A comparative study on effect of addition of clonidine and fentanyl as adjuvants to local anaesthetics for subarachnoid block in patients undergoing lumbar laminectomies.

BACKGROUND: The synergism between local anesthetic agents such as bupivacaine with intrathecal adjuvants such as opioids and clonidine is well established. AIMS: This study evaluates the clinical efficacy of clonidine75 μg versus fentanyl 25 μg as adjuvants to bupivacaine for spinal anesthesia. SETTINGS AND
DESIGN: A prospective, randomized, parallel arm study was conducted over a period of 12 months in a tertiary care hospital.
MATERIALS AND METHODS: Sixty patients were divided randomly into two groups, Group C and Group F. Patients in Group C received 2.5 ml of 0.5% bupivacaine heavy mixed with 0.5 ml (75 μg) clonidine intrathecally, and patients in Group F received 2.5 ml of 0.5% bupivacaine heavy mixed with 0.5 ml (25 μg) fentanyl intrathecally. STATISTICAL ANALYSIS: Data were analyzed using statistical tests for comparison of means.
RESULTS: The mean durations of sensory block was 253.3 and 249.6 minutes in group C and group F respectively, which was statistically not significant (P = 0.76). The mean durations of motor block were 302.3 and 293.6 min, respectively, in Group C and Group F, which were also statistically not significant (P = 0.53). The mean durations of postoperative analgesia were 653.4 and 611.2 min, respectively, in Group C and Group F, which were statistically not significant (P = 0.09). Mean heart rate after 10 min was 82.5 in Group C and 87.2 in Group F, which was statistically not significant (P = 0.29), and mean arterial pressure in mmHg after 10 min was 96.3 in Group C and 97.3 in Group F, which was also statistically not significant (P = 0.86).
CONCLUSION: Both clonidine 75 μg and fentanyl 25 μg when used as adjuvants to bupivacaine in the subarachnoid block have comparable beneficial results in terms of duration of analgesia, duration of motor blocks, and hemodynamic stability and also have a comparable incidence of complications.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

General anesthesia is the technique of choice for lumbar laminectomies; however, other alternatives include spinal or epidural anesthesia. Several studies have shown that spinal anesthesia is as safe and effective as general anesthesia for patients undergoing lumbar laminectomy.[1] The potential advantages of spinal anesthesia include decreased antiemetic and analgesic requirements and fewer complications. Spinal anesthesia avoids many of the deleterious physiological consequences of the prone position, which are seen under general anesthesia. Spinal anesthesia may reduce blood loss as an effect of decreased peripheral venous pressure. The use of spinal anesthesia has lower incidence of pulmonary complications compared with general anesthesia. Spinal anesthesia also allows the patient to position their extremities and chest as needed to avoid brachial plexus palsy or pressure necrosis.[2]

The characteristics of block after spinal anesthesia are influenced by several factors including position of the patient during and after the injection of the spinal anesthetic solution, physical properties of cerebrospinal fluid, injection technique, dose and density of spinal anesthetic solution. The addition of adjuvants to local anesthetics has gained widespread popularity mainly due to decrease in the incidence of side effects of local anesthetics and increased duration of sensory and motor blockade seen with addition of adjuvants.[3]

Clonidine, a centrally acting α2 agonist, when administered into subarachnoid space has been shown to produce dose-dependent analgesia without side effects of ventilatory depression, pruritus, nausea, and vomiting. It, however, has side effects of sedation, bradycardia, and hypotension. Fentanyl, which has strong agonist action on µ opioid receptors, has been shown to increase the intensity and duration of spinal anesthesia when used as an adjunct. The aim of the study is to compare the effects of clonidine 75 µg and fentanyl 25 µg on onset, level, duration, and quality of sensory and motor blocks when added to hyperbaric 0.5% bupivacaine for subarachnoid block (SAB).

MATERIALS AND METHODS

A prospective, randomized, parallel arm study was conducted over a period of 12 months in a tertiary care hospital, with prior permission from the Institutional Ethics Committee. Eighty-six continuous patients undergoing elective lumbar laminectomy were assessed for eligibility to be included in the study. Informed consent was taken from all the patients after describing the purpose of the study and explaining the anesthetic procedure in detail. The patients undergoing lumbar laminectomy, aged more than 18 years of either sex or body weight of 50 kg and above and the American Society of Anesthesiologists (ASA) physical status of I or II, were included in the study. Patients who were unwilling for the procedure, ASA physical status III and above, patients with a history of allergy to local anesthetics, bleeding disorders, or patients on anticoagulant therapy were excluded from the study.

