Extradural pain relief in labour: bupivacaine sparing by extradural fentanyl is dose dependent

Transcription

1 British Journal of Anaesthesia 1997; 78: CLINICAL INVESTIGATIONS Extradural pain relief in labour: bupivacaine sparing by extradural fentanyl is dose dependent G. LYONS, M. COLUMB, L. HAWTHORNE AND M. DRESNER Summary The minimum local analgesic concentration (MLAC) of bupivacaine in labour is defined as the effective concentration in 50% of subjects (EC 50 ). We have used the technique of double-blinded sequential allocation to quantify the bupivacaine sparing effect of the addition of four different doses of extradural fentanyl in 223 labouring women. There were five groups: (1) plain bupivacaine (control); (2) bupivacaine with fentanyl 1 g ml 1 ; (3) bupivacaine with fentanyl 2 g ml 1 ; (4) bupivacaine with fentanyl 3 g ml 1 ; and (5) bupivacaine with fentanyl 4 g ml 1. The MLAC of bupivacaine were 0.069% w/v, 0.057% w/v, 0.048% w/v, 0.031% w/v and 0.015% w/v, respectively. We observed a reduction in MLAC of 18%, 31% (P 0.03%), 55% (P ) and 72% (P ) with fentanyl 1, 2, 3 and 4 g ml 1, respectively, demonstrating a significant negative linear trend (P ) with increasing fentanyl dose. The incidence of pruritus was increased significantly with fentanyl 4 g ml 1 (P ). Because of this, fentanyl 3 g ml 1 may be the optimal dose when the aim is bupivacaine sparing extradural analgesia during labour. (Br. J. Anaesth. 1997; 78: ). Key words Analgesia, obstetric. Analgesic techniques, extradural. Anaesthetics local, bupivacaine. Analgesics opioid, fentanyl. The addition of extradural fentanyl to extradural bupivacaine in labouring women has been claimed to hasten onset of analgesia, increase its duration, diminish perineal discomfort 1 and reduce the amount of bupivacaine required to achieve comfort without motor block. 2 3 It improves maternal satisfaction 4 and may reduce the need for instrumental delivery. 5 Addition of fentanyl did not improve the quality of labour analgesia when given with plain bupivacaine at concentrations in excess of 0.2% w/v, 6 but permitted weaker concentrations to become effective in clinical practice. 7 This has prompted the use of dilute solutions of extradural bupivacaine in combination with opioids to achieve satisfactory analgesia but with a reduction in unwanted local anaesthetic effects such as motor block. 5 In this respect, extradural administration of sufentanil has been shown to reduce the requirement for bupivacaine in clinical practice by 20%, 8 but the relationship between varying doses of opioid and bupivacaine has never been adequately quantified. Studies comparing efficacies of extradural analgesics have been hindered by ignorance of the relative potencies of the agents concerned, whether alone or in combination. Anaesthetic potencies of volatile agents have been described in terms of minimal anaesthetic concentration (MAC), and the same concept can be applied to extradural analgesics. An equianalgesic dose or concentration, or visual analogue pain score (VAPS) for both single agents and drug combinations would provide an extradural alternative to MAC. One such equianalgesic measure is the minimum local analgesic concentration (MLAC) of bupivacaine in labour. 9 This has provided a model which allows estimation of potency, and permits the bupivacaine sparing effect of successive doses of extradural opioid to be quantified. The aim of this study was to use this clinical model to access the ability of successive doses of extradural fentanyl to reduce the requirement for extradural bupivacaine, given to women in labour, using doses of fentanyl in the clinical range. Patients and methods Our hospital Ethics Committee approved this study. After obtaining informed consent, we studied 223 women, ASA I or II, requesting extradural pain relief in the first stage of labour. We excluded those women in whom cervical dilatation exceeded 6 cm, and those who had received opioid or sedative drugs. Use of transcutaneous electrical nerve stimulator and Entonox before extradural request were not regarded as exclusion criteria. Extradural blocks were sited in a standard manner. An i.v. infusion of 0.9% saline was started via a forearm cannula. The extradural space was found using a 17-gauge Tuohy needle, either at L2 3 or L3 4, in the sitting position. Loss of resistance to saline was used to identify the extradural space, limiting the injection to 2 ml in order to minimize dilution of local anaesthetic. For the purpose of the study, the test dose was omitted. G. LYONS, FRCA, L. HAWTHORNE, FRCA, M. DRESNER, FRCA, St James s University Hospital, Beckett St, Leeds LS9 7TF. M. COLUMB, FRCA, Withington Hospital, Nell Lane, Manchester M20 2LR. Accepted for publication: January 21, 1997.

