Hydrogen therapy is more effective than oxygen therapy in COPDScientific Research

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

https://doi.org/10.1186/s12931-021-01740-w

Abstract

Background

To investigate whether the use of a hydrogen/oxygen mixture is superior to oxygen in improving symptoms in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD).

Methods

This prospective, randomized, double-blind, controlled, 10-center clinical study enrolled patients with AECOPD and a BCSS (dyspnea, cough and sputum scale) score of at least 6. Eligible patients were randomly assigned (1:1 ratio) to receive hydrogen/oxygen hybrid therapy or oxygen therapy. The primary endpoint was change from baseline in BCSS score at day 7. Adverse events (AEs) were recorded to assess safety.

Results

The change in BCSS score was greater in the hydrogen/oxygen group than in the oxygen group (-5.3 vs. -2.4 points; difference: -2.75 [95% CI -3.27 to – 2:22], which met superiority criteria). Similar results were observed at other time points from day 2 to day 6. Cough assessment test scores were significantly lower in the hydrogen/oxygen group compared to the control group (-11.00 vs -6.00, p<0.001). Changes in lung function, arterial blood gases, and noninvasive oxygen saturation did not differ significantly between groups, as well as for other endpoints. AEs were reported in 34 (63.0%) patients in the hydrogen/oxygen group and in 42 (77.8%) patients in the oxygen group. No deaths or equipment failures were reported during the study period.

References

  1. Hassett DJ, Borchers MT, Panos RJ. Chronic obstructive pulmonary disease (COPD): evaluation from clinical, immunological and bacterial pathogenesis perspectives. J Microbiol. 2014;52:211–26.

    PubMed Article Google Scholar

  2. Martinez FD. Early-life origins of chronic obstructive pulmonary disease. N Engl J Med. 2016;375:871–8.

    PubMed Article Google Scholar

  3. Shaw JG, Vaughan A, Dent AG, O’Hare PE, Goh F, Bowman RV, Fong KM, Yang IA. Biomarkers of progression of chronic obstructive pulmonary disease (COPD). J Thorac Dis. 2014;6:1532–47.

    PubMed PubMed Central Google Scholar

  4. Vargas F, Bui HN, Boyer A, Salmi LR, Gbikpi-Benissan G, Guenard H, Gruson D, Hilbert G. Intrapulmonary percussive ventilation in acute exacerbations of COPD patients with mild respiratory acidosis: a randomized controlled trial [ISRCTN17802078]. Crit Care. 2005;9:R382-389.

    PubMed PubMed Central Article Google Scholar

  5. Papaiwannou A, Zarogoulidis P, Porpodis K, Spyratos D, Kioumis I, Pitsiou G, Pataka A, Tsakiridis K, Arikas S, Mpakas A, et al. Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS): current literature review. J Thorac Dis. 2014;6(Suppl 1):S146-151.

    PubMed PubMed Central Google Scholar

  6. Ko FW, Chan KP, Hui DS, Goddard JR, Shaw JG, Reid DW, Yang IA. Acute exacerbation of COPD. Respirology. 2016;21:1152–65.

    PubMed PubMed Central Article Google Scholar

  7. Brochard L. Non-invasive ventilation for acute exacerbations of COPD: a new standard of care. Thorax. 2000;55:817–8.

    CAS PubMed PubMed Central Article Google Scholar

  8. Abdo WF, Heunks LM. Oxygen-induced hypercapnia in COPD: myths and facts. Crit Care. 2012;16:323.

    PubMed PubMed Central Article Google Scholar

  9. Osadnik CR, Tee VS, Carson‐Chahhoud KV, Picot J, Wedzicha JA, Smith BJ. Non‐invasive ventilation for the management of acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease. Cochrane Database Syst Reviews 2017.

  10. Murray I, Paterson E, Thain G, Currie GP. Outcomes following non-invasive ventilation for hypercapnic exacerbations of chronic obstructive pulmonary disease. Thorax. 2011;66:825–6.

