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Background:
Systematic Review

Oropharyngeal Interventions in Intubated Patients for Preventing Ventilator Associated Pneumonia: A Systematic Review and Multi-Variate Network Meta-Analysis Evaluating Pharmacological Agents

by
Kannan Sridharan
1,*,
Gowri Sivaramakrishnan
2 and
Ghazi Abdulrahman Alotaibi
3,4,*
1
Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, Arabian Gulf University, Manama 26671, Bahrain
2
Bahrain Defence Force Royal Medical Services, Riffa 28743, Bahrain
3
Arabian Gulf University, Manama 26671, Bahrain
4
Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
*
Authors to whom correspondence should be addressed.
J. Clin. Med. 2025, 14(22), 8174; https://doi.org/10.3390/jcm14228174
Submission received: 28 October 2025 / Revised: 14 November 2025 / Accepted: 14 November 2025 / Published: 18 November 2025
(This article belongs to the Special Issue Clinical Management of Oral Healthcare in Diverse Patient Populations: Second Edition)
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Abstract

Background: Ventilator-associated pneumonia (VAP) is a prevalent and serious complication of invasive mechanical ventilation (MV), contributing to significant mortality and increased healthcare resource utilization. While numerous oropharyngeal interventions exist, their comparative efficacy across critical outcomes remains uncertain due to a lack of direct comparisons in clinical trials. Methods: We conducted a systematic review and network meta-analysis (NMA) with a comprehensive search of MEDLINE, EMBASE, and Cochrane CENTRAL up to September 2025 for randomized and non-randomized studies comparing topical oral interventions in intubated patients. The primary outcome was VAP incidence; secondary outcomes were intensive care unit (ICU) mortality, duration of MV, and ICU length of stay (LOS). Pairwise and network meta-analyses were performed, and the certainty of evidence was assessed. The effect estimates were odds ratios (OR) for categorical outcomes and mean difference (MD) for numerical outcomes represented with 95% confidence intervals (95% CI). Results: Ninety-six studies (20,650 patients) were included, evaluating 44 interventions. For VAP prevention, several interventions were superior to reference/control, including Antimicrobial combinations (OR: 0.21, 95% CI: 0.05–0.39), Povidone-iodine (OR: 0.47, 95% CI: 0.21–0.98), and Chlorhexidine (OR 0.61, 95% CI 0.39–0.95). However, only Chlorhexidine plus toothbrushing significantly reduced mortality (OR: 0.74, 95% CI: 0.58–0.93). For resource utilization, only antimicrobial combinations significantly reduced the duration of MV (MD: −5.55 days, 95% CI: −10.75–−1.7) and ICU LOS (MD: −7.74 days, 95% CI: −13–−4). Evidence certainty (GRADE) was moderate for chlorhexidine and very low for other comparisons. Conclusions: This NMA demonstrates that while multiple oropharyngeal interventions are effective for VAP prevention, their benefits are outcome specific. The choice of intervention should be guided by clinical priorities, as the most effective strategy for preventing VAP may not concurrently reduce mortality or resource use. These findings can inform guideline development and underscore the need for standardized, multi-faceted oral care protocols in the ICU.

1. Introduction

Invasive mechanical ventilation (IMV) is a cornerstone of life support in the intensive care unit (ICU), yet it carries significant iatrogenic risks, most notably ventilator-associated pneumonia (VAP) [1]. VAP, defined as a lung parenchymal infection occurring more than 48 h after endotracheal intubation, represents a prevalent and serious complication. Its incidence is reported to range between 8–28%, equating to 1.4–16.5 episodes per 1000 ventilator days, making it the most common nosocomial infection among critically ill patients [2,3]. The clinical and economic burdens of VAP are substantial, contributing to an attributable mortality of approximately 10% (with even higher estimates in surgical ICUs), prolonged durations of mechanical ventilation, extended ICU and hospital stays, and significantly increased healthcare costs [4]. Microbiological analyses indicate that the most common pathogens responsible for VAP include Pseudomonas species (21%), Staphylococcus aureus (20.2%), and Klebsiella species (20.1%), with patient-specific risk factors such as advanced age and pre-existing chronic liver or kidney disease further compounding the risk [5].
In response to this significant challenge, multifaceted preventive strategies have been developed, primarily operationalized as “VAP bundles.” These bundles incorporate a suite of evidence-based interventions, including strict hand hygiene, daily sedation holidays and spontaneous breathing trials, elevation of the head of the bed to 30–45 degrees, and prophylaxis for stress ulcers and deep vein thrombosis [6]. The systematic implementation of such bundles has proven highly effective; a systematic review of 38 studies demonstrated a 36% reduction in VAP incidence, with nearly a third of the included studies reporting a decrease exceeding 65% [7].
A critical component within these preventive bundles is oropharyngeal care. The oral cavity is naturally protected by a sophisticated host defense system comprising physical barriers, immunological factors in saliva and gingival crevicular fluid, and a balanced oral microbiome [8]. However, critical illness and the requisite invasive interventions in the ICU profoundly compromise these defenses. Patients often experience xerostomia, impaired mucosal integrity, and a shift in oral ecology toward pathogenic colonization. This dysbiosis can transform the oropharynx into a reservoir for pathogens, facilitating their microaspiration around the endotracheal tube cuff, which can lead to systemic dissemination, bacteremia, and ultimately, VAP [9].
Consequently, a variety of oropharyngeal decontamination and hygiene interventions have been investigated to mitigate this risk. These include mechanical cleansing with toothbrushing and the application of topical pharmacological agents such as chlorhexidine gluconate and povidone-iodine. Furthermore, selective oral decontamination (SOD) with non-absorbable antimicrobial pastes or gels, containing agents like colistin, tobramycin, gentamicin, vancomycin, and amphotericin B, has been explored with variable efficacy [10]. Herbal preparations, such as those based on ginger, cinnamon, or other botanicals with purported antimicrobial and anti-inflammatory properties, have also been studied as potential alternatives. For this study, we systematically evaluated the following categories of oropharyngeal interventions against each other and against standard care or placebo: (1) mechanical hygiene (toothbrushing), (2) topical antiseptics (such as chlorhexidine, povidone-iodine), (3) selective oral decontamination (SOD) with antibiotic/antifungal pastes, and (4) herbal-based formulations. Despite its established importance, oropharyngeal care in intubated patients remains inconsistently standardized, with ongoing debate regarding the optimal choice of agent, frequency, and protocol [11]. Toothbrushing is the only recommended as the only intervention according to the expert panel convened by the International Society of Infectious Diseases [12].
The evidence for these diverse interventions has been synthesized in several conventional pairwise meta-analyses [13,14,15,16]. However, these syntheses are constrained by several limitations. First, they often fail to compare the full spectrum of available interventions, encompassing both allopathic and herbal products, on a single, unified platform. Second, many lack a thorough assessment of the certainty (or strength) of the evidence, such as through the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework. Finally, the primary obstacle to direct comparison is the scarcity of head-to-head randomized controlled trials (RCTs) comparing all relevant interventions.
Network meta-analysis (NMA) offers a powerful statistical methodology to overcome this evidence gap. By integrating direct evidence (from head-to-head trials) and indirect evidence (derived through common comparator interventions), NMA permits concurrent comparison (and ranking) of multiple interventions, despite the lack of direct comparative trials [17]. Therefore, this study aims to employ a multivariate network meta-analysis to comprehensively evaluate and rank the efficacy of all pertinent oropharyngeal interventions for the prevention of VAP in intubated patients. Our primary objective is to compare their relative effects on the incidence of VAP, with secondary outcomes including all-cause mortality, ICU length of stay, and duration of invasive mechanical ventilation.

2. Methods

2.1. Search Methods

The protocol for this review was registered with the Open Science Framework [18]. Following databases were searched for eligible studies: MEDLINE (via PubMed), EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL), from their inception until 24 September 2025, to identify studies evaluating topical oropharyngeal interventions in intubated patients. The search strategy utilized a combination of Medical Subject Headings (MeSH) and free-text terms related to both the interventions (e.g., chlorhexidine, toothbrushing, antiseptics, antibiotics, herbal extracts) and the context (e.g., mechanical ventilation, ventilator-associated pneumonia). The full search strategy for each database is provided in Electronic Supplementary Table S1. As an example, the PubMed search string is detailed in the introduction. No restrictions were placed on language or publication dates to maximize inclusivity. Conference abstracts were excluded due to typically insufficient methodological and outcome details, which would preclude a robust assessment of risk of bias.

2.2. Eligibility Criteria

Both RCTs and observational studies were considered eligible for inclusion. The inclusion criteria were as follows:
  • Population: Children and adult patients receiving invasive mechanical ventilation.
  • Interventions: Any topical oral intervention aimed at preventing VAP such as Chlorhexidine (various concentrations: 0.12%, 0.2%, 1%, 2%), Povidone-iodine, Probiotics (such as Lactobacillus), Antimicrobial drugs (such as polymyxin, tobramycin), Iseganan, Silver nanoparticles, Hydrogen peroxide, Sodium bicarbonate, Toothbrush, Potassium permanganate, Ozonated water, Nanosil, Miswak, Triclosan, Listerine, Nitrofurazone, Biotene, Amphotericin B, Chinese herbal formulation, Persica, Matrica, Achillea millefolium, Mentha spicata, Chamomile.
  • Comparators: Standard of care, placebo, water, saline or any of the above interventions.
  • Outcomes: The primary outcome was the incidence of VAP. We considered any definition used by the original study authors, such as clinical pulmonary infection score (CPIS), Centers for Disease Control and Prevention (CDC), American Thoracic Society/Infectious Disease Society of America, Chinese Society for Respiratory Disease or bacteriologic confirmation. The secondary outcomes were all-cause ICU mortality, duration of mechanical ventilation and ICU stay.

2.3. Study Selection and Data Extraction

Two authors were involved in the independent screening of the retrieved records based on titles and abstracts, and in the full-text evaluation of potentially eligible articles. Any discrepancy was resolved through a consensus or discussion with the third author. From each included study, the following data were extracted: study characteristics: first author, year, country, setting, design; participant characteristics: number randomized, age, gender, APACHE/SAPS score, ICU type; intervention and comparator details: specific drug, concentration, frequency, delivery method, co-interventions (toothbrushing); and outcomes.

2.4. Data Synthesis and Statistical Analysis

The methodological quality of included RCTs was assessed using the Cochrane risk of bias tool [19]. For observational and non-randomized studies, the Joanna Briggs Institute (JBI) critical appraisal checklist was used [20].
Quantitative synthesis was performed using a frequentist framework for network meta-analysis (NMA), employing a mixed-treatment comparison model to integrate direct and indirect evidence. Effect sizes were expressed as Odds Ratios (OR) with 95% Confidence Intervals (CI) for categorical outcomes and Mean Differences (MD) with 95% CI for numerical outcomes. The reference treatment group for comparisons comprised control interventions such as placebo, saline, water, standard of care, or no oral care. Heterogeneity was quantified using the I2 statistic, with values interpreted as follows: 0–25% (low), 25–50% (moderate), 50–75% (substantial), and 75–100% (considerable) [19]. The relative ranking of interventions for each outcome was estimated using the Surface Under the Cumulative Ranking curve (SUCRA). To assess the robustness of the findings, we performed a bootstrap analysis (1000 iterations) and a leave-one-out sensitivity analysis for key interventions (Chlorhexidine, Chlorhexidine + Toothbrush, Antimicrobial combinations, and Povidone iodine) compared to the reference.
For outcomes with significant pooled estimates in pairwise meta-analyses, we conducted cumulative meta-analysis and Trial Sequential Analysis (TSA) to evaluate the reliability of the evidence. Pre-specified subgroup analyses included: study design (RCTs only), chlorhexidine concentration, the presence or absence of toothbrushing, VAP definition, and VAP bundle adequacy. VAP bundle adequacy was scored by awarding one point for each of the following co-interventions: daily sedation interruption, stress ulcer prophylaxis, deep vein thrombosis prophylaxis, head-of-bed elevation to 30–45°, use of a subglottic suctioning endotracheal tube, and regular endotracheal cuff pressure monitoring. The total score was categorized as: 0 (inadequate), 1 (basic), 2 (moderate), 3 (good), or 4 (comprehensive). Meta-regression was performed to obtain covariate-adjusted pooled estimates, with covariates including the specific oral care intervention, mean age, percentage of males, daily frequency of the intervention, and mean APACHE II score.
Publication bias was assessed using Egger’s regression test (p ≤ 0.05 indicate potential publication bias) and funnel plots for comparisons with adequate studies. The certainty of the evidence for key estimates was evaluated using the GRADE framework [19].

2.5. Supplementary Propensity Score Analysis

To complement the primary NMA and address potential confounding in non-randomized comparisons, we conducted a propensity score matching (PSM) analysis focusing on the comparative effectiveness of Chlorhexidine versus reference interventions on VAP rates. This analysis utilized study-level aggregate data from arms included in the NMA dataset. Propensity scores were estimated using logistic regression, with mean participant age, percentage of male participants, and mean baseline illness severity score as covariates. We employed 1:1 optimal matching with a caliper width of 0.2 standard deviations of the logit propensity score, which achieved the best covariate balance. Post-matching balance was assessed using standardized mean differences (SMD), with an SMD <0.2 indicating adequate balance. Outcomes were compared between the matched groups using Welch’s t-test, and sensitivity analyses were performed using regression adjustment on the matched sample. All PSM analyses were performed using R version 4.5.1.
This systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the PRISMA checklist is available as Electronic Supplementary File S1 [21].

3. Results

3.1. Search Results

A total of 96 studies (20,650 patients) [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117] were included in the systematic review as depicted in the PRISMA flow diagram in Figure 1. Table 1 summarizes study characteristics by intervention type. The studies were primarily RCTs and were conducted across a wide range of countries, with a notable concentration of research from Iran. The ICU settings were varied, including medical, surgical, mixed, and cardiothoracic units. Patient severity at baseline was frequently assessed using the APACHE II score, with reported means typically ranging from the mid-teens to the low twenties. The mean age of enrolled patients was most reported to be between 40 and 65 years, and the proportion of male participants often varied from approximately 50% to 70%. The primary interventions investigated involved different forms of oral care, with Chlorhexidine at various concentrations being the most frequently studied agent, either used alone or in combination with toothbrushing. The definition of VAP also varied, with common criteria including the CPIS and CDC guidelines.
Eight studies did not report the values of the outcomes of interest in this study in a way amenable to statistical analysis due to which a total of 88 studies (20,131 patients) to be included in the meta-analysis. Amongst the studies included in the meta-analysis they were published between 1990 and 2025 across 24 countries, with the highest contributions from Iran (n = 25) followed by China (n = 10). The studies encompassed 189 study arms evaluating 44 unique oral care interventions. Many trials were conducted in mixed ICU settings (35.4%), followed by unclear settings (20.2%) and surgical ICUs (14.6%). Most studies employed RCT designs (79.5%), with additional contributions from cohort studies (18.2%) and non-randomized trials (2.3%). Follow-up duration primarily extended until hospital discharge or death (47.2% of studies), while VAP bundle adequacy scores ranged from 0 to 4 across the included trials. The intervention spectrum was dominated by Chlorhexidine-based regimens, with Chlorhexidine alone investigated in 54 studies (61.4%) and Chlorhexidine combined with Toothbrushing in 23 studies (26.1%). Toothbrush incorporation was reported in 46 study arms (24.3%), while 35 studies (39.8%) employed reference/control interventions. Amongst the Antimicrobial combinations (n = 5), Amphotericin B, Tobramycin and Polymyxin E were reported in three studies, Gentamicin, Colistin and Vancomycin in two and Polymyxin B, Neomycin and Vancomycin in one study. Amongst the standalone topical antimicrobial drug (n = 2), Metronidazole and Gentamicin were used in each. Outcome reporting was comprehensive for VAP (81 studies, 92% across 23 countries), though less complete for mortality (44 studies, 50% across 17 countries), duration of mechanical ventilation (40 studies, 45.5% across 17 countries), and ICU length of stay (38 studies, 43.2% across 17 countries), reflecting the primary focus on VAP prevention as the central outcome measure across this evidence base.

3.2. Network Meta-Analysis

Eighty-one studies evaluating 34 distinct oral care interventions (15,117 patients) for the prevention of VAP in critically ill patients. The network was well-connected with adequate direct and indirect comparisons with majority of studies comparing chlorhexidine (Figure 2A). The following interventions demonstrated superior efficacy in terms of reduced risk of VAP occurrence compared to the reference interventions: Miswak + Toothbrush (OR: 0.04; 95% CI: 0–0.78), Chamomile + Toothbrush (OR: 0.04; 95% CI: 0.01, 0.16), Hydrogen peroxide + Silver ions (OR: 0.05; 95% CI: 0, 0.52), Hydrogen peroxide + Vitamin E + Toothbrush (OR: 0.11; 95% CI: 0.02, 0.53), Nitrofurazone + Toothbrush (OR: 0.12; 95% CI: 0.03, 0.41), Ozonated water (OR: 0.15; 95% CI: 0.05, 0.48), Clove (OR: 0.19; 95% CI: 0.6, 0.68), Propolis (OR: 0.21; 95% CI: 0.06, 0.78), Satureja plant (OR: 0.22; 95% CI: 0.05, 0.86), Antimicrobial combination (OR: 0.31; 95% CI: 0.15, 0.64), Chlorhexidine (OR: 0.55; 95% CI: 0.39, 0.75), Chlorhexidine + Toothbrush (OR: 0.38; 95% CI: 0.25, 0.57), Povidone iodine (OR: 0.39; 95% CI: 0.21, 0.71)and Toothbrush alone (OR: 0.46; 95% CI: 0.28, 0.77) (Figure 2B). A substantial heterogeneity was observed (I2 = 61.1%).
Forty-four studies evaluating 13 interventions (12,433 patients) were included for the assessment of mortality risk. The network had adequate direct and indirect comparisons with majority of studies comparing Chlorhexidine (Figure 3A). No interventions were significantly associated with reduced risk of mortality except Chlorhexidine + Toothbrush (OR: 0.74; 95% CI: 0.58, 0.93) (Figure 3B). A low heterogeneity was observed (I2 = 19%).
Thirty-nine studies evaluating 15 interventions (7236 patients) were included for the assessment of duration of mechanical ventilation. The network had adequate direct and indirect comparisons with majority of studies comparing Chlorhexidine (Figure 4A). No significant differences were observed with any of the interventions (Figure 4B). A moderate heterogeneity was observed (I2 = 45.6%).
Thirty-nine studies evaluating 17 interventions (8956 patients) were included for the assessment of duration of ICU stay. The network had adequate direct and indirect comparisons with majority of studies comparing Chlorhexidine (Figure 5A). No significant differences were observed with any of the interventions in random effects model (Figure 5B) although Antimicrobial combination (MD: −4.13; 95% CI: −6.54 to −1.72), Colostrum + Sodium bicarbonate (MD: −3.73; 95% CI: −4.57 to −2.89), Chlorhexidine + Toothbrush (MD: −3.05; 95% CI: −4.11 to −1.99) and Colostrum (MD: −1.9; 95% CI: −2.69 to −1.11) were observed with significantly shorter ICU stay in fixed-effects model. A considerable heterogeneity was observed (I2 = 80.4%).

