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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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S. Op de Beeck et al.
associated with the upper airway collapse site [15]. A posteriorly located tongue,
dened as narrowing of the airway due to posterior displacement of the tongue, is
associated with a small NED, reected by a somewhat “at” ow shape. Isolated
palatal collapse, i.e., collapse without the involvement of the tongue, and lateral
wall collapse are associated with moderate NED, and epiglottic collapse with high
NED, reected by a large and sharp inspiratory peak [15]. The presence of high
NED during epiglottic collapse has recently been conrmed during DISE [16].
Azarbarzin etal. [17] showed it is possible to identify epiglottic collapse and
palatal prolapse using nasal pressure airow shape. Epiglottic collapse was characterized by a rapid fall in inspiratory ow (discontinuity index), high variability in
both inspiratory and expiratory ow (inspiratory and expiratory jaggedness) and
reduced tidal volume (expressed as the ratio of peak expiratory ow and tidal volume). Palatal prolapse, dened as “ballooning” of the palate into the nasopharynx
during expiration, was shown to be associated with expiratory ow limitation quantied using the expiratory ow limitation index (EFLi) [18].
Recent research could also demonstrate the potential of predicting the site collapse during DISE from a separate routine baseline PSG.In this model, CCCp and
lateral wall collapse were characterized by scoopy, left skewed breaths and opposed
to tongue base and epiglottic collapse [19].
2.3 Upper Airway Collapsibility
Upper airway collapsibility is the second pathophysiological trait and can be
regarded as both an anatomical and physiological trait (Fig.2.8). The higher the
upper airway collapsibility, the easier the upper airway will collapse and the narrower the upper airway tends to be [20]. As such, patients with a higher collapsibility will be more prone to suffer from apneas and hypopneas and will inherently be
at greater risk of developing OSA [21, 22].
Upper airway collapsibility is inuenced by obesity [21] and greater in supine
compared to lateral position [23–25], but the inuence of sleep stage [23–27] and
sex [28, 29] is ambiguous. Collapsibility was shown to differ between REM and
NREM stages [26, 27], although other studies did not seem to nd any differences
[23–25]. Sex alone does not seem to inuence upper airway collapsibility [28, 29].
However, if corrected for obesity, women tend to have a lower airway collapsibility [29].
In patients with small NED values, the upper airway likely behaves as a Starling
resistor [30–33]. In a Starling resistor model, the upper airway is modeled as a collapsible segment surrounded by the noncollapsible nasal and tracheal segments
[34]. If the upstream pressure at the nasal segment is lower than the critical closing
pressure (P
Flow limitation will occur if the downstream pressure is lower than P
), as dened by the surrounding tissue, the upper airway will collapse.
crit
, [26, 32,
crit
33]. However, in patients with large NED, the Starling resistor might not be the best
model to describe the upper airway. Alternative models are thus needed, and the
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Fig. 2.8 Upper airway collapsibility can be assessed using different techniques: by determining
the critical closing pressure of the upper airway or P
(noninvasive measurement technique). Currently, there is no clinical standard measurement
method that can be used for upper airway collapsibility assessment, yet the therapeutic CPAP level,
clinical collapsibility score and determining the upper airway collapsibility index (UACI) using a
wakefulness test holds promise for future clinical application
(gold standard) or using ow shape analysis
crit
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Starling resistor might not be usable as a universal model for upper airway collapsibility [30, 35, 36].
Upper airway collapsibility can be measured using the gold-standard technique,
which involves determining the critical closing pressure using upper airway pressure drops. However, due to the rigorousness of this method, this technique is not
used in routine clinical practice. Furthermore, it has been shown feasible to use brief
negative airway pulses in awake patients to determine the upper airway collapsibility index [37, 38]. While this technique shows great potential for application in
clinical practice, as it can be performed in awake patients, invasive techniques are
still needed, including the catheter insertion. Regarding other potential clinical measures, the therapeutic CPAP level predicts upper airway collapsibility [39], and a
clinical score was developed to distinguish between male patients with high and low
collapsibility [40]. Recently, however, a new innovative, noninvasive technique was
developed to estimate upper airway collapsibility using the airow signal as
recorded during diagnostic polysomnography (Fig.2.8).