    PubMed Article Google Scholar

  11. Murphy PB, Rehal S, Arbane G, Bourke S, Calverley PMA, Crook AM, Dowson L, Duffy N, Gibson GJ, Hughes PD, et al. Effect of home noninvasive ventilation with oxygen therapy vs oxygen therapy alone on hospital readmission or death after an acute COPD exacerbation: a randomized clinical trial. JAMA. 2017;317:2177–86.

    PubMed PubMed Central Article Google Scholar

  12. Berganza CJ, Zhang JH. The role of helium gas in medicine. Med Gas Res. 2013;3:18.

    PubMed PubMed Central Article Google Scholar

  13. Nakao A. Therapeutic Medical Gas.

  14. Vonbank K, Ziesche R, Higenbottam TW, Stiebellehner L, Petkov V, Schenk P, Germann P, Block LH. Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe COPD. Thorax. 2003;58:289–93.

    CAS PubMed PubMed Central Article Google Scholar

  15. Jolliet P, Ouanes-Besbes L, Abroug F, Ben Khelil J, Besbes M, Garnero A, Arnal JM, Daviaud F, Chiche JD, Lortat-Jacob B, et al. A multicenter randomized trial assessing the efficacy of helium/oxygen in severe exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;195:871–80.

    CAS PubMed Article Google Scholar

  16. Ohta S. Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. Pharmacol Ther. 2014;144:1–11.

    CAS PubMed Article Google Scholar

  17. Huang C-S, Kawamura T, Toyoda Y, Nakao A. Recent advances in hydrogen research as a therapeutic medical gas. Free Radical Res. 2010;44:971–82.

    CAS Article Google Scholar

  18. Kohama K, Yamashita H, Aoyama-Ishikawa M, Takahashi T, Billiar TR, Nishimura T, Kotani J, Nakao A. Hydrogen inhalation protects against acute lung injury induced by hemorrhagic shock and resuscitation. Surgery. 2015;158:399–407.

    PubMed Article Google Scholar

  19. Zhou ZQ, Zhong CH, Su ZQ, Li XY, Chen Y, Chen XB, Tang CL, Zhou LQ, Li SY. Breathing hydrogen-oxygen mixture decreases inspiratory effort in patients with tracheal stenosis. Respiration. 2019;97:42–51.

    PubMed Article CAS Google Scholar

  20. Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Chen R, Decramer M, Fabbri LM, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD Executive Summary. Am J Respir Crit Care Med. 2017;195:557–82.

    CAS PubMed Article Google Scholar

  21. AECOPD EGfDaTo. Expert consensus on the diagnosis and treatment of acute exacerbation of chronic obstructive pulmonary disease. Int J Respir. 2017;37:1041–57.

    Google Scholar

  22. Leidy NK, Schmier JK, Jones MK, Lloyd J, Rocchiccioli K. Evaluating symptoms in chronic obstructive pulmonary disease: validation of the Breathlessness, Cough and Sputum Scale. Respir Med. 2003;97(Suppl A):S59-70.

    PubMed Article Google Scholar

  23. US Department of Health and Human Services. National Cancer Institute: common terminology criteria for adverse events. Version 4.03. 2016.

  24. Leidy NK, Rennard SI, Schmier J, Jones MK, Goldman M. The breathlessness, cough, and sputum scale: the development of empirically based guidelines for interpretation. Chest. 2003;124:2182–91.

    PubMed Article Google Scholar

  25. Górecka D, Gorzelak K, Sliwiński P, Tobiasz M, Zieliński J. Effect of long-term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with moderate hypoxaemia. Thorax. 1997;52:674–9.

    PubMed PubMed Central Article Google Scholar

  26. Katsenos S, Constantopoulos SH. Long-term oxygen therapy in COPD: Factors affecting and ways of improving patient compliance. Pulm Med. 2011;2011:325362.

    PubMed PubMed Central Article Google Scholar

  27. Branson RD. Oxygen therapy in COPD. Respir Care. 2018;63:734–48.

    PubMed Article Google Scholar

  28. Liu S, Liu K, Sun Q, Tao H, Sun X-J. Hydrogen therapy may be a novel and effective treatment for COPD. Front Pharmacol 2011; 2.

