Short Communication

J Clin Med Res. 2020;12(10):674-680

Low-Flow Nasal Cannula Hydrogen Therapy
Motoaki Sanoa, b, d, Kohsuke Shirakawaa, b, Yoshinori Katsumataa, b,
Genki Ichiharaa, b, Eiji Kobayashia, b, c

Abstract
Background: Molecular hydrogen (H2) is a biologically active gas thatis widely used in the healthcare sector. In recent years, on-site H2 gas
generators, which produce high-purity H2 by water electrolysis, have begun to be introduced in hospitals, clinics, beauty salons, and fitness clubs
because of their ease of use. In general, these generators produce H2 at a
low-flow rate, so physicians are concerned that an effective blood concentration of H2 may not be ensured when the gas is delivered through anasal cannula. Therefore, this study aimed to evaluate blood concentrations of H2 delivered from an H2 gas generator via a nasal cannula.
Methods: We administered 100% H2, produced by an H2 gas generator, at a low-flow rate of 250 mL/min via a nasal cannula to threespontaneously breathing micro miniature pigs. An oxygen mask wasplaced over the nasal cannula to administer oxygen while minimizing
H2 leakage, and a catheter was inserted into the carotid artery to monitor the arterial blood H2 concentration.
Results: During the first hour of H2 inhalation, the mean (standard
error (SE)) H2 concentrations and saturations in the arterial blood of
the three pigs were 1,560 (413) nL/mL and 8.85% (2.34%); 1,190(102) nL/mL and 6.74% (0.58%); and 1,740 (181) nL/mL and 9.88%(1.03%), respectively. These values are comparable to the concentration one would expect if 100% of the H2 released from the H2 gas
generator is taken up by the body.
Conclusions: Inhalation of 100% H2 produced by an H2 gas generator, even at low-flow rates, can increase blood H2 concentrations
to levels that previous non-clinical and clinical studies demonstrated
to be therapeutically effective. The combination of a nasal cannulaand an oxygen mask is a convenient way to reduce H2 leakage while
maintaining oxygenation.
Manuscript submitted August 12, 2020, accepted August 21, 2020
Published online September 21, 2020
aDepartment of Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanbCenter for Molecular Hydrogen Medicine, Keio University, 2-15-45 Mita,
Minato-ku, Tokyo 108-8345, Japan
cDepartment of Organ Fabrication, Keio University School of Medicine, 35
Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapandCorresponding Author: Motoaki Sano, Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582,
Japan. Email: msano@a8.keio.jp

doi: https://doi.org/10.14740/jocmr4323

674

Keywords: Hydrogen gas; Pharmacokinetics; Hydrogen gas inhaler;
Hydrogen gas generator; Micro miniature pig; Combined oxygenmasks with nasal cannula; COVID-19

