Neurocritical Care

Copyright © 2005 Humana Press Inc.

All rights of any nature whatsoever are reserved.
ISSN 1541-6933/05/3:271–279
DOI: 10.1385/Neurocrit. Care 2005;03:271–279

Translational Research

Causes of Cheyne–Stokes Respiration

N. S. Cherniack,*,1 G. Longobardo, and C. J. Evangelista
1
New Jersey Medical School, Newark, NJ and the Case Western Reserve School of Medicine, Cleveland, OH

Abstract
Cheyne–Stokes respiration (CSR) is one of several types of unusual breathing with
recurrent apneas (dysrhythmias). Reported initially in patients with heart failure or
stroke, it was then recognized both in other diseases and as a component of the sleep
apnea syndrome. CSR is potentiated and perpetuated by changing states of arousal
that occur during sleep. The recurrent hypoxia and surges of sympathetic activity
that often occur during the apneas may have serious health consequences. Heart fail-
ure and stroke are risk factors for sleep apnea. The recurrent apneas and intermittent
hypoxia occurring with sleep apnea further damage the heart and brain.
Although all breathing dysrhythmias do not have the same cause, instability in the
feedback control involved in the chemical regulation of breathing is the leading cause
of CSR. Mathematical models have helped greatly in the understanding of the causes
of recurrent apneas.
Key Words: Cheyne–Stokes respiration; periodic breathing; heart failure; stroke; sleep
apnea; control system instability; feedback systems; mathematical models of breathing;
regulation of breathing; carbon dioxide; hypoxia; wakefulness drives.

(Neurocrit. Care 2005;03:271–279)

Introduction were believed to be both indicators of critical

*Correspondence and
reprint requests to:
N. S. Cherniack, 11 Wood
Drive, Morris Plains,
NJ 07950.
E-mail: cherniac@umdnj.edu
Breathing usually appears to be regular
and rarely attracts attention. However, cer-
tain forms of breathing (which we call dys-
rhythmias in this article)—particularly those
in which recurrent apneas or near apneas
occur—have fascinated physicians and phys-
iologists for years. It was almost 200 years
ago when Cheyne and Stokes separately
described a symmetrical and regularly recur-
ring waxing and waning of breathing with
apneas in patients with severe heart failure
(Figure 1). Diseases with similar types of
breathing were observed in patients with
strokes, meningitis, encephalitis, brain tu-
mors, head trauma, severe diabetes, or meta-
bolic alkalosis; although breathing was
neither always so symmetrical nor regular.
All of these forms of dysrhythmic breathing
illness and signals of imminent death.
It was later observed that dysrhythmic
breathing, both symmetrical and asymmetri-
cal, occurred in apparently normal individu-
als at both altitudes and sea level during
sleep. These recurrent apneas or near apneas,
which were often irregularly spaced, were
recognized as a pathognomic feature of a
quite common disorder: sleep apnea. These
apneas were classified as central (absent re-
spiratory efforts) or obstructive (absence of
airflow resulting from closed upper airways).
One of the earliest papers on obstructive
apneas was by Lyons, who measured esoph-
ageal pressures in a patient thought to have
Cheyne–Stokes respiration (CSR). He ob-
served persisting swings in esophageal
pressure during the period of apparent

271
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Fig. 1. Computer simulation of CSR. Tidal volume varies periodically
between apneas from 0 to 1 L. Arterial blood gases also cycle: arte-
rial PCO2 between about 30 and 50 mmHg and PO2 between 70 and
130 mmHg.
apnea (1). It is likely that the recurrent apneas during sleep
share many of the same causes as CSR.
It used to be believed that CSR signaled a poor prognosis
when occurring in cardiac or stroke patients but had no health
effects when occurring alone. However, recent studies have
shown that the intermittent hypoxia that occurs with recurrent
apneas can have serious effects on blood pressure, the forma-
tion of atherosclerotic plaques, and blood coagulation (2). The
occurrence of sleep apnea in patients with heart disease and
stroke can lead to further damage to the cardiovascular and
nervous systems.
Animal and human studies have been used to produce
recurrent apneas. However, the frequently transient nature of
the dysrythmythias and the complexity of the possible inter-
actions among the systems that might be involved have com-
plicated experimental approaches. However, there has been
substantial progress in describing the respiratory system in
mathematical models and in using them to examine the im-
pact of factors that could potentially cause recurrent apneas
(3–5). This article discusses some causes of these strange forms
of breathing, emphasizing unstable respiratory control, which
we believe is the most common cause of CSR, and using illus-
trations obtained from mathematical models to demonstrate
how these models can be used to identify the factors that
predispose to CSR.
Clinical Description of Cheyne–Stokes
Respiration
Prototypical CSR is a rather regularly recurring oscillation
of the frequency and tidal volume of breathing with apneas or
near apneas (3,6). Blood gases cycle with out-of-phase changes
in the arterial and alveolar levels of arterial and alveolar par-
tial pressure of carbon dioxide (PCO2) as well as partial pres-
sure of oxygen (PO2).
