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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4566_Библиотеки_им_академика_М_И_Перельмана
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The pathophysiological concept of
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upper airway obstruction, the arousal
threshold, muscle responsiveness and
respiratory drive
Ludovico Messineo, Luigi Taranto-Montemurro and Elisa Perger
The repetitive collapse of the pharyngeal airway, characteristic of OSA leads to
intermittent oxygen desaturations and sleep fragmentation and downstream
consequences. Intermittent hypoxaemia activates the sympathetic nervous system,
and it is the major trigger for cardiovascular and metabolic adverse consequences.
The occurrence of upper airway obstruction during sleep reflects an interplay between
the removal of the wakefulness drive (which helps to maintain airway patency) and
an individual susceptibility to collapse. Although individual risk factors are known, the
precise pathophysiological pathways leading to upper airway obstruction and their
reciprocal influence in patients with OSA need further investigation.
Research in the past decade has established that a number of key pathophysiological
traits – or endotypes – contribute to the development of OSA (figure 1). These include
not only an anatomically small, collapsible upper airway (high passive critical closing
pressure of the upper airway (P
airway dilator muscles during sleep (minimal increase in muscle activity to negative
pharyngeal pressure), waking up prematurely to airway narrowing (a low respiratory
arousal threshold) and having an oversensitive respiratory control system (high
loop gain). It is likely that other factors such as end-expiratory lung volume, arousal
intensity and redistribution of body fluid are also important.
Pharyngeal muscle relaxation during sleep and lack of sucient reactivation are key
primary pathophysiological events leading to OSA. The reduced ventilation consequent
to an obstructive event increases carbon dioxide (CO2) and ventilatory drive, which could
)), but also inadequate responsiveness of the upper-
crit
Key points
• OSA is a heterogeneous disease with highly varying underlying mechanisms.
• Four pathophysiological traits have been identified recently as responsible for
OSA aetiology: predisposing anatomically small and collapsible upper airway;
inadequate responsiveness of the upper-airway dilator muscles during sleep;
a low respiratory arousal threshold; and an oversensitive respiratory control
system (high loop gain).
• Identifying the mechanism underlying OSA for an individual will permit a
personalised therapy to be designed based on the specific characteristics of
the subject.
44
ERS Handbook: Respiratory Sleep Medicine
The pathophysiological concept of upper airway obstruction
CollapsibilityMuscle
threshold
gain
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>2
1
0
crit
P
2
2
1
O
2
cmH
0.5 0
0.5
>2
0
Loop
responsiveness
Arousal
EMG
GG
% activity per cmH
–2–2.5
–1.5 0–0.5–1
<–2
<–2
2
O
OSA
O
2
0
–7.5
–15
–22.5
–30
–30
–22.5 0–7.5–15
Epiglottic pressure swings cmH
0
–1
–1
–2
–2
1
1
V response/V disturbance
Figure 1. The interaction of four endotypic traits in OSA pathogenesis: in the presence of mildto-moderate collapsibility, indicated by P
between −2 and 2 cmH2O, other nonanatomical
crit
traits play a role in OSA pathophysiology. The inability to recruit the upper airway dilator
muscle in response to negative pharyngeal pressure swings during an obstructive event (%
activity per cmH2O close to 0), a low arousal threshold (epiglottic pressure swings before the
arousal above −15 cmH2O) and a high loop gain (close to or above 1) will contribute in dierent
degrees to OSA development. Note that the boundaries between the four traits are intentionally
blurred to show that the presence and severity of OSA is oen determined by the interaction of
these pathogenic traits. EMGGG: genioglossus EMG; V′ response/V′ disturbance: ratio between
the ventilatory response to a preceding ventilatory disturbance. Reproduced from TarantoMontemurro (2019b) with permission.
lead to the activation of the pharyngeal muscles (muscle responsiveness) followed by
the reduction of the upper airway resistance. Waking up prematurely (low arousal
threshold) to a relatively modest level of airway narrowing can limit the ability to build up
sucient respiratory stimuli to recruit the pharyngeal dilator muscles to open the upper
airway, thereby achieving breathing stability. Thus, while arousals have an important
role in protecting some patients from asphyxia during sleep, they may disrupt breathing
stability and worsen OSA severity in patients with a low arousal threshold.
