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 Table of Contents  
Year : 2017  |  Volume : 31  |  Issue : 1  |  Page : 35-40

Low-dose intravenous alpha-2 agonists as adjuvants to spinal levobupivacaine: A randomized study

Department of Anaesthesiology, SMS Medical College, Jaipur, Rajasthan, India

Date of Web Publication5-May-2017

Correspondence Address:
Pranav Jetley
A-75, Resident Doctor's Hostel, S.M.S Medical College, Jaipur - 302 004, Rajasthan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpn.ijpn_59_16

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Background: Alpha-2 agonists have been used with spinal anesthesia for anxiolysis, analgesia, and hypnosis and for postoperative pain relief. These beneficial effects may, however, be offset by their propensity to prolong the duration of motor block and adversely affect hemodynamics when used in higher doses. This study compares the effects of low-dose premedication with intravenous (IV) dexmedetomidine and IV clonidine with placebo, on spinal blockade duration, analgesia, and sedation with intrathecal levobupivacaine. Materials and Methods: In this prospective, randomized, double-blinded, placebo-controlled study, ninety American Society of Anesthesiologists Status I and II patients were randomly allocated into three groups: Group A (control) received 10 ml normal saline IV, Group B received IV dexmedetomidine 0.6 μg/kg, and Group C received IV clonidine 1.2 μg/kg over 10 min, before spinal anesthesia with 0.5% levobupivacaine. Hemodynamics, total duration of analgesia, onset and duration of sensory and motor block, visual analog scale score, and sedation score were assessed. Complications, if any, were noted. Results: The level of sensory block achieved was higher with dexmedetomidine (T4.2 ± 0.8) and clonidine (T4.4 ± 0.7) as compared to control (T5.1 ± 0.7; P< 0.001). Time to two segment regression was greater with dexmedetomidine (146.5 ± 12.5 min) and clonidine (138.9 ± 17.4 min) compared to control (90.1 ± 9.4; P< 0.001). Dexmedetomidine maximally prolonged the duration to first patient request for analgesia (245.2 ± 26.8 min), followed by clonidine (175.3 ± 20.1 min, P< 0.001) and control (121.3 ± 16.1 min, P< 0.001). The duration of motor block was similar in all three groups. Incidence of bradycardia was significantly greater with both dexmedetomidine and clonidine compared to saline (P < 0.05). Conclusion: Premedication with low-dose IV dexmedetomidine and clonidine prolonged sensory blockade and analgesic duration and provided suitable sedation, without prolonging motor blockade.

Keywords: Clonidine, dexmedetomidine, intravenous, levobupivacaine, spinal anesthesia

How to cite this article:
Jetley P, Khandelwal M, Bafna U, Sharma G, Jain S, Dutta D. Low-dose intravenous alpha-2 agonists as adjuvants to spinal levobupivacaine: A randomized study. Indian J Pain 2017;31:35-40

How to cite this URL:
Jetley P, Khandelwal M, Bafna U, Sharma G, Jain S, Dutta D. Low-dose intravenous alpha-2 agonists as adjuvants to spinal levobupivacaine: A randomized study. Indian J Pain [serial online] 2017 [cited 2022 Aug 12];31:35-40. Available from: https://www.indianjpain.org/text.asp?2017/31/1/35/205720

  Introduction Top

Alpha-2 adrenergic agonists have both analgesic and sedative properties when used as adjuvants to regional anesthesia. By action at the α2-receptor in spinal and supraspinal sites, they potentiate the effect of local anesthetics and allow a decrease in the required doses.[1],[2],[3] These salutary effects are achieved without causing respiratory depression or excessive sedation.[4],[5]

Dexmedetomidine and clonidine are the two principal α2-agonists used in anesthetic practice. These agents have been used in the past as intravenous (IV) adjuvants to spinal anesthesia, but at relatively high doses, which may have led to an increased duration of motor block [6],[7],[8] or increased incidence of hemodynamic disturbances.[6],[9],[10] Previous studies have also not evaluated the effects of IV α2 agonists on spinal block with levobupivacaine, which though similar to bupivacaine, causes an earlier recovery from motor block.[11]

The levobupivacaine and low-dose IV α2 agonist combination may have the potential advantages of providing adequate sedation and prolonging analgesia without prolonging motor block or adversely affecting hemodynamics.

