Accelerated respiratory response to moderate exercise in late pregnancy

Respiration Physiology ( 1981 ) 45, 229 241

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Elsevier/North-Holland Biomedical Press

ACCELERATED RESPIRATORY RESPONSE TO MODERATE EXERCISE IN LATE PREGNANCY*

MILES J. EDWARDS, JAMES METCALFE, MARCIA J. D U N H A M and MARILYN S. PAUL Heart Research Laboratory, Department o]' Medicine University of Oregon Health Sciences Center, Portland, OR 97201, U.S.A.

Abstract. We studied the rates of change of expired ventilation (VE, ~TPS), 02 consumption (V'O:, STPD)

and CO 2 production (Vco2, STPD) at the start and stop of 6 rain of 50-W bicycle exercise, comparing 20 healthy young women at 38 weeks of pregnancy (G) and 3 months postpartum (NG). "¢o2, ~/co2 and VE were significantly greater at rest for G than for NG. The absolute increases of Vo_~ and '¢co_~ from steady-state rest (SSR) to steady-state exercise (SSE) were the same for G and NG. The absolute increase of VE from SSR to SSE was significantly greater for G than NG. Vo:, Vco, and VE increased more rapidly in G than NG, but only during the first 90 sec of exercise. Recovery rates after exercise were equal for G and NG. We believe that lower extremity muscles of G contract on more distended veins at the onset of exercise, forcing increased volumes of venous blood through the lungs, increasing 902 and "~co_~• VE follows Vc'¢),~closely. Carbon Dioxide Production Control of Breathing Exercise

Oxygen Consumption Pregnancy

In human pregnancy, the increased circulating level of progesterone acts to stimulate respiratory drive in the mother so that her alveolar and arterial Pc,o,, decline (D6ring and Loeschcke, 1947). Increased ventilatory responsiveness to CO~ in pregnancy and with administered progesterone suggests that chemoreceptors are involved (Heerhaber et al., 1948; Lyons and Antonio, 1959). The resulting hypocapnia may be important for normal fetal development (Olsen and Lees, 1980). Exercise increases the metabolic rate. Through poorly understood mechanisms, both circulation and ventilation respond quickly to accomplish a new steady-state Accepted lor publication 1l May 1981 * This work was supported in part by U.S. Public Health Services Grant No. PO1 HD 10034 and the Oregon Heart Association. 0034-5687'81, ,;0000-0000'$0'~,,.50 © Elsevier, North-Holland Biomedical Press

230

M.J. EDWARDS ~,1a/.

of 02 supply and CO2 removal which is appropriate to meet the needs of exercise. As a result, arterial Po: and Pco~ do not change appreciably at levels of exercise below the anaerobic threshold (Wasserman et al., 1973). A rapid ventilatory response has been described which occurs in a few seconds, too soon for blood to travel from exercising lower extremity muscles to thoracic or systemic arterial (such as carotid or intracranial) chemoreceptors. Because of its rapid appearance after the onset of exercise, this response is believed to be mediated by a neural mechanism (Dejours, 1967). As exercise continues, ventilation, perhaps after a brief plateau, continues to increase until it reaches that level which it will maintain in the new steady-state. Carbon dioxide flow, the product of venous carbon dioxide content and venous return, is believed to be responsible for this slower ventilatory increment ( Y a m a m o t o and Edwards, 1960; Wasserman et al., 1974). In this study, women exercised on a bicycle ergometer near the end of pregnancy and again postpartum. We measured expired ventilation (~/E) and the concentration of O, and CO~ in expired air and calculated 02 consumption ('Vo,) and CO2 production ('V(o3 for each breath at rest, throughout moderate exercise and during recovery. We are concerned with the rate of change of each of these variables at the beginning and cessation of exercise and with the effects of pregnancy upon them.

Materials and methods We studied 20 women, 24-34 years of age (average 28.6 years), once in late pregnancy (range 34-39 weeks' gestation, average 38.1 weeks) and again postpartum (range 10-15 weeks postpartum, average 12.4 weeks). All subjects came to the laboratory in the morning after a light breakfast which did not include coffee, meat, eggs or cheese. During our measurements, the subject sat on a bicycle ergometer (Godart), breathing r o o m air through a rubber mouthpiece connected to a two-chamber valve system with a dead space of 73 ml. The nares were occluded by a sponge rubber nose clip. Expired air passed through a Hewlett-Packard pneumotachograph (4730A), providing continuous measurement of expired air flow. Air was sampled from the mouthpiece at a constant rate of 60 ml/min through a Perkin-Elmer mass spectrometer ( M G A - I I00) equipped with O~ and CO~ channels. The mass spectrometer was calibrated before each study with room air and two gas mixtures containing known concentrations of O, and CO~. The output signals of the mass spectrometer and the pneumotachograph were recorded simultaneously on a Brush M a r k 240 recorder and on magnetic tape, using a 4-channel Hewlett-Packard instrumentation recorder (Model 3960). An E C G provided continuous measurement of heart rate, recorded on the Brush recorder. Data collection and processing were done essentially as originally described by Beaver et al. (1973). Analog data, stored on magnetic tape, were later converted to digital form by a Data General Nova computer, which then integrated the expired

R E S P I R A T O R Y RESPONSE TO EXERCISE IN P R E G N A N C Y

231

air flow with the simultaneous 02 and CO2 concentrations derived from the mass spectrometer after appropriate correction for differing time constants. This integration occurred at a rate of 50 times per second and the resultant data were summed for each breath to give breath-by-breath calculations of "qE, "V'o~ and Vco2. These were printed in tabular form and also converted to a graphic format through a Versatec printer. Recordings were made with the patient seated on the bicycle ergometer during the last three minutes of a six-minute seated rest period before exercise, throughout a 6-min period of exercise (50-W intensity) and for I0 min following exercise. By the end of 3 min of exercise, stable levels of '~'E, '¢o~ and ~'co~_ were attained, so we took the average of each for the last 3 minutes of exercise to represent 1009o of the exercise steady-state. Similarly, ~'E, Vo~ and "V'co~had stabilized by the end of 7 min after cessation of exercise, so the average of each for the 8th, 9th and 10th minute was taken to represent 100~ recovery. Using these plateau values, the computer determined the time of onset (in sec) of the first of at least 3 consecutive breaths which reached each successive increment of 10°0 (from 10°,,~i to 100')~,) of the change from steady-state rest to steady-state exercise, and each decrement of 10°~o of the change from steady-state exercise to the average value for the last 3 min of recorded recovery. These times, each representing the time at which a given percentage of the difference between the previous and the subsequent plateau values of 'V'E or "qo~ or 'qco~ was first achieved, were tabulated for each subject in the pregnant and postpartum states. The differences between these paired values were compared using a paired ~t'-test and a two-tailed table of significance.

Results

Steady-state values during pre-exercise rest and during exercise are shown in table 1 for pregnant and postpartum studies together with the differences between rest and exercise. ~'o~, 'v'co: and VE were all significantly greater at rest during pregnancy than postpartum (P < 0.01 for each). Exercise produced essentially the same steadystate increments of Vo~ and '¢~p, in pregnancy as postpartum, but there was a significantly greater increase of VE with exercise during pregnancy than postpartum (P < 0.01). For approximately the first minute of exercise, the times required to achieve each percentage of the increment from resting values to the plateau values of exercise for "~'o.~,'¢co~ and "qE were consistently less during pregnancy than postpartum (see tables 2, 3 and 4). The data are presented graphically in figs. 1, 2 and 3. P values at each percentage of change are given in the tables and indicated in the graphs. All of these differences ceased to be significant after about 60 seconds of exercise and disappeared after 75-90 sec of exercise, even though steady-state levels for Vco, and VE were not reached until 140-150 sec of exercise. The percentage of change of VE closely paralleled that of "~co~ during the entire course of change

243 191 52 59 3.94 <0.01

883 847 36 105 1.53 NS

640 656 -16 104 0.69 NS

219 162 57 60 4.25 <0.01

932 873 59 144 1.83 NS

n = 20: {/o- = Oxygen consumption: Vco, = Carbon dioxide production: VE = Expired ventilation.

Pregnant (A) Postpartum (B) Difference (A - B) SD t P

Exercise

Resting

Difference

Resting

Exercise

~/CO, (STPD) ml/min

9o~ (STPD) ml/min

713 711 +2 117 0.08 NS

Difl'erence

TABLE 1 Effect of pregnancy on respiration at rest and during steady-state exercise

10.00 7.52 +2.48 2.40 4.62 <0.01

Resting

32.50 26.59 +5.91 4.24 6.23 <0.01

Exercise

~TE(BTPS)L/min

22.50 19.07 +3.43 2.80 5.47 <0.01

Difl'erence >

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RESPIRATORY RESPONSE TO EXERCISE IN P R E G N A N C Y

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234

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Exercise--Time (seconds) Fig. 4. Rates of increase of ~)E after onset of exercise in pregnancy and postpartum. The dashed line represents what should be the increase of VE in the pregnant woman if she achieved the same percentages of her total increment at the same time intervals as the postpartum subject. The shaded portion of Vr! iacrease in pregnancy can be attributed to achieving the same percentage of changes in shorter periods of time.

from steady-state rest to steady-state exercise, both occurring much more slowly than the corresponding changes of Vo,. Since the total absolute change in VE with exercise is significantly greater in pregnancy than postpartum, the absolute increases of ~'E (at any percentage of total increase) are significantly greater throughout the time required to attain the steady-state, especially during the first 90 seconds of exercise (see fig. 4). When exercise is discontinued, there are no differences between pregnant and postpartum women in their percentage rates of return from steady-state exercise to steady-state recovery for Vow, 'Vco2 or VE (see tables 2, 3 and 4). However, realizing that the absolute increase of VE with exercise is significantly greater in pregnancy (see table 1) and that the absolute decrease of ~'E with recovery from exercise is also greater in pregnancy, the absolute rate of fall of VE with recovery from exercise is greater in pregnancy.

Discussion

In this study, we used submaximal (50-W) exercise to study the time course of changes in Vo.~, Vco~, and VE at the beginning and end of exercise in physically fit women, comparing data obtained in late pregnancy with data obtained from the same women postpartum. This level of exercise is considered moderate in intensity, sufficient to evoke an average steady-state ~'o,~ of only 883 ml/min during late pregnancy and 847 ml/min postpartum. In pregnancy, the resting values of Vow, ~/co: and "VE exceed those of the non-pregnant woman (Pernoll et al.. 1975b). In addition, the pregnant woman

30 19.6 19.1 +0.5 14.2 0.16 NS

From End o['Exercise (Onset o f Recovery) °Jo 10 20 Pregnant (A) 6.9 12.0 Postpartum (B) 5.6 11.2 Difference (A - B) + 1.3 +0.8 SD 10.2 13.0 t 0.57 0.27 P NS NS

n = 20.

Pregnant (A) Postpartum (B) Difference (A - B) SD t P

30 8.1 14.3 -6.2 14.5 1.92 NS

to 5.7 8.7 -3.0 11.2 1.20 NS

20 5.7 10.4 -4.7 12.6 1.67 NS

~,;

From Onset o f ExercLs'e

40 25.9 29.7 -3.8 16.9 1.00 NS

40 10.6 19.0 -8.4 15.1 2.49 <0.05

50 37.4 39.1 -1.7 15.6 0.49 NS

50 14.5 23.4 -8.9 17.4 2.29 <0.05

TABLE 2 Vo~ Time (in sec) required to achieve each

60 48.6 48.9 -0.3 17.8 0.08 NS

60 21.9 34.3 - 12.5 16.0 3.49 <0.01

70 59.8 68.8 -8.9 22.6 1.76 NS

70 30.4 43.8 -13.4 24.8 2.42 <0.05

0'~i of total change

80 87.4 87.3 +0.1 20.1 0.02 NS

80 43.7 53.1 -9.4 19.4 2.17 <0.05

90 134.1 130.7 +3.4 76.3 0.20 NS

90 57.3 67.3 -10.0 31.3 1.43 NS

100 87.6 94.1 -6.6 53.1 0.56 NS

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:o 5.9 9.0 -3.1 I 1.2 1.24 NS

7.5 14.0 -6.4 15.2 1.88 NS

20

7.5 5.6 + 1.9 10.0 0.85 NS

Pregnant (A) Postpartum (B) Difference (A - B) SD t P

n = 20.

/o

%

11.1 9.8 + 1.3 13.9 0.42 NS

2o

From End Of Exercise (Onset 0/' Recovery)

Pregnant (A) Postpartum (B) Difference (A - B) SD t P

%

From Onset o/Exereise

-

30 23.3 17.1 +6.3 20.4 1.38 NS

20.2 2.37 <0.05

10.7

30 11.2 21.9 -

40 35.9 35.9 0.0 20.2 0.00 NS

23.4 3.00 <0.0!

