title: 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: OBJECTIVE
  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.
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Alonso-Alconada
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Broad
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Alan
authors.initials: A
authors.lastname: Bainbridge
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Manigandan
authors.initials: M
authors.lastname: Chandrasekaran
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Faulkner
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Áron
authors.initials: Á
authors.lastname: Kerenyi
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Jane
authors.initials: J
authors.lastname: Hassell
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Eridan
authors.initials: E
authors.lastname: Rocha-Ferreira
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Mariya
authors.initials: M
authors.lastname: Hristova
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Bobbi
authors.initials: B
authors.lastname: Fleiss
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Kate
authors.initials: K
authors.lastname: Bennett
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Dorottya
authors.initials: D
authors.lastname: Kelen
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Ernest
authors.initials: E
authors.lastname: Cady
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.).
authors.forename: Xavier
authors.initials: X
authors.lastname: Golay
authors.affiliation: From the Institute for Women's Health, University College London, London, United Kingdom (D.A.-A., K.D.B., M.C., S.D.F., A.K., J.H., E.R.-F., M.H., K.B., D.K., N.J.R.); Medical Physics and Bio-engineering, University College London Hospitals NHS Foundation Trust, London, United Kingdom (A.B., E.C.); Centre for the Developing Brain, King's College London, London, United Kingdom (B.F., P.G.); and Department of Brain Repair and Rehabilitation, Institute for Neurology, Queen Square, London, United Kingdom (X.G.). n.robertson@ucl.ac.uk.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Robertson
mesh_terms: D000818:Animals; D001237:Asphyxia / Q000473:pathology* / Q000628:therapy; D001921:Brain / Q000473:pathology*; D002421:Caudate Nucleus / Q000473:pathology; D016923:Cell Death; D002470:Cell Survival; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology; D007036:Hypothermia, Induced / Q000379:methods*; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology*; D011699:Putamen / Q000473:pathology; D013552:Swine; D013788:Thalamus / Q000473:pathology; D066127:White Matter / Q000473:pathology
keywords: hypothermia; hypoxia-ischemia, brain; neonatal encephalopathy; neuroprotection