[ Contemporary Reviews in Sleep Medicine ]

Control of Ventilation in Health and Disease

Susmita Chowdhuri, MD; and M. Safwan Badr, MD

Control of ventilation occurs at different levels of the respiratory system through a negative
feedback system that allows precise regulation of levels of arterial carbon dioxide and oxygen.
Mechanisms for ventilatory instability leading to sleep-disordered breathing include changes
in the genesis of respiratory rhythm and chemoresponsiveness to hypoxia and hypercapnia,
cerebrovascular reactivity, abnormal chest wall and airway reexes, and sleep state oscillations.
One can potentially stabilize breathing during sleep and treat sleep-disordered breathing by
identifying one or more of these pathophysiological mechanisms. This review describes the
current concepts in ventilatory control that pertain to breathing instability during wakefulness
and sleep, delineates potential avenues for alternative therapies to stabilize breathing during
sleep, and proposes recommendations for future research. CHEST 2017; 151(4):917-929

Control of ventilation is orchestrated at separated from the forebrain and pons.

different levels of the respiratory system and
through the entire life span of the individual.
Understanding the physiological and clinical
aspects of ventilatory control during
wakefulness and sleep and in health and
disease is a prerequisite step toward
developing therapies that stabilize ventilatory
control. This review describes ventilatory
control mechanisms during wakefulness and
sleep, with an emphasis on mechanisms that
pertain to sleep-related breathing disorders.
Respiratory Rhythm Pattern
Generators: Inspiration
and Expiration
Anatomy of the Respiratory Cycle
Breathing rhythm originates in the medulla
and continues even after the medulla is
During eupneic breathing, neuronal activity
in the brain stem can be divided into three
phases: (1) inspiratory, (2) postinspiratory,
and (3) late expiratory (or preinspiratory)
neural activity.1 Inspiration starts with the
synchronized onset of neuronal discharge
that increases to a maximum level but
suddenly ends activity. This is followed by a
secondary declining burst called
postinspiratory after discharge that
represents the active phase of the passive
exhalation from the lungs.2 Classically, two
clusters of nuclei in the medulla were
thought to regulate respiration: the dorsal
respiratory group, which was activated
immediately prior to inspiration, and the
ventral respiratory group, which modulated
phase switching to expiration. However, data
from neonatal rat studies identied an

ABBREVIATIONS: ACZ = acetazolamide; AHI = apnea-hypopnea
index; AT = apneic threshold; CBF = cerebral blood ow; CCHS =
congenital central hypoventilation syndrome; CHF = congestive
heart failure; CIH = chronic intermittent hypoxia; CSA = central sleep
apnea; CVR = cerebrovascular responsiveness; fR = respiratory
frequency; KF = Klliker-Fuse; LTF = long-term facilitation; NREM =
nonrapid eye movement; Pre-Bt C = pre-Btzinger complex;
REM = rapid eye movement; RPG = respiratory-pattern generator;
RTN = retrotrapezoid nucleus; RTN/pFRG = retrotrapezoid nucleus/
parafacial respiratory group; SCI = spinal cord injury; SIDS =
sudden infant death syndrome; V_ I = minute ventilation
AFFILIATIONS: From the John D. Dingell VA Medical Center (Drs
Chowdhuri and Badr); and Department of Medicine (Drs Chowdhuri
and Badr), Wayne State University, Detroit MI.
CORRESPONDENCE TO: Susmita Chowdhuri, MD, Medical Service
(11M), John D. Dingell VA Medical Center, 4646 John R, Detroit, MI
48201; e-mail: schowdh@med.wayne.edu
Published by Elsevier Inc. under license from the American College of
Chest Physicians.
DOI: http://dx.doi.org/10.1016/j.chest.2016.12.002

journal.publications.chestnet.org 917
oscillating respiratory-pattern generator (RPG), the Pre-
Btzinger complex (pre-Bt C), located in the ventral
medullary respiratory column caudal to the Btzinger
nucleus3 that consists of voltage-dependent neurons
with rhythmic discharge patterns. The pre-Bt C is
thought to be the primary RPG that provides inspiratory
rhythm, whereas another group of neurons, the
retrotrapezoid nucleus/parafacial respiratory group
(RTN/pFRG),4,5 provides rhythmic expiratory drive. An
opposing view is that preinspiratory neurons in the
pFRG periodically trigger the inspiratory-pattern
generator, the pre-Bt C.6 Rostrally in the pons, the
Klliker-Fuse (KF) and parabrachial nuclei are relay
nuclei for reex and higher-order CNS control of
breathing, including control of postinspiratory activity.2
The KF area also regulates the inspiratory-expiratory
phase transition and the dynamic control of upper
airway patency during the respiratory cycle7; the KF area
receives input from various visceral sensory afferents
through the vagal and glossopharyngeal nerves.7
Respiratory rhythm generation is controlled by multiple
modulators, including noradrenergic, serotonergic,
peptidergic, acetylcholine neurons, and long-term
synaptic plasticity.8,9 Moreover, the RTN/pFRG, with its
chemosensitive neurons, provides tonic excitation to the
pre-Bt C and Bt C.10
Control of Ventilation
Ventilatory control is regulated by a feedback
system that allows only small changes in arterial
PO2, PCO2, and pH under physiological states such as
rest, exercise, and sleep. Likewise, reexes from the
airways and lung also inuence respiration. The
respiratory system maintains homeostasis by
integrating chemical, metabolic, and mechanical
input during complex physiological states and
adjusting ventilatory motor output to meet
ventilatory demands (Fig 1).
Chemical Control of Ventilation
Chemical ventilatory control monitors afferent input
(PCO2 and PO2) through the peripheral and central
chemoreceptors to maintain PCO2 and PO2 within a
specic range. The central chemoreceptors modulate

Opioids Respiratory Pattern Generators
+ pre-Btz C/Preinspiratory neurons
Therapy: Ampakines RTN/pFRG

High-Altitude Peripheral Activation of Medullary CCHS-PHOX2B mutation

CHF, Opioids chemoreceptors: Respiratory Centers: RTN, SIDS - 5HT, laryngeal
Sleep apnea Pao2/Paco2 sensing serotonergic raphe, other chemoreflex?

Interdependence
Respiratory muscles, Pulmonary stretch,
HMN upper airway receptors
Central chemoreceptors*
Paco2/H+ sensing,
Potential Cerebrovascular response
Therapy: Lung inflation
Oxygen,CPAP
ACZ
Determine Loop Gain
Finasteride?
Determines CO2 reserve & AT Ventilation
Serotonergic
Hypocapnic central apnea
agonists
Upper airway narrowing
Antioxidants?
and arousal
Orexin
antagonist?

Figure 1 Ventilatory control of breathing, starting with inspiration/expiration at the respiratory-pattern generators, with ongoing modulation of
ventilation through a feedback mechanism by the peripheral and central chemoreceptors and cerebrovascular responsiveness (CVR) as well as by
airway/pulmonary receptors. Chemoreceptor sensitivity can be measured through loop gain, a measure of ventilatory responsiveness to PaCO2 levels,
which in turn determines the AT and carbon dioxide reserve during sleep and eventually the propensity for developing a hypocapnic central apnea. See
text for full explanation. Potential underlying pathophysiological mechanisms that predispose to sleep apnea, including chemoresponsiveness, CVR, and
opioid-induced inhibition of the pre-Btz C are depicted by black dashed lines. Therapeutic interventions that may target potential mechanisms are
denoted by blue dashed lines. denotes inhibition; denotes activation. 5HT serotonin related; ACZ acetazolamide; AT apneic threshold;
CCHS congenital central hypoventilation syndrome; CHF congestive heart failure; CVR cerebrovascular responsiveness to CO2. HMN
hypoglossal motor nucleus; pFRG parafacial respiratory group, Pre-Btz C pre-Btzinger complex; RTN retrotrapezoid nucleus.

