Role of Clonidine as adjuvant to intrathecal bupivacaine in patients undergoing lower abdominal surgery: A randomized control study

Abstract

Background:

Neuraxial anesthesia greatly expands the anesthesiologist armamentarium, providing alternatives to general anesthesia, especially in the lower abdominal surgeries. Clonidine, an alpha-2 adrenergic agonist, has a variety of actions, including potentiation of effects of local anesthetics. This study was undertaken to assess the degree of sensory and motor block and postoperative analgesia provided by low dose (50 mcg) intrathecal clonidine admixed with bupivacaine.

Aims:

The aim of this study is to establish efficacy and safety of intrathecal clonidine as adjuvant to bupivacaine.

Settings and Design:

The type of the study was double-blind randomized trial.

Materials and Methods:

Hundred patients were randomly allocated in two groups, A and B. Group A received bupivacaine 0.5%, 3 ml with placebo (normal saline 0.33 ml) and Group B, bupivacaine 0.5%, 3 ml with clonidine 50 μg (0.33 ml).

Statistical Analysis Used:

Statistical Package for Social Sciences version 15.0 statistical analysis software.

Results:

Mean duration of motor block was significantly higher in Group B (280.80 ± 66.88 min) as compared with Group A (183.60 ± 77.06 min). Significant difference in duration of sensory block was noted between Group B (295.20 ± 81.17 min) and Group A (190.80 ± 86.94 min). Duration of postoperative analgesia was significantly higher in Group B as compared to Group A (551.06 ± 133.64 min and 254.80 ± 84.19 min respectively). Mean visual analog scale scores at different time intervals were significantly lower in the study group (except for 4-h time interval), but the control group had better hemodynamic stability as compared with study group.

Conclusion:

The findings in this study suggested that use of clonidine 50 μg added to bupivacaine for spinal anesthesia effectively increased the duration of sensory block, duration of motor block, and duration of analgesia.

INTRODUCTION

Spinal anesthesia has been used since long to produce sensory analgesia for surgeries below the level of the umbilicus.

Duration of sensory and motor block does not last beyond 2.5-3.0 h with local anesthetic (LA) alone in spinal anesthesia. Many drugs (including opioids) have been used in past to enhance the effect of LAs, but due to catastrophic adverse events, search for an ideal agent continues.[1,2] Intrathecal clonidine has been extensively evaluated as an alternative to neuraxial opioid for control of pain and has proven to be a potent analgesic, free of at least some of the opioid-related side-effects.[2]

Sub-arachnoid block (SAB) is one of the earliest forms of regional anesthetic techniques described.[3] This technique though, suffered a great setback shortly after it was described,[4] is now widely used by anesthetists[5] and clonidine has been introduced with newer hopes.

This study was undertaken to assess the degree of sensory and motor block and postoperative analgesia provided by low dose (50 mcg) intrathecal clonidine admixed with bupivacaine as compared with bupivacaine alone in patients undergoing lower abdominal surgeries.

MATERIALS AND METHODS

After obtaining Ethical Committee approval and written informed consent from patients, we examined the effect of intrathecal bupivacaine with or without clonidine 50 mcg in those patients who were posted for lower abdominal surgeries.

The study was a randomized prospective, double-blind study carried out in 100 adult American Society of Anesthesiologists-I (ASA-I) and ASA-II patients.

Inclusion criteria

• Adult patients aged between 18 and 55

• ASA-I and ASA-II physical status

• Normotensive patient

• Scheduled for elective lower abdominal surgery under SAB

• Patient should remain in hospital for 24 h after surgery.

Exclusion criteria

• ASA Grades III and IV patients

• Patients with significant cardiovascular, renal, hepatic dysfunction

• Morbidly obese patients

• Patients having an allergy to either clonidine or bupivacaine

• Having contraindication to SAB.

Computer generated randomization was done. Patients were allocated randomly in two groups with 50 patients each. Group A received bupivacaine with placebo and Group B, bupivacaine with clonidine 50 μg. This study was conducted at Department of Anesthesiology of Era's Lucknow Medical College, Lucknow over a period of 18 months.

All patients were kept fasting overnight and premedicated with diazepam 5 mg orally night before surgery.

After wheeling the patient into the operation theatre, monitors were attached to the patient and baseline parameters including electrocardiogram, heart rate, arterial blood pressure (noninvasive blood pressure [NIBP]) and O₂ saturation were recorded and noted. Intravenous line was established with wide bore 18 G cannula.

All patients were preloaded with 20 ml/kg of Ringer Lactate 15 min before the intended time of SAB. Patients were randomly allocated to two groups by computer generated randomization.

With all aseptic precaution, SAB was given in L2-L3 interspace in a sitting position. Group A patients received injection bupivacaine 15 mg with normal saline (0.33 ml using insulin syringe) and Group B patients received injection bupivacaine 15 mg with 50 mcg clonidine (0.33 ml using insulin syringe).

