Our retrospective analysis of 777 patients who underwent pulmonary function testing prior to surgery at our institution revealed that the cut-off value for RCEXP calculated from the MEFV curves was 0.601 s with an AUC of greater than 0.9. Among the spirometric parameters that are presumed to predict peripheral airways dysfunction, RCEXP was strongly or moderately associated with FEV1/FVC, MMF, and MEF50, whereas it was less associated with MEF25 and MEF50/MEF25. Even in spontaneously breathing subjects, calculation of RCEXP was possible using the descending limb of the MEFV curve, and our findings imply that a prolonged RCEXP, especially if it is longer than 0.601 s, could be associated with airway obstruction.
Physiological interpretation of expiratory time constant
To our knowledge, this study is the first attempt to provide the reference value for RCEXP that was calculated from the effort-independent portion of the MEFV curve. In theory, RCEXP can be altered depending on the degree of airway obstruction in spontaneously breathing patients. The finding that most patients without airway obstruction had an RCEXP of shorter than 0.6 s would be comparable to that of a previous study by McIlroy et al., who reported an average time constant of 0.38 s (ranging from 0.28 to 0.51 s) in their healthy, non-intubated subjects . As might be expected, however, our reference value for RCEXP did not exceed the time constant values in mechanically ventilated patients with acute respiratory distress syndrome, which was reported to be in the range of 0.60 to 0.70 s [19, 20].
McIlroy et al. employed the slope of the line drawn using exhaled tidal volume and flow to determine values of the time constant of a relaxed expiration . The reason why their findings were in agreement with those obtained during forced expiration in our study population could be attributable to the mechanism by which forced expiration is governed. As demonstrated in the comparison between relaxed and forced expirations in the same subject, the time rate of change in volume was similar under the relaxed and forced conditions . Even when a greater expiratory flow is achieved, RCEXP will not be shorter than that during relaxed expiration, as the ratio of volume to flow is similar because of the difference in volume expired during forced and relaxed expirations . As long as the linearity of the expiratory flow-volume curves validates the assumption that the linear portion is indicative of the mechanical properties of the respiratory system, namely its resistance and compliance, the value of RCEXP remains theoretically unchanged irrespective of whether the phase of expiration ends at the residual volume or at the functional residual volume.
In contrast, the finding that RCEXP gradually increased in tandem with the decrease in FEV1/FVC, MMF, and MEF50, especially when they were decreased below a certain level, could be interpreted as collateral evidence for the uneven distribution of RCEXP in patients with airway obstruction . In a model resembling a lung unit where a single elastic element passively empties through a tube open to the atmosphere, the amount of ventilation depends on the compliance of the element and the resistance of the tube. When a particular portion of the lung unit is inadequately ventilated because of the narrowing of its airway, the increase in its airway resistance results in a prolonged RCEXP . This is because the expiratory flow of emptying such a unit is determined using its time constant, the product of its airway resistance and lung compliance. The inequality of ventilation would therefore be a possible mechanism underlying the decreased rate of emptying of lung units with a larger airway resistance, the degree of which could be expressed as a longer RCEXP observed with an increase in the proportion of poorly ventilated regions. On the basis of our previous finding that patients with an FEV1/FVC ratio of less than 0.70 showed a substantial increase in the calculated value of airway resistance prior to general anesthesia , it could be inferred that elevated airway resistance was a major contributor to the increase in RCEXP.
In the present study, we calculated RCEXP by dividing a quarter of the FVC by the gap between MEF50 and MEF25. Even in healthy subjects, a degree of variability can exist in the parameters available from spirometry, partly because of the variability in FVC values that are possibly influenced by expiratory effort . The advantage of our calculation method would lie in minimizing the variability in FVC, MEF50, and MEF25, thereby leading to decreased standard deviations of RCEXP. Even then, it would still be difficult to simply extrapolate the concept of the linearity of the flow-volume relationship to curvilinear MEFV curves scooping in toward the volume axis, considering that the MEF50/MEF25 ratio, which could be related to non-homogeneous emptying of the lung, was not constant regardless of the degree of airway obstruction.
MMF and expiratory flow at lower lung volumes
Given the phenomenon of maximal expiratory flow in which the equal pressure point shifts along the downstream segment to more peripheral airways and is eventually established in non-cartilaginous airways that are easily collapsible , the maximal expiratory flows measured at the lower range of FVC are likely sensitive to increased peripheral airway resistance where expiratory flow limitation occurs [25, 26]. For this reason, the measures derived from the middle or latter aspect of the MEFV curve, including MMF, MEF50, and MEF25, has been regarded as surrogate markers of peripheral airways obstruction.
