Exercise training after lung transplantation improves participation in daily activity: a randomized controlled trial.

The effects of exercise training after lung transplantation have not been studied in a randomized controlled trial so far. We investigated whether 3 months of supervised training, initiated immediately after hospital discharge, improve functional recovery and cardiovascular morbidity of patients up to 1 year after lung transplantation. Patients older than 40 years, who experienced an uncomplicated postoperative period, were eligible for this single blind, parallel group study. Sealed envelopes were used to randomly allocate patients to 3 months of exercise training (n = 21) or a control intervention (n = 19). Minutes of daily walking time (primary outcome), physical fitness, quality of life and cardiovascular morbidity were compared between groups adjusting for baseline assessments in a mixed models analysis. After 1 year daily walking time in the treated patients (n = 18) was 85 ± 27 min and in the control group (n = 16) 54 ± 30 min (adjusted difference 26 min [95%CI 8-45 min, p = 0.006]). Quadriceps force (p = 0.001), 6-minute walking distance (p = 0.002) and self-reported physical functioning (p = 0.039) were significantly higher in the intervention group. Average 24 h ambulatory blood pressures were significantly lower in the treated patients (p ≤ 0.01). Based on these results patients should be strongly encouraged to participate in an exercise training intervention after lung transplantation.

Accuracy of office spirometry performed by trained primary-care physicians using the MIR Spirobank hand-held spirometer.

BACKGROUND: With the availability of compact, portable, effective microspirometers, pulmonary function tests no longer need to be performed only in specialized laboratories. However, the perception persists that small flow-sensing devices are less accurate than volume-sensing spirometers. OBJECTIVES: To study the accuracy of spirometry performed with the MIR Spirobank® and to investigate how accurately trained primary-care physicians can perform spirometry using a portable electronic spirometer. METHODS: Patients with suspected occupational asthma were submitted to specific bronchial challenge tests in the pulmonary function laboratory according to published recommendations. Serial measurements were performed with the Jaeger MasterScope device (reference standard) or the Spirobank device. Data were generated from 908 parallel measurements on 34 patients. Furthermore, 16 patients with documented moderate to severe COPD were examined in a carousel set-up by four trained physicians who each used his/her own Spirobank device coupled to a laptop computer. RESULTS: The Spirobank spirometer performed very well compared with the Jaeger MasterScope in a laboratory environment, displaying an underestimation of the forced expiratory volume in 1 s (FEV(1)) and FEV(1)/forced vital capacity (FVC) of 2-5%. High correlations were found for the pulmonary function parameters. The highest correlation was for FEV(1) (r(2) = 0.949) and the lowest for the maximum expiratory flow at 25% of FVC (MEF(25)) (r(2) = 0.864). Only 2% of the observed variation in the measurement results could be explained by the type of device. CONCLUSIONS: The Spirobank device seems to be appropriate for research purposes if the standardized protocol is used correctly and the acceptability criteria are respected.

Rehabilitation and acute exacerbations.

Recent evidence indicates that acute exacerbations of chronic obstructive pulmonary disease aggravate the extrapulmonary consequences of the disease. Skeletal muscle dysfunction, a sustained decrease in exercise tolerance, enhanced symptoms of depression and fatigue are reported. Avoidance of physical activities is likely to be a key underlying mechanism and increases the risk of new exacerbations. Pulmonary rehabilitation is an intervention targeting these systemic consequences. Exercise strategies need to be adapted to the increased feelings of dyspnoea and fatigue. This review aims to describe the systemic consequences of acute exacerbations and compiles evidence for the feasibility and effectiveness of different rehabilitation strategies to counteract these consequences during and/or immediately after the acute phase of the exacerbation. Resistance training and neuromuscular electrical stimulation have been applied safely in frail, hospitalised patients and have the potential to prevent muscle atrophy. Comprehensive pulmonary rehabilitation, including general exercise training, can be implemented immediately after the exacerbation, leading to a reduction in hospital admissions and an increase in exercise tolerance and quality of life. Self-management strategies play a crucial role in changing disease-related health behaviour and preventing hospital admissions.

