Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia. Effect of allopurinol supplementation on nitric oxide levels in asphyxiated newborns. Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity.
To investigate whether postnatal allopurinol would reduce free radical induced reperfusion/reoxygenation injury of the brain in severely asphyxiated neonates.
                In an interim analysis of a randomised, double blind, placebo controlled study, 32 severely asphyxiated infants were given allopurinol or a vehicle within four hours of birth.
                The analysis showed an unaltered (high) mortality and morbidity in the infants treated with allopurinol.
                Allopurinol treatment started postnatally was too late to reduce the early reperfusion induced free radical surge. Allopurinol administration to the fetus with (imminent) hypoxia via the mother during labour may be more effective in reducing free radical induced post-asphyxial brain damage. This study aimed to investigate the effect of allopurinol in the management of cerebral hypoxia-ischemia by monitoring nitric oxide levels of serum and cerebrospinal fluid. Sixty asphyxiated infants were divided randomly into two groups. Group I infants (n = 30) received allopurinol (40 mg/kg/day, 3 days) within 2 hours after birth. Group II infants (n = 30) received a placebo. Twenty healthy neonates served as control subjects. Cerebrospinal fluid and serum nitric oxide levels were measured within 0-24 hours and 72-96 hours after birth. Both serum and cerebrospinal fluid concentrations of nitric oxide were higher in severely asphyxiated infants (40.86 +/- 8.97, 17.3 +/- 3.63 micromol/L, respectively) but lower in mildly asphyxiated infants (25.85 +/- 3.57, 5.70 +/- 2.56 micromol/L, respectively) than in moderately asphyxiated infants (35.86 +/- 5.38, 11.06 +/- 3.37 micromol/L, respectively) within the first 0-24 hours after birth. Serum nitric oxide levels in control subjects were lower than those of moderately and severely asphyxiated infants. Serum nitric oxide levels of Group I infants within 72-96 hours after birth decreased significantly from their corresponding levels within 0-24 hours after birth. The asphyxiated newborns treated with allopurinol had better neurologic and neurodevelopmental outcome at 12 or more months of age. Free radical-induced postasphyxial reperfusion injury has been recognized as an important cause of brain tissue damage. We investigated the effect of high-dose allopurinol (ALLO; 40 mg/kg), a xanthine-oxidase inhibitor and free radical scavenger, on free radical status in severely asphyxiated newborns and on postasphyxial cerebral perfusion and electrical brain activity.
                Free radical status was assessed by serial plasma determination of nonprotein-bound iron (microM), antioxidative capacity, and malondialdehyde (MDA; microM). Cerebral perfusion was investigated by monitoring changes in cerebral blood volume (delta CBV; mL/100 g brain tissue) with near infrared spectroscopy; electrocortical brain activity (ECBA) was assessed in microvolts by cerebral function monitor. Eleven infants received 40 mg/kg ALLO intravenously, and 11 infants served as controls (CONT). Plasma nonprotein-bound iron, antioxidative capacity, and MDA were measured before 4 hours, between 16 and 20 hours, and at the second and third days of age. Changes in CBV and ECBA were monitored between 4 and 8, 16 and 20, 58 and 62, and 104 and 110 hours of age.
                Six CONT and two ALLO infants died after neurologic deterioration. No toxic side effects of ALLO were detected. Nonprotein-bound iron (mean +/- SEM) in the CONT group showed an initial rise (18.7 +/- 4.6 microM to 21.3 +/- 3.4 microM) but dropped to 7.4 +/- 3.5 microM at day 3; in the ALLO group it dropped from 15.5 +/- 4.6 microM to 0 microM at day 3. Uric acid was significantly lower in ALLO-treated infants from 16 hours of life on. MDA remained stable in the ALLO group, but increased in the CONT group at 8 to 16 hours versus < 4 hours (mean +/- SEM; 0.83 +/- 0.31 microM vs 0.50 +/- 0.14 microM). During 4 to 8 hours, delta CBV-CONT showed a larger drop than delta CBV-ALLO from baseline. During the subsequent registrations CBV remained stable in both groups. ECBA-CONT decreased, but ECBA-ALLO remained stable during 4 to 8 hours of age. Neonates who died had the largest drops in CBV and ECBA.
                This study suggests a beneficial effect of ALLO treatment on free radical formation, CBV, and electrical brain activity, without toxic side effects.
The available data are not sufficient to determine whether allopurinol has clinically important benefits for newborn infants with hypoxic-ischaemic encephalopathy. Much larger trials are needed. Such trials could assess allopurinol as an adjunct to therapeutic hypothermia in infants with moderate and severe encephalopathy and should be designed to exclude important effects on mortality and adverse long-term neurodevelopmental outcomes.