Neurodevelopmental Outcomes for Individuals With Congenital Heart Disease: Updates in Neuroprotection, Risk-Stratification, Evaluation, and Management: A Scientific Statement From the American Heart Association.

Over the past decade, new research has advanced scientific knowledge of neurodevelopmental trajectories, factors that increase neurodevelopmental risk, and neuroprotective strategies for individuals with congenital heart disease. In addition, best practices for evaluation and management of developmental delays and disorders in this high-risk patient population have been formulated based on literature review and expert consensus. This American Heart Association scientific statement serves as an update to the 2012 statement on the evaluation and management of neurodevelopmental outcomes in children with congenital heart disease. It includes revised risk categories for developmental delay or disorder and an updated list of factors that increase neurodevelopmental risk in individuals with congenital heart disease according to current evidence, including genetic predisposition, fetal and perinatal factors, surgical and perioperative factors, socioeconomic disadvantage, and parental psychological distress. It also includes an updated algorithm for referral, evaluation, and management of individuals at high risk. Risk stratification of individuals with congenital heart disease with the updated categories and risk factors will identify a large and growing population of survivors at high risk for developmental delay or disorder and associated impacts across the life span. Critical next steps must include efforts to prevent and mitigate developmental delays and disorders. The goal of this scientific statement is to inform health care professionals caring for patients with congenital heart disease and other key stakeholders about the current state of knowledge of neurodevelopmental outcomes for individuals with congenital heart disease and best practices for neuroprotection, risk stratification, evaluation, and management.

Primary or Delayed Repair for Complete Atrioventricular Septal Defect, Tetralogy of Fallot, and Ventricular Septal Defect: Relationship to Country Economic Status.

OBJECTIVE: Primary repair in the first six months of life is routine for tetralogy of Fallot, complete atrioventricular septal defect, and ventricular septal defect in high-income countries. The objective of this analysis was to understand the utilization and outcomes of palliative and reparative procedures in high versus middle-income countries. METHODS: The World Database of Pediatric and Congenital Heart Surgery identified patients who underwent surgery for: tetralogy of Fallot, complete atrioventricular septal defect, and ventricular septal defect. Patients were categorized as undergoing primary repair, repair after prior palliation, or palliation only. Country economic status was categorized as lower middle, upper middle, and high, defined by the World Bank. Multiple logistic regression models were utilized to identify independent predictors of hospital mortality. RESULTS: Economic categories included high (n = 571, 5.3%), upper middle (n = 5,342, 50%), and lower middle (n = 4,793, 49.7%). The proportion of patients and median age with primary repair were: tetralogy of Fallot, 88.6%, 17.7 months; complete atrioventricular septal defect, 83.4%, 7.7 months; and ventricular septal defect, 97.1%, ten months. Age at repair was younger in high income countries (P < .0001). Overall mortality after repair was lowest in high income countries. Risk factors for hospital mortality included prematurity, genetic syndromes, and urgent or emergent operations (all P < .05). CONCLUSIONS: Primary repair was selected in >90% of patients, but definitive repair was delayed in lower and upper middle income countries compared with high-income countries. Repair after prior palliation versus primary repair was not a risk factor for hospital mortality. Initial palliation continues to have a small but important role in the management of these three specific congenital heart defects.

Cardiac surgical outcomes of patients with heterotaxy syndrome.