3.3. Ranking of Treatments by SUCRA Plots

The cumulative ranking probabilities, summarized by the SUCRA values, are presented in Figure 6. The analysis revealed that no single intervention consistently ranked best across all four: VAP prevention, mortality, duration of mechanical ventilation, and ICU length of stay. However, Antimicrobial combination ranked the best for durations of mechanical ventilation and ICU stay, and third for mortality risk reduction. Along with Toothbrush, Chamomile ranked the best for VAP prevention, and Chlorhexidine for mortality risk reduction. This outcome-specific performance highlights the trade-offs clinicians must consider when selecting a VAP prevention strategy, as the optimal choice may vary depending on the primary clinical goal.

3.4. Pairwise Meta-Analysis with Reference Intervention

Only four interventions were compared to reference intervention in head-to-head clinical trials that are amenable to direct comparison meta-analysis. In the pairwise meta-analyses comparing various interventions to reference, the only statistically significant reduction in odds was observed for Chlorhexidine (OR 0.61, 95% CI 0.39 to 0.95, p = 0.03). The point estimates for povidone iodine (OR 0.47) and the combination of Chlorhexidine + Toothbrush (OR 0.51) also suggested potential benefit, but their 95% confidence intervals were wide and included the null value (0.12 to 1.78 and 0.01 to 46, respectively), rendering them statistically non-significant (Figure 7). Similarly, the analysis for Antimicrobial combination (OR 0.21) was not statistically significant, with a confidence interval spanning from 0.02 to 2.78. Heterogeneity was consistently low across all comparisons (I2 <0.7%).
For mortality outcomes, none of the investigated interventions demonstrated a statistically significant effect. The odds ratios for antimicrobial combination (OR 0.75), povidone iodine (OR 0.97), and chlorhexidine (OR 0.94) all had 95% confidence intervals that included the null value, with ranges of 0.24 to 2.3, 0.21 to 4.45, and 0.73 to 1.2, respectively. The p-values for these comparisons were 0.38, 0.93, and 0.55, confirming the lack of statistical significance, and heterogeneity was negligible across all analyses (I2 ≤ 0.3%).
Regarding the outcome on mechanical ventilation duration, none of the interventions showed a statistically significant effect. The mean difference for Antimicrobial combination was −5.55 days (95% CI −62.41 to 51.31, p = 0.43), for Povidone iodine was −0.14 days (95% CI −0.98 to 0.69, p = 0.54), and for Chlorhexidine was 0.42 days (95% CI −0.04 to 0.88, p = 0.06). All confidence intervals crossed the null value of zero, indicating no conclusive evidence that any intervention meaningfully alters the duration of mechanical ventilation compared to the reference, with consistently low heterogeneity (I2 ≤ 0.8%) across all comparisons.
In the pairwise meta-analyses of ICU length of stay, none of the interventions demonstrated a statistically significant effect on duration. The mean difference for Antimicrobial combination was −7.74 days (95% CI −64.10 to 48.62, p = 0.33), for Povidone iodine was 0.22 days (95% CI −0.43 to 0.86, p = 0.37), and for Chlorhexidine was 1.04 days (95% CI −3.65 to 5.73, p = 0.61). The confidence intervals for all three comparisons were wide and included the null value of zero, indicating no conclusive evidence that any intervention meaningfully alters ICU stay duration compared to the reference, with heterogeneity consistently low across all analyses (I2 ≤ 0.9%).

3.5. Bootstrap Analyses

The bootstrap analysis, providing robust estimates of effect sizes and their confidence intervals, revealed distinct performance profiles across the interventions for the four primary outcomes (Electronic Supplementary Figure S1). For the prevention of VAP, the Antimicrobial combination was the most effective intervention, significantly reducing the odds of VAP (OR 0.21, 95% CI [0.05, 0.39]), followed by Povidone iodine (OR 0.47, 95% CI [0.21, 0.98]). In contrast, none of the interventions demonstrated a statistically significant effect on mortality reduction. Regarding the duration of mechanical ventilation, only the Antimicrobial combination showed a significant benefit, substantially reducing ventilation time by a mean of −5.55 days (95% CI [−10.75, −1.7]). This advantage extended to the ICU length of stay, where the Antimicrobial combination was again the sole intervention associated with a statistically significant reduction, shortening the stay by −7.742 days (95% CI [−13, −4]). Chlorhexidine-based interventions did not show significant benefits for mortality, ventilation duration, or ICU stay.

3.6. Sub-Group Analyses

The forest plots of interventions in various sub-groups are depicted in Electronic Supplementary Figure S2.
Amongst the studies with RCT design, Antimicrobial combinations, Chlorhexidine, Chlorhexidine + Toothbrush, Povidone iodine + Toothbrush and Toothbrush were observed to reduce VAP incidence; Zataria multiflora Boiss.+ Chlorhexidine significantly reduced the mortality risk; and none were observed to reduce either the duration of mechanical ventilation or ICU stay (Electronic Supplementary Figure S2A–D).
Amongst the varied definitions of VAP used, no significant differences were observed between the interventions on the outcomes except a reduction in the VAP incidence with Chlorhexidine and Antimicrobial combination when VAP is diagnosed according to CPIS (Electronic Supplementary Figure S2E).
Regarding the adequacy of VAP bundles incorporated, no significant differences were observed except a reduction in VAP incidence with antimicrobial combination in patients with basic bundle and Chlorhexidine + Toothbrush in patients without any VAP bundle (Electronic Supplementary Figure S2F).
Regarding the varied Chlorhexidine concentrations, significantly reduced duration of stay in ICU and mechanical ventilation were observed with 0.01–0.1% concentrations while 1.1–2% was observed with an increase in the duration of mechanical ventilation duration (Electronic Supplementary Figure S2G).
Regarding the concomitant use of Toothbrush, due to lack of adequate studies comparing with reference interventions, we could not estimate the pooled estimates for those using Toothbrush. However, amongst the studies without Toothbrush, Antimicrobial combination, Chlorhexidine, Hydrogen peroxide and Povidone iodine were observed with a reduction in the VAP incidence (Electronic Supplementary Figure S2H).

3.7. Multivariate Meta-Regression Analysis

The results of the multivariate network meta-regression showing the pooled intervention effects for four clinical outcomes, adjusted for covariates including age, percent male, APACHE II score, and daily frequency of the interventions are depicted in Figure 8. After the adjustment, Povidone iodine, Antimicrobial combination and Toothbrush were observed with significantly lower risk of VAP.

3.8. Publication Bias, Risk of Bias and Leave-One-Out Sensitivity Analysis

Publication bias could be assessed only for Chlorhexidine with reference interventions due to paucity of number of studies for other comparisons. No publication bias was evident both by funnel plots and Egger’s regression analyses (Figure 9).
The risk of bias assessment of RCTs revealed an overall low risk (Figure 10). Similarly, the cohort studies and the non-randomized study were determined to have moderate quality.
Leave-one-out sensitivity analysis confirmed the robustness of the pooled estimates for the reduced risk of VAP with chlorhexidine (Electronic Supplementary Table S2) with varied results for other outcomes (Electronic Supplementary Tables S3–S5).

