Kim Annink

176 Chapter 8 (12-14). Gunes et al. administered allopurinol for three days and found improved outcome at one year of age (15). All three studies were conducted before therapeutic hypothermia became standard of care, so the effect of allopurinol in addition to therapeutic hypothermia has not been investigated yet. Based on the hypothesis that administration within four hours after birth was too late to achieve a full neuroprotective effect, allopurinol was administered antenatally in case of suspected hypoxia in the antenatal allopurinol trial for reduction of birth asphyxia induced brain damage (ALLO-trial) (16). In girls, biomarkers as S100B were reduced in the allopurinol group compared to the placebo group. However, there was substantial overtreatment on the one hand and on the other moderately and severely asphyxiated infants were often missed (16). Consequently, in this study on the effects of Allopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), allopurinol will be administered intravenously within 30 (max. 45) minutes after birth to optimize the timing and inhibition of superoxide formation in asphyxiated infants with evolving HIE. Importantly, in all antenatal and neonatal studies in HIE, no severe side-effects were seen (12,13,15-19). Also, in other neonatal populations, such as preterm infants and infants with congenital cardiac abnormalities, no severe side effects have been reported following (intravenous or oral) administration of allopurinol (20-24). In the ALLO-trial, 4.5% of the mothers who received allopurinol had an irritation of the perivascular tissue, caused by the high pH of the allopurinol solution, but this was reversible in all cases (16). In adults, a rare hypersensitivity reaction to allopurinol has been described after daily administration for a median of two to three weeks (25,26). An allopurinol sensitivity reaction in neonates has never been reported and is expected to be extremely unlikely. METHODS Trial objectives The main objective of the ALBINO trial is to evaluate the effect of early postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe NDI at 24 months of age in newborns with HIE.