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the tongue base to a series of patients who underwent UPPP alone, and used the ESS
and polysomnographic measures as outcome assessments. The pre-operative AHI in
the UPPP-only group was 35.4 events/hour and in the UPPP + tongue base radiofrequency treatment was 43.9 events/hour (statistically signicantly different). The
postoperative AHI was 26.5 event/hour and 28.1 events/hour in the UPPP and UPPP
+ tongue base radiofrequency treatment group, respectively, both measures representing statistically signicant improvements compared to preoperative values, but
not when compared between groups. ESS was noted to improve from a preoperative
level of 15 to a postoperative level of 8in the UPPP + tongue base radiofrequency
treatment group; similar data was not recorded in the UPPP-only group. A step-wise
multilevel surgical series of 306 patients [31] underwent phase 1 surgery consisting
of UPPP for palatal obstruction and genioglossus advancement with hyoid
myotomy- suspension for obstruction at the level of the base of the tongue. Phase 2
surgery, consisting of maxillomandibular advancement, was offered to patients who
failed phase 1 determined by a comparison between the residual RDI of patients
after surgery and patients using nasal CPAP, and with baseline measures. The preoperative RDI was 55.8 events/hour, the RDI on nasal CPAP was 7.2 events/hour,
and the post-operative RDI was 9.2 events/hour. A similar trend was found with
oxyhemoglobin saturation nadirs with the pre-operative value of 70.5%, nasal CPAP
minimum saturation 86.7%, and post-operative saturation nadir of 86.6%.
A randomized assessment of multilevel surgery, consisting of a modied UPPP
combined with radiofrequency tongue reduction, compared with ongoing medical
management in patients with moderate to severe OSA demonstrated a statistically
signicantly greater improvement in AHI and sleepiness in patients who underwent
surgical treatment. The resulting mean AHI in the surgery group was 20.8 events/
hour (from a baseline of 47.9 events/hour), which is still in the moderate severity
OSA category; however, it should be emphasized that this was associated with
improvement in sleep-specic quality of life and general health status. The Epworth
Sleepiness Scale in the surgery group decreased from 12.4 at baseline to 5.3 after
surgery, where the ESS did not change medical management group (11.1 at baseline
vs 10.5) [19].
S. Hoff and N. Collop
Hypoglossal Nerve Stimulation (HNS)
The relationship between activation of the genioglossus and upper airway patency
was the motivation for evaluating the use of stimulation of the hypoglossal nerve as
a therapy for OSA.An impulse generator is implanted in the subcutaneous tissues
of the upper chest, typically on the right side. The medial branch of the hypoglossal
nerve typically on the right is exposed, and a stimulation lead is wrapped around it.
A sensing lead is placed between the internal and external intercostal muscles at the
fourth intercostal level. When a respiratory effort ensues, the stimulator is activated
and provides an impulse to the hypoglossal nerve causing the tongue to move anteriorly. Patients with moderate-to-severe OSA who had either not tolerated PAP
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therapy, or who declined to use it were recruited to undergo implantation of the
device. The patients had an AHI of 32 events/hour at baseline with a moderate
amount of fatigue, and daytime sleepiness with an Epworth sleepiness scale of 11.6.
Assessment after 12months of treatment revealed a drop in the median AHI from
29.3 events/hour to 9.0 events/hour, and 66% of the participants had met the coprimary outcome of a drop in AHI by at least 50% and a reduction in AHI to 20 events/
hour or less. Adverse events included tongue weakness, tongue soreness, abrasion
on the underside of the tongue, and discomfort from the stimulation; however, none
of these caused permanent issues [35]. HNS have now been implanted in over
10,000 patients worldwide. Five-year data are available from the initial trial and
demonstrate persistent reductions in AHI, ESS, and QOL scores without the need
for increased stimulation voltage [38].
Conclusion
OSA is a highly prevalent disorder that can be associated with considerable daytime
impairment and signicant cardiovascular consequences both of which provide a
compelling indication for treatment. The rationale for the use of CPAP and the body
of evidence that has accumulated provide a sound foundation supporting its use.
The variety of options for administering CPAP therapy should allow for tailoring of
treatment to an individual patient’s needs; however, a signicant minority of patients
for whom CPAP is discussed and prescribed either do not tolerate the therapy, or
refuse to use it. Therefore, alternatives to CPAP exist and should be offered when
appropriate and in a judicious fashion.
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Chapter 8
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Central Sleep Apnea: Pathophysiology
andClinical Management
M.SafwanBadr andGeoffreyGinter
Keywords Central apnea · Hypoventilation · Hyperventilation · Hypocapnia ·
Cheyne–Stokes respiration · CPAP · Adaptive servo-ventilation
Central sleep apnea is a manifestation of breathing instability in a variety of clinical
conditions and is often bundled under the rubric of obstructive sleep apnea. Central
sleep apnea occurs because of a transient cessation of ventilatory motor output,
under several physiologic or pathologic conditions. This chapter will address the
pathogenesis, clinical features, and management of central sleep apnea.
Determinants ofCentral Apnea During NREM Sleep
Hypocapnia
The sleep state (specically non-rapid eye movement or NREM sleep) removes the
wakefulness “drive to breathe” and renders respiration critically dependent on chemical inuences, especially partial pressure of carbon dioxide (PCO2). Central apnea
results if arterial PCO2 is lowered below a highly sensitive “apneic threshold.” [1, 2]
Hypocapnia is a potent but not an omnipotent mechanism of reduced ventilatory
motor output during NREM sleep. Several factors modulate and mitigate the effects
of hypocapnia on ventilatory motor output and promote stability of respiration.
M. S. Badr (*)
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine,
Harper University Hospital, Wayne State University School of Medicine, Detroit, MI, USA
e-mail: sbadr@med.wayne.edu
G. Ginter
Department of Internal Medicine, Harper University Hospital, Wayne State University School
of Medicine, Detroit, MI, USA
M. S. Badr, J. L. Martin (eds.), Essentials of Sleep Medicine,
Respiratory Medicine, https://doi.org/10.1007/978-3-030-93739-3_8
145© Springer Nature Switzerland AG 2022
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M. S. Badr and G. Ginter
Short-Term Potentiation
Actively induced hyperventilation (such as hypoxic hyperventilation) is associated with activation of an excitatory neural mechanism referred to as short-term
potentiation (STP) [3–5], which results in a gradual return of ventilation toward
the baseline upon cessation of the stimulus to breathe. STP has been demonstrated in humans as well as in animals, and is unaffected by the state of consciousness. STP may play a signicant role in preserving rhythmic respiration by
preventing abrupt drop in ventilation during transient hypocapnia such as following brief hypoxia or transient arousal. In fact, central apnea rarely occurs following termination of brief hypoxia, despite hypocapnia at or below the apneic
threshold [3–5]. Similarly, although hypocapnia occurs during transient arousals
from sleep, the activation of STP may mitigate the occurrence of central apnea
under these conditions [6]. However, prolonged hypoxia may abolish STP, which
may explain the development of periodic breathing after 20–25min of hypoxia
and the occurrence of central apnea upon termination of prolonged hypoxic exposure [5, 7].
Duration ofHyperpnea
The duration of hyperpnea is another important determinant of reduced ventilatory
motor output following hyperventilation. Central apnea does not usually occur following brief arousal in sleeping humans [8] or dogs [9] possibly due to insufcient
reduction in PCO2 at the level of the central chemoreceptors.
In summary, the balance between hypocapnia and short-term potentiation determines the occurrence of post-hyperventilation apnea during stable sleep, while the
duration of hyperventilation may determine whether the reduction in medullary
PCO2 is enough for the development of central apnea.
Role ofUpper Airway Reexes
While hypocapnia is the most common inuence leading to central apnea, other
mechanisms may also induce central apnea. For example, negative pressure–induced
deformation of the isolated upper airway causes central apnea in dogs during both
wakefulness and sleep [10]. Whether such reexes contribute to the developments
of central apnea in sleeping humans remains speculative. Conversely, central apnea
occurs more frequently in the supine position [11–13] and may be reversed with
nasal continuous positive airway pressure (CPAP) [14]. Likewise, there is evidence
of supine dependency including that the lateral position amelioration of severity of
central apnea and Cheyne–Stokes respiration [11–13].
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Mechanisms Perpetuating Breathing Instability
Central apnea does not occur as a single event, but as cycles of apnea/hypopnea
alternating with hyperpnea. Ventilatory control during sleep operates as a negativefeedback closed-loop cycle to maintain homeostasis of blood gas tensions within a
physiologic range. Many authors have adopted the engineering concept of “loop
gain” as a measure of ventilatory stability or susceptibility to central apnea and
recurrent periodic breathing [15]. Loop gain represents the overall response of the
plant (representing the lung and respiratory muscles); the controller (representing
the ventilatory control centers and the chemoreceptors); and the delay, dilution, and
diffusion inherent in transferring the signal between the plant and the controller. The
formula for loop gain is as follows:
Loop gain ControllergainPlant gain
PCO
Ventilation
PCO
2
The formula can be expanded to account for pulmonary blood ow (Q, equivalent to cardiac output) and carbon dioxide–carrying capacity of the blood (β); the
derivation for this expanded equation can be found in the study by Ghazanshahi and
Khoo [16]. These two factors comprise the rate of carbon dioxide delivery to the
chemoreceptors and the lungs, which, when delayed, can increase loop gain by
producing lag between the disturbance (initial change in ventilation or carbon dioxide) and the response. A greater loop gain represents increased reactivity of the
ventilatory circuit to disturbances and, consequently, ventilatory instability [17].
