| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Departamento de Ciencias Fisiológicas, Instituto de Investigaciones de la Altura, Universidad Peruana Cayetano Heredia, Lima 100, Peru; and University Laboratory of Physiology, Oxford OX1 3PT, United Kingdom
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
León-Velarde, Fabiola, Manuel Vargas, Carlos Monge-C.,
Robert W. Torrance, and Peter A. Robbins. Alveolar
PCO2 and
PO2 of high-altitude natives living
at sea level. J. Appl.
Physiol. 81(4): 1605-1609, 1996.
This
study was designed to determine whether subjects born at high altitude
(HA; 2,000 m or above) who subsequently move to near sea level (SL)
develop end-tidal PCO2
(PETCO2) and
PO2
(PETO2) values
that equal those of SL natives living near SL. A total of 108 male HA
natives living near SL were identified by survey of a district in Lima,
Peru, and a further 108 male SL natives from the same district were
identified as control subjects. Of these subjects, satisfactory data
for inclusion in the study were obtained from 93 HA and 82 SL subjects.
Mean PETCO2 and PETO2 values were 37.7 ± 2.5 (SD) and 104.7 ± 3.2 Torr, respectively, in HA subjects and
37.7 ± 2.2 and 104.8 ± 3.0 Torr, respectively, in SL subjects.
The average difference between SL natives and HA natives for
PETCO2 was 0.07 Torr
(
0.64 to 0.78; 95% confidence interval) and for
PETO2 was 0.05 Torr
(0.89 to 0.99, 95% confidence interval). The average age and
weight of the SL and HA subjects did not differ, but the HA subjects
were shorter and tended to have larger vital capacities, consistent
with their origin at HA. We conclude that the
PETCO2 and
PETO2 near SL of SL natives
and HA natives do not differ.
partial pressure of carbon dioxide; partial pressure of oxygen; end-tidal partial pressure of carbon dioxide; control of breathing; peripheral chemoreceptors; Andean; ventilation
INTRODUCTION HUMANS WHO ARE BORN AT SEA LEVEL (SL) acclimatize to
high altitude (HA) by increasing their ventilation and lowering their alveolar PCO2. However, it is
controversial (see Refs. 3, 6, 16) whether humans who are born at HA
and have an alveolar or arterial
PCO2 at altitude that is
below that of SL natives at sea level (4) acclimatize to low altitude by decreasing their ventilation and elevating their alveolar
PCO2.
One difference between SL natives and HA natives is that the
ventilatory response to changes in the level of hypoxia in adult HA
natives is blunted (11, 14, 15). Because a critical part of the process
of ventilatory acclimatization to altitude appears to include an
initial stimulation of the carotid bodies by hypoxia (for a review, see
Ref. 18), it may be the case that HA natives, who lack a ventilatory
sensitivity to the abolition of hypoxia, may not alter their alveolar
PCO2 on moving to SL. Alternatively, it may be the case that the ventilatory sensitivity to hypoxia is
unimportant in determining the alveolar
PCO2 at SL. If this is the case, then
the alveolar PCO2 of HA natives exposed to SL might be expected to alter to match that of SL natives at
SL.
This study has been designed to answer the question of whether HA
natives raise their alveolar PCO2
when they migrate to SL. The experimental program involved measurements
of end-tidal PCO2
(PETCO2) and end-tidal
PO2
(PETO2) in HA natives born
above 2,000 m in the Andes of Peru and living in the coastal plains
below 500 m. The results were compared with a control group of SL
natives living below 500 m.
METHODS Subject selection. Subjects were
selected from within a district (Barrios Altos) in Lima, Peru. The
district has a population of 150,000 inhabitants, 10% of whom are
migrants from HA (Prof. E. Arcy, Department of Sociology, Universidad
Peruana Cayetano Heredia). The district was divided into
four main areas. From each of these areas, residential blocks were
selected at random, with an equal number of blocks being drawn from
each area. Within each of these blocks, a survey was carried out to
determine those dwellings that had one or more migrants from HA who
fulfilled the necessary criteria to be included in the study. Control
subjects born near SL were selected from the nearest dwelling to the
right of each HA subject in which a suitable subject could be found. Where there was more than one suitable individual from a given dwelling, only one subject was selected, again at random.
