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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
REFERENCES
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In humans exposed to 8 h of isocapnic hypoxia, there is a progressive increase in ventilation that is associated with an increase in the ventilatory sensitivity to acute hypoxia. To determine the relative roles of lowered arterial PO2 and oxygen content in generating these changes, the acute hypoxic ventilatory response was determined in 11 subjects after four 8-h exposures: 1) protocol IH (isocapnic hypoxia), in which end-tidal PO2 was held at 55 Torr and end-tidal PCO2 was maintained at the preexposure value; 2) protocol PB (phlebotomy), in which 500 ml of venous blood were withdrawn; 3) protocol CO, in which carboxyhemoglobin was maintained at 10% by controlled carbon monoxide inhalation; and 4) protocol C as a control. Both hypoxic sensitivity and ventilation in the absence of hypoxia increased significantly after protocol IH (P < 0.001 and P < 0.005, respectively, ANOVA) but not after the other three protocols. This indicates that it is the reduction in arterial PO2 that is primarily important in generating the increase in the acute hypoxic ventilatory response in prolonged hypoxia. The associated reduction in arterial oxygen content is unlikely to play an important role.
hypoxia; carbon monoxide; ventilation; oxygen content
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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WHEN HUMANS ARE EXPOSED
TO an environment of low oxygen for prolonged periods,
ventilation (
E) increases progressively, and this is
accompanied by a reduction in end-tidal PCO2
(PETCO2). This process is known as
ventilatory acclimatization to hypoxia (VAH). The mechanisms that
underlie VAH are not yet fully understood. However, as part of this
process, there is an increase in the sensitivity of the ventilatory
response to acute hypoxia (AHVR) (13, 27, 32). A number of
studies in goats suggest that this increase in AHVR has its origins
within the carotid body. Hypoxia localized to the carotid body was
found to induce VAH (3, 29), whereas systemic hypoxia did
not induce VAH if the carotid body was maintained euoxic
(31). By way of contrast, in a study conducted in awake
ponies, Lowry et al. (18) reported that there was a
progressive fall in arterial PCO2 during
several hours of steady carboxyhemoglobinemia. Because this induces
tissue hypoxia within the brain but has little effect at the carotid body (9, 17), they concluded that their results were
consistent with a central nervous mechanism contributing to the early
phase of VAH in ponies.
In view of the somewhat conflicting conclusions drawn from these studies, we decided to compare, in humans, an 8-h reduction in arterial O2 content (CaO2) brought about by a reduction in arterial PO2 (PaO2) with 8-h reductions in CaO2 in which PaO2 remained unaffected. If the increase in AHVR associated with VAH is primarily due to brain hypoxia, then a rise in AHVR would be expected from both types of exposure. On the other hand, if the increase in AHVR associated with VAH is primarily due to carotid body hypoxia, then a reduction in CaO2 without a reduction in PaO2 should have little effect (3, 9, 17, 29). Rather than employ just one method to reduce CaO2 at constant PaO2, we decided to use two protocols, employing hemodilution and carbon monoxide (CO) inhalation, respectively.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Twelve healthy subjects (9 men, 3 women) participated in the study. Their age ranged between 20 and 32 yr, with an average of 23 ± 4 (SD) yr. Their average height was 180 ± 19 cm, and their average weight was 74 ± 13 kg. All were nonsmokers except for subject 1,128, who smoked 10 cigarettes per day. None of the subjects had donated blood within the 6 mo before his or her participation in the study. All were requested to have a light breakfast and refrain from alcohol, caffeine-containing drink, and cigarettes on each experimental day. Female subjects only participated in the experiments during the first 14 days of their menstrual cycles. The basic experimental procedure was explained to all subjects, but they were naive as to the exact purpose of the experiments. Each subject visited the laboratory once or twice before undertaking any of the main experimental protocols to become familiar with the laboratory and its procedures. All subjects gave informed consent before participating in the study. The study was approved by the Central Oxford Research Ethics Committee.Protocols
Each subject undertook four different protocols. Protocol IH consisted of an 8-h exposure to isocapnic hypoxia, in which end-tidal PO2 (PETO2) was held at 55 Torr and PETCO2 was maintained at the subject's air-breathing control value. During protocol PB, each subject underwent phlebotomy, with 500 ml of blood being withdrawn from an arm vein. During protocol CO, a ~10% level of carboxyhemoglobin (HbCO) was induced and maintained for 8 h by having the subjects intermittently breathe a dilute mixture of CO in air. Protocol C was a control protocol, in which the subjects breathed air with no other intervention. The order of the exposures was varied among subjects. At least 4 wk were allowed to elapse after protocol PB before another experimental protocol was undertaken. Each experiment started at 8-9 AM after the subject had rested for at least 0.5 h at the laboratory. A light lunch was served at 12:30-1 PM.Air-breathing PETCO2 was measured before
and after each 8-h protocol. AHVR was assessed before, 40 min after,
and 8 h after the start of each 8-h protocol. During each
measurement of AHVR, PETO2 was held at 100 Torr for the first 5 min. This was followed by six square waves of
PETO2, with
PETO2 alternating between 1 min at 50 Torr
and 1 min at 100 Torr. PETCO2 was held at
1-2 Torr above the subject's initial air-breathing value
throughout. The end-tidal gas profiles used are illustrated in Fig.
