Mortola, Maskrey - 2011 - Metabolism, Temperature, and Ventilation

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Metabolism, Temperature, and Ventilation

Jacopo P. Mortola*1 and Michael Maskrey2
ABSTRACT
O2 ) must pass through the lungs; hence, some degree
In mammals and birds, all oxygen used (V
O2 and pulmonary ventilation (V
E) is highly predictable. Nevertheless, V
E
of coupling between V
is also involved with CO2 elimination, a task that is often in conflict with the convection of O2 .
E and V
O2 includes the participation of the
In hot or cold conditions, the relationship between V
respiratory apparatus to the control of body temperature and water balance. Some compromise
among these tasks is achieved through changes in breathing pattern, uncoupling changes in
E. This article examines primarily the relationship between V
E and V
O2
alveolar ventilation from V
under thermal stimuli. In the process, it considers how the relationship is influenced by hypoxia,
hypercapnia or changes in metabolic level. The shuffling of tasks in emergency situations illus E-V
O2 for the protection of blood gases have ample room for
trates that the constraints on V
flexibility. However, when other priorities do not interfere with the primary goal of gas exchange,
E follows metabolic rate quite closely. The fact that arterial CO2 remains stable when metabolism
V
is changed by the most diverse circumstances (moderate exercise, cold, cold and exercise combined, variations in body size, caloric intake, age, time of the day, hormones, drugs, etc.) makes
E and metabolism are controlled in parallel by the condition responsible for the
it unlikely that V
metabolic change. Rather, some observations support the view that the gaseous component of
E.
C 2011
metabolic rate, probably CO2 , may provide the link between the metabolic level and V
American Physiological Society. Compr Physiol 1:1679-1709, 2011.
Introduction
In most air-breathing vertebrates gas convection by pul between the environment and the
monary ventilation (Ve)
lungs and gas diffusion between the lungs and the circulating
blood are the physical means necessary to meet the needs of
the organism for O2 . The possibility of O2 diffusion into the
blood stream directly through the skin, with no needs for Ve,
is realistic only when the O2 requirements are very small and
the skin is morphologically adequate for sufficient gas diffusion. Hence, skin gas exchange as a substitute or supplement
can occur only in some animals of small size living
to Ve
in aqueous or moist environments. In birds and mammals
the skin morphological properties, designed for mechanical
protection and barrier to excessive water loss, are unsuitable
for gas exchange. The sole known exceptions are the skin of
some newborn marsupials and the webbed wing of some bats
(131, 175, 251, 304). Therefore, in adult birds and mammals
all the O2 eventually used by the organism over a period of
2 ) must pass through the
time (or oxygen consumption, Vo
2 and Ve
lungs, and some degree of coupling between Vo
is involved with the
is highly predictable. Nevertheless, Ve
elimination of CO2 as much as it is with the convection of
O2 , and these two tasks are often in conflict. Furthermore, Ve

contributes to evaporative water and heat loss from upper and
2 and Ve,
lower airways. Hence, the relationship between Vo
as expected and important as it is, must have sufficient flex to acid-base
ibility to accommodate the participation of Ve
balance and thermoregulation. The balancing act between O2
requirements, acid-base regulation, and heat control reaches a
Volume 1, October 2011
further level of complexity when metabolic demands change,

is subjected to
as during exercise or hypoxia, or when Ve
chemical or hormonal stimuli. The primary goal of this article
and metabolic rate
is to examine the relationship between Ve
at rest and under thermal stimuli, focusing mainly on birds and
mammals, in particular adults. In the process, the effects that
changes in chemical stimuli and in metabolic level can have
on the Ve-metabolism
relationship will also be presented.
Terminology and Abbreviations

Most commonly, the metabolic rate of an organism is assessed
from the rate of its gaseous metabolism, that is, the rates of
2 ) and carbon dioxide production
oxygen consumption (Vo
2 ). By comparison with direct calorimetry, the measure(Vco
2 (or indirect calorimetry) involves a simple and
ment of Vo
practical methodology, usually performed by sampling the
inspired and expired O2 concentrations at the airway openings. Of course, estimates of metabolic rate from its gaseous
component are valid only when metabolic energy originates
2
entirely from aerobic sources. In nonsteady conditions, Vo
* Correspondence
to jacopo.mortola@mcgill.ca
of Physiology, McGill University, Montreal, Canada
2 Department of Anatomy and Physiology, University of Tasmania,
Hobart, Australia
Published online, October 2011 (comprehensivephysiology.com)
1 Department
DOI: 10.1002/cphy.c100008
C American Physiological Society
Copyright
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Comprehensive Physiology
2 does because
represents tissue gas exchange better than Vco
the O2 reserves in the body are very small by comparison to the
CO2 stores. A reduction or increase in CO2 body stores could,
respectively, increase or decrease the CO2 exchanged with
the environment, mismatching the measurements of gaseous
metabolism at the airway openings from the metabolic events
at the tissue level.
Because O2 is conveyed to the lungs through pulmonary
as
2 is related to Ve
ventilation (Ve),
it follows that Vo
2 = (Ve[O
Vo
2 ]insp)([O2 ]insp[O2 ] exp)/[O2 ]insp,
(1)
where [O2 ]insp and [O2 ]exp stand for the inspired and expired
O2 concentrations, respectively. This simplified formula as are identical, which
sumes that the inspired and expired Ve
can only be true when the respiratory exchange ratio (RER =
2 /Vo
2 ) equals unity. The error introduced by this assumpVco
tion depends on the RER and on the inspired concentration of
O2 . In many normal conditions, the error is very small (127,
129), but it can be taken into account by using mathematical
corrections (96, 477).
Equation (1) is an application of the Fick principle to
2)
the respiratory system, and states that the O2 used (Vo
equals the product of O2 convection (Ve [O2 ]insp) and the

extraction coefficient ([O2 ]insp [O2 ]exp)/[O2 ]insp. Hence,
for any given inspired O2 , a strict proportionality between
2 and Ve
is expected as long as the extraction coefficient
Vo
remains constant.
For CO2 , because its inspired concentration is negligible,
the equation simplifies further into
2 = Ve
[CO2 ]exp
Vco
(2)
Furthermore, because all the CO2 is endogenously produced,

2 = Va
[CO2 ]alv
Vco
(3)
and [CO2 ]alv stand for alveolar ventilation1 and

where Va
alveolar CO2 concentration, respectively. In Eq. (3), at a given
barometric pressure Pb, [CO2 ]alv can be expressed conveniently by the alveolar partial pressure Paco2 = [CO2 ]alv
Pb, and rewritten in the familiar form of the alveolar gas
equation for CO2 ,
2 /Va)
Pb
Paco2 = (Vco
(4)
Paco2 is measured at the airway opening toward the end of

expiration as the end-tidal value, or is assumed to be equal
to the arterial pressure of CO2 (Paco2 ), because of the equilibrium achieved between alveolar and arterial Pco2 . As long
are proportional to Vo
2 and Ve,
respec 2 and Va
as Vco
tively, normal values of Paco2 reflect the coupling normally
and drops or inachieved between metabolic rate and Ve,
creases in Paco2 indicate conditions of hyper- or hypoventilation, respectively. Therefore in this article, in conformity
with previous usage (83, 305), the terms hypopnea and hyperpnea are used to indicate, respectively, the drop and the
1680
By contrast, the terms

increase in the absolute level of Ve.
hypoventilation or hyperventilation are used to indicate, re relative to metabolic
spectively, a decrease or increase in Ve
may be.
rate, irrespective of what the absolute value of Ve
Heat is a manifestation of the energy resulting from molecular agitation, and temperature (T) is a measure of this energy.
The speed of chemical reactions depends on kinetic energy,
which affects the frequency of intermolecular collision, and
changes about 2% to 3% for every 1 C change in T. For biological reactions, including enzymatic activities, the effect
of T on reaction speed is quantified by the Q10 factor, or Arrhenius factor, defined as the change in reaction for a 10 C
change in T
Q10 = (v /v )(10/T T
(5)
where v and v express the velocity or activities at the corresponding T and T . To the extent that the metabolic rate
of the whole organism reflects the net rate of events at the
cellular level, the Q10 concept can be applied to quantify the
2 and to the factors involved in O2 transport,
effects of T on Vo
including Ve.
Resting Conditions
Despite the enormous variations in ambient temperature (Ta)
encountered by animals, the T range compatible with cellular survival is quite narrow, usually between a few degrees
above the water freezing point (5 C) and 43 to 45 C; at the
organismal level, though, the optimal range spans only a few
degrees. Most avian and mammalian species thermoregulate
around a body temperature (Tb) set point of 39 to 41 C and 36
to 38 C, respectively (mammals, Fig. 1, top panel). The Tb set
point is slightly lower during sleep, and can drop drastically
in some species during estivation, torpor, or hibernation.
In the context of this article, resting condition indicates
a situation of conscious inactivity in normoxia at, or close
to, thermoneutrality. Thermoneutrality is defined as the range
in Ta with Tb maintained at its set point by minimal val 2 , or basal metabolic level2 . The magnitude of the
ues of Vo
thermoneutral range depends mostly on the effectiveness of
in relation to
heat loss mechanisms. This section discusses Ve
metabolic rate during these conditions, among species, during
growth, and during daily or seasonal variations.
Interspecies comparisons
More than a century ago, Haldane and Priestley (158) devised a method to sample alveolar air from the last portion
of the expired volume. After many measurements, largely
on themselves, they concluded that Paco2 at rest was stable
over days and months. Furthermore, Paco2 deviated very little among subjects (121), although it averaged slightly less
1 Alveolar ventilation is the ventilation of the pulmonary gas exchange region,
and the ventilation of the dead space.

or the difference between Ve
2 The
metabolic rate measured at thermoneutrality under resting conditions.
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40
30
body temperature, C
20
10
than in the adult. Some marsupial neonates have very low

Ve
ventilatory equivalents, because of their reliance on skin gas
exchange (131).
In birds, the expired PCO2 has values comparable to those
of mammals (43), but the ventilatory equivalent averages only
21 to 22 mlBTPS/mlSTPD (25, 130, 472). The much lower
in birds than in mammals to fulfill their metabolic needs
Ve
results from the greater efficiency of the avian cross-current
respiratory system (42).
Growth and ageing

40
30
20
10
arterial or end-tidal PCO2, mmHg
102
103
104
105
Body weight, g
106
Figure 1 Body temperature (top) and arterial (or end-tidal) pressure

of CO2 (PCO2 ) in mammals of different body weight (in log scale).
Each symbol is the average value of a different species. Data of Tb are
collected from the literature; data of PCO2 are namely from the data
compiled in ref. (316).
in women (35 mmHg) than in men (39 mmHg) (see section

Sex steroids and other hormones). Intersubject differences
in body weight, height, or vital capacity did not introduce
systematic deviations in Paco2 . Since those years, many measurements of arterial or alveolar Paco2 have been obtained
in many animal species (233, 444); most values fall within
the 30 to 40 mmHg range, the mouse and cat (29 mmHg)
and the hamster (43 mmHg) being the main outliers (Fig. 1,
bottom panel). The average of 22 species from 20 g to almost
3 tons in weight is 37 mmHg, a value remarkably close to the
normal human value. Large aquatic mammals, despite their
peculiar breathing pattern with low breathing frequency and
end-inspiratory pauses, have similar values (316). The variability among species is about 15% of the overall average,
which is not a large scatter if one considers that the species
with
2 and Ve,
range more than 6-fold in body weight, Vo
breathing frequencies from less than 1 breath/min to more
than 150 breaths/min.
In mammals the general uniformity in the values of resting
PCO2 (and PO2 ; 233) agrees with the uniformity in the values
Vo
2 ratios, mlBTPS/mlSTPD3 ).
of ventilatory equivalent (VeThe average interspecies ventilatory equivalent of mammals,
and Vo
2 , is about
computed from the allometric curves of Ve
32 to 37 (126, 418) and similar values are observed in marsu 2 (128). Newborn
pials, despite their characteristically low Vo
Vo
2,
mammals have Paco2 values similar to the adults, but Ve/
which averages 41 mlBTPS/mlSTPD (292), is slightly higher.
This difference probably reflects the larger physiological dead
is a smaller fraction of
space of the newborn, in which Va
The fact that the values of ventilatory equivalents derived from

interspecies analysis are similar in newborn and adult mammals (see section Interspecies comparisons) should imply that
parallel those in Vo
2 . Longiduring growth changes in Ve
tudinal data are few and incomplete (15); most information
originates from cross-sectional measurements on different age
groups. In humans, if one excludes the rapidly changing events
accompanying birth (292), Paco2 is approximately constant
throughout the whole life. It is worth noting that the constancy
senin Paco2 occurs despite the characteristic decline in Ve
sitivity for CO2 with ageing (139, 225). Rats of very different
age and body weight had similar ventilatory equivalent for
O2 and CO2 and blood gases (136, 310). Very similar values of ventilatory equivalent and Paco2 have been measured
in elderly and young dogs (5, 272) and rabbits (91). In the
horse, the older animals had Paco2 values a couple of mmHg
lower than the younger ones, presumably because of the slight
hyperventilation required to maintain Pao2 (4). Indeed, it is
important to note that the constancy in Paco2 throughout life
is not necessarily accompanied by constancy in arterial PO2 ,
which, in fact, normally declines with age probably because
of the worsening of the ventilation-perfusion ratio (139, 414).
As is the case of blood gases, Tb also varies relatively little
throughout the life of an animal, and the greatest variations
occur in the immediate postnatal period. Many newborn mammals have lower Tb than the corresponding adults, although
the opposite can occur in neonates of large species (292). In
children, Tb is set at values 0.5 C higher than in adults, and
in the elderly the daily average Tb value may decrease slightly
(77, 125, 326). Nevertheless, these deviations are remarkably small if one considers the major growth-related changes
in body size, metabolism, and thermoregulatory mechanisms
throughout life.
Circadian and seasonal oscillations

