Present-day technology has greatly facilitated the

Transcription

1 Long-term Reproducibility of Respiratory Gas Exchange Measurements during Exercise in Patients ith Stable Cardiac Failure* joseph S. Janicki, Ph.D.; Sunil Gupta, M.D.; Scott T. Ferris, B.A.; and lbtricia A. McElroy, M.D. Present-day technology bas greatly facilitated the monitoring of respiratory gas exchange in the clinical exercise laboratory. Despite the groing use of these techniques to assess the severity and progression of disease or therapeutic response in patients ith heart failure, the long-term reproduca'bility of oxygen uptake {VoJ, carbon dioxide production, minute ventilation, heart rate (HR), and blood pressure at rest and during incremental exercise in such patients, to our lmoledge, bas not been evaluated. Therefore, the purpose of this study as to quantify the reproducibility of these variables along ith exercise duration, maximum Vo. <Vo.max) and anaerobic threshold in a group of 16 patients (61:t7 years, 14 male) ith chronic, stable cardiac failure of varying severity and etiology ho bad 6ve or more incremental treadmill exercise tests over a period of time that ranged from 3 to 22 months. For each variable, reproducibility as represented by the coefficient of variation (CVAR). Except for exercise duration, CVAR as not a function of the severity of heart failure and, for all variables, patient-to-patient variation in CVAR as approximately 9 percent. The maximum CVAR for HR, systolic blood pressure, Vo., and Vo.max as generally belo 1.5 percent and for exercise duration and anaerobic threshold it as less than 12.5 percent. Based on this retrospective analysis, it is concluded that reproducible respiratory gas exchange and HR exercise responses are obtainable over extended periods of time in patients ith stable, chronic cardiac failure. Exercise duration, hoever, is less reproducible in patients ith moderate to severe failure. (Chat 199; 91:12-11) Yo.=oxygen uptake; HR=heart rate; Vo.mu:=muimum Vo.; CVAR=poellieient of variation; VCJOo=cart- diodde production; VE =minute ventilation; BP =blood pressure; CPX= C&l'lliapul.-ar aerdse testing; VT =tidal volume; AT=anaerobic threshold Present-day technology has greatly facilitated the monitoring of respiratory gas exchange in the clinical exercise laboratory and has provided an important adjunct to the evaluation of patients ith stable heart failure. On-line, breath-by-breath measurements of oxygen uptake (VoJ, carbon dioxide production (VcoJ, and minute ventilation (VE) are no possible. The monitoring of these variables together ith heart rate (HR) and blood pressure (BP) during incremental exercise testing (ie, cardiopulmonary exercise testing [ CPX]) provides a comprehensive, noninvasive assessment of cardiac and ventilatory reserves in patients ith heart disease, lung disease, or both. 1 The information derived from these data can be used to do the folloing: assess the severity of the disease; evaluate the pathophysiologic responses associated ith the appearance of exertional dyspnea and fatigue; distinguish ventilatory from cardiac or circulatory impairment; and determine the response to and efficacy of medical therapy. *From the Cardiovascular Research Institute, Michael Reese Hospital, University of Chicago Pritker School of Medicine, Chicago. Manuscript received April21; revision accepted July 1. Reprint : Dr: ]ameki, CardiovclscUlar IMUute, Michael Reese Hospital, Chicago 6616 Despite the groing popularity of CPX, the longterm reproducibility of Vo 2, Vco 2, VE, HR, and BP at rest and progressive levels of ork has not been evaluated in patients ith stable cardiac failure (to our knoledge). Moreover, it is not knon hether reproducibility is a function of the severity of impairment in exercise capacity. Such information ould be invaluable hen evaluating the response to, and efficacy of, conventional as ell as experimental medical therapy. It as. therefore the purpose of this retrospective study to quantify the reproducibility of these variables in a group of patients ith stable, chronic heart failure of varying severity ho had five or more incremental