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University Laboratory of Physiology, University of Oxford, Oxford OX1 3PT, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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Hypercapnia has been shown in animal experiments to induce pulmonary hypertension. This study measured the sensitivity and time course of the human pulmonary vascular response to sustained (4 h) hypercapnia and hypocapnia. Twelve volunteers undertook three protocols: 1) 4-h euoxic (end-tidal PO2 = 100 Torr) hypercapnia (end-tidal PCO2 was 10 Torr above normal), followed by 2 h of recovery with euoxic eucapnia; 2) 4-h euoxic hypocapnia (end-tidal PCO2 was 10 Torr below normal) followed by 2 h of recovery; and 3) 6-h air breathing (control). Pulmonary vascular resistance was assessed at 0.5- to 1-h intervals by using Doppler echocardiography via the maximum tricuspid pressure gradient during systole. Results show progressive changes in pressure gradient over 1-2 h after the onset or offset of the stimuli, and sensitivities of 0.6 to 1 Torr change in pressure gradient per Torr change in end-tidal PCO2. The human pulmonary circulatory response to changes in PCO2 has a slower time course and greater sensitivity than is commonly assumed. Vascular tone in the normal pulmonary circulation is substantial.
carbon dioxide; hypoxic pulmonary vasoconstriction; pulmonary circulation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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BOTH COMPONENTS OF ASPHYXIA, namely hypoxia and hypercapnia, have long been known to contribute to constriction within the pulmonary vasculature (4, 5, 17). In anesthetized cats and dogs, in situ experiments on single lobes by Barer et al. (3) permitted a comparison between the effects of hypoxia and hypercapnia over quite wide ranges of partial pressures in alveolar gas and suggested that the two stimuli independently increased arterial resistance. In these experiments, hyperoxia had little effect on vascular resistance and the effects of hypocapnia were not well defined. The pulmonary vascular effects of hypocapnia in the right apical lobe of conscious sheep were explored by Sheehan and Farhi (22). They found that hypocapnia increased blood flow to the lobe substantially, and they suggested that variations in both CO2 and O2 about normal values play an important role in the physiological matching of ventilation to perfusion when these values are perturbed in the lung by gravity.
Because hyperoxia has been found to have little vasodilatory effect on the pulmonary circulation, it appears to be widely thought that, in the words of Fishman (6), "because of the low initial tone, attempts to vasodilate the normal pulmonary circulation are destined to be fruitless." In this study, we set out to compare the effects of sustained (4 h) hypocapnia and hypercapnia on the human pulmonary circulation, with a view to establishing whether normal tone can be reduced and whether changes in end-tidal PCO2 (PETCO2) produce substantial or small proportionate changes in an index of pulmonary vascular resistance (PVR). A second aim was to define the time course of the pulmonary vascular responses to these stimuli and of the recovery from these stimuli during a subsequent 2 h of eucapnia.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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Subjects. Twelve healthy volunteers (5 women, 7 men, age 24.8 ± 3.3 yr, mean ± SD) participated in the study. The suitability of subjects for the experiments was confirmed by echocardiographic visualization of tricuspid regurgitation during ventricular systole, which is commonly detected in most healthy individuals. Informed, written consent was obtained on each experimental day. Ethical permission was granted by the Central Oxford Research Ethics Committee.
Protocols. Subjects undertook three protocols on three separate days. In the hypercapnia protocol, subjects were exposed to euoxic hypercapnia for 4 h [end-tidal PO2 (PETO2) = 100 Torr and PETCO2 = 10 Torr above normal], followed by 2 h of euoxic eucapnia (PETO2 = 100 Torr, normal PETCO2). Hypercapnia was achieved by elevating the inspired PCO2 (PICO2) above normal. In the hypocapnia protocol, subjects were exposed to euoxic hypocapnia for 4 h (PETO2 = 100 Torr, PETCO2 = 10 Torr below normal), followed by 2 h of euoxic eucapnia (PETO2 = 100 Torr, normal PETCO2). Hypocapnia was achieved by mechanical hyperventilation via a facemask using a Siemans-Elma Servo Ventilator 900B. During the control protocol, subjects breathed air for 6 h. All three protocols started at the same time of day. The order of the protocols was varied between subjects.
