Vol. 90, Issue 4, 1607-1614, April 2001
HIGHLIGHTED TOPICS
Physiological and Genomic Consequences of Intermittent
Hypoxia
Selected Contribution: Chemoreflex responses to
CO2 before and after an 8-h exposure to hypoxia in
humans
Marzieh
Fatemian and
Peter A.
Robbins
University Laboratory of Physiology, University of Oxford, Oxford
OX1 3PT, United Kingdom
 |
ABSTRACT |
The ventilatory
sensitivity to CO2, in hyperoxia, is increased after an 8-h
exposure to hypoxia. The purpose of the present study was to determine
whether this increase arises through an increase in peripheral or
central chemosensitivity. Ten healthy volunteers each underwent 8-h
exposures to 1) isocapnic hypoxia, with end-tidal
PO2 (PETO2) = 55 Torr and end-tidal PCO2
(PETCO2) = eucapnia; 2)
poikilocapnic hypoxia, with PETO2 = 55 Torr and PETCO2 = uncontrolled;
and 3) air-breathing control. The ventilatory response to
CO2 was measured before and after each exposure with the
use of a multifrequency binary sequence with two levels of PETCO2: 1.5 and 10 Torr above the normal
resting value. PETO2 was held at 250 Torr.
The peripheral (Gp) and the central (Gc) sensitivities were calculated
by fitting the ventilatory data to a two-compartment model. There were
increases in combined Gp + Gc (26%, P < 0.05),
Gp (33%, P < 0.01), and Gc (23%, P = not significant) after exposure to hypoxia. There were no significant differences between isocapnic and poikilocapnic hypoxia. We conclude that sustained hypoxia induces a significant increase in
chemosensitivity to CO2 within the peripheral chemoreflex.
peripheral chemoreflex; central chemoreflex; multifrequency binary
sequence; altitude; acclimatization; ventilation
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INTRODUCTION |
AFTER VENTILATORY
ACCLIMATIZATION to hypoxia (VAH), the relationship between minute
ventilation (
E) and end-tidal
PCO2 (PETCO2) is
altered. There is both an increase in the slope of the
E-PETCO2 response and a
leftward shift of the intercept of this relationship with the
PETCO2 axis, and these
features persist when the relationship is determined under conditions
of acute hyperoxia (5, 12, 18, 22, 24). More recently
(10), we have reported that the increase in the slope of
the hyperoxic E-PETCO2
relationship may be detected early in VAH (within the first 8 h of hypoxia).
When measured under conditions of hyperoxia, the slope of the
E-PETCO2 relationship
has generally been associated with the central component of the
chemoreflex response to CO2, as hyperoxia has been assumed
either markedly to attenuate or to abolish the peripheral component of
this response (6, 19). More recently, however, separation
of the peripheral and central components of the chemoreflex response to
CO2 in humans on the basis of the differing dynamics of the
two chemoreflexes has suggested that a peripheral component of the
CO2 response may persist under conditions of hyperoxia
(7, 21). Such a result is in keeping with the results of
more direct experimentation in the anesthetized cat (2, 11,
16). These findings led us to question whether the increase in
the hyperoxic E-PETCO2
response slope following VAH has its origins in a change in sensitivity
of the central chemoreflex or whether this increase in slope arises
through an increase in peripheral chemoreflex sensitivity to
CO2 that persists under hyperoxic conditions. Therefore,
the purpose of the present study was to examine the hyperoxic
E-PETCO2 response
relation before and after an 8-h exposure to hypoxia using a dynamic
approach to separate the peripheral (fast) and central (slow)
chemoreflex contributions to the overall ventilatory sensitivity to
CO2.
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METHODS |
Subjects.
Ten healthy volunteers (7 men and 3 women) between 18 and 52 yr old
took part in the study. The experiment was fully explained verbally and
in written form to all participants. Informed consent was obtained from
each subject before each experiment. The study had approval from the
Central Oxford Research Ethics Committee.
Protocols.
All the subjects made short visits to the laboratory before the main
experiments. During these visits, they were familiarized with the
apparatus and initial measurements of their
PETCO2 were taken. The main experiments
were carried out in random order on 3 separate days at least 1 wk
apart. Female subjects were always studied at the same phase of their
menstrual cycle.
The subjects were told to have a good night's rest before each of the
three main experiments, to have a light breakfast, and to come to the
laboratory at a leisurely pace. After arrival, they were rested for at
least 15 min before any experimental work was started. Preexposure
measurements were then made, which lasted ~40 min. After this, the
subjects entered a chamber in which the gas composition could be
varied. The nature of the exposure in the chamber differed on the three
different experimental days. The chamber exposure lasted for 8 h.
