Reference Values for Dynamic Responses to Incremental Cycle Ergometry in Males and Females Aged 20 to 80

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1 Reference Values for Dynamic Responses to Incremental Cycle Ergometry in Males and Females Aged 20 to 80 J. ALBERTO NEDER, LUIZ E. NERY, CLOVIS PERES, and BRIAN J. WHIPP Respiratory Division, Department of Medicine, and Department of Preventive and Social Medicine, Universidade Federal de Sao Paulo Escola Paulista de Medicina (UNIFESP-EPM), Sao Paulo, Brazil; Centre for Exercise Science and Medicine, Institute of Biological and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and Department of Physiology, St. George s Hospital Medical School, University of London, London, United Kingdom Interpretation of incremental cardiopulmonary exercise tests (CPET) might be enhanced by considering the simultaneous rates of change of certain key variables, e.g., oxygen uptake/ work rate ( / WR), heart rate/ ( HR/ ), ventilation/ carbon dioxide production ( C ), and the linearized tidal volume/ E ( VT/ ln E) relationships. However, there are no published age- and sex-dependent reference values for these relationships that were appropriately obtained in randomly selected subjects. We therefore prospectively evaluated 120 sedentary individuals (60 male, 60 female, age 20 to 80 yr) who were randomly selected from more than 8,000 subjects, and submitted to standard ramp-incremental CPET on an electronically braked cycle ergometer. We found that sex and age significantly influenced several of the dynamic relationships, in addition to anthropometric attributes (p 0.05). A comprehensive set of linear prediction equations is provided; the limits of normality (at the 95% confidence level) differed substantially from previous recommendations based on single discrete values. These data therefore provide a frame of reference for assessing the normalcy of the response profiles of four standard indices of metabolic, cardiovascular, and ventilatory function during rapidly incremental cycle ergometry in sedentary males and females up to 80 yr of age. Keywords: exercise test; exertion; reference values; aging Cardiopulmonary exercise testing (CPET) provides a means of educing evidence of abnormal physiologic functioning which may not be apparent at rest and which may be pathognomonic of particular disease processes (1). Current techniques provide a means of spanning the tolerable work rate (WR) range with a single incremental test of a relatively short duration during which a high-density (e.g., breath-by-breath) computation and display of a range of physiologically relevant variables is available to the investigator for interpretation. The normalcy of response to such a test is usually considered with respect to particular functional indices, such as the peak oxygen uptake (peak ), the estimated lactate threshold ( l ), and the maximum level achieved for ventilation and heart rate (HR) with respect to some expected limiting value (1 3). A large body of work has established normal values for these indices with respect to age, sex, body dimensions, and regular level of physical activity (4 9). (Received in original form March 2, 2001; accepted in final form August 20, 2001) Partially supported by Research Grants from FAPESP/CNPq-Brazil. Dr. Neder was supported by a Postdoctoral Research Fellowship Grant from FAPESP-Brazil (no. 95/9843-0). Correspondence and requests for reprints should be addressed to J. A. Neder, M.D., Ph.D., Centre for Exercise Science and Medicine Institute of Biological and Life Sciences, University of Glasgow, West Medical Building, Glasgow G12 8QQ, Scotland, UK. jas13w@udcf.gla.ac.uk This article has an online data supplement, which is accessible from this issue s table of contents online at Am J Respir Crit Care Med Vol 164. pp , 2001 DOI: /rccm Internet address: However, consideration of a single value for the variables of interest may be unsuitable as a frame of reference for the continuous, dynamic cardiopulmonary responses that develop throughout these tests. In this regard, the regressed baseline value (intercept or constant) and the rate of change (slope) are likely to be of substantially more importance. In addition, such an analysis maximizes the use of the massive amount of data generated during routine CPET. In fact, the recent European Respiratory Society s monograph on CPET stressed the importance of interpreting the trending of the physiologic response profiles; it also recognized the paucity of the extant information on the topic (1). The trending of certain variables has been considered as a crucial component of the interpretative strategy. For example, the shift from a linearly increasing profile of oxygen uptake with respect to work rate ( / WR) to a more shallow rate of change has been shown to be indicative of circulatory dysfunction (10 13). Similarly, a steep increase of HR as a function of the metabolic demand could be regarded as indirect evidence of cardiac abnormalities or peripheral muscle impairment for oxygen utilization ( HR/ ) (2, 3, 13, 14). A high slope of the minute ventilation ( E) change as a function of pulmonary C output ( C ) is considered to be reflective of hyperventilation, an enlarged dead space fraction of the breath, or both (13, 15 18). Furthermore, ventilation could increase at the expense of a tachypneic breathing pattern with a reduced tidal volume (VT) to the ventilatory demand ( VT/ E). This pattern will, itself, reduce the efficiency of the lung as gas exchanger, consequent to the high dead space fraction of the breath (2, 3). Little is known, however, about the normal values for these trending phenomena during cycle ergometry in randomly selected subjects. Additionally, in those few studies in which such values have been provided, the cutoff value for assessing normalcy is usually given as a discrete level (2, 4, 5, 14, 19) rather than recognizing that the function may well be age-dependent and sex-dependent (20). We were therefore interested in establishing appropriate frames of reference for assessing the normalcy of the profiles of the physiologic responses to a rapidly incremental cycle ergometer test. To achieve this, we determined values for the dynamic response profiles of the most commonly used physiologic variables to an incremental exercise test in a randomly selected group of sedentary subjects, both male and female, with an age span of six decades. METHODS Study Design and Subjects This study used a random sample of ancillary staff (clerical and manual work) from a large university population in a controlled, prospective design. The subjects were chosen randomly by electronic selection from this total population (n 8,226). A total of 120 individuals (60 men, 60 women) evenly distributed in age groups were evaluated (20 to 39, 40 to

2 1482 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 1. ANTHROPOMETRIC CHARACTERISTICS AND MAXIMAL EXERCISE CAPACITY ACCORDING TO SEX AND AGE* Males (n 60) Females (n 60) Age (yr) Height (cm) Weight (kg) Peak (ml min 1 ) HRmax (% pred) Height (cm) Weight (kg) Peak (ml min 1 ) HRmax (% pred) , , , , , , All , , * Values are presented as mean SD. Twenty subjects in each age group. Significant effect among age groups within sex (p 0.01). Significant effect between sex groups (p 0.01). 59, 60 to 80 yr) (Table 1) (9, 21). Informed consent (as approved by the institutional medical ethics committee) was obtained from all subjects. Skinfold thickness was measured at four sites (biceps, triceps, subscapularis, and iliac crest) using a Harpenden skinfold caliper. Body subcutaneous fat and lean body mass were then estimated using the method of Durnin and Womersley (22). The questionnaire of Baecke and coworkers for epidemiologic studies (23) was used to detail and quantify information regarding occupation, sports activities, and leisure habits. CPET The exercise tests were carried out on an electromagnetically braked cycle ergometer (CPE 2000; Medical Graphics Corp. MGC, St. Paul, MN) with gas exchange and ventilatory variables analyzed breath by breath using a computer-based exercise system (MGC-CPX System, MGC), calibrated as previously described (9). Periodically, the overall output data system was validated against a respiratory gas exchange simulator (24). During the exercise tests, the power (W) was increased to the limit of tolerance in a linear ramp pattern (10 to 25 W min 1 in females and 15 to 30 W min 1 in males). The following variables were determined: pulmonary oxygen uptake (, ml min 1 ); pulmonary carbon dioxide output ( C, ml min 1 ); respiratory exchange ratio (R); E (L min 1 ); VT (ml); respiratory rate (f, breaths/ min); ventilatory equivalents for and C ( E/ and E/ C ); and end-tidal partial pressures of and C (PET O2 and PET CO2, mm Hg). The average for the last 15 s of the ramp was considered to be representative of the subject s peak. The at the L was estimated using both gas exchange (25) and ventilatory methods (26). The following dynamic relationships were determined to characterize the metabolic, cardiovascular, ventilatory, and breathing pattern responses, respectively: (1) / WR (ml min 1 W 1 ), i.e., normal values would indicate adequate metabolic response for a given power output (2, 10, 19); (2) HR/ (beats min 1 L min 1 ), i.e., a steeper HR response for a given metabolic demand would imply reduced stroke volume or low peripheral oxygen extraction (2, 4, 14); (3) subrespiratory compensation point C (L min 1 L min 1 ), i.e., high values would indicate excessive ventilation to the metabolic stress (2, 15); and (4) VT as a function of the linearized E response ( VT/ ln E), i.e., shallow slopes would suggest a tachypneic breathing pattern (1 3) (Figures 1A to 1D). Data Analysis Data are reported as mean values and standard deviations (SD). Association between variables was assessed by Pearson s linear correlation. Sex-grouped data were compared using Student s t test, and analysis of variance (ANOVA) was used to determine differences among age groups. Multiple linear regression was also performed with the dynamic relationships as