Introduction
Molecular hydrogen (H2) has a wide range of benefits, ranging from improving health to preventing and treating disease.
The health benefits include improving mood, reducing anxiety,and counteracting an overactive sympathetic nervous system[1]. In terms of disease prevention and treatment, H2 has beenused to treat many diseases, including lifestyle diseases [2];immune diseases, such as atopic dermatitis [2], hay fever [3],and chronic rheumatoid arthritis [4]; respiratory diseases, suchas asthma [5], chronic obstructive pulmonary disease [6], andpneumonia caused by the coronavirus disease 2019 (COVID-19) [7]; neurological diseases, such as depression [8], dementia [9], stroke [10], post-cardiac arrest syndrome [11, 12],subarachnoid hemorrhage [13], and traumatic injury fromblast shock waves [14]; myocardial infarction [15-17]; chronic
kidney disease [18]; sepsis [19] and hemorrhagic shock [20,21]; and cancer [22].
H2 exerts antioxidant and anti-inflammatory effects. As amolecular mechanism, ex vivo experiments have been shownthat H2 reduces hydroxyl radical (·OH) and peroxynitrite [10]and suppresses the propagation of the radical reaction in lipid
bilayers [23]. Clinical and animal studies have shown that H2
therapy reduces circulating levels of oxidative stress markers
and proinflammatory cytokines in shock from a wide range of
etiologies [11, 24].
H2 can be supplied from a high-pressure gas cylinder [11,12, 15-17], generated from a hydrogen-absorbing alloy [25,26] or hydride, or produced by electrolysis of water [7]. In
recent years, on-site H2 gas generators, which generate highpurity H2 by electrolysis of water, have begun to be introduced
in hospitals, clinics, beauty salons, and fitness clubs because of
their ease of handling.
Recently, the results of a clinical study on the therapeutic
effect of H2 inhalation in COVID-19 pneumonia were reported
from China [7]. In this study, the researchers used an H2 gas
generator as the source of H2 and administered a mixture of H2and oxygen (O2) gas (66% H2; 33% O2), obtained by electrolysis of water, by a nasal cannula. An improvement in clinicalsymptoms was seen in a significantly higher percentage of patients in the treatment group, who inhaled a mixture of H2 andArticles © The authors | Journal compilation © J Clin Med Res and Elmer Press Inc™ | www.jocmr.org
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J Clin Med Res. 2020;12(10):674-680

O2, than in patients in the control group, who received classic
oxygen therapy.
Because the H2 produced from an on-site H2 gas generator has a low-flow rate, clinicians are concerned that when H2
is inhaled through a nasal cannula, blood concentrations may
be lower than expected because of leakage of H2 from thenostrils. We hypothesized that the H2 concentration could bebetter ensured if patients wore an oxygen mask over the nasal
cannula. Therefore, we tested this hypothesis in pigs, whoseorgans are similar in size, anatomy, and physiology to thoseof humans.

H2 gas generator

Materials and Methods

The length of the part of the nasal cannula (Nakamura Medical
Industry Co., Ltd.) that is inserted into the nostrils was modified from the original 12 mm to 62 mm by inserting a 10-mm
silicon tube with a total length of 60 mm, an outer diameterof 3 mm, and an inner diameter of 1.5 mm into the left andright outlets. We then adjusted the nostril inserts of the nasal
cannula to fit the shape of a pig’s nose. The nasal cannula wasinserted deep into the nasal cavity of a pig under spontaneous
breathing, and 100% H2 produced from the H2 gas generator
was administered at a flow rate of 250 mL/min (Fig. 1).
A veterinary anesthesia mask (Shinano ManufacturingCo., Ltd.) was placed over the nasal cannula and an ADS 1000
(model: 2000) veterinary anesthesia delivery system (Tokushima Iryoki Co., Ltd.) was used to deliver a mixture of O2 andisoflurane (Fig. 2). The flow rate of the O2/isoflurane gas mixture was maintained above 6 L/min to avoid re-inhalation of
exhaled carbon dioxide (CO2) that would stay in the mask.

Animals
The present study was designed according to the principlesof the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines [27]. The experiments were performedin accordance with our institutional guidelines and with theJapanese law on the protection and management of animals.
Ethical approval was granted by the Research Council andAnimal Care and Use Committee of Keio University (approvalno: 12094-(8)).
The study was performed in three micro miniature pigs,
weighing 16.8 kg, 15.5 kg, and 16.8 kg, which were housed inseparate cages under temperature- and light-controlled conditions (12-h light/dark cycle) and provided with food and water
ad libitum (Supplementary Material 1, www.jocmr.org). Before surgery, the pigs were fasted for 12 h, with free access towater. Then, a xylazine hydrochloride intramuscular injection
was given 15 min before induction of isoflurane anesthesia.
Experiments were performed under anesthesia, and isoflurane
was administered to maintain immobilization.
Catheter insertion
First, a central venous catheter (14 gauge × 70 cm; Argyle)equipped with a three-way stopcock (TERUMO terufusion
three-way stopcock, R type) was filled with heparinized saline. Once at a sufficient depth of anesthesia, each pig wasplaced in the supine position. A vertical incision of about 10
cm was made in the right side of the neck to expose about
3 cm of the right external jugular vein and the right internal carotid artery. The peripheral side of the right internal
carotid artery was ligated with a 1-0 silk thread, a bulldog
clip was applied to the medial side, an incision was made,and a catheter was advanced about 5 cm into the artery andsecured. Surgery was performed by the senior author of thispaper (EK), a surgeon who has completed more than 200
clinical transplant operations and is a steering member of thetransplantation society and a permanent director of the transplantation society of Japan. Blood was collected from the intravascular catheters at 0, 10, 30, and 60 min after starting H2inhalation, and the blood H2 concentration was measured bygas chromatography.

