Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Hydrogen Gas Therapy: From Preclinical Studies to Clinical Trials

Author(s): Motoaki Sano* and Tomoyoshi Tamura

Volume 27, Issue 5, 2021

Published on: 21 December, 2020

Page: [650 - 658] Pages: 9

DOI: 10.2174/1381612826666201221150857

open access plus


Background: Mounting evidence indicates that hydrogen gas (H2) is a versatile therapeutic agent, even at very low, non-combustible concentrations. The Chinese National Health and Medical Commission recently recommended the use of inhaled H2 in addition to O2 therapy in the treatment of COVID-19-associated pneumonia, and its effects extend to anti-tumor, anti-inflammatory and antioxidant actions.

Summary: In this review, we have highlighted key findings from preclinical research and recent clinical studies demonstrating that H2 reduces the organ damage caused by ischemia-reperfusion. We have also outlined the critical role this effect plays in a variety of medical emergencies, including myocardial infarction, hemorrhagic shock, and out-of-hospital cardiac arrest, as well as in organ transplantation. H2 is compared with established treatments such as targeted temperature management, and we have also discussed its possible mechanisms of action, including the recently identified suppression of TNF-α-mediated endothelial glycocalyx degradation by inhaled H2. In addition, our new method that enables H2 gas to be easily transported to emergency settings and quickly injected into an organ preservation solution at the site of donor organ procurement have been described.

Conclusion: H2 is an easily administered, inexpensive and well-tolerated agent that is highly effective for a wide range of conditions in emergency medicine, as well as for preserving donated organs.

Keywords: Myocardial infarction, post-cardiac arrest syndrome, hemorrhagic shock, organ transplantation, COVID-19, Hyperbaric hydrogen gas (H2).

