Improved cardiac allograft function following triiodothyronine therapy to both donor and recipient.

Brain death is associated with neuroendocrine changes, in particular with a significant reduction of plasma-free triiodothyronine (T3) that results in impaired aerobic metabolism. Myocardial energy stores are reduced and tissue lactate increased. Cardiac function deteriorates. Similar metabolic changes are seen in patients undergoing open-heart surgery on cardiopulmonary bypass, including those undergoing heart transplantation. Therapy with T3 leads to a reversal of these metabolic changes, resulting in improved cardiac function. One hundred and sixteen consecutive potential donors have been so treated, as have 70 of the recipients. Immediate posttransplant cardiac function was good in all but 3, and these hearts recovered to normal within a maximum of 24 hr of mechanical support. In 2 small randomized trials in patients undergoing myocardial revascularization on cardiopulmonary bypass, postoperative T3 therapy was associated with a reduced need for inotropic support and diuretic therapy in the first study and improved cardiac output in the second study.

Specific intravenous carbohydrate therapy. A new concept in inhibiting antibody-mediated rejection--experience with ABO-incompatible cardiac allografting in the baboon.

Heterotopic allografting of ABO-incompatible donor hearts in recipient baboons "hyperimmunized" against the incompatible A or B antigen (n = 3) was followed by hyperacute antibody-mediated vascular rejection within a mean of 19 min. The A and B epitopes against which these antibodies are directed are carbohydrates that can be synthesized. The continuous i.v. infusion of the specific synthetic A or B trisaccharide, beginning immediately pre-transplant and continued posttransplant for several days, prolonged allograft survival to a mean of 8 days (n = 2) and prevented antibody-mediated rejection, graft failure resulting from acute cellular rejection. The addition of triple pharmacologic immunosuppressive therapy (n = 4) resulted in prolongation of graft survival to a mean of > 28 days, with one heart still beating at 52 days; all grafts showed features of cellular rejection. "Accommodation" would appear to have developed in several baboons as graft function continued for periods of up to 39 days after discontinuation of carbohydrate therapy. Specific i.v. carbohydrate therapy should allow organ allografting to be performed across the ABO blood group barrier in humans. Furthermore, if the carbohydrate epitopes on the organs of discordant animals (e.g., the pig) against which human xenoreactive antibodies are directed can be confirmed, then this form of therapy might allow successful discordant organ xenotransplantation in man.

Triiodothyronine as an inotropic agent after open heart surgery.

Two small, randomized, blind clinical trials comparing the administration of triiodothyronine with that of placebo have been carried out in patients undergoing myocardial revascularization. In patients with a left ventricular ejection fraction of less than 30% (study I), triiodothyronine administration at the end of operation and during the initial 24 hours after operation was associated with a significantly reduced need for conventional inotropic agents (p less than 0.02) and diuretics (p less than 0.02). In patients with a left ventricular ejection fraction of greater than 40% (study II), triiodothyronine administration resulted in significantly improved stroke volume (p less than 0.01) and cardiac output (p less than 0.02) and reduced systemic (p less than 0.01) and pulmonary (p less than 0.05) vascular resistances. There were no adverse reactions to triiodothyronine in the dosages that were used. Triiodothyronine appears to be beneficial to all patients undergoing open heart surgery.

Study of the relative incidences of psychosocial factors before and after heart transplantation and the influence of posttransplantation psychosocial factors on heart transplantation outcome.

Psychosocial factors substance abuse, noncompliance, psychiatric problems, and obesity in relation to the outcome of heart transplantation have been investigated. Data were gathered at the time of initial assessment, and patients (n = 53) were monitored during the follow-up after heart transplantation (mean 18 months). Noncompliance, psychiatric problems, or excessive weight before heart transplantation continued after heart transplantation. Significantly fewer substance abusers exhibited similar behavior after heart transplantation (p < 0.01), although in many cases this exposed other psychiatric or compliance problems. Patients with psychiatric problems after heart transplantation had a higher risk of infection (p < 0.01). Both these patients and those who were noncompliant had higher incidences of hospital readmission (p < 0.01) which were reflected in higher medical costs (p < 0.01) during the second year after heart transplantation in both subgroups. We conclude that (1) heart transplant recipients do not alter previous behavior after heart transplantation except with regard to substance abuse, (2) patients exhibiting substance abuse before heart transplantation and abstaining after heart transplantation have other psychosocial problems, (3) psychosocial problems after heart transplantation do not increase the risk for medical complications in the early posttransplantation period except with regard to infection, and (4) the presence of noncompliance and psychiatric problems after heart transplantation is related to increased readmissions and higher total medical costs.

