Effects of adding low-dose clonidine to intrathecal hyperbaric ropivacaine: A randomized double-blind clinical trial.

BACKGROUND: Clonidine added to bupivacaine prolongs the duration of anesthesia and postoperative analgesia with minimal side effects. Ropivacaine has lower lipid solubility and better safety profile as compared to bupivacaine. This study is designed to evaluate the effects of low-dose clonidine when added to hyperbaric ropivacaine.
MATERIALS AND METHODS: Ninety patients belonging to American Society of Anesthesiologists-I scheduled for lower limb or lower abdominal surgeries under spinal anesthesia were randomly allocated into three groups (n = 30). Group R: 0.5% hyperbaric ropivacaine 12 mg + saline, Group 15C: 0.5% hyperbaric ropivacaine 12 mg + 15 mcg clonidine and Group 30C: 0.5% hyperbaric ropivacaine 12 mg + 30 mcg clonidine for spinal anesthesia in a total volume of 3.2 ml. Block characteristics, hemodynamic parameters, and side effects were monitored.
RESULTS: Addition of low-dose clonidine to hyperbaric ropivacaine, significantly prolongs the duration of sensory and motor blockade as well as postoperative analgesia compared with placebo (mean ± standard deviation min; 152.50 ± 15.3, 246 ± 23.5, and 217 ± 37.73, respectively with 15 mcg clonidine, 193 ± 16.59, 284 ± 23.28, and 234.83 ± 36.45, respectively with 30 mcg clonidine, 131 ± 14.7, 211.5 ± 24.39, and 192.33 ± 37.02, respectively with saline). The addition of low-dose clonidine significantly increases the incidence of intra-operative hypotension (46.7% and 83.3%, respectively compared to 16.7%), bradycardia (6.7% and 23.3%, respectively compared to 0%).
CONCLUSIONS: Addition of low-dose clonidine to intrathecal hyperbaric ropivacaine causes a significant prolongation of the duration of sensory and motor blockade as well as postoperative analgesia compared with saline placebo. However, it increases the incidence of hypotension and bradycardia which can be managed with routine clinical measures.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Spinal anesthesia is used extensively for lower abdominal and lower extremity surgeries. Bupivacaine, the most commonly used local anesthetic agent for spinal anesthesia, is a racemic mixture with higher lipid solubility. Ropivacaine is structurally similar to bupivacaine but is a single S-enantiomer with a propyl side chain replacing the butyl group. The smaller side chain of ropivacaine contributes to less lipid solubility, less toxicity and better safety profile with an increased separation of sensory and motor blockade compared to bupivacaine[1] (a phenomenon described as differential blockade). However, the time of onset of rest pain at the surgical site and the duration of motor block is significantly shorter with ropivacaine spinal anesthesia. The duration of sensory block with ropivacaine is two-thirds and the duration of motor block is half when compared with bupivacaine. Most of the studies conducted previously have used ropivacaine as an isobaric solution, which could result in unpredictable block characteristics as compared to a hyperbaric solution.[12] By making the ropivacaine hyperbaric, the block characteristics might become more predictable similar to hyperbaric bupivacaine. Clonidine, when added as an adjuvant to hyperbaric bupivacaine as part of spinal anesthetic, has been shown to decrease the time to onset of block, increase its depth and duration, decrease the amount of bleeding from the surgical field, and provide prolonged postoperative analgesia.[345]

Clonidine added to isobaric ropivacaine in epidural anesthesia has been shown to increase the intensity of blockage and provide longer duration of analgesia.[678] Literature search did not reveal any studies of hyperbaric ropivacaine with clonidine as an adjuvant in spinal anesthesia. This study evaluates the characteristics of sensory and motor blockade and duration of analgesia with the addition of two different doses of clonidine (15 mcg and 30 mcg) to hyperbaric ropivacaine (0.5%) spinal anesthetic and their side effects.

MATERIALS AND METHODS

This study is a randomized double-blinded placebo controlled study on ninety patients who were undergoing lower limb or lower abdominal surgery, conducted after obtaining approval by the Institutional Research and Ethics Committee (JIP/IEC/SC/1/2012/9).