  29. Celli B, Halpin D, Hepburn R, Byrne N, Keating ET, Goldman M. Symptoms are an important outcome in chronic obstructive pulmonary disease clinical trials: results of a 3-month comparative study using the Breathlessness, Cough and Sputum Scale (BCSS). Respir Med. 2003;97:S35–43.

    PubMed Article Google Scholar

  30. Koo H-K, Jeong I, Kim J-H, Kim S-K, Shin J-W, Park SY, Rhee CK, Choi EY, Moon J-Y, Kim YH, et al. Development and validation of the COugh Assessment Test (COAT). Respirology. 2019;24:551–7.

    PubMed Article Google Scholar

  31. Huang L. Molecular hydrogen: a therapeutic antioxidant and beyond. Med Gas Res. 2016;6:219–22.

    CAS PubMed PubMed Central Article Google Scholar

  32. Fischer BM, Pavlisko E, Voynow JA. Pathogenic triad in COPD: oxidative stress, protease-antiprotease imbalance, and inflammation. Int J Chron Obstruct Pulmon Dis. 2011;6:413–21.

    CAS PubMed PubMed Central Article Google Scholar

  33. Domej W, Oettl K, Renner W. Oxidative stress and free radicals in COPD–implications and relevance for treatment. Int J Chron Obstruct Pulmon Dis. 2014;9:1207–24.

    PubMed PubMed Central Article Google Scholar

  34. Kirkham PA, Barnes PJ. Oxidative stress in COPD. Chest. 2013;144:266–73.

    CAS PubMed Article Google Scholar

  35. Langen RC, Korn SH, Wouters EF. ROS in the local and systemic pathogenesis of COPD. Free Radic Biol Med. 2003;35:226–35.

    CAS PubMed Article Google Scholar

  36. Barnes PJ. New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat Rev Drug Discovery. 2013;12:543–59.

    PubMed Article CAS Google Scholar

  37. Cazzola M, Page CP, Calzetta L, Matera MG. Emerging anti-inflammatory strategies for COPD. Eur Respir J. 2012;40:724–41.

    CAS PubMed Article Google Scholar

  38. Rahman I. Antioxidant therapies in COPD. Int J Chron Obstruct Pulmon Dis. 2006;1:15.

    CAS PubMed PubMed Central Google Scholar

  39. Dekhuijzen PN, Aben KK, Dekker I, Aarts LP, Wielders PL, van Herwaarden CL, Bast A. Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1996;154:813–6.

    CAS PubMed Article Google Scholar

  40. Halliwell B, Gutteridge JM. Biologically relevant metal ion-dependent hydroxyl radical generation. An update. FEBS Lett. 1992;307:108–12.

    CAS PubMed Article Google Scholar

  41. Lipinski B. Hydroxyl radical and its scavengers in health and disease. Oxid Med Cell Longev. 2011;2011:809696.

    PubMed PubMed Central Article CAS Google Scholar

  42. Ishibashi T. Molecular hydrogen: new antioxidant and anti-inflammatory therapy for rheumatoid arthritis and related diseases. Curr Pharm Des. 2013;19:6375–81.

    CAS PubMed PubMed Central Article Google Scholar

  43. Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K-i, Katayama Y, Asoh S, Ohta S. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688–94.

    CAS PubMed Article Google Scholar

  44. Kishimoto Y, Kato T, Ito M, Azuma Y, Fukasawa Y, Ohno K, Kojima S. Hydrogen ameliorates pulmonary hypertension in rats by anti-inflammatory and antioxidant effects. J Thorac Cardiovasc Surg. 2015;150:645–54.

    CAS PubMed Article Google Scholar

  45. Lu W, Li D, Hu J, Mei H, Shu J, Long Z, Yuan L, Li D, Guan R, Li Y, et al. Hydrogen gas inhalation protects against cigarette smoke-induced COPD development in mice. J Thorac Dis. 2018;10:3232–43.

