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Anesth Analg 2002;95:1396-1401 © 2002 International Anesthesia Research Society
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Abstract |
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Subarachnoid clonidine may increase the duration of spinal opioid and local anesthetic analgesia during labor, but it may also increase hypotension and sedation, and the therapeutic range is unclear. We studied 110 term parturients of mixed parity having combined spinal/epidural analgesia during labor in this randomized, double-blinded trial. All received subarachnoid fentanyl 20 µg and bupivacaine 2.5 mg, plus either saline or clonidine (15, 30, or 45 µg). Of 101 per-protocol parturients (n = 25, 24, 26, and 26 in Groups C0, C15, C30, and C45, respectively), 22 delivered before the cessation of spinal analgesia. Group demographics and pain scores from Time 0 to 120 min were similar. There was no significant difference among groups in the duration of spinal analgesia (P = 0.09) or in the duration of clonidine groups combined compared with control (median, 120 min [interquartile range, 96–139 min] versus 98 min [80–120 min]; P = 0.07). Systolic blood pressure was significantly lower in all clonidine groups between 40 and 90 min (P = 0.001). Hypotension (P = 0.05) and the requirement for ephedrine (P = 0.02) were dose dependent, but groups had a similar incidence of hypotension. The addition of clonidine 15–45 µg to subarachnoid fentanyl and bupivacaine reduced blood pressure and did not significantly increase the duration of spinal analgesia.
IMPLICATIONS: The addition of 15–45 µg of clonidine to subarachnoid fentanyl plus bupivacaine did not significantly increase the duration of spinal analgesia but did decrease maternal blood pressure. The results of this study do not support the use of subarachnoid clonidine to prolong the action of spinal labor analgesia when fentanyl plus bupivacaine are administered.
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Introduction |
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Combined spinal/epidural (CSE) analgesia is popular for labor analgesia, and in early labor, spinal analgesia may persist for 3 h or longer (1). The
2-adrenergic agonists can prolong the duration of subarachnoid opioid or opioid plus local anesthetic (2–4).
Clonidine has no effect on uteroplacental blood flow, and no adverse fetal or neonatal effects have been identified. It has been used for >15 yr as an adjunct to other intraspinal analgesics for acute pain management (5,6). Doses of 100–200 µg produce excellent labor analgesia of short duration, but sedation and hypotension are both common and severe (7). Recent research has focused on the addition of smaller doses of clonidine to opioid, with or without local anesthetic. Clonidine increases the duration of pain relief after spinal sufentanil or fentanyl with bupivacaine (3,4,8–10), but doses of 
30 µg increase hypotension and, possibly, sedation (3,7–9,11).
At the time this study commenced, subarachnoid clonidine had not been investigated at doses of <50 µg. The study aim was to determine whether the addition of subarachnoid clonidine 15–45 µg to fentanyl and bupivacaine increased the duration of labor analgesia.
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Methods |
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This randomized, double-blinded, controlled clinical trial received Institutional Research and Ethics approval. Clonidine administration was "off-label," so the trial was registered under the Clinical Trial Notification Scheme of the Australian Therapeutic Goods Administration. Term parturients of mixed parity, in active labor, who consented to CSE analgesia and gave written, informed study consent, were enrolled. Exclusion criteria were preterm gestation, multiple pregnancy, severe preeclampsia, insulin-dependent diabetes, or other major medical disease. Postrecruitment exclusion criteria were failure to identify the subarachnoid space, accidental dural puncture during epidural insertion, or delivery within 20 min of study drug injection.
To account for the potential confounding effect, randomization was stratified for nulliparous and multiparous parturients. Early labor was defined as cervical dilation <4 cm and late labor as 4–10 cm. The subarachnoid solution (2 mL) included bupivacaine 2.5 mg (1 mL of 0.25% plain bupivacaine) and fentanyl 20 µg (0.4 mL of 50 µg/mL) plus either subarachnoid saline (Group CO) or clonidine (15 µg, Group C15; 30 µg, Group C30; or 45 µg, Group C45). This solution was freshly prepared according to a computer-generated random number sequence with sealed, coded envelopes. Both the parturient and research midwife collecting data were unaware of study group allocation.
Time 0 was taken as the injection of subarachnoid solution with a single intervertebral space needle-through-needle approach, with the parturient seated. The CSE kit (B-Braun Australia Ltd.) contained a 27-gauge Whitacre spinal needle and an 18-gauge epidural needle with a closed-tip catheter. Routine monitoring included maternal blood pressure (BP), pulse rate, respiratory rate, and continuous fetal cardiotocography. An epidural bolus (4 mL of 0.25% bupivacaine) was available if the parturient deemed initial spinal analgesia unsatisfactory after 20 min.