CSR frequently is associated with cycles in systemic blood
pressure, heart rate, muscle sympathetic activity, pupillary
diameter, and, quite significantly, oscillations in the state of
arousal and electroencephalograph pattern. For example, in the
hyperpneic phase of the CSR cycle, the patient appears to be
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Cherniack et al.
Fig. 2. The neurochemical control system. Neural drives, like the
wakefulness drive, and chemical drives, PCO2 and PO2 in the brain
and at the arterial chemoreceptors, enter the respiratory controller,
which determines ventilatory drive. The respiratory pattern genera-
tor converts that drive into excitatory impulses to the chest wall
muscles (including the diaphragm) and the upper airway muscles.
Muscle compliance, airflow resistance, and fluid dynamic forces are
involved in determining the final tidal volume and frequency. Changes
in blood gases are caused by ventilatory changes.
awake but lapses back into sleep or coma as breathing slows and
apnea occurs. A relationship between cycle length and the circu-
lation time has been noted. The cycle of apnea and hyperpnea is
much shorter in patients with normal hearts compared to those
in heart failure. In cardiac patients, longer circulation times ap-
pear particularly to prolong the hyperpneic phase of the cycle.
Normal Breathing
It is commonly believed that breathing is primarily regu-
lated by feedback of signals from peripheral chemoreceptors
(the carotid and aortic bodies) that sense changes in the PO2
and PCO2 in the arterial blood and multiple central chemore-
ceptors in the brain stem, which detect changes in hydrogen
ion concentration in their intra- or extracellular environments
(refs. 3 and 7; see Figure 2). Cerebral blood flow (CBF) is an
important factor that helps determine hydrogen ion levels at
chemoreceptors. Signals from these receptors act on neurons
located mainly in the rostral medulla, which cause the respira-
tory muscles to contract, setting the tidal volume and fre-
quency of breathing. Although it was once believed that the
respiratory pattern was set by interconnected networks of
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Causes of Cheyne–Stokes Respiration
neurons (respiratory pattern generators), each of which be-
came active in different portions of the respiratory cycle, recent
studies (primarily using in vitro preparations) have indicated
that there are pacemakers in the brain that can affect, and per-
haps capture, the respiratory pattern generator. Other inputs
to the respiratory pattern generator include signals from the
pons, the raphe nuclei, the limbic system, and the cortex.
In a very simplistic way, respiratory control aims at main-
taining levels of carbon dioxide and oxygen in the blood within
narrow limits. In general terms, the system consists of two parts.
The first is a controller consisting of respiratory neurons (the
respiratory pattern generator and pacemakers), central chemo-
receptors that sense CO2/H+ changes, and peripheral chemore-
ceptors that sense changes in oxygen level. The controller directs
the second part of the system, the controlled system comprised
of the respiratory muscles and the organs and tissues, which
contain the gas stores of CO2 and O2 in solution and chemical
combinations (3,6). Increased ventilation decreases the gas
stores of CO2 and reduces PCO2, whereas decreased ventilation
has the opposite effect. Oxygen stores are quite small compared
to the CO2 stores and are only comprised of the oxygen com-
bined with hemoglobin and in solution in the blood and the gas
in the lung. The stores of oxygen fall quite rapidly during
apnea. The levels of PCO2 and PO2 in the blood are transmitted
(fed back) to the chemoreceptors by the circulation and are then
transmitted to the pattern generator via nerves.
Because it is possible to have levels of CO2 that are insuffi-
cient by themselves to produce rhythmic ventilation, apneas
occur at low levels of PCO2 in anesthetized, comatose, and
sleeping humans (8,9). As PCO2 rises and PO2 falls during the
apnea, ventilation eventually recovers, proceeding (sometimes
with oscillations) to normal values of PCO2 and O2. The oscil-
lations are not remarkable, but are the natural consequence
of the properties and the behavior of dynamic systems when
disturbed. Prolongation of the circulation time between the
lungs and the brain as well as increased sensitivity of the cen-
tral and peripheral chemoreceptors can prolong these oscilla-
tions, thus producing unstable respiratory control.
The sleep–waking cycle is of major importance in the normal
control of breathing. In conscious man, cortical projections to
the rhythm generators and, more directly, to the respiratory mo-
tor neurons can not only override automatic control for short
periods of time but, more importantly, can provide the mecha-
nism that allows excitatory stimuli from within and without the
body to maintain ventilation even at very low levels of PCO2.
This drive, known as the wakefulness drive, adds to the chemi-
cal drive arising from increases in carbon dioxide and by hy-
poxia. For example, in the so-called “Locked-in syndrome,” in
which the control of breathing by higher brain centers has been
eliminated by pontine blood vessel blockade, even a slight de-
crease in PCO2 stops breathing (10). Besides altering the excit-
ability of the respiratory system, changing states of arousal
produce disturbances in breathing and blood gas tensions that
destabilize breathing, thus leading to oscillations in ventilation.
