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Hydrogen gas can ameliorate seizure burden during therapeutic hypothermia in asphyxiated newborn piglets

Pediatric Research (2024)Cite this article

Abstract

Background

We previously reported that hydrogen (H2) gas combined with therapeutic hypothermia (TH) improved short-term neurological outcomes in asphyxiated piglets. However, the effect on seizure burden was unclear. Using amplitude-integrated electroencephalography (aEEG), we compared TH + H2 with TH alone in piglets 24 h after hypoxic–ischemic (HI) insult.

Methods

After a 40-min insult and resuscitation, 36 piglets ≤24 h old were divided into three groups: normothermia (NT, n = 14), TH alone (33.5 ± 0.5 °C, 24 h, n = 13), and TH + H2 (2.1–2.7% H2 gas, 24 h, n = 9). aEEG was recorded for 24 h post-insult and its background pattern, status epilepticus (SE; recurrent seizures lasting >5 min), and seizure occurrence (Sz; occurring at least once but not fitting the definition of SE) were evaluated. Background findings with a continuous low voltage and burst suppression were considered abnormal.

Results

The percentage of piglets with an abnormal aEEG background (aEEG-BG), abnormal aEEG-BG+Sz and SE was lower with TH + H2 than with TH at 24 h after HI insult. The duration of SE was shorter with TH + H2 and significantly shorter than with NT.

Conclusions

H2 gas combined with TH ameliorated seizure burden 24 h after HI insult.

Impact

  • In this asphyxiated piglet model, there was a high percentage of animals with an abnormal amplitude-integrated electroencephalography background (aEEG-BG) after hypoxic-ischemic (HI) insult, which may correspond to moderate and severe hypoxic-ischemic encephalopathy (HIE).

  • Therapeutic hypothermia (TH) was associated with a low percentage of piglets with EEG abnormalities up to 6 h after HI insult but this percentage increased greatly after 12 h, and TH was not effective in attenuating seizure development.

  • H2 gas combined with TH was associated with a low percentage of piglets with an abnormal aEEG-BG and with a shorter duration of status epilepticus at 24 h after HI insult.

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Fig. 1: Representative examples of aEEG in this experiment.
Fig. 2: Study flow diagram.
Fig. 3: Percentage of piglets with an abnormal aEEG-BG, BG+Sz after HI insult.
Fig. 4
Fig. 5: Duration of SE at 24 h after HI insult in the NT, TH, and TH + H2 groups.

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Data availability

The datasets generated during and/or analyzed during this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank medical students at the Faculty of Medicine, Kagawa University, Kagawa, Japan for their assistance in this study.

Funding

This study was financially supported by JSPS KAKENHI grants (19K08253 (S.N.), 19K08349 (K.K.), 22K15923 (Y.N.), and 22K07822 (T.K.), 22K15899 (T.W.), 22K15922 (A.M.), and 23K07332 (S.N.)), and Kagawa University Faculty of Medicine School of Medicine Alumni Association Sanjukai Research Aid R1-1 (S.N.).

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Authors and Affiliations

  1. Department of Pediatrics, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Toui Tsuchiya, Shinji Nakamura, Yasuhiro Nakao, Kota Inoue, Eri Inoue, Yinmon Htun, Noriko Fuke, Sonoko Kondo & Takashi Kusaka

  2. Department of Pediatrics, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Aichi, Japan

    Yuichiro Sugiyama

  3. Medical Engineering Equipment Management Center, Kagawa University Hospital, Kagawa University, Kagawa, Japan

    Tsutomu Mitsuie

  4. Maternal Perinatal Center, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Makoto Arioka, Hirosuke Morita & Kosuke Koyano

  5. Department of Anatomy and Neurobiology, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Kenichi Ohta & Takanori Miki

  6. Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Masaki Ueno

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  1. Toui Tsuchiya
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Contributions

T.T., S.N. and T.K. were involved in the initial study design and wrote the main text. K.K., Y.N., T.K. and S.N. obtained the necessary financial support for this project and provided study materials. T.T. and Y.S. were primarily responsible for evaluating the aEEG findings. Y.N., T. Mitsuie, E.I., K.I., M.A., K.K. and N.F. carried out the animal experiments and recorded blood gas and physiological data. K.M., S.K., K.O., M.U. and T. Miki. contributed to data analysis and performed the statistical analysis. All members drafted the article and critically revised it.

Corresponding author

Correspondence to Shinji Nakamura.

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The authors declare no competing interests.

Ethical approval and informed consent

The study protocol was approved by the Kagawa University Animal Care and Use Committee (15070–1) and was conducted in accordance with Animal Research: Reporting In Vivo Experiments (ARRIVE) guidelines and all other applicable guidelines and regulations.

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Tsuchiya, T., Nakamura, S., Sugiyama, Y. et al. Hydrogen gas can ameliorate seizure burden during therapeutic hypothermia in asphyxiated newborn piglets. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03041-6

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  • DOI: https://doi.org/10.1038/s41390-024-03041-6

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