Introduction
The yearly incidence rate of UGIB in the United States is estimated to be 160 cases per 100,000 people.1 Data published since 1997 indicate that advances in management have led to a gradual decline in mortality in patients with UGIB or upper GI perforation, but that the mortality rate is about 7.69% (1 in 13) overall and 20% (1 in 5) in individuals who have taken nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin.2 These rates are due to the fact that patients are older and present with more comorbidities, as well as to the underuse of endoscopic hemostatic techniques.3
Etiology
In many cases (50%-79%), UGIB is caused by peptic ulcer, followed by esophageal varices; Mallory-Weiss syndrome or tear (occurs in patients with chronic vomiting, especially alcoholics); gastroduodenal erosion (from medications or stress); renal or hepatic failure; prior GI bleeding or ulcers; and erosive esophagitis (rare).4-9 TABLE 1 lists substances that can cause peptic ulcers.9-17
The use of NSAIDs increases the risk of ulcer complications by a factor of 4.11 The risk is dose dependent and is greater when different NSAIDs are taken simultaneously. GI bleeding varies by type of NSAID and dosage, with slow-release formulations being the most likely to damage the mucosal lining.11 Whenever possible, NSAIDs should be given as monotherapy and at the lowest effective dose to reduce the risk of upper GI complications.11 Dental services in hospitals routinely prescribe oral NSAIDs to patients after dental surgical procedures.12 Hemodialysis patients have nearly three times the risk of GI bleeding than patients not taking NSAIDs.13,14 Parenteral NSAIDs (e.g., ketorolac) that are used for postsurgical pain management carry a serious risk of GI bleeding, so their use is limited to 5 days.15 This risk increases significantly in the elderly and in patients with previous GI bleeding or perforation.15
Even when low-dose aspirin is used for cardiac prophylaxis, the risk of developing UGIB increases two to three times.16 Prolonged dual-antiplatelet therapy with aspirin and clopidogrel is mandatory after drug-eluting stent implantation because of the potential increased risk of late stent thrombosis.17
No evidence of an increase in risk of UGIB with bisphosphonates has been reported. The combination of NSAIDs and bisphosphonates increased the risk, but this risk was not higher than when NSAIDs were used alone.18 If oral bisphosphonates are administered properly, there is little to no increased risk of GI bleeding.18
Guidelines for Management
Initial Clinical Assessment: The initial evaluation of patients with UGIB involves recognition of a range of symptoms depending on the source, rate, and volume of blood loss.8 Especially in the elderly, medical comorbidities and the use of antiplatelet medications can complicate the severity and management of the bleeding.19 Symptoms of UGIB include anemia, hematemesis (vomiting bright red blood or “coffee ground” material), and melena. Other symptoms may include epigastric pain, dyspnea, and syncope (from volume depletion). Bleeding may be obscure when the GI blood loss is of unknown origin.
Certain prognostic factors in patients who present with UGIB can increase the incidence of complications, including morbidity and mortality. The patient should be admitted to the ICU if one or more of the following prognostic factors is present: age greater than 60 years; shock; comorbidities (e.g., cardiac, renal, hepatic disease); current bleeding; low systolic blood pressure; need for more than 6 units of blood; and endoscopy showing major stigmata of bleeding.20
Risk Stratification: Approximately 80% of UGIB patients will stop bleeding spontaneously without recurrence; the remaining 20% will continue to bleed or have a rebleeding episode.21 Rebleeding is associated with an increased mortality rate, greater need for surgery and blood transfusions, prolonged hospital stay, and higher medical costs.22 Therefore, for proper management using clinical, laboratory, and endoscopic findings, it is essential to promptly determine whether a patient is at low or high risk for continued bleeding or rebleeding.
Before endoscopy is performed, use of the Rockall risk scoring system is recommended. This assessment tool, which predicts the patient's outcome and estimates rebleeding risk, is the most widely used scoring system and has been validated by several studies.23,24 The patient's age, systolic blood pressure, and pulse rate and the presence of comorbidities are used for scoring.23 Patients with a score of 0 should be considered for nonadmission or early discharge with outpatient follow-up; if the score is above 0, there is a significant risk of mortality, and endoscopy is recommended for a full assessment of bleeding risk.23
Patients with bleeding ulcers also should be tested for the presence of Helicobacter pylori, which survives in the acidic pH of the stomach.20
Patient Management
Once the patient is admitted, the first step in diagnosis is to obtain a medical history and perform a physical examination, including CBC, in order to identify risk factors and determine the quantity of blood lost.22 Resuscitation depends on the patient's health status and the intensity of the bleeding.25 Immediate evaluation and appropriate resuscitation are critical to proper management before endoscopy. Because of the blood loss, it is important to evaluate cardiac hemodynamic status by measuring the heart rate and blood pressure. Transfusion of red cells is required after 30% to 40% of the circulation volume is lost.7
Risk Stratification: After initial resuscitation, urgent endoscopy is performed. Endoscopy is the standard of care in the diagnosis and treatment of UGIB.3 Its functions are to identify the origin and severity of the bleeding; establish the underlying etiology; predict the risk of rebleeding; and administer endoscopic therapy (hemostasis).26
Controversy surrounds the optimal time to perform endoscopy. The American Society for Gastrointestinal Endoscopy does not give clear recommendations, but notes that early endoscopy (within 24 hours of admission) reduces length of stay and requirements for blood transfusion.26,27 Early endoscopy may prevent unnecessary hospitalization of low-risk patients (those with a clean-based ulcer or nonprotuberant black or red spots in an ulcer bed).26 These patients can be treated on an outpatient basis and do not require endoscopic hemostatic therapy because the incidence of rebleeding is neglible.5,26,27 Only patients at high risk (those with certain endoscopic stigmata of bleeding--e.g., active bleeding, nonbleeding visible vessels, or an adherent blood clot) require endoscopic therapy and should be admitted immediately; this is because approximately 90% of these lesions have a significant risk of rebleeding.25 Endoscopy significantly reduces continued bleeding, need for surgery, and mortality.3,7,25-27
Endoscopic Therapy
Endoscopic therapy has changed significantly in the past two decades. Techniques for hemostasis include injection, mechanical methods (i.e., endoclips), thermal coagulation, and laser therapy.28 The choice of therapy depends on the method's convenience and the clinician's expertise. Combination therapy with injection and either coagulation or endoclips is superior to either treatment alone.3,28,29
The injection technique involves injecting 30 mL of 1:10,000 epinephrine--a vasoconstrictor that improves platelet aggregation to promote hemostasis--around and into the bleeding point of the ulcer, which will reduce the rate of rebleeding in patients with nonbleeding visible blood vessels and ulcers with adherent blood clots. The ideal volume of injected epinephrine is 30 mL.30 Administration of IV erythromycin before emergency endoscopy empties the stomach of blood, thereby improving visibility.31
Mechanical methods of hemostasis involve the placement of endoclips that close the bleeding blood vessel via compression. Application of clips is technique sensitive. Some studies have shown that this method inhibits bleeding more effectively than thermal coagulation or injection; other studies have found that it is not superior to other endoscopic modalities.32
Rebleeding after initial endoscopic therapy increases the mortality rate. If bleeding is not controlled after endoscopy, a second endoscopy is recommended.28 If one repeat endoscopy is not successful, surgery is necessary.3
Pharmacotherapy
In patients with peptic ulcer disease, H pylori testing should be performed at the time of endoscopy, before any medications are administered. Patients positive for H pylori should receive a 1-week course of eradication therapy. An additional 3 weeks of ulcer-healing therapy is recommended.20 Omeprazole is superior to the eradication of H pylori for preventing recurrent bleeding in patients taking NSAIDs.11
In high-risk patients, acid-suppressive therapy should be started following emergency endoscopic hemostatic therapy. Acid-suppressive medications are the foundation of therapy for UGIB, but they are costly. The goal of acid-suppressive therapy is to maintain intragastric pH above 6, which stabilizes clots and prevents rebleeding.5,33-35
Both proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2-RAs) have been used in the management of UGIB; however, clinical studies have documented that PPIs are more effective than H2-RAs for preventing rebleeding; this is because H2-RAs do not inhibit the hydrogen potassium ATPase (H+/K+ ATPase), which is responsible for acid secretion.33 Also, IV infusion of PPIs over 72 hours does not lead to tolerance, as with H2-RAs.
The incidence of minor adverse effects from PPIs is relatively low (1%-3%), with no significant differences between PPIs (TABLE 2).36 Serious adverse reactions involving the liver are extremely rare.
The reduction of rebleeding rates by PPIs does not depend on the route of administration.37 Patients with high-risk endoscopic stigmata should receive high-dose IV PPIs after successful endoscopic hemostasis. A landmark article by Lau et al concluded that high-dose PPIs are the standard of care for managing high-risk patients.38 There is no documented benefit of IV PPIs after 72 hours, so patients should be switched to oral PPIs.5 Peak suppression after IV high-dose administration occurs within hours; after oral administration, it occurs within several days.34 In patients with low-risk stigmata for bleeding, the use of oral PPIs alone is recommended. The dose of PPI maintains a gastric pH of greater than 4 for 10 to 14 hours.34 See TABLE 3 for PPI dosing information. The risk of UGIB is substantially decreased by the concomitant use of PPIs in patients taking antiplatelet drugs.39
The half-life of PPIs is approximately 1 hour; the exception is 9 hours for tenatoprazole, which is available only in Japan. Since PPIs irreversibly bind to H+/K+ ATPase, the duration of action is about 48 hours. The oral bioavailability of PPIs is high: 77% for pantoprazole, 80% to 90% for lansoprazole, and 89% for esomeprazole.34
The ideal pharmacologic therapy for high-risk patients with acute peptic ulcer bleeding is an IV PPI started immediately after endoscopic hemostatic therapy. Pantoprazole, lansoprazole, and esomeprazole are the only IV formulations available in the U.S. The suggested IV omeprazole or pantoprazole dose is 80 mg bolus followed by infusion of 8 mg/h for 72 hours. If there is no rebleeding within 24 hours, the patient may be switched to oral pantoprazole 40 mg/day or omeprazole 20 mg/day for 6 to 8 weeks.5 IV pantoprazole is available as a 2-minute or 15-minute infusion.
Questions arise as to the advantages of using continuous infusion of high-dose PPIs versus regular-dose PPIs and IV or oral PPIs. Studies published after the Lau study have not found high-dose PPIs to be superior to regular-dose PPIs.3,5,37 High-dose PPI therapy is more expensive than intermittent dosing. Although current guidelines consider IV bolus followed by continuous infusion of PPIs to be the treatment of choice in high-risk patients, some studies have found that regular-dose PPIs are just as effective as high-dose PPIs and are less expensive.3,5 Thus, no optimal drug regimen has been established. High-dose IV PPIs are recommended in patients in whom endoscopy is delayed.
The oral route of administration is effective in most hospital patients requiring PPIs, unless the patient cannot take anything by mouth.34 A 2008 study suggested that frequent oral PPI administration may replace the currently recommended IV bolus followed by infusion PPI.40 Another study found that a high-dose oral PPI (pantoprazole 40 mg twice daily or omeprazole 40 mg/day) was equally effective as IV infusion after endoscopic therapy.41,42
Once endoscopic therapy is successful and the bleeding has stopped, PPIs should be continued for 6 to 8 weeks. Patients positive for H pylori should receive antibiotic therapy and be retested 6 to 10 weeks after the antibiotic regimen is completed. In patients taking low-dose aspirin or NSAIDs, indefinite PPI maintenance is recommended.31 Oral PPIs are prescribed for 1 to 2 weeks upon discharge.
Conclusion
UGIB is a common medical emergency that requires immediate hospital admission. It is most frequently caused by peptic ulcer disease. UGIB results in considerable patient morbidity and significant medical costs. Many risk factors are associated with bleeding, and these must be addressed. Pharmacists, physicians, and dentists should take patients' medical history and analgesic requirements.
Endoscopic intervention reduces the rate of rebleeding, the need for surgical intervention, and mortality in high-risk patients with UGIB. Acid-suppressive therapy is valuable in the management of UGIB. Numerous studies have shown that PPIs improve clinical outcomes of peptic ulcer bleeds and are more beneficial than H2-RAs. PPIs reduce the frequency of rebleeding, the need for surgery, and the length of hospital stay. In high-risk patients, IV high-dose PPIs should be given after successful endoscopic hemostasis. High-dose oral PPIs may be an effective alternative to continuous infusion. Medical, endoscopic, and pharmaceutical intervention can considerably improve outcomes and reduce medical costs by reducing rebleeding and the need for surgical procedures.
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