High-dose inhaled nitric oxide therapy for nosocomial pneumonia following cardiac surgical procedures

Nosocomial pneumonia is the most common infectious complication following cardiac surgical procedures. The aim was to assess the efficacy and safety of repeated inhalation sessions of 200 ppm nitric oxide for nosocomial pneumonia following cardiac surgical procedures. Methods. The pilot single-center prospective randomized study included spontaneously breathing patients with cardiovascular diseases, operated on under artificial circulation, with a complicated postoperative period in the form of nosocomial pneumonia. These patients (n = 40) underwent surgical procedures under cardiopulmonary bypass and developed nosocomial pneumonia in the postoperative period. The control group (n = 20) received standard antibacterial therapy, the experimental group (n = 20) received additional inhalation of 200 ppm nitric oxide (iNO) for 30 minutes 3 times a day before the completion of antibacterial therapy, but no more than 7 days later. We assessed the duration of antibacterial therapy, the changes in temperature, blood pressure, respiratory rate and heart rate, the oxygenation index SpO2/FiO2 and PO2/FiO2, the level of leukocytes, C-reactive protein, procalcitonin, presepsin, ferritin, and the quality of life questionnaire EQ-5D-5L score. The frequency of changes in antibacterial therapy regimens due to their ineffectiveness and the duration of hospitalization were compared. Results. iNO therapy was well tolerated, did not have a significant effect on systemic hemodynamics, and was not accompanied by a clinically significant increase in the level of methemoglobin and NO2. Its duration was 6.2 ± 0.8 days. In the iNO treatment group, there was a shorter time of antibacterial therapy (p < 0.001), a shorter duration of fever (p = 0,008), and a shorter frequency of changing antibacterial treatment regimens due to their ineffectiveness (p < 0,001). Under the influence of iNO, higher rates of oxygenation indices SpO2/FiO2 were noted on Day 3 (p = 0,034) and on the day of completion of antibacterial therapy (p = 0,009); higher PO2/FiO2 were observed on Day 3 (p = 0,002), Day 5 (p < 0,001) of the therapy and the day of the completion of antibacterial therapy (p = 0,004). In the iNO treatment group, a decrease in the level of leukocytes, procalcitonin, and the neutrophil-to-lymphocyte ratio was detected on Day 3 of the treatment, as well as lower neutrophil levels in the blood on the day of the completion of antibacterial therapy in comparison with the control group. Conclusion. iNO at a dose of 200 ppm 3 times a day in patients with nosocomial pneumonia following cardiac surgical procedures is safe, leads to a reduction in the duration of antibacterial therapy, a decrease in the frequency of changes in antibacterial therapy regimens, the improvement of oxygenation, and faster changes in the laboratory markers of inflammation. The data obtained serve as a prerequisite for the use of iNO for the treatment of nosocomial pneumonia in cardiac surgical patients.

1. Strobel R.J., Harrington S.D., Hill C. et al. Evaluating the Impact of pneumonia prevention recommendations after cardiac surgery. Ann. Thorac. Surg. 2020; 110 (3): 903–910. DOI: 10.1016/j.athoracsur.2019.12.053.

2. Ailawadi G., Chang H.L., O'Gara P.T. et al. Pneumonia after cardiac surgery: Experience of the National Institutes of Health/Canadian Institutes of Health Research Cardiothoracic Surgical Trials Network. J. Thorac. Cardiovasc. Surg. 2017; 153 (6): 1384-1391.e3. DOI: 10.1016/j.jtcvs.2016.12.055.

3. Sergevnin V.I., Kudryavtseva L.G., Lazarkov P.V. [Artificial ventilation as a risk factor causing hospital-acquired pneumonia in patients treated in the intensive care unit of a cardiac surgery hospital]. Analiz riska zdorov'yu. 2022; (1): 97–103. DOI: 10.21668/health.risk/2022.1.11.eng (in Russian).

