Nitric oxide therapy in COVID-19 patients with acute respiratory distress in intensive care unit

Abstract

Aims: The administration of inhaled nitric oxide (iNO) is a promising and new approach to treat viral load while increasing oxygenation directly. This research aimed to elucidate the clinical and laboratory response to the treatment of the patients diagnosed with Coronavirus disease-19 (COVID-19) in the intensive care unit (ICU) and followed up due to respiratory failure and given iNO. Methods: A total of 46 individuals who were diagnosed with COVID-19 and developed severe respiratory failure were followed up with or without intubation, had previously received standard care were evaluated within the study’s scope. iNO initiation time in the ICU, whether the patients were intubated, clinical and laboratory parameters before and after iNO treatment were obtained from hospital records. Results: A statistically significant difference has been achieved in arterial partial pressure of oxygen (PaO2), peripheral oxygen saturation (SpO2), and the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) ratios before and after iNO (p<0.05). While significant differences were observed in oxygenation with iNO treatment, no significant differences were observed in other parameters. When iNO onset times were evaluated, it was determined that the initiation time of iNO treatment was significantly later in patients who died. The relationship between the duration of mechanical ventilation, the duration of stay in the ICU, and the onset of iNO was a statistically significant relationship between all measurements (p<0.05). Conclusion: iNO has been suggested as an alternative rescue method before invasive treatment in guidelines, especially for the relief of hypoxemia. However, the effective dose and safety of iNO is still not clear.

Keywords

• Nitric oxide
• inhaled nitric oxide
• COVID-19
• acute respiratory distress syndrome
• intensive care unit

References

1. Erdogan C, Kılınc M, Tanrıverdi SY, Sungurtekin H. Spontaneous Pneumothorax and Pneumomediastinum in COVID-19 Pneumonia. J Crit Intens Care. 2022;13(2):79-83.
2. Zhang X, Li S, Niu S. ACE2 and COVID-19 and the resulting ARDS. Postgrad Med J. 2020; 96:403-407
3. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420–422.
4. Dalan R, Bornstein SR, El-Armouche A, et al. The ACE-2 in COVID-19: foe or friend? Horm Metab Res. 2020;52(5):257-263.
5. Batah SS, Fabro AT. Pulmonary pathology of ARDS in COVID-19: a pathological review for clinicians. Respir Med. 2021;176:106239.
6. Force A.D.T. Acute respiratory distress syndrome: the Berlin Definition. J Am Med Assoc. 2012;307(23):2526–2533.
7. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;28:1054-1062
8. Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016; 315:788–800.

9. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;1;180(7):934-943.
10. Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev. 2016;6:CD002787.
11. Papazian L, Aubron C, Brochard L, et al. Formal guidelines: management of acute respiratory distress syndrome. Ann Intensive Care. 2019;9:69.
12. Feng W-X, Yang Y, Wen J, Liu Y-X, Liu L, Feng C. Implication of inhaled nitric oxide for the treatment of critically ill COVID-19 patients with pulmonary hypertension. ESC Heart Fail. 2021;8:714–718.
13. Kobayashi J, Murata I. Nitric oxide inhalation as an interventional rescue therapy for COVID-19-induced acute respiratory distress syndrome. Ann Intensive Care. 2020;10:61. 
14. Parikh R, Wilson C, Weinberg J, Gavin D, Murphy J, Reardon CC. Inhaled nitric oxide treatment in spontaneously breathing COVID-19 patients. Ther Adv Respir Dis. 2020;14:1753466620933510.
15. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524-526.
16. Ignarro LJ, Buga GM, Wood KS,  R E Byrns, G Chaudhuri. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci. 1987;84:9265-9269.
17. Ozkan M, Dweik R. Nitric Oxide and Airway Reactivity. Clin PulmMed. 2001;8:199-206.
18. Marsden PA, Heng HHQ, Scherer SW et al. Structure and chromosomal localization of the human constitutive endothelial nitric oxidesynthase gene. J Biol Chem. 1993;268:17 478-488.
19. Chartrain NA, Geller DA, Koty PP et al. Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxidesynthase gene. J Biol Chem. 1994;269:6765-6572.
20. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med. 1998;26:15-23.
21. Ignarro L. Inhaled nitric oxide and COVID-19. Br J Pharmacol. 2020;177:3848–3849.
22. Akaberi D, Krambrich J, Ling J, et al. Mitigation of the replication of SARS-CoV-2 by nitric oxide in vitro. Redox Biol. 2020; 37:101734
23. Chen L. Liu P, Gao H, et al. Inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: A rescue trial in Beijing. Clin Infect Dis. 2004;39:1531–1535.
24. Barbaro R.P, MacLaren G, Boonstra P.S, et al. Extracorporeal membrane oxygenation support in COVID-19: An international cohort study of the Extracorporeal Life Support Organization registry. Lancet. 2020;396:1071–1078.
25. Falcoz, P.E, Monnier A, Puyraveau M, et al. Extracorporeal Membrane Oxygenation for Critically Ill Patients with COVID-19–related Acute Respiratory Distress Syndrome: Worth the Effort. Am J Respir Crit Care Med. 2020;202:460–463.
26. Ferrari M, Santini A, Protti A, et al. Inhaled nitric oxide in mechanically ventilated patients with COVID-19. J Crit Care. 2020;60:159–160.
27. Tavazzi G, Pozzi M, Mongodi S, Dammassa V, Romito G, Mojoli F. Inhaled nitric oxide in patients admitted to intensive care unit with COVID-19 pneumonia. Crit Care. 2020;24:508.
28. Fakhr B.S, Wiegand S.B, Pinciroli R, et al. High concentrations of nitric oxide ınhalation therapy in pregnant patients with severe coronavirus disease 2019 (COVID-19). Obstet. Gynecol. 2020;136:1109–1113.
29. Wiegand SB, Fakhr BS, Carroll RW, Zapol WM, Kacmarek RM, Berra L. Rescue treatment with high-dose gaseous nitric oxide in spontaneously breathing patients with severe coronavirus disease 2019. Crit. Care Explor. 2020;2:e0277.
30. Fakhr B.S, Di Fenza R, Gianni S, et al. Inhaled high dose nitric oxide is a safe and effective respiratory treatment in spontaneous breathing hospitalized patients with COVID-19 pneumonia. Nitric Oxide. 2021;116:7–13.
31. Ziehr D.R, Alladina J, Wolf M.E, et al. Respiratory physiology of prone positioning with and without ınhaled nitric oxide across the coronavirus disease 2019 Acute Respiratory Distress Syndrome Severity Spectrum. Crit Care Explor. 2021;3:e0471.