title: Immediate hypothermia is not neuroprotective after severe hypoxia-ischemia and is deleterious when delayed by 12 hours in neonatal rats.
abstract: OBJECTIVE
  Hypothermia (HT) for neonatal hypoxic-ischemic encephalopathy is advised to start within the first 6 hours after birth. There is some clinical evidence that HT is more effective against moderate than against severe hypoxic-ischemic encephalopathy, but it is unknown whether delayed HT beyond 6 hours is effective or even injurious.
  
  
  METHODS
  One-hundred seven 7-day-old rat pups underwent unilateral hypoxia-ischemia of moderate severity. Pups were randomized to receive 5 hours of normothermia (NT) or HT starting immediately, 3 hours, 6 hours, or 12 hours after the 90-minute hypoxic period. One-hundred five 7-day-old rat pups underwent severe hypoxia-ischemia lasting 150 minutes, followed by the same group design as mentioned. Relative area loss of the left/right hemisphere was measured after 1 week of survival.
  
  
  RESULTS
  In the moderate NT group, the mean area loss of the left hemisphere was 40.5%. The area loss was significantly decreased to 24.8% with immediate HT (P<0.05) and increased linearly with the delay of HT by 1.788% per hour until at least 6 hours of delay (linear regression, P=0.026). After 12-hour delayed HT, the area loss was similar to the moderate NT group (41.1%). After severe NT, the mean area loss of the left hemisphere was 59.3%. Immediate HT, 3-hour delayed HT, and 6-hour delayed HT all resulted in similar area loss, whereas the 12-hour delayed-HT resulted in significantly increased area loss (69.5%; P=0.032).
  
  
  CONCLUSIONS
  Immediate and delayed (≤6 hours) HT provides neuroprotection after moderate hypoxia-ischemia in neonatal rats. This neuroprotection decreases linearly with increasing delay. After severe insults, however, immediate or delayed HT≤6 hours provides no neuroprotection. Twelve-hour delayed hypothermia increased brain injury after severe hypoxia-ischemia, which is of clinical concern.
authors.affiliation: School of Clinical Sciences, University of Bristol, St Michael's Hospital, Bristol, BS28EG, United Kingdom.
authors.forename: Hemmen
authors.initials: H
authors.lastname: Sabir
authors.forename: Emma
authors.initials: E
authors.lastname: Scull-Brown
authors.forename: Xun
authors.initials: X
authors.lastname: Liu
authors.forename: Marianne
authors.initials: M
authors.lastname: Thoresen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D007036:Hypothermia, Induced / Q000009:adverse effects* / Q000379:methods*; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000628:therapy*; D008297:Male; D051381:Rats; D012720:Severity of Illness Index; D061665:Time-to-Treatment / Q000592:standards*; D016896:Treatment Outcome