Impact of inspiratory muscle training in patients with COPD: what is the evidence?

A meta-analysis including 32 randomised controlled trials on the effects of inspiratory muscle training (IMT) in chronic obstructive pulmonary disease (COPD) patients was performed. Overall and subgroup analyses with respect to training modality (strength or endurance training, added to general exercise training) and patient characteristics were performed. Significant improvements were found in maximal inspiratory muscle strength (P(I,max); +13 cmH2O), endurance time (+261 s), 6- or 12-min walking distance (+32 and +85 m respectively) and quality of life (+3.8 units). Dyspnoea was significantly reduced (Borg score -0.9 point; Transitional Dyspnoea Index +2.8 units). Endurance exercise capacity tended to improve, while no effects on maximal exercise capacity were found. Respiratory muscle endurance training revealed no significant effect on P(I,max), functional exercise capacity and dyspnoea. IMT added to a general exercise programme improved P(I,max) significantly, while functional exercise capacity tended to increase in patients with inspiratory muscle weakness (P(I,max) <60 cmH2O). IMT improves inspiratory muscle strength and endurance, functional exercise capacity, dyspnoea and quality of life. Inspiratory muscle endurance training was shown to be less effective than respiratory muscle strength training. In patients with inspiratory muscle weakness, the addition of IMT to a general exercise training program improved P(I,max) and tended to improve exercise performance.

The TERT-CLPTM1L locus for lung cancer predisposes to bronchial obstruction and emphysema.

Clinical studies suggest that bronchial obstruction and emphysema increase susceptibility to lung cancer. We assessed the possibility of a common genetic origin and investigated whether the lung cancer susceptibility locus on chromosome 5p15.33 increases the risk for bronchial obstruction and emphysema. Three variants in the 5p15.33 locus encompassing the TERT and CLPTM1L genes were genotyped in 777 heavy smokers and 212 lung cancer patients. Participants underwent pulmonary function tests and computed tomography of the chest, and completed questionnaires assessing smoking behaviour. The rs31489 C-allele correlated with reduced forced expiratory volume in 1 s (p=0.006). Homozygous carriers of the rs31489 C-allele exhibited increased susceptibility to bronchial obstruction (OR 1.82, 95% CI 1.24-2.69; p=0.002). A similar association was observed for diffusing capacity of the lung for carbon monoxide (p=0.004). Consistent with this, CC-carriers had an increased risk of emphysema (OR 2.04, 95% CI 1.41-2.94; p=1.73 × 10(-4)) and displayed greater alveolar destruction. Finally, CC-carriers also had an increased risk for lung cancer (OR 1.90, 95% CI 1.21-2.99; p=0.005), and were more susceptible to developing both lung cancer and bronchial obstruction than lung cancer alone (OR 2.11, 95% CI 1.04-4.26; p=0.038). The rs31489 variant on 5p15.33 is associated with bronchial obstruction, presence and severity of emphysema, and lung cancer.

Atrophy and hypertrophy signalling in the diaphragm of patients with COPD.

We investigated whether atrophy and hypertrophy signalling were altered in the diaphragm of chronic obstructive pulmonary disease (COPD) patients. We studied diaphragm fibre dimensions and proportion, expression of markers of the ubiquitin-proteasome pathway, nuclear factor (NF)-kappaB pathways, muscle regulatory factors and myostatin in diaphragm biopsies from 19 patients with severe COPD and 13 patients without COPD. Type I proportion was significantly increased in the diaphragm of COPD patients while type II proportion was decreased. The cross-sectional area of all fibre types was reduced in the COPD patients. In addition, MAFbx mRNA was higher in the diaphragm of COPD patients while Nedd4 mRNA decreased. Cytoplasmatic levels of inhibitor protein IkappaBalpha and IkappaBbeta were decreased in the COPD patients as was NF-kappaB p50 DNA-binding activity. MyoD mRNA and its nuclear protein content were decreased in the diaphragm of COPD patients and myogenin mRNA and protein levels remained unchanged. Myostatin mRNA was decreased but its protein levels in the nuclear and cytoplasmic fraction were significantly increased in the COPD patients. These data show that the ubiquitin-proteasome pathway, the NF-kappaB pathway and myostatin protein were up-regulated in the diaphragm of COPD patients while MyoD expression was reduced. These alterations may contribute to diaphragm remodeling in COPD.

