J Appl Physiol 98: 1587-1591, 2005.
First published December 10, 2004; doi:10.1152/japplphysiol.01019.2004
8750-7587/05 $8.00
Ventilatory acclimatization in response to very small changes in PO2 in humans
Simon Donoghue,
Marzieh Fatemian,
George M. Balanos,
Alexi Crosby,
Chun Liu,
David O'Connor,
Nick P. Talbot, and
Peter A. Robbins
University Laboratory of Physiology, University of Oxford, Oxford, United Kingdom
Submitted 10 September 2004
; accepted in final form 8 December 2004
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ABSTRACT
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Ventilatory acclimatization to hypoxia (VAH) consists of a progressive increase in ventilation and decrease in end-tidal PCO2 (PETCO2). Underlying VAH, there are also increases in the acute ventilatory sensitivities to hypoxia and hypercapnia. To investigate whether these changes could be induced with very mild alterations in end-tidal PO2 (PETO2), two 5-day exposures were compared: 1) mild hypoxia, with PETO2 held at 10 Torr below the subject's normal value; and 2) mild hyperoxia, with PETO2 held at 10 Torr above the subject's normal value. During both exposures, PETCO2 was uncontrolled. For each exposure, the entire protocol required measurements on 13 consecutive mornings: 3 mornings before the hypoxic or hyperoxic exposure, 5 mornings during the exposure, and 5 mornings postexposure. After the subjects breathed room air for at least 30 min, measurements were made of PETCO2, PETO2, and the acute ventilatory sensitivities to hypoxia and hypercapnia. Ten subjects completed both protocols. There was a significant increase in the acute ventilatory sensitivity to hypoxia (Gp) after exposure to mild hypoxia, and a significant decrease in Gp after exposure to mild hyperoxia (P < 0.05, repeated-measures ANOVA). No other variables were affected by mild hypoxia or hyperoxia. The results, when combined with those from other studies, suggest that Gp varies linearly with PETO2, with a sensitivity of 3.5%/Torr (SE 1.0). This sensitivity is sufficient to suggest that Gp is continuously varying in response to normal physiological fluctuations in PETO2. We conclude that at least some of the mechanisms underlying VAH may have a physiological role at sea level.
acclimatization to hypoxia; respiratory control; chemoreflexes; acute ventilatory response to hypoxia
VENTILATORY ACCLIMATIZATION to hypoxia involves a progressive rise in ventilation (
E) that in turn leads to a progressive rise in end-tidal PO2 (PETO2) and fall in end-tidal PCO2 (PETCO2). These changes begin within hours of the onset of hypoxia and take days or weeks to proceed to completion. Associated with ventilatory acclimatization to hypoxia, there are underlying rises in the acute ventilatory chemoreflex sensitivities to hypoxia (11, 20, 24) and hypercapnia (3, 14, 24). More recently, it has been shown that some of these changes can be detected with very modest levels of hypoxia, such as occur in an aircraft cabin (8), and furthermore that the converse of some of these changes can be detected after a period of moderate hyperoxia (17). These two findings raise the intriguing possibility that the mechanisms that underlie ventilatory acclimatization to altitude may have the sensitivity to be continuously "tuning" the respiratory control system in response to fluctuations in blood gas tension in normal life, rather than being responsive solely to gross changes in PO2 such as occur with exposure to high altitude.
To explore this possibility further, we sought to determine whether any of the changes associated with ventilatory acclimatization to hypoxia could be detected in response to a very small reduction in PETO2 of 10 Torr and furthermore whether the converse changes could be detected in response to a very small increase in PETO2 of 10 Torr.
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METHODS
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Subjects.
