Liver and lung transplantation in cystic fibrosis: an adult cystic fibrosis centre's experience.

Liver disease develops in one-third of patients with cystic fibrosis (CF). It is rare for liver disease to have its onset after 20 years of age. Lung disease, however, is usually more severe in adulthood. A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants. Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation.

Protective effect of short-tem calcitriol or cyclical etidronate on bone loss after cardiac or lung transplantation.

Bone loss is most rapid in the immediate period after cardiac or lung transplantation. This randomized study compared the efficacy of 6 months of treatment with either calcitriol (1,25-dihydroxyvitamin D3; 0.5 microg/day) or two cycles of etidronate plus calcium in preventing bone loss in 41 patients undergoing cardiac or lung transplantation. Patients were followed for 18 months after cessation of treatment. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). There were no significant differences between groups with respect to age or cumulative dose of prednis(ol)one or cyclosporin over the 2 years. Bone loss did not differ between groups after 6 months and, despite 6 months prophylaxis with either agent, bone loss was significant in both groups at 6 months and 12 months. However, compared with an untreated reference group, both therapies offered significant protection at 6 months and etidronate provided significant protective carryover after therapy had been discontinued. These data suggest short-term prophylaxis with calcitriol or cyclical etidronate is partially effective in reducing bone loss after cardiac or lung transplantation but treatment needs to be continued for a longer term.

Effect of calcitriol on bone loss after cardiac or lung transplantation.

Rapid bone loss after cardiac and lung transplantation results in an increased risk of osteoporotic fracture. This study examined the efficacy of treatment with calcitriol (1,25-dihydroxyvitamin D3) in preventing bone loss in patients undergoing cardiac or lung transplantation. In this 2-year double-blind, stratified study, 65 patients undergoing cardiac or single lung transplantation were randomly allocated to receive either placebo or calcitriol (0.5-0.75 microg/day), the latter for either 12 months or 24 months. All patients received 600 mg calcium/day. Bone mineral density (BMD) was measured every 6 months for 2 years by dual-energy X-ray absorptiometry. There was no significant difference between groups with respect to age or cumulative dose of prednis(ol)one or cyclosporine over the 2 years. Bone loss at the proximal femur was significantly reduced or prevented at all three sites by treatment with calcitriol for 2 years compared with treatment with calcium alone. Treatment with calcitriol for 12 months followed by calcium for 12 months resulted in similar proximal femoral bone loss to that seen in those patients treated with calcium for 24 months, suggesting calcitriol prophylaxis needs to be continued beyond 12 months. At the lumbar spine, there were no significant differences in BMD between groups. Over a period of 2 years, 22 new vertebral fractures/deformities occurred in 4 patients treated with calcium alone compared with one new vertebral fracture in 1 patient treated with calcitriol. Because the sample size was too low to provide reliable interpretation of vertebral fracture rates, this difference is likely a chance result. Mild hypercalcemia was common with calcitriol therapy, as was mild hypercalciuria (59% of patients vs. 10% controls), but there were no significant differences between groups in serum creatinine after 2 years. These data suggest calcitriol has a role in reducing proximal femur bone loss after cardiac or lung transplantation but treatment needs to be continued beyond 1 year.

Cardioprotective effects of pinacidil pretreatment and lazaroid (U74500A) preservation in isolated rat hearts after 12-hour hypothermic storage.

BACKGROUND: Two important processes in the preservation of the function of donor hearts are the maintenance of ATP-sensitive potassium channel activity during myocardial ischemia and the scavenging of reactive oxygen species formed during reperfusion. The aim of this study was to compare the effect of three protocols on the preservation of hemodynamic function in isolated rat hearts after hypothermic storage. These protocols were: (1) pretreatment of the heart with a potassium channel opener (200 microM pinacidil); (2) storage of the heart in an aspartate-enriched extracellular cardioplegic solution containing the lazaroid antioxidant, U74500A (30 microM); and (3) a combination of protocols 1 and 2. METHODS: Hearts from Wistar rats were perfused on a Langendorff apparatus. After stabilization in working mode, baseline measurements of heart rate, coronary and aortic flow, and cardiac output were performed. Hearts (n=6 in each group) were then randomized to protocols 1-3, untreated controls, or vehicle-treated controls. Hearts were stored in extracellular-based preservation solution for 12 hr at 2-3 degrees C, remounted on the perfusion apparatus, and stabilized as before; hemodynamic measurements were then repeated. RESULTS: Recovery of hemodynamic function was enhanced by pinacidil pretreatment or incorporation of lazaroid in the storage solution, but the combination of these two treatments produced the best results. CONCLUSIONS: Combined pharmacological activation of ATP-sensitive potassium channels before cardioplegia and the addition of U74500A to the preservation solution is associated with significantly enhanced hemodynamic function in the isolated rat heart after 12 hr of hypothermic storage. These data suggest a novel use for these agents in the transplantation context.

