Current study summary

Chen, K.D., W.C. Lin, and H.C. Kuo, Chemical and Biochemical Aspects of Molecular Hydrogen in Treating Kawasaki Disease and COVID-19. Chem Res Toxicol, 2021. 34(4): p. 952-958.

Kawasaki-like disease (KD) caused by COVID-19 shares some symptoms with KD, which is called multisystem inflammatory syndrome in children, and has been reported in the United States, Italy, France, England and other areas of Europe, with KD prevalence increasing 6- to 10-fold or more compared to previous years. Hydrogen gas is a stable and efficient antioxidant that has beneficial effects on oxidative damage, inflammation, cell apoptosis and abnormal blood vessel inflammation. This review describes the chemical and biochemical aspects of hydrogen gas inhalation in the treatment of KD and COVID-19.2.

Ostojic, S., COVID-19 and molecular hydrogen inhalation. Therapeutic Advances in Respiratory Disease, 2020. 14: p. 175346662095105.

Recent public reports from the National Health Commission of China and the Chinese Centre for Disease Control and Prevention have recommended effective oxygen therapy interventions as part of the overall treatment of patients with novel coronavirus pneumonia (COVID-19). The documents mentioned a rather exotic ratio of hydrogen and oxygen (66.6% H2 to 33.3% O2) as the composition of the gas mixture for inhalation. While high amounts of oxygen are administered in COVID-19 due to an apparent lung dysfunction, the mixture with hydrogen gas for a breathing mixture remains puzzling. Hydrogen is most likely added as an inert component of the breathing gas, but could also have beneficial effects on its own. A recent study suggests that hydrogen gas inhibits airway inflammation in asthma patients, an effect that could improve the state of the storm of inflammatory cytokines observed in COVID-19. Two multicentre randomised controlled trials (RCTs) of inhaled hydrogen for COVID-19 are listed in the World Health Organisation (WHO) Clinical Trials Register in February and March 2020, but there is no evidence yet to support this approach. Another factor also needs to be considered: the potential for highly concentrated hydrogen to cause an explosion triggered by static electricity. Like other promising (and much needed) therapeutics for COVID-19, gaseous hydrogen therefore requires accelerated but attentive research and approval with sufficient efficacy and safety guarantees.

V. Shogenova, T.T.T., N. O. Kryukova, K. A. Yusupkhodzhaeva, D. D. Pozdnyakova,   T. G. Kim,   A. V. Chernyak,   Е. N. Kalmanova,   O. S. Medvedev,   T. A. Kuropatkina,   S. D. Varfolomeev,   A. M. Ryabokon,   O. А. Svitich,   M. P. Kostinov,   Ibaraki Kunio,   Maehara Hiroki,   A. G. Chuchalin, Hydrogen inhalation in rehabilitation program of the medical staff recovered from COVID-19. Cardiovascular Therapy and Prevention, 2021. 20(6).

Inhalation of active hydrogen (H(H2O)m) has a strong antioxidant and anti-apoptotic effect. In recent years, it has been used in a number of experimental and clinical studies.Conclusion. Inhalation therapy with H(H2O)m in the rehabilitation programme of COVID-19 survivors during the recovery phase is a safe and highly effective method. The manifestations of silent hypoxaemia and endothelial dysfunction decreased, while exercise capacity increased. Laboratory tests showed a decrease in white blood cell count, estimated pulmonary shunt fraction and lactate levels.

Xu, K., Hydrogen-Oxygen Inhalation for Treatment of COVID-19. 2020: WORLD SCIENTIFIC. 150.

COVID-19 pneumonia is ravaging the world. Given the lack of specialised treatments, a new form of hydrogen-oxygen inhalation therapy has been successfully developed. Molecular hydrogen, a very safe “physiological gas”, has been shown to reduce lung damage caused by viruses such as COVID-19, improve dyspnoea and promote recovery from the disease due to its healing biological properties.

