Epidural Ropivacaine for the Initiation of Labor Epidural Analgesia

A Dose Finding Study

Abstract

The purpose of our study was to determine the lowest concentration of ropivacaine that offers pain relief for the initiation of labor epidural analgesia.Women in active labor were enrolled in this prospective, randomized, double-blinded study to receive either ropivacaine 0.20% (Group I), ropivacaine 0.15% (Group II), or ropivacaine 0.10% (Group III). After placement of the epidural catheter, 13 mL of the study medication was administered. Fifteen minutes later, the adequacy of analgesia was assessed. If the woman reported that her degree of analgesia was not adequate, an additional 5 mL of the study medication was given, the degree of pain relief was reassessed 15 min later, and the study was concluded. A sequential study design was used to assess the success rates. We found that 26 of 28 (93%) women in Group I had adequate analgesia, compared with only 18 of 28 (64%) in Group II (P = 0.014) and 4 of 12 (33%) in Group III (P = 0.003). We conclude that ropivacaine 0.20% offers adequate analgesia significantly more often than either ropivacaine 0.15% or ropivacaine 0.10%. If one selects ropivacaine as the sole local anesthetic for the initiation of labor epidural analgesia, the minimal concentration should be 0.20%. Implications: The lowest effective concentration of ropivacaine for the initiation of labor epidural analgesia has not been determined. We found that ropivacaine 0.20% offers adequate analgesia significantly more often than either ropivacaine 0.15% or ropivacaine 0.10%. If one selects ropivacaine as the sole local anesthetic for the initiation of labor epidural analgesia, the minimal concentration should be 0.20%.

(Anesth Analg 1999;88:1340-5)

Labor epidural analgesia often involves the use of local anesthetics. Bupivacaine is the most commonly used local anesthetic during labor, but it is more cardiotoxic than other local anesthetics, and motor blockade generally occurs along with the sensory blockade.

Ropivacaine, the S-enantiomer of N-propylpipecolic acid 2, 6-xylidine, is an amide local anesthetic that was developed to address some of these issues. In a sheep model, ropivacaine was less cardiotoxic than bupivacaine ^[1], and in human volunteers, a larger dose of IV ropivacaine than IV bupivacaine was tolerated before the development of neurologic symptoms ^[2]. Furthermore, ropivacaine may be more selective for sensory fibers than bupivacaine and may produce less motor block ^[3].

Cascio et al. ^[4] found that all women who received ropivacaine 0.20% for the initiation and maintenance of labor epidural analgesia had adequate analgesia. The trend among obstetric anesthesiologists is to use the lowest effective concentration of local anesthetics that both confers adequate analgesia and minimizes motor block. Some anesthesiologists often add opioids to the local anesthetic to further reduce the necessary concentration of local anesthetic. However, it is important to determine the lowest effective concentration of the local anesthetic without opioid as a standard by which to compare other drug combinations. No study has assessed whether concentrations of epidural ropivacaine <0.20% and without opioids offer adequate labor analgesia.

The purpose of this study was to determine whether concentrations of ropivacaine <0.20% might offer complete pain relief for the initiation of an epidural anesthetic for labor and delivery.

Methods

The protocol was approved by our institutional review board, and written, informed consent was obtained from each parturient before she requested epidural analgesia. Women in active labor who were having contractions at least once every 5 min, who had no contraindication to epidural analgesia, and who requested epidural analgesia for pain relief were enrolled in this prospective, randomized, double-blinded study. Women with 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 one of three groups based on the concentration of epidural ropivacaine that she would receive. Women in Group I received ropivacaine 0.20%, those in Group II received ropivacaine 0.15%, and those in Group III received ropivacaine 0.10%. The randomization sequence used was generated by a Table ofrandom numbers. The results of the randomization were sealed in opaque envelopes and opened sequentially by an anesthesiologist who did not participate in the study. This anesthesiologist gave the investigators a 20-mL syringe containing the study medication.

