Illness Severity of Children Admitted to the PICU From Referring Emergency Departments.

OBJECTIVES: To compare patient factors and outcomes among children admitted to PICUs from referring versus children's hospital emergency departments (EDs). METHODS: Pediatric patients (<19 years old) admitted to PICUs from referring and children's hospital EDs from July 1, 2011 to June 30, 2013. We compared demographic and clinical factors, including severity of illness as measured by a recalibrated Pediatric Index of Mortality, version 2 score. RESULTS: Of 80 045 children from 109 PICUs, 35.6% were admitted from referring EDs and 64.4% were admitted from children's hospital EDs. Children from referring EDs had higher illness severity (Pediatric Index of Mortality, version 2-predicted risk of mortality, 3.1% vs 2.2%, P < .001), were more likely to be mechanically ventilated within their first hour in the PICU (28.4% vs 23.4%, P < .001), and had higher observed mortality (3.3% vs 2.1%, P < .001). Once adjusted for illness severity and other confounders in a multivariable logistic regression model, there was no difference in the odds of mortality between children from referring and children's hospital EDs (odds ratio: 0.90; 95% confidence interval: 0.79 to 1.02, P = .09) CONCLUSIONS: Children transferred to PICUs from referring EDs had higher illness severity on arrival compared with children admitted from children's hospital EDs. Variations in patient selection for transfer or pretransfer treatment at referring EDs may contribute to the greater illness severity of transferred children. Referring hospitals may benefit from leveraging existing resources to improve patient stabilization before transfer.

Association between Down syndrome and in-hospital death among children undergoing surgery for congenital heart disease: a US population-based study.

BACKGROUND: The prevalence of Down syndrome (DS)-affected births has increased during the past 30 years; moreover, children with DS have a higher incidence of congenital heart disease compared with their peers. Whether children with DS have better or worse outcomes after repair of congenital heart disease is unclear. We sought to identify differences in in-hospital mortality after cardiac surgery in pediatric patients with and without DS using a large national database. METHODS AND RESULTS: Children aged <18 years who underwent surgical intervention for congenital heart disease were identified using the Kids' Inpatient Database (2000, 2003, 2006, and 2009). Patients were stratified using the Risk Adjustment for Congenital Heart Surgery algorithm. A total of 4231 (8.2%) of the 51 309 patients studied had a diagnosis of DS. In-hospital death for patients with DS was significantly lower than that for patients without DS overall (1.9% versus 4.3%; P<0.05) as well as within risk categories 2 (1.0% versus 1.8%; P<0.05) and 3 (2.3% versus 5.1%; P<0.05). Multivariable logistic regression showed a lower odds of death among children with DS (odds ratio=0.60; 95% confidence interval, 0.47-0.76; P<0.05) after adjusting for Risk Adjustment for Congenital Heart Surgery risk category, premature birth, major noncardiac structural anomaly, and age. CONCLUSIONS: In this large national study, children with DS who underwent repair of congenital heart disease were more likely to survive to discharge than children without DS. Future work is needed to better understand the factors underlying these differences.

Gene transfer of heme oxygenase-1 using an adeno-associated virus serotype 6 vector prolongs cardiac allograft survival.

Introduction. Allograft survival can be prolonged by overexpression of cytoprotective genes such as heme oxygenase-1 (HO-1). Modifications in vector design and delivery have provided new opportunities to safely and effectively administer HO-1 into the heart prior to transplantation to improve long-term graft outcome. Methods. HO-1 was delivered to the donor heart using an adeno-associated virus vector (AAV) with a pseudotype 6 capsid and vascular endothelial growth factor (VEGF) to enhance myocardial tropism and microvascular permeability. Survival of mouse cardiac allografts, fully or partially mismatched at the MHC, was determined with and without cyclosporine A. Intragraft cytokine gene expression was examined by PCR. Results. The use of AAV6 to deliver HO-1 to the donor heart, combined with immunosuppression, prolonged allograft survival by 55.3% when donor and recipient were completely mismatched at the MHC and by 94.6% if partially mismatched. The combination of gene therapy and immunosuppression was more beneficial than treatment with either AAV6-HO-1 or CsA alone. IL-17a, b, e and f were induced in the heart at rejection. Conclusions. Pretreatment of cardiac allografts with AAV6-HO-1 plus cyclosporine A prolonged graft survival. HO-1 gene therapy represents a beneficial adjunct to immunosuppressive therapy in cardiac transplantation.

Intragraft gene expression profile associated with the induction of tolerance.

BACKGROUND: Xenotransplantation holds the promise of providing an unlimited supply of donor organs for terminal patients with organ failure. Pre-existing natural antibodies to the Galalpha1,3Galbeta1,4GlcNac-R (alphaGal) carbohydrate xenoantigen, however, bind rapidly to the graft endothelium and initiate hyperacute rejection of wild type pig grafts in humans. Experimental procedures designed to prevent xenoantibody-mediated rejection have been tested in gal knockout mice. These mice produce anti-gal xenoantibodies and are widely used as small animal models for xenotransplantation research. In this model, chimerism for cells expressing the gal carbohydrate can be achieved by transplantation of mixed cells or by transduction of bone marrow cells with viral vectors expressing a functional alpha1,3 galactosyltransferase gene. Chimerism induces tolerance to heart grafts expressing alphaGal. The mechanisms by which tolerance is achieved include systemic changes such as clonal deletion and/or anergy. Intragraft changes that occur during the early stages of tolerance induction have not been characterized. RESULTS: Cytoprotective genes heme oxygenase-1 (HO-1), Bcl2, and A20 that have been reported to contribute to long-term graft survival in various models of accommodation were not expressed at high levels in tolerant heart grafts. Intragraft gene expression at both early (Day 10) and late (>2 month) time points after heart transplant were examined by real-time PCR and microarray analysis was used to identify changes associated with the induction of tolerance. Intragraft gene expression profiling using microarray analysis demonstrated that genes identified in the functional categories of stress and immunity and signal transduction were significantly up-regulated in early tolerant grafts compared with syngeneic control grafts. Biological process classification showed lower binomial p-values in the categories of "response to biotic stimulus, defense response, and immune response" suggesting that up-regulated genes identified in these grafts promote survival in the presence of an immune response. The expression of the incompatible carbohydrate antigen (alphaGal) was reduced by 2 months post-transplant when compared with the expression of this gene at Day 10 post-transplant. These results suggest that the gal carbohydrate antigen is downmodulated over time in grafts that demonstrate tolerance. CONCLUSION: Our study suggests that tolerance is associated with intragraft gene expression changes that render the heart resistant to immune-mediated rejection. Genes associated with stress and immunity are up-regulated, however cytoprotective genes HO-1, Bcl2 and A20 were not up-regulated. The expression of the gal carbohydrate, the key target initiating an immune response in this model, is down-regulated in the post-transplant period.