Respir Care Clin 11 (2005) 265–280

Expiratory Asynchrony
Hong-Lin Du, MDa, Yoshitsugu Yamada, MDb,*
a
Clinical Research Department, Newport Medical Instruments, Inc., PO Box 2600,
Newport Beach, CA 92658, USA
b
Department of Anesthesiology, School of Medicine, Yokohama City University,
Yokohama, Japan

Under ideal circumstances, mechanical ventilators should be in synchrony

with the patient in many aspects. These include the synchronized inspi-
ratory trigger timing between the ventilator and patient, the ventilator-
delivered flow rate matching the patient flow needs at any time during
inspiratory phase, and the synchronized transition from inspiratory phase to
expiratory phase. Expiratory asynchrony occurs when the ventilator’s
transition from inspiratory phase to expiratory phase occurs before or after
the ending of the patient’s inspiratory effort. This article explains the
importance of expiratory asynchrony in mechanical ventilation and describes
the mechanisms of expiratory asynchrony in some spontaneous breathing
modes (eg, pressure-support ventilation [PSV] and proportional-assist
ventilation [PAV]). The last section of the article explores issues with regard
to expiratory asynchrony, including expiratory asynchrony in neonates and
infants, expiratory asynchrony in patients with chronic obstructive pulmo-
nary disease (COPD), and some limitations in the tools to quantitatively
evaluate expiratory asynchrony.

Why expiratory asynchrony is important and how often it occurs

Expiratory asynchrony causes discomfort to patients and negatively
affects patient’s expiratory work of breathing, inspiratory work of
breathing, and inspiratory trigger response. Expiratory asynchrony exists
as delayed termination of ventilator flow or as premature termination of the
ventilator flow in comparison to the ending of the patient’s inspiratory
effort.

* Corresponding author.
E-mail address: yamaday@med.yokohama-cu.ac.jp (Y. Yamada).

1078-5337/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.rcc.2005.02.001 respiratorycare.theclinics.com
266 DU & YAMADA

Delayed termination of ventilator flow

When the termination of the ventilator flow occurs after the end of the
patient’s inspiratory effort (ie, delayed termination), the patient recruits his
expiratory muscles to ‘‘fight’’ against the ventilator flow, which increases
expiratory workload [1,2]. This fight between the ventilator and patient
causes an increase of the pressures in the airway, alveoli, and intrathoracic
cavity. The increase of these pressures may be associated with many
complications, including pneumothoraces, barotraumas, and cerebral blood
flow fluctuations [3,4]. The fight between the ventilator and patient
frequently requires the use of sedation or neuromuscular relaxants to
weaken the patient efforts, which may delay the weaning process [3].
Furthermore, a high lung volume at the end of expiration that is caused by
the previous breath being terminated late may result in trigger failure of the
next inspiratory effort in patients with COPD [1,5]. In patients with dynamic
hyperinflation, such as in COPD, the patient already has a high lung volume
and high elastic recoil pressure at the end of expiration and beginning of
inspiration. When the delayed termination results in more lung volume at
the end of mechanical inspiration, these patients have to generate
a substantial amount of inspiratory muscle pressure (Pmus) to overcome
the high lung volume and the associated intrinsic positive end-expiratory
pressure (PEEPi) before they can trigger the ventilator. Parthasarathy et al
[1] found that at the same level of ventilatory support, inspiratory trigger
failures were associated with a higher tidal volume in the preceding support
breath.
Although humans often can find ways to compensate for the external
challenges, a recent study by Younes et al [6] on ventilator-dependent
patients has shown that there is no effective neuromuscular response with
the use of expiratory muscles to speed up expiratory flow. There is
compensatory prolongation of neural expiratory time; however, the degree
of the prolongation is generally weak. Due to these weak compensatory
responses, delayed termination of the ventilator flow tends to exacerbate
dynamic hyperinflation and affect inspiratory trigger performance.

Premature termination of ventilator flow

When the termination of the ventilator flow occurs before the end of the
patient inspiratory effort (ie, premature termination), inspiratory muscle
work continues into or throughout the ventilator’s expiratory phase,
resulting in inefficient inspiratory muscle work [7]. Premature termination in
PSV may cause retriggering of inspiration and a stuttering pattern of
ventilatory activation if the patient effort continues and passes the trigger
block window [7]. The trigger block window, which is usually 150 to 300
milliseconds after the start of the expiratory phase of the ventilator, is built
into most ventilators to prevent autotriggering.
 EXPIRATORY ASYNCHRONY 267

How often does expiratory asynchrony occur?

