Despite their ubiquitous use, proton pump inhibitors (PPI) for the prophylactic prevention of stress ulcer formation in mechanically ventilated patients admitted to the intensive care unit (ICU) have minimal evidence supporting their use. In fact, no single study has ever demonstrated the superiority of PPIs when compared to an H2-blocker or even a placebo (1). Despite this dearth of evidence, multiple recommendations have supported their use for stress ulcer prophylaxis in mechanically ventilated patients (2,3). But like so much in medicine, someone had to go and spoil a very good theory by actually studying it.
Selvanderan et al randomized 216 patients in a single surgical-medical ICU to either 40 mg of IV pantoprazole daily or an equivalent placebo (4). The authors had an extensive list of exclusion criteria including: use of acid-suppressive therapy prior to admission, admission with gastrointestinal bleeding, history of proven peptic ulcer disease, administration of greater than 100mg daily of prednisolone (or equivalent of other corticosteroid), surgery on the upper gastrointestinal tract or cardiac surgery during the current hospital admission, pregnancy, Jehovah’s witnesses, patients who could not receive their first dose of study medication within 36 hours of initiation of mechanical ventilation, admission for the sole purpose of providing palliative care, and patients readmitted to the ICU. Because of the extensive exclusion criteria, only 216 of the 654 mechanically ventilated patients were eligible for randomization.
Of the 216 patients included in the final analysis, the authors found no difference in the rate of bleeding between the groups. 5.6% of patients in the control group and 2.8% of the patients in the pantoprazole group experienced clinically overt bleeding. There was also no difference in daily hemoglobin levels between the groups or the need for blood transfusion.
And while the authors found no difference in the rate of clinically significant gastrointenstinal bleeding, defined as an episode of overt bleeding (hematemesis, bloody gastric aspirate, melena, or hematochezia), accompanied by at least one of the following: a reduction in mean arterial blood pressure of more than or equal to 20mm Hg within 24 hours in the absence of another cause, a reduction in hemoglobin of more than or equal to 20g/L within 24 hours, or a need for endoscopy or surgery to achieve hemostasis. Nor did they observe a difference in the rate of ventilator associated pneumonias or C. difficile infections.
Although this study is too statistically undersized to rule out small benefits related to the use of PPIs, these findings are certainly consistent with the few prior small studies examining the use of PPIs for stress ulcer prophylaxis (5,6). And while for the most part the authors were cautious in their conclusions, they may have overstepped their data in regards to their statements regarding the risk of C. difficile infections and PPI use. The authors state,
Data from our study also suggest that administration of pantoprazole does not markedly increase the risk of infective ventilator-associated pneumonia or Clostridium difficile infection, a finding that contradicts previous observational studies (7,8).
The total rate of C. difficile in the entire cohort was only 3 patients (2 in the PPI arm and one in the control group). A study of this size cannot possibly assess the risk of C. difficile associated with PPI use. In fact, the two large observational cohorts referenced by Selvanderan et al are far more statistically robust and methodologically appropriate to assess rare events like C. difficile infections.
Unfortunately, the strict inclusion and broad exclusion criteria utilized by these authors will leave a large portion of patients outside the margins of application of these findings. Additionally, since the majority of patients in this cohort were receiving enteral nutrition at the time of enrollment it is difficult to extend these results to fasting patients. Some will argue that the rate of clinically important GI bleeds was too infrequent to truly rule out benefits from daily PPIs use. As such this data will likely do very little to curtail our use of PPIs, the inertia of medical dogma is too large to be shifted by such a small mass. But it is important to remember how this therapeutic strategy gained such momentum in the first place, by physiological leaps and speculation.
- Marik PE, Vasu T, Hirani A, et al: Stress ulcer prophylaxis in the new millennium: A systematic review and meta-analysis. Crit Care Med 2010; 38:2222–2228
- Vincent JL: Give your patient a fast hug (at least) once a day. Crit Care Med 2005; 33:1225–1229 11.
- Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580–637
- Selvanderan SP et al: Pantoprazole or Placebo for Stress Ulcer Prophylaxis (POP-UP): Randomized Double-Blind Exploratory Study. Crit Care Med July 12, 2016
- Kantorova I, Svoboda P, Scheer P, et al: Stress ulcer prophylaxis in critically ill patients: A randomized controlled trial. Hepatogastroenterology 2004; 51:757–761
- Powell H, Morgan M, Li SK, et al: Inhibition of gastric acid secretion in the intensive care unit after coronary artery bypass graft. A pilot control study of intravenous omeprazole by bolus and infusion, ranitidine and placebo. Theor Surg 1993; 8:125–130
- 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; 174:564–574
- Buendgens L, Bruensing J, Matthes M, et al: Administration of proton pump inhibitors in critically ill medical patients is associated with increased risk of developing Clostridium difficile-associated diarrhea. J Crit Care 2014; 29:696.e11–696.e15
University of Maryland
Resuscitation Fellowship Graduate