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. 2019 Sep 26;9(9):CD013438.
doi: 10.1002/14651858.CD013438.

Perioperative beta-blockers for preventing surgery-related mortality and morbidity in adults undergoing non-cardiac surgery

Hermann Blessberger  1 , Sharon R Lewis, Michael W Pritchard, Lizzy J Fawcett, Hans Domanovits, Oliver Schlager, Brigitte Wildner, Juergen Kammler, Clemens Steinwender
Affiliations

Perioperative beta-blockers for preventing surgery-related mortality and morbidity in adults undergoing non-cardiac surgery

Hermann Blessberger et al. Cochrane Database Syst Rev. .

Abstract

Background: Randomized controlled trials (RCTs) have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in an unselected population remains a controversial issue. A previous version of this review assessing the effectiveness of perioperative beta-blockers in cardiac and non-cardiac surgery was last published in 2018. The previous review has now been split into two reviews according to type of surgery. This is an update, and assesses the evidence in non-cardiac surgery only.

Objectives: To assess the effectiveness of perioperatively administered beta-blockers for the prevention of surgery-related mortality and morbidity in adults undergoing non-cardiac surgery.

Search methods: We searched CENTRAL, MEDLINE, Embase, CINAHL, Biosis Previews and Conference Proceedings Citation Index-Science on 28 June 2019. We searched clinical trials registers and grey literature, and conducted backward- and forward-citation searching of relevant articles.

Selection criteria: We included RCTs and quasi-randomized studies comparing beta-blockers with a control (placebo or standard care) administered during the perioperative period to adults undergoing non-cardiac surgery. If studies included surgery with different types of anaesthesia, we included them if 70% participants, or at least 100 participants, received general anaesthesia. We excluded studies in which all participants in the standard care control group were given a pharmacological agent that was not given to participants in the intervention group, studies in which all participants in the control group were given a beta-blocker, and studies in which beta-blockers were given with an additional agent (e.g. magnesium). We excluded studies that did not measure or report review outcomes.

Data collection and analysis: Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE.

Main results: We included 83 RCTs with 14,967 participants; we found no quasi-randomized studies. All participants were undergoing non-cardiac surgery, and types of surgery ranged from low to high risk. Types of beta-blockers were: propranolol, metoprolol, esmolol, landiolol, nadolol, atenolol, labetalol, oxprenolol, and pindolol. In nine studies, beta-blockers were titrated according to heart rate or blood pressure. Duration of administration varied between studies, as did the time at which drugs were administered; in most studies, it was intraoperatively, but in 18 studies it was before surgery, in six postoperatively, one multi-arm study included groups of different timings, and one study did not report timing of drug administration. Overall, we found that more than half of the studies did not sufficiently report methods used for randomization. All studies in which the control was standard care were at high risk of performance bias because of the open-label study design. Only two studies were prospectively registered with clinical trials registers, which limited the assessment of reporting bias. In six studies, participants in the control group were given beta-blockers as rescue therapy during the study period.The evidence for all-cause mortality at 30 days was uncertain; based on the risk of death in the control group of 25 per 1000, the effect with beta-blockers was between two fewer and 13 more per 1000 (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.89 to 1.54; 16 studies, 11,446 participants; low-certainty evidence). Beta-blockers may reduce the incidence of myocardial infarction by 13 fewer incidences per 1000 (RR 0.72, 95% CI 0.60 to 0.87; 12 studies, 10,520 participants; low-certainty evidence). We found no evidence of a difference in cerebrovascular events (RR 1.65, 95% CI 0.97 to 2.81; 6 studies, 9460 participants; low-certainty evidence), or in ventricular arrhythmias (RR 0.72, 95% CI 0.35 to 1.47; 5 studies, 476 participants; very low-certainty evidence). Beta-blockers may reduce atrial fibrillation or flutter by 26 fewer incidences per 1000 (RR 0.41, 95% CI 0.21 to 0.79; 9 studies, 9080 participants; low-certainty evidence). However, beta-blockers may increase bradycardia by 55 more incidences per 1000 (RR 2.49, 95% CI 1.74 to 3.56; 49 studies, 12,239 participants; low-certainty evidence), and hypotension by 44 more per 1000 (RR 1.40, 95% CI 1.29 to 1.51; 49 studies, 12,304 participants; moderate-certainty evidence).We downgraded the certainty of the evidence owing to study limitations; some studies had high risks of bias, and the effects were sometimes altered when we excluded studies with a standard care control group (including only placebo-controlled trials showed an increase in early mortality and cerebrovascular events with beta-blockers). We also downgraded for inconsistency; one large, well-conducted, international study found a reduction in myocardial infarction, and an increase in cerebrovascular events and all-cause mortality, when beta-blockers were used, but other studies showed no evidence of a difference. We could not explain the reason for the inconsistency in the evidence for ventricular arrhythmias, and we also downgraded this outcome for imprecision because we found few studies with few participants.

