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8 Central Sleep Apnea: Pathophysiology andClinical Management
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Chapter 9
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Sleep andHypoventilation
AmandaJ.Piper
Keywords Sleep hypoventilation · hypercapnia · respiratory failure · obesity
hypoventilation syndrome · neuromuscular disease · sleep disordered breathing
General Introduction
Sleep can present a signicant challenge to respiration in people with respiratory or
ventilatory control disorders. The normal physiological changes in breathing associated with sleep may be exaggerated in these populations, resulting in sleep disruption and hypoventilation. Sleep-related hypoventilation is most commonly seen in
patients with morbid obesity, neuromuscular disorders (NMD) or severe chronic
obstructive pulmonary disease (COPD). Failure to recognize and treat sleep
hypoventilation leads to eventual daytime hypercapnia and premature mortality.
However, signs and symptoms suggestive of sleep hypoventilation are often nonspecic and vague, and so the condition may be overlooked or misdiagnosed preventing timely and appropriate intervention. In this chapter, the general mechanisms
relevant to the development of sleep hypoventilation will be reviewed as well as
issues specic to the major diagnostic groups likely to present with sleep
hypoventilation.
A. J. Piper (*)
Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital,
Camperdown, NSW, Australia
Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
e-mail: amanda.piper@sydney.edu.au
M. S. Badr, J. L. Martin (eds.), Essentials of Sleep Medicine,
Respiratory Medicine, https://doi.org/10.1007/978-3-030-93739-3_9
163© Springer Nature Switzerland AG 2022
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A. J. Piper
Normal Sleep Breathing
When an individual goes from awake to sleep, a number of physiological changes
occur within the respiratory system. These include a reduction in respiratory centre
output to the upper airway and respiratory muscles, along with reduced chemoreceptor responsiveness to oxygen (O2) and carbon dioxide (CO2). As a consequence,
upper airway resistance increases, lung volumes decrease and respiration can become
more variable and shallower, resulting in a small fall in minute ventilation of around
10–15% along with rises in CO
is also lower by around 2%. During rapid eye movement (REM) sleep, inhibition of
postural muscles including the intercostal and accessory respiratory muscles leaves
the diaphragm to maintain ventilation [1, 3]. Chemosensitivity to both O2 and CO2 is
further reduced in this sleep stage [4]. These changes in ventilation and gas exchange
are relatively minor and of little clinical consequence. However, when overlaid on
pre-existing pulmonary or neuromuscular pathology, signicant reductions in ventilation and abnormalities in gas exchange can occur [3]. These reductions are generally related to falls in tidal volume, and hence alveolar ventilation, and most marked
in REM sleep [3] (Fig.9.1). However, over time with ongoing attenuation of ventilatory responsiveness to chemostimulation, extension of hypoventilation into nonREM (NREM) and wakefulness eventually occurs. In addition, the reduction in lung
volumes [5] and reduced activation of the upper airway muscles with the onset of
sleep can produce ow limitation and upper airway collapse, resulting in an added
challenge to breathing during sleep in some at risk populations.
of 2–7mmHg [1, 2]. Oxygen saturation during sleep
2
Compensatory Mechanisms inHypoventilation Syndromes
A number of defensive or compensatory mechanisms can be brought into play to
minimize disturbance of gas exchange during sleep in those experiencing sleep
hypoventilation. The most obvious of these is arousal from sleep in the face of signicant changes in gas exchange. Through arousal, albeit brief, ventilation can be
restored at least to some extent, limiting the degree of oxygen saturation fall and
carbon dioxide accumulation. However, frequent arousal from sleep will impair
sleep quality, producing daytime symptoms, and if persistent will contribute to
attenuated chemosensitivity [6]. In addition, hypoxia impairs the arousal response
to compromised ventilation [7]. In an ongoing cycle, longer periods of abnormal gas
exchange occur before arousal produces some, although incomplete, restoration of
ventilation with consequent higher levels of CO2 and lower levels of oxygen. This
further impairs ventilatory responsiveness to changes in gas exchange, eventually
seeing the development of hypoventilation throughout the sleep period and eventually wakefulness [8].