treadmill exercise tests over a period of time that exceeded three months. lbtient Population METHODS Sixteen successive outpatients ith chronic, stable, cardiac failure ere selected on the basis of their having had, in addition to their first test that as not included in the analysis, at least four exercise tests during a period of time that exceeded three months. In addition, there had to be at least five patients in each of the folloing functional exercise classes: A, B, and C. Functional class as determined at entry into the study according to the patient's maximal Vo 1 (Vo.max): functional class A, Vo_max >2 mvminlkg; 12

2 Table!-Patient Population* Study Patient No. and Period. No. of Class/Age, y/sex Etiology mo Tests la/51/m ICM AI55/M HT 1 8 3A/56/M ICM 1 5 4A/61/M AR,MR 5 4 5A/58!M IHD 1 4 6A/54/F ICM /M HT /63/M IHD /68/M AR,MR ni/M AR,MR /M IHD C/57/M ICM C/67/M IHD C/67/F ICM C/75/M ICM C/521M AR 4 6 *AR indicates aortic valve incompetence; F, female; HT, hypertension; ICM, idiopathic cardiomyopathy; IHD, ischemic heart disease; M, male; and MR, mitral valve incompetence. class 8, 16 to 2 mvminlkg; and class C, 1 to 16 mvmin/kg.z As can be seen in Table 1 there ere six class A, five class 8, and five class C patients. The range in age as 51 to 75 years (61 ± 7 years) and 14 ere male. The spectrum of heart disease included idiopathic dilated cardiomyopathy (six patients), ischemic cardiomyopathy and coronary heart disease as evidenced by clinical history or serum enyme changes during a previously knon myocardial infarction or by angiography (four patients), chronic aortic and mitral incompetence (three patients), chronic aortic incompetence (one patient), and chronic systemic hypertension (to patients). All patients ere in sinus rhythm and remained clinically stable during the study period that varied from 3 to 22 months (9 ± 5 months). Also, their Ne York Heart Association functional class did not change and there ere no significant changes in medications. The number of exercise tests per patient ranged from 4 to 8 (5 ± 1). Protocol Exercise tests ere performed using a programmable treadmill and incremental ork schedule, here every to minutes either treadmill speed, grade, or both as varied (Table 2). The patients ere exercised to exhaustion and Vo,max. Heart rate, gas exchange, and ventilation (ie, tidal volume [VT] and respiratory rate) ere measured, and Vo, and Vco, ere calculated on a breath-by-breath Table 2-Exercise Protocol Speed, Grade, Stage mph percent basis throughout the test. 2 In addition, 8P as obtained during the last minute of each stage. Folloing each test the anaerobic threshold (AT) and Vo,max ere determined from the results of the test as follos : AT as taken to be the Vo, at hich Vco, and VE began to increase at a greater rate than Vo,, and end-tidal O, began to increase relative to an invariant end-tidal CO,. The Vo,max as considered to be attained hen folloing an increment in ork equivalent to 2 to 3 mvminlkg,, uptake increased by < 1 mvminlkg. Since the necessary variables ere continuously being updated and displayed as the test progressed, it as possible to immediately verify that AT as attained and to determine that the patient a achieving Vo,max. Data and Statistical Analysis For each stage of exercise, a representative value of each variable (ie, Vo,, Vco,, VT, respiratory rate, VE, and HR) as obtained by averaging the breath-by-breath results over the last 3 s of the stage. Since there as only one determination of systolic and diastolic 8P during each stage, there as no need to calculate a representative value for these to variables. Then, for each stage, the representative values of a variable from all tests ere averaged and the mean value together ith its standard deviation ere calculated. Reproducibility as assumed to be represented by the <.>efficient of variation (CVAR) that as obtained by dividing the standard deviation by the mean. In a similar fashion the CVAR as also calculated for AT, Vo,max, and exercise duration. Finally, to test for a systemic time difference in the exercise response of each variable, an approach similar to that suggested by Wallenstein et al 3 as used. That is, for each patient (1) the response of a variable to -lilt a::: L&.. 2 u 1 L&.. () -lilt L&.. u L&.. () SYSTOLIC BLOOD PRESSURE 2 HEART RATE - ClassA!::.-!::.Class 8 - ClassC - Class A!::.-!::.Class 8 - ClassC FIGURE 1. Coefficient of variation vs exercise stage lin systolic blood pressure and heart rate li>r functional class A, 8, and C heart failure patients (see text for definition of functional class). 1 CHEST I 97 I 1 I JANUARY,

