Using the same cut-off for sulfur hexafluoride and nitrogen multiple-breath washout may not be appropriate.

Abstract

PerspectivesUsing the same cut-off for sulfur hexafluoride and nitrogen multiple-breath washout may not be appropriateSophie Yammine, Nina Lenherr, Sylvia Nyilas, Florian Singer, and Philipp LatzinSophie YammineUniversity Children's Hospital Bern, Bern, Switzerland; , Nina LenherrUniversity Children's Hospital Basel, UKBB, Basel, Switzerland; and , Sylvia NyilasUniversity Children's Hospital Bern, Bern, Switzerland; University Children's Hospital Basel, UKBB, Basel, Switzerland; and , Florian SingerUniversity Children's Hospital Zurich, Zurich, Switzerland, and Philipp LatzinUniversity Children's Hospital Bern, Bern, Switzerland; University Children's Hospital Basel, UKBB, Basel, Switzerland; and Published Online:15 Dec 2015https://doi.org/10.1152/japplphysiol.00333.2015This is the final version - click for previous versionMoreSectionsPDF (397 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat as a tidal breathing test, multiple-breath washout (MBW) allows measurement of functional residual capacity (FRC) and the lung clearance index (LCI), a measure of global ventilation distribution efficiency of the lung. Particularly for diagnosis and monitoring of cystic fibrosis (CF) lung disease, MBW has become of indisputable importance (1, 2, 9) and is starting to be used in other lung diseases such as primary ciliary dyskinesia (PCD) (4, 7, 12).Over the past years, technical advances and efforts for standardization of equipment, measurement, and analysis have enabled wide application of the MBW technique (20). First studies used nitrogen (N2) analyzer to measure the washout of lung resident N2 by application of 100% oxygen in adults (6) and children (14). Because of poor resolution of previous N2 analyzers and to avoid an overestimation of FRC based on tissue-N2 excretion into airways (16, 23), the MBW stopping point was arbitrarily set to 2.5% or 1/40th from the N2 starting concentration set to 100%. This cut-off was hardly ever challenged (28) and maintained until today, irrespective of the tracer gas in use. Meanwhile, most data in CF were gained using the foreign tracer gas sulfur hexafluoride (SF6), thus requiring a wash-in and washout phase (1, 9, 11, 17, 19). However, recently improved (indirect) N2 sensors (21, 22), as well as the greenhouse properties and restricted availability of SF6, have led to a renascence of N2-MBW (10, 26, 27). Currently both SF6- and N2-MBW are in use and the same 2.5% cut-off is recommended (20), but it is unclear how comparable those methods and the use of the same cut-off are.This discussion has been taken up recently because of different MBW results in patients with PCD (5). Two studies using SF6-MBW found no correlation between LCI and first second forced expiratory volume (FEV1) (7, 12) and also no correlation between LCI and structural lung changes in high-resolution computed tomography (12). However, Boon et al. (4) using N2-MBW found both a correlation between LCI and FEV1 and between LCI and structural lung damage. Among several other points (5), different dead space to tidal volume ratios (VD/VT) for the different pieces of equipment have been discussed as underlying reason for these differences (3). A significant difference with comparable effect sizes was also found in a study in patients with CF comparing both techniques directly (13). Although there seems to be agreement on a lack of general comparability of SF6 and N2, because of different physiological (foreign vs. lung-resident) and physical (different diffusivities) properties, the use of the same cut-off for both gases has not been discussed so far. Thus our aim is to emphasize this new and important aspect: using the same cut-off of 2.5% to terminate the washout for both gases may not be appropriate, mainly because of tissue-N2 contribution.We have chosen one example to illustrate the potential importance of using the same cut-off for both gases. We performed a simple calculation using N2-MBW traces of two 10-year-old children (one with CF, one healthy). Thereby we accounted for endogenous N2 with the intention to make N2-MBW comparable to a MBW using foreign tracer gas, such as SF6. So far, elimination of N2 was described by several exponential equations with different time constants relating to different elimination rates of the contributing compartments such as blood, highly perfused tissues and muscles, and fat (15, 18). For the example, we simplified the process, and assumed one constant tissue contribution for N2 excretion during washout, which we estimated to be 1% based on the minimal N2 fraction achievable in the healthy subject as measured during the end of N2-MBW. We subtracted this 1% tissue-N2 contribution breath-by-breath from each end-tidal N2 concentration and recalculated FRC and LCI at 1/40th.This washout trace accounting for tissue-N2 resulted in differently decreased LCI and FRC in both children. In the healthy subject, 1/40th was achieved two breaths earlier compared with