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Controlled versus free breathing for multiple breath nitrogen washout in healthy adults

Blake M. Handley, Edward Jeagal, Robin E. Schoeffel, Tanya Badal, David G. Chapman, Catherine E. Farrow, Gregory G. King, Paul D. Robinson, Stephen Milne, Cindy Thamrin
ERJ Open Research 2021 7: 00435-2020; DOI: 10.1183/23120541.00435-2020
Blake M. Handley
1Dept of Respiratory Medicine, Royal North Shore Hospital, St Leonards, NSW, Australia
2Woolcock Institute of Medical Research, University of Sydney, Glebe, NSW, Australia
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Edward Jeagal
2Woolcock Institute of Medical Research, University of Sydney, Glebe, NSW, Australia
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Robin E. Schoeffel
1Dept of Respiratory Medicine, Royal North Shore Hospital, St Leonards, NSW, Australia
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Tanya Badal
2Woolcock Institute of Medical Research, University of Sydney, Glebe, NSW, Australia
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David G. Chapman
2Woolcock Institute of Medical Research, University of Sydney, Glebe, NSW, Australia
3Translational Airways Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia
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  • ORCID record for David G. Chapman
Catherine E. Farrow
2Woolcock Institute of Medical Research, University of Sydney, Glebe, NSW, Australia
4Dept of Respiratory and Sleep Medicine, Westmead Hospital, Westmead, NSW, Australia
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Gregory G. King
1Dept of Respiratory Medicine, Royal North Shore Hospital, St Leonards, NSW, Australia
2Woolcock Institute of Medical Research, University of Sydney, Glebe, NSW, Australia
5Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
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Paul D. Robinson
6Dept of Respiratory Medicine, The Children's Hospital at Westmead, Westmead, NSW, Australia
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Stephen Milne
5Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
7Centre for Heart Lung Innovation, St Paul's Hospital and Division of Respiratory Medicine, University of British Columbia, Vancouver, BC, Canada
8These authors contributed equally
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Cindy Thamrin
2Woolcock Institute of Medical Research, University of Sydney, Glebe, NSW, Australia
5Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
8These authors contributed equally
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  • For correspondence: cindy.thamrin@sydney.edu.au
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  • FIGURE 1
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    FIGURE 1

    Functional residual capacity measured by controlled breathing (FRCCB) and free breathing (FRCFB) protocols. a) There was strong correlation between the protocols (r=0.96, p<0.0001). b) Bland–Altman plot showing good agreement between the protocols (mean difference (95% limits of agreement) −0.009 (−0.592, 0.555) L, p=0.75).

  • FIGURE 2
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    FIGURE 2

    Functional residual capacity measured by controlled breathing (FRCCB) and free breathing (FRCFB) protocols versus the gold-standard body plethysmography (FRCpleth). There was good correlation between FRC measured by both protocols and FRCpleth (r=0.86 and r=0.92, respectively, p<0.0001 for both). MBNW: multiple breath nitrogen washout.

  • FIGURE 3
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    FIGURE 3

    Lung clearance index measured by controlled breathing (LCICB) and free breathing (LCIFB) protocols. a) There was strong correlation between the protocols (r=0.82, p<0.0001). b) Bland–Altman plot showing that free breathing produced a higher LCI compared to controlled breathing (mean difference (95% limits of agreement) 0.21 (−0.44, 0.87), p=0.003)). There was a trend towards proportional bias confirmed by linear regression (p=0.07).

  • FIGURE 4
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    FIGURE 4

    Ventilation heterogeneity in conducting airways measured by controlled breathing (ScondCB) and free breathing (ScondFB) protocols. a) There was no significant correlation between the protocols (r=0.16, p=0.44). b) Bland–Altman plot showing high between-protocol variability (mean difference (95% limits of agreement) 0.0002 (−0.03, 0.03 L−1, p=0.94)). There was no evidence of proportional bias, regardless of outliers (p=0.83).

  • FIGURE 5
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    FIGURE 5

    Ventilation heterogeneity in distal/intra-acinar airways measured by controlled breathing (SacinCB) and free breathing (SacinFB) protocols. a) There was relatively poor correlation between the protocols (r=0.33, p=0.11). b) Bland–Altman plot showing that free breathing produced higher Sacin compared to controlled breathing (mean difference (95% limits of agreement) 0.03 (−0.045, 0.103) L−1, p<0.0005)). There was also significant proportional bias confirmed by linear regression (p=0.002). The between-protocol difference in Sacin (SacinFB–SacinCB) was predicted by the between-protocol differences in c) tidal volume (VTFB−VTCB, regression p=0.004) and d) respiratory rate (RRFB−RRCB, regression p=0.009). One participant was excluded from Sacin analyses due to negative value in one trial.

Tables

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  • TABLE 1

    Participant characteristics, lung function and multiple-breath nitrogen washout (MBNW) parameters

    Whole groupRepeatability subgroup
    Females/males n11/166/9
    Age years median (range)34 (19–65)30 (23–41)
    BMI kg·m−224.6±3.425.1±4.2
    Lung function
     FEV1 % predicted#105±14101±30
     FEV1/FVC %83±684±5
     TLCpleth % predicted¶101±23107±11
     FRCpleth % predicted¶97±27104±20
    MBNW parameters
     Controlled breathing
      FRCCB L2.94±0.892.96±0.88
      LCICB6.49±0.476.39±0.36
       ScondCB L−10.019±0.0110.025±0.012
       SacinCB L−10.056±0.0200.061±0.022
      VT mL1124±371127±37
      VT/FRCMBNW0.40±0.160.42±0.15
      RR breaths·min−110.2±0.899.86±1.0
     Free breathing
      FRCFB L2.92±0.863.00±0.87
      LCIFB6.70±0.596.57±0.57
       ScondFB L−10.019±0.0120.018±0.014
       SacinFB L−10.085±0.0390.091±0.041
      VT mL880±324912±304
      VT/FRCMBNW0.31±0.120.32±0.14
      RR breaths·min−112.3±3.5313.6±3.10

    Data are presented as mean±sd unless otherwise stated. For the repeatability subgroup, results are from the first visit. BMI: body mass index; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; TLC: total lung capacity; FRC: functional residual capacity; LCI: lung clearance index; Scond: conductive zone ventilation heterogeneity; Sacin: acinar zone ventilation heterogeneity; VT: mean tidal volume across measurements; RR: respiratory rate; pleth: body plethysmography; CB: controlled breathing protocol; FB: free breathing protocol. #: reference equations for predicted values from Quanjer et al. [13]; ¶: reference equations for predicted values from Quanjer et al. [14].

    • TABLE 2

      Within- and between-session variability for the controlled and free breathing protocols

      Within-session CoVBetween-session difference95% LOABetween-session ICC
      Controlled breathing
       FRCCB L3.0±1.9%−0.02±0.47−0.94–0.910.927
       LCICB2.4±1.7%0.13±0.34−0.53±0.790.849
       ScondCB L−1−0.003±0.009−0.021–0.0150.867
       SacinCB L−1−0.002±0.02−0.039–0.0340.828
      Free breathing
       FRCFB L3.9±2.4%−0.04±0.026−0.54–0.470.979
       LCIFB3.1±2.2%0.15±0.51−0.84–1.140.704
       ScondFB L−10.006±0.016−0.026–0.0380.411
       SacinFB L−10.003±0.054−0.103–0.1090.278

      Data are presented as mean±sd unless otherwise stated. Mean differences are Visit 2 minus Visit 1. CoV: coefficient of variation; 95% LOA: 95% limits of agreement; ICC: intra-class correlation coefficient; FRC: functional residual capacity; LCI: lung clearance index; Scond: conducting airways ventilation heterogeneity; Sacin: distal/intra-acinar airways ventilation heterogeneity.

      Supplementary Materials

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        Supplementary material 00435-2020.SUPPLEMENT

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      Controlled versus free breathing for multiple breath nitrogen washout in healthy adults
      Blake M. Handley, Edward Jeagal, Robin E. Schoeffel, Tanya Badal, David G. Chapman, Catherine E. Farrow, Gregory G. King, Paul D. Robinson, Stephen Milne, Cindy Thamrin
      ERJ Open Research Jan 2021, 7 (1) 00435-2020; DOI: 10.1183/23120541.00435-2020

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      Controlled versus free breathing for multiple breath nitrogen washout in healthy adults
      Blake M. Handley, Edward Jeagal, Robin E. Schoeffel, Tanya Badal, David G. Chapman, Catherine E. Farrow, Gregory G. King, Paul D. Robinson, Stephen Milne, Cindy Thamrin
      ERJ Open Research Jan 2021, 7 (1) 00435-2020; DOI: 10.1183/23120541.00435-2020
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