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Living FRIendly Summaries of the Body of Evidence using Epistemonikos (FRISBEE)
Medwave 2016; 16(Suppl5):e6819 doi: 10.5867/medwave.2016.6819
Is perioperative beta-blockade effective and safe in patients undergoing noncardiac surgery?
Andrés Armstrong, Gabriel Rada, Fernando Altermatt
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Abstract

Beta-blockade in patients undergoing noncardiac surgery has been widely recommended as a way to reduce cardiovascular adverse events during the perioperative period. However, studies have shown contradictory results. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified 22 systematic reviews comprising 131 studies addressing the question of this article, including 112 randomized trials. We extracted data, combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded perioperative use of beta-blockers in patients undergoing noncardiac surgery, although probably decreases the risk of myocardial infarction, increases the risk of stroke and total mortality.


 
Problem

The increase of catecholamines that occurs during noncardiac surgery [1] causes an elevation of blood pressure and heart rate [2],[3],[4], which contributes to the occurrence of cardiovascular adverse events. Beta-blockers suppress the effect of the rise of catecholamines, thus it is thought its administration during perioperative period could prevent these events. Initial studies showed very promising results, which led this intervention to be widely recommended for a wide range of patients undergoing noncardiac surgery. However, further trials not only cast doubts about the benefits of administering beta-blockers during the perioperative period, but also warned of possible adverse effects such as stroke, hypotension and bradycardia, among others. Furthermore, some trials on which previous recommendations were based, have been questioned due to scientific misconduct of their authors. For all these reasons, the decision whether or not to use this intervention is debated up to this day.

Methods

We used Epistemonikos database, which is maintained by screening multiple databases, to identify systematic reviews and their included primary studies. With this information we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

  • Perioperative use of beta-blockers in patients undergoing noncardiac surgery, although probably decreases the risk of myocardial infarction, increases the risk of stroke and total mortality.
  • The existence of trials whose data are potentially fraudulent would be the main explanation for the conflicting results between earlier  and subsequent trials.
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found 22 systematic reviews [5],[6],[7],[8],[9],[10],
[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],
[23],[24],[25],[26], including 131 primary studies, of which 112 correspond to randomized controlled trials. Fifty-five randomized trials [27],[28],[29],[30],[31],[32],
[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],
[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],
[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],
[69],[70],[71], [72],[73],[74],[75],[76],[77],[78],[79],[80],
[81] reported some of the outcomes of interest. This table and the overall summary are based on the latter.

What types of patients were included

The 55 trials included adult patients undergoing any type of noncardiac surgery: gastrointestinal (22%), vascular (22%), gynecological (14.6%), chest (12.2%), trauma (7.3 %), neurological (7.3%), ENT (4.9%), maxillofacial (4.9%), oral (2.4%) and emergency surgery (2.4%). 
All of the trials included both patients with and without previous use of beta-blockers.

What types of interventions were included

The type of beta-blocker most commonly used was metoprolol (35.1%), then esmolol (24.1%), atenolol (16.9%), labetalol (7.4%), bisoprolol (7.4%), propranolol (3.7%) and others (landiolol, nadolol and timolol, 5.4%).
In all of the trials, the route of administration was preoperative oral beta-blockers, intraoperative intravenous and oral postoperative.
All of the trials compared the intervention against placebo plus standard therapy. 

What types of outcomes
were measured

The systematic reviews identified grouped outcomes as follows:

  • All-cause mortality
  • Cardiac-cause mortality
  • Perioperative myocardial infarction
  • Myocardial ischemia
  • Stroke
  • Arrhythmias
  • Heart failure
  • Heart attack
  • Hospital stay
  • Hypotension
  • Bradycardia
  • Bronchospasm
  • Atrioventricular block
  • Acute pulmonary edema

Postoperative follow-up of patients in different trials varied from the day of hospital discharge until 30 days after surgery.
Summary of findings

The information on the effect of beta-blockers is based on the 29 randomized trials involving 12,644 patients, whose data could be included in a meta-analysis. All of the trials reported mortality [27],[28],[29],[31],[32],[33],[34],[36],[37],[38],[39], [40],[41],[42],[45],[46],[47],[52],[54],[56],[58],[59],[60],[62],[72],[74],[75],[77],[78], 26 trials reported perioperative myocardial infarction [27],[28],[29],[31],[33],[34],[39],[40],[41],[42],[45],[46],[47],[52],[54],[56],[58],[59],[60],[62],[63],[72],[74],[75],[77],[78] and 16 perioperative stroke [27],[28],[29],[40],[41],[42],[47],[56],[58],[59],[62],[72],[74],[75],[77],[78].The summary of findings is the following:

