Hydrogen therapy for Covid-19 acute respiratory distress syndrome (ARDS) Vaibhav Follow Mar 21 · 14 min read

Covid-19 rendering

In the cohort involving 201 patients with confirmed COVID-19 pneumonia, risk factors associated with the development of acute respiratory distress syndrome (ARDS) and progression from ARDS to death included older age, neutrophilia and organ and coagulation dysfunction. Recently, accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome and hyper inflammation. [1,2]

[Updates 27/03/2020 ]

[A] Prof. Zhong Nanshan, Chinese scientist, epidemiologist and pulmonologist who discovered the SARS coronavirus in 2003 on benefits of the oxygen-hydrogen gas mix inhalation in Chinese patients

[B] Overview of planned or ongoing studies of drugs for the treatment of COVID-19

Hydrogen-oxygen nebulizer

[C] Duried Alwazeer, Redox Research Center, Igdir Üniversitesi on Potential Cheap and effective Drug for COVID-19 https://www.researchgate.net/post/Potential_Cheap_and_effective_Drug_for_COVID-19

Given the theory that molecular hydrogen can significantly down-regulate expressions of inflammation-related genes and selectively reduce hydroxyl radical, there are reasons to believe that cytokine storm and oxidative stress can be suppressed by hydrogen when getting infected with CoVid-19 [8,9]

Hydrogen, a non-cytotoxic molecule, is one of nature’s most simple elements. Recent studies revealed that intraperitoneal injection of hydrogen-rich saline has surprising anti-inflammation, anti-oxidant, anti-apoptosis effects and protected organism against polymicrobial sepsis injury, acute peritonitis injury both by reducing oxidative stress and via decreasing mass pro-inflammatory responses. [3,4,8,9]

Studies have shown that suppressing the cytokine storm and reducing oxidative stress can significantly alleviate the symptoms of influenza and other severe viral infections diseases [5,6,7]

Proposed Hydrogen Therapy

There are several methods to ingest or consume H2; inhaling H2 gas, drinking H2-dissolved water (H2-water), injecting H2-dissolved saline (H2-saline), taking an H2 bath, or dropping H2-saline into the eyes. [11]

It would be recommended to administer a dilute (3%) hydrogen/oxy-hydrogen gas mixed with ambient air (i.e 1:33:: H2 volume: ambient air at NTP) or (1:33:: oxygen-hydrogen volume: ambient air) via inhalation route to suppress the CoVid-19 virus symptoms at its entry point. Ono et al. suggest the following H2 inhalation routine “The H2 treatment group inhaled 3% H2 gas for 1 hour twice a day for 7 days through a regular non-rebreathing facial mask” for their study on Acute Cerebral Infarction[10]. In the ERS video Prof. Zhong Nanshan proposes a hydrogen-oxygen gas mix in the following concentration (H2/O2: 66.6%/33.3%).

[Comment from the author- At very high concentrations in air, hydrogen is a simple asphyxiant gas because of its ability to displace oxygen and cause hypoxia (ACGIH 1991). Hydrogen has no other known toxic activity. https://www.nap.edu/read/12032/chapter/9

Methods of Preparation

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620630/ ]

List of Human Studies

http://www.molecularhydrogeninstitute.com/human-studies

Decentralized Hydrogen Gas Generation at Point of Care

Since the number of Covid cases is growing exponentially and there aren’t enough ventilators ($ 10000–$20000) available due to supply chain issues, we need an economic and scalable solution. A water electrolyser system generating hydrogen-oxygen gas mixture by distilled water electrolysis would be effective. Generally, these kind of systems are available in the market from $ 100 to $1000 with cheaper ones sold as brown gas/HHO generators (they aren’t medical-grade and use a catalyst NaOH/KOH) to commercial hydrogen generator available on Alibaba using solid polymer electrolyte (SPE) membrane and titanium electrodes with pure water as the electrolyte.

What’s required: A medical-grade system that utilizes electricity to generate oxygen-hydrogen / hydrogen gas using stainless steel (316/318) or better titanium coated electrodes and distilled water for hydrogen therapy for Covid-19 patients.

In case sufficient ventilators are available, a hydrogen cylinder can be attached to dispense mixed H2/O2 gas at required concentration and pressure.

