The Effect of Clonidine on the Minimum Local Analgesic Concentration of Epidural Ropivacaine During Labor Chritophe Aveline, MD, Sonia El Metaoua, MD, Anis Masmoudi, Pierre-Yves Boelle, PhD, and Francis Bonnet, MD
MD,
De´partement d’Anesthe´sie-Re´animation Chirurgicale, Hoˆpital TENON, Assistance Publique Hoˆpitaux de Paris, Paris, France
On the basis of the determination of minimum local analgesic concentration (MLAC), ropivacaine has been demonstrated to be less potent than bupivacaine during the first stage of labor. In this study we assessed the effect of clonidine on the MLAC of ropivacaine. Seventy-seven parturients of mixed parity requesting epidural analgesia for labor (cervical dilation, 3–7 cm) were included in the study. They received an epidural bolus of either ropivacaine (n ⫽ 30), ropivacaine plus clonidine 30 g (n ⫽ 28), or ropivacaine plus clonidine 60 g (n ⫽ 19) in the second part of the study. The concentration of the ropivacaine solution was determined by the response of the previous parturient in that group by using an up-down sequential
R
opivacaine has been introduced into clinical practice as a local anesthetic that is less toxic than bupivacaine (1). Epidural ropivacaine also produces less motor blockade than bupivacaine, potentially making it advantageous for labor. Several studies, however, have questioned whether potency differences between ropivacaine and bupivacaine at commonly used concentrations are clinically relevant (2,3). Capogna et al. (2) and Polley et al. (3) determined that ropivacaine was 40% less potent than bupivacaine during labor, by using the model of the minimum local analgesic concentration (MLAC). Consequently, at small concentrations, a larger dose of ropivacaine than bupivacaine may be necessary to achieve the same quality of epidural analgesia. To increase the analgesic effect of ropivacaine, it is therefore necessary either to increase its concentration (and dose) or, alternately, to use adjuvant epidural drugs. In clinical studies, clonidine, an ␣2-adrenergic agonist, improved epidural blockade (4) and enhanced analgesia (5–12).
Accepted for publication May 20, 2002. Address correspondence and reprint requests to Francis Bonnet, De´partement d’Anesthe´sie-Re´animation Chirurgicale, Hoˆpital TENON, Assistance Publique Hoˆpitaux de Paris, 4 Rue de la Chine, 75020 Paris, France. Address e-mail to
[email protected]. DOI: 10.1213/01.ANE.0000025618.43589.DA ©2002 by the International Anesthesia Research Society 0003-2999/02
allocation. A visual analog pain score of ⱕ10 mm within 30 min after the epidural bolus (20 mL) was considered an effective response. An effective result directed a 0.01% wt/vol decrement for the next patient. An ineffective result directed a 0.01% wt/vol increment. The MLAC of ropivacaine was 0.097% wt/vol (95% confidence interval, 0.085%– 0.108%). It was unaffected by a 30-g dose of epidural clonidine (0.081% [0.045%– 0.117%]) but was significantly decreased by a 60-g clonidine dose (0.035% [0.024%– 0.046%]) (P ⬍ 0.001). This study documents a decrease in the MLAC of ropivacaine by clonidine, significant for a 60-g dose. (Anesth Analg 2002;95:735–40)
Adding clonidine to ropivacaine might therefore compensate for the less dense epidural block of ropivacaine as compared with bupivacaine. However, clonidine crosses the placenta and at doses larger than 1 g/kg may cause fetal bradycardia (10,13). We thus designed a study to determine whether small doses of clonidine, compatible with obstetrical practice, would increase the potency of ropivacaine during the first stage of labor.
