Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation.

BACKGROUND: Whether proton-pump inhibitors are beneficial or harmful for stress ulcer prophylaxis in critically ill patients undergoing invasive ventilation is unclear. METHODS: In this international, randomized trial, we assigned critically ill adults who were undergoing invasive ventilation to receive intravenous pantoprazole (at a dose of 40 mg daily) or matching placebo. The primary efficacy outcome was clinically important upper gastrointestinal bleeding in the intensive care unit (ICU) at 90 days, and the primary safety outcome was death from any cause at 90 days. Multiplicity-adjusted secondary outcomes included ventilator-associated pneumonia, Clostridioides difficile infection, and patient-important bleeding. RESULTS: A total of 4821 patients underwent randomization in 68 ICUs. Clinically important upper gastrointestinal bleeding occurred in 25 of 2385 patients (1.0%) receiving pantoprazole and in 84 of 2377 patients (3.5%) receiving placebo (hazard ratio, 0.30; 95% confidence interval [CI], 0.19 to 0.47; P<0.001). At 90 days, death was reported in 696 of 2390 patients (29.1%) in the pantoprazole group and in 734 of 2379 patients (30.9%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.85 to 1.04; P = 0.25). Patient-important bleeding was reduced with pantoprazole; all other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients undergoing invasive ventilation, pantoprazole resulted in a significantly lower risk of clinically important upper gastrointestinal bleeding than placebo, with no significant effect on mortality. (Funded by the Canadian Institutes of Health Research and others; REVISE ClinicalTrials.gov number, NCT03374800.).

A Very Rare Side Effect of a Very Commonly Used Drug: Pantoprazole-induced Seizure.

Pantoprazole is an extensively used proton pump inhibitor (PPI) for acid peptic disease. PPI rarely cause hypomagnesemia. Hypomagnesemia is commonly associated with hypokalemia and hypocalcemia. Severe hypomagnesemia and hypocalcemia can cause seizures. Here, we report a patient on long-term pantoprazole who presented with generalized tonic-clonic seizures and had severe hypomagnesemia, hypocalcemia, hypokalemia, and secondary hyperparathyroidism. When patients on long-term PPI present with seizures, hypomagnesemia/hypocalcemia has to be excluded.

Pantoprazole Induced Acute Interstitial Nephritis in a Patient with Diabetic Ketoacidosis.

Childhood-onset type 1 diabetes mellitus (DM) is a common chronic metabolic disease associated with life-threatening complications. Diabetic ketoacidosis (DKA) is an acute complication of type 1 DM that has significant mortality mostly due to cerebral edema. Other putative complications of DKA include hypokalemia, hypophosphatemia, hypoglycemia, intracerebral and peripheral venous thrombosis, rhabdomyolysis, acute pancreatitis, and acute kidney injury (AKI) (Murdoch IA et al., Acta Paediatr 1993; 82:498-500).

Proton Pump Inhibitors Reduce Duodenal Eosinophilia, Mast Cells, and Permeability in Patients With Functional Dyspepsia.

BACKGROUND & AIMS: Despite the growing recognition of duodenal alterations in the pathophysiology of functional dyspepsia (FD), the effect and mechanism of proton pump inhibitors (PPIs) or first-line therapy remain unclear. We studied duodenal and systemic alterations in relation to PPI therapy in patients with FD and healthy volunteers (HVs). METHODS: We performed a prospective interventional study assessing symptoms (Patient Assessment of Gastrointestinal Symptom Severity Index), duodenal alterations, and systemic factors in patients with FD ("FD-starters") and HVs before and after PPI therapy (pantoprazole 40 mg once daily for 4 weeks). Duodenal mucosal eosinophils, mast cells and permeability were quantified. Luminal pH and bile salts were determined in duodenal aspirates. Procedures were also performed in PPI-refractory patients with FD ("FD-stoppers") before and 8 weeks after PPI withdrawal. Between- and within-group changes from baseline and associations with duodenal or systemic factors were analyzed using linear mixed models. RESULTS: The study was completed by 30 HV, 27 FD-starters, and 18 FD-stoppers. Symptoms and duodenal eosinophils, mast cells (all, P < .0001), and paracellular passage (P = .02) were significantly higher in FD-starters vs HVs and reduced with PPI therapy. Symptoms and duodenal immune cells also decreased in FD-stoppers off PPIs. In contrast, immune cells and permeability increased in HVs on PPIs. Dyspeptic symptoms correlated with eosinophils before and during PPI therapy, and increased eosinophils and permeability in HVs on PPIs were associated with changes in bile salts. CONCLUSIONS: We provide the first prospective evidence for eosinophil-reducing effects as a therapeutic mechanism of PPIs in FD, with differential effects in HVs pointing to a role of luminal changes. ClinicalTrials.gov, Number: NCT03545243.

