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Background: The results of pulmonary transplantation are compromised by acute and chronic rejection. We hypothesized that a liposomal form of aerosolized cyclosporine A (CsA) would be selectively deposited and concentrated in the lungs. The theoretical advantage of this therapy is selective pulmonary immunosuppression with prolonged utilization., Methods: Eighteen dogs were endotracheally intubated; aerosolized liposomal CsA was administered for 15 min. CsA levels were measured in whole blood, lung, trachea, heart, kidney, liver, and spleen at various times after treatment., Results: The lung rapidly absorbs aerosolized liposomal CsA; other organs have much lower concentrations. The retention of pulmonary CsA delivered by liposome aerosol is approximately 120 min in this model., Conclusions: Aerosolized liposomal CsA is selectively deposited and concentrated in the lungs; other organs absorb less CsA.

A method used clinically for anastomosing the pulmonary veins to the left atrium, in the absence of a left atrial cuff, during single-lung transplantation by reconstructing the atrium with pericardium is described. Postoperative ventilation/perfusion scans show normal pulmonary blood flow.

We present cardiac and pulmonary function data obtained at serial annual reviews in 21 heart-lung transplant (HLT) recipients followed for up to four years postoperatively, reflecting the entire Stanford experience as of June 1987. A total of 50 cardiac catheterisation procedures and endomyocardial biopsies yielded the following results: rejection on biopsy (0/50) (0% of patients), angiographic coronary artery disease (1/50) (5%), pulmonary hypertension (2/50) (10%), elevated pulmonary vascular resistance (PVR) (1/50) (5%), and low cardiac index (CI) (4/50) (14%). Systemic hypertension was common, with an elevated systemic vascular resistance (SVR) (26/44) (76%) and an elevated mean aortic pressure (MAP) (22/44) (67%). Pulmonary function testing frequently revealed abnormalities. Airflow limitation was manifested by a reduction in both FEV1/FVC ratio (17/50) (52%) and FEF25-75 (30/50) (71%), and was often associated with arterial hypoxaemia (13/50) (52%). Subsequently, five patients with these findings have died with obliterative bronchiolitis (OB), one underwent retransplantation for OB, six have stable OB, and one has progressive OB. Length of survival was highly correlated with the resting PaO2 at the first annual review (r = 0.99) (p less than 0.001), and, to a lesser degree, on the reduction in FEF25-75 (r = 0.73) (p less than 0.05) and FEV1/FVC ratio (r = 0.77) (p less than 0.05). Resting PaO2 was determined by ventilatory (r = 0.80) (p less than 0.001) rather than circulatory factors and all patients with airflow limitation who died had OB at post-mortem examination. These results support the continued study of HLT as a therapeutic modality for selected patients with irreversible pulmonary hypertension. They demonstrate that, in the absence of severe OB, haemodynamics, cardiac function, and coronary patency are preserved for several years after HLT. Whereas the value of regular pulmonary function testing has become evident, there does not appear to be a clinical need for annual surveillance with invasive cardiac procedures in long-term survivors of HLT.

Combined heart and lung transplantation was carried out in ten patients at Stanford University Medical Center between March, 1981, and December, 1982. All patients had end-stage pulmonary hypertension. 7 of them had Eisenmenger's syndrome and 3 primary pulmonary hypertension. 3 patients died within a month of operation, but the remaining recipients are well 2 months to 2 years after transplantation. The hospital stay of the survivors ranged from 38 to 85 days. All survivors have returned to normal activity. The results of heart and lung transplantation have thus been considerably superior to those reported previously for lung transplantation. It is suggested that cardiopulmonary replacement is suitable treatment for end-stage pulmonary hypertension with or without associated congenital heart disease and that its application to other forms of advanced pulmonary failure may be warranted.

