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Stress ulcer prophylaxis in the intensive care unit
Gerald L Weinhouse, MD
Scott Manaker, MD, PhD
Geraldine Finlay, MD
All topics are updated as new evidence becomes available and our peer review process is
Literature review current through: Jun 2013. | This topic last updated: Jun 6, 2013.
INTRODUCTION — 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 .
The epidemiology, pathophysiology, risk factors, and prognosis of stress ulceration in the
intensive care unit (ICU) are discussed in this topic review. In addition, stress ulcer prophylaxis
is reviewed. Diagnosis and treatment of bleeding peptic ulcers are discussed separately. (See
"Approach to acute upper gastrointestinal bleeding in adults" and "Overview of the treatment of
bleeding peptic ulcers".)
Epidemiology — Estimates of the incidence of overt GI bleeding range from 1.5 to 8.5 percent
among all ICU patients, but may be as high as 15 percent among patients who do not receive
stress ulcer prophylaxis [2-5]. Most episodes of overt GI bleeding in critically ill patients are due
to gastric or esophageal ulceration, as determined by endoscopic studies [2,5]. Stress ulceration
can also cause perforation. However, this complication is rare, occurring in fewer than 1 percent
of surgical ICU patients .
Pathophysiology — Stress ulceration generally begins in the proximal regions of the stomach
within hours of major trauma or serious illness. Endoscopy performed within 72 hours of a major
burn or cranial trauma reveals acute mucosal abnormalities in greater than 75 percent of patients
. Up to 50 percent of such lesions have endoscopic evidence of recent or ongoing bleeding,
although only a small percentage of patients experience hemodynamic compromise due to acute
blood loss . Stress ulcerations that develop after the first several days of hospitalization tend to be deeper and more distal . In a study of 67 patients with GI bleeding that occurred an average of 14 days after admission, duodenal ulceration was the most common source of bleeding . It is uncertain if early and late stress ulcerations have the same pathophysiology. However, both types probably result from an imbalance between mucosal protection and gastric acid production. Impaired mucosal protection – The stomach is normally protected by a glycoprotein mucous layer that forms a physical barrier to hydrogen ion diffusion and traps bicarbonate. The bicarbonate neutralizes gastric acid adjacent to the stomach wall. This barrier may be denuded by increased concentrations of refluxed bile salts or uremic toxins, which are common in critically ill patients [10,11]. In addition, its synthesis may be decreased when there is poor gut perfusion caused by shock, sepsis, or trauma [12,13]. Hypersecretion of acid – Hypersecretion of acid due to excessive gastrin stimulation of parietal cells has been detected in patients with head trauma [14-16]. This abnormality is probably not a factor in all ICU patients, since acid secretion tends to be normal or subnormal in most other patients. H. pylori infection may also contribute to stress ulceration, but the evidence is of limited quality. A case-control study of 50 ICU patients found that patients with GI bleeding were more likely to have H. pylori infection than patients without acute GI bleeding (36 versus 16 percent) . Conversely, another observational study of 99 ICU patients found that patients with H. pylori infection were more likely to have GI bleeding than patients without H. pylori infection (23 versus 13 percent), although the difference did not reach statistical significance . Risk factors — A multicenter prospective cohort study of 2252 ICU patients identified two major risk factors for clinically important GI bleeding (defined as overt GI bleeding leading to hemodynamic deterioration or requiring blood transfusion) due to stress ulceration : Mechanical ventilation for more than 48 hours (odds ratio 15.6) Coagulopathy (odds ratio 4.3) The incidence of clinically important GI bleeding among patients with one or both of these risk factors was 3.7 percent, compared to 0.1 percent among patients with neither risk factor. Smaller studies have reported additional risk factors for stress ulceration, including shock, sepsis, hepatic failure, renal failure, multiple trauma, burns over 35 percent of total body surface area, organ transplantation, head trauma, spinal trauma, a history of peptic ulcer disease, and a history of upper GI bleeding [1,4,19-21]. Glucocorticoid therapy is commonly cited as an indication for stress ulcer prophylaxis . However, glucocorticoid therapy alone has not been conclusively shown to be a risk factor for stress ulceration . Glucocorticoid therapy may increase the risk of stress ulceration when combined with other risk factors for GI ulceration, such as nonsteroidal antiinflammatory drugs or aspirin. (See "Major side effects of systemic glucocorticoids", section on 'Gastrointestinal tract'.) Prognosis — Overt GI bleeding due to stress ulceration is associated with increased mortality. In the prospective cohort study described above, mortality was higher among ICU patients with clinically important GI bleeding than among those without bleeding (49 versus 9 percent) . Another study used four different statistical models to adjust for confounders and found that overt GI bleeding was associated with increased mortality using three of the models (relative risk ranged from 1.8 to 4.9) . PROPHYLAXIS Indications — 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 [23,24]. 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 [26- 28]: 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: sepsis, 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. Pharmacologic agents H2 blockers – Histamine-2 receptor antagonists (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 [31,32]. 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. (See "Pharmacology of antiulcer medications", section on 'H2 receptor antagonists'.) 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. (See "Pharmacology of antiulcer medications", section on 'Proton pump inhibitors' and "Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders", section on 'Safety'.) 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 [33,34]. 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 . (See "Pharmacology of antiulcer medications", section on 'Sucralfate' and "Pharmacology of antiulcer medications", section on 'Aluminum toxicity'.) 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. (See "Causes and treatment of hypermagnesemia", section on 'Oral ingestion' and "Etiology of hypercalcemia", section on 'Milk alkali syndrome' and "Causes of hypophosphatemia", section on 'Antacids containing aluminum or magnesium' and "Pharmacology of antiulcer medications", section on 'antacids'.) 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 [36,37]. 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 [7,19]. (See "Pharmacology of antiulcer medications", section on 'Prostaglandins'.) Efficacy — Clinical trials have demonstrated that H2 blockers, PPIs, and antacids reduce the frequency of overt GI bleeding in ICU patients compared to placebo or no prophylaxis [4,38-42]. 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 13 randomized trials (1587 patients) compared stress ulcer prophylaxis with a PPI to prophylaxis with an H2 blocker . It found less GI bleeding among those who received a PPI (1.3 versus 6.6 percent, odds ratio 0.30, 95% CI 0.17-0.54). There was no difference in mortality or the incidence of nosocomial pneumonia. 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. Potential harms — 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) [38,44-47]. 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 [46,49-52]. Choosing an agent — For ICU patients who are able to receive enteral medications and in whom stress ulcer prophylaxis is indicated, we recommend an oral PPI rather than an alternative prophylactic agent. In contrast, for those who cannot receive enteral medications, we suggest an intravenous H2 blocker rather than an intravenous proton pump inhibitor. Our rationale is that intravenous H2 blockers are substantially less expensive than intravenous PPIs and the lower cost probably outweighs the modest increase in efficacy, especially since the baseline risk of stress ulcer-related gastrointestinal bleeding is low. In situations where cost is not an issue, an intravenous PPI is an appropriate choice. It is important to reiterate and emphasize that this discussion is about prophylaxis; active gastrointestinal bleeding requires a different approach. (See "Approach to acute upper gastrointestinal bleeding in adults", section on 'Medications'.) 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. We believe the prophylactic agent should be chosen on the basis of the more definitive evidence - impact on overt GI bleeding - until the relationship between the type of prophylactic agent and the incidence of nosocomial pneumonia is confirmed by more rigorous clinical trials. For this reason, we typically use H2 blockers or PPIs for stress ulcer prophylaxis in our clinical practice. 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. Such prophylaxis is unnecessary because the reduction in the rate of nosocomial gastrointestinal bleeding among non-critically ill patients is minuscule due to the low baseline risk (prophylaxis decreases the rate of gastrointestinal bleeding from 0.33 to 0.22 percent) . Despite this, several studies have demonstrated a high rate of ongoing stress ulcer prophylaxis among patients who are discharged from the ICU [56,57]. SUMMARY AND RECOMMENDATIONS 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, perforation, or both. (See 'Introduction' above.) Histamine-2 receptor antagonists (H2 blockers), proton pump inhibitors (PPI), and antacids reduce overt GI bleeding in ICU patients compared to placebo or no prophylaxis. (See 'Efficacy' above.) Prophylactic agents that increase gastric pH (PPI, H2 blockers, antacids) might increase the frequency of nosocomial pneumonia, compared to prophylactic agents that do not alter gastric pH (sucralfate). (See 'Potential harms' above.) Stress ulcer prophylaxis is indicated for any critically ill patient who has one or more of the following risk factors: mechanically ventilated for more than 48 hours, coagulopathy, GI ulceration or bleeding within the past year, traumatic brain injury, traumatic spinal cord injury, severe burns, or two or more minor risk factors. Coagulopathy is 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. Severe burns are defined as >35 percent of the body surface area. Minor risk factors include sepsis, ICU admission lasting >1 week, occult GI bleeding lasting ≥6 days, or high-dose glucocorticoid therapy (more than 250 mg hydrocortisone or the equivalent). (See 'Indications' above.) Stress ulcer prophylaxis should be considered on a case-by-case basis for patients without any of the above risk factors. Considerations include 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. (See 'Indications' above.) For ICU patients who are able to receive enteral medications and in whom stress ulcer prophylaxis is indicated, we recommend an oral PPI rather than an alternative prophylactic agent (Grade 1B). (See 'Choosing an agent' above.) For ICU patients who cannot receive enteral medications and in whom stress ulcer prophylaxis is indicated, we suggest an intravenous H2 blocker rather than an intravenous proton pump inhibitor (Grade 2B). Intravenous H2 blockers are usually much less expensive than intravenous PPIs and the lower cost probably outweighs the modest increase in efficacy, especially since the baseline risk of stress ulcer-related gastrointestinal bleeding is low. In situations where cost is not an issue, an intravenous PPI is a reasonable choice. (See 'Choosing an agent' above.) Use of UpToDate is subject to the Subscription and License Agreement.
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LEEDS METROPOLITAN UNIVERSITY FACULTY OF HEALTH (STUDENT SUPPORT OFFICE D803) COURSE: Notes to Candidates: Answer ALL questions in Section A (contributes 50% of total mark) Answer ONE question in Section B (contributes 50% of total mark) Use separate answer books for Sections A and B You may consult your Practical Portfolio for Section B only after handing in your Section A SEC