Ventilatory intolerance
mechanisms of exercise in chronic heart failure
Mechanisms that have been suggested to underlie the abnormal ventilatory response to exercise in patients with chronic congestive heart failure (CHF) include high pulmonary pressures, ventilation-perfusion mismatching, early metabolic acidosis, and abnormal respiratory control. To evaluate the role that ventilation and gas exchange play in limiting exercise capacity in patients with CHF, data from 33 patients with CHF and 34 normal subjects of similar age who underwent maximal exercise testing were analyzed. Maximal oxygen uptake was higher among normal subjects (31.7 I 6 ml/kg/min) than among patients with CHF (17.7 + 4 mllkglmin; p < 0.001). The ventilatory equivalent for oxygen, expressed as a percentage of maximal oxygen uptake, was 25% to 35% higher among patients with CHF compared with normal subjects throughout exercise (p < 0.01). A steeper component effect of ventilation on maximal oxygen uptake was observed among normal subjects compared with patients with CHF, which suggests that a significant portion of ventilation in CHF is wasted. Maximal oxygen uptake was inversely related to the ratio of maximal estimated ventilatory dead space to maximal tidal volume (VD/VT) in both groups (I = -0.73, p < 0.001). Any given oxygen uptake at high levels of exercise among patients with CHF was accompanied by a higher VDIVT, lower tidal volume, and higher respiratory rate compared with normal subjects (p < 0.01). Relative hyperventilation in patients with CHF started at the beginning of exercise and was observed both below and above the ventilatory threshold, which suggests that the excess ventilation was not directly related to earlier than normal metabolic acidosis. Thus abnormal ventilatory mechanisms contribute to exercise intolerance in CHF, and excess ventilation is associated with both a higher physiologic dead space and an abnormal breathing pattern. The high dead space is most likely due to ventilation-perfusion mismatching in the lungs, which is related to poor cardiac output, and the abnormal breathing pattern appears to be an effort to reduce the elevated work of breathing that is caused by high pulmonary pressures and poor lung compliance. (AM HEART J 1992;124:710.)
Jonathan Myers, PhD, Azar Salleh, BS, Nancy Buchanan, BA, David Smith, MD, Joel Neutel, MD, Eric Bowes, and Victor F. Froelicher, MD Palo Alto, Long Beach, and Stanford,
Calif.
Exercise intolerance is one of the important pathophysiologic consequences of chronic congestive heart failure (CHF).l Clinically, the severity of heart failure is classified in terms of the degree of dyspnea or fatigue in response to various levels of exertion. A striking characteristic of the exercise response in heart failure is relative hyperventilation. Several recent studies have demonstrated markedly elevated ventilatory responses among patients with CHF compared with normal subjects at similar work rates.“-6 Historically, the mechanism for the hyperventilatory response to exercise in these patients has
From the Cardiology Division, Medical Centers, and Stanford
Palo Alto University.
Received
29, 1992;
for publication
Reprint requests: Alto VA Medical 4/l/39281
710
Jonathan Center,
Jan.
and Long accepted
Myers, PhD, Cardiology 3801 Miranda Ave., Palo
Beach Mar.
Veterans
Affairs
10, 1992.
Division (lllCJ, Alto, CA 94304.
Palo
involved increased intrapulmonary pressures, which is related to interstitial fluid accumulation, decreased lung compliance,7-g and stimulation of pulmonary juxtacapillary receptors in the lungs.8v lo. l* However, direct evidence of a link between elevated intrapulmonary pressures and dyspnea during exercise is lacking,4, 12-14and the physiologic mechanism that underlies exertional hyperventilation in patients with CHF remains unclear.l, 2 Other mechanisms that have been proposed include elevated physiologic dead space,“, 6 early metabolic acidosis 5, 15-17 altered ventilatory control,lO, la, rg and an abnormal pattern of breathing with rapid, shallow respiration.“, & a With the use of continuous ventilatory gas exchange measurements, estimations of metabolic acidosis20 ventilatory dead space,21 breathing patterns23 5, 6, 22 and ventilatory drive2 can be made during exercise. The present study was an effort to
Volume124 Number 3
28
Ventilation
711
exercise in heart failure
50
r
I 45
25
during
CHF
o NORMALS
405 1 I
t
g
35.
