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PubMed1985

The effect of inspiratory flow rate regulation on nebulizer output and on human airway response to methacholine aerosol.

Increased inspiratory flow rate has been demonstrated to decrease pulmonary deposition of inhaled aerosols. To study the effect of inspiratory flow rate regulation on the physiologic response to an active substance administered by aerosol, we compared the effect of high unregulated flow rate (66 to 212 L/min) with regulated low flow rate (20 to 35 L/min) on nebulizer output and on the pulmonary response to methacholine in patients with asthma. Four No. 646 DeVilbiss nebulizers were used in sequence with a nebulization dosimeter to deliver tenfold incremental concentrations of methacholine aerosol (mass median aerodynamic diameter = 1.52 micron; geometric standard deviation = 1.96) ranging from 0.025 to 25 mg/ml. When flow was unregulated, nebulizer output was not greater than when flow was regulated, but coefficients of variation of output were significantly greater (p less than 0.01). The PD20 on the two unregulated days was significantly different (p = 0.01), whereas the PD20 on the two flow regulated days was not significantly different (p greater than 0.05). We conclude that regulation of inspiratory flow rate at rates within the range of tidal breathing significantly decreases variability in nebulizer output and variation of pulmonary responses to methacholine challenge.

Aerosols↗
PubMed1985

Quantitative assays of pharmacologic aerosols used in studying asthma.

To more nearly accurately quantitate the dose of pharmacologic agents delivered to human and animal airways via aerosols, we have developed a monodisperse aerosol containing either methacholine or histamine that permits a light scattering device (tyndallometry) to measure accurately the quantity of inspired and expired particles. These aerosols (described in previous studies) are simultaneously tagged with a radioactive label (technetium 99m) to permit the use of external gamma camera imaging. Present work focuses on the development of assay techniques to measure the quantity of methacholine delivered in these aerosols. The lack of specific radioimmune or radioenzyme assays coupled with the cross-reaction of organic contaminants with conventional chemical reagents for measuring methacholine required the development of separative techniques to isolate the methacholine from the organic aerosol contaminants. With aqueous extraction and column separation we have been able to completely isolate the methacholine from these contaminants. This allows the application of standard spectrophotometric assays for methacholine to quantitate the methacholine in the resulting solution. These separative techniques will permit the use of these aerosols in quantitative studies of airway reactivity.

Aerosols↗
PubMed1985

The effect of age on methacholine response.

Bronchial reactivity to inhaled methacholine exists in subjects with asthma but may occur in subjects with allergic rhinitis, chronic lung diseases, and during respiratory infections. In the absence of these factors, we found that age also has a significant effect on the methacholine response. One hundred forty-eight subjects, 5 to 76 years of age, were studied as normal control subjects in a natural history of asthma study. The methacholine response was measured by standard techniques. The analysis demonstrated that age had a significant effect on the methacholine response. In addition to known factors influencing the results of methacholine inhalation, young and older subjects may exhibit bronchial responses that may falsely suggest hyperreactive airway disease.

Adolescent↗
PubMed1985

The effect of ketotifen on bronchial hyperreactivity in childhood asthma.

Eighteen children with perennial bronchial asthma with an average age of 9.6 yr were studied with respect to the protective effect of ketotifen on bronchial hyperreactivity. All children included demonstrated bronchial reversibility after inhalation of salbutamol, and the methacholine challenge produced a decrease of the forced expiratory volume during the first second of at least 20% in the concentration interval of 0.25 mg/ml to 4.0 mg/ml. The study was double-blind with patients divided into two parallel groups treated for 12 wk with ketotifen or placebo. Methacholine provocation tests were performed every fourth week during this period. No differences between the challenges before and during the treatment period were found in either group, nor were any differences found between the ketotifen and placebo groups. Long-term treatment with ketotifen does not appear to alter the bronchial hyperreactivity in children with bronchial asthma.

Adolescent↗
PubMed1986

Increase in gastroesophageal reflux during methacholine-induced bronchospasm.

