1 Department of Anaesthesiology of Clinique St Anne-St Rémy and 2 Department of Anaesthesiology,St Luc Hospital, Catholic University of Louvain, av. Hippocrate 10-1821, 1200 Brussels, Belgium
Corresponding author. E-mail: dekock@anes.ucl.ac.be
Accepted for publication: June 24, 2003
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Abstract |
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Methods. Ninety parturients were enrolled. A combined spinal-epidural technique was used. Patients were randomly assigned to receive one of the following isobaric i.t. solutions: bupivacaine 8 mg (n=30), levobupivacaine 8 mg (n=30), or ropivacaine 12 mg (n=30), all combined with sufentanil 2.5 µg. An i.t. solution was considered effective if an upper sensory level to pinprick of T4 or above was achieved and if intraoperative epidural supplementation was not required. Sensory changes and motor changes were recorded.
Results. Anaesthesia was effective in 97, 80, and 87% of patients in the bupivacaine 8 mg, levobupivacaine 8 mg, and ropivacaine 12 mg groups, respectively. Bupivacaine 8 mg was associated with a significantly superior success rate to that observed in the levobupivacaine group (P<0.05). It also provided a longer duration of analgesia and motor block (P<0.05 vs levobupivacaine and ropivacaine).
Conclusions. The racemic mixture of bupivacaine combined with sufentanil remains an appropriate choice when performing Caesarean sections under spinal anaesthesia.
Br J Anaesth 2003; 91: 6849
Keywords: anaesthesia, obstetric, Caesarean section; anaesthetics local; anaesthetic techniques, regional
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Introduction |
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Methods |
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Before the study, patients were instructed on the method of sensory and motor assessments, and baseline measurements were performed. All parturients received oxygen (4 litre min1) via a facemask and an i.v. bolus dose of 20 ml kg1 lactated Ringers solution was administered over approximately 15 min. Patients were placed in the right lateral position. To perform a needle through needle technique, an 8-cm 16-gauge Tuohy needle (Portex Ltd, Hythe, Kent, UK) was inserted into the epidural space at the L3L4 interspace by a loss-of-resistance technique. The dura was punctured using a 29-gauge pencil-point needle (Becton-Dickinson, NJ, USA) oriented with the orifice facing cephalad. The study solution was injected and a multi-orifice epidural catheter was inserted 3 cm into the epidural space. As determined by a table of random numbers, patients received one of the following glucose-free intrathecal (i.t.) solutions: ropivacaine 12 mg (Group Ropi 12), bupivacaine 8 mg (Group Bupi 8), and levobupivacaine 8 mg (Group Levo 8). In each group, sufentanil 2.5 µg was added to the local anaesthetic. Based on previous studies by our group,7 8 sample size was determined at 30 patients per group. To facilitate blinding, the study drugs were diluted to 3.0 ml with normal saline and prepared by an anaesthetist not involved with subsequent patient assessments. After confirming free flow of cerebrospinal fluid, spinal solutions were injected over approximately 60 s.
The patients were placed supine with a left lateral tilt and a pillow under the thigh. Arterial pressure and heart rate were monitored using a non-invasive monitor (Cardiocap Datex, Helsinki, Finland) every 2 min until delivery then every 5 min during the rest of the procedure and the two first postoperative hours. I.V. ephedrine 5 mg was given concomitantly with the i.t. injection in order to prevent hypotension.9
After 20 min, surgery was allowed to start if the upper dermatome level of loss of discrimination to pinprick was at or above T4. This time was noted as the onset of sensory block. Sensory changes were recorded bilaterally along the midclavicular line by assessing changes in pinprick sensation using a 25-gauge needle protruding 2 mm through a guard. This measurement was performed before i.t. injection, then every 2 min from 6 to 20 min and then every 10 min until recovery to T12.
Motor block was assessed by the investigators using a modified Bromage scale (1=complete motor block; 2=almost complete motor blockthe patient is able to move the feet only; 3=partial motor blockthe patient is able to move the knees; 4=detectable weakness of hip flexionthe patient is able to raise the leg but unable to keep it raised; 5=no detectable weakness of hip flexionthe patient is able to keep the leg raised for 10 s or more; 6=no weakness at allthe patient is able to perform partial knee bend while supine). This test was performed at baseline, then 10, 15, and 20 min after i.t. injection and as soon as possible at the end of surgery. After surgery it was performed every 15 min. During the procedure, the surgeons evaluated muscle relaxation according to a four-point scale (1=excellent, 2=good, 3=fair, 4=poor).