Combined heart and lung transplantation was carried out in 17 patients at Stanford University between March, 1981, and December, 1983. The recipients were between 22 and 45 years old. All patients had end-stage pulmonary hypertension; 10 had Eisenmenger's syndrome and the remaining 7, primary pulmonary hypertension. Five patients died within the first few postoperative weeks. The remainder are well between four weeks and 33 months from operation. The immunosuppressive protocol has consisted of cyclosporine with an initial course of rabbit antithymocyte globulin. Azathioprine also was given for the first two weeks and then was replaced with prednisone. Rejection, as diagnosed by cardiac biopsy, was treated with high doses of methylprednisolone. Modifications of technique that have developed include the removal of the recipient heart and lungs separately, and preservation of the lungs with a modified Collins' solution instead of a cardioplegic solution. Rejection occurred in 6 of the 12 survivors. Infections developed in 9 patients, but only one resulted in a fatal outcome (Legionella). Thus, the results of clinical heart-lung transplantation have been considerably superior to clinical efforts in lung transplantation. It is suggested that the combined operation is preferable for the following reasons: (1) all diseased tissue is removed, thus eliminating recurrent infection and ventilation/perfusion disparity; (2) transplantation of the entire heart-lung block preserves coronary-bronchial vascular anastomoses and makes airway dehiscence less likely; and (3) to date, diagnosis of rejection by cardiac biopsy has appeared to be a satisfactory method of diagnosing and treating pulmonary rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical cardiopulmonary transplantation is currently limited by the availability of suitable heart-lung donors. Distant graft procurement, with pretreatment, of the donor by intravenous prostaglandin E1 and cooling of the graft with pulmonary artery perfusion, is now clinically established and should increase the number of available donors. Between March 1981 and September 1986, 40 heart-lung transplantations were performed. The characteristics of the donor pool were analyzed. Gram stain of the donor tracheal aspirate revealed gram-positive bacteria in 80% and gram-negative organisms in 35%. Yeast was present on stain in 25% of the patients. Donor arterial oxygen tension was less than 100 torr inspired oxygen concentration 40%) repeatedly in one patient; this recipient died of lung failure at operation. Severe deterioration of allograft lung function was seen in 11 (27.5%) recipients. The causes of deterioration were substantial postoperative bleeding in six patients, sepsis in two, and acute rejection, poor lung function, and allograft heart failure in one patient each. HLA-A locus mismatch, poor donor alveolar-capillary gas exchange, tracheal colonization with heavy polymorphonuclear cells, and heavy bacteria and fungus resulted in increased operative mortality. Donor pretreatment with prostaglandin E1 was associated with improved survival. Recipient selection, emphasizing adequate liver function and absence of previous thoracic operation, careful surgical technique with minimal bleeding, and brief perfusion time were factors associated with improved survival. Early morbidity and mortality were principally related to recipient risk factors, and the strict criteria observed for selection of heart-lung donors were valid. The importance of appropriate recipient selection is underscored.

Studies were performed measuring parameters of respiratory and circulatory function at rest and during maximum tolerable constant work rate treadmill exercise in 16 clinically well patients who had undergone heart-lung transplantation for end stage pulmonary hypertension. Ten patients were studied before and within eight weeks following transplantation. Long-term function with exercise was further evaluated with follow up studies at one year (n = 10) and two years (n = 6), posttransplantation. Posttransplant gas exchange and ventilation during exercise are essentially normal with neither being limiting to maximal exercise. Exercise capacity is significantly improved posttransplant, primarily as a result of improvement in the circulation over that found pretransplant in uncorrected pulmonary hypertension. Although improved, circulatory limitations of maximal exercise may still persist. Cardiorespiratory function at maximum tolerable exercise is well maintained following heart-lung transplantation for at least two years, providing no complications occur. This suggests that denervation of the heart and lungs, disruption of the bronchial circulation and pulmonary lymphatics, and the graft ischemia encountered at the time of transplantation impose no serious limitations on long-term cardiopulmonary function. The overall functional capacities of the transplanted heart and lungs are more than adequate for meeting the activities of normal life.

Between March, 1981, and August, 1985, twenty-eight heart-lung transplant operations were done in 27 patients at a single institution. 8 patients died in the perioperative period and adhesions related to previous thoracic surgery proved to be a major risk factor for postoperative haemorrhage. Obliterative bronchiolitis developed in half of the 20 long-term survivors, a mean of 11.2 months (range 2-35 months) after surgery: 4 of these patients died, 3 are functionally limited, 2 were successfully treated with corticosteroids, and the remaining patient was successfully retransplanted. The other 10 long-term survivors returned to a normal life with essentially normal pulmonary function measured at a mean of 22.6 months (range 4-42 months) after transplantation. All the surviving patients have evidence of renal impairment related to cyclosporin nephrotoxicity. The results indicate that, although heart-lung transplantation is compatible with essentially normal long-term pulmonary function, the procedure should not yet be regarded as a routine clinical intervention.

