue morphine was given if the numeric rating scale pain (NRS pain) [2] was equal to or greater than 4.
All rescue morphine administrations, including additional bolus doses and/or increases in continuous infusions, were defined as the event of interest. Repeated time-to-event (RTTE) model development was performed in NONMEM 7.5. The pharmacodynamic effects of morphine and paracetamol concentrations on the rescue event hazard were explored using concentration predictions described below. Additionally, the influence of time since previous rescue morphine event as a potential increasing factor on the hazard for rescue morphine was tested, as it was hypothesised that the common assumption of independence of events may be violated [3,4].
Individual plasma morphine and paracetamol concentrations were predicted using individual post-hoc parameters obtained in a Bayesian re-estimation and actual dosing histories. For morphine, a published and validated paediatric pharmacokinetic model [5,6] was used, while for paracetamol, an internally developed model was used. When no individual post-hoc parameters could be derived, population parameters were used.
Results:
The RTTE model was developed on data from 187 patients (aged 6 days to 3 years, median 141 days). During the postoperative period (median 48h (IQR 34.5–48)), 469 morphine rescue events (median 2 (IQR 0–4) per patient) were observed. The hazard of rescue morphine administration decreased over time, and was characterised using a Gompertz hazard model.
A strong increase in the hazard of rescue morphine was observed shortly after an event, indicating dependence between events. This was captured by an 11.2-fold increase in hazard after each event, declining exponentially with a half-life of 80.9 minutes based on time since the last rescue. A log-linear relationship best described the relationship between morphine and paracetamol concentrations and the reduced hazard of rescue morphine. Commonly quoted therapeutic concentrations (morphine 10-20mcg/L; paracetamol 10-20mg/L) decreased the hazard by 11.8-22.3% and 14.3-26.5%.
Conclusions:
In this study, the hazard for morphine rescue events decreased with both morphine and paracetamol concentrations. Our study challenges the common assumption [3,4] that rescue events are independent and identified an increase in the hazard following a rescue event, likely reflecting intra-individual fluctuations in analgesia requirements.
References:
[1] Zeilmaker-Roest GA et al., BMJ Paediatr Open. 2017;1(1): e000046
[2] Zeilmaker-Roest GA et al., Critical Care. 2024;28(1):143.
[3] Andersen P and Gill R. Ann Stat. 2015; 10:1100–20
[4] Xiberras M et al., PAGE 33 (2025) Abstr 11754
[5] Valkenburg AJ et al., Pediatric Critical Care Medicine. 2016;17(10):930–8.
[6] Xiberras M et al., PAGE 32 2024 Abstr 11133
Reference: PAGE 34 (2026) Abstr 11913 [www.page-meeting.org/?abstract=11913]
Poster: Drug/Disease Modelling - Paediatrics