3.9. Cumulative Meta-Analysis and Trial Sequential Analysis

The cumulative meta-analysis for VAP prevention demonstrated a clear hierarchy in the efficacy of the assessed oral care interventions. The Antimicrobial combination emerged as the most potent intervention, yielding a statistically significant and substantial 78.6% reduction in the odds of VAP (OR 0.21, 95% CI: 0.07–0.65; p = 0.0065). Chlorhexidine alone also demonstrated a significant protective effect, associated with a 39.5% reduction in the odds of VAP (OR 0.61, 95% CI: 0.40–0.91; p = 0.0145). In contrast, Povidone iodine (OR 0.47, 95% CI: 0.21–1.06; p = 0.0683) and Chlorhexidine combined with toothbrushing (OR 0.51, 95% CI: 0.26–1.02; p = 0.0583) showed non-significant trends towards reducing VAP incidence (Electronic Supplementary Figures S3–S6).
Trial Sequential Analysis was conducted to evaluate the robustness and conclusiveness of the evidence for VAP prevention Both Chlorhexidine (final OR 0.58, Z-score −4.607) and the Antimicrobial combination (final OR 0.25, Z-score −4.832) demonstrated statistically robust, conclusive benefits, with their cumulative Z-curves crossing the trial sequential monitoring boundary for benefit (Electronic Supplementary Figures S7 and S8). Similarly, povidone iodine also showed conclusive evidence of a significant effect (Final OR 0.3) (Electronic Supplementary Figure S9). In contrast, the evidence for Chlorhexidine combined with toothbrushing was deemed inconclusive, as its Z-curve did not cross the monitoring boundary, and the current sample size of 858 patients represents only 23.6% of its RIS of 3639 patients, indicating a clear need for further trials to reach a definitive conclusion for this specific intervention.
Since no significant differences were observed for other outcomes, neither cumulative meta-analysis nor trial sequential analysis were carried out.

3.10. Propensity Scores Matching Analysis

The propensity scores matching analysis included 50 study arms comparing chlorhexidine-based oral care (n = 30) against reference interventions (n = 20). Optimal propensity score matching successfully created 20 matched pairs, achieving adequate covariate balance across all pre-specified confounders (all standardized mean differences <0.2). Chlorhexidine interventions demonstrated significantly lower VAP rates compared to reference interventions, with a mean VAP rate of 21.2% (SD = 17.9%) versus 33.3% (SD = 20.3%), respectively (Figure 11). This translated into an absolute risk reduction of 12.1 percentage points (95% CI: 1.8 to 22.2; p = 0.02) and a relative risk reduction of 36.3%. In sensitivity analyses, regression adjustment on the matched sample yielded consistent results, with chlorhexidine remaining significantly associated with reduced VAP rates (adjusted coefficient: −0.125, p = 0.033). No significant difference in mortality was observed between groups (mean difference: 1.6%, 95% CI: −10.2 to 7.1; p = 0.72). The consistency of findings across multiple matching approaches supports the robustness of the primary result, indicating that chlorhexidine-based oral care provides clinically important and statistically significant protection against VAP development in critically ill patients.

3.11. Grading the Strength of Evidence

Grades of the strength of evidence for key comparisons are summarized in Table 2. Moderate quality was observed for Chlorhexidine while very low strength was observed for other comparisons.

4. Discussion

4.1. Key Findings

Our network meta-analysis of 96 studies, encompassing over 20,000 critically ill patients, provides a comprehensive hierarchy of oropharyngeal interventions for VAP prevention. The central finding is that while numerous interventions, including antimicrobial combinations, chlorhexidine, povidone-iodine, and several herbal and combination strategies, demonstrate significant efficacy in reducing VAP incidence compared to standard care, no single intervention was consistently superior across all patient-centered outcomes. Interestingly, the reduction in VAP did not uniformly translate into improvements in mortality or resource utilization; only the combination of chlorhexidine with toothbrushing was associated with a significant reduction in mortality, and only antimicrobial combinations significantly reduced the duration of mechanical ventilation and ICU stay. This outcome-specific efficacy, confirmed by robust sensitivity and trial sequential analyses, underscores a critical disconnect between preventing VAP and achieving broader clinical benefits, suggesting that optimal intervention may depend on the specific therapeutic goal.

4.2. Comparison with Existing Literature

Our multivariate network meta-analysis elucidates a critical paradigm in VAP prevention: the efficacy of oropharyngeal interventions is profoundly outcome specific. We identified Chlorhexidine, Antimicrobial combinations, and Povidone iodine as the most effective agents for reducing VAP incidence. However, a pivotal finding was that only the combination of Chlorhexidine with toothbrushing was associated with a significant reduction in all-cause mortality. This suggests that the benefits of oral care extend beyond mere infection control and may be linked to the systemic modulation of inflammation and bacterial load through mechanical cleansing.
The role of chlorhexidine as a mainstay for VAP prevention is reinforced by our findings, which align with extensive prior evidence. For instance, a meta-analysis of 11 trials concluded that chlorhexidine significantly reduces VAP risk without impacting mortality [118]. This was further corroborated by the comprehensive Cochrane review of 40 trials, which positioned Chlorhexidine as a moderately effective yet reliable strategy [13]. Our analysis confirms this role but, through its network structure, reveals that while chlorhexidine is not the single most potent agent, it remains one of the most consistently effective and widely studied interventions across diverse clinical settings.
A central and novel insight from our study is the significant mortality benefit observed with the combination of Chlorhexidine and toothbrushing. While previous meta-analyses have often combined toothbrushing with various antiseptics without disaggregating their effects [13], our analysis was able to isolate this combination as uniquely beneficial for survival. The biological plausibility for this is strong. Toothbrushing effectively disrupts and removes dental plaque, a complex biofilm that serves as a reservoir for pathogens and a trigger for systemic inflammation [119]. The mechanical action of brushing is crucial for dislodging biofilm from protected niches, an effect that topical antiseptics alone cannot achieve. This is supported by in vitro evidence demonstrating that a combined approach of brushing and mouth rinse reduces biofilm thickness and bacterial load far more effectively than either intervention in isolation [120]. Therefore, the synergy of mechanical debridement and chemical antisepsis may be necessary to mitigate the systemic inflammatory burden that ultimately influences mortality risk.
Our results also highlight the superior efficacy of SOD with antimicrobial drug combinations (such as polymyxins, aminoglycosides, and antifungals) for reducing VAP incidence, duration of mechanical ventilation, and ICU length of stay. These regimens offer the advantage of targeted pathogen eradication, often through synergistic mechanisms, for example, polymyxins can disrupt the outer membrane of Gram-negative bacteria, enhancing the penetration and efficacy of aminoglycosides [121]. However, this potent efficacy is counterbalanced by the formidable threat of promoting antimicrobial resistance [122,123]. As these same antibiotic classes are last-line defenses for treating multidrug-resistant infections in the ICU, the widespread, prophylactic use of antimicrobial drugs necessitates careful consideration within institutional antimicrobial stewardship programs.
Beyond conventional agents, our analysis identified several herbal products, including Chamomile, Miswak, and Propolis, with point estimates suggesting superior VAP prevention compared to Chlorhexidine. This finding is consistent with a previous meta-analysis that reported a significant protective effect for miswak [12]. While the current evidence for these natural compounds is limited by smaller sample sizes and a higher risk of bias, they represent a promising and potentially cost-effective area for future research, particularly in resource-limited settings or as alternatives in the face of emerging antiseptic resistance.
Based on the findings of this analysis, we propose a paradigm shift towards a more nuanced and outcome-driven approach to oropharyngeal care in the ICU. First, clinical practice guidelines and institutional VAP prevention bundles should be updated to mandatorily incorporate toothbrushing as a foundational component, with the combination of Chlorhexidine and toothbrushing strongly considered as a first-line strategy given its unique association with reduced mortality. Second, the use of potent topical antimicrobial combinations, while highly effective for VAP prevention and resource use, must be carefully balanced against the critical imperative of antimicrobial stewardship; their implementation should be reserved for high-risk settings with robust resistance surveillance. Finally, the research agenda must evolve to address the identified evidence gaps. Future trials should be powered for patient-centered outcomes like mortality and should directly compare the most promising strategies from this network meta-analysis, such as chlorhexidine-toothbrushing versus a leading antimicrobial combination, to definitively guide clinical practice.

4.3. Strengths and Limitations

This network meta-analysis possesses several strengths, including its comprehensive and systematic assessment of a wide spectrum of pharmacological and herbal interventions on a unified platform, its adherence to rigorous PRISMA guidelines, and the use of advanced statistical methods like TSA and PSM analyses to confirm the robustness of key findings. However, several limitations warrant consideration. The overall certainty of evidence was predominantly low to very low, as per GRADE assessment, due to heterogeneity in VAP definitions, intervention protocols, and baseline care standards (VAP bundle adequacy) and limited studies due to which risk of bias could not be assessed, except for chlorhexidine. The heavy reliance on chlorhexidine as a common comparator, while creating a well-connected network, also limited the precision of estimates for many promising but less-studied interventions. Furthermore, the aggregation of varied antimicrobial combinations into a single node, while necessary for analysis, may obscure the efficacy of specific antibiotic regimens. Also, moderate to substantial statistical heterogeneity was observed for some outcomes. For clinicians, these results underscore that the selection of an oral care strategy should be a deliberate decision based on the primary goal, whether it is VAP prevention, mortality reduction, or minimizing resource use, as no single agent excels in all domains. For researchers, these findings highlight critical evidence gaps. Future studies should prioritize direct head-to-head comparisons of the most promising agents (Antimicrobial combinations versus Chlorhexidine and Chlorhexidine + Toothbrush), standardize VAP diagnostic criteria and oral care protocols, and are powered to detect differences in patient-centered outcomes like mortality and ICU length of stay, rather than solely on VAP incidence.

