Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial.

BACKGROUND: Asthma self-management plans that include doubling the dose of inhaled corticosteroid when the condition deteriorates improve asthma control. Whether doubling the dose of corticosteroid in isolation is effective is unknown. We undertook a randomised controlled trial to investigate the effects of doubling the dose of inhaled corticosteriods when asthma deteriorates. METHODS: 390 individuals with asthma who were at risk of an exacerbation monitored their morning peak flow and asthma symptoms for up to 12 months. When peak flow or symptoms started to deteriorate, participants added an active or placebo corticosteroid inhaler to their usual corticosteroid for 14 days to produce a doubling or no change in dose. The primary outcome was the number of individuals starting oral prednisolone in each group. FINDINGS: During 12 months, 207 (53%) started their study inhaler and 46 (12%) started prednisolone--22 (11%) of 192 and 24 (12%) of 198 in the active and placebo groups, respectively. The risk ratio for starting prednisolone was therefore 0.95 (95% CI 0.55-1.64, p=0.8). INTERPRETATION: We recorded little evidence to support the widely recommended intervention of doubling the dose of inhaled corticosteroid when asthma control starts to deteriorate.

Use of sequential quadrupling dose regimens to study efficacy of inhaled corticosteroids in asthma.

BACKGROUND: Inhaled corticosteroids are widely used to treat asthma. There is a need to be able to compare different inhaled corticosteroids and different doses of an inhaled corticosteroid to determine potency and dose equivalence, but measuring efficacy in a dose related manner is difficult because of their slow onset of action. There is uncertainty about the role of sequential dosing regimens and the best end point for such studies. We have explored the use of sequential quadrupling dose regimens and a range of end points to assess the response to budesonide in subjects with asthma. METHODS: 21 subjects with mild asthma, aged 18-65, took part in a randomised three way crossover study comparing two sequential and one non-sequential regimen, separated by at least 3 weeks. The sequential regimens consisted of increasing doses of inhaled budesonide (100, 400 1600 microg/day) with each dose being given for 1 or 2 weeks; the non-sequential regimen consisted of 1600 microg/day for 2 weeks with end points measured after 1 and 2 weeks. The end points studied included the provocative dose of adenosine monophosphate causing a 20% fall in forced expiratory volume in 1 second (PD20AMP), lung function, symptoms, and bronchodilator use. RESULTS: There was a dose related increase in PD20AMP with both sequential dose regimens. The increase in PD20AMP ranged from 1.49 doubling doses (DD) following the lowest dose (100 microg/day) to 3.1 DD following the highest dose (1600 microg/day) in the 1 week sequential regimen and from 1.98 to 4.03 DD in the 2 week sequential regimen; standard deviations (SD) for the changes in PD20AMP ranged from 1.3 to 2.6 DD. Changes in forced expiratory volume in 1 second (FEV1) and morning peak expiratory flow rate (PEFR) were dose related but small and more variable (maximum change in FEV1=148 ml, SD 228 ml), while changes in evening PEFR, symptoms, and bronchodilator use were small and not dose related. Change in PD20AMP after budesonide 1600 microg did not differ significantly between regimens. CONCLUSION: Combining PD20AMP measurements with a sequential regimen of three quadrupling doses of an inhaled corticosteroid given for 1 or 2 weeks provides clear dose-response curves for comparative studies. PD20AMP is a more sensitive end point for this purpose than FEV1, PEFR, symptoms, or relief inhaler use.

Time course of action of two inhaled corticosteroids, fluticasone propionate and budesonide.

BACKGROUND: It is important to be able to compare the efficacy and systemic effects of inhaled corticosteroids but their slow onset of action makes it difficult to measure the maximum response to a given dose. Submaximal responses could be compared if the time course of action of the inhaled corticosteroids being compared was similar. We have compared the time course of action of fluticasone and budesonide, measuring response as change in the provocative dose of adenosine monophosphate causing a 20% fall in forced expiratory volume in 1 second (PD20AMP). METHODS: Eighteen subjects with mild asthma, aged 18-65, took part in a three way randomised crossover study. Subjects took fluticasone (1500 microg/day), budesonide (1600 microg/day), and placebo each for 4 weeks with a washout period of at least 2 weeks between treatments; PD20AMP and forced expiratory volume in 1 second (FEV1) were measured during and after treatment. The time taken to achieve 50% of the maximum response (T50%) was compared as a measure of onset of action. RESULTS: There was a progressive increase in PD20AMP during the 4 weeks of treatment with both fluticasone and budesonide but not placebo; the increase after 1 and 4 weeks was 2.28 and 4.50 doubling doses (DD) for fluticasone and 2.49 and 3.65 DD for budesonide. T50% was 9.3 days for fluticasone and 7.5 days for budesonide with a median difference between fluticasone and budesonide of 0.1 days (95% CI -1.4 to 2.65). There was a wide range of response to both inhaled corticosteroids but good correlation between the response to fluticasone and budesonide within subjects. FEV1 and morning peak expiratory flow rate (PEFR) increased during the first week of both active treatments and were stable thereafter. There was a small progressive improvement in nocturnal symptoms with both active treatments. CONCLUSION: PD20AMP was a more sensitive marker of response to inhaled corticosteroid therapy than FEV1 and PEFR. The time course of action of fluticasone and budesonide on PD20AMP is similar, suggesting that comparative studies of their efficacy using 1 or 2 week treatment periods are valid. When a new inhaled corticosteroid becomes available, a pilot study comparing its time course of action with that of an established corticosteroid should allow comparative studies to be performed more efficiently.

Effect of two breathing exercises (Buteyko and pranayama) in asthma: a randomised controlled trial.

BACKGROUND: Patients with asthma are interested in the use of breathing exercises but their role is uncertain. The effects of the Buteyko breathing technique, a device which mimics pranayama (a yoga breathing technique), and a dummy pranayama device on bronchial responsiveness and symptoms were compared over 6 months in a parallel group study. METHODS: Ninety patients with asthma taking an inhaled corticosteroid were randomised after a 2 week run in period to Eucapnic Buteyko breathing, use of a Pink City Lung Exerciser (PCLE) to mimic pranayama, or a PCLE placebo device. Subjects practised the techniques at home twice daily for 6 months followed by an optional steroid reduction phase. Primary outcome measures were symptom scores and change in the dose of methacholine provoking a 20% fall in FEV(1) (PD(20)) during the first 6 months. RESULTS: Sixty nine patients (78%) completed the study. There was no significant difference in PD(20) between the three groups at 3 or 6 months. Symptoms remained relatively stable in the PCLE and placebo groups but were reduced in the Buteyko group. Median change in symptom scores at 6 months was 0 (interquartile range -1 to 1) in the placebo group, -1 (-2 to 0.75) in the PCLE group, and -3 (-4 to 0) in the Buteyko group (p=0.003 for difference between groups). Bronchodilator use was reduced in the Buteyko group by two puffs/day at 6 months; there was no change in the other two groups (p=0.005). No difference was seen between the groups in FEV(1), exacerbations, or ability to reduce inhaled corticosteroids. CONCLUSION: The Buteyko breathing technique can improve symptoms and reduce bronchodilator use but does not appear to change bronchial responsiveness or lung function in patients with asthma. No benefit was shown for the Pink City Lung Exerciser.

Adverse effects of oral corticosteroids in relation to dose in patients with lung disease.

BACKGROUND: The adverse effects of oral corticosteroids are widely recognised but there are few quantitative data on which to base advice to patients. In a two part cross sectional study we compared adverse effects in patients with lung disease taking oral corticosteroids and control subjects and related the adverse effects to corticosteroid dose in the patient group. METHODS: Data on oral corticosteroid use, lifestyle, fractures, and other possible adverse effects were collected by questionnaire and compared between a community based cohort of patients taking continuous or frequent intermittent oral corticosteroids for asthma, chronic obstructive pulmonary disease, or alveolitis and age and sex matched control subjects. Dose related effects were explored in the corticosteroid group using cumulative dose quartiles and multiple logistic regression. RESULTS: A total of 367 patients (> or = 50 years, 48% female) and 734 control subjects completed the questionnaire. The cumulative incidence of fractures since the time of diagnosis was 23% for patients taking oral corticosteroids and 15% in the control group (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.3 to 2.6). Patients were more likely to have had a fracture of the vertebrae (OR 10; 95% CI 2.9 to 34), hip (OR 6; 95% CI 1.2 to 30), and ribs or sternum (OR 3.2, 95% CI 1.6 to 6.6) than control subjects. They also reported a significant increase in cataracts, use of antacids, muscle weakness, back pain, bruising, oral candidiasis, and having fewer teeth. The effects of oral corticosteroids were dose related: the odds ratio for patients in the highest compared with the lowest cumulative dose quartile (median prednisolone dose 61 g versus 5 g) ranged from 2 for all fractures to 9 for vertebral fractures and bruising. CONCLUSIONS: By quantifying the morbidity associated with the use of oral corticosteroids, this study should help to rationalise their long term use.

Systemic effects of formoterol and salmeterol: a dose-response comparison in healthy subjects.

BACKGROUND: The main adverse effects of inhaled long acting beta(2) agonists relate to their systemic activity. The systemic effects seen over eight hours after inhalation of three doses of salmeterol and formoterol were therefore compared in normal subjects. METHODS: A double blind, randomised, crossover study was carried out in 16 healthy subjects who inhaled formoterol 24, 48 and 96 microg (via Turbuhaler((R))), salmeterol 100, 200 and 400 microg (via Diskhaler((R))), or placebo on separate days. Heart rate, systolic and diastolic blood pressure, and plasma potassium and glucose concentrations were measured for eight hours following each drug and mean values were used to plot the time course of change after each dose. Mean maximum (or minimum) absolute values were used to construct dose-response curves to calculate the relative dose potency of the two drugs. Lunch was taken after the four hour readings and, since this caused additional changes to the main outcome measures, data from the first four hours are also presented in a post hoc analysis. RESULTS: Both salmeterol and formoterol caused an early dose dependent increase in heart rate and glucose concentrations and a fall in diastolic blood pressure and plasma potassium concentration; formoterol also caused an early increase in systolic blood pressure. The cardiovascular effects occurred more rapidly than the metabolic effects and the response to formoterol was faster than that of salmeterol, apart from the glycaemic response. The effects of salmeterol were slightly more prolonged than those of formoterol, although some dose related effects were apparent at eight hours with both drugs. The relative dose potency for formoterol compared with salmeterol at four and eight hours for the different end points excluding systolic blood pressure ranged from 1.6 to 7.0 after adjusting for baseline values. Relative dose potencies (95% CI) for maximum heart rate and plasma potassium concentrations were 4.1 (3.0 to 5.6) and 5.8 (4.1 to 8.6) over four hours and 2.4 (1.2 to 3.8) and 3.0 (1.2 to 5.7) over eight hours. CONCLUSIONS: Formoterol and salmeterol cause dose related changes in heart rate, diastolic blood pressure, and plasma glucose and potassium concentrations. Formoterol has a more rapid onset for most end points whereas salmeterol has slightly more prolonged activity. Both drugs have a relatively modest therapeutic window. The relative dose potencies of the two drugs for the main end points were similar to the fourfold difference in recommended doses. Some differences in the pharmacological profile of the two drugs emerged and are as yet unexplained.

Randomised placebo controlled trial of beta agonist dose reduction in asthma.

BACKGROUND: Many patients continue to take regular beta agonists, often at high doses, contrary to national and international guidelines. Some studies have suggested that this can worsen asthma control, but whether such patients can reduce their dose of beta agonist and whether they would benefit from this has not been determined. Reduction of beta agonist dose was studied in a placebo controlled parallel group study. METHODS: Following a run in period, 33 subjects with asthma taking regular beta agonists were converted to an equivalent dose of terbutaline via a Turbohaler. Two weeks later terbutaline was continued at the same dose or changed to placebo in two stages a week apart. The change over period was covered by an increased dose of inhaled steroid to attenuate any immediate effects of the change in dose. Subjects then attended weekly for six weeks for measurement of forced expiratory volume in one second (FEV1) and the dose of methacholine that produced a 20% fall in FEV1 (PD20). Peak expiratory flow (PEF) and symptom scores were recorded twice daily throughout the study. Exacerbations, lung function, bronchial responsiveness, bronchodilator response, beta agonist use, and symptoms were compared before and six weeks after reduction in the dose of beta agonist. RESULTS: Twenty five of the 33 subjects completed the study; three patients in each group withdrew due to an asthma exacerbation. The median terbutaline dose fell from 2500 to 500 micrograms/day in the beta agonist reduction group and from 3000 to 2250 micrograms/day in the control group. There were small non-significant changes in FEV1, PEF, symptom scores and PD20 methacholine over the course of the study. The FEV1 response to a beta agonist was greater in those who reduced their beta agonist dose than in the control group although the final FEV1 achieved was the same. CONCLUSIONS: Patients with asthma taking high doses of beta agonists can reduce the amount of beta agonist they use without a significant change in their asthma control. There was no evidence of improved asthma control with beta agonist dose reduction.

Effect of long-term treatment with salmeterol on asthma control: a double blind, randomised crossover study.

