Methacholine Inhalation Research Articles

Effects of inhaled histamine, methacholine and capsaicin on sputum levels of alpha 2-macroglobulin.

BACKGROUND: Plasma exudation-derived proteins and peptides contribute significantly to inflammation in the airway mucosa in vivo. In the guinea pig trachea both histamine and the neurogenic stimulant capsaicin produce acute...

Interpretation of positive results of a methacholine inhalation challenge and 1 week of inhaled bronchodilator use in diagnosing and treating cough-variant asthma

Interpretation of positive results of a methacholine inhalation challenge and 1 week of inhaled bronchodilator use in diagnosing and treating cough-variant asthma

Interpretation of Positive Results of a Methacholine Inhalation Challenge and 1 Week of Inhaled Bronchodilator Use in Diagnosing and Treating Cough-Variant Asthma

In diagnosing cough due to asthma, methacholine chloride inhalation challenge (MIC) interpreted in a traditional fashion has been shown to have positive predictive values from 60% to 82%. To determine whether any features of positive results of an MIC or the results of a 1-week trial of inhaled beta-agonist therapy were helpful in predicting when the cough was due to asthma. The study design was a prospective, randomized, double-blind, placebo-controlled, crossover format performed in adult, nonsmoking subjects, who were referred for diagnosis and treatment of chronic cough. The subjects had no other respiratory complaints or medical conditions for which they were taking medications, the results of baseline spirometry and chest roentgenograms were normal, and the results of MIC were positive. After obtaining baseline data, including MICs on 2 separate days, objective cough counting, and self-assessment of cough severity using a visual analog scale, subjects were randomized to receive 2 inhalations (1.3 mg) of metaproterenol sulfate or placebo by metered dose inhaler attached to a spacer device every 4 hours while awake. At 1 week, data identical to baseline were collected, and subjects received the other metered dose inhaler for 7 days. At 1 week, data identical to baseline were collected. After completion of the protocol, subjects were followed up in the clinic to observe the final response of the cough to specific therapy. Based on the disappearance of the cough with specific therapy, the cough was due to asthma in 9 of 15 subjects and nonasthma in 6 of 15 subjects. Baseline data were similar between groups. With respect to MICs, there were no significant differences between groups in the cumulative dose of methacholine that provoked a 20% decrease in forced expiratory volume in 1 second from the postsaline baseline value (PD20 values), slopes of dose-response curves, and maximal-response plateaus. Cough severity significantly improved after 1 week of metaproterenol use compared with the severity of the cough at baseline (P = .03) and with placebo (P = .02) only in subjects with asthma. No matter how the results are analyzed, positive MIC results, without observing response to therapy, are only consistent with asthma as the cause of the cough. The results are only diagnostic of asthma when they are followed by a favorable response to asthma therapy. After 1 week of inhaled beta-agonist, only the cough due to cough-variant asthma is significantly better.

Development of eosinophilic airway inflammation and airway hyperresponsiveness in mast cell-deficient mice.

Mast cells are the main effector cells of immediate hypersensitivity and anaphylaxis. Their role in the development of allergen-induced airway hyperresponsiveness (AHR) is controversial and based on indirect evidence. To address these issues, mast cell-deficient mice (W/W v) and their congenic littermates were sensitized to ovalbumin (OVA) by intraperitoneal injection and subsequently challenged with OVA via the airways. Comparison of OVA-specific immunoglobulin E (IgE) levels in the serum and numbers of eosinophils in bronchoalveolar lavage fluid or lung digests showed no differences between the two groups of mice. Further, measurements of airway resistance and dynamic compliance at baseline and after inhalation of methacholine were similar. These data indicate that mast cells or IgE-mast cell activation is not required for the development of eosinophilic inflammation and AHR in mice sensitized to allergen via the intraperitoneal route and challenged via the airways.