Long-term efficacy of tiotropium in relation to smoking status in the UPLIFT trial.

UPLIFT (Understanding Potential Long-Term Improvements in Function with Tiotropium), a 4-yr trial of tiotropium in chronic obstructive pulmonary disease, allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy. 5,993 patients were randomised (tiotropium/placebo). Lung function, St George's Respiratory Questionnaire, exacerbations and adverse events were followed. Patients were characterised as continuing smokers (CS), continuing ex-smokers (CE), or intermittent smokers (IS) based on self-reporting smoking behaviour. 60%, 14% and 26% of patients were CE, CS and IS, respectively. The rate of forced expiratory volume in 1 s (FEV(1)) decline for placebo patients was most rapid in CS (-52+/-4, -37+/2 and -23+/2 mL.yr(-1) in CS, IS, and CE, respectively). Tiotropium did not alter FEV(1) decline, but was associated with significant improvements in pre- and post-bronchodilator FEV(1) over placebo that persisted throughout the 4-yr trial for each smoking status (pre-bronchodilator: 127, 55 and 97 mL at 48 months in CS, IS and CE, respectively; p< or =0.0003). Tiotropium reduced exacerbation risk in CS (HR (95% CI) 0.80 (0.67-0.95)), in CE (0.85 (0.79-0.92)) and trended towards significance in IS (0.89 (0.79-1.00)). At 4 yrs, St George's Respiratory Questionnaire for tiotropium patients improved the most in CS (-4.63 units, p = 0.0006) and the least in IS (-0.60 units, p = 0.51), [corrected] compared with control. Tiotropium provided long-term benefits irrespective of smoking status, although differences among categories were observed.

Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial.

The aim of the present study was investigate the long-term effect of tiotropium as first maintenance respiratory medication in chronic obstructive pulmonary disease (COPD). A 4-yr, randomised, multicentre, double-blind, parallel-group, placebo-controlled trial (Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) was conducted. Analysis focused on the effect of tiotropium versus matching placebo in the 810 (13.5%) COPD patients not on other maintenance treatment (long-acting beta-agonists, inhaled corticosteroids, theophyllines or anticholinergics) at randomisation. Spirometry, health-related quality of life (St George's Respiratory Questionnaire (SGRQ) score), exacerbations of COPD and mortality were also analysed. 403 patients (mean+/-sd age 63+/-8 yrs, post-bronchodilator forced expiratory volume in 1 s (FEV(1)) 53+/-12% predicted) received tiotropium and 407 (64+/-8 yrs of age, post-bronchodilator FEV(1) 51+/-12% pred) received placebo. Post-bronchodilator FEV(1) decline was 42+/-4 mL.yr(-1) in the tiotropium group and 53+/-4 mL.yr(-1) in the placebo group (p = 0.026). At 48 months, the morning pre-dose FEV(1) was 134 mL higher in the tiotropium group compared to the placebo group (p<0.001). SGRQ total score declined more slowly in the tiotropium group (difference of 1.05+/-0.34 units.yr(-1); p = 0.002). This was particularly significant for the impact (difference of 1.08+/-0.37 units.yr(-1); p = 0.004) and activity (1.44+/-0.40 units.yr(-1); p<0.001) domains, but not for symptoms (0.26+/-0.50 units.yr(-1); p = 0.6). At 48 months, the difference in total score was 4.6 units (p<0.001) with tiotropium compared to placebo. In patients with COPD who are not on maintenance therapy, tiotropium is associated with significant benefits in disease progression.

Effect of creatine supplementation as a potential adjuvant therapy to exercise training in cardiac patients: a randomized controlled trial.

OBJECTIVE: To investigate the effect of oral creatine supplementation in conjunction with an exercise programme on physical fitness in patients with coronary artery disease or chronic heart failure. DESIGN: Single centre double-blind randomized placebo controlled trial. SETTING: Cardiac rehabilitation centre. SUBJECTS AND INTERVENTION: 70 (4 women) cardiac patients (age 57.5 (8.4) years) were randomized to a placebo (n = 37) or creatine (n = 33) treatment for three months. Combined aerobic endurance and resistance training (three sessions/ week) was performed during supplementation. MAIN MEASURES: Aerobic power was determined during graded bicycle testing, knee extensor peak isometric and isokinetic strength, endurance and recovery were assessed by an isokinetic dynamometer, and health related quality of life was evaluated with the SF-36 and MacNew Heart Disease questionnaires. In addition, blood samples were taken after an overnight fast and 24 hour urinary collection was performed. RESULTS: At baseline there were no significant differences between both groups. We observed main time effects for aerobic power, muscle performance, health related quality of life, high density lipoprotein cholesterol and triglycerides (pre vs post; P<0.05 for all). However, changes after training were similar between placebo group and creatine group (P>0.05). Further, no detrimental effect on renal or liver function was observed nor were there any reports of side effects. CONCLUSION: Oral creatine supplementation in combination with exercise training does not exert any additional effect on the improvement in physical performance, health related quality of life, lipid profile in patients with coronary artery disease or chronic heart failure than exercise training alone.

Skeletal muscle weakness, exercise tolerance and physical activity in adults with cystic fibrosis.

The aim of the present study was to investigate the prevalence of muscle weakness and the importance of physical inactivity in cystic fibrosis (CF), and its relationship to exercise tolerance and muscle strength. Exercise tolerance, skeletal and respiratory muscle strength were studied in a group of 64 adults with CF (age 26+/-8 yrs, FEV(1 % predicted) 65+/-19) and in 20 age-matched controls. Physical activity (PA) was assessed in 20 patients and all controls. Quadriceps muscle weakness was present in 56% of the patients. Peak oxygen uptake and 6-min walking distance were below normal in 89 and 75% of patients, respectively. Respiratory muscle strength was normal. The differences remained after correcting for PA. Quadriceps force was correlated to the 6-min walking distance but not to peak oxygen uptake. "Mild" PA (>3 metabolic equivalents (METS)) and the number of steps overlapped with controls, but CF patients had less moderate PA (>4.8 METS). Moderate PA was related to peak oxygen uptake and quadriceps force. Skeletal muscle weakness and exercise intolerance are prevalent in cystic fibrosis. Physical inactivity is a factor significantly contributing to exercise tolerance and skeletal muscle force in adults with cystic fibrosis, but these impairments are in excess to that expected from physical inactivity only.

Skeletal muscle force and functional exercise tolerance before and after lung transplantation: a cohort study.

We investigated the impact of lung transplantation and outpatient pulmonary rehabilitation after lung transplantation on skeletal muscle function and exercise tolerance. Skeletal muscle force (Quadriceps force, QF), exercise tolerance (six minute walking distance, 6MWD) and lung function were assessed in 36 patients before and after lung transplantation. Seventeen male and 19 female patients (age 57 +/- 4) showed skeletal muscle weakness before the transplantation. A further 32 +/- 21% reduction was seen 1.2 (interquartile range 0.9 to 2.0) months after LTX. The number of days on the intensive care unit was significantly related to the observed deterioration in muscle force after LTX. At this time point 6MWD was comparable to pre-LTX. Rehabilitation started 37 (IQR 29 to 61) days after LTX. 6MWD and QF improved significantly (140 +/- 91 m, and 35 +/- 48%, respectively; p < 0.05) with rehabilitation. QF remained below pre-LTX values. The evolution of the 6MWD with the transplantation and the subsequent rehabilitation was less in female compared to male subjects. We conclude that muscle strength deteriorates after lung transplantation, particularly in patients with long ICU stay. Outpatient pulmonary rehabilitation is feasible after lung transplantation and leads to recovery of skeletal muscle function. In female patients this recovery is significantly less compared to male recipients.

