To investigate the effects of methacholine (MTH) challenge on spirometry, lung mechanics, respiratory gases, and ventilation-perfusion (VA/Q) distributions, 16 subjects 16 to 58 yr of age with stable mild asthma (FEV1, 92 +/- 5% [SEM] predicted; FEF25-75, 71 +/- 7% predicted; respiratory system resistance (Rrs) at 4 Hz, 4.6 +/- 0.4 cm H2O/L-1 s; Pa(O2), 88 +/- 3 mm Hg; AaP(O2), 23 +/- 3 mm Hg) were recruited. Baseline VA/Q distributions were unimodal and relatively narrow in 12 patients and modestly bimodal in the other four. The dispersion of pulmonary blood flow (log SD Q) was slightly enlarged (0.71 +/- 0.09) and that of ventilation (log SD V) was normal (0.57 +/- 0.04) (normal range, 0.3 to 0.6); an index of overall VA/Q heterogeneity (DISP R-E*) was also mildly abnormal (5.3 +/- 0.8) (normal values < 3.0). After MTH challenge, FEV1, FEF25-75, and Pa(O2) fell (to 62 +/- 3 and 35 +/- 3% predicted, and to 71 +/- 1 mm Hg, respectively), whereas Rrs (p < 0.001 each), minute ventilation (p < 0.02), heart rate (p < 0.01), and AaP(O2) increased (p < 0.001). VA/Q relationships mildly to moderately worsened (log SD Q increased to 0.98 +/- 0.04 [p < 0.01], log SD V to 0.79 +/- 0.04, and DISP R-E* to 9.8 +/- 0.6 [p < 0.001 each]). Qualitatively, the pattern of blood flow distribution was broadly unimodal in 13 patients and modestly bimodal in three, of whom only one had a bimodal baseline distribution. Pre-MTH to post-MTH challenge changes in Rrs were correlated to the changes in both log SD V (r, 0.65) and DISP R-E* (r, 0.63) (p < 0.01 each). After these measurements (15 min after MTH), eight patients received placebo and eight received salbutamol by inhalation in randomized double-blind fashion. By 30 min after challenge, patients given placebo showed improved maximal expiratory rates, whereas Rrs and gas exchange remained essentially unchanged from the 5-min post-MTH levels. Salbutamol significantly improved not only airflow rates but also Rrs and all the indices of pulmonary gas exchange. Our results indicate that after MTH challenge there is dissociation between spirometry and gas exchange, just as is often seen in moderate to severe adult asthma. Although less severely, MTH appears to represent, at least from a gas exchange viewpoint, a model of asthma similar to what has been observed during the natural course of the disease over a much longer period of time.