The subjects were given a light lunch at ~1:00 PM. If the subjects
needed to urinate, they were free to leave the chamber briefly for that
purpose. Otherwise, they remained in the chamber for the full 8 h.
After the 8-h exposure, the subjects left the chamber and breathed room
air for 30 min. A second 40-min measurement period then followed.
Three different 8-h exposures were employed for each subject while in
the chamber: 1) isocapnic hypoxia (IH), 2)
poikilocapnic hypoxia (PH), and 3) control (C). During the
exposure associated with protocol IH, end-tidal
PO2
(PETO2) was held at 55 Torr and PETCO2 was held at the subject's
normal (prehypoxic) value. During the exposure associated with protocol
PH, PETO2 was held at 55 Torr and PETCO2 was not controlled. During
the exposure associated with protocol C, the subject was exposed to air
while in the chamber.
Air-breathing PETCO2 was determined in the
measurement periods before and 30 min after each 8-h exposure. These
measurements were taken using a nasal catheter connected to a mass
spectrometer while the subject was sitting upright and breathing
normally. To obtain good control values for normal
PETCO2, subjects were encouraged to watch
television or read during these measurements. The first measurement of
PETCO2 was used as the
control value for the subsequent tests undertaken on that day.
After the measurements of air-breathing
PETCO2 had been made, the
ventilatory response to a dynamic variation in
PETCO2 was determined in a protocol
lasting ~29 min. In this protocol, PETO2 was held at 250 Torr throughout. PETCO2
was held constant at 1.5-2.0 Torr above its normal value for the
first 5 min to ensure that ventilation reached an approximate steady
state. Next, PETCO2 was varied according
to a multifrequency binary sequence (MFBS), which lasted 1,408 s (23 min and 28 s). During this sequence, PETCO2 was switched between 1.5 and 10 Torr above the subject's normal value. The particular MFBS used was
the Van den Bos octave (see Ref. 13) with a pulse duration
of 11 s. The choice of MFBS together with the pulse duration was
based on an optimization process for maximum separation between the
fast (peripheral) and slow (central) components of the ventilatory
response to CO2 (21).
Technique.
A purpose-built chamber was used during the 8-h exposures. The chamber
had ample room, both for the subject to sit in and to move around
comfortably. The composition of gas inside the chamber could be
altered, which obviated the need for the subject to breathe via a face
mask or mouthpiece. Fine nasal catheters were held at the opening of
each of the subject's nostrils by a nasal oxygen-therapy mask. The
respired gas was sampled (80 ml/min) via these catheters and analyzed
for PO2 and PCO2 by a mass spectrometer. The subject also wore a pulse oximeter on a finger
to monitor arterial O2 saturation. The values for
PO2, PCO2, and
saturation were sampled by a computer every 20 ms. The computer program
identified the ends of inspiration and expiration from the
PCO2 profile and recorded the inspired and
end-tidal values for PO2 and
PCO2 together with saturation at the end of each breath. Before the subject entered the chamber, the composition of
the inspired gas necessary to produce the desired end-tidal partial
pressures was estimated and set manually. During the exposure, the
composition of the inspired gas was altered by a computer every 5 min
to maintain the end-tidal partial pressures at the desired level.
Manual alteration at other intervals was also possible. This system has
been described in greater detail elsewhere (14).
During the measurement periods before and 30 min after the chamber
exposures, the ventilatory response to the MFBS in
PETCO2 was determined
with the subject seated in an upright position and breathing through a
mouthpiece, with his or her nose occluded by a clip. A turbine
volume-measuring device fixed in series with the mouthpiece measured
the respiratory volumes; a pneumotachograph was used to record flows
and timing information. The total dead space associated with the
apparatus was 100 ml. Gas was sampled (20 ml/min) from this dead space,
close to the mouth, and analyzed by mass spectrometry for
PO2 and PCO2. A pulse
oximeter was attached to the forefinger to monitor the O2
saturation of the blood. All the data were sampled by a
data-acquisition computer every 20 ms, and
PETCO2,
PETO2, and inspiratory and expiratory
volumes and durations for each breath were recorded.
An end-tidal forcing system was used to generate the MFBS in
PETCO2 and concurrently control the
PETO2. Before the experiment, a "forcing
function" containing the predicted inspired gas values required to
achieve the desired PETO2 and
PETCO2 was entered into a second
(controlling) computer. During the experiment, actual values of
PETO2 and
PETCO2 were passed, breath-by-breath, to
the controlling computer from the data-acquisition computer. The actual end-tidal values were compared with the desired values, and a new
inspired gas mixture was calculated, by a computer program, using an
integral-proportional feedback scheme. The controlling computer
generated the new inspired gas mixture using a fast gas-mixing system,
which was controlled from the program. This system has been described
in more detail elsewhere (15, 23).
