Single Ventricle Reconstruction Trial Research Articles

Precision in Norwood Shunt Sizing: Single Ventricle Reconstruction Trial Public Dataset Analysis

BackgroundMorbidity and mortality after the Norwood procedure remains high. Shunt size selection is not standardized and the impact of shunt size on outcomes is poorly understood. The Single Ventricle Reconstruction trial randomized infants to modified Blalock-Taussig-Thomas shunt (MBTTS) or right ventricle-to-pulmonary artery shunt at the Norwood procedure. We assessed shunt size distribution and its association with postoperative outcomes. MethodsWe included 544 patients, excluding 5 with ambiguous shunt crossover data. Normalized shunt diameter 1 and 2 were calculated as shunt diameter divided by patient’s weight and body surface area, respectively. The primary outcome was 30-day mortality after Norwood. Secondary outcomes were intensive care and total length of stay, and survival to Glenn procedure. Logistic and ordinal regression models evaluated the association of normalized shunt diameter with outcomes. ResultsThirty-day mortality after Norwood was 11.4% (n = 62), survival to Glenn procedure was 72.6% (n = 395), median length of stay was 14.0 (interquartile range, 9.0-27.7) days and 24.0 (interquartile range, 16.0-41.0) days in the intensive care and total, respectively. Normalized shunt diameters exhibited variation in both shunt types but were not associated with 30-day mortality. Right ventricle-to-pulmonary artery shunt size was not associated with secondary outcomes. However, a MBTTS diameter ≥1.5 mm/kg predicted longer Norwood (odds ratio, 4.89; 95% CI, 1.41-16.90) and intensive care (odds ratio, 4.11; 95% CI, 1.25-13.49]) duration. ConclusionsShunt size selection was variable. Right ventricle-to-pulmonary artery shunt had a wider size range seen with favorable outcomes compared with MBTTS. A MBTTS either too large or too small is associated with worse postoperative outcomes. Refining shunt sizing practices can improve surgical outcomes after the Norwood procedure.

Using machine learning to predict five-year transplant-free survival among infants with hypoplastic left heart syndrome

Hypoplastic left heart syndrome (HLHS) is a congenital malformation commonly treated with palliative surgery and is associated with significant morbidity and mortality. Risk stratification models have often relied upon traditional survival analyses or outcomes data failing to extend beyond infancy. Individualized prediction of transplant-free survival (TFS) employing machine learning (ML) based analyses of outcomes beyond infancy may provide further valuable insight for families and healthcare providers along the course of a staged palliation. Data from both the Pediatric Heart Network (PHN) Single Ventricle Reconstruction (SVR) trial and Extension study (SVR II), which extended cohort follow up for five years was used to develop ML-driven models predicting TFS. Models incrementally incorporated features corresponding to successive phases of care, from pre-Stage 1 palliation (S1P) through the stage 2 palliation (S2P) hospitalization. Models trained with features from Pre-S1P, S1P operation, and S1P hospitalization all demonstrated time-dependent area under the curves (td-AUC) beyond 0.70 through 5 years following S1P, with a model incorporating features through S1P hospitalization demonstrating particularly robust performance (td-AUC 0.838 (95% CI 0.836–0.840)). Machine learning may offer a clinically useful alternative means of providing individualized survival probability predictions, years following the staged surgical palliation of hypoplastic left heart syndrome.

Abstract 17067: Long-Term Transplant-Free Survival is Improved in Hypoplastic Left Heart Syndrome With Cell-Based Therapy

