Stress ulcers are erosions of the stomach or upper intestinal lining that develop not from everyday psychological stress but from the physiological strain of severe illness, major surgery, or traumatic injury. They show up most often in intensive care patients and can appear within the first 72 hours of admission, sometimes before any obvious bleeding occurs. The condition has been recognized since the 1930s, when Hans Selye first described hemorrhagic gastric erosions as part of the body’s response to extreme physical stress, and prevention remains a daily question in ICUs worldwide.
How Stress Ulcers Form
The stomach lining normally protects itself from its own acid with a mucus barrier and steady blood flow to the tissue. In critically ill patients, that defense breaks down. Two things have to go wrong at once: the stomach lining loses its blood supply (ischemia), and acid is still present in the stomach. Without adequate circulation, the mucosal cells cannot repair themselves or maintain their protective coating, and the acid eats into the unprotected tissue.
Reflux of bile and other duodenal contents back into the stomach can worsen the damage by further disrupting the mucosal barrier.1PubMed. Stress ulcers: their pathogenesis, diagnosis, and treatment The result is shallow, often multiple erosions scattered across the stomach lining, rather than the single deep crater typical of a standard peptic ulcer. Endoscopic studies of critically ill patients confirm that these mucosal injuries frequently include gastric erosions, hemorrhagic gastritis, and superficial ulcers, with deeper gastric or duodenal ulcers occurring less often.
Who Is at Risk
Not every ICU patient develops clinically significant bleeding from stress ulcers, but two risk factors stand out above all others. Patients on mechanical ventilation for more than 48 hours and those with a coagulopathy (any condition that impairs blood clotting) face the highest risk.2PubMed Central. Prevention of stress-related ulcer bleeding at the intensive care unit: Risks and benefits of stress ulcer prophylaxis In one study focusing on mechanically ventilated patients, coagulopathy was the strongest independent predictor of overt gastrointestinal hemorrhage, with roughly a twelvefold increase in odds.3Journal of Intensive Care Medicine. Incidence of Clinically Important Bleeding in Mechanically Ventilated Patients
Beyond ventilation and clotting problems, several other conditions raise the risk:
- Major burns: Burns covering more than 20 percent of total body surface area are an independent risk factor. In burn patients who underwent endoscopy, about 70 percent of those with ulcers had gastric ulcers, while the rest had duodenal ulcers or both.4PubMed Central. A revised risk analysis of stress ulcers in burn patients receiving ulcer prophylaxis
- Traumatic brain injury and neurosurgery: Head injuries have long been associated with stress ulcers, historically called Cushing ulcers after the neurosurgeon Harvey Cushing.
- Sepsis, major surgery, and multi-organ failure: Any condition that severely compromises blood flow to the gut increases risk.
Cushing Ulcers and What We Got Wrong
For decades, the textbook explanation of Cushing ulcers went like this: brain injury raises pressure inside the skull, which overstimulates the vagus nerve, which floods the stomach with acid, which causes ulcers. It sounded clean. The problem is that more recent review of the evidence has poked serious holes in this story.
A 2023 narrative review found several reasons why the vagal-acid explanation falls short. Clinical and experimental studies showed only a modest increase in acid secretion in head-injured patients, not the dramatic surge the old model predicted. Increased vagal tone appears in only a minority of cases of raised intracranial pressure, and most of those involve catastrophic, non-survivable brain injury. Perhaps most telling, directly stimulating the vagus nerve does not cause peptic ulceration, and Cushing ulcers can develop after ischemic strokes that do not raise intracranial pressure at all.5PubMed. A Reappraisal of the Pathophysiology of Cushing Ulcer: A Narrative Review The true mechanism probably involves a mix of mucosal ischemia, systemic inflammation, and disrupted gut-brain signaling rather than a simple vagal reflex.
Preventing Stress Ulcers in the ICU
Stress ulcer prophylaxis, commonly abbreviated SUP, is standard practice for high-risk ICU patients. The goal is to keep gastric acid from eating through already-compromised mucosa. Three main drug classes have been used for this, and the evidence favoring each one has shifted over the decades.
Proton pump inhibitors (PPIs) like pantoprazole and omeprazole are the most powerful acid suppressors available. A large randomized trial published in the New England Journal of Medicine compared pantoprazole with placebo in mechanically ventilated patients and found that clinically important upper GI bleeding occurred in about 1 percent of the pantoprazole group versus roughly 3.5 percent of the placebo group.6PubMed. Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation That is a substantial relative reduction, though the absolute numbers remind you that even without prophylaxis, the majority of ventilated patients do not bleed.
Head-to-head comparisons consistently show PPIs outperform H2 receptor antagonists (H2RAs) like ranitidine and famotidine. A meta-analysis of 19 trials found that PPIs cut the risk of clinically important GI bleeding by about 60 percent compared to H2RAs, with no significant difference in mortality, pneumonia, or ICU length of stay between the two.7PubMed Central. Efficacy and safety of proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis of randomized trials A separate meta-analysis reached a similar conclusion, finding PPIs reduced clinically important bleeding by roughly two-thirds compared to H2RAs.8Critical Care Medicine. Proton Pump Inhibitors Versus Histamine 2 Receptor Antagonists for Stress Ulcer Prophylaxis in Critically Ill Patients
Sucralfate works differently. Instead of reducing acid, it coats the ulcer surface and strengthens the mucosal barrier. It does not raise the stomach’s pH the way PPIs and H2RAs do, which matters for infection risk. A meta-analysis comparing sucralfate to H2RAs found no significant difference in clinically important bleeding, but sucralfate was associated with a lower rate of ICU-acquired pneumonia.9PubMed. Sucralfate versus histamine 2 receptor antagonists for stress ulcer prophylaxis in adult critically ill patients: A meta-analysis and trial sequential analysis of randomized trials European guidelines have historically considered sucralfate the most cost-effective option for prophylaxis.10PubMed. Current guidelines on stress ulcer prophylaxis
The Downsides of Prophylaxis
Raising the stomach’s pH to prevent ulcers comes with a biological trade-off. Gastric acid is a first-line defense against ingested bacteria. When you suppress that acid, bacteria that would normally be killed in the stomach can colonize the upper GI tract, and from there they can be aspirated into the lungs. This is one reason ventilator-associated pneumonia (VAP) has been a persistent concern with acid-suppressive prophylaxis.
Research on this link has produced mixed signals. One study found that prolonged use of pH-raising SUP was significantly associated with subsequent VAP development.11American Journal of Infection Control. Stress ulcer prophylaxis and associated risk of ventilator-associated pneumonia However, a study in pediatric ICU patients found no increase in VAP among those receiving ranitidine, omeprazole, or sucralfate compared to patients who received no prophylaxis at all.12PubMed. Occurrence of ventilator-associated pneumonia in mechanically ventilated pediatric intensive care patients during stress ulcer prophylaxis with sucralfate, ranitidine, and omeprazole A meta-analysis of ICU patients receiving enteral nutrition found that adding SUP was associated with a roughly 50 percent higher risk of hospital-acquired pneumonia, with no reduction in GI bleeding.
Clostridioides difficile infection (C. diff) is the other major concern. A nationwide cohort study found that patients receiving PPIs for stress ulcer prophylaxis had about two and a half times the risk of C. diff infection compared to those receiving H2RAs, and the risk climbed further when acid-suppressive drugs were used for more than two weeks.13Journal of Hospital Infection. Association between stress ulcer prophylaxis and Clostridioides difficile infection among hospitalized patients: a nationwide population-based cohort study Another study looking specifically at critically ill patients on SUP found the incidence of C. diff was roughly three and a half times higher with PPIs than with H2RAs.14PubMed Central. Risk of Clostridium difficile Infection with the Use of a Proton Pump Inhibitor for Stress Ulcer Prophylaxis in Critically Ill Patients
One large retrospective study even raised a mortality concern, finding that PPIs were associated with a 28 percent higher risk of 90-day in-hospital death compared to H2RAs.15PubMed Central. Comparison of proton pump inhibitors and histamine 2 receptor antagonists for stress ulcer prophylaxis in the intensive care unit That finding has not been consistently replicated in randomized trials, where mortality differences between the two drug classes have generally been non-significant. But it underscores a growing awareness that more aggressive acid suppression is not automatically better.
Overuse Outside the ICU
If the evidence for prophylaxis is strongest in high-risk ICU patients on ventilators or with clotting disorders, you might assume the drugs would stay in the ICU. They have not. Multiple studies have found that acid-suppressive therapy for stress ulcer prevention has spread far beyond the populations where it was ever tested or shown to help.
One survey found that as many as 71 percent of patients admitted to general medicine wards were receiving some form of acid-suppressive therapy, most without an appropriate indication.16American Journal of Health-System Pharmacy. Stress ulcer prophylaxis in hospitalized patients not in intensive care units A retrospective analysis found that over 90 percent of the patients reviewed were not eligible for SUP in the first place, yet more than half were receiving it inappropriately.17PubMed. Variables associated with stress ulcer prophylaxis misuse: a retrospective analysis A prospective study in a general surgery department found that 79 percent of patients receiving PPI-based stress ulcer prophylaxis had no identifiable risk factors.18PubMed. Stress ulcer prophylaxis in non-critically ill patients: a prospective evaluation of current practice in a general surgery department
The pattern is consistent across hospitals and countries: stress ulcer prophylaxis intended for critically ill patients has become a reflex habit in settings where the risk of stress ulcers is minimal but the risks of acid suppression, including pneumonia and C. diff, remain real.
