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.

Effect of airway clearance techniques on the efficacy of the sputum induction procedure.

Sputum induction is used in the early identification of tuberculosis (TB) and pneumocystis infections of the lung. Although manual physiotherapy techniques to clear the airways are often incorporated in the sputum induction procedure, their efficacy in this setting is unknown. This randomised, crossover trial enrolled adults referred for sputum induction for suspected TB and pneumocystis infections of the lung. All participants underwent two sputum induction procedures, inhaling 3% saline via ultrasonic nebuliser. During one randomly allocated procedure, airway clearance techniques (chest wall percussion, vibration, huffing) were incorporated. In total, 59 participants completed the trial. The airway clearance techniques had no significant effect on how the test was tolerated, the volume expectorated or the quality of the sample obtained (assessed by the presence of alveolar macrophages). The techniques did not significantly affect how often the test identified a suspected organism, nor the sensitivity or specificity of sputum induction. In conclusion, the study was unable to demonstrate any effect of airway clearance techniques on the sputum induction procedure. The results provide some justification for not including airway clearance techniques as part of the sputum induction procedure.

Supported and unsupported arm exercise capacity following lung volume reduction surgery: a pilot study.

STUDY OBJECTIVES: Lung volume reduction surgery (LVRS) has been shown to improve lung function, leg exercise capacity and quality of life in subjects with severe COPD. This is the first study to examine the effect of LVRS on supported and unsupported arm exercise capacity. DESIGN: Eight subjects with COPD (% pred FEV1 +/- SD = 31.1 +/- 9.8%) completed testing. At baseline (T1), after eight weeks pulmonary rehabilitation (T2) and four months after LVRS (T3), each subject had tests of lung function, and performed three symptom-limited exercise tests to peak work capacity: supported arm exercise (SAE), unsupported arm exercise (UAE) and leg exercise (LE). MEASUREMENTS: The FEV1 (% pred) increased from 27.8 +/- 7.4 (mean +/- SD) at T2 to 36.3 +/- 7.1 at T3 (P < 0.05). Peak oxygen consumption (VO2) remained similar from T1 to T2 for SAE, UAE and LE (all P = 1.0) but increased from T2 to T3 (P < 0.05) (SAE: T2 = 0.59 +/- 0.2 L/min, T3 = 0.72 +/- 0.1 L/min; UAE: T2 = 0.45 +/- 0.1 L/min, T3 = 0.54 +/- 0.1 L/min; LE: T2 = 0.68 +/- 0.2 L/min, T3 = 0.81 +/- 0.2 L/min). The ratio of end-expiratory lung volume to total lung capacity was reduced at peak SAE and LE from T2 to T3 (P < 0.01) (SAE: T2 = 81 +/- 4.0%, T3 = 76 +/- 2.7%; LE: T2 = 81 +/- 5.1%, T3 = 75 +/- 3.6%). CONCLUSION: There was a significant increase in SAE and UAE capacity following LVRS. Dynamic hyperinflation was reduced during SAE following LVRS.

Method for detection of respiratory viruses in the sputa of patients with cystic fibrosis.

Since the role of respiratory viruses in lung exacerbations of patients with cystic fibrosis has been hampered by the difficulty of detecting viruses in viscous sputum specimens, a multiplex reverse transcriptase PCR (RT-PCR) assay combined with colorimetric amplicon detection was tested for the identification of seven common respiratory viruses in the sputa of cystic fibrosis patients. Of 52 sputa from 38 patients, 12 (23%) samples from 12 patients were positive for a respiratory virus (4 for influenza B, 3 for parainfluenza 1, 3 for influenza A and 2 for respiratory syncytial virus). These results suggest that the RT-PCR method carried out on sputum may provide a convenient means of investigating the role of virus infection in lung exacerbations of cystic fibrosis patients.

Reduction in resting energy expenditure following lung volume reduction surgery in subjects with chronic obstructive pulmonary disease.

STUDY OBJECTIVES: Some subjects with COPD have an elevated resting energy expenditure (REE) which may be related to an increased work of breathing at rest. The purpose of this study was to examine the effect of lung volume reduction surgery (LVRS) on REE and body weight. DESIGN: Ten subjects with COPD were recruited (mean age +/- SD = 61.4 +/- 6.1 years). At baseline (which was following preoperative pulmonary rehabilitation) and four months following LVRS (combined with postoperative pulmonary rehabilitation), each subject had tests of lung function, REE via indirect calorimetry using a canopy system, six minute walk distance (6MWD) and quality of life (QoL) using the St George's Hospital Respiratory Questionnaire (SGRQ). MEASUREMENTS: The FEV1 (% predicted) increased from 27.7 +/- 5.8% (mean +/- SD) at baseline to 33.9 +/- 7.8% following LVRS (P < 0.05). REE (% predicted) was 110 +/- 9.8% at baseline and decreased to 106 +/- 6.7% following LVRS (P = 0.04). Body mass index (BMI) following LVRS was unchanged (P = 0.67). No correlation between the change in BMI and change in REE was shown (r2 = 0.3, P = 0.1). There was a significant improvement in QoL following LVRS (P < 0.001). 6MWD also significantly increased from 354 +/- 83 m to 412 +/- 82 m following LVRS (P = 0.001). CONCLUSION: Whilst there was an increase in lung function and a reduction in REE following LVRS, there was no corresponding change to body weight. The improvement in REE following LVRS may be related to an improvement in work of breathing.

Adults with cystic fibrosis: meeting the challenge!

The number of adults with cystic fibrosis (CF) is increasing. They are striving for independence and a fulfilling life with focus on career, relationships, education and finances at a time when lung function is likely to be declining and complications of this multi-system disease are increasing. Maintaining the quality and improving the duration of life are continuing challenges for the -clinician and the patient. Increased hope and greater expectations have been provided by a number of recent clinical advances and active research into novel treatments, including gene therapy. There has been increased recognition of the necessity for early diagnosis, adequate monitoring and effective intervention for complications such as diabetes and osteoporosis. Research into multi-resistant bacteria and clonal strains of Pseudomonas aeruginosa is ongoing and attention has focused on infection control policies. Although more high-level evidence is required on many issues confronting people with CF, a considerable effort has been made over the last decade to provide a more evidence-based approach to therapy with a number of large controlled clinical trials. For the adult with CF, there are also more decisions to be made. There is focus on reproductive health, with most couples enjoying the real possibility of having children. For those with advanced disease, the option for lung transplantation is well established. Maintenance of quality care will require adequate planning, effective transition programmes from paediatric to adult care, specialized training for doctors, nurses and allied health professionals and the allocation of sufficient resources to accommodate the inevitable increase in patient numbers.

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.

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.

Low-flow oxygen and bilevel ventilatory support: effects on ventilation during sleep in cystic fibrosis.

We measured ventilation in all sleep stages in patients with cystic fibrosis (CF) and moderate to severe lung disease, and compared the effects of low-flow oxygen (LFO2) and bilevel ventilatory support (BVS) on ventilation and gas exchange during sleep. Thirteen subjects, age 26 +/- 5.9 yr (mean +/- 1 SD), body mass index (BMI) 20 +/- 3 kg/m2, FEV1 32 +/- 11% predicted, underwent three sleep studies breathing, in random order, room air (RA), LFO2, and BVS +/- O2 with recording of oxyhemoglobin saturation (SpO2) (%) and transcutaneous carbon dioxide (TcCO2) (mm Hg). During RA and LFO2 studies, patients wore a nasal mask with a baseline continuous positive airway pressure (CPAP) of 4 to 5 cm H2O. Minute ventilation (V I) was measured using a pneumotachograph in the circuit and was not different between wake and non-rapid eye movement (NREM) sleep on any night. However, V I was reduced on the RA and LFO2 nights from awake to rapid eye movement (REM) (p < 0.01) and from NREM to REM (p < 0.01). On the BVS night there was no significant difference in V I between NREM and REM sleep. Both BVS and LFO2 improved nocturnal SpO2, especially during REM sleep (p < 0.05). The rise in TcCO2 seen with REM sleep with both RA and LFO2 was attenuated with BVS (p < 0.05). We conclude that BVS leads to improvements in alveolar ventilation during sleep in this patient group.

