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

Molecular hydrogen (H₂) is the most abundant element in the universe but the concentration in the air at ground level is very low (0.00006 volume %) [1]. In human, however, intestinal bacteria produce a large quantity of H₂[2] and it was a common belief that the implied sufficiency and possibly continuous availability precluded any beneficial effects of the internal H₂ on human health, except perhaps in some anecdotal miracle healing water stories. Recently, however, extensive research on medical H₂ in the areas of cell biology, animal disease models and others have introduced irrefutable evidences [3, 4] that medical treatment with H₂ is feasible on human diseases. However, since H₂ exists in the close environment and in human body itself, it cannot be therapeutic to human disease unless it reaches the diseased areas much closer or directly. In that sense, delivery by the blood or vascular system from the intestine or from externally administered H₂ to the medically needed sites is essential. It is also unlikely to be therapeutic if tissue H₂ concentration (HC) after external H₂ administration remains at the same range as HC of the naturally occurring H₂. At least, the therapeutic tissue HC needs to reach the blood or tissue HC level reported by animal experiments [2]. In addition, the level should be achieved consistently each time with the external H₂ administered for the treatment. In clinical medicine, it cannot be usable unless the therapeutic HC level causes no aggravation of physiological parameters and no detrimental changes in patient’s conditions.

Since the expertise in our hospital includes treatments of ischemic cerebral disease, we are most interested in neuroprotective effects of H₂ and have treated some of these patients with H₂ after successful trials with volunteers, as has been reported elsewhere. We concluded at that time that H₂ treatment, when it was combined with other medications, provided some visible benefits to a very selective and small number of brainstem infarction patients [4].

In the present study, we intended to share basic data from our clinical experience with particular attention to the above mentioned essential factors for clinical application of H₂ treatment. HC in the arterial and venous blood during and after H₂ gas inhalation was measured with gas chromatography. For the safety evaluation, a complete set of physiological parameters was observed serially before, during and after H₂ administration and at the same time with measurement of HC in the arterial and venous blood. Although some of these data are already available in the animal experiments, we felt an additional study was needed since most of our cerebral ischemia patients belong to high age group, who have limited ability to cope with any detrimental effects of a new therapy. We also evaluated the consistency of our H₂ delivery methods by measuring the HC in the venous blood at the end of 30- min H₂ treatment on 10 patients in multiple occasions. We believe that these data are essential not only for the safety of the patients but also for objective interpretation of effects of H₂ treatment.

Thirteen patients with acute ischemic cerebral disease were involved in this study. All of the participants were provided with sufficient information regarding H₂ administration and signed a consent form which had been approved by the Nishijima hospital ethics committee, Nishijima hospital pharmacy committee and also use of the hydrogen product in the hospital had been conducted by the Nishijima Hospital Pharmacists Council and the Tokai Hokuriku District Burrow of Japanese Welfare-Labor Administration and the Pharmaceutical Affair (Regulatory Audit Section) of the Sizuoka Prefectural Administration. Before recruiting the patients to the current study, a complete PARQ conference was given to all of the patients and their family and the nature of the study was explained to them. They perfectly understood that the H₂ treatment may not provide any benefit to the patient’s condition but may help better understanding of the nature of the hydrogen treatment and may promote hydrogen research for the future and further development of cerebral ischemia treatment with hydrogen. They were also told that the study will be discontinued immediately if there occurs any sign of side effect and/or excessive discomfort and/or any other reasons for them to stop the hydrogen treatment.

A large quantity of H₂ gas is intestinally produced in human and the many animal experiments have shown some HC in the blood and tissue in a control condition without adding external H₂[7‐9].

However, in the current study, no HC in the blood was measurable by our method in the control condition where no external H₂ was administered. The internal H₂ is generated mainly in the colon by anaerobic bacteria during anaerobic metabolism as a pH dependent fermentation process [10]. Therefore, the amount of H₂ production can be minimal in fasting and at rest as has been demonstrated both in animal experiments and in clinical cases [11]. Although the intestinal H₂ production continues, the amount is reported to be only 1.6 ml/min. This can increase by 7-fold to 30-fold in various situations [1] but a large part of colonic H₂ is dissipated by three main H₂ consuming reactions (methanogenesis, sulfate reduction and acetogenesis) [12]. In addition, the residual H₂ even at the maximum volume can be exhaled by the lung rapidly [13] because of very low blood solubility of hydrogen as compared to the air and a large gas exchange up to more than 6000 ml/min in the lung in human. The discrepancy in HC in control condition between our study and reported cases may be due to our patient’s NPO (nothing by mouth) status and/or bed rest, since healthy humans do not exhale H₂ unless after food intake or in motion[1].

