Comparison of 0.25% S( )-bupivacaine with 0.25% RS-bupivacaine for epidural analgesia in labour

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1 British Journal of Anaesthesia 83 (5): (1999) Comparison of 0.25% S( )-bupivacaine with 0.25% RS-bupivacaine for epidural analgesia in labour D. Burke 1, D. J. Henderson 2, A. M. Simpson 3, K. A. Faccenda 2, L. M. M. Morrison 2, E. M. McGrady 3, G. A. McLeod 1 and J. Bannister 1 1 Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. 2 St John s Hospital, Livingston, UK. 3 Glasgow Royal Maternity Hospital, Glasgow, UK We have compared the efficacy of 0.25% S( )-bupivacaine with 0.25% RS-bupivacaine in providing epidural analgesia for labour in a randomized, multicentre, double-blind study. Analgesia was initiated with 10 ml of the study solution and maintained with 10-ml top-ups. We studied 137 women and treatments were found to be equivalent for onset, duration and quality of block. Median onset of pain relief was 12 min for both drugs and median duration was 49 (range 3 129) min and 51 (7 157) min for S( )-bupivacaine and RS bupivacaine, respectively. The estimated treatment difference for duration of pain relief was 4 (90% CI 13, 6) min. Thirty patients failed to achieve pain relief after the first injection (20 patients after S( )-bupivacaine and 10 after RS-bupivacaine; P 0.039). However, median duration of pain relief from the first top-up was 82 (range 3 164) min for S( )-bupivacaine and 76 (22 221) min for RS-bupivacaine. There were no significant differences in the quality of analgesia, as assessed by the investigators. There were no significant differences in the extent of sensory block, percentage of patients with motor block or incidence of adverse events. Br J Anaesth 1999; 83: Keywords: anaesthesia, obstetric; anaesthetic techniques, epidural; pharmacokinetics, enantiomers; anaesthetics local, bupivacaine Accepted for publication: April 20, 1999 Epidural analgesia provides excellent pain relief in labour arrythmias. 4 Potassium channel block enhances sodium and bupivacaine is well established as the most popular block and lengthens the cardiac action potential a pro- local anaesthetic in obstetric practice. Pharmacological arrythmogenic effect. 5 Indirect effects mediated via the CNS properties of bupivacaine offer advantages to mother and can play a modulatory role. 6 Both mechanisms have an fetus. Slow systemic uptake from the epidural space together enantiomer-specific component, with the S( ) isomer with a high degree of protein binding limit placental transfer possessing much lower cardiovascular toxicity. Results from to the fetus and low umbilical vein maternal blood ratios. 1 a number of in vitro and in vivo studies suggest that S( )- However, reports of cardiovascular and central nervous bupivacaine is less cardiotoxic than R( )-bupivacaine and system (CNS) toxicity associated with bupivacaine 2 led to the RS racemic mixture, while retaining the potency of the Food and Drug Administration advising against the use commercial bupivacaine. 78 of 0.75% bupivacaine in obstetric practice. In this study, we have compared the analgesic efficacy Bupivacaine is a chiral compound containing an of 0.25% S( )-bupivacaine with 0.25% RS-bupivacaine in asymmetric carbon atom and exists as two enantiomers. providing epidural analgesia for the relief of pain in labour. The current commercial preparation contains a 50:50 racemic mixture of the enantiomers levo or S( ) bupivacaine and dextro or R( ) bupivacaine. Although physical and Patients and methods chemical properties are identical, the enantiomers have We performed a randomized, double-blind study at three different pharmacodynamic and pharmacokinetic profiles. 3 centres after obtaining approval from the Local Ethics Bupivacaine-induced cardiotoxicity can be attributed to Review Committees. Written informed consent was block of myocardial sodium and potassium channels. obtained from patients in early labour requesting epidural Sodium channel block results in a dose-dependant decrease analgesia and who had not received parenteral opioids in in the maximal rate of depolarization of the cardiac action the preceding 4 h. All patients were ASA I or II with a full potential (vmax), prolongation of the QRS interval and term ( 36 weeks) singleton fetus, aged yr, height ultimately the occurrence of malignant ventricular 150 cm and weight 115 kg. Exclusion criteria were British Journal of Anaesthesia

