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Background: Exhaled nitric oxide levels are low in patients with cystic fibrosis (CF), despite the chronic inflammation present in the airways. This study aimed to determine whether levels of exhaled nitric oxide were reduced prior to the onset of respiratory symptoms in infants with CF., Methods: The levels of exhaled nitric oxide were measured using a chemiluminescence analyser in five infants with CF and 11 healthy control subjects, both groups having a mean age of 48.6 days., Results: Mean levels of exhaled nitric oxide were significantly lower in infants with CF than in the control group (4.9 ppb v 12.1 ppb; p=0.01)., Conclusions: This finding may be the key to understanding the inflammatory processes in early cystic fibrosis and may lead to novel treatment approaches.

Between October 1985 and July 1992 we performed heart-lung transplantation in 42 patients with end-stage respiratory disease caused by cystic fibrosis. Twenty-eight of these patients are alive at 3 months to 7 years after heart-lung transplantation. Actuarial survival at 1 year and 3 years after transplantation was 78% and 65%, respectively, in this group, which compares favorably with 77% and 60%, respectively, in patients without cystic fibrosis undergoing heart-lung transplantation. Similarly no significant difference was found in the incidence of postoperative infections between patients with cystic fibrosis and patients without cystic fibrosis undergoing heart-lung transplantation. Quality of life indexes analyzed by the Nottingham Health Profile reveal significant improvements for patients surviving longer than 3 months from surgery. Long-term survival is determined by the development of obliterative bronchiolitis, which has occurred in 11 patients, six of whom have died. Early postoperative survival appears to be compromised by poor preoperative nutritional status. The study provides evidence that patients with end-stage respiratory disease caused by cystic fibrosis gain a survival advantage and improvement in quality of life after heart-lung transplantation when compared with patients who do not receive this form of therapy.

Heart-lung transplantation is a successful treatment for patients with cystic fibrosis and chronic respiratory failure. Patients are assessed for surgery when life expectancy is deemed short. This study assesses the ability of measurements of pulmonary function, blood gas levels, and nutritional status to predict survival of patients awaiting heart-lung transplantation and to assess the effect of heart-lung transplantation on survival. Sixty-seven patients with cystic fibrosis were accepted for heart-lung transplantation from 1985 through 1990. Each patient underwent tests of pulmonary function, exercise tolerance, blood-gas levels, and nutritional status. Cox regression was used to analyze the prognostic value of these data. Of the 67 patients accepted for heart-lung transplantation, organs became available for 30; 24 patients died waiting, and 13 patients were on the list December 31, 1990. Eight patients died after transplantation. Patients with above-average forced expiratory volume in 1 second (FEV1) (median, 17% predicted) at assessment were half as likely to die waiting (relative risk, 0.47; 95% confidence interval, 0.23 to 0.97) as patients with below-average FEV1. The relative risk of death for patients on the waiting list was 1.44 (95% confidence interval, 1.17 to 1.77) for each increment in PCO2 of 1 kPa. No effect of nutritional status on waiting list death was found, but seven of eight patients who died after heart-lung transplantation were below 80% predicted weight for height. Using a time-dependent analysis, heart-lung transplantation almost halved the risk of death (relative risk, 0.57; 95% confidence interval, 0.22 to 1.48). Postoperative actuarial survival was 79% (95% confidence interval, 63% to 95%).(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To compare the pharmacokinetics of cyclosporine in patients with either cystic fibrosis or Eisenmenger's syndrome., Methods: Patients in the study were heart and lung transplant candidates with either cystic fibrosis (n = 6) or Eisenmenger's syndrome (n = 5), as well as patients who received heart and lung transplantation for either cystic fibrosis (n = 13) or Eisenmenger's syndrome (n = 7). This was no experimental pharmacokinetic study in transplant candidates and an exploratory population pharmacokinetic study in transplant recipients., Results: Patients with cystic fibrosis showed higher blood cyclosporine clearance, higher apparent oral clearance, shorter mean residence time, and more erratic absorption. The coefficient of variation of pharmacokinetic parameters was higher in patients with cystic fibrosis. There were no significant differences in metabolite indexes between the two groups of patients after either oral or intravenous administration. A significant negative correlation was found between cyclosporine clearance and hematocrit (r = 0.81 [95% confidence interval, -0.95 to -0.4.1]). Dose-normalized predose blood concentration measurements were lower in patients with cystic fibrosis after transplantation. There was a significant correlation between hematocrit and log dose-normalized cyclosporine concentration (r = 0.40 [95% confidence interval, 0.30 to 0.49]). The total daily dose per 100 ng/ml trough blood concentration required was estimated to be 2.36 times (95% confidence interval, 1.96 to 2.84) higher in patients with cystic fibrosis., Conclusions: Cyclosporine pharmacokinetics is more variable in patients with cystic fibrosis. The difference in cyclosporine clearance between the two groups is accounted for by differences in binding in blood rather than metabolism. The findings suggest that patients with cystic fibrosis could be conservatively given initial oral doses that are 1.5 times higher than those for patients who receive transplants because of Eisenmenger's syndrome.

Forty five patients with cystic fibrosis (age 5-15 years) were assessed for heart-lung transplantation between September 1987 and March 1990. The two main conditions for acceptance were (i) life expectancy less than 2 years and (ii) a severely impaired quality of life. Patients were accepted onto an active waiting list (n = 26), a provisional waiting list (n = 15), or not accepted (n = 4). Selection was made on clinical grounds with objective measurements used as an aid in assessment. As expected, the mean values for objective measures were significantly different between patients on the active waiting list compared with the provisional waiting list/not accepted group for resting heart rate (118/minute v 101/minute), percentage of ideal weight (83.2% v 93.1%), forced expiratory volume at one second as percent of predicted normal (27.3% v 47.6%), Shwachman-Kulczycki score (33.6 v 52.5), Chrispin-Norman x ray score (25.8 v 22.1), 12 minute walk (540 m v 854 m), and minimal oxygen saturation (81.5% v 92%). Psychological evaluation demonstrated a 55% incidence of individual and a 50% incidence of family morbidity. Of the 26 patients accepted onto the active waiting list, 11 have been transplanted (mean waiting time 3.3 months), 10 have died within a mean of 3.7 months of acceptance, and five remain on the active list (mean 5.6 months).

From March 1988 to March 1990, 11 children with cystic fibrosis (age 5-15 years) underwent combined heart-lung transplantation at our institutes. Maintenance immunosuppression consisted of cyclosporin and azathioprine with corticosteroids and antithymocyte globulin used perioperatively and during rejection episodes. Six patients (55%) survive from 1.5-23 months all of whom have improved life quality. Actuarial survival to 1 year was 55%. At six months after transplant, mean forced expiratory volume at one second was 73.5% of predicted normal, compared with 25% before transplant. There was one perioperative death, three later deaths associated with obliterative bronchiolitis at two, eight, and nine months, and one from mediastinitis at four months. Of the 15 children accepted for transplantation but not receiving grafts, 10 have died (eight within four months of being placed onto the transplant list). Early postoperative problems included acute reversible rejection (n = 10), meconium ileus equivalent (n = 3), and pancreatitis (n = 1). There was a high incidence of later pulmonary rejection with a mean of 5.7 episodes per patient in the first six months. Pulmonary infection occurred relatively infrequently, with Pseudomonas aeruginosa being the most common pathogen. Persistent diabetes mellitus requiring insulin occurred in four and systemic hypertension developed in one.

From among 112 patients with cystic fibrosis who were assessed for heart-lung transplantation, 83 were accepted. Twenty-six died while awaiting heart-lung transplantation and 32 had the operation. The management and the outcome of these 32 patients is reported. Survival, infection, and rejection rates among these patients were compared with those of 61 patients without cystic fibrosis who underwent heart-lung transplantation between 1984 and 1990. The cumulative survival rate was 72.29% +/- 94.91% at 1 year and 55.59% +/- 7.50% at 3 years. The mortality rate was slightly higher in the group with cystic fibrosis during the first year after the operation but it was lower at 3 years. The difference, however, could have been due to chance alone (p = 0.308). The same was true for the prevalence of rejection (up to 6 months: chi 2 = 1.8141, p = 0.17), and infection (up to 6 months: chi 2 = 2.20, p = 0.14), between the two groups. It is concluded that cystic fibrosis does not constitute an additional risk in terms of survival and morbidity after heart-lung transplantation.

The cyclosporin dose versus blood concentration relationship for 11 heart-lung transplant recipients with cystic fibrosis was studied retrospectively. Eleven patients, closely matched for age and gender, who received heart-lung transplantation for other diseases were selected as controls. Cystic fibrosis patients received 16.7 (SD 7.2) mg/kg/day of oral cyclosporin compared with 8.2 (SD 1.9) mg/kg/day given to the control patients (p less than 0.01). Nine of the cystic fibrosis patients received higher mean daily doses of cyclosporin. Mean blood cyclosporin concentrations were, however, not significantly different (p = 0.58), and there were no apparent differences in clinical outcome in terms of rejection, infection, and nephrotoxicity in the two groups. The apparent oral clearance of cyclosporin was significantly higher (p less than 0.01) in cystic fibrosis patients. Cyclosporin dosage individualization with the aid of cyclosporin blood concentration measurements is critically important in this subpopulation of heart-lung transplant recipients.

Cystic fibrosis (CF) is the most common fatal inherited disease in caucasian populations. Between 80-120 CF patients die each year in England and Wales, the majority from pulmonary disease. Since October 1985, 17 patients with CF have undergone heart-lung transplantation (HLT) at our institution. Only 3 early deaths have occurred in the first 2 postoperative months. Another patient died 9 months after transplantation. Thirteen patients are now alive 1-46 months (mean 14 month) post transplantation. Actuarial survival at 6 months is 80% for CF patients compared to 73% for non-CF patients. Both groups of patients have similar profiles of rejection and infection. In the Caucasian population, CF patients form the largest potential recipient group for HLT and our experience suggests that those CF patients who undergo HLT have a favourable outcome.

Bioelectrical potential difference (PD) across the respiratory mucosa is raised in cystic fibrosis (CF). We have recorded airway potentials from seven patients with CF who had undergone heart-lung transplantation and from eight patients without CF who had had transplants for cardiovascular disease; comparison of these populations controls for the effects of denervation and immunosuppressive treatment. Six patients without CF who had not had transplants formed an additional control. PD was recorded during routine fiberoptic bronchoscopy, using a Ringer's-perfused exploring bridge connected across a high impedance amplifier to an intravenous reference bridge. Bronchial lavage and sputum culture revealed no evidence of infection. Bronchial PD was similar in all three groups of patients at equivalent sites. However, nasal PD was raised in the CF group (mean value, 44 mV +/- 3.9 SE) compared with the patients who had transplants for cardiovascular disease (mean, 18 mV +/- 1.1 SE), and the control patients (mean, 15 mV +/- 1.2 SE). We conclude that the epithelial defects that result in raised airway potentials in CF do not recur in the transplanted lung.

13 patients with severe lung disease and cor pulmonale from cystic fibrosis were accepted for heart-lung transplantation (HLT). 6 have had the operation, of whom 5 are well, with normal lung function, 3-29 months after operation. 1 patient died from adult respiratory distress syndrome after reoperation to control persistent chest-wall bleeding: at necropsy, this patient proved to have cirrhosis. Respiratory tract infections and acute lung rejection after HLT for cystic fibrosis were no more common than in other HLT patients. Of the 7 patients for whom suitable donor organs were not found, 3 died within 3 months of assessment. Initial severity of disease had been similar to that in the transplant group. The cost of assessment, operation, and 1 year's treatment after HLT is similar to that of medical treatment for such patients.

Sixteen months after heart-lung transplantation, the FEV1 of a young woman, who had been in the terminal stages of cystic fibrosis, has risen from 16 percent (0.6 L) to 77 percent of her predicted value. Concomitant with the changes in pulmonary function, her ventilatory response to re-breathing carbon dioxide has improved, and so has her exercise tolerance. She has returned to work.

In this study is reviewed the experience at Papworth Hospital, Cambridgeshire, and Great Ormond Street Hospital, London, with combined heart-lung transplantation. Between April 1984 and June 1989, 73 patients have undergone heart-lung transplantation. Donors and recipients were carefully matched with regards to serology, morphology and cytomegalovirus compatibility. Heart preservation was based on use of cold St. Thomas' cardioplegic solution; a pulmonary preservation fluid has been developed that allows distant organ procurement with a single pulmonary artery flush technique (Papworth solution). The recipients were: 21 pts with Eisenmenger's syndrome, 15 pts with pulmonary hypertension, 37 pts with pulmonary disease (including 22 cystic fibrosis). The results are: no surgical mortality; no acute cardiac rejection episodes. Twenty-three patients died (16 with infections, 3 with obliterative bronchiolitis, 2 with cerebral embolism and 2 others). The actuarial survival rate at one year is 73.2%; 63% at two years and 47.4% at four years. The use of transbronchial biopsy of the lung has provided accurate early and safe diagnosis of pulmonary rejection. Development in organ preservation and patient management, as well as careful selection of recipients and donors, have led to the effective use of resources and thereby to these good results.