Extended cardiopulmonary preservation: University of Wisconsin solution versus Bretschneider's cardioplegic solution.

Application of the University of Wisconsin cold storage solution has rapidly expanded to include medium-term to long-term preservation of virtually all intraabdominal organs. Its use in intrathoracic organ transplantation has also been suggested. We therefore examined the efficacy of the University of Wisconsin solution in a primate allotransplantation model for preservation of hearts, and as a simple single-solution system for static preservation of heart-lung blocks, for periods of ischemia ranging from 6 to 24 hours. For comparison, we employed the histidine-tryptophane-ketoglutarate cardioplegic solution of Bretschneider. University of Wisconsin solution provided superior results with regard to clinical outcome and hemodynamic recovery of hearts after ischemic periods of up to 16 hours. This was in contrast to Bretschneider's solution, which allowed storage of hearts for periods of only up to 10 hours. Heart-lung blocks were equally well preserved with either University of Wisconsin or Bretschneider's solution after 6 to 12 hours, although the University of Wisconsin solution group exhibited a more notable increase in pulmonary water content. This was in accordance with histological data, which suggested that, although hemodynamic recovery of hearts stored for periods longer than 10 hours was poor, preservation of pulmonary ultrastructure was far superior using Bretschneider's solution as compared with University of Wisconsin solution after an ischemic period of up to 16 hours.

Histopathology of hyperacute rejection of the heart: experimental and clinical observations in allografts and xenografts.

The histologic findings in a total of 112 experimental heart transplants comprising allografts (baboon to baboon: n = 37), concordant xenografts (vervet monkey to baboon: n = 52), and discordant xenografts (pig to baboon: n = 23), in which the roles of ABO blood group incompatibility, corcordance, and immunosuppression were evaluated, are described. Hyperacute (vascular, humoral) rejection was characterized by disruption of the microcirculation, with interstitial hemorrhage and edema, rather than by intravascular thrombosis; the features were basically similar whether hyperacute rejection occurred in an ABO-incompatible allograft, concordant xenograft, or discordant xenograft. Hyperacute rejection was noted in all 23 discordant xenografts, in 12 to 52 concordant xenografts, and in four of 17 ABO-incompatible allografts. A unique mixture of acute and hyperacute rejection was observed in three ABO-incompatible allografts and in 10 concordant xenografts. Intensive antirejection therapy was associated with a reduced incidence of hyperacute rejection in corcordant xenografts but also with a significant number of fatal treatment-related complications.

Adenosine cardioplegia: reducing reperfusion injury of the ischaemic myocardium?

Hyperkalaemia-induced hypopolarization of the sarcolemnal membrane during standard crystalloid cardioplegic arrest potentiates calcium influx during reperfusion and is associated with depletion of high-energy phosphate reserves. Adenosine has been shown to induce fast cardiac arrest whilst preserving membrane hyperpolarization in an isolated rat heart model. In this study we compared the efficacy of adenosine, both as an arresting agent and as an ultrastructural, haemodynamic and high-energy phosphate preserving agent, in an in situ global ischemia model in the baboon with St. Thomas' Hospital solution No. 2 (ST2; n = 8) and with Krebs-Henseleit buffer (KHB; n = 7). The addition of 10 mM adenosine to the non-cardioplegic KHB (ADO; n = 8) improved haemodynamic recovery significantly in terms of cardiac index (91.6% +/- 7.2 vs 59.9% +/- 9.9) and stroke volume index (101.6% +/- 8.9 vs 55.6 +/- 10.0) and was not statistically distinguishable from the ST2 with regard to cardiac index (91.6% +/- 7.2 vs 94.8% +/- 5.8), stroke volume index (101.6% +/- 8.9 vs 114.0% +/- 8.3) or left ventricular dP/dt (73.1% +/- 9.9 vs 87.0% +/- 12.4). Adenosine triphosphate was best preserved with ADO (103.5% +/- 21.1 vs 67.9% +/- 9.3 and 48.5% +/- 8.7) although this was not statistically significant. This suggests therefore that the mechanism of cardioprotection by adenosine occurs by means other than its role as high-energy phosphate precursor.

15-Deoxyspergualin for induction of graft nonreactivity after cardiac and renal allotransplantation in primates.

In order to assess the immunosuppressive potentials of 15-deoxyspergualin (15-DS) in a preclinical experiment, heterotopic cardiac (n = 27, group I) and classic renal (n = 25, group II) allotransplantations were performed in Chacma baboons. The following immunosuppressive regimens were applied: Groups IB and IIB were treated with 15-DS alone (4 mg/kg/day) for p.o. days 0-9. Groups IC and IIC were treated with cyclosporine A (10-40 mg/kg/day) for p.o. days 0-30. Groups ID and IID received a combination of 15-DS (for p.o. days 0-9) and CsA (for p.o. days 0-30). Groups IA and IIA served as control and received no medication. The mean graft survival was 11.0 days for group IA, 28.2 days for group IB (P less than 0.05; IB vs. IA), 32.4 days for group IC, and 43.1 days for group ID (P less than 0.025; ID vs. IA). After renal transplantation, the corresponding figures were 12.3 days for group IIA, 8.5 days for group IIB, 30.4 days for group IIC and 148.9 days for group IID (P less than 0.025; IID vs. IIA). After cardiac and renal transplantation, acute rejection was the main cause of graft failure. Treatment-related side effects, mainly gastrointestinal complications, were observed only in primates, who were treated with 15-DS alone. After cardiac transplantation, permanent graft non-reactivity was not achieved, but a delayed rejection occurred within a mean of 21.8 days after immunosuppression had been stopped. Following renal transplantation, graft nonreactivity was also not achieved in groups IIB and IIC. In group IID, however, 4 of 8 animals (50%) were graft-tolerant 340, 256, 244, and 164 days after treatment discontinuation. Thus, the combination of 15-DS and CsA led to a significant prolongation of graft survival in both groups. Long-term nonreactivity was achieved only after renal transplantation, when initially treated with 15-DS and CsA.

Optimalization of immunosuppression after xenogeneic heart transplantation in primates.

Xenogeneic heart transplantation is becoming increasingly attractive because of the shortage of suitable donor organs. In small infants and neonates, for whom suitable human grafts are difficult to obtain, this may play a particularly important role. To evaluate the optimal immunosuppressive regimen after xenogeneic transplantation, cervical heterotopic heart transplantation was performed with vervet monkeys as donors and chacma baboons as recipients. The following groups were investigated: group 1 (n = 9): control, no immunosuppressive medication; group 2 (n = 5): cyclosporine in combination with azathioprine and methylprednisolone; group 3 (n = 6): cyclosporine, azathioprine, and methylprednisolone in combination with antithymocyte globulin for postoperative days 0 to 9; group 4 (n = 7): cyclosporine, azathioprine, and methylprednisolone in combination with 15-deoxyspergualin for postoperative days 0 to 9. Because of severe treatment-related side effects that were observed in group 4, further immunosuppression was modified as follows: group 5 (n = 5): 15-deoxyspergualin was combined with cyclosporine and methylprednisolone only. Acute rejection episodes were diagnosed by cytoimmunologic monitoring on alternate days and weekly myocardial biopsies and were treated with 500 mg methylprednisolone intravenously for 3 to 5 consecutive days. The graft survival after xenogeneic heart transplantation was best in group 3 with 43.3 days compared with 10.3 days in the control group. Still 2.3 acute rejections occurred, which in most cases led to graft failure in these animals. In group 4 the graft survival was prolonged to 20.1 days on average. Only 0.5 acute rejections per animal occurred, but severe gastrointestinal complications and infections were observed that made further experiments necessary to minimize these treatment-related complications.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of ABO blood group compatibility in heart transplantation between closely related animal species. An experimental study using the vervet monkey to baboon cardiac xenograft model.

The role of ABO blood group compatibility on graft survival when transplantation is performed between closely related animal species is uncertain. Heart transplants (in the neck) were performed between donor vervet monkeys and recipient baboons; no immunosuppressive therapy was given. Survival in ABO-compatible pairs (group 1, n = 9) was for a mean of 10.3 (+/- 5.2) days, which was not significantly different from that in ABO-incompatible pairs (group 2, n = 9: mean survival 7.3 +/- 5.6 days). In group 2, however, three hearts were rejected hyperacutely within 60 minutes, whereas in group 1 only one heart was rejected within 24 hours (not significant). Preformed anti-vervet monkey antibody was present in only one of 18 baboons, but developed in eight others. ABO-specific antibodies were present in all nine group 2 baboons and increased in titer in six cases. Histopathologic features of vascular (humoral) rejection, sometimes associated with cellular infiltration, were seen in a majority of hearts in both groups. Though the number of animals in this study was small, ABO-incompatibility would not appear to be a major factor in cardiac xenograft survival when transplantation is performed between closely related primate species, though early hyperacute rejection would seem more likely to occur when blood group incompatibility is present.

Effect of triiodothyronine (T3) on myocardial high energy phosphates and lactate after ischemia and cardiopulmonary bypass. An experimental study in baboons.

