Stress ulcer

# Overview
Stress ulcers are single or multiple mucosal defects which can become complicated by upper gastrointestinal bleeding during the physiologic stress of serious illness.  Ordinary peptic ulcers are found commonly in the gastric antrum and the duodenum whereas stress ulcers are found commonly in fundic mucosa and can be located anywhere within the stomach and proximal duodenum.

# Incidence/Significance
Stress ulcers, as defined by overt bleeding and hemodynamic instability, decreased hemoglobin, and/or need for transfusion, was seen in 1.5% of patients in the 2252 patients in the Canadian Critical Care Trials group study. Patients with stress ulcers have a longer ICU length of stay (upto 8 days) and a higher mortality (upto 4 fold) than compared to patients who do not have stress ulceration and bleeding . While the bleeding and transfusions associated with the stress ulcerations contribute to the increased mortality, the contribution of factors like hypotension, sepsis and respiratory failure to the mortality independently of the stress ulceration cannot be ignored.

# Risk Factors
Risk factors for stress ulcer formation that have been identified are numerous and varied.  However, two landmark studies and one position paper exist that addresses the topic of risk factors for stress ulcer formation:
- Non-critically ill medical patients with 2 or more of the following:  respiratory failure, sepsis, heart failure, hepatic encephalopathy, jaundice, renal failure, stroke, hypotension, previous gastrointestinal disease and treatment with corticosteroids, NSAIDS, heparin, or warfarin.
- In surgical critically ill patients, only those patients who are on a mechanical ventilator for more than 48 hours and/or those with a coagulopathy.
- The American Society of Health-System Pharmacists guideline recommends against the practice of stress ulcer prophylaxis in non-critically ill patients.

# Diagnosis
Stress ulcer is suspected when there is upper gastrointestinal bleeding in the appropriate clinical setting, for example, when there is upper gastrointestinal bleeding in elderly patients in a surgical intensive care unit (ICU) with heart and lung disease, or when there is upper gastrointestinal bleeding in patients in a medical ICU who require respirators.
Stress ulcer can be diagnosed after the initial management of gastrointestinal bleeding, the diagnosis can be confirmed by upper GI endoscopy.

# The site of ulcerations
The ulcerations may be superficial and confined to the mucosa, in which case they are more appropriately called erosions, or they may penetrate deeper into the submucosa. The former may cause diffuse mucosal oozing of blood, whereas the latter may erode into a submucosal vessel and produce frank hemorrhage. 

# Lesion of stress ulcers
The characteristic lesions may be multiple, superficial mucosal erosions similar to erosive gastroduodenitis. Occasionally, there may be a large acute ulcer in the duodenum (Curlings ulcer). 
Generally, there are multiple lesions located mainly in the  stomach and occasionally in the duodenum. They range in depth from mere shedding of the superficial epithelium (erosion) to deeper lesions that involve the entire mucosal thickness (ulceration). 

# Stress Ulcer formation
The pathogenic mechanisms are similar to those of erosive gastritis. 
The pathogenesis of stress ulcer is unclear but probably is related to a reduction in mucosal blood flow or a breakdown in other normal mucosal defense mechanisms in conjunction with the injurious effects of acid and pepsin on the gastroduodenal mucosa. 

# Stress Ulcer Prophylaxis (SUP)
Clinical practice guidelines inform prophylaxis decisions.

## Who should be on stress ulcer prophylaxis?
Not every patient who enters the hospital needs SUP.  Cook et al demonstrated that in surgical critically-ill patients the only risk factors associated with clinically significant bleeding from stress ulcers were mechanical ventilation for more than 48 hours and coagulopathy (OR 15.6 and 4.3, respectively). 

## Drug classes and options available
Prophylactic agents include antacids, H2-receptor blockers, sucralfate, proton pump inhibitors (PPIs), prostaglandin analogs, and nutrition.
Among recent comparisons of prophylactic agents:
- Systematic reviews find inconsiatent results between proton pump inhibitors and H2-receptor blockers.
- A more recent randomized controlled trial of proton pump inhibitors versus H2-receptor blockers found no difference but a borderling increase in mortality with PPIs.

### Proton pump inhibitors
PPIs are also widely used in SUP.  "Data regarding the efficacy and potential adverse effects of these drugs in the prevention of stress ulceration are less extensive than for antacids, H2 blockers, or sucralfate."   In one study looking at omeprazole, patients were given an oral suspension by mouth followed by nasogastric tube and there were no episodes of bleeding or signs of toxicity.    Similar results were reproduced in another study.  

### H2 Receptor antagonists
In contrast, H2-receptor blockers are widely used in SUP.  Most trials, but not all, have demonstrated their effectiveness in preventing stress ulcer formation.    

### Sucralfate
Sucralfate has not been shown to effectively decrease the incidence of stress ulcer formation.  This was demonstrated in a large randomized, double-blinded, control trial of 1200 patients and compared sucralfate to the H2-receptor blocker, ranitidine.  

### Prostaglandin analogues
This class includes Misoprostol and the likes. Significant side effects including diarrhea, drug interactions, lack of overall efficacy and availability of much better alternatives preclude its use in current medical practice.

### Antacids
Antacids have been used in SUP.  Numerous studies have shown them to be as effective in prevention when compared to H2-receptor blockers.    One study did show them to be no more effective than placebo.   Overall, all the studies show a trend towards effectiveness when compared to placebo but the effect is not as strong as other H2 receptor antagonists. Additionally, these drugs have other drawbacks such as the need for frequent administration (sometimes as often as every 2-3 hours), electrolyte imbalance, diarrhea, constipation and other important drug interactions. For these reasons, these drugs are no longer used for stress ulcer prophylaxis.

# Treatment
The principles of management are the same as for the chronic ulcer.  The steps of management are similar as in erosive gastritis.
Endoscopic means of treating stress ulceration may be ineffective and operation required.  It is believed that shunting of blood away from the mucosa makes the mucous membrane ischaemic and more susceptible to injury. 
Treatment of stress ulceration usually begins with prevention. Careful attention to respiratory status, acid-base balance, and treatment of other illnesses helps prevent the conditions under which stress ulcers occur. Patients who develop stress ulcers typically do not secrete large quantities of gastric acid; however, acid does appear to be involved in the pathogenesis of the lesions. Thus it is reasonable either to neutralize acid or to inhibit its secretion in patients at high risk. 
In case of severe hemorrhagic or erosive gastritis and stress ulcers, a combination of antacids and H2-blockers may stop active bleeding and prevent re bleeding. In selected patients, either endoscopic therapy or selective infusion of vasopressin into the left gastric artery may help control the hemorrhage. 