3 lll1 JO : 2 u 1 u -lll u 1 u 2 RESPIRATORY RATE TIDAL VOLUME - Closs A t::. - t::. Closs 8 - Closs C - Closs A t::. - t::. Closs 8 - Closs C FIGURE 2. Coefficient of variation vs exercise stage for respiratory rate and tidal volume for functional class A, B, and C heart failure patients. increments in ork as assumed to be linear and a representative slope computed for each exercise test, and (2) the slopes of all tests ere correlated ith the corresponding times the tests ere administered (le, number of months from the first exercise test). To test for a time trend in the end-exercise variables, linear regression analysis as used to determine hether the correlation coefficients beteen these variables and the time they ere acquired as statistically different from ero. In both cases, a significant correlation coefficient as evidence of a significant time trend. RESULTS The CVAR for each variable as a function of exercise stage is presented in Figures 1 through 4 for all patients. As can be seen, for all but one (systolic BP, Fig 1) of the variables, there as a tendency for CVAR to be greater at rest and the beginning stages of exercise than it as at the end of exercise. This trend as particularly evident for Vo 2 and Vco 2 (Fig 4). It also can be seen that CVAR as not a function of functional class; for each stage of exercise, the range of CVAR is essentially identical for the three classes. The range of CVAR for HR at rest as 4.9 to 15.2 percent (Fig 1). After the first to stages of exercise the upper limit of this range fell belo 9 percent in all but to patients: one in class A, the other in class C. The CVAR for this class A patient remained around 14 1 MINUTE VENTILATION lll Class A.3 t::. - t::. Class 8 - Class C 2 u 1 > O""'-!j o H s-o u FIG URE 3. Coefficient of variation vs exercise stage for minute ventilation for functional class A, B, and C heart failure patients. 1 percent throughout the test hile that for the class C patient increased from a value of 7. 7 percent at rest to 18. percent in stage 2; thereafter it declined so that at the end of exercise (stage 4) the value as 7. 7 percent. The range of CVAR for systolic BP remained beteen 1 and 15 percent throughout the test (Fig 1). The CVAR responses for respiratory rate and VT are presented in Figure 2 and that for VE in Figure 3. As -lll1 4 - JO 2 u 1 u 4 JO 2!Z u 1 u 2 2 UPTAKE C2 PRODUCTION - Cion A 1::.-t::. Cion 8 - Closs C - Closs A t::.-1::. Closs 8 - Closs C FIGURE 4. Coefficient of variation vs exercise stage for o, uptake and co, production for functional class A, B, and C heart failure patients. Respiratory Gas Exchange during Exercise In Cardiac Failure (Janicki et al) 1

4 can be seen, the range of CVAR for respiratory rate at rest is rather large (ie, 4.9 to 2.8 percent). Also, the upper value of the CVAR range remains high for all the stages, never fading belo 12. percent. The CVAR associated ith VT, on the other hand, is belo 1. pent for the ercise stages beyond stage 3. The range of CVAR for VE is similar to that obtained for respiratory rate. For rest and stages i to 4 the CVAR is beteen 2.5 and 21.5 percent and for the other stages CVAR lies beteen 1. and 14.7 percent. IQ Figure 4 CVARs associated ith Vo 1 and Vco 1 are presented. In general, CVAR as high for both of these variables during rest and stage 1. In fact one of the class C patients had values at rest of 37.2 percent for Vo 1 and 33.5 percent for Vca. Hoever, in stage 1 the CVAR for this patient fell to levels that ere belo 9 percent. Marked declines in CVAR in stage 1 ere similarly seen in most of the other patients. Thereafter, the range of CVAR generally became narroer