Physiologic Changes in the Heart Following Cessation of Mechanical Ventilation in a Porcine Model of Donation After Circulatory Death: Implications for Cardiac Transplantation.

Hearts donated following circulatory death (DCD) may represent an additional source of organs for transplantation; however, the impact of donor extubation on the DCD heart has not been well characterized. We sought to describe the physiologic changes that occur following withdrawal of life-sustaining therapy (WLST) in a porcine model of DCD. Physiologic changes were monitored continuously for 20 min following WLST. Ventricular pressure, volume, and function were recorded using a conductance catheter placed into the right (N = 8) and left (N = 8) ventricles, and using magnetic resonance imaging (MRI, N = 3). Hypoxic pulmonary vasoconstriction occurred following WLST, and was associated with distension of the right ventricle (RV) and reduced cardiac output. A 120-fold increase in epinephrine was subsequently observed that produced a transient hyperdynamic phase; however, progressive RV distension developed during this time. Circulatory arrest occurred 7.6±0.3 min following WLST, at which time MRI demonstrated an 18±7% increase in RV volume and a 12±9% decrease in left ventricular volume compared to baseline. We conclude that hypoxic pulmonary vasoconstriction and a profound catecholamine surge occur following WLST that result in distension of the RV. These changes have important implications on the resuscitation, preservation, and evaluation of DCD hearts prior to transplantation.

Hearts from DCD donors display acceptable biventricular function after heart transplantation in pigs.

Cardiac transplantation is in decline, in contrast to other solid organs where the number of solid organ transplants from donors after circulatory death (DCD) is increasing. Hearts from DCD donors are not currently utilized due to concerns that they may suffer irreversible cardiac injury with resultant poor graft function. Using a large animal model, we tested the hypothesis that hearts from DCD donors would be suitable for transplantation. Donor pigs were subjected to hypoxic cardiac arrest (DCD) followed by 15 min of warm ischemia and resuscitation on cardiopulmonary bypass, or brainstem death (BSD) via intracerebral balloon inflation. Cardiac function was assessed through load-independent measures and magnetic resonance imaging and spectroscopy. After resuscitation, DCD hearts had near normal contractility, although stroke volume was reduced, comparable to BSD hearts. DCD hearts had a significant decline in phosphocreatine and increase in inorganic phosphate during the hypoxic period, with a return to baseline levels after reperfusion. After transplantation, cardiac function was comparable between BSD and DCD groups. Therefore, in a large animal model, the DCD heart maintains viability and recovers function similar to that of the BSD heart and may be suitable for clinical transplantation. Further study is warranted on optimal reperfusion strategies.

Aortic valve replacement for late infective endocarditis after heart-lung transplantation.

Infective endocarditis is a rare but life-threatening complication of heart and heart-lung transplantation. We describe a 32-year-old woman who developed aortic valvular endocarditis following heart-lung transplantation. Enterococcus was the infective organism. The patient's condition was successfully managed using prolonged intravenous antibiotic therapy and aortic valve replacement.

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.

Risk factors for survival following combined heart-lung transplantation. The first 100 patients.

As the numbers of heart and lung transplant recipients have increased it has become possible to identify major risk factors for early (within 3 months) and later (after 3 months) death after this procedure. For 100 patients receiving organs between April 1984 and February 1991, and followed up until February 1992, patient characteristics, operative details, and early morbidity were assessed for their effects on early and later deaths. Recipient age, sex, and preoperative diagnosis did not have a significant effect on early (within 3 months) or later death. Positive cytomegalovirus antibody status of donor or recipient conferred greater risk of death within 90 days (odds ratio [OR] = 3.24, P = 0.06). Greater than 2 L blood in the first 24 hr after operation (OR = 6.00, P = 0.05), and ventilation for greater than 24 hr (OR = 4.87, P = 0.006) were significant prognostic indicators of early death. After the first 3 months, the main risk factor for death was rejection in the first 3 months (OR = 1.38 per episode, P = 0.008). Early infection in general and CMV infection in particular were associated with a small increase in risk. This study confirms the importance of matching donor and recipient for CMV and shows that difficulties during operation, reflected in postoperative bleeding and ventilation times increased the chance of early death. Later death was associated with early acute rejection. A detrimental effect of infection, including CMV infection, either does not exist, or is too small to be detected in a study of this size.

Human leukocyte antigen compatibility in heart transplantation: evidence for a differential role of HLA matching on short- and medium-term patient survival.

