Brian T. Bucher

Outcomes of congenital diaphragmatic hernia in the modern era of management.

OBJECTIVE To identify clinical factors associated with pulmonary hypertension (PH) and mortality in patients with congenital diaphragmatic hernia (CDH). STUDY DESIGN A prospective cohort of neonates with a diaphragm defect identified at 1 of 7 collaborating medical centers was studied. Echocardiograms were performed at 1 month and 3 months of age and analyzed at a central core by 2 cardiologists independently. Degree of PH and survival were tested for association with clinical variables using Fischer exact test, χ(2), and regression analysis. RESULTS Two hundred twenty patients met inclusion criteria. Worse PH measured at 1 month of life was associated with higher mortality. Other factors associated with mortality were need for extracorporeal membrane oxygenation, patients inborn at the treating center, and patients with a prenatal diagnosis of CDH. Interestingly, patients with right sided CDH did not have worse outcomes. CONCLUSIONS Severity of PH is associated with mortality in CDH. Other factors associated with mortality were birth weight, gestational age at birth, inborn status, and need for extracorporeal membrane oxygenation.

Impact of Hospital Volume on In-Hospital Mortality of Infants Undergoing Repair of Congenital Diaphragmatic Hernia

Objectives:Congenital diaphragmatic hernia (CDH) remains a significant cause of neonatal morbidity and mortality. Summary of Background Data:Previous studies have suggested that hospital volume is an independent predictor of in-hospital mortality. We sought to validate this effect using a large national database incorporating 37 free-standing childrens hospitals in the United States. Methods:Infants who underwent repair of CDH from 2000 to 2008 at Pediatric Health Information Systems-member hospitals were evaluated. Hospitals were categorized by tertiles into low-volume (≤6 cases/yr), medium-volume (6–10 cases/yr), and high-volume (>10 cases/yr). Using generalized linear mixed models with random effects, we computed the risk-adjusted odds ratio of mortality by yearly hospital volume of CDH repair, after adjustment for salient patient and hospital characteristics. Results:There were 2203 infants who underwent repair with an overall survival of 82%. Average yearly hospital volume of CDH repair varied from 1.4 to 17.5 cases per year. Smaller birthweight (adjusted odds ratio [aOR]: 0.56 per kg, P < 0.001), year of birth (P < 0.001), chromosomal abnormalities (aOR: 3.83, P < 0.01), longer time to repair (aOR: 1.12 per week, P < 0.05), the thoracic approach for repair (P < 0.02), and requirement for extracorporeal membrane oxygenation (aOR: 10.31, P < 0.0001), or inhaled nitric oxide (aOR: 5.25, P < 0.0001) were each independently associated with mortality. Compared with low-volume hospitals, medium-volume (aOR: 0.56, P < 0.05) and high-volume (aOR: 0.44, P < 0.01) hospitals had a significantly lower mortality. The rate of extracorporeal membrane oxygenation use at each facility was not independently associated with mortality. Conclusions:This large study suggests that hospitals which perform high volumes of CDH repair achieve lower in-hospital mortality. These data support the paradigm of regionalized centers of excellence for the management of infants with this morbid condition.

Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is characterized by incomplete formation of the diaphragm occurring as either an isolated defect or in association with other anomalies. Genetic factors including aneuploidies and copy number variants are important in the pathogenesis of many cases of CDH, but few single genes have been definitively implicated in human CDH. In this study, we used whole exome sequencing (WES) to identify a paternally inherited novel missense GATA4 variant (c.754C>T; p.R252W) in a familial case of CDH with incomplete penetrance. Phenotypic characterization of the family included magnetic resonance imaging of the chest and abdomen demonstrating asymptomatic defects in the diaphragm in the two “unaffected” missense variant carriers. Screening 96 additional CDH patients identified a de novo heterozygous GATA4 variant (c.848G>A; p.R283H) in a non-isolated CDH patient. In summary, GATA4 is implicated in both familial and sporadic CDH, and our data suggests that WES may be a powerful tool to discover rare variants for CDH.

Intestinal adaptation after small bowel resection in human infants.

PURPOSE In animal models, the small intestine responds to massive small bowel resection (SBR) through a compensatory process termed adaptation, characterized by increases in both villus height and crypt depth. This study seeks to determine whether similar morphologic alterations occur in humans after SBR. METHODS Clinical data and pathologic specimens of infants who had both an SBR for necrotizing enterocolitis and an ostomy takedown from 1999 to 2009 were reviewed. Small intestine mucosal morphology was compared in the same patients at the time of SBR and at the time of ostomy takedown. RESULTS For all samples, there was greater villus height (453.6 ± 20.4 vs 341.2 ± 12.4 μm, P < .0001) and crypt depth (178.6 ± 7.2 vs 152.6 ± 6 μm, P < .01) in the ostomy specimens compared with the SBR specimens. In infants with paired specimens, there was an increase of 31.7% ± 8.3% and 22.1% ± 10.0% in villus height and crypt depth, respectively. There was a significant correlation between the amount of intestine resected and the percent change in villus height (r = 0.36, P < .05). CONCLUSION Mucosal adaptation after SBR in human infants is similar to what is observed in animal models. These findings validate the use of animal models of SBR used to understand the molecular mechanisms of this important response.