Hypoplastic left heart syndrome (HLHS) is a univentricular congenital heart defect that has high morbidity and mortality and requires three-stage surgical reconstruction so that the right ventricle (RV) delivers systemic circulation. Poor outcomes result from RV failure in the systemic position. Accordingly, we conducted a phase I clinical trial (called ELPIS) of Lomecel-B™, an allogeneic bone-marrow derived cell-based therapy designed to improve cardiovascular performance, delivered as a one-time treatment during the Stage II (Glenn) surgery at approximately 4 months after birth. This trial met its primary endpoint (safety through 1-year post-treatment). To assess whether Lomecel-B™ has survival benefits, all ELPIS patients ( n=10, 7 males, and 3 females) were enrolled in a multi-year follow-on study and compared to a retrospective control group which was identified by a relevant clinical HLHS database. Patients in both studies were assessed for up to 5 years (range 3.5 - 5.0 years post-treatment for ELPIS) for mortality, heart transplants, and stage III (Fontan) surgery. Outcomes were compared with long-term historical data from patients in the Single Ventricle Reconstruction (SVR) Trial receiving the same shunt type at Stage I (Norwood) operation. 5-year Kaplan-Meier survival was 100% in ELPIS patients with none requiring heart transplant. This compared to 81.6% (95% CI= [76.5, 87.0]) transplant-free survival in the SVR trial through 5 years post-Glenn surgery, and a 5.2% (95% CI= [2.0, 8.3]) heart transplantation rate (Figure 1). No stem cell related safety issues were reported. These findings support Lomecel-B™ as a potential adjunct to HLHS reconstruction surgery to improve clinical benefits and reduce the need for subsequent heart transplantation. Further long-term follow-up and controlled trials are both warranted and underway.

School age and adolescent heart failure following the Norwood procedure

Heart failure results in significant morbidity and mortality for young children with hypoplastic left heart syndrome (HLHS) following the Norwood procedure. The trajectory in later childhood is not well described. We studied the outcome into adolescence of participants enrolled in the Single Ventricle Reconstruction (SVR) trial who underwent the Fontan procedure or survived to 6 years without having undergone Fontan procedure. The primary outcome was heart failure events, defined as heart transplant listing or death attributable to heart failure. Symptomatic heart failure for participants surviving 10 or more years was also assessed utilizing the PedsQL. Of the 345 participants who underwent a Fontan operation or survived to 6 years without Fontan, 25 (7.2%) had a heart failure event before age 12 years. Among these, 21 were listed for heart transplant and 4 died from heart failure. Nineteen participants underwent heart transplant, all of whom survived to age 12 years. Factors associated with a heart failure event included longer Norwood hospital length of stay, aortic atresia and no Fontan operation by age 6 years. Assessment of heart failure symptoms at 12 years of age revealed that 24 (12.2%) of 196 PedsQL respondents "often" or "almost always" had difficulty walking more than one block. Heart failure events occur in over 5% of children with palliated HLHS between preschool age and adolescence. Outcomes for children listed for transplant are excellent. However, a substantial portion of palliated HLHS children have significant symptoms of heart failure at 12 years of age.

Cardiac Magnetic Resonance Imaging to Determine Single Ventricle Function in a Pediatric Population is Feasible in a Large Trial Setting: Experience from the Single Ventricle Reconstruction Trial Longitudinal Follow up

The Single Ventricle Reconstruction (SVR) Trial was a randomized prospective trial designed to determine survival advantage of the modified Blalock-Taussig-Thomas shunt (BTTS) vs the right ventricle to pulmonary artery conduit (RVPAS) for patients with hypoplastic left heart syndrome. The primary aim of the long-term follow-up (SVRIII) was to determine the impact of shunt type on RV function. In this work, we describe the use of CMR in a large cohort follow up from the SVR Trial as a focused study of single ventricle function. The SVRIII protocol included short axis steady-state free precession imaging to assess single ventricle systolic function and flow quantification. There were 313 eligible SVRIII participants and 237 enrolled, ages ranging from 10 to 12.5 years. 177/237 (75%) participants underwent CMR. The most common reasons for not undergoing CMR exam were requirement for anesthesia (n = 14) or ICD/pacemaker (n = 11). A total of 168/177 (94%) CMR studies were diagnostic for RVEF. Median exam time was 54 [IQR 40–74] minutes, cine function exam time 20 [IQR 14–27] minutes, and flow quantification time 18 [IQR 12–25] minutes. There were 69/177 (39%) studies noted to have intra-thoracic artifacts, most common being susceptibility artifact from intra-thoracic metal. Not all artifacts resulted in non-diagnostic exams. These data describe the use and limitations of CMR for the assessment of cardiac function in a prospective trial setting in a grade-school-aged pediatric population with congenital heart disease. Many of the limitations are expected to decrease with the continued advancement of CMR technology.

