Si M. Pham

Inducible nitric oxide synthase suppresses the development of allograft arteriosclerosis.

In cardiac transplantation, chronic rejection takes the form of an occlusive vasculopathy. The mechanism underlying this disorder remains unclear. The purpose of this study was to investigate the role nitric oxide (NO) may play in the development of allograft arteriosclerosis. Rat aortic allografts from ACI donors to Wistar Furth recipients with a strong genetic disparity in both major and minor histocompatibility antigens were used for transplantation. Allografts collected at 28 d were found to have significant increases in both inducible NO synthase (iNOS) mRNA and protein as well as in intimal thickness when compared with isografts. Inhibiting NO production with an iNOS inhibitor increased the intimal thickening by 57.2%, indicating that NO suppresses the development of allograft arteriosclerosis. Next, we evaluated the effect of cyclosporine (CsA) on iNOS expression and allograft arteriosclerosis. CsA (10 mg/kg/d) suppressed the expression of iNOS in response to balloon-induced aortic injury. Similarly, CsA inhibited iNOS expression in the aortic allografts, associated with a 65% increase in intimal thickening. Finally, we investigated the effect of adenoviral-mediated iNOS gene transfer on allograft arteriosclerosis. Transduction with iNOS using an adenoviral vector suppressed completely the development of allograft arteriosclerosis in both untreated recipients and recipients treated with CsA. These results suggest that the early immune-mediated upregulation in iNOS expression partially protects aortic allografts from the development of allograft arteriosclerosis, and that iNOS gene transfer strategies may prove useful in preventing the development of this otherwise untreatable disease process.

Transplant candidate's clinical status rather than right ventricular function defines need for univentricular versus biventricular support☆☆☆★★★♢♢♢

We have studied our experience since 1988 with 31 patients who required a mechanical circulatory bridge to transplantation and also had biventricular failure (mean right ventricular ejection fraction 11.8%) to better define the need for biventricular or total artificial heart support versus univentricular support. Clinical factors including preoperative inotropic need, fever without detectable infection, diffuse radiographic pulmonary edema, postoperative blood transfusion, and right ventricular wall thickness were compared with hemodynamic parameters including cardiac index, right ventricular ejection fraction, central venous pressure, mean pulmonary arterial pressure, and total pulmonary resistance for ability to predict need for mechanical or high-dose inotropic support for the right ventricle. Patients were grouped according to need for right ventricular support after left ventricular-assist device implantation: none (group A, 14) inotropic drugs (group B1, 7), and right ventricle mechanical support (group B2, 10). There were no differences in preimplantation hemodynamic variables. Groups B1 and B2 had significantly lower mixed venous oxygen saturation (39.2% vs 52.5% in group A; p < 0.001), greater level of inotropic need (p < 0.02), greater impairment of mental status, and lower ratio of right ventricular ejection fraction to inotropic need (0.37 vs 0.56 for group A; p < 0.02) before left ventricular-assist device implantation. A significant discriminator between groups B1 and B2 was the presence of a fever without infection within 10 days of left ventricular-assist device implantation (43% in group B1 vs 70% in group B2). Group B2 had more patients with preimplantation pulmonary edema seen on chest radiography and a greater requirement for postoperative blood transfusion (5 units of cells in group B1 vs 14.8 units in group B2. Right ventricular wall thickness at left ventricular-assist device explantation was 0.83 cm in group B2 vs 0.44 cm in group B1 (p < 0.05). Transplantation rates after bridging were 100% in group A, 71% in group B1, and 40% in group B2. Clinical factors that reflect preimplantation degree of illness and perioperative factors that result in impairment of pulmonary blood flow or reduced perfusion of the right ventricle after left ventricular-assist device implantation are now considered to be more predictive of the need for additional right ventricular support than preimplantation measures of right ventricular function or hemodynamic variables.

A decade of lung transplantation.