Pathophysiology studies have shown that interventions aiming to lower upper
airway collapsibility, increase the activity to pharyngeal muscles, increase the arousal
threshold or lower loop gain can reduce OSA severity. Moreover, recent evidence
has demonstrated that treatment ecacy for oral appliances and pharmacological
therapies are dependent on the severity of underlying pharyngeal collapsibility in
individual patients. Taken together, all these observations indicate the necessity of
developing simplified methods to accurately quantify the pathophysiological traits of
OSA. Originally, endotype measurements were obtained by challenging upper airway
function through CPAP manipulation during sleep, using sophisticated procedures that
remained limited to specialised physiology laboratories. Further research permitted
the development of noninvasive clinically applicable techniques to quantify OSA
45ERS Handbook: Respiratory Sleep Medicine
The pathophysiological concept of upper airway obstruction
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traits. Specifically, it has become possible to estimate the contribution of ventilatory
control to OSA severity (loop gain and arousal threshold), together with pharyngeal
collapsibility and muscle compensation using automated techniques applied to
respiratory signals collected in routine clinical PSG.
Understanding OSA pathophysiology is the key to OSA precision medicine.
Functional anatomy of the upper airway
The human upper airway is a multipurpose anatomical region serving respiration,
deglutition and vocalisation. Because of these multiple functions, the pharyngeal
airway lacks a rigid bony or cartilaginous support (which would make it more stable, but
also less adaptable to dierent tasks); therefore, it is a deformable tube susceptible to
collapse if sucient transmural pressure is applied across a compliant pharyngeal wall.
The importance of an abnormal pharyngeal susceptibility to collapse in the pathogenesis
of obstructive apnoeas was demonstrated by studying the pharyngeal P
in patients
crit
with OSA and in control subjects. Flow cannot occur until the pressure upstream of the
collapsible segment exceeds the surrounding pressure, i.e. P
increase in P
P
is negative (the airways stay open at atmospheric pressure), whereas OSA patients
crit
are more likely to have positive P
from normal subjects to snorers and OSA patients. In normal conditions,
crit
, which leads to upper airway collapse.
crit
. There is a progressive
crit
The loss of the drive to breathe during wakefulness results in decreased upper airway
neuromuscular activity and responsiveness, leading to decreased calibre, increased
resistance and an increased probability of pharyngeal collapse. The response to these
physiological changes partly depends on the underlying susceptibility to pharyngeal
collapse, which is determined by baseline upper airway calibre, surrounding tissue
pressure (i.e. adipose tissue, vascular and mucosal factors and craniofacial structure)
and the intrinsic properties of the upper airway. The thoracic–upper airway link via
caudal (tracheal) traction might also influence the patency of the upper airway.
Structural factors
Support for the role of bony structures in the propensity for upper airway obstruction
comes from observational and experimental studies. Dierences in position of the
hyoid bone between patients with OSA and controls was largely determined by tongue
volume, suggesting that inferior displacement of the hyoid bone in patients with OSA
is due to relative tongue volume and increased surrounding pressure.
In a case–control study which used three-dimensional MRI, increased mandibular
length was associated with decreased risk for OSA in men, but not in women. Indeed,
OSA is more prevalent in men than in women, and the prevalence increases in both
sexes with age, independent of body weight, yet the precise mechanism behind
this dierence is not clear. It is unlikely that the variability in airway cross-sectional
area or volume, which is larger in men than in women, plays a role. A more relevant
measurement may be airway length, which seems to be predictive of pharyngeal
collapsibility based on experimental measurements and computational modelling.
Because a longer airway is more collapsible, pharyngeal airway length may explain at
least in part the male predisposition to pharyngeal collapse. Epidemiological studies
have highlighted that dierences in craniofacial indices may contribute to racial
and ethnic dierences in the prevalence of sleep apnoea. For example, compared to
Icelandic OSA patients, (male) Chinese patients have smaller so tissue volume, but
larger so palate volume, as well as smaller retropalatal airway areas and smaller
mandibular and maxillary structures.