There is an increased incidence in gastroesophageal reflux (GER) in subjects with asthma. The cause-effect relationship remains controversial. We compared 15 subjects with mild asthma to 15 control subjects (nonasthmatic) to ascertain if GER might be induced by bronchospasm. Continuous monitoring of lower esophageal sphincter pressure and pH at 5 cm above the lower esophageal sphincter was performed in seated subjects for 3 hours in total: 1 hour of baseline measurements, 1 hour of methacholine inhalation with a dosimeter, and 1 hour after the inhalation of 200 micrograms of salbutamol (albuterol). During bronchospasm, subjects with asthma had more episodes of GER (3.9 +/- 1.5) and dropped their pH to lower levels (pH 2.23 +/- 0.3) than did the control subjects (0.8 +/- 0.3 episodes, pH 3.22 +/- 0.3) p less than 0.05. We conclude that in these subjects with mild asthma, methacholine-induced bronchospasm produced GER episodes of greater frequency and severity.

Adult↗
PubMed1986

The origin of airway hyperresponsiveness.

Consideration of the origin of airway hyperresponsiveness appears central to understanding the origin of asthma. Subjects with and without asthma differ both in the ease with which airway narrowing is produced by inhalation of histamine or methacholine and in the ability to demonstrate a maximal response to these agents. The latter appears, on present evidence, to be due to an added mechanism in asthma rather than the absence of a potent inhibitory process. Airway hyperresponsiveness is probably acquired during life as a result of airway reactions to various stimuli, although genetic factors such as atopy are likely to predispose the person to develop hyperresponsiveness. Environmental stimuli include inhaled allergens, chemical sensitizers, airway infections, immunization, and ozone. Allergen-induced airway hyperresponsiveness occurs in association with late-phase asthmatic responses. This and ozone-induced hyperresponsiveness have been demonstrated to be associated with release of chemical mediators and the cellular phase of inflammation. Their effect does not appear to be accounted for by increase in airway epithelial permeability, decrease in airway caliber, reflex bronchoconstriction, or beta-adrenoceptor blockade. The mechanism(s) responsible for the induced hyperresponsiveness are unknown but may involve airway epithelial damage, edema in and around the airway walls, stimulation of the noncholinergic excitatory or inhibition of the nonadrenergic inhibitory systems, or a change in function of airway smooth muscle. Airway hyperresponsiveness can be transient or persistent. Transient increases in responsiveness are almost certainly associated with mediator release and inflammation. It is not known whether persistent hyperresponsiveness is due to the same process, fired, for example, by leaky mediator-releasing cells and/or to some persisting change in neurogenic or smooth muscle function.

Allergens↗
PubMed1986

Predictive accuracy of late asthmatic reaction to Dermatophagoides pteronyssinus.

Sixteen patients with asthma were challenged with solutions of Dermatophagoides pteronyssinus extracts. Fifteen patients demonstrated an early asthmatic reaction, and 10 patients also demonstrated a late asthmatic reaction, as demonstrated by a 15% decrease of FEV1 within 1 hour or between 3 and 8 hours after challenge, respectively. Airway responsiveness to inhaled methacholine, expressed as the dose causing a fall of FEV1 of 15% (Pd15), and the serum IgE level (RAST), expressed as percent of the total radioactivity added, were also measured. Multiple regression analysis of data demonstrated that both early asthmatic reaction, expressed as the allergen Pd15, and late asthmatic reaction, expressed as the FEV1 maximum fall from control values, can be predicted with similar accuracy (explained variance of 63% and 68%, respectively) by a model that incorporates simultaneously methacholine Pd15, percent of total radioactivity added by RAST, and baseline values of FEV1. We conclude that the late asthmatic reaction is more likely to occur and is more severe in patients with more severe underlying disease.

Adolescent↗
PubMed1986

Late bronchial response and increase in methacholine hyperresponsiveness after exercise and distilled water challenge in atopic subjects with asthma with dual asthmatic response to allergen inhalation.

