Abstract
A major challenge in modern neonatal care is to further improve outcomes after therapeutic hypothermia for hypoxic ischemic encephalopathy. In this study we tested whether extending the duration of cooling might reduce white matter damage. Term-equivalent fetal sheep (0.85 gestation) received either sham ischemia followed by normothermia (n = 8) or 30 minutes of bilateral carotid artery occlusion followed by three days of normothermia (n = 8), three days of hypothermia (n = 8) or five days of hypothermia (n = 8) started three hours after ischemia. Histology was assessed 7 days after ischemia. Ischemia was associated with loss of myelin basic protein (MBP) and Olig-2 positive oligodendrocytes and increased Iba-1-positive microglia compared to sham controls (p < 0.05). Three days and five days of hypothermia were associated with a similar, partial improvement in MBP and numbers of oligodendrocytes compared to ischemia-normothermia (p < 0.05). Both hypothermia groups had reduced microglial activation compared to ischemia-normothermia (p < 0.05). In the ischemia-five-day hypothermia group, but not ischemia-three-day, numbers of microglia remained higher than in sham controls (p < 0.05). In conclusion, delayed cerebral hypothermia partially protected white matter after global cerebral ischemia in fetal sheep. Extending cooling from 3 to 5 days did not further improve outcomes, and may be associated with greater numbers of residual microglia.
Highlights
White matter damage is common after hypoxia-ischemia at term, and is strongly associated with adverse outcomes[10]
Total numbers of oligodendrocytes were significantly improved in the ischemia-three-day hypothermia group in all regions and in the ischemia-five-day hypothermia group in the 2nd parasagittal gyrus and periventricular white matter compared to the ischemia-normothermia group (p < 0.05)
There was no significant difference in total oligodendrocyte number between the hypothermia groups in any region
Summary
White matter damage is common after hypoxia-ischemia at term, and is strongly associated with adverse outcomes[10]. We have recently shown that prolonging the duration of cerebral hypothermia after cerebral ischemia in term-equivalent fetal sheep from 72 to 120 hours had no additional beneficial effect on either electrophysiological recovery of brain activity or neuronal survival. 5 days of cooling was associated with reduced neuronal survival in the cortex and dentate gyrus and no greater suppression of microglial activation[11]. The effect of extending the duration of hypothermia on white matter damage is unknown. The aim of this study was to determine whether continuing mild cerebral hypothermia for five days compared to three days, could further improve survival of oligodendrocytes, improve myelination and reduce inflammation in the white matter after global cerebral ischemia. Hypothermia was started three hours after the end of ischemia to represent a realistic clinical delay before treatment
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