Bupivacaine is commonly used for labor epidural analgesia because of its long duration of action and relative motor sparing when compared with other local anesthetics (1). Ropivacaine and levobupivacaine are newer local anesthetics that have similar pharmacokinetic and pharmacodynamic properties as bupivacaine. These newer local anesthetics may confer less lower-extremity motor block than bupivacaine after epidural administration, which may be advantageous (2–4). Increasing the motor block to the perineal or abdominal muscles from epidural local anesthetic may interfere with normal internal rotation of the fetal head (5), whereas minimizing motor block during labor may allow for normal progression of labor that may translate into fewer instrumental deliveries and more vaginal deliveries (6), although this is controversial (7).
We are aware of only one study that specifically addressed the issue of obstetric outcome vis-a-vis mode of delivery with epidural ropivacaine versus bupivacaine in the nulliparous woman and the authors did not find a difference between the groups (8). We are not aware of any investigations specifically designed to study mode of delivery with epidural levobupivacaine versus either bupivacaine or ropivacaine, and there have been no studies comparing all three.
The primary purpose of this study was to determine if there is a difference in mode of delivery in nulliparous women among the three local anesthetics bupivacaine, ropivacaine, or levobupivacaine when administered for labor epidural analgesia. Additionally, the quality of analgesia, influence on other labor characteristics, and neonatal outcome were assessed.
The protocol was approved by our IRB, and written, informed consent was obtained from each parturient before she requested an epidural anesthetic. Nulliparous women, either in spontaneous or induced labor, between 37 and 41 wk gestational age with a singleton baby in the vertex position, whose cervix was ≤4 cm dilated and were contracting at least once every 5 min, and who requested epidural analgesia were enrolled in this prospective, randomized study. If the woman did not request an epidural catheter for pain relief or if her cervix was >4 cm at the time of epidural analgesia request, she was withdrawn from the study. Women with insulin-dependent diabetes mellitus, severe preeclampsia, spinal column disorders, including scoliosis and herniated discs, and women who had undergone spine surgery were excluded from participation.
After the woman requested labor epidural analgesia, she was randomly assigned to receive one of three local anesthetics, bupivacaine, ropivacaine, or levobupivacaine. A table of random numbers generated the randomization sequence. The results of the randomization were sealed in opaque envelopes and opened sequentially by an anesthesiologist not participating in the study. The patient, obstetrician, and anesthesiologist were unaware of group assignment.
Before placement of the epidural catheter, the woman was asked to quantify her level of pain on a verbal 0–10 scale, with 0 being no pain and 10 being the worst imaginable pain. All epidural catheters were placed with the woman in the sitting position. Using a 17-gauge Touhy needle, the epidural space was identified via a midline approach at the L3–4 or L4–5 interspace using the loss-of-resistance-to-air technique. After the epidural space was located, a 20-gauge multiorifice catheter was threaded through the cranially directed tip of the epidural needle to a depth of 5 cm into the epidural space. No local anesthetic was injected through the epidural needle before epidural catheter placement.
While the woman was still sitting, attempts to aspirate blood or cerebrospinal fluid via the catheter were made. If there was no aspirate, a 3 mL test dose of the study medication at a concentration of 0.25% was administered through the catheter. The presence of clinical signs of an intravascular injection were sought for the following 2–3 min by asking the woman if she felt dizzy, had tinnitus, or had a metallic taste in her mouth (9). If there were no signs of an intravascular injection, the catheter was secured and the woman was placed in the supine position with left uterine displacement.
Five minutes after the test dose, if there were no clinical signs of subarachnoid injection as evidenced by the woman’s ability to move her legs, the patient received 15 mL of the study local anesthetic at a concentration of 0.0625% with 2 μg/mL of fentanyl. Fifteen minutes later, the patient was asked if she required additional medication for labor analgesia. If the patient did not require additional medication, an epidural infusion of the study local anesthetic was started at a concentration of 0.0625% with 2 μg/mL of fentanyl at 10 mL/h to maintain the analgesia. Just before starting the infusion, the patient’s arterial blood pressure and a pain score (0–10) were assessed. Ephedrine to treat hypotension was at the discretion of the anesthesiologist, but was generally given if the patient was symptomatic. Additionally, the degree of motor block in the right and left lower extremities was assessed with the modified Bromage scale (0 = No motor block; 1 = unable to raise extended leg, able to move knees and foot; 2 = unable to raise extended leg or knees, able to move foot; 3 = complete motor block of lower limb), and the presence of pruritus (0–10 scale), nausea (0–10 scale), and vomiting (yes or no) was sought.
