Kim Annink

260 Chapter 12 Part II: neuroprotection Therapeutic hypothermia reduces the risk of adverse outcome in infants with HIE significantly, though still about 45% of the infants with moderate to severe HIE die in the neonatal period or have an adverse neurodevelopmental outcome (1). Add-on neuroprotective agents should be investigated to decrease the risk of an adverse outcome. Part II of this thesis focuses on a promising potential neuroprotective agent, allopurinol. Allopurinol is a xanthine-oxidase inhibitor and can thereby reduce reperfusion injury (39). Inhibition of xanthine-oxidase leads to less superoxide formation, one of the major toxic compounds leading to brain injury in HIE (39,40). Additionally, allopurinol is a direct scavenger of free radicals and can chelate non-protein-bound iron (41,42). Reperfusion injury starts immediately after birth and superoxide formation already reaches its peak within 30 minutes after birth, so early intervention with allopurinol is probably essential (4). In chapter seven this is discussed in more detail, as well as the pathophysiology of HIE and an overview of the preclinical and clinical studies on the neuroprotective effect of allopurinol in neonates with HIE. The available literature on antenatal and postnatal (within four hours after birth) administration is not conclusive (40,43–49). Allopurinol administration within four hours is probably too late (considering the early peak of superoxide formation) and the disadvantage of antenatal allopurinol is that the selection of fetuses with imminent hypoxia based on cardiotocography appeared to be difficult (43,45,48). Nevertheless, infants with moderate HIE treated with postnatal allopurinol had an improved outcome at four to six years of age compared to controls (47). Importantly, allopurinol is regarded to be a safe drug, no serious adverse events have been reported in neonates (40). A larger randomized controlled trial with very early allopurinol administration during resuscitation is needed to determine the neuroprotective effect of allopurinol. Furthermore, there is no information about the effect of allopurinol as add-on strategy in combination with therapeutic hypothermia. Therefore, the ALBINO trial was designed, registered as NCT03162653 on ClinicalTrials. gov, a large European randomized controlled trial, in which we investigate the neuroprotective effect of allopurinol administration during resuscitation in infants with HIE as add-on therapy next to therapeutic hypothermia. Near-term and term infants with perinatal asphyxia and early signs of encephalopathy receive, after short oral consent, a first dose of allopurinol or placebo within 45 minutes after birth. A second