Adding 0.12% chlorhexidine to a standardized oral-care bundle did not reduce ventilator-associated pneumonia in a pragmatic cluster-randomized crossover trial conducted in six adult medical intensive care units of a tertiary-care academic hospital in Bhubaneswar, India. The trial, published in Critical Care, enrolled 1,035 mechanically ventilated adults and accrued 10,024 ventilator-days, and found that the antiseptic rinse that has long been a fixture of ventilator-associated pneumonia prevention offered no measurable incremental benefit over the mechanical components of oral care alone.
Ventilator-associated pneumonia is one of the most consequential complications of invasive mechanical ventilation. Contemporary estimates place its incidence between roughly 7 and 43 episodes per 1,000 ventilator-days across intensive care units worldwide, a wide range that reflects differences in case-mix, diagnostic criteria, and prevention practices. A meta-analysis of randomized prevention trials estimated an overall attributable mortality of approximately 13%, and multiple cohorts have linked the infection to prolonged mechanical ventilation, longer intensive care stays, and higher costs. Because oral colonization and dental plaque biofilms are central to the pathogenesis of the disease, oropharyngeal decontamination has long seemed biologically plausible, and chlorhexidine was widely adopted on the strength of its broad antimicrobial activity and ease of use.
The clinical evidence supporting routine chlorhexidine, however, has grown increasingly inconsistent. In cardiac-surgery populations, chlorhexidine reduces lower-respiratory-tract infections with a relative risk of 0.56 (95% confidence interval 0.41–0.77), but in mixed medical–surgical intensive care populations the effect on ventilator-associated pneumonia is small or uncertain and patient-centered outcomes appear unchanged. A Cochrane systematic review concluded that chlorhexidine probably reduces ventilator-associated pneumonia (relative risk 0.67, 95% confidence interval 0.47–0.97) without affecting mortality or duration of ventilation and intensive care stay, whereas a 2024 systematic review and network meta-analysis of randomized trials found no reduction in ventilator-associated pneumonia, mortality, ventilator days, or intensive care length of stay at any chlorhexidine concentration and concluded that routine use could not be recommended.
Safety concerns have compounded the uncertainty. Reappraisal meta-analyses have reported a non-significant but consistently elevated mortality signal with chlorhexidine in non-cardiac-surgery patients (relative risk 1.13, 95% confidence interval 0.99–1.29), a network meta-analysis reported an excess mortality odds ratio of 1.25 (95% confidence interval 1.05–1.50) versus control, and a large observational cohort identified increased hospital mortality in non-cardiac-surgery patients exposed to the antiseptic. Proposed mechanisms include oral mucosal disruption with subsequent bloodstream translocation of multidrug-resistant organisms. The multicenter stepped-wedge CHORAL trial subsequently de-adopted chlorhexidine in six Canadian intensive care units and replaced it with a standardized oral-care bundle; that de-adoption strategy did not reduce intensive care mortality or time to infection-related ventilator-associated complications but was not associated with harm either. Notably, CHORAL also reported worse oral-health scores among patients who continued to receive chlorhexidine.
Against this background, the Indian research team hypothesized that in mechanically ventilated adults receiving a standardized oral-care bundle, adding 0.12% chlorhexidine would provide no clinically significant incremental benefit. They designed a prospective, pragmatic, cluster-randomized crossover (AB/BA) trial in which the unit of randomization was the intensive care unit itself. A computer-generated allocation sequence assigned three of the six units to a sequence beginning with the bundle without chlorhexidine and three to a sequence beginning with the bundle plus chlorhexidine, with each treatment period lasting approximately nine months. A one-month wash-in and re-training interval separated the two periods, during which nursing staff received protocol re-training, bundle audits were intensified, and no study data were collected.
Bundle A consisted of twice-daily oral care comprising mechanical tooth-brushing, oral and lip moisturization, oropharyngeal suctioning, and removal of pooled subglottic secretions. Bundle B was identical except for the addition of 0.12% chlorhexidine oral rinse applied twice daily after tooth-brushing. All units concurrently followed standard ventilator-associated pneumonia prevention, including head-of-bed elevation to 30–45 degrees, daily sedation assessment with spontaneous awakening trials, stress-ulcer prophylaxis, thromboprophylaxis, and subglottic secretion suctioning where supported by the endotracheal tubes in use. Consecutive adults ventilated for 48 hours or longer were eligible, with exclusions including chlorhexidine hypersensitivity, severe oral trauma, pregnancy, pre-existing tracheostomy, edentulous state, and clinically established pulmonary infection at admission. Written informed consent was obtained from each patient’s legally authorized representative.
