The maternal satisfaction score did not differ between the groups. Seventy-one per cent of the parturients in the clonidine group experienced optimal delivery compared with 65% in the control group (not significant).
A lower VAPS score was observed in the clonidine group over time than in the control group (Fig. 1). At the time of delivery, the mean VAPS score was significantly lower in the clonidine group (22.4 ± 25.1) than in the control group (34.4 ± 28.0; P = 0.03).
Comparison of the AUCs between groups showed a lower value in the clonidine group during the first hour (19.13 ± 15.99) than in the control group (26.86 ± 15.11; P = 0.002).
Midwives' satisfaction scores were similar in both groups (86 ± 19 vs. 85 ± 16; P = 0.80).
The total volumes of anaesthetic solution used per hour of labour were significantly smaller in the clonidine group than in the control group: 13.9 ± 4.3 vs. 16.3 ml ± 4.0 (P = 0.005).
More patients in the control group required rescue levobupivacaine 0.25% bolus (37 vs. 12%; P = 0.01).
The incidence of motor block was not significantly different between the two groups (12 and 13% in the clonidine and control groups, respectively; P = 0.9). Only three parturients (two control, one clonidine) experienced a motor block with a Bromage score lower than 4.
Sedation rate (resulting in a sedation scale different from 1) was similar in the control and in the clonidine group (4.3 vs. 2.0%; P = 0.61).
Pruritus was present in 46% of the patients in the control group and in 18% in the clonidine group (P = 0.004), with a mean intensity of 33 ± 22 and 23 ± 22 mm, respectively (not significant). Nausea was present in 13% of the patients in the control group and in 4% of the patients in the clonidine group (not significant), with a mean intensity of 54 ± 32 and 17 ± 10 mm, respectively (not significant).
Neonatal Apgar scores and venous cord pH were also similar in both groups (Table 3).
The time course of systolic arterial pressure during epidural analgesia was different between groups (Fig. 2). Systolic arterial blood pressure was significantly lower in the clonidine group from 20 to 360 min after epidural infusion initiation. However, systolic pressure remained above 100 mmHg over time in both groups. Only one patient in the control group experienced a systolic blood pressure below 100 mmHg. More patients required ephedrine use in the clonidine group (26.5%) than in the control group (6.5%; P = 0.01). Maternal heart rate did not differ between groups. No adverse effect was observed during the whole study.
The results of this study were that adding low-dose clonidine to local anaesthetics and opioids for labour analgesia was not associated with an improved maternal satisfaction at delivery, as evaluated by our primary outcome, but resulted in an improved VAPS score over time, a lower epidural mixture consumption and less pruritus. Moreover, these improvements were not associated with increased adverse effects.
Several studies have documented the potential benefit of spinal and epidural clonidine.3,16–20 This α-2-adrenergic agonist could be expected to be an efficient analgesic adjuvant by modulating pain perception at the spinal level.1,21,22 Clonidine also improves peripheral nerve blockade by local anaesthetics.23,24 The benefit of epidural clonidine administration in obstetrics has been evaluated in previous studies as an adjunct to local anaesthetics, opioids or both.2,3,8,18,25 This evaluation was made after bolus administration, usually 50–75 μg, up to 150 μg.26 Under these conditions, clonidine could exhibit several benefits, including the sparing of local anaesthetics and opioids, leading to less effect on motor function and opioid-induced respiratory depression, pruritus and nausea. Bolus administration of clonidine induced several side effects such as sedation and hypotension.2,8,25,27 Although pharmacodynamic studies suggest continuous infusions may be more appropriate, few studies have focused on continuous epidural clonidine administration during labour.6,7,28,29 This route of administration could be of value in respect to its simple use under clinical conditions.
In a previous study, the authors showed a local anaesthetic sparing effect, but with no change in the quality of analgesia.28 Furthermore, a subsequent study failed to show analgesic benefits, whereas the sedation scores were higher in the clonidine group.7 In the former study, the lack of analgesic or maternal satisfaction improvement was ascribed to the small power of the study. Our study confirmed the clinical advantage of this strategy based on maternal satisfaction and evaluated analgesia. However subjective, the maternal satisfaction assessment reflected the reduced requirement for rescue boluses and the lower incidence of pruritus. The large decrease in pruritus may be partially explained by the reduction in opioid administration.
