Rationale: In elderly subjects, static lung volumes are interpreted using prediction equations derived from primarily younger adult populations.
Objectives: To provide reference equations for static lung volumes for European adults 65 to 85 years of age and to compare the predicted values of this sample with those from other studies including middle-aged adults. We compare the lung volumes by plethysmography and helium dilution in elderly subjects.
Methods: Reference equations were derived from a randomly selected sample from the general population of 321 healthy never-smoker subjects 65 to 85 years of age. Spirometry and lung volume determinations by plethysmography and multibreath helium equilibration method were performed following the American Thoracic Society/European Respiratory Society recommendations. Reference values and lower and upper limits of normal were derived using a piecewise polynomial model.
Measurements and Main Results: Plethysmography provided higher values than the dilutional method for all lung volumes, with wide limits of agreement. In addition to height, our reference equations confirm the age- and body size dependence of lung volumes in older subjects. Practically all the estimations performed by extrapolating reference equations of middle-aged adults overpredicted the true lung volumes of our healthy elderly volunteers. Middle-aged reference equations classify subjects as being below the total lung capacity lower limit of normal between 17.9 and 62.5% of the women and between 12.5 and 42.2% of the men of the current study.
Conclusions: These results underscore the importance of using prediction equations appropriate to the origin, age, and height characteristics of the subjects being studied.
In elderly subjects, static lung volume measurements are interpreted using prediction equations derived from primarily younger adult populations. The current international guidelines recommend that reference equations should not be extrapolated for ages or heights beyond those covered by the data that generated them.
This study provides the first reported data on reference equations for static lung volumes in older adults.
Although the proportion of individuals older than 65 years of age is increasing, many of the reference equations commonly used for predicting normal lung volume values in North America and Europe have been derived from studies that included relatively small numbers of individuals over 65 years of age (4–11). In fact, predicted values for older individuals are often based upon few observations or upon extrapolations from data acquired in studies of younger adults. Remarkable differences in these predicted values may be ascribed to the selection of subjects and to methodologic or technical differences in the assessment. Moreover, because most of the studies were performed at least two decades ago, they may not fit present-day populations due to cohort effects.
The main limitation of applying prediction equations derived from primarily younger adult populations to older adults might come from the morphologic and functional changes in the respiratory system related to ageing (12, 13). Structural changes associated with ageing include smaller airway size, an increase in alveolar duct diameter with a concomitant change in the morphology of the alveolar sacs (which become larger), a decrease in lung elastic tissue, and an increase in lung collagen concentrations and in the proportion of type III collagen (12, 14, 15). These morphologic changes, in addition to a decrease in chest wall compliance and a decrease in respiratory muscle strength, produce several changes in the pulmonary function of elderly subjects, such as a decrease in the static elastic recoil of the lung, an increase in pulmonary compliance, and small airway closure resulting in air trapping (13, 16).
In addition to the obvious consequences that these alterations might have on static lung volumes, the calculation of these volumes might be affected by the measurement procedures used. Because the plethysmographic and dilutional methods give the same results in healthy adults, the reference values derived from these techniques are used interchangeably in adults (5, 6). However, the existence of air trapping in elderly subjects might result in a significant underestimation of true lung volumes measured by helium dilution as compared with plethysmography.
The aims of this paper are to provide reference equations for static lung volumes for a cohort of healthy never-smoking white European adults between 65 and 85 years of age and to compare the predicted values of this sample with those from other studies including middle-aged adults. In addition, we compare the measurements of lung volumes by plethysmography and helium dilution in healthy elderly subjects.
A random sample of never-smoker subjects without respiratory or cardiovascular disease was recruited from the elderly population of the Madrid metropolitan area (17).
Screening was based on a combination of questionnaire on respiratory symptoms (18), physical examination, and chest radiograph and electrocardiography evaluation. A detailed description of the exclusion criteria and the subject selection procedure is contained in the online supplement. The study was approved by the local Ethics Committee, and informed consent was obtained from all subjects.
