Rationale: Delayed (>5 minutes) epinephrine during pediatric in-hospital cardiac arrest (IHCA) is associated with worse outcomes. Epinephrine is nearly always given earlier, limiting 5 minutes as a quality target. Objectives: To assess early epinephrine administration (⩽2 minutes) on outcomes and hemodynamics during cardiopulmonary resuscitation (CPR) in pediatric IHCA from pulseless, nonshockable rhythms. Methods: This study leveraged the database of the ICU-RESUS (Intensive Care Unit Resuscitation) project (clinicaltrials.gov identifier NCT02837497). Primary exposure was the time to epinephrine bolus: early versus >2 minutes. Primary outcome was survival to discharge. Secondary outcomes included the return of spontaneous circulation (ROSC), survival with favorable neurologic outcome, change from baseline to discharge Functional Status Scale (FSS) score, total FSS score at discharge, new morbidity among survivors, and invasively measured blood pressure during the first 10 minutes of CPR. Results: Among 352 CPR events, median age was 1.0 (interquartile range [IQR], 0.3-8.0) year, 186 (53%) were male, and 185 (52.6%) had cardiac disease. Early epinephrine was administered in 273 (78%), and median time to administration was 1.0 (0.0-2.0) minute. Survival to discharge was similar between patients who received early epinephrine and those who did not. Early epinephrine administration was associated with higher ROSC, a change from baseline to discharge in FSS, lower total FSS scores at discharge, and lower rates of new morbidity compared with epinephrine administration at >2 minutes. The probability of ROSC and survival to discharge with favorable neurologic outcome decreased for each minute of delay in epinephrine administration. There was no difference in the invasive blood pressure targets during the first 10 minutes of CPR. Conclusions: Early epinephrine administration was common and was associated with higher ROSC and improved functional outcomes compared with epinephrine administration at >2 minutes in pediatric IHCA.

Rationale: Tight glycemic control (TGC) with insulin has not consistently shown benefit in critically ill patients. We previously reported that the subset of children with a hyperinflammatory subphenotype benefited from TGC in the HALF-PINT (Heart and Lung Failure - Pediatric Insulin Titration) study of hyperglycemic children with heart and lung failure and the IIT-SBPP (Intensive Insulin Treatment - Severely Burned Pediatric Patients) study in severely burned pediatric patients. However, whether this effect was mediated through a reduction in inflammation or some other biologic process is not fully understood. Objectives: To deepen the understanding of inflammatory subphenotypes and explore the biologic mechanisms underlying heterogeneous response to TGC. Methods: Plasma cytokine measurements and whole-blood transcriptomics from 740 blood samples collected on Pre- and Post-treatment Study Days 0, 2, and 4 from 293 HALF-PINT participants (n = 250 hypoinflammatory and n = 43 hyperinflammatory) were used to identify cytokine and gene expression signatures of differential responses to TGC. Measurements and Results: Patients with the hyperinflammatory subphenotype had greater baseline expression of genes relating to inflammation, cell-cycle activity, and immunometabolism. Hyperinflammatory patients treated to a target glucose range of 80-110 mg/dl experienced greater reductions in inflammatory cytokines, innate immune gene expression, and heme metabolism gene expression, as well as an increase in lymphocyte gene expression, compared with those treated to a target range of 150-180 mg/dl. Causal mediation testing indicated that these changes partly explained the observed mortality benefit of TGC in the hyperinflammatory subgroup of patients. Conclusions: These findings expand our understanding of the biology underlying inflammatory subphenotypes and provide biologic insight into the mortality benefit of TGC in hyperinflammatory children.

