Long-term lung preservation with the PAF antagonist BN 52021.

Platelet activating factor (PAF, 1-alkyl-2(R)-acetyl-glycero-3- phosphorylcholine) is a phospholipid that is released by a variety of cells. The similarity between the pathophysiological effects of PAF and posttransplant pulmonary dysfunction led to an evaluation of a PAF antagonist as an adjunct to lung preservation. The ginkgolide B, BN 52021, was selected as the PAF antagonist to be studied because of the large data base available on this compound. BN 52021 was given to the donor and recipient (10 mg/kg i.v.) prior to harvest and transplantation and was included in 1 L of preservation solution (10 mg/kg) used for flushing the pulmonary artery and for storage. Left single-lung transplantation was performed following a 22-hr preservation period at 10 degrees C. Arterial oxygen tension (pO2), pulmonary vascular resistance (PVR), alveolar arterial oxygen difference (A-aDO2), and dynamic lung compliance (DLC) were recorded for 6 hours following ligation of the native pulmonary artery. At the end of 6 hr pO2 was 243.5 +/- 61.5 vs. 71.7 +/- 10.2 mmHg (P less than 0.02) for the controls. A-aDO2 was less in the BN 52021 groups: 431.8 +/- 58.3 vs. 606.0 +/- 9.8 mmHg in the control groups (P less than 0.001), and PVR was significantly less in the BN 52021 group: 346 +/- 70.8 vs. 663 +/- 64.3 dynes/sec/cm-5 (P less than 0.035). We conclude that PAF antagonists like BN 52021 may be useful adjuncts for lung preservation. The effects of BN 52021 are easily explained by PAF antagonist activity in ischemic and reperfusion-induced pulmonary dysfunction. However this study does not exclude that BN 52021 may have direct effects.

Iron chelation therapy and lung transplantation. Effects of deferoxamine on lung preservation in canine single lung transplantation.

Reperfusion injury is a limiting factor in lung transplantation. Deferoxamine is an iron chelator that inhibits the formation of oxygen-derived free radicals. We investigated the effects of deferoxamine on posttransplantation lung function in a canine model of single lung transplantation. Twelve dogs underwent left lung transplantation after 20- to 24-hour hypothermic storage in a modified Euro-Collins solution. In six experiments donor and recipient received a 10 mg/kg dose of deferoxamine before harvest and transplantation, and 10 mg/kg was added to the preservation solution. Arterial oxygen tension, alveolar-arterial oxygen difference, pulmonary vascular resistance, and dynamic lung compliance were measured. Data were recorded for 6 hours after ligation of the native pulmonary artery. At the end of the study the mean arterial oxygen tension was 175.1 mm Hg for the deferoxamine treated group versus 71.1 mm Hg for the control group (p less than 0.001), and the alveolar-arterial oxygen difference was less in the deferoxamine-treated group: 502.3 versus 606.0 mm Hg (p less than 0.001). The mean pulmonary vascular resistance was lower throughout the study, and after 6 hours it was 455.1 dynes/sec/cm(-5) in the deferoxamine-treated group versus 663.7 dynes/sec/cm(-5) in the control group (p less than 0.035). Compliance was similar in both groups. We conclude that deferoxamine improves lung preservation and early posttransplantation function in canine single lung transplantation.

Anastomotic pulmonary hypertension after lung transplantation for primary pulmonary hypertension: report of surgical correction.

This report describes a patient who developed pulmonary hypertension 6 years after lung transplantation for primary pulmonary hypertension (PPH). Evaluation with right heart catheterization followed by pulmonary angiography, however, demonstrated that the pulmonary hypertension was secondary to an anastomotic narrowing of the pulmonary artery, rather than a recurrence of her PPH. Vascular complications of lung transplantation should be considered in patients who experience exertional dyspnea after lung transplantation. The suggestion of pulmonary hypertension on echocardiography should prompt further evaluation, including meticulous hemodynamic measurements.

Lung transplantation in a Jehovah's Witness.

