Kim Annink

156 Chapter 7 Postnatal studies in neonates in HIE Because of the promising results of allopurinol therapy in animal studies, it was decided to start an open label study in the newborn infant with perinatal asphyxia. The first study in neonates was an unblinded randomized controlled trial (RCT) in which two dosages of 20mg/kg allopurinol or placebo were given after birth to 22 neonates, the first dose up to 4 hours after birth and a second dose 12 hours later (Table 1) (46). The short-term effect of allopurinol was assessed with chemical biomarkers (lipid peroxidation and anti-oxidative parameters), the pattern of the cerebral blood flow was measured with NIRS and electrical brain function with amplitude-integrated EEG (aEEG). NPBI levels were significantly lower two days postpartum and uric acid levels were decreased from 16 hours postpartum onwards in the allopurinol group compared to the controls. However, lipid peroxidation and anti-oxidative parameters were the same in the allopurinol group and in the controls. Moreover, allopurinol induced a relative preservation of cerebral blood flow and electrical brain activity was higher in the allopurinol group suggesting less brain damage. In the allopurinol group 2 of the 11 infants died, whereas in the control group 5 out of 11 died. In conclusion, this study suggested a beneficial effect of allopurinol, without toxic side effects. However, the sample size of this study was small and the study was unblinded (46). A subsequent multicenter, double-blinded RCT was performed by Benders et al. in 2006. Allopurinol was administered to 17 infants in the same dosages at the same time points as in the previous study and a placebo was administered to 15 infants. However, only infants with perinatal asphyxia, multi-organ failure and an abnormal aEEG were included. These strict inclusion criteria led to the inclusion of only severely affected neonates. Therefore, mortality was rather high in this study: 76% in the allopurinol group and 67% in the placebo group, which was not statistically different. Short-term outcomes, namely MRI and cerebral ultrasound abnormalities, seizures and S100ß concentrations, were similar in both groups (47). This suggested that allopurinol might be more effective in moderately affected neonates than in severely affected neonates. All participants of the two above mentioned studies were seen for neurocognitive follow-up at the age of 4 to 8 years (mean of 5 years and 5 months). Children were tested with a neurological examination and the Wechsler Preschool and Primary Scale of Intelligence or the Wechsler Intelligence Scale for Children. There was