Expiratory asynchrony is common. Aside from patients who have no
inspiratory efforts and whose breaths are under the control of the
mechanical ventilation, it would be surprising to see perfect expiratory
synchrony between the patient and ventilator (ie, the ventilator terminates
its flow at the same time the patient ends his inspiratory effort). Expiratory
asynchrony exists in all breath modes. What matters is the degree of the
expiratory asynchrony (ie, how long the interval is between the ending of the
patient inspiratory effort and the ending of the ventilator inspiratory flow).
Expiratory synchrony during A/CMV modes is determined by the set
inspiratory time of the ventilator. If a clinician selects an inspiratory time
that is the same as the patient’s neural inspiratory time, a perfect expiratory
synchrony exists. However, the neural inspiratory time varies [8]. Because
clinicians do not adjust the ventilator’s inspiratory time setting every breath,
it is more frequent to have an asynchronized transition from inspiration to
expiration.
Expiratory synchrony is more of interest in partial-support breath modes,
such as PSV and PAV. With these breath types, the ventilator inspiratory
time is not set by clinicians; rather, it is determined by specific algorithms
and designs. The frequency and magnitude of expiratory asynchrony,
therefore, are determined by the algorithms of these breath modes in each
mechanical ventilator.

Expiratory asynchrony in pressure support ventilation

For a pressure-supported breath to be cycled off, all mechanical
ventilators used in intensive care units (ICUs) are built with breath
termination criteria. The primary method for ICU ventilators to terminate
their inspiratory flow delivery during PSV is flow-cycling. The ventilator is
cycled off when the inspiratory flow has decayed to a certain level (ie, flow
termination criterion or expiratory trigger sensitivity [ETS]). The flow
termination criteria have evolved through three generations in ventilator
design. The first generation uses a ventilator-preselected value for ETS. The
second generation is called ‘‘user selectable ETS,’’ with which clinicians can
manually select a value for ETS within a specific range. The newest
generation is designed to have the ventilator automatically select the value
for ETS on the basis of the automatically measured respiratory mechanics in
a breath-by-breath manner. Regardless of the flow termination criteria used,
the intention is to allow the ventilator to be cycled off when the patient stops
inspiratory effort, thus achieving expiratory synchrony. As a backup tool,
most ICU ventilators are equipped with pressure and time termination
criteria, whereby the ventilator flow is terminated when the airway pressure
rises a certain amount above the set pressure-support level or when the
elapsed inspiratory time reaches the maximal predetermined time limit. If
268 DU & YAMADA

the breath cannot be cycled off in a timely manner by the flow criteria, the
pressure termination criteria allow the ventilator flow to be cycled off
whenever the respiratory system’s recoil force or the expiratory muscle
recruitment creates an airway pressure increment above the set target
pressure. The time criteria act like a safety tool that may be activated in
situations such as massive airway leakage.

Ventilator preselected expiratory trigger sensitivity

The first generation of the ETS function uses ventilator-preselected fixed
absolute flow (eg, Nellcor 7200; Puritan Bennett, Pleasanton, CA) or a fixed
rate based on the peak inspiratory flow (eg, Siemens 900, Siemens 300;
Maquet, Bridgewater, NJ and Bird 8400ST; Viasys, Palm Springs, CA).
These values vary among ventilators (Table 1). There is no published
information documenting the scientific basis for the design of these flow-
termination criteria. Many studies have shown that patients under PSV
using a ventilator with preselected flow termination criteria experience
expiratory asynchrony [1,2,5,7].
When a patient triggers a pressure support breath, a ventilator quickly
increases its flow rate to achieve the set target pressure. After the flow
reaches its peak level, the flow decays to avoid pressure overshoot and to
maintain airway pressure at a stable target pressure. The rate of the flow
decay (Fig. 1) is determined by the patient respiratory time constant (ie, lung
compliance and airway resistance). With a shorter respiratory time constant
(eg, in patients with acute respiratory distress syndrome), the flow decay is
faster; thus, it reaches the preselected ETS level faster (eg, at 25% of peak
flow). With longer respiratory time constant (eg, in patients with COPD),

Table 1
Expiratory trigger sensitivity (ETS) in intensive care ventilators
Ventilator Expiratory trigger sensitivity
Ventilator pre-selected Adult Star 25% of peak inspiratory flow
fixed ETS Bear 1000 30% of peak inspiratory flow
Bird 8400 25% of peak inspiratory flow
Drager Evita 4 25% of peak inspiratory flow (adult)
6% of peak inspiratory flow
(pediatric and neonate)
Puritan Bennett 7200 5 L/min
Siemens Servo 300 5% of peak inspiratory flow
Siemens Servo 900 25% of peak inspiratory flow
VersaMed iVent 25% of peak inspiratory flow
User-selectable ETS Hamilton Galileo 10% to 40% of peak inspiratory flow
Puritan Bennett 840 1% to 45% of peak inspiratory flow
Cardiopulmonary Venturi 5% to 80% of peak inspiratory flow
Taema Horus 0 to 30 L/min (user-selectable)
Automated ETS Newport e500 5% to 55% of peak inspiratory flow
 EXPIRATORY ASYNCHRONY 269

