Repeated Episodes of Umbilical Cord Occlusion in Fetal Sheep Lead to Preferential Damage to the Striatum and Sensitize the Heart to Further Insults

Abstract

The effect of repeated episodes of asphyxia on the fetal cardiovascular system and CNS was examined. The umbilical cord was occluded for 5 min, four times, at 30-min intervals in 11 chronically instrumented fetal sheep (118-126 d). Fetal electrocorticogram (ECoG), cortical impedance, ECG, heart rate, and blood pressure were continuously recorded for 3 d, after which neuronal loss was determined histologically. Each occlusion resulted in fetal hypoxemia and bradycardia accompanied by increased TIQRS ratio. Progressively severe hypotension and lactic acidosis developed during successive occlusions. The ECoG was depressed and cortical impedance increased with each occlusion. During the final occlusion, blood pressure fell to 3.5 -C 1 kPa and heart rate to 93 + 9 bpm, TIQRS ratio increased to 0.44 + 0.3, and lactate rose to 7.2 2 1.2 mMIL. Three animals died from cardiac fibrillation during recirculation after the third or fourth occlusion. After the asphyxial episodes, blood pressure and heart rate returned to normal, and the T wave was inverted for 310 + 155 min. Lactate returned to baseline within 24 h. The ECoG remained depressed for 90 + 35 min, and intermittent Prenatal asphyxia is thought to be a cause of intrauterine death or impaired postnatal neurologic development in survivors. However, specific cause and effect relationships have been difficult to establish in the human fetus because of inadequate means of monitoring fetal events. W e have previously shown that repeated episodes of cerebral ischemia in the fetal sheep alter the degree and distribution of brain injury compared with single insults (1). In particular, these repeated insults result in the loss of striatal neurons.Intermittent partial umbilical cord occlusion has been reported to cause cerebral white matter injury in fetal sheep (2). Others seizures developed at 3.3 -C 1.4 h after the last occlusion. Neuronal loss was primarily found in the striatum. The extent of neuronal loss correlated with the degree of hypotension, increase in T/QRS ratio, duration of postasphyxial ECoG depression, and number of seizures. These results indicate that transient asphyxial episodes compromise the ability of the heart to tolerate additional insults and further suggest that neuronal loss is a consequence of cardiovascular compromise secondary to asphyxia. Therefore, repetitive asphyxial episodes may lead to intrauterine death or striatal damage in survivors. (Pediatr Res 37: 707-713, 1995) Abbreviations ECoG, electrocorticogram CI, cortical impedance HR, heart rate MAP, mean arterial blood pressure GABA, y-amino butyric acid have shown increasing acidosis and electrocardiographic evidence of asphyxia during repeated umbilical cord occlusions (3). However, the relationship between cardiac function, cerebral function, and neuronal loss after recurrent episodes of fetal asphyxia is not clear. W e have previously shown that systemic asphyxia induced by umbilical cord occlusion in fetal sheep results in hippocampal injury, the severity of which is related to th...

Mild chronic hypoxia modifies the fetal sheep neural and cardiovascular responses to repeated umbilical cord occlusion

“…Consistent with previous reports (Mallard et al, 1995b), repeated cord occlusion had profound effects on ECoG activity in the fetal sheep. Although the reduction in amplitude of the electrical signal observed during occlusions was similar between groups, analysis of the frequency components reveled a more pronounced reduction of the spectral edge frequency (SEF) in the hypoxic group.…”

“…These authors concluded that both the degree of hypotension and the increase in the ratio T/ QRS have an impact on the extent of striatal neuronal loss. Although we used the relatively novel fluorescent indicator Fluoro Jade-B to evaluate neuronal death in cortex and striatum, the proportion of dead cells (30%) in our study is in the same range as previously reported (Mallard et al, 1995b).…”

“…The effect of asphyxia, induced by umbilical cord occlusion, on neuronal survival is dependent of the duration and frequency of the insult. In keeping with Mallard's data (Mallard et al, 1995b), we also found that this paradigm of repeated cord occlusion results in greater neuronal damage in the striatum. These authors concluded that both the degree of hypotension and the increase in the ratio T/ QRS have an impact on the extent of striatal neuronal loss.…”

“…Neuronal loss following a severe acute hypoxic ischemic insult is dependent to a great extent on cardiovascular stability. The more severe the hypotension the greater the number of neurons lost (Mallard et al, 1995b). Similarly, a recent report shows that spontaneously hypoxic term fetuses submitted to brief repeated cord occlusions develop a more rapid cardiovascular deterioration (Westgate et al, 2005).…”

“…Fluoro Jade B, a relatively specific indicator of neuronal damage (Rocha et al, 2004;Schmued and Hopkins, 2000), was used to quantify neuronal damage in basal ganglia, the most affected brain region for this paradigm of cord occlusion (Mallard et al, 1995b) and lateral cortex to complement our previous work on Type I NOS expression in these regions following identical hypoxic conditions (Pryor et al, 2002). Fixed-frozen tissues were sectioned and equivalent sections were identified following the sheep stereotaxic atlas (Gluckman and Parsons, 1983).…”