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Publicado el 27 de diciembre de 2016 | http://doi.org/10.5867/medwave.2016.6819

¿Es efectivo y seguro el betabloqueo perioperatorio en pacientes sometidos a cirugía no cardíaca?

Is perioperative beta-blockade effective and safe in patients undergoing noncardiac surgery?

Andrés Armstrong , Gabriel Rada, Fernando Altermatt

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 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.

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.

Autores

Andrés Armstrong

fernando.altermatt@gmail.com.

Facultad de Medicina, Pontificia Universidad Católica de Chile, Lira 63, Santiago Centro, Chile

Gabriel Rada

Fernando Altermatt

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

Publicación 27/12/2016

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Notas

Referencias

  1. Sametz W, Metzler H, Gries M, Porta S, Sadjak A, Supanz S, et al. Perioperative catecholamine changes in cardiac risk patients. Eur J Clin Invest. 1999 Jul;29(7):582-7 | PubMed
  2. Parker SD, Breslow MJ, Frank SM, Rosenfeld BA, Norris EJ, Christopherson R, et al. Catecholamine and cortisol responses to lower extremity revascularization: correlation with outcome variables. Perioperative Ischemia Randomized Anesthesia Trial Study Group. Crit Care Med. 1995 Dec;23(12):1954-61 | PubMed
  3. Priebe HJ. Triggers of perioperative myocardial ischaemia and infarction. Br J Anaesth. 2004 Jul;93(1):9-20 | PubMed
  4. Weissman C. The metabolic response to stress: an overview and update. Anesthesiology. 1990 Aug;73(2):308-27 | PubMed
  5. Angeli F, Verdecchia P, Karthikeyan G, Mazzotta G, Gentile G, Reboldi G. ß-Blockers reduce mortality in patients undergoing high-risk non-cardiac surgery. Am J Cardiovasc Drugs. 2010;10(4):247-59 | CrossRef | PubMed
  6. Angeli F, Verdecchia P, Karthikeyan G, Mazzotta G, Repaci S, del Pinto M, et al. Beta-blockers and risk of all-cause mortality in non-cardiac surgery. Ther Adv Cardiovasc Dis. 2010 Apr;4(2):109-18 | CrossRef | PubMed
  7. Auerbach AD, Goldman L. beta-Blockers and reduction of cardiac events in noncardiac surgery: scientific review. JAMA. 2002 Mar 20;287(11):1435-44 | PubMed
  8. Bangalore S, Wetterslev J, Pranesh S, Sawhney S, Gluud C, Messerli FH. Perioperative beta blockers in patients having non-cardiac surgery: a meta-analysis. Lancet. 2008 Dec 6;372(9654):1962-76 | CrossRef | PubMed
  9. Bouri S, Shun-Shin MJ, Cole GD, Mayet J, Francis DP. Meta-analysis of secure randomised controlled trials of ß-blockade to prevent perioperative death in non-cardiac surgery. Heart. 2014 Mar;100(6):456-64 | CrossRef | PubMed
  10. Dai N, Xu D, Zhang J, Wei Y, Li W, Fan B, et al. Different ß-blockers and initiation time in patients undergoing noncardiac surgery: a meta-analysis. Am J Med Sci. 2014 Mar;347(3):235-44 | CrossRef | PubMed
  11. Devereaux PJ, Beattie WS, Choi PT, Badner NH, Guyatt GH, Villar JC, et al. How strong is the evidence for the use of perioperative beta blockers in non-cardiac surgery? Systematic review and meta-analysis of randomised controlled trials. BMJ. 2005 Aug 6;331(7512):313-21 | PubMed
  12. Schouten O, Shaw LJ, Boersma E, Bax JJ, Kertai MD, Feringa HH, et al. A meta-analysis of safety and effectiveness of perioperative beta-blocker use for the prevention of cardiac events in different types of noncardiac surgery. Coron Artery Dis. 2006 Mar;17(2):173-9 | PubMed