Ten healthy subjects (8 men, 2 women) were studied. All were nonsmokers and had no history of cardiovascular or respiratory disease. The two female subjects were both using a combined oral contraceptive, and experiments were time tabled so that any influence of this was constant throughout. The study was explained to the subjects both verbally and in writing, although the technical and physiological content was limited to ensure that they remained naive as to its exact purpose. Subjects were familiarized with the equipment before the experiment, and their natural values for PETCO2 and PETO2 were determined as part of this process. The study had the approval of the Central Oxfordshire Research Ethics Committee.
Protocols.
Each subject undertook two protocols. The two protocols were identical to each other except for the PO2 to which the subjects were exposed over a 5-day period of residence inside a purpose-built chamber within the laboratory. For one protocol (protocol A), the subjects' PETO2 was reduced to 10 Torr below their natural air-breathing value during the 5 days of chamber residence. For the other protocol (protocol B), the subjects' PETO2 was elevated by 10 Torr above their natural air-breathing value during the 5 days of chamber residence. The two chamber exposures for each subject were always separated from one another by a minimum period of 1 wk. Five subjects undertook protocol A before protocol B, and five subjects undertook protocol B before protocol A. The allocation of subjects to one or other order was determined by lot.
Each of the two protocols lasted a total of 13 days, with measurements being made on each morning. For the first two mornings (days –2 and –1), a control set of measurements was made, and the subject then returned home. On the third morning (day 1), a further set of control measurements was made before the subject entered the chamber. The subject then remained in the chamber for 5 days and nights, only leaving the chamber to visit the bathroom or to allow us to make our daily measurements. This time outside the chamber totaled 
1.5 h/day. The period of exposure to mild hypoxia or hyperoxia in the chamber ended on the morning of day 6. After the daily measurements had been made on the morning of day 6, the subject was allowed to go home. The subject then attended the laboratory in the morning for 5 days of follow-up measurements (days 7–11).
On the days when the subjects arrived in the laboratory from home (days –2 to 1 and 7 to 11), they rested in the laboratory for 60 min before any measurements being made. PETCO2 and PETO2 were then measured for a period of 10 min by using a fine nasal catheter connected to a Datex Normocap O2 and CO2 analyzer. This was connected to a personal computer running a program to detect and store end-tidal gas tensions in real time. An arterialized capillary blood sample was then taken from the earlobe. The blood samples were analyzed for PCO2, PO2, pH, and HCO3– concentration (these variables are subsequently notated with the modifier "ac" to indicate when the values have been obtained from arterialized capillary blood). The acute hypoxic ventilatory response (AHVR) was then assessed, and this was followed, after a 10-min break, by an assessment of the acute hypercapnic ventilatory response (AHCVR).
On mornings when the subject had spent the previous night in the chamber (days 2–6), PETCO2 and PETO2 were first measured for a period of 10 min within the chamber. With the subject still in the chamber, the arterialized capillary blood samples were taken. Once these measurements had been completed, the subject left the chamber and was allowed to breathe room air for 20 min. After this, a further measurement of PETCO2 and PETO2 was made, this time while the subject was breathing air. After these measurements, the subject's AHVR and AHCVR were assessed. Once these measurements were complete, the subject returned to the chamber except on day 6, when he or she was then allowed home.
Chamber exposure.
The hypoxic and hyperoxic exposures were conducted in a purpose-built chamber, which was large enough to allow subjects to sit or stand comfortably during the day and to sleep in a bed at night. It was equipped with a television, video, and laptop with an internet connection to entertain the subjects. Subjects were studied individually in the chamber so that the inspired gas composition could be tailored accurately to maintain their end-tidal gas composition at the predetermined level. Respired gas was sampled continuously via a fine nasal catheter at the opening of the subject's nostril and analyzed for PCO2 and PO2. Arterial O2 saturation was monitored by using a pulse oximeter. The desired value for PETO2 was entered into a computer running a program to regulate the composition of the gas within the chamber. The computer automatically adjusted the composition of the gas in the chamber every 5 min, or at manually overridden intervals, to minimize the error between desired and actual values for the end-tidal gases. This system has been described in detail elsewhere (10). Although the chamber is capable of regulating PETCO2 in addition to PETO2, this was left uncontrolled. During their time in the chamber, the subject was kept under continuous observation, and an environmental O2 monitor was employed within the chamber as a further safety precaution.