1. Bronchial responsiveness to inhaled methacholine was studied in ten heart-lung transplant (HLT) recipients a mean 10.6 months (range 1.5-28 months) post-HLT and in ten normal subjects. 2. The mean provocation dose of methacholine producing a 20% fall in FEV1 (PD20 FEV1) was significantly lower in the HLT recipients (1.70 +/- 3.96 mg vs 11.55 +/- 3.79 mg; P less than 0.001), as was the mean provocation dose of methacholine producing a 50% fall in specific airway conductance (PD50 sGAW) (0.08 +/- 0.08 mg vs 5.13 +/- 5.47 mg; P less than 0.005). 3. These results establish the presence of significant bronchial hyper-responsiveness to inhaled cholinergic agonists in the transplanted lung.

During the first 31/2 years of the Stanford heart-lung transplant program, 23 transplants have been carried out in 22 patients with severe pulmonary vascular disease. Actuarial survival curves predict 1 and 2 year survival rates of 71% and 57%, respectively, for all patients. As a result of increasing experience, the early mortality of 26% has been reduced, with only one early death occurring in the last eight patients; prior cardiac surgery was a contributing factor in three of the six patients suffering early deaths. Two late deaths occurred in the series 14 and 15 months after operation. One patient died suddenly as a result of an acute myocardial infarct and the other patient died because of respiratory failure. At autopsy, both patients had severe proliferative coronary atherosclerosis with obliterative bronchiolitis affecting the lungs. An additional patient required a retransplant for obliterative bronchiolitis 37 months after the initial procedure, and he too was found to have severe coronary artery disease. Hemodynamics and left ventricular function were normal in patients studied 1 and 2 years after undergoing the transplantation procedure. Thus, the early mortality and morbidity of combined heart and lung transplantation has been significantly reduced, but the long-term complications, particularly graft atherosclerosis and obliterative bronchiolitis, are yet to be fully controlled.

The indices of kidney function of all discharged heart-lung transplant survivors were examined before and after the introduction of a triple-drug immunosuppressive regimen comprised of low dosages of cyclosporine (to maintain a trough serum level of 75 to 100 ng/ml by radioimmunoassay), azathioprine (1 to 1.5 mg/kg/day), and prednisone. A comparison of survivors treated with either high dosages of cyclosporine (n = 19) or low dosages of cyclosporine (n = 8) revealed a lower early creatinine level postoperatively (1.84 versus 0.96 mg/dl), a higher creatinine clearance (46.33 versus 62.47 ml/min), and a lower cyclosporine level (337.96 versus 204.30 ng/ml) in the latter group. The findings from the outpatient period were similar to the above, and all findings were statistically significant (p less than or equal to 0.05). Another comparison of a subgroup of survivors (n = 11) before and after conversion to the low dosage cyclosporine triple-drug regimen demonstrated no significant difference in kidney function for nine patients and equivocal evidence of improvement in the other two patients for creatinine levels and creatinine clearance. Overall, despite the lower cyclosporine dosage used, we have not encountered an increased prevalence of acute heart or lung rejection. We conclude that early implementation of low dosages of cyclosporine, as part of a triple-drug immunosuppression regimen, is associated with preservation of kidney function while maintaining adequate immunosuppression. Patients with chronic azotemia from long-term cyclosporine therapy may still reap some benefit from this regimen.

Combined heart and lung transplantation has now been carried out in 17 patients at Stanford University Hospital. The emphasis on the management of donors is upon thorough tracheobronchial toilet and ensuring an absence of significant cardiopulmonary disease. The most important aspects of the recipient operation are to remove the heart and lungs without injury to the phrenic, vagus, or recurrent laryngeal nerves and to ensure hemostasis. This is best effected if the heart and lungs are removed separately. The operative technique for both the donor and recipient is described.