Central sleep apnea is associated with increased loop gain, which can be observed
in conditions such as congestive heart failure (CHF– increased controller gain and
prolonged circulation time) or obesity and tetraplegia (increased plant gain resulting
from decreased lung volumes) [17–19]. Conversely, a lower loop gain corresponds
to greater ventilatory stability, as is observed during REM sleep [20]. A detailed
discussion of the dynamics of ventilatory control is beyond the scope of this chapter; however, there are several excellent reviews that have discussed this aspect in
detail [21–23].
The occurrence of central apnea is associated with several consequences that
conspire to promote further breathing instability:
VVentilation
2
• Once ventilatory motor output ceases, rhythmic breathing does not resume at
eupneic arterial PCO2 (PaCO2) due to inertia of the ventilatory control system; an
increase in PaCO2 by 4–6mmHg above eupnea is required for resumption of
respiratory effort [24].
• Central apnea is associated with narrowing or occlusion of the pharyngeal air-
way [25]. Thus, resumption of ventilation requires opening of a narrowed or
occluded airway and overcoming tissue adhesion forces [26] and craniofacial
gravitational forces.
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Termination of central apnea is associated with variable changes in arterial blood
gases (hypoxia and hypercapnia) and transient EEG arousal, resulting in ventilatory
overshoot, subsequent hypocapnia, and a recurrence of apnea/hypopnea. This
sequence explains why apnea rarely occurs as a single event (i.e., “apnea begets
apnea”) and why there is an overlap between central and obstructive apnea (upper
airway obstruction often follows central apneas upon resumption of respiratory
effort, i.e., mixed apnea).
M. S. Badr and G. Ginter
Pathophysiologic Classication ofCentral Sleep Apnea
Central apnea syndrome may be present in a diverse group of conditions including
heart failure and obstructive sleep apnea. The ICSD-3 lists several categories of
central apnea: (1) Primary Central Sleep Apnea, (2) Central Sleep Apnea Due to
Cheyne–Stokes Breathing Pattern, (3) Central Sleep Apnea Due to Medical
Condition Not Cheyne–Stokes, (4) Central Sleep Apnea due to High Altitude
Periodic Breathing, (5) Central Sleep Apnea Due to Drug or Substance Use, (6)
Central Sleep Apnea of Infancy, (7) Central Sleep Apnea of Prematurity, and (8)
Treatment-Emergent Central Sleep Apnea [27]. Central apneas are caused either by
hyperventilation or hypoventilation. Primary central sleep apnea (CSA), Cheyne–
Stokes respiration with central sleep apnea (CSA-CSR), and CSA at high altitude
are examples of CSA-related to hyperventilation. Central sleep apnea due to drug or
substance use is due to hypoventilation, whereas central apnea associated with other
medical conditions may be due to either hyperventilation or hypoventilation. The
underlying mechanisms inuence the choice of therapy including optimization of
medical therapy in central apnea associated with other conditions such as heart failure, hypothyroidism, or acromegaly.
The level of arterial PCO2 during wakefulness is often used to classify central
apnea as hypercapnic or non-hypercapnic. However, such classication does not
capture the underlying pathogenesis as apnea represents hypoventilation or a consequence of hyperventilation.
Central Sleep Apnea Secondary toHypoventilation
The sleep state is associated with reduced ventilatory motor output, increased
upper airway resistance, and hypoventilation. This physiologic constellation
carries pathologic consequences in patients with an underlying abnormality in
ventilatory control or impaired pulmonary mechanics. Most aficted patients
suffer from a central nervous system disease (e.g., encephalitis), neuromuscular
disease (e.g., post-polio syndrome), or severe abnormalities in pulmonary
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mechanics (e.g., kyphoscoliosis [28]). Thus, the hallmark of this disease is alveolar hypoventilation representing nocturnal ventilatory failure or worsening of
the underlying chronic disease. Arousal from sleep restores alveolar ventilation
to a variable degree; resumption of sleep reduces ventilation in a cyclical
fashion.
