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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4704_Библиотеки_им_академика_М_И_Перельмана
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interventions in the management of CSA, from acetazolamide and overdrive atrial
pacing to the placement of implantable remedē systems.
68 A. S. BaHammam et al.
Keywords Central sleep apnea (CSA) · Cheyne–Stokes respirati
on (CSR) · Central
respiratory control · Acid-base balance · Adaptive servo-ventilation (ASV)
5.1 Introduction
Central sleep apnea (CSA) is characterized by recurrent apneic episodes with absent
respiratory effort. This is not a common clinical condition like obstructive sleep
apnea. Depending on the epidemiologic studies, this occurs only in 2–5% of sleep
clinic populations. This is more commonly seen in patients with congestive heart
failure, using narcotics, suffering from a stroke, or living in high altitudes.
5.2 Classification of Central Sleep Apnea
Central sleep apnea is diagnosed when more than 50% of the events are central
types. Apnea in adults is scored when there is a drop in the peak signal excursion by
≥90% of the pre-event baseline using an oronasal thermal sensor (diagnostic study),
PAP device flow (titration study), or an alternative apnea sensor, for ≥10 s (Berry
et al. 2020). The respiratory inductance plethysmography (RIP) signals can be
utilized as alternative sensors for the detection of apnea and hypopnea, as specified.
The task force reached consensus on the use of the same sensors for adult and pediatric
patients except for the following: (1) the end-tidal PCO
2
signal can be used as an
alternative sensor for apnea detection in children only, and (2) polyvinylidene fluoride
(PVDF) belts can be used to monitor respiratory effort(thoracoabdominal belts) and as
an alternative sensor for detection of apnea and hypopnea (PVDFsum) only in adults.
A more accurate determination of the absence of inspiratory effort would entail the use
of an esophageal balloon catheter, which is not used in daily practice. Another option
is diaphragmatic electromyography used only in research settings.
5.3 Classifications of Central Sleep Apnea
The diagnostic criteria for CSA vary according to the type of CSA (ICSD 2014)
(AASM
2014):
5.3.1 Primary CSA Requires the Following Four Findings
Polysomnography (PSG) reveals ≥5 central apneas and/or central hypopneas per
hour of sleep; the number of central apneas and/or central hypopneas is >50% of the
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total number of apneas and hypopneas, and there is no evidence of Cheyne–Stokes
breathing.
5 Central Sleep Apnea: Advances in the Last Decade 69
The patient reports sleepiness, awakening with shortness of breath, snoring,
witnessed apneas, or insomnia (difficulty initiating or
maintaining sleep, frequent
awakenings, or nonrestorative sleep).
There is no evidence of daytime or nocturnal hypoventilation.
The disorder is not better explained by another current sleep disorder, medical or
neurological disorder, medication use, or substance use disorder.
Central sleep apnea disorders include a number of disorders, which according to
the ICSD-3, can be divided into (AASM 2014):
• Central sleep apnea (CSA) with Cheyne–Stokes breathing (CSB)
• Central apnea due to a medical disorder without CSB
• Central sleep apnea due to high-altitude periodic breathing
• Central sleep apnea due to a medication or substance
• Primary central sleep apnea
• Primary central sleep apnea of infancy
• Primary central sleep apnea of prematurity
• Treatment-emergent central sleep apnea
5.3.2 CSA with Cheyne–Stokes Breathing Requires
the Following Four Findings
CSB is observed chiefly in patients with a low left ventricular ejection fraction, but it
has also been reported in patients with acute pulmonary edema, central nervous
system lesions, and advanced renal failure (AlDabal and BaHammam
2010). In
addition, the appearance of CSB in patients with heart failure is linked with increased
morbidity and mortality and diminished quality of life (Carmona-Bernal et al.
2008).
The AASM describes CSB as a breathing disorder in which there are cyclical
fluctuations in breathing, with periods of central apneas or hypopneas that substitute
with periods of hyperpnea in a regular waxing and waning fashion. Many patients
with left ventricular systolic impairment experience CSB and/or other sleep-related
breathing disorders (AlD abal and BaHammam
2010). Patients with severe heart
failure and an ejection fraction as low as 35% to 40% are predisposed to have
pulmonary congestion and raised pulmonary venous pressure (AlDabal and
BaHammam
2010). Pulmonary congestion may cause stimulation of pulmonary J
receptors and finally results in hyperventilation (AlDabal and BaHam mam
2010).
