Cerebral Oximetry Monitoring in Extremely Preterm Infants.

BACKGROUND: The use of cerebral oximetry monitoring in the care of extremely preterm infants is increasing. However, evidence that its use improves clinical outcomes is lacking. METHODS: In this randomized, phase 3 trial conducted at 70 sites in 17 countries, we assigned extremely preterm infants (gestational age, <28 weeks), within 6 hours after birth, to receive treatment guided by cerebral oximetry monitoring for the first 72 hours after birth or to receive usual care. The primary outcome was a composite of death or severe brain injury on cerebral ultrasonography at 36 weeks' postmenstrual age. Serious adverse events that were assessed were death, severe brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and late-onset sepsis. RESULTS: A total of 1601 infants underwent randomization and 1579 (98.6%) were evaluated for the primary outcome. At 36 weeks' postmenstrual age, death or severe brain injury had occurred in 272 of 772 infants (35.2%) in the cerebral oximetry group, as compared with 274 of 807 infants (34.0%) in the usual-care group (relative risk with cerebral oximetry, 1.03; 95% confidence interval, 0.90 to 1.18; P = 0.64). The incidence of serious adverse events did not differ between the two groups. CONCLUSIONS: In extremely preterm infants, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth was not associated with a lower incidence of death or severe brain injury at 36 weeks' postmenstrual age than usual care. (Funded by the Elsass Foundation and others; SafeBoosC-III ClinicalTrials.gov number, NCT03770741.).

Executive Function Assessment in 2-Year-Olds Born Preterm.

OBJECTIVE: Our objective was to investigate the executive function and its relationship with gestational age, sex, maternal education, and neurodevelopmental outcome at 2 years corrected age in children born preterm. METHOD: Executive function was assessed by means of the Multisearch Multilocation Task (MSML), Reversed Categorization Task (RevCat), and Snack Delay Task (SDT). Infant and maternal characteristics were gathered from the child's record. The developmental outcome was measured by the Bayley Scales and a multidisciplinary risk evaluation for autism. RESULTS: The executive function battery was completed by 97 children. The majority were able to successfully complete the MSML and SDT but failed RevCat. The lower the gestational age and the maternal education, the lower the executive function scores. Better cognition and motor function, as well as low autism risk, were associated with better executive function scores. Executive function was not related to sex. INTERPRETATION: This cohort study provides evidence that it is feasible to assess executive function in 2-year-olds born preterm. Executive function is related to gestational age and maternal education and is positively correlated with behavioral outcome. Therefore, executive functions can be a valuable target for early intervention, resulting in improvements in neurodevelopmental outcomes in children born preterm.

Longitudinal trajectory of medial gastrocnemius muscle growth in the first years of life.

AIM: To define the longitudinal trajectory of gastrocnemius muscle growth in 6- to 36-month-old children with and without spastic cerebral palsy (SCP) and to compare trajectories by levels of gross motor function (Gross Motor Function Classification System, GMFCS) and presumed brain-lesion timing. METHOD: Twenty typically developing children and 24 children with SCP (GMFCS levels I-II/III-IV = 15/9), were included (28/16 females/males; mean age at first scan 15.4 months [standard deviation 4.93, range 6.24-23.8]). Three-dimensional freehand ultrasound was used to repeatedly assess muscle volume, length, and cross-sectional area (CSA), resulting in 138 assessments (mean interval 7.9 months). Brain lesion timing was evaluated with magnetic resonance imaging classification. Linear mixed-effects models defined growth rates, adjusted for GMFCS levels and presumed brain-lesion timing. RESULTS: At age 12 months, children with SCP showed smaller morphological muscle size than typically developing children (5.8 mL vs 9.8 mL, p < 0.001), while subsequently no differences in muscle growth were found between children with and without SCP (muscle volume: 0.65 mL/month vs 0.74 mL/month). However, muscle volume and CSA growth rates were lower in children classified in GMFCS levels III and IV than typically developing children and those classified in GMFCS levels I and II, with differences ranging from -56% to -70% (p < 0.001). INTERPRETATION: Muscle growth is already hampered during infancy in SCP. Muscle size growth further reduces with decreasing functional levels, independently from the brain lesion. Early monitoring of muscle growth combined with early intervention is needed.

