Kim Annink

150 Chapter 7 However, until this moment, the use of allopurinol as a cardioprotective agent in adults with cardiovascular diseases remains controversial and larger prospective studies are required to determine the cardioprotective effect of allopurinol (17). The earlier mentioned cardiac studies, which showed that the production of free radicals was leading to hypoxic-ischemic damage of the heart, were the basis of the hypothesis that allopurinol might also be beneficial for the prevention of hypoxic-ischemic damage of the brain. Perinatal asphyxia in the newborn leads to the production of hypoxanthine and the activation of xanthine-oxidase leading to subsequent brain damage (5). Considering that allopurinol can inhibit the xanthine-oxidase pathway, an allopurinol-induced reduction of superoxide might be neuroprotective in hypoxic-ischemic encephalopathy (HIE). Hypoxic-ischemic encephalopathy One to eight per 1000 live born neonates experience HIE caused by perinatal asphyxia (18). Perinatal asphyxia is one of the most important causes of death and long-term neurological damage in term born neonates. The current standard of care in perinatal asphyxia is moderate hypothermia for 72 hours, starting within 6 hours after birth. In the TOBY trial, cooled infants were followed up until the age of 6 to 7 years and their outcome was compared to non-cooled infants (19,20). Despite hypothermia, approximately 45% of these neonates had an adverse outcome at the age of 2 years, defined as severely impaired neurological outcome or death, compared to 53% in the non-cooled group (RR 0.86, 95%CI 0.68-1.07) (19). At the age of 6 to 7 years, 55% of the cooled infants that survived experienced neurologic abnormalities compared to 72% in the non-cooled group (20). Neurologic abnormalities were defined as an IQ score below 85, abnormalities in neurologic examination, hearing or vision. The survival rates did not differ significantly (20). In conclusion, hypothermia is an effective neuroprotective strategy for infants with HIE, however still a sizable amount of these infants dies or has an adverse neurological outcome. Therefore, additional neuroprotective therapies are essential to reduce neurological damage in these infants. Pathophysiology of brain damage after perinatal asphyxia Brain damage after perinatal asphyxia is caused by hypoxia leading to neuronal cell damage. In neonates with perinatal asphyxia there are two moments of neuronal cell damage: a first peak caused by primary energy failure during the hypoxic event