5. Conclusions

In conclusion, this comprehensive network meta-analysis establishes that effective VAP prevention is not monolithic but intervention specific. While antimicrobial combinations, Chlorhexidine, and Povidone iodine significantly reduce the incidence of VAP, their benefits do not uniformly extend to mortality or resource utilization. The combination of chlorhexidine with toothbrushing emerges as a critical strategy for reducing mortality, whereas antimicrobial combinations show unique promise in shortening the duration of mechanical ventilation and ICU stay. Consequently, the optimal oropharyngeal care strategy in the ICU should be tailored, moving beyond a one-size-fits-all approach to one that is deliberately aligned with specific patient outcomes and institutional priorities. These findings provide a crucial evidence base to refine VAP prevention protocols and guide future clinical research.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm14228174/s1, Electronic Supplementary File S1. PRISMA 2020 Checklist; Electronic Supplementary Table S1. Search strategy; Electronic Supplementary Table S2. Leave-one-out sensitivity analysis for the risk of VAP; Electronic Supplementary Table S3. Leave-one-out sensitivity analysis for the risk of mortality; Electronic Supplementary Table S4. Leave-one-out sensitivity analysis for the duration of mechanical ventilation; Electronic Supplementary Table S5. Leave-one-out sensitivity analysis for the duration of ICU stay; Electronic Supplementary Figure S1. Histogram of bootstrap meta-analyses; Electronic Supplementary Figure S2. Forest plots for sub-group analyses; Electronic Supplementary Figure S3. Cumulative meta-analysis plot for the risk of VAP for chlorhexidine compared to reference interventions; Electronic Supplementary Figure S4. Cumulative meta-analysis plot for the risk of VAP for antimicrobial combination compared to reference interventions; Electronic Supplementary Figure S5. Cumulative meta-analysis plot for the risk of VAP for Chlorhexidine + Toothbrush compared to reference interventions; Electronic Supplementary Figure S6. Cumulative meta-analysis plot for the risk of VAP for povidone iodine compared to reference interventions; Electronic Supplementary Figure S7. Trial sequential analysis for the risk of VAP for chlorhexidine compared to reference interventions; Electronic Supplementary Figure S8. Trial sequential analysis for the risk of VAP for antimicrobial combination compared to reference interventions; Electronic Supplementary Figure S9. Trial sequential analysis for the risk of VAP for povidone iodine compared to reference interventions.

Author Contributions

Conceptualization, K.S.; methodology, K.S., G.S. and G.A.A.; software, K.S. and G.S.; validation, K.S., G.S. and G.A.A.; formal analysis, K.S. and G.S.; investigation, K.S., G.S. and G.A.A.; data curation, K.S., G.S. and G.A.A.; writing—original draft preparation, K.S., G.S. and G.A.A.; writing—review and editing, K.S., G.S. and G.A.A.; visualization, K.S.; supervision, K.S.; project administration, K.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

This study was carried out on a publicly available database due to which Ethics approval was not required.

Informed Consent Statement

Not applicable.

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgments

We wish to acknowledge the use of DeepSeek V3 for improving the language clarity and grammar in this manuscript.

