Effect of Hydrogen Gas on Hyperbaric Oxygen Toxicity

Effect of Hydrogen Gas on Hyperbaric Oxygen Toxicity - A Randomized Controlled Cross-Over Trial

The goal of this trial is to investigate whether adding a small fraction of hydrogen gas to an oxygen-enriched breathing mixture can reduce pulmonary oxygen toxicity (POT) in healthy and active divers from the Swedish Armed Forces. The main questions it aims to answer are:

• Does hydrogen gas reduce oxidative stress and changes in pulmonary function associated with prolonged hyperbaric oxygen exposure?
• What are the underlying pathophysiological mechanisms of pulmonary oxygen toxicity?

Researchers will compare oxygen-enriched breathing gas with 1-2% hydrogen to oxygen-enriched gas with 1-2% nitrogen (control) to see if hydrogen provides protective effects against POT during hyperbaric exposure.

Participants will:

• Complete two hyperbaric exposure sessions (hydrogen vs. nitrogen), each lasting 240 minutes at 1.75 ATA
• Undergo pulmonary function tests and sampling of blod and urin before and after each session
• Serve as their own controls in a double-blind, randomized, crossover study design

Study Overview

• Status: Not yet recruiting
• Conditions: Oxidative Stress; Hyperoxia; Oxygen Toxicity; Diving Medicine; Hydrogen-oxygen Gas; Healthy Subjects (HS); Hyperbaric Oxygen
• Intervention / Treatment: Other: Inhaled Hydrogen-Enriched Oxygen Gas; Other: Inhaled Nitrogen-Enriched Oxygen Gas

• Study Type: Interventional
• Enrollment (Estimated): 32
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Sweden
  • Karlskrona, Sweden
    • Swedish Armed Forces Diving and Naval Medicine Centre (DNC)
    • Contact: Johan Douglas, MD; Phone Number: +46; Email: johan.a.douglas@mil.se
    • Contact: Oscar Plogmark, MD; Phone Number: +46768899938; Email: oscar.plogmark@mil.se
  • Blekinge County
    • Karlskrona, Blekinge County, Sweden, 37179
      • Blekinge Institute of Technology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Military divers actively serving, aged 20-64 years
• Meeting the Swedish Armed Forces physical standards for diving

Exclusion Criteria:

