Biomedical subjects
Publications and source records attributed to Stephen R Large.
We report the case of a 75-year-old woman who died of liver failure following coronary artery bypass grafting. The possibility of an association with leflunomide is discussed.
BACKGROUND: Endothelial activation in the donor heart has been described variably after brain death and transplantation. We aimed to characterize the time course of endothelial activation in right ventricle (RV) and left ventricle (LV) during the acute phase of clinical transplantation. METHODS: We studied biopsy specimens from the RVs and the LVs of 40 donor hearts: at initial assessment of the donor, at end-ischemia, and after 10 minutes of reperfusion. We also included follow-up RV biopsy specimens at 1 week, 1 month, and 3 months after surgery. Six of the patients had cystic fibrosis and were domino donors. RESULTS: P-selectin and vascular cell adhesion molecule 1 (VCAM-1), but not E-selectin were up-regulated in brain-dead and in domino donors vs controls. Unused donor hearts (n = 6) had significantly less up-regulation of P-selectin and of VCAM-1. We found no difference between the RV and the LV during surgery, but we did see important time-dependent variations. P-selectin was present in 85% of vessels throughout transplantation and decreased to approximately 60% after transplantation (p < 0.001). We initially detected VCAM-1 in 20% of vessels, which decreased to 5% during storage, then increased to 47% at reperfusion, and gradually decreased thereafter (p < 0.001). E-selectin expression increased progressively from 15% initially to 45% at reperfusion and then decreased after surgery (p = 0.001). Thrombomodulin expression was decreased at baseline, and the decrease was accentuated afterward (p = 0.02). Patients with donor organ failure did not have a specific pattern of endothelial activation. CONCLUSION: Cardiac transplantation is associated with marked endothelial activation, with no difference between the two ventricles. The changes persist in the post-operative period, even in the absence of acute rejection.
BACKGROUND: According to International Society for Heart and Lung Transplantation (ISHLT) data, the 30-day survival after heart transplantation has continually improved from 84% (1979-85) to 91% (1996-2001). This has probably been achieved by better donor/recipient selection, along with improved surgical technique and immunosuppressive therapy. On the other hand, the data concerning the early causes of death after cardiac transplantation is incomplete, because in 25% of cases, an unknown cause is listed. This study investigated the incidence and causes of 30-day mortality (determined by postmortem studies) after cardiac transplantation and assessed the possibility of improvements. METHODS: A retrospective study of all patients who underwent heart transplantation at Papworth Hospital from 1979 to June 2001 (n = 879) and who died within 30 days of surgery was carried out. Postmortem examination data were available for all patients. RESULTS: The mean (standard deviation) recipient and donor ages were 46 (12) and 31 (12) years, respectively. Overall, the 30-day mortality was 8.5% (n = 75), 12.1% for the 1979 to 1985 period and 6.9% for the 1996 to 2001 period. The primary causes of death were graft failure (30.7%), acute rejection (22.7%) (1.3% for the 1996-2001 era), sepsis (18.7%) gastrointestinal problems (bowel infarction and pancreatitis; (9.3%), postoperative bleeding (6.7%), and other (12%). CONCLUSIONS: Our 30-day mortality compares favorably with the data from the ISHLT registry, with great improvement in the early mortality. Acute rejection is no longer a major cause of early mortality. Further reduction may be achieved by a better protection of the donor heart against the effects of brainstem death and ischemic injuries. However, the quest to improve early outcome should not be at the expense of needy patients by being overselective.
BACKGROUND: To ascertain survival of ischemic advanced heart failure patients by treatment allocation, we examined the outcome of transplant assessment patients allocated to medical therapy, high-risk conventional surgery, or transplantation. METHODS: Patients were identified from the Papworth transplant database and excluded if primary etiology was not ischemic. Grouping was undertaken according to treatment allocation at initial assessment, and analysis was performed by intention to treat. Survival was computed from the time of assessment and Cox regression used to stratify patients according risk with the Heart Failure Survival Score. RESULTS: From May 1993 to September 2001, a total of 755 patients were admitted for transplant assessment, with 348 (46.1%) identified as having heart failure of ischemic origin. Variables required for calculation of the Heart Failure Survival Score was available in 273 patients (78.4%), and 20 patients (7.3%) were lost to follow-up. Of the remaining 253 patients, 89 (35.2%) were allocated to medical therapy, 32 (12.6%) to surgery, and 132 (52.2%) to transplantation. The relative risk (95% confidence limit) of death compared with medical therapy was 0.62 (0.28, 1.40) for surgery and 0.38 (0.24, 0.61) for transplantation in medium- to high-risk patients. For low-risk patients, the relative risks for death compared with medical therapy were 1.87 (0.63, 5.60) for surgery and 1.97 (0.79, 4.96) for transplantation. CONCLUSIONS: Transplantation improved survival of medium- and high-risk patients compared with medical therapy. In the low-risk group, this was not evident. However, repeated assessment of risk is required because the hazard for death rises steadily after the third year in these patients.
