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Cerebrovascular reactivity defines the ability of the cerebral vasculature to regulate its resistance in response to both local and systemic factors to ensure an adequate cerebral blood flow to meet the metabolic demands of the brain. The increasing adoption of near-infrared spectroscopy (NIRS) for non-invasive monitoring of cerebral oxygenation and perfusion allowed investigation of the mechanisms underlying cerebrovascular reactivity in the neonatal population, confirming important associations with pathological conditions including the development of brain injury and adverse neurodevelopmental outcomes. However, the current literature on neonatal cerebrovascular reactivity is mainly still based on small, observational studies and is characterised by methodological heterogeneity; this has hindered the routine application of NIRS-based monitoring of cerebrovascular reactivity to identify infants most at risk of brain injury. This review aims (1) to provide an updated review on neonatal cerebrovascular reactivity, assessed using NIRS; (2) to identify critical points that need to be addressed with targeted research; and (3) to propose feasibility trials in order to fill the current knowledge gaps and to possibly develop a preventive or curative approach for preterm brain injury. IMPACT: NIRS monitoring has been largely applied in neonatal research to assess cerebrovascular reactivity in response to blood pressure, PaCO 2 and other biochemical or metabolic factors, providing novel insights into the pathophysiological mechanisms underlying cerebral blood flow regulation. Despite these insights, the current literature shows important pitfalls that would benefit to be addressed in a series of targeted trials, proposed in the present review, in order to translate the assessment of cerebrovascular reactivity into routine monitoring in neonatal clinical practice., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

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., (© 2023 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Introduction: To ensure the quality of clinical trial safety data, universal data standards are required. In 2019 the International Neonatal Consortium (INC) published a neonatal adverse event severity scale (NAESS) to standardize the reporting of adverse event (AE) severity. In this study the reliability of AE severity grading with INC NAESS was prospectively assessed in a real-world setting. Methods: Severity of AEs was assessed by two independent observers at each of four centers across the world. In each center two series of 30 neonatal adverse events were assessed by both observers: in a first phase with a generic (Common Terminology Criteria for Adverse Events, CTCAE) severity scale not specific to neonates, and in a second phase with INC NAESS (after a structured training). Intraclass correlation coefficients (ICC) were calculated to express inter-rater agreement in both phases, and bootstrap sampling was used to compare them. Results: 120 AEs were included in each of both phases. The ICC with the use of INC NAESS in phase 2 was 0.69. This represents a significant but modest improvement in comparison to the initial ICC of 0.66 in phase 1 (confidence interval of ratio of ICC in phase 2 to phase 1 = 1.005-1.146; excludes 1). The ICC was higher for those AEs for which a diagnosis specific AE severity table was available in INC NAESS (ICC 0.80). Discussion: Good inter-rater reliability of the INC NAESS was demonstrated in four neonatal intensive care units (NICUs) across the globe. The ICC is comparable to what is reported for scales with similar purposes in different populations. There is a modest, but significant, improvement in inter-rater agreement in comparison to the naïve phase without INC NAESS. The better performance when reviewers use AE-specific NAESS tables highlights the need to expand the number of AEs that are covered by specific criteria in the current version of INC NAESS., Competing Interests: Several authors of this paper (TS, TL-M, IH, MT, KA, TLe), and the INC were involved in the development of INC NAESS. There are however no commercial or financial relationships that could be construed as a potential conflict of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Salaets, Lacaze-Masmonteil, Hokuto, Gauldin, Taha, Smits, Thewissen, Van Horebeek, Shoraisham, Mohammad, Suzuki, Komachi, Michels, Turner, Allegaert and Lewis.)

