Article Information

Cordélia Salomez-Ihl^1,2*, Joris Giai³, Mathieu Roustit³, François Boucher¹, Philippe Cinquin^1,2, Jean-Paul Brion⁴

¹Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, CHU Grenoble Alpes, TIMC, UMR5525, 38000 Grenoble, France

²Université Grenoble Alpes, CHU Grenoble Alpes, Department of Pharmacy, 38000 Grenoble, France

³Université Grenoble Alpes, Inserm, CHU Grenoble Alpes, CIC1406, 38000 Grenoble, France

⁴CHU Grenoble Alpes, Department of Infectious and Tropical Diseases, 38000 Grenoble, France

*Corresponding author: Cordélia Salomez-Ihl, Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, CHU Grenoble Alpes, TIMC, UMR5525, 38000 Grenoble, France.

Received: 14 June 2024; Accepted: 20 June 2024; Published: 05 September 2024

Citation: Cordélia Salomez-Ihl, Joris Giai, Mathieu Roustit, François Boucher, Philippe Cinquin, Jean-Paul Brion. Dihydrogen inhalation in the Management of Patients with Moderate Oxygen- Requiring COVID19: Towards an Innovative Therapy. Archives of Clinical and Biomedical Research. 8 (2024): 343-346.

Abstract

Keywords

COVID 19; Anti-inflammatory Agents; Non-Steroidal; Inhalation

Article Details

1. Introduction

Coronavirus Disease 2019 (Covid-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has led to millions of deaths since its discovery in China in November 2019 [1]. The primary manifestation is severe and potentially fatal lung damage, often associated with a significant release of cytokines (particularly interleukins IL-6, IL-8, and IL-10) due to macrophagic activation, primarily at the pulmonary level. Immunization access varies widely globally, emphasizing the crucial need for ongoing research into therapeutic strategies [2].

Hyperbaric molecular hydrogen (H₂) inhalation was initially explored in the 1970s for potential cancer treatment, with the first atmospheric pressure experimental study conducted in 2007 on a rat model of cerebral infarction [3]. Subsequent research, such as that by Ito et al. [4], revealed that H₂ inhibits inflammation-related intracellular signaling pathways independently of its anti-free radical effects.

Xie et al. [5] demonstrated that two 60-minute sessions of inhaling a gaseous mixture containing 2% H₂ effectively limited multiple organ damage and reduced mortality in a mouse model of generalized inflammation [5]. Their research further revealed that H2 inhalation restored the PaO₂ / FiO₂ ratio in both a mouse model of sepsis induced by cecal ligation [6] and a model of lung damage induced by lipopolysaccharides [7]. Furthermore, although there is no reason to expect an anti-viral effect, H₂ has been identified as a factor attenuating the considerable inflammatory stress exerted on the lung parenchyma during Covid-19 [8].

Early use in conjunction with nasal oxygen therapy has shown promise in preventing respiratory deterioration. Regarding administration, various methods have been explored, with the most prevalent being the ingestion of hydrogen-enriched water and the inhalation of a gaseous mixture. Due to hydrogen's high flammability (for concentrations exceeding 4.1% in the air), recent gas mixtures have typically maintained H₂ levels between 2% and 4% [9,10].

Our ongoing phase one study assesses the safety and Dose Limiting Toxicity (DLT) of H₂ therapy delivered via a nasal cannula in addition to conventional oxygen therapy for Covid-19 patients requiring nasal oxygen (1 to 6 L/min). We present two cases from this study demonstrating the tangible benefits of inhaled H₂.

2. Case History or Examination

On September 03, 2021, a 56-year-old man was admitted in infectious diseases department for a moderate Covid-19 infection. He did not show previous diseases, was not a smoker and had a Body Mass Index of 29. He had no significant medical history. Symptoms had begun 10 days before admission. They consisted in fever (39°C), chills, anosmia, agueusia, asthenia and weight loss (5 kg). The first specific Polymerase Chain Reaction (PCR), done on 03/12/2021, was positive with English variant. C-Reactive Protein (CRP) test was high (185 mg/L), arterial gasometry showed before H₂ therapy a significant hypoxemia with adjunction of 4L/min O₂ by nasal canula (pO₂: 8,41 kPa with normal values (NV): 9,50-13,30; pCO₂: 4,98 kPa with NV: 4,70-6,10, pH: 7,44 with NV : 7,37-7,45 and bicarbonates : 24,5 mmol/L with normal values : 21,0-26,0). CT lung imaging is shown in Figure 1.

Figure 1: CT lung imaging.

Concerning thoracic auscultation, crackles were found on both sides of the lung. The respiratory frequency was about 30 cycles per minute. Concerning chest X ray, performed on the day of admission, it showed multiple opacities, with infiltration confirmed by CT scan on the same day, which also highlighted extension of infiltrates to 50%, which suggests a severe pulmonary disease, as represented in Figure 2.

Figure 2: Chest x-ray.

Figure 3: CT lung imaging.