Patients of the Jehovah's Witness faith generally do not accept transfusions of blood or blood products but some will accept cadaveric organs for transplantation. We report a left single lung transplantation in a 48-year-old Hispanic female with idiopathic pulmonary fibrosis and secondary pulmonary hypertension. We believe this is the first reported case of lung transplantation in a Jehovah's Witness.

Removal and repositioning of "permanent" expandable wire stents in bronchial airway stenosis after lung transplantation.

Significant airway stenosis occurs in 7% to 14% of lung transplant recipients. The use of permanent, nonadjustable, wire mesh stents can be of concern in the transplant recipient with nonmalignant stricture. We report the replacement and repositioning of an expandable wire mesh stent in a double lung transplantation with distal bronchial stenosis.

Increased p53 protein expression in human failing myocardium.

BACKGROUND: The p53 gene is a tumor-suppressor gene which involves apoptosis and cell-cycle arrest under certain stress stimulate. However, the status of the p53 gene expression in human myocardium in congestive heart failure (CHF) remains unclear. Therefore, the current study was designed to investigate the expression of the p53 protein in human myocardium in normal subjects and in patients with severe CHF. METHODS: Human ventricular cardiac tissue was obtained from 7 normal subjects and 7 end-stage CHF patients during cardiac transplantation. The expression of p53 protein was determined by immunohistochemical staining. The cardiac apoptosis was determined by TUNEL staining. RESULTS: The p53 protein was minimally stained in normal human ventricular cardiomyocytes. In contrast, the staining density and positive stained nuclear (%) of p53 was significantly increased in ventricular cardiomyocytes of patients with severe CHF. Apoptosis in CHF human myocardium also markedly increased. CONCLUSIONS: The significantly increased expression of p53 in CHF human cardiomyocytes suggests that p53 may play an important pathophysiological role in the process of CHF through mechanisms involving myocardial apoptosis.

The changing profile of the cardiac donor.

BACKGROUND: Expansion of traditional donor criteria has become standard in most centers. To determine how this has affected donor profiles, at our institution, we reviewed all adult (age > or = 16) cardiac donors of the past 15 years. METHODS: We separated 261 cardiac donors into 2 groups based on time periods: Group I, 1983 to 1991 (n = 131), and Group II, 1991 to 1998 (n = 130). RESULTS: The groups differed significantly in mean donor age (26.2 years vs 30.9; p < 0.001), percent older than 40 years (6% vs 27%; p < 0.001), percent female (23% vs 35%; p = 0.04), percent distant procurement (54% vs 22%; p < 0.001), and percent minority donors (14% vs 29%; p < 0.001). We found an increase in non-traumatic deaths (24% vs 40%; p = 0.008). Older donors had significantly more non-traumatic deaths than younger donors (79% vs 13%; p < 0.001). Overall 5-year survival of recipients was 64% and was not significantly different between our early and late experiences (60% vs 68%; p = not significant [NS]). Recipients with hearts from older donors had a 5-year survival similar to recipients with younger donor hearts (61% vs 64%; p = NS). Traumatic and non-traumatic donors had similar 5-year survivals (64% vs 63%, p = NS). A stepwise multivariate analysis of the entire cohort identified donor age, donor weight, recipient United Network for Organ Sharing status, and cardiopulmonary bypass time as significant independent risk factors for recipient survival. Recipients of hearts from donors < 90 kg had significantly better 5-year survivals than recipients from donors > or = 90 kg (66% vs 48%; p = 0.01). CONCLUSIONS: Our evolving cardiac donor pool now has more minorities, women, and older donors whose deaths are often non-traumatic. At our institution, donor pool expansion has had no adverse effect on the long-term survival of recipients.

Pediatric heart-lung transplantation: intermediate-term results.

