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To determine the relationship between radiologically identifiable brain injuries and delayed brain development as reflected by brain metabolic and microstructural integrity.

Background:Term newborns with congenital heart disease (CHD) show delayed brain development as early as the third trimester, especially in single-ventricle physiology (SVP). Mechanisms causing delayed brain development in CHD are uncertain but may include impaired fetal brain blood flow. Our objective was to determine if cardiac anatomy associated with obstruction to antegrade flow in the ascending aorta is predictive of delayed brain development as measured by diffusion tensor imaging and magnetic resonance spectroscopic (MRS) imaging.Methods:Echocardiograms from 36 term newborns with SVP were reviewed for the presence of aortic atresia and the diameter of the ascending aorta. Quantitative magnetic resonance imaging parameters measuring brain microstructural (fractional anisotropy (FA) and average diffusivity (Dav)) or metabolic development (N-acetylaspartate (NAA) and lactate/choline (Lac/Cho)) were recorded.Results:Increasing NAA/Cho and white matter (WM) FA, and decreasing Dav and Lac/Cho characterize normal brain development. Consistent with the hypothesis that delayed brain development is related to impaired brain perfusion, smaller ascending aortic diameter and aortic atresia were associated with higher Dav and lower WM FA. Echocardiogram variables were not associated with brain metabolic measures.Conclusions:These observations support the hypothesis that obstruction to fetal cerebral blood flow impairs brain microstructural development.

AbstractMore than 60% of newborns with severe congenital cardiac disease develop perioperative brain injuries. Known risk factors include: pre-operative hypoxemia, cardiopulmonary bypass characteristics, and post-operative hypotension. Infection is an established risk factor for white matter injury in premature newborns. In this study, we examined term infants with congenital cardiac disease requiring surgical repair to determine whether infection is associated with white matter injury. Acquired infection was specified by site – bloodstream, pneumonia, or surgical site infection – according to strict definitions. Infection was present in 23 of 127 infants. Pre- and post-operative imaging was evaluated for acquired injury by a paediatric neuroradiologist. Overall, there was no difference in newly acquired post-operative white matter injury in infants with infection (30%), compared to those without (31%). When stratified by anatomy, infants with transposition of the great arteries, and bloodstream infection had an estimated doubling of risk of white matter injury that was not significant, whereas those with single ventricle anatomy had no apparent added risk. When considering only infants without stroke, the estimated association was higher, and became significant after adjusting for duration of inotrope therapy. In this study, nosocomial infection was not associated with white matter injury. Nonetheless, when controlling for risk factors, there was an association between bloodstream infection and white matter injury in selected sub-populations. Infection prevention may have the potential to mitigate long-term neurologic impairment as a consequence of white matter injury, which underscores the importance of attention to infection control for these patients.

To describe cerebral regional oxygen saturation measured by near infrared spectroscopy in the setting of normal and increased intracranial pressure in children to evaluate the association between cerebral regional oxygen saturation and intracranial pressure in comparison with other clinical variables.

Newborns with congenital heart disease are at high risk for brain injury and adverse neurodevelopmental outcomes. MRI enables the objective determination of the severity of brain injury in critically ill newborns with congenital heart disease. We will rationalize the use of MRI as a surrogate for neurodevelopmental outcome and describe novel randomization techniques that can be used in trials in this population.

To compare changes in regional cerebral or flank oxygen saturation measured by near-infrared spectroscopy with changes in central venous oxygen saturation (Scvo2) and to determine clinical variables associated with these changes.

Neonatal stroke is a condition that leads to disability in later life, and as yet there is no effective treatment. Recently, erythropoietin (EPO) has been shown to be cytoprotective following brain injury and may promote neurogenesis. However, the effect of EPO on functional outcome and on morphologic changes in neonatal subventricular zone (SVZ) following experimental neonatal stroke has not been described. We used a transient focal model of neonatal stroke in P10 rat. Injury was documented by diffusion weighted MRI during occlusion. Immediately upon reperfusion, either EPO (5U/gm) or vehicle was administered intraperitoneally and animals were allowed to grow for 2 wk. Sensorimotor function was assessed using the cylinder rearing test and then brains were processed for volumetric analysis of the SVZ. Stroke induced SVZ expansion proportional to hemispheric volume loss. EPO treatment markedly preserved hemispheric volume and decreased the expansion of SVZ unilaterally. Furthermore, EPO treatment significantly improved the asymmetry of forelimb use following neonatal stroke. This functional improvement directly correlated with the amount of preserved hemispheric volume. These results suggest EPO may be a candidate in the treatment of neonatal stroke.