We investigated the occurrence of late asthmatic response and increased methacholine responsiveness after exercise and ultrasonically nebulized distilled water (UNDW) inhalation in 12 subjects with asthma with dual asthmatic response and increased responsiveness after allergen challenge. On 3 separate days, allergen, exercise, and UNDW challenges were performed 2 hours after methacholine. FEV1 was measured for 8 hours to detect any delayed change in airway caliber. If there were a further significant reduction in FEV1 after the recovery from the immediate bronchoconstriction, methacholine challenge was performed again when FEV1 had returned to baseline. Reproducibility of any observed late response to exercise and UNDW was also investigated by repeating these challenges on 2 subsequent days. After allergen inhalation only nine subjects had an early asthmatic response, whereas all the tested subjects demonstrated a late reaction and increased methacholine responsiveness. Ten subjects had an immediate response to exercise, and this was followed by a late response in only four patients. Nine subjects demonstrated early response to UNDW inhalation, and five subjects also had a late reaction. These late responses were associated with an increase in methacholine responsiveness in a subset of the tested subjects. Late-phase reactions to exercise and UNDW were not reproducible.

Administration, Inhalation↗
PubMed1986

Beta-adrenergic responses in drug-free subjects with asthma.

Young atopic subjects with asthma who had taken no medication for 30 days and had normal pulmonary function were compared to atopic and nonatopic control subjects in several measures of beta-adrenergic response. Subjects with asthma required a larger dose of infused isoproterenol (14.3 +/- 3.9 ng/kg/min) to increase pulse pressure by a target greater than 22 mm Hg than nonatopic control subjects (8.7 +/- 3.3 ng/kg/min). Asymptomatic atopic control subjects had intermediate sensitivity (12.0 +/- 6.0 ng/kg/min) (F = 3.67; p less than 0.05). At the dose of infused isoproterenol producing the target pulse pressure response, the increase in low-frequency (1 to 8 cycles per minute) heart rate variability was less in subjects with asthma (107 +/- 34% increase in normal subjects versus 9 +/- 21% increase in subjects with asthma; p less than 0.05). In addition, subjects with the least beta-adrenergic responsiveness had the most reactive airways. Airway reactivity (assessed by the provocative concentration of methacholine causing a 20% fall in FEV1) correlated with both the dose of isoproterenol required for the target pulse pressure response (Rs = -0.46; p less than 0.05) and the isoproterenol-induced increase in low-frequency heart-rate variability (Rs = 0.47; p less than 0.05). In contrast, in lymphocytes and granulocytes from these same subjects, the cAMP response to isoproterenol and beta-adrenergic receptor number were identical in normal subjects and subjects with asthma and unrelated to airway reactivity or to cardiovascular beta-adrenergic responses. Thus, different results for beta-adrenergic responsiveness in subjects with asthma are obtained in different tests in the same subjects.

Adult↗
PubMed1987

A new method of inhalation challenge with propranolol: comparison with methacholine-induced bronchoconstriction and role of vagal nerve activity.

To establish a safe procedure for examining propranolol-induced bronchoconstriction, we have developed a new method for performing inhalation challenge with propranolol. Monitoring respiratory resistance during tidal breathing with continuous inhalation of propranolol in 1.5-fold increasing concentrations from 0.78 to 30 mg/ml for 1 minute at each concentration, we tested 43 subjects with stable asthma and 10 normal subjects. We also compared bronchial responsiveness with responsiveness to inhaled methacholine on separate days. In addition, to determine the role of vagal nerve activity in propranolol-induced bronchoconstriction, we studied the effect of atropine. Inhaled propranolol caused dose-related bronchoconstriction in all subjects with asthma but not in normal subjects. None of the subjects suffered severe asthmatic attack during the test, which was performed in 15 minutes or less. The minimum cumulative dose of methacholine and of propranolol, at the point where respiratory conductance began to decrease, was not significantly correlated. Increased respiratory resistance was reversed by atropine in 70% of the subjects with asthma with marked individual differences. These data suggest that, although in most subjects with asthma, vagal nerve activity contributes in varying degree to bronchoconstriction, other constricting factors may contribute in the remaining subjects. It is also suggested that the mechanism of bronchial response to propranolol differs from that of the nonspecific airway reactivity estimated by methacholine challenge.

Adolescent↗
PubMed1987

The role of the methacholine challenge in children with chronic cough.

