Reference value for expiratory time constant calculated from the maximal expiratory flow-volume curve

Patients scheduled for surgery in Japan are supposed to undergo pulmonary function testing as part of routine preoperative examinations to reveal any undiagnosed respiratory dysfunction. Basically, all patients scheduled for surgery at the University of Tokyo Hospital undergo spirometry testing prior to general anesthesia, under the instruction of the attending doctor. Preoperative pulmonary function measures are occasionally screened in some patients undergoing regional anesthesia to assess their suitability to undergo general anesthesia in case of any sudden change in the type of anesthesia performed. Informed consent was obtained from each patient in advance on the use of data for scientific research.

With the approval of the institutional review board of the University of Tokyo (IRB #11108), we created a database containing information on the pulmonary function of patients scheduled for surgery in order to compare the flow-volume curves obtained prior to and during general anesthesia [13]. This database contains the records of preoperative MEFV curves that were available from patients aged 15 years or older, who were scheduled for non-cardiac surgery under general or regional anesthesia during the period between April 5 and May 31, 2016. A portion of the data, including baseline characteristics of the patients and respiratory function parameters derived from spirometry, had previously been reported [13].

In accordance with the guidelines issued by the Japanese Respiratory Society [14], spirometry testing was performed by experienced technicians at our institution to ensure measurement accuracy by diminishing the variability of the results. The acceptability criteria include (1) a continuous maximal effort throughout the maneuver without artefacts, (2) a satisfactory start of expiration with an extrapolated volume of less than 5% of FVC or 150 mL, whichever is larger, and (3) an adequate exhalation with a plateau in the volume-time curve of longer than 2 s, exhalation times of longer than 15 s, or exhalation times of longer than 6 s if the subject cannot continue further exhalation. Acceptable repeatability is achieved when the difference between the largest and the next largest FEV₁ is within 200 mL of each other and the difference between the largest and the next largest FVC is within 200 mL of each other, after a minimum of three acceptable spirograms have been obtained. The best curve that meets all the criteria above is selected from the usable curves. It also requires that the sum of FEV₁ and FVC be adequately large in the best curve.

Our database of preoperative spirometry testing was retrospectively analyzed to clarify the association between RC_EXP and other spirometric parameters, including FEV₁/FVC, MMF, MEF₅₀, MEF₂₅, and MEF₅₀/MEF₂₅, and to estimate the reference value for RC_EXP. The measured values of FEV₁/FVC, MMF, MEF₅₀, MEF₂₅, and MEF₅₀/MEF₂₅ were extracted from our database. Emphasis was also placed on clarifying the relationship between MMF and other respiratory function parameters sensitive to the degree of airway obstruction in small airways.

Based on respiratory mechanics, knowledge on the descending limb of the MEFV curve is described using the following equations: where R is airway resistance, C is lung compliance, P is pressure, V is gas volume, and \( \dot{\mathrm{V}} \) is air flow. By definition, RC_EXP is the product of airway resistance and lung compliance, and is expressed via the eqs. (1) and (2) as:

The eq. (3) refers to RC_EXP as the reciprocal of the slope of the descending limb. RC_EXP is theoretically obtained when two points along the effort-independent part of the descending limb, MEF₅₀ and MEF₂₅ for instance, are ascertained. In the present study, the value of RC_EXP was calculated as the reciprocal of the slope of the line passing through the two points corresponding to MEF₅₀ and MEF₂₅ (Fig. 1) by using the following equation:

Data are expressed as mean ± standard deviation, median and interquartile range, or n (%). The R² value was calculated for the relationships between the spirometric parameters examined. The receiver operating characteristic (ROC) curve was generated for RC_EXP to select the cut-off value in accordance with the presence of airway obstruction that was defined as a FEV₁/FVC ratio and FEV₁ below the statistically lower limit of normal (LLN) [15, 16]. The area under the ROC curve (AUC) was also obtained for RC_EXP.

All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria), which is precisely described as a modified version of R commander designed to add statistical functions used in biostatistics [17]. A P value of < 0.001 was considered statistically significant.

Our retrospective analysis of 777 patients who underwent pulmonary function testing prior to surgery at our institution revealed that the cut-off value for RC_EXP 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, RC_EXP 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 RC_EXP was possible using the descending limb of the MEFV curve, and our findings imply that a prolonged RC_EXP, especially if it is longer than 0.601 s, could be associated with airway obstruction.

To our knowledge, this study is the first attempt to provide the reference value for RC_EXP that was calculated from the effort-independent portion of the MEFV curve. In theory, RC_EXP can be altered depending on the degree of airway obstruction in spontaneously breathing patients. The finding that most patients without airway obstruction had an RC_EXP 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 [7]. As might be expected, however, our reference value for RC_EXP 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 [7]. 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 [21]. Even when a greater expiratory flow is achieved, RC_EXP 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 [7]. 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 RC_EXP 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 RC_EXP 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 RC_EXP in patients with airway obstruction [22]. 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 RC_EXP [23]. 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 RC_EXP 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 [13], it could be inferred that elevated airway resistance was a major contributor to the increase in RC_EXP.

In the present study, we calculated RC_EXP 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 [8]. The advantage of our calculation method would lie in minimizing the variability in FVC, MEF₅₀, and MEF₂₅, thereby leading to decreased standard deviations of RC_EXP. 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.

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 [24], 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 [27]. 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 [28]. 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 [27]. 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 RC_EXP 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 [2]. It also provides additional information that is overlooked by the evaluation of MEFV curves based on absolute and relative values of volume and flow [29]. In elderly healthy subjects, there is a steady increase in SR with the progression of expiration [30], and consequently the decrease in expiratory flow occurs mainly at lower lung volumes [31]. 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 [29]. 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 [32]. 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 [8]. 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 [32].

Several limitations of our study should be mentioned. First, it was not clarified whether RC_EXP was more sensitive than other spirometric parameters in detecting the pathology of small airways. Our results showed that the value of RC_EXP quantified from spirometry was associated with airway obstruction, but it was unclear whether RC_EXP could provide more useful clinical information than standard spirometric measures. It would be necessary to explore the extent to which RC_EXP 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 [8]. 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 RC_EXP could still be theoretically useful in assessing the degree of airway obstruction if it reflects the properties of the respiratory system.