BACKGROUND: Studies of the influence of human leukocyte antigen (HLA) matching on cardiac transplant outcome have proved inconclusive, mainly due to the lack of well-matched grafts. However, a growing number of studies report improved clinical course and patient survival in cases with increased HLA compatibility. Opelz et al. believe these benefits justify the introduction of prospective HLA-matching strategies. METHODS: We performed univariate and multivariate analyses to examine the short- and medium-term influence of HLA matching on 556 consecutive primary heart transplants performed at a single center between 1983 and 1994. Overall graft survival at 1, 3, and 5 years was 80%, 74%, and 67% respectively. Sixteen (2.9%) grafts failed within 5 days and were not considered in the analysis of the HLA matching and graft survival data. RESULTS: Complete HLA-A, -B, and -DR typing data were available on 477 transplant pairs. The results demonstrate a 12% 1-year survival advantage for 31 patients with zero to two HLA antigen mismatches compared with three to six mismatches. The influence of each individual locus was 6.1%, 8.4%, and 5.4% for zero HLA-A, -B, and -DR mismatches, respectively, compared with two mismatches. However, when outcome from 1 to 5 years was considered, analysis of the role of each locus revealed marked differences. HLAA-matched grafts (n=45) had a 24% lower survival rate compared with two-antigen-mismatched grafts (n=148; 88% [SE 3.1] vs. 64% [SE 8.2], respectively; P=0.009). Furthermore, 34% of HLA-A-matched grafts failed between 1 and 5 years, compared with only 5% of HLA-B-matched grafts (P=0.013). CONCLUSIONS: These data suggest that although HLA matching is effective at reducing acute graft loss, in the longer term, HLA-A matching may impair survival. HLA-A may serve as a restriction element for indirect presentation of allopeptides or tissue-specific minor histocompatibility antigens, facilitating chronic graft loss. Therefore, we advocate a differential role for HLA matching over two epochs. A blanket approach to prospective matching for heart transplants may be premature for optimal long-term survival.

Error rates with which endomyocardial biopsy specimens are graded for rejection after cardiac transplantation.

Control of the immune response to the transplanted organ is fundamental to the success of transplantation. Endomyocardial biopsy to diagnose and grade rejection is the mainstay in achieving this control. As rejection tends to be a patchy process, accurate diagnosis depends on adequate sampling from the myocardium. This study estimates the error rates with which biopsy specimens are graded. The results of 459 biopsy sets, in which at least 4 fragments were graded, were analyzed. Combinations of grades observed at the same biopsy session were used to estimate error rates. An E-M algorithm was used to estimate error rates. Predictive probabilities of true grades, given a set of 4 graded fragments, were calculated using Bayes theorem. If 4 fragments at a biopsy session were negative there was a 0.02% chance of missing clinically significant rejection (moderate or severe). Similarly, if minimal rejection was the highest grade observed, the probability of missing moderate-severe rejection was negligible, between 0.06 and 0.09%. However, where mild rejection is the highest observed on the 4 fragments, there is between a 2% (1 mild fragment) and 28% (4 mild fragments) chance of moderate-severe rejection being the underlying grade. This study concludes that 4 fragments are adequate as a minimum in most cases. However, if only 4 fragments are available, and greater than or equal to 3 are graded mild, the risk of missing moderate-severe rejection is unacceptably high, and repeat biopsy or treatment may be indicated.

Domino heart transplantation: the Papworth experience.

The use of donor hearts from heart-lung recipients, the so-called domino procedure, began at Papworth Hospital in November 1988. Between then and September 1992, 198 heart transplantations and 86 heart-lung transplantations were performed. Fifty-three heart-lung recipients donated their hearts for use in the domino procedure. Thirty-two domino hearts were transplanted at Papworth and 21 were exported to other centers. Institution of the domino procedure allowed us to perform 19% more heart transplantations (166 to 198) than would have been done had the procedure not been used. The ischemic time was significantly shorter for the domino hearts compared with organs from brain dead donors (134 minutes versus 191 minutes; p < 0.001). No difference was found in the 3-month (84% versus 83%) or 1-year (74% versus 76%) survival between domino and nondomino recipients. Other potential advantages of the domino procedure include detailed pretransplantation evaluation of the heart in live donors and the potential for human leukocyte antigen matching. Additionally many heart-lung recipients have elevated pulmonary artery pressures and a "conditioned", hypertrophied right ventricle. The use of such hearts for heart transplantation has theoretic appeal for patients with elevated pulmonary vascular resistance.