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.

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.

The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study.

It has been postulated that hypertonic saline (HS) might impair the antimicrobial effects of defensins within the airways. Alternative non-ionic osmotic agents such as mannitol may thus be preferable to HS in promoting bronchial mucus clearance (BMC) in patients with cystic fibrosis (CF). This study reports the effect of inhalation of another osmotic agent, dry powder Mannitol (300 mg), compared with its control (empty capsules plus matched voluntary cough) and a 6% solution of HS on BMC in 12 patients with cystic fibrosis (CF). Mucus clearance was measured using a radioaerosol/gamma camera technique. Post-intervention clearance was measured for 60 min, followed by cough clearance for 30 min. Neither mannitol nor HS improved BMC during the actual intervention period compared with their respective controls. However during the post-intervention measurement there was a significant improvement in BMC for both the mannitol (8.7+/-3.3% versus 2.8+/-0.7%) and HS (10.0+/-2.3% versus 3.5+/-0.8%). There was also a significant improvement in cough clearance with the Mannitol (9.7+/-2.4%) compared with its control (2.5+/-0.8%). Despite premedication with a bronchodilator, a small fall in forced expiratory volume in one second (FEV1) was seen immediately after administration of both the mannitol (7.3+/-2.5%) and HS (5.8+/-1.2%). Values of FEV1 returned to baseline by the end of the study. Inhaled mannitol is a potential mucoactive agent in cystic fibrosis patients. Further studies are required to establish the optimal dose and the long-term effectiveness of mannitol.

End-expiratory lung volume during arm and leg exercise in normal subjects and patients with cystic fibrosis.

There are no reports concerning the regulation of end-expiratory lung volume (EELV) and flow-volume relationships during upper limb exercise in health and disease. We studied EELV during such exercise in 22 adults with cystic fibrosis (CF) and nine age-matched healthy control subjects. Subjects with CF were grouped according to the severity of their lung disease, as follows: mild = FEV1 > 80% predicted; moderate = FEV1 40 to 80% predicted, and severe = FEV1 < 40% predicted. EELV was calculated from measurements of inspiratory capacity (IC) made at each workload during an incremental arm and leg ergometer test to peak work capacity. In the control group, the decrease in EELV was significantly smaller for arm than for leg exercise at peak work (-0.13 L versus -0.53 L, p < 0.001) and for arm than for leg exercise at an equivalent submaximal ventilation (-0.13 L versus -0.46 L, p < 0.01). In the groups with moderate and severe CF, arm exercise resulted in an increase in EELV from resting levels (dynamic hyperinflation) that was not significantly different from the increase observed for leg exercise. For CF subjects there was a significant inverse relationship between FEV1 and changes in EELV from rest to peak arm exercise (r = -0.46, p < 0.05). In normal subjects, there was a difference in the EELV response for arm versus leg exercise. In CF subjects with airflow limitation, dynamic hyperinflation occurred with both forms of exercise.

Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis are known to have decreased mucociliary clearance. It has previously been shown that inhalation of a 7.0% solution of hypertonic saline significantly improved mucociliary clearance in a group of adult patients with cystic fibrosis. The aim of this study was to measure the response to increasing concentrations of inhaled hypertonic saline. METHODS: Ten patients (seven men) of mean (SE) age 22 (4) years and mean forced expiratory volume in one second (FEV1) 52.0 (6.7)% predicted completed the study. Mucociliary clearance was measured using a radioaerosol technique for 90 minutes after the interventions which comprised 0.9% NaCl + voluntary cough (control), 3.0% NaCl, 7.0% NaCl, and 12% NaCl. RESULTS: There was a significant increase in the amount of activity cleared from the right lung with all concentrations of hypertonic saline (HS) compared with control. The amount cleared at 90 minutes on the control day was 12.7% (95% confidence interval (CI) 9.8 to 17.2) compared with 19.7% (95% CI 13.6 to 29.5) for 3% HS, 23.8% (95% CI 15.9 to 36.7) for 7% HS and 26.0% (95% CI 19.8 to 35.9) for 12% HS. The improvement in mucociliary clearance was not solely due to coughing as the number of coughs recorded on the control day exceeded that recorded on any other day. The hypertonic saline did not induce a clinically significant change in FEV1. CONCLUSIONS: Within the range of concentrations examined in this study, the effect of hypertonic saline appears to be dose dependent. Inhalation of hypertonic saline remains a potentially useful treatment for patients with cystic fibrosis.

Evaluation of supported upper limb exercise capacity in patients with cystic fibrosis.

Physiological responses to upper limb exercise have not been well documented in patients with cystic fibrosis (CF). This is the first study to quantify ventilatory responses to supported incremental upper limb exercise in this patient group. Twenty-four subjects with CF, with a wide range of pulmonary impairment, and ten normal control subjects were studied. Subjects performed pulmonary function tests and incremental arm and leg exercise to peak work capacity on an arm crank and bicycle ergometer. All subjects performed less work with the arms than legs. At an equivalent oxygen consumption, ventilation was higher for arm work than leg work. This higher ventilation was achieved mainly through a higher frequency of breathing. Only CF subjects with severe pulmonary impairment (FEV1 < 40% predicted, FEF25-75% < 20% predicted) had a reduced arm work capacity compared with control subjects. At peak arm work, these subjects had a mean ventilation to maximum voluntary ventilation ratio (VE/MVV) of 106% +/- 25, while maximum heart rate was less than 80% predicted. Despite the high ventilatory requirement for arm exercise, arm work capacity was well maintained in subjects with CF until severe lung disease impaired the ability to further increase ventilation.

Ventilatory mechanics at rest and during exercise in patients with cystic fibrosis.

Ventilatory mechanics were measured at rest and during steady-state (25%, 50%, 75%) and maximal exercise (W-Max) on a cycle-ergometer in eight adult patients (FEV1 22 to 114% of predicted) with cystic fibrosis (CF). Tidal flow-volume loops were measured at rest and during exercise and placed within the maximal pre- and postexercise flow-volume loops, based on measured end-expiratory lung volume (EELV). The degree of flow limitation was expressed as the percentage of the tidal flow-volume loop that met the expiratory boundary of the maximal loop (TFVL%). Pressure-volume relationships were assessed by measurement of transpulmonary pressure (PTP). Peak inspiratory PTP was compared with maximal inspiratory pressures at rest and during exercise (Pcap(i)) at the equivalent lung volume. The maximal effective expiratory pressure (Pmax(e)) was determined using the orifice technique. Three patients with milder disease (FEV1 114, 98, 89% of predicted) did not show any flow limitation at rest or 50% W-Max but two did show some flow limitation at W-Max (0, 3, 23 TFVL%) with a decrease in EELV (-400, -200, -300 ml). There was considerable reserve for inspiratory and expiratory pressure generation at W-Max. Flow limitation was noted at rest in three patients and at 50% W-Max in the five patients with more severe airways obstruction. The increased flow was achieved by an increase in EELV in all five patients (+400, +430, +330, +150, +700 ml at W-Max). Pcap(i) was reached in two patients (-28, -36 cm H2O), while Pmax(e) was exceeded by four patients suggesting inefficient pressure generation. Expiratory flow limitation, hyperinflation, and pressure swings approaching capacity severely compromised the capacity to generate ventilation in some patients with CF.