Successful management of symptomatic cytomegalovirus disease with ganciclovir after heart transplantation.

In the 30-month period from January 1987 through June 1989, 57 patients underwent heart transplantation. Immunosuppressive therapy consisted of a combination of cyclosporine, azathioprine, low-dose methylprednisolone, and antilymphoblast globulin. Clinically significant, proven cytomegalovirus (CMV) disease has developed in no fewer than 22 patients (39%), involving the lung (n = 11), colon (n = 8), stomach (n = 4), and retina (n = 1). The diagnosis was confirmed by direct fluorescent antibody (DFA) (n = 14), histologic study (n = 6), and culture (n = 6) in all cases. The onset of CMV infection occurred at a mean of 5.7 months after heart transplantation (range, 3 weeks to 18 months). All patients were treated with ganciclovir until no sign of active CMV disease could be found. The length of treatment required varied from 2 to 8 weeks (mean, 3.5 weeks). Recurrence has occurred in only one patient, necessitating a further 26-week course of therapy. There were no deaths attributed definitely to CMV disease. There was a higher incidence of acute rejection in the first 3 posttransplant months (0.68 episodes/patient) in the CMV group than in those in whom CMV disease did not develop (0.34 episodes/patient; p less than 0.02). Of the CMV patients, 25% had significant features of graft atherosclerosis during the first posttransplant year, compared with only 8% of the non-CMV patients. In conclusion, (1) there was a high incidence of CMV disease with this immunosuppressive regimen, and we have subsequently discontinued routine antilymphoblast globulin therapy and instituted a triple therapy immunosuppressive protocol with prophylactic immunoglobulin and acyclovir; (2) CMV disease was successfully treated in all cases with ganciclovir alone; and (3) there was a trend toward an increased incidence of both acute rejection and accelerated graft atherosclerosis in the CMV group of patients.

Donor-heart evaluation by monitoring the left ventricular pressure-volume relationship: clinical observations.

Fourteen donor hearts were assessed by measurement of dopamine requirement, basic hemodynamic parameters (for example, systolic blood pressure), and the left ventricular pressure-volume relationship. The latter function was measured by a combination microtipped manometer/conductance catheter placed in the left ventricle through the ascending aorta. With an isoproterenol dose 24 hours after transplantation as the measure of cardiac performance, multiple linear regression analysis indicated that the ratio of arterial elastance (Ea) to left ventricular end-systolic elastance (Ees), ventriculoarterial coupling (Ea/Ees), and myocardial ischemic time were good predictors of posttransplantation cardiac performance. Dopamine requirement and basic hemodynamic data were not. Twelve implanted hearts showed an Ea/Ees of less than 1.0 and showed good early (less than 24 hours) and late function. Two hearts considered on clinical grounds to be unsuitable for transplantation showed an Ea/Ees of more than 1.0. The data suggest that measurement of the left ventricular pressure-volume relationship would appear to be a clinically useful predictor of donor-heart performance after transplantation.

Prevention of loss of vertebral bone density in heart transplant patients.

Seventy-six patients (63 men, 13 women) have been followed up by vertebral bone density (VBD) studies from 3 to 36 months. VBD was measured by single-energy computerized tomographic scan. Before transplantation, VBD was found to be lower than in age-matched controls (less than 40 years of age [group 1], 96% of controls: 40 through 49 years of age [group 2], 77%; 50 to 60 years of age [group 3], 87%; more than 60 years of age [group 4], 76%). After transplantation, despite oral calcium supplements, VBD fell further in all but two patients (97%), which was almost certainly related to maintenance steroid and cyclosporine therapy, and was most marked in the older groups (group 2, 67% compared with age-matched controls at 6 months; group 3, 60%; group 4, 50%). Intensive therapy with synthetic salmon calcitonin (in 29 of 76 patients [38%]), testosterone (in 33 of 63 men [52%]), or estrogen (in 12 of 13 women [92%]) limited, but did not totally prevent, further loss in VBD; in patients who had shown an approximate 45% loss of VBD from pretransplantation levels, further loss was reduced to between 4% and 10%. Five patients increased bone density after calcitonin therapy. Despite significantly reduced VBD in several older patients, minor vertebral bone compression developed in only one patient. We recommend that all patients undergoing heart transplantation, particularly those over the age of 50 years, should be followed by VBD studies, and therapy should be administered to prevent VBD loss.

Identification of alpha-galactosyl and other carbohydrate epitopes that are bound by human anti-pig antibodies: relevance to discordant xenografting in man.

