Blood Pressure, Heart Rate and Arrhythmia Control in the Perioperative Setting by the Short-Acting Betablocker Esmolol – A Review 111
Citation: ”Blood Pressure, Heart Rate and Arrhythmia Control in the Perioperative Setting by the Short-Acting Betablocker Esmolol – A Review. American Research Journal of Anesthesia. 2018; 2(1), pp:1-28
Copyright This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Background: Patients who under go surgery, especially with pre existing high cardiovascular risk and high-risk surgery are vulnerable for developing myocardial ischemia or tachyarrhythmias through sympathetic stimulation during anesthesia. Aim of this systematic review is a summary of the evidence from all randomized controlled trials on the efficacy and safety of the short acting β1 -selective adrenoreceptor blocker esmolol in the prevention and treatment of tachyarrhythmias and critical rises in blood pressure to avoid myocardial ischemia.
Methods and Findings: We examined the effect of esmolol in three different settings and included 5765 participants from 110 trials in our meta-analysis. We searched Medline, Embase, the Cochrane Library and hand-searched until January 2012 with an update through additionally search via PubMed to 2017 for articles published in English and German language. Esmolol reduces blood pressure and heart rate significantly in comparison to placebo with better effects in controlling heart rate than heart rhythm. In comparison to other active drugs there are no significant benefits for esmolol in lowering blood pressure, heart rate or control of rhythm. Adverse effects of esmolol as hypotension, bradycardia
Conclusion: Esmolol shows reduction in myocardial ischemia in patients with cardiac disease, and with respect to adverse effects and careful titration we recommend esmolol to prevent and treat crisis of blood pressure and heart rate. In healthy patients the perioperative use of esmolol or other active drugs need to document its beneficial effect, further studies are necessary.
Keywords: esmolol, tachycardia, hypertension, beta(-)blocker, tachyarrhythmias
Surgery and perioperative anesthetic maneuvers like intubation and extubation stimulate sympathetic activity with the consequence of an increase in heart rate and blood pressure and – as result – of the risk of myocardial ischemia and supraventricular tachycardias like atrial fibrillation/flutter, especially in patients with preexisting heart disease.The stress of surgery and anesthesia may trigger this myocardial ischemia and these arrhythmias by an increase in myocardial oxygen demand, driven by the sympathetically mediated increase in heart rate and in blood pressure. From a pathophysiological rationale perioperative risk reduction can be achieved by suppressing the overshooting sympathetic tone by betablockers. Two approaches can be achieved to reach this goal:
a) The “preventive approach” is to continue betablocker medication in the perioperative setting in patients currently receiving this medication or to start preoperative betablocker medication in patients with myocardial ischemia, high cardiovascular risk load or scheduled for high-risk surgery.1, 2
b) The “therapeutic approach” is the acute treatment of hypertensive emergency, inadaequately high heart rate and supraventricular tachycardias in the perioperative arena by betablockers or other agents. Betablockers displace norepinephrine and epinephrine fromβ-adrenoreceptors of the heart, thereby attenuating the positive inotropic, chronotropic, bathmotropic and dromotropic effects of the sympathetic and endocrine stimulation. There are several critical stages in time, in which there are these strong hemodynamic changes triggered by the rise in sympathetic tone, depending on the type, duration and course of surgery and anesthesia. They include laryngoscopy, intubation, the first skin incision, the insertion of different surgical instruments, the transection of different anatomical structures (preparation) and other surgical stimuli.
In perioperative emergency situations, due to overshooting sympathetic activity, a short-acting betablocker for dampening of sympathetic activity would be the drug of choice from a pharmacokinetic point of view: the heart rate and blood pressure lowering effect starts immediately after intravenous application of the drug, plasma concentration is kept constant by titrated infusion of the betablocker, and drug action ebbsaway very quickly after stopping drug infusion.3
Esmololis such a fast-acting β1 -selective adrenoreceptor blocker with rapid onset within two minutes, a very short duration of action (elimination half-life:nine min, full recovery after 18 to 30 min), an effective controllability and no relevant adverse events at recommended therapeutic dosages.4, 5
This systematic review investigates the benefits and harms of esmolol in prevention and treatment of supraventricular tachyarrhythmias and critical rises in blood pressure during anesthesia and surgical interventions.