Excerpt from WHO China Office “ Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional 7th Edition) “ https://www.chinalawtranslate.com/en/coronavirus-treatment-plan-7/ (2) General treatment. 1. Treatment for mild cases includes bed rest, supportive treatments, and maintenance of caloric intake. Pay attention to fluid and electrolyte balance and maintain homeostasis. Closely monitor the patient’s vitals and oxygen saturation. 2. As indicated by clinical presentations, monitor the hematology panel, routine urinalysis, CRP, biochemistry (liver enzymes, cardiac enzymes, kidney function), coagulation, arterial blood gas analysis, chest radiography, and so on. Cytokines can be tested if possible.

3. Administer effective oxygenation measures promptly, including nasal catheter, oxygen mask, and high flow nasal cannula. If conditions allow, a hydrogen-oxygen gas mix (H2/O2: 66.6%/33.3%) may be used for breathing.

[Comment from the author- The report doesn’t mention if (H2/O2: 66.6%/33.3%) the mole ratio of gases produced on electrolysis of water inhaled in same concentration or further diluted with ambient air/oxygen ]

4. Antiviral therapies: Interferon-alpha (adult: 5 million units or equivalent can be added to 2ml sterile injection water and delivered with a nebulizer twice daily), lopinavir/ritonavir (adult: 200mg/50mg/tablet, 2 tablets twice daily; the length of treatment should not exceed 10 days), ribavirin (recommended in combination with interferon or lopinavir/ritonavir, adult: 500mg twice or three times daily via IV, the length of treatment should not exceed 10 days), chloroquine phosphate (adult 18–65 years old weighing more than 50kg: 500mg twice daily for 7 days; bodyweight less than 50kg: 500mg twice daily for day 1 and 2, 500mg once daily for day 3 through 7); umifenovir (adult: 200mg three times daily; the length of treatment should not exceed 10 days).

References

1) Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. Published online March 13, 2020. DOI:10.1001/jamainternmed.2020.0994

2) Mehta, Puja et al., COVID-19: consider cytokine storm syndromes and immunosuppression, The Lancet (https://doi.org/10.1016/S0140-6736(20)30628-0)

3) Taohong Hu, Ming Yang, Zheng Zhang. (2017) Hydrogen Medicine Therapy: An Effective and Promising Novel Treatment for Multiple Organ Dysfunction Syndrome (MODS) Induced by Influenza and Other Viral Infections Diseases?SOJ Microbiol Infect Dis 5(2): 1–6

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

5) Sordillo PP, Helson L. Curcumin suppression of cytokine release and cytokine storm. A potential therapy for patients with Ebola and other severe viral infections. In Vivo. 2015;29(1):1–4.

6) Zhao S, Mei K, Qian L, Yang Y, Liu W, Huang Y, et al. Therapeutic effects of hydrogen-rich solution on aplastic anaemia in vivo. Cell Physiol Biochem. 2013;32(3):549–560. DOI: 10.1159/000354459

7) Xia C, Liu W, Zeng D, Zhu L, Sun X. Effect of hydrogen-rich water on oxidative stress, liver function, and viral load in patients with chronic hepatitis B. Clin Transl Sci. 2013;6(5):372–375. DOI: 10.1111/ cts.12076

8) 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

9) Ohno K, Ito M, Ichihara M. Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases. Oxidative medicine and cellular longevity. 2012;2012:353152.

10) Ono, H., Nishijima, Y., Ohta, S., Sakamoto, M., Kinone, K., Horikosi, T., Takanami, H. (2017). Hydrogen Gas Inhalation Treatment in Acute Cerebral Infarction: A Randomized Controlled Clinical Study on Safety and Neuroprotection. Journal of Stroke and Cerebrovascular Diseases, 26(11), 2587–2594. doi:10.1016/j.jstrokecerebrovasdis.2017.06.012

11) Shigeo Ohta,Chapter Fifteen — Molecular Hydrogen as a Novel Antioxidant: Overview of the Advantages of Hydrogen for Medical Applications,Methods in Enzymology, Academic Press,

Volume 555, 2015,Pages 289–317, https://doi.org/10.1016/bs.mie.2014.11.038.

Here is the link to all the research papers

https://drive.google.com/drive/folders/1_GGFW2YWmhiXhO-pVNjV2xglWOw7cmwP?usp=sharing

Hydrogen therapy-related research carried over the years.