Effect of a Postoperative Multimodal Opioid-Sparing Protocol vs Standard Opioid Prescribing on Postoperative Opioid Consumption After Knee or Shoulder Arthroscopy: A Randomized Clinical Trial.

Importance: In arthroscopic knee and shoulder surgery, there is growing evidence that opioid-sparing protocols may reduce postoperative opioid consumption while adequately addressing patients' pain. However, there are a lack of prospective, comparative trials evaluating their effectiveness. Objective: To evaluate the effect of a multimodal, opioid-sparing approach to postoperative pain management compared with the current standard of care in patients undergoing arthroscopic shoulder or knee surgery. Design, Setting, and Participants: This randomized clinical trial was performed at 3 clinical sites in Ontario, Canada, and enrolled 200 patients from March 2021 to March 2022 with final follow-up completed in April 2022. Adult patients undergoing outpatient arthroscopic shoulder or knee surgery were followed up for 6 weeks postoperatively. Interventions: The opioid-sparing group (100 participants randomized) received a prescription of naproxen, acetaminophen (paracetamol), and pantoprazole; a limited rescue prescription of hydromorphone; and a patient educational infographic. The control group (100 participants randomized) received the current standard of care determined by the treating surgeon, which consisted of an opioid analgesic. Main Outcomes and Measures: The primary outcome was postoperative oral morphine equivalent (OME) consumption at 6 weeks after surgery. There were 5 secondary outcomes, including pain, patient satisfaction, opioid refills, quantity of OMEs prescribed at the time of hospital discharge, and adverse events at 6 weeks all reported at 6 weeks after surgery. Results: Among the 200 patients who were randomized (mean age, 43 years; 73 women [38%]), 193 patients (97%) completed the trial; 98 of whom were randomized to receive standard care and 95 the opioid-sparing protocol. Patients in the opioid-sparing protocol consumed significantly fewer opioids (median, 0 mg; IQR, 0-8.0 mg) than patients in the control group (median, 40.0 mg; IQR, 7.5-105.0; z = -6.55; P < .001). Of the 5 prespecified secondary end points, 4 showed no significant difference. The mean amount of OMEs prescribed was 341.2 mg (95% CI, 310.2-372.2) in the standard care group and 40.4 mg (95% CI, 39.6-41.2) in the opioid-sparing group (mean difference, 300.8 mg; 95% CI, 269.4-332.3; P < .001). There was no significant difference in adverse events at 6 weeks (2 events [2.1%] in the standard care group vs 3 events [3.2%] in the opioid-sparing group), but more patients reported medication-related adverse effects in the standard care group (32% vs 19%, P = .048). Conclusions and Relevance: Among patients who underwent arthroscopic knee or shoulder surgery, a multimodal opioid-sparing postoperative pain management protocol, compared with standard opioid prescribing, significantly reduced postoperative opioid consumption over 6 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04566250.

Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU.

BACKGROUND: Prophylaxis for gastrointestinal stress ulceration is frequently given to patients in the intensive care unit (ICU), but its risks and benefits are unclear. METHODS: In this European, multicenter, parallel-group, blinded trial, we randomly assigned adults who had been admitted to the ICU for an acute condition (i.e., an unplanned admission) and who were at risk for gastrointestinal bleeding to receive 40 mg of intravenous pantoprazole (a proton-pump inhibitor) or placebo daily during the ICU stay. The primary outcome was death by 90 days after randomization. RESULTS: A total of 3298 patients were enrolled; 1645 were randomly assigned to the pantoprazole group and 1653 to the placebo group. Data on the primary outcome were available for 3282 patients (99.5%). At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (relative risk, 1.02; 95% confidence interval [CI], 0.91 to 1.13; P=0.76). During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups. CONCLUSIONS: Among adult patients in the ICU who were at risk for gastrointestinal bleeding, mortality at 90 days and the number of clinically important events were similar in those assigned to pantoprazole and those assigned to placebo. (Funded by Innovation Fund Denmark and others; SUP-ICU ClinicalTrials.gov number, NCT02467621 .).

Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin.

BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial. METHODS: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up. RESULTS: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant. CONCLUSIONS: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.

The Effect of Proton Pump Inhibitor Withdrawal on Dabigatran Etexilate Plasma Levels in Patients With Atrial Fibrillation: A Washout Study.