Methods After approval from the local Ethics Committee and obtaining informed patient consent, we enrolled ASA I and II parturients requesting labor epidural analgesia into this randomized, double-blinded sequentialallocation study. Participants were of mixed parity, at full-term gestation, with vertex presentation and had a cervical dilation of 3–7 cm. Parturients with complicated pregnancy or multiple gestation and those receiving opioids were excluded from the study. After an IV infusion of 500 mL of lactated Ringer’s solution, epidural puncture was performed in the sitting position at the L3-4 or L4-5 interspace by using a loss of resistance to saline technique. A multiport epidural catheter (20-gauge; Braun, Melsungen, Germany) was Anesth Analg 2002;95:735–40
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advanced 4 cm into the epidural space and then aspirated. No test dose was performed. The study was performed in two phases. In the first phase, 61 women were allocated randomly to receive 20 mL of either ropivacaine (Naropeine®; Astra, Rueil Malmaison, France) or ropivacaine with clonidine 30 g (Catapressan®; Boehringer Ingelheim, Paris, France). In the second phase we studied an additional group of 20 women who received 20 mL of ropivacaine with clonidine 60 g. In each group the concentration of the solution was determined by the response of the previous parturient to the larger or smaller concentration on the basis up up-down sequential allocation. The starting concentration in each group was 0.120%. This concentration was close to the previously determined MLAC of ropivacaine (2,3). The solution was prepared at room temperature and injected within 2 min. The testing interval was 0.01% wt/vol. Maternal heart rate, noninvasive arterial blood pressure, pulse oximetry, uterine contractions, and fetal heart rate (FHR) were monitored. The efficacy of epidural injection was assessed with a 100-mm visual analog pain score (VAPS), graded from 0 (“no pain”) to 100 (“the worst pain imaginable”) before injection and every 5 min during the first 30 min, and then every 10 min until the next epidural injection. The modification of the successive injections was adapted according to three possible responses. 1. Effective: VAPS ⱕ10 mm within 30 min after epidural injection directed a decrease of 0.01% wt/vol of the allocated solution for the next woman. 2. Ineffective: VAPS ⬎10 mm within the first 30 min but decreased to ⱕ10 mm in the next 30 min after a rescue bolus of 0.2% wt/vol ropivacaine 15 mL. The next woman received the allocated solution with an increment of 0.01% wt/vol. 3. Reject: VAPS ⬎10 mm after the bolus rescue. This response was considered indicative of a misplacement of the epidural catheter. The same concentration was used for the next woman. After the first bolus injection, patients with effective analgesia were given a bolus of 0.2% wt/vol ropivacaine 10 mL with sufentanil 10 g on demand. In the patients who documented an effective response, duration of analgesia was defined by the time interval between the first injection and a value of VAPS ⬎10 mm. In addition to VAPS, maternal arterial blood pressure, maternal heart rate, pulse oximetry, and sensory level, as determined by the loss of sensation to cold, were recorded before epidural injection (baseline) and at 5-min intervals during the first 30 min. Motor blockade was assessed with the modified Bromage scale (0 ⫽ no motor block; 1 ⫽ inability to raise the extended leg and ability to move the knee and feet; 2 ⫽ inability to raise the extended leg and flex
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the knee; 3 ⫽ complete motor blockade). Sedation was scored on a four-point scale (0 ⫽ alert; 1 ⫽ slightly drowsy; 2 ⫽ rousing spontaneously; 3 ⫽ rousing only when addressed). Shivering was noted only if clinically present. Hypotension was defined as a systolic arterial blood pressure ⬍100 mm Hg. Hypotension was treated with ephedrine 6 –12 mg as needed. Maternal bradycardia was defined by a heart rate of ⬍50 bpm and was treated with atropine 0.5 mg. FHR was monitored continuously with external tococardiography, and any abnormality was interpreted by an obstetrician who was blinded to study group allocation. All parturients had at least 30 min of FHR monitoring before inclusion. The mode of delivery was noted, and neonatal Apgar scores were recorded at 1 and 5 min. All neonates were examined 24 h after delivery by a pediatrician who was unaware of parturients’ group allocation. Demographic, obstetric, and hemodynamic data and neonatal scores are reported as mean (sd), median (range), or percentage when appropriate. Median effective concentrations and confidence intervals (CIs) were calculated as described by Dixon and Massey (14), and were also estimated by probit analysis as a sensitivity test. Sample size determination was based on the sd (0.023% wt/vol) of a previous MLAC ropivacaine study (3) and the expectation of a 25% difference in potency between the two solutions. After a first statistical analysis, we decided to study an additional group of parturients who received a 20-mL epidural bolus of ropivacaine with clonidine 60 g (RC60 group), starting with the concentration of 0.120% wt/vol. On the basis of the expectation of a 50% difference in potency with the R group, we included 20 parturients in this group. This group was submitted to the study protocol applied in the two other groups (R and RC30 groups) to determine the MLAC of ropivacaine. Statistical significance was defined at a 0.05 level, and all P values were two sided. The comparison of clonidine sequences used Welch t-tests for unequal variance. The Bonferroni multiple comparison correction was applied as appropriate. The existence of a monotone dose-response relationship between MLAC and clonidine was investigated by the JonckheereTerpstra test. Comparison of demographic and obstetrical data between the groups used analysis of variance, the Kruskal-Wallis test, and Fisher’s exact test. Analyses were performed with SAS software Version 6.12 (SAS Institute, Cary, NC) and Microsoft Excel 2000 (Microsoft, Redmond, WA).