Faster flow decay at a shorter respiratory time constant

Slower flow decay at a longer respiratory time constant

25 % Peak Flow
Airway
Flow

Neural TI

Fig. 1. The airway flow profile is affected by the respiratory time constant (Tau) during pressure
support ventilation. In patients with a shorter respiratory time constant (eg, patients with adult
reparatory distress syndrome), the flow decays at a faster speed and reaches 25% expiratory
trigger threshold earlier (solid line). In patients with a longer respiratory time constant (eg,
patients with COPD), the flow decays at a slower speed and reaches 25% expiratory trigger
threshold later (dotted line).

the flow decay is slower, and it takes longer to reach the preselected ETS
level. The ventilator termination of inspiratory flow could be less dependent
on the ending of patient neural inspiratory effort and more dependent on the
respiratory time constant. Because the respiratory time constant varies
widely among patients, it is understandable why a preselected fixed ETS
causes expiratory asynchrony. Clinical studies and mathematical analysis
have shown that, with a fixed level of ETS, patients with longer time
constants tend to have delayed termination and that patients with shorter
time constants tend to have premature termination [1,2,5,9].

User-selectable expiratory trigger sensitivity

With the understanding that a single level of the flow-termination
criterion in a specific ventilator would be unlikely to satisfy all patient
categories and may cause premature termination and delayed termination,
some ventilator manufacturers have introduced user-selectable ETS into
their newest model ventilators to improve expiratory synchrony (Table 1).
Clinicians can manually select an ETS level to optimize the expiratory
synchrony. Although this function provides more flexibility to clinicians
than a fixed level of ETS built in a ventilator, it is not a practical solution. It
breaks the concept of simplicity in the application of PSV, and it is difficult
to select an ETS level appropriately with or without visual observation of
the airway pressure waveform at the bedside [10,11].
User-selectable ETS does not solve the needs of meeting pathophysio-
logic changes of the patients over time. Studies have indicated that the
270 DU & YAMADA

expiratory synchrony during PSV is affected by many factors, such as the

magnitude of the patient effort, patient respiratory time constant (ie,
respiratory compliance and airway resistance), patient neural inspiratory
time, and the set pressure support level [9]. When any of these factors
changes, the established expiratory synchrony with the selected ETS level
may change. This means that clinicians need to make frequent adjustments
to the ETS setting to accommodate the ever-changing patient conditions. It
is more reasonable for the ventilator to automatically adjust the ETS rather
than requesting the clinicians to manually adjust it.

Automated expiratory trigger sensitivity

With some reasonable assumptions and simplifications, mathematical
modeling can be a powerful tool in solving some clinical puzzles. We used
mathematical modeling to try to find a way of automating ETS adjustment.
More details of this modeling have been described elsewhere [9]. The
fundamental finding of this modeling is that the ETS setting for optimized
expiratory synchrony should be selected on the basis of the patient
respiratory time constant [12]. Based on this finding, we developed an
automatic closed-loop ETS control system.
The ETS controller automatically adjusts ETS for the upcoming
pressure-supported breath on the bases of the measured respiratory time
constant and supra-plateau pressure of the previous breath(s) (Fig. 2). The
respiratory time constant is calculated from the expiratory flow-volume
curve and determines the range of ETS within which the controller can
select. The controller selects a value of ETS within this range according to
the measured supra-plateau pressure. Supra-plateau pressure is defined as
the pressure above the set target pressure support level at the end of

Time Range Supra-plateau

Constant of ETS Pressure

ETS
Controller

Pressure
Support
Breath

Fig. 2. Automated control system of ETS during pressure support ventilation.

 EXPIRATORY ASYNCHRONY 271

inspiration. Supra-plateau pressure is introduced into the control system to

enhance the robustness of the control system. The basic rules of the
automation system are

The higher the measured respiratory time constant, the higher level of
ETS the controller selects for the upcoming breath.