2 494 British Journal of Anaesthesia The first administration of bupivacaine or bupivacaine fentanyl was a freshly prepared syringe containing 20 ml of test solution given over 5 min. This was bupivacaine diluted with 0.9% saline to achieve the desired concentration at room temperature, with or without fentanyl, according to the groups below, which were studied in sequence. CONCENTRATIONS AND DOSES OF FENTANYL STUDIED Forty women were included in each of five groups: (1) bupivacaine control, starting concentration was 0.1% w/v; (2) bupivacaine and fentanyl 1 g ml 1, starting concentration was 0.07% w/v; (3) bupivacaine and fentanyl 2 g ml 1, starting concentration was 0.06% w/v; (4) bupivacaine and fentanyl 3 g ml 1 starting concentration was 0.05% w/v; (5) bupivacaine and fentanyl 4 g ml 1, starting concentration was 0.04% w/v. Doses of fentanyl were constant for each group. The first woman in each group received an arbitrarily chosen concentration of bupivacaine based on estimations of MLAC from preceding studies. Thereafter, the concentration of the test solution in each individual syringe was determined by the response of the previous patient to the higher or lower concentration in her test syringe, according to up and down sequential allocation. Routine maternal cardiovascular and fetal monitoring were performed. ASSESSMENT The efficacy of the first dose was assessed using a 100-mm VAPS where 0 represented no pain and 100, worst pain ever, at 0, 15 and 30 min after injection of the test solution (first dose). Three outcomes were possible. Effective This required that VAPS decreased to 10 mm or less at the height of contraction, within min. This indicated the end of the study and directed a decrease of 0.01% w/v bupivacaine for the next woman. Ineffective This followed failure of the VAPS to reach 10 mm within 30 min of the test solution. If at 30 min the woman claimed satisfactory analgesia despite not reaching the VAPS target of 10 mm, the study period was extended to a maximum of 60 min. At 30 min, after failing to reach the VAPS target, rescue analgesia consisting of 0.25% w/v bupivacaine 12 ml was offered. After this, a reduction in VAPS to 10 mm or less indicated the end of the study and directed a 0.01% w/v bupivacaine increase for the next woman. Repeat Failure to achieve a VAPS of 10 mm, in the presence of pain outside T10 L1 distribution, or when the rescue bolus failed to achieve a VAPS of 10 mm or less, indicating either a source of pain other than the first stage of labour, or a technical failure of the extradural, directed that the same concentration be repeated for the next woman. For all women, age, weight, height, gestation, parity, cervical dilatation, use of oxytocin and pruritus were recorded. STATISTICAL ANALYSIS Patient and obstetric data were collected and are presented as mean (SD) and median (interquartile range) as appropriate. The median effective concentration was estimated from the up down sequences using the formula of Dixon and Massey which enabled MLAC with 95% confidence interval to be derived. 