When the PaCO
2
drops beneath the apnea threshold, central apneas are initiated.
Afterward, this cycle of hyperventilation-apnea remains during sleep.
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70 A. S. BaHammam et al.
5.3.2.1 Symptoms
It is usually challenging to distinguish heart failure symptoms from breathing-related
sleep disorders, as both may share symptoms such as poor sleep quality, daytime
sleepiness or insomnia, paroxysmal nocturnal dyspnea, and fatigue. Hence, individ-
ual clinical assessment is needed to avert delays in diagnosing comorbid sleep
disorders in heart failure patients. Commonly, patients with heart failure and CSB
have a lower body mass index than patients with concurrent OSA (Sin et al.
1999).
Moreover, CSB has been described to be more prevalent amongst men and patients
with atrial fibrillation (AlDabal and BaHammam 2010).
5.3.2.2 Diagnosis
In general, patients with CSB usually have low or normal PaCO
2
, and an enhanced
ventilatory response to CO
2
(Xie et al. 2002). However, it is not uncommon to see
patients with heart failure who have coexisting OSA and CSB (AlDabal and
BaHammam
2010). The overnight polysomnography typically exhibits periodical
changes in ventilation, with cycles of central apnea or hypopnea that alternate with
cycles of hyperpnea that prevail during stages N1 and N2 of NREM sleep. Figure 5.1
shows an example of CSB.
5.3.3 CSA Due to High-Altitude Periodic Breathing Requires
the Following Four Findings
Recent ascent to a high altitude (typically at least 2500 m, although some individuals
may exhibit the disorder at altitudes as low as 1500 m) may develop CSB.
Fig. 5.1 A 9-minute window of a sleep study displaying Cheyne-Stokes Respiration (CSR) with a
crescendo-decrescendo pattern, highlighting the characteristic fluctuations in breathing amplitude.
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5 Central Sleep Apnea: Advances in the Last Decade 71
The patient reports sleepiness, awakening with shortness of breath, snoring,
witnessed apneas, or insomnia (difficulty initiating or maintaining sleep, frequent
awakenings, or nonrestorative sleep).
Symptoms are clinically attributable to periodic high-altitude breathing. PSG, if
performed, reveals recurrent central apneas or hypopneas primarily during non-rapid
eye movement (NREM) sleep at a frequency of ≥5/h.
The disorder is not better explained by another current sleep disorder, medical or
neurological disorder, medication use (e.g., narcotics), or substance use disorder.
The periodic breathing that occurs in high altitudes is likely due to hypobaric
hypoxia stimulation of the peripheral chemoreceptors (White et al.
1987). The
periodic breathing cycle length in high-altitude CBS is shorter than that in patients
with heart failure (Wedewardt et al.
2010).
Pathophysiology of CSA: Pathophysiology varies with specific categories and
the sleep stages of CSA. In particular, the transitional pathophysiological changes
are significant between wake and sleep REM stages.