    PubMed PubMed Central Article Google Scholar

  46. Ohno K, Ito M, Ichihara M, Ito M. Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases. Oxid Med Cell Longev. 2012;2012:353152.

    PubMed PubMed Central Article CAS Google Scholar

  47. Long-Term Oxygen Treatment Trial Research G, Albert RK, Au DH, Blackford AL, Casaburi R, Cooper JA Jr, Criner GJ, Diaz P, Fuhlbrigge AL, Gay SE, et al. A randomized trial of long-term oxygen for COPD with moderate desaturation. N Engl J Med. 2016;375:1617–27.

    Article CAS Google Scholar

  48. Hanania NA, Feldman G, Zachgo W, Shim J-J, Crim C, Sanford L, Lettis S, Barnhart F, Haumann B. The efficacy and safety of the novel long-acting β2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial. Chest. 2012;142:119–27.

    CAS PubMed Article Google Scholar

  49. Ono H, Nishijima Y, Adachi N, Sakamoto M, Kudo Y, Nakazawa J, Kaneko K, Nakao A. Hydrogen(H2) treatment for acute erythymatous skin diseases. A report of 4 patients with safety data and a non-controlled feasibility study with H2 concentration measurement on two volunteers. Medical Gas Res. 2012;2:14.

    CAS Article Google Scholar

  50. Ahmadi Z, Sundh J, Bornefalk-Hermansson A, Ekstrom M. Long-term oxygen therapy 24 vs 15 h/day and mortality in chronic obstructive pulmonary disease. PLoS ONE. 2016;11:0163293.

    Article CAS Google Scholar

  51. Stoller JK, Panos RJ, Krachman S, Doherty DE, Make B. Oxygen therapy for patients with COPD: current evidence and the long-term oxygen treatment trial. Chest. 2010;138:179–87.


DOI: 10.1186

Published on: 13/05/2021


Authors:

Зе-Гуан Джън ,
Wu-Zhuang Sun ,
Джи-Ин Ху ,
Джи-Джун Джи ,
Джин-Фу Сю ,
Джи Цао ,
Песен на Юан-Лин ,
Чанг-Хуей Уанг ,
Дзин Уанг ,
Хуей Джао ,
Zhong-Liang Guo &
Нан-Шан Чжун

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

https://doi.org/10.1186/s12931-021-01740-w

Abstract

Background

To investigate whether the use of a hydrogen/oxygen mixture is superior to oxygen in improving symptoms in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD).

Methods

This prospective, randomized, double-blind, controlled, 10-center clinical study enrolled patients with AECOPD and a BCSS (dyspnea, cough and sputum scale) score of at least 6. Eligible patients were randomly assigned (1:1 ratio) to receive hydrogen/oxygen hybrid therapy or oxygen therapy. The primary endpoint was change from baseline in BCSS score at day 7. Adverse events (AEs) were recorded to assess safety.

Results

The change in BCSS score was greater in the hydrogen/oxygen group than in the oxygen group (-5.3 vs. -2.4 points; difference: -2.75 [95% CI -3.27 to – 2:22], which met superiority criteria). Similar results were observed at other time points from day 2 to day 6. Cough assessment test scores were significantly lower in the hydrogen/oxygen group compared to the control group (-11.00 vs -6.00, p<0.001). Changes in lung function, arterial blood gases, and noninvasive oxygen saturation did not differ significantly between groups, as well as for other endpoints. AEs were reported in 34 (63.0%) patients in the hydrogen/oxygen group and in 42 (77.8%) patients in the oxygen group. No deaths or equipment failures were reported during the study period.

References

  1. Hassett DJ, Borchers MT, Panos RJ. Chronic obstructive pulmonary disease (COPD): evaluation from clinical, immunological and bacterial pathogenesis perspectives. J Microbiol. 2014;52:211–26.