Cardiac biopsy remains the principal tool for diagnosis of rejection in heart and heart-lung transplantation. In rare instances pulmonary rejection may occur without cardiac rejection, but the overall incidence of cardiac rejection may be less with heart-lung transplantation than with heart transplantation. During the 6 months from March to September 1986, 40 heart transplantations and nine heart-lung transplantations were performed. Heart transplant patients received cyclosporine (8 to 10 mg/kg/day), azathioprine (1 to 2 mg/kg/day), and prednisone (0.8 mg/kg/day, with tapering). Heart-lung transplant patients received cyclosporine and azathioprine in the same dosages, but steroids were withheld for 3 weeks. Heart-lung transplant patients received three postoperative dosages of rabbit antithymocyte globulin (200 mg intramuscularly). There were five early deaths in the heart transplant group, four from infection and one from cerebrovascular accident. Since the initial rejection analysis presented here, one additional heart transplant patient died from rejection (241 days), and one heart-lung transplant patient died from infection (99 days). Cyclosporine levels were determined by radioimmunoassay, and cardiac rejection was diagnosed by serial endomyocardial biopsy. Early cardiac rejection is notably less common after heart-lung transplantation than after heart transplantation. Although the prophylactic antithymocyte globulin given in heart-lung transplantation may be important in this regard, rejection is probably inherently less common after heart-lung transplantation.

Right ventricular endomyocardial biopsy remains the gold standard for the diagnosis of acute rejection of the heart allograft. Surveillance right ventricular endomyocardial biopsies are performed routinely at 3-month intervals in heart-lung transplant patients with uncomplicated conditions who have long-term follow-up. Recent observations of asynchronous heart and lung rejection, plus the impression that acute rejection was a rare phenomenon in long-term heart-lung transplant survivors, led us to analyze our experience with this technique to determine its clinical role. During the first 6 years of the heart-lung transplantation program at Stanford University Medical Center, only one episode of moderate acute rejection has occurred at greater than 4 months after heart-lung transplantation, despite greater than 160 surveillance right ventricular endomyocardial biopsies. This was in a patient who was recovering from a viral illness and had a subtherapeutic cyclosporine level of 38 ng/ml (as measured by radioimmunoassay). Fourteen patients (40%) have never had acute rejection, but freedom from acute rejection did not correlate with freedom from obliterative bronchiolitis or concentric coronary artery intimal hyperplasia. We conclude that in the long-term management phase (greater than 6 months after heart-lung transplantation), right ventricular endomyocardial biopsy should be performed for specific indications, rather than as a surveillance procedure.

Cardiac transplantation has emerged as a standard mode of clinical therapy for end-stage heart failure, while heart-lung transplantation is still an experimental rather than a standard mode of clinical therapy for end-stage heart and lung disease. Since clinical application of heart-lung transplantation began in March 1981, there has been continual improvement in donor care, surgery, post-operative management, and the diagnosis and treatment of lung and heart rejection. According to our 6-year clinical experience, both patients with Eisenmenger's physiology and patients with primary pulmonary hypertension are considered suitable candidates for heart-lung transplantation. In the future, our recipient population will include small children and patients with cystic fibrosis. Suitable candidates must have good liver and kidney function, and freedom from previous major pulmonary emboli, systemic diseases, and previous thoracic surgery. Patients must maintain their functional and emotional status to pass successfully the difficult postoperative period. Proper donor and recipient selection in connection with improved heart-lung preservation has resulted in excellent operative survival (100%) following the last ten operations, and only the lack of suitable donors can limit the number of heart-lung transplantations in the future.

In a review of 176 patients who died after either cardiac or cardiopulmonary transplantation, 15 cases of pancreatitis were identified. The diagnosis was clinically inapparent in 11 of the 15 cases of pancreatitis. A high index of suspicion should therefore be maintained when these patients are cared for. A variety of factors may have contributed to the occurrence of pancreatitis in these patients. These include infection, steroids, azathioprine, low-flow states, extracorporeal circulation, vasopressors, renal failure, and rejection.

Severe pulmonary rejection without cardiac rejection in a patient after combined heart-lung transplantation is presented with the clinical and pathological findings. Acute lung rejection after heart-lung transplantation cannot be excluded by normal cardiac biopsy results.