OBJECTIVES:Prearrest sepsis has been associated with particularly poor outcomes among children who suffer in-hospital cardiac arrest (IHCA), but there is a paucity of dedicated studies on the topic. In this study of children receiving cardiopulmonary resuscitation (CPR) in the ICU, our objective was to determine the associations of sepsis with IHCA outcomes and intraarrest physiology. DESIGN:Prospectively designed secondary analysis of the ICU Resuscitation Project clinical trial (NCT02837497). SETTING:The 18 pediatric and pediatric cardiac ICUs at ten children's hospitals in the United States. PATIENTS:Children (≤ 18 yr) with an index IHCA event. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:The primary exposure was a prearrest diagnosis of sepsis. The primary survival outcome was survival to hospital discharge with favorable neurologic outcome (Pediatric Cerebral Performance Category score 1-3 or unchanged from baseline). The primary physiologic outcome was average diastolic blood pressure (DBP) during CPR. Multivariable regression models controlling for a priori covariates assessed the relationship between sepsis and outcomes. Of 1129 children with index IHCAs, 184 (16.3%) had prearrest sepsis. Patients with sepsis had greater prearrest comorbidities, higher prearrest severity of illness, and higher Vasoactive-Inotropic Scores than patients without sepsis. They more frequently had hypotension as the cause of IHCA, had longer durations of CPR, and more frequently received epinephrine and sodium bicarbonate during CPR. They less frequently achieved survival with favorable neurologic outcome (52/184 [28.3%] vs. 552/945 [58.4%]; p < 0.001; adjusted relative risk, 0.54; 95% CI, 0.43-0.68; p < 0.001). Intraarrest DBPs did not differ between patients with vs. without sepsis. Following IHCA, event survivors with sepsis had higher vasoactive requirements, more frequently experienced hypotension, and continued to have greater mortality rates through 48 hours postarrest. CONCLUSIONS:Children with prearrest sepsis had worse survival outcomes, similar intraarrest DBPs, and greater pre and postarrest severity of illness than children without sepsis.

Background Neurodevelopmental outcomes are impaired in significant congenital heart disease (CHD) with prenatal origins. The cerebrovascular response to maternal hyperoxia (MH) varies in fetuses with CHD, which may reflect brain health in utero. We investigated the association between lack of cerebrovascular reactivity with MH and adverse neurologic outcomes in CHD measured as brain growth and risk of postnatal white matter injury. Methods This is a prospective cohort study of pregnant participants whose fetuses had CHD requiring a neonatal operation. We performed fetal echocardiograms with MH, fetal brain magnetic resonance imaging (MRI), and postnatal preoperative brain MRI. A ≥5% change in middle cerebral artery pulsatility index with MH defined reactivity. Total brain volume was measured on MRIs. The neonatal MRI was assessed for white matter injury. Regression analyses compared responders versus nonresponders, then stratified by hypoplastic left heart syndrome and d‐transposition of the great arteries groups. Results Fifty‐five participants underwent fetal imaging. Forty‐nine neonates underwent brain MRI. Among subjects with hypoplastic left heart syndrome, at each gestational week, total brain volume was 17.8 mL greater in responders (95% CI, 3.3–32.3; P=0.02). This pattern was not seen in d‐transposition of the great arteries. Postnatal white matter injury was less common in responders. Conclusions Lack of fetal cerebrovascular response to MH is associated with smaller total brain volume beginning in utero in hypoplastic left heart syndrome. Postnatal white matter injury is more common among nonresponders. MH testing can help identify individual fetuses with CHD at highest risk for adverse neurologic outcomes, particularly those with hypoplastic left heart syndrome.

Neurodevelopmental impairments associated with congenital heart disease (CHD) may arise from perturbations in brain developmental pathways, including the formation of sulcal patterns. While genetic factors contribute to sulcal features, the association of noncoding de novo variants (ncDNVs) with sulcal patterns in people with CHD remains poorly understood. Leveraging deep learning models we examined the predicted impact of ncDNVs on gene regulatory signals. Predicted impact was compared between participants with CHD and a jointly called cohort without CHD. We then assessed the relationship of the predicted impact of ncDNVs with their sulcal folding patterns. ncDNVs predicted to increase H3K9me2 modification were associated with larger disruptions in right parietal sulcal patterns in the CHD cohort. Genes predicted to be regulated by these ncDNVs were enriched for functions related to neuronal development. This highlights the potential of deep learning models to generate hypotheses about the role of noncoding variants in brain development.

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes.