2.3.1 Critical Closing Pressure (P
The gold-standard measurement technique involves determining the critical closing
pressure (P
) using upstream (nasal) pressure drops. P
crit
nasal pressure at which the upper airway remains patent [33]. To measure P
pressure at the nose is repeatedly lowered while simultaneously monitoring airow.
After several pressure drops, a linear regression line is tted through the different
crit
)
is dened as the minimal
crit
, the
crit
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sample points. The physiological P
is dened as the zero-ow intercept from the
crit
linear portion of the ow-pressure curve [41].
P
can be measured under active (active P
crit
tions. The rst reports on measurements of P
measure active P
, the pressure is rst dialed up to the holding pressure, dened as
crit
) or passive (passive P
crit
describe active P
crit
) condi-
crit
[22, 32, 33]. To
crit
the pressure at which all apneas, hypopneas and ow limited breaths are abolished,
during steps of 5min each [33]. The holding pressure equals the “effective continuous positive airway pressure (CPAP)” or “upper airway opening pressure” [26, 42].
In a next step, the critical closing pressure is determined. Active P
is determined
crit
by gradually lowering the upper airway pressure. At each pressure level, ow is
measured. This is repeated until no stable breathing can be achieved anymore. The
results are then plotted on a pressure–ow curve, and a linear regression line is estimated. The x-intercept of this line, where ow is zero, is the critical closing pressure
[32, 33]. To assess passive P
, ow is dropped to different pressure levels from the
crit
holding pressure. After each pressure drop, the pressure is set back to the holding
pressure [4, 43]. In contrast to the active method, the passive method minimizes the
recruitment of upper airway muscles.
Upper airway collapsibility can also be quantied using ventilatory parameters.
The higher the ventilation at a certain nasal pressure, the less collapsible the airway
and vice versa [4, 43]. This method is based on the measurement methods that were
previously described in the literature for P
[4, 25, 32, 33]. However, instead of
crit
measuring pressure, ow is measured. Briey, to assess both passive and active V0
(ventilation at 0cm H2O) in one run, the mask pressure is rst dialed up to the holding pressure. Passive V0 is determined by dialing down the pressure to 0cm H2O
during 5 breaths. To determine active V0, the pressure is lowered from the holding
pressure until the minimal pressure level (CPAP
) is achieved at which no arousals
min
occur. Active V0 is then determined by an active drop [43].
Recently, P
could be measured during DISE, showing a more reliable P
crit
crit
measurement using the ventilation method. Furthermore, patients with CCCp showed a
wide range of P
values, indicating no clear association between P
crit
and CCCp [44].
crit
2.3.2 Clinical Techniques
In awake patients, upper airway collapsibility can be assessed with the upper airway
collapsibility index (UACI). The UACI is measured by applying brief (250ms)
pulses of negative airway pressure (−12cm H2O) during awake early inspiration
and is calculated as the pressure difference between the choanae and the epiglottis
during the brief pulse [37, 38]. Although collapsibility in awake conditions is systematically lower compared to during sleep, the UACI is signicantly correlated
with P
measurements [38]. A recent study even showed that the UACI value could
crit
separate individuals with subatmospheric P
atmospheric values [37]. While this technique shows great promise as a potential
clinical method, the invasiveness and used materials hamper its applicability.
values from individuals with supra-
crit
x
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Another method that could be applied in clinical practice was recently developed
by Genta etal. [40]. Combining NREM-OAI/AHI, waist circumference, obstructive
apnea duration and REM-AHI in a clinical score was able to predict a P
>2.5cm
crit
H2O.A clinical score ≥3 showed a sensitivity of 90.9% and specicity of 84.3%,
highlighting the potential clinical value of this method. Furthermore, in patients
(previously) treated with CPAP, the therapeutic CPAP level can also be used as a
surrogate for collapsibility [39]. Specically, a therapeutic CPAP level of ≤8cm
H2O showed a sensitivity of 75% and specicity of 91% in an independent dataset
for having a mildly collapsible upper airway.
2.3.3 Baseline PSG Airflow Analysis
Several problems arise in using the above explained gold-standard methods to measure P
the technique and the need for trained personnel overnight. No clinically applicable
method is currently available in routine clinical practice.
Azarbarzin etal. [45]. They showed that active P
both peak and mid-inspiratory ow (as measured during natural NREM sleep) as
well as active
tions. The rationale of this study was based on the construction of the pressure–ow
curve and the assumption that a change in pressure (x-intercept) is partly captured
by the ow (y-intercept) [45].
minimal ventilation at normal ventilatory drive is dened as passive ventilation
(V
contrast, ventilation at maximal ventilatory drive, just preceding arousal, is dened
as active ventilation (V
V
while V
including the requirement of specialized equipment, the invasiveness of
crit,
A noninvasive method to determine collapsibility was recently developed by
was signicantly correlated with
crit
, the maximal ow at atmospheric pressures under active condi-
ma
Alternatively, ventilation parameters can be used to dene collapsibility. The
). V
passive
thus reects the inherent collapsibility of the upper airway during sleep,
passive
is the ventilation at which no additional muscles are recruited. By
passive
). At V
active
considers upper airway muscle activity [4, 43, 46].
active
, upper airway muscles are optimally recruited.
active
2.4 Ventilatory Control Stability
The most commonly used ventilatory control parameter is loop gain, a measure of
the sensitivity of the ventilatory chemical control system. Loop gain can be seen as
a central component of sleep apnea and is calculated as the ratio of the ventilatory
response and its associated ventilatory disturbance (Fig.2.9) [47]. A loop gain at a
phase angle of 180° between 0 and 1 will result in a stable system. A ventilatory
disturbance will lead to a ventilatory response with a smaller magnitude than the
initial disturbance, eventually returning to the original ventilation level. A loop gain
closer to 0 will lead to a faster return to the initial ventilation level, signifying a
more stable control system. A loop gain of 1 results in a cyclical ventilation,
26
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b
Fig. 2.9 Loop gain is dened as the ratio of a ventilatory disturbance and its associated ventilatory
reaction. (a) Example of ventilation with a loop gain equaling 0.75. A ventilatory disturbance
(orange arrow) causes a ventilatory reaction (blue arrow) with a magnitude of 75% of the initial
(orange arrow) disturbance. In turn, the ventilatory response (blue arrow) becomes a ventilatory
disturbance, causing a ventilatory reaction (red arrow) of 75% of its magnitude, nally resulting in
a restoration of the initial ventilation. (b) Example trace of loop gain of 1. A ventilatory disturbance in a system with a loop gain of 1 will result in an unstable system. A loop gain of 1 will cause
a ventilatory response (blue arrow) with the same magnitude as the initial disturbance (orange
arrow). (Based on Wellman etal. [47])
uctuating around the initial ventilation level. A loop gain higher than 1 will cause
highly unstable breathing, as the ventilatory response will be higher than the ventilatory disturbance. If the loop gain is ≥1, a return to the initial ventilation is only
possible with external measures (e.g., arousal).
The major determinants of loop gain are plant gain and controller gain. Controller
gain determines the response to a change in concentration of CO2, while plant gain
is the amount that CO2 changes for a given change in ventilation [48].
Loop gain can be measured using a gold-standard measurement technique or
using recently developed noninvasive measurement methods (Fig.2.10). Currently,
no clinical standard method is available. However, recently Messineo etal. showed
that breath- holding maneuvers during wakefulness is associated with loop gain
[49]. Patients with a higher loop gain showed a shorter maximal breath-hold duration and a more signicant ventilatory response to 20-s breath-holds [49]. This technique, as such, shows promise for future clinical applications.
2.4.1 Airflow Pressure Drops
The gold-standard measurement technique involves the use of airow pressure
drops. As the upper airway has a collapsible segment, the upper airway can be held
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Fig. 2.10 Loop gain can
be measured using airow
pressure drops (gold
standard) or using PSG
ow analysis (noninvasive
technique). Currently, no
clinical measurement
method is available, but
recently Messineo etal.
[49] developed a new
technique using breath
holding
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determination of loop gain also requires pressure drops.
