A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level

Hirohisa Ono, Yoji Nishijima, Naoto Adachi, Masaki Sakamoto, Yohei Kudo, Kumi Kaneko, Atsunori Nakao, Takashi Imaoka, Hirohisa Ono, Yoji Nishijima, Naoto Adachi, Masaki Sakamoto, Yohei Kudo, Kumi Kaneko, Atsunori Nakao, Takashi Imaoka

Abstract

Background: In animal experiments, use of molecular hydrogen ( H2) has been regarded as quite safe and effective, showing benefits in multiple pathological conditions such as ischemia-reperfusion injury of the brain, heart, kidney and transplanted tissues, traumatic and surgical injury of the brain and spinal cord, inflammation of intestine and lung , degenerative striatonigral tissue and also in many other situations. However, since cerebral ischemia patients are in old age group, the safety information needs to be confirmed. For the feasibility of H2 treatment in these patients, delivery of H2 by inhalation method needs to be checked for consistency.

Methods: Hydrogen concentration (HC) in the arterial and venous blood was measured by gas chromatography on 3 patients, before, during and after 4% (case 1) and 3% (case2,3) H2 gas inhalation with simultaneous monitoring of physiological parameters. For a consistency study, HC in the venous blood of 10 patients were obtained on multiple occasions at the end of 30-min H2 inhalation treatment.

Results: The HC gradually reached a plateau level in 20 min after H2 inhalation in the blood, which was equivalent to the level reported by animal experiments. The HC rapidly decreased to 10% of the plateau level in about 6 min and 18 min in arterial and venous blood, respectively after H2 inhalation was discontinued. Physiological parameters on these 3 patients were essentially unchanged by use of hydrogen. The consistency study of 10 patients showed the HC at the end of 30-min inhalation treatment was quite variable but the inconsistency improved with more attention and encouragement.

Conclusion: H2 inhalation of at least 3% concentration for 30 min delivered enough HC, equivalent to the animal experiment levels, in the blood without compromising the safety. However, the consistency of H2 delivery by inhalation needs to be improved.

Figures

Figure 1
Figure 1
Hydrogen concentration (HC) in the blood before, during and after hydrogen (H2) inhalation. HC (micromol/L) in the arterial(red) and venous (blue) blood before (5 min. before), during (0-30min.) and after (30 min to 60 min) H2 gas inhalation. Case1 (square marks) inhaled 4% H2 gas and case 2 (triangle marks) and case 3 (round marks) inhaled 3% H2 gas. The HC at the plateau level reached the equivalent values reported in the successful animal experiments. Presence of a hump in the descending venous blood concentration curve may indicate the source of extra H2, coming out of slow blood flow/slow release compartments such as muscle and skin.
Figure 2
Figure 2
Physiological parameters before, during and after Hydrogen (H2) inhalation. Physiological parameters of case 1, before (5 min before), during (0-30min) and after (30 min to 60 min-) inhalation of H2 (4% in air), obtained simultaneously with the measurement of blood HC as in the Figure 1. These parameters and close clinical observation showed no significant changes except some indices related to respiration pattern such as hyperventilation or breath holding which were commonly seen among neurologically compromised patients with normal conscious level.
Figure 3
Figure 3
Inconsistency of blood HC after initial H2inhalation and subsequent improvement with more attention. HC in the venous blood varied widely, ranged from less than 1 microM to 25 microM/L on the first day of 30-min H2 inhalation. After closer observation at bedside and encouragement, the HC level and consistency improved. In two patients (Case No.8 and10) with pulmonary disease, the initial low HC significantly improved with simultaneous slow intravenous infusion of H2 enriched saline solution (from 1.2 to 12.1 microM/L in case No.8, from 0.5 to 8.2 microM/L in case No.10).

