Purine and Pyrimidine Metabolism and Electrocortical Brain Activity during Hypoxemia in Near-Term Lambs

Abstract

Insufficient cerebral O 2 supply leads to brain cell damage and loss of brain cell function. The relationship between the severity of hypoxemic brain cell damage and the loss of electrocortical brain activity (ECBA), as measure of brain cell function, is not yet fully elucidated in near-term newborns. We hypothesized that there is a strong relationship between cerebral purine and pyrimidine metabolism, as measures of brain cell damage, and brain cell function during hypoxemia. Nine near-term lambs (term, 147 d) were delivered at 131 (range, 120-141) d of gestation. After a stabilization period, prolonged hypoxemia (fraction of inspired oxygen, 0.10; duration, 2.5 h) was induced. Mean values of carotid artery blood flow, as a measure of cerebral blood flow, and ECBA were calculated over the last 3 min of hypoxemia. At the end of the hypoxemic period, cerebral arterial and venous blood gases were determined and CSF was obtained. CSF from 11 normoxemic siblings was used for baseline values. HPLC was used to determine purine and pyrimidine metabolites in CSF, as measures of brain cell damage. Concentrations of purine and pyrimidine metabolites were significantly higher in hypoxemic lambs than in their siblings, whereas ECBA was lower in hypoxemic lambs. Significant negative linear relationships were found between purine and pyrimidine metabolite concentrations and, respectively, cerebral O 2 supply, cerebral O 2 consumption, and ECBA. We conclude that brain cell function is related to concentrations of purine and pyrimidine metabolites in the CSF. Reduction of ECBA indeed reflects the measure of brain damage due to hypoxemia in near-term newborn lambs. Despite the increase in survival of preterm infants, long-term morbidity has not changed (1). Hypoxia-ischemia-related brain damage is an important contributor to perinatal mortality and long-term morbidity in survivors (2).The immature brain is very vulnerable to disturbances in cerebral oxygenation and hemodynamics. Cerebral O 2 supply depends on both CaO 2 and CBF. Cerebral hypoxia is defined as an insufficient O 2 supply to the brain, resulting from either hypoxemia (decreased CaO 2 ) or hypoperfusion (decreased CBF). During hypoxemia, the brain is considered to be protected adequately from injury by an increase in CBF to preserve cerebral O 2 supply and to stabilize brain metabolism, unless cerebral ischemia occurs from supervening systemic hypotension. With the neuronal oxygen and glucose debts arising from severe hypoxemia, oxidative metabolism shifts to anaerobic glycolysis, with its inefficient generation of highenergy phosphate reserves, necessary to maintain cellular ionic gradients and other metabolic processes. However, when hypoxemia progresses, cellular energy failure ultimately occurs, which, if not promptly reversed, results in decreased neuronal viability and death of the cell (3).During insufficient cerebral O 2 supply, an accumulation of purine metabolites, which are the degradation products from high-energy phosphate compounds (ATP, ADP, and AMP),...

Cerebral O2 Supply Thresholds for the Preservation of Electrocortical Brain Activity During Hypotension in Near-Term-Born Lambs

“…The result is presented as the root from this signal. ECBA thus is calculated as the root mean square value of a band-filtered (2-16 Hz) one-channel EEG (19,21) and is comparable with a voltage scale.…”

Cerebral Cortical Tissue Damage After Hemorrhagic Hypotension in Near-Term Born Lambs

“…The ewes were monitored continuously and were kept in an optimal ventilatory and circulatory condition and the umbilical cord was not obstructed during the experiments. Since an optimal oxygenation and circulation of the siblings was warranted, we used the CSF and brain tissue of the siblings to determine concentrations of glutamate, aspartate and cGMP, and MAP2 staining during normotension (8). As expected, low glutamate, aspartate, and cGMP concentrations were found in the CSF of the siblings as well as an optimal MAP2 staining.…”

“…ECBA was calculated as the root mean square (RMS) value of a band-filtered (2-16 Hz), one-channel EEG (7,8), which is comparable with a voltage scale.…”

“…Within 5 min, cerebral cortical tissue was obtained. Because the ewes were kept in an optimal ventilatory and circulatory condition until the end of the experiment, we assumed that the siblings were in a normotensive (fetal) situation (8). The glutamate and aspartate concentration in the CSF and the cGMP concentration in brain tissue as well as the MAP2 staining in the siblings were considered to be similar in the instrumented lambs during normotension, if CSF and brain tissue could have been obtained in these lambs during normotension.…”

“…Whereas brain cell dysfunction can be measured in vivo noninvasively by neurophysiological methods (7,8), brain cell death can only be assessed histologically. Microtubuleassociated proteins (MAP) are a diverse family of cytoskeletal proteins apparently present in all vertebrates including man (9).…”