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The clinical applications of xenon for the neonate include both anaesthesia and neuroprotection. However, due to the limited natural availability of xenon, special equipment is required to administer and recapture the gas to develop xenon as a therapeutic agent.In order to test the xenon recirculating ventilator for the application of neuroprotection in a preclinical trial, our primary objective was to test the efficiency, reliability and safety of administering 50% xenon for 24 h in hypoxic ischaemic piglets.A prospective observational study.Institute for Women's Health, University College London, January 2008 to March 2008.Four anaesthetised male piglets, less than 24 h old, underwent a global hypoxic ischaemic insult for approximately 25 min prior to switching to the xenon recirculating ventilator.Between 2 and 26 h after hypoxic ischaemia, anaesthetised piglets were administered a mixture of 50% xenon, air, oxygen and isoflurane.The primary outcome measure was blood gas PaCO2 (kPa) and secondary outcome measure was xenon gas use (l h−1), over the 24-h duration of xenon administration.The xenon recirculating ventilator provided effective ventilation, automated control of xenon/air gas mixtures, and stable blood gas PaCO2 (4.5 to 6.3 kPa) for 24 h of ventilation with the xenon recirculating ventilator. Total xenon use was minimal at approximately 0.6 l h−1 at a cost of approximately €8 h−1. Additional features included an isoflurane scavenger and bellows height alarm.Stable gas delivery to a piglet with minimal xenon loss and analogue circuitry made the xenon recirculating ventilator easy to use and it could be modified for other large animals and noble gas mixtures. The technologies, safety and efficiency of xenon delivery in this preclinical system have been taken forward in the development of neonatal ventilators for clinical use in phase II clinical trials for xenon-augmented hypothermia and for xenon anaesthesia.