Cardiopulmonary bypass is associated with a reduction in plasma free triiodothyronine in patients undergoing cardiac operations. A previous experimental study in pigs demonstrated a marked inotropic effect when triiodothyronine was administered after a period of myocardial ischemia and cardiopulmonary bypass; this was associated with a significant reduction in mortality compared with the mortality in control pigs. To clarify the effect of triiodothyronine on myocardial high energy phosphate stores and lactate, a series of experiments was done in baboons undergoing 3 hours of myocardial ischemia while supported by cardiopulmonary bypass. Seven baboons received no triiodothyronine and six received 6 micrograms of triiodothyronine at the end of the ischemic period. Seventy minutes after cardiopulmonary bypass, the myocardial adenosine triphosphate level was significantly higher (p less than 0.01) in the treated animals. In untreated animals, a steady increase in myocardial lactate occurred after cardiopulmonary bypass; by 120 minutes after ischemia (70 minutes after cardiopulmonary bypass) there was a significant difference in lactate levels between the two groups (p less than 0.01). We postulate that a combination of global ischemia and depletion of triiodothyronine results in reduced mitochondrial function, inhibition of the tricarboxylic acid cycle, and increased anaerobic metabolism and depletion of myocardial phosphates. Triiodothyronine replacement therapy leads to improved mitochondrial function and increased aerobic metabolism, which results in increased synthesis of myocardial phosphates. We suggest that there may be a place for the administration of triiodothyronine in patients undergoing cardiac operations with a prolonged myocardial ischemic period or in whom there is any evidence of low cardiac output after discontinuation of cardiopulmonary bypass.

Triiodothyronine therapy for heart donor and recipient.

Both (1) brain-dead donors and (2) transplant recipients on cardiopulmonary bypass suffer a depletion in plasma-free triiodothyronine (T3), which leads to metabolic changes (from inhibition of mitochondrial function), resulting in myocardial energy store depletion. Replacement therapy with T3 reverses these changes in both donor and recipient. Donor heart energy stores and function will be maintained at optimum levels if T3 therapy is administered to both donor and recipient at the time of transplantation.

Effects of cyclosporine and antibody adsorption on pig cardiac xenograft survival in the baboon.

The problem of donor heart supply would be solved if hearts could be transplanted from readily available animals such as the pig or sheep. We have investigated heterotopic heart transplantation (in the neck) with the pig as donor and baboon as recipient. Five experimental groups were studied. Control hearts (group 1, n = 4) were rejected within 4 minutes to 8 hours. Splenectomy done before transplantation (group 2, n = 3) did not extend survival significantly (30 minutes to 8 hours). Donor heart survival in baboons receiving immunosuppressive therapy of cyclosporine and methylprednisolone (group 3, n = 5) was from 15 to 75 minutes only in four animals and for 5 days in one animal. Anti-pig antibody adsorption from baboon blood by pretransplant donor-specific kidney hemoperfusion (group 4, n = 7) resulted in cardiac function for 6 to 12 hours in three cases and from 4 to 5 days in four cases (p less than 0.02). A combination of pretransplant antibody adsorption and immunosuppression (group 5, n = 4) resulted in graft survival of 8 to 20 hours in three cases and of 4 days in one case (p less than 0.03). Histopathologic features of vascular (hyperacute) rejection were seen in all hearts except one (the 5-day survivor in group 3). Pretransplant adsorption of antibody clearly prolonged survival of discordant cardiac xenografts in some cases. Further exploration of this technique appears justified.

Inotropic effect of triiodothyronine following myocardial ischemia and cardiopulmonary bypass: an experimental study in pigs.

A significant reduction (p less than 0.0001) in plasma-free triiodothyronine (T3), which is known to have an inotropic effect, has been documented in patients undergoing open-heart procedures. To investigate the effect of this observation, 22 pigs underwent 2 hours (Group 1, r = 10) or 3 hours (Group 2, r = 12) of myocardial ischemia during cardiopulmonary bypass (CPB) at 26 degrees C; the myocardium was protected by cardioplegic solution and cold saline solution at 30-minute intervals. After the pig was rewarmed to 37 degrees C, CPB was discontinued, and measurements of hemodynamic function were made 10 and 70 minutes later. Half of the pigs (Subgroup B) received 6 micrograms of T3 intravenously immediately after removal of the aortic cross-clamp; the remainder (Subgroup A) received no T3. After 2 hours of ischemia, untreated pigs showed significantly reduced myocardial function 10 minutes after discontinuation of CPB. By 70 minutes after the end of CPB, 2 of 5 untreated pigs (Subgroup A) had died of low cardiac output, but all 5 treated pigs (Subgroup B) survived. After 3 hours of ischemia, both groups showed some reduced function at 10 minutes, though the reduction was more marked in untreated animals. By 70 minutes, 4 of 6 untreated pigs had died of myocardial failure and all treated pigs remained alive (p less than 0.03). Surviving pigs in both groups still demonstrated some reduced function compared with values obtained before CPB. When all pigs are considered together, overall survival of those that did not receive T3 was significantly less than those that did (p less than 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)

Heart transplantation at Groote Schuur Hospital, Cape Town. Twenty years' experience.

