Ventilatory response to steady-state exercise in hypoxia in humans D. C. FLENLEY, H. BRASH, L. CLANCY, N. J. COOKE, A. G. LEITCH, W. MIDDLETON, AND P. K. WRAITH Department of Medicine, University of Edinburgh, The Royal Infirmary,
FLENLEY, D.C.,H. BRASH, L. CLANCY,N. J. COOKE, A.G. LEITCH, W. MIDDLETON, AND P. K. WRAITH. VentiZatory responseto steady-state exercise in hypoxia in humans. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 46( 3): 438-446, 1979.-The linear relationship between minute ventilation (VE) and COs output (vcoz) was steeper in 9 of 10 healthy subjects, when treadmill walking was carried out breathing 14% oxygen than when breathing air. This confirmed that the ventilatory response to modest exercise was usually potentiated by mild hypoxia. Arterial oxygen saturation did not significantly correlate with VE in seven healthy subjects, walking, breathing air or 14% oxygen; whereas there was a significant correlation between VE and calculated mixed venous saturation in five of these subjects. Transient relief of hypoxia, when breathing 14% oxygen, by five breaths of 30% oxygen both at rest and during walking, reduced ventilation more at higher levels of exercise. This indicated that the peripheral chemoreceptor response to a given level of arterial desaturation was enhanced by exercise. Directly measured femoral venous saturation was correlated with VE in another three subjects, and there was also a close, but curvilinear, relationship between VE and femoral venous lactate concentrations during similar exercise, when breathing 21 or 14% oxygen. We suggest that receptors in working muscle could be sensitized by muscular hypoxia during exercise when breathing 14% oxygen, and thus contribute to the potentiation of the peripheral chemoreceptor stimulation of exercise ventilation by hypoxia. respiration;
control
of breathing;
normal
man
OF EXERCISE IN MAN remains unexplained, as does the mechanism that underlies the potentiation of this exercise ventilatory drive by hypoxia. However, this potentiation was absent in seven adult asthmatics, in whom both the carotid bodies had been resected, although their ventilatory response to normoxic exercise was preserved (21). This implies that the carotid chemoreceptors are necessary for hypoxic potentiation of exercise ventilation. The problem is to explain the apparent increase in sensitivity of the carotid chemoreceptors, or of the central effects of stimulation that arise during exercise in hypoxia. Various possibilities have been proposed including a change in timing or amplitude of the oscillations in arterial blood gas tensions during hypoxic exercise (2), an increase in arterial catecholamine concentrations during hypoxic exercise, or a reflex from receptors in exercising muscles that might become sensitized by oxygen deprivation during contraction (8-10); but the problem remains unresolved.
HYPERPNEA
438
Edinburgh,
Scotland
We have studied the ventilatory response to steadystate exercise: 1) to quantitate the ventilatory effects of constant and transient changes in inspired oxygen during exercise, and 2) to see if we can relate this ventilatory response to a possible metabolic stimulus which may arise from exercising muscle during hypoxia. By measuring ventilation in both normoxia and hypoxia in the same normal subjects during steady-state exercise, we have sought to separate experimentally the known effects of hypoxia and exercise as ventilatory stimuli. This problem has important clinical implications, for arterial hypoxemia can become profound during exercise in patients, already hypoxemic at rest (18), with severe chronic obstructive lung disease. Furthermore, even partial correction of this arterial hypoxemia, by inspiring 30% oxygen, can significantly reduce the exercise ventilation in these patients. This renders them less breathless and allows them to walk further in a standard 12-min period (21). We want to know how this effect comes about. METHODS
All subjects were healthy nonsmokers (except subj 8, who smoked one pack/day) with no previous history of heart or lung disease. Their lung volumes and FE& lay within t 1 SD of the predicted normal values (6). They all gave informed consent to the study after its nature and purpose had been explained. Subjects 7-15, in whom the vascular invasive studies were carried out, were all physicians, including the authors, and were familiar with the potential hazards of these procedures before giving consent. PROCEDURE
A. Gas exchange and ventilation in steady-state exercise at three levels of inspired oxygen. Subjects l-10 walked at 3-4 mph on a treadmill, level or up a 4-6s gradient, breathing through a mouthpiece and respiratory valve with a 50.ml dead space, inspiring either air, 14% oxygen (balance nitrogen), or 30% oxygen (balance nitrogen), previously mixed in a 350.liter Tissot spirometer. Expiration was through a 3.2-liter mixing chamber (time constant 5.6 s at 22.5 l/min) to a Parkinson Cowan CD4 gasmeter modified to give a digital electrical output. Mixed inspired and expired gas was sampled with SO-ml Havard syringes; expired volume (VE) and temperature were simultaneously recorded over 7-11 and 22-26 min of each 30-min walk.
0161-7567/79/0000-0000$01.25
Copyright
0 1979 the American
Physiological
Society
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VENTILATION
IN
HYPOXIC
439
EXERCISE
B. Respiratory, metabolic, and hemodynamic measurements during steady-state normoxic and hypoxic exercise. In the male subjects 7-13 a 0.8-mm-OD catheter was inserted, under local anesthesia, percutaneously in the left brachial artery and a similar catheter was inserted in the left median basilic vein. Cardiac output was measured by indocyanine green dye dilution (29), and arterial blood was sampled during 30 min of walking on the treadmill. Each subject was studied under four conditions on one day: breathing air, level walking at 3 mph; 14% oxygen, at rest and walking at 3 mph; breathing breathing air, walking up a 5-6s gradient at 3 mph; breathing 14% oxygen, walking up this incline at 3 mph. These four conditions were assigned randomly and each walk was followed by a seated rest for at least 30 min. The subjects did not know which gas mixture they were breathing on any occasion. Ventilation (VE, 1 BTPs/min), oxygen uptake (Voz) and CO2 output (Vcoz) both as ml sTP/min, cardiac output (Q, l/min), heart rate (fo, beats/ min), arterial blood gas tensions, pH, lactate, and pyruvate were measured over 7-11 and 22-26 min of each of the four continuous 30.min walks. C. Transient relief of hypoxia during exercise. Subjects 1O-13 were given five breaths of 30% oxygen on six separate occasions when they had previously been breathing 14%oxygen, both seated and a.t rest,, and during the 7-22 minutes of a treadmill walk, on the level and 56% gradient, at 3 mph. Gas exchange was measured as in A of PROCEDURE. Ven tilation was m.easu.red, breath-bybreath, by expiration through a Fleisch no. 3 pneumbtachograph with custom-built integrator that automatically rezeroed during inspiration. Expired gas then passed to the CD4 gas meter and mixing chamber. A Varian M3 mass spectrometer, calibrated with six previously analyzed (Lloyd-Haldane) 02, N2, and CO2 mixtures continuously sampled at the lips; the four fixed collectors of the mass spectrometer simultaneously measured 02, Nz, COZ, and argon concentrations. Delay in the mass spectrometer probe was measured before and after each study. Analog signals from the integrator, CD4 gas meter, thermistor in the expired gas, mouth pressure, and mass spectrometer were sampled on-line by a PDP l1/40 (Digital Equip.). Custom-written programs provided breath-by-breath outputs of respiratory frequency (fR), tidal volume (1 BTPS, VT), instantaneous minute volume W’ Jbst = VT X fR), end-tidal POT (PETE,) and PcoZ ( PETCO,), from the four gas concentrations summed to loo%, and barometric pressure, after correction for the measured delay in the mass spectrometer probe. Off-line computer analysis provided graphic displays of these variables against breath number (Fig. 3). Arterial oxygen saturation (Sao,) was derived from the measured PETO, assuming that PETO, - Pao, was 10 Torr. This assumption was based on simultaneous measurements of PETO, and Sao, (by Hewlett-Packard ear oximeter) in subsequent steady-state studies (see D of PROCEDURE), with derivation of Pao, from a standard oxygen dissociation curve. It was also assumed that the arterial pH at rest was 7.42, 7.40 at v02 of 1.0 l/min, and 7.38 at v02 of 2.0 l/min, as measured in these subjects in the study described under B), (Table 2). Values of Sao, for each breath (x) were related to the VEht( y) of each breath by
linear regression, for five before and 10 breaths after each change from 0.14 to 0.30 FIO, . Correlation coefficients (r) of these relationships were calculated VEinst. (breath 12+ Z) = a + b (Sao,, breath n)
(1)
where z was allowed to vary from -5 to +lO (Fig. 4, A and B). The individual relationships (Fig. 4B) at the most significant value of r for each transient in each subject arose when z was +2 or +3, indicating that the response, as measured by a change in VEinat, lagged two or three breaths behind the stimulus provoking that response. This stimulus was expressed as the calculated change in Sao, that was, in turn, derived from the change in PETO, following the transient increase in inspired oxygen concentration. The slope of the VEinst/&%02 relationship at this most significant correlation was then used to express the hypoxic sensitivity to transient relief of hypoxia, in that subject at that level of Voz.
D. Femoral venous gas tenstons and lactate concentrations during steady-state normoxic and hypoxic exercise. In male subjects 13-15, a 0.8-mm-OD catheter was inserted percutaneously into the left femoral vein, with the tip lying 2-3 cm above the inguinal ligament. The position of the catheter tip was checked by fluoroscopy before and after the subjects’ four 15min treadmill walks at 3 mph, level and up a 5-6% gradient, breathing air or 14.4-14.7s oxygen. Arterial blood was not sampled in these studies, but arterial oxygen saturation was measured by a Hewlett-Packard 427201 ear oximeter. In 142 comparisons with simultaneously sampled arterial blood in the range 98-7056 Sao, , the relationship was
So2 (ear) = 1.19 (SE 1.65) + 1.00 (SE 0.02) Sao,
(2)
where r = 0.977, and the Sao, was directly measured by Instrumentation Laboratory Co-oximeter. VE, vo2, VCOZ, and fo were measured as before, and femoral venous blood was sampled for measurements of oxygen saturation, Paz, Pcoz, pH, and lactate concentrations, over the 7-9 and 14-15 min of these four 15.min walks that were again randomized in order. The subject did not know the inspired gasmixture. Each of the four walks was preceded by a 15-min seated rest. ANALYSES
Gas samples were analyzed for CO2 concentration by Uras infrared CO2 meter (Godart capnograph) and for oxygen by Servomex OAlll paramagnetic oxygen analyzer. Both instruments were calibrated before each study with two 0 2, CO2, and N2 mixtures, previously analyzed by the Lloyd-Haldane apparatus. Blood gas tensions and pH were measured with Instrumentation Laboratory 313 electrodes calibrated with tonometered blood (14), oxygen saturation by Instrumentation Laboratory Co-oximeter, and arterial lactate and pyruvate concentration by the Boehringer enzymatic method after precipitation of protein by ice-cold trichloroacetic acid. CALCULATIONS
Arterial oxygen saturation (% Sao,) was derived from the measured arterial Po2 and pH in subjects 7-13 (Table
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440
FLENLEY
ET
AL.
