Caraciolo J. Fernandes

Free Radicals and Diseases in Premature Infants

Free radicals have been implicated in the pathogenesis of a wide spectrum of human diseases. Premature infants are probably developmentally unprepared for extrauterine life in an oxygen-rich environment and exhibit a unique sensitivity to oxidant injury. Diseases associated with premature infants, including bronchopulmonary dysplasia, periventricular leukomalacia, intraventricular hemorrhage, retinopathy of prematurity, and necrotizing enterocolitis, have been linked to free radical-mediated cell and tissue injury. With the advent of therapies designed to combat the injurious effects of free radicals, the role of these highly reactive chemical molecules in the pathogenesis of neonatal diseases needs to be fully determined.

Genomic alterations that contribute to the development of isolated and non-isolated congenital diaphragmatic hernia

Background Congenital diaphragmatic hernia (CDH) is a life threatening birth defect. Most of the genetic factors that contribute to the development of CDH remain unidentified. Objective To identify genomic alterations that contribute to the development of diaphragmatic defects. Methods A cohort of 45 unrelated patients with CDH or diaphragmatic eventrations was screened for genomic alterations by array comparative genomic hybridisation or single nucleotide polymorphism based copy number analysis. Results Genomic alterations that were likely to have contributed to the development of CDH were identified in 8 patients. Inherited deletions of ZFPM2 were identified in 2 patients with isolated diaphragmatic defects and a large de novo 8q deletion overlapping the same gene was found in a patient with non-isolated CDH. A de novo microdeletion of chromosome 1q41q42 and two de novo microdeletions on chromosome 16p11.2 were identified in patients with non-isolated CDH. Duplications of distal 11q and proximal 13q were found in a patient with non-isolated CDH and a de novo single gene deletion of FZD2 was identified in a patient with a partial pentalogy of Cantrell phenotype. Conclusions Haploinsufficiency of ZFPM2 can cause dominantly inherited isolated diaphragmatic defects with incomplete penetrance. These data define a new minimal deleted region for CDH on 1q41q42, provide evidence for the existence of CDH related genes on chromosomes 16p11.2, 11q23-24 and 13q12, and suggest a possible role for FZD2 and Wnt signalling in pentalogy of Cantrell phenotypes. These results demonstrate the clinical utility of screening for genomic alterations in individuals with both isolated and non-isolated diaphragmatic defects.

Platelet transfusions in infants with necrotizing enterocolitis do not lower mortality but may increase morbidity.

OBJECTIVE:Necrotizing enterocolitis (NEC), a serious multisystemic inflammatory disease most commonly seen in premature neonates, is often associated with thrombocytopenia. Infants with severe forms of NEC commonly have platelet counts of less than 50,000/mm3, occasionally less than 10,000/mm3. Despite an absence of data to support the practice, platelet transfusions are commonly used to maintain a certain arbitrary platelet count in an effort to prevent bleeding. As platelet transfusions contain a variety of bioactive factors including pro-inflammatory cytokines, we hypothesized that a higher number and volume of platelet transfusions would not be associated with an improvement in mortality or morbidity.STUDY DESIGN:A retrospective cohort analysis was conducted of the medical records of all infants between 1997 and 2001 with Bells Stage 2 or 3 NEC associated with platelet counts of <100,000/mm3. The medical records were evaluated for the following variables: platelet counts, number and volume of platelet transfusions, symptoms of bleeding, and hospital course. Mortality and development of short bowel syndrome and/or cholestasis were correlated to the total number and volume (total ml and ml/kg) of platelet transfusions. Differences between the outcome groups were compared using the independent t-test, Fishers exact test and Mann–Whitney tests.RESULTS:A total of 46 infants met the study criteria (gestational age 28±4 weeks and birth weight 1166±756 g, mean±SD). There were a total of 406 platelet transfusions administered to the study population. Of these, 151 (37.2%) were given in the presence of active bleeding, with 62% of these resulting in the cessation of bleeding within 24 hours. Other listed indications for platelet transfusions were hypovolemia and severe thrombocytopenia. On analysis of the entire cohort, there was no statistical improvement in either mortality or morbidity (short bowel syndrome and cholestasis) with greater number and/or volume of platelet transfusions. Furthermore, we found that infants who developed short bowel syndrome and/or cholestasis had been given a significantly higher number and volume of platelet transfusions when compared to those who did not have these adverse outcomes [median (minimum – maximum)−number of transfusions : 9 (0 to 33) vs 1.5 (0 to 20), p=0.010; volume of transfusions (ml/kg) : 121.5 (0 to 476.6) vs 33.2 (0 to 224.3), p=0.013].CONCLUSION:This retrospective analysis suggests that greater number and volume of platelet transfusions in infants with necrotizing enterocolitis are associated with greater morbidity in the form of short bowel syndrome and/or cholestasis without the benefit of lower mortality.

Fetal lung volume and quantification of liver herniation by magnetic resonance imaging in isolated congenital diaphragmatic hernia.

To determine associations between fetal lung and liver herniation volumes measured by magnetic resonance imaging (MRI) and mortality/need for extracorporeal membrane oxygenation (ECMO) in cases of isolated congenital diaphragmatic hernia (CDH). A secondary objective was to compare prenatal MRI parameters with two‐dimensional ultrasound lung measurements.

