Researchers at University of Helsinki, Finland, studied the causal mechanisms of seizures associated with birth asphyxia using 6 day-old rat pups exposed for 1 hour to hypercapnia (20% C02 in inhaled gas), hypoxia (9% 02), or both (asphyxic conditions). Normocapnia was restored gradually using C02 levels of 10% and 5%. Loss of righting reflex was used to indicate the severest expression of neonatal seizure and to quantify the seizure burden during 2-hour observation following asphyxia. Intracranial EEG was also utilized. The effect of postexposure changes in brain pH on seizure burden was assessed after restoration of normoxia and normocapnia. Hypercapnia or hypoxia alone had little effect on seizure burden, but rapid recovery from asphyxia was followed by a large seizure burden that paralleled a rise in brain pH, but no change in brain oxygenation. The seizure burden and alkaline shift in brain pH were strongly suppressed by a graded restoration of normocapnia after asphyxia. Preapplication of N-methyl-isobutyl-amiloride, an inhibitor of Na+/H+ exchanger, blocked seizures completely. Brain alkalosis after recovery from birth asphyxia has a key role in the triggering of seizures. The rapid restoration of normocapnia in the immediate postasphyxia period should be avoided and a graded restoration of brain pH implemented. 
COMMENT. Seizures in the neonate with hypoxic-ischemic encephalopathy are often subtle, characterized by swimming, rowing movements, apneic spells, opisthotonus, or clonic movements. 
In newborn rats, seizures induced by electroshock vary with strength of current and with age. In 10-day-old rats, the animal exhibits hyperkinetic behavior, breaststroke swimming movements, and transient opisthotonus. At 20 days, tremor of head, and catatonic posture; and at 30 days, the seizure is a generalized symmetrical clonus with loss of posture. A stronger current is required to induce a maximal tonic clonic seizure in rats older than 15-20 days. In rats aged 1 to 15 days, a maximal tonic seizure cannot be elicited. The increased severity of seizure response with increase in age is correlated with development of brain carbonic anhydrase . If slightly older rat pups (>6 days) had been employed in the Helsinki experiment, a more definitive seizure endpoint might have been elicited. The following clinical report supports the association of PC02 and outcome of HIE in neonates, but raises questions regarding a seizure as the measure of brain damage and disability.
Pappas A and colleagues  in the Eunice Kennedy Shriver NIH Neonatal Research Network report that infants exposed to low PC02 concentrations within the first 16 hours of life during whole body cooling were at increase risk of death/disability. Disability was directly related to the degree and severity of hypocarbia. Both minimum PC02 and cumulative PC02 <35 mmHg were associated with poor outcome at 18-22 months of age. The occurrence of clinical seizures was not significantly associated with death or disability. The infants had received ventilatory resuscitation or assistance at birth, and this may have contributed to hypocarbia. Further investigation will determine whether hypocarbia is a modifiable risk factor or simply a marker of poor outcome. Clyman RI, in an editorial (Jrnl Pediatr 2011;158:A2), asks “Should cooled infants be started on lower initial ventilator settings or weaned more rapidly?” “Will avoidance of hypocarbia improve outcome?”