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ORIGINAL ARTICLE| Volume 23, ISSUE 3, P217-221, August 2014

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Evaluation of levobupivacaine passage to breast milk following epidural anesthesia for cesarean delivery

Open AccessPublished:March 20, 2014DOI:https://doi.org/10.1016/j.ijoa.2014.03.005

      Highlights

      • Levobupivacaine is the pure S(−)-enantiomer of racemic bupivacaine.
      • We investigated whether levobupivacaine passes into breast milk.
      • Levobupivacaine was detected in breast milk after 30 min of epidural administration.
      • Milk/plasma ratio of levobupivacaine based on AUC0–24 values was 0.34 ± 0.13.
      • The course of plasma and milk levels of levobupivacaine and bupivacaine were similar.

      Abstract

      Background

      Following maternal administration, local anesthetics pass into breast milk. In the present study, we aimed to compare the passage of levobupivacaine and bupivacaine into breast milk following epidural anesthesia for cesarean delivery.

      Methods

      A total of 20 women undergoing elective cesarean delivery under epidural anesthesia were randomized to receive either 0.5% levobupivacaine or 0.5% racemic bupivacaine via an epidural catheter. Immediately before and 30 min, 1 h, 2 h, 6 h, 12 h and 24 h after administration of epidural local anesthetic, maternal blood and breast milk samples were taken simultaneously. Drug concentrations in plasma and milk were determined via high-performance liquid chromatography. The infant’s drug exposure was determined by calculating milk/plasma ratios of levobupivacaine and bupivacaine.

      Results

      Both levobupivacaine and bupivacaine were detected in breast milk 30 min after epidural administration. Concentrations of both agents showed constant and similar decreases in milk and plasma and were nearly undetectable at 24 h. The milk/plasma ratios were 0.34 ± 0.13 for levobupivacaine and 0.37 ± 0.14 for bupivacaine.

      Conclusions

      Both levobupivacaine and bupivacaine pass into breast milk following epidural administration. The concentration of both drugs was approximately three times lower in breast milk than in maternal plasma.

      Keywords

      Introduction

      Although it is recommended that infants are fed breast milk for at least the first six months of life,
      • Kramer M.S.
      • Kakuma R.
      Optimal duration of exclusive breastfeeding.
      Breastfeeding and the use of human milk. American Academy of Pediatrics Work Group on Breastfeeding.
      some medications used by mothers during labor or breastfeeding can pass into breast milk and may be potential harmful to the infant.
      • Ito S.
      • Lee A.
      Drug excretion into breast milk – overview.
      • Spencer J.P.
      • Gonzales 3rd, L.S.
      • Barnhart D.J.
      Medication in the breast-feeding mother.
      Previous studies have shown that local anesthetics, such as racemic bupivacaine, lidocaine and ropivacaine pass into breast milk,
      • Ortega D.
      • Viviand X.
      • Lorec A.M.
      • Gamerre M.
      • Martin C.
      • Bruguerolle B.
      Excretion of lidocaine and bupivacaine in breast milk following epidural anesthesia for cesarean delivery.
      • Baker P.A.
      • Schroeder D.
      Interpleural bupivacaine for postoperative pain during lactation.
      • Matsota P.K.
      • Markantonis S.L.
      • Fousteri M.Z.
      • et al.
      Excretion of ropivacaine in breast milk during patient-controlled epidural analgesia after cesarean delivery.
      although it has been suggested that the use of bupivacaine for epidural anesthesia is safe with regard to breastfeeding.
      • Ortega D.
      • Viviand X.
      • Lorec A.M.
      • Gamerre M.
      • Martin C.
      • Bruguerolle B.
      Excretion of lidocaine and bupivacaine in breast milk following epidural anesthesia for cesarean delivery.
      To our knowledge, levobupivacaine transfer into human breast milk has not been studied. Therefore, we aimed to investigate the degree to which levobupivacaine passes into breast milk following epidural anesthesia for elective cesarean delivery.
      Transfer of medications into breast milk depends on pharmacological properties such as protein binding and lipid solubility, lower protein binding being associated with greater transfer.
      • Ito S.
      • Lee A.
      Drug excretion into breast milk – overview.
      Because protein binding of levobupivacaine (97%) is more than that of racemic bupivacaine (95%), we considered it might undergo less transfer into breast milk. Therefore, we also compared the maternal plasma and milk concentrations of both drugs.

