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Background: Intravenous racemic ketamine is commonly administered for procedural sedation, although few pharmacokinetic studies have been conducted among children. Moreover, an optimal sampling schedule has not been derived to enable the conduct of pharmacokinetic studies that minimally inconvenience study participants., Methods: Concentration-time data were obtained from 57 children who received 1-1.5 mg·kg(-1) of racemic ketamine as an intravenous bolus. A population pharmacokinetic analysis was conducted using nonlinear mixed effects models, and the results were used as inputs to develop a D-optimal sampling schedule., Results: The pharmacokinetics of ketamine were described using a two-compartment model. The volume of distribution in the central and peripheral compartments were 20.5 l∙70 kg(-1) and 220 l∙70 kg(-1), respectively. The intercompartmental clearance and total body clearance were 87.3 and 87.9 l·h(-1) ∙70 kg(-1), respectively. Population parameter variability ranged from 34% to 98%. Initially, blood samples were drawn on 3-6 occasions spanning a range of 14-152 min after dosing. Using these data, we determined that four optimal sampling windows occur at 1-5, 5.5-7.5, 10-20, and 90-180 min after dosing. Monte Carlo simulations indicated that these sampling windows produced precise and unbiased ketamine pharmacokinetic parameter estimates., Conclusion: An optimal sampling schedule was developed that allowed assessment of the pharmacokinetic parameters of ketamine among children requiring short-term procedural sedation., (© 2014 John Wiley & Sons Ltd.)

Aims: The aim of this study was to describe ketamine pharmacokinetics when administered orally to children suffering from burn injury in >10% body surface area., Methods: Children (n = 20) were given ketamine 5 or 10 mg·kg(-1) orally 20 min prior to presentation for surgical procedures. Anesthesia during procedures was maintained with a volatile anesthetic agent. Additional intravenous ketamine was given as a bolus (0.5-1 mg·kg(-1)) to nine children during the procedure while a further nine children were given an infusion (0.1 mg·kg(-1)·h(-1)) continued for 4-19 h after the procedure. Blood was assayed for ketamine and norketamine on six occasions over the study duration of 8-24 h. Data were pooled with those from an earlier analysis (621 observations from 70 subjects). An additional time-concentration profile from an adult given oral ketamine was gleaned from the literature (17 observations). A population analysis was undertaken using nonlinear mixed-effects models., Results: The pooled analysis comprised 852 observations from 91 subjects. There were 20 children who presented for procedures related to burns management (age 3.5 sd 2.1 years, range 1-8 years; weight 14.7 sd 4.9 kg, range 7.9-25 kg), and these children contributed 214 ketamine and norketamine observations. A two-compartment (central, peripheral) linear disposition model fitted data better than a one-compartment model. Bioavailability of the oral formulation was 0.45 (90% CI 0.33, 0.58). Absorption half-time was 59 (90% CI 29.4, 109.2) min and had high between-subject variability (BSV 148%). Population parameter estimates, standardized to a 70-kg person, were central volume 21.1 (BSV 47.1%) l·70 kg(-1), peripheral volume of distribution 109 (27.5%) l·70 kg(-1), clearance 81.3 (46.1%) l·h(-1)·70 kg(-1), and inter-compartment clearance 259 (50.1%) l·h(-1)·70 kg(-1). Under the assumption that all ketamine was converted to norketamine, the volume of the metabolite was 151.9 (BSV 39.1%) l·70 kg(-1) with an elimination clearance of 64.4 (BSV 63.4%) l·h(-1) ·70 kg(-1) and a rate constant for intermediate compartments of 26.2 (BSV 52.1%) h(-1)·70 kg(-1)., Conclusions: The ketamine pharmacokinetics in children with minor burns are similar to those without burns. The peak ratio of norketamine/ketamine at 1 h is 2.8 after oral administration allowing an analgesic contribution from the metabolite at this time. There is low relative bioavailability (<0.5) and slow variable absorption. Dose simulation in a child (3.5 years, 15 kg) suggests a dose regimen of oral ketamine 10 mg·kg(-1) followed by intravenous ketamine 1 mg·kg(-1) i.v. with the advent of short-duration surgical dressing change at 45 min., (© 2011 Blackwell Publishing Ltd.)

