Longitudinal Follow-Up of Children With HLHS and Association Between Norwood Shunt Type and Long-Term Outcomes: The SVR III Study.

OBJECTIVE: In the SVR trial (Single Ventricle Reconstruction), newborns with hypoplastic left heart syndrome were randomly assigned to receive a modified Blalock-Taussig-Thomas shunt (mBTTS) or a right ventricle-to-pulmonary artery shunt (RVPAS) at Norwood operation. Transplant-free survival was superior in the RVPAS group at 1 year, but no longer differed by treatment group at 6 years; both treatment groups had accumulated important morbidities. In the third follow-up of this cohort (SVRIII [Long-Term Outcomes of Children With Hypoplastic Left Heart Syndrome and the Impact of Norwood Shunt Type]), we measured longitudinal outcomes and their risk factors through 12 years of age. METHODS: Annual medical history was collected through record review and telephone interviews. Cardiac magnetic resonance imaging (CMR), echocardiogram, and cycle ergometry cardiopulmonary exercise tests were performed at 10 through 14 years of age among participants with Fontan physiology. Differences in transplant-free survival and complication rates (eg, arrhythmias or protein-losing enteropathy) were identified through 12 years of age. The primary study outcome was right ventricular ejection fraction (RVEF) by CMR, and primary analyses were according to shunt type received. Multivariable linear and Cox regression models were created for RVEF by CMR and post-Fontan transplant-free survival. RESULTS: Among 549 participants enrolled in SVR, 237 of 313 (76%; 60.7% male) transplant-free survivors (mBTTS, 105 of 147; RVPAS, 129 of 161; both, 3 of 5) participated in SVRIII. RVEF by CMR was similar in the shunt groups (RVPAS, 51±9.6 [n=90], and mBTTS, 52±7.4 [n=75]; P=0.43). The RVPAS and mBTTS groups did not differ in transplant-free survival by 12 years of age (163 of 277 [59%] versus 144 of 267 [54%], respectively; P=0.11), percentage predicted peak Vo2 for age and sex (74±18% [n=91] versus 72±18% [n=84]; P=0.71), or percentage predicted work rate for size and sex (65±20% versus 64±19%; P=0.65). The RVPAS versus mBTTS group had a higher cumulative incidence of protein-losing enteropathy (5% versus 2%; P=0.04) and of catheter interventions (14 versus 10 per 100 patient-years; P=0.01), but had similar rates of other complications. CONCLUSIONS: By 12 years after the Norwood operation, shunt type has minimal association with RVEF, peak Vo2, complication rates, and transplant-free survival. RVEF is preserved among the subgroup of survivors who underwent CMR assessment. Low transplant-free survival, poor exercise performance, and accruing morbidities highlight the need for innovative strategies to improve long-term outcomes in patients with hypoplastic left heart syndrome. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT0245531.

Design of a multi-institutional neurocognitive discovery study in adult congenital heart disease (MINDS-ACHD).

BACKGROUND: Neurocognitive dysfunction (NCD) is a common comorbidity among children with congenital heart disease (CHD). However, it is unclear how underlying CHD and its sequelae combine with genetics and acquired cardiovascular and neurological disease to impact NCD and outcomes across the lifespan in adults with CHD. METHODS: The Multi-Institutional Neurocognitive Discovery Study in Adults with Congenital Heart Disease (MINDS-ACHD) is a partnership between the Pediatric Heart Network (PHN) and the Adult Alliance for Research in Congenital Cardiology (AARCC) that examines objective and subjective neurocognitive function and genetics in young ACHD. This multicenter cross-sectional pilot study is enrolling 500 young adults between 18 and 30 years with moderate or severe complexity CHD at 14 centers in North America. Enrollment includes 4 groups (125 participants each): (1) d-looped Transposition of the Great Arteries (d-TGA); (2) Tetralogy of Fallot (TOF); (3) single ventricle (SV) physiology; and (4) "other moderately or severely complex CHD." Participants complete the standardized tests from the NIH Toolbox Cognitive Battery, the NeuroQoL, the Hospital Anxiety and Depression Scale, and the PROMIS Global QoL measure. Clinical and demographic variables are collected by interview and medical record review, and an optional biospecimen is collected for genetic analysis. Due to the COVID-19 pandemic, participation may be done remotely. Tests are reviewed by a Neurocognitive Core Laboratory. CONCLUSIONS: MINDS-ACHD is the largest study to date characterizing NCD in young adults with moderate or severely complex CHD in North America. Its results will provide valuable data to inform screening and management strategies for NCD in ACHD and improve lifelong care.

