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Invited Review
Department of Physiology, University of Otago, Dunedin, New Zealand; 2Department of Human Kinetics, Faculty of Health
and Social Development, University of British Columbia, Okanagan, Kelowna, Canada; and 3Departments of Anaesthesia and
Physiology, University of Toronto, Toronto, Ontario, Canada
Ainslie PN, Duffin J. Integration of cerebrovascular CO2 reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation. Am J Physiol Regul Integr Comp Physiol 296: R1473R1495, 2009. First
published February 11, 2009; doi:10.1152/ajpregu.91008.2008.Cerebral blood
flow (CBF) and its distribution are highly sensitive to changes in the partial
pressure of arterial CO2 (PaCO2). This physiological response, termed cerebrovascular CO2 reactivity, is a vital homeostatic function that helps regulate and maintain
central pH and, therefore, affects the respiratory central chemoreceptor stimulus.
CBF increases with hypercapnia to wash out CO2 from brain tissue, thereby
attenuating the rise in central PCO2, whereas hypocapnia causes cerebral
vasoconstriction, which reduces CBF and attenuates the fall of brain tissue
PCO2. Cerebrovascular reactivity and ventilatory response to PaCO2 are therefore
tightly linked, so that the regulation of CBF has an important role in stabilizing
breathing during fluctuating levels of chemical stimuli. Indeed, recent reports
indicate that cerebrovascular responsiveness to CO2, primarily via its effects at
the level of the central chemoreceptors, is an important determinant of eupneic
and hypercapnic ventilatory responsiveness in otherwise healthy humans during
wakefulness, sleep, and exercise and at high altitude. In particular, reductions
in cerebrovascular responsiveness to CO2 that provoke an increase in the gain
of the chemoreflex control of breathing may underpin breathing instability
during central sleep apnea in patients with congestive heart failure and on
ascent to high altitude. In this review, we summarize the major factors that
regulate CBF to emphasize the integrated mechanisms, in addition to PaCO2, that
control CBF. We discuss in detail the assessment and interpretation of cerebrovascular reactivity to CO2. Next, we provide a detailed update on the
integration of the role of cerebrovascular CO2 reactivity and CBF in regulation
of chemoreflex control of breathing in health and disease. Finally, we describe
the use of a newly developed steady-state modeling approach to examine the
effects of changes in CBF on the chemoreflex control of breathing and suggest avenues
for future research.
cerebral blood flow; ventilation; reactivity
RESPIRATORY-INDUCED CHANGES
concept, therefore, is that cerebrovascular reactivity and ventilatory response to PaCO2 are tightly linked, so that regulation
of CBF has an important role in stabilizing breathing during
fluctuating levels of chemical stimuli.
This review comprises four main parts. 1) We present the
major factors that regulate CBF to emphasize the integrated
mechanisms, in addition PaCO2, that control CBF. 2) We assess
and interpret cerebrovascular reactivity to CO2, with particular
focus on the integrative mechanisms linking cerebrovascular
function with ventilatory control in health and disease. The
related literature is reviewed and discussed, with particular
focus on the advantages and disadvantages of the steady-state
and rebreathing techniques for the assessment of cerebrovascular and ventilatory responsiveness to CO2; the physiological
interpretation of these different tests are critically examined,
and practical guidelines are provided, so that test results may
be collected to enhance comparisons, reproducibility, and accuracy. 3) We provide a detailed update on the integration of
the role of cerebrovascular CO2 reactivity and CBF in regula-
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(1)
and not CBF per se, only assessment of changes in flow, rather
than absolute values, can be made. Nevertheless, research
indicates that middle cerebral artery (MCA) blood flow velocity (MCAv) is a reliable and valid index of CBF (68, 100, 156,
178, 204). Moreover, since determinations of cerebrovascular
reactivity are based on stimulus-response principles, absolute
CBF values are not as important as reliable and repeatable
recordings with short (beat-to-beat) time resolution. For this
purpose, therefore, TCD is a well-suited technique in the
experimental research and clinical settings. Before we review
the evidence linking cerebrovascular CO2 reactivity with ventilatory control, we first provide a discussion of the relevant
aspects of cerebrovascular CO2 reactivity to clarify its use,
measurement, and related interpretation.
Regional differences in cerebrovascular CO2 reactivity. Although there is marked variability in the literature for normal
cerebrovascular CO2 reactivity (see below), when derived as
the average reactivity across the majority of the selected
experimental studies, the global CBF reactivity to changes in
PaCO2 is 3.8%/mmHg (72, 77, 95, 170) within the PaCO2
range of 3555 mmHg. On closer examination, however, this
reactivity is normally higher in the hypercapnic than hypocapnic range (43, 84, 221, 222). The mechanisms underlying this
greater reactivity to hypercapnia than hypocapnia may be
related to a greater influence of vasodilator than vasoconstrictive mediators on intracranial vascular tone (157, 199). From a
teleological perspective, the normal lower reactivity in the
hypocapnic than hypercapnic range might be a protective
mechanism to prevent cerebral ischemia during transient drops
in PaCO2, which are known to occur in a range of physiological
(postural change and exercise) and pathophysiological (asthma, syncope, sleep apnea, congestive heart failure, and anxiety attacks)
situations. In other words, maintaining oxygenation might be
more important than pH disturbances. In addition, it is important to note that alterations in CBF reactivity to hypocapnia
may be as important as hypercapnic reactivity for breathing
stability, especially during sleep, when the wakefulness dive is
absent and PaCO2 becomes the critical factor in maintaining
rhythmic breathing (219).
It should be noted that, partly dependent on the method used
to estimate CBF, there is marked inhomogeneity of cerebrovascular CO2 reactivity (137, 160). For example, CBF reactivity is much higher in the gray matter than in the white matter.
Thus, although TCD has many advantages because of the
noninvasive nature of measurement and continuous recordings
with high temporal resolution, TCD normally measures blood
velocity in the MCA, an area that transports blood to large
brain volumes, including gray and white matter, whereas sophisticated approaches, such as pulsed arterial spin labeling
MRI, measure the reactivity of small vessels and capillaries
within a purely cortical gray matter area, where hypercapnic
CO2 reactivity is much higher (114); potential regional differences in hypocapnic CO2 reactivity have not been reported.
Thus, because it is believed that changes in CBF are transmitted accurately to the MCA (1), it seems that the use of TCD
may be described as more of an average indicator of CBF,
whereas greater local resolution can be obtained using MRI.
In addition to the noted differences in cerebrovascular CO2
reactivity between white and gray matter, there are marked
regional differences of gray matter reactivity. A typical composite blood oxygenation level-dependent (BOLD) MR cere-
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Fig. 5. Polygraph record of a single trial during 5% CO2 exposure. CBF velocity (CBFv) progressively increased to a peak with the increase in end-tidal PCO2
(PETCO2) and then was maintained at a high level throughout hypercapnia. At termination of CO2 exposure, CBFv quickly decreased with reduction of end-tidal
PCO2. Time delay was measured from beginning of CO2 inhalation to onset of CBFv increase (T1), from establishment of the new level of end-tidal PCO2 to the
peak of CBFv (T2), and from off-stimulation to the start of the decline of CBFv (T3) as well as to the nadir of CBFv (T4). SaO2, O2 saturation of arterial blood.
[Modified from Xie et al. (221)]. Note relative drop in end-tidal PCO2 from T2 to T3 with hypercapnia-induced elevations in airflow; this observation indicates
that CBF reactivity during such steady-state testing is somewhat ventilatory dependent.
tempting to speculate that these hypercapnic-hypocapnic reactivity differences may reflect a differential control of CBF via
brain tissue PCO2 or PaCO2 during hypercapnia (65, 156, 222)
and hypocapnia (135); however, although jugular venous PCO2
is likely to be a closer index of brain tissue PCO2 than PaCO2
(10, 65, 156, 182, 222), it is difficult to clarify the mechanisms
involved with knowledge of only arterial-venous PCO2 gradients and no information related to the CO2 flux across the
brain. Thus, considerations regarding the differences in endtidal, arterial, and brain tissue PCO2 have important implications for the true representation and physiological interpretation of cerebrovascular CO2 reactivity.
Appropriate experimental change in PaCO2. In healthy subjects, an acute lowering of CBF is associated with mild symptoms of cerebral hypoperfusion. Mental confusion becomes
prominent with 50 60% reduction, and cerebral oxygenation
becomes affected (135); thus, for a safe range for human
experimentation, hypocapnia should be 20 mmHg. Similar,
marked subject discomfort is apparent with administration of
8% CO2 (15 mmHg PaCO2 above rest); thus, changes in
PaCO2 under this range are recommended for safety and related
subject comfort.
Analysis and curve-fitting considerations. Steady-state cerebrovascular CO2 reactivity testing (Figs. 5, 6, and 8) has been
assessed by least squares linear regression (165, 166, 207),
biasymptotic curve analysis (i.e., a tangent-hyperbolic function) (117), a dynamic single-compartment model (165, 166,
207), and an exponential function (56, 59, 60, 77, 125, 152). In
addition, with a steady-state change in end-tidal PCO2, the
speed (or onset response) of CBF velocity at the transition
period of on- and off-CO2 administration can be assessed (165,
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166, 221); the physiological meaning of this response, however, is unclear. Indeed, recent experimental results from our
laboratory indicate that the initial CBF response to a step
change in PaCO2 is a highly complex response with marked
intrasubject variability (Fig. 6).
Numerous studies have also used linear regression to assess
CO2 reactivity during modified rebreathing tests (5, 6, 8, 15,
19, 43, 63, 96, 105, 121, 124, 157, 171, 181, 221, 222) (Figs.
5 and 8). However, more research exploring the physiological
characteristics of cerebrovascular CO2 reactivity has demonstrated that the relationship between PaCO2 and CBF is nonlinear and might be affected by CO2-induced changes in arterial
BP (Fig. 7) (71, 94). On closer examination, during hypercapnia, increases in SNA and HR are well documented, whereas
variable changes in BP have been reported. Some studies
report an increase (40, 56, 125, 152), while others report no
change (71, 94). Methodological differences in duration and
intensity of hypercapnia and in the measurement of BP may
partly explain the discrepancies between studies.
In addition, the control mechanisms that govern the responses of CBF and arterial BP to CO2 have dynamic properties (40, 125, 126). These studies, among many others, have
quantified cerebrovascular CO2 reactivity using linear regression of steady-state responses of CBF to changes in CO2,
without incorporation of the effects of BP. The likely reason
for this simplicity is that well-controlled experiments and
complex modeling methods may not be practical for clinical
use (40). To account for the nonlinear CBF-end-tidal PCO2
relationship, the use of cerebrovascular conductance index
during this process may reveal direct effects of changes in
General organization. Breathing is stimulated via a chemoreflex arc, which includes the central and peripheral chemoreceptors, the central nervous system, and the respiratory
muscles. The chemoreflexes form the feedback part of a
negative-feedback loop (Fig. 9). The loop is completed by the
forward part, in which alveolar ventilation controls the uptake
of O2 and elimination of CO2. The forward part of the loop
relates the dependence of PCO2 and PO2 on ventilation, and, as
the alveolar air equation states, the product of ventilation and
alveolar PCO2 is proportional to the amount of CO2 eliminated;
hence, in any steady metabolic state, PCO2 depends on CO2
production divided by alveolar ventilation (52). This rectangular hyperbolic relationship is referred to as the metabolic
hyperbola. PCO2 is the major factor controlling the [H] sensed
by the chemoreceptors, but acid-base status is also involved
(Fig. 8). Stimulation of the chemoreceptors results in an increased alveolar ventilation, which results in an increased
elimination of CO2 and a fall in PCO2 and [H] stimulus at the
chemoreceptors, hence, the negative-feedback designation of
the system.
