Cees van Herwaarden

Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (bronchitis randomized on NAC cost-utility study, BRONCUS) : a randomised placebo- controlled trial

BACKGROUND Increased oxidative stress is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). We postulated that treatment with the antioxidant N-acetylcysteine would reduce the rate of lung-function decline, reduce yearly exacerbation rate, and improve outcomes. METHODS In a randomised placebo-controlled study in 50 centres, 523 patients with COPD were randomly assigned to 600 mg daily N-acetylcysteine or placebo. Patients were followed for 3 years. Primary outcomes were yearly reduction in forced expiratory volume in 1 s (FEV1) and the number of exacerbations per year. Analysis was by intention to treat. FINDINGS The yearly rate of decline in FEV1 did not differ between patients assigned N-acetylcysteine and those assigned placebo (54 mL [SE 6] vs 47 mL [6]; difference in slope between groups 8 mL [9]; 95% CI -25 to 10). The number of exacerbations per year did not differ between groups (1.25 [SD 1.35] vs 1.29 [SD 1.46]; hazard ratio 0.99 [95% CI 0.89-1.10, p=0.85]). Subgroup analysis suggested that the exacerbation rate might be reduced with N acetylcysteine in patients not treated with inhaled corticosteroids and secondary analysis was suggestive of an effect on hyperinflation. INTERPRETATION N-acetylcysteine is ineffective at prevention of deterioration in lung function and prevention of exacerbations in patients with COPD.

Slowing the Deterioration of Asthma and Chronic Obstructive Pulmonary Disease Observed during Bronchodilator Therapy by Adding Inhaled Corticosteroids: A 4-Year Prospective Study