918 Contemporary Reviews in Sleep Medicine [ 151#4 CHEST APRIL 2017 ]

ventilation in response to changes in the carbon dioxide/
H detected within the brain, whereas the faster-acting
peripheral chemoreceptors respond to changes in PO2
and PCO2 in the periphery. Moreover, oxygen sensing
also occurs in the pons.
Major central chemoreceptor sites are distributed
throughout the lower brain stem (Fig 2, Table 1).11
The central chemoreceptors are responsible for
approximately two-thirds of the ventilatory response to
carbon dioxide/pH.12 The response is linear until very
high levels of carbon dioxide are reached. The peripheral
chemoreceptors are located in the carotid body, at the
bifurcation of the carotid artery, and to a smaller extent,
at the aortic arch. The carotid bodies are highly vascular
and are the major chemoreceptor site for hypoxia,
sensing PaO2, but not oxyhemoglobin saturation or
oxygen content. The carotid bodies are also very
sensitive to changes in PCO2 and [H].13-15 The carotid
bodies hypoxic response is curvilinear, increasing in
slope once PaO2 drops to < 60 mm Hg. The steeper
slope leads to higher ventilation for a given change in
PaO2 and hence more pronounced hypocapnia. The
changing gain of the hypoxic ventilatory response may
explain the destabilizing effect of hypoxia on ventilation
through hypocapnia.16
Figure 2 Current view of locations of central chemoreceptor sites;
chemoreception is widely distributed in hindbrain. 7N facial nerve;
VII facial nucleus; AMB ambiguous; C caudal; cNTS caudal
nucleus tractus solitarious; cVLM caudal ventrolateral medulla;
DR dorsal raphe; FN fastigial nucleus; LC locus ceruleus; LHA
lateral hypothalamus; M middle; R rostral; PBC pre-Btzinger
complex; Pn pons; RTH/pFRG retrotrapezoid nucleus/parafacial
respiratory group; rVRG rostral ventral respiratory group; SO
superior olive; V4 fourth ventricle. Reproduced with permission from
Nattie and Li.11
journal.publications.chestnet.org
Peripheral and central chemoreceptors are anatomically
linked.10 Following bilateral carotid body resection in
humans, peripheral chemoresponsiveness was absent,
but there was an associated reduction in central carbon
dioxide sensitivity, indicating that the carotid bodies
exert a tonic drive or tonic facilitation on the output of
the central chemoreceptors.17 Other studies have also
demonstrated that the responses of the central
chemoreceptors are markedly inuenced by the
magnitude of sensory input from the carotid
chemoreceptor.18,19 Thus, chemoreceptor
interdependence determines the normal drive to breathe
in eupnea and in acute hypoxia.20,21
Mechanical Inuences
Afferent input from chest wall, lungs, and airways
predominantly affects the pattern of breathing and is
most apparent when increased demands are placed on
the ventilatory control system and is mediated by
receptors in the chest wall and muscles. The Hering-
Breur reex, elicited by ination of slow-adapting
chemically insensitive pulmonary stretch receptors,
causes a decrease in the frequency of inspiratory effort
following ination. It is strong in cats, dogs, and rabbits
but is almost absent in humans; it is more powerful at
birth than it is in adult mammals.22,23 Whether the
proprioceptive chest wall receptors play a role in
irregular breathing in neonates is unclear. Additionally,
the laryngeal chemoreex is a protective reex initiated
by chemical stimulation in the laryngeal lumen that
results in a series of reactions including respiratory
inhibition, closure of the glottis, and bradycardia, and it
may be implicated in the sudden infant death syndrome
(SIDS).24
TABLE 1 ] Eight Major Central Chemoreceptor Sites in
the Brain Stema
1. Retrotrapezoid nucleus (RTN)
2. Rostral medullary raphe (MR) (raphe magnus)
3. Caudal MR (raphe obscurus) indirectly through
the RTN
4. Caudal nucleus tractus solitarious
5. The region just dorsal to the caudal ventral
medullary surface
6. Pre-Btzinger region
7. Fastigial nucleus of the cerebellum
8. Orexin neuron containing regions of the hypothalamus
Responses to stimulation across the different central chemoreceptor sites
can be synergistic.11
a
See Figure 2 for a schematic diagram of the locations of central
chemoreceptor sites.
919
Metabolic Rate
Oxygen consumption and carbon dioxide production
effect alveolar ventilation by mechanisms that are not
well understood. The tracking of ventilation to
metabolic rate is very precise. For example, during
exercise, ventilation increases in a linear manner related
to metabolic rate. When an animal was placed on a
membrane oxygenator, which allowed the removal of
metabolic carbon dioxide production, ventilation was
reduced to apnea by removing increasing amounts of
carbon dioxide.25
Factors Modulating Control of Ventilation
Sleep State
The loss of the wakefulness stimulus to breathe renders
ventilation dependent on chemoreceptor and
mechanoreceptor stimuli. In addition, reduced activity
of upper airway dilators and upper airway narrowing
with increased upper airway resistance are normal
physiological events during sleep. In extreme cases of
upper airway narrowing, complete closure may occur,
leading to OSA. There is also a loss of load
compensation during sleep as loads are not perceived;
thus, ventilation decreases and PaCO2 increases.
Nonrapid eye movement (NREM) sleep removes the
wakefulness drive to breathe and renders respiration
critically dependent on metabolic control and chemical
inuences, especially PCO2. Transient breathing
instability and central apnea often occur during the
transition from wakefulness to sleep.26-29 Central apnea
results if arterial PCO2 is lowered to less than a highly
sensitive apneic threshold (AT).30 An illustrative
example is shown in Figure 3, which demonstrates
central apnea induced during NREM sleep on cessation
of noninvasive mechanical hyperventilation; the central
apnea occurred when the PaCO2 was at or less than the
hypocapnic AT level required to maintain rhythmic
breathing during sleep. Recovery from apnea is
associated with transient wakefulness and
hyperventilation. The subsequent hypocapnia elicits
apnea on resumption of sleep. Consolidation of sleep
alleviates the oscillation in sleep and respiration and
stabilizes PaCO2 at a higher set point that is greater than
the AT. Interestingly, central apnea may occur without
preceding hyperventilation at the transition from alpha

Figure 3 Representative polygraph segment from a subject during stable NREM sleep at different time points: room air control condition (C) and
mechanical ventilation (MV) leading to central apnea (A) after the cessation of MV. Note the 10-s central apnea (absence of respiratory effort on the
supraglottic pressure [PSG] tracing). EEG electroencephalogram; EOG electrooculogram; MV mechanical ventilation; NREM nonrapid eye
movement; Pmask mask pressure. Reproduced with permission from Chowdhuri et al.89

920 Contemporary Reviews in Sleep Medicine [ 151#4 CHEST APRIL 2017 ]

to theta in normal subjects and is associated with
prolongation of breath duration.31 Thus, hypocapnia is a
potent but not an omnipotent mechanism of reduced
ventilatory motor output during NREM sleep. More
importantly, the amount of reduction in PaCO2 to less
than eupneic PaCO2 (ie, the carbon dioxide reserve
equals the difference between the eupneic carbon
dioxide and the AT carbon dioxide), and therefore the
transient increase in alveolar ventilation required to
reach the AT, is not constant.
Concept of Loop Gain
Ventilatory control during sleep operates as a negative-
feedback, closed-loop cycle to maintain homeostasis of
blood gas tensions within a physiological range. Loop
gain, an engineering term, is used as a measure of
ventilatory stability32-36 and represents the overall
response of the plant (representing the lung and
respiratory muscles), the controller (representing the
ventilatory control centers and the chemoreceptors), and
the delay, dilution, and diffusion inherent in transferring
the signal between the plant and the controller.
Controller gain, or chemoresponsiveness, is the slope of
the ventilatory response, or the change in ventilation,
to hypercapnia and hypocapnia, that is, DV_ I/DPaCO2,
where V_ I is minute ventilation (Fig 4). Plant gain is
determined by the magnitude of the reduction in PaCO2
resulting from a given change in ventilation (DPaCO2/
DV_ I), that is, the efciency with which carbon dioxide is
eliminated. Hypoxia- and hypercapnia-initiated
chemoreexes are known to contribute to the regulation
of ventilation, and a high gain in any of these
chemosensory loops could contribute to breathing
instability. Increased controller gain (eg, due to
sustained hypoxia, acute intermittent hypoxia [Fig 5], or
heart failure) or increased plant gain due to metabolic
alkalosis or disorders of hypoventilation, or both, in an
individual narrows the carbon dioxide reserve to
increase breathing instability. Note that steady-state
reduction of PaCO2, that is, low plant gain, is potentially
stabilizing rather than destabilizing. Thus, decreased
controller gain or plant gain (eg, with supplemental
oxygen) will widen the carbon dioxide reserve to
stabilize breathing37-39 (Fig 4).
During rapid eye movement (REM) sleep, ventilation is
predominantly under behavioral rather than metabolic
control so that it is insensitive to changes in PaCO2.
Central sleep apnea (CSA) is uncommon during
REM sleep, as breathing during REM sleep is impervious
to chemical inuences, possibly due to increased
ventilatory motor output or reduced chemosensitivity
that blunts the hypoxic and hypercapnic ventilatory

Isometabolic line 44 44
10 Eupneic PETCO2
9 42 42

8
PETCO2 (mm Hg)

7 40 40
X P = .01
VI, L/min

6
Y
5 38 CO2 reserve 38
P < .001
4
.

3 36 36
2 AT-PETCO2
1 34 P = NS 34
0
0 5 32 A 34 36 38 B 40 42 44 32 32
PETCO2 mm Hg Pre-episodic Post-episodic
hypoxia hypoxia
Figure 4 Relationship between minute ventilation (V_ I) and PETCO2
along the isometabolic curve with sustained hyperoxia vs sham room air. Figure 5 Observed eupneic carbon dioxide, AT, PETCO2, and carbon
Note decreased eupneic PETCO2 with hyperoxia (X), compared with sham dioxide reserve (eupneic PETCO2 minus AT PETCO2) with episodic hypoxia
exposure (Y), indicative of decreased plant gain. There is also a decrease (EH), specically during the pre-EH (red bar) and post-EH (blue bar)
in the slope of V_ I/carbon dioxide with hyperoxia (solid red line) periods. The top horizontal line represents the eupneic carbon dioxide
compared with sham (dashed blue line), conrming a decline in the level, the bottom horizontal line represents the AT, and boxes between
hypocapnic ventilatory responsiveness on exposure to hyperoxia. The these two lines represent the carbon dioxide reserve (pre-EH [red box]
arrows indicate carbon dioxide reserve during the two exposure condi- and post-EH [blue box]). The carbon dioxide reserve was signicantly
tions: greater magnitude of carbon dioxide reserve with hyperoxia (solid smaller following EH (post-EH) as a result of the signicantly lower
red arrow) compared with sham room air exposure (dashed blue arrow). eupneic PETCO2, without a change in the AT. Reproduced with permis-
Points A and B represent apneic threshold (AT) during hyperoxia and sion from Chowdhuri et al.89 AT apneic threshold; AT-PETCO2
sham, respectively. PETCO2 end-tidal carbon dioxide. Reproduced with apenic threshold end-tidal CO2; NS not signicant. See Figure 4
permission from Chowdhuri et al.39 legend for expansion of other abbreviations.