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.

BACKGROUND: The 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. METHODS: Transplant-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. CONCLUSIONS: Evaluation 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.

Novel handheld ultrasound technology to enhance non-expert screening for rheumatic heart disease in the Republic of Palau: A descriptive study.

AIM: Non-expert training in rheumatic heart disease (RHD) detection is a valuable strategy in resource-limited settings. Here we present an innovative handheld ultrasound application featuring views of correct probe position, imaging protocol and echocardiographic loops of RHD pathology versus normal, accessible during real-time scanning. METHODS: This prospective study was implemented into a pre-existing school health screening programme at an elementary school in Koror, Palau. Six learners with no prior ultrasound experience were taught a simplified screening protocol in which a mitral regurgitation jet ≥1.5 cm and/or presence of aortic insufficiency were considered a positive screen. All consented children underwent echocardiographic screening by experts with standard portable echocardiography. All positive cases and 25% of negative cases were referred for handheld scans by learners. RESULTS: A total of 26 (4.1%) children were diagnosed with borderline or definite RHD. Mean sensitivity and specificity compared to expert RHD diagnosis over all learners was 71% (standard deviation (SD) 11.3) and 92% (SD 4.9), respectively. For the three highest scanning learners, mean sensitivity was 88% (SD 4.9) and mean specificity was 90% (SD 5.7). For all definite RHD cases, sensitivity was 100% for all but one learner, who achieved sensitivity of 60%. The novel application was used in 229 of 624 (36%) of all handheld scans and 50 of 112 (45%) of expert-diagnosed positive scans, with protocol and reference features most frequently used. Utilisation of the novel application overall decreased per day of scanning per learner. CONCLUSION: Adjunctive handheld ultrasound technology may help ease non-experts into RHD screening.

Transplant-Free Survival and Interventions at 6 Years in the SVR Trial.

BACKGROUND: In the SVR trial (Single Ventricle Reconstruction), 1-year transplant-free survival was better for the Norwood procedure with right ventricle-to-pulmonary artery shunt (RVPAS) compared with a modified Blalock-Taussig shunt in patients with hypoplastic left heart and related syndromes. At 6 years, we compared transplant-free survival and other outcomes between the groups. METHODS: Medical history was collected annually using medical record review, telephone interviews, and the death index. The cohort included 549 patients randomized and treated in the SVR trial. RESULTS: Transplant-free survival for the RVPAS versus modified Blalock-Taussig shunt groups did not differ at 6 years (64% versus 59%, P=0.25) or with all available follow-up of 7.1±1.6 years (log-rank P=0.13). The RVPAS versus modified Blalock-Taussig shunt treatment effect had nonproportional hazards (P=0.009); the hazard ratio (HR) for death or transplant favored the RVPAS before stage II surgery (HR, 0.66; 95% confidence interval, 0.48-0.92). The effect of shunt type on death or transplant was not statistically significant between stage II to Fontan surgery (HR, 1.36; 95% confidence interval, 0.86-2.17; P=0.17) or after the Fontan procedure (HR, 0.76; 95% confidence interval, 0.33-1.74; P=0.52). By 6 years, patients with RVPAS had a higher incidence of catheter interventions (0.38 versus 0.23/patient-year, P<0.001), primarily because of more interventions between the stage II and Fontan procedures (HR, 1.72; 95% confidence interval, 1.00-3.03). Complications did not differ by shunt type; by 6 years, 1 in 5 patients had had a thrombotic event, and 1 in 6 had had seizures. CONCLUSIONS: By 6 years, the hazards of death or transplant and catheter interventions were not different between the RVPAS versus modified Blalock-Taussig shunt groups. Children assigned to the RVPAS group had 5% higher transplant-free survival, but the difference did not reach statistical significance, and they required more catheter interventions. Both treatment groups have accrued important complications. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00115934.

A multi-national trial of a direct oral anticoagulant in children with cardiac disease: Design and rationale of the Safety of ApiXaban On Pediatric Heart disease On the preventioN of Embolism (SAXOPHONE) study.

Anticoagulation in children is problematic for multiple reasons. Currently used anticoagulants have significant disadvantages and may negatively affect quality of life (QOL). This manuscript describes the design, rationale, and methods of a prospective, randomized, open label phase II multi-national clinical trial of a direct oral anticoagulant (DOAC), apixaban, in children and infants with congenital and acquired heart disease. This trial is designed to gather preliminary safety and pharmacokinetics (PK) data, as well as generate data on QOL of individuals taking apixaban compared to the standard of care (SOC) anticoagulants vitamin K antagonists (VKA) or low molecular weight heparin (LMWH). A key issue this trial seeks to address is the practice of using therapeutics tested in adult trials in the pediatric population without robust pediatric safety or efficacy data. Pediatric heart diseases are not common, and specific diagnoses often meet the criteria of a rare disease; thus, statistical efficacy may be difficult to achieve. This trial will provide valuable PK and safety data intended to inform clinical practice for anticoagulation in pediatric heart diseases, a setting in which a fully powered phase III clinical trial is not feasible. A second consideration this trial addresses is that metrics besides efficacy, such as QOL, have not been traditionally used as endpoints in regulated anticoagulation studies yet may add substantial weight to the clinical decision for use of a DOAC in place of VKA or LMWH. This study examines QOL related to both heart disease and anticoagulation among children randomized to either SOC or apixaban. There are considerable strengths and benefits to conducting a clinical trial in pediatric rare disease populations via an industry-academic collaboration. The SAXOPHONE study represents a collaboration between Bristol-Myers Squibb (BMS)/Pfizer Alliance, and the National Heart, Lung, and Blood Institute's (NHLBI) Pediatric Heart Network (PHN) and may be an attractive model for future pediatric drug trials.

Results of a phase 1 multicentre investigation of dexmedetomidine bolus and infusion in corrective infant cardiac surgery.

BACKGROUND: Dexmedetomidine (DEX) is increasingly used intraoperatively in infants undergoing cardiac surgery. This phase 1 multicentre study sought to: (i) determine the safety of DEX for cardiac surgery with cardiopulmonary bypass; (ii) determine the pharmacokinetics (PK) of DEX; (iii) create a PK model and dosing for steady-state DEX plasma levels; and (iv) validate the PK model and dosing. METHODS: We included 122 neonates and infants (0-180 days) with D-transposition of the great arteries, ventricular septal defect, or tetralogy of Fallot. Dose escalation was used to generate NONMEM® PK modelling, and then validation was performed to achieve low (200-300 pg ml-1), medium (400-500 pg ml-1), and high (600-700 pg ml-1) DEX plasma concentrations. RESULTS: Five of 122 subjects had adverse safety outcomes (4.1%; 95% confidence interval [CI], 1.8-9.2%). Two had junctional rhythm, two had second-/third-degree atrioventricular block, and one had hypotension. Clearance (CL) immediately postoperative and CL on CPB were reduced by approximately 50% and 95%, respectively, compared with pre-CPB CL. DEX clearance after CPB was 1240 ml min-1 70 kg-1. Age at 50% maximum clearance was approximately 2 days, and that at 90% maximum clearance was 18 days. Overall, 96.1% of measured DEX concentrations fell within the 5th-95th percentile prediction intervals in the PK model validation. Dosing strategies are recommended for steady-state DEX plasma levels ranging from 200 to 1000 pg ml-1. CONCLUSIONS: When used with a careful dosing strategy, DEX results in low incidence and severity of adverse safety events in infants undergoing cardiac surgery with cardiopulmonary bypass. This validated PK model should assist clinicians in selecting appropriate dosing. The results of this phase 1 trial provide preliminary data for a phase 3 trial of DEX neuroprotection. CLINICAL TRIALS REGISTRATION: NCT01915277.

Variation in care for children undergoing the Fontan operation for hypoplastic left heart syndrome.

BACKGROUND: The Single Ventricle Reconstruction Trial randomised neonates with hypoplastic left heart syndrome to a shunt strategy but otherwise retained standard of care. We aimed to describe centre-level practice variation at Fontan completion. METHODS: Centre-level data are reported as median or median frequency across all centres and range of medians or frequencies across centres. Classification and regression tree analysis assessed the association of centre-level factors with length of stay and percentage of patients with prolonged pleural effusion (>7 days). RESULTS: The median Fontan age (14 centres, 320 patients) was 3.1 years (range from 1.7 to 3.9), and the weight-for-age z-score was -0.56 (-1.35 + 0.44). Extra-cardiac Fontans were performed in 79% (4-100%) of patients at the 13 centres performing this procedure; lateral tunnels were performed in 32% (3-100%) at the 11 centres performing it. Deep hypothermic circulatory arrest (nine centres) ranged from 6 to 100%. Major complications occurred in 17% (7-33%). The length of stay was 9.5 days (9-12); 15% (6-33%) had prolonged pleural effusion. Centres with fewer patients (<6%) with prolonged pleural effusion and fewer (<41%) complications had a shorter length of stay (<10 days; sensitivity 1.0; specificity 0.71; area under the curve 0.96). Avoiding deep hypothermic circulatory arrest and higher weight-for-age z-score were associated with a lower percentage of patients with prolonged effusions (<9.5%; sensitivity 1.0; specificity = 0.86; area under the curve 0.98). CONCLUSIONS: Fontan perioperative practices varied widely among study centres. Strategies to decrease the duration of pleural effusion and minimise complications may decrease the length of stay. Further research regarding deep hypothermic circulatory arrest is needed to understand its association with prolonged pleural effusion.

Performance and predictors of recruitment success in National Heart, Lung, and Blood Institute's cardiovascular clinical trials.

Background/Aims Identifying predictors of recruitment success in clinical trials, particularly prior to study launch, could contribute to higher study completion rates and improved scientific return on investment. This article evaluates the performance of clinical trials funded by the National Heart, Lung, and Blood Institute that began recruitment before and after implementation of National Heart, Lung, and Blood Institute's 2009 Accrual Policy and identifies study-related factors that predict recruitment success. Methods A retrospective analysis of National Heart, Lung, and Blood Institute's cardiovascular clinical trials with initial funding from 1996 to 2012 was performed to assess recruitment success. Success was defined as ≥100% enrollment of the proposed sample size within the duration initially proposed by investigators. Trials were assigned to categories (pre-policy vs post-policy) based on whether the first patient was enrolled before or after the 2009 Accrual Policy implementation. Potential determinants of successful recruitment were evaluated using multivariable logistic regression. Results Of 167 trials analyzed, 26.3% met the definition of success. Twenty-four trials (14.4%) were terminated early and 15 (62.5%) for insufficient recruitment. Trials failed due to <100% enrollment (22.8%), longer duration (19.8%), or both (31.1%). Trials testing behavioral interventions, those conducted within a National Heart, Lung, and Blood Institute-funded network, and those with normal controls were predictive of success. The proportion of successful clinical trials increased from 23% in the pre-policy era to 30% post-policy, although the difference was not statistically significant ( p = 0.29). Conclusion Enrollment success rates for National Heart, Lung, and Blood Institute's clinical trials are concerning. The 2009 National Heart, Lung, and Blood Institute Accrual Policy did not significantly improve trial success. Clinical trials testing behavioral interventions, those conducted within networks, and those with normal controls were predictive of recruitment success. Components of networks may provide model practices to help other trials attain success, including close attention to oversight activities such as recruitment plans, real-time enrollment monitoring, corrective action plans to address shortfalls, and close sponsor-investigator collaborations.

"Depupylation" of prokaryotic ubiquitin-like protein from mycobacterial proteasome substrates.

Ubiquitin (Ub) provides the recognition and specificity required to deliver proteins to the eukaryotic proteasome for destruction. Prokaryotic ubiquitin-like protein (Pup) is functionally analogous to Ub in Mycobacterium tuberculosis (Mtb), as it dooms proteins to the Mtb proteasome. Studies suggest that Pup and Ub do not share similar mechanisms of activation and conjugation to target proteins. Dop (deamidase of Pup; Mtb Rv2112c/MT2172) deamidates the C-terminal glutamine of Pup to glutamate, preparing it for ligation to target proteins by proteasome accessory factor A (PafA). While studies have shed light on the conjugation of Pup to proteins, it was not known if Pup could be removed from substrates in a manner analogous to the deconjugation of Ub from eukaryotic proteins. Here, we show that Mycobacteria have a "depupylase" activity provided by Dop. The discovery of a depupylase strengthens the parallels between the Pup- and Ub-tagging systems of prokaryotes and eukaryotes, respectively.

Predictors of Rapid Aortic Root Dilation and Referral for Aortic Surgery in Marfan Syndrome.

Few data exist regarding predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome (MFS). To identify independent predictors of the rate of aortic root (AoR) dilation and referral for aortic surgery, we investigated the data from the Pediatric Heart Network randomized trial of atenolol versus losartan in young patients with MFS. Data were analyzed from the echocardiograms at 0, 12, 24, and 36 months read in the core laboratory of 608 trial subjects, aged 6 months to 25 years, who met original Ghent criteria and had an AoR z-score (AoRz) > 3. Repeated measures linear and logistic regressions were used to determine multivariable predictors of AoR dilation. Receiver operator characteristic curves were used to determine cut-points in AoR dilation predicting referral for aortic surgery. Multivariable analysis showed rapid AoR dilation as defined by change in AoRz/year > 90th percentile was associated with older age, higher sinotubular junction z-score, and atenolol use (R2 = 0.01) or by change in AoR diameter (AoRd)/year > 90th percentile with higher sinotubular junction z-score and non-white race (R2 = 0.02). Referral for aortic root surgery was associated with higher AoRd, higher ascending aorta z-score, and higher sinotubular junction diameter:ascending aorta diameter ratio (R2 = 0.17). Change in AoRz of 0.72 SD units/year had 42% sensitivity and 92% specificity and change in AoRd of 0.34 cm/year had 38% sensitivity and 95% specificity for predicting referral for aortic surgery. In this cohort of young patients with MFS, no new robust predictors of rapid AoR dilation or referral for aortic root surgery were identified. Further investigation may determine whether generalized proximal aortic dilation and effacement of the sinotubular junction will allow for better risk stratification. Rate of AoR dilation cut-points had high specificity, but low sensitivity for predicting referral for aortic surgery, limiting their clinical use. Clinical Trial Number ClinicalTrials.gov number, NCT00429364.

Report of the National Heart, Lung, and Blood Institute Working Group: An Integrated Network for Congenital Heart Disease Research.

The National Heart, Lung, and Blood Institute convened a working group in January 2015 to explore issues related to an integrated data network for congenital heart disease research. The overall goal was to develop a common vision for how the rapidly increasing volumes of data captured across numerous sources can be managed, integrated, and analyzed to improve care and outcomes. This report summarizes the current landscape of congenital heart disease data, data integration methodologies used across other fields, key considerations for data integration models in congenital heart disease, and the short- and long-term vision and recommendations made by the working group.

Selective use of the electrocardiogram in pediatric preparticipation athletic examinations among pediatric primary care providers.

OBJECTIVES: Recent literature examining insurance administrative data suggests that a selective approach, with concurrent history and physical exam (H&P), for obtaining an electrocardiogram (ECG) as a part of a preparticipation examination (PPE) for pediatric athletes is commonly used in the primary care setting demonstrating a high rate of disease detection. We sought to understand practice patterns of providers with regard to usage of ECG as a part of PPE. METHODS: Utilizing an online survey, we queried primary care providers regarding their practice patterns, rationale, and concerns regarding use of ECGs as a part of the PPE. RESULTS: A total of 125 pediatricians completed the survey; 73.7% selectively use the ECG, 24.6% never use the ECG, and only 1.7% always obtain an ECG as part of the PPE. The most common rationale for selectively or never using the ECG is the belief that the H&P is sufficient to identify cardiac disease (70%). The most common H&P findings that lead to ECG screening include chest pain or syncope with exertion, family history of sudden cardiac death, an irregular heart rate, and a diastolic murmur. Among the diseases associated with sudden cardiac death, most pediatricians fear missing hypertrophic cardiomyopathy. CONCLUSION: Based on a survey of primary care providers, most practitioners are utilizing a selective approach of obtaining an ECG as a part of a PPE for athletic participation, which is in agreement with the current American Heart Association guidelines. Significant practice variation continues to exist, and may represent an area for future resource optimization.

Trends in National Institutes of Health-Funded Congenital Heart Disease Research from 2005 to 2015.

In an era of ongoing need for research to enable evidence-based care for the expanding population with congenital heart disease (CHD), economic fluctuations have impacted research funding. We characterize trends in NIH-funded CHD research from 2005 to 2015. We searched the NIH RePORTER database from 2005 to 2015 using the terms "congenital heart" and "cardiac morphogenesis". Projects were characterized by year, institute, mechanism, costs, type and topic, and funding trends were analyzed. From 2005 to 2015, NIH funded 633 CHD research projects with total costs of $991 million. The National Heart, Lung, and Blood Institute funded 83% of CHD projects (528, $857 million). The R01 mechanism was used for 45% of projects (288, $421 million). Projects were 70% basic/early translational research, 27% clinical research, and 3% both. Cardiac developmental biology was the most common topic (52%), followed by technology/therapy development (15%), and diagnosis/management (12%). The total number of CHD projects ranged from 153 to 221 per year (30-58 new projects/year), and costs per year ranged from $58 to $116 million. The number of projects and total costs increased until 2012, but decreased again thereafter. CHD research did not experience as much erosion as overall NIH purchasing power; in constant dollars, CHD research funding levels in 2015 were $12 million higher than those in 2005. The NIH supported a diverse portfolio of CHD projects from 2005 to 2015. Support of CHD research projects trended upward until 2012, but declined thereafter due to fiscal austerity measures.

Utilizing a Collaborative Learning Model to Promote Early Extubation Following Infant Heart Surgery.

OBJECTIVE: To determine whether a collaborative learning strategy-derived clinical practice guideline can reduce the duration of endotracheal intubation following infant heart surgery. DESIGN: Prospective and retrospective data collected from the Pediatric Heart Network in the 12 months pre- and post-clinical practice guideline implementation at the four sites participating in the collaborative (active sites) compared with data from five Pediatric Heart Network centers not participating in collaborative learning (control sites). SETTING: Ten children's hospitals. PATIENTS: Data were collected for infants following two-index operations: 1) repair of isolated coarctation of the aorta (birth to 365 d) and 2) repair of tetralogy of Fallot (29-365 d). There were 240 subjects eligible for the clinical practice guideline at active sites and 259 subjects at control sites. INTERVENTIONS: Development and application of early extubation clinical practice guideline. MEASUREMENTS AND MAIN RESULTS: After clinical practice guideline implementation, the rate of early extubation at active sites increased significantly from 11.7% to 66.9% (p < 0.001) with no increase in reintubation rate. The median duration of postoperative intubation among active sites decreased from 21.2 to 4.5 hours (p < 0.001). No statistically significant change in early extubation rates was found in the control sites 11.7% to 13.7% (p = 0.63). At active sites, clinical practice guideline implementation had no statistically significant impact on median ICU length of stay (71.9 hr pre- vs 69.2 hr postimplementation; p = 0.29) for the entire cohort. There was a trend toward shorter ICU length of stay in the tetralogy of Fallot subgroup (71.6 hr pre- vs 54.2 hr postimplementation, p = 0.068). CONCLUSIONS: A collaborative learning strategy designed clinical practice guideline significantly increased the rate of early extubation with no change in the rate of reintubation. The early extubation clinical practice guideline did not significantly change postoperative ICU length of stay.

Surgical ligation of patent ductus arteriosus in premature infants: trends and practice variation.

OBJECTIVE: We sought to analyse the variation in the incidence of patent ductus arteriosus over three recent time points and characterise ductal ligation practices in preterm infants in the United States, adjusting for demographic and morbidity factors. METHODS: Using the Kids' Inpatient Database from 2003, 2006, and 2009, we identified infants born at ⩽32 weeks of gestation with International Classification of Diseases, Ninth Revision diagnosis of patent ductus arteriosus and ligation code. We examined patient and hospital characteristics and identified patient and hospital variables associated with ligation. RESULTS: Of 182,610 preterm births, 30,714 discharges included a patent ductus arteriosus diagnosis. The rate of patent ductus arteriosus diagnosis increased from 14% in 2003 to 21% in 2009 (p<0.001). A total of 4181 ligations were performed, with an overall ligation rate of 14%. Ligation rate in infants born at ⩽28 weeks of gestation was 20% overall, increasing from 18% in 2003 to 21% in 2009 (p<0.001). The ligation rate varied by state (4-28%), and ligation was associated with earlier gestational age, associated diagnoses, hospital type, teaching hospital status, and region (p<0.001). CONCLUSION: The rates of patent ductus arteriosus diagnosis and ligation have increased in the recent years. Variation exists in the practice of patent ductus arteriosus ligation and is influenced by patient and non-patient factors.

Electrocardiogram in Preparticipation Athletic Evaluations among Insured Youths.

OBJECTIVE: To retrospectively characterize electrocardiogram (ECG) use among preparticipation history and examinations (PPEs). STUDY DESIGN: Using the 2005 to 2010 MarketScan insurance database, we identified subjects aged 5-21 years with either a PPE with an ECG or a PPE alone, excluding those with known cardiac diagnoses. We described cardiology referrals and subspecialty testing within 180 days and cardiac diagnoses within 1 year of the PPE, and the costs of testing in each group. RESULTS: From 2005-2009, 503 304 PPEs occurred in 419 456 subjects, of which 8621 (2%) included an ECG. ECG use increased from 12-20 per 1000 PPEs from 2005-2009. Females, lower socioeconomic status, and rural settings were associated with fewer ECGs. Thirteen percent of PPEs with ECG and 0.5% of PPEs alone led to a cardiology referral. After PPEs with ECG, cardiac disease was identified in 18% (2% sports-limiting); after PPEs alone, cardiac disease was identified in 0.5% (0.03% sports-limiting). The PPE had a sensitivity of 44% and a specificity of 98.6% of identifying cardiac disease. The total reimbursement cost of PPEs plus testing was $80 396 464 ($160 per PPE). CONCLUSIONS: These real-world data demonstrate that community providers selectively use the ECG as part of the PPE with a high rate of identification of cardiac disease. Mass ECG screening would need to be more efficient at identifying disease than this selective approach.

The Congenital Heart Disease Genetic Network Study: rationale, design, and early results.

Congenital heart defects (CHD) are the leading cause of infant mortality among birth defects, and later morbidities and premature mortality remain problematic. Although genetic factors contribute significantly to cause CHD, specific genetic lesions are unknown for most patients. The National Heart, Lung, and Blood Institute-funded Pediatric Cardiac Genomics Consortium established the Congenital Heart Disease Genetic Network Study to investigate relationships between genetic factors, clinical features, and outcomes in CHD. The Pediatric Cardiac Genomics Consortium comprises 6 main and 4 satellite sites at which subjects are recruited, and medical data and biospecimens (blood, saliva, cardiovascular tissue) are collected. Core infrastructure includes an administrative/data-coordinating center, biorepository, data hub, and core laboratories (genotyping, whole-exome sequencing, candidate gene evaluation, and variant confirmation). Eligibility includes all forms of CHD. Annual follow-up is obtained for probands <1-year-old. Parents are enrolled whenever available. Enrollment from December 2010 to June 2012 comprised 3772 probands. One or both parents were enrolled for 72% of probands. Proband median age is 5.5 years. The one third enrolled at age <1 year are contacted annually for follow-up information. The distribution of CHD favors more complex lesions. Approximately, 11% of probands have a genetic diagnosis. Adequate DNA is available from 97% and 91% of blood and saliva samples, respectively. Genomic analyses of probands with heterotaxy, atrial septal defects, conotruncal, and left ventricular outflow tract obstructive lesions are underway. The scientific community's use of Pediatric Cardiac Genomics Consortium resources is welcome.

The pediatric heart network: meeting the challenges to multicenter studies in pediatric heart disease.

PURPOSE OF REVIEW: Because of the relatively small numbers of pediatric patients with congenital heart disease cared for in any individual center, there is a significant need for multicenter clinical studies to validate new medical or surgical therapies. The Pediatric Heart Network (PHN), with 15 years of experience in multicenter clinical research, has tackled numerous challenges when conducting multicenter studies. RECENT FINDINGS: This review describes the challenges encountered and the strategies employed to conduct high-quality, collaborative research in pediatric cardiovascular disease. SUMMARY: Sharing lessons learned from the PHN can provide guidance to investigators interested in conducting pediatric multicenter studies.