Rates of morbidity and mortality due to asthma and chronic obstructive pulmonary disease (COPD) have increased during the last two decades [1, 2]. These increases might be related to the use of bronchodilator therapy without anti-inflammatory medication [3, 4]. Recently, two studies found that regular bronchodilator treatment had adverse effects on the control of asthma [5] and the progression of asthma and COPD [6]. In a previous study of 160 patients with asthma or COPD [6], we found that continuous treatment with a bronchodilator (ipratropium bromide, 40 g, or salbutamol, 400 g, four times daily) was associated with a much higher annual decline in the forced expiratory volume in 1 second (FEV1) compared with treatment on demand. It is unclear whether an unfavorable course of asthma or COPD during bronchodilator therapy alone can be reversed or decelerated by additional anti-inflammatory therapy with inhaled corticosteroids. We studied 56 of the 160 patients who had an unfavorable disease course during bronchodilator therapy alone (an annual decline in FEV1 of at least 80 mL/y in combination with at least two exacerbations per year). These 56 patients (28 with asthma and 28 with COPD) were also treated with an inhaled corticosteroid (beclomethasone dipropionate, 800 g daily) during years 3 and 4 of the study. We assessed whether the worsening of their disease during bronchodilator therapy alone was reversed or decelerated by additional anti-inflammatory treatment with beclomethasone. The outcome measures were dynamic lung function indices (annual decline in pre- and postbronchodilator FEV1, peak expiratory flow rate [PEFR], and forced inspiratory volume in 1 second [FIV1]), static lung function indices (residual volume [RV], ratio of residual volume to total lung capacity (RV/TLC), inspiratory vital capacity [IVC]), nonspecific bronchial responsiveness (assessed by determining the concentration of histamine that provokes a 20% decrease in FEV1 [Pc 20]), exacerbations, and respiratory symptoms. Methods Patients Patient selection has been previously described [6]. In short, 29 family physicians in the catchment area of the University of Nijmegen, Nijmegen, the Netherlands, selected all patients who were 30 years or older and had symptoms of asthma or COPD. Only patients who showed mild-to-moderate airway obstruction (FEV1 > 50% of the predicted value [7]) or bronchial hyper-responsiveness to histamine (Pc 20 8 mg/mL) were included in the study. Patients dependent on inhaled corticosteroids who had chronic heart failure, malignant disorders, or other severe life-threatening diseases were excluded from the study. Of these patients, 160 (59 with asthma and 101 with COPD) completed the bronchodilator trial. During the 2 years of bronchodilator treatment, a rapid decline in FEV1 ( 80 mL/y) and a relatively high exacerbation rate ( 1/y) were observed in a subgroup of 56 patients (35%). Because of their unfavorable disease course, these patients were selected for additional treatment with inhaled beclomethasone for 2 years. The criteria for diagnosis of asthma or COPD were based on the standards of the American Thoracic Society [8]. Asthma was defined [6, 8] by a combination of factors: bronchial hyper-responsiveness to histamine (Pc 20 8 mg/mL); reversible obstruction (an improvement in FEV1 of more than 15% of the prebronchodilator value 60 minutes after the administration of both salbutamol, 400 g, and ipratropium bromide, 80 g); dyspnea; and allergy (defined as at least one positive result on seven radioallergosorbent tests that assessed sensitivity to pollen from weeds, grasses, and trees; cats and dogs; house dust mite; and Aspergillus fumigatus) or wheezing. Chronic obstructive pulmonary disease was defined [6, 8] by the combination of chronic cough or chronic sputum production for at least 3 months during at least 2 consecutive years; and continuous bronchus obstruction (FEV1 85% of the predicted value). The separate features of asthma and COPD overlap (for instance, some asthmatic patients had chronic cough, and some COPD patients had a Pc 20 8 mg/mL), but the definitions based on feature combinations ensured that no patients with asthma also had COPD and vice versa [6]. The study was approved by the Medical Ethics Committee of the University of Nijmegen. All patients gave informed consent. Study Design and Treatment At the start of the 4-year intervention study, the patients were randomly assigned to one of two parallel treatment regimens: continuous bronchodilator therapy (four times daily) or treatment on demand (dry powder inhalations during symptomatic periods) [6]. The patients used salbutamol, 400 g, during 1 year and ipratropium bromide, 40 g, during the other year; both were administered as dry powder inhalations. The sequence of the drugs was determined by random allocation. During years 3 and 4, the 56 patients received 400 g of beclomethasone, two times daily, in combination with 400 g of salbutamol or 40 g of ipratropium bromide, four times daily (all dry powder inhalations). The bronchodilator inhaled during year 2 was also used in years 3 and 4. During the first 2 years of the study, 27 of the 56 patients received bronchodilator therapy on demand (of the 27, 15 had asthma and 12 had COPD). For patients treated on demand, the mean (SE) daily number of dry powder inhalations of salbutamol or ipratropium bromide was 1.2 0.3 in those with asthma and 0.8 0.2 in those with COPD. During years 3 and 4, 28 patients received salbutamol (15 with asthma and 13 with COPD) and 28 received ipratropium bromide (13 with asthma and 15 with COPD). Once every 3 months, inhalation technique and compliance with the prescribed medication were checked. Patients were instructed to rinse their mouths after the dry powder inhalations. During the second year of beclomethasone therapy, a single-blind prospective study was done to assess patient compliance with beclomethasone and the additional bronchodilator. Compliance was measured by counting capsules at the end of a 4-month period. Patients were unaware that their medication was counted after this period. Lung Function, Nonspecific Bronchial Responsiveness, and Reversibility All measurements were carried out by two qualified laboratory assistants during exacerbation-free periods. No bronchodilator was inhaled for at least 8 hours before the pulmonary function tests. At the start and after 24 and 48 months of the study, the inspiratory vital capacity (IVC), residual volume (RV), functional residual capacity (FRC), and total lung capacity (TLC) were assessed using the wet Gould spirometer (Sensormedics, Bilthoven, the Netherlands) according to the standards of the European Coal and Steel Community [7]. The FEV1, bronchial responsiveness to histamine, and the reversibility of airway obstruction were assessed at 6-month intervals using the Microspiro HI-298 (Chest Corporation, Tokyo, Japan) [9]. Moreover, FEV1 and reversibility were also assessed after 1 and 13 months of study [6]. The best of three forced expiratory maneuvers, with the highest sum of the forced vital capacity (FVC) and FEV1, was used for data analysis. The bronchial responsiveness to histamine was measured according to the method described by Cockcroft and colleagues [10]. Results were expressed as the concentration of histamine that provoked a 20% decrease in FEV1 (Pc 20). After the FEV1 had returned to the baseline value, the bronchodilating response (reversibility) was assessed 60 minutes after the administration of both 80 g of ipratropium bromide and 400 g of salbutamol (metered dose aerosol) [6]. The bronchodilating response was expressed as the increase in FEV1 relative to the predicted value of the FEV1. Peak Expiratory Flow Assessments Once a week (on the same day and at the same time), peak expiratory flow rate (PEFR) was measured with the Assess peak flow meter (HealthScan Products, Cedar Grove, New Jersey) [11] in the morning and in the evening. The highest value of three measurements was included in the analysis. The diurnal PEFR index (absolute difference between the evening value and the morning value divided by the highest value) was calculated. Exacerbations Our definition of exacerbation was based on that of Fletcher as modified by Boman and colleagues [12]. When an exacerbation occurred, a 10-day course of oral prednisone was administered. Patients received 25 mg for 2 days, 20 mg for 2 days, 15 mg for 2 days, and so forth. Symptoms and Adverse Effects Using a scale of 0 to 4, all patients recorded, on a weekly basis, the presence and severity of symptoms (cough, phlegm, dyspnea, fatigue, disturbed sleep at night). The adverse effects of medication (dysphonia and oropharyngeal irritation) were recorded by the patients once every 3 months. Moreover, every 6 months, the presence and severity of oral candidiasis were assessed using a questionnaire (no, light, or severe symptoms). Smoking At the start of the study, smoking history was assessed in pack-years. During the study, the average number of cigarettes smoked per day was also recorded in weekly diary entries. Power Calculations Assuming that the clinically relevant, decreased annual decline in FEV1 during beclomethasone treatment is 25 mL/y and that the residual standard deviation is 50 mL/y, the coefficient of variation is 25/50 or 0.5. Based on an of 0.05 and a of 0.20 (power:1 0.2, or 0.8), the required number of patients for the study would be 51. Based on an estimated dropout rate of 10%, the required initial number of study patients would be 56. Statistical Analysis Data on outcome variables obtained before and during beclomethasone therapy were compared. Differences were tested by repeated-measures analysis of variance, the paired Student t-test for normally distributed variables, and the Wilcoxon paired signed-rank test for non-normally distributed variables. Before the analysis, the Pc 20 values were 2log transformed. The an

Xanthine oxidase is involved in exercise-induced oxidative stress in chronic obstructive pulmonary disease

In the present study, we hypothesized that exhaustive exercise in patients with chronic obstructive pulmonary disease (COPD) results in glutathione oxidation and lipid peroxidation and that xanthine oxidase (XO) contributes to free radical generation during exercise. COPD patients performed incremental cycle ergometry until exhaustion with (n = 8) or without (n = 8) prior treatment with allopurinol, an XO inhibitor. Reduced (GSH) and oxidized glutathione (GSSG) and lipid peroxides [malondialdehyde (MDA)] were measured in arterial blood. In nontreated COPD patients, maximal exercise (approximately 75 W) resulted in a significant increase in the GSSG-to-GSH ratio (4. 6 +/- 0.9% at rest vs. 9.3 +/- 1.7% after exercise). In nontreated patients, MDA increased from 0.68 +/- 0.08 nmol/ml at rest up to 1. 32 +/- 0.13 nmol/ml 60 min after cessation of exercise. In contrast, in patients treated with allopurinol, GSSG-to-GSH ratio did not increase in response to exercise (5.0 +/- 1.2% preexercise vs. 4.6 +/- 1.1% after exercise). Plasma lipid peroxide formation was also inhibited by allopurinol pretreatment (0.72 +/- 0.15 nmol/ml preexercise vs. 0.64 +/- 0.09 nmol/ml 60 min after exercise). We conclude that strenuous exercise in COPD patients results in blood glutathione oxidation and lipid peroxidation. This can be inhibited by treatment with allopurinol, indicating that XO is an important source for free radical generation during exercise in COPD.In the present study, we hypothesized that exhaustive exercise in patients with chronic obstructive pulmonary disease (COPD) results in glutathione oxidation and lipid peroxidation and that xanthine oxidase (XO) contributes to free radical generation during exercise. COPD patients performed incremental cycle ergometry until exhaustion with ( n = 8) or without ( n = 8) prior treatment with allopurinol, an XO inhibitor. Reduced (GSH) and oxidized glutathione (GSSG) and lipid peroxides [malondialdehyde (MDA)] were measured in arterial blood. In nontreated COPD patients, maximal exercise (∼75 W) resulted in a significant increase in the GSSG-to-GSH ratio (4.6 ± 0.9% at rest vs. 9.3 ± 1.7% after exercise). In nontreated patients, MDA increased from 0.68 ± 0.08 nmol/ml at rest up to 1.32 ± 0.13 nmol/ml 60 min after cessation of exercise. In contrast, in patients treated with allopurinol, GSSG-to-GSH ratio did not increase in response to exercise (5.0 ± 1.2% preexercise vs. 4.6 ± 1.1% after exercise). Plasma lipid peroxide formation was also inhibited by allopurinol pretreatment (0.72 ± 0.15 nmol/ml preexercise vs. 0.64 ± 0.09 nmol/ml 60 min after exercise). We conclude that strenuous exercise in COPD patients results in blood glutathione oxidation and lipid peroxidation. This can be inhibited by treatment with allopurinol, indicating that XO is an important source for free radical generation during exercise in COPD.