For the delivery of H₂ to the medically needed area, H₂ needs to be in the blood first. The presence of H₂ was well demonstrated during H₂ administration by inhalation in our cases and the level was much higher than the level associated with intravenous administration as reported previously [6]. This may suggest some advantage of H₂ gas inhalation as compared to intravenous administration of H_2-enriched solution but the inconsistency associated with facial mask inhalation has to be solved first. In unattended patients particularly with neurologically compromised condition, the facial mask was frequently not on the appropriate position when our staff returned to stop the inhalation at the end of 30-min treatment. We found that a facial mask with a tightening belt around the head and face with a one way valve lessened the inconsistency but even a valve with a very light opening pressure caused sensation of respiratory obstruction in some patients. Use of respirator assistance and even a body position [14] may have to be considered for the consistency of inhalation treatment. However, use of a small, transparent mixed gas reservoir and very low one way pressure valve in our current set up significantly decreased the respiratory irregularity. Our current H₂ mixed gas generator, made by Yoji Nishijima, M.D. was designed to provide capability of altering HC in the mixed gas reservoir at normobaric pressure, since the exact correlation between the HC in the inhaled gas and the blood level was not known at that time and also premixed H₂ cylinder at high pressure, which appears to be more convenient, was initially not allowed to bring in the hospital for the fear of possible combustive accident. Intravenous administration of the H₂- enriched IV fluid, on the other hand, appears to have practical advantages such as no need for inhalation delivery system, ease and relative comfort of the patients with more consistency, if more fluid can be given in a shorter time. However, our cerebral ischemic patients are usually in old age and many of them have some cardiopulmonary diseases and occasionally with kidney dysfunction. Fluid overload may have to be avoided on these patients. Therefore, the mode of H₂ administration for a consistent delivery has to be determined by careful evaluation of general medical condition of each patient. Simultaneous administration of H₂ inhalation and slow intravenous administration of hydrogen-enriched fluid may provide a better strategy in a difficult situation. A hasty and false conclusion that H₂ was ineffective for the treatment can be easily drawn from faulty delivery without enough H₂ in the diseased area. Therefore, a blood sample for HC at the end of inhalation may be important information not only for the consistency check but also for objective evaluation of H₂ effect. It is also important not to mix H₂ only with air in order to avoid possible hypoxia. Adding oxygen to the mixed gas certainly removes the possibility of tissue hypoxia and may provide some benefits of NBO (normobaric oxygen) treatment in the ischemic brain tissue as has been reported both in animal studies[15, 16] and in clinical cases [17]. Although no conclusive evidence regarding benefit of NBO has been established yet and increased oxygen concentration in the cerebral ischemic focus may aggravate oxidative injury of the tissue [18], H₂ immediately neutralizes hydroxyl radicals, the worst kind of the reactive oxygen species [3]. Therefore, NBO with H₂ may be an ideal combination of medical gases for the treatment of cerebral ischemia, although the beneficial effects of the components may need to be evaluated separately. No significant change in the physiological parameters during and after H₂ administration was noted except in some indices associated mainly with hyperventilation or breath holding. A majority of patients sensed no foreign smell and no subjective changes of any kind and their satisfaction was very high. In animal experiments also with H₂ inhalation under more strict and defined condition, no change in the vital signs was seen. In addition to the proven safety, the total insensibility of any appreciable effects during and after H₂ administration should qualify the H₂ treatment as an ideal treatment regimen.

Our current study suffers multiple limitations. Firstly, the number of the patients recruited for the study was rather small and comparative data with other delivery methods, such as intravenous administration or ingestion of the H₂- enriched fluid, are not sufficiently available. Since our study had a restrictive consent which required exclusion of the participant who complained of unexpected discomfort and/or dissatisfaction, prolonged data collection particularly for consistency study was difficult. A study with more stable and uniform design is required for determination of usefulness of facial mask for H₂ administration. However, with improvements on the facial mask and inhalation technique, the inconsistency associated with H₂ inhalation should be lower than ours.