Demographic data included maternal age, weight, parity, stage and type of labor, and cervical dilation. Maternal BP and pulse rate between contractions were collected at 0, 3, 5, 10, 15, 20, 40, and 60 min and every 30 min thereafter. Ephedrine was administered for systolic BP (SBP) of <90 mm Hg or a decrease of >30% from baseline, with monitoring at 0, 3, 5, 10, 15, 20, 40, and 60 min and every 30 min thereafter during the study period. One hundred-mm visual analog scales (VAS) were used to measure pain (at similar intervals to SBP), sedation (0 min, then 10 min and thereafter), and itching, shivering, and nausea (0 min, then from 40 min). Lower-limb strength was assessed (at 10, 20, and 60 min) by a five-point scale (able to sustain a straight leg raise; full knee flexion only; just able to move knees; able to move only feet; unable to move feet) and by the ability to stand unsupported (at 40 min after study drug injection). The highest dermatome with loss of sensation to cold was evaluated at 10 min and intermittently thereafter. Propofol 10 mg IV was available for the treatment of severe pruritus persisting beyond 60 min.
The study period commenced at the time of subarachnoid injection (Time 0 min) and terminated at the first request for further analgesia, unless delivery (or the administration of an epidural bolus for delivery) occurred earlier. Pain score at the time of first request for epidural analgesia, epidural drug use (intermittent 10-mL boluses of 0.125% bupivacaine with fentanyl 5 µg/mL), delivery mode, and neonatal condition were noted. Within 24 h of delivery, parturients were asked to rate their satisfaction with initial spinal analgesia on a four-point scale (excellent; good; fair; inadequate) and their overall satisfaction with CSE analgesia on a VAS.
The primary outcome was the duration of spinal analgesia. The sample size of 28 per group was based on a desire to detect an increase in duration of at least 30 min ( = 0.05; ß = 0.8) on the basis of a previous study showing a SD with the control solution of 40 min. Quantitative outcome data were analyzed with the Kruskal-Wallis test, the nonparametric equivalent of analysis of variance. Those parturients who did not have spinal analgesia terminated by the intervention of delivery were used for analysis of the primary outcome, although data from all parturients were also analyzed with the Cox proportional hazards model for censored data. This procedure models the duration of analgesia and estimates the relative risk of analgesia having been complete at any given time point. The Pearson 
2 test for a contingency table was used for the analysis of categorical data, such as parity, type of labor, type of delivery, and the presence of specific side effects. Fisher’s exact test was used to analyze the proportion needing treatment with ephedrine in the control group compared with the combined clonidine groups. Logistic regression and the likelihood ratio were used to test the incidence of categorical events with an increasing dose of clonidine. A P value of <0.05 was considered significant.
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Results |
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One hundred-twelve parturients were recruited and randomized into 4 groups (C0, C15, C30, and C45) of 28 patients each. Eleven were withdrawn because of either delivery within 20 min (n = 6) or failed spinal insertion (n = 5), leaving per-protocol data from 101 parturients (n = 25, 24, 26, and 26 in Groups C0, C15, C30, and C45, respectively). Of these, 22 parturients (Group C0, n = 4; C15, n = 3; C30, n = 10; C45, n = 5; nullipara, n = 4; multipara, n = 18) either delivered or had obstetric intervention to effect delivery before the full duration of their spinal analgesia. The four groups were demographically similar (Table 1). No patient required an epidural bolus within 20 min of study drug injection.
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There was no difference among groups for the duration of spinal analgesia (Table 2; P = 0.09), including in the uncensored subset for whom the duration of spinal analgesia was not terminated by delivery intervention. There was also no significant difference among groups from the uncensored subset when all clonidine groups were combined and compared with the control group (median [interquartile range], 120 min [96–139 min] versus 98 [80–120 min]; P = 0.07). The Cox proportional hazards model showed no difference between Groups C45 and C0 for the duration of analgesia (nulliparous parturients, P = 0.74; multiparous parturients, P = 0.08).
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There was no significant difference in pain scores between the groups from Time 0 to 120 min or at the time of patient request for epidural analgesia (Table 2). The median pain score in all groups was 0 from 3 to 60 min, and except for the control group, it remained 0 at 90 min.
The SBP was significantly different among groups between 20 and 90 min (Fig. 1). This effect was greatest in multiparous parturients of Groups C30 and C45 (P = 0.036). The incidence of hypotension did not differ among groups, but logistic regression showed a trend to an increasing incidence of hypotension with increasing clonidine dose (P = 0.05). Ephedrine was used to treat a decrease in BP only in the clonidine groups (13% vs 0%; P = 0.06). The proportion requiring treatment increased as the clonidine dose increased (P = 0.02). The pulse rate was less at 60 min (P = 0.10) and 90 min (P = 0.03).
