Multiple breath nitrogen washout: a feasible alternative to mass spectrometry

Abstract

Background: The lung clearance index (LCI), measured by multiple breath washout (MBW), reflects global ventilation inhomogeneity and is a sensitive marker of early cystic fibrosis (CF) lung disease. Current evidence is based on a customized mass spectrometry system that uses sulfur hexafluoride (SF6) as a tracer gas, which is not widely available. Nitrogen (N2) washout may be better suited for clinical use and multi-center trials.

Objective: To compare the results obtained from a N2 washout system to those generated by the SF6 based system in healthy children and children with CF.

Methods: Children with CF were recruited from outpatient clinics; healthy children were recruited from the Research4Kids online portal. Participants performed MBWSF6 (Amis 2000, Innovision, Denmark) and MBWN2 (ExhalyzerD, EcoMedics, Switzerland) in triplicate, in random order on the same day. Agreement between systems was assessed by Bland-Altman plot.

Results: Sixty-two healthy and 61 children with CF completed measurements on both systems. In health there was good agreement between systems (limits of agreement -0.7 to 1.9); on average N2 produced higher values of LCI (mean difference 0.58 (95% CI 0.42 to 0.74)). In CF the difference between systems was double that in health with a clear bias towards disproportionately higher LCIN2 compared to LCISF6 at higher mean values of LCI.

Conclusion: LCIN2 and LCISF6 have similar discriminative power and intra-session repeatability but are not interchangeable. MBWN2 offers a valid new tool to investigate early obstructive lung disease in CF, but requires independent normative values.

Figure 1. Study Participant Flow Diagram.

Figure 2. Bland Altman Plot of the agreement between LCI _N2 and LCI_SF6 in a) healthy controls and b) subjects with Cystic Fibrosis.

The solid horizontal line represents the mean difference, and the dashed lines represent the limits of agreement (mean difference+/−2SD). In health, there was good agreement between the systems, the mean difference (LCI_N2−LCI_SF6 was 0.61 (95% CI 0.45 to 0.78), limits of agreement (−0.7 to 1.9)); whereas in CF there was an obvious bias (mean difference = 1.41 (95% CI 0.92 to 1.90), limits of agreement (−2.4 to 5.2)) such that LCI_N2 increased disproportionately to LCI_SF6 as mean LCI increased.

Figure 3. Bland Altman Plot of the agreement between FRC _N2 and FRC_SF6 in a) healthy controls and b) subjects with Cystic Fibrosis.

The solid horizontal line represents the mean difference, and the dashed lines represent the limits of agreement (mean difference+/−2SD). FRC was crudely corrected for body size (FRC/height*100). In health N₂ produced higher values of FRC; the mean difference (FRC_N2−FRC_SF6) was 0.21 (95%CI 0.16; 0.25), limits of agreement (−0.15; 0.56) with no bias observed between systems. In CF the mean difference was 0.33 (95%CI 0.27; 0.38), limits of agreement (−0.11; 0.76) with the difference between systems becoming disproportionately greater with higher adjusted FRC.

Figure 4. Bland Altman Plot of the agreement between a) FRC_pleth and FRC_SF6 and b) FRC_pleth and FRC_N2.

Healthy controls are represented by the open circles, and subjects with CF by the solid circles. FRC was crudely corrected for body size (FRC/height*100). FRC_N2 more closely agreed with FRC_pleth with the difference between FRC_pleth and FRC_SF6 suggestive of trapped gas volume.

Figure 5. Comparison of the mean difference in LCI between systems to volume of trapped gas (FRC_pleth−FRC_SF6).

The volume of trapped gas increased as LCI_N2 increased disproportionately to LCI_SF6 suggesting that the N₂ system was measuring volume not captured during MBW_SF6.

Figure 6. Bland Altman Plot of the agreement between CEV_N2 and CEV_SF6.

Healthy controls are represented by the open circles, and subjects with CF by the solid diamonds. CEV was adjusted for body size (CEV/height*100). In health there was good agreement between systems, mean difference (CEV_N2−CEV_SF6) was 0.20 (95% CI 0.017; 0.022), limits of agreement (−0.001; 0.041) with no bias observed between systems. In CF there was a strong bias such that CEV_N2 became disproportionately higher than CEV_SF6 with increasing mean values of CEV (mean difference (0.054 (95% CI 0.042; 0.067), limits of agreement (−0.041; 0.150)).

Figure 7. Comparison of difference in LCI (LCI_N2−LCI_SF6) to FEV₁ (% predicted).

Healthy controls are represented by the open circles and subjects with CF by the solid circles. The difference in LCI was greater as FEV₁ became lower such that on average LCI_N2 was disproportionately higher than LCI_SF6 in subjects with abnormal spirometric findings.