Single Ventricle Reconstruction III: Brain Connectome and Neurodevelopmental Outcomes: Design, Recruitment, and Technical Challenges of a Multicenter, Observational Neuroimaging Study.

Patients with hypoplastic left heart syndrome who have been palliated with the Fontan procedure are at risk for adverse neurodevelopmental outcomes, lower quality of life, and reduced employability. We describe the methods (including quality assurance and quality control protocols) and challenges of a multi-center observational ancillary study, SVRIII (Single Ventricle Reconstruction Trial) Brain Connectome. Our original goal was to obtain advanced neuroimaging (Diffusion Tensor Imaging and Resting-BOLD) in 140 SVR III participants and 100 healthy controls for brain connectome analyses. Linear regression and mediation statistical methods will be used to analyze associations of brain connectome measures with neurocognitive measures and clinical risk factors. Initial recruitment challenges occurred that were related to difficulties with: (1) coordinating brain MRI for participants already undergoing extensive testing in the parent study, and (2) recruiting healthy control subjects. The COVID-19 pandemic negatively affected enrollment late in the study. Enrollment challenges were addressed by: (1) adding additional study sites, (2) increasing the frequency of meetings with site coordinators, and (3) developing additional healthy control recruitment strategies, including using research registries and advertising the study to community-based groups. Technical challenges that emerged early in the study were related to the acquisition, harmonization, and transfer of neuroimages. These hurdles were successfully overcome with protocol modifications and frequent site visits that involved human and synthetic phantoms.

Discussion

Discussion

Preterm Birth Is Associated With Adverse Cardiac Remodeling and Worse Outcomes in Patients With a Functional Single Right Ventricle

To assess the effects of preterm birth on cardiac structure and function and transplant-free survival in patients with hypoplastic left heart syndrome and associated anomalies throughout the staged palliation process. Data from the Single Ventricle Reconstruction trial were used to assess the impact of prematurity on echocardiographic measures at birth, Norwood, Stage II, and 14months in 549 patients with a single functional right ventricle. Medical history was recorded once a year using medical records or telephone interviews. Cox regression models were applied to analyze transplant-free survival to age 6years. Causal mediation analysis was performed to estimate the mediating effect of birth weight within this relationship. Of the 549 participants, 64 (11.7%) were born preterm. Preterm-born participants had lower indexed right ventricle end-diastolic volumes at birth but higher volumes than term-born participants by age 14months. Preterm-born participants had an increased risk of death or heart transplantation from birth to age 6years, with an almost linear increase in the observed risk as gestational age decreased below 37weeks. Of the total effect of preterm birth on transplant-free survival, 27.3% (95% CI 2.5-59.0%) was mediated through birth weight. Preterm birth is associated with adverse right ventricle remodeling and worse transplant-free survival throughout the palliation process, in part independently of low birth weight. Further investigation into this vulnerable group may allow development of strategies that mitigate the impact of prematurity on outcomes in patients with hypoplastic left heart syndrome.

The pediatric heart network's study on long-term outcomes of children with HLHS and the impact of Norwood Shunt type in the single ventricle reconstruction trial cohort (SVRIII): Design and adaptations

