Molecular Hydrogen Therapy for Management of COVID-19: Review by Ministry of Health of Malaysia

 This rapid assessment was prepared by the Ministry of Health to provide urgent evidence-based input during COVID-19 pandemic. The report is prepared based on information available at the time of research and a limited literature. It is not a definitive statement on the safety, effectiveness or cost effectiveness of the health technology covered. Additionally, other relevant scientific findings may have been reported since completion of this report.


molecular hydrogen COVID-19 malaysia


Introduction

Molecular hydrogen (H2) has been proposed to have therapeutic and preventive effects for variety of diseases. Its applications range from acute illness such as ischaemia–reperfusion injury, shock and damage healing to chronic illness such as metabolic syndrome, rheumatoid arthritis and neurodegenerative diseases.1 There is a growing evidence obtained by animal model experiments on molecular hydrogen (H2) as antioxidant, anti-inflammatory, antiapoptotic and antiallergic.2-9 The claimed benefits were demonstrated through various delivery methods including drinking H2 rich water, intra-peritoneal injection, infusion of H2-rich saline, taking an H2 bath, dropping H2-saline onto the eyes and inhalation.(Table 1) 5, 6, 10-15 However, inhalation of hydrogen gas has been established as the easiest and simplest route of administration. It also allows monitoring of the dose of hydrogen. As a biological gas, hydrogen has the ability to diffuse freely across biological membranes, acting in various functional capacities.16, 17

The molecular hydrogen is claimed to be beneficial in two ways in the ongoing epidemic of coronavirus disease 2019 (COVID-19); 

1. As a therapeutic antioxidant 

One of the major mechanisms the COVID-19 virus causes illness is by oxidative stress, producing breakdown products of oxygen including superoxide radical, hydrogen peroxide and hydroxyl radical, which are referred collectively as reactive oxygen species (ROS). These unstable radicals cause damage to various molecules in the body such as fats (lipid peroxidation and cell membrane damage), DNA (genetic malformations) and proteins (enzyme damage). In acute viral-induced oxidative stress, this process is accelerated and may overwhelm the innate ROS detoxification system causing both cellular and organ damage and potential failure.18, 19 Molecular hydrogen eliminates free radicals by acting as specific scavenger of highly active oxidants, hydroxyl radical (OH) and peroxynitrite (ONOO). It also indirectly reduces oxidative stress by regulating the expression of various genes.14, 20 

2. As an anti-inflammation 

Viral infection is capable of producing an excessive immune reaction in the host by stimulating massive release of cytokines. Unfortunately, at higher levels these same cytokines, in what is sometimes called ‘cytokine storm’, may cause increased inflammation in the tissues. Dysregulation of immune responses following hyper-inflammation and cytokine storm, may lead to multiple organ failure, pulmonary tissue damage (diffuse alveolar damage with inflammatory infiltration and oedema, interstitial fibrosis) and reduced lung capacity which is well-known in patients with COVID-19 infection.19, 20 Molecular hydrogen inhibits oxidative stress-induced inflammatory tissue damage via downregulation of pro-inflammatory and inflammatory cytokines. 14, 20 

Evidence on Effectiveness and Safety

Effectiveness 

Following extensive search through available scientific databases (Ovid MEDLINE, Cochrane Database, PubMed) and Google search engine, a total of 16 articles were identified and included in this review. The articles comprise of one randomized control trial (RCT) and 15 animal studies on the effectiveness of molecular hydrogen therapy as anti-inflammatory and anti-oxidant in hypoxia/re-oxygenation induced lung injury as well as sepsis related conditions. These conditions exhibit similar mechanism of illness as COVID-19. All the studies were undertaken in China 21-25, 27-36 except for one experimental animal study 26 which was conducted in Japan. Of the 16 included studies, eight studies (one RCT 21 and seven experimental animal studies 22-28) assessed the effect of hydrogen therapy on hypoxia/re-oxygenation induced lung injury caused by various lung conditions namely asthma (two studies) 23, 24, chronic obstructive pulmonary disease/ chronic injury induced by hypoxia/re-oxygenation (four studies) 21, 22, 25, 28, hyperoxic injury (one study) 26 and ventilator induced lung injury (one study) 27. The remaining eight studies examined the preventive and therapeutic applications of molecular hydrogen in the treatment of sepsis.29-36 There were three methods of molecular hydrogen therapy utilized in the experiments: inhalation of hydrogen (H2) (11 studies) 21-27, 29-32, injection of hydrogen-saturated saline (four studies) 28, 33-35 and oral intake of hydrogen-rich water (one study) 36.

Safety 

The use of inhalational hydrogen gas among patients with tracheal stenosis in one experimental study, reported no adverse reaction or inhalation related discomfort occurred.37 Safety is a primary concern with respect to H2 transportation, storage and administration. In low concentration (4.1% in pure oxygen or 4.6% in the air), hydrogen is neither explosive nor dangerous. Previous preclinical studies highlighted explosive safety concern whereby flammable gas contained in the mixed gas cannot exceed one third of the lower explosion limit (4%) and these studies were able to administer a maximum dose of 2.9% hydrogen gas. 38-40 Others thought it was safer to dissolve hydrogen into water and administer the hydrogen-rich saline by oral or by injection (41).

