|Year : 2021 | Volume
| Issue : 4 | Page : 252-259
Clonidine versus dexmedetomidine as premedication to intrathecal 0.5% bupivacaine: A randomized, double-blind, prospective study
Arvind Khare, Beena Thada, Laxmi Narayan Solanky, Veena Mathur, Deepak Garg, Pradeep Kumar
Department of Anaesthesia, J.L.N. Medical College and Hospital, Ajmer, Rajasthan, India
|Date of Submission||20-Apr-2021|
|Date of Decision||29-Aug-2021|
|Date of Acceptance||12-Sep-2021|
|Date of Web Publication||24-Nov-2021|
Dr. Beena Thada
IW/3/7, Behind Isolation Ward, J.L.N. Hospital Campus, Ajmer, Rajasthan.
Source of Support: None, Conflict of Interest: None
Background: Alpha-2‑adrenergic agonists have synergistic action with local anesthetics and may prolong the duration of sensory and motor blockade and postoperative analgesia obtained with spinal anesthesia. The primary objective of this study was to compare the duration of analgesia, and the secondary objectives were to evaluate onset of sensory and motor blockade, perioperative sedation, hemodynamic changes, and adverse effects after intravenous (IV) infusion of clonidine and dexmedetomidine on spinal block characteristics as premedication to intrathecal 0.5% bupivacaine. Patients and Methods: This prospective, randomized, double blind study was conducted on a total of 100 patients belonging to the American Society of Anaesthesiologist class I and II undergoing lower limb and lower abdominal surgeries and were randomly allocated into two groups: Group CN (n = 50) received 1.5 µg/kg clonidine infusion and Group DM (n = 50) received 0.75 µg/kg dexmedetomidine infusion in 100 mL NS over 15 min before spinal anesthesia. Results: The duration of analgesia was statistically significantly prolonged in Group DM (251.70 ± 6.264 min) when compared with Group CN (213.02±10.374 min) (P < 0.001). The onset of sensory and motor blockade was faster in Group DM when compared with Group CN (P < 0.001). Recovery of sensory block was prolonged in Group DM when compared with Group CN (P < 0.001), but recovery of motor block was comparable in both the groups. The hemodynamic parameters were comparable in both the groups without any significant adverse effects. Conclusion: Premedication with IV dexmedetomidine infusion is better than that with IV clonidine infusion to provide intraoperative sedation and postoperative analgesia as premedication with hyperbaric bupivacaine 0.5% spinal anesthesia.
Keywords: Infraumbilical surgeries, inj. clonidine, inj. dexmedetomidine, IV infusion, spinal anesthesia
|How to cite this article:|
Khare A, Thada B, Solanky LN, Mathur V, Garg D, Kumar P. Clonidine versus dexmedetomidine as premedication to intrathecal 0.5% bupivacaine: A randomized, double-blind, prospective study. Bali J Anaesthesiol 2021;5:252-9
|How to cite this URL:|
Khare A, Thada B, Solanky LN, Mathur V, Garg D, Kumar P. Clonidine versus dexmedetomidine as premedication to intrathecal 0.5% bupivacaine: A randomized, double-blind, prospective study. Bali J Anaesthesiol [serial online] 2021 [cited 2021 Nov 28];5:252-9. Available from: https://www.bjoaonline.com/text.asp?2021/5/4/252/330950
| Introduction|| |
Spinal anesthesia is a reliable and safe technique in lower limb and lower abdominal surgeries. It is favorable when general anesthesia is contraindicated or in patients in whom anatomical abnormalities may make tracheal intubation very difficult. Many techniques and drug regimens, with partial or greater success, have been tried from time to time to alleviate anxiety and to prolong postoperative analgesia during regional anesthesia. A number of adjuvants such as midazolam, opioids, and α2-adrenoceptor agonist have been studied in this regard.
