Tuberculous Empyema Post Bilateral Lung Transplant.

Tuberculous empyema in lung transplantation recipients is a rare entity, with only a handful of cases reported in the English-language literature. We are reporting a case of tuberculous empyema 3 months after uncomplicated bilateral lung transplantation. The recipient underwent video-assisted thoracic surgery for diagnosis and decortication. Both the recipient and donor lacked a history of tuberculosis or tuberculosis exposure.

Effect of confounding factors on a phospho-flow assay of ribosomal S6 protein for therapeutic drug monitoring of the mTOR-inhibitor everolimus in heart transplanted patients.

CONTEXT: Several assays of monitoring immune cell function have been developed to enhance therapeutic drug monitoring. OBJECTIVE: An in vitro-validated whole-blood assay of phosphorylated ribosomal protein S6 (pS6RP) was evaluated for confounders to monitor the mTOR-inhibitor everolimus (ERL). MATERIALS AND METHODS: Whole blood samples from 87 heart transplant recipients were analyzed for pS6RP-expression in CD3-positive T-cells by phospho-flow analysis. RESULTS: ERL blood concentration, laboratory parameters, co-medications, demographic and clinical data were reviewed. CONCLUSION: Evaluating the pS6RP-assay revealed that pS6RP is influenced by cyclosporine A (CsA) blood concentration, duration of ERL treatment, co-medication with thiazide diuretics and different metabolic parameters.

Assessment of Immunological Biomarkers in the First Year after Heart Transplantation.

BACKGROUND: Pharmacodynamic biomarkers that detect changes of immunological functions have been recognized as a helpful tool to increase the efficacy of immunosuppressive drug therapies. However, physiological changes of immunological biomarkers following transplantation are not investigated. Therefore, we assessed frequently used immunological biomarkers of the circulating blood in the first year following heart transplantation (HTx). METHODS: Activation markers CD25 and CD95, intracellular cytokines IL-2 and IFNγ, chemokines IP10 and MIG, and subsets of dendritic cells as well as antibodies against human leukocyte antigens (HLA) and major histocompatibility complex class I-related chain A (MICA) antigens were analyzed at different time points using flow cytometry and Luminex xMAP technology. RESULTS: Expression of IL-2, IFNγ, and plasmacytoid dendritic cells (pDCs) significantly increased (p < 0.01) during the first year. Anti-HLA antibodies decreased continuously, while anti-MICA antibodies showed minor increase within the first year. An association between percentage of pDCs and anti-MICA antibody positivity was proven. pDCs, IFNγ-producing T cells, and IP10 concentration were associated in a stronger way with age and gender of HTx recipients than with antibodies against HLA or MICA. CONCLUSIONS: We conclude that certain immunological biomarkers of the circulating blood change during the first year after HTx. These changes should be considered for interpretation of biomarkers after transplantation.

Flow cytometric evaluation of T cell activation markers after cardiopulmonary bypass.

Background. Cardiopulmonary bypass surgery (CPBS) is associated with an increased risk for infections or with subsequent organ dysfunction. As T cell activation is a central mechanism during inflammatory processes, we developed an assay to evaluate T cell activation pathways in patients undergoing CPBS. Methods. Blood was obtained from eleven patients undergoing CPBS preoperatively, on postoperative day (POD)-3, and on POD-7 and was stimulated with different concentrations of Concanavalin A (ConA). Cyclosporine and sirolimus, inhibiting different pathways of the T cell cycle, were added to blood ex vivo. Expression of T cell activation markers CD25 and CD95 was analyzed by flow cytometry. Results. In untreated blood, expression of CD25 and CD95 significantly increased with higher ConA concentrations (P < 0.05) and decreased for all ConA concentrations for both antigens over the study time (P < 0.05). Independently from the ConA concentration, inhibition of CD25 and CD95 expression was highest preoperatively for sirolimus and on POD-3 for cyclosporine. At all time points, inhibition of CD25 and CD95 expression was significantly higher after cyclosporine compared to sirolimus treatment (P < 0.001). Conclusion. Our results showed that different pathways of T cell activation are impaired after CPBS. Such knowledge may offer the opportunity to identify patients at risk for postoperative complications.

Bilateral versus single lung transplant for idiopathic pulmonary fibrosis.

