Effects of Different Inhalation Therapy on Ventilator-Associated Pneumonia in Ventilated COVID-19 Patients: A Randomized Controlled Trial
Nikola Delić, Andrija Matetic, Josipa Domjanović, Toni Kljaković-Gašpić, Lenko Šarić, Darko Ilić, Svjetlana Došenović, Josipa Domazet, Ruben Kovač, Frane Runjić, Sanda Stojanović Stipić, Božidar Duplančić
Microorganisms, doi:10.3390/microorganisms10061118
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.
Conflicts of Interest: The authors declare no conflict of interest.
References
Almand, Moore, Jaykus, Virus-Bacteria Interactions: An Emerging Topic in Human Infection, Viruses,
doi:10.3390/v9030058Bennett, Henderson, Donaldson, Hydrator Therapies for Chronic Bronchitis. Lessons from Cystic Fibrosis, Ann. Am. Thorac. Soc
Bergsson, Reeves, Mcnally, Chotirmall, Greene et al., LL-37 complexation with glycosaminoglycans in cystic fibrosis lungs inhibits antimicrobial activity, which can be restored by hypertonic saline, J. Immunol,
doi:10.4049/jimmunol.0803959Blonz, Kouatchet, Chudeau, Pontis, Lorber et al., Epidemiology and microbiology of ventilator-associated pneumonia in COVID-19 patients: A multicenter retrospective study in 188 patients in an un-inundated French region, Crit. Care,
doi:10.1186/s13054-021-03493-wChang, Elhusseiny, Yeh, Sun, COVID-19 ICU and mechanical ventilation patient characteristics and outcomes-A systematic review and meta-analysis, PLoS ONE,
doi:10.1371/journal.pone.0246318Cooper, Quinton, Ballard, Mucociliary transport in porcine trachea: Differential effects of inhibiting chloride and bicarbonate secretion, Am. J. Physiol. Lung Cell. Mol. Physiol,
doi:10.1152/ajplung.00143.2012Donaldson, Bennett, Zeman, Knowles, Tarran et al., Mucus Clearance and Lung Function in Cystic Fibrosis with Hypertonic Saline, N. Engl. J. Med,
doi:10.1056/NEJMoa043891Everard, Hind, Ugonna, Freeman, Bradburn et al., SABRE: A multicentre randomised control trial of nebulised hypertonic saline in infants hospitalised with acute bronchiolitis, Thorax,
doi:10.1136/thoraxjnl-2014-205953Fumagalli, Panigada, Klompas, Berra, Ventilator-associated pneumonia among SARS-CoV-2 acute respiratory distress syndrome patients, Curr. Opin. Crit. Care,
doi:10.1097/MCC.0000000000000908Giacobbe, Battaglini, Enrile, Dentone, Vena et al., Incidence and Prognosis of Ventilator-Associated Pneumonia in Critically Ill Patients with COVID-19: A Multicenter Study, J. Clin. Med,
doi:10.3390/jcm10040555Gomez, Parazzi, Clinckspoor, Mauch, Pessine et al., Tolerability, and Effects of Sodium Bicarbonate Inhalation in Cystic Fibrosis, Clin. Drug Investig,
doi:10.1007/s40261-019-00861-xHelms, Tacquard, Severac, Leonard-Lorant, Ohana et al., High risk of thrombosis in patients with severe SARS-CoV-2 infection: A multicenter prospective cohort study, Intensive Care Med,
doi:10.1007/s00134-020-06062-xIcard, Rubio, The role of mucoactive agents in the mechanically ventilated patient: A review of the literature, Expert Rev. Respir. Med,
doi:10.1080/17476348.2017.1359090Ippolito, Misseri, Catalisano, Marino, Ingoglia et al., Ventilator-Associated Pneumonia in Patients with COVID-19: A Systematic Review and Meta-Analysis, Antibiotics,
doi:10.3390/antibiotics10050545King, Dasgupta, Tomkiewicz, Brown, Rheology of cystic fibrosis sputum after in vitro treatment with hypertonic saline alone and in combination with recombinant human deoxyribonuclease I, Am. J. Respir. Crit. Care Med,
doi:10.1164/ajrccm.156.1.9512074Luyt, Sahnoun, Gautier, Vidal, Burrel et al., Ventilator-associated pneumonia in patients with SARS-CoV-2-associated acute respiratory distress syndrome requiring ECMO: A retrospective cohort study, Ann. Intensive Care,
doi:10.1186/s13613-020-00775-4Maes, Higginson, Pereira-Dias, Curran, Parmar et al., Ventilator-associated pneumonia in critically ill patients with COVID-19, Crit. Care,