Alpha-2-adrenoceptor agonists have both analgesic and sedative properties, when used as adjuvant to regional anesthesia. Clonidine and dexmedetomidine are the two most used drugs. Oral, spinal, and epidural are the various routes of administration of these drugs to prolong the duration of spinal anesthesia.,, They prolong the duration of both motor and sensory blockade and also postoperative analgesia by potentiating the effect of local anesthesia.,
Both spinal and supraspinal mechanisms have been proposed to explain their action. In the spinal cord, stimulation of α-adrenoreceptors at the substantia gelatinosa of the dorsal horn of the spinal cord leads to inhibition of nociceptive neurons. Stimulation of the adrenoreceptors in the locus coeruleus results in sedation and anxiolysis and also terminates propagation of pain signals leading to analgesia.
Clonidine is a selective partial agonist for alpha-2-adrenoreceptors used intrathecally, with a well-established record of efficacy and safety. Dexmedetomidine is a highly selective alpha-2-adrenoreceptor agonist with the alpha-2: alpha-1 binding ratio of 1620: 1 when compared with 220:1 for clonidine which is 8—10 times higher than that of clonidine. The prolongation of spinal anesthesia after intravenous (IV) administration of dexmedetomidine and clonidine can be explained by the supraspinal effects of these drugs., There are limited studies to show the dose equivalence of these two drugs; however, some studies showed that the dose of clonidine is 1.5—2 times higher than the dose of dexmedetomidine.,
Therefore, we designed this prospective, randomized, double blind study to compare the efficacy of the IV infusion of clonidine 1.5 µg/kg vs. dexmedetomidine 0.75 µg/kg on spinal block characteristics as premedication to intrathecal 0.5% hyperbaric bupivacaine in patients undergoing various lower limb and lower abdominal surgeries.
| Patients and Methods|| |
Approval from Institutional Ethical Committee (IEC: 979/Acad-111/MCA/2019 dated 15/05/2019) and Clinical Trial Registry India was obtained (CTRI dated 24/02/2020). After obtaining written informed consent, this prospective, randomized, double blind study was conducted on 100 patients of either gender, aged between 18 and 65 years, weighing between 30 and 80 kg, belonging to the American Society of Anaesthesiologist (ASA) physical status I and II undergoing orthopedic lower limb and lower abdominal surgeries under spinal anesthesia. Patients with known allergy to study drugs, all well-known contraindications to spinal anesthesia, patients with history of respiratory, cardiac, diabetes mellitus, neurological, hepatic, or renal disease were excluded from the study.
The study population was randomly divided into two groups with 50 patients in each group (n = 50) using computer-generated tables of random numbers. Group CN received IV infusion of clonidine 1.5 μg/kg in 100 mL normal saline over 15 min. Group DM received IV infusion of dexmedetomidine 0.75 μg/kg in 100 mL normal saline over 15 min. Both groups were followed by spinal anesthesia with 2.8 mL (14 mg) 0.5% hyperbaric bupivacaine. To ensure double blinding, the study drugs were prepared by one anesthesiologist and given by another anesthesiologist who was not involved in the study. Both the anaesthesiologist and the patient were blinded to the treatment group given.
Pre-anesthetic evaluation was done on the day before surgery assessing general physical examination and routine investigations. We did not give any premedication night before surgery. After arrival of the patient in the operating room, identification of patient was done and fasting status, written informed consent, and pre-anaesthetic assessment were checked. After reassuring the patient, standard ASA monitoring was applied. Baseline values of vital parameters such as heart rate (HR), non-invasive blood pressure, oxygen saturation (SpO2), and Ramsay sedation score (RSS) were recorded. Continuous electrocardiogram was monitored. An IV cannulation using an 18-gage IV cannula was inserted in the upper limb, and preloading with 10 mL/kg Ringer’s lactate solution was done.