Subjects reported to the laboratory 60 min before the beginning of each experiment. During this period, the subject's normal PETCO2 was measured, baseline echocardiographic measurements were made, and 5 ml of blood were taken from an arm vein for measurement of hemoglobin concentration ([Hb]). Throughout all three protocols, subjects were asked to wear a comfortable facemask. This was the means of achieving passive hyperventilation during the hypocapnia protocol and for collecting expired gases in all three protocols.Control of end-tidal gases. During all three protocols, subjects were either seated or lying down in a chamber in which the inspired PO2 (PIO2) and PICO2 could be changed so as to maintain desired end-tidal values. Respired gas was sampled continuously from a nasal cannula within the facemask and was analyzed with a mass spectrometer. Inspired and end-tidal values were recorded on a computer for each breath. Computer-automated control of PETO2 and PETCO2 was achieved by adjustment of the composition of the gas in the chamber every 5 min, as previously described (7). In the hypercapnia protocol, an elevation in PETCO2 was achieved by increasing PICO2. Ventilation remained spontaneous and consequently increased to above normal values. In the presence of increased spontaneous ventilation, euoxia was maintained by a reduction in PIO2 by the computer-automated control of chamber gases. In the hypocapnia protocol, the ventilator was set to deliver to the subject gas from the chamber. For each subject, a tidal volume and respiratory rate were found empirically during a training session to permit the subject to receive a minute ventilation sufficient to lower PETCO2 to a little more than 10 Torr below normal, when no CO2 was added to inspired gas, in a manner that was comfortable and passive. This degree of hyperventilation was then maintained for 4 h, while the computer-automated control of end-tidal gases adjusted inspired partial pressures to obtain the target level of hypocapnia, which was a PETCO2 value of 10 Torr below the normal value for that subject. The subject resumed spontaneous ventilation during the 2-h recovery period at the end of the hypocapnia protocol.
Echocardiography. Echocardiographic measurements were performed with a Hewlett-Packard Sonos 5500 ultrasound machine with a S4 two-dimensional transducer (2-4 MHz). Heart rate (HR) and respiratory waveform were both recorded on this machine. Subjects were examined on a suitably modified couch rolled slightly toward the left lateral position. For each view, enough time was permitted to acquire a series of consecutive cardiac cycles and store the series to optical disk. At least three beats at, or close to, end expiration were analyzed and averaged at a later time.
Tricuspid valve maximal pressure gradient.
Most people have a detectable regurgitant jet through their tricuspid
valve during systole. Doppler echocardiography was used to visualize
the jet in our subjects and to measure the maximum velocity
(V) with which it travels from the right ventricle into the
right atrium. If the flow in the jet is regarded as steady, Bernoulli's equation (Eq. 1) can be used to relate the
maximum pressure difference across the valve (
Pmax) to
V
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(1) |
is the density of blood. Because Pmax
is a measure of the difference between systolic pressure in the right
ventricle and the fairly constant pressure in the right atrium, it can
be used as an index of PVR. Indeed, we have recently argued that it may
be a more direct indicator of smooth muscle activity in the pulmonary
arteries than PVR itself (2).
A standard technique was used for measuring
Pmax (20). Two-dimensional echocardiography
yielded a view of the tricuspid valve in an apical four-chamber view,
and then color Doppler format allowed detection of the regurgitant jet.
After proper alignment with the Doppler beam, continuous-wave spectral
analysis at a sweep speed of 50 mm/s was used to record the velocity
profile of the jet. During analysis, the maximal velocity of the jet
was measured by using an electronic calliper tool integrated with the
echocardiography machine.
Cardiac output.
