Disaggregating the Benefits of Ventilator Bundle Components

There is a very nice study by Michael Klompas and colleagues in September's JAMA Internal Medicine. The team sought to disentangle the benefits or harms of the individual components of current ventilator bundles including: head-of-bed elevation, sedative infusion interruptions, spontaneous breathing trials, thromboprophylaxis, stress ulcer prophylaxis, and oral care with chlorhexidine.

Prior studies had found potential harm associated with stress ulcer prophylaxis (pneumonia) and oral chlorhexidine (higher mortality). This same group published a meta-analysis that called into question the benefits of routine oral care with chlorhexidine (CHG) in ventilated patients. For this retrospective cohort, they examined the associations between exposure to individual ventilator bundle components on a day-by-day basis and ventilator-associated events (VAEs), duration of mechanical ventilation, ventilator mortality, hospital length of stay, and hospital mortality.

The cohort included 5539 consecutive patients who were exposed to mechanical ventilation for at least 3 days. They measured the association between individual process measures and VAEs using Cox proportional hazards regression models with fixed and time-varying covariates and censored patients on extubation or death, whichever came first. Interestingly, they calculated hazard ratios for each bundle component "as the contrast between 4 days of continually performing the process measure vs 4 days of not doing so", since they wanted to allow for the possibility that process measures might have an immediate or delayed effect on each outcome.

I have included the patient-outcomes table below. The most interesting finding, among many tested associations, was that oral care with chlorhexidine was associated with an increased risk for ventilator mortality (HR, 1.63; 95% CI, 1.15-2.31; P = .006). In another table, they reported that stress ulcer prophylaxis was associated with an increased risk for possible ventilator-associated pneumonia (HR, 7.69; 95% CI, 1.44-41.10; P = .02).

This was a very thoughtfully completed and written study - I encourage you to read it (and the accompanying invited editorial) beyond my quick overview. The authors concluded: "we should revisit the classic ventilator bundle. Possible revisions include... a reappraisal of whether oral care protocols should be revised to exclude chlorhexidine therapy, and the reservation of stress ulcer prophylaxis for patients at marked and immediate risk for upper gastrointestinal tract bleeding rather than prescribing them for all patients undergoing ventilation."  It will be interesting to see how slowly these recommended changes occur...

Pneumonia Prevention Bundle in Nursing Homes: A Cluster-randomized Trail

If you're looking for another infection prevention bundle in long-term care, look no further than the March 15th issue of CID that included a cluster-randomized trial of a pneumonia prevention bundle in 36 Connecticut nursing homes by Juthani-Mehta and colleagues at Yale. (full text free)  Residents in the intervention nursing homes with at least one risk factor (impaired oral hygiene or swallowing difficulty) received a bundle that included manual tooth/gum brushing plus 0.12% chlorhexidine oral rinse, twice per day, plus upright positioning during feeding.

The primary outcome was development of first pneumonia defined as "presence of (1) a compatible infiltrate on chest radiograph (CXR) (if previous CXR was available, the infiltrate had to be new or worsened) and (2) at least 2 of the following clinical features within 72 hours of the CXR-documented infiltrate: fever, pleuritic chest pain, respiratory rate over 25 breaths/minute, worsening functional status (ie, decline in level of consciousness or activities of daily living), or new or increased cough, sputum production, shortness of breath, or chest examination findings."  The secondary outcome was first lower respiratory tract infection (LRTI).

After enrolling 834 participants (434 to the intervention arm and 400 to the control arm), the DSMB terminated the study for futility. Results showed no significant differences for cumulative incidence of first pneumonia (Figure 2A, below) or first LRTI between intervention and control arms. In fact, you can see that the intervention arm appears to have higher incidence of first pneumonia, which is concerning. Of note, adherence was 87.9% to chlorhexidine, 75.0% to toothpaste and 100% for upright feeding position in the intervention facilities. The authors offer several explanations for the study's failure, none of which are entirely convincing. For example, adherence at these levels should have still shown some benefit and not a trend toward harm, so it's unlikely that compliance explains the results. For those interested in reading more, there is an excellent commentary by Lona Mody, who we also mentioned last week. And congratulations to the authors and journal for publishing this important negative study.

