Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia. Moderate hypothermia to treat perinatal asphyxial encephalopathy. 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. Whether hypothermic therapy improves neurodevelopmental outcomes in newborn infants with asphyxial encephalopathy is uncertain.
                We performed a randomized trial of infants who were less than 6 hours of age and had a gestational age of at least 36 weeks and perinatal asphyxial encephalopathy. We compared intensive care plus cooling of the body to 33.5 degrees C for 72 hours and intensive care alone. The primary outcome was death or severe disability at 18 months of age. Prespecified secondary outcomes included 12 neurologic outcomes and 14 other adverse outcomes.
                Of 325 infants enrolled, 163 underwent intensive care with cooling, and 162 underwent intensive care alone. In the cooled group, 42 infants died and 32 survived but had severe neurodevelopmental disability, whereas in the noncooled group, 44 infants died and 42 had severe disability (relative risk for either outcome, 0.86; 95% confidence interval [CI], 0.68 to 1.07; P=0.17). Infants in the cooled group had an increased rate of survival without neurologic abnormality (relative risk, 1.57; 95% CI, 1.16 to 2.12; P=0.003). Among survivors, cooling resulted in reduced risks of cerebral palsy (relative risk, 0.67; 95% CI, 0.47 to 0.96; P=0.03) and improved scores on the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development II (P=0.03 for each) and the Gross Motor Function Classification System (P=0.01). Improvements in other neurologic outcomes in the cooled group were not significant. Adverse events were mostly minor and not associated with cooling.
                Induction of moderate hypothermia for 72 hours in infants who had perinatal asphyxia did not significantly reduce the combined rate of death or severe disability but resulted in improved neurologic outcomes in survivors. (Current Controlled Trials number, ISRCTN89547571.)
                2009 Massachusetts Medical Society 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.