P-3-280 - The role of endothelium derived substances in mechanically induced postoperative vasospasm

Hyperresponsiveness of airway smooth muscle accounts for the susceptibility of asthmatic subjects to diverse bronchoconstrictor agents. It is widely presumed that hyperresponsiveness is not spasmogen selective. Hence, inhalation of methacholine is used routinely for clinical assessment of asthma and for evaluation of anti-asthma drugs. Comparative studies employing multiple spasmogens have revealed hyperresponsiveness to be markedly spasmogen selective. Because of this pronounced heterogeneity of hyperresponsiveness, sensitivity to methacholine cannot provide a reliable index of responsiveness. Development of exceptional hyperresponsiveness to bradykinin and to peptidoleukotrienes during allergic and other reactions could warrant the development of specific antagonists for asthma therapy. These issues are discussed here by Brian O’Connor, Simon Crowther, John Costello and John Morley.

Methacholine responsiveness using the raised volume forced expiration technique in infants.

Infant lung function can be assessed with the tidal volume "squeeze" technique or, over an extended volume range, with the newer raised volume forced expiration technique (RVFET). We assessed methacholine responsiveness in 11 infants, measuring both maximal expiratory flow at functional residual capacity (V.max,FRC)with the tidal volume technique, and forced expiratory volume/time (FEV(t)) with RVFET. We used a standard methodology for the former. FEV(t) was measured by inflating the infant's lungs to 20 cm H2O and forcing expiration using a jacket setup to transmit a pressure of 20 cm H2O to the airway. Lung function was measured at baseline and after methacholine inhalations, increasing from 0.1 g/L to 10 g/L in half log dosage increments (DI). The provocative concentrations (PC) of methacholine leading to a 40% fall in V.max,FRC and a 15 or 20% fall in FEV(t) were calculated. The mean provocative concentration of methacholine required to produce a 40% fall in V.max,FRC was less than that required to produce a 20% fall in FEV0.5 by 0.39 DI (95% CI, -0.60 to 1.38) and less than that required to produce a 20% fall in FEV0.75 by 0.42 DI (95%, CI, -0.54 to 1.39). Similarly, the provocative concentration of methacholine required to produce a 40% fall in V.max,FRC was less than that required to produce a 15% fall in FEV0.5 by 0.14 DI (95% CI, -0.99 to 1.28) or a 15% fall in FEV0.75 by 0.13 DI (95% CI, -0.80 to 1.08), but the differences were small and not significant. Despite these differences the agreement between the two methods was good, and bronchoconstriction was not attenuated by the forced inspiration delivered by the raised volume maneuver. We conclude that the raised volume forced expiration technique is able to detect methacholine-induced bronchoconstriction.

Effect of acute alterations in inspired oxygen tension on methacholine induced bronchoconstriction in patients with asthma.

BACKGROUND: Recent in vitro and in vivo studies in animals have suggested that ambient oxygen tension may influence airway responsiveness to bronchoconstrictor stimuli. These observations may have relevance to the...

Bronchial hyper-responsiveness in atopic dermatitis.

Most patients with atopic dermatitis (AD) have symptoms of asthma at some point in their lives, but some do not have any clinical evidence of asthma. Thirty-two patients with AD who had never suffered from bronchial asthma were investigated by the methacholine inhalation test for the presence of bronchial hyper-responsiveness (BHR). Serum immunoglobulin E (IgE) levels, mite specific IgE antibody, peripheral eosinophil counts, serum levels of eosinophil cationic proteins (ECP), and serum levels of major basic proteins (MBP) were determined and a skin test to acetylcholine and adrenaline was performed. The percentage of cases who showed BHR (minimum dose; Dmin < 50 units) was 31.3% in AD patients and 19.0% in 21 healthy controls. In those cases, Dmin of methacholine in AD was significantly lower than that in the controls (P < 0.01). Serum MBP levels were significantly higher in AD with BHR than in those without it (P < 0.05). These results indicate that some AD patients without asthma have BHR, and it may be related to serum MBP levels.