the original signal and changed LCI from 6.7 to 5.9 (12%) and FRC by 30 ml (2%). In CF, 1/40th was achieved 19 breaths earlier, leading to a LCI decrease from 13.7 to 10.0 (27%), whereas FRC decreased by 110 ml (9%) (see Fig. 1). This means it would have been required to wash out SF6 until 1.5% (1/66th) to be comparable to N2 washout until 2.5% (1/40th) of the starting concentration (13) or to use the values from N2 washout at 3.5% (1/28th).Fig. 1.Change in lung clearance index in recalculated washout traces after subtraction of tissue nitrogen. Two exemplary nitrogen multiple-breath washout traces of a 10-yr-old healthy child (circles) and a 10-yr-old child with cystic fibrosis (CF) (square). Original washout trace represented as end-tidal nitrogen concentration (not normalized) over washout breaths is shown in solid symbols, whereas recalculated washout trace after subtraction of the excreted tissue nitrogen (1% per breath) is shown in open symbols. For each washout trace change in lung clearance index (LCI) is illustrated by an arrow, pointing from the original target breath (gray closed symbol) to the new target breath (gray open symbol). Dashed line represents the cut-off at 1/40th of the initial N2 starting concentration, corresponding to 2.5%. The zoom in area shows the end of the nitrogen washout trace in the child with CF.Download figureDownload PowerPointThis basic physiological-mathematical consideration of tissue-N2 contribution shows that the use of the uniform 2.5% cut-off for MBW is not appropriate when comparing results from both gases. Our simple example resulted in very similar differences reported by Jensen et al. (13) comparing N2-MBW and SF6-MBW in healthy children and children with CF (13). They found higher LCI and FRC values in N2-MBW compared with SF6-MBW: in healthy children, LCI mean difference was 0.58 (95% CI 0.42 to 0.74), and in CF, the difference between systems was twice as high [mean difference 1.41 (95% CI 0.92 to 1.90)] with a clear nonlinear bias toward disproportionately higher LCI in N2-MBW if LCI exceeded 10 lung turnovers in CF. The difference was mainly assigned to contribution of N2 from very slowly ventilated lung units not captured by SF6-MBW (10). This physiological difference is additionally preceded by the fact that slowly ventilated lung units need to be open during wash-in and washout for SF6 but only during washout for N2. This additional point might explain why still some children with CF had lower LCI values from N2-MBW compared with LCI values from SF6-MBW (13).In line with Jensen et al. (13), we show that the LCI difference in the child with CF is higher compared with the healthy child (13). Thus the influence of tissue-N2—or in other words the difference between N2 and SF6 as tracer gas—gets more relevant at the end of the washout and as such will impact very differently upon MBW results in subjects with increased ventilation inhomogeneity. This means that correction for differences between N2 and SF6 does not consist of a single, fixed factor. However, an earlier cut-off in N2 (28), probably ∼3.5%, or a later cut-off in SF6 washout, probably ∼1.5%, seems to make results more comparable. This point clearly needs to be examined in future studies, especially because the different diffusivities of the two gases potentially influence agreement between N2- and SF6-MBW. Whether the specific areas of ventilated lung captured by N2- or SF6-MBW reflect a physiological signal is currently also unclear. Given the large amount of data using a SF6/helium mixture for MBW, this could be examined relatively easily (8).To sum up, our example adds further aspects to the interesting discussion why MBW measurements obtained by SF6 and N2 do not yield comparable values. This basic physiological-mathematical difference per se influences not only the lack of agreement between SF6 and N2 washout but also relates to different sensitivity of both techniques to detect structural damage, as seen in patients with PCD (4, 12). Future work in lung models and in vivo may elaborate individual stopping points for each tracer gas, with regards to comparability and best sensitivity for lung disease. 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Children's Hospital Basel UKBB, Spitalstrasse 33, 4031 Basel, Switzerland (e-mail: philipp.[email protected]ch). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByNitrogen-based lung clearance index: a valid physiological biomarker for the clinicChantal Darquenne, Rebecca J. Theilmann, Janelle M. Fine, and Sylvia A. B. Verbanck17 May 2022 | Journal of Applied Physiology, Vol. 132, No. 5Better late than never: correcting the error in the Exhalyzer nitrogen washout systemAlexander Horsley and Chantal Darquenne12 October 2021 | Journal of Applied Physiology, Vol. 131, No. 4Improved agreement between N2 and SF6 multiple-breath washout in healthy infants and toddlers with improved EXHALYZER D sensor performanceRikke M. Sandvik, Per M. Gustafsson, Anders Lindblad, Paul D. Robinson, and Kim G. 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