1, which is from an actual determination
of AHVR in one subject (subject 1,118).
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Experimental Technique
At the beginning of each experimental day, a venous blood sample of 1-2 ml was taken to determine the total concentration of hemoglobin ([Hb]; g/dl), the percentage of methemoglobin (%MetHb), and the percentage of HbCO (%HbCO).Protocol IH. To undertake the 8-h exposures to hypoxia associated with this protocol, we employed a purpose-built chamber. The subject was seated comfortably inside the chamber and wore a fine catheter at the opening of each nostril through which respired gas was sampled and analyzed by mass spectrometry for PO2 and PCO2. A pulse oximeter was attached to the forefinger to monitor percent arterial oxygen saturation (SaO2). A computer was used to analyze and log the data on-line, to identify inspiratory and end-tidal values of PO2 and PCO2, and to control the gas composition within the chamber. At the start of each experiment, the composition of the inspired gas that would be required to produce the desired PETCO2 and PETO2 was estimated and set manually before the subject entered the chamber. After the subject entered the chamber, the inspiratory gas composition was adjusted automatically by the computer every 5 min or at manually overridden intervals, to minimize the difference between the actual and the target values for PETCO2 and PETO2. The system has been described in detail before (12).
Protocol PB. The phlebotomy associated with this protocol consisted of removing 500 ml of blood from a vein in the antecubital fossa. To determine the degree of hemodilution achieved, two further venous blood samples were taken at 40 min and at 8 h after phlebotomy.
Protocol CO. The CO inhalation associated with this protocol was undertaken by asking the subject to inspire a concentration of 0.4% CO in air through a loose fitting face mask. (For subject 1,136, who was the first subject to undergo this procedure, a concentration of 0.1% CO in air was used, which was found to increase the level of HbCO rather too slowly.) Before the start of CO inhalation, a catheter was inserted into a cephalic vein. During CO inhalation, blood samples of 1-2 ml were taken every 5 min through the catheter to measure %HbCO. The period of CO inhalation lasted 10-30 min, and the inhalation was stopped when %HbCO reached ~10%. After the period of inhalation, blood samples were taken every ~1.5 h to measure %HbCO. "Topping-up" inhalations of CO were performed when %HbCO had declined to ~9%. Generally, this was necessary three to four times during the 8-h period.
Measurement of air-breathing PETCO2 and AHVR. These measurements were made with the subjects seated in an upright position. Values for air-breathing PETCO2 were determined by using a nasal catheter connected to a mass spectrometer. During measurements of AHVR, subjects breathed through a mouthpiece with their nose occluded with a clip. Ventilatory volumes were measured by a turbine volume-measuring device (15) fixed in series with the mouthpiece. Respired gas was sampled continuously and analyzed by mass spectrometry for PCO2 and PO2. A pulse oximeter was attached to the forefinger to monitor the SaO2. Data were recorded on-line by a computer, which also determined PETCO2 and PETO2 from the signals from the mass spectrometer.