In an attempt to improve sleep and breathing, patients may alter their sleeping
position. Vital capacity (VC) is reduced from the upright to supine position in those
Sleep andHypoventilation
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Fig. 9.1 In people with nocturnal hypoventilation, a signicant fall in minute ventilation (Vi) during sleep occurs, most marked during REM sleep. As shown in the top panel, this fall in ventilation
and oxygen saturation is primarily driven by a reduction in tidal volume (V
(Reprinted with permission of the American Thoracic Society. Copyright © 2020 American
Thoracic Society. All rights reserved. Becker etal. [3]. The American Journal of Respiratory and
Critical Care Medicine is an ofcial journal of the American Thoracic Society)
with diaphragmatic weakness or where diaphragmatic movement is restricted due to
abdominal obesity. In order to minimize orthopnoea, the supine position may be
avoided, or patients will use multiple pillows to assume a more upright position in
bed. Some morbidly obese individuals have spent months or years in a chair at night
in an attempt to both sleep and breathe.
) (bottom panel).
T
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A. J. Piper
Since the physiological changes occurring during sleep make breathing most
vulnerable during the REM period, a reduction or absence of this sleep stage minimizes the likelihood of signicant abnormalities in gas exchange occurring.
However, this also produces sleep disruption and has been shown to be associated
with poorer outcomes in some conditions [9].
Recruitment of accessory respiratory muscles such as the sternomastoid and scalene during inspiration and the abdominal muscle during expiration occurs in some
patients with diaphragmatic dysfunction during wakefulness and NREM sleep.
This is thought to be an adaptive mechanism to maintain ventilation particularly in
NREM sleep in response to reduced neural drive [10]. With the normal loss of postural muscle tone during REM, accessory respiratory muscles are no longer able to
contribute to maintaining ventilation, resulting in deterioration in gas exchange [11,
12]. In some patients however, persistence of extradiaphragmatic muscle activity
during REM occurs [9, 13, 14]. In a group of patients with amyotrophic lateral
sclerosis (ALS) and diaphragmatic dysfunction, those in whom sternomastoid
activity continued in REM sleep not only maintained this sleep stage for longer but
survival was also better compared to those individuals not exhibiting this behaviour
[9]. More recently, persistence of neck muscle activity during sleep was evaluated
in a group of severe COPD patients recovering from an exacerbation [14]. While no
patient showed neck muscle activity while awake, 26 of the 29 studied demonstrated inspiratory neck muscle activity during sleep. In 17 patients, this occurred
in Stage 3 sleep only while in 9, there was persistence of activity throughout sleep.
Compared to those showing no or intermittent sleep neck muscle activity, patients
where the neck muscles were activated throughout sleep experienced greater sleep
disruption, more exacerbations in the year prior to the study and were more likely
to be re-hospitalized over the next 6months with an exacerbation. However, there
was no difference between groups in awake PaCO2 or nocturnal hypoventilation/
hypoxemia.
Irrespective of the primary underlying disorder, those with sleep hypoventilation exhibit a reduced responsiveness to CO
. In response to abnormally low
2
breathing during sleep, CO2 rises transiently. If there is insufcient restorative
ventilation between these abnormal breathing periods, CO2 accumulates. In order
to maintain pH levels, renal compensation with retention of bicarbonate occurs.
However, these elevated blood bicarbonate levels blunt ventilatory responsiveness to CO2 [15], contributing to further progression of respiratory failure. In
obesity hypoventilation syndrome (OHS), patients with a lower ventilatory
response to CO2 spent a greater percentage of REM sleep in hypoventilation [16]
(Fig. 9.2). Studies investigating how nocturnal non-invasive ventilation (NIV)
achieves improved awake gas exchange in chronic hypoventilation found that an
increase in ventilatory responsiveness to CO2 was the main mechanism in patients
with restrictive thoracic disorders [17], and played a signicant role along with
reduced gas trapping in those with chronic obstructive pulmonary disease
(COPD) [18].
REM HypoVA, %
100
6
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Fig. 9.2 In obesity,
hypoventilation syndrome,
a signicant relationship
between baseline CO
sensitivity and the amount
of hypoventilation during
REM sleep has been shown
such that patients with
lower CO
responsiveness will spend
more of REM sleep in
hypoventilation. (From
Chouri-Pontarollo etal.
[
16] with permission)
ventilatory
2
2
80
60
40
20
y = –31.195*Ln(X) + 50.829
r = 0.54, p = 0.037
0
0
123
sensitivity 1/min/mmHg
CO
2
45
167
Identifying andDening Sleep Hypoventilation
Traditionally, arterial blood gas measurements have been performed to detect raised
CO2, which is the hallmark of hypoventilation. However, repeated arterial punctures
or the insertion of an arterial line to monitor CO2 during sleep is not practical or
appropriate to identify sleep hypoventilation. Furthermore, the development of
awake hypercapnic respiratory failure is considered to be a late manifestation of
sleep hypoventilation, particularly in those with neuromuscular or chest wall disorders. Consequently, clinicians have sought simpler, less invasive methods of identifying sleep hypoventilation before awake hypercapnia is present to prevent acute
respiratory decompensation.
Daytime Measures toIdentify Sleep Hypoventilation
Patients with sleep hypoventilation may complain of an array of symptoms, related
to both sleep and daytime function (Table9.1). However, symptoms alone are not a
good guide in identifying possible sleep hypoventilation due to their vague and nonspecic nature. Additionally, some individuals will not even be aware they are experiencing symptoms until effective therapy has been established. In other cases,
reported symptoms may be erroneously attributed to the underlying disorder and
further investigation of potential sleep breathing problems overlooked.
In neuromuscular disorders (NMD), a number of simple clinic tests have been
used to identify those most at risk of sleep hypoventilation. The most widely used
measure is VC, with a previous study in a mixed group of muscular dystrophies and
myopathies nding a VC <40% of predicted identied those likely to have continuous
hypoventilation while daytime respiratory failure was likely to been seen with a VC
<25% of predicted [19]. Supine VC improves the predictive value of this measure
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Table 9.1 Symptoms commonly associated with sleep hypoventilation
Daytime fatigue
Daytime sleepiness
Morning headaches
Sleep disruption
Orthopnoea
Dyspnoea
Confusion
Insomnia
Nightmares
A. J. Piper
[19], with a fall from the upright position >20% suggestive of diaphragm weakness
[20] and therefore a higher suspicion of sleep hypoventilation. In ALS, VC is widely
used as a predictor of survival and an indicator to commence nocturnal NIV [21], but
has limited predictive power in identifying sleep hypoventilation. For instance, in a
study of 250 patients with ALS, Boentert etal. [22] found that a third of those with an
upright VC >75% of predicted showed sleep hypoventilation while, in contrast,
almost half of those with a VC <in 50% predicted, no nocturnal hypoventilation was
seen. Other simple measures of inspiratory muscle strength used in conjunction with
VC measures are maximum inspiratory pressure (MIP) and sniff nasal inspiratory
pressure (SNIP). This latter measurement is particularly useful in patients with facial
muscle weakness who nd it difcult to maintain a lip seal around a mouthpiece [23].
Nocturnal hypoventilation is unlikely to occur until MIP is <40cmH2O [19], but this
test may give falsely low values in some patients due to leak around the mouthpiece
or from an inability to sustain a maximal inspiratory effort [24]. In ALS patients, a
SNIP <40 cmH2O correlates well with nocturnal hypoxia [23]. Although there is a
good correlation between MIP and SNIP in NMD, these tests are not interchangeable
and whenever possible should be performed concurrently [25].
