Background and Purpose-Hypoxic/ischemic (HI) brain injury affects 1 to 6 per 1000 live human births, with a mortality of 15% to 20%. A quarter of survivors have permanent disabilities. Hypothermia is the only intervention that improves outcome; however, further improvements might be obtained by combining hypothermia with additional treatments. Xenon is a noble anesthetic gas with an excellent safety profile, showing great promise in vitro and in vivo as a neuroprotectant. We investigated combinations of 50% xenon (Xe 50% ) and hypothermia of 32°C (HT 32°C ) as a post-HI therapy. Methods-An established neonatal rat HI model was used. Serial functional neurologic testing into adulthood 10 weeks after injury was performed, followed by global and regional brain histopathology evaluation. Results-In the combination Xe 50% HT 32°C group, complete restoration of long-term functional outcomes was seen.Hypothermia produced improvement on short-(PϽ0.001) and long-(PϽ0.001) term functional testing, whereas Xe 50% alone predominantly improved long-term function (PϽ0.05), suggesting that short-term testing does not always predict eventual outcome. Similarly, the Xe 50% HT 32°C combination produced the greatest (71%) improvement in global histopathology scores, a pattern mirrored in the regional scores, whereas Xe 50% and HT 32°C individually produced smaller improvements (PϽ0.05 and PϽ0.001, respectively). The interaction between the 2 treatments was additive. Conclusions-The xenon/hypothermia combination additively confers greater protection after HI than either treatment alone. The functional improvement is almost complete, is sustained long term, and is accompanied by greatly improved histopathology. The unique safety profile differentiates xenon as an attractive combination therapy with hypothermia to improve the otherwise bleak outcome from neonatal HI.

Combining xenon with HT is a promising therapy for severely encephalopathic infants, doubling the neuroprotection offered by HT alone.

Hypothermia (HT) improves outcome after neonatal hypoxia-ischemia. Combination therapy may extend neuroprotection. The noble anesthetic gas xenon (Xe) has an excellent safety profile. We have shown earlier that 3 h of 50% Xe plus HT (321C) additively gives more protection (72%) than either alone (HT = 31.1%, Xe = 10.2%). Factors limiting clinical use include high-cost and specialist administration requirements. Thus, combinations of 1 h of 50% Xe were administered concurrently for either the first (1 h Immediate Xe) or last (1 h Delayed Xe) of 3 h of posthypoxic-ischemic HT as compared with 3 h of 50%Xe/HT to investigate how brief Xe exposure with a delay would affect efficacy. An established neonatal rat hypoxia-ischemia model was used. Serial functional neurologic testing into adulthood was performed, followed by neuropathological examination. Xenon with HT was more effective with longer Xe duration (3 h versus 1 h) (P = 0.015). However, 1 h Xe/3 h HT resulted in better neuroprotection than 3 h HT alone (P = 0.03), this significant effect was also present with 1 h Xe after a 2-h delay. One (immediate or with a delay) or 3 h Xe also significantly improved motor function (P = 0.024). Females had significantly better motor scores than males, but no sex-dependent difference in pathology results. The neuroprotection of short, delayed Xe treatment would allow transport to specialist facilities to receive Xe.

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