Subjects were weighed and measured while wearing indoor clothing without shoes, and body mass index (BMI) and body surface area (BSA) were calculated. Age was recorded to the nearest birthday. Lung function tests were performed with a MasterLab 4.6 system (Jaeger, Wurtzburg, Germany). After a spirometry following ATS/ERS recommendations (19), lung volumes were determined using a variable-pressure plethysmograph, also in accordance with ATS/ERS recommendations (20). Thoracic gas volume at the level of functional residual capacity (FRCpleth) was measured while the subjects made gentle breathing movements against the shutter at a rate of less than 1/s (5). Expiratory reserve volume (ERV) and inspiratory VC were measured during the same maneuver. FRCpleth was reported as the mean of three or more measurements that differed by less than 5%. Residual volume (RVpleth) was calculated as FRCpleth − ERV and TLCpleth as FRCpleth + VC. Airway resistance was computed from pressure and flow measurements breathing warm, moist air fulfilling BTPS conditions (21).
Thirty minutes afterward, lung volumes were measured using the multibreath helium equilibration method. The closed circuit was filled with a mixture of 10% He, 35% O2, and 55% N2. A helium thermal conductivity analyzer was used. Helium equilibration was considered to be complete when the change in helium concentration was less than 0.02% for 30 seconds (5, 20). Rebreathing started from the resting end-expiratory position and ended after 5 to 7 minutes. FRCHe was the mean of two technically acceptable measurements that agreed by less than 10%. At the end of rebreathing, a number of ERV and VC maneuvers were performed to calculate TLCHe and RVHe.
Values are expressed as mean ± SD. Lung volumes were compared by paired Student's t test, and agreement between pairs was analyzed (21). Independent variables considered for inclusion in the models were age, standing height, weight, BMI, BSA, and their exponential, logarithmic, or square root transformations. In the multiple linear regression analysis, predictor variables were retained only if their addition significantly improved the fraction of explained variability (R2). The assumptions of linearity and distributional normality were controlled. The lower limit of normal (LLN) range was calculated as follows: predicted value – 1.645 × RSD (where RSD is the residual standard deviation).
The selection of prediction equations for comparison was based on common use (4–10). Differences between observed and predicted values are given as mean difference, mean squared difference, and standardized prediction deviation. For comparisons among authors, LLN was calculated using the RSD of the corresponding equation. The differences between predicted values based on the prediction equations from the present study and others are given as Bland and Altman plots. Statistical significance was assumed for P < 0.05.
A total of 583 subjects underwent clinical evaluation; 201 subjects were excluded due to dyspnea (n = 24), cough (n = 17), wheezing (n = 13), or for several previously undetected diseases, such COPD (n = 11), asthma (n = 8), scoliosis (n = 3), or obesity (BMI ≥30 kg/m2) (n = 125). Of the 382 subjects (231 women and 151 men) who entered into the study, we found technically acceptable tests for 321 (189 women and 132 men). Sixty-one subjects (9.8% of men and 13.4% of women) were excluded from analysis because of claustrophobia (n = 2), incapacity to perform satisfactory panting maneuvers (n = 37), or repeated disconnections from the test gas during rebreathing (n = 22) (Figure 1). The elderly subjects who were excluded or were ineligible for the study were similar in age, height, and weight as those who were included.
The age distribution of the women and men in the analyzed sample demonstrates adequate representation of the study population (see Table E1 in the online supplement). Details of the anthropometric characteristics, spirometric data, lung volumes, and airway resistance in both sexes are shown in Table 1. No significant differences in these parameters were found between excluded subjects and the analyzed sample.