The finding that there was a highly positive correlation between MMF and MEF50 is in close agreement with the finding of Bar-Yishay et al., who analyzed MEFV curves obtained from a large sample of children . MMF is a time-weighted average flow over the mid-vital capacity range, and it is, by definition, likely that MMF contains information that is responsible for the physiological events occurring at the middle aspect of the MEFV curve. On the assumption that the lung empties non-homogeneously with more than a single time constant, the difference between MMF and MEF50 would theoretically reflect the degree of airway obstruction . However, Bar-Yishay et al. presented the evidence that the ratio of MEF50 to MMF was not affected by peripheral airways obstruction, suggesting the possibility that this ratio is less reflective of the curvilinearity MEFV curve . Their conclusion was that reporting both MMF and MEF50 was redundant, considering the close correlation between them. There would nevertheless be value in reporting MEF25, as it appeared from our study that the relationship between MMF and MEF25 was rather quadratic than simply linear. This might be because of the qualitative difference between MEF50 and MEF25 in the ability to detect airway obstruction, although both are supposed to be surrogate markers of early small airway disease. The finding that RCEXP was less associated with MEF25 than with MEF50 might also be related to the different property of MEF25.
MEFV curve evaluation using the slope-ratio (SR) index, which quantifies the instantaneous slope at any point along the MEFV curve, allows for assessment of special changes in curvature over a range of lung volumes . It also provides additional information that is overlooked by the evaluation of MEFV curves based on absolute and relative values of volume and flow . In elderly healthy subjects, there is a steady increase in SR with the progression of expiration , and consequently the decrease in expiratory flow occurs mainly at lower lung volumes . The SR analysis used to detect difference in MEFV curves due to mild chronic obstructive pulmonary disease has demonstrated that the late scooping observed in these subjects is indicative of the normative aging process . The interpretation of decreased MEF50 and MEF25 should thus be made with caution especially in older subjects.
MEF50/MEF25 is occasionally used in Japan to evaluate the degree of airway obstruction [12, 32]. Patients with airway obstruction frequently exhibit a marked decrease in MEF25 compared with MEF50, resulting in an increase in MEF50/MEF25 . Some studies have suggested that an elevated MEF50/MEF25 is associated with the pathology of small airways, especially when it is greater than 4.0 [32, 33], but whether MEF50/MEF25 functions as a marker of small airway disease is still obscure because of the lack of sufficient epidemiological data for this parameter.
A Japanese study reported that MEF50/MEF25 was greater than 4.0 in many healthy subjects aged 40 years or older, with no difference in MEF50/MEF25 between smokers and non-smokers, suggesting that it could be difficult to detect the presence of airway obstruction using only MEF50/MEF25 . This tendency was consistent with our results in which MEF50/MEF25 exceeded 4.0 in more than one-third of the study population without airflow obstruction. The limited utility of MEF50/MEF25 may be explained by the qualitative difference between MEF50 and MEF25 in the degree of association with small airway pathology. MEF50/MEF25 could nevertheless be useful in younger subjects, as healthy adults aged 30 years or younger generally have a MEF50/MEF25 of less than 3.0 .
Several limitations of our study should be mentioned. First, it was not clarified whether RCEXP was more sensitive than other spirometric parameters in detecting the pathology of small airways. Our results showed that the value of RCEXP quantified from spirometry was associated with airway obstruction, but it was unclear whether RCEXP could provide more useful clinical information than standard spirometric measures. It would be necessary to explore the extent to which RCEXP reflects the different level of severity of airway obstruction because there was a limited number of patients with airway obstruction in our study population. Second, this is a retrospective study and the quality of spirometry testing performed in our patients may be questioned. Improved quality and standardization of forced expiratory maneuver is required to properly interpret the results. Every possible attempt was made to ensure quality-assured and standardized spirometry at our institution. Third, it was difficult to assess the effect of cigarette smoking on lung function because current and former smokers were included in our study. As reported before, an age-related decline has been noted in the maximal expiratory flows in the smoking population aged 40 years or older . Finally, we included only Japanese patients scheduled for surgery under general or regional anesthesia. Although our results cannot be simply applied to different races other than Asians, our reference value for RCEXP could still be theoretically useful in assessing the degree of airway obstruction if it reflects the properties of the respiratory system.