Twenty-seven years of laboratory experience in cardiac transplantation at Stanford have provided the necessary background for a moderately successful clinical program which now extends over a period of 17 years. Heart-lung transplantation, again entirely a product of intensive laboratory research, is now ready for clinical use. Certainly much work remains to be done in the area of donor tissue preservation, particularly with respect to the lungs. It appears that new and more specific immunosuppressing drugs are on the horizon, so tissue transplantation in general will be increasingly safer. Heart transplantation has come of age, and combined heart-lung transplantation is well under way.

For no organ is the need more acute than for the lung or heart-lung block. The new improved "freezing" technique with simultaneous use of intravenous prostaglandin E1 will result in reliable and adequate heart-lung block preservation. The lungs are flushed with high-volume (60 ml/kg), low-pressure (less than 20 mmHg), low-flow (15 ml/kg/min), using modified Euro-Collins solution (added 12 Meq/L of MgSO4 and 65 ml/L of 50% Dextrose). Additional topical cooling has been achieved by cold Physiosol and the excised graft is then placed in a plastic bag filled with Physiosol. This static hypothermia has been successfully used with extended ischemia times of more than six hours in primates and almost four hours in man. Forty heart-lung transplantations have been done from March 1981 to September 1986 and nine of them have been performed using this "freezing" technique with prostaglandin E1. Distant graft procurement has been used twice for heart-lung transplantation. All nine most recent patients who have received the graft harvested with this new "freezing" technique are doing well.

Obliterative bronchiolitis has been the major complication in long-term survivors of human heart-lung transplantation at our institution. We have assessed the effect of the introduction of a third immunosuppressive agent, azathioprine, on the rate of decline in airflow variables in eight heart-lung transplant recipients with obliterative bronchiolitis, and have compared this rate with that in five patients who did not receive augmented immunosuppressive therapy. Specifically, the rate of decline in forced expiratory flow rate between 25% and 75% of vital capacity improved considerably after institution of this therapy (-5.25 +/- 2.85 compared with -0.27 +/- 0.66 [mean +/- SD]; p less than 0.005), whereas the effect on the ratio of forced expiratory volume in one second to forced vital capacity was more modest (-3.61 +/- 1.52 compared with -0.54 +/- 0.93; p less than 0.005). The rate of decline in airflow variables was similar in both groups before the institution of therapy with azathioprine. These results show that augmented immunosuppressive therapy is capable of slowing the rate of progression of obliterative bronchiolitis in this population; they also suggest that the obliterative bronchiolitis may represent a form of chronic pulmonary allograft rejection.

Since March 1981, 19 patients have undergone heart-lung transplantation for end-stage pulmonary vascular disease, with 14 long-term survivors. In five of the survivors, obstructive airway disease has developed with the superimposition of a progressive restrictive ventilatory defect in three of them. None of these five patients showed a tendency for spontaneous improvement of flow rates. Biopsy and postmortem material was available in four of the five patients and showed obliterative bronchiolitis (OB) in three. A fourth patient showed clinical and physiologic data consistent with obliterative bronchitis, but histologic material was not available. Obstructive lung disease without restrictive features developed in a fifth patient, but no histologic evidence of OB was found at transbronchial biopsy. In addition to OB, recurrent lung infections were found in all patients, significant pleural fibrosis in two patients, and bronchiectasis in one patient. Despite these long-term sequelae of human heart-lung transplantation, ten of the 14 surviving patients are leading relatively normal lives.

Eighteen combined heart and lung transplant operations were performed between March, 1981, and March, 1984. Six of these patients have undergone bronchoscopy, at varying intervals after transplantation. Five of these procedures were done for specific clinical indications; one was done incidentally, during another surgical procedure requiring general anesthesia. All patients had intact, healing tracheal anastomotic suture lines; there were no instances of tracheal stenosis. The distal tracheobronchial tree appeared endoscopically normal in the transplanted lungs, except in areas of known infiltrates. Four of the patients had endobronchial biopsies, and alveolar eosinophilic proteinaceous exudate and submucosal mononuclear infiltrate were consistent features. Two of the later biopsies suggest that squamous metaplasia of the respiratory epithelium may occur with long-term follow-up. Controversy exists as to the optimal technique for tracheal anastomosis, but in the case of the steroid-treated, immunosuppressed transplant patient, continuous anastomosis with polypropylene has yielded satisfactory results.

