Triiodothyronine Supplementation for Children Undergoing Cardiopulmonary Bypass: A Meta-Analysis.

Specific pediatric populations have exhibited disparate responses to triiodothyronine (T3) repletion during and after cardiopulmonary bypass (CPB). Objective: To determine if T3 supplementation improves outcomes in children undergoing CPB. We searched randomized controlled trials (RCT) evaluating T3 supplementation in children aged 0-3 years undergoing CPB between 1/1/2000 and 1/31/2022. We calculated Hazard ratios (HR) for time to extubation (TTE), ICU length of stay (LOS), and hospital LOS. 5 RCTs met inclusion criteria with available patient-level data. Two were performed in United States (US) and 3 in Indonesia with 767 total subjects (range 29- 220). Median (IQR) age 4.1 (1.6, 8.0) months; female 43%; RACHS-1 scores: 1-1%; 2-55%; 3-27%; 4-13%; 5-0.1%; 6-3.9%; 54% of subjects in US vs 46% in Indonesia. Baseline TSH and T3 were lower in Indonesia (p < 0.001). No significant difference occurred in TTE between treatment groups overall [HR 1.09 (CI, 0.94-1.26)]. TTE numerically favored T3-treated patients aged 1-5 months [HR 1.24 (CI, 0.97-1.60)]. TTE HR for the Indonesian T3 group was 1.31 (CI, 1.04-1.65) vs. 0.95 (CI, 0.78-1.15) in US. The ICU LOS HR for the Indonesian T3 group was 1.19 vs. 0.89 in US (p = 0.046). There was a significant T3 effect on hospital LOS [HR 1.30 (CI, 1.01-1.67)] in Indonesia but not in US [HR 0.99 (CI, 0.78-1.23)]. T3 supplementation in children undergoing CPB is simple, inexpensive, and safe, showing benefit in resource-limited settings. Differences in effects between settings likely relate to depression in baseline thyroid function often associated with malnutrition.

Staged vs Complete Repair in Tetralogy of Fallot With Pulmonary Atresia.

BACKGROUND: We sought to compare outcomes for infants with tetralogy of Fallot with pulmonary atresia (TOF/PA) and confluent pulmonary arteries who underwent staged or primary complete surgical repair. METHODS: This retrospective study included infants undergoing initial surgical intervention between 0 and 60 days of age with TOF/PA without aortopulmonary collaterals from 2009 to 2018 at 20 centers. The primary outcome was days alive and out of the hospital in the first year of life (DAOH365). Secondary outcomes were mortality at 1 year of age and a composite major complication outcome. Multivariable modeling with generalized estimating equations were used to compare outcomes between groups. RESULTS: Of 221 subjects, 142 underwent staged repair and 79 underwent primary complete repair. There was no significant difference in median DAOH365 between the staged and primary repair groups (317 days [interquartile range, 278-336] vs 338 days [interquartile range, 314-348], respectively; adjusted P = .13). Nine staged repair patients (7%) died in the first year of life vs 5 primary repair patients (6%; adjusted odds ratio, 1.00; 95% CI, 0.25-3.95). At least 1 major complication occurred in 37% of patients who underwent staged repair vs 41% of patients who underwent primary complete repair (P = .75), largely driven by the need for unplanned cardiac reinterventions. CONCLUSIONS: For infants with TOF/PA with confluent pulmonary arteries, a surgical strategy of staged or primary complete repair resulted in statistically similar DAOH365, early mortality, and morbidity.

Triiodothyronine Supplementation in Infants Undergoing Cardiopulmonary Bypass: A Randomized Controlled Trial.

Cardiopulmonary bypass (CPB) profoundly suppresses circulating thyroid hormone levels in infants. We performed a multicenter randomized placebo controlled trial to determine if triiodothyronine (T3) supplementation improves reduces time to extubation (TTE) in infants after CPB. Infants (n = 220) undergoing cardiac surgery with CPB and stratified into 2 age cohorts: ≤30 days and >30 days to <152 days were randomization to receive either intravenous triiodothyronine or placebo bolus followed by study drug infusion until extubated or at 48 hours, whichever preceded. T3 did not significantly alter the primary endpoint, TTE (hazard ratio for chance of extubation (1.08, 95% CI: 0.82-1.43, P = 0.575) in the entire randomized population with censoring at 21 days. T3 showed no significant effect on TTE (HR 0.82, 95% CI:0.55-1.23, P = 0.341) in the younger subgroup or in the older (HR 1.38, 95% CI:0.95-2.2, P = 0.095). T3 also did not significantly impact TTE during the first 48 hours while T3 levels were maintained (HR 1.371, 95% CI:0.942-1.95, P = 0.099) No significant differences occurred for arrhythmias or other sentinel adverse events in the entire cohort or in the subgroups. This trial showed no significant benefit on TTE in the entire cohort. T3 supplementation appears safe as it did not cause an increase in adverse events. The study implementation and analysis were complicated by marked variability in surgical risk, although risk categories were balanced between treatment groups.

Procedural Outcomes of Pulmonary Atresia With Intact Ventricular Septum in Neonates: A Multicenter Study.

BACKGROUND: Multicenter contemporary data describing short-term outcomes after initial interventions of neonates with pulmonary atresia with intact ventricular septum (PA-IVS) are limited. This multicenter study describes characteristics and outcomes of PA-IVS neonates after their initial catheter or surgical intervention and identifies factors associated with major adverse cardiac events (MACE). METHODS: Neonates with PA-IVS who underwent surgical or catheter intervention between 2009 and 2019 in 19 centers were reviewed. Risk factors for MACE, defined as cardiopulmonary resuscitation, mechanical circulatory support, stroke, or in-hospital mortality, were analyzed using multivariable logistic regression models. RESULTS: We reviewed 279 neonates: 79 (28%) underwent right ventricular decompression, 151 (54%) underwent systemic-to-pulmonary shunt or ductal stent placement only, 36 (13%) underwent right ventricular decompression with shunt or ductal stent placement, and 11 (4%) underwent transplantation. MACE occurred in 57 patients (20%): 26 (9%) received mechanical circulatory support, 37 (13%) received cardiopulmonary resuscitation, stroke occurred in 16 (6%), and 23 (8%) died. The presence of 2 major coronary artery stenoses (adjusted odds ratio, 4.99; 95% CI, 1.16-21.39) and lower weight at first intervention (adjusted odds ratio, 1.52; 95% CI, 1.01-2.27) were significantly associated with MACE. Coronary ischemia was the most frequent presumed mechanism of death (n = 10). CONCLUSIONS: In a multicenter cohort, 1 in 5 neonates with PA-IVS experienced MACE after their initial intervention. Patients with 2 major coronary artery stenoses or lower weight at the time of the initial procedure were most likely to experience MACE and warrant vigilance during preintervention planning and postintervention management.

Pulmonary Atresia with Intact Ventricular Septum: Midterm Outcomes from a Multicenter Cohort.

Contemporary multicenter data regarding midterm outcomes for neonates with pulmonary atresia with intact ventricular septum are lacking. We sought to describe outcomes in a contemporary multicenter cohort, determine factors associated with end-states, and evaluate the effect of right ventricular coronary dependency and coronary atresia on transplant-free survival. Neonates treated during 2009-2019 in 19 United States centers were reviewed. Competing risks analysis was performed to determine cumulative risk of each end-state, and multivariable regression analyses were performed to identify factors associated with each end-state and transplant-free survival. We reviewed 295 patients. Median tricuspid valve Z-score was - 3.06 (25%, 75%: - 4.00, - 1.52). Final end-state was biventricular repair for 45 patients (15.2%), one-and-a half ventricle for 16 (5.4%), Fontan for 75 (25.4%), cardiac transplantation for 29 (9.8%), and death for 54 (18.3%). Seventy-six patients (25.7%) remained in mixed circulation. Cumulative risk estimate of death was 10.9%, 16.1%, 16.9%, and 18.8% at 1, 6 months, 1 year, and 5 years, respectively. Tricuspid valve Z-score was inversely, and coronary atresia positively associated with death or transplantation [odds ratio (OR) = 0.46, (95% confidence interval (CI) = 0.29-0.75, p < 0.001) and OR = 3.75 (95% CI 1.46-9.61, p = 0.011), respectively]. Right ventricular coronary dependency and left coronary atresia had a significant effect on transplant-free survival (log-rank p < 0.001). In a contemporary multicenter cohort of patients with PAIVS, consisting predominantly of patients with moderate-to-severe right ventricular hypoplasia, we observed favorable survival outcomes. Right ventricular coronary dependency and left, but not right, coronary atresia significantly worsens transplant-free survival.

Characteristics and Surgical Outcomes of Patients With Late Presentation of Anomalous Left Coronary Artery From the Pulmonary Artery: A Multicenter Study.

We sought to describe the clinical course and outcomes of patients who are diagnosed with anomalous left coronary artery from the pulmonary artery (ALCAPA) after infancy. We conducted a retrospective evaluation of patients who underwent ALCAPA surgery between January 2009 to March 2018 at 21 US centers. Clinical presentation, inpatient management, and postoperative outcomes of patients repaired ≥1 year of age were described. To characterize this cohort, we compared these data to patients repaired before 1 year of age. Of 248 ALCAPA patients, 71 (29%) underwent repair ≥1 year of age. Among this subset, the median age at diagnosis was 8.3 years. Chronic arrhythmia occurred in 7%. Patients had good postoperative recovery of left ventricle (LV) dysfunction (90%) and LV dilation (75%), although a low incidence of recovery of mitral regurgitation (40%). Compared to infants, older patients were more likely to present with cardiac arrest (11% vs 1%) and less likely to have moderate or worse LV dysfunction or mitral regurgitation. Older patients had significantly less postoperative extracorporeal membrane oxygenation use, and shorter ICU and hospital stay. In the older cohort, operative mortality occurred in only 1 patient and no patient died after discharge (median follow-up 2.7 years). Survival of patients who presented with ALCAPA beyond infancy was excellent, although chronic mitral regurgitation and chronic arrhythmia were not uncommon. Patients who underwent ALCAPA repair ≥1 year of age were less likely to present with LV dysfunction but more likely to present with cardiac arrest than younger patients.

Intermediate Outcomes After Repair of Anomalous Left Coronary Artery From the Pulmonary Artery.

BACKGROUND: Multicenter studies on infants with anomalous left coronary artery from the pulmonary artery (ALCAPA) are lacking. We report the intermediate-term outcomes after ALCAPA repair in a multicenter cohort and identify risk factors for reintervention or death after discharge. METHODS: We retrospectively reviewed infants under 1 year of age who underwent ALCAPA repair from January 2009 to March 2018 at 21 US centers. The primary composite outcome was freedom from reintervention or death after discharge. We used the Kaplan-Meier survival analysis to examine freedom from reintervention or death and the Cox proportional hazard analysis to identify risk factors for this composite outcome. RESULTS: One hundred seventy-seven infants underwent ALCAPA repair; 170 (97%) survived to hospital discharge without transplantation. Twenty-three patients were lost to follow-up. The median duration of follow-up in the remaining 147 patients was 3.8 years (25%, 75%: 1.9 years, 6.0 years). Echocardiographic data were available at ∼3 years after discharge in 98 patients. Left ventricular function was normal in 96 patients (98%), whereas 26 patients (27%) had greater than mild mitral valve regurgitation. Sixteen patients (11%) underwent 20 reinterventions with 1 late death. Patients undergoing the Takeuchi procedure or atypical repairs (hazard ratio, 8.0; 95% confidence interval, 2.1-30.0) or with moderate or greater mitral regurgitation on discharge echocardiogram (hazard ratio, 3.4; 95% confidence interval, 1.2-9.1) were at increased risk for reintervention. CONCLUSIONS: Intermediate-term outcomes after ALCAPA repair in infants are favorable. Persistent left ventricular dysfunction and reinterventions were uncommon, and mortality was rare. Patients who required atypical surgical repair or had moderate or greater mitral regurgitation at discharge warrant closer follow-up.

Associations between anthropometric indices and outcomes of congenital heart operations in infants and young children: An analysis of data from the Society of Thoracic Surgeons Database.

BACKGROUND: Children with congenital heart disease are at risk for growth failure due to inadequate nutrient intake and increased metabolic demands. We examined the relationship between anthropometric indices of nutrition (height-for-age z-score [HAZ], weight-for-age z-score [WAZ], weight-for-height z-score [WHZ]) and outcomes in a large sample of children undergoing surgery for congenital heart disease. METHODS: Patients in the Society of Thoracic Surgeons Congenital Heart Surgery Database having index cardiac surgery at age 1 month to 10 years were included. Indices were calculated by comparing patients' weight and height to population norms from the World Health Organization and Centers for Disease Control and Prevention. Outcomes included operative mortality, composite mortality or major complication, major postoperative infection, and postoperative length of stay. For each outcome and index, the adjusted odds ratio (aOR) (for mortality, composite outcome, and infection) and adjusted relative change in median (for postoperative length of stay) for a 1-unit decrease in index were estimated using mixed-effects logistic and log-linear regression models. RESULTS: Every unit decrease in HAZ was associated with 1.40 aOR of mortality (95% CI 1.32-1.48), and every unit decrease in WAZ was associated with 1.33 aOR for mortality (95% CI 1.25-1.41). The relationship between WHZ and outcome was nonlinear, with aOR of mortality of 0.84 (95% CI 0.76-0.93) for 1-unit decrease when WHZ ≥ 0 and a nonsignificant association for WHZ < 0. Trends for other outcomes were similar. Overall, the incidence of low nutritional indices was similar for 1-ventricle and 2-ventricle patients. Children between the age of 1 month and 1 year and those with lesions associated with pulmonary overcirculation had the highest incidence of low nutritional indices. CONCLUSIONS: Lower HAZ and WAZ, suggestive of malnutrition, are associated with increased mortality and other adverse outcomes after cardiac surgery in infants and young children. Higher WHZ over zero, suggestive of obesity, is also associated with adverse outcomes.

Preoperative malnutrition is associated with increased mortality and adverse outcomes after paediatric cardiac surgery.

BACKGROUND: Malnutrition is common in children with CHD and is likely to place them at an increased risk for adverse surgical outcomes. We sought to evaluate the impact of preoperative malnutrition on outcomes after paediatric cardiac surgery. METHODS: We conducted a retrospective analysis of patients from age 0 to 5 years undergoing cardiac surgery at Seattle Children's Hospital from 2006 to 2015. We used regression modelling to examine the impact of malnutrition on surgical outcomes. RESULTS: We found a non-linear relationship between low height-for-age and weight-for-age z-scores and mortality after surgery. In the range of z-score ⩽-2, each additional unit decrease in height-for-age or weight-for-age z-score was associated with a 2.9 or 2.1% increased risk for mortality, respectively. Each unit decrease in height-for-age z-score was associated with a 1.2% increased risk for cardiac arrest, 1.1% increased risk for infection, and an average of 1.7 additional hours of mechanical ventilation, 6 hours longer ICU stay, and 13 hours longer hospital stay. Each unit decrease in weight-for-age z-score was associated with a 0.7% increased risk for cardiac arrest, 0.8% increased risk for infection, and an average of 1.9 additional hours of mechanical ventilation and 5.3 additional hours of ICU stay. CONCLUSIONS: This study is unique in demonstrating a significant association between malnutrition and 30-day mortality and other adverse outcomes after paediatric cardiac surgery in a mixed population of CHD patients. By evaluating nutritional status as a continuous variable, we were able to clearly distinguish the point at which malnutrition begins to affect mortality.

Racial and Ethnic Variation in Pediatric Cardiac Extracorporeal Life Support Survival.

OBJECTIVES: Previous studies have suggested an association between nonwhite race and poor outcomes in small subsets of cardiac surgery patients who require extracorporeal life support. This study aims to examine the association of race/ethnicity with mortality in pediatric patients who receive extracorporeal life support for cardiac support. DESIGN: Retrospective analysis of registry data. SETTING: Prospectively collected multi-institutional registry data. SUBJECTS: Data from all North American pediatric patients in the Extracorporeal Life Support International Registry who received extracorporeal life support for cardiac support between 1998 and 2012 were analyzed. Multivariate regression models were constructed to examine the association between race/ethnicity and hospital mortality, adjusting for demographics, diagnosis, pre-extracorporeal life support care, extracorporeal life support variables, and extracorporeal life support-related complications. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 7,106 patients undergoing cardiac extracorporeal life support, the majority of patients were of white race (56.9%) with black race (16.7%), Hispanic ethnicity (15.8%), and Asian race (2.8%) comprising the other major race/ethnic groups. The mortality rate was 53.9% (n = 3,831). After adjusting for covariates, multivariate analysis identified black race (relative risk = 1.10; 95% CI, 1.04-1.16) and Hispanic ethnicity (relative risk = 1.08; 95% CI, 1.02-1.14) as independent risk factors for mortality. CONCLUSIONS: Black race and Hispanic ethnicity are independently associated with mortality in children who require cardiac extracorporeal life support.

Preoperative B-type natriuretic peptide levels are associated with outcome after total cavopulmonary connection (Fontan).

OBJECTIVE: The study objective was to determine the association between preoperative B-type natriuretic peptide levels and outcome after total cavopulmonary connection. Surgical palliation of univentricular cardiac defects requires a series of staged operations, ending in a total cavopulmonary connection. Although outcomes have improved, there remains an unpredictable risk of early total cavopulmonary connection takedown. The prediction of adverse postoperative outcomes is imprecise, despite an extensive preoperative evaluation. METHODS: We prospectively enrolled 50 patients undergoing total cavopulmonary connection. We collected preoperative clinical data, preoperative plasma B-type natriuretic peptide levels, and postoperative outcomes, including the incidence of an adverse outcome within 1 year of surgery (defined as death, total cavopulmonary connection takedown, or the need for cardiac transplantation). RESULTS: The mean age of patients was 4.7 years (standard deviation, 2.1 years). The median (interquartile range) preoperative B-type natriuretic peptide levels were higher in patients who required total cavopulmonary connection takedown and early postoperative mechanical cardiac support (n = 3; median, 55; interquartile range, 42-121) compared with those with a good outcome (n = 47; median, 11; interquartile range, 5-17) (P < .05). A preoperative B-type natriuretic peptide level of 40 pg/mL or greater was highly associated with the need for total cavopulmonary connection takedown (sensitivity, 100%; specificity, 93%; P < .05), yielding a positive predictive value of 50% and a negative predictive value of 100%. Higher preoperative B-type natriuretic peptide levels also were associated with longer intensive care unit length of stay, longer hospital length of stay, and increased incidence of low cardiac output syndrome (P < .05). CONCLUSIONS: Preoperative B-type natriuretic peptide blood levels are uniquely associated with the need for mechanical support early after total cavopulmonary connection and total cavopulmonary connection takedown, and thus may provide important information in addition to the standard preoperative assessment.

The effect of preoperative nutritional status on postoperative outcomes in children undergoing surgery for congenital heart defects in San Francisco (UCSF) and Guatemala City (UNICAR).

OBJECTIVE: The objective of this study was to determine the association between preoperative nutritional status and postoperative outcomes in children undergoing surgery for congenital heart defects (CHD). METHODS: Seventy-one patients with CHD were enrolled in a prospective, 2-center cohort study. We adjusted for baseline risk differences using a standardized risk adjustment score for surgery for CHD. We assigned a World Health Organization z score for each subject's preoperative triceps skin-fold measurement, an assessment of total body fat mass. We obtained preoperative plasma concentrations of markers of nutritional status (prealbumin, albumin) and myocardial stress (B-type natriuretic peptide [BNP]). Associations between indices of preoperative nutritional status and clinical outcomes were sought. RESULTS: Subjects had a median (interquartile range [IQR]) age of 10.2 (33) months. In the University of California at San Francisco (UCSF) cohort, duration of mechanical ventilation (median, 19 hours; IQR, 29 hours), length of intensive care unit stay (median, 5 days; IQR 5 days), duration of any continuous inotropic infusion (median, 66 hours; IQR 72 hours), and preoperative BNP levels (median, 30 pg/mL; IQR, 75 pg/mL) were associated with a lower preoperative triceps skin-fold z score (P < .05). Longer duration of any continuous inotropic infusion and higher preoperative BNP levels were also associated with lower preoperative prealbumin (12.1 ± 0.5 mg/dL) and albumin (3.2 ± 0.1; P < .05) levels. CONCLUSIONS: Lower total body fat mass and acute and chronic malnourishment are associated with worse clinical outcomes in children undergoing surgery for CHD at UCSF, a resource-abundant institution. There is an inverse correlation between total body fat mass and BNP levels. Duration of inotropic support and BNP increase concomitantly as measures of nutritional status decrease, supporting the hypothesis that malnourishment is associated with decreased myocardial function.

Pulmonary interstitial glycogenosis: an unrecognized etiology of persistent pulmonary hypertension of the newborn in congenital heart disease?

BACKGROUND: Pulmonary interstitial glycogenosis (PIG) arises from a developmental disorder of the pulmonary mesenchyme and presents clinically with reversible neonatal respiratory distress and/or persistent pulmonary hypertension of the newborn (PPHN). OBJECTIVE: We report two cases of PIG in patients with congenital heart disease (CHD) and evidence of PPHN. RESULTS: Both cases demonstrated the hallmark PIG histologic finding of diffuse, uniform interstitial thickening due to the presence of immature interstitial cells containing abundant cytoplasmic glycogen. CONCLUSIONS: We report the second and third patients with PIG associated with CHD. Because histologic examination is required to establish the diagnosis, we speculate that PIG, although rare, may be underrecognized in neonates presenting with PPHN in the setting of CHD.

Disruption of endothelial cell mitochondrial bioenergetics in lambs with increased pulmonary blood flow.

AIMS: The mitochondrial dysfunction in our lamb model of congenital heart disease with increased pulmonary blood flow (PBF) (Shunt) is associated with disrupted carnitine metabolism. Our recent studies have also shown that asymmetric dimethylarginine (ADMA) levels are increased in Shunt lambs and ADMA increases the nitration of mitochondrial proteins in lamb pulmonary arterial endothelial cells (PAEC) in a nitric oxide synthase (NOS)-dependent manner. Thus, we determined whether there was a mechanistic link between endothelial nitric oxide synthase (eNOS), ADMA, and the disruption of carnitine homeostasis in PAEC. RESULTS: Exposure of PAEC to ADMA induced the redistribution of eNOS to the mitochondria, resulting in an increase in carnitine acetyl transferase (CrAT) nitration and decreased CrAT activity. The resulting increase in acyl-carnitine levels resulted in mitochondrial dysfunction and the disruption of mitochondrial bioenergetics. Since the addition of L-arginine prevented these pathologic changes, we examined the effect of L-arginine supplementation on carnitine homeostasis, mitochondrial function, and nitric oxide (NO) signaling in Shunt lambs. We found that the treatment of Shunt lambs with L-arginine prevented the ADMA-mediated mitochondrial redistribution of eNOS, the nitration-mediated inhibition of CrAT, and maintained carnitine homeostasis. In turn, adenosine-5'-triphosphate levels and eNOS/heat shock protein 90 interactions were preserved, and this decreased NOS uncoupling and enhanced NO generation. INNOVATION: Our data link alterations in cellular L-arginine metabolism with the disruption of mitochondrial bioenergetics and implicate altered carnitine homeostasis as a key player in this process. CONCLUSION: L-arginine supplementation may be a useful therapy to prevent the mitochondrial dysfunction involved in the pulmonary vascular alterations secondary to increased PBF.