Cardiac output (
) was measured by using an apical
five-chamber view with Doppler mode to identify flow through the aortic valve during systole. The velocity profile of this flow was obtained in
pulsed-wave spectral mode at a display screen sweep speed of 100 mm/s.
Doppler sampling of the flow was made just below the orifice of the
aortic valve. The flow was quantified automatically by using the
velocity-time integral, which is the mean distance through which blood
travels in the outflow tract during ventricular contraction.
was then calculated by using Eq. 2
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(2) |
Collection of expired gas.
Mixed expired gas was collected to enable us to estimate the mixed
venous PO2 (P
O2) and CO2
elimination (CO2) that are required
for this calculation.
Estimation of gas composition of mixed venous blood.
It is known that variations in PPmax measured
during alveolar hypercapnia or hypocapnia, we estimated the mixed
venous blood gases by using measurements of
O2,
CO2, , and [Hb] (g/l), as
explained in the APPENDIX.
Statistical analysis. Repeated-measures ANOVA was undertaken to determine whether there was an interaction between time and protocol. Separate repeated-measures ANOVA were then performed on the data from just the control protocols to check that time did not have a significant effect in these protocols.
To determine the time at which steady state had been reached after the induction of hypercapnia or hypocapnia, a family of linear models was used, where the next model differed from the previous model by the inclusion of the next additional factor for time (t), starting from t = 0. With the use of the notation defined by Armitage (1), the models are given by
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(3) |
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1 are the factors that indicate the contribution of each time
point, 
is the number of time points at which data were collected,
and 
is the residual error. As each model was introduced
sequentially, the reduction in squared error over the previous model
was assessed for statistical significance (F ratio test).
The time at which steady state had been reached was taken as the first
time point for which a significant reduction in squared error did not arise.
Values given are means ± SE unless otherwise stated.
Statistical significance was assumed at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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Gas control.
Figure 1 illustrates values for
PIO2,
PICO2,
PETO2, and PETCO2.
For the hypercapnia and hypocapnia protocols, it can be seen that the
steps into and out of the conditions of altered
PETCO2 were achieved relatively rapidly
and that euoxia was maintained throughout, apart from brief deviations
in PETO2 of ~10 Torr during the first 15 min
of the hypercapnia and hypocapnia protocols. On average,
PETCO2 was maintained at 9.1 Torr above
subjects' normal values during hypercapnia and at 10.1 Torr below
subjects' normal values during hypocapnia. During the control
protocol, the end-tidal gases changed little over the 6-h period.
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Pulmonary vascular response to hypercapnia, and during recovery.
Pmax increased gradually during hypercapnia (Fig.
2). The response was significantly
different compared with control (P < 0.001, protocol
by time, repeated-measures ANOVA). Steady state had not been achieved
by 2 h (P < 0.01, ANOVA). For the period 3-4
h after the beginning of hypercapnia, the sensitivity of the change in
Pmax relative to the value at t = 0 was
0.95 Torr per Torr change in PETCO2. On
return to eucapnic conditions, Pmax was restored to
control levels after 1.5 h.
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Pulmonary vascular response to hypocapnia and during recovery.
Pmax decreased gradually during hypocapnia (Fig. 2). The
response was significantly different compared with control
(P < 0.001, protocol by time, repeated-measures
ANOVA). Steady state had not been achieved by 1.5 h
(P < 0.05, ANOVA). For the period 3-4 h after the
beginning of hypocapnia, the sensitivity of the change in
Pmax relative to the value at t = 0 was
0.63 Torr per Torr change in PETCO2. On
return to eucapnic conditions, Pmax was restored to
control levels after 1.0 h.
HR, stroke volume, and responses.
Figure 3 shows the response of HR,
stroke volume, and during the
hypercapnia, hypocapnia, and control protocols.
during hypercapnia was significantly higher when compared with
control (P < 0.005, protocol by time,
repeated-measures ANOVA). A similar statistical comparison
revealed a significant difference for HR (P < 0.005, protocol by time, repeated-measures ANOVA) but not for stroke volume.
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during hypocapnia was also significantly different when
compared with control (P < 0.005, protocol by time,
repeated-measures ANOVA). In Fig. 4,
absolute differences are plotted between hypercapnia and control, and
hypocapnia and control. This is done so that a clearer picture of the
net response of each condition can be presented, and also for effects
caused by initial anxiety and digestion to be cancelled out.
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Calculated P
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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The main findings of our study are that the human pulmonary
vascular responses to hypercapnia and hypocapnia consist, respectively, of constriction and dilatation that take 1.5-2 h to reach a steady level when resolved with measurements every 0.5-1 h over a 4-h period. The time courses for recovery in eucapnia are similar. The
cardiovascular responses to the two stimuli differed qualitatively. Hypercapnia generated a rise in by changing HR; hypocapnia produced a fall in by changing stroke volume. The finding
of marked vasodilatation in response to hypocapnia demonstrates that there is normally substantial vascular tone in the human pulmonary circulation.
Relationship between Pmax and pulmonary vascular
tone.
At a cellular level, the physiological response that is of
greatest relevance to our observations on the intact pulmonary circulation is the change that occurs in pulmonary artery smooth muscle
activity in response to hypercapnia and hypocapnia. Our echocardiographic measurement of Pmax is an indirect
index of this smooth muscle activity, which we here call pulmonary
vascular tone. In a previous study, we argued that changes in
Pmax reflect changes in pulmonary vascular tone but not
alterations in PVR brought about by changes in
(2). This study adds support to this observation; during
the first 3 h of the control protocol, fell and then
rose by ~900 ml/min (Fig. 3). This was associated with a
concurrent fall and then rise in Pmax of only ~0.9
Torr (Fig. 2).
Effects of mixed venous blood gases on pulmonary vascular tone.
There is evidence from animal experiments that both alveolar
PO2 (PAO2) and
PPmax in response to a fall
in PETCO2 than to a rise in
PETCO2 is that the relative mixed venous
blood hypoxia in the hypocapnia protocol induced a degree of hypoxic
pulmonary vasoconstriction that partially offset the effect of hypocapnia.
Relative contributions of O2 and CO2 to ventilation-perfusion matching in the lung. In the healthy lung, variations in regional ratios of ventilation and perfusion are thought to generate a range of values of PAO2 of ~80-140 Torr and a range of PACO2 values of ~42-20 Torr while breathing air at sea level (24). Pulmonary vasoconstriction in response to regional hypoxia and hypercapnia is recognized as a mechanism that is potentially capable of reducing mismatch of ventilation and perfusion, although much of the literature that has examined this phenomenon has concentrated on the oxygen signal.
Thus, for example, Mélot et al. (16), who studied humans by using the multiple inert gas elimination technique, deduced that "in normoxic conditions, active hypoxic regulation of gas exchange results in hardly or nondetectable improvements in arterial blood gases." The weakness of the hypoxic pulmonary vasoconstriction in normoxia was attributed by these authors to the fact that its potential contribution to improving matching of perfusion to ventilation was greatest for values of PAO2 of ~60 Torr, i.e., below the usual range experienced in healthy lungs ventilated with air at sea level. In experiments on sheep, Sheenhan and Farhi (22) gave attention to both the O2 and CO2 signals in the matching of perfusion to ventilation. When a model deduced from experiments on sheep was applied to humans, Sheehan and Farhi concluded that "as we stand, local blood flow control by alveolar gases halves the alveolar-arterial PO2 and PCO2 differences imposed by gravity," suggesting that the regional responses to hypercapnia and hypocapnia make a substantial contribution to the regulation of blood flow. The relative magnitudes of the pulmonary vascular effects in humans of sustained changes in PO2 and PCO2 cannot be assessed from the existing literature. Studies have been limited to brief exposures lasting up to 30 min. Thus, for example, Kilburn et al. (11) studied patients with chronic pulmonary diseases by exposing them for 10-20 min to an inspired CO2 level of 10%. They measured pulmonary artery pressure by using direct cannulation and concluded that mean pulmonary artery pressure rose by 0.85 Torr per Torr rise in arterial PCO2 in patients who were chronically hypercapnic, and by 0.59 Torr per Torr rise in arterial PCO2 in patients who were normally eucapnic. More recently, Kiely et al. (10) used echocardiography to assess hemodynamic changes after 30 min in healthy humans rendered hypercapnic (PETCO2 = 7 kPa) by inspiring CO2 mixed with air. Mean pulmonary artery pressure rose by ~0.4 Torr per Torr rise in PETCO2. In neither study was PETO2 independently controlled. The sensitivity of the whole pulmonary circulation to hypercapnia and hypocapnia measured in the present study was a change inPmax of 0.6-1 Torr per Torr rise in
PACO2. In a similar echocardiographic study in humans, we have previously measured the sensitivity of the
pulmonary circulation to a fall in PAO2
from 100 to 50 Torr to be a rise in Pmax of 15 Torr
(2). The vasoconstrictor response to hypoxia is unlikely
to be linear with respect to PO2. For data from
animal experiments, hypoxic pulmonary vasoconstriction has been modeled
as a sigmoidal function of PAO2, in which
the sensitivity of the vascular response increases as
PAO2 decreases from ~100 Torr toward
~30 Torr (13). If the human response is similar in this
respect, it is to be anticipated that the sensitivity of the pulmonary
vascular response to hypoxia in the PAO2
range of 80-140 Torr given for the normal erect lung
(24) would be considerably less that the value of the 0.3 Torr change in Pmax per Torr change in
PAO2, which is the average over the range
of 50-100 Torr in our previous study (2). In contrast
to this probably weak vascular response to hypoxia within the
physiological range of PAO2 in the healthy
lung, the results presented here show a vigorous response to changes in
PACO2 within the physiological range. This
suggests that, in the healthy lung, CO2 is a more important
regulator of perfusion than O2.
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APPENDIX |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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Mixed P, [Hb],
O2, and
CO2 by using the following relationships.
Concentration of oxygen in arterial and mixed venous blood.
The concentration of O2 (CO2) in
blood was related to the PO2 in blood according
to the equation
![C<SC>o</SC><SUB>2</SUB> = &agr;<SUB>O<SUB>2</SUB></SUB> · P<SC>o</SC><SUB>2</SUB> + [Hb] · <IT>c</IT> · (P<SC>o</SC><SUB>2</SUB>)<SUP><IT>n</IT></SUP>/ [(P<SC>o</SC><SUB>2</SUB>)<SUP><IT>n</IT></SUP> + (P<SUB>50</SUB>)<SUP><IT>n</IT></SUP>]](/content/vol94/issue4/fulltext/1543/img009.gif)
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(4) |
O2 is the solubility of
O2 in blood (0.03 ml STP · l1 · Torr1),
c is the O2 binding capacity of hemoglobin (1.31 ml STP/g), P50 is the PO2 required
to obtain 50% O2 saturation of hemoglobin, and
n is the Hill coefficient for adult hemoglobin (2.8). These physiological variables have been attributed to a variety of values by
different experimenters; the above values are in accord with the
recommendations of Nunn (18) and Stryer (23).
P50 was taken to equal 26 Torr at pH 7.4 and
PCO2 = 40 Torr, and is independently a
function of pH and PCO2 according to the
relationship presented by Kelman (8)
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(5) |
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(6) |
O2 and by the
relationship
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(7) |
Concentration of CO2 in arterial and mixed venous
blood.
The concentration of CO2 in the blood was calculated by
using the method of Kelman (9). According to this method,
the concentration of CO2 in the plasma, both as molecular
CO2 and as bicarbonate, is calculated from the
Henderson-Hasselbalch equation in the form
![C<SC>co</SC><SUB>2, plasma</SUB> = &agr;<SUB>CO<SUB>2</SUB></SUB> · P<SC>co</SC><SUB>2</SUB> [1 + 10<SUP>(pH−pK)</SUP>]](/content/vol94/issue4/fulltext/1543/img013.gif)
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(8) |
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(9) |
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(10) |
![Ca<SUB>CO<SUB>2</SUB></SUB> = 0.84 · &agr;<SUB>CO<SUB>2</SUB></SUB> · Pa<SUB>CO<SUB>2</SUB></SUB> [1 + 10<SUP>(pHa−pK)</SUP>]](/content/vol94/issue4/fulltext/1543/img016.gif)
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(11) |
![C<A><AC>v</AC><AC>&cjs1171;</AC></A><SUB>CO<SUB>2</SUB></SUB> = 0.85 · &agr;<SUB>CO<SUB>2</SUB></SUB> · P<A><AC>v</AC><AC>&cjs1171;</AC></A><SUB>CO<SUB>2</SUB></SUB> [1 + 10<SUP>(pHv−pK)</SUP>]](/content/vol94/issue4/fulltext/1543/img017.gif)
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(12) |
CO2, the solubility of molecular
CO2 in plasma, was taken to equal 0.69 ml STP
· l1 · Torr1 (18).
The concentrations of CO2 in arterial and mixed
venous blood were related to the CO2 elimination of the
body and by the relationship
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(13) |
Calculation of arterial and mixed venous values of pH. It remained to estimate the change in pH that occurs as blood passes through the lungs. We assumed that the participant's arterial blood has zero base excess, i.e., at a PCO2 of 40 Torr the pH would equal 7.4. We then derived the pH of arterial and venous blood by using the results of Lloyd and Michel (12). These give mathematical expressions for the changes in plasma pH that occur with changes in PCO2 and oxyhemoglobin saturation (SO2) in human blood in vitro. Given that blood passing through the pulmonary capillaries has only minimal opportunity to exchange bicarbonate with interstitial fluid, it is appropriate to use the relationships derived for in vitro blood rather than in vivo blood.
The calculation was based on the observation that there is a linear relationship between pH and plasma bicarbonate concentration (the Davenport diagram) in the blood in response to changes in PCO2
![pH = <IT>A</IT> + <IT>B</IT>[HCO<SUP>−</SUP><SUB>3</SUB>] = <IT>A</IT> + <IT>B</IT>&agr;<SUB>CO<SUB>2</SUB></SUB>P<SC>co</SC><SUB>2</SUB>[10<SUP>(pH−pK)</SUP>]](/content/vol94/issue4/fulltext/1543/img019.gif)
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(14) |
CO2 is the solubility of
molecular CO2 in plasma, here in units of mmol
· l1 · Torr1 (and equals 0.0308), and B (l/mmol) is
primarily a function of [Hb], according to the relationship
(12)
![B = −0.005 − 0.26/[Hb]](/content/vol94/issue4/fulltext/1543/img020.gif)
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(15) |
![B = −0.005 − 4.19/[Hb]](/content/vol94/issue4/fulltext/1543/img021.gif)
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(16) |
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(17) |
SO2) between arterial and mixed venous
blood, within Eq. 17 we made the assumption that the
dissolved component of O2 could be ignored and set
![&Dgr;S<SC>o</SC><SUB>2</SUB> = (<A><AC>V</AC><AC>˙</AC></A><SC>o</SC><SUB>2</SUB>/<A><AC>Q</AC><AC>˙</AC></A>) / ([Hb] · <IT>c</IT>)](/content/vol94/issue4/fulltext/1543/img023.gif)
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(18) |
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FOOTNOTES |
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Address for reprint requests and other correspondence: P. A. Robbins, Univ. Laboratory of Physiology, Parks Rd., Oxford OX1 3PT, UK (E-mail: peter.robbins{at}physiol.ox.ac.uk).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published December 13, 2002;10.1152/japplphysiol.00890.2002
Received 26 September 2002; accepted in final form 6 December 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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