Anesth Analg 2004;98:235-239
© 2004 International Anesthesia Research Society
OBSTETRIC ANESTHESIA
A Comparison of Duration of Analgesia of Intrathecal 2.5 mg of Bupivacaine, Ropivacaine, and Levobupivacaine in Combined Spinal Epidural Analgesia for Patients in Labor
Yvonne Lim, M.MED,
Cecilia E. Ocampo, MD, and
Alex T. Sia, M.MED
From the Department of Anesthesia, KK Women’s and Children’s Hospital, Singapore
Address correspondence to Alex T. Sia, Department of Anesthesia, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore 229899. Address email to athsia{at}kkh.com.sg
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Abstract
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We assessed the duration of labor analgesia rendered by intrathecal (IT) local anesthetics as the sole drugs. In this randomized, controlled, and double-blinded study, labor analgesia was induced using combined spinal-epidural technique in 60 ASA physical status I nulliparous parturients with IT bupivacaine 2.5 mg (group B), ropivacaine 2.5 mg (group R), or levobupivacaine 2.5 mg (group L). Pain scores (0–100 visual analog scale) and blood pressure were recorded pre-block and for the first 30 min post-block. The degree of motor block and the highest sensory block were also monitored. The duration of analgesia (our primary outcome) was the longest in group B but was similar between groups R and L (mean ± SE, 76.3 ± 5.9 min versus 52.6 ± 4.0 min and 51.5 ± 3.4 min, respectively, P < 0.05). Group B had the most frequent incidence of lower limb motor block but there was no difference between groups R and L (5 of 20 parturients versus 2 of 20 and 0 of 20, respectively, P < 0.05). The profile of the other side effects was indistinguishable between the groups. With the current regimen, IT bupivacaine produced the longest duration of labor analgesia.
IMPLICATIONS: Intrathecal 2.5 mg bupivacaine significantly prolongs the duration of analgesia in laboring patients compared with ropivacaine or levobupivacaine. This suggests that, at clinically relevant doses, bupivacaine may have greater potency.
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Introduction
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Combined spinal epidural (CSE) is an established technique for labor analgesia. Various local anesthetics and opioids, either alone or in combination, have been used to induce analgesia intrathecally (IT) when CSE is used (1). IT ropivacaine 3 mg has been shown to be adequate as an induction drug for labor analgesia, although the duration of analgesia is prolonged when sufentanil is added (2). However, the avoidance of IT opioids could potentially reduce complications, such as fetal heart rate changes, fetal bradycardia (3), pruritus (4), maternal sedation, and respiratory depression (5,6).
Our study was primarily aimed at comparing the duration of analgesia provided by 2.5 mg of IT bupivacaine, ropivacaine and levobupivacaine during early labor. Our clinical experience suggested that 2.5 mg of IT bupivacaine is effective as the sole drug to induce significant analgesia during labor for the Asian population. We chose to use 2.5 mg of ropivacaine and levobupivacaine because there have been no traditional dose-finding studies done. Because we lack conclusive evidence of compared small dose IT bupivacaine with ropivacaine or levobupivacaine, our study assumed the null hypothesis that there was no difference in the potency of ropivacaine, levobupivacaine, and bupivacaine and equivalent doses of each of the local anesthetic were used.
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Methods
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With the approval of the hospital research ethics committee and informed written consent, we recruited into our study 60 ASA physical status I nulliparous laboring parturients at term who requested neuraxial analgesia.
Parturients who had a cervical dilation >5 cm or had received parenteral opioids (e.g., IM meperidine) <2 h earlier were excluded. Parturients with obstetric complications such as preeclampsia, multiple pregnancies, macrosomia, diabetes, and malpresentation were also excluded from our study.
Each parturient received an initial infusion of IV 500 mL of Ringer’s lactate solution for hydration. Baseline pain scores on a 0–100 visual analog scale (VAS, 0 = no pain and 100 = severe pain) were obtained before CSE. Systolic blood pressure (SBP), which was measured noninvasively (Dinamap, Critikon, FL) with the parturient supine and with left uterine displacement was also recorded pre-block. The fetal heart rate was monitored via external cardiotocogram throughout the study period and the obstetricians were consulted when necessary. The use of cervical prostaglandin E2 and IV oxytocin and the amount of cervical dilation before CSE were also recorded.