Severe Thrombocytopenia Predicts Outcome in Neonates with Necrotizing Enterocolitis

OBJECTIVE:Necrotizing enterocolitis (NEC) is a common and serious gastrointestinal disorder that predominately affects premature infants. Few prognostic indices are available to guide physicians through the expected course of the disease. We hypothesized that the degree and timing of onset of severe thrombocytopenia (platelet count <100,000/mm3) would be a predictor of adverse outcome and an indication for surgical intervention in infants with NEC.STUDY DESIGN:The clinical presentation and outcome of all infants with Bell stage II or III NEC treated at Texas Childrens Hospital between 1997 and 2001 were retrospectively reviewed. Patients were stratified into two groups based on the presence (Group1) or absence (Group 2) of severe thrombocytopenia (platelet count <100,000/mm3) within 3 days of a diagnosis of NEC. Differences between groups were compared using logistic regression to estimate adjusted odds ratios.RESULTS:A total of 91 infants met inclusion criteria (average birth weight 1288±135 g; average gestational age 29.0±3.0 weeks). Compared to infants in Group 2, infants in Group 1 were more premature (28.0±4.1 vs 30.0±4.2 weeks; p=0.02), more likely to have received postnatal steroids (42.5% vs 20.4%; p=0.02), and more likely to require laparotomy for gangrenous bowel (adjusted OR 16.33; p<0. 001). The presence of severe thrombocytopenia was also a predictor of mortality (adjusted OR 6.39; p=0.002) and NEC-related gastrointestinal complications including cholestatic liver disease and short bowel syndrome (adjusted OR 5.47; p=0.006).CONCLUSION:Severe thrombocytopenia within the first 3 days after a diagnosis of NEC suggests a higher likelihood of bowel gangrene, morbidity, and mortality. Prospective studies of infants with early and severe thrombocytopenia may help determine the optimal timing of laparotomy in infants with NEC.

Use of Palivizumab for prevention of hospitalization as a result of respiratory syncytial virus in infants with cystic fibrosis.

The Palivizumab Outcomes Registry collected data on 19,548 high-risk infants who received ≥1 dose of palivizumab and followed prospectively from 2000 through 2004. Ninety-one children with cystic fibrosis (CF) were identified who received palivizumab off label. None of the infants with CF who received prophylaxis was hospitalized as a result of respiratory syncytial virus lower respiratory tract infection. Evaluations of palivizumab use in infants with CF could be warranted.

Terminal Deletion of Chromosome 15q26.1: Case Report and Brief Literature Review

Terminal deletions of chromosome 15q are rare events, with only six cases previously described. Here we describe a seventh case of a terminal deletion of the long arm of chromosome 15, with the present case exhibiting clinical features not previously described.

Diagnosing Significant PDA Using Natriuretic Peptides in Preterm Neonates: A Systematic Review

BACKGROUND AND OBJECTIVES: Echocardiogram is the gold standard for the diagnosis of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm neonates. A simple blood assay for brain natriuretic peptide (BNP) or amino-terminal pro-B-type natriuretic peptide (NT-proBNP) may be useful in the diagnosis and management of hsPDA. Our objectives were to determine the diagnostic accuracy of BNP and NT-proBNP for hsPDA in preterm neonates and to explore heterogeneity by analyzing subgroups. METHODS: The systematic review was performed as recommended by the Cochrane Diagnostic Test Accuracy Working Group. Electronic databases, conference abstracts, and cross-references were searched. We included studies that evaluated BNP or NT-proBNP (index test) in preterm neonates with suspected hsPDA (participants) in comparison with echocardiogram (reference standard). A bivariate random effects model was used for meta-analysis, and summary receiver operating characteristic curves were generated. RESULTS: Ten BNP and 11 NT-proBNP studies were included. Studies varied by methodological quality, type of commercial assay, thresholds, age at testing, gestational age, and whether the assay was used to initiate medical or surgical therapy. Sensitivity and specificity for BNP at summary point were 88% and 92%, respectively, and for NT-proBNP they were 90% and 84%, respectively. CONCLUSIONS: The studies evaluating the diagnostic accuracy of BNP and NT-proBNP for hsPDA varied widely by assay characteristics (assay kit and threshold) and patient characteristics (gestational and chronological age); therefore, generalizability between centers is not possible. We recommend that BNP or NT-proBNP assays be locally validated for specific patient population and outcomes, to initiate therapy or follow response to therapy.

Venovenous cannulation for extracorporeal membrane oxygenation using a bicaval dual-lumen catheter in neonates.

PURPOSE Venovenous extracorporeal membrane oxygenation (VV-ECMO) has been used as a management strategy for neonates with refractory pulmonary failure. However, VV-ECMO has been limited in neonates secondary to cannula design and patient size. Herein, we describe the use of a bicaval dual-lumen catheter for VV-ECMO in neonates. METHODS The medical records of all neonates cannulated for ECMO support with a bicaval dual-lumen 13F catheter from 2008 to 2010 were reviewed. RESULTS Nine neonates cannulated with this dual-lumen catheter were identified. The median gestational age was 38 weeks (range, 31-40 weeks), the median weight was 3.4 kg (range, 2.2-5.5 kg), the median age at cannulation was 2 days (range, 1-64 days), and the median duration of ECMO support was 7 days (range, 5-23 days). There were no VV-to-VA conversions. The median pump flow both at 4 and 24 hours postcannulation was 300 mL/min (range, 240-370 mL/min). One patient developed cannula thrombosis, and one required cannula repositioning because of flow recirculation. Overall survival was 56%. CONCLUSION The dual-lumen bicaval catheter can be safely used in neonates with minimal complications and is our preferred method for VV-ECMO support in the neonatal population.

Trisomy 14 Mosaicism: A Case Report and Review of the Literature

Trisomy 14 mosaicism is a rare chromosomal abnormality with distinct and recognizable clinical features. We describe two previously unreported abnormalities in this condition and delineate physical and psychomotor features and concerns for medical management. Trisomy 14 mosaicism should be suspected in individuals who have the features described herein, thus prompting cytogenetic evaluation of blood, and possibly other tissues for diagnosis.