On April 6^th 2021, a second patient was admitted to emergencies. She was 59 years old and had no specific medical history other than hypertension, treated with Lercanidipine. She was hemodynamically and respiratory stable, despite 89% saturation on room air, with a positive Covic-19 PCR. Symptoms had begun 8 days before admission She had respiratory alkalosis with mild hypoxemia (p0₂: 69.8mmHg; pC0₂:36.2mmHg; pH:7.46). She also had a biological inflammatory syndrome (CRP 69 mg/L), without hyperleukocytosis. D-Dimer were elevated at 1.02 mg/L. Troponin was 8 ng/L and BNP was 245 ng/L.

Concerning medical imaging, she had a typical Covid-19 infection, with extensive infiltration of lung parenchyma (25 - 50%), superinfection of both bases (figure 3), without additional pulmonary embolism (Figure 3).

3. Methods

An original medical delivery device has been designed by our team and has undergone a risk analysis by an independent organization. This device includes a flow regulator (a CE-marked medical device for clinical trials) allowing to guarantee a fixed flow of 1 L/min of a specific medical grade gas mixture (3,6% H₂; 96.4% N₂), manufactured and supplied by AIR PRODUCTS, packaged in B50 type cylinders. The gas mixture is combined with O₂ from the oxygen outlet of the wall (adapted to the needs of the patient in accordance to standard of care).

Patient 1 and 2 were both included in H₂ protocol for a three days treatment. They both received the usual standard of care during their hospitalization. They also required treatment with corticosteroids 0.6mg/kg for 5 days, then at half-dose for the following 5 days, combined with preventive anticoagulation. O₂ flow for these two patients was between 3 and 4 L/min, to achieve a target of 95% of O₂ saturation.

4. Results and Conclusion

Tolerance was excellent for both patients, with no adverse effect. Concerning patient 1, the clinical evolution during exposition was correct with improvement of hypoxemia and a decrease of CRP (33mg/L at the end of the 3 days of H₂-therapy). Three months later the patient was examined for a control visit. He was well and did not show any respiratory symptom. Concerning patient 2, clinical evolution during exposition was correct with improvement of hypoxemia and a decrease of CRP (on 14^th April, CRP returned to a normal value of 0 mg/L.) Hemoglobin was at 128 g/L, with no hyperleukocytosis, thrombocytosis was 591 Giga/L, neutrophils was 7.9 Giga/L. Given the good clinical and biological evolution, the patient was discharged on April 15, seven days after onset of H2-therapy.

5. Discussion

The clinical and biological observations of these clinical cases are consistent with the literature, considering that H₂ has been described as able to reduce lung injury and thus to reduce the number of critically ill patients [11]. Another review of the literature has indicated that H₂ may directly access lung tissue through respiratory activities, providing anti-inflammatory effects at various stages of the inflammatory response. This helps alleviate airway damage caused by the excessive activation of inflammatory cells and the substantial release of inflammatory factors [12]. Furthermore, in the context of Covid-19 related pulmonary injury, the activation of resident alveolar macrophages has resulted in the release of potent proinflammatory mediators and chemokines, fostering the accumulation of neutrophils and monocytes. Inhaled H₂ exhibits a non-specific anti-inflammatory impact on macrophages, neutrophils, and lymphocytes, while also inhibiting the production of reactive oxygen species (ROS) [13].
When we initiated this research, the only established therapies demonstrating effectiveness were anti-inflammatory compounds like corticosteroids. Nevertheless, their application has not been without side effects. The use of H₂ to address COVID-19 was initially proposed only in the Chinese recommendations [14,15]. Subsequently, a Chinese research team reported results in 2020 from an open-label clinical trial demonstrating efficacy. The trial involved administering a mixture comprising 67% H₂ and 33% O₂, showing statistically significant improvements in both clinical and biological parameters [16]. Our results seem to point in the same direction as this study, but our methodology does not involve use of very inflammable gas mixtures. Indeed, although our methodology does not allow us to test hypotheses of efficacy, clinicians were genuinely impressed by the positive evolution of all patients who had received hydrogen therapy. For example, at the same time as patient 1, a younger patient (54 years old, BMI 30) with no previous history and with positive PCR was admitted in infectious diseases department. He did not agree to be included in the study. He showed the same radio-clinical picture of SARS-CoV-2. He was admitted one day later in Intensive care for high flow nasal O₂ (40L/min) delivered by OPTIFLOW™.

The absence of adverse events attributed to H2 is also consistent with the literature, since the tolerability of H₂ has always been demonstrated in all clinical trials published in the literature.

These observations suggest a real efficacy of H₂-therapy during 3 days combined treatment with oxygen to accelerate clinical improvement of pulmonary Covid-19 and notably to prevent ICU transfer.

We are currently preparing a phase II/III study to confirm this positive effect of inhaled H2 versus placebo on pulmonary inflammation during SARS-CoV-2.

Author’s contribution

Conceptualisation : J.Giai, M.Roustit, F.Boucher, P.Cinquin, JP Brion

Study procedures and analysis: C.Salomez-Ihl, J.Giai, M.Roustit, F.Boucher, P.Cinquin, JP Brion

Investigation: JP Brion

Writing – original draft preparation: C.Salomez-Ihl, F.Boucher, P.Cinquin, JP Brion

Writing – review and editing: all

Consent: Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy

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