This study used the H2 inhaler H2JI1, manufactured by Doctors Man Co, Ltd. The inhaler uses a proton-exchange membrane (PEM) water electrolysis system that can continuously
generate high purity (> 99.999%) H2 at a flow rate of 250 mL/min, 24 h a day, 365 days a year (Supplementary Material 2,
www.jocmr.org).
H2 inhalation

Measurement of H2 concentration
To measure the blood H2 concentration, we first inserted a needle into the rubber lid of a 13.5-mL sealed vial, extracted 1
mL of air and injected 1 mL of blood. To prevent outgassing,
we immediately applied wax to the rubber lid to seal the injection hole. H2 in the blood was released into the air phasein the closed vial. Some of the air phase (0.2 mL, 0.4 mL,or 1 mL, depending on the H2 concentration) was collectedfrom the vial, and the H2 concentration was measured by gas
chromatography (TRIlyzer mBA-3000, Taiyo, Co., Ltd.). A
calibration curve was obtained by using standard H2 gas of0, 5, 50, and 130 ppm. Each sample was measured twice. The
concentration of the sample taken before H2 inhalation was
subtracted as the background [26].

Results
In all three pigs, the blood H2 concentrations in the carotid
arteries before inhalation were almost 0, reached peak levels
by 10 min after the start of inhalation and remained at approximately the same level until 60 min later. The means (standard error (SE)) of the H2 concentrations and saturations in the
blood from the carotid arteries during H2 inhalation in the threepigs were 1,560 (413) nL/mL and 8.85% (2.34%); 1,190 (102)nL/mL and 6.74% (0.58%); and 1,740 (181 nL/mL) and 9.88%

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J Clin Med Res. 2020;12(10):674-680

Figure 1. Hydrogen gas (H2) supply system from an H2 gas generator. (a) Specifications of H2 gas generator. The H2 gas generator is capable of continuously administering 100% H2 at a flow rate of 250 mL/min, 24 h a day, 365 days a year. (b) Structure of theelectrolyzer. The electrolysis reaction occurs in an electrolyzer, which consists of two electrodes separated by an ion exchange
membrane. When voltage is continuously applied to the electrodes in the electrolyzer, two electrons are removed from a watermolecule at the anode (negative electrode) to form one oxygen molecule (O2) and four hydrogen ions. The O2 is safely released
into the atmosphere, and the four hydrogen ions pass through the ion exchange membrane and are attracted to the cathode. At
the cathode (positive electrode), electrons are combined with hydrogen ions to produce hydrogen gas (H2).

(1.03%), respectively (Fig. 3 and Supplementary Material 3,
www.jocmr.org).
We calculated the fraction of inspiratory H2 from the H2flow rate produced by the H2 gas generator, as follows: The H2flow rate per second was 250/60 mL, so at a respiratory rate of
20 breaths per minute, the expected volume of H2 that would
accumulate in the nasopharynx during 3-s inhalation time andexhalation was 250/60 mL × 3 = 12.5 mL. If H2 was inhaled
without leakage from the nostrils, the fraction of inspiratory H2would be 12.5/150 = 0.083, or 8.3% at a tidal volume of 150
mL. In short, the measured H2 concentration (saturation) in thearterial blood agreed closely with the expected value predicted676

from the H2 gas generator’s flow rate.

