Introduction
Upper GI bleed (UGIB) is a common reason for ED visits with a major cause of morbidity, mortality and medical care costs. Peptic ulcer accounts for at least 50% of UGIB cases. Patients with UGIB usually present with hematemesis, melena and/or hematochezia.
Key Clinical Considerations
- Upon presentation, hemodynamic status should be evaluated and resuscitation provided if necessary, including blood transfusion for target hemoglobin ≥7 g/dL
- Patients can be risk stratified using the Rockall score (range 0–7) and Blatchford score (range 0–23)
- PPIs remain one of the mainstays of pharmacological therapy for the management of UGIB
- PPI can be initiated if endoscopy cannot be performed, will be delayed >24 hours after presentation, or following endoscopy
PPI Pharmacology Comparison
| Parameter | Pantoprazole | Esomeprazole | Omeprazole |
|---|---|---|---|
|
Dose
|
Initial Infusion: 80 mg bolus then 8 mg/hr continuous ×72 hrs Intermittent: 80 mg LD then 40 mg IVP Q12H Maintenance High-risk: 40 mg PO BID ×14 days, then 40 mg PO daily Low-risk: 20 mg PO daily *Duration 4–12 weeks |
Initial Infusion: 80 mg bolus then 8 mg/hr continuous ×72 hrs Intermittent: 80 mg LD then 40 mg IVP Q12H Maintenance High-risk: 40 mg PO BID ×14 days, then 40 mg PO daily Low-risk: 20 mg PO daily *Duration 4–12 weeks |
Initial IV omeprazole not available in the U.S.; give IV pantoprazole or esomeprazole Maintenance High-risk: 40 mg PO BID ×14 days, then 40 mg PO daily Low-risk: 20 mg PO daily *Duration 4–12 weeks |
|
Administration
|
IVP: Over at least 2 minutes Infusion: 8 mg/hr PO: Swallow whole 30–60 min before food |
IVP: Over at least 3 min for <80 mg; LD over 30 min Infusion: 8 mg/hr PO: Capsule oral or opened with 50 mL water for NG |
PO: Swallow whole 30–60 min before food |
|
PK/PD
|
Onset: IV 15–30 min; PO 2.5 hrs Duration: 24 hrs (IV & PO) Distribution: 98% albumin bound t½: 1 hr; 3.5–10 hrs in CYP2C19 deficiency Excretion: Urine 71%, feces 18% |
Distribution: 97% protein bound Metabolism: Hepatic via CYP2C19 t½: 1–1.5 hrs Excretion: Urine 80%, feces 20% |
Onset: PO 1 hr Duration: Up to 72 hrs Distribution: 95% albumin bound t½: 30 min–1 hr; 3 hrs hepatic impairment Excretion: Urine 77% |
|
Adverse Effects
|
Headache
Nausea
Abdominal pain
Diarrhea
Vomiting
|
Headache
Flatulence
Nausea
Dyspepsia
Diarrhea
|
Headache
Abdominal pain
Nausea
Diarrhea
Flatulence
|
|
Drug Interactions & Warnings
|
Contraindicated: Atazanavir, Rilpivirine and their combinations |
Contraindicated: Atazanavir, Rilpivirine and their combinations, CYP2C19 inducers |
Contraindicated: Atazanavir, Rilpivirine and their combinations, CYP2C19 inducers |
|
Compatibility
|
D5W, NS, or LR | D5W, NS, or LR | N/A |
Clinical Pearl
PPIs may increase the risk of Clostridium difficile associated diarrhea — use the lowest dose and shortest duration where possible.
Overview of Key Evidence
| Author / Year | Design (n) | Intervention | Key Findings |
|---|---|---|---|
| Daneshmend et al., 19924 |
RCT (Double-blind)
n=1,147 |
Omeprazole 80 mg IV bolus followed by 40 mg IV Q8H ×3, then 40 mg PO BID vs placebo. Treatment started within 12h of admission. |
No diff: transfusions, rebleeding, surgery, death
Significant reduction in endoscopic UGIB signs: 33% vs 45% (p<0.0001) |
| Andriulli et al., 20085 |
RCT (Multicenter)
n=474 |
PPI continuous (80 mg bolus then 8 mg/hr ×72h) vs PPI intermittent (40 mg IV bolus daily ×72h); switched to oral PPI after 72h |
Rebleed: 11.8% continuous vs 8.1% intermittent (P=0.18)
Continuous group had prolonged hospital stay >5 days (P=0.03) |
| Sung et al., 20096 |
RCT (Multicenter)
n=764 |
Esomeprazole 80 mg IV bolus then 8 mg/hr vs placebo ×72h after endoscopic hemostasis; both groups received esomeprazole 40 mg PO daily ×27 days |
Less rebleeding at 72h: 5.9% vs 10.3% (p=0.010)
Decreased re-treatment (6.4% vs 11.6%), surgery (2.7% vs 5.4%), mortality (0.8% vs 2.1%) |
| Sreedharan et al., 20107 |
SR & Meta-analysis
6 RCTs, n=2,223 |
PPI (oral or IV) vs placebo, H2RA, or no treatment before endoscopy |
No decrease: mortality, rebleeding, surgery
PPIs reduced endoscopic stigmata and reduced endoscopic intervention |
| Chen et al., 20128 |
RCT (Prospective)
n=201 |
Pantoprazole 80 mg IV bolus then 8 mg/hr vs pantoprazole 40 mg IV bolus once daily ×72h; both groups received PO PPI ×27 days |
No diff in transfusions, LOS, surgery, mortality
High-dose PPI not superior to standard-dose for recurrent bleeding at 30 days |
| Sachar et al., 20149 |
SR & Meta-analysis
13 RCTs |
Intermittent PPI doses (IV or PO) vs 80 mg IV bolus followed by 8 mg/hr ×72h |
Intermittent non-inferior to continuous
No difference in recurrent bleeding between intermittent vs continuous PPI |
| Rattanasupar et al., 201610 |
RCT (Prospective)
n=113 |
Pantoprazole 80 mg IV bolus then 8 mg/hr vs pantoprazole 40 mg IV twice daily |
No diff: LOS, transfusion, rebleed, mortality
Blatchford >10–12 showed high sensitivity for predicting high-risk peptic ulcer bleeding |
Clinical Conclusions
Bottom Line
PPI therapy does not reduce mortality, rebleeding, or need for surgery compared to placebo. However, PPIs reduce endoscopic signs of bleeding and need for endoscopic intervention. Continuous infusion is not superior to intermittent therapy.
Compared to placebo or other non-PPI treatment measures, evidence suggests PPI therapy did not reduce the need for blood transfusion, rebleeding rate, surgery, or death.
Compared to placebo, PPIs reduced the signs of upper gastrointestinal bleeding observed during endoscopy and reduced the need for endoscopic treatment.
Administration of PPI as continuous infusion did not impact patient outcomes and is not superior to intermittent therapy; however, high-dose PPI may be considered in patients with Blatchford scores >12.
Full Reference List
- Clinical Pharmacology [Electronic version]. Elsevier, Tampa, FL. Retrieved February 17, 2021.
- UpToDate [Electronic version]. Retrieved February 15, 2021.
- Laine L, Jensen DM. Management of Patients With Ulcer Bleeding. Am J Gastroenterol. 2012;107(3):345–360.
- Daneshmend TK, et al. Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial. BMJ. 1992;304(6820):143–147.
- Andriulli A, et al. High- versus low-dose proton pump inhibitors after endoscopic hemostasis in patients with peptic ulcer bleeding. Am J Gastroenterol. 2008;103(12):3011–3018.
- Sung JJ, et al. Intravenous esomeprazole for prevention of recurrent peptic ulcer bleeding: a randomized trial. Ann Intern Med. 2009;150(7):455–464.
- Sreedharan A, et al. Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding. Cochrane Database Syst Rev. 2010;(7):CD005415.
- Chen CC, et al. Randomised clinical trial: high-dose vs. standard-dose proton pump inhibitors for the prevention of recurrent haemorrhage after combined endoscopic haemostasis of bleeding peptic ulcers. Aliment Pharmacol Ther. 2012;35(8):894–903.
- Sachar H, et al. Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis. JAMA Intern Med. 2014;174(11):1755–1762.
- Rattanasupar A, Sengmanee S. Comparison of high dose and standard dose proton pump inhibitor before endoscopy in patients with non-portal hypertension bleeding. J Med Assoc Thai. 2016;99(9):988–995.
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