Resuscitative hypothermia protects the neonatal rat brain from hypoxic-ischemic injury.

The effect of 24 h of hypothermic recovery on moderate hypoxic-ischemic brain damage in P7-rats was investigated for 42 d after the insult, using magnetic resonance and histopathology. Occlusion of right common carotid artery and 90 min exposure to 8% O2 at 37 degrees C body temperature produced cytotoxic edema of 51(+/-11)% brain volume (BV) and depression of brain energy metabolism (PCr/Pi) from 1.43(+/-0.21) to 0.14(+/-0.11). During recovery, the body temperature was reduced to 30 degrees C for 24 h in 36 animals, but was kept at 37 degrees C in 34 animals. The edema waned upon reoxygenation leaving only the core lesion at 2 h, but reappeared reaching a maximal extent of 11+/-8% BV under hypothermia compared to 45(+/-10)% under normothermia at around 24 h. PCr/Pi recovered transiently within 13 h and declined again to 1.07(+/-0.19) under hypothermia and to 0.48(+/-0.22) under normothermia at around 24 h. Hypothermia led to significant long term brain protection, leaving permanent tissue damage of 12(+/-6)% BV compared to 35(+/-12)% BV under normothermia. However, animals with severe initial injury developed large infarctions, despite hypothermic treatment. Even then, the time to develop infarction was significantly prolonged, leaving the opportunity for additional therapeutic intervention.

Biphasic edema after hypoxic-ischemic brain injury in neonatal rats reflects early neuronal and late glial damage.

Magnetic resonance imaging with diffusion- and T2-weighted imaging and 31P magnetic resonance spectroscopy was used to investigate the relationship between development of brain edema and alterations of the brain energy metabolism after hypoxia-ischemia (HI) brain injury in 7-d-old rats. The results were correlated with histologic examinations at various times during recovery up to 5 d. Moderate HI, induced by right common carotid artery ligation and subsequent exposure to 8% O2 for 90 min, produced a cytotoxic edema of 52+/-9% brain volume and depressed the ratio of phosphocreatine to inorganic phosphate from 1.43+/-0.21 to 0.11+/-0.09. Within 1 h of reoxygenation, the edema decreased to 4+/-2% of brain volume, demarcating the core of the lesion. At 5 h of recovery, a secondary cytotoxic edema together with a newly developing vasogenic edema expanded again, reaching its maximal extent of 45+/-10% brain volume at around 24 h. The ratio of phosphocreatine to inorganic phosphate recovered slowly, reaching 1.12+/-0.27 around 13 h. Thereafter it declined again in a manner analogous to the observations made in human newborns after severe perinatal asphyxia, reaching trough values of 0.48+/-0.22 around 24 h after HI. At the cellular level, the vast majority of neuronal death occurred before 15 h. Subsequently, strong glial activation lasted 2-3 d after HI. At 5 d, a cystic infarction of 35+/-12% brain volume was found. We conclude that the biphasic evolution of brain edema and energy metabolism reflects early neuronal and late glial damage in response to moderate HI injury. Therefore, the secondary energy breakdown reflects glial activation and subsequent glial death.

Late glial swelling after acute cerebral hypoxia-ischemia in the neonatal rat: a combined magnetic resonance and histochemical study.

Secondary brain damage after transient cerebral hypoxia-ischemia (HI) is caused by a cascade of cellular events. In this study, complementary methods of magnetic resonance imaging and histochemistry were used to investigate the formation of cytotoxic and vasogenic edema during secondary brain damage induced by transient HI in 7-d-old rats. To elicit injury, 21 rats underwent right common carotid artery ligation followed by 1.5 h of 8% O2 exposure. Sequential apparent diffusion coefficient (ADC) and transversal relaxation time (T2) weighted magnetic resonance imaging were recorded for up to 3 d in 13 7-d-old rats. Eight animals were killed at various intervals between the end of HI and 21 h of recovery to perform histochemical assays using neuronal and astrocytic markers. Changes of the ADC revealed a biphasic function for the evolution of cytotoxic edema during the recovery period. At the end of HI, the ADC in the ipsilateral cortex was significantly decreased. Upon reoxygenation, it returned transiently to normal followed by a secondary, although less pronounced, decline after 8-48 h. After this, the ADC rose steadily. From 8 h of recovery, the proportion of vasogenic edema steadily increased as indicated by the T2 prolongation. At 21 h, the majority of glial cells showed immunoreactivity for glial fibrillary acidic protein and were of larger size, whereas the neurons were apoptotic. These results indicate that the delayed cerebral injury is accompanied by late glial swelling in conjunction with an enlarged interstitial space due to cell damage.