15.7

40 21.1 36.8 -

50 47.7 47.2 +0.5 19.6 0.11 NS

20.0 3.37 <0.01

15.1

50 36.2 51.2 -

60 64.4 68.5 -4.1 19.2 0.96 NS

60 51.5 62.2 10.7 20.0 2.39 <0.05

70 88.6 85.9 +2.7 17.6 0.69 NS

19.4 0.28 NS

-1.2

70 73.2 74.4

TABLE 3 Vco 2 Time (in sec) required to achieve each 100~ of total change

80 110.9 119.6 -8.7 30.8 1.26 NS

27.7 0.95 NS

-5.9

80 91.1 97.0

90 164.7 171.2 -6.4 42.3 0.68 NS

38.9 0.16 NS

+ 1.4

90 116.0 114.6

100 149.0 142.6 +6.4 47.3 0.60 NS -2

bJ f,a J

5.9 7.8 - 1.8 10.9 0.74 NS

10

8.6 12.2 -3.7 14.2 1.16 NS

20

n = 20.

Pregnant (A) Postpartum (B) Difference (A - B) SD t P

5.3 4.3 + 1.0 5.4 0.83 NS

5.7 5.8 -0.1 7.0 0.06 NS

From End o[' Exercise (Onset of Recovery) o~ 10 20

P

Pregnant (A) Postpartum (B) Difference (A - B) SD

From Onset o['Exercise o, ,o

30 17.3 13.7 +3.7 16.5 1.00 NS

30 11.9 19.4 -7.4 20.8 1.59 NS

40 26.8 22.3 +4.5 19.3 1.04 NS

40 15.9 34.4 - 18.5 25.4 3.26 <0.01

50 43.9 36.0 +7.9 21.3 1.66 NS

50 33.3 49.3 -16.0 24.1 2.97 <0.0!

60 63.1 59.4 +3.7 21.1 0.78 NS

60 52.8 64.6 - 11.8 28.4 1.86 NS

70 91.9 89. l +2.8 40.3 0.31 NS

70 63.1 77.9 - 14.8 38.9 1.70 NS

TABLE 4 VF. Time (in sec) required to achieve each 10°k of total change

111.7 +7.6 47.5 0.72 NS

119.4

80

NS

1.00

80 98.2 89.8 +8.3 37.1

90 154.2 159.5 -5.3 77.3 0.31 NS

90 115.6 114.5 +1.0 37.1 0.12 NS

100 150.7 143.7 +7.0 44.9 0.70 NS

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238

M.J. E D W A R D S et al.

hyperventilates at rest and during steady-state exercise (Pernoll et al., 1975a), with resultant hypocapnia. In this study, the increment of "~o, and Vco~ with steady-state exercise, using a bicycle ergometer (to remove weight-bearing as a consideration), is not increased by pregnancy, meaning that the mechanical efficiency of lower extremity muscular work is not changed by pregnancy. However, the increment of '¢E during steady-state exercise is significantly increased by pregnancy, so the unchanged work load and efficiency still elicit a ventilatory response which is greater in pregnancy than postpartum. Vo:, '¢co, and "~E all increase more rapidly after the onset of exercise in pregnant than in postpartum women. The difference between pregnant and postpartum values is detectable within 10 seconds and the difference diminishes with time until it becomes nonexistent by 75-90 sec after the onset of exercise. During recovery from the same exercise, there are no differences between pregnant and postpartum women in the rate of decrease of 9o:, 9~o: and VE. A faster metabolic response to exercise occurs in exercise-trained subjects, who respond to submaximal exercise with more rapid increases of "~o~, ~'co, and ~/E when exercise begins and a more rapid decrease of 90: at the cessation of exercise than before training. The difl'erence achieved by training is largest between the first and second minutes of exercise (Hagberg et al., 1980), a pattern which is clearly different from the one we are reporting here. The differences between pregnant and postpartum women with regard to the rises in V~, Vco~ and ~/E reach their maxima within 10 seconds of the onset of exercise and lessen progressively, disappearing by 75 90 sec, well before attainment of steady-state levels for V(o: and VE. Also, the recovery curves are identical in pregnant and postpartum women. Whatever accelerates the response of pregnant women operates maximally when they first begin to exercise, progressively lessens to disappear by 75-90 sec into exercise, and is not associated with a detectable change in the rate of recovery of exercise. Although numerous hormonal and metabolic changes occur in pregnancy that might effect changes in muscle enzymes and/or nutrient substrate availability (Kalkhoff et al., 1978), the pattern here does not support such a metabolic explanation. According to the Fick principle, ~/o: is the product of pulmonary blood flow and pulmonary arteriovenous oxygen content difference. Since arterial oxygen content varies little with large changes of ventilation in normal persons (Auchincloss et al., 1966), increases in arteriovenous oxygen difference are due to decreases in mixed venous oxygen content. Said another way, "~o~ at any instant is determined by the flow of deoxyhemoglobin through the lung capillaries, a product of venous return and the deoxyhemoglobin content of mixed venous blood. Both venous return and mixed venous deoxyhemoglobin content increase with exercise (/~strand et al., 1964, Raynaud el al,, 1973). Pregnancy is accompanied by changes in the veins and the venous circulation of the lower extremities. The large uterus of near-term pregnancy obstructs venous return when pregnant women lie in the supine position, so that venous pressure in

