Cooling Combined with Immediate or Delayed Xenon Inhalation Provides Equivalent Long-Term Neuroprotection after Neonatal Hypoxia—Ischemia

Abstract

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 (32°C) 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 hImmediateXe) or last (1 hDelayedXe) 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.