Fall in mean arterial pressure (MAP) of >20% from the baseline value was treated with 3 ml aliquots of injection mephentermine. Injection atropine was given in increments of 0.3 mg in case of bradycardia (fall in pulse rate of >20% from the baseline value). Heart rate and NIBP was recorded after every 5 min initially and every 15 min thereafter. After completion of surgical procedure patients were observed in the postoperative ward for degree of postoperative analgesia, postoperative motor block and return of sensory function. Degree of postoperative analgesia was assessed by using the 10-point visual analog scale (VAS) (where 0 denotes no pain and 10 denotes worst imaginable pain)[2] at 1, 2, 4, 6, 12, 18, and 24 h. Postoperative motor block was assessed by using Modified Bromage score.[2] Return of sensory function was assessed by perception of cold using ice packs.

Statistical analysis

Sample size is calculated by using formula:

σ₁ = Standard deviation (SD) of the control group

σ₂ = SD of the experimental group

d = mean SD

α =5%, alpha = level of significance

n = max (n₁, n₂, n₃)

For power 95%

n = 50 per group

For an analysis:

Paired t-test, χ² and odds ratio test were used.

The statistical analysis was done using Statistical Package for Social Sciences version 15.0 statistical analysis software. The values were represented in number (%) and mean ± SD.

Mean, SD, and level of significance were calculated.

RESULTS

Patients were comparable to each other in terms of demographic characteristics [Table 1]. Abdominal hysterectomy was the most common procedure in both groups followed by hernioplasty, vaginal hysterectomy and herniorrhaphy. Among others, ovarian cystectomy, open prostatectomy and appendicectomy were the common procedures. No, statistically significant difference was found in the mean heart rate in both groups. Minimum heart rate in the study group was observed at 55 min after the SAB, while the maximum was observed at 5 min after SAB, whereas in the control group minimum heart rate was observed at 40 min and maximum at 5 min after SAB [Figure 1].

Table 1.

Patient demography

Figure 1.

Comparison of mean heart rate in two groups at different time intervals

At 5 min interval, there was no statistically significant difference in systolic blood pressure (SBP) between two groups. However, there was a gradual decrease in mean SBP in both groups until 50 min. At 50 min and 55 min, a statistically significant difference between two groups was observed showing the mean value of the control group to be significantly higher as compared with the study group (P < 0.05). However, at 60 min time interval, once again the mean SBP of two groups was comparable [Figure 2]. There was statistically significant difference in the mean diastolic blood pressure (DBP) in both groups at 5 min (P = 0.025). However, by 10 min, no statistically significant difference between the two groups was observed. Thereafter, no significant difference between two groups was seen until 45 min. From 45 min onwards, until the end of the follow-up period at 60 min, the mean DBP in the study group was found to be significantly lower as compared with the control group [Figure 3].

Figure 2.

Comparison of mean systolic blood pressure in two groups at different time intervals

Figure 3.

Comparison of mean diastolic blood pressure in two groups at different time intervals

The mean duration of motor block was significantly higher in Group B (study group) (280.80 ± 66.88 min) as compared to Group A (control group) (183.60 ± 77.06 min) [Table 2]. There was also a statistically significant difference in the duration of sensory block between Group B (295.20 ± 81.17 min) and Group A (190.80 ± 86.94 min). The duration of postoperative analgesia was significantly higher in Group B as compared to Group A (551.06 ± 133.64 min and 254.80 ± 84.19 min, respectively). Except for the 4-h time interval, at all the time intervals the mean VAS in the control group was significantly higher as compared to that in the study group [Figure 4].

Table 2.

Duration of action for different landmarks

Figure 4.

Comparison of visual analog scale score

Comparison of the two groups for side-effects did not reveal a statistically significant difference. Both groups were matched for the side-effects nausea, vomiting, and shivering.

Need of vasopressor was observed in 3 (6%) patients of Group B (study group) as compared to none in Group A (control group). The difference between the two groups was not significant statistically.

DISCUSSION

Spinal anesthesia has been used with LA as a sole agent as well as admixed with opioid and LA in labor analgesia and orthopedic surgery.[6,7,8,9]

The alpha-2 adrenergic agonist clonidine has a variety of different actions, including the ability to potentiate the effects of LAs.[10] However, unlike spinal opioids, clonidine does not produce pruritus or respiratory depression.[10,11] It also prolongs the sensory blockade and reduces the amount or concentration of LA required to produce postoperative analgesia.[12] However, intrathecal clonidine at the usual dose (1-2 μg/kg) is associated with bradycardia, relative hypotension, and sedation. The aim of this randomized double-blinded study was to investigate the efficacy and adverse effects of a small dose of intrathecal clonidine added to hyperbaric bupivacaine for patients undergoing lower abdominal surgeries. Bupivacaine is a potent LA with a long duration of action. The amount of LA usually used for spinal anesthesia is larger in relation to the minimum concentration required to block the various types of nerve fibers. Use of smaller doses of bupivacaine reduces the duration of spinal block, but sometimes at the price of a small number of blocked dermatomes. In this study, 3 ml of injection bupivcaine 0.5% was administered to all the patients undergoing SAB.

Our results showed that the addition of a small dose of clonidine increased the duration of sensory block, motor block and duration of analgesia in patients undergoing SAB. Thus, addition of clonidine improved duration of the block and analgesia time.