The Impact of Intraventricular Hemorrhage and Periventricular Leukomalacia on Mortality and Neurodevelopmental Outcome in Very Preterm and Very Low Birthweight Infants: A Prospective Population-based Cohort Study.

OBJECTIVE: To survey the incidence of intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) by gestational age and to report the impact on mortality and neurodevelopmental outcome in very preterm/very low birthweight infants. STUDY DESIGN: This was a population-based cohort study of 1927 very preterm/very low birthweight infants born in 2014-2016 and admitted to Flemish neonatal intensive care units. Infants underwent standard follow-up assessment until 2 years corrected age with the Bayley Scales of Infant and Toddler Development and neurological assessments. RESULTS: No brain lesion was present in 31% of infants born at <26 weeks of gestation and 75.8% in infants born at 29-32 weeks of gestation. The prevalence of low-grade IVH/PVL (grades I and II) was 16.8% and 12.7%, respectively. Low-grade IVH/PVL was not related significantly to an increased likelihood of mortality, motor delay, or cognitive delay, except for PVL grade II, which was associated with a 4-fold increase in developing cerebral palsy (OR, 4.1; 95% CI, 1.2-14.6). High-grade lesions (III-IV) were present in 22.0% of the infants born at <26 weeks of gestational and 3.1% at 29-32 weeks of gestation, and the odds of death were ≥14.0 (IVH: OR, 14.0; 95% CI, 9.0-21.9; PVL: OR, 14.1; 95% CI, 6.6-29.9). PVL grades III-IV showed an increased odds of 17.2 for motor delay and 12.3 for cerebral palsy, but were not found to be associated significantly with cognitive delay (OR, 2.9; 95% CI, 0.5-17.5; P = .24). CONCLUSIONS: Both the prevalence and severity of IVH/PVL decreased significantly with advancing gestational age. More than 75% of all infants with low grades of IVH/PVL showed normal motor and cognitive outcome at 2 years corrected age. High-grade PVL/IVH has become less common and is associated with adverse outcomes.

Investigating the development of the autonomic nervous system in infancy through pupillometry.

We aim to investigate early developmental trajectories of the autonomic nervous system (ANS) as indexed by the pupillary light reflex (PLR) in infants with (i.e. preterm birth, feeding difficulties, or siblings of children with autism spectrum disorder) and without (controls) increased likelihood for atypical ANS development. We used eye-tracking to capture the PLR in 216 infants in a longitudinal follow-up study spanning 5 to 24 months of age, and linear mixed models to investigate effects of age and group on three PLR parameters: baseline pupil diameter, latency to constriction and relative constriction amplitude. An increase with age was found in baseline pupil diameter (F(3,273.21) = 13.15, p < 0.001, [Formula: see text] = 0.13), latency to constriction (F(3,326.41) = 3.84, p = 0.010, [Formula: see text] = 0.03) and relative constriction amplitude(F(3,282.53) = 3.70, p = 0.012, [Formula: see text] = 0.04). Group differences were found for baseline pupil diameter (F(3,235.91) = 9.40, p < 0.001, [Formula: see text] = 0.11), with larger diameter in preterms and siblings than in controls, and for latency to constriction (F(3,237.10) = 3.48, p = 0.017, [Formula: see text] = 0.04), with preterms having a longer latency than controls. The results align with previous evidence, with development over time that could be explained by ANS maturation. To better understand the cause of the group differences, further research in a larger sample is necessary, combining pupillometry with other measures to further validate its value.

Cerebral oxygenation and body position in the preterm infant: A systematic review and meta-analysis.

