BACKGROUND: Observational studies have demonstrated an association between the use of digoxin and reduced interstage mortality after Norwood operation for hypoplastic left heart syndrome (HLHS). Digoxin use has increased significantly but remains variable between different hospitals, independent of case-mix. Instrumental variable analyses have the potential to overcome unmeasured confounding, the major limitation of previous observational studies and to generate an estimate of the attributable benefit of treatment with digoxin.

METHODS: A cohort of neonates with HLHS born from January 1, 2007 to December 31, 2021 who underwent Norwood operation at Pediatric Health Information Systems Database hospitals and survived >14 days after operation were studied. Using hospital-specific, 6-month likelihood of administering digoxin as an instrumental variable, analyses adjusting for both unmeasured confounding (using the instrumental variable) and measured confounders with multivariable logistic regression were performed.

RESULTS: The study population included 5,148 subjects treated at 47 hospitals of which 63% were male and 46% non-Hispanic white. Of these, 44% (n = 2,184) were prescribed digoxin. Treatment with digoxin was associated with superior 1-year transplant-free survival in unadjusted analyses (85% vs 82%, P = .02). This survival benefit persisted in an instrumental-variable analysis (OR: 0.71, 95% CI: 0.54-0.94, P = .01), which can be converted to an absolute risk reduction of 5% (number needed to treat of 20).

CONCLUSIONS: In this observational study of patients with HLHS after Norwood using instrumental variable techniques, a significant benefit in 1-year transplant-free survival attributable to digoxin was demonstrated. In the absence of clinical trial data, this should encourage the use of digoxin in this vulnerable population.

BACKGROUND: Global longitudinal strain (GLS) is an echocardiographic method to identify left ventricular (LV) dysfunction after cardiac arrest that is less sensitive to loading conditions. We aimed to identify the frequency of impaired GLS following pediatric cardiac arrest, and its association with hospital mortality.

METHODS: This is a retrospective single-center cohort study of children <18 years of age treated in the pediatric intensive care unit (PICU) after in- or out-of-hospital cardiac arrest (IHCA and OHCA), with echocardiogram performed within 24 hours of initiation of post-arrest PICU care between 2013 and 2020. Patients with congenital heart disease, post-arrest extracorporeal support, or inability to measure GLS were excluded. Echocardiographic LV ejection fraction (EF) and shortening fraction (SF) were abstracted from the chart. GLS was measured post hoc; impaired strain was defined as LV GLS ≥ 2 SD worse than age-dependent normative values. Demographics and pre-arrest, arrest, and post-arrest characteristics were compared between subjects with normal versus impaired GLS. Correlation between GLS, SF and EF were calculated with Pearson comparison. Logistic regression tested the association of GLS with mortality. Area under the receiver operator curve (AUROC) was calculated for discriminative utility of GLS, EF, and SF with mortality.

RESULTS: GLS was measured in 124 subjects; impaired GLS was present in 46 (37.1%). Subjects with impaired GLS were older (median 7.9 vs. 1.9 years, p < 0.001), more likely to have ventricular tachycardia/fibrillation as initial rhythm (19.6% versus 3.8%, p = 0.017) and had higher peak troponin levels in the first 24 hours post-arrest (median 2.5 vs. 0.5, p = 0.002). There were no differences between arrest location or CPR duration by GLS groups. Subjects with impaired GLS compared to normal GLS had lower median EF (42.6% versus 62.3%) and median SF (23.3% versus 36.6%), all p < 0.001, with strong inverse correlation between GLS and EF (rho -0.76, p < 0.001) and SF (rho -0.71, p < 0.001). Patients with impaired GLS had higher rates of mortality (60% vs. 32%, p = 0.009). GLS was associated with mortality when controlling for age and initial rhythm [aOR 1.17 per 1% increase in GLS (95% CI 1.09-1.26), p < 0.001]. GLS, EF and SF had similar discrimination for mortality: GLS AUROC 0.69 (95% CI 0.60-0.79); EF AUROC 0.71 (95% CI 0.58-0.88); SF AUROC 0.71 (95% CI 0.61-0.82), p = 0.101.

CONCLUSIONS: Impaired LV function as measured by GLS after pediatric cardiac arrest is associated with hospital mortality. GLS is a novel complementary metric to traditional post-arrest echocardiography that correlates strongly with EF and SF and is associated with mortality. Future large prospective studies of post-cardiac arrest care should investigate the prognostic utilities of GLS, alongside SF and EF.

INTRODUCTION: Observational studies have demonstrated an association between use of digoxin and reduced interstage mortality after Norwood operation for hypoplastic left heart syndrome (HLHS). Digoxin use has increased significantly but remains variable between different hospitals, independent of case-mix. Instrumental variable analyses have the potential to overcome unmeasured confounding, the major limitation of previous observational studies and to generate an estimate of the attributable benefit of treatment with digoxin.

METHODS: A cohort of neonates with HLHS born from 1/1/2007 to 12/31/2021 who underwent Norwood operation at Pediatric Health Information Systems Database hospitals and survived >14 days after operation were studied. Using hospital-specific, 6-month likelihood of administering digoxin as an instrumental variable, analyses adjusting for both unmeasured confounding (using the instrumental variable) and measured confounders with multivariable logistic regression were performed.

RESULTS: The study population included 5,148 subjects treated at 47 hospitals of which 63% were male and 46% non-Hispanic white. Of these, 44% (n=2,184) were prescribed digoxin. Treatment with digoxin was associated with superior 1-year transplant-free survival in unadjusted analyses (85% vs. 82%, p=0.02). This survival benefit persisted in an instrumental-variable analysis (OR: 0.71, 95% CI: 0.54-0.94, p=0.01), which can be converted to an absolute risk reduction of 5% (number needed to treat of 20).

CONCLUSION: In this observational study of patients with HLHS after Norwood using instrumental variable techniques, a significant benefit in one-year transplant-free survival attributable to digoxin was demonstrated. In the absence of clinical trial data, this should encourage the use of digoxin in this vulnerable population.

Quality improvement efforts have focused on reducing interstage mortality for infants with hypoplastic left heart syndrome (HLHS). In 1/2016, two publications reported that use of digoxin was associated with reduced interstage mortality. The degree to which these findings have affected real world practice has not been evaluated. The discharge medications of neonates with HLHS undergoing Norwood operation between 1/2007 and 12/2018 at Pediatric Health Information Systems Database hospitals were studied. Mixed effects models were calculated to evaluate the hypothesis that the likelihood of digoxin prescription increased after 1/2016, adjusting for measurable confounders with furosemide and aspirin prescription measured as falsification tests. Interhospital practice variation was measured using the median odds ratio. Over the study period, 6091 subjects from 45 hospitals were included. After adjusting for measurable covariates, discharge after 1/2016 was associated with increased odds of receiving digoxin (OR 3.9, p < 0.001). No association was seen between date of discharge and furosemide (p = 0.26) or aspirin (p = 0.12). Prior to 1/2016, the likelihood of receiving digoxin was decreasing (OR 0.9 per year, p < 0.001), while after 1/2016 the rate has increased (OR 1.4 per year, p < 0.001). However, there remains significant interhospital variation in the likelihood of receiving digoxin even after adjusting for known confounders (median odds ratio = 3.5, p < 0.0001). Following publication of studies describing an association between digoxin and improved interstage survival, the likelihood of receiving digoxin at discharge increased without similar changes for furosemide or aspirin. Despite concerted efforts to standardize interstage care, interhospital variation in pharmacotherapy in this vulnerable population persists.

<p>For infants with shunt-dependent or ductal-dependent single ventricle heart disease, poor growth is common and associated with morbidity and impaired neurodevelopmental outcomes. Although attention has focused on nutrition to promote weight gain, little is known about the relation between heart failure and growth factors. A prospective observational pilot study was performed to assess the relation between heart failure, assessed by brain natriuretic peptide (BNP), and growth factors (insulin-like growth factor 1 [IGF-1] and insulin-like growth factor-binding protein 3) at 3 visits: (1) before discharge from neonatal intervention with the establishment of stable pulmonary blood flow, (2) immediately before superior cavopulmonary connection, and (3) before discharge after superior cavopulmonary connection operation. The relation between BNP and growth factors was analyzed using Spearman pairwise correlations at each visit and modeled over time with a linear mixed-effects model. Correlations were considered worthy of further exploration using a p &lt;0.10, given the exploratory nature of the study. The study included 38 infants (66% male, 68% hypoplastic left heart syndrome). Median BNP was elevated at visit 1 and decreased over time (287&nbsp;pg/dl [interquartile range 147 to 794], 85&nbsp;pg/dl [52 to 183], and 90&nbsp;pg/dl [70 to 138]). Median IGF-1 Z&nbsp;score was &lt;0 at each visit but increased over time (-0.9 [interquartile range -1.1 to 0.1], -0.7 [-1.2 to 0.1], and -0.5 [-1.2 to 0]). Inverse correlations were found between BNP and IGF-1 at visit 1 (r&nbsp;=&nbsp;-0.40, p&nbsp;=&nbsp;0.097), BNP and IGF-1 and insulin-like growth factor-binding protein 3 at visit 2 (r&nbsp;=&nbsp;-0.33, p&nbsp;=&nbsp;0.080 and r&nbsp;=&nbsp;-0.33, p&nbsp;=&nbsp;0.085, respectively) and BNP and IGF-1 Z&nbsp;score at visit 3 (r&nbsp;=&nbsp;-0.42, p&nbsp;=&nbsp;0.049). Significant relations were likewise found between the change in BNP and the change in IGF-1 between visits 1 and 3 (p&nbsp;=&nbsp;0.046) and between visits 2 and 3 (p&nbsp;=&nbsp;0.048). In conclusion, this pilot study demonstrates an inverse correlation between BNP and growth factors, suggesting that the heart failure state associated with this physiology may play a mechanistic role in impaired growth.</p>

<p>Patients with single ventricle (SV) heart defects have two primary surgical options for superior cavopulmonary connection (SCPC): bidirectional Glenn (BDG) and hemi-Fontan (HF). Outcomes based on type of SCPC have not been assessed in a multi-center cohort. This retrospective cohort study uses the Single Ventricle Reconstruction (SVR) Trial public use dataset. Infants who survived to SCPC were evaluated through 1&nbsp;year of age, based on type of SCPC. The primary outcome was transplant-free survival at 1&nbsp;year. The cohort included 343 patients undergoing SCPC across 15 centers in North America; 250 (73%) underwent the BDG. There was no difference between the groups in pre-SCPC clinical characteristics. Cardiopulmonary bypass times were longer [99&nbsp;min (IQR 76, 126) vs 81&nbsp;min (IQR 59, 116), p &lt; 0.001] and use of deep hypothermic circulatory arrest (DHCA) more prevalent (51% vs 19%, p &lt; 0.001) with HF. Patients who underwent HF had a higher likelihood of experiencing more than one post-operative complication (54% vs 41%, p = 0.05). There were no other differences including the rate of post-operative interventional cardiac catheterizations, length of stay, or survival at discharge, and there was no difference in transplant-free survival out to 1&nbsp;year of age. Mortality after SCPC is low and there is no difference in mortality at 1&nbsp;year of age based on type of SCPC. Differences in support time and post-operative complications support the preferential use of the BDG, but additional longitudinal follow-up is necessary to understand whether these differences have implications for long-term outcomes.</p>