the 5-6% gradient and breathing 13.6-14.41% oxygen. This arterial hypoxemia was usually accompanied by hypocapnia (arterial Pcoz, 29-40 Torr), except on one occasion in subject 12 walking uphill at 3 mph, when hypoxemia (Paz, 47 Torr) was associated with a PCO~of 47 Torr and an arterial lactate of 5.6 mmol/l. Arterial acidosis did not occur during any of these studies. When the subjects were breathing air at the higher level of exercise, the Vco2 averaged 1,339 t 307 ml sTP/min (with where Pao, = arterial oxygen tension: PVo,, mixed venous a maximum in subject 12 of 1,756 ml sTP/min), the oxygen tension; VO2, oxygen consumption; &, car- arterial lactate concentration averaged only 1.51 t 0.54 diac output; Cap, blood oxygen capacity (ml/l) = hemo- mmol/l (maximum 2.4 mmol/l in subject 12), and the gas globin concentration x 13.4. As the term 0.03 exchange ratio (R) averaged 0.84 t 0.03. This suggests (Pao, - Pvo,), the arteriovenous difference in dissolved that in most subjects the level of exercise was usually oxygen, only amounted at most to 1.5 to 0.9 ml/l in below the anaerobic threshold (33, 36). A steady state of normoxia and hypoxia, constituting only 2-3% of the exercise was demonstrated by a coefficient of variation arteriovenous difference in blood oxygen content, it was of 7.9% in the two consecutive measurements of h02 ignored and the simplified equation made during the 7-11 and 22-26 min of walking. Both ventilation and cardiac output were consistently sv -o,=Sao,(F) ($---) (4 higher during exercise in hypoxia (Table 2). Minute ventilation was not significantly correlated with the arwas used. If errors of measurement of Voz, & (29), and terial oxygen saturation at both levels of exercise, in both Peg combined so as to maximize the error in calculations hypoxia and normoxia, in any of the subjects (r = -0.253, SVo2, these calculated values could lie within 5% of the P > 0.10). Ventilation was significantly correlated (P < true values of SVo,. 0.05) with the calculated mixed venous oxygen saturation Statistical relationships were calculated by linear least- (SVO,) in five of subjects 7-l 3 (Fig. 2). squares regression. C. The ventilatory response to transient relief of hypoxia in exercise. In subjects lo-13 the slope of the RESULTS relationship between VE (breath n) and Sao, (breath n + z, where z = +2-3, Fig. 4B), was determined by the We express the metabolic cost of exercise in terms of most significant value of the correlation coefficient (Fig. the carbon dioxide output, as recently recommended (30, 4A), at rest and at two levels of exercise (Fig. 5). At rest 34). Our results confirm that the small but inevitable errors of gas analysis together with changes in body gas this slope varied from +0.2 to -0.75 1 min-’ . %Sao,-’ and stores in a subject who changes acutely to breathing a was significantly different from zero in subjects 10, 11 and 13, but not in subject 12. However, the slope changed low oxygen mixture (17), combine to give a larger scatter about the linear regression relationship between VE and markedly as the level of exercise increased, and was Voz than when the relationship is between VE and Vco2 significantly different from zero in all four subjects when (Fig. 1) at modest levels of exercise. Our analysis also v02 was about 1,000 and 2,000 ml sTP/min. There was depends on a linear relationship between arterial (or variability between the four subjects in the rate of change venous) oxygen saturation (SOL) and VE, as has been of this index of hypoxic sensitivity as the intensity of shown experimentally during progressive isocapnic hy- exercise increased (Fig. 5). The rate of change was lessin poxia (27, 37). The relationship between arterial POT and subject 11, but very similar in subjects 10-13. D. Femoral venous gas tensions and lactate concenventilation is hyperbolic in such circumstances (37). As trations during steady-state exercise in normoxia and we have only made measurements at two levels of FIN,, hypoxia (Table 3). Ventilation was again higher when we cannot determine the shape of this ~E/SO~ relationthe subjects breathed 14.3-14.7% oxygen during uphill ship from our own studies. A. Gas exchange and ventilation in steady-state ex- walking when the %02 in subjects 13-15 was 1,490, 1,835, and 2,208 ml sTP/min, as compared to TE when they ercise. Ventilation (VE) rose as a linear function of Vcoz breathed air at similar levels of exercise (Vco2, 1,409, in all subjects at these modest levels of exercise (Table 1,744,2,168 ml srp/min). This separation was not appar1). The slope of this relationship indicated a ventilatory equivalent to CO2 varying between 19 and 27 1 (BTPS) of ent at the lower level of exercise (Fig. 6). There was no v~/l (STP) of Vcoz (mean 23), when the subjects were significant relationship between arterial oxygen saturation and ventilation (Fig. 6), but there was a significant breathing air. However, when they breathed a low oxygen mixture (13.5-14.5% oxygen) the response remained lin- correlation between VE and saturation in the femoral ear (Table l), but the slope of the relationship increased venous blood (r = -0.820, P c O.OOl), and the curvilinear relationship between the lactate concentration in femoral in nine out of the 10 subjects, with a mean of 29 1 of VE/ venous blood and ventilation was particularly close (Fig. 1 of Vcof~ (range 19-31). B. Respiratory, metabolic and hemodynamic mea- 6) . surements during steady-state exercise in hypoxia and DISCUSSION normoxia (Table 2). In subjects 7-13 arterial POT was 3852 Torr during treadmill walking at 3 mph, level or up Although the linear relationship between the meta2). We assumed a standard oxygen dissociation curve with a P50 (7.4) of 26.5 Torr, as measured in similar subjects aged 20-40 yr (31). Mixed venous oxygen saturation (%SQ) was calculated from a rearrangement of the Fick equation sv -0, = sao, + O.O3(Pao, - PVo,) (3) . U/Cap) -
(%2/Q)
l
l
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VENTILATION
IN
HYPOXIC
441
EXERCISE
70 60 _
A 0
-(
Subject
loo0
2000
1500
CONSUMPTION
( V02,ml
STPImd
FIG. 1. Least-squares linear regression relationships (-) and 95% and confidence limits (----- ) between VE and Vo2 (A and C); ventilation Vcoz (B and D) in subject 7 (Table l), breathing air (A and B) and l3.5-14.5% oxygen (C and D) during steady-state treadmill walking where VE is in 1 nTPs/min, and vo2 and Vcoz in 1 sTp/min. Breathing air (A), VE = 1.62 (SE 0.67) + 21.0 (SE 0.05)Vo2, r = 0.987. Breathing
TABLE 1. Parameters Ofreg?x?SSiO?Z eqUUtiOrz $?E = a + b v COJduring steady-state exercise,
subjects breathing -
air or a hypoxic mixture
r
-
Subj, Sex
Age, Y
Ht, w m kg
-
Fro*. 0.2094 a
n
\jE, h-1.
b 1.
SD QE,
Pooled
1.82 1.69 1.60 1.59 1.65 1.60 1.80 1.72 1.74 1.85
I;IE, n$‘.
b 1.
mv2
SD VE,
vEGco2y
r
1./min
42 42 42 42 42 45 34 30 42
0.33 3.31 0.89 2.27 1.34 2.39 2.98 1.56 1.44 1.70
24 19 26 20 22 23 24 27 27 25
1.57 1.22 0.86 1.58 0.60 0.95 1.14 0.84 0.97 1.47
0.98 0.94 0.97 0.85 0.99 0.98 0.98 0.99 0.98 0.98
22 16 20 10 25 22 70 47 55 51
0.70 5.50 0.38 0.63 0.88 1.32 2.00 1.11 1.23 0.71
29 19 28 25 26 26 28 31 30 29
1.22 0.81 0.34 0.30 0.63 0.76 1.12 1.37 1.12 1.26
0.99 0.99 0.99 0.99 0.99 0.99 0.98 0.98 0.97 0.99
45E -
1.69
23
1.63
0.96 3% -
0.93
29
1.63
0.97
68.9 97 57.0 55.2 55.2 56.0 53.5 72.0 78.0 53.0 75.0
n
/min
m-2 20 19 20 26 25 25 29 27 30 27
0.1305-O. 1405 a
r
1M 2M 3F 4F 5F 6M 7M 8M 9M 10 M
minute ventilation per square meter of body surface area (~(BTPS) . min-’ mm2); h02, CO2 output (~(sTP) emin-’ mB2); FIO,, inspired oxygen concentration; 12, number of measurements; r, correlation coefficient; a, intercept on the VE axis; b, regression coefficient; SD, standard deviation about the regression line; pooled values, relationships calculated for pooled data from all subjects. VE,
l
B
7 6 29yB
500 OXYGEN
.
l
bolic cost of steady-state exercise, as measured by either ~OZ or bc02, and the VE is well known, the mechanism of this linkage remains uncertain. Mean arterial blood
2500
500
loo0
CO2 OUTPUT
1500 (Vc02,
2000
ml STPI mln)
air (B), VE = 5.67 (SE 0.64) + 23.7 (SE O.OG)ho~, r = 0.984. Breathing 13.5-14.5% 02 (C), VE = -0.21 (SE 1.25) + 27.9 (SE 0.Ol)V02, r = 0.957. Breathing 13.5-14.5% O2 (D), TE = 3.80 (SE 0.67) + 27.9 (SE 0.06)Vcoz, r = 0.984. The 95% confidence limits are lower for VE/%O~ than for vE/vO:! when subjects breathed 13.5-14.5% 02, and the slope of the lines is increased in hypoxia.