Dole M, Wilson FR, Fife WP. Hyperbaric hydrogen therapy: A possible treatment for cancer. Science 1975; 190(4210): 152-4.
[] [PMID: 1166304]
Gharib B, Hanna S, Abdallahi OM, Lepidi H, Gardette B, De Reggi M. Anti-inflammatory properties of molecular hydrogen: Investigation on parasite-induced liver inflammation. C R Acad Sci III 2001; 324(8): 719-24.
[] [PMID: 11510417]
Yanagihara T, Arai K, Miyamae K, et al. Electrolyzed hydrogen-saturated water for drinking use elicits an antioxidative effect: A feeding test with rats. Biosci Biotechnol Biochem 2005; 69(10): 1985-7.
[] [PMID: 16244454]
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): 688-94.
[] [PMID: 17486089]
Hayashida K, Sano M, Ohsawa I, et al. Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun 2008; 373(1): 30-5.
[] [PMID: 18541148]
Yamamoto R, Homma K, Suzuki S, Sano M, Sasaki J. Hydrogen gas distribution in organs after inhalation: Real-time monitoring of tissue hydrogen concentration in rat. Sci Rep 2019; 9(1): 1255.
[] [PMID: 30718910]
Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361(9351): 13-20.
[] [PMID: 12517460]
Zijlstra F, Hoorntje JC, de Boer MJ, et al. Long-term benefit of primary angioplasty as compared with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1999; 341(19): 1413-9.
[] [PMID: 10547403]
Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1997; 336(23): 1621-8.
[] [PMID: 9173270]
Yoshida A, Asanuma H, Sasaki H, et al. H(2) mediates cardioprotection via involvements of K(ATP) channels and permeability transition pores of mitochondria in dogs. Cardiovasc Drugs Ther 2012; 26(3): 217-26.
[] [PMID: 22527618]
Katsumata Y, Sano F, Abe T, et al. The effects of hydrogen gas inhalation on adverse left ventricular remodeling after percutaneous coronary intervention for ST-elevated myocardial infarction - first pilot study in humans. Circ J 2017; 81(7): 940-7.
[] [PMID: 28321000]
Nichol G, Thomas E, Callaway CW, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA 2008; 300(12): 1423-31.
[] [PMID: 18812533]
Atwood C, Eisenberg MS, Herlitz J, Rea TD. Incidence of EMS-treated out-of-hospital cardiac arrest in Europe. Resuscitation 2005; 67(1): 75-80.
[] [PMID: 16199289]
Kitamura T, Iwami T, Kawamura T, Nagao K, Tanaka H, Hiraide A. Implementation Working Group for the All-Japan Utstein Registry of the Fire and Disaster Management Agency. Nationwide public-access defibrillation in Japan. N Engl J Med 2010; 362(11): 994-1004.
[] [PMID: 20237345]
Neumar RW, Nolan JP, Adrie C, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation 2008; 118(23): 2452-83.
[] [PMID: 18948368]
Hayashida K, Sano M, Kamimura N, et al. H(2) gas improves functional outcome after cardiac arrest to an extent comparable to therapeutic hypothermia in a rat model. J Am Heart Assoc 2012; 1(5)e003459
[] [PMID: 23316300]
Hayashida K, Sano M, Kamimura N, et al. Hydrogen inhalation during normoxic resuscitation improves neurological outcome in a rat model of cardiac arrest independently of targeted temperature management. Circulation 2014; 130(24): 2173-80.
[] [PMID: 25366995]
Tamura T, Hayashida K, Sano M, et al. Feasibility and safety of hydrogen gas inhalation for post-cardiac arrest syndrome - first-in-human pilot study. Circ J 2016; 80(8): 1870-3.
[] [PMID: 27334126]
Tamura T, Hayashida K, Sano M, Onuki S, Suzuki M. Efficacy of inhaled hydrogen on neurological outcome following brain ischemia during post-cardiac arrest care (HYBRID II trial): Study protocol for a randomized controlled trial. Trials 2017; 18(1): 488.
[] [PMID: 29058596]
Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380(9859): 2095-128.
[] [PMID: 23245604]
Trunkey DD. Trauma. Accidental and intentional injuries account for more years of life lost in the U.S. than cancer and heart disease. Among the prescribed remedies are improved preventive efforts, speedier surgery and further research. Sci Am 1983; 249(2): 28-35.
[] [PMID: 6623052]
Cannon JW. Hemorrhagic Shock. N Engl J Med 2018; 378(4): 370-9.
[] [PMID: 29365303]
Oliver GJ, Walter DP, Redmond AD. Are prehospital deaths from trauma and accidental injury preventable? A direct historical comparison to assess what has changed in two decades. Injury 2017; 48(5): 978-84.
[] [PMID: 28363752]
Matsuoka T, Suzuki M, Sano M, et al. Hydrogen gas inhalation inhibits progression to the “irreversible” stage of shock after severe hemorrhage in rats. J Trauma Acute Care Surg 2017; 83(3): 469-75.
[] [PMID: 28640781]
Tamura T, Sano M, Matsuoka T, et al. Hydrogen gas inhalation attenuates endothelial glycocalyx damage and stabilizes hemodynamics in a rat hemorrhagic shock model. Shock 2020; 54(3): 377-85.
[] [PMID: 32804466]
Pries AR, Secomb TW, Gaehtgens P. The endothelial surface layer. Pflugers Arch 2000; 440(5): 653-66.
[] [PMID: 11007304]
Reitsma S, Slaaf DW, Vink H, van Zandvoort MA. oude Egbrink MG. The endothelial glycocalyx: Composition, functions, and visualization. Pflugers Arch 2007; 454(3): 345-59.
[] [PMID: 17256154]
Chignalia AZ, Yetimakman F, Christiaans SC, et al. The glycocalyx and trauma: A review. Shock 2016; 45(4): 338-48.
[] [PMID: 26513707]
Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann Surg 2011; 254(2): 194-200.
