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

Dexmedetomidine and Iatrogenic Withdrawal Syndrome in Critically Ill Children

Background Iatrogenic withdrawal syndrome is a well-known adverse effect of sedatives and analgesics commonly used in patients receiving mechanical ventilation in the pediatric intensive care unit, with an incidence of up to 64.6%. When standard sedative and analgesic treatment is inadequate, dexmedetomidine may be added. The effect of supplemental dexmedetomidine on iatrogenic withdrawal syndrome is unclear. Objective To explore the potentially preventive effect of dexmedetomidine, used as a supplement to standard morphine and midazolam regimens, on the development of iatrogenic withdrawal syndrome in patients receiving mechanical ventilation in the pediatric intensive care unit. Methods This retrospective observational study used data from patients on a 10-bed general pediatric intensive care unit. Iatrogenic withdrawal syndrome was measured using the Sophia Observation withdrawal Symptoms-scale. Results In a sample of 102 patients, the cumulative dose of dexmedetomidine had no preventive effect on the development of iatrogenic withdrawal syndrome (P = .19). After correction for the imbalance in the baseline characteristics between patients who did and did not receive dexmedetomidine, the cumulative dose of midazolam was found to be a significant risk factor for iatrogenic withdrawal syndrome (P < .03). Conclusion In this study, supplemental dexmedetomidine had no preventive effect on iatrogenic withdrawal syndrome in patients receiving sedative treatment in the pediatric intensive care unit. The cumulative dose of midazolam was a significant risk factor for iatrogenic withdrawal syndrome.

Opioid and Benzodiazepine Iatrogenic Withdrawal Syndrome in Patients in the Intensive Care Unit

Iatrogenic withdrawal syndrome is an increasingly recognized issue among adult patients in the intensive care unit. The prolonged use of opioids and benzodiazepines during the intensive care unit stay and preexisting disorders associated with their use put patients at risk of developing iatrogenic withdrawal syndrome. Although research to date is scant regarding iatrogenic withdrawal syndrome in adult patients in the intensive care unit, it is important to recognize and adequately manage iatrogenic withdrawal syndrome in order to prevent possible negative outcomes during and after a patient’s intensive care unit stay. This article discusses in depth 8 studies of iatrogenic withdrawal syndrome among adult patients in the intensive care unit. It also addresses important aspects of opioid and benzodiazepine iatrogenic withdrawal syndrome, including prevalence, risk factors, and assessment and considers its prevention and management.