10 The data were also subjected to Wilcoxon and Litchfield probit regression analysis as a back-up sensitivity test. Additional analyses included: Komolgorov Smirnov test for Gaussian distribution, ANOVA, Bonferroni correction for multiple comparisons, post-test for linear trend, Kruskal Wallis test, Fisher exact test and mid-p value estimation for discrete data All analyses were carried out on two personal computers (Dell Dimension XPS P100c and Zenith Z-Star EX 486DX 50) using the following software: Microsoft Excel 5.0a for Windows, Statistical Package for the Social Sciences (SPSS) 6.1 for Windows, GraphPad Instat 2.05a for DOS and Pharmacologic Calculation System (PCS) 4.2 for DOS. Statistical significance was defined for an overall error at the 0.05 level. All P values were two-sided with multiple comparison corrections applied as appropriate. Sample size estimations were based on the results of the first MLAC studies which showed the MLAC of bupivacaine to be 0.065% (SD 0.037%). 9 A conservative error of 0.01 was applied to allow for multiple comparisons. Power was given at 0.9, with the minimum significant difference a 50% reduction in the MLAC of bupivacaine by fentanyl. It was then estimated that a minimum of 39 women would be required per group. Results There were no significant differences in patient or obstetric characteristics between the groups (table 1). There were significant dose-dependent reductions in the MLAC of bupivacaine with fentanyl 2 g ml 1 (P 0.03), 3 g ml 1 (P ) and 4 g ml 1 (P ) compared with the bupivacaine control (table 2). This was demonstrated also by a significant negative linear trend for the MLAC of bupivacaine (P ) with increasing fentanyl doses. Sequences of effective and ineffective analgesia are shown in figure 1. There were significant reductions in the repeat rates with fentanyl 2 g ml 1 (P 0.038), 3 g ml 1 (P 0.038) and 4 g ml 1 (P 0.01) compared with bupivacaine control (table 3). Pruritis was increased significantly by fentanyl

3 Extradural pain relief in labour 495 Table 1 Patient and obstetric data. Results are expressed as mean (SD or range), median [interquartile range] and count as appropriate. VAPS Visual analogue pain score. 1 g ml 1 2 g ml 1 3 g ml 1 4 g ml 1 Age (yr) 27.5 (18 40) 27.2 (17 40) 25.4 (17 38) 27.8 (19 37) 26.7 (17 39) Height (cm) 162 (6.5) 163 (6.0) 162 (4.5) 163 (6.6) 163 (7.2) Weight (kg) 76 (12.2) 79 (13.0) 73 (10.6) 72 (14.1) 74 (15.3) Gestation (weeks) 40 [40 41] 40 [39 40] 40 [39 40] 39 [38 40] 40 [39 40] Cervical dilatation (cm) 3 [3 4] 3 [3 4] 3 [3 4] 4 [3 5] 4 [3 4] Parity 0 [0 1] 0 [0 1] 0 [0 1] 0 [0 1] 0 [0 1] Nulliparous/multiparous 27/13 28/12 28/12 27/13 26/14 Initial VAPS (mm) 75 [61 90] 80 [66 91] 65 [60 81] 66 [51 77] 68 [50 88] Table 2 MLAC of bupivacaine and fentanyl concentrations, compared with MLAC of control. MLAC Minimum local analgesic concentration using the method of Dixon and Massey. 10 P P value (95% confidence interval) using modified t tests vs MLAC of control. *P P value (95% confidence interval) with Bonferroni correction MLAC P P* ( ) 1 g ml ( ) 0.14 ( ) 0.52 ( ) 2 g ml ( ) ( ) 0.03 ( ) 3 g ml ( ) ( ) (0.018 to 0.058) 4 g ml ( ) ( ) ( ) Table 3 Distribution of repeats. **P 0.01 compared with bupivacaine control %w/v 1 g/ml 1 2 g/ml 1 3 g/ml 1 4 g/ml Table 4 Incidence of pruritus compared with bupivacaine control. *Bonferroni corrected P g ml 1 (P ) compared with the bupivacaine control (table 4). Discussion Pruritus 0 1 g ml g ml g ml g ml * We have shown that the addition of extradural fentanyl to extradural bupivacaine in labour produced a dose-dependent reduction in the requirements for bupivacaine. Significant reductions were obtained with fentanyl 2, 3 and 4 g ml 1 (40 g, 60 g and 80 g). The latter dose, however, caused a marked incidence of pruritus (23%). Although fentanyl 4 g ml 1 proved to be the most effective in terms of bupivacaine sparing, the cost in side effects may well make a dose of 3 g ml 1 