Abstract
Aim
Pharmacokinetic simulation was used to characterize levobupivacaine disposition after regional anesthetic rescue for failed spinal anesthesia in neonates and infants.
Methods
Population pharmacokinetics of levobupivacaine were estimated after spinal blockade in a cohort of neonates and infants (n = 25, postnatal age 5-18 weeks, gestation 21-41 weeks, weight 2.4-6 kg). Total levobupivacaine concentrations were assayed 3-4 times in the first hour after spinal levobupivacaine 1 mg kg-1 administration. Parameters were estimated using nonlinear mixed-effects models and supported by priors. Covariates included postnatal age and total body weight. Parameter estimates were used to simulate total levobupivacaine concentrations after a primary spinal levobupivacaine 1 mg kg-1 with rescue caudal levobupivacaine 1.5-2.5 mg kg-1 .
Results
A one-compartment model with a mature clearance 21.5 L h-1 70 kg-1 (CV 47.3%) and central volume 189 L 70 kg-1 (CV 37%) adequately described time-concentration profiles. Clearance maturation was described using a maturation half-time of 11.5 weeks postnatal age. The absorption half-time for spinal levobupivacaine was 2.6 min (CV 56.8%). The upper (97.5% prediction) for peak concentrations after rescue caudal levobupivacaine were 1.5 mg kg-1 , 2 mg kg-1 , and 2.5 mg kg-1 was 2.05 mg L-1 , 2.5 mg L-1 , and 2.9 mg L-1 respectively.
Conclusion
Total bupivacaine concentrations greater than 2.5 mg L-1 are associated with neurotoxicity in adults. Predicted concentrations after either a repeat spinal or a caudal rescue dose of levobupivacaine 1.5 mg kg-1 1 h after spinal levobupivacaine administration are below the neurotoxic concentration threshold.