Patients aged between 20 and 60 years with American Society of Anesthesiologists physical status grade 1 were included in the study after obtaining valid informed written consent from them; those with contraindications for spinal anesthesia, known allergy to the study drugs, pregnancy, and short stature (<140 cm), were excluded [Figure 1].

Figure 1

CONSORT statement for the present study

Patients were allocated into one of the following groups by computer generated random numbers to receive a total volume of 3.2 ml of intrathecal drugs: Group R (hyperbaric ropivacaine 12 mg), Group C15 (hyperbaric ropivacaine 12 mg + 15 mcg clonidine) and group C30 (hyperbaric ropivacaine 12 mg + 30 mcg clonidine). Hyperbaric ropivacaine 0.5% was prepared by adding 1 ml of 25% dextrose to 2 ml of 0.75% isobaric ropivacaine.

Sample size was calculated using OpenEpi software (opensource.org, version 3.03a), with power of 80% and confidence interval of 95%, based on findings in the study by Sagiroglu et al.,[9] in which times to two-segment regression were 96.60 ± 14.20 min with 1% ropivacaine 12 mg and 111.00 ± 19.84 min with 1% ropivacaine 12 mg + clonidine 15 μg and 119.20 ± 18.47 min with 1% ropivacaine 12 mg + clonidine 30 μg.

In the operating room, continuous monitoring of electrocardiogram, noninvasive blood pressure, and oxygen saturation was established; IV cannula secured and the patient preloaded with 15 ml/kg body weight of Ringer's lactate solution. The patient was positioned in left lateral position and under aseptic precautions lumbar puncture was done using 25-gauge Quincke needle in the midline at the L3-L4/L2-L3 space. The drug was injected at a rate of 0.2 ml/s After turning the patient supine, the following parameters were noted by independent anesthesiologists who were not involved in the study; sensory blockade characteristics noted were: Maximum level of sensory block, time to achieve maximum height of sensory block, time to two-segment regression of the sensory block, time for the height of sensory block to reduce to T10 and L1 levels, time to first sensation of pain, and time to first analgesic requirement. Motor blockade characteristics noted were: Maximum motor block level, time to achieve maximum motor block, and duration of the motor block. Intra-operative side effects noted were: Hypotension, bradycardia, sedation, respiratory depression, nausea, and shivering. Postoperative side effects noted were: Headache, backache and transient neurological symptoms (TNS). Motor block was assessed using modified Bromage score; sedation scoring was done every 15 min throughout the study using Ramsay sedation scale.

A decrease of more than 30% from the baseline value of mean arterial pressure (MAP) or below 90 mm of Hg systolic blood pressure (SBP) was considered as hypotension and was treated with mephentermine 3 mg IV. A decrease in heart rate (HR) below 50 beats/min was considered as bradycardia and atropine 0.4 mg IV was administered. Total doses of mephentermine and atropine used were recorded. Any additional analgesia or induction of general anesthesia required were noted, along with the time at which it was required. The independent investigator at the end of surgery judged the overall quality of intra-operative analgesia as excellent (no discomfort or pain), good (mild pain or discomfort, no need of additional analgesic), or poor (moderate or severe pain that require more than 100 mcg of fentanyl or general anesthesia). Time to eliciting first pain sensation (complete analgesia) and time to first request of analgesics (effective analgesia) were noted. During postoperative visits over the next 3 days, patients were evaluated for possible side effects including headache, back pain, and TNS.

Statistical methods

The Statistical software namely SAS 9.2 (SAS Institute Inc. Cary, NC, USA) and SPSS 16.0 (SPSS Inc., Chicago) were used for the analysis of the data. Descriptive and inferential statistical analysis was carried out in the present study. Results on continuous measurements were presented as mean ± standard deviation (SD) (minimum − maximum) and results of categorical measurements were presented as number (%). Significance was assessed at 5% level of significance. Analysis of variance was used to find the significance of study parameters between three or more groups of patients. Chi-square/Fisher's exact test was used to find the significance of study parameters on categorical scale between two or more groups.

