Inappropriate use of inhaled beta agonists in asthma.
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Biomedical subjects
Publications and source records attributed to R Beasley.
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Inhalation of nebulised water can provoke bronchoconstriction in asthmatic patients. In the first part of this study, a community survey identified that about 20% of patients with home nebulisers currently use water as a diluent. In the second part of this study, the airways effect of the use of water as a diluent for nebulised beta agonist was investigated. Nineteen asthmatic subjects were administered nebulised 2.5 mg salbutamol, diluted with either 2 mL water or physiological saline, and forced expiratory volume in one second (FEV1) was measured at baseline and at regular intervals for 45 minutes after nebulisation. Although there was a trend towards a reduced bronchodilator response with water as diluent, the differences between the two diluents were not significantly different. Paradoxical bronchoconstriction was not observed when salbutamol was diluted with water. We conclude that the common practice of diluting bronchodilator nebuliser solution with water does not result in a significant reduction in the overall bronchodilator response.
In this double blind study, the cardiovascular and hypokalaemic effects of equal doses of inhaled pirbuterol and salbutamol were compared in eight healthy volunteers. Increasing doses of 200, 400, 600 and 800 micrograms (total dose 2000 micrograms) were given from a metered dose inhaler at 15 min intervals, followed by measurement of heart rate, blood pressure, total electromechanical systole (QS2I) (as a measure of inotropic response) and plasma potassium (K+) concentration 15 min after each inhalation. After inhalation of the highest concentration, salbutamol resulted in a greater increase in heart rate (10.5 bpm vs 4.4 bpm, p less than 0.0007), and reduction in QS2I (-25.4 ms vs -9.6 ms, p less than 0.0001) than pirbuterol. There were no significant differences in changes in systolic blood pressure (1.9 mmHg vs 6 mmHg, p = 0.27), diastolic blood pressure (-5.8 mmHg vs -3.9 mmHg, p = 0.64) or plasma K+ (-0.21 mmol/L vs -0.15 mmol/L, p = 0.57). We conclude that the new beta-2 adrenergic agonist pirbuterol is at least as beta-2 selective as salbutamol when administered by repeated inhalation in healthy volunteers.
Trends in mortality from asthma in non-Maori New Zealanders aged 5 to 34 years were examined for the period 1908-1986. Two previously documented epidemics of death from asthma occurred in the 1960s and the late 1970s. These epidemics are most likely to have been due to changes in the management of asthma: the introduction of isoprenaline forte by metered dose inhaler in the 1960s and inhaled fenoterol in the 1970s. A previously unreported rise in mortality, which was more gradual in onset and less severe, occurred in the 1940s and 1950s; a similar pattern occurred in England and Wales during the same period. It is unlikely that this increase in mortality was solely due to changes in diagnostic fashion or disease coding. Possible explanations include changes in the management or prevalence of asthma, or in environmental factors. It is notable that mortality was below 0.5 per 100,000 person-years prior to 1940, but has subsequently increased considerably. Thus, while modern methods for treating asthma have improved the quality of life of many asthmatics, mortality has increased during the period of their introduction and use.
Interviews were conducted with 101 consecutive adult patients admitted to Wellington Hospital with a diagnosis of asthma to assess the extent to which beta agonist drugs are self-administered by asthmatic patients during severe asthma. The 99 patients prescribed an inhaled beta agonist were subdivided into two groups: group A comprising 79 patients prescribed a beta agonist for inhalation via an inhaler (metered dose aerosol or dry powder device) alone; group B comprising 20 patients prescribed beta agonist for inhalation via both an inhaler and nebuliser. In group A, the attacks of asthma lasted greater than 24 hours in 64/79 patients, and 22% of these patients reported taking more than 60 doses of their inhaler, and 52% more than 30 doses during the 24 hr period prior to admission. In group B, the attacks of asthma lasted greater than 24 h in 17/20 patients, and 35% of these patients self-administered their nebuliser more than six times, and 76% more than four times during the 24 h period prior to admission. In addition to their nebuliser use, these patients also took a median 23 doses of their inhaler during this 24 h period. This use of inhaled beta agonist contrasts with the recommended practice in both the USA and Europe, where most physicians recommend no more than 15 doses of a beta agonist as the maximal dose per day. We conclude that asthmatic patients in New Zealand self-administer high doses of inhaled beta 2 agonist drugs during severe exacerbations of asthma.
