Delayed selective head cooling begun before the onset of postischemic seizures and continued for 3 days may have potential to significantly improve the outcome of moderate to severe hypoxic-ischemic encephalopathy.

In premature fetal sheep (89‐93 days gestation) we examined the fetal response to asphyxia induced by 30 min of complete umbilical cord occlusion. Fetuses were also studied during the first 3 days after asphyxia. We measured heart rate, blood pressure, carotid and femoral blood flows, vascular resistance, electroencephalographic activity and cerebral changes in haemoglobin concentration by near infrared spectroscopy (NIRS). Fetuses tolerated 30 min of asphyxia and the cardiovascular response was characterized by three phases: initial redistribution of blood flow away from the periphery to maintain vital organ function, partial failure of this redistribution and near terminal cardiovascular collapse, with profound hypotension and cerebral and peripheral hypoperfusion. Post‐asphyxia carotid blood flow and NIRS data demonstrated that between 3‐5 h there was a significant secondary reduction in cerebral blood flow, blood volume and oxygenation despite normal perfusion pressure and heart rate. There was also a secondary fall in femoral blood flow which persisted throughout recovery. These data demonstrate that the immature fetus can survive a prolonged period of asphyxia, but paradoxically the capacity to survive exposes the fetus to profound hypotension and hypoperfusion. A secondary period of significant cerebral hypoperfusion and reduced oxygen delivery also occurred post‐asphyxia. These cardiovascular and cerebrovascular responses may contribute to the patterns of cerebral injury seen in the human preterm fetus.

No abstract

Intraventricular injection of insulin-like growth factor 1 (IGF-1) 2 h after hypoxic-ischemic injury reduces neuronal loss. To clarify the mode of action, we compared histological outcome between treatment groups in the following three studies: 0, 0.5, 5, and 50 micrograms IGF-1 given 2 h after injury; 0 and 20 micrograms IGF-1 given 1 h before; and 20 micrograms IGF-1 and insulin or vehicle alone given 2 h after. Unilateral hypoxic-ischemic injury was induced in adult rats by ligation of the right carotid and exposure to 6% O2 for 10 min. Histological outcome was evaluated in the cortex, striatum, and hippocampus 5 days later. Five to 50 micrograms IGF-1 reduced the incidence of infarction and neuronal loss in a dose-dependent manner in all regions (p < 0.05), and 50 micrograms reduced the infarction rate from 87 to 26% (p < 0.01). Pretreatment did not alter outcome. IGF-1 improved outcome compared with equimolar doses of insulin (p < 0.05) and did not affect systemic glucose concentrations or cortical temperature. The results indicate that the neuronal protective effects of IGF-1 are specific and are not mediated via insulin receptors, hypothermia, or hypoglycemic mechanisms. Centrally administered IGF-1 appears to provide worthwhile trophic support to cells within most cerebral structures after transient hypoxic-ischemic injury.

Several hours after an hypoxic-ischemic injury to the developing brain, hyperemia, then seizures, edema, and infarction can develop. The roles of nitric oxide (NO) synthesis and excitotoxin accumulation during these later phases of injury are not known. The time course of extracellular levels of amino acids within the parasagittal parietal cortex were measured with microdialysis during and for 3 d after 30 min of cerebral ischemia in nine chronically instrumented near-term fetal sheep (119-133 d). Cortical electroencephalographic (EEG) activity and extracellular space (ECS) were quantified simultaneously with real-time spectral analysis and cortical impedance measurements, respectively. Amino acid concentrations were measured using HPLC. During ischemia, citrulline (by-product of NO synthesis), glutamate, glycine, and gamma-aminobutyric acid (GABA) concentrations rose to 147 +/- 18%, 180 +/- 20%, 290 +/- 50% and 4800 +/- 1300% of baseline respectively (p < 0.05). The excitotoxic index ([glutamate] x [glycine]/[GABA]) decreased to 15 +/- 8%. Upon reperfusion, the cytotoxic edema and amino acid accumulation largely resolved within 1 h, and the EEG was depressed. Citrulline began to rise again by 4 h (p < 0.05), reaching a maximum (273 +/- 21%) at 32 +/- 2 h. Seizure activity developed at 7 +/- 2 h, and impedance plus the excitotoxic index then rose progressively and peaked at 32 +/- 2 h (480 +/- 170%). At 72 h, there was severe neuronal loss and laminar necrosis within the parasagittal cortex. These data suggest that, several hours after a severe hypoxicischemic injury, NO synthesis increased, then seizures arose, and edema developed concomitantly with the accumulation of excitotoxins.