This randomized study investigates the efficacy of low-dose IV dexmedetomidine with clonidine and placebo on spinal blockade duration, postoperative analgesia, and sedation as premedication to intrathecal levobupivacaine.

  Materials and Methods Top

This prospective, randomized, double-blind study was done at a tertiary care center after the approval of the Local Institutional Ethical Committee and obtaining written informed consent from all patients before participation. Ninety patients of the American Society of Anesthesiologists (ASA) Physical Status Grade I and II, aged 20–50 years, scheduled for elective lower abdominal surgery under subarachnoid block were included in the study.

All the patients were thoroughly examined preoperatively which included history, general physical examination, and checking the vital parameters of the patients such as blood pressure, pulse, respiratory rate and systemic examination, and ASA grading. The patients with a contraindication to spinal anesthesia (e.g., coagulation defects, infection at puncture site, and preexisting neurological deficits in the lower extremities) and cardiovascular, respiratory, psychological, and hepatic or renal disease were excluded from the study.

The visual analog scale (VAS) scoring system was explained to all the patients. The VAS consisted of a 10 cm horizontal paper strip with two endpoints labeled “No pain” and “Worst pain ever.”

After IV insertion of an 18-G cannula in the operating room, all patients were preloaded with Ringer's lactate 15 ml/kg over 10 min. All the routine monitors were attached, and the preoperative baseline readings of noninvasive blood pressure, pulse rate (PR), and saturation were noted. Using a computer-generated randomization schedule, the patients were randomly divided into three groups: Group A (n = 30) received normal saline, Group B (n = 30) received 0.6 μg/kg dexmedetomidine, and Group C (n = 30) received 1.2 μg/kg clonidine intravenously. Infusions in each group were started 5 min before spinal anesthesia. The study drugs were prepared to a total volume of 10 mL in a 10 mL syringe and were administered intravenously over a 10 min period as a single dose. Five minutes after commencement of the infusion, the patient was placed in the lateral position, and dural puncture was performed at the L3–4 interspace using a standard midline approach with a 25-G Quincke needle (Spinocan, Braun Melsungen AG, Germany). Levobupivacaine 0.5% 3 mL was injected intrathecally. The patient was placed in supine position with a head down tilt immediately after spinal injection. The anesthesiologists performing the block recorded the intraoperative data, and a nurse followed the patients postoperatively until discharged from the postanesthesia care unit (PACU). Both were blind to the group to which the patient was allocated.

Sensory blockade was assessed using pinprick method bilaterally in the midclavicular line. Onset of sensory block was defined as the time from intrathecal injection to the time taken to achieve highest dermatomal segment. Recovery time for sensory blockade was defined as two-dermatome regression of anesthesia from the maximum level. Motor block was assessed using a Modified Bromage Scale [Table 1].[12] Motor block duration was the time for return to Modified Bromage Scale to 0. Sensory and motor block was assessed every minute for the first 10 min and thereafter every 10 min during surgery and postoperatively. The highest sensory block level and recovery time of both sensory and motor block were recorded.
Table 1: Modified bromage score

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Intraoperatively, all the patients were given oxygen through a face mask at a flow rate of 4 L/min. The values of mean arterial pressure (MAP), systolic (SBP) and diastolic blood pressure, heart rate (HR), and SPO2 Were monitored till the end of the surgery. Hypotension, defined as fall of MAP by >20% from baseline or fall of SBP below 90 mmHg, was treated with incremental IV doses of mephentermine 5 mg and IV fluid as required. Bradycardia, defined as HR <50 bpm (beats per minute) or a decrease by >20%, was treated with injection atropine 0.6 mg IV.

