Doubling Doses Of Methacholine Research Articles

FEV1 recovery following methacholine challenge in asthma: Variability and comparison of methods

BackgroundMethacholine challenges have been used in clinical trials to assess therapeutic effects and potential adverse reactions of interventions on pulmonary function in a sensitive population, such as in subjects with asthma. Here, we evaluate the variability of the methacholine challenge recovery model, and compare the results obtained for both incremental and bolus challenge methods. MethodsThe extent, time course and variability of change in forced expiratory volume in 1 s (FEV1) following repeated methacholine challenges in subjects with mild asthma were investigated in an open-label, four-period, fixed-sequence, two-method, replicate crossover study. At Visits 1 and 2, subjects underwent an incremental challenge using doubling doses of methacholine until a ≥20% decrease in FEV1 was observed; at Visits 3 and 4, subjects underwent a bolus challenge, inhaling a single dose of methacholine calculated from the cumulative dose established during Visit 1. ResultsA total of 19 subjects were included in the study. Both the mean FEV1 area under the curve (FEV1 AUC0–tz) and mean maximum reductions in FEV1 (absolute and relative) 120 min post-challenge values were higher for the incremental challenges than the bolus challenges, with no reported difference between repetitions of the same methodology. FEV1 AUC0–tz decrease 120 min post challenge demonstrated an intra-subject coefficient of variation (CV) of 47.2% (incremental) and 78.3% (bolus), suggesting considerable between-visit variability. The mean absolute, and similarly relative, maximum reductions in FEV1 compared with post-diluent baseline values demonstrated lower intra-subject variability (incremental 21.16%, bolus 40.67%) than the FEV1 AUC0–tz-based endpoint.There was a trend towards faster recovery following the bolus challenge than with the incremental challenge. The provocative dose of methacholine inducing a ≥20% decrease in FEV1 resulted in a between-group mean difference of 27.20% in the incremental challenge periods, with a high intra-subject CV of 80.64%, demonstrating considerable variability. ConclusionMaximum reduction in FEV1 had the lowest variability. There was little difference between repetitions of the same methodology, as indicated by overlapping confidence intervals. There was a trend towards faster recovery following bolus challenge than with the incremental challenge. The results of this trial could be of value when designing future clinical trials using the methacholine challenge methodology.

Does a Low Sodium Diet Improve Asthma Control?

Observational studies and initial randomized trials have indicated that a low sodium diet may improve asthma control. We tested the hypothesis that a low sodium diet would improve asthma control over a 6-week period. Participants with a physician diagnosis of asthma and measurable bronchial reactivity to methacholine entered a randomized double-blind placebo-controlled trial. All adopted a low sodium diet and were randomized to receive either 80 mmol/day of oral sodium supplements (normal sodium intake) or matched placebo (low sodium intake) for 6 weeks. The primary outcome was change in bronchial reactivity to methacholine; secondary outcomes were change in lung function, morning and evening peak expiratory flow, asthma symptoms score, daily bronchodilator use, Juniper Standardized Asthma Quality of Life Questionnaire score, and atopy. A total of 220 individuals entered the study, of whom 199 completed the protocol. In the low sodium-intake group, mean daily urinary sodium excretion decreased by 20 mmol (SD, 64 mmol) and in the normal-sodium-intake group increased by 28 mmol (SD, 74 mmol). There were no differences between the two groups in the primary or secondary outcome measures; the mean difference in bronchial reactivity between the low- and normal-intake groups was -0.03 doubling doses of methacholine (95% confidence interval, -0.60 to 0.53). The use of a low sodium diet as an adjunctive therapy to normal treatment has no additional therapeutic benefit in adults with asthma and bronchial reactivity to methacholine.

The Effect of Reducing the Fine-Particle Mass of Salmeterol from Metered-Dose Inhalers on Bronchodilatation and Bronchoprotection Against Methacholine Challenge: A Randomized, Placebo-Controlled, Double-Blind, Crossover Study

This study examined the clinical relevance of fine-particle mass (FPM) delivered from metered dose inhalers (MDIs) to bronchodilatation and bronchoprotection against methacholine challenge by comparing a marketed chlorofluorocarbon (CFC) formulation of salmeterol with an investigational hydrofluoroalkane (HFA)formulation. This was a randomized, double-blind, placebo-controlled, 3-way crossover study in patients with mild to moderate asthma who had a forced expiratory volume in 1 second (FEV (1)) of > or =60% predicted and a base-line provocation dose of inhaled methacholine required to produce a 20% decrease in FEV(1) (PD (20) [methacholine]) of < or =3.2 mg. On separate occasions, patients received 2 inhalations of salmeterol 25 microg from either the CFC MDI (FPM 14 microg), the investigational HFA MDI (FPM 7 microg), or placebo via CFC MDI. Serial measurements of FEV(1) were made over 90 minutes after dosing, followed by methacholine challenge. Efficacy end points were PD(20) (methacholine) and FEV(1) AUC (inc) (incremental area under the FEV(1) curve) over 15 to 90 minutes. The study was designed to demonstrate non-inferiority of the investigational HFA formulation to the CFC formulation in terms of protection against methacholine-induced bronchial hyperresponsiveness; for PD(20) (methacholine), noninferiority was predefined as 1.0 doubling dose of methacholine. The study enrolled 40 patients (65% men; mean age, 36.9 years). Both active treatments were significantly better than placebo in terms of PD(20) (methacholine) (P < 0.001). In the per-protocol population, the mean (SE) difference in bronchoprotection between the CFC MDI and placebo was 2.7888 (0.3432) doubling doses of methacholine (n = 32), and the difference between the investigational HFA MDI and placebo was 1.8268 (0.3418) doubling doses(n = 33). The adjusted mean (SE) treatment difference between the CFC MDI and HFA MDI was 0.9621 (0.3454) doubling doses. The upperlimit of the 95% CI (0.2714-1.6527) was greater than the predefined limit for noninferiority. There was no significant difference in FEV(1) AUC(inc) between formulations (mean treatment difference, 1.895 L . min; 95% CI, -4.893 to 8.684); however, both active treatments were significantly different from placebo (P < 0.001). FPM from different MDI formulations may affect the bronchoprotective properties of salmeterol. In this study, the formulation with the smaller FPM was associated with less-effective bronchoprotection, although there was no difference in bronchodilatation. This study did not demonstrate noninferiority of the investigational HFA formulation to the CFC formulation in terms of protection against methacholine-induced bronchial hyperresponsiveness.