Authors' conclusions: The evidence for early all-cause mortality with perioperative beta-blockers was uncertain. We found no evidence of a difference in cerebrovascular events or ventricular arrhythmias, and the certainty of the evidence for these outcomes was low and very low. We found low-certainty evidence that beta-blockers may reduce atrial fibrillation and myocardial infarctions. However, beta-blockers may increase bradycardia (low-certainty evidence) and probably increase hypotension (moderate-certainty evidence). Further evidence from large placebo-controlled trials is likely to increase the certainty of these findings, and we recommend the assessment of impact on quality of life. We found 18 studies awaiting classification; inclusion of these studies in future updates may also increase the certainty of the evidence.

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Conflict of interest statement

Hermann Blessberger: none known

Sharon Lewis: none known

Michael Pritchard: none known

Lizzy Fawcett: none known

Hans Domanovits: none known

Oliver Schlager: none known

Brigitte Wildner: none known

Juergen Kammler: none known

Clemens Steinwender: I have received speaker's honoraria from MSD, Sanofi‐Aventis, Boehringer‐Ingelheim, Bayer, Medtronic, Biotronic, Abbott, St. Jude Medical and Boston Scientific. Sanofi‐Aventis, Boehringer‐Ingelheim Europe, Medtronic, Biotronik, Bayer Austria, Abbott Vascular, St. Jude Medical and Boston Scientific do not produce, market or distribute any of the studied drug entities. MSD (timolol) have a beta‐blocker in their portfolio.