2 S( )-bupivacaine compared with RS-bupivacaine in labour women who had a previous Caesarean section, insulin- measured at 5, 10, 15 and 30 min and subsequently at dependent diabetes mellitus, pre-eclampsia, psychiatric 30-min intervals. Analgesia was defined as the inability to disease, history of drug or alcohol abuse, known allergy to appreciate as sharp the prick of a short-bevel, 27-gauge amide local anaesthetics or women carrying a fetus with dental needle. known abnormalities. A medical and obstetric history was Motor block was assessed at identical times using the obtained and a physical examination performed. Gestational modified Bromage scale as follows: 0 no paralysis, full age, degree of cervical dilatation and parity were recorded. flexion of the knees and ankles, 1 inability to raise extended Women entering the study were given a patient number leg, able to move knees, 2 inability to flex knees, able to and allocated to their treatment group in a double-blind flex ankle and 3 inability to move lower limb. manner using a computer-generated randomization schedule Cardiovascular variables were recorded before insertion with stratification for parity. Study drugs were prepared of the epidural and at 2, 5, 10, 15, 20, 25, 30 and then outside the labour ward area by non-investigators. every 30 min until delivery. Hypotension was defined as a Before performing the epidural, an i.v. infusion of decrease in baseline systolic arterial pressure of 30%, Hartmann s solution was commenced and 500 ml administered. with treatment at the discretion of the investigator. Under asepsis, the procedure was performed with the Duration of the first and second stages of labour were patient in either the sitting or lateral position. The skin was recorded, as was the mode of delivery. infiltrated with a maximum of 1% lidocaine 3 ml and the epidural space was identified at L2 3 or L3 4 using a Fetal assessment midline approach and loss of resistance to saline with either Fetal heart rate was monitored continuously on a cardiotocoa 16-gauge or 18-gauge Tuohy needle. A three sidehole graph and recorded at the same times as maternal data. epidural catheter was advanced cephalad 2 3 cm into the Apgar scores were recorded 1 and 5 min after delivery and epidural space. For drug administration, patients were placed umbilical arterial and venous blood were sampled for supine with a wedge under the right hip. measurement of oxygen tension and ph (one centre only). After negative aspiration, a test dose of 3 ml of study Evaluation of the neurobehavioural status of the neonate drug was given via the catheter at a rate of 1 ml every 2 s. was made by recording the neurological and adaptive If after 5 min there was no evidence of intravascular or capacity score (NACS) at 2 and 24 h after delivery. 9 This subarachnoid injection, another 7 ml of study drug were score was recorded only in those patients who received study administered at the same rate. Completion of the injection medication alone (i.e. they had not received supplementary was deemed time zero for purposes of assessment. Further analgesia). top-up injections of 10 ml were administered as necessary All adverse events temporally associated with drug with the minimum time between top-ups being 15 min administration were recorded and defined as being possibly and the maximum amount given in any 4-h period not related, definitely related or of unknown relationship. exceeding 2 mg kg 1. These top-up injections were given Patients were followed-up at 24 h or discharge and 3 7 when the patient reported two consecutive contractions as days later by telephone. being painful. Maternal assessment The primary measure of efficacy was duration of analgesia, assessed by recording the pain of contractions using a patient verbal rating scale (VRS). This categorized each contraction as either painful, aware but not painful or unaware. Women were asked to complete this for the two contractions immediately preceding the epidural and thereafter with each contraction until the second top-up injection. Women also completed a 100-mm visual analogue pain scale (VAS) for each