To be included in the study, subjects had to be male and between the
ages of 18 and 65 yr. HA subjects had to be born in a city with a
stated elevation of >2,000 m. The precise altitude of birth was
determined by further interrogation about the district in which the
subject was born. The altitude of the district could then be obtained
from the Peruvian Geographic Census, which contains details of
altitudes at the level of the district. SL subjects had to be born at
an elevation of <500 m.
Residential history and clinical
assessment. Once a subject had been accepted as
suitable for inclusion in the study, he was invited to come to the
laboratory where a detailed residential history was taken with a
structured questionnaire and a clinical assessment was performed. HA
subjects were asked at what age they had come to live at SL and for how
long they had lived there. All subjects were asked about the frequency
and duration of any visits to altitude and when and for how long the
last visit had been. SL subjects were asked whether they had ever lived
at altitude, and HA subjects were asked whether they had ever returned
to live at altitude since migration. Responses to these questions were coded for later statistical analysis.
After the residence history was obtained, a brief clinical history and
examination were performed to exclude any subjects with chronic
obstructive respiratory disease, cardiovascular disease, and/or
renal disease. The subjects' height and weight were recorded, and
their vital capacity measured with a Wright respirometer.
Recording of end-tidal gases. All
measurements of end-tidal gas concentrations were carried out between
4:00 and 5:30 P.M. with the subject in
a sitting postion. Two different methods were employed for continously
sampling the respired gases. In the first, respiratory gases were
sampled with a fine catheter taped just inside one nostril. In the
second, the subject was asked to breathe through a short plastic tube
~1.5 cm in diameter through the side of which the sampling catheter
had been inserted. During this procedure, the nostrils were occluded
with tape. The respiratory gases were analyzed continuously for
PCO2 and
PO2 (Normocap Oxy, Datex), and the
end-tidal values were detected with the algorithim incorporated in the
instrument.
A minimum of 15 end-tidal values were recorded with each technique. The
instantaneous respiratory quotients (RQs) associated with the end-tidal
values were calculated, and values with a RQ of >0.9 or <0.75 were
discarded because these were likely to indicate the presence of
hyperventilation or hypoventilation, respectively. For the
measurement process to be considered successful, a minimum of
four acceptable pairs of end-tidal values were required for each
technique. In cases where four satisfactory values were not obtained
(generally because of hyperventilation), the measurement process was
repeated a second and, if necessary, a third time. If
satisfactory values could not be obtained with either technique, then
the subject was removed from further consideration.
Analysis. All the data were analyzed
with the statistical package SPSS Version 6.1 for Windows. The
distribution of height, weight, vital capacity,
PETCO2, and
PETO2 appeared
approximately normal when assessed graphically by plotting their cumulative proportions against the expected cumulative proportion for a normal distribution. Differences between groups were considered significant at P < 0.05.
RESULTS A total of 216 subjects were identified as suitable for inclusion in
the study. Of these subjects, 200 (94 SL and 106 HA) subsequently
attended the laboratory for further study. However, not all subjects
who attended the laboratory provided useful data for further analysis.
One SL subject was found to be living at HA and merely visiting Lima at
the time of the study. In the case of one HA subject, it was impossible
to determine the altitude of birth. Two subjects (1 SL and 1 HA) were
unable to cooperate adequately to obtain end-tidal samples. Twenty-one
subjects (10 SL and 11 HA) produced end-tidal values that consistently
yielded values for the instantaneous RQ that were >0.9, which
suggested that the sampling procedure induced hyperventilation in these subjects. These subjects were excluded from further analysis. No
subject was excluded through illness. This resulted in a total of 175 subjects (82 SL and 93 HA) from whom satisfactory data were obtained.
Anthropological and physiological data for the SL and HA groups are
shown in Table 1. There was no difference
in the average age or weight between the two groups. However, the
average height of the HA group was significantly less than that of the
SL group (P < 0.04, unpaired
two-tailed t-test), and there was a
tendency for the average vital capacity of the HA group to be more than that of the SL group (P < 0.07, unpaired two-tailed t-test). Smoking habit did not differ between the two groups
( Table 1.
Anthropological and physiological parameters of sea-level natives and
high-altitude natives living at sea level
2 test).
Altitude of Birth, m
P
0-999 (n = 82)
2,000-4,300 (n = 93)
Age, yr
33 ± 10.2
34 ± 10.7
<0.33
Age at
migration, yr
9 ± 5.4
Weight, kg
66 ± 10.8
67 ± 10.1
<0.41
Height, m
1.68 ± 0.06
1.66 ± 0.07
<0.04
Vital
capacity, l/m
2.18 ± 0.31
2.27 ± 0.33
<0.07
PETCO2, Torr
37.7 ± 2.25
37.7 ± 2.50
<0.85
PETO2, Torr
104.8 ± 3.03
104.7 ± 3.22
<0.92
Values are means ± SD; n, no. of subjects.
PETCO2, end-tidal
PCO2;
PETO2, end-tidal
PO2.
The responses of the subjects to questions concerning visits to HA are summarized in Table 2. Relatively few of the SL group had paid any visits to HA, which contrasted with the HA group where the number of subjects who had paid short-term visits to altitude was considerable. However, these visits were mostly infrequent and not of particularly long duration. A small proportion of the SL group had lived at altitude at some stage in their lives, and, similarly, a small proportion of the HA group had lived at altitude for a period of time subsequent to their initial migration to SL. The proportion of subjects who had visited altitude in the recent period before the study was quite low in both groups.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
In 130 subjects (54 SL and 76 HA), it was possible to obtain
satisfactory values of
PETCO2 and
PETO2 by sampling from both
the nose and mouth. In 8 subjects (6 SL and 2 HA), it was only possible
to get satisfactory values from the mouth, and in 37 subjects (22 SL
and 15 HA), it was only possible to get satisfactory values from the
nose. To assess whether there was any difference between the results
obtained by the two techniques, a paired comparison between the values
obtained with the two techniques was undertaken on those subjects for
whom both sets of data were available. The average difference between
samples from the mouth and from the nose was 0.25 Torr
[0.48 to 0.02 Torr; 95% confidence interval
(CI)] for PETCO2 and
0.29 Torr (0.15 to 0.74 Torr; 95% CI) for
PETO2. Because these
differences were very small and similar numbers from the SL and HA
groups had either mouth only or nose only samples, it was decided to
pool the end-tidal data from the two techniques. For the subjects in
whom both forms of end-tidal values were available, the average of the
two values was employed.
PETCO2 and
PETO2 values for each
subject plotted against altitude of birth are shown in Fig.
1, and the average
PETCO2 and
PETO2 values for the SL and HA groups are shown in Table 1. The average difference for
PETCO2 between the SL and HA
groups was 0.07 Torr (0.64 to 0.78 Torr; 95% CI), and the
average difference for PETO2
was 0.05 Torr (0.89 to 0.99 Torr; 95% CI), which suggests that
there are no differences between the two groups.
To determine whether there were any other factors that might affect PETCO2 and PETO2 in the HA group, the HA subjects were partitioned in a number of ways. First, the HA group was partitioned between those born below 3,000 m (n = 41) and those born at 3,000 m or above (n = 52). No significant differences were found between the two groups or between these groups and the SL group [analysis of variance (ANOVA)]. Second, the HA group was partitioned into those migrating to SL before the age of 12 yr (n = 69), those migrating between the ages of 12 and 15 yr (n = 13), and those migrating at the age of 16 yr or above (n = 11). Again, no significant differences were found (ANOVA). Third, the HA group was partitioned into those who had migrated to near SL <20 yr before the study (n = 28), those who had migrated 20 yr or more before the study but <35 yr before the study (n = 50), and finally those who had migrated 35 yr or more before the study (n = 15). No significant differences were found (ANOVA). Finally, the HA group was partitioned between those who had visited altitude within a period of 3 mo before the study (n = 14) and those who had not (n = 79). No significant differences were detected (ANOVA).
DISCUSSION
The major finding of this study is that PETCO2 and PETO2 values for HA natives living at SL are extremely similar to those of SL natives living at SL. The significantly shorter height and the tendency toward a greater vital capacity in the HA natives compared with the SL natives are consistent with previous anthropological observations (5) and support the concept that environmental hypoxia had indeed exerted its effects, at least in part, on the group of HA natives in this study. The relatively large number of subjects in the study and the resultant narrow CIs for the differences in PETCO2 and PETO2 values between the two groups enable us to exclude any but the most minor differences in end-tidal gas pressures with confidence.
We are unaware of any other studies of the alveolar PCO2 and PO2 in HA natives living at SL that are on the scale of the present study. Sørensen and Severinghaus (16) reported that eight Andean natives born at ~3,000 m and resident at SL for several years had normal SL values for arterial PCO2. In contrast, Hackett et al. (6) found that 25 Sherpas who were all born at 2,200 m or above and all but 3 of whom had been in Katmandu, Nepal, at 1,600 m for at least 1 mo had relatively low PETCO2 values. It is possible that the difference between this study and the others either relates to differences between Sherpas and Andeans or relates to the duration of residence at the lower altitude. However, against the latter are the observations of Coudert et al. (3), who found that, in a study of 11 Andean HA natives, arterial PCO2 was above that of control subjects 5 days after descent to low altitude.
Our finding that HA natives should develop an alveolar PCO2 that is precisely normal for SL natives at SL has a number of possible interpretations. The first is that hypoxic chemoreflex sensitivity is unimportant in determining alveolar PCO2 at SL. Thus the difference in hypoxic chemoreflex sensitivity between HA natives and SL natives would not affect their alveolar PCO2 at SL. If this hypothesis is correct, then it would seem necessary to postulate either that the HA subjects have enough residual hypoxic chemoreflex sensitivity to trigger the variation in alveolar PCO2 with altitude or, alternatively, that the variation in alveolar PCO2 is brought about by mechanisms that do not require any hypoxic chemoreflex sensitivity. The latter possibility does not fit easily with the weight of evidence that carotid bodies are required for ventilatory acclimatization to altitude to occur (for a review, see Ref. 18). A second possibility is that our HA natives did not reside long enough at altitude to develop blunting. A third possibility is that the HA subjects had been at SL for a sufficient length of time to lose their blunting.
One method of assessing the importance of hypoxic chemoreflex sensitivity in determining alveolar PCO2 in euoxia is to study the effect of carotid body denervation on PCO2. Unfortunately, there appears to be no clear consensus on the effects of carotid body denervation/resection in humans. Wade et al. (17) reported a rise of several millimeters of mercury in arterial PCO2 after carotid endarterectomy. Lugliani et al. (13) and Honda et al. (8) reported no effect of carotid body resection on arterial PCO2. However, in a later paper with a control group selected to match the level of lung disease in the resected patients, Honda et al. (9) did observe an increase in arterial PCO2 of several millimeters of mercury in the resected patients. In animals, the effects of carotid body resection/denervation may be species dependent. In awake dogs and rabbits, chronic carotid denervation caused hypoventilation and hypercapnia (2). In ponies, a similar finding has been reported (1). However, in awake cats, chemodenervation appears to have no effect on alveolar PCO2 (12). In summary, the influence of the carotid bodies on normal euoxic PCO2 remains uncertain.
The length of time required from birth for HA natives to develop blunting is not really clear. Hanson et al. (7) found in experimental animals that exposure of the newborn to hypoxia inhibits the normal postnatal development of the peripheral chemoreflex sensitivity to hypoxia. On the other hand, Lahiri et al. (10) found that much longer exposures are required and that blunting does not really begin to become apparent until after the age of 12 yr. In our study, the mean age of migration was 9 yr, but even in the subjects who had migrated after the age of 16 yr, the end-tidal values were similar to those at SL.
The question of whether HA natives can recover their hypoxic sensitivity by residence at SL for a sufficient period of time remains unclear. Sørensen and Severinghaus (16) found that eight HA natives who had been resident near SL for between 2 and 16 yr had hypoxic sensitivities that remained blunted. On the other hand, Lahiri et al. (10) suggested that the hypoxic sensitivity may be recovered by a sufficient period of residence at SL, although no data are presented. Our HA natives had been resident at SL for an average of 25 yr, with relatively few subjects who were recent migrants. However, no difference in PETCO2 was detected between a group that had been resident for <20 yr when compared with a group that had been resident for 35 yr or more. Overall from the literature, we feel it likely, but unproven, that our group of HA natives would have hypoxic sensitivities that are blunted.
In a more general context, the natural level for alveolar PCO2 at SL can be considered as being determined as part of the overall regulation of acid-base balance. Values for PCO2, pH, and bicarbonate concentration are mutually dependent through the Henderson-Hasselbalch relationship: the pH of the body fluids tends to be regulated at the expense of PCO2 and bicarbonate, and the precise relationship between PCO2 and bicarbonate is determined as a "balance" between respiratory and renal regulatory mechanisms. A consequence is that acid-base disturbances and respiratory and renal diseases all may alter alveolar PCO2 at SL, and the additional respiratory drive of hypoxia at altitude may also be seen as perturbing the balance between lung and kidney, resulting in an alteration of alveolar PCO2. In this context, our finding that the alveolar PCO2 does not differ between SL natives and HA natives living at SL leads us to conclude that birth and development at altitude confer no additional respiratory drive that cannot be reversed by residence at SL (in contrast to such developmental features as shorter stature, larger lung volumes, and, quite possibly, a blunted ventilatory sensitivity to acute hypoxia). The reason that such a respiratory drive might have been suspected is that, at altitude, HA natives possess values for alveolar PCO2 that are lower than normal for SL despite a blunted ventilatory sensitivity to hypoxia.
ACKNOWLEDGEMENTS
The authors thank Jose-Antoneo Palaceos for all his help with recruiting subjects.
FOOTNOTES
Address for reprint requests: P. A. Robbins, Univ. Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK (E-mail: peter.robbins{at}physiol.ox.ac.uk).
Received 3 October 1995; accepted in final form 21 May 1996.
REFERENCES
| 1. | Bisgard, G. E., H. V. Forster, J. A. Orr, D. D. Buss, C. A. Rawlings, and B. Brasmussen. Hypoventilation in ponies after carotid body denervation. J. Appl. Physiol. 40: 184-190, 1976. |
| 2. | Bouverot, P., V. Candas, and J. P. Liberi. Role of the arterial chemoreceptors in ventilatory adaptation to hypoxia of awake dogs and rabbits. Respir. Physiol. 17: 209-219, 1973. |
| 3. | Coudert, J., M. Paz-Zamora, and E. Vargas. Volumes pulmonaires, ventilation et pression des gaz du sang chez les residents de haute altitude transferes a basse altitude (Abstract). J. Physiol. Paris 67: 336A, 1973. |
| 4. | Fitzgerald, M. P. The changes in the breathing and the blood at various high altitudes. Phil. Trans. Roy. Soc. 203: 351-371, 1913. |
| 5. | Frisancho, A. R. Developmental adaptation to high altitude hypoxia. Int. J. Biometeorol. 21: 135-146, 1977. |
| 6. | Hackett, P. H., J. T. Reeves, C. D. Reeves, R. F. Grover, and D. Rennie. Control of breathing in Sherpas at low and high altitude. J. Appl. Physiol. 49: 374-379, 1980. |
| 7. | Hanson, M. A., P. Kumar, and B. A. Williams. The effect of chronic hypoxia upon the development of respiratory chemoreflexes in the newborn kitten. J. Physiol. Lond. 411: 563-574, 1989. |
| 8. | Honda, Y., S. Watanabe, S. Hasegawa, S. Myojo, H. Takizawa, T. Sugita, K. Kimura, T. Hasegawa, T. Kuriyama, Y. Saito, Y. Satomura, H. Katsuki, and J. W. Severinghaus. Respiration in man after chronic glomectomy. In: Morphology and Mechanisms of Chemoreceptors, edited by A. S. Paintal. Delhi, India: Vallabhbhai Patel Chest Institute, University of Delhi, 1976, p. 147-155. |
| 9. | Honda, Y., S. Watanabe, I. Hashizume, Y. Satomura, N. Hata, Y. Sakakibara, and J. W. Severinghaus. Hypoxic chemosensitivity in asthmatic patients two decades after carotid body resection. J. Appl. Physiol. 46: 632-638, 1979. |
| 10. | Lahiri, S., R. G. DeLaney, J. S. Brody, M. Simpser, T. Velasquez, E. K. Motoyama, and C. Polgar. Relative role of environmental and genetic factors in respiratory adaptation to high altitude. Nature Lond. 261: 133-135, 1976. |
| 11. | Lahiri, S., and J. S. Milledge. Sherpa physiology. Nature Lond. 207: 610-612, 1965. |
| 12. | Long, W. Q., G. G. Giesbrecht, and N. R. Anthonisen. Ventilatory response to moderate hypoxia in awake chemodenervated cats. J. Appl. Physiol. 74: 805-810, 1993. |
| 13. | Lugliani, R., B. J. Whipp, C. Seard, and K. Wasserman. Effect of bilateral carotid body resection on ventilatory control at rest and during exercise in man. N. Engl. J. Med. 285: 1105-1111, 1971. |
| 14. | Milledge, J. S., and S. Lahiri. Respiratory control in lowlanders and Sherpa highlanders at altitude. Respir. Physiol. 2: 310-322, 1967. |
| 15. | Severinghaus, J. W., C. R. Bainton, and A. Carcelen. Respiratory insensitivity to hypoxia in chronically hypoxic man. Respir. Physiol. 1: 308-334, 1966. |
| 16. | Sørensen, S. C., and J. W. Severinghaus. Irreversible respiratory insensitivity to acute hypoxia in man born at high altitude. J. Appl. Physiol. 25: 217-220, 1968. |
| 17. | Wade, J. G., C. P. Larson, R. F. Hickey, W. K. Ehrenfeld, and J. W. Severinghaus. Effect of endarterectomy on carotid chemoreceptor and baroreceptor function in man. N. Engl. J. Med. 282: 823-829, 1970. |
| 18. | Weil, J. V. Ventilatory control at high altitude. In: Handbook of Physiology. The Respiratory System. Control of Breathing. Bethesda, MD: Am. Physiol. Soc., 1986. sect. 3, vol. II, pt. 2, chapt. 21, p. 703-727. |
This article has been cited by other articles:
|
|
 |
|
  M. Rivera-Ch, A. Gamboa, F. Leon-Velarde, J.-A. Palacios, D. F. O'Connor, and P. A. Robbins Plasticity in Respiratory Motor Control: Selected Contribution: High-altitude natives living at sea level acclimatize to high altitude like sea-level natives J Appl Physiol, March 1, 2003; 94(3): 1263 - 1268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Leon-Velarde, A. Gamboa, M. Rivera-Ch, J.-A. Palacios, and P. A. Robbins Plasticity in Respiratory Motor Control: Selected Contribution: Peripheral chemoreflex function in high-altitude natives and patients with chronic mountain sickness J Appl Physiol, March 1, 2003; 94(3): 1269 - 1278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Vargas, F. Leon-Velarde, C. Monge-C., J.-A. Palacios, and P. A. Robbins Similar hypoxic ventilatory responses in sea-level natives and high-altitude Andean natives living at sea level J Appl Physiol, March 1, 1998; 84(3): 1024 - 1029. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
