Brief Repeated Umbilical Cord Occlusions Cause Sustained Cytotoxic Cerebral Edema and Focal Infarcts in Near-Term Fetal Lambs

Abstract

The aim of this study was to determine whether asphyxia induced by clinically relevant, brief repetitive umbilical cord occlusions is associated with cerebral compromise. Chronically instrumented fetal lambs were studied at 126.5 +/- 2.8 d of gestation (mean +/- SD, term 147 d). Occlusions were performed 1 out of every 2.5 min (group I, n = 7), 2 out of every 5 min (group II, n = 9), or not at all (shams, group III, n = 5), and discontinued at a predetermined threshold of severe or persistent hypotension. After 58 +/- 8 and 24 +/- 2 occlusions, in groups I and II, respectively, the pH was 6.83 +/- 0.09, Pco2 9.52 +/- 1.4 kPa, base excess -23.5 +/- 3.7 mM, and lactate 14.1 +/- 1.6 mM. Two fetuses (out of group II) did not recover from the final occlusion. Ongoing asphyxia was associated with progressive suppression of the EEG, which occurred faster and with more epileptiform and spike activity in group II. Cortical impedance remained elevated for 15.0 +/- 4.0 and 11.5 +/- 4.4 h, for groups I and II, respectively (NS). Focal infarcts occurred in the parasagittal cortex, thalamus, and cerebellum, in 6 out of 14 surviving asphyxiated fetuses. Mild selective neuronal loss was observed in these regions in 13 out of 14 fetuses. Infarction was associated with a longer period of blood pressure below baseline levels, with more epileptiform activity, and with slower normalization of the EEG. In a paradigm mimicking birth asphyxia, histologic damage similar to that observed clinically was found. The results suggest that brief repeated insults interact, leading to cardiac compromise and cumulative cell membrane damage in the fetal cerebrum.

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

“…However, there is paucity of data regarding the effects of mild chronic hypoxia on the fetal brain response to a subsequent acute hypoxic-ischemic episode or the mechanisms that underlie the increased risk for impaired neuronal functional status. The functional impact of severe hypoxia/ischemia on neuronal function has been assessed by many authors using different approaches such as raw electrocorticogram (ECoG) signals (Gunn et al, 1991;Richardson et al, 1985), spectral analysis , cortical impedance (De Haan et al, 1997), sensory and auditory evoked potentials (Gunn et al, 1991;Richardson et al, 1992). Also important is the effect hypoxia has on cardiovascular performance.…”

Real-Time Spectral Analysis of the Fetal EEG: A New Approach to Monitoring Sleep States and Fetal Condition during Labor

“…During severe fetal asphyxia induced by prolonged cord occlusion in the fetal lamb, the EEG also demonstrated different patterns. When asphyxia was induced in the near-term fetal lamb by brief repetitive umbilical cord occlusions, lowering the pH to 6.83, a progressive suppression of the EEG was observed associated with epileptiform and spike activity (24). During partial umbilical cord occlusion for 90 min (lowering the pH to 6.82), the electrocorticogram of the fetal lamb was profoundly suppressed and seizure activity was documented after release of occlusion in all surviving animals (25).…”

Antenatal Allopurinol Reduces Hippocampal Brain Damage After Acute Birth Asphyxia in Late Gestation Fetal Sheep

“…28,29,[33][34][35][36][37][38][39][40] Although a broad variation in distribution patterns of neuronal damage and apoptosis has been identified after using these different techniques, the observed (para)hippocampal vulnerability has frequently been described. 28,34,35,41 In our study, the hippocampus and the parahippocampal cortex, areas involved in memory and spatial orientation and navigation, were also the most severely damaged brain areas, results in keeping with the characteristics of such studies.…”

“…Examination was performed using a 6-point scale: 0 (0%), 1 (>0%-10%), 2 (>10% -50%), 3 (>50%-90%), 4 (>90%-99%), and 5 (100%). [28][29][30] Sections were randomly numbered and scored simultaneously using a dual viewing attachment by 2 investigators (J.J.K. and M.G.H.)…”