contraction. Scores were not recorded when a VRS of unaware was reported or the patient was asleep. Onset of analgesia was determined to be from time zero to the first report of being aware of a painless contraction. Duration of analgesia was deemed as the time from the first painless contraction until return of the second successive painful contraction. Overall assessment of the quality of analgesia was recorded by the investigator 30 min after each top-up using a three-point categorical scale (0 good, 1 fair and 2 poor). The extent of sensory analgesia was Withdrawal from the study Patients in whom pain relief was unsatisfactory despite top-ups of study medication, resulting in the need for supplementary analgesia (e.g. epidural fentanyl for rectal pressure), were withdrawn from the study. Statistical analysis Assuming a SD of 38 min in duration of pain relief after administration of 0.25% bupivacaine, 10 and a maximum difference of 20 min to conclude equivalence, it was calculated that 55 women per group were needed to give the study 95% power (α 0.1, β 0.1). Data management and statistical analysis were performed by Inveresk Clinical Research Ltd, Edinburgh, Scotland. The database used was the SAS (v. 6.07) system. Statistical analysis was performed on data from the first two injections only. Time to onset and duration of analgesia together with the visual analogue scores for each injection were compared using analysis of variance and the Student s test, following Shapiro Wilk analysis to establish normality. 751

3 Burke et al. Table 1 Maternal characteristics (mean (SD) [range] or number) S( )-bupivacaine (n 68) RS-bupivacaine (n 69) Age (yr) 27.3 [18 40] 25.8 [19 35] Height (cm) (6.0) [ ] (6.0) [ ] Weight (kg) (12.91) [53 115] (12.05) [52 105] Gestation (weeks) (1.1) [ ] (1.2)[ ] Cervical dilation (cm) 3.66 (1.8) [ ] 3.19 (1.7) [ ] Primiparae/multiparae 57/11 58/11 Table 2 Characteristics of labour (number of patients (SD)) S( )-bupivacaine (n 68) RS-bupivacaine (n 69) Management of labour Induction Augmentation Fig 1 Median (interquartile range) extent of sensory block after the first Duration of labour (h) First stage 9.38 (3.51) (5.23) injection of S( )-bupivacaine (levobupivacaine) and RS-bupivacaine. Second stage 1.45 (1.15) 1.51 (1.04) subsequent 10-ml top-up of study solution was 82 Mode of delivery (3 164) min and 76 (22 221) min for S( )-bupivacaine LUSCS Assisted delivery and RS-bupivacaine, respectively. Treatment difference SVD was 1 (90% CI 15, 12) min. Analgesia Non-parametric data were compared using a generalized Quality of analgesia observed by the investigators was not Wilcoxon model. P 0.05 was taken as significant. significantly different between groups. Ten patients were regarded as having poor pain relief after the initial injection Results in the S( )-bupivacaine group compared with six patients in the RS-bupivacaine group. For the subsequent top-up, We recruited 169 women who received the study drugs no patient receiving S( )-bupivacaine had poor analgesia and they formed the safety population. Any deviations compared with one patient who received RS-bupivacaine. from the study were identified and those patients were excluded from further analysis, leaving 137 women in the Visual analogue scores per protocol population (68 S( )-bupivacaine, 69 RS- Mean VAS before siting the epidural was 64.8 bupivacaine). Thirty women did not achieve adequate pain (15 100) mm in the S( )-bupivacaine group and 64.1 relief after the initial bolus, leaving 107 subjects available (17 100) mm in the RS-bupivacaine group and before for full statistical analysis. Patient characteristics and the first top-up was 31.6 mm for S( )-bupivacaine and obstetric data were similar between groups (Tables 1, 2) mm for RS-bupivacaine. The time-normalized area under the VAS pain score Maternal assessment vs time curve (AUC) was calculated using the linear Onset trapezoidal rule and included those patients in the per Median time to onset of pain relief after the first injection protocol group who did not obtain satisfactory analgesia was 12 min for both drugs (range 5 39 min for S( )- after administration of the initial bolus and subsequent bupivacaine and 2 50 min for RS-bupivacaine ). After top-up. After the first injection, the geometric mean