The study drug was diluted in 100 mL normal saline and infused intravenously over 10 min according to the group allocated by an anesthesiologist not involved in the study. Vital parameters were recorded after completion of infusion. Five minutes after completion of the infusion, the patient was placed in the lateral position and lumbar puncture was performed at the level of L3-L4 intervertebral space through a standard midline approach using a 25-gage Quincke spinal needle, and 2.8 mL (14 mg) of hyperbaric bupivacaine 0.5% was given and the patient was turned supine with 15—20° head down tilt. Oxygen was administered at the rate of 4—5 L/min via a face mask throughout the procedure. The time of intrathecal injection was noted. Onset of sensory block was assessed bilaterally in midclavicular line by assessing the changes in pinprick sensation with a hypodermic needle every 2 min till no sensation (Grade 2) achieved. The highest level of sensory block and time taken to achieve this were also noted. Onset of motor block was assessed every 2 min till complete motor block (Grade 3) was achieved according to the Bromage scale.
Intraoperative non-invasive monitoring of vital parameters (HR, systolic blood pressure, diastolic blood pressure, mean arterial pressure, and SPO2) was done every 2 min for the first 10 min, every 5 min for the next 20 min, and every 15 min for the next 90 min and every 30 min thereafter till the completion of surgical procedure and postoperatively every 60 min till the patient complained of pain.
Sensory and motor block was assessed every minute for the first 10 min and thereafter every 10 min during surgery and every 15 min postoperatively till recovery of both sensory and motor blockade was achieved. Recovery of sensory block was defined as the time taken by the sensory block to regress up to two segments of spinal cord level from highest segment of sensory block. Recovery of motor block was defined as the time taken to regress from maximum Bromage motor block to scale 0.
Postoperative pain was assessed by using the visual analog scale (VAS) up to first request for rescue analgesic. This finding correlated with the duration of analgesia which was defined as the time from intrathecal injection to the time when VAS score is >4 or when the patient first demands for rescue analgesia, whichever is first. Injection diclofenac sodium 75 mg intramuscularly was used as rescue analgesic.
The RSS was used to assess sedation. Excessive sedation was defined as a sedation score which was greater than four (5/6). Incidence of hypotension, bradycardia, nausea, and vomiting was observed and treated accordingly. Hypotension was defined as fall in baseline blood pressure more than 20% or a systolic blood pressure <90 mmHg and treated with IV fluids and/or injection mephentermine 6 mg IV. Bradycardia was defined as heart rate <50 beats/min and treated with injection atropine 0.6 mg IV.
Based on the previous study, a total sample size of 100 patients (n = 50 in each group) was calculated using Power and Sample Size calculator (PS version 126.96.36.199), α error of 0.05, and power of 80%. Statistical analysis was done using Statistical Package for Social Sciences (SPSS) version 21 (SPSS Inc., Chicago, IL, USA). All the numerical data were expressed as mean±standard deviation, whereas the categorical data were expressed as numbers or frequency (%). Standard qualitative and quantitative tests were used to compare the data (e.g. unpaired Student’s t-test, χ2 test).
| Results|| |
We screened 113 patients for this prospective double-blind study, and 13 patients were excluded as they did not fulfill the inclusion criteria. Hence, a total of 100 patients were allocated into two groups of 50 each. These 100 patients were followed till the endpoint of the study for data collection [Figure 1]. Comparison of demographic data (age, gender, weight, and ASA physical status) and duration of surgery showed no significant difference between the groups. The baseline vital parameters were also comparable among the groups [Table 1].
There was statistically significant difference in onset and recovery (two segment regression) of sensory and onset of motor block (P <0.05), but there was no statistical difference in recovery of motor block as shown in [Table 2].
The mean heart rate in Group DM appeared to be lower than that of Group CN, but there was no statistically significant difference among the groups except at 6 and 8 min after the subarachnoid block where the mean heart rate was significantly lower (P-value<0.05) in Group DM. However, at all time intervals, mean heart rates of both the groups were above 70/min indicating the hemodynamic stability in dexmedetomidine and clonidine groups at given doses [Figure 2].