journal.publications.chestnet.org 921
drive during REM sleep40-42 relative to NREM sleep.
The retrotrapezoid nucleus (RTN) regulates both
respiratory frequency (fR) and tidal volume when the
pontomedullary RPG is autorhythmicfor example,
with anesthesia, NREM sleep, and quiet wakefulness,42
but the RTN no longer controls fR during REM sleep.
Moreover, during REM sleep, the expiratory phase of the
breathing cycle is controlled by suprabulbar inputs that
inhibit the pre-Bt C; this could also explain the absence
of periodic breathing and CSA during REM sleep in
humans.42 However, in REM sleep, the loss of intercostal
and accessory muscle activity leads to a reduction of
alveolar ventilation and may manifest as apparent
central hypopnea in patients with compromised lung
mechanics or neuromuscular disease.
Studies have shown that CSA also occurs more
frequently in the supine position43-45 and is reversed
with nasal CPAP.46
Cerebrovascular Responsiveness
Cerebrovascular responsiveness (CVR) to carbon dioxide
is an important determinant of eupneic ventilation and
hypercapnic ventilatory responsiveness in humans,
primarily through its effects on the central
chemoreceptors.47 Changes in cerebral blood ow (CBF)
regulation modify breathing stability in healthy young
adults48-51; a decrease in CBF allows accumulation of
carbon dioxide that stimulates the medulla, whereas an
increase in CBF allows carbon dioxide removal and
depresses ventilation. In young healthy adults, CBF and
CVR to hypocapnia52 were reduced by indomethacin,
leading to increased AT and narrowed carbon dioxide
reserve, that is, increased ventilatory instability. With an
approximate 25% reduction in CBF, the subjects had
increased alveolar ventilation (arterial PCO2 decreased by
2-3 mm Hg) and increased ventilatory response to carbon
dioxide of 40%. Thus, reductions in the normal cerebral
vascular response to carbon dioxide may contribute to
breathing instability during wakefulness and sleep.48,49
Age
CSA is more prevalent in older individuals than in
middle-aged adults.53,54 Sleep state oscillations may
precipitate central apnea in older adults.26,55
Additionally, CBF regulation and CVR are reduced in
elderly adults.56-59 However, investigations into the
effect of aging on chemoresponsiveness during
wakefulness have yielded conicting results.60-67 We
demonstrated that during NREM sleep, older adults,
when compared with young adults, had increased
922 Contemporary Reviews in Sleep Medicine
chemosensitivity, with increased isocapnic hypoxic
ventilatory responsiveness and hyperoxic suppression of
ventilation (Dejours effect) despite an absence of
ventilatory long-term facilitation (plasticity) following
acute intermittent hyopoxia.68 Increased
chemosensitivity, unconstrained by respiratory plasticity
and reduced CVR, may explain the increased propensity
for central apnea in elderly individuals during sleep.
Sex
The effect of sex on ventilatory control could be due to
genetic or environmental factors; the latter is supported
by studies demonstrating increased prevalence of sleep
apnea after menopause, but there are no data in humans
regarding the former. Hormonal inuences on
ventilatory control are also supported by experimental
evidence demonstrating that the hypocapnic AT during
sleep is altered by manipulations of sex hormones. There
is evidence that women are less susceptible to the
development of hypocapnic central apnea during NREM
sleep compared with men following noninvasive
mechanical ventilation. Physiologically, the hypocapnic
AT was higher in men compared with women (AT was
3.5 mm Hg vs 4.7 mm Hg at less than room air level
in men and women, respectively69). This may explain
why CSA is uncommon in premenopausal women.70
This difference in carbon dioxide reserve is not due to
progesterone. Administration of testosterone to healthy
premenopausal women for 12 days resulted in an
elevation of the AT and a diminution in the magnitude
of hypocapnia required for induction of central apnea
during NREM sleep.69 Conversely, suppression of
testosterone with leuprolide acetate in healthy men
decreased the AT, potentially stabilizing respiration,71
whereas nasteride, a testosterone-conversion blocker of
the 5a-reductase pathway, stabilized breathing in young
healthy individuals by reducing the controller gain.72
Thus, the plasticity of the hypocapnic AT represents
strong evidence for the role of environmental factors in
ventilatory control.
Genetic Factors
Several transcription factors73,74 are responsible for
control of breathing. The transcription factor Dbx1 is
essential for pre-Bt C development; deletion of Dbx1
eliminated all pre-Bt C glutamatergic respiratory
neurons, with complete elimination of inspiratory
activity both in vitro and in vivo.75,76 Atoh1, Krox20/
Egr2, Lbx1, Lmx1b, MafB/Kreisler, PHOX2B, Tlx3, and
Tshz3 are also involved in the functioning of the
[ 151#4 CHEST APRIL 2017 ]
pre-Bt C74, whereas the lateral RTN/pFRG, the site for
active expiration, contains PHOX2B-, Atoh1-, and
Dbx1-derived neurons.74 RTN development is
particularly vulnerable to a PHOX2B mutation that
causes congenital central hypoventilation syndrome
(CCHS) in humans (PHOX2B27ala/). Mutations
affecting other transcription factors related to
respiration in mice models, involving Bdnf, Krox20,
Mash-1, and Necdin, have also been described.77 The
genetic basis for sleep apnea and SIDS is under
investigation.
Disorders With Dysfunctional Regulation of
Ventilation During Sleep
Congenital Central Hypoventilation Syndrome
Children affected by the rare condition CCHS
experience sleep-related hypoventilation and ventilatory
failure, requiring ventilatory support during NREM
sleep, although a milder degree of hypoventilation may
also be present during REM and wakefulness.78 The
RTN chemosensitive neurons express PHOX2B.79 In
CCHS, a PHOX2B gene defect with polyalanine
expansion is associated with the clinical syndrome of
autonomic dysfunction, including an abnormal
ventilatory response to carbon dioxide leading to absent
or severely reduced ventilation during sleep. Treatment
requires ventilation during sleep through tracheostomy
or noninvasive ventilation.
Sudden Infant Death Syndrome
Autonomic dysregulation, prolonged laryngeal
chemoreex, blunted chemoreexes and arousal
reexes, sleep apnea, and genotypic polymorphisms are
some of the intrinsic factors implicated in sudden
unexplained deaths in infancy during sleep.80 These
may be mediated by a decrease in serotonergic receptor
binding in the raphe medullary nuclei that modulate
respiration, central chemoreception, upper airway
integrity, and cardiovascular control Ongoing research
will likely elucidate the exact mechanisms and a cure for
SIDS.81
High-Altitude Periodic Breathing
High-altitude exposure is characterized by the
appearance of periodic breathing during sleep. The
alveolar and, concomitantly, the arterial PCO2 vary with
altitude. For people traveling to a high altitude, hypoxia
at a higher altitude increased carotid peripheral
chemosensitivity with resultant increased ventilation,
hypocapnia, and periodic breathing. In fact, periodic
journal.publications.chestnet.org
breathing increased during acclimatization over 2 weeks
at altitudes > 3,730 m, despite improved oxygen
saturation, due to an increase in loop gain of the
respiratory control system. Interventions (eg, oxygen
and acetazolamide) to reduce loop gain have been used
as potential therapies.15,82,83
Sleep-Disordered Breathing
Patients with CSA due to CHF demonstrate pulmonary
vascular congestion leading to hyperventilation and
hypocapnia; hence, they experience no rise in end-tidal
carbon dioxide (PETCO2) from wakefulness to sleep.84
The AT in patients with CHF is close to the eupneic
PCO2 owing to increased controller gain. Consequently,
small decrements in PCO2 cause central apnea despite the
stabilizing effect of a low plant gain secondary to
hyperventilation and reduced steady state PETCO2.85,86
Thus, interventions that reduce controller gain would
stabilize breathing and potentially serve as therapeutic
interventions for CSA and periodic breathing due to
CHF (see section on opioid-induced sleep apnea
further on). CBF is also reduced in severe heart failure.87
Reduced CVR to carbon dioxide (50% less than in
normal healthy adults48) has been implicated in the
pathogenesis of periodic breathing in patients with
CHF.48 Reduced CBF could lead to chronic
hyperventilation due to elevated carbon dioxide/H
at the central chemoreceptors. Reduced
cerebrovascular reactivity causes an increase in
ventilatory responsiveness to carbon dioxide that
increases the susceptibility to central apnea due to
CHF. Sustained as well as intermittent hypoxia promote
breathing instability during sleep by increasing the
susceptibility to the development of hypocapnic central
apnea and periodic breathing.85,88,89
OSA is the result of a dynamic interplay between
chemosensory, mechanosensory and genioglossus
reexes, neuromodulation, and behavioral state.90,91
Ventilatory motor output is an important determinant
of upper airway patency during sleep. Changes in
ventilatory motor output are associated with a reciprocal
change in upper airway resistance. There is evidence that
