Ropivacaine is a new long-acting amide local anesthetic, closely related in structure to bupivacaine and mepivacaine. Bupivacaine and mepivacaine are available as racemates, whereas ropivacaine is provided as the pure (s)-enantiomer. The pharmacodynamic and pharmacokinetic properties of ropivacaine resemble those of bupivacaine, both in animal [1-3] and initial open phase II clinical studies [4-6]. However, in animals, ropivacaine has a lower central nervous system and cardiotoxic potential than bupivacaine [7,8]. In human volunteers, ropivacaine is less prone than bupivacaine to produce mild central nervous system and cardiovascular changes after intravenous infusion .
In several double-blind studies comparing ropivacaine and bupivacaine in epidural anesthesia in humans, the maximum level of sensory block, as well as the overall clinical efficacy, have been comparable [10-12]. However, when used in equal concentrations, the intensity and/or duration of motor block have been less with ropivacaine.
Based on its lower toxicity and less intense motor block when compared with bupivacaine, ropivacaine may have advantages over bupivacaine for epidural pain relief during labor.
The objectives of the present study were to compare the effects of ropivacaine 0.25% with bupivacaine 0.25% with regard to efficacy and motor block when given as a continuous infusion for pain relief during labor, and to compare the effects of both drugs on neonatal outcome as determined by Apgar and neurologic and adaptive capacity scores (NACS).
The study was double-blinded and randomized with two parallel treatment groups. The drugs given to each parturient were packaged separately and labeled from 101 to 180. Parturients were randomized in balanced blocks of six, block size being unknown to the investigators. Stratification with regard to parity was made by assigning consecutive numbers to parturients on entering the study, primiparae from 101 upward and multiparae from 180 downward. The protocol was approved by the medical ethics committee of the hospital and written, informed consent was obtained from all patients.
Seventy-six parturients (ASA physical status I-II, age >or=to 18 yr, height >or=to 150 cm, body weight <or=to 110 kg, full-term pregnancy (36-42 wk), single fetus, vertex presentation, and estimated fetal weight >or=to 2500 g) in active labor requiring epidural analgesia were studied. Parturients with diabetes mellitus, significant neurologic disease, preeclampsia, significant alcohol, drug or medication abuse, a known history of allergy, sensitivity or any other form of reaction to amide type local anesthetics, or with a fetus with a known anomaly were excluded from our study. Parturients receiving any premedication other than up to one dose of meperidine (maximum 125 mg) also were excluded from our study. Oxytocin administration was allowed at any time during the study.
In all parturients, an intravenous infusion of a crystalloid solution was in progress before beginning epidural analgesia. With the parturient in the sitting position, and after local infiltration of the skin, the epidural space (L1-4) was identified with a 16-gauge Tuohy needle using the loss of resistance to saline method and a paramedian or midline approach. After identification of the epidural space and a negative aspiration test, a loading dose of 10 mL of either ropivacaine 0.25% or bupivacaine 0.25% without epinephrine was slowly administered between uterine contractions through the Tuohy needle over a 60-s period. An 18-gauge epidural catheter was then inserted 3-5 cm in a cephalad direction, after which the parturient was returned to a lateral supine position.
Maternal blood pressure and heart rate were monitored before institution of epidural analgesia, at 5, 10, 15, 20, 30, 45, and 60 min, and then every 30 min thereafter until delivery. Fetal heart rate and uterine contractions were monitored continuously until delivery using a cardiotacograph. Fetal heart rate values were recorded at the same intervals as maternal heart rates.
Fifteen minutes after the initial loading dose and after a negative aspiration test through the epidural catheter, a continuous epidural infusion with the same drug was started at a rate of 6-12 mL/h to maintain an adequate block. Top-up bolus doses of 6-10 mL were given as required, provided the total dose given did not exceed 175 mg in a 3-h period or 450 mg in 24 h The volume of the top-up dose was determined by the attending anesthesiologist based on the level of sensory block at the time, within the limits as stated in the protocol. The epidural infusion was discontinued at full cervical dilation.
