Brain Cell Death Is Reduced With Cooling by 3.5°C to 5°C but Increased With Cooling by 8.5°C in a Piglet Asphyxia Model

Background and Purpose-In infants with moderate to severe neonatal encephalopathy, whole-body cooling at 33 degrees C to 34 degrees C for 72 hours is standard care with a number needed to treat to prevent a adverse outcome of 6 to 7. The precise brain temperature providing optimal neuroprotection is unknown. Methods-After a quantified global cerebral hypoxic-ischemic insult, 28 piglets aged <24 hours were randomized (each group, n=7) to (1) normothermia (38.5 degrees C throughout) or whole-body cooling 2 to 26 hours after insult to (2) 35 degrees C, (3) 33.5 degrees C, or (4) 30 degrees C. At 48 hours after hypoxia-ischemia, delayed cell death (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling and cleaved caspase 3) and microglial ramification (ionized calcium-binding adapter molecule 1) were evaluated. Results-At 48 hours after hypoxia-ischemia, substantial cerebral injury was found in the normothermia and 30 degrees C hypothermia groups. However, with 35 degrees C and 33.5 degrees 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 degrees C and 33.5 degrees 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 degrees C (an absolute drop of 3.5 degrees C as in therapeutic hypothermia protocols) or to 33.5 degrees C provided protection in most brain regions after a cerebral hypoxic-ischemic insult in the newborn piglet. Although the relatively wide therapeutic range of a 3.5 degrees C to 5 degrees C drop in temperature reassured, overcooling (an 8.5 degrees C drop) was clearly detrimental in some brain regions.