Summary
Purpose
To assess the effects of dexmedetomidine on the duration of sensory and motor block, postoperative analgesia, hypotension, bradycardia, and side effects in patients undergoing spinal anesthesia.
Methods
Two researchers searched MEDLINE, EMBASE, and the Cochrane controlled trial register independently for randomized controlled trials comparing dexmedetomidine with a placebo without any language restrictions.
Results
A total of 412 patients from eight trials were included in this study. The results revealed that dexmedetomidine was statistically significant in prolonging the duration of sensory block (mean difference, MD = 73.55; 95% CI, [55.69, 91.40] P < 0.00001, I 2 = 89%) and motor block (MD = 59.11; 95% CI, [29.58, 88.65] P < 0.00001, I 2 = 91%) and the time to first request for postoperative analgesia (MD = 245.77, 95% CI, [143.53, 348.00] P < 0.00001, I 2 = 98%). The occurrence of hypotension (OR = 0.60, 95% CI, [0.3–1.23], P = 0.40, I 2 = 3%) and side effects (OR = 0.9, 95% CI, [0.36–2.22], P = 0.88, I 2 = 0%) was not significantly different between dexmedetomidine and placebo. However, dexmedetomidine was associated with more frequent bradycardia requiring atropine (OR = 7.55; 95% CI, [2.76–20.63], P = 0.63, I 2 = 0%).
Conclusions
This meta‐analysis has shown that dexmedetomidine prolonged the duration of spinal anesthesia and improved postoperative analgesia and did not increase the incidence of hypotension and adverse events, but needs more atropine to reverse bradycardia.
Keywords: Bradycardia, Dexmedetomidine, Duration of sensory and motor block, Hypotension, Postoperative analgesia, Side effects
Introduction
Spinal anesthesia was used widely for patients undergoing urological procedures and lower limb surgery. Different adjuvants such as morphine, fentanyl, and clonidine had been used to prolong spinal anesthesia, providing the possible advantages of the better pain control in the early postoperative period and reduced deep vein thrombosis. For example, the combination of low‐dose bupivacaine and opioids provides satisfactory analgesia for spinal anesthesia 1. Clonidine, an α2‐agonist, has been used extensively in the intrathecal route 2, 3, 4, 5. It prolongs the duration of spina blockade as well as postoperative analgesia 6, 7. Clonidine also has been used intravenously within 1 h after the spinal block and found that it prolonged bupivacaine spinal anesthesia for approximately 1 h without adverse effect 8.
Dexmedetomidine, a highly selective α2‐adrenoreceptor agonist, has been used for premedication and as an adjunct to general anesthesia. Intravenous dexmedetomidine decreases the inhalational anesthesia and opioid requirements during general anesthesia 9. Also, it has been used safely in patients undergoing surgical procedures under regional anesthesia 10, 11, and we hypothesize that intravenous or intrathecal dexmedetomidine might prolong the duration of spinal analgesia and decrease postoperative analgesia similar to clonidine.
Methods
Searching Strategy
Two researchers searched the MEDLINE, EMBASE, and the Cochrane library independently. Mesh and key words used for the searches included “dexmedetomidine,” “spinal anesthesia,” “intrathecal,” “intravenous”. References cited in these articles were also obtained to prevent missing of articles. Double blinded, randomized control trials on dexmedetomidine versus placebo, without any language restrictions, were included in this study.
Inclusion Criteria
Intravenous dexmedetomidine and intrathecal dexmedetomidine were all included, and participants of any sex but just adult were included, selecting low dose of dexmedetomidine (≤5 μg) when using in intrathecal route. Children and use high dose of dexmedetomidine were excluded.
Data Extraction
Two reviewers (Xiao‐Yin Niu and Xi‐Bing Ding) selected eligible studies independently, extracted data and recorded the trial characteristics with a standard data collection form. Any conflict was resolved by mutual agreement. The following data were collected: name of first author, publishing date, number of patients, the drugs for spinal anesthesia, the method of dexmedetomidine, the duration of sensory and motor block, postoperative analgesia, hypotension, bradycardia, and side effects (Table 1). All data collected were defined according to the definition chosen by individual trial and the data not standardized. Dexmedetomidine or saline was given by infusion in the trials by Hong 12, Kaya 13, Elcicek 14, Al‐Mustafa 15, whereas in the other trials by Solanki 16, Abu‐Halaweh 17, Kanazi 18, Gupta 19, intrathecal route was used. The first author of two studies 15, 17 was the same person, so we used the second author's name “Abu‐Halaweh” to represent 17.
