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.

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.

A randomized trial of tacrolimus (FK506) versus total lymphoid irradiation for the control of repetitive rejection after cardiac transplantation.

Recurrent cardiac rejection is a major cause of morbidity during the initial 6 months following transplantation. We compared treatment with tacrolimus versus total lymphoid irradiation in 13 heart transplant recipients on a cyclosporine, azathioprine, and prednisolone regimen, who experienced repetitive rejection. The mean number of episodes of rejection significantly decreased in both groups, with no deaths and no increase in the incidence of infection, hypertension, diabetes, or renal impairment following either treatment at 12-month follow-up. Conversion to tacrolimus or a course of lymphoid irradiation are equipotent strategies, of comparable cost, for the prevention of further rejection in patients with recurrent rejection.

Optimization of left ventricular function with carvedilol before high-risk cardiac surgery.

Patients with severe left ventricular dysfunction and symptomatic heart failure caused by ischemic or valvular heart disease face a high morbidity and mortality risk from cardiac surgery. We present data showing that excellent surgical outcome can be achieved after pre-treatment of such patients with carvedilol.

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.

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.

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.

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.

ATP-sensitive potassium channel activation mimics the protective effect of ischaemic preconditioning in the rat isolated working heart after prolonged hypothermic storage.

1. Ischaemic preconditioning (IP) can significantly reduce the extent of infarct size, contractile dysfunction and necrosis in hearts from a number of animal species. Activation of ATP-sensitive potassium channels has been implicated in this process. The aims of the present study were to determine the extent to which IP preserves haemodynamic function in the rat isolated working heart model after prolonged hypothermic storage and to examine the involvement of activation of potassium channels in this process. 2. Hearts from Wistar rats were perfused on a Langendorff apparatus. After stabilization in working mode, baseline measurements of heart rate, aortic flow, coronary flow and cardiac output were performed. Hearts were randomized to one of six treatment groups: (i) untreated control; (ii) IP; (iii) 3 min perfusion with 200 mumol/L pinacidil; (iv) pinacidil vehicle; (v) 3 min perfusion with 10 mumol/L glibenclamide before IP; and (vi) 3 min perfusion with glibenclamide then pinacidil. Hearts were stored in an extracellular-based preservation solution for 6 or 12 h at 2-3 degrees C, remounted on the perfusion apparatus, stabilized as before and then haemodynamic measurements were repeated, after which time heart water contents were determined. 3. Recovery of haemodynamic function was markedly enhanced in the IP and pinacidil-treated groups compared with untreated and vehicle controls. These beneficial effects were completely blocked by glibenclamide. These results suggest that strategies for activating potassium channels in donor hearts may protect organs during hypothermic storage prior to transplantation.

Skin cancer in Australian heart transplant recipients.

BACKGROUND: Cutaneous malignancy is a major cause of morbidity in organ transplant recipients. OBJECTIVE: Our purpose was to report on skin cancer in Australian heart transplant recipients with analysis of HLA factors. METHODS: We reviewed histologically proven skin cancers in the first 455 patients undergoing organ transplantation in Sydney, Australia. RESULTS: The cumulative incidence of skin cancer was 31% at 5 years and 43% at 10 years with a squamous cell carcinoma/basal cell carcinoma ratio of 3:1. Caucasian origin, increasing age at transplantation, and duration of follow-up were significantly associated with skin cancer. Skin cancer accounted for 27% of 41 deaths occurring after the fourth year. Recipient HLA-DR homozygosity was associated with skin cancer overall, whereas HLA-DR7 was a protective factor in skin cancer overall, squamous cell carcinoma, and Bowen's disease. HLA-A1 and HLA-A11 were significant protective factors in Bowen's disease. CONCLUSION: Skin cancer is a major cause of morbidity and long-term mortality in heart transplant patients.

The nitric oxide donor, diethylamine NONOate, enhances preservation of the donor rat heart.

BACKGROUND: Ischemia/reperfusion injury to transplanted organs may be associated with loss of endothelial release of nitric oxide. The aim of this study was to determine whether supplementation of an extracellular-based cardioplegic solution in routine clinical use at our institution with nitric oxide (as diethylamine NONOate) enhanced poststorage functionality of an isolated working heart model. METHODS: Excised hearts were ligated to an aortic cannula and immediately perfused retrogradely with oxygenated Krebs solution at a hydrostatic pressure of 100 cm H2O at 37 degrees C. This preparation was then converted to a working system by switching the supply of perfusate from the aorta to a left atrial cannula at a filling pressure of 15 cm H2O. After a 1-minute stabilization period, baseline measurements of heart rate, aortic flow, coronary artery flow, and cardiac output were performed. Oxygenated cardioplegic solution (0.1 micromol/L), with or without NONOate, was then infused into the coronary circulation. Hearts were then stored in the same solutions for 6 or 12 hours at 2 degrees to 3 degrees C. The hearts were then remounted on the perfusion apparatus and reperfused as before, and hemodynamic measurements were repeated. Water content of the hearts were then determined. RESULTS: Addition of the nitric oxide donor significantly improved all hemodynamic parameters measured after 12 hours storage and aortic flow at 6 hours storage compared with the untreated control groups. There was no significant difference between the water contents of the NONOate-treated and control groups. CONCLUSIONS: The presence of the nitric oxide donor diethylamine NONOate was associated with significantly better preservation of coronary artery flow and cardiac function in the isolated rat heart after a 12-hour period of hypothermic storage and suggests a novel use for this family of compounds in the transplantation context.

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.

Adjunctive use of inhaled nitric oxide during implantation of a left ventricular assist device.

BACKGROUND: The aim of this study was to evaluate the efficacy of inhaled nitric oxide in the prevention and reversal of pulmonary hypertension during and after left ventricular assist device implantation. METHODS: Inhaled nitric oxide (20 ppm) was administered to seven consecutive patients undergoing implantation of a left ventricular assist device at the time of implantation and for the first 24 hours after operation. RESULTS: Withdrawal of inhaled nitric oxide at 24 hours after operation was associated with a significant rise in both the transpulmonary gradient (from 8+/-1 to 14+/-2 mm Hg, p < 0.01) and in pulmonary vascular resistance (from 110+/-19 to 196+/-32 dynes x sec x cm[-5], p < 0.01). In two patients, the rise in pulmonary vascular resistance resulted in a critical fall in left ventricular assist device flow and hemodynamic deterioration, necessitating urgent reinstitution of inhaled nitric oxide. CONCLUSION: The administration of inhaled nitric oxide at the time of left ventricular assist device implantation prevents rises in pulmonary vascular resistance that in some patients result in critical reductions in left ventricular assist device flow. We suggest that inhaled nitric oxide is a useful adjunctive treatment that should be routinely available at the time of left ventricular assist device implantation.

Cholecystectomy in cardiothoracic organ transplant recipients.

OBJECTIVES: To assess the risks associated with cholelithiasis and cholecystectomy in cardiothoracic organ transplant recipients at this hospital and to identify any differences with potential causal significance between the group with known gallstones and the transplant recipient group as a whole. DESIGN: Medical records survey. SETTING: Tertiary care university hospital. PATIENTS: Six hundred forty-five patients had cardiothoracic organ transplantation at this hospital between February 1, 1984, and May 31, 1996. Gallstones were detected in 37 (5.7%) of these patients and 32 patients underwent cholecystectomy, of which 29 operations were performed primarily for symptomatic gallstone disease. All cholecystectomies were performed after transplantation. MAIN OUTCOME MEASURES: Mortality, morbidity, postoperative biliary disease. RESULTS: Patients with gallstones were significantly older than the transplant patient group as a whole (Student t test, P=.001); they were more likely to be female (chi2 test, P=.05); and they had a higher body mass index (t test, P=.001). There were no significant differences in the maximum serum bilirubin level during the transplantation admission, incidence of diabetes mellitus, cholestyramine use, or cyclosporine dosage during the first 12 months after transplantation. Cholecystectomy was performed after a median 5-month symptomatic period, mostly by the minilaparotomy method. Forty-five percent of cholecystectomies were urgent or semi-urgent. One patient died of lung infection on the second postoperative day. The median postoperative stay was 3 days. At a median 33 months' follow-up, 4 patients have had further biliary problems (2 patients with common bile duct stones, 1 patient with intrahepatic stones, and 1 patient with biliary dyskinesia). Four other patients with asymptomatic gallstones who did not receive cholecystectomy have remained asymptomatic for between 15 and 67 months. CONCLUSIONS: Cholecystectomy by the minilaparotomy or laparoscopic methods, with routine operative cholangiography, is the preferred treatment for symptomatic gallstones in cardiothoracic organ transplant recipients. Although the optimum management of asymptomatic gallstones in these patients remains unclear, our favorable experience with a policy of reserving cholecystectomy for symptomatic cases seems noteworthy.

Papaverive abolishes endothelium-dependent dilatation of human internal mammary arteries in vitro.

1. The purpose of the present study was to examine the effects of papaverine-HCl, administered into the lumen of the human internal mammary artery (IMA) during harvesting of this vessel, on vascular reactivity in vitro and to specifically test the hypothesis that intraluminal administration of papaverine-HCl impairs endothelium-dependent vasodilation. 2. The present study measured in vitro dilator and constrictor responses of terminal segments of human IMA. Internal mammary artery segments were obtained either prior to routine administration of intraluminal papaverine (pre-P) or after papaverine administration (post-P) in patients undergoing coronary artery bypass grafting. In addition, the viability of cultured human saphenous vein endothelial cells exposed to papaverine-HCl was examined. 3. Cumulative concentrations of U46619, 5-hydroxytryptamine and phenylephrine (PE) produced active contractions in post-P IMA rings. Contractile responses to low concentrations of endothelin-1 were significantly enhanced in post-PIMA compared with pre-P IMA segments. 4. Maximal endothelium-dependent vasodilator responses of pre-P IMA segments to cumulative concentrations of acetylcholine (ACh) and the calcium ionophore A23187 were 49 +/- 7 and 66 +/- 4%, respectively, of the initial active tension induced by PE (1 mumol/L). 5. Maximal endothelium-dependent vasodilator responses were markedly attenuated in post-P IMA (6 +/- 6 and 11 +/- 10% for ACh and A23187, respectively; P < 0.0001 for both vasodilators compared with pre-P). Post-P IMA relaxed completely to the endothelium-independent vasodilator sodium nitroprusside. 6. Exposure of cultured human saphenous vein endothelial cells to papaverine-HCl (1.2 and 12.0 mg/mL) for 1 h resulted in the reduced viability of these cells. 7. The loss of endothelium-dependent relaxation could dangerously predispose the IMA graft to vasospasm in the postoperative period.

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.