Every parturient received a CSE in the left lateral position at the L3-4 level. After the epidural space was located with a 17-gauge Weiss needle (the loss of resistance to air technique was used), dural puncture was performed by passing an adjustable 27-gauge Whitacre spinal needle through the epidural needle (Durasafe; BD, Franklin Lakes, NJ). The parturients were randomly allocated by blind envelope technique into 3 groups to receive one of the following: IT bupivacaine (Marcain, AstraZeneca, Sodertalje, Sweden) 2.5 mg (group B, n = 20), IT ropivacaine (Naropin, AstraZeneca) 2.5 mg (group R, n = 20) or IT levobupivacaine (Chirocaine, Abbott Laboratories, North Chicago, IL) 2.5 mg (group L, n = 20). Each of the local anesthetics was diluted with normal saline up to a total volume of 3 mL by an anesthesiologist not involved in performing the block or data collection.
The principal author (YL) who was unaware of the local anesthetic being given performed the CSE. After ensuring a free flow of cerebral spinal fluid, the IT test solution was injected over 15 s with the orifice of the spinal needle facing in the cephalad direction. A multiorifice epidural catheter was then inserted 3–4 cm into the epidural space. After excluding intravascular placement by ensuring that no blood was aspirated, 1 mL of normal saline was flushed through the epidural catheter. Patients who had blood aspirated from the catheter were withdrawn from study and a new patient recruited in her place.
Immediately after the CSE, the parturients were placed supine with a 15° left tilt. The following data were collected at 5, 10, 15 and 30 min after CSE:
- SBP.
- Pain scores using the VAS.
- Highest dermatomal sensory block (loss of cold to ice).
- The maximum motor block of either lower limb based on the modified Bromage scale (0 = no impairment, 1 = unable to raise extended legs but able to move knees and ankles, 2 = unable to raise extended legs as well as flex knees, able to move feet, 3 = not able to flex ankle, feet, or knees).
The duration of analgesia was documented from the beginning of IT injection (time0) to the time of request for additional analgesia (timeEND). During this time the parturients were observed every 15 min for shivering (0 = no, 1 = yes), nausea (0 = no, 1 = yes), and vomiting (0 = no, 1 = yes). The failure to obtain a 50% reduction of pre-block VAS after 15 min of CSE (duration of analgesia = 0 was assigned in such a case) was classified as a failed block. At timeEND, supplemental epidural analgesia (5–15 mL of 0.2% ropivacaine) was instituted. Once VAS was <30, an epidural infusion of 0.1% ropivacaine + fentanyl 2 µg/mL was started.
A reduction of SBP >20% from the baseline was promptly treated with 5 mg boluses of IV ephedrine. Nausea and vomiting were treated with metoclopramide. Fetal heart rate (from a continuous external cardiotocogram) was assessed by the attending obstetrician who was blinded to the drugs received by the parturients. New changes suggestive of an abnormal (nonreassuring) fetal heart pattern within 0.5 h after CSE resulted in appropriate obstetric intervention. These included left uterine displacement, supplemental oxygen via face mask, and tocolytic drugs if uterine hyperactivity was suspected. The pain score using the VAS, cervical dilation, and use of oxytocin at timeEND were also recorded. The mode of delivery and overall satisfaction with neuraxial analgesia were assessed and documented within 2 h of delivery on a 0–100 scale (0 = very dissatisfied and 100 = extremely satisfied)
The duration of analgesia, SBP, height, and weight were analyzed by one-way analysis of variance. Pre-block pain scores, degree of cervical dilation, highest sensory block, and satisfaction scores were analyzed with the Kruskal-Wallis test. If indicated, post hoc Bonferroni’s correction was used for pairwise comparisons. Serial data were analyzed with repeated-measures analysis of variance. Dichotomous data were analyzed with 
2 tests. Power analysis was based on difference of 30 min and estimated standard deviation of 30 min from pilot study. Sample size was calculated with 
= 0.05 and ß = 0.2 from Machin and Campbell tables (7).