RESULTS

The three groups were comparable with respect to age, sex, weight, height and baseline pulse, and SBP [Table 1].

Table 1

Demographic characteristics

Time taken to reach spinal segment T10 sensory level was significantly (P = 0.002) less in Group 30C (6.53 ± 2.02) compared to Group 15C (8.27 ± 1.36) and Group R (7.40 ± 2.11). Maximum block height achieved was T4 in all three groups, minimum block height was T8 and median block height was T6. Time to maximum block was significantly shorter with Group 30C (10.07 ± 2.82) compared to Group 15C (12.03 ± 2.68) and Group R (11.53 ± 3.34) [Table 2].

Table 2

Block characteristics (mean±SD)

The time to regression by two-segment was significantly longer in Group 30C compared to Group 15C and Group R; Group 15C also had significantly longer two-segment regression time compared to Group R. Regression of the block to T10 and L1 took significantly longer with addition of clonidine to hyperbaric ropivacaine, with 30 mcg >15 mcg >control [Table 2]. Regarding motor block, onset was faster, and recovery was delayed with the addition of clonidine [Table 2].

Time to first sensation of pain was significantly longer in both the groups with clonidine compared to control group and between the two study groups, it was longer with 30 mcg clonidine compared to 15 mcg clonidine. The time to first request for analgesic was longer with the addition of clonidine compared to control group. Between the 30 mcg clonidine and 15 mcg clonidine groups, time to first request for analgesic was not significantly different [Table 3].

Table 3

T-pain and request for analgesia

Additional intra-operative analgesia was more likely to be employed in Group R (10.0%) although such differences were not statistically significant when compared to Groups C15 and C30. Two patients in control group required supplementation with analgesic intra-operatively while both groups with clonidine did not require any analgesics intra-operatively [Table 4].

Table 4

Additional analgesic requirement

Ramsay sedation scores were similar in all the three groups with a median of 2. The addition of low-dose clonidine did not cause any significant sedation.

SBP was significantly lower in the 30 mcg clonidine group from 10 min onward till 120 min compared to other two groups. In 15 mcg clonidine group, SBP was significantly lower only up to 60 min compared to the control group. MAP was significantly lower in the 30 mcg clonidine group from 15 min onward till 120 min compared to the other two groups [Figure 2].

Figure 2

Mean arterial pressure changes in study groups

Pulse rate was significantly lower in the 30C Group compared to the 15C Group and the control group from 20 min to 120 min. There was no significant difference in pulse rates between the 15 mcg clonidine group compared to control group [Figure 3].

Figure 3

Pulse rate changes in study groups

The incidence of hypotension and use of mephentermine was significantly more with the addition of clonidine, and it was dose dependent as hypotension was more with 30 mcg clonidine compared to 15 mcg clonidine. Bradycardia and use of atropine were associated with the use of clonidine intrathecally, and it was more with the addition of 30 mcg compared to 15 mcg. The incidence of nausea, vomiting, and shivering during surgery did not differ between the groups. None of our patients had complaints of headache, backache, or TNS [Table 5].

Table 5

Side effects

DISCUSSION

Clonidine is an alpha-2 adrenoceptor agonist, which acts mainly at the level of spinal cord by blocking the conduction through C and A fibers and increases potassium conductance. It has been shown to prolong the duration and improve the quality of analgesia provided by intrathecal-local anesthetics when administered orally,[101112] intramuscularly,[12] intravenously[13] and when added as adjuvant to neuraxial[34678] and peripheral nerve blocks.[14] By making the ropivacaine hyperbaric, the block characteristics become more predictable, and the addition of clonidine is expected to prolong the duration of clinically useful block for surgeries. The present study demonstrates that clonidine when added in low doses (15 µg and 30 µg) to intrathecal-hyperbaric ropivacaine decreases the time taken to reach T10 sensory level, decreases the time taken to achieve maximum block height and increases the duration of spinal anesthesia.

