Carbon Dioxide Accumulation during Small Animal, Whole Body Plethysmography: Effects on Ventilation, Indices of Airway Function, and Aerosol Deposition

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Abstract
Barometric (whole body) plethysmography is used to examine changes in ventilation and breathing pattern in unrestrained animals during exposure to therapeutic or toxic aerosols. Whole body plethysmographs (WBP) may be operated with a bias flow in order to maintain an adequate supply of oxygen and remove expired CO2. However, some aerosol generation and delivery methods may require operation of the WBP without bias flow, which would artificially deplete aerosol concentration. Under these conditions, expired CO2 accumulates in the plethysmograph and stimulates ventilation, increasing total aerosol deposition, shifting regional deposition, and significantly altering some airway function indices. We characterized these effects in guinea pigs using a commercially available 4.5-L WBP, with and without a 1 L/min bias flow. CO2-induced changes in breathing frequency (f), tidal volume (Vt), minute ventilation (Ve), and indices of airway function - including enhanced pause (penh), flow derived parameter (FDP), and respiratory duty cycle - were measured. Without bias flow, CO2 in the plethysmograph increased steadily to 5.4% after 30 min compared to a steady state 0.9% with bias flow. This resulted in a moderate suppression of f, and significant increases in Vt and Ve by factors of 1.5 and 1.4, respectively. Changes in regional deposition were stimulated for 300 mg/m3 polydisperse aerosols with mass median aerodynamic diameters of 0.3, 1, 3, or 7 μm and geometric standard deviations of 1.7. Percent increase in aerosol deposition from CO2 inhalation ranged from 24% to 90%, by mass, depending on aerosol size distribution and respiratory tract region. In addition, fractional deposition shifted toward the pulmonary region. Empirical indices of airway constriction, penh and FDP, also were increased significantly to 1.7 and 1.3 times their respective baseline values. The study quantifies the effect of inadvertent coexposure to CO2 on ventilation, aerosol deposition, and airway function in WBP evaluation of aerosol effects in airway function.