Introduction
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.
- Dexmedetomidine has neuroprotective properties and is used for sedation in children enrolled in the TREX study
- The TREX pilot study identified that higher dexmedetomidine infusion rates were required than those initially proposed. This could be attributed to an inappropriate target concentration for sedation or incorrect initial pharmacokinetic parameter estimates.
- What this study adds
- The pharmacokinetic parameter estimates from the Italian arm of the TREX study are similar to initial estimates used in the pilot study. Pooling these observations with published data from neonates to adults strengthened a “universal” dexmedetomidine pharmacokinetic model.
- The initial dexmedetomidine target concentration (0.6 μg.L−1) used in the TREX pilot study was inadequate for sedation. Higher doses (1.0 μg.kg−1 loading dose, followed by an infusion of 1.0 μg.kg−1.h−1), reflecting a higher target concentration of 1 μg.L−1, proved adequate.