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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4538_Библиотеки_им_академика_М_И_Перельмана
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Introduction
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PeterM.Baptista andGuillermoPlazaMayor
1.1 Introduction
Obstructive sleep apnea (OSA) is one of the most prevalent sleep disorders in the
general population, with important pathophysiological sequelae that worsen the
quality of life of patients, leading to an increase in trafc accidents and a higher
mortality rate [1]. Therefore, early diagnosis and adequate treatment of OSA are of
vital importance.
1.2 Sleep Disorders
Sleep is a physiological state to which the human being dedicates a third of his life.
It is an active state, different from wakefulness, in which a series of physiological
processes occur to maintain physical and mental balance.
Sleep is made up of a series of phases in 4–6cycles that repeat throughout 7–8h
during the night. These phases are called REM (Rapid Eye Movement or rapid eye
movement) and non-REM (non-Rapid Eye Movement). The representation of these
is called hypnogram and is obtained by recording the brain electrical activity (electroencephalogram or EEG), eye movements (electrooculogram or EOG) and muscle
activity (electromyogram or EMG).
Each sleep cycle consists of about 60–90min of non-REM sleep and 15–30min
of REM sleep. By the age of 60, deep non-REM sleep starts to decrease, especially
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P. M. Baptista (*)
Clinica Universidad de Navarra, Pamplona, Spain
G. P. Mayor
Hospital Universitario de Fuenlabrada, Hospital La Zarzuela, Madrid, Spain
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
P. M. Baptista et al. (eds.), Obstructive Sleep Apnea,
https://doi.org/10.1007/978-3-031-35225-6_1
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in men, until it disappears, while REM sleep remains stable throughout life. Each
phase of sleep has specic functions, and therefore, its deprivation entails a series of
consequences.
Sleep-related disturbances have been observed in up to 15% of the current population. Given the progressive impact on health and the difcult management of all
sleep disorders, the American Academy of Sleep Medicine (AASM) in 2004 considered necessary a revision of the initial international classication of 1979 (ICSD
international classication of sleep disorders [2].
This classication subdivided all disorders into two large blocks based on the
patient’s main symptomatology: dyssomnias, for all those disorders that lead to
insomnia or excessive daytime sleepiness, which may be caused by intrinsic or
extrinsic factors, and parasomnias, disorders that occur during sleep, sleep without
producing the two previous symptoms. The ICSD-2 already describes seven large
blocks, one of them dedicated exclusively to sleep-disordered breathing, and the last
changes of the ICSD in 2014 gave rise to a third edition (ICSD-3) with minimal
differences from the previous one [3].
International classication of sleep disorders (ICSD-3 2015)
1. Insomnia
2. Sleep-associated breathing disorders (SBD)
3. Hypersomnia of central origin
4. Sleep-wake circadian rhythm disorders
5. Parasomnias
6. Sleep-related movement disorders
7. Other sleep disorders, subclassied in:
(a) Medical and neurological disorders associated with sleep
(b) Substance-induced sleep disorders
P. M. Baptista and G. P. Mayor
1.3 Sleep Breathing Disorders (SBD) andTheir
Differential Diagnosis
In the previous ICSD classications, SDBs belonged to the group of intrinsic sleep
disorders. Currently, they constitute the second group of the ICSD-3 and can be
summarized as follows [2, 4]:
1. Central sleep apnea syndromes
(a) primary
(b) secondary
2. Obstructive sleep apnea syndromes or Obstructive Sleep Apnea (OSA), previ-
ously known as OSAHS (obstructive sleep apnea–hypopnea syndrome)
(a) in the adult
(b) in the child
3. Hypoventilation disorders
(a) idiopathic
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(b) central congenital
(c) secondary
4. Sleep hypoxemia
5. Other nonspecic sleep-disordered breathing:
(a) snoring
(b) catathrenia
All these SBDs have in common a respiratory failure during sleep, which generally leads to continuous oxygen desaturations and a series of clinical manifestations
that will give rise to severe metabolic, neurological and cardiovascular sequelae [5].
