Effect of oral decontamination with chlorhexidine on the incidence of nosocomial pneumonia: a meta-analysis

Nosocomial pneumonia (NP) is a frequent complication in critically ill patients requiring mechanical ventilation and is responsible for a significant in-hospital morbidity and mortality. Multiple hospital-associated risk factors for NP have been identified. These risk factors are thought to contribute to increased bacterial colonization of the aerodigestive tract and/or facilitate entry of pathogenic bacteria to the lower respiratory tract. Among these factors are the use of nasogastric tubes, a supine position, re-intubation, manipulation of airway/ventilator circuits, pooling of subglottic secretions, transfusion of packed red blood cells, pH altering agents, and dental plaque colonization [1–4].

While the oral flora of a healthy individual is largely composed of viridans streptococcus, the oral flora undergoes a major shift during intensive care unit (ICU) stay from Gram-positive streptococci to predominantly Gram-negative organisms, including pathogens responsible for NP. The role of these pathogens are highlighted in epidemiological studies showing a high concordance between the bacteria isolated from the oropharyngeal cavity and those recovered from tracheal aspirates [4, 5]. Recently, our laboratory, using molecular genotyping, has confirmed this association between pathogens colonizing dental plaques and those responsible for NP in the critically ill institutionalized elderly [6]. As a result, multiple interventional trials have been initiated to assess the efficacy of topical oral antiseptic agents on the incidence of ventilator-associated pneumonia.

Chlorhexidine is an antimicrobial cationic compound active against aerobic and anaerobic bacteria. It increases the bacterial cell wall permeability in a dose dependent fashion by interacting with anionic receptors on the bacterial surface. Its therapeutic benefit has been demonstrated in reducing dental plaque and treating gingivitis [7]. By virtue of its rapid reduction of oropharyngeal bacterial load [8], several studies have evaluated the effectiveness of oral chlorhexidine in preventing NP [9–12]. These trials have yielded conflicting results. Hence, we conducted a meta-analysis of available clinical trials to evaluate the efficacy of oral chlorhexidine application on the incidence of NP in patients who required mechanical ventilation.

Our literature search identified 1,251 potential relevant citations. Of these, we considered seven citations for possible inclusion in the meta-analysis [9–12, 17–19]. These seven publications were identified through Medline searches. No unpublished studies, personal communications, or abstract satisfied the inclusion criteria. We excluded two out of the seven studies because they were not randomized and one because it used a single application of chlorhexidine [17–19].

As shown in Figure 1, although the point estimate for the pooled odds ratio favored chlorhexidine treatment in the prevention of NP, this difference was not statistically significant (0.42, 95% CI 0.61–1.06; p = 0.07). Similarly, there were also no significant difference in mortality rate between the two groups (0.77, 95% CI 0.28–2.11; p = 0.6; Figure 2). For these estimates, we found no evidence of statistical heterogeneity or publication bias (p = 0.13 and p = 0.68 for the incidence of pneumonia and mortality, respectively).

The results of this meta-analysis suggest that the incidence of NP and rate of mortality are not reduced by administration of the oral antiseptic agent chlorhexidine. Of the four trials that were selected for inclusion in the meta-analysis, only one trial showed a statistically significant reduction in the incidence of NP [10]; yet, the study failed to adjust for inclusion of repeated observations. Moreover, DeRiso and coworkers [9] reported a 69% reduction in overall nosocomial respiratory infections, but when a comparison of the rate of lower respiratory tract infections was presented, the difference between the treatment and control groups was not statistically significant. If chlorhexidine treatment has been proven to be an effective therapy in vitro for eradication of bacteria responsible for oropharyngeal colonization, why did it not improve the rate of lower respiratory tract infections in mechanically ventilated patients?

A review of studies that have examined oral and lung colonization have shown that changes in the microenvironment of the oral cavity likely play a key role in the colonization of the oropharynx with NP related pathogens [20, 21]. Serial examination of dental plaques of critically ill patients revealed that while the frequency of dental colonization increased in critically ill patients, the density of bacterial pathogens following treatment with chlorhexidine remained stable [11]. The lack of a complete decontaminating effect of chlorhexidine on dental plaques might suggest, among other things, impairment of innate oral immunity and/or loss of protective function of saliva. Because salivary flow provides a mechanical tool for removal of plaques and microorganisms, reduced circulation of saliva leads to microbial overgrowth, accumulation of dental plaques, and rampant dental caries [22, 23]. This constant buildup of dental plaques might explain the failure to completely eradicate microorganisms with chlorhexidine treatment.

Formation of biofilm is another potential microenvironmental factor that may influence the eradication of ventilator associated pneumonia related pathogens from dental plaques. Fourrier and colleagues [11] noted that microbiological analysis of dental plaques obtained from patients with late onset ventilator associated pneumonia revealed a high prevalence of highly resistant bacterial pathogens (Pseudomonas, Acinetobacter, and Enterobacter species) that were not eliminated by topical chlorhexidine. Notoriously, upon attachment, P. aeruginosa activates a set of genes responsible for the release of diffusible homoserine lactones (quorum sensors). These organic molecules promote biofilm formation, which protects bacteria from host defenses and antibiotics [24] and prevents antiseptic agents from reaching the bacteria embedded in the dental plaques.

If reducing bacterial growth in the dental plaques with chlorhexidine did not result in a significant reduction in NP, perhaps there are other unrecognized niches for respiratory pathogens between the oropharynx and the lungs that are implicated in the development of lower respiratory tract infections. It has been shown that the lungs of normal animals are not able to clear bacteria present in the form of biofilm fragments enclosed in artificial matrices [25]. As such, endotracheal tubes may serve as foci for bacteria in the biofilm that invariably forms on the inner lumen. Once the bacteria are well established, the bacterial burden attains high levels, and the biofilm, when fractured and displaced into the lower airways, acts as inoculum for the development of pneumonia [26]. Unless they are able to eradicate such biofilms, oral antiseptic agents alone might fall short of attaining their objective.

Our analysis has several important limitations. First, there were major differences between the studies conducted in the cardiac surgery population [9, 12] versus those performed in ICU settings [10, 11]. Patients admitted for elective cardiac surgery were likely to have different comorbid conditions and better physiological status at the time of intubation than were patients intubated emergently. Moreover, the length of mechanical ventilation for cardiac surgery and ICU patients would be significantly different such that colonization with highly resistant bacteria in ICU patients would be less amenable to chlorhexidine treatment [11]. Second, all of the trials for the meta-analysis were conducted in academic teaching centers, and so it is unclear if these results are generalizable to other institutions. Third the trials used different approaches for the control arms. Two investigations [9, 11] used placebos that were completely indistinguishable from chlorhexidine by color, taste, and odor, whereas the other trials relied on either standard oral care or Listerine. This may have resulted in confounding when the data were pooled. Fourth, even though we were able to pool results across four trials, the combined sample size may still have been inadequate for detecting important clinical differences.

In this meta-analysis, we failed to find any clinical benefits of regular oral chlorhexidine application on the incidence of NP and mortality rate in critically ill patients requiring mechanical ventilation. Although colonization of dental plaques with pathogenic bacteria may be a precursor for the disease, chlorhexidine based decontamination of oral microbial flora alone might not be sufficient to reduce the burden of bacteria responsible for NP. Routine oral care in ICU settings should be pursued along with other preventive measures aimed at reducing biofilm formation pending the results of ongoing trials addressing oral mechanical interventions and silver coated endotracheal tubes.