Discussion
In this experiment to establish a methodology for efficiently
delivering 100% H2 with an on-site H2 gas generator, we administered H2 to three pigs through a nasal cannula with an
oxygen mask worn over it. Our study showed that an effective
blood H2 concentration can be achieved even with the lowflow rates of the H2 gas generator.
The H2JI1 H2 gas generator used in this study consistently

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Figure 2. Nasal cannula and oxygen mask for micro miniature pigs. The length of the part of the nasal cannula that is inserted
into the nostrils was modified from the original 12 mm to 62 mm by inserting a 10-mm silicon tube. The nasal cannula wasthen inserted deep into the nasal cavity of a spontaneously breathing pig, and 100% H2 produced by the H2 gas generator wasadministered at a flow rate of 250 mL/min. A veterinary anesthesia mask was placed over the nasal cannula, and a veterinary
anesthesia delivery system was used to supply oxygen and anesthesia to the animals.

supplies 100% H2 with a purity greater than 99.999% at a flowrate of 250 mL/min. If such a generator is used to administer
H2 to a human, at a tidal volume of 500 mL and 20 breaths per

minute the expected inspired H2 concentration would be 2.5%.
This concentration would be even higher in the elderly, whohave a lower tidal volume.

Figure 3. Carotid artery hydrogen (H2) concentration in three micro miniature pigs (MMP1 - 3) during H2 inhalation. The concentration of H2 when it is completely dissolved in water is 17,600 nL/mL. Therefore, H2 saturation was determined by dividing themeasured value (concentration) by 17,600 nL/mL.

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In our previous clinical study to evaluate the safety andefficacy of H2 inhalation in patients with ST-segment elevation
myocardial infarction [17], we delivered H2 via high-pressurecompressed gas cylinders containing a mixture of H2 (1.3%),
O2, nitrogen, and mixed gases through a mask at a high-flowrate of 10 L/min. We chose this flow rate to ensure that theconcentration of inhaled H2 was 1.3% because this concentration was confirmed to be effective in reducing infarct size inpreclinical studies in dogs [16]. The High-Pressure Gas Safety
Act stipulates that when O2 and H2 are mixed under pressure,the H2 concentration must be no greater than 1.3%. In the present study, we found that even though the flow of 100% H2generated on site by the H2 gas generator was low, if H2 wasadministered by a nasal cannula covered with an oxygen mask
the arterial blood H2 saturation levels increased to the samelevels as when high-flow 1.3% H2 was administered fromcompressed gas high-pressure cylinders.
The H2 gas generator is lightweight and portable and canprovide H2 anywhere, as long as a power source and pure water
are available. Furthermore, the generator can supply H2 continuously for a long time. The generator represents a safe andconvenient alternative to high-pressure gas cylinders for H2
inhalation therapy and requires no replenishment of supplies.
For example, installing an H2 gas generator at the bedside ofa patient with COVID-19 pneumonia with hypoxemia allows
the patient to consistently inhale H2 through a nasal cannula. In
addition, a suitable mask (face mask, face mask with reservoir,
or Venturi mask) can be worn over the nasal cannula, depending on the patient’s level of oxygenation. Using this method,a patient can continuously inhale H2 until the pneumonia is
cured and the patient is discharged from the hospital. Similarly, patients with mild cases of COVID-19 who are waiting
outside a hospital can be given H2 inhalation to prevent theirillness becoming more severe.
Although some people experience a headache after inhaling H2, probably due to the dilatation of intracranial blood vessels, no other obvious symptoms are known that could be considered adverse events. Unlike the other bioactive gases, suchas nitric oxide (NO), carbon monoxide (CO), and hydrogensulfide (H2S), H2 does not bind to the heme in the hemoglobinin the red blood cells. Therefore, the O2 saturation and the partial pressures of O2 and CO2 in arterial blood are unaffected by
the inhalation of H2 under steady-state conditions [15].
H2 is the most abundant element in the universe, but it must
be produced because it does not occur naturally in a gaseousstate on Earth. H2 has been used in laboratories for a variety
of applications, including gas chromatography and inductively
coupled plasma-mass spectrometry. In addition, it is used in
the chemical industry to synthesize ammonia, cyclohexane,
and methanol, and in the food industry to hydrogenate oils to
make them more solid. Recently, it has been gaining attention
as a clean energy source. The best way to produce high-purity
H2 on demand is by electrolysis of water. A noteworthy innovation in this technology was water electrolysis with solid
polymer electrolyte membranes proposed by General Electricin the early 1970s. Subsequent significant research and development led to a technology for efficiently and stably generating high-purity H2 from pure water 24 h a day, 365 days a year.
This method for generating H2, which has been cultivated by678

