1 INTRODUCTION

COVID-19 is associated with respiratory failure and subsequent hypoxia. New therapies that reduce hypoxia are urgently needed. Molecular hydrogen therapy may reduce inflammation, oxidative stress, and hypoxia. This case report suggests that hydrogen-rich water may increase oxygen saturation and increase exercise tolerance in a patient with COVID-19-like symptoms.

Recent studies indicate that severe acute respiratory syndrome can develop from novel coronavirus (SARS-CoV-2), which may cause COVID-19.^{1, 2} The clinical features of SARS-CoV-2 infection may range from silent infection to serious illness including death.^{1, 2} The disease is associated with pneumonia and consolidation in the lower and upper lungs that lead to respiratory failure with hypoxia.^{1, 2} Computerized tomography of the thorax may reveal a ground glass appearance of lungs, indicating viral pneumonia. There is an unmet need to develop new therapies for this disease, because COVID-19 spreads rapidly, resulting in a pandemic with limited agents for treatment. In serious patients with COVID-19, respiratory failure results in hypoxia, which is characterized by a lower oxygen saturation in the blood circulation.^{1, 2} Long term consequences of COVID-19 include symptoms such as fatigue, headaches, joint pain, and dyspnea, as well as other neurological, lung, and heart damages.³ A recent WHO sponsored randomized trial following 11,330 adults across 30 countries and 405 hospitals found that the repurposed anti-viral drugs remdesivir, hydroxychloroquine, interferon, and lopinavir or the combination of interferon and lopinavir had little to no impact on mortality.⁴ High doses of cortisone have been found to be useful among these patients.⁵ Mutations to the SARS-CoV-2 virus have created uncertainties regarding some treatment options, with recent research suggesting that monoclonal antibody therapies may be less effective against the emerging Delta variant.⁶

Recently, molecular hydrogen (H₂) has been suggested for the treatment of COVID-19, due to its potential antioxidant and anti-inflammatory effects.^{1, 7-9} It is hypothesized that H₂ therapy may decrease inflammation by decreasing the cytokine storm and by reducing free radical-induced damage, which may decrease hypoxia and delay the need for oxygen therapy.^7-12 This hypothesis has led to the initiation of a large-scale multicenter trial in Europe utilizing hydrogen-producing tablets in high-risk patients undergoing ambulatory care.¹³ The concept that molecular hydrogen may be a beneficial treatment for severe COVID-19 is supported by a small trial in China that reported hydrogen inhalation was effective for reducing disease severity and dyspnea.¹⁴ Further, before undergoing this case report, the authors received private correspondence regarding the potential effectiveness of hydrogen-producing tablets in a small, randomized placebo-controlled trial with COVID-19 patients (n = 24). Administration of four hydrogen-producing tablets per day led to a significant reduction in interleukin-6 (IL-6) and fatigue (Sergej Ostojic MD, PhD, email correspondence May 7, 2021). Here, we report that molecular hydrogen, administered as hydrogen-rich water (HRW), may increase oxygen saturation in the blood circulation and increase exercise tolerance.

2 CASE REPORT

3 RESULTS

Treatment with HRW was associated with significant changes in the oxygen saturation as measured via oximeter and multipara monitor (Figure 1). Five minutes after H₂ treatment in the morning, mean oxygen saturation measured over the five-day period increased from 92.6% to 97.2%, and then slowly decreased to 96.4%, 95%, and 93.4% after 30, 45, and 60 min, respectively (Figure 1A). Evening H₂ treatment increased mean oxygen saturation from 92.6% to 96% after 5 min. After 30, 45, and 60, min mean oxygen saturation was 95.4%, 94.4%, and 92.6%, respectively (Figure 1B).

The effect of HRW treatment followed by exercise on oxygen saturation is presented in Figure 2. Regular HRW treatment with subsequent exercise increased basal oxygen saturation (measured before HRW administration) from 83% on day 1 to 90% on day 10. An additional marked increase in exercise tolerance was observed after 5, 30, 45, and 60 min on each day of the treatment, with the most prominent effect detected after 30 minutes (oxygen saturation ranged from 94% on day 1 to 96% on day 10).

4 DISCUSSION

This case report reveals that treatment with HRW was associated with a significant increase in oxygen saturation within 5 min of therapy in a patient with symptoms consistent with post-acute COVID-19-like side effects such as subacute to chronic hypoxia (Figure 1). The findings also reveal that treatment with HRW may have increased exercise tolerance from hypoxia to near normal oxygen saturation (Figure 2).