gas tensions are unchanged from resting values in exercise, and cannot alone provide the adequate stimulus to ventilation. Irradiation of nervous imnulses from the cortical centers to the respiratory centers driving the working muscles (19) cannot be disproved, but it is difficult to see how this can explain the increase in slope (vE/vCOa, Fig. 1) of the linear ventilatory response to hypoxic exercise. Hypoxia does not stimulate the central ventilatory drive in man (15, 24). The temporary fall in breath-by-breath ventilation was increasingly apparent at the higher levels of exercise (Fig. 5) when constant arterial hypoxemia (Pao, , 46-52 Torr) was transiently raised to 130-150 Torr by five breaths of 30% oxygen (Fig. 3). This indicated that exercise either increased the discharge of the peripheral chemoreceptors to a given Sao, or that the central effects of changes in chemoreceptor discharge were increased by exercise. This interpretation depends upon these transient responsesreflecting changes in peripheral chemoreceptor activity, such as the fall in VE inst as POT rose and the rapidity of the response. In cats, carotid afferent discharge changed within a few seconds when perfusate PO:! fell abruptly (4, 12, 26). The later rise in PETIT, (Fig. 3) followed from the fall in VE inst,and did not significantly affect the slope of the %/Sa o, relationship in similar studies of this response to transient hypoxia during normoxic exercise (P. M. A. Calverley and D. C. Flenley, unpublished
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FLENLEY
442 TABLE 2. Respiratory, metabolic, and hemodynamic variables during steady-state walking in normoxia and hypoxia in 7 normal men ~~--------_--.~~ _.._ _.._..-.---_---_-..----.---_------.-_-___ .__ ___--. Ht, m
Age, yr
7
29
W
72.0
1.80
8
27
1.72
78.0
9
30
1.74
53.0
10
27
1.85
75.0
11
27
1.82
66.5
12
30
1.77
82.5
13
40
1.75
76.0
Mean
30
1.78
71.9
4.62
tSD
FIN,, tension;
vcoz, ml/min
kg
0.046
14.10 20.94 13.85 20.94 13.60 20.94 14.03 20.94 14.04 20.94 14.05 20.94
,
I
I
1
1
70
80
90
-~-
sop3
ARTERIAL
BLOOD
I
I
lx
0.92
0.84 0.78 0.84 1.12 0.85 1.06 0.85 0.97 0.77 0.88 0.76 0.82 0.69 0.84 0.66 0.95 0.95 0.94 0.78 1.04 0.89 0.91 0.83 1.03 0.89 0.86 0.81
1,269 889
733 1,744 1,756 1,175 1,058 1,428 1,328 845 821 1,439 1,339 782 724 320.58 307.21 220.99 198.21
14.00 20.94 14.07 20.94
0.199 0.000 0.242 0.000
inspired oxygen concentration; vcoz, \jE, minute ventilation (1, BTPs/min);
Paz, Torr
1,366 1,312 655 640 1,564 1,359 730 720 827 767 466 414 1,787 1,582 715 634 1,356
13.93 20.94 13.72 20.94 14.00 20.94 14.15 20.94 14.22 20.94 14.41 20.94 14.12 20.94 14.31 20.94
9.68
R
0.98
0.84 0.90 0.78 0.096 0.094 0.033 0.068
carbon dioxide output Q, cardiac output.
(ml sTP/min);
I
1
I
I
I
20
30
UI
50
60
Soi-% I
1
I
MIXED
VENOUS
45 87 50 91 38 78 44 83 48 91 49 88 46 95 52 91 46 101 50 100 47 85 49 96 50 94 48 100
BLOOD
between VE and measured arterial oxygen FIG. 2. Relationships saturation (A) and SVo, (B) (calculated as described in text), in subjects 7-13 during steady-state treadmill walking at 3 mph, level and up a 56% gradient, when breathing air and 14% oxygen. There was no significant correlation between arterial SO:! and ventilation in any subject relationships between (A). Individual least-squares regression VE and SVo, are shown in subjects 8 I (r = 0.94, P < 0.05); 9, (r = -0.99, P C 0.01); 10, O-----e, (r = -0.99, P < 0.01); 11, 0 ---0 (r = -0.88, P < 0.05). In subjects 7 (A) and 13 (CI) the correlation 0 -----o coefficient (r) did not differ significantly from zero (P > 0.01).
45.7 90.1 48.9 92.7 3.77 7.54 2.48 6.32
AL.
_____________ ~--_ -~ __..~ _________-. -_--__--~_-_-~-__-_ Arterial
Subj
ET
PC% Torr
Blood Lactate, mmol/l
#j
35 36 36 34 29 32 35 39 38 43 42 47 30 36 36 39 39 38 39 38 47 43 40 42 35 37 34 37
7.43 7.43 7.42 7.42 7.43 7.39 7.45 7.38 7.42 7.42 7.42 7.38 7.44 7.42 7.44 7.43 7.42 7.43 7.40 7.40 7.40 7.42 7.40 7.41 7.44 7.44 7.42 7.43
1.61 1.36 1.55 1.60 2.56 1.75 1.65 1.50 2.21 1.84 1.60 1.49 1.21 1.17 1.24 1.7 0.7 0.7 0.5 5.6 2.4 1.6 0.7 2.2 1.3 0.9 0.4
0.104 0.085 0.095 0.085 0.139 0.096 0.072 0.084 0.118 0.081 0.099 0.082 0.135 0.077 0.062 0.057 0.14 0.09 0.10 0.60 0.17 0.08 0.08 0.05 0.09 0.03 0.05 0.04
36.1 37.9 37.4 39.4 6.07 3.97 2.94 4.12
7.43 7.42 7.42 7.41 0.01 0.01 0.01 0.02
2.46 1.51 1.33 1.07 1.429 0.543 0.399 0.528
0.129 0.077 0.080 0.143 0.027 0.020 0.020 0.202
R, gas exchange
1.69
ratio;
Paz,
VE, l/min
Q, l/min
43.28 39.77 21.79 22.37 50.45 42.18 23.81 23.43 27.10 23.91 16.05 13.76 57.31 49.60 23.27 43.87 38.66 28.40 26.23 48.82 40.93 32.78 28.49 47.26 42.84 28.35 27.51
11.5 10.9 6.9 6.6 11.6 9.7 8.0 7.0 9.4 9.2 8.5 7.9 18.5 16.8 11.1 9.8 14.1 11.8 11.7 11.1 13.4 12.5 12.5 12.2 16.8 15.9 13.4 10.8
45.44 39.70 24.92 23.34 9.347 7.810 5.448 4.967
13.61 12.40 10.30 9.34 3.178 2.937 2.488 2.186
pm”m’lY)?
Pco~, oxygen
21.59
and carbon
dioxide
observations). The failure of vE/vOz (or ~E/~COZ) to rise between normoxic and hypoxic exercise in asthmatics with bilateral carotid body resection (24) also indicates the importance of the carotid bodies in hypoxic exercise. Proof of this role in our transient studies would require repeating them after carotid body denervation; we do not think this ethically justifiable. In exercise, most of the rise in cardiac output goes to the working muscles, so that SVo, is particularly weighted by the oxygen content of venous effluent from these muscles. The lack of correlation between the change in Sao, and the change in VE in normoxic and hypoxic exercise (Fig. 2.A) confirms that if the arterial desaturation is used to express the stimulus to the peripheral chemoreceptors, this alone cannot account for the increased ventilation of hypoxic exercise. However, in five of seven subjects there was a significant negative correlation between \j~ and SV0, (Fig. 2B) suggesting that some stimulus related to mixed venous oxygen saturation may play a role. Furthermore, in subjects 13-15 ventilation in both normoxic and hypoxic exercise was correlated significantly with the oxygen saturation of femoral venous blood that largely drains from the working muscles. There was also a close relationship between the lactate concentration of this blood and the ventilation
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VENTILATION
5 BREATHS
IN
HYPOXIC
443
EXERCISE
OF 30% & ON EXERCISE
BREATHING
14Oh a
L
&.
SUBJECT
12
150, I
s
V
II
I I I I . I I I I I -20 -10 0 10 20 30 BREATH NUMBER FIG. 3. On-line computed values of PETO, and PETCO~,and
g3e I-e
t 40
VEinnt, 1 BTPs/min for each breath in 6 replicate studies of transient relief of hypoxia (Fro,, 14.0%) by 5 breaths of 30% oxygen, given at breath 0, during steady-state treadmill walking with an oxygen uptake of 2,200 ml sTP/min.
(Fig. 6). While accepting that correlation does not necessarily mean causation, this observation does raise the possibility that a stimulus related to the hypoxic environment of the working muscles could play a role in the increased ventilation in hypoxic exercise. This idea is not new, but remains controversial. In 1941, Asmussen and Chiodi (1) found that ventilation was higher in two normal subjects when moderate exercise was carried out in hypoxic hypoxia, with Sao, 8087%, and an alveolar Paz, 45 and 52 Torr, as compared to their ventilation in a similar exercise when they breathed carbon monoxide (CO) in air, with Sao, 70% but a normal alveolar POT. However, the venous lactate concentration was only 2.6 and 9.0 mmol/l in exercise with subjects breathing CO, as compared to 5.8 and 11.8 mmol/l in hypoxic hypoxia. This suggests that oxygen delivery to the working muscles was less impaired when breathing CO than in hypoxic hypoxia. We submit that these experiments do not exclude tissue hypoxia in muscle as a source of a ventilatory stimulus in hypoxic exercise. In their more recent studies of eight normal men, Vogel and Gleser (32) found ventilation to average 50 t 2 l/min at a Vo2 of 1,670 t 50 ml/min during exercise when the
subjects’ inhalation of CO in air gave an Sao, of 79.2 t 0.3%, as compared to a ventilation of 45 t 2 l/min at the same voz, but with Sao, of 96.7 t 0.7% when the subjects breathed air without CO. Furthermore, although the arterial lactate concentration averaged 4.0 mmol/l when Sao, was 79.2%, as opposed to 2.5 mmol/l when Sao, was 96.7%; the arterial pH was not significantly different between the two studies. These results strongly support the notion that hypoxia in exercising muscle provides some stimulus to ventilation during hypoxic exercise, as the arterial POT was almost identical (92.6 and 95.4 Torr) in their CO and air breathing studies. Any hypoxic drive at rest is probably dependent upon arterial Paz and not upon arterial oxygen content, when these two variables can be separated, as in recent studies of the ventilatory response to hypoxia in healthy children with a highaffinity hemoglobin (16). Skeletal muscle contains unencapsulated free endings of small-diameter myelinated fibers (25)) stimulation of which can increase ventilation. Changes, produced by experimental muscle ischemia, in the chemical environment of such free efferent endings in muscle were not an adequate stimulation to ventilation in man at rest (9). When this local environment was disturbed by exercise followed by experimental ischemia, further dynamic exercise did produce hyperventilation (10). This leads to the conclusion that the ventilatory stimulus from muscle receptors was “augmented by the local chemical change which occurs in the extremities during exercise.” Further evidence for such a role for muscle receptors is provided by dog studies when infusion of dinitrophenol (DNP) produced hypermetabolism by uncoupling oxidative phosphorylation, thus increasing v02 and TjE. This ventilatory stimulation was preserved when the animal’s head, including the carotid bodies and the respiratory centers, was cross-perfused with blood not containing DNP (22). When higher dosesof DNP (within the human therapeutic range) were infused only into the separately perfused dog hind limb, hyperventilation was also provoked. This was promptly abolished when all nerves from the hypermetabolic limb were severed, showing that hypermetabolism of limb muscles can stimulate ventilation by a neural pathway (20). Wasserman et al. (34) have recently marshalled evidence that ventilation during exercise is related to the flow of CO2 to the lungs via the venous circulation, but do not describe the anatomical site, structure, or mechanism of a receptor acting on such a stimulus. The old idea that a pulmonary arterial CO2 receptor contributed to the hyperpnea of exercise, by coping with the metabolic load of COz from the working muscles (23), was not supported by the failure of ventilation to rise following the infusion of blood with high PCO~into the vena cava (7). However, Stremel et al. (28) have recently shown that CO2 loading delivered into the external jugular vein of awake dogs can increase ventilation without appreciable change in arterial Pcoz. They interpret this as an indicator that either a pulmonary CO2 receptor, or some sensor of COz flow to-the lungs, can drive ventilation. However, this does not seem to explain the increased ventilation of hypoxic exercise in our studies. We are able
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444
FLENLEY SUBJECT
ET
AL.
12
60
c
1
LAG FIG. 4. A, correlation coefficient + d = o + b (Sao,, breath n), for and 10 breaths after the switch oxygen for 5 breaths, as shown in and response (T;ITEinst) is taken as
(z)
IX BRFKIW
NUMBER
DERIVED
(r) of the equation VEinst (breath n the pooled data for 5 breaths before from 14% oxygen to breathing 30% Fig. 3. Lag between stimulus (Sao,) 2 breaths (z = 2), where the most
t
90
85
d5
SaCI
100
(Breath
n)
y0
significant value of r is attained. B, least-squares linear regression line (-) and 95% confidence limits (-----) between VEinst (breath n + 2), and Sao, (breath n), for the pooled data of Fig. 3, when n = 2, as shown for r = -0.67 in A.
3. Respiratory and metabolic variables, and femoral venous blood values during steadystate walking in both normoxia and hypoxia in 3 normal men
TABLE
_.I
._ --
Femoral
c .
0
Subject 10 11 12 13
7 0A I
1
OXYGEN
13, 40 yr,
I
2 (ISTP/min)
1 CONSUMPTION
1.76 m, 78.5 kg
5. Relationship between the hypoxic sensitivity (slope of the regression line as in Fig. 4B, 1 BTPS l rein-’ %Sao.,-’ ) and oxygen consumption when hypoxia due to breathing 14% 02 was transiently believed by 5 breaths of 30% 02. FIG.
l
to calculate
FI $9 %
Subj
. 0
values for CO2 flow to the lungs as (5)
where CVco, is CO2 content of mixed venous and Caco, that of arterial blood, during exercise at two levels of FIO, (study B, Table 2). (The latter was calculated conventionally from our measurements of Pco~, pH, Sao,, and hemoglobin concentration.) Although TE was again closely correlated with \jcoz (FIN,, 2l%, r = 0.99; FIN,, 14%, r = 0.95), using pooled data from subjects 7-13, with steepening of this relationship in hypoxia, the correlation between VE and &* CVco, was less significant in both normoxia (r = 0.78) and hypoxia ( r = 0.76). -4gain the slope of the relationship remained higher in hypoxia. We
14 36 yr, 1.88 m, 68.2 kg 15,28 yr, 1.79 m, 74 kg
___
20.94 14.40 14.26 20.94 20.94 14.40 14.23 20.94 20.94 14.69 14153 20.94
_
Abbreviations oxygen saturation.
ho,, nl/min
1,076 1,033 1,490 1,409 1,370 1,283 1,835 1,744 1,197 1,057 2,208 2,168
f, c
R
0.95 1.00 1.00
0.94 0.97 0.99 0.95 0.92 0.97 0.95 1.03 0.99
as in Tables
Ieats/ min
113 122 146 135 121 134 168 154 104 110 162 154
Sm,, % Po2, Torr
95 81 77 96 96 86 86 96 97 87 83 96
25 22 19 23 24 20 20 22 25 22 18 20
‘co2 Toll-
52 46 46 49 49 43 40 49 58 47 55 60
1 and 2. Sao, , Svo,,
Venous
Blood
PH
%p %
7.36 7.38 7.37 7.37 7.35 7.40 7.39 7.35 7.32 7.38 7.32 7.32
37 29 21 32 31 27 22 28 37 31 17 23
arterial
--I VE,
Lactate mmol/l
0.52 0.61 1.58 0.64 1.00 0.95 3.09 1.79 0.90 0.79 3.63 1.79
1/
min
31.6 31.7 50.0 43.0 37.2 38.4 61.6 48.0 29.6 31.6 62.7 53.2
and venous
cannot confirm that CO2 flow to the lungs provides a more precise stimulus to ventilation, irrespective of the inspired oxygen level, than that apparent from the metabolic cost alone, expressed by the vco2 in this steadystate exercise. As the carotid bodies appear essential for hypoxic potentiation of exercise ventilation (24)) any receptor
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VENTILATION
IN
HYPOXIC
445
EXERCISE r=-0.820
70
A
C
A
A
t
4
Oxygen% Subject13
21 0 140 15A
80
90
SO2% ARTERIAL
BLOOD
IO0
20
,,
30
40
so7 % FEMORAL
012345 LACTATE VENOUS
14 l l
AI
mmol/I
,
BLOOD
FIG. 6. Relationships between minute ventilation and A, measured arterial oxygen saturation (Soz%), B, femoral venous oxygen saturation (Soz%), and C, femoral venous lactate concentration, in 3 normal men during steady-state treadmill walking at 3 mph, level and up a 5-6% gradient, when breathing air or 14% oxygen.
sensitive to the hypoxic environment of working muscles can only stimulate ventilation by interaction with these recognized peripheral chemoreceptors. Sympathetic vasoconstriction in the carotid body during exercise (3) seemed unlikely to account for this in man, as stellate ganglion blockade did not effect the ventilatory response to exercise (11). We do not propose that stimulation of such muscular efferents is the only mechanism underlying the potentiation of the hypoxic drive to breathing during exercise. Arterial norepinephrine levels are higher during hypoxic exercise at a time when the ventilation is significantly greater than at the same level of exercise in normoxia (5). Changes in amplitude or timing of the oscillations in arterial blood gas tensions during the ventilatory cycle may also be involved in this response (2). If there is indeed a contribution to the increased TE from hypoxia arising in muscles during exercise, relief of this hypoxia can improve the exercise tolerance of patients with chronic hypoxemia, even at rest, by reducing their demand for ventilation in exercise. Hypoxia can become much worse during even modest exercise in these patients W) . Received
27 September
1977; accepted
in final
form
14 October
1978.
REFERENCES 1. ASMUSSEN, E,, AND H. CHIODI. The effect of hypoxemia on ventilation and circulation in man. Am. J. Physiol. 132: 426-436, 1941. 2. BHATTACHARYYA, N. K., D. J. C. CUNNINGHAM, R. C. GOODE, M. G. HOUSON, AND B. B. LLOYD. Hypoxia, ventilation, Pee), and exercise. Respir. Physiol. 9: 329-347, 1970. 3. BISCOE, T. J., AND M. J. PURVES. Factors affecting the cat carotid chemoreceptor and cervical sympathetic activity with special reference to passive hind limb movements. J. PhysioZ. London 190: 425-441, 1967. 4. BLACK, A. M. S., D. I. MCCLOSKEY, AND R. W. TORRANCE. The response of the carotid body chemoreceptors in the cat to sudden changes of hypercapnic and hypoxic stimuli. Respir. PhysioZ. 13: 26-49, 1971. 5. CLANCY, L. J., J. A. J. H. CRITCHLEY, A. G. LEITCH, B. J. KIRBY, A. UNGAR, AND D. C. FLENLEY. Arterial catecholamines in hypoxic exercise in man. CZin. Sci. MOL. Med. 49: 503-506, 1975. 6. COTES, J. E. Lung Function (3rd ed.). Oxford: Blackwell, 1975, p. 374-394.
7. CROPP, G. J. A., AND J. H. COMROE. Role of mixed venous blood PCO~ in respiratory control. J. AppZ, Physiol. 16: 1029-1033, 1961. 8. DAVIES, R. O., AND S. LAHIRI. Absence of carotid chemoreceptor response during hypoxic exercise in the cat. Respir. PhysioZ. 18: 92100, 1973. 9. DEJOURS, P., J. C. MITHOEFER, AND Y. LABROUSSE. Influence of local chemical change on ventilatory stimulus from the legs during exercise. J. AppZ. PhysioZ. 10: 372-375, 1957. 10. DEJOURS, P., J. C. MITHOEFER, AND J. RAYNAUD. Evidence against the existence of specific ventilatory chemoreceptors in the legs. J. AppZ. PhysioZ. 10: 367-371, 1957. 11. EISELE, J. H., B. C. RITCHIE, AND J. W. SEVERINGHAUS. Effect of stellate ganglion blockade on the hyperpnea of exercise. J. AppZ. Physiol. 22: 966-969, 1967. 12. FITZGERALD, R. S., L. M. LEITNER, AND M. J. LIABUET. Carotid chemoreceptor response to intermittent or sustained stimulation in the cat. Respir. Physiol. 6: 395-402, 1969. 13. FLENLEY, D. C., L. J. FAIRWEATHER, N. J. COOKE, AND B. J. KIRBY. Changes in haemoglobin binding curve and oxygen transport in chronic hypoxic lung disease. Br. Med. J. I: 602-604, 1975. 14. FLENLEY, D. C., J. S. MILLAR, AND H. A. REES. Accuracy of oxygen and carbon dioxide electrodes. Br. Med. J. 2: 349-352, 1967. 15. Guz, A., M. I. M. NOBLE, J. G. WIDDICOMBE, D. TRENCHARD, AND W. W. MUSHIN. Peripheral chemoreceptor block in man. Respir.
Physiol. 1: 38-40, 1966. 16. HEBBEL, R. P., R. S. KRONENBURG, AND J. W. EATON. Hypoxic ventilatory response in subjects with normal and high oxygen affinity hemoglobins. J. CZin. Invest. 60: 1211-1215, 1977. 17. HILL, A. V., C. N. H. LONG, AND H. LUPTON. Muscular exercise, lactic acid, and the supply and the utilization of oxygen. Proc. R. Sot. London IV: 84-137, 1924. 18. KING, A. J., N. J. COOKE, A. G. LEITCH, AND D. C. FLENLEY. The effects of 30% oxygen on the respiratory response to treadmill exercise in chronic respiratory failure. CZin. Sci. 44: 151-162, 1973. 19. KROGH, T. A., AND J. LINDHARD. The regulation of respiration and circulation during the initial stages of muscular work. J. PhysioZ. London 47: 112-136, 1914. 20. LAING, C. S., AND W. B. HOOD. Afferent neural pathway in the regulation of cardiopulmonary responses to tissue hypermetabolism. Circ. Res. 38: 209-216, 1976. 21. LEGGETT, R. J. E., AND D. C. FI~ENLEY. Portable oxygen therapy and exercise tolerance in chronic hypoxic car pulmonale. Br. Med. J. 2: 84-86, 1977. 22. LEVINE, S., AND W. E. HUCKABEE. Ventilatory response to druginduced hypermetabolism. J. AppZ. Physiol. 38: 827-833, 1975. 23. LINDHARD, J. Uber das Minutenvolum des Herzens bei Ruhe und dei Muskerlarbet. PfZuegers Arch. 116: 233-283, 1915. 24. LUGLIANI, R., B. J. WHIPP, C. SEARD, AND K. WASSERMAN. Effect of bilateral carotid body resection on ventilatory control at rest and during exercise in man. N. EngZ. J. Med. 285: 1105-1111, 1971. 25. MCCLOSKEY, D. I., AND J. H. MITCHELL. Reflex cardiovascular and respiratory responses originating in exercising muscle. J. Physiol. London 224: 173-186, 1972. 26. PONTE, J., AND M. J. PURVES. Frequency response of the carotid body chemoreceptors in the cat to changes of Pa(yoL, Pao,, and pH. J. AppZ. Physiol. 37: 635-647, 1974. 27. REBUCK, A. S., AND E. J. M. CAMPBELL. A clinical method for assessing the ventilatory response to hypoxia. Am. Rev. Respir. Dis. 109: 345, 1974. 28. STREMEL, R. W., D. J. HUNTSMAN, R. CASABURI, B. J. WHIPP, AND K. WASSERMAN. Control of ventilation during intravenous CO? loading in the awake dog. J. AppZ. Physiol.: Respirat. Environ. 1978. Exercise PhysioZ. 44: 311-316, 29. TAYLOR, S. H. Measurement of the cardiac output in man. Proc. R. Sot. Med. SuppZ. 59: 35-53, 1966. 30. TURINO, G., D. W. CUGELL, R. M. GOLDRING, N. L. JONES, R. G.
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446 MELLINO, J. A. NADEL, AND K. M. WASSERMAN. Workshop on assessment of respiratory control in humans. VI. The use of exercise to study ventilatory control. Am. Rev. Respir. Dis. 115: 715-716, 1977. 31. TWEEDDALE, P. M., R. 3. E. LEGGETT, AND D. C. FLENLEY. Effect of age on oxygen-binding in normal human subjects. Clin. Sci. MOL. Med. 51: 185-188, 1976. 32. VOGEL, J. A., AND M. A. GLESER. Effect of carbon monoxide on oxygen transport during exercise. J. AppZ. Physiol. 32: 234-239, 1972. 33. WASSERMAN, K., A. L. VAN KESSEL, AND G. G. BURTON. Interaction of physiological mechanisms during exercise. J. AppZ. PhysioZ. 22: 71-85, 1967.
FLENLEY 34. WASSERMAN, K., B. J. WHIPP, R. CASABURI, Carbon dioxide flow and exercise hyperpnea:
ET
AL.
AND W. L. BEAVER. cause and effect. Am.
Rev. Respir. Dis. 115: 225-237, 1977. 35. WASSERMAN, K., B. J. WHIPP, AND J. CASTAGNA. Cardiodynamic hyperpnea; hyperpnea secondary to cardiac output increase. J. AppZ. Physiol. 36: 457-464, 1974. 36. WASSERMAN, K., B. J. WHIPP, S. A. KOYAL, AND W. L. BEAVER. Anaerobic threshold and respiratory gas exchange during exercise. J. AppZ. Physiol. 35: 236-343, 1973. 37. WEIL, J. V., E. BRYNNE-QUINN, I. E. SODAL, 0. FRIESEN, B. UNDERHILL, G. F. FILLEY, AND R. F. GROVER. Hypoxic ventilatory drive in normal man. J. CZin. Invest. 49: 1061-1072, 1970.
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FLENLEY, D.C.,H. BRASH, L. CLANCY,N. J. COOKE, A.G. LEITCH, W. MIDDLETON, AND P. K. WRAITH. VentiZatory responseto steady-state exercise in hypoxia in humans. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 46( 3): 438-446, 1979.-The linear relationship between minute ventilation (VE) and COs output (vcoz) was steeper in 9 of 10 healthy subjects, when treadmill walking was carried out breathing 14% oxygen than when breathing air. This confirmed that the ventilatory response to modest exercise was usually potentiated by mild hypoxia. Arterial oxygen saturation did not significantly correlate with VE in seven healthy subjects, walking, breathing air or 14% oxygen; whereas there was a significant correlation between VE and calculated mixed venous saturation in five of these subjects. Transient relief of hypoxia, when breathing 14% oxygen, by five breaths of 30% oxygen both at rest and during walking, reduced ventilation more at higher levels of exercise. This indicated that the peripheral chemoreceptor response to a given level of arterial desaturation was enhanced by exercise. Directly measured femoral venous saturation was correlated with VE in another three subjects, and there was also a close, but curvilinear, relationship between VE and femoral venous lactate concentrations during similar exercise, when breathing 21 or 14% oxygen. We suggest that receptors in working muscle could be sensitized by muscular hypoxia during exercise when breathing 14% oxygen, and thus contribute to the potentiation of the peripheral chemoreceptor stimulation of exercise ventilation by hypoxia. respiration;
control
of breathing;
normal
man
OF EXERCISE IN MAN remains unexplained, as does the mechanism that underlies the potentiation of this exercise ventilatory drive by hypoxia. However, this potentiation was absent in seven adult asthmatics, in whom both the carotid bodies had been resected, although their ventilatory response to normoxic exercise was preserved (21). This implies that the carotid chemoreceptors are necessary for hypoxic potentiation of exercise ventilation. The problem is to explain the apparent increase in sensitivity of the carotid chemoreceptors, or of the central effects of stimulation that arise during exercise in hypoxia. Various possibilities have been proposed including a change in timing or amplitude of the oscillations in arterial blood gas tensions during hypoxic exercise (2), an increase in arterial catecholamine concentrations during hypoxic exercise, or a reflex from receptors in exercising muscles that might become sensitized by oxygen deprivation during contraction (8-10); but the problem remains unresolved.
HYPERPNEA
438
Edinburgh,
Scotland
We have studied the ventilatory response to steadystate exercise: 1) to quantitate the ventilatory effects of constant and transient changes in inspired oxygen during exercise, and 2) to see if we can relate this ventilatory response to a possible metabolic stimulus which may arise from exercising muscle during hypoxia. By measuring ventilation in both normoxia and hypoxia in the same normal subjects during steady-state exercise, we have sought to separate experimentally the known effects of hypoxia and exercise as ventilatory stimuli. This problem has important clinical implications, for arterial hypoxemia can become profound during exercise in patients, already hypoxemic at rest (18), with severe chronic obstructive lung disease. Furthermore, even partial correction of this arterial hypoxemia, by inspiring 30% oxygen, can significantly reduce the exercise ventilation in these patients. This renders them less breathless and allows them to walk further in a standard 12-min period (21). We want to know how this effect comes about. METHODS
All subjects were healthy nonsmokers (except subj 8, who smoked one pack/day) with no previous history of heart or lung disease. Their lung volumes and FE& lay within t 1 SD of the predicted normal values (6). They all gave informed consent to the study after its nature and purpose had been explained. Subjects 7-15, in whom the vascular invasive studies were carried out, were all physicians, including the authors, and were familiar with the potential hazards of these procedures before giving consent. PROCEDURE
A. Gas exchange and ventilation in steady-state exercise at three levels of inspired oxygen. Subjects l-10 walked at 3-4 mph on a treadmill, level or up a 4-6s gradient, breathing through a mouthpiece and respiratory valve with a 50.ml dead space, inspiring either air, 14% oxygen (balance nitrogen), or 30% oxygen (balance nitrogen), previously mixed in a 350.liter Tissot spirometer. Expiration was through a 3.2-liter mixing chamber (time constant 5.6 s at 22.5 l/min) to a Parkinson Cowan CD4 gasmeter modified to give a digital electrical output. Mixed inspired and expired gas was sampled with SO-ml Havard syringes; expired volume (VE) and temperature were simultaneously recorded over 7-11 and 22-26 min of each 30-min walk.
0161-7567/79/0000-0000$01.25
Copyright
0 1979 the American
Physiological
Society
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VENTILATION
IN
HYPOXIC
439
EXERCISE
B. Respiratory, metabolic, and hemodynamic measurements during steady-state normoxic and hypoxic exercise. In the male subjects 7-13 a 0.8-mm-OD catheter was inserted, under local anesthesia, percutaneously in the left brachial artery and a similar catheter was inserted in the left median basilic vein. Cardiac output was measured by indocyanine green dye dilution (29), and arterial blood was sampled during 30 min of walking on the treadmill. Each subject was studied under four conditions on one day: breathing air, level walking at 3 mph; 14% oxygen, at rest and walking at 3 mph; breathing breathing air, walking up a 5-6s gradient at 3 mph; breathing 14% oxygen, walking up this incline at 3 mph. These four conditions were assigned randomly and each walk was followed by a seated rest for at least 30 min. The subjects did not know which gas mixture they were breathing on any occasion. Ventilation (VE, 1 BTPs/min), oxygen uptake (Voz) and CO2 output (Vcoz) both as ml sTP/min, cardiac output (Q, l/min), heart rate (fo, beats/ min), arterial blood gas tensions, pH, lactate, and pyruvate were measured over 7-11 and 22-26 min of each of the four continuous 30.min walks. C. Transient relief of hypoxia during exercise. Subjects 1O-13 were given five breaths of 30% oxygen on six separate occasions when they had previously been breathing 14%oxygen, both seated and a.t rest,, and during the 7-22 minutes of a treadmill walk, on the level and 56% gradient, at 3 mph. Gas exchange was measured as in A of PROCEDURE. Ven tilation was m.easu.red, breath-bybreath, by expiration through a Fleisch no. 3 pneumbtachograph with custom-built integrator that automatically rezeroed during inspiration. Expired gas then passed to the CD4 gas meter and mixing chamber. A Varian M3 mass spectrometer, calibrated with six previously analyzed (Lloyd-Haldane) 02, N2, and CO2 mixtures continuously sampled at the lips; the four fixed collectors of the mass spectrometer simultaneously measured 02, Nz, COZ, and argon concentrations. Delay in the mass spectrometer probe was measured before and after each study. Analog signals from the integrator, CD4 gas meter, thermistor in the expired gas, mouth pressure, and mass spectrometer were sampled on-line by a PDP l1/40 (Digital Equip.). Custom-written programs provided breath-by-breath outputs of respiratory frequency (fR), tidal volume (1 BTPS, VT), instantaneous minute volume W’ Jbst = VT X fR), end-tidal POT (PETE,) and PcoZ ( PETCO,), from the four gas concentrations summed to loo%, and barometric pressure, after correction for the measured delay in the mass spectrometer probe. Off-line computer analysis provided graphic displays of these variables against breath number (Fig. 3). Arterial oxygen saturation (Sao,) was derived from the measured PETO, assuming that PETO, - Pao, was 10 Torr. This assumption was based on simultaneous measurements of PETO, and Sao, (by Hewlett-Packard ear oximeter) in subsequent steady-state studies (see D of PROCEDURE), with derivation of Pao, from a standard oxygen dissociation curve. It was also assumed that the arterial pH at rest was 7.42, 7.40 at v02 of 1.0 l/min, and 7.38 at v02 of 2.0 l/min, as measured in these subjects in the study described under B), (Table 2). Values of Sao, for each breath (x) were related to the VEht( y) of each breath by
linear regression, for five before and 10 breaths after each change from 0.14 to 0.30 FIO, . Correlation coefficients (r) of these relationships were calculated VEinst. (breath 12+ Z) = a + b (Sao,, breath n)
(1)
where z was allowed to vary from -5 to +lO (Fig. 4, A and B). The individual relationships (Fig. 4B) at the most significant value of r for each transient in each subject arose when z was +2 or +3, indicating that the response, as measured by a change in VEinat, lagged two or three breaths behind the stimulus provoking that response. This stimulus was expressed as the calculated change in Sao, that was, in turn, derived from the change in PETO, following the transient increase in inspired oxygen concentration. The slope of the VEinst/&%02 relationship at this most significant correlation was then used to express the hypoxic sensitivity to transient relief of hypoxia, in that subject at that level of Voz.
D. Femoral venous gas tenstons and lactate concentrations during steady-state normoxic and hypoxic exercise. In male subjects 13-15, a 0.8-mm-OD catheter was inserted percutaneously into the left femoral vein, with the tip lying 2-3 cm above the inguinal ligament. The position of the catheter tip was checked by fluoroscopy before and after the subjects’ four 15min treadmill walks at 3 mph, level and up a 5-6% gradient, breathing air or 14.4-14.7s oxygen. Arterial blood was not sampled in these studies, but arterial oxygen saturation was measured by a Hewlett-Packard 427201 ear oximeter. In 142 comparisons with simultaneously sampled arterial blood in the range 98-7056 Sao, , the relationship was
So2 (ear) = 1.19 (SE 1.65) + 1.00 (SE 0.02) Sao,
(2)
where r = 0.977, and the Sao, was directly measured by Instrumentation Laboratory Co-oximeter. VE, vo2, VCOZ, and fo were measured as before, and femoral venous blood was sampled for measurements of oxygen saturation, Paz, Pcoz, pH, and lactate concentrations, over the 7-9 and 14-15 min of these four 15.min walks that were again randomized in order. The subject did not know the inspired gasmixture. Each of the four walks was preceded by a 15-min seated rest. ANALYSES
Gas samples were analyzed for CO2 concentration by Uras infrared CO2 meter (Godart capnograph) and for oxygen by Servomex OAlll paramagnetic oxygen analyzer. Both instruments were calibrated before each study with two 0 2, CO2, and N2 mixtures, previously analyzed by the Lloyd-Haldane apparatus. Blood gas tensions and pH were measured with Instrumentation Laboratory 313 electrodes calibrated with tonometered blood (14), oxygen saturation by Instrumentation Laboratory Co-oximeter, and arterial lactate and pyruvate concentration by the Boehringer enzymatic method after precipitation of protein by ice-cold trichloroacetic acid. CALCULATIONS
Arterial oxygen saturation (% Sao,) was derived from the measured arterial Po2 and pH in subjects 7-13 (Table
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440
FLENLEY
ET
AL.
the 5-6% gradient and breathing 13.6-14.41% oxygen. This arterial hypoxemia was usually accompanied by hypocapnia (arterial Pcoz, 29-40 Torr), except on one occasion in subject 12 walking uphill at 3 mph, when hypoxemia (Paz, 47 Torr) was associated with a PCO~of 47 Torr and an arterial lactate of 5.6 mmol/l. Arterial acidosis did not occur during any of these studies. When the subjects were breathing air at the higher level of exercise, the Vco2 averaged 1,339 t 307 ml sTP/min (with where Pao, = arterial oxygen tension: PVo,, mixed venous a maximum in subject 12 of 1,756 ml sTP/min), the oxygen tension; VO2, oxygen consumption; &, car- arterial lactate concentration averaged only 1.51 t 0.54 diac output; Cap, blood oxygen capacity (ml/l) = hemo- mmol/l (maximum 2.4 mmol/l in subject 12), and the gas globin concentration x 13.4. As the term 0.03 exchange ratio (R) averaged 0.84 t 0.03. This suggests (Pao, - Pvo,), the arteriovenous difference in dissolved that in most subjects the level of exercise was usually oxygen, only amounted at most to 1.5 to 0.9 ml/l in below the anaerobic threshold (33, 36). A steady state of normoxia and hypoxia, constituting only 2-3% of the exercise was demonstrated by a coefficient of variation arteriovenous difference in blood oxygen content, it was of 7.9% in the two consecutive measurements of h02 ignored and the simplified equation made during the 7-11 and 22-26 min of walking. Both ventilation and cardiac output were consistently sv -o,=Sao,(F) ($---) (4 higher during exercise in hypoxia (Table 2). Minute ventilation was not significantly correlated with the arwas used. If errors of measurement of Voz, & (29), and terial oxygen saturation at both levels of exercise, in both Peg combined so as to maximize the error in calculations hypoxia and normoxia, in any of the subjects (r = -0.253, SVo2, these calculated values could lie within 5% of the P > 0.10). Ventilation was significantly correlated (P < true values of SVo,. 0.05) with the calculated mixed venous oxygen saturation Statistical relationships were calculated by linear least- (SVO,) in five of subjects 7-l 3 (Fig. 2). squares regression. C. The ventilatory response to transient relief of hypoxia in exercise. In subjects lo-13 the slope of the RESULTS relationship between VE (breath n) and Sao, (breath n + z, where z = +2-3, Fig. 4B), was determined by the We express the metabolic cost of exercise in terms of most significant value of the correlation coefficient (Fig. the carbon dioxide output, as recently recommended (30, 4A), at rest and at two levels of exercise (Fig. 5). At rest 34). Our results confirm that the small but inevitable errors of gas analysis together with changes in body gas this slope varied from +0.2 to -0.75 1 min-’ . %Sao,-’ and stores in a subject who changes acutely to breathing a was significantly different from zero in subjects 10, 11 and 13, but not in subject 12. However, the slope changed low oxygen mixture (17), combine to give a larger scatter about the linear regression relationship between VE and markedly as the level of exercise increased, and was Voz than when the relationship is between VE and Vco2 significantly different from zero in all four subjects when (Fig. 1) at modest levels of exercise. Our analysis also v02 was about 1,000 and 2,000 ml sTP/min. There was depends on a linear relationship between arterial (or variability between the four subjects in the rate of change venous) oxygen saturation (SOL) and VE, as has been of this index of hypoxic sensitivity as the intensity of shown experimentally during progressive isocapnic hy- exercise increased (Fig. 5). The rate of change was lessin poxia (27, 37). The relationship between arterial POT and subject 11, but very similar in subjects 10-13. D. Femoral venous gas tensions and lactate concenventilation is hyperbolic in such circumstances (37). As trations during steady-state exercise in normoxia and we have only made measurements at two levels of FIN,, hypoxia (Table 3). Ventilation was again higher when we cannot determine the shape of this ~E/SO~ relationthe subjects breathed 14.3-14.7% oxygen during uphill ship from our own studies. A. Gas exchange and ventilation in steady-state ex- walking when the %02 in subjects 13-15 was 1,490, 1,835, and 2,208 ml sTP/min, as compared to TE when they ercise. Ventilation (VE) rose as a linear function of Vcoz breathed air at similar levels of exercise (Vco2, 1,409, in all subjects at these modest levels of exercise (Table 1,744,2,168 ml srp/min). This separation was not appar1). The slope of this relationship indicated a ventilatory equivalent to CO2 varying between 19 and 27 1 (BTPS) of ent at the lower level of exercise (Fig. 6). There was no v~/l (STP) of Vcoz (mean 23), when the subjects were significant relationship between arterial oxygen saturation and ventilation (Fig. 6), but there was a significant breathing air. However, when they breathed a low oxygen mixture (13.5-14.5% oxygen) the response remained lin- correlation between VE and saturation in the femoral ear (Table l), but the slope of the relationship increased venous blood (r = -0.820, P c O.OOl), and the curvilinear relationship between the lactate concentration in femoral in nine out of the 10 subjects, with a mean of 29 1 of VE/ venous blood and ventilation was particularly close (Fig. 1 of Vcof~ (range 19-31). B. Respiratory, metabolic and hemodynamic mea- 6) . surements during steady-state exercise in hypoxia and DISCUSSION normoxia (Table 2). In subjects 7-13 arterial POT was 3852 Torr during treadmill walking at 3 mph, level or up Although the linear relationship between the meta2). We assumed a standard oxygen dissociation curve with a P50 (7.4) of 26.5 Torr, as measured in similar subjects aged 20-40 yr (31). Mixed venous oxygen saturation (%SQ) was calculated from a rearrangement of the Fick equation sv -0, = sao, + O.O3(Pao, - PVo,) (3) . U/Cap) -
(%2/Q)
l
l
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VENTILATION
IN
HYPOXIC
441
EXERCISE
70 60 _
A 0
-(
Subject
loo0
2000
1500
CONSUMPTION
( V02,ml
STPImd
FIG. 1. Least-squares linear regression relationships (-) and 95% and confidence limits (----- ) between VE and Vo2 (A and C); ventilation Vcoz (B and D) in subject 7 (Table l), breathing air (A and B) and l3.5-14.5% oxygen (C and D) during steady-state treadmill walking where VE is in 1 nTPs/min, and vo2 and Vcoz in 1 sTp/min. Breathing air (A), VE = 1.62 (SE 0.67) + 21.0 (SE 0.05)Vo2, r = 0.987. Breathing
TABLE 1. Parameters Ofreg?x?SSiO?Z eqUUtiOrz $?E = a + b v COJduring steady-state exercise,
subjects breathing -
air or a hypoxic mixture
r
-
Subj, Sex
Age, Y
Ht, w m kg
-
Fro*. 0.2094 a
n
\jE, h-1.
b 1.
SD QE,
Pooled
1.82 1.69 1.60 1.59 1.65 1.60 1.80 1.72 1.74 1.85
I;IE, n$‘.
b 1.
mv2
SD VE,
vEGco2y
r
1./min
42 42 42 42 42 45 34 30 42
0.33 3.31 0.89 2.27 1.34 2.39 2.98 1.56 1.44 1.70
24 19 26 20 22 23 24 27 27 25
1.57 1.22 0.86 1.58 0.60 0.95 1.14 0.84 0.97 1.47
0.98 0.94 0.97 0.85 0.99 0.98 0.98 0.99 0.98 0.98
22 16 20 10 25 22 70 47 55 51
0.70 5.50 0.38 0.63 0.88 1.32 2.00 1.11 1.23 0.71
29 19 28 25 26 26 28 31 30 29
1.22 0.81 0.34 0.30 0.63 0.76 1.12 1.37 1.12 1.26
0.99 0.99 0.99 0.99 0.99 0.99 0.98 0.98 0.97 0.99
45E -
1.69
23
1.63
0.96 3% -
0.93
29
1.63
0.97
68.9 97 57.0 55.2 55.2 56.0 53.5 72.0 78.0 53.0 75.0
n
/min
m-2 20 19 20 26 25 25 29 27 30 27
0.1305-O. 1405 a
r
1M 2M 3F 4F 5F 6M 7M 8M 9M 10 M
minute ventilation per square meter of body surface area (~(BTPS) . min-’ mm2); h02, CO2 output (~(sTP) emin-’ mB2); FIO,, inspired oxygen concentration; 12, number of measurements; r, correlation coefficient; a, intercept on the VE axis; b, regression coefficient; SD, standard deviation about the regression line; pooled values, relationships calculated for pooled data from all subjects. VE,
l
B
7 6 29yB
500 OXYGEN
.
l
bolic cost of steady-state exercise, as measured by either ~OZ or bc02, and the VE is well known, the mechanism of this linkage remains uncertain. Mean arterial blood
2500
500
loo0
CO2 OUTPUT
1500 (Vc02,
2000
ml STPI mln)
air (B), VE = 5.67 (SE 0.64) + 23.7 (SE O.OG)ho~, r = 0.984. Breathing 13.5-14.5% 02 (C), VE = -0.21 (SE 1.25) + 27.9 (SE 0.Ol)V02, r = 0.957. Breathing 13.5-14.5% O2 (D), TE = 3.80 (SE 0.67) + 27.9 (SE 0.06)Vcoz, r = 0.984. The 95% confidence limits are lower for VE/%O~ than for vE/vO:! when subjects breathed 13.5-14.5% 02, and the slope of the lines is increased in hypoxia.
gas tensions are unchanged from resting values in exercise, and cannot alone provide the adequate stimulus to ventilation. Irradiation of nervous imnulses from the cortical centers to the respiratory centers driving the working muscles (19) cannot be disproved, but it is difficult to see how this can explain the increase in slope (vE/vCOa, Fig. 1) of the linear ventilatory response to hypoxic exercise. Hypoxia does not stimulate the central ventilatory drive in man (15, 24). The temporary fall in breath-by-breath ventilation was increasingly apparent at the higher levels of exercise (Fig. 5) when constant arterial hypoxemia (Pao, , 46-52 Torr) was transiently raised to 130-150 Torr by five breaths of 30% oxygen (Fig. 3). This indicated that exercise either increased the discharge of the peripheral chemoreceptors to a given Sao, or that the central effects of changes in chemoreceptor discharge were increased by exercise. This interpretation depends upon these transient responsesreflecting changes in peripheral chemoreceptor activity, such as the fall in VE inst as POT rose and the rapidity of the response. In cats, carotid afferent discharge changed within a few seconds when perfusate PO:! fell abruptly (4, 12, 26). The later rise in PETIT, (Fig. 3) followed from the fall in VE inst,and did not significantly affect the slope of the %/Sa o, relationship in similar studies of this response to transient hypoxia during normoxic exercise (P. M. A. Calverley and D. C. Flenley, unpublished
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FLENLEY
442 TABLE 2. Respiratory, metabolic, and hemodynamic variables during steady-state walking in normoxia and hypoxia in 7 normal men ~~--------_--.~~ _.._ _.._..-.---_---_-..----.---_------.-_-___ .__ ___--. Ht, m
Age, yr
7
29
W
72.0
1.80
8
27
1.72
78.0
9
30
1.74
53.0
10
27
1.85
75.0
11
27
1.82
66.5
12
30
1.77
82.5
13
40
1.75
76.0
Mean
30
1.78
71.9
4.62
tSD
FIN,, tension;
vcoz, ml/min
kg
0.046
14.10 20.94 13.85 20.94 13.60 20.94 14.03 20.94 14.04 20.94 14.05 20.94
,
I
I
1
1
70
80
90
-~-
sop3
ARTERIAL
BLOOD
I
I
lx
0.92
0.84 0.78 0.84 1.12 0.85 1.06 0.85 0.97 0.77 0.88 0.76 0.82 0.69 0.84 0.66 0.95 0.95 0.94 0.78 1.04 0.89 0.91 0.83 1.03 0.89 0.86 0.81
1,269 889
733 1,744 1,756 1,175 1,058 1,428 1,328 845 821 1,439 1,339 782 724 320.58 307.21 220.99 198.21
14.00 20.94 14.07 20.94
0.199 0.000 0.242 0.000
inspired oxygen concentration; vcoz, \jE, minute ventilation (1, BTPs/min);
Paz, Torr
1,366 1,312 655 640 1,564 1,359 730 720 827 767 466 414 1,787 1,582 715 634 1,356
13.93 20.94 13.72 20.94 14.00 20.94 14.15 20.94 14.22 20.94 14.41 20.94 14.12 20.94 14.31 20.94
9.68
R
0.98
0.84 0.90 0.78 0.096 0.094 0.033 0.068
carbon dioxide output Q, cardiac output.
(ml sTP/min);
I
1
I
I
I
20
30
UI
50
60
Soi-% I
1
I
MIXED
VENOUS
45 87 50 91 38 78 44 83 48 91 49 88 46 95 52 91 46 101 50 100 47 85 49 96 50 94 48 100
BLOOD
between VE and measured arterial oxygen FIG. 2. Relationships saturation (A) and SVo, (B) (calculated as described in text), in subjects 7-13 during steady-state treadmill walking at 3 mph, level and up a 56% gradient, when breathing air and 14% oxygen. There was no significant correlation between arterial SO:! and ventilation in any subject relationships between (A). Individual least-squares regression VE and SVo, are shown in subjects 8 I (r = 0.94, P < 0.05); 9, (r = -0.99, P C 0.01); 10, O-----e, (r = -0.99, P < 0.01); 11, 0 ---0 (r = -0.88, P < 0.05). In subjects 7 (A) and 13 (CI) the correlation 0 -----o coefficient (r) did not differ significantly from zero (P > 0.01).
45.7 90.1 48.9 92.7 3.77 7.54 2.48 6.32
AL.
_____________ ~--_ -~ __..~ _________-. -_--__--~_-_-~-__-_ Arterial
Subj
ET
PC% Torr
Blood Lactate, mmol/l
#j
35 36 36 34 29 32 35 39 38 43 42 47 30 36 36 39 39 38 39 38 47 43 40 42 35 37 34 37
7.43 7.43 7.42 7.42 7.43 7.39 7.45 7.38 7.42 7.42 7.42 7.38 7.44 7.42 7.44 7.43 7.42 7.43 7.40 7.40 7.40 7.42 7.40 7.41 7.44 7.44 7.42 7.43
1.61 1.36 1.55 1.60 2.56 1.75 1.65 1.50 2.21 1.84 1.60 1.49 1.21 1.17 1.24 1.7 0.7 0.7 0.5 5.6 2.4 1.6 0.7 2.2 1.3 0.9 0.4
0.104 0.085 0.095 0.085 0.139 0.096 0.072 0.084 0.118 0.081 0.099 0.082 0.135 0.077 0.062 0.057 0.14 0.09 0.10 0.60 0.17 0.08 0.08 0.05 0.09 0.03 0.05 0.04
36.1 37.9 37.4 39.4 6.07 3.97 2.94 4.12
7.43 7.42 7.42 7.41 0.01 0.01 0.01 0.02
2.46 1.51 1.33 1.07 1.429 0.543 0.399 0.528
0.129 0.077 0.080 0.143 0.027 0.020 0.020 0.202
R, gas exchange
1.69
ratio;
Paz,
VE, l/min
Q, l/min
43.28 39.77 21.79 22.37 50.45 42.18 23.81 23.43 27.10 23.91 16.05 13.76 57.31 49.60 23.27 43.87 38.66 28.40 26.23 48.82 40.93 32.78 28.49 47.26 42.84 28.35 27.51
11.5 10.9 6.9 6.6 11.6 9.7 8.0 7.0 9.4 9.2 8.5 7.9 18.5 16.8 11.1 9.8 14.1 11.8 11.7 11.1 13.4 12.5 12.5 12.2 16.8 15.9 13.4 10.8
45.44 39.70 24.92 23.34 9.347 7.810 5.448 4.967
13.61 12.40 10.30 9.34 3.178 2.937 2.488 2.186
pm”m’lY)?
Pco~, oxygen
21.59
and carbon
dioxide
observations). The failure of vE/vOz (or ~E/~COZ) to rise between normoxic and hypoxic exercise in asthmatics with bilateral carotid body resection (24) also indicates the importance of the carotid bodies in hypoxic exercise. Proof of this role in our transient studies would require repeating them after carotid body denervation; we do not think this ethically justifiable. In exercise, most of the rise in cardiac output goes to the working muscles, so that SVo, is particularly weighted by the oxygen content of venous effluent from these muscles. The lack of correlation between the change in Sao, and the change in VE in normoxic and hypoxic exercise (Fig. 2.A) confirms that if the arterial desaturation is used to express the stimulus to the peripheral chemoreceptors, this alone cannot account for the increased ventilation of hypoxic exercise. However, in five of seven subjects there was a significant negative correlation between \j~ and SV0, (Fig. 2B) suggesting that some stimulus related to mixed venous oxygen saturation may play a role. Furthermore, in subjects 13-15 ventilation in both normoxic and hypoxic exercise was correlated significantly with the oxygen saturation of femoral venous blood that largely drains from the working muscles. There was also a close relationship between the lactate concentration of this blood and the ventilation
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VENTILATION
5 BREATHS
IN
HYPOXIC
443
EXERCISE
OF 30% & ON EXERCISE
BREATHING
14Oh a
L
&.
SUBJECT
12
150, I
s
V
II
I I I I . I I I I I -20 -10 0 10 20 30 BREATH NUMBER FIG. 3. On-line computed values of PETO, and PETCO~,and
g3e I-e
t 40
VEinnt, 1 BTPs/min for each breath in 6 replicate studies of transient relief of hypoxia (Fro,, 14.0%) by 5 breaths of 30% oxygen, given at breath 0, during steady-state treadmill walking with an oxygen uptake of 2,200 ml sTP/min.
(Fig. 6). While accepting that correlation does not necessarily mean causation, this observation does raise the possibility that a stimulus related to the hypoxic environment of the working muscles could play a role in the increased ventilation in hypoxic exercise. This idea is not new, but remains controversial. In 1941, Asmussen and Chiodi (1) found that ventilation was higher in two normal subjects when moderate exercise was carried out in hypoxic hypoxia, with Sao, 8087%, and an alveolar Paz, 45 and 52 Torr, as compared to their ventilation in a similar exercise when they breathed carbon monoxide (CO) in air, with Sao, 70% but a normal alveolar POT. However, the venous lactate concentration was only 2.6 and 9.0 mmol/l in exercise with subjects breathing CO, as compared to 5.8 and 11.8 mmol/l in hypoxic hypoxia. This suggests that oxygen delivery to the working muscles was less impaired when breathing CO than in hypoxic hypoxia. We submit that these experiments do not exclude tissue hypoxia in muscle as a source of a ventilatory stimulus in hypoxic exercise. In their more recent studies of eight normal men, Vogel and Gleser (32) found ventilation to average 50 t 2 l/min at a Vo2 of 1,670 t 50 ml/min during exercise when the
subjects’ inhalation of CO in air gave an Sao, of 79.2 t 0.3%, as compared to a ventilation of 45 t 2 l/min at the same voz, but with Sao, of 96.7 t 0.7% when the subjects breathed air without CO. Furthermore, although the arterial lactate concentration averaged 4.0 mmol/l when Sao, was 79.2%, as opposed to 2.5 mmol/l when Sao, was 96.7%; the arterial pH was not significantly different between the two studies. These results strongly support the notion that hypoxia in exercising muscle provides some stimulus to ventilation during hypoxic exercise, as the arterial POT was almost identical (92.6 and 95.4 Torr) in their CO and air breathing studies. Any hypoxic drive at rest is probably dependent upon arterial Paz and not upon arterial oxygen content, when these two variables can be separated, as in recent studies of the ventilatory response to hypoxia in healthy children with a highaffinity hemoglobin (16). Skeletal muscle contains unencapsulated free endings of small-diameter myelinated fibers (25)) stimulation of which can increase ventilation. Changes, produced by experimental muscle ischemia, in the chemical environment of such free efferent endings in muscle were not an adequate stimulation to ventilation in man at rest (9). When this local environment was disturbed by exercise followed by experimental ischemia, further dynamic exercise did produce hyperventilation (10). This leads to the conclusion that the ventilatory stimulus from muscle receptors was “augmented by the local chemical change which occurs in the extremities during exercise.” Further evidence for such a role for muscle receptors is provided by dog studies when infusion of dinitrophenol (DNP) produced hypermetabolism by uncoupling oxidative phosphorylation, thus increasing v02 and TjE. This ventilatory stimulation was preserved when the animal’s head, including the carotid bodies and the respiratory centers, was cross-perfused with blood not containing DNP (22). When higher dosesof DNP (within the human therapeutic range) were infused only into the separately perfused dog hind limb, hyperventilation was also provoked. This was promptly abolished when all nerves from the hypermetabolic limb were severed, showing that hypermetabolism of limb muscles can stimulate ventilation by a neural pathway (20). Wasserman et al. (34) have recently marshalled evidence that ventilation during exercise is related to the flow of CO2 to the lungs via the venous circulation, but do not describe the anatomical site, structure, or mechanism of a receptor acting on such a stimulus. The old idea that a pulmonary arterial CO2 receptor contributed to the hyperpnea of exercise, by coping with the metabolic load of COz from the working muscles (23), was not supported by the failure of ventilation to rise following the infusion of blood with high PCO~into the vena cava (7). However, Stremel et al. (28) have recently shown that CO2 loading delivered into the external jugular vein of awake dogs can increase ventilation without appreciable change in arterial Pcoz. They interpret this as an indicator that either a pulmonary CO2 receptor, or some sensor of COz flow to-the lungs, can drive ventilation. However, this does not seem to explain the increased ventilation of hypoxic exercise in our studies. We are able
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444
FLENLEY SUBJECT
ET
AL.
12
60
c
1
LAG FIG. 4. A, correlation coefficient + d = o + b (Sao,, breath n), for and 10 breaths after the switch oxygen for 5 breaths, as shown in and response (T;ITEinst) is taken as
(z)
IX BRFKIW
NUMBER
DERIVED
(r) of the equation VEinst (breath n the pooled data for 5 breaths before from 14% oxygen to breathing 30% Fig. 3. Lag between stimulus (Sao,) 2 breaths (z = 2), where the most
t
90
85
d5
SaCI
100
(Breath
n)
y0
significant value of r is attained. B, least-squares linear regression line (-) and 95% confidence limits (-----) between VEinst (breath n + 2), and Sao, (breath n), for the pooled data of Fig. 3, when n = 2, as shown for r = -0.67 in A.
3. Respiratory and metabolic variables, and femoral venous blood values during steadystate walking in both normoxia and hypoxia in 3 normal men
TABLE
_.I
._ --
Femoral
c .
0
Subject 10 11 12 13
7 0A I
1
OXYGEN
13, 40 yr,
I
2 (ISTP/min)
1 CONSUMPTION
1.76 m, 78.5 kg
5. Relationship between the hypoxic sensitivity (slope of the regression line as in Fig. 4B, 1 BTPS l rein-’ %Sao.,-’ ) and oxygen consumption when hypoxia due to breathing 14% 02 was transiently believed by 5 breaths of 30% 02. FIG.
l
to calculate
FI $9 %
Subj
. 0
values for CO2 flow to the lungs as (5)
where CVco, is CO2 content of mixed venous and Caco, that of arterial blood, during exercise at two levels of FIO, (study B, Table 2). (The latter was calculated conventionally from our measurements of Pco~, pH, Sao,, and hemoglobin concentration.) Although TE was again closely correlated with \jcoz (FIN,, 2l%, r = 0.99; FIN,, 14%, r = 0.95), using pooled data from subjects 7-13, with steepening of this relationship in hypoxia, the correlation between VE and &* CVco, was less significant in both normoxia (r = 0.78) and hypoxia ( r = 0.76). -4gain the slope of the relationship remained higher in hypoxia. We
14 36 yr, 1.88 m, 68.2 kg 15,28 yr, 1.79 m, 74 kg
___
20.94 14.40 14.26 20.94 20.94 14.40 14.23 20.94 20.94 14.69 14153 20.94
_
Abbreviations oxygen saturation.
ho,, nl/min
1,076 1,033 1,490 1,409 1,370 1,283 1,835 1,744 1,197 1,057 2,208 2,168
f, c
R
0.95 1.00 1.00
0.94 0.97 0.99 0.95 0.92 0.97 0.95 1.03 0.99
as in Tables
Ieats/ min
113 122 146 135 121 134 168 154 104 110 162 154
Sm,, % Po2, Torr
95 81 77 96 96 86 86 96 97 87 83 96
25 22 19 23 24 20 20 22 25 22 18 20
‘co2 Toll-
52 46 46 49 49 43 40 49 58 47 55 60
1 and 2. Sao, , Svo,,
Venous
Blood
PH
%p %
7.36 7.38 7.37 7.37 7.35 7.40 7.39 7.35 7.32 7.38 7.32 7.32
37 29 21 32 31 27 22 28 37 31 17 23
arterial
--I VE,
Lactate mmol/l
0.52 0.61 1.58 0.64 1.00 0.95 3.09 1.79 0.90 0.79 3.63 1.79
1/
min
31.6 31.7 50.0 43.0 37.2 38.4 61.6 48.0 29.6 31.6 62.7 53.2
and venous
cannot confirm that CO2 flow to the lungs provides a more precise stimulus to ventilation, irrespective of the inspired oxygen level, than that apparent from the metabolic cost alone, expressed by the vco2 in this steadystate exercise. As the carotid bodies appear essential for hypoxic potentiation of exercise ventilation (24)) any receptor
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VENTILATION
IN
HYPOXIC
445
EXERCISE r=-0.820
70
A
C
A
A
t
4
Oxygen% Subject13
21 0 140 15A
80
90
SO2% ARTERIAL
BLOOD
IO0
20
,,
30
40
so7 % FEMORAL
012345 LACTATE VENOUS
14 l l
AI
mmol/I
,
BLOOD
FIG. 6. Relationships between minute ventilation and A, measured arterial oxygen saturation (Soz%), B, femoral venous oxygen saturation (Soz%), and C, femoral venous lactate concentration, in 3 normal men during steady-state treadmill walking at 3 mph, level and up a 5-6% gradient, when breathing air or 14% oxygen.
sensitive to the hypoxic environment of working muscles can only stimulate ventilation by interaction with these recognized peripheral chemoreceptors. Sympathetic vasoconstriction in the carotid body during exercise (3) seemed unlikely to account for this in man, as stellate ganglion blockade did not effect the ventilatory response to exercise (11). We do not propose that stimulation of such muscular efferents is the only mechanism underlying the potentiation of the hypoxic drive to breathing during exercise. Arterial norepinephrine levels are higher during hypoxic exercise at a time when the ventilation is significantly greater than at the same level of exercise in normoxia (5). Changes in amplitude or timing of the oscillations in arterial blood gas tensions during the ventilatory cycle may also be involved in this response (2). If there is indeed a contribution to the increased TE from hypoxia arising in muscles during exercise, relief of this hypoxia can improve the exercise tolerance of patients with chronic hypoxemia, even at rest, by reducing their demand for ventilation in exercise. Hypoxia can become much worse during even modest exercise in these patients W) . Received
27 September
1977; accepted
in final
form
14 October
1978.
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