May 172015

There’s always been doubt about the efficacy of the numerous "ventilator bundles" hospitals use to prevent ventilator-associated pneumonia (VAP). A provocative new analysis concludes that none of these methods save lives — except the one that almost no ICUs are using today.

Healthcare associated pneumonias (HAP), especially ventilator-associated pneumonias (VAP), are associated with increased mortality, excess antibiotic use, lengthened hospital stays and increased ventilator days. To what extent is unknown, because VAP is notoriously difficult to diagnose consistently, or to study productively.

Most cases of HAP and VAP are caused by tiny aspirations of bacteria from the mouth and throat into the airways. In mechanically ventilated patients, gram negative rods and other gut bacteria can reflux up the esophagus into the pharynx, from where they may slide down past the endotracheal tube cuff into the lower airways, causing VAP.

Numerous strategies have been investigated to prevent VAP and HAP: head-of-bed elevation; oral cleaning and/or antibiotic paste, gastric ulcer prophylaxis, acidifying enteral feedings, postpyloric feeding tubessubglottic suctioning, ventilator circuit changes, early tracheostomy, and many more. Clinical studies have reported conflicting evidence of benefit for virtually all VAP prevention techniques.

Authors of a new review and meta-analysis in Clinical Infectious Diseases examined 150 randomized trials (n~37,000) testing nearly every conceivable method of HAP and VAP prevention. No VAP prevention method reduced mortality except one: routinely giving systemic (intravenous) antibiotics to all mechanically ventilated patients early in their ICU course, in order to decontaminate their gut.

The statistical power was high, and so was the mortality benefit: a 22% relative risk reduction with antibiotic gut decontamination. (In ICUs with 15% mortality, this would be about a 3% absolute risk reduction, or a number needed to treat of 33 to save a life.)

The benefit was seen only in studies providing systemic (usually intravenous) antibiotics. Fluoroquinolones, tobramycin, and other antimicrobials with activity against gram negative rods were used.

Numerous methods were found to prevent VAP, but had no influence on mortality (e.g., postpyloric feeding, silver-coated endotracheal tubes, selective oral decontamination, subglottic suctioning, tracheal saline instillation, and PEEP use). But many experts question whether these open-label (unblinded) VAP prevention studies' conclusions are valid. When it’s discernible which patients are receiving prophylaxis, and the diagnosis of VAP is so observer-dependent, it’s too easy for investigators to overdiagnose borderline cases of VAP in the controls and ignore them in the intervention patients. Publication bias (favoring positive studies) is also a risk. That’s why the authors chose mortality as the endpoint for their analysis.

The number of randomized trials of antibiotic gut decontamination (14) and their enrollment (n=7,025) dwarfed those of the other interventions. Combining this power with its large effect, the lifesaving effects of prophylactic antibiotics are very likely to be real. (Statistical uncertainty means it’s possible, but not likely, that other VAP prevention methods could save lives.)

Antibiotic Prophylaxis for all Critically Ill Patients?

The Infectious Diseases Society of America (IDSA) seems to agree that antibiotic prophylaxis against VAP can save lives. Noting the above-mentioned studies, IDSA's experts have considered antibiotic prophlaxis a "special practice" that may be appropriate for centers with high rates of VAP persisting despite high compliance with its ventilator bundle. But they have argued against routine antibiotic prophylaxis against VAP, citing concerns for increasing antimicrobial resistance and C. difficile infections.

However, this fear may be unfounded. Antibiotic resistance (MRSA, VRE, etc) was not increased in a meta-analysis of 35 studies employing prophylactic antibiotics against VAP -- and in fact, resistance to cephalosporins and polymyxins developed less often in the group receiving antibiotics.

Antibiotic prophylaxis could have benefits beyond prevention of ventilator-associated pneumonia. Gut bacteria are a major cause of sepsis and septic shock, presumably through translocation into the bloodstream. By bringing down the bacterial load in the gut by a few orders of magnitude, a multitude of forthcoming systemic infections might be prevented in critically ill patients. This could result in lower antibiotic use (and resistance pressure) overall, and would be a more plausible explanation of the 22% mortality reduction seen with antimicrobial gut decontamination in the analyzed studies -- an effect unlikely to result just through VAP prevention.

This rationale for providing prophylactic antibiotics is already established in bone marrow transplant patients, those with HIV/AIDS, and prior to surgery. Should critically ill patients requiring mechanical ventilation join this list?

IDSA spokesperson Michael Klompas wonders in this editorial whether just such a paradigm shift might evolve from the signals in the data we have:

As an infectious disease physician, I am instinctively uncomfortable with digestive decontamination with systemic antimicrobials ... [But] it behooves us now to conduct the definitive studies of digestive decontamination in North America with long enough follow-up periods to settle the question for once and for all of the relative benefits and risks of routine digestive decontamination. We owe it to our patients.

Some of these studies are already underway. Stay tuned.

Read more:

Roquilly A et al. Pneumonia Prevention to Decrease Mortality in Intensive Care Unit: A Systematic Review and Meta-analysis. Clinical Infectious Diseases 2015;60(1):64–75.

Klompas M. Evidence vs Instinct for Pneumonia Prevention in Hospitalized Patients. Clinical Infectious Diseases 2015;60(1):76–8.

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The only VAP prevention method that saves lives is the one you’re not using