  13. Giles JW, Sear JW, Foëx P. Effect of chronic beta-blockade on peri-operative outcome in patients undergoing non-cardiac surgery: an analysis of observational and case control studies. Anaesthesia. 2004 Jun;59(6):574-83 | PubMed
  14. Guay J, Ochroch EA. ß-blocking agents for surgery: influence on mortality and major outcomes. A meta-analysis. J Cardiothorac Vasc Anesth. 2013 Oct;27(5):834-44 | CrossRef | PubMed
  15. Blessberger H, Kammler J, Domanovits H, Schlager O, Wildner B, Azar D, et al. Perioperative beta-blockers for preventing surgery-related mortality and morbidity. Cochrane Database Syst Rev. 2014 Sep 18;(9):CD004476 | CrossRef | PubMed
  16. Landoni G, Turi S, Biondi-Zoccai G, Bignami E, Testa V, Belloni I, et al. Esmolol reduces perioperative ischemia in noncardiac surgery: a meta-analysis of randomized controlled studies. J Cardiothorac Vasc Anesth. 2010 Apr;24(2):219-29 | CrossRef | PubMed
  17. McGory ML, Maggard MA, Ko CY. A meta-analysis of perioperative beta blockade: what is the actual risk reduction? Surgery. 2005 Aug;138(2):171-9 | PubMed
  18. Mostafaie K, Bedenis R, Harrington D. Beta-adrenergic blockers for perioperative cardiac risk reduction in people undergoing vascular surgery. Cochrane Database Syst Rev. 2015 Jan 14;1:CD006342 | CrossRef | PubMed
  19. Riber LP, Larsen TB, Christensen TD. Postoperative atrial fibrillation prophylaxis after lung surgery: systematic review and meta-analysis. Ann Thorac Surg. 2014 Dec;98(6):1989-97 | CrossRef | PubMed
  20. Sedrakyan A, Treasure T, Browne J, Krumholz H, Sharpin C, van der Meulen J. Pharmacologic prophylaxis for postoperative atrial tachyarrhythmia in general thoracic surgery: evidence from randomized clinical trials. J Thorac Cardiovasc Surg. 2005 May;129(5):997-1005 | PubMed
  21. Stevens RD, Burri H, Tramèr MR. Pharmacologic myocardial protection in patients undergoing noncardiac surgery: a quantitative systematic review. Anesth Analg. 2003 Sep;97(3):623-33 | PubMed
  22. Talati R, Reinhart KM, White CM, Phung OJ, Sedrakyan A, Kluger J, et al. Outcomes of perioperative beta-blockade in patients undergoing noncardiac surgery: a meta-analysis. Ann Pharmacother. 2009 Jul;43(7):1181-8 | CrossRef | PubMed
  23. Wan YD, Zhang SG, Sun TW, Kan QC, Wang LX. The effects of perioperative ß-blockers on mortality in patients undergoing non-cardiac surgery in real world: a meta-analysis of cohort studies. Int J Cardiol. 2014 Oct 20;176(3):605-10 | CrossRef | PubMed
  24. Wiesbauer F, Schlager O, Domanovits H, Wildner B, Maurer G, Muellner M, et al. Perioperative beta-blockers for preventing surgery-related mortality and morbidity: a systematic review and meta-analysis. Anesth Analg. 2007 Jan;104(1):27-41 | PubMed
  25. Wijeysundera DN, Duncan D, Nkonde-Price C, Virani SS, Washam JB, Fleischmann KE, et al. Perioperative beta blockade in noncardiac surgery: a systematic review for the 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014 Dec 9;64(22):2406-25 | CrossRef | PubMed
  26. Yu SK, Tait G, Karkouti K, Wijeysundera D, McCluskey S, Beattie WS. The safety of perioperative esmolol: a systematic review and meta-analysis of randomized controlled trials. Anesth Analg. 2011 Feb;112(2):267-81 | CrossRef | PubMed