The desired end-tidal gas profiles were generated by using an end-tidal forcing system. Before the experiment started, a forcing function was calculated. This consisted of the predicted inspired gas compositions on a second-by-second basis that would be required to produce the desired levels of PETO2 and PETCO2 in the subject. The function was input into a controlling computer, which was used to regulate the gas mixtures breathed by the subject. During the course of the experiment, measured values for PETO2 and PETCO2 were fed to the controlling computer on a breath-by-breath basis from the data-acquisition computer. The deviations of these actual values from the desired values were used to adjust the new inspiratory gas mixtures by using an integral-proportional feedback control scheme. The controlling computer adjusted the inspired partial pressures of N2, O2, and CO2 through a fast gas-mixing system (14). This control scheme has been described in more detail elsewhere (23).Data Analysis
Calculation of CaO2.
In protocol IH, CaO2 (ml/100 ml) was
calculated as
![Ca<SUB>O<SUB>2</SUB></SUB><IT>=1.39·</IT>[Hb]<IT>·</IT><FR><NU><IT>100−%</IT>HbCO<IT>−%</IT>MetHb</NU><DE><IT>100</IT></DE></FR><IT>·</IT><FR><NU>Sa<SUB>O<SUB>2</SUB></SUB></NU><DE><IT>100</IT></DE></FR>](/content/vol90/issue4/fulltext/1189/img001.gif)
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Model fitting.
To quantify AHVR from the data, the responses to the six square waves
of hypoxia were fitted by a single-compartment model (model
3) as described by Clement and Robbins (4). In this model, total E is divided into hypoxia-dependent
(peripheral; p) and hypoxia-independent (central;
c) components. In our assessment of AHVR, isocapnia
was maintained, and so c can be assumed to be
constant. As the hypoxic stimulus varied over time, p needs to be expressed in a time-varying form and
is represented in the model as
![&tgr; <FR><NU>d<A><AC>V</AC><AC>˙</AC></A><SUB>p</SUB></NU><DE>d<IT>t</IT></DE></FR><IT>+</IT><A><AC>V</AC><AC>˙</AC></A><SUB>p</SUB><IT>=</IT>G<SUB>p</SUB>[<IT>100−S</IT>(<IT>t−T</IT><SUB>d</SUB>)]](/content/vol90/issue4/fulltext/1189/img005.gif)
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is a time constant, Td is a
time delay, and S is SaO2 (%) calculated
from PETO2 as described by Severinghaus
(28).
To fit the model to the data, a difference equation was obtained from
the model to describe the model output for the current breath in terms
of the model output for the previous breath, the input function, and
the parameters of the model. These calculations were described in
detail for this model by Clement and Robbins (4).
The parameters of the model, Gp,
c, , and Td, were
estimated by nonlinear regression. This was undertaken by using the Numerical Algorithms Group (Oxford, UK) FORTRAN library routine E04FDF
to minimize the sum of squares of the residuals.
Statistical analysis. ANOVA was used to test for possible differences in the parameters among the four protocols, where protocol and time of measurements were treated as fixed factors and the subject as a random factor. Statistical significance was accepted at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
From the 12 subjects originally recruited for the study, 11 finished all of the experiments. Subject 1,132 felt faint during phlebotomy and subsequently decided to leave the study. Subject 1,138 felt faint at the end of phlebotomy, and his heart rate decreased to 45 beats/min. Atropine (0.6 mg) was administrated intravenously, the subject recovered within minutes, and he then completed the experiment. All other subjects completed all protocols uneventfully.PETO2, SaO2, [Hb], %HbCO, and CaO2 During the Protocols
Table 1 lists the values for PETO2 and SaO2 (obtained via pulse oximetry) for all 11 subjects before and during the 8 h of isocapnic hypoxia associated with protocol IH. The values indicate that PETO2 was well controlled during the 8-h exposure. CaO2 was calculated from SaO2 and the oxygen-carrying capacity of the blood, as determined from the venous blood sample drawn at the start of the experiment. These values are shown in Table 1. During the hypoxic exposure, a 7.5% reduction in CaO2 was generated.
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Table 2 lists the values for [Hb] for
all of the subjects before, 40 min after, and 8 h after the
phlebotomy associated with protocol PB. Although the blood
loss was ~10% of total blood volume, the overall change in [Hb]
after 8 h was only 0.5 g/100 ml. Values for
CaO2 were calculated from the
oxygen-carrying capacity of the blood, as determined from the venous
blood samples, by assuming that air-breathing SaO2
remained constant at the mean value determined by pulse oximetry.
Values for CaO2 are listed in Table 2. Overall, CaO2 had fallen by 4% at 8 h after phlebotomy.
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Table 3 lists the values for %HbCO for
protocol CO. The mean value for %HbCO during the 8-h period
of elevated HbCO was 9.7%, which represented an increase of 7.3% over
the control level of 2.4%. Values for CaO2 were
calculated in the manner described in METHODS and are
listed in Table 3. The mean reduction in CaO2 with CO
exposure was 7.4%.
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Air-Breathing PETCO2 and AHVR
Values for air-breathing PETCO2 before and after each protocol are shown in Table 4. ANOVA revealed that the different protocols had significantly different effects on air-breathing PETCO2 (P < 0.001). Post hoc analysis revealed that the fall in PETCO2 associated with protocol IH was significantly different from the modest rises in PETCO2 observed with the other protocols. The other protocols did not differ significantly one from another.
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The averages for Gp and c across all the
subjects are shown in Fig. 2 for the time
points of t = 0, 40 min, and 8 h for each
protocol. ANOVA revealed that there were significant differences over
time among protocols (P < 0.001). Post hoc analysis
revealed that both Gp and c had
increased significantly after 8 h in protocol IH, but
no significant differences over time were detected for either
protocol PB or protocol CO.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main finding of the present study was that, whereas 8 h
of reduced PaO2 and CaO2 induced
significant elevations in both Gp and
c and a significant decrease in air-breathing
PETCO2, 8 h of
reduced CaO2 with
PaO2 maintained at normal levels did not affect Gp,
c, or air-breathing
PETCO2. This finding
indicates that it is the prolonged reduction of PaO2
that is primarily important in inducing the increase in AHVR in the
early stages of VAH. The associated modest decrease in
CaO2 does not appear to play an important role. We consider that the results from this study provide further support for the notion that the early phases of ventilatory acclimatization to modest hypoxia arise through the effects of hypoxia
at the carotid body rather than within the central nervous system.
Experimental Limitations of the Study
The intention of the study design was to generate the same reduction in CaO2 in each of the three protocols. In protocol IH, the reduction in CaO2 was 7.5%; in protocol PB, the reduction was 4.2%; and in protocol CO, the reduction was 7.4%. Thus protocols IH and CO were well matched in terms of the reduction in CaO2, but this was not the case for protocol PB. In retrospect, a better study design for protocol PB would have been to replace the 500 ml of blood with 500 ml of a plasma expander. The relatively small fall in CaO2 in protocol PB limits the usefulness of these observations. However, our laboratory has recently observed (8) that a very modest reduction in inspired PO2 over an 8-h period, which resulted in a fall in CaO2 of only ~2.7%, can induce acclimatization in terms of a significant increase in Gp andc and fall in air-breathing PETCO2. This finding suggests that
the 4.2% reduction in CaO2 in protocol PB
should have been sufficient to induce acclimatization, if the
acclimatization process had indeed been triggered by a reduction in
CaO2 in the absence of a change in
PETO2.
Other Limitations and Assumptions of the Study
In relation to drawing any conclusions about the site of action of hypoxia in early VAH, it is necessary to make some assumptions on the likely effect of the three intervention protocols on the tissue PO2 of the sites in question. The first assumption is that protocol IH would have had a significant effect on the PO2 at the carotid body but that neither protocol PB nor protocol CO would have done so. In relation to protocol IH, it was clearly the case that the reduction in PETO2 had a substantial acute effect onE. However, Ayres et al.
(1) have reported that, during modest increases in %HbCO
of ~9% in patients, there may also be some reduction in
PaO2. They attributed this to a widening of the
alveolar-arterial PO2 gradient, brought about
by an increase in the effect of shunt within the lungs because of the
reduction of PO2 in venous blood. However,
these effects were only really significant for patients who had
abnormally high alveolar-arterial PO2
gradients; in patients with normal alveolar-arterial
PO2 gradients, the effect was small.
Furthermore, other studies in humans have found that neither 9% HbCO
(11) nor 18-20% HbCO (30)
had any significant effect on E. In
animal studies of CO inhalation, E did not increase
until %HbCO had reached 45-50% (2, 7, 9). In an
animal study of acute anemia, E did not increase until hematocrit had fallen to 50-60% of the original value
(19). In studies of carotid body function in animals,
neither increases in %HbCO that were considerably greater than in the
present study nor decreases in hematocrit that were considerably
greater than in the present study had any significant effect on the
nerve- discharge frequency from the carotid body (10, 17).
A second assumption that we make is that protocols PB and
CO would have induced a reduction in brain tissue
PO2 that would have been quantitatively similar
to that observed with protocol IH. Figure
3 illustrates the calculated fall in
venous PO2 (PvO2) as a
function of the amount of oxygen extracted from the blood for
protocol IH, and for idealized versions of protocols
PB and CO, where the initial reduction in
CaO2 is precisely matched to that of protocol
IH. The horizontal line indicates the PO2
calculated from the Adair equation (25) for a venous
O2 saturation of 60.4%, which is a typical value for
jugular venous blood under control conditions (6). The
vertical lines indicate lower and upper limits for the likely range for
jugular venous O2 content
(CO2). The vertical
line at the lower CO2
was calculated by assuming that there was no increase in cerebral blood
flow, and the vertical line at the higher
CO2 was calculated by assuming that cerebral blood flow increased by 8.7%, as measured for
isocapnic hypoxia with PETO2 of 50 Torr
(20). The calculated fall in PvO2 was
less for protocol PB than for the other two protocols and is
only ~1 Torr below normal. The calculated falls in
PvO2 for protocols IH and
CO were similar and are ~3.5 Torr below normal. The
calculated fall for protocol CO was ~0.5 Torr more marked than for protocol IH. These calculations suggest that, even
if protocol PB had engendered a reduction in
CaO2 equal to that of the other two protocols, it
would not have been as effective in lowering brain
PO2. On the other hand, protocols IH
and CO are likely to have been well matched with respect to
their effect on brain PO2.
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Another issue that is related to protocol CO is that CO
could have some physiological effects other than those associated with
the reduction in CaO2 (16, 21, 22). It
has been shown that exogenous CO at very high partial pressure
(500-550 Torr) stimulated carotid body sensory discharge under
normoxic conditions. A relatively low level of PCO 
140 Torr did not stimulate the chemosensory discharge during normoxia but
inhibited the chemosensory response to hypoxia (16).
Obviously, these levels of PCO are orders of magnitude
greater than those used in protocol CO.
Comparison of Results with Other Longer Term Studies of CO Inhalation and Hemodilution in Animals
There are very few data from animal studies to compare with our results in humans. In ponies, Lowry et al. (18) increased %HbCO to ~25% over a period of ~1 h and then maintained it at this level for a further 5 h. During this period, there was a progressive decrease in arterial PCO2, which was similar to that observed with a 5-h exposure to low PaO2. In goats, progressive hemodilution produced a consistent increase in AHVR after 3 days when [Hb] was reduced from ~10-12 to 6-7 g/100 ml. However, a reduction in [Hb] to 7-8 g/100 ml had little effect (26). In both of these studies, the stimulus employed to obtain a progressive effect of increased %HbCO or hemodilution onE
and/or AHVR was substantially greater than in the present
study. The present study suggests that these effects of %HbCO
and hemodilution do not occur in humans unless a fairly substantial
degree of tissue hypoxia is induced, and, therefore, they are unlikely
to underlie ventilatory acclimatization to mild or moderate hypoxia.
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ACKNOWLEDGEMENTS |
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We thank D. O'Connor for skilled technical assistance.
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FOOTNOTES |
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This study was supported by the Wellcome Trust. X. Ren held an Overseas Research Students Award and was supported by a K. C. Wong Scholarship.
Address for reprint requests and other correspondence: P. A. Robbins, Univ. Laboratory of Physiology, Parks Road, Oxford OX1 3PT, United Kingdom (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.
Received 29 December 1999; accepted in final form 12 October 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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