J Clin Med Res. 2020;12(10):674-680
the industry for a long time, has found many uses in humans.
The H2 gas generator H2JI1 that we used in our experiments
also uses a polymer electrolyte membrane with a durability ofmore than 50,000 h. The amount of H2 that remains in thisdevice is small, so safety is guaranteed. Also, the device is not
subject to the High-Pressure Gas Safety Act. Although the hydrogen gas generator itself is expensive, the durability of theelectrolytic cells is long and the running costs are almost zero.
Therefore, the cost per hour is as low as less than $0.47.
Of course, both high-pressure gas cylinders and H2 gas
generators must be used appropriately, depending on a patient’s situation. When administering H2 via a ventilator, physicians should choose high-pressure gas cylinders capable ofdelivering high-flow rates of gas. However, if physicians wish
to administer H2 continuously over a long period of time to patients who are breathing spontaneously, we propose that theyshould consider using a H2 gas generator that can safely produce low-flow but 100% H2 on-site.
Not much time has passed since O2 inhalation began to be
used in medical settings. First, O2 was widely used in industries such as welding and cutting because it supports combustion, but during 1918 - 1920 physicians starting using O2 totreat the “Spanish flu.” Citizens rushed to industrial O2 supply
companies and queued all night waiting for O2 to arrive. In
light of the current COVID-19 pandemic, we propose that now
is the time to reconsider the benefits of H2 inhalation therapy.

Supplementary Material
Suppl 1. Overview of the Micro Miniature Pigs Used in theExperiments.
Suppl 2. Specifications of the Hydrogen Gas Generator H2JI1.
Suppl 3. Mean Hydrogen (H2) Concentration in the Carotid
Artery of Three Micro Miniature pigs (MMP1 - 3).

Acknowledgments
The authors are grateful to Suga Kato ((Japanese Molecular Hydrogen Promotion Association (JHyPA)) and Mayumi
Takeda (JHyPA) for technical assistance.

Financial DisclosureThis work was supported by grants from Doctors Man Co.,
Ltd. The funders had no role in the study design, data collection and analysis, the decision to publish, or preparation of themanuscript.

Conflict of Interest
MS and EK receive advisory fees and research fees from Doctors Man Co., Ltd. MS receives advisory fees and research feesfrom Taiyo Nippon Sanso. The authors would like to declare

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J Clin Med Res. 2020;12(10):674-680

the following patents/patent applications associated with thisresearch: Author MS is the registered inventor of the following patents jointly filed by Keio University and Taiyo Nippon
Sanso: hydrogen mixed gas supply device for medical purposes (patent number: 5631524), medicinal composition forimproving prognosis after restart of patient’s own heartbeat,and medicinal composition for improving and/or stabilizing
circulatory dynamics after onset of hemorrhagic shock. In addition to these, there are three other patents in which the nameof the inventions are only in Japanese and not described in
English. Here are the names of the inventions, which are literaltranslation of Japanese into English: pharmaceutical compositions for reducing weight loss after organ harvesting (Joint
application with Keio University and Taiyo Nippon Sanso),
method for generating organ preservation solution containinghydrogen and organ preservation solution containing hydrogen(Joint application with Keio University and Doctors Man; Application number PCT/JP2019/045790). This does not alter ouradherence to Journal of Clinical Medicine Research policies
on sharing data and materials.