ith its upper level becoming (ie, beyond stage 4) less than 9 percent for Vo 2 and 13.5 percent forvcoll. In every test, all patients crossed their Kf. The vo.max as attained Ql at least one of the tests in patients 1 and 7, 5 to 65 percent of the tests in j:latients 2, 5, and 13, and 75 to 1 percent of the tests in the remainder of patients. For classes A, B, and C, the average duration of exercise as 17, 13, and 9 minutes, respectively; the average Vo 2inax as 26.5, 17.4, and 13.8 mllminlkg, respectively; and the average Kf as 19., 13.2, and 1.7 mllminlkg, respectively. The CVARs associated ith these variables are given for each patient in 'lll.ble 3. Also listed are the CVARs for maximum :QR and systolic BP. Of note is the fact that the CVAR for exercise duration increases ith the severity of heart failure. 7m1d Analysis There ere a fe instances in hich systematic differences over time ere found. In four functional class A patients (ie, la, 2A, 4A, and 6A) and one class B (9B) patient significant correlation coefficients ere obtained beteen the slope of the Vco ork relation and the time the test as administered. In four patients (la, 2A, 4A, and 9B) the trend as for the slope to decrease in subsequent exercise tests hile in patient 6A the trend as opposite. Also, in one or to patients, significant positive ( + ) or negative ( -) correlation coefficients beteen the slopes of the HRork (-,4A1 VE-ork ( +, 7B and -, 13C), systolic BP-ork (-,9B) VT-ork (-,9B), and RR-ork (+,lob) relations and the time the test as administered ere obed. Finally, in a fe patients, there as a time trend in some of the end-exercise variables (Table 3). DISCUSSION The measurement of gas exchange and ventilatory data during exercise testing is becoming commonplace in assessing the severity of cardiac or circulatory failure and ventilatory disease, in distinguishing cardiac and circulatory from ventilatory causes of exertional dyspnea, and in assessing the efficacy of medical therapy. To date this has been accomplished primarily on the basis of the Kf and maximal 2 uptake, particularly in patients ith chronic cardiac failure. 1 The reproducibility of Vo 1 max,1 peak Vo2'.1s JJ,.s.e maximum Table 3-Coeffidetit qfvariation Patient Maximal No. Exercise Maximal Systolic and Duration, Heart Rate Blood Pressure, Class percent percent percent la A 7.3t A A A A B B t lob l2c 6.9t C C 16.9t C C *End-exercise or peak o. uptake because of insufficient maximal 1 uptake (Vo.max) data (see text). tsigniflcant increase during subsequent exercise tests. *Signilcant decrease during subsequent exercise tests. Anaerobic vo.max, Threshold, percent percent 4.* * * 12.4* 4.4t * * t 7.3t CHEST I 97 I 1 I JANUARY

5 systolic BP, 4 and maximum HR 4 has been assessed previously. Hoever, in these studies, data ere dran from only to tests per patient separated by no more than three eeks. Reproducibility herein pertains to the ability to obtain the same value for a physiologic variable hen a repeated exercise test is performed. It can be quantified by obtaining repeated measurements of the variable and computing its mean and standard deviation. Accordingly, one is 95 percent confident that the measurement could be reproduced ithin ± 2 standard deviations of the average value. When estimating reproducibility, it is assumed that the individual being tested ill have identical results hen the test is repeated. If this assumption is not valid, then reproducibility, in addition to being a function of the resolution of the measuring device and observer variability, ill be dependent on the extent to hich the individual's performance varies from test to test. In fact there ere instances in a fe of these clinically stable patients here a significant time trend in some of the variables as identified. Here, hoever, reproducibility as not found to be consistently higher or loer than that obtained in the absence of a significant time nd (Thble 3). Finally, because of biologic variability, reproducibility ill not be the same for each individual. Therefore, it as expressed as the CVAR (ie, standard deviation divided by the average value) and the range of