AIM: After preterm birth, supine head midline position is supported for stable cerebral blood flow (CBF) and prevention of intraventricular haemorrhage (IVH), while prone position supports respiratory function and enables skin-to-skin care. The prone compared to supine position could lead to a change in near-infrared derived cerebral tissue oxygen saturation (rScO2), which is a surrogate for cerebral blood flow (CBF). By monitoring rScO2 neonatologists aim to stabilise CBF during intensive care and prevent brain injury. In this systematic review and meta-analysis, we investigate the effect of the body position on rScO2. METHODS: A comprehensive literature search was performed to identify all trials that included preterm infants in the first 2 weeks after birth and compared rScO2 in the prone versus supine head in midline position of the infant. A meta-analysis, including two subgroup analyses based on postnatal age (PNA) and gestational age (GA), was performed. RESULTS: Six observational cohort studies were included. In the second, but not the first week after birth, a significant higher rScO2 in the prone position was found with a mean difference of 1.97% (95% CI 0.87-3.07). No rScO2 difference was observed between positions in the extremely preterm nor the preterm group. CONCLUSION: No consistent evidence was found that body position influences rScO2 in the first 2 weeks after preterm birth. Subgroup analysis suggests that in the second week after birth, the prone position might result in higher cerebral rScO2 than the supine position with head in midline. Multiple factors determine the best body position in preterms.

Barriers and facilitators for parents in end-of-life decision-making for neonates at the Neonatal Intensive Care Unit: A qualitative study.

BACKGROUND: Mortality and end-of-life decision-making can occur in newborns, especially within the Neonatal Intensive Care Unit. For parents, participating in end-of-life decision-making is taxing. Knowledge is lacking on what support is helpful to parents during decision-making. AIM: To identify barriers and facilitators experienced by parents in making an end-of-life decision for their infant. DESIGN: Qualitative study using face-to-face semi-structured interviews. SETTING/PARTICIPANTS: We interviewed 23 parents with a child that died after an end-of-life decision at a Neonatal Intensive Care Unit between April and September 2018. RESULTS: Parents stated barriers and facilitators within 4 themes: 1. Clinical knowledge and prognosis; 2. Quality of information provision; 3. Emotion regulation; and 4. Psychosocial environment. Facilitators include knowing whether the prognosis includes long-term negative quality of life, knowing all treatment options, receiving information according to health literacy level, being able to process intense emotions, having experienced counseling and practical help. Barriers include a lack of general medical knowledge, being unprepared for a poor prognosis, having an uninformed psychologist. CONCLUSIONS: We found that clinical information and psychosocial support aid parents in decision-making. Information is best tailored to health literacy. Psychosocial support can be provided by experienced, informed counselors, social services and sibling support, distinguishing between verbal and non-verbal coping preferences, and calm, familiar architecture. Intense emotions may hinder absorption of clinical information, therefore interventions to aid emotion regulation and reduce cognitive load may be looked at in further research. Adjustment of the Situations, Opinions and Options, Parents, Information, Emotions framework based on our results can be evaluated.

Pre- and postnatal brain magnetic resonance imaging in congenital cytomegalovirus infection: a case report and a review of the literature.

BACKGROUND: Congenital cytomegalovirus infection (cCMV) is the most common known viral cause of neurodevelopmental delay in children. The risk of severe cerebral abnormalities and neurological sequelae is greatest when the infection occurs during the first trimester of pregnancy. Pre- and postnatal imaging can provide additional information and may help in the prediction of early neurological outcome. CASE PRESENTATION: This report presents the case of a newborn with cCMV infection with diffuse parenchymal calcifications, white matter (WM) abnormalities and cerebellar hypoplasia on postnatal brain imaging after magnetic resonance imaging (MRI) and neurosonogram (NSG) at 30 weeks showing lenticulostriate vasculopathy, bilateral temporal cysts and normal gyration pattern according to the gestational age (GA). No calcifications were seen on prenatal imaging. CONCLUSION: cCMV infection can still evolve into severe brain damage after 30 weeks of GA. For this reason, a two-weekly follow-up by fetal NSG with a repeat in utero MRI (iuMRI) in the late third trimester is recommended in cases with signs of active infection.

Consultation of parents and healthcare professionals in end-of-life decision-making for neonates and infants: a population-level mortality follow-back physician survey.

