Brain stem death induces pro-inflammatory cytokine production and cardiac dysfunction in sheep model.

INTRODUCTION: Organs procured following brain stem death (BSD) are the main source of organ grafts for transplantation. However, BSD is associated with inflammatory responses that may damage the organ and affect both the quantity and quality of organs available for transplant. Therefore, we aimed to investigate plasma and bronchoalveolar lavage (BAL) pro-inflammatory cytokine profiles and cardiovascular physiology in a clinically relevant 6-h ovine model of BSD. METHODS: Twelve healthy female sheep (37-42 Kg) were anaesthetized and mechanically ventilated prior to undergoing BSD induction and then monitored for 6 h. Plasma and BAL endothelin-1 and cytokines (IL-1ß, 6, 8 and tumour necrosis factor alpha (TNF-α)) were assessed by ELISA. Differential white blood cell counts were performed. Cardiac function during BSD was also examined using echocardiography, and cardiac biomarkers (A-type natriuretic peptide and troponin I were measured in plasma. RESULTS: Plasma concentrations big ET-1, IL-6, IL-8, TNF-α and BAL IL-8 were significantly (p < 0.01) increased over baseline at 6 h post-BSD. Increased numbers of neutrophils were observed in the whole blood (3.1 × 109 cells/L [95% confidence interval (CI) 2.06-4.14] vs. 6 × 109 cells/L [95%CI 3.92-7.97]; p < 0.01) and BAL (4.5 × 109 cells/L [95%CI 0.41-9.41] vs. 26 [95%CI 12.29-39.80]; p = 0.03) after 6 h of BSD induction vs baseline. A significant increase in ANP production (20.28 pM [95%CI 16.18-24.37] vs. 78.68 pM [95%CI 53.16-104.21]; p < 0.0001) and cTnI release (0.039 ng/mL vs. 4.26 [95%CI 2.69-5.83] ng/mL; p < 0.0001), associated with a significant reduction in heart contractile function, were observed between baseline and 6 h. CONCLUSIONS: BSD induced systemic pro-inflammatory responses, characterized by increased neutrophil infiltration and cytokine production in the circulation and BAL fluid, and associated with reduced heart contractile function in ovine model of BSD.

Endothelin receptor antagonist improves donor lung function in an ex vivo perfusion system.

BACKGROUND: A lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD). METHODS: After 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema). RESULTS: Our results showed a significant improvement in gas exchange [elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03)] in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin-eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control. CONCLUSIONS: These data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.

Bronchiolitis obliterans syndrome and survival following lung transplantation for patients with sarcoidosis.

BACKGROUND: End-stage sarcoidosis is characterized by severe pulmonary fibrosis and is often poorly responsive to medical therapy. Lung transplantation, therefore, may be the only treatment option. Currently, there are few studies evaluating long-term outcomes following transplantation for these patients. Our aim was to evaluate post-transplant morbidity and survival of patients with sarcoid compared to recipients transplanted for idiopathic pulmonary fibrosis (IPF). METHODS: We retrospectively examined 300 lung transplant recipients using a dedicated database. Over a 10-year period, 15 (5.0%) patients with sarcoidosis and 48 (16%) patients with IPF were identified. Primary outcome measures included rate and time to onset of bronchiolitis obliterans syndrome (BOS) and survival. RESULTS: Recipients in the sarcoid group were younger and predominantly female compared to recipients in the IPF group. Five of 15 (33%) sarcoid patients developed BOS versus 15 of 48 (31%) IPF patients (p=1.0). There was no significant difference in the time to BOS onset. Median survival was 1,365 days for the sarcoid group and 1,593 days for the IPF group (Hazard Ratio 0.94 by Kaplan-Meier analysis; [95% CI] 0.33-2.67; p = 0.90). CONCLUSIONS: We observe similar long term outcomes following lung transplantation for sarcoid and IPF recipients. Transplantation remains a treatment option for end-stage sarcoidosis, as BOS and survival rates are comparable to IPF.

Rejection with hemodynamic compromise: objective evidence for efficacy of photopheresis.