OBJECTIVE The experience accrued at the University of Pittsburgh between March 1982 and December 1992 in the various forms of lung transplantation, including heart-lung, double lung, and single lung, is discussed. SUMMARY BACKGROUND DATA Heart-lung (n = 97) was the most commonly performed operation followed by double lung (n = 80) and single lung (n = 68). Major indications included primary pulmonary hypertension (n = 76), obstructive lung disease (n = 57), Eisenmengers syndrome (n = 42), cystic fibrosis (n = 32), and retransplantation (n = 13). Since May 1991, 115 procedures have been performed and heart-lung transplantation has decreased from 61% to 15% of the cases with a corresponding doubling in double lung from 24% to 43% and single lung from 15% to 42%. RESULTS The 1-, 2-, and 5-year survival rates in all 232 recipients were 61%, 55%, and 44%, respectively. The actuarial survival rate was significantly better for those 107 recent recipients compared to the 125 early recipients (70% vs. 61%). Overall, the 63 single (70%) and 74 double (65%) lung procedures were more successful than heart-lung transplantation (53%). Recently, however, lung transplantation has been associated with an improvement in the survival rate from 48% to 72%. The survival rate has also improved from 53% to 77% for single lung transplant recipients. The causes of death in 106 recipients included infection (n = 40), early allograft dysfunction (n = 23), obliterative bronchiolitis (n = 13), and inoperative bleeding (n = 10). Poor outcomes also included technical problems (n = 6), lymphoma (n = 4), acute rejection (n = 3), diaphragmatic paralysis (n = 2), multisystem organ failure (n = 2), stroke (n = 2), liver failure (n = 1), and airway dehiscence (n = 1). CONCLUSIONS The long-term outlook for lung transplant recipients has improved. There appears to be significant conservation of organs with single lung and double lung transplantation, finding greater acceptance for diseases once exclusively treated by heart-lung transplantation alone. The improved long-term outlook will be dependent upon better treatment for chronic rejection of the airways that histologically is defined by obliterative bronchiolitis.

A prospective trial of tacrolimus (FK 506) in clinical heart transplantation: Intermediate-term results

Between January 1, 1989, and December 31, 1994, we have treated 122 primary heart recipients with FK 506 (group I) and 121 with cyclosporine (group II). Fifty patients in the cyclosporine (CyA) group received no lympholytic induction (CyA alone) and 71 others received lympholytic induction with either rabbit antithymocyte globulin or OKT3 (CyA+LI). The mean follow-up was longer in the FK 506 group than in the CyA groups (3.2 +/- 1.3 vs 2.3 +/- 1.8 years; p< 0.01). Patient survival did not differ on the basis of the type of immunosuppression used. At 3 months after transplantation, the freedom from rejection in the FK 506 group was higher than that of the CyA-alone group (47% vs 22%, p < 0.01) but similar to that of the CyA+LI group (47% vs 53%). The linearized rejection rate (episodes/100 patient-days) of the FK 506 group (0.09 episodes) was lower (p < 0.05) than that of the CyA-alone group (0.26) and the CyA+LI group (0.13). The requirement for pulsed steroids to treat rejection was less in common in the FK 506 group than in either CyA group. Eighteen patients in the CyA group had refractory rejections; all resolved with FK 506 rescue. Two patients in the FK 506 group had refractory rejection that resolved with total lymphoid irradiation (n=1) and methotrexate therapy (n=1). Patients receiving FK 506 had a lower risk of hypertension and required a lower dose of steroids. Although the mean serum creatinine concentration at 1 year was higher in the FK 506 group, this difference disappeared after 2 years. No patients required discontinuation of FK 506 because of its side effects. Our intermediate-term results indicate that FK 506 compares favorably with CyA as a primary immunosuppressant in heart transplantation.

A prospective randomized trial of FK506 versus cyclosporine after human pulmonary transplantation.