BACKGROUND: End-of-life decisions with potential life-shortening effect in neonates and infants are common. We aimed to evaluate how often and in what manner neonatologists consult with parents and other healthcare providers in these cases, and whether consultation is dependent on the type of end-of-life decision made. METHODS: Based on all deaths under the age of one that occurred between September 2016 and December 2017 in Flanders, Belgium, a nationwide mortality follow-back survey was performed. The survey asked about different types of end-of-life decisions, and whether and why parents and/or other healthcare providers had or had not been consulted. RESULTS: Response rate was 83% of the total population. End-of-life decisions in neonates and infants were consulted both with parents (92%) and other healthcare providers (90%), and agreement was reached between parents and healthcare providers in most cases (96%). When medication with an explicit life-shortening intent was administered parents were always consulted prior to the decision; however when medication without explicit life-shortening intention was administered parents were not consulted in 25% of the cases. CONCLUSIONS: Shared decision-making between parents and physicians in case of neonatal or infant end-of-life decision-making is the norm in daily practice. All cases without parental consultation concerned non-treatment decisions or comfort medication without explicit life-shortening intention where physicians deemed the medical situation clear and unambiguous. However, we recommend to at least inform parents of medical options, and to explore other possibilities to engage parents in reaching a shared decision. Physicians consult other healthcare providers before making an end-of-life decision in most cases.

Assessing Neurovascular Coupling Using Wavelet Coherence in Neonates with Asphyxia.

Brain monitoring is important in neonates with asphyxia in order to assess the severity of hypoxic ischaemic encephalopathy (HIE) and identify neonates at risk of adverse neurodevelopmental outcome. Previous studies suggest that neurovascular coupling (NVC), quantified as the interaction between electroencephalography (EEG) and near-infrared spectroscopy (NIRS)-derived regional cerebral oxygen saturation (rSO2) is a promising biomarker for HIE severity and outcome. In this study, we explore how wavelet coherence can be used to assess NVC. Wavelet coherence was computed in 18 neonates undergoing therapeutic hypothermia in the first 3 days of life, with varying HIE severities (mild, moderate, severe). We compared two pre-processing methods of the EEG prior to wavelet computation: amplitude integrated EEG (aEEG) and EEG bandpower. Furthermore, we proposed average real coherence as a biomarker for NVC. Our results indicate that NVC as assessed by wavelet coherence between EEG bandpower and rSO2 can be a valuable biomarker for HIE severity in neonates with peripartal asphyxia. More specifically, average real coherence in a very low frequency range (0.21-0.83 mHz) tends to be high (positive) in neonates with mild HIE, low (positive) in neonates with moderate HIE, and negative in neonates with severe HIE. Further investigation in a larger patient cohort is needed to validate our findings.

Neurocardiovascular coupling in congenital diaphragmatic hernia patients undergoing different types of surgical treatment.

BACKGROUND: The effect of peri-operative management on the neonatal brain is largely unknown. Triggers for perioperative brain injury might be revealed by studying changes in neonatal physiology peri-operatively. OBJECTIVE: To study neonatal pathophysiology and cerebral blood flow regulation peri-operatively using the neuro-cardiovascular graph. DESIGN: Observational, prospective cohort study on perioperative neuromonitoring. Neonates were included between July 2018 and April 2020. SETTING: Multicentre study in two high-volume tertiary university hospitals. PATIENTS: Neonates with congenital diaphragmatic hernia were eligible if they received surgical treatment within the first 28 days of life. Exclusion criteria were major cardiac or chromosomal anomalies, or syndromes associated with altered cerebral perfusion or major neurodevelopmental impairment. The neonates were stratified into different groups by type of peri-operative management. INTERVENTION: Each patient was monitored using near-infrared spectroscopy and EEG in addition to the routine peri-operative monitoring. Neurocardiovascular graphs were computed off-line. MAIN OUTCOME MEASURES: The primary endpoint was the difference in neurocardiovascular graph connectivity in the groups over time. RESULTS: Thirty-six patients were included. The intraoperative graph connectivity decreased in all patients operated upon in the operation room (OR) with sevoflurane-based anaesthesia ( P  < 0.001) but remained stable in all patients operated upon in the neonatal intensive care unit (NICU) with midazolam-based anaesthesia. Thoracoscopic surgery in the OR was associated with the largest median connectivity reduction (0.33 to 0.12, P  < 0.001) and a loss of baroreflex and neurovascular coupling. During open surgery in the OR, all regulation mechanisms remained intact. Open surgery in the NICU was associated with the highest neurovascular coupling values. CONCLUSION: Neurocardiovascular graphs provided more insight into the effect of the peri-operative management on the pathophysiology of neonates undergoing surgery. The neonate's clinical condition as well as the surgical and the anaesthesiological approach affected the neonatal physiology and CBF regulation mechanisms at different levels. TRIAL REGISTRATION: NL6972, URL: https://www.trialre-gister.nl/trial/6972 .