Sixty patients, who met the inclusion criteria, were divided randomly into two groups, Group C and Group F [Figure 1]. Randomization was carried out by drawing any one of the two labeled cards (Groups C and F) from a sealed opaque envelope. Patients in Group C received 2.5 ml of 0.5% bupivacaine heavy mixed with 0.5 ml (75 µg) clonidine intrathecally, and patients in Group F received 2.5 ml of 0.5% bupivacaine heavy mixed with 0.5 ml (25 µg) fentanyl intrathecally. The total volume of solution administered in the subarachnoid space was 3 ml in both groups.

Figure 1

CONSORT flow diagram

In the operation theater, monitors were connected, and baseline parameters such as heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), respiratory rate (RR), oxygen saturation (SpO2), and electrocardiograph were monitored, and a secure intravenous (IV) line was established. 15 ml/kg of IV crystalloid solution was administered as a preload, and a SAB was performed under aseptic precautions with a 25-gauge Quincke's spinal needle. After intrathecal drug administration, the patient was made to lie in the supine position. The patient was turned prone for the surgery after confirming complete motor and sensory block.

The study parameters were recorded in the intraoperative period, and the patients were followed up in the postoperative period until the regression of the motor and sensory block. Intraoperative HR, SBP, DBP, MAP, RR, and SpO2 were recorded at an interval of every 2 min for the first 30 min and thereafter at an interval of every 5 min until the end of surgery.

Sensory block was evaluated by Hollmen scale and recorded at an interval of every 2 min until the complete sensory block was achieved. Onset time of sensory block was taken as the time interval from the time of administration of SAB till sensory block, with a Hollmen score of 1, was achieved. Time for complete sensory block was taken as the duration of time in minutes from SAB till complete sensory block, with a Hollmen score of 4, was achieved. The total duration of sensory block was taken as the duration from onset of sensory block to the time when a Hollmen score of <4 was recorded in the postoperative period.

Motor block was evaluated using modified Bromage score for lower extremity, and the finding was recorded every 2 min from SAB till complete motor block was achieved. Onset time of motor block was taken as the time interval in minutes from SAB to the time, a modified Bromage score of 1 was achieved. Time for complete motor block was taken as the duration of time in minutes from SAB till complete motor block, with a modified Bromage score of 3, was achieved. Total duration of motor block was taken as the duration of time in minutes from onset to the time when a modified Bromage score of <3 was recorded in the postoperative period.

The maximum level of sensory block was also noted. The quality of SAB was recorded as “adequate” when the patient experienced total comfort and “inadequate” when there was patient discomfort, which required supplementation with analgesic agents. Block was considered as “failed” if complete sensory and motor block was not achieved even after 30 min.

All the patients were given IV midazolam 1 mg, and the level of sedation was assessed regularly. The duration of surgery was recorded, and intraoperative complications were noted.

Postoperatively, the patients were monitored for vital parameters, Hollmen score for sensory block, modified Bromage score for motor block, and visual analog scale (VAS) score for pain, every hour until the complete regression of sensory as well as motor block was achieved. When VAS score for pain was recorded more than 4, the patient was given systemic analgesics. Other complications such as neurological deficit were noted till the time of discharge.

Data was analyzed with statistical software ‘IBM SPSS Statistics for Windows, Version 20.0. (Armonk, NY: IBM Corp)’ and Chi square tests were applied for categorical variables and continuous variables were compared using one-way ANOVA test. Data are expressed in terms of mean and standard deviation. P value was reported at the 95% confidence interval, and only P < 0.05 was considered statistically significant. Sample size was calculated based on literature search for variation in studied data. The sample size was calculated using effect size of 5, with alpha error at 5% and power at 80%. As per the calculated sample size, thirty patients per group were included in the study.

