Withholding Pantoprazole for Stress Ulcer Prophylaxis in Critically Ill Patients: A Pilot Randomized Clinical Trial and Meta-Analysis.

INTRODUCTION: A decreased frequency of upper gastrointestinal bleeding and a possible association of proton pump inhibitor use with Clostridium difficile and ventilator-associated pneumonia have raised concerns recently. The Reevaluating the Inhibition of Stress Erosions Pilot Trial determined the feasibility of undertaking a larger trial investigating the efficacy and safety of withholding proton pump inhibitors in critically ill patients. METHODS: In 10 ICUs, we randomized adult ICU patients anticipated to be mechanically ventilated for greater than or equal to 48 hours to receive 40 mg of IV pantoprazole daily or placebo. We excluded patients who had acute or recent gastrointestinal bleed, used dual antiplatelet agents, had a medical condition requiring proton pump inhibitor treatment, or had already received more than one dose of acid suppression daily. Patients, families, clinicians, and research staff were blinded. We conducted a systematic review and meta-analysis of similar trials. MAIN RESULTS: Ninety-one patients (49 pantoprazole and 42 placebo) from 10 centers in Canada, Saudi Arabia, and Australia were enrolled. All feasibility goals were met: 1) recruitment rate was 2.6 patients per month; 2) consent rate was 77.8%; and 3) protocol adherence was 97.7%. Upper gastrointestinal bleeding developed in 6.1% of patients in the pantoprazole group and 4.8% in the placebo group (p = 1.0). Ventilator-associated pneumonia developed in 20.4% of patients in the pantoprazole group and 14.3% in the placebo group (p = 0.58). C. difficile was identified in 4.1% pantoprazole patients and in 2.4% placebo patients (p = 1.0). We meta-analyzed five trials (604 patients) of proton pump inhibitors versus placebo; there was no statistically significant difference in the risk of upper gastrointestinal bleeding, infections, or mortality. CONCLUSIONS: Our results support the feasibility of a larger trial to evaluate the safety of withholding stress ulcer prophylaxis. Although the results are imprecise, there was no alarming increase in the risk of upper gastrointestinal bleeding; the effect of proton pump inhibitors on ventilator-associated pneumonia and C. difficile remain unclear.

Re-evaluating the Inhibition of Stress Erosions (REVISE): a protocol for pilot randomized controlled trial.

INTRODUCTION: Clinicians routinely administer stress ulcer prophylaxis to mechanically ventilated patients in the intensive care unit (ICU), most commonly prescribing proton pump inhibitors (PPIs). However, the incidence of gastrointestinal (GI) bleeding from stress ulceration is low and recent observational studies suggest these agents may increase infections. Therefore, a large randomized clinical trial (RCT) is needed to inform modern practice. The aim of this multicenter pilot trial is to determine the feasibility of performing a large RCT to investigate the efficacy and safety of withholding intravenous pantoprazole. METHODS AND ANALYSIS: We will include adult critically ill patients who have an anticipated duration of ventilation of >=48 hours. We will exclude patients with acute or recent GI bleeding, pregnancy, dual antiplatelet therapy, poor prognosis or intent to withdraw life support, or previous enrolment in this or a confounding trial. Following informed consent, patients will be randomized to receive the intervention of placebo (0.9% NaCl) or intravenous pantoprazole 40 mg daily. Patients, families, clinicians, data collectors, adjudicators of outcome and statisticians will be blind to allocation. The three primary feasibility outcomes are the informed consent rate, recruitment rate, and protocol adherence. Clinical outcomes include clinically important upper GI bleeding, ventilator-associated pneumonia (VAP), Clostridium difficile infection, length of stay and mortality in ICU and hospital. ETHICS AND APPROVAL: This study has been approved by Health Canada, and research ethics board (REB) at each of the participating centers. TRIAL REGISTRATION NUMBER: This trial was registered on 31 October 2014. The trial registration number is NCT02290327. FUNDING: REVISE Pilot Trial is funded by Research Grant awarded by Physicians Services Incorporated, Dammam University Research Funds, Capital Health Authority Research Award Halifax, and Royal Adelaide Hospital Project Committee Grant.