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Epidural Ropivacaine Versus Bupivacaine for Labor: A Meta-Analysis

Halpern, Stephen H. MD, MSc, FRCPC; Walsh, Vivien BMed (Hons)

doi: 10.1213/01.ANE.0000052383.01056.8F
OBSTETRIC ANESTHESIA: Research Report

Numerous studies have compared ropivacaine with bupivacaine for labor analgesia. Early studies suggested that obstetrical and some neonatal outcomes were improved when ropivacaine was used. We systematically reviewed and combined the results of the randomized controlled trials that compared ropivacaine with bupivacaine to determine whether or not there was a difference in these outcomes. We searched electronic databases and journals for randomized controlled trials composed of laboring parturients. The primary outcome was the incidence of spontaneous vaginal delivery. We examined other obstetrical, neonatal, and analgesic outcomes. Where possible, these were combined by using metaanalytic techniques and random effects modeling. We found 23 randomized controlled trials composed of 1043 patients receiving ropivacaine and 1031 receiving bupivacaine. There was no significant difference in the incidence of spontaneous vaginal delivery (odds ratio, 1.17; 95% confidence interval, 0.98–1.41;P = 0.12) or any of the other outcomes. Although more studies reported a more frequent incidence of motor block with bupivacaine, the results were heterogeneous and therefore not combined. We conclude that there is no statistically significant difference between the two drugs in the incidence of any obstetrical or neonatal outcome. Further studies using clinically appropriate concentrations of drugs are required to determine whether or not there is a difference in the incidence of motor block.

Department of Anaesthesia, Sunnybrook and Women’s Health Sciences Centre, Women’s College Site and the University of Toronto, Toronto, Ontario, Canada

November 25, 2002.

Address correspondence and reprint requests to Stephen Halpern, MD, MSc, Department of Anesthesia, Sunnybrook and Women’s Health Sciences Centre, Women’s College Campus, 76 Grenville St., Toronto, Ontario, Canada, M5S 1B2. Address e-mail to stephen.halpern@swchsc.on.ca.

Epidural bupivacaine has been used for many years for labor analgesia. Although this drug provided excellent sensory analgesia, some patients experienced unacceptable motor block when large concentrations (0.25% or more) were used. Large doses of bupivacaine were associated with cardiac and central nervous system toxicity when accidentally injected IV. Ropivacaine was developed to reduce these side effects and was released for clinical use in 1996. Since then, numerous studies have been performed to determine whether or not ropivacaine is suitable for labor analgesia and to determine whether it is superior to bupivacaine.

In 1998, Writer et al. (1) published a metaanalysis of six selected clinical trials that compared epidural ropivacaine with bupivacaine. They concluded that there was an increased incidence of spontaneous vaginal delivery associated with ropivacaine and that this difference was primarily due to a reduction in the forceps delivery rate. They also reported a less frequent incidence of maternal motor block and better neuroadaptive capacity scores in the neonate.

Since then, other studies using smaller doses of both drugs have been published. The results of these studies are conflicting. Many of the trials are small and therefore do not have sufficient power to detect clinically important end-points. In addition, the equivalent concentrations of bupivacaine and ropivacaine have not been established. The purpose of this metaanalysis was to review all the studies that compare epidural bupivacaine with epidural ropivacaine, to determine whether there is a significant difference between the two drugs when they are used for labor analgesia.

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Methods

We retrieved randomized controlled trials written in English that compared epidural ropivacaine with bupivacaine, with or without the addition of opioids, for labor analgesia. We excluded studies that were specifically designed to determine the effective dose in an “up-down” fashion. Similarly, we excluded studies that used adjuvants such as clonidine or fentanyl in one group but not in the other. We searched MEDLINE from January 1966, the Science Citation index, the Cochrane Library, and EMBASE by using the MeSH headings, text words, and alternate spellings of the following terms: “obstetrical analgesia,” “epidural analgesia,” “labor analgesia,” “extradural anesthesia,” “local anesthetics,” “ropivacaine,” and “bupivacaine.” The authors hand-searched files and references of the retrieved articles and examined the bibliographies of published reviews on the subject. The tables of contents of the following journals were hand-searched from the preceding 5 yr:International Journal of Obstetric Anesthesia, British Journal of Anaesthesia, Anesthesiology, and Anesthesia & Analgesia. Published abstracts from the Society for Obstetric Anesthesia and Perinatology meetings (1995–2001) were reviewed, and an attempt was made to find unpublished data. Finally, we attempted to contact the authors of clinical trials to obtain additional data. The eligibility of each trial was assessed independently by at least two individuals. The last literature search was completed on March 15, 2002.

The quality of the studies was assessed independently by at least two individuals by using a valid and reliable quality index score (2). This scale has a maximum of five points, with zero to two points assigned to the methods of randomization and blinding (score: 0, inappropriate; 1, not described; 2, described and appropriate) and one point given if the study described the outcome of all randomized subjects. Studies were considered to be of high quality if the score was 3 or more. We re-reviewed the articles and arrived at a consensus score for each article. Data available only as a published abstract or as a personal communication were not scored. As an additional indicator of quality, we noted whether or not the treatment assignment was blinded.