Human anti-pig antibodies were obtained by perfusing pig hearts (n = 4) and kidneys (n = 8) with human AB or O plasma followed by elution with 3 M NaSCN. The antibodies were screened against a panel of 132 synthetic carbohydrates conjugated to bovine serum albumin using an enzyme-linked immunoassay. An anti-immunoglobulin antibody was also used to detect immunoglobulin deposits on pig tissues. Four carbohydrate molecules with a terminal alpha-galactose residue bound all but one of the human anti-pig kidney antibodies and most of the anti-pig heart antibodies. These were: (i) alpha Gal(1-->3)beta Gal(1-->4)beta GlcNac (linear B type 2); (ii) alpha Gal(1-->3)beta Gal(1-->4)beta Glc (linear B type 6); (iii) alpha Gal(1-->3)beta Gal(B disaccharide); and (iv) alpha Gal(alpha-D-galactose). Immunoglobulin deposition was documented post-plasma perfusion in all pig hearts and particularly strongly in all pig kidneys. These results suggest that human anti-pig antibodies are mainly directed against alpha-galactosyl structures. Extracorporeal immunoadsorption of human plasma through columns of the specific synthetic carbohydrate(s) might lead to depletion of anti-pig antibodies and allow discordant xenografting in man. Alternatively, the infusion of the specific carbohydrate(s) for a period of several days might result in neutralization of the anti-pig antibodies and allow accommodation to take place.

Triiodothyronine in the recovery of stunned myocardium in dogs.

Two groups of dogs were subjected to a 15-minute period of regional myocardial ischemia by snaring the left anterior descending coronary artery proximal to its first diagonal branch. After release of the snare, the dogs were given either placebo (group 1: n = 7) or triiodothyronine (T3) therapy (group 2: n = 6). The dose of T3 given was 0.2 microgram/kg at 30-minute intervals to a total of six doses. Plasma free T3 level fell significantly during the ischemic period in both groups and continued to fall after reperfusion in group 1. In both groups, cardiac function deteriorated significantly during the period of ischemia and rapidly returned to control level after reperfusion. After 90 minutes of reperfusion, however, deterioration of left ventricular function was observed in group 1 and was significantly worse than in group 2, in which hemodynamic function was maintained and, in fact, improved to levels superior to control. It is suggested that T3 therapy may be worthy of trial in patients in whom reperfusion of the myocardium takes place after a relatively short ischemic period (the "stunned myocardium").

Methyl methacrylate plate to prevent compression after heart transplantation.

A methyl methacrylate plate was fashioned to maintain the sternum in the open position in a patient with impaired donor heart function after transplantation. Bilateral mammary flaps enabled soft tissue and skin closure. The chest wall fixation obtained allowed extubation and spontaneous breathing. The plate was subsequently removed. The patient remains well almost 3 years later.

Interferon alpha treatment of chronic hepatitis C in patients with evidence for co-existent autoimmune dysregulation.

BACKGROUND/AIMS: We performed a prospective nonrandomized clinical trial to demonstrate that Interferon (IFN) treatment of individuals with chronic hepatitis C virus (HCV) positive hepatitis (CH-C) and serologic and/or histologic evidence of autoimmune dysregulation is feasible and whether the benefits of successfully treating CH-C are outweighed by the risk of exacerbating Autoimmune Chronic Active Hepatitis (ACAH). PATIENTS AND METHODS: 23 patients with positive autoimmune dysregulation markers underwent a 6 month course of IFN treatment for chronic HCV hepatitis and were followed for a total of 12 months. Patients were treated with 5 MU of a2b IFN administered subcutaneously 7 days a week for 6 months. Complete blood counts and a panel of liver enzymes were monitored weekly for 4 weeks and then monthly for an additional 11 months (6 months of therapy and 6 months of follow-up). Serum auto-antibodies titers were determined prior to treatment, at the end of the treatment and again after 6 months of follow-up. A liver biopsy was performed prior to, and at the end of treatment and again at 12 months. RESULTS: Using the standard ALT criteria for defining a response to IFN therapy, 14 (61%) patients experienced a full response and 3 (13%) experienced a partial response. Forty-three percent of the full responders and 33% of the partial responders experienced a relapse during the follow-up. The titer of each of the previously positive autoantibodies either remained unchanged or increased by 1 or 2 dilutions. No clinical exacerbations of a co-existent ACAH were observed. CONCLUSIONS: Individuals with combined CH-C and one or more markers of autoimmune dysregulation can be treated successfully with IFN. Such treatment does not necessarily increase or exacerbate co-existent ACAH and elevate the serum ALT level. In those who clear HCV-RNA as a result of IFN, the liver histology shifts from one consistent with CH-C to resembling ACAH.

A suggested technique for "orthotopic" heart transplantation in a patient with situs inversus.

