Stephen R. Large

Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease

BACKGROUND Endothelial cells release endothelium-derived relaxing factor (EDRF) in a variety of vascular beds, including the pulmonary circulation. However, the role of EDRF-mediated pulmonary-artery relaxation in chronic hypoxic lung disease is unknown. METHODS We studied endothelium-dependent relaxation mediated by EDRF in vitro in pulmonary arteries that had been obtained from 22 patients undergoing heart-lung transplantation for end-stage chronic obstructive lung disease. Control pulmonary arteries were obtained from 15 patients undergoing lobectomy for lung carcinoma who did not have evidence of other chronic lung disease. The responses of all vascular rings (external diameter, 1.2 to 3.4 mm) to the endothelium-dependent vasodilators acetylcholine and adenosine diphosphate were studied immediately after lung excision. RESULTS Pulmonary arterial rings from the patients with chronic lung disease developed a greater tension (2.19 +/- 0.16 g) in response to phenylephrine (10(-6) M) than the rings from control patients (1.28 +/- 0.18 g, P less than 0.05). Inhibition of EDRF synthesis by treatment with NG-monomethyl-L-arginine (10(-4) M) eliminated this difference, increasing the tension in the rings from the controls (P less than 0.01) but not in those from the patients with chronic lung disease. Rings from control patients relaxed in response to cumulative doses (10(-10) to 10(-5) M) of acetylcholine (maximal relaxation, 81.3 +/- 3.9 percent) and adenosine diphosphate (maximal relaxation, 85.3 +/- 2.6 percent). By contrast, rings from patients with chronic obstructive lung disease achieved only 41.3 +/- 4.8 percent of maximal relaxation in response to acetylcholine (n = 32) and 49.4 +/- 5.5 percent in response to adenosine diphosphate (n = 24) (P less than 0.001, as compared with control rings). Rings from both the controls and the patients with chronic lung disease relaxed similarly in response to the endothelium-independent vasodilator sodium nitroprusside (10(-4) M). There was an inverse correlation between the degree of intimal thickening and the level of maximal relaxation of the rings from the patients with chronic lung disease (r = -0.60, P less than 0.001). Maximal relaxation was also related directly to the partial pressure of arterial oxygen before transplantation (r = 0.68, P less than 0.01) and inversely to the partial pressure of arterial carbon dioxide before transplantation (r = -0.55, P less than 0.01), but not to the forced expiratory volume in one second (r = 0.19, P not significant). CONCLUSIONS Endothelium-dependent pulmonary-artery relaxation in vitro is impaired in arteries from patients with end-stage chronic obstructive lung disease. Such impairment may contribute to the development of pulmonary hypertension in chronic hypoxic lung disease.

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 ≈6000 to 8000 per year. Because the number of available donor hearts has not increased beyond ≈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 recove...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 6000 to 8000 per year. Because the number of available donor hearts has not increased beyond 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. (Circulation. 2002;106:836-841.)

Risk factor analysis for the major hazards following heart transplantation--rejection, infection, and coronary occlusive disease.

This study demonstrates the importance of analyzing survival by cause of death in order to achieve a better understanding of the prognostic indicators involved. It further emphasizes the need for analysis of risk factors in both univariate and multivariate models, and the danger of making judgements based on premature analysis of data on follow-up after heart transplantation. Survival following transplantation is characterized by the major hazards of early death due to infection and rejection and late graft loss due to coronary occlusive disease (COD). This study summarizes the first-graft survival experience for 323 transplant patients at Papworth Hospital, and assesses a number of potential risk factors for (1) early mortality, (2) late mortality from COD, and (3) development of COD. The potential risk factors considered for all hazards are donor and recipient age, sex, blood group, and matching of these factors; donor cause of death and recipient immunosuppression; inotropic support; waiting time; preoperative diagnosis and previous cardiac surgery; ischemic time; and extubation time. In addition, for development of, and graft loss from, COD, perioperative rejection and cytomegalovirus infection; hypertension at discharge; and cholesterol, triglycerides, and lipids at two years were assessed as risk factors. Advances in immunosuppression were observed to have increased overall survival rates and decreased mortality from infection, rejection, and COD, as well as decreasing morbidity from COD. Fatal rejection was found to be more likely in female recipients, recipients over 40 years, recipients of grafts from donors over 30 years old, patients who were transplanted for valvular heart disease, and patients who waited less than three months for their transplant. Male recipients of female donor organs were more likely to lose their grafts as a result of COD. Patients older than 50 and hearts from donors older than 40 conferred a high risk of development of and loss from COD. Patients transplanted for ischemic heart disease were more likely to develop COD. High cholesterol, low HDL, high LDL, and high triglycerides at two years after transplant showed some evidence of high risk for the subsequent development of COD, although these relationships are not statistically significant at this stage. Contrary to other recent studies, cytomegalovirus infection was not found to be a risk factor for the development of COD.

