Efficacy and safety of inhaled molecular hydrogen therapy in patients with respiratory failure due to chronic obstructive pulmonary disease exacerbation in post-COVID period

Molecular hydrogen (H₂) is a powerful antioxidant and anti-apoptotic agent. H₂ has been studied in a number of clinical studies in the recent years.

The aim of this research was to investigate the efficacy and safety of H₂ inhalation therapy in patients with hypoxemic and hypercapnic respiratory failure (RF) against exacerbation of chronic obstructive pulmonary disease (COPD) in the post-COVID (Corona Virus Disease 2019) period.

Methods. The randomized prospective parallel comparative study included patients (n = 60: 40 men aged 71.2 ± 1.8 years, 20 women aged 70.9 ± 2.8 years) with a post-COVID-19 exacerbation of COPD complicated by hypoxemic/hypercapnic RF. The patients were divided into 2 groups: group 1 (main) (n = 30: 18 men, 12 women), group 2 (control) (n = 30: 18 men, 12 women). To maintain arterial blood saturation ≥ 90 %, patients in both groups received respiratory support (non-invasive ventilation) using the Prisma 25ST device (Lowenstein Medical, Germany) in the BiPAP S/T mode (BiLevel Positive Airway Pressure Spontaneous/Time spontaneous/forced mode 20–24/4–6 cm H2O and O₂, respectively; the fractional oxygen concentration in the inhaled gas mixture was ≥ 24%). In addition to standard treatment, patients in the main group received additional H2 therapy (Suisonia device, Japan) through a nasal cannula for 90 minutes daily for 14 days.

Results. In patients of the main group, a decrease in the stiffness index was detected from 14.6 ± 1.2 to 6.2 ± 0.6 m/s, and the arterial blood lactate level – from 2.84 ± 0.1 to 0.02 ± 0.1 mmol/l (p < 0.001), the calculated shunt fraction Qs/Qt (venous admixture) – from 27.21 ± 3.4 to 7.14 ± 1.23 (p < 0.01) and an increase in the following parameters: reflection index – from 42.2 ± 2.0 to 66.2 ± 4.9% (p < 0.05), virus-specific IgG level – from 134 ± 125 to 669 ± 164 (p < 0. 05), blood flow velocity in arterioles – from 473 ± 108 to 868 ± 64 μm/s (p < 0.05), blood flow velocity in venules – from 299 ± 56 to 862 ± 69 μm/s (p < 0.05), the 6-minute walk distance – from 57.1 ± 4.4 to 328.9 ± 33.7 m (p < 0.05).

Conclusion. H₂ inhalations were safe and increased the therapeutic effect when added to standard therapy for patients with hypoxemic and hypercapnic RF during exacerbation of COPD in the post-COVID period.

1. Hirano S.I., Ichikawa Y., Kurokawa R. et al. A “philosophical molecule,” hydrogen may overcome senescence and intractable diseases. Med. Gas Res. 2020; 10 (1): 47–49. DOI: 10.4103/2045-9912.279983.

2. Ichihara M., Sobue S., Ito M. et al. Beneficial biological effects and the underlying mechanisms of molecular hydrogen–comprehensive review of 321 original articles. Med. Gas Res. 2015; 5: 12. DOI: 10.1186/s13618-015-0035-1.

3. Artamonov M.Yu., Martusevich A.K., Pyatakovich F.A. et al. Molecular hydrogen: from molecular effects to stem cells management and tissue regeneration. Antioxidants (Basel). 2023; 12 (3): 636. DOI: 10.3390/antiox12030636.

4. Ohsawa I., Ishikawa M., Takahashi K. et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat. Med. 2007; 13 (6): 688–694. DOI: 10.1038/nm1577.

5. Cui J., Chen X., Zhai X. et al. Inhalation of water electrolysis-derived hydrogen ameliorates cerebral ischemia-reperfusion injury in rats – a possible new hydrogen resource for clinical use. Neuroscience. 2016; 335: 232–241. DOI: 10.1016/j.neuroscience.2016.08.021.

6. Zhang Y., Xu J., Yang H. Hydrogen: an endogenous regulator of liver homeostasis. Front. Pharmacol. 2020; 11: 877. DOI: 10.3389/fphar.2020.00877.

