|Year : 2013 | Volume
| Issue : 1 | Page : 26-32
Intrathecal clonidine for perioperative pain relief in abdominal hysterectomy
Debjyoti Dutta1, Chhandasi Naskar1, Rita Wahal2, VK Bhatia2, Vinita Singh2
1 Department of Anesthesiology, College of Medicine and JNM Hospital, Kalyani, West Bengal, India
2 Department of Anesthesiology, King Georges Medical University, Lucknow, India
|Date of Web Publication||10-Jul-2013|
26K, Seven Tanks Lane, Kolkata- 700 030
Source of Support: Financial and material support - KGMU, Conflict of Interest: None
Background: Two different doses of intrathecal clonidine with hyperbaric bupivacaine fentanyl combination is compared in women undergoing abdominal hysterectomy to get best beneficial effects with minimal incidence of side effects/complications. Methods: 90 patients undergoing abdominal hysterectomy under spinal anesthesia, were randomized to 3 groups, BFC0: received 3 ml hyperbaric bupivacaine 0.5% + 25μg fentanyl, BFC30: received 3 ml hyperbaric bupivacaine 0.5% + 25μg fentanyl + 30μgm clonidine and BFC60: received 3 ml hyperbaric bupivacaine 0.5% + 25μg fentanyl + 60μgm clonidine. Time to reach peak sensory levels, sensory and motor regression times, intraoperative pain score and time for first analgesic requirement, hemodynamic changes, fluid and vasopressor requirement were recorded. Results: Addition of clonidine has not increased the rapidity of spread of sensory block to T4. Duration of motor block and time to regression to L1 is significantly less in BFC0, (167.78±25.09min and 213.59±22.99min respectively) compared to BFC30 (248.33±26.07 min and 297.33±25.96 min respectively) and BFC60 (260.18 ± 47.64min and 306.43±44.76min respectively). In patients of BFC0 intraoperative vas score (1.3±1.2) was significantly higher and demanded analgesics earlier (241.3 ± 27.76 min) compared to others. Fall in BP was observed in a dose dependent manner. Conclusions: Adding small doses of clonidine to bupivacaine-fentanyl combination improves the quality of perioperative analgesia in a dose dependent manner. However, 60μg clonidine shows significant hemodynamic changes. Hence, 30μg of intrathecal clonidine added to bupivacaine (15mg) fentanyl (25μg) combination is the preferred choice.
Keywords: α2-adrenoreceptor agonist, clonidine, intrathecal adjuvants, spinal anesthesia
|How to cite this article:|
Dutta D, Naskar C, Wahal R, Bhatia V K, Singh V. Intrathecal clonidine for perioperative pain relief in abdominal hysterectomy. Indian J Pain 2013;27:26-32
|How to cite this URL:|
Dutta D, Naskar C, Wahal R, Bhatia V K, Singh V. Intrathecal clonidine for perioperative pain relief in abdominal hysterectomy. Indian J Pain [serial online] 2013 [cited 2020 Mar 30];27:26-32. Available from: http://www.indianjpain.org/text.asp?2013/27/1/26/114863
| Introduction|| |
Spinal anesthesia is the most common approach for abdominal hysterectomy. Pain is often experienced during abdominal surgery performed under regional anesthesia. Alahuhta, et al showed that pain during surgery was recorded in nearly half of patients with epidural or spinal anesthesia. Similarly, Pedersen, et al demonstrated that, although the incidence of abdominal pain decreased with increasing doses of bupivacaine (10-12.5 vs 7.5- 10 mg), almost one third of patients experienced pain.
One disadvantage with spinal anesthesia using bupivacaine alone is the relatively short duration of action, which means that early analgesic intervention was needed in the postoperative period. Another disadvantage although infrequent is intraoperative nausea during exteriorization of uterus and during putting uterine clamps. The addition of fentanyl to hyperbaric bupivacaine increases the intraoperative and early postoperative quality of subarachnoid block Hunt, et al Addition of opioids to the local anesthetic solution has disadvantages like pruritus and respiratory depression.
Clonidine hydrochloride is an imidazoline derivative with α2 adrenergic agonistic activity. It prolongs the duration of intrathecally administered local anesthetics. Niemi, et al Racle, et al. The optimal dose in adults in terms of effects versus side effects of intrathecal clonidine by itself is controversial Elia, et al.  In the dose range of 150-450 μg, clonidine causes marked sedation Filos, et al and because of this clinically relevant side effect, there is a tendency toward the use of smaller doses (<150 μg). Clinical research using clonidine in the dose range of 15-75 μg, however, has focused primarily on labor analgesia. Sia, et al Owen, et al Gautier, et al D'Angelo, et al. The α2 adrenergic agonists also enhance analgesia from intraspinal opioids. In animals, the interaction is found clearly synergestic when both drugs are administered intrathecally.