Conflicts of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Figure 1. PRISMA flow diagram. A total of 96 studies were included in this systematic review and 88 in the meta-analysis.
Figure 1. PRISMA flow diagram. A total of 96 studies were included in this systematic review and 88 in the meta-analysis.
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Figure 2. Network and Forest plots of oral interventions for VAP prevention. Figure 2 shows the network structure, and the effect estimates from the network meta-analysis of topical interventions for VAP prevention. Panel (A) (Network of Interventions for VAP Prevention) illustrates the geometry of the network. Panel (B) (Forest Plot VAP Prevention) displays the OR and 95% CI for each intervention compared to the reference intervention.
Figure 2. Network and Forest plots of oral interventions for VAP prevention. Figure 2 shows the network structure, and the effect estimates from the network meta-analysis of topical interventions for VAP prevention. Panel (A) (Network of Interventions for VAP Prevention) illustrates the geometry of the network. Panel (B) (Forest Plot VAP Prevention) displays the OR and 95% CI for each intervention compared to the reference intervention.
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Figure 3. Network and Forest plots of oral interventions for the risk of mortality. This figure illustrates the network structure and effect estimates from the network meta-analysis of topical oral interventions on mortality risk. Panel (A) (Network of Interventions for Mortality) displays the geometry of the network. Panel (B) (Forest Plot Mortality—All Interventions vs. Reference) displays the OR and 95% CI for each intervention compared to the reference intervention.
Figure 3. Network and Forest plots of oral interventions for the risk of mortality. This figure illustrates the network structure and effect estimates from the network meta-analysis of topical oral interventions on mortality risk. Panel (A) (Network of Interventions for Mortality) displays the geometry of the network. Panel (B) (Forest Plot Mortality—All Interventions vs. Reference) displays the OR and 95% CI for each intervention compared to the reference intervention.
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Figure 4. Network and Forest plots of oral interventions for the duration of mechanical ventilation. This figure displays the network structure and effect estimates from the network meta-analysis concerning the duration of mechanical ventilation. Panel (A) (Network of interventions for mechanical ventilation duration) illustrates the geometry of the network. Panel (B) (Forest Plot mechanical ventilation duration) displays the MD and 95% CI for each intervention compared to the reference intervention.
Figure 4. Network and Forest plots of oral interventions for the duration of mechanical ventilation. This figure displays the network structure and effect estimates from the network meta-analysis concerning the duration of mechanical ventilation. Panel (A) (Network of interventions for mechanical ventilation duration) illustrates the geometry of the network. Panel (B) (Forest Plot mechanical ventilation duration) displays the MD and 95% CI for each intervention compared to the reference intervention.
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Figure 5. Network and Forest plots of oral interventions for the duration of stay in ICU. The figure displays the results of a network meta-analysis examining the effect of various interventions on ICU stay duration. Panel (A) is the network of interventions for ICU stay duration, which illustrates the comparisons made between different treatments. Panel (B) is the forest plot showing the mean difference in ICU stay duration for each intervention compared to a common reference group.
Figure 5. Network and Forest plots of oral interventions for the duration of stay in ICU. The figure displays the results of a network meta-analysis examining the effect of various interventions on ICU stay duration. Panel (A) is the network of interventions for ICU stay duration, which illustrates the comparisons made between different treatments. Panel (B) is the forest plot showing the mean difference in ICU stay duration for each intervention compared to a common reference group.
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Figure 6. Comprehensive SUCRA plot for treatment ranking. This figure displays the treatment rankings across all outcomes from the network meta-analysis using the SUCRA values derived from the random effects Model. Panel (A) ranks interventions for VAP prevention. Panel (B) ranks interventions for mortality. Panel (C) ranks interventions for mechanical ventilation duration. Panel (D) ranks interventions for ICU stay duration.
Figure 6. Comprehensive SUCRA plot for treatment ranking. This figure displays the treatment rankings across all outcomes from the network meta-analysis using the SUCRA values derived from the random effects Model. Panel (A) ranks interventions for VAP prevention. Panel (B) ranks interventions for mortality. Panel (C) ranks interventions for mechanical ventilation duration. Panel (D) ranks interventions for ICU stay duration.
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Figure 7. Pooled odds ratios for VAP prevention interventions. This forest plot displays the pooled odds ratios (OR) with 95% confidence intervals (CI) for different interventions aimed at VAP prevention, compared to a reference intervention.
Figure 7. Pooled odds ratios for VAP prevention interventions. This forest plot displays the pooled odds ratios (OR) with 95% confidence intervals (CI) for different interventions aimed at VAP prevention, compared to a reference intervention.
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Figure 8. Facet plot for pooled estimates following multivariate meta-regression. The outcomes are displayed in four separate forest plots: ICU stay (mean difference), mechanical ventilation (mean difference), mortality (odds ratio), and VAP (odds ratio). The vertical dashed red lines represent the line of no effect. Each row represents a specific Intervention. Red data points indicate the effect is statistically Significant (p ≤ 0.05), while blue data points indicate the effect is not statistically significant.
Figure 8. Facet plot for pooled estimates following multivariate meta-regression. The outcomes are displayed in four separate forest plots: ICU stay (mean difference), mechanical ventilation (mean difference), mortality (odds ratio), and VAP (odds ratio). The vertical dashed red lines represent the line of no effect. Each row represents a specific Intervention. Red data points indicate the effect is statistically Significant (p ≤ 0.05), while blue data points indicate the effect is not statistically significant.
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Figure 9. Funnel plots for assessing publication bias for chlorhexidine. Each plot presents the precision (calculated as standard error) on the y-axis against the effect size (log odds ratio or mean difference) on the x-axis. The data points represent individual studies included in the meta-analysis. The vertical dashed red line marks the null effect, and the solid green line represents the pooled effect estimate.
Figure 9. Funnel plots for assessing publication bias for chlorhexidine. Each plot presents the precision (calculated as standard error) on the y-axis against the effect size (log odds ratio or mean difference) on the x-axis. The data points represent individual studies included in the meta-analysis. The vertical dashed red line marks the null effect, and the solid green line represents the pooled effect estimate.
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Figure 10. Risk of bias assessment of RCTs.
Figure 10. Risk of bias assessment of RCTs.
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Figure 11. Box plots of propensity matched reduction in VAP and mortality with chlorhexidine.
Figure 11. Box plots of propensity matched reduction in VAP and mortality with chlorhexidine.
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Table 1. Key characteristics of included studies.
Table 1. Key characteristics of included studies.
Study IdYearCountryICU SettingStudy DesignVAP Bundle AdequacyInterventionsToothbrush Co-InterventionConcentration (%)Daily FrequencyTotal NumbersMean Age (Years)Male (%)Severity of Illness ScaleSeverity ScoreVAP
Definition
Abele-Horn [22]1997GermanyAnesthesiologyRCT1Antimicrobial combinationNo245839.950APACHE II16CPIS
Standard of careNoNANot mentioned3044.780APACHE II18CPIS
Bellissimo-Rodrigues [23] 2014BrazilMixedRCT0Chlorhexidine + ToothbrushYes2 or 0.12Not mentionedNANANANot providedNANA
ChlorhexidineNo2 or 0.12Not mentionedNANANANot providedNANA
Bergmans [24]2001NetherlandsMixedRCT2Antimicrobial combinationNo248756.668APACHE II21CDC
WaterNoNA46158.777APACHE II21.2CDC
Berry [25]2011AustraliaMixedRCT1Water + ToothbrushYesNA127859.156.4APACHE II21.64Pugin’s
Sodium bicarbonate + ToothbrushYesNA127660.455.3APACHE II22Pugin’s
