• To examine the functional effects of methacholine challenge on small airways via plethysmography and impulse oscillation techniques, to compare the sensitivity of these measurement techniques to detect changes in small airways. [ Time Frame: April 2008 ] [ Designated as safety issue: No ]
  

This study will measure changes in small airways by plethysmography and impulse oscillation following delivery of methacholine using nebulizers designed to deliver to the small (Wright), intermediate (PARI LC® Plus) and large (PARI SinuStar™ ) airways.

Assessment of small airways involvement by plethysmography will include Residual Volume (RV), Forced Vital Capacity (FVC) and Peak Inspiratory and Expiratory Flow rates (PIF and PEF, respectively). Impulse oscillation will include measures of large and small airways resistance.

Baseline Spirometry

Baseline FEV1 and VC will be registered using a water spirometer.

Methacholine Challenge (Screening)

Methacholine inhalation will be performed as described by Cockcroft (1996). Subjects are instructed to wear noseclips and to breathe normally from the mouthpiece during the 2-minute inhalation period. Subjects inhale normal saline, then doubling concentrations of methacholine from a Wright nebulizer for 2 minutes each. FEV1 is measured at 30, 90, 180 and 300 seconds after each inhalation. Spirometry is measured with a Collins water sealed spirometer and kymograph. The test is terminated when a fall in FEV1 of 20% of the baseline value occurs, and the methacholine PC20 is calculated.

Methacholine Challenge

During the second visit, subjects will be randomized to inhale from a nebulizer that generates particles with HMAD suitable for distribution either in small, intermediate or large airways. Subjects will inhale doubling concentrations of methacholine for 2 minutes each. Immediately after each inhalation, pulmonary function tests will be performed on the subjects via plethysmography. Measurements will be made at intervals of 30 seconds, 60 seconds, 3 minutes and 5 minutes (or until a fall in FEV1 of 20% or more of baseline is reached). The methacholine test is terminated when a fall in FEV1 of 20% or more of the baseline value is reached. After a recovery time of 1 hour, the same doses will be re-administered and pulmonary function tests will again be performed, this time via impulse oscillation. The same procedure will be repeated for the third and fourth visits with the remaining nebulizers (selected randomly). The nebulizers that will be used to target certain airways are the Wright nebulizer (small), the PARI LC® Plus nebulizer (medium) and the PARI SinuStar™ nebulizer (large).

Plethysmography

Pulmonary function tests will be performed on subjects after methacholine challenges via plethysmography. Various tests will be performed that will allow for different lung function measures. To characterize which measurements are indicative of large or small airways function, measurements from the three nebulizer groups will be compared. Potential measures of small airway function include Functional Residual Capacity (FRC), Residual Volume (RV), Forced Vital Capacity (FVC) and Peak Inspiratory and Expiratory Flow Rates (PIF and PEF, respectively) (Knudson et al., 1980). Nitrogen washout will also be performed with the body box to measure airway distensibility, or the relationship between airway caliber and lung volume (Brown et al., 2004).

Impulse Oscillation

Pulmonary function tests will be performed on subjects after methacholine challenges via impulse oscillation. This device uses a loudspeaker to generate pressure and flow and by generating these at various frequencies, specifically differentiates between large and small airways obstruction (Otis et al., 1956). Results will be compared between the three nebulizer groups after specifically targeting certain airways.