Abstract: microorganisms Article Effects of Different Inhalation Therapy on Ventilator-Associated Pneumonia in Ventilated COVID-19 Patients: A Randomized Controlled Trial Nikola Delić 1, *, Andrija Matetic 2 , Josipa Domjanović 3 , Toni Kljaković-Gašpić 1 , Lenko Šarić 1 , Darko Ilić 1 , Svjetlana Došenović 1 , Josipa Domazet 1 , Ruben Kovač 1 , Frane Runjić 2 , Sanda Stojanović Stipić 1 and Božidar Duplančić 1 1 2 3 * Citation: Delić, N.; Matetic, A.; Domjanović, J.; Kljaković-Gašpić, T.; Šarić, L.; Ilić, D.; Došenović, S.; Domazet, J.; Kovač, R.; Runjić, F.; et al. Effects of Different Inhalation Therapy on Ventilator-Associated Pneumonia in Ventilated COVID-19 Patients: A Randomized Controlled Trial. Microorganisms 2022, 10, 1118. https://doi.org/10.3390/ microorganisms10061118 Academic Editor: Antonella d’Arminio Monforte Received: 17 March 2022 Accepted: 25 May 2022 Published: 28 May 2022 Department of Anesthesiology, University Hospital of Split, Spinčićeva 1, 21000 Split, Croatia; tkljakgas@kbsplit.hr (T.K.-G.); lsaric@kbsplit.hr (L.Š.); dilic@kbsplit.hr (D.I.); sdosenovic@kbsplit.hr (S.D.); jdomazet@kbsplit.hr (J.D.); rkovac@kbsplit.hr (R.K.); sastojanovic@kbsplit.hr (S.S.S.); bduplanc@kbsplit.hr (B.D.) Department of Cardiology, University Hospital of Split, 21000 Split, Croatia; andrija.matetic@gmail.com (A.M.); frane.runjic@gmail.com (F.R.) Department of Nephrology, University Hospital of Split, 21000 Split, Croatia; josipa.domjanovic@gmail.com Correspondence: ndelic@kbsplit.hr; Tel.: +385-9-8900-0150 Abstract: The effect of routine inhalation therapy on ventilator-associated pneumonia (VAP) in mechanically ventilated patients with the coronavirus disease (COVID-19) has not been well-defined. This randomized controlled trial included 175 eligible adult patients with COVID-19 who were treated with mechanical ventilation at the University Hospital of Split between October 2020 and June 2021. Patients were randomized and allocated to a control group (no routine inhalation) or one of the treatment arms (inhalation of N-acetylcysteine; 5% saline solution; or 8.4% sodium bicarbonate). The primary outcome was the incidence of VAP, while secondary outcomes included all-cause mortality. Routine inhalation therapy had no effect on the incidence of bacterial or fungal VAP nor on all-cause mortality (p > 0.05). Secondary analyses revealed a significant reduction of Gram-positive and methicillin-resistant Staphylococcus aureus (MRSA) VAP in the treatment groups. Specifically, the bicarbonate group had a statistically significantly lower incidence of Gram-positive bacterial VAP (4.8%), followed by the N-acetylcysteine group (10.3%), 5% saline group (19.0%), and control group (34.6%; p = 0.001). This difference was driven by a lower incidence of MRSA VAP in the bicarbonate group (2.4%), followed by the N-acetylcysteine group (7.7%), 5% saline group (14.3%), and control group (34.6%; p < 0.001). Longer duration of ventilator therapy was the only significant, independent predictor of any bacterial or fungal VAP in the multivariate analysis (aOR 1.14, 95% CI 1.01–1.29, p = 0.038 and aOR 1.05, 95% CI 1.01–1.10, p = 0.028, respectively). In conclusion, inhalation therapy had no effect on the overall VAP incidence or all-cause mortality. Further studies should explore the secondary findings of this study such as the reduction of Gram-positive or MRSA-caused VAP in treated patients. Publisher’s Note: MDPI stays neutral with..