A lower VAPS score was obtained in the clonidine group, whereas these patients received a reduced amount of epidural solution. This paradoxical result could have at least two explanations. Either the low level of pain of lower than 30 mm in both groups did not make the patients use the patient-controlled analgesia (PCA), or the side effects encountered in the control patients led these patients to trade a slightly higher pain score for less side effects.30 These results are in line with previous studies using bolus administration of clonidine and clearly show that a continuous infusion of low-dose clonidine has the same clinical advantage on pain, avoiding the side effects such as sedation and hypotension.2,3,29
Previous studies showed that sedation could occur after bolus administration of clonidine and that a minimum dose of 50 μg seemed to be necessary to induce sleep and dozing.8 In the present study, the total amount of clonidine injected during the initial dose of epidural solution was 30 μg due to the low clonidine concentration we used. After the initial dose, the mean clonidine infusion rate was 27.7 ± 7.5 μg per hour of labour. These results were consistent with those of the study by Paech et al.,7 who found a mean infusion rate of 28 μg h−1 in a PCEA bolus mode without background infusion. In the study by Tremlett et al.,28 no maternal sedation was observed whatever the clonidine infusion rate, 19 or 37 μg h−1. This suggests that there may exist a ‘threshold effect’ with a sedation effect observed at least above the value of 37 μg h−1.
The circulatory effect of clonidine could be of actual concern in the setting of labour analgesia.2,10,11 After epidural administration of clonidine, both bradycardia and hypotension could occur due to the reduced sympathetic outflow induced by stimulation of α-2-adrenergic receptors in the brainstem and intermediolateral column of the spinal cord.4,5,9 Blood pressure is usually reduced 15–20 min after epidural clonidine boluses and may remain lower for 90–120 min.31
Using a PCEA clonidine infusion, Paech et al. 7 found a significant reduction in systolic blood pressure over time in the clonidine group. However, systolic blood pressure always remained higher than 100 mmHg and no clinical significance was found. In our study, we found similar results. Although ephedrine was more frequently used in the clonidine group, no maternal or foetal consequences were noticed.
There were no adverse effects on the newborn infants. However, some authors found a higher number of foetal cardiotocographic traces with a reduced variability in the clonidine group.28 In this study, the variability and foetal cardiotocographic data were not specifically addressed, but the lack of difference in umbilical blood pH values and Apgar scores suggests that these effects, if any, have no consequence on newborn infants.
Motor blockade could also be of concern after clonidine administration as previously described.32 However, we did not find any difference in the motor blockade rate in either of the groups. This may be explained by the low dose of clonidine administered and the low dose of local anaesthetic used.
Thus, this study shows that low-dose continuous infusion of epidural clonidine resulted in excellent obstetric analgesia without significant adverse effects that may occur after a single epidural bolus injection.
Although this was a prospective double-blind randomized trial, some methodological aspects should be addressed and shortcomings or weaknesses of the study pointed out.
One major weakness is the high number of patients excluded from analysis (33 of 128 parturients; 26%). Although all secondary endpoints were significant, the primary endpoint (maternal satisfaction score) was not. This may be explained by the high number of exclusions, in which the primary endpoint could not be assessed.
Our study was, therefore, underpowered as our pretest maternal satisfaction was quite high and, thus, the difference between the control and treatment groups was low. However, we used some strong secondary endpoints that all supported a beneficial use of low-dose clonidine.
Another possible explanation is the nature of our primary endpoint itself: ‘maternal satisfaction score’. We decided to evaluate maternal satisfaction as this seemed an essential criterion in obstetric analgesia management. Indeed, for maternal satisfaction and obstetric management, not only analgesia but also the lack of motor blockade is essential for full maternal comfort.
In conclusion, low-dose epidural clonidine (2 μg ml−1), self-administered and in combination with 0.0625% levobupivacaine and 0.25 μg ml−1 sufentanil, improved analgesia and reduced pruritus and supplementation delivery when compared with a similar PCEA solution without clonidine. We also observed a significant reduction in VAPS scores over time in the clonidine group. The maternal satisfaction score did not differ between the groups.
No difference was found in the sedation scores or in the motor blockade. As blood pressure was lowered, this effect, although, nonclinically relevant, warrants haemodynamic monitoring during the course of obstetric analgesia.
The present work was supported by institutional funding (Hospices Civils de Lyon – BP 2251, 3 quai des Célestins, 69 229 LYON Cedex 02).
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Keywords:© 2010 European Society of Anaesthesiology
clonidine; epidural analgesia; levobupivacaine; sufentanil