Paediatric Dexmedetomidine Pharmacology

Abstract

Dexmedetomidine is a highly selective alpha-2 adrenoceptor agonist. Use is increasing in the paediatric setting, but without the concomitant understanding of the pharmacokinetics and pharmacodynamics to ensure safe and effective dosing. In this thesis the pharmacokinetics and pharmacodynamics of dexmedetomidine in children after cardiac surgery were explored. The maturation of dexmedetomidine pharmacokinetics with age was determined and the effect of circadian rhythms on pharmacokinetic parameters investigated. A pooled analysis of cardiac and general surgery patients further clarified the population pharmacokinetic profile of dexmedetomidine in children. The pharmacodynamics of dexmedetomidine in the postoperative period were examined and a concentration-response relationship for dexmedetomidine and blood pressure elucidated. Dosage regimens to achieve target concentrations are suggested. Dexmedetomidine pharmacokinetic parameters and their variability (between-subject variability, CV%) for children after cardiac surgery were estimated using non-linear mixed effects models. Parameter estimates for a two-compartment model were: clearance (CL) 39.2 (30.4%) L.h-1.70kg-1, central volume of distribution (V1) 36.9 (69.5%) L.70kg-1, intercompartment clearance (Q) 68.2 (37.6%) L.h-1.70kg-1, and peripheral volume of distribution (V2) 69.9 (48.6%) L.70kg-1. Clearance at birth was 15.55 L.h-1.70kg-1 and matured with a half time of 46.5 weeks to reach 87% of adult values by 1 year of age. These parameters were not influenced by circadian rhythms. Data from these cardiac surgery children were pooled with data from children undergoing cardiac and general surgery and pooled data were reanalysed to clarify the population pharmacokinetic profile of dexmedetomidine in children. Children who received a continuous infusion after cardiac surgery had a clearance estimate that was reduced by 27% compared to those who received a bolus dose. Supplemental diazepam use in children receiving dexmedetomidine differed little from those who did not receive dexmedetomidine in the 12 h after cardiac surgery but morphine administrations were reduced by 16%. A composite Emax model was used to relate mean arterial pressure changes to dexmedetomidine plasma concentration. The peripheral vasopressor effect was directly related to plasma concentration with an Emaxpos of 50.3 iii (44.50%) mmHg, EC50pos of 1.1 (48.27%) ng.mL-1 and a Hillpos coefficient of 1.65. The delayed central sympatholytic response was described with an Emaxneg of 12.30 (37.01%) mmHg, EC50neg 0.10 (104.40%) l ng.mL-1 and a Hillneg coefficient of 2.35. The equilibration half-time (T1⁄2keo) was 9.66 (165.23%) min. The target concentration estimated to provide maximum sedation and analgesia while producing minimum effects on blood pressure differed in children who have undergone cardiac (0.6 ng.mL-1) and non cardiac surgery (1.0 ng.mL-1). For children who had undergone cardiac surgery this target concentration can be achieved by using a dosage regimen of a 0.5 μg.kg-1 loading dose over 10 min followed by a maintenance infusion of 0.28 μg.kg-1.h-1 in a neonate or a maintenance infusion of 0.46 μg.kg-1.h-1 in a 5-year-old child.