Contraction pain was measured during two uterine contractions before epidural analgesia and at 15-min intervals thereafter during a uterine contraction until full cervical dilation, using a 100-mm visual analog scale (VAS) ranging from 0 (no pain) to 100 (worst pain imaginable).
Onset of pain relief was assessed at each uterine contraction after injection of the epidural loading dose using a four-graded verbal scale: 1, no pain relief; 2, a little pain relief; 3, a lot of pain relief; 4, complete pain relief. Onset of pain relief in this respect signified the time when a lot of pain relief (Grade 3) or complete pain relief (Grade 4) had been achieved.
Overall quality of analgesia was judged by both patients and investigators after delivery as excellent, good, fair, poor, or absent.
Motor block of the lower limbs was assessed using a modified Bromage scale: 0, no motor block; 1, inability to raise the extended leg, able to move knees and feet; 2, inability to raise the extended leg and move knees, able to move feet; 3, complete motor block of the lower limbs. Motor block was assessed at 5-min intervals during the first 15 min after injection of the epidural loading dose, at 30 min after injection, and at 30 min intervals thereafter until complete recovery of motor function after discontinuation of the epidural infusion.
The mode of delivery was recorded as spontaneous, vacuum extraction, forceps or cesarean section.
Neonates were assessed by Apgar scores 1 and 5 min after delivery and by NACS as described by Amiel-Tyson et al.  2 h (+/- 30 min) and 24 h (+/- 2 h) after delivery. The NACS evaluates the neurobehavioral status of the newborn by 20 criteria, each of which is given a score of 0, 1, or 2. A score of >or=to 35 is indicative of neurologically vigorous neonates. Apgar scores were done by the attending obstetrician; all NACS scores were assessed by one investigator.
Adverse events, defined as any unfavorable, unintended events temporally associated with the administration of the study drug, whether or not considered to be drug-related, were recorded. Serious adverse events were defined as adverse events which would result in death, permanent or severe disability, prolongation of hospitalization, or which were life-threatening, a congenital anomaly, cancer, or the result of an overdose.
Parturients who required extra analgesia other than the epidural infusion, or in whom the epidural infusion had been continued for 24 h, were to be withdrawn from the study. NACS assessments of the neonate were not to be made if the birth weight was less than 2500 g, if there was an instrumental delivery other than low forceps or vacuum extraction, if birth was by cesarean section, if the mother required additional analgesics, or if there was a technical failure.
The following variables were compared by statistical analysis: the frequencies of different degrees of motor block during epidural infusion, time from end of infusion to complete recovery of motor function of the lower limbs, mean VAS scores during epidural infusion, time to onset of pain relief, and quality of analgesia. All other variables were to be evaluated by summary measures. Analysis of variance was used for interval data; quality of analgesia was assessed using the Cochran-Mantel-Haenszel test. All tests were two-tailed and performed at a significance level of 0.05.
Of the 76 parturients enrolled into the study, 39 received ropivacaine and 37 received bupivacaine. Overall, the groups were well-matched regarding demographics. One parturient in the bupivacaine group had a body weight of 122 kg; this was considered to be a minor protocol violation and the data of this patient are included in the results. Demographic data are summarized in Table 1.
Ten parturients, three in the ropivacaine group and seven in the bupivacaine group, had received meperidine prior to the institution of epidural analgesia. The dose of meperidine given was 50-75 mg in nine parturients and 100 mg in one parturient; the time interval between administration of meperidine and time of delivery ranged from 9-19 h. No parturients were withdrawn due to technical failure; none of the parturients exceeded the 175 mg/3 h or the 24 h limits defined in the protocol. Unless otherwise stated, the data presented comprise all the patients studied.