4. Wang D., Lu Y., Sun M. et al. Pneumonia after cardiovascular surgery: incidence, risk factors and interventions. Front. Cardiovasc. Med. 2022; 9: 911878. DOI: 10.3389/fcvm.2022.911878.

5. Wang D.S., Huang X.F., Wang H.F. et al. Clinical risk score for postoperative pneumonia following heart valve surgery. Chin. Med. J. (Engl.). 2021; 134 (20): 2447–2456. DOI: 10.1097/CM9.0000000000001715.

6. Wang D., Huang X., Wang H. et al. Risk factors for postoperative pneumonia after cardiac surgery: a prediction model. J. Thorac. Dis. 2021; 13 (4): 2351–2362. DOI: 10.21037/jtd-20-3586.

7. Wang D., Chen X., Wu J. et al. Development and validation of nomogram models for postoperative pneumonia in adult patients undergoing elective cardiac surgery. Front. Cardiovasc. Med. 2021; 8: 750828. DOI: 10.3389/fcvm.2021.750828.

8. Yao R., Liu X., He Y. et al. Low platelet count is a risk factor of postoperative pneumonia in patients with type A acute aortic dissection. J. Thorac. Dis. 2020; 12 (5): 2333–2342. DOI: 10.21037/jtd.2020.03.84.

9. Wang D., Abuduaini X., Huang X. et al. Development and validation of a risk prediction model for postoperative pneumonia in adult patients undergoing Stanford type A acute aortic dissection surgery: a case control study. J. Cardiothorac. Surg. 2022; 17 (1): 22. DOI: 10.1186/s13019-022-01769-y.

10. Gel'fand B.R. [Nosocomial pneumonia in adults: Russian clinical guidelines]. Moscow: Meditsinskoe informatsionnoe agentstvo; 2016. Available at: https://library.mededtech.ru/rest/documents/nozopneumonia/?anchor=list_item_fpuj5r&ysclid=m53no6jtr8734196665 (in Russian).

11. Yakovlev S.V., Suvorova M.P., Bykov A.O. et al. [An open-label, multicenter, observational study of the effectiveness of the Cefepime/Sulbactam antibiotic (Maxictam®-AF) in patients with intra-abdominal infection, nosocomial pneumonia or ventilator-associated pneumonia (Study MAXI-2019)]. Antibiotiki i khimioterapiya. 2020; 65 (11-12): 49–58. DOI: 10.37489/0235-2990-2020-65-11-12-49-58 (in Russian).

12. Pervukhin S.A., Statsenko I.A., Ivanova E.Yu. et al. [Antibiotic resistance of gram-negative pathogens causing nosocomial pneumonia in patients of the intensive care unit]. Klinicheskaya mikrobiologiya i antimikrobnaya khimioterapiya. 2019; (1): 62–68. DOI: 10.36488/cmac.2019.1.62-68 (in Russian).

13. Antonovich Zh.V. [Nosocomial pneumonia: current approaches to diagnosis and treatment]. Neotlozhnaya kardiologiya i kardiovaskulyarnye riski. 2019; 3 (2): 626–635. Available at: https://emcardio.bsmu.by/category7/article105/ (in Russian).

14. Beloborodov V.B., Gusarov V.G., Dekhnich A.V. et al. [Guidelines of the Association of Anesthesiologists-Intensivists, the Interregional Non-Governmental Organization Alliance of Clinical Chemotherapists and Microbiologists, the Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy (IACMAC), and NGO Russian Sepsis Forum Diagnostics and antimicrobial therapy of the infections caused by multiresistant microorganisms]. Vestnik anesteziologii i reanimatologii. 2020; 17 (1): 52–83. DOI: 10.21292/2078-5658-2020-16-1-52-83 (in Russian).

