Use of lorazepam for analgosedation during mechanical ventilation in pediatric intensive care.

Introduction: Lorazepam has been used off-label for analgosedation in pediatric intensive care units (PICU) as an alternative to midazolam. While its intermediate duration of action makes it suitable for continuous sedation, there is limited evidence to guide dosing in children. This study illustrates how pharmacokinetic modeling and extrapolation principles can be used to (1) identify regimens that maintain the desired analgosedation levels and (2) optimize the design of a prospective protocol in children requiring mechanical ventilation. Methods: Pharmacokinetic data and COMFORT-B scores from a preliminary pilot study in six mechanically-ventilated pediatric patients (aged 0.8-4.8 years) were available for the purpose of the current investigation. A previously published population pharmacokinetic model was used to characterize the disposition of lorazepam, accounting for developmental growth and metabolic maturation in children. Parameter distributions were used as priors. Clinical trial simulations (CTS) were subsequently performed in a virtual cohort of 100 children (aged 1.0-12 years) to explore optimized dosing regimens, combining intermittent bolus dosing and continuous infusions over a 72-h period. A target concentration of 500 ng/ml was selected considering the available clinical data and literature evidence on the analgosedative effects and safety profile of lorazepam. Simulation scenarios also explored sample size and sampling time requirements for a prospective clinical trial. Results: The pharmacokinetic model adequately described the concentration vs. time profiles, despite appreciable interindividual variability. Population estimates for clearance and volume of distribution were 0.23 L/h/kg and 2.3 L/kg, respectively. Simulation results showed that intermittent bolus dosing every 4 h, followed by continuous infusion allowed for lorazepam steady state concentrations to fluctuate around 500 ng/ml. An initial dose of 0.2 mg/kg given as bolus every 4 h over the first 24 h, followed by a similar regimen with 0.1 mg/kg over the subsequent 24 h and continuous infusion of 0.03 mg/kg/h until the end mechanical ventilation was identified as the recommended regimen to be evaluated in a prospective clinical trial. Conclusion: Our study underscores the importance of model-based approaches to identify suitable dosing regimens to be used in children when limited pharmacokinetic and pharmacodynamic data are available. The proposed dosing regimen balances efficacy and safety data, thereby offering the foundation for the repurposing of lorazepam as an alternative, second line option for analgosedation of mechanically ventilated subjects in a pediatric intensive care unit setting.