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There were no significant differences among the groups for pruritus, nausea, sedation, or maternal satisfaction, as assessed by VAS scores, verbal ratings, or observer ratings. At 40 min, pruritus scores were similar (range of medians across groups, 34–44) and had decreased (range of medians across groups, 7–36) in all groups by 120 min. Sedation scores were moderate in all groups at baseline (range of medians across groups, 21–45) and did not significantly increase either with time or increasing clonidine dose. The severity of shivering was reduced in the clonidine groups after 40 min, and the incidence was significantly smaller at 90 min (6% vs 31%; P = 0.01). At 20 min, 91% of Group C0 and 97% of Groups C15, C30, and C45 had no clinical impairment of lower-limb strength (P = 0.40). There was no significant difference in the proportion able to stand unaided at 40 min or in the thoracic sensory dermatome block at 10 and 20 min (Table 3). However, a decreasing proportion of parturients was able to bear weight as the dose of clonidine increased (P = 0.02). There were no differences among groups for epidural drug use, delivery mode, or neonatal Apgar scores (Table 1).
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Discussion |
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We found that the addition of clonidine 15–45 µg to subarachnoid bupivacaine 2.5 mg and fentanyl 20 µg did not significantly increase the duration of spinal analgesia during early labor. If clonidine in these doses has an effect on the duration of spinal opioid and local anesthetic, we do not consider it to be of clinical significance. Clonidine did not affect the quality of pain relief or the incidence or severity of side effects, except for a reduction in shivering. A sustained and dose-dependent reduction of SBP occurred; however, this was not clinically significant, as it did not increase the incidence of hypotension or the requirement for ephedrine.
The dose-dependent antinociceptive effects of clonidine were demonstrated in 1981 (12). These effects are partly mediated by spinal cord muscarinic and nicotinic receptors and the release of acetylcholine and by the activation of inhibitory noradrenergic pathways (6). In experimental studies, animal models, and clinical trials, subarachnoid opioids, local anesthetics, and 2-adrenergic agonists show synergistic or additive interactions (6). Intraspinal clonidine is not neurotoxic and has no effect on uterine blood flow or fetal outcome in animal models (5,6). Clinical experience for obstetric analgesia is limited (6), and neither epidural nor spinal clonidine is approved for obstetric indications. In the United States, epidural clonidine attracts a "black box" warning recommending against its use in this population. Consequently, the role of intraspinal clonidine for labor analgesia remains controversial. An editorial opinion was that epidural clonidine was not indicated currently, but that investigation should continue (13).
A goal of spinal analgesia in labor is the rapid onset of high-quality pain relief of prolonged duration. Subarachnoid opioid analgesia is enhanced in both onset and duration by small doses of local anesthetic, but the duration generally remains short. Multiple drug combinations have been evaluated in the hope of achieving several hours of pain relief with an acceptable side-effect profile. The 2-adrenergic agonist epinephrine (200 µg) or clonidine (50 µg) may significantly prolong spinal bupivacaine/sufentanil analgesia, reaching three hours during early labor (2,4,11). Clonidine 15–30 µg may also prolong the action of subarachnoid fentanyl, bupivacaine, or their combination (9–11). That we did not find a significant prolongation may reflect methodological differences, differences in drug interactions, or chance. We consider that a clear benefit in terms of substantial prolongation of bupivacaine and fentanyl analgesia, in association with a lack of adverse effects, should be established before clonidine is considered as an adjunct. Furthermore, the preparation of several drugs at the bedside, including the dilution of appropriate small doses, requires considerable caution because of the risk of dose error and solution contamination.
Under the conditions of this study, subarachnoid clonidine did not significantly prolong spinal analgesia in labor. On the basis of evidence from previous trials, the trends observed of a dose-dependent increase in duration and of an increased duration for combined clonidine groups versus control may have been a pharmacodynamic response, with failure to detect prolongation representing a ß error. A power analysis a posteriori indicates that an uncensored subset sample size of 110 would have been necessary to show an increase of median duration of longer than 30 minutes. We considered an increase of <30 minutes not of clinical importance, especially when the maximum duration of spinal analgesia is approximately 2 hours.