Experimental Models of Cheyne–Stokes
Respiration
Studies in animals generally have supported the idea that
feedback instability is a cause of CSR. Crowell et al. (11) generated
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273
CSR in anesthetized dogs by artificially prolonging the circulation
time. However, circulation times in the minutes were required.
Cherniack et al. (12) produced CSR in anesthetized dogs by
transiently hyperventilating them to produce apnea. The CSR
was temporary and occurred when breathing resumed, and it
was more likely to appear if the dogs had been hyperventi-
lated with a hypoxic gas mixture rather than with room air.
The hypoxia increased controller gains by enhancing the re-
sponse to changes in CO2.
More sustained CSR was produced in cats ventilated with a
respirator, the amplitude and frequency of which was gov-
erned by phrenic nerve activity (13). This allowed the effective
gain of the respiratory controller to be artificially increased.
CSR was enhanced in this situation by increasing controller
gain, hypoxia, and cooling the ventral surface of the medulla
to decrease central chemoreceptor activity. When present, CSR
can be abolished by carotid body section.
Chapman et al. (14) produced CSR in humans who were
awake by amplifying respiratory responses to blood gas
changes. Warner (15) found that hypoxia converts obstructive
apneas to central apneas as well as a picture resembling CSR,
which he believed supported prediction of mathematical mod-
els in which instability in feedback control was regarded as a
cause of central and obstructive sleep apnea.
Mathematical Models of Cheyne–Stokes
Respiration
Mathematical models have been used to examine theories
of CSR causation and to predict susceptibility to CSR (5,16–20).
Simplified models of the control system have also been de-
scribed in an attempt to derive an index or ratio to characterize
the stability characteristics of the system in different circum-
stances and, therefore, to predict when CSR will occur in pa-
tients (17). Although they can be helpful, their use is limited
because they ignore the nonlinear characteristics of the respi-
ratory control system.
Fortunately, it is possible to solve equations that include
provisions for apnea and other nonlinearities using the com-
puter. These solutions provide insight to the complex interac-
tions between the body components involved in the occurrence
of apneas in breathing. The more complex models include O2
and CO2 chemoreceptors, the effects of brain hypoxia, the
effects of hypoxia and hypercapnia on CBF in the controller,
and a compartmentalized version of the body tissues con-
nected to the controller by motor and sensory nerves and the
circulation (18–20).
Some models, like the one shown in Figure 2, include
a wakefulness drive in the controller that diminishes or dis-
appears with sleep (5). (For details of this model, consult
www.geocities.com/respmodel.) These larger models are
more biologically accurate and can be used to evaluate the im-
pact of changes in specific components of the control system
on the occurrence of CSR. However, they are too complex to
make useful predictions in individual patients.
Instabilities Arising From Feedback Control
As Causes of Cheyne–Stokes Repiration
Perhaps the most generally accepted idea is that CSR
occurs as a result of instability in the feedback control system
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that regulates ventilation and minimizes oscillations on blood
gas tensions (3,4,6). Instability in control theory is not synony-
mous with increased variability of the breathing pattern but is
a very well-defined state in control engineering with a very
specific meaning (i.e., loss of the ability to maintain constant
levels of some important factor, which instead endlessly cy-
cles). Although in an engineering sense instability in a control
system is a persistent condition, in humans, it much more
likely to be transient because the conditions for frank instabil-
ity in the biological system are rarely met. In the respiratory
system, one reason that the conditions are rarely met is the
mechanical constraints on ventilation; another is the operation
of other systems that impact the respiratory control system.
The primary purpose for feedback in a system is to reduce
excursions in blood gases from normal when disturbances
occur. A direct consequence of feedback is that the system
response is more oscillatory after being disturbed, although
the response to the disturbance is also quicker. Both controller
and body properties determine whether the system become
unstable when disturbed. Primary among system properties
are: (a) the “gain,” or sensitivity, of the controller, which is its
response to CO2 change expressed as liters/minute/millime-
ters of PCO2 change; (b) the circulation time; (c) the state of
arousal; and (d) the “gain” of the controlled system. Plant gain
is expressed as the millimeters of PCO2 change/liter/minute
of ventilation.
The higher the gain of the controller, the smaller the error
caused by a disturbance (such as inhaling a hypoxic mixture),
but the quicker and more oscillatory the response to the distur-
bance. The plant gain is the inverse of the slope of the meta-
bolic hyperbola and, therefore, is determined by where on the
metabolic hyperbola the body is operating. Plant gain is higher
at higher PCO2 levels, such as that which occurs during sleep.
Similarly to controller gain, the higher the plant gain, the more
oscillatory the response (see Figure 3A–C). Operating at higher
PCO2 is a significant cause of apneas during sleep.
