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Resúmenes Epistemonikos
Medwave 2016; 16(Suppl5):e6819 doi: 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
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Resumen

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.


 
Problema

El aumento de catecolaminas que ocurre durante una cirugía no cardiaca [1] produce una elevación de la presión arterial y de la frecuencia cardíaca [2],[3],[4] que contribuye a la ocurrencia de eventos adversos cardiovasculares. Los betabloqueadores suprimen el efecto de la elevación de catecolaminas, por lo que se piensa que su administración en el periodo perioperatorio podría prevenir estos eventos. Los estudios iniciales mostraron resultados muy prometedores, lo cual llevó a que esta intervención fuera ampliamente recomendada para un gran espectro de pacientes sometidos a cirugía no cardíaca. No obstante, estudios posteriores no sólo matizaron el posible beneficio de administrar betabloqueadores en el periodo perioperatorio, sino que alertaron sobre posibles efectos adversos como accidente cerebrovascular, hipotensión y bradicardia, entre otros. A lo anterior se suma el cuestionamiento sobre la confiabilidad de ciertos estudios en que se fundamentaron las recomendaciones previas, ya que algunos autores han sido acusados de mala conducta científica. Por todas estas razones la decisión sobre si utilizar o no esta intervención es motivo de debate hasta el día de hoy.

Métodos

Utilizamos la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos, para identificar revisiones sistemáticas y sus estudios primarios incluidos. Con esta información generamos un resumen estructurado, siguiendo un formato preestablecido, que incluye mensajes clave, un resumen del conjunto de evidencia (presentado como matriz de evidencia en Epistemonikos), metanálisis del total de los estudios, tablas de resumen de resultados con el método GRADE, y tabla de otras consideraciones para la toma de decisión.

Mensajes clave

  • 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.
  • La existencia de estudios cuyos datos son posiblemente fraudulentos sería la principal explicación de los resultados discordantes entre estudios iniciales y aquellos que les siguieron.
Acerca del conjunto de evidencia para esta pregunta

Cuál es la evidencia. 
Véase matriz de evidencia en Epistemonikos más abajo.

Encontramos 22 revisiones sistemáticas[5],[6],[7],[8],[9],
[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],
[22],[23],[24],[25],[26], que incluyen 131 estudios primarios, de los cuales 112 corresponden a estudios controlados aleatorizados. Cincuenta y cinco estudios controlados aleatorizados [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] reportaron alguno de los desenlaces de interés. Esta tabla y el resumen en general se basan en estos últimos.

Qué tipo de pacientes incluyeron los estudios

Los 55 estudios incluyeron pacientes adultos sometidos a cualquier tipo de cirugía no cardíaca: cirugía digestiva (22%), cirugía vascular (22%), ginecológica (14,6%), torácica (12,2%), traumatológica (7,3%), neurológica (7,3%), otorrinolaringológica (4,9%), maxilofacial (4,9%), oral (2,4%) y cirugía de emergencia (2,4%).
En todos los estudios primarios incluidos, se encuentran tanto pacientes con uso previo de betabloqueadores, como sin uso previo.

Qué tipo de intervenciones incluyeron los estudios

El tipo de betabloqueador más utilizado fue metoprolol (35,1%), luego esmolol (24,1%), atenolol (16,9%), labetalol (7,4%), bisoprolol (7,4%), propanolol (3,7%) y otros (landiolol, nadolol y timolol; 5,4%).
En todos los estudios la vía de administración de betabloqueadores fue oral en el preoperatorio, intravenosa en el intraoperatorio, y oral en el postoperatorio.
Todos los estudios compararon la intervención contra placebo más tratamiento estándar.

Qué tipo de desenlaces midieron

Las revisiones sistemáticas identificadas agruparon los desenlaces de la siguiente forma:

  • Mortalidad por cualquier causa
  • Mortalidad de causa cardíaca
  • Infarto miocárdico perioperatorio
  • Isquemia miocárdica
  • Accidente cerebrovascular
  • Arritmias
  • Insuficiencia cardíaca 
  • Paro cardíaco
  • Estadía hospitalaria
  • Hipotensión
  • Bradicardia
  • Broncoespasmo
  • Bloqueos aurículo-ventriculares
  • Edema pulmonar agudo

El seguimiento postoperatorio de los pacientes en los distintos estudios varió desde el día del alta hospitalaria, hasta 30 días posteriores a la cirugía.

Resumen de los resultados

La información sobre el efecto de los betabloqueadores está basada en 29 estudios aleatorizados que incluyen 12 644 pacientes, cuyos datos pudieron ser incorporados a un metanálisis. Todos los estudios midieron el desenlace mortalidad por cualquier causa [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 estudios midieron el desenlace infarto miocárdico perioperatorio [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] y 16 midieron accidentes cerebrovasculares [27],[28],[29],[40],[41],[42],[47],[56],[58],[59],[62],[72],[74],[75],[77],[78]. El resumen de los resultados es el siguiente.

  • El uso perioperatorio de betabloqueadores en pacientes sometidos a cirugía no cardíaca aumenta la mortalidad. La certeza de la evidencia es alta.
  • El uso perioperatorio de betabloqueadores en pacientes sometidos a cirugía no cardíaca probablemente disminuye el riesgo de infarto miocárdico. La certeza de la evidencia es moderada.
  • El uso perioperatorio de betabloqueadores en pacientes sometidos a cirugía no cardíaca aumenta el riesgo de accidente cerebrovascular. La certeza de la evidencia es alta.