Women (n = 189)
Men (n = 132)
|Age, years||73 ± 6*||72 ± 5|
|Height, cm||152 ± 6||166 ± 6|
|Weight, kg||61 ± 7||73 ± 8|
|BMI, kg/m2||26.4 ± 2.4||26.6 ± 2.2|
|BSA, m2||1.58 ± 0.11||1.81 ± 0.12|
|FVC, L||2.29 ± 0.47||3.46 ± 0.64|
|FEV1, L||1.80 ± 0.41||2.65 ± 0.52|
|FEV1/FVC, %||78.9 ± 5.6||76.8 ± 5.5|
|ERV, L||0.83 ± 0.40||1.20 ± 0.46|
|VC, L||2.39 ± 0.48||3.65 ± 0.65|
|IRV, L||0.92 ± 0.44||1.45 ± 0.66|
|IC, L||1.57 ± 0.47||2.45 ± 0.73|
|TLCHe, L||3.73 ± 0.68||5.41 ± 1.02|
|FRCHe, L||2.12 ± 0.46||2.91 ± 0.60|
|RVHe, L||1.40 ± 0.40||1.73 ± 0.58|
|RV/TLCHe, %||37.3 ± 7.9||31.7 ± 8.3|
|FRC/TLCHe, %||57.2 ± 8.3||54.5 ± 9.1|
|TLCpleth, L||3.91 ± 0.69||5.59 ± 0.99|
|FRCpleth, L||2.34 ± 0.47||3.14 ± 0.57|
|RVpleth, L||1.52 ± 0.43||1.94 ± 0.56|
|RV/TLCpleth, %||38.7 ± 7.7||34.3 ± 7.0|
|FRC/TLCpleth, %||60.1 ± 8.6||56.8 ± 8.7|
|IC/TLC pleth, %||39.9 ± 8.5||43.2 ± 8.7|
|Raw, kPa.l−1.s||0.49 ± 0.29||0.34 ± 0.17|
|sRaw, kPa/s||1.30 ± 0.71||1.21 ± 0.51|
In men and in women, the plethysmographic method provided higher values than the dilutional method for TLC, FRC, or RV (P < 0.001 in all comparisons) (Table 1). The mean differences of lung volumes (plethysmographic − helium dilution) and their 95% limits of agreement were wide, reflecting as great a within-subject variability as that from method-related differences (Figure 2). Because the 95% limits of agreement for static lung volumes include zero, it is not possible to conclude that the helium dilution method systematically underestimates static lung volumes in healthy individuals.
The reference equations for lung volumes from the healthy older European women and men are given in Tables 2 and 3. We did not find that the addition of transformations significantly improved the predictability of the regression equations. No significant interaction between age and height was found. Analysis of residuals showed that homoscedasticity was present in all equations. Regression analysis of these residuals showed neither statistically significant slopes nor correlation coefficients. The residuals corresponding to these models did not differ significantly from a Gaussian distribution in all lung volumes, as determined by the Shapiro-Wilk test. Therefore, one-sided lower 95% prediction intervals were used to determine the lower limit of normal lung functions (5). Because the use of weight or weight-related factors for reference equations would affect to the accuracy of prediction values among morbidly obese subjects, in Table 4 we provide the prediction equations for these lung volumes without weight-related factors.
|ERV, L||0.09238 – 0.00000059 A3 + 0.000000368 H3 – 0.00000143 W3||0.150||0.3731|
|VC, L||2.773 – 0.0339 A + 0.0000006728 H3 – 0.00000123 W3||0.552||0.3214|
|IRV, L||1.214 – 0.0234 A + 0.892 BSA||0.162||0.4068|
|IC, L||1.771 – 0.0254 A + 0.00007121 H2||0.219||0.4199|
|TLCpleth, L||11.495 – 0.208 A + 0.00001062 A3 + 0.0002588 H2 −1.654 BSA||0.437||0.5238|
|FRCpleth, L||2.276 + 0.0000008882 H3 – 1.96 BSA||0.304||0.3902|
|RVpleth, L||−1.039 + 0.01678 H||0.061||0.4168|
|RV/TLCpleth, %||29.404 + 0.00002356 A3||0.085||7.3748|
|FRC/TLCpleth, %||36.39 + 0.325 A||0.047||8.3715|
|IC/TLC, %||63.529 – 0.324 A||0.047||8.3649|