Cerebral oxygen saturation and autoregulation during hypotension in extremely preterm infants.

BACKGROUND: The impact of the permissive hypotension approach in clinically well infants on regional cerebral oxygen saturation (rScO2) and autoregulatory capacity (CAR) remains unknown. METHODS: Prospective cohort study of blinded rScO2 measurements within a randomized controlled trial of management of hypotension (HIP trial) in extremely preterm infants. rScO2, mean arterial blood pressure, duration of cerebral hypoxia, and transfer function (TF) gain inversely proportional to CAR, were compared between hypotensive infants randomized to receive dopamine or placebo and between hypotensive and non-hypotensive infants, and related to early intraventricular hemorrhage or death. RESULTS: In 89 potentially eligible HIP trial patients with rScO2 measurements, the duration of cerebral hypoxia was significantly higher in 36 hypotensive compared to 53 non-hypotensive infants. In 29/36 hypotensive infants (mean GA 25 weeks, 69% males) receiving the study drug, no significant difference in rScO2 was observed after dopamine (n = 13) compared to placebo (n = 16). Duration of cerebral hypoxia was associated with early intraventricular hemorrhage or death.  Calculated TF gain (n = 49/89) was significantly higher reflecting decreased CAR in 16 hypotensive compared to 33 non-hypotensive infants. CONCLUSIONS: Dopamine had no effect on rScO2 compared to placebo in hypotensive infants. Hypotension and cerebral hypoxia are associated with early intraventricular hemorrhage or death. IMPACT: Treatment of hypotension with dopamine in extremely preterm infants increases mean arterial blood pressure, but does not improve cerebral oxygenation. Hypotensive extremely preterm infants have increased duration of cerebral hypoxia and reduced cerebral autoregulatory capacity compared to non-hypotensive infants. Duration of cerebral hypoxia and hypotension are associated with early intraventricular hemorrhage or death in extremely preterm infants. Since systematic treatment of hypotension may not be associated with better outcomes, the diagnosis of cerebral hypoxia in hypotensive extremely preterm infants might guide treatment.

Neonatologists' decision-making for resuscitation and non-resuscitation of extremely preterm infants: ethical principles, challenges, and strategies-a qualitative study.

BACKGROUND: Deciding whether to resuscitate extremely preterm infants (EPIs) is clinically and ethically problematic. The aim of the study was to understand neonatologists' clinical-ethical decision-making for resuscitation of EPIs. METHODS: We conducted a qualitative study in Belgium, following a constructivist account of the Grounded Theory. We conducted 20 in-depth, face-to-face, semi-structured interviews with neonatologists. Data analysis followed the qualitative analysis guide of Leuven. RESULTS: The main principles guiding participants' decision-making were EPIs' best interest and respect for parents' autonomy. Participants agreed that justice as resource allocation should not be considered in resuscitation decision-making. The main ethical challenge for participants was dealing with the conflict between EPIs' best interest and respect for parents' autonomy. This conflict was most prominent when parents and clinicians disagreed about births within the gray zone (24-25 weeks). Participants' coping strategies included setting limits on extent of EPI care provided and rigidly following established guidelines. However, these strategies were not always feasible or successful. Although rare, these situations often led to long-lasting moral distress. CONCLUSIONS: Participants' clinical-ethical reasoning for resuscitation of EPIs can be mainly characterized as an attempt to balance EPIs' best interest and respect for parents' autonomy. This approach could explain why neonatologists considered conflicts between these principles as their main ethical challenge and why lack of resolution increases the risk of moral distress. Therefore, more research is needed to better understand moral distress in EPI resuscitation decisions. CLINICAL TRIAL REGISTRATION: The study received ethical approval from the ethics committee of UZ/KU Leuven (S62867). Confidentiality of personal information and anonymity was guaranteed in accordance with the General Data Protection Regulation of 25 May 2018.

