Hydrogen potential therapy with clinical relevanceScientific Research

Safety of Prolonged Inhalation of Hydrogen Gas in Air in Healthy Adults
Critical Care Explorations: October 2021 – Volume 3 – Issue 10 – p e543Abstract
Background
Ischemia-reperfusion injury is common in critically ill patients, and targeted therapy is lacking. Hydrogen inhalation reduces ischemia-reperfusion injury in models of shock, stroke, and cardiac arrest. The purpose of this study was to investigate the safety of inhaled hydrogen at doses required for clinical efficacy studies.
Design
Prospective single-arm study.
Setting
Tertiary care hospital.
Patient/Subjects:
Eight healthy adult participants.
Intervention
Subjects were exposed to 2.4% hydrogen gas in medical-grade air for 24 (n=2), 48 (n=2), or 72 (n=4) hours through a high-flow nasal cannula (15 L/min) in the hospital.
Measurements and main results
Endpoints included vital signs, patient and caregiver-reported signs and symptoms (stratified by clinical significance), pulmonary function tests, 12-lead electrocardiogram, mini-mental status tests, neurological examinations, and serology before and after exposure. All adverse events were verified by two clinicians outside the study team and an external data and safety monitoring team. All eight participants (18-30 years; 50% female; 62% non-Caucasian) completed the study without early discontinuation. No patients experienced clinically meaningful adverse events. Compared with baseline measurements, vital signs, pulmonary function test results, summary mental status test results, neurological examination results, electrocardiogram measurements, or blood serology tests (except for clinically insignificant increases in hematocrit and hematocrit values). platelet count), kidney, liver, pancreas, or heart damage associated with hydrogen inhalation.
Conclusion
Inhalation of 2.4% hydrogen does not appear to cause any clinically meaningful side effects in healthy adults. Although these data suggest that inhaled hydrogen may be well tolerated, future studies are needed to further assess safety. These data will form the basis for future intervention studies of hydrogen inhalation in injured states, including after cardiac arrest.
REFERENCES
1. Chan PS, Nallamothu BK, Krumholz HM, et al. Long-term outcomes in elderly survivors of in-hospital cardiac arrest. N Engl J Med. 2013; 368:1019–10262. Moler FW, Silverstein FS, Holubkov R, et al.; THAPCA Trial Investigators. Therapeutic hypothermia after in-hospital cardiac arrest in children. N Engl J Med. 2017; 376:318–3293. Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007; 13:688–6944. Yu J, Yu Q, Liu Y, et al. Hydrogen gas alleviates oxygen toxicity by reducing hydroxyl radical levels in PC12 cells. PLoS One. 2017; 12:e01736455. Iuchi K, Imoto A, Kamimura N, et al. Molecular hydrogen regulates gene expression by modifying the free radical chain reaction-dependent generation of oxidized phospholipid mediators. Sci Rep. 2016; 6:189716. Ichihara M, Sobue S, Ito M, et al. Beneficial biological effects and the underlying mechanisms of molecular hydrogen – Comprehensive review of 321 original articles. Med Gas Res. 2015; 5:127. Hayashida K, Sano M, Kamimura N, 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:e0034598. Nagatani K, Wada K, Takeuchi S, et al. Effect of hydrogen gas on the survival rate of mice following global cerebral ischemia. Shock. 2012; 37:645–6529. Hayashida K, Sano M, Kamimura N, et al. Hydrogen inhalation during normoxic resuscitation improves neurological outcome in a rat model of cardiac arrest independently of targeted temperature management. Circulation. 2014; 130:2173–218010. Huo TT, Zeng Y, Liu XN, et al. Hydrogen-rich saline improves survival and neurological outcome after cardiac arrest and cardiopulmonary resuscitation in rats. Anesth Analg. 2014; 119:368–38011. Wang P, Jia L, Chen B, et al. Hydrogen inhalation is superior to mild hypothermia in improving cardiac function and neurological outcome in an asphyxial cardiac arrest model of rats. Shock. 2016; 46:312–31812. Chen G, Chen B, Dai C, et al. Hydrogen inhalation is superior to mild hypothermia for improving neurological outcome and survival in a cardiac arrest model of spontaneously hypertensive rat. Shock. 2018; 50:689–69513. Cole AR, Perry DA, Raza A, et al. Perioperatively inhaled hydrogen gas diminishes neurologic injury following experimental circulatory arrest in swine. JACC Basic Transl Sci. 2019; 4:176–18714. Huang JL, Liu WW, Manaenko A, et al. Hydrogen inhibits microglial activation and regulates microglial phenotype in a mouse middle cerebral artery occlusion model. Med Gas Res. 2019; 9:127–13215. Htun Y, Nakamura S, Nakao Y, et al. Hydrogen ventilation combined with mild hypothermia improves short-term neurological outcomes in a 5-day neonatal hypoxia-ischaemia piglet model. Sci Rep. 2019; 9:408816. Yu Y, Yang Y, Bian Y, et al. Hydrogen gas protects against intestinal injury in wild type but not NRF2 knockout mice with severe sepsis by regulating HO-1 and HMGB1 release. Shock. 2017; 48:364–37017. 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; 34:90–9718. Cole AR, Raza A, Ahmed H, et al. Safety of inhaled hydrogen gas in healthy mice. Med Gas Res. 2019; 9:133–13819. Tamura T, Hayashida K, Sano M, et al. Feasibility and safety of hydrogen gas inhalation for post-cardiac arrest syndrome – First-in-human pilot study. Circ J. 2016; 80:1870–187320. Ono H, Nishijima Y, Ohta S, et al. Hydrogen gas inhalation treatment in acute cerebral infarction: A randomized controlled clinical study on safety and neuroprotection. J Stroke Cerebrovasc Dis. 2017; 26:2587–259421. Katsumata Y, Sano F, Abe T, 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; 81:940–94722. Akagi J, Baba H. Hydrogen gas restores exhausted CD8+ T cells in patients with advanced colorectal cancer to improve prognosis. Oncol Rep. 2019; 41:301–31123. Chen JB, Kong XF, Mu F, et al. Hydrogen therapy can be used to control tumor progression and alleviate the adverse events of medications in patients with advanced non-small cell lung cancer. Med Gas Res. 2020; 10:75–8024. Ward JJ. High-flow oxygen administration by nasal cannula for adult and perinatal patients. Respir Care. 2013; 58:98–122