Gudrun Aspelund

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.

Ultrasonography/mri versus ct for diagnosing appendicitis

BACKGROUND: Cross-sectional imaging increases accuracy in diagnosing appendicitis. We hypothesized that a radiation-free imaging pathway of ultrasonography selectively followed by MRI would not change clinical end points compared with computed tomography (CT) for diagnosis of acute appendicitis in children. METHODS: We retrospectively reviewed children (<18 years old) who had diagnostic imaging for suspected acute appendicitis between November 2008 and October 2012. Before November 2010 CT was used as the primary imaging modality (group A); subsequently, ultrasonography was the primary imaging modality followed by MRI for equivocal findings (group B). Data collected included time from triage to imaging and treatment and results of imaging and pathology. RESULTS: Six hundred sixty-two patients had imaging for suspected appendicitis (group A = 265; group B = 397, of which 136 [51%] and 161 [41%], respectively, had positive imaging for appendicitis). Negative appendectomy rate was 2.5% for group A and 1.4% for group B. Perforation rate was similar for both groups. Time from triage to antibiotic administration and operation did not differ between groups A and B. There was higher proportion of positive imaging and appendectomies in group A and thus more negative imaging tests in group B (ultrasonography and MRI), but diagnostic accuracy of the 2 imaging pathways was similar. CONCLUSIONS: In children with suspected acute appendicitis, a radiation-free diagnostic imaging of ultrasonography selectively followed by MRI is feasible and comparable to CT, with no difference in time to antibiotic administration, time to appendectomy, negative appendectomy rate, perforation rate, or length of stay.

Treatment of necrotizing enterocolitis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review

OBJECTIVE The optimal treatment of necrotizing enterocolitis (NEC) is a common challenge for pediatric surgeons. Although many studies have evaluated prevention and medical therapy for NEC, few guidelines for surgical care exist. The aim of this systematic review is to review and evaluate the currently available evidence for the surgical care of patients with NEC. METHODS Data were compiled from a search of PubMed, OVID, the Cochrane Library database, and Web of Science from January 1985 until December 2011. Publications were screened, and their references were hand-searched to identify additional studies. Clinicaltrials.gov was also searched to identify ongoing or unpublished trials. The American Pediatric Surgical Association Outcomes and Clinical Trials Committee proposed six questions deemed pertinent to the surgical treatment of NEC. Recent Cochrane Reviews examined three of these topics; a literature review was performed to address the additional three specific questions. RESULTS The Cochrane Reviews support the use of prophylactic probiotics in preterm infants less than 2500 grams to reduce the incidence of NEC, as well as the use of human breast milk rather than formula when possible. There is no clear evidence to support delayed initiation or slow advancement of feeds. For surgical treatment of NEC with perforation, there is no clear support of peritoneal drainage versus laparotomy. Similarly, there is a lack of evidence comparing enterostomy versus primary anastomosis after resection at laparotomy. There are little data to determine the length of treatment with antibiotics to prevent recurrence of NEC. CONCLUSION Based on available evidence, probiotics are advised to decrease the incidence of NEC, and human milk should be used when possible. The other reviewed questions are clinically relevant, but there is a lack of evidence-based data to support definitive recommendations. These areas of NEC treatment would benefit from future investigation.

Limb ischemia after common femoral artery cannulation for venoarterial extracorporeal membrane oxygenation: an unresolved problem

PURPOSE Extracorporeal Life Support Organization Registry data confirm that the number of pediatric patients being supported by extracorporeal membrane oxygenation (ECMO) is increasing. To minimize the potential neurologic effects of carotid artery ligation, the common femoral artery (CFA) is frequently being used for arterial cannulation. The cannula has the potential for obstructing flow to the lower limb, thus increasing ischemia and possible limb loss. We present a single institutions experience with CFA cannulation for venoarterial (VA) ECMO and ask whether any precannulation variables correlate with the development of significant limb ischemia. METHODS We reviewed all pediatric patients who were supported by VA ECMO via CFA cannulation from January 2000 to February 2010. Limb ischemia was the primary variable. The ischemia group was defined as the patients requiring an intervention because of the development of lower extremity ischemia. The patients in the no-ischemia group did not develop significant ischemia. Continuous variables were reported as medians with interquartile ranges and compared using Mann-Whitney U tests. Differences in categorical variables were assessed using χ² testing (Fishers Exact). Statistical significance was assumed at P < .05. RESULTS Twenty-one patients (age, 2-22 years) were cannulated via the CFA for VA ECMO. Significant ischemia requiring intervention (ischemia group) occurred in 11 (52%) of 21. In comparing the 2 groups (ischemia vs no ischemia), no clinical variables predicted the development of ischemia (Table 1). In the ischemia group, 9 (81%) of 11 had a distal perfusion catheter (DPC) placed. Complications of DPC placement included one case of compartment syndrome requiring a fasciotomy and one patient requiring interval toe amputation. Of the 2 patients in the ischemia group who did not have a DPC placed, 1 required a vascular reconstruction of an injured superficial femoral artery and 1 underwent a below-the-knee amputation. Mortality was lower in the ischemia group (27% vs 60%). CONCLUSIONS Limb ischemia remains a significant problem, as more than half of our patients developed it. The true incidence may not be known as a 60% mortality in the no-ischemia group could mask subsequent ischemia. Although children are at risk for developing limb ischemia/loss, no variable was predictive of the development of significant limb ischemia in our series. Because of the inability to predict who will develop limb ischemia, early routine placement of a DPC at the time of cannulation may be warranted. However, DPCs do not completely resolve issues around tissue loss and morbidity. Prevention of limb ischemia/loss because of CFA cannulation for VA ECMO continues to be a problem that could benefit from new strategies.

Early recurrence of congenital diaphragmatic hernia is higher after thoracoscopic than open repair: a single institutional study.

INTRODUCTION Experience in thoracoscopic congenital diaphragmatic hernia (CDH) repair has expanded, yet efficacy equal to that of open repair has not been demonstrated. In spite of reports suggesting higher recurrent hernia rates after thoracoscopic repair, this approach has widely been adopted into practice. We report a large, single institutional experience with thoracoscopic CDH repair with special attention to recurrent hernia rates. METHODS We reviewed the records of neonates with unilateral CDH repaired between January 2006 and February 2010 at Morgan Stanley Childrens Hospital. Completely thoracoscopic repairs were compared to open repairs of the same period. In addition, successful thoracoscopic repairs were compared with thoracoscopic repairs that developed recurrence. Data were analyzed by Mann-Whitney U and Fisher exact tests. RESULTS Thirty-five neonates underwent attempted thoracoscopic repair, with 26 completed. Concurrently, 19 initially open CDH repairs were performed. Preoperatively, patients in the open repair group required more ventilatory support than the thoracoscopic group. Recurrence was higher after thoracoscopic repair (23% vs 0%; P = .032). In comparing successful thoracoscopic repairs to those with recurrence, none of the factors analyzed were predictive of recurrence. CONCLUSIONS Early recurrence of hernia is higher in thoracoscopic CDH repairs than in open repairs. Technical factors and a steep learning curve for thoracoscopy may account for the higher recurrence rates, but not patient severity of illness. In an already-tenuous patient population, performing the repair thoracoscopically with a higher risk of recurrence may not be advantageous.

Strategies for the prevention of central venous catheter infections: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review

PURPOSE The aim of this study is to review the current evidence-based data regarding strategies for prevention of central venous catheter (CVC) infections at the time of catheter insertion and as a part of routine care. METHODS We conducted a PubMed search from January 1990 to November 2010 using the following keywords: central venous catheter, clinical trials, pediatric, infection, prevention, antibiotic, chlorhexidine, dressing, antiseptic impregnated catheters, ethanol lock, impregnated cuff, insertion site infection, and Cochrane systematic review. Seven questions, selected by the American Pediatric Surgical Association Outcomes and Clinical Trials Committee, were addressed. RESULTS Thirty-six studies were selected for detailed review based on the strength of their study design and relevance to our 7 questions. These studies provide evidence that (1) chlorhexidine skin prep and chlorhexidine-impregnated dressing can decrease CVC colonization and bloodstream infection, (2) use of heparin and antibiotic-impregnated CVCs can decrease CVC colonization and bloodstream infection, and (3) ethanol and vancomycin lock therapy can reduce the incidence of catheter-associated bloodstream infections. CONCLUSION Grade A and B recommendations can be made based on available evidence in adult and limited pediatric studies for multiple components of proper CVC insertion practices and subsequent management. These strategies can minimize the risk of CVC infections in pediatric patients.

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.

Developmental outcomes of children with congenital diaphragmatic hernia: a multicenter prospective study.

PURPOSE To determine developmental outcomes and associated factors in patients with congenital diaphragmatic hernia (CDH) at 2 years of age. METHODS This is a multicenter prospective study of a CDH birth cohort. Clinical and socioeconomic data were collected. Bayley Scales of Infant Development (BSID-III) and Vineland Adaptive Behavior Scales (VABS-II) were performed at 2 years of age. RESULTS BSID-III and VABS-II assessments were completed on 48 and 49 children, respectively. The BSID-III mean cognitive, language, and motor scores were significantly below the norm mean with average scores of 93 ± 15, 95 ± 16, and 95 ± 11. Ten percent (5/47) scored more than 2 standard deviations below the norm on one or more domains. VABS-II scores were similar to BSID-III scores with mean communication, daily living skills, social, motor, adaptive behavior scores of 97 ± 14, 94 ± 16, 93 ± 13, 97 ± 10, and 94 ± 14. For the BSID-III, supplemental oxygen at 28 days, a prenatal diagnosis, need for extracorporeal membrane oxygenation (ECMO) and exclusive tube feeds at time of discharge were associated with lower scores. At 2 years of age, history of hospital readmission and need for tube feeds were associated with lower scores. Lower socioeconomic status correlated with lower developmental scores when adjusted for significant health factors. CONCLUSION CDH patients on average have lower developmental scores at 2 years of age compared to the norm. A need for ECMO, oxygen at 28 days of life, ongoing health issues and lower socioeconomic status are factors associated with developmental delays.

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.

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.