Before placement of the epidural catheter, the woman was asked to quantify the pain she was experiencing on a verbal scale of 0-10, with 0 = no pain and 10 = the worst imaginable pain. All epidural catheters were placed with the woman in the sitting position. Using an 18-gauge Hustead needle, the epidural space was identified via a midline approach at the L2-3 or L3-4 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, we attempted to aspirate blood or cerebrospinal fluid via the catheter using a 3-mL syringe. If there was no aspirate, a 3-mL test dose of the study medication 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 patient whether she felt dizzy, had tinnitus, or had a metallic taste in her mouth. 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 min after the test dose, if there were no clinical signs of subarachnoid injection (as evidenced by the patient's ability to move her legs and the absence of hypotension), an additional 10 mL of the study solution was administered in two equal divided doses 5 min apart. If the epidural catheter had been placed into the intravascular space, it was removed, and the procedure was repeated at a different interspace. If the catheter had been placed in the subarachnoid space, the patient was withdrawn from the study.

The adequacy of analgesia was assessed 15 min after the last dose of local anesthetic had been administered. Analgesia was assessed by asking the patient whether she felt pain at the peak of a contraction. She was also asked to rate her level of pain on the same verbal scale. Analgesia was considered to be adequate if the patient reported acceptable pain relief even if the pain score was not zero. If she said that analgesia was not adequate, an additional 5 mL of study medication was administered, and the analgesia was reassessed in the same manner 15 min later. If pain relief was still inadequate after the second assessment, 10 mL of epidural lidocaine 2% was administered in two divided doses. If pain relief was adequate at the peak of a contraction, 15 min after the second dose of lidocaine was administered, the epidural anesthetic was classified as a ropivacaine failure, and the study was concluded. If adequate pain relief was not achieved, the epidural catheter was replaced, the initial failure was attributed to a technical problem and not to the ropivacaine, and the study was concluded.

If the analgesia was adequate after the administration of either 13 or 18 mL of medication, the patient was assessed for the presence of motor block in the lower extremities using a modified Bromage scale (Table 1). The patient was then assessed every 15 min for the presence of pain and degree of motor block until she required additional local anesthetic for pain relief, at which time the study was concluded.

Table 1: Bromage Scale

Arterial blood pressure was recorded at least every 5 min for the first 30 min, then every 30 min until the study was completed, using an automated blood pressure monitor. Fetal heart rate was monitored throughout the study by using either a Doppler ultrasound transducer or fetal scalp electrocardiogram electrode, and any evidence of fetal heart rate decelerations was recorded.

A restricted randomization scheme was used to assign an equal number of patients to receive ropivacaine 0.20%, 0.15%, or 0.10%. To minimize the number of patients exposed to a smaller dose, should it prove to be associated with a reduced success rate, a sequential study design was used. The study was designed to provide 80% power to detect a decrease in success rate from 90% to 70% with a one-tailed test at the 5% significance level. Outcomes connected with each coded treatment were sent to the statistician (CAB) periodically for monitoring. Only CAB was aware of the interim results, which were tracked using the computer program PEST (University of Reading, Reading, UK). The significance levels quoted in this manuscript are the adjusted P-values computed by the PEST program after taking into account the effects of multiple testing.

For each patient, the outcome was considered a success or a failure according to whether she stated that she was in pain 15 min after the administration of the last 5 mL of medication. The proportion of successes in each reduced-dose group was compared with that in the 0.20% dose group using one-sided z-tests. When the comparison yielded an adjusted P value of <or=to0.05, that arm of the study was terminated.