Figures

1
1
Study flow diagram for updated search on 28 June 2019
2
2
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies
3
3
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study
4
4
Forest plot of comparison 1. Beta‐blockers vs control, outcome: 1.1 Early all‐cause mortality
5
5
Funnel plot of comparison 1. Beta‐blockers vs control, outcome: 1.1 Early all‐cause mortality
6
6
Forest plot of comparison: 1 Beta‐blockers vs control, outcome: 1.9 Hypotension
1.1
1.1. Analysis
Comparison 1 Beta‐blockers vs control, Outcome 1 Early all‐cause mortality.
1.2
1.2. Analysis
Comparison 1 Beta‐blockers vs control, Outcome 2 Long‐term mortality.
1.3
1.3. Analysis
Comparison 1 Beta‐blockers vs control, Outcome 3 Death due to cardiac causes.
1.4
1.4. Analysis
Comparison 1 Beta‐blockers vs control, Outcome 4 Acute myocardial infarction.
1.5
1.5. Analysis
Comparison 1 Beta‐blockers vs control, Outcome 5 Cerebrovascular events.
1.6
1.6. Analysis
Comparison 1 Beta‐blockers vs control, Outcome 6 Ventricular arrhythmias.
1.7
1.7. Analysis
Comparison 1 Beta‐blockers vs control, Outcome 7 Atrial fibrillation and flutter.
1.8
1.8. Analysis
Comparison 1 Beta‐blockers vs control, Outcome 8 Bradycardia.
1.9
1.9. Analysis
Comparison 1 Beta‐blockers vs control, Outcome 9 Hypotension.
1.10
1.10. Analysis
Comparison 1 Beta‐blockers vs control, Outcome 10 Congestive heart failure.
1.11
1.11. Analysis
Comparison 1 Beta‐blockers vs control, Outcome 11 Length of stay (in days).
2.1
2.1. Analysis
Comparison 2 Beta‐blockers vs control: subgroup by type of beta‐blocker, Outcome 1 Early all‐cause mortality.
2.2
2.2. Analysis
Comparison 2 Beta‐blockers vs control: subgroup by type of beta‐blocker, Outcome 2 Acute myocardial infarction.
2.3
2.3. Analysis
Comparison 2 Beta‐blockers vs control: subgroup by type of beta‐blocker, Outcome 3 Bradycardia.
2.4
2.4. Analysis
Comparison 2 Beta‐blockers vs control: subgroup by type of beta‐blocker, Outcome 4 Hypotension.
3.1
3.1. Analysis
Comparison 3 Beta‐blockers vs control: subgroup by start of beta‐blocker therapy, Outcome 1 Early all‐cause mortality.
3.2
3.2. Analysis
Comparison 3 Beta‐blockers vs control: subgroup by start of beta‐blocker therapy, Outcome 2 Acute myocardial infarction.
3.3
3.3. Analysis
Comparison 3 Beta‐blockers vs control: subgroup by start of beta‐blocker therapy, Outcome 3 Bradycardia.
3.4
3.4. Analysis
Comparison 3 Beta‐blockers vs control: subgroup by start of beta‐blocker therapy, Outcome 4 Hypotension.
4.1
4.1. Analysis
Comparison 4 Beta‐blockers vs control: subgroup by risk status, Outcome 1 Early all‐cause mortality.
4.2
4.2. Analysis
Comparison 4 Beta‐blockers vs control: subgroup by risk status, Outcome 2 Acute myocardial infarction.
4.3
4.3. Analysis
Comparison 4 Beta‐blockers vs control: subgroup by risk status, Outcome 3 Bradycardia.
4.4
4.4. Analysis
Comparison 4 Beta‐blockers vs control: subgroup by risk status, Outcome 4 Hypotension.
See this image and copyright information in PMC