The data were extracted independently by at least two individuals on a standardized data collection sheet. These were compared, and differences were resolved by reexamination of the original manuscripts. The data were then entered into the computer by one of the authors and checked by the second.

The primary outcome was the incidence of spontaneous vaginal delivery. Secondary obstetrical outcomes included the incidence of instrumental vaginal delivery and cesarean delivery. Other important secondary maternal outcomes included the incidence of no motor block, full motor block, duration of block, inadequate analgesia, block failure, excellent analgesia, hypotension, duration of labor, and the time to onset of analgesia. Because of the numerous times at which motor block was reported, we summarized these data in one of two ways. If the total number of patients who had no motor block throughout the study was reported, this number was used in our summary. If a total number was not available, we used the incidence of motor block at 2 h after the induction of analgesia—a time when the initial dose of local anesthetic and the test dose were relatively unimportant. Neonatal outcomes included the incidence of 1- and 5-min Apgar scores of <7 and an umbilical artery pH of <7.2.

Published data were compared with unpublished (abstracts and personal communications) data for the primary outcome. Nulliparous patients were analyzed separately for obstetrical outcomes.

Metaanalytic techniques were used to combine the data available from the retrieved studies by using Metaview 4.1 software (Update Software, San Diego, CA). The data were checked for heterogeneity by using χ2 analysis, and a P value of <0.05 was considered statistically significant. We chose not to statistically combine results from studies that showed significant heterogeneity. These are described qualitatively.

For dichotomous data, the odds ratio (OR) and 95% confidence interval (CI) were calculated. For continuous data, the weighted mean difference (WMD) and 95% CI were calculated. A statistical difference was considered to occur if the 95% CI excluded 1.0 for the OR and 0 for the WMD. All data were combined by using a random effects model.

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Results

We retrieved 96 articles, of which 23 met the inclusion criteria (3–25). We eliminated the remainder of the studies for the following reasons: 40 were review articles, 13 examined inappropriate study groups, 10 were not randomized trials, and 6 consisted of groups of letters and comments to the editor. We eliminated 4 studies, composed of 182 patients, that were not available in English (26–29).

The studies that met our criteria consisted of 1043 patients in the ropivacaine group and 1031 patients in the bupivacaine group. One study had data in two articles (16,17), and one contained two separate comparisons (“large dose” and “small dose”) (19). The patient populations included 10 studies of nulliparous patients only, 11 of mixed parity, and 2 unknown parity. Five studies were available in abstract form only (3,11,13,15,24), and data from corresponding authors were available for eight studies (3,21). The year of the study, quality scores, number of patients, and interventions are shown in Table 1.

Table 1

Table 1

Data were available on the number of spontaneous vaginal deliveries from 20 of the 23 studies, which included 930 patients who received ropivacaine and 917 who received bupivacaine (3–12,14,16–22,24,25). When the results of the studies were pooled, there was no statistically significant difference in the incidence of spontaneous vaginal delivery between the two local anesthetics (pooled OR, 1.17; 95% CI, 0.96–1.44;P = 0.12) (Fig. 1). This was also true when only published studies were pooled (OR, 0.99; 95% CI, 0.76–1.26;P = 0.9). Similarly, there was no difference between groups when only studies composed of nulliparous patients were compared (OR, 1.12; 95% CI, 0.86–1.45;P = 0.4). Of note, there was no statistical evidence of heterogeneity (P = 0.58) in the primary outcome.

Figure 1

Figure 1

The results of the metaanalysis are shown in Table 2. There was no difference in any of the obstetrical outcomes, including mode of delivery, duration of labor, or duration of the second stage of labor. There was significant heterogeneity in the incidence of motor block between studies (P = 0.002). In studies that reported the absence of motor block, four favored bupivacaine, and one was statistically significant (10). The remaining 19 of 23 favored ropivacaine, and 5 were statistically significantly different (8,9,12,18,19). There was no difference between the groups in any of the other analgesic outcomes (Table 2). There were no statistically significant differences in any of the neonatal outcomes (Table 2).

Table 2

Table 2

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Discussion

In the four years between the publication of the previous metaanalysis (1) and this investigation, a considerable number of new data have become available addressing the comparison of ropivacaine and bupivacaine for labor analgesia. During that time, 17 new, independent studies have been performed and are available either in abstract form or as full published articles. Whereas the previous metaanalysis confined itself to selected studies, we attempted to systematically review all relevant studies. Further, we obtained data on a broad range of clinical doses that are relevant to clinical labor analgesia rather than confining the investigation to relatively large doses of local anesthetic. It is not surprising, therefore, that some of our results disagree with those previously published.

