Medication Summary
Rebleeding in patients with upper gastrointestinal (GI) hemorrhage (UGIB) is associated with increased morbidity and mortality; therefore, prevention of rebleeding is the major goal of therapy.
Proton pump inhibitors (PPIs)
There are two approved intravenous (IV) PPIs in use in the United States, pantoprazole (Protonix IV formulation) and esomeprazole magnesium (Nexium IV formulation).
These agents suppress gastric acid secretion by specifically inhibiting the H+/K+/ATPase enzyme system at the secretory surface of gastric parietal cells. Use of the IV preparation has been studied only for short-term therapy (ie, 7-10 d) and may be a useful adjunct via stabilization of the clot by increasing intragastric pH. High-dose IV treatment is the norm; however, high-dose oral therapy may be able to maintain the intragastric pH at about 6 as well. [86]
In severe acute upper GI bleeding (UGIB), IV proton pump inhibition should be initiated once the patient's hemodynamic status has been addressed and appropriate resuscitation measures have been implemented. [132] Lau and colleagues reported the benefit of a high-dose bolus followed by continuous infusion of omeprazole before patients underwent endoscopy. [155] Endoscopic treatment was required in 19.1% of patients who received omeprazole compared to 28.4% of patients who received placebo (P = 0.007). Similarly, among patients with peptic ulcer disease, there were fewer patients with active bleeding in omeprazole group (6.4% vs 14.7%; P = 0.01) and more had clean-based ulcers (64.2% vs 47.4%; P = 0.001). [155]
A Cochrane systematic review and meta-analysis of six randomized trials (N = 2,223) of pre-endoscopic PPI therapy found no significant differences between the PPI and control groups with respect to mortality (6.1% vs 5.5%), rebleeding (13.9% vs 16.6%), or surgery (9.9% vs 10.2%). [88]
Another Cochrane meta-analysis of 24 trials comprising 4,373 patients with peptic ulcer bleeding who did not consistently receive endoscopic hemostatic therapy found that PPI therapy was associated with reduced rebleeding and need for surgery, but not mortality except among those at the highest risk. [156] This suggests that if endoscopy will be delayed or cannot be performed, PPI therapy may improve clinical outcomes.
PPI therapy should be discontinued after endoscopy unless the patient has a source for which PPIs may be beneficial (e.g., ulcers and erosions). [65]
The use of H2-receptor antagonists has not been shown to be effective in altering the course of UGIB. A meta-analysis concluded that there was a possible minor benefit with intravenous H2 antagonists in bleeding gastric ulcers but no benefit in duodenal ulcers. [157]
Prokinetics such as metoclopramide or erythromycin
The use of a prokinetics agent to empty the stomach of retained blood or clots to improve endoscopic visualization has been extensively studied. To date, four large randomized controlled trials and three meta-analyses have shown that erythromycin reduces the need for second-look endoscopy but did not significantly reduce clinical outcomes such as blood transfusions, hospital stay, or surgery. [158, 159, 160, 161, 162, 163, 164]
In a meta-analysis by Barkun et al, there were no significant benefits to pre-esophagogastroduodenoscopy metoclopramide therapy, but the findings were limited by the small sample of patients (n = 28), which was represented in abstract form only. [158] Darum and Garretson reported on their experience in a single institution utilizing metoclopramide as a prokinetic in UGIB and found that metoclopramide did not improve visualization during endoscopy when compared with placebo. [165]
The potential side effects of metoclopramide, such as extrapyramidal symptoms or tardive dyskinesia are primarily associated with chronic use; however, due to an FDA black box warning on metoclopramide, the risks have to be balanced against the potential benefit in this setting. [166]
H pylori eradication
Eradication of H pylori can reduce the risk of rebleeding. [65] Current anti-H pylori regimens include a variety of drug combinations.
The treatment regimens approved by FDA have 70%-90% H pylori eradication rates. [16]
The common regimens of “triple therapy” with a PPI, clarithromycin, and amoxicillin, or bismuth “quadruple therapy” consisting of a PPI, bismuth, tetracycline, and a nitroimidazole for 10-14 days remain as options for first-line therapy.
Clarithromycin resistance should be taken into consideration, as should previous macrolide exposure and penicillin allergy when considering a H pylori eradication regimen.