    PubMed Article Google Scholar

  2. Martinez FD. Early-life origins of chronic obstructive pulmonary disease. N Engl J Med. 2016;375:871–8.

    PubMed Article Google Scholar

  3. Shaw JG, Vaughan A, Dent AG, O’Hare PE, Goh F, Bowman RV, Fong KM, Yang IA. Biomarkers of progression of chronic obstructive pulmonary disease (COPD). J Thorac Dis. 2014;6:1532–47.

    PubMed PubMed Central Google Scholar

  4. Vargas F, Bui HN, Boyer A, Salmi LR, Gbikpi-Benissan G, Guenard H, Gruson D, Hilbert G. Intrapulmonary percussive ventilation in acute exacerbations of COPD patients with mild respiratory acidosis: a randomized controlled trial [ISRCTN17802078]. Crit Care. 2005;9:R382-389.

    PubMed PubMed Central Article Google Scholar

  5. Papaiwannou A, Zarogoulidis P, Porpodis K, Spyratos D, Kioumis I, Pitsiou G, Pataka A, Tsakiridis K, Arikas S, Mpakas A, et al. Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS): current literature review. J Thorac Dis. 2014;6(Suppl 1):S146-151.

    PubMed PubMed Central Google Scholar

  6. Ko FW, Chan KP, Hui DS, Goddard JR, Shaw JG, Reid DW, Yang IA. Acute exacerbation of COPD. Respirology. 2016;21:1152–65.

    PubMed PubMed Central Article Google Scholar

  7. Brochard L. Non-invasive ventilation for acute exacerbations of COPD: a new standard of care. Thorax. 2000;55:817–8.

    CAS PubMed PubMed Central Article Google Scholar

  8. Abdo WF, Heunks LM. Oxygen-induced hypercapnia in COPD: myths and facts. Crit Care. 2012;16:323.

    PubMed PubMed Central Article Google Scholar

  9. Osadnik CR, Tee VS, Carson‐Chahhoud KV, Picot J, Wedzicha JA, Smith BJ. Non‐invasive ventilation for the management of acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease. Cochrane Database Syst Reviews 2017.

  10. Murray I, Paterson E, Thain G, Currie GP. Outcomes following non-invasive ventilation for hypercapnic exacerbations of chronic obstructive pulmonary disease. Thorax. 2011;66:825–6.

    PubMed Article Google Scholar

  11. Murphy PB, Rehal S, Arbane G, Bourke S, Calverley PMA, Crook AM, Dowson L, Duffy N, Gibson GJ, Hughes PD, et al. Effect of home noninvasive ventilation with oxygen therapy vs oxygen therapy alone on hospital readmission or death after an acute COPD exacerbation: a randomized clinical trial. JAMA. 2017;317:2177–86.

    PubMed PubMed Central Article Google Scholar

  12. Berganza CJ, Zhang JH. The role of helium gas in medicine. Med Gas Res. 2013;3:18.

    PubMed PubMed Central Article Google Scholar

  13. Nakao A. Therapeutic Medical Gas.

  14. Vonbank K, Ziesche R, Higenbottam TW, Stiebellehner L, Petkov V, Schenk P, Germann P, Block LH. Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe COPD. Thorax. 2003;58:289–93.

    CAS PubMed PubMed Central Article Google Scholar

  15. Jolliet P, Ouanes-Besbes L, Abroug F, Ben Khelil J, Besbes M, Garnero A, Arnal JM, Daviaud F, Chiche JD, Lortat-Jacob B, et al. A multicenter randomized trial assessing the efficacy of helium/oxygen in severe exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;195:871–80.

    CAS PubMed Article Google Scholar

  16. Ohta S. Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. Pharmacol Ther. 2014;144:1–11.

    CAS PubMed Article Google Scholar

  17. Huang C-S, Kawamura T, Toyoda Y, Nakao A. Recent advances in hydrogen research as a therapeutic medical gas. Free Radical Res. 2010;44:971–82.

    CAS Article Google Scholar

  18. Kohama K, Yamashita H, Aoyama-Ishikawa M, Takahashi T, Billiar TR, Nishimura T, Kotani J, Nakao A. Hydrogen inhalation protects against acute lung injury induced by hemorrhagic shock and resuscitation. Surgery. 2015;158:399–407.

