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Resúmenes Epistemonikos
Medwave 2017 Nov-Dic;17(9):e7113 doi: 10.5867/medwave.2017.09.7113
¿Es flumazenil una alternativa para el tratamiento de la encefalopatía hepática?
Is flumazenil an alternative for the treatment of hepatic encephalopathy?
Diego Reyes, Francisco Barrera
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Abstract

INTRODUCTION
Flumazenil is an antagonist of the GABA/benzodiazepines receptor complex that might play a role in the treatment of hepatic encephalopathy. However, its efficacy and safety are a matter of debate.

METHODS
To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.

RESULTS AND CONCLUSIONS
We identified two systematic reviews including fourteen randomized trials. We concluded flumazenil does not reduce mortality in patients with hepatic encephalopathy and it is not clear whether it leads to any clinical improvement because the certainty of the evidence is very low.


  Error Content : No se econtro el path especificado
Error Content : No se econtro el path especificado
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.

 

INTRODUCTION
Flumazenil is an antagonist of the GABA/benzodiazepines receptor complex that might play a role in the treatment of hepatic encephalopathy. However, its efficacy and safety are a matter of debate.

METHODS
To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.

RESULTS AND CONCLUSIONS
We identified two systematic reviews including fourteen randomized trials. We concluded flumazenil does not reduce mortality in patients with hepatic encephalopathy and it is not clear whether it leads to any clinical improvement because the certainty of the evidence is very low.

Autores: Diego Reyes[1,2], Francisco Barrera[2,3]

Filiación:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

E-mail: fjbarrer@gmail.com

Correspondencia a:
[1] Centro Evidencia UC
Pontificia Universidad Católica de Chile
Centro de Innovación UC Anacleto Angelini
Avda.Vicuña Mackenna 4860
Macul
Santiago
Chile

Citación: Reyes D, Barrera F. Is flumazenil an alternative for the treatment of hepatic encephalopathy?. Medwave 2017 Nov-Dic;17(9):e7113 doi: 10.5867/medwave.2017.09.7113

Fecha de envío: 18/11/2017

Fecha de aceptación: 4/12/2017

Fecha de publicación: 26/12/2017

Origen: Este artículo es producto del Epistemonikos Evidence Synthesis Project de la Fundación Epistemonikos, en colaboración con Medwave para su publicación.

Tipo de revisión: Con revisión por pares sin ciego por parte del equipo metodológico del Epistemonikos Evidence Synthesis Project.