Measures of daytime pulmonary function have not been shown to be sufciently
sensitive to predict hypoventilation in OHS or COPD.In patients presenting with
obesity and potential sleep disordered breathing, the goal is to identify those in
whom an arterial blood gas should be taken in order to conrm a diagnosis of
OHS.In this population, oxygen saturation by pulse oximetry (SpO
) rather than
2
spirometric measures is generally used as a screening tool to identify those at risk
for awake hypercapnia. Chung etal. [26] showed an awake supine SpO2 <91% had
a 34.8% sensitivity and 96.6% specicity for detecting daytime hypercapnia in a
group of super-obese individuals (body mass index [BMI] >50kg/m2) presenting to
a sleep laboratory. In another study, a combination of clinic SpO2 and FVC was
found to be highly sensitive in detecting awake hypercapnia in obese individuals
with an abnormal nocturnal oximetry, although specicity was low [27]. Only one
study has sought to identify obesity-related sleep hypoventilation, a potential early
stage of OHS [28, 29]. In a group of morbidly obese patients (BMI>40kg/m
2
), an
awake SpO2 measured in the supine position of ≤93% was found to predict sleep
9 Sleep andHypoventilation
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169
hypoventilation with a sensitivity of 39% and specicity of 98% [30]. However,
recent guidelines on evaluating and managing OHS suggest that SpO2 during wakefulness should not be used to screen for OHS in obese patients with obstructive
sleep apnoea (OSA) due to insufcient data [31]. Although patients with low awake
PaO2 or SpO2 are more likely to desaturate at night [32], this is not necessarily
related to hypoventilation alone, and overall daytime awake pulmonary function
values do not correlate well with nocturnal desaturation [33].
Elevated levels of bicarbonate or base excess measured by venous or arterial
bloods can be useful to suggest or screen out sleep hypoventilation. Base excess
>3mmol/L has been reported to be a signicant predictor of sleep hypoventilation
in ALS [22] and Duchenne muscular dystrophy (DMD) [34], although with only
moderate sensitivity. In obese individuals with OSA, a serum bicarbonate
<27 mmol/L makes the diagnosis of OHS very unlikely [31]. However, caution
needs to be exercised when interpreting bicarbonate levels, as these can be inuenced by factors other than a raised CO2 [35].
Nocturnal Monitoring toIdentify Sleep Hypoventilation
While awake testing in some populations can raise the suspicion of sleep hypoventilation, as discussed previously these measures remain limited in their ability to
predict sleep hypoventilation and detect its severity. Consequently, more direct
monitoring of gas exchange during sleep is needed to identify sleep hypoventilation
at an earlier stage.
Nocturnal oximetry has been widely used as a potential surrogate for detecting
sleep disordered breathing and hypoxemia. Although cyclical episodes of desaturation–resaturation may be suggestive of obstructive breathing, it does not reveal
anything about CO2 levels. Even if sustained hypoxemia is present, this cannot be
used as evidence for hypoventilation, as this pattern can also occur with ventilation–perfusion mismatching. Furthermore, oximetry can miss sleep hypoventilation in around a third of individuals with NMD [22], and is not informative in
those using supplemental oxygen. Adding a morning blood gas to nocturnal oximetry may still miss the presence of nocturnal hypoventilation in 20–30% of patients
with neuromuscular disorders [22, 36]. Despite some technical limitations, transcutaneous carbon dioxide (TcCO
tilation across a range of respiratory disorders [37], with monitoring able to be
performed both within sleep laboratories and in patient homes [38]. While
advances in technology have signicantly improved the relationship between
PaCO2 and TcCO2 (Fig.9.3), there may be an overestimation of CO2 over time due
to signal drift [40]. However, correction for this drift considerably improves the
reliability of the measurement [39]. The addition of polygraphy and polysomnography to the assessment of patients with potential sleep hypoventilation provides
additional information about the nature of the respiratory events, or in the case of
polysomnography, sleep quality and duration. However, limited access, wait times,
) is now recommended to identify sleep hypoven-
2
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Fig. 9.3 Signicant uctuations in nocturnal CO2 can occur which may be missed if a single blood
gas measure is made. In this illustration, continuous monitoring by two transcutaneous carbon
dioxide devices (the solid and broken lines) capture the variability in CO
in this patient who is using nocturnal ventilatory support. Blood gases (represented by the grey
boxes) can only capture CO
Improvements in technology in recent years have signicantly improved the accuracy and reliability of transcutaneous CO
at a single point in time and can easily miss this variability.