|Raw, kPa/L/s||−0.923 + 0.0000591 A2 − 0.0000009 W3 + 0.04985 BMI||0.155||0.2659|
|sRaw, kPa/s||−1.737 + 0.02386 A + 0.04914 BMI||0.069||0.6912|
|TLC He, L||−0.00889 – 0.0365 A + 0.05085 H – 0.0518 BMI||0.412||0.5232|
|FRC He, L||−3.896 + 0.06151 H − 2.135 BSA||0.243||0.3999|
|RV He, L||−2.07 + 0.02266 H||0.120||0.3753|
|RV/TLC He, %||27.091 + 0.00002554 A3||0.086||7.5377|
|FRC/TLC He, %||44.46 + 0.393 A – 0.61 BMI||0.092||7.9339|
|ERV, L||−3.907 + 0.000001217 A3 + 0.03028 H – 0.000000959 W3||0.139||0.4299|
|VC, L||2.064 – 0.00000320 A3 + 0.0000006171 H3||0.476||0.4738|
|IRV, L||2.037 – 0.00000257 A3 + 0.0000009746 W3||0.179||0.6054|
|IC, L||2.327 – 0.00000455 A3 + 0.0000004124 H3||0.435||0.5545|
|TLCpleth, L||2.321 – 0.00000309 A3 + 0.0000009765 H3||0.354||0.8001|
|FRCpleth, L||−1.425 + 0.02188 A + 0.0000007418 H3 – 0.00000103 W3||0.282||0.4865|
|RVpleth, L||0.315 + 0.0000003551 H3||0.095||0.5369|
|RV/TLCpleth, %||11.590 + 0.314 A||0.059||6.8354|
|FRC/TLCpleth, %||32.759 + 0.00006201 A3||0.403||6.7594|
|IC/TLC, %||67.229 – 0.0000620 A3||0.402||6.7669|
|Raw, kPa/L/s||1.717 + 0.005391 A – 0.0117 H + 0.000000414 W3||0.136||0.1564|
|sRaw, kPa/s||−1.750 + 0.02208 A + 0.05122 BMI||0.091||0.4901|
|TLC He, L||2.530 + −0.00000352 A3 + 0.0000009212 H3||0.335||0.8429|
|FRC He, L||0.838 + 0.0000004526 H3||0.132||0.5626|
|RV He, L||−2.703 + 0.03978 A + 0.02261 W||0.187||0.6184|
|RV/TLC He, %||23.79 + 0.00002066 A3||0.054||8.1326|
|FRC/TLC He, %||34.716 + 0.00005152 A3||0.278||7.7813|
|ERV, L||0.07476 – 0.0000002534 H3||0.080||0.3859|
|VC, L||2.90 – 0.03375 A + 0.0000005504 H3||0.524||0.3301|
|IRV, L||1.932 – 0.02309 A + 0.0000001885 H3||0.149||0.4099|
|TLCpleth, L||12.383 – 0.243 A + 0.00001271 A3 + 0.0001824 H2||0.416||0.5223|
|FRCpleth, L||0.563 + 0.0000004998 H3||0.233||0.4083|
|Raw, kPa/L/s||0.546 + 0.009432 A – 0.00003178 H2||0.100||0.2735|
|sRaw, kPa/s||−0.542 + 0.02527 A||0.041||0.6996|
|TLC He, L||−1.690 – 0.03779 A + 0.05354 H||0.379||0.5358|
|FRC He, L||−2.427 + 0.02976 H||0.159||0.4199|
|FRC/TLC He, %||29.951 + 0.372 A||0.060||8.0392|
|ERV, L||−2.131 + 0.000001359 A3 + 0.01691 H||0.098||0.4384|
|IRV, L||2.543 – 0.00000285 A3||0.143||0.6162|
|FRCpleth, L||−1.215 + 0.02434 A + 0.0000005659 H3||0.251||0.4949|
|Raw, kPa/L/s||1.443 – 0.006653 H||0.056||0.1621|
|sRaw, kPa/s||−0.204 + 0.01949 A||0.043||0.5008|
| RV He, L||0.771 + 0.0000002113 H3||0.037||0.5313|
Tables 5 and 6 show the differences between the observed values found in the subjects of our study and the values calculated from several prediction equations. Aside from our equations, the closest agreements for plethysmographic lung volumes were with Cordero and colleagues (9) and ECSC (5) in women and with Crapo and coworkers (4) in men. Regarding dilutional lung volumes, in women the closest agreements for TLC were with Crapo and colleagues (4) and ECSC (5), whereas the closest for FRC was with Cordero and coworkers (9) and ECSC (5) and for RV with Cordero and colleagues (9) and Matthys and coworkers (7). In men, the closest TLC agreements were with Crapo and colleagues (4) and Cordero and coworkers (9), for FRC with Crapo and coworkers (4) and Cotes and colleagues (10), and for RV with Matthys and colleagues (2) and Crapo and coworkers (4).