CVAR reported. There are many additional factors that could affect reproducibility and most are beyond the control of the physician. For example, hile all patients ere instructed to eat nothing or at most a light meal several hours prior to testing, there is no guarantee that this as indeed the case. Other patients may have smoked immediately prior to the test or skipped medication. Other causes include variations in the amount of sleep, degree of activity during the previous day, dietary salt load and Ouid intake, emotional state, and general health. Obviously this list is far from complete. Its purpose is to indicate the scope of uncontrollable factors that could inouence the results of an exercise test and hence its reproducibility. It should be emphasied that, because this study as retrospective and the patients used ere selected on a consecutive basis, it could be considered a blinded study. That is, at the time the tests ere being administered, neither the technician nor the attending physician had any idea that the results ould one day be used to assess reproducibility. Instead, the tests ere administered in a routine fashion hereby objective criteria (ie, AT and Vo 2max) ere used to determine the endpoint of the exercise test. The results of this study indicate that, except for exercise duration, CVAR as not a function of the severity of heart failure, and that, for all variables, patient-to-patient variation in CVAR as approximately 9 percent. The maximum CVAR for HR, systolic BP, Vo 2, and Vo 2max as generally belo 1.5 percent and for exercise duration and AT it as less than 12.5 percent. Thus, it can be concluded that reproducible respiratory gas exchange and HR exercise responses are obtainable over extended periods oftime in patients ith stable, chronic cardiac failure. It is of interest to contrast these results ith those from clinically unstable patients. One such patient, a 38-yeaM>ld man ith an idiopathic dilated cardiomyopathy, as folloed up for three years (21 exercise tests) during hich time his Vo 2max declined from 3 to 1 mvminlkg. With the exception of HR and BP, systematic differences over time ere observed along ith a CVAR that as typically to to three times greater than that seen in patients ith stable, chronic cardiac failure. For example, CVAR as 26 percent for exercise duration, 31 percent for Vo 2max, and 3 percent for AT. Similar significant time trends and large CVAR values ere obtained from another patient ho as folloed up for three years folloing aortic valve replacement. During this period, his Vo 2max decreased steadily from 38 to 15 mvminlkg. To illustrate ho the results of this study can be applied to determine hether a particular variable is significantly different from that obtained previously, consider the folloing example. The maximum CVAR value for Vo 2max as found to be 9.2 percent (Thble 3). If the baseline value for Vo 2max as 14. mvmin/ kg, then the standard deviation associated ith reproducibility ould be ± 1.29 mvminlkg. Accordingly, if the Vo 2max value determined subsequently as >16.6 mvminlkg (ie, 14+2 SD mvminlkg), then it ould represent a signifipant (p<.5) increase. Neither Kappler et al, 4 Simonton et al, 5 nor Weber and Janicla"6 expressed reproducibility in terms of standard deviation. Instead they correlated the results obtained in many patients from one test ith those of another; a slope close to one and an intercept close to ero, 6 a significant correlation >.77,-H> or a lo standard error of the estimate> as considered to indicate good reproducibility. Thus, the results of this study cannot be compared directly ith their results. Hoever, one could compute the 95 percent confidence limits for a given value of a variable as as done in the above example and compare these limits ith the range of values reported by these investigators. For example, the range ofvo 2max (ie, test to results) for 14 mvminlkg (ie, test one value) as reported to be 11.5 to 18. mvminlkg by Kappler et al4 and 13 to 14.5 mvminlkg by Weber and Janicki. 6 There as only one patient in the Kappler et al report and none in the Weber and Janicki report ho exceeded the upper value of 16.6 mvminlkg that the reproducibility results of this study ould have predicted for 14 mvminlkg. 18

