Caudal Levobupivacaine Supplemented with Caudal or Intravenous Clonidine in Children Undergoing Infraumbilical Surgery: A Randomized, Prospective Double-blind Study.

BACKGROUND: Caudal analgesia is the most popular regional anesthesia technique in pediatric population for intraoperative and postoperative analgesia. Clonidine, an α2 agonist, prolongs analgesia without causing significant respiratory depression after systemic or neuraxial administration. However, the most beneficial route of its administration is still controversial. Thus, we compared the effects of caudal and intravenous (i.v) clonidine on postoperative analgesia produced by caudal levobupivacaine in children undergoing infraumbilical surgery.
METHODS: A comparative three group study was carried out in seventy-five pediatric patients who underwent elective surgery for infraumbilical procedures, under general anesthesia with caudal block. Group A (n = 25) received levobupivacaine 0.25% 1 mL/kg caudally and 5 mL of normal saline i.v, Group B (n = 25) received levobupivacaine 0.25% 1 mL/kg with 1 μg/kg clonidine caudally and 5 mL of normal saline i.v, and Group C (n = 25) received levobupivacaine 0.25% 1 mL/kg caudally and 1 μg/kg clonidine in 5 mL normal saline i.v. Postoperative pain was assessed for 24 h using the Children and Infants Postoperative Pain Scale Score. Ramsay sedation scale and modified Bromage scale were assessed at predetermined time intervals for sedation and motor blockade, respectively.
RESULTS: The mean duration of postoperative analgesia was significantly longer in Group B (16.68 ± 4.7 h) than in Group A (4.24 ± 1.42) and Group C (9.44 ± 3.88 h): P < 0.001. The number of patients not requiring rescue analgesia in Group B was 5, which was significantly higher than in Group C (one patient) and Group A (zero patient): P < 0.001. No motor blockade or sedation was observed in any of the groups.
CONCLUSIONS: Clonidine in a dose of 1 μg/kg added to 0.25% levobupivacaine for caudal analgesia significantly prolongs the duration of analgesia, without any side effects.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Caudal analgesia is a commonly used and a popular method of regional anesthesia for providing intra- and post-operative analgesia in children.[1] It is a simple procedure with relatively few side effects. However, the duration of action is relatively short even with the use of long-acting local anesthetics such as bupivacaine.[2] In view of this, several adjuvants such as adrenaline, opioids, ketamine, and neostigmine have been added to the local anesthetics to prolong its duration of action.[1] All these agents have their own potential side effects.

Clonidine, an alpha-2 agonist, has been shown to have analgesic effect when administered epidurally.[3] In recent times, clonidine has gained popularity in pediatric anesthesia and is being used increasingly as an adjuvant to local anesthetics for caudal blockade.[4] The analgesic effect of epidural clonidine is not associated with significant respiratory depression, and in the doses normally used in children (1–2 µg/kg), serious adverse effects are rare.[56789]

The α2 receptors, on which clonidine acts, are widely distributed in the central nervous system, with three isoreceptors (α2A, α2B, and α2C) recognized so far.[410] These α2 receptors are found primarily on afferent terminals, both centrally and peripherally. In addition, they are found in the superficial laminae of the spinal cord and in several brainstem nuclei, which are known to be involved in analgesia. These three sites have been demonstrated in animal studies, as potential sites of analgesic action, but their relative clinical importance is still controversial.[410]

Therefore, we designed a prospective, randomized, double-blind controlled study to compare the effects of caudal and intravenous (i.v) clonidine on postoperative analgesia after caudal levobupivacaine in children posted for infraumbilical surgeries,

METHODS

Written informed consent from the parents and approval from the ethics committee were obtained. Seventy-five children aged 2–12 years, ASA physical status I–II, weight between 5 and 20 kg and posted for elective infraumbilical surgeries were recruited to the study. Any contradiction for caudal epidural and the study drugs was taken as exclusion criteria. Administration of any analgesic in the past 24 h was also an exclusion criteria.

Patients were randomly allocated to one of the three groups by a computer-generated list and delivered in opaque, sealed numbered envelopes. All children were kept nil orally for standard fasting times. Oral promethazine 1 mg/kg, the night before surgery and in the morning of surgery was used as premidicant. Patients were induced with sevoflurane 8% in oxygen 100% via a facemask or propofol 2–3 mg/kg i.v, if an i.v canula was already present. Infusion of normal saline 5–10 mL/kg/h was started after an i.v line was sited. Maintenance of anesthesia was with oxygen 40% in nitrous oxide, isoflurane 0.5–1.0%, and fentanyl 2 µg/kg i.v. An appropriate sized laryngeal mask airway was inserted in all patients and maintained on spontaneous respiration.