Luo, P., et al., Hydrogen-oxygen therapy alleviates clinical symptoms in twelve patients hospitalized with COVID-19: A retrospective study of medical records. Medicine, 2022. 101(9).

A retrospective medical record study was conducted at Shishou Hospital for Traditional Chinese Medicine in Hubei, China. COVID-19 patients (aged ≥ 30 years) admitted to the hospital between 29 January and 20 March 2020 were divided into a control group (n = 12) receiving routine therapy and a case group (n = 12) receiving additional hydrogen-oxygen therapy. The clinical characteristics of the COVID-19 patients were analysed. The physiological and biochemical indices, including immune inflammation indicators, electrolytes, cardiac muscle enzyme profile, and liver and kidney functions were tested and studied before and after hydrogen-oxygen therapy. The results showed that the percentage of neutrophil granulocytes and the concentration and abnormal level of C-reactive protein decreased significantly in COVID-19 patients who received additional hydrogen-oxygen therapy. This novel therapeutic agent could alleviate the clinical symptoms of COVID-19 patients by suppressing inflammatory responses.

Milovancev, A., et al., Hydrogen-rich water alleviates inflammation and fatigue in COVID-19: A pilot study. European Journal of Inflammation, 2022. 20: p. 1721727X221094197.

Our results are consistent with previous studies that have shown the anti-fatigue potential of HRW after sleep deprivation, heavy exercise and other stress-related conditions. Nevertheless, here we recruited a rather small number of COVID-19 patients, with a gender imbalance (e.g. there were 1.5 times as many women as men), a limited age range (e.g. no younger or older people were included) and a short list of biochemical indicators associated with inflammation and fatigue and were monitored in this pilot study.

Tian, Y., et al., Hydrogen, a Novel Therapeutic Molecule, Regulates Oxidative Stress, Inflammation, and Apoptosis. Front Physiol, 2021. 12: p. 789507.

Molecular hydrogen (H(2)) is a colourless and odourless gas. Studies have shown that inhalation of H(2) has a therapeutic effect in many animal and clinical trials, and its use is recommended in the new guidelines for the treatment of coronavirus pneumonia in China. H(2) has a relatively low molecular mass, which allows it to spread rapidly and penetrate cell membranes to exert a wide range of biological effects. It may play a role in the treatment and prevention of a number of acute and chronic inflammatory diseases, e.g. acute pancreatitis, sepsis, respiratory diseases, ischaemia-reperfusion injury, autoimmune diseases, etc. H(2) is mainly administered by inhalation, drinking H(2)-rich water or injection of H(2) saline. It may be involved in anti-inflammatory and antioxidant effects (mitochondrial energy metabolism), immune system regulation and cell death (apoptosis, autophagy and pyroptosis) by destroying excess reactive oxygen species production and modulating nuclear transcription factor. However, the underlying mechanism of H(2) is not yet fully understood. Due to its safety and potential efficacy, H(2) has promising potential for clinical use in many diseases. In this review, the role of H(2) in antioxidant, anti-inflammatory and anti-apoptotic effects and the underlying mechanism, particularly in coronavirus disease-2019 (COVID-19), are highlighted and strategies for the medical use of H(2) for various diseases.

Yang, M., et al., Hydrogen: A Novel Option in Human Disease Treatment. Oxid Med Cell Longev, 2020. 2020: p. 8384742.

H2 has been shown to have anti-inflammatory and antioxidant properties in many clinical trials, and its use is recommended in recent Chinese guidelines for the treatment of novel coronavirus pneumonia (NCP). Clinical experiments have yielded the surprising finding that H(2) gas can protect the lungs and extrapulmonary organs of NCP patients from pathological stimuli. The possible mechanisms underlying the effect of H(2) gas are not clear. H(2)-gas may regulate anti-inflammatory and antioxidant activity, mitochondrial energy metabolism, endoplasmic reticulum stress, the immune system and cell death (including apoptosis, autophagy, pyroptosis, ferroptosis and the circadian clock) and has therapeutic potential for many systemic diseases. This article reviews basic research and recent clinical applications of H(2) gas in multiple organ system diseases to develop strategies for the clinical treatment of various diseases.