The mean total dose given was 128 +/- 54 mg (range, 28-269 mg) in the ropivacaine group and 124 +/- 62 mg (range, 33-250 mg) in the bupivacaine group. The median duration of epidural infusion, defined as the time from injection of the loading dose until discontinuation of the epidural infusion, was 4.4 h (range, 0.5-10) in the ropivacaine group and 3.6 h (range, 0.6-10.7) in the bupivacaine group. The median time from injection of the loading dose until transition from Stage 1 to Stage 2 (full cervical dilation and urge to push) was 5.9 h (range, 0.6-11.5 h) in the ropivacaine group (n = 31; eight patients with cesarean section excluded) and 5.6 h (range, 0.7-10.2 h) in the bupivacaine group (n = 31; six patients with cesarean section excluded). The median time from injection of the loading dose until delivery was 6.5 h (range, 0.7-12.4 h) in the ropivacaine group (n = 31; eight patients with cesarean section excluded) and 6.1 h (range, 0.8-10.7) in the bupivacaine group (n = 31; six patients with cesarean section excluded).
In the ropivacaine group, 8/39 (21%) parturients progressed to cesarean section, 14/39 (36%) parturients required an instrumental delivery, and 17/39 (44%) delivered spontaneously. In the bupivacaine group, there were 6/37 (16%) cesarean sections, 17/37 (46%) instrumental deliveries, and 14/37 (38%) spontaneous deliveries. There was no significant difference between the two groups in the incidence of instrumental deliveries.
The median time to onset of pain relief (Grade 3 or 4 on a verbal scale) after administration of the epidural loading dose was 10 min in both groups (range, 1-58 and 2-99 for ropivacaine and bupivacaine, respectively). The median VAS score before institution of epidural analgesia was 90 mm (range, 38-100) in the ropivacaine group and 88.5 mm (range, 35-100) in the bupivacaine group. The median average VAS score during treatment, that is from the time of injection of the epidural loading dose until discontinuation of the epidural infusion, was 12 mm (range, 0-60) in the ropivacaine group and 5 mm (range, 0-59) in the bupivacaine group. Overall quality of analgesia as judged by parturients and investigators (n = 31 in both groups, cesarean sections excluded), is summarized in Table 2. There were no statistically significant differences regarding onset of pain relief, VAS scores, and quality of analgesia between the two groups.
Thirty-one of 39 (79%) parturients in the ropivacaine group and 25/37 (68%) in the bupivacaine group were free of disturbing motor block (disturbing defined as >or=to 2 on the modified Bromage scale) of the lower limbs during the epidural infusion. Fourteen of 39 (36%) parturients in the ropivacaine group and 19/37 (51%) in the bupivacaine group had some degree of motor block at the time of discontinuation of the epidural infusion; in four of these patients (two in each group), regression times of motor block could not be obtained due to progression to cesarean section before complete recovery of motor function. For the remaining patients (12 in the ropivacaine group and 17 in the bupivacaine group), the median time to complete recovery of motor function of the lower limbs from the time of discontinuation of the epidural infusion was 65.5 min (range, 13-122) in the ropivacaine group and 40 min (range, 18-213) in the bupivacaine group. The differences between the two groups regarding intensity and duration of motor block were not significant statistically.
Maternal systolic and diastolic blood pressures and heart rates were stable in both groups. Only occasional changes in fetal heart rate were observed, occurring in both groups. No abnormal pattern was recorded in any fetus.
All 76 neonates were assessed for Apgar score at 1 and 5 min postpartum. At 1 min postpartum, 85% of the neonates in the ropivacaine group and 81% in the bupivacaine group had a normal Apgar score (>or=to7). The corresponding figures at 5 min were 92% and 97%, respectively.
NACS was not performed on the neonates born by cesarean section; a further two neonates, both in the bupivacaine group, were not analyzed for NACS; one neonate had an unexpectedly low birth weight of 2060 g and was therefore excluded, the other suffered from severe asphyxia after a prolonged vacuum extraction, necessitating immediate intubation and ventilation. From the remaining 60 neonates, 31 in the ropivacaine group and 29 in the bupivacaine group, a NACS was obtained. The number of neonates with a score >or=to35 at 2 h postpartum was 84% for the ropivacaine group and 62% for the bupivacaine group. After 24 h, all neonates, except for one in the bupivacaine group, had a NACS >or=to35.