Objective: To test the potential utility of applying machine learning methods to regional cerebral (rcSO 2 ) and peripheral oxygen saturation (SpO 2 ) signals to detect brain injury in extremely preterm infants., Study Design: A subset of infants enrolled in the Management of Hypotension in Preterm infants (HIP) trial were analysed ( n = 46). All eligible infants were <28 weeks' gestational age and had continuous rcSO 2 measurements performed over the first 72 h and cranial ultrasounds performed during the first week after birth. SpO 2 data were available for 32 infants. The rcSO 2 and SpO 2 signals were preprocessed, and prolonged relative desaturations (PRDs; data-driven desaturation in the 2-to-15-min range) were extracted. Numerous quantitative features were extracted from the biosignals before and after the exclusion of the PRDs within the signals. PRDs were also evaluated as a stand-alone feature. A machine learning model was used to detect brain injury (intraventricular haemorrhage-IVH grade II-IV) using a leave-one-out cross-validation approach., Results: The area under the receiver operating characteristic curve (AUC) for the PRD rcSO 2 was 0.846 (95% CI: 0.720-0.948), outperforming the rcSO 2 threshold approach (AUC 0.593 95% CI 0.399-0.775). Neither the clinical model nor any of the SpO 2 models were significantly associated with brain injury., Conclusion: There was a significant association between the data-driven definition of PRDs in rcSO 2 and brain injury. Automated analysis of PRDs of the cerebral NIRS signal in extremely preterm infants may aid in better prediction of IVH compared with a threshold-based approach. Further investigation of the definition of the extracted PRDs and an understanding of the physiology underlying these events are required.

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.)., (Copyright © 2023 Massachusetts Medical Society.)

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., (© 2022 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objective: Neonates with Congenital Heart Disease (CHD) have structural delays in brain development. To evaluate whether functional brain maturation and sleep-wake physiology is also disturbed, the Functional Brain Age (FBA) and sleep organisation on EEG during the neonatal period is investigated., Methods: We compared 15 neonates with CHD who underwent multichannel EEG with healthy term newborns of the same postmenstrual age, including subgroup analysis for d-Transposition of the Great Arteries (d-TGA) (n = 8). To estimate FBA, a prediction tool using quantitative EEG features as input, was applied. Second, the EEG was automatically classified into the 4 neonatal sleep stages. Neonates with CHD underwent neurodevelopmental testing using the Bayley Scale of Infant Development-III at 24 months., Results: Preoperatively, the FBA was delayed in CHD infants and more so in d-TGA infants. The FBA was positively correlated with motor scores. Sleep organisation was significantly altered in neonates with CHD. The duration of the sleep cycle and the proportion of Active Sleep Stage 1 was decreased, again more marked in the d-TGA infants. Neonates with d-TGA spent less time in High Voltage Slow Wave Sleep and more in Tracé Alternant compared to healthy terms. Both FBA and sleep organisation normalised postoperatively. The duration of High Voltage Slow Wave Sleep remained positively correlated with motor scores in d-TGA infants., Interpretation: Altered early brain function and sleep is present in neonates with CHD. These results are intruiging, as inefficient neonatal sleep has been linked with adverse long-term outcome. Identifying how these rapid alterations in brain function are mitigated through improvements in cerebral oxygenation, surgery, drugs and nutrition may have relevance for clinical practice and outcome., Competing Interests: Declaration of competing interest None., (Copyright © 2021. Published by Elsevier Ltd.)

Background: The impact of the permissive hypotension approach in clinically well infants on regional cerebral oxygen saturation (rScO 2 ) and autoregulatory capacity (CAR) remains unknown., Methods: Prospective cohort study of blinded rScO 2 measurements within a randomized controlled trial of management of hypotension (HIP trial) in extremely preterm infants. rScO 2 , 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 rScO 2 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 rScO 2 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 rScO 2 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., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Many neonates undergoing whole body hypothermia (WBH) following moderate to severe perinatal asphyxia may also suffer from renal impairment. While recent data suggest WBH-related reno-protection, differences in serum creatinine (Scr) patterns to reference patterns were not yet reported. We therefore aimed to document Scr trends and patterns in asphyxiated neonates undergoing WBH and compared these to centiles from a reference Scr data set of non-asphyxiated (near)term neonates. Using a systematic review strategy, reports on Scr trends (mean ± SD, median or interquartile range) were collected (day 1-7) in WBH cohorts and compared to centiles of an earlier reported reference cohort of non-asphyxia cases. Based on 13 papers on asphyxia + WBH cases, a pattern of postnatal Scr trends in asphyxia + WBH cases was constructed. Compared to the reference 50th centile Scr values, mean or median Scr values at birth and up to 48 h were higher in asphyxia + WBH cases with a subsequent uncertain declining trend towards, at best, high or high-normal creatinine values afterwards. Such patterns are valuable for anticipating average changes in renal drug clearance but do not yet cover the relevant inter-patient variability observed in WBH cases, as this needs pooling of individual Screa profiles, preferably beyond the first week of life.