Russell, G., Thomas, A., Nenov, A., & Hancock, J., The influence of molecular Hydrogen therapies in managing the symptoms of acute and chronic COVID-19. Medical Research Archives, 2022. 10(9).

Oxyhydrogen (HHO) is a gaseous mixture of molecular hydrogen (H2) and molecular oxygen (O2) produced by the electrolysis of water and delivered in a 2:1 ratio (66% and 33% respectively) via non-invasive inhalation devices such as nasal cannulas or nebulisers. Although there is limited scientific evidence to support this new and emerging therapy, preliminary research suggests that oxyhydrogen has cytoprotective properties by reducing oxidative stress and attenuating the inflammatory response. These aspects are particularly favourable when considering respiratory medicine, as underlying inflammation is known to determine the pathological course of many respiratory diseases, including asthma, chronic obstructive pulmonary disease and, most importantly, COVID-19. Direct delivery to the lung parenchyma is also likely to increase the efficacy of this new medical therapy. This review describes how this particular combination of gases can affect cellular processes at the molecular level, with a focus on the evolutionary requirement for O2 and H2. In addition, the authors evaluate the currently available data on the safety and efficacy of HHO in a clinical setting.

Lucas, K., M. Rosch, and P. Langguth, Molecular hydrogen (H(2) ) as a potential treatment for acute and chronic fatigue. Arch Pharm (Weinheim), 2021. 354(4): p. e2000378.

In summary, molecular hydrogen has an excellent profile as an anti-apoptotic, anti-inflammatory and antioxidant agent, with properties that can be used for a range of human diseases. The variety of delivery mechanisms available allows H2 to be used in numerous scenarios, ranging from daily nutritional supplementation to chronic and acute nosocomial treatment. In addition, advanced innovations such as inhalers, patches and tablets provide a convenient and portable method of administering hydrogen that is easy to administer and therefore has great potential for use in chronic, emergency and convalescent care.

Singh, R.B., et al., Molecular hydrogen as an adjuvant therapy may be associated with increased oxygen saturation and improved exercise tolerance in a COVID-19 patient. Clin Case Rep, 2021. 9(11): p. e05039.

Treatment with HRW can improve oxygen saturation in patients with hypoxia, as shown in this case study. Hydrogen therapy can also improve exercise tolerance, resulting in significantly fewer episodes of hypoxia. during exercise. It is suggested that hydrogen supplementation may induce selective antioxidation, anti-inflammation, anti-apoptosis and favourable changes in gene expression, and may act as a therapeutic gas signalling modulator.Hydrogen-rich water may exert a protective effect on individuals suffering from symptoms associated with post-acute COVID-19 disease, whether induced by viral infection or as a rare side effect of vaccination. Well-controlled clinical trials are needed to confirm this preliminary case report.

Fu, Z. and J. Zhang, Molecular hydrogen is a promising therapeutic agent for pulmonary disease. J Zhejiang Univ Sci B, 2022. 23(2): p. 102-122.

Molecular hydrogen exerts biological effects on almost all organs. It has antioxidant, anti-inflammatory and anti-ageing effects and contributes to the regulation of autophagy and cell death. As the primary organ for gas exchange, the lungs are constantly exposed to various harmful environmental stimuli. Short- or long-term exposure to these pollutants often damages the lungs and causes respiratory and lung diseases. Acute and chronic respiratory diseases have a high morbidity and mortality rate and have become a major public health problem worldwide. For example, the 2019 coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. A growing number of studies have shown that hydrogen can protect the lungs from various diseases, including acute lung injury, chronic obstructive pulmonary disease, asthma, lung cancer, pulmonary arterial hypertension and pulmonary fibrosis. In this review, we highlight the multiple functions of hydrogen and the mechanisms underlying its protective effects in various lung diseases, with a focus on its role in disease development and its clinical significance.