Apneas occur when the controller has an apneic threshold,
which is a level of chemical drive necessary for ventilation.
This threshold becomes greater with sleep, coma, and anesthe-
sia. If drive is low enough for apnea to occur, then CO2 rises
until the threshold is reached and breathing resumes. This
occurs more rapidly because of the mounting hypoxia dur-
ing apnea, which increases controller gain. If the ventilatory
response is sufficiently high to lower CO2 below the threshold
again, apnea re-occurs. This is more likely to occur when circu-
latory delay is increased. If the circulation delay is long enough,
then the apneas persist.
Table 1 summarizes major factors contributing to instability
and stability (21–34). The importance of each of these factors
depends on their interrelationships. For example, the longer
the circulatory delay, the less the system gain needs to be for
instability to occur (Figure 4).
The central chemoreceptors have long been recognized as a
stabilizing influence on respiration. This is in contrast to the
peripheral chemoreceptors, which, driven by the small oxygen
store and the wide swings in PO2 during cyclic breathing, are
extremely volatile and have little calming influence on the
ventilation once it starts cycling. The stabilizing influence
takes place because the brain CO2 level changes relatively
slowly, with a time-constant of about 1 minute at normal
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Cherniack et al.
Table 1
Factors Destabilizing Breathing
Heart failure Stroke Sleep apnea
Increased controller gain X X
Increased plant gain X
Changing states of alertness X
Coma X
Increased circulation time X X
Decreased CBF responsiveness
to hypoxia and hypercapnia X
CBF, cerebral blood flow.
conditions. This time-constant is determined by brain mass
and CBF; the higher the CBF, the lower the time-constant. CBF
varies linearly with PCO2, helping to maintain brain PCO2 at a
constant. Similarly, it is likely that CBF variation with oxygen
levels keeps oxygen delivery to the brain constant. The effect is
that disturbances to brain CO2 from changes in arterial PO2
and PCO2 are countered by CBF changes, thereby maintaining
stable control (see Figure 5).
Control System Instability in the Production
of Cheyne–Stokes Respiration in Heart Failure,
Stroke, and Sleep Apnea Syndrome
Heart failure, stroke, and sleep apnea produce changes in
respiratory control that predispose to CSR, as shown in Table
1. In patients with heart failure, other factors besides long cir-
culation may provoke CSR (35–40). Lung congestion interferes
with ventilation/perfusion matching in the lungs and causes
hypoxia. Hypoxia increases controller gain. Congestion of the
pulmonary vasculature also stimulates vagally innervated J
and irritant receptors, which also increases controller gains.
Sleep apneas, both central and obstructive, are common in
patients with heart failure. Continuous applied pressure with
or without inspiratory increases is reported to eliminate CSR
in patients with heart failure (41; however, the mechanism is
unclear. There are several attractive possibilities that are not
mutually exclusive. It could improve cardiac function by re-
ducing venous return to the heart, thereby preventing ventric-
ular overdistention. It may act to increase the functional
residual capacity of the lung, reduce shunting, increase oxy-
gen stores, and improve oxygen levels. Additionally, it may act
to relieve an obstructive component in the apneas, which pro-
longs them and intensifies the hypoxia they produce.
Cases of CSR persisting after treatment of heart failure may
be related to residual central nervous system (CNS) damage,
which produces instability (as described later). Woo et al. (42)
reported generalized gray matter loss in six patients with con-
gestive heart failure studied by magnetic resonance imaging.
Interestingly, following cardiac transplantation, recurrent cen-
tral sleep apneas may convert to obstructive apneas, indicat-
ing the close relationship between the central and obstructive
forms of the syndrome.
CSR occurs in as many as 50% of patients with supratenten-
torial strokes but can occur after infratentorial strokes as well
(43–48). The type of respiratory dysrhythmia occurring after a
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Causes of Cheyne–Stokes Respiration 275

Fig. 3. (A) Ventilatory sensitivity to PCO2. Controller gain is the change of ventilation with PCO2 change. Ventilation varies approximately
linearly with PCO2 until PCO2 reaches a threshold level determined by states of alertness or sleep. The level of alertness raises or lowers
the PCO2 threshold. The lower alertness of sleep creates greater possibilities for apneas, which occur at higher levels of PCO2 during
sleep. (B) Ventilatory sensitivity to PO2. Hypoxia increases ventilation hyperbolically and increases controller gain. It is responsible for
excessive ventilatory response when breathing begins again after apnea. If the hypoxia is sufficiently severe, the high ventilation drives
PCO2 below its threshold, and another apnea ensues. With large circulation delays or abnormally high controller sensitivities, the breath-
ing becomes periodic, with apneas. (C) Plant gain variation with PCO2. Plant gain is the change in PCO2 when ventilation changes. The
graph is based on a metabolic rate of 300 mL/minute and an equilibrium of 7 L/minute ventilation at 40 mmHg of arterial PCO2. Plant gain
increases as PCO2 increases, and the system becomes less damped and unstable. This is one factor that makes sleep a more unstable state
than wakefulness.
