Objectives Ex vivo lung perfusion (EVLP) is a promising modality for the evaluation and treatment of marginal donor lungs. The optimal timing of EVLP initiation and potential for rehabilitation of donor lungs with extended warm-ischemic times is unknown. This study compares the efficacy of different treatment strategies for uncontrolled non-heart-beating donor lungs. Methods Mature swine underwent hypoxic arrest followed by 60 minutes of no-touch warm-ischemia. Lungs were harvested and flushed with 4°C Perfadex®. Three groups (n=5/group) were stratified according to preservation method: cold-static preservation (CSP: 4 hrs 4°C storage), immediate EVLP (I-EVLP: 4 hrs EVLP at 37°C), and delayed EVLP (D-EVLP: 4 hrs cold storage followed by 4 hrs EVLP). EVLP groups were perfused with Steen solution™ supplemented with heparin, methylprednisolone, cefazolin, and an adenosine 2A receptor agonist. Lungs then underwent allotransplantation and four hours of recipient reperfusion prior to allograft assessment for resultant ischemia-reperfusion injury. Results Donor blood oxygenation (PO2:FiO2) prior to euthanasia was not different between groups. Oxygenation after transplantation was significantly higher in the D-EVLP group compared to the I-EVLP or CSP groups. Mean airway pressure, pulmonary artery pressure, and expression of IL-8, IL-1β, and TNF-α were all significantly reduced in the D-EVLP group. Importantly, post-transplant oxygenation exceeded acceptable clinical levels only in D-EVLP lungs. Conclusions Uncontrolled non-heart-beating donor lungs with extended warm-ischemia can be reconditioned for successful transplantation. The combination of CSP and EVLP present in the D-EVLP group was necessary to obtain optimal post-transplant function. This finding, if confirmed clinically, will allow expanded use of non-heart-beating donor lungs.

Adenosine A2A receptor activation with ATL-313 results in the greatest protection against lung ischemia-reperfusion injury when given before ischemia and during reperfusion. Improved pulmonary function observed with adenosine A2A receptor activation was correlated with decreased bronchoalveolar lavage tumor necrosis factor alpha and decreased lung myeloperoxidase. The loss of protection observed with the concurrent administration of the adenosine A2A receptor antagonist, ZM 241385, supports that the mechanism of ATL-313 protection is specifically mediated via adenosine A2A receptor activation.

Purpose Current healthcare reform efforts have highlighted the potential impact of insurance status on patient outcomes. The influence of primary payer status (PPS) within the pediatric surgical patient population remains unknown. The purpose of this study was to examine risk-adjusted associations between PPS and postoperative morbidity, mortality, and resource utilization in pediatric surgical patients within the United States. Methods A weighted total of 153,333 pediatric surgical patients were evaluated using the national Kids’ Inpatient Database (2003 and 2006): appendectomy, intussusception, decortication, pyloroplasty, congenital diaphragmatic hernia repair, and colonic resection for Hirschsprung’s disease. Patients were stratified according to PPS: Medicare (n=180), Medicaid (n=51, 862), uninsured (n=12,539), and private insurance (n=88,753). Multivariable hierarchical regression modeling was utilized to evaluate risk-adjusted associations between PPS and outcomes. Results Overall median patient age was 12 years, operations were primarily non-elective (92.4%), and appendectomies accounted for the highest proportion of cases (81.3%). After adjustment for patient, hospital, and operation-related factors, PPS was independently associated with in-hospital death (p<0.0001) and postoperative complications (p<0.02), with increased risk for Medicaid and uninsured populations. Moreover, Medicaid PPS was also associated with greater adjusted lengths of stay and total hospital charges (p<0.001). Importantly, these results were dependent on operation type. Conclusions Primary payer status is associated with risk-adjusted postoperative mortality, morbidity, and resource utilization among pediatric surgical patients. Uninsured patients are at increased risk for postoperative mortality while Medicaid patients accrue greater morbidity, hospital lengths of stay, and total charges. These results highlight a complex interaction between socioeconomic and patient-related factors, and primary payer status should be considered in the preoperative risk stratification of pediatric patients.