Morphological quantification of emphysema in small human lung specimens: Comparison of methods and relation with clinical data

Small human lung specimens are frequently used for cell biological studies of the pathogenesis of emphysema. In general, lung function and other clinical parameters are used to establish the presence and severity of emphysema/chronic obstructive pulmonary disease without morphological analysis of the specimens under investigation. In this study we compared three morphological methods to analyze emphysema, and evaluated whether clinical data correlate with the morphological data of individual lung samples. A total of 306 lung specimens from resected lung(lobes) from 221 patients were inflated and characterized using three morphological parameters: the Destructive Index, the Mean Linear Intercept, and Section Assessment. Morphological data were related to each other, to lung function data, and to smoking behavior. Significant correlations (P < .001) were observed between Section Assessment and Destructive Index (r = 0.92), Mean Linear Intercept with Destructive Index (r = 0.69) and Mean Linear Intercept with Section Assessment (r = 0.65). Section Assessment, being much less time consuming than Mean Linear Intercept and Destructive Index, is the parameter of choice for initial analysis. Destructive Index is the most sensitive parameter. There was a significant (P < .001), but weak correlation for all three parameters with the diffusion capacity for CO (KCO) (Destructive Index: r = −0.28; Mean Linear Intercept: r = −0.34; Section Assessment: r = −0.32), and with FEV1/IVC (Destructive Index: r = −0.29; Mean Linear Intercept: r = −0.33; Section Assessment: r = −0.28), but not with other lung function parameters. A significant difference (P < .05) between (ex-) smokers and never-smokers was observed for Destructive Index and Section Assessment. It is concluded that the application of the three morphological parameters represents a useful method to characterize emphysematous lesions in a (semi-)quantitative manner in small human lung specimens, and that Section Assessment is a suitable and fast method for initial screening. The extent of emphysema of individual lung specimens should be established by means of morphometry, rather than lung function data.

Clinical predictors of bacterial involvement in exacerbations of chronic obstructive pulmonary disease.

BACKGROUND The wide use of antibiotics for treatment of exacerbations of chronic obstructive pulmonary disease (COPD) lacks evidence. The efficacy is debatable, and bacterial involvement in exacerbation is difficult to verify. The aim of this prospective study was to identify factors that can help to estimate the probability that a microorganism is involved in exacerbation of COPD and, therefore, predict the success of antibiotic treatment. METHODS Clinical data and sputum samples were obtained from 116 patients during exacerbation of COPD. Bacterial infection was defined by the abundant presence of >or=1 potential pathological microorganism in relation to the normal flora in sputum. RESULTS Of 116 exacerbations, 22 (19%) had bacterial involvement. The combination of a negative result of a sputum Gram stain, a relevant nonclinical decrease in lung function (compared with baseline measurements), and occurrence of <2 exacerbations in the previous year were 100% predictive of a nonbacterial origin of the exacerbation. The presence of all 3 of these clinical characteristics yielded a positive predictive value of 67% for a bacterial exacerbation. CONCLUSIONS Patients presenting with an exacerbation who have a negative result of sputum Gram stain, do not have a clinically relevant decrease in lung function, and have experienced <2 exacerbations of COPD in the previous year do not require antibiotic treatment [corrected]. A treatment protocol taking into account these variables might lead to a 5%-24% reduction in unnecessary treatment with antibiotics, depending on actual prescription rates.

A pulmonary rehabilitation program for patients with asthma and mild chronic obstructive pulmonary diseases (COPD)

The effects of a pulmonary rehabilitation program on 44 patients with chronic obstructive pulmonary disease (COPD) were compared to a control group. The treated group was admitted to the program for a period of three months. The program consisted of several parts, such as physical training, health education, and psychological and social matters. Before participation, the patients were thoroughly examined and provided with optimal medical treatment. Both groups were assessed by means of biometrical tests and questionnaires for a period of 2 years. The rehabilitation group improved significantly in endurance, psychological parameters, and consumption of medical care. Working days increased and their way of life became more active. Smoking habits and body fat percentage decreased. Bronchial hyperreactivity, need for pulmonary drugs, and coughing and sputum production did not improve in the rehabilitation group compared to the control group. Airway obstruction, expressed as forced expiratory volume in one second, and complaints of dyspnea, allergy and hyperreactivity scores on questionnaires improved only in the short term (<1 year), but did not improve significantly in the long term. This study shows that pulmonary rehabilitation can result in improvements in patients with asthma or COPD who have many complaints despite the fact that their pulmonary function is not severely disturbed.

