Investigating the pharmacodynamics of ketamine in children

Abstract

Background: The aim of this study was to describe ketamine pharmacodynamics (PD) in children. Adult ketamine concentrations during recovery are reported as 0.74 mg.l(-1) (sd 0.24 mg.l(-1)) with an EC(50) for anesthesia of 2 mg.l(-1) (sd 0.5 mg.l(-1)), but pediatric data are few.

Methods: Children presenting for painful procedures in an Emergency Department were given ketamine 1-1.5 mg.kg(-1) i.v. Blood was assayed for ketamine on three to six occasions (median 3) over the subsequent 14-152 min (median 28.5). Procedures were videotaped. Level of sedation (0-5; unresponsive - spontaneously awake without stimulus) and a test of memory were recorded. PD was investigated using a variable slope E(max) model (sedation) or logistic regression (arousal time, memory) with nonlinear mixed effects models.

Results: In total 60 children were enrolled. Pharmacokinetic data were collected in 54 of these children and there were 43 children available for PD study. The mean age was 8.15 years (sd 3.5 years) and weight was 34.9 kg (sd 15.8 kg). The half-time describing equilibration between the effect compartment and central compartment was 11 s (95% CI 0.07-20 s). The EC(50) for arousal was 0.52 (90% CI 0.22-1.17) mg.l(-1). The E(max) model with a baseline (E(0)) of five (spontaneously awake without stimulus) yielded a fractional E(max) 0.939 [coefficient of variability (CV) 24%], an EC(50) 0.56 (CV 136%) mg.l(-1) and a Hill coefficient 3.71. The EC(50) for recall memory was 0.44 (90% CI 0.09-1.70) mg.l(-1). The EC(50) for remembering was 0.38 (90% CI 0.12-1.75) mg.l(-1).

Conclusions: Concentrations associated with arousal in children are analogous to adults. The ability to recall and remember occurs at similar concentrations to those associated with arousal. A concentration of 1 mg.l(-1) was associated with a sedation level of three or less (arouses to consciousness with moderate tactile or loud verbal stimulus) in 95% of children while 1.5 mg.l(-1) was associated with a sedation level of two or less (rouses slowly to consciousness with sustained painful stimulus) in 95% of children. These concentrations can be attained for 3-4 min after 1 mg.kg(-1) and 1.5 mg.kg(-1) ketamine IV bolus, respectively. The mean arousal time can be anticipated at approximately 10 min (1 mg.kg(-1)) and 15 min (1.5 mg.kg(-1)).