We have conducted a unique prospective randomized study to compare the effect of FK506 and cyclosporine (CsA) as the principal immunosuppressive agents after pulmonary transplantation. Between October 1991 and March 1993, 74 lung transplants (35 single lung transplants [SLT], 39 bilateral lung transplant [BLT]) were performed on 74 recipients who were randomly assigned to receive either FK or CsA. Thirty-eight recipients (19 SLT, 19 BLT) received FK and 36 recipients (16 SLT, 20 BLT) received CsA. Recipients receiving FK or CsA were similar in age, gender, preoperative New York Heart Association functional class, and underlying disease. Acute rejection (ACR) was assessed by clinical, radiographic, and histologic criteria. ACR was treated with methylprednisolone, 1 g i.v./day, for three days or rabbit antithymocyte globulin if steroid-resistant. During the first 30 days after transplant, one patient in the FK group died of cerebral edema, while two recipients treated with CsA died of bacterial pneumonia (1) and cardiac arrest (1) (P = NS). Although one-year survival was similar between the groups, the number of recipients free from ACR in the FK group was significantly higher as compared with the CsA group (P < 0.05). Bacterial and viral pneumonias were the major causes of late graft failure in both groups. The mean number of episodes of ACR/100 patient days was significantly fewer in the FK group (1.2) as compared with the CsA group (2.0) (P < 0.05). While only one recipient (1/36 = 3%) in the group treated with CsA remained free from ACR within 120 days of transplantation, 13% (5/38) of the group treated with FK remained free from ACR during this interval (P < 0.05). The prevalence of bacterial infection in the CsA group was 1.5 episodes/100 patient days and 0.6 episodes/100 patient days in the FK group. The prevalence of cytomegaloviral and fungal infection was similar in both groups. Although the presence of bacterial, fungal, and viral infections was similar in the two groups, ACR occurred less frequently in the FK-treated group as compared with the CsA-treated group in the early postoperative period (< 90 days). Early graft survival at 30 days was similar in the two groups, but intermediate graft survival at 6 months was better in the FK group as compared with the CsA group.

Solid tumors after heart transplantation: Lethality of lung cancer

BACKGROUND Prolonged nonspecific immunosuppression after solid-organ transplantation is associated with an increased risk of certain cancers. This study examined the development of solid-organ tumors after cardiac transplantation. METHODS Thirty-eight solid tumors were identified in 36 (5.9%) of 608 cardiac transplant recipients who survived more than 30 days. Two patients had two types of skin tumors (basal cell and squamous cell). The tumors included the following types: skin (15), lung (10), breast (1), bladder (2), larynx (2), liver (1), parotid (1), testicle (1), uterus (2), melanoma (2), and Merkels cell (1). Four immunosuppression regimens based on cyclosporin A or FK 506 were used during this period. RESULTS There was no association between the incidence of solid tumors and the use of lympholytic therapy. After the diagnosis of tumor was made, the actuarial 2-year survival rates of recipients with skin, lung, and other solid tumors were 71%, 22%, and 23%, respectively. Eight of 10 patients with lung cancer were in stage IIIA or higher at the time of diagnosis. CONCLUSION Skin and lung tumors are the most frequent solid tumors in heart transplant recipients. Skin tumors (except Merkels cell carcinoma and melanoma) usually have a benign course, whereas lung and other tumors developing in cardiac transplant recipients carry a poor prognosis. Advanced disease stage at the time of diagnosis is responsible for the dismal outcome of recipients in whom solid tumors develop. Close postoperative tumor surveillance after cardiac transplantation is warranted.

RISK STRATIFICATION USING THE SOCIETY OF THORACIC SURGEONS PROGRAM

In an era of progressive cost containment and public scrutiny, the wisdom of aggressive surgical therapy for high-risk candidates has been questioned. At our center in the previous 24 months, 728 patients with coronary artery disease were entered into The Society of Thoracic Surgeons national database, and the hospital outcomes plus length of stay were analyzed. Patients were separated according to the predicted mortality based on the groupings in The Society of Thoracic Surgeons database: 0 to 5% (453 patients); 5% to 10% (126 patients); 10% to 20% (96 patients); 20% to 30% (17 patients); and 30% and greater (36 patients). There was a close correlation with the predicted rates of mortality. Importantly, the preoperative risk stratification demonstrated a strong correlation with the significant morbidity and excessive length of stay in the highest-risk groups (predicted risk of 20% to > or = 30%). The incidences of the most common complications in the group with the highest predicted risk (> or = 30%) were 28%, renal failure; 33%, ventilator dependence; and 17%, cardiac arrest. In addition, at short-term follow-up (6 to 8 months), a 24.3% mortality was identified in patients with a predicted mortality that exceeded 20%. These data quantify the risks and morbidities associated with the care of seriously ill patients with coronary artery disease and demonstrate the need for professional and public discussions focusing on the association of a high preoperative risk status and the consumption of resources.