There are only a few clinical studies testing such doses in combination with intrathecal opioids, in surgical procedures Dobrydnjov, et al Juliao, et al Sites, et al. The most effective dose of intrathecal clonidine with fentanyl for abdominal hysterectomy is not yet known. To achieve high quality perioperative analgesia of consistently prolonged duration is the goal of present study. Provided the intrathecal additive used has an acceptable side effect profile. The aim of this study was to evaluate and compare two different doses of intrathecal clonidine with hyperbaric bupivacaine fentanyl combination in a prospective randomized double blind fashion in women undergoing abdominal hysterectomy.
| Materials and Methods|| |
After getting institutional research and ethics committee approval, an informed written consent was taken from the patient for this prospective, double blind, randomized control study.
The patients were recruited from a group of 124 possible candidates. 34 patients were excluded at initial evaluation as per exclusion criteria. Exclusion criteria were; patient's refusal for consent, contraindication for spinal anesthesia, patient on analgesic or steroid therapy for past one month and hypersensitivity to study medications.
Ninety females aged 30-60 years belonging to ASA physical status I or II, undergoing abdominal hysterectomy under spinal anesthesia, with ±20% ideal body weight and height. Patients were randomized to one of three groups using a computer-derived random-number sequence and sealed opaque envelopes.
After an overnight fast ringer lactate 10ml/kg body weight was infused before the intrathecal injection over 15 minutes to preload the intravascular compartment. A midline spinal puncture was performed at L3/4 (at L2/3 if for an anatomical reason it was not possible at L3/4) with the patient in the sitting position using a 25-gauge pencil point spinal needle (Pancan, B.Braun, Melsungen, Germany). The patients were randomized into following three groups using a computer derived random number sequence and sealed opaque envelops.
Group 1(BFC0): Patients received 3 ml hyperbaric bupivacaine 0.5% + 25μg fentanyl + 0.5 ml distilled water.
Group 2(BFC30): Patients received 3 ml hyperbaric bupivacaine 0.5% + 25μg fentanyl + 30μgm clonidine in 0.5 ml distilled water.
Group 3(BFC60): Patients received 3 ml hyperbaric bupivacaine 0.5% + 25μg fentanyl + 60μgm clonidine in 0.5 ml distilled water.
Patients were monitored for Heart rate, electrocardiogram, noninvasive arterial blood pressure and peripheral oxygen saturation. The hemodynamic data was recorded at the baseline there after it was performed at 15, 30, 45, and 60 min in the first hour and every hour up to 12 h and 3 hourly for the next 24 hours post operatively after intrathecal drug injection.
Analgesia was evaluated every 5 minutes using pin prick method at each dermatomal level with 23 gauge hypodermic needle and surgery was allowed to proceed when a T4 upper level was consistently obtained. The time to onset of highest level of block was recorded. Intraoperatively, pain score was observed every 5 minutes using a 0 to 10 cm visual analogue pain scale (VAS) in which 0 represents no pain and 10 represents unbearable pain. The use of VAS has been explained to each patient before surgery. Duration of analgesia was evaluated by measuring the time of regression to two segments and the time interval between intrathecal injection and regression of the sensory block below L1 and it was monitored by pin prick method by a 25-G hypodermic needle every 10 minutes after 1 hour. Time for next analgesic (iv/im) requirement for pain was noted.
Motor block was evaluated every 5 min during surgery and every 15 min postoperatively by using the Bromage scale (0 = no motor block to 3 = complete motor block of both lower limbs).
A decrease in systolic blood pressure (SBP) more than 20% from the baseline was treated with i.v. fluid and SBP less than 90 mmHg was treated with mephentermine 6mg i.v. boluses. IV ondansetron 4 mg was administered to all the patients5 minutes before spinal anesthesia. Heart rate <55/min or <25% of the baseline value was decided to be treated with IV boluses of atropine 0.6 mg. Oxygen supplementation was given if SpO2 falls below 95%. Age, weight, height, and duration of surgery were recorded. In addition data collected included hemodynamic comparison, additional i.v. fluid (after preloading) and total mephentermine requirement.