A prospective randomized study of prophylactic OKT3 versus equine antithymocyte globulin after heart transplantation--increased morbidity with OKT3.

The aim of this study was to compare the efficacy and toxicity of prophylactic OKT3 and equine antithymocyte globulin when each drug was administered for a similar duration after heart transplantation. Forty-one patients (35 males, 6 females; mean age 46 +/- 2 years) were randomized to receive either OKT3 for 10 days (20 patients) commencing within 24-48 hr of transplantation or ATGAM for 8 days (21 patients) commencing on the day of transplantation. All patients were maintained on triple-agent immunosuppression with prednisolone, azathioprine, and cyclosporine. The two groups were well matched with respect to age, sex distribution, pretransplant cardiac diagnosis, and donor heart ischemic time. Mean duration of follow-up was 14 months (range 9-19 months): Actuarial survival at 12 months was 83 +/- 9 in the OKT3 group and 81 +/- 9 in the ATG group (P = NS). Mean time to first cardiac rejection was 33 +/- 8 days in the OKT3 group compared with 27 +/- 5 days in the ATG group (P = NS). Linearized rejection rate did not differ between the two groups at any time point up to 12 months posttransplant. Viral infections were significantly more common in the OKT3 group: 1.6 +/- 0.3 vs. 0.8 +/- 0.2 infections per patient (P < 0.05). Adverse reactions were more common in patients who received OKT3 prophylaxis and included three patients who developed acute respiratory distress, two of whom required assisted ventilation. In conclusion, prophylactic OKT3 and ATGAM result in comparable rejection rates and survival when administered for a similar duration after cardiac transplantation. OKT3, however, is associated with increased morbidity due to a higher incidence of adverse reactions and of viral infections. These findings suggest that ATGAM is the more suitable cytolytic agent for rejection prophylaxis after heart transplantation.

Selective inhibition of nitric oxide production during cardiac allograft rejection causes a small increase in graft survival.

Nitric oxide production is increased in allograft rejection and may have both beneficial and deleterious effects on graft function and survival. In animal models, conventional immunosuppressive agents have been shown to decrease nitric oxide production. The aim of our study was to determine what effect augmentation and selective inhibition of nitric oxide production may have on graft survival by using the model of heterotopic cardiac transplantation in the rat. L-Arginine, the naturally occurring substrate for nitric oxide production, was administered subcutaneously at 200 mg/kg/day. L-NG-monomethyl-L-arginine (L-NMMA) is a selective inhibitor of nitric oxide synthase and was administered at 500 mg/kg/day to allograft recipients from the day of operation. Endogenous nitric oxide production was quantified by analysis of urinary nitrate excretion, and time to rejection was determined by graft palpation. L-Arginine did not significantly alter urinary nitrate excretion by iso- or allografts, suggesting that nitric oxide production is not a substrate-limited process in this model. Graft survival in this group was unchanged. L-NMMA produced a small increase in graft survival from 5.1 +/- 0.1 to 6.3 +/- 0.3 days compared with control allografts (P = 0.001) and abolished the rise in urinary nitrate excretion seen with control allografts. Lower doses of L-NMMA produced dose-related decrements in urinary nitrate excretion, but did not alter graft survival. We found that allograft rejection can proceed to graft loss despite complete inhibition of the increase in nitric oxide production that occurs during untreated rejection. The small increase in graft survival suggests that nitric oxide plays a minor role as a cytotoxic effector molecule in this model of acute rejection.

Urinary nitrate excretion is a noninvasive indicator of acute cardiac allograft rejection and nitric oxide production in the rat.