      Methods

      The study was approved by the Firat University School of Medicine Clinical Research Ethics Committee, and written informed consent was obtained from all participants. Twenty American Society of Anesthesiologists physical status I or II parturients aged 18–40 years with singleton uncomplicated full-term pregnancy undergoing elective cesarean delivery under epidural anesthesia were included in this prospective, randomized, double-blind study. Exclusion criteria were obstetric problems (fetal anomaly, fetal growth restriction, fetal distress, preeclampsia, eclampsia, Rh incompatibility or congenital malformations), cardiac, renal or metabolic disorders, allergy or sensitivity to local anesthetics and use of medications known to affect the metabolism of levobupivacaine and bupivacaine. All participants underwent pre-anesthetic examination one day before surgery.
      Participants were randomized to one of two groups, by using a random number table, to receive either 0.5% bupivacaine (Group B, n = 10) or 0.5% levobupivacaine (Group L, n = 10). Parturients were blinded to randomization. Each woman received intravenous famotidine 40 mg and metoclopramide 10 mg, 30–45 min before induction of epidural anesthesia. In the operating room, electrocardiogram, heart rate, non-invasive arterial blood pressure and peripheral oxygen saturation (SpO2) were continuously monitored. An 18-gauge venous catheter was inserted into the dorsum of one hand and lactated Ringer’s solution 10 mL/kg was administered over 30 min before epidural anesthesia. An 18-gauge venous catheter was inserted into the dorsum of the other hand for blood sampling.
      An epidural catheter was inserted at the L3–4 vertebral level. The epidural space was identified using loss-of-resistance to saline with an 18-gauge Tuohy needle. After a test dose of 2% lidocaine 3 mL, 0.5% levobupivacaine (Chirocaine, Abbott, Elverum, Norway) was administered to parturients in Group L, and 0.5% racemic bupivacaine (Marcaine AstraZeneca, Istanbul, Turkey) to those in Group B. The study drugs were given as fractionated doses (initial dose 5 mL and further 5 mL increments as required to a maximum of 150 mg) via the epidural catheter until a sensory block extending to T6 to pinprick was achieved. Motor block was evaluated by using a modified Bromage scale (1: no block, ability to move feet and legs; 2: ability to move feet and knees and inability to flex hip; 3: ability to move feet only; 4: complete block, inability to move feet and legs). The beginning of the administration of study medications was considered time 0 for evaluation of both sensory and motor blockade. When a T6 sensory block was achieved, surgery was allowed to start. If adequate epidural anesthesia was not achieved, general anesthesia was administered and these parturients were excluded from subsequent analysis. Both sensory and motor block assessments were conducted by a researcher blinded to group allocation. The total amount of local anesthetic required and the duration of sensory and motor blockade were recorded.
      Immediately before and 30 min, 1 h, 2 h, 6 h, 12 h and 24 h after administration of epidural drugs, 2 mL samples of maternal blood and 2 mL samples of breast milk were taken simultaneously. Breast milk samples were collected with a milking pump (Pump-egnell, Ameda AG, Zug, Switzerland). Blood samples were centrifuged immediately after collection and the plasma extracted. Plasma and milk samples were stored at −20°C until analyses. Quantification of levobupivacaine and racemic bupivacaine was performed using high-performance liquid chromatography (HPLC; HP Agilent 1100, Germany) with fluorescence detection, using the method described by Papini et al.
      • Papini O.
      • Mathes A.C.
      • Cunha S.P.
      • Lanchote V.L.
      Stereoselectivity in the placental transfer and kinetic disposition of racemic bupivacaine administered to parturients with or without a vasoconstrictor.
      An HPLC C18 column (250 mm × 4.6 mm × 5 μm) was used as the stationary phase, and a mixture of acetonitrile methanol–water was used as the mobile phase. Levobupivacaine and bupivacaine solutions were prepared at methanol concentrations of 0.2, 0.4, 0.8, 1.6 and 2.4 μg/mL. The lower limit of detection was 5 ng/mL and values for intra-assay and inter-assay coefficients of variation were 9.5% and 4.9%, respectively.

      Statistical analysis

      Data are presented as median or mean ± standard deviation (SD) as appropriate. Data were analyzed using the Mann–Whitney U test, the chi-square test and the Wilcoxon signed-rank test using SPSS version 15.0 (IBM SPSS Inc., Chicago, IL, USA). Values of P < 0.05 were considered statistically significant. For analysis of concentrations of drugs in plasma and breast milk, the area under the concentration–time curve from time 0 to time 24 h (AUC0–24) was calculated using the trapezoidal rule using SigmaPlot version 8.0 (Systat Software Inc., Chicago, IL, USA). The two enantiomers of bupivacaine were measured separately, then summed. The milk/plasma (M/P) ratio for levobupivacaine and bupivacaine was calculated with the following formula:
      M/P ratio=Milk AUC024((μg/mL)·h)/Maternal plasma AUC024((μg/mL)·h)


      A power calculation for sample size was not performed as the primary aim of the study was to establish transfer of the study drugs into breast milk.

