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Anesth Analg 2002;95:728-734
© 2002 International Anesthesia Research Society

OBSTETRIC ANESTHESIA

The Dose-Sparing Effect of Clonidine Added to Ropivacaine for Labor Epidural Analgesia

Ruth Landau, MD*, Eduardo Schiffer, MD*, Michel Morales, MD{dagger}, Georges Savoldelli, MD*, and Christian Kern, MD*

*Division d’Anesthésiologie, Département d’Anesthésiologie, Pharmacologie et Soins Intensifs de Chirurgie (APSIC), and {dagger}Clinique d’Obstétrique, Département de Gynécologie et Obstétrique, Hôpitaux Universitaires de Genève (HUG), Genève, Suisse

Address correspondence and reprint requests to Ruth Landau, MD, Division d’Anesthésiologie, APSIC, Hôpitaux Universitaires de Genève (HUG), Rue Micheli-du-Crest 12, 1211 Genève 14, Switzerland. Address e-mail to ruth.landau{at}hcuge.ch


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
To determine the effects of clonidine with ropivacaine during epidural labor analgesia, we studied 66 nulliparous women in early active labor. Women were randomized to receive ropivacaine 0.1% 8 mL plus 75 µg of clonidine (Group 1), ropivacaine 0.2% 8 mL plus 0.5 mL of NaCl 0.9% (Group 2), or ropivacaine 0.2% 8 mL plus 75 µg of clonidine (Group 3) 5 min after a bupivacaine 7.5 mg with epinephrine 15 µg test dose. Upon request, additional analgesia with ropivacaine 0.1% 8 mL followed by ropivacaine 0.2% 8 mL/h was administered. With clonidine, duration of analgesia was increased (132 ± 48 min [Group 1] and 154 ± 42 min [Group 3] versus 91 ± 44 min [Group 2]; P < 0.05), and total ropivacaine dose over the first 4 h was significantly reduced (40.5 ± 15 mg [Group 1] and 47.0 ± 16 mg [Group 3] versus 72.5 ± 18 mg [Group 2]; P < 0.01). The incidence of more profound motor block was more frequent in Group 2 (P < 0.05). Although there was a trend for more women receiving clonidine to require ephedrine for treatment of hypotension, this did not seem to have an impact on fetal outcome or incidence of cesarean deliveries for nonreassuring fetal heart rate tracings. This study demonstrates the dose-sparing effect of clonidine when added to ropivacaine.

IMPLICATIONS: The effect of adding 75 µg of clonidine to ropivacaine for epidural labor analgesia was studied. Clonidine increased analgesia duration and produced dose sparing compared with ropivacaine alone. Despite a tendency for hypotension in women receiving clonidine, there was no apparent effect on delivery mode or neonatal outcome.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Ropivacaine produces less motor block than bupivacaine with similar analgesia (1,2), which makes it an interesting drug for obstetrical analgesia delivered by the epidural route. Clonidine is a {alpha}2-adrenergic agonist that produces analgesia via a non-opioid mechanism, and the combination of epidural clonidine with bupivacaine for labor analgesia has been previously studied (3–11). However, the fact that clonidine has not been approved by the Food and Drug Administration for use in obstetric anesthesia and its relatively high cost in certain countries have limited its use (12). Despite the continuing concern about its hemodynamic effects (maternal hypotension and bradycardia) and potential consequences on uteroplacental flow, in addition to maternal sedative effects, clonidine has not been clearly associated with altered Apgar scores or poor neonatal outcomes. In fact, only few cases of abnormal fetal heart rate tracings were reported with the use of epidural clonidine for labor analgesia; these have been shown to occur either when clonidine was given as a bolus of 150 µg (4) or with repeated boluses of 75 µg (5).

We postulated that adding clonidine to ropivacaine for epidural analgesia during labor should allow good analgesia with minimal motor block. The purpose of this prospective, randomized, double-blinded study was to examine whether 75 µg of clonidine increases the analgesic properties (intensity and duration) of an initial ropivacaine dose and produces dose sparing of ropivacaine. We also collected data on any adverse neonatal outcome occurring after the epidural administration of clonidine.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval from the Institutional Ethics Committee and obtaining informed written consent, we studied 66 healthy (ASA physical status I or II) nulliparous women in active labor. Women requesting epidural analgesia were considered for inclusion in the study if they presented with a singleton pregnancy of more than 37 wk gestation in early labor (cervix dilation <5 cm) with a normal fetal heart rate tracing. Exclusion criteria included pregnancy-induced hypertension, multiple pregnancies, breech presentation, multiparity, and gestational diabetes.

