Methacholine Inhalation Research Articles

Prolonged asthmatic responses to inhaled methacholine

The pattern of asthmatic response after inhalation of atropine and methacholine was studied in six adult asthmatics. After pretreatment with atropine, the provocation concentration of methacholine to cause a fall in FEV 1 of 20% was increased from 0.66 ± 2.09 to 94.90 ± 1.78 mg/ml. In the subsequent 7 hr, four subjects developed prolonged asthmatic responses. These occurred after concentrations of methacholine higher than those used clinically but did not directly relate to the dose of methacholine or to the increase in dose after atropine. In one subject the prolonged response was not accompanied by increased methacholine responsiveness and was not prevented by pretreatment with cromolyn sodium (40 mg). These results show that high doses of methacholine inhaled after pretreatment with atropine can induce prolonged asthmatic responses but the mechanism is unclear.

214 Mediator release after induction of bronchospasm by inhalation of methacholine vs. treadmill exercise

214 Mediator release after induction of bronchospasm by inhalation of methacholine vs. treadmill exercise

75 Usefulness of V50 in the interpretation of the methacholine inhalation challenge test

75 Usefulness of V50 in the interpretation of the methacholine inhalation challenge test

Allergy and immunology: an annotated bibliography of recent literature. Allergy and Immunology Committee, American College of Physicians.

Allergy and immunology: an annotated bibliography of recent literature. Allergy and Immunology Committee, American College of Physicians.

Stability of stored methacholine chloride solutions: clinically useful information.

Methacholine inhalation challenge (MIC) has been shown to be an extremely useful diagnostic test. Because a decrease in the time and expense involved in the preparation of methacholine chloride solutions might encourage more laboratories to perform MIC, we assessed the stability of several different concentrations of methacholine chloride in solution over a period of 4 months. We used and compared 2 different assay techniques: a high pressure liquid chromatography assay and a colorimetric assay. Comparable results were obtained by both assays and demonstrated that methacholine solutions stored either at room temperature or at 4 degrees C showed no significant decomposition over a period of 4 months. From our results, we conclude that: (1) methacholine chloride solutions are much more stable than stated in the Merck Manual, (2) the original data of MacDonald and coworkers on the stability of methacholine chloride solution are accurate, (3) our high pressure liquid chromatography method is an accurate and highly specific technique for measuring methacholine chloride solutions. The major clinical implication of our results is that the time and cost necessary to prepare methacholine chloride solutions is much less than previously thought. This should encourage a more widespread use of this important diagnostic technique for the demonstration of bronchial hyperreactivity.

Exercise-induced release of histamine and neutrophil chemotactic factor in atopic asthmatics

Concentrations of plasma histamine and serum neutrophil chemotactic factor (NCF) were measured in seven atopic asthmatics who developed exercise-induced asthma (EIA) after a treadmill task. The results were compared with those obtained after inhalation of specific antigen or methacholine. Plasma histamine concentrations were measured with a novel double-isotope radiometric assay, and NCF was identified by its elution in the void volume fractions of Sephadex G-200 and as a single peak of activity at approximately 0.20 molar NaCl after anion exchange chromatography on diethylaminoethyl-Sephacel (pH 7.8). After exercise or antigen challenge, the time courses of appearance of both mediators were virtually identical and accompanied the increase in airways obstruction. There was a statistically significant correlation between the concentrations of histamine or NCF and the magnitude of airflow obstruction after exercise and antigen challenge. This suggested that there may be a direct association between mediator release and EIA or antigen-induced bronchoconstriction. In contrast, there were no significant elevations in circulating histamine and NC'F after inhalation of methacholine, at concentrations giving a fall in FEV 1 comparable to that induced by exercise or antigen. The prior administration of cromolyn to three asthmatics inhibited both their EIA and the release of histamine and NCF. When four asthmatics were exercised for periods of 1, 3, and 6 min, the release of NCF and fall in peak expiratory flow rate were directly related to the duration of the exercise. The rise of NCF activity in subjects with EIA was fivefold greater than that observed in asthmatics who did not experience airways obstruction when subjected to the same exercise task. These results provide further evidence that mediators of hypersensitivity are released during EIA.