Transforming the "unacceptable" donor: outcomes from the adoption of a standardized donor management technique.

BACKGROUND: Donor management remains one of the most neglected areas of transplantation. A comprehensive donor management regimen has been developed. The results of the application of this strategy form the basis of this report. METHODS: Full hemodynamic data were collected from 150 multiorgan donors between October 1990 and August 1993. The data were collected at the time of donor team arrival, after insertion of a pulmonary artery floatation catheter and immediately before cardiac excision. RESULTS: Fifty-two donors (35%) fell well outside our minimum acceptance criteria on arrival. Twenty-one of fifty-two had a mean arterial pressure less than 55 mm Hg (mean 47 mm Hg) despite inotropic support in most cases; 10 of 52 had a central venous pressure greater than 15 mm Hg (mean 18.0 mm Hg); 2 of 52 had a high inotrope requirement greater than 20 micrograms/kg/min (mean 25 micrograms/kg/min). After the insertion of a pulmonary artery floatation catheter, an additional 13 of 52 donors were found to have a pulmonary capillary wedge pressure greater than 15 mm Hg (mean 19.8 mm Hg), and the final 6 of 52 had a low left ventricular stroke work index, less than 15 gm (mean 12.8 gm). After optimal management, including hormone replacement 44 of 52 donors yielded transplantable organs (29 hearts, 15 heart and lung blocks). Thirty-seven of forty-four patients (84%) were alive and well from 13 to 48 months after transplantation. There were five early deaths (11%) caused by infection (heart), adult respiratory distress syndrome (heart), arrhythmia (heart), cerebrovascular event (heart and lung), and infection (heart, lung, and liver). Two late deaths (5%) occurred as a result of tamponade (3 months, heart) and infection (14 months, heart and lung). Eight of fifty-two organs were still unsuitable for transplantation after optimum management during the splanchnic dissection as a result of inotrope dependency (n = 4), left ventricular hypertrophy (n = 2), and coronary artery disease (n = 2). CONCLUSIONS: The data indicate that, of the organs which initially fall outside our transplant acceptance criteria, 92% are capable of functional resuscitation. Conversely, superficial assessment may not show compromised function. Optimizing cardiovascular performance also has important implications for the viability of all transplantable organs. This aggressive approach to donor management has resulted in the transplantation of 44 donor hearts that may otherwise have been turned down or inappropriately managed.

Heart transplantation in the United Kingdom: who waits longest and why.

BACKGROUND: This study aims to identify characteristics that increase the chance of death of potential cardiac transplant recipients before donor organs become available. METHODS: Between June 1, 1988, and May 31, 1993, 332 patients were accepted for heart transplantation; 235 underwent surgery. Ninety-seven patients had not received transplants; of these, 71 died, 13 were transferred to other lists, and 13 were awaiting organs at the close of the study. Median waiting time for those patients who received organs was 109 days, whereas patients who did not receive organs spent a median of 94 days on the list. Recipients are matched to donor organs according to blood group, size (height), and, recently, preoperative transpulmonary pressure gradient. Recently cytomegalovirus antibody mismatches (positive donor to negative recipient) have been avoided where possible. These factors, together with age, gender, underlying diagnosis, previous heart surgery, and Toxoplasma antibody status were studied to assess their influence on waiting time and survival. RESULTS: No characteristics were found significantly to influence survival after acceptance, so that the chance of death while the patient was waiting for heart transplantation is mainly affected by the severity of disease and the length of time a patient waits. In multivariate analyses the following were independently significantly associated with shorter waiting times: small patients (< 1.7 m tall; p = 0.005), patients with blood types B and AB (p = 0.003), and patients with cardiomyopathy (p < 0.001). CONCLUSIONS: These results can be used by cardiologists to help assess the time at which a patient should be referred for transplantation.

Atrial transplantation for recurrent cardiac sarcoma.

Cardiac transplantation for sarcomas has met with little success and the surgical treatment remains controversial. We describe the case of a 56-year-old woman who was referred for transplantation after two procedures in which undifferentiated atrial sarcoma was locally excised successfully. The patient underwent atrial homograft transplantation, the first reported to date. Advantages of the procedure include wide atrial resection and no need for immune suppression.

Lack of association between endomyocardial evidence of rejection in the first six months and the later development of transplant-related coronary artery disease.

The development of transplant-related coronary artery disease (TCAD) is the major determinant of long-term heart transplant survival. To test the hypothesis that TCAD might be related to cellular myocardial rejection, the grades of rejection seen at all biopsies performed in the first 6 months after heart transplantation were analyzed in 108 patients who survived more than 6 months. The development of TCAD was assessed at routine follow-up coronary angiography in 101 patients and at necropsy in seven patients. This data was analyzed with Kaplan-Meier survival curves and Cox proportional hazard regression analysis. No significant association was found between either moderate rejection or any level of rejection and the later development of TCAD, nor did the absence of any rejection protect against its development.

A method of analyzing the onset and progression of coronary occlusive disease after transplantation and its effect on patient survival.

The development of transplant-acquired coronary occlusive disease is monitored with serial angiography and is graded on a three-point scale as normal, mild (< 50% stenosis), or severe (> or = 50% stenosis). Previous studies have provided information about the time to the first sign of disease on angiography or empirical descriptions of progression. The number of observed transitions between grades of disease has been recorded, and a Markov model based on these transitions is used to estimate the rate of progression through angiographically defined disease grades and the mortality rates from each grade. Five hundred thirty-six angiograms from 240 patients were analyzed. Fifty-three graft failures occurred. The annual transition rate per patient year from normal to mild disease was low, 0.120 (95% credible interval, 0.096 to 0.154), although the transition from mild to severe disease was relatively high, 0.482 (95% credible interval, 0.325 to 0.671). Annual death rates from normal, mild, and severe grades were 0.032 (95% credible interval, 0.016 to 0.052), 0.076 (95% credible interval, 0.007 to 0.187) and 0.415 (95% credible interval, 0.244 to 0.640), respectively. Before onset of disease patients have a hazard-free course, and mild disease displayed on angiography is relatively non-life-threatening. However, once mild disease has been detected by angiography, progression to severe disease is rapid, and severe disease carries a very poor prognosis.

A prospective randomized trial of complete atrioventricular transplantation versus ventricular transplantation with atrioplasty.

BACKGROUND: The standard technique of ventricular transplantation with atrioplasty (SOHT) distorts atrial anatomy. This may compromise diastolic ventricular function, impair atrioventricular valve competence and elevate resting ANP secretion. In contrast, complete atrioventricular anastomosis (CAVT) preserves atrial geometry. METHODS: We evaluated long term outcome in a prospective randomized trial of CAVT vs. SOHT. The primary outcome measures were peak oxygen uptake, atrioventricular valve regurgitation and ANP secretion. RESULTS: 58 recipients (median age 49 years; range 21-64) were consecutively randomized (29 CAVT; 29 SOHT). There were no differences in total ischaemic time, cardiopulmonary bypass time, postoperative bleeding or immunosuppression. Cardiopulmonary exercise tolerance testing was performed by 29 recipients at 742 to 1825 days. Pulmonary function was equivalent. Peak oxygen consumption expressed as a percentage of predicted maximum was 53.5% with CAVT and 63.8% with SOHT (p = 0.14). Echocardiography was performed on 41 recipients at 944 to 1665 days. There was less tricuspid regurgitation with CAVT (3/22 [13.6%] CAVT vs. 10/19 [52.6%] SOHT; p = 0.019). The incidence of mitral regurgitation was similar (5/22 [22.7%] CAVT vs. 4/19 [21.1%] SOHT; p = 0.803). Resting ANP secretion was assessed in 17 recipients at 1013 to 1812 days. All were hemodynamically stable and none had concurrent rejection. Resting ANP secretion was less with CAVT (CAVT: 283 pg/ml; SOHT: 521.4; p = 0.041). CONCLUSIONS: Peak oxygen consumption was not influenced by implantation technique. However, CAVT reduced the incidence of tricuspid regurgitation and attenuated the elevation in resting ANP secretion.

Influence of recipient and donor gender on outcome after heart transplantation.

To investigate the effect of recipient and donor genders on the outcome after heart transplantation, a retrospective survey was undertaken of 356 patients (366 transplants: 316 males, 40 females) undergoing transplantation between January 1979 and December 31, 1989, at Papworth Hospital. Ninety-three organs came from female donors; 263 organs came from males. Twelve females (30%; 95% confidence interval 16% to 44%) and 51 males (16%; 95% confidence interval 12% to 20%) died in the early postoperative period (within 90 days of operation). To date, two females (5%) and 51 males (16%) have died in the late postoperative period. Comparison between recipient genders showed no statistically significant difference in early mortality rates from any cause or in actuarial survival overall, although fatal acute rejection was significantly more common in female recipients (7 of 40 female recipients versus 19 of 316 male recipients). The higher incidence of fatal rejection among female recipients was related to the higher proportion of female donors in this group, because recipients of female donor grafts had significantly higher mortality rates, particularly in the early postoperative period and as a result of acute rejection, than did recipients of organs from male donors. Death from rejection after the first 3 months and death from infection were not gender-related. Recipients of grafts from female donors did not suffer significantly more early morbidity, such as rejection and infection, or late morbidity in the form of coronary artery disease. Acute rejection episodes were more common in female recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

Heart-lung transplantation in situs inversus and chest wall deformity.