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Fig. 4. The relationship between controller gain, circulation time, and
oscillatory ventilation.With normal controller gain of about 2 L/min-
ute/mmHg of PCO2, and normal circulation time of 8 to 10 seconds,
the effect of this hyperventilation disturbance to breathing dies
down. However, as the circulation time increases, the same distur-
bance can result in continuous oscillations without apnea. With fur-
ther increases in delay, the continuous oscillations include apneas.
Increases in controller gain can arise in stroke, produced by the
removal of an inhibitory cortical effect on breathing from cortical
lesions and high circulation times from congestive heart failure.
stroke does not provide a useful clue regarding the location of
the CNS problem. The cerebral cortex has an inhibiting action
on respiratory reflexes. Patients with bilateral hemispheric
disease may experience a heightened responsiveness to CO2
(increased controller gain). Additionally, in healthy awake in-
dividuals, a drive originating from inside the brain and from
stimuli arising from the external environment prevents apnea
from occurring after hyperventilation. However, this protec-
tive effect often disappears after strokes.
As many as 26% of patients have recurrent central apneas
in the first 24 hours after a stroke, and even more experience
obstructive sleep apneas (44). Sleep apneas are believed to in-
crease the likelihood of strokes and to worsen the outcome if
they are present following a stroke. One explanation for this is
that cerebral vascular reactivity to hypoxia is reduced during
sleep. Parra et al. (44) suggested that although obstructive
sleep apneas appear to precede strokes, CSR and recurrent
central apneas seem to be a consequence of strokes, and they
tend to diminish as patients become stable. They found no
correlation between the location of the stroke and apnea type.
Nasal continuous positive airway pressure (CPAP) has been
used successfully to treat obstructive apneas in patients with
stroke, but its efficacy has not been studied as extensively as it
has been in patients with heart failure; however, compliance in
patients with stroke and CPAP appears to be compromised by
cognitive defects and other functional impairments in elderly
patients with stroke (48).
Apneas during sleep commonly appear during state
changes from wakefulness to sleep or during nonREM (NREM)
sleep. During the process of falling asleep, ventilation de-
creases, and the body operates at higher CO2 levels during
sleep than during wakeful periods. Whether or not apneas oc-
cur during the transition depends on the speed of transition
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Cherniack et al.
Fig. 5. Effect of CBF on the stability of breathing. The figure demon-
strates brain PCO2, total ventilation, and component of ventilation
caused by changes in brain PCO2 (central ventilation) after a period
of hyperventilation that was sufficient to decrease PCO2 and cause
apnea. The solid line shows what occurs when CBF is variable (as
it is usually increasing with hypoxia and PCO2), and the dashed line
shows the effects when CBF is constant. The hyperventilation
disturbance starts at 5 minutes and ends at 10 minutes. In the stable
response, the central ventilation is gradually above the threshold for
brain PCO2 needed to produce breathing, thus eliminating apneas,
whereas in the unstable case, the central ventilation oscillates about
the brain threshold.
(Figure 6). During sleep, PCO2 is elevated; however, the venti-
lation thresholds are also elevated because of the loss of wake-
fulness drives. Because ventilation is low and PCO2 is high
during sleep, smaller disturbances are capable of triggering
apneas (increased plant gain). Therefore, some of the apneas
occurring during sleep may result from instabilities in ventila-
tory control (4,5,32,33). Meza et al. (49) used proportional-
assist breathing to obtain an estimate of loop gain in patients
with sleep apnea and reported that sleeping patients with
apnea have increased loop gains.
The apneas during sleep can be central (i.e., no ventilatory
drive is generated because PO2 and PCO2 are below the central
threshold) or obstructive (i.e., collapse of the upper airway so
that despite ventilatory drive and diaphragmatic effort, there
is no ventilation) (29–34). Obstructive apneas tend to occur in
patients with narrower or more compliant upper airways.
Often, they are mixed, having an initial central component
followed by an obstructive component. The obstructive apnea
is relieved either by stiffening of the airway walls via contrac-
tion of the upper airway muscles by low PO2 or high PCO2 or
by awakening as a result of discomfort caused by increased
respiratory efforts or the high PCO2 and/or low oxygen. Be-
cause of the muscles of the upper airway like the muscles of the
chest wall respond to hypercapnia and hypoxia, their control
can potentially become unstable. However, because the upper
airway muscles can have different CO2 thresholds and can
respond differently to hypercapnia and hypoxia than chest wall
muscles, the oscillatory pattern of the two sets of muscles pro-
duced by the instability may not coincide; therefore, central, ob-
structive, or mixed types of sleep apnea may occur.
