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Measurement of Cardiac Output by CO2 Rebreathing in Unsteady State Exercise
-------4
&11111 clinical inveSliglliOns Measurement of Cardiac Output by CO2 Rebreathing in Unsteady State Exercise* Robert S. McKelvie, M.D.; George]. F. Heigenhauser, Ph.D.; and Norman L. Jones, M.D.
The ability to determine cardiac output (Q) noninvasively during a nonsteady state (NSS)incremental exercise test was assessed. Seven healthy subjects performed two maximal incremental cycle ergometer exercise tests (100 kpmlmin increments every minute), and also steady state exercise (S8) at 25, 50, and 75 percent of their maximum power output. The Q was determined by the indirect CO 2 Fick method; mixed venous Poo, was calculated using the exponential CO! rebreathing method. No significant differences were observed for the cardiac output/oxygen uptake relationship (QIV O 2) obtained between the two incremental exercise
tests. During NSS, the QNo. was linear (r= .89; intercept = 5.69 Umin; slope = 5.39). During the S8, QIV02 was linear (r = .90; intercept = 5.47 Umin; slope = 4.87). No significant difference was observed between the S8 and NSS QIVo! relationships (p>0.05), and the NSS relationship was similar to QNotvalues previously reported in the literature. Accurate and reproducible measurements of Q can be obtained noninvasively in healthy subjects using the exponential CO! rebreathing method during incremental progressive exercise tests, with similar values at comparable VOl to those obtained in the steady state.
Several techniques have been used to measure cardiac output (Q) both at rest and during exercise, but most are invasive procedures and require a steady state of exercise, limiting their use during a progressive incremental exercise test. The noninvasive estimation of Q by both the equilibrium and exponential CO 2 rebreathing methods has been found to be reliable and reproducible.!" especially during steady state exercise.!" Although it is generally assumed that a strict steady state during exercise is required for valid measurements with this technique, there have been reports of Q being measured in the unsteady state following exercise and during the first minute of exercise.I" However, no studies have examined the validity and reproducibility of Q measurement made noninvasively during an incremental progressive cycle ergometer test. Measurements of Q at several levels of exercise during unsteady state exercise would add to other noninvasive information and would provide a more complete picture of the response to exercise than can be obtained from measurements at a single level of steady state exercise. In the present study, a recently described' modifica-
tion of the exponential CO 2 rebreathing technique first proposed by Defares" was applied during incremental exercise, and the derived cardiac output was compared to measurements made in steady state exercise. The purpose of this study was to determine whether Q could be estimated reliably during the unsteady state of an incremental progressive cycle ergometer test in healthy subjects, and whether Q was the same at comparable levels of O 2 intake under steady state conditions.
*From the Ambrose Cardiorespiratory Unit, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada. This study was supported by the Heart and Stroke Foundation of Ontario. Manuscript received December 29; revision accepted April 3. Reprint requests: Dr. jones, Ambrose Cardiorespiratory Unit, McMaster University Medical Centre, Hamilton, Ontario, Canada
LBN 3Z5
METHODS
Seven healthy volunteers, four men and three women, age 30±(SD) 2.6 years and weighing 65.3±9.6 kg were studied. The procedure was fully explained, and informed consent was obtained prior to the study. This investigation was approved by the institution's ethics committee. Two continuous incremental exercise tests were performed on a cycle ergometer in which the power output was increased by 100 kpm/min at one minute intervals until exhaustion. The two tests were separated by a IS-minute rest period. Measurements used to calculate the cardiac output (mixed venous Pco., arterial Pco, and carbon dioxide output) were obtained in each test during the final 15 seconds of alternate workloads. Following another 15 minute rest period, the subjects performed steady state exercise for five minutes at 25,50, and 75 percent of the maximum power output achieved on the incremental exercise test, and the same measurements were obtained. The subjects breathed through a low resistance, low dead space valve, and end tidal gas was sampled at the mouth with a respiratory mass spectrometer. Expired gas was passed through an automated exercise system for the measurement of oxygen intake (VoJ and carbon dioxide output (VcoJ as previously described. 10 The elecCHEST / 92 / 5 / NOVEMBER, 1987
777
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FIGURE 1. A recording of the end-tidal CO 2 values measured by the mass spectrometer prior to and during rebreathing.