Objectives: The study objectives were to analyze the outcomes of pediatric patients with heterotaxy syndrome undergoing cardiovascular surgery and to determine the predictors of mortality. Methods: A retrospective analysis of 82 patients diagnosed with heterotaxy syndrome who underwent cardiovascular surgery between January 2008 and December 2017 was performed. Univariate and multivariable Cox regression analyses to determine risk factors for mortality and Kaplan-Meier analysis for survival were performed. Results: Patient mortality in the cohort was 34% (28/82), including 36% (20/55) for single ventricle palliation and 30% (8/27) for biventricular repair. At 5 years, the probability of survival did not differ between the groups by log-rank testing (P = .829). Multivariable analysis found extracorporeal membrane oxygenation support (hazard ratio, 10.4; 95% confidence interval, 4.3-25.4; P < .001), total anomalous pulmonary venous return (hazard ratio, 4.3; 95% confidence interval, 1.7-10.8; P = .002), and birth weight 2.5 kg or less (hazard ratio, 2.4; 95% confidence interval, 1.0-5.4; P = .041) to be independent risk factors for mortality in all-comers. Pulmonary vein stenosis was a univariate predictor of mortality among all patients with heterotaxy (hazard ratio, 3.0; 95% confidence interval, 1.4-6.4; P = .005) and in the subgroup of patients with single ventricles (hazard ratio, 4.0; 95% confidence interval, 1.7-9.7; P = .002). Overall survival was 66% (54/82) at a median follow-up time of 2.2 years (0.4-4.1) from the initial surgery. Conclusions: Outcomes of children with heterotaxy syndrome, irrespective of the operative pathway, remain suboptimal in the current era. Risk factors for mortality in this population include birth weight 2.5 kg or less, extracorporeal membrane oxygenation, pulmonary vein stenosis, and total anomalous pulmonary venous return, which may help to further optimize surgical decision making. Multiorgan system involvment is frequently encountered in these patients.

Fate of aortic regurgitation after isolated repair of ventricular septal defect with concomitant aortic regurgitation in children.

Objectives: The aim of the study was to evaluate the course of aortic valve regurgitation in patients with preoperative aortic valve regurgitation and ventricular septal defect who underwent repair of the ventricular septal defect without aortic valve repair. Methods: A total of 37 consecutive patients with a ventricular septal defect and aortic regurgitation who underwent surgery between April 2007 and March 2016 were included in the study. Demographic, echocardiographic, operative, and clinical data were reviewed. Early and late mortality and morbidity were analyzed. Aortic regurgitation grade, left ventricular function, and dimensions were compared between the preoperative transesophageal echocardiography and postoperative transthoracic echocardiogram at last follow-up. Multivariate logistic regression analysis was performed to determine factors associated with improvement of aortic valve function. Results: There was no early or late mortality. No reoperations or reinterventions were required. A total of 17 patients had mild or greater aortic regurgitation preoperatively. Only 5 patients had mild or greater aortic regurgitation at follow-up of 4.3 years (0.5-10.1). Twenty-eight (76%) of the 37 patients showed an improvement in their aortic regurgitation grade. Left ventricular end-systolic and end-diastolic diameter z-scores were significantly lower at follow-up (P = .007 and P = .001, respectively). Multivariable logistic regression identified low preoperative left ventricular ejection fraction as the only predictor of nonimprovement of aortic regurgitation (95% confidence interval, 0.732-0.999, P = .002). Conclusions: Repair of a ventricular septal defect with accompanying aortic regurgitation can be performed with excellent results without surgical intervention on the aortic valve. Accompanying aortic regurgitation, especially trivial to mild, at the time of ventricular septal defect repair improves in the majority of cases. Low preoperative left ventricular ejection fraction is predictive of nonimprovement of aortic regurgitation grade.

Dose Effect of Mesenchymal Stromal Cell Delivery Through Cardiopulmonary Bypass.