BACKGROUND: Several studies demonstrated that proton pump inhibitors (PPIs) co-administrated with dabigatran in patients with atrial fibrillation (AF) decreased dabigatran trough and peak plasma levels. However, it is still unknown whether this interaction is reversible or not, and whether the withdrawal of PPI would lead to normalization of dabigatran plasma levels. AIM OF STUDY: The aim of this study was to determine the effect of PPI withdrawal on dabigatran plasma levels in patients with AF. METHODS: This pilot prospective study enrolled 23 AF patients on long-term dabigatran and PPI therapy (omeprazole 20 mg twice daily or pantoprazole 40 mg once daily). Dabigatran trough and peak levels (ng/mL) were tested on PPI and after a 2-week period of PPI withdrawal with Hemoclot Thrombin Inhibitor Assay. RESULTS: The analysis of dabigatran plasma levels demonstrated significant elevation in trough dabigatran levels after 2 weeks of PPI withdrawal (97.2 ± 79.7 vs. 163.8 ± 105.5 ng/mL; P < 0.05). Moreover, significantly higher peak dabigatran levels were observed after 2 weeks of PPI withdrawal (142.4 ± 102.8 vs. 255 ± 129.5 ng/mL; P ≤ 0.001). CONCLUSIONS: This study showed that a 2-week period of PPI withdrawal lead to a significant increase in dabigatran trough and peak plasma levels in patients with AF.

Pantoprazole Affecting Docetaxel Resistance Pathways via Autophagy (PANDORA): Phase II Trial of High Dose Pantoprazole (Autophagy Inhibitor) with Docetaxel in Metastatic Castration-Resistant Prostate Cancer (mCRPC).

BACKGROUND: Enhancing the effectiveness of docetaxel for men with metastatic castration-resistant prostate cancer (mCRPC) is an unmet clinical need. Preclinical studies demonstrated that high-dose pantoprazole can prevent or delay resistance to docetaxel via the inhibition of autophagy in several solid tumor xenografts. MATERIALS AND METHODS: Men with chemotherapy-naive mCRPC with a prostate-specific antigen (PSA) >10 ng/mL were eligible for enrolment. Men received intravenous pantoprazole (240 mg) prior to docetaxel (75 mg/m2) every 21 days, with continuous prednisone 5 mg twice daily. Primary endpoint was a confirmed ≥50% decline of PSA. The trial used a Simon's two-stage design. RESULTS: Between November 2012 and March 2015, 21 men with a median age of 70 years (range, 58-81) were treated (median, 6 cycles; range, 2-11). Men had received prior systemic therapies (median, 1; range, 0-3), and 14 had received abiraterone and/or enzalutamide. PSA response rate was 52% (11/21), which did not meet the prespecified criterion (≥13/21 responders) to proceed to stage 2 of the study. At interim analysis with a median follow-up of 17 months, 18 (86%) men were deceased (15 castration-resistant prostate cancer, 2 unknown, 1 radiation complication). Of the men with RECIST measurable disease, the radiographic partial response rate was 31% (4/13). The estimated median overall survival was 15.7 months (95% confidence interval [CI], 9.3-19.6) and median PFS was 5.3 months (95% CI, 2.6-12.9). There were no toxic deaths, and all adverse events were attributed to docetaxel. CONCLUSION: The combination of docetaxel and pantoprazole was tolerable, but the resultant clinical activity was not sufficient to meet the ambitious predefined target to warrant further testing. IMPLICATIONS FOR PRACTICE: To date, no docetaxel combination regimen has reported superior efficacy over docetaxel alone in men with metastatic castration-resistant prostate cancer (mCRPC). The PANDORA trial has demonstrated that the combination of high dose pantoprazole with docetaxel is tolerable, but the clinical activity was not sufficient to warrant further testing. The chemotherapy standard of care for men with mCRPC remains docetaxel with prednisone. Future studies of autophagy inhibitors will need to measure autophagy inhibition accurately and determine the degree of autophagy inhibition required to produce a meaningful clinical response.

Drug incompatibilities in intravenous therapy: evaluation and proposition of preventive tools in intensive care and hematology units.

