1. Calculation of conductive inhomogeneity in children with Cystic Fibrosis lung disease: which method works?
Verger N2, Arigliani M1, Raywood E3, Duncan J3, Bush A4 and Aurora P3,5 on behalf of the London Cystic Fibrosis Collaboration
1 Department of Clinical and Experimental Medical Sciences, Unit of Paediatrics, University Hospital of Udine, Udine, Italy, 2Université Pierre et Marie Curie, Paris, France, 3Respiratory, Critical Care and Anaesthesia Section, IIIP, UCL Institute of Child Health, London, United Kingdom; 4The National Heart and Lung Institute, Imperial College, London, United Kingdom, 3Department of Respiratory Medicine, Great Ormond Street Hospital for Children, London, United Kingdom.
Background
Methods
Children aged 6-18 with CF and healthy controls (HC) attending Great Ormond Hospital Street for longitudinal cohort studies (ucl.ac.uk/london-cystic-fibrosis) were studied.  MBW was  measured using an Amis 2000 respiratory Mass Spectrometer (Innovision ApS, Glamsbjerg, Denmark) as previously described4.  
LCI and SnIII results were reported as the mean from 3 acceptable runs. Results were analysed as previously reported1 using custom software in windows XP (Test Point). SnIII slopes throughout the washout were measured at 65-95% of the SF6 expirogram (Fig 1b). Scond was calculated as the SnIII from 1.5 to 6 turnovers and Scond* from the SnIII from breath 2 to 3 turnovers(Fig 1c)3.
Figure 1: SF6 washout with expirograms and SnIII slope vs TO CF HC
p value n
Mean sd
Age (years) 67
14.1
2.5 62
14.3
2.4
0.686
Weight (kg)
46.6
11.8
52.8
15.3
0.011*
Height (cm)
154.8
14.8
161.3
14.7
0.013*
LCI
10.7
3.1 61
6.8
0.6
p<0.0001
Scond 51
0.068
0.027 42
0.014
0.011
Scond*
0.098
0.044
0.017
0.019
Table 1 : Demographics CF and HC mean and standard deviation (sd) with p-value of differences between groups (independent T-test)
Results
Cystic Fibrosis (CF) is a progressive genetic disease, affecting breathing and digestion from a young age. There is no cure for CF but early treatments may improve quality and length of life. Multiple breath inert-gas washout (MBW) using sulphur hexafluoride (SF6) measured by mass spectrometry (MS), and is sensitive to early lung disease in children with CF by quantifying ventilation inhomogeneity (VI)1. The Lung Clearance Index (LCI) is the number of lung volume turnovers (TO) required to reduce end tracer gas concentration to 1/40th of its starting value (Fig 1a). This represents an overall measure of inhomogeneity.
Further information can be obtained by calculating the progression of the phase III slope through the washout. It is measured from the plot of the expired volume vs gas concentration for each breath (Fig 1b). This slope is then normalized for the mean gas concentration (SnIII) and then plotted against TO (Fig 1c). The relationship between SnIII and TO is dependent on two mechanisms of generation of gas mixing inhomogeneity: these being diffusion-convection interaction dependent (Sacin-not shown), and convection dependent (Scond-fig 1c) 2, these indices can be calculated from SIII vs TO.
The validity of the standard Scond derivation, calculated from 1.5 to 6TO, has been demonstrated in experimental studies in mammals, and also in human subjects in hyper and microgravity. More recently, it has been demonstrated that this is not valid in subjects with moderate to severe lung disease, as the value of Scond appears to reach a plateau and then fall with worsening VI. An alternative index, termed Scond* has been proposed3, from Breath 2 to 3 TO.
Aim: To confirm that the Scond derivation is invalid in paediatric subjects with moderate to severe lung disease, and determine to what extent and for which subjects the Scond* derivation can provide a substitute analysis.
Of 129 children tested 123 (95%) LCI results were able to be reported. Following a strict quality control process , 93 (72%) children’s phase III results were able to be reported.
Children with CF vs HC Children in both groups were a similar age but children with CF were significantly lighter and shorter. All measures of VI were significantly higher for CF than control, mean difference: LCI 3.9, Scond 0.054, Scond* (table 1).
LCI vs Scond and Scond* In CF for LCI values between 6 and 11, Scond and LCI show a linear correlation; whilst above LCI 11, the relationship between Scond and LCI disappears. In contrast, Scond* shows a correlation with LCI throughout all the range of LCI values (Table 2), though the correlation is not linear throughout the range. If children with moderate-severe ventilation inhomogeneity were excluded (LCI >11), then the correlation between Scond and LCI improved.
Table 2 (right): Correlation of Scond and Scond* to LCI
Figure 2 (left): Graphs plotting a. Scond vs LCI and b. Scond* vs LCI c. Scond* vs Scond (CF Green, HC Blue)
References 1 Aurora et al Respiratory Physiology & Neurobiology 2 Robinson et al European Respiratory Journal 3 Verbanck et al Respiratory Physiology & Neurobiology 4 Robinson et al Respiration
Conclusions
Scond reaches a maximum value at moderate VI (around LCI of 11), therefore it is not informative about the mechanism of VI in moderate to severe CF lung disease. Scond* continues to demonstrate a relationship with LCI at higher values, so could provide an alternate index in this situation.
ucl.ac.uk/london-cystic-fibrosis
This research was funded by The Cystic Fibrosis Trust, Action Medical Research for Children and the Henry Smith Charity.