Background: Evidence to support a fortnightly scan protocol for monochorionic diamniotic (MCDA) pregnancies to detect twin-twin transfusion syndrome (TTTS) is scarce. Also, TTTS-related mortality in an unselected cohort is not well documented. Finally, common knowledge suggests that a more frequent follow-up may pick up the disease at a milder stage, but little is known on the ultrasound findings before the diagnosis., Objectives: We examine if a fortnightly ultrasound scan from 16 weeks onward detects TTTS in time. Also, we document the outcomes in a large unselected cohort of MCDA twins and examine the ultrasound findings within 14 days before diagnosis., Methods: Retrospective cohort of 675 MCDA twin pregnancies followed with a fortnightly scan protocol from 16 weeks onward. Timely detection of TTTS was defined as before fetal demise (stage V), ruptured membranes, or a dilated cervix. We compared the ultrasound findings before the diagnosis between stage I-II and stage III-IV., Results: A total of 82/675 (12%) pregnancies developed TTTS, of which 74/82 (90%) were detected in time. In 8/82 (10%), TTTS was diagnosed in stage V: 5 before 16 weeks and 2 after 26 weeks. Fetoscopic laser photocoagulation (FLP) of the placental anastomoses was performed in 48/82 (59%). The survival of TTTS in the entire cohort was 105/164 (64%). In contrast, survival after FLP was 77/96 (80%). In 16/19 (84%) of stage III-IV TTTS, abnormal Doppler findings preceded the diagnosis of TTTS., Conclusions: A scheme of fortnightly ultrasound scans from 16 weeks onward detects 9 out of ten TTTS pregnancies in time. Most stage V cases presented outside the typical time window of 16 and 26 weeks. Survival rates after FLP underestimate the mortality of TTTS. Most stage III-IV cases have abnormal Doppler findings before the diagnosis of TTTS., (© 2021 S. Karger AG, Basel.)

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.

In this paper we explore the use of updated tensor decompositions for the monitoring of brain hemodynamics in neonates. For this study, we used concomitant measurements of heart rate, mean arterial blood pressure, arterial oxygen saturation, EEG, and brain oxygenation - measured using near-infrared spectroscopy. These measurements were obtained from 22 neonates undergoing an INSURE procedure (INtubation, SURfactant and Extubation) and sedation using propofol. To develop the monitoring framework using tensors, we used radial basis kernel function (RBF) to construct a similarity matrix for consecutive segments of the signals. These matrices were concatenated forming a tensor. Updating canonical polyadic decomposition was used to evaluate the impact of propofol in the coupling between the different signals. Results indicate, as previously reported, a drop in the interaction between signals due to propofol administration. This shows that tensor decompositions can be useful in order to monitor the coupling between different physiological signals.