BACKGROUND: Photopheresis therapy (photo) has been advocated as a therapy to improve outcome after recalcitrant or severe rejection, but objective evidence of a beneficial effect has been elusive. This study examined the hypothesis that photo provides protection against rejection, rejection with hemodynamic compromise (HC), and death from rejection after cardiac transplantation. METHODS: Between 1990 and 2003, 36 adult patients (from 343 adult transplant recipients) received at least 3 months of photo (2-day treatment every 3 to 6 weeks for a target of 18 months) after HC rejection (n = 12), recurrent/recalcitrant rejection (n = 20), or as prophylaxis in the presence of anti-donor antibodies (n = 4). Survival and risk factors were examined by analysis using multivariate hazard function modulated renewal function. RESULTS: Patients selected for photo were at greater risk for rejection (p < 0.0001) and HC rejection (p < 0.0001) than non-photo patients. After 3 months of photo therapy, rejection risk was decreased (p = 0.04). More importantly, the hazard for subsequent HC rejection or rejection death was significantly reduced toward the risk-adjusted level of lower-risk non-photo patients (p = 0.006). CONCLUSIONS: This study provides objective evidence that photo reduces the risk of subsequent HC rejection and/or death from rejection when initiated for patients with high rejection risk. Photopheresis is recommended as an important therapeutic modality after rejection with hemodynamic compromise, although further studies are needed to define the precise mechanism of the effect and the potential for benefit in other patient sub-sets.

Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial.

Everolimus is a proliferation signal inhibitor with immunosuppressive activity that may reduce the rate of progression of chronic rejection, bronchiolitis obliterans syndrome (BOS), after lung transplantation. In a randomized, double-blind clinical trial, 213 BOS-free maintenance patients received everolimus (3 mg/day) or azathioprine (AZA, 1-3 mg/kg/day) in combination with cyclosporine and corticosteroids. The prospectively defined primary endpoint was the incidence of efficacy failure (decline in FEV1 >15%[deltaFEV1 >15%], graft loss, death or loss to follow-up) at 12 months. Incidence of efficacy failure at 12 months was significantly lower in the everolimus group than AZA (21.8% vs. 33.9%; p = 0.046); at 24 months, rates of efficacy failure became similar between the groups. At 12 months, the everolimus group had significantly reduced incidences of deltaFEV1 >15%, deltaFEV1 >15% with BOS, and acute rejection. At 24 months, only incidence of acute rejection remained significantly less in the everolimus group. Treatment discontinuations (particularly due to adverse events), serious adverse events and high serum creatinine values were more common with everolimus. For the first time, a drug has demonstrated significant slowing of loss in lung function, suggesting that patients kept on prolonged maintenance treatment with everolimus may benefit from replacing AZA with everolimus 3 months after lung transplantation.

Evolving trends in risk profiles and causes of death after heart transplantation: a ten-year multi-institutional study.

BACKGROUND: As therapeutic options evolve for advanced heart failure, the appropriate role for cardiac transplantation will require survival analyses that reflect changing trends in causes of death and patient and institutional risk profiles. Results from multi-institutional studies could be used to monitor progress in individual centers. METHODS: Between 1990 and 1999, 7290 patients undergoing cardiac transplantation in 42 institutions entered a formal outcomes study. Changing survival, causes of death, and patient risk profiles were analyzed. Multivariable risk-factor equations were applied to a single institution (300 primary heart transplants) to examine differences in risk-adjusted expected versus observed actuarial outcomes over time. RESULTS: Overall survival in the 42 institutions improved during the decade (P =.02). One- and 3-year cardiac transplant research database survival was as follows: era 1 (1990-1992), 84% and 76%, respectively; era 2 (1993-1995), 85% and 79%, respectively; and era 3 (1996-1999), 85% and 79%, respectively. Causes of death changed over time. Pretransplantation risk profiles increased over time (P =.0001), with increases in reoperations, devices, diabetes, severely ill recipients, pulmonary vascular resistance, sensitization, ischemic times, donor age, and donor inotropic support. Three-year actuarial survival in a single institution was 3% less than risk-adjusted predicted survival in era 1, 1% higher than predicted in era 2, and 7% higher than predicted in era 3. CONCLUSIONS: Survival after cardiac transplantation is gradually improving, despite increasing risk profiles. Further improvement requires periodic re-evaluation of risk profiles and causes of death to target areas of surveillance, therapy, and research. By using these methods, progress at individual institutions can be assessed in a time-related, risk-adjusted manner that also reflects changing institutional experience, expertise, or both.

Hemostatic analysis of a patient with hereditary angioedema undergoing coronary artery bypass grafting.

IMPLICATIONS: Hereditary angioedema is a disease associated with acute complement-mediated inflammation and swelling of the airway and other vital organs. This case describes the impact of hereditary angioedema and cardiopulmonary bypass on hemostasis as assessed by thrombelastography.

Management of congenital abnormalities of the donor lung.

Congenital abnormalities were encountered in three donor lungs. A donor tracheal bronchus was incorporated into the right bronchial anastomosis. Anomalous pulmonary venous return of the right upper lobe to the superior vena cava and the left upper lobe to the innominate vein were managed by bridging the anomalous veins to the left atrial cuff with autologous pericardium and donor iliac vein, respectively.

A multicenter, randomized, controlled trial of Celsior for flush and hypothermic storage of cardiac allografts.