patients with sleep apnea and snorers with inspiratory
ow limitation are dependent on ventilatory motor
output to preserve upper airway patency.92 In these
individuals, pharyngeal obstruction occurs when
ventilatory drive reaches a nadir during induced
periodic breathing. Likewise, using beroptic
nasopharyngoscopy, Badr et al93 found that central
apnea was associated with pharyngeal narrowing or
923
Figure 6 Oropharyngeal airway occlusion during spontaneous central apnea in patient with central sleep apnea syndrome. Beginning of central apnea
is identied by open arrow. Complete occlusion (image 4) occurred before generation of subatmospheric intraluminal pressure. Last image shows upper
airway opening occurred with arousal. Pes esophageal pressure. Reproduced with permission from Badr et al.93
occlusion, or both (Fig 6). The occurrence of complete
pharyngeal collapse during central apnea, combined
with mucosal and gravitational factors, may impede
pharyngeal opening and necessitate a substantial
increase in drive that eventually leads to arousal,
ventilatory overshoot, and subsequent apnea/hypopnea.
Instability in ventilatory control is also increased with
OSA.90,94 Specically, elevated controller gain and
narrow carbon dioxide reserve were present in patients
with OSA and were reversed after treatment with
CPAP.94 Intermittent hypoxia of OSA may further
increase the controller gain and destabilize the
ventilatory control system.89 Noradrenergic, muscarinic,
and serotonergic drive are reduced during sleep and may
contribute to, or exaggerate, the instabilities associated
with OSA,9 since during sleep, the central respiratory
drive to the genioglossus muscle is reduced, leading to
anatomical occlusion of a narrow airway.95,96
Termination of central or obstructive apnea is associated
with variable asphyxia (hypoxia and hypercapnia) and
transient arousal with ventilatory overshoot, subsequent
hypocapnia, and further apnea/hypopnea. This sequence
explains why apnea rarely occurs as a single event and
why there is an overlap between central and obstructive
apnea (upper airway obstruction often follows central
apnea on resumption of respiratory effort, ie, mixed
apnea). Thus, the mechanisms underlying the cause of
central and obstructive apneas are tightly intertwined,
and central apnea may also inuence the development of
OSA.
Ablation of the pre-Bt C results in the cessation of
rhythmic discharge in pre-Bt C neurons97 and apnea.
Possibly, degeneration of the pre-Bt C neurons may
924 Contemporary Reviews in Sleep Medicine
contribute to CSA in the elderly and death during
sleep.98 Moreover, increased irregular output from the
pre-Bt C to the XIIn hypoglossal motor nuclei
following chronic intermittent hypoxia (CIH) has been
mitigated by antioxidant treatment.99 Thus, CIH may
also explain irregular breathing in OSA and apnea of
prematurity.
Opioid-Induced Sleep Apnea
Multiple endogenous opioids in the medullary and
pontine respiratory regions are tonically active and
depressant to the respiratory network, suggested by the
fact that the opioid-receptor blocker naloxone stimulates
respiratory output in anesthetized normoxic
normocapnic cats100 and unanesthetized hypoxic or
hypercapnic animals.101 Opioids depress the rate and
depth of respiration at the pre-Bt C to induce
ventilatory depression102,103; this was reversed by
injection of naloxone into the pre-Bt C.104,105 Opioids
also hyperpolarize the KF neurons, contributing to
opioid-induced loss of the postinspiration phase of the
respiratory cycle and induction of apneusis.106 Opioids
alter the discharge properties of cranial motoneurons of
the larynx and pharynx and the bulbospinal neurons
controlling the diaphragm, chest wall, and expiratory
abdominal muscles to induce chest and abdominal wall
rigidity, reduce genioglossus muscle activity and upper
airway patency, and acutely blunt hypoxic and
hypercapnic responsiveness.107 The elderly, newborns,
and patients with COPD are very susceptible to the
effects of opioids.108-111 An exponential increase in
prescription opioid use has been reported in the United
States. About 30% of chronic methadone users had
ataxic Biots respiration or periodic breathing during
[ 151#4 CHEST APRIL 2017 ]
sleep,112 and this was dose related.113 Chronic stable
doses of methadone signicantly decreased hypercapnic
ventilatory responsiveness but increased hypoxic
ventilatory responsiveness compared with control
subjects, suggesting that chronic opioid use may blunt
central chemoresponsiveness but potentially elevate
peripheral chemoresponsiveness, probably due to
hypoxia114 during sleep.
Tetraplegia
Patients with spinal cord injury (SCI), especially cervical
injury, have derangements that impair the ability of the
ventilatory system to compensate for physiological
challenges, including neuromuscular weakness, small
lung volume, abnormal chest wall mechanics, and an
unopposed parasympathetic system promoting airway
narrowing. Ninety percent of patients with cervical SCI
had CSA not explained by daytime hypoventilation,
cardiac dysfunction, or the use of narcotics.115 Patients
with cervical SCI predominantly demonstrated CSA,
whereas the thoracic SCI group demonstrated OSA
during sleep. In addition, there was narrowing of the
carbon dioxide reserve in individuals with cervical SCI
compared with patients with thoracic SCI or able-bodied
individuals. Increased propensity to CSA was associated
with increased plant gain but not controller gain. This
was likely due to accentuated sleep-related
hypoventilation in patients with cervical SCI.115
Pathophysiology-Based Therapies of
Sleep Apnea
CPAP
The salutary effects of CPAP could be due to the
prevention of upper airway obstruction following central
apnea, resulting in dampening of ventilatory overshoot
and mitigation of subsequent hypocapnia. Increased
lung volume is associated with decreased plant gain and
reduced propensity to central apnea. Moreover,
prolonged use of CPAP therapy in patients with OSA
has resulted in decreased propensity for hypocapnic
central apnea by reducing the controller gain.94,116 The
latter nding may explain the resolution of central apnea
following positive airway pressure (PAP) therapy in a
majority of patients with PAP-emergent CSA.
Supplemental Oxygen
Exposure to sustained hyperoxia over 30 min stabilized
breathing (increased PCO2 reserve) in healthy young
individuals during NREM sleep by stimulating steady
state hyperventilation to reduce the plant gain and,
journal.publications.chestnet.org
additionally, decreased peripheral chemosensitivity to
reduce the controller gain39 (Fig 4). Moreover, in
patients with OSA who had high loop gain, oxygen
effectively reduced loop gain with a corresponding
reduction in the apnea-hypopnea index (AHI).117
Hence, supplemental oxygen has been used to stabilize
respiration by reducing the frequency of central apneas
and percent apneic time in patients with and those
without heart failure.118-120
Acetazolamide
Acetazolamide (ACZ) has also been used to stabilize
breathing in patients with CSA due to heart failure.121
ACZ produces a metabolic acidosis-induced rise in
normoxic ventilation,122 although the exact mechanism
by which it improves CSA is not clear. In humans
with OSA, ACZ has reduced loop gain by 41% in
patients during sleep and was associated with a
51% improvement in the AHI,30 although it did not
affect sleep architecture.123 Preliminary studies showed
that ACZ stabilized breathing by widening the carbon
dioxide reserve through a reduction in the plant gain in
older healthy adults.124 ACZ also increased the CVR to
hypercapnia at sea level during wakefulness125 and
enhanced brain blood ow responses to carbon dioxide,
in addition to increasing resting V_ I and stabilizing
breathing. Administration of ACZ increased middle
cerebral artery velocity (during wakefulness) with
increased CVR to hypercapnia. In humans and cats,
ACZ exerted inhibitory effects on carotid body-
mediated reexes. In both species, low IV doses reduced
both steady state hypoxic sensitivity and the oxygen/
carbon dioxide interaction.126-128
Sex Hormone-Based Therapy
The marked sex difference in the propensity to the
development of hypocapnic central apnea suggests that
alterations in sex hormone levels may inuence
breathing instability. Earlier studies focused on the use
of medroxyprogesterone to correct diurnal carbon
dioxide retention.129,130 Similarly, female hormone
replacement therapy widened the carbon dioxide reserve
and decreased the propensity to induced central apnea
in healthy postmenopausal women.131-133
Male sex hormones also modulate the plasticity of the
AT. Administration of testosterone to healthy women
was associated with narrowing of the PCO2 reserve to
male levels.69 Conversely, the use of leuprolide, a
gonadotropin-releasing hormone analog, was associated
with a decreased serum testosterone level and widening
925
of the PCO2 reserve in young men.71 The noted widening
of the PCO2 reserve following administration of
nasteride, a 5a-reductase blocker, indicated that this
pathway may contribute to increased breathing
instability and sleep apnea in men.72 However, the
efcacy and effectiveness of hormone-based therapy is
