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Medwave 2016;16(Suppl 2):e6476 doi: 10.5867/medwave.2016.6476
¿Vale la pena utilizar dosis altas de inhibidores de la bomba de protones en la hemorragia péptica aguda?
Are higher doses of proton pump inhibitors better in acute peptic bleeding?
Alejandro Villalón, Roberto Olmos, Gabriel Rada
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Abstract

Although there is broad consensus about the benefits of proton pump inhibitors in acute upper peptic bleeding, there is still controversy over their optimal dosing. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including 27 randomized trials addressing this question. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded high-dose proton pump inhibitors probably result in little or no difference in re-bleeding rate or mortality. The risk/benefit and cost/benefit balance probably favor use of low-doses.


 
Problem

Acute upper peptic bleeding is a serious clinical problem often requiring management in critical care units, and is associated with important morbidity and mortality.Proton pump inhibitors effectively block gastric acid secretion, favoring the healing of ulcer and halting of bleeding. The benefits of these drugs in acute upper peptic bleeding are widely recognized, but there is still controversy over their optimal dosing in this setting.

Methods

We used Epistemonikos database, which is maintained by screening more than 30 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

  • High-dose proton pump inhibitors probably result in little or no difference in re-bleeding
  • The risk/benefit and cost/benefit balance probably favor the use of low-doses.
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found six systematic reviews [1],[2],[3],[4],[5],[6] that included 27 randomized controlled trials [7],[8],[9], [10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20], [21],[22],[23],[24],[25],[26],[27],[28],[29],[31],[32],[33].

What types of patients were included

All of the studies included adult patients hospitalized for acute upper peptic bleeding.

In 19 studies all patients achieved endoscopic hemostasis prior to receiving proton pump inhibitors [7],[8],[11],[13],[14], [15],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27], [28],[31],[32]. In six studies prior endoscopic hemostasis was achieved in some but not all patients [10],[12],[16],[25],[30],[33]. In two studies the information about endoscopic hemostasis was not available [9],[29].

In 14 studies ulcer characteristics were used as inclusion criteria. Thirteen studies exclusively included patients with bleeding secondary to Forrest IA to IIB ulcers [7],[8],[14],[15],[16],[17],[18],[19],[26],[27],[28],[31],[32], and only one study included Forrest IA to III ulcers [9].

What types of interventions were included

All studies compared ‘high-dose’ proton pump inhibitors (accumulated dose of 600 mg or more in the first 72 hours) against ‘non-high’ dose (accumulated dose of less than 600 mg in first 72 hours).

In all studies 'high-dose' consisted in 80 mg bolus followed by a continuous infusion of 8 mg/hour for at least 72 hours.

In 18 studies ’non-high’ dose was administered by intermittent intravenous bolus [7],[8],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20], [22],[24],[26],[28],[30],[31]. In eight studies it was administered orally [9],[15],[21],[23],[25],[27],[29],[32], while only one study used a low dose continuous infusion [33].

What types of outcomes
were measured

The systematic reviews identified pooled the following outcomes:

  • Mortality
  • Re-bleeding
  • Need for new endoscopic therapy
  • Need of surgery
  • Need of transfusions
  • Length of hospital stay
Summary of findings

The information about the effects of different doses of proton pump inhibitors in acute upper peptic bleeding is based on 21 of 27 randomized studies identified, including 2565 patients. Thirteen studies evaluated mortality [7],[9],[10],[13],[16],[19],[21],[25],[26],[29],[30],[31],[33] and 21 studies evaluated re-bleeding [7],[8],[9],[10],[13],[14],[15],[16],[17],[18],[19],[21],[25],[26],[27],[28],[29],[30],[31],[32],[33]. In the remaining six studies the data could not be extracted for meta-analysis [11],[12],[20],[22],[23],[24]. The summary of the results is the following:

  • High dose proton pump inhibitors may result in little or no difference in mortality. The certainty of the evidence is low.
  • High dose proton pump inhibitors probably result in little or no difference in re-bleeding risk. The certainty of the evidence is moderate.