Wakefulness and sleep alternate with periods of various durations. In humans and a few other species, sleep occurs
in time-blocks of several hours and contributes to the daily
3 Lung
volumes and their rate of change are measured and expressed at

body conditions of temperature, pressure, and water vapor saturation (BTPS).
Volumes of gases, including the rates of O2 usage and of CO2 production,
usually are expressed at standard temperature, pressure, and dry conditions
Vo
2 ratio, therefore, cannot be considered a dimensionless
(STPD). The Veparameter.
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oscillations of metabolic rate and Tb. During sleep, humans

experience a modest decrease in Tb and metabolism with a
mild hypoventilation reflected by the 3 to 5 mmHg increase in
Paco2 (349). In the so-called constant routine, during which
the subject stays awake in bed rest for 24 to 36 h under constant dim light with evenly spaced small caloric intakes, the
2 almost disappear.
oscillations in Tb persist but those in Vo
In this situation, the daily oscillation of Paco2 is almost undetectable (286, 416, 422, 452), in agreement with the conclusion of Fitzgerald and Haldane (121) of no definite diurnal
variations in Paco2 during wakefulness. Hence, in humans
the change in the state of arousal is the primary reason for the
oscillation in Paco2 during the 24 h. In rats, which similarly to
many other species alternate wakefulness with short-lasting
2 , and Ve
present very clear
2 , Vco
bouts of sleep, Tb, Vo
circadian oscillations in phase with each other, with constant
Ve-metabolism
ratio throughout the 24 h (293, 399, 421). In
cows, standing and awake, the circadian oscillations in Tb
and breathing rate are very obvious, with complete stability
of Paco2 (351).
The robustness of the Ve-metabolism

linkage throughout
the 24 h was put to test in an experiment on behaving rats,
2 by
Vo
2 , and Vco
designed to disrupt the oscillations of Ve,
sudden perturbations of the light-dark regime (298). This approach was based on the notion that, following a prolongation
of the light or dark phase, the re-entrainment of various physiological variables occurs at different rates. It was found that
the re-entrainment of the Tb oscillation after a perturbation
2 . On the other hand,
Vo
2 , or Vco
mismatched that of Ve,
2 were essentially in phase
2 and Vco
the oscillations in Vo
Had the results been different, for example,
with those of Ve.
been leading Vo
2 , the conclusion could have been
had Ve
was not caused by
reached that the daily oscillation of Ve
that in metabolism; in fact, a rhythm that phase-leads another
rhythm cannot be caused by it. At present, though, the simplest interpretation of the data is that the daily changes in
metabolic rate are the primary cause of the 24-h oscillation in
superimposed on this primary metabolic drive, changes
Ve;
in activity level and in the state of arousal act as additive
modifiers of the Ve-metabolism

ratio.
Some mammals and birds periodically enter bouts of inactivity, lasting just a few hours (daily torpor) up to many days or
weeks (hibernation), with major drops in metabolic rate, physiological functions, and Tb. In many ectotherms, when Tb decreases the ventilatory equivalent increases to eliminate CO2
(303); the ensuing hypocapnic alkalosis matches the T-related
changes in neutral pH and ensures a constancy of the pHdependent properties of proteins, a process known as alphastat
regulation (329, 360, 361). On the contrary, some mammals
in torpor or hibernation maintain arterial pH and PCO2 close
to the normothermic values (32, 218, 252), meaning that they
have a profound relative acidosis. The acidosis may favor the
maintenance of the hypometabolic state (253), although some
observations do not support the idea of a relationship between
acidemia and hypometabolism (444, 476). Nevertheless, the
fact that their Paco2 can be slightly below the euthermic value
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reflects some increase of the Ve-metabolism

ratio, as indeed
is the case (273). Hence, the T-induced relative acidosis in hibernation occurs despite some hyperventilation, because the
very low Tb raises the solubility of blood CO2 and because
of the increased neutral pH at low T (273).
Differently from other mammals, bats in torpor or hibernation follow the ectothermic pattern. As their Tb drops to
just a few degrees above freezing T, bats increase the ventilatory equivalent and pH (430, 431). The desert ground squirrel during torpor maintains constant pH; during wakefulness,
however, the spontaneously occurring large oscillations in
Tb characteristic of this species are accompanied by changes
in blood acid-base similar to those seen in ectotherms (32).
In summary, mammals during periods of inactivity with hypometabolism and low Tb generally maintain a constant or
slightly elevated ventilatory equivalent with acidosis. However, there are instances of evident hyperventilation, seemingly in agreement with the alphastat regulation of lower vertebrates.
Changes in Temperature
In most cases mammals and birds are considered
homeotherms, meaning that their Tb is constant, or nearly
so, even in front of important changes in Ta. Homeothermy
is the result of behavioral mechanisms and of a fine balance
of autonomic control of heat production (thermogenesis) and
heat dissipation (thermolysis). A substantial T gradient exists between the body surface, or shell, which presents large
variations among regions, and the deep tissues, or core. In
extreme cases (like mammals in the Arctic winter and possibly aquatic mammals at depth) the shell-core gradient can
exceed 60 C (322). Hence, homeothermy refers to core T,
or Tb, although some differences among body regions do exist. For examples, tracheal T can be several degrees below
Tb when breathing in a cold environment, liver T varies with
the metabolic activity of the organ, the T of muscles varies
with their degree of activity, and in some animals a specific
vascular network regulates brain T separately from the rest
of the body. The skin thermoreceptors provide the inputs for
the behavioral and autonomic responses coordinated by the
thermoregulatory centers of the hypothalamus (375, 408).
During cold exposure, despite the peripheral vasoconstriction, thermolysis increases because of the larger T gradient
between body core and shell; hence, protection of Tb requires
an increase in thermogenesis. The heat is produced largely by
skeletal muscle contraction (shivering, which is skeletal muscle tremor) and by uncoupling oxidation from phosphorylation in the mitochondria of specialized tissues (nonshivering
2 rises and this entails an
thermogenesis). In either case, Vo
increase in Ve.
In the heat, peripheral vasodilation favors heat loss from
the body shell and the skin becomes the primary effector
organ for thermolysis through conduction, radiation and convection. When skin T equals Ta, these mechanisms are no
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longer operational and evaporation is the only possible means

to dissipate heat (latent heat of vaporization), as long as the
pressure of water vapor in the ambient air does not exceed that
at the dew point temperature of the body. The upper airways
and the first generations of intrapulmonary airways usually
have T and humidity higher than the air inside them; hence,
during breathing the passage of air over this large airway surface plays an important role in the control of Tb and brain
T by evaporation (235, 344, 371). Indeed, in some animals
with minimal sweating possibilities, evaporation via the respiratory tract represents the only means of evaporative heat
is expected to increase above its therloss. In conclusion, Ve
moneutral resting value both in cold and warm conditions,
but for different reasons; in the cold, to accommodate the
2 , in the heat as an effector organ for thermolincrease in Vo
to the control of
ysis. In either case, the participation of Ve
Tb must involve compromise with the common duties of gas
exchange and acid-base control, especially in conditions of
elevated demands for O2 or CO2 convection, such as during
muscle exercise, in hypoxia or hypercapnia. The following
sections examine the effects of these interactions on Ve.
Cold exposure
Shivering and nonshivering mechanisms are under the control of thermoregulatory centers in the hypothalamus and are
mediated, respectively, by somatic and sympathetic pathways
(173, 198). In addition to the severity of the cold, the magnitude of the metabolic increase (up to five times basal) depends on the state of arousal, age, and size of the animal
(small animals tend to lose more heat owing to a larger body
surface-volume ratio). In birds and mammals sustained cold
exposure enhances the ability to face a new acute cold challenge (29, 59, 390, 409). Equally, exposure to cold in the
late phases of incubation augments the thermogenic capacity
of the hatchling (297). Under anesthesia, which impairs the
thermoregulatory mechanisms (305, 479), cold often causes
hypothermia (215); in these cases, metabolism not only in plummets
creases but actually drops, as in ectotherms, and Ve
accordingly (341).
In conscious adult animals, as long as the cold is not so
severe as to cause hypothermia, the typical respiratory re approximately proportional to
sponse is an increase in Ve
the increase in Vo2 . Representative examples from birds and

mammals are shown in Figure 2. A careful scrutiny of these
and many other published data reveals that in some species the
Vo
2 declines slightly (between 5% and 15%) as cold proVegresses. Yet, Paco2 rarely increases (22, 45, 245, 380) (Fig. 3).
The combination of normocapnia and a decline in ventilatory
equivalent is explained by the fact that tidal volume (Vt) increases in the cold, while the response of breathing frequency
(f ) is more variable, especially in large species. Therefore,
exceeds the increase in Ve
(245).
the relative increase in Va
Unusual cases of modest hyperpnea in the cold have been
observed in the coot (49), pig (194), and sheep (210). In the
Eland, an African antelope with minimal insulation, during
10:31
2 does not prevent some

the cold of the night the rise in Vo
fall in Tb. In this situation, Ve does not increase, probably

to avoid further heat and water loss, but the breathing pattern
(440). The same response
becomes deep and slow, raising Va
has been observed in calves, where these animals at 4 C in
2 (+28% above the resting value) and dropped Ve
creased Vo
(6%). Despite the Ve decline, the deep and slow breathing

limiting the hypoxemia and
pattern succeeded in raising Va,
maintaining Paco2 only a few mmHg higher than in warm
conditions (97). In conclusion, the change in breathing pattern in the cold accommodates the greater metabolic demands
while limiting the thermolysis of the increased Ve.

The thermogenic response is part of the autonomic response to cold coordinated in the hypothalamus, upon activation of the cutaneous cold receptors and of receptors in
deeper thermosensitive structures, including the spinal cord
(21, 63, 375, 408). The hypothalamic neurons are located
in the preoptic anterior nucleus; a decrease in their tonic
activity under inputs from cold receptors initiates the autonomic response to cold. It is possible that these are the same
neurons that, under inputs from warm receptors, initiate the
autonomic response to warm (375). The stimulatory effect
2 of some tissues is likely to be mediof cold on the Vo
ated by thyroid hormones, because hypothyroidism reduces
the thermogenic response (183, 465) and pharmacological
block of thyroid hormones inhibits the developmental maturation of thermogenesis in avian embryos and hatchlings
(299). Experiments on rats with a heat exchanger implanted
in the abdomen have indicated that both superficial and core
2 , although the latter is
cooling can independently raise Vo
much more effective (308). Spinal cooling in pigeons more
than doubled the metabolic rise caused by skin cooling, with
(26). From the data of
2 and Ve
proportional effects on Vo
2,
Giesbrecht et al. (149), a 3 C drop in core T doubled Vo
and from those of Maskrey (258) the same drop in core T dou In another study which combined the measurements
bled Ve.
a 1.3 C drop in core T increased both Ve
2 and Ve,
of Vo
responds appro 2 in proportion (263). Therefore, Ve
and Vo
2 change whether the thermogenic stimulus
priately to the Vo
originates from cutaneous or body core cooling. The hypotha
lamic neurons are probably not directly responsible for the Ve
response to cold, not even when hypothermia intervenes, because focal cooling of the hypothalamus with a cold probe
did not stimulate breathing (97). However, anterior and posterior hypothalamic nuclei involved in thermoregulation have
connections to centers of the pons and medulla engaged in
cardio-respiratory regulation, such as the nucleus of the tractus solitarius and the rostral ventrolateral medulla (154, 203,
458). In rats, electrolytic lesions of the anterior or posterior hypothalamus did not modify breathing at rest, but disrupted the
and Ve Vo
2 responses to cold (182, 260). Hence, it seems
Ve
reasonable to postulate that the thermoregulatory nuclei of the
hypothalamus integrate cutaneous and deep thermal sensory
information and send the appropriate output through sympa and
thetic and somatic pathways with influence on both Ve
thermogenesis.
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400
honey possum
350
numbat
Ventilation in cold (% of warm)
deer mouse
300
kowari dunnart
cluditch
lemmings
vole
bat
bandicoot
250
man
chipmunk
200
chukar
pigeon
150
cat
marmot
penguin
rat
squirrels
sheep
weasel
parrot
pig
Tasmanian devil
100
50
50
100
150
200
250
300
350
400
Oxygen consumption in cold (% of warm)
Figure 2 Responses of pulmonary ventilation (V E) and oxygen consumption (V O2 ) to cold,

expressed in percent of the values in warm conditions. Each symbol is the average of literature
data pertinent to some avian (open triangles) or mammalian species (open circles). In first
E and V
O2 increase in proportion, although in the large majority of cases the
approximation, V
data points are slightly below the line of identitiy (dashed line), indicating a small tendency for
a reduction of the ventilatory equivalent in the cold. Data of birds refer to pigeons [averaged
from refs (22, 26, 45)], parrots (52), chuckars (68), and penguins (70). Data of mammals are
for deer mouse, marmot, rat, chipmunk, and other small rodents (62, 66, 67, 142, 380), bat
(69), cat (anesthetized) (144), pig (194), sheep (210), man (188, 331), and some marsupials
[Tasmanian devil, during nonshivering conditions (333); kowari, at 0-15 C (167); bandicoot
(236); numbat (81); sandhill dunnart (478); chuditch (394); honey possum (80)].
The carotid bodies are not required for the proportional

and metabolism in the cold. In fact, peripheral
increase in Ve
chemodenervation reduces the ventilatory equivalent, as expected, but does not modify the linear response in metabolism
(142). The activity of chemoreceptors, just like that
and Ve
of the airway receptors, is T-sensitive; however, their Q10 of
2 to 3 (278, 342) implies that the change in firing rate is
too small to play a role of importance during modest changes
in Tb. Rather, the involvement of the chemoreceptors and of
response to cold is likely to be
the airway receptors in the Ve
the usual one of monitoring blood gases and providing some
(chemoreceptors) and of shortening
O2 -related drive on Ve
the inspiratory time when Vt increases (pulmonary stretch
receptors).
In summary, in the cold the same thermoregulatory centers
that provide the sympathetic and somatic output for thermogenesis are probably responsible for the increased respiratory
increases in proportion to, or slightly
drive that raises Vt. Ve
1684
2 , usually with stability of blood gases (Fig. 4,

less than, Vo
left). In this respect, it is noteworthy, the general consideration, that stability in blood gases together with an increase in
Vt (and no changes in dead space) cannot take place other
than with some drop in the ventilatory equivalent. Hence,
in the cold the balance between the increased hypothalamic
drive to breathe and the chemoreceptor control of blood gases
2 demands
achieves the goal of accommodating the greater Vo
with a breathing pattern that limits the heat loss resulting from
the hyperpnea.
Cold in the neonatal period

