ACUTE STRESS ULCERATION

Author: Philip Cumpston
P.Cumpston@mailbox.uq.oz.au
February 1991.
Converted to WWW and .HTML format by Allan Palmer

Contents:

    1. Introduction
    2. Definition
    3. Aetiology
    4. Pathogenesis
    5. Clinical features and diagnosis
    6. Management
    7. Prevention
    8. Measurement of gastric pH
    9. References

Introduction

With the introduction of the Intensive Care Unit has come the survival of patients who would otherwise have perished from their disease processes. This has led to the development of a new pattern of diseases, the so- called 'Intensive Care Syndromes'. One of the earliest noted, (and most dramatic), was a very high incidence of acute life-threatening upper gastrointestinal bleeding from stress ulceration. In 1971, one study demonstrated extensive mucosal erosions in all patients with multiple organ failure or sepsis.

In the 1970's Stress Ulceration and upper gastrointestinal haemorrhage was both common and feared, as the treatment was unsatisfactory, and the morbidity and mortality high. In fact, massive gastrointestinal bleeding in critically ill patients was said to carry a mortality approaching 80%. The cure was often no better, with a mortality of approximately 70% associated with surgery for this condition.

Definition

The term 'stress ulcer' is usually reserved for a mucosal abnormality of oesophagus, stomach or duodenum found in the critically ill or otherwise stressed patient. A wide range of mucosal lesions may be included, ranging from small petechial haemorrhages and erosions to deep ulceration and occasional perforation.

Aetiology

'Stress'

Evidence that environmental stress itself can lead to the development of peptic ulceration comes from a study of institutionalised and mentally-handicapped patients in 1985 (Ref.1)

Matched groups of patients were compared and it was found that those who developed peptic ulcers were more limited by chronic disease and ability to ambulate. It was concluded that helplessness in responding to environmental demands produced stress sufficient to induce peptic ulcers.

Environmental factors.

There is strong evidence that cigarette smoking, regular use of aspirin and prolonged use of steroids are associated with the development of peptic ulcer. (Ref.2)

There is some evidence that coffee and aspirin substitutes may affect ulcers, but most studies do not implicate alcohol, food or psychological stress as causes of ulcer disease. Genetic factors play a role in both gastric and duodenal ulcer.

Associated Diseases and Conditions.

It was recognised early that the chance of overt bleeding occurring increased with the increase in number of risk factors. In the Intensive Care setting, these risk factors included renal failure, peritonitis, hypotension, jaundice, major operative procedures and respiratory failure.

In addition, specific diseases, drugs and injuries have become associated with a high incidence of ulceration and bleeding:-

Patients with head injuries have a high incidence of acute lesions in stomach, duodenum and oesophagus. This includes "Cushing's Ulcer", which is seen classically in patients suffering from prolonged coma from any cause.

Stress ulcer is common in patients with burns to more than 35% of their body surface area. (Curling - 1842)

Often complicated by acute upper gastrointestinal haemorrhage and bleeding.

Severe sepsis is commonly associated with stress ulceration. This may take the form of gastric erosions or more severe bleeding, and may remain resistant to therapy until the sepsis is brought under control.

Aspirin, non-steroidal anti-inflammatory agents (especially those interfering with prostaglandins) and alcohol.

Up to 10% of the population has at one stage developed a chronic peptic ulcer.

Pathogenesis

Stress ulceration occurs in the presence of a breach of the 'mucosal barrier'. Although this structure is not completely understood, it serves as a valuable concept in understanding the pathogenesis of peptic ulcer disease.

There are three factors that seem more important than others:

    1. gastric acid and pepsin
    2. altered gastric blood flow
    3. increased mucosal permeability

gastric acid and pepsin

Stress ulceration will only occur in the presence of acid. It is known that if the gastric pH is kept above 7.0, stress ulceration does not occur. This is the basis for prophylactic treatment with antacids or H2-receptor antagonists.

It is important to recognise that the damage caused by hydrogen ions is probable more closely related to the way that the gastric mucosa deals with back-diffusing hydrogen ions than the gastric pH per se.

It appears that a critical amount of luminal acid and pepsin is needed for ulceration to develop, but this amount varies according to the patient and the underlying clinical condition.

altered gastric blood flow

The blood flow to the mucosa is obviously important to the normal functioning of defence mechanisms. like any organ system, if oxygen delivery is impaired, function suffers. Hypotension or any other cause of impaired oxygen delivery will affect gastric mucosal blood flow adversely. Interestingly, Cimetidine has been shown to increase gastric blood flow. ranitidine does not do this, however.

increased mucosal permeability

The integrity of the mucosal barrier is associated with the integrity of mucosal blood flow. In addition, it has been suggested that local factors, including prostaglandins, afford a degree of cytoprotection to the stomach independent of their ability to decrease gastric secretion. (Ref. 3)

Clinical Features and Diagnosis

The most reliable means of diagnosing stress ulceration is at endoscopy. This should be employed if significant malaena, 'coffee ground' aspirate or bright blood is seen. It is not justified in routine use. In early studies, up to 100% of critically ill patients were demonstrated to have endoscopically verifiable stress ulceration.

On the other hand, only about 25% of untreated lesions show clinical evidence of bleeding, and only about 5% of these require active resuscitation and treatment.

Guaiac and Hemoccult tests are mentioned only to point out their unreliability.

Radionucleotide studies and angiography may prove necessary and useful in those patients presenting with more obscure causes of bleeding into the gut, particularly in the conditions of haematobilia and pseudoaneurysm.

Management.

Depends on the severity of the condition. The management of upper gastrointestinal haemorrhage is well covered in standard texts. The cause must be determined as soon as practicable, but the blood loss must be replaced at a rate to account for ongoing losses.

If active bleeding is present:

Review any precipitating factors and deal appropriately

Prevention.

Treat the underlying cause, and limit the effect of risk factors.
Treat renal failure, sepsis, hepatic failure, respiratory failure. Avoid the use of Prostaglandin inhibitors, aspirin and non-steroidal anti-inflammatory agents. Limit the use of steroids to short bursts. Avoid hypotension, anaemia, hypoxaemia.

Start Enteral feeding as soon as possible.
Enteral feeding has been shown to significantly reduce the incidence of gastrointestinal bleeding, although neither intragastric nor intraduodenal feeding adequately neutralises gastric acidity in critically ill patients. (Ref. 4)

Drug prophylaxis
There has been considerable controversy over the effectiveness of drug prophylaxis, such that many people remain to be convinced of the necessity of drug prophylaxis. In one early prospective clinical trial, however, 25% of untreated patients bled.

In a recent randomised, placebo-controlled, double-blind study in which serial endoscopy was used to examine patients without clinical evidence of bleeding who were admitted to a medical intensive care unit, it was found that patients treated with Cimetidine had a significantly greater chance of having normal or improved gastroduodenal mucosa compared with those treated with a placebo.

In addition, endoscopic signs of bleeding cleared or did not develop in significantly more patients treated with Cimetidine than those treated with a placebo.

Significantly fewer blood transfusions were given to those patients with endoscopic signs of bleeding in the Cimetidine group than in the placebo group.

The mortality rate was not statistically different between the groups.

The conclusion reached was that although the mortality was not altered, the use of pH control with Cimetidine was able to prevent established gastroduodenal stress lesions from progressing in severity, thereby decreasing both bleeding and the need for blood transfusions. (Ref. 5)

Antacids Vs Histamine 2 antagonists.
This is probably a non-issue. The important point appears to be adequate pH control, by whatever mechanism is used. Neither Histamine antagonists nor antacids appear to be able to adequately control gastric pH completely in all patients when used alone. Enteral feeds all have a high pH, and their ability to protect against stress ulcers may be a function of their ability to alter gastric pH.

Choosing between antacids and H2 antagonists.
This is a function of relative risks and benefits. it is left as an exercise for the reader to outline the relative risks and benefits of both groups of agents. it is worth remembering that the effects of Cimetidine and Ranitidine on the liver appear to be unique to each compound, and related to the structure of the drug molecule. This explains their relative differences on cytochrome P-450

Pirenzapine

A relatively new anti-muscarinic drug with anticholinergic effects.

It appears useful when used in conjunction with ranitidine, but is ineffective in stress ulcer prophylaxis when used alone.

Substituted benzimidazoles - e.g. omeprazole

These substances inhibit the Potassium/Hydrogen - dependent ATPase enzyme at the secretory membrane of the parietal cell. The selective and potent effect on acid production may make this and related agents the drug(s) of choice in the future. Unfortunately, there will almost certainly be a new crop of unwanted effects accompanying their use.

Sucralfate and Bismuth compounds

May be useful in established cases of stress ulceration. Sucralfate is said to selectively adhere to damaged mucosa.

Prostaglandins

Prostaglandins are particularly important as potent antisecretory and effective antiulcer agents. Animal studies have shown that prostaglandins at non-antisecretory doses prevent the development of gastric ulcers caused by virtually any insult. (Ref. 6)

Several prostaglandins have been shown to exert five major gastrointestinal functions:

Some protect against aspirin-induced bleeding

Secretin

neutralises acidity in the duodenum by stimulating bicarbonate production from the pancreas, inhibiting acid secretion and reducing gastrin. Not very effective.

Measurement of gastric pH

Because prophylaxis is directed toward elevating gastric pH, and gastric pH varies so much, both in the one patient over time, and between patients, it is essential to carry out reliable and frequent measurements of pH of gastric juice. It is also important to note that the introduction of enteral feeding does not necessarily guarantee that gastric pH will be at the appropriate level.

A suitable compromise is to check gastric pH before the next dose of Cimetidine or Ranitidine is given. Should the pH be below a suitable cut-off point (say 4 - 5 pH units), the dose should be increased, or the time interval between doses reduced.

References

1) Inability to cope with environmental stress: peptic ulcers in mentally retarded persons. Chaney RH;Eyman RK; Givens CA; Valdes CD. J. Psychosom Res. 1985;29 (5):519-24

2) Epidemiology of peptic ulcer disease. Kurata JH; Haile BM Clin Gastroenterol 1984 May;13(2):289- 307

3) Prostaglandins: effects on the gastrointestinal tract. Robert A Clin Physiol Biochem 1984;2(2-3):61-9

4) Does nasoenteral feeding afford adequate gastroduodenal stress prophylaxis? Valentine RJ; Turner WW Jr; Borman KR; Weigelt JA Crit Care Med 1986 Jul;14(7):599-601

5) Cimetidine for prevention and treatment of gastroduodenal mucosal lesions in patients in an intensive care unit. Peura DA; Johnson LF; Annals of Internal Medicine August 1985;103:173-177

6) Therapeutic aspects of prostaglandins in the treatment of peptic ulcer disease. Wilson DE Dig Dis Sci 1986 Feb;31(2 Suppl):42s-46s

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Allan Palmer
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