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J Appl Physiol 90: 1607-1614, 2001;
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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
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

AFTER VENTILATORY ACCLIMATIZATION to hypoxia (VAH), the relationship between minute ventilation (VE) and end-tidal PCO2 (PETCO2) is altered. There is both an increase in the slope of the VE-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 VE-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 VE-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 VE-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 VE-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.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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
<A><AC>V</AC><AC>˙</AC></A><SC>e</SC><IT>=</IT><A><AC>V</AC><AC>˙</AC></A>c<IT>+</IT><A><AC>V</AC><AC>˙</AC></A>p<IT>+</IT>C<IT>t</IT>

&tgr;c <FR><NU>d<A><AC>V</AC><AC>˙</AC></A>c</NU><DE>d<IT>t</IT></DE></FR><IT>+</IT><A><AC>V</AC><AC>˙</AC></A>c<IT>=</IT>Gc[P<SC>et</SC><SUB>CO<SUB>2</SUB></SUB>(<IT>t−</IT>dc)<IT>−</IT>B]

&tgr;p <FR><NU>d<A><AC>V</AC><AC>˙</AC></A>p</NU><DE>d<IT>t</IT></DE></FR><IT>+</IT><A><AC>V</AC><AC>˙</AC></A>p<IT>=</IT>Gp[P<SC>et</SC><SUB>CO<SUB>2</SUB></SUB>(<IT>t−</IT>dp)<IT>−</IT>B]
where VE is the continuous output describing the breath-to-breath ventilation response, Vc and Vp 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 tau  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 VE = 0, extrapolated from the steady-state relationship between VE 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)
x(n+1)=f<IT>x</IT>(<IT>n</IT>)<IT>+</IT>v(<IT>n</IT>)

y(n)=x(<IT>n</IT>)<IT>+</IT>w(<IT>n</IT>)
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 (tau c, dc, tau 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.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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

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 (Delta 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.

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 (diamond ) 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.

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, VE was higher for the data obtained following the hypoxic exposures than for those obtained before the hypoxic exposures; furthermore, this difference in VE 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 VE but that the sensitivity of VE 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 · Torr-1; protocol PH, from 2.22 to 3.00 l · min-1 · Torr-1) compared with the control exposure (protocol C, from 2.59 to 2.46 l · min-1 · Torr-1). 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 · min-1 · Torr-1) and by ~29% after protocol PH (from 1.63 to 2.10 l · min-1 · Torr-1) but was hardly changed (0.5% increase) after protocol C (from 1.57 to 1.65 l · min-1 · Torr-1). 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 · min-1 · Torr-1) and by ~52% after protocol PH (from 0.59 to 0.90 l · min-1 · Torr-1) but decreased by ~20% after protocol C (from 1.02 to 0.81 l · min-1 · Torr-1). 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.

                              
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  		Table 2.   Model parameters for isocapnic hypoxia protocol


                              
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  		Table 3.   Model parameters for poikilocapnic hypoxia protocol


                              
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  		Table 4.   Model parameters for control protocol


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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 VE-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 · min-1 · Torr-1 (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 · min-1 · Torr-1 (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 · min-1 · Torr-1 or 26% of total CO2 sensitivity (combined data from protocols IH and PH). This compares with an increment of 1.0 l · min-1 · Torr-1 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 VE-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 VE-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 · min-1 · Torr-1, protocols IH and PH combined) was greater than for Gp (0.22 l · min-1 · Torr-1, 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.


    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.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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J APPL PHYSIOL 90(4):1607-1614
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