Brain Alkalosis Causes Birth Asphyxia Seizures, Suggesting Therapeutic Strategy

Objective: The mechanisms whereby birth asphyxia leads to generation of seizures remain unidentified. To study the
possible role of brain pH changes, we used a rodent model that mimics the alterations in systemic CO2 and O2
levels during and after intrapartum birth asphyxia.
Methods: Neonatal rat pups were exposed for 1 hour to hypercapnia (20% CO2 in the inhaled gas), hypoxia (9%
O2), or both (asphyxic conditions). CO2 levels of 10% and 5% were used for graded restoration of normocapnia.
Seizures were characterized behaviorally and utilizing intracranial electroencephalography. Brain pH and oxygen were
measured with intracortical microelectrodes, and blood pH, ionized calcium, carbon dioxide, oxygen, and lactate
with a clinical device. The impact of the postexposure changes in brain pH on seizure burden was assessed during 2
hours after restoration of normoxia and normocapnia. N-methyl-isobutyl-amiloride, an inhibitor of Naþ/Hþ exchange,
was given intraperitoneally.
Results: Whereas hypercapnia or hypoxia alone did not result in an appreciable postexposure seizure burden,
recovery from asphyxic conditions was followed by a large seizure burden that was tightly paralleled by a rise in
brain pH, but no change in brain oxygenation. By graded restoration of normocapnia after asphyxia, the alkaline
shift in brain pH and the seizure burden were strongly suppressed. The seizures were virtually blocked by
preapplication of N-methyl-isobutyl-amiloride.
Interpretation: Our data indicate that brain alkalosis after recovery from birth asphyxia plays a key role in the
triggering of seizures. We question the current practice of rapid restoration of normocapnia in the immediate
postasphyxic period, and suggest a novel therapeutic strategy based on graded restoration of normocapnia.