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BackgroundRapid genome sequencing (rGS) has been shown to improve the care of critically ill infants. Congenital heart disease (CHD) is a leading cause of infant mortality, and is often caused by genetic disorders, yet the utility of rGS has not been prospectively studied in this population.MethodsWe conducted a prospective evaluation of the use of rGS to improve the care of infants with CHD in our cardiac neonatal intensive care unit (CNICU).ResultsIn a cohort of 48 infants with CHD, rGS diagnosed 14 genetic disorders in 13 (27%) individuals and led to changes in clinical management in eight (62%) cases with diagnostic results. These included two cases in whom genetic diagnoses helped avert intensive, futile interventions prior to CNICU discharge, as well as three cases in whom eye disease was diagnosed and treated in early childhood. Genetic disorders were associated with small for gestational age birth weight.ConclusionsOur study provides the first prospective evaluation of rGS for infants with CHD to our knowledge. We found that rGS diagnosed genetic disorders in 27% of cases and led to changes in management in 62% of cases with diagnostic results. Our model of care was enabled by multidisciplinary coordination between neonatologists, cardiologists, surgeons, geneticists, and genetic counselors. These findings highlight the important role for rGS in CHD and demonstrate the need for expanded study of how to implement this resource to a broader population of infants with CHD.

Background The adequacy of tissue O2 delivery in infants receiving intensive care is difficult to measure directly. Regional O2 (rSO2) and fractional tissue O2 extraction (FTOE), the ratio of O2 consumption to O2 delivery, obtained from newer noninvasive tools, such as near-infrared spectroscopy (INVOS) and microvascular tissue oximetry (T-Stat) can provide important information on the adequacy of tissue oxygenation and aid in managing critically ill infants. Methods We prospectively evaluated differences in rSO2 and FTOE in 26 infants with hypoplastic left heart syndrome (HLHS) (n = 12) or d-transposition of the great arteries (d-TGA) (n = 14). Continuous noninvasive monitoring of SpO2, heart rate, and perfusion index with pulse oximetry, cerebral-rSO2 and renal-rSO2 with INVOS, and buccal tissue oxygenation using T-Stat were performed during immediate postoperative period for 24 hours. Results The SpO2 and rSO2 in infants with d-TGA were higher compared with the infants with HLHS at all measured sites (buccal mucosa, cerebral, and renal). Significant regional differences were also observed in FTOE across all infants with the highest at the buccal mucosa tissue level, followed by cerebral and renal measurement sites. As compared with infants with d-TGA, infants with HLHS had higher regional FTOE and heart rate, with a lower arterial O2 content and perfusion index. Conclusions Our study demonstrates the utility of noninvasive hemodynamic monitoring to assess regional oxygenation and perfusion, as evidenced by significant differences in infants with HLHS and d-TGA, conditions with different circulation physiologies. Such comprehensive monitoring can potentially aid in evaluating treatment strategies aimed at preventing organ damage from O2 insufficiency.

This manuscript is one component of a larger series of articles produced by the Neonatal Cardiac Care Collaborative that are published in this supplement of Pediatrics. In this review article, we summarize the contemporary physiologic principles, evaluation, and management of acute care issues for neonates with complex congenital heart disease. A multidisciplinary team of authors was created by the Collaborative’s Executive Committee. The authors developed a detailed outline of the manuscript, and small teams of authors were assigned to draft specific sections. The authors reviewed the literature, with a focus on original manuscripts published in the last decade, and drafted preliminary content and recommendations. All authors subsequently reviewed and edited the entire manuscript until a consensus was achieved. Topics addressed include cardiopulmonary interactions, the pathophysiology of and strategies to minimize the development of ventilator-induced low cardiac output syndrome, common postoperative physiologies, perioperative bleeding and coagulation, and common postoperative complications.

The aim of this study was to assess the significance of post-operative troponin levels as a surrogate for left ventricular (LV) dysfunction measured by global longitudinal strain (GLS) in patients with dextro-transposition of the great arteries (d-TGA) who undergo an arterial switch operation (ASO), and to explore the LV GLS recovery in the mid-term follow-up period. Seventy-eight neonates were included, of whom 41 had troponin-I measurements and 37 had troponin-T measurements. The primary outcome of LV GLS was assessed and compared with healthy controls at the pre-operative stage and time of discharge, 3 months, 6 months and 12 months of age. Secondary outcomes included deaths or transplantations and other clinical markers such as length of hospital stay. D-TGA patients had worse LV GLS post-operatively compared to age-matched controls (p 0.01) which improved by 12 months of age (p = 0.53). No association was found between changes in troponin-I or troponin-T levels and LV GLS at the time of discharge (r = 0.4, p = 0.64 and r = -0.5, p = 0.91, respectively). In addition, there were no deaths or transplantations in this cohort over a period of 12 months. LV GLS appears to worsen in the early post-operative period for d-TGA patients who undergo neonatal ASO but this recovers through the first post-operative year. Troponin levels have limited value in predicting early or midterm LV dysfunction and recovery.

Background: Our understanding of the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pregnancies and perinatal outcomes is limited. The clinical course of neonates born to women who acquired coronavirus disease 2019 (COVID-19) during their pregnancy has been previously described. However, the course of neonates born with complex congenital malformations during the COVID-19 pandemic is not known. Methods: We report a case series of seven neonates with congenital heart and lung malformations born to women who tested positive for SARS-CoV-2 during their pregnancy at a single academic medical center in New York City. Results: Six infants had congenital heart disease and one was diagnosed with congenital diaphragmatic hernia. In all seven infants, the clinical course was as expected for the congenital lesion. None of the seven exhibited symptoms generally associated with COVID-19. None of the infants in our case series tested positive by nasopharyngeal test for SARS-CoV-2 at 24 hours of life and at multiple points during their hospital course. Conclusions: In this case series, maternal infection with SARS-CoV-2 during pregnancy did not result in adverse outcomes in neonates with complex heart or lung malformations. Neither vertical nor horizontal transmission of SARS-CoV-2 was noted.

Prematurity is a risk factor for in-hospital mortality after cardiac surgery. The structure of intensive care unit models designed to deliver optimal care to neonates including those born preterm with critical congenital heart disease is unknown. The objective of this study was to evaluate in-hospital outcomes after cardiac surgery across gestational ages in an institution with a dedicated neonatal cardiac program.This study is a single-center, retrospective review of infants who underwent cardiac surgical interventions from our dedicated neonatal cardiac intensive care program between 2006 and 2017. We evaluated in-hospital mortality and morbidity rates across all gestational ages.A total of 1238 subjects met inclusion criteria over a 11-year period. Overall in-hospital mortality after cardiac surgery was 6.1%. The mortality rate in very preterm infants (n = 68;34 weeks' gestation at birth) was 17.6% (odds ratio, 3.52 [1.4-8.53]), versus 4.3% in full-term (n = 563; 39-40 weeks) referent/control infants. Very preterm infants with isolated congenital heart disease (without evidence of other affected organ systems) experienced a mortality rate of 10.5% after cardiac surgery. Neither the late preterm (34-36In this study of a single center with a dedicated neonatal cardiac program, we report some of the lowest mortality and morbidity rates after cardiac surgery in preterm infants in the recent era. The potential survival advantage of this model is most striking for very preterm infants born with isolated congenital heart disease.

This article is based on a composite of talks presented during the Double Jeopardy: Prematurity and Congenital Heart Disease Plenary Session at NeoHeart 2020, a global virtual conference. Prematurity and low weight remain significant risk factors for mortality after neonatal cardiac surgery despite a steady increase in survival. Newer and lower weight thresholds for operability are constantly generated as surgeons gather proficiency, technical mastery, and experience in performing complex procedures on extremely small infants. The relationship between birth weight and survival after cardiac surgery is nonlinear with 2 kilograms (kg) being an inflection point below which marked decline in survival occurs. The prevalence of congenital heart disease (CHD) in premature infants is more than twice that in term born infants. Increased risk of preterm birth in infants with CHD is most commonly due to spontaneous preterm birth and remains poorly understood. Advances in Neonatal-Perinatal medicine have led to a marked improvement in survival of neonates born prematurely over the last several decades. However, the risk of severe morbidities including retinopathy of prematurity, intraventricular hemorrhage, bronchopulmonary dysplasia and necrotizing enterocolitis remains significant in extremely low birth weight infants. Premature infants with CHD are at a greater risk of prematurity related morbidities than premature infants without CHD. Interventions that have been successful in decreasing the risk of these morbidities are addressed.

Background We sought to assess the impact and predictors of coronavirus disease 2019 (COVID‐19) infection and severity in a cohort of patients with congenital heart disease (CHD) at a large CHD center in New York City. Methods and Results We performed a retrospective review of all individuals with CHD followed at Columbia University Irving Medical Center who were diagnosed with COVID‐19 between March 1, 2020 and July 1, 2020. The primary end point was moderate/severe response to COVID‐19 infection defined as (1) death during COVID‐19 infection; or (2) need for hospitalization and/or respiratory support secondary to COVID‐19 infection. Among 53 COVID‐19‐positive patients with CHD, 10 (19%) were P =0.0002), and in adults, physiological Stage C or D (OR, 19.38; P =0.002) were significantly associated with moderate/severe infection. Conclusions At our CHD center, the number of symptomatic patients with COVID‐19 was relatively low. Patients with CHD with a genetic syndrome and adults at advanced physiological stage were at highest risk for moderate/severe infection.

Background: Thrombotic events contribute significantly to early mortality in neonates with CHD requiring a systemic-to-pulmonary artery shunt. However, thromboprophylaxis remains suboptimal with few pharmacological agents studied and shown to be of benefit. The P2Y 12 inhibitor cangrelor is effective in preventing early coronary artery stent thrombosis in adults. Cangrelor dosing and safety have yet to be established in neonates. Hypotheses: (1) Cangrelor administered by infusion will yield drug levels capable of inhibiting maximal platelet aggregation by > 90% without causing an increase in bleeding. (2) A novel microfluidic technology can yield robust results related to inhibition of thrombus formation using significantly less blood than for LTA. Methods: This IRB approved, prospective, open-label, single-arm study was conducted between January 2017 and August 2019. Cangrelor, 0.5 μg/kg/min (n=7) or 0.25 μg/kg/min (n=8), was administered intravenously 6-10h after placement of a systemic-to-pulmonary artery shunt (n=8), right ventricle-to-pulmonary artery shunt (n=6), or ductal stent (n=1) for 1h. Plasma levels and PD properties of cangrelor were determined, the latter by light transmission aggregometry (LTA) and microfluidic assay (MFA). Informed consent was obtained (NCT02765633). Results: 15 participants that received cangrelor had single ventricle physiology (12 of 15) and underwent a Norwood procedure (11 of 15). Cangrelor 0.5 μg/kg/min dosing met all PD endpoints, yielding a higher level of platelet inhibition (mean ± SD) than the 0.25 μg/kg/min dose as assessed by LTA (89 ± 11.4% vs 73.3 ± 16.9%, respectively). Results from MF studies were comparable but required 3-fold less blood for testing. PK analysis revealed rapid drug clearance with 86.7% of participants having undetectable levels by 10 minutes post-infusion and 70% with full recovery in platelet function at 1 hour. SAEs and AEs that occurred were not related drug administration, including bleeding. Conclusion: Favorable PK and PD properties of cangrelor 0.5 μg/kg/min dosing and an acceptable safety profile warrant further evaluation in neonates following palliative cardiac procedures.

Objective:To describe changes in the environmental microbiota of a new neonatal intensive care unit (NICU) and potential implications for infection prevention and control (IPC) efforts.Design:Prospective observational study.Setting:A newly constructed level IV neonatal cardiac intensive care unit (NCICU) before and after patient introduction and the original NICU prior to patient transfer.Methods:Environmental samples were obtained from the original NICU prior to patient transfer to a new NCICU. Serial sampling of patient rooms and provider areas of the new NICU was conducted immediately prior to patient introduction and over an 11-month study period. Microbiota at each sampling point were characterized using Illumina sequencing of the V3/V4 region of the 16S rRNA gene. Microbiota characteristics (α and β diversity and differential abundance) were compared based on time, location, and clinical factors (room-level antibiotic use and patient turnover).Results:An immediate increase in the environmental differential abundance of gut anaerobes were seen after patient introduction. There was an increase in the relative abundance of Staphylococcus spp, Klebsiella spp, Pseudomonas spp, and Streptococcus spp over time. The new NCICU consistently showed more diverse microbiota and remained distinct from the original NICU. The microbiota of the provider areas of the NCICU eventually formed a cluster separate from the patient rooms. Patient turnover increased room-level microbiota diversity.Conclusion:Microbiota characteristics of the new NICU were distinct from the original ICU despite housing similar patients. Patient and provider areas developed distinct microbiota profiles. Non–culture-based methods may be a useful adjunct to current IPC practice.

As we confront COVID-19, the global public health emergency of our times, new knowledge is emerging that, combined with information from prior epidemics, can provide insights on how to manage this threat in specific patient populations. Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), both caused by coronaviruses, caused serious respiratory illness in pregnant women that resulted in adverse perinatal outcomes. Thus far, COVID-19 appears to follow a mild course in the vast majority of pregnant women. A significant proportion of pregnant women appear to be asymptomatic carriers of SARS-CoV-2. However, there is limited information on how COVID-19 impacts the fetus and whether vertical transmission occurs. While these knowledge gaps are addressed, it is important to recognize the highly efficient transmission characteristics of SARS-C0V-2 and its potential for causing serious disease in vulnerable individuals, including health care workers. This review provides perspectives from a single center in New York City, the epicenter of the pandemic within the United States. It offers an overview of the preparations required for deliveries of newborns of mothers with COVID-19 and the management of neonates with particular emphasis on those born with complex issues.

The aims of this study were (1) to describe the additive risk of performing cardiac surgery in neonates born ≤ 2.0 kg, after accounting for the baseline risks of low birth weight, and (2) to describe the additive risk of being born ≤ 2.0 kg in neonates undergoing cardiac surgery. We used a risk difference analysis in a retrospective cohort, 2006–2016. Neonates born ≤ 2.0 kg undergoing congenital heart surgery during initial postnatal admission were included. Data were standardized alternatingly for birth weight and cardiac surgical risk using national population data to estimate the number of deaths expected had they not required cardiac surgery or were they of normal weight. Of 105 neonates ≤ 2 kg, median birth weight was 1.6 kg (IQR 1.3–1.8 kg). Median gestational age was 33 weeks (IQR 31–35 weeks). Observed operative mortality was 14.3%; 0% for neonates ≤ 1.0 kg (CI 0–33.6%), 20.6% for neonates > 1.0–1.5 kg (CI 8.7–37.9%), and 12.9% for neonates > 1.5–2.0 kg (CI 5.7–23.9%). Among neonates ≤ 2.0 kg not undergoing cardiac surgery, expected mortality was 4.8% (CI 1.6–10.8); cardiac surgery increased the risk of mortality 9.5% (CI 1.7–17.4%). Conversely, the expected risk for normal birth weight neonates undergoing cardiac surgery was 5.7% (CI 2.1–12.0%); low birth weight increased the risk of mortality 8.6% (CI 0.5–16.6%). To continue making advancements in cardiac surgery, we must understand that the rate of mortality observed in normal weight infants is not a realistic target and that, despite advances, the risk attributable to the surgery remains higher among low birth weight patients.

Prematurity and low weight remain significant risk factors for mortality after neonatal cardiac surgery despite steady gains in survival. Newer and lower weight thresholds for operability are constantly generated as surgeons gather proficiency, technical mastery, and experience in performing complex procedures on extremely small infants. Relationship between birth weight and survival after cardiac surgery is nonlinear with 2 kg being an inflection point below which marked decline in survival occurs. If strides toward improved survival in this weight category are to be made, understanding the inherent vulnerabilities of the premature and low birth weight infant is important in addition to acknowledging the vulnerabilities of the system in which care is delivered.

Every year in the United States approximately 40,000 infants are born with congenital heart disease. Many of these infants require corrective or palliative surgery in the neonatal period. Mortality rates after cardiac surgery are highest among neonates and higher still in those born prematurely, of low birth weight, and with significant associated medical conditions or genetic syndromes. We will outline the immature organ systems that complicate care of the neonate—especially premature and low-birth-weight babies. We also describe three major noncardiac conditions that impose increased mortality risk when combined with congenital heart disease.

Introduction:Infants with hypoplastic left heart syndrome are at risk for growth failure, particularly after stage 1 procedures. The effect of continuous enteral feedings on weight gain has not been previously investigated.Methods:A randomized controlled trial was performed in infants with hypoplastic left heart syndrome and single ventricle variants after stage 1 procedures. Eligible infants were randomized to a continuous and intermittent feeding regimen or an exclusive intermittent feeding regimen after stage 1 procedures and continued until hospital discharge. Anthropometric measures and markers of nutritional status were assessed throughout hospitalization.Results:Twenty-six infants completed the study. There were no significant differences in weight gain, growth, or nutritional status. Weight gain on full enteral feedings was 24.3 versus 23.6 g/d ( P = .88) for the combination (continuous and intermittent) versus intermittent feeding groups. Weight-for-age Z scores at discharge were −1.37 versus −1.2 ( P = .59) for the combination versus intermittent groups.Conclusions:No significant differences in weight gain, growth, or nutritional status were observed at hospital discharge between the two feeding strategies. Despite both groups achieving target daily weight gain after attaining full feeds, growth failure continued to be a problem after stage 1 procedures. Further strategies to improve growth during initial hospitalization are needed.

The evolution and development of pediatric cardiac critical care as a distinct subspecialty have occurred rapidly over the past 20 years. As the field has grown, models for education, training, and care delivery have changed as well. This review will highlight the current state of education, training, and parental involvement in care delivery for pediatric cardiac critical care as initially

During the early months of the COVID-19 pandemic, infection prevention and control (IP&C) for women in labor and mothers and newborns during delivery and receiving post-partum care was quite challenging for staff, patients, and support persons due to a relative lack of evidence-based practices, high rates of community transmission, and shortages of personal protective equipment (PPE). We present our IP&C policies and procedures for the obstetrical population developed from mid-March to mid-May 2020 when New York City served as the epicenter of the pandemic in the U.S. For patients, we describe screening for COVID-19, testing for SARS-CoV-2, and clearing patients from COVID-19 precautions. For staff, we address self-monitoring for symptoms, PPE in different clinical scenarios, and reducing staff exposures to SARS-CoV-2. For visitors/support persons, we address limiting them in labor and delivery, the postpartum units, and the NICU to promote staff and patient safety. We describe management of SARS-CoV-2-positive mothers and their newborns in both the well-baby nursery and in the neonatal ICU. Notably, in the well-baby nursery we do not separate SARS-CoV-2-positive mothers from their newborns, but emphasize maternal mask use and social distancing by placing newborns in isolates and asking mothers to remain 6 feet away unless feeding or changing their newborn. We also encourage direct breastfeeding and do not advocate early bathing. Newborns of SARS-CoV-2-positive mothers are considered persons under investigation (PUIs) until 14 days of life, the duration of the incubation period for SARS-CoV-2. We share two models of community-based care for PUI neonates. Finally, we provide our strategies for enhancing communication and education during the early months of the pandemic.

Although low birth weight is a known risk factor for mortality in congenital heart lesions and may consequently delay surgical repair, outcomes in low-weight neonates undergoing the arterial switch operation (ASO) have not been well described. Our objective was to assess the safety of this procedure in infants weighing ≤2.5 kg at the time of surgery. We retrospectively analyzed outcomes for all neonates undergoing the ASO at our institution from 2005 to 2015. Our primary outcome of interest was major morbidity or operative mortality, assessed as a composite outcome. From 2005 to 2015, 217 neonates underwent the ASO, with 31 (14%) weighing ≤2.5 kg at the date of surgery, and 8 weighing2.0 kg. Neonates weighing ≤2.5 kg were more likely to be premature than those weighing2.5 kg, but there was no difference in the age at operation between these groups. Overall, 32 infants experienced a major morbidity or mortality, including 37.5% (n = 3) weighing2.0 kg, 8.7% (n = 2) weighing 2.0-2.5 kg, and 14.5% (n = 7) weighing2.5 kg (P = 0.141). One infant weighing2.0 kg (1.1 kg) and 4 infants weighing2.5 kg died. In multivariable models, odds of major morbidity or mortality were significantly higher for infants weighing2 kg compared with infants weighing2.5 kg (odds ratio 3.93, 95% confidence interval 1.04-14.85, P = 0.044), but there was no difference between infants weighing 2.0-2.5 kg and those weighing2.5 kg (P = 0.225). The ASO can be performed safely in 2.0- to 2.5-kg neonates and yields results comparable with higher weight infants. Imposed delays for corrective surgery may not be necessary for these low-weight infants with transposition of the great arteries.

The increase in pediatric cardiac surgical procedures and establishment of the practice of pediatric cardiac intensive care has created the need for physicians with advanced and specialized knowledge and training. Current training pathways to become a pediatric cardiac intensivist have a great deal of variability and have unique strengths and weaknesses with influences from critical care, cardiology, neonatology, anesthesiology, and cardiac surgery. Such variability has created much confusion among trainees looking to pursue a career in our specialized field. This is a report with perspectives from the most common advanced fellowship training pathways taken to become a pediatric cardiac intensivist as well as various related topics including scholarship, qualifications, and credentialing.

Background Hospital mortality of stage I palliation in patients with hypoplastic left heart syndrome and weighing less than or equal to 2.5 kg remains high. We aimed to (1) assess outcomes in this specific population in a dedicated neonatal cardiac program and (2) determine factors associated with poor outcomes. Methods We retrospectively analyzed outcomes in patients weighing less than or equal to 2.5 kg who underwent a stage I palliation at our institution (2006 to 2014) and performed a risk analysis. Twenty-eight patients were included. Mean follow-up was 26.2 ± 27 months. Results Median weight at surgery was 2.29 kg (range, 1.3 to 2.5 kg). A Sano conduit as opposed to a Blalock-Taussig shunt was placed in 22 patients (78.6%). Timing of surgery was delayed in 5 patients (18%) because of prematurity or extracardiac condition. Coronary fistulae, ventricular dysfunction, and greater than moderate atrioventricular valve regurgitation were present in 2 patients each. Hospital mortality rate was 10.7% (3 of 28 patients). One patient (3.7%) required an early, unplanned reintervention, and 1 patient underwent a late arch revision at the time of stage II. Late mortality or heart transplant rate was 8% (2 of 25 patients). Stage II and stage III procedures were performed in 19 (76%) and 8 (32%) survivors. Survival after stage 2 palliation was 100% (19 of 19 patients) and 87% after Fontan (7 of 8 patients). On univariate analysis, low birthweight ( p = 0.03), delayed surgery ( p = 0.05), preoperative comorbidities ( p = 0.03), postoperative extracorporeal membrane oxygenation ( p = 0.04), neurologic complications ( p = 0.03), and dialysis ( p = 0.04) were associated with higher hospital mortality. Conclusions Stage-I palliation in patients with hypoplastic left heart syndrome weighing less than or equal to 2.5 kg can be achieved with good early and late outcomes. Very low birth weight, delayed surgery, comorbidities, and severe postoperative complications were associated with higher hospital mortality.

Hypoplastic left heart syndrome (HLHS) is not only a devastating disease, but also the most expensive birth defect managed in the US. Nosocomial bloodstream infections (NBIs) are common in neonates with HLHS. We examined the effects of NBIs on in-hospital mortality, length of stay, and costs for late preterm and term infants with HLHS undergoing stage 1 palliation, at both individual patient and hospital levels.We conducted a retrospective study of infants 35 weeks or greater gestation with HLHS, admitted to our institution January 1, 2003 to January 1, 2013. Children with other cardiac abnormalities, major comorbid conditions, or perinatal infections were excluded. Univariable and multivariable analyses were performed. To estimate the effects of reduced NBI incidence on resource utilization, predictive models were used.One hundred forty-three children met inclusion criteria. In-hospital mortality was 9.1% (n = 13). Postoperative infection was observed in 12.6% (n = 18). Median length of stay was 23 days for survivors (IQR, 17 to 40; range, 9 to 132). Median costs were $83,000 for survivors, in 2013 dollars (IQR, $62,000 to $123,000; range, $17,000 to $517,000). NBIs were not associated with changes in mortality. In multivariable analyses, at a patient level NBIs were associated with a 74% increase in length of stay (95% confidence interval [CI], 31% to 132%, p0.001) and a 65% increase in costs (95% CI, 28% to 114%, p0.001). On a hospital level, in this cohort a 50% reduction in the incidence of NBIs would be expected to yield a 4.3% decrease in average length of stay and a 3.8% decrease in average in-patient costs.Nosocomial bloodstream infections in neonates with HLHS are associated with large increases in lengths of stay and costs on a patient level, but not a hospital level. For hospitals without particularly high incidences, studies are needed to identify additional targets for quality improvement.

Survival is significantly compromised in infants born with congenital diaphragmatic hernia and major cardiac anomalies. Mortality is highest when congenital diaphragmatic hernia occurs in association with d-transposition of the great arteries. We present three infants with congenital diaphragmatic hernia associated with d-transposition of the great arteries from a single institution. All three infants survived to discharge after surgical repair/palliation of both the diaphragmatic hernia and heart defect and are doing well at last follow-up. The clinical course and management of these three patients are described.

Every year in the United States approximately 40,000 infants are born with congenital heart disease. Several of these infants require corrective or palliative surgery in the neonatal period. Mortality rates after cardiac surgery are highest amongst neonates, particularly those born prematurely. There are several reasons for the increased surgical mortality risk in neonates. This review outlines these risks, with particular emphasis on the relative immaturity of the organ systems in the term and preterm neonate.

From the Department of Pediatric Cardiac Surgery, Division of Neonatalogy and Perinatology, and Division of Pediatric Cardiology, Morgan Stanley Children’s Hospital, NewYork-Presbyterian, Columbia University Medical Center, New York, NY. Disclosures: Authors have nothing to disclose with regard to commercial support. Received for publication April 3, 2016; accepted for publication April 4, 2016; available ahead of print May 6, 2016. Address for reprints: David Kalfa, MD, PhD, Pediatric Cardiac Surgery, Morgan Stanley Children’s Hospital, NewYork-Presbyterian, Columbia University Medical Center, New York, NY (E-mail: dk2757@cumc. columbia.edu). J Thorac Cardiovasc Surg 2016;152:505-6 0022-5223/$36.00 Copyright 2016 by The American Association for Thoracic Surgery http://dx.doi.org/10.1016/j.jtcvs.2016.04.013

Pediatric cardiac surgery, especially for small neonates, typically requires blood products to counter hemodilution during cardiopulmonary bypass. Children with congenital heart defects whose families adhere to faith-based proscriptions against blood transfusion therefore represent a challenging surgical population. Here, we report the case of a ten-day-old, 3.6-kg patient of Jehovah’s Witness faith, who was diagnosed with unilateral pulmonary artery discontinuity, bilateral patent ductus arteriosus, and an otherwise structurally normal heart. Pulmonary artery reimplantation was successfully performed without giving blood products. This case adds to previous reports of successful bloodless cardiac surgery in neonates and describes the specific strategies that contributed to successful pulmonary artery reimplantation.

Objectives Our primary objective was to test the effects of first postoperative hematocrit on early shunt occlusion for children undergoing systemic to pulmonary artery shunt placement. Because any intervention to reduce shunt occlusion is only beneficial if it reduces mortality or is, at least, mortality neutral, we also tested the effects of first postoperative hematocrit on in-hospital mortality. Methods We conducted a retrospective study on all neonates who underwent primary systemic to pulmonary artery shunt placement, with or without a Norwood/Damus–Kaye–Stansel procedure, at Columbia University Medical Center between January 2010 and July 2015. Univariable regression was used to test the effects of first postoperative hematocrit on early shunt occlusion and 30-day mortality, clustering standard errors by surgeon. In secondary analyses, we also tested associations between red blood cell transfusion volumes in the first 24 postoperative hours and first postoperative hematocrit, shunt occlusion, and mortality. Results Eighty infants met inclusion criteria. Median initial postoperative hematocrit was 41.7% (interquartile range, 37.9-46.0). Six infants (7.5%) died. Four infants (5.0%) died within the first 30 days. Five infants (6.3%) experienced early shunt occlusion. No children with early shunt occlusion died. In univariable models, for every 5 additional percentage points of hematocrit, an infant's odds of early shunt occlusion more than doubled (odds ratio, 2.70; P = .009). The odds of all-cause 30-day mortality remained unchanged. Conclusions Higher postoperative hematocrit levels are associated with early shunt occlusions in infants undergoing primary systemic to pulmonary artery shunt placement. Multicenter investigations are warranted to validate these findings and to determine ideal postoperative hematocrit targets for this population.

Recent studies have shown that phagosome maturation depends on the balance between pro-inflammatory and anti-inflammatory cytokines, indicating that cytokine modulates phagosome maturation. However, the mechanism of cytokine-mediated modulation of intracellular trafficking remains to be elucidated. Here, we have shown that treatment of macrophages with IL-6 specifically induce the expression of Rab5 through the activation of extracellular signal-regulated kinase, whereas IL-12 exclusively upregulate the expression of Rab7 through the activation of p38 MAPK. We have cloned the 5′-flanking regions of the rab5c or rab7 into the promoterless reporter vector. Our results have shown that cells transfected with rab5c chimera are transactivated by IL-6, and IL-12 specifically transactivates cells containing rab7 chimera. Moreover, our results also show that IL-12 induces lysosomal transport, whereas IL-6 stimulates the fusion between early compartments in macrophages and accordingly modulates Salmonella trafficking and survival in macrophages. This is the first demonstration showing that cytokine differentially regulates endocytic trafficking by controlling the expression of appropriate Rab GTPase, and provides insight into the mechanism of cytokine-mediated regulation of intracellular trafficking.

Objectives We tested the hypothesis that the developmental changes occurring in I Kr and I Ks can be explained by changes in the expression of ERG encoding I Kr , and KCNQ1, the β subunit minK, and the recently reported subunit FHL2 encoding I Ks . Background The delayed rectifier current contributes importantly to the developmental evolution of the canine myocardial action potential. Specifically, in left ventricular epicardial myocytes, I Ks is absent and I Kr is the major repolarizing current until age 4 weeks. With subsequent development, I Ks density increases and I Kr decreases, resulting in an altered voltage-time course of repolarization. Methods We used Western blotting and real-time polymerase chain reaction to compare the expression of ERG, KCNQ1, minK, and FHL2 in 1-week-old pups and adult dogs. Results ERG levels are high at 1 week and decrease significantly with age, consistent with developmental decrease in I Kr . Whereas expression of KCNQ1 and FHL2 is unchanged between the two age groups, minK is minimally expressed at 1 week and increases in adults, consistent with developmental increase in I Ks . Conclusions A reduction in ERG explains the developmental decrease in I Kr , whereas the accessory subunit minK appears to be the critical determinant of developmental evolution of I Ks .

Background— Calcium-insensitive transient outward current ( I to ) is important to the development of cardiac memory (CM), which itself reflects the capacity of the heart to remodel electrophysiologically. We used cardiac pacing to test the hypothesis that CM evolution can be explained by developmental maturation of I to . Methods and Results— Acutely anesthetized dogs from 1 day old to adult were paced from the left ventricle (VP, n=29) or left atrial appendage (AP, n=12) to induce CM. T-wave vector displacement (TVD) obtained during VP was greater than with AP (adults, 0.39±0.06 mV; neonates, 0.04±0.01 mV; P r =−0.65, P Conclusions— The inducibility of CM gradually increases with age in association with evolution of the epicardial action potential notch and mRNA expression for KChIP2 and Kv4.3. This suggests that the capacity of the heart to remodel electrophysiologically and to manifest memory during development depends in part on evolution of the determinants of I to .

ObjectiveA recent Society of Thoracic Surgeons database study showed that low weight (

Background A lack of perioperative antibiotic prophylaxis guidelines for neonates undergoing cardiac surgery has resulted in a wide variation in practice. We sought to do the following: (1) Determine the safety of a perioperative antibiotic prophylaxis protocol for neonatal cardiac surgery as measured by surgical site infections (SSIs) rates before and after implementation of the protocol; and (2) evaluate compliance with selected process measures for perioperative antibiotic prophylaxis. Methods This quasi-experimental study included all cardiac procedures performed on neonates from July 2009 to June 2012 at a single center. An interdisciplinary task force developed a standardized perioperative antibiotic prophylaxis protocol in the fourth quarter of 2010. The SSI rates were compared in the preintervention (July 2009 to December 2010) versus the postintervention periods (January 2011 to June 2012). Compliance with process measures (appropriate drug, dose, timing, and discontinuation of perioperative antibiotic prophylaxis) was compared in the 2 periods. Results During the study period, 283 cardiac procedures were performed. The SSI rates were similar in the preintervention and postintervention periods (6.21 vs 5.80 per 100 procedures, respectively). Compliance with the 4 process measures significantly improved postintervention. Conclusions Restricting the duration of perioperative antibiotic prophylaxis after neonatal cardiac surgery to 48 hours in neonates with a closed sternum and to 24 hours after sternal closure was safe and did not increase the rate of SSIs. Compliance with selected process measures improved in the postintervention period. Additional multicenter studies are needed to develop national guidelines for perioperative prophylaxis for this population.

A premature infant with tetralogy of Fallot with pulmonary atresia and prenatal compression of the left main bronchus by a large and ectatic patent ductus arteriosus is presented. Survival to surgery was accomplished by transcatheter placement of a coronary stent into the left mainstem bronchus.

Leishmaniasis is a severe infectious disease. Drugs used for leishmaniasis are very toxic, and no vaccine is available. We found that the hemoglobin receptor (HbR) of Leishmania was conserved across various strains of Leishmania, and anti-HbR antibody could be detected in kala-azar patients' sera. Our results showed that immunization with HbR-DNA induces complete protection against virulent Leishmania donovani infection in both BALB/c mice and hamsters. Moreover, HbR-DNA immunization stimulated the production of protective cytokines like interferon-γ (IFN-γ), interleukin-12 (IL-12), and tumor necrosis factor-α (TNF-α) with concomitant down-regulation of disease-promoting cytokines like IL-10 and IL-4. HbR-DNA vaccination also induced a protective response by generating multifunctional CD4(+) and CD8(+) T cells. All HbR-DNA-vaccinated hamsters showed sterile protection and survived during an experimental period of 8 months. These findings demonstrate the potential of HbR as a vaccine candidate against visceral leishmaniasis.

Phagocytosis is a process by which invading organisms are taken up by macrophages and targeted to the lysosomes, where they are degraded. However, many pathogens modulate this central process of macrophage-mediated killing by inhibiting their transport to the lysosomes through a variety of pathogen-derived mechanisms. Given the importance of Rab proteins in the regulation of intracellular transport pathways, we investigated the role of different host endocytic Rabs on the maturation of Salmonella-containing phagosomes in macrophages. Initially, we have developed a ligand mixing assay to measure the transport of the Salmonella-containing phagosomes to lysosomes. Using this assay we have shown that Salmonella decline their transport to the lysosomes. In order to determine whether inhibition of Salmonella transport to lysosomes is due to their sustained fusion with early endosomes, we have developed an in vitro fusion assay between Salmonella-containing phagosomes and early endosomes. Here, we have discussed how these methodologies are helpful to determine the mechanism of evasion of Salmonella transport to the lysosomes.

Phagocytosis is a process by which invading organisms are taken up by macrophages and targeted to the lysosomes, where they are degraded. However, many pathogens modulate this central process of macrophage-mediated killing by inhibiting their transport to the lysosomes through a variety of pathogen-derived mechanisms. Given the importance of Rab proteins in the regulation of intracellular transport pathways, we investigated the role of different host endocytic Rabs on the maturation of Salmonella-containing phagosomes in macrophages. Initially, we have developed a ligand mixing assay to measure the transport of the Salmonella-containing phagosomes to lysosomes. Using this assay we have shown that Salmonella decline their transport to the lysosomes. In order to determine whether inhibition of Salmonella transport to lysosomes is due to their sustained fusion with early endosomes, we have developed an in vitro fusion assay between Salmonella-containing phagosomes and early endosomes. Here, we have discussed how these methodologies are helpful to determine the mechanism of evasion of Salmonella transport to the lysosomes.

Hb endocytosis in Leishmania is mediated through a 46-kDa protein located in the flagellar pocket. To understand the nature of the Hb receptor (HbR), we have purified the 46-kDa protein to homogeneity from Leishmania promastigote membrane. Purified HbR specifically binds Hb. The gene for HbR was cloned, and sequence analysis of the full-length HbR gene indicates the presence of hexokinase (HK) signature sequences, ATP-binding domain, and PTS-II motif. Four lines of evidence indicate that HbR in Leishmania is a hexokinase: 1) the recombinant HbR binds Hb, and the Hb-binding domain resides in the N terminus of the protein; 2) recombinant proteins and cell lysate prepared from HbR-overexpressing Leishmania promastigotes show enhanced HK activity in comparison with untransfected cells; 3) immunolocalization studies using antibodies against the N-terminal fragment (Ld-HbR-DeltaC) of Ld-HbR indicate that this protein is located in the flagellar pocket of Leishmania; and 4) binding and uptake of (125)I-Hb by Leishmania is significantly inhibited by anti-Ld-HbR-DeltaC antibody and Ld-HbR-DeltaC, respectively. Taken together, these results indicate that HK present in the flagellar pocket of Leishmania is involved in Hb endocytosis.

MinK-related protein (MiRP1 or KCNE2) interacts with the hyperpolarization-activated, cyclic nucleotide-gated (HCN) family of pacemaker channels to alter channel gating in heterologous expression systems. Given the high expression levels of MiRP1 and HCN subunits in the cardiac sinoatrial node and the contribution of pacemaker channel function to impulse initiation in that tissue, such an interaction could be of considerable physiological significance. However, the functional evidence for MiRP1/HCN interactions in heterologous expression studies has been accompanied by inconsistencies between studies in terms of the specific effects on channel function. To evaluate the effect of MiRP1 on HCN expression and function in a physiological context, we used an adenovirus approach to overexpress a hemagglutinin (HA)-tagged MiRP1 (HAMiRP1) and HCN2 in neonatal rat ventricular myocytes, a cell type that expresses both MiRP1 and HCN2 message at low levels. HA-MiRP1 co-expression with HCN2 resulted in a 4-fold increase in maximal conductance of pacemaker currents compared with HCN2 expression alone. HCN2 activation and deactivation kinetics also changed, being significantly more rapid for voltages between -60 and -95 mV when HA-MiRP1 was co-expressed with HCN2. However, the voltage dependence of activation was not affected. Co-immunoprecipitation experiments demonstrated that expressed HA-MiRP1 and HCN2, as well as endogenous MiRP1 and HCN2, co-assemble in ventricular myocytes. The results indicate that MiRP1 acts as a beta subunit for HCN2 pacemaker channel subunits and alters channel gating at physiologically relevant voltages in cardiac cells.

To understand the trafficking of endocytosed hemoglobin (Hb) in Leishmania, we investigated the characteristics of in vitro fusion between endosomes containing biotinylated Hb (BHb) and avidin-horseradish peroxidase (AHRP). We showed that early endosome fusion in Leishmania is temperature and cytosol dependent and is inhibited by ATP depletion, ATPgammaS, GTPgammaS and N-ethylmaleimide treatment. The Rab5 homolog from Leishmania donovani, LdRab5, was cloned and expressed. Our results showed that homotypic fusion between the early endosomes in Leishmania is Rab5 dependent. Early endosomes containing BHb fused efficiently with late endosomes in a process regulated by Rab7, whereas no fusion between early and late endosomes was detected using fluid phase markers. Pre-treatment of early endosomes containing BHb with monoclonal antibody specific for the C-terminus of the Hb receptor (HbR) or the addition of the C-terminal cytoplasmic fragment of the HbR specifically inhibited the fusion with late endosomes, suggesting that signal(s) mediated through the HbR cytoplasmic tail promotes the fusion of early endosomes containing Hb with late endosomes.

Previously, we showed that live Salmonella-containing phagosomes(LSP) recruit early acting Rab5 and promote fusion with early endosomes, thus avoiding transport to the lysosomes. Therefore, live Salmonellasurvive in a specialized compartment. Here we show that scavenger-receptor-mediated intracellular delivery of muramyl dipeptide (MDP)to macrophages leads to efficient killing of Salmonella both in vitro and in vivo. To understand the intracellular trafficking modulation of Salmonella by delivery of MDP, we investigated the levels of endocytic Rab proteins, which are the major regulators of vesicular transport. Western blot analysis reveals reduced Rab5 and enhanced Rab7 content in the maleylated bovine serum albumin-MDP (MBSA-MDP)-treated cells. The reduced content of Rab5 in the treated cells and on phagosomes inhibits the fusion of Salmonella-containing phagosomes with early endosomes, and the enhanced Rab7 content in these cells facilitated targeting of LSP to lysosomes, which contain cathepsin D and vacuolar ATPase, for killing. In vitro reconstitution of lysosomal transport demonstrated that a reduced content of Rab5 and an enhanced level of Rab7 in MBSA-MDP-treated cells is primarily responsible for targeting Salmonella to lysosomes. Intracellular delivery of MDP thus offers a general strategy against macrophage-associated infections caused by intracellular pathogens that survive in the host cell by resisting transport to lysosomes.