There was a decrease in mean arterial blood pressure after premedication in both groups DM and CN which was not significant (P > 0.05) up to 2 min after subarachnoid block. Mean arterial pressure in Group DM appears to be lower than that of Group CN, but there was no statistically significant difference among the groups except at 4, 6, 8, and 10 min after subarachnoid block where the mean arterial pressure was significantly lower (P-value < 0.05) in Group DM when compared with Group CN [Figure 3].
In our study, mean RSSs were significantly higher in Group DM (P-value<0.001) from 8 to 150 min after SAB when compared with Group CN. Patients with sedation scores greater than 3 were 20% in the dexmedetomidine group, whereas no patients in the clonidine group [Figure 4].
In our study, VAS scores were zero up to 25 min after subarachnoid block; thereafter, VAS score was lower in Group DM than Group CN at all time intervals except at 240 and 300 min where it was higher in Group DM because of rescue analgesic (75 mg inj. diclophenac intramuscular) given in Group CN at around 210 min (mean duration of analgesia was 213.02 ± 10.374 min in Group CN when compared with Group DM in which it was 251.70 ± 6.264 min) [Figure 5].
In our study, hypotension was observed in six (12%) patients in Group CN and three (6%) patients in Group DM which was statistically not significant (P-value =0.295). Bradycardia was observed in three (6%) patients in Group CN and one (2%) in Group DM (P-value 0.307). Postoperative nausea and vomiting were observed in one (2%) patient in Group CN only. In Group DM, there was no patient complaining of nausea and vomiting.
| Discussion|| |
Pain following any type of surgery is one of the most distressing complains of a patient. It amplifies the surgery-induced stress response, hinders early ambulation, and can prolong the time of discharge. In a systematic review and meta-analysis of study done by Abdallah et al. on facilitatory effects of IV dexmedetomidine on subarachnoid block, the dexmedetomidine dosage ranged from 1 to 4 μg/kg over 10—20 min with or without a maintenance infusion. The drug was given either before, just after, or 20 minutes after spinal anesthesia. Though the dose equivalence of clonidine and dexmedetomidine has not yet been conclusively established, studies indicate that the required dose of clonidine should be around 1.5—2 times that of dexmedetomidine. Dexmedetomidine has been used intravenously in doses ranging from 0.1 to 10 μg/kg/h, but higher doses have been associated with a significant incidence of bradycardia and hypotension.
The bolus and infusion doses of clonidine and dexmedetomidine used are different among different studies.,, We therefore used a single dose infusion of dexmedetomidine 0.75 μg/kg and clonidine 1.5 μg/kg over 15 min each. As the infusion was started 15 min before the spinal anesthesia, we were able to compare the effect of these drugs on the onset of sensorimotor block and the highest level of block was achieved.
Alpha-2‑adrenergic agonists produced analgesia by their action at spinal, supraspinal, direct analgesic, and/or vasoconstricting actions on blood vessels. The locus coeruleus and the dorsal raphe nucleus are the important central neural structures where these drugs act to produce sedation and analgesia. This supraspinal action could explain the prolongation of spinal anesthesia after IV administration of dexmedetomidine and clonidine.
In our study, the mean duration of analgesia was significantly longer in Group DM when compared with Group CN (P < 0.001). Thus, we observed that IV dexmedetomidine led to prolongation of duration of analgesia when compared with IV clonidine. Our result coincides with several studies that found that postoperative analgesia was significantly prolonged in the dexmedetomidine group.,,
In our study, the mean onset of sensory block was significantly faster in Group DM when compared with Group CN. Our result was comparable with that of Reddy et al.’s study in which effect of dexmedetomidine 0.5 µg/kg was compared with that of clonidine 1.0 µg/kg intravenously before spinal anesthesia with 15 mg of 0.5% hyperbaric bupivacaine. Onset of sensory blockade was faster in Group DE when compared with Group CL. Also, in our study, the highest level achieved was higher in Group DM (T4±1) when compared with Group CN (T6±1) and time taken to achieve this highest level was also faster in Group DM, which was statistically significant with P-value <0.001 and our result coincides with previous studies.,,
In our study, the mean time of onset of motor block was significantly faster in Group DM when compared with Group CN. The result of our study was comparable with that of Reddy et al., but the recovery of motor block was comparable in both the study groups. Similarly, Kaya et al. and Reddy et al. reported no significant difference in prolongation of the duration of motor block in the dexmedetomidine group. The mechanism of motor block produced by alpha-2-adrenoreceptor agonist is unclear, but there is some evidence that clonidine and dexmedetomidine differentially block the Aα and C fibers. Motor blockade results from direct inhibition of impulse conduction in the large, myelinated Aα fibers. The 50% effective concentration (EC50%) measured to block motor fibers is approximately four‑folds that of small, unmyelinated C fibers., This is probably the cause of increased sensory block leading to prolonged analgesia when compared with the motor block.,
In our study, we observed excessive sedation (RSS ≥3) in 37 patients in Group DM and 16 patients in Group CN, which was statistically significant. This can be attributed to a selective action of dexmedetomidine at α2A subtype of alpha-adrenoceptor. The quality of sedation produced by dexmedetomidine is different when compared with sedatives acting through gamma-aminobutyric acid systems. Sedation caused by dexmedetomidine is similar to natural sleep. Patients are easily arousable and stay cooperative which is a definite advantage, especially when used along with regional anesthesia. Natural sleep and hypnosis caused by dexmedetomidine are similar due to ion conductance inhibition through L- and P-type calcium channels and facilitation of conductance through voltage-gated potassium ion channels.
Mean heart rate and systolic, diastolic, and mean arterial blood pressures in Group DM appeared to be lower than those of Group CN, but there was no statistically significant differences among the groups except early periods after subarachnoid block where these parameters were significantly lower in Group DM but these changes were clinically not significant. There was no significant difference in oxygen saturation in both the groups and was comparable at all time intervals. These hemodynamic changes were due to decrease in central sympathetic outflow after the effect of subarachnoid block.
There was no statistically significant difference in the postoperative complications such as hypotension, bradycardia, postoperative nausea, and vomiting between the two groups. In our study, hypotension was observed in six (12%) patients in Group CN and three (6%) patients in Group DM, which was statistically not significant (P = 0.295) and was treated with mephentermine 6 mg. Bradycardia was observed in three (6%) patients in Group CN and one (2%) in Group DM (P-value =0.307), which was treated with atropine 0.6 mg. In contrast to the study results of Reddy et al. and Agrawal et al., we observed a lower incidence of hypotension (6% compared with 12.5% and 20%, respectively) and bradycardia (2% compared with 2.5% and 20%, respectively) in Group DM, whereas the incidence of hypotension was similar to the findings of Lugo et al. and Reddy et al., and bradycardia was lower in comparison to the above two studies (6% compared with 8% and 16%, respectively) in Group CN.
Postoperative nausea and vomiting were observed in only one (2%) patient in Group CN, which was treated with inj. ondansetron 4 mg. In Group DM, there was no patient complaining of nausea and vomiting similar to the study by Agrawal et al. when compared with Lugo et al. and Reddy et al., in which 4% and 8% patients were complaining of nausea and vomiting, respectively.
The limitations of our study included that the assessment of VAS is subjective and varies with the level of understanding between patient and anesthesiologist. This study was done on ASA I and ASA II patients only, which cannot be extrapolated for higher ASA grades and pediatric age groups.
| Conclusion|| |
From our study, we concluded that single dose of IV dexmedetomidine 0.75 µg/kg infusion as premedication before spinal anesthesia prolonged the duration of analgesia with rapid onset of sensory and motor blockade without prolonging motor blockade duration with stable hemodynamic parameters and arousable sedation when compared with IV clonidine 1.5 µg/kg infusion. So, IV dexmedetomidine may be used as more effective adjuvant than IV clonidine as premedication before spinal anesthesia.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]