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    1. Shukla S, Gupta K, Gurha P, Sharma M, Sanjay RR, Shukla R, et al. Role of β blockade in anaesthesia and postoperative pain management after major lower abdominal surgery. Internet Journal of Anesthesiology 2010;25(1):pagination not available. [DOI: 10.5580/170f] - DOI
Singh 1995 {published data only}
    1. Singh H, Vichitvejpaisal P, Gaines GY, White PF. Comparative effects of lidocaine, esmolol, and nitroglycerin in modifying the hemodynamic response to laryngoscopy and intubation. Journal of Clinical Anesthesia 1995;7(1):5‐8. [PUBMED: 7772359] - PubMed
Singh 2010 {published data only}
    1. Singh SP, Quadir A, Malhotra P. Comparison of esmolol and labetalol, in low doses, for attenuation of sympathomimetic response to laryngoscopy and intubation. Saudi Journal of Anaesthesia 2010;4(3):163‐8. [PUBMED: 21189853] - PMC - PubMed
Singh 2012 {published data only}
    1. Singh S, Laing EF, Owiredu W, Singh A. Attenuation of cardiovascular response by ß‐blocker esmolol during laryngoscopy and intubation. Journal of Medical and Biomedical Sciences 2012;1(4):27‐33.
Srivastava 2015 {published data only}
    1. Srivastava VK, Agrawal S, Gautam SK, Ahmed M, Sharma S, Kumar R. Comparative evaluation of esmolol and dexmedetomidine for attenuation of sympathomimetic response to laryngoscopy and intubation in neurosurgical patients. Journal of Anaesthesiology, Clinical Pharmacology 2015;31(2):186‐90. [PUBMED: 25948898] - PMC - PubMed
Stone 1988 {published data only}
    1. Stone JG, Foex P, Sear JW, Johnson LL, Khambatta HJ, Triner L. Myocardial ischemia in untreated hypertensive patients: effect of a single small oral dose of a beta‐adrenergic blocking agent. Anesthesiology 1988;68(4):495‐500. [PUBMED: 2895596] - PubMed
Sugiura 2007 {published data only}
    1. Sugiura S, Seki S, Hidaka K, Masuoka M, Tsuchida H. The hemodynamic effects of landiolol, an ultra‐short‐acting beta1‐selective blocker, on endotracheal intubation in patients with and without hypertension. Anesthesia and Analgesia 2007;104(1):124‐9. [PUBMED: 17179256] - PubMed
Tendulkar 2017 {published data only}
    1. Tendulkar MP, Ninave SS. Prospective comparison of pressor and airway responses to IV esmolol and IV dexmedetomidine during emergence from general anaesthesia and extubation. Journal of Krishna Institute of Medical Sciences University (JKIMSU) 2017;6(1):49‐56.
Ugur 2007 {published data only}
    1. Ugur B, Ogurlu M, Gezer E, Nuri Aydin O, Gursoy F. Effects of esmolol, lidocaine and fentanyl on haemodynamic responses to endotracheal intubation: a comparative study. Clinical Drug Investigation 2007;27(4):269‐77. [PUBMED: 17358099] - PubMed
Unal 2008 {published data only}
    1. Unal Y, Ozsoylar O, Sargnüney D, Arslan M, Tardim RS. The efficacy of esmolol to blunt the haemodynamic response to endotracheal extubation in lumbar disc surgery. Research Journal of Medical Sciences 2008;2(2):99‐104.
Urias 2016 {published data only}
    1. Urias E, Ochoa RC, Sandoval A, Arce B, Martinez JI, Chacon E. Perioperative metoprolol effectiveness in patients scheduled for laparoscopic cholecystectomy. Regional Anesthesia and Pain Medicine 2016;41(5 Suppl 1):e161.
Van den Berg 1998 {published data only}
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Verma 2018 {published data only}
    1. Verma A, Srivastava D, Paul M, Chatterjee A, Chandra A. Effect of esmolol and diltiazem infusions on hemodynamic response to pneumoperitoneum on laparoscopic simple nephrectomy: a randomized controlled trial. Anesthesia, Essays and Researches 2018;12(1):85‐91. [PUBMED: 29628560] - PMC - PubMed
Wajima 2011 {published data only}
    1. Wajima Z, Tsuchida H, Shiga T, Imanaga K, Inoue T. Intravenous landiolol, a novel β(1)‐adrenergic blocker, reduces the minimum alveolar concentration of sevoflurane in women. Journal of Clinical Anesthesia 2011;23(4):292‐6. [PUBMED: 21663813] - PubMed
Wallace 1998 {published data only}
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Ward‐Booth 1983 {published data only}
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White 2003 {published data only}
    1. White PF, Wang B, Tang J, Wender RH, Naruse R, Sloninsky A. The effect of intraoperative use of esmolol and nicardipine on recovery after ambulatory surgery. Anesthesia and Analgesia 2003;97(6):1633‐8. [PUBMED: 14633533] - PubMed
Whitehead 1980 {published data only}
    1. Whitehead MH, Whitmarsh VB, Horton JN. Metoprolol in anaesthesia for oral surgery. Anaesthesia 1980;35(8):779‐82. [PUBMED: 7004258] - PubMed
Yamazaki 2005 {published data only}
    1. Yamazaki A, Kinoshita H, Shimogai M, Fujii K, Nakahata K, Hironaka Y, et al. Landiolol attenuates tachycardia in response to endotracheal intubation without affecting blood pressure. Canadian Journal of Anaesthesia 2005;52(3):254‐7. [PUBMED: 15753495] - PubMed
Yang 2006 {published data only}
    1. Yang H, Raymer K, Butler R, Parlow J, Roberts R, Tech M. The effects of perioperative beta‐blockade: results of the metoprolol after vascular surgery (MaVS) study, a randomized controlled trial. American Heart Journal 2006;152(5):983‐90. [PUBMED: 17070177] - PubMed
Yang 2008 {published data only}
    1. Yang X, Wu X, Wang S, Wang Q. Effects of metoprolol on perioperative cardiovascular events in patients with risk or at high risk for coronary artery disease undergoing non‐cardiac surgery. Chinese Medical Journal 2008;88(21):1476‐80. [PUBMED: 18953854] - PubMed
Yoshida 2017 {published data only}
    1. Yoshida T, Furukita Y, Yamamoto Y, Nishino T, Inoue S, Morimoto M, et al. A randomized, open label study of the efficacy of prophylactic 24‐h low‐dose landiolol for atrial fibrillation in transthoracic esophagectomy. Esophagus 2017;14(1):97‐103.
Zaugg 1999 {published data only}
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References to studies excluded from this review