In this study, there was no significant difference in the maximum block height achieved among the three groups (maximum block height - T4, minimum block height - T8, and median block height - T6); this is in keeping with the previous study by Sagiroglu et al.[9] (T8.12 ± 2.51 in control group, T7.16 ± 2.43 in 15 mcg clonidine group and T7.28 ± 2.54 in 30 mcg clonidine group). De Kock et al.[15] achieved a median level of T10 (T4-T12) with isobaric ropivacaine 8 mg, T8 (T4-L3) in isobaric ropivacaine 8 mg with 15 mcg clonidine, and T4 (T3-L2) in isobaric ropivacaine 8 mg with 45 mcg clonidine. Isobaric ropivacaine used in their study would explain this finding compared to our study in which hyperbaric ropivacaine was used.

In our study, there was no significant difference in time to achieve maximum block between both clonidine groups when compared with control group (11.53 ± 3.34 min) separately. Time to maximum block was significantly shorter with 30 mcg clonidine (10.07 ± 2.82 min) compared to 15 mcg clonidine (12.03 ± 2.68 min) when added to hyperbaric ropivacaine; though statistically significant, the values are clinically insignificant. Sagiroglu et al.[9] and De Kock et al.[15] reported that there were no differences between the groups with or without clonidine in terms of time to onset of maximum sensory and motor blocks.

Motor block was achieved faster in 30 mcg clonidine (6.80 ± 1.94 min) group than 15 mcg (9.40 ± 2.66 min) group, and both groups with clonidine achieved motor block faster compared to control group (11.83 ± 3.23 min). De Kock et al.[15] reported no differences in the time to onset of the maximum sensory and motor blocks with isobaric ropivacaine 8 mg with various doses of clonidine (15, 45, 75 mcg). This difference may be due to the use of isobaric ropivacaine instead of hyperbaric ropiovacaine.

The time to regression by two-segment was significantly longer in 30 mcg (157.00 ± 13.49 min) group compared to 15 mcg (124.00 ± 14.17 min) and control group (111.83 ± 14.35 min). Patients who received 15 mcg of clonidine had longer two segment regression time as compared to control group (P < 0.05). Sagiroglu et al.[9] also had similar results with two-segment regression time of 119.20 ± 18.47 min in 30 mcg clonidine group, 111.00 ± 19.84 min in 15 mcg clonidine group, and 96.60 ± 14.20 min in control group. Similar findings were also reproduced in the study by De Kock et al.[15] with two-segment regression time of 75 ± 22 min in control, 90 ± 32 min with 15 mcg clonidine, 96 ± 28 with 45 mcg clonidine and 100 ± 31 min with 75 mcg clonidine. Regression of the block to T10 and L1 took significantly longer with addition of clonidine to hyperbaric ropivacaine, with 30 mcg >15 mcg >control, similar prolongation of the time to regression of the block to S2 was observed in the study by Sagiroglu et al.[9] De Kock et al.[15] also recorded time to reduction of sensory level to S2 and duration of the motor block were significantly longer in the 15 mcg, 45 mcg, and 75 mcg clonidine groups. Sagiroglu et al.[9] reported that the duration of motor block is significantly longer in group with 15 mcg clonidine and group with 30 mcg clonidine compared to control group (P < 0.05). However, there were no significant differences between groups with 15 mcg and 30 mcg clonidine in their study. Sethi et al.[16] also recorded a longer duration for two-segment regression of sensory level and recovery from motor blockade with the addition of 1 mcg/kg clonidine. Similar findings were recorded in studies using bupivacaine with clonidine.[35]

De Kock et al.[15] reported that analgesic use was necessary in 1 patient in the clonidine-free group and two patients in the 15 μg group while there was no need for extra doses of analgesics in the 45 mcg and 75 μg clonidine groups. In our study, only two patients in R Group and none of the patients in the clonidine groups required additional analgesics. The use of hyperbaric ropivacaine instead of isobaric preparation may have led to better blockade in the 15 mcg group in our study. Also in study by Sagiroglu et al.,[9] the need for additional analgesics was diminished in the 30 mcg clonidine group compared to the other groups (16%, 16%, and 8%, respectively). In this study, isobaric ropivacaine was used, which is probably the reason for additional analgesic requirement intra-operatively in all the groups.