Polysomnography (PSG) is considered the reference or gold standard sleep test
[6–14]. It consists of recording neurophysiological and cardiorespiratory parameters during sleep. It allows us to classify the different respiratory events, distinguish
pathological from physiological apneas, obstructive from central apneas, or demonstrate the transition from apnea to breathing, in any sleep position [14].
Currently the relatively high and increasing prevalence of OSA [15] and consequent economic burden and limited access to PSG has led to the development of less
costly procedures like home sleep apnea testing (HSAT) for patients with suspected
obstructive sleep apnea (OSA) and has become widespread [16–18]. Clinical studies have shown that HSAT when used in uncomplicated patients with a high probability of moderate to severe OSA may provide similar diagnostic accuracy as PSG
for moderate and severe OSA [19, 20]. Also, health care insurance companies and
third-party payers accept HSAT diagnostic ndings for payment of treatment for
OSA with CPAP in many countries [16, 21, 22].
Therefore, according to the AASM (American Association of Sleep Medicine),
HSAT is recommended as an alternative to PSG for diagnosis of OSA only in medically uncomplicated adult patients with a high pretest probability of moderate-tosevere OSA [23, 24]. With “medically uncomplicated” adult patients being dened
as those with an absence of conditions associated with increased risk of nonobstructive sleep-disordered breathing (SDB), including signicant cardiopulmonary disease, potential respiratory muscle weakness due to neuromuscular conditions,
history of stroke or chronic opioid use, and no potential indications of a signicant
central sleep disorder, such as central sleep apnea, parasomnia, narcolepsy or severe
insomnia [25].
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1.4 Pathophysiology ofOSA
Under normal conditions, during sleep, there are changes in the caliber of the upper
airway (UA) that lead to a reduction in airow with a stable airway in healthy
patients but with a collapse in OSA patients with variable manifestations (Fig.1.1).
These changes are due to three main factors [26–30].
1. During non-REM sleep, hypotonia appears in the dilator muscles of the pharynx,
which are the ones that while awake, maintain the caliber of the upper airway. In
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Fig. 1.1 Summary of consequences of OSA
P. M. Baptista and G. P. Mayor
patients with OSA, there is an airway collapse during inspiration, called dynamic
collapse, due to negative pressures, and during expiration (static collapse) caused
principally by muscular hypotonia.
2. Ventilatory function, lung volume and ventilatory response to hypoxia and
hypercapnia decrease. In the OSA patient, airway collapse produces a state of
hypoxemia and hypercapnia, which stimulates chemoreceptors. This produces
overexertion of the inspiratory muscles, which stimulate the mechanoreceptors,
activating the CNS, ending in microarousals or arousals as a defense mechanism
to resume correct breathing. These states of hypoxemia, hypercapnia and continuous microarousals will give rise to a series of serious clinical consequences.
3. The anatomical reduction of the upper airway due to excess fat or small bony
structure, or other anatomical factors cause a reduction in the caliber of the airway, and more so in a supine position. In patients with OSA, these anatomical
factors, associated with general and functional characteristics, predispose to the
collapse of the UA during sleep. Any structure of the UA that reduces the size of
the pharyngeal lumen is also a factor that favors OSA.However, a narrower
pharynx is not synonymous with OSA since women have a smaller UA than men
and suffer from this problem less frequently, in a 2:1 ratio.
1.5 Phenotypes andEndotypes ofOSA
In the last decade, Eckert etal. have made progress in understanding the pathophysiology of OSA, describing at least four phenotypes/endotypes that contribute to its
pathogenesis and opened new therapeutic alternatives aimed at more personalized
medicine [30–58].
The increased collapsibility of the UA is mainly due to the narrowing of the
upper airway (anatomical factor). However, the fact that OSA does not occur during
wakefulness demonstrates that it is not just an anatomical problem [30]. Thus, functional (nonanatomical) factors include:
• A lack of efcient muscle contraction during sleep (muscular factor).