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The cardiovascular, respiratory, and hypokalemic effects of repeated inhalation of fenoterol, albuterol, and isoproterenol were compared in 12 subjects with stable asthma according to a double-blind, crossover design. Ipratropium bromide served as a control providing bronchodilatation without extrapulmonary effects. Subjects inhaled the beta-agonists on an equal-weight basis (400 micrograms) at 0, 30, 40, and 45 minutes. Measurements of heart rate, blood pressure, total electromechanical systole (measure of inotropic activity), preejection period, QTc interval, plasma potassium levels, and forced expiratory volume in 1 second were made 5 minutes after each dose and again at 60 and 75 minutes. There were no differences in the bronchodilating effect between the beta-agonists. However, both fenoterol and isoproterenol resulted in greater positive inotropic stimulation than did albuterol, and fenoterol caused a greater fall in plasma potassium levels than did the other beta-agonists.
The cardiovascular effects of equal doses (5 mg) of nebulised fenoterol, salbutamol and terbutaline were compared in 12 healthy individuals in a double-blind, placebo-controlled study. Measurements of heart rate, blood pressure, systolic time intervals, QTc interval and T-wave amplitude were made at baseline and at 15, 30, 45, 60 and 90 minutes after nebulisation. Fenoterol caused significantly greater chronotropic electrocardiographic and inotropic effects than either salbutamol or terbutaline. The peak effects after terbutaline occurred later than those after fenoterol or salbutamol.
Selenium is an essential component of glutathione peroxidase, an enzyme that helps protect cells against oxidation damage and modulates the lipoxygenase pathway of arachidonic acid metabolism. Low selenium concentrations might therefore influence the inflammatory process in asthma by reducing the activity of glutathione peroxidase. Whole blood and plasma selenium concentrations and glutathione peroxidase activity have been measured in 56 asthmatic patients and 59 non-asthmatic control subjects in New Zealand, a country with a low dietary selenium intake and a high prevalence of asthma. When compared with control subjects the asthmatic patients had lower values for whole blood selenium concentrations (-4.9, 95% confidence interval -10.2 to 0.4 ng/ml) and glutathione peroxidase activity (-3.3, 95% CI -5.8 to -0.8 units/g Hb). There was a 1.9 and 5.8 fold increased risk of asthma in subjects with the lowest range of whole blood selenium concentration and glutathione peroxidase activity respectively (95% CI 0.6 to 5.6 and 1.6 to 21.2). Levels were lower in patients and control subjects without an atopic predisposition, but were not affected by prednisone use. Similar differences between the asthmatic and control subjects were not observed for selenium concentration or glutathione peroxidase activity measured in plasma, which reflects short term rather than long term selenium content. These findings are consistent with the hypothesis that low selenium concentrations may have a role in the pathogenesis of asthma in New Zealand.