OBJECTIVES:Data to support epinephrine dosing intervals during cardiopulmonary resuscitation (CPR) are conflicting. The objective of this study was to evaluate the association between epinephrine dosing intervals and outcomes. We hypothesized that dosing intervals less than 3 minutes would be associated with improved neurologic survival compared with greater than or equal to 3 minutes. DESIGN:This study is a secondary analysis of The ICU-RESUScitation Project (NCT028374497), a multicenter trial of a quality improvement bundle of physiology-directed CPR training and post-cardiac arrest debriefing. SETTING:Eighteen PICUs and pediatric cardiac ICUs in the United States. PATIENTS:Subjects were 18 years young or younger and 37 weeks old or older corrected gestational age who had an index cardiac arrest. Patients who received less than two doses of epinephrine, received extracorporeal CPR, or had dosing intervals greater than 8 minutes were excluded. INTERVENTIONS:The primary exposure was an epinephrine dosing interval of less than 3 vs. greater than or equal to 3 minutes. MEASUREMENTS AND MAIN RESULTS:The primary outcome was survival to discharge with a favorable neurologic outcome defined as a Pediatric Cerebral Performance Category score of 1-2 or no change from baseline. Regression models evaluated the association between dosing intervals and: 1) survival outcomes and 2) CPR duration. Among 382 patients meeting inclusion and exclusion criteria, median age was 0.9 years (interquartile range 0.3-7.6 yr) and 45% were female. After adjustment for confounders, dosing intervals less than 3 minutes were not associated with survival with favorable neurologic outcome (adjusted relative risk [aRR], 1.10; 95% CI, 0.84-1.46; p = 0.48) but were associated with improved sustained return of spontaneous circulation (ROSC) (aRR, 1.21; 95% CI, 1.07-1.37; p < 0.01) and shorter CPR duration (adjusted effect estimate, -9.5 min; 95% CI, -14.4 to -4.84 min; p < 0.01). CONCLUSIONS:In patients receiving at least two doses of epinephrine, dosing intervals less than 3 minutes were not associated with neurologic outcome but were associated with sustained ROSC and shorter CPR duration.

Tracheal intubation (TI)-associated cardiac arrest (TI-CA) occurs in 1.7

Introduction: Fetuses with CHD have smaller total brain volume (TBV) and are at risk for acquired brain white matter injury (WMI), both of which are linked to neurodevelopmental impairments. Social determinants of health (SDOH) and other fetal environmental factors have been linked to fetal brain health in other populations. Our aim was to test our hypothesis that these exposures influence fetal brain growth and postnatal WMI risk in severe CHD. Methods: Our prospective longitudinal cohort study enrolled fetuses with severe CHD to undergo fetal brain MRI and postnatal pre-operative brain MRI. Participants completed home environment surveys on individual SDOH and exposures. Community SDOH metrics were determined using Child Opportunity Index (COI) based on home address. An ‘at risk’ fetus composite was created if there was exposure to: personal/household smoking, welfare/food stamps, or poverty. TBV was calculated at both time points. Presence/degree of WMI was determined on postnatal MRI. Repeated measures analysis and logistic regression were performed to determine association between individual and community SDOH metrics with rate of TBV growth and risk of WMI. Results: 55 participants enrolled (54 fetal scans: mean GA 33.9 wks, 95%CI: 33.7,34.1; 47 neonatal scans: mean GA 39.3 wks 95%CI: 38.9,39.6). Fetal sex, smoking exposure, and several individual SDOH were associated with TBV growth. Adjusting for fetal sex and GA at scan, rate of TBV growth was slower with smoking exposure (coeff: -5.2, 95%CI: -10.3, -0.2, p= 0.04) and trended towards significance for those with welfare/food stamps or poverty. ‘At risk’ fetuses had slower rate of TBV growth than those without risk (coeff: -2.5, 95%CI: -5.0, -0.07, p= 0.04) (Figure 1). There were lower odds of pre-operative WMI with high COI compared to low after adjusting for GA at scan (OR= 0.16, 95%CI: 0.03, 0.9, p= 0.04). Conclusion: Smoking exposure and individual-level SDOH influence brain growth, while community COI is associated with risk of postnatal pre-op WMI in CHD. Our findings identify targets for intervention to optimize brain growth and outcomes in the CHD population, including smoking cessation programs, and nutritional and needs assessment during pregnancy.

Background: Neurodevelopmental impairments associated with congenital heart disease (CHD) may arise from perturbations in brain developmental pathways, including the formation of sulcal patterns. While genetic factors contribute to sulcal features, the association of noncoding de novo variants (ncDNVs) with sulcal patterns in people with CHD remains poorly understood. Methods: Leveraging deep learning models Basenji and Enformer, we examined the predicted impact of ncDNVs on gene regulatory signals such as histone modifications. Predicted impact was compared between participants with CHD from the Pediatric Cardiology Genomics Consortium and a jointly called cohort without CHD. We then assessed the relationship of the predicted impact of ncDNVs with their sulcal folding patterns. Findings: ncDNVs predicted to impact H3K9me2 modification were associated with larger disruptions in right parietal sulcal patterns in the CHD cohort. Genes predicted to be regulated by these ncDNVs were enriched for functions related to neuronal development. Interpretation: ncDNVs prioritised in this analysis could impact both heart and brain development by increasing the level of H3K9me2 modification. This highlights the potential of deep learning models to generate hypotheses about the role of noncoding variants in brain development.Funding: National Center for Research Resources, National Center for Advancing Translational Sciences, National Institutes of Health, NIH Centers for Mendelian Genomics, American Heart Association Career Development Award, Farb Family Fund, and Kostin Family Innovation Fund.Declaration of Interest: E.G. reported receiving grants from the NIH during the conduct of the study. M.B. reported receiving grants from the National Heart, Lung, and Blood Institute, NIH during the conduct of the study. T.A.M reported receiving grants from the NIH during the conduct of the study. P.M. reported receiving grants from the NIH during the conduct of the study. G.A.P. reported receiving grants from the University of Rochester Medical Center. A.E.R. reported receiving grants from the NIH during the conduct of the study. D.J.H. reported having a nonexclusive, royalty-free patent licensed to GEHC. J.W.N. reported receiving grant funding from the NIH, US Department of Defense, Centers for Disease Control and Prevention, Novartis, Bristol Myers Squibb, and Pfizer; being a consultant for Pfizer; and receiving honoraria from Daiichi Sankyo. C.K.R., M.T., K.I., and S.U.M. reported receiving grants from the NIH during the conduct of the study. No other disclosures were reported.Ethical Approval: The study was approved by the central Institutional Review Board on December 18, 2016, and reliance agreements were approved at each study centre. Written informed consent was obtained from participants or their parents; written informed assent was obtained from competent older children.

OBJECTIVES:Viral lower respiratory tract infection (vLRTI) contributes to substantial morbidity and mortality in children. Diagnosis is typically confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) of nasopharyngeal specimens in hospitalized patients; however, it is unknown whether nasopharyngeal detection accurately reflects presence of virus in the lower respiratory tract (LRT). This study evaluates agreement between viral detection from nasopharyngeal specimens by RT-PCR compared with metagenomic next-generation RNA sequencing (RNA-Seq) from tracheal aspirates (TAs). DESIGN:This is an analysis of of a seven-center prospective cohort study. SETTING:Seven PICUs within academic children's hospitals in the United States. PATIENTS:Critically ill children (from 1 mo to 18 yr) who required mechanical ventilation via endotracheal tube for greater than or equal to 72 hours. INTERVENTIONS:We evaluated agreement in viral detection between paired upper and LRT samples. Results of clinical nasopharyngeal RT-PCR were compared with TA RNA-Seq. Positive and negative predictive agreement and Cohen's Kappa were used to assess agreement. MEASUREMENTS AND MAIN RESULTS:Of 295 subjects with paired testing available, 200 (68%) and 210 (71%) had positive viral testing by RT-PCR from nasopharyngeal and RNA-Seq from TA samples, respectively; 184 (62%) were positive by both nasopharyngeal RT-PCR and TA RNA-Seq for a virus, and 69 (23%) were negative by both methods. Nasopharyngeal RT-PCR detected the most abundant virus identified by RNA-Seq in 92.4% of subjects. Among the most frequent viruses detected, respiratory syncytial virus demonstrated the highest degree of concordance (κ = 0.89; 95% CI, 0.83-0.94), whereas rhinovirus/enterovirus demonstrated lower concordance (κ = 0.55; 95% CI, 0.44-0.66). Nasopharyngeal PCR was more likely to detect multiple viruses than TA RNA-Seq (54 [18.3%] vs 24 [8.1%], p ≤ 0.001). CONCLUSIONS:Viral nucleic acid detection in the upper versus LRT reveals good overall agreement, but concordance depends on the virus. Further studies are indicated to determine the utility of LRT sampling or the use of RNA-Seq to determine LRTI etiology.

Background: Resuscitation with chest compressions and positive pressure ventilation in Bidirectional Glenn (BDG) or Fontan physiology may compromise passive venous return and accentuate neurologic injury. We hypothesized that arterial pressure and survival would be better in BDG than Fontan patients. Methods: Secondary analyses of the Pediatric Intensive Care Quality of CPR and Improving Outcomes from Pediatric Cardiac Arrest databases. P-values were considered significant if < 0.05. Results: In total, 64 patients had either BDG (42/64, 66%) or Fontan (22/64, 34%) anatomy. Return of spontaneous circulation was achieved in 76% of BDG patients versus 59% of Fontan patients and survival with favorable neurologic outcome in 22/42 (52%) BDG versus 6/22 (27%) Fontan patients, p = 0.067. Twelve of 24 (50%) BDG and 2/7 (29%) Fontan patients who survived to discharge suffered new morbidity as defined by worsening Functional Status Score. More BDG patients achieved adequate DBP (>= 25 mmHg for neonates and infants; >= 30 mmHg for children) than Fontan patients (21/23 (91%) vs. 5/11 (46%), p = 0.007). Conclusions: Only 27% of Fontan patients survived to hospital discharge with favorable neurologic outcome after CPR, likely driven by inadequate diastolic blood pressure during resuscitation. One half of the BDG patients who survived to hospital discharge had new neurologic morbidity. BackgroundCardiac arrest in patients with congenital heart disease (CHD) may present challenges to resuscitation based on the unique cardiovascular physiology resulting from surgical palliation. Recent resuscitation guidelines for CHD patients highlight the lack of data surrounding these special patient populations.1 Univentricular heart disease is palliated by a series of cardiac surgeries that stepwise result in passive pulmonary perfusion from the systemic venous system directly to the pulmonary vascular bed. The bidirectional Glenn (BDG) palliation directly anastomoses the superior vena cava (SVC) to the pulmonary arterial system and leaves normal inferior vena cava (IVC) venous return to the heart.2 The Fontan palliation baffles IVC flow directly to the pulmonary vascular bed which relieves cyanosis due to right to left shunting, but requires systemic ventricular preload to be directly dependent upon pulmonary vascular resistance and intrathoracic pressures.3 Impact statementHemodynamic waveforms from 2 large prospective observational studies now allow for exploration of physiology during cardiopulmonary resuscitation for unique anatomy associated with single ventricle congenital heart disease.Fewer patients with Fontan physiology (46%) achieved an adequate diastolic blood pressure (defined as >= 25 mmHg for neonates and infants and >= 30 mmHg for children) than bidirectional Glenn patients during cardiopulmonary resuscitation (91%, = 0.007).Only 27% of Fontan patients survived to hospital discharge with favorable neurologic outcome after cardiopulmonary resuscitation.Of the bidirectional Glenn patients who survived, 50% developed a new morbidity as quantified by the Functional Status Score.

Viral lower respiratory tract infection (vLRTI) is a leading cause of hospitalization and death in children worldwide. Despite this, no studies have employed proteomics to characterize host immune responses to severe pediatric vLRTI in both the lower airway and systemic circulation. To address this gap, gain insights into vLRTI pathophysiology, and test a novel diagnostic approach, we assayed 1,305 proteins in tracheal aspirate (TA) and plasma from 62 critically ill children using SomaScan. We performed differential expression (DE) and pathway analyses comparing vLRTI (n = 40) to controls with non-infectious acute respiratory failure (n = 22), developed a diagnostic classifier using LASSO regression, and analyzed matched TA and plasma samples. We further investigated the impact of viral load and bacterial coinfection on the proteome. The TA signature of vLRTI was characterized by 200 DE proteins (P-adj <0.05) with upregulation of interferons and T cell responses and downregulation of inflammation-modulating proteins including FABP and MIP-5. A nine-protein TA classifier achieved an area under the receiver operator curve (AUC) of 0.96 (95% CI: 0.90-1.00) for identifying vLRTI. In plasma, the host response to vLRTI was more muted with 56 DE proteins. Correlation between TA and plasma was limited, although ISG15 was elevated in both compartments. In bacterial coinfection, we observed increases in the TNF-stimulated protein TSG-6, as well as CRP, and interferon-related proteins. Viral load correlated positively with interferon signaling and negatively with neutrophil-activation pathways. Taken together, our study provides fresh insights into the lower airway and systemic proteome of severe pediatric vLRTI and identifies novel protein biomarkers with diagnostic potential. IMPORTANCE We describe the first proteomic profiling of the lower airway and blood in critically ill children with severe viral lower respiratory tract infection (vLRTI). From tracheal aspirate (TA), we defined a proteomic signature of vLRTI characterized by increased expression of interferon signaling proteins and decreased expression of proteins involved in immune modulation including FABP and MIP-5. Using machine learning, we developed a parsimonious diagnostic classifier that distinguished vLRTI from non-infectious respiratory failure with high accuracy. Comparative analysis of paired TA and plasma specimens demonstrated limited concordance, although the interferon-stimulated protein ISG15 was significantly upregulated with vLRTI in both compartments. We further identified TSG-6 and CRP as airway biomarkers of bacterial-viral coinfection, and viral load analyses demonstrated a positive correlation with interferon-related protein expression and a negative correlation with the expression of neutrophil activation proteins. Taken together, our study provides new insights into the lower airway and systemic proteome of severe pediatric vLRTI.

Half of pediatric in-hospital cardiopulmonary resuscitation (CPR) events have an initial rhythm of non-pulseless bradycardia with poor perfusion. Our study objectives were to leverage granular data from the ICU-RESUScitation (ICU-RESUS) trial to: (1) determine the association of early epinephrine administration with survival outcomes in children receiving CPR for bradycardia with poor perfusion; and (2) describe the incidence and time course of the development of pulselessness. Prespecified secondary analysis of ICU-RESUS, a multicenter cluster randomized trial of children (< 19 years) receiving CPR in 18 intensive care units in the United States. Index events (October 2016–March 2021) lasting ≥ 2 min with a documented initial rhythm of bradycardia with poor perfusion were included. Associations between early epinephrine (first 2 min of CPR) and outcomes were evaluated with Poisson multivariable regression controlling for a priori pre-arrest characteristics. Among patients with arterial lines, intra-arrest blood pressure waveforms were reviewed to determine presence of a pulse during CPR interruptions. The temporal nature of progression to pulselessness was described and outcomes were compared between patients according to subsequent pulselessness status. Of 452 eligible subjects, 322 (71

ObjectiveFetuses with complex congenital heart disease have altered physiology, contributing to abnormal neurodevelopment. The effects of altered physiology on brain development have not been well studied. We used multi-modal imaging to study fetal circulatory physiology and brain development in hypoplastic left heart syndrome (HLHS) and d-transposition of the great arteries (TGA).MethodsThis prospective, cross-sectional study investigated individuals with fetal congenital heart disease and controls undergoing fetal echocardiography and fetal brain MRI. MRI measured total brain volume and cerebral oxygenation by the MRI quantification method T2*. Indexed cardiac outputs (CCOi) and vascular impedances were calculated by fetal echocardiography. Descriptive statistics assessed MRI and echocardiogram measurement relationships by physiology.ResultsSixty-six participants enrolled (control = 20; HLHS = 25; TGA = 21), mean gestational age 33.8 weeks (95% CI: 33.3-34.2). Total brain volume and T2* were significantly lower in fetuses with cardiac disease. CCOi was lower in HLHS, correlating with total brain volume - for every 10% CCOi increase, volume increased 8 mm3 (95% CI: 1.78-14.1; p = 0.012). Echocardiography parameters and cerebral oxygenation showed no correlation. TGA showed no CCOi or aortic output correlation with MRI measures.ConclusionsIn HLHS, lower cardiac output is deleterious to brain development. Our findings provide insight into the role of fetal cardiovascular physiology in brain health. What is already known about this topic?Fetuses with complex congenital heart disease are at risk of abnormal brain development and impaired neurodevelopmental outcomes.Causes of abnormal brain development in fetuses with congenital heart disease are multi-factorial including abnormal cardiovascular physiology.What does this study add?Lower cardiac output measured by fetal echocardiography is associated with smaller total brain volume in hypoplastic left heart syndrome but not d-transposition of the great arteries, providing new insight into the relationship between fetal physiology and brain development.

