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Laboratory of Physiology, University of Oxford, Oxford OX1 3PT, United Kingdom
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Tansley, J. G., C. Clar, M. E. F. Pedersen, and P. A. Robbins. Human ventilatory response to acute hyperoxia during and
after 8 h of both isocapnic and poikilocapnic hypoxia.
J. Appl. Physiol. 82(2): 513-519, 1997.
During 8 h of either isocapnic or poikilocapnic hypoxia,
there may be a rise in ventilation
(
E) that
cannot be rapidly reversed with a return to higher
PO2 (L. S. G. E. Howard and P. A. Robbins. J. Appl. Physiol. 78:
1098-1107, 1995). To investigate this further, three
protocols were compared: 1) 8-h
isocapnic hypoxia [end-tidal
PCO2
(PETCO2 ) held at
prestudy value, end-tidal PO2
(PETO2) = 55 Torr],
followed by 8-h isocapnic euoxia
(PETO2 = 100 Torr);
2) 8-h poikilocapnic
hypoxia followed by 8-h poikilocapnic euoxia; and
3) 16-h air-breathing control.
Before and at intervals throughout each protocol, the
E response to eucapnic
hyperoxia (PETCO2 held
1-2 Torr above prestudy value,
PETO2 = 300 Torr) was
determined. There was a significant rise in hyperoxic E over 8 h
during both forms of hypoxia (P < 0.05, analysis of variance) that persisted during the subsequent 8-h
euoxic period (P < 0.05, analysis of
variance). These results support the notion that an 8-h period of
hypoxia increases subsequent
hyperoxic E, even if acid-base changes have been minimized through maintenance of
isocapnia during the hypoxic period.
hypoxic ventilatory response; hyperoxic ventilatory response; altitude; acclimatization
INTRODUCTION IN HUMANS, ventilatory acclimatization to altitude is
characterized by a progressive rise in ventilation
( To assess the importance of the hypocapnia and associated alkalosis in
driving the acclimatization processes, a recent study from our
laboratory (9, 10) investigated a period of 8 h of hypoxia
[end-tidal PO2
(PETO2) of 55 Torr] during which the
PETCO2 was not allowed to
fall but held constant at prehypoxic values. The rise in
In addition to the above findings, the results from these experiments
also raised the possibility that, in both the isocapnic and
poikilocapnic exposures, there might be a component of the rise in
In the previous studies (9, 10), the underlying changes in respiratory
control with poikilocapnic and isocapnic hypoxic exposures appeared
similar. This suggests that any changes in hyperoxic
Full recovery of the leftward shift of the hyperoxic
Therefore, this study aims to answer the following
questions. Over an 8-h period of hypoxia in humans
1) are there progressive changes in
the METHODS
E) accompanied by a fall in
end-tidal PCO2
(PETCO2), which begins
within hours of exposure to hypoxia and is mostly complete within a few
days. There appear to be at least two distinct processes underlying
acclimatization. First, there appears to be a general increase in
ventilatory sensitivity to hypoxia (14, 18), and, second, there is a
leftward shift of the
E-PETCO2
response curve (12) that persists under hyperoxic conditions and
hence should be considered as distinct from the increase in
hypoxic sensitivity.
E over the
8 h was shown to be dramatic, which demonstrated, first, that
substantial changes could be detected in
E over a much shorter exposure to hypoxia than is required to produce full acclimatization, and second, that hypocapnia was not required for these progressive responses to hypoxia (i.e., responses that develop over hours) to
occur. Intermittent brief tests of hypoxic sensitivity involving rapid
(90-s period) alternation of
PETO2 at fixed
PETCO2 (held constant at
1-2 Torr above initial prehypoxic values) demonstrated that
there was an associated increase in the sensitivity of
E to rapid
variations in PO2 throughout the 8-h
period. Similar results were observed in experiments involving 8 h of hypoxia (PETO2 = 55 Torr),
during which the PETCO2 was allowed to fall naturally (the brief measurements of
hypoxic sensitivity again being made at a
PETCO2 of 1-2 Torr above prehypoxic levels). This increase might be thought of as corresponding to the early stages of the rise in ventilatory
sensitivity to hypoxia associated with acclimatization to altitude.
