J Appl Physiol 94: 1279–1287, 2003.

First published November 27, 2002; 10.1152/japplphysiol.00859.2002.

highlighted topics
Plasticity in Respiratory Motor Control
Selected Contribution: Ventilatory response to CO2 in high-
altitude natives and patients with chronic mountain sickness

MARZIEH FATEMIAN,1 ALFREDO GAMBOA,2 FABIOLA LEÓN-VELARDE,2

MARIA RIVERA-CH,2 JOSE-ANTONIO PALACIOS,2 AND PETER A. ROBBINS1
1
University Laboratory of Physiology, University of Oxford, Oxford OX1 3PT,
United Kingdom; and 2Department De Ciencias Biologicas y Fisiologicas/IIA,
Universidad Peruana Cayetano Heredia, Lima 100, Peru
Submitted 19 September 2002; accepted in final form 25 November 2002

Fatemian, Marzieh, Alfredo Gamboa, Fabiola León-
Velarde, Maria Rivera-Ch, Jose-Antonio Palacios, and
Peter A. Robbins. Selected Contribution: Ventilatory re-
sponse to CO2 in high-altitude natives and patients with
chronic mountain sickness. J Appl Physiol 94: 1279 – 1287,
2003. First published November 27, 2002; 10.1152/japplphysiol.
00859.2002.—The ventilatory responses to CO2 of high-alti-
tude (HA) natives and patients with chronic mountain sick-
ness (CMS) were studied and compared with sea-level (SL)
natives living at SL. A multifrequency binary sequence
(MFBS) in end-tidal PCO2 was employed to separate the fast
(peripheral) and slow (central) components of the chemore-
flex response. MFBS was imposed against a background of
both euoxia (end-tidal PO2 of 100 Torr) and hypoxia (52.5
Torr). Both total and central chemoreflex sensitivity to CO2
in euoxia were higher in HA and CMS subjects compared
with SL subjects. Peripheral chemoreflex sensitivity to CO2
in euoxia was higher in HA subjects than in SL subjects.
Hypoxia induced a greater increase in total chemoreflex
sensitivity to CO2 in SL subjects than in HA and CMS
subjects, but peripheral chemoreflex sensitivity to CO2 in
hypoxia was no greater in SL subjects than in HA and CMS
subjects. Values for the slow (central) time constant were
significantly greater for HA and CMS subjects than for SL
subjects.
regulation of ventilation; hypercapnic ventilatory response;
human; Andean natives; blunting
PULMONARY VENTILATION can be stimulated by CO2
through both the central and peripheral chemorefl
pathways. To assess central chemorefl sensitivity,
investigators have commonly employed a back-
ground of high O2, which minimizes, but probably
does not abolish, the component of the response to
Address for reprint requests and other correspondence: P. A.
Robbins, Univ. Laboratory of Physiology, Parks Rd., Oxford OX1
3PT, UK (E-mail: peter.robbins@physiol.ox.ac.uk).
CO2 that arises from the peripheral chemoreceptors.
An alternative, more recent approach has been to use
the difference in response speeds of the peripheral
chemorefl (fast) and central chemorefl (slow) to
separate the contributions of the central and periph-
eral chemorefl to the overall ventilatory re-
sponse to CO2 (1, 6, 20).
There have been a number of studies of the ventila-
tory response to CO2 in both high-altitude (HA) natives
and patients with chronic mountain sickness (CMS).
Some studies have reported that the ventilatory sensi-
tivities to CO2 of HA natives are similar in magnitude
to those of sea-level (SL) natives at SL and lower than
those of newly acclimatized SL natives at HA (3, 9),
whereas others have found that they are similar to
those of SL natives newly acclimatized to HA (18, 23).
In general, these studies have been conducted on rel-
atively few subjects, and the comparisons lack a rigor-
ous statistical basis. Studies of patients with CMS
have generally found that their ventilatory sensitivi-
ties to CO2 are similar to those of healthy HA natives
(12, 23). However, there are the same drawbacks to
these comparisons as with those for normal HA sub-
jects. Furthermore, to the best of our knowledge, there
have been no attempts to separate the peripheral and
central chemoreflex components on the basis of their
relatively different speeds of response.
The purpose of the present study was primarily
descriptive and was to improve our understanding of
the ventilatory chemoreflex response to CO2 in HA
natives and patients with CMS. In particular, the
present study used a dynamic technique to separate
the peripheral and central components of the chemore-
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby
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solely to indicate this fact.

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1280 VENTILATORY RESPONSE TO CO2 AT HIGH ALTITUDE

Table 1. Physical characteristics of subjects but this was changed to +10 Torr to match the other subjects
once it was clear that this value did not cause discomfort.
SL (n = 35) HA (n = 29) CMS (n = 14) Apparatus and techniques. During the experiments, sub-
jects sat upright in a chair and breathed through a mouth-
Age, yr 30.7 ± 6.2 35.0 ± 6.0* 41.2 ± 9.9†‡
Weight, kg 67.5 ± 12.6 60.5 ± 6.8* 62.6 ± 8.3
piece with the nose of the subject occluded with a clip.
Height, m 1.66 ± 0.06 1.62 ± 0.07* 1.62 ± 0.06 Respired volumes were measured with a turbine volume-
Surface area, m2 1.33 ± 0.19 1.22 ± 0.11* 1.25 ± 0.13 measuring device (VMM 400, Interface Associates, Laguna
Hematocrit, % 54.7 ± 2.4 67.5 ± 3.6‡ Niguel, CA), and respired gases were analyzed with a fast gas
Altitude of birth, m 150 4,287 ± 161* 4,131 ± 478† analyzer (Datex Ohmeda, Hatfield, UK). Data were logged to
PETCO2, Torr 38.1 ± 2.5 26.8 ± 2.1* 29.5 ± 1.8†‡ computer by using National Instruments interface cards
PETO2, Torr 106.1 ± 2.8 52.9 ± 5.8* 51.2 ± 2.3†‡ (types DAQCard-1200 and DAQCard-AO-2DC).
Gph-45, l/min/% 0.85 ± 0.60 0.36 ± 0.26* 0.29 ± 0.19† PETCO2 and PETO2 were regulated breath by breath by using
V̇c-45, l/min 9.2 ± 3.6 12.1 ± 4.6* 13.3 ± 4.2†
Gph-34, l/min/% 0.52 ± 0.30 0.29 ± 0.27‡
the technique of dynamic end-tidal forcing (22). Before the
V̇c-34, l/min 14.1 ± 5.0 14.5 ± 4.4 experiment started, values for inspiratory PCO2 and PO2 that
were likely to produce the desired PETCO2 and PETO2 were
Values are means ± SD. SL, sea-level natives; HA, high-altitude calculated by using a model of the cardiorespiratory system.
natives; CMS, patients with chronic mountain sickness; PETCO2, At the start of the experiment, the inspiratory gas was mixed
air-breathing end-tidal PCO2; PETO2, air-breathing end-tidal PO2. to the correct composition by using a fast gas-mixing system
Gph, ventilatory sensitivity to hypoxia estimated by fitting a dy-
constructed from commercially available mass flow control-
namic model; V̇c, calculated ventilation in absence of hypoxia esti-
mated by fitting a dynamic model. Variable x in the expression — x
lers (type 1559A, MKS Instruments, Altringham, UK). Devi-
following parameters of the hypoxic response indicates the lowest ations in PETCO2 and PETO2 away from their desired values
PETO2 used in the experimental protocol. * HA significantly different were calculated breath by breath during the experiment, and
from SL. † CMS significantly different from SL. ‡ HA significantly these deviations were used as feedback through an integral
different from CMS. Values are significant when P < 0.05. Hypoxic proportional controller to modify the inspiratory PCO2 and
responses are from previous studies (10, 16). PO2 as required.
Data analysis. To separate the fast (peripheral) and slow
(central) components of the ventilatory reponse to hypoxia, a
mathematical model was fitted to the data. This model is
flex response to CO2. The dynamic variation in end- model 2 of Pedersen et al. (20). Each component of the model
tidal PCO2 (PETCO 2) followed a multifrequency binary has a gain term (G), a time constant (T), and pure delay (d);
sequence (MFBS) that had been optimized for separat- for the peripheral component of the model, these are denoted
ing the central and peripheral components of the re- as Gp, Tp, and dp, respectively, and for the central compo-
sponse (20). These measurements were made against a nent of the model, these are denoted as Gc, Tc, and dc,
background end-tidal PO2 (PETO2) of 100 and 52.5 Torr. respectively. In addition to these terms, there was a single
bias term, B, denoting the extrapolated PETCO2 for which
METHODS minute ventilation (V̇E) = 0, and a linear trend term, C. To fit
these equations to the data, we assumed that PETCO2 was
Subjects. Originally, it was planned to recruit 25 SL na- constant within each breath, which enabled the differential
tives, 25 healthy HA natives (who had spent their life at an equations to be solved to provide a set of difference equations
altitude of >3,500 m) and 15 patients with CMS (who had an that could be used in the parameter-estimation process. This
excessive degree of erythrocytosis, defined as a hematocrit of process is described in more detail in Ref. 20.
>63%). However, not all subjects completed both protocols,
and so additional subjects were recruited as necessary to
ensure that that the total number of repeats of each protocol
was adhered to, except in the case of the patients with CMS, Table 2. Number of subjects common
where only 14 patients were successfully recruited. SL na- to any pair of protocols
tives for the experiments at SL were recruited in Lima, Peru,
and subjects for the experiments at HA (healthy HA natives AHVR-45 AHVR-34 MFBS-100 MFBS-52.5

and patients with CMS) were recruited from among the SL

residents of Cerro de Pasco, Peru (altitude 4,300 m; baromet- AHVR-45 35
ric pressure of laboratory 450 Torr, personal communication MFBS-100 25 25
from C. Monge). MFBS-52.5 25 15 25
Protocols. Two protocols were employed. They differed HA
from one another in relation to the background level of PO2; AHVR-45 23
AHVR-34 21 22
in one protocol, PETO2 was held at 100 Torr, and in the other 23 22 25
protocol PETO2 was held at 52.5 Torr. Both protocols used a MFBS-100 21 20 21 25
MFBS-52.5
MFBS in PETCO2 that lasted for 1,408 s and had been opti- CMS
mized to separate the peripheral and central chemoreflex AHVR-45 14
contributions to the overall ventilatory sensitivity to CO2 AHVR-34 14 14
(20). Before the start of the MFBS, the subjects’ PETCO2 was MFBS-100 14 14 14
held at +2 Torr above their normal air-breathing value for 5 MFBS-52.5 14 14 14 14
min. The lower value of PETCO2 for the MFBS was always the
AHVR, protocols for measuring acute hypoxic ventilatory re-
same as for the lead-in period of 5 min. For SL natives and sponse; MFBS, protocols that used multifrequency binary sequence
patients with CMS,+10theTorr
upper value
the for the PETCO2 value.
of the in
MFBS was always above air-breathing — xPETCO2 to measure ventilatory response to CO2. Parameter x in
the protocols indicates, in the case of AHVR, the lowest
For the first few experiments on the healthy HA natives, we following
employed a value of +8 Torr above the air-breathing value, level of PETO2 used and, in the case of MFBS, the background level of
PETO2 employed. AHVR data are from previous studies (10, 15).

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 VENTILATORY RESPONSE TO CO2 AT HIGH ALTITUDE 1281

Fig. 1. Examples of data and model fits for the multifrequency binary sequence (MFBS) in end-tidal PCO2 (PETCO2)
at a constant end-tidal PO2 (PETO2) of 100 Torr. Left, sea-level (SL) native; middle, high-altitude (HA) native; right,
patient with chronic mountain sickness (CMS). PETCO2 (A), PETO2 (B), ventilatory response (F) and deterministic
component of the model fit (line) together with associated residuals (C), and residuals from overall model fitting
process (deterministic model plus noise model; D).

The deterministic model was fitted in conjunction with a
parallel noise model that was used to model the correlation
that exists between breaths. The two parameters associ-
ated with this model are the system gain (f ) and the ratio
of the variances between the process and measurement
noise (Rv/Rw). Further details of this process are given
elsewhere (17, 20).
These two models were fitted concurrently to the data by
using a standard algorithm for minimizing a sum of squared
residuals (subroutine E04FDF, Numerical Algorithms Group,
Oxford, UK).
For the purposes of displaying an average response,
breath-by-breath data were first interpolated over 1-s inter-
vals and then averaged across subjects. The same procedure
was employed for the breath-by-breath model output for
comparison.
Statistical comparisons were generally undertaken by us-
ing ANOVA. For the comparisons between PETO2 = 100 Torr
and PETO2 =52.5 Torr, subjects were used as a random factor;
for comparisons across groups, this was, of course, not possi-
ble. Post hoc comparisons were drawn in cases where the
overall result from ANOVA was significant by using the least
significant difference technique. Where correlations were
drawn, these were undertaken by using the product-moment
J Appl Physiol • VOL
correlation coefficient. Statistical significance was accepted
at P < 0.05.
RESULTS
Subjects. The physical characteristics of the subjects
are given in Table 1, and the numbers of subjects
common to the protocols are given in Table 2. The HA
natives were ~4 yr older than the SL controls, and the
CMS subjects were ~10 yr older than the SL controls.
The HA and CMS subjects were, on average, lighter
and shorter than the SL controls, although this only
reached significance for the HA group of subjects. As
expected, the patients with CMS had higher hemat-
ocrits than the HA subjects. All HA and CMS subjects
were scored for symptoms of CMS (15), where a score of
Š12 is taken as evidence of significant symptomatol-
ogy. HA subjects scored an average of 6.8 ± 5.6
(mean ± SD), and CMS subjects scored an average of
15.6 ± 3.7. The difference between these was highly
significant (P < 0.001). Patients with CMS had higher
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1282 VENTILATORY RESPONSE TO CO2 AT HIGH ALTITUDE

values for ambient, air-breathing PETCO 2 and lower
values for ambient, air-breathing PETO2.
Values for the acute ventilatory responses to hypoxia
were available for almost all subjects (Table 2) from
previous studies (10, 16), and the average values are
listed in Table 1. Values for the ventilatory sensitivi-
ties to acute hypoxia were substantially lower for HA
and CMS subjects compared with SL subjects, and, for
the data for more severe hypoxia, values for CMS
subjects were significantly below those for healthy HA
subjects.
Responses to MFBS in PETCO 2. Example data for
individual subjects are shown for the MFBS in PETCO2
against a background PETO2 of 100 Torr in Fig. 1 and
against a background PETO2 of 52.5 Torr in Fig. 2.
PETCO 2 followed the desired pattern of the MFBS rea-
sonably in all cases. PETO2 was well controlled in all
cases, with the exception of a glitch at ~8 min in the SL
subject under conditions of hypoxia. Such problems are
usually associated with disturbances of respiratory
rhythm, e.g., coughing. V̇E for all subjects and protocols
can be seen to be following the pattern of stimulation
by the MFBS in all cases, although the variation in
sensitivity between different subjects is clearly wide,
as is the general breath-by-breath variability.
Also shown in Figs. 1 and 2 are example fits of the
respiratory model to the data. The deterministic com-
ponent of the model appears to describe the pattern of
response within the data reasonably well, although the
individual data points are quite variable. The process
of fitting the deterministic and noise models simulta-
neously to the data provides residuals that are close to
white (they lack longer term trends) compared with the
residuals when just the deterministic component of the
model is considered. For each fit, cross-correlations
were calculated between PETCO2 and the residuals from
the fitting process and averaged for each subject group
and protocol. Very few of these exceeded the 95% con-
fidence interval (CI) of ±0.02, which if they had might
have indicated an inadequacy of the model. Average
parameter values from the fitting process are given in
Table 3.
Not all subjects undertook both euoxic and hypoxic
MFBS protocols, and some of the earlier HA subjects
had amplitudes for PETCO 2 in the MFBS of 6 Torr
rather than the 8 Torr used elsewhere. Figure 3 shows

Fig. 2. Examples of data and model fits for the MFBS in PETCO2 against a background PETO2 of 52.5 Torr. Left, sea-
level (SL) native; middle, high-altitude (HA) native; right, patient with chronic mountain sickness (CMS). PETCO2
(A), PETO2 (B), ventilatory response (F) and deterministic component of the model fit (line) together with associated
residuals (C), and residuals from overall model fitting process (deterministic model plus noise model; D).

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 VENTILATORY RESPONSE TO CO2 AT HIGH ALTITUDE 1283

Table 3. Parameter values for the model fits to the the start of the MFBS record was higher for SL sub-
MFBS data under euoxic and hypoxic conditions for jects than for healthy HA natives and patients with
all subjects in the SL, HA, and CMS subject groups CMS. Third, for all groups and protocols except the SL
group at a PETO2 of 52.5 Torr, there is a trend toward an
SL HA CMS increase in V̇E over time. For the SL group at a PETO 2 of
MFBS, 100 Torr (n = 25) (n = 25) (n = 14) 52.5 Torr, this trend is absent with the result that V̇E
PETCO2, Torr 38.1 ± 2.5 27.7 ± 1.7* 29.6 ± 2.0†‡ is broadly similar between the two protocols at the
Gtot, l • min
—1 • Torr
—1
—1
—1
2.6 ± 1.0 5.0 ± 2.3* 4.3 ± 1.3† lower PETCO at the end of the MFBS sequence. These
Gp, l • min • Torr 0.85 ± 0.46 1.46 ± 0.84* 0.85 ± 0.41 findings are2 consistent with the known slow progres-
Tp, s 14.7 ± 7.4 15.0 ± 7.7 14.5 ± 6.8
dp, s 7.1 ± 3.8 6.1 ± 1.9 7.9 ± 3.6 sive stimulatory effect of hypercapnia on V̇E and, in the
Gc, l • min—1 • Torr—1 1.7 ± 0.8 3.6 ± 1.8* 3.4 ± 1.3† case of SL subjects at a PETO 2 of 52.5 Torr, the progres-
Tc, s 115 ± 83 185 ± 86* 206 ± 95† sive development of hypoxic ventilatory decline (see
dc, s 11.1 ± 5.7 11.6 ± 5.5 9.0 ± 6.0 Parameter B and trend term C in DISCUSSION). Fourth, for
B, Torr 32.7 ± 7.0 25.7 ± 2.0* 28.2 ± 2.3†
C, l • min—1 • min—1 0.40 ± 0.46 0.65 ± 2.0 0.37 ± 0.37 healthy HA natives and subjects with CMS, the progres-
f 0.79 ± 0.13 0.84 ± 0.08 0.82 ± 0.08 sive rise in V̇E appears slightly greater for the MFBS
Rv/Rw 0.57 ± 0.63 0.62 ± 0.66 0.51 ± 0.41 protocol at a PETO2 of 100 Torr than for the protocol at a
MFBS, 52.5 Torr (n = 25) (n = 25) (n = 14) PETO 2 of 52.5 Torr, such that by the end of the protocol, V̇E
PETCO2, Torr 39.2 ± 1.2 26.8 ± 2.1* 29.5 ± 1.8†‡ against a background PETO2 of 100 Torr slightly exceeds
Gtot, l • min—1 • Torr—1 4.2 ± 1.5§ 5.3 ± 2.9 5.1 ± 1.6
Gp, l • min—1 • Torr—1 1.9 ± 1.2 2.1 ± 1.4 1.8 ± 1.1 V̇E against a background PETO2 of 52.5 Torr. This is
Tp, s 10.9 ± 7.2 12.0 ± 6.9 12.7 ± 6.8 consistent with a continued, slow stimulatory effect of the
dp, s 4.5 ± 3.4§ 5.0 ± 2.3 6.1 ± 3.0§ higher PETO2 in HA and CMS subjects.
Gc, l • min—1 • Torr—1 2.3 ± 1.0§ 3.2 ± 1.9* 3.3 ± 1.2 The mean parameter estimates for the trend term
Tc, s 107 ± 107 175 ± 112* 231 ± 93†
dc, s 9.0 ± 5.8§ 12.0 ± 5.3 11.2 ± 5.4 (parameter C) for the different protocols and subject
B, Torr 33.3 ± 3.8§ 25.5 ± 2.6* 28.6 ± 2.3†‡ groups (Tables 3 and 4) are consistent with these
C, l • min—1 • min—1 —0.15 ± 0.31 0.20 ± 0.46 0.24 ± 0.35 observations. Parameter C is negative for the SL sub-
f 0.88 ± 0.09 0.83 ± 0.1 0.84 ± 0.09 jects at a PETO2 of 52.5 Torr and positive for all other
Rv/Rw 0.46 ± 0.51 0.93 ± 0.83 0.44 ± 0.31
groups/protocols. For the HA and CMS groups, the
Values are means ± SD. Gtot, total chemoreflex sensitivity to CO2; trend term is larger at a PETO 2 of 100 Torr than at a
Gp, peripheral chemoreflex sensitivity; Tp, peripheral chemoreflex PETO2 of 52.5 Torr.
time constant; dp, peripheral chemoreflex delay; Gc, central chemo- The presence of different starting values for V̇E and
reflex sensitivity; Tc, central chemoreflex time constant; dc, central
chemoreflex delay; B, bias term equivalent to PETCO2 for which different long-term trends within the data make the
ventilation is zero; C, ventilatory trend; f, system gain for noise visual comparison of ventilatory sensitivities to CO2 and
component; Rv/Rw, variance ratio for process to measurement noise. the interactions between CO2 and hypoxia difficult. In
* HA significantly different from SL. † CMS significantly different Fig. 3C, the ventilatory data and model responses have
from SL. ‡ HA significantly different from CMS. § Value in hypoxia
significantly different from value in euoxia. Values are significant been replotted so that all responses are aligned to start at
when P < 0.05. a V̇E of 10 l/min, and the model trend terms have been
subtracted away from both the data and model output.
There are three features of note. First, the total ventila-
averaged records for the subset of subjects for whom tory sensitivity to CO2 at a PETO 2 of 100 Torr appears
there were MFBS sequences at an amplitude for PETCO 2 greatest for healthy HA subjects, intermediate for CMS
of 8 Torr at both a PETO 2 of 100 and 52.5 Torr. The subjects, and least for SL subjects. Second, the interac-
parameter values for this subset of subjects are given tion between CO2 and hypoxia appears greatest for SL
in Table 4. subjects, intermediate for the healthy HA natives, and
Figure 3A shows that the MFBS in PETCO 2 was well least for the patients with CMS. Third, although subtrac-
matched between the data gathered at a PETO 2 of 100 tion of the model trend has removed all the apparent slow
Torr and the data gathered at a PETO 2 of 52.5 Torr, increase in V̇E over time for SL subjects, this is not the
although for the SL level subjects, the absolute values case for both the HA and CMS groups, where some
for PETCO2 were ~1 Torr higher at a PETO 2 of 52.5 Torr progressive increase in V̇E over time remains.
than at a PETO 2 of 100 Torr. Parameters for ventilatory sensitivity to CO2. At a
Figure 3B shows the averaged V̇E for the subjects for PETO2 of 100 Torr, the total ventilatory sensitivity to
both the euoxic and hypoxic protocols. There are a CO2 in the HA native group was ~5 l • min—1 • Torr—1,
number of features of note. First, in marked contrast to which was around double that of the SL group. The
SL subjects, there is no perceptible effect of the two sensitivity of the CMS group, at ~4.4 l • min—1 •
different levels of PETO2 on V̇E at the start of the MFBS Torr—1, was also significantly greater than for the SL
sequence for either healthy HA natives or subjects with group, with the difference between the HA and CMS
CMS. This suggests that, in HA and CMS groups, any groups not attaining significance. These differences
reduction in peripheral chemoreflex discharge at the can be attributed primarily to significant differences in
onset of the higher level of PETO2 has been matched by Gc, although the value for Gp for the HA natives was
an equivalent increase in central stimulation of V̇E also significantly higher than for the SL natives.
through the 5-min period of euoxia that precedes the The presence of a background of hypoxia (PETO 2 =
start of the MFBS record in the figure. Second, V̇E at 52.5 Torr) increased the total ventilatory sensitivity
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1284 VENTILATORY RESPONSE TO CO2 AT HIGH ALTITUDE

Fig. 3. Averaged MFBS in PETCO2, ventilatory response to MFBS, and model fits for a group of 15 SL residents
(left), 15 HA residents (middle), and 13 patients with CMS (right). This subset of subjects has undertaken both
MFBS protocols with an MFBS amplitude of 8 Torr. A: averaged PETCO2 at a PETO2 of 100 Torr (solid line) and at
a PETO2 of 52.5 Torr (broken line). B: averaged ventilatory response to MFBS at a PETO2 of 100 Torr (E) and a PETO2
of 52.5 Torr (F). Solid lines are model fits. C: same as B, except data and model fits have all been aligned to start
at a ventilation of 10 l/min and have had the fitted trend removed from the responses.

to CO2 compared with euoxia. This increase was
greater for the SL group than for the HA and CMS
groups combined (P < 0.05). Interestingly, the incre-
ments in Gp with hypoxia did not differ between
groups, but there was a significant increase in Gc in
the SL group that did not occur in the HA and CMS
groups (P < 0.05).
Parameter B. For the HA and CMS groups, average
values for parameter B were very similar for the euoxia
and hypoxia protocols. For the SL group, there was a
small but statistically significant difference in the val-
ues for parameter B between protocols, which possibly
is explained by small differences in the control values
for air-breathing PETCO between the two protocols. Of
2
greater significance is that, for the SL subjects, the
average difference between normal air-breathing
PETCO 2 and parameter B was ~5.5 Torr, whereas for
HA and CMS subjects this difference was ~1.5 Torr.
These differences are consistent with the higher start-
ing level for V̇E in the SL group compared with the HA
and CMS groups, and also the much greater effect of
J Appl Physiol • VOL
hypoxia at the lower value for PETCO2 in the SL group,
especially when this is combined with the greater effect
of hypoxia on the total ventilatory sensitivity to CO2 in
the SL group of subjects.
Dynamic parameters of the peripheral chemoreflex
loop. For Tp, there were no differences between groups
or protocols. For dp, there were no differences between
the groups, but the values for dp were lower in hypoxia
than euoxia (P < 0.001, ANOVA).
Dynamic parameters of the central chemoreflex loop.
A striking finding of this study is that Tc was very
much slower for the HA and CMS groups compared
with the SL group. This finding was present in both
euoxia and hypoxia and did not differ between proto-
cols. This finding is consistent with the observation
that, after removing trend, V̇E was similar at the be-
ginning and end of the MFBS for the SL subjects but
remained somewhat elevated at the end for both HA
and CMS subjects (Fig. 3). Values for dc did not differ
significantly.
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 VENTILATORY RESPONSE TO CO2 AT HIGH ALTITUDE 1285

Table 4. Parameter values for the model fits to the greater than that of SL natives at SL and was not
MFBS data under euoxic and hypoxic conditions significantly different from healthy HA natives.
for the subset of SL, HA, and CMS subjects Second, under conditions of euoxia, peripheral (fast)
whose responses are plotted in Fig. 3 chemoreflex sensitivity to CO2 was higher in healthy
HA natives than in SL natives at SL. Fast chemoreflex
SL HA CMS
sensitivity in CMS subjects was not different from SL
MFBS, 100 Torr (n = 15) (n = 15) (n = 13) natives at SL.
PETCO2, Torr 38.4 ± 2.2 27.9 ± 1.4 29.8 ± 1.9 Third, hypoxia caused a greater increase in total CO2
Gtot, l • min—1 • Torr—1 2.4 ± 0.7 5.3 ± 2.4* 4.4 ± 1.4† sensitivity in SL subjects than in the HA and CMS
Gp, l • min—1 • Torr—1 0.7 ± 0.4 1.5 ± 0.9* 0.9 ± 0.4
Tp, s 12.8 ± 7.3 14.7 ± 7.0 14.2 ± 7.0
subjects combined.
dp, s 6.9 ± 3.0 6.2 ± 2.1 7.3 ± 2.9 Fourth, values for parameter B, the extrapolated
Gc, l • min—1 • Torr—1 1.7 ± 0.6 3.8 ± 1.8* 3.5 ± 1.3† value for PETCO 2 for which V̇E = 0 were higher for
Tc, s 102 ± 71 171 ± 95* 218 ± 86† patients with CMS compared with healthy HA natives.
dc, s 11.1 ± 5.7 11.7 ± 5.9 9.2 ± 6.1
B, Torr 32.7 ± 4.3 25.8 ± 1.6* 28.5 ± 2.1†‡
Fifth, the values for Tc were significantly higher in
C, l • min—1 • min—1 0.37 ± 0.20 0.33 ± 0.5 0.29 ± 0.23 the HA and CMS groups combined than in the SL
f 0.76 ± 0.14 0.84 ± 0.08* 0.82 ± 0.08 group.
Rv/Rw 0.68 ± 0.75 0.66 ± 0.71 0.50 ± 0.42 Ventilatory response to CO2 of the SL subjects. For
MFBS, 52.5 Torr (n = 15) (n = 15) (n = 13) the SL group, the parameters of the respiratory model
PETCO2, Torr 39.0 ± 1.3 28.0 ± 1.5 29.7 ± 1.8
Gtot, l • min—1 • Torr—1 4.4 ± 1.7§ 6.5 ± 2.4*§ 5.0 ± 1.6‡
mostly correspond very well with those previously pub-
Gp, l • min—1 • Torr—1 1.8 ± 1.3§ 2.7 ± 1.3§ 1.7 ± 0.9‡§ lished using a MFBS in PETCO2 to stimulate breathing
Tp, s 10.5 ± 8.0 13.7 ± 4.6 12.6 ± 7.0 (8, 20). Under hyperoxic conditions, values of total
dp, s 4.3 ± 1.6§ 5.0 ± 2.1 6.0 ± 3.1 chemoreflex sensitivity to CO2 (Gtot) have been given
Gc, l • min—1 • Torr—1 2.7 ± 0.7 3.9 ± 1.6* 3.3 ± 1.3
Tc, s
as 2.75 and 2.5 l • min—1 • Torr—1 (in the present study,
102 ± 98 212 ± 110* 228 ± 96†
dc, s 7.3 ± 5.0 12.0 ± 5.6* 11.2 ± 5.6 Gtot in euoxia was 2.4 l • min—1 • Torr—1), and under
B, Torr 34.2 ± 3.0§ 26.8 ± 1.3* 28.8 ± 2.2†‡ hypoxic conditions (PETO2 = 50 Torr), a value for Gtot
C, l • min—1 • min—1 —0.04 ± 0.29§ 0.08 ± 0.47§ 0.19 ± 0.31 was given as 4.1 l • min—1 • Torr—1 (in the present
f 0.84 ± 0.10 0.83 ± 0.1 0.84 ± 0.09 study, Gtot in hypoxia was 4.4 l • min—1 • Torr—1).
Rv/Rw 0.62 ± 0.60 0.88 ± 0.88 0.41 ± 0.29
Values for parameter B from these studies have been
given as 33.3 and 34.7 Torr (in the present study,
parameter B = 33.5 Torr).
Correlations between CO2 responsiveness and mea- One area in which the correspondence between the
sures of acute hypoxic ventilatory response and hemat- present study and a previous study using an MFBS in
ocrit. Correlations were undertaken for the HA and PETCO 2(20) is less good relates to the changes in the
CMS groups combined. Gp under euoxic conditions individual sensitivities with hypoxia. In particular, in
exhibited a weak correlation with hematocrit (r = the study by Pedersen et al. (20), there was a nonsig-
—0.39, P < 0.02). However, neither Gp under hypoxic nificant decrease in Gc, from 2 to 1.7 l • min—1 • Torr—1,
conditions nor Gc in either euoxia or hypoxia correlated rather than the significant increase from 1.7 (95% CI,
significantly with hematocrit. 1.40–2.05 l • min—1 • Torr—1) to 2.3 l • min—1 • Torr—1
Both the values for Gp in hypoxia and the increase in (95% CI, 1.96–2.74 l • min—1 • Torr—1) of the present
Gp from euoxia to hypoxia correlated significantly with study. Studies that model the ventilatory response to
measures of acute hypoxic ventilatory response step changes in PETCO2 have not found a significant
(Gph-45 for data gathered by using a protocol lowering increase in Gc in hypoxia, with a small, nonsignificant
PETO2 to 45 Torr and Gph-34 for data gathered by using fall in Gc occurring in one (6) and a small, nonsignifi-
a protocol lowering PETO2 to 34 Torr) from our labora- cant rise in Gc occurring in another (1). Given the
existing literature, we do not feel confident that this
tory’s previous studies (10, 16) for these subjects (for
Gp in hypoxia with Gph-45, r = 0.39, P < 0.05; and result is one that can be generalized beyond our par-
with Gph-34, r = 0.56, P < 0.001; for the difference in ticular sample of SL natives without it first being
Gp between hypoxia and euoxia with Gph-45, r = 0.47, repeated.
P < 0.005; and with Gph-34, r = 0.52, P < 0.002). Ventilatory sensitivity to CO2 of the HA and CMS
Neither Gp under euoxic conditions nor Gc under ei- subject groups. Chiodi (3) gave data for four HA sub-
ther euoxic or hypoxic conditions correlated signifi- jects showing a mean total sensitivity to CO2 of ~2 l •
cantly with either measure of acute hypoxic ventilatory min—1 • Torr—1, which was close to our values for SL
response (Gph-45 or Gph-34). natives at SL. Forster et al. (9) gave data on 10 HA
natives
1 with a1mean total sensitivity to CO2 of ~2.4 l •
• Torr— , which was again close to our values for
DISCUSSION
min—
SL natives. On the other hand, Severinghaus et al. (23)
The major findings of this study were as follows. gave a mean value for six HA natives of 4.0 l • min—1 •
First, under conditions of euoxia (PETO 2 = 100 Torr), Torr—1 and for six patients with CMS of 3.8 l • min—1 •
total ventilatory sensitivity to CO2 in HA natives is Torr—1, both of which are well in excess of both his and
around double that of SL natives at SL. Total ventila- our values for SL natives. Similarly, Milledge and
tory sensitivity to CO2 in patients with CMS was also Lahiri (18) gave a value of 4.2 l • min—1 • Torr—1 for
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1286 VENTILATORY RESPONSE TO CO2 AT HIGH ALTITUDE
four Sherpas. These differences between studies in the
total ventilatory sensitivity to CO2 in euoxia/hypoxia
are difficult to reconcile. However, the present study
provides a considerably larger sample of values from
HA natives; indeed, the total number of HA and CMS
subjects in the present study exceeds the combined
total number of subjects from all four of the previous
studies.
The effect of hypoxia on the total ventilatory sensi-
tivity to CO2 was greater in the SL subjects than in the
HA subjects and patients with CMS. This is very much
in keeping with the observations of both Severinghaus
et al. (23) and Milledge and Lahiri (18). However, the
values obtained for Gp in euoxia and hypoxia provide
no evidence to support the notion that peripheral che-
moreflex sensitivity to CO2 is reduced in HA natives
compared with SL natives at SL. Indeed, the values for
Gp in euoxia for the HA natives were clearly above
those for SL natives. Values for Gp for the patients
with CMS appeared to be lower than those for the
healthy HA natives, but this did not reach significance
(except for the subset of subjects in Fig. 3 under con-
ditions of hypoxia). The one note of caution in these
observations is that the increment in sensitivity in Gp
in the SL natives with hypoxia may have been under-
estimated because of the increase in Gc with hypoxia in
these subjects (see Ventilatory response to CO2 of the
SL subjects). Even so, if, in SL subjects, the entire
increment in Gc with hypoxia is attributed instead to
an increase in the value of Gp, then the value for Gp in
these subjects in hypoxia would still not be much
greater than the value for HA natives.
Parameter B and trend term C. In each of the proto-
cols, a trend term was present that reflected the known
slow effects of altering a subject’s PETCO 2 and PETO2
away from their ambient values. In the case of lower-
ing the PETO2 of the SL subjects, there was a trend
associated with ventilatory depression by hypoxia (7,
11). In the case of raising the PETO 2 of HA natives and
patients with CMS, there was a trend associated with
the slow rise in V̇E under these conditions (13, 14, 16).
In the case of raising PETCO 2 in all subject groups, there
is a slow trend toward increased V̇E (25). These factors
necessarily mean that values of parameter B will de-
pend on how long these trends have been continuing;
for example, the longer PETO2 has been raised in HA
natives before a ventilatory sensitivity to CO2 is mea-
sured, the higher the value of parameter B will be. This
implies that drawing any meaningful comparison for
values of parameter B across studies where the proto-
cols differ is difficult.
Within our study, it was clear that parameter B for
patients with CMS was significantly above parameter
B for healthy HA natives. This correlated tightly with
the significant difference in ambient air-breathing
PETCO 2 between these two subject groups. A perhaps
more surprising observation was that the difference
between ambient air-breathing PETCO and parameter
2
B was very much greater for SL subjects than for HA
natives. For SL natives, this implies that the back
projection of the V̇E-PETCO2 response line will pass
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above the value for normal V̇E and PETCO 2 breathing
room air. This observation is consistent with data from
other studies (8, 20), and it would seem to relate to
another observation made on SL subjects that there is
a degree of discontinuity in the V̇E-PETCO 2 response
relation just above a subject’s normal value for PETCO 2
(2, 4).
Tc in HA subjects and patients with CMS. Reported
values for Tc can differ substantially (5). Nevertheless,
mean values for Tc for both the HA and CMS groups
were slower than reported from a collection of other
studies of SL natives at SL (5, 8, 20), as well as
strikingly slower than in the control SL group of the
present study.
One possible explanation for the increase in Tc in the
HA and CMS groups is that there is some new, uniden-
tified slow component of the ventilatory response to
CO2 that is not present in the SL group. The presence
of such a slow component would imply that the “two-
compartment plus trend” model of the ventilatory re-
sponse to CO2 is not appropriate in these subjects and
that an apparent increase in Tc arises because an
inappropriate model has been fitted to the data.
Assuming the two-compartment plus trend model is
appropriate, the relatively slow time constant of the
central component is normally attributed to the well-
buffered environment within which the chemorecep-
tors reside. The time constant of such a system will
depend on the cerebral blood flow per unit volume of
brain tissue together with the ratio between blood and
brain for the buffering capacity of CO2 (21). Of these
factors, it is well recognized that CBF is decreased in
natives of HA (19, 24). Within this, the oxygen delivery
is relatively well protected because of the increased
hematocrit (24). However, it is not immediately appar-
ent whether CO2 removal is similarly protected. On
one hand, the increase in hematocrit will increase the
proton buffering and carbamino compound formation,
but, on the other hand, the increase in hematocrit will
compound the reduction in plasma flow (and hence
bicarbonate space in the blood). It is possible that a
quantitative analysis of these factors could reveal a
relative slowing of rate of change of PCO2 within the
brain in response to changes in PCO2 of the arterial
blood.
This study was supported by the Wellcome Trust.
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