Chae 1990 {published data only}
    1. Chae DH, Yoo KY, Park CJ, Ha IH. Effects of verapamil and propranolol on hemodynamic responses to laryngoscopy and tracheal intubation in hypertensive patients. Korean Journal of Anesthesiology 1990;23(3):366‐72.
Coleman 1980 {published data only}
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Marwick 2009 {published data only}
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Sandler 1990 {published data only}
    1. Sandler AN, Leitch LF, Badner NH, Colmenares M, Kimball B. Esmolol compared with placebo in preventing increases in heart rate and blood pressure during rigid bronchoscopy. Journal of Cardiothoracic Anesthesia 1990;4(5 Suppl 2):44‐50.
Sezai 2015 {published data only}
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Taenaka 2013 {published data only}
    1. Taenaka N, Kikawa S. The effectiveness and safety of landiolol hydrochloride, an ultra‐short‐acting beta1‐blocker, in postoperative patients with supraventricular tachyarrhythmias: a multicenter, randomized, double‐blind, placebo‐controlled study. American Journal of Cardiovascular Drugs 2013;13(5):353‐64. [PUBMED: 23818039] - PMC - PubMed
Tan 2002 {published data only}
    1. Tan PH, Yang LC, Shih HC, Lin CR, Lan KC, Chen CS. Combined use of esmolol and nicardipine to blunt the haemodynamic changes following laryngoscopy and tracheal intubation. Anaesthesia 2002;57(12):1207‐12. [PUBMED: 12479191] - PubMed
Vucevic 1992 {published data only}
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Zmora 2016 {published data only}
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References to studies awaiting assessment