References

    1. Glueckauf E, Kitt G. The hydrogen content of atmospheric air at ground level. Quart J Royal Met Society. 1957;83:522–528. doi: 10.1002/qj.49708335808.
    1. Levitt MD. Production and excretion of hydrogen gas in man. N Eng J Med. 1969;281:122–127. doi: 10.1056/NEJM196907172810303.
    1. Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688–694. doi: 10.1038/nm1577.
    1. Eckermann S, Kraft PR, Shoemaker L, Lieberson RE, Chang SD, Colohan A. Potential application of hydrogen in traumatic and surgical brain injury, stroke and Neonatal hypoxia-ischemia. Mrdical Gas Research. 2012;2:12–20. doi: 10.1186/2045-9912-2-12.
    1. Ono H, Nishijima Y, Adachi N, Tachibana S, Chitoku S, Mukaihara S, Sakamoto M, Kudo Y, Nakazawa J, Kaneko K, Nawashiro H. Improved brain MRI indices in the acute brain stem infarct sites treated with hydroxyl radical scavengers, Edaravone and hydrogen as compared to Edaravone alone, A non-randamized study. Medical Gas Research. 2011;1:12–20. doi: 10.1186/2045-9912-1-12.
    1. Ono H, Nishijima Y, Adachi N, Tachibana S, Chitoku S, Mukaihara S, Sakamoto M, Kudo Y, Nakazawa J, Kaneko K, Nakao A. Hydrogen(H2) treatment for acute erythematous skin diseases. A report of 4 patients with safety data and a non-controlled feasibility study with H2 concentration measurement on two volunteers. Medical gas Research. 2012;2:14. doi: 10.1186/2045-9912-2-14.
    1. Nagata K, Nakashima-Kamimura N, Mikami T, Ohsawa I, Ohta S. Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsychopharmacology. 2009;34:501–508. doi: 10.1038/npp.2008.95.
    1. Nakashima-Kamimura N, Mori T, Ohsawa I, Asoh S, Ohta S. Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Cancer Chemother Pharmacol. 2009;64:753–761. doi: 10.1007/s00280-008-0924-2.
    1. Cardinal JS, Zhan J, Wang Y, Sugimoto R, Tsung A, McCurry KR, Billar R, Nakao A. Oral administration of hydrogen water prevents chronic allograft nephropathy in rat renal transplantation. Kidney Int. 2010;77:101–109. doi: 10.1038/ki.2009.421.
    1. Perman JA, Modler S, Olson AC. Role of pH in production of hydrogen from arbohydrates by colonic bacterial flora. Studies in vivo and in vitro. J Clin Invest. 1981;67:643–650. doi: 10.1172/JCI110079.
    1. Eisenmann A, Amann A, Said M, Datta B, Ledochowski M. Implementation and interpretation of hydrogen breath test. J Breath Res. 2008;2:1–9.
    1. Hertzler SR, Savaiano DA, Levitt MD. Fecal hydrogen production and consumption measurements. Response to daily lactose ingestion by lactose maldigesters. Dig Dis Sci. 1997;42:348–353. doi: 10.1023/A:1018822103911.
    1. Christl SU, Murgatroyd PR, Gibson GR, Cummings JH. Production, metabolism, and excretion of hydrogen in the large intestine. astroenterology. 1992;102:1269–1277.
    1. Kagaya M, Iwata M, Toda Y, Nakae Y, Kondo T. Circadian rhythm of breath hydrogen in young women. J Gastroenterol. 1998;33:472–476. doi: 10.1007/s005350050117.
    1. Henninger N, Bouley J, Nelligan JM, Sicard KM, Fisher M. Normobaric hyperoxia delays perfusion/diffusion mismatch evolution, reduces infarct volume, and differentially affects neuronal cell death pathways after suture middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab. 2007;27:1632–1642. doi: 10.1038/sj.jcbfm.9600463.
    1. Wenlan L, Qingquan C, Jie L, Ke Jian L. Normobaric hyperoxia protects the blood brain barrier through inhibiting Nox2 containing NADPH oxydase in ischemic stroke. Medical Gas Research. 2011;1:22–30. doi: 10.1186/2045-9912-1-22.
    1. Singhal AB, Benner T, Roccatagliata L, Koroshetz WJ, Schaefer PW, Lo EH. et al.A pilot study of normobaric oxygen therapy in acute ischemic stroke. Stroke. 2005;36:797–802. doi: 10.1161/01.STR.0000158914.66827.2e.
    1. Cornet AD, Kooter AJ, Mike JL P. Supplemental oxygen therapy in medical emergencies: More harm than benefit? Arch Intern Med. 2012;172(3):289–290. doi: 10.1001/archinternmed.2011.624.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi