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1 Departmento De Ciencias Biologicas y Fisiologicas/IIA, Universidad Peruana Cayetano Heredia, Lima 100, Peru; and 2 University Laboratory of Physiology, University of Oxford, Oxford OX1 3PT, United Kingdom
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ABSTRACT |
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 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Sea-level (SL) natives acclimatizing to high altitude (HA) increase their acute ventilatory response to hypoxia (AHVR), but HA natives have values for AHVR below those for SL natives at SL (blunting). HA natives who live at SL retain some blunting of AHVR and have more marked blunting to sustained (20-min) hypoxia. This study addressed the question of what happens when HA natives resident at SL return to HA: do they acclimatize like SL natives or revert to the characteristics of HA natives? Fifteen HA natives resident at SL were studied, together with 15 SL natives as controls. Air-breathing end-tidal PCO2 and AHVR were determined at SL. Subjects were then transported to 4,300 m, where these measurements were repeated on each of the following 5 days. There were no significant differences in the magnitude or time course of the changes in end-tidal PCO2 and AHVR between the two groups. We conclude that HA natives normally resident at SL undergo ventilatory acclimatization to HA in the same manner as SL natives.
regulation of ventilation; human; Andean natives; chemoreflex; blunting
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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HIGH-ALTITUDE (HA) NATIVES residing at HA have certain characteristics in relation to respiratory control that distinguish them from sea-level (SL) natives. They have an end-tidal PCO2 (PETCO2) that has been described as below that for unacclimatized SL natives, but somewhat above the PETCO2 associated with SL natives after they have acclimatized to HA (3, 22, 25). HA natives residing at HA have ventilatory responses to hypoxia that are blunted compared with SL natives (8, 12, 14, 17, 24, 29, 30).
On moving to SL, HA natives develop a PETCO2 that is very similar to that of SL natives resident at SL (15). However, the blunting of the ventilatory response to hypoxia is thought to persist (13, 26, 29). More recently, the persistent blunting of the acute hypoxic ventilatory response (AHVR) of HA natives living at SL has been shown to be much less marked than previously thought (9, 28). However, the ventilatory response to sustained (20-min) hypoxia (i.e., after hypoxic ventilatory depression has had a chance to develop) of HA natives is much less than for SL control subjects (9).
These findings at SL raise the interesting question of what happens to HA natives, resident at SL, who are reexposed to HA. Do they develop the profile of a HA native resident at HA, with a blunted AHVR and a PETCO2 that is intermediate between unacclimatized and fully acclimatized SL natives? Alternatively, do they acclimatize as SL natives do, with a similar fall in PETCO2 and increase in AHVR? This study sought answers to these questions by exposing a group of HA natives resident at SL, together with a control group of SL natives, to 5 days of HA at Cerro de Pasco, Peru (4,300 m).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subject Selection
Fifteen HA natives living in Lima at SL were selected for study. All had lived at >3,500 m for the first
20 yr of their lives. Fifteen SL natives living in Lima acted as controls. All subjects had
taken part in a previous study that had involved determining their
ventilatory sensitivities to hypoxia at SL (9). The SL controls were selected so as to have similar ages and values for AHVR
as the group of HA natives.
Protocols
Preliminaries. The preliminaries to be conducted at SL on these subjects had been completed as part of our previous study (9). These included taking a brief residence history, noting their general physical characteristics, and conducting a brief medical history and examination to exclude major disease. In addition to this, the subjects' air-breathing PETCO2 and end-tidal PO2 (PETO2) were determined by using a fine nasal catheter to disturb ventilation as little as possible. Values for the instantaneous respiratory quotient were calculated from these measurements to check that the subjects were not hyperventilating. Finally, the subjects' acute and sustained (20-min) ventilatory responses to hypoxia were determined at a PETCO2 of 2 Torr above the subjects' natural air-breathing value as detailed in Ref. 9. All SL measurements were made before any subject was taken to altitude.
Studies at HA. The first study was conducted on a group of six subjects (three HA natives and three SL natives). This was followed by two further studies with 12 subjects in each group (six HA natives and six SL natives on each occasion). Each group of subjects was transported from Lima to Cerro de Pasco on day 0 of the study, and the subjects were then accommodated at a local hotel in Cerro de Pasco for the duration of the study. Subjects were studied on 5 consecutive days in the laboratory (barometric pressure of 450 mmHg, C. Monge, personal communication), starting on the first day after arrival at Cerro de Pasco.
Each subject was studied at the same time of day on each occasion. Air-breathing PETCO2 and PETO2 were measured by using a fine nasal catheter. This was followed by a measurement of PETCO2 and PETO2 after 3-10 min of breathing gas enriched with O2 through a face mask to bring PETO2 to ~100 Torr. After this, AHVR was measured by using the protocol of Mou et al. (18). For this protocol, PETCO2 was held at 2 Torr above the value that had been obtained while the subject breathed the gas mixture that had been supplemented with O2 to bring PETO2 to ~100 Torr. PETO2 was held at 100 Torr for 5 min and then at a series of seven decreasing levels of PETO2, starting at a PETO2 of 100 Torr and finishing at a PETO2 of 45 Torr, with each level lasting 50 s. These levels were spaced so that there would be an approximately linear fall in arterial oxygen saturation and, consequently, an approximately linear rise in ventilation (
E) over time.
Apparatus and Techniques
Respired gas concentrations were measured by using a Datex Normocap-Oxy gas analyzer in which the software had been modified to disable the automatic hourly zeroing of the instrument (this was done manually at appropriate times throughout the experiment). Respired gas volumes were measured by using a turbine volume-measuring device (10). Data were logged to a personal computer by using National Instruments interface cards (DAQCard-1200 and DAQCard-AO-2DC).The protocol for assessing AHVR was implemented via the end-tidal forcing technique (19). In this technique, before an experiment starts, an estimate of the inspiratory PO2 and PCO2 profile necessary to generate the desired PETO2 and PETCO2 values, respectively, for the protocol is made by using a respiratory model. During the experiment, the inspiratory gases are mixed via a fast gas-mixing system controlled by a computer. The composition of these inspiratory gases is based on the profile calculated from the respiratory model, but the composition is also corrected by feedback of the actual PETO2 and PETCO2 values achieved on a breath-by-breath basis (using an integral-proportional controller). The real-time software for controlling the experiments was written in LabView (National Instruments, Austin, TX), and the fast gas-mixing system was constructed by using mass flow controllers (MKS Instruments, Altringham, UK).
In these experiments, the subjects sat upright and breathed the gases via a mouthpiece with their nose occluded with a clip.
Data Analysis
Values for AHVR were calculated from the data in two ways. In the first method, average values forE and
PETO2 were calculated from the last
20 s of data from each of the seven levels of
PETO2. Calculated values for arterial
saturation were obtained from the values for
PETO2 (23). A linear
regression was then performed between the values for
E and arterial desaturation to give a slope
(SAHVR) as a measure of AHVR and an intercept
(KAHVR) as a measure of hypoxia-independent
E. In the second method, a dynamic model of the
respiratory response to acute hypoxia [model 3 of Clement
and Robbins (5)] was fitted to the entire data set from
the seven levels of PETO2. The gain term
(Gp) gave an analogous measure of AHVR to SAHVR,
and the intercept term (c), an analogous measure of
hypoxia-independent E to
KAHVR. The procedure also yielded a time
constant (T) and pure delay (d) for the response.
Statistical significance was assessed by using repeated-measures ANOVA. For the various variables measured during acclimatization, a significant value for the interaction between subject type and time would indicate that the HA and SL natives differed in their acclimatization response. Statistical significance was taken 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
All 15 SL natives completed the full 5-day study at altitude. Of the 15 HA natives recruited, two withdrew from the study: one after 2 days at HA and the other after 3 days at HA. Both withdrew because they did not feel comfortable undertaking the protocol. It was not clear that either was suffering from acute mountain sickness. The results presented relate just to those subjects who completed the full study.The physical characteristics for the subjects are given in Table
1. The HA natives did not differ
significantly from the SL natives in any physical respect, but there
was a tendency for the HA natives to have a higher vital capacity
normalized to body surface area.
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Responses at SL
The responses of these subjects at SL are a subset of the data previously reported in Ref. 9. SL values for air-breathing PETCO2 and PETO2, together with values for AHVR, are contained within Table 2. Values for SL PETCO2 were significantly lower in the HA native group (by 1.9 Torr) compared with the SL control group (P < 0.05). No other differences were significant between the two groups at SL.
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Responses to Acclimatization
Values for air-breathing PETCO2 and AHVR during acclimatization are shown in Fig. 1, both for individual subjects and for the SL and HA groups. Average values for these and other variables are shown in Table 2 for the HA and SL groups at SL and on each of the 5 days of acclimatization.
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There was an obvious drop in air-breathing PETCO2 on day 1 of HA in both HA and SL natives. There was a progressive further fall in PETCO2 over the remaining 4 days of the exposure. These changes over time in air-breathing PETCO2 were significant (P < 0.001, ANOVA), but there was no significant interaction between time and subject type (SL vs. HA natives). The fall in PETCO2 over time appeared close to exponential, and fitting to the data provided a T of 1.3 ± 0.2 days (mean ± SE) and an asymptotic value for PETCO2 of 26.0 ± 0.5 Torr. The pattern of response for PETCO2 measured at PETO2 of ~100 Torr was similar to that observed for air-breathing PETCO2 (Table 2). During the acclimatization process, the average difference between PETCO2 measured at a PETO2 of ~100 Torr and PETCO2 measured under air-breathing conditions was 0.53 ± 1.5 Torr (mean ± SD). This did not vary significantly, either with subject type or over time during acclimatization.
Numerical values for AHVR were obtained both by linear regression (SAHVR) and from fitting a dynamic model (Gp). The results from both approaches were very similar, and so only the values for Gp are presented. There was a rise in Gp during acclimatization (P < 0.001), but there was no significant difference with subject type and no significant interaction between time and subject type.
The calculated values for E in the absence of any
hypoxic stimulus (parameter c from the dynamic model) appeared
to decrease somewhat from the values measured at SL. However, this did
not reach significance. Again, there were no significant differences between subject type and no significant interaction between subject type and time.
In addition to Gp and c, fitting the dynamic model to the data
also provided values for T and d. There were no significant effects of acclimatization on T, whereas d fell with the
hypoxic exposure (P < 0.05). The HA native and SL
control groups did not differ in their values for these variables.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The major finding of this study is that HA natives resident at SL acclimatize to HA in a very similar manner to SL natives. There were no significant differences in time profile or in the magnitude of fall in PETCO2 between the two groups. AHVR increased in both groups in a very similar manner during the acclimatization process. These values should be contrasted with values for HA natives resident at HA, in whom values for AHVR would be expected to be well below the SL values for our subjects (8, 12, 14, 17, 24, 29, 30).
The SL controls were not perfectly matched with the HA subjects,
although their ages were very similar. In particular, the HA natives
had an air-breathing PETCO2 that was
significantly lower than that of the SL natives. This difference does
not appear to be a general finding (9, 15). Although not
significantly different, the values for AHVR were not as perfectly
matched as we had intended, with the average values for the HA natives
being somewhat lower than those for the SL natives. Part of this arises because two HA natives did not complete the study. As we did not attempt to match the subjects for their sustained ventilatory response
to hypoxia (E response to 20-min hypoxia), we might expect the HA natives to have a lower response in this respect than
their SL controls (9). In fact, this did not reach
significance (data from Ref. 9 for our subset of
subjects), although numerically the average value for the HA natives
was less than one-half that for the SL natives.
One of the biggest problems associated with assessing the change in
AHVR during acclimatization is choosing the level of
PETCO2 against which it should be
measured. Sato et al. (21) adopted quite a sophisticated
approach to this problem. They used 15-20 min of hyperoxia
(PETO2 ~200 Torr) to reverse any hypoxic
ventilatory depression that was present at altitude and then
determined a level for PETCO2 that would
produce a E under hyperoxic conditions of 140 ml · kg
1 · min1.
The rationale was that this would enable AHVR to be determined against
a constant level of central chemoreflex stimulation. It is
not clear that this rationale is correct. Indeed, although it remains
unclear whether peripheral and central chemoreflexes interact (4,
6, 16, 27), it is very clear, at both neural (carotid sinus
nerve) and reflex levels, that the magnitude of the acute response to
hypoxia depends on the degree of arterial acidosis. The values for
arterial pH from Sato et al. (21) suggest that their
protocol results in an arterial pH that is more alkaline at HA than at
SL, and, therefore, any increase in AHVR with HA would be underestimated.
In our study, we simply increased the
PETCO2 to 2 Torr above the ambient value
on each day before measuring AHVR. If anything, this should result in
less disparity in arterial pH between the HA and SL measurements of
AHVR than would have been present in the study of Sato et al.
(21). This is because Sato et al. elevated PETCO2 less at HA when arterial pH was
more alkaline and more at SL when arterial pH was more acid. With
respect to central drive, our study differs from that of Sato et al. in
two conflicting ways. First, we did not increase
PETO2 to ~200 Torr for a 15- to 20-min
period before our measurements of AHVR. Our protocol had a 5-min period
of PETO2 = 100 Torr before the
measurement of AHVR. On its own, this would result in less central
stimulation by hyperoxia (or relief of central depression by hypoxia)
in our study than in that of Sato et al. Second, at HA, we elevated
PETCO2 by the same amount (2 Torr) as at
SL, despite the fact that the acute ventilatory response to hypercapnia
would have increased with exposure to HA. This should tend to result in
more central stimulation at HA than in the study of Sato et al., in
which PETCO2 was chosen to provide, under
hyperoxic conditions, the same level of ventilatory stimulation at HA
as at SL. Experimentally, c provides a measure of what has
happened to central drive in the absence of peripheral hypoxic
stimulation, and the values for this variable appeared to decrease with
exposure to altitude, although this observation failed to reach
statistical significance. This decrease is surprising because, at HA,
the combination of an increased E in the absence of
added CO2, coupled with a steeper E-PETCO2 response
relation, might reasonably be expected to result in an increase in
c.
There remains the question of whether Gp could have been suppressed at HA by inadequate preoxygenation before the measurements of AHVR were made. Although it is certainly the case that measurements of AHVR made after 20 min of hypoxia will be lower than those made without such exposure to hypoxia (1, 2, 11), Sato et al. (20) did not find the rapid change in ventilatory response in response to a rapid change in PETO2 to be greatly increased by preoxygenation after the much longer exposure to hypoxia associated with acclimatization to HA. A similar finding has been made in relation to a 1-h exposure to room air after an 8-h exposure to hypoxia (7). These results suggest that, as long as AHVR is determined rapidly so that baseline changes in central drive do not have time to occur to any significant extent, substantial preoxygenation may not be necessary to obtain reasonable values for AHVR in acclimatizing humans.
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ACKNOWLEDGEMENTS |
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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 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.
First published November 27, 2002;10.1152/japplphysiol.00857.2002
Received 19 September 2002; accepted in final form 25 November 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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