BACKGROUND: Adult heart-lung transplantation was initiated at Stanford in 1981 and the first pediatric heart-lung transplantation was done in 1986. Intermediate-term results of pediatric heart-lung transplantation at Stanford University are presented. METHODS: A retrospective review of the records of all pediatric heart-lung transplantations done since 1986 was conducted. RESULTS: Nineteen heart-lung transplantations were done in 17 patients. Ages ranged from 2 months to 18 years with a median age of 10 years. At the time of transplantation 5 patients were infants, 7 children, and 7 adolescents. The mean follow-up was 29 +/- 6.2 months (range 1 to 77, median 16) and follow-up was 100% complete. Diagnoses were congenital heart disease in 13, primary pulmonary hypertension in 2, and cystic fibrosis, cystic lymphangiectasia, viral pneumonia, and obliterative bronchiolitis in 1 each. Median wait on the heart-lung transplantation list was 91 days (range 2 to 707). All patients had New York Heart Association class III to IV symptoms, two were receiving ventilator support, and six were receiving oxygen. Fifteen of 19 transplant recipients were discharged from the hospital. The 30-day operative mortality rate was 5.2% (1 of 19). The actuarial survival at 1, 3, and 5 years for all patients was 67%, 51%, and 41%, respectively, and for hospital survivors was 82%, 62%, and 51%. The cause of death was obliterative bronchiolitis in 4, multisystem organ failure in 3, and graft coronary artery disease and chronic airway disease in 1 each. Three patients required retransplantation, 2 because of obliterative bronchiolitis and 1 because of viral pneumonia. Two patients underwent repeat heart-lung transplantation and 1 patient underwent single lung transplantation. Rejection was diagnosed in 73% of recipients, and obliterative bronchiolitis has developed in 32% of recipients. CONCLUSIONS: Survival in pediatric heart-lung transplantation approximates that in the adult procedure at 1, 3, and 5 years. Long-term survival has been achieved but the primary factors limiting further improved survival remain infection and obliterative bronchiolitis.

The influence of continuous intravenous prostacyclin therapy for primary pulmonary hypertension on the timing and outcome of transplantation.

BACKGROUND: Primary pulmonary hypertension (PPH) is a progressive disease with a median survival of less than 3 years from diagnosis. Medical management has typically consisted of anticoagulation and oral calcium channel blocking agents, whereas lung transplantation (LT) has been reserved for patients who are unresponsive to medical therapy. Continuous intravenous prostacyclin was introduced for patients who did not respond to calcium channel blockers and who would have required LT. We reviewed our experience with prostacyclin in LT candidates to study its effects on the timing and outcome of LT. METHODS: We retrospectively reviewed the clinic and hospital records of patients with PPH who were both treated with prostacyclin and evaluated for LT. Additional information was obtained from the pulmonary vascular disease and lung transplantation databases. RESULTS: A total of 42 patients were identified who received prostacyclin for the treatment of PPH and were evaluated for LT. Thirty-seven patients were accepted as LT candidates, 22 at The University of Maryland Medical Center (UMMC), 15 at other LT programs. Overall, 70% (27/37) of LT candidates were removed from the LT waiting list or had listing for LT deferred because of clinical improvement. In patients listed for LT before initiation of prostacyclin therapy, 55% (12/22) were removed from the active waiting list for 27.2+/-17 months (range 8 to 60), and 92% (11/12) remain on the inactive status. In patients who received prostacyclin before listing for LT, listing for LT was deferred in 94% (14/15) for 17.4+/-9 months (range 6 to 33 months) because of clinical stability or improvement. In all, 93% of patients (39/42) experienced an improvement in 1 or more New York Heart Association functional class. The hemodynamic profiles of the eight patients removed from the active waiting list at UMMC demonstrated increases of 55%+/-18% in cardiac output, and decreases of 14.3%+/-4.9% in mean pulmonary artery pressure and 36%+/-8.3% in total pulmonary resistance (p < 0.05). The 1-year survival rate for LT after prostacyclin therapy was 88% (7/8) at UMMC and 60% (3/5) at the other centers. CONCLUSION: We conclude that prostacyclin therapy is an effective means of delaying, possibly indefinitely, the need for LT in patients with PPH and that excellent results can be obtained when LT is performed after prostacyclin therapy. Consideration should be given to initiating prostacyclin therapy in all patients whose conditions do not respond to conventional therapy before proceeding with transplantation.

Patterns and significance of exhaled-breath biomarkers in lung transplant recipients with acute allograft rejection.

