Stress ulcer prophylaxis

Introduction

Stress ulcer is a superficial lesion of mucosal layer of the stomach after traumatic event; can develop into deeper lesion with significant gastroduodenal bleeding (may occur within first 24hr of ICU admission). See "algorithm of pathophysiology of stress ulcer".

Figure (1)

Pathophysiology of stress ulcer.

NPS-adv

Etiology

Decrease mucosal blood flow then ischemia then acid hypersecretion; due to excessive gastrin stimulation of parietal cells and alteration of normal protective mechanisms (epithelial turnover in gastric mucosa, change in mucus and bicarbonate secretion). Frequency of clinically important bleeding: 1–5%.

Table (1). Risk factors for stress ulcers
Treatment regimen
Respiratory failure (defined by mechanical ventilation > 48hr) Coagulopathy (INR > 1.5 or platelets < 50) General (medical, surgical, respiratory) ICU populations Head injury (GCS ≤ 10) or inability to obey commands Thermal injury > 35% BSA Hypotension Severe sepsis Partial hepatectomy Hepatic or renal transplantation Multiple trauma with injury severity score of ≥ 16 Spinal cord injury Hepatic failure History of gastric ulceration or bleeding during year before admission Presence of at least 2 of the following: sepsis, ICU stay > 1 wk, occult or overt bleeding for ≥ 6 days, corticosteroid therapy (> 250 mg hydrocortisone or equivalent daily)
Important Note Risk of bleeding in the absence of these risk factors: < 0.1% Risk of bleeding increases with ↑ number of risk factors present

NPS-adv

Treatment and follow-up

Pharmacological treatment

Treatment Goal is to prevent clinically significant bleeding (hemodynamic compromise or need for blood transfusion). No clear preference of using the H2-receptor antagonists (H2RA) or Proton pump inhibitors (PPI). PPIs weakly preferred over H2-blockers by Danish stress ulcer prophylaxis (SUP) guidelines based on low quality evidence. H2-blockers may be more cost-effective than PPIs.

H2-receptor antagonists (H2RA) include famotidine, ranitidine, nizatidine and cimetidine. Famotidine can be prescribed by dose 20 mg IV/PO/NG every 12 hr OR ranitidine 50 mg IV every 8 hr or 150 mg PO/NG every 12 hr. Halve the dose or double the dosing interval for CrCl < 50 mL/min. Recently, Food and Drug Administration (FDA) REMOVED all ranitidine products from the market. For further information, see note "Pharmacology of H2-receptor antagonists (H2RA). H2-receptor antagonists inhibit gastric acid secretion by antagonizing the histamine-2 receptor on parietal cells; may have immunomodulatory effects. Dose-limiting side effects include CNS toxicity (confusion, agitation, seizures), thrombocytopenia and increase risk of C. difficile diarrhea (↓ risk vs PPIs). Using of H2-receptor antagonists may develop tolerance with prolonged use.

Proton pump inhibitors (PPI) include esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole. PPI inhibit proton pump in parietal cell, the final step in gastric acid production. The available parentral PPIs in Egypt are esomeprazole (Nexium 40 mg) and pantoprazole (Controloc 40 mg). Esomeprazole dose 20 to 40 mg IV/PO every 24 hr. Pantoprazole is used by dose 40 mg IV/PO/NG every 24 hr. Dose-limiting side effects of PPIs include thrombocytopenia, ↑ risk of C. difficile diarrhea, ↑ rate of Ventilator acquired pneumonia and community acquired pneumonia. PPIs decrease effectiveness of clopidogrel and also decrease atazanavir concentrations. For further information, see note "Pharmacology of Proton pump inhibitors (PPI)".

Sucralfate, this agent becomes polar at acidic pH and binds to granulation tissue of ulcer to form a protective layer on gastric mucosa; also stimulates prostaglandin production, modulates pepsin, mucus activity, arachidonic acid metabolism, bicarbonate secretion, tissue growth and repair; does not increase gastric pH. Sucralfate may increase serum aluminum concentrations in elderly, renal insufficiency; may contribute to esophageal and GI bezoar formation; binds phosphate in gut and may lead to hypophosphatemia. Sucralfate must be separated by at least 2 hr from other oral drugs; do NOT administer through a duodenal or jejunal tube (will miss site of action).

Antacids (neutralize acid) may cause some adverse effects like electrolyte accumulation (hypermagnesemia, hypophosphatemia), constipation, diarrhea, NG tube obstruction; ↑ aspiration pneumonia. Monitoring K, Mg, Phosphate, Ca. Antacids may bind with fluoroquinolones, tetracyclines; must separate administration. Must be administered every 1–2 hr so NOT routinely used.

Misoprostol is a synthetic prostaglandin analog; antisecretory, cytoprotective. Dose-limiting side effects incude diarrhea, nausea, abdominal pain and pregnancy category X. Side effects with no efficacy data of misoprostol = NOT routinely used.

Non-pharmacological treatment

Enteral nutrition to maintains structural, functional integrity of mucosa. Efficacy (prevention of clinically significant bleeding) of PPIs = H2RAs > sucralfate, antacids, misoprostol. See additional note "Peptic ulcer, assessment and management".

Important Note

Summary of important adverse effects

• Nosocomial pneumonia incidence: PPIs > H2RAs > antacids
• Clostridium difficile associated diarrhea (CDAD): ↑ risk with PPIs > H2RAs.
• Thrombocytopenia: H2RAs > PPIs

When should SUP be stopped? Discontinue stress ulcer prophylaxis as soon as the patient’s risk factors are resolved. Stress ulcer prophylaxis discontinuation may be considered for mechanically ventilated patients without other risk factors who are tolerating enteral nutrition. Ensure that stress ulcer prophylaxis is stopped when patients are transferred out of ICU. Consider requiring an indication for H2-blocker and PPI orders to help target unnecessary use. Assess appropriateness of H2-blocker and PPI order continuation before hospital discharge.

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References

1. Stollman, N. and Metz, D.C. (2005). Pathophysiology and prophylaxis of stress ulcer in intensive care unit patients. Journal of Critical Care, 20(1), pp.35–45.
2. American Society of Health-System Pharmacists. ASHP therapeutic guidelines on stress ulcer prophylaxis. ASHP Commission on Therapeutics and approved by the ASHP Board of Directors on November 14, 1998. Available at: Am J Health Syst Pharm 1999;56:347-79.
3. ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis. (1999). American Journal of Health-System Pharmacy, 56(4), pp.347–379.
4. Dial, S. (2005). Use of gastric acid–suppressive agents and the risk of community-acquired Clostridium difficile associated disease. JAMA, 294(23), p.2989.
5. Cook D, Guyatt G. Prophylaxis against Upper Gastrointestinal Bleeding in Hospitalized Patients. N Engl J Med. 2018 Jun 28;378(26):2506-2516.

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