From survival to long-term health : understanding and improving outcomes for children undergoing congenital heart surgery

Background: Congenital heart disease (CHD) is the most common major congenital anomaly and continues to drive significant infant morbidity and mortality worldwide. As survival improves, the focus of CHD care has shifted toward optimizing perioperative recovery, minimizing complications, and understanding long-term health trajectories. This thesis investigates perioperative determinants of outcomes in CHD through four retrospective clinical studies and one translational pilot study, examining: predictors of postoperative course after repair of four common lesions (Study I); perioperative physiology and outcomes in neonates undergoing PDA stenting (Study II); determinants and outcomes of early postoperative ECMO (Study III); long-term non-cardiac surgical needs and perioperative risk across the lifespan (Study IV); and preliminary molecular pathways underlying myocardial recovery using single-nucleus RNA sequencing (Study V - preliminary results). Together, these studies integrate clinical, physiologic, and molecular dimensions to inform future precision-based care strategies in CHD. Methods: Studies I-IV used retrospective cohorts from a tertiary pediatric cardiac center, encompassing over 4,000 cardiac and non-cardiac surgical encounters. Analyses included descriptive statistics, multivariable regression, and stratified subgroup analyses. Primary outcomes were ventilation duration, ICU and hospital length of stay, vasoactive-inotropic score (VIS), ECMO initiation, survival, and perioperative complications. Study I: 897 children undergoing VSD, CAVC, TOF, or TGA repair. Study Il: 68 neonates with ductal-dependent pulmonary blood flow undergoing PDA stenting. Study III: 115 children requiring ECMO within 24 hours of cardiac surgery. Study IV: 3,010 non-cardiac surgical encounters in CHD patients across childhood and into adulthood. Study V analyzed myocardial tissue from pediatric patients with end-stage heart failure before and after VAD therapy using single-nucleus RNA-sequencing, followed by integration, clustering, pseudobulk differential expression and pathway enrichment analysis. This work is still ongoing. Results: Across Studies I-III, preoperative physiologic vulnerability was a consistent determinant of postoperative course. Prematurity, neonatal age, low weight, syndromic status, metabolic acidosis, elevated lactate, and hypoxemia predicted prolonged ventilation and ICU stay. Intraoperative physiology - including longer cardiopulmonary bypass (CPB) and cross-clamp times, higher VIS, transfusion burden, and ventricular dysfunction - was the strongest predictor of postoperative instability. Lesion-specific differences were noted, including the influence of bypass duration in CAVC and benefits of valve-sparing approaches in TOF. In Study II, neonates undergoing PDA stenting demonstrated high acuity with frequent intraoperative events (ductal spasm, arrhythmias, thrombosis) and postoperative complications such as NEC and vascular injury, contributing to wide variability in ICU stay. Study III identified children requiring early postoperative ECMO as an extremely high-risk population with 50% mortality. In-OR ECMO was associated with higher mortality but reduced postoperative cardiac arrest. Severe preoperative ventricular dysfunction strongly predicted in-OR ECMO initiation, and survivors consistently had shorter CPB times, lower lactate, and higher intraoperative pH. Study IV demonstrated substantial lifetime surgical needs in CHD, with 68% of non-cardiac procedures occurring before age five and a 16.2% intraoperative complication rate. Risk was highest among single-ventricle patients (30.7%), adults with CHD, those with prior cardiac surgery, and patients with ventricular dysfunction. Procedure type varied with lesion and stage of palliation, emphasizing the need for condition-specific perioperative pathways. Study V applied single-nucleus RNA sequencing to pediatric myocardial tissue to explore molecular programs associated with myocardial recovery following heart failure therapy. Distinct transcriptional patterns differentiated recovery from non-recovery samples, characterized by downregulation of maladaptive stress, metabolic, and inflammatory signaling alongside coordinated shifts in endothelial cell states. Differential expression analyses highlighted cell-type-specific changes across fibroblast, endothelial, and immune populations, identifying candidate pathways that may underlie recovery potential in pediatric patients with heart failure. These preliminary findings demonstrate the feasibility of high-resolution molecular profiling in archived pediatric myocardium and provide early mechanistic insights that may ultimately support biomarker development and precision-based approaches to predicting and enhancing myocardial recovery. Conclusions: Across five studies, this thesis demonstrates that perioperative outcomes in CHD are governed by the interaction of preoperative physiology, surgical complexity, intraoperative stress, and postoperative management. Together, these studies provide a comprehensive clinical-to-translational framework for understanding and advancing precision-based perioperative care and improving outcomes for children with congenital heart disease. List of scientific papers I. Hamilton ARL, Yuki K, Fynn-Thompson F, DiNardo JA, Odegard KC, Perioperative outcomes in congenital heart disease: a review of clinical factors associated with prolonged ventilation and length of stay. J Cardiothorac Vasc Anesth. 2025; 39(3): 692-701. https://doi.org/10.1053/j.jvca.2024.11.008 II. Hamilton ARL, Staffa SJ, Yuki K, Odegard KC, Perioperative considerations for placement of Patent Ductus Arteriosus stents in infants with ductal-dependent pulmonary blood flow. [Submitted] III. Hamilton ARL, Nathan M, Thiagarajan RR, DiNardo JA, Odegard KC. Extracorporeal membrane oxygenation following congenital heart surgery: an evaluation of clinical factors associated with ECMO requirements in the immediate postoperative period. [Submitted] IV. Hamilton ARL, Odegard KC, Yuki K. Exploring the lifespan of non-cardiac surgical needs from infancy to adulthood in patients with congenital heart disease. J Cardiothorac Vasc Anesth. 2022;36(12):4364-4369. https://doi.org/10.1053/j.jvca.2022.09.076 V. Hamilton ARL, Ramsköld D, Papaz T, Maynes J, Jeewa A, Honjo O, Sandberg R, Mital S. Cell-specific transcriptional programs associated with myocardial recovery in pediatric heart failure (Preliminary Work, ongoing). [Manuscript]