The anesthetist who performed the spinal puncture was not present with the patient for rest of the duration of operation. The anesthetist assessing hemodynamic profile, motor and sensory block was blinded to the dose used and was not present during the spinal puncture and therefore unaware of group allocation.
The collected data was subjected to statistical analysis. The power of study was predetermined. The sample size of minimum 20 patients per group was based on the assumption that an increase of 60 min in the duration of spinal anesthesia and an increase of 30% in the time interval from spinal anesthesia to the first request for supplemental analgesia would be detected (α=0.05; β= 0.8), both of which were considered clinically meaningful. Unless stated otherwise, data is being expressed as mean ± SD and analyzed using one way analysis of variance. For a contingency table, nominal categorical data among the groups were compared using chi-square analysis. Probability value (P) < 0.05 was considered statistically significant.
| Results|| |
Among ninety patients, data from 5 patients were not analyzed because of conversion to general anesthesia 3 in BFC0 group and 1 in BFC60 group and 1 patient of BFC60 group requested for withdrawal at the time of anesthesia. Two patients in group BFC0 were supplemented with i.v. ketamine and nitrous oxide and two patients (one from BFC0 and other from BFC60) required endotracheal intubation due to surgical prolongation. This left 85 patients (Group BFC0 n = 27, Group BFC30 n = 30, Group BFC60 n = 28).
The demographic data and duration of surgery did not differ between the three study groups [Table 1]. The differences between the groups in the mean times to reach T4 sensory block (group BFC0, 7.074±2.81min; group BFC30, 6.93±2.42min; group BFC60, 6.93±2.39 min) did not reach statistical significance (P >0.05). The duration of motor block and time to regression to L1 sensory level is significantly less in group BFC0, (167.78±25.09 min and 213.59±22.99 min respectively) compared to group BFC30 (248.33±26.07 min and 297.33±25.96 min respectively) and Group BFC60 (260.18 ± 47.64min and 306.43 ± 44.76min respectively) but the difference between BFC30 and BFC60 in not significant [Table 2]. In patients of BFC0 intra operative vas score (1.3 ±1.2) was significantly higher and they demanded analgesics earlier (241.3 ± 27.76 min) when compared to Group BFC30 and BFC60. But the differences in intra operative vas score and the time to first supplementary analgesic between group BFC30 (0.2 ± 0.48 and 326.33 ± 27.23 min respectively) and group BFC60 (0.07 ± 0.26 and 334.29 ± 42.66 min respectively) was statistically non significant. [Table 3]
|Table 3: Intra operative vas score and time to fi rst supplementary analgesic|
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To maintain hemodynamic stability patients of groups BFC30 (1383.33 ± 239.37 ml) and BFC60 (1425 ± 279.72ml) required significantly more i.v. fluid than patients of groups BFC0 (1101.85±194.38 ml). Vasopressor was required in 13, 17 and 24 patients of BFC0, BFC30 and BFC60 groups respectively. Mean dose of mephentermine required in group BFC0 (n=27) was 6.22 mg, 7.20 mg in group BFC30 and 15.21mg in group BFC60. The difference was statistically significant between group BFC60 compared to both BFC0 and BFC30. But the difference between BFC0 and BFC30 was not significant. [Table 4]
|Table 4: I.V. Fluid requirement after preloading and requirement of vasopressor|
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Changes in systolic blood pressure (SBP) Diastolic Blood Pressure (DBP) and Heart Rate (HR) shows there was significant difference in SBP between groups BFC0 and BFC60 at 15 min, SBP was significantly lower in group BFC60 compared to BFC0 and BFC30 from 30 min to 5 hours. From 6 hour onwards there was no significant difference in SBP between the groups, [Figure 1] DBP was significantly lower in group BFC60 compared to BFC0 and BFC30 from 15 min to 6 hours. From 7 hour onwards there was no significant difference in diastolic blood pressure between the groups [Figure 2] HR were comparable between the three groups throughout the intra and post-operative periods [Figure 3].