Arousal occurring as a result of increasing hypoxia and hy-
percapnia increases upper airway muscle activity and allows
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Causes of Cheyne–Stokes Respiration
Fig. 6. (A) The effect of the speed of falling to sleep. A rapid transi-
tion to sleep can produce apneas and oscillatory behavior compared
to a slower transition. The heavy line shows the response of a 5-
minute transition. Referring to Figure 3, if awake equilibrium is at the
intersection of the metabolic hyperbola and the “very alert” control-
ler is characteristic, a sudden transition to “sleep” leaves the system
in apnea until the body chemistry “catches up” with the new equilib-
rium point. (B) The effect of circulatory time on transition to sleep.
For the same 5-minute transition to sleep, increased circulation time
resulted in more persistent and greater oscillations in ventilation.
sudden increases in breathing. Recurrent apneas are produced
by an interaction of the arousal–asleep mechanisms with the
control system for ventilation and the effects of fluctuating
levels of carbon dioxide and oxygen on the upper airway and
chest wall muscles. Although recurrent sleep apneas may pro-
duce a classic Cheyne–Stokes pattern of breathing, the apneas
are often more irregular in occurrence, and the breathing is
more ragged (33,34).
Because obstructive apneas during sleep can trigger insta-
bilities in respiratory control, nasal CPAP to maintain upper
airway patency not only can prevent apneas resulting from
airway obstruction but can also reduce the number of central
apneas occurring during sleep and has been proposed as a
treatment for CSR.
More recently, atrial overdrive pacing and cardiac resyn-
chronization therapy have been used in selected patients to
treat CSR and other forms of recurrent apneas during sleep.
Even without ventilatory support, they have been beneficial,
presumably by improving cardiovascular function (50).
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277
Oscillation in Other Systems As a Cause
of Periodic Breathing: Interaction of the
Respiratory Controller With Other
Control Systems
Besides respiration, other physiological systems oscillate in
typical patients with CSR (6). This arises from the many link-
ages between breathing and other physiological systems
allowing instability in one system to be transmitted to another.
Similarly, fluctuations in other systems and interactions be-
tween other systems and the respiratory control system can
gives rise to CSR and Cheyne–Stokes look-alikes.
For example, the system that regulates blood pressure in
animals may oscillate because it has become unstable, produc-
ing cyclic changes in both systolic and diastolic blood pres-
sure, which are sometimes termed “Traube-Hering-Mayer
Waves.” These oscillations in blood pressure can give rise to
oscillations in breathing. However, the blood pressure waves
are primary, as shown by their persistence even after respira-
tion is regularized by artificial ventilation. On the other hand,
the oscillations in blood pressure in most patients with CSR
disappear when breathing is regularized by mechanical
ventilation.
Recurrent Apneas Arising
From the Respiratory Pattern Generator
For many years, it was accepted that a neuronal network
whose units were linked by inhibitory and excitatory synapses
produced the breathing cycle (7). It has been believed that
extensive disease of the hindbrain, produced for example by
infection or vascular disease, can produce sufficient damage to
the pattern generator so that a disorganized type of breathing
with apneas occurs that may be similar in appearance to CSR.
The rhythm produced by the pattern generator depends on
synaptic strengths and membrane potential. The pattern gen-
erator is believed to be located in the pre-Boetzinger complex
in the rostral ventrolateral medulla. Recently, in the same loca-
tion, pacemaker cells have been discovered whose activity
appears to depend on currents triggered by transmembrane
fluxes of sodium and calcium. These pacemaker cells may be
more important in driving the respiratory rhythm in the
neonatal than in the mature medulla. Nonetheless, whether a
network or pacemakers drive the rhythm depends on the pres-
ence of excitatory stimuli. This usually requires some mini-
mum level of carbon dioxide during sleep, although other
stimuli seem to be sufficient in the fully awake state. At low
levels of this drive, this rhythm is particularly susceptible to
disturbances from other parts of the body or the environment.
This may account for the recurrent apneas and irregular breath-
ing observed in premature infants and during REM sleep.
Future Directions
There is room for much additional research. It is clear that
states of arousal play an important role in the generation of
CSR. We do not yet have a simple quantitative way of assess-
ing arousal. We have only fragmentary information on the
anatomy, physiology, and biochemistry of arousal. Undoubt-
edly, newer techniques of brain imaging and methods of as-
sessing brain function in situ will be valuable in obtaining the
necessary information.
♦ Volume 3, 2005
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On the practical side, exploration of new techniques of
mathematical analysis that would allow simpler models re-
quiring less data to be used to accurately forecast the occur-
rence of CSR is an important area for future research.
References
1. Lyons HA, Burno F, Stone RW. Pulmonary complicance in pa-
tients with periodic breathing. Circulation 1958;17:1056–1061.
2. Cherniack NS. Oxygen sensing; applications in humans. J Appl
Physiol 2004;96:352–358.
3. Cherniack NS, Longobardo GS. Cheyne-Stokes breathing. An
instability in physiologic control. N Engl J Med 1973;288:
952–957.