• Ongoing infection or illness that may impact pulmonary function
• Use of alcohol or smoking cigarettes within 48 hours
• Diving with any breathing gas within 48 hours
• Diving with oxygen-enriched gas (100% O₂) within 2 weeks
• Use of medications that could affect oxidative stress, lung function, or neurological status
• Medical history of serious diving-related injuries or long-term complications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hydrogen Gas Intervention; In this arm, participants will undergo a single hyperbaric exposure breathing a gas mixture composed of 98-99% oxygen and 1-2% hydrogen (H₂) at a partial pressure of 1.75 ATA for 240 minutes. The intervention aims to evaluate whether hydrogen gas has protective effects against pulmonary oxygen toxicity. Pulmonary function tests and blood and urin sampling for oxidative stress biomarkers will be performed both before and after the exposure session. The order of intervention and control exposures is randomized and the study is conducted in a double-blind fashion. A washout period of at least two weeks will follow before the control	Other: Inhaled Hydrogen-Enriched Oxygen Gas; Participants will inhale a gas mixture consisting of 98-99% oxygen and 1-2% hydrogen via a breathing circuit during a single hyperbaric exposure. The exposure will be conducted at a partial pressure of 1.75 ATA for 240 minutes. The intervention aims to evaluate the protective effect of hydrogen gas against pulmonary oxygen toxicity.; Other: Inhaled Nitrogen-Enriched Oxygen Gas; Participants will inhale a gas mixture consisting of 98-99% oxygen and 1-2% nitrogen via a breathing circuit during a single hyperbaric exposure. The exposure will be conducted at a partial pressure of 1.75 ATA for 240 minutes. The intervention aims to evaluate the protective effect of hydrogen gas against pulmonary oxygen toxicity.
Active Comparator: Nitrogen Gas Control; In this arm, participants will undergo a single hyperbaric exposure breathing a gas mixture composed of 98-99% oxygen and 1-2% nitrogen (N₂) at a partial pressure of 1.75 ATA for 240 minutes. This exposure serves as the control condition and represents the standard oxygen-enriched breathing gas currently in use. Pulmonary function tests and blood and urin sampling for oxidative stress biomarkers will be performed both before and after the exposure session. Participants will be randomized to the order of exposures, and both participants and investigators will be blinded to the gas composition. A washout period of at least two weeks will follow before the intervention.	Other: Inhaled Hydrogen-Enriched Oxygen Gas; Participants will inhale a gas mixture consisting of 98-99% oxygen and 1-2% hydrogen via a breathing circuit during a single hyperbaric exposure. The exposure will be conducted at a partial pressure of 1.75 ATA for 240 minutes. The intervention aims to evaluate the protective effect of hydrogen gas against pulmonary oxygen toxicity.; Other: Inhaled Nitrogen-Enriched Oxygen Gas; Participants will inhale a gas mixture consisting of 98-99% oxygen and 1-2% nitrogen via a breathing circuit during a single hyperbaric exposure. The exposure will be conducted at a partial pressure of 1.75 ATA for 240 minutes. The intervention aims to evaluate the protective effect of hydrogen gas against pulmonary oxygen toxicity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Vital Capacity (ΔVC)	Absolute change in vital capacity (VC), calculated as the difference in liters (L) between pre-exposure and post-exposure spirometry values, measured after each hyperbaric oxygen exposure session.	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced Expiratory Volume in One Second (FEV₁)	As part of the spirometric and plethysmographic measurements, Forced Expiratory Volume in 1 second (FEV₁) will be analyzed. This represents the change (ΔFEV₁) in liters (L) between pre- and post-exposure spirometry, indicating expiratory flow capacity. Measurements follow ATS/ERS 2019 standards.	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure
Change in FEV₁/FVC ratio	As part of the spirometric and plethysmographic measurements, the ratio between Forced Expiratory Volume in 1 second and Forced Vital Capacity (FEV₁/FVC) will be calculated. The change (ΔFEV₁/FVC) is expressed as a percentage (%) to assess airflow limitation or restriction following hyperbaric oxygen exposure.	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure
Change in Forced Expiratory Flow 25-75% (FEF25-75%)	As part of the spirometric and plethysmographic measurements, the mid-expiratory flow (FEF25-75%) will be assessed. This parameter reflects the mean expiratory flow between 25% and 75% of FVC and serves as an indicator of small airway function. Values are expressed in liters per second (L/s).	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure.
Change in Peak Expiratory Flow (PEF)	As part of the spirometric and plethysmographic measurements, Peak Expiratory Flow (PEF) will be analyzed. The change (ΔPEF) represents the maximum flow achieved during forced exhalation, measured in liters per second (L/s). This outcome evaluates large airway performance.	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure.
Change in Inspiratory Capacity (IC)	As part of the spirometric and plethysmographic measurements, Inspiratory Capacity (IC) will be determined. The change (ΔIC) in liters (L) reflects the maximal volume of air that can be inspired after a normal exhalation, providing insight into potential restrictive changes following exposure.	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure.
Change in Total Lung Capacity (TLC)	As part of the spirometric and plethysmographic measurements, Total Lung Capacity (TLC) will be assessed. The change (Δ TLC) in liters (L) represents the total volume of air contained in the lungs after maximal inspiration, used to detect restrictive or hyperinflation patterns following hyperbaric oxygen exposure.	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure.
Residual Volume (Δ RV)	As part of the spirometric and plethysmographic measurements, Residual Volume (RV) will be assessed. The change (Δ RV) in liters (L) represents the volume of air remaining in the lungs after maximal exhalation, used to detect gas-trapping or hyperinflation patterns associated with pulmonary oxygen toxicity	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure.
Functional Residual Capacity (Δ FRC)	As part of the spirometric and plethysmographic measurements, Functional Residual Capacity (FRC) will be assessed. The change (Δ FRC) in liters (L) represents the volume of air remaining in the lungs at the end of a normal tidal exhalation, used to detect early alterations in lung compliance or airway closure during hyperbaric oxygen exposure.	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure.
Change in Diffusing Capacity for Carbon Monoxide (ΔDLCO)	Absolute change in lung diffusing capacity for carbon monoxide (DLCO) , measured (mmol/min/lkPa) with single-breath DLCO test before and after each exposure, to evaluate alveolar-capillary gas exchange efficiency. DLCO values are adjusted for hemoglobin levels to improve measurement accuracy.	Pre-exposure, 30-120 minutes post-exposure and 24-36 hours post-exposure.
Airway Resistance (Impulse Oscillometry, Tremoflo™)	Assessment of central and peripheral airway resistance (R5, R20, X5) using impulse oscillometry (Tremoflo™) before and after exposure. Evaluates small airway mechanics related to hyperbaric oxygen exposure with or without hydrogen supplementation. Unit of Measurement: cmH₂O·s/L	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure.
Index of Oxygen Stress (ΔiOS)	Composite index derived from impulse oscillometry (Tremoflo™) representing the mean relative change from baseline in airway impedance parameters (R5, R20, X5). The Index of Oxygen Stress (iOS) quantifies oxidative stress-related changes in small airway mechanics following hyperbaric oxygen exposure with or without hydrogen supplementation.	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure.
Change in Fractional Exhaled Nitric Oxide (ΔFeNO)	Measurement of airway inflammation and oxidative stress via fractional exhaled nitric oxide (FeNO) levels measured in parts per billion (ppb).	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure.
Change in Exhaled Breath Particle Analysis (ΔPExA)	Change in exhaled particle count and biochemical composition (lipids, proteins, coagulation factors) reflecting epithelial lining fluid alterations.	Pre-exposure and follow-up 24-36 hours post-exposure after each intervention.
Blood and Urinary Biomarkers of Oxidative Stress and Inflammation	Analysis of venous blood and urine samples for biomarkers of oxidative stress (e.g., 8-isoprostane, MDA, 8-OHdG) and inflammation (e.g., IL-6, TNF-α) to evaluate systemic effects of hyperbaric oxygen exposure with or without hydrogen supplementation. Concentrations will be quantified in standard laboratory units, for example ng/mL, pg/mL, or other equivalent measures.	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure.
Biomarkers of Neuronal Injury	Analysis of venous plasma samples for fluid biomarkers of neuronal injury (e.g., NfL, GFAP, Tau, UCH-L1) using NULISA™ or Simoa® HD-1 assay technologies, to evaluate central nervous system effects of hyperbaric oxygen exposure with or without hydrogen supplementation. Concentrations will be quantified in pg/mL.	Pre-exposure, 30-120 minutes post-exposure, and 24-36 hours post-exposure.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anthropometric Measurements (Weight, Height, Sex, Age, BMI)	Anthropometric data will be recorded to assess body composition and physical characteristics of the study population and to enable adjustment for potential confounders in pulmonary function outcomes. This includes body weight (kg), height (cm), biological sex (M/F), age (years), and body mass index (BMI). These variables will not serve as primary endpoints but will describe baseline characteristics and support interpretation of within-subject changes in lung function.	Baseline (Pre-exposure, prior to first dive session)

