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Cardiovascular response and seizure frequency of 78 hours xenon inhalation with hypothermia following global hypoxic-ischaemia: feasibility study

Presented at the Neonatal Society 2016 Autumn Meeting.

Dingley J2, Thoresen M1,3, Okano S1, Scull Brown E1, Liu X1, Lee Kelland R1, Thyagarajan B1, Chakkarapani E1

1 School of Clinical Sciences, University of Bristol, Bristol
2 Department of Anaesthetics, Morriston Hospital, University of Swansea
3 Department of Physiology, University of Oslo

Background: In newborn infants with hypoxic-ischaemic encephalopathy (HIE), xenon (Xe) is currently investigated as adjunct neuroprotectant to Therapeutic Hypothermia (TH). Neuroimaging biomarkers of later neurodevelopment measured at 10 days of age were comparable between infants who received TH72h and TH72h+Xe24h30% (1). Hypothesis: Administering Xe during entire duration of TH and rewarming period of 78h may enhance neuroprotection offered by TH. It is unknown whether it is feasible to administer Xe for > 24h in humans. We aimed to compare the cardiovascular response and seizure frequency between TH72h and TH72h+Xe50%78h interventions in a newborn global HIE pig model (2).

Methods: We conducted all experiments in accordance with the UK home office license regulations. We randomised 12 newborn pigs following a 45min global hypoxic-ischaemic (HI) insult under maintenance sedation/anaesthesia to receive TH72h at rectal temperature 35°C using whole body cooling or TH72h+Xe50%78h. Xenon was administered using a newly developed automated closed circuit device (Xe50%, O225%, N225%). Only 0.2 L/h of Xe gas was used (£30/L).3 We measured cardiovascular response using heart rate, blood pressure, blood lactate and duration of inotropic support in all pigs. We measured blood gases and treatment for clinical or electrical seizures.

Results: Age, weight, sex and insult severity were similarly distributed between TH-only and TH+Xe groups. At the end of HI, median pH was 7.04 and 7.18 and median lactate was 14.4mmol/L and 14.9mmol/L in the two groups. Heart rate, blood pressure (fig), plasma lactate and blood gases were comparable between TH72h+Xe50%78h and TH72h. Median duration of inotropic support did not differ between the two groups, (40h and 33h respectively). Seizures were treated in 83% of TH-only pigs compared with 50% of TH+Xe pigs.

Conclusion: It is feasible to administer 78hours of 50% xenon concurrently with 72h of therapeutic hypothermia with stable haemodynamics in newborn pigs that underwent a global hypoxic-ischaemic insult. Pigs receiving xenon with cooling had less post hypoxic seizures.

Corresponding author: ela.chakkarapani@bristol.ac.uk

References
1. Azzopardi D, et al. Lancet Neurol 2015 Dec 18
2. Chakkarapani E, et al Ann Neurol 2010;68(3):330-41. 3. Dingley J, et al. Pediatrics 2014;133(5):809-18

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