Only randomized controlled trials (RCT) that evaluated efficacy and safety of esmolol were eligible for inclusion in this review. The review considered all trials in three different peri-operative settings:
1. Perioperative treatmentand emergency therapy of supraventricular tachyarrhythmias
2. Prevention and treatment of increased blood pressure during intubation and extubation
3. Prevention and treatment of increased blood pressure during surgery or interventions like electroconvulsive therapy
We searched Medline, Embase and the Cochrane Libraryuntil January 2012for articles published in English and German language (appendix 1). We also searched in registries of on-going trials, hand-searched annual conference proceedings of cardiologic and anesthesia societies (2000-2012), contacted the manufacturer of esmolol (Baxter Germany GmbH) and scanned reference lists of eligible trials. We contacted first authors of eligible trials to obtain further information. In January2017 we updated our latest results up to 01.01.2017 with an additionally search via PubMed.
Trial selection, classification of strategies and quality assessment
All steps were done by at least two independent authors. We screened all trials identified using the search strategy by title, keywords and abstract and carefully read and discussed full-text versions of potential relevant trials with respect to our inclusion criteria.
We extracted general information of all included trials, trial characteristics including trial design, timing and follow-up, information describing participants, intervention and primary and secondary outcomes per treatment group. Primary endpoints varied in the indications for esmolol use. The success of treatment with esmolol in emergency or perioperative treatment of supraventricular tachyarrhythmias was measured either as decrease in frequency below 100bpm, as reduction in initial heart rate by about 20%, or as conversion to sinus rhythm. This information was extracted and analyzed as primary endpoint. The control and decrease of high blood pressure was the main aim of the treatment with esmolol in participants under general anesthesia and generally during surgery. Therefore, in this setting systolic blood pressure or mean arterial pressure were used as primary endpoint.
Finally, we assessed the internal validity of eligible trials according to the Cochrane Collaboration risk of bias tool.6 Disagreements were resolved by discussion until consensus was obtained. Risk of bias was judged as high, low or unclear in six specific domains. These domains describe bias in random sequence generation, allocation concealment, blinding of participants, physician and outcome assessors, documentation of incomplete outcome data with causes and selective reporting, baseline comparability between treatment groups and the frequency of cross-over. Publication bias was assessed visually using funnel plots.
We used RevMan 5© for the meta-analysis. Effect measures are presented as relative risks (RRs) and mean difference (MD) with their 95 % confidence intervals (CI). Outcome was recorded so that aRR greaterthan one and negativeMD indicated a beneficial effect with more successful control of supraventricular tachyarrhythmias or smaller rise in blood pressure in the treatment group with esmolol. If more than one measurement was reported, the treatment effects on the maximal increase were estimated. Intervention arms with different esmolol dosages and control arms with various other effective drugs were pooled.
We used the random-effects model for meta-analysis of the relevant trials. Statistical heterogeneity between trials was quantified into categories of small, moderate, substantial and considerable heterogeneity on the basis of an I2 statistic. 6 We decided not to pool studies with considerable heterogeneity (I2 >60 %). In all of the three settings we differentiated the comparison of esmolol to placebo and to other effective drugs. Patients were allocated pursuant their different interventions specially modes of cardiac surgery or between cardiac healthy and pre-stressed participants.
Results of the search
Having used the above search strategies to identify potentially relevant articles, we identified a total of 1540 records and assessed 257 regarding in- and exclusion criteria. Of these, 221 trials met our pre-defined inclusion criteria. Altogether 16 trials investigated esmolol fortreatment of supraventricular tachyarrhythmias and tachycardias, 60 trials during intubation or extubation in operative interventions and 52 trials during surgical interventions. Altogether seven trials were used in more than one topic(figure 1).
