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

Sebastiaan C Goulooze,Dick Tibboel,Erwin Ista,Monique Van Dijk,Elke H J Krekels,Catherijne A J Knibbe

doi:10.1208/s12248-021-00586-w

Abstract

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

Highlights

Opioids and sedatives are crucial in ensuring critically ill children’s well-being and comfort [1]
We explored whether drugs used to manage iatrogenic withdrawal syndrome (IWS) during weaning could lower the IWS severity caused by other drugs, whether drugs would influence the IWS caused by drugs from the same class, and whether the development of tolerance could be modelled with an additional compartment
We included data from 81 children, which included 1782 NRSwithdrawal scores collected during a median PICU stay of 16 days (IQR 10– 34), with 198 (11.1%) of the scores above 3, indicating the presence of IWS

Summary

Introduction

Opioids and sedatives are crucial in ensuring critically ill children’s well-being and comfort [1]. Even though prolonged treatment may be required for clinical reasons, drug dependency and iatrogenic withdrawal syndrome (IWS) may occur during weaning of these drugs and subsequently hamper patient recovery [2, 3]. Effective weaning strategies are crucial to prevent IWS itself but may reduce situations where concerns about IWS lead to the undertreatment of pain and distress in critically ill children [1, 4]. 5 Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands. Prolonged treatment and high cumulative drug doses are the most commonly reported risk factors for IWS [1, 3]. To reduce the risk of IWS in clinical practice, we need weaning strategies based on a patient’s characteristics and type of drug and dosing history over time

Methods

Results

Discussion

Conclusion