5.

6.

7.

8.
9.

Informed Consent
Not applicable.

10.

Author Contributions
MS designed the study, oversaw data collection, reviewed theliterature, analyzed and interpreted the data, and drafted themanuscript. EK contributed to the design of the study, engaged
in data collection and provided critical reviews of the manuscript. KS, YK, and GI contributed to data collection and provided critical reviews of the manuscript.

11.

12.

Data Availability
The authors declare that data supporting the findings of thisstudy are available within the article.

13.

References
1.

2.

3.

4.

Mizuno K, Sasaki AT, Ebisu K, Tajima K, Kajimoto O,
Nojima J, Kuratsune H, et al. Hydrogen-rich water for
improvements of mood, anxiety, and autonomic nerve
function in daily life. Med Gas Res. 2017;7(4):247-255.
Yoon YS, Sajo ME, Ignacio RM, Kim SK, Kim CS,
Lee KJ. Positive Effects of hydrogen water on 2,4-dinitrochlorobenzene-induced atopic dermatitis in NC/Nga
mice. Biol Pharm Bull. 2014;37(9):1480-1485.
Fang S, Li X, Wei X, Zhang Y, Ma Z, Wei Y, Wang
W. Beneficial effects of hydrogen gas inhalation ona murine model of allergic rhinitis. Exp Ther Med.
2018;16(6):5178-5184.
Ishibashi T, Sato B, Rikitake M, Seo T, Kurokawa R,

14.

15.

16.

Hara Y, Naritomi Y, et al. Consumption of water containing a high concentration of molecular hydrogen reduces
oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study. Med Gas Res.
2012;2(1):27.
Zhang N, Deng C, Zhang X, Zhang J, Bai C. Inhalation ofhydrogen gas attenuates airway inflammation and oxidative stress in allergic asthmatic mice. Asthma Res Pract.
2018;4:3.
Lu W, Li D, Hu J, Mei H, Shu J, Long Z, Yuan L, etal. Hydrogen gas inhalation protects against cigarettesmoke-induced COPD development in mice. J Thorac
Dis. 2018;10(6):3232-3243.
Guan WJ, Wei CH, Chen AL, Sun XC, Guo GY, Zou X,
Shi JD, et al. Hydrogen/oxygen mixed gas inhalation
improves disease severity and dyspnea in patients withCoronavirus disease 2019 in a recent multicenter, openlabel clinical trial. J Thorac Dis. 2020;12(6):3448-3452.
Zhang Y, Su WJ, Chen Y, Wu TY, Gong H, Shen XL,Wang YX, et al. Effects of hydrogen-rich water on depressive-like behavior in mice. Sci Rep. 2016;6:23742.
Li J, Wang C, Zhang JH, Cai JM, Cao YP, Sun XJ. Hydrogen-rich saline improves memory function in a rat modelof amyloid-beta-induced Alzheimer's disease by reduction of oxidative stress. Brain Res. 2010;1328:152-161.
Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, et al. Hydrogen acts as atherapeutic antioxidant by selectively reducing cytotoxic
oxygen radicals. Nat Med. 2007;13(6):688-694.
Hayashida K, Sano M, Kamimura N, Yokota T, Suzuki
M, Maekawa Y, Kawamura A, 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.
Hayashida K, Sano M, Kamimura N, Yokota T, Suzuki M,
Ohta S, Fukuda K, 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):21732180.
Kumagai K, Toyooka T, Takeuchi S, Otani N, Wada K,
Tomiyama A, Mori K. Hydrogen gas inhalation improvesdelayed brain injury by alleviating early brain injury after experimental subarachnoid hemorrhage. Sci Rep.
2020;10(1):12319.
Satoh Y, Araki Y, Kashitani M, Nishii K, Kobayashi Y,
Fujita M, Suzuki S, et al. Molecular hydrogen preventssocial deficits and depression-like behaviors induced by
low-intensity blast in mice. J Neuropathol Exp Neurol.
2018;77(9):827-836.
Hayashida K, Sano M, Ohsawa I, Shinmura K, Tamaki K, Kimura K, Endo J, et al. Inhalation of hydrogengas reduces infarct size in the rat model of myocardialischemia-reperfusion injury. Biochem Biophys Res Commun. 2008;373(1):30-35.
Yoshida A, Asanuma H, Sasaki H, Sanada S, Yamazaki S,
Asano Y, Shinozaki Y, et al. H(2) mediates cardioprotection via involvements of K(ATP) channels and permeability transition pores of mitochondria in dogs. Cardiovasc

