POP-UP

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Selvanderan SP. "Pantoprazole or Placebo for Stress Ulcer Prophylaxis (POP-UP): Randomized Double-Blind Exploratory Study". Crit Care Med. 2016. 44:1842-1850.
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Clinical Question

In critically ill, intubated patients, did the administration of parenteral pantoprazole compared to placebo prevent major or minor bleeding event or put patients at risk of adverse events such as c. diff infection.

Bottom Line

In critically ill patients with anticipated ventilation time greater than 24 hours with enteral feeding initiated within 24 hours and without previous history of peptic ulcer disease, concurrent corticosteroid or previous acid-suppressing therapy, there is no evidence that proton pump inhibitor therapy provides benefit or harm in respect to stress-ulcer prophylaxis.

Major Points

Research on stress ulcers in the critically ill date back decades. These describe multiple concerns and risk factors to be weary of in patients and to then consider medical prophylaxis. When most of the historical research was done, feeding was delayed thinking that the critically ill could not use their GI tract and that their energy should be used for healing, not processing enteral feeds. Since that time "early feeding" has become much more common practice. Medical prophylaxis with proton pump inhibitors and histamine antagonists are not totally free from risks, on top of the costs associated with such therapy. With evidence suggesting the protective effects of feeding [1] and emerging data that these therapies carry increased risks such as thinning bones and C. Diff infection, wide spread use of these agents may not be warranted. This trial, like several other negative trials before it, suggest that these agents may not be necessary if feeding is initiated early, as suggested in the Surviving Sepsis Guidelines last update in 2012. An update to supportive care is slated to be published in the coming year. After recruiting over 200 patients with low risk of stress ulcers (no concurrent steroids, expected feeding within 24hrs, no history of acid suppression), this trial showed neither a protective or deleterious effect using medical management as prophylaxis for stress ulcer, suggesting that only the patients at highest risk will benefit from therapy, and more research into these specific patients may be needed. The SUP-ICU trial [2] which is currently recruiting may help illustrate the population that will benefit but unfortunately is using a PPI as active treatment.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2012, adapted)[3]:

Section U. Stress Ulcer Prophylaxis
  1. H2-blocker or proton pump inhibitor given to patients with severe sepsis/septic shock and bleeding risk factors (grade 1B)
  2. Proton pump inhibitors over H2RA (grade 2D)
  3. Patients without risk factors do not receive prophylaxis (grade 2B).

Design

  • Exploratory, Prospective, randomized, double-blind, parallel-group
  • N=216
    • Pantoprazole (n=106)
    • Placebo (n=108)
  • Setting: Royal Adelaide Hospital, the major quaternary referral center in the state of South Australia
  • Enrollment: 28 January 2014 to 27 January 2015
  • 1:1 ratio computer generated randomization
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • Clinically significant gastrointestinal bleeding
    • Infective 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 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
  • patients readmitted to the ICU.

Baseline Characteristics

Presented as Placebo group

  • Male sex(%): 72(67)
  • Age(yr): 52(17)
  • Acute Physiology and Chronic Health Evaluation III score: 66(28)
  • 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 dosea (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% (upper 97.5% CIs, 3.36) vs. 0% (upper 97.5% CIs, 3.42); P=NS
Infective ventilator associated complication or pneumonia
0.9% (95% CI, 0.02–5.1) vs. 1.9% (95% CI, 0.2–5.1); P=NS
Clostridium difficile infection
0% (97.5% CI, 3.4) vs. 0.9% (95% CI, 0.02–5.1); P=NS

Secondary Outcomes

Time from initiation of mechanical ventilation to the first dose of study drug, hours
17(16-19) vs. 16(15-18); P=NS
Number of doses of study drug administered per patient, Median
3(2-7) vs. 3(1-7); P=NS
Overt bleeding
5.6% (95% CI 2.1– 11.7) vs. 2.8% (95% CI 0.6–8.0); P=NS
Daily hemoglobin concentrations
Adjusted for transfusions P=NS
Group-by-time effect P=NS
Clinician-adjudicated ventilator-associated pneumonia
7.4% (95% CI 3.3–14.1) vs. 11.3% (95% CI 6.0– 18.9); P=NS
Ventilator-free days at day 28
21 (4–25) vs. 21 (0–25); P=NS
ICU length of stay, days
7(4–14) vs. 6(3–11); P=NS
Hospital length of stay, days
18(9–25) vs. 16(8–31); P=NS
90-day all-cause mortality
23.1% (95% CI 15.6–32.2) vs. 28.3% (95% CI 20.0–37.9); P=NS

Subgroup Analysis

Cox proportional hazards model significant covariates (P<0.1)
APACHE III Score
Age

Criticisms

  • Selection bias
    • including only patients anticipated to commence enteral feeding within 48hrs
    • 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
    • sample may not accurately reflect the sepsis population
  • Possibly underpowered: Convenience sample used, no power calculation completed
  • 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. Dellinger RP et al. "Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012." Critical Care Medicine (2013) 41(2) 580-637.