Effect of hydrogen gas inhalation on patient QOL after hepatectomy: protocol for a randomized controlled trial

Introduction Molecular hydrogen had been considered inactive in vivo but is an antioxidant that selectively reduces highly toxic reactive oxygen species (ROS). Animal studies have reported that hydrogen gas inhalation helped alleviate cerebral and cardiac ischemia-reperfusion injuries. In humans, hydrogen inhalation therapy is presently approved as a treatment under Advanced Medical Care B in Japan (jRCTs031180352: limited to adult patients who suffered out-of-hospital cardiac arrest and are in a continuous coma) and its effectiveness is being examined in a clinical trial. The Japanese government has introduced the “Advanced Medical Care System” to promote the development of drugs and devices under governmental regulations. Advanced Medical Care B is a system designed for unapproved or off-label drugs or medical technologies used in a clinical trial setting. Hepatectomy is generally performed with repeated hepatic blood-flow occlusion and then reperfusion (ischemia and reperfusion). No report, however, has been made on ROS inhibition by hydrogen inhalation therapy or its effectiveness in post-hepatectomy patients. Hydrogen gas inhalation in the early stages after hepatectomy is anticipated to inhibit liver dysfunction by inhibiting ROS. Methods and analysis This study is a randomized, controlled, double-blind superiority trial, which will be conducted as a “specified clinical trial” in accordance with the Clinical Trials Act in Japan. Trial registration was prospectively completed before the first participant was enrolled. The subjects will be patients who will undergo hepatectomy and will be allocated randomly into group A with hydrogen gas inhalation or group B with air inhalation after hepatectomy. The study will examine if hydrogen gas inhalation improves QOL of post-hepatectomy patients. The primary endpoint is patient QOL (score of a 40-item quality of recovery questionnaire, QoR40) on postoperative day 3 and the secondary endpoints are QoR40s besides that on postoperative day 3, grade of postoperative complications (Clavien-Dindo score), level of pain (Numerical Rating Scale (NRS)), amount of dietary intake, liver function, inflammation level, 8-hydroxydeoxyguanosine (urinary 8-OHdG) level, and number of pedometer-assessed steps. Ethics and dissemination The study protocol has been approved by the Niigata University Central Review Board of Clinical Research. The findings of this study will be widely disseminated through peer-reviewed publications and conference presentations. Trial registration jRCTs 03220332. Registered on 21 January 2021

A Comparison of the Antioxidant Effects Between Hydrogen Gas Inhalation and Vitamin C Supplementation in Response to a 60-Min Treadmill Exercise in Rat Gastrocnemius Muscle

The reactive oxygen species (ROS) produced during exercise act as a double-edged sword because they may cause oxidative damage but also play a role in the signaling pathways. A supplementation of exogenous antioxidants can reduce the total amount of ROS during exercise while it may also affect the ROS’ role in the signaling pathways of mitochondrial biogenesis. It has been suggested that hydrogen gas, as an antioxidant, can selectively scavenge hydroxyl radicals but does not affect superoxide anion’s signal transduction. The aim of this study was to compare the effects of 1-h hydrogen gas inhalation 30min prior to a treadmill exercise on the key biomarkers of mitochondrial biogenesis and related signaling pathways, and the activities of endogenous antioxidant enzymes, with those of vitamin C, in the rat skeletal muscle. Eighty-one 8-week-old male Sprague–Dawley (SD) rats were randomly assigned to three interventions (exercise-only, exercise+4%H2, and exercise+vitamin C at 500mg/kg weight, with 27 rats under each intervention), and sampled at pre-, immediately post and 4h post a 60-min treadmill exercise at speed of 27m/min and flat inclination, with nine rats in each sub-group. Expression of mitochondrial biogenetic markers and related signaling molecules in gastrocnemius muscle, and concentrations of oxidative stress markers in serum were measured. Two-way ANOVA or Kruskal–Wallis analyses showed that both hydrogen inhalation and vitamin C supplementation significantly reduced serum levels of MDA immediately after exercise and AGEs 4h after exercise. The pre-exercise supplement of vitamin C significantly reduced mitochondrial complex IV concentrations and PGC-1α, NRF-1, TFAM gene expression levels compared to the pre-exercise group, but the hydrogen gas intervention did not result in a reduction in these measurements. Unlike vitamin C, hydrogen inhalation did not blunt post-exercise mitochondrial biogenetic signals, but resulted in an increase in complex IV concentration, activation of PGC-1α, and TFAM and NRF-2 gene transcription, and up-regulation of PGC-1α protein expression. The findings indicated that hydrogen gas inhalation could play the role as an effective antioxidant in response to the exercise, whilst it did not significantly affect mitochondrial biogenesis. The dose–response relationship and antioxidant effects in different types of exercise for hydrogen inhalation require further investigation.

Effect of Hydrogen Gas Inhalation on Patient QOL After Hepatectomy: Protocol for a Randomized Controlled Trial

Introduction: Molecular hydrogen had been considered inactive in vivo but is an antioxidant that selectively reduces highly toxic reactive oxygen species (ROS). Animal studies have reported that hydrogen gas inhalation helped alleviate cerebral and cardiac ischemia-reperfusion injuries. In humans, hydrogen inhalation therapy is presently approved as a treatment under Advanced Medical Care B in Japan (jRCTs031180352: limited to adult patients who suffered out-of-hospital cardiac arrest and are in a continuous coma) and its effectiveness is being examined in a clinical trial. The Japanese government has introduced the “Advanced Medical Care System” to promote the development of drugs and devices under governmental regulations. Advanced Medical Care B is a system designed for unapproved or off-label drugs or medical technologies used in a clinical trial setting. Hepatectomy is generally performed with repeated hepatic blood-flow occlusion and then reperfusion (ischemia and reperfusion). No report, however, has been made on ROS inhibition by hydrogen inhalation therapy or its effectiveness in post-hepatectomy patients. Hydrogen gas inhalation in the early stages after hepatectomy is anticipated to inhibit liver dysfunction by inhibiting ROS.Methods and analysis: This study is a randomized, controlled, double-blind trial which will be conducted as a “specified clinical trial” in accordance with the Clinical Trials Act in Japan. The subjects will be patients who will undergo hepatectomy and will be allocated randomly into group A with hydrogen gas inhalation or group B with air inhalation after hepatectomy. The study will examine if hydrogen gas inhalation improves QOL of post-hepatectomy patients. The primary endpoint is patient QOL (score of a 40-item quality of recovery questionnaire, QoR40) on postoperative day 3 and the secondary endpoints are QoR40s besides that on postoperative day 3, grade of postoperative complications (Clavien-Dindo score), level of pain (NRS: Numerical Rating Scale), amount of dietary intake, liver function, inflammation level, 8-hydroxydeoxyguanosine (urinary 8-OHdG) level, and number of pedometer-assessed steps.Ethics and dissemination: The protocol has been approved by the Niigata University Central Review Board of Clinical Research. The findings of this study will be disseminated widely through peer-reviewed publications and conference presentations.Trial registration number: jRCTs No. 03220332. Approved on 21 January 2021.