Stress ulcerations usually occur in the fundus and body of the stomach, but sometimes develop in the antrum, duodenum, or distal esophagus. They tend to be shallow and cause oozing of blood from superficial capillary beds. Deeper lesions may also occur, which can erode into the submucosa and cause massive hemorrhage or perforation.
Clinical trials have demonstrated that histamine-2 receptor antagonists (H2 blockers), proton pump inhibitors (PPIs), and antacids reduce the frequency of overt GI bleeding in ICU patients compared to placebo or no prophylaxis. Comparative trials have also been performed; despite this, the body of evidence is relatively poor because many of the studies were imprecise or had other significant methodologic flaws. This section describes the moderate to high quality comparative evidence:
- H2 blockers versus PPI — A meta-analysis of seven randomized trials (936 patients) compared stress ulcer prophylaxis with a PPI to prophylaxis with an H2 blocker. It found a trend toward less GI bleeding among those who received a PPI (absolute risk reduction [ARR] 4 percent, 95% CI -1 to 9 percent). The magnitude of effect was smaller after an outlying trial was excluded (ARR 2 percent, 95% CI -1 to 5 percent). This suggests that PPIs might be more effective than H2 blockers, but the difference is small, if real.
- H2 blockers versus antacids — A meta-analysis that compared H2 blockers to antacids in critically ill patients found that the H2 blocker group had a significantly lower rate of overt GI bleeding (odds ratio 0.56, 95% CI, 0.33-0.97).
- H2 blockers versus sucralfate — A trial randomly assigned 1200 mechanically ventilated patients to receive sucralfate suspension via nasogastric tube plus an intravenous placebo, or an H2 blocker (intravenous ranitidine) plus a placebo suspension via nasogastric tube. The H2 blocker decreased overt GI bleeding compared to sucralfate (1.7 versus 3.8 percent).
- Sucralfate versus antacids — A meta-analysis that compared sucralfate to antacids in ICU patients found that the antacids group had a lower rate of clinically important GI bleeding, but the difference was not statistically significant.
- Other comparisons — There are a lack of moderate or high quality trials comparing PPIs to sucralfate, PPIs to antacids, sucralfate to placebo in critically ill patients.
Randomized trials and meta-analyses suggest that prophylactic agents that increase gastric pH (eg, PPIs, H2 blockers, and antacids) may increase the frequency of nosocomial pneumonia compared to agents that do not alter gastric pH (eg, sucralfate). As an example, a trial that randomly assigned 1200 mechanically ventilated patients to receive either an intravenous H2 blocker (ranitidine) or sucralfate found that ventilator-associated pneumonia was more frequent in the H2 blocker group, although the difference was not statistically significant (19 versus 16 percent, RR 1.18, 95% CI 0.92-1.51).
The clinical importance of the evidence that certain prophylactic agents may increase the incidence of nosocomial pneumonia is uncertain because many of the studies did not achieve statistical significance. However, the direction of the effect was the same in most of the studies, indicating that insufficient sample size may be the reason that the results were not statistically significant.
The impact of different prophylactic agents on the incidence of nosocomial pneumonia may be variable. This was suggested by an observational study in cardiothoracic surgery patients that found a higher incidence of nosocomial pneumonia among patients who received a PPI than among those who received an H2 blocker, as well as a randomized trial that found a higher risk of nosocomial pneumonia among mechanically ventilated patients who received an H2 blocker than among those who received an antacid.
A potential mechanism for prophylaxis-related nosocomial pneumonia has been proposed. Agents that raise gastric pH promote the growth of bacteria in the stomach, particularly gram-negative bacilli that originate in the duodenum. Esophageal reflux and aspiration of gastric contents along the endotracheal tube may then lead to endobronchial colonization or pneumonia.
It is widely accepted that prophylaxis is indicated for ICU patients who are at high risk for stress ulceration, although there is disagreement about which clinical characteristics define high risk.
The American Society of Health System Pharmacists developed clinical practice guidelines based upon studies that compared prophylaxis to no prophylaxis and used clinically important GI bleeding as an endpoint. The guidelines recommend stress ulcer prophylaxis for ICU patients with any of the following characteristics: coagulopathy, mechanical ventilation for more than 48 hours, history of GI ulceration or bleeding with the past year, and two or more minor risk factors. Minor risk factors included sepsis, ICU admission lasting >1 week, occult GI bleeding lasting ≥6 days, and glucocorticoid therapy.
Many clinicians also provide stress ulcer prophylaxis to patients with traumatic brain injury, traumatic spinal cord injury, or thermal injury (>35 percent of the body surface area). Their rationale is that such patients have been routinely excluded from studies of stress ulcer prophylaxis because of a presumed high risk of stress ulceration.
It is frequently asked whether a patient who is receiving enteral nutrition also requires pharmacological stress ulcer prophylaxis. This question is based upon reports that enteral nutrition alone may reduce the risk of overt GI bleeding due to stress ulceration and that stress ulcer prophylaxis may be ineffective or harmful among patients who are receiving enteral nutrition:
- Enteral nutrition alone may reduce the risk of overt GI bleeding due to stress ulceration: In one observational study performed using data from a randomized trial, enteral nutrition independently reduced overt GI bleeding (relative risk 0.30, 95% CI, 0.13-0.67) in 1077 critically ill patients who were mechanically ventilated for more than 48 hours. Another observational study of 526 patients in a burn intensive care unit found that the incidence of overt GI bleeding was lower among patients who received early enteral nutrition alone than among patients who received an H2 blocker without early enteral nutrition (3 versus 8 percent). While these observational data suggest that enteral nutrition may be an adequate substitute for pharmacologic stress ulcer prophylaxis in ICU patients, controlled clinical trials are necessary for confirmation.
- Pharmacological stress ulcer prophylaxis may be ineffective or harmful among patients who are receiving enteral nutrition: A quantitative systematic review of randomized trials comparing H2 blockers to placebo for the prevention of stress ulceration found that the effect of the H2 blockers varied according to whether the patients were receiving early enteral nutrition. Among patients not receiving early enteral nutrition, H2 blockers reduced the incidence of GI bleeding and had no significant effect on mortality or the rate of hospital-acquired pneumonia. Among patients receiving early enteral nutrition, however, H2 blockers increased mortality and the incidence of hospital-acquired pneumonia, without reducing the rate of GI bleeding. This systematic review had several important limitations. Among the limitations, it included both patients who are at high risk and low risk for stress ulceration. Thus, it is possible that the harmful effects of prophylaxis seen among patients receiving enteral nutrition were due to unnecessary prophylaxis in low risk patients, rather than a more general harmful effect among all patients.
While such reports are thought provoking and warrant further study, we believe that the evidence is insufficient to justify withholding stress ulcer prophylaxis from patients who are at high risk for gastrointestinal bleeding even if they are receiving enteral nutrition. Putting the evidence together, we suggest that stress ulcer prophylaxis be administered to all critically ill patients who are at high risk for gastrointestinal bleeding. This includes patients with any of the following characteristics:
- Coagulopathy, defined as a platelet count <50,000 per m3, an International Normalized Ratio (INR) >1.5, or a partial thromboplastin time (PTT) >2 times the control value.
- Mechanical ventilation for >48 hours.
- History of GI ulceration or bleeding within the past year.
- Traumatic brain injury, traumatic spinal cord injury, or burn injury.
- Two or more of the following:
- an ICU stay >1 week,
- occult GI bleeding for ≥6 days,
- or glucocorticoid therapy (more than 250 mg hydrocortisone or the equivalent).
Among patients who are not considered high risk for gastrointestinal bleeding, we believe that stress ulcer prophylaxis should be administered on a case-by-case basis. Among the considerations are whether the patient is receiving enteral nutrition, how long the patient is expected to be without enteral nutrition, the severity of the patient’s illness, and the patient’s comorbidities.
- H2 blockers — H2 blockers antagonize the H2 receptors on the parietal cell, resulting in diminished gastric acid secretion. They can be given orally, via nasogastric tube, or intravenously. The dose depends on which H2 blocker is used (cimetidine, ranitidine, famotidine, nizatidine). Continuous intravenous infusion is more effective than bolus intravenous infusion at controlling gastric pH. However, there is no moderate or high quality data indicating that it is more effective at preventive clinically significant GI bleeding. H2 blockers are generally well tolerated, but a number of uncommon side effects have been reported.
- Proton pump inhibitors — Proton pump inhibitors (PPIs) block acid secretion by irreversibly binding to and inhibiting the hydrogen-potassium ATPase pump that resides on the luminal surface of the parietal cell membrane. They can be given orally, via nasogastric tube, or intravenously. The dose depends on which PPI is used (omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole). PPIs are an extremely safe class of drugs, although some risks have been described.
- Sucralfate — Sucralfate is a sulfated polysaccharide complexed with aluminum hydroxide. It exerts its effects by coating and protecting the gastric mucosa, without altering gastric acid secretion or significantly buffering acid. Sucralfate is administered orally or via nasogastric tube at a dose of 1 gram four times per day. It is generally well tolerated, except for infrequent aluminum toxicity. In a prospective cohort study of 11 mechanically ventilated patients who received sucralfate (6 grams per day) for 14 days, none of the patients developed an elevated plasma aluminum concentration, even in the presence of renal impairment.
- Antacids — Antacids neutralize gastric acid and protect the gastric mucosa. Antacids are generally administered every one to two hours at a dose of 30 to 60 mL either orally or via nasogastric tube. Nasogastric tube obstruction can be problematic. Side effects of antacids include hypermagnesemia, hypercalcemia, hypophosphatemia, constipation, and diarrhea. (
- Prostanoids — Prostanoids (ie, prostaglandin analogs), such as misoprostol, inhibit gastric acid secretion by selectively reducing the ability of the parietal cell to generate cyclic AMP in response to histamine. They also exert a cytoprotective effect by enhancing mucosal defense mechanisms. As an example, prostanoid-induced capillary bed vasodilation may protect against local ischemia. Prostanoids are not commonly used for stress ulcer prophylaxis in ICU patients because there are a paucity of data regarding their impact on clinically important outcomes and they have a propensity to cause diarrhea.
Choosing an agent
The major factors on which a prophylactic agent is chosen are the balance between efficacy and potential harm, as well as cost.
- Efficacy versus potential harm — The evidence indicates that those prophylactic agents that reduce the frequency of overt GI bleeding in ICU patients most effectively (H2 blockers and PPIs) might be associated with more frequent nosocomial pneumonia. In contrast, a less effective prophylactic agent (sucralfate) may be associated with fewer nosocomial pneumonias. Thus, clinicians need to consider the following when choosing a prophylactic agent: whether prevention of overt GI bleeding or minimizing the incidence of nosocomial pneumonia is of greater clinical importance and the strength of the nosocomial pneumonia data.
- Cost — Choosing less expensive prophylactic agents or administering prophylaxis only to patients who are at high risk for stress ulceration can diminish the cost of stress ulcer prophylaxis:
- Choosing less expensive prophylactic agents - One analysis found that prophylaxis with oral PPI may be more cost-effective than intravenous H2 blockers. This was a consequence of the lower cost of oral medications and fewer treatment failures in the oral PPI group.
- Administering prophylaxis only to patients who are at high risk for stress ulceration - It is estimated that only 30 patients who are at high risk for stress ulceration need to receive prophylaxis to prevent one GI bleed, compared to nearly 900 low risk patients. This approach has the added advantage of decreasing the risk of adverse effects related to stress ulcer prophylaxis.
In addition, remembering to discontinue prophylaxis when the patient is no longer at high risk for stress ulceration can reduce the cost of stress ulcer prophylaxis. Several studies have demonstrated a high rate of ongoing and inappropriate stress ulcer prophylaxis among patients who are discharged from the ICU and no longer at increased risk for stress ulceration.