Effects of cystic fibrosis lung disease on gas mixing indices derived from alveolar slope analysis

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Abstract

Scond and Sacin are derived from analysis of concentration-normalized phase III slopes (SnIII) of a multiple breath inert gas washout. Studies in healthy and COPD subjects suggest these reflect ventilation heterogeneity in conducting and acinar airway zones respectively, but similar studies in cystic fibrosis (CF) are lacking. Scond, Sacin and lung clearance index (LCI, a measure of overall gas mixing efficiency) were measured in 22 adults and 18 children with CF and 17 adult and 29 child controls. Plethysmography and gas transfer measurements were performed in adults, and spirometry in all subjects. Scond was elevated in almost all CF patients, including children with mild disease and normal LCI. However, Scond did not correlate with other measurements and appeared to reach a maximum; further increase in ventilation heterogeneity being restricted to Sacin. The nature and/or severity of CF lung disease may invalidate assumptions underlying the ability to separate phase III slope analysis of ventilation heterogeneity into proximal and peripheral components, and LCI may be a better indicator of gas mixing in this population.

Introduction

The last few years has seen an expansion of interest in the use of inert gas washout tests to measure non-uniformity of ventilation distribution in the lung. This has been driven both by improvements in technology and also by a growing appreciation of the need for more sensitive measures of small airway function (Venegas, 2007). These tests are now moving from the arena of experimental physiological studies to a role as outcome measures in clinical studies and trials (Davies et al., 2008).

Using the single breath washout (SBW) test, ventilation heterogeneity is determined from the slope of the alveolar plateau, also referred to as the phase III slope. Imperfect convective (bulk flow) gas mixing between regions of the lung, sequencing between these regions, and interaction between convective and diffusive gas mixing in the periphery all contribute to variations in ventilation efficiency and a sloping alveolar plateau (Prisk et al., 1996, Dutrieue et al., 2000). Although SBW tests using a single inert marker gas are useful clinical tools (Estenne et al., 2000), they are not able to inform us about the mechanisms responsible for the observed inhomogeneity.

An alternative, more complex, analysis describes how the phase III slope for an inert marker gas changes over successive breaths of a multiple breath washout, in an attempt to separate the contribution of the different gas mixing processes (Verbanck et al., 1997, Aurora et al., 2005). This analysis is explained in more detail in the online supplement. In summary however, the concentration-normalized phase III slope of the individual breaths of the washout are first plotted against the lung volume turnover (TO) (obtained by dividing the cumulative expired volume by the FRC). This profile is then divided into two separate components, each reflecting a different aspect of gas mixing. The first component can be derived from the increase in normalised phase III slope with successive breaths after the five first breaths, or 1.5 lung volume turnovers, of the washout. This occurs because successive breaths of the washout preferentially deplete the best ventilated lung regions (those with the highest specific ventilation) first, exaggerating differences in tracer gas distribution. Sequential filling and emptying among these regions results in an increasing concentration-normalized phase III slope (SnIII). This index is called Scond since it is considered to be determined purely by convective gas mixing in the conducting airways.

The second component is not linearly progressive, but has reached an asymptote after approximately 1.5 TO. It is affected by molecular mass of the tracer gas, and is understood to originate from interaction between diffusion and convection in the zone where these processes contribute similarly to the movement of a gas molecule, i.e. in the zone of the diffusion–convection front (Paiva and Engel, 1984). This component has been termed Sacin because the interaction between diffusion and convection occurs in the acinar zone in healthy lungs (Verbanck et al., 1997).

Recently, we have reported on the measurement of lung clearance index (LCI) in adult patients with cystic fibrosis (CF), using a novel gas analyser that is capable of following very low concentrations of the inert marker gas sulphur hexafluoride (SF6) (Horsley et al., 2008). LCI is a simple measure of overall ventilation heterogeneity, derived from analysis of multiple breath washouts. Early CF lung disease primarily affects the peripheral conducting airways, and spares the alveoli (Sobonya and Taussig, 1986). In adult CF patients however the picture is more complex. Possible mechanisms by which regional ventilation could be affected include different time constants between lung units of varying sizes, variations in airway calibre (due to inflammation, mucus collection or airway remodelling), reductions in the density of small airways, bullous disease and gas trapping (Hamutcu et al., 2002). In order to try to better understand how gas mixing is affected in CF, we have performed inert gas washout tests in CF patients at the same time as performing plethysmography and gas transfer. SnIII analysis has been included in order to separate those effects due to variability in convective gas mixing and those due to interaction between diffusion and convection. Finally, following our initial observations, a cohort of children with CF was assessed in order to extend the range of disease severity and to investigate the relationship between age and SnIII variables. We hypothesised that increase in Scond would be an early event in CF, and would correlate best with overall ventilation heterogeneity, as measured by LCI, whereas Sacin would not increase until the lungs were more severely affected. We also hypothesised that Scond would correlate with measures of central airway function, such as airways resistance and spirometry, whereas Sacin would correlate best with measures of peripheral airway function, such as gas transfer factor and RV/TLC.

Section snippets

Subjects

Seventeen healthy non-smokers (less than 10 pack years smoking history) with no known lung disease and on no regular respiratory medications were recruited as normal volunteers. Twenty-nine healthy child controls, with no history of wheeze, asthma or prematurity (<34 weeks), were recruited from amongst those attending follow-up of stable upper-limb fractures as well as children of hospital staff. Twenty-two CF adults were recruited from the Scottish Adult CF Service, and eighteen children with

Results

Twenty-two CF adults completed MBW, spirometry and diffusing capacity assessments. Plethysmography was not completed in one adult patient because of technical problems with the apparatus. Seventeen adult healthy volunteers completed inert gas washout, and diffusing capacity. Plethysmography was not completed in 5 controls. A single CF adult was excluded from SnIII analysis because she was only able to produce two reproducible washouts, which due to variability in breathing pattern could not be

Discussion

From first principles it might be expected that CF patients with more severe lung disease would have more inhomogenous convective gas mixing. However, we were unable to demonstrate this using a method based upon phase III slope analysis. Although the convection dependent component (Scond) was elevated in almost all CF subjects, including children with mild disease and normal LCI, Scond did not continue to rise with increasing disease severity (as expressed by deteriorating FEV1 or LCI) and

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