AJA Asian Journal of Anesthesiology

Advancing, Capability, Improving lives

Research Paper
Online ahead of print
Amit Kumar Saha 1 , Bani P. M. Hembrom 2 , Baisakhi Laha 3 , Tapobrata Mitra 1 , Avijit Hazra 4
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Abstract

Background

Infraumbilical surgery today is done preferentially under subarachnoid block. The relatively short duration of analgesia is a limiting factor which is overcome by adding an adjuvant to intrathecal bupivacaine. We aimed to determine optimum dose of intrathecal dexmedetomidine as adjuvant to 0.5% hyperbaric bupivacaine in infraumbilical surgery.

Methods

A parallel group, double blind, randomized controlled trial was done with 105 adult patients posted for infraumbilical surgery under subarachnoid block. All subjects received 3.0 mL (15.0 mg) of 0.5% hyperbaric bupivacaine. Groups D5.0, D7.5, and D10.0 (n = 35 each) received additionally 5.0, 7.5, and 10.0 mcg intrathecal dexmedetomidine as adjuvant. The onset time of sensory block, its peak level and time to this level, maximum motor block and time to it, total duration of analgesia (time to first rescue), and vital parameters were recorded at intervals. Postoperative analgesia was assessed by visual analog scale score at 15 and 30 minutes, then every 30 minutes until 2 hours and then every hour until 6 hours. Treatment emergent adverse events (bradycardia, hypotension, and sedation) were documented.

Results

Maximum sensory level achieved was higher in Group D10.0 than in the other two groups. There was significant and dose-dependent shortening of the mean time to peak sensory block (3.9, 3.3, and 2.9 min; P < 0.001) and peak motor block (5.6, 5.3, and 4.8 min; P < 0.001), and prolongation of postoperative analgesia duration (206.9, 220.8, and 244.0 min; P < 0.001) with escalating doses (5.0, 7.5, and 10.0 mcg, respectively) of dexmedetomidine. Hemodynamic effects and adverse events were comparable in the three groups.

Conclusions

Intrathecal dexmedetomidine (10.0 mcg), as adjuvant to 0.5% hyperbaric bupivacaine (15.0 mg), facilitates rapid onset sensory and motor block and prolongs duration of postoperative analgesia in spinal anesthesia without significant adverse effects. Although absolute differences are modest, the results are better compared to 5.0 and 7.5 mcg doses.

Keywords

bupivacaine, dexmedetomidine, infraumbilical surgery, postoperative analgesia, subarachnoid block


Introduction

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. A pain free and stress free postoperative period helps in early mobilization and recovery of surgical patients, thereby reducing morbidity. Intraoperative and postoperative pain relief is a fundamental component of anesthesia. Accordingly, anesthesiologists constantly strive to offer the best possible anesthetic technique with emphasis on minimum adverse effects and satisfactory perioperative analgesia. Spinal anesthesia is a preferred technique to administer anesthesia for infraumbilical operations. However, postoperative pain control is a matter of concern with spinal anesthesia using only local anesthetics, as the analgesic effect lasts for relatively short duration. Thus, early analgesic intervention is needed in the postoperative period.1

Various adjuvants, such as opioids,2 epinephrine,3 neostigmine,4 magnesium,5 midazolam,6 ketamine,7 clonidine,8 have been used with intrathecal local anesthetics in attempts to prolong analgesia and reduce the incidence of adverse events. In recent years, α2-adrenergic receptor agonists have gained popularity as an important adjunct in anesthetic practice, whether it be general or regional anesthesia.9 Their primary effect is sympatholytic. They reduce peripheral norepinephrine release by the stimulation of prejunctional inhibitory α2-adrenoceptors. They also inhibit central neural transmission in the dorsal horn by presynaptic and postsynaptic mechanisms. They may also have direct sympatholytic effect on spinal preganglionic sympathetic neurons. Sedative, anxiolytic, and analgesic properties of these alpha agonists favor their increasing clinical use. Their use also circumvents the problems of respiratory depression, pruritus and urinary retention that may be associated with opioid adjuvants.10