Ficha PubMed

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  1. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35. | CrossRef | PubMed |
  2. Goulenok C, Bernard B, Cadranel JF, Thabut D, Di Martino V, Opolon P, et al. Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis. Aliment Pharmacol Ther. 2002 Mar;16(3):361-72. | PubMed |
  3. Goh ET, Andersen ML, Morgan MY, Gluud LL. Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. Cochrane Database Syst Rev. 2017 Jul 26;7:CD002798. | CrossRef | PubMed |
  4. Gyr K, Meier R, Häussler J, Boulétreau P, Fleig WE, Gatta A, et al. Evaluation of the efficacy and safety of flumazenil in the treatment of portal systemic encephalopathy: a double blind, randomised, placebo controlled multicentre study. Gut. 1996 Aug;39(2):319-24. | PubMed |
  5. Lotterer E, Hoppe M, Balzer C, Fleig WE.. Short-term effects of flumazenil in early stage of portosystemic encephalopathy (PSE): a placebo-controlled, prospective, randomized study. Gastroenterology. 2001;120:376-77. | Link |
  6. Groeneweg M, Gyr K, Amrein R, Scollo-Lavizzari G, Williams R, Yoo JY, et al. Effect of flumazenil on the electroencephalogram of patients with portosystemic encephalopathy. Results of a double blind, randomised, placebo-controlled multicentre trial. Electroencephalogr Clin Neurophysiol. 1996 Jan;98(1):29-34. | PubMed |
  7. Meier R, Gyr K, Häussler R, and the PSE-Study Group. Treatment of portosystemic encephalopathy with the benzodiazepine-receptor antagonist flumazenil (a randomized, double-blind, placebo-controlled, multicenter study). Gastroenterology 1994;106 Suppl(4):A942. | Link |
  8. Van der Rijt CC, Schalm SW, Meulstee J, Stijnen T. Flumazenil therapy for hepatic encephalopathy. A double-blind cross over study. Gastroenterol Clin Biol. 1995 Jun-Jul;19(6-7):572-80. | PubMed |
  9. Van der Rijt CCD, Schalm SW, Meulstee J, Stijnen T.. Flumazenil therapy for hepatic encephalopathy: a double-blind cross-over study. Hepatology (Baltimore, Md.). 1989;10:4. | Link |
  10. Van der Rijt CCD.. Hepatic Encephalopathy: Clinical and Experimental Studies. Alblasserdam, Netherlands: Offsetdrukkerij Haveka BV. 1991. | Link |
  11. Cadranel JF, el Younsi M, Pidoux B, Zylberberg P, Benhamou Y, Valla D, et al. Flumazenil therapy for hepatic encephalopathy in cirrhotic patients: a double-blind pragmatic randomized, placebo study. Eur J Gastroenterol Hepatol. 1995 Apr;7(4):325-9. | PubMed |
  12. Cadranel JF, El Younsi M, Pidoux B, Zylberberg P, Benhamou Y, et al.. Immediate improvement of hepatic encephalopathy (HE) in cirrhotic patients by flumazenil. Journal of Hepatology. 1991;13(Suppl(2)):104. | Link |
  13. El Younsi M, Cadranel JF, Pidoux B, Zylberberg P, Valla D, et al. The immediate effect on the clinical grade and electroencephalogram of cirrhotic patients with hepatic encephalopathy [Effets immediats du flumazenil sur le degre clinique et electroencephalographique de l’encephalopathie hepatique chez le cirrhotique [abstract]]. Gastroenterologie Clinique et Biologique 1991; Vol. 15, issue 2:A216. | Link |
  14. Amodio P, Marchetti P, Comacchio F, Beghi A, Del Piccolo F, Merkel C, et al. Effects of flumazenil on subclinical hepatic encephalopathy (SHE): preliminary data. Italian Journal of Gastroenterology. 1993;23:179. | Link |
  15. Amodio P, Marchetti P, Del Piccolo F, Beghi A, Comacchio F, Carraro P, et al. The effect of flumazenil on subclinical psychometric or neurophysiological alterations in cirrhotic patients: a double-blind placebo-controlled study. Clin Physiol. 1997 Sep;17(5):533-9. | PubMed |
  16. Amodio P, Marchetti P, Comacchio F, Beghi A, del Piccolo F, et al. Effects of flumazenil on subclinical hepatic encephalopathy (SHE) [EASL abstract]. Journal of Hepatology 1993;18 Suppl(1):88. | Link |
  17. Barbaro G, Di Lorenzo G, Soldini M, Giancaspro G, Bellomo G, Belloni G, et al. Flumazenil for hepatic encephalopathy grade III and IVa in patients with cirrhosis: an Italian multicenter double-blind, placebo-controlled, cross-over study. Hepatology. 1998 Aug;28(2):374-8. | PubMed |
  18. Barbaro G, Di Lorenzo G, Soldini M, Marziali M, Bellomo G, Belloni G, et al. Flumazenil for hepatic coma in patients with liver cirrhosis: an Italian multicentre double-blind, placebo-controlled, crossover study. Eur J Emerg Med. 1998 Jun;5(2):213-8. | PubMed |
  19. Giger-Mateeva VI, Reits D, Liberov B, Jones EA, Spekreijse H. The effect of flumazenil on visual event-related potentials of clinically non-encephalopathic patients with cirrhosis. Neurosci Lett. 1999 Dec 10;276(3):173-6. | PubMed |
  20. Jones EA, Giger-Mateeva VI, Reits D, Riemslag FC, Liberov B, Spekrijse H. Visual event-related potentials in cirrhotic patients without overt encephalopathy: the effects of flumazenil. Metab Brain Dis. 2001 Jun;16(1-2):43-53. | PubMed |
  21. Pomier-Layrargues G, Giguère JF, Lavoie J, Perney P, Gagnon S, D'Amour M, et al. Flumazenil in cirrhotic patients in hepatic coma: a randomized double-blind placebo-controlled crossover trial. Hepatology. 1994 Jan;19(1):32-7. | PubMed |
  22. Klotz U, Walker S. Flumazenil and hepatic encephalopathy. Lancet. 1989 Jan 21;1(8630):155-6. | PubMed |
  23. Gooday R, Hayes PC, Bzeizi K, O'Carroll RE. Benzodiazepine receptor antagonism improves reaction time in latent hepatic encephalopathy. Psychopharmacology (Berl). 1995 Jun;119(3):295-8. | PubMed |
  24. Laccetti M, Manes G, Uomo G, Lioniello M, Rabitti PG, Balzano A. Flumazenil in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double blind randomized placebo controlled study. Dig Liver Dis. 2000 May;32(4):335-8. | PubMed |
  25. Dursun M, Caliskan M, Canoruc F, Aluclu U, Canoruc N, Tuzcu A, et al. The efficacy of flumazenil in subclinical to mild hepatic encephalopathic ambulatory patients. A prospective, randomised, double-blind, placebo-controlled study. Swiss Med Wkly. 2003 Feb 22;133(7-8):118-23. | PubMed |
  26. Zhu C, Wang J, Liu T. Flumazenil in the treatment of cirrhotic patients with hepatic encephalopathy: A randomized doubled-blind clinical trial. Chinese Journal of Digestion 1998;18:355–8. | Link |
  27. Hermant JL, Levacher S, Frenkel AL, Blaise M, Volter F, et al. The clinical and electroencephalographic effects of flumazenil in acute hepatic encephalopathy [Effets cliniques et electroencephalographiques du flumazenil dans l’encephalopathie hepatique aigue]. Annales Francaises d’Anesthesie et de Reanimation 1991;10 Suppl:R172. | Link |
  28. Li F, Lei L, Wei L.. Clinical study of flumazenil on severe hepatic encephalopathy. Practical Pharmacy and Clinical Remedies. 2009;12:79-81. | Link |
  29. Treatment of Hepatic Encephalopathy with Flumazenil and change in Cortical GABA levels in MRS. NCT02048969. | Link |
  30. Cadranel JF, el Younsi M, Pidoux B, Zylberberg P, Benhamou Y, Valla D, et al. Flumazenil therapy for hepatic encephalopathy in cirrhotic patients: a double-blind pragmatic randomized, placebo study. Eur J Gastroenterol Hepatol. 1995 Apr;7(4):325-9. | PubMed |
Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35. | CrossRef | PubMed |