BACKGROUND: Neurologic impairments are a significant concern for survivors after pediatric cardiac surgery with cardiopulmonary bypass (CPB). We have previously shown that mesenchymal stromal cell (MSC) delivery through CPB has the potential to mitigate the effects of CPB on neural stem/progenitor cells. This study assessed the dose effects of MSCs. METHODS: Piglets (n = 20) were randomly assigned to 1 of 4 groups: control, CPB, or CPB followed by MSC administration with low and high doses (10 × 106 and 100 × 106 cells per kilogram). We assessed acute dose effect on cell distribution, multiorgan functions, systemic inflammation, microglia activation, and neural stem/progenitor cell activities. RESULTS: By magnetic resonance imaging, approximately 10 times more MSCs were detected within the entire brain after high-dose delivery than after low-dose delivery. No adverse events affecting hemodynamics, various biomarkers, and neuroimaging were detected after high-dose MSC delivery. High-dose MSCs significantly increased circulating levels of interleukin 4 after CPB. Both MSC groups normalized microglia activation after CPB, demonstrating MSC-induced reduction in cerebral inflammation. There was a significant increase in neuroblasts in the subventricular zone in both treatment groups. The thickness of the most active neurogenic area within the subventricular zone was significantly increased after high-dose treatment compared with CPB and low-dose MSCs, suggesting dose-dependent effects on the neurogenic niche. CONCLUSIONS: MSC delivery through CPB is feasible up to 100 × 106 cells per kilogram. MSC treatment during cardiac surgery has the potential to reduce systemic and cerebral inflammation and to modulate responses of an active neurogenic niche to CPB. Further investigation is necessary to assess the long-term effects and to develop a more complete dose-response curve.

Defining the optimal historical control group for a phase 1 trial of mesenchymal stromal cell delivery through cardiopulmonary bypass in neonates and infants.

OBJECTIVE: The Mesenchymal Stromal Cell Delivery through Cardiopulmonary Bypass in Pediatric Cardiac Surgery study is a prospective, open-label, single-centre, dose-escalation phase 1 trial assessing the safety/feasibility of delivering mesenchymal stromal cells to neonates/infants during cardiac surgery. Outcomes will be compared with historical data from a similar population. We aim to define an optimal control group for use in the Mesenchymal Stromal Cell Delivery through Cardiopulmonary Bypass in Pediatric Cardiac Surgery trial. METHODS: Consecutive patients who underwent a two-ventricle repair without aortic arch reconstruction within the first 6 months of life between 2015 and 2020 were studied using the same inclusion/exclusion criteria as the Phase 1 Mesenchymal Stromal Cell Delivery through Cardiopulmonary Bypass in Pediatric Cardiac Surgery trial (n = 169). Patients were allocated into one of three diagnostic groups: ventricular septal defect type, Tetralogy of Fallot type, and transposition of the great arteries type. To determine era effect, patients were analysed in two groups: Group A (2015-2017) and B (2018-2020). In addition to biological markers, three post-operative scoring methods (inotropic and vasoactive-inotropic scores and the Pediatric Risk of Mortality-III) were assessed. RESULTS: All values for three scoring systems were consistent with complexity of cardiac anomalies. Max inotropic and vasoactive-inotropic scores demonstrated significant differences between all diagnosis groups, confirming high sensitivity. Despite no differences in surgical factors between era groups, we observed lower inotropic and vasoactive-inotropic scores in group B, consistent with improved post-operative course in recent years at our centre. CONCLUSIONS: Our studies confirm max inotropic and vasoactive-inotropic scores as important quantitative measures after neonatal/infant cardiac surgery. Clinical outcomes should be compared within diagnostic groupings. The optimal control group should include only patients from a recent era. This initial study will help to determine the sample size of future efficacy/effectiveness studies.

Mesenchymal Stromal Cell Delivery Via Cardiopulmonary Bypass Provides Neuroprotection in a Juvenile Porcine Model.

Oxidative/inflammatory stresses due to cardiopulmonary bypass (CPB) cause prolonged microglia activation and cortical dysmaturation, thereby contributing to neurodevelopmental impairments in children with congenital heart disease (CHD). This study found that delivery of mesenchymal stromal cells (MSCs) via CPB minimizes microglial activation and neuronal apoptosis, with subsequent improvement of cortical dysmaturation and behavioral alteration after neonatal cardiac surgery. Furthermore, transcriptomic analyses suggest that exosome-derived miRNAs may be the key drivers of suppressed apoptosis and STAT3-mediated microglial activation. Our findings demonstrate that MSC treatment during cardiac surgery has significant translational potential for improving cortical dysmaturation and neurological impairment in children with CHD.

