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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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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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High-altitude (HA) natives have blunted ventilatory responses to
hypoxia (HVR), but studies differ as to whether this blunting is lost
when HA natives migrate to live at sea level (SL), possibly because HVR
has been assessed with different durations of hypoxic exposure (acute
vs. sustained). To investigate this, 50 HA natives (>3,500 m,
for >20 yr) now resident at SL were compared with 50 SL natives as
controls. Isocapnic HVR was assessed by using two protocols:
protocol 1, progressive stepwise induction of hypoxia over
5-6 min; and protocol 2, sustained (20-min) hypoxia
(end-tidal PO2 = 50 Torr). Acute HVR was
assessed from both protocols, and sustained HVR from protocol
2. For HA natives, acute HVR was 79% [95% confidence interval
(CI): 52-106%, P = not significant] of SL
controls for protocol 1 and 74% (95% CI: 52-96%,
P < 0.05) for protocol 2. By contrast,
sustained HVR after 20-min hypoxia was only 30% (95% CI:
7-67%, P < 0.001) of SL control values. The
persistent blunting of HVR of HA natives resident at SL is substantially less to acute than to sustained hypoxia, when hypoxic ventilatory depression can develop.
regulation of ventilation; human; Andean natives; hypoxic ventilatory depression; chemoreflex; blunting
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IT HAS LONG BEEN RECOGNIZED that natives of high altitude (HA) have a blunted respiratory response to hypoxia (4, 6, 8, 10, 15, 19, 21). Furthermore, a number of reports have suggested that, once this blunting has developed, it is permanent and cannot be reversed by subsequent residence at sea level (SL) (7, 16, 19). More recently, however, a study by Vargas et al. (18) found that natives of HA who were resident at SL had a relatively normal acute ventilatory response to hypoxia (AHVR). They speculated that the difference between their findings and those of previous studies lay in the duration of the hypoxic exposure. In the study by Vargas et al., they had attempted to minimize the total exposure to hypoxia to minimize the degree of hypoxic ventilatory depression (HVD) that occurred during the measurement of the ventilatory response to hypoxia.
The first part of this study sought to repeat the measurements of Vargas et al. (18), while, at the same time, address a number of the technical concerns associated with that study. The second part of this study explicitly sought to test the speculation of Vargas et al. that there was a much greater difference in the ventilatory response to sustained hypoxia between SL natives and HA natives resident at SL than in the ventilatory responses to acute hypoxia.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects.
One hundred subjects who were living in Lima, Peru, were recruited for
this study. All were men and between the ages of 20 and 65 yr. Fifty
were natives of SL (SL group), and 50 were natives of HA
(HAT group). All HA natives had lived at >3,500m for the first 
20 yr of their lives. Twenty-five had the additional criteria that they had resided at SL for <5 yr (HA1 group), and 25 that they
had resided at SL for >5 yr (HA2 group). The SL natives were recruited
from the same neighborhoods as the HA natives.
Protocols. In a preliminary procedure, the subjects' residence history was documented, their general physical characteristics noted, and a brief medical history and examination conducted to exclude major disease. The end-tidal PCO2 (PETCO2) and end-tidal PO2 (PETO2) of each subject were determined by using a fine nasal catheter so as to disturb the subject as little as possible. An instantaneous value for the respiratory quotient was calculated as a further check to ensure that the subject was not hyperventilating.
After the preliminary procedures had been completed, the subjects undertook three protocols, each of which involved imposing certain profiles for PETCO2 and PETO2 using an end-tidal forcing system. Protocol 1 was designed to assess AHVR by a short, progressive, stepwise induction of hypoxia. Protocol 2 was designed to assess the ventilatory response to sustained (20-min) hypoxia. However, it also provided a second, alternative index of AHVR from the response to the first 2 min of hypoxia. Protocol 3 was a control protocol for protocol 2. Protocol 1 had been devised by Mou et al. (11) and validated further by Zhang and Robbins (22). Its purpose was to determine a value for AHVR by progressive induction of hypoxia over a sufficiently brief time interval so as to minimize the confounding effects of HVD on the assessment of AHVR. PETCO2 was held at ~2 Torr above the subjects' natural value throughout. A settling period of 5 min was employed, during which PETO2 was held at 100 Torr. After this settling period, PETO2 was lowered stepwise in a set of seven steps from 100 to 45 Torr, with each step lasting for 50 s. Values for PETO2 for the five intervening steps had been calculated so as to provide approximately even reductions in saturation between steps and, consequently, approximately even increases in ventilation between steps. The second and third protocols were directed at determining the subjects' response to sustained hypoxia, although, by analyzing the first 2 min of the response to hypoxia, an alternative measure of AHVR was also obtained. In both protocols, PETCO2 was again held at ~2 Torr above the subjects' natural resting value throughout. In protocol 2, PETO2 was held at 100 Torr for the first 10 min, then at 50 Torr for the next 20 min, and finally at 100 Torr again for a final 10 min. Protocol 3 served as a control protocol in relation to protocol 2. In this protocol, PETO2 was held at 100 Torr throughout.Apparatus and techniques. The technique of end-tidal forcing was used to generate the desired profiles in PETCO2 and PETO2. In this technique, a computational model of the cardiorespiratory system and gas stores is first used to calculate the profiles for inspiratory PCO2 and PO2 that are likely to generate the desired PETCO2 and PETO2, respectively. Once these values have been calculated, a computer connected to a fast gas-mixing system can be used to generate the inspiratory gas mixtures. The experiment starts with the computer mixing the predicted inspiratory gas mixtures. In general, these predicted inspiratory gas mixtures will not of themselves generate the desired end-tidal values with sufficient precision because the physiology of the individual deviates from the assumptions of the cardiorespiratory model. To overcome this, these predicted inspiratory values are modified during the course of the experiment by using breath-by-breath feedback from the measured PETCO2 and PETO2. These measured values for PETCO2 and PETO2 are compared with the desired values, and an integral-proportional feedback control algorithm is used to calculate the actual adjustments required for the inspiratory PCO2 and PO2.
The apparatus and software for undertaking these studies in Peru were revised and updated from those that had been in use in our laboratory in Oxford (5, 13). In this implementation, the gas was still mixed in a small mixing chamber close to the subject, and inspiratory and expiratory volumes were still recorded via a turbine volume-measuring device (VMM 400, Interface Associates, Laguna Niguel, CA). However, the fast gas-mixing system was constructed by using commercially available mass flow controllers (type 1559A, MKS Instruments, Altringham, UK), and a commercially available medical gas analyzer (Normocap Oxy, Datex Ohmeda, Hatfield, UK) was used to measure inspiratory PCO2, inspiratory PO2, PETCO2, and PETO2 (in the instrument used, the software was modified to disable the hourly automatic zeroing to ensure that it did not interfere with the experiment). The real-time software was written in LabView (National Instruments, Austin, TX) and run on a portable computer under the Microsoft Windows operating system. The equipment was interfaced to the computer by using National Instruments interface cards (DAQCard-1200 and DAQCard-AO-2DC). In all experiments, the subject sat upright and breathed to and from the gas-mixing chamber via a mouthpiece while wearing a nose clip.Data analysis.
Numerical values for AHVR were calculated from the data from the first
protocol in two different ways. In the first, average values for
ventilation (
E) and
PETO2 were calculated over the last
20 s for each of the seven steps. The average values for PETO2 were converted into calculated
values for arterial saturation (14), and a slope and
intercept were calculated via linear regression for the relationship
between E and desaturation. In the second method, a dynamic respiratory model [model 3 of Clement and
Robbins (2)] was fitted to the whole data set for the
seven steps. This yielded a gain term (Gp) as the measure of AHVR and
a bias term (c) that reflects
E in the absence of hypoxia. (The
values for Gp and c are directly comparable with the
values of the slope and intercept of AHVR from the first method of
calculation.) In addition, the model yielded values for the time
constant and pure delay for the chemoreflex response to hypoxia.
E, PETCO2, and
PETO2 for the last minute of euoxia before
the induction of hypoxia at minute 10 of the protocol
[denoted as E(P2-10), where P2 indicates
that the value comes from protocol 2, which involves
hypoxia, and 10 indicates that the value is the mean for the 10th min
of the protocol]; for the 2nd min of the period of hypoxia at
minute 12 of the protocol
[E(P2-12)]; for the last minute of the
period of hypoxia at minute 30 of the protocol [E(P2-30)]; and for the 2nd min of the
period of euoxia following hypoxia at minute 32 of the
protocol [E(P2-32)]. Control values for
these variables were calculated at the same time periods from the data
from protocol 3 [denoted as
E(P3-x), where P3 indicates that the
value comes from protocol 3, which involved just
euoxia, and x indicates that the value is the mean for the
xth minute of the protocol]. In addition to us obtaining a
measure of the sustained ventilatory response to hypoxia, we calculated
measurements of AHVR at the onset and offset of hypoxia, together with
measures of HVD during hypoxia, from these values, as described in
RESULTS.