Psychological support in end-of-life decision-making in neonatal intensive care units: Full population survey among neonatologists and neonatal nurses.

BACKGROUND: Moral distress and burnout related to end-of-life decisions in neonates is common in neonatologists and nurses working in neonatal intensive care units. Attention to their emotional burden and psychological support in research is lacking. AIM: To evaluate perceived psychological support in relation to end-of-life decisions of neonatologists and nurses working in Flemish neonatal intensive care units and to analyse whether or not this support is sufficient. DESIGN/PARTICIPANTS: A self-administered questionnaire was sent to all neonatologists and neonatal nurses of all eight Flemish neonatal intensive care units (Belgium) in May 2017. The response rate was 63% (52/83) for neonatologists and 46% (250/527) for nurses. Respondents indicated their level of agreement (5-point Likert-type scale) with seven statements regarding psychological support. RESULTS: About 70% of neonatologists and nurses reported experiencing more stress than normal when confronted with an end-of-life decision; 86% of neonatologists feel supported by their colleagues when they make end-of-life decisions, 45% of nurses feel that the treating physician listens to their opinion when end-of-life decisions are made. About 60% of both neonatologists and nurses would like more psychological support offered by their department when confronted with end-of-life decisions, and 41% of neonatologists and 50% of nurses stated they did not have enough psychological support from their department when a patient died. Demographic groups did not differ in terms of perceived lack of sufficient support. CONCLUSION: Even though neonatal intensive care unit colleagues generally support each other in difficult end-of-life decisions, the psychological support provided by their department is currently not sufficient. Professional ad hoc counselling or standard debriefings could substantially improve this perceived lack of support.

Ethics of resuscitation for extremely premature infants: a systematic review of argument-based literature.

OBJECTIVE: To present (1) the ethical concepts related to the debate on resuscitation of extremely premature infants (EPIs) as they are described in the ethical literature; and (2) the ethical arguments based on these concepts. DESIGN: We conducted a systematic review of the ethical literature. We selected articles based on the following predefined inclusion/exclusion criteria: (1) English language articles (2) presenting fully elaborated ethical arguments (3) on resuscitation (4) of EPIs, that is, infants born before 28 weeks of gestation. ANALYSIS: After repeated reading of articles, we developed individual summaries, conceptual schemes and an overall conceptual scheme. Ethical arguments and concepts were identified and analysed. RESULTS: Forty articles were included out of 4709 screened. Personhood, best interest, autonomy and justice were concepts grounding the various arguments. Regarding these concepts, included authors agreed that the best interest principle should guide resuscitation decisions, whereas justice seemed the least important concept. The arguments addressed two questions: Should we resuscitate EPIs? Who should decide? Included authors agreed that not all EPIs should be resuscitated but disagreed on what criteria should ground this decision. Overall, included authors agreed that both parents and physicians should contribute to the decision. CONCLUSIONS: The included publications suggest that while the best interest is the main concept guiding resuscitation decisions, justice is the least important. The included authors also agree that both parents and physicians should be actively involved in resuscitation decisions for EPIs. However, our results suggest that parents' decision should be over-ridden when in contrast with the EPI's best interest.

Neonatologists and neonatal nurses have positive attitudes towards perinatal end-of-life decisions, a nationwide survey.

