By Arzo Hamidi, PharmD, BCCCP
Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago
Decades ago, postmortem endoscopies in ill and critically ill patients found stress-related mucosal changes in nearly all patients.1 The risk factors for these stress-related mucosal changes include decreased cardiac output, decreased bicarbonate secretion, decreased gastrointestinal motility, and ischemia and reperfusion injury.1,2 The development of esophageal, gastric, and duodenal erosions or ulcers may increase the morbidity and mortality of critically ill patients. Stress ulcer prophylaxis can be administered pharmacologically to prevent gastrointestinal bleeding (GIB) from the ulcers.
Overall, the incidence of overt bleeding and clinically significant bleeding has decreased in recent years to 5% or less based on the definitions used.2,3 Overt bleeding is defined as having hematemesis, bloody gastric aspirate, melena, and/or hematochezia.4 Clinically significant bleeding (CSB) is defined as the presence of overt bleeding and one of the following: spontaneous drop in systolic blood pressure (SBP) or diastolic blood pressure (DBP) of at least 20 mmHg, orthostatic increase in pulse rate of 20 beats/minute and a decrease in SBP of at least 10 mmHg, or decrease in hemoglobin of at least 2 g/dL and transfusion of at least two units of packed red blood cells.4
Current practices focused on early administration of enteral nutrition (EN), advancements in practice to minimize splanchnic and mesenteric ischemia, optimization of mechanical ventilation (MV), and fluid resuscitation have resulted in decreases in the incidence of GIB.3,5 Overall, the strategy for stress ulcer prophylaxis (SUP) is to provide either pharmacological or enteral nutrition to increase mucosal perfusion, induce prostaglandin production, and buffer gastric acid.
Guideline Recommendations
A landmark trial published in 1994 by Cook and colleagues studied the risk factors for GIB in intensive care unit (ICU) patients. In this prospective, multicenter cohort study with 2,252 medical and surgical ICU patients, the authors identified risk factors for overt or CSB. Through a multiple regression model, they found that respiratory failure requiring MV over 48 hours and coagulopathy (defined as prothrombin time above 20 seconds, international normalized ratio [INR] above 1.5, or platelets below 50,000 × 106) were independent risk factors for GIB. Dependent risk factors included hypotension, sepsis, hepatic failure, EN, glucocorticoid administration, organ transplantation, and anticoagulant therapy.6 From this study, the American Society of Health System Pharmacists published a set of guidelines that still are used often in practice today.7
More recently, Wang and colleagues conducted a systematic review and network meta-analysis to determine the efficacy and safety of GIB prophylaxis in ICU patients.8 They found that the highest-risk and high-risk patients should receive pharmacological prophylaxis based on the calculation of bleeding risk. These highest-risk and high-risk patients include those with chronic liver disease, those with coagulopathy, those who require MV without EN, and those who have two or more of the moderate risk factors. Moderate risk factors include MV with EN, acute kidney injury, sepsis, and shock. These findings were published as a clinical practice guideline.9
What Has Changed in Recent Literature?
EN is emphasized to start early in critically ill patients. This probably also has played a role in reducing the risk of stress-induced GIB. EN can maintain the GI barrier function and stimulate blood flow.2 In a review of recent literature, EN was found to be protective against stress ulcer development.
A meta-analysis completed by Huang and colleagues included seven randomized controlled trials with a total of 889 ICU patients comparing pharmacological prophylaxis to placebo in patients receiving EN.5 There were no significant differences found in the incidence of overt bleeding or CSB in these patients. This meta-analysis did show that among ICU patients receiving enteral feeding, pharmacologic SUP exerted no impact on overall mortality, C. difficile infection, duration of MV, and length of ICU stay, but it led to an increased risk of hospital-acquired pneumonia (HAP). However, since this meta-analysis only included seven studies, this needs to be studied further explicitly.5
This topic has been explored further since this meta-analysis. Additional studies are featured in Table 1, with an emphasis on comparing pharmacological prophylaxis with a proton pump inhibitor (PPI) to placebo for SUP. In these studies, nearly all patients received early EN. None of these studies had a significant increase in CSB or overt bleeding. This supports the recommendation by the recent clinical practice guideline that those receiving EN may not require pharmacological prophylaxis.9
Table 1. Pantoprazole for Pharmacological Prophylaxis vs. Placebo |
Study |
Study Design |
Outcomes
(PPI vs. Placebo) |
Enteral Nutrition |
Selvanderan11
“POP-UP”
(n = 214) |
Prospective, blinded, parallel group of mixed ICU patients who were mechanically ventilated for more than 24 hours |
- No CSB in either group
- Overt bleed: 3% vs. 6%, P = 0.5
- 90-day mortality: 28% vs. 23%, log-rank P = 0.33
|
- 85% received liquid EN
- Median start time 16 hours
|
El-Kersh12
(n = 102) |
Prospective, multicenter, cohort study of a medical ICU |
- CSB: 1.8% vs. 2.1%, P = 0.99
- Overt bleed: 1.8% vs. 2.1%, P = 0.99
- Mortality: 12.7% vs. 17%, P = 0.54
|
- 100% received within 24 hours
|
Krag13
“SUP-ICU”
(n = 3291) |
International, multicenter, parallel-group, placebo-controlled, blinded of mixed ICU patients |
- CSB: 2.5% vs. 4.2%; RR, 0.58; (95% CI, 0.4-0.86)
- Overt bleed: 5.4% vs. 9%
- Mortality: 31% vs. 30%; RR, 1.02. (95% CI, 0.91-1.3)
|
- 80% received within 72 hours
|
ICU: intensive care unit; PPI: proton pump inhibitor; CSB: clinically significant bleeding; EN: enteral nutrition; RR: relative risk; CI: confidence interval |
Pharmacologic Review
The two most common pharmacological classes used for SUP are PPIs and histamine type-2 receptor antagonists (H2RA). Each class has several agents to choose from with varying potency. PPIs block gastric H, K-ATPase, resulting in the inhibition of gastric acid secretion. There are both intravenous (IV) and oral (capsule or suspension) agents, including omeprazole, lansoprazole, and pantoprazole. None of these agents require hepatic or renal dose adjustment and they can be administered once a day. H2RAs act by binding to histamine type 2 receptors on the surface of gastric parietal cells, interfering with pathways of gastric acid production and secretion. Options most commonly include famotidine since it comes in both oral and IV formulations, but it requires renal dose adjustment. Famotidine can be administered once or twice daily. The decision to choose an agent has historically been based on formulary options, dosing frequency, and a concern for adverse effects.
A recent single-center pharmacoepidemiologic study assessed the effectiveness and safety of PPI against H2RA. This study included more than 3,800 adults who required MV over 24 hours and were started on SUP within 48 hours. Overall, the incidence of GIB was less than 1% in the study. The overall occurrence of any GIB was not different between the two groups (0.58% vs. 0.44%, respectively; relative risk [RR] 1.32, 95% confidence interval [CI], 0.54-3.22; P = 0.54). The authors also found that there was no significant difference in rates of C. difficile infection or ventilator-associated pneumonia.3
Another large study assessed the comparative effect of in-hospital mortality in more than 26,000 adults requiring mechanical ventilation over 24 hours. The “PEPTIC” study was an international multicenter, randomized, open-label, cluster cross-over study. The primary outcome was 90-day mortality, which was found to not be significantly different in the group receiving PPI as compared to the H2RA (18.3% vs. 17.5%, P = 0.054). The authors also found that there was no significant difference in rates of C. difficile infection or ventilator-associated pneumonia between the groups.10
In summary, both PPI and H2RA are effective at reducing the risk of GIB; however, studies are now showing that adverse effects, such as nosocomial infections, are rare in either group. While it was previously thought that PPIs had more adverse effects, current studies have found that these adverse effects are rare and similar among agents.1,5,8 Adverse effects that should be explored further stem from trends seen toward increased mortality and ICU delirium with PPI over H2RA.3,10 To reduce these possible adverse effects, it is important to always discontinue the medication when it is no longer indicated.
Conclusion
SUP is indicated in patients who are mechanically ventilated without EN, have coagulopathy, or have liver disease. SUP also may be necessary if a patient has two or more other risk factors. The adverse effects of PPI and H2RA likely are not significant between the two groups but should be considered when using any pharmacological prophylaxis in general. The SUP agent should be discontinued when no longer indicated. Future studies should explore the role of EN as a method of SUP.
REFERENCES
- Cook D, Guyatt G. Prophylaxis against upper gastrointestinal bleeding in hospitalized patients. N Engl J Med 2018;378:2506-2516.
- Al-Dorzi HM, Arabi YM. Prevention of gastrointestinal bleeding in critically ill patients. Curr Opin Crit Care 2021;27:177-182.
- Boyd C, Hassig T, MacLaren R. A pragmatic assessment of proton pump inhibitors vs. histamine type 2 receptor antagonists on clinically important gastrointestinal bleeding and mortality when used for stress ulcer prophylaxis in the ICU. Pharmacotherapy 2021;41:820-827.
- Granholm A, Zeng L, Dionne JC, et al; GUIDE Group. Predictors of gastrointestinal bleeding in adult ICU patients: A systematic review and meta-analysis. Intensive Care Med 2019;45:1347-1359.
- Huang HB, Jiang W, Wang CY, et al. Stress ulcer prophylaxis in intensive care unit patients receiving enteral nutrition: A systematic review and meta-analysis. Crit Care 2018;22:20.
- Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. N Engl J Med 1994;330:377-381.
- [No authors listed]. ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis. Am J Health Syst Pharm 1999;56:347-379.
- Wang Y, Ye Z, Ge L, et al. Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: Systematic review and network meta-analysis. BMJ 2020;368:I6744.
- Ye Z, Blaser AR, Lytvyn L, et al. Gastrointestinal bleeding prophylaxis for critically ill patients: A clinical guideline. BMJ 2020;368:I6722.
- PEPTIC Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group, Alberta Health Services Critical Care Strategic Clinical Network, and the Irish Critical Care Trials Group, et al. Effect of stress ulcer prophylaxis with proton pump inhibitors vs histamine-2 receptor blockers on in-hospital mortality among ICU patients receiving invasive mechanical ventilation: The PEPTIC Randomized Clinical Trial. JAMA 2020;323:616-626.
- Selvanderan SP, Summers MJ, Finnis ME, et al. Pantoprazole or placebo for stress ulcer prophylaxis (POP-UP): Randomized double-blind exploratory study. Crit Care Med 2016;44:1842-1850.
- El-Kersh K, Jalil B, McClave SA, et al. Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomized controlled exploratory study. J Crit Care 2018;43:108-113.
- Krag M, Marker S, Perner A, et al. Pantoprazole in patients at risk for gastrointestinal bleeding in the ICU. N Engl J Med 2018;379:2199-2208.
