Proton pump inhibitors in critically ill mechanically ventilated patients with COVID-19: protocol for a substudy of the Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial

Brittany B Dennis; Lehana Thabane; Diane Heels-Ansdell; Joanna C Dionne; Alexandra Binnie; Jennifer Tsang; Gordon Guyatt; Aijaz Ahmed; François Lauzier; Adam Deane; Yaseen Arabi; John Marshall; Nicole Zytaruk; Lois Saunders; Simon Finfer; John Myburgh; John Muscedere; Shane English; Marlies Ostermann; Miranda Hardie; Serena Knowles; Deborah Cook; REVISE Investigators the Canadian Critical Care Trials Group

doi:10.1186/s13063-023-07589-2

Proton pump inhibitors in critically ill mechanically ventilated patients with COVID-19: protocol for a substudy of the Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial

Trials. 2023 Aug 30;24(1):561. doi: 10.1186/s13063-023-07589-2.

Authors

Brittany B Dennis¹, Lehana Thabane^{2

3

4}, Diane Heels-Ansdell², Joanna C Dionne⁵, Alexandra Binnie⁶, Jennifer Tsang^{1

6}, Gordon Guyatt⁵, Aijaz Ahmed⁷, François Lauzier⁸, Adam Deane⁹, Yaseen Arabi^{10

11

12}, John Marshall¹³, Nicole Zytaruk^{2

4}, Lois Saunders⁴, Simon Finfer¹⁴, John Myburgh^{14

15}, John Muscedere¹⁶, Shane English^{17

18}, Marlies Ostermann¹⁹, Miranda Hardie¹⁴, Serena Knowles¹⁴, Deborah Cook^{20

21}; REVISE Investigators the Canadian Critical Care Trials Group

Affiliations

¹ Department of Medicine, McMaster University, Hamilton, ON, Canada.
² Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
³ Biostatistics Unit, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
⁴ Division of Critical Care, Research Institute, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
⁵ Departments of Medicine and Health Research Methods, Evidence, and Impact, McMaster University, McMaster University Health Sciences Center, Room 2C11, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.
⁶ Department of Critical Care Medicine, Niagara Health System, St. Catharines, ON, Canada.
⁷ Department of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA, USA.
⁸ Departments of Anesthesiology and Medicine and Critical Care Medicine, Université Laval, Québec, Québec, Canada.
⁹ Department of Critical Care Medicine, University of Melbourne, Melbourne Medical School, Parkville, VIC, Australia.
¹⁰ Intensive Care Department, Ministry of the National Guard-Health Affairs, Riyadh, Kingdom of Saudi Arabia.
¹¹ King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia.
¹² King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia.
¹³ Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON, Canada.
¹⁴ Critical Care Program, The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
¹⁵ Intensive Care Unit, St. George Hospital, Sydney, Australia.
¹⁶ Department of Critical Care Medicine, Queen's University, Kingston, ON, Canada.
¹⁷ Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
¹⁸ Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
¹⁹ Department of Critical Care, King's College London, Guy's & St Thomas' Hospital, London, UK.
²⁰ Division of Critical Care, Research Institute, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada. [email protected].
²¹ Departments of Medicine and Health Research Methods, Evidence, and Impact, McMaster University, McMaster University Health Sciences Center, Room 2C11, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada. [email protected].

Abstract

Background: Critically ill patients commonly receive proton pump inhibitors (PPIs) to prevent gastrointestinal (GI) bleeding from stress-induced ulceration. Despite widespread use in the intensive care unit (ICU), observational data suggest that PPIs may be associated with adverse outcomes in patients with COVID-19 infection. This preplanned study is nested within a large randomized trial evaluating pantoprazole versus placebo in invasively ventilated patients. The 3 objectives are as follows: (1) to describe the characteristics of patients with COVID-19 in terms of demographics, biomarkers, venous thromboembolism, tracheostomy incidence and timing, and other clinical outcomes; (2) to evaluate the impact of COVID-19 infection on clinically important GI bleeding, 90-day mortality, and other outcomes compared to a propensity-matched non-infected cohort; and (3) to explore whether pantoprazole has a differential treatment effect on clinically important GI bleeding, 90-day mortality, and other outcomes in patients with and without COVID-19 infection.

Methods: The ongoing trial Re-EValuating the Inhibition of Stress Erosions (REVISE) compares pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important GI bleeding and the primary safety outcome of 90-day mortality. The protocol described in this report is for a substudy focused on patients with COVID-19 infection that was not in the original pre-pandemic trial protocol. We developed a one-page case report form to characterize these patients including data related to biomarkers, venous thromboembolism, COVID-19 therapies, tracheostomy incidence and timing, duration of mechanical ventilation, and ICU and hospital stay. Our analysis will describe the trajectory of patients with COVID-19 infection, a propensity-matched analysis of infected and non-infected patients, and an extended subgroup analysis comparing the effect of PPI among patients with and without COVID-19 infection.

Discussion: Prophylactic acid suppression in invasively ventilated critically ill patients with COVID-19 infection has unknown consequences. The results of these investigations will inform practice, guidelines, and future research.

Trial registration: REVISE Trial [NCT03374800 December 15, 2017], COVID-19 Cohort Study [NCT05715567 February 8, 2023].

Keywords: COVID-19 pandemic; Critically ill; Gastrointestinal bleeding; Hospital transfers; Randomization; Stress ulceration; Ventilator-associated pneumonia.

Publication types

Clinical Trial Protocol

MeSH terms

COVID-19*
Cohort Studies
Critical Illness
Gastrointestinal Hemorrhage
Humans
Pantoprazole / adverse effects
Proton Pump Inhibitors / adverse effects
Randomized Controlled Trials as Topic
Respiration, Artificial
Venous Thromboembolism* / diagnosis
Venous Thromboembolism* / prevention & control

Proton pump inhibitors in critically ill mechanically ventilated patients with COVID-19: protocol for a substudy of the Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial

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