The Papworth Experience With the Levitronix CentriMag Ventricular Assist Device

OBJECTIVES The Levitronix CentriMag ventricular assist device (VAD) is a centrifugal pump designed for short-term extracorporeal support in cardiogenic shock. The aim of this study is to report our clinical experience with the Levitronix CentriMag for uni- and biventricular support. METHODS Between July 2004 and December 2006, 27 patients were supported using the Levitronix CentriMag device. Nineteen were male. Mean age was 47.9 (range 19 to 72) years. Indications for support at implantation were cardiogenic shock that included: end-stage heart failure and too ill to undergo transplantation, with questionable neurologic status (9 subjects); right ventricular failure after left VAD (LVAD) implantation (5 subjects); post-cardiotomy status (7 subjects); and acute donor graft failure after heart transplantation (6 subjects). RESULTS Post-VAD 30-day survival was 30% (8 patients). Mean support time was 11 days for all patients (range 1 to 51 days). Mean support time for 14 Levitronix biventricular VADs was 11 (range 1 to 51) days. Mean support time for 7 Levitronix LVADs was 13.7 (range 1 to 30) days. The highest survival rates after Levitronix support were after donor graft failure (50%) and after cardiotomy (42%). Levitronix right VAD (RVAD) support after long-term LVAD insertion incurred 100% hospital mortality. Of those who survived, 8 patients were discharged home after VAD support and remain alive to date. Two patients were bridged to primary and another bridged to repeat heart transplantation. Five patients were weaned to recovery. Re-operation for bleeding occurred in 8 patients, clinical evidence of cerebral thromboembolism in 3, overwhelming sepsis in 1, and aortic thrombus formation in 1. Clot formation in the tubing was observed in 1 patient, necessitating emergent replacement at bedside, which was successful. CONCLUSIONS The Levitronix CentriMag system is a reliable and facile temporary circulatory support system as a bridge to decision in patients with refractory acute cardiogenic shock.

Diagnostic accuracy of coronary angiography and risk factors for post–heart-transplant cardiac allograft vasculopathy

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 2,168 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.

Effect of surgical training on outcome and hospital costs in coronary surgery

BACKGROUND There is a perceived conflict between the need for service provision and surgical training within the National Health Service (NHS). Trainee surgeons tend to be slower (thereby reducing theatre throughput), and may have more complications (increasing hospital stay and costs). OBJECTIVE To quantify the effect of training on outcome and costs. DESIGN Data on 2740 consecutive isolated coronary artery bypass (CABG) operations were analysed retrospectively. Redo and emergency procedures were excluded. The seniority of the operating surgeon was related to operating times, risk stratified outcome, and overall hospital costs. SETTING Regional cardiothoracic surgery unit. MAIN OUTCOME MEASURES Postoperative mortality; hospital costs. RESULTS Consultants, senior trainees, intermediate trainees, and junior trainees performed 1524, 759, 434, and 23 procedures, respectively. Trainees at the three different levels were directly supervised by a consultant in 55%, 95%, and 100% of cases. The unadjusted mortalities were 3.2%, 2.0%, 2.3%, and 4.3%, respectively (NS). There were no significant differences between the groups with respect to time in the intensive care unit and length of hospital stay. The mean cost per patient was £6619, £6572, £6494, and £6404 (NS). CONCLUSIONS Trainees performed 44.4% of all CABG operations. There was no detrimental effect on patient outcome, length of hospital stay, or overall hospital costs. There need be little conflict between service and training needs, even in hospitals with extensive training programmes.