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ERS Handbook: Respiratory Sleep Medicine
The pathophysiological concept of upper airway obstruction
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So-tissue characteristics
The upper airway lumen is surrounded by the so tissue of the neck, including
connective, adipose, vascular and lymphatic tissue. Consequently, factors that increase
surrounding tissue pressure tend to promote its narrowing. Several so-tissue factors
are associated with higher risk of OSA, including increased tongue size, increased
size of lateral pharyngeal walls and increased total so-tissue volume. Enlarged
tonsils can raise the susceptibility to upper airway obstruction by encroaching on the
pharyngeal lumen. Increased so tissue may be a heritable trait, as evidenced by the
familial aggregation of so tissue structure in normal individuals and those with OSA,
independent of BMI and neck circumference. Increased adipose tissue in the upper
airway or the tongue secondary to obesity may also increase collapsing tissue pressure.
Confirming diagnostic evidence, interventions that decrease surrounding tissue
pressure such as tonsillectomy or weight loss have been seen to reduce OSA severity.
Overnight rostral fluid shi
During the day, fluid accumulates in the intravascular and interstitial spaces of the
legs due to gravity, and is redistributed rostrally upon lying down at night. Some of
this fluid may accumulate in the neck, increasing tissue pressure and causing the
upper airway to narrow, thereby increasing its collapsibility and predisposing to OSA.
This pathogenic mechanism is particularly important for patients with fluid-retaining
states, such as HF, renal failure or venous insuciency, and reducing lower extremity
fluid volume (e.g. compression stockings, diuresis) may attenuate this process.
Lung volume
Changes in lung volume during the respiratory cycle are related to changes in
upper airway calibre. Independent of dilating muscle activity, there is an inspiratory
increase and an expiratory decrease in upper-airway luminal size. In fact, pharyngeal
cross-sectional area reaches a nadir at end expiration, especially in patients with
sleep apnoea. Decreased lung volumes during sleep are associated with increased
upper airway collapsibility, perhaps via a reduction in the longitudinal tension of the
pharyngeal airway. This could be attributed to tracheal displacement playing a role
in upper airway stability; indeed, inspiratory activity displaces the trachea caudally
and stretches the connective tissue linking the trachea to the upper airway. From a
mechanical standpoint, caudal traction promotes upper airway patency by increasing
transmural pressure and stiening the pharyngeal wall.
Upper airway muscles
Since humans have no fixed bone to support the pharynx, it is maintained open by
the surrounding musculature. The most important and studied pharyngeal dilator
muscle is genioglossus, whose activity is characterised by a tonic (measured during
expiration) and a phasic (displayed during inspiration) component, which are essential
to prevent posterior collapse of the tongue when the pressure becomes negative
in the compliant pharynx. The levator and tensor palatini advance and elevate the
so palate, while the geniohyoid and stylopharyngeus oppose medial collapse of the
lateral pharyngeal walls. Relaxation of these muscles during sleep and lack of sucient
reactivation are key primary pathophysiological events leading to OSA. Thus, to
maintain a patent upper airway while awake, OSA patients activate the upper airway
dilators during wakefulness more than healthy subjects. At sleep onset, all individuals
physiologically reduce the activity of the pharyngeal dilator muscle. This, together
with anatomic predisposition and/or unstable control of breathing, oen leads to
47ERS Handbook: Respiratory Sleep Medicine
The pathophysiological concept of upper airway obstruction
a)
GenioglossusP
Epiglottic
Flow
b)
GenioglossusP
Epiglottic
Flow
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OSA during the lighter stages of sleep. Epiglottic pressure swings and CO2 increase
with deeper stages of sleep and during obstructive events, generally determining
a reflexive reactivation of pharyngeal muscle with the consequent restoration of
upper airway patency. This reflex is widely variable between individuals, with some
showing eective recruitment and the ability to partially reopen the upper airway and
increase ventilation during an obstructive respiratory event (muscle compensation),
and others showing minimal or no upper airway muscle compensation during sleep
(figure 2). Preventing the sleep-related relaxation of upper airway dilator muscles,
mask
pressure
mask
pressure
Figure 2. Examples of OSA patients with low versus high genioglossus responsiveness to negative
upper airway pressure reflex during sleep. a) Genioglossus activity of a patient with OSA during
manipulation of upper airway physiology using the CPAP drop technique. The patient is sleeping
on CPAP at a therapeutic level that avoids flow limitation (see the Flow channel), when CPAP
pressure is abruptly reduced for five breaths, inducing flow limitation. In this patient, the response
of the genioglossus activity to the progressively more negative epiglottic pressure is minimal or
absent. b) Genioglossus response to the same upper airway challenge performed with the CPAP
drop in a patient with simple snoring without OSA. In this case, the progressive lowering of
epiglottic pressure during the CPAP drop induces a proportional increase in genioglossus activity.
