DMCO, Vc and 1/theta

Roughton and Forester’s seminal paper from the 1950’s showed that DLCO was a function of two resistances: the alveolar-capillary membrane and the rate of CO uptake by red blood cells. This relationship is shown by:

Formula 1 DLCO conductances

Roughton and Forster also showed that the membrane diffusing capacity (DMCO) and pulmonary capillary blood volume (Vc) could be calculated by performing the DLCO test at different oxygen concentrations and then plotting the results.

Modifed from: Pulmonary Function Testing Guidelines and Controversies, Jack Clausen ed., page 166.

Modifed from: Pulmonary Function Testing Guidelines and Controversies, published 1982, Jack Clausen ed., page 166.

Since the 1950’s DMCO and Vc have been measured for research fairly often. I first performed this test around 30 years ago mostly because I was interested in the technical aspects. I’ve tried to keep current with the research using DMCO and Vc ever since and have come to realize that there are several important details with a significant effect on how this test is performed and calculated.

From the formula it can be seen that DMCO and Vc depend on how theta is calculated. Theta (or more specifically 1/theta) is the rate of CO uptake by red blood cells. The original and most commonly used formula for calculating 1/theta was:

Formula 2 Theta 1

where:

PcO2 = pulmonary capillary partial pressure of O2

Hgb = hemoglobin (grams/decaliter)

The constants in this equation mostly come from laboratory bench-top research that measured the reaction rates of CO and hemoglobin, but they also depend on some assumptions. One of these is that CO has to travel past the exterior membrane of the red blood cell and then through the interior of the red blood cell before encountering a hemoglobin molecule. The ratio between these two resistances was originally measured as being 2.5, but when this value was used the DMCO and Vc results did not match what was known about lung physiology. If it was assumed that there was no cell membrane resistance at all the constants for 1/theta formula produced physiologically consistent results. A zero resistance is unlikely to be true but it has been used because it appears to match reality better. Some researchers however, have insisted on using the laboratory measured ratio of 2.5 instead and when this is used the equation becomes:

Formula 3 theta 2_5

Laboratory research on the CO-hemoglobin reaction rate has been re-performed and at different times and places researchers have since used a variety of constants:

Formula 4 theta multiple

Unfortunately there is a distinct lack of any consensus regarding which set of constants should be used. There valid arguments that can be (and have been) used for and against each set. The fact that there is a certain level of discrepancy between reaction rates determined on a laboratory bench and those indicated by real world in-vivo measurements complicates the ability to choose one set over another.

Because carbon monoxide and oxygen both compete for sites on the hemoglobin molecule a second critical factor is that 1/theta (and DLCO) will therefore vary with the O2 concentration. The pulmonary capillary O2 concentration cannot be measured directly however, and must be estimated. There are several different approaches for doing this. The simplest is to subtract a constant (usually 10) from the alveolar PO2 (although I’ve seen that at least one researcher added 5 to PAO2 instead) to derive PcO2. A more rigorous approach is to calculate PcO2 from:

Formula 6 PcO2

Most researchers however, have just substituted PAO2 for PcO2, but frustratingly how PAO2 has been determined is often not reported. When it is reported it has been most frequently been determined from the alveolar sample used to measure DLCO, which does make a certain amount of sense. Less frequently it has been estimated using the alveolar air equation or from measured from end-tidal PO2.

Although using PAO2 instead of PcO2 simplifies the measurement process greatly, PAO2 is not PcO2, and it is not clear to me what effect using it has on the derived DMCO and Vc. This is in a sense a core problem with Roughton and Forster’s original equation for DLCO’s serial resistances. PcO2 is more a concept than an actual thing since strictly speaking it is different for each alveoli and capillary. Arterial PO2 is the closest we can come to actually measuring it and since there are known differences between PAO2 and PaO2 that depend both on disease states and measurement conditions (like during exercise) it would seem the same applies to PcO2.