AIM: Perinatal death is often preceded by an end-of-life decision (ELD). Disparate hospital policies, complex legal frameworks and ethically difficult cases make attitudes important. This study investigated attitudes of neonatologists and nurses towards perinatal ELDs. METHODS: A survey was handed out to all neonatologists and neonatal nurses in all eight neonatal intensive care units in Flanders, Belgium in May 2017. Respondents indicated agreement with statements regarding perinatal ELDs on a Likert-scale and sent back questionnaires via mail. RESULTS: The response rate was 49.5% (302/610). Most neonatologists and nurses found nontreatment decisions such as withholding or withdrawing treatment acceptable (90-100%). Termination of pregnancy when the foetus is viable in cases of severe or lethal foetal problems was considered highly acceptable in both groups (80-98%). Physicians and nurses do not find different ELDs equally acceptable, e.g. nurses more often than physicians (74% vs 60%, p = 0.017) agree that it is acceptable in certain cases to administer medication with the explicit intention of hastening death. CONCLUSION: There was considerable support for both prenatal and neonatal ELDs, even for decisions that currently fall outside the Belgian legal framework. Differences between neonatologists' and nurses' attitudes indicate that both opinions should be heard during ELD-making.

Nonlinear Transfer Entropy to Assess the Neurovascular Coupling in Premature Neonates.

In the adult brain, it is well known that increases in local neural activity trigger changes in regional blood flow and, thus, changes in cerebral energy metabolism. This regulation mechanism is called neurovascular coupling (NVC). It is not yet clear to what extent this mechanism is present in the premature brain. In this study, we explore the use of transfer entropy (TE) in order to compute the nonlinear coupling between changes in brain function, assessed by means of EEG, and changes in brain oxygenation, assessed by means of near-infrared spectroscopy (NIRS). In a previous study, we measured the coupling between both variables using a linear model to compute TE. The results indicated that changes in brain oxygenation were likely to precede changes in EEG activity. However, using a nonlinear and nonparametric approach to compute TE, the results indicate an opposite directionality of this coupling. The source of the different results provided by the linear and nonlinear TE is unclear and needs further research. In this study, we present the results from a cohort of 21 premature neonates. Results indicate that TE values computed using the nonlinear approach are able to discriminate between neonates with brain abnormalities and healthy neonates, indicating a less functional NVC in neonates with brain abnormalities.

Towards integrative neuromonitoring of the surgical newborn: A systematic review.

BACKGROUND: The altered neurodevelopment of children operated on during the neonatal period might be due to peri-operative changes in the homeostasis of brain perfusion. Monitoring of vital signs is a standard of care, but it does not usually include monitoring of the brain. OBJECTIVES: To evaluate methods of monitoring the brain that might be of value. We also wanted to clarify if there are specific risk factors that result in peri-operative changes and how this might be evaluated. DESIGN: Systematic review. DATA SOURCES: A structured literature search was performed in MEDLINE in Ovid, Embase, Cochrane CENTRAL, Web of Science and Google Scholar. ELIGIBILITY CRITERIA: Studies in neonates who received peri-operative neuromonitoring were eligible for inclusion; studies on neurosurgical procedures or cardiac surgery with cardiopulmonary bypass and/or deep hypothermia cardiac arrest were excluded. RESULTS: Nineteen of the 24 included studies, totalling 374 infants, reported the use of near-infrared spectroscopy. Baseline values of cerebral oxygenation greatly varied (mean 53 to 91%) and consequently, no coherent results were found. Two studies found a correlation between cerebral oxygenation and mean arterial blood pressure. Five studies, with in total 388 infants, used (amplitude-integrated) electro-encephalography to study peri-operative brain activity. Overall, the brain activity decreased during anaesthesia and epileptic activity was more frequent in the peri-operative phase. The association between intra-operative cerebral saturation or activity and neuro-imaging abnormalities and/or neurodevelopmental outcome was investigated in six studies, but no association was found. CONCLUSION: Neuromonitoring with the techniques currently used will neither help our understanding of the altered neonatal pathophysiology, nor enable early detection of deviation from the norm. The modalities lack specificity and are not related to clinical (long-term) outcome or prognosis. Accordingly, we were unable to draw up a monitoring guideline.

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.