C.L.A. van Herwaarden

Increased bronchial hyperresponsiveness after inhaling salbutamol during 1 year is not caused by subsensitization to salbutamol

Recently, it was suggested that long-term administration of an inhaled beta 2-agonist might increase bronchial hyperresponsiveness (BHR) to histamine, possibly as a consequence of subsensitization to the inhaled beta 2-agonist. To test this hypothesis, we studied two groups of patients with asthma or with chronic obstructive pulmonary disease. An experimental group of 15 patients, inhaling 400 micrograms of salbutamol four times daily during 1 year and subsequently 40 micrograms of ipratropium bromide four times daily for 6 months, and a control group, consisting of 22 patients with the opposite treatment regimen. The BHR, the response in FEV1 to cumulative doses of salbutamol, and the number of beta 2-adrenoceptors and antagonist affinity of these receptors on circulating lymphocytes were assessed at the start of the study and at 6-month intervals for 1 1/2 years. The BHR increased significantly (p = 0.001) during the year salbutamol was inhaled and returned to about the value at the start of the study after inhaling ipratropium bromide for 6 months. No change occurred in the bronchodilating responses to cumulative doses of salbutamol, nor was any change observed in the number and the affinity of beta 2-adrenoceptors on lymphocytes. It was concluded that long-term use of salbutamol caused a small but significant increase in BHR. The increase in BHR was not caused by subsensitization of beta 2-adrenoceptors to salbutamol.

Long term effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a meta-analysis.

BACKGROUND The role of inhaled corticosteroids in the long term management of chronic obstructive pulmonary disease (COPD) is still unclear. A meta-analysis of the original data sets of the randomised controlled trials published thus far was therefore performed. The main question was: “Are inhaled corticosteroids able to slow down the decline in lung function (FEV1) in COPD?” METHODS A Medline search of papers published between 1983 and 1996 was performed and three studies were selected, two of which were published in full and one in abstract form. Patients with “asthmatic features” were excluded from the original data. Ninety five of the original 140 patients treated with inhaled corticosteroids (81 with 1500 μg beclomethasone daily, six with 1600 μg budesonide daily, and eight with 800 μg beclomethasone daily) and 88 patients treated with placebo (of the initial 144 patients) were included in the analysis. The effect on FEV1 was assessed by a multiple repeated measurement technique in which points of time in the study and treatment effects (inhaled corticosteroids compared with placebo) were investigated. RESULTS No baseline differences were observed (mean age 61 years, mean FEV145% predicted). The estimated two year difference in prebronchodilator FEV1 was +0.034 l/year (95% confidence interval (CI) 0.005 to 0.063) in the inhaled corticosteroid group compared with placebo. The postbronchodilator FEV1 showed a difference of +0.039 l/year (95% CI –0.006 to 0.084). No beneficial effect was observed on the exacerbation rate. Worsening of the disease was the reason for drop out in four patients in the treatment group compared with nine in the placebo group. In the treatment group six of the 95 subjects dropped out because of an adverse effect which may have been related to the treatment compared with two of the 88 patients in the placebo group. CONCLUSIONS This meta-analysis in patients with clearly defined moderately severe COPD showed a beneficial course of FEV1 during two years of treatment with relatively high daily dosages of inhaled corticosteroids.

Underdiagnosis of asthma: is the doctor or the patient to blame? The DIMCA project

BACKGROUND It is important to diagnose asthma at an early stage as early treatment may improve the prognosis in the long term. However, many patients do not present at an early stage of the condition so the physician may have difficulty with the diagnosis. A study was therefore undertaken to compare the proportion of patients who underpresented their respiratory symptoms with the proportion of underdiagnosed cases of asthma by the general practitioner (GP). A secondary aim was to investigate whether bad perception of dyspnoea by the patient was a determining factor in the underpresentation of asthma symptoms to the GP. METHODS A random sample of 1155 adult subjects from the general population in the eastern part of the Netherlands was screened for respiratory symptoms and lung function and the results were compared with the numbers of asthma related consultations registered in the medical files of the GP. In subjects with reduced lung function the ability to perceive dyspnoea was investigated during a histamine provocation test in subjects who did and did not report their symptoms to their GP. RESULTS Of the random sample of 1155 subjects 86 (7%) had objective airflow obstruction (forced expiratory volume in one second (FEV1) below the reference value corrected for age, length, and sex minus 1.64SD on two occasions) and had symptoms suggestive of asthma. Of these 86 subjects only 29 (34%) consulted the GP, which indicates underpresentation by 66% of patients. Of all subjects with objective airflow obstruction who presented to their GP with respiratory symptoms, 23 (79%) were recorded in the medical files as having asthma, indicating underdiagnosis by the GP in 21% of cases. Of the subjects with objective airflow obstruction who visited the GP with respiratory symptoms 6% had bad perception of dyspnoea compared with 26% of those who did not present to the GP in spite of airflow obstruction (χ2 = 3.02, p = 0.08). CONCLUSIONS Underpresentation to GPs of respiratory symptoms by asthmatic patients contributes significantly to the problem of underdiagnosis of asthma. Underdiagnosis by the GP seems to play a smaller role. Furthermore, there are indications that underpresentation of symptoms by the patient is at least partly explained by a worse perception of dyspnoea.