BackgroundThe Single Ventricle Reconstruction (SVR) Trial was the first randomized clinical trial of a surgical approach for treatment of congenital heart disease. Infants with hypoplastic left heart syndrome (HLHS) and other single right ventricle (RV) anomalies were randomized to a modified Blalock Taussig Thomas shunt (mBTTS) or a right-ventricular-to-pulmonary-artery shunt (RVPAS) at the time of the Norwood procedure. The aim of the Long-term Outcomes of Children with HLHS and the Impact of Norwood Shunt Type (SVR III) study is to compare early adolescent outcomes including measures of cardiac function, transplant-free survival, and neurodevelopment, between those who received a mBTTS and those who received an RVPAS. MethodsTransplant-free survivors of the SVR cohort were enrolled at 10 to 15 years of age for multifaceted in-person evaluation of cardiac function (cardiac magnetic resonance [CMR], echocardiogram and exercise test) and neurodevelopmental evaluation. Right ventricular ejection fraction measured by CMR served as the primary outcome. Development of arrhythmias, protein losing enteropathy, and other comorbidities were assessed through annual medical history interview. Through the course of SVR III, protocol modifications to engage SVR trial participants were designed to enhance recruitment and retention. ConclusionsEvaluation of long-term outcomes will provide important data to inform decisions about the shunt type placed at the Norwood operation and will improve the understanding of cardiovascular and neurodevelopmental outcomes for early adolescents with HLHS.

Shunt resistance is associated with clinically important outcomes after the Norwood operation

BackgroundIn single-ventricle physiology, focus on pulmonary vascular resistance neglects the resistance in the conduit supplying the pulmonary inflow. MethodsConduit length and diameter, which can approximate conduit resistance, are available in the public dataset of Single Ventricle Reconstruction (SVR) trial. Conduit resistance was then calculated for SVR trial participants and the relationship with clinically important variables (death or transplant at 1 year, pulmonary artery size at second-stage palliation, pulmonary-to-systemic blood flow ratio, and supplemental oxygen requirement) was explored. To validate this calculated resistance, calculated resistance was compared with catheterization measurements at a single institution (not included in the SVR trial). ResultsIn the institutional dataset, calculated and measured resistances had an intraclass correlation of 0.78 for modified Blalock–Taussig shunts (MBTS). Within the SVR trial, transplant-free survivors had a lower MBTS resistance (median, 8.3 Woods Units [WU]. interquartile range [IQR], 6.5-11.1 WU) than patients who died or required transplantation (median, 13.0 WU; IQR, 9.4-16.6 WU, P = .0001). When we controlled for left pulmonary artery diameter after the Norwood procedure in the SVR trial, for each unit increase in MBTS resistance, the left pulmonary artery diameter at stage II decreased (–0.006 ± 0.002 cm, P = .005). When we controlled for pulmonary vascular resistance, greater MBTS resistance was associated with a decrease in log pulmonary-to-systemic blood flow ratio (–0.04 ± 0.015, P = .0048) in the SVR trial. Patients in the SVR trial requiring supplemental oxygen on admission for stage II palliation had greater MBTS resistance (median. 11.1 WU; IQR, 6.6-16.6 WU) than patients not requiring oxygen (median 8.3, WU; IQR, 6.5-11.1 WU, P = .015). ConclusionsConduit resistance is associated with important clinical outcomes after Norwood; however, further studies are required to guide conduit resistance optimization.

Association of Digoxin With Preserved Echocardiographic Indices in the Interstage Period: A Possible Mechanism to Explain Improved Survival?

BackgroundFor patients with hypoplastic left heart syndrome, digoxin has been associated with reduced interstage mortality after the Norwood operation, but the mechanism of this benefit remains unclear. Preservation of right ventricular (RV) echocardiographic indices has been associated with better outcomes in hypoplastic left heart syndrome. Therefore, we sought to determine whether digoxin use is associated with preservation of the RV indices in the interstage period.Methods and ResultsWe conducted a retrospective cohort study of prospectively collected data using the public use data set from the Pediatric Heart Network Single Ventricle Reconstruction trial, conducted in 15 North American centers between 2005 and 2008. We included all patients who survived the interstage period and had echocardiographic data post‐Norwood and pre‐Glenn operations. We used multivariable linear regression to compare changes in RV parameters, adjusting for relevant covariates. Of 289 patients, 94 received digoxin at discharge post‐Norwood. There were no significant differences in baseline clinical characteristics or post‐Norwood echocardiographic RV indices (RV end‐diastolic volume indexed, RV end‐systolic volume indexed, ejection fraction) in the digoxin versus no‐digoxin groups. At the end of the interstage period and after adjustment for relevant covariates, patients on digoxin had better preserved RV indices compared with those not on digoxin for the ΔRV end‐diastolic volume (11 versus 15 mL, P=0.026) and the ΔRV end‐systolic volume (6 versus 9 mL, P=0.009) with the indexed ΔRV end‐systolic volume (11 versus 20 mL/BSA1.3, P=0.034). The change in the RV ejection fraction during the interstage period between the 2 groups did not meet statistical significance (−2 versus −5, P=0.056); however, the trend continued to be favorable for the digoxin group.ConclusionsDigoxin use during the interstage period is associated with better preservation of the RV volume and tricuspid valve measurements leading to less adverse remodeling of the single ventricle. These findings suggest a possible mechanism of action explaining digoxin’s survival benefit during the interstage period.

