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ORIGINAL ARTICLE
Year : 2021  |  Volume : 15  |  Issue : 1  |  Page : 81-86  

Comparison of oral versus intramuscular clonidine for prolongation of bupivacaine spinal anesthesia in patients undergoing total abdominal hysterectomy


1 Department of Anesthesia and Critical Care, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Anesthesia and Critical Care, Tirthanker Mahaveer Medical College and Research Centre, Moradabad, Uttar Pradesh, India

Date of Submission15-Jun-2021
Date of Acceptance29-Jun-2021
Date of Web Publication30-Aug-2021

Correspondence Address:
Dr. Manoj Tripathi
Department of Anesthesia and Critical Care, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aer.aer_84_21

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   Abstract 

Background: Clonidine is a commonly used agent for premedication through oral, intravenous, and intramuscular route. Very few studies mentioned intramuscular clonidine as premedication. Aims and Objectives: The aim of the present study is to compare oral and intramuscular clonidine as predication agent in bupivacaine spinal anesthesia patients. Materials and Methods: In our study, recruited patients were randomly allocated in three groups of 32 each. All patients received intrathecal bupivacaine heavy 3 mL with oral 150 μg clonidine in Group 1, intramuscular 150 μg clonidine in Group 2, and oral placebo tablet in Group 3 1 h before taking the patient in operation theater. We have assessed for duration of sensory block, duration of motor block, duration of analgesia, sedation score, and hemodynamic changes in groups. Statistical Analysis: The parametric data were expressed as mean ± standard deviation. Primary analysis of parametric data between the two groups was done by student's t-test, and among three groups, analysis of variance was used. Results: Duration of motor block was found significantly high in Group 2 than Group 1 (208.06 ± 9.48 vs. 200.25 ± 9.42; P < 0.05). Duration of sensory block was also found significantly high in Group 2 than Group 1 (219.69 ± 9.44 vs. 210.25 ± 9.68; P < 0.05). Time to give first dose of analgesia was also found greater in Group 2 than Group 1 (234.66 ± 11.76 vs. 217.75 ± 10.09; P < 0.05). Sedation score and other side effects were found statistically nonsignificant between Group 1 and 2. Conclusion: We can conclude that preoperative intramuscular clonidine is a better alternate of oral clonidine for bupivacaine spinal anesthesia in terms of long duration of motor and sensory block and less requirement of analgesic with clinically insignificant side effects.

Keywords: Bupivacaine, clonidine, duration of sensory block, Ramsay sedation score


How to cite this article:
Mishra S, Gogia P, Singh P, Tripathi M, Yadav S, Malviya D. Comparison of oral versus intramuscular clonidine for prolongation of bupivacaine spinal anesthesia in patients undergoing total abdominal hysterectomy. Anesth Essays Res 2021;15:81-6

How to cite this URL:
Mishra S, Gogia P, Singh P, Tripathi M, Yadav S, Malviya D. Comparison of oral versus intramuscular clonidine for prolongation of bupivacaine spinal anesthesia in patients undergoing total abdominal hysterectomy. Anesth Essays Res [serial online] 2021 [cited 2021 Dec 6];15:81-6. Available from: https://www.aeronline.org/text.asp?2021/15/1/81/325036


   Introduction Top


Hysterectomy is very common surgical procedure undergone by women in India. Total abdominal hysterectomy (TAH) is performed for malignant as well as benign indications such as uterine leiomyoma, persistent vaginal bleeding, or pelvic organ prolapse. TAH is associated with a medium-to-high pain level. Few decades back TAH was performed under general anesthesia;[1] however, general anesthesia provides effective intraoperative analgesia, muscle relaxation, and unawareness; yet it contributes to unfavorable postoperative symptoms such as postoperative nausea and vomiting, fatigue, and drowsiness. In recent years, regional blocks such as spinal, epidural, and a combination of spinal epidural blocks with general anesthesia have gained widespread acceptance.

Clonidine, an α-2 adrenergic agonist that produces analgesia through a nonopioid mechanism, is used as an adjuvant in regional anesthesia in various settings.[2],[3] However, most of the studies have focused on the use of clonidine as an admixture during spinal anesthesia itself, and there are limited studies on other routes. Oral clonidine premedication is convenient and has additional benefit of subsiding anxiety as well as potentiating the anesthetic effect of spinal bupivacaine apart from enhancing its analgesic action.[4],[5],[6],[7],[8] Researchers say that oral route is preferred over other routes as it has a better compliance owing to avoidance of a potential needle prick. Evaluation of intramuscular route of clonidine for postoperative analgesic efficacy has been done in only a limited number of studies.[9],[10]

Primary objective of the present study was to compare the efficacy of oral versus intramuscular clonidine as an adjuvant to bupivacaine for prolongation of duration of sensory and motor block in patients undergoing TAH under subarachnoid block. Secondary objective was to compare hemodynamic parameters, sedation, analgesia, and adverse effects between the groups.