the choice for P clinical practice. Doses in excess of 4 g ml 1 were not studied because of the increasing incidence of pruritus. Eight patients in the 4- g ml 1 group received test solutions that did not contain local anaesthetic. Further reductions in MLAC could be achieved only by an increase in opioid only recipients, up to a maximum number of study patients. Clearly, at a dose somewhere in excess of 4 g ml 1, clinically important reductions in bupivacaine concentration would become hard to achieve. Comfort in labour has been achieved with fentanyl alone. 2 TEST DOSE In common with others, we did not use a test dose. 7 Because of its sensitivity and specificity in the d etection of i.v. injection, 13 we used 2% w/v lignocaine 1 mg kg 1 as an extradural test dose. Our earlier study 9 suggested that this dose can have a therapeutic effect. The MLAC of lignocaine was 0.37% w/v, which corresponds to a median effective dose of 74 mg. It is clear that a test dose of this magnitude might interact with the efficacy of subsequently administered extradural analgesics. We have found in our own clinical practice that

4 496 British Journal of Anaesthesia Figure 1 EC 50 of bupivacaine, fentanyl 1, 2, 3 and 4 g ml 1, as determined by the technique of up down sequential allocation. Error bars represent 95% confidence interval. Testing interval was 0.01% w/v. 2% w/v extradural lignocaine 1 mg kg 1 achieves satisfactory comfort in approximately 40% of women, and its inclusion would have interfered with interpretation. TARGET VAPS Determining the EC 50 for an analgesic implies that analgesia fails in 50% of the sample. Brownridge has shown that in labour, a VAPS of 30 mm or less corresponds to comfort. 14 Sensitive to the request for pain relief, we chose as our target a VAPS of 10 mm. While making the required degree of analgesia more exacting, it ensured that approximately 30% of the ineffective solutions produced VAPS below Brownridge s comfort line. RESCUE After an ineffective solution it was important that pain was abolished rapidly. There was also a concern that failure to meet the target VAPS might be caused by a technical problem of the extradural or by pain from a source outside the normal distribution of first stage pain, and not a genuine therapeutic failure. To achieve comfort rapidly, and simultaneously demonstrate that the extradural was capable of analgesia with bupivacaine alone, the rescue was devised in a volume, and at a concentration that we considered would meet these aims unequivocally. Milligan and colleagues showed that 0.25% w/v bupivacaine 12 ml produced analgesia to at least the T10 dermatome in 80 women. 15 REPEATS When the test solution produced analgesia in a first stage distribution, but the VAPS exceeded 10 mm because of persistent, generally perineal, discomfort, we chose to repeat that concentration. While there was a subjective element to this assessment, it was necessary to ensure that only the concentration of local anaesthetic, decided therapeutic efficacy. The degree of subjectivity in making this assessment influenced directly the number of repeats. Any bias this introduced operated equally for all groups as the investigators were blinded to the concentrations used throughout the studies. The addition of fentanyl 2 g ml 1 or greater reduced significantly the number of instances when therapeutic failure was in doubt. Failure of rescue indicated the need to resite the extradural, and necessitated a repeat of the test solution in the subsequent woman.