Neonatal stroke is a condition that leads to disability in later life, and as yet there is no effective treatment. Recently, erythropoietin (EPO) has been shown to be cytoprotective following brain injury and may promote neurogenesis. However, the effect of EPO on functional outcome and on morphologic changes in neonatal subventricular zone (SVZ) following experimental neonatal stroke has not been described. We used a transient focal model of neonatal stroke in P10 rat. Injury was documented by diffusion weighted MRI during occlusion. Immediately upon reperfusion, either EPO (5U/gm) or vehicle was administered intraperitoneally and animals were allowed to grow for 2 wk. Sensorimotor function was assessed using the cylinder rearing test and then brains were processed for volumetric analysis of the SVZ. Stroke induced SVZ expansion proportional to hemispheric volume loss. EPO treatment markedly preserved hemispheric volume and decreased the expansion of SVZ unilaterally. Furthermore, EPO treatment significantly improved the asymmetry of forelimb use following neonatal stroke. This functional improvement directly correlated with the amount of preserved hemispheric volume. These results suggest EPO may be a candidate in the treatment of neonatal stroke.

Objectives:Vulnerability to brain injury in infants with congenital heart disease (CHD) may differ by CHD lesion. However, the link between arterial ischemic stroke (AIS) and neurodevelopment, and whether it differs by CHD lesion, is unknown. We sought to determine whether: (1) Stroke topologydiffers between infants with Transposition of the Great Arteries (TGA) and single ventricle physiology (SVP), and relationship with neurodevelopment;(2) Associations between stroke volumeand neurodevelopment are CHD lesion specific.Methods:64 of 312 CHD infants (TGA n=38, SVP n=26) studied prospectively with pre- and/or post-operative brain MRIs had AIS. AIS were segmented on 3DT1 and/or ADC images. 39 infants completed 18-month neurodevelopmental assessments with Bayley Scales (2ndor 3rdEdition); scores were adjusted to account for differences between versions. Adverse neurodevelopment was defined as <85 points. We used multivariable linear regression models to study associations between AIS volume and neurodevelopment, stratifying by CHD lesion and adjusting for study site. Probability maps demonstrating areas vulnerable to AIS and odds ratio maps reflecting likelihood of a lesion predicting adverse outcomes were developed.Results:Most AIS were in MCA territories, with a left-sided predominance (Fig 1A). Stroke volume did not differ between CHD groups (p=0.8). Basal ganglia lesions were most predictive of cognitive (max OR=11) and motor (max OR=6) outcomes (Fig 1B). Stratifying by CHD lesion, AIS volume predicted 18-month cognitive outcomes in infants with TGA (β=-0.6, 95%CI -1.0-(-0.1), p=0.02) but not SVP (β=7.9, 95%CI -72-88). AIS volume did not predict motor outcomes in infants with TGA (β=-0.6, 95%CI -1.6-0.3) or SVP (β=-19.7, 95%CI -91-52).Conclusions:Neonatal AIS topology does not differ between infants with TGA and SVP. AIS location and size are important predictors of neurodevelopment at 18 months though this association differs by CHD lesion.