E with 8 h of
hypoxia that is not rapidly reversed by a rise in
PO2, possibly not even by a period of
hyperoxia. Such a change could be thought of as corresponding
to the leftward shift of the
E-PETCO2
curve. Thus the first question this study set out to investigate was
whether there is indeed a progressive rise in
E that
develops over 8 h of hypoxia and that is not rapidly reversed by a rise
in PO2, even with the use of
hyperoxia.
E that may
occur might be similar for the two types of hypoxic exposure. If this
were the case for a change in hyperoxic E, it would
imply that not only is the hypocapnia that normally occurs with
exposure to hypoxia not necessary to generate changes in hypoxic
sensitivity but also that the hypocapnia is not necessary to generate
an increase in
E that
persists under conditions of hyperoxia (i.e., one which may be thought
of as corresponding to a leftward shift of the
E-PETCO2
curve). However, related work carried out on goats does not support
this notion (5). In goats, an effect of hypoxia on
E that was not
rapidly reversible by an elevation of
PO2 was only found after
poikilocapnic hypoxia and not after exposure to isocapnic hypoxia. This
leads to the second question to be addressed: If there is a rise in hyperoxic E, does this occur in
both poikilocapnic and isocapnic exposures or is it confined to
poikilocapnic exposure where there is an associated alkalosis, as
suggested by evidence from the experiments on goats?
E-PETCO2
curve generated by acclimatization requires several days (12). This
observation raises our third question, which is, If there is a rise in
hyperoxic E induced by 8-h
hypoxia, does recovery occur over a similar 8-h time scale or does the
rise in hyperoxic E persist for
longer, as is the case with the leftward shift occurring with
acclimatization to altitude? In particular, we ask whether it persists
during an 8-h period of euoxia after the hypoxic exposure.
E observed
during brief periods of hyperoxia? 2) If there are changes, do they
differ between isocapnic and poikilocapnic hypoxic exposures?
3) If there are changes, do they persist during a subsequent period of 8 h after a return to euoxia?
E
values were taken over the second 5 min of each hyperoxic period. An
analysis of variance employing a general linear model was used to test
for differences between the hyperoxic E over time
and among protocols. The analysis was undertaken in two parts relating
to the first 8 h and the second 8 h. With the use of the notation
defined by Armitage (2), the model took the form
![(<A><AC>V</AC><AC>˙</AC></A><SC>e</SC>)<SUB>i jkl</SUB> = &mgr; + S<SUB><IT>i</IT></SUB> + (C − IP)<SUB><IT>j</IT></SUB> + (I − P)<SUB><IT>k</IT></SUB> + <IT>T<SUB>l</SUB></IT> + [S(C − IP)]<SUB><IT>i j</IT></SUB>](/content/vol82/issue2/fulltext/513/img001.gif)
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![+ [S(I − P)]<SUB><IT>ik</IT></SUB> + (ST)<SUB><IT>il</IT></SUB> + [(C − IP)<IT>T</IT> ]<SUB><IT>jl</IT></SUB> + [(I − P)<IT>T </IT>]<SUB><IT>kl</IT></SUB> + <IT>e</IT><SUB><IT>i jkl</IT></SUB>](/content/vol82/issue2/fulltext/513/img002.gif)
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RESULTS
E
during the last hours of hypoxia.
End-tidal gas control in the chamber.
Figure 1 shows the end-tidal gases recorded
from each of the eight subjects while they were in the chamber,
averaged every 5 min, for each of the three protocols
(I,
P,
C). These plots illustrate the
quality of control achieved. The mean values for PETO2 and
PETCO2 and SD on the
basis of averages taken every 5 min for each protocol are given in
Table 1.
E) were
averaged every 5 min from data collected breath by breath over 16 h for
all 8 subjects during 3 protocols.
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E response
over the second 5-10 min of the acute hyperoxic exposure.
E (C) were recorded breath
by breath during a 10-min hyperoxia step in subject
983 at time (t) = 4 h during isocapnic protocol.
Figure 3 shows the ventilatory responses to acute hyperoxia during the first 8 h of each protocol (tests 1-4) averaged over all eight subjects. It can be seen that gas control was well matched both within each protocol and across protocols. In isocapnic and poikilocapnic hypoxia, there is the appearance of a rise in hyperoxic
E at 4 and 8 h
when compared with 0 and 20 min. This appearance was not present in
protocol C. The significance of this
observation was determined by applying the general linear model
described in the methods to the 5-min averages for
E from these protocols (mean
values for these
E are given in
Table 2). With the use of this linear
model, a significant effect of time was detected, which was different
between hypoxic protocols and control
(P < 0.05). No significant
difference between the two types of hypoxic protocol was detected.
E profiles are
shown for 10-min assessments of acute hyperoxic response averaged
across all 8 subjects at t = 0, 20 min, 4 h, and 8 h, respectively, during 3 protocols.
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E toward
prehypoxic levels was apparent over the 8-h period for the hypoxic
protocols. Statistically, the mean values for
E from the
last 5 min of hyperoxia differ significantly between hypoxic protocols
and control (P < 0.05),
with no significant difference between the two types of hypoxic
exposure. However, there is no significant change over time for
E for either
hypoxic or control protocols. Mean values for these
E are given in
Table 3.
E profiles are
shown for 10-min assessments of acute hyperoxic response averaged
across all 8 subjects at t = 8 h, 8 h
20 min, 12 h, and 16 h, respectively, during 3 protocols.
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DISCUSSION
The main findings of this study are that over the course of an 8-h
exposure to hypoxia, there is a progressive increase in E observed
during brief periods of acute hyperoxia and that this increase persists
over an ensuing 8 h period of euoxia. These findings were not shown to
be significantly different between isocapnic and poikilocapnic hypoxic
exposures, suggesting that these changes do not depend on acid-base
alterations in the blood and are, therefore, the result of some other
effect of hypoxia.
E is observed
throughout these 10-min tests. Although we are unsure of its origin, it
is observed during the control experiments and is, therefore, unlikely
to be attributable to the hypoxic exposures. One possibility
is that it is related to the slight elevation of
PETCO2 in these tests.
Comparison with other studies.
In humans, it is well recognized that after the prolonged poikilocapnic
hypoxia associated with altitude, there is an increase in E that is not totally
relieved by either return to sea level or by hyperoxia (see Ref. 3 for
review). Furthermore, it is generally accepted that this effect is due,
either wholly or in part, to the acid-base adjustments that occur in
response to the initial respiratory alkalosis. The findings from our
study suggest that such changes in
E can occur
with much shorter exposures to hypoxia, during which little by way of
compensatory acid-base changes to the initial respiratory alkalosis
would be expected, and with isocapnic hypoxia, where the initial
respiratory alkalosis has been prevented.
Our results are broadly consistent with a previous study in humans by
Eger et al. (4), in which subjects were made hypoxic by breathing gas
from a facemask for 8 h. They found a leftward shift in the hyperoxic
E-PETCO2
response curve after 8 h of hypoxia at various levels of
PCO2. However, one difference in the
results from their study as compared with ours was that they found the
leftward shift was greater with lower levels of
PETCO2. Our results are also
consistent with an earlier study (9) of the change in
ventilatory sensitivity to hypoxia over 8 h of either poikilocapnic or
isocapnic hypoxia. In addition to the increase in hypoxic sensitivity
observed in this study, there was also an increase in the parameter of
the model that reflected baseline (or hyperoxic)
E. The changes in baseline E
were not significantly different between the isocapnic and
poikilocapnic exposures.
Comparisons with animal studies need to be drawn with care because of
the very different time courses that may be associated with ventilatory
acclimatization to altitude. In the goat, which acclimatizes very
rapidly, there is an increase in
E in euoxia and hyperoxia after 4 h of poikilocapnic hypoxia (5).
However, in contrast to our study, such a change was not observed if
the exposure to hypoxia was isocapnic. Thus the investigators
attributed this change in
E with
poikilocapnic exposure to the associated respiratory alkalosis.
Underlying mechanisms.
The results from this study indicate that, in humans, an 8-h period of
hypoxia may alter
E in
subsequent hyperoxia. Our finding that, in humans, the shift in
hyperoxic E is
similar in both the isocapnic and poikilocapnic exposures to hypoxia
suggests that additional factors other than acid-base changes are
associated with this response to hypoxia. There are a number of
possibilities. First, although the isocapnic exposure will have
attenuated any acid-base changes in the systemic circulation, it is
nevertheless possible that pH changes still occur in the vicinity of
the central chemoreceptors. In awake chronically instrumented goats, a
fall in pH at the medullary surface was reported with both isocapnic and poikilocapnic hypoxia (19). Interestingly, there appeared to have
been little effect on
E during the
development of the acidosis. On the other hand, another study of
hypoxia in awake goats (1) suggests that inhibiting the production of
lactate by using intravenous infusion of dichloroacetate results in
enhanced hyperventilation, which would suggest that brain lactic
acidosis induced by hypoxia may in fact depress breathing. This study
found that the progressive fall in
PETCO2 over
a 1.5-h period with standard hypoxia was not detected when hypoxia was
administered in conjunction with dichloroacetate. This suggests that
the reduction of brain lactic acidosis over time might underlie part of
the ventilatory acclimatization to hypoxia. The study by Xu et al. (19) found a relatively rapid return to normal pH after
the relief of hypoxia. If this is the case in humans, then it would be
difficult to explain the persistence of the effect in the subsequent 8-h recovery by this mechanism. Also set against this is a further study in awake goats (17), which investigated the effects of systemic
[central nervous system (CNS)] hypoxia in the absence of
carotid body hypoxia and found only mild hyperventilation of rapid
onset and no progressive or persistent changes, i.e., no acclimatization.
A second possible explanation of our results is related to the
phenomenon of "hyperventilation-induced hyperpnea." Smith et al.
(15) have found that spontaneous hyperventilation occurs in humans
after a period of increased breathing (produced by a ventilator) during
which CO2 is kept at normal
levels. They attributed this effect to direct facilitation of CNS
activity by hyperventilation. However, although this phenomenon may
have some relevance to the isocapnic hypoxic conditioning in which an
increase in E
is observed, its role in poikilocapnic hypoxia, in which the rise in
E is much more
modest, is unclear.
A third possible mechanism underlying our results is that hypoxia
exerts effects directly on the CNS. Gallman and Millhorn (7) have
suggested that there are two opposing effects after a period of central
hypoxia in peripherally chemodenervated anesthetized cats. Their
findings are 1) facilitation of
E by mild
hypoxia; ablation studies demonstrate that the presence of higher brain structures, notably the diencephalon, is necessary;
2) inhibition of
E by more
severe hypoxia; the mesencephalon seems to be important and,
furthermore, it appears that in the absence of the mesenephalon neither
prolonged inhibition nor prolonged facilitation can be produced after a
period of hypoxia. The two effects appear to be simultaneous, the level
of hypoxia determining which predominates. It is possible that we are
seeing predominantly the effects of mild hypoxia on the brain in our
study, resulting in the facilitation of
E posthypoxia.
Again, however, the findings in conscious goats (17) suggest that
central effects are of rapid onset and offset, and it is therefore
difficult to establish their role in acclimatization. Furthermore,
studies involving carotid body resection in awake cats (6) and awake
goats (16) indicate that carotid bodies are required for
acclimatization to occur; thus it seems unlikely that the phenomenon we
observe can be explained through an entirely central effect of hypoxia.
A fourth possible mechanism is that hypoxia causes a progressive rise
in carotid body activity in such a way that a component of this
response is not rapidly reversible by hyperoxia. However we know of no
evidence to support this possibility.
ACKNOWLEDGEMENTS
This study was supported by the Wellcome Trust. J. G. Tansley is a Medical Research Council student, and C. Clar holds a Biotechnology and Biosciences Research Council studentship.
FOOTNOTES
Address for reprint requests: P. A. Robbins, Univ. Laboratory of Physiology, Univ. of Oxford, Parks Road, Oxford OX1 3PT, UK (E-mail: peter.robbins{at}physiol.ox.ac.uk).
Received 9 July 1996; accepted in final form 16 October 1996.
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