Otras consideraciones para la toma de decisión

A quién se aplica y a quién no se aplica esta evidencia

  • Esta evidencia se aplica a pacientes adultos, sometidos a cualquier tipo de cirugía no cardíaca, especialmente pacientes con factores de riesgo cardiovascular (como diabetes, hipertensión, enfermedad arterial periferica, entre otros) y con enfermedad coronaria conocida.
  • Esta evidencia se aplica a pacientes con y sin uso previo de betabloqueadores.
Sobre los desenlaces incluidos en este resumen
  • Los desenlaces seleccionados en la sección de resumen de resultados corresponden a aquellos críticos para la toma de decisión de acuerdo a la opinión de los autores de este resumen. En general coinciden con los desenlaces utilizados por las revisiones identificadas y por las principales guías clínicas.
  • Otros desenlaces mencionados en los estudios incluyen efectos adversos como isquemia miocárdica, bradiarritmias, hipotensión, broncoespasmo y edema pulmonar, entre otros. Estos probablemente forman parte del mecanismo fisiopatológico por el cual se originan los desenlaces críticos mencionados en este resumen. 
Balance riesgo/beneficio y certeza de la evidencia
  • Si bien existe un beneficio probable sobre el infarto agudo al miocardio durante el periodo perioperatorio, éste es contrarrestado por un aumento en la mortalidad y el riesgo de accidente cerebrovascular.
  • El balance entre beneficios y riesgos es desfavorable a la intervención.
Qué piensan los pacientes y sus tratantes
  • Todos los pacientes y clínicos debieran inclinarse en contra de la utilización de esta intervención en base a la evidencia existente.
Consideraciones de recursos
  • Si bien los betabloqueadores tienen un costo bajo y están ampliamente disponibles, por tratarse de una intervención con más riesgos que beneficios, no corresponde realizar un balance entre costos y beneficios.
Diferencias entre este resumen y otras fuentes
  • Las conclusiones expuestas difieren con algunas revisiones sistemáticas incluidas en este resumen. La principal explicación por la cual algunas revisiones concluyeron que el betabloqueo disminuye la incidencia de mortalidad e infarto perioperatorio es que consideraron estudios primarios [44],[53] cuya veracidad ha sido puesta en duda, al comprobarse manipulación y omisión de datos en la entrega de resultados [82],[83]. Además, sus resultados no fueron reproducidos por los estudios posteriores.
  • Las revisiones sistemáticas que toman en cuenta este hecho no incluyeron los estudios previamente mencionados. Sus conclusiones son concordantes con las expuestas en este resumen.
¿Puede que cambie esta información en el futuro?
  • La probabilidad que en el futuro la evidencia cambie las conclusiones de este resumen es muy baja, debido a la certeza de la evidencia. 
Cómo realizamos este resumen

Mediante métodos automatizados y colaborativos recopilamos toda la evidencia relevante para la pregunta de interés y la presentamos en una matriz de evidencia.

Siga el enlace para acceder a la versión interactiva: Betabloqueo perioperatorio en cirugía no cardíaca

Notas

Si con posterioridad a la publicación de este resumen se publican nuevas revisiones sistemáticas sobre este tema, en la parte superior de la matriz se mostrará un aviso de “nueva evidencia”.  Si bien el proyecto contempla la actualización periódica de estos resúmenes, los usuarios están invitados a comentar en Medwave o contactar a los autores mediante correo electrónico si creen que hay evidencia que motive una actualización más rápida.

Luego de crear una cuenta en Epistemonikos, al guardar las matrices recibirá notificaciones automáticas cada vez que exista nueva evidencia que potencialmente responda a esta pregunta. El detalle de los métodos para elaborar este resumen están descritos aquí: http://dx.doi.org/10.5867/medwave.2014.06.5997.

La Fundación Epistemonikos es una organización que busca acercar la información a quienes toman decisiones en salud, mediante el uso de tecnologías. Su principal desarrollo es la base de datos Epistemonikos (www.epistemonikos.org).

Los resúmenes de evidencia siguen un riguroso proceso de revisión por pares interno.

Declaración de conflictos de intereses
Los autores declaran no tener conflictos de intereses con la materia de este artículo.

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.

 

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.

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

Filiación:
[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, Santiago, 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

Correspondencia a:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Lira 63
Santiago Centro
Chile

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

Fecha de publicación: 27/12/2016

Ficha PubMed

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  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 |
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  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.
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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 |

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 |

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 |

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 |

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 |

Yang H, Raymer K, Butler R, et al. Metoprolol after vascular surgery (MAVS). Can J Anaesth 2004;51: A7 | Link |

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 |

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 |

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 |

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 |

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 |

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 |

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 |

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 |

Mackenzie JW, Bird J. Timolol: a non-sedative anxiolytic premedicant for day cases. BMJ. 1989 Feb 11;298(6670):363-4 | PubMed |

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 |

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 |

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 |

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 |

Coleman AJ, Jordan C. Cardiovascular responses to anaesthesia. Influence of beta-adrenoreceptor blockade with metoprolol. Anaesthesia. 1980 Oct;35(10):972-8. | PubMed |

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.