Neurovascular coupling refers to the mechanism that links the transient neural activity to the subsequent change in cerebral blood flow, which is regulated by both chemical signals and mechanical effects. Recent studies suggest that neurovascular coupling in neonates and preterm born infants is different compared to adults. The hemodynamic response after a stimulus is later and less pronounced and the stimulus might even result in a negative (hypoxic) signal. In addition, studies both in animals and neonates confirm the presence of a short hypoxic period after a stimulus in preterm infants. In clinical practice, different methodologies exist to study neurovascular coupling. The combination of functional magnetic resonance imaging or functional near-infrared spectroscopy (brain hemodynamics) with EEG (brain function) is most commonly used in neonates. Especially near-infrared spectroscopy is of interest, since it is a non-invasive method that can be integrated easily in clinical care and is able to provide results concerning longer periods of time. Therefore, near-infrared spectroscopy can be used to develop a continuous non-invasive measurement system, that could be used to study neonates in different clinical settings, or neonates with different pathologies. The main challenge for the development of a continuous marker for neurovascular coupling is how the coupling between the signals can be described. In practice, a wide range of signal interaction measures exist. Moreover, biomedical signals often operate on different time scales. In a more general setting, other variables also have to be taken into account, such as oxygen saturation, carbon dioxide and blood pressure in order to describe neurovascular coupling in a concise manner. Recently, new mathematical techniques were developed to give an answer to these questions. This review discusses these recent developments.

Background: Despite increasing use of propofol in neonates, observations on cerebral effects are limited., Aim: To investigate cerebral autoregulation (CAR) and activity after propofol for endotracheal intubation in preterm neonates., Methods: Twenty-two neonates received propofol before intubation as part of a published dose-finding study. Mean arterial blood pressure (MABP), near-infrared spectroscopy-derived cerebral oxygenation (rScO 2 ), and amplitude-integrated electroencephalography (aEEG) were analyzed until 180 min after propofol. CAR was expressed as transfer function (TF) gain, indicating % change in rScO 2 per 1 mmHg change in MABP. Values exceeding mean TF gain + 2 standard deviations (SD) defined impaired CAR., Results: After intubation with a median propofol dose of 1 (0.5-4.5) mg/kg, rScO 2 remained stable during decreasing MABP. Mean (±SD) TF gain was 0.8 (±0.3)%/mmHg. Impaired CAR was identified in 1 and 5 patient(s) during drug-related hypotension and normal to raised MABP, respectively. Suppressed aEEG was observed up to 60 min after propofol., Conclusions: Drug-related hypotension and decreased cerebral activity after intubation with low propofol doses in preterm neonates were observed, without evidence of cerebral ischemic hypoxia. CAR remained intact during drug-related hypotension in 95.5% of patients. Cerebral monitoring including CAR clarifies the cerebral impact of MABP fluctuations.