dependent variables (27). The probability of a Type I error was established at 0.05 for all tests. RESULTS / WR Data were pooled only after establishing the response linearity for each individual (Figure 1A). The age-corrected coefficient of variability [CV (SD/mean) 100] for this relation- ship was consistently below 10% in males and 15% in females (Table 2). We found that anthropometric characteristics and age (Table 2 and Figure 2A) did not influence / WR, independent of sex (p 0.05). On the other hand, males presented higher values than females in all age groups. The lower limit of normal at the 95% confidence limit, therefore, was sex-specific: 9.8 ml min 1 W 1 for men and 8.5 ml min 1 W 1 for women (Table 2). Interestingly, / WR was positively correlated with both peak (r 0.48 and 0.39 in males and females, respectively) and L (r 0.32 and 0.29, p 0.01). HR/ The CV for the individually determined HR/ throughout the linear range of the responses (Figure 1B) was typically less than 15% in females and 20% in males (Table 2). We found that age and sex significantly influenced this relationship (Table 2), in such a way that aged females manifested the steepest slopes (p 0.01); the descriptive equations are presented in Figure 2B. In addition, weight (kg) independently influenced this relationship, i.e., HR/ (beats min 1 ml min 1 ) 0.42 (0.08) age 0.53 (0.12) weight 73.5 (9.8), r , standard error of the estimate (SEE) 11.2 in males, and 0.42 (0.09) age 0.28 (0.10) weight 78.1 (10), r , SEE 12.1 in females. Although body mass index, lean body mass, and the level of regular physical activity were also individually associated with lower HR/ (p 0.01), these variables did not appreciably improve the residuals dispersion when used instead of body weight. Not surprisingly, HR/ was negatively correlated with peak (r 0.44 and 0.47 in males and females, respectively), L (r 0.49 and 0.34), and / WR (r 0.45 and 0.31, p 0.01). C Both age and sex significantly influenced the dynamic E/ C relationship, as was the case for HR/. The CV for this relationship was within 10% for each age group, independent of sex (Table 2). In addition, C was negatively correlated with height in females (r 0.31, p 0.05). However, in a multiple regression analysis, only age remained an independent predictor for this relationship, independent of sex (Figure 2C, males on left, females on right). Interestingly, C was negatively related to both peak (r 0.51 and 0.49) and L (r 0.35 and 0.30, p 0.01) in males and females, respectively. We also sought to characterize the relationship between PET CO2 (mm Hg) and the metabolic demand (, L/min) from the unloaded control condition to L, and also from L to the limit of tolerance (peak ). PET CO2 was lower at each of these three points as a function of age: females tended to present lower val-

3 Neder, Nery, Peres, et al.: Dynamic Responses to Exercise 1483 L 1 for the 20 to 39, 40 to 59, and 60 to 80 age groups, respectively (Figure 3, lower panels). VT/ ln E The CV for the individually determined VT/ ln E (Figure 1D) was near 20% for each age group in both sexes (Table 2). We found that sex was a significant determinant in this relationship, with males presenting higher values than females in all age groups. In addition, we found a negative relation between VT/ ln E and age only in females (Table 2, Figure 2D) but a positive association with height (r 0.40, p 0.05). As with C, however, only age remained an independent predictor of VT/ ln E. Figure 2D depicts the age-corrected prediction equation for this relationship in females. Furthermore, VT/ ln E was negatively related to C in both sexes (r 0.33 and r 0.25, in males and females, respectively). Figure 1. Procedures used to establish four dynamic indices of exercise function during incremental CPET in representative young (24-yr-old, left panels) and old (70-yr-old, right panels) subjects. (A) A metabolic index ( / WR, ml min 1 W 1 ). (B) A cardiovascular index ( HR/, beat min 1 L min 1 ). (C) A ventilatory index ( C, L min 1 L min 1 ). (D) A breathing pattern index ( VT/ln E), derived from the nonlinear relationship between VT and E (inserted graph). These dynamic relationships were obtained by simple linear regression; arrows show the range of values considered for analysis. RCP respiratory compensation point. ues than males at L (Figure 3, upper panels). The actual values (mean SD) at unloaded cycling, at L, and at peak were in males: , , and mm Hg (at 20 to 39 yr); , , and mm Hg (at 40 to 59 yr); and , , mm Hg (at 60 to 80 yr). For the female group, these values were as follows: , , and mm Hg (at 20 to 39 yr); , , and mm Hg (at 40 to 59 yr); and , , mm Hg (at 60 to 80 yr) (Figure 3, upper panels). On the other hand, there was no significant effect of age on unloaded L PET CO2 / ; males, however, did present significantly lower values of this relationship than females ( and mm Hg L 1, respectively; p 0.05) (Figure 3, lower panels). The negative PET CO2 / relationship between L and peak, however, did increase with age in both sexes, with females also