Kishan Patel, Mercer University College of Pharmacy
Stress ulcer prophylaxis is recommended for adult ICU patients with coagulopathy or patients that require mechanical ventilation for more than 48 hours according to guidelines by the American Society of Health System Pharmacists (ASHP) and the Society for Critical Care Medicine. [1,2] However, there have only been two studies that compare the use of proton pump inhibitors (PPIs) with placebo for the prevention of gastrointestinal (GI) bleeding in adult patients in the ICU. Furthermore, neither study results provide robust evidence that supports the use of PPI in for stress ulcer prophylaxis.  Moreover, several other observational studies have seen a strong association between stress ulcer prophylaxis treatment and Clostridium difficile infections and ventilator-associated pneumonia. Therefore, some suggest that the use of PPIs for prophylaxis in critically ill patients may be causing more harm than benefit. [4,5]
Despite the limited evidence and potential harm, use of PPI for stress ulcer prophylaxis is a common practice. Therefore, the Pantoprazole or Placebo for Stress Ulcer Prophylaxis (POP-UP) trial was designed as an exploratory study to evaluate whether the benefits of stress ulcer prophylaxis outweigh its potential harm. 
|Pantoprazole or Placebo for Stress Ulcer Prophylaxis (POP-UP): Randomized Double-Blind Exploratory Study.|
|Design||Prospective, randomized, double-blind, parallel-group study; (N= 214)|
|Objective||To evaluate benefit or harm associated with pantoprazole administration|
|Study Groups||Pantoprazole (40 mg IV daily) (n= 106)
Placebo (saline) (n= 108)
· Patients anticipated to be invasively mechanically ventilated > 24 hours
· Receive enteral nutrition within 48 hours of admission
· Use of acid-suppressive therapy prior to admission
· Admission with gastrointestinal bleeding
· History of proven peptic ulcer disease
· Administration of greater than 100 mg daily of prednisolone (or equivalent corticosteroid)
· Surgery on the upper gastrointestinal tract or cardiac surgery during the current hospital admission
· 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
· Patients readmitted to the ICU
Clinically significant GI bleeding was determined in cases of overt bleeding (hematemesis, bloody gastric aspirate, melena, or hematochezia), along with at least one of the following:
1) a reduction in mean arterial blood pressure ≥ 20 mm Hg within 24 hours in the absence of another cause
2) a reduction in hemoglobin of ≥ 20 g/L within 24 hours,
3) a need for endoscopy or surgery to achieve hemostasis
Definitions from the Center for Disease and Control (CDC) were used to determine cases of infective ventilator-associated complications of pneumonia. Stool testing for Clostridium difficile toxin B were sent when patients had ≥ 3 bowel movements within 24 hours.
|Duration||January 2014 – January 2015|
|Primary Outcome Measure||· Clinically significant gastrointestinal (GI) bleeding
· Ventilator-associated complication or pneumonia
· Clostridium difficile infection
IQR = interquartile range.
|Adverse Events||Common Adverse Events: not disclosed|
|Serious Adverse Events: not disclosed|
|Percentage that Discontinued due to Adverse Events: not disclosed|
|Study Author Conclusions||There is no evidence of any benefit or harm with the use of pantoprazole for stress ulcer prophylaxis in critically ill, mechanically ventilated patients. The current practice of using acid-suppressive drugs for stress ulcer prophylaxis in critically ill patients needs to be further evaluated.|
According to the results of the POP-UP trial, there is a lack of evidence to warrant the use of pantoprazole for stress ulcer prophylaxis. However, this study was completed with a relatively small sample size, and may have been underpowered. Therefore, the results should not be considered definitive. Additionally, including only patients receiving enteral nutrition within 48 hours of admission may be a limitation as enteral feeding has been associated with prevention of stress ulcers.  Finally, including only patients that had been on ventilator support for ≥ 24 may limit the study results’ generalizability. Strengths of this study is the robust study design such as randomization of all patients and blinding all study participants. Based on the evidence, it may be prudent for prescribers who currently use PPIs for stress ulcer prophylaxis in the ICU to consider the uncertainty of true benefits of stress ulcer prophylaxis in the ICU setting. However, future randomized controlled trials with larger sample sizes may be warranted to further evaluate the risks and benefits of the current practices for stress ulcer prophylaxis.
 ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis. ASHP Commission on Therapeutics and approved by the ASHP Board of Directors on November 14, 1998. Am J Health Syst Pharm. 1999;56(4):347-79.
 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, 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(10):1842-50.
 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
 Hurt RT, Frazier TH, Mcclave SA, et al. Stress prophylaxis in intensive care unit patients and the role of enteral nutrition. JPEN J Parenter Enteral Nutr. 2012;36(6):721-31.