Abstract 10502: Impact of Norwood Shunt Type on Cardiac Function and Clinical Outcomes in Survivors to Early Adolescence with Hypoplastic Left Heart Syndrome and Other Single Right Ventricular Anomalies: A Report from the Single Ventricle Reconstruction (SVR) III Study

Introduction: The SVR Trial demonstrated that the right ventricle-to-pulmonary artery shunt (RVPAS) vs. modified Blalock-Taussig-Thomas shunt (MBTTS) at Norwood operation was associated with better early survival for children with hypoplastic left heart syndrome (HLHS). However, it remains unclear if shunt type is associated with cardiac function, morbidities or survival in older children. Methods: SVR Trial survivors were followed annually. Cardiac MRI and cycle ergometry were performed at 10-12 years (y) of age for SVR III participants. Outcomes were compared by shunt type received (presented) and intention to treat, using linear, Poisson and Cox proportional hazards regression. Results: Among 549 children in the SVR Trial, 237 of 313 eligible transplant-free survivors returned for follow-up at median (IQR) 10.9 (10.4-11.5) y. Transplant-free survival at 12 y was 59% for the RVPAS vs 54% for the MBTTS, with no difference in survival conditional on Stage II survival. Ejection fraction (EF) was measured by MRI in 168 participants, with no difference between groups (RVPAS median 53 [IQR 46-58] and MBTTS 52 [IQR 48-56], p=.38). In multivariable modeling, the percent variance in EF explained by pre-Norwood and Norwood variables including shunt type was low (R 2 < .2). Cycle ergometry was performed in 181 participants with no difference by shunt type in peak VO 2 (ml/kg/minute) (RVPAS 30 [IQR 25-36] vs. MBTTS 29 [IQR 24-33], p=.26) or in peak work rate (RVPAS 67±24 watts vs MBTTS 66±20 watts, p=.61). By age 12 y, the RVPAS group had a higher rate of PLE (5% vs. 2%, p =.04) and catheter interventions (14 vs 10 per 100 pt-y; p=0.01). Otherwise the cumulative incidence of events and complications were similar for shunt groups with stroke in 7%, seizure 14%, plastic bronchitis 1%, atrial tachyarrhythmias 7% and ventricular tachyarrhythmias 3%. Conclusion: By 12 y after Norwood, shunt type has minimal effect on post-Stage II transplant-free survival, cardiac function or exercise performance. EF is preserved in most transplant-free survivors. However, low and declining transplant-free survival, poor exercise performance, and accruing morbidities highlight the critical need for innovative strategies to improve long-term outcomes in patients with HLHS.