   Materials and Methods Top


This is a prospective interventional randomized double-blinded study conducted in the department of anaesthesiology of a tertiary care center over 18 months from August 2019 to February 2021. Approval for the study was obtained from the institutional ethics committee. This study was followed the ethical principles for medical research involving human subjects according to the Helsinki Declaration 2013. All the patients were informed regarding the procedure and about the anesthetic agents used in the study and were allowed to raise queries regarding the same. Consent of each patient was obtained before inclusion in the study.

Inclusion criteria

The American Society of Anesthesiologists (ASA) physical status Classes I and II, age group of 40–65 years, patients scheduled to undergo TAH under spinal anesthesia.

Exclusion criteria

Patient's refusal for spinal anesthesia/enrollment in the study, patients with cardiovascular disease, renal failure, hepatic dysfunction and chronic pulmonary disease, obesity (body mass index ≥30), bleeding disorders (platelet count <50,000/mm3), infections at site of block, history of allergy, or sensitivity to any of the study drug.

As shown in [Flow Chart 1], a total of 96 patients were enrolled in the study, who were further randomly allocated into three groups of 32 patients each. Randomization was done using computer-generated tables.



  • Group 1 – Bupivacaine 0.5% (heavy) 3.0 mL and premedication oral clonidine 150 μg
  • Group 2 – Bupivacaine 0.5% (heavy) 3.0 mL and premedication intramuscular clonidine 150 μg
  • Group 3 – Control group: Bupivacaine 0.5% (heavy) 3 mL and premedication 1 oral placebo tablet.


We have blinded participants as well as resident doctor, who was observing and noting data of analysis. Preanesthetic checkup was done, and patients were assessed the night before surgery. Patients were kept nil orally from midnight. Tablet alprazolam 0.5 mg and tablet ranitidine 150 mg orally on the night before surgery were advised. Patients were shifted to preoperative room on the morning of surgery. Groups 1, 2, and 3 patients were given oral clonidine 150 μg, intramuscular clonidine 150 μg, and oral placebo tablet, respectively, 1 h before taking the patient inside operation theater. On arrival of patients in the operation theater, intravenous (i.v.) access was secured with an 18G cannula. Standard monitors such as pulse oximeter, noninvasive blood pressure (NIBP), and 5-lead electrocardiogram were attached, and baseline readings were recorded. All patients were preloaded with 10 mL.kg−1 of Ringer's lactate. Heart rate (HR), NIBP, respiratory rate (RR), and peripheral oxygen saturation (SpO2) were monitored throughout the surgery. The surgeries were carried out under spinal anesthesia using midline approach at L3–L4 level in sitting position with 3 mL of 0.5% bupivacaine heavy. HR, NIBP, RR, and peripheral SpO2 were monitored throughout the surgery. Sensory blockade was assessed using pin prick. After achieving the sensory block, up to T6 dermatome level and motor block of 3 on Bromage scale surgery was allowed to begin. Motor block was assessed immediately after sensory block assessment using Modified Bromage score [Table 1]:
Table 1: Modified Bromage scale

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Recovery time for sensory blockade was defined as dermatome regression of anesthesia from the maximum level to T12. Motor block duration was the time for return to Bromage scale score of “0.” Time to highest sensory block level and recovery times of both sensory and motor block were recorded. HR, NIBP, RR, and peripheral SpO2 were recorded. The recordings were noted at various intervals T0 – preoperatively, just before administration of drug; T1 – just before spinal anesthesia; T 2 – 5 min after administration of drug; and T3 and so on – every 5 min thereafter till the end of surgery. Time to first analgesic dose requirement was noted. Assessment was based on visual analog scale (VAS) score on 0–10 scale, 0 represents no pain and 10 represents worst pain. First complaint of pain (VAS >4) in the postoperative period was recorded, and injection paracetamol 15 mg.kg− 1 body weight i.v. was given as rescue analgesic. Hypotension (defined by a decrease in mean arterial pressure below 20% of baseline or systolic blood pressure (BP) <90 mmHg) was treated by injection mephentermine 6 mg i.v. stat. bradycardia (HR <50 bpm) was treated by injection atropine 0.6 mg i.v. stat. Respiratory depression (RR <8 breaths per min or SpO2 <95%) was managed by oxygen supplementation and respiratory support if required. We have also assessed sedation by Ramsay Sedation Score (RSS) at start of operation (TS0), after 1 h (TS1), 2 h (TS2), and 4 h (TS4) of start. Patients having sedation score of ≥2 were considered sedated. Postoperatively, patients were also observed for the occurrence of nausea, vomiting, and other side effects such as headache, dizziness, visual disturbances, and somnolence were also recorded. Patients were asked to rate their nausea on a four-point scale of none, mild, moderate, and severe. i.v. ondansetron (4 mg i.v.) was given if the patients had moderate or severe nausea or an episode of vomiting.

