Maturational Change in the Cortical Response to Hypoperfusion Injury in the Fetal Sheep

Abstract

A characteristic of perinatal encephalopathies are the distinct patterns of neuronal and glial cell loss. Cerebral hypoperfusion is thought to be a major cause of these lesions. Gestational age is likely to influence outcome. This study compares the cortical electrophysiologic and histopathologic responses to hypoperfusion injury between preterm and near term fetuses. Chronically instrumented 0.65 (93-99-d, n = 9) and 0.9 (119-133-d, n = 6) gestation fetal sheep underwent 30 min of cerebral hypoperfusion injury. The parasagittal cortical EEG and impedance (measure of cytotoxic edema) responses plus histologic outcome (3 d) were compared. The acute rise in impedance was similar in amplitude, but the onset was delayed (5.0 +/- 0.7 versus 9.1 +/- 1.1 min, p < 0.05) in the preterm fetuses relative to those near term. In contrast the extent of the secondary rise was reduced (p < 0.01) and peaked earlier in the preterm fetuses (19.8 +/- 1.0 versus 40.5 +/- 3.5 h, p < 0.01). Both groups had a similar fall in EEG spectral edge frequency. The preterm fetuses had a milder loss of EEG intensity at 72 h (-7.7 +/- 1.5 versus -12.8 +/- 0.9 dB, p < 0.05). At both ages there was a predominantly parasagittal cortical distribution of damage with a similar pattern of neuronal loss in the thalamus and striatum. There was extensive selective neuronal loss within the upper layers of the cortex in those near term. In contrast the preterm fetuses developed subcortical infarcts (p < 0.05). The cortical response to injury altered during the last trimester. The results suggest the severity of the delayed phase of cortical neuronal injury and selective neuronal loss increased near term. In contrast, the preterm fetuses had a more rapidly evolving injury leading to necrosis of the subcortical white matter.

Regulation of cytochrome oxidase redox state during umbilical cord occlusion in preterm fetal sheep

“…The marked delay between initial inhibition of cerebral activity and mitochondrial function in contrast with the later final plateau of CytOx levels and the onset of cytotoxic edema is consistent with our previous reports showing that the rise in cerebral impedance is much slower during ischemia in preterm fetal sheep than at term (15,44). This suggests that actively regulated metabolism is effective in protecting the very immature brain for much longer than at term.…”

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

“…Chronic instrumentation also allows a wide range of practical and clinically pertinent cerebral insults to be administered. These include global cephalic ischemia [65], systemic hypotension or hypoxemia [66][67][68], single or repeated cord occlusion [69][70][71], increased intracranial pressure [72], and administration of infectious agents or exogenous inflammatory mediators [73][74][75]. These insults can be graded in intensity and duration to mimic the human situation.…”

“…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].…”

“…Unlike in utero systemic hypoxemia or asphyxia models, the models that use carotid or brachiocephalic artery (BCA) occlusions cause an immediate fall in perfusion pressure and CBF, and thus have a well-defined onset of the insult [41,65,110]. Cerebral ischemia in these models is generally global and severe but not complete, especially when collateral circulation is left intact (discussed as follows).…”

“…The OVA is small but potentially important in models where cephalic occlusions are studied [65,102]. They provide an important anastomosis between the anterior circulation provided by the carotid arteries and the posterior circulation derived from the vertebral arteries.…”