Intracranial hemorrhage is an important cause of brain injury in the neonatal population and bedside percutaneous needle aspiration has emerged as an alternative due to the major risks that can be caused by standard neurosurgical decompression. We aimed to assess the effectiveness of this minimally invasive bedside technique and conducted a retrospective analysis of all newborn infants with a large extra-axial hemorrhage associated with a parenchymal hemorrhage causing a midline shift, managed at three academic centers over a 15-year period. Collected data included clinical history, laboratory results, review of all imaging studies performed, and neurodevelopmental follow-up. Eight infants (3 preterm and 5 full-term) presented on day 1 to 2 with seizures ( n  = 6) and apneas ( n  = 5), signs of increased intracranial pressure ( n  = 4), and coning ( n  = 1). Risk factors were present in six. Cranial ultrasound and computed tomography showed a midline shift in all; two infants showed status epilepticus on amplitude-integrated electroencephalography with complete resolution after the procedure. Between 7 and 34 mL could be aspirated associated with a decrease in the midline shift as seen by ultrasonography performed during the puncture. No complications were seen related to the procedure and none of the infants required further acute neurosurgical intervention. On follow-up, three had mild sequelae, including motor coordination problems ( n  = 1) and hemianopia ( n  = 2); none developed cerebral palsy or postneonatal epilepsy. Neonates, presenting with severe symptoms, can be managed successfully using ultrasound-guided needle aspiration and this minimally invasive bedside method should be kept in mind before performing neurosurgical decompression., Competing Interests: The authors have no financial relationship or any other conflict of interest to declare., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Cerebral autoregulation (CAR), the ability of the human body to maintain cerebral blood flow (CBF) in a wide range of perfusion pressures, can be calculated by describing the relation between arterial blood pressure (ABP) and cerebral oxygen saturation measured by near-infrared spectroscopy (NIRS). In literature, disturbed CAR is described in different patient groups, using multiple measurement techniques and mathematical models. Furthermore, it is unclear to what extent cerebral pathology and outcome can be explained by impaired CAR. Aim and methods: In order to summarize CAR studies using NIRS in neonates, a systematic review was performed in the PUBMED and EMBASE database. To provide a general overview of the clinical framework used to study CAR, the different preprocessing methods and mathematical models are described and explained. Furthermore, patient characteristics, definition of impaired CAR and the outcome according to this definition is described organized for the different patient groups. Results: Forty-six articles were included in this review. Four patient groups were established: preterm infants during the transitional period, neonates receiving specific medication/treatment, neonates with congenital heart disease and neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia. Correlation, coherence and transfer function (TF) gain are the mathematical models most frequently used to describe CAR. The definition of impaired CAR is depending on the mathematical model used. The incidence of intraventricular hemorrhage in preterm infants is the outcome variable most frequently correlated with impaired CAR. Hypotension, disease severity, dopamine treatment, injury on magnetic resonance imaging (MRI) and long term outcome are associated with impaired CAR. Prospective interventional studies are lacking in all research areas. Discussion and conclusion: NIRS derived CAR measurement is an important research tool to improve knowledge about central hemodynamic fluctuations during the transitional period, cerebral pharmacodynamics of frequently used medication (sedatives-inotropes) and cerebral effects of specific therapies in neonatology. Uniformity regarding measurement techniques and mathematical models is needed. Multimodal monitoring databases of neonatal intensive care patients of multiple centers, together with identical outcome parameters are needed to compare different techniques and make progress in this field. Real-time bedside monitoring of CAR, together with conventional monitoring, seems a promising technique to improve individual patient care.

Objective: Hypertensive disorders of pregnancy (HDP) affect foetal outcome. Labetalol is frequently used to lower maternal blood pressure and prolong pregnancy. Conflicting evidence exists for specific neonatal side effects described after maternal labetalol treatment. Our aim was to investigate neonatal effects of foetal exposure to labetalol on cerebral oxygenation and extraction., Methods: In a prospective observational study, clinical characteristics, vital parameters and cerebral oxygen delivery and extraction were collected during the first 24 h of life in labetalol-exposed preterm neonates and compared with two control groups., Results: Twenty-two infants with a mean gestational age of 28.9 weeks, born from labetalol-treated mothers with HDP were included and matched with 22 infants with non-labetalol-treated mothers with HDP and 22 infants without maternal HDP. No significant differences between groups were found neither in heart rate, blood pressure and inotropic support, nor in mean regional cerebral oxygen saturation and fractional tissue oxygen extraction., Conclusion: Foetal labetalol exposure associated effects on preterm heart rate, blood pressure, cerebral oxygenation and extraction are not demonstrated. Maternal disease severity seems to play a more important role in neonatal cerebral haemodynamics. Maternal labetalol treatment has no clinically important short term side effects in the preterm neonate.

