Pharmacokinetics of bupivacaine after continuous epidural infusion in infants with and without biliary atresia

Background: Continuous epidural infusion of bupivacaine is widely practiced for postoperative pain relief in pediatric patients. However, bupivacaine may induce adverse effects in infants (convulsions or cardiac arrhythmias), Likely because of decreased hepatic clearance and serum protein binding capacity, The authors wanted to examine the complex relations between age, alpha -1 acid glycoprotein (AAG) concentration, and unbound and total bupivacaine serum concentrations in infants receiving bupivacaine epidurally for 2 days. Methods: Twenty-two infants aged 1-7 months (12 with biliary atresia and 10 with another disease) received a continuous epidural infusion of 0.375 mg (.) kg(-1) (.) h(-1) bupivacaine during 2 days (during and after surgery). Unbound and total bupivacaine concentration in serum was measured 0.5, 4, 24, and 48 h after infusion initiation. AAG concentration was measured in serum before and 2 days after surgery. In eight additional infants, the blood/plasma concentration ratio was measured in vitro at whole blood concentrations of 2 and 20 mug/ml. Bupivacaine concentration was fitted to a one-compartment model to calculate basic pharmacokinetic parameters. Results: No adverse effects were observed. AAG increased markedly after surgery, and the increase was correlated to both age and preoperative AAG concentration. Two infants aged 1.8 months had unbound concentrations greater than 0.2 mug/ml. Clearance of unbound drug significantly increased with age. Because of increased drug binding, clearance of bound drug decreased both with time (from 0.5 to 48 h) and with age. Blood/plasma ratio was 0.77 +/- 0.08 and 0.85 +/- 0.24 at 2 and 20 mug/ml, respectively. Conclusions: Because of a low AAG concentration and a low intrinsic clearance, unbound bupivacaine increased to concentrations greater than 0.2 mug/ml in two infants younger than 2 months, after 2 days of infusion at a rate of 0.375 (.) mg (.) kg(-1) (.) h(-1). The increase in AAG observed after surgery did not fully buffer this unbound fraction. Similarly, the buffer capacity of erythrocytes did not sufficiently increase at high concentration to compensate the saturation of the AAG system. Thus, we propose the use of a maximum dose of 0.25 mg kg(-1) (.) h(-1) in infants younger than 4 months and a maximum of 0.3 mg (.) k(-1) (.) h(-1) in infants older than 4 months.