Justification of empiric methodology to determine dexmedetomidine dose for the TREX study

INTRODUCTION: Dexmedetomidine is the sedative agent administered in combination with remifentanil and low dose of sevoflurane in the interventional arm of the ongoing TREX trial (Trial Remifentanil DExmedetomidine). The TREX pilot study (published in Paediatr Anaesth 2019;29:59–67) established infusion rates higher than those initially proposed. This could be attributed to an inappropriate target concentration for sedation or incorrect initial pharmacokinetic parameter estimates. METHODS: The TREX study is a Phase III, randomized, active controlled, parallel group, blinded evaluator, multicenter, superiority trial comparing neurological outcome after standard sevoflurane anesthesia with dexmedetomidine/remifentanil, and low dose sevoflurane anesthesia in children aged less than 2 years undergoing anesthesia of 2 h or longer. In this report, dexmedetomidine pharmacokinetics were analyzed in the interventional arm of the Italian population. RESULTS: There were 162 blood samples from 32 infants (22 male and 10 female). The median (IQR) age was 12 (5.2–15.5) months, weight 9.9 (7.3–10.8) kg. Duration of anesthesia ranged from 2 to 6 h. None of the children were born premature (median postnatal age 39 weeks, IQR 38–40 weeks). A 3‐compartment PK model that incorporated allometric scaling and a maturation function demonstrated plasma concentration observations from the current Italian arm of the TREX study were consistent with those predicted by a “universal” model using pooled data obtained from neonates to adults. CONCLUSIONS: This current PK analysis from the Italian arm of the TREX study confirms that plasma concentration of dexmedetomidine is predictable using known covariates such as age and size. The initial target concentration (0.6 μg.L(−1)) used to sedate children cared for in the intensive care after cardiac surgery was inadequate for infants in the current TREX study. A target concentration 1 mcg.L(−1), corresponding to a loading dose of 1 mcg.kg(−1) followed by an infusion of 1 mcg.kg(−1).h(−1), provided adequate sedation.