Infectious complications in heart-lung transplant recipients.

Infectious complications were studied in 14 patients who received heart-lung transplants at Stanford University Medical Center from March 1981 to November 1983. Twenty-nine infections occurred in 12 patients: 18 bacterial, nine viral, and two fungal. Sixteen (89 percent) of the bacterial infections occurred in the lung. Because of frequent colonization of the lower respiratory tract, the specificity of transtracheal aspiration and bronchoscopy was low. Empiric broad-spectrum antibiotic therapy was usually successful, and no patient died of bacterial infection. Cytomegalovirus infection occurred in six and herpes simplex virus infection in three patients. Two patients had invasive candidiasis at postmortem examination. This series emphasizes the importance of infection, particularly of the lung, in causing morbidity and mortality in heart-lung transplant recipients.

(Nva2)-cyclosporine--less potent than cyclosporine A in rats with lung and heart transplants.

The ability of a new cyclosporine (Cs) derivative, (Nva2)-Cs (CsG), to suppress rejection of lung and heart allografts in rats was determined and compared with that of CsA. Left lungs were transplanted orthotopically; hearts were transplanted heterotopically into the abdomen. (Nva2)-Cs was used in three experimental protocols: (1) single or three (Nva2)-Cs injections given to lung-transplanted rats, (2) daily oral (Nva2)-Cs treatment at different doses compared with similar CsA treatments in heart allografted rats, and (3) An 11-day (Nva2)-Cs treatment starting at increasing intervals after transplantation of hearts. (Nva2)-Cs was found to be immunosuppressive, and effective even when the treatment started as late as four days after transplantation. However, (Nva2)-Cs was less effective than CsA in suppressing rejection of lung and heart allografts at low doses. Because (Nva2)-Cs is possibly not nephrotoxic, it might be a useful drug if used in higher doses than CsA or in combination with other immunosuppressive agents.

Potentiation of cyclosporine nephrotoxicity by nafcillin in lung transplant recipients.

The interaction between nafcillin and cyclosporine was examined in lung transplant recipients receiving cyclosporine-based immunosuppression. Nine recipients received nafcillin for one week posttransplant and 10 recipients did not receive nafcillin. Age, sex, pretransplant renal function, type of transplant procedure, use of cardiopulmonary bypass, and initial cyclosporine dose were not significantly different between groups. The degree of renal dysfunction during the early postoperative period was significantly greater in the lung recipients receiving nafcillin. Although cyclosporine doses were significantly higher in the nafcillin group, this was not reflected by differences in cyclosporine levels. No difference in survival or incidence of allograft rejection was seen--however, the incidence of viral infection was significantly higher in the patients who received nafcillin. Based on our findings the use of an alternative antibiotic for antistaphylococcal prophylaxis in transplant recipients receiving cyclosporine is recommended.

Pathogenesis and prevention of graft arteriosclerosis in an experimental heart transplant model.

Accelerated graft arteriosclerosis is a major cause of death in human heart transplantation. Despite many investigations, the pathogenesis of this disease remains undetermined and its control inadequate. In this study using a rat heart transplant model and cyclosporin A, a new immunosuppressant, acute rejection was prevented but arteriosclerotic-like vessel disease still developed consistently as early as 20 days postoperatively. The combination of cyclosporin A and dipyridamole prevented the development of this vessel disease in transplanted hearts at 20 and 50 days postoperatively. Sulfinpyrazone and cyclosporin A reduced but did not prevent the disease. These findings suggest that immunologically induced graft arteriosclerosis can be prevented in transplanted rat hearts by the combination of cyclosporin A and dipyridamole.

Rejection of rat skin xenografts by either murine CD4 or CD8 T cells.

Although xenografts can be rejected by humoral or cellular mechanisms, the relative contribution of each remains unknown for any given recipient-donor combination. Moreover, the cells involved in cell-mediated events, as well as the mechanisms by which these cells recognize xenoantigens, remain controversial. It would be advantageous to have a model in which either, as well as various parts of either, could be investigated in the absence of the other, as well as in the absence of events taking place during organ engraftment. In the present report, rejection of rat skin xenografts was monitored after adoptive transfer of unique populations of highly purified lymphoid cells to previously transplanted immunodeficient C.B17 Scid/Scid mice. Purified T cells and, unexpectedly, purified CD4+ T cells alone and purified CD8+ T cells alone rejected rat xenografts. Alternatives that may explain these findings are discussed.

A new concept for successful long-term pulmonary preservation in a dog model.