Women were randomly assigned in a double-blinded fashion to one of three groups. Group 1 received 8 mL of ropivacaine 0.1% with clonidine 75 µg (0.5 mL), Group 2 received 8 mL of ropivacaine 0.2% with NaCl 0.9% (0.5 mL), and Group 3 received 8 mL of ropivacaine 0.2% with clonidine 75 µg (0.5 mL). Randomization was performed by random computer allocation with numbered envelopes. The study syringe was prepared at the time of randomization by a nurse anesthetist who was not present on the labor floor and not involved with the study case. Pharmacological preparations for epidural infusion of ropivacaine (Naropin®, Astra-Zeneca, Switzerland) with the addition of clonidine (Catapressan®, Boehringer, Germany) were tested for safety in terms of solubility and chemical stability (HUG, Central Pharmacy, Geneva, Switzerland). Since the time of this study design, compatibility of ropivacaine with clonidine has further been demonstrated (13). Placement of the epidural catheter, management of labor analgesia, and all data recordings were performed by members of the anesthesia team blinded to group allocation throughout the entire case.

Before epidural analgesia, IV fluid loading was initiated with 500 mL of Ringer’s lactate solution. Women were placed in the left lateral decubitus position, and local anesthesia of skin and subcutaneous tissues was performed at lumbar level L2-3 or L3-4 with lidocaine 1% 1–2 mL. Thereafter, the epidural space was localized with the loss of resistance to saline technique using an 18-gauge Tuohy needle. A 20-gauge multi-orifice epidural catheter was then inserted 5 cm into the epidural space in a cephalad direction and aspirated for detection of cerebrospinal fluid or blood. After the catheter was taped, subjects were repositioned with left uterine displacement, and 3 mL of 0.25% bupivacaine with 15 µg of epinephrine as a test dose was administered, as was standard practice at our institution at the time of this study. In the absence of intravascular or intrathecal placement of the catheter, the study drug was administered 5 min after the test dose. Timing of the injection of study drug was defined as T = 0, and assessments were scheduled accordingly. Pain was assessed with a 10-cm linear visual analog scale (VAS) immediately before epidural placement and at 5, 10, 15, 20, 30, 60, 120, 180, and 240 min after injection of the study drug. Onset of analgesia was taken as time to achieve VAS <=3. Duration of analgesia was considered as time elapsed between T = 0 and breakthrough pain, which was defined as VAS >3, and/or request for additional analgesia and treated in a similar fashion in all three groups. Management of breakthrough pain consisted of a bolus of 8 mL of ropivacaine 0.1% followed by a continuous infusion of ropivacaine 0.2% 8 mL/h and additional doses of 6–8 mL of ropivacaine 0.1% when required. A maximum of three top-ups over the first 4 h of the study was allowed before alteration of the epidural analgesic regimen and removal of the case from the study. On the first postpartum day, global maternal satisfaction was assessed with a 10-cm VAS by a blinded observer, 10 being maximal satisfaction.

Sensory levels were determined with changes to cold (ether) at 5, 10, 15, 20, 30, 60, 120, 180, and 240 min after study drug injection. Motor block using a modified Bromage scale (0 = no block, 1 = inability to raise extended leg, 2 = inability to flex knee, and 3 = inability to flex ankle and foot) were also recorded at the same intervals. With a Bromage score >=2, the infusion rate of ropivacaine was reduced until the Bromage score was found to be <=1. Sedation was recorded with a four-point score (0 = no sedation, 1 = slight sedation or patient responding to verbal stimulation, 2 = moderate sedation or patient responding to tactile stimulation, and 3 = deep sedation or patient not responding to tactile stimulation) as used by others (4,14).

Maternal monitoring included arterial blood pressure every 5 min during the first hour and then every 15 min and continuous heart rate measures and axillary temperature once every hour. Cervical dilation at entry of study, duration of first and second stage of labor, and oxytocin use for the induction or augmentation of labor were recorded. Hemodynamic variables, motor, and sensory assessments were discontinued after 4 h, but recording of total and hourly drug administration was continued until delivery.

Adverse effects, such as nausea, vomiting, itching, maternal bradycardia, or hypotension were reported. Hypotension was defined as systolic blood pressure measurement <100 mm Hg and/or >=25% baseline decrease and was treated with 5–10 mg of ephedrine with additional doses when required.

