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Intersubject variability in particle deposition does not explain variability in responsiveness to methacholine
P J Anderson1, E Garshick, J D Blanchard
1Respiratory Biology Program, Harvard School of Public Health, Boston, Massachusetts 02115.
Abstract:
How variable is the deposition of inhaled methacholine (MCH) in the respiratory tract during a challenge test? Does this variability contribute to the variability of airway responsiveness? To examine these questions we estimated the deposition of polydisperse MCH droplets by measuring the deposition of surrogate diethylhexyl sebacate (DEHS) droplets that were similar in size (1.5 microns) but monodisperse. Light scattering photometry and flow measurements were used to compute inspired and expired DEHS particle number. Deposition of DEHS during 4 breaths was measured twice at baseline and after every dose of MCH during an abbreviated challenge test in 16 subjects. Deposition was then compared with reactivity. Reactivity to MCH was expressed as the dose-response slope; it was calculated as percent final change in FEV1/cumulative dose MCH inhaled. Dose-response slopes ranged from zero (nonreactive) to -15.0 (very reactive) %/mumol (mean -3.2 +/- 5.3 SD). Seven subjects had a 20% or greater decrement in FEV1 after their highest MCH dose. Baseline DEHS deposition, which ranged from 66 to 84% (mean 77 +/- 5 SD), was not significantly different between responders and nonresponders and was not a significant predictor of the dose-response slope. Reactivity was significantly associated with an increase in deposition produced by MCH (p less than 0.007). This increase was small, however (relative change less than 7%), so that the effect on the deposited dose of MCH was minimal. We conclude that, with the breathing pattern used, individual differences in DEHS (and MCH) deposition were small and contributed little to intersubject variability of responsiveness to inhaled MCH.
Insights
Individual differences in inhaled methacholine (MCH) deposition are small and do not significantly impact airway responsiveness variability during challenge tests. This suggests other factors are more influential in determining reactivity.
Area of Science:
- Respiratory Physiology
- Pulmonary Medicine
- Pharmacology
Background:
- Airway hyperresponsiveness is a hallmark of asthma.
- Methacholine (MCH) challenge tests are used to assess airway responsiveness.
- Variability in MCH deposition may influence test results.
Purpose of the Study:
- To quantify the variability of inhaled methacholine (MCH) deposition in the respiratory tract.
- To determine if deposition variability contributes to intersubject differences in airway responsiveness.
- To investigate the relationship between MCH deposition and airway reactivity.
Main Methods:
- Diethylhexyl sebacate (DEHS) droplets (1.5 microns) were used as surrogates for MCH deposition measurement.
- Light scattering photometry and flow measurements assessed DEHS deposition during 4 breaths.
- Deposition was measured at baseline and after MCH doses in 16 subjects.
- Airway responsiveness was quantified as the dose-response slope of FEV1 change versus cumulative MCH dose.
Main Results:
- Baseline DEHS deposition ranged from 66-84% (mean 77%), with no significant difference between responders and non-responders.
- Baseline deposition did not predict the dose-response slope.
- MCH reactivity was associated with a small, non-significant increase in DEHS deposition (relative change <7%).
Conclusions:
- Individual differences in inhaled methacholine (MCH) deposition are minimal with the breathing pattern used.
- Deposition variability contributes little to the intersubject variability of airway responsiveness to MCH.
- Factors other than deposition likely explain most of the variability in MCH challenge test outcomes.