We developed a dextran-glucose-based extracellular perfusion solution (DGX) that supports limited aerobic metabolism to maintain cellular integrity of an inflated donor lung during long-term ischemia and a storage temperature of 10 degrees C. In a dog model, we compared respiratory and hemodynamic function of orthotopically transplanted left lungs preserved using this method (DGX, group I, n = 6) with function of those preserved with EuroCollins solution (EC) stored at a temperature of 4 degrees C (group II, n = 6). All lungs were inflated with room air and stored for 12 hr. Pulmonary function was monitored for 5 hr of reperfusion. Values expressed below are group means with standard deviation. Statistical significance was calculated using a two-tailed t test. For PO2 (mmHg) (FiO2 = 0.4), group I (EC): control = 193 +/- 8, 30 min p.o. = 87 +/- 20*, 300 min p.o. = 174 +/- 13*; and group II (DGX): control = 217 +/- 28, 30 min p.o. = 184 +/- 46*, 300 min p.o. = 248 +/- 5*. For pulmonary vascular resistance (dynes), group I: control = 389 +/- 22, 30 min p.o. = 1209 +/- 301, 300 min p.o. = 1025 +/- 204*; and group II: control = 401 +/- 31, 30 min p.o. = 522 +/- 129, 300 min p.o. = 458 +/- 137* (*P < 0.05 DGX vs. EC). Gas analysis performed on air samples taken from the ischemic donor lung immediately after harvest and after 12-hr storage showed (calculated as group means) a significant decrease of PO2 and a significant increase of PCO2, respectively. Histology of the lungs after 5 hr of reperfusion showed essentially normal-appearing lungs in the DGX group, whereas lungs in the EC group showed thickening of the intra-alveolar septi, marked cellular infiltration, and accumulation of protein-like material in the alveoli. In this study, preservation with DGX resulted in satisfactory respiratory and hemodynamic function of the transplanted lung even after 12 hr of ischemia. It does not cause an increase of pulmonary vascular resistance as seen after preservation with EC. Data from the intrabronchial air analysis of the donor lung suggest that aerobic metabolism continues even under preservation conditions.

An assessment of Nva2-cyclosporine in primate cardiac transplantation.

The immunosuppressive potency, hepatotoxicity, and nephrotoxicity of Norvaline2-cyclosporine (Nva2-CsA), an analog of cyclosporine (CsA), were tested in a primate cardiac transplant model. After orthotopic cardiac transplantation in cynomolgus monkeys, immunosuppression was maintained with 16 mg/kg/day of either CsA or Nva2-CsA given intramuscularly in two divided daily doses. Immunosuppression was augmented with i.m. methyl-prednisolone, 1.0 mg/kg/day, which was tapered weekly by .1 mg/kg/day to a maintenance dose of .1 mg/kg/day. A group of 6 untransplanted monkeys were treated for a year with this dose of either CsA or Nva2-CsA and steroids. Renal biopsies were performed at one year. Among the transplanted monkeys, mean survival was 77.3 +/- 73 days for the CsA group and 16 +/- 8 days for the Nva2-CsA group. All 11 animals in the Nva2-CsA group died of cardiac rejection, but only 7 of 10 treated with CsA died of rejection. There was mild hepatic and renal dysfunction in both treatment groups, but no significant difference between groups as judged by blood urea nitrogen, creatinine, total bilirubin, serum glutamic oxaloacetic transaminate, and alkaline phosphatase. Cyclosporine levels were significantly higher in the CsA group. There were important morphological changes in both groups on histological examination of the kidneys, with proximal tubular vacuolation and enlargement of the juxtaglomerular apparatus predominating. It is concluded that Nva2-CsA is a less effective immunosuppressant than CsA when given parenterally in equal doses.

Long-term cardiac and pulmonary histology in primates following combined heart and lung transplantation.

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.

Clinical heart-lung transplantation.

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.

Primary diagnosis predicts prognosis of lung transplant candidates.

Optimal timing for consideration of lung transplantation remains unknown. This study examined survival in patients with end-stage lung disease awaiting transplantation. Primary disease group and relevant indicators were evaluated. Ninety-three patients who met selection criteria for lung transplantation were included in this retrospective review. Of this total, 31% underwent transplantation, 38% remain waiting, and 31% died. Results demonstrate that the six-month actuarial survival rate was 89% for Eisenmenger's syndrome, 81% for emphysema, 74% for cystic fibrosis, 60% for primary pulmonary hypertension, and 38% for interstitial lung disease. Parameters found to be significant included a higher mean right atrial pressure in primary pulmonary hypertension patients who died awaiting transplantation, and lower forced expiratory volume in one second and forced vital capacity measurements in cystic fibrosis patients who died awaiting transplantation. We conclude that primary disease significantly affects survival in candidates awaiting transplantation. Reliable indicators predictive of survival are not available. Earlier referral for consideration of lung transplantation is recommended.

Accessory hepatic vein to pulmonary venous atrium as a cause of cyanosis after the Fontan operation.

The presence of an accessory hepatic vein to the pulmonary venous atrium should be considered in the setting of progressive cyanosis following the Fontan procedure. An inferior vena caval angiogram with "levo-phase" should demonstrate it. Surgical intervention or transcatheter occlusion should lead to prompt resolution of cyanosis.

Atrial septostomy as a bridge to lung transplantation in patients with severe pulmonary hypertension.

Long waiting times for lung transplantation have limited the survival of patients with advanced pulmonary hypertension. Atrial septostomy has been used in this group of patients in an attempt to prolong survival. We evaluated the results of atrial septostomy in 12 patients using the static graded balloon dilation technique. Between December 1990 and May 1998, 10 women and 2 men (ages 13 to 56 years, mean 37 years) underwent atrial septostomy. Nine patients had primary and 3 patents had secondary pulmonary hypertension. Five patients deteriorated despite long-term intravenous prostacyclin infusions. The atrial septum was crossed with a Brockenbrough needle, followed by an 0.035-J exchange wire and progressively larger catheter balloons for atrial septal dilation, until systemic oxygen saturation decreased 5% to 10%. An atrial septal defect was successfully created in each patient. The mean right atrial pressure decreased from 23 to 18 mm Hg and the mean systemic oxygen saturation decreased from 93% to 85%. The mean cardiac index increased from 1.7 to 2.1 L/min/m2 and the mean systemic oxygen transport increased from 268 to 317 ml/min/m2. Complications occurred in 3 patients: transient hypotension during transesophageal echocardiography, a femoral pseudoaneurysm, and a femoral arteriovenous fistula. After septostomy, 6 patients had clinical improvement (resolution of ascites, edema, and no further episodes of syncope); 5 of these 6 patients underwent lung transplantation a mean of 6.1 months after septostomy. Six patients did not have clinical improvement after septostomy. Atrial septostomy improves the hemodynamic status and may be useful as a bridge to lung transplantation in selected patients with pulmonary hypertension.

Operative technique for heart-lung transplantation.

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.

Translocation of the aortic valve for prosthetic valve endocarditis.

Aortic prosthetic valve endocarditis is frequently associated with a perivalvular ring abscess which destroys the normal annulus, so that it is difficult to seat a new prosthesis. Between November, 1974, and January, 1980, we treated four patients with aortic prosthetic endocarditis by translocation of the aortic valve, closure of the native coronary artery ostia, and placement of saphenous vein bypass grafts to the coronary arteries. In each case operation was undertaken because of progressive congestive heart failure resulting from aortic regurgitation; two patients had systemic emboli, and two patients had uncontrolled infection. Infection was due to Enterococcus in three instances and to an unknown organism in one. Total ischemic times averaged 2 hours, 15 minutes; a 25 mm Dacron graft containing a porcine valve was used to replace the ascending aorta and aortic valve, and two or three saphenous vein grafts were placed to distal coronary arteries. One patient died 40 days postoperatively of renal failure and Pseudomonas pneumonia with an intact repair. The other three patients were hospital survivors, with one doing well until dying of chronic active hepatitis 12 months postoperatively. The other two patients are alive at 4 months and 18 months with satisfactory hemodynamic function and are free of infection. Translocation of the aortic valve for prosthetic valve endocarditis is a useful alternative when conventional replacement techniques cannot be utilized.

Primary pulmonary hypertension and pregnancy.

Despite the preponderance of primary pulmonary hypertension (PPH) in young female subjects, documented cases of PPH in association with pregnancy are uncommon. During a 12-month period, 73 female patients with PPH were evaluated as potential recipients of a heart-lung transplant; and in six (8 percent), PPH appeared to be related to pregnancy. Histologic confirmation of the diagnosis was available in four patients, and other causes of pulmonary hypertension were excluded as far as possible in the remaining two patients.

Reversible hyperinflation in emphysema.

Pulmonary emphysema results in hyperinflation of the lungs and concomitant changes in the configuration of the thoracic cavity. We describe a patient who underwent bilateral lung transplantation for emphysema due to alpha 1 antitrypsin deficiency. Dramatic changes in chest dimensions and configuration occurred following transplantation, demonstrating the dynamic and reversible nature of the thoracic cavity abnormalities of emphysema.

Surgical management of congenital obstruction of the left main coronary artery with supravalvular aortic stenosis.

OBJECTIVE: Stenosis of the left main coronary artery is a recognized complicating feature of supravalvular aortic stenosis. We have retrospectively identified three anatomic subtypes of left main coronary obstruction in patients with supravalvular aortic stenosis, each necessitating a distinct surgical approach. METHODS: From 1991 to 1998, 9 patients underwent surgical repair of supravalvular aortic stenosis and left main coronary stenosis. Five patients (group 1) had obstruction from near-circumferential thickening of the left main ostium, 2 patients (group 2) had restricted coronary flow due to fusion of an aortic valve leaflet to the supravalvular ridge, and 2 patients (group 3) had diffuse narrowing of the left main coronary artery. Group 1 patients were treated with patch aortoplasty encompassing the left main ostium and supravalvular aortic stenosis. Group 2 patients were treated with excision of the fused leaflet from the aortic wall and patch aortoplasty. Group 3 patients were treated with bypass grafting and aortoplasty. RESULTS: Surgical strategy was determined by coronary angiography and intraoperative assessment of coronary anatomy. There was 1 early death. All surviving patients underwent echocardiography with or without postoperative catheterization. The mean postoperative supravalvular gradient for 7 patients was 8 mm Hg (range 2-15 mm Hg). One patient required reoperation for a residual aortic gradient as a result of aortic arch involvement. No evidence of left main coronary artery stenosis was seen in groups 1 and 2; bypass grafts were patent in group 3 patients at a mean follow-up of 54.8 months. CONCLUSION: Three subtypes of left main coronary stenosis with supravalvular aortic stenosis are described. Each anatomic type mandates an individual surgical approach. Favorable surgical outcomes are achievable with each category.

Aneurysm of the diverticulum of the ductus arteriosus in the adult. Successful surgical treatment in five patients and review of the literature.

Sixteen aneurysms of the diverticulum of the ductus arteriosus in adults have been previously reported. Ten patients died of rupture of the aneurysm or died at surgical exploration. Only one previous patient underwent successful aneurysmectomy. Five new cases of aneurysm of the adult ductal diverticulum, all diagnosed preoperatively and successfully repaired, are presented. All five patients are alive 6 to 33 months postoperatively. Our experience with these patients suggests several important features of these aneurysms: (1) Diagnosis may be difficult and may require multiple-view aortography or computed tomographic (CT) scanning to differentiate from tumor. (2) The operative approach, either left thoracotomy or median sternotomy, may be determined by the necessity for concomitant procedures. (3) Unlike true atherosclerotic aneurysms of the aortic arch, these aneurysms can be repaired effectively by aneurysmorrhaphy. (4) Because of their critical location and the high incidence of complications in reported cases, aneurysms greater than 3 cm in diameter, those producing symptoms, or those showing progressive enlargement should be surgically resected.

Successful human double-lung transplantation after five and one-half hours of preservation.

Successful clinical double-lung transplantation after 5 1/2 hours of pulmonary ischemia is reported. Static hypothermic preservation with a high-volume, high flow rate-modified Collin's solution pulmonary artery flush was used. Excellent early and late pulmonary function demonstrates the efficacy of the technique that is described in detail. Lung transplantation remains limited by the lack of reliable methods of long-term storage of donor organs, but refinement of current techniques may soon allow its wider application.

Degenerative and atherosclerotic aneurysms of the thoracic aorta. Determinants of early and late surgical outcome.

To identify significant predictors of early and late mortality, multivariate discriminant analyses were applied to the clinical outcome of 175 consecutive patients with thoracic aortic aneurysms operated upon over a 20 year span. Only atherosclerotic and degenerative aneurysms were included; the patients were segregated into two groups according to location of the aneurysm. The ascending aortic aneurysm group consisted of 124 patients, 85% of whom required concomitant aortic valve replacement. There were 51 patients in the descending aortic aneurysm group. Mean follow-up was 4.9 years (maximum of 19 years), with a total of 860 patient-years of follow-up. Multivariate analyses revealed that surgical priority and advanced age were independent determinants of hospital mortality in the ascending group; for the descending group, surgical priority and the presence of congestive heart failure were the strongest predictors of hospital mortality. Late mortality in the ascending group correlated with advanced age. Hypertension and the presence of preoperative congestive heart failure were independent determinants of late mortality in the descending group. Several variables did not have any independent bearing on hospital or late mortality, including etiology and location of the aneurysm, previous myocardial infarction, chronic lung disease, and concomitant aortic valve replacement. High-risk subgroups of patients with thoracic aortic aneurysms can be identified by these variables. Aggressive medical plus surgical management and operation prior to aneurysm rupture is necessary to improve both early and long-term survival rates.