Inspiratory flow rates at different levels of resistance in elderly COPD patients.

Dry powder inhalers (DPIs) are increasingly replacing metered dose inhalers in elderly chronic obstructive pulmonary disease (COPD) patients. However, most DPIs are dependent on inspiratory flow, which is compromised by the ageing process itself. Using the in-check dial method, the present study compared peak inspiratory flow (PIF) rates in 26 elderly COPD patients and 14 matched control subjects, at a pre-set resistance level of the Aeroliser, Diskus and Turbuhaler inhalers. It was found that the PIF measured by the in-check method positively correlated with the PIF derived from spirometry, forced vital capacity and maximal inspiratory pressure, while a negative, but significant, correlation was observed with age. PIF derived from spirometry and age were independent variables which determined PIF across the device, whereas the presence or absence of COPD was not related. When comparing elderly COPD patients with matched elderly controls no difference could be found in PIF at the different resistances. However, an important number of patients did not reach the recommended flow rate, especially when using the Turbuhaler (30%). In conclusion, the present study demonstrates that, in elderly patients, the ability to generate sufficient inspiratory flow across a dry powder inhaler is compromised, irrespective of the presence of chronic obstructive pulmonary disease.

Primary care spirometry.

Primary care spirometry is a uniquely valuable tool in the evaluation of patients with respiratory symptoms, allowing the general practitioner to diagnose or exclude chronic obstructive pulmonary disease (COPD), sometimes to confirm asthma, to determine the efficacy of asthma treatment and to correctly stage patients with COPD. The use of spirometry for case finding in asymptomatic COPD patients might become an option, once early intervention studies have shown it to be beneficial in these patients. The diagnosis of airway obstruction requires accurate and reproducible spirometric measurements, which should comply with the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines. Low acceptability of spirometric manoeuvres has been reported in primary care practices. This may hamper the validity of the results and affect clinical decision making. Training and refresher courses may produce and maintain good-quality testing, promote the use of spirometric results in clinical practice and enhance the quality of interpretation. Softening the stringent ATS/ERS criteria could enhance the acceptability rates of spirometry when used in a general practice. However, the implications of potential simplifications on the quality of the data and clinical decision making remain to be investigated. Hand-held office spirometers have been developed in recent years, with a global quality and user-friendliness that makes them acceptable for use in general practices. The precision of the forced vital capacity measurements could be improved in some of the available models.

Bronchodilator responsiveness in patients with COPD.

The degree of acute improvement in spirometric indices after bronchodilator inhalation varies among chronic obstructive pulmonary disease (COPD) patients, and depends upon the type and dose of bronchodilator and the timing of administration. Acute bronchodilator responsiveness at baseline was examined in a large cohort of patients with moderate-to-very-severe COPD participating in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial, a 4-yr randomised double-blind trial evaluating the efficacy of 18 mug tiotropium daily in reducing the rate of decline in lung function. After wash-out of respiratory medications, patients received 80 mug ipratropium followed by 400 mug salbutamol. Spirometry was performed before and 90 min following ipratropium administration. The criteria used for forced expiratory volume in one second (FEV(1)) responsiveness were: >or=12% increase over baseline and >or=200 mL; >or=15% increase over baseline; and >or=10% absolute increase in the percentage predicted value. Of the patients, 5,756 had data meeting the criteria for analysis (age 64.5 yrs; 75% male; baseline FEV(1) 1.10 L (39.3% predicted) and forced vital capacity (FVC) 2.63 L). Compared with baseline, mean improvements were 229 mL in FEV(1) and 407 mL in FVC. Of these patients, 53.9% had >or=12% and >or=200 mL improvement in FEV(1), 65.6% had >or=15% improvement in FEV(1), and 38.6% had >or=10% absolute increase in FEV(1) % pred. The majority of patients with moderate-to-very-severe chronic obstructive pulmonary disease demonstrate meaningful increases in lung function following administration of inhaled anticholinergic plus sympathomimetic bronchodilators.

