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The Safety of Perioperative Esmolol: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Yu, Savio K. H. BHSc; Tait, Gordon PhD; Karkouti, Keyvan MD, MSc, FRCPC; Wijeysundera, Duminda MD, FRCPC; McCluskey, Stuart MD, PhD, FRCPC; Beattie, W. Scott MD, PhD, FRCPC

doi: 10.1213/ANE.0b013e3182025af7
Cardiovascular Anesthesiology: Research Reports
Chinese Language Editions

BACKGROUND: Although β blockers have been found to decrease perioperative myocardial infarction (MI), β-blocker-mediated hypotension is associated with postoperative stroke and mortality. In this systematic review we assessed the safety and efficacy of the β1-specific, adrenergic receptor antagonist esmolol in noncardiac surgery. Safety was assessed by analyzing the incidence of postoperative hypotension and bradycardia, and efficacy was assessed by analyzing the incidence of myocardial ischemia.

METHODS: We searched electronic databases for randomized placebo-controlled trials of the perioperative use of esmolol in noncardiac surgery. We abstracted data on design, demographics, hemodynamic changes (planned or unplanned), myocardial ischemia, and MI. Heterogeneity was assessed via meta-regression.

RESULTS: Our search identified 67 trials, which were well matched for study characteristics. The quality of the studies was limited by small sample size and poorly defined allocation concealment. Overall, the analysis demonstrates an increased incidence of unplanned hypotension (OR 2.13; 95% confidence interval [CI], 1.48 to 3.04), which was found to be dose related (R2 = 0.408). An increased incidence of significant bradycardia was not demonstrated (OR 1.18; 95% CI, 0.69 to 2.02). Dose titration was shown to influence both the change in arterial blood pressure and heart rate. In comparison with placebo, esmolol decreased the frequency of myocardial ischemia in the 7 evaluating studies (OR 0.17; 95% CI, 0.02 to 0.45). We did not assess the effects of esmolol on the incidence of MI or stroke because the incidence of these events was too infrequent in the retrieved studies.

CONCLUSION: This review suggests that titration of esmolol to a hemodynamic end point can be safe and effective. Safety data from studies in higher-risk patients are needed to establish a perioperative safety and efficacy profile of esmolol.

Published ahead of print December 2, 2010 Supplemental Digital Content is available in the text.

From the Department of Anesthesia and Pain Management, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Funding: No funding.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to W. Scott Beattie, MD, PhD, FRCPC, R. Fraser Elliot Chair in Cardiac Anesthesia, Department of Anesthesia and Pain Management, University Health Network, Eaton North 3-464, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada. Address e-mail to scott.beattie@uhn.on.ca.

Accepted August 30, 2010

Published ahead of print December 2, 2010

Perioperative myocardial infarction (MI) is a leading cause of postoperative morbidity and mortality.1 The etiology of postoperative MI is the subject of some debate but is thought to include prolonged ischemia resulting from tachycardia.2,3 As a class of drugs, β-adrenergic receptor blockers have been advocated to reduce the incidence of postoperative MI because they almost universally reduce myocardial oxygen consumption and hence the incidence and degree of ischemia.4 Meta regression has shown that the degree of cardio protection afforded by β-blockers is directly related to the degree of heart rate reduction.5

In the POISE trial the β-blocker metoprolol succinate was demonstrated to result in a reduced incidence of perioperative MI. Nonetheless, in that study there was a 30% increase in all-cause mortality in the metoprolol treated group due, in part, to a 2-fold increase in the incidence of stroke. A post hoc analysis of POISE found that both stroke and death were associated with an increased incidence of hypotension, bradycardia, and significant bleeding.a6 It has been proposed that titration of β-blockers may result in less-frequent hypotension, thereby increasing both the safety and efficacy of perioperative β blockade.7 Bisoprolol was found to provide significant cardioprotection, in the DECREASE-1 through DECREASE-5 randomized trials, without increased adverse events in comparison with placebo.811 Although the results of the DECREASE studies are at odds with the findings of the POISE trial,12,13 it has been postulated that the differences may be explained in part by the study design in which bisoprolol was titrated to heart rate effect over a period of 30 days before surgery. Unfortunately, the protocol adopted by the DECREASE group, [titration 30 days before surgery] would be difficult to implement in North America. Alternatively, the use of the short-acting β-selective drug esmolol (effective half life of ∼9 minutes) may allow for individualizing drug dosage, by titrating the drug to a specific hemodynamic end point, thus providing for cardioprotection while minimizing drug-induced bradycardia and hypotension. In cardiac surgery, esmolol has been shown to reduce myocardial ischemia, however, while increasing the incidence of both hypotension and bradycardia.14

The purpose of this systematic review and meta-analysis was to assess the effect of esmolol on the incidence of unplanned hypotension in the perioperative period. The secondary objectives were to assess the effects of a dose of esmolol on dose-related changes in heart rate and arterial blood pressure. Finally, we assessed whether esmolol was associated with a reduction in myocardial ischemia and MI when titrated to hemodynamic end points.

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METHODS

Objectives and Definitions

The safety of the varied doses or titrated infusions of esmolol was assessed by comparing the incidence of hypotension and bradycardia with that occurring in control patients. Because of the lack of direct patient involvement, IRB approval was waived. To be eligible for inclusion, studies had to be prospective randomized trials comparing esmolol with a control and include both the dose of esmolol, details of the bolus or infusion protocols, or both. Second, groups had to be similar in all respects except for administration of esmolol. In multiple armed studies, at least 2 of the arms must have met the aforementioned criteria to be eligible. Studies were excluded if they included the use of other vasoactive medications, because this would alter the incidence of hypotension and bradycardia obscuring the effect of esmolol. The definitions of hypotension and bradycardia were those used by the individual study authors. The cardioprotective efficacy of esmolol was assessed by comparing the incidence of perioperative myocardial ischemia or MI in the 2 arms of the studies. We used the definition of myocardial ischemia and MI of the individual study authors.

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Search Strategy

Two investigators (SY, WSB) devised the search strategy for identification of relevant articles. The initial search terms were esmolol, Brevibloc®, or esmolol hydrochloride used as keywords with the definition exploded. The “and” function was used to combine this with the term surgery [exploded]. The search was limited to human subjects and controlled clinical trials. MEDLINE was searched from 1960 to June 2009. Related articles of all the identified citations were then searched using PUBMED. Studies that were selected on the basis of information in the title and abstract were secondarily searched in Science Citation Index for additional citations. No language restrictions were applied. We contacted the manufacturer of esmolol (BAXTER HEALTHCARE Corp., New Providence, New Jersey) for data used for the initial U.S. Food and Drug Administration registration of esmolol that remained unpublished; however, no further studies were identified by this strategy. Finally, the reference lists of selected studies and review articles were reviewed for additional citations. One investigator (WSB) performed the searches, and the abstracts of the 84 articles selected for review on the basis of information in the titles and abstracts. Studies evaluating cardiac surgery were eliminated. Full-text versions of the remaining articles were retrieved, and 2 reviewers (SY, WSB) made independent assessments of study eligibility. Disagreements were resolved by consensus. All articles were then reassessed by all investigators to determine whether they met inclusion criteria. Reviewers were not blinded to authors, institutions, journal of publication, or study results.

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Data Synthesis and Analysis

Data were extracted from the selected trials by 2 reviewers (SY, WSB) and included patient characteristics (age, weight, gender, ASA class types of surgery), study quality (size of trials, randomization, blinding allocation concealment, and intention to treat), drug dosages, method of administration (bolus vs. titrated infusion), changes in arterial blood pressure, heart rate, incidence of unplanned hypotension, bradycardia, myocardial ischemia, MI, and death. Selected authors were contacted for missing information, unpublished data, or clarification of the results. For continuous data with a normal distribution, the mean value and SD for each group were recorded for each study arm. The text of each study was scanned for all adverse events, and thus all were included in the primary analysis.

We expected the studies selected for review to vary in design, quality, and the definitions of perioperative safety outcomes. We thus adopted the random effects model as our default pooling strategy. Statistical heterogeneity was assessed using the I2 statistic (16), and evaluated primarily using meta-regression (I2 ≤25%). Miller et al.15 found a significant difference in the incidence of hypotension on the basis of esmolol dose, and thus we planned a priori to assess dose–response relationships using meta-regression. In these analyses, dose was expressed on the basis of mg/kg. In studies in which the initial dose was reported as fixed dose, we estimated dose in mg/kg by dividing the fixed dose by the mean patient weights reported for that arm of the study. In the studies in which >1 dose was assessed, we compared each dose to the control arm (thus the control would be counted twice). The hemodynamic (heart rate and arterial blood pressure) response to varied doses of esmolol was assessed by calculating the maximal difference between the esmolol group and the control group in each study using the weighted mean difference (WMD). The meta-regression was then performed using the STATA (Statcorp, version 11.0, College Station, Texas) macrofunction “metaregress.” Several study-specific characteristics were also considered, including primarily dosing regimen and the infusion characteristics.

Overall characteristics of the participants—including age, gender, proportion with coronary artery disease, and proportion with diabetes—were assessed for equality in each arm of the study. The effect of study quality on the outcome was compared using blinded outcome adjudication, allocation concealment, and trial size. Our default outcome measure were summarized as odds ratios (OR) and 95% confidence interval (CI). For studies with multiple treatment arms, comparisons were made between individual doses of esmolol and control; if comparisons between individual doses of esmolol and placebo were not possible, then the esmolol arms were combined and compared with placebo. REVMAN (V.5.0, available free from the Cochrane Collaboration) and STATA software were used to pool the data.

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Sensitivity Analysis

We planned 3 subgroup analyses a priori. First, it was anticipated that in a number of studies, the dichotomous safety data (hypotension and bradycardia) would contain cells with “0” values in both the esmolol and control arms. The standard REVMAN software ignores studies in which 0 events are reported in both arms. We assessed the effect this had on outcome by using a continuity correction by adding 0.5 to each cell using STATA (v. 11) and the “metan” function to calculate the Mantel–Haenszel OR (ORMH). Second, sensitivity analyses were performed to assess the effects of model type (random vs. fixed effects). The third sensitivity analysis was conducted to assess whether the method of administration (i.e., bolus vs. infusion) affected the safety outcomes.

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RESULTS

The search strategy, outlined in Figure 1, yielded 67 trials of randomized assessments of esmolol in elective noncardiac surgery.1581 We found that these trials could be broadly classified as assessing (a) the treatment of established intraoperative hypertension20,23,27,44,70,73,81; (b) the induction of planned intraoperative controlled hypotension46,47,52,53,64; (c) the effect of esmolol administration on the need for anesthesia20,31,32,35,36,71,74,75; and (d) prophylaxis against hypertension, tachycardia, or myocardial ischemia.

Figure 1

Figure 1

Because the primary goal of this analysis was to define the safety of esmolol in patients undergoing noncardiac surgery, we conducted a post hoc subanalysis in which we eliminated (a) the studies in which the goal was to induce hypotension and (b) studies designed to treat hypertension, tachycardia, or both. We felt that this was necessary because in the treatment of hypertension, the incidence of hypotension would be less frequent, and in studies deliberately inducing hypotension, unwanted hypotension would be underreported. These studies were, however, included in the efficacy analysis. Thirteen of the studies defined significant hemodynamic adverse events a priori. These definitions generally defined bradycardia as a heart rate <50 beats per minute (bpm) (which required therapy) or hypotension as a systolic blood pressure below 90 mm Hg or a mean arterial blood pressure below 70 mm Hg. The details of the studies included in this analysis are listed in Table 1. The study populations were well matched for patient demographics and were predominately conducted in patients with few cardiac risk factors. The notable exceptions were the trials assessing the effects of esmolol on myocardial ischemia. Bolus dosing of esmolol was evaluated in 33 trials, with doses varying between 1 and 4 mg/kg. Infusion of esmolol was evaluated in 34 trials using a combination of a bolus dose and infusion (with initial bolus dosing ranging from 0.3 mg/kg to 2.3 mg/kg). Esmolol was found to significantly decrease arterial blood pressure in the 3 scenarios in which it was evaluated: (a) the unplanned occurrence of hypotension; (b) the hemodynamic effect in normotensive patients; and (c) in response to perioperative surgical hypertension.

Table 1

Table 1

The quality of the studies included in this analysis was mixed. All were randomized, but 4 studies had no blinding protocol. Allocation concealment was reported in only 5 studies. Of the 67 evaluated trials, only 3 trials specifically mention intention-to-treat analysis. Ten trials stated specifically that the intention-to-treat analysis was not conducted; in these trials, reasons for withdrawal were stated. The sample size was generally small, with only 4 studies enrolling >100 patients. The median size of the trials was 40 patients.

The incidence of unplanned hypotension and bradycardia is listed in Table 2. The frequency of unplanned hypotension in the reviewed articles is shown in Figure 2. The OR for hypotension in trials in which the definition of hypotension was defined a priori was 2.13 (95% CI, 1.49 to 3.04; OR 2.15; 95% CI, 1.49 to 3.11 after continuity correction). Hypotension was more common in patients given bolus doses of esmolol than in patients given esmolol infusions (relative risk 1.47; 95% CI, 1.40 to 1.56, P = 0.002). The median bolus dose before the initiation of an infusion was 500 μg/kg, whereas bolus studies used an initial dose of >1 mg/kg. Development of unplanned hypotension was related to the initial dose r2 = 0.408 (Fig. 3). Hypotension was less frequent in studies with an initial bolus of <500 mcg/kg. The meta-regression result is strongly influenced by 1 study15; in a sensitivity analysis in which this study was removed, the result is unchanged (this analysis is not shown). A post hoc sensitivity analysis assessing the incidence of unplanned hypotension found that 90% (217 of the 238 episodes in this analysis) of hypotension was associated with the studies that included patients with an ASA class >1 (OR 2.26; 95% CI,1.56 to 3.29, P < 0.0001). Unplanned hypotension occurred mainly in the patients having a fixed esmolol-dosing schedule. Esmolol was not found to induce clinically significant unplanned bradycardia. Normotensive patients, receiving an infusion of esmolol for planned hypotension or to assess the effects of the drug on the depth of anesthesia, had a significant decrease in blood pressure (WMD, 13.4 mm Hg; 95% CI ,11.2 to 15.1, I2 = 92%). The heterogeneity was partially on the basis of dose (r2 = 0.66; Fig. 4). As was expected, higher doses of esmolol were associated with a larger reduction in blood pressure. In this scenario, esmolol was found to cause a dose-related reduction in heart rate (WMD, −13.5; 95% CI, −15.6 to 11.5; I2 = 76%) (r2 = 0.57), as is shown in Figure 5. In established perioperative hypertension, a bolus dose of esmolol was found to reduce blood pressure (WMD, 19.6 mm Hg; 95% CI, 6.2 to 33.0; I2 = 86%). This heterogeneity was explained on the basis of esmolol dose (r2 = 0.44; Fig. 6).

Table 2

Table 2

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

Figure 5

Figure 5

Figure 6

Figure 6

Myocardial ischemia was assessed infrequently in the retrieved studies. In the 7 trials reporting the effect of esmolol on the frequency or magnitude of myocardial ischemia, esmolol was found to decrease the incidence of myocardial ischemia in comparison with placebo (OR 0.17; 95% CI, 0.02 to 0.45, P < 0.001). In the 67 studies there were 6 documented MIs and there were no reported cerebrovascular accidents. Thus we did not conduct a meta-analysis on these outcomes.

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DISCUSSION

This meta-analysis of 67 controlled clinical trials in 3766 patients undergoing noncardiac surgery found that esmolol was associated with an increase in the incidence of unplanned hypotension. Low initial bolus doses of esmolol, with a continuous infusion strategy, resulted in fewer episodes of hypotension. This report documents that titration of esmolol can achieve a targeted reduction in both heart rate and blood pressure. Similar to other β blockers, esmolol infusions were found to decrease myocardial ischemia.12 More important, the potential cardioprotective effect of esmolol is predominately seen in patients receiving the small initial dose and a continuous infusion, a situation in which hypotension is less frequent. There were insufficient data to assess whether esmolol reduces the frequency of perioperative MI or stroke after noncardiac surgery.

The finding of a dose–response relationship between esmolol and hypotension has been previously demonstrated. Figueredo and Garcia-Fuentes,84 in an earlier and smaller meta-analysis, showed a dose–response relationship between esmolol and hypotension. Conversely, the present report is at odds with the recent meta-analysis by Landoni et al.,85 which did not demonstrate a relationship between esmolol and hypotension. There are important differences between that analysis and the present study. First, there were only 31 studies in the meta-analysis, which is less than half the number of the studies we have identified. Second, one of the excluded studies is the only investigation with both the power (over 500 patients) and follow-up to demonstrate unplanned hypotension.15

Several investigations have evaluated the effect of β-blockers as a strategy to reduce the frequency of perioperative MI in patients undergoing noncardiac surgery. In the multicenter prospectively randomized, placebo-controlled POISE trial6 involving 8534 patients undergoing noncardiac surgery, the use of metoprolol succinate started on the day of surgery was found to reduce the incidence of perioperative MI. Nonetheless, the frequency of 30-day mortality and stroke was higher in patients receiving metoprolol than in those receiving placebo. These findings seem to be explained in part by a higher frequency of hypotension in patients receiving metoprolol.

The POISE trial has been criticized on the basis of an empiric fixed dose of metoprolol succinate, which may have increased the incidence of unplanned hypotension.7 This view stems from the DECREASE series of trials811 in which bisoprolol titrated to effect, on average 30 days before surgery, offered substantial cardioprotection with little or no side effects. The present meta-analysis suggests that infusions of esmolol may be a safe alternative method of administering perioperative β-blockers. Our results suggest that the frequency of hypotension can be reduced with the use of a low initial bolus dose and infusions titrated to a hemodynamic end point.

There are a number of limitations to this analysis. Most of the publications reviewed were >15 years old and contain few details of adverse outcomes, including the incidence of hypotension. Furthermore, because the studies were conducted in that time frame, much of the data on adverse events could not be verified or updated. Second, the occurrence of adverse events in randomized controlled trials may be less than the true incidence of such events because of the rigid entry criteria and strict adherence to the protocols. The trials included in this meta-analysis were generally small. Small trials have a tendency to overestimate efficacy and are underpowered to show adverse events. It is also possible that small negative trials would not have been published, thus overestimating the efficacy. Although we found that infusions with a titrated dose– response decreased the incidence of unplanned hypotension, the data on esmolol infusion were generally limited to short duration of infusion. Data on esmolol infusions that lasted >24 hours are limited to 125 patients. One study83 has shown that infusions up to 48 hours are not effective in controlling tachycardia in the postoperative period. Of note, in that investigation, there was a steady progressive increase in heart rate postoperatively above the target heart rate of 80 bpm, which could not be decreased to the target despite an open loop (nursing protocol) feedback algorithm for dose adjustment of esmolol. Importantly, this investigation was also unable to show that esmolol decreased the incidence of myocardial ischemia. The inclusion of Miller et al.15 could be considered a limitation by some readers or could be criticized, because there was no requirement for patients to have chronically administered β-blockers withdrawn before the study. Thus, it is possible that the increased hypotension related to esmolol boluses seen in that study could have been due to patients receiving a higher dose of β-blockade than was planned for in the protocol. However, it should be noted that the increase in the incidence of hypotension seen in the esmolol-treated patients is still evident in the sensitivity analysis in which this study was eliminated.

In conclusion, this comprehensive systematic review and meta-analysis of 67 randomized clinical trials shows that esmolol effectively decreased both heart rate and arterial blood pressure in a dose-dependent manner. The use of esmolol, however, is associated with an increased incidence of unplanned hypotension. The incidence of hypotension is reduced when esmolol is given as a continuous infusion. Importantly, titration of esmolol to a hemodynamic end point was associated with a decreased incidence of myocardial ischemia. Therefore, it is feasible that esmolol has the potential to be both safe and effective in providing protection against myocardial ischemia in patients undergoing noncardiac surgery. Further studies, in higher-risk patients, using longer-duration infusions are needed to investigate the safety and efficacy of esmolol to reduce the frequency of MI after noncardiac surgery.

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DISCLOSURES

Name: Savio Yu, BHSc.

Conflict of Interest: None.

Name: Gordon Tait, PhD.

Conflict of Interest: None.

Name: Keyvan Karkouti, MD, MSc, FRCPC.

Conflict of Interest: Dr. Karkouti is supported in part by merit awards from the University of Toronto, Department of Anesthesia.

Name: Duminda Wijeysundera, MD, FRCPC.

Conflict of Interest: Dr. Wijeysundera is supported in part by merit awards from the University of Toronto, Department of Anesthesia, and by the Canadian Institute of Health Research.

Name: Stuart McCluskey, MD, PhD, FRCPC.

Conflict of Interest: None.

Name: W. Scott Beattie, MD, PhD, FRCPC.

Conflict of Interest: Dr. Beattie has received honoraria from Baxter Healthcare Corporation to speak on the subject of Perioperative Beta Blockade and to attend an International Advisory Board for BREVIBLOC (BREVIBLOC is a trademark of Baxter International, Inc.). In addition, Baxter has made a contribution to The University Health Network Department of Anesthesia and Pain Management's Education Research and Innovation Fund. Baxter has not participated in the analysis of the retrieved data, or in the writing of this paper. The decision to conduct the analysis here presented and the opinions expressed in the discussion are entirely those of the authors. Dr. Beattie is supported in part by merit awards from the University of Toronto, Department of Anesthesia. Dr. Beattie is the R. Fraser Elliot Chair in Cardiac Anesthesia and is supported in part through the R. Fraser Elliot Endowment.

a See Table 5 of the POISE publication.
Cited Here...

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