Results

Seventy-seven women consented to participate in the study, and the 72 women who received an epidural anesthetic were enrolled and completed the protocol. No patient was excluded because the catheter was placed in the subarachnoid space. Two patients-one in Group I and one in Group II-had an epidural catheter unintentionally placed in an epidural vein, as documented by the presence of blood in the epidural catheter. In all three of these patients, the catheter was successfully reinserted at a different interspace. We were not able to detect a difference in demographics or initial labor characteristics among the three groups (Table 2). After the first 36 women were enrolled (second interim analysis), we found that significantly more women in Group I (11 of 12; 92%) reported that they had adequate pain relief, compared with women in Group III (4 of 12, 33%) (adjusted P = 0.003). After this analysis, patients were randomized only to Groups I and II. After an additional 36 patients were enrolled-18 each in Groups I and II-we performed another interim analysis. Four patients-two in Group I and two in Group II-were excluded from this analysis because their epidural failed due to technical problems. Only replacement of the epidural catheter provided satisfactory analgesia for these women. Significantly more patients in Group I reported that they had complete pain relief (26 of 28, 93%), compared with those in Group II (18 of 28, 64%) (adjusted P = 0.014).

Table 2: Patient Demographic and Labor Characteristics

There were 9 (32%) patients in Group I, 7 (25%) in Group II, and 2 (17%) in Group III who achieved adequate analgesia after receiving only 13 mL of the study medication. In women who achieved adequate analgesia, the duration of analgesia was greater in Group I (110 min) than in Group II (96 min) or Group III (64 min) (P = 0.011 for Group I versus Group III). There were six women who developed a motor block during the study: four in Group I and two in Group II. In all patients, the intensity of motor block was a Bromage score of 1. No patient developed a motor block greater than Bromage 1. The duration of the motor block was 60 min in four patients and 90 min in two. The two patients whose motor block lasted 90 min were in Group I (Table 3).

Table 3: Success Rates and Duration of Analgesia by Group

Three women in the study-two in Group I and one in Group II-developed hypotension (systolic blood pressure [BP] <100 mm Hg) required treatment with IV ephedrine. The decrease in BP was mild in all cases (84/49 mm Hg, initial BP 110/66 mm Hg, and 90/56 mm Hg, initial BP 112/65 mm Hg in the women in Group I, and 80/56 mm Hg, initial BP 110/70 mm Hg for the woman in Group II), occurred within the first 15 min of drug administration, and responded immediately to 10 mg of IV ephedrine. There were no episodes of fetal heart rate decelerations during the study period (Table 4).

Table 4: Motor Block and Complications by Group

Discussion

Initial studies of ropivacaine suggested that it may be less cardiotoxic and produce less motor block than bupivacaine, thus making it an ideal drug for labor analgesia. Feldman et al. ^[5] found, in a canine model, that the lethal dose of IV ropivacaine was greater than that of bupivacaine. Scott et al. ^[2] found, in human volunteers, that a larger dose of IV ropivacaine than IV bupivacaine was tolerated before the onset of neurologic symptoms. In the surgical patient, Brockway et al. ^[3] found that less motor block developed in patients who received ropivacaine than in those who received bupivacaine. In the parturient, however, both McCrae et al. ^[6] and Stienstra et al. ^[7] were unable to detect less motor block when ropivacaine was used for labor analgesia compared with bupivacaine.

The trend among obstetric anesthesiologists is to use the lowest possible concentration of a local anesthetic that offers adequate pain relief for labor epidural analgesia. Using the lowest concentration reduces the resultant motor block, which may decrease the incidence of either instrumental deliveries ^[8,9] or cesarean sections ^[10], although this is controversial ^[11]. The doses of ropivacaine used for labor epidural analgesia tend to be low: the maximal concentration used is 0.20%. Because of the low concentrations used, the main advantage of ropivacaine for labor analgesia is probably the selective blocking characteristics of ropivacaine, not necessarily the decreased risk of cardiotoxicity.

Palmer et al. ^[12] reported the results of a study that compared the analgesia obtained with ropivacaine 0.20% with that obtained with lower concentrations of ropivacaine for the initiation of epidural lumbar analgesia. However, either fentanyl or epinephrine was added to all concentrations of ropivacaine <0.20%. We are not aware of any study that has determined whether concentrations of ropivacaine <0.20%, without adjuvants, provide adequate analgesia for this same purpose. Owen et al. ^[13] recently found that an infusion of ropivacaine 0.125% is as effective in maintaining analgesia during labor and delivery as bupivacaine 0.125%. However, these results cannot be compared with ours because we studied ropivacaine for the initiation of epidural analgesia, whereas Owen et al. ^[13] studied ropivacaine for the maintenance of analgesia.

We administered a 3-mL test dose of ropivacaine to rule out an intravascular or intrathecal catheter. We are not aware of any study that has identified the appropriate dose of ropivacaine that should be used as a test dose, i.e., a nonlethal dose that will yield signs of an intravascular or intrathecal injection. We did not want to administer a different local anesthetic, such as lidocaine, for the test dose, as that would have interfered with our study results. Norris et al. ^[14] have recommended eliminating the test dose completely if dilute concentrations of bupivacaine are used. We did not believe that we could extrapolate their results to our study and eliminate the test dose because they used bupivacaine, and ropivacaine 0.20% is not a dilute solution. However, we recognize that 3 mL of ropivacaine may not have been an adequate test dose, especially with the lower concentrations of ropivacaine (0.15% and 0.10%).

We found that, for the initiation of labor epidural analgesia, ropivacaine 0.20% provided adequate analgesia for labor pain in 93% of the patients. This was significantly more often than the other concentrations tested. Ropivacaine 0.15% provided adequate analgesia in 64% of patients, whereas ropivacaine 0.10% provided adequate analgesia in only 33%. The verbal pain scores (Table 3) further support the patient report of adequate analgesia. The median pain scores in those who reported adequate analgesia were less than the median pain scores for those who did not report adequate analgesia after the administration of both 13 and 18 mL of ropivacaine. However, we defined a successful epidural anesthetic as one in which the patient reported that pain relief was adequate even if the pain score was not zero. We believe that asking the patient whether she has pain is more reliable than using a pain scale, because pain scales are subject to patient interpretation and are not accurate. Indeed, DeLoach et al. ^[15] found that verbal analog scores (0-10) correlate with visual analog scores and that any individual determination on a 100-mm visual analog scale should be interpreted as having an error of +/- 20 mm. We obtained pain scores before placement of the epidural catheter to show the results of our randomization, that all three groups of patients were similar at the beginning of the study. Because we only compared ropivacaine 0.20% with two other concentrations, a concentration between 0.15% and 0.20% might be as effective as ropivacaine 0.20%.

Another finding of our study was that the incidence and intensity of motor block with ropivacaine 0.20% are small (14%), as is the incidence of hypotension (7%). It is possible that there were subtle differences in motor block among the groups that were not detectable using the Bromage scale. More sophisticated tests, such as isometric abdominal wall assessment ^[16], may have detected subtle differences in motor block among the groups, but this assessment is difficult to use, and any such subtle differences may be clinically insignificant. We chose the Bromage scale because it is easy to use and is clinically effective in detecting gross differences in motor block.

Using a sequential analysis design permitted us to analyze the results periodically as the study progressed. We chose this design because we did not have any data to support the contention that concentrations of ropivacaine <0.20% would be sufficient to provide analgesia for the initiation of labor epidural analgesia. If, as it turned out, many women did not obtain adequate analgesia with the lower concentrations, we wanted a design that would allow us to minimize the number of patients exposed to inadequate labor analgesia.

Because we only used ropivacaine for the initiation of the anesthetic and all patients subsequently received epidural bupivacaine, we did not assess obstetric outcome in terms of forcep deliveries, cesarean sections, or neonatal outcome. Thus, any effect that we might have found could not be attributable solely to ropivacaine.

In conclusion, 13 mL of ropivacaine 0.20% offers adequate analgesia more often than either ropivacaine 0.15% or ropivacaine 0.10%. Furthermore, we found that, when ropivacaine 0.20% is used, the resultant motor block and hemodynamic effects are minimal. We recommend that if one selects ropivacaine as the sole local anesthetic for the initiation of labor epidural analgesia, the minimal concentration should be 0.20%.

We thank James B. Eisenkraft, MD, The Mount Sinai Medical Center, New York, NY, for his help with the study design and for his critical review of the manuscript.