Conclusion

There was very limited evidence on the effectiveness of molecular hydrogen therapy. Animal studies indicated this treatment may have protective and therapeutic effects in patients with lung injury and sepsis. More clinical trials are needed to prove the clinical safety of its use and the therapeutic effects of molecular hydrogen in human subjects.


References

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2. Li J, Dong Y, Chen H et al. Protective effects of hydrogen-rich saline in a rat model of permanent focal cerebral ischemia via reducing oxidative stress and inflammatory cytokines. Brain Res. 2012;1486:103-111. 
3. Li Y, Xie K, Chen H et al. Hydrogen gas inhibits high-mobility group box 1 release in septic mice by upregulation of heme oxygenase 1. J Surg Res. 2015;196(1):136-148. 
4. Liu L, Xie K, Chen H et al. Inhalation of hydrogen gas attenuates brain injury in mice with cecal ligation and puncture via inhibiting neuroinflammation, oxidative stress and neuronal apoptosis. Brain Res. 2014;1589:78-92. 
5. Liu Y, Liu W, Sun X et al. Hydrogen saline offers neuroprotection by reducing oxidative stress in a focal cerebral ischemia-reperfusion rat model. Med Gas Res. 2011;1(1):15. 
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18. Kouhpayeh, S.; Shariati, L.; Boshtam, M.; Rahimmanesh, I.; Mirian, M.; Zeinalian, M.; Salari-jazi, A.; Khanahmad, N.; Damavandi, M.S.; Sadeghi, P.; Khanahmad, H. The Molecular Story of COVID-19; NAD+ Depletion Addresses All Questions in this Infection. Preprints2020, 2020030346 (doi: 10.20944/preprints202003.0346.v1). 
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20. Perspective of the management of COVID-19 infection in China_HHO Gas Cures Used by Prof Dr. Nanshan Zhong, Director of National Clinical Research Centre for Respiratory Disease. Available from: https://www.youtube.com/watch?v=S2n_peRIHic&feature=youtu.be . Accessed on 7 April 2020. 
21. Gong ZJ, Guan JT, Ren XZ et al. Protective effect of hydrogen on the lung of sanitation workers exposed to haze. Zhonghua Jie He He Hu Xi Za Zhi. 2016;39(12):916-923. 
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23. Huang P, Wei S, Huang W et al. Hydrogen gas inhalation enhances alveolar macrophage phagocytosis in an ovalbumin-induced asthma model. Int Immunopharmacol. 2019;74:105646. 
24. Zhang N, Deng C, Zhang X et al. Inhalation of hydrogen gas attenuates airway inflammation and oxidative stress in allergic asthmatic mice. Asthma Res Pract. 2018;4:3-3. 
25. Liu X, Ma C, Wang X et al. Hydrogen coadministration slows the development of COPD-like lung disease in a cigarette smoke-induced rat model. Int J Chron Obstruct Pulmon Dis. 2017;12:1309-1324. 26. Kawamura T, Wakabayashi N, Shigemura N et al. Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo. Am J Physiol Lung Cell Mol Physiol. 2013;304(10):L646- L656. 
27. Huang CS, Kawamura T, Lee S et al. Hydrogen inhalation ameliorates ventilator-induced lung injury. Crit Care. 2010;14(6):R234. 
28. 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. 
29. Liu W, Shan L-P, Dong X-S et al. Combined early fluid resuscitation and hydrogen inhalation attenuates lung and intestine injury. World J Gastroenterol. 2013;19(4):492-502. 
30. Xie K, Yu Y, Zhang Z et al. Hydrogen gas improves survival rate and organ damage in zymosan-induced generalized inflammation model. Shock. 2010;34(5):495-501.
31. Xie K, Yu Y, Pei Y et al. Protective effects of hydrogen gas on murine polymicrobial sepsis via reducing oxidative stress and HMGB1 release. Shock. 2010;34(1):90-97. 
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34. Chen HG, Xie KL, Han HZ et al. Heme oxygenase-1 mediates the anti-inflammatory effect of molecular hydrogen in LPS-stimulated RAW 264.7 macrophages. Int J Surg. 2013;11(10):1060-1066. 35. Li GM, Ji MH, Sun XJ et al. Effects of hydrogen-rich saline treatment on polymicrobial sepsis. J Surg Res. 2013;181(2):279-286. 
36. Zhang J, Wu Q, Song S et al. Effect of hydrogen-rich water on acute peritonitis of rat models. Int Immunopharmacol. 2014;21(1):94-101. 
37. Zhou ZQ, Zhong CH, Su ZQ et al. Breathing Hydrogen-Oxygen Mixture Decreases Inspiratory Effort in Patients with Tracheal Stenosis. Respiration. 2019;97(1):42-51. 
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Based on available evidence up to 29 May 2020

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