Other considerations for decision-making

To whom this evidence does and does not apply
  • This evidence applies to adult patients hospitalized for acute upper peptic bleeding, after endoscopy and hemostatic procedures if needed. This evidence does not apply to patients with variceal upper bleeding.
About the outcomes included in this summary
  • The selected outcomes were mortality and re-bleeding, which are critical for decition making in clinical practice based on the opinion of the authors of this summary. These are the outcomes mentioned in the main guidelines too [34],[35],[36].
Balance between benefits and risks, and certainty of the evidence
  • The outcome for which more certainty exists is re-bleeding, with higher-doses of proton pump inhibitors probably not modifying its incidence. Although the certainty of the evidence is lower for mortality, because of its tight relationship with re-bleeding there is no reason to expect a different effect over it.
  • In theory, some known adverse effects of proton pump inhibitors such as Clostridium difficile infection and pneumonia may be influenced by the dose used. This would turn the balance even more towards the use of non-high doses.
Resource considerations
  • High-dose proton pump inhibitors are associated with higher costs, considering the amount of drug used and the need for a continous infusion pump.
  • Considering there is probably no clinical benefit with higher doses of proton pump inhibitors, the cost/benefit balance favors non-high dose.

Differences between this summary and other sources
  • The conclusions of this summary agree with most systematic reviews identified [2],[3],[5],[6], but partially disagree with two of them, which point out that more evidence is needed before making any conclusion [1],[4].
  • The conclusions of this summary disagree with the most important clinical guidelines. While the NICE guideline does not make a specific statement about the dose of proton pump inhibitors, both the American Collegue of Gastroenterology [34] and the American Society of Gastrointestinal Endoscopy guidelines recommend  the use of proton pump inhibitors in high dose in patients with “high risk” ulcers. It is important to highlight that these guidelines have considered only a small amount of the evidence included in this summary, basing their recommendation mostly in studies comparing proton pump inhibitors with placebo. None of them cites the available systematic reviews comparing high versus non-high doses, and only cite a small number of the primary studies included in this summary. For example, the American College of Gastroenterology guideline [34] cites only five of them [7],[14],[17],[19],[31], while the American Society of Gastrointestinal Endoscopy guideline does not cite any of them. 
Could this evidence change in the future?
  • The probability that future studies change the conclusions of this summary is low because of the certainty of the available evidence
  • A substantial proportion of the studies is lacking in all systematic reviews, so a new or updated review may increase the certainty of the 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: High-dose versus non-high-dose proton pump inhibitors for bleeding peptic ulcer

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.

 

Although there is broad consensus about the benefits of proton pump inhibitors in acute upper peptic bleeding, there is still controversy over their optimal dosing. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including 27 randomized trials addressing this question. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded high-dose proton pump inhibitors probably result in little or no difference in re-bleeding rate or mortality. The risk/benefit and cost/benefit balance probably favor use of low-doses.

Autores: Alejandro Villalón[1,2], Roberto Olmos[1,2], Gabriel Rada[1,2,3,4,5]

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

E-mail: radagabriel@gmail.com

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

Citación: Villalón A, Olmos R, Rada G. Are higher doses of proton pump inhibitors better in acute peptic bleeding? . Medwave 2016;16(Suppl 2):e6476 doi: 10.5867/medwave.2016.6476

