Immediate Hypothermia Is Not Neuroprotective After Severe Hypoxia-Ischemia and Is Deleterious When Delayed by 12 Hours in Neonatal Rats

BACKGROUND AND PURPOSE: 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.