RESULTS

Out of total sixty patients, majority of the patients were in the age group of 51–60 years in both groups. The mean age was 54.8 years in Group C and 54.7 years in Group F, which was statistically not significant. The mean weights of patients were 60.9 and 64.5 kg and mean heights were 166.5 and 166.1 cm in Group C and Group F, respectively, and were statistically not significant [Table 1]. Both groups were comparable with respect to age, sex, and ASA grade distribution.

Table 1

Comparison of demographic profile

The mean onset of sensory block was 3.23 and 3.69 min in Group C and Group F while complete sensory block was achieved in 10.1 and 10.6 min, respectively, which was statistically not significant (P = 0.09). The total mean durations of sensory block were 253.3 and 249.6 min in Group C and Group F, respectively, which were again statistically not significant (P = 0.76) [Table 2].

Table 2

Comparison of sensory block

The mean onset periods of motor block were 3.27 and 3.0 min in Group C and Group F and the time to complete motor block were 12.8 and 13.2 min in Group C and Group F, respectively. The differences in onset and time to complete motor block were statistically not significant. The total duration of motor block was 302.3 and 293.6 min, respectively, in Group C and Group F. The differences in total duration of motor block were statistically not significant (P = 0.53) [Table 3]. Most of the patients had achieved height of sensory block up to T10 level by 15 min [Table 4]. The quality of SAB was “adequate” in all cases, with no “failed” blocks.

Table 3

Comparison of motor block

Table 4

Comparison of level of block

Total mean durations of surgery were 100.0 and 103.5 min, respectively, in Group C and Group F. The mean duration of postoperative analgesia, with VAS score for pain <4, was 653.4 and 611.2 min, respectively, in Group C and Group F [Table 5]. There was no statistically significant difference between the two groups when the mean duration of postoperative analgesia was compared (P = 0.09).

Table 5

Comparison of duration of surgery and post operative analgesia

Mean HR after 10 min was 82.5 in Group C and 87.2 in Group F. Difference in the mean HR after 10 min was statistically not significant in the two groups (P = 0.29). Mean MAP in mmHg after 10 min was 96.3 in Group C and 97.3 in Group F. Mean MAP after 10 min was not statistically significant in the two groups (P = 0.86). Differences in mean HR and MAP were statistically not significant in the two groups, even at 30 and 60 min after SAB [Table 6]. There were no episodes of tachypnea or hypoxemia among the patients in any of the groups.

Table 6

Comparison of heart rate and mean arterial pressure

Hypotension (decrease of MAP > 20%) was noted in three patients (10%) in Group C and three patients (10%) in Group F. Complaints of postoperative nausea and vomiting were noted in five patients (16.6%) in Group C and three patients (10%) in Group F. No other complications in the intra-operative and post-operative period such as bradycardia, shivering, and pruritus were observed in any of the patients.

DISCUSSION

Decompressive laminectomies of the lumbar spine have been practiced extensively both under general or central neuraxial blockade. The advantages of using general anesthesia for lumbar laminectomies include the ability to carry out prolonged operations in the prone position, with adequate airway control. Alternatively, the advantages of spinal anesthesia are, decrease in intraoperative blood loss and consequently improved operative conditions, decreased postoperative hypoxemic episodes, decreased arterial and venous thrombosis, lesser incidence of brachial plexus injury and pressure necrosis, and better postoperative pain control.[45]

Opioids and α2 agonists are used as adjuncts to SAB to improve the quality of block, quality of anesthesia, and prolongation of analgesia in the postoperative period. Efficacy of intrathecal opioid to relieve visceral pain and somatic pain is well established.[67] Antinociceptive action of clonidine also exists for both somatic and visceral pain. Clonidine being a lipophilic drug, it is possible to achieve analgesia, with its systemic, epidural, or intrathecal administration. However, clonidine is more potent after neuraxial than systemic administration, indicating a spinal site of action.[8]

Literature search reveals that different studies have used different doses of clonidine, ranging from 15 to 200 µg intrathecally. Chiari et al. reported dose-dependent analgesia when 50–200 µg clonidine was administered intrathecally as sole an agent in labor. They found that risk of hypotension is higher with use of higher doses.[9] The studies with higher doses of 2 µg/kg body weight of clonidine added to 0.5% hyperbaric bupivacaine for spinal anesthesia in children shows that intrathecal clonidine 2 µg/kg body weight is associated with extended duration of postoperative analgesia, but with moderate side effects.[10] Based on the review of literature, doses of 15–37.5 µg were shown to be effective for surgeries requiring early ambulation or for elderly patients. Most studies with doses of 100–200 µg reported minimal to moderate side effects of clonidine. Hence, a dose of 75 µg of preservative-free clonidine as an adjuvant to intrathecal bupivacaine for spinal anesthesia was chosen for this study.

Fentanyl, a highly lipophilic opioid, has been combined with bupivacaine for SAB. The synergism between intrathecal local anesthetic agents and opioids such as fentanyl is well established. Various doses from 10 to 30 µg have been used intrathecally for labor and postoperative pain relief for lower abdominal surgeries.[1112] Lower doses do not enhance postoperative analgesia and doses higher than 30 µg cause mild to moderate side effects such as pruritus. Hence, a dose of 25 µg fentanyl for intrathecal administration was chosen for this study.

Clonidine is available as 150 µg/ml, and fentanyl is available as 50 µg/ml solution. Hence, clonidine 75 µg in 0.5 ml and fentanyl 25 µg in 0.5 ml solutions have been chosen, to be added directly to the local anesthetic, without any dilution, thus maintaining sterility.

In this study with clonidine 75 µg in 0.5 ml and fentanyl, 25 µg in 0.5 ml as adjuvants to SAB with bupivacaine, the difference in onset of sensory block, onset of motor block, and time to complete sensory and motor block were statistically not significant. The total duration of analgesia was also statistically not significant with the use of either adjuvant.

Singh et al. studied the effect of oral clonidine 200 µg and intrathecal fentanyl 10 µg on the onset and duration of hyperbaric tetracaine-induced spinal block.[13] In their study, intrathecal fentanyl 10 µg did not change the onset or duration of tetracaine-induced spinal block. However, oral clonidine 200 µg shortened the onset time of tetracaine's sensory block and prolonged the duration of sensory and motor block. However, clonidine premedication increased the risk of hypotension and bradycardia. However, in our study 75 µg clonidine and 25 µg fentanyl were administered intrathecally, and no difference was observed in complication rate in intra-operative and post-operative period between the two groups.

Islam et al. compared the complications, quality of anesthesia, and duration of postoperative analgesia with the use of adjuvant clonidine 75 µg or fentanyl 25 µg with hyperbaric bupivacaine in SAB for cesarean section.[14] The study revealed that subarachnoid clonidine and fentanyl, as adjuvant with low-dose hyperbaric bupivacaine, provides better quality of block, better quality of anesthesia, more hemodynamic stability, and longer duration of postoperative analgesia, compared to bupivacaine alone. It is also revealed that clonidine is a better alternative to fentanyl as an adjuvant with bupivacaine in SAB. However, in this study, we found that both clonidine 75 µg and fentanyl 25 µg as adjuvants to bupivacaine in SAB have comparable results in terms of duration of motor and sensory blocks and duration of analgesia.

Baseline hemodynamic parameters were also comparable, and no significant difference was observed between groups. Hypotension was the only intraoperative complication, which was treated with fluids. No major complications in the postoperative period were observed in any of the patients. Respiratory depression, the serious side effect of opioid administration, was not observed, possibly due to the dose of opioid used. In addition, bradycardia, a potential risk of clonidine administration, was not observed.

This study was conducted on patients undergoing lumbar laminectomies, and most of the patients had achieved height of sensory block up to T10 level. The quality of SAB was “adequate” in all cases. Hence, both clonidine 75 µg and fentanyl 25 µg, when used as adjuvants to bupivacaine in SAB, will also be beneficial to patients undergoing not only lumbar laminectomies but also any infraumbilical surgery. Both the adjuvants at these doses can be used interchangeably with each other for their beneficial effects, without encountering complications of either drug.

CONCLUSION

Both clonidine 75 µg and fentanyl 25 µg when used as adjuvants to bupivacaine in SAB have comparable results in terms of duration of motor and sensory blocks and duration of analgesia. This study was conducted on patients undergoing lumbar laminectomies; however, both clonidine and fentanyl at these doses, when used as adjuvants to bupivacaine in SAB, will be beneficial to patients undergoing any infraumbilical surgery.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.