time- the first top-up, median time to onset of pain relief was normalized AUC (adjusted for baseline pain score) was 22.7 (SD 7 (1 41) min for S( )-bupivacaine and 6 (2 16) min for 21.9) mm for S( )-bupivacaine and 15.8 (17.8) RS-bupivacaine. The treatment difference was estimated at mm for RS-bupivacaine (P 0.75). After the first top-up, 1 min (90% CI 0, 3 min). the geometric time-normalized AUC was 7.3 (19.3) mm for S( )-bupivacaine and 6.6 (12.2) mm for RS-bupivacaine Duration (P 0.12). Median duration of pain relief after the first injection was Sensory analgesia 49 (3 129) min for S( )-bupivacaine and 51 (7 157) min Median extent of sensory block after the first injection was for RS-bupivacaine. The treatment difference was estimated T8 S2 for S( )-bupivacaine and T9 S5 for RS-bupivacaine. as 4 (90% CI 13, 6) min. As the 90% confidence limits After the first top-up, median extent was T8 S5 for both were within 20 min, we concluded that the treatments were drugs (Figs 1, 2). equivalent. Thirty patients failed to achieve adequate pain relief after the first injection (20 patients after S( )- Motor block bupivacaine and 10 patients after RS-bupivacaine; P After the first injection, 84% of patients who received 0.039). However, median duration of pain relief after the S( )-bupivacaine had Bromage grade 0 motor block com- 752

4 S( )-bupivacaine compared with RS-bupivacaine in labour patients (25 in the S( )-bupivacaine group and 17 in the racemic group) with the most commonly reported being fetal distress and delayed delivery. Discussion We have demonstrated that 0.25% S( )-bupivacaine and 0.25% RS-bupivacaine provided equivalent pain relief for epidural analgesia in labour. Both drugs produced a similar spread of sensory analgesia, degree of motor block and reduction in visual analogue pain scores. Our data are in keeping with other clinical studies which have shown that sensory block produced by S( )-bupivacaine is essentially indistinguishable from that produced by Fig 2 Median (interquartile range) extent of sensory block after the first RS-bupivacaine top-up of S( )-bupivacaine (levobupivacaine) and RS-bupivacaine. Failure to achieve pain relief after the initial injection occurred in 30 patients (22%). This reflects the conservative pared with 83% of RS-bupivacaine patients (95% CI 0.38, dose of the initial injection (10 ml) and is in agreement 2.33). The number of patients free of motor block after with other studies. 13 However, more women in the S( )- the first top-up was reduced to 66% and 63% for S( )- bupivacaine than in the RS-bupivacaine group failed to bupivacaine and RS-bupivacaine, respectively. achieve pain relief after the first injection (20 compared Mode of delivery with 10). This may be related to a greater degree of cervical Labour was induced with Prostin gel in 17 patients in the dilatation in this group and more frequent use of Prostin S( )-bupivacaine group and in 11 in the RS-bupivacaine gel for induction of labour, which may have resulted in group (P 0.19). After epidural insertion, labour was more painful labour. 14 Of the 30 patients who failed to augmented with a variable rate Syntocinon infusion in 17 achieve adequate analgesia after the first injection, eight patients in the S( )-bupivacaine group and in 26 in the RSwith Prostin compared with two in the RS-bupivacaine patients in the S( )-bupivacaine group had been induced bupivacaine group. Duration of the first and second stages of labour and mode of delivery are shown in Table 2. group. The overall quality of analgesia after the first injection, Withdrawal as assessed by the investigators, did not differ between Eight women who received S( )-bupivacaine were with- groups, and subsequent administration of a top-up resulted drawn from the study because they needed supplement- in both drugs having an equivalent duration of action and ary analgesia compared with 17 patients in the RS- quality of block. bupivacaine group. The incidence of adverse events was similar in the two Cardiovascular stability groups. Our study revealed little difference in the mode of Mean arterial pressure and maternal heart rate did not delivery between the groups or in neonatal outcome. Apgar differ significantly between groups (Tables 3 5). Hypogroups, as were NAC scores. scores and