P
: CPAP mask pressure. Reproduced from Perger et al. (2021) with permission.
mask
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The pathophysiological concept of upper airway obstruction
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and in particular the genioglossus, has become a successful strategy to develop
alternative treatments for OSA. A surgically implanted device that stimulates the
hypoglossal nerve which controls the genioglossus represents a treatment option
to prevent upper airway collapse by increasing genioglossus activity through direct
electrical stimuli in a selected population. Medical interventions targeting upper
airway muscle activation have shown the most promising results in OSA treatment.
Theoretically, during sleep, dilator muscles could be stimulated using medications
if the specific neurotransmitters mediating their activity were identified. Over the
past several years, advancements in the field of OSA pharmacotherapy have helped
to refine the choice of monoamines that may be helpful in stimulating the upper
airway dilator muscles. Specifically, the impairment of noradrenergic, histaminergic
and muscarinic activity is thought to play a key role in the sleep-related hypotonia
of pharyngeal muscles. The loss of pharyngeal muscle tone during sleep has been
largely attributed to the withdrawal of endogenous noradrenergic drive and to active
muscarinic inhibition at the hypoglossal motor pool, the latter especially during
REM sleep, yet the role of histaminergic stimulation seems marginal in OSA. Thus,
a combination of norepinephrine reuptake inhibitor and antimuscarinic medications
taken at bedtime may provide a sucient stimulus to the pharyngeal dilator muscles
to alleviate OSA in most patients.
Ventilatory drive and loop gain
Breathing is a complex automated process that, in passive, healthy conditions, goes
unnoticed. Respiration originates in the brainstem, in separate areas that are intimately
connected. These neural networks contribute to the generation and pacemaking of the
rhythm of respiration, i.e. ventilatory drive. Ventilatory drive is influenced by mechanoreceptors
within the lungs (i.e. stretch receptors, J-receptors, C-fibres) and peripheral and central
chemoreceptors. The activity of mechanoreceptors is also conditioned by emotions and
behaviour such as vocalisation, sneezing, coughing, etc. Therefore, ventilatory drive can be
subdivided into mechanical-behavioural drive (or wake drive), which overall quantifies the
mechanical load on the respiratory muscles and, in healthy conditions, is exquisitely statedependent, and chemical drive. Of note, since oxygen contributes to chemosensitivity only
during severe hypoxaemia, CO2 is the main determinant of chemical drive.
Regulation of chemical drive is fine-tuned by a precise negative feedback mechanism
(loop gain) that keeps gas tension levels in the blood within homeostatic limits. Loop
gain is the product of dierent components: 1) plant, namely the pulmonary response
that processes gas tension variations following a ventilatory disturbance; 2) controller,
which drives the ventilatory response to changes in gas tensions; and 3) mixing (with
negligible physiological impact on breathing instability), which further adjusts gas
tensions when the blood passes from the pulmonary capillary to the larger chest vessels.
Low loop gain leads to negligible changes in ventilation in response to larger variations
in blood gas tensions; conversely, high loop gain, a marker of breathing instability,
responds to minimal changes in blood gas tensions with an exaggerated increase in
ventilation. Subsequently, this response becomes a disturbance itself and will propagate
breathing instability at a rate determined by the plant (i.e. if the plant is high, it will
lead to CO2 accumulation in the lungs in response to a minimal disturbance, which
favours frequent further ventilatory disturbance) and at an amplitude determined by
the controller. Of note, a high baseline chemical drive does not necessarily mean a
high loop gain; rather, it can lead to decreased loop gain in healthy conditions (by
reducing the plant). However, if the controller is increased by a larger magnitude than
the decrease in the plant, a high drive will reflect a high loop gain.
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Loop gain is also a function of the lung-to-chemoreceptor circulation time, or
circulatory delay, which influences the duration of each sleep apnoea cycle; however,
since circulatory delay increases when cardiac output decreases, in otherwise healthy
individuals with OSA, circulatory delay is generally not prolonged and does not
contribute to greater loop gain and sleep apnoea severity.
Measuring ventilatory drive and loop gain with gold-standard techniques (e.g.
rebreathing systems, intra-oesophageal catheterisation) requires dedicated sta,
specialised equipment and high patient collaboration; however, a more feasible way
to precisely estimate (through ventilators and PSG) ventilatory drive and loop gain has
been introduced recently.
During sleep, in healthy conditions, wake drive falls to minimal levels and chemical
drive becomes predominant. During sleep, chemical drive is also reduced compared
to wakefulness, which leads to slightly higher CO2 levels (∼0.3–0.5 kPa (∼2–4 mmHg))
during sleep. A decreased chemical drive during sleep is generally accompanied by a
lower or unchanged controller gain versus wakefulness, and a modestly higher plant
gain. Overall, this may result in a higher loop gain during sleep versus wakefulness
that, along with other mechanisms, increases susceptibility to a greater ventilatory
instability during sleep. Such instability may be the precipitating factor for OSA
exacerbation in predisposed individuals. Indeed, a high loop gain cyclically drives CO2
under the threshold for apnoea through recurring swings in chemical drive. This may
seem reminiscent of CSA; however, in OSA, in contrast to CSA, flow reductions are
always larger in magnitude than the reductions in drive, probably due to a mismatch
between the neural drive to the pump and the pharyngeal muscles.
Elevated loop gain has been described as one of the nonanatomical determinants of
OSA; however, in the prevailing view, OSA onset was mainly thought to follow a statedependent loss of pharyngeal muscle function, with subsequent flow reduction and
reflex increase in ventilatory drive. REM-predominant OSA specifically seemed to be
highly influenced by a loss of preferential neural drive to the upper airway muscles,
with lower controller and loop gain being protective mechanisms instead. Recently,
withdrawal of chemical drive has been identified as a key feature of OSA pathogenesis
in NREM and REM, where falls in drive closely accompany reductions in flow and
pharyngeal muscle activity (figure 3).
Preventing breathing instability and dips in chemical drive is arguably a major goal to
address OSA exacerbation during either NREM or REM. Oxygen administration was
shown to have an eect on OSA severity in selected individuals and in combination
with other medical agents. Similarly, increasing chemical drive via hypercapnia (and
thus lowering loop gain through a reduction in the plant) proved eective in treating
OSA in most patients. Acetazolamide was also shown to attenuate loop gain and the
ventilatory response to arousal, another potential contributor to breathing instability.
During a respiratory arousal, wake drive is reinstated, as well as the CO2 wake set
point, and leads to an increase in ventilation: in the presence of an elevated loop gain,
a further increase in chemical drive (consequence of a high controller) will add up
through the course of the arousal and conduce additional breathing oscillations, due
to CO2 intermittently sinking below the apnoea threshold.
Acetazolamide and novel carbonic anhydrase inhibitors such as sulthiame consistently
reduced OSA in REM and NREM, through a reduction in plant gain and possibly an
increase in ventilatory drive. Importantly, drugs or agents that promote a reduction
in ventilatory drive, such as opioids, some benzodiazepines and ethanol, should be
cautioned in OSA.
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ERS Handbook: Respiratory Sleep Medicine
300
Obstructive event
Ventilation (% eupnoea)
Ventilation (% eupnoea)
Ventilatory drive (% eupnoea)
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c)
250
Drive
200
150
The pathophysiological concept of upper airway obstruction
Ventilation
Time course
0
50
100
Ventilatory drive (% eupnoea)
Ventilation (% eupnoea)
Arousal threshold
Ventilation
Drive
Time course
50
150
b)
passiveVactive
V
100
120
a)
100
80
40
60
Arousal threshold
Obstructive event
50 100 250
Ventilatory drive (% eupnoea)
0 150 200 300
0
Ventilation (% eupnoea)
50 100 250
Ventilatory drive (% eupnoea)
0 150 200 300
0
20
300
e)
d)
250
100
150
200
60
80
0
50
100
Ventilatory drive (% eupnoea)
Ventilation (% eupnoea)
Arousal threshold
50 100 250
0 150 200 300
20
0
40
Figure 3. Legend overleaf.
51ERS Handbook: Respiratory Sleep Medicine
The pathophysiological concept of upper airway obstruction
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Respiratory arousal threshold
The respiratory arousal threshold is the level of ventilatory drive or inspiratory mechanical
eort required to wake up an individual in response to the narrowing of the upper airway
during sleep. Traditionally, respiratory arousals were considered necessary to reinstate
upper airway patency aer a ventilatory disturbance; thus, a low arousal threshold was
long thought to be protective from deep, event-related, hypoxaemia. It is now clear that
the pharyngeal muscles can overcome respiratory obstruction without the onset of an
arousal, yet the arousal is oen concurrent due to similar thresholds for upper airway
reopening and arousal inception. In addition, respiratory arousals are responsible for
increased sympathetic activation at event termination. Therefore, it has been postulated
that a low arousal threshold is not only nonprotective in most cases, but also increases
the risk of OSA exacerbation and OSA-related cardiovascular morbidity.
There are several reasons why a low arousal threshold is responsible for OSA
pathogenesis in a third of cases, and even more frequently in certain populations. First,
it produces sleep fragmentation and prevents deep sleep, notoriously protective against
respiratory events. Second, with an arousal abruptly interrupting a respiratory event,
there is less time and fewer respiratory stimuli (e.g. CO2 levels that ‘do not have time’ to
increase enough) for the pharyngeal muscles to be eectively recruited; consequences
are shorter event duration and more frequent event cycling. Third, arousals imply a
ventilatory response with quick intrusions of wake drive and subsequent rapid CO2
swings (discussed earlier), which can contribute to further breathing instability and
greater OSA severity; not surprisingly, shorter event duration is associated with elevated
loop gain. Fourth, arousals are characterised by dierent levels of intensity, and greater
arousal intensity is accompanied by larger ventilatory responses.
a) Endogram of an individual without OSA. The continuous black line illustrates median
ventilation at each drive decile. Ventilation when the pharyngeal muscles are passive (V′
sits at the intersection between eupnoeic (i.e. 100%) ventilation and drive. Activation of
pharyngeal muscles (V′
active
already patent, even in passive conditions (ceiling eect). Ventilation does not fall significantly
following reductions in drive (V′
range. b) Endogram illustrating drive-dependent OSA. Note the linear relationship between
ventilation and drive (i.e. decrements in drive lead to corresponding falls in ventilation). In
addition, dips in drive beyond V′
Although evocative of CSA, where the flow–drive ratio equals 1 and is represented by the identity
line, in OSA, flow versus drive reductions are bigger (i.e. the endogram is more shied down
and to the right (see also c). c) Ensemble average of ventilation and ventilatory drive signals
in the OSA patient presented in b. Contrary to the common knowledge that respiratory events
arise from preferential deficits in pharyngeal muscle function, here ventilation and drive fall in
synchrony during the obstructive event, so that drive withdrawal is accompanied by a decline in
ventilation of a similar slope. Conversely, ventilation increases when drive starts to be elevated.