Botek, M., et al., Molecular Hydrogen Positively Affects Physical and Respiratory Function in Acute Post-COVID-19 Patients: A New Perspective in Rehabilitation. International Journal of Environmental Research and Public Health, 2022. 19: p. 1-14.

Molecular hydrogen (H(2)) is potentially a novel therapeutic gas for patients with acute post-coronavirus disease 2019 (COVID-19) due to its antioxidant, anti-inflammatory, anti-apoptosis and anti-fatigue properties. The aim of this study was to investigate the effect of 14 days of H(2) inhalation on the respiratory status and physical fitness of patients after acute COVID-19 disease. This randomised, single-blinded, placebo-controlled study involved 26 men (44 ± 17 years) and 24 women (38 ± 12 years) who performed a 6-minute walk test (6 MWT) and a pulmonary function test, specifically forced vital capacity (FVC) and expiratory volume in the first second (FEV1). Symptomatic participants were recruited between 21 and 33 days after a positive polymerase chain reaction test. The experiment consisted of H(2)/placebo inhalation, 2 × 60 min/day for 14 days. The results showed that H(2) therapy significantly increased 6 MWT distance by 64 ± 39 m, FVC by 0.19 ± 0.24 L and FEV1 by 0.11 ± 0.28 L compared with placebo (all p ≤ 0.025). In conclusion, H(2) inhalation had beneficial health effects in terms of improved physical and respiratory function in patients with acute post-COVID-19 infection. Therefore, H(2) inhalation could be a safe and effective procedure to accelerate the early recovery of function in post-COVID-19 patients.

Li, Y., et al., Molecular Hydrogen: A Promising Adjunctive Strategy for the Treatment of the COVID-19, Frontiers in Medicine 2021 Vol. 8

Coronavirus disease 2019 (COVID-19) is an acute respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for which there is no specific and effective treatment. The pathophysiological process of COVID-19 is an excessive inflammatory response following infection of an organism with a virus. Inflammatory storms play an important role in the development of COVID-19, and numerous studies have confirmed that hydrogen has a therapeutic effect on many diseases by inhibiting excessive inflammatory cells and factors. Recently, a study led by Academician Zhong Nanshan in China on the treatment of patients with COVID-19 by inhalation of a mixed gas of hydrogen and oxygen attracted much international attention, and hydrogen therapy was also included in a new treatment plan for COVID-19 in China. This study mainly describes the mechanism of occurrence of COVID-19, summarises the therapeutic effects and underlying mechanisms of hydrogen on the critical illness, and analyses the feasibility and potential therapeutic targets of hydrogen for the treatment of COVID-19.

Perveen, I., et al., Hydrogen Therapy and Its Future Prospects for Ameliorating COVID-19: Clinical Applications, Efficacy, and Modality. Biomedicines, 2023. 11(7).

Molecular hydrogen is known to be an odourless and colourless gas. Recommendations developed by China suggest that inhalation of hydrogen molecules is currently recommended in the treatment of COVID-19 pneumonia. The therapeutic effect of molecular hydrogen has been confirmed in numerous clinical trials and experiments on animal models, where hydrogen was found to diffuse easily through cell membranes and exert a variety of biological effects due to its low molecular weight. A wide range of chronic and acute inflammatory diseases such as sepsis, pancreatitis, respiratory diseases, autoimmune diseases, ischemia-reperfusion injury, etc. can be treated and prevented by its use. H(2) can be inoculated into the body primarily by inhalation, by drinking water (which already contains H(2)) or by administering H(2) in the form of saline. It can play a central role as an antioxidant, in the regulation of the immune system, in anti-inflammatory activities (mitochondrial energy metabolism) and in cell death (apoptosis, pyroptosis and autophagy) by reducing the formation of overly reactive O(2) species and altering transcription factors in cell nuclei. However, the basic process of molecular hydrogen is not yet fully understood. Molecular hydrogen H(2) has a promising future in therapy due to its safety and potential benefits. This review addresses the antioxidant, anti-apoptotic and anti-inflammatory effects of hydrogen molecules, as well as the underlying principle and mechanism, focusing on the coronavirus disease of 2019 (COVID-19). Strategies and recommendations for the therapeutic and medical application of hydrogen molecules are also provided.