|Mean Difference (%)||Mean Squared Difference||Standardized Prediction Deviation||% Observed Values below the LLN or over ULN*||Rank||Mean Difference (%)||Mean Squared Difference||Standardized Prediction Deviation||% Observed Values Below the LLN or over ULN*||Rank|
| Matthys (7)||−31.1||0.660||−1.173||0||3||−29.1||0.627||−0.536||0||2|
|Mean Difference %||Mean Squared Difference||Standardized Prediction Deviation||% Observed Values below the LLN or over ULN†||Rank||Mean Difference %||Mean Squared Difference||Standardized Prediction Deviation||% Observed Values below the LLN or over ULN†||Rank|
| Matthys (7)||−48.6||0.700||−1.417||0||3||−29.1||0.627||−0.536||0||2|
To compare our reference equations with other prediction equations, the difference in predicted lung volumes (present study equation – every other equation) by the mean predicted lung volumes were plotted for women and men, respectively. In women, Matthys and colleagues (7) and Roca and coworkers (8) overestimated FRCpleth and FRCHe, whereas Cotes and coworkers (10) underestimated this lung volume (Figure 3). In men, the ratio increased proportionally when the present prediction values for FRCpleth were compared with those from ECSC (5), whereas it decreased proportionally with respect to Cordero and coworkers (9) and Cotes and colleagues (10) (Figure 4). Roca and coworkers (8) and Matthys and colleagues (7) clearly overestimated FRCpleth in men. For women and for men, all the analyzed adult-derived reference equations overpredicted TLCpleth, TLCHe, and RVpleth (Figures E1–E12).
To our knowledge, the current study provides the first data in the international literature on reference values for static lung volumes and airway resistance in healthy older adults. Our results confirm that reference equations should not be extrapolated, in general, for ages or heights beyond those covered by the data that generated them. For patients over 65 years of age, the current study shows that the most commonly used sets of reference equations may lead to inaccurate interpretations.
The exact definition of a “healthy” group is difficult to agree upon. Although criteria to define subjects as healthy have been established in previous ATS statements (22), previous studies have used many different criteria. The ECSC reference equations (5, 6) were not based on original data; rather, they were derived from previously published reference equations. Moreover, the data on TLC, RV, and FRC are derived from populations that include smokers and exsmokers (6); therefore, these equations may not be representative of a healthy nonsmoking population. In the study by Cotes and colleagues (10), some exsmoker women were included in the reference group. In contrast, all of the current study patients were lifelong nonsmokers. Also, notable differences exist in the technique used to determine lung volumes. In some cases, the reference equations were obtained from measurements for single-breath helium dilution (4), in others from multiple breath helium dilution (5, 9, 10), and in others by plethysmography (7, 8).
Although it has been proposed to use the same reference values for plethysmographic and dilutional methods in middle-aged adults (6), the comparison of lung volumes measured by plethysmography and helium dilution shows statistically significant differences despite substantial interindividual variation (see Table 1; Figure 2). As a consequence of the reduction in supporting tissue around the airways, distal airways begin to close at a higher lung volume in elderly people than in younger people (12). Despite the absence of airway obstruction in our subjects, the existence of poorly- or nonventilated airspaces or a premature closure of the airways during tidal breathing (13) could explain the lower lung volumes obtained by helium dilution. In any case, the differences obtained between plethysmography and helium dilution are notable, as demonstrated by the wide limits of agreement for TLC (−0.29 to 0.73 L in women and −0.22 to 0.79 L in men) (see Figure 2). Because the difference obtained between the two procedures is not calculable beforehand, it seems necessary to use specific sets of reference equations for every procedure in elderly subjects.
Usually, lung volumes are related to body size, with standing height being the most important factor (19), but our results support the importance of other factors.