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Results
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All three groups were similar in terms of age, weight, height, cervical dilation score, use of prostaglandin E2, use of oxytocin, baseline values of SBP, and VAS before CSE (Table 1).
The duration of analgesia was the longest in group B (mean ± SE, 76.3 ± 5.9 min; 95% confidence interval [CI], 64.0–88.7 min), but there was no differences between R and L (52.6 ± 4.0 min; 44.2–60.9 min and 51.5 ± 3.4 min; 44.4–58.7 min respectively, P < 0.05) (Fig. 1). None of the parturients delivered before the loss of spinal analgesia.
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Figure 1. Duration of analgesia. The mean and 95% confidence interval values for bupivacaine, l-bupivacaine, and ropivacaine are shown. Significant difference (P < 0.05) was found between bupivacaine and the other two groups. No significant difference was found between l-bupivacaine and ropivacaine. Analysis by analysis of variance and post hoc Bonferroni’s test for pairwise comparison.
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There were no failed blocks. All the parturients had VAS reduction by >50% 15 min after CSE. In fact, the patients in all three groups achieved VAS <10 within 15 min after CSE. There was no difference in the serial VAS or SBP during the first 30 min post-block among the three groups. (Fig. 2)
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Figure 2. Pain scores for the first 30 min post-block. No significant difference was detected among the 3 groups. VAS = visual analog scale; CSE = combined spinal epidural.
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Group B had the most frequent incidence of lower limb motor block (all parturients had a Bromage score of either 0 or 1), but there was no difference between groups R and L (5 of 20 subjects in B had a Bromage score of 1 versus 2 of 20 and 0 of 20, respectively, P < 0.05).
The three groups were similar in their highest dermatomal block to cold and side effect profile (Table 2). Two parturients in each of the groups B, R, and L had non-reassuring fetal heart tracings. None of them required operative intervention.
VAS, oxytocin usage, and degree of cervical dilation at timeEND were similar among the study groups. There was no difference in the overall satisfaction score with neuraxial analgesia (Table 3).
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Discussion
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These data demonstrated that with the current regimen, 2.5 mg of IT bupivacaine provided a significantly longer duration of analgesia compared with levobupivacaine and ropivacaine.
Previous studies showed ropivacaine to be significantly less potent than bupivacaine when these drugs were used for epidural analgesia during labor (8,9). They estimated ropivacaine to have a potency of 0.5–0.67 of bupivacaine for epidural analgesia in labor. These studies were based on an updown sequential allocation study design. They compared values of ED50, rather than ED95, a value that is more clinically relevant (10). Although efficient at estimating ED50, updown sequential allocation studies do not provide information regarding the slope or shape of the dose-response curves or ED95 values. The slope and shape of dose-response curves for ropivacaine and bupivacaine may be different, and their relative potencies at ED50 cannot be extrapolated to ED95. This might explain why several recent studies showed ropivacaine and bupivacaine to be equipotent at clinically relevant doses (11–13).
Our study also suggested that IT ropivacaine might have less potency compared with bupivacaine, even at clinically relevant doses. Until there is a proper dose-finding study done to compare the local anesthetics, the relative potency of ropivacaine and bupivacaine when given IT at clinically relevant doses cannot be verified definitively.
A review of levobupivacaine showed that the d-isomer was a more potent channel blocker and associated with a slower recovery of channel blockade when compared with the l-isomer (14). However, comparison between levobupivacaine and its racemic counterpart would be difficult. The concentration of levobupivacaine is expressed in mg/mL of base whereas racemic bupivacaine is expressed as mg/mL of hydrochloride (15). Levobupivacaine has more active molecules than its racemic counterpart. Despite this fact, the duration of analgesia from levobupivacaine in our study was considerably shorter. This would suggest a possible difference in potency between these two drugs. In another study comparing IT levobupivacaine with racemic bupivacaine (16), duration of labor pain relief was found to be similar. However, this study used adjuncts (opioids and epinephrine), which precluded any meaningful comparison with our study. The issue of potency difference would be resolved by future dose-finding studies and research.
