Kim Annink

175 ALBINO trial: study protocol INTRODUCTION Neonatal hypoxic-ischemic encephalopathy (HIE) as a result of perinatal asphyxia is a major cause of death and long-term disability in term neonates. About 1-4 per 1000 live births and consequently about 5000-20,000 infants per year are affected in Europe (1). In regions with lower level perinatal care it is even more common. HIE affects about one million infants worldwide each year. Up to now, the only established therapy to improve outcome in infants with HIE is therapeutic hypothermia (2,3). However, despite therapeutic hypothermia and modern supportive neonatal intensive care, 45-50% of the infants with moderate or severe HIE (i.e., 2500-10,000 infants per year in Europe) still die or suffer from long-term neurodevelopmental impairment (NDI) such as cerebral palsy (CP), cognitive or behavioral problems (2,4). Therefore, additional therapies, including pharmacotherapy, are investigated to further improve the neurodevelopmental outcome of infants with HIE. One of the potential beneficial pharmacological interventions is allopurinol. Allopurinol is a xanthine-oxidase inhibitor, which reduces the production of oxygen radicals, most importantly of superoxide (5). Superoxide radicals damage mitochondria resulting in secondary energy failure and apoptosis affecting neurons and glial cells after reperfusion of hypoxic brain tissue, this is called reperfusion injury (6,7). This reperfusion injury leads to additional brain injury occurring in the hours after birth and may affect much larger areas of brain tissue than the area primarily affected during the sentinel event (7). Superoxide production, which is reduced by allopurinol, reaches its peak within 30 minutes after birth and therefore early administration is important to reduce reperfusion injury (8). Furthermore, allopurinol, especially in higher concentrations, possibly chelates non-protein-bound iron and scavenges the hydroxyl free radicals (9,10). Allopurinol also prevents adenosine degradation, which is an anti-excitatory neuromodulator (11). Thereby, allopurinol might reduce reperfusion injury and improve outcome in neonates with HIE. Several preclinical and three small clinical studies in neonates with HIE suggested a possible neuroprotective effect of allopurinol (recently reviewed in Annink et al. (8)). In the first two studies of van Bel et al. and Benders et al . allopurinol was administered within four hours after birth. Allopurinol improved neurodevelopmental outcome in infants with moderate HIE, but not in severe HIE 8