yet to be determined.
Neurotransmitter-Based Therapy
Several pharmacologic agents have been used
experimentally to stabilize respiration. In animal studies,
amino-3-hydroxy-5-methyl-D-aspartate receptor
agonists (ampakines) when administered to the pre-
Btzinger area offset the respiratory depressant effects of
opioids drugs without affecting their analgesic
effects.103,134 Several human studies are currently under
way to test the potential utility of ampakines for the
treatment of opioid-induced CSA.135,136
Likewise, serotonin agonists showed promising results in
animal studies but not in humans.137-139 Clonidine, an
alpha-2 agonist decreased the AT and increased the
carbon dioxide reserve by decreasing the controller gain
TABLE 2 ] Recommendations for Future Research
1. Develop clinical tests that detect and classify the
physiological mechanisms for breathing instability
during sleep and wakefulness
2. Determine the genetic basis of individual susceptibility
to sleep-disordered breathing in adults and children
3. Systematically evaluate pharmacologic agents that
stabilize breathing during NREM sleep to delineate their
effects on chemoresponsiveness, CVR to carbon
dioxide, upper airway tone, and EEG arousal.
4. Clarify the role of chronic intermittent hypoxia and
LTF: is LTF benecial or harmful for patients with
sleep apnea?
5. Based on ndings from Nos. 1-3, develop therapies
that specically target chemoresponsiveness and other
pathophysiological mechanisms
6. Perform clinical trials to study the physiological effects
of sex hormones, ampakines, antioxidants, orexin
antagonists, and other agents on breathing stability in
individuals with high loop gain
7. Perform prospective randomized placebo-controlled
clinical trials using supplemental oxygen or ACZ alone
or in combination with other therapies in patients with
CHF with CSA
8. Perform prospective randomized clinical trials of
ampakine alone or in combination with other
interventions in patients with CSA due to opioid use
ACZ acetazolamide; CHF congestive heart failure; CSA central sleep
apnea; CVR cerebrovascular responsiveness; LTF long-term facilitation;
NREM non-rapid eye movement.
926 Contemporary Reviews in Sleep Medicine
during NREM sleep.140 Finally, noradrenergic agents
that increased genioglossus tone showed minimal or no
effect of noradrenergic agents on the severity of sleep
apnea.141-143 Overall, pharmacologic therapy for central
apnea is a major unmet need, especially in patients with
heart failure or those using opioid analgesia.
Conclusions and Recommendations for Future
Research
There are limited physiological studies that have
analyzed the exact pathophysiological mechanisms of
sleep-related breathing disorders in humans. Clinical
diagnostic tests that easily detect abnormal
chemoresponsiveness, CVR, and other facets of
respiratory control are nonexistent. There are no clinical
trials of therapies that seek to systematically modulate
chemoreceptor and cerebrovascular traits of ventilatory
control to alleviate breathing instability during sleep.
Table 2 provides directions for future research in this
eld. Multipronged therapeutic approaches based on
pathophysiology are required to treat disorders of
ventilatory instability during sleep across the life span.
Acknowledgments
Financial/nonnancial disclosures: None declared.
References
1. Richter DW, Spyer KM. Studying rhythmogenesis of breathing:
comparison of in vivo and in vitro models. Trends Neurosci.
2001;24(8):464-472.
2. Richter DW, Smith JC. Respiratory rhythm generation in vivo.
Physiology (Bethesda). 2014;29(1):58-71.
3. Smith JC, Ellenberger HH, Ballanyi K, Richter DW, Feldman JL.
Pre-Btzinger complex: a brain stem region that may generate
respiratory rhythm in mammals. Science. 1991;254(5032):726.
4. Feldman JL, Mitchell GS, Nattie EE. Breathing: rhythmicity,
plasticity, chemosensitivity. Annu Rev Neurosci. 2003;26:239-266.
5. Feldman J, Janczewski W. Point: Counterpoint: The parafacial
respiratory group (pFRG)/pre-Botzinger complex (preBotC) is the
primary site of respiratory rhythm generation in the mammal.
Counterpoint: the pre-BtC is the primary site of respiratory
rhythm generation in the mammal. J Appl Physiol (1985).
2006;100(6):2096.
6. Onimaru H, Homma I, Feldman J, Janczewski W. The para-facial
respiratory group (pFRG)/pre Botzinger Complex (preBotC) is the
540 primary site of respiratory rhythm generation in the mammal.
J Appl Physiol (1985). 2006;100(6):2094-2095.
7. Dutschmann M, Dick TE. Pontine mechanisms of respiratory
control. Compr Physiol. 2012;2(4):2443-2469.
8. Garcia AJ III, Zanella S, Koch H, Doi A, Ramirez JM. Chapter
3networks within networks: the neuronal control of breathing.
Prog Brain Res. 2011;188:31-50.
9. Ramirez J-M, Garcia AJ, Anderson TM, et al. Central and
peripheral factors contributing to obstructive sleep apneas. Respir
Physiol Neurobiol. 2013;189(2):344-353.
10. Guyenet PG. The 2008 Carl Ludwig Lecture: retrotrapezoid
nucleus, CO2 homeostasis, and breathing automaticity. J Appl
Physiol. 2008;105(2):404-416.
[ 151#4 CHEST APRIL 2017 ]
 11. Nattie E, Li A. Central chemoreceptors: locations and functions.
Compr Physiol. 2012;2(1):221-254.
12. Forster HV, Smith CA. Contributions of central and peripheral
chemoreceptors to the ventilatory response to CO2/H. J Appl
Physiol. 2010;108(4):989-994.
13. Lahiri S, Mulligan E, Nishino T, Mokashi A, Davies R. Relative
responses of aortic body and carotid body chemoreceptors to
carboxyhemoglobinemia. J Appl Physiol. 1981;50(3):580-586.
14. Prabhakar N, Peng Y-J, Kumar G, Nanduri J, Di Giulio C, Lahiri S.
Long-term regulation of carotid body function: acclimatization and
adaptationinvited article. Adv Exp Med Biol. 2009:307-317.
15. Lahiri S, Forster RE. CO2/H sensing: peripheral and central
chemoreception. Int J Biochem Cell Biol. 2003;35(10):
1413-1435.
16. Lahiri S, DeLaney R. Stimulus interaction in the responses of
carotid body chemoreceptor single afferent bers. Respir Physiol.
1975;24(3):249-266.
17. Dahan A, Nieuwenhuijs D, Teppema L. Plasticity of central
chemoreceptors: effect of bilateral carotid body resection on central
CO2 sensitivity. PLoS Med. 2007;4(7):e239.
18. Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey JA.
Carotid body denervation eliminates apnea in response to transient
hypocapnia. J Appl Physiol. 2003;94(1):155-164.
19. Smith CA, Rodman JR, Chenuel B, Henderson KS, Dempsey JA.
Response time and sensitivity of the ventilatory response to CO2 in
unanesthetized intact dogs: central vs. peripheral chemoreceptors.
J Appl Physiol. 2006;100(1):13-19.
20. Smith CA, Chenuel BJ, Henderson KS, Dempsey JA. The AT
during non-REM sleep in dogs: sensitivity of carotid body vs.
central chemoreceptors. J Appl Physiol. 2007;103(2):578-586.
21. Dempsey JA, Smith CA, Blain GM, Xie A, Gong Y, Teodorescu M.
Role of central/peripheral chemoreceptors and their interdependence
in the pathophysiology of sleep apnea. Adv Exp Med Biol. 2012:
343-349.
22. Trippenbach T. Pulmonary reexes and control of breathing
during development. Neonatology. 1994;65(3-4):205-210.
23. Bodegrd G, Schwieler GH, Skoglund S, Zetterstrm RI. The
development of the Hering-Breuer ination reex. Acta
Paediatrica. 1969;58(6):567-571.
24. Van Der Velde L, Curran AK, Filiano JJ, Darnall RA, Bartlett D Jr,
Leiter JC. Prolongation of the laryngeal chemoreex after inhibition
of the rostral ventral medulla in piglets: a role in SIDS? J Appl
Physiol (1985). 2003;94(5):1883-1895.
25. Phillipson EA, Dufn J, Cooper JD. Critical dependence of
respiratory rhythmicity on metabolic CO2 load. J Appl Physiol
Respir Environ Exerc Physiol. 1981;50(1):45-54.
26. Pack A, Cola M, Goldszmidt A, Ogilvie M, Gottschalk A.
Correlation between oscillations in ventilation and frequency
content of the electroencephalogram. J Appl Physiol. 1992;72(3):
985-992.
27. Trinder J, Whitworth F, Kay A, Wilkin P. Respiratory instability
during sleep onset. J Appl Physiol. 1992;73(6):2462-2469.
28. Dunai J, Kleiman J, Trinder J. Ventilatory instability during sleep
onset in individuals with high peripheral chemosensitivity. J Appl
Physiol. 1999;87(2):661-672.
29. Dunai J, Wilkinson M, Trinder J. Interaction of chemical and state
effects on ventilation during sleep onset. J Appl Physiol. 1996;81(5):
2235-2243.
30. Skatrud JB, Dempsey JA. Interaction of sleep state and chemical
stimuli in sustaining rhythmic ventilation. J Appl Physiol.
1983;55(3):813-822.
31. Thomson S, Morrell MJ, Cordingley JJ, Semple SJ. Ventilation is
unstable during drowsiness before sleep onset. J Appl Physiol.
2005;99(5):2036-2044.
32. Khoo MC, Kronauer RE, Strohl KP, Slutsky AS. Factors inducing
periodic breathing in humans: a general model. J Appl Physiol
Respir Environ Exerc Physiol. 1982;53(3):644-659.
journal.publications.chestnet.org
33. Cherniack NS, Longobardo GS. Mathematical models of periodic
breathing and their usefulness in understanding cardiovascular and
respiratory disorders. Exp Physiol. 2006;91(2):295-305.
34. Khoo MC. Determinants of ventilatory instability and variability.
Respir Physiol. 2000;122(2):167-182.
35. Harms CA, Zeng Y, Smith CA, Vidruk EH, Dempsey JA.
Negative pressure-induced deformation of the upper airway causes