The primary outcome was ventilator-associated pneumonia ascertained by the treating team using the Clinical Pulmonary Infection Score, with a score greater than 6 defining infection, analyzed on the incidence-density scale per 1,000 ventilator-days. The primary model was a population-averaged Poisson generalized estimating equation adjusted for treatment, period, sequence, age, sex, APACHE II, and SOFA, with intensive care unit-level clustering and a small-sample correction appropriate for the six clusters. The two groups were well balanced at baseline: mean age was approximately 55 years in both arms, APACHE II scores were 19.7 versus 19.5, and SOFA scores were 13.4 in both groups. Chronic comorbidity documentation was substantially incomplete, so these variables were not used for adjustment, a limitation the authors acknowledge explicitly.
The results were unambiguous on the primary endpoint. A total of 177 first ventilator-associated pneumonia events were recorded: 100 in the group without chlorhexidine, corresponding to 16.90 per 1,000 ventilator-days, and 77 in the chlorhexidine group, corresponding to 18.75 per 1,000 ventilator-days. The adjusted incidence rate ratio for chlorhexidine versus no chlorhexidine was 1.08 (95% confidence interval 0.84–1.38; p = 0.56), and a negative binomial sensitivity analysis gave a concordant estimate. Twenty-eight-day all-cause mortality was 28.7% without chlorhexidine and 26.4% with it, an adjusted odds ratio of 0.87 (95% confidence interval 0.65–1.15; p = 0.33). Ventilator-free days to day 28 did not differ significantly. Patient-level summary Beck Oral Assessment Scale and Critical-Care Pain Observation Tool scores were similar between groups, with no subcomponent differing after false-discovery-rate adjustment, indicating that chlorhexidine did not demonstrably improve oral health or alter procedural pain during oral care.
One secondary finding did reach statistical significance: intensive care length of stay was modestly longer in the chlorhexidine arm, 11.6 versus 10.7 days, an adjusted mean difference of +0.89 days (95% confidence interval +0.19 to +1.58; p = 0.013), consistent across log-normal and gamma models. The duration of mechanical ventilation was numerically longer with chlorhexidine (+0.78 days) but did not reach significance. The authors caution that the length-of-stay signal may partly reflect the chlorhexidine arm’s numerically higher survival, since survivors necessarily accrue more intensive care days, and they report it as an observed signal in this cohort rather than a mechanistic claim. An exploratory analysis stratified by APACHE II tertile showed numerically heterogeneous effects with an interaction p-value of 0.023, but the authors emphasize these hypothesis-generating results should not drive clinical decisions given modest stratum-specific event counts and the absence of a single stratum showing benefit.
The trial’s limitations temper generalizability. It was conducted at a single tertiary-care center whose six units shared an institutional culture and staffing model; with only six clusters, residual small-sample uncertainty remains despite the applied correction; ventilator-associated pneumonia was ascertained by Clinical Pulmonary Infection Score rather than the CDC/NHSN Ventilator-Associated Event algorithm; no formal a-priori sample-size calculation was performed, leaving the study underpowered to exclude small differences; ventilator-day exposure was asymmetric between arms (5,918 versus 4,106 days); blinding of clinical staff was not feasible; and formal quantitative compliance rates were not recorded. The authors conclude that adding 0.12% chlorhexidine twice daily to a standardized oral-care bundle did not reduce ventilator-associated pneumonia incidence density or 28-day mortality, and was associated with a modestly longer intensive care stay, providing no clear incremental benefit in this mixed medical intensive care population. Taken together with the 2024 network meta-analysis and the CHORAL trial, the findings are consistent with a broader pattern of limited incremental benefit from routine chlorhexidine when a standardized mechanical oral-care bundle is delivered, and they underscore the need for adequately powered multicenter trials in low- and middle-income intensive care settings, where case-mix and antibiotic-resistance patterns differ materially from those that shaped the current evidence base.
Subject of Research: A cluster-randomized crossover trial testing whether chlorhexidine added to a standardized oral-care bundle prevents ventilator-associated pneumonia in medical intensive care units.
Article Title: Chlorhexidine within a standardized oral-care bundle for the prevention of ventilator-associated pneumonia: a pragmatic cluster-randomized crossover trial in six medical intensive care units
Article References: Anushapreethi, S., Chhotray, P., Samal, S., Panda, S., Patnaik, R., & Mishra, S. B. (2026). Chlorhexidine within a standardized oral-care bundle for the prevention of ventilator-associated pneumonia: a pragmatic cluster-randomized crossover trial in six medical intensive care units. Critical Care, 30(1), Article 553. https://doi.org/10.1186/s13054-026-06217-0
Image Credits: AI Generated
DOI: 10.1186/s13054-026-06217-0
Keywords: chlorhexidine, ventilator-associated pneumonia, oral-care bundle, intensive care unit, cluster-randomized crossover trial, mechanical ventilation, incidence density, 28-day mortality, ICU length of stay, CPIS, infection prevention, critical care
