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Stephen R Large

Publications and source records attributed to Stephen R Large.

27 records · Page 2Linked to original sources
PubMed2003

Heat shock protein, inducible nitric oxide synthase and apoptotic markers in the acute phase of human cardiac transplantation.

OBJECTIVE: Solid organ transplantation is associated with activation of apoptotic pathways and other stress markers. We aimed to describe the expression of Bax, Bcl-2, iNOs and Hsp-70 in the endothelium and myocytes of both ventricles and to see if there is any relationship with clinical donor organ failure. METHODS: Twelve patients undergoing heart or heart-lung transplantation (including three domino cases) were studied with transmural biopsies from the right (RV) and the left ventricles (LV) at the following points: after donor optimisation; at the end of ischaemic time; and after 10 min of reperfusion. The 1-week endomyocardial RV biopsy was also examined. Five donor hearts turned down purely on functional grounds were analysed also. RESULTS: There was no difference between the RV and the LV for any of the markers at intraoperative assessment. The pattern of expression was not predictive of allograft failure. Donor hearts, however, have a strong pro-apoptotic phenotype, which is largely unopposed by the protective factors Bcl-2 and Hsp-70. Furthermore, the intensity of myocyte staining increases over time for Bax (P<0.001) and iNOs (P=0.02). Domino hearts showed a similar pattern. Compared to usable organs, poorly functioning donor hearts have stronger myocardial staining for Bax (P=0.002) and iNOs (P=0.01). CONCLUSIONS: Clinical cardiac transplantation is associated with activation of the Bax and iNOs pathways in both ventricles. The myocardium is affected in time-dependent fashion but this is compatible, to a certain extent, with satisfactory allograft function. Donor hearts turned down on the basis of poor haemodynamic performance have significantly higher expression of Bax and iNOs.

Adult↗
PubMed2003

Does cytomegalovirus status influence acute and chronic rejection in heart transplantation during the ganciclovir prophylaxis era?

BACKGROUND: The effect of cytomegalovirus (CMV) status on acute rejection in heart transplantation is not well understood. Furthermore, there is some evidence to suggest that CMV antibody positivity is associated with cardiac allograft vasculopathy (CAV). METHODS: This study compared the effect of CMV antibody status in heart transplant donors (D) and recipients (R) on acute and chronic rejection episodes during the ganciclovir prophylaxis era. RESULTS: All heart transplant recipients at Papworth Hospital during the ganciclovir prophylaxis era were included (n = 374). They were grouped according to recipients and their respective donor CMV serology: R(-)/D(-) (n = 82); R(+)/D(-) (n = 114); R(-)/D(+) (n = 73); and R(+)/D(+) (n = 105). Ganciclovir prophylaxis was administered to the R(-)/D(+) group. The mean (SD) recipient and donor ages were 46 (11), 51 (9), 47 (11) and 52 (8) years (p < 0.001), and 32 (11), 33 (14), 36 (12) and 38 (14) years (p = 0.01), respectively, for the CMV groups. The mean number of acute rejection episodes (as confirmed by cardiac biopsy) per 100 patient-days was 0.13 (0.36), 0.11 (0.34), 0.12 (0.34) and 0.12 (0.34), respectively (p > 0.05) There was no statistical difference in the development of CAV as assessed by angiography (p = 0.92). At 2 years, the "freedom from CAV" rates were 96%, 97%, 97% and 98%, respectively. The 5-year post-operative survival rates were 83%, 79%, 67% and 73% (p = 0.08 overall). CONCLUSIONS: CMV status of heart transplant recipients and their respective donors does not influence acute or chronic rejection in terms of cardiac allograft vasculopathy.

Antiviral Agents↗
PubMed2002

Consensus conference report: maximizing use of organs recovered from the cadaver donor: cardiac recommendations, March 28-29, 2001, Crystal City, Va.

The shortage of available donor hearts continues to limit cardiac transplantation. For this reason, strict criteria have limited the number of patients placed on the US waiting list to approximately 6000 to 8000 per year. Because the number of available donor hearts has not increased beyond approximately 2500 per year, the transplant waiting list mortality rate remains substantial. Suboptimal and variable utilization of donor hearts has compounded the problem in the United States. In 1999, the average donor yield from 55 US regions was 39%, ranging from 19% to 62%. This report provides the detailed cardiac recommendations from the conference on "Maximizing Use of Organs Recovered From the Cadaver Donor" held March 28 to 29, 2001, in Crystal City, Va. The specific objective of the report is to provide recommendations to improve the evaluation and successful utilization of potential cardiac donors. The report describes the accuracy of current techniques such as echocardiography in the assessment of donor heart function before recovery and the impact of these data on donor yield. The rationale for and specific details of a donor-management pathway that uses pulmonary artery catheterization and hormonal resuscitation are provided. Administrative recommendations such as enhanced communication strategies among transplant centers and organ-procurement organizations, financial incentives for organ recovery, and expansion of donor database fields for research are also described.