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Fig. 1.2 Modication Eckert etal. [30–35]: four types of phenotypes/endotypes
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• Instability of respiratory control (respiratory control or loop gain).
• A low threshold for arousal (Fig.1.2).
The standard reference for quantifying airway alteration is done by calculating
the collapse-inducing tissue pressure, the so-called critical collapse pressure (P
crit
[29]. It is dened as the minimum intraluminal pressure necessary to keep the collapsible segment of the UA open. However, a negative critical pressure characterizes normal UA.This P
OSA.The increase in P
value is lower in normal subjects than in snorers and
crit
may be due to anatomical abnormalities or functional or
crit
nonanatomical abnormalities.
1.5.1 Anatomical Phenotype
The factors that reduce the caliber of the UA involve an increase in its resistance,
generating negative pharyngeal pressure during inspiration that predisposes it to
collapse. Undoubtedly, altered UA anatomy is a critical factor in OSA.Anatomical
factors range from nasal obstruction (nasal valve, septal deviation, turbinates), craniofacial anomalies (size and shape), anomalies of the oral cavity (macroglossia,
tonsillar hypertrophy, abnormal hard and soft palate congurations), alterations of
the pharynx at its three levels (nasopharynx, oropharynx and hypopharynx) and
laryngeal alterations.
)
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In addition, anatomical factors have an impact on other factors (muscular and
neurological response). Micrognathia, for example, moves the base of the tongue
backward and interferes with the genioglossus’s muscular efciency. Obesity is the
leading cause of decreased pharyngeal space since adipose tissue deposition in the
regions surrounding the UA directly reduces pharyngeal space. Additionally, it has
been shown that fatty deposits in specic places, such as the tongue, can play an
essential role in the collapsibility of the UA.Obese individuals also tend to have
lower lung volumes and signicantly lower functional residual capacity, which
decreases the caudal traction of the trachea and predisposes to the collapse of the
UA and its narrowing. Fat deposits between muscle bers have also been described
in obese subjects, reducing their contractile capacity.
The UA’s size and shape also inuence the pharynx’s cross-sectional area. The
smaller size of the craniofacial structures has shown to be a critical anatomical factor in OSA patients of Asian descent. Additionally, other nonanatomical factors,
such as edema, may be involved in the collapsibility of the UA and, consequently,
in the appearance of obstructive events.
P. M. Baptista and G. P. Mayor
1.5.2 Muscle Factor
Far from being a rigid structure, the UA’s permeability depends mainly on its muscles’ dilator activity. Within the muscle factor, three key elements have been dened
in the pathophysiology of OSA: Neural control, response and muscle efciency.
Given its location and participation in multiple functions (speech, swallowing
and breathing), the neural control of the muscles is highly complex. The onset of
sleep dramatically inuences the neural drive of these muscles. The primary dilator
muscle of the UA, the genioglossus muscle, is mainly cyclically activated and
receives neural input from the brainstem, the UA mechanoreceptors and changes in
hypoxia and PaCO2. The sum of these impulses results in the activation of the genioglossus muscle during inspiration to counteract the negative pressure exerted by the
inspiratory muscles and thus to prevent the collapse of the UA.The onset of sleep
and changes highly inuence this activity during the different sleep phases (progressively decreases during N1, N2 and REM, increases in N3). Other muscles, such as
the tensor veli palatine, have a more tonic activity that decreases at the onset of
sleep and is not as phase dependent. Apart from the neural response to sleep onset
and its different sleep phases, the pharyngeal musculature can increase its activity
in response to PaCO2 and pressure changes. This concept refers to muscle response.
It has been reported that muscle activity does not increase in the face of obstruction
in a third of patients with OSA.Finally, muscular efciency converts the neural
input received by the airway dilator muscles into a contraction that will increase
ow in response to an obstructive event.
