Towards Evidence-Based Weaning: a Mechanism-Based Pharmacometric Model to Characterize Iatrogenic Withdrawal Syndrome in Critically Ill Children

For the management of iatrogenic withdrawal syndrome (IWS) in children, a quantitative understanding of the dynamics of IWS of commonly used opioids and sedatives is lacking. Here, we introduce a new mechanism-based pharmacokinetic-pharmacodynamic (PKPD) modeling approach for studying IWS in pediatric clinical datasets. One thousand seven hundred eighty-two NRSwithdrawal scores of IWS severity were analyzed, which were collected from 81 children (age range: 1 month–18 years) that received opioids or sedatives by continuous infusion for 5 days or more. These data were successfully fitted with a PKPD model consisting of a plasma and a dependence compartment that well characterized the dynamics of IWS from morphine, fentanyl, and ketamine. The results suggest that (1) instead of decreasing the infusion rate by a set percentage at set intervals, it would be better to lengthen the weaning period when higher infusion rates are administered prior to weaning; (2) for fentanyl specifically, the risk of IWS might be lower when weaning with smaller dose reductions every 12 h instead of weaning with greater dose reductions every 48 h. The developed PKPD model can be used to evaluate the risk of IWS over time and the extent to which it is affected by different weaning strategies. The results yield hypotheses that could guide future clinical research on optimal weaning strategies. The mechanism-based PKPD modeling approach can be applied in other datasets to characterize the IWS dynamics of other drugs used in pediatric intensive care. Graphical abstract