One of the recommendations in the 2017 ERS/ATS DLCO standards was that VA should be calculated using a mass balance equation. I’ve discussed this approach previously, but basically the volume of the exhaled tracer gas is accumulated over the entire exhalation and the amount of tracer gas presumed to remain in the lung is used to calculate VA. The conceptual problem with this for DLCO measurements is that VA is calculated using the entire exhalation but CO uptake is based solely on the CO concentration in the alveolar sample. Since VA calculated using mass balance tends to be larger than VA calculated traditionally in subjects with ventilation inhomogeneities this mean that DLCO calculated with a mass balance VA is also going to be proportionally larger as well.
This problem has concerned me for a while but what wasn’t clear was what difference should be expected in the VA (and DLCO) when it is calculated both ways. In order to figure this out I’ve taken a real-world example of a subject with severe COPD and calculated the difference in VA and DLCO.
Fortunately, my lab software lets me download the raw data for DLCO tests (volume, CH4, CO at 10 msec intervals) into a spreadsheet. The PFT results for the subject looked like this:
| Observed: | %Predicted: | |
| FVC (L): | 2.39 | 97% |
| FEV1 (L): | 0.66 | 36% |
| FEV1/FVC: | 27 | 38% |
| TLC (L): | 6.11 | 126% |
| FRC (L): | 4.84 | 174% |
| RV (L): | 4.04 | 171% |
| DLCO: | 9.21 | 57% |
| VA (L): | 3.19 | 68% |
| Vinsp (L): | 2.32 |
In order to use the mass balance approach with the spreadsheet I found that I could determine the start of exhalation after the breath-holding period but determining where the alveolar plateau started was much more difficult. For this reason I had to include the dead space but made adjustments for this when calculating VA.
To start off with, using the inspired volume and concentration of CH4 in the DLCO test gas mixture, the volume of inhaled CH4 was:
2.32 L x 0.003 = 6.96 ml.
Integrating the exhaled CH4 throughout the exhalation showed a total volume of 2.567 ml, which leaves a volume of 4.393 ml remaining in the lung at the end of exhalation. The average CH4 concentration at the end of exhalation (averaged over the remaining 250 msec, per the 2017 DLCO standard) was 0.1601 percent. This means the volume of the lung at end-exhalation was:
0.004303 L / 0.001601 = 2.74 L.
The total volume exhaled was 1.32 L so total lung volume was:
2.74 L + 1.32 L = 4.06 L.
The dead space in our test systems defaults to 0.32 L (0.07 mouthpiece + 0.25 anatomical). VA is therefore:
4.06 L – 0.32 L = 3.74 L.
Since the VA calculated using the traditional approach was 3.23 L, the difference in VA was a factor of
3.74 L / 3.23 L = 1.16
and since DLCO scales directly with VA the DLCO calculated with the mass balance VA would have been:
9.21 ml/min/mmHg x 1.16 = 10.68 ml/min/mmHg.
Which is an increase in percent predicted from 57% to 66%.
I repeated this for a couple more subjects with severe COPD and was mildly surprised to get very similar results (VA factor range was 1.12 to 1.16) . Since these patients have fairly severe ventilation inhomogeneities these results would seem to set an upper limit in the difference between VA calculation methods. To some extent this comparison of VA methods is limited by the fact that we don’t have our patients exhale all the way to RV after the breath-holding period (part of the 2017 DLCO recommendations) but for those patients with COPD exhaling completely both at the beginning and the end of the single-breath maneuver is problematic anyway.
The point of using the mass balance method is get a more accurate VA but in patients with ventilation inhomogeneities the difference was not as great as I expected it might be. This is not the first time VA was corrected to reflect “true” lung volume since up until the mid-1960’s a number of researchers advocated adding the RV (measured either by helium dilution or plethysmography) to the inspired volume to calculate VA. This practice fell by the wayside for a number of reasons, one of which was that DLCO measured this way assumed that the test gas mixture (and CO uptake) was homogeneously distributed throughout the lung and this is often not the case.
The problem as I see it is that the DLCO measured using the mass balance method extrapolates the rate of CO uptake to the parts of the lung that either do not contribute or contribute poorly to the alveolar sample and this may or not be reasonable. The difference in VA and DLCO using the two methods has not been studied to any degree in either normal subjects or those with various lung disorders and this makes it difficult to say whether the ATS/ERS recommendation actually makes sense.
The biggest difference in VA between the two methods would be expected in patients with ventilation inhomogeneities. In my lab, the DLCO re-calculated using the mass balance method in a patient with a severe ventilation inhomogeneity would have changed the interpretation from a “moderate” to a “mild” gas exchange defect”. In one sense that’s a significant change but I suspect that for most patients, even those with some degree of ventilation inhomogeneity, the difference will likely be small.
References:
Graham BL, et al. 2017 ERS/ATS standards for the single-breath carbon monoxide uptake in the lung. Eur Respir J 2017; 49: 1600016.