    PubMed Article Google Scholar

  19. Zhou ZQ, Zhong CH, Su ZQ, Li XY, Chen Y, Chen XB, Tang CL, Zhou LQ, Li SY. Breathing hydrogen-oxygen mixture decreases inspiratory effort in patients with tracheal stenosis. Respiration. 2019;97:42–51.

    PubMed Article CAS Google Scholar

  20. Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Chen R, Decramer M, Fabbri LM, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD Executive Summary. Am J Respir Crit Care Med. 2017;195:557–82.

    CAS PubMed Article Google Scholar

  21. AECOPD EGfDaTo. Expert consensus on the diagnosis and treatment of acute exacerbation of chronic obstructive pulmonary disease. Int J Respir. 2017;37:1041–57.

    Google Scholar

  22. Leidy NK, Schmier JK, Jones MK, Lloyd J, Rocchiccioli K. Evaluating symptoms in chronic obstructive pulmonary disease: validation of the Breathlessness, Cough and Sputum Scale. Respir Med. 2003;97(Suppl A):S59-70.

    PubMed Article Google Scholar

  23. US Department of Health and Human Services. National Cancer Institute: common terminology criteria for adverse events. Version 4.03. 2016.

  24. Leidy NK, Rennard SI, Schmier J, Jones MK, Goldman M. The breathlessness, cough, and sputum scale: the development of empirically based guidelines for interpretation. Chest. 2003;124:2182–91.

    PubMed Article Google Scholar

  25. Górecka D, Gorzelak K, Sliwiński P, Tobiasz M, Zieliński J. Effect of long-term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with moderate hypoxaemia. Thorax. 1997;52:674–9.

    PubMed PubMed Central Article Google Scholar

  26. Katsenos S, Constantopoulos SH. Long-term oxygen therapy in COPD: Factors affecting and ways of improving patient compliance. Pulm Med. 2011;2011:325362.

    PubMed PubMed Central Article Google Scholar

  27. Branson RD. Oxygen therapy in COPD. Respir Care. 2018;63:734–48.

    PubMed Article Google Scholar

  28. Liu S, Liu K, Sun Q, Tao H, Sun X-J. Hydrogen therapy may be a novel and effective treatment for COPD. Front Pharmacol 2011; 2.

  29. Celli B, Halpin D, Hepburn R, Byrne N, Keating ET, Goldman M. Symptoms are an important outcome in chronic obstructive pulmonary disease clinical trials: results of a 3-month comparative study using the Breathlessness, Cough and Sputum Scale (BCSS). Respir Med. 2003;97:S35–43.

    PubMed Article Google Scholar

  30. Koo H-K, Jeong I, Kim J-H, Kim S-K, Shin J-W, Park SY, Rhee CK, Choi EY, Moon J-Y, Kim YH, et al. Development and validation of the COugh Assessment Test (COAT). Respirology. 2019;24:551–7.

    PubMed Article Google Scholar

  31. Huang L. Molecular hydrogen: a therapeutic antioxidant and beyond. Med Gas Res. 2016;6:219–22.

    CAS PubMed PubMed Central Article Google Scholar

  32. Fischer BM, Pavlisko E, Voynow JA. Pathogenic triad in COPD: oxidative stress, protease-antiprotease imbalance, and inflammation. Int J Chron Obstruct Pulmon Dis. 2011;6:413–21.

    CAS PubMed PubMed Central Article Google Scholar

  33. Domej W, Oettl K, Renner W. Oxidative stress and free radicals in COPD–implications and relevance for treatment. Int J Chron Obstruct Pulmon Dis. 2014;9:1207–24.

    PubMed PubMed Central Article Google Scholar

  34. Kirkham PA, Barnes PJ. Oxidative stress in COPD. Chest. 2013;144:266–73.

    CAS PubMed Article Google Scholar

  35. Langen RC, Korn SH, Wouters EF. ROS in the local and systemic pathogenesis of COPD. Free Radic Biol Med. 2003;35:226–35.