7. Danilova D.A., Brichkin Y.D., Medvedev A.P. et al. [The use of molecular hydrogen in cardiac surgery under conditions of artificial circulation]. Sovremennye tekhnologii v meditsine. 2021; 13 (1): 71–77. DOI: 10.17691/stm2021.13.1.09 (in Russian).

8. Kawamura T., Huang C.S., Tochigi N. et al. Inhaled hydrogen gas therapy for prevention of lung transplant-induced ischemia/reperfusion injury in rats. Ransplantation. 2010; 90 (12): 1344–1351. DOI: 10.1097/TP.0b013e3181fe1357.

9. Russell G., Rehman M., LeBaron T.W. et al. An overview of SARS-CoV-2 (COVID-19) infection and the importance of molecular hydrogen as an adjunctive therapy. Reactive Oxygen Species. 2020; 10 (28): 150–165. Available at: https://www.rosj.org/index.php/ros/article/view/271

10. Liu Z., Geng W., Jiang C. et al. Hydrogen-rich saline inhibits tobacco smoke-induced chronic obstructive pulmonary disease by alleviating airway inflammation and mucus hypersecretion in rats. Exp. Biol. Med. (Maywood). 2017; 242 (15): 1534–1541. DOI: 10.1177/1535370217725249.

11. Wang T., Zhao L., Liu M. et al. Oral intake of hydrogen-rich water ameliorated chlorpyrifos-induced neurotoxicity in rats. Toxicol. Appl. Pharmacol. 2014; 280 (1): 169–176. DOI: 10.1016/j.taap.2014.06.011.

12. Chen X., Liu Q., Wang D. et al. Protective effects of hydrogen-rich saline on rats with smoke inhalation injury. Oxid. Med. Cell. Longevity. 2015; 2015: 106836. DOI: 10.1155/2015/106836.

13. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2023 Report. Available at: https://goldcopd.org/wp-content/uploads/2023/03/GOLD-2023-ver-1.3-17Feb2023_WMV.pdf [Accessed: January 25, 2024].

14. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015; 385 (9963): 117–171. DOI: 10.1016/S0140-6736(14)61682-2.

15. Lopez A.D., Shibuya K., Rao C. et al. Chronic obstructive pulmonary disease: current burden and future projections. Eur. Respir. J. 2006; 27 (2): 397–412. DOI: 10.1183/09031936.06.00025805.

16. Mathers C.D., Loncar D. Projections of mortality and causes of death, 2016 and 2060, online information available here. PLoS Med. 2006; 3 (11): e442. DOI: 10.1371/journal.pmed.0030442.

17. Adeloye D., Chua S., Lee C. et al. Global and regional estimates of COPD prevalence: systematic review and meta-analysis. J. Glob. Health. 2015; 5 (2): 020415. DOI: 10.7189/jogh.05.020415.

18. Lamprecht B., McBurnie M.A., Vollmer W.M. et al. COPD collaborative research group: COPD in never smokers: results from the population-based burden of obstructive lung disease study. Chest. 2011; 139 (4): 752–763. DOI: 10.1378/chest.10-1253.

19. Berganza C.J., Zhang J.H. The role of helium gas in medicine. Med. Gas Res. 2013; 3 (1): 18. DOI: 10.1186/2045-9912-3-18.

20. Liu S., Liu K., Sun Q. et al. Hydrogen therapy may be a novel and effective treatment for COPD. Front. Pharmacol. 2011; 2: 19. DOI: 10.3389/fphar.2011.00019.

21. Ohta S. Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. Pharmacol. Ther. 2014; 144 (1): 1–11. DOI: 10.1016/j.pharmthera.2014.04.006.

22. Steinhubl S.R. Why have antioxidants failed in clinical trials? Am. J. Cardiol. 2008; 101 (10A): 14–19D. DOI: 10.1016/j.amjcard.2008.02.003.

23. Fischer B.M., Voynow J.A., Ghio A.J. COPD: balancing oxidants and antioxidants. Int. J. Chron. Obstruct. Pulmon. Dis. 2015; 10: 261–276. DOI: 10.2147/COPD.S42414.