Altogether 16 trials evaluated the effect of esmolol for control and treatment of supraventricular tachyarrhythmias and tachycardia (setting one). Information on our pre-defined primary or secondary endpoints were available from 14 trials with a total of 692 participants. Altogethers even trials were exclusively performed in the intra- and postoperative setting, four trials describe the use of esmolol independent from the operative setting and three trials included both. Only one trial included more than two treatment arms. Three trials were multicenter trials7–9 and two trials used a cross-over design7, 10.
Eight trials compared esmolol to placebo7, 10–16, four to diltiazem15, 17–19 and each one to propranolol8 , acebutolol20, verapamil9 or ibutilide-monotherapy11. Some trials included only participants with atrial fibrillation or atrial flutter9, 11, 15, 18, 19, supraventricular tachyarrhythmias7, 8, 10, 17 or intra - or postoperative tachycardia12, 13, 13, 14, 16, 20. Trials were mostly conducted in the USA, as well in Germany, Greece, England and India. All trials included only participants over 18 years with an average age of 60 years with a higher proportion of man (between 32 and 100 %).
Sixty trials evaluated the effect of esmolol under intubation or extubation during operative interventions (setting two). Of them, 50 trials with 3,446 participants reported information on the primary or secondary endpoint and were included into meta-analyses. Participants in 36 trials under went elective surgery. The remaining 14 trials included a variety of surgeries (fivewith coronary artery bypass grafting). A total of 22 trials had three, nine21–29 had four and one30 had six treatment arms. Only one trial31 was a multicenter trial. Fourty-two trials compared esmolol to placebo and eight to opioids as alfentanil32–34, local anaesthetic drugs as lidocaine35–37, hypnotics as propofol35, calcium channel blockers as nicardipine38 or α2 -receptor-agonistsas clonidine32, 39. Trials were predominantly conducted in Western Hemisphere (USA, Great Britain, Canada, Finland, Switzerland), ten trials were conducted in India, fourin Turkey and two in Taiwan. The mean patient age varied between 15 and 85 years. Only two trials included participants under 18 years of age.30,40 Altogether 51% of participants were male, two trials included only female 30, 41 and two other trials only male participants12, 28. ASA (American Society of Anaesthesiologists) scores varied from ASA I/II in 31trials ( 62%) and ASA III/IV42, 43 in 12 studies (24%) due to differences in inclusion and exclusion criteria.
Fifty-two trials investigated the efficacy of esmolol during surgical interventions(setting three) and 46 trials of them which included 1,627 patients were included in meta-analyses. A total of 16 trials13, 14, 20, 43–55 including 486 participants with cardiac surgeries and 21 trials including 929 participants with another surgical procedure were performed12, 16, 56–74. Ofthem, four trials57, 59, 60, 63 with 104 participants were performed having a forced controlled hypotension during the surgical procedure and 212 participants in nine trials under went electroconvulsive therapy.75–83 Totally 36 trials were carried out with a parallel-group design and ten trials used a cross-over design. In 14 trials, there were more than two treatment arms. Only one trial was a multi-center trial.62
In the subgroup of cardiac surgery, eleven trials13, 14, 43, 45–47, 49–52, 55 compared an intervention group with esmolol to placebo, three 44, 48, 54 to sodium nitroprusside, one 53 to diltiazem, and one20 toacebutolol. In terms of noncardiac surgeries, ten trials12, 16, 56, 58, 66–68, 70, 72, 74 compared an intervention group with esmolol to placebo, two trials respectively to labetalol61, 65 or sodium nitroprusside,62, 73and one trial each to atenolol73, remifentanil69, alfentanil64, thiopental64, xylocaine64, magnesium sulfate67, lidocaine67, dexmedetomidine71 and nitroglycerine67. In the non-cardiac surgeries with controlled hypotension, participants with esmolol were compared to sodium nitroprusside57, 59, 60, 63 or isoflurane59. Participants with electroconvulsive therapy received during electroconvulsive therapy sessions either esmolol vs. placebo75–78, 81–83, labetalol80, 81, 83, fentanyl81, lidocaine81 or nitroglycerine78. Most trials were conducted in USA, Germany, Canada, Finland and Spain. The range of age of participants with cardiac surgery varied between 18 and 68 years, participants with non-cardiac surgery were between 25 and 78 years of age, participants with electroconvulsive therapy were older, with ages between 42 and 73 years. Participants with non-cardiac surgery with controlled hypotension had the lowest age between 22 and 42 years, which is probably due to the increased risk of complications in a forced hypotension during surgery. In only four trials54, 55, 60, 74 children (two months to 18 years) were included in the trial and only one trial71 defined a maximum age of 60 years. Only 20 trials provide information on gender distribution. Altogether 76 % of participants in the included trials on cardiac surgery were male, 5 3% in non-cardiac surgery, 34 % in electroconvulsive therapy and 55 % in non-cardiac operations with controlled hypotension. One trial included only female participants during gynecological procedures70.