central apnea in awake and sleeping dogs. J Appl Physiol.
1996;80(5):1528-1539.
36. Chapman K, Bruce E, Gothe B, Cherniack N. Possible
mechanisms of periodic breathing during sleep. J Appl Physiol.
1988;64(3):1000-1008.
37. Dempsey JA. Crossing the apnoeic threshold: causes and
consequences. Exp Physiol. 2005;90(1):13-24.
38. Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey JA. Effect
of ventilatory drive on carbon dioxide sensitivity below eupnea
during sleep. Am J Respir Crit Care Med. 2002;165(9):1251-1260.
39. Chowdhuri S, Sinha P, Pranathiageswaran S, Badr MS. Sustained
hyperoxia stabilizes breathing in healthy individuals during NREM
sleep. J Appl Physiol (1985). 2010;109(5):1378-1383.
40. Orem J. Neuronal mechanisms of respiration in REM sleep. Sleep.
1979;3(3-4):251-267.
41. Lovering AT. Tonic activity in the respiratory system in
wakefulness, NREM and REM sleep. Sleep. 2002;25(5):488.
42. Burke PG, Kanbar R, Basting TM, et al. State-dependent control of
breathing by the retrotrapezoid nucleus. J Physiol. 2015;593(13):
2909-2926.
43. Sahlin C, Svanborg E, Stenlund H, Franklin K. Cheyne-
Stokes respiration and supine dependency. Eur Respir J. 2005;25(5):
829-833.
44. Oksenberg A, Arons E, Snir D, Radwan H, Soroker N. Cheyne-
Stokes respiration during sleep: a possible effect of body position.
Med Sci Monit. 2002;8(7):CS61-CS65.
45. Szollosi I, Roebuc T, Thompson B, Naughton MT. Lateral sleeping
position reduces severity of central sleep apnea/Cheyne-Stokes
respiration. Sleep. 2006;29(8):1045.
46. Issa FG, Sullivan CE. Reversal of central sleep apnea using nasal
CPAP. Chest. 1986;90(2):165-171.
47. Ainslie PN, Dufn J. Integration of cerebrovascular CO2 reactivity
and chemoreex control of breathing: mechanisms of regulation,
measurement, and interpretation. Am J Physiol Regul Integr Comp
Physiol. 2009;296(5):R1473-R1495.
48. Xie A, Skatrud JB, Khayat R, Dempsey JA, Morgan B, Russell D.
Cerebrovascular response to carbon dioxide in patients with
congestive heart failure. Am J Respir Crit Care Med. 2005;172(3):
371-378.
49. Xie A, Skatrud JB, Morgan B, et al. Inuence of cerebrovascular
function on the hypercapnic ventilatory response in healthy
humans. J Physiol. 2006;577(1):319-329.
50. Ainslie PN, Poulin MJ. Ventilatory, cerebrovascular, and
cardiovascular interactions in acute hypoxia: regulation by carbon
dioxide. J Appl Physiol. 2004;97(1):149-159.
51. Kety SS, Schmidt CF. The effects of altered arterial tensions of
carbon dioxide and oxygen on cerebral blood ow and cerebral
oxygen consumption of normal young men. J Clin Invest.
1948;27(4):484.
52. Xie A, Skatrud JB, Barczi SR, et al. Inuence of cerebral blood ow
on breathing stability. J Appl Physiol. 2009;106(3):850-856.
53. Bixler EO, Vgontzas AN, Lin H-M, et al. Prevalence of sleep-
disordered breathing in women: effects of gender. Am J Respir Crit
Care Med. 2001;163(3):608-613.
54. Ancoli-Israel S, Kripke DF, Klauber MR, Mason WJ, Fell R,
Kaplan O. Sleep-disordered breathing in community-dwelling
elderly. Sleep. 1991;14(6):486.
55. Pack AI, Silage DA, Millman RP, Knight H, Shore ET, Chung D.
Spectral analysis of ventilation in elderly subjects awake and asleep.
J Appl Physiol. 1988;64(3):1257-1267.
927
 56. Lu H, Xu F, Rodrigue KM, et al. Alterations in cerebral metabolic
rate and blood supply across the adult lifespan. Cerebral Cortex.
2010:bhq224.
57. Mayhan WG, Arrick DM, Sharpe GM, Sun H. Age-related
alterations in reactivity of cerebral arterioles: role of oxidative
stress. Microcirculation. 2008;15(3):225-236.
58. Fu JH, Lu CZ, Hong Z, Dong Q, Ding D, Wong KS. Relationship
between cerebral vasomotor reactivity and white matter lesions in
elderly subjects without large artery occlusive disease. J Neuroimaging.
2006;16(2):120-125.
59. Reich T, Rusinek H. Cerebral cortical and white matter reactivity to
carbon dioxide. Stroke. 1989;20(4):453-457.
60. Vovk A, Smith WDF, Paterson ND, Cunningham DA,
Paterson DH. Peripheral chemoreceptor control of ventilation
following sustained hypoxia in young and older adult humans. Exp
Physiol. 2004;89(6):647-656.
61. Pokorski M, Marczak M. Ventilatory response to hypoxia in elderly
women. Ann Hum Biol. 2003;30(1):53-64.
62. Poulin MJ, Cunningham D, Paterson D, Kowalchuk J, Smith W.
Ventilatory sensitivity to CO2 in hyperoxia and hypoxia in older
aged humans. J Appl Physiol. 1993;75(5):2209-2216.
63. Ahmed M, Giesbrecht G, Serrette C, Georgopoulos D,
Anthonisen N. Ventilatory response to hypoxia in elderly humans.
Respir Physiol. 1991;83(3):343-351.
64. Kronenberg RS, Drage CW. Attenuation of the ventilatory and
heart rate responses to hypoxia and hypercapnia with aging in
normal men. J Clin Invest. 1973;52(8):1812.
65. Peterson DD, Pack AI, Silage DA, Fishman AP. Effects of aging on
ventilatory and occlusion pressure responses to hypoxia and
hypercapnia 14. Am Rev Respir Dis. 1981;124(4):387-391.
66. Chapman KR, Cherniack NS. Aging effects on the interaction of
hypercapnia and hypoxia as ventilatory stimuli. J Gerontol.
1987;42(2):202-209.
67. Martinez D. Effects of aging on peripheral chemoreceptor CO2
response during sleep and wakefulness in healthy men. Respir
Physiol Neurobiol. 2008;162(2):138-143.
68. Chowdhuri S, Pranathiageswaran S, Franco-Elizondo R, et al. Effect
of age on long-term facilitation and chemosensitivity during
NREM sleep. J Appl Physiol. 2015;119(10):1088-1096.
69. Zhou XS, Rowley JA, Demirovic F, Diamond MP, Badr M. Effect of
testosterone on the AT in women during NREM sleep. J Appl
Physiol. 2003;94(1):101-107.
70. Rowley JA, Zhou XS, Diamond MP, Badr MS. The determinants of
the apnea threshold during NREM sleep in normal subjects. Sleep.
2006;29(1):95.
71. Mateika JH, Omran Q, Rowley J, Zhou X, Diamond MP, Badr MS.
Treatment with leuprolide acetate decreases the threshold of the
ventilatory response to carbon dioxide in healthy males. J Physiol.
2004;561(2):637-646.
72. Chowdhuri S, Bascom A, Mohan D, Diamond MP, Badr MS.
Testosterone conversion blockade increases breathing stability in
healthy men during NREM sleep. Sleep. 2013;36(12):1793.
73. Briscoe J, Pierani A, Jessell TM, Ericson J. A homeodomain protein
code species progenitor cell identity and neuronal fate in the
ventral neural tube. Cell. 2000;101(4):435-445.
74. Feldman JL, Del Negro CA, Gray PA. Understanding the rhythm of
breathing: so near, yet so far. Annu Rev Physiol. 2013;75:423-452.
75. Bouvier J, Thoby-Brisson M, Renier N, et al. Hindbrain
interneurons and axon guidance signaling critical for breathing.
Nat Neurosci. 2010;13(9):1066-1074.
76. Gray PA, Hayes JA, Ling GY, et al. Developmental origin of
preBotzinger complex respiratory neurons. J Neurosci. 2010;30(44):
14883-14895.
77. Gaultier C, Matrot B, Gallego J. Transgenic models to study
disorders of respiratory control in newborn mice. ILAR J.
2006;47(1):15-21.
78. Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, et al. An ofcial
ATS clinical policy statement: congenital central hypoventilation
928 Contemporary Reviews in Sleep Medicine
syndrome: genetic basis, diagnosis, and management. Am J Respir
Crit Care Med. 2010;181(6):626-644.
79. Croix CMS, Satoh M, Morgan BJ, Skatrud JB, Dempsey JA. Role of
respiratory motor output in within-breath modulation of muscle
sympathetic nerve activity in humans. Circ Res. 1999;85(5):457-469.
80. Kinney HC, Richerson GB, Dymecki SM, Darnall RA, Nattie EE.
The brain stem and serotonin in the sudden infant death
syndrome. Annu Rev Pathol. 2009;4:517.
81. Panigrahy A, Filiano J, Sleeper LA, et al. Decreased serotonergic
receptor binding in rhombic lip-derived regions of the medulla
oblongata in the sudden infant death syndrome. J Neuropathol Exp
Neurol. 2000;59(5):377-384.
82. Dempsey JA, Powell FL, Bisgard GE, Blain GM, Poulin MJ,
Smith CA. Role of chemoreception in cardiorespiratory
acclimatization to, and deacclimatization from, hypoxia. J Appl
Physiol (1985). 2014;116(7):858-866.
83. Ainslie PN, Lucas SJ, Burgess KR. Breathing and sleep at high
altitude. Respir Physiol Neurobiol. 2013;188(3):233-256.
84. Bradley TD, Floras JS. Sleep apnea and heart failure part II: central
sleep apnea. Circulation. 2003;107(13):1822-1826.
85. Xie A, Skatrud JB, Puleo DS, Rahko PS, Dempsey JA. Apnea-
hypopnea threshold for CO2 in patients with congestive heart
failure. Am J Respir Crit Care Med. 2002;165(9):1245-1250.
86. Dempsey JA, Smith CA, Przybylowski T, et al. The ventilatory
responsiveness to CO2 below eupnoea as a determinant of
ventilatory stability in sleep. J Physiol. 2004;560(1):1-11.
87. Rajagopalan B, Raine AE, Cooper R, Ledingham JG. Changes
in cerebral blood ow in patients with severe congestive
cardiac failure before and after captopril treatment. Am J Med.
1984;76(5):86-90.
88. Xie A, Skatrud JB, Dempsey JA. Effect of hypoxia on the
hypopnoeic and apnoeic threshold for CO2 in sleeping humans.
J Physiol. 2001;535(1):269-278.
89. Chowdhuri S, Shanidze I, Pierchala L, Belen D, Mateika JH,
Badr MS. Effect of episodic hypoxia on the susceptibility to
hypocapnic central apnea during NREM sleep. J Appl Physiol.
2010;108(2):369-377.
90. Wellman A, Jordan AS, Malhotra A, et al. Ventilatory control and
airway anatomy in obstructive sleep apnea. Am J Respir Crit Care
