Safety of Inhalation of Hydrogen GasScientific Research
Safety of Prolonged Inhalation of Hydrogen Gas in Air in Healthy Adults
Critical Care Explorations: October 2021 – Volume 3 – Issue 10 – p e543 Abstract
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.
Prospective, single-arm study.
Tertiary care hospital.
Eight healthy adult participants.
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 side effects. 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.
Inhalation of 2.4% hydrogen does not appear to cause any clinically significant 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 interventional studies of hydrogen inhalation in injured states, including after cardiac arrest.
Ischemia-reperfusion injury (IRI) leads to end-organ damage in many clinical situations, including myocardial infarction, stroke, and cardiac arrest, resulting in significant morbidity in surviving patients (1). Treatment modalities for these disorders focus on timely restoration of optimal blood flow and prevention of sequelae; therapies targeting the IRI itself are often lacking. A notable exception is targeted temperature management, which has not shown consistent therapeutic benefit in randomized controlled trials in older children and adults (2). The need for targeted therapies to treat IRI is enormous.
Hydrogen gas (i.e. molecular dihydrogen [H2]) has recently been found to have therapeutic benefits by selectively reducing hydroxyl radicals (3,4) in the body, which are responsible for the formation of excess oxygen radicals and direct damage to DNA during reperfusion injury and lipid membranes. H2 administration has been shown to reduce nuclear factor-activated T cell-activated calcium signaling (central to apoptosis), activate the NF-E2 p45-related factor 2 pathway (regulate protective proteins such as glutathione and catalase) production), and down-regulation of pro-inflammatory cytokines (eg, interleukin-1, tumor necrosis factor-a) (5,6). There are numerous preclinical studies showing that near-injury H2 inhalation causes cardiac arrest (7-12), cardiopulmonary bypass (13), stroke (3,14), hypoxic-ischemic encephalopathy (15), and sepsis (16, 17).
To date, rigorous clinical studies on the safety of H2 are lacking. Previously, our group found that mice exposed to 2.4% hydrogen in air for 72 hours had no clinically significant changes in neurological or lung function compared to controls exposed to medical air (18). In addition, numerous clinical H2 exposures have been reported in early clinical trials, including cardiac arrest (19), stroke (20), coronary reintervention (21), colorectal cancer (22), and lung cancer (23). Although adverse events were rarely reported in these studies, H2 dose and duration of H2 administration varied widely among them and were generally limited to a few hours per day. Because these patients were otherwise ill, disease-related findings could confound the identification of H2-related findings. Finally, although each of these studies was well performed, there was no reference to the rigor of good clinical practice, nor was it intended as a screening study for adverse events. The purpose of this study was to rigorously screen for adverse effects (AEs) associated with H2 exposure in healthy subjects at the dose and duration we plan to use for future efficacy studies.
Of the nine subjects examined, eight met all eligibility criteria and gave written consent. All participants completed the described study protocol without early discontinuation (Table 1). The study cohort was 20.8 ± 4.1 years old, and 50% were male. In one subject, needle displacement was observed for less than 1 hour during sleep, and the duration of exposure was extended by one hour. No environmentally harmful events occurred during the study period. No patients experienced clinically significant symptoms or side effects. In particular, there were no complaints of shortness of breath, chest tightness and wheezing or shortness of breath. In addition, no clinically significant changes (p=0.607) were detected on neurological examinations (pre- or post-exposure) or MMSE scores over time (Figure 2). During follow-up, there were no headaches, malaise, fatigue or other systemic symptoms during or after H2 exposure.
TABLE 1. – Demographics of Study Participants
Characteristics n (%) Total Enrolled Sex Male 4 (50) Female 4 (50) Ethnicity Hispanic or Latino 0 (0) Not Hispanic or Latino 8 (100) Unknown or not reported 0 (0) Race White 3 (38) Black/African American 2 (25) Asian 1 (13) Native American/Alaskan Native 0 (0) Native Hawaiian/other Pacific Islander 0 (0) Multiracial 2 (25) Other 0 (0) Unknown 0 (0) Descriptor Value Weight (kg) Mean 73.9 Median 76.7 sd 11.0 Minimum 56.7 Maximum 86.5 Age at enrollment (yr) Mean 22.1 Median 20.8 sd 4.1 Minimum 18.5 Maximum 30.7
Vital Signs and ECG
Compared with baseline findings (HFNC breathing), there were no significant changes in systolic or diastolic blood pressure, respiratory rate, or oxygen saturation over time (Supplemental Fig. 1, https://links.lww.com/CCX/A804). There was a statistically significant but clinically insignificant decrease in heart rate over time (p < 0.05). There was no evidence of ectopic rhythm or conduction abnormality in any patient on telemetry or on 12-lead ECG (Supplemental Fig. 2, https://links.lww.com/CCX/A805).
Compared with HFNC breathing, there were no changes over time in percent predicted FEV1, FVC, or FEV1/FVC ratio (Fig. 3). There was a statistically significant but clinically insignificant increase in PEFR over time during and following H2 breathing (p = 0.038).
Compared with baseline findings, there were no significant changes in WBC count. There were statistically significant but clinically insignificant pre- versus postexposure increases in hemoglobin (mean increase, 1.3 g/dL [95% CI, 0.8–1.7 g/dL]), hematocrit (mean increase, 4.0% [2.4–5.6%]), and platelet count (mean increase, 22 cells/µL [4–41 cells/µL]) (Supplemental Fig. 3 A–D, https://links.lww.com/CCX/A806). Compared with baseline findings, there were no significant changes in serum chemistry profile (Supplemental Fig. 3 E–N, https://links.lww.com/CCX/A806). There was a decrease in serum chloride by 2.0 mmol/L (0.27–3.7 mmol/L) (p = 0.0391). Similarly, there were no significant changes in hepatic or pancreatic enzymes, coagulation profile, or cardiac troponin (Supplemental Fig. 3 O–AA, https://links.lww.com/CCX/A806).
Inhaled 2.4% H2 appeared to be well tolerated with no clinically significant side effects. Compared with baseline measurements, there were no clinically significant changes in vital signs, neurological examinations, pulmonary function tests, or electrocardiographic changes, or any laboratory variable associated with H2 inhalation for up to 72 hours. Although these data suggest that inhaled H2 may be well tolerated, future studies are needed to further assess safety. These data should enable future studies of inspired H2 in the injured state.
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