4. Khoo MC, Gottschalk A, Pack AI. Sleep-induced periodic breath-
ing and apnea: a theoretical study. J Appl Physiol 1991;70:
2014–2024.
5. Longobardo G, Evangelisti CJ, Cherniack NS. Effects of neural
drives on breathing in the awake state in humans. Respir Physiol
2002;129:317–333.
6. McNaughton MT. Pathophysiology and treatment of Cheyne-
Stokes respiration. Thorax 1998;53:514–518.
7. Feldman JL, Mitchell GS, Nattie EE. Breathing: rhythmicity, plas-
ticity, chemosensitivity. Annu Rev Neurosci 2003;26:239–266.
8. Dempsey JA, Skatrud JB. A sleep-induced apneic threshold and
its consequences. Am Rev Respir Dis 1986;133:1163–1170.
9. Younes M, Ostrowski M, Thompson W, Leslie C, Shewchuk W.
Chemical control stability in patients with obstructive sleep
apnea. Am J Respir Crit Care Med 2001;163:1181–1190.
10. Heywood P, Murphy K, Corfield DR, Morrell MJ, Howard RS,
Guz A. Control of breathing in man; insights from the ‘locked-in’
syndrome. Respir Physiol 1996;106:13–20.
11. Crowell JW, Guyton AC, Moore JW. Basic oscillating mechanism
of Cheyne-Stokes breathing. Am J Physiol 1956;187:395–398.
12. Cherniack NS, Longobardo GS, Levine OR, Mellins R, Fishman
AP. Periodic breathing in dogs. J Appl Physiol 1966;21:
1847–1854.
13. Cherniack NS, von Euler C, Homma I, Kao FF. Experimentally
induced Cheyne-Stokes breathing. Respir Physiol 1979;37:
185–200.
14. Chapman KR, Bruce EN, Gothe B, Cherniack NS. Possible mech-
anisms of periodic breathing during sleep. J Appl Physiol
1988c;64:1000–1008.
15. Warner G, Skatrud JB, Dempsey JA. Effect of hypoxia-induced
periodic breathing on upper airway obstruction during sleep.
J Appl Physiol 1987;62:2201–2211.
16. Khoo MC. Determinants of ventilatory instability and variability.
Respir Physiol 2000;122:167–182.
17. Carley DW, Shannon DC. A minimal mathematical model of
human periodic breathing. J Appl Physiol 1988;65:1400–1409.
18. Longobardo GS, Cherniack NS, Fishman AP. Cheyne-Stokes
breathing produced by a model of the human respiratory system.
J Appl Physiol 1966;21:1839–1846.
19. Khoo MC, Kronauer RE, Strohl KP, Slutsky AS. Factors inducing
periodic breathing in humans: a general model. J Appl Physiol
1982;53:644–659.
20. Longobardo GS, Evangelista CJ, Cherniack NS, Longobardo, GS,
Evangelisti CJ, Cherniack NS. Effect of controller dynamics on
simulations of irregular and periodic breathing. In: Pequignot J-M
Gonzalez C, Nurse CA, Prabhakar N, and Dalmaz Y, eds.
Chemoreception: From Cellular Signaling to Functional Plasticity.
New York: Kluwer Academic/Plenum Press, 2003, pp. 385–400.
21. Cherniack NS. Apnea and periodic breathing during sleep. N
Engl J Med 1999;341:985–987.
22. Hall MJ, Xie A, Rutherford R, Ando S, Floras JS, Bradley TD.
Cycle length of periodic breathing in patients with and without
heart failure. Am J Respir Crit Care Med 1996;154:376–381.
23. Hermann DM, Bassetti CL. Sleep apnea and other sleep-wake
disorders in stroke. Curr Treat Options Neurol 2003;5:241–249.
Neurocritical Care
Cherniack et al.
24. Hudgel DW, Devadatta P, Quadri M, Sioson ER, Hamilton H.
Mechanism of sleep-induced periodic breathing in convalescing
stroke patients and healthy elderly subjects. Chest 1993;104:
1503–1510.
25. Ahmed M, Serrette C, Kryger MH, Anthonisen NR. Ventilatory
instability in patients with congestive heart failure and nocturnal
Cheyne-Stokes breathing. Sleep 1994;17:527–534.
26. Mortara A, Sleight P, Pinna GD, et al. Association between
hemodynamic impairment and Cheyne-Stokes respiration and
periodic breathing in chronic stable congestive heart failure sec-
ondary to ischemic or idiopathic dilated cardiomyopathy. Am J
Cardiol 1999;84:900–904.
27. Poulin MJ, Robbins PA. Influence of cerebral blood flow on the
ventilatory response to hypoxia in humans. Exp Physiol 1998;
83:95–106.
28. Rubin AE, Gottlieb SH, Gold AR, Schwartz AR, Smith PL. Elimi-
nation of central sleep apnoea by mitral valvuloplasty: the role of
feedback delay in periodic breathing. Thorax 2004;59:174–176.
29. Tkacova R, Niroumand M, Lorenzi-Filho G, Bradley TD. Over-
night shift from obstructive to central apneas in patients with
heart failure: role of PCO2 and circulatory delay. Circulation
2001;103:238–243.
30. Blackshear JL, Kaplan J, Thompson RC, Safford RE, Atkinson EJ.
Nocturnal dyspnea and atrial fibrillation predict Cheyne-Stokes
respirations in patients with congestive heart failure. Arch Intern
Med 1995;155:1297–1302.
31. Onal E, Burrows DL, Hart RH, Lopata M. Induction of periodic
breathing during sleep causes upper airway obstruction in
humans. J Appl Physiol 1986;61:1438–1443.
32. Xie A, Rutherford R, Phillipson EA, Slutsky AS, Bradley TD.
Hypocapnia and increased ventilatory responsiveness in patients
with idiopathic central sleep apnea. Am J Respir Crit Care Med
1995;152:1950–1955.
33. Xie A, Wong B, Phillipson EA, Slutsky AS, Bradley TD. Interac-
tion of hyperventilation and arousal in the pathogenesis of idio-
pathic central sleep apnea. Am J Respir Crit Care Med
1994;150:489–495.
34. Longobardo GS, Gothe B, Goldman MD, Cherniack NS. Sleep
apnea considered as a control system instability. Respir Physiol
1982a;50:311–333.
35. Javaheri S. Treatment of central sleep apnea in heart failure.
Sleep 2000;23 (Suppl 4):S224–S227.
36. Hanly PJ, Millar TW, Steljes DG, Baert R, Frais MA, Kryger MH.
The effect of oxygen on respiration and sleep in patients with
congestive heart failure. Ann Intern Med 1989;111:777–782.
37. Ingbir M, Freimark D, Motro M, Adler Y. The incidence, patho-
physiology, treatment and prognosis of Cheyne-Stokes breathing
disorder in patients with congestive heart failure. Herz 2002;
27:107–112.
38. Javaheri S, Ahmed M, Parker TJ, Brown CR. Effects of nasal O2
on sleep-related disordered breathing in ambulatory patients
with stable heart failure. Sleep 1999;22:1101–1106.
39. Ponikowski P, Anker SD, Chua T, et al. Oscillatory breathing
patterns during wakefulness in patients with chronic heart fail-
ure: clinical implications and role of augmented peripheral che-
mosensitivity. Circulation 1999;100:2418–2424.
40. Ribeiro JP, Knutzen A, Rocco MB, Hartley LH, Colucci WS.
Periodic breathing during exercise in severe heart failure. Rever-
sal with milrinone or cardiac transplantation. Chest 1987;
92:555,556.
41. Arzt M, Schulz M, Wensel R, et al. Nocturnal continuous positive
airway pressure improves ventilatory efficiency during exercise
in patients with chronic heart failure. Chest 2005;127:794–802.
42. Woo MA, Macey PM, Fonarow GC, Hamilton RM. Regional brain
matter loss in heart failure. J Appl Physiol 2003;95:677–684.
43. Martinez Garcia MA, Galiano BR, Cabero SL, Soler Cataluna JJ,
Escamilla T, Roman SP. [Prevalence of sleep-disordered breath-
ing in patients with acute ischemic stroke: influence of onset time
of stroke]. Arch Bronconeumol 2004;40:196–202.
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Causes of Cheyne–Stokes Respiration
44. Parra O, Arboix A, Bechich S, et al. Time course of sleep-related
breathing disorders in first-ever stroke or transient ischemic
attack. Am J Respir Crit Care Med 2000;161:375–380.
45. Turkington PM, Elliot MW. Sleep disordered breathing following
stroke. Monaldi Arch Chest Dis 2004;61:157–161.
46. Yaggi H, Mohsenin V. Obstructive sleep apnea and stroke. Lancet
Neurol 2004;3:333–342.
47. Franklin KA. Cerebral hemodynamics in obstructive sleep
apnea and cheyne-stokes respiration. Sleep Med Rev 2002;6:
429–441.
Neurocritical Care
279
48. Sandberg O, Franklin KA, Bucht G, Eriksson S, Gustafson Y.
Nasal continuous positive pressure breathing in stroke patients
with sleep apnoea:a randomized treatment study. Eur Respir J
2001;18:630–634.
49. Meza S, Mendez M, Ostrowski M, Younes M. Susceptibility to
periodic breathing with assisted ventilation during sleep in nor-
mal subjects. J Appl Physiol 1998;85:1929–1940.
50. Kato I, Shiomi T, Sasanabe R, et al. Effects of physiological cardiac
pacing on sleep-disordered breathing in patients with chronic
bradydysrhythmias. Psychiatry Clin Neurosci 2001;55:257,258.
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