2
monitoring. (From Storre etal. [39] with permission)
2
levels that are occurring
2
A. J. Piper
cost and a lack of facilities to properly care for individuals with signicant physical impediments in sleep laboratories often mean that more limited nocturnal monitoring is undertaken.
One of the difculties in comparing studies of sleep hypoventilation has been the
various denitions that have been employed to describe this phenomenon. Ogna and
colleagues [41] compared the prevalence of hypoventilation in an unselected adult
NMD population according to eight different denitions commonly found in the
literature. Depending on the denition used, hypoventilation ranged from 10% to
61%, even when only denitions around TcCO2 were used (Fig. 9.4). The most
widely recognized denition at present is that proposed by the American Academy
of Sleep Medicine [37] which suggests “an increase in the arterial PaCO2 (or surrogate) to a value > 55mmHg for ≥ 10minutes, or a ≥ 10mmHg increase in PaCO2
(or surrogate) during sleep (in comparison to an awake supine value) to a value
exceeding 50 mmHg for ≥ 10 minutes.” However, these thresholds are based on
expert consensus and may be less sensitive than other denitions in identifying
patients with NMD and daytime normocapnia likely to require ventilatory support
Prevalence (%)
70
Hypoventilation definition
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61
PaCO
2
BaseExc
SpO
[1]
2
SpO
[2]
2
TcCO
2
TcCO
2
TcCO
2
TcCO
2
[1]
[2]
[3]
[4]
40 50 60
0102030
38
10
43
20
13
23
11
171
Fig. 9.4 Numerous denitions of sleep hypoventilation have appeared in the literature which will
signicantly impact on the prevalence of the disorder. This is illustrated by a study of 232 patients
with neuromuscular disorders where the prevalence of sleep hypoventilation ranged from 10.3% to
61.2% depending on the denition used. Legend– PaCO
awake base excess ≥4mmol/L; SpO
[2]: mean nocturnal SpO
TcCO
>55mmHg; TcCO2 [2]: increase in TcCO2 ≥10mmHg (in comparison to an awake supine
2
<90% or SpO2 <90% during >10% of recording time; TcCO2 [1]:
2
[1]: nocturnal SpO2≤88% for 5 consecutive minutes; SpO2
2
value) to a value exceeding 50mmHg for ≥10min; TcCO
[4]: mean TcCO
>50mmHg; TcCO2: transcutaneous carbon dioxide. (From Ogna etal. [41] with
2
: awake PaCO2 >45mmHg; BaseExc:
2
[3]: peak TcCO2 >49mmHg; TcCO2
2
permission)
within the next 24months [42, 43]. There is also limited information around how
these denitions relate to other clinical and patient reported outcomes [44].
Disease-Specic Issues inSleep Hypoventilation
Obesity Hypoventilation Syndrome
Obesity hypoventilation syndrome (OHS) is diagnosed in obese individuals
(BMI>30kg/m2) who present with awake hypercapnia (PaCO2>45mmHg) when
other known causes of hypoventilation such as lung or neuromuscular disease cannot be identied. Obstructive sleep apnoea is present in 90% of these individuals,
with 70% showing an apnoea hypopnea index ≥30/hour [45]. In the remaining 10%
hypoventilation alone is seen, particularly marked during REM sleep. The prevalence of OHS varies depending on the clinical setting these individuals are seen in
and the BMI of the population. Current estimates put the prevalence of OHS in the
general community at around 0.3%, [46] with the likelihood of OHS increasing with
BMI.In obese patients referred to sleep clinics, 10–20% will have OHS [47, 48].
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