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Hypothermia (HT) reduces neuronal injury after perinatal asphyxia. The anesthetic gas xenon (XE) may enhance this effect. We investigated the sedative and respiratory effects of variable XE concentrations at 37°C normothermia (NT) or 32°C HT after a hypoxic-ischemic (HI) insult to determine the concentration at which XE was a respiratory depressant in spontaneously breathing 7-day-old rat pups.(I) In three control groups, the effects of fasting at NT and HT were investigated. (II) Six groups were subjected to a HI insult (left carotid ligation then 90 min breathing 8% oxygen); three then breathed Air, 50%Xe or 70%Xe for 5 h at NT (NTAir, NT50%Xe, NT70%Xe), while three breathed identical mixtures during HT (HTAir, HT50%Xe, or HT70%Xe), in addition to a control group. Blood gases, glucose, and lactate were measured. Sedation (spontaneous movement/respiratory rate) was recorded.Blood chemistry data were successfully obtained from 70 pups. (I) Pups maintained normal blood gas, glucose, and lactate values after 9 h fasting at NT or HT. (II) After HI insult, in comparison with control and NTAir groups, 70%Xe at both NT and HT produced higher PCO2 and lower pH values while the HTAir and HT50%Xe groups only had lower pH values. The HT70%Xe combination produced the highest PCO2 and lowest pH values (56.8 mm Hg, 7.35, respectively) and the greatest sedative effect.After HI insult, 70%Xe at both NT and HT induced sedation, respiratory depression, CO2 retention, and a decrease in pH relative to air and control groups. The effects were largely avoided with 50%Xe.