Available at NCBI https://www.ncbi.nlm.nih.gov/

1. Hydrogen protects lung from hypoxia/reoxygenation injury by reducing hydroxyl radical production and inhibiting inflammatory responses

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964155/

Conclusion:

In this study, its found that mice exposed to chronic H/R exhibited significant lung injury, which was significantly improved by 4% H2 inhalation.

H2 treatment inhibited the generation of hydroxyl radicals and down-regulated GM-CSF and G-CSF, which may attenuate infiltration by neutrophils and M1 macrophages, as well as the release of pro-inflammatory factors. H2 may also protect the progenitor cells by inactivating hydroxyl radicals.

Studies have shown that CSFs, especially GM-CSF, aggravate inflammation by enhancing proinflammatory cytokine production and mobilizing leukocytes, promoting their survival, proliferation, differentiation, and stimulating their activation and migration.

2. Hydrogen coadministration slows the development of COPD-like lung disease in a cigarette smoke-induced rat model

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422326/

Conclusion:

Hydrogen coadministration reduces the infiltration of inflammatory cells in a cigarette smoke-induced rat model. The number of total white blood cells, neutrophil granulocytes, and macrophages were significantly increased in the BALF of the COPD group (all P<0.01). Compared with the COPD group, these cells were decreased in the Hl, Hm, and Hh groups (P<0.01 or P<0.05).

Hydrogen coadministration ameliorates ultrastructural changes of the lung in a cigarette smoke-induced rat model. SEM observations showed alveolar septa with a smooth surface with no fracture in the control group. The alveoli were well inflated; there was no alveolar hemorrhage, exudation, or inflammatory cell infiltration present. Compared with the control group, the alveolar septum in the COPD group was thinner and showed a subsequent fracture.

3. Protection by Inhaled Hydrogen Therapy in a Rat Model of Acute Lung Injury Can Be Tracked In vivo Using Molecular Imaging

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636640/

Conclusion:

The study detects and tracks the anti-oxidant and anti-apoptotic properties of H2 therapy in vivo and to demonstrate protection after as early as 24 hrs of hyperoxia exposure. The results demonstrate the ability of the two molecular biomarkers 99mTc-HMPAO and 99mTc-duramycin to quantify lung injury and the response to H2 treatment in vivo in rats exposed to hyperoxia as a model of human ALI/ARDS.

Several gaseous therapies have been evaluated for hyperoxia-induced ALI/ARDS, including nitric oxide (NO), carbon monoxide (CO), and H2. Like NO and CO, H2 is highly permeable across various cellular barriers and hence capable of accessing key cellular compartments such as mitochondrion which appear to play a key role in the pathogenesis of human ALI/ARDS. However, H2 is advantageous since it does not affect the physiological or immune response of key ROS (superoxide and hydrogen peroxide). Moreover, H2 is not toxic at high concentrations and is safe at concentrations < 4.1% when mixed with O2

4. Inhalation of hydrogen gas attenuates airway inflammation and oxidative stress in allergic asthmatic mice

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856384/

Conclusion:

The study concluded that inhalation of hydrogen gas protects against asthma in mouse models by improving lung function, ameliorating mucus production and decreasing inflammation and oxidative stress markers.

Meanwhile, hydrogen gas inhalation decreased the level of the typical Th2-type cytokines IL-4 and IL-13 in BALF and/or in serum; these cytokines are the two major mediators responsible for the eosinophil recruitment, airway function decreases and mucus hypersecretion. Inhibition of these cytokines could be used to partially explain the simultaneous airway resistance decrease and pathophysiologic inflammatory cell accumulation in pulmonary tissues and BALF.

5. Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652058/

Conclusion:

The study suggests that hydrogen protects against hyperoxic lung injury both by decreasing the extent of oxidative injury caused by ROS, perhaps through hydrogen’s free radical scavenging activities, and by inducing Nrf2-dependent protective signalling pathways.

One possible explanation for the protective role of HO-1 induced by hydrogen seen in our study may be a removal of free heme. HO-1 degrades heme, which, when released from damaged cells, is highly lipophilic and detrimental. Free heme not only directly induces tissue injury of the lung cells but is also a major source of iron, which generates highly detrimental hydroxyl radicals through the Fenton reaction

6. Hydrogen-rich saline inhibits tobacco smoke-induced chronic obstructive pulmonary disease by alleviating airway inflammation and mucus hypersecretion in rats

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648294/

Conclusion:

The data indicated hydrogen-rich saline can improve pulmonary function and mitigate lung pathological impairment in COPD rats, the curative mechanism is probably related to alleviating inflammation, reducing oxidative stress and lessening mucus hypersecretion.