Wang, S.T., et al., Hydrogen gas (XEN) inhalation ameliorates airway inflammation in asthma and COPD patients. Qjm, 2020. 113(12): p. 870-875.

BACKGROUND: Hydrogen has been shown to have antioxidant and anti-inflammatory effects on various diseases. OBJECTIVE: We aim to investigate the acute effects of inhaled hydrogen on airway inflammation in patients with asthma and chronic obstructive pulmonary disease (COPD). DESIGN: Prospective study. METHODS: A total of 10 patients with asthma and 10 patients with COPD were inhaled 2.4% hydrogen-containing mixed vapour gas (XEN) once for 45 min. The levels of granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin-1β (IL-1β), IL-2, IL-4, IL-6, etc. in peripheral blood and exhaled breath condensate (EBC) before and after ‘XEN’ inhalation were measured. RESULTS: A 45-minute XEN inhalation decreased the level of monocytochemotactic protein 1 in both the COPD (564.70-451.51 pg/mL, P = 0.019) and asthma groups (386.39-332.76 pg/mL, P = 0.033), while the level of IL-8 decreased only in the asthma group (5.25-4.49 pg/mL, P = 0.023). The level of soluble cluster of differentiation-40 ligand in EBC in the COPD group increased after inhalation (1.07-1.16 pg/mL, P = 0.031), while IL-4 and IL-6 levels in EBC were significantly lower after inhalation in the COPD (0.80-0.64 pg/mL, P = 0.025) and asthma (0.06-0.05 pg/mL, P = 0.007) groups, respectively. CONCLUSIONS: A single inhalation of hydrogen for 45 minutes reduced the inflammatory status in the airways of patients with asthma and COPD.

Guan, W.J., et 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(6): p. 3448-3452.

This is the first multicentre randomised clinical trial demonstrating the efficacy and safety of H2-O2 inhalation in patients with COVID-19. The clinical benefits are likely due to the ability of H2-O2 to reduce inspiratory effort due to significantly lower resistance to airway flow compared to room air (previously verified with pulse oscillometry). Patients with COVID-19 frequently experienced dyspnoea, cough, chest pain and discomfort, and oxygen desaturation that did not improve rapidly with other existing therapies (including oxygen therapy). The therapeutic effect of H2-O2 was evident by day 2 and 3, and improvement in most respiratory symptoms persisted until the end of treatment, again not readily explained by various supportive therapies, including oxygen therapy. Heliox inhalation was reported to improve dyspnoea and reduce airway resistance in adults and children. However, due to its lower cost-effectiveness, Heliox has not been recommended for routine clinical use. H2-O2 can be generated by direct electrolysis of water using commercially available equipment, which has enabled clinical use at home and in hospitals (especially in medical settings where oxygen supply is critical). The safety profiles make H2-O2 inhalation particularly suitable for the relief of dyspnoea and other respiratory symptoms in patients with COVID-19, regardless of disease severity. Our study was limited by the open-label design and variable duration of H2-O2 inhalation due to urgency. We did not randomly assign patients with COVID-19 on the basis of urgency or match patients with propensity scores, which may have introduced selection bias. The protocol for H2-O2 inhalation was empirical and should possibly be optimised. Nevertheless, H2-O2 inhalation could be considered useful for patients with dyspnoea or for patients in facilities without adequate oxygen supply.

Alwazeer, D., F.F. Liu, X.Y. Wu, and T.W. LeBaron, Combating Oxidative Stress and Inflammation in COVID-19 by Molecular Hydrogen Therapy: Mechanisms and Perspectives. Oxid Med Cell Longev, 2021. 2021: p. 5513868.