Self-management education for patients with chronic obstructive pulmonary disease: a systematic review

Background: The idea of self-management is to teach patients how to carry out the activities of daily living optimally in the face of their physiological impairment, and to prevent or decrease the severity of exacerbations by means of life style adaptation. In chronic obstructive pulmonary disease (COPD) the value of self-management education is not clear. This review was undertaken to clarify the effectiveness of self-management programmes in COPD. Methods: A search was made of the Cochrane Airways Group trial registers, Medline, reference lists, and abstracts of medical conferences for controlled trials of self-management education in patients with COPD. Two reviewers independently assessed each paper for methodological quality and extracted the data. Results: The reviewers included 12 articles describing eight randomised controlled trials and one controlled clinical trial in which self-management education was compared with usual care. The studies assessed a broad spectrum of outcome measures with different follow up times so meta-analysis could not be undertaken. Self-management education had no effect on hospital admissions, emergency room visits, days lost from work, and lung function. Inconclusive results were observed on health related quality of life, COPD symptoms, and use of healthcare facilities such as doctor and nurse visits. Self-management education reduced the need for rescue medication and led to increased use of courses of oral steroids and antibiotics for respiratory symptoms. Conclusions: Insufficient data were obtained to make recommendations because of the wide variation in outcome measures used and other limitations to generalisations in the current published literature. Further research in this area is needed.

The effects of the inhaled corticosteroid budesonide on lung function and bronchial hyperresponsiveness in adult patients with cystic fibrosis

Bronchial hyperresponsiveness is present in 40-60% of adult patients with cystic fibrosis (CF). Drugs which alter airway hyperresponsiveness have not yet been studied in CF. In this randomized placebo-controlled study, we investigated the effects of an inhaled corticosteroid, budesonide, on lung function and bronchial hyperresponsiveness in adult CF patients, with proven bronchial hyperresponsiveness to histamine. Twelve patients were treated with budesonide, 1600 micrograms day-1, and with placebo during two periods of 6 weeks in a randomized, double-blind, cross-over study. Drug effects were assessed with regard to bronchial hyperresponsiveness to histamine, spirometry and clinical symptom scores. After treatment with budesonide, no significant differences in spirometry were seen, however, bronchial hyperresponsiveness to histamine significantly improved as compared to baseline. Fifty-eight percent of the patients showed at least one doubling-dose increase in PC20 histamine. Daily symptom scores showed small, but statistically significant, improvements in dyspnoea and cough after budesonide treatment. There is increasing evidence suggesting that excessive inflammatory responses contribute to the pulmonary damage that characterizes CF. Treatment with oral corticosteroids improved the clinical course of selected CF patients, but was associated with unacceptable adverse effects. We conclude that daily inhalation of 1600 micrograms day-1 budesonide for 6 weeks induced a small, but significant, improvement in bronchial hyperresponsiveness to histamine, and symptoms of cough and dyspnoea in adult CF patients. Longer observations are needed to establish whether inhaled corticosteroids improve the long term outcome of CF.

Effects of hypercapnia and hypocapnia on respiratory resistance in normal and asthmatic subjects.

The effects of hypercapnia and hypocapnia on respiratory resistance were studied in 15 healthy subjects and 30 asthmatic subjects. Respiratory resistance (impedance) was measured with the pseudo-random noise forced oscillation technique while the subjects rebreathed from a wet spirometer in a closed respiratory circuit in which end tidal carbon dioxide tension (PCO2) could be controlled. Hypercapnia was induced by partially short circuiting the carbon dioxide absorber, and hypocapnia by voluntary hyperventilation. The circulating air was saturated with water vapour and kept at body temperature and ambient pressure. A rise of end tidal PCO2 of 1 kPa caused a significant fall in respiratory resistance in both normal and asthmatic subjects (15% and 9% respectively). A fall of PCO2 of 1 kPa did not cause any significant change in impedance in the control group. In the asthmatic patients resistance increased by 13%, reactance fell by 45%, and the frequency dependence of resistance rose 240%. These findings confirm that hypocapnia may contribute to airway obstruction in asthmatic patients, even when water and heat loss are prevented.

Effects of house dust mite avoidance measures on Der p 1 concentrations and clinical condition of mild adult house dust mite-allergic asthmatic patients, using no inhaled steroids

Exposure to house dust mite (HDM) allergens often results in worsening of asthma. Therefore, avoidance of exposure to HDM allergens is often proposed. Unfortunately, the most effective and feasible avoidance strategy is still not completely assessed. Consequently, we investigated the effects of a combined HDM avoidance strategy on HDM allergen concentrations and clinical condition of allergic, mild asthmatic, patients using no inhaled steroids.