Abstract 6961: Anesthetic Management During Pre-Stage II Intracardiac Hemodynamic Assessment: An Analysis of the Single Ventricle Reconstruction Trial Dataset

Background: Intracardiac hemodynamics are often obtained with cardiac catheterization prior to proceeding with Stage II palliation for infants with single ventricle anatomy. There is little data examining the hemodynamic impact of anesthetic strategy during catheterization. Methods: Data from the Pediatric Heart Network Single Ventricle Reconstruction Trial was used for analysis. In addition to anesthetic strategy, data reported from cardiac catheterization prior to Stage II palliation included mean systemic venous atrial pressure (MSVAP), end diastolic ventricular pressure (EDVP), pulmonary flow (Q p )/systemic flow (Q s ) ratio, and indexed pulmonary vascular resistance (PVRi). Indexed systemic vascular resistance (SVRi), Q p , and Q s were calculated using available hemodynamic data. Results: Of 549 subjects, pre-Stage II cardiac catheterization data following palliation with a modified Blalock-Taussig-Thomas shunt (mBTTS) or right ventricle to pulmonary artery conduit (RV2PA) was available for 390, of which 219 had adequate hemodynamic data for inclusion in analysis. Intracardiac hemodynamic comparisons were made with respect to anesthetic approach and shunt type. Moderate sedation was utilized in 90 (41%) and general anesthesia in the remaining 129 subjects. A moderate sedation strategy was associated with significantly higher Q p /Q s (1.2 [0.9, 1.6] v. 1.0 [0.7, 1.3], p<0.001) and estimated SVRi (15 Wu•m 2 [11,19] v. 10 [7.8,15], p<0.001), a difference consistent among both mBTTS and RV2PA subgroups. There were no differences between anesthetic groups with respect to PVRi or calculated Q s in either shunt group. Independent of shunt type, PVRi, and patient weight at catheterization, moderate sedation at catheterization was associated with a two-fold odds of a reported Q p /Q s >1 (OR 2.03, 95%CI 1.13-3.63, p=0.017). Conclusions: Anesthetic strategy and alterations in SVRi represent an important consideration when evaluating hemodynamics in a shunt dependent single ventricle circulation. Future investigations may aid in understanding the relationship between anesthetic approach during catheterization and the resulting hemodynamic data employed in perioperative decision-making.

Estimating the optimal timing of surgery by imputing potential outcomes.

Hypoplastic left heart syndrome is a congenital anomaly that is uniformly fatal in infancy without immediate treatment. The standard treatment consists of an initial Norwood procedure (stage 1) followed some months later by stage 2 palliation (S2P). The ideal timing of the S2P is uncertain. The Single Ventricle Reconstruction Trial (SVRT) randomized the procedure used in the initial Norwood operation, leaving the timing of the S2P to the discretion of the surgical team. To estimate the causal effect of the timing of S2P, we propose to impute the potential post-S2P survival outcomes using statistical models under the Rubin Causal Model framework. With this approach, it is straightforward to estimate the causal effect of S2P timing on post-S2P survival by directly comparing the imputed potential outcomes. Specifically, we consider a lognormal model and a restricted cubic spline model, evaluating their performance in Monte Carlo studies. When applied to the SVRT data, the models give somewhat different imputed values, but both support the conclusion that the optimal time for the S2P is at 6months after the Norwood procedure.

Six-Year Neurodevelopmental Outcomes for Children With Single-Ventricle Physiology.

To determine if neurodevelopmental deficits in children with single-ventricle physiology change with age and early developmental scores predict 6-year outcomes. In the Single Ventricle Reconstruction Trial, Bayley Scales of Infant Development, Second Edition, were administered at 14 months of age, and parents completed the Behavior Assessment System for Children, Second Edition (BASC-2) annually from the ages of 2 to 6 years. Scores were classified as average, at risk, or impaired. We calculated sensitivities, specificities, and positive and negative predictive values of earlier tests on 6-year outcomes. Of 291 eligible participants, 244 (84%) completed the BASC-2 at 6 years; more Single Ventricle Reconstruction participants than expected on the basis of normative data scored at risk or impaired on the BASC-2 Adaptive Skills Index at that evaluation (28.7% vs 15.9%; P < .001). Children with Adaptive Skills Composite scores <2 SD below the mean at the age of 6 were more likely to have had delayed development at 14 months, particularly on the Psychomotor Development Index (sensitivity of 79%). However, the positive predictive value of the 14-month Mental Development Index and Psychomotor Development Index for 6-year BASC-2 Adaptive Scores was low (44% and 36%, respectively). Adaptive Skills Composite score impairments at the age of 6 were poorly predicted by using earlier BASC-2 assessments, with low sensitivities at the ages of 3 (37%), 4 (48%), and 5 years (55%). Many children with hypoplastic left heart syndrome who have low adaptive skills at the age of 6 years will not be identified by screening at earlier ages. With our findings, we highlight the importance of serial evaluations for children with critical congenital heart disease throughout development.

Abstract 13533: Acute Post-operative Renal Failure and Mortality Risk Following Norwood Surgical Palliation: A Secondary Analysis of the Pediatric Heart Network Single Ventricle Reconstruction Trial Public Use Database

Introduction: The Single Ventricle Reconstruction (SVR) trial randomized neonates with a single morphologic right ventricle undergoing Norwood to a modified Blalock-Taussig shunt (mBTS) or a right ventricle-to-pulmonary artery shunt at 15 centers. The trial demonstrated increased risk of death or heart transplant at one-year post-Norwood in subjects randomized to a mBTS. Using SVR public data, we evaluated incidence and risk factors for post-op renal failure after Norwood, and evaluated the relationship between renal failure, shunt type and one-year post-Norwood mortality. Methods: Post-op renal failure was defined a-priori as a 3-fold rise in creatinine from baseline, or dialysis use within 7 days of Norwood. We used multivariate logistic regression to evaluate risk factors for post-op renal failure and Cox hazard regression to determine the association between post-op renal failure and one-year post-Norwood mortality. Results: Overall 46/544 (8.4%) SVR trial subjects developed post-op renal failure, the majority (32/46, 69.6%) by post-op day 3. In multivariate analysis, risk factors for post-op renal failure included receipt of a mBTS (aOR 3.3, p=0.02), center volume &lt;15 cases/year (aOR 2.7, p=0.005), presence of ≥ 2 pre-op complications (aOR 4.0, p&lt;0.001), low birth weight (aOR 3.2, p=0.002), post-op heart block (aOR 8.5, p=0.001), and delayed sternal closure (aOR 5.3, p=0.026). Renal failure was an independent risk factor for one-year post-Norwood mortality (aHR 1.9, CI 1.1-3.2, p=0.019). When renal failure and shunt type were included as model covariates, there was interaction (p=0.049) with renal failure attenuating the mortality risk associated with receipt of a mBTS (p=0.24), Figure. Conclusions: In the SVR trial, post-op renal failure was relatively common but with modifiable risk factors including receipt of a mBTS. Our findings suggest that post-op renal failure accounts for some of the increased mortality risk associated with the mBTS.

Socioeconomic Status and Long-term Outcomes in Single Ventricle Heart Disease.

Low socioeconomic status (SES) has emerged as an important risk factor for higher short-term mortality and neurodevelopmental outcomes in children with hypoplastic left heart syndrome and related anomalies; yet little is known about how SES affects these outcomes over the long-term. We linked data from the Single Ventricle Reconstruction trial to US Census Bureau data to analyze the relationship of neighborhood SES tertiles with mortality and transplantation, neurodevelopment, quality of life, and functional status at 5 and 6 years post-Norwood procedure (N = 525). Cox proportional hazards regression and linear regression were used to assess the association of SES with mortality and neurodevelopmental outcomes, respectively. Patients in the lowest SES tertile were more likely to be racial minorities, older at stage 2 and Fontan procedures, and to have more complications and fewer cardiac catheterizations over follow-up (all P < .05) compared with patients in higher SES tertiles. Unadjusted mortality was highest for patients in the lowest SES tertile and lowest in the highest tertile (41% vs 29%, respectively; log-rank P = .027). Adjustment for patient birth and Norwood factors attenuated these differences slightly (P = .055). Patients in the lowest SES tertile reported lower functional status and lower fine motor, problem-solving, adaptive behavior, and communication skills at 6 years (all P < .05). These differences persisted after adjustment for baseline and post-Norwood factors. Quality of life did not differ by SES. Among patients with hypoplastic left heart syndrome, those with low SES have worse neurodevelopmental and functional status outcomes at 6 years. These differences were not explained by other patient or clinical characteristics.

