Increase in Bronchial Responsiveness to Methacholine and Late Asthmatic Response Outcomes

Team of Asthma Inhalers Online presents this topic overview in article “Increase in Bronchial Responsiveness to Methacholine and Late Asthmatic Response“.

Preliminary Study

The mean values for PC20UNDW (± SD in log scale) observed during three successive challenges with ultrasonically nebulized distilled water were 2.24 ± 0.80, 2.15±0.69, and 2.04±0.62 ml/min. These values were not significantly different by analysis of variance (p>0.1). No subject showed any progressive shifting to the right of the output-response curve indicative of refractoriness (Fig 1).

Spontaneous Variability of FEV1 and PC20M

On the first day, no subject had a change in FEV1 greater than 10 percent from the initial baseline value over the eight-hour period of study; thus, any fall in FE Vx greater than 10 percent occurring after the recovery from the immediate response to inhalation of distilled water was regarded as indicative of a late response. On the second and third days the response to inhaled methacholine was reproducible (Table 2). In all of the tested subjects, PC20M varied by less than twofold (Table 2); a decrease in this value greater than twofold was therefore regarded as indicative of increased hyperresponsiveness.
Ultrasonically Nebulized

Methacholine Challenge After Stimulation with Distilled Water

The subjects had a range of responsiveness to ultrasonically nebulized distilled water (Table 3). All showed a significant increase in responsiveness to methacholine soon after the recovery from broncho-constriction induced by distilled water (p<0.01) (Table 4 and Fig 2).

After two hours the mean PC20M was still significantly lower than mean baseline value (p<0.05) (Table 4); at this time the reduction in PC20M waned in eight of the tested subjects, and PC20M returned to within a twofold concentration difference from the baseline PC20qM in five of them (Table 4). On the contrary, subjects 3 and 9 had a further increase in hyperresponsiveness to methacholine (Table 4 and Fig 2).

The change in responsiveness to methacholine was not due to differences in the FEVX before methacholine because resting values for FEVx (mean percent predicted ± SD) before the first (90.9 ±11.2) and the second challenge (94.5 ± 11.9) with methacholine were not significantly different from the values obtained on the second and third days averaged (93.6 ± 10.5; p>0.1 for both comparisons).

Late Response to Distilled Water

On the fifth day the values for PO20UNDW did not significantly differ from the values obtained on the fourth day (p>0.1) (Table 3). All patients recovered spontaneously from the early asthmatic reactions induced by inhalation of ultrasonically nebulized distilled water. Only the two subjects who had shown the greatest increase in responsiveness to methacholine during the second challenge with methacholine on the fourth day (subjects 3 and 9) experienced a further fall in FEV1 (Fig 3). The reduction in FEVx was well beyond the spontaneous variability measured on the first day; it began three hours after inhalation of distilled water and persisted for four to five hours (Fig 3). These late responses were both less severe than the initial responses.

On both the fourth and fifth days, subject 9 had symptoms of chest tightness and coughing between four and six hours after inhalation of ultrasonically nebulized distilled water. During this period of time, he also showed the maximal delayed decrease in FEV1 on the fifth day (Fig 3). After the spontaneous recovery from the late-phase reaction, both of the two subjects had an increase in responsiveness to methacholine, but the reduction in PC20M was not greater than twofold from the mean baseline value (Fig 3).

Table 2—Reproducibility of Response to Inhaled Methacholine

Subject PC20M, mg/ml*
Second Day Third Day
1 0.52 0.35
2 0.41 0.34
3 2.20 3.61
4 0.79 1.35
5 1.11 1.41
6 11.20 11.40
7 16.90 12.70
8 0.49 0.50
9 0.18 0.15
10 2.35 2.28
Geometric mean 1.32 1.35
SDt 1.46 1.50
Rt 0.99

Table 3—Response to Inhaled Ultrasonically Nebulized Distilled Water (UNDW)

Subject POaoUNDW, ml/min*
Fourth Day Fifth Day
1 3.60 (15) 2.45 (20)
2 3.82 (40) 2.61 (40)
3 1.11 (30) 1.54 (25)
4 1.48 (20) 1.68 (25)
5 1.96 (25) 1.92 (30)
6 5.22 (20) 4.36 (25)
7 4.44 (30) 4.74 (35)
8 4.94 (30) 4.52 (35)
9 0.91 (40) 0.90 (40)
10 0.64 (10) 0.87 (15)
Geometric mean 2.22 2.17t
SD$ 0.75 0.62

Table 4—Change in Response to Methacholine Inhalation after Prior Stimulation with Ultrasonically Nebulized Distilled Water (UNDW)

Subject PCjqM, mg/ml*
Baselinet Soon after UNDW 2 hr after UNDW
1 0.43 0.07 0.31
2 0.37 0.06 0.30
3 2.90 0.43 0.38
4 1.07 0.06 0.26
5 1.26 0.30 0.73
6 11.30 3.32 7.36
7 14.80 5.16 8.38
8 0.50 0.19 0.35
9 0.17 0.05 0.04
10 2.31 0.14 1.53
Geometric mean 1.35 0.24§ 0.62||
SD* 1.47 1.66 1.62


effects-of-increasing-nebulizerFigure 1. Effects of increasing nebulizer volume output on FEVX during repeated stimulation with ultrasonically nebulized distilled water (UNDW). Time interval between first, second, and third tests is recovery time.


Response to Inhaled MethacholineFigure 2. Change in response to inhaled methacholine after prior stimulation with ultrasonically nebulized distilled water (UNDW). Concentration-response curves were obtained soon after recovery from water-induced bronchoconstriction (open squares) and two hours after recovery (solid squares). Baseline curves (circles) were constructed by averaging responses obtained at each concentration of methacholine on second and third days.


Percentage of Fall in FEVFigure 3. Percentage of fall in FEV, induced by inhalation of ultrasonically nebulized distilled water (UNDW) from time of maximal bronchoconstriction during immediate response up to eight hours after challenge in subjects 3 (solid circles) and 9 (open circles). Shaded area at top indicates spontaneous variability of FE^ determined on first day. Open arrows mark time at which challenge with methacholine (M) was performed. Concentration of methacholine provoking 20 percent fall in FEV! (PC^M) was compared with baseline values obtained on second and third days, averaged.