Results Eighty-one parturients were enrolled in the complete study, and four were then rejected for inadequate epidural catheter placement (two in Group R, one in
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Table 1. Demographic and Obstetrical Data
Variable
Ropivacaine (n ⫽ 30)
Ropivacaine ⫹ clonidine 30 g (n ⫽ 28)
Ropivacaine ⫹ clonidine 60 g (n ⫽ 19)
Age (yr) Height (cm) Weight (kg) Gestation (days) Cervical dilation (cm) Nulliparous (%) Oxytocin (%) Induced labor (%)
30 (5) 163 (6) 70 (8) 278 (9) 3.6 (0.8) 60 100 30
27 (5) 162 (6) 71 (11) 278 (7) 3.8 (0.9) 68 93 29
31 (5) 162 (6) 71 (11) 271 (16) 4.1 (1.1) 42 95 42
Results are expressed as mean (sd) and percentage when appropriate.
Group RC30, and one in Group RC60), leaving 77 for analysis. There was no difference among the three groups for demographic and obstetrical data (Table 1). Oxytocin was often used in the study, in accordance with the routine obstetrical management in our institution (Table 1). A higher initial VAPS was documented in Group RC30 (Table 2). After the epidural bolus, the lowest value of VAPS was comparable in the three groups, as was the duration of effective analgesia, measured only in women with VAPS ⬍10 mm (Table 2). Figures 1, 2, and 3 show the sequence of effective and ineffective analgesia in the parturients of the three groups. The MLAC of ropivacaine was 0.097% wt/vol (95% CI, 0.085%– 0.108%) with the formula of Dixon and Massey, which was consistent with the probit regression analysis (0.094% wt/vol; 95% CI, 0.084%– 0.103%). In Group RC30, the MLAC of ropivacaine was 0.081% (95% CI, 0.045%– 0.117%) with the formula of Dixon and Massey. The probit regression analysis yielded a smaller estimate for the MLAC and a larger se (0.056% wt/vol; 95% CI, 0.003%– 0.109%). The MLAC of ropivacaine with 30 g of clonidine was not different from the control value (P ⫽ 0.4). The relative requirement for ropivacaine was 0.84 (95% CI, 0.52– 1.31) with clonidine 30 g and was not significantly different from 1.0. The MLAC of ropivacaine calculated by the formula of Dixon and Massey was 0.035% wt/vol (95% CI, 0.024%– 0.046%) in the RC60 group and was consistent with the probit analysis (0.034% wt/vol; 95% CI, 0.029%– 0.039%). In this group, the value of the MLAC was significantly smaller than that in Group R (P ⬍ 0.02). The relative requirement of ropivacaine was reduced significantly to 0.36 (95% CI, 0.08 – 0.84) by clonidine 60 g. Clonidine 30 and 60 g thus resulted in 16% and 64% reductions in ropivacaine MLAC, respectively. Altogether, there was a decreasing trend for the MLAC of ropivacaine when the clonidine dose increased (P ⬍ 0.007). In parturients who were successfully controlled by the initial ropivacaine concentration, no difference was noted in the duration of effective analgesia (84 ⫾ 14 min, 81 ⫾ 25 min, and 87 ⫾ 32 min in Groups R,
RC30, and RC60, respectively) (Table 2). The incidence of cesarean delivery was comparable in the three groups: two cases in Group R (one case related to fetal bradycardia and one to failed progress of labor), four in Group RC30 (two cases of FHR abnormalities and nuchal cord and two cases of labor stagnation at complete cervical dilation), and three in Group RC60 (two cases of labor stagnation and one case of fetal bradycardia). The incidence of instrumental delivery was also similar (five cases in Group R, seven in Group RC30, and three in Group RC60). All instrumental deliveries were indicated for ineffective maternal expulsive efforts. Motor blockade was comparable in the three groups, and no woman had a Bromage score of ⬎1. The upper-most dermatome of analgesia was not different in the three groups along the study period (Table 3). Maternal side effects were different, with decreased systolic arterial blood pressure in Group RC60 (Table 3) and more frequent hypotension in Group RC 60 (five cases [26%] versus four [13%] and three [11%] cases in Groups R and RC30, respectively), and the lowest median value of systolic arterial blood pressure was lower in Group RC60 (Table 3). All hypotensive episodes occurred at least 15 min after the epidural injection. There was no case of maternal bradycardia. The lowest median values of maternal arterial oxygen saturation were also comparable (Table 3). The sedation score was higher in the parturients receiving clonidine 60 g compared with the two other groups (Table 3). No parturient complained of shivering during the first 30 min after epidural injection. Mean Apgar scores were comparable in the three groups at 1 and 5 min (Table 3). Two hours after delivery and on the next day, there were no neonatal neurological abnormalities.
