In our September 2, 2008 Patient Safety Tip of the Week “Updates on VAP Prevention” we discussed the recent NICE evidence-based guidance on technical patient safety solutions for prevention of ventilator-associated pneumonia. In that they noted that evidence suggests that selective decontamination of the digestive tract (SDD) using topical antibiotics may reduce the incidence of ventilator-associated pneumonia (VAP) and also reduce mortality. However, concerns about the risk of infection with Clostridium difficile and the induction and/or selection of resistant, including multiresistant, microorganisms as a result of SDD kept them from recommending this.
Now a new study from the Netherlands (de Smet et al 2009) published in the New England Journal of Medicine suggests that overall ICU mortality can be reduced by selective decontamination of the digestive tract (SDD) or by selective oropharyngeal decontamination (SOD) without emergence of antibiotic resistance or increase in C. diff infections. This study was not about preventing just VAP but rather preventing all ICU infectious complications and improving mortality. Eligibility for the trial required expected duration of intubation of more than 48 hours or expected ICU length of stay of more than 72 hours. Patients in the SDD group also received 4 days of systemic antibiotics (intravenous cefotaxime) in addition to topical application of tobramycin, colistin, and amphotericin B in the oropharynx and stomach. SOD consisted of oropharyngeal application of the same paste used for SDD. Both groups were compared to a group receiving standard treatment. Also, in the SDD group only, systemic antibiotics with antianaerobic activity were discouraged.
The study utilized a cluster methodology in which all 3 study regimens were administered in each ICU over the course of 6 months, with the order being randomly assigned. The randomization procedure was scientifically sound but there were differences in baseline characteristics of the patients (with patients in the standard care group being younger, having lower APACHE II scores, less likely to be mechanically ventilated, and more likely to be admitted for surgical reasons).
The primary outcome measure was mortality at Day 28. In a random-effects logistic regression model adjusted for multiple covariates, the odds ratios for death at Day 28 compared to standard treatment were 0.83 for SDD and 0.86 for SOD, both statistically significant. The respective absolute risk reductions were 3.5% for SDD and 2.9% for SOD (respective numbers needed to treat = 29 and 34). Trends toward improvement in secondary outcomes such as ICU and total LOS, and time on ventilator in the SDD and SOD groups did not reach statistical significance. Median number of systemic antibiotic doses did not differ significantly among the three groups. Importantly, surveillance revealed no increase in antibiotic resistance nor increase in C. diff prevalence during the study period. Both SDD and SOD were low-cost (SOD costing about $1 per day and SDD about $12 per day).
But there are numerous issues with this study. Most importantly, benefit in the primary outcome measure was seen only after adjustment for covariates. The study analysis plan had to be changed from its original plan. The investigators had intended to use in-hospital mortality as the primary outcome measure. However, for a variety of theoretical statistical reasons that apply to cluster-randomization trials, the plan was changed and called for the Day 28 mortality as the primary outcome measure and use of the random effects model to account for effect of covariates. Also, as mentioned previously, the randomization procedure did not result in study groups with similar baseline characteristics. The study was also not blinded (the treating physicians and investigators were aware of the treatment group randomization).
So what are the take-home lessons here? Perhaps the best lesson is that the SOD group had essentially as good outcomes as the SDD group. The authors themselves note that this may also mean that oropharyngeal decontamination with agents such as chlorhexidine might be a potential alternative approach.
While the findings of this study are exciting, we remain conservative in endorsing their conclusions. We’d like to see another study confirm that one of these interventions (SOD would be the obvious one to choose) reduces mortality in ICU populations elsewhere. Hopefully that study will avoid some of the methodological problems and issues encountered in the current study.
This is particularly important since some other new studies are demonstrating that some rather simple interventions may be effective in preventing VAP. An article in Nursing Times cites a research study to be published soon in the Journal of Intensive Care Medicine showing that teeth cleaning in ventilated patients cuts the rate of VAP in half. Twice daily brushing for one minute, followed by application of mouthwash, cut the VAP rate from 5.2% to 2.4%, an improvement that was sustained over time. However, we are awaiting publication of that study to see whether the more important clinical parameters improved. In our November 11, 2008 Patient Safety Tip of the Week “Probiotics and VAP Prevention” we had mentioned that oral decontamination with chlorhexidine (CHX) has been shown to prevent VAP (Chlebick 2007) but does not reduce the time on the ventilator, the length of stay (LOS) in the ICU or rates of mortality (Chan 2007). The incidence of VAP and other ICU infections is of interest but the more important clinical outcomes are outcomes like mortality, time on the ventilator, ICU and hospital LOS, and costs.
Update: The article referenced above has now been published in the Journal of Intensive Care Medicine (Sona 2009). Their protocol consisted of brushing the patients' teeth with toothpaste, rinsing with tap water, and subsequent application of a 0.12% chlorhexidine gluconate chemical solution done twice daily at 12-hour intervals. Their VAP rate fell from 5.2 cases per 1000 ventilator days to 2.4 cases per 1000 ventilator days after institution of the protocol, a 46% reduction. The intervention was very low cost and nursing compliance with the protocol was over 80%. They did not actually measure savings but estimate that the 14 VAP cases prevented in one year would have saved $140,000 to $560,000 based on the literature estimates that VAP cases cost $10,000 to $40,000 per case.
NICE. PSG002 Technical patient safety solutions for prevention of ventilator-associated pneumonia in adults: guidance. 27 August 2008 http://www.nice.org.uk/nicemedia/pdf/PSG002Guidance.pdf
de Smet AMGA, Kluytmans JAJW, Cooper BS, et al. Decontamination of the Digestive Tract and Oropharynx in ICU Patients. New England Journal of Medicine 2009; 360(1):20-31, January 1, 2009
Ford S. Pneumonia rates in ICU can be halved by cleaning teeth. Nursing Times. December16, 2008
Chlebick MP, Safdar N: Topical chlorhexidine for prevention of ventilator-associated
pneumonia: A meta-analysis. Crit Care Med 2007, 35:595–602 http://www.ccmjournal.com/pt/re/ccm/abstract.00003246-200702000-00037.htm;jsessionid=JYzZFqbp77jdqFqLrhwhZ1cbDLbnBwLvyYMRxvhTwWK48kjGpw9B!-1031399950!181195629!8091!-1?index=1&database=ppvovft&results=1&count=10&searchid=2&nav=search
Chan EY, Ruest A, O Meade M and Cook DJ: Oral decontamination for prevention of
systematic review and meta-analysis pneumonia in mechanically ventilated adults.
Sona CS, Zack JE, Schallom ME, McSweeney M, McMullen K, Thomas J, Coopersmith CM, Boyle WA, Buchman TG, Mazuski JE, Schuerer DJE.The Impact of a Simple, Low-cost Oral Care Protocol on Ventilator-associated Pneumonia Rates in a Surgical Intensive Care Unit. J Intensive Care Med 2009 24: 54-62