Does Stress Cause Stress Ulcers? The Etiology and Pathophysiology of Stress Ulcers

July 14, 2016

AnxietyPlease enjoy this post from the archives dated August 22, 2012

Sara-Megumi Naylor, MD

Faculty Peer Reviewed

When Warren and Marshall were awarded the Nobel Prize in Physiology or Medicine in 2005 for their work on Helicobacter pylori and peptic ulcer disease [1], a long-standing controversy concerning the major cause of peptic ulcers was settled. They are not due to the reasons—spicy food, excessive coffee consumption, poor sleep, a stressful lifestyle—that we have heard from relatives and perhaps believed over the years. It is now well accepted that the leading causes of peptic ulcers are infection with the H. pylori bacterium and the use of non-steroidal anti-inflammatory drugs (NSAIDs) [2]. But what causes the stress ulcers that we see in patients who have experienced prolonged stays in the intensive care unit (ICU)? Why are they called “stress ulcers”? And why do we place at-risk individuals on prophylactic acid-inhibiting therapies?

The “stress” of stress ulcers specifically refers to the physiologic stress of serious illness [3]. Stress ulcers lie on the continuum of stress related mucosal disease (SRMD), a term used to describe the range of changes seen in the gastrointestinal (GI) mucosa of individuals who are critically ill [2]. On one end of the spectrum are patients with stress related injury which consists of diffuse, superficial, small erosions that do not extend into the submucosa, and thus do not reach submucosal blood vessels and do not lead to hemodynamically significant bleeding. On the other end of the spectrum are patients with true stress ulcers, which are discrete, deeper lesions that can extend into the submucosa, reaching significant blood vessels that, when compromised, can result in hemodynamically significant GI bleeding [2]. Other terms commonly used for conditions related to, or synonymous with, SRMD include stress erosions, stress gastritis, hemorrhagic gastritis, and erosive gastritis [4].

The mucosa of the GI tract consists of a single layer of cells approximately 0.1 mm thick [5]. This seemingly frail layer protects our body from the external environment and is maintained by multiple defense mechanisms. These include: (1) pre-epithelial factors like the mucus-bicarbonate-phospholipid barrier, (2) epithelial factors, such as the layer of simple columnar epithelial cells that is hydrophobic and interconnected by tight joints and continuous, and well-coordinated cell renewal which maintains constant structural integrity of the mucosa, and lastly (3) post-epithelial factors such as the continuous blood flow that delivers oxygen and nutrients with the simultaneous removal of toxic substances, an endothelial barrier that produces nitric oxide and prostacyclin to oppose the damaging effects of vasoconstrictors and inflammation in the microcirculation, and sensory innervation which helps regulate mucosal blood flow and gastric motility [6]. These critical mechanisms exist under normal conditions to balance out injurious factors and prevent the development of ulcers and their complications.

Contrary to popular belief as shown by the widespread practice of stress ulcer prophylaxis, bleeding is very rare in patients who are under significant “physiologic stress”. Within 24 hours of admission to the ICU, 75-100% of critically ill patients demonstrate evidence of SRMD [3]. However, only 25% percent of these patients will have clinical apparent bleeding [5], and only about 1-4% will have clinically significant bleeding [7], which is defined as overt bleeding (ie. hematemesis, gross blood, or “coffee ground” material in the nasogastric aspirate, hematochezia, or melena) complicated by one of the following within 24 hours after the onset of bleeding: (1) a spontaneous decrease of more than 20 mm Hg in systolic blood pressure, (2) an increase of more than 20 beats per minute in heart rate, or a decrease of more than 10 mm Hg in systolic blood pressure measured sitting up, or (3) a decrease of more than 2 g/dl of hemoglobin level and need for subsequent blood transfusion, after which the hemoglobin level does not increase by a value defined as the number of units of blood transfused minus 2 g/dl. [4, 7]. Those at highest risk for clinically significant bleeding are patients on mechanical ventilation for greater than 48 hours and those with a coagulopathy defined as INR >1.5 or a platelet count <50,000 platelet/uL [4, 7]. Providing stress ulcer prophylaxis to patients at highest risk for bleeding is evidence-based and of upmost importance. Guidelines for starting acid-inhibiting therapies in the ICU focus on these groups of patients.

How do stress ulcers form in these critically ill patients? While the association between severe physiologic stress and GI ulceration is well established, the mechanism by which stress ulcers form is multifactorial and still incompletely understood [4]. Given the numerous recent publications addressing the overuse of stress ulcer prophylaxis both inside and outside of the ICU [4, 8, 9, 10], it is crucial to understand the pathogenesis of stress ulcers, including the role of gastric acid, against which our prophylactic measures are directed.

The surprising truth about all ulcers (including stress ulcers) is that acid, even excessive acid, is not the primary cause of ulcers [2]. Instead, acid is only one of multiple pathogenic factors involved, and contributes to the persistence and worsening of already-formed ulcers [6]. The major cause of stress ulcers appears to be splanchnic hypoperfusion in critically ill patients [4, 5, 11]. Common stress-related responses are seen in patients who are seriously ill, including those with respiratory failure requiring mechanical ventilation, and/or those with coagulopathy, acute renal insufficiency, acute hepatic failure, sepsis, hypotension, and severe head or spinal cord injury [4]. These include sympathetic nervous system activation, increased catecholamine release, vasoconstriction, and secretion of pro-inflammatory cytokines [12]. These effects are initially beneficial because they shift blood away from the GI tract and to critical organs such as the brain [11]. However, when they persist they cause damage by breaking down gastric mucosal defenses, leading to injury and ulceration.

Decreased blood flow results in poor oxygen delivery and ischemic damage which have structural and chemical consequences. Loss of the epithelial cell layer that separates the contents of the gastric lumen with the body’s interior milieu leads to increased permeability and back-diffusion of protons and pepsin which further damages the mucosa [3, 4, 11]. Hypoperfusion also triggers the production of oxygen radicals and the decreases synthesis of gastro-protective prostaglandins which can lead to an aggressive inflammatory response [3, 6]. Interestingly, reperfusion injury also plays a significant role in the pathogenesis of stress ulcers [4]. Once blood flow is restored to ischemic tissue, the sudden hyperemia brings in an influx of inflammatory cells and cytokines that result in even more cell death. Both ischemia and reperfusion cause and worsen gastric dysmotility through the effect of cytokines on the enteric nervous system [3, 13]. Poor motility aggravates the situation because the persistence of acidic material and other irritants increase the risk of ulcer formation and persistence [3].

As explained, the pathogenesis of stress ulcer formation is complex. While acid plays a role, acid alone does not cause stress ulcers. Physiologic stress leading to splanchnic hypoperfusion, ischemic and reperfusion damage, and a cascade of inflammatory responses are the key causes. In this sense, stress does cause stress ulcers, though the stress responsible is of significant severity. Understanding the pathogenesis of stress ulcers is critical to appreciating what occurs at the level of the GI mucosa in critically ill patients. Therefore, the next time you start stress ulcer prophylaxis on a patient, keep in mind all of the factors that are at play, and that perhaps you should also focus your energy on improving the hemodynamics, gastric motility, and the overall medical status of your patients to help prevent splanchnic hypoperfusion, as well as providing acid suppression, typically with a proton pump inhibitor.

Dr. Sara-Megumi Naylor is a a recent graduate of NYU School of Medicine

Peer reviewed by Michael Poles, MD, Section Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


1 The Nobel Prize in Physiology or Medicine 2005. Available at:

2 Spirit MJ. Stress-related mucosal disease: risk factors and prophylactic therapy. Clin Ther. 2004 Feb;26(2):197-213. Review. Available from:

3 Fennerty MB. Pathophysiology of the upper gastrointestinal tract in the critically ill patient: rationale for the therapeutic benefits of acid suppression. Crit Care Med. 2002 Jun;30(6 Suppl):S351-5. Review. Available from:

4 Quenot JP, Thiery N, Barbar S. When should stress ulcer prophylaxis be used in the ICU? Curr Opin Crit Care. 2009 Apr;15(2):139-43. Review. Available from:

5 Marino P, Sutin K. The ICU book. 3rd Edition.

6 Laine L, Takeuchi K, Tarnawski A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology. 2008 Jul;135(1):41-60. Epub 2008 Jun 10. Review. Available from:

7 Cook DJ, Fuller HD, Guyatt GH, Marshall JC, Leasa D, Hall R, Winton TL, Rutledge F, Todd TJ, Roy P, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med. 1994 Feb 10;330(6):377-81. Available from:

8 Heidelbaugh JJ, Inadomi JM. Magnitude and economic impact of inappropriate use of stress ulcer prophylaxis in non-ICU hospitalized patients. Am J Gastroenterol. 2006 Oct;101(10):2200-5. Epub 2006 Sep 4. Available from:

9 Grube RR, May DB. Stress ulcer prophylaxis in hospitalized patients not in intensive care units. Am J Health Syst Pharm. 2007 Jul 1;64(13):1396-400. Available from:

10 Fohl AL, Regal RE. Proton pump inhibitor-associated pneumonia: Not a breath of fresh air after all? World J Gastrointest Pharmacol Ther. 2011 Jun 6;2(3):17-26. Available from:

11 Sesler JM. Stress-related mucosal disease in the intensive care unit: an update on prophylaxis. AACN Adv Crit Care. 2007 Apr-Jun;18(2):119-26; quiz 127-8. Review. Available from:

12 Martindale RG. Contemporary strategies for the prevention of stress-related mucosal bleeding. Am J Health Syst Pharm. 2005 May 15;62(10 Suppl 2):S11-7.Review. Available from:

13 Ritz MA, Fraser R, Tam W, Dent J. Impacts and patterns of disturbed gastrointestinal function in critically ill patients. Am J Gastroenterol. 2000 Nov;95(11):3044-52. Review. Available from: