Brain cell death is reduced with cooling by 3.5 degrees C to 5 degrees C but increased with cooling by 8.5 degrees C in a piglet asphyxia model

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 Ushaped 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 hypoxicischemic insult in the newborn piglet. While the relatively wide therapeutic range of a 3.5-5°