Dexmedetomidine is a novel selective α-2 adrenoceptor agonist1 primarily used for IV sedation. The off-label use of dexmedetomidine as a local anesthetic adjuvant has been increasingly reported to prolong the duration of anesthesia produced by single-injection neuraxial2–6 and peripheral7–10 nerve blockade. Central mechanisms11–13 have been proposed to explain this phenomenon, suggesting that routes of administration other than intrathecal application may produce similar effects. In fact, clonidine, another α-2 adrenoceptor agonist,14 has been shown to prolong neuraxial15–19 and peripheral20–23 nerve blockade when administered either as a local anesthetic admixture, IV, or even orally. However, most trials examining the effects of IV dexmedetomidine on the duration of regional anesthesia are limited by their small sample size and have generated quantitatively heterogeneous results.24–31 This systematic review and meta-analysis primarily evaluated whether IV dexmedetomidine can prolong the duration of sensory block associated with spinal anesthesia.
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)32 recommendations were followed in the preparation of this review.
We sought to identify randomized controlled trials (RCTs) that investigated the facilitatory effects of IV administration of dexmedetomidine (dexmedetomidine group) compared with placebo (control group) on single-injection local anesthetic-based spinal anesthesia as a primary or secondary outcome measure. RCTs were excluded if dexmedetomidine was tested against an active comparator26 that may also possess facilitatory effects on local anesthetic action, if dexmedetomidine was administered intrathecally as part of a local anesthetic admixture2 or administered via a non-IV route,33–35 or no spinal blocks were performed.24,36–39
RCTs were retrieved from the United States National Library of Medicine database, MEDLINE; the Excerpta Medica database, Embase; Cochrane Database of Systematic Reviews; and Cochrane Central Register of Controlled Trials databases (January 1985–July 2012). The search terms dexmedetomidine, medetomidine were used in combination with the search terms intravenous, IV, systemic, and sedation. The results of the search were combined by the Boolean operator AND with medical subject headings spinal block/spinal anesthesia/intrathecal anesthesia/subarachnoid block and the medical subject headings analgesia/pain relief/pain control/pain prevention/and pain management. Additionally, we hand-searched the bibliographies of relevant reviews and identified RCTs that met the inclusion criteria. The search was restricted to articles in the English language. Unpublished trials were excluded. A final list of qualifying studies was derived by consensus; the authors disagreed over the eligibility of 1 trial,40 which was resolved by majority vote.
Data Collection and Presentation
The quality of the reviewed RCTs was assessed independently by 2 of the authors (FWA and RB) using the Jadad score,41 with a final score assigned for each trial by consensus. The outcomes sought in each trial assessed included block characteristics, postoperative analgesia,42,43 and the common dexmedetomidine-related adverse effects.44,45 For the purposes of the present review, we sought to evaluate the durations of sensory and motor block, the onset times of sensory and motor block, pain visual analog scale scores, time to first analgesic request, postoperative analgesic consumption, and dexmedetomidine-related adverse effects (hypotension, bradycardia, respiratory depression, and postoperative sedation). Using a standardized data collection form, data were extracted and recorded independently by the authors. Any discrepancies were resolved by reinspection of the original data.
Data were entered into the statistical program (by FWA) and rechecked (by RB). When possible, meta-analytic techniques (Revman 5.1, Cochrane Library, Oxford, England) were used to combine the data. To facilitate clinical interpretation, the ratio of means, standard error, and 95% confidence intervals (CIs) were calculated for continuous outcomes that examined change from baseline by measuring the time-to-event.46,47 Random effect modeling48 was used to analyze the remaining continuous and dichotomous outcomes. The odds ratio and 95% CI were calculated for the dichotomous outcomes, whereas the standardized mean difference and 95% CI were calculated for the continuous outcomes. Differences were considered statistically significant when the 95% CI did not include 0 for the standardized mean difference and 1 for odds ratio. The I2 statistic was used to assess heterogeneity.49
We identified 7 intermediate to high-quality trials29,31,40,50–53 that investigated the facilitatory effects of IV dexmedetomidine on spinal anesthesia and met our inclusion criteria. The 7 trials included 364 patients, 184 in the dexmedetomidine group and 180 in the control group, who qualified for analysis. Figure 1 summarizes the search results, including the RCTs retrieved, excluded, and presently reviewed. Tables 1 and 2 summarize the characteristics and the outcomes sought in each of the reviewed trials.
Sensory Block Duration
The duration of sensory block was assessed in all 7 trials and is presented in Figure 2. When IV dexmedetomidine was administered to patients undergoing surgery under spinal anesthesia, a prolongation of the sensory block duration was observed compared with placebo. This prolongation, expressed as the lower CI limit (point estimate), was at least 34% (point estimate: 38%), P < 0.00001, I2 = 87%.
The duration of motor block was assessed in all 7 trials and is presented in Figure 3. Motor block was prolonged by at least 17% (point estimate: 21%), P < 0.00001, I2 = 85% in patients receiving IV dexmedetomidine compared with placebo (Table 3).
Qualitatively, only 2 trials40,51 examined sensory block onset time and detected no difference between the dexmedetomidine and control groups. The onset time of motor block was assessed by 2 trials;50,51 whereas one50 described no difference in the onset time of motor block without providing the raw data, another51 reported a 1-minute difference in favor of the dexmedetomidine group.
Postoperative pain scores and time to first analgesic request were evaluated by 229,31 and 329,31,50 trials, respectively. IV dexmedetomidine reduced postoperative visual analog scale pain scores at 6 hours by 6 mm (95% CI, −1.19 to −0.03, P = 0.04), or a relative reduction of 61%. IV dexmedetomidine also prolonged the time to first analgesic request by at least 53% (point estimate: 60%), P<0.00001, I2 = 98% in patients undergoing surgery under spinal anesthesia (Table 3).
None of the trials examined analgesic consumption, although 1 trial29 reported fewer patients requesting postoperative analgesic supplementation in the dexmedetomidine group.
Dexmedetomidine-Related Adverse Effects
Because of the diversity of definitions of dexmedetomidine-related adverse effects used by investigators, we reported the results of these outcomes as “standardized units.” Hypotension and bradycardia were reported in all 7 trials,29,31,40,50–53 respiratory depression was examined in 6,29,31,40,51–53 and postoperative sedation was assessed in 4.29,51–53 Although there was no difference in the incidence of hypotension and postoperative sedation between the groups, bradycardia was more common (3.7-fold increase, 95% CI, 1.53–8.82, P = 0.004) among patients who received IV dexmedetomidine (Table 3).
The incidence of bradycardia was higher in trials where the dexmedetomidine initial loading dose was infused over a shorter duration, such as 531 or 1051 minutes, compared with those trials where the initial loading dose was administered over 20 minutes.50 Bradycardia was transient and easily reversed with IV atropine; no delayed bradycardia was reported. None of the patients in the reviewed trials experienced serious respiratory complications.
The maximal level of sensory block produced by spinal anesthesia was reported in 5 trials.29,31,40,50,51 Quantitative analysis of the pooled results showed no difference in maximal sensory block level between the dexmedetomidine and control groups (Table 3).
Our review suggests that IV dexmedetomidine can prolong the duration of sensory block when administered to patients undergoing spinal anesthesia. Additionally, IV dexmedetomidine can prolong the duration of motor block to a lesser extent and delay the time to first analgesic request after spinal anesthesia. These effects are accompanied by an increased risk of transient reversible bradycardia.
Clonidine, another α-2 adrenoceptor agonist, has long been known to prolong spinal anesthesia when administered IV.18,54,55 Compared with clonidine,18 our findings suggest that IV dexmedetomidine produces a greater degree of differential blockade by preferentially blocking myelinated A α-fibers involved in sensory conduction over unmyelinated C fibers involved in motor conduction. Such selectivity may be useful in settings where prolonged analgesia but not necessarily prolonged motor block is desirable, such as with low-dose spinal anesthesia used in cesarean deliveries.56 IV dexmedetomidine may actually serve a dual purpose in the setting of spinal anesthesia, both by enhancing the local anesthetic effects and providing intraoperative sedation, the latter often implicated in unsuccessful neuraxial techniques.57 Although the present analysis failed to detect any differences in postoperative sedation between groups, this finding most likely reflects the very short half-life of IV dexmedetomidine,58 which is one of several unique features that makes this drug such a useful sedative drug.
The results of this review are subject to several limitations. First, the limited number of small trials included in this review is marked by considerable heterogeneity that may undermine the generalizability of our results. The range of doses and types of local anesthetics used for spinal anesthesia as well as the doses of IV dexmedetomidine may also affect the reliable translation of our results into clinical practice. Specifically, initial loading doses of dexmedetomidine varied between 0.529 and 1 µg/kg;31,40,50–53 most trials also included a maintenance dexmedetomidine infusion,40,50–53 with rates varying between and 0.252 and 0.550 µg/kg/h, over a duration varying between 50 minutes40,51 and the entire length of surgery50,53 (Table 2). Furthermore, the duration of administration of the initial dexmedetomidine dose varied between 5,31 10,29,40,51–53 and 2050 minutes among the various trials. Although these variations likely reflect the absence of dose-ranging studies investigating the optimal dose of IV dexmedetomidine, it is nonetheless noteworthy that a significant prolongation of anesthetic effect was observed with doses as low as 0.5 µg/kg29 administered as isolated boluses in the absence of maintenance infusion. The lack of standardized assessment of sensory block duration (e.g., time to 2-dermatome regression,29,31,40,51 time to S1 regression,52,53 and to L5–S2 regression)50 may also limit the generalizability of our results. Similar variability was observed in the measurement of other outcomes such as motor block duration and time to first analgesic.
In summary, IV dexmedetomidine can prolong the duration of sensory and motor blocks as well as the time to first analgesic request of spinal anesthesia. Our findings suggest that the administration of IV dexmedetomidine may limit the role, if any, for the direct intrathecal application of dexmedetomidine, which lacks adequate safety data at the present time.
Name: Faraj W. Abdallah, MD.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Faraj W. Abdallah has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Amir Abrishami, MD.
Contribution: This author helped analyze the data.
Attestation: Amir Abrishami has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Richard Brull, MD, FRCPC.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Richard Brull has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
This manuscript was handled by: Terese T. Horlocker, MD.
The authors thank Dr. Jan O. Friedrich, from the Departments of Medicine, Critical Care, and the Keenan Research Centre in the Li Ka Shing Knowledge Institute at the St. Michael’s Hospital, University of Toronto, Canada, for his valuable contribution.
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