Fetal heart rate was recorded continuously on a cardiotocograph (Hewlett-Packard 80300A, Hewlett Packard, Palo Alto, CA). Fetal heart rate tracings were monitored by obstetricians blinded to group allocation and reviewed again postpartum for detection of fetal heart rate abnormalities (MM). Analysis compared tracings obtained at least 30 min before epidural placement with those recorded during epidural analgesia. Fetal heart rate abnormalities such as late decelerations, bradycardia (defined as fetal heart rate <100 bpm lasting for 5 min or more), and decreased fetal heart rate variability according to criteria used at our institution (at least two accelerations of 15 bpm lasting 15 s for 40 min) were noted. Fetal events were managed with standard measures such as oxygen, left or right lateral uterine displacement, ephedrine when required, cessation of oxytocin, and tocolytic treatment when required. Fetal scalp pH value was determined when appropriate, and instrumental or cesarean delivery was performed when indicated. Mode of delivery, neonatal weight, and umbilical cord blood-gas were recorded. Apgar scores and clinical evaluation at 24 h after birth were performed in all neonates by pediatricians blinded to group allocation.

Expecting that clonidine will prolong analgesia duration by approximately 60 min (15), thus decreasing by 20% the dose of ropivacaine administered over 4 h (40 mL to 32 mL of ropivacaine 0.2%), power test analysis resulted in a calculated sample of 22 subjects per group to obtain statistical relevance of our hypothesis (assuming a {alpha} error of 0.05 and a power of 0.80). Data are presented as mean ± SD. For all calculations, INSTAT computer software package (GraphPad Instat, San Diego, CA) and Statistica for Windows 1993, Release 4.5A (Statsoft Inc, Tulsa, OK) were used. The statistical analysis was performed using analysis of variance for comparison between groups and Fisher’s exact test for categorical variables. A value of P < 0.05 was considered significant.


   Results
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 Abstract
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 Methods
 Results
Discussion
 References
 
Seventy-two women were enrolled in the study and six cases were excluded (four unilateral blocks identified within the first hour of the study and two displaced catheters requiring replacement of the catheter within the first 4 h). Groups were comparable with regard to demographic data and cervical dilation upon entry, duration of first and second stages, oxytocin use for the induction or augmentation of labor, mode of delivery, and Apgar scores (Table 1).


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  		Table 1. Table 1. Patient Demographics and Obstetric Characteristics
 
Onset of analgesia was shorter in Group 3, with a trend at 5 min (P = 0.07) becoming significant at 10 min (Table 2). At 10 and 30 min, the number of subjects reporting a pain score <=3 was significantly more in Group 3 (Table 2). Duration of analgesia was significantly prolonged with the addition of clonidine (Table 2). The number of women requiring additional boluses of ropivacaine was significantly greater in Group 2 (Fig. 1). There was no difference in sensory level among groups throughout the study. Despite a trend for a higher satisfaction score in Group 3 on the first postpartum day, there was no difference in maternal satisfaction among groups (8.7 ± 1.4 in Group 1, 8.5 ± 2.0 in Group 2, and 9.5 ± 0.8 in Group 3; P = 0.07).


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  		Table 2. Table 2. Analgesia Characteristics, Ropivacaine Dose, and Side Effects
 


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  		Figure 1. Distribution of additional doses after the study drug during the 4 h of the study. With the first additional dose (ropivacaine 0.1% 8 mL), a continuous infusion of ropivacaine 0.2% was started at 8 mL/h. After the study drug, two women in Group 2, versus seven in Group 1 and 11 in Group 3, never requested additional dosing until delivery (relative risk, 1.59; 95% confidence interval, 1.19–2.13; P < 0.01). Overall, women in Group 2 required significantly more additional doses than women in Groups 1 and 3 (*P < 0.05, analysis of variance). Group 1, ropivacaine 0.1% 8 mL with clonidine 75 µg; Group 2, ropivacaine 0.2% 8 mL with NaCl 0.9%; and Group 3, ropivacaine 0.2% 8 mL with clonidine 75 µg.

 
During the first hour, there was no difference in the incidence of motor block among groups, with no woman developing a significant motor block (i.e., Bromage score >=2) (Fig. 2). However, with time and during the 4 h of the study, the incidence of motor block was significantly more frequent in Group 2 versus Groups 1 and 3 (Fig. 2). The total ropivacaine dose was also different among groups, with Group 2 requiring significantly more ropivacaine (Table 2).



