Presented at the Neonatal Society 2010 Autumn Meeting.
Dingley J2, Liu X1, Tooley J1, Chakkarapani E1, Elstad M1, Thoresen M1
1 School of Clinical Sciences, University of Bristol, Bristol BS2 8EG, UK
2 School of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK
Background: Four large randomised hypothermia trials showed a relative risk reduction in death/disability of 16.7% (CoolCap), 22.4% (US body cooling NICHD),15.8% (TOBY UK) and 22.6% (ICE trial Australia) suggesting a need for more effective treatment of HIE. We have shown in newborn rats and pigs that adding 50% xenon (Xe) while cold doubles the neuroprotection after a hypoxic-ischemic insult (1,2,3). In the global pig HIE model we showed that xenon had no adverse effects on cardiovascular or organ function. We developed a Xe rebreathing delivery system (4) using ~0.2L Xe/h ($6/h), obtained MHRA (devices) approval for clinical use and received MHRA (medicines) approval to use Xe as a potential neuroprotective drug in babies for the first time. We started enrolment on 28/03/10 with ethical permission for an initial (n=12) feasibility study adding xenon to the inspiratory gas in mechanically ventilated infants undergoing cooling therapy for perinatal asphyxia.
Methods: Hypothermia for moderate or severe HIE is standard of care in our regional cooling centre. Ventilated infants who also fulfilled criteria of FiO2<0.35, BP in the normal range and seizures under control were eligible for entry into the “CoolXenon” study with written parental consent. Infants were reintubated with a cuffed tracheal tube and blood gases were confirmed as normal before xenon delivery commenced. Double monitoring (for safety) was used for Xe/O2 gas concentrations in the breathing mixture. End-expired PaCO2 was continuously recorded at the tracheal tube. The low pressure (<10cm H2O) cuff was only inflated during xenon delivery. BP, cardiac output (CO) and aEEG were continuously recorded. Xenon was started before 18h of age and in subsequent patients was increased stepwise from 25% to 50% (target concentration) and 3 to 12h duration such that infants number 6-12 receive 50% xenon continuously for 12h.The physiological responses to starting/stopping xenon both slowly and more rapidly were observed. As this is the first human long term xenon ventilation, as a precaution, the xenon system was flushed with fresh gas every 2h.
Results: Median gestational age was 40 weeks, weight 3.5kg and 90% were out-born. Passive cooling started in the local hospital and active cooling (Criticool) started during transport with target rectal temperature at 33.5ºC at 5h of age (median). Xenon was started at 10h of age (median). Worst initial pH was 6.9. EEG before 6h showed a burst suppression pattern in 80%. 70% had seizures and received phenobarbital before active cooling. 40% were receiving inotropes before xenon. Infants were on morphine 10-20 μg/kg/h before, during and after Xe-delivery. Median FiO2 did not change during Xe delivery. Xenon at 50% had a significant and variable sedative effect. Commencing Xe produced no hypotension and heart rate varied <5%, with no changes in CO. On stopping Xe there was a small increase in MABP and HR. Maintenance xenon requirement was 0.14 L/h.
Conclusion: Adding up to 50% xenon for up to 12h while undergoing cooling therapy for HIE did not change BP, HR or FiO2. However Xe has a strong sedative effect with fast onset/offset. Infants recovered spontaneous movements within 2 min after Xe discontinuation.
Corresponding author: j.dingley@swansea.ac.uk
References
1. Hobbs C et al Stroke 2008
2. Chakkarapani E et al Annals of Neurology 2010
3. Thoresen M et al JCBFM 2009
4. Chakkarapani E et al Anaesthesia and Analgesia 2009