This metaanalysis shows the incidence of spontaneous vaginal delivery is similar whether or not ropivacaine or bupivacaine is used for labor analgesia. A number of factors make this result reliable. First, there is a large degree of agreement between studies, as shown by the lack of statistical heterogeneity between groups and by the grouping of the point estimates of the ORs of each study around 1.0 (Fig. 1). Second, the quality of the studies is high. Because virtually all of the studies were appropriately blinded, it is unlikely that bias significantly contributed to the result. Third, a large number of patients contributed to this result (n = 930 in the ropivacaine group;n = 917 in the bupivacaine group). The absolute difference between groups was 3.4% (588 [57.4%] of 930 vs 499 [54.4%] of 917;Fig. 1). Assuming a power of 0.8, a post hoc power analysis shows that an absolute difference of 7% would be detected in this outcome. This analysis has the power to detect a small difference (i.e., <10%) according the definition of Cohen (30). Fourth, the OR of the largest study (3) agrees fairly closely with the pooled estimate of all the studies (1.24 versus 1.12) even though it contributes only 35% to the calculated value with the random effects model. Finally, when a sensitivity analysis is performed by removing unpublished data (abstracts and personal communications), the OR is 0.99, meaning that the incidence of spontaneous vaginal delivery was almost identical in this subset of studies. Similarly, none of the other obstetrical outcomes are different.

The incidence of motor block was more frequent in the bupivacaine group in 19 of 23 studies. Although there was no difference in the incidence of ambulation as a measure of motor block, this may have been due to an insufficient number of patients in studies that reported those outcomes (Table 2), or it may have been due to other obstetric and patient factors that influence the patient’s choice to ambulate.

The results related to motor block were not combined statistically because of the large amount of statistical heterogeneity among studies. This reflected differences in drug doses and concentrations among studies. In addition, there was a wide variation in the way in which motor block was measured. This makes quantitative comparisons between drugs difficult to interpret.

Most of the investigators chose to compare equal concentrations of ropivacaine and bupivacaine, given either as a continuous infusion or as patient-controlled epidural analgesia, although two studies used a larger concentration of bupivacaine (8,15) and two studies used a larger concentration of ropivacaine (7,8) (Table 1). Two groups of investigators have suggested (31,32), using an up-down, randomized study design, that the 50% effective dose of ropivacaine is approximately 40% larger than that of bupivacaine and that, therefore, when doses are compared, the concentration of ropivacaine should be increased. Owen et al. (21) noted that the 50% effective dose may be a poor predictor of the clinically relevant outcome of the 95% effective dose for analgesia. In this review, 19 of the 23 studies compared equal concentrations of both drugs. Further, in studies that used patient-controlled epidural analgesia for analgesia maintenance, there was no significant difference in the volume of local anesthetic used by each group (3,4,9,18,21,22,24). Whether or not the increased incidence of motor block was due to an intrinsic property of the drugs or the concentrations used by the investigators cannot, with certainty, be determined from this review. Further studies using smaller concentrations of both local anesthetics are required.

Few studies considered patient satisfaction as an important outcome. Those that attempted to measure patient satisfaction did not do so with a validated satisfaction tool. Although there are some data on maternal satisfaction with analgesia, they are related only to the pain relief and not specifically to other characteristics of the block. As noted in Table 2, almost 80% of women in both groups classified their analgesia as “excellent,” and this figure would be very hard to improve. The area of overall maternal satisfaction deserves further attention.

None of the indicators of neonatal well-being that we examined were different between the two groups. This included the incidence of low umbilical artery cord pH and Apgar scores at one and five minutes. Writer et al. (1) found a difference in the neurologic and adaptive capacity score, favoring ropivacaine, at 24 hours after birth, but not at 2 hours after birth. We did not examine this outcome because recent evidence suggests that the neurologic and adaptive capacity score is unreliable (33), and, therefore, any result would be impossible to interpret.

Because this is a metaanalysis of previously reported studies, one must be careful when interpreting the results. We confined this analysis to the English language only. This may introduce a reporting bias, although the number of patients in the studies we found in the non-English literature was small compared with the total. Second, there may have been unpublished data that we did not find in our search. Because “positive” studies are preferentially published, this may have led to a publication bias. Of interest, none of the studies in our review showed a statistically significant difference in the primary outcome. Finally, a wide range of doses and dose regimens was used in the included studies. This makes it difficult to apply the results directly to an individual patient in a clinical setting.

In conclusion, this metaanalysis shows that both ropivacaine and bupivacaine provide excellent labor analgesia for most obstetrical patients. There is no significant difference between the two drugs in the incidence of spontaneous vaginal delivery or any other obstetrical outcome. Similarly, there is no difference in neonatal outcomes. Although more studies reported a reduced incidence of motor block in the ropivacaine group, this result must be interpreted with caution because of the heterogeneity in the results. There was no difference in measures of the quality of analgesia or maternal satisfaction with analgesia. We conclude that more research is needed to compare the potencies of ropivacaine and bupivacaine in the doses normally used for clinical analgesia, to resolve the issue of motor block.

We would like to thank Geena Joseph, BSc, and Todd Calhoun, MD, for their help in researching this article and extracting data and to Drs. Pamela Angle and Joanne Douglas for their editorial suggestions in preparing the manuscript. We would also like to thank Dr. Jan Henriksson of Astra-Zeneca for supplying additional unpublished data.

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