The efficacy of acid suppression in the prevention of stress ulcers using antacids was first investigated more than four decades ago among burns patients (1). Many different classes of acid suppressant medication have evolved since then, but their utility in the prevention of stress ulcers in critically ill patients remains unresolved. It has been hypothesized that stress ulcers may be more related to impaired mucosal blood flow and ischemia reperfusion-related injury; hence, in contrast to peptic ulceration, the evolution and propagation of such ulcers may be less related to gastric acidity.
The reported incidence of clinically important gastrointestinal bleeding is variable and probably related to the heterogeneity among patient populations studied, non-uniform definitions, and the lack of distinction between true stress ulceration and other unrelated causes of bleeding. Although not approved by the Food and Drug Administration for this indication, proton pump inhibitors (PPIs) are among the most common medications administered to critically ill (2) and perhaps to all hospitalized patients. In a study from two Australian ICUs, acid suppressant medication was inappropriately continued in 63% of patients after ICU and in 39% of patients after hospital discharge (3).
Most of the current recommendations regarding stress ulcer prophylaxis are based on results from studies and risk factors identified several decades ago. Changes in clinical practice, particularly with the increased emphasis on expeditious resuscitation and early commencement of enteral nutrition may have reduced the risk of stress ulceration and clinically important bleeding in the ICU. Do we need to rethink and modify our approach with the use of acid suppressant medication in the light of more contemporaneous evidence?
Harmful effects of acid suppression
A cohort study of patients on mechanical ventilation for more than 24 hours compared the use of PPI with H2 receptor antagonists (H2RA). After propensity-matched multivariate analysis, PPIs were associated with a significantly higher incidence of pneumonia and C. difficile infection; surprisingly, the incidence of gastrointestinal hemorrhage was also higher with PPI use (4). A recent meta-analysis investigated the risk of C. difficile infection associated with the use of PPIs. Among the 23 observational studies included, 10,307 cases of C. difficile infection were observed, with a significantly higher incidence with the use of PPIs (5). There is concern regarding adverse cardiovascular events associated with the use of PPIs. In a cohort study of 56,406 patients from Denmark, PPI use was associated with a significantly increased risk of cardiovascular death and readmission to hospital with myocardial infarction or stroke (hazard ratio: 1.29; CI, 1.21 to 1.37) (6). Among 244,679 subjects who underwent elective gastroscopy, there was a dose-related increase in the risk of first-time ischemic stroke with PPI use. No such association was observed with the use of H2RAs (7). Concern has also been raised regarding thrombocytopenia in patients with upper gastrointestinal bleeding who are treated with continuous infusions of PPIs (8).
Early enteral nutrition as prophylaxis
Continuous enteral feeds may be more effective at maintaining a higher gastric pH (above 3.5) compared to PPIs and H2RAs. In a randomized controlled trial (RCT), intravenous pantoprazole was compared to placebo in 214 mixed medical-surgical patients on mechanical ventilation who were expected to be commenced on enteral nutrition within 48 hours of ICU admission. No clinically significant gastrointestinal bleeding was observed in either group of patients (9). In a similar RCT of critically ill patients on mechanical ventilation who were expected to receive enteral nutrition within the first 24 hours of ICU admission, there was no overt or significant gastrointestinal bleeding with intravenous pantoprazole administration compared to placebo (10).
The SUP-ICU trial investigated the effects of intravenous pantoprazole in critically ill adult patients at high risk of gastrointestinal bleeding (11). The study was conducted across 33 ICUs in six countries between January 2016 to October 2017. In this randomized controlled trial, 3298 patients were enrolled to receive intravenous pantoprazole or placebo. The primary outcome, which the study was powered for, was the 90-d mortality. There was no significant mortality difference between pantoprazole (31.1%) and placebo (30.4%). The secondary outcome, a composite endpoint of gastrointestinal bleeding, pneumonia, C. difficile infection, and acute myocardial ischemia, was not different between groups. Clinically important bleeding was lower with pantoprazole compared to placebo (2.5 vs. 4%); the significance of this finding was not evaluated, as no adjustments were made for multiple comparisons. The power calculation of this study may have been flawed because it was based on a previous report that revealed no increase of mortality secondary to gastrointestinal bleeding. The composite secondary endpoint has also not been evaluated previously. The source of bleeding was not confirmed endoscopically, to differentiate from causes other than stress ulceration. Besides, there was no information on whether enteral nutrition had been established at baseline. This study confirms that the overall incidence of gastrointestinal bleeding is very low in today’s world (3.3% overall); adequately powered studies to prove a difference in the incidence may be difficult to carry out in practice.
The bottom line
- With an increased focus on early resuscitation, the incidence of clinically important gastrointestinal bleeding has probably decreased compared to previous reports.
- Widespread use of acid-suppressant medication has been linked to several adverse effects, including pneumonia, C. difficile infection, and cardiovascular events in critically ill patients.
- Routine use of stress ulcer prophylaxis may be unnecessary in patients who can be initiated on early enteral nutrition within the first 24–48 hours.
- Risk factors identified in earlier studies, including mechanical ventilation for more than 48 hours, may not necessitate routine prophylaxis.
- Future studies should be directed towards identification of patients who may be truly “at risk” for stress ulcer-related bleeding.
- McAlhany JC, Colmic L, Czaja AJ, Pruitt BA. Antacid control of complications from acute gastroduodenal disease after burns. J Trauma. 1976 Aug;16(08):645–8.
- Barletta JF, Lat I, Micek ST, Cohen H, Olsen KM, Haas CE, et al. Off-label use of gastrointestinal medications in the intensive care unit. J Intensive Care Med. 2015 May;30(4):217–25.
- Farley KJ, Barned KL, Crozier TM. Inappropriate continuation of stress ulcer prophylaxis beyond the intensive care setting. Crit Care Resusc J Australas Acad Crit Care Med. 2013 Jun;15(2):147–51.
- MacLaren R, Reynolds PM, Allen RR. Histamine-2 receptor antagonists vs proton pump inhibitors on gastrointestinal tract hemorrhage and infectious complications in the intensive care unit. JAMA Intern Med. 2014 Apr;174(4):564–74.
- Arriola V, Tischendorf J, Musuuza J, Barker A, Rozelle JW, Safdar N. Assessing the Risk of Hospital-Acquired Clostridium Difficile Infection With Proton Pump Inhibitor Use: A Meta-Analysis. Infect Control Hosp Epidemiol. 2016;37(12):1408–17.
- Charlot M, Ahlehoff O, Norgaard ML, Jørgensen CH, Sørensen R, Abildstrøm SZ, et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med. 2010 Sep 21;153(6):378–86.
- Sehested Thomas S, Fosbøl Emil L, Hansen Peter W, Charlot Mette G, Torp-Pedersen Christian, Gislason Gunnar H. Abstract 18462: Proton Pump Inhibitor Use Increases the Associated Risk of First-Time Ischemic Stroke. A Nationwide Cohort Study. Circulation. 2016 Nov 11;134(suppl_1):A18462–A18462.
- Binnetoğlu E, Akbal E, Şen H, Güneş F, Erbağ G, Aşık M, et al. Pantoprazole-induced thrombocytopenia in patients with upper gastrointestinal bleeding. Platelets. 2015;26(1):10–2.
- Selvanderan SP, Summers MJ, Finnis ME, Plummer MP, Abdelhamid YA, Anderson MB, et al. Pantoprazole or Placebo for Stress Ulcer Prophylaxis (pop-up): Randomized Double-blind Exploratory Study*. Crit Care Med. 2016 Oct 1;44(10):1842–50.
- El-Kersh K, Jalil B, McClave SA, Cavallazzi R, Guardiola J, Guilkey K, et al. Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomized controlled exploratory study. J Crit Care. 2018 Feb;43:108–13.
- Krag M, Marker S, Perner A, Wetterslev J, Wise MP, Schefold JC, et al. Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU. N Engl J Med. 2018 Dec 6;379(23):2199–208.