Kommersiellt obunden läkemedelsinformation riktad till läkare och sjukvårdspersonal

Drugline nr 11607

Publicerat 1994-09-30

Question

What is known about passage of lidocaine and bupivacaine into breast milk?

Answer

The disposition kinetics and placental transfer of the amide type local anesthetics (lidocaine and bupivacaine) have been well characterized. Very little is known, however, about their excretion to milk, and even less information is available concerning the ensuing concentrations or effects in breast milk fed infants. For local anesthetics in general, it is characteristic that relatively low systemic levels are seen in relation to clinically applicable doses. This is partly due to usual routes of administration (aiming at local instead of systemic effects). This can also be due to the pharmacokinetic characteristics of these drugs.

The pH of milk favors passive diffusion of basic drugs like amide type local anesthetics to milk due to ion trapping. Increases in the unbound fractions of lidocaine and bupivacaine have been observed during pregnancy (1). Thus, this represents another factor which could increase the milk to plasma (M/P) ratio and excretion of these agents in milk - at least in the early post-partum period. In addition, plasma protein binding of lidocaine and bupivacaine in cord or infant serum are lower than in adult serum (2). Our current knowledge about lidocaine and bupivacaine milk concentrations is based on a few case reports described in the literature. A Medline search covering years 1966-1994 was performed for this review.

There is a case report describing lidocaine excretion in milk during intravenous treatment of ventricular arrhythmias (3). Concentration of lidocaine in milk was 40 per cent of mother's serum concentration (ie M/P ratio of 0.4). It was calculated that if a maximum allowed serum concentration (5 ug/ml) is maintained, the total daily dose for the infant would be 1.4 mg (0.35 mg/kg) assuming a daily milk consumption of 700 ml. The weight-adjusted relative dose would be less than one per cent. Thus, the dose to the infant appears to be very small even in this "worst case" scenario. A newborn child or even a fetus are capable of metabolizing lidocaine. An elimination half-life of approximately 3 h has been reported in infants (4,5), ie almost double to that of adults. This is most probably due to increased volume of distribution. Total plasma clearance normalized to body weight showed no significant difference between neonates and adults (6).

The plasma concentrations of lidocaine in the nursing mother remain, however, much lower than 5 ug/ml in most clinical situations (ie after local or regional anesthesia). In a recent case report, a significantly higher M/P ratio (1.1 for lidocaine, 1.8 for monoethylglycinexylidine) was found after a single 20 mg lidocaine injection for dental extraction (7). The calculated daily infant doses for the parent drug and the metabolite were both less than 0.01 mg/kg. In studies using relatively rough estimates of the well-being of newborn infants (eg Apgar score, weight gain), no harmful effects associated with the use of local anesthetics have been observed (8). The American Academy of Pediatrics considers lidocaine as a safe drug for nursing mothers (9).

In a case report, milk bupivacaine concentrations were below the detection limit (0.02 ug/ml) after cesarean section under epidural anesthesia (10). This finding fits to the high plasma protein binding and ionisation of the drug. There is also an interesting case report where bupivacaine was given as a continuous infusion into the interpleural space for postoperative pain control to a nursing mother (11). After a bolus dose of 50 mg a maintenance infusion was given for 5 days at a rate of 25 mg/h. Concentration in the milk was 0.4 ug/ml after 6 hours and declined thereafter to 0.1 ug/ml. 60 h after starting the treatment no detectable plasma levels were observed in the infant. The total daily amount to the newborn would thus be only 0.06 mg/kg even using the higher concentration in the calculation. The respective weight-adjusted relative dose would thus be only 0.6 per cent.

The blood levels of bupivacaine after lumbar epidural anesthesia have been measured in 6 mothers and their infants during and after the delivery (12). Maternal blood levels were over three times higher than umbilical vein levels at delivery. The disappearance of bupivacaine from the blood was, however, significantly lower in newborns than in adults. An average plasma half-life of 25 h was observed. These results strongly suggest that neonates are less able to metabolize this drug than adults.

Conclusion

Systematic documentation of milk passage of lidocaine and bupivacaine is missing. Based on case reports described in the literature small amounts are excreted into milk, but total amounts to the infants appear to be negligible.

Scheinin H
Alvan G

References

  1. Perucca E, Crema A: Plasma protein binding of drugs in pregnancy. Clin Pharmacokinet 1982; 7: 336-352
  2. Tucker GT, Boyes RN, Bridenbaugh PO: Binding of anilide-type local anesthetics in human plasma. II Implications in vivo, with special reference to transplacental distribution. Anesthesiology 1970; 33: 304-314
  3. Zeisler JA, Gaarder TD, De Mesquita SA: Lidocaine excretion in breast milk. Drug Intell Clin Pharm 1986; 20: 691-693
  4. Brown WU Jr, Bell GC, Lurie AO, Weiss JB, Scanlon JW, Alper MH: Newborn blood levels of lidocaine and mepivacaine in the first postnatal day following maternal epidural anesthesia. Anesthesiology 1975: 42: 698-707
  5. Kuhnert BR, Knapp DR, Kuhnert PM, Prochaska AL: Maternal, fetal, and neonatal metabolism of lidocaine. Clin Pharmacol Ther 1979; 26: 213-220
  6. Mihaly WG, Moore RG, Thomas J, Triggs EJ, Thomas D, Shanks CA: The pharmacokinetics and metabolism of the anilide local anaesthetics in neonates. I Lignocaine. Eur J Clin Pharmacol 1978; 13: 143-152
  7. Lebedevs TH, Wojnar-Horton RE, Yapp P, Roberts MJ, Dusci LJ, Hackett LP, Ilett K: Excretion of lignocaine and its metabolite monoethylglycinexylidine in breast milk following its use in a dental procedure. A case report. J Clin Periodontol 1993; 20: 606-608
  8. Abouleish E, Van der Donck A, Meeuwis H, Talylor F: Effect of anaesthesia for delivery on the weight of infants during the first 5 days of life. Br J Anaesth 1978; 50: 569-574
  9. American Academy of Pediatrics: Transfer of drugs and other chemicals into human milk. Pediatrics 1989; 84: 924-936
  10. Naulty JS, Ostheimer G, Datta S, Weiss JB: Bupivacaine in breast milk following epidural anesthesia for vaginal delivery. Regional Anesthesia 1983; 8: 44-45
  11. Baker PA, Schroeder D: Intrapleural bupivacaine for postoperative pain during lactation. Anesth Analg 1989; 69: 400-402
  12. Caldwell J, Mofatt JR, Smith RL, Lieberman BA, Cawston MO, Beard RW: Pharmacokinetics of bupivacaine administered epidurally during childbirth. Br J Clin Pharmacol 1976; 3: P956-957

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