If the patient required additional medication for analgesia at 15 min, an additional 8 mL of study local anesthetic at a concentration of 0.125% with 100 μg of fentanyl was administered in divided doses. Fifteen minutes later, the patient was asked if she required additional medication for analgesia. If so, then 5 mL of the study medication at a concentration of 0.25% was administered. If the patient was not comfortable 15 min after this dose, the study was concluded. If the patient did not require additional local anesthetic for analgesia, then an epidural infusion of the study local anesthetic at a concentration of 0.0625% with 2 μg/mL of fentanyl at 10 mL/h was started. Just before starting the infusion, the patient was monitored as described above.
The woman was monitored throughout labor at 1-h intervals until delivery, in the same manner as she was monitored before the infusion was started. If during labor the patient required additional medication for analgesia (top-up doses), she first received 8 mL of the study local anesthetic at a concentration of 0.125% with 100 μg of fentanyl. If this was not sufficient, then 5 mL of the study local anesthetic at a concentration of 0.25% was administered. If this was not sufficient, additional study local anesthetic or lidocaine 2% was administered at the discretion of the anesthesiologist. The epidural infusion was continued through the second stage of labor until delivery of the fetus.
The obstetricians at our hospital use an active management of labor protocol including early amniotomy and aggressive oxytocin use. Oxytocin is started at 1–2 mU/min and increased by 1–2 mU/min until contractions occur every 2–3 min. During the second stage of labor, the mother is encouraged to “bear down” during the contraction to aid with fetal head descent. If after 2–3 h the baby has not yet delivered vaginally, either a low outlet forcep delivery or cesarean delivery would be performed, as indicated. The final decision for forcep or cesarean delivery is at the discretion of the obstetrician.
At the time of delivery, the mode of delivery (vaginal, instrumental-assisted vaginal delivery, or cesarean) as well as the total dose of local anesthetic and fentanyl, and the total number of top-up doses were recorded. The neonate was assessed at birth with the Apgar score at 1 and 5 min postdelivery. Additionally, the need for ventilatory assistance and intensive care unit admission was recorded.
The primary end-point of this study was whether there was a difference in the operative delivery rate (instrumental-assisted vaginal delivery plus cesarean delivery) among groups. The study was planned originally to test whether the operative delivery rate among patients randomized to receive ropivacaine and those randomized to receive levobupivacaine differed from patients randomized to receive bupivacaine. However, part way through the study (after 37 women were randomized to the levobupivacaine group), the manufacturer of levobupivacaine (Purdue Pharma, LP, Norwalk, CT) stopped marketing the medication in the United States. Although differences among the three original groups are still considered of interest, the study is now only powered to compare bupivacaine and ropivacaine. The statistical analysis is therefore presented separately for ropivacaine versus bupivacaine and again comparing all three groups.
The sample size was originally set to enroll 110 patients receiving each of the three drugs, to assure 80% power for two 2-tailed tests: bupivacaine versus ropivacaine and bupivacaine versus levobupivacaine, each at the 0.025 significance level. When levobupivacaine was withdrawn, only 37 patients in that arm had been enrolled, and the decision was made to focus the study on the first comparison, but to report the levobupivacaine results for their general interest. At that time, the sample size calculations were modified to reflect this change, resulting in the sample size of 91 patients in each of two groups to assure 80% power for one continuity corrected χ2 test at the 0.05 two-sided significance level, if the “true” proportions in the two groups were 0.40 and 0.20. Differences among groups were analyzed with the χ2, Kruskal–Wallis, or Wilcoxon’s ranked sum test, as appropriate. Bromage scores were classified as positive (≥1) or negative. Differences among groups in the odds of a positive Bromage score were tested using Generalized Estimating Equation methodology, with repeated observations clustered within individuals and an autoregressive correlation structure. The same method was used to analyze the repeated observations of pruritus and nausea. Differences were considered significant at P < 0.05.
We consented 278 women and enrolled 232. Some women (n = 46) were not studied because they did not request an epidural anesthetic, or because they requested analgesia after the woman’s cervix was >4 cm dilated, or because they requested analgesia when the research team was unavailable. Of the 232, 100 were randomized to the bupivacaine group, 95 to the ropivacaine group, and 37 to the levobupivacaine group. Ten were withdrawn from the study because they did not achieve analgesia during the initial part of the study, two in the bupivacaine group, five in the ropivacaine group, and three in the levobupivacaine group. This left 222 women for complete analysis, 98 in the bupivacaine group, 90 in the ropivacaine group, and 34 in the levobupivacaine group. There were six women who received epidural lidocaine during labor, four in the bupivacaine group, and one each in the ropivacaine and levobupivacaine groups. Demographic and initial labor characteristics are presented in Table 1.