Cadaver↗
PubMed2002

The endothelium in clinical cardiac transplantation.

Cardiac transplantation is the most successful therapy for refractory heart failure, but clinical transplantation is still confronted with the problems of acute rejection and acute pump failure. The limiting factor in achieving prolonged survival remains cardiac allograft vasculopathy. In recent years it has become apparent that from brain death onward, the cardiac endothelium plays a key role in these acute and chronic events. Brain death is associated with an inflammatory response that primes the endothelium for cumulative injury during the subsequent stages of ischemic cold storage, reperfusion and allorecognition. As a structural and functional interface, the endothelium is the site at which inflammatory cells move from the bloodstream through the vessel wall into the parenchyma. The endothelium interacts with the complement system, the coagulation and inflammatory cascades, circulating leukocytes, the immune system, the smooth muscle in the vessel wall, and the surrounding matrix and cardiomyocytes. A better understanding of its many roles may lead to expansion of our therapeutic possibilities and better outcomes overall. This article reviews the possible roles of the endothelium in relation to cardiac transplantation, and discusses the diagnostic and therapeutic modalities that are available to date.

Animals↗
PubMed2002

And hemolysis goes on: ventricular assist device in combination with veno-venous hemofiltration.

BACKGROUND: Ventricular Assist Device (VAD) is an accepted treatment as a bridge to cardiac transplantation, and may be of help in patients as destination therapy for end-stage cardiac failure. The low output state associated with end-stage cardiac failure predisposes patients to renal dysfunction and the need for short-term renal support. The use of cardiopulmonary bypass for VAD insertion, VAD, and hemofiltration expose the blood to mechanical trauma and activated inflammatory cascades that can result in hemolysis. This produces free hemoglobin, a known nephrotoxin; this is a further renal insult. This study assesses the effect of VAD alone and in combination with continuous veno-venous hemofiltration (CVVHF) on hemolysis. METHODS AND RESULTS: From July 1999 to December 2000, Thoratec VAD was used in 11 patients. Nine (all males) were included in this study as all had laboratory profiles. Hemolysis was quantified by plasma free hemoglobin (PFHb) and hydroxybuterate dehydrogenase (HBD) levels measured daily, defined as PFHb level greater than 40 mg/L and HBD greater than 250 IU/L. Data relate to the following time intervals while the VAD was still in situ: T1 = 24 hours post-VAD insertion, T2 = 24 hours post-CVVHF start, T3 = 48 to 72 hours with the same CVVHF circuit, T4 = 24 hours post-stopping of CVVHF, and T5 = CVVHF off for over 48 hours. The mean (SD) PFHb levels were 19.6 (10.9) at T1, 31.7 (0.6) at T2, 93.7 (16.4) at T3 (p < 0.05), 32.5 (20.9) at T4, and 14.2 (3.8) at T5 (p < 0.05). These changes were paralleled by the mean (SD) HBD levels: T1 = 1,337 (616), T2 = 2,025 (509), T3 = 2,676 (1,170) (p < 0.05), T4 1,780 (618), and T5 = 1,310 (436). CONCLUSIONS: Thoratec VAD was associated with a mild degree of hemolysis. This was worsened by concomitant use of CVVHF. The effect was accentuated if the same CVVHF circuit was used for over 48 hours but was reversible within 24 hours of stopping the hemofilter.

Adult↗
PubMed2002

Preoperative risk prediction and intraoperative events in cardiac surgery.

OBJECTIVE: To examine the relationship between preoperative risk prediction and intraoperative events. METHODS: A total of 3118 patients operated in 1999 and 2000 at our institution were analysed, all of whom had their EuroSCORE collected prospectively. The intraoperative variables studied were consultant or trainee operating, long bypass time, long ischaemic time, return on bypass in theatre and use of intra-aortic balloon pump at the end of the procedure. The outcomes are reported as hospital mortality, prolonged length of stay in the intensive therapy unit (pLOS-ITU, >48 h) and death or pLOS-ITU. Risk models were constructed by logistic regression for predicting these three outcomes. RESULTS: With the exception of prolonged cross-clamp time, all variables analysed were independently predictive of a negative outcome. Trainee operating had an apparent protective effect. All risk models performed well. The area under the receiver operating characteristic (ROC) curve (95% CI) increased from 0.857 (0.81, 0.90) for EuroSCORE to 0.874 (0.83, 0.92) for the risk of death model. Similarly, the area under the ROC curve for the pLOS-ITU model increased from 0.687 (0.642, 0.732) to 0.734 (0.691, 0.777) and for the death or pLOS-ITU model from 0.717 (0.677, 0.756) to 0.757 (0.719, 0.795). CONCLUSIONS: Knowledge of adverse intraoperative events enhances preoperative risk prediction. This type of analysis could be used for identifying "near miss" outcomes in adult cardiac surgery.