The clinical impact of a longer duration of analgesia with IT bupivacaine compared with the other two drugs is debatable (17). Differences in patient satisfaction with analgesia among the three drugs could not be detected in this study. However, our study was probably underpowered in this respect. Parturients with a short duration of labor may deliver before breakthrough pain occurs if the analgesia provided by the intrathecal component of CSE is prolonged. Prolonging analgesia could potentially allow this group of parturients to deliver before epidural analgesia needs to be started. The practice of starting the epidural infusion soon after CSE induction (before the loss of spinal analgesia) is becoming more common among anesthesiologists (17,18). A longer duration of spinal analgesia may allow the epidural infusion of local anesthetics to reach a steady-state and thus decrease the incidence of breakthrough pain. The benefits of a longer duration of spinal analgesia will be clearer if further research is done to determine the exact onset time of epidural infusion of various local anesthetics to provide continuous labor analgesia.
A previous study had also demonstrated that IT ropivacaine 3 mg was adequate for induction of labor analgesia (2). The addition of IT sufentanil did prolong the duration of analgesia but also introduced opioid-related side effects. Indeed, a recent meta-analysis comparing IT opioids with conventional epidural analgesia showed an increased incidence of pruritus when IT opioids were used (4). Although this might be dismissed as innocuous, some anesthesiologists would still be concerned with the rare but potentially serious respiratory depression and fetal bradycardia (3,5,6). The induction of CSE with an appropriate dose of local anesthetic devoid of opioids could potentially overcome these issues. In another study comparing IT bupivacaine and the effect of IT fentanyl, the authors defined the mean duration of analgesia when using IT bupivacaine alone was 43 minutes, with a dose-dependent increase in duration of analgesia with addition of IT fentanyl (19). The shorter duration of analgesia seen in this study could be attributed to several factors. Their patient demographic profile differed from ours and included recruiting multiparous parturients. Different dosages of IT bupivacaine were used when measuring mean duration of analgesia because of the updown sequential allocation study design. Finally, they defined their duration of effective analgesia as the time taken for the first uncomfortable contraction to be felt, whereas our study defined it as the time taken for patients to request for additional analgesia. In clinical practice, many women might choose to ask for analgesia at a later time, thereby prolonging the duration. Another study that demonstrated mean duration of analgesia with IT bupivacaine 2.5 mg alone to be 39 minutes concluded that it did not provide satisfactory analgesia (20). However, this study was conducted in parous patients and could not be meaningfully compared with our study.
IT bupivacaine 2.5 mg also produced a significant increase in the incidence of motor impairment of lower limbs compared with IT ropivacaine 2.5 mg and IT levobupivacaine 2.5 mg. Although an earlier study found no motor blockade with IT bupivacaine 2.5 mg plus IT sufentanil 10 µg (1), it was not powered to detect differences in motor blockade. The demographic profile of the population in the study was also inherently different from our study population. Our study also demonstrated that IT bupivacaine resulted in a more frequent incidence of lower limb motor blockade compared with levobupivacaine during the first 30 minutes after CSE. In one study, motor block was found to be as frequent as 40% when IT bupivacaine 2.5 mg and fentanyl 25 µg were used (13). Another study comparing IT levobupivacaine with racemic bupivacaine (16) found that levobupivacaine produced less motor block at similar doses. All these suggest that levobupivacaine, despite having more active molecules than its racemic counterpart, causes less motor block, and thus larger doses of levobupivacaine could be used. The possibility that the parturients might not be ambulatory, may feel uncomfortable, and might not be able to actively participate in delivery when our regimen was used to induce labor analgesia must be considered.
In conclusion, our study showed that a dose of 2.5 mg of IT bupivacaine, levobupivacaine or ropivacaine could be used to induce labor analgesia. However, IT bupivacaine produced the longest duration of analgesia but at the expense of a more frequent incidence of motor blockade.
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References
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Accepted for publication August 19, 2003.
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Abstract
Introduction