Background: Drugs acting on the cardiovascular and central nervous system often display relatively fast clinical responses, which may differ in neonates compared to children and adults. Introduction of bedside monitoring tools might be of additional value in the pharmacodynamic (PD) assessment of such drugs in neonates., Methods: We aim to provide an overview of the frequently used monitoring tools to assess drug effects on the hemodynamic status as well as the cerebral circulation, oxygenation and cerebral metabolism in neonates., Results: The use of blood pressure measurements, heart rate variability, functional echocardiography, nearinfrared spectroscopy and (amplitude-integrated) electroencephalography in neonates is discussed, as well as new parameters introduced by these tools. Based on the 'brain circulation model', the hemodynamic effects on the brain and their interplay are summarized. In this model, 3 processes (i.e. blood processes, vascular smooth muscle processes and tissue processes) and 3 mechanisms (i.e. autoregulation, blood flow metabolism coupling and cerebral oxygen balance) are distinguished, which all may be influenced by drug administration. Finally, propofol, sevoflurane, midazolam and inotropes are used as examples of which PD has been studied using the available hemodynamic and/or cerebral monitoring tools., Conclusion: The implementation of (non-)invasive monitoring tools to document hemodynamic and cerebral PD effects in neonates is of relevance both in a neonatal research and intensive clinical care setting. We highlight the need to integrate these tools in future PD research. Furthermore, besides short-term drug effects, long-term outcome of drug therapy in neonates also warrants further attention., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

This study investigates the relationship between brain oxygenation, assessed by means of near infrared spectroscopy (NIRS), and brain function, assessed by means of electroencephalography (EEG). Using NIRS signals measuring the regional cerebral oxygen saturation (rScO 2 ) and computing the fractional tissue oxygen extraction (FTOE), we compared how these variables relate to different features extracted from the EEG, such as the inter-burst interval (IBI) duration and amplitude, the amplitude of the EEG, and the amplitude of the burst. A cohort of 22 neonates undergoing sedation by propofol was studied and a regression of the NIRS-derived values to the different EEG features was made. We found that higher values of FTOE were related to higher values of EEG amplitude. These results might be of used in the monitoring of proper brain function in neonates.

Objective: To define the effective dose for 50% of patients (ED 50 ) of propofol for successful intubation and to determine the rate of successful extubation in those patients with planned intubation, surfactant administration, and immediate extubation (INSURE procedure). In addition, pharmacodynamic effects were assessed., Study Design: Neonates (n = 50) treated with propofol for (semi-)elective endotracheal intubation were stratified in 8 strata by postmenstrual and postnatal age. The first patient in each stratum received an intravenous bolus of 1 mg/kg propofol. Dosing for the next patient was determined using the up-and-down method. A propofol ED 50 dose was calculated in each stratum with an effective sample size of at least 6, via the Dixon-Masey method, with simultaneous assessment of clinical scores and continuous vital sign monitoring., Results: Propofol ED 50 values for preterm neonates <10 days of age varied between 0.713 and 1.350 mg/kg. Clinical recovery was not attained at the end of the 21-minute scoring period. Mean arterial blood pressure showed a median decrease between 28.5% and 39.1% from baseline with a brief decrease in peripheral and regional cerebral oxygen saturation. Variability in mean arterial blood pressure area under the curve could not be explained by weight or age., Conclusions: Low propofol doses were sufficient to sedate neonates for intubation. Clinical recovery was accompanied by permissive hypotension (no clinical shock and no treatment). The propofol ED 50 doses can be administered at induction, with subsequent up-titration if needed, while monitoring blood pressure. They can be used for further dosing optimalization and validation studies., Trial Registration: ClinicalTrials.gov: NCT01621373; EudraCT: 2012-002648-26., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Brain function is supported by an appropriate balance between the metabolic demand and the supply of nutrients and oxygen. However, the physiological principles behind the regulation of brain metabolism and demand in premature infants are unknown. Some studies found that changes in hemodynamic variables in this population precede changes in EEG activity; however, these studies only used descriptive statistics. This paper describes the relationship between changes in cerebral oxygenation, assessed by means of near-infrared spectroscopy (NIRS), and changes in EEG, using mathematical methods taken from information dynamics. In a cohort of 35 neonates subjected to sedation by propofol, we quantified the direction of information transfer between brain oxygenation and EEG. The results obtained indicate that, as reported in other studies, changes in NIRS are likely to precede changes in EEG activity.