Aim: We aimed to produce a racemic ketamine manual infusion regimen capable of maintaining a steady-state blood concentration associated with anesthesia in children aged 1.5-12 years., Method: The literature was searched for a ketamine blood concentration associated with anesthesia in humans. Pharmacokinetic parameter estimates were taken from published studies of infusion data in children and used in a pharmacokinetic simulation program to predict likely ketamine blood concentrations during infusions. A variability of 10% was allowed about the chosen target concentration., Results: A target concentration of 3 mg.l(-1) was chosen for simulation modeling. This target is greater than that associated with anesthesia when supplemented by nitrous oxide or midazolam in adults. Arousal to light touch or voice appears to occur at a mean plasma concentration of 0.5 mg.l(-1) in both children and adults. A loading dose of 2 mg.kg(-1) followed by an infusion rate of 11 mg.kg(-1).h(-1) for the first 20 min, 7 mg.kg(-1).h(-1) from 20 to 40 min, 5 mg.kg(-1).h(-1) from 40 to 60 min and 4 mg.kg(-1).h(-1) from 1 to 2 h resulted in a steady-state target concentration of 3 mg.l(-1) in children 1.5-12 years. Arousal, either spontaneous or to speech, is anticipated 3 h 47 min after a 2 h infusion in an average 6-year-old child. The context sensitive half-time in children was shorter than in adults after 1.5 h, rising from 30 min at 1 h to 55 min at 5 h after an infusion of 3 mg.kg(-1).h(-1) in a 10 kg child., Conclusion: Children require higher infusion rates than adults to maintain steady-state concentrations of 3 mg.l(-1) and have shorter context sensitive half-times than adults after prolonged infusion. These differences can be attributed to age-related pharmacokinetics. We anticipate slow return to full consciousness after prolonged infusion, suggesting that a lower target concentration with supplementation from adjuvant short acting anesthetic drugs may be advantageous.

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)).

Background: Norketamine, a metabolite of ketamine, is an analgesic with a potency one-third that of ketamine. The aim of this study was to describe norketamine pharmacokinetics in children in order to predict time-concentration profiles for this metabolite after racemic ketamine single dose and infusion administration. The possible analgesic potential resulting from norketamine concentration may then be predicted using simulation., Methods: Ketamine and norketamine data were available from two sources: (i) children presenting for procedural sedation in an emergency department given ketamine 1-1.5 mg.kg(-1) IV as a bolus dose; and (ii) a literature search of those studies describing ketamine and norketamine time-concentration profiles after either IV or IM single-dose ketamine in adults and children. A population pharmacokinetic analysis was undertaken using nonlinear mixed effects models (NONMEM). A two-compartment (central, peripheral) linear disposition model was used to fit the parent drug. An additional metabolite compartment was linked to the central compartment by series of intermediate compartments to account for norketamine delayed formation. Norketamine volume of distribution was fixed equivalent to central volume. Simulation was used to predict norketamine time-concentration profiles in children given either ketamine as an i.v. bolus 2 mg.kg(-1) or as an analgesic infusion 0.2 mg.kg(-1).h(-1) for 24 h., Results: The analysis comprised 621 observations from 70 subjects. There were 57 children (age 8.3, sd: 3.5 years, range: 1.5-14; weight 32.5, sd: 15.6 kg, range: 10.8-74.8) and 13 adults. Population parameter estimates for the parent drug, standardized to a 70 kg person using allometric models were central volume (V1) 22 (BSV 89.6%) l.70 kg(-1), peripheral volume of distribution (V2) 129 (30.9%) l.70 kg(-1), clearance other than that metabolized to norketamine (CLother) 47.8 (37.7%) l.h(-1).70 kg(-1) and intercompartment clearance (Q) 216 (54.5%) l.h(-1).70 kg(-1). The norketamine formation clearance (CL2M) was 12.4 (127%) l.h(-1).70 kg(-1), elimination clearance (CLM) was 13.5 (145%) l.h(-1).70 kg(-1), and the rate constant for intermediate compartments was 26.5 (59.1%) h(-1)., Conclusions: Ketamine has a longer elimination half-life (2.1 h) than norketamine (1.13 h). Simulation suggested that norketamine contributes to analgesia for 4 h after 2 mg.kg(-1) i.v. bolus, provided the assumption that a norketamine concentration above 0.1 mg.l(-1) contributes analgesia is true. Similarly, the norketamine metabolite may contribute to analgesia for 1.5 h after low-dose infusion (0.2 mg.kg(-1).h(-1)) cessation.