The 2017 American College of Gastroenterology (ACG) clinical guideline endorses additional regimens as potential first-line H pylori eradication therapy as follows [146] :
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Sequential therapy: A PPI and amoxicillin for 5-7 days, followed by a PPI, clarithromycin, and a nitroimidazole for 5-7 days
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Hybrid therapy: A PPI and amoxicillin for 7 days, followed by a PPI, amoxicillin, clarithromycin, and a nitroimidazole for 7 days
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Fluoroquinolone sequential therapy: A PPI and amoxicillin for 5-7 days, followed by a PPI, fluoroquinolone, and nitroimidazole for 5-7 days
Aspirin, NSAIDs, and anti-thrombotics
Aspirin and nonsteroidal anti-inflammatory agents (NSAIDs) are very common causes of ulcer bleeding. Antiplatelet drugs are often associated with an increased severity of UGIB and may pose unique challenges in management. [37, 38, 57, 167]
Discontinue NSAIDs when feasible in patients with bleeding from gastric or duodenal ulcers. Selective cyclooxygenase (COX)-2 inhibitors could be substituted, with a reduction in the risk of recurrent ulcer bleeding. Continued concomitant use of PPIs also reduces the risk of recurrent ulcer bleeding.
Take into account concerns for an associated risk of increased cardiovascular and/or cerebrovascular side effects in patients taking selective COX-2 inhibitors and the potential side effects associated with long-term PPI use when managing relative risk reduction. [133]
As noted earlier, al-Assi et al demonstrated that the combination of H pylori infection and NSAID use may increase the risk of ulcer hemorrhage; however, the treatment of H pylori in patients who are taking NSAIDs remains controversial. [1]
In general, aspirin and antithrombotic agents should be withheld until the bleeding is controlled, particularly if serious or life-threatening bleeding is apparent. In patients with significant risk factors or known cardiovascular indications for antithrombotic use, however, these agents should be started back as soon as possible. [167] A study by Sung et al showed that in patients who had their aspirin held after treatment for a bleeding peptic ulcer, there was a clear increase in 30-day mortality, whereas those who continued taking their aspirin had no increased risk of postprocedure bleeding. [168]
Iron supplementation
Iron supplementation therapy is commonly used for anemia following UGIB. Oral iron and parenteral iron are both effective when compared with placebo. [169]
GI tolerance, cost, and availability should be considered when determining the best regimen for supplementation, if utilized.
Proton Pump Inhibitors
Class Summary
PPIs inhibit gastric acid secretion by inhibition of the H+/K+/ATPase enzyme system in the gastric parietal cells. IV therapy may be a useful adjunct via stabilization of the clot by increasing intragastric pH. High-dose intravenous treatment is the norm; however, high-dose oral therapy may be able to maintain the intragastric pH about 6 as well. [86]
Omeprazole (Prilosec, Prilosec OTC)
Omeprazole decreases gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump. It usually is given with clarithromycin and amoxicillin (or metronidazole if the patient is allergic to penicillin) when administering proton pump inhibitor–based triple therapy. It might decrease the incidence of NSAID-induced peptic ulcers and can be used to help prevent peptic ulcers in long-term NSAID users at high risk.
Lansoprazole (Prevacid, Prevacid 24HR, Prevacid Solu Tab)
Lansoprazole decreases gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump. It usually is given with clarithromycin and amoxicillin (or metronidazole if the patient is allergic to penicillin) when administering proton pump inhibitor–based triple therapy. It might decrease the incidence of NSAID-induced peptic ulcers and can be used to help prevent peptic ulcers in long-term NSAID users at high risk.
Esomeprazole (Nexium, Nexium 24HR)
Esomeprazole is an S-isomer of omeprazole. It inhibits gastric acid secretion by inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.
Pantoprazole (Protonix)
Pantoprazole suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells. Use of the intravenous preparation has only been studied for short-term use (ie, 7-10 d).
Prokinetic Agents
Class Summary
The use of the prokinetics agent to empty the stomach of retained blood or clots to improve endoscopic visualization has been extensively studied. To date, four large randomized controlled trials and three meta-analyses have shown that erythromycin reduces the need for second-look endoscopy but did not significantly reduce clinical outcomes such as blood transfusions, hospital stay, or surgery. [158, 159, 160, 161, 162, 163, 164]
Metoclopramide (Metozolv ODT, Reglan)
Metoclopramide blocks dopamine receptors (at high dose) and serotonin receptors in chemoreceptor trigger zone of the CNS; and sensitizes tissues to acetylcholine; increases upper GI motility but not secretions; increases lower esophageal sphincter tone.
Erythromycin ethylsuccinate (E.E.S., EryPed)
The prokinetic action of the macrolide antibiotic erythromycin is related to its action as a motilin-receptor agonist in the gut and gallblader to stimulate the GI tract.
H pylori Agents
Bismuth subsalicylate (Kaopectate, Kaopectate Extra Strength, Maalox Total Relief)
This agent has a cytoprotective effect on the GI mucosa, probably due to the stimulation of prostaglandin production and modulation of the immune response. In addition, it has been demonstrated that some deposits (probably bismuth salts) appear on both surfaces of the cell wall of H pylori from antral epithelium.
Non-steroidal Anti-inflammatory Drug
Aspirin (Acetylsalicylic acid, ASA, Bayer Advanced Aspirin)
Aspirin inhibits the synthesis of prostaglandin by cyclooxygenase; inhibits platelet aggregation; and has antipyretic and analgesic activity. It is metabolized by the liver via microsomal enzyme system.
Histamine H2 Antagonists
Ranitidine (Zantac, Zantac 150 Maximum Strength, Zantac 75)
Ranitidine reduces basal and nocturnal gastric acid secretion by competitive inhibition of binding of histamine to receptors (H2 receptor) on the gastric parietal cells. As of April 1, 2020, ranitidine was withdrawn from the market due to an increasing number of products containing the contaminant known as N-Nitrosodimethylamine (NDMA).
Famotidine (Acid Controller, Act, Dyspep HB)
Famotidine competitively inhibits histamine at H2 receptor of gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen ion concentrations.
Iron Products
Class Summary
These agents are used to provide adequate iron for hemoglobin synthesis and to replenish body stores of iron.
Ferrous sulfate (Feosol, Fer-In-Sol, Feratab)
Ferrous sulfate is the mainstay treatment for treating patients with iron deficiency anemia. They should be continued for about 2 months after correction of the anemia and its etiologic cause in order to replenish body stores of iron. Ferrous sulfate is the most common and cheapest form of iron utilized. Tablets contain 50-60 mg of iron salt. Other ferrous salts are used and may cause less intestinal discomfort because they contain a smaller dose of iron (25-50 mg). Oral solutions of ferrous iron salts are available for use in pediatric populations.
Carbonyl iron (Feosol (Carbonyl Fe), Icar C, Icar Pediatric)
Carbonyl iron is used as a substitute for ferrous sulfate. It has a slower release of iron and is more expensive than ferrous sulfate. The slower release affords the agent greater safety if ingested by children. On a milligram-for-milligram basis, it is 70% as efficacious as ferrous sulfate. Claims are made that there is less gastrointestinal (GI) toxicity, prompting use when ferrous salts are producing intestinal symptoms and in patients with peptic ulcers and gastritis. Tablets are available containing 45 mg and 60 mg of iron.
Ferric carboxymaltose (Injectafer)
Ferric carboxymaltose is a nondextran IV colloidal iron hydroxide in complex with carboxymaltose, a carbohydrate polymer that releases iron. It is indicated for iron deficiency anemia (IDA) in adults who have intolerance or an unsatisfactory response to oral iron.
Ferrous gluconate (Fergon)
Ferrous gluconate replaces iron found in hemoglobin, myoglobin, and enzymes; allows the transportation of oxygen via hemoglobin. It is indicated in the prevention and treatment of iron-deficiency anemias.
Ferrous fumarate (Feostat, Ferro-Sequels, Hemocyte)
Ferrous fumarate is a replacement of iron stores found in hemoglobin, myoglobin, and enzymes; works to transport oxygen via hemoglobin. It is indicated in the prevention and treatment of iron-deficiency anemias.
Ferumoxytol (Feraheme)
Ferumoxytol is iron-carbohydrate complex released within macrophage vesicles; either enters intracellular iron storage (eg, ferritin) or transferred to plasma transferrin for transport to erythroid precursor cells for hemoglobin incorporation. It is indicated for iron deficiency anemia (IDA) in adults who have intolerance to oral iron or have had unsatisfactory response to oral iron.
Ferric maltol (Feraccru)
An oral iron replacement that delivers iron for uptake across the intestinal wall and transfer to transferrin and ferritin. It is indicated for iron deficiency in adults.
Antibiotics
Amoxicillin (Amoxil, Moxatag (DSC), Trimox)
Amoxicillin inhibits the final stage of bacterial cell wall synthesis by binding to specific PBPs on the inner part of the bacterial wall, leading to bacterial lysis.
Metronidazole (Flagyl, Flagyl ER, Flagyl IV RTU)
Metronidazole is reduced to its active form intracellularly only by anaerobic organisms, then disrupts the helical structure of DNA and inhibits bacterial nucleic acid synthesis.
Levofloxacin (Levaquin, Levofloxacin Systemic)
Levofloxacin is an L-stereoisomer of its parent compound ofloxacin; the D-isomer form is inactive
This agent inhibits DNA gyrase activity, which in turn promotes breakage of DNA strands.
Levofloxacin is a good monotherapy, with extended coverage against Pseudomonas spp, as well as excellent activity against pneumococcus.
Clarithromycin
Clarithromycin inhibits bacterial growth, possibly by blocking the dissociation of peptidyl tRNA from ribosomes, causing the arrest of RNA-dependent protein synthesis.
Ciprofloxacin (Cipro, Cipro XR, ProQuin XR)
Ciprofloxacin inhibits the relaxation of DNA; inhibits DNA gyrase in susceptible organisms; and promotes breakage of double-stranded DNA.
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Upper gastrointestinal bleeding (UGIB). Ulcer with active bleeding.
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Upper gastrointestinal bleeding (UGIB). Ulcer with a clean base.
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Upper gastrointestinal bleeding (UGIB). Diagram of an ulcer with a clean base.
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Upper gastrointestinal bleeding (UGIB). Ulcer with an overlying clot.
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Upper gastrointestinal bleeding (UGIB). Ulcer with a visible vessel.
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Upper gastrointestinal bleeding (UGIB). Diagram of an ulcer with a visible vessel.
Tables
- Table 1. Probable Source of GI Bleeding Within the Gut
- Table 2. Estimated Fluid and Blood Losses in Shock
- Table 3. Effect of Number of Packed Erythrocyte Transfusions on Need for Surgery and Mortality from UGIB
- Table 4. Effect of the Color of the Nasogastric Aspirate and of the Stool on UGIB Mortality Rate
- Table 5. Ulcer Characteristics and Correlations
Clinical Indicator |
Probability of Upper GI Source |
Probability of Lower GI Source |
Hematemesis |
Almost certain |
Rare |
Melena |
Probable |
Possible |
Hematochezia |
Possible |
Probable |
Blood-streaked stool |
Rare |
Almost certain |
Occult blood in stool |
Possible |
Possible |
GI = gastrointestinal. |
||
Class 1 |
Class 2 |
Class 3 |
Class 4 |
|
Blood Loss, mL |
Up to 750 |
750-1500 |
1500-2000 |
>2000 |
Blood Loss, % blood volume |
Up to 15 |
15-30 |
30-40 |
>40 |
Pulse Rate, bpm |
< 100 |
>100 |
>120 |
>140 |
Blood Pressure |
Normal |
Normal |
Decreased |
Decreased |
Respiratory Rate |
Normal or Increased |
Decreased |
Decreased |
Decreased |
Urine Output, mL/h |
>35 |
30-40 |
20-30 |
14-20 |
CNS/Mental Status |
Slightly anxious |
Mildly anxious |
Anxious, confused |
Confused, lethargic |
Fluid Replacement, 3-for-1 rule |
Crystalloid |
Crystalloid |
Crystalloid and blood |
Crystalloid and blood |
bpm = beats per minute; CNS = central nervous system |
||||
Number of Units Transfused |
Need for Surgery, % |
Mortality, % |
0 |
4 |
4 |
1-3 |
6 |
14 |
4-5 |
17 |
28 |
>5 |
57 |
43 |
Nasogastric Aspirate Color |
Stool Color |
Mortality, % |
Clear |
Brown or red |
6 |
Coffee-ground |
Brown or black |
8.2 |
Red |
19.1 |
|
Red blood |
Black |
12.3 |
Brown |
19.4 |
|
Red |
28.7 |
|
UGIB = upper gastrointestinal bleeding. |
||
Ulcer Characteristics |
Prevalence Rate, % |
Rebleeding Rate, % |
Surgery Rate, % |
Mortality, % |
Clean base |
42 |
5 |
0.5 |
2 |
Flat spot |
20 |
10 |
6 |
3 |
Adherent clot |
17 |
22 |
10 |
7 |
Visible vessel |
17 |
43 |
34 |
11 |
Active bleeding |
18 |
55 |
35 |
11 |
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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Approach Considerations
- Proton-Pump Inhibitors
- Therapeutic Endoscopy
- Bleeding Peptic Ulcer Treatment
- Bleeding Gastric Ulcer Treatment
- Stress Ulcer Treatment
- Mallory-Weiss Syndrome Treatment
- Dieulafoy Lesion Treatment
- Angiodysplasia Treatment
- Aortoenteric Fistula
- Treatment Complications
- Posttreatment Monitoring and Care
- Deterrence and Prevention of UGIB
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- Medication
- Questions & Answers
- Media Gallery
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