A 2024 guideline developed by the Society of Critical Care Medicine and the American Society of Health-System Pharmacists provides detailed recommendations for the prevention of stress-related upper gastrointestinal bleeding (UGIB) in critically ill adults. The guideline identifies several factors that increase the risk of clinically important stress-related UGIB, including coagulopathy, shock, and chronic liver disease, and recommends pharmacologic stress ulcer prophylaxis (SUP) with a proton pump inhibitor or histamine-2 receptor antagonist in critically ill patients with these risk factors. Additional recommendations address the role of enteral nutrition, preferred pharmacologic agents, route of administration, dosing considerations, and discontinuation of prophylaxis once risk factors resolve. Notably, corticosteroid therapy is not identified as a risk factor for stress-related UGIB in this guideline, and no recommendations are provided regarding the use of SUP based on corticosteroid dose, prednisone or methylprednisolone equivalent thresholds, or duration of corticosteroid therapy. As such, the guideline does not specify circumstances in which high-dose or prolonged corticosteroid therapy alone would warrant initiation of stress ulcer prophylaxis. [1]

A 2023 institutional guideline reviewing evidence on stress ulcer prophylaxis in critically ill patients also highlights several established and potential risk factors for clinically significant UGIB. Early multicenter work involving 2,252 ICU patients identified respiratory failure requiring mechanical ventilation for at least 24 hours and coagulopathy (platelet count <50,000 mm³, INR > 1.5, or aPTT > 2 times control) as independent risk factors for clinically important bleeding. A subsequent multivariate analysis also identified maximum serum creatinine as a risk factor, while enteral nutrition and ranitidine appeared protective against stress ulceration. Additional factors have been described in the literature but remain less well studied. These include sepsis, prolonged ICU stay (>1 week), persistent occult bleeding, and high-dose corticosteroid therapy. The guideline notes that corticosteroid exposure exceeding approximately 250 mg/day of hydrocortisone (or equivalent) has been reported as a possible risk factor; however, supporting data are limited. The document also emphasizes that the likelihood of stress ulceration may increase when multiple risk factors are present, rather than from a single factor alone. [2]

According to the 2008 Eastern Association for the Surgery of Trauma (EAST) Practice Management Guidelines Committee, recommendations for stress ulcer prophylaxis in critically ill patients were stratified by strength of evidence. Prophylaxis was strongly recommended (Level 1) for patients with major risk factors such as mechanical ventilation, coagulopathy, traumatic brain injury, or major burn injury, while Level 2 recommendations supported use in ICU patients with conditions such as multi-trauma, sepsis, or acute renal failure. High-dose corticosteroid therapy was addressed in a lower-strength (Level 3) recommendation, in which prophylaxis was suggested for ICU patients receiving doses greater than 250 mg/day of hydrocortisone or equivalent. The guideline also noted that in selected patient populations without significant risk factors, routine prophylaxis may not be necessary. [3]

Similarly, older guidance from 1999 by the American Society of Health-System Pharmacists (ASHP) on management of stress ulcer prophylaxis recommend prophylaxis in ICU patients with coagulopathy, or who require mechanical ventilation for more than 48 hours. Additionally, patients who have a history of GI ulceration or bleeding <1 year prior to admission, or patients with more than 1 risk factor for bleeding (sepsis, ICU stay of more than one week, occult bleeding lasting six days or more, and use of high-dose corticosteroids) are recommended to receive prophylaxis. High-dose corticosteroids are defined as a quantity greater than 250 mg/day of hydrocortisone, or the equivalent. [4]

A 2013 editorial delved into the longstanding belief regarding the ulcerogenic potential of corticosteroids. Despite experimental evidence suggesting that corticosteroids can promote peptic ulcers by inhibiting cytoprotective prostaglandins and suppressing gastric defense mechanisms, the actual incidence of steroid-induced ulcers in clinical settings remains significantly lower than anticipated. This discrepancy is highlighted by meta-analyses from the 1990s, which revealed no significant increase in the relative risk of gastric and duodenal ulcers in steroid-treated patients compared to untreated controls. The editorial underscores the lack of robust, contemporary clinical studies to further illuminate this issue—owing largely to insufficient interest and the logistical challenges of recruiting large patient cohorts to detect such low-incidence events. The analysis indicates that corticosteroids might exacerbate ulcer healing, particularly when co-administered with NSAIDs. The association of both types of drugs has a synergic and lethal effect, increasing by 3-6 times the relative risk. Corticosteroids on their own become ulcerogenic if treatment lasts for more than one month, with a total intake higher than 1000 mg of prednisolone. However, pharmacological prophylaxis is seldom warranted in most steroid-treated patients. Current clinical guidelines suggest that protective measures may only benefit patients undergoing long-term, high-dose steroid therapy or those concurrently taking NSAIDs. While proton pump inhibitors are frequently prescribed, their efficacy in this specific context lacks empirical validation through controlled studies. The editorial advocates for a cautious approach, suggesting that the myth of steroid ulcers persists more from historical dogma than from evidence-based medicine, as the available clinical data does not support widespread prophylactic use of gastroprotective agents in steroid therapy. [5]

A 2014 systematic review and meta-analysis aimed to evaluate whether the use of corticosteroids is associated with an increased risk of gastrointestinal bleeding or perforation. This extensive review included 159 randomized, double-blind, controlled trials involving a total of 33,253 participants, comparing corticosteroids to placebo for various medical conditions. Only studies employing systemic corticosteroids—administered orally, intravenously, or intramuscularly—were considered, whereas studies with local steroid administration, single doses, or crossover designs were excluded. Findings indicated that corticosteroid use increased the overall risk of gastrointestinal bleeding or perforation by 40%, with an odds ratio (OR) of 1.43 (95% confidence interval [CI], 1.22 to 1.66). Despite this, the increased risk was statistically significant predominantly among hospitalized patients (OR, 1.42; 95% CI, 1.22 to 1.66), while in ambulatory settings, the risk elevation was not statistically significant (OR, 1.63; 95% CI, 0.42 to 6.34), with only a small number of events occurring. Subgroup analyses revealed consistency across studies, even when excluding those with concomitant NSAID use and gastroprotective drug use, suggesting that hospitalized patients, due to their potentially more severe conditions, might be more vulnerable to these adverse effects. [6]

A 2019 systematic review and meta-analysis evaluated the effect of systemic corticosteroids on the incidence of gastrointestinal bleeding in critically ill adult patients. This review incorporated data from 25 trials totaling 14,615 participants for the primary outcome, which was the incidence of clinically significant gastrointestinal bleeding within 90 days, and 55 trials involving 21,792 participants for secondary outcomes encompassing any severity of gastrointestinal bleeding within the same period. The review utilized randomised clinical trials that compared systemic corticosteroids administered for more than 24 hours with either placebo or no treatment. The review indicated a pooled incidence of clinically important gastrointestinal bleeding of 2.3% in the corticosteroid group compared to 1.8% in the control group, suggesting a relative risk of 1.26, with a 95% confidence interval of 1.01 to 1.57. In contrast, no significant difference was observed in the risk of gastrointestinal bleeding of any severity, showing a relative risk of 1.10 with a 95% confidence interval of 0.92 to 1.32. The results signified a slight increase in clinically significant gastrointestinal bleeding associated with corticosteroid use, yet the rarity of events and a high risk of bias diminished the quality of evidence. The GRADE assessment reflected low-quality evidence due to these biases and imprecision. Despite employing a detailed methodology, the findings highlighted a need for cautious interpretation due to the overall low incidence of bleeding events and the lack of comprehensive reporting across trials. [7]