Central apnea secondary to hypoventilation does not necessarily meet the strict
denition of “apnea,” since feeble ventilatory motor output may persist albeit below
the thresholds required to preserve alveolar ventilation. Likewise, it may not meet
the denition of “central” in patients with respiratory muscle disease or skeletal
deformities. Consequently, the presenting clinical picture includes both features of
the underlying ventilatory insufciency (e.g., morning headache, cor pulmonale,
peripheral edema, polycythemia, and abnormal pulmonary function tests) and features of the sleep apnea/hypopnea syndrome (e.g., poor nocturnal sleep, snoring,
and daytime sleepiness).
A rare but interesting group of patients present with primary alveolar hypoventilation manifesting by daytime hypoventilation without an apparent identiable
cause and blunted chemo responsiveness [29, 30]. Congenital central hypoventilation syndrome (CCHS) results from a mutation in the gene that encodes the homeobox (PHOX) 2B gene.
The mechanism(s) responsible for hypercapnic central sleep apnea in a given
patient inuence(s) the management strategy, which aims to restore effective alveolar ventilation during sleep. Treatment of choice is assisted ventilation; nasal CPAP
and supplemental oxygen are unlikely to alleviate the condition.
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Central Apnea Secondary toHyperventilation
Hypocapnia secondary to hyperventilation is the most common underlying mechanism of central apnea. A typical patient with non-hypercapnic central apnea has no
evidence of a neuromuscular disorder, abnormal lung mechanics, or impaired
responses to chemical stimuli. Accordingly, apnea is a result of a transient instability rather than a ventilatory control defect.
How does the rst apnea begin? Several transient perturbations may trigger the
initial event, including oscillation in sleep state [31], or transient hypoxia possibly
due to retention of secretions or reduced lung volumes at sleep onset. Thus, hypoxia
stimulates ventilation, subsequently leading to hypocapnia and apnea. The occurrence of apnea initiates the repetitive process of apnea–hyperpnea and leads to sustained breathing instability, manifested as periodic breathing (see above). In
summary, non-hypercapnic central apnea is a heterogeneous entity that may be an
idiopathic or a secondary condition. The pathogenesis may vary depending upon the
clinical condition. However, hypocapnia secondary to hyperventilation is the common denominator in this group of disorders.
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M. S. Badr and G. Ginter
Central Apnea Risk Factors
Sleep State
Transient breathing instability and central apnea may occur during the transition
from wakefulness to NREM sleep. As sleep state oscillates between wakefulness
and light sleep [32–34], the level of PaCO2 is at or below the hypocapnic level
required to maintain rhythmic breathing during sleep (i.e., the “apneic threshold”),
resulting in central apnea. Recovery from apnea is associated with transient wakefulness and hyperventilation. The subsequent hypocapnia elicits apnea upon
resumption of sleep. Consolidation of sleep alleviates the oscillation in sleep and
respiration and stabilizes PaCO
Sleep onset is also associated with another type of central apnea, not preceded by
hyperventilation. The transition from alpha to theta in normal subjects is associated
with prolongation of breath duration [35].
Central apnea at sleep onset if often considered “physiologic,” albeit not universal. Furthermore, events that occur during epochs scored as “wakefulness” are not
captured. Whether sleep-onset central apnea is truly physiologic, or a reection of
increased loop gain is yet to be determined. The clinical implications and natural
history of this “phenomenon” is unknown.
Central sleep apnea is uncommon during REM sleep as many studies suggest
that breathing during REM sleep is impervious to chemical inuences (REF), possibly due to increased ventilatory motor output during REM sleep [36, 37] relative
to NREM sleep. In addition, there is evidence in animal studies that hypocapnia, per
se, may decrease the amount of REM sleep [38]. The major barrier to answering this
question in humans is the difculty in conducting such experiments without disrupting REM sleep.
The loss of intercostal and accessory muscle activity during REM sleep leads to
a reduction of alveolar ventilation. This may manifest as apparent central apnea or
hypopnea in patients with compromised lung mechanics or neuromuscular disease.
If severe diaphragm dysfunction is present, nadir tidal volume may be negligible
and the event may appear as central apnea. Thus, central apnea during REM sleep
represents transient hypoventilation rather than post-hyperventilation hypocapnia.
at a higher set point above the apneic threshold.
2
Age andGender
Central sleep apnea is more prevalent in older adults relative to middle-aged individuals [39–41]. Physiologically, sleep state oscillations may precipitate central
apnea in older adults [42]. Increased prevalence of comorbid conditions such as
thyroid disease [43], congestive heart failure [44], atrial brillation [45], and cerebrovascular disease [46] may also contribute to increased susceptibility to develop
central apnea in older adults.
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