Obstetric outcomes, including the duration of the first and second stage of labor, were similar among groups (Table 2). The operative delivery rate was greatest in the bupivacaine group (46%, confidence interval: 36%–56%), intermediate in the ropivacaine group (39%, confidence interval: 29%–49%) and smallest in the levobupivacaine group (32%, confidence interval 16%–48%), P = 0.35. The spontaneous vaginal delivery rate was smallest in the bupivacaine group (54%), intermediate in the ropivacaine group (61%), and greatest in the levobupivacaine group (68%). The cesarean delivery rate was greatest in the bupivacaine group (33%), intermediate in the ropivacaine group (30%), and smallest in the levobupivacaine group (26%).
We did not find a statistically significant difference among groups with regard to the percentage of women who achieved analgesia after the first 15 mL of medication, P = 0.31 (Table 2). Also, there was no significant difference among groups in the total milligram dose of local anesthetic received per hour or the number of top-up doses per hour required during labor.
There was more motor block on the left than on the right in all three groups, and we found that the incidence of motor block increased as the duration of labor increased. On the left side, we found the greatest degree of motor block in the bupivacaine group followed by the ropivacaine group followed by the levobupivacaine group, P < 0.05 (Fig. 1). On the right side, there was significantly more motor block in the bupivacaine group than in the ropivacaine or levobupivacaine group, but there was no significant difference between the ropivacaine and levobupivacaine group (Fig. 2). Very few women required ephedrine during the study, two were in the bupivacaine group and six were in the ropivacaine group. The decrease in arterial blood pressure was mild in all cases (systolic blood pressure was always >80) and was treated with ephedrine 10 mg. We did not find a significant difference in the incidence of nausea among groups (Fig. 3), but there was significantly more pruritus in the bupivacaine and ropivacaine groups when compared with the levobupivacaine group, P = 0.04 (Fig. 4).
There was no significant difference in neonatal outcome among groups, including the average Apgar score and the percentage with an Apgar score <7 both at 1 and 5 min postdelivery. Furthermore, there was no significant difference in the need for neonatal resuscitation (Table 3).
We did not find a statistically significant difference in the operative delivery rate among nulliparous women who received low-dose epidural bupivacaine, ropivacaine, or levobupivacaine for labor analgesia before 5 cm dilation. We cannot be certain that had we enrolled the full complement of levobupivacaine patients their spontaneous vaginal delivery rate would have remained the same (68%). However, if that were the case, the conclusion would not have changed, although the P value would have been reduced from 0.35 to 0.17. Furthermore, there was no significant difference in other labor characteristics among the groups, including the duration of either the first or second stage of labor.
We are aware of only two other studies that were specifically designed to address the question of obstetric outcome when women were randomized to low-dose bupivacaine versus ropivacaine (8,10). Similar to the results of our study, neither of these found a difference between groups. However, there are important differences in study design. We only enrolled nulliparous women with a cervical dilation <4 cm, but Halpern et al. (8) enrolled nulliparous women at all cervical dilations, and Lee et al. (10) enrolled women of mixed parity, also at all cervical dilatations. Another important consideration is that the instrumental delivery rate is >70% at Lee et al.’s hospital (10), which may be more than that found at other hospitals and extrapolation to other places with smaller operative delivery rates may not be suitable. It should be noted that in both our study and that done by Halpern et al. (8) the operative delivery rate was approximately 40%, which still may be more than that found at other centers.
Halpern and Walsh (11) also performed a meta-analysis of published studies in which women received epidural ropivacaine or bupivacaine for labor analgesia to determine if there would be a difference in obstetric outcome and they were not able to find one. However, the meta-analysis primarily included women who received large concentrations (>0.125%) of local anesthetics as well as low concentration. We are not aware of any study that specifically addressed obstetric outcome with levobupivacaine versus either bupivacaine or ropivacaine.
There have been a number of additional studies in which women were randomized to receive epidural ropivacaine or bupivacaine (12–15), or ropivacaine versus levobupivacaine (16), or bupivacaine versus levobupivacaine (17) for labor analgesia with the goal to assess the efficacy of analgesia or optimal dose for analgesia. The primary end-point of these studies, however, was not mode of delivery, and the studies were not adequately powered to address that issue, although it was reported. Similar to our results, none of these studies found a difference in mode of delivery between groups.
In contrast to the results of these studies, Writer et al. (18) performed a meta-analysis of six prospective studies that compared bupivacaine 0.25% to ropivacaine 0.25% and they found fewer instrumental-assisted vaginal deliveries in the ropivacaine group. But, none of those studies were specifically designed to study obstetric outcome, and all the studies included in the meta-analysis used large concentrations of local anesthetics.
