EARLY DEVELOPMENT OF SYNCHRONY IN CORTICAL ACTIVATIONS IN THE HUMAN

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Detailed statistical analysis plan for the SafeBoosC III trial : a multinational randomised clinical trial assessing treatment guided by cerebral oxygenation monitoring versus treatment as usual in extremely preterm infants

Background: Infants born extremely preterm are at high risk of dying or suffering from severe brain injuries. Treatment guided by monitoring of cerebral oxygenation may reduce the risk of death and neurologic complications. The SafeBoosC III trial evaluates the effects of treatment guided by cerebral oxygenation monitoring versus treatment as usual. This article describes the detailed statistical analysis plan for the main publication, with the aim to prevent outcome reporting bias and data-driven analyses. Methods/design: The SafeBoosC III trial is an investigator-initiated, randomised, multinational, pragmatic phase III trial with a parallel group structure, designed to investigate the benefits and harms of treatment based on cerebral near-infrared spectroscopy monitoring compared with treatment as usual. Randomisation will be 1:1 stratified for neonatal intensive care unit and gestational age (lower gestational age (< 26 weeks) compared to higher gestational age ( 65 26 weeks)). The primary outcome is a composite of death or severe brain injury at 36 weeks postmenstrual age. Primary analysis will be made on the intention-to-treat population for all outcomes, using mixed-model logistic regression adjusting for stratification variables. In the primary analysis, the twin intra-class correlation coefficient will not be considered. However, we will perform sensitivity analyses to address this. Our simulation study suggests that the inclusion of multiple births is unlikely to significantly affect our assessment of intervention effects, and therefore we have chosen the analysis where the twin intra-class correlation coefficient will not be considered as the primary analysis. Discussion: In line with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines, we have developed and published this statistical analysis plan for the SafeBoosC III trial, prior to any data analysis. Trial registration: ClinicalTrials.org, NCT03770741. Registered on 10 December 2018

Cerebral near-infrared spectroscopy monitoring versus treatment as usual for extremely preterm infants : a protocol for the SafeBoosC randomised clinical phase III trial

Background: Cerebral oxygenation monitoring may reduce the risk of death and neurologic complications in extremely preterm infants, but no such effects have yet been demonstrated in preterm infants in sufficiently powered randomised clinical trials. The objective of the SafeBoosC III trial is to investigate the benefits and harms of treatment based on near-infrared spectroscopy (NIRS) monitoring compared with treatment as usual for extremely preterm infants. Methods/design: SafeBoosC III is an investigator-initiated, multinational, randomised, pragmatic phase III clinical trial. Inclusion criteria will be infants born below 28 weeks postmenstrual age and parental informed consent (unless the site is using 'opt-out' or deferred consent). Exclusion criteria will be no parental informed consent (or if 'opt-out' is used, lack of a record that clinical staff have explained the trial and the 'opt-out' consent process to parents and/or a record of the parents' decision to opt-out in the infant's clinical file); decision not to provide full life support; and no possibility to initiate cerebral NIRS oximetry within 6 h after birth. Participants will be randomised 1:1 into either the experimental or control group. Participants in the experimental group will be monitored during the first 72 h of life with a cerebral NIRS oximeter. Cerebral hypoxia will be treated according to an evidence-based treatment guideline. Participants in the control group will not undergo cerebral oxygenation monitoring and will receive treatment as usual. Each participant will be followed up at 36 weeks postmenstrual age. The primary outcome will be a composite of either death or severe brain injury detected on any of the serial cranial ultrasound scans that are routinely performed in these infants up to 36 weeks postmenstrual age. Severe brain injury will be assessed by a person blinded to group allocation. To detect a 22% relative risk difference between the experimental and control group, we intend to randomise a cohort of 1600 infants. Discussion: Treatment guided by cerebral NIRS oximetry has the potential to decrease the risk of death or survival with severe brain injury in preterm infants. There is an urgent need to assess the clinical effects of NIRS monitoring among preterm neonates. Trial registration: ClinicalTrial.gov, NCT03770741. Registered 10 December 2018

Neonatal Seizure Detection Using Deep Convolutional Neural Networks

Identifying a core set of features is one of the most important steps in the development of an automated seizure detector. In most of the published studies describing features and seizure classifiers, the features were hand-engineered, which may not be optimal. The main goal of the present paper is using deep convolutional neural networks (CNNs) and random forest to automatically optimize feature selection and classification. The input of the proposed classifier is raw multi-channel EEG and the output is the class label: seizure/nonseizure. By training this network, the required features are optimized, while fitting a nonlinear classifier on the features. After training the network with EEG recordings of 26 neonates, five end layers performing the classification were replaced with a random forest classifier in order to improve the performance. This resulted in a false alarm rate of 0.9 per hour and seizure detection rate of 77% using a test set of EEG recordings of 22 neonates that also included dubious seizures. The newly proposed CNN classifier outperformed three data-driven feature-based approaches and performed similar to a previously developed heuristic method

Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO) : Study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)

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. © 2019 The Author(s).Peer reviewe

Neonatal factors predictive for respiratory and gastro-intestinal morbidity after esophageal atresia repair

Background: Esophageal atresia is a major congenital foregut anomaly. Affected patients often suffer from respiratory and gastro-intestinal morbidity. The objective of this study is to identify possible neonatal predictive factors contributing to a long-term complicated clinical course in patients after repair of esophageal atresia. Methods: A total of 93 patients born between 1993 and 2013, with esophageal atresia and surviving the neonatal period were included in this retrospective study. A complicated clinical course was defined as the occurrence of 1 of these complications: severe gastroesophageal reflux, esophageal stricture requiring dilatations, need for tube feeding for >100 days, severe tracheomalacia, severe chronic respiratory disease and death. We used linear models with a binomial distribution to determine risk factors for gastro-intestinal or respiratory complicated evolution and a backward stepwise elimination procedure to reduce models until only significant variables remained in the model. Multinomial logistic regression was used to assess risk factors for different evolutions of complication. Model parameter estimates were used to calculate odds ratios for significant risk factors. Results: Fifty-seven patients (61%) had a complicated clinical course in the first year of life and 47 (51%) had a complicated evolution during years 1e6. In the first year, prematurity was a significant factor for complicated gastro-intestinal (OR 2.84) and respiratory evolution (OR 2.93). After 1 year, gastro-intestinal morbidity in childhood was associated with VACTERL association (OR 12.2) and a complicated first year (OR 36.1). Respiratory morbidity was associated with congenital heart disease (OR 12.9) and a complicated first year (OR 86.9). Multinomial logistic regression showed that premat

Automated EEG background analysis to identify neonates with hypoxic-ischemic encephalopathy treated with hypothermia at risk for adverse outcome: A pilot study

Background: To improve the objective assessment of continuous video-EEG (cEEG) monitoring of neonatal brain function, the aim was to relate automated derived amplitude and duration parameters of the suppressed periods in the EEG background (dynamic Interburst Interval= dIBIs) after neonatal hypoxic-ischemic encephalopathy (HIE) to favourable or adverse neurodevelopmental outcome. Methods: Nineteen neonates (gestational age 36-41 weeks) with HIE underwent therapeutic hypothermia and had cEEG-monitoring. EEGs were retrospectively analyzed with a previously developed algorithm to detect the dynamic Interburst Intervals. Median duration and amplitude of the dIBIs were calculated at 1h-intervals. Sensitivity and specificity of automated EEG background grading for favorable and adverse outcomes were assessed at 6h-intervals. Results: Dynamic IBI values reached the best prognostic value between 18 and 24h (AUC of 0.93). EEGs with dIBI amplitude ≥15 μV and duration 10s were specific for adverse outcome (89-100%) at 18-24h (n = 10). Extremely low voltage and invariant EEG patterns were indicative of adverse outcome at all time points. Conclusions: Automated analysis of the suppressed periods in EEG of neonates with HIE undergoing TH provides objective and early prognostic information. This objective tool can be used in a multimodal strategy for outcome assessment. Implementation of this method can facilitate clinical practice, improve risk stratification and aid therapeutic decision-making. A multicenter trial with a quantifiable outcome measure is warranted to confirm the predictive value of this method in a more heterogeneous dataset

Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): Study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)

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 65 36 weeks and a birth weight 65 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

Uso de espectroscopia de infrarrojo cercano en la unidad de cuidados intensivos neonatales

Near-infrared spectroscopy was first described in 1977 as a non-invasive technique to measure the cerebral oxygenation and cytochrome oxydase. Different techniques have been developed resulting in new instruments that make it possible to measure cerebral oxygenation in a non-invasive way. In this chapter the physiology and pathophysiology in relation to the measurement of cerebral oxygenation are explained and the direct possible clinical use enlightened, with special focus on measurement of ischemic cerebral hypoxia. The measurement of other organs like the liver, the bowel and the peripheral circulation are described. At the end, a short overview of future possible bed-side measurements like functional near-infrared spectroscopy, near-infrared imaging and photoacoustic measurements are given