Human allogeneic heart transplantation was started at Groote Schuur Hospital in Cape Town in 1967. Since then 110 hearts (61 heterotopic and 49 orthotopic) and 12 heart-lung transplantations have been performed in the unit. Ten procedures were retransplantations including 2 third interventions. The patients fall into three groups according to their immunosuppressive therapy: group A (N = 55) from 1967 to 1982 received the so-called 'conventional treatment' (azathioprine, methylprednisolone and antithymocyte globulin (ATG)); group B (N = 15) from 1983 to 1984 received cyclosporin A in high dosage, together with methylprednisolone; and group C (N = 30) received quadruple drug therapy of low-dose cyclosporin A, together with azathioprine, methylprednisolone in lower dosages and antithymocyte globulin (for the first 4-6 days and rescue-ATG for severe rejection). The results have improved significantly over the years. The actuarial survival rate after heart transplantation within the last 12 months is 94%. Several important steps have been inaugurated: in 1973 heterotopic heart transplantation was initiated and in 1984 hormonal therapy of brain-dead organ donors was started. Radionuclide scanning, in combination with endomyocardial biopsies, has proved to be a very sensitive means of monitoring rejection.

Twenty years of heart transplantation at Groote Schuur Hospital.

Between December 1967 and July 1987, 110 heart transplantations (61 heterotopic and 49 orthotopic) and 12 heart-lung transplantations were done at Groote Schuur Hospital in Cape Town, South Africa. Twelve procedures were retransplantations, including two third interventions. The patients were divided into three groups: Group A (n = 55) from 1967 to 1982 received so-called conventional treatment of azathioprine, methylprednisolone, and antithymocyte globulin. Group B (n = 15) from 1983 to 1984 had cyclosporine in high dosages together with methylprednisolone. Group C (n = 30) received quadruple drug therapy of low-dosage cyclosporine, together with azathioprine, methylprednisolone in lower dosages, and antithymocyte globulin (for the first 4 to 6 days and rescue antithymocyte globulin for severe rejection). From Group A, nine of 55 patients are alive up to 17 years after transplantation. The main causes of death were acute rejections and infections (in 60% altogether). From group B, six of 15 patients are alive. Acute rejections and infections were the causes of death in 12% of the patients, but multiple organ failure was a major cause in 24% most probably because of the high dosages of cyclosporine. From group C, 23 of 30 patients have survived. In this group the results after heterotopic heart transplantation do not differ significantly from orthotopic transplantation, which justifies this procedure in particular situations. If all heterotopic and orthotopic transplantations are compared, orthotopic procedures have a substantially better outcome. With the modified immunosuppressive regimen (group C) combined with precise donor and recipient selection and more sophisticated rejection monitoring, the actuarial survival rate within the last 12 months is 94%.

Is pulmonary ischemia a factor in the reperfusion response? An experimental study in the chacma baboon.

A reimplantation or reperfusion response has been described in both the experimental animal and the human patient after various procedures involving pulmonary ischemia. We have investigated this phenomenon in a primate model. Ten chacma baboons were placed on cardiopulmonary bypass and cooled to 20 degrees C. Circumferential segments of the right main bronchus and pulmonary artery were denuded of all surrounding tissue. Each structure was then cross-clamped, which rendered the lung ischemic, during which time the organ was immersed in cold saline solution. Ischemia was maintained for 1.5 to 5 hours; after reperfusion and discontinuation of bypass, the right lung was biopsied and the chest closed. Chest radiographs, lung biopsies, and arterial blood gases were taken at intervals for up to 16 to 28 days. Right lung shadowing on chest radiography with concomitant histopathologic changes, indicative of a reperfusion reaction, were seen in only one animal, which had undergone lung ischemia for 1.5 hours. In one other animal that was ischemic for 5 hours, patchy opacification of the lung was seen on two occasions (days 8 and 15) with concomitant mild histopathologic changes. In conclusion, therefore, a major reperfusion response after pulmonary ischemia in the chacma baboon is possible but unusual. This would suggest that the appearance of pulmonary opacification on chest radiography within the first 4 weeks after heart-lung transplantation in humans is most likely attributable to some other condition, such as isolated lung rejection or infection.