r
I* *
30 1
* I I *1 I* 7 I" P *
* PC.01 0" >
16
l i
.a
l
20
44
56
75
65
62
90
MAX
%V02MAx
Fig. 2. Changesin VE/VOs expressedas a percentage of maximal oxygen uptake for patients with CHF and normal subjects (mean t 2 SEM). Table I. Clinical characteristics of patients with chronic CHF and normal subjects Fig. 1. The relationship between resting left ventricular ejection fraction and maximal oxygen uptake (VOz MAX) in patients with chronic CHF (r = 0.13, not significant).
elucidate these mechanisms by measuring respiratory gas exchange responsesto a progressive maximal exercise test in a group of stable ambulatory patients with chronic CHF and to determine the magnitude of the ventilatory factors that underlie exercise intolerance in patients with CHF. These responses were compared with those from a control group who were similar in age and had normal cardiac function. METHODS Patient population. Thirty-three male patients with chronic CHF (mean age, 56 -t 10 years) and 34 men with normal cardiac function (mean age,53 t 9 years) participated in the study. Chronic CHF wasdocumentedby clinical history and a resting ejection fraction of lessthan 40% . Clinical characteristics of the subjects are presented in Table I. The normal therapeutic medication regimen was maintained. Volunteers who demonstrated no evidence of cardiovascular diseaseand who were approximately the sameage asthe patients with CHF were chosento constitute the control group. All rights and privileges were honored in accordance with an established human subjects protocol at the Veterans Affairs Medical Center, and informed consent was obtained from each subject. Exercise testing. Patients with CHF performed a maximal exercisetest on a motor-driven treadmill with either Naughtonz3 or ramp protocols.24 All had recently completed or were in the baseline phase of a pharmaceutical trial; thus, all had recent treadmill experience. All normal
Patientswith CHF (n = 33) Age (yr) Height (in) Weight (lb) Ejection fraction (%#) Disease etiology Ischemic Hypertensive Alcoholic Idiopathic Medications Digoxin Captopril Lasix Calcium antagonist Isordil Antihypertensive P-blocker Antihyperlipidemic Antiarrhythmic
56 69.4 186 25.2 16 4 6 13
-t + ? zt
10 2 36 9
(47 ‘im) (12LP,) (18%) (38%)
30 (88 % ) 21 (62%) 28 (82%) 6 (18%) 7 (20%) 5 (157;) 1(3%) 2 (6S) l(3s;)
Normal subjects (n = 34) 53 f 9 69.9 k 3 188.4 i 28
None
None
subjectsperformed individualized ramp treadmill tests as recently described.24Briefly, a baselinetest was initially performed to habituate subjectsto the protocol and to establish peak oxygen uptake. On the basis of a given subject’s peak oxygen uptake, the treadmill speed and ramp rate were individualized to yield a test duration of approximately 10 minutes. Subjective levels of exertion were quantified with the useof the Borg 6 to 20 scale.25All tests werecontinued until volitional fatigue or dyspneawas experienced. Respiratory gas exchange. Respiratory gasexchange variables were determined continuously throughout the
712
Myers et al.
Table
II. Hemodynamic
American
and gas exchange
data at rest and during
exercise (Mean
September 1992 Heart Journal
t SD)
Patients uiith CHF Rest Heart rate (beats/min) Blood pressure (systolic/diastolic, Ventilatory threshold Heart
rate
mm Hg)
(beatdmin)
Blood pressure (systolic/diastolic, mm Hg) Oxygen uptake (ml/kg/min) Percent peak oxygen uptake Minute ventilation (L/min, BTPS) CO2 production (L/min, STPD) Respiratory exchange ratio Oxygen
pulse
(ml/beat)
Perceived exertion Estimated VD/VT VE/V02 VE/VC02 Maximal Exercise Heart rate (beats/min) Blood pressure (systolic/diastolic, mm Hg) Oxygen uptake (ml/kg/min) Minute ventilation (L/min, BTPS) CO2 production (L/min, STPD) Respiratory exchange ratio Oxygen pulse (ml/heat) Perceived exertion Exercise time (min) Estimated VDNT VEA’O:! VE/VCOI_
81 t 15”
65 + IO
127 t 15182 i 9
130
118 k 19 138 t 22/76 13.0 t 2.2*
121 2 13 168 k 18/86 2 10 19.6 i 4.4 61 T 9 42.8 ? 11.5 1.444 i 0.466 0.86 i 0.09 13.6 i 2.9 13.0 k :! 0.22 F 0.05 25.8 i- 2 X0.X ? :3
+ lO*
72 i 8* 36.6 + 8.4t 0.9272 * 240* 0.84 + 0.06 9.5 T 2.5* 11.1 i 2i
0.29 t o.os* 33.9 + 7* 40.5 i i3* 141 163 17.7 65.5
k t * I
‘I* 26/‘84 3.9* 16*
i
+
12/82
k 7
165 + 14 201 _t 21/87 5 10 31.7 t 6.3 102 f 29.1 3.282 I 0.987 1.20 -t 0.10 16.6 + 4.7 19.1 k 1.9 9.52 + 1.5 0.16 r 0.04 37.6 1+ 6 31.3 t 3
13’
1.578 I 0.488* 1.05 + 0.11* 10.6 i 3.0 19.1 t 1.4
8.61 f 2.3 0.28 f o.os* 45.9 + 12* 43.7 -t 11*
*p < 0.001. tp < 0.05.
exercise test with the Medical Graphics Corporation 2001 system (Medical Graphics Corp., St. Paul, Minn.). The gas exchange variables that were analyzed were oxygen uptake 0’02 ml/kg/min, STPD); CO2 production (VCO~ L/min, STPD); minute ventilation (VE IL/min], BTPS); oxygen pulse (VOZ ml/min divided by heart rate); respiratory exchange ratio (VCO~/VO~; end-tidal 02 and CO? pressures (mm Hg); the ventilatory equivalents for 0s and COz (VE/ VOZ and VE/VCO~); and estimated ventilatory dead space to tidal volume ratio (VD/VT). VD/VT was calculated with an estimation of arterial CO2 pressure from PETCOz as described by Jones and Campbell.21 The ventilatory threshold was determined by four independent observers, who were blinded to each subject’s status, as outlined previously.26 Statistics. All data were entered into a Lotus 123 spreadsheet, which calculated means and standard deviations. The Statistical Graphics Corproation program (Bethesda, Md.) was used to perform unpaired t tests among hemodynamic and gas exchange responses between normal subjects and patients with CHF. Correlation coefficients were calculated to quantify the relationships between various ventilatory variables and maximal oxygen uptake. A stepwise multiple regression procedure was performed to determine predictors of peak oxygen uptake.
RESULTS Hemodynamic and gas exchange variables at rest, at the ventilatory threshold, and at levels of maximal exercise for patients with CHF and normal subjects are presented in Table II. Gas exchange determinants of peak oxygen uptake derived from stepwise multiple regression are presented in Table III. Fig. 1 shows the relationship between resting ejection fraction and peak oxygen uptake for patients with CHF. The correlation between the two was not significant (r = 0.13). Fig. 2 presents VE/Voz values at matched
percentages of maximal oxygen uptake for each group. VE/Vos was significantly (25 9, to 35°C; p < 0.001) higher among patients with CHF throughout exercise testing. Fig. 3 shows the component effect
of maximal
ventilation
on
maximal
oxygen
uptake for both groups. The relationship between maximal oxygen uptake and maximal VD/VT among normal subjects and patients with CHF is shown in Fig. 4; the correlation between the two was -0.73 (p < 0.001). Fig. 5 shows contrasts in tidal volume, respiratory rate, and VD/VT between groups for minutes 2 and 6, and for maximal exercise. Among
Volume Number
124 3
Ventilation
MAXIMAL
VENTILATION
during
exercise in heart failure
713
(L/min)
Fig. 3. Componenteffect plot for the influence of maximal ventilation oxygen uptake amongpatients with CHF (open circles) and normal subjects (closed circles). Individual values for maximal ventilation are plotted on the x axis, and the effect of each on maximal oxygen uptake, relative to the average (zero), is plotted on the y axis. The correlation coefficient betweenthe two variables was0.34 (p = 0.05) for patients with CHF and 0.84 (p < 0.001) for normal subjects. Table III. Explanation of maximal oxygen uptake with stepwiseregressionanalysisfor each group
Patients with CHF Variables entered Maximal VE/VCOz Maximal ventilation (L/min, BTPS) Change in VE/VCO:! Normal subjects Variables entered Maximal ventilation (L/min, BTPS) Change in VE/VC02
R’
0.65
0.42
42
-co.01
0.75 0.82
0.56 0.67
14 11
mechanisms of exercise in chronic heart failure
Mechanisms that have been suggested to underlie the abnormal ventilatory response to exercise in patients with chronic congestive heart failure (CHF) include high pulmonary pressures, ventilation-perfusion mismatching, early metabolic acidosis, and abnormal respiratory control. To evaluate the role that ventilation and gas exchange play in limiting exercise capacity in patients with CHF, data from 33 patients with CHF and 34 normal subjects of similar age who underwent maximal exercise testing were analyzed. Maximal oxygen uptake was higher among normal subjects (31.7 I 6 ml/kg/min) than among patients with CHF (17.7 + 4 mllkglmin; p < 0.001). The ventilatory equivalent for oxygen, expressed as a percentage of maximal oxygen uptake, was 25% to 35% higher among patients with CHF compared with normal subjects throughout exercise (p < 0.01). A steeper component effect of ventilation on maximal oxygen uptake was observed among normal subjects compared with patients with CHF, which suggests that a significant portion of ventilation in CHF is wasted. Maximal oxygen uptake was inversely related to the ratio of maximal estimated ventilatory dead space to maximal tidal volume (VD/VT) in both groups (I = -0.73, p < 0.001). Any given oxygen uptake at high levels of exercise among patients with CHF was accompanied by a higher VDIVT, lower tidal volume, and higher respiratory rate compared with normal subjects (p < 0.01). Relative hyperventilation in patients with CHF started at the beginning of exercise and was observed both below and above the ventilatory threshold, which suggests that the excess ventilation was not directly related to earlier than normal metabolic acidosis. Thus abnormal ventilatory mechanisms contribute to exercise intolerance in CHF, and excess ventilation is associated with both a higher physiologic dead space and an abnormal breathing pattern. The high dead space is most likely due to ventilation-perfusion mismatching in the lungs, which is related to poor cardiac output, and the abnormal breathing pattern appears to be an effort to reduce the elevated work of breathing that is caused by high pulmonary pressures and poor lung compliance. (AM HEART J 1992;124:710.)
Jonathan Myers, PhD, Azar Salleh, BS, Nancy Buchanan, BA, David Smith, MD, Joel Neutel, MD, Eric Bowes, and Victor F. Froelicher, MD Palo Alto, Long Beach, and Stanford,
Calif.
Exercise intolerance is one of the important pathophysiologic consequences of chronic congestive heart failure (CHF).l Clinically, the severity of heart failure is classified in terms of the degree of dyspnea or fatigue in response to various levels of exertion. A striking characteristic of the exercise response in heart failure is relative hyperventilation. Several recent studies have demonstrated markedly elevated ventilatory responses among patients with CHF compared with normal subjects at similar work rates.“-6 Historically, the mechanism for the hyperventilatory response to exercise in these patients has
From the Cardiology Division, Medical Centers, and Stanford
Palo Alto University.
Received
29, 1992;
for publication
Reprint requests: Alto VA Medical 4/l/39281
710
Jonathan Center,
Jan.
and Long accepted
Myers, PhD, Cardiology 3801 Miranda Ave., Palo
Beach Mar.
Veterans
Affairs
10, 1992.
Division (lllCJ, Alto, CA 94304.
Palo
involved increased intrapulmonary pressures, which is related to interstitial fluid accumulation, decreased lung compliance,7-g and stimulation of pulmonary juxtacapillary receptors in the lungs.8v lo. l* However, direct evidence of a link between elevated intrapulmonary pressures and dyspnea during exercise is lacking,4, 12-14and the physiologic mechanism that underlies exertional hyperventilation in patients with CHF remains unclear.l, 2 Other mechanisms that have been proposed include elevated physiologic dead space,“, 6 early metabolic acidosis 5, 15-17 altered ventilatory control,lO, la, rg and an abnormal pattern of breathing with rapid, shallow respiration.“, & a With the use of continuous ventilatory gas exchange measurements, estimations of metabolic acidosis20 ventilatory dead space,21 breathing patterns23 5, 6, 22 and ventilatory drive2 can be made during exercise. The present study was an effort to
Volume124 Number 3
28
Ventilation
711
exercise in heart failure
50
r
I 45
25
during
CHF
o NORMALS
405 1 I
t
g
35.
r
I* *
30 1
* I I *1 I* 7 I" P *
* PC.01 0" >
16
l i
.a
l
20
44
56
75
65
62
90
MAX
%V02MAx
Fig. 2. Changesin VE/VOs expressedas a percentage of maximal oxygen uptake for patients with CHF and normal subjects (mean t 2 SEM). Table I. Clinical characteristics of patients with chronic CHF and normal subjects Fig. 1. The relationship between resting left ventricular ejection fraction and maximal oxygen uptake (VOz MAX) in patients with chronic CHF (r = 0.13, not significant).
elucidate these mechanisms by measuring respiratory gas exchange responsesto a progressive maximal exercise test in a group of stable ambulatory patients with chronic CHF and to determine the magnitude of the ventilatory factors that underlie exercise intolerance in patients with CHF. These responses were compared with those from a control group who were similar in age and had normal cardiac function. METHODS Patient population. Thirty-three male patients with chronic CHF (mean age, 56 -t 10 years) and 34 men with normal cardiac function (mean age,53 t 9 years) participated in the study. Chronic CHF wasdocumentedby clinical history and a resting ejection fraction of lessthan 40% . Clinical characteristics of the subjects are presented in Table I. The normal therapeutic medication regimen was maintained. Volunteers who demonstrated no evidence of cardiovascular diseaseand who were approximately the sameage asthe patients with CHF were chosento constitute the control group. All rights and privileges were honored in accordance with an established human subjects protocol at the Veterans Affairs Medical Center, and informed consent was obtained from each subject. Exercise testing. Patients with CHF performed a maximal exercisetest on a motor-driven treadmill with either Naughtonz3 or ramp protocols.24 All had recently completed or were in the baseline phase of a pharmaceutical trial; thus, all had recent treadmill experience. All normal
Patientswith CHF (n = 33) Age (yr) Height (in) Weight (lb) Ejection fraction (%#) Disease etiology Ischemic Hypertensive Alcoholic Idiopathic Medications Digoxin Captopril Lasix Calcium antagonist Isordil Antihypertensive P-blocker Antihyperlipidemic Antiarrhythmic
56 69.4 186 25.2 16 4 6 13
-t + ? zt
10 2 36 9
(47 ‘im) (12LP,) (18%) (38%)
30 (88 % ) 21 (62%) 28 (82%) 6 (18%) 7 (20%) 5 (157;) 1(3%) 2 (6S) l(3s;)
Normal subjects (n = 34) 53 f 9 69.9 k 3 188.4 i 28
None
None
subjectsperformed individualized ramp treadmill tests as recently described.24Briefly, a baselinetest was initially performed to habituate subjectsto the protocol and to establish peak oxygen uptake. On the basis of a given subject’s peak oxygen uptake, the treadmill speed and ramp rate were individualized to yield a test duration of approximately 10 minutes. Subjective levels of exertion were quantified with the useof the Borg 6 to 20 scale.25All tests werecontinued until volitional fatigue or dyspneawas experienced. Respiratory gas exchange. Respiratory gasexchange variables were determined continuously throughout the
712
Myers et al.
Table
II. Hemodynamic
American
and gas exchange
data at rest and during
exercise (Mean
September 1992 Heart Journal
t SD)
Patients uiith CHF Rest Heart rate (beats/min) Blood pressure (systolic/diastolic, Ventilatory threshold Heart
rate
mm Hg)
(beatdmin)
Blood pressure (systolic/diastolic, mm Hg) Oxygen uptake (ml/kg/min) Percent peak oxygen uptake Minute ventilation (L/min, BTPS) CO2 production (L/min, STPD) Respiratory exchange ratio Oxygen
pulse
(ml/beat)
Perceived exertion Estimated VD/VT VE/V02 VE/VC02 Maximal Exercise Heart rate (beats/min) Blood pressure (systolic/diastolic, mm Hg) Oxygen uptake (ml/kg/min) Minute ventilation (L/min, BTPS) CO2 production (L/min, STPD) Respiratory exchange ratio Oxygen pulse (ml/heat) Perceived exertion Exercise time (min) Estimated VDNT VEA’O:! VE/VCOI_
81 t 15”
65 + IO
127 t 15182 i 9
130
118 k 19 138 t 22/76 13.0 t 2.2*
121 2 13 168 k 18/86 2 10 19.6 i 4.4 61 T 9 42.8 ? 11.5 1.444 i 0.466 0.86 i 0.09 13.6 i 2.9 13.0 k :! 0.22 F 0.05 25.8 i- 2 X0.X ? :3
+ lO*
72 i 8* 36.6 + 8.4t 0.9272 * 240* 0.84 + 0.06 9.5 T 2.5* 11.1 i 2i
0.29 t o.os* 33.9 + 7* 40.5 i i3* 141 163 17.7 65.5
k t * I
‘I* 26/‘84 3.9* 16*
i
+
12/82
k 7
165 + 14 201 _t 21/87 5 10 31.7 t 6.3 102 f 29.1 3.282 I 0.987 1.20 -t 0.10 16.6 + 4.7 19.1 k 1.9 9.52 + 1.5 0.16 r 0.04 37.6 1+ 6 31.3 t 3
13’
1.578 I 0.488* 1.05 + 0.11* 10.6 i 3.0 19.1 t 1.4
8.61 f 2.3 0.28 f o.os* 45.9 + 12* 43.7 -t 11*
*p < 0.001. tp < 0.05.
exercise test with the Medical Graphics Corporation 2001 system (Medical Graphics Corp., St. Paul, Minn.). The gas exchange variables that were analyzed were oxygen uptake 0’02 ml/kg/min, STPD); CO2 production (VCO~ L/min, STPD); minute ventilation (VE IL/min], BTPS); oxygen pulse (VOZ ml/min divided by heart rate); respiratory exchange ratio (VCO~/VO~; end-tidal 02 and CO? pressures (mm Hg); the ventilatory equivalents for 0s and COz (VE/ VOZ and VE/VCO~); and estimated ventilatory dead space to tidal volume ratio (VD/VT). VD/VT was calculated with an estimation of arterial CO2 pressure from PETCOz as described by Jones and Campbell.21 The ventilatory threshold was determined by four independent observers, who were blinded to each subject’s status, as outlined previously.26 Statistics. All data were entered into a Lotus 123 spreadsheet, which calculated means and standard deviations. The Statistical Graphics Corproation program (Bethesda, Md.) was used to perform unpaired t tests among hemodynamic and gas exchange responses between normal subjects and patients with CHF. Correlation coefficients were calculated to quantify the relationships between various ventilatory variables and maximal oxygen uptake. A stepwise multiple regression procedure was performed to determine predictors of peak oxygen uptake.
RESULTS Hemodynamic and gas exchange variables at rest, at the ventilatory threshold, and at levels of maximal exercise for patients with CHF and normal subjects are presented in Table II. Gas exchange determinants of peak oxygen uptake derived from stepwise multiple regression are presented in Table III. Fig. 1 shows the relationship between resting ejection fraction and peak oxygen uptake for patients with CHF. The correlation between the two was not significant (r = 0.13). Fig. 2 presents VE/Voz values at matched
percentages of maximal oxygen uptake for each group. VE/Vos was significantly (25 9, to 35°C; p < 0.001) higher among patients with CHF throughout exercise testing. Fig. 3 shows the component effect
of maximal
ventilation
on
maximal
oxygen
uptake for both groups. The relationship between maximal oxygen uptake and maximal VD/VT among normal subjects and patients with CHF is shown in Fig. 4; the correlation between the two was -0.73 (p < 0.001). Fig. 5 shows contrasts in tidal volume, respiratory rate, and VD/VT between groups for minutes 2 and 6, and for maximal exercise. Among
Volume Number
124 3
Ventilation
MAXIMAL
VENTILATION
during
exercise in heart failure
713
(L/min)
Fig. 3. Componenteffect plot for the influence of maximal ventilation oxygen uptake amongpatients with CHF (open circles) and normal subjects (closed circles). Individual values for maximal ventilation are plotted on the x axis, and the effect of each on maximal oxygen uptake, relative to the average (zero), is plotted on the y axis. The correlation coefficient betweenthe two variables was0.34 (p = 0.05) for patients with CHF and 0.84 (p < 0.001) for normal subjects. Table III. Explanation of maximal oxygen uptake with stepwiseregressionanalysisfor each group
Patients with CHF Variables entered Maximal VE/VCOz Maximal ventilation (L/min, BTPS) Change in VE/VCO:! Normal subjects Variables entered Maximal ventilation (L/min, BTPS) Change in VE/VC02
R’
0.65
0.42
42
-co.01
0.75 0.82
0.56 0.67
14 11