Additionally, it has been shown that even within OSA patients, there are different
patterns of muscle efcacy. While some patients have an adequate increase in muscle activity against obstruction (good muscle response) and good effectiveness in
dilating the UAW, others show a low muscular response to obstruction and therefore
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fail to open the UA (low muscular efciency). Additionally, there are patients who,
despite having an excellent muscular response, do not have UA dilation and therefore have low muscular efciency.
In addition, the predominance in patients with OSA of type IIA muscle bers has
been described, compared to type I, which presents little resistance to prolonged
anaerobic efforts, signicantly reducing their performance during hypoxemia [50].
Therefore, a therapeutic option would be the “training” of these muscles through
exercises proposed with myofunctional therapy. Other therapeutic options would be
the hypoglossal implant or myotonic drugs such as desimipramine [51] or atomoxetine/oxybutynin [52, 53].
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1.5.3 Loop Gain
After an obstructive event, there is a hyperventilation of a variable amplitude that
depends on the individual. An elevated response to hypoxia and hypercapnia secondary to apnea due to hypersensitivity of the chemoreceptors will lead to hyperventilation, decreased PaCO2 and the efferent impulse of the respiratory centers that
will give an excessive response (very often present in the patients with severe OSA)
and that will determine the instability of the respiratory system, in an increase in
collapsibility and therefore favor the appearance of new obstructive apneas.
Alternatively, postapnea hyperventilation can decrease PaCO2 and favor central
apneas, which explains the coexistence of obstructive and central episodes in the
same patient [32].
The sensitivity of the respiratory center can be quantied as the increase in ventilation in response to an alteration and return to homeostasis (loop gain). Therefore,
a high loop gain is considered a negative aspect of UA collapsibility, while a low
loop gain, by stabilizing respiration, can prevent the collapse of the UA and is therefore considered positive. One-third of OSA patients are considered to have increased
loop gain. Like the concept of decreased muscle efciency, it may be especially
important in patients with mild-moderate OSA.
In cases like these, CPAP may not be effective [55], and there will be a need for
other therapeutic options like respiratory re-education [49], additional oxygen therapy [55], or UA surgery [56].
1.5.4 Awakening Threshold
Apneas produce a transient or arousal awakening that creates the characteristic fragmentation of sleep but favors the opening of the UA due to muscle activation.
However, despite this effect, which has been considered protective until now, it has
been shown that it can have a harmful effect for the patient. Awakening produces
hyperventilation that can promote ventilatory instability and thus promote collapse.
Each person has a different threshold for awakening, which can change depending
on the stage of sleep. Usually, the N3 phase has a high wake-up threshold, implying
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P. M. Baptista and G. P. Mayor
little respiratory variability and, as has been explained, greater activation of the UA
muscles; therefore, fewer obstructive events occur. Thus, in general, a high arousal
threshold is considered protective of the UA’s patency.
This is why, in some cases of OSA, mild hypnotics such as zopiclone or zolpidem can reduce the awakening threshold without modifying muscle tone [57].
1.6 From Phenotypes toEndotypes
Although initially described by Eckert as phenotypes, in OSA, there are underlying
endotypes following the PALM (P
-arousal-loop-muscle) classication, which are
crit
the ones that will determine the most appropriate treatment for each patient, following increasingly personalized methods.
As we determine each patient’s endotype, we can offer a more precise and personalized treatment, increasing adherence to CPAP and the supply of surgical and
pharmacological treatments.
However, for this personalized approach, it is necessary to determine the P
crit
, the
loop gain and the awakening threshold through certain studies that, at this moment,
may be complex [58–63].
1.7 Factors Defining Severity ofOSA
In OSA, the most widely accepted marker of the severity of disease is the apnea–
hypopnea index (AHI), which represents the number of apneas and hypopneas per
hour of sleep. The AHI is used not only to diagnose OSA (AHI>ve events/h
together with daytime hypersomnia or other clinical manifestations) but also to
classify the severity of the condition: mild OSA (AHI between 5 and 15), moderate
OSA (AHI between 16 and 29) and severe OSA (AHI equal to or greater than 30).