BACKGROUND: Over 50,000 heart transplants have been performed in the last 3 decades. The global shortage of donor organs and the relaxation of candidate selection criteria over time has resulted in recent controversy about the benefits of heart transplantation for some risk groups. We assessed the survival benefit acquired in the Papworth Hospital heart transplant population overall, taking into account resuscitated marginal donors and high-risk recipients. METHODS: All heart transplant patients listed between 1979 and June 2002 were analyzed (n = 1,212). Of these, 931 cardiac transplantations were done, including the use of 126 marginal donors. High-risk recipients (n = 163) were defined as patients being in the hospital, on intravenous inotropic drugs, and/or with a high transpulmonary gradient (>15 mm Hg). Using Cox regression with transplantation as a time-dependent covariate, we assessed the survival benefit of transplantation. In our model we assumed that after transplantation the initial risk of death is high relative to continued waiting, followed by an exponential decline in risk. The crossover point (COP) is the time at which the risk of death after transplantation is equal to that of continued waiting (i.e., the relative risk is 1). The equity point (EP) determines the time at which the early post-operative risk is offset by the later period of lower risk and, therefore, the time at which transplantation has a survival advantage. RESULTS: Overall, the COP was at 54 days and EP at 141 days. In the marginal donor sub-group, COP was achieved at 32 days with EP at 72 days, indicating a survival benefit. The difference in the COP and EP between the borderline donor and normal donor sub-groups was not statistically significant. Post-transplant survival was not significantly different from recipients of normal cardiac allografts (p = .43). Likewise, for the high-risk recipient group, the COP and EP were at 72 and 203 days. Although post-op survival was significantly shorter than the normal-risk group, both groups achieved survival benefits. CONCLUSION: Heart transplantation provides survival benefit in these risk groups of recipients in our population. This is a reflection of our active donor management protocol and rigorous donor and recipient selection process.
Explore the source record for details and available documents.
BACKGROUND: Experimental and clinical studies suggest that brain death (BD)-associated cardiac dysfunction is related to the neurohormonal storm and subsequent exposure to intravenous catecholamines. We aimed to describe the relationship between empirical noradrenaline treatment and donor heart function, described for the first time with load-independent indices of right ventricular contractility. METHODS: Twenty-seven BD patients were divided in three groups based on noradrenaline at time of offer, started by the donor hospital: group 1=no noradrenaline (n=11); group 2=low dose (n=8); group 3=high dose (n=8). After protocol-guided optimization by our retrieval team using a Swan-Ganz catheter, pressure-volume data were obtained from the right ventricle. Ten patients undergoing coronary revascularization served as controls. RESULTS: Twenty hearts were transplanted, seven of them as heart and lung blocks. Right ventricular end-systolic elastance (E(es)) was lower in BD donors compared with controls (mean 0.28 vs. 0.46 mm Hg/mL, P< or =0.01). There was no difference in terms of Swan-Ganz derived data between the BD subgroups, but E(es) was lower in groups 2 and 3 (P=0.04). Eight patients died within a year (four from graft failure), and they had a donor heart E(es) significantly lower than that of survivors (mean 0.20 vs. 0.33 mm Hg/mL, P=0.01). CONCLUSION: Hearts from BD donors have subclinical right ventricular impairment in contractility. E(es), a load-independent measure of contractile function, seems to be inversely correlated with empirical use of noradrenaline in the donor and with recipient survival at 1 year. This has implications for refining donor selection and management.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
BACKGROUND: The deleterious effects of brainstem death (BSD) on donor cardiac function and endothelial integrity have been documented previously. Domino cardiac donation (heart of a heart-lung recipient transplanted into another recipient) is a way to avoid the effects of brainstem death and may confer both short- and long-term benefits to allograft recipients. METHODS: This study evaluates short- and long-term outcome in heart recipients of BSD donors (cadaveric) as compared with domino hearts explanted from patients who underwent heart-lung transplantation. RESULTS: Patients having undergone cardiac transplantation between April 1989 and August 2001 at Papworth Hospital were included (n = 571). Domino donor hearts were used in 81 (14%) of these cases. The pre-operative transpulmonary gradient was not significantly different between the two groups (p = 0.7). There was no significant difference in 30-day mortality (4.9% for domino vs 8.6% for BSD, p = 0.38) or in actuarial survival (p = 0.72). Ischemic time was significantly longer in the BSD group (p < 0.001). Acute rejection and infection episodes were not significantly different (p = 0.24 vs: 0.08). Relative to the BSD group, the risk (95% confidence interval) of acute rejection in the domino group was 0.89 (0.73 to 1.08). Similarly, the relative risk of infection was 0.78 (0.59 to 1.03). The 5-year actuarial survival rates (95% confidence interval) were 78% (69% to 87%) and 69% (65% to 73%) in the domino and BSD groups respectively. Angiography data at 2 years were available in 50 (62%) and 254 (52%) patients in the domino and BSD groups, respectively. The rates for 2-year freedom from cardiac allograft vasculopathy (CAV) were 96% (91% to 100%) and 93% (90% to 96%), respectively. CONCLUSION: Despite the lack of endothelial cell activation after brainstem death and a shorter ischemic time, the performance of domino donor hearts was similar to that of BSD donor hearts. This may indicate a similar pathology (i.e., endothelial cell activation) in the domino donors.