Time for first sensation of pain in our study was significantly longer in both groups with clonidine compared to control group (165.17 ± 35.80 min) and also there was significant difference between 30C Group (216.50 ± 28.86 min) and 15C Group (190.00 ± 33.73 min) (P = 0.007). In our study, the time for request for analgesic was longer with addition of clonidine compared to control group, (P < 0.001), but 30 mcg clonidine and 15 mcg clonidine groups had similar time for request for analgesic. (mean ± SD, 234.83 ± 36.45 min and 217.00 ± 37.73 min, respectively with P = 0.158). This is similar to the study by Dobrydnjov et al.,[3] which concluded that increasing the dose of clonidine from 15 to 30 mcg did not increase the duration of analgesia (mean ± SD 274 ± 94 min and 253 ± 71 min). The difference in the actual duration of analgesia between the two studies can be attributed to the different local anesthetic preparation used. The data obtained from the study by Sethi et al.,[16] indicate that addition of 1 mcg/kg of clonidine (much higher dose of clonidine, mean dose of 57.93 mcg) to 0.5% bupivacaine significantly prolongs the analgesia (223 min and 614 min respectively) and thus reduced the postoperative analgesic requirement.

SBP and MAP were significantly lower in both 15 and 30 mcg clonidine groups. Our study findings in this regard are similar to previous studies.[915] The maximum dose of clonidine used in the study by Sethi et al.[16] was 70 mcg along with bupivacaine 12.5 mg 0.5%. Although a statistically significant decrease in MAP and HR was noted in the clonidine group compared to the control group, none of the patients required any therapeutic intervention.

Incidence of hypotension and use of mephentermine were significantly more with addition of clonidine, and it was dose dependent as hypotension was more with 30 mcg clonidine (83.3%) compared to 15 mcg clonidine (46.7%). The previous studies also reported higher requirement of vasopressor drugs in intrathecal-clonidine, which is in agreement with our study results.[9] The maximum sensory level achieved was higher in our study (T6) compared to the study by Sagiroglu et al.[9] (T8), which probably explains the higher requirement of vasopressor in our study.

Bradycardia and use of atropine were associated more often with the use of clonidine intrathecally, and such use was greater with addition of 30 mcg (23.3%) compared to 15 mcg (6.7%) of the drug. This finding is in agreement with the previous studies.[9] Sethi et al.[16] did not report increased requirement of mephentermine or atropine even though 70 mcg clonidine was used with 0.5% hyperbaric bupivacaine. This may have been due to lower volumes of drug used in them (2.5 ml) as compared to our study (3.2 ml).

In our study, the addition of low-dose clonidine did not cause any significant sedation as measured using Ramsay sedation scale. Previous studies reported sedation in 20–53.33% of cases.[91516] The different types of sedation scale and cut-off values used could be the reasons for the differences in the number of patients classified as sedated. No significant respiratory depression was seen in their study, which is similar to our finding. The incidence of nausea, vomiting, and shivering during surgery did not differ between the different groups in our study. None of our patients had complaints of headache, backache, or TNS. There is wide variation with respect to the occurrence of postoperative complications in previous studies, and none of the studies could actually reproduce any kind of pattern that is similar to other studies in this regard.

CONCLUSIONS

The addition of low-dose clonidine to intrathecal hyperbaric ropivacaine causes a significant prolongation of the duration of sensory and motor blockade as well as postoperative analgesia compared with saline placebo. This increased duration could potentially be helpful when a certain surgery gets prolonged beyond its anticipated duration. Further, such effect could extend into the postoperative period and result in better analgesia with reduced need for additional polypharmacy directed at pain relief. Even though 30 mcg clonidine significantly prolonged the duration of sensory and motor blockade compared to 15 mcg clonidine group, the duration of postoperative analgesia was similar between these two groups. However, the addition of clonidine significantly increases the incidence of intra-operative hypotension and bradycardia, which can be easily managed with routine clinical measures.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest