Steven R. Neish

Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn

We studied the effects of inhaled nitric oxide (NO) in 9 newborn infants with severe persistent pulmonary hypertension (PPHN) who were candidates for extracorporeal membrane oxygenation treatment. With low doses of NO (10-20 ppm) all showed rapid improvement in oxygenation without reduction of systemic blood pressure. In 6 infants treated with inhaled NO for 24 h, clinical improvement was sustained at 6 ppm.

Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide

We studied the efficacy of low-dose nitric oxide inhalation in nine consecutive patients with severe persistent pulmonary hypertension of the newborn (PPHN) who were candidates for extracorporeal membrane oxygenation (ECMO). All patients had marked hypoxemia despite aggressive ventilator management and echocardiographic evidence of pulmonary hypertension. Associated diagnoses included meconium aspiration syndrome (3 patients), sepsis (3 patients), and congenital diaphragmatic hernia (2 patients). Infants were initially treated with inhaled nitric oxide at 20 ppm for 4 hours and then at 6 ppm for 20 hours. In all infants, oxygenation promptly improved (arterial/alveolar oxygen ratio, 0.077 +/- 0.016 at baseline vs 0.193 +/- 0.030 at 4 hours; p < 0.001) without a decrease in systemic blood pressure. Sustained improvement in oxygenation was achieved in eight patients treated with inhaled nitric oxide for 24 hours at 6 ppm (arterial/alveolar oxygen ratio, 0.270 +/- 0.053 at 24 hours; p < 0.001 vs baseline). One patient with overwhelming sepsis had an initial improvement of oxygenation with nitric oxide but required ECMO for multiorgan and cardiac dysfunction. We conclude that low doses of nitric oxide cause sustained clinical improvement in severe PPHN and may reduce the need for ECMO. However, immediate availability of ECMO is important in selected cases of PPHN complicated by severe systemic hemodynamic collapse.

Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation

CHARGE syndrome is a well-established multiple-malformation syndrome with distinctive consensus diagnostic criteria. Characteristic associated anomalies include ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogenital anomalies, and growth retardation. Recently, mutations of the chromodomain helicase DNA-binding protein gene CHD7 were reported to be a major cause of CHARGE syndrome. We sequenced the CHD7 gene in 110 individuals who had received the clinical diagnosis of CHARGE syndrome, and we detected mutations in 64 (58%). Mutations were distributed throughout the coding exons and conserved splice sites of CHD7. Of the 64 mutations, 47 (73%) predicted premature truncation of the protein. These included nonsense and frameshift mutations, which most likely lead to haploinsufficiency. Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations (54 of 59 in the mutation-positive group vs. 30 of 42 in the mutation-negative group; P=.014), coloboma of the eye (55 of 62 in the mutation-positive group vs. 30 of 43 in the mutation-negative group; P=.022), and facial asymmetry, often caused by seventh cranial nerve abnormalities (36 of 56 in the mutation-positive group vs. 13 of 39 in the mutation-negative group; P=.004). Mouse embryo whole-mount and section in situ hybridization showed the expression of Chd7 in the outflow tract of the heart, optic vesicle, facio-acoustic preganglion complex, brain, olfactory pit, and mandibular component of the first branchial arch. Microarray gene-expression analysis showed a signature pattern of gene-expression differences that distinguished the individuals with CHARGE syndrome with CHD7 mutation from the controls. We conclude that cardiovascular malformations, coloboma, and facial asymmetry are common findings in CHARGE syndrome caused by CHD7 mutation.

Genetic Predictors and Remodeling of Dilated Cardiomyopathy in Muscular Dystrophy

Background— Dystrophin gene mutations cause 2 common muscular dystrophies, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Both are frequently associated with dilated cardiomyopathy (DCM) and premature death. We hypothesized that early diagnosis and treatment of DCM in DMD/BMD patients would lead to ventricular remodeling and that specific dystrophin gene mutations would predict cardiac involvement. Methods and Results— Sixty-nine boys with DMD (n=62) and BMD (n=7) (mean age, 12.9 and 13.7 years, respectively) were referred to our Cardiovascular Genetics Clinic for evaluation, including echocardiography and DNA analysis. Follow-up evaluations were scheduled yearly until the first abnormal echocardiogram indicative of DCM and quarterly thereafter. After the first abnormal echocardiogram, angiotensin-converting enzyme inhibitor or &bgr;-blocker therapy was started. &bgr;-Blockers were added if echocardiography showed no ventricular remodeling in angiotensin-converting enzyme inhibitor–treated patients after 3 months. DCM was diagnosed in 31 subjects (DMD, 27/62, 44%; BMD, 4/7, 57%) (mean age at onset, 15.4±2.8 years; range, 10.4 to 21.2 years). All 31 subjects were begun on pharmacological therapy after diagnosis. On follow-up (n=29), 2 subjects (both DMD) showed stable DCM, 8 subjects (all DMD) showed improvement, and 19 subjects (16 DMD; 3 BMD) showed normalization of left ventricular size and function (total improvement, 27/29 [93%]). DNA analysis in 47 cases (68%) revealed a significant association between DCM and exon 12 and 14 to 17 mutations, possible protection against DCM by exon 51 to 52 mutations, and a trend toward significant association between onset of DCM and exon 31 to 42 mutations. Statistical significance was based on nominal probability values. Conclusions— Early diagnosis and treatment of DCM may lead to ventricular remodeling in DMD/BMD patients. Specific dystrophin gene mutations appear to be predictive of cardiac involvement, while other mutations may protect against or inhibit development of DCM. Further studies evaluating the impact of early intervention strategies on left ventricular geometry and function in muscular dystrophy patients seem warranted.

Response to Cardiac Arrest and Selected Life-Threatening Medical Emergencies The Medical Emergency Response Plan for Schools: A Statement for Healthcare Providers, Policymakers, School Administrators, and Community Leaders

This document introduces a public health initiative, the Medical Emergency Response Plan for Schools. This initiative will help schools prepare to respond to life-threatening medical emergencies in the first minutes before the arrival of emergency medical services (EMS) personnel. This statement is for healthcare providers, policymakers, school personnel, and community leaders. It summarizes essential information about life-threatening emergencies, including details about sudden cardiac arrest (SCA). This statement describes the components of an emergency response plan, the training of school personnel and students to respond to a life-threatening emergency, and the equipment required for this emergency response. Detailed information about SCA and cardiopulmonary resuscitation (CPR) and automated external defibrillator (AED) programs is provided to assist schools in prioritizing and preparing for emergencies to maximize the number of lives saved. Life-threatening emergencies can happen in any school at any time. These emergencies can be the result of preexisting health problems, violence, unintentional injuries, natural disasters, and toxins. In recent years, stories in the lay press have documented tragic premature deaths in schools from SCA, blunt trauma to the chest, firearm injuries, asthma, head injuries, drug overdose, allergic reactions, and heatstroke. School leaders should establish an emergency response plan to deal with life-threatening medical emergencies in addition to the emergency plan for tornados or fires. This statement has been endorsed by the following organizations: American Heart Association (AHA) Emergency Cardiovascular Care Committee, American Academy of Pediatrics, American College of Emergency Physicians, American National Red Cross, National Association of School Nurses, National Association of State EMS Directors, National Association of EMS Physicians, National Association of Emergency Medical Technicians, and the Program for School Preparedness and Planning, National Center for Disaster Preparedness, Columbia University Mailman School of Public Health. This statement was also reviewed by the Centers for Disease Control Division of School and Adolescent …

Development of a pediatric cardiology quality improvement collaborative: From inception to implementation. From the joint council on congenital heart disease quality Improvement task force

While clinical outcomes in pediatric cardiac disease have improved in recent years, marked institutional and individual cardiology practice variability exists. Quality improvement science has demonstrated that reducing process variation leads to more favorable outcomes, safer practices, cost savings, and improved operating efficiency. This report describes the process undertaken to develop the first collaborative quality improvement project of the Joint Council on Congenital Heart Disease. The project chosen aims to reduce mortality and improve the quality of life of infants with hypoplastic left heart syndrome during the interstage period between discharge from the Norwood procedure and admission for the bidirectional Glenn procedure. The objective of this special article is to inform the pediatric cardiology and cardiac surgery communities of the project to help ensure that the early work by the project pilot participants will spread to clinicians caring for children with cardiovascular disease. It is anticipated that this project will add to our understanding of care for this challenging group of children with hypoplastic left heart syndrome, identifying clinical care changes with the potential to lead to improvements in outcome. It will also introduce the field of pediatric cardiology to the science of collaborative quality improvement and assist in reducing clinical process variation and improving patient outcomes across centers. Finally, it will establish an ongoing network of pediatric cardiologists and their teams linked through a longitudinal data set and collaboration for improvement and research.

Variation in interstage outpatient care after the Norwood procedure: a report from the Joint Council on Congenital Heart Disease National Quality Improvement Collaborative.

OBJECTIVE The National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) is the first quality improvement collaborative in pediatric cardiology, and its registry captures information on interstage care and outcomes of infants after the Norwood procedure. The purpose of this study was to evaluate variation in interstage outpatient clinical care practices for infants discharged home after the Norwood procedure. DESIGN Data for the first 100 infants enrolled in the NPC-QIC registry were evaluated. The care domains assessed for variation included: (1) discharge communication with outpatient cardiologist and primary care physician (PCP); (2) nutrition plan at hospital discharge; and (3) planned use of home surveillance strategies. RESULTS One hundred infants were discharged home between July 2008 and February 2010, from 21 participating US pediatric cardiac programs. Median age at discharge was 29 (11-188) days. Interstage outpatient care was provided at the Norwood center for 62 infants, at other centers for 25, and at a combination of centers for 13. Complete discharge communication (defined as written communication of medication list, nutrition plan, and red flag checklist) was relayed to only 45 outpatient cardiologists and to 26 PCPs. Nutrition route at discharge was exclusively oral in 49, combined oral and nasogastric (NG)/nasojejunal (NJ) in 38, exclusively NG/NJ in six, combined oral and gastrostomy tube (GT) in six, and exclusively GT in one infant. Home surveillance strategies were utilized for 81 infants (oximetry and weight monitoring in 77, oximetry alone in four), with no home surveillance in 19 infants. CONCLUSIONS Considerable variation exists in interstage outpatient care after the Norwood procedure in the care domains of discharge communication, nutrition, and home surveillance. Standardizing care around evidence-based practices may improve the outcomes for these very high-risk children.

Prevalence and outcomes of pediatric in-hospital cardiopulmonary resuscitation in the United States: an analysis of the Kids' Inpatient Database*.

Objective:Population-based data on pediatric in-hospital cardiopulmonary resuscitation in the United States are scarce. Single-center studies and voluntary registries may skew the estimated prevalence and outcomes. This study aimed to determine the prevalence and outcomes of pediatric cardiopulmonary resuscitation on a national scale. Design:A retrospective analysis of the Healthcare Cost and Utilization Project 2006 Kids’ Inpatient Database was performed. Sample weighting was employed to produce national estimates. Setting:Three thousand seven hundred thirty-nine hospitals in 38 states participating with the Kids’ Inpatient Database. Patients:All patients <20 yrs of age hospitalized in participating institutions in 2006. Measurements and Main Results:Cardiopulmonary resuscitation was performed in 5,807 (95% confidence interval 5259–6355) children with prevalence of 0.77 per 1,000 admissions. Most patients (68%) were <1 yr old, and 44% were female. On multivariable analysis, cardiopulmonary resuscitation was associated with respiratory failure (odds ratio 41.5, 95% confidence interval 35.4–48.8), myocarditis (odds ratio 36.6, 95% confidence interval 21.9–61.0), acute renal failure (odds ratio 21.6, 95% confidence interval 17.5–26.7), heart failure (odds ratio 3.8, 95% confidence interval 3.0–4.8), and cardiomyopathy (odds ratio 3.8, 95% confidence interval 3.2–4.7). Overall mortality was 51.8% and greater among patients ≥1 yr (68%) vs. <1 yr (44%) (odds ratio 2.7, 95% confidence interval 2.3–3.2). Factors associated with mortality among patients receiving cardiopulmonary resuscitation on multivariable analysis included acute renal failure (odds ratio 1.5, 95% confidence interval 1.1–1.9), hepatic insufficiency (odds ratio 1.5, 95% confidence interval 1.01–2.4), sepsis (odds ratio 1.2, 95% confidence interval 1.01–1.4), and congenital heart disease (odds ratio 1.2, 95% confidence interval 1.01–1.5). Conclusions:Cardiopulmonary resuscitation is performed in approximately one in 1,300 pediatric hospitalizations. Approximately half of patients receiving cardiopulmonary resuscitation do not survive to discharge. Independent risk factors for mortality after receiving cardiopulmonary resuscitation included congenital heart disease, age ≥1 yr, acute renal failure, hepatic insufficiency, and sepsis.

Improvement in Interstage Survival in a National Pediatric Cardiology Learning Network

Infants with univentricular congenital heart disease (CHD), including those with hypoplastic left heart syndrome (HLHS), regularly pose dilemmas in decision-making because their anatomy and physiology are often unique and variable. The typical staged surgical course for infants with complex univentricular anatomy with systemic outflow obstruction begins with the Norwood (stage 1) operation or variant shortly after birth, followed several months later by superior cavopulmonary anastomosis (stage 2 palliation) with an ultimate goal of a Fontan-type operation several years later.1–3 Improvement in surgical and postoperative management has led to considerable improvement in early post-Norwood survival in the recent era.4–7 However, after the Norwood procedure and before stage 2 palliation, a high-risk time period termed interstage, mortality has been previously been reported at 10% to 15%.8–10 The rare nature of this disorder has limited robust learning about successful strategies to improve survival undertaken by single-surgical centers, and a gap exists in our ability to further improve mortality in this population. The National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC), the first multicenter learning network within pediatric cardiology,11 was established with the goal of improving care and outcomes for children with univentricular heart after the Norwood operation and specifically to (1) improve interstage mortality, (2) decrease interstage growth failure, and (3) reduce interstage hospital readmissions for major medical events. There were several perceived challenges to success in changing clinical outcomes before starting the NPC-QIC collaborative. A primary challenge in collaboration among multiple sites can be agreement on best practices that should be implemented. This is especially true for rare diseases, such as univentricular heart disease, where evidence-based clinical guidelines are not available to clinicians. As noted above, major variation persists in management practices among individuals and institutions caring for children with HLHS and other …

Variation in Preoperative and Intraoperative Care for First‐stage Palliation of Single‐ventricle Heart Disease: A Report from the Joint Council on Congenital Heart Disease National Quality Improvement Collaborative

BACKGROUND AND METHODS As the first multicenter quality improvement collaborative in pediatric cardiology, the Joint Council on Congenital Heart Disease National Pediatric Cardiology Quality Improvement Collaborative registry collects information on the clinical care and outcomes of infants discharged home after first-stage palliation of single-ventricle heart disease, the Norwood operation, and variants. We sought to describe the preoperative and intraoperative characteristics of the first 100 patients enrolled in the National Pediatric Cardiology Quality Improvement Collaborative registry. RESULTS From 21 contributing centers, 59% of infants were male, with median birth weight of 3.1 kg (1.9-5.0 kg); the majority had hypoplastic left heart syndrome (71%). A prenatal diagnosis of congenital heart disease was made in 75%; only one had fetal cardiac intervention. Chromosomal anomalies were present in 8%, and major noncardiac organ system anomalies were present in 9%. Preoperative risk factors were common (55%) but less frequent in those with prenatal cardiac diagnosis (P= .001). Four patients underwent a preoperative transcatheter intervention. Substantial variation across participating sites was demonstrated for choice of initial palliation for the 93 patients requiring a full first-stage approach, with 50% of sites performing stage I with right ventricle to pulmonary artery conduit as the preferred operation; 89% of hybrid procedures were performed at a single center. Significant intraoperative variation by site was noted for the 83 patients who underwent traditional surgical stage I palliation, particularly with use of regional perfusion and depth of hypothermia. CONCLUSIONS In summary, there is substantial variation across surgical centers in the successful initial palliation of infants with single-ventricle heart disease, particularly with regard to choice of palliation strategy, and intraoperative techniques including use of regional perfusion and depth of hypothermia. Further exploration of the relationship of such variables to subsequent outcomes after hospital discharge may help reduce variability and improve long-term outcomes.