{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T13:35:36Z","timestamp":1769520936987,"version":"3.49.0"},"reference-count":44,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,5,28]],"date-time":"2022-05-28T00:00:00Z","timestamp":1653696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>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 &gt; 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 &lt; 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\u20131.29, p = 0.038 and aOR 1.05, 95% CI 1.01\u20131.10, 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.<\/jats:p>","DOI":"10.3390\/microorganisms10061118","type":"journal-article","created":{"date-parts":[[2022,5,29]],"date-time":"2022-05-29T23:43:03Z","timestamp":1653867783000},"page":"1118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Effects of Different Inhalation Therapy on Ventilator-Associated Pneumonia in Ventilated COVID-19 Patients: A Randomized Controlled Trial"],"prefix":"10.3390","volume":"10","author":[{"given":"Nikola","family":"Deli\u0107","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, University Hospital of Split, Spin\u010di\u0107eva 1, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9272-6906","authenticated-orcid":false,"given":"Andrija","family":"Matetic","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7003-8192","authenticated-orcid":false,"given":"Josipa","family":"Domjanovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toni","family":"Kljakovi\u0107-Ga\u0161pi\u0107","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Hospital of Split, Spin\u010di\u0107eva 1, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5621-580X","authenticated-orcid":false,"given":"Lenko","family":"\u0160ari\u0107","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Hospital of Split, Spin\u010di\u0107eva 1, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darko","family":"Ili\u0107","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Hospital of Split, Spin\u010di\u0107eva 1, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svjetlana","family":"Do\u0161enovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Hospital of Split, Spin\u010di\u0107eva 1, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josipa","family":"Domazet","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Hospital of Split, Spin\u010di\u0107eva 1, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruben","family":"Kova\u010d","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Hospital of Split, Spin\u010di\u0107eva 1, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frane","family":"Runji\u0107","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanda Stojanovi\u0107","family":"Stipi\u0107","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Hospital of Split, Spin\u010di\u0107eva 1, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6913-5531","authenticated-orcid":false,"given":"Bo\u017eidar","family":"Duplan\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University Hospital of Split, Spin\u010di\u0107eva 1, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1001\/jama.2020.2648","article-title":"Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases from the Chinese Center for Disease Control and Prevention","volume":"323","author":"Wu","year":"2020","journal-title":"JAMA"},{"key":"ref_2","unstructured":"(2022, January 15). COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health, Available online: https:\/\/www.covid19treatmentguidelines.nih.gov\/."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ippolito, M., Misseri, G., Catalisano, G., Marino, C., Ingoglia, G., Alessi, M., Consiglio, E., Gregoretti, C., Giarratano, A., and Cortegiani, A. (2021). Ventilator-Associated Pneumonia in Patients with COVID-19: A Systematic Review and Meta-Analysis. Antibiotics, 10.","DOI":"10.3390\/antibiotics10050545"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2736","DOI":"10.1097\/CCM.0b013e3182281f33","article-title":"Estimating the attributable mortality of ventilator-associated pneumonia from randomized prevention studies","volume":"39","author":"Melsen","year":"2011","journal-title":"Crit. Care Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1097\/MCC.0000000000000908","article-title":"Ventilator-associated pneumonia among SARS-CoV-2 acute respiratory distress syndrome patients","volume":"28","author":"Fumagalli","year":"2022","journal-title":"Curr. Opin. Crit. Care"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1080\/17476348.2017.1359090","article-title":"The role of mucoactive agents in the mechanically ventilated patient: A review of the literature","volume":"11","author":"Icard","year":"2017","journal-title":"Expert Rev. Respir. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s40261-019-00861-x","article-title":"Safety, Tolerability, and Effects of Sodium Bicarbonate Inhalation in Cystic Fibrosis","volume":"40","author":"Gomez","year":"2020","journal-title":"Clin. Drug Investig."