We read with interest the article by Arias-Rivera et al. in a supplementary issue of Enfermería Intensiva (September 2022)1 reporting on an update on the Zero Pneumonia recommendations in view of the overall increase in ventilator-associated pneumonia (VAP) cases in Spain during the SARS-Cov-2 pandemic. However, we question the continued endorsement of chlorhexidine mouthwashes to prevent VAP in all critically ill patients. Firstly, the evidence underpinning the widespread application of oral chlorhexidine mouthwashes for the prevention of VAP is of low certainty. Secondly, and even so important, chlorhexidine interferes with important physiological processes in the oral cavity and triggers antimicrobial resistance. Furthermore, large studies suggest an association with mortality.
The complex flora in the human oral cavity has critical physiological functions, including an active role in food digestion, metabolic regulation, detoxification, and immunological barrier functions which prevent the growth of disease-promoting microorganisms.2 This suggests there is a physiological equilibrium between pro-inflammatory and anti-inflammatory processes, which can be substantially deranged by oral antiseptics.
A recent review hypothesises that the elimination of oral bacteria by antiseptic mouthwashes may have a detrimental influence on the nitrate-nitrite-nitric oxide pathway (N-N-NO pathway).3 The latter is an important mechanism for nitric oxide (NO) generation in which oral bacteria play a vital role by reducing nitrate to nitrite. Nitrite-rich saliva is subsequently swallowed and absorbed into the system where it is further reduced to NO. NO has multiple beneficial effects including vascular tone regulation, wound healing, and antiseptic properties. Interruption of this pathway by killing essential oral bacteria results in a condition of deficient NO bioavailability. This impairs metabolic functions and affect patient outcomes, particularly in septic and cardiovascular patients. Likewise, in intubated patients, the swallowing of nitrite-rich saliva is already compromised, and oral antiseptics will add to this disrupted pathway.
While it is unclear whether oral antiseptics are harmful in patients with extreme disease severity, the evidence suggests that patients with a more favourable prognosis have an increased risk of mortality when exposed to antiseptic mouthwashes.4
Moreover, xerostomia, a recognised side effect of the use of antiseptics, may increase the development of oral lesions with increased infection risk, an important consideration in immuno-compromised patients. Furthermore, recent advances in antimicrobial stewardship initiatives that focused on acquired bacterial resistance have warned of emerging resistance against chlorhexidine, especially in Gram-negative bacteria.5 Additionally, low-level exposure to chlorhexidine triggers cross-resistances to antibiotics thereby constituting a clinical threat beyond chlorhexidine-resistance.5 Therefore, antiseptic stewardship initiatives have been suggested restricting the use of chlorhexidine and carefully assess the application of the agent where benefits to patient care are questionable.
Consequently, the argument in favour of de-adoption of chlorhexidine mouthwashes has gained momentum. A review that included the paper from Dale and colleagues observed an overall improvement in oral health with a de-adoption strategy and detected no difference in mortality regardless of whether chlorhexidine was administered or not. As such, oral bacteria and their role in metabolic homeostasis are likely to be more important than previously thought.6
The need for oral care should not be questioned, however, we must be aware that antiseptics are not harmless and their application needs to be individualised. Future research needs to point out how to perform oral care with respect to the commensal flora. For now, some evidence points out that we should toothbrush 2–3 times/day without applying oral antiseptics6 and future research should measure the benefits of additional interventions to provide the best standard of care.