  • Perioperative use of beta-blockers in patients undergoing noncardiac surgery increases mortality. The certainty of the evidence is high.
  • Perioperative use of beta-blockers in patients undergoing noncardiac surgery probably decreases the risk of myocardial infarction. The certainty of the evidence is moderate.
  • Perioperative use of beta-blockers in patients undergoing noncardiac surgery increases the risk of stroke. The certainty of the evidence is high.

Other considerations for decision-making

To whom this evidence does and does not apply
  • This evidence applies to adult patients undergoing any type of noncardiac surgery, especially those with cardiovascular risk factors (such as diabetes, hypertension, peripheral arterial disease, among others) and with known coronary artery disease.
  • This evidence applies to patients with or without previous use of beta-blockers. 
About the outcomes included in this summary
  • The outcomes selected for the summary of findings table correspond to those critical for decision-making according to the opinion of the authors of this summary. This is generally in line with the outcomes used by the identified reviews and main clinical guidelines.
  • Other outcomes mentioned in the trials include adverse effects such as myocardial ischemia, bradyarrhythmia, hypotension, bronchospasm, pulmonary edema, among others. These probably are part of the pathophysiological mechanism by which the critical outcomes mentioned in this summary originate. 
Balance between benefits and risks, and certainty of the evidence
  • While there is a likely benefit on acute myocardial infarction in the perioperative period, this is offset by an increase in mortality and the risk of stroke.
  • The balance between benefits and risk is unfavorable to the intervention.
What would patients and their doctors think about this intervention
  • All patients and clinicians should lean against the use of this intervention based on the existing evidence. 
Resource considerations
  • Although beta-blockers are inexpensive and are widely available, they  carry more risks than benefits, so a benefit/risk balance is not appropriate. 

Differences between this summary and other sources
  • The above findings differ with some systematic reviews included in this summary. The main explanation why some reviews concluded beta-blockade reduces the incidence of perioperative mortality and myocardial infarction is because they considered trials [44],[53] whose reliability has been questioned, based on accusations of data manipulation and omissions in reported results [82],[83]. In addition, the results were not reproduced by subsequent trials.
  • Systematic reviews that take into account this fact did not include the previously mentioned trials. Their conclusions are consistent with this summary. 
Could this evidence change in the future?
  • The probability that the conclusions of this summary change with future information is very low, because of the certainty of existing evidence. 
How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Perioperative beta-blockers for noncardiac surgery

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

El betabloqueo en pacientes sometidos a cirugía no cardíaca ha sido ampliamente recomendado como una forma de disminuir los eventos adversos cardiovasculares durante el periodo perioperatorio. Sin embargo, los estudios han mostrado resultados discordantes. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos, identificamos 22 revisiones sistemáticas que en conjunto incluyen 131 estudios, entre ellos 112 estudios aleatorizados. Extrajimos los datos, realizamos un metanálisis y preparamos tablas de resumen de los resultados utilizando el método GRADE. Concluimos que el uso perioperatorio de betabloqueadores en pacientes sometidos a cirugía no cardíaca, si bien probablemente disminuye el riesgo de infarto miocárdico, aumenta el riesgo de accidente cerebrovascular y la mortalidad total.

Authors: Andrés Armstrong[1,2], Gabriel Rada[2,3,4,5,6], Fernando Altermatt[2,7]

Affiliation:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Programa de Salud Basada en Evidencia, Facultad de Medicina, Pontificia Universidad Católica de Chile
[4] Departamento de Medicina Interna, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[5] GRADE working group
[6] The Cochrane Collaboration
[7] Departamento de Anestesiología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

E-mail: fernando.altermatt@gmail.com

Author address:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Lira 63
Santiago Centro
Chile

Citation: Armstrong A, Rada G, Altermatt F. Is perioperative beta-blockade effective and safe in patients undergoing non-cardiac surgery?. Medwave 2016; 16(Suppl5):e6819 doi: 10.5867/medwave.2016.6819