The microvasculature and macrovasculature undergo extensive, organ-specific perinatal maturation. Multiple studies show associations between low birth weight and subsequent cardiovascular dysfunction in adulthood, suggesting that extreme preterm birth interferes with this maturation process. Therefore, we designed PREMATCH (PREMATurity as predictor of Cardiovascular-renal Health) to phenotype the microcirculation and macrocirculation during childhood in former preterm infants. A well-characterized cohort of former extreme preterm birth survivors and gender- and age-matched controls (aged 8-13 years) will be investigated for microvascular and macrovascular structure and function. In addition to cognitive performance and anthropometrics, we will investigate (i) the microvascular structure and function by endothelial function (photoplethysmography), sublingual capillary glycocalyx function (sidestream dark field imaging) and retinal structure (diameters of arterioles and venules); and (ii) the macrovascular phenotype by cardiac and renal ultrasound, repeated blood pressure measurements and arterial pulse-wave recordings. The PREMATCH study is unique in its design, and ongoing recruitment demonstrates excellent feasibility. The expectation is that the results of this study will identify risk factors during childhood for subsequent cardiovascular-renal disease in the adult life of former preterm infants, while further analysis on mediators in neonatal life of this cardiovascular-renal outcome may provide new information on perinatal risk factors.

Labetalol is a drug used in the treatment of hypertensive disorders of pregnancy (HDP). In a previous study we investigated the influence of the maternal use of labetalol on the cerebral autoregulation (CA) mechanism of neonates. In that study, we found that labetalol induces impaired CA during the first day of life, with CA returning to a normal status by the third day after birth. This effect was hypothesized to be caused by labetalol-induced vasodilation. However, no strong evidence for this claim was found. In this study we aim to find stronger evidence for the vasodilation effect caused by labetalol, by investigating its effect on the neurogenic mechanism (NM) involved in CA. The status of the NM was assessed by means of transfer function analysis between the low frequency content of the autonomic control activity (LFA), obtained by processing of the heart rate (HR), and the regional cerebral oxygen saturation (rScO₂). We found that neonates from mothers treated with labetalol presented a lower LFA and an impaired NM response during the first day of life, with values returning to normal by the end of the third day. These results reflect a vasodilation effect caused by labetalol, and indicate that the impaired CA observed in the previous study is caused by vasodilation.

Background: Indomethacin has vasoactive properties in cerebral and systemic vascular beds, and it improves cerebral autoregulatory ability. We speculated that tocolytic indomethacin will improve cerebral autoregulatory ability in the very preterm infant in early postnatal life., Methods: Eighteen stable preterm infants gestational age (GA) 25.3-29.6 weeks, birth weight (BW) 660-1430 grams), whose mothers had received 50-150 mg of tocolytic indomethacin within 24 h before birth, and 18 individually matched controls (GA 25.0-29.7 weeks, BW 700-1390 grams) were studied four times for 15 min in the first 24 h of life. Autoregulation was assessed by determining correlations between mean arterial blood pressure (MABP (mm Hg)) and near-infrared spectroscopy-monitored cerebral oxygenation (rScO2)., Results: MABPs were significantly higher in the indomethacin infants than in the control infants (p=0.03). A decreased ability to autoregulate was found in four of the indomethacin infants, and in six of the control infants, which is not significantly different., Conclusions: Prenatally administered indomethacin, given as a tocolytic in doses of 50-150 mg per day, improved transitional circulation in very preterm infants by significantly raising the MABP. It did not have an effect on the ability to autoregulate the cerebral circulation. In this study, no differences in short-term outcomes, like haemorrhagic or ischaemic cerebral lesions, were observed.