The higher the supra-plateau pressure, the higher level of ETS the
controller selects for the upcoming breath.
This automated ETS has been implemented in the Newport e500
ventilator (Newport Medical Instruments, Inc., Newport Beach, CA). An
example of the relationship between the ETS range selection and respiratory
time constant is shown in Table 2.
The efficacy of automated ETS has been evaluated through a bench study
using a drive-dependent lung setup [12]. When compared with the Siemens
Servo 300 ventilator, which has a fixed level of ETS, the Newport e500
ventilator with automated ETS demonstrated much better expiratory
synchrony. The ETS function in the e500 was able to terminate ventilator
flow delivery within 0.1 second of the completion of ‘‘patient’’ inspiratory
effort in all test conditions, whereas the Servo 300 delayed the inspiratory
termination by up to 1.0 second.
Automated ETS has shown promising results on patients in the past 2
years. Although there has not been a published controlled study of
automated ETS in patients, preliminary reports by clinicians claim that their
patients experience improved expiratory synchrony with automated ETS.

Expiratory asynchrony in proportional assist ventilation

PAV is a ventilatory mode that partially supports a patient’s spontaneous
inspiratory effort. When PAV is applied through a mechanical ventilator,
the ventilator assists the patient’s spontaneous effort through flow assist and
volume assist. Flow assist is used to unload flow-related airway resistance,
whereas volume assist used is to unload volume-related respiratory
elastance. Clinicians have to set flow-assist gain (Kf) and volume-assist
gain (Kv). When Kf and Kv are expressed as a percentage of the patient’s
airway resistance and respiratory elastance, respectively, the pressure output

Table 2
An example of expiratory trigger sensitivity ranges in relation to the respiratory time constants
for adult applications
Measured respiratory time constant (sec) Range of ETS
\0.8 10% to 35%
0.8 to 1.2 20% to 45%
[1.2 30% to 55%
Abbreviation: ETS, expiratory trigger sensitivity.
272 DU & YAMADA

from the ventilator at any instant, Paw(t), is adjusted by the ventilator

control system according to the following equation:
Paw ðtÞ ¼ Kf  R  V_ ðtÞ þ Kv  E  DVðtÞ ð1Þ
In theory, with PAV, ventilator pressure output (Paw) is proportional to
instantaneous patient effort. It is assumed that there is automatic synchrony
between the end of the patient’s effort and of the ventilator cycling the
inspiratory flow-off [13–15]. As more studies have been done in the past
decade on PAV, however, it has become clear that expiratory asynchrony
also occurs in PAV.

Causes of expiratory asynchrony in proportional assist ventilation

Overestimation of respiratory elastance and airway resistance
PAV is a positive feedback system. The system may ‘‘run away’’ if the
pressure generated by the ventilator is more than the pressure that is needed
to offset the passive properties of the respiratory system. In other words,
when respiratory elastance or airway resistance is overestimated (ie, the
measured elastance or resistance is higher than the true value), the ventilator
may not be able to terminate its flow in a timely manner. The ventilator flow
is prolonged markedly into the patient’s neural expiratory phase, thus
causing expiratory asynchrony (Fig. 3). To avoid this problem, clinicians
need to reduce the assist levels and measure respiratory elastance and airway
resistance accurately.
In bedside applications of PAV, system run-away or expiratory
asynchrony seems to happen much more frequently and more severely
with volume assist than with flow assist. In a study on a group of patients
with COPD, Ranieri et al [16] revealed that during PAV volume assist with
a gain of 44% resulted in an average ventilator inspiratory time of 1.75
seconds, which was significantly longer than the ventilator inspiratory time
of 0.96 seconds when flow assist with a gain of 82% was used and longer
than the patient inspiratory time of 0.93 seconds with pure spontaneous
breathing. In a study on patients with acute respiratory failure, Navalesi
et al [17] showed data indicating a tendency of prolonged ventilator
inspiratory time as volume-assist gain was increased from 20% to 60% and
80%.
It is not clear why expiratory asynchrony is associated more with volume
assist than with flow assist. One explanation might be that when the breath
approaches the end of inspiration, the volume-related elastic recoil pressure
approaches its maximum. In the mean time, the flow-related pressure
becomes minimal because the flow has tapered down toward zero.
Therefore, at the end of inspiration, any error caused by volume assist
(eg, inaccurate estimation of respiratory elastance or a significant control
system delay) has a greater effect. To overcome this limitation, a new
concept of ventilatory assist has been proposed that boosts ventilator
 EXPIRATORY ASYNCHRONY 273

Fig. 3. Waveforms showing ‘‘run-away’’ of proportional assist ventilation. Note that the
second breath has markedly longer ventilator inspiratory time when compared with the first
breath. The flow and positive pressure in the second breath continue after the end of the
patient’s inspiratory effort. (From Ambrosino N, Rossi A. Proportional assist ventilation
(PAV): a significant advance or a futile struggle between logic and practice. Thorax 2002;
57:272–6; with permission.)