Profile of bronchial responsiveness in children with respiratory symptoms.

A postal questionnaire inquiring into the presence of respiratory symptoms was sent to 3698 children aged 7 and 8 years. Those reporting either cough or wheeze were randomised, and a sample invited to attend for skin testing. A total of 192 symptomatic children, half of whom were atopic and half non-atopic, were randomly selected to enter the study. All children performed and recorded best of three peak expiratory flow measurements twice a day and completed a 10 point respiratory symptom score card each day for one year. They also recorded all treatment taken and made a note of relevant life events. Each child was seen monthly for general assessment and for measurement of nonspecific bronchial responsiveness to methacholine. Of the 192 children, 183 successfully completed the study. For six subjects 11 measurements of the provocation dose required to cause a 20% fall in forced expiratory volume in one second (PD20) were available for analysis and on the remaining 177, greater than or equal to 12 measurements. The prevalence and degree of bronchial hyper-responsiveness (PD20 less than 6.4 mumol) and its relationship to atopy was examined by comparing the percentage of members of each symptom group demonstrating bronchial hyper-responsiveness and the number of occasions on which they did so, and by comparison of minimum and median PD20 values. The range of bronchial responsiveness shown during the study period by each child was expressed as doubling doses of methacholine and compared between symptom groups. Atopy and wheeze were both independently associated with an increased prevalence and greater degree of bronchial hyper-responsiveness when compared with non-atopy and cough respectively, all differences being significant a the 0.001 level.. Thirty three per cent of subjects demonstrated a rnge of methacholine responsiveness of >4 and 13.4% of >6 doubling doses during one year.

The daily variability of bronchial responsiveness to methacholine

Ten mild atopic asthmatics on inhaled beta 2-agonists alone were studied in order to determine the repeatability of methacholine inhalation provocation tests at 24 h intervals over a period of 5 days. Such patients are most frequently studied in therapeutic trials of anti-asthmatic medications. There were no significant differences in results obtained on any of the days and no evidence for the development of tolerance to methacholine in this group of patients at one day intervals. The 95% confidence interval for repeatability of the results was +/- 1.05 doubling doses of methacholine, and 95% range +/- 2.36 doubling doses, comparable to the results obtained by other investigators on similar patients. Some investigators have produced more highly repeatable results but these have generally been obtained using highly selected groups of patients.

Effect of inhaled frusemide on the early response to antigen and subsequent change in airway reactivity in atopic patients.

The purpose of this study was to investigate whether inhaled frusemide was able to inhibit the increase in nonspecific bronchial reactivity that occurs after the early response to allergen exposure in subjects with allergic rhinitis or asthma (or both). Ten symptom free patients initially underwent a challenge with methacholine, to determine the dose of methacholine that caused a 15% fall in FEV1 (PD15 FEV1 meth) and a challenge with a specific allergen, to determine the concentration of allergen that caused a fall in FEV1 of at least 15%. On two further occasions they inhaled allergen concentration that had caused the greater than or equal to 15% fall in FEV1 preceded by inhaled frusemide (40 mg frusemide in 4 ml buffered saline) or placebo (4 ml of diluent solution), according to a randomised, double blind, crossover design. All allergen studies were separated by at least seven days. A methacholine challenge was performed two hours after the allergen challenge, a time when the early response to allergen had completely resolved. Frusemide inhibited the early response to antigen, causing mean (95% confidence interval) protection of 87.6% (96-80%) for the maximum fall in FEV1. The increase in non-specific airway reactivity that occurred after antigen when this was preceded by placebo was reduced by frusemide. The mean (95% CI) difference in PD15 values between the placebo and the frusemide days was 1.73 (2.30-1.16) doubling doses of methacholine. These results confirm that frusemide is highly effective in preventing the early response to allergen, and show that it inhibits the increase in reactivity to methacholine that follows the early response.

Methacholine bronchial challenge using a dosimeter with controlled tidal breathing.

A new inhalation synchronised dosimeter triggered by low inspiratory flow rates has been assessed. The methacholine challenge test using dosimeter nebulisation with controlled tidal breathing was compared with continuous nebulisation using De Vilbiss No 40 nebulisers with deep inhalations in 11 asthmatic subjects. Within subject PD20 FEV1 values were lower with the dosimeter method than with the continuous nebulisation method (geometric means 158 and 588 micrograms). The repeatability of the dosimeter method with controlled tidal breathing was studied in 11 asthmatic subjects, and the 95% range for a single measurement was +/- 0.72 doubling doses of methacholine. The dosimeter method has greater efficacy because aerosol is delivered during the first part of an inhalation, minimising loss of aerosol outside the respiratory tract. The dosimeter technique combined with controlled tidal breathing appears to be a useful method for carrying out standardised non-specific bronchoprovocation tests.