Objective: Circulatory failure due to acute arterial hypertension in the neonatal period is rare. This study was undertaken to assess the clinical and echocardiographic manifestations of circulatory failure resulting from acute neonatal hypertensive crisis., Methods: Neonatal and cardiology databases from 2007 to 2010 were reviewed. An established diagnosis of circulatory failure due to neonatal hypertension before the age of 14 days was required for inclusion. Six patients were identified., Results: Five patients presented with circulatory failure due to an acute hypertensive crisis. The median age at presentation was 8.5 days (range: 6.0-11.0) with a median body weight of 3.58 kg (range: 0.86-4.70). Echocardiography demonstrated mild left ventricular dysfunction [median shortening fraction (SF) 25%, range 10-30] and mild aortic regurgitation in 83% (5/6) of patients. One patient with left ventricular dysfunction (SF = 17%) had a large apical thrombus. Two patients were hypotensive, and hypertension only became evident after restoration of cardiac output. Administration of intravenous milrinone was successful, with rapid improvement of the clinical condition. Left ventricular function normalised in all survivors., Conclusion: Early neonatal circulatory collapse due to arterial hypertension is a rare but potentially life-threatening condition. At presentation, hypotension, especially in the presence of a dysfunctional left ventricle, does not exclude a hypertensive crisis being the cause of circulatory failure. The echocardiographic presence of mild aortic regurgitation combined with left ventricular hypocontractility in a structurally normal heart should alert the physician to the presence of underlying hypertension.

Hypertensive disorders of pregnancy (HDP) are normally treated to avoid maternal complications. In this study we aimed to investigate if there was an effect of maternal HDP treatment on the cerebral autoregulation of the neonates by analysing measurements of mean arterial blood pressure (MABP) and rScO2 by means of correlation, coherence, and transfer function analysis. We found that these infants presented higher values of transfer function gain, which indicates impaired cerebral autoregulation, with a decreasing trend towards normality. We hypothesised that this trend was due to a vasodilation effect of the maternal use of labetalol due to accumulation, which disappeared by the third day after birth. Therefore, we investigated the values of pulse pressure in order to find evidence for a vasodilatory effect. We found that lower values of pulse pressure were present in these infants when compared with a control population, which, together with increased transfer function gain values, suggests an effect of the drug on the cerebral autoregulation.

Approximately 30 years ago, the myth that nervous system immaturity precluded neonates from pain perception and its negative effects was rejected. Neurobiologists further explored neurodevelopmental nociception. These observations strongly suggest that early pain experience contributes to neurodevelopmental outcome, pain thresholds, pain or stress-related behaviour and physiological responses in later life. Effective management of pain therefore remains an important indicator of the quality of care provided to neonates, not only from an ethical, but also from a short and long-term outcome perspective. Simultaneously, neonatal care itself has changed and data on neuro-apoptosis and impaired synaptogenesis following exposure to analgosedatives emerged. When developmental pharmacology concepts are applied to neonatal analgosedation, this means that this should be based on systematic assessment, followed by titrated administration of the most appropriate analgesic(s) with subsequent re-assessment to adapt treatment. This review will focus on the limitations of the available assessment tools, newly emerging analgosedatives in neonates to illustrate how these compounds can be integrated into the changing concepts of neonatal care.

Background: Cerebrospinal fluid (CSF)-containing cysts at the level of the choroidal fissure are rare embryological entities infrequently described in the literature because of their benign nature. On the occasion of a case series, we present an overview of the literature and discuss anatomical and embryological location, imaging characteristics, presenting symptoms, and treatment indication of these lesions., Methods: We identified, in a retrospective study of a database with 81 patients harboring 86 supratentorial intracranial cysts, six patients with a CSF-containing cyst at the level of the choroidal fissure. In all cases, presenting symptoms were mild and the cysts were considered a fortuitous diagnosis. None of the patients was treated surgically, and the cysts remained stable at radiological follow-up. We performed a literature search for cerebral cysts and choroidal fissure cysts in particular., Results: Only one large study purely addressing choroidal fissure cysts was found in the literature., Conclusions: CSF-containing cysts at the level of the choroidal fissure may be of the arachnoid or the neuroepithelial type, but pathological confirmation of a CSF-containing cyst at this specific location has never been published. Very infrequently they are symptomatic, and surgical treatment is hardly ever necessary., (Copyright © 2011 Elsevier Inc. All rights reserved.)