Impact of the duration of antibiotic therapy on relapse and survival following surgery for active infective endocarditis.

OBJECTIVES: Surgery is often required for acute infective endocarditis (IE) to repair or replace damaged heart valves. Traditionally, long courses of antibiotic treatment have been prescribed after surgery for active IE for fear of infecting newly implanted/repaired valves, but the need for this, in the present era of enhanced antimicrobial stewardship, has been questioned. In our institution, the choice and duration of antimicrobial therapy is tailored to individual patients by a multidisciplinary team with an interest in IE. The influence of the duration of postoperative antibiotic therapy on outcomes was studied in patients requiring surgery prior to the completion of a planned course of antibiotic therapy. METHODS: This was a retrospective observational study on patients with acute IE requiring surgery between January 2004 and December 2015. The primary outcome was relapse. Secondary outcomes were early reoperation and 1-year mortality. RESULTS: In total, 182 IE episodes were included in the final analysis. The median duration of postoperative antibiotic therapy was 23.5 days (interquartile range 12-40 days) and decreased significantly during the period of study (P < 0.001). There were 2 relapses (1.1%) and 18 (9.9%) postoperative deaths within 1 year. Nine (5%) patients underwent early reoperation. The duration of postoperative antibiotic therapy did not affect either the primary or the secondary outcomes. CONCLUSIONS: This work supports previous findings that selected patients who require surgery during active IE can be safely given shorter courses of postoperative antibiotics without an impact on relapse of infection or survival.

Age and neo-adjuvant chemotherapy increase the risk of atrial fibrillation following oesophagectomy.

OBJECTIVES: Atrial tachyarrhythmias occur in up to 25% of patients after major thoracic surgery. We examined risk factors for new-onset atrial fibrillation (AF) following oesophagectomy in an attempt to guide prophylactic use of anti-arrhythmic strategies. METHODS: Data were extracted from a database of patients who underwent oesophagectomy between 1991 and 2009. Patients with pre-operative arrhythmias were excluded leaving 997 patients for further analysis. Univariate and multivariate logistic regression analyses were performed to identify factors predicting AF, and receiver operating characteristic curves were generated from a model using these predictors. Statistical significance was reflected in a P-value of <0.05. RESULTS: Patients who developed AF (n = 209; 20.96%) were older (median age 70.54 years vs. 66.9 years; P < 0.01) and included 141 males (67.4%) (P = 0.11). Patients with AF were noted to have a higher in-hospital mortality rate (n = 17; 8.1% vs. n = 34; 4.8%) (P = 0.04) and a longer stay in hospital (14 days vs. 12 days; P < 0.01). Multivariate analysis identified advanced age and neo-adjuvant chemotherapy to be independent predictors of the risk of developing AF. Assessment of discriminative ability of a predictive model revealed a c-statistic of just 0.62. CONCLUSIONS: Despite the identification of age and neo-adjuvant chemotherapy as predictors of AF, the moderate discriminative ability of predictive modelling does not support the use of prophylactic anti-arrhythmic drugs. However, the high incidence of AF after major thoracic surgery makes it necessary to understand its underlying mechanisms better before prophylactic strategies are considered.

Patient satisfaction following minimally invasive repair of pectus excavatum: single surgeon experience.

BACKGROUND: Pectus excavatum (PE) is the most common chest wall deformity in adolescent life. Nuss procedure is a well-established technique for the repair of PE. The indication for correction is mainly medical aesthetic. Advantages of Nuss over conventional methods include reduced length of hospital stay, smaller incisions, and absence of need for osteochondrectomies. Here, we describe our experience with this procedure. MATERIALS AND METHODS: This was a retrospective study of patients who underwent Nuss procedure by a single surgeon between 2006 and 2010 in a regional center. Indications for surgery included the following: Progressive deformity and psychological stress. All patients underwent chest X-ray and pulmonary function testing. A standard Nuss procedure was performed using a single bar. Patients' satisfaction was assessed by a questionnaire and follow-up clinic letters. Satisfaction with body image was scored on a scale of 1-10. RESULTS: Eleven patients with PE underwent correction by Nuss procedure. Mean age of the patient was 19 years (range: 15-30). The average hospital stay was 7 days (range: 4-23 days). There was no mortality and no episodes of wound infection. In the immediate post-operative period, three patients (12.5%) were noted to have poor pain control. The post-operative course was uneventful in all cases except one patient who developed lung collapse, pleural effusion, and bar dislocation. Hundred percent of patients were satisfied with the scar. Seven patients scored 7 out of 10 on satisfaction with body image and two patients scored 6 or less. None of the patients complained of chronic pain. CONCLUSION: Nuss procedure is an effective method for the correction of PE. Most patients were satisfied with the outcome and none experienced chronic pain.

Salvage use of activated recombinant factor VII in the management of refractory bleeding following cardiac surgery.

BACKGROUND: Refractory post cardiopulmonary bypass (CPB) bleeding continues to cause concern for cardiac surgeons and intensivists. Massive postoperative hemorrhage following CPB is multifactorial and not fully understood, and it is also associated with increased mortality and morbidity. Activated recombinant factor VII (rFVIIa) has emerged as possible salvage medication in refractory post cardiac surgical bleeding. This observational study sought to identify the pattern of use of rFVIIa in cardiac surgery, its effectiveness, and risk. METHODS: This study involved a retrospective case review of medical records of ten patients undergoing a variety of cardiac surgery procedures and who developed life-threatening bleeding during surgery or after surgery despite conventional medical therapy, including transfusion of blood and blood products, and received rFVIIa at a regional center between August 2007 and April 2009. RESULTS: All ten patients received two consecutive doses of rFVIIa (average dose 65 µg/kg) at a 2-hour interval. Eight patients were re-explored due to massive postoperative bleeding or cardiac tamponade before receiving rFVIIa. Surgical sources of bleeding were not identified in any cases. A second re-exploration was carried out in two cases. Two patients (20%) died in ITU from problems not related to bleeding and thromboembolism. Blood loss was significantly reduced after administration of rFVIIa. Blood loss 6 hours prior to treatment was 1758.5 ± 163.9 mL and blood loss in the 6-hour period post treatment was 405.6 ± 50.5 mL (P < 0.05). Blood and blood products used in the 6-hour period before and after administration of rFVIIa were 19.6 ± 1.5U and 4.4 ± 0.6U, respectively (P < 0.05). No adverse reactions or thrombotic complications related to rFVIIa were noted. CONCLUSION: In our limited study, use of rFVIIa in refractory post surgical bleeding was significantly reduced blood loss and use of blood and blood products. We concluded that rFVIIa can be used satisfactorily and safely as a rescue therapy in the management of post cardiac surgical bleeding.

Proteomic identification of non-Gal antibody targets after pig-to-primate cardiac xenotransplantation.

BACKGROUND: Experience with non-antigenic galactose alpha1,3 galactose (alphaGal) polymers and development of alphaGal deficient pigs has reduced or eliminated the significance of this antigen in xenograft rejection. Despite these advances, delayed xenograft rejection (DXR) continues to occur most likely due to antibody responses to non-Gal endothelial cell (EC) antigens. METHODS: To gauge the diversity of the non-Gal antibody response we used antibody derived from CD46 transgenic heterotopic cardiac xenografts performed without T-cell immunosuppression, Group A (n = 4) and Gal knockout (GT-KO) heart transplants under tacrolimus and sirolimus immunosuppression, Group B (n = 8). Non-Gal antibody was measured by flow cytometry and by western blots using GT-KO EC membrane antigens. A nanoLC/MS/MS analysis of proteins recovered from 2D gels was used to identify target antigens. RESULTS: Group A recipients exhibited a mixed cellular and humoral rejection. Group B recipients mainly exhibited classical DXR. Western blot analysis showed a non-Gal antibody response induced by GT+ and GT-KO hearts to an overlapping set of pig aortic EC membrane antigens. Proteomic analysis identified 14 potential target antigens but failed to define several immunodominant targets. CONCLUSIONS: These experiments indicate that the non-Gal antibody response is directed to a number of stress response and inflammation related pig EC antigens and a few undefined targets. Further analysis of these antibody specificities using alternative methods is required to more fully define the repertoire of non-Gal antibody responses.

Efficient and durable gene transfer to transplanted heart using adeno-associated virus 9 vector.

BACKGROUND: In this investigation we studied the efficacy and durability of recombinant adeno-associated virus serotype 9 (rAAV9) vector-mediated gene transfer to the transplanted rat heart. METHODS: A rAAV9-CMV-lacZ vector diluted in cold (4 degrees C) University of Wisconsin solution was used to perfuse the rat coronary vasculature for 20 minutes prior to syngeneic heterotopic transplantation. Perfusion experiments (six groups, n = 3/group) were performed without rAAV9 and at four separate doses ranging from 2 x 10(9) to 2 x 10(12) viral genomes/ml. The transplanted heart was recovered 10 days or 3 months after transplantation and expression of lacZ assessed by histology, enzyme-linked immunoassay and real-time reverse transcript-polymerase chain reaction (RT-PCR). In a final group (n = 3), rAAV9 was administered systemically to compare the cardiac transduction efficiency and viral distribution to other organs. RESULTS: Transduction efficiency of perfused virus correlated with vector dose (p < 0.0001), with myocardial transduction ranging up to 71.74% at the highest dose. Cardiac expression of lacZ was equivalent at 10 days and 3 months. There was no evidence of viral gene transfer to other organs after heart transplantation. CONCLUSIONS: Our findings demonstrate efficient and durable rAAV9-mediated gene transfer to the transplanted heart after ex vivo perfusion and suggest that AAV9 is a promising vector for cardiac gene therapy.

Non-invasive radioiodine imaging for accurate quantitation of NIS reporter gene expression in transplanted hearts.

OBJECTIVE: We studied the concordance of transgene expression in the transplanted heart using bicistronic adenoviral vector coding for a transgene of interest (human carcinoembryonic antigen: hCEA - beta human chorionic gonadotropin: betahCG) and for a marker imaging transgene (human sodium iodide symporter: hNIS). METHODS: Inbred Lewis rats were used for syngeneic heterotopic cardiac transplantation. Donor rat hearts were perfused ex vivo for 30 min prior to transplantation with University of Wisconsin (UW) solution (n=3), with 10(9) pfu/ml of adenovirus expressing hNIS (Ad-NIS; n=6), hNIS-hCEA (Ad-NIS-CEA; n=6) and hNIS-betahCG (Ad-NIS-CG; n=6). On postoperative day (POD) 5, 10, 15 all animals underwent micro-single photon emission computed tomography/computed tomography (SPECT/CT) imaging of the donor hearts after tail vein injection of 1000 microCi (123)I and blood sample collection for hCEA and betahCG quantification. RESULTS: Significantly higher image intensity was noted in the hearts perfused with Ad-NIS (1.1+/-0.2; 0.9+/-0.07), Ad-NIS-CEA (1.2+/-0.3; 0.9+/-0.1) and Ad-NIS-CG (1.1+/-0.1; 0.9+/-0.1) compared to UW group (0.44+/-0.03; 0.47+/-0.06) on POD 5 and 10 (p<0.05). Serum levels of hCEA and betahCG increased in animals showing high cardiac (123)I uptake, but not in those with lower uptake. Above this threshold, image intensities correlated well with serum levels of hCEA and betahCG (R(2)=0.99 and R(2)=0.96, respectively). CONCLUSIONS: These data demonstrate that hNIS is an excellent reporter gene for the transplanted heart. The expression level of hNIS can be accurately and non-invasively monitored by serial radioisotopic SPECT imaging. High concordance has been demonstrated between imaging and soluble marker peptides at the maximum transgene expression on POD 5.

Recombinant adenoviral gene transfer does not affect cardiac allograft vasculopathy.

BACKGROUND: Adenovirus serotype 5 has remained the pre-eminent vector in pre-clinical gene therapy applications in cardiac transplantation. Concerns over the potential effects of adenoviral vectors on the later development of cardiac allograft vasculopathy (CAV) are addressed in this study. METHODS: Hearts (n = 22) harvested from Brown Norway rats were perfused ex vivo with either University of Wisconsin (UW) solution with no virus, Ad-CMV-LacZ or Ad-CMV-Null. Donor hearts were transplanted heterotopically into the abdomen of Lewis rats. All recipients received cyclosporine for the duration of the experiment. Transplanted hearts were recovered for analysis at 120 days. Sections of the heart were stained with elastic-van Gieson stain for morphometric analysis of the vessels to ascertain the degree of vascular luminal occlusion. Hematoxylin-eosin staining facilitated diagnosis of chronic rejection. RESULTS: Seventy-seven percent of transplanted hearts showed signs of chronic rejection with no difference in the proportion of animals between groups (p = 0.797). No difference was noted in the degree of vascular luminal occlusion between the Ad-Null (0.57 +/- 0.22), Ad-LacZ (0.62 +/- 0.19) and UW (0.47 +/- 0.29) groups (p = 0.653). CONCLUSIONS: Vascularized cardiac allografts transplanted from Brown Norway to Lewis rats demonstrated cardiac allograft vasculopathy CAV at 120 days. Adenoviral perfusion of the donor heart ex vivo did not affect the development of CAV.

The utility of right ventricular endomyocardial biopsy for the diagnosis of xenograft rejection after CD46 pig-to-baboon cardiac transplantation.

INTRODUCTION: Endomyocardial biopsy is the standard means of establishing cardiac allograft rejection diagnosis. The efficacy of this procedure in xenotransplantation has not been determined. In this study we compare the histology of right ventricular endomyocardial biopsy specimens with the corresponding full cross sections of explanted right ventricle (RV). We also compare RV with the related left ventricle (LV) cross sections. METHODS: Heterotopic CD46 pig-to-baboon cardiac xenotransplants (n = 64) were studied. RV endomyocardial biopsy specimens were taken at cardiac explant by using a standard bioptome (n = 24) or by sharp dissection (n = 40). Hematoxylin and eosin stained sections of RV and LV cross-section and RV endomyocardial biopsy specimens were compared in a blinded fashion. Characteristics of delayed xenograft rejection and a global assessment of ischemia were scored from 0 to 4 according to the percentage of myocardium involved (0, 0%; 1, 1%-25%; 2, 26%-50%; 3, 51%-75%; and 4, 76%-100%). RESULTS: Median graft survival was 30 days (range, 3-137 days). Linear regression analysis of histology scores demonstrated that specimens from both bioptome and sharp dissection equally represented the histology of the RV cross section. Global ischemic injury was strongly correlated between RV and RV endomyocardial biopsy (R(2) = 0.84) and between RV and LV cross sections (R(2) = 0.84). Individual characteristics of delayed xenograft rejection showed no significant variation between RV and RV endomyocardial biopsy or between RV and LV (p < 0.05). CONCLUSIONS: These results indicate that delayed xenograft rejection is a widespread process involving both right and left ventricles similarly. This study shows that histologic assessment of RV endomyocardial biopsy specimens is an effective method for the monitoring of delayed xenograft rejection after cardiac xenotransplantation.