  27. Miller DR, Martineau RJ, Wynands JE, Hill J. Bolus administration of esmolol for controlling the haemodynamic response to tracheal intubation: the Canadian Multicentre Trial. Can J Anaesth. 1991 Oct;38(7):849-58 | PubMed
  28. Lai RC, Xu MX, Huang WQ, Wang XD, Zeng WA, Lin WQ. [Beneficial effects of metoprolol on perioperative cardiac function of elderly esophageal cancer patients]. Ai Zheng. 2006 May;25(5):609-13 | PubMed
  29. Wallace A, Layug B, Tateo I, Li J, Hollenberg M, Browner W, Miller D, Mangano DT. Prophylactic atenolol reduces postoperative myocardial ischemia. McSPI Research Group. Anesthesiology. 1998 Jan;88(1):7-17 | PubMed
  30. Apipan B, Rummasak D. Efficacy and safety of oral propranolol premedication to reduce reflex tachycardia during hypotensive anesthesia with sodium nitroprusside in orthognathic surgery: a double-blind randomized clinical trial. J Oral Maxillofac Surg. 2010 Jan;68(1):120-4 | CrossRef | PubMed
  31. Urban MK, Markowitz SM, Gordon MA, Urquhart BL, Kligfield P. Postoperative prophylactic administration of beta-adrenergic blockers in patients at risk for myocardial ischemia. Anesth Analg. 2000 Jun;90(6):1257-61 | PubMed
  32. Magnusson J, Thulin T, Werner O, Järhult J, Thomson D. Haemodynamic effects of pretreatment with metoprolol in hypertensive patients undergoing surgery. Br J Anaesth. 1986 Mar;58(3):251-60 | PubMed
  33. Magnusson H, Pontén J, Sonander HG. Methohexitone anaesthesia for microlaryngoscopy: circulatory modulation with metoprolol and dihydralazine. Br J Anaesth. 1986 Sep;58(9):976-82 | PubMed
  34. Neary WD, McCrirrick A, Foy C, Heather BP, Earnshaw JJ. Lessons learned from a randomised controlled study of perioperative beta blockade in high risk patients undergoing emergency surgery. Surgeon. 2006 Jun;4(3):139-43 | PubMed
  35. Jakobsen CJ, Bille S, Ahlburg P, Rybro L, Hjortholm K, Andresen EB. Perioperative metoprolol reduces the frequency of atrial fibrillation after thoracotomy for lung resection. J Cardiothorac Vasc Anesth. 1997 Oct;11(6):746-51 | PubMed
  36. Kawaguchi M, Utada K, Yoshitani K, Uchino H, Takeda Y, Masui K, et al; Intraoperative Landiolol for Intracranial Aneurysm Surgery Trial (ILAST) Investigators. Effects of a short-acting [beta]1 receptor antagonist landiolol on hemodynamics and tissue injury markers in patients with subarachnoid hemorrhage undergoing intracranial aneurysm surgery. J Neurosurg Anesthesiol. 2010 Jul;22(3):230-9 | CrossRef | PubMed
  37. Suttner S, Boldt J, Mengistu A, Lang K, Mayer J. Influence of continuous perioperative beta-blockade in combination with phosphodiesterase inhibition on haemodynamics and myocardial ischaemia in high-risk vascular surgery patients. Br J Anaesth. 2009 May;102(5):597-607 | CrossRef | PubMed
  38. Burns JM, Hart DM, Hughes RL, Kelman AW, Hillis WS. Effects of nadolol on arrhythmias during laparoscopy performed under general anaesthesia. Br J Anaesth. 1988 Sep;61(3):345-6 | PubMed
  39. Miller D, Martineau R, Hull K, Hill J. Bolus administration of esmolol for controlling the hemodynamic response to laryngoscopy and intubation: efficacy and effects on myocardial performance. J Cardiothorac Anesth 1990; 4: 31–36 | Link
  40. Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med. 1996 Dec 5;335(23):1713-20. | PubMed
  41. Cucchiara RF, Benefiel DJ, Matteo RS, DeWood M, Albin MS. Evaluation of esmolol in controlling increases in heart rate and blood pressure during endotracheal intubation in patients undergoing carotid endarterectomy. Anesthesiology. 1986 Nov;65(5):528-31 | PubMed