5 Extradural pain relief in labour 497 STATISTICAL ANALYSIS The formula of Dixon and Massey was used to derive MLAC and 95% confidence interval from the results of sequential allocation. 9 Regression techniques have been used by other workers to analyse similar up down data, so we applied probit regression as a back-up sensitivity test. 16 We believe that the former test is more appropriate even though the latter is generally less conservative with the data. Regression analysis is usually applied to randomly rather than sequentially allocated data. This is in keeping with theoretical arguments that the observations in up down allocation are not completely independent and that the possibility of heteroscadesis is not necessarily examined. In stating this, however, we do not wish to be critical of other workers as the two analyses return reasonable approximations to each other. The power of these studies (1.0, range for the observed results) suggests overestimation of the required sample size to find significance for a 50% reduction in the MLAC of bupivacaine by fentanyl. This was probably caused by an initial overestimation of the SD. We believe that comparisons of arbitrarily chosen analgesic recipes are an inappropriate method of dose finding in labour and that there is a need to create a benchmark for extradural analgesics. A suggestion that this can be done with equimolar solutions 17 has some value, but clinical practice requires a benchmark for analgesia. Estimation of equianalgesia (MLAC) allows the contribution of components of a drug cocktail to be quantified, and doses adjusted for best effect. When comparative studies are performed with equianalgesic combinations, best solutions are identified, not in terms of analgesia, but in terms of undesirable effects In summary, we have shown that extradural fentanyl reduced the requirement for extradural bupivacaine d uring the first stage of labour in a dose-dependent manner. We have also shown that by combining it with bupivacaine, the number of blocks deemed to be deficient in spread (repeats) was reduced significantly. By inference, increasing doses of extradural fentanyl should permit greater motor sparing, but this requires further study. 4 g ml 1, while producing the greatest depression of MLAC (78%), produced a significant amount of pruritus, and for this reason fentanyl 3 g ml 1 may represent the optimum dose. References 1. Reynolds F, O Sullivan G. Epidural fentanyl and perineal pain in labour. Anaesthesia 1989; 44: Breen TW, Shapiro T, Glass B, Foster-Payne D, Oriol NE. Epidural anesthesia for labor in an ambulatory parturient. Anesthesia and Analgesia 1993; 77: Dick W. Obstetric anesthesia and analgesia. Current Opinions in Anesthesiology 1996; 9: Murphy JD, Henderson K; Bowden MI, Lewis M, Cooper GM. versus bupivacaine plus fentanyl for epidural analgesia: effect on maternal satisfaction. British Journal of Anaesthesia 1991 ; 302: Russell R, Quinlan J, Reynolds F. Motor block during epidural infusions for nulliparous women in labour. International Journal of Obstetric Anaesthesia 1995; 4: Cohen SE, Tan S, Albright GA, Halpern J. Epidural fentanyl/bupivacaine mixtures for obstetric analgesia. Anesthesiology 1987; 67: Yau G, Gregory MA, Gin T, Bogod DG, Oli TE. The addition of fentanyl to epidural bupivacaine in first stage of labour. Anaesthesia and Intensive Care 1990; 18: Vertommen JD, Vandermeulen E, Van Aken H, Vaes L, Soetens M, Van Steenberge A. The effects of the addition of sufentanil to 0.125% bupivacaine on the quality of analgesia during labour and the incidence of instrumental deliveries. Anesthesiology 1991; 74: Columb MO, Lyons G. Determintion of the minimum local analgesic concentrations of epidural bupivacaine and lidocaine in labour. Anesthesia and Analgesia 1995; 81: Dixon WJ, Massey FJ. Introduction to Statiatical Analysis, 4th Edn. New York: McGraw-Hill, 1983; Armitage P, Berry G. Statistical Methods in Medical Research, 3rd Edn. Oxford: Blackwell Scientific Publications, 1994; Altman DG. Practical Statistics for Medical Research. London: Chapman and Hall, 1991; Michels AMJ, Lyons G, Hopkins PM. Lignocaine test dose to detect intravenous injection. Anaesthesia 1995; 50: Brownridge P. Epidural analgesia in the first stage of labour. Current Anaesthesia and Critical Care 1991; 2: Milligan KR, Cramp P, Schatz L, Johnston D, Carp H. The effect of position and obesity on the spread of epidural analgesia. International Journal of Obstetric Anaesthesia 1993; 2: Inomata S, Watanabe S, Masakazu T, Okada M. End tidal sevoflurane concentration for tracheal intubation and minimum alveolar concentration in pediatric patients. Anesthesiology 1994; 80: Leon-Casasola OA, Lema MJ. Postoperative epidural opioid analgesia: What are the choices? Anesthesia and Analgesia 1996; 83: