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.

Phase II trial of carboplatin in the management of malignant mesothelioma.

Thirty-one patients with advanced malignant mesothelioma, previously untreated or having received only one prior cytotoxic regimen, were treated in a prospective, single-arm phase II trial with carboplatin (NSC 241240) at a dose of 150 mg/m2 per day intravenously (IV) for 3 days (450 mg/m2/course). One complete remission and four partial remissions were achieved, yielding an overall objective response rate of 16% (95% confidence interval [CI], 5.4% to 34%). The median duration of remission was 8 months (range, 5 to 17). Nonhematological toxicity was mild (only 12% with World Health Organization [WHO] grade 3 vomiting); 16% suffered WHO grade 3 to 4 hematological toxicity, but there were no life-threatening episodes and no treatment-related deaths. Carboplatin has modest activity against malignant mesothelioma and, because of its low toxicity, has a role in the management of this disease.

Noninvasive ventilatory support during sleep improves respiratory failure in kyphoscoliosis.

We investigated the effect on daytime respiratory function and quality of sleep, of providing adequate ventilation either by intermittent positive pressure ventilation (IPPV) or by continuous positive airways pressure (CPAP) both administered through a nose mask in a group of seven patients with severe thoracic kyphoscoliosis. All night control sleep studies were performed with and without ventilatory assistance. Patients underwent standard polysomnography including all night measurements of transcutaneous CO2 (tcCO2) and arterial oxyhemoglobin saturation (SaO2). Awake arterial blood gas tensions (ABGs), respiratory muscle strength (Pmus), and lung function tests were measured in the sitting position. Follow-up studies after three months of treatment showed normal sleep patterns, improvement in daytime ABGs, lung volumes, and respiratory muscle strength. We concluded that maintenance of nocturnal ventilation by either nasal CPAP or nasal IPPV in patients with nocturnal respiratory failure does significantly improve clinical measurements of respiratory function and quality of sleep.

Nocturnal nasal IPPV stabilizes patients with cystic fibrosis and hypercapnic respiratory failure.

Nocturnal nasal intermittent positive pressure ventilation (nIPPV) has been used successfully in the management of patients with respiratory failure due to chest wall deformity and neuromuscular disease. In order to determine if nIPPV is useful in patients with cystic fibrosis (CF) complicated by respiratory failure, we treated four hypercapnic patients for up to 18 months. All patients had failed to respond to intensive conventional therapy, including nocturnal nasal CPAP in three of the patients. Within a few days of commencing nIPPV, all reported improved length and quality of sleep. There was lessening of the degree of hypercapnia and an increase in respiratory muscle strength. After stabilization in the hospital, all patients were able to be discharged home receiving nocturnal assisted ventilation. The improvements seen in these patients have been maintained for up to 18 months. We believe nIPPV offers an effective therapeutic approach for patients with end-stage CF in hypercapnic respiratory failure and may be particularly advantageous for those awaiting heart-lung transplant.

Benefits of nocturnal nasal CPAP in patients with cystic fibrosis.

Patients with cystic fibrosis (CF) often hypoventilate during sleep with marked falls in oxygen saturation (SaO2%). This occurs most commonly during REM sleep, when there is a reduction in rib cage excursion and a fall in end-expiratory lung volume (EELV). The aim of this study was to examine the effect of nocturnal nasal continuous positive airway pressure (nCPAP) on SaO2 and the respiratory disturbance index (RDI) during sleep in patients with CF and severe lung disease. Seven patients (FEV1% pred, 23 +/- 5; range, 14 to 28%) were evaluated during sleep on two nights, control and nCPAP (11 +/- 2 cm H2O; range, 8 to 16 cm H2O), with four patients breathing room air and three patients breathing supplemental oxygen on both nights. Mean awake SaO2 was 91 +/- 1% (range, 89 to 93%). All patients showed significant oxyhemoglobin desaturation and respiratory disturbance in the control study. The maximal falls in SaO2 (15 +/- 10%) were most often associated with phasic eye movements, and a decline in rib cage excursion and the sum signal (Respitrace) during REM sleep. Nasal CPAP resulted in a significant improvement in the mean minimum oxygen saturation (MMOS) during both NREM (nCPAP 91 +/- 3% vs control 88 +/- 2%, p < 0.05) and REM sleep (nCPAP 89 +/- 6% vs control 83 +/- 6%, p < 0.05). Transcutaneous CO2 measurements were not significantly different between the control and the nCPAP studies. The RDI was also significantly reduced with nCPAP especially during REM sleep (9 +/- 7 events per hour vs control 25 +/- 11 events per hour, p < 0.05). Nasal CPAP caused no change in total sleep time or sleep efficiency yet significantly reduced the RDI and improved baseline SaO2 during both NREM and REM sleep.

Predicting sleep-disordered breathing in patients with cystic fibrosis.

STUDY OBJECTIVES: To examine predictors of sleep-disordered breathing in patients with cystic fibrosis (CF) and moderate-to-severe lung disease using a comprehensive evaluation of both sleep and daytime function. DESIGN: Cross-sectional analysis of sleep studies, lung function, respiratory muscle strength, and evening and morning arterial blood gas measurements in patients with stable CF. A questionnaire addressing sleep quality was administered. Forward stepwise regression analysis was used to identify the parameters that best predict sleep-related desaturation, hypercapnia, and respiratory disturbance. SETTING: Sleep investigation unit and lung function laboratory. PATIENTS: Thirty-two patients with CF and FEV(1) < 65% predicted, in stable clinical condition. Patients were aged 27 +/- 8 years (mean +/- 1 SD) with FEV(1) of 36 +/- 10% predicted, evening PaO(2) of 68 +/- 8 mm Hg, and PaCO(2) of 43 +/- 5 mm Hg. RESULTS: Evening PaO(2) (p < 0.0001) and morning PaCO(2) (p < 0.01) were predictive of the average minimum oxyhemoglobin saturation per 30-s epoch of sleep (r(2) = 0.74; p < 0.0001). Evening PaO(2) (p < 0.001) was predictive of the rise in transcutaneous carbon dioxide (TcCO(2)) seen from non-rapid eye movement (NREM) to rapid eye movement (REM) sleep (r(2) = 0.37; p < 0.001). In addition, there was some relationship between expiratory respiratory muscle strength and the REM respiratory disturbance index (r(2) = 0.22; p < 0.01). CONCLUSION: Evening PaO(2) was found to contribute significantly to the ability to predict both sleep-related desaturation and the rise in TcCO(2) from NREM sleep to REM sleep in this subgroup of patients with CF.

Diaphragmatic fatigue in normoxia and hyperoxia.

Diaphragmatic fatigue was induced in six normal young men inspiring against a variable alinear resistance. Breathing pattern was rigidly controlled (tidal volume 0.75 liter, 12 breaths . min-1). Fatigue was defined as an inability to continue to generate a target transdiaphragmatic pressure (Pdi = 0.65 - 0.84 Pdimax). Diaphragmatic electromyogram (EMG, esophageal electrode) and perceived effort (PE, open-ended scale) were recorded. Subjects were tested on an identical resistance inspiring air or 100% O2 in random order on different days. They were unaware of the gas mixture inspired. Mean endurance time (tlim) +/- SE for air was 4.1 +/- 1.4 min and for O2 was 8.6 +/- 2.7 min (P less than 0.005). The increased tlim in O2 was associated with a delay in onset of EMG changes heralding diaphragmatic fatigue and a decrease in PE at any time during the study compared with the level of PE in air. Arterial O2 saturation (ear oximeter) remained at the resting level of 99.0 +/- 0.2% in O2 and decreased from the resting level of 97.2 +/- 0.2% by 2.8 +/- 0.7% (P less than 0.01) in air. The end-tidal CO2 fraction increased to a similar degree in air and O2 studies. We conclude that when breathing pattern, minute ventilation, and Pdi are held constant during inspiratory resistive loading, breathing O2 delays the onset of diaphragm fatigue and decreases PE.

The impact of pan-resistant bacterial pathogens on survival after lung transplantation in cystic fibrosis: results from a single large referral centre.

Reported actuarial one-year survival for patients with cystic fibrosis (CF) after lung transplant is 55-91%. Infection is the most common cause of early death. Colonization with Burkholderia cepacia complex is associated with reduced survival and international lung transplant referral guidelines support individual unit assessment policies for patients colonized with other pan-resistant bacteria. We examined local data on survival after transplant for CF to determine the impact of colonization with pan-resistant bacteria. A retrospective review of all CF patients from Royal Prince Alfred Hospital (RPAH), Sydney, who underwent lung transplantation at St Vincent's Hospital, Sydney, 1989-2002, was performed. Sixty-five patients were listed for lung transplantation with 54 (male: female=29:25) receiving transplants. Of the 11 patients (17%) who died on the waiting list, six were colonized with pan-resistant Pseudomonas aeruginosa. Thirty of the 54 transplanted patients had at least one pan-resistant organism before transplant. In 28 this included P. aeruginosa. Overall one-year survival was 92% with a median survival of 67 months. Overall survival for the pan-resistant group (N = 30) was not significantly different to survival in those with sensitive organisms (N = 24) (Logrank chi square = 1.6, P = 0.2). Three patients colonized with B. cepacia complex pre-transplant survive at 11, 40 and 60 months post-transplant. Infection contributed to 11 of the 18 post-transplant deaths, with pre-transplant-acquired bacterial pathogens responsible in two cases. Patients continued to acquire multiresistant bacteria post-transplantation. Lung transplant survival at St Vincent's Hospital for CF adults from RPAH compares favourably with international benchmarks. Importantly, colonization with pan-resistant bacteria pre-transplant did not appear to adversely affect survival post-transplant.

Effect of a short course of rhDNase on cough and mucociliary clearance in patients with cystic fibrosis.

The aim of the study was to measure the effect of a short course of recombinant human deoxyribonuclease I (rhDNase) on ciliary and cough clearance in a group of cystic fibrosis patients, using a radioaerosol and gamma camera technique. Patients were initially randomized to receive either rhDNase (2.5 mg qd) or placebo. Following the measurement of baseline clearance, patients were given a 7-day course of either rhDNase or placebo. The patient then returned on the seventh day for follow-up clearance measurements. This was followed by a 2-week washout period before the whole process was repeated with the alternative inhalation solution. On each of the study days, mucociliary clearance was initially measured for a period of 60 min (IC). This was followed by cough clearance (CC) measurements for 30 min, during which patients were requested to cough a total of 120 times. Post-cough clearance (PCC) was then measured for a further 60 min. Thirteen patients completed the study. Patients' age ranged between 18-38 years, and they had baseline values of FEV(1) of 27-103% of predicted values. Following completion of the course of rhDNase, there was a mean percent increase from baseline of 7.5% for FEV(1) and 5.4% for FVC% (P = 0. 03). There was a small, nonsignificant increase in IC (6.2 +/- 3.6%) on the rhDNase arm compared with the placebo arm (-2.3 +/- 2.9%), P = 0.1. No changes were seen in either CC (1.0 +/- 3.2% [rhDNase] vs. 1.9 +/- 2.4% [placebo], P = 0.9) or PCC (-0.7 +/- 1.5% [rhDNase] vs. 0.9 +/- 1.7% [placebo], P = 0.3). Patients who achieved a 10% or greater improvement in FEV(1) (n = 5) in response to rhDNase did not show any greater change in clearance than nonresponders. In conclusion, we were unable to demonstrate any improvements in either ciliary or cough clearance in response to a short course of rhDNase. The mechanism of action of this drug in vivo remains uncertain.

Pharmacokinetics of different doses of norethisterone oenanthate.

Doses of norethisterone oenanthate of 300, 150, 100 and 50 mg were administered to four groups of subjects. Due to wide intersubject variations there were no statistically significant differences in the pharmacokinetic parameters for the different groups but there were significant correlations between the dose and the mean values for these parameters. There was little difference between the groups in the duration for which ovarian function was suppressed due to the inter-subject variation being greater than the inter-dose effect. The duration of the antifertility action of norethisterone oenanthate cannot be increased by increasing the dose above the standard 200 mg; however, with an injection interval of 60 to 70 days, it seems likely that the dose could be reduced to 150 mg.

PIP: Doses of norethisterone enathate of 300, 150, 100, and 50 mg were administered to 4 groups of subjects. Due to wide intersubject variations, there were no statistically significant differences in the pharmacokinetic paraetmers for the different groups but there were significant correlations between the dose and the mean values for these parameters. There was little difference between the groups in duration for which ovarian function was suppressed due to the intersubject variation being greater than the interdose effect. The duration of the antifertility action of norethisterone enanthate cannot be increased by increasing the dose above the standard 200 mg; however, with an injection interval of 60-70 days, it seems likely that the dose could be reduced to 150 mg.

Some estrogenic effects of two oral contraceptives consisting of norgestrel and two different doses of ethynylestradiol.

Some biological and biochemical effects (i.e. KPI, cervical mucus, SHBG and ceruloplasmin) as well as serum ethynylestradiol and serum norgestrel, following the use of two oral contraceptives containing the same amount of norgestrel (dl-norgestrel 0.5 mg) and either 30 microgram or 50 microgram of ethynylestradiol were compared. There was no difference in the clinical features in either group of patients. There was a statistically significant difference in the levels of unconjugated ethynylestradiol but not in the other biochemical parameters studied. It is concluded that the absence of any such difference might be attributable to the strong antiestrogenic effects of dl-norgestrel.

PIP: This study determined whether a reduction in ethinyl estradiol (EE) dosage from 50-30 mcg was associated with any change in biological features of estrogenic effects in the genital tract (karyopyknotic index, ferning, spinnbarkeit, volume, and clarity of cervical mucus) or biochemical effects (ceruloplasmin and sex hormone binding globulin). 11 healthy women (aged 18-25 years) with normal menstrual cycles were studied for 6 months. Alternate subjects took either Eugynon 30 or 50. There was no correlation of the index with time or with the amount of EE in the pill. Cervical mucus could only be obtained in 1/3 of examinations, and they were of low volume. Spinnbarkeit was never greater than 1 cm; no spinnbarkeit could be demonstrated in 7 specimens. Ferning was not seen in any specimen. Cervical mucus did not vary in character by dosage. Mean EE and norgestrel levels were higher in patients on Eugynon 50. Mean SHBG activity and ceruloplasmin level tended to be higher at 6 months, whereas EE and norgestrel levels diminished. The only values between which there were any statistically significant differences were those of unconjugated EE when the 2 different dosage regimes were compared (P .01). The absence of other effects may result from the strong antiestrogenic effects of dl-norgestrel.

Occurrence of ovulation in women receiving the injectable contraceptive norethisterone oenanthate.

Ovarian function was studied in ten women receiving a single intramuscular injection of 200 mg norethisterone oenanthate. Two of the ten women appeared to ovulate within 60 days of injection and a further four within 90 days. Follicular activity probably not followed by ovulation occurred in five subjects within 60 days of the injection and in a further subject within 90 days. Only one subject showed no evidence of follicular or luteal activity during the course of this study. There was wide variation in the rate at which the administered gestagen was metabolised and no correlation between the rate of metabolism of norethisterone and the return of ovarian function or the ponderal index, height or weight of the subjects.

Plasma levels of norethisterone after single and multiple injections of norethisterone oenanthate.

PIP: To study the likelihood of accumulation of norethisterone enanthate (NE) with repeated administrations, 15 women were given 200 mg NE in a single intragluteal injection (Group 1) and 15 others weere given from 5 to 11 such injections at from 12- to 10-week intervals (Group 2). Blood samples were taken and serum NE concentrations were determined. NE levels fell on a straight regression line when plotted semilogarithmically against number of days postinjection in both groups, but the slopes differed significantly (p .01) with plasma NE decreasing more slowly over time in Group 2. Extrapolated estimations of the time required for NE levels to become undetectable were 107 days for Group 1 and 152 days for Group 2. It is suggested that the steroid metabolic rate may have decrease in Group 2. These findings also offer some rationale for the suggestion that NE be administered at 60-day intervals for the 1st 3 injections and at 90-day intervals thereafter.^ieng

Pharmacokinetics of norethisterone oenanthate in humans.

The pharmacokinetics of a dose of 200 mg NET-OEN were studied after intramuscular injection into nine subjects. Blood levels of NET and NET-OEN increased rapidly, reaching peaks in most subjects within seven days. At all times after injection, serum levels of NET exceeded those of NET-OEN. The half-life of absorption varied from 5.4 to 22.3 days and the half-life of elimination varied from 7.5 to 22.5 days; there was a significant correlation (R = 0.78) between these two half-lives. There were significant correlations between the absorption half-lives and the peak values of NET and NET-OEN, the time to reach peak values and the time for which NET was detectable in serum. In all subjects NET was detectable in the circulation for a longer time after injection (mean value 74 days) than NET-OEN (mean value 43 days). The time for which the two steroids were detectable in the circulation showed a significant correlation with the elimination half-lives but there was no correlation with the peak values attained, the time taken to reach peak values and bioavailability. There was a two-fold variation between the subjects in the bioavailability of NET, less than 5% of the bioavailable NET was released after day 60.

A clinical trial of norethisterone oenanthate (Norigest) injected every two months.

A clinical trial was carried out in which Norigest (200 mg norethisterone oenanthate) was administered by intramuscular injection every 56 days into 383 women studied for 5,521 woman-months of use. No pregnancies occurred. Continuation rates at the end of one, two and three years were 76.6%, 63.7% and 33.8%. Only minor side-effects were recorded. After one year of use, 20.1% women had gained more than 2 kg in weight and 14.8% had lost more than 2 kg. There was marked disruption of the menstrual pattern and irregular bleeding was the major cause of discontinuation. In 38% of the injection intervals analysed, women were amenorrhoeic. Norigest proved an effective and acceptable method of fertility control.

The effect of a comprehensive, intensive inpatient treatment program on lung function and exercise capacity in patients with cystic fibrosis.

BACKGROUND AND PURPOSE: The purpose of this investigation was to measure the effects of a 10- to 14-day comprehensive, intensive hospital treatment program on peak exercise capacity, endurance capacity, respiratory function, weight change, and maximum inspiratory and expiratory mouth pressures in patients with cystic fibrosis with a pulmonary exacerbation. SUBJECTS: Fourteen young adults with cystic fibrosis admitted to a hospital for an exacerbation of their pulmonary disease were studied. METHODS: Subjects performed pulmonary function tests, inspiratory and expiratory mouth pressure tests, and stationary bicycle exercise tests at admission and discharge. Comprehensive therapy provided during the hospital admission consisted of intravenous antibiotics, physical therapy, high-calorie diet, and daily medical review. RESULTS: The patients showed improvements in forced expiratory volume in 1 second (46%-55% of predicted values) and forced vital capacity (62%-68% of predicted values). Maximum inspiratory and expiratory mouth pressures also improved (118%-131% and 78%-92% of predicted values, respectively). There was a mean weight gain of 2 kg. Maximum work capacity on a bicycle ergometer improved from a mean of 45% to 52% of predicted values. The most impressive result was the marked increase in exercise endurance time from a mean of 9.5 minutes on admission to 16.6 minutes at discharge. CONCLUSION AND DISCUSSION: This study indicates that young adults with cystic fibrosis and an exacerbation of their pulmonary disease obtain measurable benefits from a comprehensive, intensive treatment program, particularly improvement in their capacity for endurance exercise.

Osmotic stimuli increase clearance of mucus in patients with mucociliary dysfunction.

Mucociliary dysfunction results in mucus accumulation, airway obstruction, bacterial colonization, recurrent infective exacerbations, and an increase in morbidity and mortality. Studies in patients with cystic fibrosis, established that inhalation of hypertonic saline (HS) increases clearance of mucus acutely in a dose-dependent manner. Clearance over 90 min was 23.8 +/- 4.0% and 26.0 +/- 3.1% in response to 7% and 12% saline, which was significantly enhanced compared to 12.7 +/- 1.4% and 19.7 +/- 3.1% in response to 0.9% and 3% saline. Mannitol (approximately 300 mg) inhaled as a dry powder had a marked acute effect in patients with bronchiectasis. Clearance over 75 min was 34.0 +/- 5.0% with mannitol, 17.4 +/- 3.8% with control, and 11.7 +/- 4.4% at baseline. Further studies in patients with bronchiectasis showed that mannitol reduces the 24-h retention of radiolabeled mucus, suggesting that the effect of mannitol extends beyond the acute phase. Mannitol helped patients to clear mucus within 2 h that would have taken 24 h to clear without mannitol. A further study in CF patients showed that mannitol was equally effective as 6% HS at improving ciliary and cough clearance. The total clearance over 120 min with mannitol (27.6 +/- 3.7%) and with HS (31.0 +/- 5.5%) was significantly increased compared to their respective controls (18.6 +/- 3.8% and 20.9 +/- 3.6%). These preliminary results suggest that long-term treatment with HS or mannitol may benefit patients with mucociliary dysfunction.

Regional mucociliary clearance in patients with cystic fibrosis.

This paper reports on a large retrospective analysis of mucociliary clearance (MCC) studies in a group of 59 patients with cystic fibrosis (CF) and 17 age-matched healthy subjects. As many of the CF patients were studied on multiple occasions, a total of 184 patient studies are presented. MCC was measured using a radioaerosol and gamma camera technique. In addition to whole lung clearance, MCC was measured from the central, intermediate, peripheral, basal, mid and apical regions of the lung. MCC was markedly decreased in the CF patient group. Not only was whole lung clearance (14.2 +/- 1.4% vs. 28.0 +/- 3.7%) impaired, but also clearance from the central (19.1 +/- 1.9% vs. 35.6 +/- 4.3%), intermediate (10.7 +/- 1.6% vs. 25.5 +/- 3.7%), apical (12.4 +/- 2.6% vs. 31.6 +/- 4.6%) and mid (14.0 +/- 1.9% vs. 30.4 +/- 4.0%) regions. Attempts were made to identify factors that may have influenced MCC in both the normal subjects and CF patients. Age, gender, body mass index, patient genotype, penetration index, spontaneous cough, and various lung function parameters were entered into a stepwise multiple regression model, but none of the factors proved to be statistically important in determining MCC. Both intrasubject repeatability and intersubject variability estimates are presented for the patients and normal subjects that had multiple studies. The values were found to be remarkably similar for both CF patients and normal subjects and for both intra- and intersubject repeatability. With marked deviation from normal ranges and good repeatability, the measurement of MCC in CF patients would seem to be a valuable outcome measure for clinical trials involving new pharmaceuticals and physical therapy designed to improve removal of secretions from the airways.