Hybrid strategy in neonates with ductal-dependent systemic circulation and multiple risk factors.

OBJECTIVE: The study objective was to analyze outcomes of the hybrid strategy for ductal-dependent systemic circulation consisting of bilateral pulmonary artery banding with or without ductal stenting followed by delayed Norwood-type palliation or comprehensive stage II operation in high-risk neonates. METHODS: A retrospective analysis was performed between December 2017 and March 2021. Thirty high-risk neonates underwent palliation with bilateral pulmonary artery banding: 11 with prostaglandin therapy and 19 with ductal stenting. Median (range) age and body weight of patients at hybrid stage I were 3 days (0-43) and 2.9 kg (1.1-4.2), respectively. Operative and interstage mortality, morbidity, and reintervention rates were assessed. RESULTS: Overall survival was 70% (21/30) at a median follow-up time of 9 months (range, 0-37) from hybrid stage I. Operative survival for hybrid stage I was 90% (27/30), of which 2 patients received palliative care, and there was 1 interstage death (4%, 1/27). After hybrid stage I, 37% of patients had a reintervention, and 3% (n = 1) used extracorporeal membrane oxygenation before the next stage of repair. Five patients are awaiting second-stage operation, and 9 patients are awaiting Fontan completion. CONCLUSIONS: High-risk neonates with hypoplastic left heart syndrome or its variants can be successfully palliated using the hybrid strategy and bridged to a delayed Norwood or comprehensive stage II operation with satisfactory survival. This operative approach is a promising alternative pathway for neonates deemed to be high risk due to multiple preoperative risk factors.

Compression Device-Assisted Extracorporeal Cardiopulmonary Resuscitation Cannulation in Pediatric Patients-A Simulation Study.

Background: Surgical neck cannulation for pediatric extracorporeal cardiopulmonary resuscitation (ECPR) requires multiple interruptions of manual chest compressions to facilitate the procedure. Effective uninterrupted CPR is essential to prevent neurological injury. We hypothesized that an automated chest compression device can be used to provide effective and uninterrupted chest compressions during pediatric neck ECPR cannulation. The feasibility of surgically cannulating the right carotid artery and right internal jugular vein in an infant during ongoing automated chest compressions was tested in a simulation study. Methods: A working prototype of a pediatric chest compression device was designed to provide automated chest compressions on an infant CPR manikin at the rate of 120 compressions/minute. A feedback device attached to the manikin was used to monitor the effectiveness of CPR. A synthetic artery, vein along with carotid sheath and skin was utilized to simulate surgical neck exploration. ECPR simulation was conducted using the compression device to provide chest compressions. Results: Four ECPR simulations were conducted during which vessel sparing (n = 2) and non-vessel sparing (n = 2) cannulation of the right internal carotid artery and right internal jugular vein were performed during ongoing mechanical chest compressions. All four cannulations were successfully performed without the need to interrupt chest compressions. Conclusions: In a simulated environment, pediatric ECPR neck cannulation with uninterrupted chest compressions may be accomplished using an automated chest compression device. The strategy of compression device-assisted ECPR cannulation requires further study and could potentially reduce the neurological complications of ECPR.

A comparison of autologous pericardium with Dacron™ for closure of ventricular septal defect in infants.

OBJECTIVES: Glutaraldehyde-treated autologous pericardium (GtAP) and Dacron™ are 2 patch materials commonly used to repair ventricular septal defects (VSDs) in children. The primary objective of this study was to test the hypothesis that GtAP is as effective as Dacron for the repair of isolated VSD in infants. METHODS: Data were collected retrospectively from all infants who underwent repair of isolated VSD at our institution between January 2009 and April 2017. A total of 156 patients were divided into 2 groups: 99 underwent repair with Dacron patch and 57 with GtAP. The primary end point was the need for reintervention for significant residual VSD. Adjusted hospital charges were also compared. RESULTS: The 2 groups were comparable in their baseline characteristics. There was no significant difference in postoperative morbidity indicators. One patient in each group underwent reintervention for the closure of residual VSD. The GtAP group had a higher incidence trivial and small residual VSD at discharge than the Dacron group (65% vs 39%, P = 0.007). The median duration of follow-up was 37 (15-75) months with no difference between the 2 groups. Forty-five percentage of the residual VSDs in the Dacron group (19/42) and 54%in the GtAP group (21/39) had closed. There was no difference in hospital charges and clinical outcomes. CONCLUSIONS: GtAP for the closure of isolated VSD in infants is comparable to Dacron. Although the incidence of trivial or small residual VSD is higher with the use of pericardium immediately after surgery, this difference disappears over time.

The Current Status of Neuroprotection in Congenital Heart Disease.

Neurological deficits are a serious and common sequelae of congenital heart disease (CHD). While their underlying mechanisms have not been fully characterized, their manifestations are well-known and understood to persist through adulthood. Development of therapies to address or prevent these deficits are critical to attenuate future morbidity and improve quality of life. In this review, we aim to summarize the current status of neuroprotective therapy in CHD. Through an exploration of present research in the pre-operative, intra-operative, and post-operative phases of patient management, we will describe existing clinical and bench efforts as well as current endeavors underway within this research area.

The evolution of cardiac care for children in Washington, DC.

Cardiac surgery for CHD was pioneered in Washington, DC by Charles Hufnagel and Edgar Davis working at Georgetown University and Children's Hospital of the District of Columbia. Children's Hospital, now Children's National Hospital, had been established just 5 years after the end of the Civil War. In the 1950s, Davis and Hufnagel undertook many open-heart operations using the technique of surface cooling, hypothermia, and circulatory arrest. Hufnagel and Lewis Scott, who founded the cardiology department at Children's, were trained in Boston by Gross and Nadas. Judson Randolph, also a trainee of Gross, introduced cardiac surgery using cardiopulmonary bypass and established the General Pediatric Surgery department at Children's in the 1960s. The transition of hospital staffing from community-based private physicians to full-time hospital employees was often controversial but was complete by the turn of the millennium. The 21st century has seen continuing growth of the new Children's National Heart Institute and consolidation of several congenital cardiac programmes in Washington, DC.

Impact of Cardiopulmonary Bypass on Neurogenesis and Cortical Maturation.

OBJECTIVE: Neurodevelopmental delays and frontal lobe cortical dysmaturation are widespread among children with congenital heart disease (CHD). The subventricular zone (SVZ) is the largest pool of neural stem/progenitor cells in the postnatal brain. Our aim is to determine the effects of cardiopulmonary bypass (CPB) on neurogenesis and cortical maturation in piglets whose SVZ development is similar to human infants. METHODS: Three-week-old piglets (n = 29) were randomly assigned to control (no surgery), mild-CPB (34°C full flow for 60 minutes) and severe-CPB groups (25°C circulatory-arrest for 60 minutes). The SVZ and frontal lobe were analyzed with immunohistochemistry 3 days and 4 weeks postoperatively. MRI of the frontal lobe was used to assess cortical development. RESULTS: SVZ neurogenic activity was reduced up to 4 weeks after both mild and severe CPB-induced insults. CPB also induced decreased migration of young neurons to the frontal lobe, demonstrating that CPB impairs postnatal neurogenesis. MRI 4 weeks after CPB displayed a decrease in gyrification index and cortical volume of the frontal lobe. Cortical fractional anisotropy was increased after severe CPB injury, indicating a prolonged deleterious impact of CPB on cortical maturation. Both CPB-induced insults displayed a significant change in densities of three major inhibitory neurons, suggesting excitatory-inhibitory imbalance in the frontal cortex. In addition, different CPB insults altered different subpopulations of inhibitory neurons. INTERPRETATION: Our results provide novel insights into cellular mechanisms contributing to CHD-induced neurological impairments. Further refinement of CPB hardware and techniques is necessary to improve long-term frontal cortical dysmaturation observed in children with CHD. ANN NEUROL 2021;90:913-926.