Natural antiseptics versus chlorhexidine in the prevention of ventilator-associated pneumonia: a critical and qualitative review of clinical trials

Introduction Natural extract–based mouthwashes have been investigated as potential alternatives to chlorhexidine due to their lower toxicity, ability to reduce oral microbial load, and fewer reported side effects. This review aimed to assess their effectiveness compared with chlorhexidine in preventing ventilator-associated pneumonia (VAP) in adult ICU patients. Methods A qualitative critical review of clinical trials was conducted following PRISMA and Cochrane recommendations, with a registered protocol (PROSPERO: CRD420251043018). Searches were performed in five databases and the gray literature to identify trials comparing natural extract–based mouthwashes with chlorhexidine in mechanically ventilated adults. Four independent reviewers performed study selection, data extraction, and methodological appraisal using a CONSORT-based tool. Results Thirteen clinical trials met the inclusion criteria, all conducted in Iran between 2012 and 2024. Mouthwashes containing Zataria multiflora, chamomile, clove, or Ortodentol demonstrated effects that were generally comparable to those of chlorhexidine and were associated with fewer adverse reactions. However, variation in herbal formulations, sample sizes, and methodological quality, as well as the concentration of studies in a single geographic region, may limit the broader applicability of the findings. Conclusion Natural mouthwashes show promise as alternatives to chlorhexidine for reducing the risk of ventilator-associated pneumonia. Nevertheless, additional well-designed trials in diverse settings are required to confirm their clinical utility and improve the generalizability of available evidence.