Sinonasal pathology in nonallergic asthma and COPD: 'united airway disease' beyond the scope of allergy.

BACKGROUND: In contrast to the epidemiological and clinical association between allergic rhinitis and asthma, upper airway inflammation is less characterized in patients with nonatopic asthma and virtually unexplored in chronic obstructive pulmonary disease (COPD). Here, sinonasal pathology is studied in patients with allergic asthma, nonallergic asthma and COPD. METHODS: Ninety patients with stable bronchial disease were included in the study, of which 35 were diagnosed with allergic asthma, 24 with nonallergic asthma and 31 with COPD. Concurrently, 61 control subjects without pulmonary disease were included and matched for age and smoking habits respectively with the asthma and the COPD group. Sinonasal symptoms were evaluated on a visual analogue scale and rhinosinusitis-related impairment of quality of life was assessed with the sino-nasal outcome test-22 (SNOT-22) questionnaire. Nasal mucosal abnormalities were quantified with nasal endoscopy and nasal secretions collected for measuring inflammatory mediators. RESULTS: Allergic asthmatics, nonallergic asthmatics and COPD patients reported more nasal symptoms than their respective control subjects, had a higher SNOT-22 score and presented more mucosal abnormalities in the nose. Nasal secretions of both allergic and nonallergic asthmatics contained higher levels of eotaxin, G-CSF, IFN-gamma and MCP-1 than controls. Allergic asthmatics had higher nasal IP-10 levels as well. COPD-patients had higher nasal levels of eotaxin, G-CSF and IFN-gamma than controls. CONCLUSION: Patients with allergic and nonallergic asthma and COPD show increased nasal symptoms and more nasal inflammation. Hence, our data confirm the 'united airways' concept to be beyond the scope of allergic asthma.

Triamcinolone and prednisolone affect contractile properties and histopathology of rat diaphragm differently.

Diaphragm atrophy and weakness occur after administration of massive doses of corticosteroids for short periods. In the present study the effects of prolonged administration of moderate doses of fluorinated and nonfluorinated steroids were investigated on contractile properties and histopathology of rat diaphragm. 60 rats received saline, 1.0 mg/kg triamcinolone, or 1.25 or 5 mg/kg i.m. prednisolone daily for 4 wk. Respiratory and peripheral muscle mass increased similarly in control and both prednisolone groups, whereas triamcinolone caused severe muscle wasting. Maximal tetanic tension averaged 2.23 +/- 0.54 kg/cm2 (SD) in the control group. An increased number of diaphragmatic bundles in the 5-mg/kg prednisolone group generated maximal tetanic tensions < 2.0 kg/cm2 (P < 0.05). In addition, fatigability during the force-frequency protocol was most pronounced in this group (P < 0.05). In contrast, triamcinolone caused a prolonged half-relaxation time and a leftward shift of the force-frequency curve (P < 0.05). Histological examination of the diaphragm showed a normal pattern in the control and 1.25-mg/kg prednisolone group. Myogenic changes, however, were found in the 5-mg/kg prednisolone group and, more pronounced, in the triamcinolone group. Selective type IIb fiber atrophy was found in the latter group, but not in the prednisolone groups. In conclusion, triamcinolone induced type IIb fiber atrophy, resulting in reduced respiratory muscle strength and a leftward shift of the force-frequency curve. In contrast, 5 mg/kg prednisolone caused alterations in diaphragmatic contractile properties and histological changes without fiber atrophy.