24. Schaberg T., Klein U., Rau M. et al. Subpopulations of alveolar macrophages in smokers and nonsmokers: relation to the expression of CD11/CD18 molecules and superoxide anion production. Am. J. Respir. Crit. Care Med. 1995; 151 (5): 1551–1558. DOI: 10.1164/ajrccm.151.5.7735614.

25. Dekhuijzen P.N., Aben K.K., Dekker I. et al. Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1996; 154 (3, Pt 1): 813–816. DOI: 10.1164/ajrccm.154.3.8810624.

26. Maziak W., Loukides S., Culpitt S. et al. Exhaled nitric oxide in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 1998; 157 (3, Pt 1): 998–1002. DOI: 10.1164/ajrccm.157.3.97-05009.

27. Praticò D., Basili S., Vieri M. et al. Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2a-III, an index of oxidant stress. Am. J. Respir. Crit. Care Med. 1998; 158 (6): 1709–1714. DOI: 10.1164/ajrccm.158.6.9709066.

28. Montuschi P., Collins J.V., Ciabattoni G. et al. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am. J. Respir. Crit. Care Med. 1998; 158 (6): 1709–1714. DOI: 10.1164/ajrccm.158.6.9709066.

29. Kanazawa H., Shoji S., Yoshikawa T. et al. Increased production of endogenous nitric oxide in patients with bronchial asthma and chronic obstructive pulmonary disease. Clin. Exp. Allergy. 1998; 28 (10): 1244–1250. DOI: 10.1046/j.1365-2222.1998.00342.x.

30. Kishimoto Y., Kato T., Ito M. et al. Hydrogen ameliorates pulmonary hypertension in rats by anti-inflammatory and antioxidant effects. J. Thorac. Cardiovasc. Surg. 2015; 150 (3): 645–654. DOI: 10.1016/j.jtcvs.2015.05.052.

31. Lu W., Li D., Hu J. et al. Hydrogen gas inhalation protects against cigarette smoke-induced COPD development in mice. J. Thorac. Dis. 2018; 10 (6): 3232–3243. DOI: 10.21037/jtd.2018.05.93.

32. Barnes P.J. New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat. Rev. Drug Discovery. 2013; 12 (7): 543–559. DOI: 10.1038/nrd4025.

33. Cazzola M., Page C.P., Calzetta L., Matera M.G. Emerging anti-inflammatory strategies for COPD. Eur. Respir J. 2012; 40 (3): 724–741. DOI: 10.1183/09031936.00213711.

34. Paredi P., Kharitonov S.A., Leak D. et al. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2000; 162 (2, Pt 1): 369–373. DOI: 10.1164/ajrccm.162.2.9909025.

35. Li Y., Wang Z., Lian N. et al. Molecular hydrogen: a promising adjunctive strategy for the treatment of the COVID-19. Front. Med. (Lausanne). 2021; 8: 671215. DOI: 10.3389/fmed.2021.671215.

36. Zheng Z.G., Sun W.Z., Hu J.Y. et al. Hydrogen/oxygen therapy for the treatment of an acute exacerbation of chronic obstructive pulmonary disease: results of a multicenter, randomized, double-blind, parallel-group controlled trial. Respir. Res. 2021; 22 (1): 149. DOI: 10.1186/s12931-021-01740-w.

37. Shogenova L.V., Truong T.T., Kryukova N.O. et al. [Inhalation hydrogen in the rehabilitation program of medical workers who underwent COVID-19]. Kardiovaskulyarnaya terapiya i profilaktika. 2021; 20 (6): 24–32. DOI: 10.15829/1728-8800-2021-2986 (in Russian).

38. Koyama Y., Taura K., Hatano E. et al. Effects of oral intake of hydrogen water on liver fibrogenesis in mice. Hepatol. Res. 2014; 44 (6): 663–677. DOI: 10.1111/гепр.12165.

39. Zhang Y., Sun Q., He B. et al. Anti-inflammatory effect of hydrogen-rich saline in a rat model of regional myocardial ischemia and reperfusion. Int. J. Cardiol. 2011; 48 (1): 91–95. DOI: 10.1016/j.ijcard.2010.08.058.