Table 1.
The design of the included studies
| Author | Years | Application | NO. | Blind | Treatment | Operation | Drug for spinal anaesthesia | Primary endpoint | Secondary endpoints |
|---|---|---|---|---|---|---|---|---|---|
| Hong | 2012 | DM/NS | 26 vs. 25 | Double | Intravenous | TURP | Bupivacaine | Duration of sensory and motor block | Hypotension, bradyandia, side effects, pain after operation |
| Kaya | 2010 | DM/MZ/NS | 25 vs. 25 vs. 25 | Double | Intravenous | TURP | Bupivacaine | Duration of sensory and motor block | Hypotension, bradyandia, pain after operation |
| Elcicek | 2010 | DM/NS | 30 vs. 30 | Double | Intravenous | Lower limb surgery | Ropivacaine | Duration of sensory and motor block | Bradycardia, side effects |
| Al‐Mustafa | 2009 | DM/NS | 24 vs. 24 | Double | Intravenous | TURP | Bupivacaine | Duration of sensory and motor block | Hypotension, bradycardia side effects |
| Solanki | 2013 | D/C/B | 30 vs. 30 vs. 30 | Double | Intrathecal | Lower limb surgery | Bupivacaine | Duration of sensory and motor block | Hypotension, side effects pain after operation |
| Abu‐Halaweh | 2009 | D5/D10/DN | 21 vs. 21 vs. 22 | Double | Intrathecal | TURP/TURBT/TVT | Bupivacaine | Duration of sensory and motor block | Hypotension, bradycardia side effects |
| Kanazi | 2006 | D/C/B | 20 vs. 20 vs. 20 | Double | Intrathecal | TURP/TURBT | Bupivacaine | Duration of sensory and motor block | Hypotension, bradycardia side effects |
| Gupta | 2011 | DM/NS | 30 vs. 30 | Double | Intrathecal | Lower limb surgery | Ropivacaine | Duration of sensory and motor block | Hypotension, bradycardia, side effects, pain after operation |
DM,D, Dexmedetomidine; NS, B, Saline; D5, 5 μg dexmedetomidine; D10, 10 μg dexmedetomidine; C, Clonidine; TURP, Transurethral resection of the prostate; TURBT, Transurethral resection of bladder tumors; TVT, Placement of tension‐ free vaginal tape.
The level of sensory block was assessed with the patients in the supine position using pinpricks or ice cubes in the mid‐thoracic line. Motor block was assessed immediately after sensory block assessment using a Modified Bromage Scale 20 (0 = no paralysis; 1 = unable to raise extended leg; 2 = unable to flex knee; 3 = unable to flex ankle).
Assessment of Bias Risk
We used Cochrane Handbook v5.0.2 to assess the risk of bias for all eligible studies 21. The following information was evaluated: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and each of them was graded as “high risk of bias,” “low risk of bias,” and “uncertain of bias.” Two reviewers (Xiao‐Yin Niu and Xi‐Bing Ding) evaluated the studies independently, while discrepancies were discussed with the third reviewer (Quan Li) until consensus was achieved.
Statistical Analysis
The main outcomes of this study were the duration of sensory and motor block, hypotension, side effects, and the time to first request for postoperative analgesia and the request for atropine. To assess the duration of sensory and motor block, we performed a subgroup analysis comparing intravenous and intrathecal dexmedetomidine. The duration of sensory and motor block and the time to first request for postoperative analgesia are continuous data, so they are reported as mean difference (MD) with 95% confidence interval (CI), using a random effects model. The occurrence of hypotension, side effects, and the request of atropine are categorical outcomes, so they are reported as relative risk (RR) with 95% confidence interval (CI), using a fixed effects model. Statistical heterogeneity was assessed using the I 2‐test.