Statistical analysis

Sample size calculation

Sample size (N) was calculated by following formula-

  • Sample Size (N) = (Zα/2 + Zβ)212+ σ22)/(μ1−μ2)2
  • Zα/2 = Level of significance, we are taking 95% level of significance = 1.96
  • Zβ =0.84 for 80% power of study
  • σ1 = Standard deviation (SD) of Group 1
  • σ2 = SD of Group 2
  • μ1 = Mean of Group 1
  • μ2 = Mean of Group 2.


We have taken reference of study by Dziubdziela et al., in which oral and intramuscular clonidine had shown the prolongation of sensory block (216.2 ± 69.4; vs. 254.2 ± 76.8) in comparison to control. By calculating with the above formula, the sample size comes out to be n = 32 in each group.

The statistical analysis was done using SPSS 23.0 version (Chicago, Inc., USA) statistical Analysis Software. The parametric data were expressed as mean ± SD. Primary analysis of parametric data between the two groups was done by student t-test, and among three groups, analysis of variance was used. For continuous variables and for categorical variables, the Chi-square test was used for analysis. A P < 0.05 was considered statistically significant and a P > 0.05 was considered statistically nonsignificant.


   Results Top


In the present study, we had compared among the groups with regard to demographic variables such as age, weight, and other variables such as ASA physical status classes, duration of surgery, and baseline hemodynamic variables and found no statistically significant difference (P > 0.05) [Table 2]. HR of patients of above three groups was comparable at all the periods of observation except at T1–T5 and at T11 and T12. It was observed that HR of patients of Group III was significantly higher as compared to that of Group 1 and Group 2, and mean HR of patients of Group 2 was significantly lower as compared to Group 1 at different time intervals. Mean BP of patients of Group 3 was found significantly higher than Group 1 and 2 at different time periods (P < 0.05). As shown in [Table 3], no significant difference of onset of motor block was found among the groups (P > 0.05). On comparison of onset of sensory block, highly significant difference was found among groups (P < 0.001), while no significant difference was found between Group 1 and 2. As shown in [Table 3], difference in duration of motor block among patients of above three groups was found to be highly significant (P < 0.001). Duration of motor block was found significant statistically between Group 1 and 2, 2 and 3, and 1 and 3, and it was highest in Group 2. Similarly duration of sensory block was also found highly significant among the groups (P < 0.001), and it was found highest in Group 2 that is significantly higher than Group 1. We have also compared the time of first requirement of analgesic and difference in time of requirement of first analgesia among patients of above three groups and were found to be statistically highly significant (P < 0.001). It was found significant statistically between Group 1 and 2, 2 and 3, and 1 and 3, and it was found highest in Group 2 [Table 3]. We have also assessed sedation score by RSS. At all time periods, statistically highly significant difference was found among the groups (P < 0.001) [Table 4]. No significant difference was found between Group 1 and 2 at all time periods, while highly significant difference was found between Group 1 and 3 and 2 and 3. As shown in [Table 5], we have not found any incidence of hypotension or respiratory depression in any patient. On comparing bradycardia among groups, it was found statistically significant (P < 0.05). While no significant difference was found between Group 1 and 2. On comparing nausea and vomiting among groups, no significant difference was found (P > 0.05).
Table 2: Comparison of demographic variables

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Table 3: Comparison of parameters between the groups

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Table 4: Comparison of Ramsay sedation score among groups

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Table 5: Comparison of side effects among groups

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   Discussion Top


Clonidine, an α-2 adrenergic agonist produces analgesia through a nonopioid mechanism, is being successfully used as intrathecal, oral, or i.v. adjuvant to spinal anesthesia with each route being preferred for its different characteristics. As far as intramuscular route is concerned, there are only a few researchers who attempted to evaluate its efficacy in patients undergoing lower limb or under abdomen surgeries; however, there are no exclusive studies conducted on its efficacy among patients undergoing TAH. Hence, the present study was carried out with an aim to compare the efficacy of oral versus intramuscular clonidine as an adjuvant to bupivacaine for prolongation of duration of sensory and motor block in patients undergoing TAH under subarachnoid block. We had planned a placebo-controlled randomized clinical trial. The reason behind conducting the placebo-controlled clinical trial was to assess the benefit of intramuscular clonidine against a placebo as well as against a well-established modality that is oral route. The dose selection was done keeping in view patient safety into consideration. A number of previous studies have used 150 μg oral clonidine and did not report any substantial side effect.[6],[11],[12],[13] The dose of 150 μg has also been tested by Bonnet et al.[14] for intramuscular route and has been found to be suitable for prolonging the block duration without causing substantial increase in side effects.