Note: While reviewing articles on DMCO and Vc I found that the constants used for the 1/theta calculations were reported relatively often but by no means all of the time. As mentioned the method by which PAO2 was determined was reported somewhat infrequently. Most frustrating however, is that many research papers only stated that DMCO and Vc were determined by the method of Roughton and Forster (or some other prior study, usually in an obscure or out of print journal) and gave no details at all.

It’s not particularly clear what level of accuracy or precision can be expected from DMCO and Vc measurements. The ATS-ERS statement on DLCO testing asks for a repeatability of 10%. Because DMCO is determined from the intercept of the 1/DLCO axis and Vc from the slope of the regression line small differences in the DLCO measurements can make a significant difference in the calculated DMCO and Vc. An error bar of 10% in individual DLCO measurements likely translates into a much larger error bar for DMCO and Vc.

I was an advocate for performing DMCO and Vc testing on and off for years, but to be honest that had more to do with the technical challenge than with any clinical relevance. I think that DMCO and Vc testing still has an important place in research (although I’d certainly like a better consensus and more clarity in reporting details). For routine clinical testing in a Pulmonary Function Lab, likely not so much. DMCO and Vc have been studied in COPD, asthma, sarcoidosis, sleep apnea, pulmonary fibrosis, pulmonary hypertension and various forms of heart disease. These studies have improved our understanding the physiology of these conditions but I don’t see where it has improved our ability to either diagnose or monitor them. At this time I can’t see that DMCO and Vc are any more clinically significant than just DLCO, and given the uncertainties in how these results are derived, probably less.

References:

Bosisio E, Grisetti GC, Panzutti F, Sergi M. Pulmonary diffusing capacity and its components (DM and Vc) in young, health smokers. Respiration 1980; 40: 307-310.

Ceridon ML, Beck KC, Olson TP, Bilezikian JA, Johnson BJ. Calculating alveolar capillary conductance and pulmonary capillary blood volume: comparing the multiple- and single-inspired oxygen tension method. J Appl Physiol 2010; 109: 643-653.

Georges R, Saumon G, Loiseau A. The relationship of age to pulmonary membrane conductance and capillary blood volume. Am Rev Resp Dis 1978; 117: 1069-1078.

Jain BP, Pande JN, Guleria JS. Membrane diffusing capacity and pulmonary capillary blood volume in chronic obstructive pulmonary disease. Am Rev Resp Dis 1972; 105: 900-907.

Kleerup EC, Koyal SN, Marques-Magallanes JA, Goldman MD, Tashkin DP. Chronic and acute effects of “crack” cocaine on diffusing capacity, membrane diffusion and pulmonary capillary blood volume in the lung. Chest 2002; 122: 629-638.

Lamberto C, Nunes H, Le Toumelin P, Duperron F, Valeyre D, Clerici C. Membrane and capillary blood components of diffusion capacity of the lung for carbon monoxide in pulmonary sarcoidosis: relation to exercise gas exchange. Chest 2004; 125: 2061-2068.

Overbeek MJ, Groepenhoff H, Voskuyl AE, Smit EF, Peeters JWL, Vonk-Noordefraaf A, Spreeuwenberg MD, Dijkmans BC, Boonstra A. Membrane diffusion- and capillary blood volume measurements are no useful as screening tools for pulmonary arterial hypertension in systemic sclerosis: a case control study. Respiratory Research 2008; 9: 68

Pande JN, Gupta SP, Guleria JS. Clinical significance of the measurement of membrane diffusing capacity and pulmonarycapillary blood volume. Respiration 1975; 32: 317-324.

Roughton FJW, Forster RE. Relative importance of diffusion and chemical reaction in determining rate of exchange of gases in the human lung with special reference to true diffusing capacity of pulmonoary membrane and volume of blood in the pulmonary capillaries. J Appl Physiol 1957; 11: 291-302.

Sansores RH, Pare P, Abboud RT. Effect of smoking cessation of pulmonary carbon monoxide diffusing capacity and capillary blood volume. Am Rev Resp Dis 1992; 146: 959-964

Zanen P, van der Lee I, van der Mark T, van den Bosch JMM. Reference values for alveolar membrane diffusion capacity and pulmonary capillary blood volume. Eur Respir J 2001; 18: 764-769.

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