# Footnote
-  Jump up to: 1.0 1.1 Cook, DJ, Fuller, HD, Guyatt, GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. N Engl J Med 1994; 330:377.PMID 8284001
-  Cook DJ, Griffith LE et al. The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Critical Care 2001 Dec;5(6):368-75. Epub  2001 Oct 5 PMID 11737927
-   Manual of Gastroenterology by Gregory L. Eastwood, M.D. &Canan Avunduk, M.D., Ph.D.(1994)
-  TEXTBOOK OF SURGERY ISBN 0-07-4621-149-1 page 409
-   Robbins PATHOLOGIC BASIS OF DISEASE 6TH Edition ISBN 81-7867-052-6 page 796
-   Robbins PATHOLOGIC BASIS OF DISEASE 6TH Edition ISBN 81-7867-052-6 page 796
-   Manual of Gastroenterology
Gregory L. Eastwood, M.D.& Canan Avunduk, M.D., Ph.D.(1994)
-  Ye Z, Reintam Blaser A, Lytvyn L, Wang Y, Guyatt GH, Mikita JS;  et al. (2020). "Gastrointestinal bleeding prophylaxis for critically ill patients: a clinical practice guideline". BMJ. 368: l6722. doi:10.1136/bmj.l6722. PMID 31907223.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
-  Cook, DJ, Fuller, HD, Guyatt, GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. N Engl J Med 1994; 330:377.
-  Wang Y, Ye Z, Ge L, Siemieniuk RAC, Wang X, Wang Y;  et al. (2020). "Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: systematic review and network meta-analysis". BMJ. 368: l6744. doi:10.1136/bmj.l6744. PMID 31907166.CS1 maint: Multiple names: authors list (link)
-  Toews I, George AT, Peter JV, Kirubakaran R, Fontes LES, Ezekiel JPB;  et al. (2018). "Interventions for preventing upper gastrointestinal bleeding in people admitted to intensive care units". Cochrane Database Syst Rev. 6: CD008687. doi:10.1002/14651858.CD008687.pub2. PMC 6513395 Check |pmc= value (help). PMID 29862492.CS1 maint: Multiple names: authors list (link)
-  PEPTIC Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group, Alberta Health Services Critical Care Strategic Clinical Network, and the Irish Critical Care Trials Group. Young PJ, Bagshaw SM, Forbes AB, Nichol AD, Wright SE;  et al. (2020). "Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial". JAMA. doi:10.1001/jama.2019.22190. PMID 31950977.CS1 maint: Multiple names: authors list (link)
-  Phillips, JO, Metzler, MH, Palmieri, MT, et al. A prospective study of simplified omeprazole suspension for the prophylaxis of stress-related mucosal damage. Crit Care Med 1996; 24:1793.
-  Lasky, MR, Metzler, MH, Phillips, JO. A prospective study of omeprazole suspension to prevent clinically significant gastrointestinal bleeding from stress ulcers in mechanically ventilated trauma patients. J Trauma 1998; 44:527.
-   Shuman, RB, Schuster, DP, Zuckerman, GR. Prophylactic therapy for stress ulcer bleeding: A reappraisal. Ann Intern Med 1987; 106:562.
-  Messori, A, Trippoli, S, Vaiani, M, et al. Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials. BMJ 2000; 321:1103.
-  Cook, D, Guyatt, G, Marshall, J, et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. N Engl J Med 1998; 338:791.
-   Shuman, RB, Schuster, DP, Zuckerman, GR. Prophylactic therapy for stress ulcer bleeding: A reappraisal. Ann Intern Med 1987; 106:562.
-   Cook, DJ, Reeve, BK, Guyatt, GH, et al. Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses. JAMA 1996; 275:308.
-  Bailey & Loves SHORT PRACTICE OF SURGERY 23rd Edition ISBN 0 340 75949 6 page 916
-  TEXTBOOK OF SURGERY ISBN 0-07-4621-149-1 page 409
-  Bailey & Loves SHORT PRACTICE OF SURGERY 23rd Edition ISBN 0 340 75949 6 page 916
-  TEXTBOOK OF SURGERY ISBN 0-07-4621-149-1 page 409
-   Manual of Gastroenterology priyank sinha
Gregory L. Eastwood, M.D. & Canan Avunduk, M.D., Ph.D.(1994)
-   A Practical Approach to Emergency Medicine by Robert J. Stine, M.D., Carl R. Chudnofsky, M.D., Cynthia K. Aaron, M.D. (1994)
Bailey & Love's, Short Practice of Surgery (23rd ed.), New York, USA: Arnold, Co-published in the USA by Oxford University press Inc., New York 2000 Unknown parameter |coauthors= ignored (help)

# Selected Readings
- Cheung, L. Y. Pathogenesis, prophylaxis and treatment of stress gastritis. Am. J. Surg. 156:437, 1988.
- Craven, D. E., et al. Risk factors for pneumonia and fatality in patients receiving continuous mechanical ventilation. Am. Rev. Respir. Dis. 133:792, 1986.
- Driks, M. R., et al. Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histamine type 2 blockers. N. Engl. J. Med. 317:1376, 1987.
- DuMoulin, G. C., et al. Aspiration of gastric bacteria in antacid-treated patients: A frequent cause of postoperative colonisation of the airway. Lancet 1:242, 1982.
- Lamothe, P. H., et al. Comparative efficacy of cimetidine, famotidine, ranitidine, and Mylanta in postoperative stress ulcers: Gastric pH control and ulcer prevention in patients undergoing coronary artery bypass graft surgery. Gastroenterology 100:1515, 1991.
- Priebe, H. J., et al. Antacid versus cimetidine in preventing acute gastrointestinal bleeding: A randomized trial in 75 ill patients. N. Engl. J. Med. 302:426, 1980.
- Shuman, R. B., Schuster, D. P., and Zuckerman, G. R. Prophylactic therapy for stress ulcer bleeding: A reappraisal. Ann Intern. Med. 106:562, 1987.
- Tryba, M. Stress bleeding prophylaxis with sucralfate: Pathophysiologic basis and clinical use. Scand. J. Gastroenterol.  25:22, 1990.