Collaborators and Investigators

• Sponsor: Blekinge Institute of Technology
• Collaborators: Karolinska Institutet; Lund University; Göteborg University; Swedish Armed Forces Diving and Naval Medicine Centre

Publications and helpful links

General Publications

• New Jersey hospital keeps detailed tracking records. OR Manager. 1989 Apr;5(4):8-9. No abstract available.
• Samuels BL, Vogelzang NJ, Ruane M, Simon MA. Continuous venous infusion of doxorubicin in advanced sarcomas. Cancer Treat Rep. 1987 Oct;71(10):971-2.
• Lynam C, Jennings K, Nolan K, Kane P, McKervey MA, Diamond D. Tuning and enhancing enantioselective quenching of calixarene hosts by chiral guest amines. Anal Chem. 2002 Jan 1;74(1):59-66. doi: 10.1021/ac010153k.
• 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 Jun;13(6):688-94. doi: 10.1038/nm1577. Epub 2007 May 7.

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: September 29, 2025
• First Submitted That Met QC Criteria: December 1, 2025
• First Posted (Estimated): December 4, 2025

Study Record Updates

• Last Update Posted (Estimated): December 4, 2025
• Last Update Submitted That Met QC Criteria: December 1, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Hyperbaric Oxygen; Lung Function; Human Study; Pulmonary Oxygen Toxicity; Hydrogen Gas; Diving Physiology; Military Divers
• Additional Relevant MeSH Terms: Signs and Symptoms, Respiratory; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Hyperoxia
• Other Study ID Numbers: BTH-6.1.1-0165-2025; 5005113/22FMV2951 (Other Grant/Funding Number: Swedish Armed Forces Material Administration)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No