OBJECTIVES: It is unknown if uni- or bilateral lung transplant is best for treatment of usual idiopathic pulmonary fibrosis. We reviewed our single-center experience comparing both treatments. MATERIALS AND METHODS: Between 2002 and 2011, one hundred thirty-eight patients at our institution underwent a lung transplant. Of these, 58 patients presented with idiopathic pulmonary fibrosis (56.9%) and were the focus of this study. RESULTS: Thirty-nine patients received a single lung transplant and 19 patients a bilateral sequential lung transplant. The mean patient age was 54 ± 10 years, and 69% were male. The intraoperative course was uneventful, save for 7 patients who needed extracorporeal membrane oxygenation support. Three patients had respiratory failure before the lung transplant that required mechanical ventilation and was supported by extracorporeal membrane oxygenation. Elevated pulmonary artery pressure > 40 mm Hg was identified as an independent predictor of early mortality by uni- and multivariate analysis (P = .01; OR 9.7). Using a Cox regression analysis, postoperative extracorporeal membrane oxyge-nation therapy (P = .01; OR 10.2) and the need for > 10 red blood cell concentrate during the first 72 hours after lung transplant (P = .01; OR 5.6) were independent predictors of long-term survival. Actuarial survival at 1 and 5 years was 65.6% and 55.3%, with no significant between-group differences (70.6% and 54.3%). CONCLUSIONS: Lung transplant is a safe and curative treatment for idiopathic pulmonary fibrosis. According to our results, unilateral lung transplant for idiopathic pulmonary fibrosis is an alternative to bilateral lung transplant and may affect the allocation process.

A rare case of sinus of valsalva-right atrial fistula secondary to an abscess perforation from underlying aortic valve endocarditis.

Sinus of Valsalva-right atrial fistulas are abnormal connections between the aorta and the right atrium, and present challenging surgical conditions. An extremely rare etiology of aorto-right atrial fistula is infective endocarditis. This case report presents a 21 year old Caucasian female patient who had native aortic valve Staphylococcus aureus endocarditis complicated by sinus of Valsalva abscess perforation associated with an acute heart block, an aorto-right atrial fistula, severe heart failure, and cardiogenic shock. She underwent emergent aortic valve replacement and complex sinus of Valsalva fistula pericardial patch reconstruction and repair. This case report further explores the advantages and disadvantages of different valves for different patient populations, and evaluates the patient's prosthesis mismatch and effective orifice area.

Extracorporeal membrane oxygenation: experience in acute graft failure after heart transplantation.

INTRODUCTION: Acute graft failure is the leading cause of early mortality after heart transplantation (HTx). Extracorporeal membrane oxygenation (ECMO) is an efficient therapeutic option to treat various pathologies, unburden the left and right ventricle, and allow for functional recovery of the transplanted heart. We reviewed our ECMO experience and outcomes in HTx patients. METHODS: Retrospectively, we analyzed all patients who received an orthotopic HTx (n = 298) in our department over a 15-yr period (1997 through 2011) to assess the incidence of post-HTx ECMO implantation, perioperative complications, early and one-yr mortality as well as causes of death. RESULTS: ECMO therapy was utilized to treat graft failure in 28 patients (10.6%) with a mean duration of ECMO support of 4.2 d (six h to 9.4 d). Multivariate analysis revealed as independent predictors for mortality low cardiac output (p = 0.028; odds ratio (OR) = 11.3) and stroke (p = 0.008; OR = 19.7). Cumulative survival rates were 46.4 ± 9.4% within 30 d and 25.0 ± 8.2% at one yr. Causes of death were multiorgan failure (n = 9), sepsis (n = 9), lung failure (n = 2), and intracerebral bleeding (n = 2). ECMO was implanted due to primary graft failure (PGF, n = 16), sepsis (n = 4), and right heart failure (n = 6). CONCLUSION: Temporary ECMO support for postoperative output failure is an acceptable option as a last resort for otherwise doomed patients with fatal graft failure after HTx. The small fraction of patients surviving appear to have a decent long-term prognosis.

Role of dendritic cells in the context of acute cellular rejection: comparison between tacrolimus- or cyclosporine A-treated heart transplanted recipients.