Postoperative pain was assessed by the patient using the VAS [Table 2]. VAS score was serially assessed at half an hour interval starting from 60 min to 300 min or till the patient complained of pain (VAS 3). Duration of effective analgesia was measured as the time from intrathecal drug administration to the first administration of analgesic either in the recovery room or the ward and was recorded in minutes. Patient's VAS >3 or administration of rescue analgesia on patient request constituted the end point of the study. Diclofenac (75 mg) IV was given as rescue analgesic.
Table 2: Visual analogue scale grading

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Postoperative sedation level was noted according to the “Four-Point Sedation Scale” [Table 3]. Complications such as nausea, vomiting, hypotension; bradycardia, and respiratory depression were noted and managed accordingly.
Table 3: Four point sedation score

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Statistical analysis

The sample size was calculated by conducting a pilot study with thirty patients in three groups. With minimal detectable difference in means of duration of analgesia 26.5 ± 26.17 min, with an alpha error of 0.05 and study power at 90%, the sample size was calculated as twenty patients per group. For the purpose of our study, we included thirty patients in each group.

Statistical analysis was done using SPSS (Statistical Package for the Social Sciences) software version 20.0.0 (IBM Inc., Chicago, Illinois, USA). Kruskal–Wallis test was used to assess differences among the three groups with respect to nonparametric variables. If this revealed significant differences, Mann–Whitney U-test was used to analyze differences between the groups in pairs. Parametric testing was done using analysis of variance. Categorical data were analyzed using Chi-square test. Data are presented as mean ± standard deviation or number of patients (percentage) as per category. P< 0.05 was considered statistically significant.

  Results Top

Spinal anesthesia was successful in all patients, and all patients completed the study. All groups were comparable with respect to age, weight, ASA status, type of surgery, and duration of surgery. There were no statistically significant differences in the demographic characteristics between the groups (P > 0.05) [Table 4].
Table 4: Demographic Data (Mean±S.D)

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Onset of sensory block [Table 5] was fastest with dexmedetomidine (4.99 ± 0.52 min) as compared to both clonidine (5.5 ± 0.40 min; P< 0.001) and control (5.85 ± 0.71; P< 0.001). The onset of sensory block was faster with clonidine as compared to control (P < 0.05). The level of sensory blockade with dexmedetomidine (T4.2 ± 0.8) and clonidine (T4.4 ± 0.7) was higher than control (T5.1 ± 0.7; P< 0.001), while there was no statistically significant difference between the two alpha-2 agonists (P > 0.05). The time for two segment regression was significantly longer with dexmedetomidine (146.5 ± 12.5 min; P< 0.001) and clonidine (138.9 ± 17.4 min; P< 0.001) as compared to control (90.1 ± 9.4 min) although there was no significant difference between the two (P > 0.05). Duration of analgesia was maximum with dexmedetomidine (245.2 ± 26.8 min) when compared with clonidine (175.3 ± 20.1 min; P< 0.001) and control (121.3 ± 16 min; P< 0.001). The duration of analgesia was significantly longer with clonidine when compared with control (P < 0.001).
Table 5: Characteristics of motor and sensory block

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Mean HR [Figure 1] and mean MAP [Figure 2] were significantly lower in dexmedetomidine and clonidine group during the first 15 min of procedure (P < 0.05). There was no significant difference in mean HR and MAP after 15 min between the groups. There was no significant difference between the mean HR and MAP of dexmedetomidine and clonidine throughout the observation period. Incidence of bradycardia was greater in the dexmedetomidine (30%) and clonidine (20%) groups as compared to control (3.3%; P< 0.05) although there was no difference between the two. The incidence of hypotension, although greater in the dexmedetomidine (33.3%) and clonidine (40%) groups than with control (23.3%), was not statistically significant (P > 0.05) [Table 6].
Figure 1: Mean heart rate versus time

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Figure 2: Mean arterial blood pressure versus time

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Table 6: Incidence of adverse events

