Levobupivacaine plasma concentrations following repeat caudal anesthetics

Aim A single caudal anesthetic at the start of lower abdominal surgery is unlikely to provide prolonged analgesia. A second caudal at the end of the procedure extends the analgesia duration but total plasma concentrations may be associated with toxicity. Our aim was to measure total plasma levobupivacaine concentrations after repeat caudal anesthesia in infants and to generate a pharmacokinetic model for prediction of plasma concentrations after repeat caudal anesthesia in neonates, infants and children. Methods Infants undergoing definitive repair of anorectal malformations or Hirschsprung's disease received a second caudal anesthesia at the end of the procedure. Total levobupivacaine concentrations were assayed 3-4 times in the first 6 h after the initial caudal. These data were pooled with data from four studies describing plasma concentrations after levobupivacaine caudal or spinal anesthesia. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects models. Covariates included postmenstrual age and body weight. Parameter estimates were used to simulate concentrations after a repeat levobupivacaine 2.5 mg kg(-1) caudal at 3 or 4 h following an initial levobupivacaine 2.5 mg kg(-1) caudal. Results Twenty-one infants (postnatal age 11-32 weeks, gestation 37-39 weeks, weight 5.2-8.6 kg) were included. The measured peak plasma concentration after repeat caudal levobupivacaine 2.5 mg kg(-1) 4 h after initial caudal was 1.38 mg L-1 (95% prediction interval 0.60-2.6 mg L-1) and 3 h after initial caudal was 1.46 mg L-1 (0.60-2.80) mg L-1. Simulation of total plasma concentrations in neonates (7 kg, 57 weeks postmenstrual age) given caudal levobupivacaine 4 h after the initial caudal were 1.76 mg L-1 (0.68-3.50) mg L-1 if 2.5 mg kg(-1) levobupivacaine was used and 0.88 mg L-1 (0.34-1.73) mg L-1 if 1.25 mg kg(-1) of 0.125% levobupivacaine was used. In simulated older children (20 kg, 6 years), the mean maximum concentration was 1.43 mg L-1 (0.60-2.70) mg L-1 if 2.5 mg kg(-1) levobupivacaine was repeated at 3 h. Conclusion Repeat caudal levobupivacaine 2.5 mg kg(-1) at 3 h after an initial 2.5 mg kg(-1) dose does not exceed the concentration associated with systemic local anesthetic toxicity. In 2.5% of simulated neonates (weight 3.8 kg, PMA 40 weeks), repeat caudal anesthesia demonstrates broaching of the lower concentration limit associated with toxicity at both 3 and 4 h after initial caudal.

Automated summary

This study aimed to measure the total plasma concentrations of levobupivacaine in infants after repeat caudal anesthesia and to establish a pharmacokinetic model to predict plasma concentrations after repeat caudal anesthesia in neonates, infants, and children. The results showed that repeat caudal levobupivacaine at 2.5 mg/kg, 3 hours after an initial dose, did not exceed the concentration associated with systemic local anesthetic toxicity. However, in some simulated neonates, repeat caudal anesthesia breached the lower concentration limit associated with toxicity at both 3 and 4 hours after the initial caudal.