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Argon Augments Therapeutic Hypothermia in a Piglet Model of Perinatal Asphyxia

Presented at the Neonatal Society 2015 Summer Meeting (programme).

Hassell J1, Fleiss B2,3, Broad KD1, Fierens I1, Alonso-Alconada D1, Rocha-Ferreira E1, Bainbridge A4, Price D4, Kawano G1, Ezzati M1, Hristova M1, Sanders RD5, Golay X6, Gressens P2,3, Robertson NJ1

1 Institute for Women's Health, UCL, UK
2 Centre for the Developing Brain, King's College London, UK
3 INSERM, Paris, France
4 Medical Physics, University College London Hospital, UK
5 University of Wisconsin, Madison, USA
6 Institute of Neurology, UCL, UK

Background: Therapeutic Hypothermia (HT) is standard care for Hypoxic Ischaemic Encephalopathy (HIE), however 50% of treated infants still have adverse outcomes. Phase II clinical trials of Xenon-augmented HT are underway (1), however Xenon is rare, expensive and requires a specialist ventilator. Argon, another noble gas, is safe, 200 times cheaper than Xenon, and provides protection at least equal to Xenon in rodent models (2). We hypothesised that Argon would augment hypothermic neuroprotection in our piglet model of perinatal asphyxia.

Methods: All experiments were performed under UK Home Office Guidelines [Animals (Scientific Procedures) Act, 1986]. This study was funded by a grant from Action Medical Research. Eighteen newborn piglets (<24h) were surgically prepared and intensively monitored. Following quantified transient HI insult piglets were randomised to: (i) HT alone (2-26h, 33.5șC) or (ii) HT + 50% Argon (2-26h). 1H and 31P Magnetic Resonance Spectra were recorded at 2, 24, 48h. Electroencephalogram (EEG) was monitored throughout. Piglets were euthanised after 48h. Brains were fixed and stained for TUNEL (cell death).

Results: Argon was straightforward to deliver through a standard SLE ventilator and was well tolerated. MRS showed significant preservation of wholebrain NTP/ePP and PCr/Pi at 48h after HI in the Argon-HT group compared to HT alone (p=0.01). Protection occurred predominantly in the white matter, with significantly reduced white matter Lac/NAA at 48h (p=0.04). Cell death (TUNEL+ cells) was lower in the Argon-HT group, significant across whole-brain and in caudate and putamen (p<0.02). We observed striking recovery in amplitude-integrated EEG in Argon- HT animals only, with higher mean Hellstrom-Westas scores (3) from 12h onwards compared to HT (p<0.001).

                                                6-hourly group mean aEEG scores

Conclusion: Argon 50%+cooling conferred significant neuroprotection after hypoxia-ischaemia when compared to cooling alone. Both our MRS biomarkers and aEEG recovery speed strongly correlate to neurodevelopmental outcome in babies with HIE (4,5). Argon may provide a cheaper, more practical alternative therapy to Xenon.

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2. Zhuang et al., Crit Care Med 2012; 40: 1724-30
3. Hellstrom-Westas et al., ADC Fetal Neonatal Ed 1995; 72: F34-8
4. Toet et al., ADC Fetal Neonatal Ed 1999; 81: 12-23
5. Thayyil et al., Pediatrics 2010; 125: e382-95

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