Results
Characteristics of Eligible Trials
A total of eight randomized controlled trials involving 412 patients were identified (206 received dexmedetomidine and 206 did not). The process is shown by The QUOROM 22 flowchart in detail in Figure 1. The design of the included studies in the meta‐analysis is shown in Table 1. The summary of results from each individual study is shown in Table 2. Six studies 12, 13, 15, 16, 17, 18 used bupivacaine and two studies 14, 19 used ropivacaine for spinal anesthesia. Four studies 12, 13, 14, 15 used dexmedetomidine in the intravenous route and four studies 16, 17, 18, 19 used it in the intrathecal route. In the four studies that used intravenous route, one compared dexmedetomidine with midazolam and saline 13, whereas the remaining three compared dexmedetomidine with saline. In the four studies that used intrathecal route, two compared low dose of dexmedetomidine (≤5 μg) with clonidine and saline 16, 18, the third study compared low dose of dexmedetomidine (5 μg) with high dose of dexmedetomidine (10 μg) and saline 17, and the fourth study compared low dose of dexmedetomidine (5 μg) with saline 19, and in the first three studies, the dexmedetomidine or the saline was supplemented with bupivacaine, and in the last study, it was supplemented with ropivacaine. This meta‐analysis just compared dexmedetomidine with saline, so we ignored clonidine and midazolam. Besides, we selected the low dose of dexmedetomidine. We excluded one study because it compared the high dose of dexmedetomidine (10 μg) with saline.
Figure 1.
Flowchart.
Table 2.
The summary of results from individual study
| Author | Duration of sensory block (min) | Duration of motor block (min) | The time to first request for post‐operative analgesia | The occurrence of hypotension | The side effects | The requirement of atropine |
|---|---|---|---|---|---|---|
| Hong | ||||||
| DM | 78 ± 35 | 46 ± 42 | 6.6 ± 2.5 h | 1/26 | 2/26 | 10/25 |
| NS | 39 ± 18 | 24 ± 33 | 2.1 ± 1.8 h | 2/25 | 2/25 | 1/26 |
| Kaya | ||||||
| DM | 145 ± 26 | 193 ± 27 | 216 ± 3 min | 2/25 | 2/25 | |
| NS | 97 ± 27 | 180 ± 34 | 122 ± 34 min | 4/25 | 1/25 | |
| Elcicek | ||||||
| DM | 249 ± 56 | 284 ± 63 | 3/30 | 9/30 | ||
| NS | 195 ± 53 | 225 ± 53 | 2/30 | 0/30 | ||
| Al‐Mustafa | ||||||
| DM | 262 ± 35 | 200 ± 43 | 0/24 | 0/24 | 2/24 | |
| NS | 165 ± 32 | 138 ± 31 | 4/24 | 1/24 | 0/24 | |
| Solanki | ||||||
| DM | 302 ± 68 | 279 ± 67 | 824 ± 244 min | 7/30 | 3/30 | |
| NS | 224 ± 44 | 209 ± 45 | 406 ± 118 min | 5/30 | 2/30 | |
| Abu‐Halaweh | ||||||
| DM | 277 ± 23 | 246 ± 26 | 0/21 | 0/21 | 0/21 | |
| NS | 166 ± 33 | 140 ± 32 | 4/22 | 1/22 | 0/22 | |
| Kanazi | ||||||
| DM | 303 ± 75 | 250 ± 76 | 1/20 | 0/20 | 0/20 | |
| NS | 190 ± 48 | 163 ± 47 | 1/20 | 0/20 | 0/20 | |
| Gupta | ||||||
| DM | 126 ± 17 | 478 ± 21 min | 2/30 | 0/30 | 2/30 | |
| NS | 63 ± 8 | 242 ± 22 min | 1/30 | 1/30 | 0/30 | |
In the four studies that used intravenous dexmedetomidine, two used a loading dose of 1 μg/kg dexmedetomidine over 10 min: the maintenance dose in one study was 0.5 μg/kg/h 15 and another was 0.4 μg/kg/h 14. In the remaining two studies, one study received dexmedetomidine 0.5 μg/kg 13 and another was 1 μg/kg 12. The treatment of bupivacaine was also different: two studies used 12.5 mg, one study used 6 mg, two studies used 15 mg, and one study used 12 mg. One study used 22.5 mg ropivacaine.
Risk of Bias
The risk of bias assessment in the included studies showed that most of the studies had low risk of bias (Table 3). As we could not access each study's original protocol, all studies were considered free from “selective reporting” bias.
