Shape and position of the complete dose-response curve for inhaled methacholine in normal subjects.

Plateaus on the inhalation concentration-response curve have been described in normal subjects and patients with mild asthma. To determine the prevalence of plateaus on inhalation concentration-response curves, and the position of the curves in normal subjects, we measured complete dose-response curves for methacholine (1 mg/ml to 256 mg/ml) in 73 nonatopic, nonsmoking, nonasthmatic normal subjects between the ages of 20 and 76 yr. Measurements included FEV1, maximal expiratory flow at 50% and 30% of vital capacity on partial and complete forced expiratory flow-volume curves (Vmax50p, Vmax50c, Vmax30p, Vmax30c) and pulmonary resistance (RL). Plateau responses, EC50 values and slopes were measured. Plateaus were present in 25, 27, 24, 34, 35, and 16 subjects for FEV1, Vmax50c, Vmax30c, Vmax50p, Vmax30p, and RL, respectively. In those who achieved a plateau, the mean maximal decrease in FEV1 (+/- SD) was 21 +/- 8%, in Vmax50c it was 46 +/- 16%, in Vmax50p it was 67 +/- 12%, in Vmax30c it was 58 +/- 21%, and in Vmax30p it was 75 +/- 15%, and the increase in RL was 213 +/- 89%. In summary, the results of this study showed that easily identifiable plateaus develop on the inhalation concentration-response curves of approximately 40% of normal subjects after only moderate decreases in maximum flow and increases in RL. Maximal response at the plateau was greater on partial flow-volume curves and at lower lung volumes (30% versus 50% of VC). Comparison of these data with data from patients at risk for airway hyperresponsiveness will allow definition of the mechanisms leading to airway hyperresponsiveness.

The time course of bronchoconstriction in asthmatics during and after isocapnic hyperventilation.

We studied the effect of changing the duration of isocapnic hyperventilation on the time course of bronchoconstriction in five subjects with asthma. Each subject performed hyperventilation challenges of 4, 8, and 16 min. No significant bronchoconstriction occurred until the hyperventilation was stopped, regardless of its duration. We found increased bronchoconstriction as the duration of hyperventilation increased. The declines in FEV1 (mean +/- SD) from baseline were 13 +/- 10%, 22 +/- 7%, and 29 +/- 12% for 4, 8, and 16 min of hyperventilation, respectively (1 versus 3, p less than 0.01). Mean times after hyperventilation until maximal bronchoconstriction were 12 +/- 4 min, 9 +/- 6 min, and 6 +/- 4 min. We also found slight bronchodilation during the first 4 min of hyperventilation. After 2 and 4 min of hyperventilation, the FEV1 was 103 +/- 5% and 103 +/- 3% of baseline, respectively (both p less than 0.05, compared to baseline). We conclude that increasing the duration of hyperventilation delays the onset of bronchoconstriction but causes greater bronchoconstriction once the hyperventilation is stopped. These results suggest that either hyperventilation itself inhibits bronchoconstriction or that the mechanisms that induce bronchoconstriction in response to hyperventilation operate after, rather than during, hyperventilation.

A model of the mechanics of airway narrowing.

To examine the interaction between airway smooth muscle shortening and airway wall thickening on changes in pulmonary resistance, we have developed a model of the tracheobronchial tree that allows simulation of the mechanisms involved in airway narrowing. The model is based on the symmetrical dichotomous branching tracheobronchial tree as described by Weibel and uses fluid dynamic equations proposed by Pedley et al. to calculate inspiratory resistance during quiet tidal breathing. To allow for changes in lung volume, we used the airway pressure-area curves developed by Lambert et al. The model is easily implemented with a spreadsheet and personal computer that allows calculation of total and regional pulmonary resistance. At each airway generation in the model, provision is made for airway wall thickness, the maximal airway smooth muscle shortening achievable, and an S-shaped dose-response relationship to describe smooth muscle shortening. To test the validity of the model, we compared pressure-flow curves generated with the model with measurements of pulmonary resistance while normal subjects breathed air and 20% O2-80% He at a variety of lung volumes. By simulating progressive airway smooth muscle shortening, realistic pulmonary resistance vs. dose-response curves were produced. We conclude that this model provides realistic estimates of pulmonary resistance and shows potential for examining the various mechanisms that could produce excessive airway narrowing in disease.

Changes in total lung capacity during acute spontaneous asthma.

An increased TLC has been reported during exacerbations of asthma, but the methods used (helium, dilution, plethysmography) have been subsequently found unreliable in the assessment of lung volumes in patients with obstructive lung disease. To address this problem, we measured TLC (TLC-XR) from posteroanterior and lateral chest roentgenograms obtained during exacerbations (E) of asthma and after recovery (R) using planimetry in 12 asthmatic subjects. At recovery, TLC was also measured by plethysmography or by helium dilution for comparison with the radiographic measurement. The plethysmographic measurements were made with a panting frequency less than 1 Hz to allow for airway obstruction. A chest radiologist also used independent radiologic measurements of hyperinflation (lung height, diaphragmatic arc height, rib counts) to assess lung volumes. Mean FEV1 during E was 1.43 +/- 0.38 L, and significant improvement occurred at R (FEV1 = 2.81 +/- 0.58 L, p less than 0.05). Of the independent radiologic variables measured, only an increase in lung height distinguished the two sets of radiographs. Mean TLC-XR (E) (6.01 +/- 1.62 L) was significantly greater than mean TLC-XR (R) (5.44 +/- 1.17 L, p less than 0.05). TLC measured radiographically at recovery was strongly correlated (r = 0.94) with TLC measured by plethysmography or helium dilution. We conclude that acute reversible increases in TLC do occur during exacerbations of asthma and that these changes are only readily detected by formal planimetry.

Respiratory muscle weakness and dyspnea in thyrotoxic patients.

Dyspnea on exertion is a frequently reported symptom of thyrotoxicosis. In the majority of cases, there is no obvious cause of dyspnea, but as skeletal myopathy is also common in thyrotoxic patients, it has been postulated that increased dyspnea could be secondary to respiratory muscle weakness. We sought to determine whether thyrotoxic patients were in fact more dyspneic on exertion than age- and sex-matched controls, and if so, whether the increased dyspnea was secondary to respiratory muscle weakness. The study group consisted of 12 thyrotoxic patients and 12 control subjects matched for age and gender. We measured lung volumes, compliance, elastic recoil, respiratory muscle strength, maximal exercise performance, and the intensity of breathlessness (modified Borg scale) at various levels of exercise in all subjects. The respiratory muscles were weaker in patients than controls. This weakness improved in treated patients (p less than 0.05) with concomitant increases in VC, IC, and TLC (all p less than 0.05). Despite this, we found no differences in breathlessness intensity scores between patients and controls or in patients before and after successful antithyroid therapy.