doi:10.1186/s13054-021-03460-5Masoompour, Anushiravani, Tafaroj Norouz, Evaluation of the Effect of Nebulized N-Acetylcysteine on Respiratory Secretions in Mechanically Ventilated Patients: Randomized Clinical Trial, Iran. J. Med. Sci
Mccullers, The co-pathogenesis of influenza viruses with bacteria in the lung, Nat. Rev. Microbiol,
doi:10.1038/nrmicro3231Melsen, Rovers, Koeman, Bonten, Estimating the attributable mortality of ventilator-associated pneumonia from randomized prevention studies, Crit. Care Med,
doi:10.1097/CCM.0b013e3182281f33Michon, Jumas-Bilak, Chiron, Lamy, Marchandin, Advances toward the elucidation of hypertonic saline effects on Pseudomonas aeruginosa from cystic fibrosis patients, PLoS ONE,
doi:10.1371/journal.pone.0090164Moretti, Van Laethem, Minini, Pierard, Malbrain, Ventilator-associated bacterial pneumonia in coronavirus 2019 disease, a retrospective monocentric cohort study, J. Infect. Chemother,
doi:10.1016/j.jiac.2021.01.011Máiz Carro, Martínez-García, Nebulized hypertonic saline in noncystic fibrosis bronchiectasis: A comprehensive review, Ther. Adv. Respir. Dis,
doi:10.1177/1753466619866102Pickens, Gao, Cuttica, Smith, Pesce et al., Bacterial Superinfection Pneumonia in Patients Mechanically Ventilated for COVID-19 Pneumonia, Am. J. Respir. Crit. Care Med,
doi:10.1164/rccm.202106-1354OCQu, Ren, Guo, Liang, Xu et al., ffect of N-acetylcysteine inhalation on ventilator-associated pneumonia caused by biofilm in endotracheal tubes, Zhonghua Er Ke Za Zhi
Ranieri, Rubenfeld, Thompson, Ferguson, Caldwell et al., Acute Respiratory Distress Syndrome: The Berlin Definition, JAMA
Rawson, Moore, Zhu, Ranganathan, Skolimowska et al., Bacterial and Fungal Coinfection in Individuals with Coronavirus: A Rapid Review to Support COVID-19 Antimicrobial Prescribing, Clin. Infect. Dis,
doi:10.1093/cid/ciaa530Razazi, Arrestier, Haudebourg, Benelli, Carteaux et al., 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, Crit. Care,
doi:10.1186/s13054-021-03517-5Robinson, Hemming, Regnis, Wong, Bailey et al., Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis, Thorax,
doi:10.1136/thx.52.10.900Rogers, Mucoactive agents for airway mucus hypersecretory diseases, Respir. Care
Rouyer, Strazzulla, Youbong, Tarteret, Pitsch et al., Ventilator-Associated Pneumonia in COVID-19 Patients: A Retrospective Cohort Study, Antibiotics,
doi:10.3390/antibiotics10080988Rouzé, Martin-Loeches, Povoa, Makris, Artigas et al., Relationship between SARS-CoV-2 infection and the incidence of ventilator-associated lower respiratory tract infections: A European multicenter cohort study, Intensive Care Med,
doi:10.1007/s00134-020-06323-9Stigliani, Manniello, Zegarra-Moran, Galietta, Minicucci et al., Rheological Properties of Cystic Fibrosis Bronchial Secretion and in Vitro Drug Permeation Study: The Effect of Sodium Bicarbonate, J. Aerosol Med. Pulm. Drug Deliv,
doi:10.1089/jamp.2015.1228Van Meenen, Van Der Hoeven, Binnekade, De Borgie, Merkus et al., 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, JAMA,
doi:10.1001/jama.2018.0949Wardeh, Conklin, Ko, Case reports of observed significant improvement in patients with ARDS due to COVID-19 and maximum ventilatory support after inhalation of sodium bicarbonate, J. Clin. Intensive Care Med,
doi:10.29328/journal.jcicm.1001029Wicky, Niedermann, Timsit, Ventilator-associated pneumonia in the era of COVID-19 pandemic: How common and what is the impact?, Crit. Care,
doi:10.1186/s13054-021-03571-zWills, Hall, Chan, Cole, Sodium chloride increases the ciliary transportability of cystic fibrosis and bronchiectasis sputum on the mucus-depleted bovine trachea, J. Clin. Investig,
doi:10.1172/JCI119138Wu, Mcgoogan, 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, JAMA,
doi:10.1001/jama.2020.2648Zhang, Mendoza-Sassi, Wainwright, Klassen, Nebulised hypertonic saline solution for acute bronchiolitis in infants, Cochrane Database Syst. Rev,
doi:10.1002/14651858.CD006458.pub3