    CAS PubMed Article Google Scholar

  36. Barnes PJ. New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat Rev Drug Discovery. 2013;12:543–59.

    PubMed Article CAS Google Scholar

  37. Cazzola M, Page CP, Calzetta L, Matera MG. Emerging anti-inflammatory strategies for COPD. Eur Respir J. 2012;40:724–41.

    CAS PubMed Article Google Scholar

  38. Rahman I. Antioxidant therapies in COPD. Int J Chron Obstruct Pulmon Dis. 2006;1:15.

    CAS PubMed PubMed Central Google Scholar

  39. Dekhuijzen PN, Aben KK, Dekker I, Aarts LP, Wielders PL, van Herwaarden CL, Bast A. Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1996;154:813–6.

    CAS PubMed Article Google Scholar

  40. Halliwell B, Gutteridge JM. Biologically relevant metal ion-dependent hydroxyl radical generation. An update. FEBS Lett. 1992;307:108–12.

    CAS PubMed Article Google Scholar

  41. Lipinski B. Hydroxyl radical and its scavengers in health and disease. Oxid Med Cell Longev. 2011;2011:809696.

    PubMed PubMed Central Article CAS Google Scholar

  42. Ishibashi T. Molecular hydrogen: new antioxidant and anti-inflammatory therapy for rheumatoid arthritis and related diseases. Curr Pharm Des. 2013;19:6375–81.

    CAS PubMed PubMed Central Article Google Scholar

  43. Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K-i, Katayama Y, Asoh S, Ohta S. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688–94.

    CAS PubMed Article Google Scholar

  44. Kishimoto Y, Kato T, Ito M, Azuma Y, Fukasawa Y, Ohno K, Kojima S. Hydrogen ameliorates pulmonary hypertension in rats by anti-inflammatory and antioxidant effects. J Thorac Cardiovasc Surg. 2015;150:645–54.

    CAS PubMed Article Google Scholar

  45. Lu W, Li D, Hu J, Mei H, Shu J, Long Z, Yuan L, Li D, Guan R, Li Y, et al. Hydrogen gas inhalation protects against cigarette smoke-induced COPD development in mice. J Thorac Dis. 2018;10:3232–43.

    PubMed PubMed Central Article Google Scholar

  46. Ohno K, Ito M, Ichihara M, Ito M. Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases. Oxid Med Cell Longev. 2012;2012:353152.

    PubMed PubMed Central Article CAS Google Scholar

  47. Long-Term Oxygen Treatment Trial Research G, Albert RK, Au DH, Blackford AL, Casaburi R, Cooper JA Jr, Criner GJ, Diaz P, Fuhlbrigge AL, Gay SE, et al. A randomized trial of long-term oxygen for COPD with moderate desaturation. N Engl J Med. 2016;375:1617–27.

    Article CAS Google Scholar

  48. Hanania NA, Feldman G, Zachgo W, Shim J-J, Crim C, Sanford L, Lettis S, Barnhart F, Haumann B. The efficacy and safety of the novel long-acting β2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial. Chest. 2012;142:119–27.

    CAS PubMed Article Google Scholar

  49. Ono H, Nishijima Y, Adachi N, Sakamoto M, Kudo Y, Nakazawa J, Kaneko K, Nakao A. Hydrogen(H2) treatment for acute erythymatous skin diseases. A report of 4 patients with safety data and a non-controlled feasibility study with H2 concentration measurement on two volunteers. Medical Gas Res. 2012;2:14.

    CAS Article Google Scholar

  50. Ahmadi Z, Sundh J, Bornefalk-Hermansson A, Ekstrom M. Long-term oxygen therapy 24 vs 15 h/day and mortality in chronic obstructive pulmonary disease. PLoS ONE. 2016;11:0163293.

    Article CAS Google Scholar

  51. Stoller JK, Panos RJ, Krachman S, Doherty DE, Make B. Oxygen therapy for patients with COPD: current evidence and the long-term oxygen treatment trial. Chest. 2010;138:179–87.

References