The addition of dexmedetomidine, also an α2-adrenoceptor agonist, to local anesthetics provides effective analgesia for acute and chronic pain.3 Although originally approved by the United States Food and Drug Administration as an intravenous (IV) additive for intensive care unit sedation, it is, of late, increasingly used as an adjuvant in local anesthesia. Its affinity for the α2-adrenoceptor is more than 7 times greater than clonidine, with a shorter distribution and elimination half-life.10 This panorama of properties makes the drug an attractive option to use as an adjuvant in locoregional and general anesthesia.

Evidence indicates that neuraxial administration of dexmedetomidine produces spinal analgesia as efficiently as clonidine.11-13 Kanazi et al.14 demonstrated a significant prolongation in the duration of sensory and motor block with dexmedetomidine used as intrathecal additive for 0.5% hyperbaric bupivacaine. However, there is some uncertainty over the dose of dexmedetomidine to be used as intrathecal adjuvant to prolong the duration of blocks as well as postoperative analgesia without causing undue sedation. With this background, we evaluated the postoperative analgesic characteristics, and compared the onset and the maximum level of sensory block, quality and duration of motor block and adverse effects of different doses of intrathecal dexmedetomidine, added to hyperbaric bupivacaine, in elective infraumbilical surgery.

Methods

This randomized controlled trial (RCT) was duly approved by the Institutional Ethics Committee (IEC Memo No. MMC/IEC-2017/1505 dated 12.07.2017) and conformed to the Declaration of Helsinki (2013 revision). Written informed consent was obtained from all participants at the time of recruitment after the study purpose, procedure, and potentials risk and benefits were explained.

The study was conducted at the surgical, orthopedic, and gynecological operation theaters (OT) of a tertiary care teaching hospital, catering predominantly to rural population, over a period of 12 months. Patients of either sex, of American Society of Anesthesiologists (ASA) grade 1 and 2 status, aged from 18 to 60 years, were randomly assigned to three groups of 35 each. Patient refusal, any known allergy to bupivacaine or dexmedetomidine, critical illness of vital organs, spinal deformities, bleeding disorders and use of antiarrhythmics, beta blockers, or anticoagulants were exclusion criteria.

All patients received 3.0 mL (15.0 mg) of 0.5% hyperbaric bupivacaine by intrathecal route. In addition, patients in groups D5.0, D7.5, and D10.0 received 5.0 mcg, 7.5 mcg, and 10.0 mcg intrathecal dexmedetomidine, respectively, as adjuvant, with the total volume being made up to 3.5 mL using normal saline. Both patient and anesthesiologist attending in the OT were unaware of the group allocation. Randomization was by WINPEPI version 11.65 (Abranson JH, 2016, http://www.brixtonhealth.com/pepi4windows.html) software and allocation concealment was by means of the sequentially numbered opaque sealed envelope technique with the envelopes being handed over to anesthesiology residents who loaded the syringes but otherwise did not get involved in patient monitoring. Double blinding was thereby achieved.

As premedication, subjects received oral ranitidine 150 mg the night before surgery. In the morning, ranitidine 150 mg and metoclopramide 10 mg were given orally with sips of water two hours before surgery. On arrival in the OT, the patient was received, identification confirmed, and the anesthetic procedure and expected outcomes were again explained in their own language. Before anesthesiologists performed the subarachnoid block, standard equipment such as non-invasive blood pressure, pulse oximeter and electrocardiogram, were attached to monitor intraoperative blood pressure, heart rate (HR), oxygen saturation, and respiratory rate. After 18 G IV canula was secured, the patient was preloaded with 15 mL/kg Ringer’s lactate solution and maintained at 10 mL/kg/h thereafter. Oxygen was given through face mask at 2 L/min. When anesthesiologists took all aseptic precautions, a subarachnoid block was performed at L3–L4 or L4–L5 intervertebral space, in the seated position, by standard midline approach using a 25 G Quincke spinal needle. After anesthesiologists obtained free flow of cerebrospinal fluid, 3.5 mL spinal drug (blinded) was injected at the rate of 0.2 mL/s. Patient position was changed from sitting to supine immediately after the spinal injection. Sensory block onset was checked by loss of pin prick sensation along both mid-clavicular lines using 23 G hypodermic needle every 2 minutes until stabilization of the level on four consecutive tests. Motor blockade was assessed by 4-point modified Bromage scale, with grades 0, 1, 2, and 3 (where 0 = free movement of leg and 3 = inability to raise leg). Sedation was assessed by 6-point Ramsay sedation scale (RSS) (where levels 1–3 are awake level and levels 4–6 are asleep levels, with level 2 denoting co-operative, oriented and tranquil patient).

