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 (clinical/pre-endoscopy; range 0–7, full Rockall 0–11) 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: Rilpivirine-containing products

Avoid / not recommended: Atazanavir, nelfinavir (ARV label-specific); CYP2C19 inducers (rifampin, St. John’s wort)

Contraindicated: Rilpivirine-containing products

Avoid / not recommended: Atazanavir, nelfinavir (ARV label-specific); CYP2C19 inducers (rifampin, St. John’s wort)

Contraindicated: Rilpivirine-containing products

Avoid / not recommended: Atazanavir, nelfinavir (ARV label-specific); CYP2C19 inducers (rifampin, St. John’s wort)
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)
Lau et al., 200011
Landmark		 RCT (Double-blind)
n=240 		Omeprazole 80 mg IV bolus then 8 mg/hr ×72h vs placebo, after endoscopic hemostasis of actively bleeding ulcers or non-bleeding visible vessels
30-d rebleeding 6.7% vs 22.5% (HR 3.9, 95% CI 1.7–9.0)

Foundational trial establishing high-dose IV PPI after endoscopic therapy. Most rebleeds occurred during the 72h infusion.
Lau et al., 200712 RCT (Double-blind)
n=638 		Omeprazole 80 mg IV bolus then 8 mg/hr vs placebo, before endoscopy (pre-emptive; next-morning endoscopy)
Less need for endoscopic Rx: 19.1% vs 28.4% (P=0.007)

Pre-endoscopy PPI downstaged lesions but did not reduce rebleeding, surgery, or mortality.
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% (difference 4.4%, P=0.026; sustained at 7 & 30 d, 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

Timing relative to endoscopy is everything. Before endoscopy, high-dose IV PPI downstages high-risk stigmata and reduces the need for endoscopic therapy, but does not improve mortality, rebleeding, or surgery. After endoscopic hemostasis of high-risk stigmata, high-dose PPI significantly reduces rebleeding and is standard of care. Continuous and intermittent high-dose PPI regimens are equivalent.

Before endoscopy: high-dose IV PPI downstages high-risk endoscopic stigmata and reduces the need for endoscopic therapy, but does not improve mortality, rebleeding, or surgery (Lau 200712; Sreedharan Cochrane 20107; Daneshmend 19924).

After endoscopic hemostasis of high-risk stigmata: high-dose PPI significantly reduces rebleeding and is standard of care (Lau 200011: 6.7% vs 22.5%, HR 3.9; Sung 20096: 5.9% vs 10.3% at 72h, P=0.026). This is the pearl’s key teaching point.

Continuous and intermittent high-dose PPI are equivalent — intermittent dosing is non-inferior to the classic 80 mg bolus + 8 mg/hr continuous infusion (Sachar 20149; ACG 202114).

What the guidelines say

  • After endoscopic hemostasis of high-risk ulcers (active spurting/oozing or a non-bleeding visible vessel): high-dose PPI — given continuously OR intermittently — for 3 days, then twice-daily oral PPI for the first 2 weeks (ACG 202114; International Consensus/ICON 201913).
  • Intermittent PPI is non-inferior to the classic 80 mg bolus + 8 mg/hr continuous infusion (Sachar meta-analysis 20149) — guidelines now explicitly permit either.
  • Pre-endoscopy PPI reduces high-risk endoscopic stigmata and the need for endoscopic therapy but does not change rebleeding, surgery, or mortality (Lau 200712; Sreedharan Cochrane 20107). It is optional and should never delay endoscopy.
  • Note: IV omeprazole is not marketed in the U.S.; equivalent high-dose regimens use IV pantoprazole or esomeprazole. Verify your institution's protocol and formulary.

Full Reference List

  1. Clinical Pharmacology [Electronic version]. Elsevier, Tampa, FL. Retrieved February 17, 2021.
  2. UpToDate [Electronic version]. Retrieved February 15, 2021.
  3. Laine L, Jensen DM. Management of Patients With Ulcer Bleeding. Am J Gastroenterol. 2012;107(3):345–360.
  4. Daneshmend TK, et al. Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial. BMJ. 1992;304(6820):143–147.
  5. 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.
  6. Sung JJ, et al. Intravenous esomeprazole for prevention of recurrent peptic ulcer bleeding: a randomized trial. Ann Intern Med. 2009;150(7):455–464.
  7. Sreedharan A, et al. Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding. Cochrane Database Syst Rev. 2010;(7):CD005415.
  8. 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.
  9. 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.
  10. 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. PMID: 29927201.
  11. Lau JY, Sung JJ, Lee KK, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med. 2000;343(5):310–316. PMID: 10922420.
  12. Lau JY, Leung WK, Wu JC, et al. Omeprazole before endoscopy in patients with gastrointestinal bleeding. N Engl J Med. 2007;356(16):1631–1640. PMID: 17442905.
  13. Barkun AN, Almadi M, Kuipers EJ, et al. Management of Nonvariceal Upper Gastrointestinal Bleeding: Guideline Recommendations From the International Consensus Group. Ann Intern Med. 2019;171(11):805–822. PMID: 31634917.
  14. Laine L, Barkun AN, Saltzman JR, Martel M, Leontiadis GI. ACG Clinical Guideline: Upper Gastrointestinal and Ulcer Bleeding. Am J Gastroenterol. 2021;116(5):899–917. PMID: 33929377.
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