A Screening Test for Airways Reactivity: An Abbreviated Methacholine Inhalation Challenge

A screening test to measure nonspecific airways reactivity was developed and compared to a standard methacholine inhalation challenge in 13 asthmatic patients and ten normal control subjects. The screening challenge consisted of one deep breath, then four breaths of a 5 mg/ml methacholine solution followed by one and four breaths of 25 mg/ml of methacholine. Subjects with a history of wheezing received the 5 mg/ml of methacholine first while those without a history of asthma began the challenge at the 25 mg/ml methacholine concentration. Spirometric test were employed and the challenge was terminated when FEV1 fell 20 percent from baseline. The standard methacholine challenge used a dosimeter and all subjects took five breaths of saline solution followed by seven increasing concentrations of methacholine. Dose response curves were constructed and the provocation dose of methacholine that caused a 20 percent fall in FEV1 was calculated for each protocol. Results of the screening methacholine challenge correlated with those obtained from the more lengthy standard protocol (r = 0.94), and correctly identified levels of airways reactivity in asthmatic patients and normal subjects. The abbreviated protocol was rapid (6-12 min), safe, and inexpensive. Since the equipment is readily available and easy to transport, it could be used at sites outside the hospital as a screening test for nonspecific airways reactivity.

Bronchial responsiveness to inhaled methacholine in young asymptomatic smokers

Methacholine inhalation challenges were performed in 10 young smokers who denied having respiratory symptoms and in 10 nonsmokers of the same age. There were five males and five females in each group. The bronchoconstriction was evaluated with specific lung conductance (sGL), maximum partial (initiated from end-inspiratory lung volume) expiratory flows assessed at 40% vital capacity breathing air (Vmax40p air), and a He-O2 mixture (Vmax40p He), and with maximum complete flows breathing He-O2 [forced expiratory volume at 1 s (FEV1), Vmax50c He]. Dose-response curves were studied for 1) threshold concentration (TC) where values depart by more than two SD from base line; 2) provocative concentration (PC) causing a fixed fall in a parameter. Smokers differed significantly from nonsmokers for TC and PC accessed by Vmax40p He (P less than 0.001 and P less than 0.01, respectively), Vmax40p air (P less than 0.01), and Vmax50c He (P less than 0.01 and P less than 0.05, respectively). TC and PC estimated by sGL and FEV1 were not significantly different. Males and females showed a similar reaction.

Arterial desaturation during continuous methacholine inhalation in rhinitis suspected and proven asthma

Arterial desaturation during continuous methacholine inhalation in rhinitis suspected and proven asthma

Comparison of cold air hyperventilation challenges (CAHC) and methacholine inhalation challenges (MIC) in asthmatics

Comparison of cold air hyperventilation challenges (CAHC) and methacholine inhalation challenges (MIC) in asthmatics

Inhalation patterns and predominant site of bronchoconstriction in healthy subjects.

To determine the relationship between changes in density dependence of maximal expiratory flow and changes in the predominant site of bronchoconstriction, we altered the pattern of inhalation of a methacholine aerosol to achieve deposition either centrally (by short choppy breaths) or peripherally (by slow deep breaths). Partial expiratory flow volume curves on air and on 80% helium-20% oxygen (HeO2) were recorded in six healthy subjects before and after each pattern of methacholine inhalation. We varied concentrations of methacholine and number of inhalations to achieve equivalent degrees of bronchoconstriction as assessed by decreases in maximal flow (Vmax) on air, which fell 27% from control values. Vmax on HeO2 also fell after both inhalation patterns. Density dependence (Vmax on HeO2 divided by Vmax on air) decreased following slow deep breaths of bronchoconstrictor aerosol, and increased following short choppy breaths. In three subjects, inhalation of radiolabeled methacholine aerosol confirmed that the slow deep pattern was associated with a diffuse, more peripheral deposition, whereas the short choppy pattern led to central deposition. We conclude that changes in density dependence reflect the predominant site of obstruction after acute methacholine aerosol challenge in healthy subjects.

Direct graphical recordings of the cumulative dose-response curves of the airway to methacholine in normal, bronchitic and asthmatic subjects.

