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There is currently interest in whether high-dose continuous drip proton pump inhibitor therapy is superior to intermittent bolus proton pump inhibitor therapy in the treatment of upper gastrointestinal bleeding. Upper gastrointestinal bleeding is a common cause of emergency room visits along with high rates of mortality in patients admitted to the hospital for gastrointestinal issues. This is commonly found to have an exponentially higher rate of poor outcomes amongst lower socioeconomic populations when compared to individuals of higher socioeconomic status. The current standard of care provided to patients experiencing an upper gastrointestinal bleed (UGIB) is to intravenously receive 72hrs of a Proton Pump Inhibitor (PPI) medication. Therapeutic treatment with this class of drug has been shown to reduce incidences of mortality, recurrent bleeding, and further intervention when compared to placebo. This literature review will attempt to answer the following question: In patients with non-variceal UGIB and high risk endoscopic features, is treatment with high dose bolus proton pump inhibitor (PPI) therapy inferior to the current guideline recommendation of a high dose intravenous PPI bolus plus continuous infusion in preventing recurrent bleeding in the first 72 hours.

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Patients with an UGIB due to a non-variceal gastric ulcer may feel differently depending on the severity of their ulcer and how much blood they have lost. Often patients will describe a gnawing abdominal pain, nausea, vomiting, hematemesis, hematochezia, and changes in abdominal pain relating to food intake.1 If an ulceration has progressed to the point of causing significant blood loss you may hear the patient describe feeling lightheaded, dizzy or even describing an instance where they lost consciousness. A patient with these symptoms may have findings of hypotension which is low blood pressure or tachycardia, which is an increased heart rate. Individuals who present like this are at high risk for mortality and should receive expedited care.

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Ulcers typically occur within the stomach or duodenum and are commonly caused by peptic ulcer disease, NSAID use, H. Pylori bacteria, esophageal varices, and cancer.
There is a strong association between H. pylori infection and gastroduodenal ulcers.

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While a gastric ulcer which has perforated may be diagnosed with the use of computerized tomography (CT Scanning), the diagnosis of a symptomatic non-perforated ulcer would be suspected during the discussion of your patients history and their physical examination. Definitive diagnosis of an ulcer required direct visualization by way of an upper gastrointestinal endoscopy. This procedure is performed by a physician with the use of general anesthesia to help the patient sleep through it. With the use of a small camera mounted on the tip of the endoscope a provider threads the device down the esophagus into the stomach and duodenum. This imaging allows for close examination of the upper gastrointestinal tracts mucosal lining and direct visualization of any ulcerations which may be present.

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The current guidelines for managing a non-variceal upper gastrointestinal bleed includes a primary management of prompt fluid replacement, treatment of comorbidities, administration of acid-suppressing agents, endoscopic therapy and surgery if needed.
After the endoscopic intervention achieves hemostasis the patient is placed on a therapeutic regimen of PPIs. PPIs have the pharmacodynamic effect of inhibiting the proton pump which promotes gastric acid secretion from the stomach’s parietal cells. PPIs have well understood pharmacodynamics and are generally used to reduce the secretion of gastric acids in patients thereby increasing the pH level of the stomach. To date, In vitro studies have demonstrated an improvement in platelet aggregation and coagulation in the stomach at pH levels above 6, this is important because platelet aggregation and coagulation are part of how peptic ulcers heal.

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An UGIB originates from above the ligament of Treitz and is usually the result of an ulcer.
H. pylori causes an inflammatory response in gastric mucosa. NSAID-induced ulcers form an important subset of ulcers that occur due to suppression of gastric prostaglandin synthesis. Prostaglandins are important for gastric mucosal integrity as they help to reduce acid secretion while stimulating mucus & bicarbonate secretion. The greatest risk factors which increase the likelihood of  developing a gastric ulcer include the use of NSAIDs, Tobacco, Alcohol, and Coffee.

The annual incidence between 2001 and 2009 decreased from 78 to 61 cases per 100,000 persons with a higher average number of cases manifesting amongst lower socioeconomic populations.

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The current standard of practice guideline of a continuous intravenous drip infusion was laid out by multiple professional organizations including the American College of Gastroenterology, European Society of Gastrointestinal Endoscopy and the International Consensus Group.
However, recently they have been questioned by healthcare institutions hypothesizing whether a non-high-dose bolus regimen of proton pump inhibitor therapy would yield comparable patient outcomes. An apparent motivation for the comparison of these treatments was because while use high-dose drip PPIs are currently the standard of care they are “significantly more expensive” than non-high-dose bolus PPIs.

This literature review demonstrates that continuous proton pump inhibitor drip infusion therapy should remain the standard of care for patients with upper gastrointestinal bleeding and high-risk features

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The review of the literature showed that the primary motivations in determining whether patient outcomes with standard-dose bolus PPI regimens are comparable to high-dose continuous PPI regimens is the perceived ease of administration and a potential reduction of healthcare costs. Although there were several randomized controlled trials and meta-analyses which indicated intermittent bolus PPI therapy isn’t inferior to high-dose continuous PPI therapy, the generalization of these findings is questionable. This is most evident in the systematic review and meta-analysis from Sachar et al,11 who concluded that intermittent bolus PPI therapy was not inferior to the high-dose continuous regimen based on 13 studies, 12 of which were conducted in primarily Asian populations. These findings are also difficult to generalize as CYP450 genotyping demonstrates a statistically significant reduction in metabolism of PPIs amongst Asian populations.14 In the context of testing standard-dose PPI regimens, this may result in a prolonged serum concentration, improved therapeutic half-life and improved treatment outcomes in comparison to diverse cultural populations with average CYP2C19 activity.14

Similarly, the motivation of fiscal gain when choosing standard-dose intermittent bolus PPI therapy is negated by the potential additional costs associated with patients who experience poor outcomes and need further medical intervention due to inadequate PPI therapy. The cost saving described by Kumar et al13 has merit only if a patient’s risk of poor outcomes does not increase with the change of practice. While it may be argued on the basis of financial gain that a certain amount of increased risk to the patient is acceptable if the added costs of continued care does not outweigh the monetary savings found in changing practice guidelines, this would be an unethical argument and should be deemed an inappropriate cost-benefit analysis. As healthcare providers, it is our duty is to ensure the wellness of our patients and provide the highest quality of care possible, it is not our duty to prioritize the monetary gain of any institution over the value of human life.

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1. Saltzman JR. Approach to acute upper gastrointestinal bleeding in adults. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate, Inc; 2020. https://www.uptodate.com/contents/approach-to-acute-upper-gastrointestinal-bleeding-in-adults. Accessed October 20, 2020.

2.  Wang CH, Ma MH, Chou HC. High-dose vs non–high-dose proton pump inhibitors after endoscopic treatment in patients with bleeding peptic ulcer: a systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2010;170(9):751–758.

3.  Barkun AN, Almadi M, Kuipers, et al. Management of Nonvariceal Upper Gastrointestinal Bleeding: Guideline Recommendations from the International Consensus Group. Annals of internal medicine. 2019;171(11):805–822.

4. Green FW, Kaplan MM, Curtis LE, Levine PH. Effect of acid and pepsin on blood coagulation and platelet aggregation. A possible contributor to prolonged gastroduodenal mucosal hemorrhage. Gastroenterology. 1978;74(1):38-43.

5. Laine L, McQuaid KR. Endoscopic therapy for bleeding ulcers: an evidence-based approach based on meta-analyses of randomized controlled trials. Clin Gastroenterol Hepatol. 2009;7(1):33-47. doi: 10.1016/j.cgh.2008.08.016

6. Laine L, Jensen, Dennis M. Management of Patients With Ulcer Bleeding. American Journal of Gastroenterology. 2012;107 (3):345-360. doi: 10.1038/ajg.2011.480

7. Gralnek IM, Dumonceau JM, Kuipers EJ, et al. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2015;47(10):a1-46. doi: 10.1055/s-0034-1393172.

8. Udd M, Miettinen P, Palmu A et al.  Regular-dose versus high-dose omeprazole in peptic ulcer bleeding: a prospective randomized double-blind study. Scand J Gastroenterol. 2001;36(12):1332-1338

9. Chen CC, Lee JY, Fang YJ 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. doi: 10.1111/j.1365-2036.2012.05047.x.

10. Neumann I, Letelier LM, Rada G et al. Comparison of different regimens of proton pump inhibitors for acute peptic ulcer bleeding. Cochrane Database of Systematic Reviews. 2013;6: CD007999. doi: 10.1002/14651858.CD007999.pub2

11.  Sachar H, Vaidya K, Laine L. Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis. JAMA internal medicine. 2014;174(11):1755–1762. https://doi.org/10.1001/jamainternmed.2014.4056

12. Khan RS, Hadi YB, Chima, N, Kupec J. Skipping the Drip: Intravenous Proton Pump Inhibitor Bolus Therapy Leads to Poor Outcomes in High-Risk Bleeding. Cureus. 2020;12(5):e8362. https://doi.org/10.7759/cureus.8362

13. Kumar VCS, Patthipatti VS, Mani KK, Elangovan A, Goldstein L. The costly case of proton-pump inhibitors: a single-center experience. Therapeutic advances in gastrointestinal endoscopy. 2020;13: 2631774520919367. https://doi.org/10.1177/2631774520919367

14. Dean L. Omeprazole Therapy and CYP2C19 Genotype. 2012 Oct 1 [Updated 2016 Mar 8]. In: Pratt VM, McLeod HL, Rubinstein WS, et al., editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012. Available from: https://www.ncbi.nlm.nih.gov/books/NBK100895

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In conclusion, further studies with larger sample sizes and diverse patient populations would be needed to justify a change in this practice.
The unjustifiable cost saving potential as well as questionable reliance of a non-generalizable population study is underscored by the findings of Khan et al12 who demonstrated that with a heterozygous Caucasian population, worse patient outcomes were seen with the use of standard non-high-dose intermittent bolus PPIs when compared with the high-dose continuous infusion PPI regimen. These findings are evidence of the potentially detrimental outcomes a change in protocol may have on patient health if new guidelines are implemented without further research.

It is my conclusion that the current guidelines provided by multiple international professional organizations 3,6-7 suggest the PPI regimen of a high-dose bolus followed by continuous intravenous infusion for 72 hours is the most appropriate and evidence-based standard of care for patients with non-variceal upper gastrointestinal bleeds and high-risk endoscopic findings. Further studies with larger sample sizes and diverse patient populations would be needed to justify a change in this practice.