It has been confirmed that chronic inflammation in airway and lung tissue occurs in all the stages of COPD, in which the release of multiple cytokines plays an important role. IL-8 is a potent attractant for neutrophils and has been demonstrated to be responsible for acute exacerbation and disease progression of COPD.

7. Protective effect of hydrogen on the lung of sanitation workers exposed to haze

Source: https://www.ncbi.nlm.nih.gov/pubmed/27938540

Conclusion:

The treatment group inhaled H2∶O2 mixture (66.67%∶33.33%) 1 hour per day for 30 days, while the control group inhaled N2∶O2 mixture (66.67%∶33.33%) 1 hour per day for 30 days.

Inhalation of hydrogen gas could alleviate airway inflammation and oxidative stress of sanitation workers exposed to air pollution. There was even a significant inhibitory effect on the level of systemic inflammatory response. Importantly, inhalation of hydrogen could improve respiratory symptoms such as cough.

8. Molecular hydrogen: a preventive and therapeutic medical gas for various diseases

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731988/

Conclusion:

Evidence suggests that H2 treatment protects against myocardial injury and development of atherosclerosis and other vascular diseases.

H2 administration also has been shown to effectively treat stress-associated gastric mucosa damage and aspirin-induced gastric lesions

H2 treatment is beneficial in treating diverse respiratory system diseases. HS injection is protective against acute pulmonary I/R injury in rat and rabbit models via anti-oxidative, anti-inflammatory, and anti-apoptotic mechanisms.

Studies have also shown that H2 improves lung injuries induced by many other factors, such as hyperoxia, lipopolysaccharides, smoke inhalation, paraquat, monocrotaline, and extensive burns.

9. Anti-inflammatory and antitumor action of hydrogen via reactive oxygen species

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096066/

Conclusion:

H2 reduces the risk of lifestyle-related oxidative stress by reacting with strong reactive oxygen/nitrogen species in cell-free reactions. It is easy to apply H2 in cases of oxidative stress, inflammation and tumours. Due to the lack of adverse effects and the high efficacy for the majority of pathogenic statuses involved, H2 gas, H2 water and HS are increasingly being accepted as promising candidates for therapeutic approaches.

10. A New Approach for the Prevention and Treatment of Cardiovascular Disorders. Molecular Hydrogen Significantly Reduces the Effects of Oxidative Stress

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600250/

Conclusion:

H2 has been demonstrated to reduce the expression of several pro-inflammatory mediators and markers of oxidative stress and apoptosis including TNF-α, IL-6, IL-1β, IL-10, IL-12, chemokine ligand 2 (CCL2), intercellular adhesion molecule 1, NF-κB, nuclear factor of activated T-cells (NFAT), high mobility group box 1 protein, prostaglandin E2, cyclooxygenase-2 (COX2), serum diamine oxidase, tissue MDA, protein carbonyl, TBARs, myeloperoxidase activity, JNK, and caspase-3 bringing their levels within or preventing their levels from diverging away from normal the homeostatic range

The favourable chemical, physical and biological properties of H2 qualify it as an excellent candidate for the prevention and treatment of I/R injury. Gut microbiota-derived H2 slightly, but significantly, reduces myocardial infarct size

H2 administered to excised cardiac grafts during cold preservation significantly reduced cold-induced I/R injury in grafts from syngeneic older donors and in allografts subjected to extended cold storage.

11. Therapeutic efficacy of hydrogen-rich saline alone and in combination with PI3K inhibitor in non-small cell lung cancer

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072234/

Conclusion:

The study initially applied hydrogen-rich saline alone to lung cancer cells. Subsequently, the effect of hydrogen-rich saline on apoptosis and inflammatory cytokines, and the pathway involved in this process, was investigated. The results demonstrated the following:

i) Hydrogen-rich saline treatment alone inhibited A549 cell proliferation;

ii) Hydrogen-rich saline treatment alone decreased MDA expression and increased SOD activity;

iii) Hydrogen-rich saline treatment alone induced A549 cell apoptosis;

iv) In in vitro experiment, treatment with hydrogen significantly suppressed the effect on protein and mRNA expression of HO-1 and NF-κB p65 in A549 cell and

v) Hydrogen-rich saline suppressed the expression of p-Akt and the expression levels of HO-1 and p65.