Although many reference equations for FRC only consider age and height (4–7), those of Cordero (9), Roca (8), and Cotes (10) include other body measurements, such as weight, BMI, or BSA. In our case, we verify that body size is an important factor related to FRC, expressed essentially as BSA. This result is consistent with the clinical observation that obesity has the greatest effect on FRC because the effect of body fat on lung volumes is determined by the decrease of total and chest wall compliance (13), which reduces FRC (23). However, the inclusion of BSA in the prediction equations for FRC may lead to misinterpretation of the results. Likewise, it has been suggested that the incorporation of body composition measurements, especially fat-free mass index, increases the accuracy of the reference equations for lung volumes (10). Nevertheless, it is difficult to recommend the incorporation of these measurements in all routine explorations, except in the most sophisticated lung function laboratories. The application of our reference equations to morbidly obese subjects might reduce their accuracy, and this would result in a significant tendency toward misclassification of obesity-associated restriction by undepredicting lung volumes. To avoid this problem, we have generated another set of reference equations without weight-related factors (see Table 4). The use of both prediction equations allows for distinguishing if high weight is the sole cause for a low lung volume or whether there is some other contributing process.
In addition to height dependence, our reference equations confirm the importance of incorporating age in the prediction of TLC in women and in elderly men. The age-related decrease in diaphragmatic strength (24) reduces maximal respiratory pressures in healthy elderly subjects (25) and can consequently reduce inspiratory capacity. A reduction in diaphragmatic strength, by about 25% in healthy elderly subjects compared with young adults (25), must have some effect on TLC.
Similarly, age was directly related to RV in women and in men. In addition to the increased closing volume, this can be justified by the age-related weakness of the expiratory muscles. Previously, it has been demonstrated that the expiratory intercostal muscles undergo atrophy with a decrease of approximately 20% in the mean cross-sectional area after the fifth decade (26). Moreover, with increasing age, the chest wall becomes less compliant, and the lungs become more distensible. As a result of the diminished lung elastic recoil, an increase in RV by approximately 50% between 20 and 70 years of age has been reported (13).
Practically all the estimations made by extrapolation of reference equations for middle-aged adults overpredicted the true lung volumes of our healthy elderly volunteers. An increase in static lung volume has been reported during normal ageing as a consequence of the decrease in the elastic recoil of the lung secondary to changes in the lung connective tissue (12). However, it is possible that these changes mimic those observed in emphysema and are of a lesser magnitude than expected. Biochemical studies suggest that the total lung content of collagen and elastin does not change with ageing and that the collagen becomes more stable because of increased numbers of intermolecular crosslinks (27). Morphometric studies in senescence-accelerated animal models have not shown evidence of cellular infiltration or a decrease in the ratio of lung weight to body weight, suggesting little or no lung destruction, as opposed to what is seen in emphysema (28). As a consequence of changes in the spatial arrangement or crosslinking of the elastic fiber network (29), a homogeneous enlargement of air spaces occurs, followed by discrete lung hyperinflation. The changes observed in senile lungs are morphologically and histologically different from emphysema, and their major consequences seem to be a tendency toward small airway collapse and a decrement in expiratory flow with ageing (13, 17).
An example of the overprediction of lung volumes is provided by the estimation of healthy subjects below or over the limits of normal. Because prediction equations derived from cross-sectional data are primarily used as a screening tool to identify individuals with lung function outside the expected range, the utility of any particular reference equation depends upon its ability to correctly identify individuals with lung function below the lower limit of normal (LLN) or over the upper limit of normal. Some authors have defined the LLN as that value above which the results of 95% of the normal population lie, working under the assumption that larger values have larger variances. However, if skewed distributions are transformed to normalize their shape, the subtraction of 1.645 SD may still be used to estimate the LLN. Middle-aged reference equations classify subjects as being below the plethysmographic TLC LLN between 11.8 and 55.5% of the women and between 14.1 and 25.9% of the men of the current study. In contrast, only 0.6 to 1.7% of the women and 0.1 to 0.3% of the men were above the upper limit of normal of plethysmographic RV.
In conclusion, we have developed reference equations for the prediction of static lung volumes in older adults. Differences among studies in predictions of lung volumes or in the identification of individuals with lung function values outside the limits of normal may be due to differences in the age range of the reference subjects but are also likely to be contributed to by different measurement methods and other differences in the underlying populations. These results underscore the importance of using prediction equations appropriate to the age and height characteristics of the population to whom inferences are to be applied. Our reference equations may be used for the prediction of lung volumes in white patients 65 to 85 years of age with standing heights for women between 144 and 174 cm and men between 152 and 181 cm. The use of our reference equations beyond these age and height limits may lead to inaccuracies.
The authors thank A. Alvarez. P. Librán, A. Pérez, and C. Suárez for technical assistance.
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