Estimating the optimal timing of surgery from observational data.

Infants with hypoplastic left heart syndrome require an initial Norwood operation, followed some months later by a stage 2 palliation (S2P). The timing of S2P is critical for the operation's success and the infant's survival, but the optimal timing, if one exists, is unknown. We attempt to identify the optimal timing of S2P by analyzing data from the Single Ventricle Reconstruction Trial (SVRT), which randomized patients between two different types of Norwood procedure. In the SVRT, the timing of the S2P was chosen by the medical team; thus with respect to this exposure, the trial constitutes an observational study, and the analysis must adjust for potential confounding. To accomplish this, we propose an extended propensity score analysis that describes the time to surgery as a function of confounders in a discrete competing-risk model. We then apply inverse probability weighting to estimate a spline hazard model for predicting survival from the time of S2P. Our analysis suggests that S2P conducted at 6 months after the Norwood gives the patient the best post-S2P survival. Thus, we place the optimal time slightly later than a previous analysis in the medical literature that did not account for competing risks of death and hearttransplantation.

Deep Learning for Improved Risk Prediction in Surgical Outcomes

The Norwood surgical procedure restores functional systemic circulation in neonatal patients with single ventricle congenital heart defects, but this complex procedure carries a high mortality rate. In this study we address the need to provide an accurate patient specific risk prediction for one-year postoperative mortality or cardiac transplantation and prolonged length of hospital stay with the purpose of assisting clinicians and patients’ families in the preoperative decision making process. Currently available risk prediction models either do not provide patient specific risk factors or only predict in-hospital mortality rates. We apply machine learning models to predict and calculate individual patient risk for mortality and prolonged length of stay using the Pediatric Heart Network Single Ventricle Reconstruction trial dataset. We applied a Markov Chain Monte-Carlo simulation method to impute missing data and then fed the selected variables to multiple machine learning models. The individual risk of mortality or cardiac transplantation calculation produced by our deep neural network model demonstrated 89 ± 4% accuracy and 0.95 ± 0.02 area under the receiver operating characteristic curve (AUROC). The C-statistics results for prediction of prolonged length of stay were 85 ± 3% accuracy and AUROC 0.94 ± 0.04. These predictive models and calculator may help to inform clinical and organizational decision making.

Recurrent Pulmonary Artery Interventions Following the Norwood Procedure Are Not Associated With Conduit Type

Given pulmonary artery interventions following the Norwood procedure can recur, the average number of occurrences per patient over time is likely more informative than the crude percentage of patients who required an intervention. Pulmonary artery intervention was defined as any surgical or catheter-based procedure after the Norwood procedure. The number of pulmonary artery interventions for patients with hypoplastic left heart syndrome were compared between patients with modified Blalock-Taussig Shunts (MBTS) and right ventricle-to-pulmonary artery conduits (RVPA) at a single institution from 2011 to 2018. The comparison was replicated using data from the Single Ventricle Reconstruction Trial (SVR), a nonoverlapping dataset. The mean number of pulmonary artery interventions per patient over time (mean cumulative function, MCF) is described using Nelson-Aalen estimates and compared using the pseudo-score test. The number of patients requiring intervention was compared using the chi-square test. Using our institutional dataset, the Norwood operation was performed on 117 patients (59 MBTS, 58 RVPA). In total, 73 patients had a pulmonary artery intervention, including 32 of 58 (55%) after MBTS and 41 of 59 (69%) after RVPA (P= 0.11). The MCF did not vary between cohorts (P = 0.55). Using the SVR trial dataset, 140 of 549 patients required pulmonary artery intervention, including 55 (21%) after MBTS and 85 (30%) after RVPA (P = 0.0090). The MCF did not vary between cohorts (P = 0.067). Although more patients with RVPA than MBTS require pulmonary artery interventions after the Norwood procedure, the MCFs are not different, which may be of greater importance to patients and families.