Molecular hydrogen has been shown to protect the lungs from hypoxia/re-oxygenation injury in mice by lowering free radical and inflammatory damages.¹⁶ Similar benefits were seen in a recent multicenter clinical trial utilizing hydrogen gas inhalation for chronic obstructive pulmonary disease (COPD).¹⁷ Hydrogen therapy improved breathlessness, cough, and sputum scale (BCSS) as compared to placebo. However, in this multicenter trial, there was no improvement in SpO₂ in the hydrogen group as compared to the placebo group and change from baseline. Nevertheless, there were time by group interactions with respect to the changes from baseline in SpO₂ (p < 0.0001).¹⁷ In data obtained via private correspondence, hydrogen water prepared via hydrogen-producing magnesium tablets led to significantly lower fibrinogen levels (p = 0.03), prothrombin time (p = 0.02), and INR (p = 0.03) in COVID-19 patients complicated with pneumonia, although this data set was from only five patients, so no concrete conclusions can be drawn (Sergej Ostojic MD, PhD, email correspondence May 7, 2021). Additionally, similarly prepared HRW demonstrated a significant improvement in VO₂ and various exercise indices in middle-aged overweight women after 28 days intake.¹⁸ Similarly, a lower hydrogen dosage of ~2 mg/day for 14 days also demonstrated improvements in peak oxygen uptake.¹⁹ Overall, hydrogen therapy has shown significant promise as an ergogenic agent for improved exercise performance and recovery.²⁰ No study is available on the role of hydrogen showing increased oxygen saturation among patients with hypoxia or border line lower oxygen saturation, in COVID-19 or from any other cause. Therefore, direct comparisons between this case report and the established literature are not possible.

Human studies have demonstrated that chronic consumption of hydrogen water may lower heart rate in subjects with metabolic syndrome (n = 60, 24 weeks),²¹ and acutely lower heart rate during strenuous exercise.²² Conversely another study reported that hydrogen water consumption has a heart rate raising effect in women observed at rest.²³ Importantly, molecular hydrogen has been shown to potentiate the beneficial post-infarct effects of hypoxic conditioning on rat hearts^{24, 25} and has shown to ameliorate the deleterious effects of intermittent hypoxia in rodent models.^25-29

It seems that hydrogen therapy as HRW, may be an effective and novel adjuvant treatment against acute and post-acute COVID-19. Although the exact molecular mechanism of how hydrogen therapy provides benefits to COVID-19 patients is not known, several mechanisms have previously been suggested.^7-12

Fatigue remains a common reported side effect of acute COVID-19, with chronic fatigue being reported as one of the most common side effects of post-acute COVID-19.³⁰ HRW as delivered by hydrogen-producing magnesium tablets has shown to improve alertness equivalent to caffeine in a head-to-head crossover study in young, healthy, sleep-deprived individuals (n = 23).³¹ Additionally, HRW was shown to result in a more robust stimulation of brain metabolism compared to caffeine, as measured via MRI, in a double-blinded, placebo-controlled RCT in young, healthy sleep-deprived individuals.³² Molecular hydrogen was also shown to reduce both temporary and prolonged fatigue,³³ suggesting it could be effective in eradicating post-acute COVID-19 weakness.

5 CONCLUSIONS

Treatment with HRW may enhance oxygen saturation in patients with hypoxia, as presented in this case study. Hydrogen therapy may also enhance exercise tolerance resulting in significantly lower episodes of hypoxia during physical training. It is proposed that hydrogen supplementation may produce selective anti-oxidation, anti-inflammation, anti-apoptosis, favorable gene expression alterations, and act as a therapeutic gaseous-signal modulator.

Hydrogen-rich water may exert protective effects on individuals experiencing symptoms consistent with post-acute COVID-19, whether induced by viral infection or as a rare adverse event experienced by vaccination. Well-controlled clinical trials are needed to confirm this preliminary case report.

CONFLICTS OF INTEREST

AT is involved in commercial entities with interest in the marketing of hydrogen-rich water. TWL has received travel reimbursement, honoraria, and speaking and consultancy fees from various academic and commercial entities regarding molecular hydrogen. All other authors report no conflict of interest.

AUTHOR CONTRIBUTIONS

RBS, GH, GF, and RHR were involved in concept/design and data collection. RBS, ATT, and TWL wrote the article. All authors read and approved the final version of the manuscript.

ETHICAL APPROVAL

This case report was conducted in accordance with the Declaration of Helsinki.

CONSENT

Written and signed consent of the patient was obtained in accordance with journal's consent policy.