In the present study, in both the intervention groups, a significant decline in HR was observed between baseline and just before spinal anesthesia, whereas in placebo group, there was a significant increase in HR during that period. One of the reasons for this could be the anxiolytic effect of clonidine. In fact, a number of researchers have used oral clonidine for the purpose of anxiolysis.[15],[16],[17] As far as intramuscular clonidine is concerned, it is also known to cause bradycardia.[14],[18] In the present study, though both oral as well as intramuscular routes showed reduction in HR, yet it was more pronounced in intramuscular group but not found significant in comparison to oral clonidine. These findings are similar to the observations made by Dziubdziela et al.,[18] who also observed that intramuscular clonidine produced bradycardia in significantly higher proportion of cases as compared to that of oral route. In the present study, after the administration of atropine, the HR was normalized in both the intervention group and remained comparable to placebo group throughout the study period after T5 (20 min postspinal anesthesia induction) interval.

Mean BP of patients of Group 3 was found significantly higher than Group 1 and 2 at almost all time periods (P < 0.05). However, none of these differences converted into hypotensive or hypertensive events in any of the three groups under study. Bacsik et al.[19] and Harjai et al.[20] in their study reported hypotension in both controls and cases of oral clonidine (100 μg) group when systolic BP was <30% of baseline but did not find a significant difference between cases and controls. Dziubdziela et al.,[18] on the other hand, found incidence of hypotension to be greater in intramuscular as compared to control group. However, in the present study, no such hypotensive event was noted in any of the study groups. The difference between two studies could be owing to difference in study protocol. In their study, they had premedication of midazolam 0.1–0.15 mg.kg−1 1 h before anesthesia and oral and intramuscular dosages were given at the time of surgery only. Moreover, in their study, patients received 10–20 mg of 0.5% hyperbaric bupivacaine, whereas in the present study, fixed dose of 3 mL 0.5% bupivacaine was used.

In the present study, no significant difference in onset time of motor block was observed among different groups; however, sensory block onset was earlier in oral and intramuscular clonidine group as compared to placebo. Clonidine is known to have a rapid onset of action.[21]

In the present study, duration of both sensory and motor block durations was maximum in intramuscular clonidine group followed by oral clonidine group and minimum in control group. Statistically, these differences had significant too. Bonnet et al.[14] in their study found that both 75 μg and 150 μg intramuscular clonidine prolong the duration of sensory and motor blockades. With respect to difference in intramuscular and oral routes, the findings in the present study are in agreement with the observations made by Dziubdziela et al.,[18] who observed that intramuscular route had an edge over oral route with respect to duration of sensory and motor blocks.

In the present study, analgesic effect of oral and intramuscular clonidine groups was similar as observed for duration of blocks. It was observed that first rescue analgesic need was earliest in control group (mean: 204.44 min) followed by oral clonidine (mean: 217.75 min) and latest in intramuscular clonidine group (mean 234.66 min). Thus, as compared to control group, the oral clonidine group was able to prolong the analgesic effect by 6.5%, while intramuscular clonidine group was able to prolong this effect by 14.8%. Statistically, these differences were significant. Thus, addition of clonidine oral or intramuscular route helped to manage postoperative pain for a significantly longer time. However, as far as difference between oral and intramuscular routes is concerned, the single study comparing the two routes[18] did not report any significant difference. However, in the present study, the analgesic effect was 16.91 min longer in intramuscular group as compared to oral clonidine group and was found statistically significant.

We had also compared sedation by RSS at start of surgery, 1 h, 2 h, and 4 h after surgery. RSS was found highest in Group 2, and among groups, it was found highly significant. However, RSS in Group 2 was not significantly high than Group 1. We fairly know that clonidine has sedative properties when given either by oral, i.v. or intramuscular route. That is why RSS is found significantly high in both clonidine groups than control group. We have a number of studies, which suggest increased sedation due to oral clonidine. Dziubdziela et al.[18] concluded in his study that intramuscular clonidine intensifies sedative properties of midazolam. They have used midazolam also as premedication.

In the present study, no significant difference in events of nausea, and vomiting was observed among the three groups under the study. None of the previous studies have also reported any such additional impact on the incidence of nausea and vomiting either for oral clonidine or for intramuscular clonidine groups. Hypotension and respiratory depression was not found in any patient.


   Conclusion Top


We can conclude that preoperative intramuscular clonidine is a better alternate of oral clonidine for bupivacaine spinal anesthesia in terms of long duration of motor and sensory block and less requirement of analgesic with clinically insignificant side effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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