Chlorhexidine + ToothbrushYes0.2127158.249.3APACHE II22.8Pugin’s
Berry [26]2013AustraliaMixedRCT4Listerine + ToothbrushYesNA212759.9657.5APACHE II21.21Pugin’s
Sodium bicarbonate + ToothbrushYesNA1213354.9359.4APACHE II21.38Pugin’s
Water + ToothbrushYesNA1213858.8260.9APACHE II20.86Pugin’s
Chacko [27]2017IndiaMedicalRCT2ChlorhexidineNo0.2810445.9167.3Not providedNACDC
Chlorhexidine + ToothbrushYes0.2810241.0244.1Not providedNACDC
Chen [28]2016ChinaEmergencyRCT2Antimicrobial drugNo0.0824064.760APACHE II16.1CPIS
ChlorhexidineNo0.2215562.699APACHE II16.1CPIS
Chua [29]2004PhilippinesMixedRCT2Povidone iodineNo132251.431.8APACHE II15.9CDC
WaterNoNA32055.250APACHE II17CDC
Dahiya [30]2012IndiaMedicalRCT0ChlorhexidineNo0.2235NANANot providedNANot specified
Hydrogen peroxideNoNA235NANANot providedNANot specified
Darbanian [31]2024IranMedicalRCT2PropolisNo0.06255NA49.1Not providedNACPIS
ChlorhexidineNo0.2255NA49.1Not providedNACPIS
de Lacerda Vidal [32]2017BrazilMixedRCT3Chlorhexidine + ToothbrushYes0.12210559.448.6APACHE II21.9ATS/IDSA
ChlorhexidineNo0.12210863.250APACHE II22.2ATS/IDSA
De Riso [33]1996USACardiothoracicRCT1ChlorhexidineNo0.12217364.168.8Not providedNANA
WaterNoNA218063.568.3Not providedNANA
Deschepper [34]2018BelgiumMixedCohort0ChlorhexidineNo0.05 or 0.122 or 3NANANANot providedNANA
No ChlorhexidineNoNA2 or 3NANANANot providedNANA
Dobakhti [35]2023IranSurgicalRCT0ChlorhexidineNo0.2332NA62.5APACHE II18.12CPIS
ChlorhexidineNo0.2332NA56.2APACHE II18.9CPIS
Dobakhti [36]2023IranSurgicalRCT0Rose water + ChlorhexidineNo0.1234045.7560APACHE II18.25CPIS
ChlorhexidineNo0.1234045.9962.5APACHE II19.37CPIS
Enwere [37]2016USASurgicalCohort2Chlorhexidine + ToothbrushYes0.122645767.2Not providedNACDC
ToothbrushYesNA2945971.3Not providedNACDC
Feng [38]2012ChinaMedicalRCT0Povidone iodine + ToothbrushYes0.0547143.7NANot providedNACSRD
Nitrofurazone + ToothbrushYesNA46538.5NANot providedNACSRD
Saline + ToothbrushYesNA46840.3NANot providedNACSRD
Fourrier [39]2000FranceMedicalRCT0ChlorhexidineNo0.233051.263.3APACHE II37NA
Sodium bicarbonate + SalineNoNA43050.463.3APACHE II33NA
Fourrier [40]2005FranceMedicalRCT0ChlorhexidineNo0.231146172.8Not providedNAClinical + Radiological + Microbiological
PlaceboNoNA311461.164Not providedNAClinical + Radiological + Microbiological
Franata [41]2025IndonesiaUnclearRCT0ChlorhexidineNo0.1221039.2NANot providedNACPIS
Fluoride toothpaste + ToothbrushYesNA21048.5NANot providedNACPIS
Galhardo [42]2020BrazilUnclearCohort0Chlorhexidine + ToothbrushYes0.12Not mentioned329NANANot providedNAClinical
No ChlorhexidineNoNANot mentioned229NANANot providedNAClinical
Genuit [43]2000USASurgicalNon-randomized0ChlorhexidineNo0.1225668.8100Not providedNANA
No ChlorhexidineNoNANot mentioned3969.298Not providedNANA
Gharebaghi [44]2020IranMedicalRCT0Antimicrobial combinationNo2452NANANot providedNAClinical + Radiological + Microbiological
ChlorhexidineNo0.2453NANANot providedNAClinical + Radiological + Microbiological
Gholami [45]2021IranUnclearRCT0Zataria multiflora Boiss.No10330NA73.3Not providedNANA
ChlorhexidineNo0.2330NA66.7Not providedNANA
SalineNoNA330NA46.7Not providedNANA
Haghighat [46]2022IranMixedRCT0ChlorhexidineNo0.2220NA70Not providedNACPIS
Chlorhexidine + ToothbrushYes0.2240NA62.5Not providedNACPIS
Hanifi [47]2017IranSurgicalRCT0Ozonated waterNoNA33944.4264.1Not providedNACPIS
ChlorhexidineNo0.233044.6171.4Not providedNACPIS
Hashemi [48]2018IranUnclearRCT0ChlorhexidineNo0.244348.4460.46Not providedNACDC
Stop-snoring herbal mouthwashNoNA44354.0660Not providedNACDC
Hu [49]2009ChinaUnclearRCT0SalineNoNA225NA64Not providedNAClinical + Radiological + Microbiological
SalineNoNA222NA59.1Not providedNAClinical + Radiological + Microbiological
Long [50]2012ChinaUnclearRCT0Povidone iodine + ToothbrushYesNA33160.0664.5APACHE II17.94Clinical + Radiological + Microbiological
Povidone iodineNoNA33063.6760APACHE II18.23Clinical + Radiological + Microbiological
Mo [51]2016ChinaCardiothoracicRCT0SalineNoNA410559.1457.1Not providedNACSRD
SalineNoNA410556.7164.8Not providedNACSRD
Xu [52]2007ChinaUnclearRCT0SalineNoNA244NANANot providedNACSRD
SalineNoNA258NANANot providedNACSRD
SalineNoNA262NANANot providedNACSRD
Xu [53]2008ChinaUnclearRCT0Saline NoNA264NANANot providedNACSRD
SalineNoNA252NANANot providedNACSRD
Zhao [54]2012ChinaUnclearRCT0TriclosanNoNA4162NANANot providedNAMicrobiological
SalineNoNA4162NANANot providedNAMicrobiological
Irani [55]2019IranSurgicalRCT1Miswak + ToothbrushYesNA23533.6582.9Not providedNACPIS
ChlorhexidineNo0.223534.8374.3Not providedNACPIS
Izadi [56]2023IranUnclearRCT0ChlorhexidineNo0.233763.734.2Not providedNACPIS
Ozonated waterNoNA33660.358.3Not providedNACPIS
Jacomo [57]2011BrazilCardiothoracicRCT0ChlorhexidineNo0.122871.0248PRISM3CDC
WaterNoNA2730.948PRISM3CDC
Jahanshir [58]2023IranUnclearRCT0CloveNo6.6628455.2161.9Not providedNACPIS
ChlorhexidineNo0.1228459.767.9Not providedNACPIS
Jamshidi [59]2015IranUnclearRCT0ChlorhexidineNo0.236041.353.9Not providedNACPIS
ToothbrushYesNA36141.353.9Not providedNACPIS
Chlorhexidine + ToothbrushYes0.235941.353.9Not providedNACPIS
Karakaya [60]2022TurkeyPICURCT3ChlorhexidineNo0.126884.347.7PRISM18CDC
SalineNo0.96863.230.2PRISM18CDC
Kawyannejad [61]2020IranUnclearRCT3Satureja plantNoNA34042.2257.5Not providedNACPIS
ChlorhexidineNo0.234044.7660Not providedNACPIS
Khaky [62]2018IranUnclearRCT0Hydrogen peroxide + Silver ionsNoNA33741.672.5SOFA7.5CPIS
ChlorhexidineNo233844.167.5SOFA7.3CPIS
Kiabi [63]2023IranUnclearRCT2PersicaNoNA225NA45.04SOFA8.8CPIS
ChlorhexidineNo0.2225NA45.04SOFA7.72CPIS
Klarin [64]2018SwedenMedicalRCT0ProbioticNoNA2696658APACHE II22Clinical + Radiological + Microbiological
Chlorhexidine + ToothbrushYes0.126865.552.9APACHE II24Clinical + Radiological + Microbiological
Koeman [65]2006NetherlandsMixedRCT2ChlorhexidineNo2412760.952APACHE II22.2Clinical + Radiological + Microbiological
Chlorhexidine + ColistinNo2412862.456APACHE II23.7Clinical + Radiological + Microbiological
SalineNo0.9413062.172APACHE II21.8Clinical + Radiological + Microbiological
Kollef [66]2006MultinationalMixedRCT0IsegananNoNA636260.562.9APACHE II19.6Clinical + Radiological + Microbiological
PlaceboNoNA634757.557.5APACHE II19.3Clinical + Radiological + Microbiological
Kushara [67]2012BrazilPICURCT2Chlorhexidine + ToothbrushYes0.12246160.9Not providedNACPIS/CDC/NHSN
ToothbrushYesNA2502.964Not providedNACPIS/CDC/NHSN
Lev [68]2015IsraelMixedRCT0Sodium bicarbonate + Hydrogen peroxide + Vitamin E + ToothbrushYesNA34568.755.5APACHE II19.1NHSN
ChlorhexidineNo0.234571.853.3APACHE II18.2NHSN
Leyderman [69]2024RussiaSurgicalRCT3Chlorhexidine + ToothbrushYes0.0532565NAAPACHE II13.05CPIS
ChlorhexidineNo0.0522270NAAPACHE II13.1CPIS
Li [70]2021ChinaNICURCT0Colostrum + Sodium bicarbonateNo2.5440NANANot providedNAClinical + Radiological + Microbiological
ColostrumNoNA440NANANot providedNAClinical + Radiological + Microbiological
Sodium bicarbonateNo2.5440NANANot providedNAClinical + Radiological + Microbiological
Li-Yin [71]2011TaiwanSurgicalRCT2Water + ToothbrushYesNA22860.760.7APACHE II19.6CPIS
WaterNoNA22560.568APACHE II19.4CPIS
Lorente [72]2012SpainMixedRCT3Chlorhexidine + ToothbrushYes0.1232176167.3APACHE II17.88Clinical + Radiological + Microbiological
ChlorhexidineNo0.12321960.466.2APACHE II19.16Clinical + Radiological + Microbiological
Maarefvand [73]2015IranUnclearRCT0ChamomileNoNA23045.9346.7APACHE II17.7CPIS
ChlorhexidineNo0.1226051.6350APACHE II17.63CPIS
Meidani [74]2018IranUnclearRCT0ChlorhexidineNo0.235050.674Not providedNACDC
Potassium permanganateNo0.0135049.874Not providedNACDC
PlaceboNoNA35051.766Not providedNACDC
Meinberg [75]2012BrazilSurgicalRCT0Chlorhexidine + ToothbrushYes242840.1NAAPACHE II17.9Clinical + Radiological + Microbiological
ToothbrushYes242441NAAPACHE II16.7Clinical + Radiological + Microbiological
Moghaddam [76]2022IranUnclearRCT2Chamomile + ToothbrushYes1024045.1NANot providedNACPIS
Chlorhexidine + ToothbrushYes0.224039.85NANot providedNACPIS
Mohseni [77]2024IranUnclearRCT2Tea tree oil + Aloe vera+ ToothbrushYesNA2314564.5Not providedNACPIS
Chlorhexidine + ToothbrushYes0.22314564.5Not providedNACPIS
Mori [78]2006JapanMixedCohort0Povidone iodineNoNot known812485362APACHE II13.9Clinical + Radiological + Microbiological
No oral careNoNANA4145366APACHE II13.4Clinical + Radiological + Microbiological
Nasiriani [79]2016IranUnclearRCT0Chlorhexidine + Saline+ ToothbrushYesNot known28444.966.7Not providedNACPIS
Chlorhexidine + SalineNoNot known28444.267.9Not providedNACPIS
Nicolosi [80]2014ArgentinaCardiothoracicCohort0Chlorhexidine + ToothbrushYes0.12215062.381.3Not providedNAClinical + Radiological
Standard of careNoNA215063.186Not providedNAClinical + Radiological
Nobahar [81]2016IranMixedRCT1Hydrogen peroxideNo32346650Not providedNACPIS
SalineNo0.923463.447.1Not providedNACPIS
Ory [82]2017FranceMixedCohort0ChlorhexidineNo0.5393264.669.3SAPS254Clinical + Radiological + Microbiological
Chlorhexidine + ToothbrushYes0.53115163.667.5SAPS253.3Clinical + Radiological + Microbiological
Ozcaka [83]2012TurkeyRespiratory RCT0ChlorhexidineNo0.242960.5NAAPACHE II23.9Not specified
SalineNo0.943256NAAPACHE II24.7Not specified
Panchabai [84]2009IndiaMedicalRCT3ChlorhexidineNo0.2288NANANot providedNAClinical + Radiological + Microbiological