None of the adverse or serious adverse events reported were considered to be related to the study drugs.
The results of this study show that ropivacaine 0.25%, when given as a continuous epidural infusion during labor, is as effective as bupivacaine 0.25% with respect to onset and intensity of pain relief and overall quality of analgesia. We found no statistically significant difference in intensity and duration of motor block between the two groups.
There has been some debate in the literature regarding the equipotency of ropivacaine and bupivacaine. In an in vitro study using an isolated rabbit vagus nerve model, it was found that the depressant effect of bupivacaine on motor fibers was 16% greater than that of an equal dose of ropivacaine, but only 3% greater on sensory fibers, suggesting a potential for ropivacaine for more differential sensory block . In a double-blind study comparing the effects of epidurally administered ropivacaine 0.75% with bupivacaine 0.75% in human subjects, Kerkkamp et al.  found that both intensity and duration of motor block were significantly less with ropivacaine; although spread and quality of analgesia were similar, their data also show that the duration of sensory block was significantly shorter for ropivacaine. Similar results were reported by Brockway et al. , although their data on duration of sensory block when comparing equal concentrations were inconsistent for different dermatomes, and not statistically significant. In a study comparing the effects of epidurally administered ropivacaine 0.5% with bupivacaine 0.5%, Brown et al.  found both drugs to be clinically similar in both sensory- and motor blocking characteristics, although bupivacaine produced a sensory block of slightly, but statistically significantly longer, duration; the intensity of motor block in their study was similar, but duration of Bromage Level 1 motor block was significantly longer when using bupivacaine.
Whether these clinical studies support the claim that ropivacaine produces a more differential sensory block when compared with bupivacaine is disputable. The assessment of intensity of sensory block under clinical conditions is qualitative rather than quantitative, i.e., the presence or absence of adequate analgesia at the operative site, and therefore a clinically similar intensity of sensory block is not necessarily identical with pharmacodynamic equipotency. Since it has been shown that the duration of sensory block is significantly shorter for ropivacaine [10,11], the differences in sensory and motor block characteristics between ropivacaine and bupivacaine reported in the literature may also be explained on the basis of a lower, although still adequate, overall potency of ropivacaine compared to bupivacaine.
Five neonates in the ropivacaine group and 11 neonates in the bupivacaine group had a NACS of less than 35 2 h after delivery. Seven parturients in the bupivacaine group received meperidine before beginning epidural analgesia as opposed to three parturients in the ropivacaine group. It is possible that meperidine may have adversely affected the NACS scores. However, this seems unlikely, since only two neonates, both of whose mothers had received meperidine, in the bupivacaine group had a NACS of <35 and the interval between the time of meperidine administration (75 mg in both parturients) and delivery was 9.5 h and 17 h, respectively. Thus, it is possible that there is a difference in neurobehavioral performance during the first hours of life in favor of ropivacaine, although more studies are needed to substantiate this, and the clinical significance of this observation remains unclear.
The number of instrumental deliveries in our study was high in both groups. However, it should be taken into consideration that, in The Netherlands, only 60% of deliveries take place in hospital, the remaining 40% taking place at home. Furthermore, in The Netherlands, epidural analgesia for pain relief during labor is not as widely accepted as in other western countries. For these reasons, the parturients delivering under epidural analgesia in The Netherlands form a relatively select group with a comparatively smaller chance of spontaneous delivery.
In conclusion, under the conditions of the present study, ropivacaine 0.25% and bupivacaine 0.25% were equally effective and well tolerated when given as a continuous epidural infusion for pain relief during labor. Based on its lower cardio- and neurotoxic potential, ropivacaine may be preferable to bupivacaine for epidural administration.
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