support through flow assist on the basis of the measured P0.1 (an indicator of
the magnitude of patient inspiratory effort) and does not require accurate
measurement of respiratory elastance or airway resistance [18]. The efficacy
of this new breath type has yet to be validated.
Although PAV has attracted clinicians and researchers as a promising
addition to more conventional modes of mechanical ventilation, the request
of measuring respiratory elastance and airway resistance has been
practically challenging. At bedside, it is impractical to sedate a patient to
obtain accurate measurements of respiratory elastance and airway re-
sistance in a repeated manner. This is especially true for patients in the
weaning process. It is this group of patients who might benefit the most
from the use of PAV. To improve the usability of PAV at the bedside,
Younes et al [19,20] recently proposed a method for the noninvasive
estimation of inspiratory resistance and passive elastance. Farre et al [21]
have proposed that the forced oscillation technique applied by the
ventilator during noninvasive PAV could be useful in estimating ventilator
resistance. These techniques may turn PAV into a practically useful mode,
but evaluations of these techniques in terms of simplicity, reproducibility,
reliability, and robustness under bedside applications have yet to be
conducted.
274 DU & YAMADA

Airway leakage
Expiratory asynchrony during PAV may occur if there is airway leakage.
Unlike other breathing modes whereby leaks cause less ventilator assistance,
during PAV a small or medium leak at the airway (eg, leakage through an
uncuffed endotracheal tube) may result in greater and longer assistance from
the ventilator because the ventilator pressure is generated in proportion to
all gases delivered regardless of whether the delivered gases go into the
patient or leak out.
Medium or large leaks at airway may cause expiratory asynchrony during
PAV due to the leak’s effect on the measurements of respiratory elastance
and airway resistance. In children under mechanical ventilation, Main et al
[22] demonstrated that leaks larger than 20% resulted in gross overesti-
mation of respiratory elastance and airway resistance. The overestimation of
these parameters can contribute to expiratory asynchrony or run-away in
PAV.

Control system delay in ventilators

Even if there is no airway leakage or overestimation of respiratory
mechanics, expiratory asynchrony may occur as a result of control system
delay. Every ventilator has a control system delay time—a time lag between
the input (eg, the measured flow and pressure) and the output (eg,
ventilator’s delivered response). From a control system standpoint,
a ventilator needs to measure the airway pressure and flow from a pressure
sensor and a flow sensor (ie, mechanical delay), to use electronic filters to
reduce high-frequency noise in signals to reduce the potential for system
oscillation, and to send the signals through an analog-digital converter (ie,
electronic delay). The processor in the ventilator then needs to process the
signals, integrate the flow into volume, and make a decision on the flow rate
for the next time point (ie, software control delay). To further complicate
the matter, in a servo-controlled system, to deliver a predetermined flow rate
a time delay occurs because the command to the inspiratory flow valve that
is predetermined by the processor does not necessarily result in the same
flow rate as expected, thus requiring time for adjustment. In the case of
PAV, a delay exists because the target for the control system is the pressure,
which is a function of the combination of flow, respiratory mechanics, and
patient spontaneous effort. Control system delay is composed of all these
delays [23]. In the ventilator used for PAV as described by Younes et al, the
control system delay is at least 20 to 40 milliseconds to maintain a stable
control system [14,24].
When PAV was initially studied by Younes [25] using a computer model,
the results showed a well-synchronized breath ending between the ventilator
and simulated patient. However, in this study, the computer model did not
account for the control system delay. When the control system delay was
included in the study of PAV using the same computer modeling approach,
we found that significant expiratory asynchrony may occur [23]. The
 EXPIRATORY ASYNCHRONY 275

ventilator flow termination may occur after the completion of patient

inspiration by as much as 0.33 seconds under the selected simulation
conditions. The inspiratory termination delay time during PAV changes in
proportion to three factors: the control system delay time, the respiratory
time constant (ie, respiratory elastance and airway resistance), and the assist
gain setting. The higher these three factors, the more delay time in ventilator
flow termination and thus the more expiratory asynchrony (Fig. 4). Our
data in healthy volunteers [23] indicate that the ventilator flow termination
may occur after the ending of the patient inspiratory effort by as much as
0.86 seconds. Because control system delay is unavoidable in all ventilators,
expiratory asynchrony might be an inherent shortcoming associated with
PAV.

Other issues in expiratory asynchrony

Expiratory asynchrony in neonates and infants
Intermittent mandatory ventilation (IMV) used to be a popular mode in
mechanical ventilation of infants and neonates. Two or three decades ago,
synchronized IMV (SIMV) was introduced into the mechanical ventilation
of infant patients. SIMV was designed to improve the synchrony between
the ventilator and infants in the onset of inspiration. However, little
attention has been paid to the synchrony between the ventilator and infants
in the onset of exhalation (ie, expiratory synchrony).
Inspiratory Termination Delay Time(s)

50% Gain 80% Gain

0.4

0.3

0.2

0.1

0
0 0.2 0.4 0.6 0.8 1.0 1.2 0 0.2 0.4 0.6 0.8 1.0 1.2
Respiratory time constant τ (s)
System control delay: 5ms 20ms 40ms

Fig. 4. Ventilator inspiratory termination delay time at various levels of respiratory time
constant and assist gains during proportional-assist ventilation. Ventilator inspiratory
termination delay time is defined as the interval from the end of the patient inspiratory effort
to the end of the ventilator inspiratory flow. (From Du HL, Ohtsuji M, Shigeta M, et al.
Expiratory asynchrony in proportional assist ventilation. Am J Respir Crit Care Med
2002;165:972–7; with permission.)
276 DU & YAMADA

Infants are a special group of patients from a mechanical ventilation

perspective. In adults, the neural inspiratory time is usually 1.0 to 1.2
seconds. Therefore, even if the ventilator has an inspiratory termination
delay of 0.2 to 0.3 seconds, the patient gets enough synchronized assist from
the ventilator. Infants normally have a neural inspiratory time between 0.3
and 0.5 seconds. The same amount of inspiratory termination delay may
mean that most of time the ventilator is not in synchrony with the infant.
Some pediatricians and neonatologists feel, on the basis of their bedside
experiences, that there may be no marked difference in clinical outcome
between IMV and SMIV in infants.
This issue was not scientifically illustrated until recently. Sinderby et al
[26] evaluated patient–ventilator interaction in 14 infants who were under
SIMV mode with the Babylog 8000 (Dräger Medical, Lübeck, Germany)
ventilator. The inspiratory trigger sensitivity was set at the most sensitive
level to minimize any delay in inspiratory trigger. To detect the onset points
of the patient neural inspiration and expiration, they used a multiple-array
esophageal electrode to measure the electrical activity of the diaphragm.
This study reported the following results (Fig 5):

The ventilator and patient were in asynchrony for 53% of the breathing
interval and in synchrony for only 47% of the breathing interval.

The average neural inspiratory time in these infants was 330 milli-
seconds. Out of this neural inspiratory time, the patients were supported
by the ventilator for 230 milliseconds. This means that the ventilator and
patient were in asynchrony for 30% of the neural inspiratory phase.

Neural
Neural TI Neural TE
Timing

Insp Trigger Exp Trigger

Delay Delay
Ventilator
Ventilator TI
Timing

Asynchronized period (53%)

Synchrony period (47%)

Fig. 5. Patient–ventilator interaction during patient-triggered mandatory breaths in SIMV in

infants. The schematics indicate inspiratory trigger delay and expiratory trigger delay in infants
under mechanical ventilation. The total time when the ventilator was in synchrony with the
patient is only 47%; during the remaining 53% of time the ventilator and the patient were in
asynchrony. (Adapted from Beck J, Tucci M, Emeriaud G, et al. Prolonged neural expiratory
time induced by mechanical ventilation in infants. Pediatr Res 2004;55:1–8; with permission.)
 EXPIRATORY ASYNCHRONY 277

The average neural expiratory time was 950 milliseconds. Out of this
expiratory time, the ventilator mandatory flow delivery continued for
500 milliseconds after the end of the neural inspiratory time. This means
that the ventilator and patient were in asynchrony for 53% of the neural
expiratory phase.
Obviously, when SIMV is used in infants, there is an unacceptable
amount of expiratory asynchrony.
There has been no study on expiratory asynchrony in infants during PSV
or PAV using a reliable method of estimating onset timings of neural
inspiration and expiration. The patient-ventilator synchrony during PSV
and PAV relies heavily on the flow profile at the airway opening, which is
a result of Pmus, respiratory elastance, and airway resistance. Because infants
usually have a weak Pmus and high airway resistance, the flow profile at
airway opening in infants is not as representative of the patient neural effort
profile as it is in adults. Therefore, it can be assumed that there are more
chances of expiratory asynchrony with these two modes in infants than in
adults. The fact that most infants have airway leakage [27] further increases
the chances of expiratory asynchrony during PSV and PAV.

Expiratory asynchrony in patients with chronic obstructive pulmonary

disease
COPD is a challenging condition for ventilators when it comes to
patient–ventilator interaction. Patients with COPD experience more chances
of expiratory asynchrony as a result of PEEPi, high airway resistance, and
high respiratory compliance (thus a long respiratory time constant). The
existence of PEEPi is associated with a delay in inspiratory trigger, which
can lead to a delay in termination of inspiratory flow if the mandatory
breath inspiratory time is fixed at a user-selected level. A long respiratory
time constant contributes to more expiratory asynchrony during PSV and
PAV. This group of patients is fragile in terms of tolerability to expiratory
asynchrony because they need a longer expiratory time to exhale all of their
inspired gases. The result is the exacerbation of PEEPi again; thus, there is
a vicious circle. Ventilator designs need to be tailored for this group of
patients to improve patient-ventilator synchrony and weaning outcome.

Limitations in tools to detect the onset point of neural expiration

Research in expiratory asynchrony is handicapped by the lack of simple
and accurate tools for detecting the onset point of neural expiration. Airway
pressure and flow signals cannot be used to detect the onset point of neural
expiration because they represent the information of onset and ending of
ventilator inspiration, not patient inspiration. The most convenient tool for
making this measurement is the esophageal balloon catheter that is used to
monitor the esophageal pressure tracing. When appropriately positioned in
278 DU & YAMADA

the esophagus, the esophageal pressure tracing approximates patient

inspiratory muscle pressure after the deduction of the recoil pressure.
However, the esophageal balloon catheter is semi-invasive, it is difficult to
get patient consent (especially in the developed countries), and its reliability
in accurately detecting the onset of neural expiration is limited. The tracing
could be contaminated by heart beats, swallowing, displacement of the
balloon position, body position change, and many other artifacts. When
a high level of support is applied from the ventilator, the magnitude of the
esophageal pressure signal becomes smaller, making it more difficult to
detect the onset point of neural expiration.
Parthasarathy et al [28] assessed neural inspiratory time using di-
aphragmatic electromyogram (EMGdi) in a group of patients with COPD.
When they compared the measurement from this reference method with
indirect measurement from esophageal balloon pressure tracings, the onset
point of the neural expiratory phase during spontaneous breathing was
approximately 90 to 160 milliseconds different from that measured from
esophageal pressure tracings. This difference increased during mechanical
ventilation. Whether the patients are breathing spontaneously or under
mechanical ventilation, the esophageal pressure tracing provides a poor
estimation of expiratory asynchrony.
The only reliable method in detecting the onset of expiratory phase is
believed to be the monitoring of EMGdi. Due to the high cost, cumbersome
procedures, and invasive nature of the device, this technique has not become
a bedside tool.

Which physiologic signal should the ventilator synchronize with?

When the respiratory neurons discharge signals to start the neural
inspiratory phase, there is an initial delay in transmission of output from the
central nervous system to muscle cells of about 8 milliseconds for the
phrenic nerve in humans. Next, approximately 10 milliseconds are needed
for the biochemical processes of muscle to generate the active state before
muscle tension appears. There is a further delay between the neuromuscular
activation and the alveolar occlusion pressure change. In experiments on
humans, after square-wave electrophrenic stimulation, the alveolar occlu-
sion pressure increases exponentially, with a time constant of approximately
70 milliseconds [29]. Furthermore, the ending of patient neural inspiration
does not happen as distinctly and instantaneously as the ventilator’s
inspiration ending does. Rather, the phrenic activity generally extends into
the neural expiratory phase for approximately 100 to 200 milliseconds [30].
Should the ventilator’s ending of inspiratory phase be synchronized with
the central neural signal, the EMGdi signal, or the inspiratory muscle
pressure signal? Although it is unknown whether the answer to this question
has any clinical implication, it does deserve elaboration once the physiologic
research tools become more advanced.
 EXPIRATORY ASYNCHRONY 279

Summary
Expiratory asynchrony is a universal phenomenon, and expiratory
synchrony occurs only by chance. Expiratory asynchrony exists in all
breath modes and has a significant impact on the patient’s work of
breathing and the weaning process. Advancements in ventilator designs and
basic physiologic science could lead to the improvement of the expiratory
asynchrony.

