Pharmacokinetic considerations for pediatric patients receiving analgesia in the intensive care unit; targeting postoperative, ECMO and hypothermia patients

ABSTRACT

Introduction: Adequate postoperative analgesia in pediatric patients in the intensive care unit (ICU) matters, since untreated pain is associated with negative outcomes. Compared to routine postoperative patients, children undergoing hypothermia (HT) or extracorporeal membrane oxygenation (ECMO), or recovering after cardiac surgery likely display non-maturational differences in pharmacokinetics (PK) and pharmacodynamics (PD). These differences warrant additional dosing recommendations to optimize pain treatment.

Areas covered: Specific populations within the ICU will be discussed with respect to expected variations in PK and PD for various analgesics. We hereby move beyond maturational changes and focus on why PK/PD may be different in children undergoing HT, ECMO or cardiac surgery. We provide a stepwise manner to develop PK-based dosing regimens using population PK approaches in these populations.

Expert opinion: A one-dose to size-fits-all for analgesia is suboptimal, but for several commonly used analgesics the impact of HT, ECMO or cardiac surgery on average PK parameters in children is not yet sufficiently known. Parameters considering both maturational and non-maturational covariates are important to develop population PK-based dosing advices as part of a strategy to optimize pain treatment.

KEYWORDS:

• Pediatric
• intensive care
• post-operative
• hypothermia
• ECMO
• cardiac surgery
• pharmacokinetics
• pharmacodynamics
• population PK

Article highlights

• PK-based dosing regimens are lacking for routinely used analgesics in specific groups of (preterm) neonates, infants or children in specific subgroups, like e.g. HT, ECMO, or cardiac surgery.

• PK parameters depend not only on maturational, but also on non-maturational changes. These covariates, combined with intra-patient variability throughout the disease process further add to the variability in PK/PD of analgesics and the choice of the drug throughout childhood.

• PD assessment is necessary but difficult given the diversity of the patient population and their disease characteristics. Its variability further adds to the intra- and interpatient variability observed in the PK/PD relationship.

• New techniques in modelling, such as (semi-)physiologic models and PK/PD-based models, may better describe the clinical situation and estimate the extent of differences between specific subpopulations.

This box summarizes key points contained in the article

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

P. Pokorna was supported by the General University Hospital RV- project [64165/2012]and an unrestricted research grant of the Intensive Care department in the Erasmus MC-Sophia Children’s Hospital. G.A. Zeilmaker was supported by the ZonMw project [80836009840108]. P. Mian was supported by the Sophia Stichting Wetenschappelijk Onderzoek [SSWO S1608]. K Allegaert was supported by the Fund for Scientific Research, Flanders [fundamental clinical investigatorship 1800214N]. The research activities were further facilitated by the agency for innovation by Science and Technology in Flanders (IWT) through the SAFEPEDRUG project [IWT/SBO 130033].