The single-breath (SB) method for determining the transfer factor for carbon monoxide (TLCO) is of limited value for the detection of diffusion disorders on the alveolar level, because the results are influenced by unequal distribution of ventilation and diffusion. The rebreathing method (RB) is thought not to be influenced by these inequalities. To the authors' knowledge, no study has measured both TLCORB and TLCOSB systematically and compared them with regard to the influence of unequal ventilation and diffusion. Therefore, the present study measured total lung capacity (TLC) as well as TLCO, both with the RB vital capacity method and the SB method, using the same apparatus in 10 healthy subjects and in 35 patients with chronic obstructive pulmonary disease (COPD). These patients are known to have increased unequal ventilation and diffusion in comparison with healthy subjects. In the healthy subjects, a small difference was found between TLC measured with the RB method (TLCRB) divided by the predicted value (TLCRB/pred) and TLCSB/pred (mean difference 0.07; SE = 0.02); no significant difference was found between TLCORB divided by the predicted value of TLCOSB (TLCORB/pred) and TLCOSB/pred. In the COPD patients, however, TLCRB/pred was larger than TLCSB/pred (mean difference 0.17; SE = 0.02) and TLCORB/pred was larger than TLCOSB/pred (mean difference 0.23; SE = 0.05). Multiple regression analysis revealed that in the COPD patients, 54% of the variance of the difference between TLCRB/pred and TLCSB/pred, and 76% of the variance of the difference between TLCORB/pred and TLCOSB/pred, were explained by parameters related to unequal ventilation and diffusion. In 25 of the 35 COPD patients, TLCOSB/pred was less than 0.8, whereas in 11 of these 25 patients, TLCORB/pred was more than 0.8. This difference was significant (P = 0.0005). In these 11 patients, the SB measurement resulted in the incorrect diagnosis of a diffusion disorder on the alveolar level. The RB method, however, never resulted in the diagnosis of a diffusion disorder when TLCOSB/pred was larger than 0.8. It is concluded that in a significant number of COPD patients, TLCOSB is below the normal range, whereas TLCORB is not below the normal range. This difference between TLCORB and TLCOSB is related to the combined effect of unequal ventilation and diffusion, and is of clinical importance for the detection of a diffusion disorder on the alveolar level.

The influence of unequal ventilation on the differences between the rebreathing (RB) and the single breath (SB) measurement of the transfer factor of the lung for carbon monoxide (TL_CO) was investigated. An apparatus was developed which measured both TL_CORB and TL_COSB. Unequal ventilation increases with lung volume, caused by the combined effect of increasing ratio of total volume to RV from apex to basis, the fact that apex inspires before basis and asymmetric intra-acinar branching patterns. Therefore measurements were done at three different values of inspired volume (VI) in 10 normal subjects. To separate the effects of gas mixing and diffusion, residual volume (RV) was measured by He dilution in addition to TL_CO We found that RV and TL_CO increase with increasing VI. The increase is larger with RB. We also found that RV_RB is larger than RV_SB at the three values of VI. TL_CORB is smaller than TL_COSB except at vital capacity (VC). We concluded from the different behavior of RV_RB and RV_SB as a function of VI that the SB measurement increasingly underestimated RV with increasing unequal ventilation. This is also reflected in the measurement of TL_COSB. From the different behavior of TL_CORB and TL_COSB as a function of VI we concluded that TL_CORB was smaller than TL_COSB when unequal ventilation was minimal. This is caused by the smaller mean alveolar volume during RB. But increasing unequal ventilation causes an increasing underestimation with the SB method, resulting in TL_COSB being equal to TL_CORB at VC.

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Background: The single breath (SB) method for determining the transfer factor for carbon monoxide is influenced by an unequal distribution of diffusion and ventilation. The rebreathing (RB) method is thought not to be influenced by these inequalities. Therefore, a comparison of the results of the two methods enables us to investigate unequal ventilation and diffusion. We have previously shown that even in normal subjects unequal ventilation influences the relation between the transfer factor as measured by the RB method and by the SB method. Objectives: To investigate to what extent unequal diffusion influences the relation between the RB and SB transfer factor in normal subjects. Methods: Measurements were performed in 8 normal subjects. Differences in alveolar volume as measured by the RB and SB method were prevented from influencing the results by comparing the RB and SB transfer factor per liter of alveolar volume, i.e. the RB and SB Krogh factor, instead of the RB and SB transfer factor. The effect of the known dependence of the Krogh factor on inspired volume was prevented by measuring the SB Krogh factor at an inspired volume equal to the mean inspired volume of the RB measurement. This SB Krogh factor was compared with the RB Krogh factor calculated as the quotient of the RB transfer factor and the mean alveolar volume during the RB measurement. Results: This RB Krogh factor was always larger than the corresponding SB Krogh factor. The difference was significant (p = 0.006). A high percentage (80%) of the variance in the quotient of the two Krogh factors, which can be considered as a parameter for unequal diffusion, was explained by the variance in the quotient of the mean RB volume and the corresponding SB volume. The latter quotient is a measure of unequal ventilation. Conclusions: The finding suggests a physiological relation between unequal diffusion and unequal ventilation. A plausible explanation was found in the decrease of the Krogh factor with an increasing ratio of inspired volume to residual volume for each part of the lung separately. The consequence is that in the absence of unequal ventilation the RB transfer factor is equal to the SB transfer factor measured at an inspired volume equal to the mean RB inspired volume.