The Effects Of Methacholine Challenge Administered Using Three Different Nebulizers On Small Airways Function
Condition: Asthma
Study type: Interventional

Summary: 
      The objective of this study is to examine the functional effects of methacholine challenge on
      small airways using three different nebulizers to generate particles with HMAD suitable for
      distribution in small, intermediate and large airways.Pulmonary function will be assessed
      using plethysmography and impulse oscillation techniques. Eight asthmatic subjects (>18
      years, both sexes) who are stable clinically and require only intermittent ß2-agonist
      treatment will be recruited to undergo methacholine challenges for an in vivo, dose-finding
      observational study. Three separate methacholine challenges will be carried out using each of
      the three different nebulizers. After each challenge, pulmonary function tests will be
      performed on subjects to assess functional changes in large and small airways. Results of the
      tests will be compared between the three nebulizers. These experiments will demonstrate
      whether or not functional changes occur in small airways in response to methacholine, as
      measured by pulmonary function tests after selectively targeting small airways using the
      nebulizer which generates small particles. The results from these experiments will give us a
      better understanding of the role of small airways in methacholine-induced bronchoconstriction
      in asthmatics, and will compare sensitivity of plethysmography compared to forced oscillation
      for detecting changes in small airways.
    

Detailed description: 
      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.
    

Intervention name(s): 1. Wright Nebulizer; Pari LC Nebulizer; The Pari Sinustar Nebulizer
Intervention type(s): Other; Other; Other
Intervention description(s): The Wright nebulizer will be used to perform the methacholine challenge.; The Pari LC nebulizer will be used to perform the methacholine challenge.; The Pari Sinustar nebulizer will be used to perform the methacholine challenge.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science