Fecha de publicación: 24/6/2016

Ficha PubMed

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  2. Wang CH, Ma MH, Chou HC, Yen ZS, Yang CW, Fang CC, et al. High-dose vs non-high-dose proton pump inhibitors after endoscopic treatment in patients with bleeding peptic ulcer: a systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2010 May 10;170(9):751-8. | CrossRef | PubMed |
  3. Tsoi KK, Hirai HW, Sung JJ. Meta-analysis: comparison of oral vs. intravenous proton pump inhibitors in patients with peptic ulcer bleeding. Aliment Pharmacol Ther. 2013 Oct;38(7):721-8. | CrossRef | PubMed |
  4. El Ouali S, Barkun A, Martel M, Maggio D. Timing of rebleeding in high-risk peptic ulcer bleeding after successful hemostasis: a systematic review. Can J Gastroenterol Hepatol. 2014 Nov;28(10):543-8 | PubMed |
  5. Wu LC, Cao YF, Huang JH, Liao C, Gao F. High-dose vs low-dose proton pump inhibitors for upper gastrointestinal bleeding: a meta-analysis. World J Gastroenterol. 2010 May 28;16(20):2558-65. | PubMed |
  6. Sachar H, Vaidya K, Laine L. Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis. JAMA Intern Med. 2014 Nov;174(11):1755-62. | CrossRef | PubMed |
  7. Andriulli A, Loperfido S, Focareta R, Leo P, Fornari F, Garripoli A, et al. High- versus low-dose proton pump inhibitors after endoscopic hemostasis in patients with peptic ulcer bleeding: a multicentre, randomized study. Am J Gastroenterol. 2008 Dec;103(12):3011-8. | CrossRef | PubMed |
  8. Yamada S, Wongwanakul P. Randomized controlled trial of high dose bolus versus continuous intravenous infusion pantoprazole as an adjunct therapy to therapeutic endoscopy in massive bleeding peptic ulcer. J Med Assoc Thai. 2012 Mar;95(3):349-57. | PubMed |
  9. Mostaghni AA, Hashemi SA, Heydari ST. Comparison of oral and intravenous proton pump inhibitor on patients with high risk bleeding peptic ulcers: a prospective, randomized, controlled clinical trial. Iran Red Crescent Med J. 2011 Jul;13(7):458-63. | PubMed |
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  12. Dokas SM, Lazaraki GI, Kontoninas Z, Kouklakis GS, Adamidou A, Tsiaousi E, et al. Bolus intravenous omeprazole B.I.D. vs. continuous intravenous omeprazole infusion combined with endoscopic hemostasis in the treatment of peptic ulcer bleeding. Preliminary results. Gut. 2004 2004;53(Suppl VI):A290 (Abstract WED-G-6). | Link |
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  16. Cheng HC, Kao AW, Chuang CH, Sheu BS. The efficacy of high- and low-dose intravenous omeprazole in preventing rebleeding for patients with bleeding peptic ulcers and comorbid illnesses. Dig Dis Sci. 2005 Jul;50(7):1194-201. | PubMed |
  17. Javid G, Zargar SA, U-Saif R, Khan BA, Yatoo GN, Shah AH, et al. Comparison of p.o. or i.v. proton pump inhibitors on 72-h intragastric pH in bleeding peptic ulcer. J Gastroenterol Hepatol. 2009 Jul;24(7):1236-43. | CrossRef | PubMed |
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  20. Mesihovic R, Vanis N, Mehmedovic A, Gornjakovic S, Gribajcevic M. Proton pump inhibitors after endoscopic hemostasis in patients with peptic ulcer bleeding. Med Arh. 2009;63(6):323-7. | PubMed |
  21. Jang JY, Dong SH, Jung JH, Chae MJ, Kim NH, Lee SK, et al. High-dose oral proton pump inhibitor is as effective as intravenous administration in the aspect of increasing intragastric pH and reducing rebleeding after endoscopic treatment of bleeding peptic ulcers. Digestive Disease Week; 20062006. p. TI067. | Link |
  22. Chilovi F, Piazzi L, Zancanella L, De Guelmi A, Grasso T, Di Fede F, et al. Intravenous omeprazole and pantoprazole after endoscopic treatment of bleeding peptic ulcers. Gastrointestinal Endoscopy. 2003 2003;57(5):AB150. | Link |
  23. Focareta R, Ciarleglio A, Piai G, Levoli F, Forte G. Proton-pump inhibitor (PPI) and acute peptic ulcer bleeding: effectiveness of oral esomeprazole vs intravenous omeprazole in reducing the risk of recurrent bleeding. X Congresso Nazionale delle Malattie Digestive. 2004. | Link |
  24. Oh JH, Choi MG, Dong MS, Park JM, Paik CN, Cho YK, et al. Low-dose intravenous pantoprazole for optimal inhibition of gastric acid in Korean patients. J Gastroenterol Hepatol. 2007 Sep;22(9):1429-34. | PubMed |
  25. Bajaj JS, Dua KS, Hanson K, Presberg K. Prospective, randomized trial comparing effect of oral versus intravenous pantoprazole on rebleeding after nonvariceal upper gastrointestinal bleeding: a pilot study. Dig Dis Sci. 2007 Sep;52(9):2190-4. | PubMed |
  26. Hsu YC, Perng CL, Yang TH, Wang CS, Hsu WL, Wu HT, et al. A randomized controlled trial comparing two different dosages of infusional pantoprazole in peptic ulcer bleeding. Br J Clin Pharmacol. 2010 Mar;69(3):245-51. | CrossRef | PubMed |
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  30. Udd M, Miettinen P, Palmu A, Heikkinen M, Janatuinen E, Pasanen P, Tarvainen R, Kairaluoma MV, Lohman M, Mustonen H, Julkunen R. Regular-dose versus high-dose omeprazole in peptic ulcer bleeding: a prospective randomized double-blind study. Scand J Gastroenterol. 2001 Dec;36(12):1332-8. | PubMed |
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Neumann I, Letelier LM, Rada G, Claro JC, Martin J, Howden CW, et alI. Comparison of different regimens of proton pump inhibitors for acute peptic ulcer bleeding. Cochrane Database Syst Rev. 2013 Jun 12;(6):CD007999. | CrossRef | PubMed |