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The VAS scores [Figure 3] were lowest with dexmedetomidine among the three groups up to 4.5 h (P < 0.001). The VAS scores were lower in the clonidine group up to 4 h compared to control (P < 0.001).
Figure 3: Mean visual analog scale scores versus time. Values significantly different up to 4 h by Kruskal–Wallis H test

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Patients in dexmedetomidine group had the highest sedation scores throughout the postoperative observation period (P < 0.001) [Figure 4]. Clonidine had the second highest sedation scores up to 150 min (P < 0.001). After this period, there was no statistically significant difference between control group and clonidine group. There were three patients with sedation score = 4 (excessive sedation) in the dexmedetomidine group. The incidence of postoperative nausea and vomiting was not significantly different among the three groups (P > 0.05) [Table 6].
Figure 4: Mean sedation scores versus time. Values were significantly different up to 4.5 hours by Kruskal–Wallis H test

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  Discussion Top

Many techniques and drug regimens, to partial or greater success, have been tried from time to time to alleviate anxiety and to prolong postoperative analgesia during regional anesthesia. Opioid adjuvants prolong analgesic duration without affecting motor blockade but are associated with side effects such as respiratory depression, pruritus, nausea and vomiting, hemodynamic instability, and urinary retention.[13] Apha-2 agonists share these analgesic properties and are devoid of excessive sedation and respiratory depression.[14],[15] The primary target for producing analgesia is the locus coeruleus, which is also the main center for regulation of sleep. Action at presynaptic α2 receptors causes decreased outflow of norepinephrine accounting for the analgesic and sedative properties of α2 agonists. Analgesia is also mediated by interruption of nociceptive impulse transmission at spinal cord level.

Kim et al.[16] reported that dexmedetomidine as a single dose of 0.57 μg/kg provided adequate sedation to patients aged 45–64 years, undergoing spinal anesthesia with intrathecal bupivacaine for transurethral prostatectomy. Since the dose of clonidine has been studied to be 1.5–2 times that of dexmedetomidine, the respective doses for our study were chosen.

Results from our study showed that single doses of both dexmedetomidine (0.6 μg/kg) and clonidine (1.2 μg/kg) hastened the onset and prolonged duration of sensory block, provided adequate procedural and postoperative sedation and prolonged analgesic duration, without affecting motor block.

Synergistic interactions between α2 agonists and intrathecal local anesthetics have been observed in earlier studies. The degree of prolongation of motor blockade appears to be dependent on the dosage regimen (continuous intraoperative infusion) of the α2 agonists. Lugo et al.[9] compared dexmedetomidine (1 μg/kg loading and 0.5 μg/kg/h infusion) and clonidine (4 μg/kg) and noted prolongation of sensory block and duration of analgesia, without a prolongation of motor block. Other studies that have administered α2 agonists in the form of a loading dose followed by an infusion, by Harsoor et al.[6] (dexmedetomidine at 0.5 μg/kg loading followed by 0.5 μg/kg/h) and Al-Mustafa et al.[7] (dexmedetomidine at 1 μg/kg loading followed by 0.5 μg/kg/h) demonstrated similar effects on sensory block with significant prolongation of motor block. Elcicek et al.[17] noted similar effects on ropivacaine spinal block. When dexmedetomidine was investigated as a single dose before spinal anesthesia, Hong et al.[18] reported a prolongation of motor block with dexmedetomidine at 1 μg/kg but not with 0.5 μg/kg. Reddy et al.[14] reported similar findings, i.e., no effect of α2 agonists on motor block, when comparing IV dexmedetomidine (0.5 μg/kg) and IV clonidine (1.0 μg/kg) as adjuvants to intrathecal bupivacaine. These observations correlate with the finding that the 50% effective concentration of clonidine required to block motor fibers is approximately 4 fold that of pain carrying, small, unmyelinated C fibers.[19] Similar mechanisms may be extrapolated to dexmedetomidine, which works identically, explaining the dose-dependent effects of α2 agonists on motor blockade. These findings lead us to believe that the minimum dose required for prolongation of motor block is >0.6 μg/kg for dexmedetomidine and 1.2 μg/kg for clonidine.

