Ropivacaine in neonates and infants: a population pharmacokinetic evaluation following single caudal block.

BACKGROUND: The aims of this study were to evaluate pharmacokinetics, efficacy and safety of ropivacaine in infants aged 0-12 months following a single caudal injection.

METHODS: Term ASA I-III patients, scheduled for surgery, with a body weight of > or = 2500 g received a caudal block with ropivacaine 2 mg x ml(-1), 1.0 ml x kg(-1). Plasma samples were collected at different time intervals up to 30 h, for analysis of total and unbound ropivacaine and alpha-1-acid glycoprotein (AAG). Pharmacokinetic data were characterized by population analysis. Unbound and total concentrations from 35 patients, median (min-max) postnatal age of 66 (4-351) days, were included in the nonlinear mixed effects modeling to provide estimates of pharmacokinetic parameters and the exploration of covariate relationships. Simulations were made to test the predictive performance of the final model and to describe the effect of significant covariates on systemic exposure.

RESULTS: The mean (min-max) peak plasma concentration of total ropivacaine was 0.83 (0.05-1.57) mg x l(-1) at 0.5-5.7 h (median: 1.0 h) and the plasma concentration of unbound ropivacaine was 0.042 (0.012-0.081) mg x l(-1) within 0.5-1 h. The observed unbound fraction in plasma was 6% (1%-14%). A one-compartment open model with first-order absorption and elimination, incorporating a linear-binding model of ropivacaine to AAG best described the data. The only significant covariate relationship was that of age on Clu/F according to the following relationship Clu/F = 3.01 x e0.00474 x Age. This predicts a Clu/F of 3.5 l x h(-1) x kg(-1) at 30 days and 10.8 l x h(-1) x kg(-1) at 270 days with corresponding terminal half-lives of 6.7 and 2.2 h. The interindividual variability (coefficient of variation, CV) in Clu/F was 39%. The population estimate (CV) of ka was 1.65 h(-1) (30%), Vu/F was 33.6 (l x kg(-1)) (45%) and Ka was 1.78 l x mg(-1) (14%). Thirty-five infants received supplementary analgesics (mostly paracetamol). The median time to first supplementary analgesic (based on all 37 patients) was 3.9 h. No safety concerns or signs of systemic toxicity were observed.

CONCLUSIONS: Following a caudal block with ropivacaine 2 mg x kg(-1) plasma concentrations of unbound ropivacaine were well below threshold levels for toxicity in adults. Apparent volume of distribution is unchanged, apparent unbound clearance increases and the terminal half-life decreases with age in 0-12-month-old neonates and infants. The postoperative pain management provided adequate analgesia and was well tolerated.