presenting higher values than males, i.e., males , , and mm Hg L 1 ; females , , and mm Hg DISCUSSION This study presents a systematic evaluation of selected dynamic submaximal relationships for rapidly incremental cycle ergometry in a randomly selected sample of sedentary males and females, up to 80 yr of age, providing age- and sex-specific indices of metabolic ( / WR), cardiovascular ( HR/ ), and ventilatory ( C and VT/ ln E) function (Table 2, Figures 1 and 2). These normative data therefore provide a frame of reference for the normalcy of the submaximal responses during clinical incremental CPET for use in conjunction with the readily available discrete reference values. / WR The linear phase of the / WR relationship during rapidly incremental exercise has been demonstrated to be a useful noninvasive index of aerobic work efficiency in normal subjects (2, 10). In several patient groups, however, this index is lower (2, 10, 12, 19), indicating increased energetic contribution from anaerobic sources of ATP regeneration. In addition, the linearity of the -WR relationship can be lost in patients with cardiac impairment, for example, because of decreased oxygen flow to the exercising muscles. As expected, this is more likely to occur above the anaerobic (lactic) threshold (10, 12). Previous normative values for the / WR relationship were obtained in volunteers, typically involving higher-thanaverage fit males with narrow ranges of age (10 12, 19). Although the average values obtained in women and aged men in this study are not appreciably different from those published by Hansen and coworkers (10, 19), our younger sedentary men clearly presented higher values comparable, however, with those reported by others (11). In addition, we confirm that although overweight does not change the response slope, it does displace this relationship upwards (data not shown). In reality, we recently demonstrated that this should be better related to leg than total body mass during cycle ergometric exercise (28). Interestingly, this ratio has long been considered to be independent of age, sex or physical fitness (2); however, it would be expected that the less fit subjects (who would rely more on anaerobic energetic sources) would present lower slopes, as was the case in our study for female subjects (Table 2). Additionally, the fitness dependence of / WR is consistent with the observed positive correlation between / WR and the level of regular physical activity (p 0.01) and peak, and the inverse relationship between / WR and HR/ in both sexes.

4 1484 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 2. DYNAMIC EXERCISE RELATIONSHIPS ACCORDING TO SEX AND AGE* Age (yr) / WR (ml min W 1 ) Males (n 60) Females (n 60) HR/ C / WR HR/ C (beat L min 1 ) (L L 1 ) VT/ ln E (ml min W 1 ) (beat L min 1 ) (L L 1 ) VT/ ln E (9.8) (61.7) (27.9) (0.68) (8.5) (85.4) (32.0) (0.49) (10.0) (73.6) (31.8) (0.62) (8.1) (105.7) (33.6) (0.44) (9.6) (88.5) (33.4) (0.50) (8.0) (109.7) (35.3) (0.37) All (9.8) (78.4) (32.3) (0.60) (8.0) (104.4) (34.2) (0.41) * Values are expressed as mean SD, with one-sided 95% confidence interval in parentheses. Twenty subjects in each age group. Significant effect among age groups within sex: versus and (also significant for versus in E/ CO in males and HR/ 2 O in females, p ). Significant effect between sex groups within age and for all subjects (p 0.05). HR/ The HR/ might also be considered to represent a useful index of overall cardiovascular fitness because reductions on stroke volume and peripheral oxygen extraction are both expected to steepen this relationship, assuming the normal independence of training on the linear cardiac output relationship (2, 13, 14). This is particularly true in this study where the use of rigorous exclusion criteria allowed us to avoid other confounding factors such as anemia, carboxyhemoglobinemia, hypoxemia, or clinically significant shunts (9, 21). It is not surprising therefore that the prediction equations developed by Fairbarn and coworkers (14), who evaluated a group of volunteers, significantly underestimated the HR/ slope of our randomly selected subjects (p 0.01, comparison not shown). The inverse relationships between HR/ and weight and lean body mass in both sexes are likely to be related to the well-known stroke volume body mass relationship, a training effect of chronic overweight, and to the underlying relationship between lean body mass and regular physical activity. C Relationship Although it is well known that the ventilatory response to muscular exercise as a function of metabolic rate increases with age (29), it is less known how it changes with aging and also with respect to rapidly incremental tests now common to clinical exercise testing. There is therefore a paucity of appropriate reference values for the C relationship; the few available studies also used somewhat fitter volunteers (20, 30). Normal values for the slope of increase in E as a function of C ( C ) during exercise are presented, as this approach is commonly used in the assessment of