Discussion The MLAC model was used by Columb and Lyons (15) and Columb et al. (16) to determine the effective local anesthetic concentrations in 50% of patients, thus
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Table 2. Analgesic Effects of the Epidural Block
Variable
Ropivacaine (n ⫽ 30)
Ropivacaine ⫹ clonidine 30 g (n ⫽ 28)
Ropivacaine ⫹ clonidine 60 g (n ⫽ 19)
Initial VAPS (mm) Lowest VAPS (mm) Pain relief duration (min)†
70 [23–100] 51 [10–100] 84 (14)
81 [44–100]* 65 [20–100] 81 (25)
70 [30–90] 40 [0–80] 87 (32)
Results are expressed as means (sd) and medians [range] when appropriate. VAPS ⫽ visual analog pain score. * Intergroup comparison; P ⬍ 0.05. † Only for the women who responded to the initial ropivacaine dose.
Figure 1. Minimum local analgesic concentration of ropivacaine determined by up-down sequential allocation. Error bars represent 95% confidence intervals. The testing interval was 0.01% wt/vol. (䡵) Women who had effective analgesia after the epidural bolus; (䡺) parturients who did not experience adequate pain relief despite correct positioning of the epidural catheter.
Figure 2. Minimum local analgesic concentration of ropivacaine with clonidine 30 g, determined by up-down sequential allocation. Error bars represent 95% confidence intervals. The testing interval was 0.01% wt/vol. (䡵) Women who had effective analgesia after the epidural bolus; (䡺) parturients who did not experience adequate pain relief despite correct positioning of the epidural catheter.
allowing comparison of local anesthetic concentrations when they are used in the lower part of their dose-response curve for epidural analgesia in labor. The MLAC varies with the stage of labor (17). It is higher during the second stage than during the first stage, and it is preferable that measurements be performed during the first stage of labor (2,3,15,16). The
Figure 3. Minimum local analgesic concentration of ropivacaine with clonidine 60 g, determined by up-down sequential allocation. Error bars represent 95% confidence intervals. The testing interval was 0.01% wt/vol. (䡵) Women who had effective analgesia after the epidural bolus; (䡺) parturients who did not experience adequate pain relief despite correct positioning of the epidural catheter.
MLAC has been determined for lidocaine, chloroprocaine, bupivacaine, and, more recently, ropivacaine (2,3,15,16). The value of ropivacaine MLAC documented in this study during the first stage of labor (0.097 [0.085– 0.108]) is comparable to that documented by Polley et al. (3) (0.111 [0.100 – 0.122]) and smaller than that reported by Capogna et al. (2), who only studied nulliparous women (0.156 [0.136 – 0.176]). Indeed, differences in parity, cervical dilation, or the percentage of induced labor and statistical variability may explain these variations (17,18). Although we included parturients with mixed parity in this study, the distribution of nulliparous and multiparous women was comparable in the three groups, thus allowing valuable comparison. It is also worth noting that the epidural ropivacaine dose corresponding to the MLAC in this study (19.4 [17.4 –21.4] mg) is close to the 50% effective dose determined by Beng Lee et al. (19), who performed a traditional dose-response study in Chinese parturients. In this study, the addition of 30 g of clonidine did not significantly reduce the MLAC of epidural ropivacaine, whereas a 60-g dose resulted in a ⬎50% decrease in the local anesthetic requirement. The first dose of clonidine (30 g) was chosen on the basis of previous studies to determine the minimal
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Table 3. Features of Local Anesthetic Block, and Maternal and Neonatal Side Effects
Variable Maximum number of segments blocked above L1 at 30 min Highest Bromage score Lowest SAP (mm Hg) Lowest HR (bpm) Lowest O2 saturation (%) Highest sedation score Apgar (1 min) Apgar (5 min)
Ropivacaine (n ⫽ 30)
Ropivacaine ⫹ clonidine 30 g (n ⫽ 28)
Ropivacaine ⫹ clonidine 60 g (n ⫽ 19)
10 (7–14) 0 (0–1) 112 (67–137) 70 (54–83) 98.1 (97–99) 0 (0–1) 10 (5–10) 10 (9–10)
11 (8–14) 0 (0–0) 114 (89–133) 74 (55–90) 98 (94–99) 0 (0–1) 10 (5–10) 10 (8–10)
12 (9–17) 0 (0–0) 104 (75–135)* 70 (55–89) 98 (96–99) 2 (1–3)* 10 (3–10) 10 (9–10)
Results are expressed as median (range). HR ⫽ heart rate; SAP ⫽ systolic arterial blood pressure. * Intergroup comparison; P ⬍ 0.05.
dose capable of decreasing the requirement of an epidural local anesthetic without inducing maternal or fetal side effects. Indeed, others have documented that larger doses of clonidine (75–150 g) not only prolonged the duration of analgesia in women in labor, but also induced side effects such as sedation, maternal bradycardia, and hypotension (6,7,10). Even a smaller, although effective, clonidine dose (50 g) may induce hypotension, sedation, or both when it is combined with another epidural adjuvant (epinephrine or sufentanil) (11). However, a 30-g epidural dose of clonidine, used as an adjunct to epidural bupivacaine in combination with epidural epinephrine and sufentanil and repeated during labor, did not prolong analgesia but decreased bupivacaine bolus requirements and improved pain control during episiotomy without side effect (5). Moreover, Paech et al. (12) reported that the addition of clonidine 22– 45 g/h, in combination with bupivacaine 0.0625% and fentanyl 2 g/mL, reduced the need for patientcontrolled epidural boluses and produced better overall pain relief during the first stage of labor (12). In this study, the initial VAPS were higher in the group of parturients receiving 30 g of clonidine and may have prevented the achievement of statistical significance. Because clonidine 30 g reduced the requirement for epidural ropivacaine by only 16%, we decided to perform a second phase of the study with a 60-g clonidine dose in a comparable series of parturients. Obviously, this part of the study was not randomized, but demographic and obstetrical data of this group were comparable to those of the two other groups, allowing comparison between groups. In addition, duration of analgesia in parturients with an effective response was also comparable in the three groups, suggesting that the same criteria were actually applied to determine the response to epidural injections. The 60-g dose of epidural clonidine decreased the MLAC of ropivacaine by 64%. Furthermore, the decreasing trend in the MLAC of epidural ropivacaine
was statistically significant when the clonidine dose was increased. Clonidine is an adjuvant to local anesthetics that can be used as an alternative to opioids. Previous studies have documented that the effect of opioids on the MLAC of local anesthetics could be similar or greater than that of clonidine. Polley et al. (20) have demonstrated that a 60-g dose of epidural fentanyl decreased the MLAC of chloroprocaine by 40%, and Lyons et al. (21) found out that the same dose of fentanyl decreased the MLAC of bupivacaine by 55%. A 78% decrease in bupivacaine MLAC was documented with an 80-g epidural fentanyl dose in the same study (21). In another study, epidural sufentanil 10 g reduced the MLAC of bupivacaine by 54%, whereas 20- and 30-g doses resulted, respectively, in an 80% and 92% decrease in bupivacaine MLAC (22). We found that the 60-g dose of epidural clonidine induced maternal side effects such as sedation and maternal hypotension. Maternal hypotension has no fetal consequences if treated promptly, and no study, including this one, reported worrisome fetal status after an episode of hypotension in parturients who received clonidine epidurally. In this study, fetal bradycardia was not more frequent in parturients receiving 30 and 60 g of clonidine, but it has been reported to occur with a 150-g dose of clonidine and was thought to be related to placental transfer of clonidine into the fetal circulation (7,10). Sedation is another well-documented side effect of clonidine, without deleterious consequence in mothers and neonates, but it may impair mothers’ participation in labor and delivery. Of note, clonidine did not significantly intensify the motor block, an undesirable consequence of epidural analgesia during labor. Nevertheless, because of the side effects seen in this study, the administration of larger doses per bolus, although probably more effective, may not be clinically appropriate. In conclusion, this study documents a decrease in the MLAC of ropivacaine by epidural clonidine at a
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dose of 60 g, confirming that clonidine increases the local anesthetic block.
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