[] [PMID: 21772125]
Torres Filho IP, Torres LN, Salgado C, Dubick MA. Plasma syndecan-1 and heparan sulfate correlate with microvascular glycocalyx degradation in hemorrhaged rats after different resuscitation fluids. Am J Physiol Heart Circ Physiol 2016; 310(11): H1468-78.
[] [PMID: 27037369]
Henry CB, Duling BR. TNF-alpha increases entry of macromolecules into luminal endothelial cell glycocalyx. Am J Physiol Heart Circ Physiol 2000; 279(6): H2815-23.
[] [PMID: 11087236]
Sato T, Mimuro S, Katoh T, et al. 1.2% Hydrogen gas inhalation protects the endothelial glycocalyx during hemorrhagic shock: A prospective laboratory study in rats. J Anesth 2020; 34(2): 268-75.
[] [PMID: 31997005]
Moon DH, Kang DY, Haam SJ, et al. Hydrogen gas inhalation ameliorates lung injury after hemorrhagic shock and resuscitation. J Thorac Dis 2019; 11(4): 1519-27.
[] [PMID: 31179095]
Kohama K, Yamashita H, Aoyama-Ishikawa M, et al. Hydrogen inhalation protects against acute lung injury induced by hemorrhagic shock and resuscitation. Surgery 2015; 158(2): 399-407.
[] [PMID: 25983276]
Haam S, Lee JG, Paik HC, Park MS, Lim BJ. Hydrogen gas inhalation during ex vivo lung perfusion of donor lungs recovered after cardiac death. J Heart Lung Transplant 2018; 37(10): 1271-8.
[] [PMID: 30100327]
Ishikawa T, Shimada S, Fukai M, et al. Post-reperfusion hydrogen gas treatment ameliorates ischemia reperfusion injury in rat livers from donors after cardiac death: A preliminary study. Surg Today 2018; 48(12): 1081-8.
[] [PMID: 29980846]
Tamaki I, Hata K, Okamura Y, et al. Hydrogen flush after cold storage as a new end-ischemic ex vivo treatment for liver grafts against ischemia/reperfusion injury. Liver Transpl 2018; 24(11): 1589-602.
[] [PMID: 30120877]
Uto K, Sakamoto S, Que W, et al. Hydrogen-rich solution attenuates cold ischemia-reperfusion injury in rat liver transplantation. BMC Gastroenterol 2019; 19(1): 25.
[] [PMID: 30736744]
Buchholz BM, Masutani K, Kawamura T, et al. Hydrogen-enriched preservation protects the isogeneic intestinal graft and amends recipient gastric function during transplantation. Transplantation 2011; 92(9): 985-92.
[] [PMID: 21956195]
Shimada S, Wakayama K, Fukai M, et al. Hydrogen gas ameliorates hepatic reperfusion injury after prolonged cold preservation in isolated perfused rat liver. Artif Organs 2016; 40(12): 1128-36.
[] [PMID: 27140066]
Tan M, Sun X, Guo L, Su C, Sun X, Xu Z. Hydrogen as additive of HTK solution fortifies myocardial preservation in grafts with prolonged cold ischemia. Int J Cardiol 2013; 167(2): 383-90.
[] [PMID: 22264873]
Noda K, Shigemura N, Tanaka Y, et al. A novel method of preserving cardiac grafts using a hydrogen-rich water bath. J Heart Lung Transplant 2013; 32(2): 241-50.
[] [PMID: 23273745]
Yamada T, Uchida K, Onuma K, et al. Hydrogen supplementation of preservation solution improves viability of osteochondral grafts. ScientificWorldJournal 2014; 2014109876
[] [PMID: 25506061]
Abe T, Li XK, Yazawa K, et al. Hydrogen-rich University of Wisconsin solution attenuates renal cold ischemia-reperfusion injury. Transplantation 2012; 94(1): 14-21.
[] [PMID: 22683850]
Kobayashi E, Sano M. Organ preservation solution containing dissolved hydrogen gas from a hydrogen-absorbing alloy canister improves function of transplanted ischemic kidneys in miniature pigs. PLoS One 2019; 14(10)e0222863
[] [PMID: 31574107]
Iketani M, Ohsawa I. Molecular hydrogen as a neuroprotective agent. Curr Neuropharmacol 2017; 15(2): 324-31.
[] [PMID: 27281176]
Kura B, Bagchi AK, Singal PK, et al. Molecular hydrogen: potential in mitigating oxidative-stress-induced radiation injury. Can J Physiol Pharmacol 2019; 97(4): 287-92.
[] [PMID: 30543459]
Iida A, Nosaka N, Yumoto T, et al. The clinical application of hydrogen as a medical treatment. Acta Med Okayama 2016; 70(5): 331-7.
[PMID: 27777424]
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.
[] [PMID: 24769081]
Tao G, Song G, Qin S. Molecular hydrogen: Current knowledge on mechanism in alleviating free radical damage and diseases. Acta Biochim Biophys Sin (Shanghai) 2019; 51(12): 1189-97.
[] [PMID: 31738389]
Ostojic SM. Molecular hydrogen in sports medicine: New therapeutic perspectives. Int J Sports Med 2015; 36(4): 273-9.
[PMID: 25525953]
LeBaron TW, Kura B, Kalocayova B, Tribulova N, Slezak J. A new approach for the prevention and treatment of cardiovascular disorders. Molecular hydrogen significantly reduces the effects of oxidative stress. Molecules 2019; 24(11): 2076.
[] [PMID: 31159153]
Zheng Y, Zhu D. Molecular hydrogen therapy ameliorates organ damage induced by Sepsis. Oxid Med Cell Longev 2016; 20165806057
[] [PMID: 27413421]
Chinese Non-government Medical Institutions Association. Recommendation for hydrogen-oxygen nebulizer: notice of clinical treatment for novel coronavirus pneumonia 2020. Available from:
Guan WJ, Wei CH, Chen AL. Hydrogen/oxygen mixed gas inhalation improves disease severity and dyspnea in patients with Coronavirus disease 2019 in a recent multicenter, open-label clinical trial. J Thorac Dis 2020; 12: 3448-52.

© 2022 Bentham Science Publishers | Privacy Policy