Clonidine is a selective partial agonist for alpha-2 adrenoreceptors. It is known to increase both sensory and motor block of LA.[13] Since clonidine is a mixed α₁-α₂-adrenergic agonist, high clonidine doses cause peripheral vasoconstriction, which results in a U-shaped hemodynamic dose-response curve.[14] The analgesic effect following its intrathecal administration is mediated spinally through activation of postsynaptic alpha-2 receptors in substantia gelatinosa of spinal cord and it works by blocking the conduction of C and A delta fibers, increases potassium conductance in isolated neurons in vitro and intensifies conduction block of LA.[2] Roh et al.,[15] recently suggested that one of the mechanisms for the enhanced potency of intrathecal clonidine administration in a rat model of neuropathic pain is its ability to modulate spinal cord N-methyl-D-aspartate receptor activation via suppression of NR1 phosphorylation.

A small dose of intrathecal clonidine is not usually associated with systemic side-effects such as bradycardia, hypotension, or sedation.[16]

Accordingly, studies using very low doses of intrathecal clonidine such as 15-30 mcg[2,16] in humans found no hemodynamic instability. Most of studies using 37.5-150 mcg of clonidine intrathecally reported significant hypotension and bradycardia[2,17] while with higher doses of 300 and 450 mcg, relative hemodynamic instability was observed, suggesting a pressor effect on peripheral sites.[18]

The hemodynamic stability of our patients was better maintained in the control group than in the study group comparing the number of patients who needed a vasopressor. This was similar to the findings of Dobrydnjov et al.,[16] where only one patient each in 15 μg and 30 μg group needed vasopressor or atropine. The average percentage fall from the baseline was also comparable in our study.

We did not see statistically significant hypotension in the study group except at 50 min and 55 min, compared to control as far as SBP was concerned. Statistically, significant difference was noted in the study group at 5 min and 45-60 min when compared with the control as far as DBP is concerned, which was in contrast to the findings of Strebel et al.,[19] and similar to the findings of some other authors, such as Niemi,[11] Sethi et al.,[2] and Grandhe et al.,[17] who used higher doses of clonidine.

In this study too, we observed significantly lower mean values for SBP and DBP in the study group as compared to control group at different time intervals.

Duration of motor block was prolonged after the addition of clonidine to bupivacaine. The results were comparable to the studies of Niemi,[11] and Grandhe et al.[17]

Duration of sensory block was also prolonged in the study group. Similar observation were seen in the studies conducted by Niemi,[11] Sethi et al.,[2] and Grandhe et al.[17]

A major finding in this study was the efficacy of the study group to prolong the analgesic effect, which is reflected in longer duration of time for analgesia requirement and lower VAS scores for pain at different time intervals. Intrathecal clonidine clearly increases the duration of both sensory and motor block, as well as postoperative pain relief.[12]

The findings in this study are thus in conformity with the findings of Dobrydnjov et al.[16] who reported that the addition of clonidine 15 and 30 μg to bupivacaine prolonged time to first analgesic request and decreased postoperative pain with minimal risk of hypotension.

Three studies conducted with isobaric bupivacaine and clonidine reported no significant hypotension. The doses used were 75 and 100 μg clonidine with 13.75 mg bupivacaine,[20,21] and 150 μg clonidine with 15 mg bupivacaine.[20] On the other hand, Klimscha et al.,[22] have reported a significant fall of MAP and heart rate after the intrathecal injection of 150 μg clonidine and 5 mg isobaric bupivacaine. These authors argued that the hypotensive effect of clonidine was revealed because a low dose of bupivacaine was used. They hypothesized that when a larger dose of LA is used, the hypotensive action of clonidine is masked by dense axonal blockade produced by the LA. In this study, a 3 ml dose of 0.5% bupivacaine was used in combination with 50 μg of clonidine and three cases of hypotension were reported in the study group as against none in the control group.

De Kock et al.,[23] recommended a dose of 15-45 μg of clonidine as optimal for supplementing spinal anesthesia. In our study, 50 μg clonidine supplementation was compared with placebo. Kaabachi et al.[24] investigated the efficacy and safety of intrathecal clonidine 1 μg/kg in adjunction to bupivacaine in spinal anesthesia in adolescent. The duration of sensory block was the primary outcome measure. They found that clonidine prolonged the duration of both the sensory and motor block.

Saxena et al.,[25] in a study aimed to evaluate the lowest dose of intrathecal clonidine as adjuvant to hyperbaric bupivacaine that would produce maximum benefit with minimum side-effects. The mean time from injection to onset of block was lower, while duration of analgesia and motor blockade was longer in all the clonidine groups. The authors concluded that addition of clonidine to bupivacaine significantly reduces the onset time with increase in the duration of spinal block as compared to bupivacaine alone with 30 μg as optimum dose, which is similar to our study.

CONCLUSION

We hereby conclude that use of clonidine 50 μg added to bupivacaine for spinal anesthesia effectively increases the duration of sensory block, duration of motor block and duration of analgesia.