Vital parameters—namely HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), respiration rate (RR), peripheral oxygen saturation (SpO2)—were measured before starting block as baseline value, then at 0 minute and every 5 minutes for the first 15 minutes after spinal anesthesia, and then every 15 minutes up to the end of operation. Occurrence of adverse events, like bradycardia, hypotension, respiratory depression, and sedation, was recorded. For study purpose, hypotension was defined as SBP reduction by > 20% from baseline or fall to < 90 mmHg and was managed with incremental IV doses of mephentermine 6 mg and IV fluid as required. Bradycardia was defined as HR < 50 beats/min and was managed by IV atropine 0.6 mg. Respiratory depression (RR < 10 or SpO2 < 92%) was managed by supplemental oxygen and respiratory support.

Postoperative analgesia was the primary outcome measure, and this was assessed by visual analog scale (VAS) score at 15 minutes and 30 minutes, then every 30 minutes until 2 hours and then every hour until 6 hours. IV diclofenac sodium (aqueous base) 75 mg was offered as rescue analgesic on the first complaint of pain or when VAS score exceeded 3 cm.

The sample size was calculated on the basis of the duration of postoperative analgesia. It was calculated that 35 subjects will be required per group to detect a difference of 30 minutes between groups in this parameter with 80% power and 5% probability of Type I error. This calculation assumed a standard deviation (SD) of 45 minutes for the duration of postoperative analgesia and two-sided testing. After we extrapolated to three groups, the recruitment target was set at 105 subjects overall.

For statistical analysis, data were entered into a Microsoft excel spreadsheet and then analyzed by IBM SPSS version 24 (IBM Corp., Armonk, NY, USA) and GraphPad Prism version 5 (GraphPad Software, San Diego, CA, USA) software. Data have been summarized as mean and SD for numerical variables and as count and percentages for categorical variables. One-way analysis of variance (ANOVA) has been used to compare normally distributed numerical variables between groups and repeated measures ANOVA was used to assess for significant change over time. Chi-square test or Fisher’s exact test, as appropriate, were employed for comparison of unpaired proportions. For all comparisons, P < 0.05 was considered statistically significant.

Results

We assessed 112 patients for eligibility and randomized 105 patients equally to the three study groups. Seven were not randomized as they either did not meet all eligibility criteria or declined to consent. Figure 1 presents a consolidated standards of reporting trialsstyle diagram depicting patient flow in the study.

Subjects recruited were between 21 and 57 years of age and the majority were males and of ASA grade I. Table 1 presents a summary of the baseline parameters, and these are comparable between the three groups.

Table 2 shows that the duration of surgery was about 1.5 hours on average in all three groups. Subarachnoid block could be achieved in all study subjects. The maximum sensory block attained was T4 but only 8.6% subjects attained this in group D5.0, compared to 71.4% in group D10.0. The distribution of maximum sensory block attained was statistically highly significant (P < 0.001). By modified Bromage scale, the maximum motor block achieved was 3 in all study groups.

Figure 1.
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Fig. 1. Flow of Study Participants

Table 1. Baseline Profile of the Study Subjects
Table 1.
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Table 2. Comparison of Efficacy Parameters Between the Study Groups
Table 2.
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There was significant and dose-dependent shortening of the mean time to peak sensory block (mean ± SD, 3.90 ± 0.30, 3.30 ± 0.28, and 2.90 ± 0.11 min; P < 0.001) and peak motor block (5.60 ± 0.31, 5.30 ± 0.29, and 4.80 ± 0.27 min; P < 0.001) with escalating doses (5.0, 7.5, and 10.0 mcg, respectively) of dexmedetomidine.

Regarding time to administration of first rescue analgesic, this was 244.00 ± 6.33 min in group D10.0, compared to 206.90 ± 5.05 in group D5.0 and 220.8 ± 7.04 in group D7.5 (P < 0.001). Thus, maximum prolongation of duration of postoperative analgesia was achieved with the 10.0 mcg dose of intrathecal dexmedetomidine.

Though there were statistically significant variations over time within a group, vital parameters (HR, SBP, DBP, MAP, and RR) remained comparable between study groups at all assessment time points, namely at 0, 5, 10, 15, 30, 45, 60, 75, 90, and 105 minutes into the operation. These data have not been shown.

Treatment emergent adverse events have been summarized in Table 3. Bradycardia occurred in 3 patients in each group while hypotension occurred in a small proportion of patients in dexmedetomidine groups. All instances of bradycardia could be managed successfully with IV atropine while hypotension was managed with IV fluids and mephentermine. The SpO2 stayed at over 95% in all patients throughout the study. Respiratory depression was not encountered. Postoperative nausea, without vomiting, occurred in few patients but did not require rescue in any.

Table 3. Frequency of Adverse Events in the Study Groups
Table 3.
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Discussion

In this RCT, we have found a dose-dependent effect of dexmedetomidine on the onset time of both sensory and motor block without hemodynamic instability or other adverse events. In addition, the duration of postoperative analgesia was significantly prolonged with the use of dexmedetomidine 10.0 mcg compared to lower doses of the drug. Age, gender, body mass index, and ASA status were comparable between groups at baseline which provided us with a balanced baseline to compare the pharmacological effects.

Halder et al.11 found that median height of sensory block in the 10.0 mcg dexmedetomidine group was one segment higher than 5.0 mcg dexmedetomidine group but the result was statistically insignificant. Gupta et al.12 also found that there was no difference in highest level of sensory block within their study groups. In our study, by contrast, we found that most of the patients in 10.0 mcg dexmedetomidine arm reached highest sensory level of T4 dermatome in comparison to 5.0 mcg (T6) and 7.5 mcg (T6) doses.

Shaikh and Mahesh13 found that the mean time to reach maximum sensory level after spinal anesthesia was the fastest in 10.0 mcg dexmedetomidine group (4.30 ± 0.47 min) when compared to 5.0 mcg dexmedetomidine (4.60 ± 0.37 min) and normal saline (5.20 ± 1.49 min). Halder et al.11 also found that the onset of sensory block was earlier with 10.0 mcg than with 5.0 mcg dexmedetomidine dose. We also observed a dose-dependent effect in this regard. The time to maximum sensory block with 10.0 mcg dexmedetomidine was, on average, a full minute earlier than with the 5.0 mcg dose. This difference is clinically modest but statistically significant.

The maximum motor block achieved in all three groups as per Bromage scale was 3, and there was no statistically significant difference between groups in this regard. Time to reach maximum motor block, however, showed a progressive and statistically significant decline with increasing dose of dexmedetomidine. Kanazi et al.14 showed that supplementation of bupivacaine with low dose intrathecal dexmedetomidine (3.0 mcg) produced significantly shorter onset of motor block and prolongation of sensory and motor block than bupivacaine plain group. Al-Mustafa et al.15 conducted a study on 66 patients undergoing urological procedures randomized to three groups—normal saline, dexmedetomidine 5.0 mcg, and dexmedetomidine 10.0 mcg by intrathecal route—in addition to spinal bupivacaine 12.5 mg. They found that the maximum motor block was reached in the shortest time with 10.0 mcg dexmedetomidine. Our study results are thus in conformity with these reports although, admittedly, the absolute differences are small.