IMPORTANCE: Short- and long-term functional impairment after pediatric injury may be more sensitive for measuring quality of care compared with mortality alone. The characteristics of injured children and adolescents who are at the highest risk for functional impairment are unknown. OBJECTIVE: To evaluate categories of injuries associated with higher prevalence of impaired functional status at hospital discharge among children and adolescents and to estimate the number of those with injuries in these categories who received treatment at pediatric trauma centers. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study (Assessment of Functional Outcomes and Health-Related Quality of Life After Pediatric Trauma) included children and adolescents younger than 15 years who were hospitalized with at least 1 serious injury at 1 of 7 level 1 pediatric trauma centers from March 2018 to February 2020. EXPOSURE: At least 1 serious injury (Abbreviated Injury Scale score, ≥3 [scores range from 1 to 6, with higher scores indicating more severe injury]) classified into 9 categories based on the body region injured and the presence of a severe traumatic brain injury (Glasgow Coma Scale score &lt;9 or Glasgow Coma Scale motor score &lt;5). MAIN OUTCOMES AND MEASURES: New domain morbidity defined as a 2 points or more change in any of 6 domains (mental status, sensory, communication, motor function, feeding, and respiratory) measured using the Functional Status Scale (FSS) (scores range from 1 [normal] to 5 [very severe dysfunction] for each domain) in each injury category at hospital discharge. The estimated prevalence of impairment associated with each injury category was assessed in the population of seriously injured children and adolescents treated at participating sites. RESULTS: This study included a sample of 427 injured children and adolescents (271 [63.5%] male; median age, 7.2 years [interquartile range, 2.5-11.7 years]), 74 (17.3%) of whom had new FSS domain morbidity at discharge. The proportion of new FSS domain morbidity was highest among those with multiple injured body regions and severe head injury (20 of 24 [83.3%]) and lowest among those with an isolated head injury of mild or moderate severity (1 of 84 [1.2%]). After adjusting for oversampling of specific injuries in the study sample, 749 of 5195 seriously injured children and adolescents (14.4%) were estimated to have functional impairment at hospital discharge. Children and adolescents with extremity injuries (302 of 749 [40.3%]) and those with severe traumatic brain injuries (258 of 749 [34.4%]) comprised the largest proportions of those estimated to have impairment at discharge. CONCLUSIONS AND RELEVANCE: In this cohort study, most injured children and adolescents returned to baseline functional status by hospital discharge. These findings suggest that functional status assessments can be limited to cohorts of injured children and adolescents at the highest risk for impairment.

Background:Early delivery and size at birth are known to be independent risk factors for neurodevelopmental (ND) impairments among patients with complex congenital heart disease (CHD). The aim of this study was to explore the interaction between gestational age (GA) and size at birth and their relationship with postnatal brain injury and developmental outcomes among patients with CHD.Methods:This was an analysis of a prospective study of neonates with d-transposition of the great arteries (TGA) or single ventricle physiology (SVP) that underwent pre- and post-operative brain MRIs and ND testing. The primary outcome was white matter injury (WMI) on the pre-operative MRI. Secondary outcomes included fractional anisotropy (FA) in white matter as a measure of microstructural development and psychomotor (PDI) and mental development indices (MDI) on the Bayley scale of infant development-II at 30 months. Primary predictors included z-scores for birth weight (WZ), length (LZ) and head circumference (HCZ) and GA at birth categorized as early term (37-38 weeks) or term (>39 weeks). Growth asymmetry was measured by the difference in WZ and HCZ and categorized as symmetric, asymmetric with a small head relative to body and asymmetric with a large head relative to body.Results:187 subjects (112- TGA; 75- SVP) were analyzed of which 74 were early term and 113 were term. There was no relationship between growth parameters with WMI or white matter FA on the pre-operative brain MRI. WZ, LZ and HCZ were not associated with MDI or PDI at 30 months of age in either GA category. However, there was a significant association between growth asymmetry and MDI after adjusting for hospital length of stay and GA at birth. Compared with symmetric infants, SVP infants with a small head relative to body had significantly lower MDI scores (?= -38, 95%CI: -65, -11; p= 0.01) while there was a trend in TGA infants (?= -8, 95%CI: -19, 4; p= 0.1)Conclusions:Size at birth is not associated with early measures of brain injury or development. However, asymmetric size at birth regardless of GA is associated with worse cognitive outcomes at 30 months of age, particularly for SVP patients. These findings suggest that ND impairment in CHD is multi-factorial with early origins.