Med. 2004;170(11):1225-1232.
91. Wellman A, Eckert DJ, Jordan AS, et al. A method for measuring
and modeling the physiological traits causing obstructive sleep
apnea. J Appl Physiol (1985). 2011;110(6):1627-1637.
92. Warner G, Skatrud JB, Dempsey JA. Effect of hypoxia-induced
periodic breathing on upper airway obstruction during sleep. J Appl
Physiol. 1987;62(6):2201-2211.
93. Badr MS, Toiber F, Skatrud JB, Dempsey J. Pharyngeal narrowing/
occlusion during central sleep apnea. J Appl Physiol. 1995;78(5):
1806-1815.
94. Salloum A, Rowley JA, Mateika JH, Chowdhuri S, Omran Q,
Badr MS. Increased propensity for central apnea in patients with
obstructive sleep apnea: effect of nasal continuous positive airway
pressure. Am J Respir Crit Care Med. 2010;181(2):189-193.
95. Remmers JE, deGroot WJ, Sauerland EK, Anch AM. Pathogenesis
of upper airway occlusion during sleep. J Appl Physiol Respir
Environ Exerc Physiol. 1978;44(6):931-938.
96. Eastwood PR, Szollosi I, Platt PR, Hillman DR. Comparison of
upper airway collapse during general anaesthesia and sleep. Lancet.
2002;359(9313):1207-1209.
97. Ballanyi K, Onimaru H, Homma I. Respiratory network function in
the isolated brain stem-spinal cord of newborn rats. Prog Neurobiol.
1999;59(6):583-634.
98. McKay LC, Feldman JL. Unilateral ablation of pre-Botzinger
complex disrupts breathing during sleep but not wakefulness. Am J
Respir Crit Care Med. 2008;178(1):89-95.
99. Garcia AJ III, Zanella S, Dashevskiy T, et al. Chronic intermittent
hypoxia alters local respiratory circuit function at the level of the
preBtzinger complex. Front Neurosci. 2016:10.
[ 151#4 CHEST APRIL 2017 ]
100. Lawson E, Waldrop T, Eldridge F. Naloxone enhances respiratory
output in cats. J Appl Physiol. 1979;47(5):1105-1111.
101. Schlenker EH, Inamdar SR. Effects of naloxone on oxygen
consumption and ventilation in awake golden Syrian hamsters.
Physiol Behav. 1995;57(4):655-658.
102. Janczewski WA, Onimaru H, Homma I, Feldman JL. Opioid-
resistant respiratory pathway from the preinspiratory neurones to
abdominal muscles: in vivo and in vitro study in the newborn rat.
J Physiol. 2002;545(3):1017-1026.
103. Greer JJ, Carter JE, Al-Zubaidy Z. Opioid depression of respiration
in neonatal rats. J Physiol. 1995;485(3):845-855.
104. Montandon G, Qin W, Liu H, Ren J, Greer JJ, Horner RL.
PreBtzinger complex neurokinin-1 receptor-expressing neurons
mediate opioid-induced respiratory depression. J Neurosci.
2011;31(4):1292-1301.
105. Montandon G, Horner R. CrossTalk proposal: the preBtzinger
complex is essential for the respiratory depression following
systemic administration of opioid analgesics. J Physiol. 2014;592(6):
1159-1162.
106. Levitt ES, Abdala AP, Paton JF, Bissonnette JM, Williams JT.
m-Opioid receptor activation hyperpolarizes respiratory-controlling
Klliker-Fuse neurons and suppresses post-inspiratory drive.
J Physiol. 2015;593(19):4453-4469.
107. Santiago TV, Edelman N. Opioids and breathing. J Appl Physiol.
1985;59(6):1675-1685.
108. Moss I, Scott S, Inman J. Hypoxia, sleep and respiration in relation
to opioids in developing swine. Respir Physiol. 1993;92(1):115-125.
109. Taylor S, Kirton OC, Staff I, Kozol RA. Postoperative day one: a high
risk period for respiratory events. Am J Surg. 2005;190(5):752-756.
110. Moss IR, Laferrire A. Central neuropeptide systems and
respiratory control during development. Respir Physiol Neurobiol.
2002;131(1):15-27.
111. Zhang C, Moss IR. Age-related mu-, delta-and kappa-opioid
ligands in respiratory-related brain regions of piglets: effect of
prenatal cocaine. Brain Res Dev Brain Res. 1995;87(2):188-193.
112. Wang D, Teichtahl H, Drummer O, et al. Central sleep apnea in
stable methadone maintenance treatment patients. Chest.
2005;128(3):1348-1356.
113. Walker JM, Farney RJ, Rhondeau SM, et al. Chronic opioid use is a
risk factor for the development of central sleep apnea and ataxic
breathing. J Clin Sleep Med. 2007;3(5):455-461.
114. Teichtahl H, Wang D, Cunnington D, et al. Ventilatory responses
to hypoxia and hypercapnia in stable methadone maintenance
treatment patients. Chest. 2005;128(3):1339-1347.
115. Sankari A, Martin JL, Bascom AT, Mitchell MN, Badr MS.
Identication and treatment of sleep-disordered breathing in
chronic spinal cord injury. Spinal Cord. 2015;53(2):145-149.
116. Dempsey JA, Veasey SC, Morgan BJ, ODonnell CP.
Pathophysiology of sleep apnea. Physiol Rev. 2010;90(1):47-112.
117. Wellman A, Malhotra A, Jordan AS, Stevenson KE, Gautam S,
White DP. Effect of oxygen in obstructive sleep apnea: role of loop
gain. Respir Physiol Neurobiol. 2008;162(2):144-151.
118. Sasayama S, Izumi T, Seino Y, Ueshima K, Asanoi H. Effects of
nocturnal oxygen therapy on outcome measures in patients with
chronic heart failure and Cheyne-Stokes respiration. Circ J.
2006;70(1):1-7.
119. Martin RJ, Sanders MH, Gray BA, Pennock BE. Acute and Long-
term ventilatory effects of hyperoxia in the adult sleep apnea
syndrome 1-3. Am Rev Respir Dis. 1982;125(2):175-180.
120. Chowdhuri S, Ghabsha A, Sinha P, Kadri M, Narula S, Badr MS.
Treatment of central sleep apnea in US veterans. J Clin Sleep Med.
2012;8(5):555-563.
121. Javaheri S. Acetazolamide improves central sleep apnea in heart
failure: a double-blind, prospective study. Am J Respir Crit Care
Med. 2006;173(2):234-237.
122. Swenson ER, Hughes J. Effects of acute and chronic acetazolamide
on resting ventilation and ventilatory responses in men. J Appl
Physiol. 1993;74(1):230-237.
journal.publications.chestnet.org
123. Edwards BA, Sands SA, Eckert DJ, et al. Acetazolamide improves
loop gain but not the other physiological traits causing obstructive
sleep apnoea. J Physiol. 2012;590(5):1199-1211.
124. Pranathiageswaran S, Badr MS, Chowdhuri S. Acetazolamide
stabilizes breathing in healthy older adults during NREM sleep.
B110. Upper Airway and Respiratory Control During Sleep. ATS J.
2014:A3903-A3903.
125. Fan JL, Burgess KR, Thomas KN, et al. Effects of acetazolamide on
cerebrovascular function and breathing stability at 5050 m.
J Physiol. 2012;590(5):1213-1225.
126. Teppema LJ, Dahan A. Acetazolamide and breathing: does a
clinical dose alter peripheral and central CO2 sensitivity? Am J
Respir Crit Care Med. 1999;160(5):1592-1597.
127. Teppema LJ, Dahan A. Low-dose acetazolamide reduces the
hypoxic ventilatory response in the anesthetized cat. Respir Physiol
Neurobiol. 2004;140(1):43-51.
128. Teppema LJ, Dahan A, Olievier CN. Low-dose acetazolamide reduces
CO2-O2 stimulus interaction within the peripheral chemoreceptors
in the anaesthetised cat. J Physiol. 2001;537(1):221-229.
129. Skatrud JB, Dempsey JA, Iber C, Berssenbrugge A. Correction of
CO2 retention during sleep in patients with chronic obstructive
pulmonary diseases. Am Rev Respir Dis. 1981;124(3):260-268.
130. Skatrud JB, Dempsey JA, Bhansali P, Irvin C. Determinants of
chronic carbon dioxide retention and its correction in humans.
J Clin Invest. 1980;65(4):813-821.
131. Javaheri S, Guerra LF. Effects of domperidone and medroxypro-
gesterone acetate on ventilation in man. Respir Physiol. 1990;81(3):
359-370.
132. Morikawa T, Tanaka Y, Maruyama R, Nishibayashi Y, Honda Y.
Comparison of two synthetic progesterones on ventilation in
normal males: CMA vs. MPA. J Appl Physiol (1985). 1987;63(4):
1610-1615.
133. Milerad J, Lagercrantz H, Lofgren O. Alveolar hypoventilation
treated with medroxyprogesterone. Arch Dis Child. 1985;60(2):
150-155.
134. Ren J, Poon BY, Tang Y, Funk GD, Greer JJ. Ampakines alleviate
respiratory depression in rats. Am J Respir Crit Care Med.
2006;174(12):1384-1391.
135. Van Der Schier R, Roozekrans M, Van Velzen M, Dahan A,
Niesters M. Opioid-induced respiratory depression: reversal by
non-opioid drugs. F1000Prime Rep. 2013;6:79-79.
136. Oertel B, Felden L, Tran P, et al. Selective antagonism of
opioid-induced ventilatory depression by an ampakine molecule
in humans without loss of opioid analgesia. Clin Pharmacol Ther.
2010;87(2):204-211.
137. Dahan A, Aarts L, Smith TW. Incidence, reversal, and prevention
of opioid-induced respiratory depression. Anesthesiology.
2010;112(1):226-238.
138. Manzke T, Guenther U, Ponimaskin EG, et al. 5-HT4 (a) receptors
avert opioid-induced breathing depression without loss of
analgesia. Science. 2003;301(5630):226-229.
139. Smales ET, Edwards BA, Deyoung PN, et al. Trazodone effects on
obstructive sleep apnea and non-REM arousal threshold. Ann
Thorac Surg. 2015;12(5):758-764.
140. Sankri-Tarbichi AG, Grullon K, Badr MS. Effects of clonidine on
breathing during sleep and susceptibility to central apnoea. Respir
Physiol Neurobiol. 2013;185(2):356-361.
141. Hanzel DA, Proia NG, Hudgel DW. Response of obstructive
sleep apnea to uoxetine and protriptyline. Chest. 1991;100(2):
416-421.
142. Sangal RB, Sangal JM, Thorp K. Atomoxetine improves sleepiness
and global severity of illness but not the respiratory disturbance
index in mild to moderate obstructive sleep apnea with sleepiness.
Sleep Med. 2008;9(5):506-510.
143. Taranto-Montemurro L, Edwards BA, Sands SA, et al. Desipramine
increases genioglossus activity and reduces upper airway
collapsibility during non-REM sleep in healthy subjects. Am J
Respir Crit Care Med. 2016;194(7):878-885.
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