5.4 Breathing in Non-Rapid Eye Movement (NREM) Sleep
Skatrud and Dempsey studied the effect of sleep state on ventilatory rhythmicity
following graded hypocapnia was determined in two normal subjects and one patient
with a chronic tracheostomy. Passive positive-pressure hyperventilation (PHV) was
performed for 3 min awake and during non-rapid eye movement (NREM) sleep with
hyperoxia [fractional inspired O
2
concentration (FIO
2
) = 0.50], normoxia, and
hypoxia (FIO
2
= 0.12). They concluded that effective ventilatory rhyth mogenesis
in the absence of stimuli associated with wakefulness is critically dependent on
chemoreceptor stimulation secondary to PCO
2
-
[H
+
]. This is also accompanied by
increased upper airway resistance (Skatrud and Dempsey
1983). An average of 2 to
8 mmHg rise in PaCO
2
is seen during NREM sleep. During NREM sleep, ventilation
is totally under metabolic control (Muza
2015
). Douglas et al. measured the venti-
latory response to hypercapnia in 12 sleeping adults using a modified rebreathing
method. The HCVR (hypercapnic ventilatory response) was significantly reduced in
all stages of sleep compared with that during wakefulness (1.60 ± 0.19 SEM L/min/
mmHg CO
2
), falling to less than half the waking HCVR during non-REM sleep
(0.75 ± 0.08 L/min/mmHg CO
2
), with a further significant drop during REM sleep
when HCVR was less than a third of that during wakefulness (0.45 ± 0.10 L/min/
mmHg CO
2
) (Douglas et al. 1982). The decreased ventilatory responses to hyper-
capnia and hypoxia in REM sleep help explain rapid eye movement (REM)-related
hypoxemic episodes (Sin et al.
1999; Douglas et al. 1982).
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72 A. S. BaHammam et al.
5.5 Breathing in REM Sleep
Irregular breathing is a common feature of REM sleep. Several studies have inves-
tigated the correlation between phasic eye movements and changes in respiratory
patterns. Gould et al. showed that increasing eye-movement activity was associated
with a reduction in tidal volume (VT) and a shortening of total breath time (TT),
whereas inspiratory time (TI) was unchanged (Gould et al.
1988). This association of
phasic events and changes in respiration causing the irregularity remained
unchanged in the night, although the frequency of events increased from early to
late REM sleep. Schafer and Schafke showed that the typical changes in respiration
associated with rapid eye movements, for example, rapid, shallow breathing with
predominant effects on rib cage excursions and TE, are by no means attenuated
during increased respiratory drive during hypercapnia but are even more pronounced
(Schafer and Schlafke 1998).
In general, central apnea is less frequent during REM sleep than NREM sleep
(particularly the lighter stage s of NREM sleep), which is thought to be related to the
greater arousability during the lighter stages of NREM sleep (Xie et al.
1994),
decreased hypercapnic and hypoxic ventilatory responses during REM sleep, and
hence reduced loop gain probably due to inhibition of accessory chest wall muscles
(Douglas et al. 1982 ; Badr et al. 2019).
5.6 Cheyne–Stokes Breathing Pattern
CSR is a breathing pattern characterized by cycles of crescendo-decrescendo
changes in tidal volume followed by central sleep apneas. This condition leads to
variations in hemodynamic, respiratory, and neurologic functions, as well as in acid-
base balance. Both historical and current theories regarding its causation emphasize
a disruption in central respiratory control as the primary factor in the development of
periodic respiration. Tissue perfusion and metabolically determined changes in acid-
base balance have dominant roles in the production of CSR (Dowell et al. 1971).
In patients with heart failure, a complete cycle of apnea, hypopnea, hyperpnea,
and hypopnea leading to the next apnea usually takes about 45 seconds but longer.
At least ten consecutive minutes of these cycles should be recorded before CSR can
be diagnosed. The ICSD-3 specifies that at least ten central apneas and hypopneas
per hour of sleep should occur, accompanied by arousals and derangement of sleep
structure (AASM 2014).
5.6.1 Predisposing Factors
Congestive heart failure
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5 Central Sleep Apnea: Advances in the Last Decade 73
Stroke
Renal failure
Lower resting PaCO
2
than normal
Narcotics
It is challenging to distinguish heart failure symptoms from sleep-related breath-
ing disorders, as both may have overlapping symptoms like poor sleep quality,
daytime somnolence or insomnia, paroxysmal nocturnal dyspnea, and easy fatiga-
bility. Central apneas with CSB and heart failure characteristically have a long cycle,
typically in the 40 seconds or more. Polysomnographic studies demonstrate, a typical
crescendo-decrescendo pattern. Due to longer circulation time, there is a long delay
in the nadir in the oxygen saturation tracing after event termination. The typical CSB
cycle time is long at 60–90 s. It is associated with left ventricular systolic dysfunc-
tion but has also been seen with diastolic dysfunction. Cardiovascular diseases are
by far the most relevant causes of central disturbances, especially HF and atrial
fibrillation (Randerath and Javaheri
2016). Most of these episodes are explained by
an increase in loop gain, with overshooting and undershooting of the ventilation
resulting in the pattern of periodic breathing. Even the arousals may play a role in
these events (Douglas et al.