Thirty-nine male and 35 female subjects, aged 6 to 20 years, with chronic cough were studied with spirometry and standard methacholine (MCH) challenge. The duration of their cough before the MCH challenge ranged from 2 months to 13 years. Their FEV1 ranged 62% to 132% predicted. Thirty-six (49%) patients had a positive MCH challenge. The MCH concentration inhaled to decrease the FEV1 by 20% ranged from 0.55 to 25 mg/ml. Follow-up data (mean 14 months) were available on all 74 patients. Fifty-four patients received asthma medications, and 93% improved in mean 3.6 weeks. At the end of the follow-up, 22 (30%) were asymptomatic, 39 (53%) were improved, and 13 patients (17%) were symptomatic. We were unable to predict bronchial hyperreactivity in this population on the basis of duration of the cough, personal or family history of allergies, or baseline spirometry. Thus, MCH challenge is helpful in evaluating children with chronic cough and in guiding therapy. Follow-up of children with chronic cough is important. Eleven percent of this study population progressed to develop bronchial asthma. Forty percent of these patients, initially doing well, were asymptomatic at the end of the follow-up period.

Adolescent↗
PubMed1987

Effect of terfenadine on methacholine-induced bronchoconstriction in asthma.

The dose-response effect of nonsedating H1 histamine-receptor antagonist, terfenadine, administered orally in single doses, was studied on methacholine-induced bronchoconstriction in nine patients with extrinsic bronchial asthma in a double-blind, placebo-controlled, crossover trial. The doses of terfenadine used were 60 mg, 120 mg, and 180 mg, producing small but significant bronchodilator effect with all three doses at 2 hours. This response was still present at 4 hours. However, the provocative dose causing a 20% fall in FEV1 for methacholine was unaffected by all three doses of terfenadine. The bronchodilator response induced by antihistamines, including terfenadine, suggests an increased resting tone mediated by the constant presence of free histamine in the vicinity of H1 receptors in the airways and that methacholine acts directly on the airway muscarinic receptors and is not involved in local histamine release.

Adolescent↗
PubMed1987

Prevalence and characteristics of late asthmatic responses to exercise.

The prevalence and characteristics of late asthmatic responses to exercise were studied in an adult asthmatic population. Twenty-four subjects (eight male and 16 female), aged 17 to 39 years (mean, 23.7 years), performed a 6-minute exercise on a bicycle ergometer at 75% of their maximum oxygen intake. FEV1 was measured at regular time intervals up to 8 hours after exercise. Seven subjects demonstrated a late asthmatic reaction defined as a fall in FEV1 greater than 10% between 2 to 8 hours. Bronchial reactivity to histamine was unchanged 24 hours after the exercise, compared to baseline. On a control day, a fall in FEV1 similar to the one observed after exercise was induced by methacholine inhalation. Measurements of FEV1 were done at the same time intervals as on exercise day. Neutrophil chemotactic activity was measured in the serum of 15 subjects, on exercise day for early responders, and on the 3 test days for subjects with a dual response. There was no difference between subjects with an isolated early or late response for age, sex, or atopic status. Baseline expiratory flows and nonspecific bronchial reactivity to histamine were similar in both groups. These results demonstrate the occurrence of a late asthmatic response in 30.4% of the population studied. There was no significant change of nonspecific bronchial responsiveness after the late asthmatic response to exercise. No significant increase in neutrophil chemotactic activity could be observed.

Adolescent↗
PubMed1987

The relationship between mast cell-mediator release and bronchial reactivity in allergic asthma.