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  		Figure 2. Number of women with motor block (Bromage score 1) at 60, 120, 180, and 240 min (shaded bars). Number of women developing more intense motor block (Bromage score 2) are represented with hatched vertical bars (one woman in Group 1, six women in Group 2, and three women in Group 3). Because the ropivacaine infusion rate was reduced in women developing an intense motor block, Bromage score 2 was never noted twice (on two different assessment times) in the same woman. Women in Group 2 developed significantly more motor block than women in Groups 1 and 3 (*P < 0.05, analysis of variance). Group 1, ropivacaine 0.1% 8 mL with clonidine 75 µg; Group 2, ropivacaine 0.2% 8 mL with NaCl 0.9%; and Group 3, ropivacaine 0.2% 8 mL with clonidine 75 µg.

 
The mean dose of ephedrine among women requiring ephedrine for hypotension was similar among groups (16 ± 9 mg in Group 1, 14 ± 5 mg in Group 2, and 11 ± 6 mg in Group 3; P = 0.30). There was a tendency for more women in Group 1 (n = 7 of 22) and Group 3 (n = 9 of 22) versus women in Group 2 (n = 4 of 22) to be treated with ephedrine during the 4 h of the study; however, this did not reach statistical significance (rela-tive risk, 0.55; 95% confidence interval, 0.19–1.31; P = 0.16). All women were treated with incremental doses of 5 mg of ephedrine, with no woman requiring more than 30 mg. Three women in each group required multiple ephedrine doses; all women were treated within the first hour of the study, with the exception of one woman in Group 3 requiring 20 mg of ephedrine 120 min after the study dose (case h, Table 3).


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  		Table 3. Table 3. Characteristics of the 10 Cases in Which Fetal Heart Rate Abnormalities Were Noted
 
There was no difference in the incidence of nausea, vomiting, or sedation (Table 2). There were no cases of maternal bradycardia, itching, or hyperthermia (T >=37.8°C) recorded at any time during the study.

Fetal heart rate abnormalities were diagnosed in 10 different parturients and managed with standard measures (Table 3). No tocolytic treatment was required. Fetal heart rate variability was normal in all cases. Episodes of fetal bradycardia directly related to maternal hypotension were observed in one woman per group and required no other treatment than ephedrine. These events occurred 60 (case b), 20 (case c), and 120 (case h) min after the study drug, respectively (Table 3). In Group 1, one case of fetal bradycardia was associated with a prolapsed cord and required an immediate cesarean delivery (case a). In Group 2, two cases of bradycardia shortly after study drug administration (cases c and d) and two cases of late decelerations (cases e and f) were recorded. In Group 3, one case of late deceleration occurring 80 min after study drug administration not related to an episode of maternal hypotension required an immediate cesarean delivery (case i). No neonate was admitted to the neonatal intensive care unit. Pediatricians reported a normal clinical status within the first 24 h in all six neonates born to mothers receiving clonidine in which abnormal fetal heart rate tracings had been recorded.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This is the first study demonstrating the additive analgesic effect in the first stage of labor of an epidural bolus of 75 µg of clonidine administered with ropivacaine. We decided to study two doses of ropivacaine, 8 mg (0.1%) and 16 mg (0.2%), because ropivacaine dose-response studies for initiation of epidural analgesia were not available at the time of study design. In addition, because ropivacaine was studied without opioids, we decided not to administer the smaller dose (8 mg) without clonidine because we expected this dose to be insufficient to provide adequate analgesia. This assumption was confirmed in a study showing that the optimal concentration of ropivacaine as a sole anesthetic for the initiation of epidural analgesia is 0.2% (13 mL) (16). We are aware that the administration of 7.5 mg of bupivacaine with 15 µg of epinephrine as a test dose could interfere with the interpretation of our results; yet, at the time of the study design, it was felt that ropivacaine was not a suitable drug to detect an intravascular or intrathecal catheter and should not be used as a test dose. Nonetheless, because all three groups received a similar bupivacaine-epinephrine test dose, this should minimize any confounding effect.

Clonidine was administered as a bolus of 75 µg because smaller doses (30 µg) have been shown not to improve analgesia significantly (8), whereas larger doses (150 µg) have resulted in maternal bradycardia (one case requiring atropine) (4), decreased fetal heart rate variability and late decelerations (4), and maternal sedation (120 µg) (15). In an early dose-finding study, 75 µg of clonidine was indeed the optimal epidural dose to add to bupivacaine for labor analgesia1 and provided approximately two hours of satisfactory analgesia when added to bupivacaine (5). Furthermore, we decided to limit the clonidine administration to one single bolus because fetal heart rate abnormalities have been associated with repeated doses of 75 µg of clonidine (5).