Bronchial Hyperreactivity in Children With Sickle Cell Thalassemia

Background: Pulmonary damage and frequent infections are common in children with thalassemia or sickle-cell disease, an inherited disorder of hemoglobin structure. Objective: Although bronchial hyperreactivity is widely used in the assessment of other pulmonary diseases, such as asthma, it has not previously been studied in relation to sickle-cell disease. Methods: We investigated the bronchial response to a methacholine inhalation test in a group of 23 children with compound heterozygous sickle-cell disease (βsβ+th/βsβoth), comparing these results with reference data from a group of normal children, obtained in an earlier control study. Asthmatic patients were excluded on the basis of diagnostic history, past and present therapies, clinical assessment, and evidence of basal FEV1 less than 80% of that predicted for the age (range 6-12 years). Increasing doses of methacholine were inhaled at 2-min intervals, allowing a cumulative dose range of 30–2490 μg and measuring FEV1 after each inhalation in order to...

Methacholine Challenge in Detecting Bronchial Hyperreactivity in Children

Background The diagnosis of bronchial asthma is usually apparent from presenting signs and symptoms. Occasionally, however, there is uncertainty and clinicians may use bronchial hyperreactivity, determined by methacholine inhalation challenge, as a diagnostic aid. Children are known to be more sensitive to methacholine than adults; doses used in adults will result in false-positive responses. Objective To determine the optimal methacholine inhalation challenge dose providing sensitive and specific discrimination between bronchial hyperreactivity and normal reactivity in children. A second objective was to determine whether gender, baseline spirometry values, race, tobacco smoke exposure, and family income affect methacholine response. Method In 71 children aged 7 to 15 years airway hyperreactivity was determined by history and physical findings. Methacholine challenge was performed using an established protocol. Sensitivity and specificity of the challenge were calculated at 50, 100, and 225 breath units ...

Aspirin-Induced Asthma as a Risk Factor for Asthma Mortality

We have recently reported severe airway obstruction and bronchial hyperre-sponsiveness (BHR) in fatal asthma compared with patients without a history of near-fatal asthma. Based on these findings, we evaluated whether aspirin-induced asthma (AIA) is a risk factor for asthma mortality by analyzing pulmonary function and BHR. FEV1.0% and methacholine inhalation threshold were significantly lower in the fatal asthma group compared with the AIA and non-AIA groups. However, there were no significant differences between the AIA and non-AIA groups. Our results suggested that AIA is not a risk factor for asthma mortality if avoidance of aspirin and aspirin-like drugs is assured.

Effects of Industrial Air Pollution on Pulmonary Response to Methacholine in Schoolchildren

The present study was performed to compare bronchial reactivity, measured by methacholine inhalation test, in a group of school children living in an industrialized area (Priolo, Siracusa, Italy) with another group of children living in a nonpolluted, nonindustrialized area (Scicli, Ragusa, Italy). All the children came from the fifth primary class of their school and represented all the children of that age group in each school. Eighty-nine children in Priolo and 93 in Scicli were enrolled in the study. The information on asthma, bronchitis, and passive smoking exposure was collected by a standardized and validated questionnaire. No statistical differences were recorded between the study and the control group for age, gender, cigarette smoking by parents or the children themselves, and parents' educational level. A statistically different significance was recorded for paternal job, which were workers in Priolo industries and farmers in Scicli (p < 0.01). No differences between the two groups were reported for asthma diagnosis and atopic status, but in the study group there was a statistical significant increase of bronchitis (tracheobronchial inflammation with mucus hyperproduction), 13 at Priolo and 3 at Scicli (p < 0.01). The methacholine was administered with the nebulizer connected to a dosimeter using a compressed air source (Mefar dosimeter). Bronchial reactivity of children living in the Priolo area was statistically higher (p < 0.001) than that of the control group living in Scicli. In the study group, 23 children (26%) demonstrated a 20% fall in forced expiratory volume at the first second (FEV1), while only 4 (4.3%) from the control group presented a similar reduction. The mean PD20 of the Priolo group was significantly lower (ie, 832 ± 591 mg), than the mean of the Scicli group (ie, 1215 ± 675 mg). The results of the present study suggest that industrial pollution can be responsible for an increase in bronchial reactivity, and could, therefore, potentially contribute to an increase in the incidence and severity of respiratory disease in children.