A previous New Zealand case-control study of asthma deaths in the 5-45 year age group during 1981-3 found that prescription of fenoterol (by metered dose inhaler) was associated with an increased risk of death in patients with severe asthma. One major criticism of this study was that drug data for the cases and controls came from different sources. A new case-control design has been used to evaluate the same hypothesis, with a different set of asthma deaths, the same source for drug information being used for both cases and controls. This depended on identifying deaths from asthma during 1977-81 from national mortality records, and ascertaining which patients from those who died had been admitted to a major hospital for asthma during the 12 months before death. The study was confined to this subgroup, which accounted for about 20% of all asthma deaths in the areas served by a major hospital. For each of the eligible patients who died four age matched controls were selected from patients admitted to hospital for asthma during the year that the death occurred who had also had an admission for asthma in the previous 12 months. For the 58 cases and 227 control subjects information on prescribed drugs was collected from the hospital records relating to the previous admission. The odds ratio of asthma death in patients prescribed inhaled fenoterol was 1.99 (95% confidence interval 1.12-3.55, p = 0.02). As in the previous study, subgroups defined by markers of chronic asthma severity were also considered. The inhaled fenoterol odds ratio was 2.98 (95% CI 1.15-7.70, p = 0.02) in patients prescribed three or more categories of asthma drugs, 3.91 (95% CI 1.79-8.54, p less than 0.01) in patients with a previous admission for asthma in the past 12 months, and 5.83 (95% CI 1.62-21.0, p = 0.01) in patients prescribed oral corticosteroids at the time of admission. In patients with the most severe asthma (defined by a previous admission for asthma during the past 12 months and prescribed oral corticosteroids at time of admission) the inhaled fenoterol odds ratio was 9.82 (95% CI 2.23-43.4, p less than 0.01). These findings add further support to the hypothesis that inhaled fenoterol increases the risk of death in patients with severe asthma.
A standardised management protocol has been developed for the assessment and treatment of adults with acute asthma attending an emergency department. The management protocol consists of an assessment sheet for recording essential features of the history and examination findings and a flow diagram with guidelines for initial management that were based on spirometric recordings. The protocol was introduced at Wellington Hospital in 1986. The effect of this intervention was assessed by analysing emergency department records during the three months before and one year after the introduction of the protocol. The use of the assessment sheet improved history taking and led to the increased use of serial measures of airflow obstruction and improved documentation of follow up arrangements. The provision of management guidelines influenced the emphasis of management, including an increased use of corticosteroids intravenously and more frequent use of an additional dose of nebulised bronchodilator. In the light of the initial experience the protocol has been modified and its use either in an emergency department or in general practice is recommended.
Chlorbutol is an antibacterial and antifungal agent incorporated in terbutaline (Bricanyl) nebulizer solution. Ten stable atopic asthmatic subjects undertook bronchial challenge testing, according to a double-blind protocol. Patients inhaled doubling concentrations of either methacholine (0.13-4.0 mg.ml-1) or chlorbutol (0.16-5.0 mg.ml-1) for 2 min until the forced expiratory volume in one second (FEV1) had fallen by 20% from baseline. If this had not occurred following the administration of the final concentration, then this highest concentration was repeated for 4 min. The nine subjects completing the study had a geometric mean provocation concentration producing a 20% fall from baseline FEV1 (PC20) methacholine of 0.16 mg.ml-1 (range less than 0.125-0.475 mg.ml-1). After inhalation of 2.5 mg.ml-1 chlorbutol one subject experienced a fall in FEV1 greater than 20%. In the remaining eight subjects, inhalation of chlorbutol did not affect airway calibre. We conclude that chlorbutol, in the concentration present in Bricanyl nebulizer solution, has no clinically significant effect on airway calibre.
We reviewed the medical assessment and treatment of 108 consecutive adult asthmatic patients who attended the Wellington Hospital emergency department for treatment of asthma. Almost 90% of these patients were self referred. Systemic corticosteroids were administered or increased in dose during this asthma attack in only 14% of the 93 patients in whom prior drug therapy was recorded. In the emergency department measurement of either peak expiratory flow or forced expiratory volume in one second was made before treatment in 89% of patients, and after treatment in 77%. About 50% received systemic corticosteroids during their attendance, and of the 66 who were subsequently discharged, 40% were prescribed oral prednisone. Communication with general practitioners concerning patients discharged was poor. We conclude that although the medical assessment and management of severe asthma in this emergency department was of a high standard, there were problems relating to the increased reliance by asthmatic patients on this hospital based service.
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