15. Sukhorukova M.V., Eydel'shteyn M.V., Ivanchik N.V. et al. [Antimicrobial resistance of nosocomial Enterobacterales isolates in Russia: results of multicenter epidemiological study “MARATHON 2015–2016”]. Klinicheskaya mikrobiologiya i antimikrobnaya khimioterapiya. 2019; (2): 147–159/ DOI: 10.36488/cmac.2019.2.147-159 (in Russian).

16. Kamenshchikov N.O., Safaee Fakhr B., Kravchenko I.V. et al. Assessment of continuous low-dose and high-dose burst of inhaled nitric oxide in spontaneously breathing COVID-19 patients: a randomized controlled trial. Nitric Oxide. 2024; 149: 41–48. DOI: 10.1016/j.niox.2024.06.003.

17. Wiegand S.B., Safaee Fakhr B., Carroll R.W. et al. Rescue treatment with high-dose gaseous nitric oxide in spontaneously breathing patients with severe coronavirus disease. 2019. Crit. Care Explor. 2020; 2 (11): e0277. DOI: 10.1097/CCE.0000000000000277.

18. Kamenshchikov N.O., Kuznetsov M.S., Diakova M.L. et al. [Inhalation therapy with high doses of nitric oxide in a comorbid patient with COVID-19: a clinical case]. Sibirskiy zhurnal klinicheskoy i eksperimental'noy meditsiny. 2022; 37 (4): 180–187. DOI: 10.29001/2073-8552-2022-37-4-180-187 (in Russian).

19. Nguyen H.C., Pozdnyakova D.D., Baranova I.A., Chuchalin A.G. [Use of inhaled nitric oxide in COVID-19]. Pul’monologiya. 2024; 34 (3): 454–463. DOI: 10.18093/0869-0189-2024-4305 (in Russian).

20. Kamenshchikov N.O., Berra L., Carroll R.W. Therapeutic effects of inhaled nitric oxide therapy in COVID-19 patients. Biomedicines. 2022; 10 (2): 369. DOI: 10.3390/biomedicines10020369.

21. Kamenshchikov N.O., Kozlov B.N, Dish A.Y. et al. A safety study of intermittent versus continuous inhaled NO therapy in spontaneously breathing COVID-19 patients: a randomized controlled trial. Circulation. 2021; 144 (1): A11986. DOI: 10.1161/circ.144.suppl_1.11986.

22. Safaee Fakhr B., 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. DOI: 10.1016/j.niox.2021.08.003.

23. Safaee Fakhr B., Wiegand S.B., Pinciroli R. et al. High concentrations of nitric oxide inhalation therapy in pregnant patients with severe coronavirus disease 2019 (COVID-19). Obstet. Gynecol. 2020; 136 (6): 1109–1113. DOI: 10.1097/AOG.0000000000004128.

24. Goldbart A., Lavie M., Lubetzky R. et al. Inhaled nitric oxide for the treatment of acute bronchiolitis: a multicenter randomized controlled trial to evaluate dose response. Ann. Am. Thorac. Soc. 2023; 20 (2): 236–244. DOI: 10.1513/AnnalsATS.202103-348OC.

25. Miller C.C., Hergott C.A., Rohan M. et al. Inhaled nitric oxide decreases the bacterial load in a rat model of Pseudomonas aeruginosa pneumonia. J. Cyst. Fibros. 2013; 12 (6): 817–820. DOI: 10.1016/j.jcf.2013.01.008.

26. Kalashnikova T.P., Arsenyeva I.A., Kamenshchikov N.O. et al. [Antibacterial effect of nitric oxide on the causative agents of hospital-acquired pneumonia (experimental study)]. Obshchaya reanimatologiya. 2024; 20 (3): 32–41. DOI: 10.15360/1813-9779-2024-3-2424 (in Russian).

27. Sorbo L.D., Michaelsen V.S., Ali A. et al. High doses of inhaled nitric oxide as an innovative antimicrobial strategy for lung infections. Biomedicines. 2022; 10 (7): 1525. DOI: 10.3390/biomedicines10071525.