Nonspecific Airway Hyperresponsiveness in HIV Disease

HIV disease is frequently complicated by episodic acute bronchitis, suggesting the presence of chronic bronchial inflammation. To further examine this concept, we investigated the possible association of nonspecific airway hyperresponsiveness (AHR) and HIV disease. Methacholine inhalation challenge studies were performed on 66 HIV-seropositive and 8 HIV-seronegative members of the Pulmonary Complications of HIV Infection Study Cohort. AHR was defined as 20% or more decline in FEV1 from the postdiluent value after inhalation of 125 or less cumulative breath units. The prevalence of AHR in HIV-seropositive cohort members was compared with that in matched control subjects who had undergone methacholine challenge testing for two unrelated studies. Demographic, behavioral, and clinical features in HIV cohort members with and without AHR were contrasted. The relationship between AHR and the occurrence of episodic airway disease or symptoms suggestive of airway disease was examined. AHR was not more prevalent in HIV-seropositive cohort members than control subjects (19.3% vs 12.9%; p > 0.1). Within the cohort, AHR was detected more frequently in members with than without a history of asthma (60% vs 16%; p < 0.05). A greater proportion with than without AHR had 1 or more episode of pneumonia within 2 years (46% vs 9%; p < 0.01), 1 or more asthma episode during the study period (39% vs 1.9%; p < 0.001), or wheeze noted during clinic visits (62% vs 17%; p < 0.01). The proportion that experienced acute bronchitis did not differ in the two groups. This study suggest that HIV-infected persons do not have increased prevalence of nonspecific AHR. In HIV disease, AHR is associated asthma, but not episodic acute bronchitis. Thus, the possibility that airway injury without demonstrable AHR might complicate HIV disease remains.

Detection of Fluctuating Bronchial Obstruction by Electrical Impedance Measurement

The confirmation of asthma diagnosis and the evaluation of asthma severity pose time-consuming and expensive inhalation challenges. Their objective is to provoke and register by means of spirometry or airway resistance measurements the naturally occurring asthmatic episodes, and rely on the intelligent and conscientious cooperation on the part of the tested subjects. An alternative method for detection of airway obstruction was developed using measurement of the changes in chest basic electrical impedance Zo during methacholine inhalation challenges. A large surface tetrapolar electrode arrangement was applied to reduce motion artifacts to an acceptable level. A coherent association between spirometric and Zo changes was obtained in all tested subjects. As Zo measurements are not dependent on the cooperation of those tested, this approach has the potential to be used for fluctuating airway obstruction monitoring.

Effect of age, height, and prechallenge respiratory resistance on bronchial hyperresponsiveness in childhood asthma using the forced oscillation technique.

To evaluate the effects of age, height and prechallenge respiratory system resistance (Rrs) on bronchial responsiveness to methacholine inhalation (BRm) as measured by the oscillation technique in children with mild asthma, we studied BRm in 92 atopic children aged from 8 to 13 years (mean +/- SD, 10.5 +/- 1.7 years). Inhalation challenge was performed by administering progressively doubling doses of methacholine, until a twofold increase in Rrs from baseline had been reached. The minimum cumulative dose of methacholine (Dmin) at which Rrs deviated from baseline was identified by the point of deflection of the continuously recorded Rrs tracing. The Dmin represented the amount of methacholine which elicited BRm. By using single-regression analysis, height was negatively correlated with Rrs (p < 0.001). Height was positively and Rrs was negatively correlated with age (p < 0.001 and p < 0.001, respectively). Furthermore, height and age were correlated with Dmin (p < 0.001 and p < 0.001, respectively), but prechallenge Rrs was not correlated with Dmin (p > 0.1). To minimize the effect of height and prechallenge Rrs on BRm, the relationships between Dmin and age was studied in a subgroup with a narrow range of heights (135-155 cm, n = 32), and a narrow range of prechallenge Rrs (5.0-6.9 cmH2 O/L/s, n = 42); there remained a statistically significant correlation between Dmin and age in the groups with comparable heights (p = 0.026) and Rrs (p = 0.003). These data suggest that the BHR in childhood asthma may be affected by height and age when measured by the oscillation technique. Considering the many advantages of the oscillation method, this technique may be very suitable for measuring BHR in childhood asthma.