},{"key":"ref_8","first-page":"309","article-title":"Evaluation of the Effect of Nebulized N-Acetylcysteine on Respiratory Secretions in Mechanically Ventilated Patients: Randomized Clinical Trial","volume":"40","author":"Masoompour","year":"2015","journal-title":"Iran. J. Med. Sci."},{"key":"ref_9","first-page":"Cd001506","article-title":"Nebulised hypertonic saline for cystic fibrosis","volume":"9","author":"Wark","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_10","unstructured":"ARDS Definition Task Force, Ranieri, V.M., Rubenfeld, G., Thompson, B., Ferguson, N., Caldwell, E., Fan, E., Camporota, L., and Slutsky, A.S. (2012). Acute Respiratory Distress Syndrome: The Berlin Definition. JAMA, 307, 2526\u20132533."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13054-021-03460-5","article-title":"Ventilator-associated pneumonia in critically ill patients with COVID-19","volume":"25","author":"Maes","year":"2021","journal-title":"Crit. Care"},{"key":"ref_12","first-page":"S186","article-title":"Hydrator Therapies for Chronic Bronchitis. Lessons from Cystic Fibrosis","volume":"13","author":"Bennett","year":"2016","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1056\/NEJMoa043891","article-title":"Mucus Clearance and Lung Function in Cystic Fibrosis with Hypertonic Saline","volume":"354","author":"Donaldson","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1136\/thx.52.10.900","article-title":"Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis","volume":"52","author":"Robinson","year":"1997","journal-title":"Thorax"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1164\/ajrccm.156.1.9512074","article-title":"Rheology of cystic fibrosis sputum after in vitro treatment with hypertonic saline alone and in combination with recombinant human deoxyribonuclease I","volume":"156","author":"King","year":"1997","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1172\/JCI119138","article-title":"Sodium chloride increases the ciliary transportability of cystic fibrosis and bronchiectasis sputum on the mucus-depleted bovine trachea","volume":"99","author":"Wills","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"543","DOI":"10.4049\/jimmunol.0803959","article-title":"LL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline","volume":"183","author":"Bergsson","year":"2009","journal-title":"J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Michon, A.L., Jumas-Bilak, E., Chiron, R., Lamy, B., and Marchandin, H. (2014). Advances toward the elucidation of hypertonic saline effects on Pseudomonas aeruginosa from cystic fibrosis patients. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090164"},{"key":"ref_19","first-page":"1753466619866102","article-title":"Nebulized hypertonic saline in noncystic fibrosis bronchiectasis: A comprehensive review","volume":"13","year":"2019","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1136\/thoraxjnl-2014-205953","article-title":"SABRE: A multicentre randomised control trial of nebulised hypertonic saline in infants hospitalised with acute bronchiolitis","volume":"69","author":"Everard","year":"2014","journal-title":"Thorax"},{"key":"ref_21","first-page":"1176","article-title":"Mucoactive agents for airway mucus hypersecretory diseases","volume":"52","author":"Rogers","year":"2007","journal-title":"Respir. Care"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"L542","DOI":"10.1152\/ajplung.00180.2010","article-title":"A new role for bicarbonate in mucus formation","volume":"299","author":"Chen","year":"2010","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"016","DOI":"10.29328\/journal.jcicm.1001029","article-title":"Case reports of observed significant improvement in patients with ARDS due to COVID-19 and maximum ventilatory support after inhalation of sodium bicarbonate","volume":"5","author":"Wardeh","year":"2020","journal-title":"J. Clin. Intensive Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/s13054-021-03517-5","article-title":"Correction to: Risks of ventilator-associated pneumonia and invasive pulmonary aspergillosis in patients with viral acute respiratory distress syndrome related or not to Coronavirus 19 disease","volume":"25","author":"Razazi","year":"2021","journal-title":"Crit. Care"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s13613-020-00775-4","article-title":"Ventilator-associated pneumonia in patients with SARS-CoV-2-associated acute respiratory distress syndrome requiring ECMO: A retrospective cohort study","volume":"10","author":"Luyt","year":"2020","journal-title":"Ann. Intensive Care"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1007\/s00134-020-06323-9","article-title":"Relationship between SARS-CoV-2 infection and the incidence of ventilator-associated lower respiratory tract infections: A European multicenter cohort study","volume":"47","author":"Povoa","year":"2021","journal-title":"Intensive Care Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chang, R., Elhusseiny, K.M., Yeh, Y.C., and Sun, W.Z. (2021). COVID-19 ICU and mechanical ventilation patient characteristics and outcomes-A systematic review and meta-analysis. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0246318"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/s13054-021-03571-z","article-title":"Ventilator-associated pneumonia in the era of COVID-19 pandemic: How common and what is the impact?","volume":"25","author":"Wicky","year":"2021","journal-title":"Crit. Care"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1007\/s00134-020-06062-x","article-title":"High risk of thrombosis in patients with severe SARS-CoV-2 infection: A multicenter prospective cohort study","volume":"46","author":"Helms","year":"2020","journal-title":"Intensive Care Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.jiac.2021.01.011","article-title":"Ventilator-associated bacterial pneumonia in coronavirus 2019 disease, a retrospective monocentric cohort study","volume":"27","author":"Moretti","year":"2021","journal-title":"J. Infect. Chemother."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Giacobbe, D.R., Battaglini, D., Enrile, E.M., Dentone, C., Vena, A., Robba, C., Ball, L., Bartoletti, M., Coloretti, I., and Di Bella, S. (2021). Incidence and Prognosis of Ventilator-Associated Pneumonia in Critically Ill Patients with COVID-19: A Multicenter Study. J. Clin. Med., 10.","DOI":"10.3390\/jcm10040555"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Almand, E.A., Moore, M.D., and Jaykus, L.A. (2017). Virus-Bacteria Interactions: An Emerging Topic in Human Infection. Viruses, 9.","DOI":"10.3390\/v9030058"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrmicro3231","article-title":"The co-pathogenesis of influenza viruses with bacteria in the lung","volume":"12","author":"McCullers","year":"2014","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.mib.2016.11.003","article-title":"Viral-bacterial co-infections in the respiratory tract","volume":"35","author":"Bakaletz","year":"2017","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1016\/S2666-5247(20)30009-4","article-title":"Co-infections: Potentially lethal and unexplored in COVID-19","volume":"1","author":"Cox","year":"2020","journal-title":"Lancet Microbe"},{"key":"ref_36","first-page":"2459","article-title":"Bacterial and Fungal Coinfection in Individuals with Coronavirus: A Rapid Review to Support COVID-19 Antimicrobial Prescribing","volume":"71","author":"Rawson","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zhang, L., Mendoza-Sassi, R.A., Wainwright, C., and Klassen, T.P. (2013). Nebulised hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst. Rev., Cd006458.","DOI":"10.1002\/14651858.CD006458.pub3"},{"key":"ref_38","first-page":"278","article-title":"ffect of N-acetylcysteine inhalation on ventilator-associated pneumonia caused by biofilm in endotracheal tubes","volume":"54","author":"Qu","year":"2016","journal-title":"Zhonghua Er Ke Za Zhi"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1001\/jama.2018.0949","article-title":"Effect of On-Demand vs Routine Nebulization of Acetylcysteine with Salbutamol on Ventilator-Free Days in Intensive Care Unit Patients Receiving Invasive Ventilation: A Randomized Clinical Trial","volume":"319","author":"Binnekade","year":"2018","journal-title":"JAMA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"L184","DOI":"10.1152\/ajplung.00143.2012","article-title":"Mucociliary transport in porcine trachea: Differential effects of inhibiting chloride and bicarbonate secretion","volume":"304","author":"Cooper","year":"2013","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1089\/jamp.2015.1228","article-title":"Rheological Properties of Cystic Fibrosis Bronchial Secretion and in Vitro Drug Permeation Study: The Effect of Sodium Bicarbonate","volume":"29","author":"Stigliani","year":"2016","journal-title":"J. Aerosol Med. Pulm. Drug Deliv."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s13054-021-03493-w","article-title":"Epidemiology and microbiology of ventilator-associated pneumonia in COVID-19 patients: A multicenter retrospective study in 188 patients in an un-inundated French region","volume":"25","author":"Blonz","year":"2021","journal-title":"Crit. Care"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Rouyer, M., Strazzulla, A., Youbong, T., Tarteret, P., Pitsch, A., de Pontfarcy, A., Cassard, B., Vignier, N., Pourcine, F., and Jochmans, S. (2021). Ventilator-Associated Pneumonia in COVID-19 Patients: A Retrospective Cohort Study. Antibiotics, 10.","DOI":"10.3390\/antibiotics10080988"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1164\/rccm.202106-1354OC","article-title":"Bacterial Superinfection Pneumonia in Patients Mechanically Ventilated for COVID-19 Pneumonia","volume":"204","author":"Pickens","year":"2021","journal-title":"Am. J. Respir. Crit. Care Med."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/10\/6\/1118\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:20:43Z","timestamp":1760138443000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/10\/6\/1118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,28]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["microorganisms10061118"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms10061118","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,28]]}}}