abnormal ventilatory response to exercise. However, this slope should be used with caution, as it is not the constant, but the variable E/ C that is important in establishing arterial blood gas and acid base status, i.e., E m C c, where m is the slope and c the intercept. Rearrangement of this equation yields E/ C m c/ C. It should be noted, however, that physiologically E (BTPS) 863 C (STPD)/Pa CO2 (1-VD/VT) where VD dead space ventilation. For a linear response, therefore, E/ C at the lactate threshold will closely approximate C when isocapnic buffering begins at a high value of C but will be higher if it begins at low C. Figure 2. The four submaximal relationships during incremental CPET as a function of age in males (n 60, left panels) and females (n 60, right panels). Although age did not influence / WR (A), aging was significantly associated with increased HR/ (B) and C (C) in both sexes. On the other hand, a negative effect of age on VT/ ln E was found in females (D). Females presented higher values of HR/ and C but lower values of / WR and VT/ ln E than males. Regression lines are shown with their respective 95% confidence intervals for those relationships in which the variables were influenced by age. Regression coefficients and intercepts of the linear prediction equations are depicted with their respective standard errors. SEE standard error of the estimate.

5 Neder, Nery, Peres, et al.: Dynamic Responses to Exercise 1485 Figure 3. PET CO in males (left panels) and females (right panels), age 2 20 to 39 (squares), 40 to 59 (circles), and 60 to 80 (triangles), respectively. The upper panels depict the values at the unloaded condition (UNLOAD), at the estimated lactate threshold (LT), and at peak (PEAK), regardless of the metabolic demand. There was an inverse relationship between this variable and age, independent of sex. The lower panels show these values expressed as a function of the actual metabolic demand ( ) at the same points (i.e., UNLOAD, LT, and PEAK). Note that steeper PET C / relationships, either before or after LT, were found in females and older (60- to 80-yr-old group) subjects. In fact, our previously reported values of E/ C at L (in this population) (9) were higher than the C reported here in women and older subjects, i.e., the less fit subjects. This, we believe, is an important distinction. In this context, it should be emphasized that C and not (4, 5, 31) is the more appropriate independent variable in this relationship. In fact, the CV for the individually determined values (15 to 20%) in the present study was substantially higher than C (5 to 10%), independent of sex and age. As was the case in the studies of Poulin and coworkers (30) and Habedank and coworkers (20), we found that age presented a more definitive influence in reducing the ventilatory efficiency in men than women. Whether this relates to a steeper increase in the physiologic dead space or reduced C set-point in men remains to be determined. In fact, we found that women and older subjects tended to present lower sub- L PET CO2 values than men and younger subjects, respectively (see RESULTS). Importantly, however, age and female sex were related to a more tachypneic breathing pattern a well-known negative influence on the end-tidal values (Figure 2D). VT/ ln E Relationship With respect to the breathing pattern, E seems to change as an effectively linear function of VT up to a critical value VT which has been shown to be related to an age-specific and height-specific fraction of the resting vital capacity (50 to 60%) (7, 8) or, more properly, the inspiratory capacity (6) (up to 85% in this population) (9). Hey and coworkers (32) termed this phase as range 1 with the respiratory rate (f) contribution depending on a positive intercept in the E-VT relationship (Figure 1D, insert). In the range 2, the E-VT relation is steeper as a result of the more dominant influence of f: the asymptote value of VT is thought to be linked to elastic work of breathing and a critical lung volume threshold for vagally mediated mechanoreception (32). We needed therefore to linearize the relationship over the entire work rate range before applying regression analysis: as shown in Figure 2D, females did present significantly shallow slopes (i.e., a more tachypneic breathing pattern). This relationship is likely to be useful in assessing malingering or subjectively mediated changes in breathing pattern during CPET (33), in addition to being reflective of thoracic mechanical function. In summary, this study constitutes, we believe, the first characterization of reference values for certain widely recommended (1 3) submaximal indices of metabolic, cardiovascular, and ventilatory function for clinical exercise testing interpretation using incremental cycle ergometry and a randomly selected sample of adults up to 80 yr of age. Our results demonstrate that sex, age, and anthropometric characteristics should be considered in the assessment of the normalcy of these dynamic exercise responses. 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