Allopurinol: Old Drug, New Indication in Neonates?

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is an important cause of neonatal mortality and neurological morbidity, even despite hypothermia treatment. Neuronal damage in these infants is partly caused by the production of superoxides via the xanthine-oxidase pathway and concomitant free radical formation. Allopurinol is a xanthine-oxidase inhibitor and can potentially reduce the formation of these superoxides that lead to brain damage in HIE. METHODS: The aim of this review is to provide an overview of the animal and clinical data about the neuroprotective effect of allopurinol in HIE and the relevant mechanisms leading to brain injury in HIE. RESULTS: A possible neuroprotective effect of allopurinol has been suggested based on several preclinical studies in rats, piglets and sheep. Allopurinol seemed to inhibit the formation of superoxide and to scavenge free radicals directly, but the effect on brain damage was inconclusive in these preclinical trials. The neuroprotective effect was also investigated in neonates with HIE. In three small studies, in which, allopurinol was administered postnatally and a pilot and one multi-center study, in which, allopurinol was administered antenatally, a possible beneficial effect was found. After combining the data of 2 postnatal allopurinol studies, long-term follow-up was only beneficial in infants with moderate HIE, therefore, large-scale studies are needed. Additionally, safety, pharmacokinetics and the neuroprotective effect of allopurinol in other neonatal populations are discussed in this review. CONCLUSION: The available literature is not conclusive whether allopurinol is a neuroprotective add-on therapy in infants with HIE. More research is needed to establish the neuroprotective effect of allopurinol especially in combination with hypothermia.

Drugs for neuroprotection after birth asphyxia: Pharmacologic adjuncts to hypothermia.

An adverse outcome is still encountered in 45% of full-term neonates with perinatal asphyxia who are treated with moderate hypothermia. At present pharmacologic therapies are developed to be added to hypothermia. In the present article, these potential neuroprotective interventions are described based on the molecular pathways set in motion during fetal hypoxia and following reoxygenation and reperfusion after birth. These pathways include excessive production of excitotoxins with subsequent over-stimulation of NMDA receptors and calcium influx in neuronal cells, excessive production of reactive oxygen and nitrogen species, activation of inflammation leading to inappropriate apoptosis, and loss of neurotrophic factors. Possibilities for pharmacologic combination therapy, where each drug will be administered based on the optimal point of time in the cascade of destructive molecular reactions, may further reduce brain damage due to perinatal asphyxia.

Cerebral and somatic NIRS-determined oxygenation in IUGR preterm infants during transition.

BACKGROUND: Fetal growth restriction (intra-uterine growth restriction [IUGR]) has a considerable impact on perinatal morbidity. Preterm IUGR infants are prone to impaired intestine function. Near-infrared spectroscopy (NIRS) has been used to monitor oxygenation status of the brain and of the intestine. PATIENTS AND METHODS: We conducted a prospective case-control study at our NICU in 20 preterm infants of whom 10 infants complicated by compared with 10 non-IUGR preterm infants. Splanchnic and cerebral regional oximetry values were measured with NIRS. Three hours of consecutive recordings were performed in the first 24 h of life, T0, and during the transitional period, T1. The cerebral/splanchnic oxygenation ratio, CSOR, (cerebral regional saturations [rScO2]/splanchnic regional saturations [rSsO2]) was also calculated. RESULTS: Both in the IUGR and the non-IUGR infants, at T0 and T1 monitoring time-points, the rSO2 values were higher in the cerebral district when compared to those of the splanchnic area. Comparison of the NIRS parameters between the IUGR and non-IUGR infants at T0 showed no difference in rScO2, while rSsO2 was significantly lower in the IUGR group. At T1, rScO2 was significantly lower and rSsO2 higher in the IUGR group. CONCLUSIONS: Cerebral/splanchnic vascular adaptation of IUGR infants to the extra-uterine environment is characterized by a postnatal persistence of the brain sparing effect with reperfusion in the transitional period.

Antenatal Maternal Antidepressants Drugs Affect S100B Concentrations in Fetal-Maternal Biological Fluids.

INTRODUCTION: Antidepressant treatment during pregnancy is speedily increasing in developed countries and this phenomenon has occurred without firm evidence on safety and/or efficacy. AIMS: The present study investigated from mid-trimester of pregnancy up to 24 hours after birth the pattern of a brain damage marker, namely S100B, in maternal fetal and neonatal biological fluids of pregnant women and their newborns antenatally treated by antidepressant drugs such as selective serotonin re-uptake inhibitors (SSRI). METHODS: we conducted an observational study on 75 pregnant women treated in the mid -third trimester by antidepressant drugs and 231 healthy pregnancies. S100B concentrations were measured at 7 predetermined monitoring time-points before, during and after treatment in maternal, fetal and neonatal biological fluids and correlated with neurological follow-up at 7 days from birth. RESULTS: In SSRI group S100B concentrations were significantly higher in SSRI than controls (P<0.001, for all) in maternal blood, in amniotic fluid, in arterial and venous cord blood and at 24-h from birth. Highest (P<0.05) S100B levels were found in SSRI infants showing major neurological symptoms at 7-d follow-up. CONCLUSION: The present data on increased S100B levels in maternal, fetal and neonatal biological fluids suggest that SSRI administration although beneficial to the mother, presents some risks for the infant.

Cerebral oxygen saturation and electrical brain activity before, during, and up to 36 hours after arterial switch procedure in neonates without pre-existing brain damage: its relationship to neurodevelopmental outcome.

OBJECTIVE: To monitor the pattern of cerebral oxygen saturation (rSat), by use of NIRS, in term infants before, during and after the arterial switch operation and to evaluate its relation to neurodevelopmental outcome. METHODS: In 20 neonates without pre-existing brain damage hemodynamics and arterial oxygen saturation (AO2-Sat) were monitored simultaneously with rSat and amplitude-integrated EEG (aEEG) from 4 h to 12 h before up to 36 h after cardiopulmonary bypass (CPB) and short duration of cardiac arrest during deep hypothermia (DHCA). The Bayleys developmental scale was performed at 30 months. RESULTS: Before surgery rSat was <50% in 16 patients. During CPB rSat increased to normal values, with a sharp decrease during brief CA (median 6.5 min). Post-CPB rSat showed a transient decrease (30-45%) despite normal PaO2 with sustained normalization after 6-26 h. Recovery time of the rSat seemed longer when pre-operative rSat was below 35%, and for lower minimum nasopharyngeal temperature and longer duration of CPB and of DHCA. Recovery time of the aEEG varied and did not correlate with normalization of rSat. Neurodevelopmental outcome was normal in all but two patients. Patients with lower pre-operative rSat (<35%) tended to have lower DQ (developmental quotient) scores at 30-36 months. (median: mental 102 and motor 101 (range 58-125) compared with mental 100 and motor 110 (range 83-125)) CONCLUSION: Despite prompt normalization of circulation and oxygenation after surgery, recovery of rSat of the brain took 6-26 h, probably because of higher energy demand after CPB. Pre-operative cerebral oxygenation may be underestimated as a possible cause of adverse post-operative outcome.