Shading represents 95% CI. d) Endogram of classic OSA. No relationship between ventilation
and drive is evident. In addition, note that V′
muscle responsiveness and ventilatory compensation. However, similarly to b, at minimal drive
levels (V′
), there is a substantial drop in ventilation. e) Ensemble average of ventilation and
min
ventilatory drive signals in the OSA patient presented in d. The temporal association between
ventilation and drive during the event course is lost (the continuous fall in ventilation is not
matched by a parallel drop in drive, which in fact starts to increase soon into the event), thus
OSA probably onsets from a state-dependent loss of pharyngeal muscle function (i.e. poor upper
airway muscle responsiveness).
52
),
passive
) leads to negligible increases in ventilation as the upper airway is
, the area below V′
min
(i.e. V′
passive
min
) account for further reductions in ventilation.
active
). Shading represents interquartile
passive
<V′
, which denotes poor pharyngeal
passive
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The pathophysiological concept of upper airway obstruction
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Since the respiratory arousal threshold can be quantified as the ventilatory drive
needed to awaken, gold-standard measures include oesophageal catheterisation,
or, although less reliable, surrogates such as recording of epiglottic or oesophageal
pressure. Sensitive alternative methods to calculate the arousal threshold have been
introduced using PSG or clinical parameters.
Increasing arousal threshold to improve OSA severity has been the object of several
studies in recent years, due to wide pharmacological accessibility to arousal threshold
modulation. Indeed, many hypnotics, such as trazodone, eszopiclone, zopiclone
and zolpidem proved eective for increasing the respiratory arousal threshold (via
decreasing brain arousability). However, in numerous studies in which increases in
arousal threshold were observed, a parallel AHI drop was not evident. Arousal threshold
was also targeted using an antagonist of serotonin receptors, pimavanserin, which
was demonstrated to delay CO2-mediated arousal in animal models, yet preserving
the upper airway response to arousal. Although preliminary analyses showed that
increasing the duration of pimavanserin administration could lead to a beneficial
eect on OSA severity, pimavanserin did not yield a systematic increase in the arousal
threshold.
These results have questioned the importance of an increased arousal threshold as
a major OSA pathogenic feature. It is debated whether the magnitude of increase
in arousal threshold, which is not necessarily dose-dependent, was sucient to
generate a meaningful AHI improvement. Additionally, the interaction with other OSA
traits may play a role in yielding negligible changes in the AHI for significant arousal
threshold variations; for example, delaying arousals in subjects with poor pharyngeal
muscle responsiveness would allow limited clinical benefit and rather increase the
risk of severe overnight hypoxaemia.
Assessment of endotypic traits
In the past, gold-standard measurements of pharyngeal collapsibility and other
endotypic traits were based on manipulation of CPAP during sleep to assess the
critical pressure at which the airway completely collapses (P
remained limited to specialised physiology laboratories. Recently, an attempt has
been made to identify simpler ways of measuring the entity of pharyngeal collapse
(P
) and the related muscle compensation\responsiveness, with the goal of allowing
crit
widespread clinical use of these metrics. These models are based on the estimation of
ventilatory drive during spontaneous breathing, and subsequently assess pharyngeal
collapsibility, upper airway muscle compensation, arousal threshold and loop
gain. Pharyngeal collapsibility has been identified as the level of ventilation that
can be achieved at eupnoeic ventilatory drive (V′
of P
), where a more collapsible airway is captured by lower ventilation. Muscle
crit
compensation is the increase in ventilation that occurs in conjunction with a rise in
ventilatory drive (from eupnoeic levels to the level that triggers arousal from sleep).
Thus, compensation can be taken as the simple dierence between V′
where V′
is the level of ventilation at maximum drive that can be achieved during
active
sleep (arousal threshold). More recently, other polysomnographic surrogate measures
of collapsibility have been presented as candidate to clinically quantify V′
responsiveness. The concomitant assessment of V′
can be visualised on the patient endogram (examples are shown in figure 3) which
represents the relationship between the ventilatory drive (x-axis) and actual ventilation
(y-axis) during sleep for the whole night. The endogram derived from the clinical
PSG, together with the automated calculation of loop gain, have the potential in the
). These procedures
crit
, the ventilatory equivalent
passive
active
, V′
passive
and arousal threshold
active
and V′
passive
passive
and
,
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