BACKGROUND Brain injury is common in neonates with complex neonatal congenital heart disease (CHD) and affects neurodevelopmental outcomes.OBJECTIVES Given advancements in perioperative care, we sought to determine if the rate of preoperative and postoperative brain injury detected by using brain magnetic resonance imaging (MRI) and associated clinical risk factors have changed over time in complex CHD.METHODS A total of 270 term newborns with complex CHD were prospectively enrolled for preoperative and post-operative brain MRIs between 2001 and 2021 with a total of 466 MRI scans. Brain injuries in the form of white matter injury (WMI) or focal stroke and clinical factors were compared across 4 epochs of 5-year intervals with logistic regression.RESULTS Rates of preoperative WMI and stroke did not change over time. After adjusting for timing of the postoper-ative MRI, site, and cardiac group, the odds of newly acquired postoperative WMI were significantly lower in Epoch 4 compared with Epoch 1 (OR: 0.29; 95% CI: 0.09-1.00; P 1/4 0.05). The adjusted probability of postoperative WMI declined significantly by 18.7% from Epoch 1 (24%) to Epoch 4 (6%). Among clinical risk factors, lowest systolic, mean, and diastolic blood pressures in the first 24 hours after surgery were significantly higher in the most recent epoch.CONCLUSIONS The prevalence of postoperative WMI has declined, whereas preoperative WMI rates remain constant. More robust postoperative blood pressures may explain these findings by minimizing periods of ischemia and supporting cerebral perfusion. These results suggest potential modifiable clinical targets in the postoperative time period to mini-mize the burden of WMI. (J Am Coll Cardiol 2023;81:253-266) (c) 2023 by the American College of Cardiology Foundation.

Objectives: Infants with congenital heart disease (CHD) are at risk for stroke, although associations with neurodevelopmental outcomes have varied. In adults with stroke, location and altered structural connectivity (disconnections) have been linked to neurologic symptoms. We assessed whether stroke (1) location and (2) white matter disconnections are related to neurodevelopment in infants with CHD. Methods: Infants underwent pre- and post-operative brain MRI in prospective studies at 3 centres (UBC, UCSF, SickKids) and completed 18-month neurodevelopmental assessments using Bayley Scales with separate motor and cognitive composites. Adverse outcomes were defined as composite score <85. Strokes were manually segmented. Voxel-wise lesion symptoms maps (VLSM) were used to assess relationships between lesion location and neurodevelopment. Disconnectomes were generated using stroke segmentations as seeds for tractography and diffusion MRI from healthy controls. Voxel-wise disconnectome-symptoms maps (VDSM) of associations between structural disconnections and neurodevelopment were developed. Results: 50 infants with strokes had neurodevelopmental outcomes data. Most strokes were small (<1/3 of arterial territory; n= 33) and in the left MCA territory (Fig 1A). However, strokes in the right basal ganglia and adjacent central white matter were most strongly associated with adverse motor and cognitive outcomes (Fig 1B). White matter disconnections extended beyond areas of injury (Fig 1C); these were extensive even in small strokes. Disconnections of tracts passing through the right basal ganglia were most strongly associated with adverse motor and cognitive outcomes (Fig 1D). Conclusions: Strokes involving the basal ganglia, particularly in the right hemisphere, were associated with worse motor and cognitive outcomes in infants with CHD. These data draw increasing attention to the right hemisphere in early-life stroke and neurodevelopment.

OBJECTIVE:Persons with congenital heart disease (CHD) are at increased risk of neurodevelopmental disabilities, including impairments to executive function. Sulcal pattern features correlate with executive function in adolescents with single-ventricle heart disease and tetralogy of Fallot. However, the interaction of sulcal pattern features with genetic and participant factors in predicting executive dysfunction is unknown.METHODS:We studied sulcal pattern features, participant factors, and genetic risk for executive function impairment in a cohort with multiple CHD types using stepwise linear regression and machine learning.RESULTS:Genetic factors, including predicted damaging de novo or rare inherited variants in neurodevelopmental disabilities risk genes, apolipoprotein E genotype, and principal components of sulcal pattern features were associated with executive function measures after adjusting for age at testing, sex, mother's education, and biventricular versus single-ventricle CHD in a linear regression model. Using regression trees and bootstrap validation, younger participant age and larger alterations in sulcal pattern features were consistently identified as important predictors of decreased cognitive flexibility with left hemisphere graph topology often selected as the most important predictor. Inclusion of both sulcal pattern and genetic factors improved model fit compared to either alone.INTERPRETATION:We conclude that sulcal measures remain important predictors of cognitive flexibility, and the model predicting executive outcomes is improved by inclusion of potential genetic sources of neurodevelopmental risk. If confirmed, measures of sulcal patterning may serve as early imaging biomarkers to identify those at heightened risk for future neurodevelopmental disabilities.