We studied bronchial responsiveness to methacholine in 10 normal subjects, in 60 patients with bronchial asthma and in 30 patients with bronchitis using a new device, with which we were able to obtain the dose-response curve of respiratory resistance (Rrs) continuously and graphically by the 3 Hz oscillation method during inhalation of methacholine. All normal subjects were non-responders, while all of the bronchial asthma cases, 63% of the chronic bronchitis cases and 50% of the acute bronchitis cases were responders. Among responders we found a very poor correlation between the initial respiratory conductance (Grs.cont) and the bronchial sensitivity (defined as the reverse of the cumulative dose until Rrs starts to increase); yet we found a good correlation between Grs.cont and the bronchial reactivity (defined as the slope of the decreasing rate of Grs). Metaproterenol and atropine decreased the bronchial sensitivity and reactivity in 28 asthmatic patients. We concluded that for clinical purposes the new method was very useful for assessing bronchial responsiveness to inhalation challenge because of its simplicity of operation as well as the quantitative differentiation between bronchial sensitivity and reactivity. Our results suggest that the bronchial response system to methacholine is explainable by a model of multiple dose-response curves without any parallel shift.

Effects of volume history and time dependence of flow-volume curves on assessment of bronchial response to inhaled methacholine in normals.

The behavior of maximum expiratory flow-volume curves and partial expiratory flow-volume curves with and without volume history of total lung capacity was studied in 11 healthy subjects before and after methacholine inhalation challenge. Flow-volume curves were superimposed at absolute lung volumes by measuring thoracic gas volumes at which inspiratory maneuvers began. The results show that maximum inspiratory effort reduced significantly residual volume, either before or after challenge, while flow rates at 40% of control total lung capacity achieved with partial expiratory flow-volume curves with history of total lung capacity were significantly greater than those without history of maximal inflation. These findings are explained by the stress relaxation as an effect of volume history ot total lung capacity and by the appearance of time dependence as an index of inhomogeneity of lung emptying. After methacholine the effects of volume history on maximum flows and residual volume were increased. In conclusion, the results of this study emphasize the probability of errors when only maximum expiratory flow-volume curve are used in assessment of bronchial responses.

Bronchial hyperreactivity to methacholine in farmers' lung disease

Methacholine inhalation challenges were performed in five groups: 14 patients with history of farmers' lung disease (FLD), nine well farmers with precipitating antibodies to Micropolyspora faeni antigen, 11 normal subjects, 12 asthmatic patients, and 10 patients with interstitial lung disease (ILD) other than hypersensitivity pneumonitis. After calculating the mean areas under the dose-response curves, FLD patients had a significantly greater degree of methacholine sensitivity than did well farmers with M. faeni antibody and normals. However, the methacholine sensitivity of FLD patients was indistinguishable from a group of patients with ILD and significantly less than the asthmatic group. Fifty percent of patients with FLD had positive methacholine challenges (≥20% decrease in their 1-sec forced vital capacity [FEV 1 ] from the control FEV 1 ). Hyperirritable airways was a common finding in FLD.

Comparison of plasma histamine and cyclic nucleotides after antigen and methacholine inhalation in man

Serial determinations of plasma histamine and cyclic nucleotides (adenosine monophosphate [AMP] and guanosine monophosphate [GMP]) were performed after inhalation of antigen and methacholine in four groups of subjects. In the first group, consisting of six antigen-sensitive subjects exhibiting bronchospasm after inhalation of ragweed or grass antigen, plasma histamine was elevated within 2 min and persisted for 30 min after inhalation of antigen. Peak histamine levels were between 18 to 80 ng/ml. In the second group, consisting of four nonatopic subjects, neither bronchospasm nor histamine was observed, despite inhalation of the same or 10-fold increased concentrations of antigen. In the third group, consisting of six subjects (three atopic and three nonatopic) exhibiting bronchospasm after inhalation of 2.5 to 10 mg of methacholine, sustained increases of histamine began at 1 min and persisted for 60 min after inhalation of methacholine. In the fourth group, seven subjects (two atopic, five nonatopic) without demonstrable bronchospasm despite inhalation of 2.5- to 10-fold increased doses of methacholine, no histamine was detected in the plasma at any time after inhalation of methacholine. Serial measurements of cyclic nucleotides showed no consistent changes in serum levels of cyclic AMP or cyclic GMP following inhalation challenge. We conclude that serum levels of histamine but not cyclic nucleotides change during bronchospasm induced by either antigen or methacholine.