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trocardiograph was monitored continuously using a Vs lead. The tidal CO 2 concentration was recorded on a multichannel recorder and also entered into a Digital Equipment PDP 11-23 computer with a sampling frequency of 200 Hz. A calibration curve for PeD 2 was constructed using five known PeD 2 concentrations, two in 16 percent and 18 percent oxygen (for end tidal analysis) and three in 40 percent oxygen (for rebreathing). End expired CO 2 (PETCOJ was determined through computer analysis of the recorded data. Mixed venous PeD I (PVCOJ was determined using the exponential CO 2 rebreathing technique. The subject rebreathed a mixture of 4 percent COl and 96 percent O 2 from an anesthesia bag for a period of up to 12 seconds. A total of 118 rebreathing maneuvers were performed by the subjects. Figure 1 shows a typical example of the end tidal CO 2 values obtained just prior to and during rebreathing. An iterative method, using the computer, estimated PVC0 2 from the PETC02 values obtained during rebreathing, I During rebreathing of a 4 percent CO 2 mixture, the rise in CO 2 followed a monoexponential curve." This curve is expressed by the
equation:
PETC02 = PexC02 (1- K,e -Ie 1t) (1) where PETC02 is the end tidal Pco, for each breath during rebreathing: t is any time in seconds during the rebreathing, PexC0 2 is the asymptote of the exponential curve; and Koe and KI are the parameters of the curve. An iterative procedure is used to obtain the value of PexC0 2 that minimizes the variance of the measured points from the derived line that is of the form: P IC0 2 = In (1- PETm CO/PexCOJ (2) The constant Koeis the intercept and KI the slope of this relationship; P IC0 2 is the logarithmically transformed end tidal CO 2 ; PETm CO 2 is the measured end tidal CO 2 ; PexC02 is an assumed equilibrium point which initially is greater by 2 percent than the greatest measured end tidal CO 2 value. The P lC0 2 values are related to time and a least squares linear regression analysis is performed. Thus, the computer program iterates to obtain the line of best fit for different values of PexflO, until successive iterations lead to a variation of less than 0.1 mm Hg of PexC02 • The PexC0 2 obtained by the iteration is Rebr••th .nd tld., C02(tt)
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4 <: FIGURE 2. Curve derived by the computer + !!. , + program to allow Pco, to be obtained at any + given time of rebreathing. The x-axis is + b c + time in seconds and the y-axis is end tidal + 7 <: + CO 2% during the rebreathing period. MeaB ;: sured values (asterisk) are plotted along with the predicted values (plus). The o (-------------------------------------------------------------+ 10.28 asymptote value represents the equilib• + 1 .:: rium CO 2 value in the absence of recirculation. Mixed venous CO 2 is taken as the 3 ( value obtained if the rebreathing had con+ tinued for a period of 20 seconds. (Note+ 4 < + small deviation between derived and pre,:: dicted curve is due to the printer used to e <: obtain the computer output, and offsetting between the two curves) PREDICTED • + ACTUAL • • ~
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Measurement of Cardiac Output (McKelvie. Heigenhauser, Jones)
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o i FIGURE 3. Comparison of the oxygen uptakeo power output relationship during nonsteady state (solid line and dots) and steady state (dashed line and open circles) exercise. substituted back into equation 1, allowing Pe02 to be obtained at any given time of rebreathing (Fig 2). The Pe02 obtained by substituting t = 20 sec in the equation was taken as PVC02, as described in detail by Alves da Silva et al.' Measurement of the prebreathing PETC0 2 was obtained by averaging the five PETC0 2 values immediately preceding the rebreathing maneuver, and used to estimate PaC0 2 as previously described. 12 Measurements of PVC0 2 and PaC02 were used to estimate the mixed venous-arterial CO 2 content difference as described elsewhere," and cardiac output was derived using the Fick principle applied to carbon dioxide. The cardiac outputs calculated for the incremental exercise test were plotted against \702 , These values were compared with the QrV02 relationships previously reported in the literature. 14 Reproducibility of the Q measurement, at any given
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Workload (kpm/mln)
v0 2, was obtained by comparing the Qmeasurements from the two incremental exercise tests. The relationship between Qand \702 in the incremental test was compared to the steady state relationship. A paired Student's t-test was used to test for difference between the slopes and intercepts of the QrV02 relations. Statistical significance was accepted at the p
The subjects achieved a maximum power output in the incremental exercise study of 1,214± 329 kpm/ min. At rest, the \10 2 for the group was 3.6 ± 1.14 mllkg/ min, and during maximum exercise was 33.7±6.49 ml/kg/min,
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FIGURE 4. Comparison of the cardiac output-oxygen uptake relationship between the first nonsteady state exercise test (solidline and dots) and the second nonsteady state exercise test (dashed line and pluses) for all subjects. CHEST I 92 I 5 I NOVEMBER, 1987
n9
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.
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20 CARDIAC OUTPUT (L/MIN)
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FIGURE 5. Comparison of the oxygen uptake vs cardiac output relationship between the first nonsteadv state exercise test (dashed line and dots) and the second nonsteady state exercise test (solid line and pluses) for one subject. ----. First test Q= 6.15 + 5.25 X V0 2 L'min: r=.94 3.0 Second test Q= 6.28 + 5.41 x V0 2 Umin; r= .98
+
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The relationship between \702 and power output during incremental exercise (Fig 3) was expressed by the equation: \702= .206+ .0017 XW r= .98, standard error of estimate (SEE) = .022 where VI is power output in kpm/min and \702 is in
Umin; no significant difference between the two tests (p>0.1). The relationship between \702 and W for the steady state exercise (Fig 3) was \702=.296+.00195XW (r=.99, SEE=.04) This was significantly different from the nonsteady state exercise relationship (p<0.02).
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CARDIAC OUTPUT (L IMIN)
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FIGURE6. Comparison of the oxygen uptake vs cardiac output relationship for steady state exercise (dashed line and pluses) and nonsteady state exercise (solid line and dots) for all subjects.