Haemodynamic effects of adrenaline during treatment of hypertensive patients with propranolol and metoprolol.

SummaryA double blind cross-over trial of propranolol and metoprolol was carried out in eight hypertensive patients. At the end of each four-week period of medication, blood pressure and heart rate at rest were measured, and the haemodynamic effects of adrenaline infusion were studied. At rest, propranolol and metroprolol reduced the blood pressure and pulse rate to the same degree. Adrenaline infusion during propranolol medication caused a marked increase both in systolic and diastolic blood pressure, the blood flow in the forearm was unchanged, and the calculated vascular resistance showed a marked increase. Adrenaline infusion during metoprolol medication caused a less marked increase in systolic blood pressure and the diastolic pressure remained unchanged. Blood flow in the forearm increased and the vascular resistance in the forearm tended to decrease. Adrenaline infusion, therefore, caused different haemodynamic effects during non-selective β-blockade with propranolol and during β1-selective blockade with metoprolol. It seems probable that the adrenaline infusion test is comparable with adrenaline release during stress situations and the results may indicate that a β1-selective blocker is to be preferred to a non-selective one as a therapeutic agent in the treatment of hypertension.

The Bronchitis Randomized On NAC Cost-Utility Study (BRONCUS): hypothesis and design. BRONCUS-trial Committee.

Chronic obstructive pulmonary disease (COPD) is an irreversible disorder characterized by airflow obstruction and a progressive decline in forced expiratory volume in one second (FEV1). At present, no treatment except quitting smoking appears to affect the progression of the disease. Oxidative stress has been implicated in its pathogenesis. The Bronchitis Randomized on NAC Cost-Utility Study (BRONCUS) is a phase III, randomized, double-blind, placebo-controlled, parallel group, multicentre study designed to assess the effectiveness of the antioxidant agent N-acetylcysteine (NAC) in altering the decline in FEV1, exacerbation rate, and quality of life in patients with moderate to severe COPD. In addition, cost-utility of the treatment will be estimated. Patients will be followed for 3 yrs and evaluated every 3 months. The necessary sample size to demonstrate an effect on the decline in FEV1 of 20 mL x yr(-1) was estimated to be 478 patients. Five hundred and twenty-three patients with moderate to severe COPD were recruited from 10 European countries from June 1, 1997-December 31, 1999. They were 63+/-8 yrs old and consisted of 243 (46%) current smokers and 280 (54%) exsmokers. Patients had on the average 4.9+/-1.6 exacerbations during the last 2 yrs. Postbronchodilator FEVI averaged 57+/-9% and the reversibility after 400 microg of Salbutamol averaged 4+/-4% predicted. The final results of the trial will be available in about 2 yrs. The study will provide objective data on the effects of N-acetylcysteine on outcome variables in chronic obstructive pulmonary disease.

Compliance During Long-Term Treatment with Fluticasone Propionate in Subjects with Early Signs of Asthma or Chronic Obstructive Pulmonary Disease (COPD): Results of the Detection, Intervention, and Monitoring Program of COPD and Asthma (DIMCA) Study

In a prospective study, we investigated the long-term compliance to fluticasone propionate (FP) by dry powder inhalation (Rotadisk®) in subjects with early signs of asthma and chronic obstructive pulmonary disease (COPD) without an established diagnosis. Subjects were selected from a large screening program on early stages of asthma and COPD (Detection, Intervention, and Monitoring Program of COPD and Asthma [DIMCA] program) in the general practice. Forty-eight adult subjects with “early signs of COPD” (slightly increased forced expiratory volume in 1 sec [FEV1] decline of >0.04L/year) and 29 adult subjects with “early signs of asthma” (signs of bronchial hyperresponsiveness or reversibility) participated in a randomized placebo-controlled trial with FP (Flixotide® 500 jag daily) versus placebo with a duration of 2 years or 1 year, respectively. Compliance was measured by counting Rotadisks returned. By means of a questionnaire, participants were asked about perceived effects and/or side effects of the trial drug. The mean overall individual compliance rates of 72% (range 7%-102%) in the early COPD trial and 71% (range 8%-99%) in the early asthma trial were maintained throughout the study. Perceived effectiveness (12% of the participants) or side effects (30% of the participants) of the trial drug were not related to compliance. The willingness of patients to use the trial drug in daily practice if efficacy would be proved was statistically significantly related to compliance during the trial (p = 0.017). It was concluded that the compliance rates found were relatively high in patients with symptoms of mild asthma or COPD without an established diagnosis. Conviction of the importance of treatment influenced compliance more positively than perceived (side) effects. These results again emphasize the importance of patient education in establishing early treatment with inhaled corticosteroids.