An approach for dose finding of drugs in infants: sedation by midazolam studied using the continual reassessment method

Aims No drug has been demonstrated to provide simultaneously appropriate sedation, safety and lack of disturbance of the measured parameters during cardiac catheterization in infants. The objective of this study was to estimate the dose of midazolam, administered rectally, that would provide a 90% probability of adequate sedation in infants during cardiac catheterization. A sedation score ≥4 (six‐point scale) 30 to 60 min after dosing was rated as a success. Methods A double‐blind, continual reassessment method using a Bayesian approach has been used. Sixteen infants were administered a single midazolam dose, within a 0.1 to 0.6 mg kg−1 dose range. Results Consecutive failures led to allocation of the highest dose to 15 out of 16 patients. The final estimated probability of failure of the 0.6 mg kg−1 dose was 81% (95% CI: 78.5 to 84%). The time to reach a score ≥4 was longer than expected and the median duration‐time at score ≥4 was shorter (15 min) than expected. Conclusions Delayed absorption and low rectal bioavailability may explain these data. Higher doses or different routes of administration may lead to the expected sedation, but the safety of doses higher than 0.6 mg kg−1 administered rectally has not been evaluated. The therapeutic strategy for sedation of this category of infants in the hospital has now been changed based on the present results in that rectal midazolam has been abandoned in this indication.