Table 3.
The risk of bias assessment in the included studies
| Author | Random sequence generation | Allocation concealment | Blinding | Incomplete outcome data | Selective reporting |
|---|---|---|---|---|---|
| Hong | Low | Unclear | Low | Low | Low |
| Kaya | Low | Unclear | Low | Low | Low |
| Elcicek | Low | Low | Low | Low | Low |
| Al‐Mustafa | Unclear | Unclear | Low | Low | Low |
| Solanki | Low | Unclear | Low | Low | Low |
| Abu‐Halaweh | Low | Low | Low | Low | Low |
| Kanazi | Low | Unclear | Low | Low | Low |
| Gupta | Low | Unclear | Low | Low | Low |
The Duration of Sensory and Motor Block
Whatever intravenous route (sensory: MD = 59.25; 95% CI, [33.58, 84.91] P < 0.0001, I 2 = 87%, motor: MD = 37.79; 95% CI, [12.53, 63.05] P = 0.0009, I 2 = 82%) or intrathecal route (sensory: MD = 89.59; 95% CI, [59.09, 120.10] P < 0.00001, I 2 = 90%, motor: MD = 90.18; 95% CI, [66.27, 114.10] P = 0.1, I 2 = 56%) or pooled (sensory: MD = 73.55; 95% CI, [55.69, 91.40] P < 0.00001, I 2 = 89%, motor: MD = 59.11; 95% CI, [29.58, 88.65] P < 0.00001, I 2 = 91%), dexmedetomidine could prolong the duration of sensory and motor block. But there was significant heterogeneity in the duration of sensory (I 2 = 87%) and motor (I 2 = 82%)block when intravenous dexmedetomidine, whereas the heterogeneity was not evident in motor block but still significant in sensory block when intrathecal dexmedetomidine (sensory: I 2 = 90%, motor: I 2 = 56%); however, when pooled, the heterogeneity of both was significant (sensory: I 2 = 89%, motor: I 2 = 91%; Figures 2 and 3).
Figure 2.
Forest plot for duration of sensory block in minutes.
Figure 3.
Forest plot for duration of motor block in minutes.
The Side Effects and the Occurrence of Hypotension
Seven studies recorded the side effects 12, 14, 15, 16, 17, 18, 19 and seven studies recorded the occurrence of hypotension 12, 13, 15, 16, 17, 18, 19. But in one study, there were no any adverse events occurring in the dexmedetomidine and saline group. The side effects included nausea, headache, vomiting, shivering. The effects of dexmedetomidine on the side effects (OR = 0.9; 95% CI, [0.36–2.22], P = 0.88, I 2 = 0%) and hypotension (OR = 0.60; 95% CI, [0.3–1.23], P = 0.40, I 2 = 3%) both were not significantly different from saline (Figures 4 and 5). And the heterogeneity of both was not significant. When studying the effects of dexmedetomidine on the side effects and hypotension, we pooled the articles of intravenous and intrathecal dexmedetomidine.
Figure 4.
The effect of dexmedetomidine on the side effects.
Figure 5.
The effect of dexmedetomidine on the occurrence of hypotension.
The Time to First Request for Postoperative Analgesia
In the eight studies, there were four studies 12, 13, 16, 19 described the time to first request for postoperative analgesia. Dexmedetomidine could prolong the time to first request for postoperative analgesia (MD = 245.77; 95% CI, [143.53, 348.00], P < 0.00001, I 2 = 98%). There was significant heterogeneity in the time to first request for postoperative analgesia among the four studies (Figure 6).
Figure 6.
Forest plot for the time to first request for postoperative analgesia.
The Requirement of Atropine
There were seven studies reporting the requirement of atropine 12, 13, 14, 15, 17, 18, 19, and in two studies 17, 18, the requirement of atropine was zero in the two groups. However, the analysis still indicated that dexmedetomidine could cause bradycardia in many cases, requiring atropine (MD = 7.55 95% CI [2.76, 20.63], P = 0.63, I 2 = 0%; Figure 7).
Figure 7.
The effect of dexmedetomidine on the requirement of atropine.
Discussion
Dexmedetomidine is a new drug for anesthesia, and more and more anesthesiologists use it to improve the quality of anesthesia. In this meta‐analysis, using dexmedetomidine during spinal anaesthesia prolonged the duration of sensory and motor block and the time to ?rst request for post‐operative analgesia. The use of dexmedetomidine made more patients need atropine but did not increase the risk of side effects and hypotension.
Our results showed that dexmedetomidine might be able to prolong the duration of sensory and motor block. But there was high level of heterogeneity between the studies in this outcome. The possible explanations could be the following aspects. First, the dose of bupivacaine and dexmedetomidine was different; second, the method of using dexmedetomidine is not unified, including intravenous dexmedetomidine and intrathecal dexmedetomidine; third, the evaluation criteria of the sensory and motor block recovery was different, using the Modified Bromage Scale 20 (0 = no paralysis; 1 = unable to raise extended leg; 2 = unable to flex knee; 3 = unable to flex ankle) to evaluate the motor block recovery. Motor block duration of some studies was the time required to return to Modified Bromage Scale 1, the remaining was Modified Bromage Scale 0; and fourth, the type of surgery was variable.
Our results showed that dexmedetomidine would not increase the risk of side effects, such as nausea, headache, vomiting, shivering, and hypotension. Al‐Ghanem 23 had reported intrathecal dexmedetomidine without any adverse neurological consequences, and four articles 12, 15, 17, 18 in this study demonstrated that no patient reported neurological impairment within 2 weeks after surgery. Previous studies reported that dexmedetomidine caused no or minimal respiratory depression 24. Dexmedetomidine is usually used in general anesthesia, and it could reduce blood pressure and heart rate. Besides, we all know that hypotension occurs easily in spinal anesthesia and it can be treated with either ephedrine or phenylephrine 25. When used in spinal anesthesia, it did not induce hypotension. However, we found that it increased the risk of bradycardia requiring atropine. The bradycardia could be reversed by atropine, so serious outcome would not happen. The heterogeneity between the studies in these outcomes was not significant.
Patients usually feel so pain that they need analgesia after surgery. The use of dexmedetomidine in spinal anesthesia might prolong the time to first request for postoperative analgesia. But the heterogeneity was significant. Only four articles involved this outcome, and the subjectivity of different patients and the type of surgery may cause the significant heterogeneity. The mechanism of the analgesic effect of dexmedetomidine remains unclear and may be related to the involvement of Protein Kinase B/Akt 26.
There are several limitations in our study. First, there were high levels of heterogeneity when evaluating the duration of sensory and motor block and the time to first request for postoperative analgesia due to different intrathecal drugs (bupivacaine, ropivacaine), patient cohorts, evaluation criteria, type of surgery. Second, the sample sizes of these studies were small which may lead to a small‐study effect; thus, we should be cautious of the application of this meta‐analysis. Furthermore, the safety of dexmedetomidine that used in intrathecal route in humans has not been extensively studied. Dexmedetomidine may appear safe in the short term 27, 28, but subsequent long‐term human neurotoxicity data, including the investigation of potential delayed adverse neurological effects, are lacking 29. Third, two studies 14, 15 used a loading dose of dexmedetomidine and maintained at a certain dose, another two studies 12, 13 just maintained at a certain dose. The difference between them may cause the different outcomes, which we did not analyse. Fourth, dexmedetomidine is known to have a sedative effect, providing better conditions for patients 30. Patients may be easily aroused and remain cooperative, which is different from other sedatives 31. It is reported that dexmedetomidine may cure the bipolar disorder 32, 33. We did not study the sedative effect because the data in the studies were not uniform. Intravenous and intrathecal dexmedetomidine were both involved in this meta‐analysis, but we cannot analyse the difference between them. We will pay close attention to the clinical trials about this.
In summary, we found that the use of dexmedetomidine including intravenous and intrathecal could statistically significantly prolong the duration of sensory and motor block and the time to first request for postoperative analgesia. There was no increased risk of the side effects and the occurrence of hypotension, but the risk of bradycardia increased.
Funding
This study was supported financially by the National Natural Science Foundation (81270135) and Shanghai Education Committee Key Project (13ZZ024).
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgments
We are grateful for the support from the National Natural Science Foundation. We also acknowledge all the authors whose publications were included in this study.
The first two authors contributed equally to this work.
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