To investigate the long-term histologic consequences of combined heart and lung transplantation, heart and lung biopsies were obtained from six rhesus monkeys; two had undergone heart-lung autotransplantation 3.5 and 4.5 years previously, two were the recipients of heart-lung allografts 4.1 and 4.5 years previously, and the results were compared with two normal control animals. Cyclosporine had been used as maintenance immunosuppression in the allograft group. The heart and lung biopsies in the autograft animals were essentially normal. Dense adhesions were noted in the allografts, adn in one the visceral pleura was grossly thickened. Cardiac biopsies in the allografts were unimpressive, with a normal myocardium in one, and minimal interstitial fibrosis in the other. Intimal hyperplasia was present in the pulmonary arterioles of one of the allografted animals. Focal scarring was present in the lung of one allograft recipient, and the other animal showed severe thickening and fibrosis of the alveolar septae, as well as marked interstitial fibrosis such that large areas of the specimen were replaced by connective tissue. Histologic abnormalities in the allografted lungs correlated with the abnormal hemodynamics in these animals reported in a previous study. It is suggested that the histologic appearances in the lung are a consequence of chronic rejection, and that these findings may become a significant problem in human heart-lung transplant recipients.

Data were analyzed from 19 long-term survivors of cardiopulmonary transplantation in this institution, including nine patients with normal pulmonary function and 10 recipients with posttransplant obliterative bronchiolitis. In all cases, donor cytomegalovirus titers (IgG), preoperative recipient titers (IgG), and serial postoperative recipient titers (IgM, IgG, and complement fixation) were available. In addition, surveillance cytomegalovirus cultures and pulmonary function tests were obtained prospectively after surgery in all 19 patients. A total of 12 patients developed active cytomegalovirus infection (serologic conversion confirmed by positive cultures) after transplantation, six of whom subsequently developed obliterative bronchiolitis. However, infection was clinically associated with pulmonary deterioration in only four of these patients, three of whom had cytomegalovirus pneumonitis. With the exception of obliterative bronchiolitis, no other permanent sequelae of cytomegalovirus infection were evident in this small group. Progressive obliterative bronchiolitis was also seen in four of the seven recipients who had no evidence of cytomegalovirus infection at any time. Although viral causes have been associated with obliterative bronchiolitis, the current data suggest that cytomegalovirus infection in the absence of pneumonitis does not appear to be a significant risk factor for obliterative bronchiolitis in cardiopulmonary transplant recipients. A larger group of patients will be required to ultimately establish the role of cytomegalovirus infection in this setting.

Combined heart and lung transplantation was carried out in thirteen patients at Stanford University between March 1981 and May 1983. The recipients were between 22 and 45 years old. All patients were suffering from end-stage pulmonary hypertension; nine patients had Eisenmenger's syndrome; the remaining four were transplanted for primary pulmonary hypertension. Three patients died within one month of surgery. The remainder are well at between 22 months and three weeks from operation. The duration of stay in the hospital for the surviving patients ranged from 38 to 85 days. The immunosuppressive protocol has been essentially the same for all recipients, and has consisted of cyclosporine with an initial course of rabbit antithymocyte globulin (RATG) with azathioprine given for the first two weeks, and then replaced with prednisone. Rejection, as diagnosed by cardiac biopsy, was treated with pulses of methylprednisolone. Early complications included bleeding that necessitated reexploration (five patients); damage to the vagus, recurrent laryngeal, or phrenic nerves (three patients); and failure of the donor lungs (one patient). Modifications of technique that have developed include removal of the recipient heart and lungs separately, and preservation of the lungs with a modified Collins' solution instead of a cardioplegic solution. The results of this operation are considerably superior to clinical efforts in lung transplantation. The combined operation may be preferable for the following reasons: All diseased tissue is removed, thus eliminating recurrent infection, and also perfusion/ventilation disparity. Transplantation of the entire heart and lung block preserves coronary-tracheal vascular anastomoses and makes airway dehiscence less likely. Diagnosis of rejection by cardiac biopsy seems to be a satisfactory method of diagnosis and treatment of pulmonary rejection.