1982; Xie et al. 1994; Badr et al. 2019).
5.7 Treatment-Emergent Central Sleep Apnea (Formerly
Complex Sleep Apnea)
Treatment-emergent central sleep apnea (TECSA, formerly complex sleep apnea)
describes the appearance of central sleep apnea (CSA) and/or hypopnea while
undergoing treatment for obstructive sleep apnea (OSA) (AASM
2014). Some
patients with OSA or mixed apneas developed central sleep apnea after the signif-
icant resolution of the obstructive events by treatment with a positive airway
pressure (PAP) device without a backup rate therapeutic failure (BaHammam
2017). However, new-onset CSA has also been reported during other non-CPAP
treatments for OSA, including endoscopic sinus and nasal surgery and the use of oral
appliances (Goldstein and Kuzniar 2012). Additionally, TECSA has been reported
following tracheostomy, mandibular-advancement device (MAD), and
maxillomandibular advancement surgery (BaHammam 2017).
Mohan et al noted that a patient with moderate OSA who used MAD initially had
CSA (Mohan et al. 2016). The spontaneous resolution of MAD-emergent CSA was
observed in this patient 1 year after MAD treatment. There have been three reports
on the occurrence of similar MAD-emergent CSA during treatment with MAD.
Therefore, the definition of TECSA should include both transient and persistent CSA
that may occur after not only CPAP treatment but also following any form of therapy
for OSA (Avidan et al.
2006).
The reported prevalence rate of TECSA has been strikingly inconsistent; a
systemic review that included nine studies reported prevalence rates of 5.0% to
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20.3% (Nigam et al. 2016). The prevalence of TECSA during whole-night titration
studies varies from 5.0% to 12.1%, whereas it was between 6.5% and 20.3% during
split-night titration studies (Nigam et al. 2016). However, the cumulative prevalence
of TECSA was 8% (Nigam et al.
2016). This broad difference in prevalence can be
attributed to the characteristics of the study groups like patient demographics, body
mass index (BMI), gender, age, comorbidities, and causes related to the diagnostic
method such as split-night titration and titration in the supine position (Liu et al.
2017).
74 A. S. BaHammam et al.
An extensive study that tracked
patients with OSA for 90 days after the start of
CPAP therapy found that older age, higher residual AHI and central apnea index
(CAI), and higher leak are the main predictors of TECSA; henceforth, patients with
these characteristics should always necessitate early and close monitoring (Liu et al.
2017). In general, patients with TECSA have reduced adherence to PAP therapy.
5.7.1 Pathophysiology of TECSA
To comprehend the pathophysiology of TESCA, we need to investigate the patho-
physiology of central sleep apnea. During sleep, in the absence of a wakefulness
drive to breathe, metabolic control is solely responsible for breathing. Additionally,
the hypercapnic and hypoxic drives are reduced, and there is also increased upper
airway resistance. The pathophysiological mechanism of this phenomenon revolves
around the “loop gain,” which has two components: plant gain and controller gain.
Controller gain refers to the chemosensitivity and ventilatory responses to hypoxia
and hypercapnia. On the other hand, plant gain refers to the changes in PaCO
2
levels
resulting from a given change in ventilation. Central sleep apnea can result second-
ary to unstable breathing caused by high loop gain, or secondary to reduced output
from the central neurons. Therefore, high loop gain results in hyperventilation and a
lower PaCO
2
level below the apneic threshold. When the PaCO
2
level drops below
the apneic threshold, ventilation will cease, and apnea will oc cur and last until the
PaCO
2
level increases above the threshold (BaHammam 2017). This phenomenon is
more profound and common during non-rapid eye movement sleep when the CO
2
reserve, which is the difference between eupneic PaCO
2
and the apneic threshold, is
highly labile.
PAP therapy settings have a minor influence on the emergence of TECSA;
nevertheless, high PAP pressure, quick titration, and the usage of BPAP therapy
are allegedly connected with more mask leaks and pressure intolerance and, conse-
quently, sleep disruption and consequent CSA. Several theories have been proposed,
including that the upper airway resistance owing to OSA can reduce the ventilatory
control system, thus dropping the efficiency of CO
2
washout; when the resistance
improves by PAP therapy, PaCO
2
washout occurs, hence reducing the PaCO
2
tension to a value under the CO
2
apnea threshold resulting in CSA. Over several
days to weeks, the CO
2
apnea threshold is known to adjust, causing the resolution of
CSA. Another suggested theory is that, in the occurrence of a significant mask leak
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or mouth breathing, when a nasal mask is used, it may lead to a washout of CO
2
from
the anatomical dead space, which causes in a fall in CO
2
below the apnea threshold.
A third theory, though less probable, is that PAP therapy may deteriorate sleep
quality, resulting in recurrent shifts from sleep to wake and wake to sleep conditions,
causing repeated arousals with resultant stimulation of the ventilatory drive, which
decreases PaCO
2
below the CO
2
apnea threshold and the appearance of CSA during
consequent sleep.
5 Central Sleep Apnea: Advances in the Last Decade 75
5.8 High-Altitude Periodic Breathing
The term “high-altitude illness” is used to describe the cerebral and pulmonary
syndromes that can develop in unacclimatized persons shortly after ascent to high
altitude. Acute mountain sickness and high-altitude cerebral edema refer to cerebral
abnormalities and high-altitude pulmonary edema to pulmonary abnormalities
(Hackett and Roach 2001). Most people will gradually acclimatize to altitude if
there is a gradual ascent. Polysomnographic studies demonstrate recurrent central
apneas primarily during NREM sleep at a frequency of >5/h. The cycle length is
shorter than central apneas in heart failure in the range of 12–34 s (Muza 2015).
5.9 CSA Due to Medications (Narcotics/Opiates)
Most used drugs include morphine, fentanyl, and methadone—both prescriptions
use and illicit drug abuse. Some of these patients may exhibit a low respiratory rate,
accompanied by prolonged episodes of both obstructive and central sleep apneas.
They also can have variations in tidal volume and ataxic breathing. The most
important risk factors for the severity of CSA are morphine equivalent daily dose
(MEDD) >200 mg and low or normal body mass index (Correa et al.
2015).
5.10 Differential Diagnosis
Most of the patients with central sleep apnea manifest with excessive daytime
drowsiness, daytime fatigue, and/or fragmented sleep; nevertheless, some may
present with insomnia as central apneas may manifest during the transition from
wake to sleep causing disruption of sleep. As usual, it is essential to take a detailed
patient history, conduct a physical exami nation, and review all medications being
taken by the patient, including prescribed, over-the-counter, and any substances of
illicit use. If CSA is a consideration, they should undergo diagnostic
polysomnography. Other differential diagnosis includes:
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76 A. S. BaHammam et al.
– Obstructive sleep apnea (OSA)
– Periodic limb movements of sleep (PLMS)
– Rotating shift workers
– Narcolepsy
5.11 Management of Central Sleep Apnea
Treatment of CSA should be individualized based on the patient’s severity of
symptoms and the presence or absence of known comorbidities and risk factors.
When CSA is discovered incidentally, the treatment can also be watchful waiting
and close follow-up. At least 15–20% of patients with CSA resolve with no
significant intervention. This applies to TECSA, where most apnea events during
initial PAP titration are self-limited and go away over time. A follow-up is necessary
to make sure that the emergent central apneas disappeared. This can be accomplished
by tracing the PAP stored data. Nonetheless, the therapist should search for problems
causing TECSA and resolve them. If over-titration is suspected, reducing the PAP
settings may be necessary to resolve the issue. When a significant mask leak is
identified, the mask should be adapted or changed.