Results between the different groups of subjects were compared by using
ANOVA. Where any comparisons were drawn within a group of subjects, the
intersubject variability was removed from the comparison by including
"subjects" as a random factor. Statistical significance was
accepted at P < 0.05. For post hoc tests following ANOVA, the least squared difference technique was used, which makes an
allowance for the total number of comparisons being drawn.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects.
General characteristics of the subjects are shown in Table
1. As well as showing average data for
the entire HAT group, the HA natives were also split into
the HA1 and HA2 groups. The HA2 group was significantly older than the
SL or HA1 groups. This age difference is presumably an effect arising
from the selection criteria in which the subjects in the HA2 group had
to have lived at HA for >20 yr and then at SL for >5 yr. It is also
worth noting that the HAT group was both significantly
shorter and had significantly greater lung volumes than the SL group,
which is in keeping with their HA origins.
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Resting PETCO2.
Perhaps the most important physiological observation to note is
that the HA2 group had an air-breathing
PETCO2 that was ~1.5 Torr below that for
both the SL and HA1 groups (Table 1). The reasons for this are unclear.
The instantaneous respiratory exchange ratios associated with these
observations were not different between groups, which suggests that the
subjects of the HA2 group were not hyperventilating relative to the
subjects of the SL and HA1 groups during these measurements.
Incorporating age as a covariate in the ANOVA conducted on the resting
PETCO2 of the three groups rendered the
differences between the three groups just not significant (P = 0.051), although the regression coefficient for
the fall in PETCO2 with age of 0.05
Torr/yr [95% confidence interval (CI): 0.10-0.02] failed to
reach significance. Selection of a subset (n = 25) of
the SL group to form an age-matched control group for the HA2 group
also resulted in a comparison that was just nonsignificant (SL subset
PETCO2 = 38.4 Torr, HA2
PETCO2 = 37.3 Torr, P = 0.072). Thus age probably underlies part, but not all, of the difference.
Measurements of AHVR from protocol 1.
Example breath-by-breath records of the measurement of AHVR using
incremental steps of hypoxia are shown in Fig.
1. Figure 2
illustrates the variability in individual responses to hypoxia in the
form of 20-s average values for each subject for each level of
PETO2. Figure
3 shows the 20-s average values averaged
over all subjects in each group, together with the regression lines resulting from averaging the regression coefficients.
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E in
the absence of hypoxia.
Parameter estimates from the measurements made in protocol 1 are given in Table 2. The two techniques
(linear regression and modeling) for estimating AHVR from these data
gave very similar results, so only the values from the modeling
procedure have been reported. The average
PETCO2 over the test was significantly
lower in the HA2 group compared with the SL and HA1 groups, reflecting their lower initial values for PETCO2.
However, E at
PETO2 = 100 Torr was not different
between the groups, suggesting that, on average, the subjects were
subjected to the same degree of ventilatory stimulation before the
induction of hypoxia.
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c, which provides an estimate for
E in the absence of hypoxic stimulation, were
significantly larger for the HA1 group compared with the SL group, but
other comparisons were not significant. There were no significant
differences in the dynamic parameters from the model for any of the
protocols. Normalization of the ventilatory parameters by body surface
area did not alter these statistical comparisons.
Measurements of ventilatory responses to sustained hypoxia from
protocol 2.
Example responses (1-min averages) for two subjects (one SL, one HA) to
the 20-min period of hypoxia are shown in Fig.
4. The individual responses for the two
subjects show abrupt changes in
PETO2 at the onset and offset of hypoxia,
with good control over PETCO2. This
was the case for almost all subjects and is reflected in the averaged
responses in Fig. 5.
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E for protocol 2 at 10, 12, 30, and
32 min of the protocol, and E for protocol
3 at 12 and 30 min of the protocol, together with parameters that
have been derived from these values. The background
PETCO2 against which the experiment was
conducted was lower in the HA2 group compared with the other groups,
which is a result of their lower average value for resting PETCO2. However, in contrast to the data
from protocol 1, E at a
PETO2 of 100 Torr was lower for HA2 than
for the other subject groups [see E(P2-10)
and E(P3-12) of Table 3]. This implies that the hypoxic stimulus was introduced against a lower prevailing background level of ventilatory stimulation than for the other two
groups.
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E(P2-30) and
E(P3-30), which is a measure of the
ventilatory stimulation by hypoxia that remained after 20-min exposure
to hypoxia. This index was denoted as ONs (sustained on
response), from which a corresponding ventilatory sensitivity to
sustained hypoxia was also calculated. ONs was markedly
reduced in both HA groups to 30% (95% CI: 7-67%) of the value
for the SL group. This reduction in ONs would appear to
have its origins in two distinct components of the ventilatory response
to hypoxia. The first of these is a more modest reduction in AHVR, and
the second of these is an increase in HVD (see following paragraphs).
An index of AHVR was calculated as the difference between
E(P2-12) and
E(P2-10). This index was denoted as
ONf (fast on response), from which a corresponding estimate
of AHVR per %desaturation was also calculated. ONf was
well correlated with the measurements obtained from the incremental
steps into hypoxia of protocol 1 (r = 0.79, P < 0.001). In addition, the relative differences in AHVR between the different groups are similar for the two protocols (as
a proportion of the SL values, the ONf response was 85, 62, and 74% for the HA1, HA2, and HAT groups compared with 97, 60, and 78%, respectively, for the measures of AHVR from the
incremental steps of hypoxia in protocol 1). Interestingly,
the difference between the HAT and SL groups reached
significance for the ONf response, whereas this was not the
case for the measures of AHVR from protocol 1. Although this
might be related to a lower prevailing level of ventilatory stimulation
before the induction of sustained hypoxia in the HA2 group (see above),
there was nevertheless no reduction in the magnitude of AHVR (as a
fraction of the AHVR of the SL group) in the data from protocol
2 compared with those from protocol 1 in this group.
The difference between E(P2-12) and
E(P2-30) or HVD gives a measure of the
decline in E over the sustained hypoxic period. This appears somewhat greater in the HA subjects compared with the SL
group (by ~50%), but this did not reach significance. One complication is that, in the control data, there is a progressive increase in E over this period. This may be
calculated as the difference between
E(P3-30) and
E(P3-12) and has been termed drift. The
value for HVD may be corrected for this progressive rise to give the
parameter HVDc. For this corrected parameterization, the magnitude of
ventilatory decline with sustained hypoxia in the HA1 group was
significantly larger than in the SL group.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study has confirmed a previous result (18) that the irreversible reduction in AHVR associated with growth to adulthood at HA (>3,500 m) measured after a period of residence at SL is modest. For the HA group overall, AHVR was 79% of the response of SL natives from the incremental step protocol and 74% of the response of SL natives measured from the protocol involving sustained hypoxia. However, this study has also shown that the effects of growth to adulthood at HA on the response to sustained hypoxia are far greater. For the overall HA group, the sustained ventilatory response to hypoxia was only 30% of that of the SL group. This arises from the combined effects of the (more modest) reduction in AHVR coupled with an increase in the magnitude of HVD.
This study, highlighting the differences between the ventilatory responses to acute and sustained hypoxia between SL and HA natives at SL, probably reconciles a number of studies in the literature. Studies of HA natives at SL that employed sustained hypoxia (7, 16) found markedly blunted responses, whereas, with a hypoxic stimulus sufficiently acute to avoid HVD, Vargas et al. (18) did not find the responses to be blunted. Patients who were chronically hypoxic from cyanotic heart disease before corrective surgery were found to remain blunted in studies in which sustained hypoxic stimuli were employed to assess AHVR (17), whereas, in studies in which shorter duration hypoxic stimuli were employed, this was not the case (1, 3).
The reasons why the HA group should show more marked HVD are not clear,
not least because there is not agreement on the origins of HVD itself
(12, 20). In humans, a study fitting mathematical models
to data for the ventilatory response to sustained hypoxia found that
only ~10% of HVD resulted from a central depression independent of
the peripheral chemoreflexes in four out of six subjects, but that, in
the other two subjects, this figure was ~50% (9). In
the present study, the percent reduction in AHVR with sustained hypoxia
[calculated as 100 * (ONf OFFf)/ONf, where OFFf is a measure
of AHVR after it has decreased after 20 min of sustained hypoxia] was
significantly greater for the HAT group than for the SL
controls [52 ± 6 (SE) % for the HAT group; 30 ± 9% for the SL group; P < 0.05], which suggests
that HA natives and SL natives differ in the degree to which sustained
hypoxia alters peripheral chemoreflex sensitivity. However, there may also be a difference between the two groups in relation to a mechanism that is independent of the peripheral chemoreflex, because the undershoot in E after the relief of hypoxia
appears larger for the HAT group than for the SL group
[2.27 ± 0.75 (SE) l/min for the HAT group; 1.09 ± 0.63 l/min for the SL group], although this difference did not
reach significance.
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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.00856.2002
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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, Protocol 2; 
,
protocol 3.
