Use of lorazepam for analgosedation during mechanical ventilation in paediatric intensive care

Paul Healy¹Marco Marano²Marcello Montibeller²Bianca Goffredo²Giuseppe Pontrelli²Oscar Della Pasqua^1*

• ¹Clinical Pharmacology & Therapeutics Group, University College London, London, United Kingdom
• ²Bambino Gesù Children's Hospital (IRCCS), Rome, Lazio, Italy

Introduction: Lorazepam has been used off-label for analgosedation in paediatric 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 paediatric dosing. This study illustrates how pharmacokinetic modelling and extrapolation principles can be used to 1) identify regimens that maintain the desired analgosedation levels and 2) optimise the design of a prospective protocol in mechanically-ventilated children. Methods: Pharmacokinetic data and COMFORT-B scores from a pilot study in six mechanically-ventilated paediatric 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 characterise 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 optimised dosing regimens, combining intermittent bolus and continuous infusions over a 72-h period. Simulation scenarios also investigated 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 allows 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 hours, followed by a similar regimen with 0.1 mg/kg over the subsequent 24 hours 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 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 paediatric intensive care unit setting