We have read with great interest the yet unpublished letter from Blot and Deschepper analyzing our article,1 about oral care with chlorhexidine in critically ill patients, and we have some comments to make regarding the authors' considerations.

Due to the evidence of the association between oral care with chlorhexidine and increased risk of mortality, the International SHEA/IDSA/APIC 2022 Guidelines, in their ventilator-associated pneumonia (VAP) prevention bundles, recommend providing oral hygiene, but without chlorhexidine.2 However, the pathophysiological mechanisms that explain this association are not well understood.

Indeed, micro-aspirations of chlorhexidine, an acidic substance, which could lead to lung injury, alone do not justify the mechanism of increased mortality. So much so that, in our article,2 we have presented this as just one, among several, of the possible justifications. Therefore, other theories should be evaluated, including the suggestion by Blot and Deschepper that a disturbance in the enterosalivary nitrate-nitrite-nitric oxide (NO) pathway could help explain the increased mortality risk observed in patients exposed to chlorhexidine mouthwashes. According to the authors, oral antiseptics eradicate the anaerobic bacteria located on the posterior surface of the tongue, interrupting the process of reducing nitrate to nitrite, which occurs in the oral cavity, thus reducing the bioavailability of NO, a condition that could lead to increased mortality due to ischemic events and sepsis.

This theory is attractive, however, it does not fully explain the phenomenon, because: (1) studies evaluating selective oral decontamination with topical antibiotics, in critically ill patients on mechanical ventilation, reported lower hospital mortality2,3; (2) reduced bioavailability of the NO could actually be associated with an increased risk for ischemic cardiac events, however, there is evidence of increased mortality with the use of oral chlorhexidine also in young people without heart disease4 and, in patients undergoing cardiac surgery, the use of oral chlorhexidine is associated with better outcomes1; and (3) if, on the one hand, the vasoconstrictor effect of low NO levels can be harmful for septic patients, on the other hand, high levels of this inflammatory mediator are associated with worse outcomes and increased mortality.5 NO exerts an important role in the pathophysiology of sepsis, systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS), by causing increased endothelial permeability, vascular leakage, mitochondrial dysfunction, impaired migration of neutrophils to the focus of infection and worsened cardiovascular responsiveness in severe cases of sepsis.5

Besides the various possible justifications described in our article,1 and the NO theorem proposed by Blot and Deschepper, other pathophysiological mechanisms that could explain the increased mortality risk observed in patients undergoing oral care with chlorhexidine should be sought and evaluated.

To our knowledge, there are no studies reporting increased mortality with the use of other oral antiseptics. Therefore, we believe that the issue of not using any antiseptic mouthwash, in the care of critically ill patients, should be explored in research comparing oral hygiene with chlorhexidine, with an alternative antiseptic, and with no antiseptic at all.