Pain was assessed with a 10-cm linear visual analogue scale (VAS) at incision, birth and peritoneal closure and at 15 min intervals after surgery. Before anaesthesia, parturients were instructed that fetal extraction might be associated with some degree of discomfort. In the case of unbearable discomfort (score of 5 or greater on a 10-point numerical score or maternal request for rescue), 10 ml of lidocaine 2% plus epinephrine 1/200 000 were injected epidurally. Rescue epidural analgesic administration was considered indicative of a failure of the i.t. technique. Consequently, subsequent data concerning pain, sensory and motor block were not taken into account. In these patients, however, data for the onset of spinal anaesthesia before epidural top-up were included for analysis.
For assessment of the onset of anaesthesia, the time for sensory block to develop to maximum block height and the time to achieve maximum Bromage score were recorded. To assess the duration of the sensory block, the two-segment regression time from the maximum block height and time for regression to T10 were used. Duration of motor block was assessed by recording the time elapsed from the maximum to the lowest Bromage score. The duration of analgesia provided by the i.t. solutions was taken as the time elapsed between i.t. injection and the first additional analgesic request.
Immediately after surgery, parturients were questioned about the quality of their anaesthesia using a four-point scale (1=perfect, 2=some feelings but no discomfort, 3=some discomfort but rescue analgesia unnecessary, 4=major discomfort and rescue analgesia mandatory). The incidence of side effects such as nausea, vomiting, hypotension (defined by a drop in systolic arterial pressure below 100 mm Hg or less than 80% of the baseline), and pruritus were noted. All parturients were examined for transient radicular irritation syndrome on days 1 and 3 and after 1 month.
Statistical analysis
Comparison of the primary variable, namely the success rate in the different groups, was assessed by the Fishers Exact test using subsequently the superiority approach and the non-inferiority method.10 In the superiority approach, the null hypothesis implies that the success rate in the groups which are being compared is equal. In case the null hypothesis has to be rejected after the statistical test (P<0.05) it is concluded that one of the groups is superior to the others in terms of success rate. In case of the non-inferiority approach, the null hypothesis states that one group is inferior to the other. When this null hypothesis is rejected (P<0.05) then the alternative hypothesis, namely that the groups are not inferior to each other, becomes more probable. Another way of describing non-inferiority is that one treatment is not worse than the other. In the non-inferiority approach, clinical relevance is expressed by means of the 97.5% upper confidence level (CL). The maximum allowed difference of 20% is considered as a clinically relevant boundary.
Values below 20% indicate non-inferiority. The exact power of tests for non-inferiority of two binomial populations with a maximum allowable difference of 20%, type I error (alpha) of 0.025, probabilities of no response in the two study groups of 87 and 80%, respectively, and 30 patients in each study group is 79.2%.
Statistical analysis for the primary variable was carried out by the software package PROC STATXACT version 5 for SAS users (Statistical Software for Exact Nonparametric Inference (February 2002), CYTEL Software Corporation, Cambridge, MA, ISBN).
For the secondary variables, the following methods were applied: continuous variables among groups were compared by one-way analysis of variance (ANOVA) followed by Students NewmanKeuls tests for multiple comparisons. Nominal categorical data among study groups were compared using Fishers Exact test. For the comparison of ordinal categorical data between the three groups, the KruskallWallis test, was applied followed by the Wilcoxon Rank Sum test for multiple comparisons with bupivacaine 8 mg as the reference control group. P<0.05 was considered significant. Data are presented as mean (SD) or median and range where appropriate. Statistical analysis for the secondary variables was carried out by the software package SAS version 8.2 (SAS Institute Inc., Cary, NC).