780
Measurement of Cardiac Output (McKelvie, Heigenhauser, Jones)
500
400
CARDIAC OUTPUT (Mll KG/ MIN)
300
200
100
10
20
30
40
50
OXYGEN UPTAKE (Mll KG/MIN)
FIGURE 7. Comparison of the nonsteady state QrVo 2 relationship (dots) with the steady state data (95 percent confidence limits, (dashed lines) of Faulkner et al." The cardiac outputs were normalized to body size.
The QNO 2 relationship (Fig 4) of the first incremental exercise test Q=5.93+5.33x\102 Umin, (r=.89, SEE=.41) was not significantly different (p>O.l) from that of the second exercise test Q=5.46+5.46X\102 Umin, (r=.88, SEE=.41) The relationship between Q and \10 2for one subject during an incremental exercise test is demonstrated in Figure 5. When the QN02 relationship (Fig 6) for the steady state Q=5.47+4.87x\102 Umin, (r=.90, SEE=.51) and nonsteady state exercise Q=5.69+5.39x\102 Umin, (r=.89, SEE=.28) was compared, no significant difference was found (p>0.05). The measured 0. in each subject was compared to that predicted for the \10 2 (Fig 7) from the equation of Faulkner, Heigenhauser and Schork, 14 0.=66+5.2 X \10 2 mllkg/min. When the relationship of Q and \10 2 for the measured and predicted values Q= 87.52 + 5.59 x \70 2 ml/kg/rnin, (r=.86, SEE=6.43) were compared no significant difference was found (p>O.l). DISCUSSION
Mixed venous Pco, can be determined using the equilibrium (Collier) CO 2 rebreathing technique" or the exponential (Defares) CO 2 rebreathing technique," but the equilibrium technique is difficult to apply during unsteady state exercise. Due to the initial high concentration of CO 2 and the large accumulation of CO 2in the bag, it is difficult for the subject to carry out rebreathing at high power outputs. Also, it is technically difficult because the bag concentration of CO 2has to be carefully chosen and may require more than one rebreathing to obtain an acceptable record.
The exponential technique does not suffer these drawbacks as the initial CO 2 concentration in the bag is always 4 percent. This low CO 2 concentration is acceptable to the subject, is technically feasible at any workload, and is associated with less accumulation of CO 2 • Defares" was the first to develop the exponential technique of determining PVC0 2, and subsequent studies have demonstrated the technique to be reliable, especially during exercise. 1-6 Although previously thought to be more variable than the equilibrium method,":" a recent study' demonstrated that if an iterative statistical analysis was used, the exponential method was equally precise. The same study showed that the estimated cardiac output values compared well with values determined using the equilibrium technique,' and were within the previously published normal range for cardiac output in exercise. In the present study at a given workload, the \10 2 during steady state exercise was greater than \10 2 measured during incremental progressive exercise, demonstrating that the subjects were in an unsteady state during the incremental test. In spite of this finding, the relationship between \10 2 and Q during progressive exercise was similiar to steady state exercise. This relationship has been demonstrated in other studies during steady state exercise. 14.17-20 Faulkner et aP4 used the exponential CO 2 rebreathing technique to measure PVC0 2in healthy men ages 17 to 50 years. The QN02 relationship in their study had a slope of5.2 and an intercept of 66 mllkg/min. These authors also reviewed other studies in the literature" that had measured cardiac output using invasive techniques; the range in the slope was from 5.0 to 6.1 and the range in mean intercept was from 53 to 77 mllkg/min. In the present study, the measured values for the intercept (87.5 mllkg/min) and slope (5.6) of the relationship are not different from those determined in previous studies, suggesting that an accurate estimate of cardiac output is being obtained during the unsteady state exercise. Various studies have examined the variability of repeated measurements of Q performed at the same workload. Hanson and 'Iabakin" used the dye-dilution method to measure 0. repeatedly during various levels of exercise up to maximum, with 50 to 60 seconds between each measurement. They demonstrated that the mean difference between Q measured at different times was 13 to 26 percent of the mean Q with an increase with increasing levels of exercise. In the study of Grimby et al," cardiac output measurements were made every two to five minutes during a 30-minute exercise period at power outputs of 600 or 900 kpm/min: a variance of 12.1 percent was found. In the present study, the test-retest variance of the measurement of Q in the nonsteady state was 13 percent, similar to that found with invasive techniques in these CHEST / 92 / 5 / NOVEMBER. 1987
781
previous studies. 21.22 A concern when measuring cardiac output during the unsteady state, using the indirect Fick method, is that the values may change over the period of time the measurements are being made. An advantage of the rebreathing method is that rebreathing occurs immediately following measurements of CO 2 output and prerebreathing PETC0 2 , and mixed venous Pco, cannot be altered by the procedure. Thus, the estimate of mixed venous Pco, is very closely related to the other measurements. Only two studies have used CO 2 rebreathing to measure cardiac output during an unsteady state. Goldberg and Shephard? used the equilibrium technique to measure cardiac output during the early recovery period following exercise, and concluded that the mixed venous Pco, value was reasonably stable over short periods of time and could be used to determine cardiac output. Auchincloss et al" compared cardiac output estimates using the exponential CO 2 rebreathing method with dye-dilution at one minute, three minutes, and five to seven minutes of exercise. The results showed a correlation coefficient for the cardiac outputs determined during unsteady state exercise for the two methods of 0.97. Incremental progressive exercise is widely used in routine exercise testing. The results of this present study indicate that in normal subjects, cardiac output estimations can be performed during such tests with acceptable accuracy and precision. Although in the presence of abnormal gas exchange, the results may be unreliable, our own experience with the method has indicated that it may be applied to routine exercise studies of postmyocardial infarction patients. This method may be a useful addition to routine studies in patients with cardiac disease. ACKNOWLEDGMENT: We thank Tanya Chypchar for valuable technical assistance.
REFERENCES 1 Alves da Silva G, EI-Manshawi A, Heigenhauser GJF, Jones NL. Measurement of mixed venous carbon dioxide pressure by rebreathing during exercise. Resp PhysioI1985; 59:379-92 2 Ferguson RJ, Faulkner JA, Julius S, Conway J. Comparison of cardiac output determined by CO 2 rebreathing and dye-dilution methods. J Appl Physiol 1968; 25:450-54
782
3 Heigenhauser GJF, Jones NL. Comparison of two rebreathing methods for the determination of mixed venous partial pressure of carbon dioxide during exercise. Clin Sci 1979; 56:433-37 4 jernerus R, Lundin G, Thomson D. Cardiac output in healthy subjects determined with a CO 2 rebreathing method. Acta Physiol Scand 1963; 59:390-99 5 Muiesan G, Sorbini A, Solinas E, Grassi V, Casucci G, Petz E. Comparison of CO 2-rebreathing and direct Fick methods for determining cardiac output. J Appl Physiol 1968; 24:424-29 6 Clausen J~ Larsen OA, Trap-Jensen J. Cardiac output in middleaged patients determined with CO 2 rebreathing method. J Appl Physiol 1970; 28:337-42 7 Goldberg DI, Shephard RJ. Stroke volume during recovery from upright bicycle exercise. J Appl Physiol 1980; 48:833-37 8 Auchincloss JH, Gilbert R, Kuppinger M, Peppi D, TeperowPutter K. One and three-minute exercise response in coronary artery disease. J Appl Physiol 1979; 46:1132-37 9 Defares JG. Determination of PvC0 2 from the exponential CO 2 rise during rebreathing. J Appl Physiol1958; 13:159-64 10 Jones NL. Evaluation of a microprocessor-controlled exercise testing system. J Appl PhysioI1984; 57:1312-18 11 Chilton AB, Stacy RW. A mathematical analysis of carbon dioxide respiration in man. Bull Math Biophys 1952; 14:1-18 12 Jones NL, Robertson DG, Kane J\V. Difference between endtidal and arterial PC0 2 in exercise. J Appl Physiol 1979; 47:954-60 13 Jones NL, Campbell EJM. Clinical exercise testing, 2nd ed. Philadelphia: WB Saunders Company, 1982: 131 14 Faulkner JA, Heigenhauser GJF, Schork MA. The cardiac output-oxygen uptake relationship of men during graded bicycle ergometry. Med Sci Sports 1977; 9:148-54 15 Collier CR. Determination of mixed venous CO 2 tensions by rebreathing. J Appl Physiol 1956; 9:25-29 16 Godfrey D, Wolf E. An evaluation of rebreathing methods for measuring mixed venous PC02 during exercise. Clin Sci 1972; 42:345-53 17 Wilmore JH, Farrell PA, Norton AC, et al. An automated indirect assessment of cardiac output during rest and exercise. J Appl Physiol 1982; 52:1493-97 18 Grimby G, Nilsson NJ, Saltin B. Cardiac output during sub maximal and maximal exercise in active middle-aged athletes. J Appl Physioll966; 21:1150-56 19 Hossack KF, Bruce RA, Green B, Kusumi F, DeRouen TA, Trimble S. Maximal cardiac output during upright exercise: approximate normal standards and variations with coronary heart disease. Am J Cardio11980; 46:204-12 20 Bevegard S, Holmgren A, Jonsson B. Circulatory studies in well trained athletes at rest and during heavy exercise with special reference to stroke volume and the influence of body position. Acta Physiol Scand 1963; 57:26-50 21 Hanson JS, Tabakin BS. Simultaneous and rapidly repeated cardiac output determination by dye-dilution method. J Appl Physiol 1964; 19:275-78 22 Grimby G, Nilsson NJ, Sanne H. Repeated serial determination of cardiac output during 30 minute exercise. J Appl Physioll966; 21:1750-56
Measurement of Cardiac Output (McKelvie. Heigenhauser, Jones)
&11111 clinical inveSliglliOns Measurement of Cardiac Output by CO2 Rebreathing in Unsteady State Exercise* Robert S. McKelvie, M.D.; George]. F. Heigenhauser, Ph.D.; and Norman L. Jones, M.D.
The ability to determine cardiac output (Q) noninvasively during a nonsteady state (NSS)incremental exercise test was assessed. Seven healthy subjects performed two maximal incremental cycle ergometer exercise tests (100 kpmlmin increments every minute), and also steady state exercise (S8) at 25, 50, and 75 percent of their maximum power output. The Q was determined by the indirect CO 2 Fick method; mixed venous Poo, was calculated using the exponential CO! rebreathing method. No significant differences were observed for the cardiac output/oxygen uptake relationship (QIV O 2) obtained between the two incremental exercise
tests. During NSS, the QNo. was linear (r= .89; intercept = 5.69 Umin; slope = 5.39). During the S8, QIV02 was linear (r = .90; intercept = 5.47 Umin; slope = 4.87). No significant difference was observed between the S8 and NSS QIVo! relationships (p>0.05), and the NSS relationship was similar to QNotvalues previously reported in the literature. Accurate and reproducible measurements of Q can be obtained noninvasively in healthy subjects using the exponential CO! rebreathing method during incremental progressive exercise tests, with similar values at comparable VOl to those obtained in the steady state.
Several techniques have been used to measure cardiac output (Q) both at rest and during exercise, but most are invasive procedures and require a steady state of exercise, limiting their use during a progressive incremental exercise test. The noninvasive estimation of Q by both the equilibrium and exponential CO 2 rebreathing methods has been found to be reliable and reproducible.!" especially during steady state exercise.!" Although it is generally assumed that a strict steady state during exercise is required for valid measurements with this technique, there have been reports of Q being measured in the unsteady state following exercise and during the first minute of exercise.I" However, no studies have examined the validity and reproducibility of Q measurement made noninvasively during an incremental progressive cycle ergometer test. Measurements of Q at several levels of exercise during unsteady state exercise would add to other noninvasive information and would provide a more complete picture of the response to exercise than can be obtained from measurements at a single level of steady state exercise. In the present study, a recently described' modifica-
tion of the exponential CO 2 rebreathing technique first proposed by Defares" was applied during incremental exercise, and the derived cardiac output was compared to measurements made in steady state exercise. The purpose of this study was to determine whether Q could be estimated reliably during the unsteady state of an incremental progressive cycle ergometer test in healthy subjects, and whether Q was the same at comparable levels of O 2 intake under steady state conditions.
*From the Ambrose Cardiorespiratory Unit, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada. This study was supported by the Heart and Stroke Foundation of Ontario. Manuscript received December 29; revision accepted April 3. Reprint requests: Dr. jones, Ambrose Cardiorespiratory Unit, McMaster University Medical Centre, Hamilton, Ontario, Canada
LBN 3Z5
METHODS
Seven healthy volunteers, four men and three women, age 30±(SD) 2.6 years and weighing 65.3±9.6 kg were studied. The procedure was fully explained, and informed consent was obtained prior to the study. This investigation was approved by the institution's ethics committee. Two continuous incremental exercise tests were performed on a cycle ergometer in which the power output was increased by 100 kpm/min at one minute intervals until exhaustion. The two tests were separated by a IS-minute rest period. Measurements used to calculate the cardiac output (mixed venous Pco., arterial Pco, and carbon dioxide output) were obtained in each test during the final 15 seconds of alternate workloads. Following another 15 minute rest period, the subjects performed steady state exercise for five minutes at 25,50, and 75 percent of the maximum power output achieved on the incremental exercise test, and the same measurements were obtained. The subjects breathed through a low resistance, low dead space valve, and end tidal gas was sampled at the mouth with a respiratory mass spectrometer. Expired gas was passed through an automated exercise system for the measurement of oxygen intake (VoJ and carbon dioxide output (VcoJ as previously described. 10 The elecCHEST / 92 / 5 / NOVEMBER, 1987
777
12 10 8 C02(tt)
8 Rebre.thlng------
4
4-. C02 8e-. 02 2
o pre-rebre.thlng4
~
I
I
I
I
I
I I
I
I
I
I
I
FIGURE 1. A recording of the end-tidal CO 2 values measured by the mass spectrometer prior to and during rebreathing.
1 I
Tlme(.ec)
trocardiograph was monitored continuously using a Vs lead. The tidal CO 2 concentration was recorded on a multichannel recorder and also entered into a Digital Equipment PDP 11-23 computer with a sampling frequency of 200 Hz. A calibration curve for PeD 2 was constructed using five known PeD 2 concentrations, two in 16 percent and 18 percent oxygen (for end tidal analysis) and three in 40 percent oxygen (for rebreathing). End expired CO 2 (PETCOJ was determined through computer analysis of the recorded data. Mixed venous PeD I (PVCOJ was determined using the exponential CO 2 rebreathing technique. The subject rebreathed a mixture of 4 percent COl and 96 percent O 2 from an anesthesia bag for a period of up to 12 seconds. A total of 118 rebreathing maneuvers were performed by the subjects. Figure 1 shows a typical example of the end tidal CO 2 values obtained just prior to and during rebreathing. An iterative method, using the computer, estimated PVC0 2 from the PETC02 values obtained during rebreathing, I During rebreathing of a 4 percent CO 2 mixture, the rise in CO 2 followed a monoexponential curve." This curve is expressed by the
equation:
PETC02 = PexC02 (1- K,e -Ie 1t) (1) where PETC02 is the end tidal Pco, for each breath during rebreathing: t is any time in seconds during the rebreathing, PexC0 2 is the asymptote of the exponential curve; and Koe and KI are the parameters of the curve. An iterative procedure is used to obtain the value of PexC0 2 that minimizes the variance of the measured points from the derived line that is of the form: P IC0 2 = In (1- PETm CO/PexCOJ (2) The constant Koeis the intercept and KI the slope of this relationship; P IC0 2 is the logarithmically transformed end tidal CO 2 ; PETm CO 2 is the measured end tidal CO 2 ; PexC02 is an assumed equilibrium point which initially is greater by 2 percent than the greatest measured end tidal CO 2 value. The P lC0 2 values are related to time and a least squares linear regression analysis is performed. Thus, the computer program iterates to obtain the line of best fit for different values of PexflO, until successive iterations lead to a variation of less than 0.1 mm Hg of PexC02 • The PexC0 2 obtained by the iteration is Rebr••th .nd tld., C02(tt)
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4 <: FIGURE 2. Curve derived by the computer + !!. , + program to allow Pco, to be obtained at any + given time of rebreathing. The x-axis is + b c + time in seconds and the y-axis is end tidal + 7 <: + CO 2% during the rebreathing period. MeaB ;: sured values (asterisk) are plotted along with the predicted values (plus). The o (-------------------------------------------------------------+ 10.28 asymptote value represents the equilib• + 1 .:: rium CO 2 value in the absence of recirculation. Mixed venous CO 2 is taken as the 3 ( value obtained if the rebreathing had con+ tinued for a period of 20 seconds. (Note+ 4 < + small deviation between derived and pre,:: dicted curve is due to the printer used to e <: obtain the computer output, and offsetting between the two curves) PREDICTED • + ACTUAL • • ~
778
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Measurement of Cardiac Output (McKelvie. Heigenhauser, Jones)
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o i FIGURE 3. Comparison of the oxygen uptakeo power output relationship during nonsteady state (solid line and dots) and steady state (dashed line and open circles) exercise. substituted back into equation 1, allowing Pe02 to be obtained at any given time of rebreathing (Fig 2). The Pe02 obtained by substituting t = 20 sec in the equation was taken as PVC02, as described in detail by Alves da Silva et al.' Measurement of the prebreathing PETC0 2 was obtained by averaging the five PETC0 2 values immediately preceding the rebreathing maneuver, and used to estimate PaC0 2 as previously described. 12 Measurements of PVC0 2 and PaC02 were used to estimate the mixed venous-arterial CO 2 content difference as described elsewhere," and cardiac output was derived using the Fick principle applied to carbon dioxide. The cardiac outputs calculated for the incremental exercise test were plotted against \702 , These values were compared with the QrV02 relationships previously reported in the literature. 14 Reproducibility of the Q measurement, at any given
i i i
200
400 600
i i i
i i '
800 1000 1200 1400 1600 1800
Workload (kpm/mln)
v0 2, was obtained by comparing the Qmeasurements from the two incremental exercise tests. The relationship between Qand \702 in the incremental test was compared to the steady state relationship. A paired Student's t-test was used to test for difference between the slopes and intercepts of the QrV02 relations. Statistical significance was accepted at the p
The subjects achieved a maximum power output in the incremental exercise study of 1,214± 329 kpm/ min. At rest, the \10 2 for the group was 3.6 ± 1.14 mllkg/ min, and during maximum exercise was 33.7±6.49 ml/kg/min,
30
25 + +~
20
CARDIAC OUTPUT (L /MIN)
+
••
15
+
+~. + • +
10
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+ •
+
+
1
~~
+ +~ • • + + .... ~ + +.
5
+
-+t
+
• ......
.
.++~ t
+ +
+
+
+
+
+
• +
O ' - - - - - -__------~------__r------__._1.0
2.0
3.0
4.0
OXYGEN UPTAKE(L/MIN)
FIGURE 4. Comparison of the cardiac output-oxygen uptake relationship between the first nonsteady state exercise test (solidline and dots) and the second nonsteady state exercise test (dashed line and pluses) for all subjects. CHEST I 92 I 5 I NOVEMBER, 1987
n9
30
.
//
20 CARDIAC OUTPUT (L/MIN)
10
FIGURE 5. Comparison of the oxygen uptake vs cardiac output relationship between the first nonsteadv state exercise test (dashed line and dots) and the second nonsteady state exercise test (solid line and pluses) for one subject. ----. First test Q= 6.15 + 5.25 X V0 2 L'min: r=.94 3.0 Second test Q= 6.28 + 5.41 x V0 2 Umin; r= .98
+
0'---
,...-
.....-
2.0
1.0
OXYGEN UPTAKE (LI MIN.)
The relationship between \702 and power output during incremental exercise (Fig 3) was expressed by the equation: \702= .206+ .0017 XW r= .98, standard error of estimate (SEE) = .022 where VI is power output in kpm/min and \702 is in
Umin; no significant difference between the two tests (p>0.1). The relationship between \702 and W for the steady state exercise (Fig 3) was \702=.296+.00195XW (r=.99, SEE=.04) This was significantly different from the nonsteady state exercise relationship (p<0.02).
30
25 +
20
CARDIAC OUTPUT (L IMIN)
15
. ... .
+
~
+.
..+//...
10
. .~. -:= ~ -+:"4 . ... .. +. •
~.
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+
5
+
+
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OL.-------....------,..--------r-------r1.0
2.0
3.0
4.0
OXYGEN UPTAKE(L / MIN)
FIGURE6. Comparison of the oxygen uptake vs cardiac output relationship for steady state exercise (dashed line and pluses) and nonsteady state exercise (solid line and dots) for all subjects.
780
Measurement of Cardiac Output (McKelvie, Heigenhauser, Jones)
500
400
CARDIAC OUTPUT (Mll KG/ MIN)
300
200
100
10
20
30
40
50
OXYGEN UPTAKE (Mll KG/MIN)
FIGURE 7. Comparison of the nonsteady state QrVo 2 relationship (dots) with the steady state data (95 percent confidence limits, (dashed lines) of Faulkner et al." The cardiac outputs were normalized to body size.
The QNO 2 relationship (Fig 4) of the first incremental exercise test Q=5.93+5.33x\102 Umin, (r=.89, SEE=.41) was not significantly different (p>O.l) from that of the second exercise test Q=5.46+5.46X\102 Umin, (r=.88, SEE=.41) The relationship between Q and \10 2for one subject during an incremental exercise test is demonstrated in Figure 5. When the QN02 relationship (Fig 6) for the steady state Q=5.47+4.87x\102 Umin, (r=.90, SEE=.51) and nonsteady state exercise Q=5.69+5.39x\102 Umin, (r=.89, SEE=.28) was compared, no significant difference was found (p>0.05). The measured 0. in each subject was compared to that predicted for the \10 2 (Fig 7) from the equation of Faulkner, Heigenhauser and Schork, 14 0.=66+5.2 X \10 2 mllkg/min. When the relationship of Q and \10 2 for the measured and predicted values Q= 87.52 + 5.59 x \70 2 ml/kg/rnin, (r=.86, SEE=6.43) were compared no significant difference was found (p>O.l). DISCUSSION
Mixed venous Pco, can be determined using the equilibrium (Collier) CO 2 rebreathing technique" or the exponential (Defares) CO 2 rebreathing technique," but the equilibrium technique is difficult to apply during unsteady state exercise. Due to the initial high concentration of CO 2 and the large accumulation of CO 2in the bag, it is difficult for the subject to carry out rebreathing at high power outputs. Also, it is technically difficult because the bag concentration of CO 2has to be carefully chosen and may require more than one rebreathing to obtain an acceptable record.
The exponential technique does not suffer these drawbacks as the initial CO 2 concentration in the bag is always 4 percent. This low CO 2 concentration is acceptable to the subject, is technically feasible at any workload, and is associated with less accumulation of CO 2 • Defares" was the first to develop the exponential technique of determining PVC0 2, and subsequent studies have demonstrated the technique to be reliable, especially during exercise. 1-6 Although previously thought to be more variable than the equilibrium method,":" a recent study' demonstrated that if an iterative statistical analysis was used, the exponential method was equally precise. The same study showed that the estimated cardiac output values compared well with values determined using the equilibrium technique,' and were within the previously published normal range for cardiac output in exercise. In the present study at a given workload, the \10 2 during steady state exercise was greater than \10 2 measured during incremental progressive exercise, demonstrating that the subjects were in an unsteady state during the incremental test. In spite of this finding, the relationship between \10 2 and Q during progressive exercise was similiar to steady state exercise. This relationship has been demonstrated in other studies during steady state exercise. 14.17-20 Faulkner et aP4 used the exponential CO 2 rebreathing technique to measure PVC0 2in healthy men ages 17 to 50 years. The QN02 relationship in their study had a slope of5.2 and an intercept of 66 mllkg/min. These authors also reviewed other studies in the literature" that had measured cardiac output using invasive techniques; the range in the slope was from 5.0 to 6.1 and the range in mean intercept was from 53 to 77 mllkg/min. In the present study, the measured values for the intercept (87.5 mllkg/min) and slope (5.6) of the relationship are not different from those determined in previous studies, suggesting that an accurate estimate of cardiac output is being obtained during the unsteady state exercise. Various studies have examined the variability of repeated measurements of Q performed at the same workload. Hanson and 'Iabakin" used the dye-dilution method to measure 0. repeatedly during various levels of exercise up to maximum, with 50 to 60 seconds between each measurement. They demonstrated that the mean difference between Q measured at different times was 13 to 26 percent of the mean Q with an increase with increasing levels of exercise. In the study of Grimby et al," cardiac output measurements were made every two to five minutes during a 30-minute exercise period at power outputs of 600 or 900 kpm/min: a variance of 12.1 percent was found. In the present study, the test-retest variance of the measurement of Q in the nonsteady state was 13 percent, similar to that found with invasive techniques in these CHEST / 92 / 5 / NOVEMBER. 1987
781
previous studies. 21.22 A concern when measuring cardiac output during the unsteady state, using the indirect Fick method, is that the values may change over the period of time the measurements are being made. An advantage of the rebreathing method is that rebreathing occurs immediately following measurements of CO 2 output and prerebreathing PETC0 2 , and mixed venous Pco, cannot be altered by the procedure. Thus, the estimate of mixed venous Pco, is very closely related to the other measurements. Only two studies have used CO 2 rebreathing to measure cardiac output during an unsteady state. Goldberg and Shephard? used the equilibrium technique to measure cardiac output during the early recovery period following exercise, and concluded that the mixed venous Pco, value was reasonably stable over short periods of time and could be used to determine cardiac output. Auchincloss et al" compared cardiac output estimates using the exponential CO 2 rebreathing method with dye-dilution at one minute, three minutes, and five to seven minutes of exercise. The results showed a correlation coefficient for the cardiac outputs determined during unsteady state exercise for the two methods of 0.97. Incremental progressive exercise is widely used in routine exercise testing. The results of this present study indicate that in normal subjects, cardiac output estimations can be performed during such tests with acceptable accuracy and precision. Although in the presence of abnormal gas exchange, the results may be unreliable, our own experience with the method has indicated that it may be applied to routine exercise studies of postmyocardial infarction patients. This method may be a useful addition to routine studies in patients with cardiac disease. ACKNOWLEDGMENT: We thank Tanya Chypchar for valuable technical assistance.
REFERENCES 1 Alves da Silva G, EI-Manshawi A, Heigenhauser GJF, Jones NL. Measurement of mixed venous carbon dioxide pressure by rebreathing during exercise. Resp PhysioI1985; 59:379-92 2 Ferguson RJ, Faulkner JA, Julius S, Conway J. Comparison of cardiac output determined by CO 2 rebreathing and dye-dilution methods. J Appl Physiol 1968; 25:450-54
782
3 Heigenhauser GJF, Jones NL. Comparison of two rebreathing methods for the determination of mixed venous partial pressure of carbon dioxide during exercise. Clin Sci 1979; 56:433-37 4 jernerus R, Lundin G, Thomson D. Cardiac output in healthy subjects determined with a CO 2 rebreathing method. Acta Physiol Scand 1963; 59:390-99 5 Muiesan G, Sorbini A, Solinas E, Grassi V, Casucci G, Petz E. Comparison of CO 2-rebreathing and direct Fick methods for determining cardiac output. J Appl Physiol 1968; 24:424-29 6 Clausen J~ Larsen OA, Trap-Jensen J. Cardiac output in middleaged patients determined with CO 2 rebreathing method. J Appl Physiol 1970; 28:337-42 7 Goldberg DI, Shephard RJ. Stroke volume during recovery from upright bicycle exercise. J Appl Physiol 1980; 48:833-37 8 Auchincloss JH, Gilbert R, Kuppinger M, Peppi D, TeperowPutter K. One and three-minute exercise response in coronary artery disease. J Appl Physiol 1979; 46:1132-37 9 Defares JG. Determination of PvC0 2 from the exponential CO 2 rise during rebreathing. J Appl Physiol1958; 13:159-64 10 Jones NL. Evaluation of a microprocessor-controlled exercise testing system. J Appl PhysioI1984; 57:1312-18 11 Chilton AB, Stacy RW. A mathematical analysis of carbon dioxide respiration in man. Bull Math Biophys 1952; 14:1-18 12 Jones NL, Robertson DG, Kane J\V. Difference between endtidal and arterial PC0 2 in exercise. J Appl Physiol 1979; 47:954-60 13 Jones NL, Campbell EJM. Clinical exercise testing, 2nd ed. Philadelphia: WB Saunders Company, 1982: 131 14 Faulkner JA, Heigenhauser GJF, Schork MA. The cardiac output-oxygen uptake relationship of men during graded bicycle ergometry. Med Sci Sports 1977; 9:148-54 15 Collier CR. Determination of mixed venous CO 2 tensions by rebreathing. J Appl Physiol 1956; 9:25-29 16 Godfrey D, Wolf E. An evaluation of rebreathing methods for measuring mixed venous PC02 during exercise. Clin Sci 1972; 42:345-53 17 Wilmore JH, Farrell PA, Norton AC, et al. An automated indirect assessment of cardiac output during rest and exercise. J Appl Physiol 1982; 52:1493-97 18 Grimby G, Nilsson NJ, Saltin B. Cardiac output during sub maximal and maximal exercise in active middle-aged athletes. J Appl Physioll966; 21:1150-56 19 Hossack KF, Bruce RA, Green B, Kusumi F, DeRouen TA, Trimble S. Maximal cardiac output during upright exercise: approximate normal standards and variations with coronary heart disease. Am J Cardio11980; 46:204-12 20 Bevegard S, Holmgren A, Jonsson B. Circulatory studies in well trained athletes at rest and during heavy exercise with special reference to stroke volume and the influence of body position. Acta Physiol Scand 1963; 57:26-50 21 Hanson JS, Tabakin BS. Simultaneous and rapidly repeated cardiac output determination by dye-dilution method. J Appl Physiol 1964; 19:275-78 22 Grimby G, Nilsson NJ, Sanne H. Repeated serial determination of cardiac output during 30 minute exercise. J Appl Physioll966; 21:1750-56
Measurement of Cardiac Output (McKelvie. Heigenhauser, Jones)