Cardiac Surgical Procedures↗
PubMed2002

The incidence of end-stage renal failure in 17 years of heart transplantation: a single center experience.

BACKGROUND: Predictions of the incidence of renal failure within a heart transplant population are based on the early experiences of cyclosporine (CsA)-based immunosuppression. We report a single-center experience of end-stage renal failure (ESRF) during a 17-year period encompassing current lower dose CsA regimens. METHOD: Prospectively collected data were analyzed on all patients who underwent first heart transplants between April 1982 and February 1999 (n = 697). We further categorized patients by the date of transplantation into a higher and lower dosage maintenance CsA group. RESULTS: End-stage renal failure developed in 44 patients. The median time to dialysis was 87 months after transplantation and was independent of the initial CsA regimens used (p = 0.798). In the ESRF group, 14 underwent hemodialysis, 28 underwent peritoneal dialysis, and 9 underwent renal transplantation. One- and 5-year survival rates after dialysis were 82% and 62% respectively. The incidence of ESRF at our institution was 5.8%. It increased with post-operative survival and was independent of the initial CsA regimen used. We found no difference in pre-transplant age, sex, diagnosis, immediate post-operative creatinine, or the development of diabetes between the ESRF group and controls. The ESRF group received higher dosages of CsA within the first post-transplant year, although this did not reach significance (CsA dosage, 5.9 microg/kg/day vs 5.1 microg/kg/day, respectively p = 0.075). CONCLUSIONS: Lower dosage CsA regimes have not altered the incidence of ESRF at our institution, suggesting an individual predisposition to nephropathy. Therefore, reduction in the future incidence of ESRF may rely on extremely low-dose or calcineurin-free immunosuppression regimes.

Adult↗
PubMed2002

Swan-Ganz catheter assessment of donor hearts: outcome of organs with borderline hemodynamics.

BACKGROUND: High-dosage inotrope use or periods of hypotension may cause rejection of donor hearts for transplantation. At our institution, we do not refuse potential donor organs based on these criteria alone before Swan-Ganz catheter (SGC) assessment. In this study, we evaluate the role of the SGC in donor heart resuscitation and selection and assess the outcome of using borderline organs. METHODS: We retrospectively analyzed 129 donors assessed between 1996 and 1999, all with complete hemodynamic data. Two sets of SGC measurements were analyzed: one set from the initial assessments, and one set from assessments made just before organ harvesting. The physiologic targets were mean blood pressure >60 mm Hg, central venous pressure <12 mm Hg, pulmonary capillary wedge pressure <12 mm Hg, left ventricular stroke work index >15 x g.m/m(2), and use of only one inotrope. A poorly functioning heart was defined as an organ failing on 2 or more of these criteria. Hemodynamic categories were defined as A, good function throughout assessment; B, sub-optimal function and then improvement; and C, decreasing or poor function throughout. We have a policy to avoid allocating sub-optimal organs to high-risk recipients. RESULTS: One hundred fourteen donor hearts went on to be transplanted: 75 as orthotopic hearts and 39 as heart-lungs (5 of these were heart, lung, and liver transplantations, not reported further here). Of the 75 donor hearts used for heart transplantations, 53 were from Category A, 9 were from Category B, and 13 were from Category C. Of the donor hearts used for the 34 heart-lung transplantations 16 were from Category A, 10 were from Category B, and 8 were from Category C. Three patients died of donor organ failure: 1 of the corresponding hearts was from Category B, and 2 were from Category C. When comparing separately the outcome of the 2 procedures, we found no significant difference in duration of stay in the intensive care unit, requirement for mechanical support, 30-day mortality, or 1-year survival among patients with hearts from Categories A, B, and C. Ischemic time was the only significant risk factor for death (p = 0.006). CONCLUSIONS: Use of organs from Categories B and C permitted expansion of the donor pool without compromising short-term outcome. However, these organs should be used with caution in combination with other risk factors, in particular long ischemic time.

Adult↗