BACKGROUND: Obliterative bronchiolitis (OB) remains one of the leading causes of death in lung transplant recipients after 2 years, and acute rejection (AR) of lung allograft is a major risk factor for OB. Treatment of AR may reduce the incidence of OB, although diagnosis of AR often requires bronchoscopic lung biopsy. In this study, we evaluated the utility of exhaled-breath biomarkers for the non-invasive diagnosis of AR. METHODS: We obtained breath samples from 44 consecutive lung transplant recipients who attended ambulatory follow-up visits for the Johns Hopkins Lung Transplant Program. Bronchoscopy within 7 days of their breath samples showed histopathology in 21 of these patients, and we included them in our analysis. We measured hydrocarbon markers of pro-oxidant events (ethane and 1-pentane), isoprene, acetone, and sulfur-containing compounds (hydrogen sulfide and carbonyl sulfide) in exhaled breath and compared their levels to the lung histopathology, graded as stable (non-rejection) or AR. None of the study subjects were diagnosed with OB or infection at the time of the clinical bronchoscopy. RESULTS: We found no significant difference in exhaled levels of hydrocarbons, acetone, or hydrogen sulfide between the stable and AR groups. However, we did find significant increase in exhaled carbonyl sulfide (COS) levels in AR subjects compared with stable subjects. We also observed a trend in 7 of 8 patients who had serial sets of breath and histopathology data that supported a role for COS as a breath biomarker of AR. CONCLUSIONS: This study demonstrated elevations in exhaled COS levels in subjects with AR compared with stable subjects, suggesting a diagnostic role for this non-invasive biomarker. Further exploration of breath analysis in lung transplant recipients is warranted to complement fiberoptic bronchoscopy and obviate the need for this procedure in some patients.

Induction therapy in lung transplantation: a prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab.

BACKGROUND: Because acute rejection is associated with inferior outcomes in lung transplantation, we have routinely employed OKT3, anti-thymocyte globulin (ATG), or daclizumab as adjuncts to reduce rejection. METHOD: We performed a 4-year prospective, controlled clinical trial of these 3 therapies to determine differences in post-operative infection, rejection, survival, and bronchiolitis obliterans syndrome (BOS). Eighty-seven consecutive lung transplant patients received OKT3 (n = 30), ATG (n = 34), and daclizumab (n = 23) as induction agents. The groups had similar demographics and immunosuppression protocols differing only in induction agents used. RESULTS: No differences were observed in immediate post-operative outcomes such as length of hospitalization, ICU stay, or time on ventilators. Twelve months post-transplant, OKT3 had more infections per patient than the other agents, a difference that only became significant 2 months post-operatively (p = 0.009). The most common infection was bacterial and OKT3 had more bacterial infections than any other agent. Daclizumab had more patients remain infection free in the first year (p = 0.02), having no fungal infections and a low rate of viral infections. No patient receiving daclizumab developed drug specific side-effects. Only those patients with episodes of acute rejection developed BOS. There were no significant differences in the freedom from acute rejection or BOS between the groups. The 2-year survival for the entire cohort was 68%, with no differences observed in patient survival. CONCLUSIONS: This study again reveals the importance of acute rejection in the subsequent development of BOS. Although daclizumab offers a low risk of post-transplant infection and drug specific side-effects, no drug is superior in delaying rejection or BOS or in prolonging long-term survival.

Lung transplantation from dialysis dependent donors.

Lung transplantation from a donor with chronic renal failure has never been reported. This paper reports our successful experience with 2 transplants from donors with end-stage renal disease who were on chronic hemodialysis, and reviews the relevant literature on the effects of renal failure on pulmonary function and on the use of marginal donors.

Risk factors for the development of obliterative bronchiolitis after lung transplantation.

