Ketamine disposition in children presenting for procedural sedation and analgesia in a children's emergency department

Background: The aim of this study was to describe ketamine pharmacokinetics in children to simulate time-concentration profiles to predict duration of concentrations associated with anesthesia, arousal and analgesia. Methods: Children presenting for painful procedures in the Emergency Dept were given ketamine 1-1.5 mg.kg(-1) i.v. Blood was assayed for ketamine on 3-6 occasions (median 3) over the subsequent 14-152 min (median 28.5). A population pharmacokinetic analysis was undertaken by using nonlinear mixed effects models (NONMEM). Simulation was used to predict time-concentration profiles in this cohort Results: There were 188 observations from 54 children (age 8.3 SD 3.5 years, weight 32.5 SD 15.6 kg). A two-compartment (central, peripheral) linear disposition model fitted data better than a one-compartment model. Population parameter estimates and their between subject variability (BSV), standardized to a 70-kg person using allometric models, were central volume (V1) 38.7 (BSV 64%) 1.70 kg(-1), peripheral volume of distribution (V2) 102 (51.7%) 1.70 kg(-1), clearance (CL) 90 (38.1%) 1.h(-1) 70 kg(-1) and intercompartment clearance (Q) 215 (19%) 1.h(-1) 70 kg(-1). At 10 min half of the children given 1 mg.kg(-1) will have a serum concentration below 0.75 mg.l(-1). This is a concentration associated with 'awakening' in adults. However, almost all the children will still have a serum concentration above 0.1 mg.l(-1), a level associated with analgesia in adults. Conclusions: Ketamine 1 mg.kg(-1) i.v. provides satisfactory serum concentrations for children undergoing sedation for painful procedures of < 5-min duration and produces concentrations associated with analgesic effect for more than 10 min. Clearance increases with decreasing age in children. The relationship between serum concentration and effect is poorly defined in children.