Central chemoreflex. The central chemoreceptors are stimulated by the [H] of their local environment in the medulla
(scattered within and near the ventrolateral surface of the
medulla) (129, 132). Since [H] is directly dependent on the
PCO2 of chemoreceptor tissue, they are often thought of as CO2
receptors, but this simplification can be misleading. Although
CO2 passes freely across the blood-brain barrier, H ions do
not; therefore, central [H] may differ from arterial [H]. As
a consequence, medullary acid-base conditions determine the
PCO2-[H] relationship at the central chemoreceptors, and the central chemoreceptors are isolated from arterial acid-base disturbances, except as they involve changes in PaCO2. The control of
central acid-base status to keep central [H] at normal values
may result in differences in the PCO2-central [H] relationship
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taste the blood approaching the brain, signaling the respiratory controller in the medulla via the carotid sinus nerve (a
branch of the glossopharyngeal or IXth cranial nerve) (87,
88). In the same way as for the central chemoreceptors,
acid-base conditions, in this case in the arterial blood,
determine the PaCO2-[H] relationship at the peripheral
chemoreceptors.
Models of the drive to breathe from the peripheral chemoreceptors (Fig. 11) assume that the neural drive to breathe from
peripheral chemoreceptors increases linearly with [H] above
a chemoreceptor threshold [H] with a constant slope (sensitivity); therefore, sensitivity and threshold determine the response to any particular stimulus. However, in contrast to the
central chemoreceptors, the sensitivity of the peripheral chemoreflex response to [H] also depends on PaO2. Thus, hypoxia acts by increasing the peripheral chemoreceptor response
to [H]; therefore, the receptors are maximally stimulated by a
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Fig. 10. Drive to breathe from central chemoreceptors assumes that central
drive increases linearly with [H] above a chemoreceptor threshold [H] with
a constant slope (sensitivity); therefore, sensitivity (DcS) and threshold (Tc)
determine the response to any particular stimulus.
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A close relationship between changes in CBF and ventilatory output has been shown in animal studies. Results of the
first major study on the interrelationship between CBF and
ventilation in anesthetized dogs reported in 1928 (176) showed
that if CBF was increased from low levels, ventilation increased if the animals were hypoxic but decreased if the
animals were breathing room air. It was suggested that the
former response was indicative of removal of brain hypoxic
depression by the increasing CBF, and the latter response
(ventilatory depression) was a consequence of the removal of
accumulated brain CO2 and acid metabolites. Other studies
investigated the ventilatory responses to acute reductions of
CBF by clamping the vertebral artery and/or the common
carotid artery (78, 161). After total or partial reduction of CBF,
ventilation is usually increased and, depending on the degree of
CBF reduction, apnea may develop. However, although brain
hypoxia and brain acidosis were evident in these studies,
because the animals were anesthetized and the contribution of
the carotid chemoreceptors to the ventilatory response was
unknown, interpretation of these data is difficult.
Evidence for the increased sensitivity of ventilation to a
change in PaCO2 by reduced CBF and cerebrovascular CO2
reactivity was first provided in highly controlled studies in the
unanesthetized goat (36) (Fig. 14). This study demonstrated
that when CBF was reduced by 30%, the cerebrovascular
response was attenuated, whereas the ventilatory responsiveness to CO2 was increased. This observation suggests that CBF
affects ventilation through modification of tissue PCO2 in the
region of the medullary chemoreceptor area. With poor brain
perfusion, the central chemoreceptor will sense a relatively
higher [H] for a given change of PaCO2 and will correspondingly trigger a more vigorous ventilatory response. However,
when CBF was further reduced to 50%, which nearly abolished
CBF-CO2 reactivity, there was a marked blunting of the minute
E)-PaCO2 response, possibly as a consequence of
ventilation (V
hypoxic depression of the respiratory neurons (36). Thus, on
the basis of these animal experiments, there seems to be a
threshold at which changes in CBF and cerebrovascular CO2
reactivity may lead to differential alterations in the ventilatory
responsiveness to CO2.
Experimental evidence for the close relationship between
changes in CBF and ventilatory control in humans is mostly
based on early studies in a range of pathological conditions.
For example, elevations in ventilatory CO2 responsiveness
have been found primarily in clinical studies of patients with
moderate cerebrovascular disease. Heyman et al. (79) used the
steady-state method to determine ventilatory responsiveness to
CO2 in a group of patients with chronic bilateral forebrain
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heart failure (8, 174, 230). The key pathophysiological mechanism(s) leading to Cheyne-Stokes respiration is a fluctuation
of PaCO2 above and below the so-called apneic threshold (50,
221). In addition to the common occurrence of CSA in patients
with congestive heart failure and in healthy individuals after
ascent to high altitude, periodic breathing during sleep is
almost universal, occurring in 90% of humans (5). A reduction in cerebrovascular CO2 reactivity during wakefulness has
been identified in patients with congestive heart failure and
CSA; this reduction may affect stability of the breathing
pattern (26, 28, 50, 109, 111). More recently, a comparable
finding has been shown at high altitude (8). Such reductions in
cerebrovascular responsiveness to CO2 that provoke an increase in the sensitivity or gain of the chemoreflex control of
breathing may underpin breathing instability during CSA observed in patients with congestive heart failure and on ascent to
high altitude (Fig. 15).
In patients with congestive heart failure, however, a number
of destabilizing factors contribute to fluctuations in PaCO2.
First, a low PaCO2 close to the apneic threshold predisposes to
the development of central apneas (50); however, this will only
occur if the resting PCO2 is decreased because the chemoreflex
gain has increased. In support of this, a number of studies have
reported that PaCO2 is lower in patients with congestive heart
failure and Cheyne-Stokes respiration (75, 92, 112, 133, 198,
223). Naughton et al. (133) and Hanly et al. (75) found lower
PaCO2 during wakefulness and non-REM (NREM) sleep in
patients of comparable age, left ventricular ejection fraction,
PaO2, and lung-to-chemoreceptor circulatory delay with congestive heart failure with Cheyne-Stokes respiration than in
patients without congestive heart failure with Cheyne-Stokes
respiration. All episodes of Cheyne-Stokes respiration starting
during stage 2 sleep were almost always precipitated by hyperventilation in association with arousals from sleep. Furthermore, during Cheyne-Stokes episodes in stage 2 sleep, PaCO2
Fig. 15. Mechanisms involved in the genesis of CheyneStokes respiration and related overlap between congestive heart failure and high altitude. Alterations in cerebrovascular reactivity (in hyper- and hypocapnic range)
to CO2 as a consequence of congestive heart failure or
exposure to high altitude may affect chemosensitivity
and lead to elevations in total loop gain of the respiratory chemoreflex and breathing instability. Dashed lines
denote an additional influence, e.g., augmented gain of
chemoreceptors, secondary to pulmonary edema (as a
consequence of exposure to high altitude or congestive
heart failure), that destabilizes the respiratory control
system by making it more prone to ventilatory overshoot; or if inappropriate elevations in SNA occur
during development of congestive heart failure or at
high altitude, then its potential influence on constraining
cerebrovascular reactivity may affect breathing stability.
Balance between sleep and arousals also affect ventilation
and related arterial blood gases and stability. LF, left
ventricular. , Additive factors that may propagate development of central sleep apnea, e.g., development of hypocapnia as a consequence of congestive heart failure and
exposure to high altitude, acting to dive PaCO2 below the
apneic threshold during sleep; arousals, through promotion of hyperventilation, appear to facilitate, rather than
provoke, periodic breathing directly. Sleep-wakefulness
transitions may also produce respiratory control instability
via related alterations in upper airway resistance (for review
see Refs. 120 and 200).
AJP-Regul Integr Comp Physiol VOL
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E
fell on average by 1.5 mmHg, which mirrored a 23% rise in V
(223). A lower resting PCO2 can be the result of chemoreflex
feedback gain increases and, also, chemoreflex threshold decreases; total loop gain (and thus stability) is determined in part
by the balance of feedback and plant gain (50). For example, if
feedback gain alone decreases the resting PCO2, the decrease in
plant gain will offset the increase in feedback gain, so that loop
gain increases only if the feedback gain increases more than
plant gain decreases; if loop gain increases, then stability will
be decreased (Fig. 15). Under this condition, a relatively small
increase in ventilation would drive PaCO2 below threshold and
trigger a central apnea (75). It is unknown how CBF and
CBF-reactivity might be altered during sleep in congestive
heart failure patients with and without CSA.
Patients with congestive heart failure and Cheyne-Stokes
respiration have an unusual response to sleep, in that their
PaCO2 levels do not increase in the progression from wakefulness to sleep (112), and, as a consequence, PaCO2 is closer
to their apneic threshold during sleep (112). Lorenzi-Filho
et al. (111, 112) abolished Cheyne-Stokes respiration in
congestive heart failure patients by inhalation treatment
with small concentrations of CO2 delivered by a mask.
Stabilization of breathing was achieved by a small (2
mmHg), but significant, increase in transcutaneous PCO2. In
contrast, supplemental O2 was not able to raise transcutaneous PCO2 and had no significant impact on the frequency
of Cheyne-Stokes respiration. This study reveals the critical
importance of small variations in PaCO2: a decline in PaCO2
below the apneic threshold triggers central apneas and
Cheyne-Stokes respiration. Arousals, through promotion of
hyperventilation, appear to facilitate, rather than provoke,
periodic breathing directly. More recently, we reported a
reduction of cerebrovascular CO2 reactivity at high altitude
compared with low altitude and a greater decrease in CBF
and loss of CA during sleep (8). The lowered CBF and
impaired CA during sleep at high altitude may cause
changes in central chemoreceptor stimulation and, thus, the
apneic threshold, which potentially could promote the
breathing instability at high altitude. This would seem
especially likely if the reduced CBF-CO2 reactivity, especially reductions in the CBF response to hypocapnia, during
wakefulness also occurs during sleep. The critical role of the
CBF response to hypocapnia during sleep has recently been
reported (219). In support of this notion, a strong correlation
was found between the severity of CSA and the change in
CBF (8). In other words, at high altitude, subjects with the
largest decrease in CBF during sleep had the highest number of
central events per hour (Fig. 16), suggesting a link between central
chemoreceptor stimulation and CBF. More recently, we extended these findings in a placebo-controlled, randomized
design (n 12), where indomethacin (100 mg po) and acetazolamide (10 mg/kg iv) were used during wakefulness and
before sleep to alter CBF and cerebrovascular reactivity to CO2
(11). These measures and blood gases were obtained before
and during each intervention at sea level and high altitude
(5,050 m, 6 days of acclimatization). Sleep, including CBF
monitoring, was studied using full polysomnography. Acetazolamide, relative to indomethacin, halved the frequency of
CSA (54 46 vs. 101 28 events/h, P 0.01) and elevated
MCAv more during NREM sleep. These results indicate that
reductions in CBF and CBF-CO2 reactivity play a key role in
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Fig. 16. Relationship between degree of central sleep apnea and change in
MCAv from wakefulness to sleep at high altitude. Each point represents an
individual subject. Since there was no central sleep apnea at low altitude, there
was no relationship with the change in MCAv between wakefulness and sleep
(r 0.05). [Modified from Ainslie et al. (8).]
the pathogenesis of CSA at altitude (unpublished observations). Although acetazolamide-induced elevations in MCAv
may also provide additional protection against development of
CSA, we cannot dissociate this effect from its other known
prophylactic benefits (91, 106, 197).
Interestingly, our ongoing studies have shown a potential
difference in the influence of indomethacin between sea level
and high altitude. For example, in contrast to the findings at sea
level, administration of indomethacin (100 mg po) at 5,050 m
resulted in a greater reduction in MCAv-CO2 reactivity
(47 27% vs. 88 62%, P 0.01), led to periodic
breathing in 10 subjects during wakefulness (62) (see supplementary video in the online version of this article), and increased occurrence of CSA (Ainslie et al., unpublished observations).
In summary, reductions in CBF and cerebrovascular responsiveness to CO2, which provoke an increase in the sensitivity
or gain of the chemoreflex control of breathing, may underpin
breathing instability during CSA in patients with congestive
heart failure and on ascent to high altitude. However, many
other factors are also important in the development of CSA.
The integration of these key factors and the related comparison
between CSA in congestive heart failure and CSA at high
altitude are illustrated in Fig. 15, which shows considerable
overlap between the pathogenesis of CSA in congestive heart
failure and CSA that develops as a consequence of exposure to
high altitude. For example, the reduction in CO2 reactivity
results in larger changes in the [H] presented to the central
chemoreceptors (50, 186, 222). The potential changes in CBFCO2 reactivity are not exclusive to hypercapnia; rather, a
reduction in the CBF response to hypocapnia seems to be a
critical response. For example, a ventilatory overshoot would
lead to a greater fall in PaCO2, so the CBF response within the
hypocapnic range (in the context of CSA) is probably more
important (or at least equally important) during sleep than the
CBF response within the hypercapnic range (219). However, it
would seem likely that an inappropriate CBF response in either
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range would promote breathing instability. Therefore, a reduced cerebrovascular response to CO2 (to hyper- or hypocapnia) might directly increase the susceptibility for periodic
breathing by increasing the central chemoreceptors contribution to loop gain. In support of this concept is the aforementioned study indicating that an indomethacin-induced alteration
in the cerebrovascular response to CO2 is sufficient to change
the ventilatory response to CO2 (Ainslie et al., unpublished
observations; 62, 219, 222). However, changes in cerebral
responsiveness to CO2 may only be partly sufficient to destabilize breathing, inasmuch as the carotid bodies play a significant role in the rapid ventilatory response to CO2 challenge
(184, 187, 188) (see Role of the carotid bodies in breathing
stability: interactions with central chemoreceptor stimulation
and CBF). Finally, within the hypocapnic range, input from the
central chemoreceptors would actually be reduced owing to a
maintained CBF (from a reduced CBF sensitivity) (219).
Role of the carotid bodies in breathing stability: interactions
with central chemoreceptor stimulation and CBF. Although we
have emphasized the influence of CBF in determining the PCO2
stimulus at central chemoreceptors, it is the degree of hypocapnia sensed at the carotid bodies that seems critical for the
development of a central apnea, especially during NREM sleep
(184, 187, 188). Moreover, the carotid bodies are an important
determinant in breathing stability at rest through tonic inputs
and, possibly, through compensation for a reduced central CO2
sensitivity (50, 98, 147, 186, 220). However, there may be a
marked degree of interaction between the peripheral and central chemoreceptors (46 48, 219). For example, elegant animal studies using an in situ dual-perfused preparation demonstrated that a single bout of hypoxia or hypercapnia elicited a
larger phrenic response when the brain stem was held at 25
mmHg PCO2 than at 50 mmHg PCO2. More recently, this study
was extended to show that the peripheral chemoreceptors were
more responsive to the lower brain stem PCO2, whether the
peripheral chemoreceptors received stimuli that increased (hypercapnia or hypoxia) or decreased activation (hyperoxia or
hypocapnia). These findings clearly demonstrate a negative
interaction between brain stem and peripheral chemosensitivity
in animals, and if such an interaction occurs in humans, it may
contribute to increased controller gain associated with sleeprelated breathing disorders. Moreover, because brain stem PCO2
affects the degree of peripheral chemosensitivity (48), these
findings again highlight the critical importance of CBF reactivity in determining the brain PCO2. Thus it seems possible that
the interactions of CBF reactivity that determine brain PCO2 at
the level of the central chemoreceptors might have a significant
influence on peripheral chemosensitivity.
It is tempting to speculate that any conditions that result in
chronic hypocapnia (e.g., congestive heart failure and high
altitude) and related alterations in cerebrovascular CO2 reactivity may result in different degrees of hypocapnia in the central
and peripheral compartments and, subsequently, breathing instability. Consistent with this notion, Xie et al. (219) recently suggested that the predominant role of peripheral vs. central chemoreceptors in causing apnea may be explained, in part, by preservation of PCO2 and [H] at the central chemoreceptors by
hypocapnia-induced cerebrovascular constriction. In their study,
indomethacin-induced reduction of cerebrovascular CO2 led to
higher CBF during hypocapnia, leading to instability and related
apnea (219). Another interpretation of these novel findings is that,
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CO2/ K*Q
rQ
s*PaCO PaCO
PbCO2 PaCO2 V
2
2r
Fig. 17. Isoxic hyperoxic (PO2 150 mmHg) and hypoxic (PO2 50 mmHg)
ventilatory responses to PCO2 for modified rebreathing and steady-state (SS)
testing methods. Steady-state method responses show effect of cerebrovascular
reactivity (see model equation). Modified rebreathing method responses show
the effect of equalizing central-arterial PCO2 difference to mixed venous PCO2.
Chemo, responses to eliminating the effect of cerebrovascular reactivity by
assuming a constant 10-mmHg central-arterial PCO2 difference.
end-tidal PCO2 and MCAv (at maximal intensity). These findings are consistent with another recent study (13) that showed
a greater lowering of MCAv and cerebral oxygenation during
hypoxic exercise after acclimation to intermittent or continuous
hypoxia; these changes were mediated by a greater chemoreflex-induced hypocapnia, rather than a compromise in dynamic
cerebral autoregulation or alterations in MCAv-CO2 reactivity
(13). Thus, during strenuous or hypoxic exercise, hyperventilation lowers the PaCO2 and blunts the increase in CBF, which
can lead to an inadequate O2 delivery to the brain and contribute to the development of fatigue (for review see Ref. 138).
Further research is required to clearly establish whether the
modulation of CBF during exercise may influence central
motor drive and potentially limit peripheral muscle fatigue.
(4)
and with resting numerical values
s*PaCO 40
PbCO2 40 3/0.005*55 Q
2
(5)
PbCO2 PaCO2 V
(2)
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R1490
Control
Indomethacin
42.0
41.0
46.1
6.6
40.0
6.1
1.1
6.9
7.5
42.2
39.8
44.2
7.0
40.0
4.2
1.7
6.3
10.6
H, H concentration.
E-venous PCO2
subsequently greater elevations in rebreathing V
The authors thank Karen Peebles, Kate Thomas, and Dr. Sam Lucas for
skilled input and feedback.
Symbol
Wakefulness
Control
Indomethacin
PO2 asymptote
DpS asymptote
Area const
SIDa
Alba
PO
4 a
SIDc
Albc
PO
4 c
PO2 (hyperoxic)
PO2 (hypoxic)
Tp
Tc
DcS
W
TD
CO2
V
s
Q
r
Q
PaCO2(r)
30
0
17.8
38
4.2
1.16
31
1.25
0.61
150
50
34
34
1.8
7
18.5
300
2
55
40
30
0
17.8
38
4.2
1.16
38
1.25
0.61
150
50
34
34
3
0
18.5
230
2
42
40
30
0
17.8
38
4.2
1.16
39.2
1.25
0.61
150
50
34
34
3
0
18.5
230
0.3
38
40
, cardiac output.
See Ref. 52 for a detailed description of model equations. CBF, cerebral blood flow; SID, strong ion difference; Q
AJP-Regul Integr Comp Physiol VOL
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Invited Review
INFLUENCE OF BRAIN BLOOD FLOW ON VENTILATORY CONTROL
GRANTS
This study was supported by the New Zealand Lottery Grants Board, a
University of Otago Research Grant, Otago Medical Research Funding, the
Health Research Council of New Zealand, and the Marsden Fund.
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