Cytokine induction of calcium-independent nitric oxide synthase is associated with production of large amounts of nitric oxide (NO). NO is a free radical that is rapidly degraded to nitrite and nitrate. Measurement of plasma and urinary nitrate is an indirect marker of NO production and previous studies have demonstrated that plasma nitrate rises with allograft rejection. The purpose of this study was to examine the temporal relationship between the rise in urinary nitrate excretion and the onset of graft rejection, and to determine the effect of conventional immunosuppression on nitrate excretion. The heterotropic model of cardiac transplantation in the rat was used, with Brown-Norway to Lewis allografts and Lewis to Lewis isograft controls. Twenty-four-hour urine specimens were collected before and after transplantation. Urinary nitrate excretion was measured by gas chromatography/mass spectrometry. Each group was treated with (1) no immunosuppression, (2) dexamethasone (3 mg/kg), or (3) CsA (10 mg/kg) on days 0, 1, and 2. Time to rejection for untreated allografts was 5.1 +/- 0.1 days, extending to 8.4 +/- 0.5 and 9.6 +/- 0.4 days with dexamethasone and CsA treatment, respectively. There was a significant rise in nitrate excretion on days 4, 7, and 9 for control, dexamethasone-treated, and CsA-treated allografts, respectively, preceding evidence of rejection. Untreated allograft rejection was associated with a peak in nitrate excretion 8 times that of basal excretion by isografts. Treatment of the allografts with dexamethasone and CsA significantly attenuated peak nitrate excretion compared with untreated allografts with a only a 2- to 3-fold rise preceding rejection. Results indicate that allograft rejection is associated with a dramatic increase in peak urinary nitrate excretion that is attenuated by standard immunosuppressive therapy. An increase in nitrate excretion precedes evidence of graft rejection, and may serve as a noninvasive marker of graft rejection.

Interventional bronchoscopy for the management of airway complications following lung transplantation.

STUDY OBJECTIVES: To assess the efficacy and complications of different interventional bronchoscopic techniques used to treat airway complications after lung transplantation. DESIGN: Retrospective study. SETTING: Heart-lung transplant unit of a university hospital. PATIENTS: From November 1986 to January 2000, interventional bronchoscopy was performed in 41 of 312 lung transplant recipients (13.1%) for tracheobronchial stenosis, bronchomalacia, granuloma formation, and dehiscence. INTERVENTIONS: Dilatation, stent placement, laser or forceps excision. MEASUREMENTS AND RESULTS: Mean (+/- SE) improvement in FEV(1) in 26 patients undergoing dilatation for a stenotic or a combined lesion was 93 +/- 334 mL or 8 +/- 21%. In seven of these patients not proceeding to stent placement, mean improvement in FEV(1) was 361 +/- 179 mL or 21 +/- 9%. Patients needing stent placement after dilatation had a mean change in FEV(1) after dilatation of - 5 +/- 325 mL or 3 +/- 23%, and an improvement of 625 +/- 480 mL or 52 +/- 43% after stent insertion. Mean improvement in FEV(1) for patients treated with stent insertion for bronchomalacia was 673 +/- 30 mL or 81 +/- 24%. Complications of airway stents were migration (27%), mucous plugging (27%), granuloma formation (36%), stent fracture (3%), and formation of a false passage (6%). Mortality associated with interventional bronchoscopy was 2.4% (1 of 41 patients). For patients with airway complications successfully undergoing interventional bronchoscopy, the overall 1-year, 3-year, and 5-year survival rates were 79%, 45%, and 32%, respectively, vs 87%, 69%, and 56% for those without airway complications (p < 0.05). CONCLUSION: Only a small number of patients with airway stenosis after lung transplantation will respond to bronchial dilatation alone. Patients with airway complications after lung transplantation have a higher mortality than patients without airway complications.

Role of routine endomyocardial biopsy to monitor late rejection after heart transplantation.

Endomycardial biopsy remains the standard used to monitor rejection after heart transplantation. There is, however, no consensus as to how often surveillance endomyocardial biopsy should be carried out after heart transplantation. We have analyzed 131 patients undergoing orthotopic heart transplantation during the first 4 years of the transplant program at St. Vincent's Hospital. The majority of endomyocardial biopsies that showed acute rejection occurred in the first 3 months after transplantation; after 9 months only 2.5% of endomyocardial biopsies performed showed rejection. Of those patients with rejection, 47% had symptoms. Seven patients experienced late rejection and all made a good recovery with normal cardiac function. We conclude that the incidence of acute rejection decreases significantly more than 3 months after-transplantation; after 9 months only 2.5% of endomyocardial biopsies will show rejection. Of these, 47% will be associated with symptoms. On the basis of experience, we believe that in our own unit, endomyocardial biopsy more than 9 months after transplantation seems unwarranted unless clinically indicated.

Heart transplantation in females.

To confirm reports of a higher rate of rejection in female recipients of cardiac allografts and to determine whether infection rates and actuarial survival differ from that in males, we reviewed the results of 150 consecutive heart transplant procedures. Of these, 27 were in females and 123 were in males. Three different regimens were used over a 5-year period: group 1 (n = 37), cyclosporine and prednisolone; group 2 (n = 61), cyclosporine, azathioprine, and prednisolone; group 3 (n = 52), cyclosporine and azathioprine. All groups received a 7- to 10-day induction course with antithymocyte globulin. Female recipients had significantly more rejection episodes than male recipients to 3 months after transplantation (females 2.3 vs males 1.5 episodes/patient, p less than 0.01) and to 12 months (females 2.4 vs males 1.5 episodes/patient, p less than 0.02). These differences were largely caused by higher rates of rejection in females in both "double" therapy groups (groups 1 and 3). All surviving females in group 3 required the addition of maintenance steroids to control rejection. Gender mismatching of donors (male donor, female recipient) was identified as a factor associated with this requirement for conversion. Augmented treatment for rejection resulted in a higher rate of infection at 12 months in female recipients (females 1.5 vs males 0.7 episodes/patient, p less than 0.02), yet no female died of infection, and actuarial survival was comparable to that in male recipients. In view of the propensity of females to reject more frequently and earlier than males, triple therapy is currently the regimen of choice for female patients in the first 3 to 6 months after heart transplantation. Steroid withdrawal may be possible at a later time in those in whom this is indicated.

Pulse wave analysis in the assessment of patients with left ventricular assist device.

Central aortic pressure determines perfusion of vital organs, and its precise determination is particularly important in low-output syndromes. Because peripheral pressure values are not equal to the corresponding pressures in the aorta, we used a validated system that employs the principle of applanation tonometry for non-invasive recording of radial arterial pulse and determination of central aortic pressure waveform in patients who underwent implantation of left ventricular assist device. We observed significant improvement after assist device implantation; however, a discrepancy between peripheral and central pressure values was evident both before and after implantation. This non-invasive technique may prove particularly useful in repeat evaluation of patients in long-term follow-up and may provide valuable insights for coupling between the assist device and the vascular system.

Ischemic preconditioning enhances donor lung preservation in the rat.

BACKGROUND: Ischemic preconditioning achieved by brief periods of ischemia and reperfusion before a prolonged period of ischemia can significantly reduce the extent of cardiac damage in many mammalian species and human beings. In this study we used a rat model of single lung transplantation to show that ischemic preconditioning also occurs in the lung. METHODS: Rats randomly selected for ischemic preconditioning had their left main bronchus and pulmonary artery occluded for 5 minutes, followed by 10 minutes of reperfusion and ventilation. Lungs of control rats were ventilated for 15 minutes. The lungs were perfused with University of Wisconsin solution, then heart and lungs were excised en bloc and stored in University of Wisconsin solution at 0 degree C for 6 or 12 hours. After left pneumonectomy, the left lung of the donor was then implanted into the recipient via left thoracotomy. After 1 hour of ventilation and reperfusion, a right pneumonectomy was performed making the animal completely dependent on the transplanted lung. Samples of arterial blood from the left ventricle were then taken for arterial oxygen tension and arterial carbon dioxide tension determination. Water contents of the donor lungs were measured before and after reperfusion. Thiobarbituric acid reactive substances were measured in the right donor lung after storage. RESULTS: Lungs transplanted after 12 hours of storage had profoundly impaired gas exchange (arterial oxygen tension = 34 +/- 5; arterial carbon dioxide tension = 69 +/- 7 mm Hg) compared with the normal levels in the 6-hour storage group (arterial oxygen tension = 308 +/- 22; arterial carbon dioxide tension = 17 +/- 1 mm Hg). Ischemic preconditioning significantly improved gas exchange in the 12-hour storage group (arterial oxygen tension = 83 +/- 11; arterial carbon dioxide tension = 40 +/- 4 mm Hg). Ischemic preconditioning also significantly decreased thiobarbituric acid reactive substances formation at both 6- and 12-hour storage. CONCLUSIONS: These results show that the phenomenon of ischemic preconditioning occurs in the lung and that it may reduce injury to the donor lung during prolonged cold ischemic storage.

HLA mismatching and outcome in heart, heart-lung, and single lung transplantation.

BACKGROUND: To determine the influence of HLA mismatching on rejection after cardiothoracic organ transplantation, we analyzed results in 243 recipients. METHODS: There were 183 heart, 25 heart-lung, and 35 single lung recipients, all receiving triple-drug immunosuppression with anti-thymocyte globulin induction. Zero, one, and two mismatches occurred by chance at each locus in between 0% to 9%, 26% to 35%, and 47% to 70% of recipients, respectively. RESULTS: In heart recipients, compared with a two mismatch, a zero mismatch was associated with a lower linearized rejection rate in the first 6 months. A zero B locus mismatch was likewise associated with less rejection in month 1, and DR zero mismatch with reduced rejection in the first 3 months. Steroid withdrawal was more successful in those with zero mismatch at any locus. In heart-lung recipients linearized rejection was significantly lower in those with lesser degrees of A and DR locus mismatching, and after single-lung transplantation linearized rejection was significantly lower with lesser degrees of A and B locus mismatching from 3 to 6 months only. Actuarial survival did not differ for any organ with any degree of mismatch at any locus. CONCLUSIONS: HLA mismatching affects rejection, but the effect is limited to the early postoperative period for heart and heart-lung recipients. Lower grades of mismatch increase the likelihood of successful steroid withdrawal for heart recipients. The chance occurrence of no mismatch at any locus is rare, making prospective matching infeasible. HLA mismatching identifies patients at higher risk of rejection. The best use of this information may be to guide early immunosuppression, limiting prospective matching to retransplants or with presensitized recipients.

Initial steroid-free versus steroid-based maintenance therapy and steroid withdrawal after heart transplantation: two views of the steroid question.

To determine any benefit of maintenance steroids in a cyclosporine and azathioprine immunosuppressive regimen, 112 heart transplant recipients were prospectively randomized to receive cyclosporine, azathioprine, and prednisolone (n = 59) or cyclosporine and azathioprine (n = 53). Of the 53 double-therapy patients, 47% were converted to maintenance steroids for resistant rejection or renal dysfunction. In a comparison of true double-therapy (n = 28) versus true triple-therapy (n = 59) groups, actuarial survival and systolic function did not differ. Linearized rejection during the first 3 months was lower with triple therapy than with double therapy (1.5 +/- 0.18 vs 2.3 +/- 0.23 episodes/100 patient-days; p less than 0.01) as were requirements for cytolytic therapy for rejection with hemodynamic compromise. Patients receiving triple therapy had significantly higher serum cholesterol levels and antihypertensive agent requirements at all annual time points up to 5 years. The rate of steroid-related morbidity (diabetes, bone complications, cataracts, and obesity) was low in both groups and did not differ significantly. Of the 204 patients receiving triple therapy at this unit, 45 underwent steroid withdrawal. The initial success rate was 69%, and an additional 14% of those who initially failed succeeded on the second attempt. Any rejection after steroid cessation tended to occur within 6 weeks. There were, however, no substantial short-term benefits in body weight or lipid or blood pressure control. In patients in whom infection or growth retardation was an indication for steroid withdrawal, these generally improved after cessation. Until predictive markers for the likely success of steroid withdrawal are identified, the case for steroid withdrawal, as opposed to steroid minimization, does not seem compelling.

Outcome in peripartum cardiomyopathy after heart transplantation.

From 1983 to 1991, 27 women with peripartum cardiomyopathy were considered for heart transplantation. Of 27 patients, 11 (41%) improved with medical therapy, 10 (37%) underwent transplantation, and six (22%) died. Results in the 10 patients with peripartum cardiomyopathy who underwent transplantation were compared with results in 39 women who underwent transplantation for dilated cardiomyopathy (idiopathic, Adriamycin, valvular, or familial) to determine whether there were differences in survival, rejection, or infection rates. The two groups were, by chance, well matched for number of pregnancies, peak panel reactivity, and cross-match. Mean time from delivery to transplantation was 24 weeks (range 2 to 188 weeks), and this time did not correlate with rejection rates. The linearized rate of rejection from 0 to 3 months was 30% higher in the group with peripartum cardiomyopathy (3.4 +/- 0.7 vs 2.6 +/- 0.3 episodes/100 patient days; p = 0.05). The mean postoperative day to first rejection was day 26 for peripartum cardiomyopathy and day 28 for women with dilated cardiomyopathy. Rejection requiring cytolytic therapy occurred in 40% of women with peripartum cardiomyopathy and 21% of the comparison group (difference not significant). Linearized (treated) infection rates were 1.8 +/- 0.5 for the group with peripartum cardiomyopathy versus 1.5 +/- 0.2 episodes/100 patient days for others (p = 0.05). Actuarial survival was excellent in both groups with 88% and 86% 2-year survival rates, respectively. In conclusion, women who undergo transplantation for peripartum cardiomyopathy have a 30% higher rate of early rejection than do those who undergo transplantation for idiopathic cardiomyopathy and tend to have a greater need for cytolytic therapy. Infection rates are consequently higher.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial overdrive pacing for reversion of atrial flutter after heart transplantation.

Atrial overdrive pacing is an effective treatment to terminate classic (type 1) atrial flutter. After heart transplantation, the appearance of atrial flutter may be an indication of acute allograft rejection, and in patients who have this arrhythmia we routinely perform endomyocardial biopsy. In this study we examined the efficacy of atrial overdrive pacing performed at the time of endomyocardial biopsy in the termination of atrial flutter. Endomyocardial biopsy was performed with a Caves-Scholten bioptome via a right internal jugular venous sheath. After completion of the biopsy, a J-shaped 5F bipolar pacing lead was inserted via the sheath and positioned with the lead tip directed medially against the interatrial septum or right atrial appendage. Atrial pacing was performed with stimulation rates up to 450 beats/min at 20 mA for 15 seconds. Since July 1989, 16 episodes of atrial flutter have occurred in nine patients. Twelve episodes (75%) were associated with acute rejection, which was moderate or severe in nine cases. Atrial overdrive pacing was successful in restoring sinus rhythm in 13 of 14 episodes during which it was attempted (success rate, 93%). The procedure was uncomplicated and produced minimal patient discomfort. In comparison, of eight episodes of atrial flutter (in six patients) that occurred before the routine use of atrial overdrive pacing, seven were associated with rejection. With treatment of rejection, two episodes reverted spontaneously, but on six occasions cardioversion with patients under general anesthesia was necessary to restore sinus rhythm. In conclusion, atrial flutter occurring after heart transplantation is usually associated with acute allograft rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of chronic amiodarone therapy before transplantation on early cardiac allograft function.

Because of its long half-life, there has been concern that chronic amiodarone therapy before heart transplantation may adversely affect early cardiac allograft function and delay patient recovery. We retrospectively analyzed the outcome of the last 50 patients undergoing heart transplantation at our institution (between September 1988 and September 1989). Nineteen patients had been taking amiodarone at the time of transplantation (mean daily dose, 247 +/- 31 mg; mean duration of treatment, 9.0 +/- 2.2 months). These patients did not differ from the remaining 31 patients with respect to age, sex, or cause of disease. Donor organ ischemic time was also similar in the two groups (158 +/- 11 vs 153 +/- 10 minutes, NS). Patients who had received amiodarone before transplantation had significantly lower heart rates at 1 and 4 weeks after transplantation. They required atrial pacing for a longer time after transplantation compared with the remaining patients (7.3 +/- 1.4 vs 3.4 +/- 0.8 days, p less than 0.02). There was, however, no detectable effect of prior amiodarone therapy either on early allograft inotropic function or on clinical outcome. The mean time to hospital discharge was similar in the two groups. We believe that acceptance for heart transplantation should not be regarded as a contraindication to amiodarone therapy.

Five-year follow-up of a randomized double-drug versus triple-drug therapy immunosuppressive trial after heart transplantation.

To determine the role of maintenance steroids in a cyclosporine and azathioprine immunosuppressive regimen, 112 heart transplant recipients were prospectively randomized to group I (n = 59; cyclosporine, azathioprine, and prednisolone) or group II (n = 53; cyclosporine and azathioprine). All patients received 7 days of induction with antithymocyte globulin. Patients receiving double-drug therapy who required four treatments for rejection were converted to maintenance steroids. This was necessary in 47% of the patients. Actuarial survival at 5 years was 82% in group I and 85% in group II. Linearized rejection in the first 3 months was lower with triple-drug therapy than with double-drug therapy (1.5 +/- 0.18 versus 2.3 +/- 0.23 episodes/100 patient days, p less than 0.01) but did not differ beyond 3 months. No significant differences were noted in 3-year left ventricular ejection fraction (0.56 +/- 0.09 versus 0.58 +/- 0.12 units), serum creatinine level (0.14 +/- 0.04 versus 0.14 +/- 0.03 mmol/L), or number with coronary artery disease (10 versus 13), diabetes, or bone complications. Patients receiving triple-drug therapy, however, had higher serum cholesterol level at 3 years (6.2 +/- 0.9 versus 5.4 +/- 1.2 mmol/L; p = 0.022) and required more antihypertensive agents (1.3 +/- 0.8 versus 0.8 +/- 0.6; p = 0.016). Similar trends emerged when patients receiving true double-drug therapy were compared with those patients who were "converted." Therapy with double versus triple immunosuppressive therapy results in similar 5-year survival and systolic function, using this protocol of converting recurrent rejectors on double-drug therapy to maintenance steroids.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and safety of pravastatin vs simvastatin after cardiac transplantation.

Prior studies of cardiac transplant recipients have shown that pravastatin reduces 12-month rejection and mortality after cardiac transplantation and simvastatin reduces 4-year mortality, low-density lipoprotein (LDL) cholesterol levels, and intimal thickening. In a 12-month observational study, cardiac transplant recipients received open-label pravastatin 40 mg (n = 42) or simvastatin 20 mg daily (n = 45) on an alternating basis from the time of transplantation. Lipid levels, safety, and post-transplant outcomes were compared. We found no significant differences in total LDL or high-density lipoprotein cholesterol, triglycerides, linearized infection or rejection rates, liver function tests, or immunosuppressant dosages between groups at 1, 3, 6, or 12 months. Rhabdomyolysis or myositis occurred only in patients on simvastatin (n = 6, 13.3%) with no episodes for patients on pravastatin (p = 0. 032). Survival at 12 months on an actual treatment basis was 97.6% for patients on pravastatin and 83.7% for those on simvastatin (p = 0.078). Immunosuppression-related deaths occurred in only 2.4% (1 patient) on pravastatin vs 15.6% (n = 7) on simvastatin (p = 0.06). Pravastatin and simvastatin resulted in comparable lipid profiles. Pravastatin use was however free from the high rates of rhabdomyolysis and myositis seen with simvastatin use. Pravastatin was additionally associated with a trend toward superior survival, attributable to fewer immunosuppression-related deaths. For safety and pharmacokinetic reasons, pravastatin should be considered the statin of choice after heart transplantation.

Pilot study of low-dose azathioprine in presensitized patients awaiting heart or lung transplantation.

In an effort to reduce the level of presensitization in patients on our heart and lung transplant waiting list, ten patients with random panel reactivity above 10% on monthly screening for durations of 2 to 59 months were given low-dose azathioprine (25 to 75 mg/day) for 1 to 22 months. All patients had positive T-cell panel reactivity (10% to 70%) against specific (n = 6), multi-specific (n = 1), or undefined (n = 3) HLA loci, and four additional patients had positive B-cell panel reactivity (5% to 40%). No effect of azathioprine on panel reactivity was seen in four of ten patients (40%), whereas a significant and sustained reduction in panel reactivity occurred in six patients (60%), all within 2 months of commencing azathioprine. All nonresponders had antibodies with class I (A locus) specificity, whereas all six responders had multi-specific or undefined antibody specificities. A formal trial of low-dose azathioprine in presensitized recipients is warranted.