Wang CH, Ma MH, Chou HC, Yen ZS, Yang CW, Fang CC, et al. High-dose vs non-high-dose proton pump inhibitors after endoscopic treatment in patients with bleeding peptic ulcer: a systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2010 May 10;170(9):751-8. | CrossRef | PubMed |

Tsoi KK, Hirai HW, Sung JJ. Meta-analysis: comparison of oral vs. intravenous proton pump inhibitors in patients with peptic ulcer bleeding. Aliment Pharmacol Ther. 2013 Oct;38(7):721-8. | CrossRef | PubMed |

El Ouali S, Barkun A, Martel M, Maggio D. Timing of rebleeding in high-risk peptic ulcer bleeding after successful hemostasis: a systematic review. Can J Gastroenterol Hepatol. 2014 Nov;28(10):543-8 | PubMed |

Wu LC, Cao YF, Huang JH, Liao C, Gao F. High-dose vs low-dose proton pump inhibitors for upper gastrointestinal bleeding: a meta-analysis. World J Gastroenterol. 2010 May 28;16(20):2558-65. | PubMed |

Sachar H, Vaidya K, Laine L. Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis. JAMA Intern Med. 2014 Nov;174(11):1755-62. | CrossRef | PubMed |

Andriulli A, Loperfido S, Focareta R, Leo P, Fornari F, Garripoli A, et al. High- versus low-dose proton pump inhibitors after endoscopic hemostasis in patients with peptic ulcer bleeding: a multicentre, randomized study. Am J Gastroenterol. 2008 Dec;103(12):3011-8. | CrossRef | PubMed |

Yamada S, Wongwanakul P. Randomized controlled trial of high dose bolus versus continuous intravenous infusion pantoprazole as an adjunct therapy to therapeutic endoscopy in massive bleeding peptic ulcer. J Med Assoc Thai. 2012 Mar;95(3):349-57. | PubMed |

Mostaghni AA, Hashemi SA, Heydari ST. Comparison of oral and intravenous proton pump inhibitor on patients with high risk bleeding peptic ulcers: a prospective, randomized, controlled clinical trial. Iran Red Crescent Med J. 2011 Jul;13(7):458-63. | PubMed |

Garrido A, Giráldez A, Trigo C, Leo E, Guil A, Márquez JL. [Intravenous proton-pump inhibitor for acute peptic ulcer bleeding--is profound acid suppression beneficial to reduce the risk of rebleeding?]. Rev Esp Enferm Dig. 2008 Aug;100(8):466-9. | PubMed |

Lin HJ, Lo WC, Cheng YC, Perng CL. Role of intravenous omeprazole in patients with high-risk peptic ulcer bleeding after successful endoscopic epinephrine injection: a prospective randomized comparative trial. Am J Gastroenterol. 2006 Mar;101(3):500-5. | PubMed |

Dokas SM, Lazaraki GI, Kontoninas Z, Kouklakis GS, Adamidou A, Tsiaousi E, et al. Bolus intravenous omeprazole B.I.D. vs. continuous intravenous omeprazole infusion combined with endoscopic hemostasis in the treatment of peptic ulcer bleeding. Preliminary results. Gut. 2004 2004;53(Suppl VI):A290 (Abstract WED-G-6). | Link |

Schonekas H, Ahrens H, Pannewick U, Ell C, Koop H, Petritsch W, et al. Comparison of two doses of intravenous pantoprazole in peptic ulcer bleeding. Gastroenterology. 1999;116(4 Part 2):A305 (G1336). | Link |

Choi KD, Kim N, Jang IJ, Park YS, Cho JY, Kim JR, et al. Optimal dose of intravenous pantoprazole in patients with peptic ulcer bleeding requiring endoscopic hemostasis in Korea. J Gastroenterol Hepatol. 2009 Oct;24(10):1617-24. | CrossRef | PubMed |

Sung JJ, Suen B-y, Ching J, Chan FKL, Wu JC, Chiu PW, et al. 1079 Effects of Intravenous and Oral Esomeprazole in Prevention of Recurrent Bleeding From Peptic Ulcers After Endoscopic Therapy. Gastroenterology. 2012 2012;142(5):S-192-S-3. | CrossRef |

Cheng HC, Kao AW, Chuang CH, Sheu BS. The efficacy of high- and low-dose intravenous omeprazole in preventing rebleeding for patients with bleeding peptic ulcers and comorbid illnesses. Dig Dis Sci. 2005 Jul;50(7):1194-201. | PubMed |