The Deprescribing Problem
Even when prophylaxis is appropriate during an ICU stay, stopping it afterward turns out to be surprisingly difficult. One study tracked patients from the ICU through discharge and found that 80 percent continued receiving acid-suppressive drugs when transferred to a regular ward, with 60 percent of those prescriptions being inappropriate. About a quarter of critically ill patients left the hospital with stress ulcer prophylaxis still on their medication list.19PubMed. Inappropriate continuation of stress ulcer prophylactic therapy after discharge
An international survey of ICU practices found that while adequate enteral feeding was the most common trigger for stopping prophylaxis, nearly one in five units simply continued the drugs when patients left the ICU.20PubMed. Stress ulcer prophylaxis in the intensive care unit: an international survey of 97 units in 11 countries Once a drug appears on a patient’s medication list, it tends to stay there. Patients who were started on a PPI for a legitimate ICU indication can end up taking it for months or years without anyone questioning whether it is still needed. This contributes to the broader problem of long-term PPI use in the general population, with its own set of concerns around kidney health, bone density, and nutrient absorption.
Does Enteral Feeding Replace Drug Prophylaxis?
Feeding patients through the gut (enteral nutrition) has long been thought to protect against stress ulcers on its own, partly by buffering stomach acid and partly by maintaining blood flow to the intestinal lining. Many ICUs use the start of enteral feeding as the signal to stop prophylactic drugs. But the evidence for this swap is surprisingly thin.
A systematic review and meta-analysis of seven trials involving nearly 900 patients compared adding drug prophylaxis versus not adding it in ICU patients already receiving enteral nutrition. There was no significant difference in GI bleeding between the two groups. Adding SUP also did not improve mortality, reduce C. diff infections, shorten ICU stays, or reduce time on the ventilator. The only statistically significant finding was that SUP on top of enteral nutrition was associated with a higher risk of hospital-acquired pneumonia. In other words, for patients already being fed through the gut, adding acid suppression provided no measurable benefit and may have caused harm.
Stress Ulcers in Children
Critically ill children develop stress-related mucosal injury much like adults, and the reflexive response in many pediatric ICUs has been to prescribe prophylaxis broadly.21PubMed. Stress ulcer, gastritis, and gastrointestinal bleeding prophylaxis in critically ill pediatric patients: a systematic review But the pediatric evidence tells a cautionary story. A study in a pediatric ICU found that while overt upper GI bleeding occurred in about 27 percent of patients, only around 6 percent had clinically significant bleeding. Prophylaxis with omeprazole did not reduce bleeding compared to no prophylaxis in children with mild-to-moderate organ dysfunction, and it was associated with an increase in bloodstream infections. The only independent predictor of bleeding was mechanical ventilation, which led the authors to argue that routine PPI use in all critically ill children should stop and prophylaxis should be reserved for those on ventilators.22Anales de PediatrÃa (English Edition). Stress ulcer prophylaxis for critically ill children: routine use needs to be re-examined
When Stress Ulcers Bleed Despite Prevention
When prophylaxis fails and stress ulcer bleeding occurs, management depends on severity. Most stress ulcer bleeding is diffuse, oozing from many shallow erosions rather than spurting from a single artery, which makes it a different challenge than a typical peptic ulcer bleed. Endoscopy is used to visualize the damage and, where possible, to treat specific bleeding points. For diffuse hemorrhagic gastritis that resists endoscopic treatment, options become more limited.
One approach documented over a seven-year period involved continuous gastric lavage with cold Ringer’s solution to stop active bleeding, followed by high-dose sucralfate administered through a gastric tube in a tapering schedule. All 23 patients treated this way responded successfully, with none requiring surgery, even though four had already been scheduled for total gastrectomy as a last resort.23PubMed. Conservative treatment of stress ulcer bleeding: a new approach Surgery for stress ulcer bleeding is rare today, largely because prophylaxis has reduced severe cases and because endoscopic and pharmacological tools have improved.
The Cost Question
The economics of stress ulcer prophylaxis are not straightforward, because the costs of both the drugs and their complications need to be weighed. A cost-effectiveness analysis comparing PPIs and H2RAs estimated that the probability of stress ulcer bleeding was about 1.3 percent with PPIs versus roughly 6.6 percent with H2RAs, while pneumonia rates were similar between the two. When the total costs of ICU stay, bleeding complications, and pneumonia were added up, PPIs came out ahead, with lower average costs per patient without complications.24PubMed. Cost-effectiveness analysis: stress ulcer bleeding prophylaxis with proton pump inhibitors, H2 receptor antagonists However, these analyses typically do not factor in the downstream costs of inappropriate continuation after discharge or the treatment of C. diff infections acquired during prophylaxis.
Predicting Who Will Develop Stress Ulcers
One area of active research involves using routine blood tests to identify patients most likely to develop stress ulcers, which could help target prophylaxis more precisely. After brain hemorrhage surgery, for example, researchers found that combining two common inflammatory markers from a standard blood count, the neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio, could predict stress ulcer development with high accuracy.25Clinical Neurology and Neurosurgery. Application value of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in predicting stress ulcer after acute cerebral hemorrhage surgery These are not yet standard clinical tools, but they represent a move toward individualizing risk assessment rather than giving every ICU patient the same blanket prophylaxis. If future validation studies hold up, such markers could help clinicians distinguish the patients who genuinely need acid suppression from the majority who would do fine without it.