BACKGROUND: A multicenter, randomized, controlled, open-label trial was conducted to evaluate the safety and efficacy of Celsior when used for flush and hypothermic storage of donor hearts before transplantation. METHODS: Heart transplant recipients were randomized to one of two treatment groups in which donor hearts were flushed and stored in either Celsior or conventional preservation solution(s) (control). Study subjects were followed for 30 days after transplantation. RESULTS: A total of 131 heart transplant recipients were enrolled (Celsior, n = 64; control, n = 67). The treatment groups were evenly distributed in donor and recipient base line characteristics. Graft loss rate was lower in the Celsior group on day 7 (3% versus 9%) and on day 30 (6% versus 13%), but the difference was not statistically significant based on 95% confidence interval analysis. No significant difference was measured between the Celsior and control groups in 7-day patient survival (97% versus 94%) and the proportion of patients with one or more adverse events (Celsior, 88%; control 87%) or serious adverse events (Celsior, 38%; control, 46%). Significantly fewer patients in the Celsior group developed at least one cardiac-related serious adverse event (13% versus 25%). CONCLUSIONS: Celsior was demonstrated to be as safe and effective as conventional solutions for flush and cold storage of cardiac allografts before transplantation.

Association of reactive nitrogen species metabolites, myeloperoxidase, and airway inflammation in lung transplants.

BACKGROUND: We have previously reported that patients who had single or double lung transplants had higher concentrations than controls of nitrite and nitrate, which are metabolites of reactive nitrogen species (RNS), in bronchoalveolar lavage fluid (BALF) and serum. METHODS: This study investigates implications of RNS metabolites as markers of airway inflammation in a distinct group of lung transplant patients (n = 40). All patients underwent spirometry, routine surveillance transbronchial lung biopsies, and bronchoalveolar lavage as required by clinical protocol. Four normal controls also had bronchoscopy for measurement of BALF nitrite (NO2-) and nitrate (NO3-). BALF NO2- and NO3-, myeloperoxidase (MPO), protein, and urea were assayed. Total nitrite (NO2- plus enzymatically reduced NO3-) and urea were measured in serum. RESULTS: BALF RNS metabolites were mainly NO3-. Forced expiratory volume in 1 s (FEV1) obtained near bronchoscopy was compared with best postoperative FEV1. Total nitrite in transplant patients' BALF and serum were 3.8 +/- 0.2 and 49 +/- 5 microM, respectively. Total nitrite in controls' BALF and serum were 2.2 +/- 0.7 and 19 +/- 2 microM, respectively (P < 0.05 compared with transplant values). Serum total nitrite correlated (Pearson product moment) with percentage of neutrophils in BALF (R = 0.650, P < 0.0001), MPO (R = 0.431, P = 0.0055), change in FEV1 from baseline (deltaFEV1) (R = -0348, P = 0.0298), and days after transplantation (R = 0.345, P = 0.0294). None of the associated variables, airway inflanmmation (quantified as a score, "B"), deltaFEV1, serum, or BALF total nitrite, were explained by infection. Univariate analysis of airway inflammation in patients showed that it was associated with BALF neutrophils, deltaFEV1, and serum total nitrite. CONCLUSIONS: Serum nitrite appears to reflect the degree of airway inflammation in this lung-transplant study group.

Self-report measures among transplant candidates: the impact of evaluative situations.

Experiment 1 was a between-subjects design comparing transplant candidates completing self-report measures under an evaluative versus an anonymous research condition. A cardiac disease group and a healthy community group served as controls. Transplant candidates in the anonymous research condition reported significantly more depression, anxiety, and negative affectivity as compared with transplant candidates in the evaluative condition and community controls. In contrast, the evaluative transplant group (a) did not differ from the community controls on any of the self-report measures, and (b) reported significantly less depression than cardiac disease controls. Experiment 2 was a within-subjects design with transplant candidates completing self-report measures under both an evaluative and an anonymous research condition. Significantly greater anxiety was reported under the anonymous research condition. Social desirability was significantly related to change in self-reported anxiety and depression across conditions, but was unrelated to change in endorsement of personality characteristics.

Combined cardiac surgery and liver transplantation.

During evaluation for liver transplantation, a 63-year-old man with cirrhosis secondary to hepatitis C was diagnosed with severe aortic stenosis (aortic valve area, 0.87 cm(2)) and coronary artery disease. A combined procedure involving aortic valve replacement (pericardial xenograft), coronary artery bypass surgery, and orthotopic liver transplantation was performed. Convalescence was uneventful, and at 2 years after the procedure, the patient has normal cardiac function, good prosthetic valve function, and biochemically normal liver function.

Fibrotic aortic stenosis in a patient with dwarfism.