BACKGROUND: Acute rejection has emerged as an important risk factor for obliterative bronchiolitis after lung transplantation. We performed a multivariate analysis to assess the impact of additional variables. METHODS: Seventy-four recipients (48 heart-lung, 18 single-lung, and 8 bilateral-lung recipients) who survived longer than 90 days and underwent transplantation more than 15 months before data analysis were included in this study. Several variables were entered into a Cox regression analysis to determine their association with the development of bronchiolitis obliterans syndrome. RESULTS: Bronchiolitis obliterans syndrome developed in 48 (65%) of 74 patients. Significant correlations were detected for acute rejection score, defined as the sum of pathologic grades of each separate acute rejection episode (p = 0.0004, likelihood ratio test value = 12.4) and for lymphocytic bronchiolitis (p = 0.03). In a bivariate model, episodes of organizing pneumonia and bacterial or fungal pneumonia significantly increased the likelihood ratio test value of the acute rejection score. The addition of the cytomegalovirus infection score, reflecting the frequency and severity of infection, to the combination of the acute rejection score and episodes of bacterial or fungal pneumonia resulted in a further significant increase in the likelihood ratio test value. Significant risk factors for moderate to severe stages of airflow limitation were at least one episode of acute rejection of grade > or = 2, younger recipient age, and any acute rejection episode 180 days or longer after transplantation. CONCLUSIONS: Increasing frequency and severity of acute rejection episodes are strongly associated with the development of bronchiolitis obliterans syndrome. Lymphocytic bronchiolitis appeared to be significant by univariate analysis, but in a two-risk factor model, it did not augment the influence of acute rejection. Organizing pneumonia, bacterial or fungal pneumonia, and increasing severity and frequency of cytomegalovirus infections potentiate the effect of acute rejection. Late episodes of acute rejection and younger recipient age increase the risk for development of advanced disease.

Lung transplantation for primary and secondary pulmonary hypertension.

BACKGROUND: Single lung transplantation (SLT) and bilateral lung transplantation (BLT) are routinely performed in patients with primary pulmonary hypertension (PPH) and secondary pulmonary hypertension (SPH). It is unclear which procedure is preferable. We reviewed our experience with lung transplants for PPH and SPH to determine if any advantage exists with SLT or BLT for either PPH or SPH. METHODS: We reviewed the outcomes of all lung transplants performed for PPH or SPH for 4.5 years (July 1995 to January 2000). Survival was reported by the Kaplan-Meier method, and log rank analysis was used to determine significance. Statistical analyses of clinical data were performed using analysis of variance and chi2 analysis. RESULTS: A total of 57 recipients met criteria for pulmonary hypertension with a mean pulmonary artery pressure of greater than or equal to 30 mm Hg. There were 15 patients with PPH and 40 patients with SPH. There were 6 patients who had SLTs and 9 patients who had BLTs in the PPH group; and there were 9 patients who had SLTs and 21 patients who had BLTs in the SPH group. We found a survival advantage for PPH patients who underwent BLTs at all time points up to 4 years (100% vs 67%; p < or = 0.02). There was no clear advantage to SLTs or BLTs for SPH. At 4 years there was a trend toward improved survival with SLTs (91% vs 75%) in SPH patients with a mean pulmonary artery pressure less than or equal to 40 mm Hg (p < or = 0.11) with equivalent survival (80%) in patients with a mean pulmonary artery pressure greater than or equal to 40 mm Hg. There was also a trend toward improved survival in patients with a mean pulmonary artery pressure greater than or equal to 40 mm Hg (PPH and SPH) with BLTs (88% vs 62%; p = 0.19). The incidence of rejection, infection, and other complications was comparable between SLTs and BLTs in each group. CONCLUSIONS: We believe that BLT is the procedure of choice for PPH. The procedure of choice is less clear for SPH. Patients with SPH and a mean pulmonary artery pressure greater than 40 mm Hg may benefit from a BLT and those with a mean pulmonary artery pressure less than or equal to 40 mm Hg may do better with an SLT; however, no clear advantage is seen.

Obliterative bronchiolitis after lung and heart-lung transplantation.

Obliterative bronchiolitis (OB) has emerged as the main cause of morbidity and mortality in the long-term follow-up after lung and heart-lung transplantation. The pathogenesis of OB is multifactorial, with acute rejection and cytomegalovirus infection being the main risk factors for the development of OB. The final common pathway of all inciting events seems to be an alloimmune injury, with subsequent release of immunologic mediators and production of growth factors leading to luminal obliteration and fibrous scarring of the small airways. Analyzing the 14 years of experience in 163 patients at Stanford University, we found a current incidence of bronchiolitis obliterans syndrome or histologically proven OB within the first 3 years after lung and heart-lung transplantation of 36.3%, with an overall prevalence of 58.1% after heart-lung and 51.4% after lung transplantation. Both pulmonary function indices (forced expiratory flow between 25% and 75% of forced vital capacity and forced expiratory volume in 1 second) and transbronchial biopsies have proven helpful in diagnosing bronchiolitis obliterans syndrome or OB at an early stage. Early diagnosis of OB and improved management have achieved survival rates in patients with OB after 1, 3, 5, and 10 years of 83%, 66%, 46%, and 22%, compared with 86%, 83%, 67%, and 67% in patients without OB. Recently, different experimental models have been developed to investigate the cellular and molecular events leading to OB and to evaluate new treatment strategies for this complication, which currently limits the long-term success of heart-lung and lung transplantation.

Lung transplantation and systemic sclerosis.

We performed lung transplantation in nine patients with Scleroderma related lung disease. Patient characteristics included: 7 (78%) females, 6 (67%) with limited and 3 (33%) with diffuse Scleroderma. Pulmonary fibrosis was present in 7 (78%) and pulmonary hypertension in 4 (44%). All patients were carefully screened by the Johns Hopkins and University of Maryland Scleroderma Center and only referred for transplantation when concomitant renal insufficiency (creatinine clearance < or = 50 ml/min), aspiration, and skin brakdown were excluded. When compared to a similar group of transplant patients with nonscleroderma lung disease (primary pulmonary fibrosis), there was no significant difference in post-transplant survival at four years (76.2 +/- 0.15% vs. 69.2% +/- 0.12%), mean annual incidence rate for acute rejection (0.14 +/- 0.14 vs. 0.47 +/- 0.13) and infection (viral 0.17 +/- 0.17 vs. 0.29 +/- 0.11) (bacterial 0.17 +/- 0.17 vs. 1.4 +/- 0.4) (fungal 0.99 +/- 0.69 vs. 0.36 +/- 0.16) or serum creatinine (1.55 +/- 0.34 mg/dl vs. 1.15 +/- 0.09 mg/dl). We conclude that lung transplantation is viable option for carefully selected patients with scleroderma related lung disease.

Relative importance of patient, procedural and anatomic risk factors for early vein graft thrombosis after coronary artery bypass graft surgery.

AIM: The aim of the present study was to investigate the relative importance of a wide array of patient demographic, procedural, anatomic and perioperative variables as potential risk factors for early saphenous vein graft (SVG) thrombosis after coronary artery bypass graft (CABG) surgery. METHODS: The patency of 611 SVGs in 291 patients operated on at four different hospitals enrolled in the Reduction in Graft Occlusion Rates (RIGOR) study was assessed six months after CABG surgery by multidetector computed tomography coronary angiography or clinically-indicated coronary angiography. The odds of graft occlusion versus patency were analyzed using multilevel multivariate logistic regression with clustering on patient. RESULTS: SVG failure within six months of CABG surgery was predominantly an all-or-none phenomenon with 126 (20.1%) SVGs totally occluded, 485 (77.3%) widely patent and only 16 (2.5%) containing high-grade stenoses. Target vessel diameter ≤ 1.5 mm (adjusted OR 2.37, P=0.003) and female gender (adjusted OR 2.46, P=0.01) were strongly associated with early SVG occlusion. In a subgroup analysis of 354 SVGs in which intraoperative graft blood flow was measured, lower mean flow was also significantly associated with SVG occlusion when analyzed as a continuous variable (adjusted OR 0.984, P=0.006) though not when analyzed dichotomously, <40 mL/min versus ≥ 40 mL/min (adjusted OR 1.86, P=0.08). CONCLUSION: Small target vessel diameter, female gender and low mean graft blood flow are significant risk factors for SVG thrombosis within six months of CABG surgery in patients on postoperative aspirin therapy. This information may be useful in guiding revascularization strategies in selected patients.