Bupivacaine Plasma Concentrations During Continuous Epidural Anesthesia in Infants and Children

Abstract

Venous bupivacaine plasma concentrations were measured in six neonates and infants aged 4 days to 3.9 mo (mean, 2.1 mo) and 10 infants and children aged 9 mo to 6 yr (mean, 3.1 yr) after administration of an initial bolus of 0.5 mL/kg bupivacaine 0.25%, followed by a continuous infusion of local anesthetic (0.25 mL.kg-1.h-1) over a period of 4 h (first hour: bupivacaine 0.25%, then reduced to 0.125%). Plasma concentrations of local anesthetic measured at 180 min and 300 min after beginning of bupivacaine administration were significantly higher in younger infants when compared to older infants and children (180 min: 0.67 +/- 0.24 micrograms/mL [0.25-0.97] vs 0.27 +/- 0.11 micrograms/mL [0.19-0.55], P < 0.01; 300 min: 0.86 +/- 0.36 micrograms/mL [0.35-1.25] vs 0.34 +/- 0.12 micrograms/mL [0.18-0.57], P < 0.01). The results of our study show that despite applying the same dosage of epidural bupivacaine significantly higher plasma concentrations were seen after short periods of continuous infusion in infants up to 4 mo than in children older than 9 mo.

Benefit and Risks of Local Anesthetics in Infants and Children

“…While the specific relationship between free bupivacaine concentration and toxicity has not been studied in infants and children, measured free bupivacaine concentrations exceeding 0.2 μg/ml are a cause for concern. The principal binding protein for bupivacaine is α 1 -acid glycoprotein; [21][22][23][24][25][26] α 1 -acid glycoprotein levels, and thus bupivacaine free fractions, in older infants and children are comparable to the values seen in adults. [22,23,25] On the other hand, α 1 -acid glycoprotein levels in neonates and infants younger than 6 months can be less than 50% of those seen in children and adults, and free bupivacaine concentrations can exceed 20%.…”

“…The principal binding protein for bupivacaine is α 1 -acid glycoprotein; [21][22][23][24][25][26] α 1 -acid glycoprotein levels, and thus bupivacaine free fractions, in older infants and children are comparable to the values seen in adults. [22,23,25] On the other hand, α 1 -acid glycoprotein levels in neonates and infants younger than 6 months can be less than 50% of those seen in children and adults, and free bupivacaine concentrations can exceed 20%. [21][22][23][24][25][26]158] Levels of α 1 -acid glycoprotein can be particularly low in premature infants, [22] but increase during early infancy and approach adult values by 6 months of age.…”

“…Of greater concern, neonates have decreased plasma concentrations of albumin and α 1 -acid glycoprotein, the principal binding protein for local anesthetics; [21][22][23][24][25][26] decreased levels of α 1 -acid glycoprotein may persist until 3 to 6 months of age. As a result, the free fraction of highly protein-bound local anesthetics such as bupivacaine and etidocaine may be elevated in younger infants, even if the absolute plasma concentration is within the accepted 'safe' range.…”

“…First, except in neonates, the Vd ss , clearance and t 1 ⁄2 values for bupivacaine in infants and children are comparable to those seen in adults. [21,[23][24][25]54,77,93,96,97,[151][152][153][154][155][156][157][158][159][160][161][162][163][164][165][166][167][168] Second, in neonates and younger infants, although the clearance is still comparable to that in adults, the Vd ss , and thus the t 1 ⁄2 , are greater than the corresponding values in adults. [21,164] Third, in many of the studies looking at continuous infusions of bupivacaine, the maximum concentration of bupivacaine was seen either at or near the termination of the infusion or at the time of the last sample, suggesting that accumulation of bupivacaine was occurring during the infusion.…”

“…[21,164] Third, in many of the studies looking at continuous infusions of bupivacaine, the maximum concentration of bupivacaine was seen either at or near the termination of the infusion or at the time of the last sample, suggesting that accumulation of bupivacaine was occurring during the infusion. [23,53,144,156,157,166] Finally, many of the studies of continuous infusion of bupivacaine in infants and children found at least some individuals to have bupivacaine concentrations approaching or exceeding the accepted toxic threshold of 4 μg/ml. [54,144,145,157,165,166] Also of concern, some studies examining bupivacaine pharmacokinetics in infants found at least some individuals with elevated free (unbound) bupivacaine concentrations.…”