Kim Annink

18 Chapter 1 months for children in the hypothermia group (46). The health care costs in two cooled infants with severe disabilities raised until £20,000 to £40,000 per patient per 6 months (46). Healthcare costs are an additional argument that add-on neuroprotective therapies are necessary. In low and middle income countries therapeutic hypothermia is less feasible because of fewer resources (cooling with ice packs, fans or gel packs) and the neuroprotective effect is not entirely clear because of differences in clinical characteristics (47). This is currently further investigated in the HELIX trial (48). Here, pharmacologic neuroprotection might be a good alternative (49). With pharmacological interventions in the destructive molecular pathways leading to brain injury (see also Figure 1) additional neuroprotection may be established. In preclinical research several pharmacological interventions have been tested, targeting oxidative, inflammatory/apoptotic and anti-trophic pathways. Several promising drugs and compounds have been or are being investigated in phase II and phase III studies such as Xenon ventilation (an NMDA-antagonist), 2-iminibiotin (a selective nNOS inhibitor), melatonin (seems to have anti-oxidative and anti- inflammatory effects) and erythropoietin (anti-oxidative, anti-inflammation and trophic activities) (5,50–53). A potential important anti-oxidative neuroprotective agent is allopurinol. Allopurinol is a xanthine-oxidase inhibitor (54). By inhibiting xanthine-oxidase, the conversion of hypoxanthine and oxygen into xanthine, uric acid and the free radical superoxide is reduced upon reperfusion and reoxygenation after (fetal) hypoxia (54). It is hypothesized that allopurinol decreases reperfusion injury by reducing superoxide formation, but also by scavenging free radicals and chelating non-protein-bound iron (5,55,56). Chapter seven provides an overview of the existing literature about allopurinol as a neuroprotective agent in infants with HIE. Literature of earlier preclinical and clinical studies in infants with HIE suggests that allopurinol is neuroprotective on the long-term in infants with moderate HIE (57). In these earlier postnatal studies, allopurinol was administered within four hours after birth (58,59). Although there was an effect on the long-term in moderately affected infants, administration of allopurinol within 4 hours after birth is probably too late since the superoxide production reaches its peak around 30 minutes after birth. Therefore, an antenatal study followed, in which allopurinol was administered to the mother in case of imminent fetal hypoxia (60). This study showed a beneficial effect in girls on chemical