In this report, we present an adult patient with dwarfism who had severe aortic stenosis with markedly thickened fibrotic valve leaflets without calcification. These findings were well demonstrated by both two- and three-dimensional transesophageal echocardiography and confirmed at surgery and by pathological examination.

The effect of synthetic patch repair of coarctation on regional deformation of the aortic wall.

BACKGROUND: A long-term complication of synthetic patch repair of coarctation is true aneurysm formation. AIM: An in vitro study was undertaken to determine the effects of patch angioplasty on aortic geometry and strain adjacent to the patch. METHODS: Segments of human descending thoracic aorta were subject to 10 pressure loading cycles (10-120 mm Hg; 1.36-16.32 kPa) before and after simulated coarctation repair with a synthetic patch. Local curvature and strain were estimated by fitting a geometric model to reconstructed three-dimensional surface marker points. RESULTS: In the control aortas, when pressure increased from 11 +/- 1.0 to 124 +/- 4.0 mm Hg (1.5 +/- 0.14 to 16.86 +/- 0.54 kPa), average circumferential curvature decreased from 0.1543 +/- 0.03 to 0.1065 +/- 0.03 mm(-1). The average major extension reached a maximum of 1.43 +/- 0.08. After patch implantation, the average circumferential curvature was reduced relative to control at all pressures. Average major extensions were significantly greater than paired control values and reached a maximum of 1.55 +/- 0.08 at 122 +/- 4.0 mm Hg (16.59 +/- 0. 54 kPa). Substantial strain inhomogeneity was observed and major extensions were greatest immediately adjacent to the patch. INFERENCE: Synthetic patch repair of coarctation of the aorta increases wall strain and produces significant regional gradients in strain. With control aortic material properties there may be a substantial increase in wall stress immediately adjacent to the aorta, which could lead to true aneurysm formation.

Prophylactic value of preincision intra-aortic balloon pump: analysis of a statewide experience.

OBJECTIVE: The objective of this study was to determine whether preincision use of an intra-aortic balloon pump improves survival and shortens postoperative length of stay in hemodynamically stable, high-risk patients undergoing coronary artery bypass grafting. METHODS: A post hoc analysis of the Alabama CABG Cooperative Project database was performed by using propensity scores to model the likelihood of receiving a prophylactic preincision intra-aortic balloon pump. Every patient receiving a prophylactic preincision balloon pump was matched with another patient of similar propensity score who did not receive one. We then compared outcomes for matched pairs. RESULTS: There were 7581 patients of whom 592 received a prophylactic preincision balloon pump. Patients with preoperative renal insufficiency, heart failure, or left main coronary artery disease, or who had undergone previous bypass grafting were significantly more likely to receive a prophylactic preincision balloon pump. By using propensity scores, we matched 550 patients who received a prophylactic preincision balloon pump with 550 who did not. Survival did not significantly differ by whether a prophylactic preincision balloon pump was used. However, surviving patients who received a preincision balloon pump had a significantly shorter postbypass length of stay (7 +/- 7.3 days) than did matched patients not receiving a balloon pump (8 +/- 6.2 days; P <.05). CONCLUSIONS: No survival advantage was found for use of a prophylactic intra-aortic balloon pump in hemodynamically stable, high-risk patients undergoing bypass grafting, as opposed to placing a balloon pump on an "as needed" basis during or after the operation. However, the patients receiving the balloon pump had improved convalescence as shown by significantly shorter length of stay.

Cost-benefit analysis of extended antifungal prophylaxis in ventricular assist devices.

This report defines the cost and benefit of extended antifungal prophylaxis in ventricular assist device (VAD) patients (pts). Extended antifungal prophylaxis is defined as prophylaxis with fluconazole or nystatin that is given until pts are extubated and off antibiotics. These data are compared with that obtained from earlier VAD patients who only received anti-fungal drugs for documented fungal colonization or infection. Thirty-six patients had HeartMate (n = 15) or Thoratec (n = 21) VADs between 1989 and 1997. Cultures positive for fungus (n = 52 cultures) were obtained from 16 of 36 patients (44% of patients). Forty-three fungal cultures were in the preprophylaxis and nine in the postprophylaxis era. There was one death attributable to fungal sepsis in the preprophylaxis era and none in the postprophylaxis era. The total cost of antifungal drugs in the preprophylaxis era was $3,840 over 1,498 patient days (PD) (mean $2.56 per PD), versus $70,670 over 1,525 PD in the postprophylaxis era (mean $46.34 per PD). Extended antifungal prophylaxis was not cost effective in VAD patients at this institution. However, short-term perioperative antifungal prophylaxis was not addressed by this study. We are now using short-term antifungal prophylaxis with fluconazole and nystatin in VAD patients because of the potential for serious morbidity and mortality that is associated with fungal device infections. A future analysis will determine the usefulness of this change in strategy.