It has been argued that this classication is arbitrary because there are scarce data
to assess the relationship between AHI and the importance of daytime signs and
symptoms. However, the usefulness of AHI as a predictor of cardiovascular morbidity and mortality has recently been demonstrated in long-term cohort studies
[64–70].
Oxygen desaturation, sleep interruption and total sleep time are important pathological parameters associated with apnea episodes. However, it is possible that these
factors could serve as biomarkers of OSA severity, but there is still little data in the
literature. However, until a specic “pattern marker” is widely accepted, the AHI
can be considered the best option to dene the severity of OSA as sleep-disordered
breathing.
OSA is considered part of an uninterrupted pathophysiological process in which
the upper airway (UAV) presents a high resistance to airow [71] (Fig.1.3). Initially,
this dysfunction does not present symptoms or manifests through snoring (susceptibility stage). Subjects predisposed to develop OSA probably have a high burden of
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Fig. 1.3 Observe the smaller airway in the right gure of a patient with OSA compared to a normal patient, due to collapse of the airway, enlarged palate and tongue
susceptibility of unknown origin. As individuals age and reach adulthood, in addition to weight gain, epigenetic factors may accentuate the collapsibility of the UA.
In the presymptomatic stage, snoring worsens and nocturnal apneas appear;
however, the individual may not report any limitations in his daily activities.
If there isn’t any interruption, the patient develops nocturnal clinical manifestations (e.g., nonpositional snoring, bed partner reported apneas, nocturia) and daytime (morning headache, asthenia, excessive sleepiness) that are increasingly
disabling (stage of the clinical disease). At this phase, comorbidities may develop at
an early age compared to populations without OSA, in a context that we can consider accelerated aging. If the illness is not identied and treated, the natural evolution is directed toward disability and premature death (recovery stage, disability or
death), mainly due to cardiovascular problems.
Most adults with OSA are overweight or obese [72]. Obesity is related to
decreased thoracic cage distention capacity, reduced lung volumes and increased
upper airway resistance. Furthermore, cervical fat also facilitates the collapse of the
upper airway during sleep. These factors increase the frequency and duration of
nocturnal respiratory events. On the other hand, there is a linear relationship between
body weight and AHI.However, it has been mentioned that since obesity itself leads
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Fig. 1.4 Relationship
between OSA, obesity and
sleep disorders
P. M. Baptista and G. P. Mayor
to increased cardiovascular morbidity and mortality, it is most likely that excess
weight and not the AHI value is responsible for the increased morbidity and mortality in patients with OSA.
The prevalence of OSA in obese patients exceeds 30%; in cases of morbid obesity, it reaches 98%. It is estimated that a 10% weight gain increases the AHI by
32%, while a 10% reduction can improve the AHI by 26% [72]. Numerous studies
have shown that weight gain is related to the development of OSA or its worsening
[73]. Obesity aggravates OSA because the increase in fat in the UA favors the collapse of its lumen. The cervical circumference has been shown to be a better predictor of OSA severity than body mass index (BMI); also, adults with OSA have high
levels of leptin (a satiating hormone in thin individuals) and ghrelin (appetitestimulating hormone) and lower levels of adiponectin (an anti-inammatory cytokine that increases insulin sensitivity). A vicious circle exists where obesity and
OSA worsen each other (Fig.1.4).
The following chapters of this book will review in a comprehensive way the
main medical consequences of suffering from OSA in adults in diverse elds of
medicine.
1.8 Mortality
Death is the most determining “result” or nal effect of the natural history of any
chronic medical entity. Premature death, however, comes to represent the sum of
“unhealthy” risk factors that aggravate the progression of the index disease, in this
case, OSA (Fig.1.5). In sleep medicine, some clinical signs or symptoms, such as
drowsiness or snoring, are easy to measure in routine practice and the development
of a clinical trial. However, cardiovascular events and death are subject to comorbid
conditions that make it more challenging to establish the denitive role of OSA.
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