BACKGROUND: In the last years many studies have been designed to predict risk of acute rejection and to adapt the immunosuppressive therapy. The importance of dendritic cells (DCs) in the immune response, especially their role in tolerance is known. Thus, we investigated the influence of tacrolimus (TAC)-based and of cyclosporine A (CsA)-based immunosuppressive therapies on dendritic cells and the incidence of rejection in heart transplant recipients. METHODS: Groups consisted of 14 CsA treated and 15 TAC treated patients. At different study time points (0, 3 and 6 months after study begin) peripheral blood from the patients was drawn to analyse (1) blood concentration of CsA or TAC (trough value) and (2) percentages of plasmacytoid and myeloid DC (p and mDC) subsets using flow cytometry. Histological rejection grading was performed of endomyocardial biopsies. RESULTS: TAC treated patients had significantly higher values of pDCs (CsA group 53.9%±13.0%; TAC group 67.5%±8.4%; p<0.05) and significantly lower values of mDCs than CsA treated patients (CsA group 58%±19.0%; TAC group 45.2%±10.7%; p<0.05). In general, HTx patients with rejection grade of ≥2 had significant lower values of pDCs (55.1%±16.2%) compared to patients without rejection (63.6%±10.5%; p<0.05). TAC-treated patients had significantly less rejections CsA-treated patients (CsA group 0.86±0.95; TAC group 0.2±0.4; p<0.05). CONCLUSIONS: Our results showed that HTx patients with high pDCs had a lower risk for rejection and that TAC-treated patients had higher pDCs values compared to CsA-treated patients. Future studies need to define individual pDC values to predict acute cellular rejection.

Heart transplantation and left ventricular assist device therapy: two comparable options in end-stage heart failure?

Heart transplantation is the only curative therapy for chronic heart failure, and it plays an important role in the treatment of chronic heart failure with a survival rate of approximately 50% of all patients after 10 years. This has to be kept in mind when alternative therapies enter into our daily routine in treating this patient population. However, the shortage of appropriate donor organs and the expanding pool of patients waiting for heart transplantation have led to growing interest in alternative strategies, particularly in left ventricular assist device (LVAD) therapy. With growing clinical experience and continued technical advances, continuous-flow pumps are evolving as a bridge to transplantation or as a destination therapy for advanced heart failure. Nevertheless, the importance of this new indication of chronic cardiac support compared to heart transplantation is still completely open and the object of controversial ongoing discussion. This review (1) describes the clinical use and long-term outcome of a currently available miniaturized LVAD in the context to the standard of care-heart transplantation, (2) provides an outlook of the ongoing process of further optimization of LVADs, and (3) comments on the challenges with assist devices as alternatives to transplantation with a 5-year outlook.

Fluoroscopy-guided resolution of ingested thrombus leading to functional disturbance of a continuous-flow left ventricular assist device.

The third generation of left ventricular assist devices (LVADs) has been shown to improve outcome and quality of life in patients suffering from acute and chronic heart failure. However, VAD-associated complications are still a challenge in the clinical practice. Here we report the resolution of a mobile thrombus formation in the proximity of the inflow cannula of a third generation of LVADs (HVAD Pump, HeartWare, Inc.) in a patient with chronic heart failure 4 months after implantation.

Outcome of extracorporeal membrane oxygenation as a bridge to lung transplantation and graft recovery.

BACKGROUND: Indications for extracorporeal membrane oxygenation (ECMO) use in lung transplantation are (1) temporary assistance as a bridge to transplantation, (2) stabilization of hemodynamics during transplantation in place of cardiopulmonary bypass, and (3) treatment of severe lung dysfunction and primary graft failure after transplantation. This study compares the survival of lung transplant recipients requiring ECMO support with survival of patients without ECMO. METHODS: A retrospective database review was performed for 108 consecutive patients who underwent single-lung or bilateral-lung transplantation at our center between 2002 and 2009. RESULTS: Of 108 transplant recipients, 27 (25%) required venoarterial ECMO compared with 81 patients who did not. Nine patients required ECMO preoperatively (87±102 hours), and ECMO was continued for 5 patients during the lung transplant operation. Seven additional patients received ECMO during transplantation. Six patients required early (<7 days) and 5 patients delayed (≥7 days) postoperative ECMO for treatment of allograft dysfunction. The subgroup with support showed the most favorable patient discharge rate (66.7%). ECMO support was a significant risk factor for death (p<0.001). Survival was significantly reduced with the use of ECMO: 30-day, 90-day, 1-year, and 5-year survival was 97%, 91%, 83%, and 58% in the patients without ECMO compared with 63%, 44%, 33%, and 21% in those with ECMO, respectively. CONCLUSIONS: Survival after lung transplantation was significantly reduced with ECMO. However, patients who survived the first year showed similar long-term survival as those patients who did not need perioperative ECMO support.