OBJECTIVES: To determine the effect of adding salmeterol 50 micrograms twice daily for six months to current treatment in subjects with asthma who control their inhaled corticosteroid dose according to a management plan. DESIGN: A double blind, randomised crossover study. SETTING: Nottingham. SUBJECTS: 101 subjects with mild or moderate asthma taking at least 200 micrograms twice daily of beclomethasone dipropionate or budesonide. INTERVENTIONS: Salmeterol 50 micrograms twice daily and placebo for six months each, with a one month washout. Subjects adjusted inhaled steroid dose according to guidelines. MAIN OUTCOME MEASURE: Reduction in inhaled steroid use, exacerbations of asthma, and use of oral steroids. RESULTS: Data were available for 87 subjects. When compared with placebo salmeterol treatment was associated with a 17% reduction in inhaled steroid use (95% confidence interval 12% to 22%) with no significant difference in the number of subjects who had an exacerbation (placebo 25%, salmeterol 16%) or use of oral steroids. For secondary end points salmeterol treatment was associated with higher morning and evening peak expiratory flow and forced expiratory volume in one second; a reduction in symptoms, bronchodilator use and airway responsiveness to methacholine; and no effect on serum potassium concentration, 24 hour heart rate, or the final forced expiratory volume in one second achieved during a salbutamol dose-response study. CONCLUSIONS: In subjects who adjusted their inhaled steroid treatment according to guidelines the addition of salmeterol 50 micrograms twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control.

Effects of hormone replacement therapy on muscle performance and balance in post-menopausal women.

1. A randomized controlled trial of the effect of oral hormone replacement therapy plus calcium compared with calcium alone on balance, muscle performance and falls was conducted over 48 weeks in 116 post-menopausal women (aged 45-70 years), all of whom had suffered a distal radial fracture during the previous 3 months. Treatment was with Prempak C or Premarin 0.625 mg in the test group with 1 g calcium daily (Sandocal) in both groups. Measurements were made of balance, assessed as sway, leg extensor power and self-paced walking speed, at 12-week intervals over 24 weeks. Hand grip strength was measured every 12 weeks for 48 weeks, and falls in the preceding 12 weeks were recorded at each visit. 2. There was no relation between initial levels of oestradiol and any other variable assessed, except body mass. Levels of follicle-stimulating hormone in the test group were in the premenopausal range. There was no significant change attributable to hormone replacement therapy at any time point in any of the outcome variables. The only significant difference was an increase of 4.2% (95% confidence interval 0.7-7.6%) in leg extensor power in the control group (calcium alone) compared with the group treated with hormone replacement therapy. 3. Of the total group, 37% fell again during the year, with three patients suffering a further fracture. Frequent fallers swayed significantly more often than the others, but there was no evidence that their muscle strength was poorer or that the group treated with hormone replacement therapy fell less frequently. 4. Hormone replacement therapy did not increase muscle performance, improve balance or reduce falls over a year in middle-aged women.

Effect of regular terbutaline on the airway response to inhaled budesonide.

BACKGROUND: The rebound increase in bronchial reactivity and fall in forced expiratory volume in one second (FEV1) following treatment with beta agonists seen in several studies has occurred regardless of concurrent steroid therapy. Little is known about the effect of adding beta agonists to corticosteroids, but in a recent study regular treatment with terbutaline appeared to reduce some of the beneficial effects of budesonide. The effects of budesonide alone and in combination with regular terbutaline treatment on lung function, symptom scores, and bronchial reactivity were therefore examined. METHODS: Sixteen subjects with mild stable asthma inhaled budesonide 800 micrograms twice daily for two periods of 14 days with terbutaline 1000 micrograms three times daily or placebo in a double blind crossover fashion. FEV1 and the dose of histamine or adenosine monophosphate (AMP) causing a 20% fall in FEV1 (PD20) were measured before and 12 hours after the final dose of treatment, and changes from baseline were compared. Seven day mean values for daily morning and evening peak expiratory flow (PEF) values, symptom scores, and rescue medication were compared before and during treatment. RESULTS: Morning and evening PEF rose more with budesonide plus terbutaline than with budesonide alone, with a mean difference of 19 l/min occurring in the evening (95% confidence interval (CI) 2 to 36). There was no difference in symptom scores during treatment. Following treatment the mean increase in FEV1 was 150 ml higher with budesonide alone (95% CI-10 to 300). There was no difference between treatments in change in histamine and AMP PD20. CONCLUSIONS: Evening PEF was greater when budesonide was combined with regular terbutaline. There was no evidence of a difference in bronchial reactivity following the two treatment regimens. The findings of a previous study were not confirmed as the reduction in FEV1 after budesonide and terbutaline was smaller and not statistically significant. Further work is needed to determine whether this disparity in findings in the two studies is due to a type 2 statistical error in this study or a spurious finding in the previous study.

Continuous assessment of knee function and patient mobility.

A technique is described for measuring and analysing the load profile of the knees during daily routine. The method has been used on patients with chronic arthritis of the knee, both before and after joint replacement. Results are presented, and the logistics of carrying out such work are discussed. The method is applicable to joints other than the knee, diseases other than arthritis, and treatments other joint replacement.