ACTRN12605000639628 {published data only}
    1. ACTRN12605000639628. Effect of preoperative atenolol on mortality and cardiovascular morbidity after non‐cardiac surgery [A prospective, double‐blind randomised control study comparing the effect of atenolol versus placebo on mortality and cardiovascular morbidity in patients undergoing non‐cardiac surgery]. www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=828&isRevie... (first received 11 October 2005).
ACTRN12615000889 {published data only}
    1. ACTRN12615000889550. A phase II randomized study of perioperative beta‐blocker vs placebo on gene expression in newly diagnosed breast cancer [Investigating whether, in patients receiving breast cancer surgery, pre‐operative propranolol compared with placebo, changes the cancer's gene expression]. anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12615000889550 (first received 25 August 2015).
Birbicer 2007 {published data only}
    1. Birbicer H, Yapici D, Camsari A, Doruk, N, Atici S, Bilgin E, et al. Evaluation of esmolol on P‐wave dispersion. Gogus‐Kalp‐Damar Anestezi ve Yogun Bakim Dernegi Dergisi 2007;13(3):105‐8.
Boussofara 2001 {published data only}
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Boussofara 2004 {published data only}
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Gong 1999 {published data only}
    1. Gong Z, Luo A. Effects of alfentanil and esmolol on hemodynamic and catecholamine response to tracheal intubation. Chinese Medical Sciences Journal 1999;14(3):189‐92. - PubMed
Hornamand 2017 {published data only}
    1. Honarmand A, Safavi M, Kiani N, Keshavarzi E. Comparative evaluation of the effects of different doses of labetalol on cardiovascular response to tracheal intubation. Journal of Isfahan Medical School 2016;34(393):893‐900.
    1. Honarmand A, Safavi M, Mirjalali K. The effect of labetalol or remifentanil on blood pressure and heart rate after laryngoscopy and intubation. Journal of Isfahan Medical School 2017;34(408):1395‐400.
Inada 2002 {published data only}
    1. Inada Y, Namiki A, Shimizu R, Hanaoka K, Ogawa R, Shimoji K, et al. Clinical evaluation of a short acting beta‐blocker (MR5H3; esmolol hydrochloride) on perioperative tachycardia ‐ an open label, multi‐center clinical trial. Anesthesia and Resuscitation 2002;38(3):131‐44.
Itani 2013 {published data only}
    1. Itani M, Tatara T, Hashimoto K, Shii H, Hirose M. Continuous administration of landiolol during general anesthesia for hepatectomy increases plasma epinephrine concentrations but does not affect the magnitude of tachycardia after tracheal extubation. Anesthesia and Analgesia 2013;116(Suppl 1):no pagination.
Joo 2010 {published data only}
    1. Joo J, Lee J, Kim JE, Park J. Optimal dose of esmolol in combination with nicardipine to stabilize cardiovascular response during anesthetic induction in ambulatory patients. Anesthesia and Pain Medicine 2010;5(4):288‐94.
Kajiura 2013 {published data only}
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Kawano 2005 {published data only}
    1. Kawano T, Eguchi S, Iseki A, Oshita S. Effects of landiolol on cardiovascular responses, bispectral index and body movement during endotracheal intubation. Masui. The Japanese Journal of Anesthesiology 2005;54(6):610‐4. [PUBMED: 15966376] - PubMed
NCT02466542 {published data only}
    1. NCT02466542. Analgesic effect of intraoperative esmolol in mastectomies [Analgesic effect of intraoperative esmolol in mastectomies: single center, prospective, double‐blind, randomized and placebo controlled study]. www.clinicaltrials.gov/ct2/show/record/NCT02466542 (first received 9 June 2015).
Tangoku 2016 {published data only}
    1. Tangoku A, Yoshida T, Inoue S. Efficacy of prophylactic landiolol for atrial fibrillation in transthoracic esophagectomy. Diseases of the Esophagus 2016;29(Suppl 1):93A.
UMIN000024040 {published data only}
    1. UMIN000024040. Evaluation of perioperative landiolol administration for preventing atrial fibrillation during esophagectomy. upload.umin.ac.jp/cgi‐open‐bin/ctr_e/ctr_view.cgi?recptno=R000027684 (first received 13 September 2016).
Wang 1994 {published data only}
    1. Wang SC, Wu CC, Lin MS, Chang CF. Use of esmolol to prevent hemodynamic changes during intubation in general anesthesia. Acta Anaesthesiologica Sinica 1994;32(3):141‐6. [PUBMED: 7921857] - PubMed
Wang 1999 {published data only}
    1. Wang L, Luo A, Wu X. Bolus administration of esmolol for preventing the haemodynamic response to tracheal intubation: a multicentre clinical study. Zhonghua Yi Xue Za Zhi 1999;79(11):828‐31. [PUBMED: 11715490] - PubMed
Yuan 1994 {published data only}
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References to ongoing studies

EUCTR2010‐021844‐17 {published data only}
    1. EUCTR2010‐021844‐17. Perioperative esmolol infusion for haemodynamic stability during major vascular surgery. www.clinicaltrialsregister.eu/ctr‐search/search?query=2010‐021844‐17 (first received 27 July 2010).
NCT01555554 {published data only}
    1. NCT01555554. Perioperative propranolol in patients with post traumatic stress disorder (PTSD) [Effect of prophylactic, perioperative propranolol on peri‐ and postoperative complications in patients with post traumatic stress disorder]. www.clinicaltrials.gov/ct2/show/record/NCT01555554 (first received 15 March 2012).
NCT03138603 {published data only}
    1. NCT03138603. Metoprolol to reduce perioperative myocardial injury. www.clinicaltrials.gov/ct2/show/results/NCT03138603 (first received 3 May 2017).

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References to other published versions of this review

Blessberger 2014
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