Objectives Orthotopic heart transplantation is the standard of care for end-stage heart disease. Left ventricular assist device implantation offers an alternative treatment approach. Left ventricular assist device practice has changed dramatically since the 2008 Food and Drug Administration approval of the HeartMate II (Thoratec, Pleasanton, Calif), but at what societal cost? The present study examined the cost and efficacy of both treatments over time. Methods All patients who underwent either orthotopic heart transplantation (n = 9369) or placement of an implantable left ventricular assist device (n = 6414) from 2005 to 2009 in the Nationwide Inpatient Sample were selected. The trends in treatment use, mortality, and cost were analyzed. Results The incidence of orthotopic heart transplantation increased marginally within a 5-year period. In contrast, the annual left ventricular assist device implantation rates nearly tripled. In-hospital mortality from left ventricular assist device implantation decreased precipitously, from 42% to 17%. In-hospital mortality for orthotopic heart transplantation remained relatively stable (range, 3.8%–6.5%). The mean cost per patient increased for both orthotopic heart transplantation and left ventricular assist device placement (40% and 17%, respectively). With the observed increase in both device usage and cost per patient, the cumulative Left ventricular assist device cost increased 232% within 5 years (from $143 million to $479 million). By 2009, Medicare and Medicaid were the primary payers for nearly one half of all patients (orthotopic heart transplantation, 45%; left ventricular assist device, 51%). Conclusions Since Food and Drug Administration approval of the HeartMate II, mortality after left ventricular assist device implantation has decreased rapidly, yet has remained greater than that after orthotopic heart transplantation. The left ventricular assist device costs have continued to increase and have been significantly greater than those for orthotopic heart transplantation. Because of the evolving healthcare economics climate, with increasing emphasis on the costs and comparative effectiveness, a concerted effort at LVAD cost containment and judicious usage is essential to preserve the viability of this invaluable treatment.

Ischemia-reperfusion (I/R) injury leads to increased mortality and morbidity in lung transplant patients. Lung I/R injury involves inflammation contributed by innate immune responses. IL-17 and TNF-α, from iNKT cells and alveolar macrophages, respectively, contribute importantly to lung I/R injury. This study tests the hypothesis that IL-17 and TNF-α synergistically mediate CXCL1 (a potent neutrophil chemokine) production by alveolar type II epithelial (ATII) cells via an NADPH oxidase-dependent mechanism during lung I/R. Using a hilar clamp model, wild-type and p47(phox-/-) (NADPH oxidase-deficient) mice underwent left lung I/R, with or without recombinant IL-17 and/or TNF-α treatment. Wild-type mice undergoing I/R treated with combined IL-17 and TNF-α had significantly enhanced lung dysfunction, edema, CXCL1 production, and neutrophil infiltration compared with treatment with IL-17 or TNF-α alone. However, p47(phox-/-) mice had significantly less pulmonary dysfunction, CXCL1 production, and lung injury after I/R that was not enhanced by combined IL-17-TNF-α treatment. Moreover, in an acute in vitro hypoxia-reoxygenation model, murine ATII cells showed a multifold synergistic increase in CXCL1 expression after combined IL-17-TNF-α treatment compared with treatment with either cytokine alone, which was significantly attenuated by an NADPH oxidase inhibitor. Conditioned media transfer from hypoxia-reoxygenation-exposed iNKT cells and macrophages, major sources of IL-17 and TNF-α, respectively, to ATII cells significantly enhanced CXCL1 production, which was blocked by NADPH oxidase inhibitor. These results demonstrate that IL-17 and TNF-α synergistically mediate CXCL1 production by ATII cells after I/R, via an NADPH oxidase-dependent mechanism, to induce neutrophil infiltration and lung I/R injury.