Methodological variation may explain why some investigators have found that clonidine significantly increases the duration of bupivacaine and opioid to longer than three hours. The timing of the administration (a longer duration of spinal analgesia in early compared with late labor) (14) and the choice of spinal opioid (fentanyl has a shorter duration than sufentanil) (15) are relevant. In contrast to our results, Owen et al. (10) found that clonidine 30 µg increased the duration of fentanyl 25 µg and bupivacaine 2.5 mg by 30–120 minutes. The intensity of pain at the time of a request to initiate epidural analgesia is likely to vary among different populations and will influence the measured duration of "effective" pain relief. Lower scores (median, 23–35) at request in our study may partly explain the shorter duration compared with similar studies by Mercier et al. (3) (scores 46–49) and Gautier et al. (8) (scores 32–55).
Although smaller doses have not been studied, some investigators have suggested that the optimal dose of clonidine in this setting is 15 µg. This dose is unsatisfactory as a sole drug, and 30 µg alleviates pain only briefly (for approximately 30 minutes in 80% of parturients in early labor) (8). When added to bupivacaine and sufentanil 2.5 or 5 µg, however, the duration of analgesia is prolonged (8,11). We were unable to determine any dose of clonidine that significantly increased spinal analgesia.
Abouleish et al. (14) observed that 35% of parturients given spinal analgesia in labor delivered before the initiation of epidural analgesia, and this was so in 22% of parturients in our study. If several hours of spinal analgesia could be achieved, either "single-shot" or repeat spinal injection might be feasible and attractive options, avoiding catheter-related problems with CSE analgesia. The limited duration of spinal analgesia with current regimens is such that some anesthesiologists favor restriction of spinal or CSE analgesia to late labor (1).
We had also hoped to identify a clinically useful adjuvant dose of subarachnoid clonidine that was free of side effects. Doses of 30–200 µg produce undesirable dose-dependent sedation, mediated in the brainstem locus ceruleus by plasma clonidine concentrations that are detectable within 10–60 minutes (6–8,16). Drowsiness is also absent or minimal after epidural clonidine 75–100 µg, which is consistent with an intrathecal/epidural potency ratio of more than 6:1 (17). Although Sia (9) detected sedation after sufentanil and clonidine 30 µg, but not 15 µg, as with most other studies we found no effect from 15 to 45 µg (3,4,8). Changes in conscious state appear more likely to be influenced by factors such as elimination of pain in the presence of fatigue and concurrent systemic opioid effects.
CSE analgesia is notable for the high retention of normal mobility and thus ambulatory potential. Our control group received fentanyl with bupivacaine 2.5 mg, a combination associated with a rapid onset of analgesia, a small incidence of motor block, and a duration of >90 minutes (18). Intraspinal epinephrine may markedly increase the density of motor block (2,4), and clonidine also potentiates sensory and motor block, probably mediated by a direct effect on neural transmission and local vasoconstriction (6). Clonidine, however, has not been associated with increased motor block in this setting (4,8), and we found that lower limb weakness was infrequent (<5%). We postulate that the association between clonidine dose and failure to ambulate in our study was due to postural hemodynamic change. Sia (9) found a higher level of sensory block with additional clonidine, but this study and others (3,8,10) report no change.
Maternal shivering is more common after epidural than spinal analgesia (19) and is inhibited by systemic or epidural clonidine (20,21). This may be an inhibitory noradrenergic action on hypothalamic thermoregulation, and this study suggests that subarachnoid clonidine has a similar effect.
Hypotension is undesirable in this setting. Although cardiovascular responses are biphasic, typical doses of intraspinal clonidine may reduce BP by inhibition of spinal cord preganglionic sympathetic neural tone and activation of postsynaptic 2-receptors in the brainstem and periphery. In the presence of local anesthetic for spinal anesthesia, hypotension is not increased, but this may not pertain during labor analgesia. Although BP may decrease after subarachnoid fentanyl in the absence of sympathectomy (22), treatment of hypotension is not normally required (23). Neither D’Angelo et al. (4) nor Owen et al. (10) found more frequent hypotension when clonidine 30–50 µg was added to bupivacaine (60% vs 33% and 27% vs 13%, respectively), but this may have been a Type II error. Our results confirm that subarachnoid clonidine consistently decreases BP, although no group had more hypotensive episodes or a larger ephedrine requirement (8,9).
In conclusion, subarachnoid clonidine 15–45 µg altered maternal hemodynamics, but the effect on the duration of spinal analgesia from bupivacaine and fentanyl during labor was neither statistically nor clinically significant.
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Acknowledgments |
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This study was funded by a research grant from the Australian and New Zealand College of Anaesthetists.
We acknowledge the members of the Department of Anaesthesia and the hospital midwifery staff, in particular research midwives Hiliary McKibbon, Samantha Davies, Andrea Zulch, Gabrielle Dunn, Tracy Bingham, and Desiree Osgood.
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References |
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