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BACKGROUND: Despite therapeutic hypothermia (TH) and neonatal intensive care, 45-50% of children affected by moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE) die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective therapies are sought, besides TH, to further improve the outcome of affected infants. Allopurinol - a xanthine oxidase inhibitor - reduced the production of oxygen radicals and subsequent brain damage in pre-clinical and preliminary human studies of cerebral ischemia and reperfusion, if administered before or early after the insult. This ALBINO trial aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to (near-)term infants with early signs of HIE. METHODS/DESIGN: The ALBINO trial is an investigator-initiated, randomized, placebo-controlled, double-blinded, multi-national parallel group comparison for superiority investigating the effect of allopurinol in (near-)term infants with neonatal HIE. Primary endpoint is long-term outcome determined as survival with neurodevelopmental impairment versus death versus non-impaired survival at 2 years. RESULTS: The primary analysis with three mutually exclusive responses (healthy, death, composite outcome for impairment) will be on the intention-to-treat (ITT) population by a generalized logits model according to Bishop, Fienberg, Holland (Bishop YF, Discrete Multivariate Analysis: Therory and Practice, 1975) and ."will be stratified for the two treatment groups. DISCUSSION: The statistical analysis for the ALBINO study was defined in detail in the study protocol and implemented in this statistical analysis plan published prior to any data analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.

BACKGROUND Most extremely low gestational age neonates (ELGANS, postmenstrual age at birth (PMA) < 28 completed weeks) require supplemental oxygen and experience frequent intermittent hypoxemic and hyperoxemic episodes. Hypoxemic episodes and exposure to inadequately high concentrations of oxygen are associated with an increased risk of retinopathy of prematurity (ROP), chronic lung disease of prematurity (BPD), necrotizing enterocolitis (NEC), neurodevelopmental impairment (NDI), and death beyond 36 weeks PMA. Closed-loop automated control of the inspiratory fraction of oxygen (FiO$_{2}$-C) reduces time outside the hemoglobin oxygen saturation (SpO$_{2}$) target range, number and duration of hypo- and hyperoxemic episodes and caregivers' workload. Effects on clinically important outcomes in ELGANs such as ROP, BPD, NEC, NDI and mortality have not yet been studied. METHODS An outcome-assessor-blinded, randomized controlled, parallel-group trial was designed and powered to study the effect of FiO$_{2}$-C (in addition to routine manual control (RMC) of FiO$_{2}$), compared to RMC only, on death and severe complications related to hypoxemia and/or hyperoxemia. 2340 ELGANS with a GA of 23 + 0/7 to 27 + 6/7 weeks will be recruited in approximately 75 European tertiary care neonatal centers. Study participants are randomly assigned to RMC (control-group) or FiO$_{2}$-C in addition to RMC (intervention-group). Central randomization is stratified for center, gender and PMA at birth (< 26 weeks and ≥ 26 weeks). FiO$_{2}$-C is provided by commercially available and CE-marked ventilators with an FiO$_{2}$-C algorithm intended for use in newborn infants. The primary outcome variable (composite of death, severe ROP, BPD or NEC) is assessed at 36 weeks PMA (or, in case of ROP, until complete vascularization of the retina, respectively). The co-primary outcome variable (composite outcome of death, language/cognitive delay, motor impairment, severe visual impairment or hearing impa

BACKGROUND Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. METHODS This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. DISCUSSION This trial will provide data

[Background]: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia., [Methods]: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion., [Discussion]: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia., [Trial registration]: NCT03162653, www.ClinicalTrials.gov, May 22, 2017.

BACKGROUND: What constitutes a hemodynamically relevant patent ductus arteriosus (hrPDA) in preterm infants is unclear. Different clinical and echocardiographic parameters are used, but a gold standard definition is lacking. Our objective was to evaluate associations between regional cerebral tissue oxygen saturation (rcStO2), fraction of tissue oxygen extraction (rcFtO2E) measured by frequency domain near-infrared spectroscopy (fd-NIRS) and their correlation to echocardiographic, Doppler-ultrasound, and clinical parameters in preterm infants with and without a hrPDA. METHODS: In this prospective observational study, 22 infants < 1500 g (mean [± SD]: gestational age 28.6 [±1.8] weeks, birth weight 1076 [±284] g, median (interquartile range) postnatal age at measurement 7.6 (4.6-12.9) d) with a clinical suspicion of hrPDA were analysed. Twelve infants had left-to-right shunt through PDA, and in 6 of these the PDA was classified as hrPDA based on pre-defined clinical and echocardiographic criteria. fd-NIRS, echocardiographic and Doppler-ultrasound examinations were performed. After identification of blood hemoglobin (Hb) as confounding factor, rcStO2 and rcFtO2E were corrected for this effect. RESULTS: Overall mean ± standard deviation (normalised to a median Hb of 13.8 mg/dl) was 57 ±5% for rcStO2 and 0.39 ±0.05 for rcFtO2E. Comparing no-hrPDA with hrPDA infants, there were no significant differences in mean rcStO2 (58 ±5% vs. 54 ±5%; p = .102), but in mean rcFtO2E (0.38 ±0.05 vs. 0.43 ±0.05; p = .038). Echocardiographic parameter and Doppler indices did not correlate with cerebral oxygenation. CONCLUSION: Oxygen transport capacity of the blood may confound NIRS data interpretation. Cerebral oxygenation determined by fd-NIRS provided additional information for PDA treatment decisions not offered by routine investigations. Whether indicating PDA therapy based on echocardiography complemented by data on cerebral oxygenation results in better outcomes should be investig

BACKGROUND Brain-water content (BWC) decreases with maturation of the brain and potentially affects parameters of cerebral oxygenation determined by near-infrared spectroscopy (NIRS). Most commercially available devices do not take these maturational changes into account. The aim of this study was to determine the effect of different assumptions for BWC on parameters of cerebral oxygenation in preterm infants. METHODS Concentrations of oxy-, deoxy- and total hemoglobin and regional cerebral oxygen saturation (rcStO2) were calculated based on absolute coefficients of absorption and scattering determined by multi-distance Frequency-Domain-NIRS assuming BWCs of 75-95%, which may be encountered in newborn infants depending on gestational and postnatal age. RESULTS This range of BWC gave rise to a linear modification of the assessed NIRS parameters with a maximum change of 10%. This may result in an absolute overestimation of rcStO2 by (median (range)) 4 (1-8)%, if the calculation is based on the lowest BWC (75%) in an extremely preterm infant with an anticipated BWC of 95%. CONCLUSION Clinicians wishing to rely on parameters of cerebral oxygenation determined by NIRS should consider that maturational changes in BWC not taken into account by most devices may result in a deviation of cerebral oxygenation readings by up to 8% from the correct value.