|Figure 1: Comparison of changes in systolic blood pressure in different groups|
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|Figure 2: Comparison of changes in diastolic blood pressure in different groups|
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Nausea/ Vomiting was noted in 2, 3 and 3 cases of BFC0, BFC 30 and BFC60 group respectively. Pruritus was noted in 4, 3 and 3 cases of BFC0, BFC 30 and BFC60 group respectively. Shivering was noted in 4, 2 and 4 cases of BFC0, BFC 30 and BFC60 group respectively. There is no incidence of any bradycardia, respiratory depression or excessive sedation in any of the groups. Analyzing the above data, there was no statistically and clinically significant difference in incidence of side effects among the groups. Hence groups are comparable in terms of incidence of side effects. [Table 5]
| Discussion|| |
Intrathecal lipophilic opioids (e.g., fentanyl and sufentanil) are already in use as adjuncts to local anaesthetics. They enhance spinal anesthesia without prolonging motor recovery and discharge time Chilvers, et al. But increasing dose of intrathecal fentanyl increases the side effects like pruritus and respiratory depression. Liu, et al found that the addition of 20 μg of fentanyl intrathecally led to pruritus in all patients. Therefore we feel the need of additional adjuvant for pronging spinal anaesthesia, for patients, undergoing abdominal hysterectomy.
The commonly used doses in the range of 150-300 μg were arbitrarily chosen; a real dose-response study for intrathecal clonidine has not been performed in humans. Marked decrease in arterial blood pressure (BP) was observed with 75μg of intrathecal clonidine (in combination with intrathecal morphine) Grace, et al whereas relative hemodynamic stability was maintained with doses >150 μg, as demonstrated by using clonidine as a sole analgesic. However, in the dose range of 150-450μg, clonidine causes marked sedation Filos KS, et al. Because of this clinically relevant side effect, there is a tendency toward the use of smaller doses (<150 μg). Such doses of clonidine producing only minimal side effects would be a true alternative to other technical or pharmacological procedures aimed at prolonging spinal anesthesia and analgesia. Sia, et al Paech, et al and there are only a few clinical studies testing such doses, often in combination with intrathecal opioids, in surgical procedures Dobrydnjov, et al Juliao, et al
Our results showed that addition of 30μg or 60μg of clonidine in bupivacaine fentanyl has not increased the rapidity of spread of sensory block to T4 dermatome, this result is in accordance with the study done by Racle JP, et al although the dose of clonidine added by them was much higher i.e. 150 μg with 15 mg bupivacaine.
Time required for regression of sensory block to L1 dermatome is significantly prolonged with clonidine(30μg or 60μg), Kaabachi et al also showed that very small amounts of intrathecal clonidine 2μg/kg increased the duration of pain-free interval compared with only spinal local anaesthetics without causing significant side effects. Bonnet, et al and Strebel et al also shown that small doses of intrathecal clonidine (150μg) significantly prolong the anaesthetic and analgesic effects of bupivacaine in a dose-dependent manner. Addition of clonidine therefore increases the duration of sensory block in a dose dependent manner.
We found significant increase in the duration of motor block in addition of clonidine. This result is in accordance with the study done by Juliao, et al although they used lower dose of clonidine i.e. 15 μg of clonidine plus 5 μg of sufentanil with 15 mg of bupivacaine. Addition of clonidine dose dependently increases the duration of motor block.
Mean intraoperative VAS score was significantly reduced in bupivacaine-fentanyl-clonidine 30μg and bupivacaine-fentanyl-clonidine 60μg group compared to bupivacaine-fentanyl group. Benhamou, et al also found similar result. In their study addition of clonidine 75 μg and fentany1 12.5 μg with bupivacaine 0.06 mg/cm of body height reduced the intraoperative pain score to 2 ± 1 mm compared to 23 ±7 mm with same dose of bupivacaine with placebo. Addition of clonidine therefore definitely improves the quality of pain relief in dose dependent manner. Increasing the dose of clonidine definitely improves the quality of analgesia as evident by reduced VAS score.
Mean time of request for supplemental analgesia is also significantly increased in our study by addition of clonidine, Strebel et al also found that first request for supplemental analgesia was significantly delayed by addition of clonidine in 18mg bupivacaine. They used 37.5μg, 75μg, and 150μg of clonidine and the prolongation was dose dependent.