Behavioural effect of self-treatment guidelines in a self-management program for adults with asthma.

To assess the efficacy of self-management programs it is important to know what behavioural changes take place. This paper assesses whether including self-treatment guidelines (action plans) in a self-management program for adult asthmatics, leads to greater behavioural changes than a program without these guidelines. Patients were randomised into a self-treatment group (n=123) or an active control group (n=122). All subjects received self-management training. Discussed topics included the pathophysiology of asthma, medication and side-effects, triggers, symptoms, smoking, physical exercise, and compliance. The only difference was that the self-treatment group received instructions about self-treatment of exacerbations and the control group did not. At 1 year of follow-up asthma-specific self-efficacy expectancies, outcome expectancies, and asthma-specific knowledge improved significantly in all patients. Only self-treatment group patients demonstrated favourable changes in generalised self-efficacy, social support, and self-treatment and self-management behaviour, in case of a hypothetical scenario of a slow-onset exacerbation. We conclude that our self-management program is effective in changing the behavioural variables, and including self-treatment guidelines (action plans) has added benefit.

Management of stable COPD.

Chronic obstructive pulmonary disease (COPD) is a systemic disease with major impact worldwide. In the treatment of COPD a holistic approach should be taken. In order to reach this, an individual treatment plan should be made which includes at least elements of smoking cessation, optimisation of pulmonary status by pharmacotherapy and exercise embedded in a new lifestyle. Furthermore, more research on nutritional and metabolic intervention strategies for COPD patients is needed. With the availability of all these treatment options, a nihilistic attitude toward the patient with COPD is no longer justified.

Late asthmatic responses after exercise challenge are reproducible

In this study the reproducibility of a late asthmatic reaction (LAR) after exercise challenge (EC) has been documented. Eighty-three hospitalized patients with asthma were challenged with exercise. The patients were examined according to a standardized protocol that comprised 8 minutes of bicycling at 90% of predicted heart rate. An LAR after EC was considered to have occurred when there was a fall in peak expiratory flow rate greater than or equal to 20% on three or more time points on the exercise day compared to corresponding clock time on a control day. According to these criteria, 11 patients (13.3%) experienced an LAR. Those patients were rechallenged 21 to 150 days after the first EC, without changing the therapy regimen of the patients, to study its reproducibility. Eight patients (73%) demonstrated a reproducible LAR after EC based on the criteria for a positive LAR. Although the LAR after EC was reproducible, the time points at which the LAR took place after the second EC differed from LARs after the first EC. Our results indicate that the LAR after EC occurs in a considerable number of patients with bronchial asthma and is quite reproducible.

Visual attention in patients with chronic obstructive pulmonary disease.

The selective visual attention of 39 patients with chronic obstructive pulmonary disease (COPD) was measured by the Bourdon-Vos test and compared with the attention performance of 38 healthy controls of the same age range. The correlation between the attention of the COPD patients and day- and night-time parameters was determined. Furthermore, in 44 other COPD patients with daytime hypoxaemia, the effect of one night of oxygen supplementation and of a 7-day treatment with two respiratory stimulants (chlormadinone acetate) (CMA) or acetazolamide (ACET) on attention performance was studied. The results showed that the attention performance of COPD patients was lower than that of controls. Significant correlations were found between the mean line time (attention parameter) and the following parameters: age, inspiratory vital capacity (IVC), hypercapnic ventilatory response (HCVR), daytime arterial oxygen saturation (SaO2), daytime arterial oxygen pressure (PaO2), daytime arterial carbon dioxide pressure (PaCO2), mean nocturnal SaO2, lowest nocturnal SaO2 and the standard deviation of the mean nocturnal SaO2. Multiple linear regression analysis showed that, apart from age, only the nadir of the nocturnal SaO2 contributed to the prediction of the attention. No clinically important short-term effect of oxygen or respiratory stimulating therapy on the attention performance was found.