We describe a technique for "orthotopic" heart transplantation in a patient with situs inversus. The left atrial, aortic, and pulmonary artery anastomoses were performed directly, in the usual manner. The recipient's right atrium was converted into a tunnel, and the donor's right atrium was left intact. Anastomoses were therefore required between the 2 inferior venae cavae (by direct end-to-end anastomosis) and the 2 superior venae cavae (necessitating the insertion of a Dacron-graft). We suggest that even simpler techniques, perhaps not requiring the use of an artificial vascular prosthesis, are possible.

Donor organ availability.

As the results of organ transplantation show steady improvement, we have seen a marked increase in the number of potential organ recipients. During this time however, the number of donor organs becoming available has remained little changed. The reasons for this phenomenon and some potential solutions for improving the supply of donor organs are reviewed.

The gastrointestinal management of patients undergoing heart transplantation.

Between March 1985 and December 1989, 86 patients underwent heart (80) or heart-lung (6) transplantation. Thirty-seven (43%) developed one or more significant gastrointestinal problems. Dyspepsia and gallbladder disease were common, but easily managed. Cytomegalovirus disease occurred in 25 patients (29%) and required aggressive investigation and early therapy with ganciclovir; all patients so treated responded satisfactorily. Features of acute peritonitis were seen in 6 patients and required exploratory laparotomy in 4. Non-Hodgkin's lymphoma of the stomach in one patient has regressed following a combination of reduction in immunosuppressive therapy and a course of chemotherapy. The development of hepatitis or severe liver dysfunction of unknown cause has been associated with significant morbidity and mortality. Since this study was undertaken, the incidence of gastrointestinal complications has been greatly reduced by modifications to our immunosuppressive and anti-infection prophylactic drug protocols. Nevertheless, such complications still occur and it is important that the gastroenterologist should understand the need for urgent and intensive investigation and therapy.

Cardiac transplantation in patients aged 60 years or older.

One hundred eighty-four consecutive patients who underwent heart transplantation from January 1987 to December 1994 have been reviewed. Patients who were 60 years of age or older at the time of transplant (Group A, n = 50) showed improved overall survival when compared with younger patients (Group B, n = 134), though this was not statistically significant. Survivals in groups A and B were 94% and 90%, respectively, at 1 year; 86% and 80% at 5 years; and 86% and 78% at 8 years. Overall survival of older patients in the U.S. and worldwide is inferior when compared with younger patients. More thorough pretransplant evaluation of the older patient and improved compliance post-transplantation may be factors in the good results obtained in this group at our own center.

Experience with cardiorespiratory support devices in patients undergoing heart and heart-lung transplantation.

During the 2-year period 1987 through 1988, 124 patients were assessed for heart or heart-lung transplantation. Sixty were accepted for heart transplantation, of whom 49 received transplants. Nine required pretransplant intra-aortic balloon pump support (+/- positive-pressure ventilation) for periods ranging from 2 to 15 days (mean 5 days). One patient was supported successfully by a pneumatic biventricular assist device for 70 days pretransplant. The 30-day survival in this group of 10 critically unstable patients was 100% and the 6-month survival 90% (one death). This experience compares well with survival rates of 100% at 30 days and 92% at 6 months in the 39 patients who required no form of pretransplant circulatory support. The biventricular assist device also has been used in 2 other patients; one did not survive to transplant and the other was deemed unsuitable by virtue of cerebral injury. Extracorporeal membrane oxygenation supported 2 posttransplant patients (one heart and one heart-lung) with grossly impaired pulmonary function for periods of 5 and 2 days respectively, but both died before lung function had recovered.

Survival following organ transplantation in an Oklahoma institution, 1985-1993.

Since 1985, a total of 413 patients have undergone 439 solid organ transplants at the authors' institution. The current actuarial one-year survival rate of patients undergoing heart, kidney, lung, or liver transplantation at our center is 94%, 90%, 87%, and 91%, respectively. Five-year survival of heart and kidney recipients is 80% and 75%, respectively. In view of these excellent results and the excellent quality of life that successful organ transplants provide patients with end-stage organ failure, every possible effort should be made to increase organ donation.

Experience with endomyocardial biopsy in 23 patients with heart transplants.

In the 33-month period April 1985 to December 1987, endomyocardial biopsy was performed 314 times in 23 patients with orthotopic (21) or heterotopic (2) heart transplants at Baptist Medical Center. The technique is described. Adequate tissue was obtained in 99% of cases and there was only one complication from the procedure. Mild to severe acute rejection was seen in 105 specimens (33%). The histopathological interpretation has proved invaluable in the care of patients with heart transplants.