Javid G, Zargar SA, U-Saif R, Khan BA, Yatoo GN, Shah AH, et al. Comparison of p.o. or i.v. proton pump inhibitors on 72-h intragastric pH in bleeding peptic ulcer. J Gastroenterol Hepatol. 2009 Jul;24(7):1236-43. | CrossRef | PubMed |

Uçbilek E, Sezgin O, Altintas E. Low Dose Bolus Pantoprazole Following Succesful Endoscopic Treatment for Acute Peptic Ulcer Bleeding Is Effective: A Randomised, Prospective, Double-Blind, Double Dummy Pilot Study. Gastroenterology. 2013 2013;144(5, Supplement 1):S-506. | CrossRef |

Yüksel I, Ataseven H, Köklü S, Ertuğrul I, Başar O, Odemiş B, et al. Intermittent versus continuous pantoprazole infusion in peptic ulcer bleeding: a prospective randomized study. Digestion. 2008;78(1):39-43. | CrossRef | PubMed |

Mesihovic R, Vanis N, Mehmedovic A, Gornjakovic S, Gribajcevic M. Proton pump inhibitors after endoscopic hemostasis in patients with peptic ulcer bleeding. Med Arh. 2009;63(6):323-7. | PubMed |

Jang JY, Dong SH, Jung JH, Chae MJ, Kim NH, Lee SK, et al. High-dose oral proton pump inhibitor is as effective as intravenous administration in the aspect of increasing intragastric pH and reducing rebleeding after endoscopic treatment of bleeding peptic ulcers. Digestive Disease Week; 20062006. p. TI067. | Link |

Chilovi F, Piazzi L, Zancanella L, De Guelmi A, Grasso T, Di Fede F, et al. Intravenous omeprazole and pantoprazole after endoscopic treatment of bleeding peptic ulcers. Gastrointestinal Endoscopy. 2003 2003;57(5):AB150. | Link |

Focareta R, Ciarleglio A, Piai G, Levoli F, Forte G. Proton-pump inhibitor (PPI) and acute peptic ulcer bleeding: effectiveness of oral esomeprazole vs intravenous omeprazole in reducing the risk of recurrent bleeding. X Congresso Nazionale delle Malattie Digestive. 2004. | Link |

Oh JH, Choi MG, Dong MS, Park JM, Paik CN, Cho YK, et al. Low-dose intravenous pantoprazole for optimal inhibition of gastric acid in Korean patients. J Gastroenterol Hepatol. 2007 Sep;22(9):1429-34. | PubMed |

Bajaj JS, Dua KS, Hanson K, Presberg K. Prospective, randomized trial comparing effect of oral versus intravenous pantoprazole on rebleeding after nonvariceal upper gastrointestinal bleeding: a pilot study. Dig Dis Sci. 2007 Sep;52(9):2190-4. | PubMed |

Hsu YC, Perng CL, Yang TH, Wang CS, Hsu WL, Wu HT, et al. A randomized controlled trial comparing two different dosages of infusional pantoprazole in peptic ulcer bleeding. Br J Clin Pharmacol. 2010 Mar;69(3):245-51. | CrossRef | PubMed |

Kim HK, Kim JS, Kim TH, Kim CW, Cho YS, Kim SS, et al. Effect of high-dose oral rabeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. Gastroenterol Res Pract. 2012;2012:317125. | CrossRef | PubMed |

Chen CC, Lee JY, Fang YJ, Hsu SJ, Han ML, Tseng PH, et al. Randomised clinical trial: high-dose vs. standard-dose proton pump inhibitors for the prevention of recurrent haemorrhage after combined endoscopic haemostasis of bleeding peptic ulcers. Aliment Pharmacol Ther. 2012 Apr;35(8):894-903. | CrossRef | PubMed |

Yilmaz S, Bayan K, Tüzün Y, Dursun M, Canoruç F. A head to head comparison of oral vs intravenous omeprazole for patients with bleeding peptic ulcers with a clean base, flat spots and adherent clots. World J Gastroenterol. 2006 Dec 28;12(48):7837-43. | PubMed |

Udd M, Miettinen P, Palmu A, Heikkinen M, Janatuinen E, Pasanen P, Tarvainen R, Kairaluoma MV, Lohman M, Mustonen H, Julkunen R. Regular-dose versus high-dose omeprazole in peptic ulcer bleeding: a prospective randomized double-blind study. Scand J Gastroenterol. 2001 Dec;36(12):1332-8. | PubMed |

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Edición Julio 2022
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