Compared with no treatment, xenon-augmented hypothermia reduced cerebral MRS abnormalities and cell death markers in some brain regions. Compared with hypothermia, xenon-augmented hypothermia did not reach statistical significance for any measure. The safety and possible improved efficacy support phase II trials.

Background and Purpose In infants with moderate to severe neonatal encephalopathy, whole body cooling to 33-34°C for 72 hours is standard care with a number needed to treat to prevent one adverse outcome of 6-7. The precise brain temperature providing optimal neuroprotection is unknown. Methods After a quantified global cerebral hypoxic-ischemic insult, 28 piglets aged <24h were randomized (each group n=7) to: (i) normothermia (38.5°C throughout), or whole-body cooling 2-26 h post-insult to (ii) 35°C, (iii) 33.5°C or (iv) 30°C. At 48h post-insult, delayed cell death (TUNEL and cleaved caspase 3) and microglial ramification (Iba-1) were evaluated. Results At 48h post-insult, substantial cerebral injury was found in the normothermia and 30°C-hypothermia groups. However, with 35°C and 33.5°C cooling, a clear reduction in delayed cell death and microglial activation was observed in most brain regions (P<0.05), with no differences between 35°C and 33.5°C cooling groups. A protective pattern was observed, with U-shaped temperature dependence in delayed cell death in periventricular white matter, caudate nucleus, putamen, hippocampus and thalamus. A microglial activation pattern was also seen, with inverted U-shaped temperature dependence in periventricular white matter, caudate nucleus, internal capsule and hippocampus (all P<0.05). Conclusions Cooling to 35°C (an absolute drop of 3.5°C as in therapeutic hypothermia protocols) or to 33.5 °C provided protection in most brain regions after a cerebral hypoxic-ischemic insult in the newborn piglet. While the relatively wide therapeutic range of a 3.5-5°C drop in temperature was reassuring, overcooling (an 8.5°C drop) was clearly detrimental in some brain regions.

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