  42. Jakobsen CJ, Grabe N, Christensen B. Metoprolol decreases the amount of halothane required to induce hypotension during general anaesthesia. Br J Anaesth. 1986 Mar;58(3):261-6 | PubMed
  43. Jakobsen CJ, Blom L. Effect of pre-operative metoprolol on cardiovascular and catecholamine response and bleeding during hysterectomy. Eur J Anaesthesiol. 1992 May;9(3):209-15 | PubMed
  44. Poldermans D, Boersma E, Bax JJ, Thomson IR, van de Ven LL, Blankensteijn JD, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. 1999 Dec 9;341(24):1789-94 | PubMed
  45. Zaugg M, Tagliente T, Lucchinetti E, Jacobs E, Krol M, Bodian C, et al. Beneficial effects from beta-adrenergic blockade in elderly patients undergoing noncardiac surgery. Anesthesiology. 1999 Dec;91(6):1674-86. | PubMed
  46. Davies MJ, Dysart RH, Silbert BS, Scott DA, Cook RJ. Prevention of tachycardia with atenolol pretreatment for carotid endarterectomy under cervical plexus blockade. Anaesth Intensive Care. 1992 May;20(2):161-4 | PubMed
  47. Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008 May 31;371(9627):1839-47 | CrossRef | PubMed
  48. Stone JG, Foëx P, Sear JW, Johnson LL, Khambatta HJ, Triner L. Risk of myocardial ischaemia during anaesthesia in treated and untreated hypertensive patients. Br J Anaesth. 1988 Dec;61(6):675-9 | PubMed
  49. Leslie JB, Kalayjian RW, McLoughlin TM, Plachetka JR. Attenuation of the hemodynamic responses to endotracheal intubation with preinduction intravenous labetalol. J Clin Anesth. 1989;1(3):194-200 | PubMed
  50. Inada E, Cullen DJ, Nemeskal AR, Teplick R. Effect of labetalol or lidocaine on the hemodynamic response to intubation: a controlled randomized double-blind study. J Clin Anesth. 1989;1(3):207-13 | PubMed
  51. London MJ, Zaugg M, Schaub MC, Spahn DR. Perioperative beta-adrenergic receptor blockade: physiologic foundations and clinical controversies. Anesthesiology. 2004 Jan;100(1):170-5 | PubMed
  52. Raby KE, Brull SJ, Timimi F, Akhtar S, Rosenbaum S, Naimi C, Whittemore AD. The effect of heart rate control on myocardial ischemia among high-risk patients after vascular surgery. Anesth Analg. 1999 Mar;88(3):477-82 | PubMed
  53. Dunkelgrun M, Boersma E, Schouten O, Koopman-van Gemert AW, van Poorten F, Bax JJ, et al. Bisoprolol and fluvastatin for the reduction of perioperative cardiac mortality and myocardial infarction in intermediate-risk patients undergoing noncardiovascular surgery: a randomized controlled trial (DECREASE-IV). Ann Surg. 2009 Jun;249(6):921-6 | CrossRef | PubMed
  54. Stone JG, Foëx 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 Apr;68(4):495-500 | PubMed
  55. Yang H, Raymer K, Butler R, et al. Metoprolol after vascular surgery (MAVS). Can J Anaesth 2004;51: A7 | Link
  56. Bayliff CD, Massel DR, Inculet RI, Malthaner RA, Quinton SD, Powell FS, et al. Propranolol for the prevention of postoperative arrhythmias in general thoracic surgery. Ann Thorac Surg. 1999 Jan;67(1):182-6 | PubMed
  57. Oxorn D, Knox JW, Hill J. Bolus doses of esmolol for the prevention of perioperative hypertension and tachycardia. Can J Anaesth. 1990 Mar;37(2):206-9. | PubMed
  58. Yang H, Raymer K, Butler R, Parlow J, Roberts R. The effects of perioperative beta-blockade: results of the Metoprolol after Vascular Surgery (MaVS) study, a randomized controlled trial. Am Heart J. 2006 Nov;152(5):983-90 | PubMed