After spinal anesthesia statistically and clinically significant reduction in systolic blood pressure from baseline is observed for up to 4 hours in bupivacaine fentanyl group and bupivacaine-fentanyl-clonidine 30μg group and up to 6 hours in bupivacaine-fentanyl-clonidine 60μg group. Maximum fall was 20% at 30 minute in bupivacaine fentanyl group and bupivacaine-fentanyl-clonidine 30μg, whereas in bupivacaine-fentanyl-clonidine 60μg group a maximum fall of 30% is observed at 30 minutes. SBP was significantly lower in bupivacaine-fentanyl-clonidine 60μg group for up to 5 hours. Significant reduction in diastolic blood pressure from baselines was observed up to 3 hours in bupivacaine-fentanyl and bupivacaine-fentanyl-clonidine 30μg group, whereas with bupivacaine-fentanyl-clonidine 60μg, significant reduction in mean DBP was of longer duration, i.e. up to 6 hours after spinal anesthesia. Maximum fall was 14% at 15 minute in bupivacaine fentanyl group and 10% at 15 minute in bupivacaine-fentanyl-clonidine 30μg, whereas in bupivacaine-fentanyl-clonidine 60μg group a maximum fall of 22% is observed at 30 minutes. Mean diastolic blood pressure was also significantly lower in bupivacaine-fentanyl-clonidine 60μg group compared to both bupivacaine-fentanyl group and bupivacaine-fentanyl-clonidine 30μg group from 15 min to 6 hours. Grace et al showed a significant decrease of mean arterial BP with 75 μg of intrathecal clonidine (albeit in combination with 0.5 mg of intrathecal morphine). But Racle JP, et al have observed no significant change in hemodynamic variables with 150 μg clonidine, Fogarty et al reported relative cardiovascular stability with using intrathecal clonidine in a dose of 75-100 μg although they did not add opioids with clonidine. In our study significantly decreased systolic and diastolic pressure in bupivacaine-fentanyl-clonidine 60 μg groups is observed probably due to co-administration with fentanyl. Combining α2-adrenergic receptor agonists with fentanyl and local anaesthetics potentially increase the degree of sympatholysis and result in hypotension. Strebel et al also recorded a significant fall of diastolic blood pressure. They used 37.5μg, 75μg, and 150μg of clonidine with 18mg bupivacaine. Statistically significant decrease in diastolic BP was observed in 37.5μg clonidine group at 0.5 h, 2 h, 3 h, and 4 h, in 75μg clonidine group at 1 h, 2 h and 3 h, and in 150 μg clonidine group at 3 h and 6 h. Addition of clonidine results in fall of both systolic and diastolic blood pressure. Fall of blood pressure was significantly raised by increasing the dose of intrathecal clonidine in our study.
We did not find any statistically significant difference in change in mean heart rate among the groups at any time interval. Juliao, et al found no statistically significant difference in intraoperative heart rate, although they used lower dose of clonidine i.e. 15 μg of clonidine plus 5 μg of sufentanil with 15 mg of bupivacaine. Neither addition nor the increase in dose of the intrathecal clonidine changed the heart rate significantly.
We found significantly higher additional fluid requirement in bupivacaine-fentanyl-clonidine 30μg group and bupivacaine-fentanyl-clonidine 60μg group compared to bupivacaine fentanyl group. Therefore more fluid was required to compensate for hypotension caused by the addition of clonidine. Bonnet, et al used colloid solution for maintenance of blood pressure and recorded an increased colloid requirement in group containing 150μg and 15 mg of 0.5% hyperbaric tetracaine, although they did not added opioid. We also observed significantly higher vasopressor requirement in bupivacaine-fentanyl-clonidine 60μg group compared to other two groups. In a similar study Juliao, et al found no difference in ephedrine requirement, as they used lower dose of clonidine i.e. 15 μg of clonidine plus 5 μg of sufentanil with 15 mg of bupivacaine. Strebel, et al used 37.5μg, 75μg, and 150μg of clonidine with 18mg bupivacaine. They found that total IV ephedrine administration was not statistically different among the groups. Therefore we can infer that addition of clonidine up to 30μg with bupivacaine-fentanyl combination did not increased the requirement of vasopressure but addition of higher dose i.e. 60 μg of clonidine increased the vasopressure requirement in our study.
Incidence of side effects like purities, nausea / vomiting, shivering, respiratory depression and sedation are similar among the groups.
| Conclusion|| |
Adding small doses of clonidine (30μg or 60μg) to bupivacaine-fentanyl combination further improves the quality of perioperative analgesia in a dose dependent manner. However, 60μg clonidine intrathecally shows significant hemodynamic changes, hypotension for up to 6 hours which therefore requires additional fluid and vasopressure to maintain blood pressure. Hence, 30μg of intrathecal clonidine added to bupivacaine (15mg) fentanyl (25μg) combination is the preferred choice in terms of beneficial effects vs. side effects, for prolongation of spinal anesthesia.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]