POP-UP

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Selvanderan SP, et al. "Pantoprazole or Placebo for Stress Ulcer Prophylaxis (POP-UP): Randomized Double-Blind Exploratory Study". Critical Care Medicine. 2016. 44(10):1842-1850.
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Clinical Question

Among intubated patients, does routine administration of pantoprazole reduce the risk of stress ulcer-associated bleeding or increase the risk of infections such as C. difficile-associated diarrhea or ventilator-associated pneumonia?

Bottom Line

Among intubated patients in the ICU suitable for enteral nutrition, daily intravenous pantoprazole did not have any impact on the rates of significant gastrointestinal bleeding, C. difficile-associated diarrhea, or ventilator-associated pneumonia, and thus the routine use of PPIs in these patients should be reconsidered.

Major Points

Classical teaching holds that critical illness is associated with gut dysmotility and inability to tolerate enteral feeding, as well as stress ulcers. Historically these issues have been addressed by routinely delaying enteral nutrition and by routinely using prophylactic acid suppression in critically ill patients. However, these classical teachings were reconsidered when several studies subsequently demonstrated that early feeding yields several benefits,[1] and that routine stress ulcer prophylaxis may be associated with infectious complications including C. difficile-associated diarrhea and pneumonia.

The POP-UP trial was carried out in a medical-surgical ICU, and randomized 216 intubated ICU patients at low risk of stress ulcer development (e.g., anticipated initiation of enteral feeding within 48 hours, no high-dose corticosteroids) to either daily IV pantoprazole or placebo. The primary endpoints were clinically significant gastrointestinal bleeding attributed to stress ulcers, as well as rates of infections such as C. difficile-associated diarrhea and ventilator associated pneumonia during their ICU admission or up to 7 days after discontinuing the study drug. At the completion of the study, there was no statistically significant difference in the rates of significant bleeding, C. difficile infections, or of ventilator-associated complications or pneumonia. The authors conclude that there is no evidence of benefit or harm to the use of routine PPIs for stress ulcer prophylaxis in intubated patients at low risk for the development of stress ulcers.

This trial was limited by its small sample size and exploratory design in which power calculations were not performed nor P values provided for major outcomes. Generalizability is limited as patients enrolled in this study were at relatively low risk for stress ulcer development based on the exclusion of patients who had previously received high-dose corticosteroids, prior acid suppression, or who were not expected to receive enteral nutrition within 48 hours of study randomization; thus the study's results may not be applied to high-risk patients. The SUP-ICU trial[2] may shed further light on this question.

Guidelines

Surviving Sepsis Campaign (2016, adapted):[3]

  • We recommend that stress ulcer prophylaxis be given to patients with sepsis or septic shock who have risk factors for gastrointestinal bleeding (strong recommendation, low quality of evidence).
  • We suggest using either proton pump inhibitors or histamine-2 receptor antagonists when stress ulcer prophylaxis is indicated (weak recommendation, low quality of evidence).
  • We recommend against stress ulcer prophylaxis in patients without risk factors for gastrointestinal bleeding.

Design

  • Exploratory, Prospective, randomized, double-blind, parallel-group
  • N=216
    • Pantoprazole (40 mg IV daily) (n=106)
    • Placebo (saline) (n=108)
  • Setting: Royal Adelaide Hospital, the major quaternary referral center in the state of South Australia
  • Enrollment: 2014-2015
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • Clinically significant gastrointestinal bleeding
    • Ventilator-associated complication or pneumonia
    • Clostridium difficile infection

Population

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/d 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
  • Aatients readmitted to the ICU

Baseline Characteristics

From the placebo group.

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

Interventions

  • Randomly assigned to receive Pantoprazole 40mg IV once daily vs. placebo IV
  • Intervention stopped once patients no longer mechanically ventilated or maximum of 14 days

Outcomes

Comparisons are placebo vs. pantoprazole.

Primary Outcomes

Clinically Significant Gastrointestinal Bleeding
0 vs. 0 (P not provided)
Ventilator-associated complication or pneumonia
0.9% vs. 1.9% (P not provided)
Clostridium difficile infection
0% vs. 0.9% (P not provided)

Secondary Outcomes

Overt bleeding
5.6% vs. 2.8% (P=0.50)
Clinician-adjudicated ventilator-associated pneumonia
7.4% vs. 11.3% (P=0.35)
Ventilator-free days at day 28
21 vs. 21 (P=0.69)
ICU length of stay, days
7 vs. 6 (P=0.16)
Hospital length of stay, days
18 vs. 16 (P=0.88)
90-day all-cause mortality
23.1% vs. 28.3% (P not provided)

Criticisms

  • Selection bias:
    • Included only patients anticipated to commence enteral feeding within 48 hours
    • Only randomized patients thought to be mechanically ventilated for more than 24hrs
    • Low-risk patients: excluded patients receiving acid-suppression prior to ICU admission, concurrent steroids, and peptic ulcer disease, and thus sample may not accurately reflect the sepsis population
  • Possibly underpowered: Convenience sample used, no power calculation completed. P values not provided for major outcomes.
  • Primary outcomes are surrogates and hard outcomes may have been more meaningful but would have required a much larger sample size.

Funding

  • Royal Adelaide Hospital Research Foundation (project grant)
  • Conflict of interest potential for one author receiving funding from industry

Further Reading

  1. Marik PE, Vasu T, Hirani A, Pachinburavan M: Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med 2010; 38(11):2222-8.
  2. Krag M et al. Stress ulcer prophylaxis with a proton pump inhibitor versus placebo in critically ill patients (SUP-ICU trial): study protocol for a randomised controlled trial. Trials 2016. 17:205.
  3. Rhodes A, et al. "Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016." Critical Care Medicine: March 2017 - Volume 45 - Issue 3 - p 486–552