Methacholine inhalation challenge studies

Methacholine sensitivity has become a valuable and widely used technique for studying the irritability of the airways. Asthmatics are lOOto l,OOO-fold more sensitive than normal subjects to various mediators such as methacholine (P-acetyl methacholine).‘-” This degree of sensitivity has been used to define asthma and also as a genetic marker.l The methacholine responsiveness may be determined by 1 of 2 methods: (1) by determining dose-response curves to increasing concentrations of methacholine while keeping the number of breaths and the volume of methacholine inhaled constant” and (2) by determining dose-response curves by keeping the concentration constant while increasing the number of inhalations of methacholine.” The first method is currently being used more widely and has been recommended by the American Academy of Allergy to provide a standard and uniform method. It is described in detail elsewhere.” The second method has been used since 1962 and has been the basis for a number of short-term and long-term studies. We have recently compared both of these methods to determine the short-term reliability of each method. The dose-response curves and thus the degree of bronchial sensitivity were determined in 19 subjects in a randomized 4-way crossover study. Each subject was challenged twice by each method at 1-wk intervals. The short-term reproducibility for both methods was good (r = 0.934 and 0.942). The correlation between methods was also significant (r =0.953). The various pulmonary function parameters that can be evaluated during an inhalation challenge are numerous and include the FVC, FEV,, SG,,,, FEF,,-,,, PEFR, flow volume loops, etc. The easiest and the most widely used currently is the FEV,, which is the minimum requirement for comparison of responses as recommended by the Standardization Committee, j

Relationship between airways response to allergens and nonspecific bronchial reactivity

Bronchial inhalation challenges to histamine, methacholine, and at least one antigen were performed on 183 asthmatic patients who previously had received skin tests to at least 16 different antigens. Individuals with a positive skin test and a positive antigen inhalation challenge to the same antigen had lower thresholds of response to both histamine and methacholine. This pattern was statistically significant for mixed trees, mixed grasses, mixed molds, and house dust but not for mixed ragweed. For those individuals who had a negative antigen inhalation challenge, skin test reactivity (positive or negative) alone was not associated with a different threshold of response to histamine or methacholine. Also, a higher percentage of positive antigen inhalation challenges were seen in the group of individuals with a low threshold of response to both histamine and methacholine than in groups with either a moderate or high threshold of response to these chemical agents. The results imply that at least two factors are associated with a positive bronchial inhalation challenge to a specific antigen: nonspecific airways hyperreactivity, as indexed by a methacholine or histamine inhalation challenge, and a positive skin test.

Bronchial inhalation challenge with antigens

In the following discussion, we will cover certain aspects of (1) antigen inhalation challenge with emphasis on clinical usefulness and (2) recent observations regarding methacholine and histamine inhalation challenges which have not been discussed by the other speakers at this Workshop. Due to time limitations we will present generalizations and hope that the details of these generalizations will emerge during subsequent sessions.

Methacholine and histamine inhalation challenges in asthma: relationships to age of onset, length of illness, and pulmonary functions.

Levels of airways hyperreactivity, as indexed by methacholine and histamine thresholds, were determined for hospitalized asthmatic patients using the serial concentration, constant-breath method. Airways hyperreactivity was categorized into low and high based on a split of the sample of subjects tested. These categories were unrelated to pulmonary function measurements obtained throughout hospitalization. Patients having high airways hyperreactivity to histamine or methacholine were admitted for intensive inpatient care at a young age, had an earlier age of onset, and had asthma of longer duration than patients having low airways hyperreactivity. These latter results suggested that relatively greater airways hyperreacticity is more likely to be associated with early onset of the illness.

Airway Response to Hair Spray in Normal Subjects and Subjects with Hyperreactive Airways

Short-term 20-second exposure to hair sprays A and B failed to show significant decreases in maximum expiratory flow rates at low pulmonary volumes in normal subjects; however, significant decreases were observed with hair spray B in eight subjects with hyperractive airways (abnormal response to inhalation of methacholine). On the partial flow-volume curves, flows at 40 percent and 25 percent of forced vital capacity decreased 8.9 to 10.3 percent and 14 to 18.7 percent, respectively. The hair sprays differed in their content of perfume and plasticizer, and since the latter is generally considered nontoxic at room temperature, the perfume may be the responsible agent. It would appear from this study that normal healthy individuals are at little risk, at least from brief exposure to hair spray; however, in the presence of hyperreactive airways, as seen in asthmatic subjects and in some people with allergic rhinitis and viral respiratory infections, an immediate response of the airways may result from exposure to some hair sprays.