Luciana de Barros Duarte

Distribution of fentanyl in the placental intervillous space and in the different maternal and fetal compartments in term pregnant women

BackgroundFentanyl is used in obstetrical practice to promote analgesia and anesthesia during labor and in cesarean delivery, with rapid and short-term effects.ObjectiveTo determine fentanyl concentrations in maternal plasma, in the placental intervillous space, and in the umbilical artery and vein in term pregnant women.Patients and methodsTen healthy pregnant women underwent epidural anesthesia with fentanyl plus bupivacaine and lidocaine, and fentanyl concentrations were determined in the various maternal and fetal compartments, including the placental intervillous space, which has not been previously studied in the literature.ResultsThe ratios of fentanyl concentrations in the various maternal and fetal compartments revealed an 86% rate of placental fentanyl transfer. The highest fentanyl concentrations were detected in the placental intervillous space, being 2.19 times higher than in maternal plasma, 2.8 times higher than in the umbilical vein and 3.6 times higher than in the umbilical artery, with no significant differences between the umbilical vein and artery, demonstrating that there was no drug uptake by fetal tissues nor metabolism of the drug by the fetus despite the high rates of placental transfer.ConclusionThe present study demonstrated that the placental intervillous space acted as a site of fentanyl deposit, a fact that may be explained by two hypotheses: (1) the blood collected from the placental intervillous space is arterial and, according to some investigators, the arterial plasma concentrations of the drugs administered to patients undergoing epidural anesthesia are higher than the venous concentrations, and (2) a possible role of P-glycoprotein (P-gp).

Distribution of Bupivacaine Enantiomers and Lidocaine and Its Metabolite in the Placental Intervillous Space and in the Different Maternal and Fetal Compartments in Term Pregnant Women

The aim of this study is to determine the concentrations of lidocaine and its metabolite, monoethylglycine xylidide (MEGX), and of the enantiomers of bupivacaine in maternal and fetal compartments. Ten healthy pregnant women were submitted to epidural anesthesia. Drug concentrations were determined in the maternal vein, fetal umbilical artery and vein, and the placental intervillous space. The highest concentrations of the bupivacaine enantiomers lidocaine and of lidocaine and of its MEGX metabolite were detected in maternal plasma and in the placental intervillous space. The placental transfer was 33% for the (+)‐(R)‐bupivacaine enantiomer and 31% for the (−)‐(S)‐bupivacaine enantiomer. For lidocaine and its MEGX metabolite, respective placental transfers were 60% and 43%. Lidocaine concentration in the fetal umbilical vein was 1.46 times higher than in the fetal umbilical artery. The highest concentrations of lidocaine and its metabolite and of the enantiomers of bupivacaine were detected in the placental intervillous space. The higher lidocaine concentrations in the fetal umbilical vein than in the fetal umbilical artery suggest that there was tissue uptake of the drug or drug metabolization by the fetus.

Placental transfer of bupivacaine enantiomers in normal pregnant women receiving epidural anesthesia for cesarean section

Professor Dahlqvist, Bupivacaine [(±)-1-butyl-N-(2,6-dimethylphenyl)-2piperidine carboxamide] is probably the most frequently used drug for epidural anesthesia in obstetrics and is available as a racemic mixture of the (+)-(R) and (−)-(S) enantiomers [1, 2]. It has been that reported bupivacaine can cause adverse cardiovascular events in pregnant women, but only following its accidental injection into the intravascular space during anesthetic procedures [2]. However, other investigators have reported that the concentrations used in obstetrical procedures are so low that they do not raise concern in terms of adverse effects, even when accidentally injected into the intravascular space [3]. Bupivacaine is a chiral drug, and one of its enantiomers has been found to have a less toxic profile than that of racemic bupivacaine itself: (−)-S bupivacaine is equal to racemic bupivacaine in terms of local anesthetic potency, but it has a reduced potential for central nervous system and cardiovascular toxicity [4]. Studies on human volunteers have demonstrated differences in cardiotoxicity between (−)-S bupivacaine and racemic bupivacaine, with the reduction in myocardia mobility being 40–60% less following the infusion of the former than after racemic bupivacaine infusion, as measured by acceleration index, stroke index and ejection fraction [1]. Epidural 0.5% (−)-S bupivacaine and 0.5% racemic bupivacaine are equally efficacious anesthesia in cesarean deliveries. In addition, following the administration of (−)-S bupivacaine and racemic bupivacaine, no significant differences were observed between them in terms of maximum plasma concentration or area under the plasma drug concentration versus time curve [4]. Based on these findings, the use of racemic bupivacaine is currently being questioned, and it has been proposed that it should be definitively replaced with its enantiomers, which are considered to be safer. We report here a clinical evaluation of mothers and newborn infants that was carried out with the aim of determining maternal concentrations and the placental transfer of the enantiomers of bupivacaine in pregnant women undergoing cesarean section with epidural anesthesia. The concentrations of the enantiomers of bupivacaine and their placental transfer were determined in ten healthy pregnant women with similar anthropometric characteristics who were being given a cesarean section due to obstetrical indication. The patients were selected in an aleatory manner, without randomization. The study was approved by the Ethics Committee of the University Hospital, Faculty of Medicine of Ribeirão Preto, University of São Paulo, and all patients gave written informed consent to participate. Eur J Clin Pharmacol (2007) 63:523–526 DOI 10.1007/s00228-007-0275-7