12. Hydrogen Attenuates Allergic Inflammation by Reversing Energy Metabolic Pathway Switch

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005324/

Conclusion:

Allergic airway inflammation is associated with an energy metabolic pathway switch from mitochondrial oxidative phosphorylation to aerobic glycolysis.

H2 reverses this metabolic pathway switch and mitigates allergic airway inflammation. H2 appears to regulate the allergic inflammation-associated energy metabolic pathway switch by multiple mechanisms. H2 directly inhibits glycolytic enzyme activities and stimulates mitochondrial OXPHOS enzyme activities.

H2 acts at upstream regulatory elements and regulates co-factor production in the energy metabolism regulation pathways, reversing the upregulation of glycolytic enzyme activities and the downregulation of OXPHOS enzyme activities, and energy metabolic pathway switch. The data uncover a novel mechanism that H2 mitigates allergic airway inflammation by reversing the energy metabolic pathway switch.

13. Effects of hydrogen-rich saline on early acute kidney injury in severely burned rats by suppressing oxidative stress-induced apoptosis and inflammation

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467622/

Conclusion:

The study first demonstrated the protective effects of H2 against early AKI following severe burn in rats. The beneficial effects of this treatment are a result of its ability to relieve oxidative stress, apoptosis and inflammation and may be mediated by the complex modulation of the MAPKs, Akt and NF-κB signalling pathways.

14. Hydrogen Gas Presents a Promising Therapeutic Strategy for Sepsis

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009185/

Conclusion:

Hydrogen is electronically neutral and has favourable distribution characteristics: it can penetrate biomembranes and diffuse into the cytosol, mitochondria, and nucleus. Despite the moderate reduction activity of H2, its rapid gaseous diffusion might make it highly effective for reducing cytotoxic radicals. Besides, it stands to reason that H2 will react with only the strongest oxidants. H2 is mild enough not to disturb metabolic oxidation-reduction reactions or to disrupt ROS involved in cell signalling — unlike some antioxidant supplements with strong reductive reactivity, which increase mortality, possibly by affecting essential defensive mechanisms.

Thus, H2 treatment is advantageous for medical procedures without serious unwanted side effects. Furthermore, H2 is neither inflammable nor explosive at low concentrations (<4.6% in air and 4.1% in pure oxygen). Moreover, only 2% hydrogen gas can have obvious protective effects on sepsis. Meanwhile, hydrogen-rich saline is also available and safe for medical applications.

15. Hydrogen inhalation ameliorates ventilator-induced lung injury

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219999/

Conclusion:

In this study, its demonstrated that administration of hydrogen gas mitigated VILI and VILI-associated oxidative and inflammatory responses as well as VILI-induced apoptotic cell death of bronchial epithelial cells. This is the first study to demonstrate that hydrogen gas significantly reduces VILI. Since VILI is a major concern with intensive care, approaches to minimize VILI will advance critical care medicine and could have substantial clinical impact.

16. Molecular Hydrogen Therapy Ameliorates Organ Damage Induced by Sepsis

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931094/

Conclusion:

Molecular hydrogen therapy has a protective effect on sepsis, which has been proved by pathological biopsy, level of inflammatory factors/anti-inflammatory factors, oxidative stress reaction, behavioural experiment, and other related indicators of organ function. Although there is a dispute of affections of molecular hydrogen therapy in liver and kidney, the mainstream view shows molecular hydrogen therapy is benefit to organs, such as brain, lung, liver, kidney, and small intestine.

Molecular hydrogen therapy combining with oxygen therapy or fluid resuscitation can reduce oxygen free radical damage, the amount of fluid and vasoactive drugs, and the overload of liquid. As a result, molecular hydrogen therapy may reduce the complications of oxygen therapy and fluid resuscitation.

However, most of the study conclusion came from animal experiment while reports of clinical research were rare. Much more clinical evidence is still demanded.

In conclusion, molecular hydrogen therapy is a promising method to alleviate organ damage, improve outcome, and reduce mortality rate in sepsis.

H2 Discussion with Dr. Ohta, July 2017

More studies available at http://www.molecularhydrogeninstitute.com/studies