Xenon/Hypothermia Neuroprotection Regimes in Spontaneously Breathing Neonatal Rats After Hypoxic-Ischemic Insult: The Respiratory and Sedative Effects John Dingley, MD*† Catherine Hobbs, PhD* James Ferguson, BSc* Janet Stone, PhD‡ Marianne Thoresen, MD, PhD* BACKGROUND: 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 normother- mia (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. METHODS: (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 (NT Air , NT 50%Xe , NT 70%Xe ), while three breathed identical mixtures during HT (HT Air , HT 50%Xe , or HT 70%Xe ), in addition to a control group. Blood gases, glucose, and lactate were measured. Sedation (spontaneous movement/respiratory rate) was recorded. RESULTS: 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 NT Air groups, 70%Xe at both NT and HT produced higher PCO 2 and lower pH values while the HT Air and HT 50%Xe groups only had lower pH values. The HT 70%Xe combination produced the highest PCO 2 and lowest pH values (56.8 mm Hg, 7.35, respectively) and the greatest sedative effect. CONCLUSION: After HI insult, 70%Xe at both NT and HT induced sedation, respira- tory depression, CO 2 retention, and a decrease in pH relative to air and control groups. The effects were largely avoided with 50%Xe. (Anesth Analg 2008;106:916 –23) Hypoxic-ischemic (HI) brain injury, such as perina- tal asphyxia, can result in lifelong motor and cognitive impairment. 1–3 These injuries are characterized by an encephalopathy created by a primary insult, followed by a self-sustaining destructive cascade over hours or days. 1 This cascade suggests that an effective post- insult therapy for babies might limit the eventual damage. However, no clinical intervention, except hypothermia (HT), has been shown to alter neurologi- cal outcome in babies. 4–6 There is still room for improvement as only 1 in 6 children so treated will benefit, which leads us to consider and seek combina- tion therapies. The noble gas xenon (XE), which has received a marketing license as an anesthetic drug in Europe, is also showing great promise as a neuropro- tectant in experimental studies. 7–9 It is attractive for combination therapy with HT as it is almost chemi- cally inert and free of adverse clinical side effects or toxicity, particularly fetotoxicity. 10 –12 In addition, XE exhibits rapid onset/offset characteristics and has long been used in neonates for radiological studies. 13 It antagonizes the N-methyl-d-aspartate receptor and possibly others, reducing receptor over-stimulation triggered cell death. 14 –16 There may be additional mechanisms as XE appears more protective than drugs that antagonize these receptors alone. XE has been shown to be neuroprotective both in vitro and in vivo in neonatal rats when administered both before, 17 during, 8 and after a HI insult. 7 The published human trials of HT involved neonates at high risk of brain injury in which 90% needed mechanical ventila- tion. 4,5,18 It may be desirable in the future to use XE-HT therapy in neonates at less extreme risk. Con- sequently, a significant proportion of future candi- dates may be breathing spontaneously. There is some evidence that the neuroprotective effect of XE is dose-related, and so it may prove desirable to use as high a XE concentration as possible. 19,20 From the *Clinical Science at South Bristol, Child Health, Uni- versity of Bristol, St. Michael’s Hospital, Bristol, UK; †University of Wales Swansea, Singleton Park, Swansea, UK; and ‡Department of Biochemistry, Children’s Hospital, Bristol, UK. Accepted for publication November 2, 2008. Address correspondence and reprint requests to J. Dingley, Department of Anaesthetics, Morriston Hospital, Swansea SA6 6NL, UK. Address e-mail to j.dingley@swansea.ac.uk. Copyright © 2008 International Anesthesia Research Society DOI: 10.1213/ane.0b013e3181618669 Vol. 106, No. 3, March 2008 916