Articles © The authors | Journal compilation © J Clin Med Res and Elmer Press Inc™ | www.jocmr.org

679

Low-Flow Hydrogen Therapy
Drugs Ther. 2012;26(3):217-226.
17. Katsumata Y, Sano F, Abe T, Tamura T, Fujisawa T, Shiraishi Y, Kohsaka S, 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):940-947.
18. Chen J, Zhang H, Hu J, Gu Y, Shen Z, Xu L, Jia X, etal. Hydrogen-rich saline alleviates kidney fibrosis following AKI and retains klotho expression. Front Pharmacol.
2017;8:499.
19. Qiu P, Liu Y, Zhang J. Recent advances in studies
of molecular hydrogen against sepsis. Int J Biol Sci.
2019;15(6):1261-1275.
20. Matsuoka T, Suzuki M, Sano M, Hayashida K, Tamura T,
Homma K, Fukuda K, 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):469-475.
21. Tamura T, Sano M, Matsuoka T, Yoshizawa J, Yamamoto
R, Katsumata Y, Endo J, et al. Hydrogen gas inhalation
attenuates endothelial glycocalyx damage and stabilizes
hemodynamics in a rat hemorrhagic shock model. Shock.
2020;54(3):377-385.
22. Li S, Liao R, Sheng X, Luo X, Zhang X, Wen X, Zhou

680

J Clin Med Res. 2020;12(10):674-680

23.

24.

25.

26.

27.

J, et al. Hydrogen gas in cancer treatment. Front Oncol.
2019;9:696.
Iuchi K, Imoto A, Kamimura N, Nishimaki K, Ichimiya
H, Yokota T, Ohta S. Molecular hydrogen regulates gene
expression by modifying the free radical chain reactiondependent generation of oxidized phospholipid mediators. Sci Rep. 2016;6:18971.
Tamura T, Suzuki M, Hayashida K, Kobayashi Y, Yoshizawa J, Shibusawa T, Sano M, et al. Hydrogen gas inhalation alleviates oxidative stress in patients with post-cardiac arrest syndrome. J Clin Biochem Nutr. 2020; Epubahead of print.
Kobayashi E, Sano M. Organ preservation solution
containing dissolved hydrogen gas from a hydrogenabsorbing alloy canister improves function of transplanted ischemic kidneys in miniature pigs. PLoS One.
2019;14(10):e0222863.
Sano M, Ichihara G, Katsumata Y, Hiraide T, Hirai A,
Momoi M, Tamura T, et al. Pharmacokinetics of a single inhalation of hydrogen gas in pigs. PLoS One.
2020;15(6):e0234626.
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the
ARRIVE guidelines for reporting animal research. PLoS
Biol. 2010;8(6):e1000412.

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