Goulenok C, Bernard B, Cadranel JF, Thabut D, Di Martino V, Opolon P, et al. Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis. Aliment Pharmacol Ther. 2002 Mar;16(3):361-72. | PubMed |

Goh ET, Andersen ML, Morgan MY, Gluud LL. Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. Cochrane Database Syst Rev. 2017 Jul 26;7:CD002798. | CrossRef | PubMed |

Gyr K, Meier R, Häussler J, Boulétreau P, Fleig WE, Gatta A, et al. Evaluation of the efficacy and safety of flumazenil in the treatment of portal systemic encephalopathy: a double blind, randomised, placebo controlled multicentre study. Gut. 1996 Aug;39(2):319-24. | PubMed |

Lotterer E, Hoppe M, Balzer C, Fleig WE.. Short-term effects of flumazenil in early stage of portosystemic encephalopathy (PSE): a placebo-controlled, prospective, randomized study. Gastroenterology. 2001;120:376-77. | Link |

Groeneweg M, Gyr K, Amrein R, Scollo-Lavizzari G, Williams R, Yoo JY, et al. Effect of flumazenil on the electroencephalogram of patients with portosystemic encephalopathy. Results of a double blind, randomised, placebo-controlled multicentre trial. Electroencephalogr Clin Neurophysiol. 1996 Jan;98(1):29-34. | PubMed |

Meier R, Gyr K, Häussler R, and the PSE-Study Group. Treatment of portosystemic encephalopathy with the benzodiazepine-receptor antagonist flumazenil (a randomized, double-blind, placebo-controlled, multicenter study). Gastroenterology 1994;106 Suppl(4):A942. | Link |

Van der Rijt CC, Schalm SW, Meulstee J, Stijnen T. Flumazenil therapy for hepatic encephalopathy. A double-blind cross over study. Gastroenterol Clin Biol. 1995 Jun-Jul;19(6-7):572-80. | PubMed |

Van der Rijt CCD, Schalm SW, Meulstee J, Stijnen T.. Flumazenil therapy for hepatic encephalopathy: a double-blind cross-over study. Hepatology (Baltimore, Md.). 1989;10:4. | Link |

Van der Rijt CCD.. Hepatic Encephalopathy: Clinical and Experimental Studies. Alblasserdam, Netherlands: Offsetdrukkerij Haveka BV. 1991. | Link |

Cadranel JF, el Younsi M, Pidoux B, Zylberberg P, Benhamou Y, Valla D, et al. Flumazenil therapy for hepatic encephalopathy in cirrhotic patients: a double-blind pragmatic randomized, placebo study. Eur J Gastroenterol Hepatol. 1995 Apr;7(4):325-9. | PubMed |

Cadranel JF, El Younsi M, Pidoux B, Zylberberg P, Benhamou Y, et al.. Immediate improvement of hepatic encephalopathy (HE) in cirrhotic patients by flumazenil. Journal of Hepatology. 1991;13(Suppl(2)):104. | Link |

El Younsi M, Cadranel JF, Pidoux B, Zylberberg P, Valla D, et al. The immediate effect on the clinical grade and electroencephalogram of cirrhotic patients with hepatic encephalopathy [Effets immediats du flumazenil sur le degre clinique et electroencephalographique de l’encephalopathie hepatique chez le cirrhotique [abstract]]. Gastroenterologie Clinique et Biologique 1991; Vol. 15, issue 2:A216. | Link |