At Stanford University Medical Center from January 1968 until January 1984, 288 patients received 313 heart transplants. The immunosuppressive regimen before December 1980 consisted of azathioprine and prednisone, with or without rabbit antithymocyte globulin. After that time cyclosporine replaced azathioprine. In 92 recipients of 95 heart allografts, the 1- and 3-year survival rates were 82% and 65% to 70% respectively. In the 3 years from March 1981 to March 1984, successful heart-lung transplantation was accomplished in 13 of 19 recipients, using cyclosporine-based immunosuppression. Survival ranged from 1 to 38 months. While it is true that cyclosporine has improved survival in heart transplant recipients, has allowed successful heart-lung transplantation to be performed, has shortened intensive care unit and total hospital stays and therefore hospital costs, and has allowed easier management of rejection and infection, several disconcerting problems have not yet been resolved. These include hypertension that is difficult to control and renal dysfunction in all patients, and the fact that cellular and humoral rejection still occurs, as manifested by graft atherosclerosis, bronchiolitis obliterans and classic acute rejection. Better understanding and application of cyclosporine immunosuppression will undoubtedly minimize both cyclosporine- and non-cyclosporine-related postoperative complications and will improve survival even further.

Combined heart and lung transplantation was performed in 12 cynomolgus or rhesus monkeys. The donor heart was preserved with 10 ml/kg of cold crystalloid potassium cardioplegia. The lungs were preserved by perfusing the pulmonary artery over 4 minutes with 60 ml/kg donor weight of cold Euro-Collins solution modified with 8 mEq/L of MgSO4. For six animals in group A, the heart and lungs were immediately transplanted with a mean ischemic time of 1 hour 54 minutes. For six animals in group B, the heart and lungs were stored in a cold extracellular electrolyte solution at 2 degrees to 3 degrees C and transplantation was delayed, with a mean ischemic time of 6 hours and 15 minutes. Anesthesia and mechanical volume ventilation were continued for 8 hours postoperatively with the Fio2 regulated to 40% and with 2 cm positive end-expiratory pressure. Arterial Po2 was sampled at 1, 2, 3, 4, 6, and 8 hours after removal of the aortic cross clamp. Animal survival and cause of death were recorded. All animals were successfully extubated by 10 hours after transplantation. The mean arterial Po2 for group B was initially depressed (89 mm Hg 1 hour after removal of the aortic cross clamp) but rapidly recovered. The mean Po2 for both groups A and B was 184 mm Hg 8 hours after reperfusion. There was no significant difference in the mean hourly Po2 between groups A and B except for the first hour after reperfusion. One animal in each group died of pulmonary insufficiency in the early postoperative period.(ABSTRACT TRUNCATED AT 250 WORDS)

Between May, 1981, and December, 1984, thirteen combined heart-lung transplants were performed in 12 patients for the treatment of Eisenmenger's syndrome. The age range of the recipients was 22 to 42 years. Two patients had undergone previous open cardiac operations; in addition, one had had closure of a persistent ductus arteriosus, one an open lung biopsy, one a pulmonary artery banding, and one patient received a second heart-lung transplant after 3 years. Four recipients died before hospital discharge, one at operation and three at 4, 10, and 33 days after operation. Early symptomatic results and cardiopulmonary function were excellent in all of the survivors. Two patients died 14 and 15 months after transplantation of accelerated graft arteriosclerosis and respiratory failure, respectively, and six remain alive 7 to 44 months after transplantation. Four of these surviving patients and the two patients who died late subsequently had major pulmonary complications. Symptoms included progressive breathlessness, cough (often productive), and fever with physical signs of diffuse crepitations and expiratory rhonchi. Serial pulmonary function tests showed progressive obstructive physiology in all six patients with superimposed restrictive defects in four. Histologic examination of tissue from open lung biopsy or autopsy displayed bronchiolitis obliterans in five of these patients, one of whom required retransplantation. It is possible that these late changes are the result of rejection, since similar changes in one other patient have now been reversed with augmented immunosuppression. Further understanding of the causes and manifestations of late pulmonary deterioration should improve the late functional results of this operation for Eisenmenger's syndrome.