      Results

      Patient characteristics were similar between groups (Table 1). Epidural anesthesia was adequate in all patients and general anesthesia was not administered to any patient. There were no differences between groups in the characteristics of epidural anesthesia (Table 2). Nausea was observed in two patients in Group L and two patients in Group B; nausea and vomiting was observed in one patient in Group B.
      Table 1Patient characteristics
      Group L

      (n = 10)
      Group B

      (n = 10)
      Age (years)25.9 ± 7.028.8 ± 6.1
      Weight (kg)69.6 ± 9.471.5 ± 2.9
      Height (cm)160 ± 6.4159 ± 4.1
      ASA Physical Status Class I/II9/18/2
      Data are mean ± SD or number. ASA: American Society of Anesthesiologists.
      Table 2Characteristics of epidural anesthesia
      Group L

      (n = 10)
      Group B

      (n = 10)
      Total dose of local anesthetic (mg)80.0 ± 10.582.5 ± 12.1
      Time to achieve T6 block (min)16.3 ± 3.015.3 ± 3.4
      Maximum modified Bromage scale score33
      Duration of sensory block (min)320 ± 59332 ± 68
      Duration of motor block (min)142 ± 90135 ± 105
      Data are mean ± SD or number.
      Levobupivacaine was detected in both maternal plasma and breast milk 30 min after epidural administration. However, concentrations of levobupivacaine in breast milk were approximately three times lower than those in plasma. Plasma and milk concentrations of levobupivacaine showed constant and similar declines and were nearly undetectable 24 h after drug administration. The two enantiomers of racemic bupivacaine, (S(−)-bupivacaine and R(+)-bupivacaine), were also detected in both maternal plasma and breast milk 30 min after epidural administration. The course of both plasma and breast milk concentrations of bupivacaine was similar to that of levobupivacaine. As with levobupivacaine, the concentrations of racemic bupivacaine in breast milk were almost one-third of those in maternal plasma (Table 3). The profiles of plasma and breast milk concentrations versus time for levobupivacaine and bupivacaine are shown in Fig. 1, Fig. 2, respectively. There were no significant differences between the mean concentrations of levobupivacaine and bupivacaine in either plasma or breast milk at all evaluation points. In addition, no significant difference in AUC0–24 for both drugs was found. M/P ratios based on AUC0–24 values were 0.34 ± 0.13 and 0.37 ± 0.14 for levobupivacaine and racemic bupivacaine, respectively. There was no significant difference in M/P ratios between the two groups.
      Table 3Plasma and breast milk concentrations of levobupivacaine and bupivacaine
      Plasma AUC0–24

      ((μg/mL)·h)
      Milk AUC0–24

      ((μg/mL)·h)
      Milk/plasma ratio
      Levobupivacaine5.17 ± 0.981.71 ± 0.650.34 ± 0.13
      Bupivacaine (total)4.79 ± 1.901.73 ± 0.930.37 ± 0.14
      S(−)-bupivacaine2.60 ± 0.980.85 ± 0.620.32 ± 0.21
      R(+)-bupivacaine2.19 ± 0.930.88 ± 0.360.44 ± 0.19
      Values are mean ± SD. AUC0–24: area under the concentration–time curve from 0 to 24 h.
      Figure thumbnail gr1
      Fig. 1Mean maternal plasma and breast milk levobupivacaine concentration versus time. Period 1: immediately before drug administration. Periods 2, 3, 4, 5, 6 and 7: 30 min, 1, 2, 6, 12 and 24 h after drug administration.
      Figure thumbnail gr2
      Fig. 2Mean maternal plasma and breast milk racemic bupivacaine concentration versus time. Period 1: immediately before drug administration. Periods 2, 3, 4, 5, 6 and 7: 30 min, 1, 2, 6, 12 and 24 h after drug administration.

