Sue Cooper

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 (⩾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.

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 FEV1 (PD20) during the first 6 months. Results: Sixty nine patients (78%) completed the study. There was no significant difference in PD20 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 FEV1, 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.

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

Abstract Objectives: To determine the effect of adding salmeterol 50 μg 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 μg twice daily of beclomethasone dipropionate or budesonide. Interventions: Salmeterol 50 μg 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 μg twice daily was associated with a reduction in inhaled steroid use and improved lung function and symptom control. Key messages One hundred and one subjects with mild or moderate asthma took salmeterol 50 μg and placebo for six months each in a crossover study Subjects adjusted their inhaled steroid dose according to a management plan based on peak flow recordings and symptoms The dose of inhaled steroids was reduced by 17% with salmeterol, with no change in exacerbations or use of oral steroids Despite the reduction in inhaled steroid dose, salmeterol was associated with bronchodilatation and a reduction in symptoms The efficacy of salmeterol was maintained over the six months

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

BACKGROUND The main adverse effects of inhaled long acting β2 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 μg (via Turbuhaler®), salmeterol 100, 200 and 400 μg (via Diskhaler®), 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.

Morbidity from asthma in relation to regular treatment: a community based study

BACKGROUND The extent to which asthma morbidity in the community occurs in patients who are having relatively little treatment or in those on step 3 or above of the British asthma management guidelines is uncertain. We have looked at this in a community population in southern Nottinghamshire. METHODS A cross sectional review of treatment in all patients over the age of four with diagnosed asthma was carried out in five large general practices (population 38 865) in 1995/6 using computerised general practice records. The patients’ usual treatment was obtained from prescription data and categorised by the appropriate step on the British guidelines on asthma management. Two measures of morbidity, the request for 10 or more short acting β agonist inhalers a year or the need for a course of oral corticosteroids in the last year, were related to the regular treatment of the patients. RESULTS Of the 3373 patients (8.7%) given a diagnosis of asthma, the percentage on steps 1, 2, 3, 4, and 5 of treatment were 54%, 22%, 11%, 3.6%, and 1%, respectively, with a further 8% having had no treatment. During the past year 13.6% had been prescribed 10 or more β agonist inhalers and 12.5% had received at least one course of oral corticosteroids. Both measures occurred more frequently in patients taking more prophylactic treatment (step 3 or above). Nevertheless, because most patients were on steps 1 and 2 of the treatment guidelines, more than half the patients requiring high doses of inhaled β agonists or a course of oral prednisolone came from those taking low dose or no regular inhaled corticosteroid. CONCLUSIONS Evidence of morbidity from asthma was found in many patients taking little or no prophylactic medication and this should be amenable to improved education. A different approach may be needed for patients with continuing morbidity who are already taking higher doses of prophylactic medication.

Poor adherence with inhaled corticosteroids for asthma: can using a single inhaler containing budesonide and formoterol help?

BACKGROUND Poor adherence with inhaled corticosteroids is an important problem in asthma management. Previous approaches to improving adherence have had limited success. AIM To determine whether treatment with a single inhaler containing a long-acting beta(2)-agonist and a corticosteroid for maintenance treatment and symptom relief can overcome the problem of poor adherence with inhaled corticosteroids. DESIGN OF STUDY Randomised, parallel group, open-label trial. SETTING Forty-four general practices in Nottinghamshire. METHOD Participants who used less than 70% of their prescribed dose of inhaled corticosteroid and had poorly controlled asthma were randomised to budesonide 200 microg one puff twice daily plus their own short-acting beta(2)-agonist as required (control group), or budesonide/formoterol 200/6 microg one puff once daily and as required (active group) for 6 months. The primary outcome was inhaled corticosteroid dose. RESULTS Seventy-one participants (35 control, 36 active group) were randomised. Adherence with budesonide in the control group was approximately 60% of the prescribed dose. Participants in the active group used approximately 80% more budesonide than participants in the control group (448 versus 252 microg/day, mean difference 196 mug, 95% confidence interval 113 to 279; P<0.001) and were less likely to withdraw from the study (3 versus 13; P<0.01). No safety issues were identified. CONCLUSION Using a single inhaler for both maintenance treatment and symptom relief approximately doubled the dose of inhaled corticosteroid taken, suggesting this could be a useful strategy to overcome the problems related to poor adherence with inhaled corticosteroids.

Predictors of Children's Secondhand Smoke Exposure at Home: A Systematic Review and Narrative Synthesis of the Evidence

Background Childrens exposure to secondhand smoke (SHS) has been causally linked to a number of childhood morbidities and mortalities. Over 50% of UK children whose parents are smokers are regularly exposed to SHS at home. No previous review has identified the factors associated with childrens SHS exposure in the home. Aim To identify by systematic review, the factors which are associated with childrens SHS exposure in the home, determined by parent or child reports and/or biochemically validated measures including cotinine, carbon monoxide or home air particulate matter. Methods Electronic searches of MEDLINE, EMBASE, PsychINFO, CINAHL and Web of Knowledge to July 2014, and hand searches of reference lists from publications included in the review were conducted. Findings Forty one studies were included in the review. Parental smoking, low socioeconomic status and being less educated were all frequently and consistently found to be independently associated with childrens SHS exposure in the home. Children whose parents held more negative attitudes towards SHS were less likely to be exposed. Associations were strongest for parental cigarette smoking status; compared to children of non-smokers, those whose mothers or both parents smoked were between two and 13 times more likely to be exposed to SHS. Conclusion Multiple factors are associated with child SHS exposure in the home; the best way to reduce child SHS exposure in the home is for smoking parents to quit. If parents are unable or unwilling to stop smoking, they should instigate smoke-free homes. Interventions targeted towards the socially disadvantaged parents aiming to change attitudes to smoking in the presence of children and providing practical support to help parents smoke outside the home may be beneficial.

Relation of pulmonary lymphangio-leiomyomatosis to use of the oral contraceptive pill and fertility in the UK: a national case control study.

BACKGROUND--Pulmonary lymphangioleiomyomatosis is a rare progressive disease of unknown aetiology affecting premenopausal women. Since the oral contraceptive pill has been implicated in its pathogenesis, a case control study was carried out to determine whether women with the disease were more likely to have taken the oral contraceptive pill, and whether the disease was associated with other conditions related to sex hormones including pregnancy, parity, and fibroids. METHODS--All chest physicians in the UK were asked for details of all live patients with pulmonary lymphangioleiomyomatosis; the patients family doctor was then asked for four age and sex matched control subjects from their patient register. Details of lifetime use of the oral contraceptive pill, pregnancy, parity, history of fibroids, and smoking were obtained from cases and controls. Relative odds of exposure to potential risk factors were estimated by conditional logistic regression. RESULTS--Medical details were obtained from all 23 cases of lymphangioleiomyomatosis identified; questionnaires were completed by 21 cases (one by proxy) and by 46 matched controls of mean (SD) age 43 (10) and 44 (11) years, respectively. The patients had a mean age of 34 (9) years at onset of symptoms and a median (range) time of 2 (0-29) years from onset of symptoms to diagnosis. Compared with control subjects, cases did not differ in the use of the oral contraceptive pill (odds ratio (OR) 0.39, 95% CI 0.09 to 1.68), diagnosis of fibroids (OR 3.12; 95% CI 0.52 to 18.7), age of menarche, menstrual history, or lifetime smoking. They were, however, less likely to have been pregnant (OR 0.14, 95% CI 0.03 to 0.71) or to have had children (OR 0.13, 95% CI 0.03 to 0.67). More pregnancies had ended in spontaneous abortion (28% v 8%) but the proportion of women undergoing spontaneous abortion was similar in cases and controls (OR 2.13, 95% CI 0.47 to 9.3). CONCLUSIONS--This study does not support the hypothesis that use of the oral contraceptive pill is causally associated with the development of pulmonary lymphangioleiomyomatosis. Sex hormones may be involved, however, since patients were less likely to have been pregnant or to have had children, and tended to have had more spontaneous abortions and an increased incidence of fibroids.

Steroid sparing effect of nedocromil sodium in asthmatic patients on high doses of inhaled steroids

Nedocromil sodium is a non‐steroidal prophylactic agent developed for the management of asthma. We have assessed the steroid sparing potential of inhaled nedocromil sodium 4 mg four limes daily in a randomized, double blind, placebo controlled study in 69 asthmatic subjects controlled on inhaled beclomethasone dipropionate in the dose range 1000 2000 μg daily. Following a 4 week run‐in period subjects added nedocromil sodium or placebo by metered dose inhaler to their usual medication for a further 4 weeks. The dose of inhaled steroid was then reduced at fortnightly intervals according to a predetermined schedule, with monitoring of asthma severity, symptom scores, bronchodilator use and peak flow recordings. Sixty subjects entered the steroid reduction phase and achieved median (range) % decreases in steroid dose of 80 (17‐100)% with nedocromil sodium compared to 65 (0‐100)% with placebo (P = 0.34) with 14 patients in the nedocromil sodium group and 10 in the placebo group being withdrawn completely from inhaled steroids. Subjective global assessment scores were significantly better with nedocromil sodium (mean 2.14) than with placebo (2.93; P<0.02) though there was no difference between individual daily symptom scores. In this study therefore in asthmatic patients controlled on high doses of inhaled steroids, nedocromil sodium was well tolerated but the smalt differences in steroid sparing effect between nedocromil and placebo were not statistically significant.

Factors Associated With Smoking Cessation in Early and Late Pregnancy in the Smoking, Nicotine, and Pregnancy Trial: A Trial of Nicotine Replacement Therapy

Introduction: Previous studies have found partners’ smoking status, multiparity, and nicotine dependence to be associated with smoking cessation in pregnancy. However, no studies have investigated influences on cessation among women using nicotine replacement therapy (NRT). We analyzed data from a trial of NRT in pregnancy to determine factors associated with shorter- and longer-term cessation. Methods: Data were collected at baseline, 1 month, and delivery from 1,050 pregnant women. Two multivariable logistic models for validated cessation at 1 month and delivery were created with a systematic strategy for selection of included factors. Results: All findings are from multivariable analyses. At 1 month, odds of cessation were greater among those who completed full time education at >16 years of age (odds ratio [OR] = 1.82, 95% confidence interval CI = 1.24–2.67, p = .002) but they were lower in women with higher baseline cotinine levels (OR = 0.93, 95% CI = 0.90–0.95, p < .001). At delivery, the odds of cessation were greater among those who completed full time education at >16 years of age (OR = 1.89, 95% CI = 1.16–3.07, p = 0.010) but were inversely associated with higher baseline cotinine levels (OR = 0.96, 95% CI = 0.92–0.99, p = .010). Conclusions: Women who are better educated and have lower pretreatment cotinine concentrations had higher odds of stopping smoking and factors associated with shorter and longer term cessation were similar.