Ventilatory Response to Continuous Incremental Changes in Respiratory Resistance in Patients With Mild Asthma

Conflicting results from previous studies on the effect of bronchial challenge on ventilatory patterns in asthmatics may be due to airflow obstruction present before induction of bronchospasm onset, as well as the different degrees of bronchoconstriction induced. We examined the ventilatory response to stepwise increments in respiratory resistance (Rrs) induced by continuous methacholine inhalation in eight patients with mild stable asthma without airway obstruction and eight normal subjects. Methacholine was inhaled continuously during tidal breathing until a nearly two-fold increase in Rrs was observed. Respiratory parameters, including tidal volume (VT), respiratory frequency (f), inspiratory ventilation (VI), mean inspiratory flow (VT/TI), and duty ratio (TI/TT), were measured simultaneously by respiratory inductive plethysmograph (RIP). Arterial oxygen saturation (SaO2) was examined by pulse oximetry. The end-tidal CO2 fraction (FETCO2) was measured with a rapid-response infrared analyzer at the mouthpiece. Rrs, SaO2, FETCO2, and respiratory parameters, measured after saline solution inhalation, were not different between the two groups. Inhaled methacholine first decreased and then increased VI in both groups. However, changes in VI occurred earlier and to a greater extent in asthmatics than in normal subjects. At 200% Rrs (percent control), %VI was greater in asthmatics than in normal subjects (p<0.005) because of significant differences in %VT and %VT/TI between the two groups. For a given degree of bronchoconstriction, the ventilatory response was more rapid and greater in patients with mild stable asthma without airway obstruction than in normal subjects. The different response to bronchial challenge between the two groups may be due to different increases in drive due to irritant receptor stimulation.

High-resolution computed tomography of airway changes after induced bronchoconstriction and bronchodilation in asthmatic volunteers

We examined whether high-resolution computed tomography (HRCT) would detect and quantify induced airway changes in asthmatic volunteers. We performed pulmonary function tests and HRCT on eight asthmatic adults and two nonasthmatic control adults under three conditions: baseline, after methacholine inhalation, and after albuterol inhalation. Changes in pulmonary function, airway internal luminal diameter (AILD), and airway wall thickness (AWT) in the three conditions were compared. After methacholine inhalation, pulmonary function showed significant airflow obstruction in the asthmatic volunteers compared with two nonasthmatic control volunteers. The median value for AILD decreased by 17% (p = .04). After subsequent inhalation of albuterol, pulmonary function improved to above the baseline levels in the eight asthmatic volunteers. The median value for AILD increased by 18% above the baseline value (p = .001). No changes in pulmonary function or AILD were seen in the two nonasthmatic volunteers. AWT did not change significantly in either the asthmatic or nonasthmatic volunteers after inhalation of methacholine or albuterol. HRCT can quantify changes in the internal luminal diameter of asthmatic airways provoked by methacholine and albuterol inhalation.

Inhaled Corticosteroids Do Not Prevent the Development of Tolerance to the Bronchoprotective Effect of Salmeterol

Twice-daily inhaled salmeterol produces rapid reduction in its acute bronchoprotective effect against methacholine in patients with mild asthma. This investigation examined this effect in patients with moderate asthma who were using inhaled corticosteroids. Eight asthmatic volunteers who required inhaled corticosteroids for control of their symptoms and who were able to withhold treatment with beta 2-agonists for 4 weeks before and during the study participated in a double-blind, crossover, placebo-controlled study with two random-order treatment periods: inhaled salmeterol, 50 microg twice a day for seven doses, and placebo in similar fashion, with a 7-day or greater washout between these periods. Methacholine inhalation tests were done 1 h after doses 1, 3, 5, and 7, and then 24 h after the last dose of the study inhaler, 10 min post-200 microg salbutamol. Baseline FEV1 measurements before doses 3, 5, and 7 of salmeterol, ie, 12 h after salmeterol, were significantly higher than all other baseline values. Twenty-four hours after the last dose of salmeterol, the FEV1 was no different from that during the placebo period. The geometric mean methacholine concentration causing a 20% fall in FEV1 (PC20) following the third dose of salmeterol (6.8 mg/mL) was significantly lower than after the first dose of salmeterol (12.0 mg/mL; p=0.031), and this reduction of bronchoprotection persisted following doses 5 and 7. The methacholine PC20 10 min postsalbutamol measured after the salmeterol period was significantly lower than after placebo (5.6 vs 13.3 mg/mL; p<0.001). Tolerance to the acute bronchoprotective effect of salmeterol was significant after the first two doses and persisted after the seventh dose. Tolerance to the acute bronchoprotective effect of salbutamol was also significant after regular use of salmeterol for seven doses. These effects, in subjects using inhaled corticosteroids regularly, were similar to the those previously seen in patients with mild asthma using as-required beta 2-agonists only, indicating that tolerance is not prevented by use of inhaled corticosteroids.

Effect of capsaicin inhalation on methacholine responsiveness in normal subjects.

It has been reported that capsaicin stimulates bronchial C-fibers to release neuropeptides and enhances bronchial responsiveness in animal studies. This study was conducted to examine the effect of inhaled capsaicin on bronchial responsiveness in humans. A provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20-FEV1) was measured before and one hour after, one minute inhalation of 15.6 microM capsaicin solution (capsaicin day) or saline (saline day) in seven normal subjects whose PC20-FEV1 values were 40 mg/ml or less. Geometric mean value of PC20-FEV1 measured one hour after saline inhalation following pretreatment methacholine challenge was 89.3 (GSEM, 1.69) mg/ml which was significantly (p = 0.018) greater than that of the pre-treatment methacholine challenge [19.1 (GSEM, 1.37) mg/ml] on a saline day. However, PC20-FEV1 was not different before and one hour after inhalation of capsaicin [18.1 (GSEM, 1.40) and 23.1 (GSEM, 1.80) mg/ml] on a capsaicin day. The PC20-FEV1 value of the post-treatment methacholine test was significantly (p = 0.0277) lower after capsaicin inhalation than after saline inhalation while the value of pre-treatment methacholine provocation was not different between capsaicin and saline days. Change of the post-treatment PC20-FEV1 from the pre-treatment value shown as doubling concentrations was 0.35 +/- 0.60 on a capsaicin day which was significantly lower than that (2.23 +/- 0.47) on a saline day. These results confirm the decreased responses to repeated inhalation of methacholine (methacholine tachyphylaxis) in normal subjects and indicate that capsaicin inhalation reduces the methacholine tachyphylaxis.

BAY u3405, a Thromboxane A2 Antagonist, Reduces Bronchial Hyperresponsiveness in Asthmatics

Thromboxane A2 (TXA2) is reported to induce bronchial hyperresponsiveness along with the well-documented bronchoconstrictor action on smooth muscles. We examined the effect of the TXA2 antagonist, BAY u3405, on bronchial hyperresponsiveness to methacholine (MCh) in asthmatics. Twelve adult asthmatics were studied in a randomized, double-blind, placebo-controlled, crossover fashion. Following a 2-week run-in period, the subjects were administered 75 mg of BAY u3405 or placebo orally, twice a day for 2 weeks each in a crossover design, interposing a 2-week washout period. Bronchial hyperresponsiveness was measured by the astograph method. Briefly, the respiratory resistance (Rrs) was measured by the forced oscillation method during continuous inhalation of MCh in stepwise incremental concentrations, until Rrs reached twice the baseline value. Bronchial hyperresponsiveness was evaluated as the minimum cumulative dose (Dmin) of MCh that induced an increase in Rrs. Dmin was calculated so that 1 U of Dmin equals to 1 min of inhalation of aerosol solution at 1.0 mg/mL during quiet breathing. Three subjects were withdrawn from the evaluation because they had asthmatic attacks or wheezing during the study. The Dmin value of 0.533 U (GSEM 1.675) after the BAY u3405 treatment was significantly greater than that of 0.135 U (GSEM 1.969) after the placebo treatment (p = 0.0139). There were no safety concerns in either treatment group. We conclude that BAY u3405 may be a useful drug for attenuating bronchial hyperresponsiveness in bronchial asthma.