Risk of bias in included trials
In only 16 of the 221 trials, the method of randomization was reported in the text. Treatment allocation of clusters or participants was described as concealed in 22 trials. A total of 73 trials were double-blinded, outcome assessment was blinded in eight additional trials. In 97 trials, the analysis was done by intention-to-treat. Total numbers of drop-outs were low (<10 %) and their causes were given per group. Pre-planned primary endpoints were adequately reported in 18 trials. Other Risk of bias was evident in 66 trials. These sources of bias included the intake of other interventions that may influence the effect of esmolol as additional antihypertensive or anaesthetic drugs8, 9, 17, 18, 21, 23, 31, 32, 34, 55, 74, 84–88 or long-term medication12, 23, 31, 36, 42, 89. Most included trials were conducted as single-center trials with lessthan 20 participants per intervention group. Especially in trials published before the CONSORT statement90 demographic and clinical characteristics of participants were not adequately described.
Effects of intervention
Perioperative treatment and emergency therapy of supraventricular tachyarrhythmias
In comparison to placebo four trials7, 10, 11, 15, including a total of 197 participants, showed ahigher rate of successful conversion to sinus rhythm with esmolol (Risk Ratio ( RR)1.24; 95 % CI 0.76 to 2.03) with moderate heterogeneity between treatment effects of individual trials (I2 =40%) (figure 2). Two trials7, 10with 79 participants demonstrated a higher success rate on the combined outcome (conversion to sinus rhythm or decreased heart rate) with esmolol compared to placebo(RR 12.37; 95 % CI 3.67to 41.64).
Another group of six trials8, 9, 15, 17–19 (322 participants) documented a non-significant benefit of esmolol in comparison to other effective drugs with more successful conversions and one trial8 stated no relevant difference between esmolol and propranolol (table 1). Two9, 18of the mentioned six trials reported absolute values. Esmolol reduced heart rate from 134±19 bpm to 91±14 bpm compared to diltiazem with a reduction from 144±17 bpm to 79±9 bpm.18 In comparison to verapamil with reductions from 142±4 bpm to 98±3 bpm, heart rate in the esmolol group decreased from 139±4 bpm to 106±3 bpm.9
Prevention and treatment of increased blood pressure under general anesthesia during intubation and extubation
Summarizing treatment effects on MAP of seven trials including 301 participants during intubation21, 28, 41, 87, 91–93resulted in a lowering of the maximal MAP by 10.1 mmHg (95 %CI 4.8 to 15.4) with esmolol compared to placebo with substantial heterogeneity (I2 =56 %) (figure 3). Two92, 93 of the trails showed a change in absolute values. MAP decreased after administered study drug (before laryngoscopy) from 88±12 mmHg to 77±14 mmHg92 and from 100±11 mmHg to 76±18 mmHg93 by esmolol compared to placebo with reduction from 86±14 mmHg to 79±15 mmHg92 and 94±11 mmHg to 73±12 mmHg93
However, four additional trials32, 34, 37, 39 with 242 participantscompared esmolol to other effective drugs as alfentanil and/or clonidine or lidocaine and stated a higher maximal MAP during intubation in patients treated with esmolol (Mean Difference (MD)19.2 mmHg; 95 % CI 4.8 to33.7) (table 2).