Single- Versus Double-Lung Transplantation For Pulmonary Hypertension

OBJECTIVES Uncertainty persists as to the best lung transplant operation for patients with pulmonary hypertension. To quantify short- and long-term outcomes after single- and double-lung transplantation for pulmonary hypertension, we reviewed our clinical experience. METHODS A retrospective review of 58 lung transplants at a single institution between 1989 and 1996 was performed. Recipients had primary (n = 19) or secondary (n = 39) pulmonary hypertension. RESULTS Thirty-seven double- and 21 single-lung transplants were performed. The groups were well matched with regard to preoperative characteristics. Cardiopulmonary bypass time was longer (151 vs 250 minutes) in the double-lung group. Excluding 10 patients surviving less than 30 days (6 double- and 4 single-lung transplants), median duration of intubation (7.5 vs 10 days), length of stay in the intensive care unit (10 vs 16 days), and hospital stay (32 vs 52 days) were not significantly different for the single- and double-lung groups, respectively. Actuarial survival was nearly identical, with 81% and 84% 1-month survivals for the single- and double-lung groups, and identical 1-year (67%) and 4-year (57%) survivals for both groups. Late functional status was similar for recipients of single- and double-lung grafts. During the period of this study, 58 patients with pulmonary hypertension died on our centers waiting list before coming to transplantation. CONCLUSIONS These data suggest that lung transplant recipients with pulmonary hypertension have similar outcomes after single- or double-lung transplantation. These results support cautious preferential application of single-lung transplantation for pulmonary hypertension.

Cardiopulmonary bypass is associated with early allograft dysfunction but not death after double-lung transplantation

OBJECTIVES To assess the effect of cardiopulmonary bypass on allograft function and recipient survival in double-lung transplantation. METHODS Retrospective review of 94 double-lung transplantations. RESULTS Cardiopulmonary bypass was used in 37 patients (CPB); 57 transplantations were accomplished without bypass (no-CPB). Bypass was routinely used for patients with pulmonary hypertension (n = 27) and for two recipients undergoing en bloc transplantation. Cardiopulmonary bypass was required in eight (12.3%) of the remaining 65 patients. Mean ischemic time was longer in the CPB group (346 vs 315 minutes, p = 0.04). The CPB group required more perioperative blood (11.4 vs 6.0 units, p = 0.01). Allograft function, assessed by the arterial/alveolar oxygen tension ratio, was better in the no-CPB group at 12 and 24 hours after operation (0.54 vs 0.39 at 12 hours, p = 0.002; and 0.63 vs 0.38 at 24 hours, p = 0.001). The CPB group had more severe pulmonary infiltrates at both 1 and 24 hours (p = 0.005). Diffuse alveolar damage was more common in the CPB group (69% vs 35%, p = 0.002). Median duration of intubation was longer in the CPB group (10 days) than in the no-CPB group (2 days, p = 0.002). The 30-day mortality rate (13.5% vs 7.0% in the CPB and no-CPB groups) and 1-year survival (65% vs 67%, CPB and no-CPB) were not significantly different. CONCLUSIONS In the absence of pulmonary hypertension, cardiopulmonary bypass is only occasionally necessary in double-lung transplantation. Bypass is associated with substantial early allograft dysfunction after transplantation.

Extracorporeal membrane oxygenation as an adjunct treatment for primary graft failure in adult lung transplant recipients.

Primary graft failure is a catastrophic event in lung transplantation. Failure is characterized by profound abnormalities of gas exchange that are frequently unresponsive to alterations in mechanical ventilation. This condition can be fatal and, if less severe, is usually associated with significant permanent damage to the allograft. We report the use of extracorporeal membrane oxygenation as a means to support lung transplant recipients with severe graft failure. Since 1991, extracorporeal membrane oxygenation has been used on 17 occasions for the temporary support of 16 adult lung transplant recipients. All patients met or exceeded standard National Institutes of Health guidelines for institution of extracorporeal membrane oxygenation. Nine double lung, six single lung, and one heart-lung recipients were supported for 1 to 12 days (mean 4.6 +/- 2.2 days). Extracorporeal membrane oxygenation was instituted early, within 7 days of transplantation, in ten patients. Eight early patients (80%) were successfully weaned from extracorporeal membrane oxygenation. Seven of ten (70%) patients were long-term survivors, and five of the seven had normal lung function. In comparison, there were no survivors among six recipients placed on extracorporeal membrane oxygenation for late (> or = 7 days) graft dysfunction. Extracorporeal membrane oxygenation is a lifesaving adjunct in recipients with acute graft failure after lung transplantation. Ischemia-reperfusion injury and acute graft dysfunction after lung transplantation can be successfully reversed with early aggressive intervention.