Methods: We will include ICU patients >18 years old who have an anticipated duration of mechanical ventilation of ≥48 hours. Exclusion criteria are acute or recent GI bleeding, dual antiplatelet therapy, combined antiplatelet and anticoagulant therapy, hopeless prognosis or intent to withdraw advanced life support, and previous enrolment in this or a confounding trial. Patients will be randomized in a fixed 1:1 allocation, stratified by center and pre-ICU acid suppression ('start or no start' strata, and 'continue or discontinue' strata). Research Coordinators will obtain informed consent using a deferred or a priori consent model. Study Pharmacists will obtain concealed allocation from the REVISE website; all research team and clinical team members, patients and families will be blinded. Patients will receive pantoprazole 40 mg or identical placebo intravenously daily while in ICU up to 60 days. Patients will receive the trial intervention from the first administration until 60 days or: 1) successful discontinuation of mechanical ventilation for >48 hours; 2) development of clinically important GI bleeding, or 3) death in ICU. Analyses will be by intention-to-treat and per protocol. The sample size is based on the logic of a non-inferiority trial; if the absolute increase in bleeding as a result of withholding pantoprazole is sufficiently low (in this case, 1.5% or less), we will conclude that withholding a PPI is non-inferior to administering a PPI. This non-inferiority threshold was selected on the basis that avoiding the risk of VAP and CDI with pantoprazole would warrant accepting an absolute increase in bleeding of up to 1.5%. REVISE will enrol 4,800 patients, conducted in collaboration with the Canadian Critical Care Trials Group, the Australian and New Zealand Intensive Care Society Critical Care Trials Group, other consortia and collaborators under the auspices of the International Forum for Acute Care Trialists.