Donor type impact on ischemia-reperfusion injury after lung transplantation.

BACKGROUND: Extended criteria donors, non-heart-beating donors (NHBD), and living donation are options to overcome the organ shortage for lung transplantation (LTx). However little is known about the impact of the donor lung on ischemia-reperfusion injury (IRI), which often leads to high mortality rates. METHODS: Recipient pigs (N=32) were divided equally into 4 groups according to their donor status: (1) living donor=control group, (2) conventional heart-beating donor, (3) non-heart-beating donor according to Maastricht category I (NHBD-I), and (4) Maastricht category IV (NHBD-IV). After cold flush and 3 hours of hypothermic preservation, a single left LTx was performed. Thereafter only the transplanted left lung was ventilated and perfused to assess isolated left lung function at 1 and 2 hours after LTx compared with before LTx. RESULTS: No significant differences were seen between the 4 groups regarding wet-to-dry weight ratio, mean airway pressure, or compliance. Arterial oxygenation and alveolar-arterial difference showed significant differences between the groups (p<0.05). Two-way analysis of variance (ANOVA) for the factors brain death and cardiac arrest found significantly increased alveolar-arterial differences for the brain-death group but not for the beating-heart donor group. CONCLUSIONS: The use of lungs from brain-death donors and NHBDs has different effects on the occurrence of symptoms of IRI after LTx. Further observations and therapeutic strategies are necessary to minimize IRI when grafts from NHBDs are used.

Assay validation of phosphorylated S6 ribosomal protein for a pharmacodynamic monitoring of mTOR-inhibitors in peripheral human blood.

BACKGROUND: Therapeutic drug monitoring (TDM) of immunosuppressive drugs after organ transplantation is based on measuring blood levels alone, which often results in under- or over-immunosuppression. Previous studies have shown the potential of measuring pharmacodynamic drug effects for TDM, but assessment of biomarkers for individual drugs is still not clinical routine. Therefore, we validated a specific assay to measure the pharmacodynamic effects of mammalian target of rapamycin (mTOR)-inhibitors on phosphorylated S6 ribosomal protein (p-S6RP), a downstream target of mTOR. METHODS: Clinical relevant concentrations of sirolimus (SRL, 0.9-91.4 µg/L), cyclosporine A (CsA, 75.1-1202 µg/L), mycophenolate acid (MPA, 0.08-3.2 mg/L), or dexamethasone (DEX, 0.5-200 ng/mL) were added to whole-blood from healthy volunteers. Activated whole-blood was analyzed by phospho-flow cytometry to measure p-S6RP in T cells. RESULTS: Phospho-flow analysis revealed that SRL suppressed p-S6RP in human T cells in a dose-dependent manner with a half-maximal inhibitory concentration (IC(50)) at 19.8 nM and a maximal inhibitory effect (I(max) %) at 91.9%. Neither CsA, MPA, nor DEX inhibited mTOR-related S6RP-phosphorylation. Coefficient of variations from 0.03 to 0.05, 0.12 to 0.25, and 0.14 to 0.38 for intra-, interassay, and interindividual variability respectively, showed robustness of our assay. Furthermore, samples can be stored at RT or 4°C up to 2 h after withdrawal. CONCLUSION: We validated a robust whole-blood assay that allows the specific measurement of SRL- and everolimus-induced inhibition of T cells' function through detection of p-S6RP. Future studies in organ transplanted recipients will show if this assay has the potential to enhance a TDM for mTOR-inhibitor drugs in combination therapies.

Impact of clopidogrel on bleeding complications and survival in off-pump coronary artery bypass grafting.

