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

Abstract

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.

Dexmedetomidine Combined with Therapeutic Hypothermia Is Associated with Cardiovascular Instability and Neurotoxicity in a Piglet Model of Perinatal Asphyxia

“…This may explain our observation of a significantly lower body temperature at 2-3.5 h in the hypothermia + dexmedetomdine group, although this was not below the target TH range. We have previously shown that the depth of hypothermia is critical for its efficacy in this model [48] .…”

Using animal models to improve care of neonatal encephalopathy

“…In other cases, animal studies indicated futility, which was later borne out in clinical studies. For example, animal studies suggested the futility of deeper cooling following perinatal HI;13 this was seen in the randomised controlled trial of deeper and longer therapeutic hypothermia for NE, which was subsequently stopped due to safety concerns14 There are calls for more systematic reviews of animal studies and higher standards of research conduct and reporting 10…”

Design of a fuzzy logic controlled thermoelectric~brain hypothermia system

“…The brain needs to be cooled to limit neurologic complications in patients during sudden strokes and heart attacks. For cases where hypothermia cannot be applied, local cooling of the brain prevents neurological damage that may subsequently take place like restrictions in memory, speech, and movement [9][10][11][12][13].…”