Potassium permanganateNo0.01283NANANot providedNAClinical + Radiological + Microbiological
Pedreira [85]2009BrazilPICURCT0Chlorhexidine + ToothbrushYes0.12227NANANot providedNANA
ToothbrushNoNA229NANANot providedNANA
Pobo [86]2009SpainMixedRCT1ChlorhexidineNo0.1237352.663APACHE II18.7ATS/IDSA
Chlorhexidine + ToothbrushYes0.1237455.366.2APACHE II18.8ATS/IDSA
Pugin [87]1991SwitzerlandSurgicalRCT1Antimicrobial combinationNoNA1254576APACHE II15.8CPIS
PlaceboNoNA1274674.1APACHE II14.7CPIS
Rezvani [88]2018IranMixedRCT0ChamomileNoNA34560.7860Not providedNANot specified
ChlorhexidineNo0.234559.1855Not providedNANot specified
Rodriguez-Roldan [89]1990SpainMixedRCT1Chlorhexidine + Antimicrobial combinationN00.14135453.8APACHE II16Clinical + Radiological + Microbiological
ChlorhexidineNo0.14154966.7APACHE II18Clinical + Radiological + Microbiological
Kes [90]2021TurkeySurgicalRCT0ChlorhexidineNo0.1232972.7962.1APACHE II16.1CPIS
Sodium bicarbonateNoNA32877.3757.1APACHE II16.6CPIS
Houston [91]2002USACardiothoracicRCT0ChlorhexidineNo0.12219NANANot providedNACDC
ListerineNoNA218NANANot providedNACDC
Saito [92]2022VietnamMixedCohort1ToothbrushYesNANot mentioned30057.556.3APACHE II20CPIS
Standard of careNoNANot mentioned3035658.1APACHE II17CPIS
Scannapieco [93]2009USAUnclearRCT0ChlorhexidineNo0.1214744.891.5APACHE II18.5CPIS
ChlorhexidineNo0.1225047.688APACHE II19.7CPIS
WaterNo0.121495073.5APACHE II19.1CPIS
Sebastian [94]2012IndiaPICURCT2ChlorhexidineNo1341NA56.1PIM219CDC
PlaceboNoNA345NA60PIM223.5CDC
Seguin [95]2006FranceSurgicalRCT2Povidone iodineNo106363878SAPS239BAL + Microbiological
SalineNo0.96313877SAPS241BAL + Microbiological
Standard of careNoNA6314174SAPS240BAL + Microbiological
Seguin [96]2013FranceSurgicalRCT2Povidone iodineNo106854871SAPS247Clinical + Radiological + Microbiological
WaterNoNA6824878SAPS246Clinical + Radiological + Microbiological
Sharma [97]2012IndiaMixedRCT0ChlorhexidineNo0.122130NA74.6Not providedNACPIS
SalineNo0.92130NA72.3Not providedNACPIS
Shorofi [98]2025IranMixedRCT0Zataria multiflora Boiss. + ChlorhexidineNo0.226046.5766.7Not providedNACPIS
ChlorhexidineNo0.226050.5866.7Not providedNACPIS
Singh [99]2022IndiaUnclearRCT3Chlorhexidine + ToothbrushYes0.2211039.0250Not providedNANot specified
ChlorhexidineNo0.2211039.150.9Not providedNANot specified
Siriyanyongwong [100]2022ThailandMedicalRCT0Chlorhexidine + Moraceae + ToothbrushYes0.023156853.3SOFA9CDC
ChlorhexidineNo0.123156353.3SOFA8CDC
Stefanescu [101]2013USANICURCT1BioteneNoNA6200.535APGAR3CDC
WaterNoNA6210.4852APGAR4CDC
Takeyasu [102]2014JapanUnclearRCT2Povidone iodine + ToothbrushYes138467.965.5Not providedNANot specified
ToothbrushYesNA35867.965.5Not providedNANot specified
Tantipong [103]2008ThailandMixedRCT0Chlorhexidine + ToothbrushYes2410256.549.1APACHE II16.7Clinical + Radiological + Microbiological
Saline + ToothbrushYes0.9410560.348.6APACHE II18.2Clinical + Radiological + Microbiological
Tuon [104]2017BrazilMixedRCT0ChlorhexidineNo22853.162.5APACHE IINACDC
SalineNo0.92842.850Not providedNACDC
Vyas [105]2020IndiaUnclearRCT1ChlorhexidineNo0.123704778.57Not providedNACPIS
ChlorhexidineNo0.237048.568.57Not providedNACPIS
Yadav [106]2022IndiaUnclearRCT1Antimicrobial drugNo248233.2150APACHE II21.9CPIS
ChlorhexidineNo246933.7547.8APACHE II22.58CPIS
Yu [107] & [108]2021ChinaNICURCT0Breast milkNoNA8310.15NANot providedNAClinical + Radiological + Microbiological
SalineNoNA8310.14NANot providedNAClinical + Radiological + Microbiological
Sodium bicarbonateNoNA8310.15NANot providedNAClinical + Radiological + Microbiological
Zand [109]2017IranMixedRCT1ChlorhexidineNo0.225745.4380.7APACHE IV61.33CPIS
ChlorhexidineNo225744.4580.7APACHE IV56.01CPIS
Zarinfar [110]2021IranMixedRCT4Standard of careNoNANot mentioned4360.448.8APACHE IINACPIS
ChlorhexidineNo0.1224353.560.5APACHE IINACPIS
ChlorhexidineNo0.122435044.2APACHE IINACPIS
Bellissimo-Rodrigues [111]2009BrazilMixedRCT2ChlorhexidineNo0.1239862.548APACHE II17CDC
PlaceboNoNA3965453APACHE II19CDC
Bopp [112]2006USAMixedRCT0ChlorhexidineNo0.12224050Not providedNANot specified
Hydrogen peroxide or ListerineNoNA6373.733Not providedNANot specified
Cabov [113]2010CroatiaSurgicalRCT0ChlorhexidineNo0.23305763.3SAPS230Clinical + Radiological + Microbiological
PlaceboNoNA3305266.7SAPS228.2Clinical + Radiological + Microbiological
de Smet [114]2009NetherlandsMixedRCT0Antimicrobial combinationNo24190461.463.7APACHE II19.5Not specified
Standard of careNoNANot mentioned199061.461.3APACHE II18.6Not specified
Loha [115]2022IndiaUnclearRCT5ChlorhexidineNo234456.8650APACHE II21.21CPIS
Chlorhexidine + Sodium bicarbonateNo2 & 0.924454.9647.7APACHE II21.28CPIS
Munro [116]2009USAMixedRCT0ToothbrushYesNA34947.157APACHE III76.4Not specified
ChlorhexidineNo0.1224446.159APACHE III80.4Not specified
Chlorhexidine + ToothbrushYes0.1234847.358APACHE III76.2Not specified
Standard of careNoNANot mentioned5146.873APACHE III76.2Not specified
Zambrano [117]2024BrazilUnclearRCT0ChlorhexidineNo0.122456355Not providedNANot specified
Chlorhexidine + ToothbrushYes0.122456569Not providedNANot specified
RCT: Randomized clinical trial; CPIS: Clinical Pulmonary Infection Score; NA: Not available/Not applicable; CDC: Centers for Disease Control and Prevention; APACHE: Acute Physiology And Chronic Health Evaluation; ATS/IDSA: American Thoracic Society/Infectious Disease Society of America; CSRD: Chinese Society for Respiratory Disease; and NHSN: National Healthcare Safety Network; PICU: Pediatric intensive care unit; SOFA: Sequential organ failure assessment; PRISM: Pediatric Risk of Mortality; PIM 2: Pediatric index of mortality 2; APGAR: Appearance, Pulse, Grimace, Activity, and Respiration; SAPS2: Simplified acute physiology score II; BAL: Bronchoalveolar lavage.
Table 2. Grading the strength of estimates of key comparisons.
Table 2. Grading the strength of estimates of key comparisons.
Comparisons with Reference Interventions for the Risk of VAPComparative Risks of VAP per 1000 Patients with Reference Interventions
(95% Confidence Intervals)		Effect Estimates (ORs) and the Quality of Evidence
Assumed Risk 1Corresponding Risk
Random effect estimates from network meta-analysis
Chlorhexidine311199 (151 to 258)0.55 [0.39, 0.77]; Moderate 2
Antimicrobial combination123 (63 to 224)0.31 [0.15, 0.64]; Very low 2,3
Povidone iodine150 (87 to 243)0.39 [0.21, 0.71]; Very low 2,3
Chlorhexidine + Toothbrush147 (102 to 205)0.38 [0.25, 0.57]; Very low 2,3
Toothbrush alone172 (112 to 258)0.46 [0.28, 0.77]; Very low 2,3
Miswak + Toothbrush18 (0 to 260)0.04 [0, 0.78]; Very low 2,3
Chamomile + Toothbrush18 (4 to 67)0.04 [0.01, 0.16]; Very low 2,3
Hydrogen peroxide + Silver ions22 (0 to 190)0.05 [0, 0.52]; Very low 2,3
Hyrogen peroxide+ Vitamin E + Toothbrush47 (9 to 193)0.11 [0.02, 0.53]; Very low 2,3
Nitrofurazone + Toothbrush51 (13 to 156)0.12 [0.03, 0.41]; Very low 2,3
Ozonated water63 (22 to 178)0.15 [0.05, 0.48]; Very low 2,3
Clove79 (26 to 235)0.19 [0.06, 0.68]; Very low 2,3
Propolis87 (26 to 260)0.21 [0.06, 0.78]; Very low 2,3
Satureja plant90 (22 to 280)0.22 [0.05, 0.86]; Very low 2,3
Random effect estimates from pairwise comparisons
Chlorhexidine300208 (143 to 289)0.61 [0.39, 0.95]; Moderate 2
VAP: Ventilator-associated pneumonia. 1—Assumed risk was the median risk of VAP with reference interventions across the studies; 2—Downgraded one level due to heterogeneity of studies; 3—Downgraded two levels as publication bias could not be assessed/ruled out. Moderate: The true effect of an intervention is close to the estimate, but there is a possibility it could be different; Very low: We have very little confidence in the effect estimate.
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Sridharan, K.; Sivaramakrishnan, G.; Alotaibi, G.A. Oropharyngeal Interventions in Intubated Patients for Preventing Ventilator Associated Pneumonia: A Systematic Review and Multi-Variate Network Meta-Analysis Evaluating Pharmacological Agents. J. Clin. Med. 2025, 14, 8174. https://doi.org/10.3390/jcm14228174

AMA Style

Sridharan K, Sivaramakrishnan G, Alotaibi GA. Oropharyngeal Interventions in Intubated Patients for Preventing Ventilator Associated Pneumonia: A Systematic Review and Multi-Variate Network Meta-Analysis Evaluating Pharmacological Agents. Journal of Clinical Medicine. 2025; 14(22):8174. https://doi.org/10.3390/jcm14228174

Chicago/Turabian Style

Sridharan, Kannan, Gowri Sivaramakrishnan, and Ghazi Abdulrahman Alotaibi. 2025. "Oropharyngeal Interventions in Intubated Patients for Preventing Ventilator Associated Pneumonia: A Systematic Review and Multi-Variate Network Meta-Analysis Evaluating Pharmacological Agents" Journal of Clinical Medicine 14, no. 22: 8174. https://doi.org/10.3390/jcm14228174

APA Style

Sridharan, K., Sivaramakrishnan, G., & Alotaibi, G. A. (2025). Oropharyngeal Interventions in Intubated Patients for Preventing Ventilator Associated Pneumonia: A Systematic Review and Multi-Variate Network Meta-Analysis Evaluating Pharmacological Agents. Journal of Clinical Medicine, 14(22), 8174. https://doi.org/10.3390/jcm14228174

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