Difference between SF₆ and N₂ multiple breath washout kinetics is due to N₂ back diffusion and error in N₂ offset

Measurement of lung clearance index (LCI) by multiple breath washout (MBW) is a sensitive method for monitoring lung disease in patients with cystic fibrosis (CF). To compare nitrogen MBW (N₂-MBW) and sulfur hexafluoride MBW (SF₆-MBW), we connected these two gas analysis systems in series to obtain truly simultaneous measurements, with no differences other than the gas used. Nonsmoking healthy controls (HC) and subjects with CF were recruited at two institutions. The Exhalyzer-D (for N₂-MBW measurement) was connected in series with the Innocor (for SF₆-MBW measurement). Subjects washed in SF₆ from a Douglas bag with tidal breathing and washed out SF₆ and nitrogen with 100% oxygen provided as bias flow. Washout of both gases was continued past the LCI point (1/40th of equilibration concentration) in triplicate. N₂-MBW resulted in higher cumulative exhaled volume, functional residual capacity (FRC), and LCI when compared with SF₆-derived parameters in HC subjects (P < 0.0001 for all comparisons). All N₂-MBW parameters were also significantly higher than SF₆-MBW parameters in subjects with CF (P < 0.01 for all comparisons). After recalculation with a common FRC, N₂-MBW LCI was higher than SF₆-MBW LCI in subjects with CF (19.73 vs. 11.39; P < 0.0001) and in HC (8.12 vs. 6.78; P < 0.0001). Adjusting for N₂ back diffusion and an offset error in the nitrogen measurement resulted in near complete agreement between the two methodologies. We found significant differences in LCI and FRC measurements using two different gases for MBW. This may have significant implications for the future use and interpretation of LCI data in clinical trials and routine clinical care.NEW & NOTEWORTHY This study provides important insights into the differences between the two techniques used for measuring lung clearance index (LCI): N₂ and SF₆ multiple breath washout. Differences between measurements made by these two methods in subjects with cystic fibrosis and healthy controls could be explained by nitrogen back diffusion and N₂ offset error. This is important for use and interpretation of LCI data as an outcome measure for clinical trials and in routine clinical care.