umbilical cord gases were similar in the two tensive episodes considered to be causally related to drug administration were experienced in eight patients in the In the only other published study comparing S( )- S( )-bupivacaine group and in five in the RS-group. bupivacaine with RS-bupivacaine for obstetric use, the Vasopressors and additional i.v. fluids were given to two drugs were shown to be essentially equivalent in potency. patients in the S( )-bupivacaine group and to one patient Using up down sequential allocation, the minimum local in the RS-bupivacaine group. analgesic concentration (MLAC) for S( )-bupivacaine and bupivacaine was calculated. This has been defined as the Neonatal assessment median effective concentration (EC 50 ) for epidural analgesia in the first stage of labour. 15 The MLAC for S( )-bupivacaine A summary of neonatal outcome is shown in Table 6. Birth was calculated as 0.083%w/v and that for RS-bupivacaine, weight was similar between groups. The neonatal condition 0.081%w/v, a potency ratio of This would support at delivery, as assessed by Apgar score, umbilical cord our findings that the two drugs are equivalent in terms of acid base status and NAC score, did not differ between quality of sensory block. groups. Also, NAC scores repeated at 24 h did not differ While it is not possible to make inferences of safety between groups. with such small numbers, there is evidence that S( )- Adverse events bupivacaine has less potential for cardiotoxicity than RS- At least one adverse event was experienced by 25% of bupivacaine This is particularly important in the patients. A total of 53 adverse events were recorded in 42 pregnant population, who are more vulnerable in the 753

5 Burke et al. Table 3 Maternal systolic arterial pressure after initial epidural injection and subsequent boluses of study drug. Results are expressed as mean (SD) mm Hg, mean (%) change in blood pressure from baseline and number (n) of patients S( )-bupivacaine RS-bupivacaine Mean (SD) Mean change from pre-dose (%) n Mean (SD) Mean change from pre-dose (%) n Pre-dose (16.3) (16.4) 87 1st injection (15.4) (15.3) st top-up (14.3) (14.9) nd top-up (14.5) (13.6) rd top-up (15.0) (9.5) Table 4 Maternal diastolic arterial pressure after initial epidural injection and subsequent boluses of study drug. Results are expressed as mean (SD) mm Hg, mean (%) change in blood pressure from baseline and number (n) of patients S( )-bupivacaine RS-bupivacaine Mean (SD) Mean change from pre-dose (%) n Mean (SD) Mean change from pre-dose (%) n Pre-dose 79.0 (11.7) (13) 87 1st injection 76.2 (11.4) (12.7) st top-up 74.3 (10.9) (13.4) nd top-up 73.8 (11.2) (12.2) rd top-up 75.9 (11.8) (10) Table 5 Maternal heart rate after initial epidural injection and subsequent boluses of study drug. Results are expressed as mean (SD) beat min 1 and % change from baseline S( )-bupivacaine RS-bupivacaine Mean (SD) Mean change from pre-dose (%) n Mean (SD) Mean change from pre-dose (%) n Pre-dose 83.3 (13.8) (15.8) 87 1st injection 83.1 (13.7) (16.9) st top-up 85.2 (14.6) (16.5) nd top-up 88.9 (14) (14.8) rd top-up 87.0 (13.6) (16.6) Table 6 Summary of neonatal outcome (mean (SD) or numbers) n S( )-bupivacaine n RS bupivacaine tion has focused on their stereoselective effects on cardiac electrophysiology in vitro. Vanhouette and colleagues 19 studied the electrophysiological effects of bupivacaine Birth weight (g) (500) (470) isomers on guinea-pig isolated papillary muscle at different Apgar 7 membrane potentials and stimulation frequencies. R( )- 1 min min bupivacaine produced a greater degree of reduction in the maximal rate of cardiac depolarization (vmax) ( % Umbilical vein P O2 (kpa) (0.87) (1.2) vs %). This was attributed to a slower rate of ph (0.05) (0.08) diastolic dissociation with R( )-bupivacaine. Reduction in Umbilical artery vmax resulting in slowed conduction of the cardiac action P O2 (kpa) (0.84) (1.01) potential is manifest by prolongation of the PR and QRS ph (0.08) (0.07) intervals. Slowed conduction may additionally result in NACS 35 2h re-entrant phenomena explaining the sudden onset of 24 2 h ventricular arrhythmias. Based on the original observations by Aberg 20 that the event of cardiac arrest, with faster onset of hypoxaemia LD 50 value was 30 40% lower for