  59. Marwick TH, Branagan H, Venkatesh B, Stewart S; STRATIFY investigators. Use of a nurse-led intervention to optimize beta-blockade for reducing cardiac events after major noncardiac surgery. Am Heart J. 2009 Apr;157(4):784-90 | CrossRef | PubMed
  60. Jakobsen CJ, Bille S, Ahlburg P, Rybro L, Pedersen KD, Rasmussen B. Preoperative metoprolol improves cardiovascular stability and reduces oxygen consumption after thoracotomy. Acta Anaesthesiol Scand. 1997 Nov;41(10):1324-30. | PubMed
  61. Miller DR, Martineau RJ. Bolus administration of esmolol for the treatment of intraoperative myocardial ischaemia. Can J Anaesth. 1989 Sep;36(5):593-7 | PubMed
  62. Brady AR, Gibbs JS, Greenhalgh RM, Powell JT, Sydes MR; POBBLE trial investigators.. Perioperative beta-blockade (POBBLE) for patients undergoing infrarenal vascular surgery: results of a randomized double-blind controlled trial. J Vasc Surg. 2005 Apr;41(4):602-9 | PubMed
  63. Liu Y, Huang CL, He M, Zhang LN, Cai HW, Guo QL. [Influences of perioperative metoprolol on hemodynamics and myocardial ischaemia in elderly patients undergoing noncardiac surgery]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2006 Apr;31(2):249-53 | PubMed
  64. Mackenzie JW, Bird J. Timolol: a non-sedative anxiolytic premedicant for day cases. BMJ. 1989 Feb 11;298(6670):363-4 | PubMed
  65. Whitehead MH, Whitmarsh VB, Horton JN. Metoprolol in anaesthesia for oral surgery. The effect of pretreatment on the incidence of cardiac dysrhythmias. Anaesthesia. 1980 Aug;35(8):779-82 | PubMed
  66. Moon YE, Hwang WJ, Koh HJ, Min JY, Lee J. The sparing effect of low-dose esmolol on sevoflurane during laparoscopic gynaecological surgery. J Int Med Res. 2011;39(5):1861-9 | PubMed
  67. Böhm M, Maack C, Wehrlen-Grandjean M, Erdmann E. Effect of bisoprolol on perioperative complications in chronic heart failure after surgery (Cardiac Insufficiency Bisoprolol Study II (CIBIS II)). Z Kardiol. 2003 Aug;92(8):668-76. | PubMed
  68. Gibson BE, Black S, Maass L, Cucchiara RF. Esmolol for the control of hypertension after neurologic surgery. Clin Pharmacol Ther. 1988 Dec;44(6):650-3. | PubMed
  69. Coleman AJ, Jordan C. Cardiovascular responses to anaesthesia. Influence of beta-adrenoreceptor blockade with metoprolol. Anaesthesia. 1980 Oct;35(10):972-8. | PubMed
  70. 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
  71. 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
  72. 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
  73. 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
  74. 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
  75. 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
  76. 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
  77. 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
  78. 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
  79. 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
  80. 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
  81. 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
  82. Erasmus MC Follow-up Investigation Committee. Investigation into Possible Violation of Scientific Integrity: Report Summary. November 16, 2011.
  83. Erasmus MC Follow-up Investigation Committee. Report on the 2012 Follow-Up Investigation of Possible Breaches of Academic Integrity. September 30, 2012.