5.11.1 Continuous Positive Airway Pressure
Continuous positive airway pressure (CPAP) improves cardiac function in patients
with congestive heart failure (CHF) who also have Cheyne–Stokes’s respiration and
central sleep apnea (CSR-CSA). Sin et al. conducted a randomized, controlled trial
that showed that CPAP improves cardiac function in CHF patients with CSR-CSA
but not in those without it. Stratified analysis of patients with and without CSR-CSA
revealed that those with CSR-CSA experienced both a significant improvement in
LVEF at 3 months and a relative risk reduction of 81% in the mortality-cardiac
transplantation rate of those who used CPAP (Sin et al.
2000). However, the
Canadian prospective continuous positive airway pressure (CANPAP) trial had
different results. Bradley et al. conducted the study and tested the hypothesis that
CPAP would improve the survival rate without heart transplantation of patients with
central sleep apnea and heart failure (Bradley et al. 2005). Although CPAP attenu-
ated central sleep apnea, improved nocturnal oxygenation, increased the ejection
fraction, lowered norepinephrine levels, and increased the distance walked in 6 min,
it did not affect survival. Thus, the data do not support the use of CPAP to extend life
in patients who have central sleep apnea and heart failure (Bradley et al.
2005).
Nevertheless, in the post hoc analysis of the study, patients with residual AHI < 15/h
on CPAP had improvement in LVEF and heart transplant-free survival (Arzt et al.
2007). Thus, the authors advocated a 1-month trial of CPAP, to be maintained only if
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it significantly reduces AHI. Based on those findings, CPAP should not be consis-
tently used to manage CSR in patients with heart failure and CSR.
5 Central Sleep Apnea: Advances in the Last Decade 77
The goals of PAP titration in CSA are
extrapolated from the studies in patients
with obstructive sleep apnea. The strict criteria for real success are AHI < 5/h, even
though some clinicians do accept AHI < 15/h as a partial success criterion. The
therapy needs to be individualized.
5.11.2 Bilevel Positive Airway Pressure
Bilevel positive airway pressure (BIPAP) is an effective therapy for treating patients
with central sleep apnea. Cheyne–Stokes respiration with central sleep apnea
(CSR-CSA) is not associated with a good prognosis in patients with CHF. However,
some patients do not respond to CPAP, so other therapeutic modalities should be
considered, such as bilevel positive airway pressure (BPAP).
Dohi et al. studied 20 patients with HF because of left ventricular systolic
dysfunction. The AHI improved signi ficantly in 11 (AHI <15), but only slightly
in 9, in whom the AHI remained high (>or = 15). Bilevel PAP titration significantly
improved the AHI in the latter group. Those who were unresponsive to CPAP had
significantly lower PaCO
2
, higher plasma brain natriuretic peptide (BNP), longer
mean duration of CSR, and fewer obstructive episodes than CPAP responders.
Bi-level PAP could be an effective alternative for patients with HF and pure
CSR-CSA who are unresponsive to CPAP (Dohi et al.
2008).
5.11.3 Oxygen
Sasayama et al. studied the sustained efficacy of HOT (home oxygen therapy) in the
long-term treatment in 51 patients with CSA and CHF [New York Heart Association
(NYHA) functional classes II – III] assigned to receive either nocturnal oxygen or
usual breathing for 52 weeks (Sasayama et al. 2009). In the HOT group, Sasayama
et al. (2009) observed a more significant reduct ion in apnea and hypopnea events,
along with a notable increase in nocturnal oxygen saturation (Sasayama et al. 2009).
These changes correlated with a marked improvement in the Specific Activity Scale,
NYHA functional class, and ejection fraction. Consequently, HOT may be consid-
ered a valuable non-pharmacological therapeutic addition for HF patients with CSA
(Sasayama et al.
2009).
Campbell et al. compared two common treatments for CSA-CSR. Subjects with
CSA-CSR and stable congestive heart failure were randomized to 8 weeks of treat-
ment: oxygen 2 L/min through nasal prongs and concentrator or 8 weeks adaptive
servo-ventilation (ASV) using a crossover design separated by a 3-week washout
(Campbell et al.
2012). Ten subjects (age 64 ± 10 years, left ventricular ejection
fraction (LVEF) 28 ± 10.5%, apnoea-hypopnoea index (AHI) 63 ± 30/h) were
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