PURPOSE: Physicochemical incompatibility (PCI) between drugs infused together is frequent, but under-recognized. PCI can lead to drug inactivity, catheter occlusion, embolism or inflammatory reactions. The aims of this work were to identify most frequent and relevant drug incompatibilities and to review and develop strategies for their prevention. METHOD: This was an observational prospective survey conducted between January and March 2015 in an intensive care unit (ICU) and in September 2014 in a hematology sterile unit (HSU). Drugs administered to patients were recorded and their compatibility assessed based on published compatibility data. RESULTS: Drug incompatibilities accounted for 12% (23/189) and 17% (116/686) of drug pairs infused in the ICU and the HSU, respectively. Pantoprazole was the most frequent drug implied in PCI. Regarding drug classes, anti-infective agents and gastrointestinal drugs were the most frequently implied. Among the incompatible pairs, 78% and 61% implicated a drug with extreme pH in the ICU and HSU, respectively. The tools proposed to reduce the frequency of PCI included: compatibility cross-tables, labeling of drugs with extreme pH and optimized administration schedules. CONCLUSIONS: Given the frequency and the potential for severe consequences of PCI, pharmacists have a role to play in raising awareness of nurses and practitioners, and proposing adequate tools and solutions to reduce their incidence.

Prescription pattern & adverse drug reactions of prokinetics.

Background & objectives: Prokinetics are extensively prescribed leading to several adverse events (AEs). The aim of this study was to assess the prescription pattern in patients receiving prokinetics, and characteristics of adverse drug reactions (ADRs) in an outpatient department set up in a tertiary care hospital in western India. Methods: Patients attending outpatient departments of a tertiary care hospital and who had received prokinetic agent for at least seven days over the last one month were enrolled. Causality assessment of AEs was done and assessed for severity, preventability, seriousness and predictability. Results: A total of 304 patients [161 males (52.96%); 143 females (47.04%)] were enrolled. Most prescriptions (299/304, 98%) included domperidone, most commonly prescribed as fixed-dose combination (FDC) with pantoprazole (274/304, 90%). Prokinetic dose was not mentioned in 251/304 (83%) prescriptions, and 18/304 (6%) did not mention frequency. Of the 378 AEs reported from 179 patients (47.35%), 306 (81%) were mild, all non-serious; 272 (72%) not preventable and 291 (77%) predictable in nature. Decreased appetite (n=31, 8.2%) and fatigue (n=27,7.14%) were most commonly reported. Causality assessment by the World Health Organization-Uppsala Monitoring Centre scale showed that 180 AEs were related to suspected drug (17 probable and 163 possible ADRs). Significant correlation was observed for AEs with increasing number of drugs per prescription (Spearman's R=+0.8, P =0.05) and with increasing therapy duration (Spearman's R=+1.00, P <0.001). Interpretation & conclusions: Our findings showed that prokinetics were often prescribed as FDCs, with incomplete prescriptions. Domperidone was found to be associated with multiple AEs. It is suggested that regular prescription monitoring should be done in hospitals to encourage rational use of drugs.

Pantoprazole-induced autoimmune chronic hepatitis.

BACKGROUND: Although very rare, pantoprazole can result in acute hepatitis. It has yet to be reported, however, that it can also cause chronic autoimmune hepatitis. AIM, METHOD AND RESULTS: We report the case of a patient in whom pantoprazole administration for 2 months was followed by acute liver injury with severe jaundice and features of autoimmunity. A liver biopsy revealed acute hepatocellular lesions associated with cholestasis, acute cholangitis and polymorphous inflammatory infiltration suggestive of drug-induced liver injury. The jaundice disappeared following discontinuation of the pantoprazole. There was, however, chronic autoimmune liver injury, with the occurrence of extensive liver fibrosis within a few months. This led to the administration of immunosuppressive agents, which led to progressive and complete recovery associated with the disappearance of autoantibodies. CONCLUSION: This observation further supports the notion that pantoprazole can induce acute hepatocellular hepatitis, and it strongly suggests that it may trigger acute cholangitis and autoimmune liver injury. This case also helps document that some drugs can induce chronic autoimmune hepatitis that can resolve with immunosuppressive treatment.

[Immediate type reactions to proton pump inhibitors using pantoprazole and omeprazole as examples]. / Soforttypreaktionen auf Protonenpumpeninhibitoren am Beispiel von Pantoprazol und Omeprazol.

Proton pump inhibitors (PPIs) belong to the most frequently taken drugs worldwide. Hypersensitivity to these medications is rare, but can lead to severe immediate type reactions. Especially cross-reactivity between the different PPIs can occur. In this case series, we describe 4 patients with immediate type reactions to pantoprazole and/or omeprazole.

Lower Risk of Upper GI Bleeding with Pantoprazole in Adults Receiving Mechanical Ventilation.

According to this study.

Pantoprazole associated dyspepsia hypocalcemia and hyponatremia: A disproportionality analysis in FDA adverse event reporting system (FAERS) database.