COVID-19 is a widespread global pandemic with nearly 185 million confirmed cases and about four million deaths. It is caused by infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which primarily affects alveolar type II pneumocytes. The infection triggers pathological responses, including increased inflammation, oxidative stress and apoptosis. This leads to impaired gas exchange, hypoxia and other sequelae leading to multisystem organ failure and death. As summarised in this article, numerous interventions and therapeutics have been proposed and investigated to address the inflammation and oxidative stress triggered by viral infection, which contribute to the aetiology and pathogenesis of COVID-19. However, these methods have not significantly improved treatment outcomes. This may be due in part to their inability to restore redox and inflammatory homeostasis, to which molecular hydrogen (H(2)), a novel medical gas, may contribute. In this paper, the antioxidant, anti-inflammatory and anti-apoptotic mechanisms of H(2) are systematically investigated. Due to its small molecular size and non-polarity, H(2) can rapidly diffuse through cell membranes and enter cell organelles. H(2) has been shown to suppress NF-κB inflammatory signalling and induce the Nrf2/Keap1 antioxidant pathway, improve mitochondrial function and increase cellular bioenergetics. Numerous preclinical and clinical studies have demonstrated the beneficial effects of H(2) in various diseases, including COVID-19. However, the exact mechanisms, primary mechanisms of action and actual clinical effects remain to be described and verified. Accordingly, additional mechanistic and clinical research on this novel medical gas to combat COVID-19 complications is warranted.

Iida, A., et al., The Clinical Application of Hydrogen as a Medical Treatment. Acta Med Okayama, 2016. 70(5): p. 331-337.

In recent years, molecular hydrogen has been shown to be a particularly effective treatment for various disease models such as ischaemia-reperfusion injury; as a result, research on hydrogen has progressed rapidly. Hydrogen has been shown to be effective not only by ingestion as a gas, but also as a liquid drug taken orally, intravenously or locally. The effectiveness of hydrogen is therefore manifold. In this article, we review recent research on hydrogen-rich water and explore the possibilities of its clinical application. Now that hydrogen is in the spotlight as a gaseous signalling molecule due to its potential ability to inhibit signalling in oxidative stress, new research developments are eagerly anticipated.

M. Ostojic, Does H(2) Alter Mitochondrial Bioenergetics via GHS-R1α Activation? Theranostics 2017 Vol. 7 Issue 5 Pages 1330-1332

The above mechanisms may be at least partly responsible for the beneficial effects of H2 on diseases of animals and humans with disturbed cellular bioenergetics. From a therapeutic perspective, exogenous H2 should be evaluated as an experimental biomedical agent that could influence energy metabolism in many neurodegenerative and cardiometabolic diseases. Translating the preliminary transcriptomic findings into a cause-effect relationship between H2 and specific gene-regulated metabolic outcomes in the clinical setting remains a very warranted area for future study in the emerging field of hydrogen medicine.

Nicolson, de Mattos, G. , Settineri, R. , Costa, C. , Ellithorpe, R. , Rosenblatt, S. , La Valle, J. , Jimenez, A. and Ohta, S. Clinical Effects of Hydrogen Administration: From Animal and Human Diseases to Exercise Medicine, International Journal of Clinical Medicine 2016 Vol. 7 Pages 32-76

Here we review the literature on the effects of molecular hydrogen (H2) on normal human subjects and patients with a variety of diagnoses, including metabolic, rheumatic, cardiovascular, neurodegenerative and other diseases, infections and physical and radiation injury, as well as effects on ageing and physical activity. Although the effects of H2 have been studied in numerous animal models of human disease, these studies are not detailed here. H2 can be administered as a gas, in the form of saline implants or infusions, as topical solutions or baths, or by drinking water fortified with H2. The latter is the simplest and least expensive method of administration. There are no safety issues with hydrogen; it has been used for years in gas mixtures for deep diving and in numerous clinical trials with no adverse events, and there are no warnings in the literature about its toxicity or the effects of long-term exposure. Molecular hydrogen has been shown to be useful and practical as a novel antioxidant and as a means of affecting gene expression in many conditions where oxidative stress and changes in gene expression lead to cell damage.