Publication date: 27/12/2016

PubMed record

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Sandler AN, Leitch LF, Badner NH, et al. Esmolol compared with placebo in preventing increases in heart rate and blood pressure during rigid bronchoscopy. J Cardiothorac Anesth 1990; 4:44 –50 | Link |

Lee SJ, Lee JN. The effect of perioperative esmolol infusion on the postoperative nausea, vomiting and pain after laparoscopic appendectomy. Korean J Anesthesiol. 2010 Sep;59(3):179-84 | CrossRef | PubMed |

Yang XY, Wu XM, 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]. Zhonghua Yi Xue Za Zhi. 2008 Jun 3;88(21):1476-80 | PubMed |

Liu PL, Gatt S, Gugino LD, Mallampati SR, Covino BG. Esmolol for control of increases in heart rate and blood pressure during tracheal intubation after thiopentone and succinylcholine. Can Anaesth Soc J. 1986 Sep;33(5):556-62 | PubMed |

Jakobsen CJ, Blom L, Brondbjerg M, Lenler-Petersen P. Effect of metoprolol and diazepam on pre-operative anxiety. Anaesthesia. 1990 Jan;45(1):40-3 | PubMed |

Zaugg M, Bestmann L, Wacker J, Lucchinetti E, Boltres A, Schulz C, et al. Adrenergic receptor genotype but not perioperative bisoprolol therapy may determine cardiovascular outcome in at-risk patients undergoing surgery with spinal block: the Swiss Beta Blocker in Spinal Anesthesia (BBSA) study: a double-blinded, placebo-controlled, multicenter trial with 1-year follow-up. Anesthesiology. 2007 Jul;107(1):33-44 | PubMed |

Gupta D, Srivastava S, Dubey RK, Prakash PS, Singh PK, Singh U. Comparative evaluation of atenolol and clonidine premedication on cardiovascular response to nasal speculum insertion during trans-sphenoid surgery for resection of pituitary adenoma: A prospective, randomised, double-blind, controlled study. Indian J Anaesth. 2011 Mar;55(2):135-40 | CrossRef | PubMed |

Juul AB, Wetterslev J, Gluud C, Kofoed-Enevoldsen A, Jensen G, Callesen T, et al. Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery: randomised placebo controlled, blinded multicentre trial. BMJ. 2006 Jun 24;332(7556):1482 | PubMed |

Rosenberg J, Overgaard H, Andersen M, Rasmussen V, Schulze S. Double blind randomised controlled trial of effect of metoprolol on myocardial ischaemia during endoscopic cholangiopancreatography. BMJ. 1996 Aug 3;313(7052):258-61 | PubMed |

Juul AB, Wetterslev J, Kofoed-Enevoldsen A, Callesen T, Jensen G, Gluud C; Diabetic Postoperative Mortality and Morbidity group. The Diabetic Postoperative Mortality and Morbidity (DIPOM) trial: rationale and design of a multicenter, randomized, placebo-controlled, clinical trial of metoprolol for patients with diabetes mellitus who are undergoing major noncardiac surgery. Am Heart J. 2004 Apr;147(4):677-83 | PubMed |

Shukla S, Gupta K, Gurha P, Sharma M, Sanjay RR, Shukla R, et al. Role of beta blockade in anaesthesia and postoperative pain management after major lower abdominal surgery. The Internet Journal of Anesthesiology 2010;25(1) | Link |

Juul AB, Wetterslev J, Enevoldsen AK, et al. Randomized, blinded trial on perioperative metoprolol versus placebo for diabetic patients undergoing non-cardiac surgery. Circulation 2005; 111:1725 | Link |

Erasmus MC Follow-up Investigation Committee. Investigation into Possible Violation of Scientific Integrity: Report Summary. November 16, 2011.

Erasmus MC Follow-up Investigation Committee. Report on the 2012 Follow-Up Investigation of Possible Breaches of Academic Integrity. September 30, 2012.

July 2022, Vol 22, Issue 6
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Association of biomarkers and severity of COVID-19: A crosssectional study

Systematization of initiatives in sexual and reproductive health about good practices criteria in response to the COVID-19 pandemic in primary health care in Chile

Clinical, psychological, social, and family characterization of suicidal behavior in Chilean adolescents: a multiple correspondence analysis

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