De novo copy number variants are associated with congenital diaphragmatic hernia

Background Congenital diaphragmatic hernia (CDH) is a common birth defect with significant morbidity and mortality. Although the aetiology of CDH remains poorly understood, studies from animal models and patients with CDH suggest that genetic factors play an important role in the development of CDH. Chromosomal anomalies have been reported in CDH. Methods In this study, the authors investigated the frequency of chromosomal anomalies and copy number variants (CNVs) in 256 parent–child trios of CDH using clinical conventional cytogenetic and microarray analysis. The authors also selected a set of CDH related training genes to prioritise the genes in those segmental aneuploidies and identified the genes and gene sets that may contribute to the aetiology of CDH. Results The authors identified chromosomal anomalies in 16 patients (6.3%) of the series including three aneuploidies, two unbalanced translocation, and 11 patients with de novo CNVs ranging in size from 95 kb to 104.6 Mb. The authors prioritised the genes in the CNV segments and identified KCNA2, LMNA, CACNA1S, MYOG, HLX, LBR, AGT, GATA4, SOX7, HYLS1, FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, HOMER2, BNC1, BID, and TBX1 as genes that may be involved in diaphragm development. Gene enrichment analysis identified the most relevant gene ontology categories as those involved in tissue development (p=4.4×10−11) or regulation of multicellular organismal processes (p=2.8×10−10) and ‘receptor binding’ (p=8.7×10−14) and ‘DNA binding transcription factor activity’ (p=4.4×10−10). Conclusions The present findings support the role of chromosomal anomalies in CDH and provide a set of candidate genes including FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, SOX7, BNC1, BID, and TBX1 for further analysis in CDH.

Risk Factors and Outcomes of Surgical Site Infection in Children

BACKGROUND Indices for prediction of surgical site infection (SSI) are well documented in the adult population; however, these factors have not been validated in children. STUDY DESIGN A retrospective case-control study was performed by examining the medical records of children (0 to 18 years) who developed an SSI within 30 days of selected class I and class II procedures at our institution from 1996 to 2008. Two controls were selected from among patients undergoing identical procedures within 12 months of each case. Statistical analysis was performed using Wilcoxon test for continuous and chi-square test for categorical variable. Factors thought a priori to be associated with risk of SSI and statistically significant variables from a univariate analysis were used to create a logistic regression model. RESULTS Of 16,031 patients, 159 children (0.99%) developed an SSI. Univariate analysis showed race, postoperative location, skin preparation, urinary catheter, procedure duration, and implantable device as risk factors for development of an SSI. Independent predictors of SSI in multiple conditional logistic regression were age (adjusted odds ratio [aOR] 4.97 neonate vs adolescent; 95% CI 1.38 to 17.90), race (aOR 2.36 for African American vs white; 95% CI 1.32 to 4.18), postoperative location (aOR 6.55 ICU vs home; 95% CI 1.58 to 27.21), urinary catheter placement (aOR 3.56; 95% CI 1.50 to 8.48), and implantable device (aOR 3.05; 95% CI 1.14 to 8.21). Wound classification and antibiotic administration were not independent predictors of SSI. CONCLUSIONS Postoperative location, urinary catheter insertion, and use of an implantable device are potentially modifiable risk factors for an SSI in children. The higher risk of SSI in younger patients and non-white race suggest a possible developmental, socioeconomic, or genetic marker for impaired host defense.

Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia

Background Congenital diaphragmatic hernia (CDH) is a common birth defect affecting 1 in 3000 births. It is characterised by herniation of abdominal viscera through an incompletely formed diaphragm. Although chromosomal anomalies and mutations in several genes have been implicated, the cause for most patients is unknown. Methods We used whole exome sequencing in two families with CDH and congenital heart disease, and identified mutations in GATA6 in both. Results In the first family, we identified a de novo missense mutation (c.1366C>T, p.R456C) in a sporadic CDH patient with tetralogy of Fallot. In the second, a nonsense mutation (c.712G>T, p.G238*) was identified in two siblings with CDH and a large ventricular septal defect. The G238* mutation was inherited from their mother, who was clinically affected with congenital absence of the pericardium, patent ductus arteriosus and intestinal malrotation. Deep sequencing of blood and saliva-derived DNA from the mother suggested somatic mosaicism as an explanation for her milder phenotype, with only approximately 15% mutant alleles. To determine the frequency of GATA6 mutations in CDH, we sequenced the gene in 378 patients with CDH. We identified one additional de novo mutation (c.1071delG, p.V358Cfs34*). Conclusions Mutations in GATA6 have been previously associated with pancreatic agenesis and congenital heart disease. We conclude that, in addition to the heart and the pancreas, GATA6 is involved in development of two additional organs, the diaphragm and the pericardium. In addition, we have shown that de novo mutations can contribute to the development of CDH, a common birth defect.

Intussusception in children: cost-effectiveness of ultrasound vs diagnostic contrast enema

PURPOSE The aim of the study was to compare the cost-effectiveness of different imaging strategies for the diagnosis of pediatric intussusception using a decision analytic model. METHODS A Markov decision model was constructed to model effects of radiation exposure at the time of intussusception in a hypothetical cohort of 2-year-old children. The 2 strategies compared were ultrasound followed conditionally by contrast enema (US/CE) vs contrast enema (CE) alone. The model simulated short-term and long-term outcomes of the patients, calculating the average quality-adjusted life years (QALYs) and health care costs associated with each arm. RESULTS The use of ultrasound as a first-line diagnostic modality would result in a decrease of 79.3 and 59.7 cases of radiation-induced malignancy per 100,000 male and female children evaluated, respectively. For male and female children with intussusception, US/CE was both the most costly initial imaging strategy and the most effective compared with CE. The incremental cost-effectiveness ratios of US/CE to CE was

Antibiotic prophylaxis and the prevention of surgical site infection.

70,100 (boy) and

Bacterial DNA content in the intestinal wall from infants with necrotizing enterocolitis

92,227 (girl) per quality-adjusted life years gained. CONCLUSIONS In a Markov decision model of pediatric acute intussusception, initial US/CE was both the most costly and the most effective strategy.