Cardiac allograft vasculopathy (CAV) is a common cause of death after heart transplantation. Coronary angiography is used to monitor the progress of recipients. Diagnostic accuracy of angiography and risk factors for CAV have not been clearly established. Between August 1979 and January 2002, 566 1-year survivors of heart transplantation underwent 2168 angiograms and were classified as having no CAV (0% stenosis), mild-moderate CAV (up to 70% stenosis), or severe CAV (>70% stenosis). We used serial measurements of stenosis to estimate the diagnostic accuracy of angiography and to assess the following risk factors for CAV onset, progression, and survival: recipient and donor age and sex, preoperative ischemic heart disease (IHD), acute rejection rates, cytomegalovirus (CMV) infection, and serologic status. CAV was diagnosed by angiography in 248 of 556 (45%) 1-year survivors, with a mean onset time of 8.6 years. Patients spent a mean of 3.4 years with mild-moderate disease and 3.4 years with severe disease before death. Angiography specificity was 97.8%, and sensitivity was 79.3%. The following variables were found to significantly increase the risk of CAV onset: recipient age relative rate (95% confidence interval) 1.16 (1.01-1.34), donor age by 1.27 (1.13-1.43), male recipient by 2.00 (1.11-2.57), pretransplant IHD by 1.75 (1.30-2.36), cumulative rejection by 1.13 (1.05-1.21), and CMV infection by 1.42 (1.06-1.92). Acute rejection increased risk of death by 1.48 (1.19-1.85). Angiography is highly specific and moderately sensitive for diagnosis of CAV. Risk of CAV onset is related to donor age and recipient history of pretransplant IHD and is further increased by immune-related insults of acute rejection and CMV infection.
Operations for aneurysms of the descending thoracic aorta are still fraught with danger. Spinal cord injury remains a major cause of morbidity. Many therapeutic strategies have been suggested to reduce the incidence of this devastating complication, including reimplantation of intercostal vessels. However, reimplantation of intercostal vessels, both individually or in groups, is time consuming and compounded by the absence of a reliable means of identifying which vessels actually supply the cord. We present a technique that allowed inclusion of all potentially important descending aortic branching vessels into the repair leading to a favorable outcome in a series of patients.
Explore the source record for details and available documents.
OBJECTIVE: Brain death appears to predominantly affect the right ventricle (RV) and right ventricular failure is a common complication of clinical cardiac transplantation. It is not clear to what extent myocardial energy stores are affected in the operative sequence. We aimed to describe the time-dependent variation in high energy phosphate (HEP) metabolism of the two ventricles, and the relationship with endothelial activation and postoperative functional recovery. METHODS: Fifty-two human donors had serial biopsies from the RV and the left ventricle (LV) at (1) initial evaluation, (2) after haemodynamic optimisation, (3) end of cold ischaemia, (4) end of warm ischaemia, (5) reperfusion, and (6) at 1 week postoperatively. HEP was measured by chemiluminescence in biopsies 1-5 and adhesion molecules (P-selectin, E-selectin, VCAM-1) and thrombomodulin were analysed by immunohistochemistry in biopsies 5-6. Seventeen donors and five recipients had RV intraoperative pressure-volume recordings by a conductance catheter. Six patients served as live controls. RESULTS: Brain death did not affect HEP metabolism quantitatively. There was no difference between the RV and LV at any time point, but significant time-dependent changes were observed. The RV was prone to HEP depletion at retrieval, with ATP/ADP falling from 3.89 to 3.13, but recovered during cold ischaemia. During warm ischaemia the ATP/ADP ratio fell by approximately 50%, from 5.48 for the RV and 4.26 for the LV, with partial recovery at reperfusion (P<0.005). Hearts with impaired function in the recipient showed marked variations in HEP levels at reperfusion, and those organs with RV dysfunction failed to replenish their energy stores. However, these organs were not different from normally functioning allografts in terms of endothelial activation and clinical risk factors. There was poor correlation between pressure-volume and HEP data in either donor or recipient studies. Hearts followed-up with HEP and pressure-volume studies showed improvement in the recipient, despite functioning against a higher pulmonary vascular resistance. CONCLUSIONS: HEP are preserved over a wide range of contractile performance in the donor heart, with no metabolic difference between the two ventricles. No correlation with endothelial activation was seen either. Preservation efforts should be directed to the vulnerable periods of implantation and reperfusion.
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.
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.
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.