28. Bartley B.L., Gardner K.J., Spina S. et al. High-dose inhaled nitric oxide as adjunct therapy in cystic fibrosis targeting Burkholderia multivorans. Case Rep. Pediatr. 2020; 2020:1536714. DOI: 10.1155/2020/1536714.

29. Bogdanovski K., Chau T., Robinson C.J. et al. Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease. Access Microbiol. 2020; 2 (9): acmi000154. DOI: 10.1099/acmi.0.000154.

30. Yaacoby-Bianu K., Gur M., Toukan Y. et al. Compassionate nitric oxide adjuvant treatment of persistent mycobacterium infection in cystic fibrosis patients. Pediatr. Infect Dis. J. 2018; 37 (4): 336–338. DOI: 10.1097/INF.0000000000001780.

31. Goldbart A., Gatt D., Golan Tripto I. Non-tuberculous mycobacteria infection treated with intermittently inhaled high-dose nitric oxide. BMJ Case Rep. 2021; 14 (10): e243979. DOI: 10.1136/bcr-2021-243979.

32. Bentur L., Gur M., Ashkenazi M. et al. Pilot study to test inhaled nitric oxide in cystic fibrosis patients with refractory Mycobacterium abscessus lung infection. J. Cyst. Fibros. 2020; 19 (2): 225–231. DOI: 10.1016/j.jcf.2019.05.002.

33. Pichugin V.V., Domnin S.E., Bautin A.E. et al. [The influence of various technologies for the use of gaseous nitric oxide on the functional and morphological state of the lungs, markers of myocardial damage and clinical outcomes in cardiosurgical interventions with cardiopulmonary bypass]. Pul'monologiya. 2024; 34 (3): 364–374. DOI: 10.18093/0869-0189-2024-34-3-364-374 (in Russian).

34. Ghaffari A., Neil D.H., Ardakani A. et al. A direct nitric oxide gas delivery system for bacterial and mammalian cell cultures. Nitric Oxide. 2005; 12 (3): 129–140. DOI: 10.1016/j.niox.2005.01.006.

35. Moeen Rezakhanlou A., Miller C., McMullin B. et al. Gaseous nitric oxide exhibits minimal effect on skin fibroblast extracellular matrix gene expression and immune cell viability. Cell Biol. Int. 2011; 35 (4): 407–415. DOI: 10.1042/CBI20100420.

36. Ghaffari A., Jalili R., Ghaffari M. et al. Efficacy of gaseous nitric oxide in the treatment of skin and soft tissue infections. Wound Repair Regen. 2007; 15 (3): 368–377. DOI: 10.1111/j.1524-475X.2007.00239.x.

37. Yakovleva S.V., Briko N.I., Sidorenko S.V., Protsenko D.N., eds. [Russian guidelines: SKAT (Antimicrobial Therapy Control Strategy) program for inpatient medical care]. Moscow: Izdatel'stvo “Pero”; 2018. Available at: https://library.mededtech.ru/rest/documents/Skat2018/?ysclid=m53vvgwmvp327960818 (in Russian).

38. Petit P.C., Fine D.H., Vásquez G.B. et al. The pathophysiology of nitrogen dioxide during inhaled nitric oxide therapy. ASAIO J. 2017; 63 (1): 7–13. DOI: 10.1097/MAT.0000000000000425.

39. Cutruzzolà F, Frankenberg-Dinkel N. Origin and Impact of nitric oxide in Pseudomonas aeruginosa biofilms. J. Bacteriol. 2016; 198 (1): 55–65. DOI: 10.1128/JB.00371-15.

40. Barraud N., Kelso M.J., Rice S.A., Kjelleberg S. Nitric oxide: a key mediator of biofilm dispersal with applications in infectious diseases. Curr. Pharm. Des. 2015; 21 (1): 31–42. DOI: 10.2174/1381612820666140905112822.