Data analysis.
The fast (peripheral) and the slow (central) components of the
ventilatory response to CO2 were identified by fitting a
two-compartment model (25) to the ventilatory data
where E is the continuous output describing
the breath-to-breath ventilation response, c and p are
the slow (central) and fast (peripheral) components of this response,
respectively, and C is a trend term. G represents the sensitivity for
the chemoreflex loops,
PETCO2(t 
d) is the stimulus to the chemoreflex loops at time (t)
delayed by d, and 
represents the time constant. The indexes c and p
denote the parameters associated with the slow (central) and fast
(peripheral) chemoreflex loops, respectively. B is the value for
PETCO2 at
E = 0, extrapolated from the steady-state relationship between E and
PETCO2.
If PETCO2 is assumed to remain constant
over a single breath, a solution to these differential equations can be
obtained as a set of difference equations. These relate the peripheral
and central chemoreflex outputs for the current breath to the
PETCO2, the breath duration, and the
peripheral and central chemoreflex outputs for the previous breath.
To model the stochastic component of the data, a state-space model was
used that has previously been shown to describe the correlation that
exists between successive breaths (17)
where x(n) is the system state for
breath n, y(n) is the observation at
breath n, and f is the system gain; v(n)
and w(n) are mutually independent, white noise
sequences, representing the process and the measurement noise,
respectively, with means of zero and a constant variance ratio of
Rv/Rw. If f, Rv, and Rw are known, the system state (and variance) for
breath n + 1 can be predicted from the measurement
y(n) through a Kalman filter (1) and
updated once y(n + 1) becomes known. The Kalman
filter equations for the particular model that was employed are given by Liang et al. (17).
The parameters of the model were obtained by using a standard
subroutine to minimize the sum of squares of the residuals (subroutine E04FDF, Numerical Algorithms Group, Oxford, UK). To detect any statistically significant changes after the 8-h exposures, the estimated values of all the parameters of the model were compared using
ANOVA. Fixed factors in the analysis were protocol and time (i.e.,
before vs. after the exposure), and subjects were treated as a random
factor. Because the variations in the dynamic parameters (c, dc,
p, and dp) and Kalman filter parameters (f and Rv/Rw) were
negligible between the different fixed factors in the ANOVA, the model
was refit to the data with a constraint that there should be a common
estimate for these parameters for each pair of data sets that were
obtained before and after the 8-h exposure. This method of fitting the
model to the data reduced the variances associated with the remaining
parameters. ANOVA was then performed on Gc, Gp, B, and C. The
statistical package SPSS was used for these analyses.
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RESULTS |
Subjects.
All subjects completed the series of experiments and provided data that
were suitable for analysis. During the 8-h exposures, subjects were
generally comfortable and spent their time reading, watching
television, or playing computer games. Some subjects reported mild
headaches toward the end of some of the exposures, and one subject had
a more severe headache for all exposures. Control values for
PETCO2 for each subject
for each protocol are given in Table
1.
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Table 1.
Air-breathing PETCO2 before and after
chamber exposure and PETCO2 in chamber at
beginning and end of exposure
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Chamber control.
Figure 1 shows the end-tidal gases
recorded while the subjects were in the chamber, averaged every 5 min,
for all three protocols for all 10 subjects. Initial and final values
of PETCO2 in the chamber are given in
Table 1. Generally, the control over the end-tidal gases was good.
PETO2 for protocols IH and PH and
PETCO2 for protocol IH
were maintained at the desired levels throughout the 8-h exposure. In
protocol PH, in which PETCO2 was
unregulated, there was a progressive fall in
PETCO2 over the 8-h period of hypoxia
(P < 0001, paired t-test). Average values
for saturation obtained from the pulse oximeter at the beginning and
end of the chamber exposure were 90.5 ± 3.0% (mean ± SD)
and 89.8 ± 1.0% for protocol IH, 89.2 ± 1.6% and
89.2 ± 1.4% for protocol PH, and 97.6 ± 1.1% and
97.8 ± 0.6% for protocol C, respectively.
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Fig. 1.
Control of end-tidal gases in
chamber. Deviation of end-tidal PCO2
(PETCO2) from the prechamber control value
( PETCO2;
top) and PETCO2
(middle) and end-tidal PO2
(PETO2; bottom) values averaged
every 5 min from data collected breath-by-breath over 8 h for all
10 subjects during isocapnic hypoxia (IH; left),
poikilocapnic hypoxia (PH; middle), and control (C;
right) protocols.
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Air-breathing PETCO2.
Values for air-breathing PETCO2 30 min
after the end of the chamber exposures are given along with the
control values in Table 1.
PETCO2 fell after the
completion of protocol IH by 3.3 Torr, fell after protocol PH by 3.6 Torr, but was unaltered after protocol C (rise of 0.1 Torr). ANOVA
revealed that the fall in PETCO2
associated with the hypoxic protocols was significantly different from
protocol C (P < 0.001) but that any difference between
protocol IH and protocol PH was not significant.
Ventilatory response to MFBS in
PETCO2.
An example of the MFBS in PETCO2 is shown
in Fig. 2, top. In general,
the sequence was produced well by dynamic end-tidal forcing. Average
sequences for all 10 subjects for one protocol (both before and after
the chamber exposure) are shown in Fig. 3, top. Only slight
differences between the sequences before and after the chamber exposure
were observed. PETO2 was well controlled at 250 Torr (Fig. 2).
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Fig. 2.
Example of data and model fit
before (AM, left) and after (PM, right) an 8-h
exposure for 1 subject. From top to bottom:
multifrequency binary sequence (MFBS) in
PETCO2,
PETO2, model fit without noise model, and
model fit with noise model. In the bottom 2 panels, dots
represent ventilation data, and lines represent the model output;
residuals are shown below each fit.
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Fig. 3.
Average data and model fits for all 10 subjects.
Top: MFBS in PETCO2 before
( ) and after ( ) the 8-h exposure. The
other 3 panels show ventilation data and model fits for protocol IH
(2nd panel), protocol PH (3rd panel), and protocol C
(bottom) before (AM) and after (PM) the 8-h exposure. Dots
represent the ventilation data, and lines represent the model output.
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An example of the ventilatory response to the MFBS in
PETCO2 together with an example of the fit
of the model to the data is shown in Fig. 2. The fit of the model to
data is illustrated both including and excluding the stochastic
component of the model that was obtained as part of the overall fitting
process. Residuals calculated using just the deterministic component of
the model were clearly nonwhite, but they appeared to become white when the stochastic component of the model was included. Ensemble averages, obtained by first interpolating data and model output every second, are
shown in Fig. 3. During the MFBS, E was higher for
the data obtained following the hypoxic exposures than for those
obtained before the hypoxic exposures; furthermore, this difference in E appeared greater in those sections of the MFBS
that were associated with higher levels of ventilation. This suggests
that the change was not just an upward displacement of
E but that the sensitivity of E
to CO2 had also increased. No differences in the response to the MFBS were apparent in the data obtained before and after exposure in the control protocol.
Individual and mean parameter values for the model fits are given in
Tables
2-4
for the three protocols. There was a significant increase (ANOVA,
P < 0.01) in the total ventilatory sensitivity to
CO2 (Gp + Gc) following the hypoxic exposures
(protocol IH, from 2.24 to 2.63 l · min
1 · Torr1; protocol
PH, from 2.22 to 3.00 l · min1 · Torr1)
compared with the control exposure (protocol C, from 2.59 to 2.46 l · min1 · Torr1). The
chemoreflex sensitivity of the slow (central) component of the
ventilatory response to CO2, Gc, increased by ~17% after protocol IH (from 1.51 to 1.77 l · min1 · Torr1) and by
~29% after protocol PH (from 1.63 to 2.10 l · min1 · Torr1) but
was hardly changed (0.5% increase) after protocol C (from 1.57 to 1.65 l · min1 · Torr1).
However, this increase in Gc following the two types of hypoxic exposure did not reach statistical significance. The chemoreflex sensitivity of the fast (peripheral) component of the ventilatory response to CO2, Gp, increased by ~18% after protocol IH
(from 0.73 to 0.86 l · min1 · Torr1) and by
~52% after protocol PH (from 0.59 to 0.90 l · min1 · Torr1) but
decreased by ~20% after protocol C (from 1.02 to 0.81 l · min1 · Torr1). This
difference between the hypoxic protocols and control was significant
(ANOVA, P < 0.005). No statistically significant
effects were detected for parameters B or C of the model.
| |
DISCUSSION |
General findings.
The results from this study confirm those of our previous report
(10) that there is a significant rise in ventilatory
sensitivity to CO2, in hyperoxia, following an 8-h exposure
to hypoxia. The results suggest that there may have been a rise in both
slow (central) and fast (peripheral) chemoreflex sensitivity. However,
in this study, only the results for the fast component (Gp) reached
significance. The statistically insignificant change in B suggests that
the intercept of the
E-PETCO2 relationship
is not affected early in the acclimatization process, a result that is
in keeping with our previous report.
Relationship between fast and slow components of CO2
response and peripheral and central chemoreflex sensitivities.
A fundamental assumption of this study is that the fast component of
the CO2 response reflects that part of the chemoreflex response arising from the peripheral chemoreceptors and that the slow
component of the CO2 response reflects that part of the
response arising from the central chemoreceptors. This issue has been
discussed in detail elsewhere (21). In brief, in
experimental animals, the fast and slow components of the
CO2 response have been shown to correlate well with
sensitivities obtained subsequently with an artificial brain stem
perfusion technique (8). Step changes in the arterial
PCO2 of blood perfusing just the brain stem
produce a single, slow component within the ventilatory response
(4). In humans who have undergone bilateral carotid body
resection, the fast component of the ventilatory response to
CO2 is very small (3).
Comparison with previous studies.
The total combined ventilatory sensitivity to CO2 in this
study was 2.35 l · min1 · Torr1 (combined
preexposure values from all three protocols). This is similar to values
obtained from previous studies under hyperoxic conditions from our
laboratory of 2.75 (21) and 2.35 l · min1 · Torr1
(10) (combined preexposure values). In the present study,
the fast component of the CO2 response accounted for 33%
of the total CO2 response (combined preexposure values from
all three protocols). This is broadly similar to the 27% determined in
a previous study using MFBS (21) but substantially greater
than the 13% that was obtained with PETO2
>500 Torr (7).
The increment in total CO2 sensitivity after the 8-h
exposure to hypoxia in the present study was 0.59 l · min1 · Torr1 or
26% of total CO2 sensitivity (combined data from protocols IH and PH). This compares with an increment of 1.0 l · min1 · Torr1 or 43% of
total CO2 sensitivity in a previous study of the effects of
8 h of hypoxia (10) and an increment of ~44% of
total CO2 sensitivity in a previous study of the effects of
48 h of hypoxia (26). Longer studies involving
acclimatization to the hypoxia of altitude have recorded increments
of ~47% (4 days at 3,100 m; Ref. 12), ~128% (6 days at 3,810 m; Ref. 24), and ~115% (45 days at
3,100 m; Ref. 12).
Mechanisms underlying the changes in the acute ventilatory
sensitivity to CO2.
The finding of a significant rise in the peripheral chemoreflex
sensitivity to CO2 following sustained hypoxia does not on its own help to localize the effect of hypoxia, as this may be anywhere
in the peripheral chemoreflex loop. However, in experimental studies
conducted on goats, it was possible to localize the site of action of
hypoxia to the carotid bodies. Dwinell et al. (9) found
that sustained exposure of a single carotid body to hypoxia altered the
E-PETCO2 relationship.
In contrast, Weizhen et al. (27), who rendered the central
nervous system hypoxic while maintaining a normal
PO2 at the peripheral chemoreceptors, found that hypoxia had no effect on the
E-PETCO2 relationship.
The absence of a significant effect of sustained hypoxia on central
chemoreflex sensitivity in the present study should be treated with
some caution because the absolute magnitude of the increase in Gc (0.37 l · min1 · Torr1, protocols
IH and PH combined) was greater than for Gp (0.22 l · min1 · Torr1, protocols
IH and PH combined). This raises the possibility that a type II
statistical error has occurred. In general, the increase in overall
ventilatory sensitivity to CO2 was not as great as that
observed in other studies (see above), and it may be that a repeat of
this study on more completely acclimatized individuals would clarify
this point. If there is an increase in central chemoreflex sensitivity,
then an interesting question that arises is whether this is due to
central nervous system hypoxia or whether it is due to increased
peripheral stimulation slowly increasing central chemoreflex
sensitivity. In relation to the latter, it is noteworthy that Pan et
al. (20) have reported that removal of peripheral chemoreceptor input has a slow effect in reducing the sensitivity of
the central chemoreflex response to CO2.
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ACKNOWLEDGEMENTS |
We thank David O'Conor for skilled technical assistance.
| |
FOOTNOTES |
This study was funded by the Wellcome Trust.
Address for reprint requests and other correspondence: P. A. Robbins, Univ. Laboratory of Physiology, Parks Road, 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.
Received 12 September 2000; accepted in final form 1 December 2000.
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J APPL PHYSIOL 90(4):1607-1614
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ABSTRACT
INTRODUCTION
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