To measure loop gain, the mask pressure (P
) is abruptly lowered by decreas-
mask
ing the applied pressure from the holding level, dened as the minimal pressure
needed to keep the upper airway patent. After a minor delay, the upper airway muscles will be recruited to increase airow and partially restore ventilation. Under the
reduced pressure, a new steady-state ventilation will be achieved. The difference
between the normal ventilation and the new steady state is called the disturbance.
Due to this suboptimal new steady state, CO2 will accumulate in the body and ventilatory drive increases. The mask pressure is dialed up again to the normal level to
measure this ventilatory drive. The ventilatory sensitivity will cause an overshoot in
ventilation (response). Loop gain is dened as the ratio of the response and the disturbance [4]. In general, loop gain is measured during NREM sleep and tends to be
lower in REM compared to NREM sleep [50].
2.4.2 Baseline PSG Airflow Analysis
The rationale behind the noninvasive technique using ow signals to measure
loop gain, is that the apneas and hypopneas that naturally occur during sleep, will
cause disturbances in ventilation [51]. These disturbances will cause a change in
the ventilatory drive. The magnitude of this change is determined by loop gain
(ratio of response and disturbance). By tting a ventilatory control model,
adjusted for changes in ventilatory drive due to arousals and/or changes in chemical concentrations, loop gain can be calculated from a standard baseline polysomnography [51].
A second ventilatory control stability parameter is the ventilatory response to
arousal, dened as the increase in ventilatory drive attributed to arousal from sleep
[51, 52]. The ventilatory response to arousal cannot be explained by an increase in
chemical drive, which is attributed to loop gain [46].
,
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2.5 Pharyngeal Muscle Responsiveness
During the transition between wake and sleep, the odds of collapse are higher due
to a decrease in muscle activity. Pharyngeal muscle responsiveness is dened as a
patient’s ability to prevent or overcome upper airway collapse by recruiting the
upper airway muscles during sleep. In addition, high pharyngeal muscle responsiveness implies strong muscle recruitment to keep the upper airway patent, reducing
the chances of upper airway collapse.
Pharyngeal muscle responsiveness can be measured using a gold-standard technique involving diaphragm EMG measurements using pressure drops or ow analysis techniques (Fig.2.11).
2.5.1 Airflow Pressure Drops
As for the other traits, the gold-standard technique to measure pharyngeal muscle
response requires pressure drops. By dropping the upper airway pressure from the
holding pressure to suboptimal pressures, ventilation will also suddenly drop. This
drop in ventilation will cause an increase in ventilatory drive achieved by an increase
in pharyngeal muscle activity. In turn, the increased muscle activity will lead to rise
in ventilation toward a new, suboptimal steady-state ventilation.
The gold-standard method to measure muscle activity uses intramuscular electrodes. In this way, muscular activity can be determined as the response to the intraluminal pressure associated with lowering the applied pressure from the holding
pressure [53].
Alternatively, ventilation measures during airow pressure drops can dene
upper airway muscle responsiveness. Using this technique, the difference between
the ventilation immediately after the airow pressure drop and the new, suboptimal,
steady state is dened as the pharyngeal muscle responsiveness [4].
Fig. 2.11 Upper airway
muscle responsiveness can
be measured using airow
pressure drops (gold
standard) or using PSG
ow analysis (noninvasive
technique)
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2.5.2 Baseline PSG Airflow Analysis
Using polysomnography signal analysis, pharyngeal muscle compensation is calculated based on ventilatory parameters. As described earlier, passive ventilation is
dened as the ventilation at which no additional muscles are recruited. Furthermore,
active ventilation is the ventilation just before arousal, at maximal ventilatory drive
and as such at maximal muscle recruitment. Therefore, compensation is dened by
the difference between active ventilation (V
) and passive ventilation (V
active
passive
) [46].
2.6 Arousal Threshold
Arousal threshold is the threshold at which an arousal stimulus will lead to an
arousal response [54]. This arousal stimulus can be external (e.g., noise) but can
also be triggered by the central nervous system [55, 56]. An internal trigger can be
an increased ventilatory drive to restore ventilation during a ventilatory disturbance.