The caudal block was performed using 23-gauge hypodermic needle in the left lateral decubitus position, by an anesthesiologist, who was blinded to the study drug, with aseptic precautions. The study drugs were prepared by an anesthesiologist who did not participate in the study. One milliliter of clonidine (150 µg/mL) was diluted with 9 mL of normal saline in a 10 mL syringe to obtain a concentration of 15 µg/mL. The caudal block was performed by the anesthetist in the left lateral position under due aseptic precautions. After negative aspiration of blood or cerebrospinal fluid, levobupivacaine 0.25%, 1 mL/kg was injected caudally together with or without clonidine 1 µg/kg. Simultaneously, the second syringe containing 5 mL of 0.9% saline with or without clonidine 1 µg/kg was injected intravenously. Heart rate (HR), mean arterial pressure, peripheral oxygen saturation (SpO2), temperature, and end-tidal CO2 were monitored throughout the surgery.

Group A (n = 25) patients received levobupivacaine 0.25% 1 mL/kg caudally and 5 ml of normal saline i.v

Group B (n = 25) patients received levobupivacaine 0.25% 1 mL/kg and 1 µg/kg clonidine caudally and 5 mL of normal saline i.v

Group C (n = 25) patients received levobupivacaine 0.25% 1 mL/kg caudally and 1 µg/kg clonidine in 5 mL normal saline i.v.

In all the three groups, surgery was initiated after 10 min so that caudal block was effective. The intraoperative successful blockade was defined as a hemodynamic response <20% compared with baseline, in response to the surgical stimulation. Hemodynamic response >20% was considered as an inadequate caudal block, and such cases were excluded from the study.

The patients were extubated at the end of procedure, and the duration of anesthesia was noted in all groups. Children were transferred to the recovery room for observation. After emergence from anesthesia, the degree of motor blockade was assessed by modified Bromage scale [Table 1]. Postoperative analgesia was assessed using the Children and Infants Postoperative Pain Scale (CHIPPS) Score [Table 2]. Patients with CHIPPS score ≥4 were given paracetamol 10 mg/kg i.v infusion over 10 min as rescue analgesia. The CHIPPS score was assessed every hourly for the first 10 h, and 2nd hourly till 24 h. The time to the first rescue analgesia was noted which indicated the duration of adequate caudal analgesia. A number of patients not requiring rescue analgesia after caudal block were noted. Sedation was assessed by Ramsay sedation score [Table 3] at the same time intervals. In the postoperative period, patients were also monitored for adverse effects including respiratory depression, nausea, vomiting, hypotension, bradycardia, and urinary retention.

Table 1

Modified Bromage scale

Table 2

Children and Infants Postoperative Pain scale

Table 3

Modified Ramsay sedation scale

Statistical analysis

The sample size required in each group was determined using a power calculation with data obtained from earlier similar studies. Power analysis indicated that a sample size of 25 would be required in each group. All the quantitative variables such as age, weight, surgical duration, etc., were summarized in terms of descriptive statistics such as mean and standard deviation or median and range. All qualitative variables such as postoperative pain scale, variables in sedation scale were expressed in terms of proportion.

Parametric data were analyzed using one-way ANOVA with the Bonferroni corrections where appropriate. The Kruskal–Wallis test was used to compare CHIPPS pain scores. Chi-square analysis or Fisher's exact test was used to compare the rate and the proportions of patients requiring rescue analgesia.

RESULTS

Seventy-five children were included in the study. Age, weight, and the duration of surgery were comparable among the three study groups [Table 4].

Table 4

Demographics, surgical duration, and types of surgeries

All caudal blocks were judged to be clinically successful based on the lack of a significant intraoperative hemodynamic response to surgical incision. None of the children required additional intraoperative fentanyl dose.

There were no significant changes in the hemodynamic variables throughout the study period. No episodes of hypotension or bradycardia were noted in any of the groups.

The CHIPPS scores of the patients in the groups are shown in Tables 5–7. In Group A, two children had a CHIPPS score of more than 4 by the 2nd h and by the 8th h, all the 25 children had a score of 4 and above and thus received rescue analgesia. In Group B, none of the children had a CHIPPS score of 4 and above till the 10th h. By 12th h, 6 children had a score above 4 and received rescue analgesia. At the end of 24 h, five patients never had a score of 4 and above and never received rescue analgesia. In Group C, CHIPPS score of 4 and above was reached by one child by the 5th h and by 14th h, 24 children had reached a score of 4 and above. Only one child did not receive any rescue analgesia.

Table 5

Children and Infants Postoperative Pain Scale scores of Group A children at different time interval

Table 7

Children and Infants Postoperative Pain Scale scores of Group C children at different time interval

The duration of postoperative analgesia recorded a mean of 16.68 ± 4.7 h in Group B, as compared to 9.44 ± 3.88 h in Group C, and 4.24 ± 1.42 h in Group A, with a P < 0.001 [Figure 1]. There was a statistically significant difference between the duration of analgesia between the A Group and B Group (P < 0.001), A Group and C Group (P < 0.001), and B Group and C Group (P < 0.001). The number of patients requiring rescue analgesia was compared between the three groups, and it was found to be statistically significant (P < 0.001), with five children in Group B not requiring rescue analgesia postoperatively for 24 h, compared to one child in Group C, and none of the children in Group A [Figure 2].