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Results |
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Discussion |
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Comparison of the success rate in the different groups was based on the notion of non-inferiority trials. According to the recent International Conference of Harmonisation E9 Guidance Statistical Principles for Clinical Trials, efficacy of new treatment modalities is established by demonstrating superiority to placebo, by showing superiority to an active control or by demonstrating a doseresponse relationship. These represent the so-called superiority trials. Nevertheless, in clinical situations where the use of placebo is not applicable (for ethical or practical reasons) and where active treatment with established efficacy exists, active control trials designed to show that the efficacy of investigational products are not significantly worse than that of the active drug that can be used (non-inferiority trials). After having confirmed non-inferiority, superiority of the alternative test treatment over reference treatment can additionally be tested without the need to adjust the significance level. This method has been used for comparison of psychiatric, anaesthetic and oncological treatments.1113
In the present study, the dose of ropivacaine 12 mg was used for comparison with bupivacaine 8 mg. We chose a different dose because ropivacaine is not equipotent to bupivacaine after i.t. administration.1 2 7 8 As revealed by our pilot study, the dose of 12 mg is the lowest dose of ropivacaine that produces anaesthesia comparable with bupivacaine 8 mg in parturients. Indeed, inadequate anaesthesia levels before surgery were recorded in 40 and 10% of patients having received, respectively, i.t. ropivacaine 8 and 10 mg with sufentanil 2.5 µg. Moreover, unsatisfactory pain relief during surgery was observed in 40% of patients who received these low doses of ropivacaine.
When considering the recent work performed by Khaw and colleagues14 in similar clinical settings and using the same end-points, it is possible to get a precise idea of the local anaesthetic sparing effect of i.t. sufentanil. These authors studied the doseresponse relationship for spinal ropivacaine alone. They were able to determine the ED50, ED90, and ED95 to be 16.7, 24.5, and 26.8 mg, respectively. Taking our results into account, the addition of sufentanil 2.5 µg allows a reduction of nearly 50% of the dose of ropivacaine required for the ED90. Such sparing effect is in accordance with the data obtained by others for fentanyl.5 6
Epidural ropivacaine has been regarded previously as having specific effects on sensitive nervous fibres thereby producing less motor impairments than the other local anaesthetics. Using the i.t. route, however, this assumption is challenged by our results and by those of Khaw and colleagues14 who clearly report an increasing proportion of patients developing full motor block with increasing dosage of ropivacaine.
It is interesting to consider the differences observed between bupivacaine and levobupivacaine. First, the success rate is in favour of the racemic mixture, levobupivacaine appearing to be less effective. Secondly, the duration of analgesia provided by the levovbupivacaine was significantly shorter. Thirdly, the motor block induced by the racemic mixture is characterized by a longer duration than the pure S(-)-enantiomer. This contrasts with previous reports comparing large doses of both local anaesthetics for epidural or brachial plexus anaesthesia and with two recent studies comparing the i.t. administration of hyperbaric solutions in human volunteers15 and in patients undergoing hip replacement.16 It is even more surprising knowing that levobupivacaine contains approximately 11% more active drug than the racemic mixture per millilitre.17 The apparent equipotency of bupivacaine and levobupivacaine reported in these studies may be explained by the large dose of local anaesthetics used. The administration of supramaximal doses may have masked subtle potency differences. Recent work by Polley and colleagues18 supports this hypothesis. These authors compared ropivacaine and levobupivacaine in advanced labour (cervical dilatation >7 cm). Taking into account the results of previous mean local anaesthetic concentration studies performed in early labour comparing bupivacaine vs ropivacaine19 20 and bupivacaine vs levobupivacaine,21 a 40% difference favouring levobupivacaine would have been expected. Yet surprisingly, in Polleys study, the two drugs have identical ED50. Our study, while confirming the lower potency of levobupivacaine compared with bupivacaine, shows that the more invasive and sensitive the procedure, the more apparent the differences in efficiency between the drugs. Indeed, the quality of the pain relief needed during advanced labour or abdominal surgery with visceral traction appears to be very different from that of the pain relief required during early labour, knee arthroscopy, transurethral resection procedures, or simply testing in volunteers.1 15 16 In this regard, it is interesting to note that some differences in the intensity of motor block have already been reported.4 22
In conclusion, we have shown that the racemic mixture of bupivacaine combined with sufentanil remains an adequate choice when performing Caesarean sections under spinal anaesthesia. Moreover, as a result of the particular study design (strong surgical stimulus and submaximal doses) our data support a potency hierarchy amongst the long-acting local anaesthetics.
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Acknowledgements |
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References |
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