Heart-lung transplantation in the presence of complex congenital heart disease including situs inversus and significant chest wall deformity can be accomplished successfully. However, the postoperative course is apt to be prolonged because of mechanical respiratory problems, which will respond to a protocol of weaning and nutritional supplementation.

Alternative method for cardiac transplantation: surgical considerations and technical aspects.

A simplified technique for complete orthotopic cardiac transplantation is described. The potential technical difficulties and surgical considerations are discussed.

Improved outcome with organs from carbon monoxide poisoned donors for intrathoracic transplantation.

BACKGROUND: The success of intrathoracic organ transplantation has lead to a growing imbalance between the demand and supply of donor organs. Accordingly, there has been an expansion in the use of organs from nonconventional donors such as those who died from carbon monoxide poisoning. We describe our experience with 7 patients who were transplanted using organs after fatal carbon monoxide poisoning. METHODS: A retrospective study of the 1,312 intrathoracic organ transplants between January 1979 and February 2000 was completed. Seven of these transplants (0.5%) were fulfilled with organs retrieved from donors after fatal carbon monoxide poisoning. There were six heart transplants and one single lung transplant. The history of carbon monoxide inhalation was obtained in all of these donors. RESULTS: Five of 6 patients with heart transplant are alive and well with survival ranging from 68 to 1,879 days (mean, 969 +/- 823 days). One patient (a 29-year-old male) died 12 hours posttransplant caused by donor organ failure. The patient who had a right single lung transplant did well initially after the transplant, but died after 8 months caused by Pneumocystis carinii pneumonia. All those recipients who were transplanted from carbon monoxide poisoned donors and ventilated for more than 36 hours, survived for more than 30 days. Moreover, these donors were assessed and optimized by the Papworth donor management protocol. CONCLUSIONS: Carbon monoxide poisoned organs can be considered for intrathoracic transplantation. In view of the significant risk of donor organ failure, a cautious approach is still warranted. Ideally, the donor should be hemodynamically stable for at least 36 hours from the time of poisoning and on minimal support. A formal approach of invasive monitoring and active management further improves the chances of successful outcome.

Heart-lung transplantation for Eisenmenger syndrome: early and long-term results.

BACKGROUND: Heart-lung transplantation (HLT) for Eisenmenger syndrome (ES) provides superior early and intermediate survival when compared with other forms of transplantation. The early risk factors and long-term outcome of HLT for ES are less well defined. METHODS: We analyzed 263 patients who had undergone HLT at our institution during more than 15 years. Fifty-one consecutive patients with ES who underwent HLT, 33 (65%) of which had simple anatomy, were compared with 212 cases having HLT for other indications (non-ES). RESULTS: Female sex and previous thoracotomy were more prevalent in the ES group. Patients with ES had greater postoperative blood loss and returned more frequently to the operating room for control of bleeding. There were 8 (16%) early deaths in the ES group compared with 27 (13%) in non-ES (p = 0.65). One-, 5-, and 10-year survival rates for ES were 72.6%, 51.3%, and 27.6%, respectively, compared with non-ES of 74.1%, 48.1%, and 26.0%, respectively, and there was no difference in survival overall (p = 0.54). Among ES patients, previous thoracotomy was a risk factor for hospital death. A subgroup analysis based on simple versus complex type of ES did not show statistically significant differences in terms of postoperative course or early or late survival. CONCLUSIONS: Heart-lung transplantation is a successful procedure for ES. Despite a greater frequency of risk factors and a more difficult operative course, early and late outcome with HLT is comparable to non-ES recipients.

Coronary artery bypass grafting nine years after cardiac transplantation.

Angina and increasing exertional dyspnea developed in a 53-year-old man 9 years after cardiac transplantation. Left heart catheterization revealed severe proximal triple coronary artery disease, and he underwent surgical revascularization. Now 18 months after the operation he continues to be free of symptoms.