Figure 1

Comparison of the time required for the first rescue analgesia (mean duration of analgesia in hours).

Figure 2

Number of patients not requiring rescue analgesia.

The sedation score was assessed using modified Ramsay sedation scale postoperatively, and most patients of all the groups had sedation score 2. The mean sedation scores in the postoperative period between the groups were comparable and not statistically significant (P > 0.05) [Table 8]. All the patients had a Bromage score of 0 throughout the study period.

Table 8

Mean sedation scores

No episodes of clinically significant postoperative complications such as nausea, vomiting, respiratory depression, urinary retention, pruritus, hypotension, and bradycardia were observed in any of the groups.

DISCUSSION

The main inference from our study is that caudal clonidine prolonged the duration of analgesic effects of caudal levobupivacaine and that the number of patients requiring rescue analgesia was reduced. Our results confirm the findings from a similar study conducted by Akin et al.,[11] who concluded that this effect might be due to the spinal mode of action of caudal clonidine rather than its systemic absorption.

The duration of analgesia in our study, after supplementaion with caudal clonidine, recorded a mean of 16.68 ± 4.7 h. The duration of analgesia observed in other studies varies between 5.8 and 16.5 h.[4567891011] This wide variability might be due to differences in the dose of clonidine and the local anesthetic agents used, use of various premedication, indications for rescue analgesia, drugs used for rescue analgesia, and different scales of pain assessment and different statistical analysis. Other major factor might be due to use of nonstandardized surgeries and anesthetic techniques. We included children undergoing infraumbilical surgeries such as inguinal hernias and hypospadias surgeries and thus not standardized. This was a major limitation in our study.

The α2-adrenoreceptor agonists, administered caudally, have been observed to prolong the motor and sensory block effects of local anesthetics. However, the precise mechanism of action has not been completely clarified. Certain pharmacodynamic and pharmacokinetic mechanisms have been suggested for clonidine-induced prolongation of caudal/epidural analgesia, although the precise one is not yet clarified. It has been suggested that epidural clonidine exerts an analgesic action through its direct suppression of nociceptive neurons in the spinal cord.[5812]

The studies have been reported suggesting that clonidine is more potent after neuraxial than systemic administration, thus suggesting a spinal site of action. A study conducted by De Kock et al.[13] showed that epidural clonidine reduced the analgesic requirements both in intraoperative and early postoperative period when compared with the same dose given intravenously. Bernard et al.[14] in their study demonstrated that caudal clonidine was approximately twice as potent as i.v clonidine. These studies provide indirect evidence that the spinal cord might be the site of analgesic action of clonidine.

On the contrary, there are some studies which show that analgesic effect of clonidine may be due to mechanisms other than by its direct effect on spinal cord. It has been shown by various authors that both oral as well as spinal clonidine prolonged the duration of analgesic effects of clonidine[15] and also that clonidine was equally effective when given intramuscularly or epidurally.[16] This effect might probably be due to the vasoconstriction effect of clonidine, thus reducing the systemic absorption of epidural administered clonidine, Hansen et al.[17] similarly concluded that epidural clonidine was equally as effective as its i.v administration. In their study, they had used a small volume of bupivacaine (0.5 mL/kg), and this volume might have been inadequate to deliver the clonidine up to the spinal cord.

Epidural clonidine has been associated with sedation reflecting systemic absorption and action on higher centers. A delayed sedation might as well as be due to the cephalad migration of the drug in the cerebrospinal fluid. Sedation is a desired effect in most children, thus reducing the requirement of sedatives and anxiolytics in the postoperative period. However, in our study, the mean sedation scores in all the groups were comparable. We used clonidine in a dose of 1 µg/kg1 and this might explain the lack of significant sedation in our study groups. The determination of serum levels of clonidine would have helped in improving our study.

Decrease in HRs and blood pressures have been associated with the use of a higher dose of clonidine (5 µg/kg) caudally.[18] Clonidine in doses below 2 µg/kg has shown not to affect HRs, blood pressure, SpO2 with no side effects such as urinary retention, nausea and vomiting. In our study too, we demonstrated that there was no difference in the groups in terms of these vital signs and other side effects.

CONCLUSION

Caudal clonidine results in increased duration of analgesia when supplemented to levobupivacaine with no increased frequency of side effects. In addition, when compared with i.v clonidine, caudal clonidine had a prolonged duration of analgesia, probably due to its direct effect on the spinal cord. This finding needs further studies to support this mechanism of action.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Table 6

Children and Infants Postoperative Pain Scale scores of Group B children at different time interval