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

Daniel Alonso-Alconada, Kevin D. Broad, Alan Bainbridge, Manigandan Chandrasekaran, Stuart D. Faulkner, Áron Kerenyi, Jane Hassell, Eridan Rocha-Ferreira, Mariya Hristova, Bobbi Fleiss, Kate Bennett, Dorottya Kelen, Ernest Cady, Pierre Gressens, Xavier Golay, Nicola J. Robertson

Research output: Contribution to journalArticle

Abstract

Background and Purpose-In infants with moderate to severe neonatal encephalopathy, whole-body cooling at 33°C to 34°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°C throughout) or whole-body cooling 2 to 26 hours after insult to (2) 35°C, (3) 33.5°C, or (4) 30°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°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. Although the relatively wide therapeutic range of a 3.5°C to 5°C drop in temperature reassured, overcooling (an 8.5°C drop) was clearly detrimental in some brain regions.

Original languageEnglish (US)
Pages (from-to)275-278
Number of pages4
JournalStroke
Volume46
Issue number1
DOIs
StatePublished - Jan 3 2015

Keywords

  • hypothermia
  • hypoxia-ischemia, brain
  • neonatal encephalopathy
  • neuroprotection

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

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    Alonso-Alconada, D., Broad, K. D., Bainbridge, A., Chandrasekaran, M., Faulkner, S. D., Kerenyi, Á., Hassell, J., Rocha-Ferreira, E., Hristova, M., Fleiss, B., Bennett, K., Kelen, D., Cady, E., Gressens, P., Golay, X., & Robertson, N. J. (2015). 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. Stroke, 46(1), 275-278. https://doi.org/10.1161/STROKEAHA.114.007330