The faster onset of and delayed recovery from sensory block may be due to α2 receptor activation-induced inhibition of nociceptive impulse transmission. Vasoconstricting and analgesic actions by agonism at spinal α2 receptors in the substantia gelatinosa may lead to a delay of absorption of intrathecal local anesthetic and prolong duration of spinal anesthesia.[20]

PR and blood pressure were monitored from the start of infusion till end point of the study. The drops in PR and mean arterial pressure were short lived in our study, with the hemodynamic perturbations lasting only up to 15 min after beginning of anesthesia. Both blood pressure and HR were significantly decreased during this period. Although there was significantly high incidence of bradycardia with dexmedetomidine (9 out of 30; 30%) and clonidine (6 out of 30; 20%) as compared to control Group (P < 0.05), these episodes were adequately managed with IV atropine. The incidence of hypotension was not significantly different between the groups. Hemodynamic response following clonidine and dexmedetomidine infusion depends on the dose and speed of infusion. A sequence of transient hypertension with reflex bradycardia followed by hypotension is seen with a higher dose and rapid infusion. Bradycardia commonly seen after administration of α2 adrenoceptor agonists may be due to the central sympatholytic action of these drugs leaving vagal tone unopposed. It may also be due to presynaptic-mediated reduction of noradrenaline release or a direct vagomimetic action.[21] Hong et al. found a significantly higher incidence of bradycardia with dexmedetomidine (single dose of 1 μg/kg) than control (24% vs. 3.8%; P< 0.05).[18] Park et al. noted higher incidences of bradycardia with dexmedetomidine at both 0.5 μg/kg and 1 μg/kg, compared with placebo, in a comparatively older study population (aged ≥60 years) more prone to the hemodynamic depressant effects of dexmedetomidine.[22] Reddy et al.[14] and Kaya et al.[4] (single dose dexmedetomidine at 0.5 μg/kg) reported an increased incidence of bradycardia and hypotension with dexmedetomidine, compared to placebo, although this difference was not statistically significant.

The α2 agonists cause sedation by their action on the locus coeruleus. This mechanism acts in synergy with the sedation caused by spinal anesthesia due to decreased afferent proprioceptor discharge. Light sedation in the form of anxiolysis may be beneficial at the time of administering spinal anesthesia, and intraoperatively during the procedure, to improve patient comfort. In our study, dexmedetomidine had highest sedation scores throughout the observation period. Excessive sedation (Four point sedation score of 4) was observed in three patients in this group. Excessive sedation in the postoperative period may delay return to oral intake, discharge from PACU, and increase hospital costs. Al-Mustafa et al.[7] and Hong et al.[18] used higher doses of dexmedetomidine and noted excessive sedation in 3 out of 25 and 2 out of 26 patients, respectively, in their studies. Reddy et al.[14] noted significantly greater number of cases of excessive sedation with dexmedetomidine (n = 17; P< 0.05) in their study. The sedation offered by alpha-2 agonists is one, from which the patient is easily arousable. This was demonstrated by Kaya et al.[4] who showed excessive sedation (Ramsay sedation score of 4) to be more frequent with midazolam (0.05 mg/kg) than with dexmedetomidine (0.5 μg/kg).

One limitation of our study was that a therapeutic end point of VAS score >3 or request for analgesic was used. Twenty-four hours total analgesic requirements were not recorded which would have better demonstrated the analgesic qualities of the studied drugs. Nevertheless, within the constraints of our present study design, dexmedetomidine and clonidine were both found to prolong analgesia and decrease postoperative VAS scores.

  Conclusion Top

By prolonging analgesia and providing adequate sedation, premedication with IV dexmedetomidine at a dose of 0.6 μg/kg may be a better adjuvant to 0.5% hyperbaric levobupivacaine than clonidine at a dose of 1.2 μg/kg in infraumbilical surgeries, with complications of excessive sedation and bradycardia occurring at acceptable incidences.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]

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