VAS scoring is a standard technique for evaluating postoperative analgesia, and we used the same method in our study at appropriately spaced out intervals. At 244 minutes, the mean duration of postoperative analgesia was substantially longer in the 10.0 mcg group than the 221 minutes in the 7.5 mcg and 207 minutes in the 5.0 mcg group. This half hour gain in analgesia duration is not large but may be important from the patient’s perspective. Halder et al.11 documented similar difference. In their study in the setting of lower limb orthopedic surgery in trauma patients, mean duration of analgesia was 242 minutes with 10.0 mcg of adjuvant dexmedetomidine compared to 227 minutes with 5.0 mcg. Gupta et al.16 observed that the addition of intrathecal dexmedetomidine significantly prolonged the analgesia duration (478 min) compared to plain intrathecal ropivacaine (242 min). Other studies report similar findings in other types of surgery, such as urological procedures,15,17,18 and also in children19 and elderly patients.20

Though there were variations over time, vital parameters (HR, SBP, DBP, MAP, and RR) remained comparable between study groups at all assessment time points. Similar findings have been reported in other studies with intrathecal dexmedetomidine as adjuvant to bupivacaine.1,13

Bradycardia, hypotension, and postoperative nausea were encountered in a few subjects. However, the figures were comparable between groups and no serious or unexpected events were encountered. When administered intrathecally, α2-agonists have dose dependent sedative effects. Doses of dexmedetomidine selected in our study covered a relatively narrow range which explains the comparable sedation in all the groups. The RSS in fact did not exceed 2 in any subject which is reassuring from the safety point of view. Thus, dexmedetomidine is safe as an adjuvant to spinal anesthesia with bupivacaine. The safety aspect is corroborated in multiple other studies.1,12-15

The exact mechanisms by which α2-adrenoceptor agonists prolong the duration of sensory and motor block, and the duration of analgesia, are not well understood. Local anesthetics exert their action after binding to voltage gated sodium channels whereas α2-adrenoceptor agonists exert their action by binding to pre-synaptic C fibers and post-synaptic dorsal horn neurons. Possibly, these agents inhibit the release of C fiber transmitters and hyperpolarize the post-synaptic dorsal horn neurons.21,22 Potential local anesthetic toxicity may be reduced by using α2-adrenoceptor agonists that can prolong sensory and motor blocks and reduce local anesthetic requirement. Interestingly, in addition to subarachnoid block as in our study, dexmedetomidine as adjuvant has been researched in various other regional blocks (axillary, paravertebral, infraclavicular brachial plexus, or interscalene) and shows promising results in most situations.23

There are limitations to our study. The postoperative observation period was relatively short, and our VAS assessment was no more frequent than hourly after 2 hours. Also, our findings are not generalizable to younger (< 20 years) or older (> 60 years) patients as these age ranges are not represented in the recruited subjects. Finally, the improvements we observed in in our primary and secondary efficacy measures, though statistically significant are clinically modest and may not represent a substantial advantage in all cases.

Conclusions

Despite these limitations, we can conclude that intrathecal dexmedetomidine (10.0 mcg), as adjuvant to 0.5% hyperbaric bupivacaine (15.0 mg) in spinal anesthesia, facilitates rapid onset sensory and motor block and satisfactorily prolongs the duration of postoperative analgesia. Although absolute differences are modest, the results are better compared to 5.0 and 7.5 mcg doses. Hemodynamic parameters remain stable, and undue sedation or serious adverse events are unlikely at this dose.

Acknowledgments

Authors wish to acknowledge the cooperation received from OT sisters and support staff during the conduct of the study and Prof. Panchanan Kundu, Principal, Midnapore Medical College, Midnapore, India, for providing logistical support.

Conflict of Interest

None of the authors declare any conflict of interest, financial or otherwise, in the results of the study.


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