Amodio P, Marchetti P, Comacchio F, Beghi A, Del Piccolo F, Merkel C, et al. Effects of flumazenil on subclinical hepatic encephalopathy (SHE): preliminary data. Italian Journal of Gastroenterology. 1993;23:179. | Link |

Amodio P, Marchetti P, Del Piccolo F, Beghi A, Comacchio F, Carraro P, et al. The effect of flumazenil on subclinical psychometric or neurophysiological alterations in cirrhotic patients: a double-blind placebo-controlled study. Clin Physiol. 1997 Sep;17(5):533-9. | PubMed |

Amodio P, Marchetti P, Comacchio F, Beghi A, del Piccolo F, et al. Effects of flumazenil on subclinical hepatic encephalopathy (SHE) [EASL abstract]. Journal of Hepatology 1993;18 Suppl(1):88. | Link |

Barbaro G, Di Lorenzo G, Soldini M, Giancaspro G, Bellomo G, Belloni G, et al. Flumazenil for hepatic encephalopathy grade III and IVa in patients with cirrhosis: an Italian multicenter double-blind, placebo-controlled, cross-over study. Hepatology. 1998 Aug;28(2):374-8. | PubMed |

Barbaro G, Di Lorenzo G, Soldini M, Marziali M, Bellomo G, Belloni G, et al. Flumazenil for hepatic coma in patients with liver cirrhosis: an Italian multicentre double-blind, placebo-controlled, crossover study. Eur J Emerg Med. 1998 Jun;5(2):213-8. | PubMed |

Giger-Mateeva VI, Reits D, Liberov B, Jones EA, Spekreijse H. The effect of flumazenil on visual event-related potentials of clinically non-encephalopathic patients with cirrhosis. Neurosci Lett. 1999 Dec 10;276(3):173-6. | PubMed |

Jones EA, Giger-Mateeva VI, Reits D, Riemslag FC, Liberov B, Spekrijse H. Visual event-related potentials in cirrhotic patients without overt encephalopathy: the effects of flumazenil. Metab Brain Dis. 2001 Jun;16(1-2):43-53. | PubMed |

Pomier-Layrargues G, Giguère JF, Lavoie J, Perney P, Gagnon S, D'Amour M, et al. Flumazenil in cirrhotic patients in hepatic coma: a randomized double-blind placebo-controlled crossover trial. Hepatology. 1994 Jan;19(1):32-7. | PubMed |

Klotz U, Walker S. Flumazenil and hepatic encephalopathy. Lancet. 1989 Jan 21;1(8630):155-6. | PubMed |

Gooday R, Hayes PC, Bzeizi K, O'Carroll RE. Benzodiazepine receptor antagonism improves reaction time in latent hepatic encephalopathy. Psychopharmacology (Berl). 1995 Jun;119(3):295-8. | PubMed |

Laccetti M, Manes G, Uomo G, Lioniello M, Rabitti PG, Balzano A. Flumazenil in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double blind randomized placebo controlled study. Dig Liver Dis. 2000 May;32(4):335-8. | PubMed |

Dursun M, Caliskan M, Canoruc F, Aluclu U, Canoruc N, Tuzcu A, et al. The efficacy of flumazenil in subclinical to mild hepatic encephalopathic ambulatory patients. A prospective, randomised, double-blind, placebo-controlled study. Swiss Med Wkly. 2003 Feb 22;133(7-8):118-23. | PubMed |

Zhu C, Wang J, Liu T. Flumazenil in the treatment of cirrhotic patients with hepatic encephalopathy: A randomized doubled-blind clinical trial. Chinese Journal of Digestion 1998;18:355–8. | Link |

Hermant JL, Levacher S, Frenkel AL, Blaise M, Volter F, et al. The clinical and electroencephalographic effects of flumazenil in acute hepatic encephalopathy [Effets cliniques et electroencephalographiques du flumazenil dans l’encephalopathie hepatique aigue]. Annales Francaises d’Anesthesie et de Reanimation 1991;10 Suppl:R172. | Link |

Li F, Lei L, Wei L.. Clinical study of flumazenil on severe hepatic encephalopathy. Practical Pharmacy and Clinical Remedies. 2009;12:79-81. | Link |

Treatment of Hepatic Encephalopathy with Flumazenil and change in Cortical GABA levels in MRS. NCT02048969. | Link |

Cadranel JF, el Younsi M, Pidoux B, Zylberberg P, Benhamou Y, Valla D, et al. Flumazenil therapy for hepatic encephalopathy in cirrhotic patients: a double-blind pragmatic randomized, placebo study. Eur J Gastroenterol Hepatol. 1995 Apr;7(4):325-9. | PubMed |