BACKGROUND AND STUDY AIM: The study was designed to detect novel Adverse Events (AEs) of pantoprazole by disproportionality analysis in the FDA (Food and Drug Administration) database of Adverse Event Reporting System (FAERS) using Data Mining Algorithms (DMAs). Pantoprazole, the most commonly over-utilized Over The Counter (OTC) medication, was selected to assess any short-term or long-term AEs. The study aimed to analyze the novel adverse events of pantoprazole using the FAERS database. MATERIALS AND METHODS: A retrospective case/non-case disproportionality analysis was performed in the FAERS database. This study was based on AEs reported to FAERS from 2006Q1-2021Q3. Openvigil 2.1 was used for data extraction. Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and Information Component (IC) were applied to measure the disproportionality in reporting. A value of ROR-1.96SE > 1, PRR ≥ 2, and IC-2SD > 0 were considered as the threshold for a positive signal. RESULTS: A total of 1050 reports of dyspepsia, 7248 reports of hypocalcemia and 995 reports of hyponatremia were identified. A potential positive signal for dyspepsia (ROR-1.96SE = 2.231, PRR = 2.359, IC-2SD = 1.13), hypocalcemia (4.961, 5.45, 2.23) and hyponatremia (3.948, 4.179, 1.92) were identified for pantoprazole. CONCLUSION: Data mining in the FAERS database produced three potential signals associated with pantoprazole. As a result, further clinical surveillance is needed to quantify and validate potential hazards associated with pantoprazole-related adverse events.

Pantoprazole-induced Thrombocytopenia: Unresponsive to Corticosteroid and Thrombocyte Concentrate Transfusion.

Introduction: Pantoprazole is a proton pump inhibitor (PPI) class drug that is widely used in the treatment of SRMD (stress-related mucosal disease in critical ill patients. PPI are one class of drugs used commonly both for treatment and prophylactic therapy for stress ulcers in intensive care unit (ICU). Case: We report a case of a 51-year old male who was referred to PKU Hospital. He was admitted to ICU with diagnosis of Hyperosmolar Hyperglymic State and bronchopneumonia. Thrombocytopenia was noted in admission. There was more than 70% decrease in platelet count after initiation of pantoprazole. Patient received Thrombocyte Concentrate (TC) transfusion and corticosteroid iv for several days, but only had minor increase in platelet count. The platelets recovered after stopping pantoprazole. Discussion: In the present case report, another exposures to parenteral pantoprazole in a dose of 40 mg once daily reproduced the same adverse drug reaction. In comparison to lansoprazole, thrombocytopenia from pantoprazole is more severe that necessitate TC transfusion and corticosteroid trial. However, in the present case, TC transfusion and corticosteroid fail to escalate platelet count. This finding suggests probability of non-immune mechanism of pantoprazole-induced thrombocytopenia. Conclusion: Pantoprazole may induce thrombocytopenia with new features that were immediately developed, resulting a decrease in platelet count >70%. The mechanism found in this case may be non-immune. Drug-induced thrombocytopenia is one of the rare complications that has to be kept in mind with the use of pantoprazole.

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.

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].

REVISE: re-evaluating the inhibition of stress erosions in the ICU-statistical analysis plan for a randomized trial.

BACKGROUND: The REVISE (Re-Evaluating the Inhibition of Stress Erosions in the ICU) trial will evaluate the impact of the proton pump inhibitor pantoprazole compared to placebo in invasively ventilated critically ill patients. OBJECTIVE: To outline the statistical analysis plan for the REVISE trial. METHODS: REVISE is a randomized clinical trial ongoing in intensive care units (ICUs) internationally. Patients ≥ 18 years old, receiving invasive mechanical ventilation, and expected to remain ventilated beyond the calendar day after randomization are allocated to either 40 mg pantoprazole intravenously or placebo while mechanically ventilated. RESULTS: The primary efficacy outcome is clinically important upper GI bleeding; the primary safety outcome is 90-day mortality. Secondary outcomes are ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine concentration, and duration of mechanical ventilation, ICU, and hospital length of stay. Following an interim analysis of results from 2400 patients (50% of 4800 target sample size), the data monitoring committee recommended continuing enrolment. CONCLUSIONS: This statistical analysis plan outlines the statistical analyses of all outcomes, sensitivity analyses, and subgroup analyses. REVISE will inform clinical practice and guidelines worldwide. TRIAL REGISTRATION: www. CLINICALTRIALS: gov NCT03374800. November 21, 2017.