References
[1] Parthasarathy S, Jubran A, Tobin MJ. Cycling of inspiratory and expiratory muscle groups
with the ventilator in airflow limitation. Am J Respir Crit Care Med 1998;158:1471–8.
[2] Jubran A, Van de Graaff WB, Tobin MJ. Variability of patient-ventilator interaction with
pressure support ventilation in patients with chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 1995;152:129–36.
[3] Greenough A, Wood S, Morley CJ, et al. Pancuronium prevents pneumothoraces in
ventilated premature babies who actively expire against positive pressure ventilation. Lancet
1984;1:1–13.
[4] Lipscomb AP, Thorburn RJ, Reynolds EO, et al. Pneumothorax and cerebral haemorrhage
in preterm infants. Lancet 1981;1:414–6.
[5] Nava S, Bruschi C, Fracchia C, et al. Patient-ventilator interaction and inspiratory effort
during pressure support ventilation in patients with different pathologies. Eur Respir J 1997;
10:177–83.
[6] Younes M, Kun J, Webster K, et al. Response of ventilator-dependent patients to delayed
opening of exhalation valve. Am J Respir Crit Care Med 2002;166:21–30.
[7] Van de Graaff WB, Gordey K, Dornseif SE, et al. Pressure support: changes in ventilatory
pattern and components of the work of breathing. Chest 1991;100:1082–9.
[8] Tobin MJ, Yang KL, Jubran A, et al. Interrelationship of breath components in neighboring
breaths of normal eupneic subjects. Am J Respir Crit Care Med 1995;152:1967–76.
[9] Yamada Y, Du HL. Analysis of the mechanisms of expiratory asynchrony in pressure
support ventilation: a mathematical approach. J Appl Physiol 2000;88:2143–50.
[10] Branson RD, Campbell RS. Pressure support ventilation, patient-ventilator synchrony, and
ventilator algorithm [editorial]. Respir Care 1998;43:1045–7.
[11] Kacmarek RM. NIPPV: patient-ventilator synchrony, the difference between success and
failure? Intensive Care Med 1999;25:645–7.
[12] Du HL, Amato MBP, Yamada Y. Automation of expiratory trigger sensitivity in pressure
support ventilation. Respir Care Clin North Am 2001;7:503–17.
[13] Younes M. Proportional assist ventilation: a new approach to ventilatory support. Am Rev
Respir Dis 1992;145:114–20.
[14] Younes M, Puddy A, Roberts D, et al. Proportional assist ventilation: results of an initial
clinical trial. Am Rev Respir Dis 1992;145:121–9.
[15] Giannouli E, Webster K, Roberts D, et al. Response of ventilator-dependent patients to
different levels of pressure support and proportional assist. Am J Respir Crit Care Med 1999;
159:1716–25.
[16] Ranieri VM, Grasso S, Mascia L, et al. Effects of proportional assist ventilation on
inspiratory muscle effort in patients with chronic obstructive pulmonary disease and acute
respiratory failure. Anesthesiology 1997;86:79–91.
[17] Navalesi P, Hernandez P, Wongsa A, et al. Proportional assist ventilation in acute
respiratory failure: effects on breathing pattern and inspiratory effort. Am J Respir Crit Care
Med 1996;154:1330–8.
280 DU & YAMADA

[18] Du HL. Breathing apparatus and method. United States Patent no. 6,622,726. September 23,
2003.
[19] Younes M, Kun J, Masiowski B, et al. A method for noninvasive determination of inspi-
ratory resistance during proportional assist ventilation. Am J Respir Crit Care Med 2001;
163:829–39.
[20] Younes M, Webster K, Kun J, et al. A method for measuring passive elastance during
proportional assist ventilation. Am J Respir Crit Care Med 2001;164:50–60.
[21] Farre R, Mancini M, Rotger M, et al. Oscillatory resistance measured during noninvasive
proportional assist ventilation. Am J Respir Crit Care Med 2001;164:790–4.
[22] Main E, Castle R, Stocks J, et al. The influence of endotracheal tube leak on the assessment
of respiratory function in ventilated children. Intensive Care Med 2001;27:1788–97.
[23] Du HL, Ohtsuji M, Shigeta M, et al. Expiratory asynchrony in proportional assist
ventilation. Am J Respir Crit Care Med 2002;165:972–7.
[24] Younes M, Bilan D, Jung D, et al. An apparatus for altering the mechanical load of the
respiratory system. J Appl Physiol 1987;62:2491–9.
[25] Younes M. Patient-ventilator interaction with pressure-assisted modalities of ventilatory
support. Semin Respir Med 1993;14:299–322.
[26] Beck J, Tucci M, Emeriaud G, et al. Prolonged neural expiratory time induced by mechanical
ventilation in infants. Pediatr Res 2004;55:1–8.
[27] Bernstein G, Knodel E, Heldt G. Airway leak size in neonates and autocycling of three flow-
triggered ventilators. Crit Care Med 1995;23:1739–44.
[28] Parthasarathy S, Jubran A, Tobin MJ. Assessment of neural inspiratory time in ventilator-
supported patients. Am J Respir Crit Care Med 2000;162:546–52.
[29] Milic-Emili J, Zin WA. Relationship between neuromuscular respiratory drive and
ventilatory output. In: Fishman AP, editor. Handbook of physiology. Section 3: the
respiratory system, vol. III. Bethesda (MD): American Physiological Society; 1986.
p. 631–46.
[30] Mognoni P, Saibene F, Sant’Ambrogio G, et al. Dynamics of the maximal contraction of the
respiratory muscles. Respir Physiol 1963;4:193–202.