Randomized Cross-Over Analysis of the Influence of Nitrogen Multiple Breath Washout on Spirometry in Monitoring Lung Function in Patients With Cystic Fibrosis and Primary Ciliary Dyskinesia

Abstract

Background: When monitoring lung function in patients with Cystic Fibrosis (pwCF) and Primary Ciliary Dyskinesia (pwPCD), nitrogen multiple breath washout (N₂MBW) is usually performed before spirometry to prevent forced expiratory maneuvers from altering N₂MBW results. The N₂MBW may affect spirometry if cooperation decreases after a long period of examination or due to prolonged oxygen inhalation. The equivalence of these concepts has never been investigated in a randomized cross-over trial. We hypothesized that the order of pulmonary function tests (PFTs) would not influence the z-score FEV₁.

Methods: A total of 47 clinically stable outpatients (36 pwCF, 11 pwPCD; 16.7 ± 8.1 years) were randomized into two groups. Each patient underwent N₂MBW and spirometry at two consecutive visits (median interval 104 days): Group I: Spirometry followed by N₂MBW (A), reversed order at the second visit (B), Group II reversed (B→A).

Statistics: For the equivalence test, a change in z-score FEV1 (primary endpoint) ±0.2 and lung clearance index (LCI_2.5, secondary endpoint) ±15% was not considered relevant; therefore, changes outside this range were considered an intervention effect in the linear mixed model (p < 0.05).

Results: There was a significant deterioration in z-score FEV1 between the two appointments (period effect: -0.177; p = 0.012). The intervention effect and 95% confidence interval were within the equivalence range in both groups (z-score FEV1: 0.039; -0.0765 to 0.1539, LCI_2.5: -0.082; -0.3691 to 0.2054).

Discussion: In our cohort the order of PFTs has no influence on the results suggesting that a greater flexibility in practice is possible without the risk of falsifying results.

Trial registration: German Clinical Trials Register (No. DRKS00027473).

Keywords: cystic fibrosis; multiple breath washout; primary ciliary dyskinesia; spirometry.

Figure 1

Flowchart of the recruitment process of the study. PCD = primary ciliary dyskinesia; CF = cystic fibrosis, N₂MBW = nitrogen multiple breath washout, FEV₁ = forced expiratory volume after 1 s, A: spirometry first, nitrogen multiple breath washout second, B: nitrogen multiple breath washout first, spirometry second.

Figure 2

(A) Bland–Altman plot for z‐score FEV₁ (N = 47); x‐axis: average of both appointments, y‐axis: difference between both measurements (Appointment A − Appointment B), gray dashed lines: upper and lower 95% confidence interval, black dots: mean values of the individuals in relation to the difference of the values. (B) Bland–Altman plot for LCI_2.5 (N = 44); x‐axis: average of both appointments, y‐axis: difference between both measurements (Appointment A − Appointment B), gray dashed lines: upper and lower 95% confidence interval, black dots: mean values of the individuals in relation to the difference of the values, FEV₁ = forced expiratory volume after 1 s, z‐score: calculation according to Global Lung Initiative reference values (see methods), LCI_2.5 = lung clearance index. Appointment A: spirometry first, nitrogen multiple breath washout second. Appointment B: nitrogen multiple breath washout first, spirometry second.

Figure 3

(A) Visualization of confidence interval of intervention effect on z‐score FEV₁ with equivalence range; x‐axis: changes in z‐score FEV₁; black line: 95% confidence interval of the Intervention effect N₂MBW‐spirometry on z‐score FEV₁; black dashed lines mark the equivalence range, black dot: intervention effect. (B) Visualization of confidence interval of intervention effect on LCI_2.5; x‐axis: changes in LCI_2.5; black line: 95% confidence interval of the intervention effect spirometry–N₂MBW on LCI_2.5, black dashed lines mark the maximum accepted change between appointments, black dot: intervention effect. FEV₁ = forced expiratory volume after 1 s, z‐score: calculation according to Global Lung Initiative reference values (see Methods), N₂MBW = nitrogen multiple breath washout; LCI_2.5 = lung clearance index.