Our findings are consistent with several studies examining the effect of clonidine added to ropivacaine in peripheral blocks (17,18) as a spinal adjunct for orthopedic surgery (19) or by the caudal route for pediatric surgery (20), which all showed prolongation of analgesia.

In our study, onset of analgesia was significantly shorter among women receiving clonidine with the larger dose of ropivacaine 0.2% (8 mL). A reduced onset of action with clonidine has not been reported in previous studies examining the combination of clonidine with bupivacaine (4,6,15). It is possible that our definition of analgesia onset differs from that of other authors. We defined good analgesia as a VAS <=3 and recorded VAS precisely at five and 10 minutes to determine the number of cases reporting VAS scores <=3 at these time intervals. Our data strongly suggest that the addition of clonidine impacts favorably both on the number of women with a VAS <=3 and on the average VAS at 10 minutes. The exact mechanism by which the addition of clonidine might shorten the onset of analgesia produced by ropivacaine is not clear; the possibility of a positive interaction between the intrinsic vasoconstricting effect of ropivacaine (21) and clonidine remains to be determined.

Duration of action was substantially increased in both groups with clonidine. There was no significant advantage of ropivacaine 0.2% 8 mL with clonidine over ropivacaine 0.1% 8 mL with clonidine in terms of duration of analgesia. The addition of clonidine to 0.2% ropivacaine prolonged by approximately one hour the analgesia time produced by 0.2% ropivacaine alone. The hourly dose for the four first hours was significantly reduced by the addition of clonidine, with no difference in dose of ropivacaine between the two groups receiving clonidine. This is because of the fact that in Group 1, the smaller initial ropivacaine dose was compensated with subsequent ropivacaine doses when required, and in Group 3, fewer additional doses were required after a larger initial study bolus. Furthermore, the reduced dose of ropivacaine required over the study period in both groups receiving clonidine produced less motor block over time.

We report no episodes of maternal bradycardia in women receiving clonidine, probably as a result of the relatively small dose of clonidine administered. Sedation has been reported to occur as soon as 15 to 60 minutes after doses of 120 µg of clonidine (15) and 60 to 120 minutes after 150 µg of clonidine (14) or 75 µg of clonidine with 50 µg of fentanyl (14). We did not observe significant sedation in either group, probably because of the small dose of clonidine and the absence of concurrent opioid administration.

In our study, 44 women (Groups 1 and 3) received 75 µg of epidural clonidine. Episodes of fetal bradycardia directly attributed to maternal hypotension occurred between 20 and 120 minutes after the injection of the study drug. This finding is consistent with other reports of decreased mean arterial blood pressure occurring 20 to 140 minutes after the clonidine administration (4). Although there was a tendency for more women who received clonidine to require ephedrine, this did not seem to impact fetal outcomes, as monitored by Apgar scores and umbilical cord blood-gas values. Our data show that despite some changes in maternal hemodynamic status, which may occur up to two hours after 75 µg of epidural clonidine, hypotension can be managed efficiently with ephedrine, with no apparent adverse effect on obstetrical and fetal outcome. However, because our study was not specifically designed to detect differences in adverse neonatal effects, larger studies are required to further confirm that 75 µg of epidural clonidine does not impact on neonatal well being.

In conclusion, our results demonstrate a dose-sparing effect of clonidine added to ropivacaine for epidural labor analgesia during the first stage of labor, resulting in a reduced motor block. However, because of the potential for maternal hypotension, we recommend that laboring women be closely monitored for several hours after receiving epidural clonidine.


   Footnotes
 
Presented, in part, at the 31st Annual Meeting of the Society for Obstetric Anesthesia and Perinatology (SOAP), Denver, CO, May 1999, and the Annual Meeting of the American Society of Anesthesiologists (ASA), Dallas, October 1999.

1 Brichant JF, Bonhomme V, Mikulski M, et al. Admixture of clonidine to epidural bupivacaine for analgesia during labor: effect of varying clonidine doses [abstract]. Anesthesiology 1994;81:A1136. Back


   References
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 Abstract
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 Methods
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 Discussion
 References
 

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Accepted for publication May 14, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press