Consensus Conference Report

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 ≈6000 to 8000 per year. Because the number of available donor hearts has not increased beyond ≈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 recove...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 6000 to 8000 per year. Because the number of available donor hearts has not increased beyond 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. (Circulation. 2002;106:836-841.)

Indirect comparison meta-analysis of aspirin therapy after coronary surgery.

Objectives To evaluate the efficacy of low and medium dose aspirin therapy after coronary surgery by using an indirect comparison meta-analysis. Data sources Systematic literature search of Medline, Embase, Cochrane controlled trials register, and trial register sites on the internet. Study selection Outcome was evaluated by angiography and reported as graft occlusion and rate of events in patients. Trials that did not include aspirin as the sole therapy or did not have a placebo control arm were excluded. Articles were assessed for eligibility and quality and grouped according to dosage. The estimated difference in effect of low and medium dose aspirin on graft occlusion was obtained by combining the estimated log relative risks of low dose with placebo and medium dose with placebo. Results For graft occlusion, the medium dose trials yielded a relative risk reduction of 45% compared with 26% for the low dose trials. The greater effect in the medium dose trials is summarised by a relative risk ratio of 0.74 (95% confidence interval 0.52 to 1.06; P = 0.10) for graft occlusion and 0.81 (0.57 to 1.16; P = 0.25) for events in patients. Conclusions Medium dose aspirin may more successfully reduce graft occlusion than low dose regimens within the first year after coronary surgery.

Lethal mesenteric ischaemia after cardiopulmonary bypass: a common complication?

OBJECTIVES The purpose of the study was twofold: (1) to identify the incidence of acute mesenteric ischaemia (A.M.Isc.) following cardiopulmonary bypass and (2) to identify factors associated with its development. METHODS A retrospective review of all autopsy reports from 1st January 1994 to 31st December 2000 was undertaken. Fifty-two patients were identified with acute mesenteric ischaemia at post-mortem following cardiac surgery. Demographic, pre-, intra- and post-operative variables were collected from their case notes. Four age, sex and period matched controls [n=208 (4 x 52)] were randomly selected for each case. Conditional logistic regression was used to compare the cases and controls. RESULTS A total of 11,202 patients underwent surgery requiring cardiopulmonary bypass (CPB) during the study period with an overall mortality rate of 3%. The autopsy rate was 95% throughout the study period. From autopsy reports 52 patients (corrected for autopsy rate: 0.49% of group) were identified with A.M.Isc. Comparing controls with A.M.Isc. cases by univariate analysis, significant associations (P</=0.001) with A.M.Isc. were identified. These included: (1) peripheral vascular disease [15 (7%) vs. 14 (27%)]; (2) intraaortic balloon pump (IABP) use [5 (2%) vs. 22 (42%)]; (3) post-operative renal failure [2 (1%) vs. 32 (61%)]; (4) operation type (coronary artery bypass graft (CABG) alone [143 (69%) vs. 25 (48%)], valve alone [35 (17%) vs. 5 (10%)], valve+CABG [23 (11%) vs. 11 (21%)], major cardiac [7 (3%) vs. 11 (21%)]); (5) priority of operation (elective [155 (75%) vs. 27 (52%) emergency 52 (25%) vs. 25 (48%)]; and (6) smoking 12 (7%) vs. 9 (17%). CPB and cross-clamp times (minutes) were also significantly different between the groups [median (inter-quartile range (IQR)); 72 (55,96) vs. 100 (76,128) and 39 (30,54) vs. 56 (37,84), respectively]. Neither diabetes 23 (11%) vs. 6 (12%) nor hypertension 102 (49%) vs. 26 (50%) achieved significance (P<0.001). CONCLUSION The incidence of acute mesenteric ischaemia is 0.49% of all cases undergoing CPB. A.M.Isc. is a common association with death following CPB (11%). It appears to be significantly associated with the presence of peripheral vascular disease, IABP use, the development of post-operative renal failure, operation type and priority, smoking, duration of CPB and cross-clamp time. Surprisingly, it was not linked to general risk factors for vascular disease.

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.