This study investigated the impact of preoperative clopidogrel on bleeding complications and survival during and after off-pump coronary artery bypass grafting (OPCABG) and assessed the possible role of the antifibrinolytic agent aprotinin for attenuating blood loss after clopidogrel exposure. Prospectively collected data of 753 consecutive adult patients undergoing OPCABG were retrospectively reviewed; 139 (18.5%) patients received clopidogrel preoperatively. Statistical methods used were student paired t-test, Mann-Whitney U, Kruskal-Wallis, chi-square analysis and Kaplan-Meier with log-rank analysis. Clopidogrel was associated with a significant increase in perioperative blood loss (P = 0.003) and more excessive postoperative haemorrhage (P = 0.04). Overall transfusion rates (P = 0.02) and the amount of administered blood products (P = 0.01) were also higher after clopidogrel exposure. Intraoperative aprotinin reduced postoperative bleeding significantly in patients administered clopidogrel [18.7% after 24 h (P = 0.006) and 15.2% after 48 h (P = 0.03)] and attenuated excessive postoperative haemorrhaging. Five-year survival was markedly improved in clopidogrel-treated patients. Preoperative clopidogrel exposure does increase perioperative blood loss and blood transfusion requirements in patients undergoing OPCABG but has an otherwise excellent safety profile with a 94% 5-year survival rate. Aprotinin attenuated this blood loss. Based on these results a recommendation to discontinue clopidogrel prior to coronary artery bypass grafting cannot be maintained, if OPCABG strategies are considered.

Effects of donor pre-treatment with dopamine on survival after heart transplantation: a cohort study of heart transplant recipients nested in a randomized controlled multicenter trial.

OBJECTIVES: We determined the outcome of cardiac allografts from multiorgan donors enrolled in a randomized trial of donor pre-treatment with dopamine. BACKGROUND: Treatment of the brain-dead donor with low-dose dopamine improves immediate graft function after kidney transplantation. METHODS: A cohort study of 93 heart transplants from 21 European centers was undertaken between March 2004 and August 2007. We assessed post-transplant left ventricular function (LVF), requirement of a left ventricular assist device (LVAD) or biventricular assist device (BVAD), need for hemofiltration, acute rejection, and survival of recipients of a dopamine-treated versus untreated graft. RESULTS: Donor dopamine was associated with improved survival 3 years after transplantation (87.0% vs. 67.8%, p = 0.03). Fewer recipients of a pre-treated graft required hemofiltration after transplant (21.7% vs. 40.4%, p = 0.05). Impaired LVF (15.2% vs. 21.3%, p = 0.59), requirement of a LVAD (4.4% vs. 10.6%, p = 0.44), and biopsy-proven acute rejection (19.6% vs. 14.9%, p = 0.59) were not statistically different between groups. Post-transplant impaired LVF (hazard ratio [HR]: 4.95; 95% confidence interval [CI]: 2.08 to 11.79; p < 0.001), requirement of LVAD (HR: 6.65; 95% CI: 2.40 to 18.45; p < 0.001), and hemofiltration (HR: 2.83; 95% CI: 1.20 to 6.69; p = 0.02) were predictive of death. The survival benefit remained (HR: 0.33; 95% CI: 0.12 to 0.89; p = 0.03) after adjustment for various risks affecting mortality, including pre-transplant LVAD/BVAD, inotropic support, and impaired kidney function. CONCLUSIONS: Treatment of brain-dead donors with dopamine of 4 µg/kg/min will not harm cardiac allografts but appears to improve the clinical course of the heart allograft recipient. (Prospective Randomized Trial to Evaluate the Efficacy of Donor Preconditioning With Dopamine on Initial Graft Function After Kidney Transplantation; NCT00115115).

Current trends in implantable left ventricular assist devices.

The shortage of appropriate donor organs and the expanding pool of patients waiting for heart transplantation have led to growing interest in alternative strategies, particularly in mechanical circulatory support. Improved results and the increased applicability and durability with left ventricular assist devices (LVADs) have enhanced this treatment option available for end-stage heart failure patients. Moreover, outcome with newer pumps have evolved to destination therapy for such patients. Currently, results using nonpulsatile continuous flow pumps document the evolution in outcomes following destination therapy achieved subsequent to the landmark Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure Trial (REMATCH), as well as the outcome of pulsatile designed second-generation LVADs. This review describes the currently available types of LVADs, their clinical use and outcomes, and focuses on the patient selection process.