Role of the Cerebrovascular and Metabolic Responses in the Delayed Phases of Injury After Transient Cerebral Ischemia in Fetal Sheep

Abstract

Background and Purpose-Perinatal hypoxic-ischemic injuries can trigger a cascade of events leading to delayed deterioration and cell death several hours later. The objective of this study was to characterize the cerebral blood flow responses and the changes in extracellular glucose and lactate during the delayed phases of injury and to determine their relationships with the pathophysiological events after hypoxic-ischemic injury. Methods-Two groups of near-term chronically instrumented fetal sheep were subjected to 30 minutes of cerebral hypoperfusion. In the first group, regional cerebral blood flow was measured over the next 24 hours with radiolabeled microspheres. In the second, cortical extracellular glucose and lactate were measured by microdialysis. Parietal electrocorticographic activity and cortical impedance were recorded continuously in both groups, and the extent of neuronal loss was determined histologically at 72 hours after injury. Results-Cerebral blood flow was transiently impaired in the cortex during reperfusion, whereas during the delayed phase, there was a marked increase in cerebral blood flow. The severity of cortical neuronal loss was related to the degree of hypoperfusion in the immediate reperfusion period and inversely related to the magnitude of the delayed hyperperfusion. Cortical extracellular lactate was elevated after injury, and both glucose and lactate secondarily increased during the delayed phase of injury. Conclusions-The delayed phase is accompanied by a period of hyperperfusion that may protect marginally viable tissue.

Spatial Heterogeneity in Oligodendrocyte Lineage Maturation and Not Cerebral Blood Flow Predicts Fetal Ovine Periventricular White Matter Injury

“…In the immature fetus, shorter periods of ischemia than used here caused damage primarily to subcortical white matter Raad et al, 1999). PVWM lesions were infrequently detected in midgestation models of hypoxemia, where a restriction in uteroplacental blood flow resulted in decreased oxygen delivery and mild acidemia to the fetus without systemic hypotension or cerebral hypoperfusion (Rees et al, 1997(Rees et al, , 1999Mallard et al, 1998).…”

“…We took several departures from previous approaches (Penning et al, 1994;Mallard et al, 1998;Reddy et al, 1998;Matsuda et al, 1999;Raad et al, 1999;Petersson et al, 2002) to develop a model of selective PVWM injury. To identify potential target populations of preOLs, we defined OL lineage maturation in the immature ovine brain.…”

“…In fact, a more variable degree of white matter injury was detected in near-term sheep after several insults (Clapp et al, 1988;Penning et al, 1994;Mallard et al, 1998;Ikeda et al, 1999;Ohyu et al, 1999;Raad et al, 1999). Future studies are needed to determine whether acceleration of OL differentiation might be a feasible strategy to reduce the incidence and severity of PWMI.…”

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

“…These experimental studies support that a complex interplay of factors related to cerebrovascular immaturity predispose preterm cerebral white matter to injury from hypoxia-ischemia. Studies of global cerebral hypoperfusion found that the mid-gestation animal displayed a predilection to subcortical WMI, whereas the near term animal displayed predominantly parasagittal cortical neuronal injury [65,87]. A variable degree of WMI was also detected after systemic hypotension arising from intermittent or partial umblical cord occlusion [88,89].…”

Maturation-Dependent Vulnerability of Perinatal White Matter in Premature Birth

“…33,34 The immature ovine brain is also similar to preterm humans between 24 to 28 weeks in terms of the completion of neurogenesis, the onset of cerebral sulcation, the detection of the cortical component of the auditory and somatosensory evoked potentials, and an increased predilection for white matter injury. [35][36][37][38] Thus, the cephalically hypotensive immature ovine fetus appears to be particularly susceptible to hypoxia-ischemia, but prior studies provided no data regarding blood flow to periventricular white matter.…”