R( )- bupivacaine than and difficulties in performing effective cardiopulmonary S( )-bupivacaine, evidence now exists that S( )-bupivacaine resuscitation. In providing effective epidural analgesia for is consistently less cardiotoxic in all animal species tested. labour which is comparable with that provided by racemic bupivacaine, S( )-bupivacaine represents an enhanced Acknowledgements margin of safety in the obstetric population. Drs Burke, Simpson and Henderson were in receipt of research fellowships In an attempt to explain the observed in vivo toxicity from Chiroscience Ltd. S( )-bupivacaine was supplied by Chiroscience differences between the enantiomers of bupivacaine, atten- Ltd, Cambridge. 754

6 S( )-bupivacaine compared with RS-bupivacaine in labour References double-blind comparison of 0.25% ropivacaine and bupivacaine for extradural analgesia in labour. Br J Anaesth 1996; 76: Reynolds F. Fred Hehre lecture: In defence of bupivacaine. Int J 11 Cox CR, Faccenda KA, Gilhooly C, Bannister J, Scott NB, Morrison Obstet Anaesth 1995; 4: LMM. Extradural S( )-bupivacaine: comparison with racemic RS- 2 Albright GA. Cardiac arrest following regional anesthesia with bupivacaine. Br J Anaesth 1998; 80: etidocaine or bupivacaine. Anesthesiology 1979; 51: Cox CR, Checketts MR, Mackenzie N, Scott NB, Bannister J. 3 Burm GL, Van der Meer AD, Van Kleef JW, Zeijlmans PWM, Comparison of S( ) bupivacaine with racemic bupivacaine in Groen K. Pharmacokinetics of the enantiomers of bupivacaine supraclavicular brachial plexus block. Br J Anaesth 1998; 80: following intravenous administration of the racemate. Br J Clin 13 Russell R, Reynolds F. Epidural infusion of low-dose bupivacaine Pharmacol 1994; 38: and opioid in labour. Does reducing motor block increase the 4 Clarkson CW, Hondghem LM. Mechanism for bupivacaine spontaneous delivery rate? Anaesthesia 1996; 51: depression of cardiac conduction: fast block of sodium channels 14 Chamberlain G, Wraight A, Steer P. Pain and its Relief in Childbirth. during the action potential with slow recovery from the block The Results of a National Survey Conducted by the National Birthday during diastole. Anesthesiology 1985; 62: Trust. Edinburgh: Churchill Livingstone, Valenzuela C, Delpon E, Tamkun MM, Tamargo J, Snyders DJ. 15 Colomb MO, Lyons G.Determination of minimum analgesic Stereoselective block of a human cardiac potassium channel (Kv concentrations of epidural bupivacaine and lidocaine in labor. 1.5) by bupivacaine enantiomers. Biophys J 1995; 69: Anesth Analg 1995; 81: Thomas RD, Behbehani MM, Coyle DE, Denson DD. 16 Lyons G, Colomb MO, Wilson RC, Johnson RV. Epidural pain relief Cardiovascular toxicity of local anesthetics: an alternative in labour: relative potencies of bupivacaine and levobupivacaine. Br hypothesis. Anesth Analg 1986; 65: J Anaesth 1998; 81: Mazoit JX, Boico O, Samii K. Myocardial uptake of bupivacaine: 17 Bardsley H, Gristwood R, Baker H, Watson N, Nimmo W. A comparison of the cardiovascular effects of levobupivacaine and II Pharmacodynamics of bupivacaine enantiomers in the isolated rac-bupivacaine following intravenous administration to healthy perfused rabbit heart. Anesth Analg 1993; 77: volunteers. Br J Clin Pharmacol 1998; 46: Denson DD, Behbehani MM, Greggs RV. Enantiomer specific 18 Huang YF, Pryor ME, Veering BT, Mather LE. Cardiovascular and effects of an intravenously administered arrhythmogenic dose of central nervous system effects of intravenous levobupivacaine and bupivacaine on neurons of the nucleus tractus solitarius of the bupivacaine in sheep. Anesth Analg 1998; 86: cardiovascular system of the anesthetised rat. Reg Anesth 1992; 19 Vanhoutte F, Vereeke J, Verbeke N, Carmeliet E. Stereoselective 17: effects of the enantiomers of bupivacaine on the 9 Amiel-Tison C, Barrier G, Shnider SM, Levinson G, Hughes SC, electro physiological properties of the guinea-pig papillary Stefani SJ. A new neurologic and adaptive capacity scoring system muscle. Br J Pharmacol 1991; 103: for evaluating obstetric medications in full-term newborns. 20 Aberg G. Toxicological and local anaesthetic effects of optically Anesthesiology 1982; 56: active isomers of two local anaesthetic compounds. Acta Pharmacol 10 Eddleston JM, Holland JJ, Griffin RP, Corbett A, Horsman EL. A Toxicol 1972; 31: