Rethinking GI Prophylaxis for the Critically Ill

Medscape

2 days ago

Prevention doesn't come easy. The bar is high. The decision to act medically because an untoward outcome could occur means creating intervention side-effect risk that's otherwise absent. Large patient numbers must be subjected to that side-effect risk to obtain net benefit. Last, your bedside modeling must be tight, and in medicine it never is.
The story of gastrointestinal (GI) prophylaxis in ICU highlights these challenges. It is best told by Deborah Cook, the godmother of ICU research. It's told through her work. She's randomized more patients than a sequence generator. Her name is the most critical MeSH term for your systematic review. If Churg, Strauss, and Wegener hadn't ruined the disease eponym practice, she'd have several to her name. Just as well; we're all transgressing some currently unidentified but soon-to-be-coined "-ism."
Cook's work has dominated the GI prophylaxis space since the early 1990s. If you're new to it, start with her New England Journal of Medicine (NEJM) review from 2018. It was published on the heels of the latest randomized control trial on GI prophylaxis in the ICU. The SUP-ICU trial, which randomized patients to pantoprazole vs placebo and was also published in NEJM, had equivocal results. The accompanying editorial provided a tepid endorsement of continued prophylaxis with proton pump inhibitors (PPI), but only for those at high risk for bleeding.
Two years later, a systematic review and another randomized trial (PEPTIC) found a mortality signal with PPIs, but in the wrong direction. This drove some back to H2 blockers even though they are less effective than PPI for preventing bleeding. Where I practice I see an equal number of ICU patients on PPI or H2 blockers. There seems to be no clear preference or consensus.
The indomitable Dr Cook just investigated the mortality difference in the REVISE trial, published last year. She and her colleagues also produced an updated systematic review. REVISE made me feel better. I've been a PPI-for-prophylaxis guy for anyone on mechanical ventilation. I held on after PEPTIC and SUP-ICU created doubt, and REVISE seemed to vindicate my practice. REVISE found that PPI decreased bleeding without increasing mortality. PPI didn't increase pneumonia or Clostridioides difficile infections either.
Unfortunately, it's never that simple. The mortality signal was still present in the updated systematic review. The mortality "noise" is dependent on severity of illness. It's the sicker patients who have a higher mortality when given PPI for prophylaxis. Why? I'm not sure. The pneumonia and C diff associations were absent in SUP-ICU, REVISE, and the updated systematic review. The systematic review authors list multiple possible explanations, given that PPI are associated with an altered microbiome, endothelial changes, and delirium. If there is a causal mechanism affecting mortality, it's not clear why the direction is discordant across levels of illness severity.
Conclusions drawn by the editorials accompanying SUP-ICU and REVISE are also discordant. Seven years ago, the idea was that PPIs were most beneficial in those who are 'seriously ill with a high risk of complications.' Fast-forward and the REVISE editorial suggests PPI for those on mechanical ventilation and an APACHE II score of less than 25. Figure 2 in Dr Cook's 2018 review lists risk factors for bleeding— lots of overlap with the APACHE and other illness severity scores. Can a patient be at high bleeding risk but have an APACHE II score less than 25? I'm sure they can, but that needle won't be easy to thread at the bedside.
Can Dr Cook snatch clarity from the jaws of this data quagmire? Perhaps. Her group just published another paper on GI bleeding in the ICU. The focus was on bleeding events that are considered important by ICU survivors and family members. This was a preplanned analysis of data from the REVISE trial. PPI shined again, reducing patient-important events regardless of illness severity. They used a proportional hazards model, that accounts for the competing risk for death, to analyze their primary outcome. Not sure if this provides clarity per se but it does make me feel better about continuing to use prophylactic PPI for my mechanically ventilated patients.