Central Sleep Apnea: S. Javaheri and J.A. Dempsey

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JWBT335-c110057 JWBT335/Comprehensive Physiology October 20, 2012 8:10 Printer Name: Yet to Come
Central Sleep Apnea

S. Javaheri*1,2 and J.A. Dempsey3,4
ABSTRACT
Neurophysiologically, central apnea is due to a temporary failure in the pontomedullary pace-
maker generating breathing rhythm. As a polysomnographic finding, central apneas occur in
many pathophysiological conditions. Depending on the cause or mechanism, central apneas
may not be clinically significant, for example, those that occur normally at sleep onset. In contrast,
central apneas occur in a number of disorders and result in pathophysiological consequences.
Central apneas occur commonly in high-altitude sojourn, disrupt sleep, and cause desaturation.
Central sleep apnea also occurs in number of disorders across all age groups and both genders.
Common causes of central sleep apnea in adults are congestive heart failure and chronic use of
opioids to treat pain. Under such circumstances, diagnosis and treatment of central sleep apnea
may improve quality of life, morbidity, and perhaps mortality. The mechanisms of central sleep
apnea have been best studied in congestive heart failure and hypoxic conditions when there is in-
creased CO2 sensitivity below eupnea resulting in lowering eupneic PCO2 below apneic threshold
causing cessation of breathing until the PCO2 rises above the apneic threshold when breathing
resumes. In many other disorders, the mechanism of central sleep apnea (CSA) remains to be
investigated.
C 2013 American Physiological Society. Compr Physiol 3:141-163, 2013.
Introduction structive apnea. Most difficult, however, is the distinction be-

tween obstructive versus central hypopneas. This distinction
Neurophysiologically, central apnea is due to a temporary is critical to determine if the sleep-related breathing disor-
failure in the pontomedullary pacemaker generating breath- der is predominantly obstructive or “central” in nature as the
ing rhythm. Therefore, there is no brainstem inspiratory neu- primary disorders associated with these two different forms
ral output and the nerves innervating all inspiratory thoracic of sleep apnea, the targeted therapeutic options and response
pump muscles are silent. This results in the loss of inspiratory to therapy could be potentially different. Simplistically, the
ventilatory effort, polygraphically characterized by the ab- best description of a central hypopnea, to be polygraphically
sence of naso-oral airflow and thoracoabdominal excursions distinguished from an obstructive hypopnea, is a proportional
(Fig. 1). Arbitrarily, absence of naso-oral airflow should be diminution in both naso-oral airflow and thoracoabdominal
10 s or more to be considered an apnea. excursions. However, the neurophysiology of central breath-
In contrast to central apnea, in obstructive apnea, the ing disorders is complex. In this regards, like in obstructive
rhythmic activity of inspiratory thoracic pump muscles sleep disordered breathing events, upper airway narrowing,
remains uninterrupted and out of proportion to diminished and complete upper airway occlusion may also occur in cen-
activity of the dilator muscles of the oropharynx. The absence tral disordered breathing events. It is well known that the drive
of airflow is due to upper airway occlusion secondary to to muscles of the upper airway decreases considerably at the
inward collapse of the relaxed dilator muscles of the orophar- nadir of ventilation, predisposing the upper airway to collapse
ynx, which cannot compensate for the airway resistance (101, 102) especially in those subjects with already anatomi-
and the negative intra-airway pressure during inspiration. cally compromised airways lumens. In a study (53) of patients
However, it is noted that upper airway may narrow and close with systolic heart failure and CSA in whom an esophageal
also at end expiration (i.e., in the absence of any inspiratory balloon was placed, multiple obstructive events at the end of
effort) (4, 161, 189). CSAs (defined as mixed apneas) were observed in some of
Polygraphically, an obstructive apnea is characterized by the patients. These results are consistent with endoscopicly
the absence of naso-oral airflow in spite of continual thora-
coabdominal excursions. Similarly, in obstructive hypopnea, * Correspondence to [email protected]
the naso-oral airflow decreases because of out of proportion 1 Universityof Cincinnati College of Medicine, Cincinnati, Ohio
2 Sleepcare Diagnostics, Cincinnati, Ohio
diminution in pontomedullary neural output to upper airway
3 Department of Population Health Sciences, University of
dilator muscles relative to thoracic pump muscles. Vibratory
Wisconsin-Madison, Madison, Wisconsin
snoring is present and airflow limitation may be observed on 4 John Rankin Laboratory of Pulmonary Medicine, University of
the pressure probe tracing of the naso-oral airflow. Wisconsin-Madison, Madison, Wisconsin
In the absence of esophageal pressure measurements (a Published online, January 2013 (comprehensivephysiology.com)
surrogate of pleural pressure), at times, though not commonly, DOI: 10.1002/cphy.c110057
it becomes difficult to distinguish a central apnea from an ob- Copyright
C American Physiological Society
Volume 3, January 2013 141

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Central Sleep Apnea Comprehensive Physiology
EOG
EOG
CHIN EMG
EEG C3A2
EEG O1A2
EKG
50 mV
CO2
RC + ABD
RC
ABD
5.0 s
PES (CmH2O)
20
10
0
–10
–20
95
%SaO2 85
75
65
Figure 1 A 30-s epoch of a polysomnogram of a patient with systolic heart failure showing a central apnea in N2 nonrapid eye movement
sleep. Note the gradual decrease in PES, ABD, RC, and RC + ABD followed by a gradual symmetric increase in these tracings out of central apnea
sandwiched between the thoracoabdominal excursions. During central apnea, PES remains constant indicating lack of any activity of thoracic
pump muscles. Desaturation occurs later in the epoch because of the long circulation time. Note the arousal at the peak of hyperventilation.
Also, note relatively large excursions in the PES at the time of hyperventilation. The latter occurs because of the stiff lung. From top to bottom:
EOG, electrooculogram; EEG, electroencephalogram; EKG, electrocardiogram; CO2 , naso-oral CO2 tracing representing airflow; RC, ribcage;
ABD, abdominal wall movement measured by respitrace belts; RC + ABD, respitrace sum tracing; PES, esophageal pressure; SaO2 , arterial
oxyhemoglobin saturation.
observed upper airway narrowing and collapse during central significant threshold of central disordered breathing events is
apneas (4, 82). We therefore, consider upper airway narrow- compounded by lack of inclusion of the number of hypop-
ing as part of neurophysiology of central disordered breathing neas in the index. This is in sharp contrast to the use of both
events. We also note that reduced lung volumes exacerbated obstructive apneas and hypopneas used to define an abnor-
by recumbency during sleep are also susceptible to airway mal threshold (an obstructive apnea hypopnea index ≥5 per
narrowing and closure during central apneas because of re- hour is considered abnormal). As noted earlier, it is difficult
duced magnitude of caudal traction of chest wall musculature to accurately distinguish central hypopneas from obstructive
on upper airway patency (53). hypopneas; whereas in garden variety obstructive sleep ap-
nea, virtually all hypopneas are considered to be obstructive,
in certain disorders such as heart failure and opioid-associated
sleep apnea, both central and obstructive hypopneas (mixed
Central Sleep Apnea as a Disorder pattern of breathing) are present making accurate classifica-
CSA is a polysomnographic finding. A central apnea index tion difficult.
of 5 or more per hour of sleep is considered abnormal (118).
However, the minimum number of CSAs that need to be
present to cause a distinct disorder or syndrome (a condi- Mechanisms of Central Sleep Apnea
tion associated with consequences, for example, insomnia,
excessive daytime sleepiness, impaired quality of life, mor- From the mechanistic point of view, an important concept
bidity, or mortality) is not known. This issue of a clinically which could explain development of instability of breathing
142 Volume 3, January 2013

