The pharmacokinetics of methadone and its metabolites in neonates, infants, and children.

BACKGROUND: The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg·l(-1) , while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg·l(-1) . The racemate of methadone which is commonly used in pediatric and anesthetic care is metabolized to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP). METHODS: Data from four studies (age 33-week PMA-15 years) were pooled (n = 56) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70-kg person using an allometric model approach. Investigation was made of the racemate and metabolite (EDDP and EMDP) dispositions. In addition, neonatal data (n = 7) allowed further study of R- and S-enantiomer pharmacokinetics. RESULTS: A three-compartment linear disposition model best described the observed time-concentration profiles with additional compartments for metabolites. Population parameter estimates (between-subject variability) were central volume (V1) 21.5 (29%) l.70 kg(-1) , peripheral volumes of distribution V2 75.1 (23%) l.70 kg(-1) and V3 484 (8%) l.70 kg(-1) , clearance (CL) 9.45 (11%) l·h(-1) .70 kg(-1) , and intercompartment clearances Q2 325 (21%) l·h(-1) .70 kg(-1) and Q3 136 (14%) l·h(-1) .70 kg(-1) . EDDP formation clearance was 9.1 (11%) l·h(-1) .70 kg(-1) , formation clearance of EMDP from EDDP 7.4 (63%) l·h(-1) .70 kg(-1) , elimination clearance of EDDP was 40.9 (26%) l·h(-1) .70 kg(-1) and the rate constant for intermediate compartments 2.17 (43%) h(-1) . CONCLUSIONS: Current pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2 mg·kg(-1) per 8 h in neonates achieves a target concentration of 0.06 mg·l(-1) within 36 h. Infusion, rather than intermittent dosing, should be considered if this target is to be achieved in older children after cardiac surgery.

Propofol for pediatric tracheal intubation with deep anesthesia during sevoflurane induction: dosing according to elapsed time for two age groups.

STUDY OBJECTIVE: To determine, for two different age groups, the effect of duration of sevoflurane administration on the amount of propofol needed when performing tracheal intubation. DESIGN: Classic Dixon's Up-and-Down sequential method. SETTING: University based operating rooms. PATIENTS: 106 ASA physical status 1 and 2 patients aged one to 11 years. INTERVENTIONS: Patients were allocated to the 1-6 year (≥ 12 and < 72 mos) and 6-11 year (≥ 72 and < 132 mos) age groups. Midazolam 0.5 mg/kg was given orally to the 1-6 year group, and all patients were induced with 8% dialed sevoflurane and 67% nitrous oxide (N2O), with N2O discontinued and sevoflurane dialed to 5% after one minute and 1.5 minutes for the younger and older age groups, respectively. Intravenous access was obtained and propofol was promptly administered. Propofol dose was determined according to age group and whether propofol was given 2-4, 4-6, or 6-8 minutes after the start of sevoflurane induction, with Dixon's Up and Down Method used separately for each specific age/time group. Tracheal intubation conditions one minute after propofol were evaluated. MEASUREMENTS: Isotonic regression determined propofol ED50 estimates for excellent tracheal intubation conditions, and linear regression determined the effect of propofol dose on change in systolic blood pressure (SBP). MAIN RESULTS: Estimated propofol ED50 doses for 1-6 year olds, with 95% confidence intervals (CIs), were 1.48 mg/kg (0.80, 2.03), 0.00 mg/kg (0.00, 0.38), and 0.07 mg/kg (0.00, 0.68) in the 2-4, 4-6, and 6-8 minute groups, respectively, with estimated differences between the 2-4 minute group versus the 4-6 and 6-8 minute groups being 1.47 mg/kg (95% CI = 1.04, 2.06) and 1.41 mg/kg (95% CI = 0.74, 2.04), respectively. Estimated propofol ED50 doses for 6-11 year olds, with 95% CIs, were 2.35 mg/kg (1.97, 2.45) and 2.33 mg/kg (1.59, 2.45) in the 2-4 and 4-6 minute groups, respectively. Diminutions in SBP at one minute and two minutes after propofol administration were dose dependent for children 1-6 years of age, decreasing 5.3% and 8.1% for each 1 mg/kg of propofol, respectively. CONCLUSION: The amount of propofol needed to supplement sevoflurane in children 1-6 years of age can be expected to decrease after 4 minutes of sevoflurane.

High-fidelity simulation is superior to case-based discussion in teaching the management of shock.

BACKGROUND: Case-based discussion (CBD) is an established method for active learning in medical education. High-fidelity simulation has emerged as an important new educational technology. There is limited data from direct comparisons of these modalities. AIMS: The primary purpose of this study was to compare the effectiveness of high-fidelity medical simulation with CBD in an undergraduate medical curriculum for shock. METHODS: The subjects were 85 third-year medical students in their required surgery rotation. Scheduling circumstances created two equal groups. One group managed a case of septic shock in simulation and discussed a case of cardiogenic shock, the other group discussed septic shock and experienced cardiogenic shock through simulation. Student comprehension of the assessment and management of shock was then evaluated by oral examination (OE). RESULTS: Examination scores were superior in all comparisons for the type of shock experienced through simulation. This was true regardless of the shock type. Scores associated with patient evaluation and invasive monitoring, however, showed no difference between groups or in crossover comparison. CONCLUSIONS: In this study, students demonstrated better understanding of shock following simulation than after CBD. The secondary finding was the effectiveness of an OE with just-in-time deployment in curriculum assessment.

The pharmacokinetics of methadone in adolescents undergoing posterior spinal fusion.

BACKGROUND: The optimal methadone dosing regimen for children undergoing spinal surgery is uncertain because of sparse pediatric pharmacokinetic data and a paucity of analgesic effect data. The minimum effective analgesic concentration of methadone in opioid naïve adults is 58 mcg · L(-1). METHODS: Adolescents aged 12-19 years undergoing idiopathic scoliosis correction were administered 0.25 mg · kg(-1) racemic methadone IV prior to surgical incision. Arterial blood samples for methadone assay were obtained at 0 min, 5 min, 10 min, 15 min, 20 min, 40 min, 1 h, 2 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 48 h. Compartment analysis was undertaken using nonlinear mixed effects models. Parameter estimates were standardized to a 70-kg person using allometric models. RESULTS: A three-compartment linear disposition model best described observed time-concentration profiles. Population parameter estimates (between-subjects variability) were central volume (V1) 19.1 (126%) L 70 kg(-1), peripheral volumes of distribution V2 65.5 (60%) L 70 kg(-1), V3 485 (23%) L 70 kg(-1), clearance (CL) 9.3 (11%) L · h(-1) · 70 kg(-1), and inter-compartment clearances Q2 282 (95%) L · h(-1) 70 kg(-1), Q3 139 (42%) L · h(-1) 70 kg(-1). The terminal elimination half-life was 44.4 h. The mean observed methadone concentration was <58 mcg · L(-1) by the first hour after administration. CONCLUSIONS: Current pharmacokinetic parameter estimates in adolescents are similar to those reported in adults. Methadone undergoes rapid redistribution after bolus administration. This may result in plasma concentrations that provide inadequate analgesia postoperatively. We would suggest following the bolus (0.25 mg.kg(-1)) with an infusion (0.1-0.15 mg · kg(-1) · h(-1) for 4 h) during spinal surgery to ensure adequate plasma concentrations for 24 h.