Pantoprazole or Placebo for Stress Ulcer Prophylaxis?

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. [3] 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. [3]


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)

Methods Inclusion Criteria

·   Patients anticipated to be invasively mechanically ventilated > 24 hours

·   Receive enteral nutrition within 48 hours of admission
Exclusion Criteria

·   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

·   Pregnancy

·   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
The intervention was given once daily until the patient no longer required mechanical ventilation or for 14 days. Interventions were also discontinued at the request of the physician or due to withdrawal of consent. Patients were randomly assigned in a 1:1 ratio to receive either pantoprazole or placebo.

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

Baseline Characteristics
Data Field Placebo (n= 108) Pantoprazole (n= 106)
Male sex (%) 72 (67) 68 (64)
Age (yr) 52 (17) 52 (18)
Acute Physiology and Chronic Health Evaluation III score 66 (28) 66 (26)
Medications prescribed at enrollment
Nonsteroidal anti-inflammatory drug, n (%) 16 (15) 15 (14)
Oral/IV corticosteroids, n (%) 15 (14) 9 (8)
Inotrope/vasoconstrictor infusion, n (%) 57 (53) 52 (49)
Maximum inotrope dose* (μg/min), median (IQR) 10 (6–18) 10 (5–21)
Receiving vasopressin, n (%) 1 0
Other previous medical history
Kidney failure (Risk, Injury, Failure, Loss of Function, End-stage Renal Failure score)
Risk 6 9
Injury 5 5
Failure   2 1
End-stage renal failure 0 1
Clostridium difficile infection 0 0
Immunosuppressed   9 3
Drug related 4 0
Hematological malignancy 0 0
Disseminated malignancy 3 3
HIV   1 0
Chronic liver disease 2 0
Other cause 1 0
Primary ICU diagnostic group (nonoperative/postoperative)
Trauma 20/12 18/13
Neurologic 18/8 27/8
Respiratory 14/10 15/4
Cardiovascular 13/1 7/2
Sepsis 3/— 3/—
Gastrointestinal 1/4 0/3
Metabolic 1/— 5/—
Renal 1/— 0/—
Source of ICU admission, n (%)
Operating theatre 53 (49) 47 (45)
Emergency department 36 (33) 31 (30)
General ward 12 (11) 17 (16)
Transfer from other hospitals 7 (6) 8 (8)
Transfer from other emergency department/ICU 0 2 (2)

IQR = interquartile range.

*Maximum inotrope dose = maximum combined noradrenaline and adrenaline dose (μg/min) recorded.

Outcome Placebo (n= 108) Pantoprazole (n= 106) Total (n= 214)
Episodes CI Episodes CI Episodes CI
GI bleeding 0 Upper 97.5% CI, 3.36 0 Upper 97.5% CI, 3.42 0 Upper 97.5%, 1.71
Infective ventilator associated complication or pneumonia 1 (0.9%) 95% CI, 0.02-5.1 2 (1.9%) 95% CI, 0.2-5.1
Clostridium difficile infection 0 97.5% CI, 3.4 1 (0.9%) 95% CI, 0.02-5.1)
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. [6] 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.  


[1] 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.

[2] 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 

[3] 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.

[4] 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 

[5] 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 

[6] 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.


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