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Comprehensive Physiology Central Sleep Apnea
and central apnea during sleep has to do with unmasking While the hypocapnic-induced apnea threshold is highly
of the apneic threshold and the CO2 chemosensitivity both sensitive and reproducible in NREM sleep, there is no appar-
above and below eupnea. This will be discussed in detail ent threshold in phasic REM sleep even with marked reduc-
below. tions in Pet CO2 produced by either mechanical ventilation or
by ventilatory overshoots in response to experimental airway
occlusion (237). The central apneas and the periodic breath-
Unmasking a sensitive apneic threshold ing accompanying heart failure or high-altitude hypoxia are
Central apneas and instabilities in humans occur primarily also less commonly present in REM sleep (9, 89). Perhaps,
in non-rapid random eye movement (NREM) sleep because analogous to the wakeful state, the erratic, sporadic increases
of the critical dependence of the ventilatory control system in central inspiratory neural drive during REM (172) override
on chemical stimuli-principally PaCO2 . Thus, when normal hypocapnic inhibition.
subjects are mechanically ventilated in NREM sleep, Although hypocapnia is required during the ventilatory
transiently induced increases in tidal volume and small overshoot to cause subsequent apnea, lung stretch (238),
reductions in PaCO2 only to waking levels (−3 to −5 mmHg) and/or increases in systemic blood pressure and barorecep-
are sufficient to induce central apnea (92, 155, 204, 219). A tor stimulation (192,236) accompanying the ventilatory over-
similar sensitive hypocapnic-induced apneic threshold can be shoot may also contribute to the ventilatory depression fol-
demonstrated in sleeping, tracheostomized obstructive sleep lowing the overshoot. Several reflex effects of airway negative
apnea (OSA) patients (104) or dogs (31) by causing brief pressure sensitive mechanoreceptors on ventilatory control
airway occlusions which in turn cause chemoreceptor (and have also been demonstrated in the sleeping canine with an
often arousal) driven transient ventilatory overshoots upon isolated upper airway. These include: (i) the inhibitory effects
termination of the occlusion with subsequent central apneas of flow through the upper airway, or lung inflation on the rate
(upon resumption of sleep). So, apnea occurs whether the of rise of diaphragmatic electromyogram (EMG) activity and
transient hyperventilation and hypocapnia are produced via (ii) the apnea caused by either negative pressure pulses or low-
“active” or “passive” means. pressure high-frequency pressure oscillations (akin to human
Normally, in wakefulness, a transient increase in central snoring) applied to the upper airway during early expiration
respiratory motor output and hyperventilation are not fol- (55, 91, 180).
lowed by apneas, because a centrally mediated short-term
potentiation of central respiratory motor output lingers fol-
lowing cessation of the ventilatory stimulus and ventilation Sites of chemoreception causing apnea
returns gradually to its control eupneic levels (3,56). However, At what chemoreceptor site is transient hypocapnia acting
in sleep this stabilizing influence is apparently overridden by predominantly in causing central apnea and periodic breath-
a transient reduction in the CO2 drive to breathe, that is, a ing? Carotid body denervation studies in the sleeping animal
sensitive apneic threshold is unmasked. Further evidence for showed that neither apnea nor periodic breathing could be
a pivotal role for hypocapnia is the consistent evidence that elicited even when substantial levels of transient hypocapnia
the prevention of central apnea and periodic breathing during were produced via mechanical ventilation (17,164). Similarly,
sleep in heart failure (239) or in hypoxic environments (9) is using an isolated perfused carotid body preparation in the neu-
readily achieved by the addition of even very small amounts rally intact sleeping canine (205, 207) central chemoreceptor
of inspired PCO2 , that is, just sufficient to prevent the occur- hypocapnia (alone) was shown to produce little prolongation
rence of transient hypocapnia, regardless of the magnitude of of expiratory time (TE) despite marked reductions in PaCO2
any ventilatory overshoot. (−8 to −15 mmHg), whereas transient hypocapnia of only
Of course, to reach the apneic threshold, we need a source 3 to 5 mmHg produced apnea and periodic breathing when
of transient ventilatory overshoots. Transient arousals from both chemoreceptors were able to sense the hypocapnia in the
sleep provide a common source of this transient extradrive intact animal.
to breathe and the accompanying reductions in upper airway At first glance, these data are strongly supportive
resistance permit a greater hyperventilatory manifestation of of peripheral over central chemoreceptors in eliciting
this increased drive (100, 244, 250). Arousals are effective hypocapnic-induced apneas. On the other hand, we also
in causing ventilatory overshoots, especially when combined know that perfusion of the isolated carotid chemoreceptor
with increasing chemoreceptor drives from the preceding ven- alone with severely hypocapnic (or hyperoxic) blood will
tilatory undershoot (31, 104). Furthermore, the PaCO2 re- reduce tidal volume (VT) but also not cause apnea (208).
quired to terminate apnea is estimated to be 1 to 4 mmHg Accordingly, while the CB denervation findings show that
higher than the threshold PaCO2 needed to initiate the apnea, the CBs are required for apnea, the isolated perfusion studies
reflecting a so-called control system “inertia” which delays show that neither the peripheral nor central chemoreceptors,
the resumption of breathing rhythm (141, 191). The resul- by themselves, can account for hypocapnic-induced apnea.
tant apnea prolongation presents an enhanced chemoreceptor These apparent contradictions point to a new perspec-
stimulus to ventilatory overshoot and to cortical arousal at tive put forward primarily by Guyenet et al. (85) which
apnea termination. emphasizes the potential importance of interdependence

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between peripheral and central chemoreceptors in ventilatory and central chemoreceptors to ventilatory control. Further,
control. this interdependence questions the validity of conventional
Neuroanatomical evidence in the rodent model shows that means of assessing specific chemoreceptor sensitivities via
paired-like homeobox 2B gene (PHOX2B) gene expression the use of such tests as iso-capnic hypoxia or hyperoxic hy-
delineates an unbroken chain of neurons in a circuit which percarbia. What remains is further testing of the nature of this
includes carotid bodies and their afferent projections (42), interdependence and the effects of varying types of carotid
chemoreceptor projections of the nucleus tractus solitarius chemoreceptor stimulation and their combination on central
to the ventral lateral medulla (216) and to CO2 -sensitive CO2 responsiveness.
chemoreceptor neurons in the retrotrapezoid nucleus (RTN)
(211). Functionally, an important interdependence between
the various chemo- and mechanoreceptor afferents in the res- Variations in susceptibility to central apnea
piratory control system has also been demonstrated in reduced and ventilatory instability
preparations by: (i) the marked effect of systemic hypoxia The occurrence of central apneas with repeated cyclic periods
increasing the activity of central CO2 -sensitive neurons in of over- and under-ventilation during sleep vary markedly de-
the RTN—an effect which was subsequently eliminated via pending upon the gains(s) of the respiratory control system
carotid body denervation (211,216); (ii) the powerful hypoad- and the stability of the sleeping state. The tendency toward in-
ditive effects of varying levels of PCO2 in the isolated per- stability depends upon the respiratory control system’s “loop
fused medulla on the ventilatory response to specific carotid gain,” an engineering term which defines the “gain” of the
body stimulation in the decerebrate rat (45); and (iii) the negative feedback loop and regulates ventilation in response
effect of vagal inhibition via lung stretch on carotid chemore- to a ventilatory disturbance (137). For example (see Fig. 2), if
ceptor (5) and medullary chemoreceptor responsiveness (85). the magnitude of the increase in ventilation is greater than or
Recently, an unanesthetized, neurally intact canine prepara- equal to the magnitude of the preceding apnea or hypopnea,
tion with isolated, perfused carotid chemoreceptor was used that is, a high loop gain, then the system is highly unstable
to show that inhibition of the isolated carotid chemorecep- and will fluctuate between under- and overventilation (231).
tor (via hyperoxic hypocapnia) markedly reduced the gain of The loop gain of the negative feedback system control-
the central CO2 response, whereas stimulation of the isolated ling breathing has three major components. The controller
carotid chemoreceptor (via normocapnic hypoxia) increased
the slope of the central CO2 response (13). This hyperaddi-
tive, interactive effect of peripheral chemoreceptor sensory
(A)
input on central chemoreceptor gain is qualitatively opposite 8
Ventilation (L/min)
to the hypoadditive effects previously proposed in reduced

preparations (44, 45). b
6
Does this hyperadditive interdependence of central
chemosensitivity on peripheral chemoreceptor input apply to c
humans? In the intact human, attempts to study this interde- a
4
pendence require a temporal separation of peripheral from (B) 0 30 60 90 120 150
central chemoresponses to inhaled CO2 and most of these 8
Ventilation (L/min)
studies claim purely additive effects of the two inputs on the

ventilatory response to CO2 (38). However, if indeed, periph-
eral input does influence central chemoreceptor sensitivity 6
then this approach in the intact human does not achieve “sep-
aration” of the chemoreceptors and cannot be used to deter-
4
mine the nature of their interdependence. On the other hand, 0 30 60 90 120 150
a few studies have achieved true separation through testing Time (s)
of “early” and “late” ventilatory responses to CO2 before and
Figure 2 Loop gain (LG) depicts the ratio of ventilatory response
after bilateral carotid body denervation in humans. These data to disturbance ratio. (A) Example of a LG of 0.72. The ventilatory
in humans showed a marked depression in the late portion of control system is disturbed with a transient reduction in ventilation (a).
the response to CO2 following carotid chemoreceptor dener- This produces a response (b) in the opposite direction that is 72% as
large as the disturbance. The next response (c) will also be 72% as
vation, thereby providing evidence in the human for a strong large as (b), etc. Thus, a LG of 0.72 produces transient fluctuations
hyperadditive influence of peripheral chemoreceptor input on in ventilation, but ventilation eventually returns to baseline. (B) A LG
central CO2 responsiveness (41, 63). ≥ 1 will produce a response that is equal or greater in magnitude to
the disturbance. Ventilation, therefore, oscillates without returning to
So, these recent neuroanatomical and physiologic find- baseline. The system in B is highly unstable. The closer LG is to zero,
ings point strongly to an interdependence effect of central the smaller the fluctuations in ventilation, and thus the more stable
chemoreceptor gain on peripheral chemoreceptor input. This the system (Fig. 7 below, illustrates how the magnitude of ventilatory
overshoots and undershoots, that is, stability, are determined by two
concept represents a radical change in traditional concepts key components of loop gain, namely, controller and plant gains).
of only interdependent, additive contributions of peripheral Reproduced, with permission, from Wellman et al. (231).

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gain (ventilatory response to PO2 , and PCO2, above and below 12 Effect of hyper hypoventilation Δ plant gain)
eupnea mediated by the carotid body and the central chemore-
10
ceptors), the plant gain (changes in pulmonary capillary blood
PO2 and PCO2 in response to changes in ventilation) and the 8
VA (L/min)
mixing gain (the effective circulation time determining the (VCO2~250 mL/s)
speed by which changes in pulmonary capillary blood PCO2 6
and PO2 from the plant is detected by the controllers) which 4

serves as the feedback between the plant and the controller
Plant gain
(30, 134, 137). These three gains are briefly reviewed next. 2 Plant gain
First, we illustrate the effects of changing the controller
[Apnea] 0
and the plant gains on CO2 responsiveness above and below 20 25 30 35 40 45 50 55
eupnea in Figure 2, which in turn will determine the ten- PACO2 (Torr)
dency of ventilatory drive to overshoot in response to a rising
12 Effect of changing the CO2 response slope (Δ controller gain)
chemoreceptor stimulus or to be overly depressed in response
to the ensuing hypocapnia (47). For example, Figure 3A illus- 10
trates the effect of changing the background drive to breathe Hypoxia CHF Normoxia
which will displace the eupneic PaCO2 along the isometabolic 8 Hyperoxia
VA (L/min)
line defining the hyperbolic relationship of PaCO2 to alveolar 6
ventilation. This hyperventilation, per se, protects against ap-
nea and ventilatory instability by requiring a larger additional 4
transient hyperventilation and hypocapnia to reach the apneic
2
threshold (i.e., decreased plant gain); whereas a reduced drive
and hypoventilation make one highly susceptible to apnea, [Apnea] 0
requiring only very small further transient ventilatory over- 20 25 30 35 40 45 50 55
shoots and reduction in PaCO2 (increased plant gain) (163) to PACO2 (Torr)
cross the apneic threshold. The other means of changing the

Figure 3 Diagrammatic representation of the steady-state relation-
magnitude of the CO2 reserve below eupnea is to change the ship between alveolar ventilation V̇A and alveolar PCO2 (PaCO2 )
slope of the change in ventilation above and below eupnea, at a fixed resting CO2 production (of 250 mL/min); PaCO2 =
respectively, in response to induced hyper or hypocapnia (see V̇CO2 /V̇A × K. The schematic figure shows how changing plant gain
(A, top) or controller gain (B, bottom) will influence the “CO2 reserve”
Fig. 3B, bottom). Thus, the magnitude of loop gain and of or PaCO2 between eupnea and apnea. (A) Changing the back-
the CO2 reserve, and therefore, the propensity for ventilatory ground drive to breathe without changing the slope of the V̇A versus
instability in sleep is determined by the net effects of any PaCO2 relationship above or below eupnea. For example, back-
ground hyperventilation (via metabolic acidosis or specific CB stimula-
changes or abnormalities in controller gain versus plant gain. tion with Almitrine) raises V̇A and lowers PACO2 along the isometabolic
These effects of changing controller and plant gain on hyperbola. This means that a greater transient increase in V V̇A and
ventilatory stability were originally proposed by mathemat- reduction in PACO2 is required to reach the apneic threshold than it
would be under control, normocapnic conditions. The reverse is true for
ical modelers (134,135,136). Experimental manipulation of conditions that reduce the background drive to breathe and cause hy-
the gains in healthy sleeping animals and humans has verified poventilation [for example, metabolic alkalosis (163)]. (B) At any given
the importance of these changing gains as critical determi- level of background PACO2 , changing the slope (or responsiveness) of
the V̇A − PACO2 relationship below eupnea would alter the CO2
nants of the apneic threshold and CO2 reserve and of breath- reserve or the amount of reduction in PACO2 required to cause apnea.
ing stability (see Fig. 3) (47, 163). For example, if plant gain Changing the slope of the ventilatory response to CO2 above eupnea
is increased via decreasing the drive to breathe and increasing would alter the susceptibility for transient ventilatory overshoots. Often
both plant and controller gains may change together, that is, note the
PaCO2 with NaHCO3 infusion then the CO2 reserve is re- reduced plant gains and increased controller gain, with hypoxia or with
duced and instability promoted; conversely decreasing plant CHF patients. The increased control gain dominates and the net effect
gain by increasing the drive to breathe via the metabolic acido- is a decreased CO2 reserve and instability. See text for a discussion of
conditions that change controller and/or plant gain, and therefore, the
sis of acetazolamide or the carotid chemoreceptor stimulant. susceptibility to transient ventilatory overshoots to apnea and ventila-
Almitrine widened the CO2 reserve and stabilized breathing. tory instability in sleep. Detailed discussions of the components of loop
Acute hypoxia was more complex because it caused hyper- gain may be found in references (135; 251).
ventilation and reduced plant gain but this stabilizing influ-
ence was preempted by an increased controller gain which
enhanced the slope of the CO2 response below (and above) Finally, the third gain of the negative feedback system, the
eupnea and markedly reduced the CO2 reserve and destabi- mixing gain is the effective circulation time and is the speed
lized breathing. of the blood traveling from pulmonary capillary bed carry-
The importance of the controller gain both below and ing the information regarding changes in blood gases to the
above eupnea has also been demonstrated in patients with controllers. A long circulation time, a pathological feature of
heart failure with and without CSA showing a heightened congestive heart failure converts a negative feedback system
controller gain in the former group that will be discussed later. to a positive one.

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SaO2 that these changes contribute to increases in controller gain

75 and to the increased prevalence of sleep-induced ventilatory
instability observed in these conditions.
65
Gender and ventilatory instability

55
Pa, CO2 = 38.4 ± 0.6 mmHg Pa, CO2 = 39.5 ± 0.7 mmHg Ventilatory instability during sleep, including obstructive and
pH .= 7.426 ± 0.004 pH. = 7.419 ± 0.001 central disordered breathing is significantly higher in males
VE = 7.9 L/min VE = 12.4 L/min than in females. In regards to the latter, an epidemiological
study shows a low prevalence of CSA in women compared to
VT men (12).
This difference in ventilatory instability is well demon-
15 s strated in heart failure, the most common cause of CSA in
↑ FICO2 general population. Combining the results of several stud-
ies in systolic heart failure, 40% of the male subjects have
Figure 4 Representative tracings of SaO2 and tidal volume taken CSA, which is significantly higher than the 18% prevalence
from one subject during administration of CO2 in hypoxia nonrapid in female subjects (121). However, the prevalence of CSA in
eye movement sleep. CO2 is added at arrow during the initial night at
4300 m simulated altitude. Nitrogen was also added to the inspirate
women with systolic heart failure varies with age; the risk
(along with CO2 ) so that the average SaO2 was unchanged. Note that for CSA is increased considerably in those 60 years or older
periodic breathing was completely eliminated with an average increase when compared to those less than 60 years old (201).
of about 1 mmHg in PaCO2 . Similarly, the periodic breathing in CHF
patients is eliminated via the use of added FICO2 via rebreathing (see
The reasons for increased prevalence of CSA in post-
text). Reproduced, with permission, from Berssenbrugge et al. (9). menopausal women are not well understood, but female hor-
mones may play an important role. Progesterone is a known
respiratory stimulant; in a double blind placebo controlled
The controller gain, plant gain, and the mixing gain will study in man (125) administration of medroxyprogesterone
be discussed later in the context of congestive heart failure, acetate increased ventilation and decreased by PaCO2 sev-
periodic breathing, and CSA. eral mmHg. Progesterone, therefore, could decrease the plant
gain, similar to acetazolamide, decreasing the likelihood of
ventilatory instability during NREM sleep. In this regard, pre-
Cerebral blood flow and ventilatory instability menopausal women have a significantly lower apneic thresh-
Cerebral vascular responsiveness to CO2 is an important pro- old than men (254).
tector of brain extracellular fluid PCO2 and [H+] by means
of regulating cerebral blood flow (CBF) and the arterial to
brain PCO2 difference (193,195). For example, with CO2 re-
tention, the cerebral vessels dilate and CBF increases (∼3%
Causes of Central Sleep Apnea
CBF/mmHg PaCO2 ) thereby augmenting CO2 removal Table 1 shows the various physiological and pathological con-
from the brain and reducing the arterial to brain PCO2 differ- ditions associated with CSA (118). Because the mechanisms
ence. Thus, a normally sensitive cerebral vascular respon- underlying various disorders associated with CSA are largely
siveness to CO2 reduces the impact of arterial hypercap- unknown, the classification is in part mechanistic and in part
nia/hypocapnia on brain and, therefore, medullary chemore- based on the clinical conditions associated with CSA.
ceptor PCO2 and pH. Accordingly, any reduction in cerebral
vascular responsiveness and CBF to hypo- or hypercapnia
will mean a greater brain (and central chemoreceptor) PCO2 Physiologic central apnea
(and [H+]) for any given arterial PCO2 . The conditions causing or associated with CSA in this cate-
The highly sensitive effects of changes in cerebral vascular gory are considered normal sleep phenomena and not surpris-
responsiveness to CO2 on the control of eupneic ventilation, ingly, the frequency of occurrence of such central apneas is
the slope of the ventilatory responsiveness to CO2 , that is, normally minimal. We observe such central apneas with onset
controller gain, and the apneic threshold and CO2 reserve of sleep, after an arousal or a sigh and occasionally during
have been demonstrated experimentally during sleep: a) in phasic REM sleep.
animal models using mechanical occlusion of carotid inflow
(24, 25, 175); and b) in humans, (240, 242) through the use
Sleep-onset central apnea
of the cyclooxygenase inhibitor indomethecin to selectively
depress cerebral vascular reactivity to CO2 . Reductions in With onset of sleep (removal of wakefulness drive), the CO2 -
baseline CBF and in the cerebrovascular responsiveness to sensitive apneic threshold is exposed and a higher than awake
CO2 do occur with aging (8, 105), in severe OSA patients PaCO2 level is a prerequisite to maintain rhythmic breathing.
(52, 179) and with congestive heart failure. In turn, it is likely This is because, normally, the apneic threshold PaCO2 is close

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Table 1 Central Sleep Apnea Postarousal/postsigh central apnea

I. Physiological CSA During an arousal, which represents temporary return of
1. Sleep onset wakefulness, the prevailing sleeping PaCO2 (which is higher
than wake PaCO2 ) becomes hypercapnic for the aroused
2. Postarousal/post-sigh
brain; therefore, ventilation rises and PCO2 decreases pro-
3. Phasic REM sleep portional to CO2 chemosensitivity above eupnoea. When the
II. Hypocapnic CSA arousal is over and the sleep resumes, the prevailing aroused
1. Heart failure with low ejection fraction PCO2 is considered hypocapnic for the sleeping brain result-
2. Heart failure with normal ejection fraction ing in a central apnea. Similarly, after a sigh, even without
an arousal, if PCO2 decreases below apneic threshold, cen-
3. Idiopathic
tral apnea ensues. A neuromechanical inhibitory effect of
4. Idiopathic pulmonary arterial hypertension vagal feedback via lung stretch has also been implicated in
5. High altitude reducing inspiratory motor output, although the accompany-
6. Poststroke ing hypocapnia appears to be required to cause breath timing
changes and apnea (164, 186).
7. Chronic renal failure and patients on dialysis
III. Hypercapnic CSA*
1. Alveolar hypoventilation with normal pulmonary function Phasic REM sleep
a. Congenital central hypoventilation syndrome With onset of phasic REM sleep, there is variability in
b. Primary chronic alveolar hypoventilation syndrome breathing and blood pressure. Studies of Orem (173) in
2. Brainstem and spinal cord disorders cats indicate that the variability in breathing is associated
with pontogeniculo-occipital (PGO) waves (recorded in the
Encephalitis; tumors; infracts
activity of geniculate body) bypassing medullary respiratory
Cervical cordotomy centers, and resulting in intermittent inhibition of the
Anterior cervical spinal artery syndrome diaphragm. At times, PGO waves resulted in fractionation
Neurodegenerative disorders of diaphragmatic activity. These observations in cats are
Amyotrophic lateral sclerosis
analogous to irregular breathing in phasic REM sleep in
humans. Other recordings showed virtual suppression of
Multiple sclerosis,
diaphragmatic EMG associated with bursts of PGO waves
Chiari malformation which may be the basis for central apneas observed during
3. Muscular disorders phasic REM sleep in human.
Myotonic and Duchenne dystrophies We should emphasize, however, that both obstructive and
central apneas may be observed in association with pha-
Acid maltase deficiency
sic REM activities. We speculate that with total inhibition
Guillian-Barre syndrome of diaphragmatic activity, central apnea occurs. However,
4. Opioids when there is predominant inhibition of inspiratory drive
IV. CSA with endocrine disorders to the muscles of the upper airway, with relative preserva-
1. Acromegaly tion of diaphragmatic inspiratory activity, obstructive apneas
occur.
2. Hypothyrodism
V. CSA with obstructive sleep apnea
1. A minor component of OSA Hypocapnic-eucapnic (nonhypercapnic) CSA
2. With CPAP therapy (complex sleep apnea) These disorders are characterized by (i) an awake steady-state
3. Posttracheotomy PaCO2 which is either within the low range of or less than
VI. CSA with upper airway disorders normal value (<36 mmHg at sea level) and (ii) increased
ventilatory response above eupnea and below eupnea (when
* PCO2, however, could be normal; REM, rapid eye movement; CSA,
studied) to changes in PCO2. Hypoxic ventilatory response
central sleep apnea; OSA, obstructive sleep apnea [modified from may also be augmented.
reference (118)]. During sleep, the prevailing PCO2 may fall below the ap-
neic threshold (resulting in a central apnea), either because of
inability to increase the PCO2 or because the apneic threshold
to the level of awake PCO2 . Consequently, with sleep onset, PCO2 rises (e.g., due to hypoxemia), or a combination of the
few central apneas (sleep-onset central apneas) occur, and two. In addition, in these disorders (Table 1), the hypercapnic
along with a decrease in ventilation, PCO2 rises. When PaCO2 ventilatory response is invariably increased, both above and
is above apneic threshold rhythmic breathing is maintained. below eupnoea. The increase in ventilatory response above

P1: OTA/XYZ P2: ABC
Hunter- Cheyne-Stokes breathing in SHF
LEOG
REOG
C3A2
01A2
Chin
LEMG
ECG
*FLOW
*CHEST
*ABDO
95 97 96 93 97 97 94 96 98 95 93 95 98 97 93 97 97 94 96
SAO2 90 90 93 91 90 92 90 90 90 90 94 91 90 92
STAGE
S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2
60'' 120'' 180'' 240'' 30
Figure 5 A 10-min epoch of periodic breathing with central sleep apnea in a patient with systolic heart failure, a pattern referred to as
Hunter-Cheyne-Stokes breathing. Note the gradual reduction in various respiratory channels followed by central apnea and then a gradual rise
in thoracoabdominal excursions following the apneas. Also, note that the central apneas are virtually of the same duration. This is in contrast
to opioid-induced central apneas depicted in Figure 7.
eupnoea will increase the likelihood of developing central failure, and during hypoxemia to explain the mechanism of
apnea. This is because anytime an arousal occurs, the im- high-altitude periodic breathing.
mediate prearousal sleeping PCO2 becomes hypercapnic for
the aroused brain, and therefore, intense hyperventilation oc-
curs which could drive the prevailing PCO2 below apneic Heart failure with low ejection fraction
threshold, causing a central apnea as sleep is resumed. Fol- (systolic heart failure)
lowing central apnea, PCO2 increases until an arousal recurs. There is a distinct pattern of periodic breathing in systolic
Based on studies which caused nonchemoreceptor apnea uti- heart failure in that the breathing cycle has long crescendo-
lizing controlled, isocapnic mechanical ventilation (186) or decrescendo arms. This is the reflection of the increased mix-
laryngeal nerve stimulation on upper airway negative pres- ing gain and is due to a prolonged arterial circulation time,
sure (91, 140), it is clear that neural inspiratory effort is not a pathophysiological feature of systolic heart failure. This
reinitiated following a central apnea until a PaCO2 is reached pattern of periodic breathing is best referred to as Hunter-
which exceeds the normal eupneic PaCO2 . This so called Cheyne-Stokes breathing (Fig. 5) since John Hunter described
“inertial” after-effect means that the apnea is prolonged and it 37 years before John Cheyne’s description (103, 227).
chemoreceptor drive is intensified, thereby augmenting the Heart failure is a highly prevalent syndrome with an esti-
effects of arousal and airway opening on the post-apnea ven- mated annual incidence of half a million (144). It is estimated
tilatory overshoot. In this way, the cycle of apnea-hyperpnea that about 5 to 6 million Americans, about 2% of the popula-
is perpetuated. The increase in CO2 chemosensitivity below tion, and 10% of those above 65 years age have heart failure.
eupnoea is critical and has been best studied in systolic heart Because heart failure is highly prevalent and CSA is common

P1: OTA/XYZ P2: ABC
Prevalence of sleep apnea in systolic (n = 1250) physiology (23%). Forty eight percent had an AHI 15 or more
and diastolic heart failure (n = 244) per hour, of whom 23% had CSA. With increasing impairment
60
of diastolic dysfunction, the prevalence of SA, and CSA in
52
50 48 particular increased. Patients with CSA had lower PCO2 , but
higher left ventricular end-diastolic and pulmonary capillary
40 (wedge) pressure. The latter finding is critical to development
31 of periodic breathing and CSA; as will be discussed below,
%
30 high wedge pressure and pulmonary congestion decreases the

25
23
21 PCO2 reserve, the major mechanism underlying CSA.
20
10 Mechanisms of central sleep apnea in heart failure

Mechanisms of CSA and periodic breathing have been most
0 systematically studied in heart failure with low ejection frac-
AHI ≥ 15 CSA OSA AHI ≥ 15 OSA CSA tion. We discussed the concept of the loop gain and its com-
ponents earlier; below we will apply these concepts to heart
Figure 6 Prevalence of sleep apnea in systolic heart failure in 1250
consecutive patients gathered from combining studies from different failure. For simplicity, we make a distinction between mecha-
countries. AHI, apnea hypopnea index; CSA, central sleep apnea; OSA, nisms of central apnea in heart failure which are sleep-related
obstructive sleep apnea. Adapted, with permission, from Javaheri et al. (e.g., increased CO2 chemosensitivity below eupnoea, the
(119).
PCO2 reserve and the lack of increase in PCO2 with sleep on-
set), and the mechanisms mediating periodic breathing which
in the setting of the failing heart, heart failure is the most have to do with the pathological processes of heart failure and
common cause of CSA in general population [for review, see are not state specific (i.e., are present during both wakeful-
references (117, 119, 121)]. ness and sleep). These various mechanisms will be discussed
Multiple studies (65,116,117,119,121,127,129,139, 145, in detail in the following section.
146, 171, 201, 209, 224, 226) of consecutive ambulatory pa-
tients with stable heart failure and left ventricular systolic dys- Lack of increase in PCO2 at sleep onset in heart
function show that in average, 52% have an apnea-hypopnea failure Normally, with onset of sleep, ventilation decreases
index 15 or more per hour (107,119). The index includes both and PCO2 increases. This maintains the prevailing PCO2
central and obstructive sleep apnea, events that commonly oc- above the apneic threshold PCO2 , and rhythmic breathing oc-
cur together during sleep in a patient with heart failure. curs. However, in some patients with heart failure, the prevail-
In early though most systematic and complete studies ing awake PCO2 does not increase at sleep onset (220, 243).
(209) which involved 100 (of 114) eligible male veterans with This sets the stage for developing central apnea (163, 243).
stable, treated heart failure 49 subjects (49% of all patients) The reason for the lack of increase in PCO2 is likely due to
had moderate to severe (an apnea-hypopnea index of 15 per the lack of decrease in ventilation that normally occurs at
hour or greater as the threshold), with an average apnea hy- sleep onset. Presumably, in heart-failure patients with severe
popnea index (AHI) of 44 per hour. This index included both left ventricular diastolic dysfunction (and stiff left ventricle
central and obstructive events. Being an early study, 10% of which is the hallmark of left ventricular diastolic dysfunc-
the patients were on B-blockers; however, the results of recent tion and also invariably accompanies systolic dysfunction),
studies (146,171,226) in which 80% of the patients were on a when in supine position venous return increases, pulmonary
B-blocker are consistent with the earlier reports (209) show- capillary pressure could rise. This results in a small increase
ing a high prevalence of sleep apnea, both CSA and OSA. in respiratory rate and ventilation, preventing the normally
Combining the results of these studies (88, 220, 226, 243) and observed rise in PCO2 .
using an AHI of 15/hour of sleep as the threshold, 52% of
the 1250 consecutive patients with systolic heart failure have Why in the absence of increased CO2 chemosensi-
moderate to severe sleep apnea, 31% have CSA, and 21% tivity is low awake arterial PCO2 per se protective?
have OSA (Fig. 6). Several studies (88, 124, 165) have shown that subjects with
heart failure and low awake steady-state arterial PCO2 have a
high probability of developing CSA during sleep. These find-
Heart failure with preserved left ventricular ejection ings have been misinterpreted to mean that this low awake
fraction (isolated diastolic heart failure)
PCO2 predisposes patients to CSA. In contrast, in the absence
There is also a high prevalence of sleep apnea in heart fail- of an increase in CO2 chemosensitivity below eupnoea, low
ure with preserved ejection fraction. In a large study (11), awake eupneic PCO2 , per se, should be protective in the sense
244 consecutive patients (87 women) underwent polygraphy, that it reduces plant gain, thereby decreasing the likelihood
heart catheterization, and echocardiography. Causes of di- of developing central apnea during sleep. For example, with
astolic heart failure included systemic hypertension (44%), nonhypoxic chemoreceptor stimulation such as metabolic aci-
coronary artery disease (33%), and hypertrophic/restrictive dosis or administration of almitrine (which stimulates carotid

P1: OTA/XYZ P2: ABC
bodies), ventilation increases and PCO2 decreases, without crease the PCO2 reserve, thereby increasing the likelihood of
changing the chemosensitivity below eupnoea (163). Under developing CSA (26). We do not as yet fully understand why
such conditions, the hyperbolic nature of the alveolar venti- increasing pulmonary vascular pressures, per se, would pre-
lation versus PaCO2 relationship dictates a considerable in- cipitate an increased gain in hypercapnic/hypocapnic respon-
crease in ventilation to decrease an already low PCO2 below siveness. However, these changes are consistent with reports
the apneic threshold PCO2 . This is referred to as decreased of significant influences of lung vagal afferents on both carotid
plant gain (which is dictated by where PaCO2 resides on the chemoreceptor (5) and medullary chemoreceptors (159) re-
alveolar air equation isometabolic curve) with an increase in sponsiveness. It is emphasized that although a low awake
PCO2 making it less probable to develop CSA (see Fig. 3). PaCO2 is highly predictive of CSA, it is not a prerequisite.
In regard to aforementioned discussion, two clinical ex- Many patients with heart failure and CSA have normal awake
amples are noted. In one study (123), polysomnograms of PaCO2 (110,129). What is important is increased chemosensi-
13 hypocapnic (PaCO2 < 36 mmHg, mean = 33 mmHg) tivity above (109) and below eupnoea (243), that is, increased
patients with heart failure, mean left ventricular ejection controller gain, as it determines the proximity of the apneic
fraction of 23%, were compared with ten age, gender, and threshold to the prevailing PaCO2 (163, 243).
PaCO2 matched hypocapnic (PaCO2 < 36 mmHg, mean =
32 mmHg) patients with cirrhosis of the liver and normal
Mechanisms of periodic breathing in heart failure
ejection fraction (60%). In the former group, the mean apnea-
hypopnea index was 28 per hour and CSA accounted for most In heart failure, CSA occurs in the background of periodic
of the breathing disorders; in patients with cirrhosis, the mean breathing characterized by long crescendo-decrescendo ven-
AHI was 2 per hour and maximum CAI was 0.2 per hour. tilation arms (Figs. 1 and 5), a reflection of prolonged arterial
There were no significant differences in age, demographics, circulation time, a unique feature of heart failure. In addition
pulmonary function tests, PaO2 , PaCO2 , minute and alveolar in some heart-failure patients enhanced gain of the chemore-
ventilation, and ventilatory responses to CO2 between the two ceptors (enhanced CO2 /O2 chemosensitivity) and enhanced
groups. We concluded that in contrast to heart failure, pres- plant gain collectively increase the likelihood of periodic
ence of daytime hypocapnia does not predict central apnea in breathing (23, 27,29, 37, 87, 109, 135, 137, 156, 249).
cirrhosis. Similar conclusion, regarding PCO2 was reached in In heart failure, effective arterial circulation time referred
a study with acetazolamide. In a double blind placebo con- to as mixing gain is increased due to a combination of
trolled crossover study (115) of 12 patients with heart failure, several factors including pulmonary congestion, left atrial
the central apnea index decreased significantly with acetazo- and ventricular enlargement, and diminished stroke volume
lamide (49±28 vs. 23±21, mean±SD, P = 0.004). Apnea when present; plant gain is also increased because of a
episodes decreased in spite of the fall in waking PaCO2 , from low functional residual capacity also due to a variety of
38 to 34 mmHg, P = 0.0003. These data along with findings in reasons including pleural effusion, cardiomegaly, pulmonary
cirrhosis emphasize that it is not the absolute value of steady- congestion, or edema.
state PaCO2 that increases the likelihood of developing central Regarding controller gain, we already have discussed the
apnea. Rather, it is the difference between the prevailing eu- enhanced CO2 sensitivity below eupnea; another component
pneic PCO2 and apneic threshold PCO2 that is important. As of the controller gain is enhanced CO2 sensitivity above eup-
noted earlier, in the face of background increased stimulus to nea. In heart-failure patients with CSA, hypercapnic ventila-
breathing, there is widening of the differences between the tory response is increased (Table 2) (109) and the chemore-
prevailing PCO2 minus apneic threshold PCO2 (144). This ceptors elicit a large ventilatory response whenever the partial
widening decreases the likelihood of developing CSA. pressure of carbon dioxide rises, particularly in the face of an
arousal. The consequent intense hyperventilation, by driving
Then why in heart failure, is a low awake steady-state the PCO2 below the apneic threshold, results in central apnea.
PaCO2 highly predictive for development of central Due to central apnea, PCO2 rises and the cycles of hyperven-
sleep apnea? In systolic heart failure, the low PaCO2 has tilation and hypoventilation are maintained.
to do with the severity of the ventricular diastolic dysfunction. Other potential sources of the increased controller gain
Heart-failure patients with hypocapnia have a more severe left in Congestic heart failure (CHF) include increased carotid
ventricular diastolic dysfunction and a higher wedge pressure chemoreceptor sensitivity (achieved in part via a reduced
than eucapnic patients (201). Wedge pressure will further rise expression of nitric oxide and/or an increased expression
during supine position with the increase in venous return, of angiotension II at the carotid chemoreceptor) (181, 212),
stimulating J receptors. Consequently, such patients are not acute stimulation of lung vascular receptors via increases in
able to appropriately decrease their ventilation with sleep left atrial and pulmonary vascular pressures (26, 209) and
onset and their PCO2 remains close to apneic threshold. a reduced cerebrovascular response to CO2 (241) discussed
Furthermore, via mechanisms as yet to be discovered, earlier.
acute pulmonary congestion and increased pulmonary vascu- Because the aforementioned alterations are not
lar pressures, per se, were shown in a sleeping canine model sleep/wake-specific, periodic breathing may occur dur-
to increase the CO2 chemosensitivity below eupnea and de- ing both states, and even in exercise though most frequently

P1: OTA/XYZ P2: ABC
Table 2 HCVR in 20 Heart Failure Patients, 10 without and 10 with cause hypercapnia and may increase the number of arousals
Central Sleep Apnea and sympathetic activity. Dynamic selective administration
of CO2 (72), that is, during only a portion of the breathing
Variable Without CSA With CSA cycle if proven effective may have therapeutic potentials, but
systematic studies are lacking.
Slope, L/min 2.06 5.1* Finally, a preliminary study shows that phrenic nerve stim-
Slope/BSA, L/min/m2 1.0 2.76* ulation is quite effective in eliminating CSA in patients with
Slope/MVV† 2 7*
Slope/FVC, L/min 0.5 1.58* heart failure (108).
Slope/VO2 † 0.7 1.6*
Slope/VCO2 † 0.8 2.1*
Idiopathic central sleep apnea
*P < 0.05; † values multiplied by 100
Modified from Javaheri et al. (109). This is an extremely rare disorder (20, 234) and a diagno-
The slope of hypercapnic ventilatory response (HCVR) was significantly sis of exclusion. A systematic study in which other causes
higher in heart-failure patients with central sleep apnea (CSA) than of CSA (such as asymptomatic left ventricular systolic and
those without. The significance remained when the slope was normal-
ized to a number of other variables. diastolic dysfunction and multiple small infarcts) have been
BSA, body surface area; MVV, maximum voluntary ventilation; FVC, excluded has not yet been done. This is important as patients
forced vital capacity; VO2 , oxygen consumption; VCO2 , carbon diox- with idiopathic CSA are commonly older males and cardio-
ide consumption.
cerbrovascular diseases are common in this population.
Polysomnographically, idiopathic CSA is characterized
by repetitive episodes of central apnea. The cycles, however,
during sleep. During sleep, cardiac output decreases (further are shorter than those in systolic heart failure and breaths
prolonging arterial circulation time), and also both functional out of apnea are not gradual and smooth as they are in heart
residual capacity (supine position) and metabolic rate failure.
decrease enhancing the plant gain. These alterations along Patients with idiopathic CSA may present with complaints
with and a highly sensitive apneic threshold and reduced CO2 of restless sleep, insomnia, and/or daytime symptoms such as
reserve set the stage for development of profound periodic sleepiness and fatigue related to insomnia, sleep fragmenta-
breathing and CSA during NREM sleep. tion, and arousals. Long-term cardiovascular consequences,
Although treatment of CSA in heart failure is beyond if any are not known.
the scope of this article (19, 70, 111,113, 117, 119, 121, Patients with idiopathic central apnea commonly have
122, 128, 166, 202, 218), some therapeutic options which increased hypercapnic ventilatory response (20, 234) during
give insight into the mechanisms of periodicity and CSA wakefulness that facilitates development of central apnea dur-
are briefly mentioned. Continuous positive airway pressure ing sleep as discussed earlier. Conceivably, these patients also
(CPAP) devices suppress CSA in about 50% of patients with have increased hypocapnic ventilatory response (that is below
heart failure (18, 111). The mechanisms of improvement are eupnea) during sleep, though this has not been tested.
multifunctional and relate to the physiological cardiac and Although there are no randomized therapeutic trials, two
pulmonary effects of CPAP. CPAP by increasing intrathoracic nonrandomized open studies (46, 98) have shown efficacy of
pressure decreases both venous return, and left ventricular af- acetazolamide in treatment of idiopathic CSA. These results
terload. These physiological consequences of CPAP decrease are consistent with the results of the double blind placebo
pulmonary congestion and capillary pressure (which should controlled study in systolic heart failure showing the efficacy
widen PCO2 reserve as discussed earlier), and increase stroke of acetazolamide in treatment of CSA (115). In all these stud-
volume (which should decrease arterial circulation time). ies, administration of acetazolamide decreased arterial PCO2
CPAP should also increase functional residual capacity that (i.e., plant gain), yet the number of central apneas decreased.
decreases plant gain, and CPAP opens the upper airway, as
in some patients with CSA upper airway closure occurs.
Idiopathic pulmonary arterial hypertension
Supplemental administration of nasal oxygen may de-
crease periodic breathing by several mechanisms (113) which This disorder is characterized by pulmonary arterial hyper-
include reducing controller gain and increasing the difference tension with normal pulmonary capillary pressure indicating
between the prevailing PCO2 and the PCO2 at the apneic that left ventricular diastolic pressure is normal (60).
threshold (an effect opposite to hypoxia) (32), reduction in In more advanced hemodynamic state of this disorder,
ventilatory response to carbon dioxide and perhaps to hypox- there is severe pulmonary arterial hypertension, right ventric-
emia and an increase in body stores (e.g., lung contents) of ular failure, and diminished cardiac output. In one study (197)
oxygen which decreases plant gain. of 20 patients with idiopathic pulmonary artery hypertension
Low-level inhalation of CO2 and addition of external dead (3 men and 17 women), 6 had moderately severe sleep ap-
space by increasing PCO2 prevent PaCO2 from reaching the nea with an apnea-hypopnea index of 37 per hour resulting
apneic threshold, thus improving the likelihood of developing in desaturation. The mean PaCO2 did not significantly differ
CSA. However, the continuous administration of CO2 will between the two groups, but patients with periodic breathing

P1: OTA/XYZ P2: ABC
had significantly more hemodynamic abnormalities than those Accordingly, in hypoxia apneas are elicited via very minimal
without. Presumably, diminished stroke volume and increased amounts of transient hypocapnia because the CO2 reserve
arterial circulation time were the underlying mechanisms in in hypoxia approximates 1 to 2 mmHg. During each apnea,
mediating periodic breathing in this disorder. PaCO2 rises commensurate with sharp reductions in PaO2
It is emphasized that in the study of Schulz et al. (197), below an already hypoxemic baseline and the interaction of
3 out of the 3 men, but only 3 of 17 women had periodic these asphyxic stimuli greatly enhances carotid chemorecep-
breathing. This gender distribution (women less likely than tor activity and the drive to breathe. When increased FIO2
men in developing CSA) is similar to that in systolic heart is used to rapidly restore normoxic SaO2 , periodic breathing
failure, and may have to do with gender differences in apneic continues with prolonged apneic periods until hyperventila-
threshold PCO2 (253, 254). tion is gradually reduced and PaCO2 returns to normal.
For treatment of CSA in idiopathic pulmonary arterial Unlike the gradual waxing and waning of periodic breath-
hypertension, nocturnal supplemental nasal oxygen is rec- ing in CHF, periodic breathing in hypoxia occurs in breath
ommended (197). As noted earlier, oxygen administration “clusters” with tidal volume increasing from zero to three
improves CSA by a variety of mechanisms (113). In one pa- to four times control, almost instantaneously following each
tient with idiopathic pulmonary hypertension, hypocapnia, apnea. We believe this implies the presence of a transient
and low cardiac output, CSA was eliminated after lung trans- arousal at apnea termination which would further augment the
plantation (200) suggesting causation. Use of bilevel positive responsiveness of the respiratory control system and produce
airway pressure therapy was associated with death in a case the sudden ventilatory overshoot (67, 136). Although cortical
report (200). Though cause and effect cannot be proven, sev- EEG arousals have not been consistently observed throughout
eral possibilities including worsening of CSA, and reduction periodic breathing in hypoxia (9, 136), it is still feasible that
in cardiac output with use of bilevel device may be speculated. arousal only at the level of the brainstem (99) could greatly
It is emphasized, however, that obstructive sleep apnea magnify this chemoreceptor responsiveness. Marked dynamic
is a known cause of secondary pulmonary hypertension [for fluctuations in cerebral blood flow also occur during periodic
review, see reference (230)]. Therefore, in patients with pul- breathing in hypoxic sleep (49). An additional as yet untested
monary arterial hypertension, obstructive sleep apnea should influence in this dynamic, physiologically complex condition
be ruled out by polysomnography. If obstructive sleep apnea would be brain hypoxia acting independently as a ventilatory
is present, use of a CPAP device is the treatment of choice. stimulant (40, 59, 206); an effect which may be sensitized via
Pulmonary arterial hypertension may improve with effective a simultaneously enhanced carotid chemoreceptor input.
treatment of obstructive sleep apnea with CPAP (230). Over several days residence at high altitudes the amount
of periodic breathing in sleep persists, but is usually reduced
in magnitude (9, 10) or when chronic respiratory stimulants
High altitude
(such as acetazolamide or doxapram) are administered to
Periodic breathing commonly occurs at high altitude (232). sleeping sojourners at high-altitude periodic breathing is
The cycle of periodic breathing is short which is in contrast markedly attenuated (185, 214). Perhaps then, in short-term
to the long cycle of periodic breathing in heart failure. hypoxia the stabilizing effect of a reduction in plant gain
Sojourners to high altitude commonly experience rest- associated with a reduced PaCO2 is offset by the marked
lessness and nonrefreshing sleep, in part due to the common effect of hypoxia on increasing controller gain and, therefore,
occurrence of periodic breathing. During NREM or REM loop gain; whereas with acclimatization or superimposed
sleep, hyperventilation begins immediately upon hypoxic ex- chronic stimuli, the further reductions in PaCO2 and plant
posure and intensifies with time (9). After about 10 min of gain override the increased controller gain. As with other
hypoxia in the sleeping human tidal volume begins to oscil- types of periodic breathing and central apnea, administering
late in a waxing and waning pattern. These oscillations keep small amounts of inspired CO2 will remove all of the
increasing in magnitude as hypoxia is maintained and PaCO2 periodicity (9) (See Fig. 4).
falls further to the level of the apneic threshold. Commonly The underlying mechanism of high altitude periodic
then an augmented inspiration occurs and the subject begins breathing is hypoxemia which narrows the difference between
overt periodic breathing cycles of about 15 to 25 s duration, eupneic PCO2 minus apneic threshold PCO2 , and increases
characterized by two or three huge tidal volumes followed hypocapnic chemosensitivity below the apneic threshold, that
by apneas of 5 to 15 s duration as well as large swings in is, controller gain (163). Meanwhile, it has been shown that
cerebral blood flow (49) (see Fig. 4). During these periodic the quantity of periodic breathing during sleep tends to be
cycles, arterial SaO2 swings wildly along the steep part of the more in individuals with enhanced ventilatory response to
oxygen dissociation curve. both hypercapnia (above eupnea), and hypoxia (232).
As with CHF, the principle reason for apnea and peri- Inhalation of small amounts of CO2 decreases periodic
odic breathing in hypoxic sleep is likely to be the increased breathing by mechanisms discussed earlier. Furthermore,
controller gain—as evidenced by the steep increase in CO2 administration of acetazolamide improves desaturation
response slope above and below eupnea and the greatly nar- and ameliorates the symptoms of acute mountain sickness
rowed CO2 reserve (163,243) (see hypoxia example in Fig. 3). in man at high altitude (77, 247). As discussed earlier,

P1: OTA/XYZ P2: ABC
acetazolamide (163) reduces plant gain and widens the of CSA in heart failure. As noted earlier, the presence of
difference between eupneic and apneic threshold PCO2 (in pulmonary congestion results in the narrowing of the PCO2
contrast to hypoxemia), resulting in improvement of periodic reserve resulting in CSA. Similar to findings in heart failure,
breathing at high altitude. increased chemosensitivity has been reported in patients with
The induction of periodic breathing and CSA imposed chronic renal failure with sleep apnea and this decreases in
upon normal individuals at high altitude, does not exclude pa- patients whose sleep apnea responds to dialysis (6, 7). Fi-
tients with obstructive sleep apnea. Such individuals develop nally, similar to multiple reports in heart failure, preliminary
central apneas when traveling to high altitudes (170) and the findings in chronic renal failure suggest that presence of sleep
severity is altitude dose dependent. This could make CPAP apnea predicts mortality (151).
less effective at high altitude.
Hypercapnic CSA
Poststroke These heterogeneous disorders are characterized by daytime
steady-state hypercapnia or an awake PCO2 level close to
A number of studies (16, 21, 54, 94, 96, 162, 169, 176, 199, upper normal limits. According to alveolar ventilation equa-
246) have shown that patients with stroke (acute, chronic,
tion, PaCO2 is proportional directly to CO2 production and
ischemic, and nonischemic) have obstructive and CSA. In inversely to alveolar ventilation. In these disorders, the rise
a meta-analysis (132) of 29 articles involving 2343 patients in PaCO2 is due to decreased global ventilation, and there-
(some with transient ischemic attack), 72% and 38% of the
fore, the term hypoventilation is appropriate (114,118). How-
patients, respectively, had an AHI more than 5 and more ever, hypoventilation and hypercapnia become profound dur-
than 20 per hour, with 7% of the disorders being primarily
ing sleep. Normally with the removal of wakefulness drive
CSA. Although obstructive sleep apnea could either precede
to breathe, ventilation decreases with sleep onset and PCO2
(cause or contribute to development of) or be caused by stroke, rises slightly. However, such a small physiological decrease
central apneas are caused by the stroke and normally decrease
in ventilation results in a large increase in PCO2 , if hypercap-
with time (21) unless they are due to underlying heart failure.
nia is already present. This is dictated by alveolar ventilation
In general, periodic breathing in stroke has no relation to site equation and has to do with the hyperbolic relation of PCO2
of pathology.
with alveolar ventilation (Fig. 3). Furthermore, in the pres-
In patients with stroke, CSA may occur in the background ence of hypercapnia, if an arousal occurs, because of return of
of two different patterns of breathing. A pattern of breathing wakefulness drive to breathe, ventilation increases somewhat
similar to Hunter-Cheyne-Stokes breathing with long cycle
but PCO2 decreases considerably (increased plant gain). The
time is observed in those with left ventricular dysfunction and increased plant gain increases the probability of developing
reflects the long circulation time associated with heart failure central apnea, if apneic threshold PCO2 is also elevated (154).
(167). In those without underlying cardiac dysfunction, the
Another pathophysiological consequence of sleep-
cycle length of periodic breathing is shorter (16,96,162,169). induced hypercapnia is the development of severe desatu-
However, HCSB has also been reported in stroke patients ration. When PCO2 rises considerably, severe hypoxemia
with normal left ventricular ejection fraction (94) and CSA
ensues, given the reciprocal relation between alveolar PCO2
improves with both theophylline and oxygen administration and PO2 .
(162), observations similar to those in CSA due to systolic
In some of the disorders in this category, the pathologi-
heart failure. One may argue, however, that in these patients,
cal process involves brainstem medullary respiratory centers
HCSB was due to diastolic dysfunction rather than stroke. responsible for automatic breathing (either for anatomical or
functional reasons, e.g., due to use of opioids). Consequently,
Chronic renal failure and patients on dialysis when wakefulness drive to breathe is absent, hypoventilation
with or without central apneas occur during sleep.
CSA has also been reported in patients with renal failure
REM sleep may be associated with CSA in neuromuscular
(90, 215) In a study from Japan involving 30 patients with re- disorders involving the diaphragm. During REM sleep, there
nal failure on hemodialysis, Tada et al. (215) reported the pres- is costal muscle atonia and diaphragm is the only inspiratory
ence of sleep apnea with an AHI of about 53 per hour. Twenty-
thoracic pump muscle active. Therefore, with diaphragmatic
three percent had CSA and the rest had obstructive sleep ap- weakness or paralysis, during REM sleep, airflow ceases, and
nea. In OSA patients, the obstructive apnea-hypopnea index thoraco-abdominal tracings look like a central apnea. This
was significantly correlated with BUN, creatinine, and body
is a pseudocentral apnea (!) and may occur in a variety of
mass index whereas the CSA index was conversely correlated disorders associated with diaphragmatic paralysis (203).
with PaCO2 (r = −0.39, P < 0.05) and also tended to be
correlated with the cardiothoracic ratio (r = 0.035, P = 0.06).
The latter two observations and that patients with chronic re-
Alveolar hypoventilation syndromes with normal
pulmonary function
nal failure are commonly volume overloaded strongly suggest
that in these patients CSA is pathophysiologically linked to These central nervous system disorders are characterized by
pulmonary congestion, consistent with the pathophysiology chronic alveolar hypoventilation with daytime hypercapnia,

P1: OTA/XYZ P2: ABC
diminished or absence CO2 chemosensitivity, and normal pul- Depending on the site of pathology, a specific pathophys-
monary function. iological breathing disorder could occur during sleep. With
These disorders could be either genetic [congenital cen- diaphragmatic involvement, however, breathing is particularly
tral hypoventilation syndrome (CCHS) and perhaps its adult compromised in REM sleep when hypoventilation and poly-
form, primary hypoventilation syndrome], or acquired (a va- graphically what appears to be a central apnea (discussed
riety of brainstem and spinal cord disorders). The unique earlier) may occur. In disorders with involvement of pharyn-
feature of all of these disorders, however, is the failure of au- geal muscles, obstructive apneas and hypopneas may occur
tomatic/metabolic control of breathing which becomes man- during sleep.
ifest during sleep when breathing is controlled by the auto- In neuromuscular disorders, as respiratory muscle weak-
matic/metabolic pathway. If this pathway is defective, ven- ness progresses and daytime hypercapnia develops, more pro-
tilation will decrease dramatically and hypoventilation with found hypoventilation and hypercapnia, and therefore, more
or without central apneas could occur. PHOX2B has recently severe desaturation and perhaps more central apneas occur
been identified as the disease-defining gene for CCHS (177). during sleep. These phenomena have to do with where PCO2
CCHS and primary (idiopathic) alveolar hypoventilation resides on the isometabolic hyperbolic curve of alveolar ven-
syndrome, the genetic mutations, and various treatment op- tilation equation discussed earlier.
tions are reviewed elsewhere (1, 14, 15, 22, 33, 35, 42, 61, 66, Treatment of sleep-related breathing disorders in neuro-
68, 69, 73, 84, 147, 152, 174, 184, 190, 221,223, 229, 233). muscular diseases should be individualized and are reviewed
elsewhere (57, 74, 133, 168).
Brainstem and spinal cord disorders
Opioids
Brainstem and spinal cord disorders constitute a number of
heterogeneous pathological processes, which could result in The analgesic properties of opioids are well known and opi-
severe hypoventilation and central apnea during sleep. In re- oid drugs as part of the mainstay of pain management are
gard to brain stem pathology, it is not surprising, because in widespread use. However, a major and potentially fatal
central chemoreceptors and respiratory centers are located in side effect of opioids is ventilatory depression. Although with
this region. Various pathological processes such as compres- chronic use, daytime hypoventilation is generally mild, during
sion, edema, ischemia, infarct, tumor, encephalitis, neurode- sleep, disordered breathing events including hypoventilation,
generative disorders, and Chiari malformation have been as- obstructive and central apneas, and hypopneas become preva-
sociated with CSA (39, 51, 138, 143, 149, 196, 198, 233, 248). lent (Fig. 7). Conceivably, these sleep-related breathing dis-
The latter disorder is unique in that it commonly occurs in orders could be a cause of death, as many young individuals
young individuals presenting with headache and polysomnog- are found dead in bed and at autopsy, no cause is found.
raphy shows CSA that is eliminated with posterior fossa Three relatively large studies have shown the various phe-
decompression. notypes of sleep-related breathing disorders in patients on
Cervical cordotomy (148) and anterior cervical spinal chronic opioids (62, 64, 81, 131, 225, 228). In a case control
artery syndrome (with consequent ischemia of the ventral study (228) of 60 patients taking opioids for pain manage-
spinal cord) (71) result in automatic failure of breathing. In ment, matched for age, gender and body mass with 60 pa-
these two conditions, the process involves the descending tients not taking opioids, the former group had a significantly
pathways subservient to the automatic control of breathing higher apnea-hypopnea index, primarily due to an increase in
with preservation of voluntary pathway. Therefore, during the number of central apneas than the control group. In another
sleep when wakefulness drive to breathe ceases, hypoventila- study (228) of patients in a pain clinic in which polysomnogra-
tion, and central apnea occur. This phenomenon is in a way phy was routinely recommended, 140 of the 392 consecutive
similar to CCHS as well. subjects were studied in their institution. Of these, 75% had
For treatment of central apneas and hypoventilation in an AHI 5or more per hour, 50% had an AHI 15 or more per
this category, therapy should be individualized. A number hour and 36% had severe sleep apnea with an index of AHI 30
of modalities including bilevel ventilation in time-mode, tra- or more per hour of sleep. CSA was the predominant form in
cheostomy with mechanical ventilation, phrenic nerve, or di- many of these patients with 33%, 23%, and 14% having CAI
aphragm pacing could be used. of 515 or more and 30 or more per hour of sleep, respectively.
However, as noted above, obstructive sleep apnea is also
common. Guilleminault and associates (81) reported presence
Neuromuscular disorders
of primarily obstructive sleep apnea in 44 patients on chronic
This category (Table 1) includes a large number of neuromus- opioids. Importantly, central apneas resulting in sleep frag-
cular disorders (71) that may affect respiratory muscles (mus- mentation emerged with use of CPAP (referred to as complex
cular dystrophies such as myotonic dystrophy and idiopathic sleep apnea discussed later), eventually necessitating use of
diaphragmatic paralysis), neuromuscular junction (myasthe- bilevel device with back up rate.
nia gravis), and phrenic and intercostal nerves (amyotrophic Episodes of obstructive and central apneas and hypopneas
lateral sclerosis). occur in the background of two unique patterns of breathing.

P1: OTA/XYZ P2: ABC
Sleep apnea associated with opioids

S S S S S S S S S S S S S S S S S S S S S S S S S S S S
Body Baseline
100
~LEOG 0
μV –100
100
~REOG 0
μV –100
200
~-Chin 0
50
~C4A1 0
μV –50
50
~O1A2 0
μV –50
100
~LEMG 0
–100
200
ECG 0
pFlow 128
192
Chest 128
64
192
ABDO 128
64
SAO2 90 92 92 90 90 90 90 90 89
89 89 89 88 88 89 89 89 89 88 88 87
STAGE
S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2
394 395 395 396 396 397 397 398 398 399 399 400 400 401 401 402 402 403 403 404 404 405 405 406 406 407 407 408 408 409 409 410 410 411 411 412
120- 240- 360- 480-
Figure 7 A 10-min epoch of a polysomnogram of a patient on chronic opioids. The tracings are the same as in Figure 1. Note the differences
in the pattern of breathing between this patient and the patient with heart failure in Figure 5. The central apneas are of different duration. There
are obstructive hypopneas and apneas also present. Note that out of apnea, there are at times very large breaths.
One, the cluster breathing is characterized by cycles of deep Treatment of opioids-induced sleep apnea is reviewed
breaths in which the amplitude of tidal volume is relatively elsewhere (80,126). Withdrawal of opioids is the treatment of
stable with interspersed central apneas of variable duration choice, but generally not acceptable by the patient. Positive
(Fig. 7). The other pattern is Biot’s breathing (ataxic breath- airway pressure devices have been used. However, CSA is
ing) which is characterized by variable amplitude of tidal CPAP resistant and is best treated with adaptive servoventila-
volume and breathing rate. tion devices (126). We emphasize, however, that randomize
As noted above, chronic opioids use can also be associ- clinical trials have not been performed.
ated with hypoventilation that could be profound if there is Obstructive sleep apnea can be easily treated with CPAP,
concomitant steady state hypercapnia, as dictated by alveolar but CSA also emerges with therapy of OSA with CPAP (81)
ventilation equation. necessitating use of other positive airway pressure devices
Given the high prevalence of sleep apnea in patients on (bilevel with backup rate or adaptive servoventolation) to
opioids, it is noted that during the last few years, there has been abort central apneas.
a marked acceleration in the use of opioids for management For treatment of CSA, one attractive and yet untested
of chronic pain. Consequently, a large number of patients suf- hypothesis is respiratory stimulants such as acetazoalamide,
fer from unrecognized severe sleep apnea and several studies which has been shown to be effective in treatment of periodic
have suggested that sleep apnea, both obstructive and CSA in breathing in heart failure, high altitude, and idiopathic CSA.
(130, 150, 252), particularly when severe, are associated with We hypothesize that acetazolamide should be also effective
mortality. We, therefore, suspect that sleep apnea and hy- in treatment of opioid-induced CSA.
poventilation contribute to excess mortality associated with The mechanisms of opioid-induced central and obstruc-
use of opioids as many victims are discovered dead in the tive sleep apnea remain to be fully explained. Opioids may
morning or in bed during the day, with mortality remaining cause CSA and respiratory depression via their effect on
unexplained at autopsy, except for presence of opioids and opioid-μ receptor in pre-Botzinger complex (64, 75, 76). In
other potentially respiratory depressant drugs in the blood the latter study (158) in adult rats intravenous administra-
(182, 217). tion of μ agonists-induced respiratory depression which was

P1: OTA/XYZ P2: ABC
Quiet wakefulness NERM sleep

Naloxone
DAMGO Naloxone DAMGO 100 μmol/L
Mock CSF Mock CSF
20 μmol/L 100 μmol/L 20 μmol/L +Mock CSF
+Mock CSF +Mock CSF +Mock CSF
(min–1)
100 100 100

Rate
100 100 100

50 50 50
50 50 50
∫ Dia
EEG
1s
Figure 8 Modulation of breathing patterns by the mu-opioid agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) at the pre-Botzinger
complex across sleep-wake states in adult rats during wakefulness and sleep. Please note the depression in respiratory rate by application of
DAMGO which is reversed by naloxone, a mu-receptor antagonist. These changes are particularly pronounced in nonrapid eye movement
(NREM) sleep. There is a significant reduction in respiratory rate as noted by diaphragmatic activity both during wakefulness and NREM sleep.
The reduction in respiratory rate is primarily due to prolongation of the expiratory time. EEG, electroencephalogram; DIA, diaphragm. Adapted,
with permission, from Montandon et al. (158).
reversed by local application of naloxone, μ receptor antag- Several studies (36, 80, 95) show that patients with
onist, at the pre-Botzinger complex. Respiratory depression acromegaly also suffer from CSA, and this correlated with lev-
was due to prolongation of expiratory time (Fig. 8) (158). els of hGH, IGF-1, and hypercapnic ventilatory response. The
The mechanisms of obstructive sleep apnea have to do enhanced ventilatory response could increase the likelihood
with impairment in genioglossus muscle ability to maintain of developing CSA. Interestingly, treatment with octreotide
upper airway patency during sleep. In an animal study, (86) improves CSA (95). As some patients with acromegaly may
application of opioids at the hypoglossal motor neuron pool suffer from heart failure that could cause or contribute to
diminished the activity of the genioglossus muscle, leading CSA, improvement in CSA by octreotide could be in part due
to increased upper airway resistance (Fig. 9). Furthermore, to improved cardiac function.
a distinct anatomical region of medulla in close proximity
to pre-Botzinger complex is another site for opioid-induced
Hypothyroidism
suppression of genioglossus muscle activity (64, 158).
Similar to acromegaly, both obstructive (183) and central
(157) sleep apneas occur in patients with hypothyroidism,
Central sleep apnea in endocrine disorders though CSA is much less frequent than obstructive apneas.
Central sleep apnea has been observed in two endocrine dis- The mechanisms of CSA are not understood, but excess pha-
orders, acromegaly and hypothyroidism. In both disorders, ryngeal soft tissue, similar to acromegaly should account for
however, obstructive sleep apnea is the predominant form. obstructive sleep apnea
Acromegaly CSA with obstructive sleep apnea

Several studies have reported a relatively high prevalence Few central apneas are observed in polysomnograms of pa-
of sleep apnea, both obstructive and central in patients tients with obstructive sleep apnea and are appropriately ig-
with acromegaly (36, 78, 187). Excess pharyngeal soft tis- nored because they are of no clinical significance. However,
sue (due to cellular hyperplasia, excess connective tissue, some patients referred for evaluation of OSA may have ex-
and extracellular water) and macroglossia should account cess central apneas or develop CSA during initiation of CPAP
for obstructive sleep apnea that may contribute to high therapy. These include patients with severe OSA, those with
prevalence and progression of cardiovascular disease of systolic heart failure, atrial fibrillation, neuromuscular disor-
acromegaly (78). Obstructive sleep apnea should be treated ders, or on opioids.
with CPAP, though treatment with octreotide (a somatastatin Presence of CSA (CAI ≥ 5 per hour) on CPAP could,
analog) could result in tissue regression and improvement therefore, be either emergent [i.e., was not present on
in sleep apnea (36, 79, 95). However, this may take several diagnostic sleep study, a condition referred to as complex
months, and sleep apnea may persist in spite of therapy of sleep apnea, (160)] or considered persistent (CSA was
acromegaly. present on diagnostic Polysomnography (PSG) as well).

P1: OTA/XYZ P2: ABC
Mock CSF Fentany| Naloxone

1 μmol/L 10 μmol/L 100 μmol/L 100 μmol/L
150 mmHg
Blood
pressure
0
Diaphragm
MTA AU
Genioglossus
MTA AU
Genioglossus
EMG 250 μV
EEG 250 μV
5s
Figure 9 Modulation of the genioglossus muscle activity by application of fentanyl, mu-opioid receptor agonist
at the hypoglossal motor pool in adult rats. Note the progressive increase of genioglossus moving time average
(MTA) that parallels increasing concentration of fentanyl at the hypoglossal motor neuron pool. There is a
similar reduction in genioglossal electromyogram (EMG) without a significant change in diaphragmatic MTA.
Intravenous administration of naloxone, a mu-opioid antagonist reverses changes in genioglossus muscle EMG
and MTA. Adapted, with permission, from Hajiha et al. (86).
Such patients commonly continue to have both obstructive tients with systolic heart failure (48). Increased controller gain
and CSA on CPAP with an estimated prevalence of 5% to could also be in part due to chronic intermittent hypoxia that
20% (50, 58, 131, 142, 160, 245), with most recent studies increases hypoxic chemosensitivity (178).
(58, 131, 245), showing a prevalence of about 5% to 6%. Meanwhile, there are also multiple reasons for improve-
In the largest study (126), which included 1286 patients ment in CSA after long-term use of CPAP (131) including a
referred for evaluation of OSA, the monthly incidence of decrease in CO2 chemosensitiviy below eupnea (188).
CSA during initial CPAP titration (CPAP1) varied from 3%
to 10% during a 1-year period, with an average of 6.5%. This
study (131) also looked at the evolution of CSA after several CSA with upper airway disorders
weeks of CPAP therapy. Of the 42 patients who had devel- The nose, larynx, and pharynx are replete with receptors (210,
oped CPAP1-CSA, CSA was eliminated in most of them with 235) and animal and preterm infants studies (2, 43, 91, 140)
long-term use of CPAP. However, 9 of the 42 patients (an have demonstrated that stimulation of upper airway receptors
estimated 1.5% of 1286 patients with OSA) had persistent may cause central apnea. Apnea may be produced by water,
CSA with long-term use of CPAP and some were on opi- chemical, or mechanical stimulation of these receptors.
oids. Initial emergence and elimination of CSA in most of Studies in normal adults (213, 255) have shown that nasal
the patients is consistent with results of two long-term stud- obstruction results in central apneas. This finding has not been
ies (34, 83) with tracheotomy. Guilleminault and colleagues reproduced in allergic rhinitis; however, McNicholas and col-
noted that patients with OSA who underwent tracheostomy leagues (153) studied seven subjects when asymptomatic and
initially had CSA, the number of which decreased (83) when during exacerbation of allergic rhinitis; central apnea index
repeat polysomnography was performed after period of time. did not change significantly, though obstructive apnea index
Coccagna and colleagues reported a similar observation (34). increased significantly.
The mechanisms and the reasons for development of Meanwhile both high frequency (30 Hz) low-pressure
CPAP-emergent CSA are multiple varying from one patient to ventilation (93) and CPAP (97; 106) have been shown to im-
another as discussed previously (131). Some of these reasons prove CSA suggesting that upper airway receptors and closure
are increased number of arousals observed in some patients may induce central apnea in man.
during titration that increase the likelihood of occurrence of
central apneas, occurrence of oral leak, and overtitation with
increased functional residual capacity inhibiting stretch re-
ceptors. Another predictor of CPAP-emergent CSA is the
Summary and Future Directions
severity of OSA (120). Patients with severe OSA may have In the last decade, there has been considerable progress in our
increased controller gain manifested in increased chemosen- understanding of the mechanisms and the disorders associated
sitivity above (251), and below eupnea (188), similar to pa- with CSA. We have learned much about the contribution of

P1: OTA/XYZ P2: ABC
increased loop gain both above and below eupnea to increas- tive sleep apnea. If these results are further confirmed and
ing the likelihood of developing breathing instabilities during molecular mechanisms be uncovered, the door may open for
NREM sleep both in animal models as well as in humans. pharmacological therapy of opioid-induced sleep apnea.
Many disorders are associated with CSA but perhaps the
two most common causes in the general population are con-
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P1: OTA/XYZ P2: ABC

Central Sleep Apnea

Introduction structive apnea. Most difficult, however, is the distinction be-

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142 Volume 3, January 2013

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to the hypoadditive effects previously proposed in reduced

studies claim purely additive effects of the two inputs on the

144 Volume 3, January 2013

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and PO2 from the plant is detected by the controllers) which 4

cross the apneic threshold. The other means of changing the

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SaO2 that these changes contribute to increases in controller gain

Gender and ventilatory instability

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Table 1 Central Sleep Apnea Postarousal/postsigh central apnea

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Hunter- Cheyne-Stokes breathing in SHF

60'' 120'' 180'' 240'' 30

148 Volume 3, January 2013

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30 high wedge pressure and pulmonary congestion decreases the

10 Mechanisms of central sleep apnea in heart failure

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154 Volume 3, January 2013

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Sleep apnea associated with opioids

120- 240- 360- 480-

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Quiet wakefulness NERM sleep

100 100 100

100 100 100

Acromegaly CSA with obstructive sleep apnea

156 Volume 3, January 2013

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Mock CSF Fentany| Naloxone

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