      Discussion

      This study demonstrated that levobupivacaine, like racemic bupivacaine, passes into breast milk. The concentration of levobupivacaine was approximately three times lower in breast milk than in plasma. The amount of both drugs in plasma and breast milk continuously decreased and was nearly undetectable 24 h after administration. Previous studies have shown that bupivacaine is transferred into breast milk,
      • Ortega D.
      • Viviand X.
      • Lorec A.M.
      • Gamerre M.
      • Martin C.
      • Bruguerolle B.
      Excretion of lidocaine and bupivacaine in breast milk following epidural anesthesia for cesarean delivery.
      • Baker P.A.
      • Schroeder D.
      Interpleural bupivacaine for postoperative pain during lactation.
      but to our knowledge this is the first report showing that levobupivacaine also passes into breast milk.
      Although breast milk is an optimal food for infants, transmission of medicines used by the mother to breast milk can potentially cause adverse effects in infants. Therefore, when a new medicine is given to a nursing mother, there is concern about exposure through milk. It has been suggested that medications can be easily transferred to milk, especially during the first two weeks postpartum because gaps between mammary cells are not yet closed during that period.
      • Spencer J.P.
      • Gonzales 3rd, L.S.
      • Barnhart D.J.
      Medication in the breast-feeding mother.
      It is, therefore, important to know whether anesthetics and/or analgesics administered to the parturient during delivery are transferred to breast milk. Previous studies have shown that some local anesthetics can be transferred to breast milk.
      • Ortega D.
      • Viviand X.
      • Lorec A.M.
      • Gamerre M.
      • Martin C.
      • Bruguerolle B.
      Excretion of lidocaine and bupivacaine in breast milk following epidural anesthesia for cesarean delivery.
      • Matsota P.K.
      • Markantonis S.L.
      • Fousteri M.Z.
      • et al.
      Excretion of ropivacaine in breast milk during patient-controlled epidural analgesia after cesarean delivery.
      • Giuliani M.
      • Grossi G.B.
      • Pileri M.
      • Lajolo C.
      • Casparrini G.
      Could local anesthesia while breast-feeding be harmful to infants?.
      In the present study, we have demonstrated that levobupivacaine also passes into breast milk.
      The passage of drugs into breast milk usually occurs via passive diffusion proportional to the concentration of drug in maternal plasma. In addition, physicochemical characteristics such as molecular weight, lipid solubility, protein-binding and pKa are important.
      • Spencer J.P.
      • Gonzales 3rd, L.S.
      • Barnhart D.J.
      Medication in the breast-feeding mother.
      • Hale T.W.
      Maternal medications during breastfeeding.
      High rates of transfer of levobupivacaine to breast milk may be expected because of its low molecular weight, lipophilicity, weak basic structure and ease of transport to the central nervous system.
      • McLeod G.A.
      • Burke D.
      Levobupivacaine.
      However, in the present study, levobupivacaine was detected in breast milk at approximately one-third of the concentration in maternal plasma. This might be because levobupivacaine is 97% bound to plasma proteins, especially α1-acid glycoprotein. Only non-ionized portions of compounds that are not bound to plasma proteins can be transferred to breast milk.
      It is also important to quantify infant drug exposure, for which M/P ratio is the most commonly used parameter. This can be calculated using several formulae.
      • Fleishaker J.C.
      Models and methods for predicting drug transfer into human milk.
      Ortega et al.
      • Ortega D.
      • Viviand X.
      • Lorec A.M.
      • Gamerre M.
      • Martin C.
      • Bruguerolle B.
      Excretion of lidocaine and bupivacaine in breast milk following epidural anesthesia for cesarean delivery.
      reported the M/P ratio for bupivacaine as 0.34 for women undergoing cesarean delivery, which was dependent on the AUC0–12 values for bupivacaine when administered epidurally. In our study, the M/P ratio was calculated via a formula dependent on AUC0–24 values. We found levobupivacaine and bupivacaine M/P ratios were <1 (0.34 and 0.36, respectively), statistically indistinguishable from each other, and consistent with the findings of Ortega.
      • Ortega D.
      • Viviand X.
      • Lorec A.M.
      • Gamerre M.
      • Martin C.
      • Bruguerolle B.
      Excretion of lidocaine and bupivacaine in breast milk following epidural anesthesia for cesarean delivery.
      Santos et al.
      • Santos A.C.
      • Karpel B.
      • Noble G.
      The placental transfer and fetal effects of levobupivacaine, racemic bupivacaine, and ropivacaine.
      administered levobupivacaine, racemic bupivacaine and ropivacaine to pregnant ewes intravenously. Following administration, they detected these drugs in fetal plasma and tissues. Bader et al.
      • Bader A.M.
      • Tsen L.C.
      • Camann W.R.
      • Nephew E.
      • Datta S.
      Clinical effects and maternal and fetal plasma concentrations of 0.5% epidural levobupivacaine versus bupivacaine for cesarean delivery.
      administered levobupivacaine and bupivacaine epidurally to women undergoing elective cesarean delivery. They determined that concentrations of these two drugs in umbilical venous blood samples taken during delivery were one-third lower than those in the maternal plasma. These two studies demonstrate that both levobupivacaine and bupivacaine cross the placenta to the fetus. Therefore, it should be taken into account that, in addition to breast milk, infants are exposed to local anesthetic drugs via the placental pathway.
      In conclusion, both levobupivacaine and racemic bupivacaine pass into breast milk following epidural administration. In both groups, maternal plasma and milk concentration–time profiles were similar.

      Disclosure

      The study was supported by departmental funds and the authors have no conflicts of interest to declare.

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