To the Editor:
A recent editorial in the European Respiratory Journal [1] recognises that the fundamental scientific data on lung clearance index (LCI) obtained by sulfur hexafluoride (SF6) multiple-breath washout (MBW) have paved the way for clinical use of LCI. Although the editorial stresses the need for standardisation, it also appears to suggest that SF6 can be replaced by nitrogen (N2) as the washout gas.
We (Innovision ApS, Odense, Denmark) are the manufacturer of the AMIS 2000 medical mass spectrometer system that, using user-specific software and hardware, was adapted to perform MBW. The AMIS 2000-based devices are now considered the “gold standard” device for SF6 LCI measurements in cystic fibrosis patients by opinion leaders in the field [2]. This device has been used in the vast majority of studies demonstrating the clinical value of SF6 LCI in cystic fibrosis patients, with one recent notable exception: the demonstration of the change in LCI caused by Ivacaftor in cystic fibrosis patients with normal forced expiratory volume in 1 s, where a prototype version of our other system, Innocor, adapted for open-circuit SF6 LCI, was used [3].
The AMIS 2000 adapted MBW system is too complex and too expensive for routine clinical use, and the LCI version and the required SF6 gas mixture have no regulatory approval (CE mark or US Food and Drug Administration approval). To facilitate the clinical availability of SF6-based MBW, we have introduced the Innocor system, which, together with the gases used, is approved for clinical use and provides a much less complex and cheaper alternative to the mass spectrometer system.
In the light of the strong emphasis on standardisation in the editorial, we find the suggestion to replace SF6 with N2 surprising, as this is a major change both from a technological and a physiological standpoint for the following reasons. 1) As N2 cannot be measured by clinically available technologies, it is necessary to rely on indirect measurements, i.e. assuming that whatever is not recorded as oxygen (O2) or carbon dioxide (CO2) must be N2. At the LCI point, where the N2 concentration is only ∼2%, the ability to accurately identify the N2 concentration is significantly below that recommended by the expert consensus statement to which the editorial refers [2]. 2) Washout with 100% O2 is not equivalent to that performed with room air. During N2 washout using 100% O2, gas viscosity changes by ≥10%, which causes a significant dynamic change in the gas analyser delay time during the test and affects flow resistance in the upper airways. O2 flow across the alveolar membrane in poorly ventilated regions with end-capillary O2 saturations <98% will also be affected when breathing 100% O2. As this effect is smaller in well ventilated regions, distribution of ventilation will change. 3) As N2 is not insoluble in blood and tissue, the washout curve is affected by a simultaneous washout of N2 from blood and tissue (back diffusion).
Does all of this matter? Mathematically, the use of indirect measurement of N2 amplifies the relative measurement error in the sum of CO2 and O2 concentrations at the LCI point by a factor of 49. Assuming no measurement error in CO2:
At a relative error in O2 measurement of 0.2%:
This means that if there is a relative measurement error in the sum of O2 and CO2 concentrations of, say, ±0.2% (as seen with the best O2 analysers), the relative error in the N2 concentration at the end of the washout will be ±10%, far in excess of that recently recommended [2].
As recognised by the consensus statement [2], the physiological impact of the use of 100% O2 is unclear: “Thresholds at which factors such as age, sleep state and sedation interact with 100% O2 to affect breathing pattern remain unclear”.
With a reference to a study published in 1953, the consensus statement [2] states that only limited data are available on N2 back diffusion. However, a much more recent study [4] has shown a very significant N2 back diffusion from blood and tissue within the time frame of a normal washout test. The data from this study imply that almost 25% of the N2 in the lungs at the LCI point stems from back diffusion of N2.
A recent study [5] has compared N2 LCI with SF6 LCI obtained with the gold standard method. Significant differences were found, and the authors concluded that independent normative values are required and that interventional studies are needed to clarify the role of N2 LCI as an outcome measure in clinical trials in cystic fibrosis patients. The limits of agreement between N2 and SF6 LCI in cystic fibrosis patients were >7 LCI units, far in excess of the treatment related change reported in the Ivacaftor study of 2.1 units [3].
Finally, both the editorial [1] and the consensus statement [2] reported that the SF6 mixture required to perform LCI testing is often not universally available and not approved. This is a misunderstanding. The mixture used with the Innocor system is an off-the-shelf, 150-mL gas tank in the European Union, the USA, Canada and in all other European countries where Innocor is used.
If the reference for clinical use of the LCI test is the scientific data obtained with the gold standard mass spectrometer device over many years of research, the suggestion to switch to N2 LCI is premature and scientifically unfounded. Notwithstanding the well recognised problems of indirect N2 measurement and the physiological effects of pure O2, recent research has also highlighted that N2 back diffusion may be much more important than previously thought.
Footnotes
Conflict of interest: Disclosures can be found alongside the online version of this article at www.erj.ersjournals.com
- Received April 19, 2013.
- Accepted July 31, 2013.
- ©ERS 2014