R E S P I R A T O R Y RESPONSE TO EXERCISE 1N P R E G N A N C Y

239

the legs increases (McLennan, 1943) and venous return decreases (Wright and Osborn, 1950). When women in the third trimester of pregnancy are in the standing position, popliteal venous pressures average 70 cm H20 (SD = 17 cm H20) (Veal and Hussey, 1947), a value which is explainable by the weight of venous blood between the heart and the site of measurement and thus appears to exclude venous obstruction as a significant factor. The pregnant woman seated on the bicycle ergometer before exercise has dependent lower extremities which are not bearing her weight. The calculated arteriovenous difference across the lungs in this position is the same in late pregnancy as postpartum (Ueland et al., 1973), suggesting that there is no important venous obstruction by the uterus. Venous distensibility increases during pregnancy (McCausland et al., 1961), so venous volume is increased at equivalent distending pressure. When the pregnant woman begins exercise, the contraction of lower extremity muscles on this larger volume of blood should produce a greater increase in venous return to the heart and lungs. (This may be particularly evident because our experimental protocol required that our subjects use greater isometric muscle contraction for the first few seconds to initiate pedal movement). Since blood in the veins of the lower extremities and the inferior vena cava exists as a continuous column extending from the veins of the feet to the heart, the sudden application of muscle pressure to the lower extremity veins would result in a virtually instantaneous increase of distal venous pressure and venous return to the heart (analogous to squeezing the lower end of a full tooth-paste tube). This might explain the accelerated increase of ~'{}~ and "v'co~ with the onset of exercise in pregnancy compared with postpartum. The fact that we do not see differences of '¢o.~, ~'co., and "~E between pregnant and postpartum women during recovery suggests that the refilling of lower extremity veins occurs over a longer period of time than the sudden emptying which occurs at the start of exercise. As already stated, the pregnant woman hyperventilates due to increased circulating levels of progesterone, a known respiratory stimulant (Heerhaber et al., 1948; Lyons and Antonio, 1959; Knuttgen and Emerson, 1974). She, therefore, has an exaggerated ventilatory response to existing gas exchange requirements at any metabolic level. As she goes from one metabolic level (rest) to another (exercise), '~E increases more during pregnancy than postpartum without greater increases in 9(}, or V{,o, (see table 1). If the pregnant subject achieved the same percentages of her total increment at the same time interval as the nonpregnant (postpartum) subject, the dashed line in fig. 4 would result. The non-shaded area between that line and that of the postpartum subject represents the contribution of the change in respiratory sensitivity which accompanies pregnancy. That component of the increase in VE (pregnant over postpartum) which can be attributed to achieving the same percent change in shorter periods of time is shown in fig. 3 and the shaded portion of fig. 4. This also appears as the pregnantpostpartum difference for VE (fig. 3) which is maximal at 10-20 sec and then decreases, corresponding closely with the pregnant-postpartum differences for Vo: (fig. 1) and Vco: (fig. 2). This similarity suggests that blood flow (carrying deoxy-

240

M.J. E D W A R D S et al.

hemoglobin and/or carbon dioxide) to the lungs regulates '~'E. When the individual curves are considered, the percent changes of "V'Ecorrespond more closely to the percent changes of Vco; (compare fig. 3 with fig. 2); they are virtually identical throughout their courses and reach steady-state values for exercise at 140-150 sec. The data support the view that increased carbon dioxide flow causes the hyperpnea of exercise (Yamamoto and Edwards, 1960; Wasserman et al., 1974), and that the accelerated ventilatory increment with exercise during pregnancy is due to augmented carbon dioxide flow.

References /~strand, P.O., T. E. Cuddy, B. Saltin and J. Stenberg (1964). Cardiac output during submaximal and maximal work. J. Appl. Physiol. 19: 268-274. Auchincloss, J. H., R. Gilbert and G . H . Baule (1966). Effect of ventilation on oxygen transfer during early exercise. J. Appl. Physiol. 21 : 810 818. Beaver, W. L., K. Wasserman and B.J. Whipp (1973). On-line computer analysis and breath-by-breath graphical display of exercise function tests. J. Appl. Physiol. 34: 128- 132. Dejours, P. (1967). Neurogenic factors in the control of ventilation with exercise. Circ. Rcs. 2021 (Suppl. 1): 146 153. D6ring, G . K . and H . H . Loeschcke (1947). Atmung und Saure-basengleichgewicht in der Schwangerschaft, pJ'liiger's Arch. Ges. Physiol. 249: 437-451. Hagberg, J.M., R.C. Hickson, A.A. Ehsani and J.O. Holloszy (1980). Faster adjustment to and recovery from submaximal exercise in the trained state. J. Appl. Physiol. 48:218 224. Heerhaber, I., H. H. Loeschcke and U. Westphal (1948). Eine Wirkung des Progesterons auf die Atmung. P[liiger's Arch. Ges. Physiol. 250:42 55. Lyons, H.A. and R. Antonio (1959). The sensitivity of the respiratory center in pregnancy and after the administration of progesterone. Trans. Assoc. Am. Phys. 72:173 180. Kalkhoff, R.K., A.H. Kissebah and H . L Kim (1978). Carbohydrate and lipid metabolism during normal pregnancy: Relationship to gestational hormone action. Seminars in Perinatology 2 : 291-307. Knuttgen, H.G. and K. Emerson (1974). Physiological response to pregnancy at rest and during exercise. J. Appl. Physiol. 36:549 553. McCausland, A.M., C. Hyman. T. Winsor and A.D. Trotter (1961). Venous distensibility during pregnancy. Am. J. Obstet. Gynecol. 31:472 479. Mckennan, C. E. (1943). Antecubital and femoral venous pressure in normal and toxemic pregnancy. Am. J. Obstet. Gynecol. 45: 568-591. Olsen, G. D. and M. H. Lees (1980). Ventilatory response to carbon dioxide of infants following chronic prenatal methadone exposure. J. Pediatr. 96:983 989. Pernoll, M. L., J. Metcalfe, P.A. Kovach, R. Wachtel and M.J. Dunham (1975a). Ventilation during rest and exercise in pregnancy and postpartum. Respir. Physiol. 25:295 310. Pernoll, M. L., J, Metcalfe, T.L. Schlenker, J.E. Welch and J.A. Matsumoto (1975b). Oxygen consumption at rest and during exercise in pregnancy and postpartum. Respir. Physiol. 25:285 293 Raynaud, J., H. Bernal, J.P. Bourdarias, P. David and J. Durand (1973). Oxygen delivery and oxygen return to the lungs at onset of exercise in man. J. Appl. Physiol. 35:259 262. Ueland, K., M.J. Novy and J. Metcalfe (1973). Cardiorespiratory responses of pregnancy and exercise in normal women and patients with heart disease. Am. J. Obstet. Gynecol. 113:47 59. Veal, J. R. and H. H. Hussey (1947). The venous circulation in the lower extremities during pregnancy. Surg. Gynecol. Obstet. 72:841 847. Wasserman, K., B. J. Whipp and J. Castagna (1974). Cardiodynamic hyperpnea: Hyperpnea secondary to cardiac output increase. J. Appl. Physiol. 36:457 464.

RESPIRATORY RESPONSE TO EXERCISE IN P R E G N A N C Y

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Wasserman, K., B. J. Whipp, S. N. Koyal and W. L. Beaver (1973). Anaerobic threshold and respiratory gas exchange during exercise. J. Appl. Physiol. 35 : 236-243. Wright, H. P. and S. B. Osborn (1950). Changes in the rate of flow of venous blood in the leg during pregnancy, measured with radioactive sodium. Surg. Gycwcol. Obstet. 90: 481-485. Yamamoto, W.S. and M . W . Edwards (1960). Homeostasis of carbon dioxide during intra-venous infusion of carbon dioxide. J. Appl. Physiol. 15: 807-818.