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• W3117771556 abstract "Central MessageAdministration of continuous high-dose (200 ppm) inhaled nitric oxide during 12-hour porcine ex vivo lung perfusion (EVLP) is safe and may be a novel treatment for lung infection during EVLP.See Article page 841. Administration of continuous high-dose (200 ppm) inhaled nitric oxide during 12-hour porcine ex vivo lung perfusion (EVLP) is safe and may be a novel treatment for lung infection during EVLP. See Article page 841. Normothermic ex vivo lung perfusion (EVLP) holds great promise as a platform to recondition donor lungs of unacceptable quality to make them suitable for transplantation. Experimental studies using EVLP as a platform for therapeutic interventions have included strategies to treat aspiration and hepatitis C, among others.1Nakajima D. Liu M. Ohsumi A. Kalaf R. Iskender I. Hsin M. et al.Lung lavage and surfactant replacement during ex vivo lung perfusion for treatment of gastric acid aspiration-induced donor lung injury.J Heart Lung Transplant. 2017; 36: 577-585Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar,2Cypel M. Feld J.J. Galasso M. Pinto Ribeiro R.V. Marks N. Kuczynski M. et al.Prevention of viral transmission during lung transplantation with hepatitis C-viraemic donors: an open-label, single-center, pilot trial.Lancet Respir Med. 2020; 8: 192-201Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar If successful and adopted broadly, such strategies could significantly diminish the persistent shortfall of suitable lungs available for transplantation. In this issue of the Journal, Michaelsen and colleagues3Michaelsen V.S. Ribeiro R.V.P. Ali A. Wang A. Gazzalle A. Keshafjee S. et al.Safety of continuous 12-hour delivery of antimicrobial doses of inhaled nitric oxide during ex vivo lung perfusion.J Thorac Cardiovasc Surg. 2022; 163: 841-849.e1Abstract Full Text Full Text PDF Scopus (10) Google Scholar present a study examining the feasibility and safety of high-dose inhaled nitric oxide (iNO) as potential antimicrobial treatment during porcine lung EVLP. Lung infection is a common reason for declining donor lungs and can result in poor post-transplant outcomes.4Ruiz I. Gavaldà J. Monforte V. Len O. Román A. Bravo C. et al.Donor-to-host transmission of bacterial and fungal infections in lung transplantation.Am J Transplant. 2006; 6: 178-182Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar,5Avlonitis V.S. Krause A. Luzzi L. Powell H. Phillips J.A. Corris P.A. et al.Bacterial colonization of the donor lower airways is a predictor of poor outcome in lung transplantation.Eur J Cardiothorac Surg. 2003; 24: 601-607Crossref PubMed Scopus (80) Google Scholar Several studies have used high-dose, broad-spectrum antibiotics to treat infected human or pig lungs over 3 to 12 hours of EVLP with good results (reduction in bacterial counts and improved lung function).6Andreasson A. Karamanou D.M. Perry J.D. Perry A. Ӧzalp F. Butt T. et al.The effect of ex vivo lung perfusion on microbial load in human donor lungs.J Heart Lung Transplant. 2014; 33: 910-916Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 7Zinne N. Krueger M. Hoeltig D. Tuemmler B. Boyle E.C. Biancosino C. et al.Treatment of infected lungs by ex vivo perfusion with high dose antibiotics and autotransplantation: a pilot study in pigs.PLoS One. 2018; 13: e0193168Crossref PubMed Scopus (19) Google Scholar, 8Nakajima D. Cypel M. Bonato R. Machuca T.N. Iskender I. Hashimoto K. et al.Ex vivo perfusion treatment of infection in human donor lungs.Am J Transplant. 2016; 16: 1229-1237Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar With such promising studies, why consider the use of iNO? At high doses, NO has broad-spectrum antimicrobial activity.9Miller C. McMullin B. Ghaffari A. Stenzler A. Pick N. Roscoe D. et al.Gaseous nitric oxide bactericidal activity retained during intermittent high-dose short duration exposure.Nitric Oxide. 2009; 20: 16-23Crossref PubMed Scopus (78) Google Scholar Recent clinical studies have used high-dose iNO to successfully treat antibiotic-resistant infections in patients with cystic fibrosis.10Deppisch C. Herrmann G. Graepler-Mainka U. Wirtz H. Heyder S. Engel C. et al.Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study.Infection. 2016; 44: 513-520Crossref PubMed Scopus (68) Google Scholar,11Bentur L. Gur M. Ashkenazi M. Livnat-Levanon G. Mizrahi M. Tal A. et al.Pilot study to test inhaled nitric oxide in cystic fibrosis patients with refractory Mycobacterium abscessus lung infection.J Cyst Fibros. 2020; 19: 225-231Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Due to the time- and dose-dependent oxidation of hemoglobin to methemoglobin, as well the potential production of the toxic molecules nitrogen dioxide and peroxynitrite in the presence of oxygen, these studies used intermittent (3-5 times/day), short-duration (30 minutes) exposure to high-dose (160 ppm) iNO. Michaelsen and colleagues postulated that high-dose iNO could be used in acellular EVLP to treat infection while avoiding the in vivo toxicities. This EVLP strategy could be more efficacious than antibiotics, avoid potential induction of antimicrobial resistance with antibiotic use, and avoid the conundrum of selecting antibiotics without knowing the sensitivity profile of the microbial flora. Using normal pig lungs, Michaelsen and colleagues demonstrated that exposure to continuous iNO at 200 ppm during 12 hours of acellular EVLP did not negatively impact physiological parameters and further demonstrated that there was no difference in histology or levels of proinflammatory cytokines compared with nontreated EVLP controls. Using ventilation with an inspired oxygen fraction of 0.21, and with absence of hemoglobin in acellular EVLP, nitrogen dioxide levels were low, as were perfusate methemoglobin levels. As an initial safety and feasibility study, Michaelsen and colleagues are to be congratulated for their novel and important work. Many questions remain, however. The major limitation of the study, as noted by the authors, is that although they propose to treat lung infection, they did not use infected lungs in their study, as the development of a porcine lung infection model is ongoing. This leaves unanswered questions, such as the ability of an airway-based treatment to reach areas of consolidated lung, the potential synergy of iNO with antibiotics, and the necessary time of iNO exposure (most clinical EVLP is limited to 3-6 hours). Will 3-6 hours be sufficient time for an inhaled therapy? Based on the trials in cystic fibrosis, it might, but whether NO is the answer will have to await evaluation in infection models. Safety of continuous 12-hour delivery of antimicrobial doses of inhaled nitric oxide during ex vivo lung perfusionThe Journal of Thoracic and Cardiovascular SurgeryVol. 163Issue 3PreviewHigh-dose nitric oxide (NO) has been shown effective against a variety of micro-organisms in vitro, including common bacteria found in donor organs. However, clinical obstacles related to its implementation in vivo are the formation of methemoglobin and the accumulation of toxic nitrogen compounds. Ex vivo lung perfusion (EVLP) is a platform that allows for organ maintenance with an acellular perfusion solution, thus overcoming these limitations. The present study explores the safety of continuous high-dose inhaled (iNO) during EVLP for an extended period of 12 hours. Full-Text PDF" @default.
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• W3117771556 title "Commentary: To use or not to use…Is NO the answer?" @default.
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