Measurements of AHVR and AHCVR.
During these measurements, the subject sat in a chair and was distracted by watching television. The subject breathed through a mouthpiece with his or her nose occluded by a clip. Respiratory volumes were measured by using a bidirectional turbine volume-measuring device (12), and respiratory phase transitions were detected by using a pneumotachograph. Respired gas was sampled via a fine catheter close to the mouth and analyzed continuously for PCO2 and PO2 by mass spectrometry. Inspired and expired volumes, end-inspiratory and end-expiratory gas tensions, and saturation were determined in real time by a computer.
A dynamic end-tidal forcing system was used to maintain the end-tidal gases at predetermined levels. A mathematical model was used to generate a file that contained the breath-by-breath predictions for the inspired PCO2 and PO2 necessary to produce the desired end-tidal sequences. During the experiment, a computer-controlled gas-mixing system was used to produce this sequence in a modified manner. The modifications resulted from feedback control based on the deviations of the measured PETCO2 and PETO2 from the desired values. For the measurement of AHVR, PETCO2 was held constant throughout the protocol at 1–2 Torr above the subject's natural air-breathing value. For the first 5 min of the protocol, PETO2 was held constant at 100 Torr. After this, PETO2 was altered to produce a series of six square waves, each 120 s long, with PETO2 alternating between 100 Torr for 60 s and 50 Torr for 60 s. For the measurement of AHCVR, PETO2 was held at 100 Torr throughout. For the first 5 min, PETCO2 was held at 2 Torr above the subject's air-breathing PETCO2. After this, PETCO2 was varied dynamically according to a multifrequency binary sequence known as the Van den Bos Octave (9, 15). PETCO2 was switched repeatedly between a low value of +2 Torr above and a high value of +10 Torr above the subject's air-breathing PETCO2. Overall, the sequence lasted for a period of 1,408 s.
Modeling of the hypoxic and hypercapnic ventilatory responses.
To quantify the ventilatory responses to acute variations in hypoxia and hypercapnia, dynamic models relating E to the end-tidal gas profiles were fitted to the data. For the measurements of AHVR, model 3 of Clement and Robbins (4) was employed. This is a single-compartment model in which the parameter 
reflects the ventilatory sensitivity to hypoxia, and the parameter c reflects residual E in the absence of hypoxia. For the measurements of AHCVR, model 2 of Pedersen et al. (15) was used. This is a two-compartment model in which the individual compartments describe separate peripheral and central chemoreflex contributions to E. In this model, the parameter 
reflects the ventilatory sensitivity of the peripheral chemoreflex to CO2, and parameter Gc reflects the sensitivity of the central chemoreflex to CO2. The parameter B is the calculated PETCO2 for which E = 0 l/min. Both models were fit in conjunction with a stochastic model based on a Kalman filter to describe the correlation that is present between successive breaths (13).
Statistical analysis.
Repeated-measures ANOVA was used as the principal method for assessing the statistical significance of the observations made in this study. The three baseline measurements before the chamber exposure, the measurements from the last 3 days of the chamber exposure and the measurements from the final 3 days of the follow-up period were included in the ANOVA to assess whether the changes over time were different for the hypoxic and hyperoxic protocols. The SPSS statistical package was used for all statistical analysis. Statistical significance was assumed at P < 0.05.
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RESULTS
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Subjects.
The average age for the subjects was 24.1 yr (SD 4.5). Their average height was 177 cm (SD 9.5), and average weight was 76.4 kg (SD 9.4). Their mean resting values for PETCO2 and PETO2 were 37.2 Torr (SD 1.7) and 105.4 Torr (SD 2.2), respectively.
Control over PO2 of subjects within the chamber.
Figure 1 shows the daily measurements of PcO2 made within the chamber together with the associated averages for PETO2. Also shown are the daily measurements of PacO2 and PETO2 made before and after the chamber exposure. The figure shows that the experiment has been successful in generating the 10-Torr decrease (protocol A) or increase (protocol B) in PETO2 and that this has been reflected in the values for PacO2. There was a relatively consistent small difference between the values for PETO2 and PacO2 of 7.4 Torr (SD 6.3), in keeping with previous experience (5).
Effects of altered PO2 on blood-gas and end-tidal values.
Figure 2 shows the arterialized capillary blood-gas data relating to CO2 together with the associated averages for PETCO2. On days 2–6, the samples were taken from the subjects while they were inside the chamber. On the other days, samples were taken from the subjects while they were outside the chamber breathing air. The plots suggest that there may have been some increase in PacCO2 during the exposure to the mild hyperoxia of protocol B. However, this result was not statistically significant, nor was there a comparable change in the associated values for PETCO2.
Figure 3 shows the values for PETCO2 and PETO2 for the subjects that were obtained on each day after they had been removed from the chamber and allowed to breathe room air for 20 min. Also shown are the air-breathing data for the measurements made before and after the chamber exposure. In keeping with the measurements made inside the chamber, values for PETCO2 did not differ between protocols. Values for PETO2 appeared to be slightly higher on the chamber days (days 2–6) than on the days before and after chamber exposure. This result was statistically significant, but the effect did not differ between protocol A and protocol B.
Effect of altered PO2 on AHVR.
Figure 4 shows the average parameter values obtained from the measurement made of AHVR on each day of the protocol. For protocol A, Gp
promptly rose on the first day of exposure to mild hypoxia in the chamber and promptly fell again on the first day of returning to air breathing at the end of the chamber exposure. For protocol B, the pattern was reversed, with Gp falling on the first day of exposure to mild hyperoxia in the chamber and Gp rising on the first day of returning to air breathing at the end of the hyperoxic exposure. During the chamber exposures, the average value for Gp for protocol A was always above that for protocol B. This was never the case before or after the chamber exposures. Overall, the effect of chamber exposure on Gp differed significantly between protocol A and protocol B (P < 0.05, repeated-measures ANOVA). No comparable pattern was discernible in the values for parameter c.
Although not quite statistically significant, a noticeable feature of Fig. 4 is that the control values for Gp obtained before the chamber exposure did not match well between the two protocols. Analysis of the individual subject data revealed one subject for whom this was particularly noteworthy and for whom the difference between these values for the two protocols was significantly different compared with the other subjects (P < 0.05, after correction for multiple comparisons). Figure 5 shows the mean parameter values after the data obtained from this subject had been removed. First, it is clear that some difference between the control values before the chamber exposure still remains. However, this is now noticeably smaller than the difference that is present during the chamber period. Furthermore, the postexposure values for Gp (which form a second control period) match closely. When the analysis was restricted to these nine subjects, the level of statistical significance associated with the different effects of the chamber exposures between the two protocols rose to P < 0.002 (repeated-measures ANOVA).
Effect of altered PO2 on AHCVR.
Figure 6 shows the average parameter values obtained from the measurement made of AHCVR on each day of the protocol. There was no discernible effect of either protocol A or protocol B on any of these parameter values.
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DISCUSSION
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The small changes in PETO2 that were generated in this study did not generate or relieve a detectable degree of ventilatory acclimatization to hypoxia as judged by a significant change in PETCO2, nor did they generate any change in the acute ventilatory sensitivity to hypercapnia, which normally would occur as part of the acclimatization process. However, the small changes in PETO2 did generate quite marked changes in the acute ventilatory sensitivity to hypoxia, with the reduction in PETO2 generating an increase in Gp and the increase in PETO2 generating a decrease in Gp.
Comparison with other studies.
Figure 7 illustrates the percent change in Gp obtained from a number of studies from our laboratory in Oxford (8, 11, 17, 22) plotted against the PETO2 of the exposure (with 100 Torr taken as the normal air-breathing value). For some studies, the actual change in Gp has had to be extrapolated so that all points relate to an exposure of 48-h duration. With the exception of the exposure to moderate hyperoxia, the percent changes in Gp relate reasonably linearly to the actual variations in PETO2. This is in contrast to the acute effects of hypoxia on ventilation where the relationship between E and PETO2 is curvilinear. (Although the effects of acute hypoxia are mediated through changes in arterial PO2 and not saturation, the size of the effect nevertheless tends to be linearly related to the degree of desaturation of arterial blood rather than to the fall in PO2.)
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Fig. 7. Percent change in Gp from control (100%) at several different levels of conditioning PETO2 calculated from a number of studies (8, 11, 17, 22) undertaken with the chamber in Oxford, including the present one. Data have been extrapolated for studies (8, 11, 17) to provide a common duration exposure to hypoxia of 48 h. Regression line has been fitted to all data except for (17). Slope of the regression line is 3.5%/Torr (SE 1.0).
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Relationship to ventilatory acclimatization to altitude.
Over the past two decades, considerable evidence has accumulated to suggest that ventilatory acclimatization to hypoxia, at least during the early stages, is driven to a large degree by a specific effect of sustained hypoxia at the carotid body (for reviews, see Refs. 1, 2). However, in addition to this, there is also evidence that ventilatory acclimatization to hypoxia may arise in part through alterations within the central nervous system that affect the peripheral chemoreflex sensitivity to hypoxia (6), and there may also be effects arising through "hyperventilation-induced hyperpnea" (7, 18, 21). In the present study, the alterations in PO2 clearly affected the sensitivity of the peripheral chemoreflex but failed to affect either E or air-breathing PETO2 or PETCO2, despite the fact that changes in these variables form the cardinal feature of ventilatory acclimatization to hypoxia. One possible explanation for our observations is that, for the progressive increase in Gp to feed through into changes in E and consequently PETO2 and PETCO2, a significant degree of peripheral chemoreceptor stimulation is required, and this simply would not have occurred in relation to the very modest changes in PO2 of the present study. A similar explanation can be evoked for the failure to observe any change in the acute ventilatory sensitivity to CO2.
Significance for control of breathing near sea level.
Figure 7 illustrates a regression line for the relationship between Gp and PETO2. The slope of this relationship is 3.5%/Torr (SE 1.0), which suggests that small variations over time in arterial PO2 would have marked effects on the ventilatory sensitivity to acute hypoxia. For example, there is a natural fall in arterial PO2 of 3–18 Torr with sleep (16), which if sustained would result in a rise in Gp of 10–60%. Interestingly, it has previously been reported that sleep deprivation results in a substantial reduction in the acute ventilatory sensitivity to hypoxia (23).
It is a relatively well-known phenomenon that the ventilatory sensitivity to hypoxia varies markedly within an individual from day to day for reasons that are not understood (19, 25). This study indicates that natural variations in PO2 over the course of the day may underlie at least part of this observation. Overall, it would seem likely that this phenomenon is part of an overall process of continuous calibration of the respiratory chemoreflexes to ensure that the respiratory control system remains stable and effective over time. However, the exact nature of how such regulatory mechanisms may function remains poorly understood.
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GRANTS
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This study was supported by the Wellcome Trust.
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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.
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Copyright © 2005 by the American Physiological Society.
TOP
ABSTRACT
METHODS
) or mild hyperoxia (protocol B, 
). Error bars, 1 SE.
). Middle: slow (central) chemoreflex sensitivity to CO2 (Gp). Bottom: extrapolated value for PETCO2 for which ventilation is zero (B). Solid bars and dashed lines indicate period of exposure in chamber to either mild hypoxia (protocol A,