The association between epidural analgesia and operative delivery has been debated. One theory is that an increase in the operative delivery rate from epidural analgesia may be related to motor block in the perineal or abdominal muscles generated by the epidural local anesthetic leading to dystocia (5). The resultant motor block may lead to abnormal internal rotation of the fetal head. This hypothesis has been supported by investigators who found a greater operative delivery rate in women randomized to receive high concentration (>0.125%) of local anesthetics versus low concentration (6,19). Therefore, a local anesthetic that confers the least amount of motor block may be the best choice for labor epidural analgesia. It would be best to measure perineal or abdominal muscle tone, but this is difficult to accomplish clinically, and we therefore chose to measure lower extremity motor block, as do most investigators (6,8), as a surrogate for perineal muscle blockade.
At our hospital, management of labor was fairly consistent among groups. However, the ultimate decision of when to perform an instrumental-assisted vaginal delivery or cesarean delivery was at the discretion of the individual obstetricians. Individual practice should not have influenced our results since women were randomized to treatment group. It is important to note that at our hospital overall the instrumental vaginal delivery rate is approximately 10% and the operative delivery rate is approximately 40%. Results should be extrapolated only to hospitals with similar practice patterns.
Lacassie et al. (20,21) found, in two separate studies, that the minimum local anesthetic concentration for motor block of both ropivacaine and levobupivacaine is more than that of bupivacaine. Most studies designed to compare the resultant motor block of epidural bupivacaine versus ropivacaine have found less motor block with ropivacaine, although the differences are usually most pronounced after many hours of labor (3,4,8,22). Vercauteren et al. (17) also found less motor block with levobupivacaine than bupivacaine, but Purdie and McGrady (16) did not find a difference in motor block between levobupivacaine and ropivacaine. Camorcia and Capogna (23), in the only study that compared all three local anesthetics at low concentrations for labor epidural analgesia, did not find any difference in the motor block among groups. But, they administered only one bolus of the local anesthetic and assessed motor block 30 min later, not throughout the course of a potentially long labor. We found that levobupivacaine conferred the least amount of motor block followed by ropivacaine and then bupivacaine. Nonetheless, we did not find a statistically significant difference in mode of delivery, although there was a trend for a smaller operative delivery rate in the levobupivacaine group (32%) versus the ropivacaine (46%) and bupivacaine (49%) group. This may warrant further study, since few patients were enrolled to receive levobupivacaine.
It should be mentioned that we found more motor block in each group in the left leg than in the right leg. Our patients were positioned in the left uterine placement during labor and this probably accounted for the difference since gravity affects spread of epidural local anesthetic (24).
There has been debate whether the three local anesthetics we studied are equipotent. Although Lyons et al. (25) found bupivacaine and levobupivacaine to be equipotent, some investigators have found that ropivacaine is less potent than bupivacaine by a factor of 0.60 (26,27). The problem with the above studies is that they all evaluated the ED50 of the drug, which is only one point on the dose-response curve, and that point on the curve (ED50) may not be clinically relevant, since anesthesiologists tend to administer the ED95 of a drug. Since it is unclear if the medications are equipotent, we initiated the anesthetic with a dose around the ED50 (0.0625%) and titrated to effect. We did not find any difference in analgesic effects among the local anesthetics, including the percentage of patients who achieved adequate analgesia after the initial dose of local anesthetic, the total milligram dose per hour of labor, or the total number of top-up doses per hour required during labor. These results would suggest that at low concentrations the drugs are clinically equipotent, as others have proposed (28).
Regarding the neonates, we were not able to find any difference in our measured parameters including Apgar scores, Apgar scores <7, need for respiratory assistance, tracheal intubation, or intensive care unit admission among the groups. Our results are consistent with the results of Halpern et al. (8) who found no difference in neonatal outcome with bupivacaine versus ropivacaine, and of Burke et al. (29) who found no difference in neonatal outcome with bupivacaine versus levobupivacaine. It should be noted that Writer et al. (18) found lower neurobehavior scores with bupivacaine versus ropivacaine, an outcome we did not assess.
One limitation of our study is that few patients were enrolled in the levobupivacaine group. This occurred because part way through the study the manufacturer of levobupivacaine (Purdue Pharma, LP, Norwalk, CT) stopped marketing the drug in the United States, and we therefore enrolled only 37 women in that group. Our study was therefore ultimately only powered to assess bupivacaine versus ropivacaine.
In summary, we confirmed that all three local anesthetics at low doses when combined with fentanyl confer adequate labor epidural analgesia. We also found that there is less motor block with levobupivacaine and with ropivacaine compared with bupivacaine. However, the difference in motor block did not carry over to differences in mode of delivery. We conclude that all three local anesthetics confer adequate analgesia and that the choice does not influence mode of delivery.
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© 2007 International Anesthesia Research Society
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