The arousal threshold is then dened as the ventilatory drive causing arousal.
An increased ventilatory drive will activate and stiffen the upper airway muscles.
Therefore, a high arousal threshold allows the ventilatory drive to rise to levels
needed for the upper airway muscles to restore ventilation [57]. However, a high
arousal threshold is also associated with longer apneas/hypopneas and can cause
deeper oxygen desaturations. By contrast, a low arousal threshold is associated with
an increased propensity to wake up, preventing stable sleep and perpetuating cyclical breathing [57].
Arousal threshold can be assessed using invasive gold-standard techniques or
noninvasive alternatives including ow analysis. Currently, there is no clinical standard method available; however, a model including clinical parameters was recently
developed (Fig.2.12).
Fig. 2.12 The arousal
threshold can be measured
using airow pressure
drops (gold standard) or
using baseline
polysomnography (PSG)
analysis (noninvasive
technique). Currently, no
clinical standard method is
available; however, a
model using clinical
parameters shows potential
for future clinical
application
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S. Op de Beeck et al.
2.6.1 Airflow Pressure Drops
Like the previously described techniques, the gold-standard technique to determine
arousal threshold includes pressure drops. To assess arousal threshold, adequate
ventilatory drive measurements are needed. This can be achieved by measuring epiglottic pressure, diaphragm EMG or esophageal pressure or mathematical modeling.
Using an epiglottic catheter, the arousal threshold is determined as the epiglottic
pressure immediately preceding an arousal [57]. Similarly, diaphragm activity can
be measured using an intraesophageal diaphragm EMG catheter. Using esophageal
pressure measurements, increasing or decreasing pressure swings reect increasing
or decreasing ventilatory drive [57–59].
In another method [4], ventilatory drive is determined using a mathematical
model with parameters derived from the individual ventilation signal. An exponential decay characterizes ventilation after an arousal. The delay and time constant
characterizing this exponential decay can be used to determine the ventilatory drive
at each time point during a ventilatory disturbance. This method assumes that the
delay and time constant of the increase in ventilatory drive (which is modeled)
equals the time constant and delay of ventilation after arousal (which is observed).
As such, these parameters can be used to model the ventilatory drive in time. The
calculated ventilatory drive before arousal, is then dened as the arousal threshold.
2.6.2 Clinical Parameters
Alternative techniques to determine the arousal threshold have been developed.
Edwards etal. [57] showed that combining the apnea–hypopnea index, oxygen saturation and the fraction of hypopneas could estimate the chance of a patient having a
low arousal threshold (dened as less than −15cm H2O peak epiglottic pressure).
However, this metric is not able to determine the exact arousal threshold.
2.6.3 Baseline PSG Airflow Analysis
Furthermore, recently, an algorithm to estimate the arousal threshold was developed
by Sands etal. [58]. This algorithm was based on the method of Wellman etal. [4]
in which the ventilatory drive was modeled based on the exponential decay of the
ventilatory signal. However, instead of using external pressure drops to provoke
airow disturbances, the naturally occurring apneas and hypopneas in OSA patients
are used.
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2.7 Interplay Between theDifferent
Pathophysiological Traits
To prevent OSA, the major traits of each OSA patient must interact to produce stable breathing during sleep that does not cause arousal [60].
To show the interactions between the different traits, the traits can be plotted on
a graph of ventilatory drive against ventilation (Fig.2.13) [4, 43]. When the airway
is patent during resting breathing (eupnea), ventilation matches the ventilatory drive
(V
). The arousal threshold is dened as the ventilatory drive at which a patient
eupnea
arouses and can be plotted as a vertical line (green dashed line). V
ventilation that can be tolerated without arousal. Loop gain is then dened as the
reciprocal of the slope connecting V
by V
Fig. 2.13 Interplay
between the different
pathophysiological traits.
The pathophysiological
traits can be plotted on a
graph explaining
ventilation as a function of
ventilatory drive. (Based
on Wellman etal. [43])
, which is the ventilation that can be achieved through the upper airway
passive
eupnea
and V
. Passive collapsibility is reected
arousal.
is the lowest
arousal
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