During ontogenesis the response to cold of mammals and
birds is often intermediate between the typical endothermic
2 can
and ectothermic patterns, meaning that the increase in Vo
be small, not sustained, or absent. Experimental cooling of the
fetus in utero triggers minimal thermogenic response (151,
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60
50
40
ventilation (ml kg-1 min-1)
1800
1600
(35, 26)
30
1400
1200
(33, 25)
25 C
10 C
(89, 38)
1000
800
(PaO2 91,PaCO2 40)
600
20
30
40
Oxygen consumption (ml kg-1 min-1)
Figure 3 Ventilation (V E)-Oxygen consumption (V O2 ) values in rats

during normoxia (open symbols) and hypoxia (filled symbols) in warm
(circles, 25 C) and cold conditions (triangles, 10 C). Oblique dashed
E/V
O2 ); in brackets are the
lines indicate isoventilatory equivalents (V
mean partial pressures of arterial O2 and CO2 , respectively. During
cold, the ventilatory equivalent may be slightly lower than in warm
conditions, with normal blood gases. [Redrawn from ref. (380)].
356). The same occurs in avian embryos for the most part of
incubation (306, 427). At birth, many mammals and birds have
minimal shivering capacity and some degree of nonshivering
thermogenesis, which improves in the early hours or days of
the postnatal period (8, 38, 178, 299), although behavior and
reliance on the parents remain the major mechanisms for the
body
temperature
oxygen
consumption
Tb
protection of Tb. In those species showing a drastic drop in

2 in the cold, like newborn marsupials (132, 249), or in
Vo
2 , like the neonatal rat
those unable to sustain an elevated Vo
decreases together with the decrease in Vo
2
(301, 383), Ve
is largely due to a decrease in f ,
and Tb. The drop in Ve
rather than Vt (249, 437), as is the response to cold of avian
embryos close to hatching (280, 324). In precocial newborns,
like the lamb, which have a greater thermogenic capacity, Ve

2 (15, 405).
increases in the cold together with Vo
2 response, a deIrrespective of the magnitude of the Vo
crease in Tb is a very common occurrence in newborns exposed to cold. The hypothermia triggers a vicious cycle that
2 because of the Q10 effect, and can imfurther lowers Vo
pair behavioral means of thermogenesis, like locomotion and
huddling. It is interesting to note that when the thermogenic
response to cold was not sufficient to maintain Tb, that is,
increased too (Fig.
2 increased and Tb dropped, Ve
when Vo
more than offset
5), meaning that the metabolic drive on Ve
the Q10 effect of the drop in Tb on the mechanisms regulating
Ve.
It is believed that an important goal of homeostasis is the
stability of the net charges of proteins, specifically, constancy
of the fraction of dissociated imidazole group (alphastat) of
histidine, commonly found at the functional site of proteins
(329, 360, 361). Because when Tb drops the pH of electrochemical neutrality increases, respiratory alkalosis would
VO2/kg
VA/kg
25
500
20
400
15
300
10
200
100
VO2
ventilation
Tb
VE
VE/VO2
ventilatory
equivalent
PaCO2
39
38
37
arterial
CO2 pressure
PaCO2
tidal volume
36
VT
0
45
44
43
42
41
40
39
38
37
36
35
0
30C
20C
30C
20C
Figure 5 Newborn dogs, 1-week old, in warm (30 C) and cold (20
frequency
f
cold
neutral
warm
Figure 4 Schematic summary of common effects of cold (left portion)

and warm exposure (right portion) on some respiratory variables.
C) conditions. In the cold, the thermogenic effort (increased in oxy O2 ) was not sufficient to maintain body tempergen consumption, V
A) increased appropriately to mainature (Tb). Alveolar ventilation (V
tain arterial PCO2 . Hence, the Q10 effect of Tb had no negative im A. [Reconstructed from the data of
pact on the metabolic stimulus on V
ref. (374)].
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Growing in the cold

Experimental exposures to prolonged cold conditions offer an
opportunity to investigate the structural response of the lungs
and the functional adaptation of the respiratory system to a
sustained increase in metabolic demands. The results in rats
(148), hamsters (447), and guinea pigs (238) have been consistent in indicating that cold-adapted animals have larger lung
volumes and pulmonary gas exchange surface than controls,
although the differences seem to decrease the older the age
of exposure. Probably some morphological rearrangement of
the respiratory membrane occurs in mammals living in arctic
regions (404).
Rat pups born from dams kept in the cold during pregnancy had smaller body weight, lung weight, and lung volume
and Vo
2 (378).
than controls, with normal weight-specific Ve
Lambs in which growth had been retarded by the sustained
cold had smaller lungs and (at thermoneutrality) the same f
as controls (Vt was not measured) (426). In rats raised in the
cold, the ventilatory equivalent and the metabolic and ventilatory responses to hypoxia and hypercapnia were similar to
controls (390). These rats also had normal thermogenic responses to cold, after normalization of the data to take into
account their smaller body size.
In summary, the sustained hypermetabolism of the prolonged cold exposure has an impact on body and lung growth,
but no major interference with the mechanisms regulating
other than differences related to body size.
2 and Ve,
Vo
These results agree with those observed in rats with sustained
hypometabolism, growth-limited because of a restriction in
caloric intake (389). Presumably, the independency of the
from the metabolic developmental pathway is
control of Ve
an example of the necessity to guarantee the normal development of regulatory functions irrespective of the individuals
metabolic history.
Cold and muscle exercise

It will be seen that during work the alveolar ventilation was
increased in exact proportion to the extra CO2 produced. In
other words, the increased alveolar ventilation was sufficient
to keep the alveolar CO2 constant. This is what Haldane and
Priestly (158) wrote in commenting on their first measurements of Paco2 during muscle exercise. One century later,
the substance of their statement remains valid for low and
moderate levels of exercise. During strenuous exercise, hyperventilation occurs; the multiple factors possibly involved
1686
60
Ventilation (1 min-1)
be the appropriate response for alphastat regulation. Hyperventilation is the response of many ectotherms to the drop
in Tb (303, 361, 402). There is no specific evidence suggesting alphastat regulation in newborn mammals during a
cold-induced drop in Tb. Indeed, a review of the few limited
observations published (296) suggests otherwise as during
hypothermia a drop, rather than an increase, in ventilatory
equivalent is the most common occurrence.
30
0
0
1.2
Oxygen consumption (1 min-1)
2.4
Figure 6 Oxygen consumption-ventilation relationship in human

subjects during cold exposure at rest (open circles) and during muscle
exercise (filled circles). The data points follow a unique relationship,
irrespective of the factor raising metabolic rate. [Redrawn from (331)].
in determining the hyperventilation have been discussed elsewhere (94, 216) and are presented in a separate article of
this volume in Comprehensive Physiology (see Control of
Breathing in Exercise by Forster, H.). Here, it is interesting
effects of muscle exercise in combination
to observe the Ve
with cold.
In humans exercising below the anaerobic threshold, the
2 was not affected by additional cold, indicating
level of Vo
that the heat generated by the exercise was sufficient to compensate for the heat loss to the cold (53b, 331). In other words,
exercise acted as a form of behavioral thermogenesis, with the
effect of protecting Tb better than in the cold at rest, and with
was found to be proporno impact on Paco2 (108). In fact, Ve
tional to Vo2 whether the metabolic increase was due to cold

alone or combined with muscular exercise (217a, 331) (Fig.
6). This would mean that extremely different stimuli, as those
initiated either by cold or by muscular exercise, somehow in that is perfectly adequate for
tegrate in producing a level of Ve
2 . One could speculate that the hypothalamus is a likely
Vo
region of integration for such various stimuli, because it is
the site of thermoregulatory control (37, 408) and the source
of output to the cardiorespiratory centers during locomotion
responds
(98, 105, 457). The simpler interpretation that Ve
2 ) per se, irrespective of
2 or Vco
to the metabolic level (Vo
the causes determining the metabolic increase, is a logical
proposition, but at present it must remain speculative because
no plausible mechanistic basis has yet been identified (see
section Concluding Remarks).
Cold and hypoxia

The physiologists of the 19th century probably were already
aware that hypoxia can decrease metabolism and Tb (27b,
217b). In the last 50 years, the phenomenon has received
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1. Hypoxic hypometabolism largely originates from the hypoxic decrease in heat production (thermogenesis) and
body growth.
2. In a given individual, the greater the thermogenesis, the
larger the hypometabolic response to hypoxia.
From 1, it follows that hypoxic hypometabolism is more pro 2 per unit of
nounced in young animals (that have higher Vo
body weight) than at older ages, and in small and mediumsize species (that spend more energy per unit of body weight
to maintain Tb) than in larger species (Fig. 7). The early
suggestion by McCance and Widdowson (274) that adults
2 against hypoxia as
of smaller species do not defend Vo
well as larger species finds an explanation in the fact that
small-size species need a relatively greater amount of thermogenesis to maintain their Tb. In some adult mammals,
like goats, ponies, and humans at thermoneutrality, hypoxia
2 (93, 221); presumably, in these cases
does not lower Vo
the stimulation of metabolism prevails over the reduction in
thermogenesis.
From point 2 above, it follows that hypoxic hypometabolism is more pronounced in the cold than at thermoneutrality (145, 301) and at hours of the day that cor 2 (317,
respond to the peak of the circadian oscillation in Vo
382), while is minimal under anesthesia or other conditions of
0
Hypoxic drop in VO2 (ml kg-1min-1)
more attention with respect to its mechanisms and, more re A pivotal study
cently, the implications on the control of Ve.
was that by Cross et al. (86), who indicated that in human
infants modest levels of hypoxia (15% O2 ) triggered the hypometabolic response. Two other studies around the same
years (181, 442), based on observations on kittens, newborn
rats and adult guinea pigs, stressed that the magnitude of hypoxic hypometabolism was dependent on Ta. It is this aspect
that makes the topic of hypoxic hypometabolism of major
importance within the context of this article.
Hypoxia affects all aerobic processes and influences an
enormous range of cellular and organ functions, from cellular excitability and muscle tone to cell repair, maintenance
and tissue growth, from locomotion, intestinal secretion, and
motility to sleep organization, circadian patterns, and state
of alertness. Each function contributes differently to the total metabolic rate of the animal and has a different impact on
2 during the hypoxic metabolic depression. For example, in
Vo
2 reflects
the early embryonic stages the hypoxic drop in Vo
mainly the depression of tissue growth because at this age
growth is the most energy-demanding function. After birth,
in mammals thermogenesis becomes a major source of energy
expenditure; hence, the depression of thermogenesis becomes
2 . The
the major factor responsible for the hypoxic drop in Vo
effects of hypoxia on thermogenesis and its implications on
have been the basis of numerous studies on many species
Ve
and on different age groups (reviewed in 141, 292, 305). With
respect to the effects of hypoxia on thermogenesis, the main
results can be summarized as follows.
(normoxic level)
10
20
30
adult species
newborn species
10
20
30
40
50
Normoxic VO2 (ml kg-1min-1)
60
Figure 7 Difference between hypoxic (10% inspired O2 ) and nor O2 ), normalized by body weight in newmoxic oxygen consumption (V
born (open symbols) and adult mammals (filled symbols). Each symbol
refers to a different species, listed in ref. 126, 292. Horizontal dashed
O2 .
line indicates no difference between the hypoxic and normoxic V
O2
The oblique line is the line of identity. In general, the higher the V
(per unit weight) in normoxia the greater its hypoxic drop. [Slightly
modified from ref. (294)].
depressed thermogenesis. Large species, including humans,

2 when their thercan experience the hypoxic decline in Vo
mogenesis is increased by cold exposure (208, 372). Broadly,
it could be stated that hypoxic hypometabolism in mammals
does not depend on age or body size per se, rather, it depends
2 /W).
2 (Vo
on the level of W-specific Vo
Several considerations and observations indicate that the
drop in Tb is the consequence, not the cause, of hypoxic hypometabolism. Had the drop in Tb been the primary event,
as in the case of cold-induced hypothermia, it would cause
2 , contrary to what is observed. In addian increase in Vo
2 does not follow temporarily
tion, the hypoxic drop in Vo
the decrease in Tb (142, 143), artificial warming during hy 2 (345), and clamppoxic hypometabolism does not raise Vo
ing Tb does not impede the manifestation of hypoxic hypometabolism (149). All these results are indications that the
hypometabolism is responsible for the drop in Tb, not vice
versa. Nevertheless, the decrease in Tb, once manifest, should
assist the hypometabolism because of the Q10 effect.
During hypoxia, lower vertebrates, invertebrates and unicellular organisms (255), when given the choice, prefer Ta
values lower than in normoxia, a phenomenon interpreted as
a downregulation of the set point for Tb. In mammals, the
behavioral responses to hypoxia (73, 102, 153, 302, 480) provide evidence for the concept that in hypoxia Tb is regulated
around a value lower than in normoxia. Hence, the drop in
thermogenesis, the lowering of the threshold for the responses
to cold with a drop in Ta (24, 35, 103, 146) or with a drop
in hypothalamic temperature (439), the decrease in the uncoupling protein and blood perfusion of the brown adipose
tissue (311-313), and the augmentation of heat loss (438) are
various facets of the downregulation of the Tb set point. An
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1688
Bhx
Ventilatory rate (arbitrary units)
increase in heat loss presumably aimed to achieve a lower Tb

during hypoxia has been observed also in birds (398). The
survival significance of the drop in Tb in low O2 has been
known for a long time, and has astonishing effects especially
at young ages (274, 381). Artificial warming of the hypoxic
animal generates responses suggestive of a relative hyperthermia (345, 373, 400) that could jeopardize the chances of
survival (237, 291).
2 is not compensated
The energy shortfall of the drop in Vo
by anaerobic metabolism, and no O2 debt is generated unless
the hypoxia is severe (3, 113, 127, 300, 319, 406). This is explainable by the consideration that hypometabolism, although
triggered by hypoxia, is a regulated response (or regulated
conformism; 294) that saves energy by lowering Tb and shutting down on O2 -expensive functions like heat production and
2 is not limited
body growth. The indication that hypoxic Vo
by O2 availability comes from the fact that, for a given level
2 can still rise to, or above, the normoxic level
of hypoxia, Vo
with adequate physiological or pharmacological stimuli (142,
306, 374, 384).
The cellular events that contribute to the regulated conformism are largely conjectural (305). The possibility that
2 not as a substrate but as a reguO2 itself influences Vo
latory molecule has many plausible arguments (184, 209).
What is clear is that the peripheral chemoreceptors, despite
their projections to the thermoregulatory centers (320), are
not involved in the hypometabolic response to hypoxia (34,
118, 142, 145, 146, 270, 271, 461). Wood (480), on the basis
of various arguments, suggested that arginine and vasopressin
(AVP), an hormone stimulated by hypoxia, could be one of the
central mediators lowering the set point for thermoregulation
during various conditions of tissue hypoxia.
2 dur 2 and the decrease in Vo
The level of normoxic Vo
ing hypoxia have a profound effect on the magnitude of the
hypoxic hyperpnea. Schematically (Fig. 8), it can be stated
that, for a given hypoxic stimulus, (i) the higher the metabolic
level the greater the hyperpnea, and (ii) the greater the hypometabolism the lower the hypoxic hyperpnea. This means
that similar values of hypoxic hyperventilation (measured as
the increase in ventilatory equivalent or as a drop in Paco2 )
can be reached with many combinations of hypometabolism
2 ) and hyperpnea (increase in Ve).

Because, as
(drop in Vo
mentioned above, the hypoxic drop in Vo2 is particularly pronounced in newborns, the hypoxic hyperpnea is smaller in the
younger age groups (290). In addition, because the hypoxic
2 is larger during a thermogenic effort, the
decrease in Vo
hypoxic hyperpnea is less pronounced in cold than in warm
conditions (Figs. 3 and 9), especially in newborns, in which
can fall below the normoxic level (290). It is
hypoxic Ve
interesting that even in the cases of hypoxic hypopnea, endtidal (and arterial) PCO2 may remain the same as in normoxia
(48, 368, 481) or fall below it (12, 156, 309, 314, 373) (Fig.
9). This remarkable association between hypopnea (drop in
and hyperventilation (drop in PCO2 )
absolute value of Ve)
is an unusual combination when looked at from the perspective of the adult human, and it occurs because of the major
hy H
(P per ypo
aC ve xic
n
O
2 = tila
0. tio
5k n
)
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HVR
Bhx
ia
ox )
m =k
r
No C O 2
a
(P
Bhx
B
Ahx
HVR
Ahx
A
Metabolic rate (arbitrary units)
Figure 8 Schema of the metabolism-ventilation relationship in normoxia (any point on the continuous line, PaCO2 = k) and hypoxia
(dashed oblique line). Any point on the hypoxic line indicates the same
degree of hyperventilation (PaCO2 = 0.5 k). A greater hyperpnea (or
hypoxic ventilatory response, HVR) is required when metabolic rate is
high. Hence, at B the HVR, represented by Bhx -B, is greater than at A,
represented by Ahx -A. The dashed arrows to Ahx , Bhx , and Bhx indicate instances of hypoxic hypometabolism. In these cases, the HVR is
less than in the absence of hypoxic hypometabolism and could have a
negative value (cases Bhx and Ahx ), even though the hyperventilation
remains the same.
in hypoxia,
drop in metabolic rate. Indeed, the level of Ve
taken in isolation, is an incomplete and sometimes misleading representation of the hypoxic response. For example, in
one experiment on adult rats (340) during the first hours of
changed minimally while Paco2 dropped from 40
hypoxia Ve
to 25 mmHg, indicating a profound hyperventilation caused
rose some 50%,
2 . In the following days, Ve
by the fall in Vo
while Paco2 remained stable because of the proportional in 2 , indicating a steady degree of hyperventilation.
crease in Vo
The combination of cold and hypoxia can cause an important drop in Tb, especially in young animals. In these cases,
the hypoxic ventilatory equivalent may be less than when hypoxia occurs in warm conditions (Fig. 3), possibly because
the animal is maximizing the alveolar ventilation to reduce
pulmonary heat loss (see section Cold exposure). It is also
exceeds that on Vo
2 , limitpossible that the Q10 effect on Ve
ing the hyperventilation. In one experiment on rats breathing
hypercapnic and hypoxic mixtures, the ventilatory equivalent
and Tb were lower at 11 than at 27 C; however, when Tb was
artificially maintained at the control value by a heat exchanger
Vo
2 in the
chronically implanted in the animal abdomen, Vecold was similar to that in warm conditions (308).
In summary, several points are worth emphasizing. First,
hypoxia lowers the set-point of Tb regulation, a central action
2 (in adult mammals) by lowering thermothat reduces Vo
genesis. The magnitude of the hypoxic ventilatory response
reflects the balance between the activation of the chemoreceptors, the central hypoxic influence on breathing and the
metabolic level. This last factor determines the degree of hypoxic hyperpnea because (i) the larger the normoxic value of
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Ambient temperature:
30 C
VO2 (ml kg-1min-1)
20 C
PaCO2 (mmHg)
25
40
20
35
15
30
10
25
0
VA (ml kg-1 min-1)
Tb (C)
0
40
38
600
36
400
34
32
200
30
0
10 12 14 16 18 20
6 8 10 12 14 16 18 20
inspired oxygen concetration, %
Figure 9 Data of oxygen consumption (V O2 ), alveolar ventilation (V A), body temperature (Tb), and arterial pressure of CO2 (PaCO2 ) in 11-day-old dogs exposed to various
concentrations of O2 , from normoxia (21%) to medium and severe hypoxia, in warm
O2 is high be(ambient temperature 30 C) and cold (20 C) conditions. In the cold, V
A responses vary drastically
cause of thermogenesis, and it plummets in hypoxia. The V
with temperature, even though the degree of hypoxic hypeventilation (drop in PaCO2 )
is the same. Note that the important decrease in Tb during hypoxia in the cold does not
modify the hyperventilation. [Reconstructed from the original data of ref. (374)].
response, and (ii)

metabolic rate the greater the hypoxic Ve
the greater the metabolic drop in hypoxia the smaller the hy response
poxic hyperpnea (Fig. 8). Measurements of the Ve
to hypoxia in isolation, especially in young animals, without
some indication of the metabolic level, can give a partial and
chemosensitivpossibly misleading representation of Ve
response to hypoxia in cases of hyity. Finally, the Ve
pometabolism is a remarkable example of the extent of
and the organisms
the matching between the level of Ve
metabolic rate.
Heat exposure
Evaporation is an important means of thermolysis. In mammals, it commonly occurs by sweating, spreading saliva on
the skin, or from the airways. Just like a breeze favors water
contributes to evaporation from
evaporation from the skin, Ve
the upper and lower airways, which are a large wet surface in
can
contact with the environment, with the difference that Ve
be regulated. The importance of the upper airway to thermoly-
sis has been demonstrated by studies in which tracheostomies

have been produced in panting mammals, leading to disruptions in thermoregulation (232, 425). The lower airway is
also involved in evaporative heat loss and here may impinge
on the processes of respiratory gas exchange (282). In birds,
respiratory evaporation is possibly even more important than
in mammals, and favored by the large surface of the air sacs
(365). In cases of extreme hyperpnea, the heat lost by evaporation from the airways can assume enormous proportions
(212), raising the risk of dehydration. Two phases characterize
the involvement of breathing in the process of thermolysis,
the rapid and shallow pattern of the first phase of thermal
tachypnea, and the slow and deep pattern of the second phase
of thermal hyperventilation.
Thermal tachypnea
The breathing response to moderate warm conditions in many
birds and mammals is typically a rapid and shallow breathing, or thermal tachypnea. Marsupials in the heat abandon
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their normal deep and slow breathing pattern in favor of a

rapid and shallow pattern (236, 332, 333). Panting is a case
of thermal tachypnea designed to increase dead space ventilation for the sole purpose of evaporative heat loss. In birds this
can be accompanied by rapid vibration of the throat region,
or gular flutter (365). It can occur under modest heat exposure at normal values of Tb in species like dog, sheep, and
other Carnivora and Artiodactyla that have limited sweating
capacity, but also in the ox and cattle, which have good sweating capabilities. Cats respond to heat with rapid and shallow
breathing (377), particularly when Ta exceeds 35 C, reaching almost 300 breaths/min at T = 41 C (2). Horses, camels,
humans, and other Primates with well-developed sweating
mechanisms make limited or no use of panting as a response
to heat stress. It was speculated that panting is the more primitive form of heat dissipation by evaporation, and that sweating
had evolved in larger species as a supplementary mechanism
of evaporation (371).
The work of the respiratory muscles involved in thermal
tachypnea or in panting is not high, because the breathing
frequencies of these patterns are close to the resonant frequency of the respiratory system (85, 164). At the resonant
frequency, the inertial (acceleration-dependent) and the elastic (volume-dependent) pressures cancel out because they are
equal in magnitude and opposite in phase; hence, the work
of breathing depends only on the airflow-dependent resis 2 of the respiratory
tive pressure. The possible increase in Vo
2 of
muscles is compensated by some reduction in the Vo
the nonexercising muscles (159), with minimal changes in
2 . On theoretical grounds, the fast and shalwhole body Vo
solely by increasing dead space
low pattern could increase Ve
similarly to the highventilation, without interfering with Va,
frequency-ventilation performed in some clinical settings (74,
101, 133, 224, 419). Panting dogs have a particularly efficient
mode of circulating air through the nasal and oral pathways,
with most of the air inhaled through the nose and exhaled
through the mouth (395), though this pattern can be modified
to adapt respiratory requirements to a wide range of prevailing conditions (152). In reality, some hypocapnia does occur
both in birds and mammals (256, 282, 365, 371), even in
during large increases
species quite capable of defending Va
in Ve, like the sheep and the ox. Under moderate heat, oxen
three times and dropped Vt to about half the
increased Ve
control value, with the effect of raising the dead space ventilation many times more than alveolar ventilation (Fig. 10;
163). A similar pattern occurred in panting dogs, in which the
rose from 25% to
contribution of dead space ventilation to Ve
70% (200). In a detailed study of panting in dogs, Meyer et al.
(282) measured the distribution of ventilation during normal
breathing and during panting. In normal breathing, 31% of total ventilation was confined to the anatomical dead space, 9%
ventilated alveolar dead space, and 60% ventilated functional
alveoli. Panting animals showed a 10-fold increase in overall
ventilation compared with controls. In panting dogs, ventilation of the anatomical dead space increased to 77%, alveolar
dead space increased slightly to 13%, and alveolar ventilation
1690
150
f
(breaths/min)
100
50
0
2
VT
(liter)
1
0
200
100
VE
(liters/min)
0
40
VA
(liters/min)
20
0
200
VD
100 (liters/min)
0
40
PaCO2
(mmHg)
30
20
39
40
41
Body temperature (C)
Figure 10 Oxen in severe heat. V E, pulmonary ventilation; V A, alve D, dead space ventilation; VT, tidal volume; f, breatholar ventilation; V
ing frequency. PaCO2 , arterial pressure of CO2 . As hyperthermia progressed, the breathing pattern switched from rapid and shallow to
deep and slow, aggravating the hypocapnia. [From the data published
in ref. (163, Table 4)].
fell to a mere 10% of the total. In Pekin ducks at the Ta of 30

increased 6 to 7 times above the normothermic
to 35 C, Ve
value because of a large increase in f (>200 breaths/min);
the drop in Paco2 was not significant (44). By contrast, in
the dik-dik antelope, heat stress caused an extremely rapid
breathing (> 400 breaths/min) and a major drop in Paco2 (<
15 mmHg) (261). Hypocapnia has also been reported during
thermal tachypnea in the goat (172).
Early experiments aimed to explore the mechanistic basis
of thermal tachypnea gave conflicting results, partly because
of confusing effects of anesthesia, partly because methods
used to record respiration (e.g., face masks) seriously compromised the respiratory pattern, and partly because they did
not recognize that, during naturally occurring hyperthermia,
the brain usually maintains a T lower than the rest of the body.
Eventually, working on conscious sheep, Bligh (36) was able
to confirm his earlier results on calves that warming of the
skin was a sufficient stimulus for thermal tachypnea. Some
10 years later, in reviewing the data available, Richards (365)
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concluded Nevertheless, there is good evidence in support of

Blighs contention that peripheral thermal stimuli alone can
elicit panting. In dogs (207, 222) and in pigeons and other
birds (23, 408) heating the peridural space of the spinal cord,
with no change in hypothalamic T, elicited panting. In fact,
in a warm environment panting can originate before a rise in
core T (262, 365, 377).
In conscious animals, the rapid and shallow breathing of
the thermal tachypnea phase is reminiscent of the pattern often seen during hypoxia, and, similarly to hypoxia, it can be
reversed by hypercapnia. The tachypnea can no longer be
evoked after transection of the midbrain, and decortication
with the hypothalamus intact produces rapid breathing (168,
244, 352, 446). Hence, the tachypnea is believed to originate
in the midbrain diencephalon, most likely in the hypothalamus. This region exerts a tonic facilitatory action on the frequency of breathing, and is kept in check by forebrain regions,
probably the cortex. In paralyzed, vagotomized, and mechanically ventilated cats, mild hypocapnia reduced the amplitude
and increased the frequency of the phrenic discharge, further
enhanced by forebrain section and abolished by midbrain
section (76). Under similar experimental conditions, a rise
in Tb caused an acceleration of the phrenic nerve discharge
with reduced amplitude, further magnified by hyperventilatory hypocapnia (65). Whether or not the hypocapnia favors
the shallow breathing pattern is not completely clear. What is
clear is that experimental administration of CO2 causes the
tachypnea to revert to a less rapid and deeper breathing pattern
(7, 202, 259, 262, 264, 265, 353, 377).
The possibility of an involvement of the chemoreceptors
and pulmonary receptors in the origin of thermal tachypnea
has been addressed, and the results are negative. In fact, peripheral chemodenervation does not preclude the tachypnea
of midbrain origin, whether provoked by hypoxia (283) or
by thermal stress (40, 162), as first reported in dogs without
carotid bodies (168). On the contrary, stimulation of the peripheral chemoreceptors inhibits the thermal tachypnea (40,
41), in agreement with the point made above that a modest hypocapnia may favor the tachypnea of thermal origin
and hypercapnia inhibits this. Despite the importance of the
pulmonary vagal afferents in the regulation of the breathing
pattern, vagotomy did not stop the manifestation of thermal
tachypnea in mammals, but it did in some species of birds
(110, 364, 365, 471) where discharge from intrapulmonary
chemoreceptors and mechanoreceptors are able to keep pace
with respiratory frequencies of as high as 350 breaths/min
(321). In addition, the inhibition of breathing with lung inflation (Hering-Breuer inspiratory-inhibitory reflex) is absent
during panting (168, 365), while it was found to be increased
in other experiments on anesthetized cats in hyperthermia
(111). It needs to be noted, though, that the early experiments
were performed under anesthesia, a condition that seriously
alters the thermoregulatory mechanisms and could confuse
the results. For example, in anesthetized cats, Tb as high as
41 C did not evoke panting (47, 111, 448, 471), while in
conscious animals panting is initiated at about 39 C (2).
10:31
In conclusion, the thermoregulatory centers of the hypothalamus are essential for the manifestation of thermal
tachypnea, a breathing pattern that appears to be free from
vagal control. The chemoreceptors are not essential for the
origin of thermal tachypnea; their role is the usual one of
adequate
keeping blood gases in check by maintaining a Va
for the metabolic level in face of the increase in Ve.
Thermal hyperventilation
When in the heat, despite the efforts for thermolysis, Tb increases into frank hyperthermia, thermal tachypnea gives way
to thermal hyperventilation, as first hinted by Haldane (157)
and confirmed by many others (467) (Fig. 10). During thermal hyperventilation the breathing pattern becomes deeper
and slower in many mammals and birds (365). In nonpanting
species, including humans, nonhuman primates and horses,
thermal hyperventilation becomes evident when Tb rises by
about 1 C (54, 391, 467). Below this threshold, the level of Ve

does not contribute to heat dissipation, although f is higher
and Vt is shallower than in normothermia (89, 179), and
thermolysis relies on cutaneous vasodilation and sweating. In
panting species, the breathing pattern switches from rapid and
shallow to deep and slow in an extreme effort to dissipate heat
(30, 160-163, 165, 166, 259, 332, 371). The battle against the
enormous risks of the hyperthermia gains top priority, even if
the hyperventilation aggravates the hypocapnia (140) that can
reach extreme levels (160, 161, 163, 259) (Fig. 10). During
2 rises for various reasons (365), including the
this phase Vo
Q10 effect of the hyperthermia (about 10% increase for each
degree Celsius rise in Tb) and the cost of the hyperventilation.
Hence, a vicious cycle can be initiated, whereby the rise in
2 offsets the advantages of the thermolysis by hyperpnea.
Vo
The precise mechanisms responsible for the origin and
maintenance of the thermal hyperventilation and for the
choice of priorities between thermal and acid-base control are
largely unknown (371, 467). Inputs from the cutaneous and
spinal thermo-receptors reach the diencephalic thermoregulatory areas via spino-thalamo-cortical pathways, which also
project to the lateral parabrachial nucleus (191). This nucleus
is itself connected to the hypothalamic thermoregulatory nuclei (375), while involved in the control of breathing activity
response to CO2 (412, 413). Hence, in addition
and the Ve
to the hypothalamic region, it has been proposed that the nu
cleus parabrachialis may be a site for the optimization of Ve
in balancing thermal and acid-base demands (354).
It is unclear whether or not stimuli from regions other
than the cutaneous warm-receptors can be involved in the
transition between thermal tachypnea and hyperventilation.
Theoretically, because at this stage of the thermal stress Tb
stimuli could originate from any deep
is above normal, Ve
site sensitive to T and projecting, directly or indirectly, to
the respiratory centers. The thermoregulatory centers of the
hypothalamus should not be themselves one of these sensory
regions because during hyperthermia selective brain cooling can maintain brain T close to normal (60, 206, 467).
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Furthermore, in hyperthermic oxen, lowering the hypothalamic T did not reduce the established hyperventilation, and
peripheral cooling of the animal, while holding the hypothalamic T high reversed the pattern to thermal tachypnea (120). In
rats with a chronically implanted abdominal heat exchanger
that permitted a change in core T without modifying body sur (contrary to
face T, a 3 C increase in Tb had no effects on Ve
see
the opposite situation, a drop of 3 C, which doubled Ve;
section Cold exposure) (258). This result does not exclude the
possibility that stimuli of T-sensitive core regions may contribute to the thermal hyperventilation, but should indicate
that, at least in the rat, stimuli from cutaneous warm receptors
are necessary for the manifestation of thermal tachypnea.
Many nerve endings and receptors have positive T sensitivity, including those involved in the regulation of the breathing pattern, like the laryngeal mechano- and thermoreceptors
(387, 388) and the airway stretch receptors (46, 397). However, it is difficult to conceive that the thermal activation of
because their reflex effects
these receptors could stimulate Ve
are characteristically inhibitory to breathing, and continue to
be so in hyperthermia (281, 471). The firing rates of the carotid
and aortic bodies increase with T (112, 278, 342); likewise,
the central region of the medulla oblongata responsible for
chemoreception is T sensitive (63, 64, 71). Hence, the T sensitivity of the peripheral and central chemosensory regions
has been considered a possible mechanism for the thermal
hyperventilation (467). However, the fact that hyperthermia
chemosensitivity (see section Interaction with
increases Ve
hypercapnia) does not mean that chemoreceptors contribute to
the thermal hyperventilation. In any case, findings from studies in humans suggest that although hyperthermia increases
chemoreceptor ventilatory O2 drive, the relative contribution
of this to hyperventilation is likely to be small (135).
In fact, an opposite proposition could be advanced, given
that during thermal hyperventilation arterial PCO2 is much below the apnea-threshold and the respiratory alkalosis reaches
values that normally would stop breathing. In sheep during
heat stress the Paco2 averaged less than 10 mmHg (162, 259)
and in one animal was close to an astonishing low value of 5
mmHg (Fig. 1 from ref. 259); to restore normocapnia Paco2
had to be raised some 25 mmHg. Such correction did not
modify the time-trajectory of Tb, Pao2 , blood pressure, and
heart rate in the heat (259), implying that the level of CO2
and cerebral blood flow, which is CO2 -dependent, are not involved in the process of thermal adaptation. Therefore, the
chemoreceptors not only do not increase, but actually lose
their tonic influence on breathing during the severe hypocapnia of the thermal hyperventilation. Entin et al. (109), from
experiments involving CO2 loads in sheep exercising in the
heat, concluded that the set point of Paco2 regulation dropped,
and this reduced the influence of thermal hyperventilation
on acid-base regulation. Chronic denervation of the carotid
body did not modify the occurrence of thermal tachypnea
and thermal hyperventilation in sheep exposed to heat (162).
It is interesting that as the heat stimulus was removed, the
chemoreceptors regained their importance. In fact, after heat
1692
stress, the chemodenervated sheep found themselves in the

unusual condition of hypocapnia and hypoventilation with a
marked hypoxemia that was not present in the intact sheep
(162). Although rats are generally considered to be a nonpanting species, nonetheless similar relationships appear to
apply to rats as to panting animals in that the apnea threshold
for CO2 is lowered when the body core T is raised (39).
With respect to O2 transport, the severe hypocapnia shifts
the hemoglobin O2 dissociation curve to the left, while the
hyperthermia shifts it to the right. The net balance varies with
the magnitude of the Tb and Paco2 change; hence, the effect
of severe heat on the O2 dissociation curve is not uniform
among species (83).
dedIn conclusion (Fig. 4, at right), during heat stress Ve
icates itself to the battle against hyperthermia. The rapid and
shallow breathing pattern of the tachypnea phase is the ob without compromising Va,
a
vious attempt to increase Ve
goal requiring the collaboration of the chemoreceptors. When
hyperthermia becomes too serious a problem, the thermoregulatory drive on breathing overrides the requirements for stability of acid-base and downregulates the braking action of
the feedback control from the chemoreceptors.
Interaction with water balance

Evaporation in the heat, whether by spreading saliva to the
skin or through sweating or panting, entails loss of water, and
the necessity for water conservation is in conflict with heat dissipation (408). Reducing the latter to prevent excessive water
loss aggravates the hyperthermia; yet, in hot and arid regions,
the ability to tolerate high Tb by inhibiting panting is central
to water conservation and survival (396, 441). In conditions
of dehydration, dogs, sheep, goats suppress panting and humans suppress sweating; rehydration immediately reinstates
these evaporative heat loss mechanisms (275). Various experimental modes and protocols of rehydration have led to the
conclusion that rapid resumption of panting and sweating in
hyperthermic and dehydrated conditions occurs with drinking itself (that is, from signals from the upper portion of the
digestive tract before water is absorbed). The maintenance of
these and other autonomic responses requires water absorption through the lower gastrointestinal tract and a reduction
in plasma osmolality (275). While there are various plausible
mechanisms to explain the effects of osmolality on peripheral
vasodilation and sweating (124, 403, 432, 449), less clear is
how osmolality can influence breathing.
In dogs, infusion of a hypertonic solution into the carotid
artery inhibited the high f of thermal hyperpnea, while infusion into the jugular vein had no effect; this suggested that
brain receptors sensitive to extracellular solute concentration
mediated the effects of osmolality on f (20). Similar results
were obtained in rabbits with injections into the brain lateral cerebral ventricles (449). Several experiments in dogs
have shown that decreased osmolality, obtained with gastric water loads or sustained changes in Na+ intake, lowered
(13, 14, 203). Osmotic
Paco2 and [H+ ] and increased Ve
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changes at the level of the carotid bodies (137, 138) or the hy effects
pothalamic neurons (325, 407) could mediate the Ve
of changes in plasma osmolality. Additional possibilities include involvement of the renin-angiotensin system, known to
control plasma volume through the regulation of renal fluid
absorption by aldosterone or the involvement of anti-diuretic
hormone ADH (or AVP). In conscious rabbits, injection of
angiotensin II (AII) into the cerebral ventricles increased pulmonary evaporative heat loss (246). In anesthetized dogs,
systemic infusion of AII stimulated breathing, especially after both carotid sinus and vagus nerves were cut (9, 355).
Qualitatively, similar results were obtained in conscious rabbits (355) and awake dogs, particularly when blood pressure
was kept constant (338). Several considerations suggested
that AII acted centrally by stimulating the circumventricular
organ of the brain; these are sensory regions that lack a bloodbrain barrier and have efferent connections to the medullary
cardiorespiratory centers (203). The Ve-stimulatory

action
of AII could be modulated by AVP, which, released by activation of the renin-angiotensin system, inhibits breathing
because it raises blood pressure and because it antagonizes
renin release. In conscious dogs with low plasma osmolality
following a water-load, the block of the renin activity with
AVP (with minimal changes in blood pressure) eliminated the
hyperventilation (14, 459).
As appealing as the hypothesis of a hormonal regulation
of breathing via the renin-AII system may be, its applicability
in explaining the effects of osmolality on thermal tachypnea requires additional experimental confirmation. First of
response to water load and
all, it seems that in rat the Ve
the effect of AVP differ from the dog (335, 460); such species
difference needs to be understood and probably calls for additional observations in other species. Secondly, the role of the
renin-angiotensin system still needs to be tested in conditions
of hyperthermia, before and after rehydration. Finally, small
changes in blood pressure can affect breathing (337) and they
may be difficult to control, confounding the interpretation of
the results attributed to hormonal activities.
Exercise in the heat

Prolonged muscle exercise in a warm environment causes an
increase in Tb greater than it does at a lower Ta, with breathing responses qualitatively similar, but more marked, than
those described above for heat exposure at rest. Experimental aggravation of the hyperthermia during exercise further
increases the hyperventilation, and experimental cooling reduces the exercise hyperpnea (1, 84, 108, 334, 347). In humans, the breathing pattern during prolonged exercise in the
heat is more rapid and less deep than when the same exercise
is performed in normothermia (257, 347). Similar differences
occur with short bouts of exercise, whether the hyperthermia
originates from a previous long exercise or is caused passively
by a warm bath (257). The fact that with the progression of
hyperthermia breathing becomes faster and shallower implies
Vo
2 ratio does not increase as much as it may
that the Va-
seem from the increase in ventilatory equivalent, limiting the

fall in Paco2 . In fact, hypocapnia reduces cerebral blood flow,
a phenomenon more severe when exercise occurs in the heat
(334).
The above results raise the possibility that the increase in
Tb contributes to the exercise hyperpnea, and, specifically, to
the hyperventilation of severe exercise. In the sheep during
moderate and strenuous exercise the increase in Tb was identified as the most important variable correlated to the level
of the exercise hyperventilation (108), explaining 77% of the
variance in Paco2 . The authors (108) suggested that during
exercise, temperature regulation appears to be a higher homeostatic priority than acid-base regulation, a concept in agreement with what is observed during extreme hyperthermia at
rest (see section Thermal hyperventilation). As mentioned
above, in humans at rest Tb must increase almost 1 C before
causing thermal hyperventilation. It is not clear whether the
same occurs during exercise. In fact, some reports indicated
during exercise,
that small changes in Tb did not affect Ve
implying the existence of a Tb threshold as is the case at
rest (92, 174, 347, 468). Other studies did not demonstrate
any clear threshold for the effects of hyperthermia on exer (135, 171, 334). Notwithstanding, the experimental
cise Ve
evidence to suggest that the increase in Tb is an important factor for exercise hyperventilation at elevated levels of exercise
is abundant (467, 468). One possible mechanism that could
explain this is an increased chemosensitivity during hyperthermia (see section Interaction with hypercapnia). Because
tympanic T increases less than Tb, presumably the hyperventilation helps in limiting the rise of brain T during strenuous
exercise (468).
An intriguing finding is that, once the Tb threshold of the
hyperthermic hyperventilation has been reached, passive body
ventilatory equivalent,
warming evokes larger increases in Ve,
Vt and f than does exercise-induced hyperthermia (134). In
part, this difference may be determined by mechanical restrictions on the respiratory system during exercise hyperpnea, not
present during passive body warming. Nevertheless, the finding would indicate the existence of some factors, currently
unknown, that during exercise limit the Ve-sensitivity

to hyperthermia.
Heat and hypoxia

can be exThe interactive effects of hypoxia and heat on Ve
amined from two angles, how hypoxia influences the thermal
responses, and how heat influences the Ve
response to
Ve
hypoxia.
Some studies in anesthetized animals indicated that hypoxia reduced the thermal tachypnea (123, 376). However,
this result most probably was caused by the anesthesia. In
fact, in conscious sheep and cats, hypoxia facilitated the
thermal tachypnea, an effect more apparent after peripheral
chemodenervation (40, 162). It is likely that hypoxia interacts
with thermal tachypnea at two levels, as a central facilitatory mechanism, probably on the hypothalamic regions of
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the diencephalon (see section Thermal tachypnea), and as an

inhibitory stimulus through the activation of the carotid bodies (320). Under anesthesia, the latter prevails because of the
generalized central depression.
response to
In humans, hyperthermia enhanced the Ve
hypoxia, especially if normocapnia was maintained by judiciously adding CO2 to the inspired air (90, 327). Another
study, in which Tb was increased 1.4 C by means of a heated
flying suit, obtained a similar result (348). Both studies suggested a multiplicative interaction between heat and hy sensitivity to hypoxia, meaning that heat increased the Ve
poxia. Muscle exercise is known to increase the magnitude
response (464), and hyperthermia further
of the hypoxic Ve
magnifies this effect (72).
In animals, most studies of the effects of hyperthermia on
response were performed under anesthesia.
the hypoxic Ve
In one study on mice with partial recovery from anesthesia,
response to
when Tb was raised by an external heater the Ve
hypoxia was greater than in normothermia (196). In conscious
rats, a heat exchanger chronically implanted in the abdomen
allowed Tb to be raised by 3 C; this caused only modest
(258), presumably because cutaneous
effects on f and Ve
response to
stimuli need to be present to evoke a sizable Ve
heat (see section Thermal hyperventilation).
In summary, from the data currently available it appears
that heat and hypoxia interact with each other in a multiplicative way, hypoxia facilitating the tachypnea during heat
exposure, and hyperthermia facilitating the hypoxic hyperventilation.
Heat in the neonatal period

Similarly to adults (see section Thermal tachypnea), newborns respond to a warm condition with thermal tachypnea
and a large increase in evaporative heat loss (366, 367). In
the neonatal period, thermolysis by pulmonary evaporation
is probably of major importance because at this age thermoneutrality has a narrow range, indicating a small capacity for heat loss mechanisms (292). In a warm environment
breathing irregularities and apneas have been reported often
(296), a phenomenon of interest given the correlation between warm conditions and sudden infant death. The possible
mechanistic basis for a causative link between warm conditions and breathing irregularities has been addressed in two
studies on neonatal rats (56, 88). Both studies found that in
warm conditions breathing variability increased, accompanied by high Tb and low metabolism. Out of the four possible combinations between normoxia/hypoxia and warm/cold
conditions, the highest breathing variability occurred in the
warm-normoxia combination (56). Furthermore, the breathing variability in warm-normoxic conditions was less if cold
immediately preceded the warm exposure, so that the animal
in warm conditions was still experiencing the high metabolism
of the cold-induced thermogenesis. The interpretation of these
data was that breathing variability was reduced by the presence of a chemical stimulus, whether it was externally pro-
1694
vided (hypoxia) or of inborn origin (cold-induced thermogenesis). Hence, in normoxic-warm conditions, the breathing
irregularities were maximal because the chemical drive was
minimal. During sleep, the absence of wakefulness and the
which, in
drop in metabolic rate reduce the stimuli on Ve,
combination with the increased gain of the chemo-reflexes,
predispose to ventilatory instability (95). In newborns during sleep a moderate rise in Tb further increases breathing
irregularities and periodic breathing (28).
Fever
To reach the higher value of Tb seen at the onset of fever
(chill phase), heat production must increase, possibly in
combination with a reduction in heat loss. One of the first
studies in humans, made febrile by injection of typhoid vac 2 increased by about 7% per C during
cine, has shown that Vo
the fever onset (chill), and remained slightly elevated during
the phase of steady Tb plateau and the defervescence (flush
phase) (11). Many other studies have confirmed the increase
2 during fever in humans (57, 79, 187, 318) and in aniin Vo
mals (31, 82, 115, 377, 428). As is the case for cold-induced
thermogenesis (see section Cold and hypoxia), hypoxia in 2 caused by pyrogenic agents (100, 114,
hibits the rise in Vo
363).
and breathing pattern during these
The changes in Ve
events reflect how breathing responds to various conflicting
priorities. These include meeting the metabolic increase to
maintain acid-base homeostasis, which would entail a rise
contributing to the establishment of fever by limiting
in Ve,
or
pulmonary heat loss, which would entail a drop in Ve,
aiming for Tb homeostasis, which would entail an increase in
as for any case of hyperthermia.
Ve
2 because of bacterial fever preCats with increased Vo
(377). Therefore, in
sented only a transient elevation of Ve
these species, Ve seemed to favor the upregulation of Tb by

limiting the heat loss during the chill phase. By contrast, in
2- to 3-week-old lambs, bacterial pyrogen increased Tb and
2 (117) with no changes in Paco2 (115). In adult humans,
Vo
during fever is a consistent finding (11, 57,
the rise in Ve
318, 358). In a study on adult humans injected with typhoid
increased in the chill phase more than Vo
2
vaccine (11) Ve
did, with a significant drop in alveolar PCO2 ; the hyperventilation decreased in the flush phase. In another study (57),
increased in proportion with Vo
2 ; during the chill phase,
Ve
because of the prevalent rise in Vt, probably the subjects
were hyperventilating. Two following studies have indicated
a modest degree of hyperventilation (3 mmHg drop in Paco2 )
during fever (318, 424), while a more recent work found that
during fever did not entail any significant
the increase in Ve
drop in Paco2 (358).
In adults, the hyperpnea is usually characterized by an
increase in f , at least during the chill phase. An increase in
f is a well known symptom of fever in children (336). Some
experiments in rabbits and rams have indicated a drop in f
following administration of pyrogens; however, in all these
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experiments during control normothermic conditions f was

unusually high (82, 254, 429, 455).
In summary, the data in humans seem to indicate that dur primarily fulfills
ing fever, out of the various possibilities, Ve
the needs to accommodate the increased metabolic requirements, prioritizing acid-base control. Some hyperventilation
during fever occurs when Tb rises excessively or rapidly; at
begins to respond to fever as if it was a case
which point Ve
of hyperthermia (see section Thermal hyperventilation).
Interaction with hypercapnia

Exposures to hypercapnia are rare events in nature. Yet, experimental increases of Paco2 during cold or warm conditions permit additional insights into the mechanisms balancing thermoregulation with acid-base control. Specifically, two
responds
approaches have been used. One examines how Ve
to T challenges under the additional demands of the chemical stimulus (i.e., hypercapnia during cold or heat), the other
chemosensitivity (i.e.,
one how changes in T influence Ve
Vo
2 response to CO2 ). The former
changes in T on the Ve to accommodate a disturbance in
represents a demand on Ve
acid-base while engaged in thermoregulatory responses; the
to contribute to thermoregulatory
latter, is a demand on Ve
tasks while engaged in acid-base control.
Hypercapnia and the responses to changes

in temperature
The effect of CO2 on metabolic rate is the result of many
factors. Some of these have been known for a long time and
may have opposing effects; for example, the metabolic depression of the acidosis opposes the thermogenic action of
catecholamine release and the cost of the hypercapnic hyperventilation (119, 214, 423, 443). In addition, CO2 often
causes a decrease in Tb (see below) and this could stimulate
thermogenesis. These effects, and the net effect of their interaction, can vary greatly with the concentration of CO2 and the
duration of the hypercapnia, because of the time-dependent
changes in buffering capacity. Hence, the question does CO2
influence metabolic rate? does not have a unique answer,
and the experimental results are variable. For modest inspired
2 are small and
CO2 concentrations usually the changes in Vo
in either direction, both in adult (e.g., see references 199, 201,
213, 264, 383) and newborn mammals (307, 383, 453). After
2 as controls
3 weeks of 5% CO2 , guinea pigs had the same Vo
(239). However, important changes in Vo2 during hypercapnia have been reported, and they could be in the upward (147,
234, 343) or downward direction (377). In kittens, 1% CO2
2 , while 5% CO2 had a depressant effect
had no effect on Vo
(309). Large CO2 concentrations, for example, 10% or more
2 , and higher concentrations
(289, 392) definitely decrease Vo
begin to approach the anesthetic effects (401). Irrespective of
the metabolic response, a common finding in adults during
hypercapnia is the drop in Tb, at least during the first hours
of exposure (147, 199, 201, 234, 383, 392, 423), which is
10:31
attributed to the heat loss of the hypercapnic hyperpnea and

to some peripheral vasodilation. By contrast, in hypercapnic
newborns the drop in Tb is small and inconsistent (307, 383),
presumably because at this age the capacity for heat dissipation through peripheral vasodilation is very small (292).
During cold exposure, in small mammals and newborns
CO2 -breathing either reduced thermogenesis and the critical
T for cold-induced thermogenesis, or had no significant effects (226, 383, 393). Very high CO2 concentrations (10%)
totally depressed thermogenesis (346, 423). Modest hypercapnia (2.5-3% inspired CO2 ) reversed the hypoxic inhibition
of thermogenesis in adult cats (145, 146). Hence, as in normothermia, during cold the metabolic effects of CO2 are dose
dependent. In humans during cold exposure, breathing 6%
CO2 caused a reduction of thermogenesis (53a) or had no
effects (456); in either case Tb dropped. The decrease in Tb
and, when it occurs, the drop in thermogenesis do not depend on the function of the peripheral chemoreceptors (147).
They may result from a central action (stimulation) of CO2
on the warm-sensitive neurons of the hypothalamic preoptic
nucleus (433, 434, 482). The decrease in Tb, in those cases
with no inhibition of thermogenesis, must reflect an increased
thermolysis, of which probably the prominent mechanism is
heat loss through the hyperventilation. In conclusion, in normothermia and in the cold CO2 breathing has variable and
2 , because of the comsometimes unpredictable effects on Vo
bination of many factors the importance of which can vary
with the level and duration of the hypercapnia. It is probably
correct to state that, in general, the effects of modest levels of
2 and thermogenesis are small, at
hypercapnia on resting Vo
least by comparison to the large and consistent hypometabolic
effects of hypoxia (see section Cold and hypoxia). Nevertheless, the possibility of a change in metabolic rate needs to be
response to CO2 , as
taken into account in interpreting the Ve
was well emphasized by Pappenheimer (343).
In the heat, CO2 breathing inhibited the tachypnea and
promoted a deeper and slower breathing pattern, both at rest
2 (259, 264,
and during exercise, with no major effects on Vo
377). The increase in Tb in the heat is less during CO2 breathing than during air breathing, presumably because the CO2 hyperventilation favors heat loss through pulmonary evaporation (264). Given the uncertainties regarding the mechanistic
basis of thermal tachypnea (see section Thermal tachypnea),
the mechanisms of the inhibitory action of CO2 remain elusive. CO2 could act peripherally, because the pharmacologic
activation or inhibition of the carotid chemoreceptors respectively inhibits or favors thermal tachypnea (41). It is equally
probable that CO2 acts centrally, for example via changes in
brain blood flow or through direct action on the hypothalamic
thermosensory neurons.
Changes in temperature and the

hypercapnic ventilation
The majority of experiments on anaesthetized animals have
or that
indicated that during CO2 -breathing the level of Ve,
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of the phrenic nerve discharge, are increased at high Tb and

decreased at low Tb (110, 328, 353, 471), although insignificant effects have also been reported (339). The general pattern
observed on anesthetized animal models agrees with observa at any given
tions in human subjects; with no exceptions, Ve
PCO2 was higher when Tb was increased 1 to 3 C above the
normothermic value (84, 89, 327, 454). In conscious dogs, a
very modest increase in Tb (<0.5 C) gave inconsistent results
(201, 262). In conscious rabbits, a species characteristic for
extremely fast thermal tachypnea, a drop in Ta from 20 C
(Tb = 39.1 C) to 5 C (Tb = 39.1 C) had no major effects
response to 6% CO2 . However, ambient warming
on the Ve
to 35 C (Tb = 40.3 ) reduced Vt and increased f to an extraordinary 440 breaths/min; at this point, breathing 6% CO2
response to CO2 had
caused such a drop in f that the Ve
a negative slope (265). In both newborn and adult rats, the
responses to CO2 in cold conditions were significantly
Ve
less than in the warm (88, 308, 383). Maskrey (258) changed
core T of conscious rats with an abdominal heat exchanger;
response to CO2 in hyhe found that the slope of the Ve
perthermia was slightly increased, and in hypothermia was
definitely decreased, compared to the normothermic state. In
conscious subjects with a rebreathing technique in hyperoxia
(to eliminate the activity of the peripheral chemoreceptors)
and with prior hyperventilation an increase in Tb of 1.5 C did
threshold and increased the Ve
sensitivity
not modify the Ve
to CO2 by about 50% (19) (Fig. 11).
In summary, from the data provided by the majority of
studies in conscious subjects and animals it seems possible to
conclude that during CO2 breathing an increase in Tb raises
for two reasons, because of the
the absolute value of Ve
manifest also in normocapnia (see section
T effect on Ve,
Ventilation (liters/min)
30
Hypometabolic and Hypermetabolic

Conditions
In animals at rest, Ta or Tb (see section Changes in Temperature), body size, age, and hours of the day (see section Resting
Conditions) are common causes of changes in metabolic rate.
However, many other conditions impact on the level of resting metabolism. The present section briefly examines some
of these conditions and their effects on the coupling between
and the metabolic level.
Ve
20
Hormones
10
0
30
40
50
end-tidal PCO2 (mmHg)
60
Figure 11 Breath-by-breath relationship of end-tidal pressure of

CO2 and pulmoanry ventilation in one human subject at normal (open
circles) and elevated (closed circles) body temperature during hyperoxic rebreathing after prior hyperventilation. The arrow indicates the
threshold of the response. Elevated temperature did not modify the
threshold but increased the slope of the curve above the threshold, or
E sensitivity to CO2 [Redrawn from ref. (19)].
V
1696
sensitivity
Heat exposure), and because of the increased Ve
to CO2 . This is a multiplicative interaction similar to that
occurring between hyperthermia and muscular exercise (see
section Exercise in the heat). On the other hand, a drop in Tb
as it does in normocapnia (see
increases thermogenesis and Ve
sensitivity to
section Cold exposure), but also reduces the Ve
CO2 . The net result of these two effects is that during CO2
can be the same or below
breathing in the cold the level of Ve
the corresponding value in normothermia.
have
Some potential mechanisms of the action of T on Ve
been presented in the discussion of thermal hyperventilation
(see section Thermal hyperventilation); the same mechanisms
could be involved in the multiplicative effect of T on CO2 sensitivity. Because hyperoxia, which silences the carotid bodies,
does not preclude the stimulatory effect of hyperthermia on
the Ve-sensitivity
to CO2 (19), it seems unlikely that the
chemoreceptors participate in the interaction. In addition, the
T sensitivity of the carotid sinus nerve (slope of the T-nerve
activity curve) is unaffected by CO2 (278). Irrespective of
what the mechanisms may be, it is worth noting that the increased sensitivity to CO2 implies that a CO2 change not
in normothermia may do so in hysufficient to stimulate Ve
perthermia. This could be an additional factor in the mechanisms of exercise hyperventilation, in which the increased
stimulus of the
Tb could play an enhancing role for the Ve
metabolically produced CO2 .
Extreme cases of endocrine disturbances can have catastrophic effects, with respiratory depression and coma, as can
be the case with diabetes or myxedema (268). What is interesting in the context of this article is the relatively small and
well-tolerated hormonal alterations that modify the metabolic
level, as occur during the menstrual cycle and pregnancy or
with modest dysfunction of the thyroid.
Sex steroids and other hormones

2 than males, both in huIn general, females have lower Vo
mans and animal species. Often, normalization by height,
body weight, or body surface area, or by other size-related
parameters, eliminates the difference (266, 267). However,
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most studies, in humans and animals, are based on rather

small samples. A study of a large population (several hundred
subjects) of 18 to 80 years old men and women has detected
2 values in women even after accountsignificantly lower Vo
ing for the differences in body composition, cardiovascular
fitness, menopausal status or age (17). Similar large-scale
studies in animals are not available.
In their seminal work, Fitzgerald and Haldane (121) reported that the average Paco2 in women at rest averaged 5
mmHg less than in men. The authors could not be aware of
the fact that progesterone is a powerful stimulus to breathing (248, 410), and its surge occurs in the second phase of the
menstrual cycle. During the first (follicular) phase of the cycle
in women the Paco2 is either the same (469) or slightly less
(2 mmHg) than in men (6). By contrast, in the second (luteal)
phase of the menstrual cycle the surge of progesterone causes
some hyperventilation (Fig. 12) (107, 250, 469), probably
through a combined central (hypothalamic) and peripheral
(carotid body) action (410, 436). Oral contraceptives block
the phasic menstrual fluctuation of progesterone and the oscillation in Paco2 (330). The hyperventilation of the luteal
phase occurs with the upregulation of the Tb set point (420).
In fact, in the luteal phase, Tb increases by 0.5 C (219), with
similar increases in the critical temperatures of the responses
to cold and warm stimuli (176, 177). After menopause, the
total plasma CO2 increases slightly, but is still lower than
stimulus in
in men, suggesting the persistence of some Ve
women not related to sex steroids (277). In animals, gender
differences in Paco2 , and their possible relation to the female
estrous cycle, have not been extensively studied. The few data
available are contradictory. In rats, resting Paco2 averaged a
couple of mmHg higher in females than in males, even though
the values of ventilatory equivalent were similar between gen 2 (315). In female cats,
ders over a wide range of resting Vo
the reported resting Paco2 of 35 mmHg (170) corresponds to
the normal value for this species (444). In miniature swine,
Paco2 in females averaged significantly less (3 mmHg) than
in males, both in normoxia and hypoxia (276). The Prairie
n = 39
= 0.944 0.0215
Y = 5.802 log +38.658
mean SD
50
PaCO2
follicular phase
mmHg
luteal phase
40
early pregnancy
late pregnancy
30
20
pueperium
0.4
1
10
100
serum progesterone (ng/ml)
Figure 12 Relationship between the concentration of serum progesterone (in log scale) and arterial PCO2 in women during various phases
of the reproductive cycle [redrawn from ref. 250)].
falcon is one of the species with reversed sexual dimorphism,
2 than males; Ve
where females have larger body size and Vo
Vo
2 ratio is the same in both
differs accordingly, and the Vegenders (211).
Testosterone administration in hypogonadal men or cas (269) or
2 and Ve
trated male cats had either no effects on Vo
increased both, in either case with no changes in Paco2 (435,
470).
In addition to sex steroids, many other hormones have an
and blood gases have
2 , but their effects on Ve
impact on Vo
received only sparse attention. The hyper- or hyposecretion
2 (183).
of the thyroid, respectively, decreases or increases Vo
Hyperthyroid patients probably have normal PCO2 (106b).
Return to euthyroid state in hyperthyroid patients lowered
Paco2 in five patients and increased it in two patients, with
a mean drop of less than 2 mmHg (450). In patients with
and Vo
2
thyrotoxicosis, ablation of the thyroid reduced Ve
almost in proportion (484), and thyroid hormone replacement
in hypothyroidism or myxedema did not alter Paco2 (485).
In acromegalia, an oversecretion of growth hormone (soma 2 , the resting
totropin) often associated with an increase in Vo
alveolar or arterial PCO2 averaged between 39 and 42 mmHg
(50, 155, 192); hence, the values were within the normal
range.
Pregnancy
One of the priorities of the female mammal during pregnancy
is to maintain adequate uterine T. Bats, which like other small
mammals can experience daily periods of torpor and low Tb,
during pregnancy avoid the torpor in an effort to maintain
normothermia and expedite embryonic growth (87). In the
majority of mammals, because of the metabolic heat consequent to fetal growth and the increase in maternal metabolic
rate (150), the risk of overheating is more common than that
of hypothermia, with potentially deleterious effects on fetal
development (27a, 415). Presumably for this reason maternal
Tb decreases during pregnancy (106a, 116, 231, 323), a process mediated by brain angiotensin (55). With a Tb 0.5 C
lower than fetal Tb, the mother provides a heat sink for fetal
heat dissipation. Maternal exercise reduces the fetal- maternal
T gradient (230, 231, 247), and sustained heavy exercise in
hot environment may increase risks for the fetus (415).
Despite the drop in Tb, pregnant rats placed in a thermocline did not choose a Ta higher than that chosen when they
were not pregnant (106a). In addition, during pregnancy, the
thermogenic response to a cold stimulus is reduced, that to a
hot condition is increased, and thermoneutrality is shifted to
a lower T-range (16, 106a, 193, 475). All these changes indicate that in pregnancy Tb is regulated around a lower value
than in the nonpregnant state.
increases more
In women during pregnancy resting Ve
than Vo2 , because of the high progesterone and estrogen levels (288, 362), with a significant decrease in Paco2 (248, 250)
(Fig. 12). Pregnant women have also been shown to have
a greater response to CO2 than nonpregnant women during
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Nutritional status
The role of the nutritional intake on lung function has received
attention in recent years, especially with respect to the value
of nutrition in some chronic pulmonary diseases (379, 417,
474). From our perspective, it is of interest to examine what
effects differences in nutrition-related metabolism may have
and blood gases.
on Ve
A meal causes an acute hypermetabolism. A 1000-cal
2
meal rich in proteins or in carbohydrate increased both Vo
and Ve by approximately proportional amounts (486). In an

earlier study it was shown that with a meal of carbohydrates
2 , Va
maintained a better
2 more than Vo
that increased Vco
proportionality with Vco2 than with Vo2 , so that Paco2 was

unaltered (385).
A prolonged weight-reduction diet can reduce
metabolism, although, in prolonged animal studies, it
can also compromise lung structure (295). Healthy subjects
during a 10-day period of semi-starvation lost weight and
was small (7%)
2 by 20%, while the drop in Ve
decreased Vo
and insignificant. Therefore, by the end of the test-period this
group of subjects probably hyperventilated (18b). In another
study, a modest hyperventilation (2 mmHg) occurred at
times during a 10-day semi-starvation; however, by day 10,
2 , Paco2 did
with a 4 kg weight loss and a 20% drop in Vo
not differ significantly from the prestarvation period (99).
In protein-deprived neonatal piglets, amino-acid admin 2 with no changes in Paco2 (411). On the
istration raised Vo
1698
other hand, in adults a diet rich in proteins caused a modest

hyperventilation (2 mmHg) (18a). One-month old rats of
2 than rats from
large litters had smaller body weight and Vo
was appropriate for
small-size litters; nevertheless, their Ve
the metabolic level (389).
In conclusion, as a first approximation, nutrition-related
hypo- or hypermetabolism caused minimal alterations in ventilatory equivalent and Paco2 . Most of the studies quoted
response to hypoxia. Invariably,
above also measured the Ve
response
they found that the magnitude of the hypoxic Ve
correlated with the metabolic level, no differently from that
discussed previously with respect to the ventilatory response
to hypoxia in cold conditions (see section Cold and hypoxia;
Fig. 8).
Pharmacological hypermetabolism
Uncouplers of oxidative phosphorylation (such as ethyl
methylene blue or various isomers of dinitrophenol) increase
2 by freeing the oxidative processes of the mitocellular Vo
chondrial respiratory chain from the constraint of high-energy
phosphorylation (51). Hence, they are used often as pharmacological models of hypermetabolism. In some cases, hyperthermia occurs presumably because the energy produced is
not converted to energy used in cellular processes but instead
dissipated as heat.
The majority of studies on the effect of mitochondrial un have been conducted on anesthetized animals
couplers on Ve
was
(190, 240-243, 284, 359). In general, the increase in Ve
2 , so that the changes
quasi-proportional to the increase in Vo
in Paco2 were minimal even for some 10-fold increase in
2 (Fig. 13). However, one study on both anesthetized and
Vo
conscious dogs has shown an important decrease in Paco2 at
the maximal doses of dinitrophenol (473). Similarly, in conscious rats during hypoxic hypometabolism, administration
2 and lowered Paco2 5 mmHg
of dinitrophenol raised Vo
(384). Hence, mitochondrial uncouplers can cause some degree of hyperventilation, especially in conscious animals. Presumably, the pharmacologic hypermetabolism may produce a
delta PaCO2 (mmHg)
rebreathing trials (205). Jensen et al. (204) have reported that

during their third trimester of pregnancy women display a
relative hyperventilation, with a decrease in threshold and an
relationship when
increase in slope of the end-tidal PCO2 -Ve
compared with postpartum values. The authors explain this in
terms of a subtle interaction between gestational hormones,
cerebral circulation, and central chemoreceptors (204). Similarly, pregnant cats close to term hyperventilate with a resting
Paco2 slightly lower (3 mmHg) than in nonpregnant cats
(170). The authors (170) showed that, in response to hypoxia,
the afferent activity of the carotid sinus nerve increased more
in pregnant than in nonpregnant cats; a similar increase can
be reproduced in castrated males by progesterone administration (169). The progesterone-mediated increase in hypoxic
sensitivity of the peripheral chemoreceptors contributes to
response typical of pregnancy (170,
the higher hypoxic Ve
287, 288, 362). From the current data, it is difficult to decide whether or not the increased sensitivity of the peripheral
chemoreceptors is accompanied by a greater tonic (normoxic)
activity. Hence, it is still unclear to what extent the carotid
bodies contribute to the normoxic hyperventilation induced
by sex steroids.
and Ve Vo
2 increase in preg 2 , Ve,
In conclusion, Vo
nancy. The rise in sex steroids is the main factor responsible for the hyperventilation. The hyperpnea, through the
pulmonary water evaporation, could contribute to downregu 2.
lation of Tb despite the rise in Vo
8
6
4
2
0
-2
-4
-6
-8
x1
x2
x4
x6
x8
x10
Increase in oxygen consumption
Figure 13 Pharmacologic increase in metabolic rate (in multiples of

resting oxygen consumption) with uncouplers of oxidative phosphory O2 caused no or small degree of
lation. Often, large increases in V
hyperventilation. Dashed line, no change in arterial PCO2 . Symbols
are mean values in dogs (triangles) and rats (squares). Compiled from
the data of refs 190, 240-242, 359, 384.
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generalized neuronal activation, including, possibly, the normal wakefulness drive on breathing. In addition, the hyperthermia often caused by the mitochondrial uncouplers can be
(see section Thermal tachypnea). In dogs
a stimulus on Ve
with peripheral chemodenervation it has been shown that the
effects of the uncouplers are both central and peripheral
Ve
(473).
2 (75, 189)
Like dinitrophenol, salicylates also increase Vo
probably by uncoupling oxidative-phosphorylation, a mechanism unrelated to the familiar antipyretic action of salicylatederivatives. In fact, in high dosages, salicylates induce hyperthermia (10, 51, 483). In some instances the increase in
with salicylates has been fully attributed to the increase
Ve
2 (61, 229b). Other studies reported no or very modin Vo
est hyperventilatory effects of salicylates at rest (369, 386),
and some moderate enhancement (2 mmHg in Paco2 ) of the
hypercapnic hyperventilation (386). An extremely large hyperventilation (10 to 16 mmHg in Paco2 ) has been reported
in anesthetized dogs (104) with toxic doses of salicylates that
(483). Like other micaused up to a 6- to 8-fold increase in Ve
tochondrial uncouplers, in addition to the hypermetabolic ef at multiple sites. In fact,
fect salicylates probably influence Ve
salicylates stimulate the respiratory neurons directly (284,
285, 445), and this central action may be more important on
than the hypermetabolic effect (122). In addition, salicyVe
lates stimulate the peripheral chemoreceptors (279). Finally,
it has been observed that keeping the experimental animal
cool during salicylates-induced hypermetabolism can reduce
the hyperventilation (462). Hence, a variety of central and
peripheral mechanisms can explain why, in large dosages,
beyond the level strictly approsalicylates can stimulate Ve
2.
priate to meeting the increase in Vo
Extrapulmonary Gas Exchange

maintain its proportionality to Vo
2
To what extent does Ve
during hypometabolism? In other words, in steady-state conditions of aerobic metabolism (see section Terminology and
2 (x-axis)
Abbreviations) does the relationship between Vo
and Ve (y-axis) (e.g., Figs. 6 and 8) start from the origin?

Of course, we can immediately exclude the possibility of
a Y-intercept, because an organism with zero metabolic rate
Hence, the question becomes whether
cannot produce any Ve.
2Ve is present whenever there is some metabolic rate (Vo
Ve relationship from the origin), or whether Ve starts when

2 reaches some threshold (intercept on the x-axis). There
Vo
are many physiological and experimental situations that have
2 threshold, and some will be
indicated the existence of a Vo
summarized below. What remains controversial is the identi 2 threshold and
fication of the factors responsible for the Vo
for the maintenance of the Ve-Vo2 coupling above threshold.

During the life of a mammal, the most common situation
is before birth. During
of active metabolism in absence of Ve
prenatal development, the fetal metabolism and PO2 are low,
and fetal-placental gas exchange suffices for the control of
10:31
fetal Pao2 and Paco2 . Hypercapnia increases fetal breathing

movements in both human and animal fetuses (78, 195, 197,
227, 370, 451). Indeed, various considerations have led to the
hypothesis that the level of fetal CO2 represents an important
background drive for fetal respiratory activity, which can
be modulated by various inputs, such as those related to sleep
state (33).
At birth, the transition from placental to pulmonary gas
exchange is very rapid, and many hormonal and physical
stimuli of very different nature could contribute to the maintenance of a steady breathing pattern (292). It is possible that
the common mechanism of all these assorted stimuli is the in 2 . Excreased metabolic level, specifically, the increased Vco
periments on fetal lambs with extracorporeal circulation have
permitted manipulation of PCO2 while keeping oxygenation
and T constant (227, 228, 229a). In these experiments, clamping the umbilical cord in the exteriorized fetus did not trigger
breathing as long as the CO2 was not allowed to rise. Similar results were obtained in goat fetuses with extracorporeal
circulation (223). In neonatal lambs, extracorporeal CO2 re the point of apneas was usually, but not
moval reduced Ve;
always, below the eupneic Paco2 (58, 357). In the context of
this article these results are of particular interest because they
depends on a
suggest that the maintenance of a steady Ve
critical value of metabolically produced CO2 .
The same concept emerges from observations in birds
during hatching. As birth in mammals, hatching in a bird
represents a switch from extrapulmonary gas exchange (provided by the chorio-allantoic membrane) to pulmonary gas
exchange; however, unlike mammals, in birds the transition
is a gradual process of many hours or days, during which
chorioallantoic and pulmonary gas exchange operate together.
In the first hours of the hatching process, because metabolism
is relatively low and the chorioallantoic membrane fulfills gas
and the ventilatory equivalent are low. In the
exchange, Ve
later hours of the hatching process, as metabolism rises above
the gas exchange capability of the chorioallantoic membrane,
and Ve/
Vo
2 increase (Fig. 14). This indicates that durVe
is coupled not to the embryos total tissue
ing hatching Ve
metabolism, but to that fraction of gaseous metabolism that
exceeds the gas exchange properties of the chorioallantoic
membrane. Experimental changes of the embryos metabolic
level through changes in T produced a similar conclusion.
In fact, when the low T caused metabolism to remain low,
the chorioallantoic membrane was sufficient to provide for
was small or absent. As
the embryos gas exchange, and Ve
initiated
T and the metabolic level increased, eventually Ve
and rose in proportion to the fraction of Vo2 that exceeded

the maximal gas exchange of the chorioallantoic membrane
is absent or minimal
(280). In some marsupial neonates Ve
for some days after birth, because gas diffusion through the
skin is sufficient to provide for the newborns gas exchange
needs (132, 304). In summary, the results of all these exper relationship has
2 -Ve
iments indicate, first of all, that the Vo
an X-intercept, because Ve is not present as long as extrapulmonary organs (the placenta, the chorioallantoic membrane
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0.8
VO2, ml/min
0.7
0.6
0.5
0.4
f, breaths/min
90
80
70
ercise (463, 466). In an earlier study (220), removal of CO2 in

conscious lambs by an external membrane exchanger reduced
stopped, at
when the removal approximated Vco
2 , Va
Va;
Paco2 values not statistically different from those before the
extracorporeal removal. In agreement with the results of these
experiments, in lamb and goat fetuses after disconnection of
the placenta, the maintenance of fetal blood gases by the
extracorporeal exchanger prevented the initiation of regular
breathing (223, 228, 229a).
60
Concluding Remarks
250
200
150
VT, 1
100
VE, ml/min
16
14
12
10
8
6
22
20
18
16
14
VE/VO2
IP
EP
Embryos
18 hours
Hatchlings
Figure 14 Mean values of oxygen consumption (V O2 ), pulmonary
E/V
O2 ) in chickens during
E), and ventilatory equivalent (V
ventilation (V
the hatching process. IP and EP refer, respectively, to the early hatching phases of internal and external pipping. During these phases, the
ventilatory equivalent is low because gas exchange is primarily through
the chorioallantoic membrane. [Modified from ref. 299)].
or the skin) fulfill the gas exchange needs of the organism.

Second, they suggest that CO2 may be the important variable
to Vo
2 . This would mean that the commonly
that links Ve
occurs beobserved coupling between metabolism and Ve
cause of mechanisms sensing the CO2 component of gaseous
metabolism.
Experimentally, the gas exchange duties of the lungs can
be substituted in animals with extracorporeal circulation arranged in series with O2 and CO2 membrane exchangers. In
one such experiment in conscious sheep, Phillipson et al. (350)
found that the spontaneous breathing of the sheep decreased
ceased
as the external gas exchange increased; eventually, Ve
when the extracorporeal exchanger eliminated CO2 at the
same rate of its metabolic production, while Pao2 and Paco2
remained at their eupneic levels. This study also clearly in 2,
correlated much better with Vco
2 than Vo
dicated that Ve
similarly to what is observed in the hyperpnea of muscle ex-
1700
The response to changes in T is an excellent example of the

and its coupling with Vo
2.
interplay of factors controlling Ve
In hot conditions, at first the tachypneic breathing pattern
to become dissociated from Ve,
and the respipermits Va
ratory system can contribute to Tb control without serious
interference with normal gas exchange (see section Thermal
tachypnea). With the progression of the heat challenge, the
priority of the respiratory system shifts toward heat loss at
the expense of PCO2 homeostasis (see section Thermal hyperventilation). Eventually, when the risk of dehydration encroaches, water conservation rises to the top of the priorities
changes accordingly (see section Interaction with waand Ve
ter balance). The shuffling of tasks in emergency situations
Vo
2 for the protection of
illustrates that the constraints on Veblood gases have ample room for tolerance. However, when
other priorities do not interfere with the primary goal of gas
follows metabolic rate quite closely. Indeed,
exchange, Ve
one can but marvel at the fact that irrespective of the causes
of hyper- or hypometabolism, and for enormous variations in
Vo
2 from its resting
2 (e.g., Fig. 13) the deviations of VeVo
value are usually modest, and the factors responsible for the
deviations are usually identifiable. The fact that Paco2 remains
stable when metabolism is changed by the most diverse circumstances (moderate exercise, cold, cold and exercise combined, variations in body size, caloric intake, age, time of
and
the day, hormones, drugs, etc.) makes it unlikely that Ve
metabolism are controlled in parallel by the condition responsible for the metabolic change. It seems much more probable
that in all instances the level of metabolism represents the
even though each condicommon denominator driving Ve,
tion may add its own modifier, facilitatory or inhibitory on Ve.

For example, in the cold, a drop in Tb (inhibitory stimulus
can limit the hyperpnea associated with cold-induced
on Ve)
hypermetabolism (see section Cold exposure); in pregnancy,
stimulates Ve
beyond what
progesterone (facilitatory on Ve)
dictated by the pregnancy-induced hypermetabolism (see section Pregnancy); during the hypometabolic state of sleep, the
absence of wakefulness (facilitatory on breathing) reinforces
the hypopnea (see section Circadian and seasonal oscillations).
The metabolic information could originate at the tis via neural or humoral pathways
sue level and drive Ve
(243). Metabolites of cellular energetics, specifically, the
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high-energy phosphates and their derivatives proposed as

regulators of tissue respiration (185, 186), are potential candidates as informers on metabolic state because of their universal locations (see Forster et al., Control of Breathing during
Exercise, this series in Comprehensive Physiology). However, the observations that, as hypometabolism progresses,
relationship hits a threshold whenever Vo
2 (or
2 -Ve
the Vo
2 ) is provided by a nonpulmonary exchanger (see section
Vco
Extrapulmonary Gas Exchange) argue against the possibility
is controlled by tissue metabolites. Rather, those obthat Ve
servations strongly support the view that the link between the
is provided by the gaseous component
metabolic level and Ve
of metabolic rate. O2 and CO2 are the only metabolites used
and produced irrespective of which organ or tissue contributes
to the hyper- or hypometabolic state. Although few experi 2
2 and Vco
ments have examined separately the role of Vo
some results have indicated that Vco
2 was the varion Ve,
(e.g., see sections Growth and
able more closely linked to Ve
ageing, Nutritional status, Extrapulmonary Gas Exchange).
Then, the daunting question is how the metabolically pro The peripheral and central chemoreduced CO2 regulates Ve.
ceptors would be the most logical candidates. Experiments on
chemodenervated animals have indicated that the peripheral
chemoreceptors are not essential for the coupling between Ve

and gaseous metabolism in hyper- or hypometabolic conditions (e.g., see section Cold exposure). In addition, the close
and Vco
2 should imply a very
proportionality between Ve
response to changes in CO2 . This is usuhigh gain of the Ve
ally not the case, especially in the neonatal period, which is
chemosensitivity. In
typically characterized by a modest Ve
those extraordinary rare cases of complete absence of cortical and peripheral inputs to the medulla, as in the human
locked-in syndrome, the PCO2 apnea threshold can be extremely close (1 mmHg) to the eupneic PCO2 (180). This
means that, in the absence of other inputs, at the central level
the sensitivity to CO2 can be much higher than apparent in
intact and awake preparations.
also the hypoxic ventilatory response
Like normoxic Ve,
varies with the metabolic level. In fact, for the same hypoxic
stimulus, the magnitude of the hypoxic hyperpnea is proportional to the level of normoxic metabolism, irrespective of
the causes determining hypo- or hypermetabolism (reviewed
in ref. 290). It would be interesting to know if, in addition
to the hypoxic ventilatory response, other ventilatory reflexes
change their gain according to the metabolic level. A positive answer might mean that the sensitivity to metabolic CO2
needs not to involve the chemoreceptors or other specific afferents or feed-back loops, but could be a property of the
central respiratory neurons involved in the generation of the
breathing pattern.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18a.
18b.
19.
20.
21.
22.
23.
24.
25.
26.
27a.
27b.
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May 20, 2011

Printer Name: Yet to Come

Metabolism, Temperature, and Ventilation

O2 , and these two tasks are often in conflict. Furthermore, Ve

Volume 1, October 2011

further level of complexity when metabolic demands change,

Terminology and Abbreviations

May 20, 2011

Printer Name: Yet to Come

Metabolism, Temperature, and Ventilation

equals the product of O2 convection (Ve [O2 ]insp) and the

Furthermore, because all the CO2 is endogenously produced,

and [CO2 ]alv stand for alveolar ventilation1 and

Paco2 is measured at the airway opening toward the end of

By contrast, the terms

Q10 = (v /v )(10/T T

and the ventilation of the dead space.

metabolic rate measured at thermoneutrality under resting conditions.

Volume 1, October 2011

May 20, 2011

Printer Name: Yet to Come

Metabolism, Temperature, and Ventilation

than in the adult. Some marsupial neonates have very low

Growth and ageing

Figure 1 Body temperature (top) and arterial (or end-tidal) pressure

in women (35 mmHg) than in men (39 mmHg) (see section

Volume 1, October 2011

The fact that the values of ventilatory equivalents derived from

Circadian and seasonal oscillations

volumes and their rate of change are measured and expressed at

May 20, 2011

Metabolism, Temperature, and Ventilation

oscillations of metabolic rate and Tb. During sleep, humans

The robustness of the Ve-metabolism

modifiers of the Ve-metabolism

Printer Name: Yet to Come

reflects some increase of the Ve-metabolism

Volume 1, October 2011

May 20, 2011

longer operational and evaporation is the only possible means

sections examine the effects of these interactions on Ve.

the increase in Vo2 . Representative examples from birds and

Volume 1, October 2011

Printer Name: Yet to Come

Metabolism, Temperature, and Ventilation

2 does not prevent some

fall in Tb. In this situation, Ve does not increase, probably

(6%). Despite the Ve decline, the deep and slow breathing

while limiting the thermolysis of the increased Ve.

May 20, 2011

Printer Name: Yet to Come

Metabolism, Temperature, and Ventilation

Ventilation in cold (% of warm)

Oxygen consumption in cold (% of warm)

Figure 2 Responses of pulmonary ventilation (V E) and oxygen consumption (V O2 ) to cold,

The carotid bodies are not required for the proportional

2 , usually with stability of blood gases (Fig. 4,

Cold in the neonatal period

Volume 1, October 2011

May 20, 2011

Printer Name: Yet to Come

Metabolism, Temperature, and Ventilation