6 Similar findings ere obtained hen the 95 percent confidence limits of maximum HR (determined for 15 beats per minute), maximum systolic BP (16 mm Hg), and exercise duration (8 s) ere compared ith the range of to test values reported by Kappler et al. 4 That is, in no case did more than one patient lie outside the confidence limits. As discussed above the 95 percent confidence limits associated ith HR, systolic BP, respiratory rate, VT, VE, 2 uptake, and C 2 production can be calculated at rest and each stage of exercise from the results of this study, as ell as the confidence limits for Vo 2max, AT, and exercise duration. In general, the CVAR values at rest and the early stages of exercise ere found to be greater than CVAR values for the latter stages. This in all likelihood reflects to things: (1) anticipation and apprehension of the test, for it is not unusual for the patient to be hyperventilating and to have an elevated HR at the onset of the test; and (2) a degree of voluntary control over respiration. As the level of ork increases ventilation becomes progressively an involuntary process. Beyond exercise stage 4, hich is associated ith a Vo 2 of 5 met, 1 maximum CVAR as belo 1.5 percent for HR, VT, and 2 uptake. Maximum CVARs for the remainder of the variables ere beteen 11.9 percent (AT) and 16.9 percent (exercise duration). The existence of a poorer reproducibility at lo levels of ork should be considered hen designing or utiliing submaximal aerobic exercise tests. Since gas exchange variables ere monitored continuously throughout the exercise program, e kne ho close the patient as to attaining Vo 2max. This may have resulted in an underestimation of CVAR for exercise duration. That is, exercise durations from multiple tests are expected to be more consistent in a ptient ho is monitored and consequently encouraged to attain his or her Vo 2max as opposed to a situation here the physician must depend primarily on feedback from the patient to determine hen to end the exercise test. Obviously, in the latter case, exercise duration is a function of patient motivation and perception and, as a result, may not be as reproducible. Also, exercise duration as the only variable in this study hose CVAR as dependent on the severity of heart failure. Finally, it should be stressed that hen patient results obtained before and after some perturbation are statistically compared, the difference (be it paired or unpaired variates) does not have to be greater than the 95 percent confidence limits associated ith reproducibility in order for it to be significantly different from ero. Herein the statistical test (ie, analysis of variance) takes into account the variance from patient to patient that exists at both instances. ACKNOWLEDGEMENT: We are grateful to David Ward for his support regarding data analysis, Thelma Johnson-Morris for her effort in finaliing the illustrative materiaf, and Patricia Jones for her secretarial assistance in the preparation of the manuscript. REFERENCES 1 Weber KT, Janicki JS, eds. Cardiopulmonary exercise testing: physiologic principles and clinical correlates. Philadelphia: Saunders; Weber KT, Kinaseit GT, Janicki JS, Fishman AP. Oxygen utiliation and ventilation during exercise in patients ith chnmic cardiac failure. Circulation 1982; 65: Wallenstein S, Zucker CL, Fleiss JL. Some statistical methods useful in circulation research. Circ Res 198; 47:9 4 Kappler J, Ziesche S, Nelson J, Francis GS. The reproducibility of hemodynamics and gas exchange data during exercise in patients ith stable congestive heart failure. Heart Failure 1986; 2: Simonton CA, Higginbotham MB, Cobb FR. The ventilatory threshold: quantitative analysis of reproducibility and relation to arterial lactate concentration in normal subjeds and in patients ith chronic congestive heart failure. Am J Cardiol1988; 62: 7 6 Weber KT, Janicki JS. Lactate production during maximal and suhmaximal exercise in patients ith chronic heart failure. J Am Coli Cardiol1985; 6: CHEST I 97 I 1 I JANUARY,