The relationship between mast cell-mediator release and nonspecific bronchial reactivity was investigated in allergen-induced asthma. Two groups of subjects with asthma, one group with markedly reactive airways (provocative concentration of methacholine causing a 20% fall in FEV1, 0.07 mg/ml) and the other group with less reactive airways (provocative concentration of methacholine causing a 20% fall in FEV1, 3.83 mg/ml), had allergen bronchoprovocation. After challenge, bronchoconstriction was measured as change in specific airway conductance (SGaw), and mast cell-mediator release was measured as change in both plasma histamine and serum neutrophil chemotactic activity (NCA). In the group with more reactive airways, allergen challenge, while it produced a mean fall in SGaw of 58.1%, was not associated with any significant increase in plasma histamine from a mean resting level of 3.69 nmol/L-1. In contrast, a comparable mean fall in SGaw of 52.4% in the group with less reactive airways was associated with a significant (p less than 0.005) increase in plasma histamine from 1.17 to 3.60 nmol/L-1, maximal 5 minutes after allergen challenge. There were, however, significant increments in serum NCA in both groups with asthma after allergen challenge. The changes in NCA in the group with less reactive airways (136.7 +/- 38.1% above baseline; p less than 0.01; 1% sera dilution) were significantly greater (p less than 0.05) than changes identified in the group with more reactive airways (68.3% above baseline; p less than 0.01; 20% sera dilution). These findings directly support the concept that both mast cell-mediator release and nonspecific bronchial reactivity are separate factors that influence the airway response to inhaled allergen in asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Distribution of methacholine inhalation challenge responses in a selected adult population.

To determine bronchial reactivity patterns in adults, 211 subjects, 22 to 86 years of age, underwent a methacholine challenge in a Natural History of Asthma study. The diagnosis of asthma or nonasthmatic allergic diseases was based on a standardized respiratory questionnaire. Subjects were nonsmokers and had not had an infection for 1 month. Intradermal skin tests were done to a battery of common antigens. The methacholine challenge response was expressed as the area under the dose-response curve integrated to a 35% fall in the FEV1 or 800 breath units. Thirty-three subjects with asthma, 47 normal subjects from normal families (NF), 59 normal subjects from families with asthma (AF), 31 allergic subjects without asthma, 23 subjects with questionable asthma, and 18 subjects with prior asthma were studied. Overall, 50% of the subjects without asthma had a negative response to methacholine. There was a difference (p less than 0.02) in the distribution of log10 methacholine area under the dose-response curve integrated to a 35% fall in the FEV1 or 800 breath units responses in normal subjects from NFs compared to normal subjects from AFs. The allergic subjects from AF had a greater degree of bronchial reactivity compared to normal individuals from NF. The age of the normal subjects had an influence on the degree of bronchial reactivity. Methacholine challenge studies in adult patients need to be interpreted with age and family history in mind.

Administration, Inhalation↗
PubMed1988

Cat- or dog-induced immediate and late asthmatic responses before and after immunotherapy.

To assess the effect of specific immunotherapy (IT) on the immediate and late asthmatic responses induced by cat or dog extract bronchial provocation testing, we studied seven cat-sensitive and six dog-sensitive subjects with asthma. Among the cat-sensitive subjects, two of three subjects displaying only an immediate asthmatic response before IT lost the response after 3 months of IT with cat extract, whereas only one of four subjects with the dual (immediate and late) asthmatic responses had ablation of such responses (no significance for the one-tailed test). Three subjects had worsening of the immediate response after IT. Among dog-sensitive subjects with asthma, three of five subjects with only an immediate response demonstrated an ablation of the immediate response, whereas the one subject who was the only subject with a dual response before IT lost the dual response after dog-extract IT (p value of 0.005 on one-tailed test). Immediate systemic side effects, including one episode of anaphylaxis, occurred on seven occasions of 326 injections with cat extract compared to only one episode of rhinitis of 289 injections with dog extract.

Adult↗
PubMed1988

Leukocyte count and bronchial hyperresponsiveness.

The relationship of total and differential blood leukocyte counts with bronchial methacholine response was studied in a population-based sample of 324 men. Geometric mean total leukocyte counts were significantly higher in reactors (6567 cells/mm3) than in nonreactors (5732 cells/mm3; p = 0.003). After adjusting for smoking habits, a factor contributing to both an elevation in peripheral leukocyte count and an increased level of airway responsiveness, reactor status remained significantly associated with leukocyte count. This association also persisted after controlling, with a logistic model, for atopy and common cold (marker of infection) and after excluding men with a history of asthma, chronic bronchitis, or low FEV1. Study of the differential leukocyte counts has shown that an increase was present for almost every type of leukocyte, and particularly evident for neutrophils. Whether these findings reflect an association between bronchial hyperresponsiveness and cellular inflammation needs more investigation.

Adult↗