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Pantoprazole or Placebo for Stress Ulcer Prophylaxis (POP-UP): Randomized Double-Blind Exploratory Study*

Selvanderan, Shane P. BMEdSci (Hon), MBBS; Summers, Matthew J. BSc, MDiet; Finnis, Mark E. MBBS, MBiostat; Plummer, Mark P. MBBS, PhD; Ali Abdelhamid, Yasmine MBBS; Anderson, Michael B. MBChB; Chapman, Marianne J. MBBS, PhD; Rayner, Christopher K. MBBS, PhD; Deane, Adam M. MBBS, PhD

doi: 10.1097/CCM.0000000000001819
Clinical Investigations

Objectives: Pantoprazole is frequently administered to critically ill patients for prophylaxis against gastrointestinal bleeding. However, comparison to placebo has been inadequately evaluated, and pantoprazole has the potential to cause harm. Our objective was to evaluate benefit or harm associated with pantoprazole administration.

Design: Prospective randomized double-blind parallel-group study.

Setting: University-affiliated mixed medical-surgical ICU.

Patients: Mechanically ventilated critically ill patients suitable for enteral nutrition.

Interventions: We randomly assigned patients to receive either daily IV placebo or pantoprazole.

Measurements and Main Results: Major outcomes were clinically significant gastrointestinal bleeding, infective ventilator-associated complication or pneumonia, and Clostridium difficile infection; minor outcomes included overt bleeding, hemoglobin concentration profiles, and mortality. None of the 214 patients randomized had an episode of clinically significant gastrointestinal bleeding, three patients met the criteria for either an infective ventilator-associated complication or pneumonia (placebo: 1 vs pantoprazole: 2), and one patient was diagnosed with Clostridium difficile infection (0 vs 1). Administration of pantoprazole was not associated with any difference in rates of overt bleeding (6 vs 3; p = 0.50) or daily hemoglobin concentrations when adjusted for transfusion rates of packed red cells (p = 0.66). Mortality was similar between groups (log-rank p = 0.33: adjusted hazard ratio for pantoprazole: 1.68 [95% CI, 0.97–2.90]; p = 0.06).

Conclusions: We found no evidence of benefit or harm with the prophylactic administration of pantoprazole to mechanically ventilated critically ill patients anticipated to receive enteral nutrition. The practice of routine administration of acid-suppressive drugs to critically ill patients for stress ulcer prophylaxis warrants further evaluation.

1Discipline of Acute Care Medicine, the University of Adelaide, Adelaide, SA, Australia.

2Department of Critical Care Services, Royal Adelaide Hospital, Adelaide, SA, Australia.

3National Health and Medical Research Council of Australia Centre for Research Excellence in Nutritional Physiology and Outcomes, Adelaide, SA, Australia.

4Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA, Australia.

5Discipline of Medicine, the University of Adelaide, Adelaide, SA, Australia.

*See also p. 1939.

This work was performed at the Intensive Care Unit, Royal Adelaide Hospital.

Supported, in part, by a project grant from the Royal Adelaide Hospital Research Foundation.

Dr. Selvanderan contributed to study concept and design, acquisition, analysis, and interpretation of data and drafting of the article. Mr. Summers contributed to the acquisition, analysis and interpretation of data and critical revision of the manuscript for important intellectual content. Dr. Finnis contributed to study concept and design, acquisition, analysis and interpretation of data, statistical analysis, and critical revision of the article for important intellectual content. Dr. Plummer contributed to study concept and design, acquisition, analysis, and interpretation of data, and critical revision of the article and obtained funding for important intellectual content. Dr. Ali Abdelhamid contributed to acquisition, analysis, and interpretation of data and critical revision of the article for important intellectual content. Dr. Anderson contributed to acquisition, analysis, and interpretation of data and critical revision of the article for important intellectual content. Dr. Chapman contributed to acquisition, analysis, and interpretation of data and critical revision of the article for important intellectual content. Dr. Rayner contributed to acquisition, analysis, and interpretation of data and critical revision of the article for important intellectual content. Dr. Deane contributed to study concept and design, acquisition, analysis, and interpretation of data, drafting of the article and study supervision and obtained funding.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest.

All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Trial Registration: Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au, trial ID: ACTRN12613000807752).

Dr. Selvanderan received funding from the Royal Adelaide Hospital Research Foundation (honours scholarship). His institution received funding from the Royal Adelaide Hospital Research Foundation (project grant). Mr. Summers’ institution received funding from the Royal Adelaide Hospital Research Foundation (project grant). Dr. Ali Abdelhamid received funding (the project was funded by a project grant from the Royal Adelaide Hospital Research Foundation). Dr. Rayner disclosed off-label product use (pantoprazole for prevention of stress ulceration). His institution received funding from the Royal Adelaide Hospital Research Foundation (project grant), AstraZeneca, Merck, and Novartis. Dr. Deane was supported by an early career fellowship from the National Health and Medical Research Council. His institution received funding from the Royal Adelaide Hospital Research Foundation (project grant). The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: adam.deane@adelaide.edu.au

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