Save your mupirocin for SSI prevention in cardiac and orthopedic surgery

As our guest blogger, Marc-Oliver Wright, posted last week, widespread use of mupirocin was associated with 400% increase in mupirocin resistance at his hospital. Many are very concerned about widespread and non-selective use of mupirocin as a result of the REDUCE MRSA trial, particularly since the incremental benefit of mupirocin added to CHG is not known. Based on prior studies, it is possible that many of the benefits seen were due to CHG and not necessarily mupirocin.

With that in mind, why should we care about mupirocin resistance? Well, there are instances were mupirocin has more established benefits in the literature and one is in surgical site infection prevention. The issue with most infection prevention intervention studies is that most outcomes like SSIs are rare (fortunately) and research budgets are small, which leads to numerous underpowered quasi-experimental studies. The problem with this type of literature base is that it can lead to unnecessary controversy with clinicians cherry-picking study results to support their specific hypothesis.

To make use of such a literature base and scientifically determine the benefits of nasal decolonization (and other interventions), Marin Schweizer and Loreen Herwaldt at the University of Iowa completed a meta-analysis of SSI prevention intervention studies in cardiac and orthopedic surgery, which was published today in the BMJ (free open access). (COI note: I'm a co-author on the paper and was an independent reviewer/data abstracter) After screening 1423 articles published between 1995 and 2012, they identified 39 studies of moderate to high quality. 17 studies assessed the benefits of nasal decolonization (16 mupirocin and 1 nasal CHG), 15 studied glycopeptide prophylaxis and seven examined the bundle: screening+nasal decolonization+vancomycin). The pooled effects were quite impressive.

Nasal decolonization was associated with a 61% reduction in S. aureus SSIs, a 70% reduction in MRSA SSIs and a 50% reduction in MSSA SSIs. Glycopeptide prophylaxis was associated with a 60% reduction in MRSA SSIs while the full bundle was associated with a significant reduction in S. aureus, MRSA, MSSA and Gram-positive SSIs. I have pasted the table below (click to magnify), but since the full article is open access, you can also read the full article at BMJ.

This meta-analysis guided the implementation of an ongoing trial funded by AHRQ, so more data are coming soon. But what to make of this paper in the context of the recent REDUCE MRSA trial?  I myself am concerned that widespread mupirocin use in all ICU patients will select for resistant S. aureus isolates and render this highly-effective SSI bundle ineffective in short order. It will be sad to watch this example of the 'tragedy of the commons' play out in real time, as I suspect we will. And we will only have ourselves to blame. The data is right before our eyes.

Bundle fumble?

This week's JAMA has an excellent review (free full text here) on the prevention of ventilator-associated pneumonia (VAP). Specifically, the authors offer a critical assessment of the widely utilized IHI VAP bundle. They offer two important conclusions:

• "The ability of the bundle to prevent VAP has not been definitively established with high quality studies."
• "No large randomized study has demonstrated that reducing VAP using any strategy, including the IHI bundle, is associated with improvements in clinical outcomes."

Here's another example where an intervention has been touted as gospel, pushed hard and implemented broadly without the evidence necessary for a hardline approach.

Photo: OregonLive

"You destroyed the bundles"

While at ICAAC over the weekend, I attended a symposium on infection prevention bundles. This excellent session began with Marc Bonten doing a (very) critical review of the literature in support of bundles for VAP and MRSA prevention, after which our own Eli Perencevich discussed how one might begin to parse out which elements of our current bundles are the most important. After these two compelling talks, a young man (an infection preventionist from Italy, I think) approached the microphone with a declaration and a question: “You have destroyed the bundles! What shall we do now?”

I’m hard-pressed to answer this question, except to say that it would be wise to refrain from starting with bundles that have one element that is hugely expensive and of uncertain effectiveness, lest we end up wasting millions on expensive screening tests when “horizontal” infection control measures will suffice.

In other news, R.E.M. has broken up after 31 years. R.E.M. was my soundtrack through medical school and residency training, and their pre-1994 repertoire is still in heavy rotation in my head and on my iPod. So in honor of R.E.M. and in honor of Eli, destroyer of bundles, I give you R.E.M.’s Cuyahoga: