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Curran, Aidan K., Joshua R. Rodman, Peter R. East- demonstrated in anesthetized animals that have been
wood, Kathleen S. Henderson, Jerome A. Dempsey, and carotid body denervated, have been made hypoxemic
Curtis A. Smith. Ventilatory responses to specific CNS with CO (27, 28, 32), or have specific pontomedullary
hypoxia in sleeping dogs. J Appl Physiol 88: 18401852, hypoxia (51). In contrast, when hypoxia was applied to
2000.Our study was concerned with the effect of brain carotid body-denervated awake animals, most studies
hypoxia on cardiorespiratory control in the sleeping dog.
reported that ventilation was unchanged or increased
Eleven unanesthetized dogs were studied; seven were pre-
rather than depressed (46, 8, 13, 20, 22, 25, 35, 45).
OUR STUDY WAS CONCERNED with the effect of brain Chronic Instrumentation
hypoxia on cardiorespiratory control in the sleeping Two surgical sessions were required, separated by $2 wk.
dog. The effects of central nervous system (CNS) hyp- All surgery was performed under general anesthesia (,1%
oxia are controversial; some of this controversy may halothane in O2) with use of sterile technique. Appropriate
result because the effects of CNS hypoxia appear to be pre- and postoperative medications were administered (anti-
critically dependent on the experimental preparation biotics and analgesics).
used. Hypoxic depression of ventilation has been clearly In the first surgical session, we implanted a catheter in the
abdominal aorta via a small branch of the right femoral
artery. Fine-wire electrodes were sewn into the crural dia-
The costs of publication of this article were defrayed in part by the phragm via a small thoracotomy at T89. A five-lead electroen-
payment of page charges. The article must therefore be hereby cephalogram (EEG)/electrooculogram montage was installed
marked advertisement in accordance with 18 U.S.C. Section 1734 subcutaneously over the cranium and near each orbit. All
solely to indicate this fact. catheters and electrode leads were tunneled subcutaneously
1840 8750-7587/00 $5.00 Copyright r 2000 the American Physiological Society http://www.jap.org
CNS HYPOXIA IN SLEEP 1841
The carotid body-denervated dogs were exposed to three per se has no effect on ventilation when perfusate blood
levels of hypoxia similar to those described above for 510 gases and pH values are matched to eupneic values.
min each during periods of wakefulness or non-REM sleep. At
least 15 min elapsed between trials. Transient Ventilatory Responses to Hypoxia
Data Analysis Whole body hypoxia. We use data from our most
severe level of hypoxia (PaO2 5 37.5 6 0.8 Torr) to
Mean data were collected from 1-min segments of data for a illustrate the transition from air breathing to hypoxia
given condition and time point. Statistical comparisons were
made with Friedmans repeated-measures test on ranks
(Fig. 2). All dogs responded rapidly to hypoxia; inspired
combined with Dunnetts test for multiple comparisons with minute ventilation (VI) and VT increased significantly
control. Changes were considered significant if P , 0.05. and end-tidal PCO2 (PETCO2) decreased significantly by
2040 s of hypoxic exposure (P , 0.05). Breathing
RESULTS frequency also tended to increase slightly, particularly
after ,40 s of hypoxic exposure, but did not achieve
Eupneic Control
statistical significance. Occasional brief episodes of
Eupneic, air-breathing control measurements were changes in sleep state occurred in some dogs during
obtained in each dog in two different conditions: 1) these trials; data from these periods were not used.
before surgical preparation for carotid body perfusion The time course of the ventilatory responses obtained
(i.e., both carotid bodies were intact) and 2) after the during the transitions from air breathing to mild or
dogs had been surgically prepared for carotid body moderate hypoxia was similar to that obtained with
concentration; TI, inspiratory duration; TE, expiratory duration; f, breathing frequency; VI, inspired minute ventilation; VT/TI, inspiratory
duty cycle; VT, tidal volume; TT, respiratory cycle duration.
CNS HYPOXIA IN SLEEP 1843
Fig. 4. Polygraph record of air breathing-to-hypoxia transition in a dog in which carotid bodies were maintained
normocapnic, normoxic, and normohydric via perfusion. Relative to control, between 20 and 40 s of CNS hypoxic
exposure (starting from point at which PETO2 # 60 Torr), breathing frequency increased 2 breaths/min, PETCO2
decreased 2 Torr, heart rate increased 11 beats/min, and mean arterial blood pressure increased 6 Torr. EMGdi,
diaphragmatic electromyogram; BP, blood pressure; EOG, electrooculogram; EEG, electroencephalogram.
CNS HYPOXIA IN SLEEP 1845
entirely to increases in breathing frequency mostly as a (PaO2 5 37.5 6 0.8 Torr) for up to 1525 min. Occasional
result of decreases in TE and lesser decreases in TI. VT brief EEG arousals occurred, but the steady-state data
was unchanged or tended to decrease, so neither VT/TI shown in Fig. 6 were obtained in stable non-REM sleep.
nor the rate of rise of the crural diaphragm EMG Arterial PCO2 (PaCO2) tended to reach a plateau or
changed significantly. The increased ventilation was a continued to decrease slightly after 5 min of hypoxia.
true hyperventilation, inasmuch as PETCO2 decreased VT and breathing frequency were more variable, but
progressively with severity of hypoxia in all dogs. the net result was VI that reached a plateau by 5 min of
Prolonged Hypoxia (1025 min) hypoxic exposure or decreased slightly relative to the
5-min point.
Whole body hypoxia. Four of the seven dogs were CNS hypoxia. The same four dogs were exposed to
exposed to our most severe level of whole body hypoxia our most severe level of whole body hypoxia (PaO2 5
CNS HYPOXIA IN SLEEP 1847
increased 26 breaths/min and VT decreased 50 to CNS hypoxia (31). We presume that this increased
100 ml. cerebral blood flow also occurred in our studies of CNS
hypoxia, at least when PaO2 was ,50 Torr, but we
DISCUSSION
cannot be sure that this increase in cerebral blood flow
In summary, we have found that 525 min of expo- does indeed occur in our preparation with potentially
sure to specific CNS hypoxia (PaO2 5 3555 Torr) compromised cerebral blood flow. If this mechanism of
during non-REM sleep in dogs did not depress ventila- increased cerebral blood flow/CNS hypocapnia was
tion; rather, there was significant hyperventilation. reduced in our preparation, then the net effect of any
The hyperventilation was mediated entirely by in- direct hypoxic CNS stimulation and inhibition due to
creased breathing frequency, unlike the larger hyper- hypocapnia would be biased against ventilatory depres-
ventilation observed during whole body hypoxia, which sion. However, the absence of increased cerebral blood
was mediated by increases in breathing frequency and flow would not explain the ventilatory stimulation we
VT. Initiation of the ventilatory response to CNS hy- showed with CNS hypoxia. We do not believe that brain
poxia was rapid: the time course was comparable to blood flow is compromised in our preparation because
that observed during whole body hypoxia. Most dogs of the extensive collateral circulation in the canine
maintained hyperventilation for up to 1525 min of brain (12) and the fact that basilar artery flow in the
CNS hypoxia; only one of the four dogs studied over the dog has been shown to increase more than threefold
longer term manifested hypoxic ventilatory depression. with acute occlusion of both common carotid arteries
Blood pressure and heart rate did not change signifi- (44). However, there is also evidence to suggest that the
28, 32). The major limitation here is that anesthesia tions reported in the literature. The first advantage is
obtunds the entire nervous system and therefore re- lack of anesthesia. Anesthetized preparations consis-
sponses may not reflect the physiology of the unanesthe- tently depress ventilation in response to CNS hypoxia;
tized state. unanesthetized preparations do not. Another advan-
Carotid body-denervated models. Awake, carotid body- tage is intact carotid bodies. Preparations with one
denervated dogs, in which denervation was confirmed intact carotid body maintain some low level of tonic
independently with cyanide injection, show virtually no chemoreceptor input to the respiratory controller, and
ventilatory response (i.e., 61 Torr PETCO2 or PaCO2) to the intact connections appear to prevent central remod-
PaO2 between ,25 and 35 Torr (5, 20) (Fig. 8). The use of eling that may occur in response to denervation. Fi-
sodium cyanide to test for peripheral chemosensitivity nally, we believe that sleep is an advantage, in that
is important in carotid body denervation studies, be- non-REM sleep eliminates behavioral responses unre-
cause it provides an independent test of peripheral lated to the ventilatory effects of CNS hypoxia. Further-
chemosensitivity; denervations can be incomplete, re- more, given the marked qualitative differences in the
turn of peripheral chemosensitivity is possible, and/or response to CNS hypoxia between sleep and anesthe-
other peripheral chemoreceptors (e.g., aortics) could be sia, it is clear that extrapolations from the anesthetized
upregulated over time. In awake rabbits, goats, and to the unanesthetized but sleeping animal are unwar-
ponies, again in which denervation was confirmed ranted.
independently with cyanide injection, virtually no ven-
CNS Hypoxia: Implications for Respiratory
tilatory response to acute hypoxia has been observed (5,
and Cardiovascular Control in Sleep
A time-dependent ventilatory response to hypoxia ever, the role of carotid sinus nerve sympathetic effer-
has been described whereby the response peaks in the ents, if any, is controversial. Electrical stimulation of
first few minutes and then gradually declines toward sympathetic fibers inhibits (36) or augments (30, 36)
control values (24). Furthermore, the ventilatory re- carotid body output. Some found an augmentation of
sponse to acute hypoxia does not return for a substan- the carotid body hypoxic response when sympathetics
tial time period after the sustained hypoxic exposure to the carotid body were cut (16, 21, 41), whereas others
(24). An effect of sustained hypoxia causing CNS depres- found no significant effect on the ventilatory responses
sion of ventilation has been proposed to explain this to acute or chronic hypoxia in awake (43) and anesthe-
hypoxic ventilatory decline (roll-off) (31). However, tized (9, 26) preparations. Furthermore, we observed
our data in CNS hypoxia sustained for up to 25 min that CNS hypoxia caused hyperventilation exclusively
showed a persistent hyperventilatory response in three by increased breathing frequency, whereas hypoxic
of the four dogs tested, even in the face of a reduction in carotid body stimulation increased VT and breathing
PaCO2 (Fig. 6). These data in sleep confirm the persis- frequency (11, 46). Regardless of whether sympathetics
tent hyperventilation seen over several minutes of have a role in the response to specific CNS hypoxia, it
sustained CNS hypoxia in the awake goat with intact seems clear to us that the hypoxia is sensed initially by
perfused carotid bodies that were maintained normoxic the CNS.
and normocapnic (11, 46). Accordingly, we favor the A role for CNS lactacidosis? Another possible mecha-
explanation that the source of hypoxic ventilatory nism of the ventilatory response to CNS hypoxia is the
decline in prolonged hypoxia may be the time-depen- elaboration of lactic acid by the brain. It is known that
late that this tachypneic response was due to CNS 9. Davies RO, Nishino T, and Lahiri S. Sympathectomy does not
hypoxic depression of cortical structures, which in turn alter the response of carotid chemoreceptors to hypoxemia
during carboxyhemoglobinemia or anemia. Neurosci Lett 21:
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be especially important in non-REM sleep, during 11. Engwall MJA, Smith CA, Dempsey JA, and Bisgard GE.
Ventilatory afterdischarge and central respiratory drive interac-
which higher CNS structures may be more susceptible
tions in the awake goat. J Appl Physiol 76: 416423, 1994.
to depression by hypoxia. 12. Evans HE. Millers Anatomy of the Dog. Philadelphia, PA:
Our data do not permit us to say whether the Saunders, 1993.
hyperventilation we observed is due to a true chemore- 13. Forster HV, Bisgard GE, Rasmussen B, Orr JA, Buss DD,
flex or a hitherto unappreciated nonspecific effect of and Manohar M. Ventilatory control in peripheral chemorecep-
CNS hypoxia. In any case, it has been demonstrated tor-denervated ponies during chronic hypoxemia. J Appl Physiol
41: 878885, 1976.
that many respiratory- or cardiovascular-related neu- 14. Georgopoulos D, Bshouty Z, Younes M, and Anthonisen
rons in the medulla or hypothalamus depolarize in NR. Hypoxic exposure and activation of the afterdischarge
response to hypoxia (10, 17, 19, 34, 42, 48, 49). The fact mechanism in conscious humans. J Appl Physiol 69: 11591164,
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Yamamoto H. Hypoxia-mediated in vivo release of dopamine in
transduction of CNS hypoxia to enhanced neural respi-
nucleus tractus solitarii of rabbits. J Appl Physiol 70: 2395
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