Although combined heart and lung transplantation has great potential for improving survival and rehabilitation in selected patients with pulmonary vascular disease, the lack of suitable donor organs has restricted the number of operations performed. We report a heart and lung transplantation operation for Eisenmenger's syndrome in which distant donor graft procurement was used with a simple system for preservation.

This report describes the clinical course of a patient who developed obliterative bronchiolitis after viral infection on three separate occasions. Long-term follow-up is given. It is suggested that the syndrome of late pulmonary deterioration after transplantation may be steroid responsive if treatment is initiated early in the natural history of the syndrome. In addition, it is suggested that increased emphasis should be placed on the documentation of viral infection in transplant recipients to define a possible interaction between infection and rejection.

Using cardiopulmonary bypass to cool the graft and flushing the lungs with cold crystalloid solution are the most popular methods for clinical cardiopulmonary preservation. Heart-lung transplantation was carried out in 11 cynomolgus monkeys. Donor cardiac preservation was achieved with cold crystalloid cardioplegic solution (10 ml per kilogram of body weight) in all animals. Lung preservation was achieved with a rollerhead pump and by cooling (12 degrees C) the donor in one group of 4 animals (deep hypothermia group) and infusing cold (4 degrees C) modified Euro-Collins solution (15 ml/kg X 4 minutes) into the main pulmonary artery of 7 donors pretreated with prostaglandin E1 (PGE1) (PGE1 group). PGE1 was given intravenously (0.5 to 4.0 micrograms/kg/min) beginning 15 minutes prior to aortic cross-clamping and was continued during administration of the pulmonary cooling solution. In the deep hypothermia group, no pharmacotherapy was used. Grafts were stored at 4 degrees C for about 6 hours. After heart-lung transplantation, arterial blood gases were measured on 40% inspired oxygen and 2 to 3 cm of positive end-expiratory pressure, and were significantly higher in the PGE1 group than the deep hypothermia group after 8 hours of reperfusion (p = 0.04). The partial pressure of arterial oxygen decreased significantly during the 8 hours of reperfusion in the deep hypothermia group (153 to 108 mm Hg; p = 0.01) and increased in the PGE1 group (189 to 218 mm Hg;p = 0.0002). Eighty-six percent of the animals in the PGE1 group survived more than 24 hours (p = 0.03). There were no survivors in the deep hypothermia group.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship of heart-lung allograft-related death and obliterative bronchiolitis (OB) to human leukocyte antigen (HLA) matching was studied in 40 consecutive heart-lung transplant patients operated on between March 1981 and September 1986. Mismatch was defined as an antigen present in the donor but not in the recipient. Patients with only one antigen identified at a given locus were presumed to be homozygous for that antigen. The results were obtained from the patients who survived more than 3 months after surgery. The patients with zero to one mismatches in the HLA locus A (10 patients) had a tendency toward less OB, less severe OB, and fewer deaths from OB than the patients (15) with two mismatches in HLA locus A. However, only graded OB (1, mild; 2, moderate; 3, severe) was significantly different (p = 0.05) in these groups. There was one patient with no A locus mismatches; she survived 62 months, and no OB was found at her autopsy. This limited experience suggests that HLA-A locus match may have a salutary effect on long-term results and that OB may be at least partly a result of chronic rejection.

Transplantation for end-stage pulmonary disease is now established as an effective therapy for selected patients. Initially, combined heart and lung transplantation was the only therapeutic option for these patients. Recent developments that include improved immunosuppression, preservation of grafts and technical advances and markedly decreasing bronchial anastomotic complications have made unilateral pulmonary transplantation a clinical reality.

Unilateral (left) lung allotransplantation was performed on six monkeys (Macaca fascicularis). Intravenous infusion of prostaglandin E-1 into the donor and cooling of the graft by perfusing the pulmonary artery with modified Euro-Collins solution were used for lung preservation. All six primates survived the operation, with good graft function, and were extubated after 4-6 hours. Mild pulmonary densities were found in all of them 3 days postoperatively. Two monkeys died, after 7 and 16 days, due to allograft failure. Autopsy in both cases showed bronchial stenosis, despite omental wrapping around the anastomosis. No other technical problems arose in the early postoperative course. It is concluded that prostaglandin E-1 pretreatment of the donor and single crystalloid flush of the donor lung improves the function of a single lung graft as well as that of a heart-lung transplant.